Boron reagents in synthesis 9780841231825, 0841231826

Table of contents :
Content: Boron Chemistry: An Overview / DeFrancesco, Heather
Dudley, Joshua
Coca, Adiel / Lewis Acids / Hatano, Manabu
Ishihara, Kazuaki / Allylboration / Jonnalagadda, Subash C., Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States, Department of Biomedical and Translational Sciences, Rowan University, Glassboro, New Jersey 08028, United States
Suman, Pathi, Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
Patel, Amardeep, Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
Jampana, Gayathri, Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
Colfer, Alexander, Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States / Boron Enolate Chemistry / Abiko, Atsushi / Unstable Intermediates as Keys to Synthesis with Organoboron Compounds / Matteson, Donald S. / Current Developments in the Catalyzed Hydroboration Reaction / Geier, Stephen J.
Vogels, Christopher M.
Westcott, Stephen A. / Synthesis of Pinacolboronates via Hydroboration / Karatjas, Andrew G.
McBriarty, Heidi A.
Braye, Stephan I.
Piscitelli, David / Boron Hydride Reduction / Itsuno, Shinichi / The Petasis Borono-Mannich Multicomponent Reaction / Guerrera, Cessandra A.
Ryder, Todd R. / Copper-Catalyzed Coupling Reactions of Organoboron Compounds / Verma, Astha
Santos, Webster L. / Introduction, Interconversion and Removal of Boron Protecting Groups / Churches, Quentin I.
Hutton, Craig A. / B-Protected Boronic Acids: Methodology Development and Strategic Application / Molloy, John J.
Watson, Allan J. B. / Di- and Polyboron Compounds: Preparation and Chemoselective Transformations / Xu, Liang, Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi, 710054 China, School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang, 832003 China
Zhang, Shuai, Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi, 710054 China
Li, Pengfei, Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi, 710054 China / Acylation Reactions of Organoborons / Mondal, Manoj, Department of Chemistry, Dibrugarh University, Dibrugarh 786004, Assam, India
Bora, Utpal, Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India / Development of Organic Transformations Based on Protodeboronation / Lee, Chun-Young
Cheon, Cheol-Hong / Editor’s Biography /

Citation preview

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.fw001

Boron Reagents in Synthesis

Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.fw001

Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

ACS SYMPOSIUM SERIES 1236

Boron Reagents in Synthesis

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.fw001

Adiel Coca, Editor Southern Connecticut State University New Haven, Connecticut

American Chemical Society, Washington, DC Distributed in print by Oxford University Press

Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.fw001

Library of Congress Cataloging-in-Publication Data Names: Coca, Adiel, editor. Title: Boron reagents in synthesis / Adiel Coca, editor, Southern Connecticut State University, New Haven, Connecticut. Description: Washington, DC : American Chemical Society, [2016] | Series: ACS symposium series ; 1236 | Includes bibliographical references and index. Identifiers: LCCN 2016048749 (print) | LCCN 2016049052 (ebook) | ISBN 9780841231832 | ISBN 9780841231825 (ebook) Subjects: LCSH: Boron compounds. | Organic compounds--Synthesis. Classification: LCC QD181.B1 B6757 2016 (print) | LCC QD181.B1 (ebook) | DDC 547/.05671--dc23 LC record available at https://lccn.loc.gov/2016048749

The paper used in this publication meets the minimum requirements of American National Standard for Information Sciences—Permanence of Paper for Printed Library Materials, ANSI Z39.48n1984. Copyright © 2016 American Chemical Society Distributed in print by Oxford University Press All Rights Reserved. Reprographic copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Act is allowed for internal use only, provided that a per-chapter fee of $40.25 plus $0.75 per page is paid to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. Republication or reproduction for sale of pages in this book is permitted only under license from ACS. Direct these and other permission requests to ACS Copyright Office, Publications Division, 1155 16th Street, N.W., Washington, DC 20036. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by ACS of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, specification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission to the holder, reader, or any other person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. Registered names, trademarks, etc., used in this publication, even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN THE UNITED STATES OF AMERICA Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Foreword The ACS Symposium Series was first published in 1974 to provide a mechanism for publishing symposia quickly in book form. The purpose of the series is to publish timely, comprehensive books developed from the ACS sponsored symposia based on current scientific research. Occasionally, books are developed from symposia sponsored by other organizations when the topic is of keen interest to the chemistry audience. Before agreeing to publish a book, the proposed table of contents is reviewed for appropriate and comprehensive coverage and for interest to the audience. Some papers may be excluded to better focus the book; others may be added to provide comprehensiveness. When appropriate, overview or introductory chapters are added. Drafts of chapters are peer-reviewed prior to final acceptance or rejection, and manuscripts are prepared in camera-ready format. As a rule, only original research papers and original review papers are included in the volumes. Verbatim reproductions of previous published papers are not accepted.

ACS Books Department

Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.pr001

Preface This book is a direct result of a symposium on the use of boron reagents in synthesis held during the 2013 American Chemical Society Northeast Regional Meeting in New Haven, CT. During this meeting, senior editors from the Books Publications Division of the American Chemical Society extended a gracious invitation to submit a book on this topic. The use of boron in synthesis is rich in history which goes back more than 150 years. Some of the best known reactions in synthesis, such as the Suzuki-Miyaura cross-coupling and the hydroboration reaction, involve boron compounds. Giants in chemistry, such as Herbert C. Brown and Akira Suzuki, have been recognized for their contributions to this field with Nobel prizes in chemistry. However, many other chemists, such as Teruaki Mukaiyama, Norio Miyaura, Dominic Chan, Patrick Lam, Donald Matteson, Nicos Petasis, Edwin Vedejs, Elias J. Corey, David A. Evans, Gary Molander, William R Roush, among many others, have left their mark as well. Several natural products containing boron have been isolated in the last 50 years, including ionophoric macrodiolide antibiotics boromycin, borophycin, aplasmomycins A, B, and C, and tartrolons B, C, and E, as well as autoinducer-2. In the last 15 years, pharmaceuticals having a boronic acid have been introduced into the market to treat several diseases through the inhibition of proteases. These include bortezomib, ixazomib, and tavaborole. Several more boron-based drugs are currently in clinical trials. Boron neutron capture therapy has the potential to provide a treatment for various cancers. In addition, materials bearing boronic acids are been studied as potential sensors for biological molecules, such as saccharides and glycoproteins that possess cis-1,2- or cis-1,3-diols. With these recent advances, surely this is an exciting time for this area of research. As the editor, I have many thanks for the authors that contributed to this project. Their professionalism and prompt responses made my job as editor quite enjoyable. Furthermore, thanks to the staff at the American Chemical Society (ACS) as well as the book reviewers for their constructive criticism. This book would not be possible without their contributions. In particular, I like to thank ACS staff members Elizabeth Hernandez, Aimee Greene, Arlene Furman, and senior editor Bob Hauserman for their work on this project.

Adiel Coca Chemistry Department Southern Connecticut State University New Haven, Connecticut ix Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Chapter 1

Boron Chemistry: An Overview

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Heather DeFrancesco, Joshua Dudley, and Adiel Coca* Chemistry Department, Southern Connecticut State University, 501 Crescent St., New Haven, Connecticut 06515, United States *E-mail: [email protected]

Boron compounds have been used extensively in organic synthesis for more than sixty years. Some of the best known organic reactions such as hydroboration and the Suzuki–Miyaura coupling reaction involve organoboron derivatives. The study of compounds containing boronic acids for application in pharmaceuticals and materials science has grown tremendously over the last few decades. Several boron-containing protease inhibitors have been approved by the U.S. Food and Drug Administration recently. This chapter will introduce the reader to some of the basic properties and applications of boron compounds.

Introduction Boron (B) is a group 13 (IIIA) metalloid element. The chemical properties of boron are more similar to carbon and silicon than other group 13 elements, although boron is more electron deficient, as discussed below, than both carbon and silicon. Elemental boron was first isolated in 1808 independently by British chemist Sir Humphry Davy and by French chemists Joseph Louis Gay-Lussac and Louis Jaques Thénard (1, 2). The relative abundance of boron in the Earth’s crust is approximately 10 parts per million, making boron the second most abundant group 13 element after aluminum and 38th most abundant element overall (3). Important sources of boron are the minerals borax, Na2[B4O5(OH)4]·8H2O, and kernite, Na2[B4O6(OH)2]·3H2O (4). Large deposits of these minerals are found in Kern County, California and in parts of Turkey. Boron has three valence electrons and has a ground state electron configuration of 1s22s22p1. Boron typically forms trivalent neutral compounds © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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such as boron trifluoride (BF3) in which the boron has six valence electrons. Thus, the boron atom is sp2 hybridized, has an empty p-orbital, and has a trigonal planar geometry. These types of compounds are electron-deficient due to the empty p-orbital on boron and are isoelectronic with carbocations. The Lewis acidity of trivalent boron compounds has been exploited in a number of reactions. Boron can also form negatively charged tetravalent compounds, which adopt a tetrahedral geometry. The carbon-boron bond (1.55-1.59 Å) in tricoordinated boron compounds is longer than a typical carbon-carbon bond (5). On the other hand, the boron-oxygen bond in trivalent organoboron compounds is relatively short and in the range of 1.31-1.38 Å compared to an ether C-O bond (1.43 Å). This bond shortening is a result of the partial double bond character in the B-O bond due to the lone pairs on oxygen interacting with the empty p-orbital on boron. The difference in electronegativity between boron (2.05) and carbon (2.55) explains the observed weak electron donation of boron functional groups. B-C π-conjugation due to the empty p-orbital on boron has been confirmed in aryl- and alkenylboron compounds. In these compounds, boron groups behave as weak electron withdrawing groups. This phenomenon is illustrated, for example, in the fact that the beta carbon of alkenylboronic acids and esters is typically deshielded slightly in 13C NMR spectra.

Figure 1. Structures of boromycin, aplasmomycin A, tartrolon B, and AI-2. 2 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Few boron-containing natural products have been isolated. These include the boric acid-based ionophoric macrodiolide antibiotics boromycin, borophycin, aplasmomycins A, B, and C, and tartrolons B, C, and E (Figure 1) (6–11). Boromycin was isolated in 1967 from Streptomyces antibioticus and it was the first natural product isolated containing boron. Exposure to boromycin causes the release of potassium ions in Gram-positive bacteria. It also has shown anti-HIV activity (12). Borophycin, the aplasmomycins and the tartrolons were isolated from marine bacteria. Another boron-containing natural product is autoinducer-2, AI-2 (13). The bacterial signaling molecule AI-2 has been reported to be involved in intercellular communication between bacteria through a process called quorum sensing. To date, no natural product having either a tricoordinated boronic acid or boronic ester group has been isolated. Organoboron compounds have found many uses over the last sixty years. These uses include being involved in several important reactions such as hydroboration and the Suzuki–Miyaura reaction, among others. In addition, organoboron compounds have found several applications in the pharmaceutical industry, as neutron capture therapy agents, and in materials science and molecular imaging. In this chapter, a very brief overview of organoboron compounds will be covered to introduce the reader to this highly impactful area of research. Other chapters in this book will cover in more detail recent advances in different aspects of boron chemistry. This chapter as well as the rest of the book is primarily concerned with small-molecule boron chemistry.

Boron Compounds Organoboron compounds contain at least one carbon-to-boron bond and can be classified as boranes, borohydrides (which may or may not contain a carbon-to-boron bond), borinic acids, borinic esters, boronic acids, boronic (boronate) esters, boronamides, boryl anions, and borate anions, among others (Figure 2). It should be mentioned that the classification of boron compounds in the literature varies greatly. Boranes include trivalent boron compounds bearing any combination of organic groups and/or hydrogen atoms on boron. Thus, these can be further classified into boron hydrides (contain at least one hydrogen atom on boron) and triorganoboranes (contain three organic groups on boron). Borinic acids contain one hydroxyl group and two organic groups on boron. Borinic esters contain an alkoxy group instead of the hydroxyl group. Boronic acids and esters are perhaps the most studied and most synthetically useful organoboron compounds. These species contain two hydroxyl (boronic acids) or two alkoxy (boronic esters) groups along with one organic group. Boronamides contain two nitrogen atoms bonded to boron. Boryl anions can be formed from reduction of a boron halogen bond and are isoelectronic with N-heterocyclic carbenes (NHC). Borohydrides have a central negatively charged tetrahedral boron atom bearing at least one hydrogen atom. Borate anions describe tetrahedral boron anion salts such as boron oxyanions and organotrifluoroborates (RBF3-). There are other boron compounds that, although are not technically organoboron compounds, are utilized in synthesis as well. These compounds include borate (boric) esters and 3 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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boron trihalides (containing three halogens on boron). Borate esters are trivalent and contain three alkoxy groups on boron. Borate esters can be easily made from boric acid, B(OH)3. Boric acid is a fairly non-toxic compound that is the metabolic end-product of many organoboron compounds. In humans, boric acid has a lethal dose level similar to table salt. In plants, boric acid is an essential nutrient as boron helps bind polysaccharides in the cell wall and maintains plasma membranes and metabolic pathways (14). Below is a brief introduction to some important boranes, borohydrides, boronic acids, boronic esters, and borates in synthesis.

Figure 2. Select examples of boron compounds.

Boranes and Borohydrides Between 1912 and 1936, Alfred Stock discovered that boron forms a range of hydrides. Stock synthesized a series of boron hydrides whose structures could not be explained simply by using valence bond theory (15). Stock was able to successfully synthesize and characterize a series of boranes including B2H6, B4H10, B5H9, B5H11, B6H10, and B10H14. Boron hydrides contain multi-center bonding which allows for the formation of clusters, where the atoms form a cage-like structure. In the structure of these compounds, each boron forms a 2-center 2-electron bond with terminal hydrogen atoms, with the remaining hydrogen atoms forming 3-center 2-electron (2 electrons shared by three atoms) bonds that bridge two boron atoms (Figure 3). Boron hydrides generally form dimers unless restricted by sterics around boron. For example, borane (BH3) generally prefers to form the dimer diborane (B2H6), which allows the boron atoms to have a complete octet of valence shell electrons. Borane only exists as a monomer at high temperatures or when it forms a 1:1 adduct with Lewis basic solvents/ligands such as tetrahydrofuran, amines, and dimethylsulfide (Eq 1).

Figure 3. Structure of diborane.

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The structures of other important neutral boron hydrides are shown in Figure 4. Among these boranes are catecholborane and pinacolborane, which have been used to synthesize precursors for the Suzuki–Miyaura reaction. Sterically hindered boranes such as thexylborane, disiamylborane, and 9-borabicyclo[3.3.1]nonane (9-BBN-H) have been used for highly regioselective and stereoselective hydroborations (16, 17). Asymmetric hydroborations have also been accomplished with chiral boranes such as diisopinocampheyl borane (Ipc2BH) (18).

Figure 4. Structures of some boron hydrides.

Unlike boranes, which are strong Lewis acids, borohydrides are nucleophilic in nature. In 1940, Hermann Irving Schlesinger and Herbert Charles Brown reported the synthesis of lithium borohydride, the first alkali metal borohydride described (Figure 5) (19). Perhaps the most important borohydride is sodium borohydride, which has been used for numerous reductions of aldehydes, ketones, enones, acid chlorides, and other functional groups (20). Superhydride (lithium triethylborohydride) is even more reactive due to the electron-donating alkyl groups; it reduces numerous other functional groups (21, 22). Other important borohydrides include sodium cyanoborohydride and sodium triacetoxyborohydride, which have been used often in reductive aminations (23, 24). Sterically hindered tri-sec-butylborohydrides such as L-selectride (lithium tri-sec-butylborohydride) and K-selectride (potassium tri-sec-butylborohydride) have been used for asymmetric carbonyl reductions of hindered cyclic and bicyclic ketones (25).

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Figure 5. Structures of some borohydrides. Triorganoboranes have served as useful alkylating agents. For example, these compounds have extensively been studied in the allylation of carbonyl groups with allylboranes such as triallylboron (Figure 6) (26). Many chiral triorganoboranes have been developed since the 1980s for asymmetric allylborations as well, such as the α-pinene derived B-allyldiisopinocamphenylborane (Ipc2Ballyl) (27). Most triorganoboranes are prone to air oxidation and are often oxidized to borinic acids. Many borinic acids are also fairly air sensitive and are oxidized to the more stable boronic acids. The oxidation of triorganoboranes and borinic acids is the result of the large difference between the B-C and B-O bond strengths. In fact, B-C bonds (323 kJ/mol) are weaker compared to C-C bonds (358 kJ/mol), whereas B-O bonds (519 kJ/mol) are much stronger than C-O bonds (384 kJ/mol) (28). The stronger B-O bonds are due to their partial double bond character as a result of the π-dative interaction between the lone pairs on oxygen and the empty p-orbital on boron.

Figure 6. Structures of some allylboranes. Boronic Acids and Boronic Esters Boronic acids and boronic (boronate) esters exemplified by phenylboronic acid and phenylboronic acid pinacol ester in Figure 7 are extremely useful functionalities in synthesis. As previously mentioned, they serve as precursors for the Suzuki–Miyaura reaction. In addition, boronic acids are very popular in medicinal chemistry as discussed later. Most boronic acids and boronic esters are fairly air stable and moderately stable to most reaction conditions (except those mentioned below). Aliphatic boronic acids and esters tend to oxidize more easily than aryl- and alkenyl boronic acids and esters. These compounds are also susceptible to deboronation with aqueous bases, aqueous acids, nucleophiles, 6 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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and oxidants due to the empty p-orbital on boron. Boronic acids with relatively small organic groups are very polar and water soluble. Thus, boronic acids often present problems in chromatographic separation and during extractions. Additionally, boronic acids that have been scrupulously dried are converted to boronic anhydrides (boroxines), which complicates characterization (Figure 8). Since boronic acids and boronic esters can be routinely interconverted, boronic esters are usually preferred as they are easier to purify and characterize. Acyclic boronic esters are susceptible to hydrolysis yielding boronic acids, whereas bulky cyclic boronic esters such as pinacol boronic esters are more robust. Boronic esters containing a trivalent ligand such as N-methyliminodiacetic acid (MIDA) that effectively rehybridizes the boron atom from sp2 to sp3 (thus removing the empty p-orbital through a dative bond) have been used to improve the stability towards air and other reaction conditions of the boron partner in the Suzuki–Miyaura reaction (29). Since MIDA boronate esters are easily cleaved under mildly basic conditions, they have been used as a boronic acid protecting group and have allowed for an iterative cross-coupling strategy to be developed (29).

Figure 7. Structures of some boronic acids and boronic esters.

Figure 8. General structure of a boroxine.

Unlike carboxylic acids, boronic acids do not behave as Brønsted acids, but are instead mild Lewis acids. Boronic acids and boronic esters are weaker Lewis acids than boranes due to the interaction in boronic acids and boronic esters between the lone pairs on the oxygen atoms with the empty p-orbital on boron. Boronic acids and boronic esters ionize water to form a borate anion and hydronium ion (Eq 2). Thus, the pKa of boronic acids and boronic esters in water is indirectly related to their Lewis acidity.

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Electron withdrawing groups on the organic group of boronic acids and boronic esters increases their Lewis acidity (lower pKa), whereas sterically hindered groups (such as ortho substituents in phenylboronic acids) decreases their Lewis acidity. The pKa value for boronic acids range from approximately 4.0 to 10.5 (Figure 9) (5). Boronic esters typically have lower pKa values than their corresponding boronic acids by about 2-4 units (30).

Figure 9. Representative boronic acids with corresponding pKa’s. Borates Boron has a high affinity for oxygen, leading to the formation of borates, which are boron-containing oxyanions. Other borates include trifluoroborates. Trifluoroborates have been successfully used as boronic acid protecting groups, similarly to MIDA boronate esters, due to the tetracoordinated boron in these compounds (Figure 10). They also have been employed in a number of reactions including the Suzuki–Miyaura reaction. Trifluoroborates can be hydrolyzed efficiently with silica gel and water (31). One major issue with them is their insolubility in apolar solvents. However, trifluoroborates are often purified in these solvents through crystallization.

Figure 10. Structure of a trifluoroborate.

Reactions In this section, a very short overview of some of the reactions that involve boron compounds will be discussed as it is impossible to do justice to all of the important research that has been done involving the synthesis of or the use of 8 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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boron compounds. More details can be found in other chapters of this book or in the references below. Edward Franlkand is credited with the first reported synthesis of an organoboron compound more than 150 years ago as he synthesized triethylborane (BEt3) by reacting triethylborate (B(OEt)3) with an excess of diethylzinc, Et2Zn (Scheme 1) (32). The resulting air-sensitive triethylborane (BEt3) was then carefully air oxidized to diethyl ethylboronic ester, EtB(OEt)2, which was then hydrolyzed to ethylboronic acid, EtB(OH)2. Other "hard" organometallic reagents such as organolithium or Grignard reagents also have been used to synthesize boronic acids and boronic esters from borate esters at low temperatures (Scheme 1) (33). This method is limited in scope due to the intolerance by the organometallic reagents for several functional groups.

Scheme 1. Reactions of organometallic reagents with borate esters.

The convenient reduction of aldehydes, ketones, and acid chlorides to alcohols with sodium borohydride (NaBH4) was described in 1949 (Eq 3) (20). Although NaBH4 is easier to handle than lithium aluminum hydride (LiAlH4), it typically doesn’t reduce carboxylic acids, amides or other functional groups that are susceptible to LiAlH4 reduction. The related reagent lithium borohydride (LiBH4) has been reported to be more reactive than NaBH4 as it reduces esters to alcohols more readily (34). This difference in reactivity is due to the better carbonyl activation by the tighter binding to the oxygen with the smaller lithium cation. Choosing the appropriate solvent can also increase the reactivity of the borohydride reagents significantly. Generally, protic solvents such as methanol increase the reactivity of borohydride reagents by forming alkoxyborohydrides, which are more reactive than both NaBH4 and LiBH4. As a result, NaBH4 in methanol reduces most esters (albeit slowly) to primary alcohols and primary amides are converted to amines with LiBH4 in a methanol/THF mixture (35, 36). In the presence of Lewis acidic lanthanide chlorides such as cerium chloride, NaBH4 in methanol will reduce α,β-unsaturated ketones to allylic alcohols with only very small amounts of the saturated alcohol (Eq 4) (37). This reaction is often referred to as the Luche reduction. Trialkylborohydrides such as Superhydride (LiEt3BH) are even stronger reducing agents due to the electron donating alkyl groups. These can reduce sterically hindered ketones, alkyl halides, sulfonate esters, epoxides, tertiary amides, among other functional groups (21, 22). Sterically hindered borohydrides such as L-selectride, Li(sec-Bu)3BH, can introduce steric control in the reduction of ketones such as 2-methylcyclohexanone and camphor (25). Reductive amination of ketones 9 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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and aldehydes in a one-pot reaction has been carried out with the use of sodium cyanoborohydride, Na(CN)BH3, at a pH of 6-8 in methanol (Eq 5) (23). Sodium triacetoxyborohydride, NaBH(OAc)3, has been reported as a more selective alternative to sodium cyanoborohydride for direct reductive aminations of ketones and aldehydes (24). This reagent also avoids the production of toxic byproducts such as HCN and NaCN.

In 1956, H. C. Brown discovered that sodium borohydride and aluminum chloride convert olefins at elevated temperatures to trialkylboranes, which could subsequently be oxidized to alcohols with a sodium hydroxide and hydrogen peroxide treatment (38). A year later, Brown found a more convenient procedure utilizing diborane in ether solvents that converts olefins into organoboranes (or the corresponding alcohol if oxidized) at room temperature (39). Borane-methyl sulfide provides the added advantage that it is exceptionally stable at 0 ºC and can even be stored at room temperature, unlike BH3-THF which must be stored at 0 ºC (40). Alkene hydroboration reactions generally give syn addition where both the BH2 group and hydrogen atom add to the alkene from the same face of the double bond (Eq 6) (41). When the hydroboration is performed with unsymmetrical alkenes, the reaction affords the anti-Markovnikov product as the boron generally adds to the less substituted carbon of the alkene. Alkynes also participate in this reaction. For example, boranes such as catecholborane add to alkynes to afford (E)-alkenylboronic esters, which are valuable intermediates in synthesis as described later (Eq 7) (42). For his contribution to boron chemistry, Brown shared the 1979 Nobel prize in chemistry.

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The transfer of an allyl group from triallylboron to aldehydes and ketones via an allylic rearrangement was reported in 1964 (Eq 8) (26). Many allylboranes, allylboronic esters, and allylboronamides participate in this reaction. Allylboration involves a six-membered chair-like transition state and the reaction can be performed at temperatures as low as -100 °C. In addition, asymmetric versions of this reaction also have been developed using various chiral allylboron reagents such as B-allyldiisopinocampheylborane (Ipc2Ballyl) (27).

The cross-Aldol reaction between a ketone enolate and an aldehyde electrophile produces complex product mixtures due to equilibrating enolate anions. One elegant and practical solution to this problem was provided by Teruaki Mukaiyama. Mukaiyama showed that vinyloxyboranes reacted competently in the cross-aldol reaction without formation of products derived from enolate equilibration (Scheme 2) (43). Vinyloxyboranes are formed from ketones and dialkylboron halides or triflates. Over the years, diastereoselective and enantioselective versions of this transformation have been developed.

Scheme 2. Cross-Aldol using Boron Enolates. In 1979, Akira Suzuki reported the palladium-catalyzed cross-coupling of 1-alkenylboranes to 1-alkenyl, 1-alkynyl, and aryl halides (Eq 9) (44, 45). This reaction, which is now known as the Suzuki-Miyaura cross-coupling, has been developed extensively and now allows for the coupling of a very broad range of organic fragments. In additon, the Suzuki-Miyaura cross-coupling is able to tolerate a broad scope of functional groups. Regio- and stereoselectivity is highly controllable in the Suzuki-Miyaura cross-coupling. It has been used in numerous syntheses of natural products and pharmaceuticals. Thus, it is one of the most important reactions in chemistry. It has also spurred great interest in the development of methods that provide access to boronic acids and boronic 11 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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esters. In order to facilitate the transmetalation step in the Suzuki-Miyaura cross-coupling, the reaction is carried out under basic conditions which converts the boronic acid or boronic ester into a borate anion. The basic conditions of the Suzuki-Miyaura cross-coupling occasionally lead to protodeboronation. Performing the Suzuki-Miyaura cross-coupling in an atmosphere of carbon monoxide affords ketones (Eq 10) (46). This variant is often referred to as the carbonylative Suzuki-Miyaura cross-coupling. Suzuki shared the Nobel prize in chemistry in 2010 for these discoveries.

The Miyaura borylation, which was described by Norio Miyaura in 1995, allows for the synthesis of boronic esters (Eq 11) (47). In this reaction, palladium catalyzes the borylation of alkenyl and aryl halides with alkoxydiboron compounds such as bis(pinacolato)diboron.

Arylboronic acids also can be coupled at room temperature with N-H and O-H containing compounds such as phenols, amines, anilines, amides, imides, ureas, carbamates, sulfonamides, and various heterocycles (Eq 12) (48, 49). The reaction is promoted by Cu(OAc)2 and a tertiary amine base. The Chan-Lam coupling was quickly employed to synthesize thyroxine (Scheme 3) (50).

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Scheme 3. Synthesis of thyroxine utilizing the Chan-Lam coupling.

The neighboring group effect that boron provides has been exploited to displace halogens from α-haloalkylboronic esters. Nucleophiles such as organometallic reagents add first to boron to form a tetravalent boron anion which rearranges to quickly displace the halogen on the adjacent carbon atom (51). A similar 1,2-migration is observed when dichloromethyl lithium is added to alkylboronic esters whereby the alkyl group migrates to displace one of the chlorine atoms from the dichloromethyl group (Scheme 4) (52). The remaining chlorine atom in the resulting α-haloalkylboronic esters has been displaced by various nucleophiles including organometallic reagents, amines, alkoxides, and thiolates utilizing this neighboring group effect. Donald Matteson has developed this chemistry to perform homologations of boronic esters. Asymmetric versions of this reaction have been reported using chiral boronic esters (substrate control) or chiral carbanions (reagent control) (53, 54). This reaction is essential for the asymmetric syntheses of various chiral α-aminoboronic acid-based enzyme inhibitors, which are discussed below.

Scheme 4. Homologation of alkylboronic esters.

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Alkenylboronic acids were found to add to the adduct of a secondary amine and paraformaldehyde at room temperature to produce (E)-allylamines (Scheme 5) (55). The Petasis borono-Mannich reaction has been extended to include arylboronic acids as well. Stereoselective syntheses of α-amino acids using this method have been disclosed (56).

Scheme 5. Petasis borono-Mannich reaction. The Lewis acidity of trivalent boron compounds has been utilized for many years to catalyze a wide range of organic reactions. Boron trihalides such as boron tribromide (BBr3), boron trichloride (BCl3), and boron trifluoride (BF3) have been used as Lewis acids regularly in synthesis. Among these three, boron tribromide is the strongest Lewis acid, whereas boron trifluoride is the weakest. This difference in Lewis acidity is a result of stronger π-bonding between fluorine and boron due to better orbital overlap since boron and fluorine are on the same row of the periodic table. The lone pairs on chlorine and bromine overlap poorly with the empty porbital on boron, which makes the p-orbital on boron more available as a Lews acidic site. Both BCl3 and BBr3 are capable of dealkylating alkyl ethers (Eq 13) (57). Over the last few decades, many examples of chiral boron catalysts have been described. For example, Elias James Corey developed a triflic acid activated chiral oxazaborolidine catalyst for asymmetric Diels-Alder reactions (Eq 14) (58).

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Robust tetrahedral boron compounds, which are readily made from boronic acids, have been described. For example, boronic acids can be converted to potassium organotrifluoroborate salts when treated with aqueous potassium hydrogenfluoride (potassium bifluoride), KHF2 (Eq 15) (59). Similarly, MIDA boronic esters can be prepared by reacting boronic acids with N-methyliminodiacetic acid (Eq 16) (29). Both potassium organotrifluoroborate salts and MIDA boronic esters serve as protecting groups for boronic acids as well as starting materials in reactions such as the Suzuki-Miyaura cross-coupling.

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Characterization Boron has two stable isotopes, 10B and 11B, as well as 14 other known radioactive isotopes (60). Both stable boron nuclei are active in nuclear magnetic resonance (NMR) spectroscopy. 11B NMR spectroscopy is routinely used for the characterization of boron-containing compounds and it is preferred for NMR studies for several reasons. Boron-10 has a 19.6 percent natural abundance and has a nuclear spin (I) of 3, whereas boron-11 has an 80.4 percent natural abundance and has a nuclear spin of 3/2. Boron-11 also has a higher magnetic receptivity and wider chemical shift range. However, small coupling constants in 11B NMR spectra, i.e., less than10 Hz, are difficult to measure. The signal from boron trifluoride diethyl etherate, BF3·O(C2H5)2, is typically used as the external reference. The chemical shift value for trivalent boron compounds ranges from approximately -10 to +100 ppm in 11B NMR spectra whereas tetravalent boron compounds typically have chemical shift values between +10 to -130 ppm. For example, the 11B resonance for boronic acids and boronic esters is typically between 25 to 35 ppm and trialkylboranes are generally around 75 to 95 ppm. The quadrupolar relaxation mechanism of 11B nuclei often leads to broadening of the 13C NMR signal of carbon atoms directly attached to boron. Thus, quaternary carbons with attached boryl groups are often not detected in 13C NMR spectra. Boronic acids, boronic esters, borinic acids, and borinic esters show a very strong B-O IR stretching frequency around 1350 to 1310 cm-1 (61). Similarly, the B-N bond of boronamides shows a strong band between 1378 and 1332 cm-1. Boronic acids and borinic acids will also have a strong broad hydrogen bonded OH frequency around 3300 to 3200 cm-1. The B-Cl stretching frequency of trivalent boron chloride compounds is around 910 to 890 cm-1 whereas the B-F stretching frequency in trifluoroborates has been reported to vary from 1227 to 951 cm-1 (59). Borane hydrides have a B-H stretching mode near 2630 to 2350 cm-1. The isotopic pattern due to the ratio of 10B and 11B (~1:4) is well observed in mass spectrometry for boron compounds.

Applications of Organoboron Compounds Many boron compounds have found applications in medicinal chemistry and materials science. For example, α-aminoboronic acids are capable of forming dative bonds with nucleophilic amino acid residues such as serine and threonine, which are found in the active site of proteases. These dative bonds, which are reversible, are stronger than non-bonding intermolecular interactions. The best known example is the anticancer drug bortezomib (marketed as Velcade), which was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of relapsed or refractory multiple myeloma (Figure 11). Multiple myeloma is a cancer of plasma cells. Bortezomib has the distinction of being the first approved proteasome inhibitor as well as the first approved boronic acid-based drug on the market. The dipeptidyl boronic acid binds reversibly with the chymotrypsin-like (CT-L) subunit of the proteasome through its boronic acid group (62). The proteasome is responsible for the degradation of misfolded proteins and ubiquitylated proteins. Proteasome inhibition leads to the 16 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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accumulation of pro-apoptotic proteins (proteins that regulate the cell suicide process) in tumorigenic cells but not normal tissue. In 2006, bortezomib was also approved by the FDA for the treatment of mantle cell lymphoma.

Figure 11. Structures of bortezomib, ixazomib, and delanzomib.

The second generation proteasome inhibitor ixazomib (marketed as Ninlaro) has improved characteristics compared to bortezomib. For example, it has a shorter half-life and wider distribution in blood compared to bortezomib. It inhibits the CT-L subunit as well as the trypsin-like (T-L) and caspase-like (C-L) subunits of the proteasome. Ixazomib is typically administered orally as a citrate boronic ester prodrug which hydrolysis in the plasma to the active boronic acid form shown in Figure 11. Ixazomib was approved by the FDA in late 2015 as the first oral proteasome inhibitor for the treatment of multiple myeloma. It is used in combination with lenalidomide and dexamethasone. Another related boronic acid-based proteasome inhibitor is delanzomib, which reversibly inhibits CT-L and C-L. Delanzomib is also administered orally and in combination with lenalidomide and dexamethasone. It is currently in clinical studies. The boron atom in bortezomib interacts with the hydroxyl group in a nucleophilic terminal threonine residue whereas several intermolecular interactions hold this small molecule in the active site of the CT-L subunit of the proteasome (Figure 12). The tetrahedral borate anion is a transition state analogue that resembles the tetrahedral intermediate of amidolysis which is formed when proteases hydrolyze peptides. Tavaborole (marketed under Kerydin) is an oxaborole topical antifungal, which was approved in 2014 by the FDA for the treatment of onychomycosis (Figure 13). Onychomycosis is a fungal infection of the toenail. Tavaborole interferes with fungal protein synthesis through the inhibition of cytoplasmic leucyl-tRNA synthetase (63). The related crisaborole is currently in clinical trials for the treatment of psoriasis and eczema (Figure 13). Crisaborole inhibits phosphodiesterase-4 (PDE-4), which reduces the release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) (64). 17 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 12. Key interaction of bortezomib with a terminal threonine residue in the CT-L subunit of the proteasome (other interactions not shown).

Figure 13. Structures of tavaborole and crisaborole.

Compared to arylboronic acids, oxaboroles are more electrophilic due to the ring strain caused by the short B-O bond within the ring. This ring strain is released when the boron is hydroxylated to form a tetrahedral borate anion. Tavaborole, for example, reacts with the cis diol of the ribose unit in the terminal adenosine of leucyl-tRNA, which renders the cytoplasmic leucyl-tRNA synthetase enzyme inactive (Eq 17) (65).

The inhibition of PDE-4 is also a target to treat type 2 diabetes since PDE4 degrades incretin hormones such as glucagon-like peptide 1 (GLP-1). This hormone degradation results in increased levels of GLP-1, which inhibits glucagon release and increases the release of insulin from the pancreas. Thus, serum sugar levels decrease. Dipeptide boronic acids such as talabostat (Figure 14) are not only capable of inhibiting PDE-4 but also other related enzymes such as PDE-2, PDE-8, PDE-9, and FAP (fibroblast activation protein). The inhibition of FAP by talabostat was investigated in clinical trials for the treatment of colorectal cancer (65). 18 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 14. Structure of talabostat. Boron neutron capture therapy (BNCT) has been used to treat brain and neck tumors. The therapeutic potential of BNCT has been recognized since 1936 (66). In BNCT, a compound such as p-borono-L-phenylalanine and sodium borocaptate (Na2B12H11SH) containing the non-radioactive isotope 10B is delivered to a tumor to release α-particles (4He nucleus) after being irradiated with thermal neutrons (Figure 15). The capture of the neutrons by 10B nuclei causes fission reactions that release α-particles and lead to the death of cancer cells. Since the depth penetration of α-particles is only limited to about one cell, the damage to nearby healthy cells is limited in BNCT.

Figure 15. Structures of p-borono-L-phenylalanine and sodium borocaptate. As discussed above for tavaborole, boronic acids are capable of reversibly binding cis-1,2- or cis-1,3-diols. This characteristic has been utilized in the development of potential sensors for saccharides such as glucose. Reliable measuring of blood glucose levels is critically important for patients with diabetes. Although many sensors utilizing biological recognition elements have been developed for sensing saccharides, synthetic chemosensors have the potential to be more stable and less expensive (30). Since boronic esters have a slightly lower pKa than boronic acids, the binding of a diol to a boronic acid will typically lead to slight favoring of the anionic borate anion over the neutral boronic esters. This increase in ionization can be measured through differences in either solubility or fluorescence intensity, among other characteristics. The incorporation of multiple 19 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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boronic acid groups has led to increased binding affinity for saccharides. Selection of an appropriate spacer helps with selectivity between different saccharides. For example, Drueckhammer developed a diboronic acid sensor that has a 400-fold greater affinity for glucose compared to fructose (Eq 18) (67).

Similar strategies have been used for the separation and immobilization of glycoproteins such as antibodies (68). Immobilized boronic acids have been developed that bind diols on the carbohydrate chains of various antibodies. This immobilization strategy has many potential uses, such as the detection of antigens. Soluble electrochemical sensing redox probes such as ferrocenylboronic acid-based systems have been employed to directly measure changes in electrochemical response as they bind a ligand such as a diol from a sugar or glycoprotein (Figure 16) (69). Similarly, probes bearing a boronic acid have been used to monitor catechol-based biomolecules such as dopamine as well as hard anions such as fluoride. The applications of boronic acid-based polymers has recently been reviewed (70).

Figure 16. Structure of ferrocenylboronic acid redox probe.

Conclusion Although the first organoborane compound was synthesized more than 150 years ago, it was almost another century before boron reagents first saw significant application in synthesis. Beginning in the 1940s, the potential of borohydride and borane reagents in synthesis was first recognized. However, it was not until the discovery of the Suzuki-Miyaura coupling reaction in the late 1970s that this area of chemistry really took off. Since then, many new reactions and advances have been reported; too numerous to mention here. The reader will find more recent advances and details in the remaining chapters of this book. The discovery that boronic acids can inhibit proteases has led to the approval of boronic acid-centered pharmaceuticals for the treatment of several diseases. Three boronic acid-based drugs (bortezomib, ixazomib, and tavaborole) have been approved for human use since 2003 with many more in the pipeline. Furthermore, boronic acid-based 20 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

materials are currently being studied as potential probes for important biological molecules such as saccharides, glycoproteins, and catecholamines as well as hard anions such as fluoride. These developments will no doubt spur further research in the area of organoboron chemistry in the upcoming years and many new exciting discoveries in their applications (including in synthesis) will be made as a result.

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44. Miyaura, N.; Yamada, K.; Suzuki, A. A New Stereospecific Cross-Coupling by the Palladium-Catalyzed Reaction of 1-Alkenylboranes with 1-Alkenyl or 1-Alkynyl Halides. Tetrahedron Lett. 1979, 20, 3437–3440. 45. Miyaura, N.; Suzuki, A. Stereoselective Synthesis of Arylated (E)-Alkenes by the Reaction of Alk-1-enylboranes with Aryl Halides in the Presence of Palladium Catalyst. J. Chem. Soc., Chem. Commun. 1979, 866–867. 46. Wakita, Y.; Yasunaga, T.; Akita, M.; Kojima, M. Carbonylative CrossCoupling Reactions of Organoboranes with Aryl Iodides and Benzyl Halides Successfully Catalyzed by Dichlorobis(triphenylphosphine)palladium(II) in the Presence of Bis(acetylacetonato)zinc(II) Produce Unsymmetrical Ketones in Reasonable Yields. J. Organomet. Chem. 1986, 301, C17–C20. 47. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-Catalyzed CrossCoupling Reaction of Alkoxydiboron with Haloarenes: A Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995, 60, 7508–7510. 48. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. New N- and O-Arylations with Phenylboronic Acids and Cupric Acetate. Tetrahedron Lett. 1998, 39, 2933–2936. 49. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. New Aryl/Heteroaryl C-N Bond Cross-Coupling Reactions via Arylboronic Acid/Cupric Acetate Arylation. Tetrahedron Lett. 1998, 39, 2941–2944. 50. Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of Diaryl Ethers Through the Copper-Promoted Arylation of Phenols with Arylboronic Acids. An Expedient Synthesis of Thyroxine. Tetrahedron Lett. 1998, 39, 2937–2940. 51. Matteson, D. S.; Mah, R. W. H. Neighboring Boron in Nucleophilic Displacement. J. Am. Chem. Soc. 1963, 85, 2599–2603. 52. Matteson, D. S.; Majumdar, D. α-Chloro Boronic Esters from Homologation of Boronic Esters. J. Am. Chem. Soc. 1980, 102, 7588–7590. 53. Matteson, D. S.; Majumdar, D. Directed Chiral Synthesis with Pinanediol Boronic Esters. J. Am. Chem. Soc. 1980, 102, 7590–7591. 54. Aggarwal, V. K.; Fang, G. Y.; Schmidt, A. T. Synthesis and Applications of Chiral Organoboranes Generated from Sulfonium Ylides. J. Am. Chem. Soc. 2005, 127, 1642–1643. 55. Petasis, N. A.; Akritopoulou, I. The Boronic Acid Mannich Reaction: A New Method for the Synthesis of Geometrically Pure Allylamines. Tetrahedron 1993, 34, 583–586. 56. Petasis, N. A.; Akritopoulou, I. A New and Practical Synthesis of α-Amino Acids from Alkenyl Boronic Acids. J. Am. Chem. Soc. 1997, 119, 445–446. 57. Benton, F. L.; Dillon, T. E. The Cleavage of Ethers with Boron Bromide. I. Some Common Ethers. J. Am. Chem. Soc. 1942, 64, 1128–1129. 58. Corey, E. J.; Shibata, T.; Lee, T. W. Asymmetric Diels−Alder Reactions Catalyzed by a Triflic Acid Activated Chiral Oxazaborolidine. J. Am. Chem. Soc. 2002, 124, 3808–3809. 59. Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of Arylboron Difluoride Lewis Acids. J. Org. Chem. 1995, 60, 3020–3027. 24 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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60. Gunther, H. NMR Spectroscopy: Basic Priciples, Concepts, and Applications in Chemistry, 3rd ed.; Wiley VCH: Weinheim, Germany, 2013. 61. Bellamy, L. J.; Gerrard, W.; Lappert, M. F.; Williams, R. L. 481. Infrared Spectra of Boron Compounds. J. Chem. Soc. 1958, 2412–2415. 62. Accardi, F.; Toscani, D.; Bolzoni, M.; Palma, B. D.; Aversa, F.; Giuliani, N. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Mieloma Cells and the Bone Microenvironment: Impact on MyelomaInduced Alterations of Bone Remodeling. BioMed Res. Int. 2015, 2015, 1–13. 63. Jinna, S.; Finch, J. Spotlight on Tavaborole for the Treatment of Onychomycosis. Drug Des., Dev. Ther. 2015, 9, 6185–6190. 64. Baker, S. J.; Tomsho, J. W.; Benkovic, S. J. Boron-Containing Inhibitors of Synthetases. Chem. Soc. Rev. 2011, 40, 4279–4285. 65. Touchet, S.; Carreaux, F.; Carboni, B.; Bouillon, A. Aminoboronic Acids and Esters: from Synthetic Challenges to the Discovery of Unique Classes of Enzyme Inhibitors. Chem. Soc. Rev. 2011, 40, 3895–3914. 66. Locher, G. L. Biological Effects and Therapeutic Possibilities of Neutrons. Am. J. Roentgenol. 1936, 36, 1–13. 67. Yang, W.; He, H.; Drueckhammer, D. G. Computer-Guided Design in Molecular Recognition: Design and Synthesis of a Glucopyranose Receptor. Angew. Chem., Int. Ed. 2001, 40, 1714–1718. 68. Duval, F.; van Beek, T. A.; Zuilhof, H. Key Steps Towards the Oriented Immobilization of Antibodies Using Boronic Acids. Analyst 2015, 140, 6467–6472. 69. Li, M.; Zhu, W.; Marken, F.; James, T. D. Electrochemical Sensing Using Boronic Acids. Chem. Commun. 2015, 51, 14562–14573. 70. Brooks, W. L. A.; Sumerlin, B. S. Synthesis and Applications of Boronic Acid-Containing Polymers: From Materials to Medicine. Chem. Rev. 2016, 116, 1375–1397.

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Chapter 2

Lewis Acids

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Manabu Hatano and Kazuaki Ishihara* Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan *E-mail: [email protected]; Tel.: +81-52-789-3331; Fax: +81-52-789-3222

This chapter reviews recent progress on boron(III) Lewis acids. Due to the chemical stability and easy molecular design of boron(III) compounds, boron(III) Lewis acids have been used in organic synthesis for more than 80 years both stoichiometrically and catalytically. In particular, this chapter focuses on the recent application of boron(III) Lewis acid catalysts in asymmetric reactions. Recent advances in supramolecular cooperative catalysts involving chiral boron(III) Lewis acids are also reviewed. Moreover, recent interesting examples of acid or base cooperative boronic acid catalysts and recent synthetically important advances with electron-deficient triarylborane(III) are described.

Introduction Boron(III) compounds are some of the most useful Lewis acids among main group elements. Boron(III) Lewis acids have been used in organic synthesis for more than 80 years both stoichiometrically and catalytically. In particular, due to the chemical stability and easy molecular design of boron(III) compounds, boron(III) Lewis acid catalysts have been shown to be valuable in asymmetric catalysis. Many excellent textbooks and reviews of chiral boron(III) Lewis acid catalysts have been published (1–8). Moreover, over the past decade there have been outstanding advances in frustrated Lewis pair (FLP) chemistry with the use © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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of bulky boron(III) compounds (e.g., B(C6F5)3) and silanesa and bulky boron(III) compounds and hosphines/amines/N-heterocyclic carbenes (NHC) to activate small molecules such as hydrogen. Therefore, very comprehensive information is now available (9–22). This chapter will not address these topics and instead will focus on a recent trend for the application of boron(III) Lewis acid catalysts in an asymmetric manner. This chapter reviews recent advances with supramolecular cooperative catalysts involving chiral boron(III) Lewis acids based on acid–base combined chemistry (23–26). Moreover, recent interesting examples of acid or base cooperative boronic acid catalysts and synthetically important advances with electron-deficient triarylboranes(III) are also described.

Preface to Cooperative Chiral Boron(III) Lewis Acid Catalysts The concept of ‘combined chiral acid catalysts’ was established by Yamamoto, and these can be classified into Brønsted acid-assisted chiral Lewis acids (chiral BLA), Lewis acid-assisted chiral Lewis acids (chiral LLA), Lewis acid-assisted chiral Brønsted acids (chiral LBA), and Brønsted acid-assisted chiral Brønsted acids (chiral BBA) (27, 28). In early asymmetric boron(III) Lewis acid catalysis, some chiral BLA catalysts were predominantly used in the enantioselective Diels–Alder reaction, hetero Diels–Alder reaction, Hosomi–Sakurai reaction, and Mukaiyama aldol reaction (Figure 1). The first outstanding chiral boron(III) catalyst 1 reported by Yamamoto was based on tartaric acid ligands (29–38). The high reactivity of the chiral acyloxyborane (CAB) catalysts 1 might be caused by intramolecular hydrogen bonding of the terminal carboxylic acid to the alkoxy oxygen atom. Later, Ishihara and Yamamoto developed BLA catalyst 2, which was highly effective for the Diels–Alder reaction (39, 40). The coordination of a proton of the 2-hydroxyphenyl group would trigger hydrogen-bonding, through which the Lewis acidity of the boron(III) center should increase. Moreover, introduction of a further electron-deficient moiety such as in catalyst 3 reported by Ishihara and Yamamoto, which was derived from 3,5-bis(trifluoromethyl)benzeneboronic acid, compensated for the narrow substrate scope of catalyst 2 (41). Moreover, Ishihara and Yamamoto developed a quite simple BLA 4 from a 1:2 molar ratio mixture of a trialkylborate and optically pure simple 1,1′-bi-2-naphtol (BINOL), which was highly effective for the enantioselective aza-Diels–Alder reaction of aldimines (42).

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Figure 1. Early chiral BLA catalysts in the enantioselective Diels–Alder reaction.

Intermolecular chiral BLA systems were developed alongside these early intramolecular chiral BLA systems. Mukaiyama developed a combined catalyst consisting of chiral prolinol 5 and BBr3 for a catalytic enantioselective Diels–Alder reaction (Scheme 1) (43). Later, Aggarwal investigated whether the corresponding catalysts 6 and 7 would be prepared in situ due to the release of HBr, which can coordinate nitrogen of the prolinol-ligand and effectively activate the boron(III) center (44).

Scheme 1. Chiral Prolinol-Derived Boron(III) Catalyst for the Diels–Alder Reaction.

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As one of the most powerful and useful chiral BLA catalysts to date, Corey developed chiral oxazaborolidine catalysts 8 and 9 with trifluoromethanesulfonic acid (TfOH) and bis(trifluoromethane)sulfonimide (Tf2NH) for the catalytic enantioselective Diels–Alder reaction (Scheme 2) (45–47). The generation of cationic boron(III) Lewis acids is the key to greatly enhancing the catalytic activity for a variety of substrates, such as poorly reactive but synthetically useful quinones, which are scarcely usable with other conventional Lewis acid catalysts.

Scheme 2. Brønsted Acid-Assisted Cationic Chiral Oxazaborolidine Catalysts for the Diels–Alder Reaction.

Oxazaborolidines alone are weak bases in principle, and their full protonation can only be achieved by using a very strong Brønsted acid such as TfOH or Tf2NH. In place of these strong Brønsted acids, Corey used the very strong Lewis acid AlBr3 for the oxazaborolidine as a Lewis acid-assisted Lewis acid (LLA) catalyst (Scheme 3) (48, 49). As a result, LLA catalyst 10 showed a greater turnover efficiency than BLA catalysts 8 and 9. The high catalytic activity of catalyst 10 might be the result of greater steric screening of various Lewis acids, and the activated boron(III) site by the adjacent AlBr3 subunit would also diminish product inhibition more effectively than other possible Lewis acids. In this regard, Sakata reported a quantum-chemical study which used DFT calculations in an AlBr3-activated oxazaborolidine-catalyzed Diels–Alder reaction (50). The calculations clearly showed that the attachment of AlBr3 to the nitrogen atom of oxazaborolidine would enhance the Lewis acidity of its boron(III) center and enable it to coordinate to methacrolein. Moreover, the calculation supported 30 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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the notion that AlBr3 would also facilitate the reaction by reducing the overlap repulsion between the diene and the dienophile.

Scheme 3. AlBr3-Assisted Cationic Chiral Oxazaborolidine Catalyst for the Diels–Alder Reaction.

Very recently, Corey developed much more active acid-assisted cationic chiral oxazaborolidine catalysts for the Diels–Alder reaction (51). The catalytic activity could be further enhanced by the judicious placement of fluorine substituents in the chiral ligand, and a Tf2NH-assisted chiral oxazaborolidine catalyst 11 and an AlBr3-assisted chiral oxazaborolidine catalyst 12 were designed (Scheme 4). A probe reaction between cyclopentadiene and ethyl crotonate clearly showed an order-of-magnitude increase in catalytic power when β-CH2 was replaced by CF2 in the chiral catalysts 11 and 12. Moreover, catalyst 13, in which a 2,5difluorophenyl moiety replaced the o-tolyl moiety, showed much higher catalytic activity than 12. For a variety of substrates, excellent reaction rates, product yields, and enantioselectivities have been achieved through the use of 1−2 mol% of these cationic chiral fluorinated oxazaborolidine catalysts (Figure 2).

Scheme 4. Cationic Chiral Fluorinated Oxazaborolidines. 31 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 2. Scope of substrates with the use of 1 mol% of cationic chiral fluorinated oxazaborolidines.

As overviewed in these pioneering studies by Yamamoto, Corey, and Mukaiyama, the combined use of suitable Brønsted acids or Lewis acids and chiral boron(III) Lewis acids might make it possible to achieve high reactivities and high enantioselectivities, particularly in catalytic enantioselective Diels–Alder reactions. Activation by the further attachment of a strong proton or strong Lewis acid to a complex provides a way to overcome the deactivating effect of a chiral ligand. In this context, this chapter will review very recent advances by using mostly intermolecular acid-assisted–acid catalyst systems, and particularly with B(C6F5)3-assisted chiral boron(III) Lewis acid catalysts and boron(III) Lewis acid-assisted chiral phosphoric acid catalysts.

B(C6F5)3-Assisted Chiral Boron(III) Lewis Acid Catalysts General Properties of the Diels–Alder Reaction The Diels–Alder reaction is one of the most fundamental higher-ordered stereoselective reactions that involve the formation of two carbon–carbon bonds through [4 + 2] cycloadditions. The corresponding cyclohexane skeletons with possibly four successive chiral carbon centers can offer synthetic versatility, particularly in natural products, pharmaceuticals, and agrochemicals (52–57). In several studies to date, enantioselectivity in the Diels–Alder reaction has been successfully controlled by a variety of chiral catalysts or chiral auxiliaries in the substrates. On the other hand, endo/exo-selectivity in the Diels–Alder reaction strongly depends on the substrates, based on the Woodward–Hoffmann rule and Fukui’s conservation rule of orbital symmetry interactions and steric interactions between dienes and dienophiles via pericyclic transition states under thermodynamic or photoreaction conditions (Figure 3) (58–64). 32 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 3. Substrate-controlled endo/exo-selectivity in the Diels–Alder reaction.

Therefore, it is quite difficult to control not only enantioselectivity but also substrate-independent anomalous endo/exo-selectivity, since, while most conventional chiral catalysts can discriminate the enantiofaces of dienophiles, they cannot discriminate the approach of dienes. Many combinations of dienes with dienophiles allow a well-known endo-rule that is based on second-order orbital interactions (Figure 3, left). However, when steric interactions between dienes and dienophiles overcome the second-order orbital interactions in endo-transition states, less-familiar exo-adducts are often predominantly obtained in opposition to the endo-rule (Figure 3, right). For example, in the reaction between cyclopentadiene 15 and acrolein 16, an endo-preference is observed with regard to second-order orbital interactions without significant steric interactions (Scheme 5). In sharp contrast, in the reaction between 15 and methacrolein 18, an exo-preference is observed with regard to steric interaction between the methylene moiety of 15 and the methyl moiety of 18. Thermodynamically more stable optically active exo-17, which has a chiral tertiary carbon center, can also be generated by the epimerization of endo-17, since optically active endo-17 has been synthesized using many conventional chiral catalysts. In contrast, optically active endo-19, which has a chiral quaternary carbon center, cannot be generated by the epimerization of easily available exo-19.

Scheme 5. Second-Order Orbital Interactions and Steric Interactions on endo/exo-Selectivity in the Diels–Alder Reaction.

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Anomalous Endo/Exo-Selective Diels–Alder Reaction with Chiral Supramolecular Boron(III) Catalysts To directly address the anomalous endo/exo control in the Diels–Alder reaction, catalysts must be able to accurately discriminate a chiral transition state by recognizing not only the re/si-face of dienophiles but also the endo/exo-approach of dienes. However, it might be easier to design promising catalysts for anomalous exo-control than for anomalous endo-control, since the external exo-approach can be realized when the internal endo-approach would be effectively prevented even with single-molecule catalysts with a relatively small structure. In this regard, anomalous exo-selective Diels–Alder reactions of α-non-substituted acroleins against the original endo-rule have been investigated by a few research groups through the use of single-molecule catalysts. The landmark anomalous exo-induced bulky aluminum(III) Lewis acid catalyst ATPH was developed by Yamamoto (65). Later, anomalous exo-induced chiral Lewis acid catalysts were independently developed by Kündig (Ru(III) catalysts) (66), Sibi (Yb(III) catalysts) (67), Maruoka (diamine catalysts) (68, 69), and Hayashi (prolinol silyl ether catalysts) (70). In sharp contrast to these anomalous exo-induced Diels–Alder reactions with α-non-substituted acroleins, a reaction intermediate in the anomalous endo-induced Diels–Alder reaction with an α-substituted acrolein should have a folding structure regardless of considerable steric repulsion between the reactants. Therefore, a deep and narrow cavity in the catalyst is needed to hold a diene and a dienophile together throughout the transition states. To realize this strategy, the rational design of conformationally flexible chiral supramolecular catalysts, similar to natural enzymes, might be possible. Moreover, according to Lehn’s original definition of a ‘supramolecule’ (71), which contains more than two molecules with non-covalent intermolecular bonds, supramolecular catalysts might be a simple extension from single-molecule catalysts. A useful coordination bond to generate a chiral supramolecular catalyst, PO···B(C6F5)3 (72), is highly attractive since Shibasaki pioneeringly used phosphine oxides as functionalized Lewis base moieties based on acid–base combination chemistry (73–84). Ishihara developed a conformationally flexible, highly active, chiral supramolecular catalyst based on well-designed single-molecule components (85, 86). A chiral supramolecular catalyst 24 was readily prepared in situ from three components such as chiral (R)-3,3′-((RO)2PO)2-BINOL 20 (87–94), 3,5-bis(trifluoromethyl)phenylboronic acid 21, and tris(pentafluorophenyl)borane 23 (Scheme 6). 31P NMR analysis in CD2Cl2 showed a corresponding peak shift of phosphoryl moieties at 19.16 ppm for 20, 17.91 ppm for 22, and 9.42 ppm for 24. Compound 23 would act as a bulky functional group to make a chiral, narrow and deep cavity around the Lewis acidic boron(III) center. Moreover, the strong electron-recipient ability of Lewis acid 23 would increase the Lewis acidity of the central boron(III) through conjugate bonds, which would take advantage of Lewis acid-assisted chiral Lewis acid (chiral LLA) catalysts.

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Scheme 6. Preparation of a Chiral Supramolecular Boron(III) Catalyst.

In the presence of chiral supramolecular catalyst 24, a probe Diels–Alder reaction between 15 and 18 was conducted (Scheme 7) (85, 86). As a result, anomalous endo-(2S)-19 was obtained as a major product (99% yield, endo:exo = 83:17) with excellent enantioselectivity (99% ee). In sharp contrast, 20 and incomplete complexes 22 (i.e., [20 + 21]) and 25 (i.e., [20 + 23]) showed almost no catalytic activity (0–2% yield). Catalyst 22 was also not reactive, since it lacks conjugated activation by Lewis acid 23. Moreover, 21 and 23 gave the normal exo-19 as a major product. According to a working model to explain the anomalous stereoselectivity, a chiral, narrow, and deep cavity was assumed (85, 86). A theoretical study for a complex of 18 and 24 at the B3LYP/6-31G* level supported the notion that the two non-covalent P=O···B(C6F5)3 moieties have a syn-conformation (syn-26) on one hand and an anti-conformation (anti-26) on the other hand (Figure 4). As a result, syn-26 was more stable than anti-26 by 3.86 kcal/mol, since significant steric repulsion would be observed among the C6F5 moieties and the central 3,5(CF3)2C6H3B moiety in anti-26.

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Scheme 7. Anomalous endo-Selective Diels–Alder Reaction of Methacrolein.

Figure 4. Theoretical calculations for supramolecular boron(III) complexes.

In syn-26, the formyl moiety of 18 with a favored s-trans geometry was doubly coordinated with the B-O(Naph) moiety at the C(=O)H and C(=O)H parts (Figures 4 and 5). In a possible transition state 27, an endo-approach inside the cavity via a re-face attack would be relevant, while an exo-approach via a re-face attack would be unlikely because of the bulkiness of another C6F5 group.

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Figure 5. A possible transition state for anomalous endo-selectivity.

Other anomalous endo-selective Diels–Alder reactions of α-haloacroleins are shown in Scheme 8 (85, 86). In the reaction of α-bromoacrolein, supramolecular catalyst 24 was ineffective, and normal exo-28 was obtained as a major product with low enantioselectivity (>99% yield, endo:exo = 16:84, 10–11% ee). In contrast, another supramolecular catalyst 29 with chiral biphenol in place of chiral binaphthol 24 was extremely effective, and the anomalous endo-selectivity was dramatically improved (94% yield, endo:exo = 93:7) with excellent enantioselectivity for endo-(2R)-28 (>99% ee). Another supramolecular catalyst 30 was effective for the reaction of α-chloroacrolein, and an anomalous endo-(2R)-31 was obtained (>99% yield, endo:exo = 88:12) with excellent enantioselectivity (99% ee). Moreover, another optimum supramolecular catalyst 32 was used in the reaction of α-fluoroacrolein, and anomalous endo-(2R)-33 was obtained (>99% yield, endo:exo = 82:18) with high enantioselectivity (96% ee). As with an enzymatic methodology, fine-tuning of the conformationally flexible supramolecular catalysts for each α-haloacrolein was essential for establishing anomalous endo-selectivity as well as excellent enantioselectivity. As the halogen in α-haloacrolein become smaller, larger components at the central aryl borane moiety and the biphenyl moiety were effective. The greater bulkiness may directly or indirectly create a smaller cavity that could suitably recognize a smaller substrate (Figure 6).

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Scheme 8. Anomalous endo-Selective Diels–Alder Reaction of α-Haloacroleins.

Figure 6. Optimum size of a suitable chiral cavity for each substrate. As a possible explanation for why the anomalous endo-selectivity of 28 was significantly improved when biphenyl catalyst 29 was used in place of binaphthyl catalyst 24, there might be a slight difference in the dihedral angle of the binaphthyl or biphenyl skeleton. As another possible explanation, the electron-donating ability of the 6,6′-ether moieties in 29 through a resonance 38 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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effect in the conjugate system might induce a stronger intermolecular acid–base coordination of non-covalent P=O···B(C6F5)3 (Figure 7). This coordination bond stabilization might reduce the adventitious dissociation of achiral B(C6F5)3 23. Consequently, normal Diels–Alder reactions with low enantioselectivity by incomplete supramolecular catalysts and/or 23 would be prevented.

Figure 7. A resonance effect in chiral biphenol catalysts.

Anomalous exo-selective Diels–Alder reaction of α-non-substituted acrolein 16 was also established by another optimal chiral supramolecular catalyst 34 (Scheme 9) (85, 86). In general, the reaction of 15 with 16 was endo-selective under substrate-control (endo:exo = 80:20 under thermal conditions). In sharp contrast, supramolecular catalyst 34 with amido moieties in place of phosphoryl moieties was highly effective for the anomalous exo-induced Diels–Alder reaction of 16 with high enantioselectivities (94% ee for exo-(2S)-17, endo:exo = 20:80).

Scheme 9. Anomalous exo-Selective Enantioselective Diels–Alder Reaction. 39 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Similar to catalyst 24 with phosphoryl moieties, a possible transition state for catalyst 34 with amide moieties is shown in Figure 8 (85, 86). Unlike the pseudo-tetrahedral phosphorous structure, the amide has a less-hindered planar structure, and the non-covalent amide–B(C6F5)3 moiety may turn outside in the transition states. As a result, a shallow and wide cavity, which would promote the anomalous exo-approach, would be provided in 35.

Figure 8. A possible transition state for anomalous exo-selectivity.

Moreover, molecular recognition was performed under substrate-competitive Diels–Alder reaction conditions (85, 86). For a 1:1:1 equimolar mixture of 15, 16, and 18, exo-inducing supramolecular catalyst 34 promoted the reaction of 16 exclusively, and anomalous exo-(2S)-17 was obtained as a major product (endo:exo-17 = 20:80, 95% ee for exo-(2S)-17) (Scheme 10). In sharp contrast, achiral catalyst 23 gave a mixture of endo-17 and exo-19 with low substrate-selectivity (16:18 = 63:37) and normal endo/exo-selectivity (endo:exo-17 = 87:13, endo:exo-19 = 9:91). This result strongly suggests that the catalyst exhibits an induced-fit to adapt to a specific substrate.

Scheme 10. Molecular Recognition in the Substrate-Competitive Reaction. 40 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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As another useful coordination bond to generate a new type of chiral supramolecular catalyst, CN···B(C6F5)3 (95) is highly attractive. Ishihara developed chiral Lewis acid catalyst 36, which was prepared in situ from chiral 3-substituted-BINOL, (2-cyanophenyl)boronic acids, and tris(pentafluorophenyl)borane based on CN···B and PO···B coordination bonds, for the enantioselective Diels–Alder reaction (Scheme 11) (96). A probe reaction between cyclopentadiene and methacrolein clearly showed the effectiveness of 36. Catalyst 37 without the CF3 moiety in aryl boronic acid decreased the enantioselectivity. Moreover, the PO···B(C6F5) moiety was also important for inducing high enantioselectivity, and the significantly bulky electron-deficient aryl moiety as seen in catalyst 39, unlike less bulky 38, was needed to keep the high enantio-induction in place of the PO···B(C6F5)3 moiety. Optimization of bulkiness of the aryl moiety might still be needed to further improve the enantioselectivity. Therefore, the concise in situ-construction of the bulky PO···B(C6F5)3 moiety that is achieved by mixing the PO moiety and B(C6F5)3 would be very advantageous by reducing the need for catalyst optimization.

Scheme 11. A Probe Diels–Alder Reaction that Uses Supramolecular Catalysts with CN···B and PO···B Coordination Bonds. 41 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Various acroleins could be used, and the corresponding normal products from acrolein, ethylacrolein, tiglic aldehyde, and ethyl trans-4-oxo-2-butenoate were obtained with high enantioselectivities (Scheme 12). Moreover, acyclic diene 40 could be used in place of cyclopentadiene, and 41 was obtained in 97% yield with 85% ee (Scheme 13).

Scheme 12. Reactions of Various Acroleins through the Use of the Supramolecular Catalyst with CN···B and PO···B Coordination Bonds.

Scheme 13. A Reaction with the Acyclic Diene through the Use of the Supramolecular Catalyst with CN···B and PO···B Coordination Bonds.

Overall, in these Diels–Alder reactions with the use of catalyst 36, anomalous endo/exo-selectivities were not observed, unlike the results with previous supramolecular catalysts, such as 24. Although catalyst 36 would have a chiral cavity in a possible transition state 42 in Figure 9, the structure might be too flexible to control anomalous endo/exo-selectivities. Therefore, a moderately rigid conformationally flexible supramolecular catalyst such as 24 might be essential for inducing anomalous endo/exo-selectivities. Instead, more flexible catalyst 36 showed a relatively wide scope for substrates to induce high enantioselectivities, whereas more rigid catalyst 24 showed narrower substrate specificity to induce high enantioselectivities with anomalous endo/exo-selectivities. 42 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 9. Possible transition state with catalyst 36.

Boron(III) Lewis Acid-Assisted Chiral Phosphoric Acid Catalysts Direct Boron(III) Lewis Acid-Assisted Chiral Phosphoric Acid Catalysts Chiral phosphoric acids are highly useful acid–base cooperative organocatalysts for a variety of asymmetric catalyses (97–101). However, their Brønsted acidity is generally not strong enough to activate less-basic aldehydes compared to more-basic aldimines. To overcome this serious issue, the addition of an achiral Lewis acid to the chiral phosphoric acid would be a highly promising option since the conjugate acid–base moiety of the phosphoric acid is suitable for the Lewis acid-assisted Brønsted acid (LBA) catalyst system (Figure 10). Ishihara developed a BBr3-assisted chiral phosphoric acid catalyst, which was highly effective for the catalytic enantioselective Diels–Alder reaction toward a concise synthesis of isoquinuclidine alkaloids (102).

Figure 10. BBr3-Assisted chiral phosphoric acid catalysts. A probe reaction between cyclopentadiene and methacrolein was promoted in the presence of chiral phosphoric acid (R)-43 and BBr3, and normal exo-product 19 was obtained with 89% ee (Scheme 14). The reaction did not proceed in the absence of BBr3, and the reaction proceeded in the presence of BBr3 alone. Therefore, the cooperative catalyst BBr3-(R)-43 was much more active 43 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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than either BBr3 or (R)-43. Moreover, BBr3 was essential for inducing high enantioselectivity, and other similar boron(III) compounds, such as BF3·Et2O, BCl3, BI3, and B(C6F5)3, were less effective. When cyclohexadiene was used in place of cyclopentadiene, endo-product 44 was also obtained with 87% ee. Therefore, this catalyst was effective for both normal endo- and exo-control.

Scheme 14. BBr3-Assisted Chiral Phosphoric Acid catalyst for Diels–Alder Reactions.

The cooperative catalyst BBr3-(R)-43 showed low catalytic activity (16% ee) for much less reactive acyclic diene 40 (Scheme 15). In sharp contrast, another cooperative catalyst BBr3–N-sulfonyl phosphoramide 45 was effective, and endo46 was obtained in 82% yield with 89% ee (102). Although only specialized examples have been reported to date, the possibility of using this catalytic system with phosphoric acids and N-sulfonyl phosphoramides (103) might be attractive for catalyst optimization in general asymmetric catalysis. To demonstrate the synthetic utility of this approach, Ishihara performed a formal total synthesis of (+)-catharanthine, which is an important indole alkaloid that forms vinblastine (Scheme 16) (102). A key Diels–Alder reaction between 1,2-dihydropyridine 47 and α-bromoacrolein proceeded successfully with the use of cooperative catalyst BBr3-(R)-43, and the corresponding product endo-48 was obtained with 98% ee. Subsequent transformations ultimately provided the desired key intermediate 49 (104) without a loss of optical purity. 44 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. BBr3-Assisted Chiral N-Sulfonyl Phosphoramide Catalyst for the Diels–Alder Reaction.

Scheme 16. Formal Total Synthesis of (+)-Catharanthine.

Moreover, Ishihara performed a transformation to the key intermediate of (+)-allocatharanthine, which is another component of vinblastine (Scheme 17) (102). The key enantioselective Diels–Alder reaction of ethyl-substituted 1,2-dihydropyridine 50 gave the desired endo-51 with 97% ee with the use of BBr3–(S)-43. After some transformations of the isoquinuclidine structure, condensation with 3-indoleacetic acid gave the desired key intermediate 52 (105) without a loss of optical purity. 45 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 17. Formal Total Synthesis of (+)-Allocatharanthine.

Remote Boron(III) Lewis Acid-Assisted Chiral Phosphoric Acid Catalysts Based on previous study about B(C6F5)3-assisted chiral boron(III) Lewis acid catalysts in the Diels–Alder reaction, Ishihara developed a remote B(C6F5)3-assisted chiral phosphoric acid catalyst 53 for the enantioselective Diels–Alder reaction of α-substituted acroleins with cyclopentadiene as a probe reaction (106). Introduction of the phosphoric acid to the center of supramolecular catalysts might provide additional opportunities for versatile molecular recognition according to the size and/or substitution pattern of the acroleins. Unlike a previous simple boron(III) Lewis acid center such as 24, the highly conjugated Brønsted acid–Brønsted base bifunction of chiral phosphoric acid 53 should be able to doubly coordinate (107–109) to acroleins (Figure 11, left). Moreover, the addition of an achiral Lewis acid (MLn) should provide bifunctional Lewis acid–Brønsted base catalysts (Figure 11, right). ESI-MS analysis and 1H, 19F, and 31P NMR analysis of catalyst 53 suggested that coordination to B(C6F5)3 at the carbonyl groups of the 3,3′-substituents would proceed via coordination at the central P=O moiety, probably due to steric constraints at the narrow inner space. As a result, with the use of catalyst 53, the Diels–Alder product 19 was obtained from methacrolein in 92% yield with 90% ee (Scheme 18). However, the scope of substrates was narrow, and the Diels–Alder products from α-ethylacrolein, α-isopropylacrolein, and α-bromoacrolein showed lower enantioselectivities (84% ee for exo-54, 23% ee for exo-56, and 18% ee for exo-29, respectively). Moreover, anomalous endo/exo-selectivities were not observed in these probe reactions, probably due to the poor cavity effect. 46 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 11. Possible reaction mechanism in remote boron(III) Lewis acid-assisted chiral phosphoric acid catalysts.

Scheme 18. Diels–Alder Reaction Catalyzed by Remote B(C6F5)3-Assisted Chiral Phosphoric Acid. For a much less reactive α,β-disubstituted acrolein such as tiglic aldehyde, catalyst 53 showed low reactivity, and the product was obtained in 38% yield with 56% ee (Scheme 19). To overcome this issue, the Brønsted acid–Brønsted base catalyst system was changed to a Lewis acid–Brønsted base catalyst system through the use of an additional achiral Lewis acid partner. After acid sources were screened, catecholborane (110) was found to be a highly effective boron(III) Lewis acid center, and the product was obtained in 71% yield with 75% ee with the use of catalyst 57 (106). 47 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 19. Remote B(C6F5)3-Assisted Chiral Boron(III) Phosphate Catalyst for the Diels–Alder Reaction.

Acid or Base Cooperative Arylboronic Acid Catalysts Intramolecular Cooperative System with Brønsted Base-Assisted Arylboronic Acid A variety of boronic acid catalysts have been developed to activate carboxylic acids as mixed anhydrides through dehydrative condensation (111–113). More recent research has focused on the rational design of acid or base cooperative arylboronic acid catalysts to promote various reactions using carboxylic acids as substrates. Ishihara developed the first successful method for the catalytic dehydrative self-condensation of carboxylic acids with the use of the Brønsted base-assisted boronic acid catalyst 58 (Scheme 20) (114, 115). An arylboronic acid bearing bulky (N,N-dialkylamino)methyl groups at the 2,6-positions can catalyze the intramolecular dehydrative condensation of aromatic and aliphatic di- and tetracarboxylic acids. As Whiting pioneeringly reported in dehydrative amide condensation with (2-((N,N-diisopropylamino)methyl)phenyl)boronic acid catalyst (116–119), steric hindrance of the (N,N-dialkylamino)methyl groups might prevent the intramolecular interaction between the boronic acid group and the (N,N-dialkylamino)methyl groups (N → B chelation) that causes inactivation of the boronic acid group. Moreover, the introduction of two bulky substituents at the 2,6-positions might prevent the formation of less active species such as triarylboroxines (120, 121). 48 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 20. Catalytic Dehydrative Condensation of Aromatic and Aliphatic Dicarboxylic Acids. A model plausible reaction mechanism is shown in Figure 12. The condensation of phthalic acid would occur via monoacyl boronate 59 as an active intermediate. The N,N-dialkylamino nitrogen and the N,N-dialkylammonium proton of 59 would then synergistically promote intramolecular cyclization to 60. The former would act as a Brønsted base to activate the carboxyl group, and the latter would act as a Brønsted acid to activate the carbonyl group through two consecutive hydrogen-bonding interactions supported by the B-hydroxyl group. The subsequent elimination of phthalic anhydride from intermediate 60 would also be synergistically promoted by the N,N-dialkylamino nitrogen and the N,N-dialkylammonium proton of 60.

Figure 12. Possible reaction mechanism in catalytic dehydrative condensation. Intermolecular Cooperative System with Arylboronic Acid and Nucleophilic Base The catalytic dehydrative condensation reaction between carboxylic acids and amines is one of the most ideal methods for synthesizing the corresponding amides. To date, some excellent arylboronic acid catalysts have been developed, as shown in Scheme 21; 61 and 62 by Ishihara and Yamamoto in 1996 (122–126), 49 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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63 by Whiting in 2006 (116–119) 64 by Hall in 2008 (127–131). In addition to these arylboronic acids, boric acid (132, 133), benzo[1,3,2]dioxaborol-2-ol (134–136), and methylboronic acid (137) have been reported to be useful as amidation catalysts. In arylboronic acid-catalysis, a mixed anhydride intermediate 65 is generated at the initial stage from the carboxylic acid and arylboronic acid under azeotropic reflux conditions or in the presence of drying agents (Schemes 21 and 22). As the second activation stage, if a nucleophilic additive (Nu) reacts with 65 to generate a more active cationic intermediate 67 via a tetrahedral intermediate 66, the amide condensation may proceed more rapidly.

Scheme 21. Dehydrative Condensation of Carboxylic Acids with Amines Catalyzed by Arylboronic Acids, and Representative Examples of Catalysts.

Scheme 22. The Second Activation by Nucleophilic Additives in the Presence of Arylboronic Acids. 50 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In this context, Ishihara recently found that arylboronic acids and N,N-dimethylaminopyridine N-oxide (DMAPO) cooperatively promote dehydrative condensation between various carboxylic acids and amines (138). A probe reaction between 2-phenylbutyric acid and benzylamine was examined in the presence of 5 mol% each of arylboronic acid 62 and an additive (Scheme 23). As a result, arylboronic acid 62 alone did not promote the reaction. N,N-Diisopropylethylamine, 4-(N,N-dimethylamino)pyridine (DMAP), and 4-methoxypyridine N-oxide (MPO) were not effective. In contrast, a weak but more nucleophilic base, DMAPO, was quite effective for amide condensation. A more nucleophilic additive such as 4-(pyrrolidin-1-yl)pyridine N-oxide (PPYO) was less effective than DMAPO, since the strong nucleophilicity of PPYO might reduce the activity of intermediate 67.

Scheme 23. Effects of Additives on the Dehydrative Condensation between 2-Phenylbutyric Acid and Benzylamine. Both the nucleophilicity of the additive and the Lewis acidity and steric effect of the boronic acid are important in the cooperative catalysis. Actually, the cooperative effects of boronic acids were compared in the condensation reaction between bulky 2-phenylbutyric acid or less bulky benzoic acid and benzylamine (Scheme 24). Both catalysts 62–DMAPO and 64b–DMAPO efficiently promoted the reaction of 2-phenylbutyric acid. Interestingly, 62–DMAPO was much more effective than 64b–DMAPO for the amide condensation of benzoic acid. Moreover, Whiting’s catalyst 63–DMAPO was still effective for the reaction of benzoic acid, while the catalytic activity of 63–DMAPO was almost suppressed in the reaction of 2-phenylbutyric acid. In these mismatch situations among the catalysts, additives, and substrates, a less active species 68 would be generated according to the X-ray analysis of an inert species (138).

Scheme 24. Cooperative Effects of Arylboronic Acid and DMAPO. 51 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Overall, 62–DMAPO could be used with both types of these substrates. Notably, not only aliphatic primary amines but also sterically hindered aliphatic secondary amines, less nucleophilic anilines and alkoxyamines reacted with these carboxylic acids (Scheme 25) (138). Moreover, this cooperative method can be scaled to practical volumes of up to an 80 mmol scale. The utility of the cooperative catalyst 62–DMAPO was also demonstrated for the selective amide condensation of β-substituted acrylic acids, and the corresponding amides were obtained in high yields. In general, the reactions without DMAPO gave the corresponding products in low yields (data in brackets in Scheme 25).

Scheme 25. Catalytic Dehydrative Condensation between Carboxylic Acids and Amines. Data in Brackets are the Results without DMAPO.

Intermolecular Cooperative System with Arylboronic Acid and Chiral Aminothiourea Takemoto developed the intramolecular aza- and oxa-Michael reactions of α,β-unsaturated carboxylic acids for the first time with the use of a bifunctional aminoboronic acid 63 (Scheme 26) (139). Not only pyrrolidines but also piperidines, imidazolidinone, dihydrobenzofurans, and chromanes could be synthesized successfully. A plausible mechanism is similar to the previous proposal by Whiting and Ishihara regarding the dehydrative condensation of dicarboxylic acids and amines. The trigonal planar boron(III) species would form an acyloxyborane complex 70 bearing the carboxylic acid moiety of the substrate with the aid of the Lewis acidity of the boron(III) atom and the Brønsted basic moiety of 63. 52 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 26. Intramolecular Aza-Michael Reaction of α,β-Unsaturated Carboxylic Acid. As shown in the proposed mechanism, the amino group of the aminoboronic acid 63 would not be directly involved in the activation of the nucleophilic moiety of the substrate. Therefore, the reaction would be further facilitated by the addition of an external base, and the use of a chiral base catalyst would induce enantioselectivity. The combined use of an arylboronic acid 62 and a chiral aminothiourea 71 allowed the reaction to proceed in an enantioselective manner, and the desired heterocycles were obtained in high yields with high enantioselectivities (Scheme 27) (139).

Scheme 27. Intramolecular Michael Addition to α,β-Unsaturated Carboxylic Acids.

Synthesis of Electron-Deficient Triarylboranes(III) for Catalysis Preparation of Tris[3,5-bis(trifluoromethyl)phenyl]borane Traditionally, tris(pentafluorophenyl)borane (B(C6F5)3) has been recognized as an excellent co-catalyst in homogeneous Ziegler–Natta olefin-polymerization reactions (140–143). The special properties of B(C6F5)3 have made this strong boron(III) Lewis acid increasingly used as a catalyst and/or a stoichiometric reagent in organic and organometallic chemistry (144–148). Over the 53 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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past decade, B(C6F5)3 has been considered to be one of the most effective Lewis acid components in frustrated Lewis pairs (FLPs) (9–22). For the development of further promising FLPs, some novel homo- and hetero tri(aryl)boranes(III) were recently synthesized, as shown in Figure 13, and their properties have been evaluated with respect to their NMR spectra, X-ray crystal structures, electrochemical studies, etc. (149–151). In this regard, tris[3,5-bis(trifluoromethyl)phenyl]borane(III) 72 would be favored due to the very strong electron-withdrawing ability of its six trifluoromethyl moieties (8). Nevertheless, the synthesis of 72 had not been reported before Ashley and Tamm independently and almost simultaneously reported a preparative procedure in 2012 (Scheme 28) (152, 153). In fact, the synthesis of 72 had been considered to be difficult, since 72 can easily transform to tetra[3,5-bis(trifluoromethyl)phenyl]borate during its preparation due to its strong Lewis acidity. Therefore, stoichiometric control of the starting borane, such as BF3·Et2O, and an extremely pure Grignard reagent should be essential.

Figure 13. Preparation yields of novel homo- and hetero tri(aryl)boranes(III).

Scheme 28. Preparation of Tris[3,5-bis(trifluoromethyl)phenyl]borane(III). As a result, their final optimum procedures turned out to be quite similar, as shown in Scheme 28. According to the Knochel method (154), the corresponding Grignard reagent was prepared from 3,5-bis(trifluoromethyl)phenyl bromide and i-PrMgCl in THF. Next, BF3·Et2O was added to give tris[3,5bis(trifluoromethyl)phenyl]borane(III) as a white crystal. Subsequent sublimation and recrystallization provided 72 in 62–79% yields. The obtained 72 was investigated analytically and used in some probe FLP reactions. As a result, 72 was estimated to be slightly more Lewis acidic (6%) than B(C6F5)3 in a 31P NMR 54 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

analysis with Et3PO, and studies of its FLP features are anticipated in the near future.

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Hydrogenation of Unactivated Aldehydes Uozumi developed a good method for the hydrogenation of unactivated aldehydes by using a Hantzsch ester in the presence of an electron-deficient triarylborane(III) 72 as a strong Lewis acid catalyst (Scheme 29) (155). As an initial screening of boron(III) Lewis acid catalysts for the hydrogenation of cyclohexanecarboxaldehyde in toluene at 60 °C, catalyst 72 showed much higher catalytic activity than BF3·Et2O and B(C6F5)3. This result strongly suggests that 72 is more Lewis acidic than B(C6F5)3, as Ashley demonstrated (152).

Scheme 29. Screening of Boron(III) Catalysts in the Hydrogenation of Cyclohexanecarboxaldehyde.

After further optimization of the reaction conditions, tris[3,5bis(trifluoromethyl)phenyl]borane 72 efficiently catalyzed the hydrogenation of unactivated aliphatic aldehydes with a Hantzsch ester in 1,4-dioxane at 100 °C to give the corresponding aliphatic primary alcohols in high yield (Scheme 30). Unactivated aromatic aldehydes also undergo hydrogenation even at 25 °C to furnish the corresponding aromatic primary alcohols in up to 100% yield.

Scheme 30. Scope of Unactivated Aliphatic Aldehydes and Aromatic Aldehydes. 55 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Conclusion

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In conclusion, this chapter reviewed the recent progress on boron(III) Lewis acids. Although boron(III) Lewis acids have been used more than 80 years ago, the synthetic potential of boron(III) Lewis acids has still continued to increase, due to the chemical stability and easy molecular design of boron(III) compounds. In particular, the developments of acid–base cooperative catalysts involving boron(III) Lewis acids are remarkable in this field. Based on innovative scientific and new technological approaches, continued exploratory research will be expected to provide more efficient and practical methods for advanced molecular transformation in the near future.

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136. Maki, T.; Ishihara, K.; Yamamoto, H. New boron(III)-catalyzed amide and ester condensation reactions. Tetrahedron 2007, 63, 8645–8657. 137. Yamashita, R.; Sakakura, A.; Ishihara, K. Primary alkylboronic acids as highly active catalysts for the dehydrative amide condensation of α-hydroxycarboxylic acids. Org. Lett. 2013, 15, 3654–3657. 138. Ishihara, K.; Lu, Y. Boronic acid–DMAPO cooperative catalysis for dehydrative condensation between carboxylic acids and amines. Chem. Sci. 2016, 7, 1276–1280. 139. Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma, T.; Takemoto, Y. A dual arylboronic acid–aminothiourea catalytic system for the asymmetric intramolecular hetero-Michael reaction of α,β-unsaturated carboxylic acids. Org. Lett. 2014, 16, 4256–4259. 140. Bochmann, M. Cationic group 4 metallocene complexes and their role in polymerisation catalysis: the chemistry of well defined Ziegler catalysts. J. Chem. Soc., Dalton Trans. 1996, 255–270. 141. Piers, W. E.; Chivers, T. Pentafluorophenylboranes: from obscurity to applications. Chem. Soc. Rev. 1997, 26, 345–354. 142. Chen, E. Y.-X.; Marks, T. J. Cocatalysts for metal-catalyzed olefin polymerization: activators, activation processes, and structure−activity relationships. Chem. Rev. 2000, 100, 1391–1434. 143. Erker, G. Tris(pentafluorophenyl)borane: a special boron Lewis acid for special reactions. Dalton Trans. 2005, 1883–1890. 144. Focante, F.; Mercandelli, P.; Sironi, A.; Resconi, A. Complexes of tris(pentafluorophenyl)boron with nitrogen-containing compounds: synthesis, reactivity and metallocene activation. Coord. Chem. Rev. 2006, 250, 170–188. 145. Beringhelli, T.; Donghi, D.; Maggioni, D.; D’Alfonso, G. Solution structure, dynamics and speciation of perfluoroaryl boranes through 1H, 11B and 19F NMR spectroscopy. Coord. Chem. Rev. 2008, 252, 2292–2313. 146. Ishihara, K.; Funahashi, M.; Hanaki, N.; Miyata, M.; Yamamoto, H. Tris(pentafluorophenyl)boron as an efficient catalyst in the aldol-type reaction of ketene silyl acetals with imines. Synlett 1994, 1994, 963–964. 147. Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.; Yamamoto, H. Tris(pentafluorophenyl)boron as an efficient, air stable, and water tolerant Lewis acid catalyst. Bull. Chem. Soc. Jpn. 1995, 68, 1721–1730. 148. Ishihara, K.; Hanaki, N.; Yamamoto, H. Tris(pentafluorophenyl)boron as an efficient catalyst in the stereoselective rearrangement of epoxides. Synlett 1995, 1995, 721–722. 149. Ashley, A. E.; Herrington, T. J.; Wildgoose, G. G.; Zaher, H.; Thompson, A. L.; Rees, N. H.; Krämer, T.; O’Hare, D. Separating electrophilicity and Lewis acidity: The synthesis, characterization, and electrochemistry of the electron deficient tris(aryl)boranes B(C6F5)3–n(C6Cl5)n (n = 1–3). J. Am. Chem. Soc. 2011, 133, 14727–14740. 150. Blagg, R. J.; Lawrence, E. J.; Resner, K.; Oganesyan, V. S.; Herrington, T. J.; Ashley, A. E.; Wildgoose, G. G. Exploring structural and electronic effects in three isomers of tris{bis(trifluoromethyl)phenyl}borane: towards 65 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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the combined electrochemical-frustrated Lewis pair activation of H2. Dalton Trans. 2016, 45, 6023–6031. Blagg, R. J.; Simmons, T. R.; Hatton, G. R.; Courtney, J. M.; Bennett, E. L.; Lawrence, E. J.; Wildgoose, G. G. Novel B(Ar′)2(Ar′′) heterotri(aryl)boranes: a systematic study of Lewis acidity. Dalton Trans. 2016, 45, 6032–6043. Herrington, T. J.; Thom, A. J. W.; White, A. J. P.; Ashley, A. E. Novel H2 activation by a tris[3,5-bis(trifluoromethyl)phenyl]borane frustrated Lewis pair. Dalton Trans. 2012, 41, 9019–9022. Kolychev, E. L.; Bannenberg, T.; Freytag, M.; Daniliuc, C. G.; Jones, P. G.; Tamm, M. Reactivity of a frustrated Lewis pair and small-molecule activation by an isolable Arduengo carbine–B{3,5-(CF3)2C6H3}3 complex. Chem. Eur. J. 2012, 18, 16938–16946. Abarbri, M.; Dehmel, F.; Knochel, P. Bromine-magnesium-exchange as a general tool for the preparation of polyfunctional aryl and heteroaryl magnesium-reagents. Tetrahedron Lett. 1999, 40, 7449–7453. Hamasaka, G.; Tsuji, H.; Uozumi, Y. Organoborane-catalyzed hydrogenation of unactivated aldehydes with a Hantzsch ester as a synthetic NAD(P)H analogue. Synlett 2015, 26, 2037–2041.

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Chapter 3

Allylboration

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Subash C. Jonnalagadda,*,1,2 Pathi Suman,1 Amardeep Patel,1 Gayathri Jampana,1 and Alexander Colfer1 1Department

of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States 2Department of Biomedical and Translational Sciences, Rowan University, Glassboro, New Jersey 08028, United States *E-mail: [email protected]

Allylboration involves the addition of “allyl” boron species across multiple bonds (most commonly aldehydes, ketones, and imines). This chapter will focus on the recent advances in the area of stereoselective allylboration with a main emphasis on the boranes derived from chiral auxiliaries such as α-pinene, tartrate, borabicylo[3.3.2]decane, and camphor. Other topics include catalytic enantioselective allylboration and the chemistry of chiral α–substituted allylboranes. Allylboration of other functional groups including epoxides, nitriles, lactams, and heteroaromatics are also discussed.

Introduction Allylboration is a carbon-carbon bond forming reaction that deals with the addition of an “allyl” boron species across a multiple bond (e.g. C=O, C=N, C=C, N=N, S=O, C≡N, C≡C, etc.) or even a strained single bond. While this reaction is routinely observed with carbonyl compounds such as aldehydes, ketones, and the corresponding imines, there are several instances in which these reactions happen with substrates such as alkenes, alkynes, allenes, amides, lactams, nitriles, pyrazines, pyridines, pyrroles, etc. Allylboration of aldehydes and ketones using B-allyl dialkylboranes as the allylating reagents is known to be a very fast reaction and it proceeds even at very low temperatures (-100 °C). This has subsequently led to the development © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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of several chiral allylboranes for the stereoselective allylboration of aldehydes and ketones. The stereoselectivity could in general be enhanced by lowering the temperature of these reactions. In most cases, allylboration is predicted to occur via an allylic rearrangement involving a six-membered chair-like transition state. While several allyl metal reagents have been developed for the allylation of carbonyl compounds, allylboron reagents hold a special place in organic chemistry and synthesis owing to multiple reasons. Firstly, boron offers an environmental-friendly alternative to most other toxic metals that are routinely used for this reaction. Secondly, allylboranes provide very high levels of stereocontrol as these reactions proceed via a rigid six-membered chair-like transition state. Accordingly, there have been extensive investigations on the use of chiral auxiliaries for carrying out enantio- and diastereoselective allylboration reactions. Finally, many of the allyl boron reagents are economical as they can be readily accessed from simple precursors such as sodium borohydride, and chiral pool materials such as camphor, α-pinene, tartaric acid, etc. Owing to their importance, utility, and applications, thousands of papers dealing with the preparation of new allylboron reagents and their use in natural product syntheses have appeared in the past four decades and it would be impractical to cover all aspects of this topic in one chapter. Needless to mention, allylation of carbonyl compounds using boron reagents has been extensively reviewed (1–6). Due to the extensive amount of research that has been undertaken in this area, it is prohibitive to cover all topics in a single chapter and we apologize in advance for any unintentional omissions due to oversight. This chapter will primarily deal with the preparation of various highly functionalized chiral allylboranes (with particular emphasis on α-pinene based chiral auxiliaries), along with a few of the recent developments on the design of catalytic enantioselective allylboration and a brief discussion on α-substituted chiral allylboranes.

Stereoselective Allylboration of Carbonyl Compounds Mikhailov and Bubnov first reported the synthesis of triallylborane (7) and its further reaction with carbonyl compounds (8–10). The reaction of aldehydes and ketones with allylboranes involves the addition of an allyl group via allylic rearrangement and most commonly, the γ-carbon in the allylborane adds to the carbonyl carbon (8–10). Hoffmann introduced the first chiral allylborane (1) (11, 12) derived from camphor for the enantioselective synthesis of homoallylic alcohols which was then utilized for the stereoselective synthesis of natural products (13–15). Apart from camphor, Hoffmann also introduced several chiral vicinal diol based boronates (2) (16) for allylboration. Corey was able to improve the stereoselectivity of these boronates further by the introduction of chiral vicinal sulfonamide derived allylboranes (17). Yamamoto introduced tartarate ester based allenylboronate and 68 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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propargylboronate for the stereoselective synthesis of homopropargylic alcohols and homoallenyl alcohols respectively (18, 19). Roush developed this area in a significant manner and he was able to synthesize a diverse scaffold of higher order allylborane reagents derived from chiral tartrate esters (3) (20, 21) and tartaramide (22). Brown discovered the α-pinene based B-allyldiisopinocampheylborane (4) in 1983 and ever since, these reagents have been very well studied (23). These reagents have attained immense significance owing to the excellent levels of reagent-based stereocontrol observed during their reactions with aldehydes and imines. Reetz introduced chiral diamine-derived 1,3,2-dizaboroles (5) as stereoselective allylborating agents (24, 25) and Itsuno was further able to develop these reagents for solid phase applications (26). Masamune introduced chiral borolane (6) prepared via kinetic resolution methodology for chiral allylation (27, 28). Soderquist was further able to extend the stereoselective allylation to ketones and ketimines via the introduction of borabicyclo[3.3.2]decane (7) as the chiral auxiliary (29). Kauffman (30) introduced binaphthol based allylborane (8) for the allylboration of carbonyl compounds (Figure 1).

Figure 1. Chiral auxiliary-based allylboranes.

Based on the exceptional success of α-pinene, Brown investigated the use of several terpenoid allylboranes derived from β-pinene (9), ethylapopinene (10), limonene (11), 2-carene (12), 3-carene (13), and longifolene (14) (Figure 2) (31–34). While 2-carene and 3-carene based reagents do often provide higher levels of enantioselectivity, α–pinene has still proven to be the most popular chiral auxiliary because of the excellent levels of stereocontrol that it offers in addition to being cost-effective as both antipodes of this compound are abundantly available from pine trees. 69 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 2. Chiral terpenoid-derived allylboranes.

Preparation of Allylboranes via “Allyl”transmetalations Standard methods for the preparation of allylboranes involve the generation of allyl metal species (via deprotonation or dehalogenation) and subsequent transmetalation with dialkylborinates or trialkylborates. Alternatively, allylboranes could also be synthesized via hydroboration of 1,2-dienes (allenes) or 1,3-dienes. Another method of preparation includes homologation of vinylboranes or boronates. This section has been categorized based on the method of preparation of the chiral allylboranes. Most of the functionalized allylboranes reported below have been prepared using chiral auxiliaries derived from α-pinene as well as tartarate esters. In order to avoid redundancy, for the most part, we have focused on functionalized B-“Allyl”diisopinocampheylboranes.

(B)-Allyldiisopinocampheylborane Introduced by Brown and Jadhav (35), B-Allyldiisopinocampheylborane 4 has attracted significant attention from the organic chemistry community. This reagent is prepared by the reaction of B-chloro or B-methoxydiisopinocampheylborane (Ipc2BCl 16 or Ipc2BOMe 17) with allyl Grignard, followed by the filtration of the magnesium salts under inert-atmosphere. Ipc2BCl 16 and Ipc2BOMe 17 are in turn obtained from diisopinocampheylborane Ipc2BH 15 upon treatment with HCl and MeOH respectively (Scheme 1). Ipc2BH is easily obtained via hydroboration of α-pinene. Allylborane 4 reacts with a wide variety of aldehydes to provide the homoallylic alcohols in excellent enantiomeric excess (ee). As mentioned earlier, α-pinene provides exceptional levels of stereocontrol independent of the inherent chirality of the substrates. As both enantiomers of α-pinene are readily available, it is possible to obtain both enantiomers of the homoallylic alcohols with the appropriate choice of the stereoisomer of α-pinene. The high levels of selectivity can be explained based on the rigid six-membered chair like transition states (TS1 & TS2). The 1,3-diaxial 70 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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strain forces the aldehyde to approach the allylborane preferentially from one side (TS2). These reagents are quite stable and they are even commercially available as 1M solutions in pentane (36). They could be stored under an inert atmosphere for longer periods of time without appreciable decomposition or loss of enantioselectivity (35). Recently Singaram et al. were able to show that even indium is able to promote the formation of B-allyldiisopinocampheylborane 4 upon reaction with allyl bromide (37).

Scheme 1. Allylboration of aldehydes with B-allyldiisopinocampheylborane.

Allylation of Imines Using B-Allyldiisopinocampheylborane Itsuno reported the allyboration of N-silylaldimines and N-aluminoaldimines 20 with a variety of allylborane reagents, and it was noticed that the allylboration with allylborane 4 seemed to provide lower enantioselectivities (38–40). Brown demonstrated that the reaction of N-silyl imines with 4 was indeed taking place during work up (as observed by the exothermicity during work up). Accordingly, Brown et al. were able to enhance the enantioselectivity of this reaction by the addition of a stoichiometric amount of water to the reaction mixture at low temperature (-78 °C) (Scheme 2) (41). Later Ramachandran and co-workers applied this methodology for the synthesis of diverse homoallylic amines and azaheterocyclic compounds (42–44). 71 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 2. Allylboration of aldimines and acylsilanes.

Allylation of Acylsilanes Using B-Allyldiisopinocampheylborane Asymmetric allylboration of acylsilanes 22 has also been reported with Ballyldiisopinocampheylborane 4 furnishing the tertiary homoallylic alcohols 23 in varying levels of enantioselectivity (2-90% ee) (Scheme 2) (45).

(B)-(Z or E)-γ-Methylallyldiisopinocampheylborane (B)-(Z or E)-γ-Methylallyldiisopinocampheylborane reagents are obtained by the deprotonation of cis or trans 2-butene respectively, using Schlosser’s base (nBuLi, KOtBu) followed by transmetallation with Ipc2BOMe 17 or Ipc2BCl 16. Temperature plays a critical role in this reaction as the cis and trans crotyl anions Z-25 and E-25 undergo rapid interconversion at higher temperature, which leads to scrambling of the reagent stereochemistry. The potassium counter ion is required for maintaining the integrity of the double bond because of its ability to form a stable η3 linkage with crotyl anion at lower temperature. The reaction of crotylboranes 26 with aldehydes results in the formation of homoallylic alcohols 27a-d in high diastereomeric excess (de) and enantiomeric excess (ee) (46, 47). Crotylboration offers a valuable tool to the synthetic chemist for the synthesis of all four diastereomers of the propionate motif in the homoallylic alcohols 27a-d, via an appropriate choice of (Z or E)-2-butene and (+ or -) α-pinene (Scheme 3).

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Scheme 3. Crotylboration of aldehydes.

(B)-β-Methylallyldiisopinocampheylborane (B)-β-Methylallyldiisopinocampheylborane is prepared by the reaction of 2-methylpropene 28 with n-butyl lithium and subsequent treatment with Ipc2BOMe 17 (48, 49). The resulting “ate” complex is treated with BF3.Et2O to release the methallylborane 30, which upon reaction with aldehydes furnishes the β-methylhomoallylic alcohols 31 in very good ee (Scheme 4).

Scheme 4. β-Methylallylboration of aldehydes. 73 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

1,3-Bis(diisopinocampheylboryl)-2-methylenepropane

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Barrett et al. demonstrated the synthesis of bis-allylborane 33 via a double deprotonative lithiation of 2-methylpropene 28 with excess n-butyl lithium and treatment with Ipc2BCl 16. This reagent furnished, upon reaction with two equivalents of aldehyde followed by oxidative work up, the C2-symmetric bis homoallylic alcohols 34 in good yields and selectivity (Scheme 5) (50, 51).

Scheme 5. 1,3-Bis(diisopinocampheylboryl)-2-methylenepropane. (B)-γ,γ-Dimethylallyldiisopinocampheylborane Brown and Jadhav reported the synthesis of γ,γ-dimethylallyldiisopinocampheylborane 36 via the hydroboration of 1,1-dimethylallene 35 with Ipc2BH 15, however this method required the use of expensive dimethylallene reagent, thus rendering it difficult for large scale applications (52). We then demonstrated the use of 4-chloro-2-methylbut-2-ene 37 (readily obtained from inexpensive prenyl alcohol) for the preparation of 36. Thus, the conversion of 37 into the corresponding Grignard and subsequent treatment with Ipc2BOMe 17 provided ready access to the allylborane 36, which upon reaction with aldehydes yielded β,β-dimethyl homoallyl alcohols 38 in high ee (Scheme 6) (53, 54).

Scheme 6. γ,γ-Dimethylallylboration of aldehydes. 74 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(B)-Isoprenyldiisopinocampheylborane

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Brown and Randad reported the preparation of B-isoprenylborane 42 via the deprotonation of isoprene 39 with potassium tetramethylpiperidide 40 followed by the addition of Ipc2BOMe 17 to the resulting allylpotassium 41. These reagents were then used for the synthesis of ipsenol 43 and ipsdienol 44 by reaction with appropriate aldehydes (Scheme 7) (55, 56).

Scheme 7. Isoprenylboration of aldehydes.

(B)-(Z)-γ-Alkoxyallyldiisopinocampheylborane The reaction of allyl alkyl ethers 45 with sbutyl lithium results in the formation of (Z)-olefinyl anion 46 due to the strong coordination between ether oxygen and lithium (57, 58). Brown et al. were able to convert 46 to (Z)-γ-alkoxyallylborane reagent 47 upon further treatment with Ipc2BOMe 17 (59). Allylboration of aldehydes with 47 provides excellent de and ee for the corresponding syn β-alkoxyhomoallylic alcohol 48. While this reagent was initially developed using allyl methyl ether 47a, subsequently, several new reagents have also been prepared using different alcohol protecting groups such as methoxymethyl (MOM) 47b, 2-(trimethylsilyl)ethoxymethyl (SEM) 47c, methoxyethoxymethyl (MEM) 47d, p-methoxyphenyl (PMP) 47e, tetrahydropyranyl (THP) 47f, etc. (Scheme 8). These protecting groups offer greater versatility for further chemical manipulations of the syn β-alkoxyalcohols (60–63). 75 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 8. (Z)-γ-Alkoxyallylboration of aldehydes.

(B)-(E)-γ-Methoxyallyldiisopinocampheylborane

While the deprotonative lithiation of allyl methyl ethers provides the (Z)-stereochemistry for the methoxyallyl anion as mentioned above (Scheme 8), Hoffmann was able to show that reduction of (E)-1-methoxy-3-(phenylthio)propene 49 with two equivalents of potassium naphthalenide 50 at -120 °C, afforded the potassium (E)-alkoxyallyl anion 51 (64, 65). Ganesh and Nicholas trapped the allyl anion 51 with Ipc2BOMe 17 to provide the elusive (E)-γ-alkoxyallylborane reagent 52 (66). As expected, this reagent provided anti stereochemistry for the homoallylic alcohols 53 upon reaction with aldehydes (Scheme 9).

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Scheme 9. (E)-γ-Alkoxyallylboration of aldehydes.

(B)-(Z)-γ-Chloroallyldiisopinocampheylborane Hertweck carried out the deprotonation of allyl chloride 54 with lithium dicyclohexylamide (Chx2NLi) which resulted in the formation of (Z)-olefin 55, because of the Li-Cl coordination as seen above (Scheme 8) during the deprotonation of allyl alkyl ethers. Treatment of 55 with Ipc2BOMe 17 yielded the requisite allylborane which upon reaction with aldehydes resulted in the syn β-chlorohomoallyl alcohols 58 (67, 68). It should be noted that the regular alkaline peroxide work up of this reaction would lead to the epoxidation to produce the vinyloxiranes. Accordingly, mild work up with 8-hydroxyquinoline is typically employed to obtain β-chloro-homoallylic alcohols (Scheme 10).

Scheme 10. (Z)-γ-Chloroallylboration of aldehydes.

77 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(B)-(E)-γ-(N,N-Diphenylamino)allyldiisopinocampheylborane

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Lithiation of allyl diphenylamine 59 with n-butyl lithium in the presence of tetramethylethylenediamine was effective in the preparation of (E)- anion 60, which upon sequential treatment with Ipc2BOMe 17, aldehyde, and alkaline peroxide workup produced anti β-diphenylaminohomoallyl alcohols 63 (Scheme 11) (69).

Scheme 11. (E)-γ-(Diphenylamino)allylboration of aldehydes.

(B)-(E)-γ-(Diphenylmethyleneamino)allyldiisopinocampheyl Borane While the allyl diphenylamine based allylborane 61, was useful for the synthesis of β-diphenylaminoalcohol 63, Barrett and co-workers were able to extend this methodology for the preparation of β-amino homoallylic alcohols 69 as well (70, 71). Accordingly, they initiated their synthesis with the deprotonation of benzophenone-allylimine 64, with LDA followed by the addition of Ipc2BCl 16 to yield the allylborane 66. This reagent upon addition of aldehyde, alkaline work up and deprotection of the imine yielded the expected anti β-amino homoallyl alcohols 69. Barrett et al. were able to further expand this methodology for the preparation of β-amino allylalcohol 70. This was accomplished by the treatment of intermediate imine 68 with triflic anhydride and acidic work up (Scheme 12).

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Scheme 12. Reaction of (B)-(E)-γ-(Diphenylmethyleneamino)allyldiisopinocampheylborane with aldehydes.

(B)-(E)-γ-((N,N-Diisopropylamino)dimethylsilyl)allyldiisopino Campheylborane

Barrett reported an elegant method for the preparation of anti diols 74 via a similar deprotonation, borylation, allylboration, and oxidative desilylation protocol (Scheme 13) (72–75). The requisite allylborane 73 was synthesized starting from allylsilane 71.

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Scheme 13. Reaction of (B)-(E)-γ-(N,N-Diisopropylamino)dimethylsilyl)allyldiisopinocampheylborane with aldehydes. (B)-γ-(Dimethylphenylsilyl)allyldiisopinocampheylborane Roush reported the synthesis of diisopinocampheyborane reagent 76 via the reaction of allyl dimethylphenylsilane 75 with Schlosser’s base, Ipc2BOMe 17 and BF3.Et2O. Allylboration of this reagent 76 with aldehydes and subsequent work up under mild pH 6 buffer conditions resulted in the formation of anti αdimethylphenylsilyl homoallylic alcohols 77 (Scheme 14) (76–79).

Scheme 14. Reaction of (B)-γ-(Dimethylphenylsilyl) allyldiisopinocampheylborane with aldehydes. (B)-γ-(Trimethylsilyl)propargyldiisopinocampheylborane The lithiation of trimethylsilylpropyne 78 with tbutyl lithium followed by the treatment of the resulting propargyllithium 79 with Ipc2BOMe 17 resulted in the formation of (γ-trimethylsilyl) propargylborane 80. This reagent upon treatment with aldehydes yielded the homoallenyl alcohols 81 in good yield and selectivity (Scheme 15) (80). 80 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. Reaction of (B)-(γ-trimethylsilyl)propargyl-diisopinocampheylborane with aldehydes.

(B)-β-(Alkyldimethylsilyl)allyldiisopinocampheylborane Barrett demonstrated the synthesis of γ-silylhomoallylic alcohols 85 using a double transmetalation protocol, first via lithiation of allylstannane 82 and latter via the treatment of allyl lithium 83 with Ipc2BCl 16. The allylborane 84 upon allylboration with aldehydes yielded the vinylsilanes 85 (Scheme 16) (81).

Scheme 16. Reaction of (B)-β-(Alkyldimethylsilyl)-allyldiisopinocampheylborane with aldehydes.

Preparation of Allylboranes via Hydroboration of Dienes/Allenes This section deals with the preparation of chiral allylboranes employing hydroboration of 1,3-dienes or allenes. 81 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(B)-2-Cyclohexen-1-yldiisopinocampheylborane

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Brown reported the hydroboration of 1,3-cyclohexadiene 86 with Ipc2BH 15 to yield cyclohexenylborane 87, that upon reaction with aldehydes and alkaline peroxide work up produced the cyclohexenyl alcohols 88 (Scheme 17) (82).

Scheme 17. Cyclohexenylboration of aldehydes.

(B)-(E)-γ-(1,3,2-Dioxaborinanyl)allyldiisopinocampheylborane Brown and Narla reported the hydroboration of boronoallene 89 with Ipc2BH 15 to furnish the (E)-γ-borinanylallylborane 90, which upon reaction with aldehydes followed by alkaline work up yielded the vicinal anti diols 92 in high yield and stereoselectivity (Scheme 18) (83). It should be noted that the intermediate 91 (obtained from the reaction of allylborane 90 with aldehydes) is also an allylboronate, which could still undergo another allylation with a second aldehyde. Roush cleverly made use of the differential reactivity of the allylborane 90 (which readily reacts with aldehydes even at -100 °C) and the allylboronate 91 (which reacts slowly even at higher temperatures) for carrying out the double allylation of two different aldehydes (84–87). Roush noted that the steric bulk on the boronates 91a-b was able to impact the olefin stereochemistry in the product diols E-94 and Z-94. The sterically unencumbered 1,3,2-dioxaborinane 91a upon reaction with aldehydes yielded the (E)-alkene E-94 while the hindered dioxaborolane 91b produced the (Z)-olefin Z-94 upon reaction with aldehydes. They were able to explain the difference in stereochemistry by invoking different transitions states (93a-b) so as to minimize the 1,3-pseudodiaxial interactions (Scheme 18).

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Scheme 18. Double allylboration of aldehydes with (B)-(E)-γ-(1,3,2Dioxaborinanyl)allyldiisopinocampheylborane.

Roush was able to further exploit the kinetic and thermodynamic differences in the hydroboration of 1-methyl-1-borinanylallene 95 with Ipc2BH 15, for the synthesis of (Z)- and (E)-pentenediols 97 employing the double allylboration protocol (Scheme 19) (88).

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Scheme 19. Hydroboration of 1,1-disubstituted allenes.

Roush further expanded this protocol for the enantiodivergent (89, 90) and enantioconvergent (91, 92) hydroboration of racemic 1,3-disubstituted silyl allene 98a, and stannyl allene 98b respectively (Scheme 20). These racemic allenes upon hydroboration with Ipc2BH yielded the enantiomerically pure allylboranes 99 which upon allylboration with aldehydes furnished the (E)-anti homoallylic alcohols 100.

Scheme 20. Hydroboration of 1,3-disubstituted allenes.

The same group also prepared higher order allylboranes 102 via hydroboration of 1,1-disubstituted allenes 101 for the synthesis of homoallylic alcohols 103 containing quaternary chiral centers (Scheme 21) (93).

Scheme 21. Preparation of higher order allylboranes. 84 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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(B)-(Z)-γ-(Trifluoromethyl)allyldiisopinocampheylborane

Ramachandran reported the preparation of “fluoro” allylboranes for the synthesis of fluorinated homoallylalcohol derivatives. As is evident from above, hydroboration of monosubstituted allenes with silyl (101), boryl (89), or alkyl (35) side chains typically yields the (E)-allylboranes as the thermodynamic product. However, the hydroboration of trifluromethylallene with Ipc2BH yielded the (Z)-allylborane 105 and the regioisomeric vinylborane 106 in ~3:1 ratio. A weak coordination of fluorine and boron atoms might be able to explain the different stereochemical outcome during the hydroboration of 104 with Ipc2BH, thereby producing the (Z)-allylborane 105. The separation of regioisomers 105 and 106 was not necessitated as the allylborane 105 preferentially reacts with aldehydes at -100 °C generating the homoallylic alcohols 107 upon diethanolamine workup (Scheme 22) (94).

Scheme 22. γ-(Trifluoromethyl)allylboration of aldehydes.

Masamune Borolane

Masamune reported the reaction of chiral borolanes and aldehydes to produce the homoallylic alcohols in high levels of enantioselectivity (90-97% ee). The requisite allylboranes were prepared via the hydroboration of 1-trimethylsilyl-1,3-butadiene 108 followed by methanolysis and kinetic resolution with N-methylpseudoephedrine. The allylborane 6 was obtained from the chiral oxazaborolane 112 upon treatment with allyl magnesium bromide (Scheme 23) (27).

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Scheme 23. Allylboration of aldehydes with B-allylborolanes.

Preparation of Allylboranes via Homologation or Isomerization (B)-(γ,γ-Difluoroallyl)diisopinocampheylborane Ramachandran demonstrated the preparation of γ,γ-difluoroallylborane 118 via the hydroboration of difluoroallene 117. The allylboration with 118 furnished difluorohomoallyl alcohols 119 in high ee. They also noted that an analogous Hoffmann’s camphor based reagent 116 which was obtained via Matteson homologation, did not provide good ee, even with the rate acceleration using Sc(OTf)3 (Scheme 24) (95).

Scheme 24. γ,γ-Difluoroallylboration of aldehydes. 86 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(B)-Homoallenylboronate via Matteson Homologation

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Brown reported the synthesis of homoallenylboronate 121 from tartrate ester derived allenylboronate 120 employing Matteson homologation (Scheme 25) (96). This reagent upon allylboration with aldehydes furnished α-methylenylhomoallylic alcohols 122 in 60-90% ee.

Scheme 25. Homoallenylboration of aldehydes.

Iridium Catalyzed Isomerization of Vinylboranes Miyaura and co-workers demonstrated the use of transition metal catalyzed isomerization of vinylboronates 124 for the preparation of allylboronates 125 (97). The requisite vinylboronates 124 were obtained via hydroboration of propargyl silyl ether 123 with Ipc2BH 15 followed by the conversion to the tartarate ester. These allylboronates provided good enantioselectivity for the product β-alkoxyalcohols 126 upon allylboration with aldehydes (Scheme 26).

Scheme 26. Preparation of (E)-γ-alkoxyallylboronates via Iridium catalyzed isomerization. 87 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Borabicyclo[3.3.2]decane Chiral Auxiliary

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(B)-“Allyl”-borabicyclo[3.3.2]decane: While α-pinene and tartrate based chiral reagents are effective towards allylboration of aldehydes and aldimines, they fail to provide good ee for ketones and ketimines. Soderquist was able to demonstrate the robustness of 10-trimethylsilyl/phenyl-9-borabicyclo[3.3.2]decanes (BBD) 7 towards the enantioselective “allyl”boration of ketones and ketimines as well. The requisite BBDs are obtained via Matteson homologation/ring expansion of B-methoxy-9-borabicyclo[3.3.1]-nonane 127 with trimethylsilyl-diazomethane followed by kinetic resolution with pseudoephedrine. Further treatment of the resulting oxazaborole 130 with allyl Grignard furnishes B-AllylBBD (7) which upon reaction with aldehydes and ketones yields the homoallylic alcohols in exceptional levels of enantioselectivity (generally >96% ee) (Scheme 27) (29).

Scheme 27. Allylboration of aldehydes with B-allyl-9-borabicyclo[3.3.2]decane.

Soderquist’s borane provides very high enantioselectivities in the allyl and crotylboration (131a) of a wide range of aldehydes (29) (>95% ee), ketones (80-99% ee) (98) and ketimines (99). Even in the case of α-chiral aldehydes, consistently higher enantio- and diastereoselectivities have been reported for the matched as well as the mismatched examples using BBDs as chiral auxiliary (100). Excellent selectivity was also reported for the methallylboration (131b) (101), allenylboration (131c) (102, 103), and propargylboration (131d) (104, 105) of a variety of aldehydes, ketones and imines (Scheme 28). Several other higher order allylborations of aldehydes and ketones including cyclohexenylboration 88 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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(106) α-methylene-γ-alkyl-allylboration (107, 108), bisallylboration (109) etc. have also been reported to proceed with very good selectivities.

Scheme 28. Preparation of higher order B-“Allyl”-9-borabicyclo[3.3.2]decanes.

(B)-γ-Alkoxyallyl-borabicyclo[3.3.2]decane The (Z)-γ-alkoxyallylborane Z-133 reacts with aldehydes and aldimines to provide excellent diastereoselectivity for the product alcohols 134 and amines 135. While Brown’s alkoxyallylborane 47 fails to provide higher ee for ketones and ketimines, Soderquist’s γ-alkoxyallylborane 133 readily reacts with these substrates to provide very high ee and de for the homoallylic alcohol products (110, 111). Further it was observed that, while the faster reacting substrates such as alkyl aryl ketones and alkyl vinyl ketones provided the expected syn diastereomer of the product 136, the slower reacting ketones such as pinacolone 89 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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resulted in the formation of the anti diastereomer of the 137 presumably due to the rapid isomerization of (Z)- γ-alkoxyallylborabicyclo[3.3.2]-decane Z-133 to the corresponding (E)-diastereomer E-133 (Scheme 29).

Scheme 29. Allylboration of carbonyl derivatives with B-(γ-alkoxy)allylborabicyclo[3.3.2]decane.

Binaphthol Based Chiral Auxiliary Kaufmann reported the synthesis of B-allylbinaphtholboronate 8 via the reaction of triallylborane with binaphthol and this reagent upon allylboration furnished the homoallylic alcohol in 88% ee (30). Chong and co-workers were able to extend this protocol further by using 3,3′-disubstituted binaphthols for this reaction with dramatic improvement in enantioselectivities for aldehydes as well as several ketones (112). They were also able to carry out allylboration of cyclic imines 141 with this disubstituted binaphtol reagent and extend this methodology for the synthesis of alkaloids 142 (113). Significant enhancement of enantioselectivity was observed for these reactions especially by the modification of the 3,3′-side chains on binaphthol to include groups such as trifluoromethyl and 3,5-bis(trifluoromethyl)phenyl (Scheme 30).

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Scheme 30. Reaction of binaphthol derived allylboranes with carbonyl derivatives.

Schaus et al. reported the use of 3,3′-dibromobinaphthol 138 as a chiral catalyst for the allylboration of ketones with B-allyl diisopropylboronate 143a furnishing the product homoallylic alcohols 144a in high enantioselectivity. The corresponding reaction with (Z)- and (E)-crotylboronate reagents 143b-c furnished syn and anti β-methyl homoallylic alcohols 144b-c in >95% de and ee (114). An analogous reaction of N-acyl imines 145 with B-allyl diisopropylboronate 143a in the presence of 3,3′-diphenylbinaphthol 138 provided the corresponding homoallylic amine derivatives in excellent enantioselectivities. The crotylboration of acyl imines 145 with (E)-crotylboronate 143b yielded the expected anti product 146 as the major diastereomer in high yields and stereoselectivities. Interestingly however, the reaction of (Z)-crotylboronate 143c with acyl imines did not furnish the expected syn product and even in this case, the anti product 146 was still the predominant product albeit in lower yield and enantioselectivity. This reactivity pattern was presumably due to the trans diaxial interactions in the chair transition state, which forces the reaction of acylimines 145 with (Z)-crotylboronate 143c to assume a boat transition state thereby leading to the formation of the anti diastereomer 146 (Scheme 31) (115).

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Scheme 31. Binaphthol catalyzed allylboration of carbonyl derivatives.

Ferrocene Based Chiral Allylboranes Jaekle and co-workers reported the use of ferrocene based chiral reagents for the allylboration of ketones to provide the products 150 with varying degrees of enantiocontrol ranging between 40-80% ee (Scheme 32). It is surprising to note that these allylboranes failed to provide any enantioselectivity for aldehydes (20:1) for both Z- and E-enolates (20). The 9-BBN enolate of phenyl thiopropionate gave the syn-aldol product selectively (21) (Scheme 4).

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Scheme 3. Stereospecificiy of the aldol reaction: ethyl ketones, tert-butyl thiopropionate.

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Scheme 4. Aldol reaction of phenyl thiopropionate. To develop practical asymmetric reagents, a selective and convenient procedure for the synthesis of either Z- or E-enolate and the elucidation of the conditions of the isomerization of enolates (or the avoidance of isomerization) must be found. Although Mukaiyama’s protocol for the direct enolization seemed most convenient, the factors affecting the stereochemical outcome of the enolate formation were found to be complex. Intensive studies concluded that the stereoselective synthesis of E- and Z- enolates occurred from ketones, thioesters and carboxylic esters. For ketones, Z-enolates could be synthesized with high selectivity using a combination of small boron triflate (Bu2BOTf) and bulky tertiary amine (i-Pr2EtN) at a low temperature (16, 20, 22) (Scheme 5, Eq 1). E-enolate was synthesized using dialkylboron chloride with a sterically demanding ligand on boron (e.g., cHex) with a small amine base (Et3N) (23, 24) (Scheme 5, Eq 2). The reactivity of the parent carbonyl components and the selectivity of the enolate formation were rationalized as summarized in Scheme 6. The boron compounds (R2BOTf or R2BCl) are Lewis acids, and when the Lewis basicity of an amine is too strong, boron compounds form a tight amine-borane complex (Scheme 6, Eq 1). A tertiary amine is not sufficiently basic to deprotonate carbonyl compounds; enolization must proceed through the activation of carbonyl compounds by complexation with a Lewis acid (e.g., a boron compound) (Scheme 6, Eq 2, path b). The balance of Lewis acidity and Lewis basicity is critical for the success of enolate formation. Carboxylic esters, a carbonyl family with relatively less acidic α-protons, were claimed to be unreactive for enolization under the standard conditions (16, 24–26) (Scheme 6). Later, a reinvestigation by Abiko and Masamune corrected the misconception regarding the reactivity of the esters (27, 28). Treatment of benzyl propionate with certain pairs of dialkylboron triflates (1.3 equiv) and an amine (1.5 equiv) in dichloromethane at −78 °C for 2 h and then with isobutyraldehyde provided the corresponding aldol product in high yield. Both the size of the boron triflate and that of the amine were very important for successful aldol reactions, and the combination of a smaller boron triflate (Bu2BOTf) and a smaller amine (Et3N) led to failure of enolization of the ester (Scheme 7). 129 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 5. Selective generation of Z- or E-enolate from ethyl ketones.

Scheme 6. Enolate formation from ethyl ketone with a boron compound and an amine. 130 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 7. Enolate formation from carboxylic ester with a boron compound and an amine.

Scheme 8. Enolate formation with a boron compound and an amine showing the stereochemistry. Stereoselectivity of the enolate was explained based on the ground state conformation of the boron-carbonyl complex: Z-enolate formation from the extended conformation and E-enolate formation from the U-shaped conformation. Thus, the steric effect of the substituents R of the carbonyl compound and R1 of the boron reagent sensitively affect the stereochemistry of the resulting enolate (Scheme 8). 131 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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For carboxylic esters, the syn:anti selectivity was sensitively affected by the alcohol residue of the ester and the enolization reagents. A bulkier ester or a smaller amine produces more of the anti isomer (compare Table 1, entries 1, 2, 3; 4, 6, 9; 5, 7, 10, 12; 8, 11). The ratio was highly dependent on the enolization temperature. The lower the temperature, the more of the anti isomer produced (compare Table 1, entries 6, 7, 9; 10, 11, 12). The varying syn:anti ratios depending on the enolization temperature was shown due to the isomerization of the enolate. For benzyl propionate, enolization at 0, -78 and -90 °C gave the aldol products in the ratio of anti:syn = 10:90, 90:10 and >95:5, respectively (Table 2, entries 1, 2, 3). Enolization was conducted in two steps: first enolization at −90 °C for 1 h [providing the enolate with Z:E = 5:>95] and then standing at 0 °C for 2 h. The aldol reaction in the standard manner afforded the product with syn:anti = 90:10, which corresponds to the enolate with Z:E = 90:10 (Table 2, entry 4). Similar experiments using propiophenone did not show isomerization of the enolate (Table 2, entries 5-9). The difference in the isomerization is attributed to the contribution of the C-bound form in the enolate (vide infra).

Table 1. Enolate formation from carboxylic ester

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Table 2. Isomerization of boron enolate

Enol Borate Concerning the stereospecificity of the stereochemistry of the enolates and the resulting aldol products, enol borates were shown to behave differently (29). Z- and E-enol borates were synthesized by the specific reactions: Z-enolate was synthesized by the Grignard reaction of Z-butenyl magnesium bromide and a borate followed by oxidation using trimethylamine oxide (Scheme 9, Eq 1), and E-enolate was synthesized by hydroboration of 2-butyne followed by oxidation (Scheme 9, Eq 2). Both of the enol borates, irrespective of the stereochemistry, gave syn-aldol products preferentially (30) ( Scheme 9). Enol borates derived from phenyl thiopropionate behaved similarly. The Eor Z- enriched mixture of enol borates, which were prepared by the reaction of phenyl thiopropionate and chlorodioxaborolane at specific temperatures, produced the aldol products with aldehydes having similar syn:anti ratios favoring the synisomer (31–34) (Scheme 10).

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Scheme 9. Stereoselective synthesis and aldol reaction of Z-and E-enol borates.

Scheme 10. Aldol reaction of phenyl thiopropionate. 134 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The results were rationally explained by the involvement of different transition states for the enolates: boat-TS for E-enolate and chair-TS for Z-enolate (35) (Scheme 11).

Scheme 11. Transition state model for the aldol reaction of phenyl thiopropionate.

Asymmetric Aldol Reaction The most important reaction in the enolate chemistry is the aldol reaction. From a synthesis perspective, asymmetric aldol reactions could be categorized into four types, depending on the chirality of the reaction components (Scheme 12).

Scheme 12. Asymmetric aldol reaction categories. 135 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Substrate Control When a chiral aldehyde is reacted with achiral enolates, the selectivity of the reaction is explained by the Felkin-Anh model or the Cram’s chelate model, depending on the substituents of the aldehyde (Scheme 13). In the Felkin-Anh model, the largest (L) or polar (X) α-substituent occupies the conformation perpendicular to the plane of the carbonyl group, and the nucleophile approaches from the least hindered trajectory (Scheme 13, Eq 1). Typically, substrate-controlled reactions do not show significant selectivity, except for some special cases. Alpha substituents with lone pairs can coordinate metal ions together with carbonyl lone pairs (Scheme 13, Eq 2). The chelation ring becomes the dominant factor in determining the conformation and gives very high selectivity for nucleophilic attack.

Scheme 13. Models for carbonyl conformations and diastereoselective nucleophilic attack.

Double Stereodifferentiation When both reaction components are chiral, the net selectivity is affected by the stereoselectivity of each component. When the diastereofacial selectivity of the enolate of a chiral carbonyl compound is sufficiently high (e.g. >20:1), the stereochemistry of the product aldols can be determined by the stereochemistry (sense of chirality) of the enolate chiral reagent. Thus, the stereochemistry of the aldol product can be controlled by the selection of the sense of chirality of these enantiomeric chiral reagents. This strategy of reagent-oriented stereocontrol is defined as double asymmetric synthesis (36). Reagent-controlled reactions are categorized into internal chiral reagent control and external chiral reagent control. 136 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Internal Chiral Reagent Control

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When the chiral moiety is covalently connected to the enolate as an auxiliary, the reagent is called an internal chiral reagent. The auxiliary group is readily introduced and removed after the reaction. Chiral imides, α-oxyketones and esters have been developed as asymmetric aldol reagents (Scheme 14, Eq 1).

Scheme 14. Chiral reagent control

External Chiral Reagent Control When a chiral controller unit is not covalently connected, the reagent is called an external chiral reagent and can be used for unit-elongation type reactions and for fragment-coupling-type reactions (Scheme 14, Eq 2). As an external chiral reagent, the chiral controller unit could be stoichiometric as a ligand of metal or catalytic as an asymmetric catalyst. Chiral reagent control asymmetric aldol reactions involving boron enolate are discussed below in detail.

Internal Chiral Reagent Control In the reaction of a chiral substrate with a chiral reagent, the use of an S or R reagent with a large diastereofacial selectivity enhances the apparent facial selectivity of the substrate in the matched pair reaction and overrides it in the mismatched pair reaction. In this manner, the stereochemical course of the reaction is controlled by the reagent.

Imide Auxiliary Chiral imide reagents derived from valinol or phenylalaninol, and norephedrine are particularly important (16, 37–40) (Scheme 15). 137 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. Internal chiral reagent: imide-type reagents

The derived (Z)-dibutylboron enolates react with a broad range of aldehydes, including chiral α-substituted aldehydes, in near perfect stereoselectivities for both newly formed asymmetric centers. Furthermore, a wide range of enolate substituents, R1, such as n-alkyl, -CH2COOMe, -CH=CH2, -OMe, OBn, and -SMe, are tolerated without loss of reaction stereoselectivity. Scheme 16 represents an application to the double asymmetric synthesis. The diastereomer ratio 36:64 is the diastereoselectivity of the substrate aldehyde (substrate-controlled reaction). When chiral imide XV was used for the aldol reaction, 2R, 3R isomer predominated over 400:1. The “enantiomeric” chiral imide XN overrode the selectivity to 1: >500 favoring the 2S, 3S-isomer (Scheme 16). The chiral auxiliary group can be removed from the aldol products or the derived compounds to produce carboxylic acids (37, 41, 42), alcohols (43–46), esters (47, 48), aldehydes or ketones via thioesters (49–51) or Weinreb amides (46, 52–54), without loss of the stereochemical integrity (Scheme 17). The power of this methodology has been exhibited in many natural product syntheses. Lewis acid catalysis makes the aldol reaction of the boron enolate and related systems derived from propionylimides anti-selective via the acyclic transition state. The selectivity was sensitively affected by the choice of Lewis acid. With a small Lewis acid, such as TiCl4, the major product of the reaction became the non-Evans syn isomer, and with a large Lewis acid, such as Et2AlCl, the reaction was anti-selective (55–58) (Scheme 18). The chiral bornanesultam reagent shows similar selectivity with higher crystallinity (59, 60) (Scheme 19).

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Scheme 16. Reagent-controlled aldol reaction of chiral imide reagents

Scheme 17. Transformation of the aldol product.

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Scheme 18. Lewis acid-catalyzed aldol reaction of a boron enolate of an imide reagent.

Scheme 19. Bornanesultam reagent for an asymmetric aldol reaction. 140 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Chiral α-Oxyketone Reagents Chiral α-oxyketone reagents were developed as asymmetric aldol reagents. The chiral ethyl ketone reagent was easily prepared from R- or S-mandelic acid in 3 steps (Scheme 20). The Z-boron enolate, generated with dialkylboron triflate and diisopropylethylamine, selectively reacted with aldehydes including α-chiral ones, to give syn-aldol products with high diastereofacial control. The facial selectivity was affected by the bulkiness of the boron reagent, and the use of 9-BBNOTf for aldehydes with an α-substituent and that of c-Pen2BOTf for aldehydes carrying no α-substituent were recommended. The chiral controller moiety could be oxidatively cleaved to β-hydroxy-α-methyl carboxylic acids (Scheme 20). The selection of the appropriate enantiomeric reagent led to the creation of the syn-3-hydroxy-2-methylcarbonyl system with a selected absolute configuration, as depicted in Scheme 21 (61, 62).

Scheme 20. Preparation and aldol reaction of a chiral ethyl ketone reagent derived from mandelic acid.

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Scheme 21. Reagent-controlled aldol reaction of a chiral ethyl ketone reagent.

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Complementary syn- and anti- selective asymmetric aldol reactions of lactic acid-derived chiral ketones were developed by Paterson et al. (63). The enolization conditions used for these reactions were originally designed for the synthesis of E-enolate. The benzoyloxy-substituted ethyl ketone afforded anti-β-hydroxy-α-methyl ketones with high selectivity (Scheme 22, Eq 1). In contrast, the benzyloxy substituent caused the formation of the chelate complex of boron to facilitate the Z-enolate formation (Scheme 22, Eq 2). The aldol products were transformed to ethyl ketones or aldehydes, after protection of the β-hydroxyl group by SmI2 reduction or oxidative cleavage, respectively (Scheme 22, Eq 3).

Scheme 22. Asymmetric aldol reaction of lactate-derived ethyl ketones.

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The absolute stereochemistry of the products shown in Scheme 22, Eqs 1 and 2 shows the opposite sense of facial selectivity of Z- and E-enolate. This was rationalized by the cyclic transition state model described in Scheme 23.

Scheme 23. Transition state model for E- and Z-enolates.

Chiral Carboxylic Ester Reagent It is possible to control the stereochemical course of the aldol reaction of propionate esters by the judicious choice of enolization conditions. Thus, the combination of Bu2BOTf-i-Pr2EtN leads to the predominant formation of the synaldol products (Scheme 24, Eq 4), while the enolization of a bulkier ester with c-Hex2BOTf-Et3N at a lower temperature affords the corresponding anti-aldol products selectively (64) (Scheme 24, Eq 2). Two complementary esters were developed for the asymmetric aldol reaction (65–67). Both reagents were prepared from readily available nor-ephedrine (68) (Scheme 24, Eq 1) or ephedrine (Scheme 24, Eq 3) in easily scalable operations, and upon aldol reaction, they exhibited excellent diastereo- (>98:2) and diastereofacial (>95:5) selectivities with a wide range of aldehydes (Scheme 24).

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Scheme 24. Anti- and syn-selective asymmetric aldol reaction of chiral esters. It should be added that the stereochemistry of the major product of the antiand syn-aldol reaction is a result of the opposite diastereofacial selection of the intermediate enolates. This implies that the conformation of the transition states leading to anti-aldol from E-enolate and syn-aldol from Z-enolate are different.

Double Aldol Reaction: Doubly Borylated Enolate A natural extension of the syn- and anti-selective aldol reaction of propionate or ethyl ketone is an acetate aldol reaction. The aldol reaction of the boron enolate of acetate was shown to be a complex process (69). When the chiral acetate was treated with c-Hex2BOTf (2.0 equiv) and trimethylamine (2.4 equiv) in CH2Cl2 at -78 °C for 15 min, followed by isobutyraldehyde (3.0 equiv), three stereoisomeric bis-aldols were obtained in over 95% yield with a diastereomer ratio of 90:8:2. 145 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The major bis-aldol product, obtained as a pure crystalline compound, was fully characterized by NMR and X-ray crystallography. Under the optimized reaction conditions, the double aldol reaction proceeded with high yield (>90 %) and selectivity (ds >84 %) (Scheme 25).

Scheme 25. Asymmetric double aldol reaction of chiral acetate ester.

The bis-aldol products were transformed to chiral triols of C3-symmetry in 5 steps (Scheme 26). After protection of the diol as acetonide, chiral auxiliary was removed by LiAlH4 reduction in 80-95% yield. PDC oxidation followed by the Grignard reaction in THF afforded the secondary alcohol in high stereoselectivity. (dr >10:1) With i-PrMgBr, however, reduction of the aldehyde was an accompanying reaction (35 %). Chiral triols of C3-symmetry were obtained after removal of the acetonide group.

Scheme 26. Synthesis of chiral triols of C3-symmetry. 146 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The unique and unprecedented double aldol reaction was characterized as two aldol reactions occurring in one operation. The mechanism of this reaction was thoroughly investigated by a spectroscopic method; the novel doubly borylated enolate was identified as an intermediate, and more significantly, for the first time, the C-bound enolate was characterized to be responsible for this reaction. The proposed mechanism is summarized in Scheme 27 (70, 71).

Scheme 27. Mechanism of the double aldol reaction.

A boron triflate forms a complex with both a carbonyl compound and an amine reversibly. When the boron triflate-carbonyl compound complex is more favorable than the boron triflate-amine complex and the acidity of the α-proton of the boron-carbonyl complex is sufficiently high to be deprotonated with the amine, enolization proceeds (step 1). The initial product, an oxygen-bound mono-enolate, rapidly equilibrates with the carbon-bound enolate, and the latter is again enolized with the aid of boron triflate and an amine (step 2). This second enolization proceeds with an acetate ester (along with a thioacetate, acetyl-2-oxazolidinone and certain ketones), irrespective of the amount of the carbon-bound enolates. For acetates with a smaller alcohol residue, “step 2” is faster than “step 1”; thus, only the doubly borylated enolate is produced, even with 1 equivalent of boron triflate. For larger esters, “step 2” becomes slower because of steric hindrance. For acetophenone or 2-butanone, the concentration of the carbon-bound enolate 147 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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is too small to form the boron-carbonyl complex for further enolization to the doubly borylated enolate. In the enolization of acetate esters with a sufficiently large R, the configuration of the initially formed doubly borylated enolate is E occurs at a low temperature, and this enolate may isomerize to the Z-isomer upon warming. This facile isomerization implies that it also proceeds through a carbonbound boron enolate. The aldol reaction naturally proceeds in a stepwise manner to afford an α-boryl-β-boryloxy carbonyl intermediate, which isomerizes to the second (oxygen-bound) enolate with an E configuration. Then, the bis-aldol is produced after reaction with the second equivalent of the aldehyde. Naturally, the double aldol reaction is not limited to acetate esters. Under the standard reaction conditions (carbonyl compound (1.0 equiv), c-Hex2BOTf (2.5 equiv) and Et3N (3.0 equiv) in CDCl3 at 0 °C 5 min), the corresponding doubly borylated enolates were spectroscopically identified from methoxyacetone, acetic acid (with c-Hex2BOTf (4.0 equiv) and Et3N (5.0 equiv)), N,N-dimethylacetamide, and 2-acetylpyridine. Only an oxygen-bound mono-enolate, however, was detected from PhSCOCH3, acetophenone, 2-butanone, 4-methoxyacetophenone, or 2-methoxyacetophenone. With 1 equiv of the boron triflate, methoxyacetone and 3-acetyl-2-oxazolidinone afforded the oxygen-bound mono-enolate in >98% and 72% yields, respectively (condition [B]). The monoenolate of PhSCOCH3 and 2-methoxyacetophenone was slowly converted to the doubly borylated enolate after prolonged reaction at 0 °C with excess boron triflate (condition [C]) (Table 3). From these results, it is conceivable that the formation of the doubly borylated enolate, as well as the success of the double aldol reaction, should be attributed to the stability of the carbon-bound boron enolate species. Resonance stabilization of the carbon-bound enolates of carboxylic ester, thioester, and ketone diminished in this order, and the nearby chelating functional group stabilized the carbon-bound enolate intermediate of methoxyacetone, 2-acetylpyridine and 2-methoxyacetophenone. It is particularly interesting that, acetyl-2-oxazolidinone was converted to the corresponding doubly borylated enolate under the “standard reaction conditions”. In addition to the well-established asymmetric aldol reaction of the propionate derivative of chiral oxazolidinones, a few examples of asymmetric aldol reaction of acetyl oxazolidinones have been reported to afford the corresponding mono aldol products (72–74). With 2.5 equiv of n-Bu2BOTf and 3 equiv of triethylamine, (R)-acetylimide exhibited excellent stereocontrol of the aromatic aldehydes, even at room temperature, to afford (S,S)-diol as a major product (>95% ds) (75) (Scheme 28).

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Table 3. Doubly borylated enolate formation from acetyl derivatives.

Scheme 28. Asymmetric double aldol reaction of chiral acetylimide.

149 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

External Chiral Reagent Control

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Using an external chiral reagent, it is possible to skip the step of removing the chiral controller moiety from the product. In the process, which involves the assembly of the two prefixed chiral fragments with the concomitant creation of a stereogenic center or centers, the crucial role of the external chiral reagent control becomes even more evident. Chiral boron reagents, such as 2,5-disubstituted borolane reagents, diazaborolidine reagents and diisopinocampheylborane (IPC) regents, have been used for simple acetate-type and anti-selective asymmetric aldol reactions and for fragment coupling aldol reactions.

Borolane Reagents 2,5-Dimethylborolane was developed and its utility was evaluated for asymmetric hydroboration, carbonyl reduction, crotylboration and the aldol reaction (76–79). An asymmetric aldol reaction of propionate ester of bulky thiol (3-ethyl-3pentanethiol) produced anti-aldol product with high diastereo- (30-33: 1) and enantioselectivity (>97.9% ee) (Scheme 29). The corresponding acetate reactions proceeded to give the aldol product enantioselectively (89.4-98.4% ee).

Scheme 29. R*2BOTf=2,5-Dimethylborolane-mediated asymmetric aldol reaction.

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In the aldol reaction with a chiral aldehyde, the newly formed stereo-center(s) were controlled by the chirality of the boron reagent. (double asymmetric synthesis) (Scheme 30).

Scheme 30. 2,5-Dimethylborolane-mediated asymmetric aldol reaction: Double asymmetric synthesis.

Although the ability to control the asymmetric reactions is excellent, the preparation of the reagent is tedious. The borolane structure as a mixture of diastereomers was prepared by the Grignard reaction followed by methanolysis. The cis-isomer was removed from the mixture by complexation with dimethylaminoethanol. Then, trans-borolane was resolved by selective complex formation with prolinol and valinol to afford the stable aminoalcohol complex of each enantiomer. The triflate reagent used for the aldol reaction was liberated via trifluoromethanesulfonic acid treatment of the dihydridoborate (Scheme 31). Reetz et al. reported the related chiral 2,5-diphenylborolane with comparable selectivity. The boron enolate was generated via transmetallation of the ketene silyl acetal with the chloro borane (80, 81) (Scheme 32).

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Scheme 31. Preparation of chiral 2,5-dimethylborolane.

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Scheme 32. 2,5-Diphenylborolane-mediated asymmetric aldol reaction.

Diazaborolidine Reagents Corey et al. developed chiral diazaborolidine reagents, which could be prepared in situ from C2-chiral bis-sulfonamide and boron tribromide (82, 83) (Scheme 33, Eq 1). Enolization of diethyl ketone with the toluenesulfonamide reagent and diisopropylethylamine gave the syn-isomer of the aldol product predominantly with high enantioselectivity (Scheme 33, Eq 2). In addition, phenyl thioacetate was enolized with the toluenesulfonamide reagent and triethylamine to give the aldol product with high enantioselectivity (Scheme 33, Eq 3). For phenyl thiopropionate, the related 4-nitrobenzenesulfonamide reagent was used to realize the syn-selective aldol reaction (Scheme 33, Eq 4). Carboxylic esters were used as substrates for the anti-selective aldol reaction using the 3,5-bistrifluoromethylbenzenesulfonamide reagent. Under the specified conditions, the propionate of sterically demanding alcohols (tert-butyl or (+)-menthyl) were reacted with aldehydes to give anti-aldol products with high diastereo- and enantioselectivity (Scheme 34).

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Scheme 33. Diazaborolidine-mediated asymmetric aldol reactions.

It should be noted that regarding the diastereofacial selection of these aldol reactions, the anti- and acetate reactions exhibited the opposite sense to the synaldol reaction. Naturally, it is conceivable that the syn- and anti-aldol products were products of Z- and E- boron enolates, respectively. The stereochemistry of the enolate formation was rationalized as a result of the change in the ground state conformation of the borane-carbonyl complex (Scheme 35).

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Scheme 34. Diazaborolidine-mediated anti-selective asymmetric aldol reactions.

Scheme 35. Stereochemistry of the enolate formation.

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IPC and Related Reagents Diisopinocampheylborane was synthesized by hydroboration of α-pinene followed by crystallization, which was transformed to the triflate or chloride (Scheme 36, Eq 1). Boron enolates, derived from achiral ethyl and methyl ketones by enolization with diisopinocamphenylboron triflate or diisopinocamphenylchloroborane in the presence of tertiary amine bases (i-Pr2NEt or Et3N), underwent enantio- and diastereoselective aldol reactions with aldehydes (84–86). The aldol reaction between ethyl ketones and aldehydes using (+)- or (-)-(IPC)2BOTf/i-Pr2Net in dichloromethane via the derived chiral Z-boron enolates gave syn-α-methyl-β-hydroxy ketones in good enantiomeric excess (66 ~ 90% ee) and with high diastereoselectivity (>90%) (Scheme 36, Eq 2). In contrast, the anti-selective aldol reaction of diethylketone via the isomeric E-enolate by enolization with (-)-(IPC)2BCl) with methacrolein proceeded with negligible enantioselectivity (Scheme 36, Eq 3). Use of both the triflate and chloride reagents in the aldol reaction of methyl ketones with aldehydes gave β-hydroxy ketones in moderate enantiomeric excess (57 ~ 78% ee) (Scheme 36, Eq 4). A reversal in the enantioface selectivity of the aldehyde compared to the corresponding ethyl ketone syn aldol was observed. This variable selectivity is interpreted as evidence for the participation of competing chair and boat transition states. Specifically for the development of an anti-selective asymmetric aldol reaction, the new chiral ligand was designed based on computer-aided transition state modeling. The chloroborane derived from (-)-menthone in two steps followed by crystallization (Scheme 37) gave high diastereoselectivity (86:14 to 100:0 anti:syn) and in good enantiomeric excess (56 ~ 88% ee) for the aldol reactions of a range of cyclic and acyclic ketones with an aldehyde (87–89) (Scheme 38). Unsubstituted and anti-aldol products with excellent diastereo- and enantioselectivity were formed when enolates, generated from the corresponding thioacetates and thiopropionates using bromoborane and triethylamine, were treated with aldehydes (Scheme 38).

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Scheme 36. Preparation and aldol reaction of IPC reagent.

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Scheme 37. Synthesis of the [(Menth)CH2]2BCl-OEt2 reagent.

Scheme 38. Asymmetric aldol reaction mediated by the [(Menth)CH2]2BCl-OEt2 reagent.

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The syn-selective asymmetric aldol reaction of methyl propionate using (-)-IPC2BOTf-Et3N at 0 °C exhibited excellent selectivity for achiral or chiral aldehydes. Z-enolate was produced at a higher enolization temperature (0 °C) with a small ester (methyl propionate) (90, 91) (Scheme 39, Eq 1). The anti-selective reaction, using tert-butyl propionate as a substrate and enolization at a low temperature (-78 °C), however, showed high diastereoselectivity and moderate to good enantioselectivity (Scheme 39, Eq 2) (92).

Scheme 39. Asymmetric aldol reaction of propionate esters mediated by the IPC-boron reagent.

The reaction was extended to the phenylacetate system. For the syn-selective reaction, a higher temperature was applied for enolization in CH2Cl2 to facilitate isomerization. The anti-isomer was obtained by enolization at a low temperature in pentane to prevent isomerization (Scheme 40).

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Scheme 40. Asymmetric aldol reaction of phenylacetate esters mediated by the IPC-boron reagent.

Stereochemical Control in Fragment-Assembly Aldol Reactions Stereochemical control in the formation of a stereogenic center or centers is crucial in fragment assembly for a convergent synthesis of a complex natural product. Consider an aldol reaction that involves a chiral or achiral aldehyde and an enolate derived from a chiral ketone. For this purpose, the use of an enantiomerically pure reagent to mediate the ketone enolization and the subsequent aldol reaction predictably modifies the selectivity intrinsic to the corresponding enolate prepared from an achiral reagent. Selection of an R- or S- external chiral reagent provides a method of control (93–95). In example 1, the diastereofacial selectivity of a chiral methyl ketone was evaluated as 2:1 favoring the C9 S isomer by the reaction with diethylboron triflate as a borylating reagent. With R,R-dimethylborolane triflate, the diastereoselectivity was increased to 6:1, and with the S,S-dimethylborolane reagent, the major product changed to the C9 R isomer in 1:2 (Scheme 41). Examples 2 and 3, represent the assembly of a chiral aldehyde and a chiral methyl ketone. In both cases, inherent diastereofacial selectivity was enhanced using the chiral borolane reagent (Schemes 42 and 43).

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Scheme 41. Example of external reagent control in fragment assembly reaction 1.

Scheme 42. Example of external reagent control in fragment assembly reaction 2.

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Scheme 43. Example of external reagent control in fragment assembly reaction 3.

The IPC reagent is also useful for the fragment-coupling type aldol reaction. Inherent diastereofacial selectivity was reversed or enhanced using a chiral boron reagent (96–98) (Schemes 44 and 45).

Scheme 44. Example of external reagent control in fragment assembly reaction 4. 162 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 45. Example of external reagent control in fragment assembly reaction 5.

Generation of Boron Enolate via the 1,4-Addition of an Organoboron Compound to α,β-Unsaturated Compounds Alkylative Reaction The 1,4-addition of alkylboranes to α,β-unsaturated carbonyl compounds was reported by Suzuki et al in 1967 (99) (Scheme 46). The mechanism of the reaction was proved to involve a radical mechanism (100), and the structure of the intermediate boron enolate was determined by Köster (101).

Scheme 46. Generation of boron enolate via the 1,4-addition of an organoboron compound. Based on these findings, further investigation expanded the scope of the reaction to the addition of an alkyl radical to methyl vinyl ketone (Scheme 47, Eq 1), the reductive generation of boron enolate from α-haloketone (Scheme 47, Eq 2), and the intramolecular cyclization of ω-haloenone (Scheme 47, Eq 3) (102–104). 163 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 47. Generation of boron enolates via 1,4-addition with a radical mechanism.

The sources of alkylboranes were expanded to the hydroboration products of catecholborane (105) (Scheme 48).

Scheme 48. One-pot reaction involving hydroboration, radical generation and 1,4-addition. 164 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Reductive Generation of the Boron Enolate

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Although 1,2-reduction is a major pathway for the hydroboration of cyclohexenone, and acyclic α,β-unsaturated carbonyl compounds can proceed in a 1,4-fashion to produce boron enolate as an intermediate. α,β-Unsaturated ketones, which can readily adopt an s-cis conformation, undergo conjugate reduction by catecholborane at room temperature. α,β-Unsaturated imides, esters, and amides are unreactive under the same conditions. The Rh(PPh3)Cl catalyst greatly accelerates the 1,4-addition process, resulting in the conjugate reduction of these substrates by catecholborane at -20 °C. A concerted pericyclic [4p + 2σ] mechanism was proposed for this reaction (106) (Scheme 49).

Scheme 49. Conjugate reduction of α,β-unsaturated carbonyl compounds by catecholeborane. Especially, β-substituted (E)-α,β-uneaturated ketones reacted with dialkylboranes to selectively form Z-boron enolate. Using chiral IPC2BH, an asymmetric reductive aldol reaction was reported (107–110) (Scheme 50). An intramolecular reaction was also reported (111) ( Scheme 51).

Scheme 50. Reductive aldol reaction.

Scheme 51. Intramolecular reductive aldol reaction. 165 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Roush et al. reported that morpholine acrylamide is a particularly good substrate for the syn-selective reductive asymmetric aldol reaction using IPC2BH hydroboration, with dr, syn:anti = 13~20:1 and 96~98% ee (112, 113) (Scheme 52, Eq 1). A high ee for the anti-selective variant was achieved using 3-ethylpentyl acrylate as a substrate, dr anti:syn = 10~20:1, 83~87% ee (114) (Scheme 52, Eq 2).

Scheme 52. Diisopinocampheylborane-mediated reductive aldol reactions.

Conclusion In this chapter, advances in boron enolate chemistry were overviewed with a focus on the aldol reaction. Currently, boron aldol chemistry appears to have matured with the development of many convenient and reliable methodologies, which enable the synthesis of complex molecules in a stereo-defined manner. Eventually, some of the reagents were used, even in a practical synthesis. Moreover, the identification of a carbon-bound form of boron enolates as an important species in the boron enolate synthesis introduced a new direction in boron enolate chemistry. Boron enolate chemistry and the boron aldol reaction will continue to be an important research area in the future. 166 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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32. Gennari, C.; Bernardi, A.; Carani, S.; Scolastico, C. Tetrahedron 1984, 40, 4059–4065. 33. Gennari, C.; Colombo, L.; Poli, G. Tetrahedron Lett. 1984, 25, 2279–2282. 34. Gennari, C.; Cardani, S.; Colombo, L.; Scolastico, C. Tetrahedron Lett. 1984, 25, 2283–2286. 35. Hoffamnn, R. W.; Ditrich, K.; Froech, S. Tetrahedron 1985, 41, 5517–5524. 36. Masamune, S.; Choi, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. 1985, 24, 1–30. 37. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129. 38. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 60, 83–87. Coll. Vol. VIII, 339–343. 39. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 60, 77–82. Coll. Vol. VIII, 528–531. 40. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109–1127. 41. Savdra, J.; Descoins, C. Synth. Commun. 1987, 17, 1901–1906. 42. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141–6144. 43. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–1739. 44. Evans, D. A.; Sheppard, G. S. J. Org. Chem. 1990, 55, 5192–5194. 45. Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B. W.; Wu, S. S. Synth. Commun. 1980, 20, 307–312. 46. Evans, D. A; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434–9453. 47. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–1739. 48. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030. 49. Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849–2852. 50. Thioesters to aldehydes: Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. 51. Evans, D. A; Ng, H. P. Tetrahedron Lett. 1993, 34, 2229–2232. 52. To Weinreb amides: Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506–2526. 53. Weinreb amides to ketones or aldehydes: Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171–4172. 54. Levin, J. L.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989–993. 55. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173–181. 56. Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747–5750. 57. Raimundo, B. C.; Heathcock, C. H. Synlett 1995, 1213–1214. 58. Wang, Y.-C.; Hung, A.-W.; Chang, C. -S.; Yan, T.-H. J. Org. Chem. 1996, 61, 2038–2043. 59. Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767–2772. 168 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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60. Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321–4324. 61. Masamme, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566–1568. 62. Masamme, S.; Hirama, M.; Mori, S.; Ali, S. K.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103, 1568–1571. 63. Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083–9086. 64. Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61, 2590–2591. 65. Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586–2587. 66. Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S. Tetrahedron Lett. 1998, 39, 1873–1876. 67. Inoue, T.; Liu, J.-f.; Buske, D. C.; Abiko, A. J. Org. Chem. 2002, 67, 5250–5256. 68. Abiko, A. Org. Synth. 2002, 79, 116–121. 69. Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.; Masamune, S. J. Am. Chem. Soc. 1999, 121, 7168–7169. 70. Abiko, A.; Inoue, T.; Furuno, H.; Schwalbe, H.; Fieres, C.; Masamune, S. J. Am. Chem. Soc. 2001, 123, 4605–4606. 71. Abiko, A.; Inoue, T.; Masamune, S. J. Am. Chem. Soc. 2002, 124, 10759–10764. 72. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129. 73. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. Tetrahedron 1995, 51, 3549–3558. 74. Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301–3306. 75. Furuno, H.; Inoue, T.; Abiko, A. Tetrahedron Lett. 2002, 43, 8297–8299. 76. Masamune, S.; Kim, B.-M.; Petersen, J. S.; Sato, T.; Veenstra, S. J. J. Am. Chem. Soc. 1985, 107, 4549–4551. 77. Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollmann, T. A.; Kennedy, R. M.; Masamune, S. J. Am. Chem. Soc. 1986, 108, 7402–7404. 78. Masamune, S.; Kennedy, R. M.; Petersen, J. S. J. Am. Chem. Soc. 1986, 108, 7404–7405. 79. Masamune, S.; Sato, T.; Kim, B.-M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108, 8279–8281. 80. Reetz, M. T.; Kunisch, F.; Heitmann, P. Tetrahedron Lett. 1986, 27, 4721–4724. 81. Reetz, M. T.; Rivadeneira, E.; Niemeyer, C. Tetrahedron Lett. 1990, 31, 3863–3866. 82. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493–5495. 83. Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976–4977. 84. Paterson, I.; Lister, M. A.; McClure, C. K. Tetrahedron Lett. 1986, 27, 4787–4790. 85. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663–4684. 169 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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86. Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997–1000. 87. Gennari, C.; Hewkin, C. T.; Molinari, F.; Bernardi, A.; Comotti, A.; Goodman, J. M.; Paterson, I. J. Org. Chem. 1992, 57, 5173–5177. 88. Gennari, C.; Moresca, D.; Vieth, S.; Vulpetti, A. Angew. Chem., Int. Ed. 1993, 32, 1618–1621. 89. Gennari, C.; Vulpetti, A.; Moresca, D. Tetrahedron Lett. 1994, 35, 4857–4860. 90. Ramachandran, P. V.; Pratihar, D. Org. Lett. 2009, 11, 1467–1470. 91. Ramachandran, P. V.; Chanda, P. B. Chem. Commun. 2013, 49, 3152–3154. 92. For anti-selective reactions, the absolute stereochemistry of the aldol product was reported erroneously. Allais, C.; Nuhant, P.; Roush, W. R. Org. Lett. 2013, 15, 3922–3925. 93. Masamune, S.; Sato, T.; Kim, B.-M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108, 1279–1281. 94. Short, R. P.; Masamune, S. Tetrahedron Lett. 1987, 28, 2841–2844. 95. Duplantier, A. J.; Nantz, M. H.; Roberts, J. C.; Short, R. P.; Somfai, P.; Masamune, S. Tetrahedron Lett. 1989, 30, 7357–7360. 96. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int. Ed. 2000, 39, 377–380. 97. Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935–6939. 98. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. A J. Am. Chem. Soc. 2001, 123, 9535–9545. 99. Suzuki, A.; Arase, A.; Matsumoto, H.; Ito, M. J. Am. Chem. Soc. 1967, 89, 5708–5709. 100. Kabalka, G. W.; Brown, H. C.; Suzuki, A.; Honma, S.; Arase, A.; Ito, M. J. Am. Chem. Soc. 1980, 92, 710–712. 101. Fenzl, W.; Köster, R.; Zimmermann, H.-J. Justus Liebigs Ann. Chem. 1975, 2200–2210. 102. Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1041–1044. 103. Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 403–409. 104. Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R.; Reddy, M. S. Tetrahedron Lett. 2003, 44, 2583–2585. 105. Ollivier, C.; Renaud, P. Chem. Eur. J. 1999, 5, 1468–1473. 106. Evans, D. A.; Fu, G. C. J. Org. Chem. 1990, 55, 5678–5680. 107. Boldrini, G. P.; Mancini, F.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Chem. Soc., Chem. Commun. 1990, 1680–1681. 108. Boldrini, G. P.; Bortolotti, M.; Tagliavini, E.; Trombini, C.; UmaniRonchi, A. Tetrahedron Lett. 1991, 32, 1229–1232. 109. Boldrini, G. P.; Bortolotti, M.; Mancini, F.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1991, 56, 5820–5826. 110. Matsumoto, Y.; Hayashi, T. Synlett 1991, 349–350. 111. Huddleston, R. R.; Cauble, D. F.; Krische, M. J. J. Org. Chem. 2003, 68, 11–14. 112. Nuhant, P.; Allais, C.; Roush, W. R. Angew. Chem., Int. Ed. 2013, 52, 8703–8707. 170 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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113. Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R. Angew. Chem., Int. Ed. 2013, 52, 12888–12891. 114. Allais, C.; Nuhant, P.; Roush, W. R. Org. Lett. 2013, 15, 3922–3925.

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Chapter 5

Unstable Intermediates as Keys to Synthesis with Organoboron Compounds Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch005

Donald S. Matteson* Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, United States *E-mail: [email protected]

The role of unstable intermediates is often the key to understanding and optimizing organoborane reactions. The examples described are selected from the author’s experience, with emphasis on reactions that were initially overlooked or not understood until an unstable intermediate was recognized. The topics chosen are Unsolvated Boranes in Hydroboration, (α-Haloalkyl)borate Rearrangements, (Halomethyl)lithiums, and (α-Aminoalkyl)boronic Esters. This brief review is not comprehensive but emphasizes the observations that enabled the original discoveries.

Introduction The theme that connects the diverse boron chemistry included in this brief review is the role of reactive intermediates that are not isolable in syntheses of boron compounds that were discovered in the author’s laboratory. In some cases the intermediates were understood before the research was undertaken, in others the results were a total surprise. It was my policy to encourage students and postdoctoral associates to try their own ideas in the lab. There were occasions where the professor could have told the student that his/her idea wouldn’t work, but trying the experiment produced an unexpected result that was useful after it was interpreted correctly. Some of my most important discoveries were made that way, and without revealing forgotten and possibly embarrassing ideas that led to the experiments, the pathway to these discoveries is described here.

© 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Unsolvated Boranes in Hydroboration This section covers a convenient and useful method of hydroboration with haloboranes and silanes developed in our laboratory and how it was discovered. It has not been as widely publicized as other methods and it appears that few chemists have been aware of it. Brown and coworkers have provided convincing evidence that hydroboration of alkenes with 9-borabicyclo[3.3.1]nonane (9-BBN) dimer proceeds via dissociation to 9-BBN monomer (1, 2). If the alkene reacts rapidly with the 9-BBN monomer, the reaction is first-order in (9-BBN)2 and unaffected by the alkene concentration since every dimer that dissociates is consumed. However, a slower reacting alkene such as cyclohexene allows time for the monomer-dimer equilibrium to occur, the monomer concentration becomes proportional to the square root of that of the dimer, and the rate becomes half-order in (9-BBN)2 and first-order in alkene. The mechanism of the reaction of (9-BBN)2 with cyclohexene in carbon tetrachloride or other inert solvent to produce cyclohexyl-(9-BBN) (1) is illustrated in Scheme 1.

Scheme 1. Mechanism of reaction of (9-BBN)2 with cyclohexene The reaction of 9-BBN dimer with 2-methyl-1-pentene in carbon tetrachloride with THF is first-order in (9-BBN)2 and first-order in THF. It was concluded that the accelerating effect of ethers involves attack of the ether on the BH2B bridge bonded dimer, which liberates 9-BBN monomer and 9-BBN-THF, which then dissociates much faster than (9-BBN)2 does. The proposed mechanism that leads to 2-methylpentyl-(9-BBN) (2) is illustrated in Scheme 2.

Scheme 2. Mechanism of hydroboration with (9-BBN)2 in THF Wang and Brown extrapolated their results to all borane reactions, and concluded that free BH3 is the active hydroborating agent in borane-THF reactions (1). They attributed significance to a report by Klein et al. that pseudo-first-order 174 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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hydroboration of an aged sample of a methoxystyrene in excess THF-BH3 was delayed up to six half-lives by an undetected impurity but proceeded normally after the sample was distilled (3). However, the fact that hydroboration is not a chain reaction was overlooked in this interpretation. Several mols of the undetected impurity would be required to scavenge most of the free BH3 and delay hydroboration so long. The half-lives measured were only a few seconds, a flow system was used, and the likely explanation for the anomaly is an experimental error such as failure of mixing the rapidly reacting reagents. Otherwise, the normal kinetics first-order in styrene are in agreement with other observations, and citation of this work is merely a cautionary tale of Murphy’s Law. Although it is clear that ethers accelerate hydroboration by breaking the strong BH2B bridge bond in borane dimers and reducing the activation energy by delivering a single borane unit at a time to the alkene substrate, it is not clear whether borane etherates may also react directly with alkenes. Pasto and coworkers found that hydroboration of tetramethylethylene with BH3-THF in THF is first-order in BH3-THF as well as first-order in tetramethylethylene (4). The observed activation energy was 9.2±0.4 kcal/mol and the activation entropy -27±1 eu. These results are consistent with a direct reaction between BH3-THF and tetramethylethylene. If the mechanism involves irreversible dissociation of the BH3-THF and rapid reaction of the free BH3 with the alkene, the rate should be insensitive to the alkene concentration. The second mechanism allowed by the experimental data would be reversible dissociation of BH3-THF followed by reaction of the equilibrium concentration of free BH3 with the alkene. The half-order dependence of free BH3 on BH3-THF would be masked by the use of THF as solvent and measurement of pseudo-first-order rates exclusively. The activation energy for reaction of free BH3 with ethylene in the gas phase was estimated by Fehlner to be 2±3 Kcal-mol–1, not clearly distinguishable from zero (5). The BH3 was generated by thermolysis of BH3PF3 in a flow system with helium as carrier gas and the reaction products were identified by mass spectroscopy. Quantum mechanical calculations at the 6-31G** level (6) and more recently at the B3LYP/6-31G(d) level with corrections for solvation (7) have left unresolved the question of whether the active hydroborating agent is free BH3 or BH3-THF. The calculated results suggest that the activation energy is higher than the value measured by Pasto’s group, and leave open the possibility that hydroboration by BH3 might involve both pathways simultaneously. Several calculations are in accord in suggesting that the first step in hydroboration is formation of a borane–hydrocarbon π-complex, which subsequently forms the product-determining four-center transition state (6–8). Experimental evidence that hydroboration can involve direct transfer of borane from a complex with a base to an alkene is provided by Narayana and Periasamy, who found that hydroboration of a dihydrofuran with N-isobornyl-N-methylaniline-borane led to (R)-3-tetrahydrofuranol in up to 19% enantiomeric excess (ee) (9). This result requires that at least part of the reaction pathway involve the amine-borane directly reacting with the substrate, and since there is reason to expect that chiral induction would not be very high, allows the possibility that no free BH3 is involved. 175 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In accord with the mechanistic data, hydroboration with HBCl2-THF is much slower than with BH3-THF, generally requiring hours at room temperature (10, 11). Addition of boron trichloride to a solution of an alkene and HBCl2-Et2O in pentane precipitates boron trichloride etherate and results in rapid hydroboration to form the alkylboron dichloride (12). Perhaps the hydroboration is so fast as unsolvated HBCl2 is liberated from its etherate that disproportionation does not occur, but as described in the following paragraph, the alkylboron dichloride will be the product as long as the proportion of chloride to hydride is at least 2:1. Hydroboration with HBCl2-SMe2 requires boron trichloride in order to proceed satisfactorily, but unexpectedly HBBr2-SMe2 alone is an efficient hydroborating agent in refluxing dichloromethane (13). My interest in hydroboration with unsolvated haloboranes arose when Raman Soundararajan tried a reaction of tributyltin hydride with catechol bromoborane and got a mixture of catechol butylboronate with catechol borane. Might the reaction with trialkylsilanes be more selective? It is, and it quickly developed that addition of a trialkylsilane or diethylsilane (which transfers only one hydride) to an equimolar mixture of boron trichloride and an alkene with no solvent or in an inert solvent resulted in immediate formation of the corresponding alkylboron dichloride (14, 15). Reaction of diethylsilane with approximately equimolar boron trichloride at –78 °C in an NMR tube and measurement of the 64 MHz 11B spectrum below –40 °C revealed a mixture of unchanged boron trichloride, both geometric isomers of (H2BCl)2, and ClB2H5. No clear evidence for HBCl2 or its dimer was seen, though a small amount could have been present. At –25 °C the mixture disproportionated to boron trichloride and B2H6. Checking the literature for precedent revealed that the Haszeldine group had already shown that enantiopure (methyl)(phenyl)(naphthyl)silane exchanges hydride for chloride with boron trichloride with retention of configuration at silicon (16). However, the reaction was not run under conditions that would allow observation of the borane products before total disproportionation to boron trichloride and diborane The most convenient procedure is to add an equimolar mixture of the alkene and either triethylsilane or diethylsilane dropwise to stirred boron trichloride either neat (bp 12 °C) or in an inert solvent such as dichloromethane or pentane. Trimethylsilane requires a cylinder for storage and is accordingly less convenient, but it transfers hydride very rapidly. It appears that trimethyl- and diethylsilane have comparable reactivities. Tributylsilane and triphenylsilane react more slowly. Chlorodimethylsilane transfers hydride very slowly to boron trichloride but could be useful at somewhat elevated temperature and pressure (15). An alternative is to mix the silane and boron trichloride first at –78 °C, then add the alkene. Either way, the product and yield are the same, even though HBCl2 is only a minor constituent of the preformed hydroborating agent, because redistribution of hydride and chloride between boranes is very rapid. Another alternative is the use of BBr3 in place of boron trichloride. One consequence of the rapid halide-hydride redistribution is that it makes no difference which alkyl group is joined to boron first for synthesis of a dialkylchloroborane, RR′BCl, having two different alkyl groups. Equilibrium control prevails at each step, in contrast to hydroboration with BH3-THF, which 176 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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can only be paused cleanly after the first or second group is hydroborated if the group has sufficient steric bulk to slow further reaction. The facile hydroboration of 1-hexene to (dichloro)(1-hexyl)borane followed by subsequent reaction with cyclohexene to form (chloro)(cyclohexyl)(1-hexyl)borane (3) was reported as an example of the flexibility provided by hydroboration with haloboranes and silanes (Scheme 3) (15).

Scheme 3. Sequential hydroborations with BCl3 and Et3SiH Ethyldichloroborane was made in good yield by passing a slow stream of ethylene through a solution of boron trichloride in dichloromethane at –78 °C while adding triethylsilane dropwise. In spite of its high chlorine content (64%) the product is spontaneously flammable, though the flame did not char paper. Accordingly, methanol was added and dimethyl ethylboronate was isolated (15). Hydroboration of terminal alkynes with dichloroborane is easily controlled to produce the E-alkenyldichloroborane (4) or the 1,1-bis(dichloroboryl)alkane (5) by using the appropriate ratio of reactants, and 5 can be converted to the corresponding bis(boronic ester) (6) by treatment with an alcohol or reduced with excess silane to form the cyclic borane dimer (7). (Scheme 4).

Scheme 4. Product options from hydroboration of 1-hexyne with BCl3/Et3SiH Hydroboration of internal alkynes has yielded more complicated results. Brown and Gupta reported that catecholborane hydroborates alkynes stereospecifically cis to yield exclusively the Z-alkeneboronic esters (17), but when we tried to repeat that result with 3-hexyne and catecholborane we obtained gross mixtures of E- and Z-isomer (18). Reaction of 3-hexyne with boron trichloride and triethylsilane at –78 °C produced ~30% 3-(dichloroboryl)-4-chloro-3-hexene 177 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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(8) and very little hydroboration product. Efficient hydroboration was achieved with boron trichloride and the more reactive diethylsilane, and the NMR spectrum of the crude dimethyl 3-hexenyl-3-boronate obtained after methanolysis indicated that it was pure Z-isomer (9), but it partially isomerized to E-isomer (10) on distillation (18). Evidence that the Z/E isomerization is radical catalyzed includes an decreased proportion of 10 when the hydroboration with catecholborane was run in the presence of the radical inhibitor galvinoxyl and production of ~90% 10 when the free radical initiator AIBN was used. We did not find any way to obtain pure 9. These results are illustrated in Scheme 5.

Scheme 5. Results of hydroboration of 3-hexyne with BCl3 and Et3SiH or Et2SiH2 Addition of equimolar (+)-α-pinene and triethylsilane to neat boron trichloride stirred in a –78 °C bath resulted in complete conversion to dichloroisopinocampheylborane (11) within 5 minutes. The crude product was then mixed with a second mol of (+)-α-pinene and triethylsilane and was completely converted to diisopinocampheylchloroborane (12) at room temperature overnight (Scheme 6) (15).

Scheme 6. Hydroboration of 2 mols of (+)-α-pinene with BCl3/ 2Et3SiH Dhokte, Kulkarni, and Brown subsequently reported that the reaction of trimethylsilane with 11 is “...extremely slow in pentane, probably proceeding to the formation of a small equilibrium concentration of IpcBHCl (19)...” However, their data require that the equilibration not be slower than that with triethylsilane reported previously (15), since 3-methyl-2-butene was hydroborated by 11 and trimethylsilane in pentane at 0 °C in 24 h (19). The thermodynamic balance is shifted in diethyl ether, and IpcBHCl-Et2O was formed within minutes. It was also noted that equimolar amounts of 11, (+)-α-pinene, and trimethylsilane in diethyl ether were converted to 12 within 15 minutes at 0 °C. Hydroboration of 1-(1-cyclohexenyl)naphthalene with boron trichloride and triethylsilane in dichloromethane has provided clean alkyldichloroborane rac-13, 178 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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which was resolved via crystallization of the (–)-menthone complex of (R,R)-13 as illustrated in Scheme 7. In Diels-Alder reactions of esters the BCl2 group complexes with the ester carbonyl oxygen and the naphthalene substituent orients the remainder of the ester while blocking access of the diene to one side, making (R,R)-13 a highly effective asymmetric Diels-Alder catalyst (20).

Scheme 7. Preparation of (R,R)-1-(α-naphthyl)-2-dichloroborylcyclohexane The reaction of boron trichloride with silanes was not explored with any functionalized alkenes as hydroboration targets. A very brief investigation has shown that cyclohexylboron dichloride, derived from defluoridation of the trifluoroborate, does react with diethylsilane in refluxing THF and hydroborates alkenes rather slowly to form trialkylboranes (21). The reaction with 1-hexene does not stop cleanly at the dialkylchloroborane stage but proceeds to the trialkylborane. Reaction of diethylsilane with 1,5-cyclooctadiene in the presence of (dimethylamino)naphthalene produced cyclohexyl-(9-BBN) (1) (Scheme 8) (21).

Scheme 8. Hydroboration with RBCl2/Et2SiH2 in the presence of THF

(α-Haloalkyl)borate Rearrangements Synthetic organoboron chemistry in 1958 presented numerous obstacles that may be difficult for younger chemists to imagine. Normant’s discovery that vinyl Grignard reagents could be made in THF was recent (22), and the synthesis of a vinylboronic ester (14) became possible (23, 24). Free radical addition of bromotrichloromethane to dibutyl vinylboronate provided the first example of an (α-haloalkyl)boronic ester (15) (24, 25). With a very naive idea of what might be done with the product, I suggested to Raymond Mah, my first graduate student, that he phenylate the boron atom of 15 with the Grignard reagent (26), a well known process (27). The elemental analysis of his product did not yield the expected percentages, but repeated attempts to purify the material produced consistent numbers. The work of Kuivila on the 179 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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mechanism of the peroxidic oxidation of phenylboronic acid (28, 29) as well as the familiar Wagner-Meerwein rearrangement suggested that a rearrangement of intermediate anion 16 via phenyl migration to form boronic ester 17 might have occurred (26). The commercial analytical service could not distinguish between chlorine and bromine, and an inquiry about whether the halogen determination was titrimetric or gravimetric was needed to verify the result. Norman Bhacca of Varian Associates took the NMR spectrum, which was too poorly resolved for interpretation by novices, and assured us that it was consistent with our postulated structure. The mechanism was definitively proved by acidification of the cold reaction mixture prior to rearrangement, which did yield the expected borinic ester 18, and also by an alternative synthesis of 18 via radical addition of bromotrichloromethane to (butoxy)(phenyl)(vinyl)borane (19) (Scheme 9) (26, 30).

Scheme 9. Evidence for the rearrangement of an (α-bromoalkyl)borate anion

The first (α-bromoalkyl)boronic ester was an interesting curiosity for reaction mechanism studies but not much else. It was obvious that the rearrangement process ought to proceed with stereospecific retention at the migrating carbon and inversion at the displacement site, but without a general route to other structures, let alone to a pure single enantiomer, the potential synthetic utility was inaccessible. Radical addition is limited to a few unusual reagents. Radical addition of bromomalononitrile to dibutyl vinylboronate (14) yielded the (α-bromoalkyl)boronic ester 20, but the only reaction found with the few nucleophiles tested was deprotonation and closure to (cyclopropyl)boronic ester 21 (Scheme 10) (31).

180 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 10. Products from bromomalononitrile and dibutyl vinylboronate

(α-Haloalkyl)boronic esters that could be made by hydrogen halide addition to unsaturated boronic esters were limited to adducts of a vinylboronic ester or of (sec-alkenyl)boronic esters (31, 32). Otherwise polar hydrogen halide addition puts the halogen in the β-position, where the only known reaction with nucleophiles (except iodide ion) is elimination of boron and halide, as illustrated with the synthesis and decomposition of 22 (Scheme 11).

Scheme 11. Formation and β-elimination of a (β-bromoalkyl)boronic ester

Attempted chlorination of di-t-butyl methylboronate with t-butyl hypochlorite resulted in very little chlorination of the B-methyl group (33). Light-initiated bromination of secondary alkylboronic esters has proved successful (34). Secondary alkylboronic anhydrides are more reactive in radical bromination, and tri(bromoisopropyl)boroxine is produced very efficiently (35). Dibutyl (iodomethyl)boronate, (BuO)2BCH2I, was first made via reaction of boron tribromide with (iodomethyl)mercuric iodide (36, 37), not a reaction anyone would want to repeat. The first practical synthesis of pinacol (iodomethyl)boronate, reaction of pinacol (phenylthiomethyl)boronate with methyl iodide and sodium iodide in acetonitrile (38), was based on the homologation of alkyl iodides by Corey and Jautelat (39). The lithiation of pinacol (phenylthiomethyl)boronate to 23 and alkylation with benzyl bromide to 24 enabled extension of this approach to a potential general synthesis of (α-iodoalkyl)boronic esters such as 25 (Scheme 12) (40, 41). That route was quickly superseded by the discovery of homologation of boronic esters with (dihalomethyl)lithiums described in the following section.

Scheme 12. Preparation of an (α-iodoalkyl)boronic ester via a thioether

181 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(Halomethyl)lithiums

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Precursor One-Carbon Chain Extensions (Dichloromethyl)lithium, LiCHCl2, was discovered by Köbrich and coworkers and shown to react with triphenylborane, Ph3B, with rearrangement to (diphenyl)(α-chlorobenzyl)borane, Ph2BCHClPh (42, 43). Ultimately this reagent became the key to useful syntheses with (α-chloroalkyl)boronic esters, but we reached this goal via a roundabout route. Our interests at that time were centered on boron substituted carbanions, beginning with deboronation of a tetraborylmethane ester, C[B(OMe)2]4 (44), and a triborylmethane ester (45). Deprotonation of a (methylene)diboronic ester, CH2[BO2(CH2)3]2, followed (46). Preparation these di-, tri-, and tetraboronic esters was hazardous, involving lithium dispersion, dichloromethane, and dimethoxyboron chloride in THF, and yields varied for no known reason. Unstable (chloromethyl)lithium intermediates with several combinations of halogen and boronic ester substitution are no doubt involved in these reactions, but our ignorance of what relations there are between their rates of formation and borylation precludes meaningful discussion. Dimethoxyboron chloride was the only successful borylating agent found. Cyclic boron substrates did not work, and transesterification of tetramethyl (methylene)diboronate with 1,3-propanediol was required for preparation of an improved substrate 26 for lithiation to 27 and typical carbanion reactions such as alkylation to 28 (Scheme 13).

Scheme 13. Alkylation of a lithiated methylenediboronic ester

The deboronation of triboronic ester 29 to lithiated derivative 30 and reaction with acetaldehyde yielded trans-propenylboronic ester 31 (Scheme 14) (47). The E/Z ratio was 93:7, and bulkier aldehydes yielded higher E/Z ratios.

Scheme 14. Reaction of a lithiated methylenediboronic ester with acetaldehyde 182 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The reaction of 30 with a highly functionalized aldehyde was used in an essential step in the Kishi group’s famous palytoxin synthesis after it had been found that hydroboration of the corresponding alkyne resulted in reduction of a urethane function that was faster than the hydroboration (48). Perhaps Morken’s recently reported catalytic preparation of a diboronic ester from dibromomethane and pinacol diborate, B2(O2C2Me4)2, will make this chemistry more accessible and useful (49). We turned our attention to easier carbanion sources to prepare, such as the [(trimethylsilyl)methyl]boronic ester 32 (50). Alkylation of the lithiated species 33 provided the expected (α-trimethylsilylalkyl)boronic esters, for example 34 (Scheme 15).

Scheme 15. Alkylation of a lithiated [(trimethylsilyl)methyl]boronic ester

However, condensation with aldehydes or ketones unexpectedly resulted in elimination of the trimethylsilyl group and not the boronic ester function. The second surprise was that heptanal yielded predominantly the Z-alkenylboronic ester 35, Z/E ratio ~70:30 (Scheme 16), and the only other aldehyde tested, benzaldehyde, produced a similar Z/E ratio.

Scheme 16. Reaction of a lithiated silyl boronic ester with an aldehyde

Considering the possible lability of the Z/E ratios of alkenylboronic esters noted much later (see isomerization of 9 to 10) (18) and that these were distilled samples, it might be worthwhile to check whether the initial Z/E ratios were higher. It is also possible that higher Z/E ratios could result from different combinations of boronic ester and trialkylsilyl groups. It has been noted in the preceding section that pinacol (α-phenylthiomethyl)boronate is easy to make, lithiate to 23, and alkylate with benzyl bromide to 24, which can be converted to the (α-iodoalkyl)boronic ester 25. It is also easy to make bis(phenylthio)boronic esters, deprotonate them with LDA, and react the anion with a carbonyl compound to make a 1,1-bis(phenylthio)alkene, as illustrated with the conversion of 36 to 37 (Scheme 17). 183 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 17. A bis[(phenylthio)methyl]boronic ester and reaction with a ketone In the hope that we might be able to alkylate the boron atom of 36, methylate sulfur, and rearrange the borate complex with displacement of PhSMe, Abel Mendoza tried treatment of 36 with butyllithium, then methyl iodide, but only obtained (PhS)2CHCH3 and BuB(O2C3H6). He then tried the reaction of 36 with methyl fluorosulfonate followed by butyllithium and obtained ~30% of what the NMR spectrum indicated was the desired product 38 in a gross mixture with (PhS)2CH2 (erroneously called “diphenylmethane” in our publication) (Scheme 18) (51). At that point a tragic fatality from an accidental spill of methyl fluorosulfonate was reported (52), and we immediately quit using that exceedingly dangerous reagent.

Scheme 18. Replacement of a phenylthio of a bis(phenylthio) boronic ester (Dichloromethyl)lithium A methylthio group would be easier to methylate than phenylthio, and perhaps the methylthio analogue of 36 could be methylated with methyl iodide and an efficient way to carry out a reaction analogous to the conversion of 36 to 38 could be found. Debesh Majumdar didn’t like that idea and wanted to try reaction of a boronic ester with (dichloromethyl)lithium. I unwisely tried to discourage that approach, doubting both the feasibility and the novelty of it. Köbrich and Merkle required –100 °C to prepare the reagent, not the most practical of reaction conditions, and had inserted the CHCl group into triarylboranes (43). Rathke, Chao, and Wu had already made diisopropyl (dichloromethyl)boronate, alkylated the boron with butyllithium, and rearranged the intermediate to insert the CHCl group and make an (α-chloropentyl)boronic ester (53). The intermediate was the same as would result from adding LiCHCl2 to an alkylboronic ester. The Rathke group had used several different (dichloromethyl)boronic esters and different organometallic partners but had oxidized all the other (α-chloroalkyl)boronic esters to aldehydes, with consistent 75% yields. Fortunately Debesh had learned that the professor is not always right, and he went ahead and tried the experiment. He immediately got consistent 80-90% isolated yields of (α-chloroalkyl)boronic esters (54, 55). We already knew that the α-halide could be displaced by a variety of nucleophiles (26). The products are, of course, boronic esters, and the reaction with LiCHCl2 could be repeated to produce a new (α-chloroalkyl)boronic ester. The rearrangement of the intermediate borate complex was slowed and yields were lower but still good when an α-alkoxy or a 184 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

remote carboxylic ester or dioxolane substituent was present. We also found the literature method of generating and capturing LiCHCl2 in situ (56), which allows temperatures as high as –30 °C. The homologation of pinacol butylboronate to 39 on a 0.1-mole scale using convenient dry ice cooling is illustrated in Scheme 19 (55).

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Scheme 19. Homologation of an alkylboronic ester with (dichloromethyl)lithium The one glaring deficiency in the chemistry at that point was the lack of stereocontrol, which was needed in order to make it a truly useful procedure. Any organic chemist is well aware of the use of α-pinene as the source of asymmetric control in the first truly successful enantioselective synthesis, that of (–)-2-butanol via hydroboration of cis-2-butene by Brown and Zweifel (57). Both enantiomers of α-pinene are commercially available. The diol that results from osmium tetroxide oxidation of α-pinene seemed a possibility, but a catalytic route would be needed in order to make it practical, and hydrogen peroxide as the oxidizer destroys pinanediol (42). Rahul Ray found the Van Rheenen amine oxide procedure (58, 59), and since he did not have the recommended N-methylmorpholine N-oxide immediately available, tried the trimethylamine N-oxide he did have (60, 61). When he tried the less expensive N-methylmorpholine N-oxide, the yield was not as high. One necessary precaution with the t-butyl alcohol solvent used was that the reflux be very gentle, because the higher temperature reached with a more vigorous reflux decreased the yields. Recent unpublished work in our laboratory with K. S. Hanes has indicated that acetone is a better solvent for the reaction and provides nearly quantitative yields. A study of the kinetics suggests the catalytic cycle outlined, in which the amine oxide converts 40 to the Os(VIII) ester, which adds to a second molecule of α-pinene to form the stable Os(VI) ester 41, which liberates 40 + pinanediol (42) on oxidative hydrolysis (Scheme 20). Also, it should be noted that bis(pinanediol) osmate 41 is a very stable intermediate that remains at the end of the reaction (62), and it may be possible to distill the diol without intervening workup and recover the osmium from the residue, but this investigation has not yet been completed, and 41 has not been isolated for proof of the oxidation state of the osmium.

Scheme 20. Oxidation of (+)-α-pinene to (1S,2S,3R,5S)-pinanediol Pinanediol (42) as chiral director was just a wild guess, and it proved far more stereoselective than we had expected. Diastereomeric ratios near 10:1 were 185 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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generally achievable (63, 64). α-Pinene was only available as impure enantiomers, but 42 can be recrystallized from heptane (65), and our original route to pure enantiomers (64) is obsolete. The problem of epimerization of pinanediol (αchloroalkyl)boronates quickly became obvious. At first, the best option was to get the product away from lithium chloride as soon as the reaction was complete. Alkyl migrations generally required several hours, most conveniently overnight, but aryl migrations were done within an hour. Best results for alkylated derivatives seemed to be obtained when a Grignard reagent was added to the reaction mixture without isolation of the (α-chloroalkyl)boronic ester intermediate. We chose to make the four stereoisomers of 3-phenyl-2-butanol, which had been previously fully characterized and the absolute configurations assigned by Cram (66, 67), as a demonstration of the power of the method. The synthesis of the diastereomeric pair derived from (1S,2S,3R,5S)-pinanediol phenylboronate (43), called “(+)-” or “(s)-pinanediol” in our earlier publications, is illustrated. The first reaction with LiCHCl2 produced (1S,2S,3R,5S)-pinanediol (S)-(α-chlorobenzyl)boronate (44), and alkylation in situ with methylmagnesium bromide yielded ~86% of (S)-(1-phenylethyl)boronic ester 45a with the diastereomer ratio (dr) estimated to be 98% (64). Further homologation and methylation in situ produced 46a, which was oxidized in the usual manner with alkaline hydrogen peroxide to (2S,3S)-3-phenyl-2-butanol (47a). The yield of 47a from 43 was 67% and the dr was 94:6. Hydrolysis of the (1S,2S,3R,5S)-pinanediol ester 45a to produce (S)-1-(phenylethyl)boronic acid (48) is contrathermodynamic. The destruction of the pinanediol with boron trichloride that was resorted to has been superseded by the du Pont two-phase transesterification method for water-soluble boronic acids (65) or the conversion of the boronic acid to a cesium trifluoroborate salt (68). Conversion of 48 to (1R,2R,3S,5R)-pinanediol (S)-1-(phenylethyl)boronate (45b) and on to 46b and to (2R,3S)-3-phenyl-2-butanol, dr 96:4, was routine (Scheme 21) (64).

Scheme 21. Preparation of two diastereomers of 3-phenyl-2-butanol 186 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Although the preparations of diastereomers 47a and 47b produced high drs, other substrates usually yielded drs in the 90:10 to 95:5 range. The problem of epimerization of (α-chloroalkyl)boronic esters by chloride exchange was an obvious contributing factor, and we undertook a kinetic investigation of the epimerization of 44 in THF, which occurs at a rate convenient for following by polarimetric measurements (69). The kinetics indicated that free chloride ion attacked 44 in the rate determining step of the major pathway. Lithium chloride is an ion tetramer in THF, and if the ion cluster dissociates to Li2Cl+ + Cl–, half-order dependence is expected. At the lower concentrations of LiCl, 0.075-0.25 M, the measurements best fit 0.62-order, but increased to 0.75-order when concentrations up to 0.45 M were included in a least squares plot. This was considered consistent with half-order plus a salt effect. Very small amounts of added water greatly increased the epimerization rate, and zinc chloride or mercuric chloride strongly inhibited epimerization (69). In my application for an NSF grant renewal, I suggested that addition of a Lewis acid such as zinc chloride might catalyze the rearrangement step as well as inhibit epimerization, but the referee ratings were too low to allow funding, the only time that NSF failed to renew funding for my boron chemistry. In the meantime, Matthew Sadhu had tried adding 0.5 mol of rigorously anhydrous zinc chloride to the reaction of LiCHCl2 with pinanediol (isobutyl)boronate (49), one of the few homologations that had provided poor yields (30%) previously. The results were immediately spectacular: dr 99.5:0.5, yield 89% for (α-chloroalkyl)boronic ester 51 (Scheme 22) (70, 71). Catalysis of the rearrangement of intermediate borate 50 and sequestering of the chloride byproduct as ZnCl42– had solved the problem.

Scheme 22. Zinc chloride catalyzed homologation of a pinanediol boronic ester

Not surprisingly, the NSF funded my revised proposal at a higher level than the first request. We were lucky to have chosen to begin with pinanediol alkylboronates and (dichloromethyl)lithium rather than pinanediol (dichloromethyl)boronate (52) and alkyllithium or Grignard reagents. The latter pairing produces intermediate 53, a diastereomer of 50, and poor stereoselection between diastereomers 54a and 54b follows, as illustrated in Scheme 23 (72). Zinc chloride altered the various 54a:54b ratios but did not make the two that were tested useful, and work with 52 was terminated. 187 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 23. Poor diastereoselection with pinanediol (dichloromethyl)boronate

At first, we were cautious about adding too much zinc chloride, because our kinetic study had suggested that there was a term in the rate law that included (ZnCl2)(ZnCl3–) at high concentrations, consistent with a plausible push/pull mechanism for chloride exchange (69). However, in many years of subsequent work, much of which has involved homologations in the presence of polar functional substituents, no example in which an excess amount of zinc chloride had a deleterious effect on the dr has ever been encountered (73). What has been encountered is an absolute requirement for an increased amount of zinc chloride when substituents that coordinate with it are present, and a need to work up reaction mixtures in such a way that the (α-chloroalkyl)boronic ester product is never in the same phase with water and chloride salts (74). Adding pentane to the THF phase and beginning the extraction with saturated ammonium chloride rather than plain water is effective. It seems likely that the increased epimerization rates in concentrated solutions may have been an artifact caused by the difficulty of keeping lithium and zinc chlorides strictly anhydrous. C2-Symmetric chiral directors make the two faces of the boron atom identical and thus produce the same intermediate borate anion regardless of whether the dichloromethyl group is added to the boronic ester or an organometallic reagent is added to the (dichloromethyl)boronic ester. Our first example was (S,S)-diisopropylethanediol (DIPED), made initially via straightforward homologation of (1R,2R,3S,5R)-pinanediol isopropylboronate and appropriate subsequent steps (75), later in a synthesis beginning from tartaric acid (76). DIPED boronic esters produced higher drs than pinanediol boronic esters. How much higher was not realized until Pran Tripathy laboriously made (S,S)-DIPED (1S)-(1-chlorobutyl)boronate (55), the minor diastereomer (99% de) in good yield and the auxiliary could be smoothly removed by hydrogenation to reveal the free amino acid. The Petasis borono-Mannich (PBM) reaction is categorized as a type II multicomponent reaction since it involves a series of reversible steps in equilibrium, followed by a final, irreversible step that drives the reaction to completion (Scheme 1) (4). Although the exact details of the mechanism are not known with certainty, it is generally believed that formation of the boron “ate” complex 4 is followed by intramolecular delivery of the boron substituent with concomitant formation of the new carbon-carbon bond. As mentioned above, most examples in the literature involve substrates bearing a heteroatom adjacent to the carbonyl group (e.g., glyoxylic acid, salicylaldehydes, α-hydroxyaldehydes, etc.), although this is not strictly required. The reaction is compatible with both primary and secondary amines; for the boronic acid component, vinyl and aryl substituents are most common. Operationally, the PBM reaction compares favorably to other well-known multicomponent processes that can be used to prepare similar compounds. For example, cyanide is the nucleophile in the Strecker reaction and presents toxicity issues, while the widely used Ugi condensation uses isocyanides, which often have a pungent odor. Both of these reactions (and others such as the Bucherer-Bergs hydantoin synthesis) also require a subsequent hydrolysis step that proceeds under harsh conditions (e.g., refluxing 6 N HCl) and thus limits their functional group compatibility. In contrast, the PBM products can be deprotected or converted to the free amino acid under mild conditions. Further, a large number of boronic acids (as well as amines and aldehydes) are commercially available and do not require rigorous exclusion of air and moisture like highly reactive organometallic nucleophiles such as Grignard reagents and organolithiums. The Petasis reaction has been the subject of several excellent reviews that include a comprehensive discussion of the mechanistic and experimental details mentioned above, most recently in 2010 and 2011 (5–8). Since then, the field has continued to advance on a variety of fronts. Major themes include the development of new catalysts and reaction conditions, expanded scope both from a methodology perspective and via the application of the PBM reaction to problems in organic synthesis; diversity-oriented approaches that use both the multicomponent nature of the Petasis reaction as well as the functional groups in the products to generate large numbers of molecules in an efficient fashion; and a variety of asymmetric approaches using both chiral substrates and catalysts. In addition, a few miscellaneous reports have appeared and suggest that new contexts for the Petasis reaction remain to be discovered. It should be noted that many of the papers have aspects that touch on more than one category (some of which are mentioned in the text). A number of other examples can also be found in patent literature but are not covered here. This review is intended to highlight results reported after the preceding reviews through mid-2016. 277 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Catalysts, Reaction Conditions, and Methodology

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Lamaty and co-workers reported the PBM reaction of secondary amines, salicylaldehyde, and a variety of boronic acids under solvent-free conditions using microwave (MW) irradiation (Equation 3) (9). The reactions proceeded cleanly and only an aqueous work-up was required to yield the desired products in pure form. For example, a labile benzofuran derivative (5) was prepared in 95% isolated yield without chromatography. Yields with primary amines were lower and no product was obtained with glyoxylic acid as the aldehyde component.

The use of solvent-free conditions was also investigated by Wang, who found that salicylaldehyde reacted with a range of boronic acids and amines under thermal rather than microwave conditions to give the PBM products in moderate to good yield (10). A temperature of 80 °C gave the highest yields and the reactions were complete after 2 hours. The Candeias group used glycerol as a solvent in the PBM reaction of salicylaldehydes and 2-pyridinecarbaldehyde with secondary amines (Equation 4) (11). In some cases, yields were similar to other solvents such as ethanol or acetonitrile. Density functional theory calculations suggested that a reaction pathway involving glycerol boronates is competitive with that of the free boronic acid. In a separate experiment, a pre-formed mixture of glycerol boronate esters gave the Petasis product in moderate yield.

Fluorous-tagged benzylic (f-Bn) hydroxylamines such as 7 were used by Kristensen and co-workers as the amine component in the Petasis reaction to generate N-alkyl amino acids with good results (Equation 5) (12). Yields for the cleavage of the tag by hydrogenolysis were found to be substrate-dependent, while use of the previously-reported Mo(CH3CN)3(CO)3 conditions and subsequent purification was non-trivial due to metal complexation by the amino acid product. However, this issue could be circumvented by preliminary esterification with TMS-CH2N2 before treatment with the molybdenum reagent. 278 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Jensen and co-workers demonstrated the use of an automated microreactor system to optimize and investigate the kinetics of multicomponent reactions (13). In particular, a tandem Petasis-Ugi sequence based on glyoxylic acid was examined both stepwise and in series to monitor and optimize the formation of product at various times and temperatures and to extract kinetic parameters such as activation energies. Mass spectrometry-based methods were applied by two groups to investigate the Petasis reaction. Thomson and co-workers rapidly screened >1800 conditions using a high-throughput self-assembled monolayer/MALDI-Tof mass spectrometry (SAMDI) platform (14). In these experiments, the aldehyde component was immobilized on a gold surface and product formation was quantified relative to an internal standard. The optimized reaction conditions were later successfully transferred to the solution phase. Meanwhile, the Neto group applied a charge-tag strategy to monitor intermediates in solution as part of mechanistic studies for a model PBM reaction using benzylamine, salicylaldehyde, and phenylboronic acid (15). Interestingly, they were also able to isolate and characterize by x-ray crystallography the methanol adduct of a cyclized zwitterionic intermediate (9) formed prior to transfer of the boronic acid substituent (Figure 1).

Figure 1. Zwitterionic Intermediate Characterized by X-Ray Crystallography.

Several reports of novel metal-catalyzed variants of the PBM reaction have been disclosed. The Bergin group developed conditions using 4Å molecular sieves (MS) and a Cu(I) additive that promoted reaction of some substrate combinations with low reactivity such as 2-pyridinecarboxaldehyde with arylboronic acids (Equation 6) (16). The exclusion of air and moisture was required and the highest yields were obtained with a coordinating group on the aldehyde. Reactions with dicyclohexylamine or arylboronic acids lacking an ortho-substituent were unsuccessful. 11B-NMR studies suggested that the reaction mechanism included a transmetallation from boron to copper. 279 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The Arndsten group developed a Petasis-like multicomponent reaction of imines, acid chlorides, and tetraalkylborates (instead of boronic acids) catalyzed by CuCl and a Lewis base to give α-substituted amides (Equation 7) (17). The general reaction conditions (CH2Cl2, rt, 18 h) were compatible with a wide range of imines, including those lacking a directing group. One example with an enolizable imine was also reported under slightly different conditions.

Beisel and Manolikakes developed a Petasis-like reaction of amides, aldehydes, and aryl boronic acids (Equation 8) (18). Yb(OTf)3 hydrate was used as a Lewis acid catalyst to promote formation of the reactive acyl imine species and Pd(TFA)2/2,2-bipyridine activated the arylboronic acid for addition. The reaction scope was wide and included electron-deficient arylboronic acids and carbamates in place of the amide. Yields ranged from 34-93% and the reaction was compatible with air and water.

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The use of 4Å molecular sieves was shown by Shi and co-workers to accelerate the PBM reaction to prepare the core of BIIB-042 (13), a γ-secretase modulator of interest as potential therapy for Alzheimer’s disease (Equation 9) (19). In the absence of a dehydrating agent, the reaction required heating and reached only 70-80% conversion over a period of several days. During this time, significant epimerization of an enolizable chiral center was observed in both the starting material and product. The inclusion of molecular sieves accelerated the reaction and complete conversion was obtained after 24-48 hours at room temperature without loss of stereochemical integrity. In situ FTIR monitoring of the reaction mixture suggested that dehydration of a hemiaminal intermediate to the iminium ion was responsible for the observed effect. The reaction conditions were also applied to several other secondary amines and a variety of arylboronic acids.

As described in earlier reviews, a variety of additives have been reported to increase the rate of the Petasis reaction. Since then, recent studies have demonstrated modest rate enhancements in the presence of chitosan (20), cobalt ferrite nanoparticles (21), metal-doped molecular sieves (22), protonated trititanate nanotubes (23), and La(OTf)3 with microwave irradiation (24).

Synthetic Applications The utility of the PBM reaction is amply demonstrated by the number of synthetic applications that have continued to appear in the literature. In this section, the reports are loosely arranged from general to specific: expansions in the scope of the reaction and approaches to various classes of compounds are described first, followed by examples in the context of particular synthetic targets. A group at Syngene described the preparation of fused triazepinediones (15) and related systems using a three step procedure that started with the Petasis reaction of glyoxylic acid and an alkyl-substituted BOC-hydrazide as the amine component (Scheme 2) (25). The sequence proceeded in reasonable yield without purification of the intermediates.

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Scheme 2. Synthesis of Triazepinediones. A following paper similarly presented a telescoped route to 1,2,3,4tetrahydrocarbazoles (17) in 20-50% overall yield starting instead with a BOC-protected phenyl hydrazine as the Petasis substrate to deliver an intermediate suitable for a subsequent Fischer indole synthesis (Scheme 3) (26).

Scheme 3. Synthesis of 1,2,3,4-Tetrahydrocarbazoles. Jurczak and co-workers prepared a series of hexahydropyrazino[1,2a]pyrazine-1,2-dione β-turn mimetics (20) using the Petasis reaction of a solid-supported (S)-piperazine-2-carboxylic acid (18) with glyoxylic acid as the key step (Scheme 4) (27). The same group also reported a related sequence that delivered fused benzodiazepine derivatives (28). 282 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 4. Solid-Phase Synthesis of β-Turn Mimetics.

The PBM reaction of 2-pyridine-carboxaldehydes was explored by the Mandai group using a variety of cyclic and acyclic secondary amines and styrenyl vinylboronic acids or electron-rich arylboronic acids in refluxing acetonitrile (Equation 10) (29, 30). Yields were mostly in the 70-90% range except for several 6-substituted pyridines which were significantly lower. Other heteroaromatic aldehydes gave poor conversion or complex mixtures of products. In the case of dibenzylamine, the products could be further derivatized by treatment with CAN to deliver the mono-benzylamine or by catalytic hydrogenation to cleave the amine substituent entirely. Interestingly, the electron-rich 4-dimethylaminopyridine-2-carboxaldyde gave an unexpected side product in nearly quantitative yield by direct alkylation of the aldehyde.

The Nielsen group reported the Petasis reaction of acyl hydrazides with hydroxyaldehydes and aryl boronic acids in hexafluoroisopropanol (HFIP) to yield 1,2-hydrazidoalcohols 22 (Scheme 5) (31). These intermediates could be carried on via treatment with bis(trichloromethyl)carbonate (BTC) to either the corresponding oxadiazolones 23 or oxazolidinones 24 by varying the stoichiometry and reaction conditions.

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Scheme 5. Synthesis and Cyclization of Hydrazidoalcohols. Li and co-workers prepared 2-arylimidazo[1,2-a]pyridin-3-ols by a PBM reaction of 2-aminopyridines with glyoxylic acid and aryl boronic acids under microwave irradiation (Scheme 6) (32). The initial Petasis adduct undergoes spontaneous cyclization followed by dehydration and aromatization to give the observed product.

Scheme 6. Reaction of 2-Aminopyridines. The Petasis reaction of cyclic amino alcohols, glyoxal, and arylboronic acids was used by Song and colleagues to prepare fused morpholine-pyrrolidine (27) or piperidine derivatives with good yields (Equation 11) (33). Several of the synthesized compound displayed insecticidal activity against armyworms and root-knot nematodes.

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A series of 2-hydroxy-2H-1,4-benzoxazine derivatives (31) was generated through the PBM reaction of N-substituted 2-aminophenols with glyoxal and arylboronic acid (Scheme 7) (34). The authors suggest that addition of the aryl group to the iminium species 28 is directed by the acetal OH group, followed by equilibration to the more-stable trans stereoisomer.

Scheme 7. Synthesis of 1,4-Benzoxazines.

Verbitskiy and co-workers reported the synthesis of several 5-aryl-6heteroaryl-substituted 1,6-dihydropyrazine derivatives such as 32 by the addition of electron-rich (benzo)furan or thiophene boronic acids to the hydroxy adduct of pyrazinium salts (Equation 12) (35). The most active of the resulting compounds exhibited anti-tuberculosis activity comparable to standard drugs. A later study extended this methodology to trans-styrenyl boronic acids (36).

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Aryl-substituted 1,4-benzodiazepine-3,5-diones (33) were prepared by Noushini and colleagues using the PBM reaction of 2-aminobenzamides with glyoxal and an arylboronic acid (Equation 13) (37). The reactions proceeded in 62-78% yield with 4Å molecular sieves at room temperature in CH2Cl2.

Shang and co-workers reported that the Petasis adducts can be converted to tetrahydro-1H-xanthen-1-ones (34) in 70-95% yield by FeCl3-catalyzed reaction with 1,3-diketones (Equation 14) (38). The authors propose that the FeCl3 coordinates the basic amine moiety and activates it for departure in a substitution reaction with the enol form of the diketone, followed by ring closure.

Mizuta and Onomura reported the diastereoselective addition of arylboronic acids to acylpiperidinium ions generated from N,O-acetals in the presence of BF3·OEt2 at low temperature to yield cis-2-aryl-3-hydroxypiperidines 35 (Equation 15) (39). The reaction was applied to a short synthesis of (±)-L-773,060, a piperidine neurokinin-1 receptor antagonist (Ar = Ph), by O-alkylation and deprotection of the Cbz group.

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Jarvis and Charrette prepared pyrrolinol derivatives using the PBM reaction of optically-active α-hydroxyaldehydes and allylamines with styrenylboronic acid in ethanol at reflux, followed by ring-closing metathesis with the Grubbs second-generation catalyst (Scheme 8) (40). The sequence gave similar yields when run without purification of the intermediate PBM adduct. The pyrrolinols were subsequently carried on to an aziridination/nucleophilic ring-opening sequence to yield enantiopure substituted piperidines.

Scheme 8. Synthesis of Enantiopure Substituted Piperidines.

An impressive application of the PBM reaction was reported by the Yudin group, who reacted aziridine aldehyde dimers 40 along with cyclic or acyclic amines and vinyl, alkynyl, aryl, or heteroarylboronic acids in hexafluoroisopropanol to yield syn-α-amino-aziridines (41) in moderate yields (Scheme 9) (41). The intermediates could then be carried on by an anchimerically-assisted nucleophilic ring opening to syn-1,2 or -1,3 diamines 42-44 with up to three contiguous stereocenters.

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Scheme 9. Petasis Reaction of Aziridine Aldehyde Dimers. More recently, Beau and co-workers described the diastereoselective PBM reaction of optically-active N-protected α-amino aldehydes with secondary amines and various vinyl and arylboronic acids to generate 1,2-trans-diamines 45 in moderate to good yields and up to 98% ee (Equation 16) (42). The substituents on the aminoaldehyde had a major impact on the success of the reaction, as did the choice of solvent and inclusion of 4Å molecular sieves. Conditions were also reported for orthogonal deprotection of the various N-protecting groups.

Another interesting example was disclosed by the Yang group, who reacted the unusual 4-substituted 1,2-oxaborol-2(5H)-ols 46 with salicylaldehydes and an amine promoter to yield the PBM product. This is turn underwent an intramolecular SN2 cyclization with loss of the amine to yield disubstituted 2,5-dihydrofurans 47 in 70-92% yield (Equation 17) (43).

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Tao and co-workers synthesized an N-glycosyl amino acid in 88% yield via the PBM reaction of a protected glucosamine with a vinylboronic acid and glyoxylic acid in CH2Cl2 at room temperature (Equation 18) (44). Unfortunately, the stereoinduction at the newly formed amino acid chiral center was low.

The solid-phase synthesis of β-lactams substituted at the 3-position with α-amino acids was developed by the Mata group (Equation 19) (45). A polymer-supported methylamino-β-lactam (49) underwent a Petasis reaction with arylboronic acids and glyoxylic acid (both in excess) in CH2Cl2 at room temperature for 72 hours. The use of hexafluoroisopropanol (neat or as a co-solvent) gave lower yields resulting from partial cleavage of the substrate from the resin at longer reaction times. The authors suggested that this cleavage was promoted by the acidic nature of the solvent.

The Nielsen group reported that treatment of β,γ-dihydroxy-γ-lactams (51) with BF3·OEt2 in hexafluoroisopropanol generated N-acyliminium ions which reacted with vinyl and arylboronic acids and esters via a Petasis-like process in moderate yields (Equation 20) (46). Relatively electron-poor boronic acids gave the cis isomer, while more reactive ones gave a mixture of cis and trans isomers.

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Mandia and co-workers reported the PBM reaction of optically-active lactol 53 prepared from D-araboascorbic acid to obtain polyhydroxy trans-1,2-amino alcohols (54) with three continuous stereogenic centers as chiral building blocks (Equation 21) (47). Chemistry was also developed to carry on the Petasis adducts using a variety of selective functional group transformations.

Bering and Antonchick presented a method to prepare 2-substituted quinolines (55) by N-oxidation followed by reaction with electron-rich aryl or alkenylboronic acids in DMSO at elevated temperature (Equation 22) (48). The authors proposed a Petasis-like mechanism in which the boronic acid is activated by coordination to the anionic oxygen of the N-oxide, followed by delivery of the nucleophile to the iminium carbon and subsequent rearomatization.

A two-step route to 2,3-diaryl-quinoxalines (57) was developed by the Hulme group (Scheme 10) (49). It involved the PBM reaction of a mono-protected orthophenylenediamine with an arylboronic acid and phenylglyoxal upon microwave irradiation in moderate to good yield. Deprotection was followed by cyclization in situ to give the heterocyclic product. The analogous reaction with BOC-protected ethylenediamine was unsuccessful.

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Scheme 10. 2,3-Diaryl-Quinoxalines.

The Thomson group reported a PBM approach to allenyl alcohols (61) that relies on the reaction of an arylsulfonylhydrazide with glycoaldehyde dimer and an alkynylboron nucleophile (Scheme 11) (50). The initially-formed adduct undergoes loss of sulfinic acid to yield the diazene and a retro-ene process to give the allene. The reaction was also shown to proceed smoothly and with high stereoselectivity when other carbonyl components such as (D)-glyceraldehyde, α-hydroxyketones, and β-hydroxyaldehydes were used.

Scheme 11. Generation of Allenyl Alcohols.

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Sun and co-workers disclosed the PBM reaction of formaldehyde with benzylamine and arylboronic acids in DCE at 45-60 °C (Equation 23) (51). In this work, the initially-formed hemiaminal proceeds to form an iminium species which is intercepted in situ by propiolic acid in a decarboxylative coupling process that leads to propargylamines 62 in moderate to high yields. Similar results were also reported by a different group using toluene at 80 °C (52).

The Pyne (53) and Petasis (54) groups independently reported in early 2015 that allenylboron species undergo component-selective reactions with aldehydes and amines to yield either allenyl (63) or propargyl (64) amino acid products in good yield depending on whether a primary or secondary amine is used (Scheme 12). In either case, the stereoselectivity was generally excellent.

Scheme 12. Synthesis of Allenyl or Propargyl Amino Acids. The use of aminophosphonates in the PBM reaction with electron-rich arylboronic acids and glyoxylic acid was disclosed in two reports by Khukar and co-workers (Equation 24) (55, 56). The reactions were run in refluxing ethyl acetate and the diastereoselectivity was higher (9:1) for secondary amines.

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Two interesting examples of the PBM reaction were reported by the Carboni (57) and Song (58) groups. The former used Z-alkenyl 1,2-bis(boronates) 66 with glyoxylic acid and secondary amines in hexafluoroisopropanol at room temperature to generate unsaturated γ-boronated amino esters 67 upon esterification with diazomethane (Equation 25) (57). These products could be carried on to a Suzuki coupling or other transformations.

The latter generated tertiary aromatic amines (68) using a double Petasis reaction of aniline with two equivalents of formaldehyde and an aryl or styrenyl boronic acid in refluxing toluene (Equation 26) (58). Yields were generally in the 60-96% range for a range of substituted anilines. The aniline could be replaced with 2-aminopyridine (27%) or 2-aminopyrazine (34%) to give the corresponding PBM products, albeit in lower yield.

Pyne and co-workers applied the PBM reaction at the start of a ten step chiral pool synthesis of the alkaloid calystegine B4 (Scheme 13) (59). (–)-D-lyxose, benzylamine and [(E)-2-phenylvinyl]boronic acid gave the aminotetrol in 82% yield. This intermediate was carried on through a RCM (ring-closing metathesis) reaction to give a 7-membered ring precursor for the final intramolecular aminal formation. A concise synthesis of zanamavir congeners based on the PBM reaction was reported by Norsikian, Beau, and co-workers (Scheme 14) (60). The key step involved the reaction of a diallyl or dibenzylamine with a vinylboronic acid and an unstable α-hydroxyaldehyde derived from (R)-glycidol (both prepared in two steps) in CH2Cl2/HFIP under thermal conditions or in CH2Cl2 with microwave irradiation. The product was obtained in 95% yield and carried on to the final product via an FeCl3·6H2O-catalyzed cyclization. 293 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 13. Synthesis of Calystegine B4.

Scheme 14. Preparation of Zanamavir Congeners. Rozwadowska and co-workers efficiently prepared the tetrahydroisoquinoline alkaloid (±)-calycotomine and its N-methyl analog 75 using the PBM reaction of an aminoaldehyde acetal with glycoaldehyde dimer and an electron-rich arylboronic acid, followed by a Pomeranz-Fritsch-Bobbitt cyclization (Scheme 15) (61). The overall yield for the three step sequence was 61%. Recently, a following report from the same authors described the synthesis of the related 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid in optically-active form by a similar approach using a chiral amine (62). Moderate stereoinduction (70:30 dr) was observed and the major enantiomer was enriched by fractional crystallization. 294 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. Synthesis of Calycotamine. Seeberger reported the synthesis of orthogonally-protected legionaminic acids (77) using a PBM reaction between an aldehyde, (E)-styrenylboronic acid, and an allylamine (Scheme 16) (63). The reaction proceeded in 76% yield at room temperature in ethanol to give the anti amino alcohol which was carried on to the final products.

Scheme 16. Preparation of Protected Legionaminic Acids. The Scheerer group recently presented a second-generation synthesis of the endophyte-derived (+)-loline alkaloids (81) using the PBM reaction of a pyrrolidine derived from a chiral pool starting material, (S)-4-amino-2hydroxybutanoic acid (Scheme 17) (64). Treatment with BF3·OEt2 promoted formation of the N-acyliminium ion, which reacted with the interesting methylpentanediol vinyl boronate 78 to give the desired product 80 as single diastereomer in good yield. 295 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 17. Petasis Reaction in Synthesis of Loline Alkaloids. Norsikian and Beau reported the use of an intramolecular PBM reaction on an advanced intermediate in the synthesis of ent-conduramine A1 (Scheme 18) (65). A functionalized boronic acid (82) was prepared in 9 steps from a protected ribose derivative and reacted with diallylamine in 4:1 ethanol/water at 80 ºC for 192 h to effect an intramolecular PBM reaction. The cyclized product 85 was obtained in 72% yield as a single diastereomer and converted to the final product 86 by palladium-catalyzed deprotection of the allyl groups. A similar route led to the related conduramine C4 in a shorter, six step sequence.

Scheme 18. Synthesis of ent-Conduramine A1.

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A formal synthesis of (+)-conduramine E and its enantiomer was reported by Ghosal and Shaw using a different PBM reaction (Scheme 19) (66). In this case, the α-hydroxyaldehyde 87 was prepared in five steps from methyl-α-D-galactopyranoside and reacted with t-butylamine and styrenylboronic acid in ethanol at 80 °C to yield diene intermediate 88. This intermediate underwent treatment with (BOC)2O and a subsequent ring-closing metathesis reaction to afford the conduramine core, followed by acid-catalyzed cleavage of the ketal protecting group to intercept an intermediate from a previous synthesis.

Scheme 19. Synthesis of Conduramine E.

Bouillon and Pyne synthesized the polyhydroxylated pyrrolidine alkaloids DMDP and DAB using the PBM reaction of a masked aldehyde (91) derived from L-xylose in four steps with E-styrenylboronic acid and benzylamine (Scheme 20) (67). The reaction proceeded with high diastereoselectivity to yield anti amino alcohol 92. Use of a fluorinated alcohol solvent such as hexafluoroisopropanol or trifluoroethanol was found to give higher yields than methanol or ethanol. Selective mesylation followed by cyclization provided a pyrrolidine which was smoothly carried on to the two natural products (93 and 94) via a 2 or 3 step sequence.

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Scheme 20. Synthesis of DMDP and DAB Alkaloids. A group at Bristol-Myers Squibb reported the synthesis of phenylpyrrolidine phenylglycine derivatives as inhibitors of Tissue Factor/Factor VIIa (TF-FVIIa) using the PBM reaction of an aminoisoquinoline with arylboronic acids and glyoxalate (Scheme 21) (68). The reactions proceeded in moderate to good yield affording a racemic phenylglycine intermediate (95) that was resolved by chiral HPLC after the final step in the sequence.

Scheme 21. Aminoisoquinoline Petasis Reaction.

Asymmetric Methods Many of the examples described above include the induction of relative or absolute stereochemistry directed by chiral centers in the substrates. Alternatively, 298 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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some groups have reported new examples and approaches to asymmetric PBM reactions using a chiral catalyst or auxiliary. The Hutton group reported the PBM reaction of substituted styrenylboronic acids and glyoxylic acid with Ellman’s tert-butylsulfinamide auxiliary as a chiral amine equivalent to produce β,γ-dehydrohomoarylalanine derivatives (97) in a highly diastereoselective fashion (Equation 27) (69). The reaction displayed a sensitive dependence on concentration. Yields improved to >94% from 55% when the reaction was run in CH2Cl2 at 0.33 M rather than 0.2 M. The authors suggested that this may be due in part to second-order kinetic effects combined with precipitation of the products at higher concentrations. The use of 10 mol % InBr3 as a Lewis acid additive was later reported by a different group to result in slight increases in diastereoselectivity under very similar conditions (70).

Schreiber and co-workers found that the PBM reaction of α-hydroxyaldehydes with secondary amines could be biased using 20 mol % of a BINOL-derived catalyst to favor the syn amino alcohol over the anti stereoisomer that is typically observed (Equation 28) (71). The reaction gave moderate to excellent diastereoselectivity and a detailed study of the interplay between the chiral centers in the amine and aldehyde with matched or mis-matched catalyst stereochemistry was also presented.

The use of BINOL-derived catalysts to promote the enantioselective Petasis reaction was later extended to salicylaldehydes by Yuan (72) and Shi (73). The latter found that the stereoselectivity was improved by the addition of 4Å MS. 299 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The Takemoto group explored an asymmetric PBM reaction of vinylboronic acids with anilines and glyoxamides in the presence of a thiourea catalyst (Equation 29) (74). The α-N-arylamino amide products (99) were obtained in good yield and 80-93% ee for a wide range of substrates, including electron-poor boronic acids.

Yuan and co-workers also investigated enantioselective PBM reactions using a thiourea catalyst (Equation 30) (75). Salicylaldehydes and cyclic secondary amines were reacted with aryl or vinylboronic acids to give the products in good yields and moderate to excellent stereoselectivity. An adjacent hydroxyl group on the aldehyde was required and the reaction was limited to primary or acyclic secondary amines.

Finally, a sui generis report emerged from the Hutton group describing variable stereoselectivity in synthesis of functionalized homoarylalanine derivatives via the PBM reaction of N-benzylphenylglycinol, glyoxylic acid, and styrenylboronic acids (76). The issue was traced to an unidentified impurity in the boronic acid sample purchased from a commercial vendor that afforded improved diastereoselectivity over cleaner batches prepared in-house. 300 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Diversity-Oriented Approaches Along with other multicomponent processes, the modular nature of the PBM reaction has been exploited to efficiently generate libraries of analogs. Some of these approaches take advantage of the functional groups in the products by using them for subsequent reactions in domino or cascade sequences. In this way, large numbers of compounds with diverse molecular structures can be rapidly accessed. The Schreiber group reported using the Petasis reaction followed by intramolecular 1,3-dipolar cycloadditions to prepare functionalized isoxazoles, isoxazolines, and isoxazolidines (Scheme 22) (77). The reaction of a lactol, aminoacetal, and aryl boronic acid in CH2Cl2 at room temperature proceeded in 79% yield with good diastereoselectivity. From here, alkylation of the amine and allylic alcohol rearrangement set the stage for nitrone or nitrile oxide generation and subsequent intramolecular cycloadditions to generate the products.

Scheme 22. Synthesis of Isoxazolidines.

Nielsen and co-workers employed a build-couple-pair strategy in which various alkene-containing components underwent PBM reactions to generate intermediates (103) that were then subjected to ring-closing metathesis (Scheme 23) (78). This yielded cyclic compounds (104-107) whose structure varied according to the placement of the alkenes in the starting materials. Two azepine products were further subjected to palladium-catalyzed isomerization to yield vinyl pyrrolidines. 301 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 23. Build-Couple-Pair Approach Using the Petasis Reaction.

The same group reported a second application of this approach using the PBM reaction of hydrazides, α-hydroxyaldehydes, and boronic acids to give acylhydrazido alcohols (Scheme 24) (79). These intermediates could be carried to the products (109-113) by RCM reactions as before, or via an intramolecular Diels-Alder (IMDA) reaction using a tethered furan moiety as the diene. Most recently, the Nielsen group has reported a new application of this methodology in which the initial furan cycloadduct (115) undergoes oxidative cleavage to a tetrahydrofuran dialdehyde (116) which is in turn a substrate for reduction and Mitsunobu reaction or reductive amination with a primary amine to give a bridged azepine (Scheme 25) (80). Further elaboration of these compounds was also presented. Using this methodology, a library of 1617 analogs was prepared and submitted for high-throughput screening. Meanwhile, the Beau group has explored tandem reactions of PBM adducts (119) derived from dienylboronic acids, α-hydroxyaldehydes (including sugars), and diallylamine (Scheme 26) (81, 82). Here, an intramolecular Diels-Alder reaction yielded bicyclic structures (120) with pendant moieties that were used for further transformations: cross-metathesis reaction of the second N-allyl group 302 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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with methyl vinyl ketone was followed by intramolecular conjugate addition to give the interesting polycyclic products (121) shown below. This sequence could be carried out in an impressive one-pot procedure with only moderate diminution in yield compared to the stepwise process. A subsequent paper expanded the scope of this approach to include a wider range of secondary amines and dienylboronic acids. NMR studies and DFT calculations were used to assign and explain the observed stereochemistry in the Diels-Alder reactions. Finally, a handful of miscellaneous reports have appeared recently in the literature. One used the Petasis reaction as a derivatization method for the HPLC analysis of glyoxylic acid in urine samples (83). Two others presented adaptations of the reaction for use in the undergraduate organic teaching laboratory, a development that speaks clearly to its reliability and ease of use (84, 85).

Scheme 24. Synthesis and Reaction of Acyl Hydrazido Alcohols. 303 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 25. Oxidative Cleavage of Petasis Product and Cycloaddition.

Scheme 26. Petasis Sequence with Tandem Reactions. 304 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Conclusion The Petasis borono-Mannich reaction has emerged over the past two decades as a valuable method for the synthesis of biologically-relevant molecules. The favorable features that led to its adoption by the synthetic organic chemistry community will continue to recommend it for extensive use in the future. Further advances in the scope of the reaction, asymmetric variants, and applications to challenging synthetic problems will undoubtedly follow as well.

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Chapter 10

Copper-Catalyzed Coupling Reactions of Organoboron Compounds Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch010

Astha Verma and Webster L. Santos* Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States *E-mail: [email protected]

Copper-catalyzed coupling reactions provide a unique and inexpensive alternative to noble transition-metal catalyzed cross-couplings for the construction of carbon-carbon and carbon-heteroatom bonds. Significant progress has been made using organoboron reagents as the coupling partners in these copper-catalyzed reactions. Important contributions in the field ranging from seminal work to recent advances in the area of copper-catalyzed coupling reactions using organoboron compounds are discussed.

Introduction Transition metal-catalyzed cross-coupling reactions have emerged as a powerful tool to achieve ubiquitous C-C and C-heteroatom bond formations. The area of cross-coupling reactions is closely associated with palladium catalysis due to the monumental development of palladium-catalyzed cross-coupling reactions in the last half of the 20th century. The rapid development of palladium-catalyzed reactions is attributed to their low catalytic loading, mild reaction conditions, and high product yields. However, a careful search of the literature reveals that copper catalysis is actually several decades older than palladium catalysis (1–6). In 1901, Ullmann reported the homo-coupling of bromo-2-nitrobenzene in the presence of copper powder to give the corresponding biaryl product (7). The work was later extended to carbon-nitrogen (C-N) and carbon-oxygen (C-O) bond formation (1, 2). An important limitation of these copper-mediated couplings was the requirement of stoichiometric amounts of copper and harsh conditions © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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(high reaction temperatures ≥ 200 °C) (8). A major breakthrough was achieved in the early 21st century when Buchwald demonstrated that incorporation of chelating ligands such as a diamine allows for the coupling between aryl halides and amides to be performed under milder conditions such as lower temperature, non-polar solvents, and most importantly in the presence of catalytic amounts of copper (9). As a consequence, a resurgence in copper-catalyzed reactions ensued. These developments have been summarized in excellent reviews (10–20); however, none exclusively focused on copper-catalyzed cross-coupling reactions with organoborons for C-C and C-heteroatom bond construction. Organoboron compounds benefit from their air- and moisture stability, non-toxicity, and commercial availability (21). Further, copper is abundant, inexpensive, and can access four oxidation states ranging from 0 to +3, which makes it a versatile catalyst that can undergo one electron or two electron processes (22). This chapter focuses on C-C and C-heteroatom (N, S, O) bond formations utilizing copper in catalytic amounts. Reactions employing stoichiometric amounts of copper are discussed when pertinent to the development of catalytic processes. Furthermore, both traditional cross-coupling reactions and oxidative cross-coupling reactions are reviewed. In traditional coupling reactions, a nucleophile couples to an electrophile in the presence of a catalyst. However, in an oxidative coupling a nucleophile couples to another nucleophile in the presence of a catalyst and an oxidant (23). Reactions involving miscellaneous C-heteroatom bond formations such as C-P, C-Se, C-Te; where P = phosphorus, Se = selenium and Te = tellurium are excluded (20, 22).

Bond Formation Coupling of Aryl Organoborons with Aryl Substrates In 2002, Thathagar et al. first reported copper or copper-based nanocolloid catalyzed C-C cross-coupling of an aryl halide with aryl boronic acids (24). However, the substrate scope of their investigation was limited to phenyl iodide and phenyl boronic acid when copper nanocolloid was used as the catalyst (Equation 1) (24, 25).

Demir and co-workers reported the first example of oxidative self coupling of aryl boronic acids to give symmetrical biaryls in the presence of Cu(OAc)2 and oxygen as the oxidant (Scheme 1) (26). The homocoupled products were obtained in moderate to good yield. The reaction was sensitive to steric effects, and 2,6-disubstituted boronic acid substrates did not undergo coupling. 314 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 1. Copper-Mediated Oxidative Dimerization of Aryl Boronic Acids (26). An improved protocol was developed by Kirai and co-workers (27). Homo-coupling of aryl boronic acids was achieved in the presence of 2-4 mol % of copper(II) bis-μ-hydroxo adduct with 1,10-phenanthroline (Phen) ligand (Scheme 2). Their protocol’s success was attributed to the use of a binuclear (μ-hydroxido)copper(II) complex that facilitated transmetalation. Twenty five different substituted aryl boronic acids were investigated to afford the desired biaryls in 19-92% yields. Low yields were observed in case of ortho-substituted aryl boronic acids due to substantial protodeboration.

Scheme 2. Homocoupling of Aryl Boronic Acids Catalyzed by 1,10-Phenanthroline-Ligated Copper (II) Complex (27). Later, Li and co-workers reported a CuI/DABCO system (DABCO = 1,4diazabicyclo[2.2.2]octane) for efficiently coupling aryl iodides and aryl bromides with aryl boronic acids (Scheme 3) (28). A diverse range of aryl iodides underwent cross-coupling in the presence of CuI (10 mol %), DABCO (20 mol %) using Cs2CO3 in DMF at 125-130 °C. The desired products were obtained in good yields; 315 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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however, aryl bromides were inefficient coupling partners. Hence, the reaction was performed using stoichiometric quantities of CuI and tetra-n-butylammonium bromide (TBAB) as an additive at elevated temperature (150 °C) to achieve the desired products. Aryl chlorides remained unreactive under the given reaction conditions, and only trace amount of product was obtained. It was found that this catalytic system could be extended to include vinyl halides (I, Br) as the coupling partner (29). Subsequently, a copper-catalyzed ligand-free TBAB promoted crosscoupling of aryl halides (I, Br) with aryl boronic acid in DMSO was also developed (30).

Scheme 3. Copper-Catalyzed Cross-Coupling Reaction of Aryl Halides and Aryl Boronic Acids (28). Mao et al. developed a reusable catalytic system consisting of copper powder in polyethylene glycol 400 (PEG 400) for cross-coupling of aryl halides with aryl boronic acids (Scheme 4) (31). PEG is speculated to play the dual role of solvent and ligand for the copper catalyst (31). Coordinating alcohols such as ethanediol and propanediol were also considered as alternatives but gave poor results. Aryl iodides conveniently reacted under the optimized reaction conditions to yield the cross-coupled products in excellent yields. Molecular iodine (KI and CuI gave inferior results) was used as an additive when aryl bromides and aryl chlorides were used as substrates for in-situ formation of aryl iodides.

Scheme 4. Copper-Catalyzed Cross-Coupling Reaction of Aryl Halides and Aryl Boronic Acids (31). Fu and co-workers disclosed the copper-catalyzed Suzuki-Miyaura cross-coupling of aryl boronic acids with primary and secondary benzyl halides (Scheme 5) (32). Optimization of the reaction conditions using benzyl chloride (1) and phenyl boronate (2) as the model substrates revealed that CuI (20 mol %), and diketone ligand (L1, 20 mol %) in N-methylcaprolactam (NMCPL) formed the coupling product (3) in high yields. Nickel or palladium contamination in the 316 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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catalyst was ruled out by conducting reactions using Pd(OAc)2 or NiI2 that gave the desired product in low yield. Investigation of primary benzyl halide substrate scope demonstrated that functional groups on the aryl ring such as ethers, esters, trifluoromethyl, olefins, and halogens were tolerated under the reaction conditions (Scheme 5A). Competition experiments established the selectivity for benzyl C-X (X = Cl, Br) over alkyl C-X (X = OTs, Br, I; OTs = tosylate). Notably, sterically hindered and β-hydrogen containing secondary benzyl substrates gave the cross-coupled products in good yields without observable β-hydride elimination (Scheme 5B). Subsequently, they also investigated a copper-catalyzed cross-coupling of alkyl/aryl epoxides and N-sulfonyl aziridines with aryl boronate esters (33). Ring opening of epoxides and aziridines gave the desired secondary alcohols and secondary amines in good yields (33).

Scheme 5. Copper-Catalyzed Cross-Coupling of Primary (A) and Secondary Benzyl Halides (B) with Arylboronates (32).

While Pd- (34–37), Ni- (38–44), and Fe- (45) catalyzed coupling of alkyl halides with organoboron compounds have been widely developed; the analogous reactions using copper catalysts were unprecedented. Liu et al. were the first to report the coupling of primary halides and pseudo halides containing C-X bond (X= I, Br, Cl, OMs, and OTs; Ms = methanesulfonyl, Ts = p-toluenesulfonyl) with organoboron compounds using CuI in the presence of LiOtBu as the base 317 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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in DMF (Scheme 6) (46). Catalysts such as CuBr, CuI, Cu(OTf)2, Pd(OAc)2, NiI2 and bases such as Cs2CO3, K3PO4, CsOAc, NaN(SiMe3)2, KOtBu, NaOtBu, Li2CO3, LiOMe, LiOEt were explored as alternatives. Electron-rich and electron-deficient aryl rings and heterocycles were tolerated on the boronate ester substrate. Different boron-containing derivatives (Scheme 6, compounds 9-11) were also viable coupling partners. Higher temperatures were employed when alkyl chlorides were used as substrates. Furthermore, the reactivity of different leaving groups on the alkyl halides was tested using competition experiments and revealed the following activity trend: I > Br > OTs > OMs > Cl (Table 1). Unlike nickel-catalyzed Suzuki coupling of alkyl halides, the possibility of a radical mechanism was excluded (39).

Scheme 6. Copper-Catalyzed Cross-Coupling of Alkyl Electrophiles with Aryl Boronates (46).

In 2011, Brown and co-workers reported a copper-catalyzed cross-coupling of aryl iodides with aryl boronates (Scheme 7A) and demonstrated its application in carboboration of alkynes and allenes (47). The foundation of the cross-coupling was built on a putative catalytic cycle (Scheme 7B). According to the investigators, CuAr1 intermediate formed by initial transmetalation of aryl boronic acid (Ar1B(OR)2) with Cu catalyst could undergo oxidative addition followed by reductive elimination to form the desired cross-coupled product Ar1-Ar2. It should be noted that in palladium-catalyzed Suzuki-Miyaura cross-coupling, oxidative addition of Ar2-X precedes transmetalation with Ar1-B(OR)2. CuCl with Xantphos as the ligand effectively catalyzed the C-C coupling between a broad range of aryl halides and aryl boronate esters at 80 °C in toluene within 15 h. In the case of sterically hindered aryl boronic esters, Cy3PCuCl was used.

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Table 1. Selectivity of Various Alkyl Electrophiles in Competition Experiments (46).

Scheme 7. General Reaction Scheme (A) and Catalytic Cycle (B) for Copper-Catalyzed Cross-Coupling of Cryl Boronates with Aryl Halides (47).

319 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Coupling of Aryl Boronic Acid Derivatives with Alkyne Substrates

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In 2008, Mao and co-workers reported the CuBr-catalyzed cross-coupling of aryl boronic acids with terminal alkynes (Scheme 8) (48). Although the desired coupling products were obtained in low yields, it offered an unprecedented protocol for performing Sonogashira reaction using terminal alkynes and aryl boronic acids under phosphine- and palladium-free conditions.

Scheme 8. Copper-Catalyzed Sonogashira Coupling Reactions of Alkynes with Aryl Boronic Acids (48).

Subsequently, a mild, efficient and ligand-free protocol was developed by Pan et al. for Sonogashira coupling of terminal alkynes with aryl boronic acids (Scheme 9A) (49). Notably, electron-deficient terminal alkynes gave the desired cross-coupling product in moderate to good yield in the presence of CuI as the catalyst and silver (I) oxide as the oxidant. Although the reaction showed no sensitivity to electronic effects of the boronic acids, diminished yields were observed with sterically hindered boronic acid substrates. Remarkably, no homocoupling by-products were obtained in the reaction. The proposed mechanism proceeds through the formation of a Cu(I)-alkyne complex followed by oxidation to a Cu(III)-alkyne complex using Ag2O that undergoes transmetalation, and subsequent reductive elimination to give the desired product (Scheme 9B). Rao and co-workers used molecular oxygen as the oxidant for cross-coupling of terminal alkynes with aryl boronic acids at room temperature, thereby limiting the use of metal oxidants (Scheme 10) (50). Depending on the substrate under investigation, either pyridine or a 1:1 ratio of pyridine and methanol as the additive with Cu2O open to air afforded the desired internal alkynes in good to excellent yields. Aryl boronic acids containing halogens, aldehydes, ethers, and nitro functional groups were tolerated and terminal alkynes containing esters, alcohols, and amino groups performed well under the reaction conditions. 320 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 9. Ligand-free Copper-Catalyzed Sonogashira Reactions of Alkynes with Aryl Boronic Acids (A) and the Proposed Catalytic Cycle (B) (49).

Scheme 10. Copper-Catalyzed Aerobic Oxidative Coupling of Terminal Alkynes with Aryl Boronic Acids (50). Similarly, Yasukawa and co-workers reported the cross-coupling of alkynes with aryl boronic acids utilizing molecular oxygen as the oxidant and low catalytic loading of copper catalyst (0.15-3.0 mol % of CuBr) in the presence of 2,6-lutidine as the additive (Equation 2) (51). Notably, the concentration of the reaction and catalyst loading dramatically affected the outcome of the reaction. The high catalyst loading as well as reaction concentration promoted 321 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

the undesired homocoupling of alkyne and aryl boronic acid substrates. Further, amongst the pyridine bases investigated only 2,6-lutidine gave good results.

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Coupling of Aryl Organoborons with Heteroarene Substrates Shen and co-workers developed a one-pot protocol for C-H arylation of pyridine N-oxides with aryl boronate esters to give 2-aryl pyridines (Equation 3) (52). Amongst a variety of copper catalyst and bases screened, Cu(acac)2, t-BuOK, and toluene in air gave the best results. 2-Unsubstituted pyridine N-oxides underwent the cross-coupling with aryl boronic acids smoothly; however, low yields were obtained with electron deficient N-oxides such as 4-cyano pyridine N-oxides. Further, the reaction was found sensitive to steric crowding in aryl boronate ester substrates.

Yang et al. reported the copper-catalyzed oxidative arylation of benzoxazoles, benzothiazoles, oxazoles, and thiazoles with aryl boronate esters using molecular oxygen as the oxidant (Scheme 11) (53). Amongst the catalyst and solvents investigated, CuCl and DMF gave the best yields. Lower yields were obtained when aryl boronate esters were replaced with aryl boronic acids. The reaction of oxazoles and thiazoles with aryl boronate esters required 80 °C and t-BuONa as the base while full conversion was observed at 40 °C when benzoxazole and benzothiazole were used as substrates. A wide range of electron-deficient and electron-rich boronate esters were also investigated under their reaction conditions and the desired products were obtained in good to excellent yields.

Scheme 11. Copper-Catalyzed Oxidative Coupling of Heteroarenes with Aryl Boronate Esters (53). Coupling of Alkyl Organoborons with Alkenyl- and Alkyl Substrates Liwosz and Chemler reported copper-catalyzed C(sp3)-C(sp2) oxidative Heck-type coupling of alkyltrifluoroborates and vinyl arenes (Scheme 12) (54). 322 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Cu(OTf)2/1,10-phenanthroline in the presence of MnO2 as the terminal oxidant effectively promoted the cross-coupling of potassium benzyltrifluoroborate and 1,1-diphenylethylene (DPE) in high yields. Wide substrate scope with respect to vinyl arenes and alkylborates was investigated. Although, alkyltrifluoroborates gave the cross-coupled product in good yields, aryl or vinyltrifluoroborates were unreactive under their reaction conditions.

Scheme 12. Copper-Catalyzed Oxidative Coupling of Alkyltrifluoroborates and Vinyl Arenes (54). Yang and co-workers disclosed the C(sp3)-C(sp3) coupling of alkyl 9-BBN (9-BBN = 9-borabicyclo[3.3.1]nonane) organoboron compounds with primary alkyl halides using a CuI/LiOtBu catalytic system (Scheme 13) (46). Alkyl boronate esters were not suitable coupling partners and limited alkyl 9-BBN substrate scope was explored in their report. Further, 9-BBN organoboron compounds are difficult to handle due to their high reactivity and they have limited commercially availability (36).

Scheme 13. Copper-Catalyzed Cross-Coupling of Alkyl 9-BBN Reagents with Primary Electrophiles (46). To address this problem, Zhang et al. developed a C(sp3)-C(sp3) bond formation utilizing gem-diborylalkanes and alkyl halides in copper-catalyzed/ promoted conditions leading to alkyl boronic esters in moderate to good yields (Scheme 14) (55). In a model study, it was shown that the coupling of n-hexyl bromide and diborylmethane proceeded smoothly in the presence CuI (20 mol %), LiOtBu (3 equiv) as the base and tetra-n-butylammonium iodide (TBAI, 1 equiv) 323 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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as the additive in DMF at 60 °C (Scheme 14A). Tosylates were also efficient. However, in the case of more reactive alkyl iodides, milder conditions employing 10 mol % of CuI and LiOMe (3 equiv) as the base at 40 °C or room temperature provided the desired transformation. Broad substrate scope with respect to the primary alkyl electrophiles bearing functional groups such as acetals, olefins, esters, cyano, heterocylces (thiophene, phthalimide) were tolerated. Stoichiometric amounts of CuI and 4 equivalents of the LiOtBu were sufficient for the coupling of 1,1-diboryl alkanes to give the secondary alkyl boronic esters (Scheme 14B). However, the synthesis of tertiary alkylboronic esters required 3 equivalents of CuI and 8 equivalents of the LiOtBu (Scheme 14C). In 2015, the scope of the reaction was extended to include primary/secondary/tertiary halides with allyl boronate esters (Scheme 15) (56). In the presence of 10 mol % CuI and 2 equivalents of LiOtBu the cross-coupling product was formed in good yield. Primary alkyl iodides and bromides were suitable substrate; however, the corresponding chlorides proved to be unreactive. Low product yield was obtained when substrates containing secondary amines were used due to the presence of an acidic N-H hydrogen. Unactivated alkanes prone to β-hydride elimination were also viable substrates for coupling with allyl boronate esters (57, 58) when a catalytic amount of TMEDA was used as an additive.

Scheme 14. Cross-Coupling of Gem-diborylalkanes with Non-activated Primary Alkyl Halides (55). 324 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. Cross-Coupling of Allyl Boronic Esters with Primary Alkyl Halides (56).

Recently, Li et al. developed a copper-catalyzed oxidative coupling of aryl boronic acids with alkyltrifluoroborates (Equation 4) (59). Remarkably, cross-coupling of 4-methoxyphenyl boronic acids with potassium 3-phenylpropyl trifluoroborate using Cu(OAc)2, Ag2O as the oxidant, and sodium methoxide as the base in the presence of water effectively gave the desired product 29 in 86% yield within 10 mins at room temperature. In the absence of water, lower yields were observed. Water was thought to convert the trifluoroborate salt into the more reactive boronic acid derivate. A wide range of substrates were tolerated. Mechanistically, the transformation was proposed to proceed through a single electron transmetalation step. As shown in Scheme 16, transmetalation of the aryl boronic acid with the copper catalyst generates a ArCu(II)X species. A second transmetalation of an alkyl radical generated by the oxidation of an alkyl trifluoroborate salt generates a ArCu(III)RX complex. This hypervalent intermediate undergoes facile reductive elimination to furnish the desired product.

Trifluoromethylation and Carboxylation of Aryl- and Alkenyl Organoborons Xu et al. reported a copper-catalyzed trifluoromethylation of aryl boronic acids using an electrophilic trifluoromethyl cation source (Scheme 17) (60). Earlier strategies for trifluoromethylation of aryl boronic acids required stoichiometric transition metal catalyst and trifluoromethylating agent (61–64). The reaction of the model substrate diphenylboronic acid with (trifluoromethyl)dibenzothiophenium triflate as the trifluoromethylating reagent in the presence of CuI, 2,4,6-trimethylpyridine, and sodium acetate gave the desired product in only 4% yield. The low yield was attributed to the formation of 325 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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by-products such as protodeborated starting material, homo-coupled product and diphenyl acetate. After an extensive screen of copper catalyst and nitrogen ligands, CuOAc and 2,4,6-trimethylpyridine in dimethylacetamide gave the desired product in 80% yield. 2,4,6-Trimethylpyridine acted as ligand and a base, thereby dramatically decreasing the formation of diphenyl acetate by-product. 1.0:1.6 ratio of the diphenyl boronic acid to trifluoromethylating reagent was essential to obtain high yields. Further, no reaction was observed in the absence of copper catalyst. Electron donating and electron withdrawing groups on aryl boronic acids were tolerated under the reaction conditions. Un-protected functional groups such as OH and NH, carbonyl, chloro, ortho-substituted or heteroaryl boronic acids gave the desired product in good yield. Trifluoromethylation of phenyl vinyl boronic acids demonstrated their utility as substrates. Furthermore, the reaction proved insensitive to moisture. Later, Li et al. demonstrated the copper-catalyzed trifluoromethylation of aryl- and vinyl boronic acids using CF3 radical (Scheme 18) (65). In situ generation of CF3 radical was achieved through reaction of Langlois reagent (CF3SO2Na) and TBHP (t-BuOOH). The reaction of aryl boronic acids with CF3 radical in the presence of Cu(OAc)2, 2,4,6-collidine as the ligand, imidazole as the additive in DCM and water mixture at room temperature gave the desired product in good yield. Further, improved chemoselectivity and yield was observed in the presence of slightly acidic conditions and higher TBHP to NaSO2CF3 ratio. Aryl boronic acids with electron-donating functional groups gave the desired products in good yields; however, lower yields were observed with aryl boronic acids with ortho-substitution and electron-withdrawing substituents. Higher catalyst loading was necessary with halide substituted aryl boronic acids. Although heteroaryl boronic acids yielded the trifluoromethylated product in moderate yield; no reaction was observed when alkyl boronic acids were used as substrates. Further, vinyl boronic acids were viable substrates for trifluoromethylation and demonstrated exclusive (E) stereoselectivity when (E)-vinyl boronic acids were employed. On the contrary, (Z)-vinyl boronic acids gave mixture of (Z) and (E) product owing to higher stability of (E)-isomer. Takaya et al. reported a Cu(I)-catalyzed carboxylation of aryl- and alkenyl boronic esters (Scheme 19) (66). Amongst the catalyst and ligands screened, 5 mol % of CuI and 6 mol % of bisoxazoline in the presence of 3 equiv of CsF in DMF at 90 °C gave the desired aryl carboxylic acids in good yields. In the case of heteroaryl boronic esters, 1 mol % of CuI at 60 °C was sufficient to obtain the corresponding products in high yields. When alkenyl boronic esters were used as substrates, ligandless conditions in the presence of 3 mol % of CuI efficiently promoted the reaction to give the corresponding α,β-unsaturated carboxylic acids in good yields. Both β-alkyl and aryl substituents were tolerated on alkenyl boronic acids. Moreover, under their optimized conditions, a number of substituted aryl and alkenyl boronic esters that resulted in no carboxylated products under their complimentary Rh(I)-catalyzed conditions, gave the desired products in good yields.

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Scheme 16. Catalytic Cycle for Oxidative Copper-Catalyzed Cross-Coupling of Aryl Boronic Acids with Alkyltrifluoroborates (59).

Scheme 17. Copper-Catalyzed Trifluoromethylation of Aryl Boronic Acids (60).

Scheme 18. Copper-Catalyzed Trifluoromethylation of Aryl and Vinyl Boronic Acids (65).

327 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 19. Copper-Catalyzed Carboxylation of Aryl and Alkenyl Boronic Esters (66).

Later, Ohishi and co-workers also developed carboxylation of aryl- and alkenyl boronic esters catalyzed by N-heterocyclic carbene (NHC) copper complex (Scheme 20) (67). The carboxylation of 4-methoxylphenyl boronic ester with CO2 using 5 mol % of CuCl with 5 mol % of IPr·HCl in the presence of 2 mmol of KOt-Bu at 70 °C in THF yielded the desired product in quantitative yield. The catalyst loading was reduced to 1 mol % when isolated [(IPr)-CuCl] complex was used as the catalyst with 1.05 mmol of KOt-Bu. Further, no reaction was observed in the absence of Cu catalyst, or NHC ligand or KOt-Bu. The reaction showed insensitivity to substituent effect on the aryl ring of boronic ester substrate. A wide range of substituents were tolerated under the reaction conditions such as epoxy, carbonyl, vinyl, propargyl ether, and halides. Additionally, boronic esters including heteroaryl derivatives, alkenyl, and sterically hindered aryl groups were viable substrates for carboxylation. Later, they also reported NHC copper-catalyzed carboxylation of alkyboranes with CO2 (68). Alkyl boranes synthesized from insitu hydroboration of terminal alkynes with 9-BBN-H underwent carboxylation to give the corresponding carboxylic acids in good yields.

Scheme 20. Copper-Catalyzed Carboxylation of Organoboronic Esters (67). 328 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Around the same time, Ohmiya and co-workers reported a similar protocol for synthesis of alkynoic acids from carboxylation of in-situ generated alkylboranes (alkyl-9-BBN) using Cu(OAc), 1,10 phenanthroline and KOt-Bu at 100 °C for 12 h (Scheme 21) (69). Copper catalysts such as Cu(OAc)2, CuCl(IPr) lead to lower product yield; although CuCl showed efficacy similar to Cu(OAc). No reaction was observed in the absence of KOt-Bu. Further, temperature control was crucial to avoid deborylation of the alkylborane starting material. Extensive substrate scope with respect to the terminal alkenes bearing functional groups such as siloxy ester, acetal, methoxy, bromo, phthalimide and benzyloxy groups was tolerated. β-Branched terminal alkenes such as 1,1-diphenylethylene were viable substrates for the reductive carboxylation protocol; however, secondary alkyl boranes synthesized from internal alkenes were unreactive under the reaction conditions.

Scheme 21. Copper-Catalyzed Carboxylation of Alkylboranes (69).

Carbon-Heteroatom (N, O, S) Cross-Coupling In 1903, Ullmann reported the condensation of aryl halides with phenols, and anilines for the construction of C-O, and C-N bonds (Scheme 22) (1, 2, 10, 11, 70). Although pioneering, the major drawback of this protocol was the harsh reaction conditions involving elevated temperature, strong base, and the need for a stoichiometric amount of copper to achieve the required transformations. In 1998, the introduction of boronic acids as coupling partners for N- and O- nucleophiles revolutionized copper-mediated heteroatom arylation chemistry (10). In a series of independent publications, Chan (71), Lam (72), and Evans (73) reported copper-promoted, simple and mild routes for achieving N- and O- arylation using aryl boronic acids as the electrophilic partner. These groundbreaking reports marked the renaissance of copper-mediated heteroatom-carbon coupling (10). Copper-promoted, carbon-heteroatom cross-coupling (where copper is used stoichiometrically) has recently been reviewed and is beyond the scope of this chapter (74). However, a few reactions will be discussed in detail when pertinent to the discussion. 329 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 22. Ullmann Carbon-Heteroatom Cross-Coupling (1, 2).

C-N Bond Formation Nitrogen-containing heterocycles and aromatic amines are important structures in agrochemical and pharmaceutical industries (75). Several methods have been reported for the construction of these compounds. For a long time, synthetic chemists relied on the palladium-catalyzed amination protocol developed by Buchwald and Hartwig; however, the high cost and moisture sensitivity associated with palladium catalysis is a major road block in the scalability of these reactions (76, 77). Therefore, more economical alternatives such as copper have attracted the attention of chemists (11). Chan et al. (71) developed a mild, Cu(OAc)2-promoted, room temperature protocol for the cross-coupling of N-nucleophiles with aryl boronic acids. The substrate scope for this novel methodology ranged from amines, anilines, amides, imides, ureas, carbamates to sulfonamides. The nature of the substrate and the substituent on aryl boronic acid played a crucial role in determining the yield of the reaction. Further, the reaction was highly dependent on the choice of the amine base such as triethylamine and pyridine. However, the optimal base is difficult to determine since no clear substrate-based trend emerged from their study and no reaction optimization was conducted. In a concurrent publication, Lam et al. reported the cross-coupling of aryl boronic acids with a wide range of N-heterocycles such as imidazoles, pyrazoles, triazoles, tetrazoles, benzamides, and indoles using stoichiometric quantities of Cu(OAc)2 and pyridine (Scheme 23) (72). While the reaction has a wide substrate scope, less nucleophilic heteroarenes such as triazoles 32 and tetrazoles 33 were problematic. Symmetrical diaryl ether 38 was observed as by-product due to the oxidation of p-tolyl boronic acid 36 to p-cresol 37 and the subsequent reaction of p-cresol 37 with p-tolyl boronic acid 36 (Scheme 24). The by-product formation was alleviated by introducing 4Å molecular sieves to the reaction. 330 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 23. N-Arylation of Aryl/Heteroaryl Rings (72).

Scheme 24. Formation of Biphenyl Ether (38)

Following these pioneering discoveries, numerous reports emerged during the last 17 years for N-arylation or N-alkylation of sulfonamides (78, 79), Oacetyl hydroxamic acids (80), amines (81–85), α-amino esters (86), anilines (82, 83, 87–90), heterocylces (79, 91, 92), and sulfonimidamides (93) with aryl/alkyl 331 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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boronic acids using stoichiometric or more quantities of copper catalyst. These reports are beyond the scope of this chapter. Although the use of aryl boronic acids was a substantial improvement over previously reported methods, N-arylation of imidazoles reported by the Chan and Lam group at Dupont required more than equivalent amounts of Cu(II) salts, long reaction times, and large excess of the amine base and aryl boronic acid (71, 72). Collman et al. were the first to report N-arylation of imidazoles using a catalytic amount of Cu(OH)Cl•TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenediamine), providing an excellent substitute for the Cu(II) salt and amine base (Scheme 25) (94). Oxygen was crucial for the regeneration of the catalyst in the catalytic cycle. Molecular oxygen has been speculated to aid in the oxidation of Cu(II) to Cu(III). The higher oxidation state of Cu(III) facilitates the reductive elimination to give the cross-coupled product (95, 96). Addition of pure oxygen gave a high yield of the N-arylated imidazole product while slightly lower yields were obtained when pure O2 was replaced by air. No product formation occurred under a N2 atmosphere. Further, a 2:1 ratio of aryl boronic acid and imidazole with 10 mol % of the catalyst in anhydrous dichloromethane proved optimal for the C-N coupling reaction.

Scheme 25. Copper-Catalyzed N-Arylation of Imidazole Using [(Cu(OH)•TMEDA)]2Cl2 (94). 332 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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As shown in Scheme 25, a range of aryl boronic acid substrates with varying electronic and steric properties were efficient for this catalytic C-N coupling, which afforded products in good to excellent yields. To further improve the above reaction, Collman and co-workers studied the effect of different bidentate nitrogen ligands (sp2-N, sp3-N) and tested Cu(I) salts with various counter anions (Cl−, Br−, CI−, −OTf) for N-arylation of imidazoles. From their study, it was evident that TMEDA was the most efficient ligand for the coupling reaction (97). In search of greener alternatives they also investigated the same reaction with the same substrates in water (98); however, slightly lower product yields were observed. Furthermore, neutral pH proved optimal for the reaction as acidic and basic pH resulted in diminished yields. Following these studies, Wang and Gogoi et al. demonstrated the cross-coupling of aryl boronic acids with imidazole and anilines, respectively, in water using Cu(II)-salen type complexes (99, 100). In addition, there are few reports where the N-arylation of imidazoles with aryl boronic acids was carried out in protic solvents (101–103). Rossi et al. successfully performed the cross-coupling of primary amides with primary alkyl boronic acids in t-butanol (Equation 5) (104). Due to their lack of reactivity towards transmetalation, they were not widely explored in Chan-Lam coupling (105). As a consequence, the substrate scope with respect to alkyl boronic acids in these couplings were limited to methyl or cyclopropylboronates to alleviate β-hydride elimination (79, 87, 88, 106). Remarkably, use of the mild base NaOSiMe3 and di-tert-butyl peroxide (DTBP) as the oxidant in the presence of CuBr efficiently gave the desired secondary amides in moderate to good yield. In a separate report, Won-suk Kim’s group reported an open-to-air, room temperature Chan-Lam coupling of sulfonyl azides with aryl/heteroaryl boronic acids in methanol that proceeded to completion within 2 h (71, 72, 107). As an extension of their work, N-aryl carbamates were synthesized by reacting azidoformates and boronic acids under similar conditions (108). The application of N-aryl carbamates was demonstrated in the synthesis of N-aryl N′-ureas via a two-step, one-pot reaction by reacting N-aryl carbamates with aluminum−amine complexes.

Lam et al. studied the effect of stoichiometric oxidants such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), pyridine N-oxide (PNO), and O2 on the catalytic cross-coupling of amines and N-heterocycles with aryl and vinyl boronic acids (109). However, the ideal oxidant varied with the choice of amine substrate (109). Subsequently, Buchwald et al. reported the coupling of aryl boronic acids with amines using Cu(OAc)2, 2,6 lutidine, and myristic acid (n-C13H27COOH) as the additive at room temperature (Scheme 26) (75). According to the authors, myristic acid increased the solubility of the copper catalyst, thereby increasing the reaction rate. Further, vigorous stirring of the reaction mixture presumably resulted in improved oxygen uptake for oxidation 333 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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of in-situ generated Cu(I) catalyst to Cu(II) and larger volume (100 mL vs 2 mL) of solvent was essential for complete conversion. Substrates such as substituted anilines provided the diarylamine products in good to excellent yields; however, the coupling of alkyl amines gave the coupled N-alkyl anilines in only moderate yields (75).

Scheme 26. Copper-Catalyzed Cross-Coupling of Amines with Aryl Boronic Acid (75).

Sasaki et al. employed the above developed protocol for the synthesis of N-aryl aziridines by cross-coupling N-H aziridines with aryl boronic acids (110). With the resurgence of interest in visible light photocatalysis, Kobayashi modified Buchwald’s conditions (75) and reported a visible-light mediated photoredox cross-coupling of anilines with aryl boronic acids that is catalyzed by a copper (II) and an iridium-based photocatalyst (Equation 6) (111). Optimization of the previously reported reaction conditions revealed that fac-[Ir(ppy)3] as a co-catalyst with Cu(OAc)2 in a 1:1 mixture of toluene and acetonitrile (MeCN) under blue LED irradiation was optimal. Substrates such as electron-deficient boronic acids that were unsuccessful under traditional Chan-Lam conditions were viable substrates for visible-light-mediated reactions. A range of primary aryl amines with electron-donating and electron-deficient functional groups were coupled with electron-deficient aryl boronic acids and in each case the desired N,N-diaryl amines were obtained in moderate to excellent yields. However, 2-chlorophenyl boronic acid was a poor substrate under their reaction conditions. No reaction was observed in the absence of the iridium photocatalyst and blue LED.

Owing to the low yield of aliphatic amines under previously reported copper promoted cross-coupling reactions, Quach and Batey devised a ligand- and base free Cu(II)-catalyzed C-N cross-coupling of aliphatic amines and anilines with aryl boronic acids and potassium aryltrifluoroborate salts in the presence of 4Å molecular sieves and oxygen (Scheme 27A) (112). Trifluoroborate salts offer 334 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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several advantages such as air and moisture stability. Many are commercially available and can be stored for extended periods of time under atmospheric conditions. Further, they can be conveniently prepared from the corresponding boronic acids using KHF2 (113). The investigators attributed the low yields of C-N cross-coupling of aliphatic amines under standard Chan-Lam’s and Buchwald’s coupling conditions to the formation of diphenylamine side product 53. Presumably, alkyl arylamine formed after the first cross-coupling reaction undergoes copper-promoted C(alkyl)-N bond scission, and the intermediate 52 undergoes another cross-coupling with aryl boronic acid forming the diarylamine 53 as the by-product (Scheme 27B). This assumption was supported by previous studies conducted by Tolman and co-workers, who observed increased dealkylation of aliphatic amines in the presence of bis(μ-oxo)dicopper complexes (95, 114). Therefore, the reaction was carried out using catalytic amounts of copper and reduced concentrations to prevent the formation of 53. The reaction conditions used by Quach and Batey were adapted from their previously reported copper-catalyzed O-arylation protocol of phenols with aryl boronic acids (115). Nonetheless, the coupling reaction of primary and secondary amines with aryl boronic acids and aryl trifluoroborate salts gave moderate to excellent yields of the product, although yields were lower with anilines. Diverse functional groups on amines (alkenes, esters, ketones, ketals) were tolerated under the optimized reaction conditions; however, chelating substituents on the aliphatic chain gave incomplete conversion at room temperature. Notably, α-amino acid derivatives showed no epimerization upon subjection to coupling conditions. Aryl boronic acids containing both electron-donating and electron-withdrawing substituents reacted well; however, substitution at the ortho-position resulted in reduced yields. The same authors recently developed an efficient base-free synthesis of enamides using Cu(OAc)2-catalyzed cross-coupling of alkenyl trifluoroborate salts with amides under an O2 atmosphere at 40 °C (116). While the oxidative amination developed by Chan and Lam has been widely used for the synthesis of anilines derivatives as describe above, it is highly sensitive to steric properties of the nucleophilic amine partner, resulting in lower yields when hindered amines are used. Electrophilic amination offers a complementary approach for the construction of C-N bonds (17). Contrary to oxidative cross-coupling, electrophilic amination involves C-N bond formation using an electrophilic nitrogen source and a carbon nucleophile. In 2012, Lalic reported a CuOtBu-catalyzed electrophilic amination for the synthesis of hindered anilines from O-benzoyl hydroxylamines and aryl/heteroaryl boronic acids (Equation 7) (117). Notably, the steric properties of the electrophiles had no effect on the reaction outcome, as can be seen in Equation 7.

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Scheme 27. (A) Ligand- and Base-Free Copper-Catalyzed Cross-Coupling Reactions of Aliphatic Amines and Anilines with Organoboron Compounds. (B) Copper-Promoted Diaryl Amine by-Product Formation (112).

The Liebeskind group developed a copper-catalyzed N-imination of aryl, heteroaryl, and alkenyl boronic acids with oxime O-carboxylates (Scheme 28) (118). Oximes derived from aldehydes were not suitable substrates for the coupling and underwent β-hydride elimination to yield the corresponding nitriles. A similar protocol employing stoichiometric quantities of CuTC catalyst was developed by their group for N-amidation of boronic acids using O-acetyl hydroxamic acids (80). Additionally, they developed a simple and modular synthesis for the construction of highly substituted pyridines (119). Utilizing N-chloroamides as the electrophilic partner, another group reported electrophilic amination of aryl boronic acids (120). The transformation gave high yields of diaryl amides, and functional groups such as iodo, bromo, and chloro that are generally problematic in palladium-catalyzed reactions were tolerated under the reaction conditions. 336 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 28. Copper-Catalyzed N-Imination of Boronic Acids with O-Acyl Ketoximes (118).

C-O Bond Formation The Chan (71) and Evans (73) groups simultaneously reported novel protocols for the cross-coupling of aryl boronic acids with oxygen nucleophiles. Their simple and mild methods offered a complementary approach for transition-metal promoted C-O bond formation reactions (121). The strikingly similar methodologies employed phenol (1 equiv), aryl boronic acid (3 equiv), anhydrous Cu(OAc)2 (1-2 equiv), Et3N (2-5 equiv), and the reaction mixtures were stirred for 1-2 days open to air at room temperature (Scheme 29A). Subsequently, the unsymmetrical diaryl ethers 54 were isolated in good to excellent yields. Inert atmosphere led to lower yield of the desired products while dry, pure oxygen atmosphere gave identical results to ambient atmosphere. The crude reaction mixtures were analyzed using GC-MS; significant phenol and diphenyl ether side products were observed (see Scheme 24 for details). It was speculated that water was being generated during the triphenyl boroxine formation from phenyl boronic acid. This was indeed the case since substituting phenyl boronic acid with 0.33 equivalents of triphenyl boroxine gave the desired coupling product in a similar yield. Hence, 4Å molecular sieves were added to the reaction with aryl boronic acids. Higher equivalents of the base did not impede the reaction suggesting that the base could also be acting as a ligand for copper. Both electron-rich and electron-poor phenols were tolerated under their protocols. O-alkyl and ortho-heteroatom substituted phenols were viable substrates, although o-heteroatom substituted boronic acids gave lower yields of the desired product. When the substrate scope was extended to racemization-prone substituted amino acids derivatives, Et3N was necessary to afford the desired diaryl ethers in good yield without racemization of the substrates. Further, the above protocol was utilized for the synthesis of thyroxine derivatives 55a and 55b (Scheme 29B). For these particular substrates, a 1:1 mixture of pyridine and Et3N (5 equiv) was used. The choice of bases was highly substrate dependent. The usefulness of this protocol was demonstrated in the total synthesis of the antibiotic teicoplanin agylcon (122).

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Scheme 29. O-Arylation of Phenols (A) and its Application in the Synthesis of Thyroxine Derivatives (B) (73).

The Sharpless group modified Evans’s C-O cross-coupling conditions for the synthesis of N-aryl hydroxylamines using N-hydroxyphthalimide and phenyl boronic acid. Stoichiometric amount of CuCl, pyridine, and 4Å molecular sieves gave the desired products in moderate to good yields (123). Although Evans et al. attempted a catalytic variant of their methodology for the synthesis of 56 (73), the use of substoichiometric quantities of Cu(OAc)2 (10 mol %) gave the desired product in low yield (Equation 8).

Lam et al. further developed the catalytic version by incorporating a co-oxidant in the coupling of 3,5-di-tert-butylphenol with p-tolyl boronic acid (Equation 9) (109). While Cu(OAc)2 with O2 gave the best results (79%, Equation 9), oxidants such as TEMPO and PNO achieved the desired cross-coupling albeit in low yields. In all these cases, a major limitation was the unreactive nature of the aliphatic alcohols even in the presence of stoichiometric amounts of the catalyst (73, 109, 123). Thus, the substrate scope for the nucleophilic counterpart was limited to phenol derivatives.

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A solution was proposed by the Batey group, which developed a Cu(II)-catalyzed cross-coupling of alkenyl and aryl trifluoroborate salts with primary and secondary alkyl alcohols under neutral conditions at room temperature (Scheme 30A) (115). Preliminary studies were performed with cinnamyl alcohol and phenyl trifluoroborate salts (Scheme 30B). Optimization of the catalyst and nitrogen ligand revealed that Cu(OAc)2•H2O and 4-dimethylaminopyridine (DMAP) in the presence of 4Å molecular sieves and O2 were optimal, respectively. Other screened bases such as N,N′-Dimethylethylenediamine (DMEDA), N,N-diisopropylethylamine (DIPEA), TMEDA, Et3N, 1,10-phenanthroline, pyridine, and imidazole were inefficient. After establishing the optimized conditions, the substrate scope was examined. Phenols, alkenes, allylic, and internal propargylic alcohols were suitable substrates. Functionalities such as aryl halides, which do not participate in cross-couplings, performed well. No alkene isomerization or epimerization of an α-stereocenter in an enantiomerically pure ester was noticed. Notably, the reaction is highly sensitive to steric effects. Although secondary alcohols underwent cross-coupling, tertiary alcohols were unreactive. Further, aryl boronic acids are good substitutes for trifluoroborate salts; however, lower yields were observed with the former (Scheme 30B). The oxidation product of the phenyl trifluoroborate salt and phenol as well as homocoupled by-product (diphenyl ether) were observed; nevertheless, they were more pronounced when phenyl boronic acid was used (see Scheme 24 for details). Furthermore, terminal alkynes and N-H amine substrates were incompatible with the reaction conditions and oxidative homocoupling (Egliston reaction) (124, 125) occurred and N-arylation byproducts were formed. Wang et al. used a similar catalytic system, Cu(OAc)2/DMAP/O2 to achieve trifluoroethoxylation of aryl and heteroaryl boronic acids using 2,2,2-trifluoroethanol as the solvent. Although the reaction times were shorter, higher temperatures were required to achieve the desired transformation (126).

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Scheme 30. Copper-Catalyzed Cross-Coupling of Potassium Organotrifluoroborate Salts with Aliphatic Alcohols (115). Oxygen nucleophiles such as phenol and alkyl/aryl alcohols have been extensively used in Chen-Evans-Lam coupling. On the contrary, carboxylic acids are rarely employed because of competitive decarboxylation occurring under an array of conditions (127–129). As a result, they are mainly used in C-C bond formation reactions as a nucleophilic partner (130). Jacobsen et al. therefore investigated Chan-Lam methylation of carboxylic acids using methylboronic acid (Scheme 31) (131). This method offers a safer alternative to current toxic methylating agents such as such as methyl iodide, dimethyl sulfate, and diazomethane or its substitute (trimethylsilyl) diazomethane (132–136). Upon treating a carboxylic acid with methyl boronic acid in the presence of CuCO3.Cu(OH)2 and pyridine in dimethyl carbonate (DMC) gave the desired methyl ester carboxylic acid in 76% yield (Scheme 31). Keeping the reaction open to air ensured catalytic turnover by utilizing oxygen in air as an oxidant. Similar yields were obtained under inert atmosphere by employing t-BuOOt-Bu as the terminal oxidant. Thus, offering a parallel route to previous reported copper-catalyzed alkylation conditions (104, 137). The reaction tolerated a broad range of structurally and electronically diverse substrates with functionalities such as aryl bromides and chlorides (iodides were unreactive), ketones, nitriles, and esters. The reaction was insensitive to steric effects; o-methyl, o-methoxy-substituted phenyl carboxylic acids gave the desired product in 68% and 78%, respectively. Although, no product was observed with N-H indoles, the N-derivatized indoles produced the desired product in 67% yield. The scope of methylation was extended to aliphatic and alkenyl carboxylic acids. Isotopic labeling studies were conducted to rule out the possible oxidation of methyl 340 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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boronic acid to methanol and the subsequent reaction of methanol with carboxylic acid leading to the product (Scheme 32). The Batey group also developed a CuBr-catalyzed nondecarboxylative cross-coupling of alkenyl trifluoroborates with carboxylate salts or carboxylic acids utilizing DMAP as the nitrogen ligand and 4Å molecular sieves in the presence of O2 atmosphere at 60 °C (138). The regioselective and stereoselective protocol gave the desired enol esters in good yields.

Scheme 31. Copper-Catalyzed Methylation of Carboxylic Acid Derivatives with Methylboronic Acid (131).

Scheme 32. A) Alternate Mechanism for Copper-Catalyzed Aerobic O‐Methylation of Carboxylic Acid Derivatives with Methylboronic Acid. B) Isotope Labeling Studies for Copper-Catalyzed O‐Methylation of Phenyl Carboxylic Acid (131). C-S Bond Formation Guy et al. reported the cross-coupling of alkyl thiols with aryl boronic acids using stoichiometric amounts of copper catalyst (139). The investigation was motivated by a need for a milder synthesis of cysteine derivative 62, an intermediate in the synthesis of the HIV protease inhibitor nelfinavir (63) (Scheme 33). Using previously developed conditions for O-arylation of phenols (73), 341 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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the observed rate of S-arylation was slow due to competing disulfide formation from the oxidation of thiol. However, when the reaction was performed under an inert atmosphere in the presence of pyridine, Cu(OAc)2, and DMF at 155 °C, a significant rate enhancement led to the desired product in good yield (Scheme 34). The reaction was insensitive to electronic effects; however, it was moderately affected by steric hindrance. Prolonged reaction times and low yields were observed with sterically hindered substrates such as o-toluene boronic acid (64b, Scheme 34). Tertiary thiols gave trace amount of the product, whereas thio acids and α-carboxy thiols were unreactive. Further, the desired S-aryl cysteine derivative (62) was obtained in good yield with no observed racemization.

Scheme 33. Synthesis of Cysteine Derivative 62 (139).

Scheme 34. Copper-Mediated Cross-Coupling of Alkyl Thiols with Aryl Boronic Acids (139). Subsequently, the Liebeskind group developed a copper(I)-catalyzed reaction of boronic acids with thiols under non-basic, mild conditions (140). Their investigation was based on the premise that Guy’s protocol proceeds through a Cu(I) catalysis instead of Cu(II) as implied by the authors. The harsh conditions 342 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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and Cu(II) catalyst in Guy’s conditions can easily convert thiols into disulfides and Cu(I) as previously proposed by Smith et al. (141). The speculations were confirmed when the reaction of phenyl boronic acid (70) reacted with diphenyl disulfide (71) and Cu(I)-3-methylsalicylate [CuMeSaI] in DMA at 100 °C for 18 h afforded the product diphenyl sulfide (67) in 74% yield (Equation 10). The requirement for stoichiometric Cu(I) for the S-arylation was due to the partial inactivation of the catalyst from the formation of inactive Cu(I) thiolate 72. This led the investigators to employ N-thioimides as an alternative electrophilic sulfide surrogate. A diverse set of boronic acid substrates underwent cross-couplings with N-thioimides in the presence of CuMeSal (20-30 mol %) in THF at 45 °C to form the desired thioethers in moderate to good yield (Scheme 35). These results were remarkable since the transformations were achieved under non-basic and mild conditions. Later, Taniguchi (142, 143), Li (144), and Yu (145) demonstrated copper-catalyzed C-S cross-coupling of aryl boronic acids with diaryldisulfane in DMSO/H2O at 100 °C.

Scheme 35. Copper-Catalyzed Cross-Coupling of Boronic Acids with N-Thioimides (140).

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Scheme 36. Copper-Catalyzed Cross-Coupling of Thiols with Boronic Acids at Room Temperature (146).

Scheme 37. Proposed Reaction Pathway for Copper(I)-Catalyzed Trifluoromethylthiolation of Aryl Boronic Acid with TMSCF3 Using Elemental Sulfur (S8) (148).

Succeeding this work, Hua-Jian Xu et al. established a room temperature S- arylation of thiols with aryl/heteroaryl boronic acids (Scheme 36) (146). An extensive optimization of the reaction conditions was conducted. Various metal salts (CuSO4, CuI, CuCl2, FeCl3), bases (Na2CO3, C2CO3, KOt-Bu, n-Bu4NOH) and solvents (MeOH, EtOH, DMSO, THF, DMF) were examined. The optimized reaction condition (phenyl boronic acid, phenyl thiophenol, CuSO4, 1,10-phenanthroline:H2O in a 1:1 mixture of n-Bu4NOH and ethanol under O2 atmosphere) generated the product diphenyl sulfide in excellent yield (Scheme 36). The generality of the transformation was demonstrated with a range of substituted boronic acids and aryl/heteroaryl boronic acids. No reaction occurred with aliphatic thiols and alkyl boronic acids. C-S bond formation using aryl boronic acids and aryl thiols have also been reported in the presence of [Cu(DMAP)4I]I catalyst at room temperature (147). 344 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 38. Copper-Catalyzed Trifluoromethylthiolation of Aryl Boronic Acids with (Trifluoromethyl)trimethylsilane (TMSCF3) Using Elemental Sulfur (S8) (148). The utility of elemental sulfur in cross-coupling reactions was shown by Chen et al. They demonstrated the trifluoromethylthiolation of aryl boronic acids with (trifluoromethyl)trimethylsilane (TMSCF3, Ruppert-Prakash reagent) using elemental sulfur (S8) and Cu(I) catalyst (148). The investigators speculated the formation of a stable copper disulfide complex from the reaction of Cu(I) complex with elemental sulfur (149). The transmetalation of the disulfide complex with boronic acid, followed by reductive elimination of the complex was speculated to give the desired product (Scheme 37). Added oxidant regenerated the catalyst. In the presence of CuSCN, 1,10-phenanthroline, K3PO4 as the base, and Ag2CO3, the trifluoromethylthiolation of phenyl boronic acid yielded the desired product in 95% yield. No product was observed in the absence of catalyst, ligand, or oxidant. A diverse range of aryl boronic acids containing esters, amides, vinylic, halides, nitriles, ketones and sulfonyl groups were tolerated (Scheme 38). The importance of this cross-coupling is highlighted in its high efficiency, commercial 345 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

availability inexpensive starting materials, and mild reaction conditions. In 2014, Yu and co-workers demonstrated a one-pot S-arylation of aryl boronic acids using elemental sulfur and CuF2 as a catalyst (150). Further, Shen and co-workers also achieved a copper-catalyzed trifluoromethylation of primary and secondary alkyl boronic acids using an electrophilic trifluoromethylating source (151).

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Conclusion In the last decade tremendous growth has been made in copper-catalyzed cross-coupling reactions using organoborons as the coupling partners. The low cost of copper, mild reactions conditions, and commercial availability of organoborons renders these reactions especially attractive from a synthetic perspective. In spite of these advances, limitations still exists that demand attention. Low atom economy is often an issue due to competing protodeboration and oxidation of organoboron compounds. Further, additives such as base and oxidant, and sometimes higher copper catalyst loading is necessary. These limit the application of cross-coupling reactions on industrial scale. Notably, a better understanding of the mechanistic detail such as the active copper species involved, effect of copper-ligand-nucleophile interactions, clarity of different steps in the catalytic cycle is required to expand the application of copper-catalyzed cross-coupling reactions with organoborons.

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117. Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. Synthesis of hindered anilines: Copper-catalyzed electrophilic amination of aryl boronic esters. Angew. Chem., Int. Ed. 2012, 51, 3953–3956. 118. Liu, S.; Yu, Y.; Liebeskind, L. S. N-substituted imines by the coppercatalyzed N-imination of boronic acids and organostannanes with O-acyl ketoximes. Org. Lett. 2007, 9, 1947–1950. 119. Liu, S.; Liebeskind, L. S. A simple, modular synthesis of substituted pyridines. J. Am. Chem. Soc. 2008, 130, 6918–6919. 120. He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Aryl halide tolerated electrophilic amination of arylboronic acids with N-chloroamides catalyzed by CuCl at room temperature. Angew. Chem., Int. Ed. 2008, 47, 6414–6417. 121. Hartwig, J. F. Carbon-heteroatom bond formation catalysed by organometallic complexes. Nature 2008, 455, 314–322. 122. Evans, D. A.; Katz, J. L.; Peterson, G. S.; Hintermann, T. Total synthesis of teicoplanin aglycon. J. Am. Chem. Soc. 2001, 123, 12411–12413. 123. Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. The copper-mediated cross-coupling of phenylboronic acids and N-hydroxyphthalimide at room temperature: Synthesis of aryloxyamines. Org. Lett. 2001, 3, 139–142. 124. Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. 722. Macrocyclic acetylenic compounds. Part ii. 1,2:7,8-dibenzocyclododeca-1,7-diene3,5,9,11-tetrayne. J. Chem. Soc. 1960, 3614–3625. 125. Hay, A. S. Oxidative coupling of acetylenes. II. J. Org. Chem. 1962, 27, 3320–3321. 126. Wang, R.; Wang, L.; Zhang, K.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Facile synthesis of trifluoroethyl aryl ethers through copper-catalyzed coupling of CF3CH2OH with aryl- and heteroaryl boronic acids. Tetrahedron Lett. 2015, 56, 4815–4818. 127. Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Carboxylic acids as substrates in homogeneous catalysis. Angew. Chem., Int. Ed. 2008, 47, 3100–3120. 128. Bhadra, S.; Dzik, W. I.; Goossen, L. J. Decarboxylative etherification of aromatic carboxylic acids. J. Am. Chem. Soc. 2012, 134, 9938–9941. 129. Jiang, Y.; Pan, S.; Zhang, Y.; Yu, J.; Liu, H. Copper-catalyzed decarboxylative methylation of aromatic carboxylic acids with PhI(OAc)2. Eur. J. Org. Chem. 2014, 2014, 2027–2031. 130. Rodriguez, N.; Goossen, L. J. Decarboxylative coupling reactions: A modern strategy for C-C-bond formation. Chem. Soc. Rev. 2011, 40, 5030–5048. 131. Jacobson, C. E.; Martinez-Muñoz, N.; Gorin, D. J. Aerobic copper-catalyzed O-methylation with methylboronic acid. J. Org. Chem. 2015, 80, 7305–7310. 132. Hite, M.; Rinehart, W.; Braun, W.; Peck, H. Acute toxicity of methyl fluorosulfonate (magic methyl). Am. Ind. Hyg. Assoc. J. 1979, 40, 600–603. 133. Hodnett, N. S. Trimethylsilyldiazomethane. Synlett 2003, 2003, 2095–2096. 134. Rippey, J. C. R.; Stallwood, M. I. Nine cases of accidental exposure to dimethyl sulphate—A potential chemical weapon. Emerg. Med. J. 2005, 22, 878–879. 354 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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135. Mileson, B. E.; Sweeney, L. M.; Gargas, M. L.; Kinzell, J. Iodomethane human health risk characterization. Inhalation Toxicol. 2009, 21, 583–605. 136. Kemsley, J. Femptosecond science technique tracks structure, electron dynamics during reactions. Chem. Eng. News 2010, 88, 15. 137. Sueki, S.; Kuninobu, Y. Copper-catalyzed N- and O-alkylation of amines and phenols using alkylborane reagents. Org. Lett. 2013, 15, 1544–1547. 138. Huang, F.; Quach, T. D.; Batey, R. A. Copper-catalyzed nondecarboxylative cross coupling of alkenyltrifluoroborate salts with carboxylic acids or carboxylates: Synthesis of enol esters. Org. Lett. 2013, 15, 3150–3153. 139. Herradura, P. S.; Pendola, K. A.; Guy, R. K. Copper-mediated cross-coupling of aryl boronic acids and alkyl thiols. Org. Lett. 2000, 2, 2019–2022. 140. Savarin, C.; Srogl, J.; Liebeskind, L. S. A mild, nonbasic synthesis of thioethers. The copper-catalyzed coupling of boronic acids with N-thio(alkyl, aryl, heteroaryl)imides. Org. Lett. 2002, 4, 4309–4312. 141. Smith, R. C.; Reed, V. D.; Hill, W. E. Oxidation of thiols by copper(II). Phosphorus, Sulfur Silicon Relat. Elem. 1994, 90, 147–154. 142. Taniguchi, N. Aryl- or alkylation of diaryl disulfides using organoboronic acids and a copper catalyst. Synlett 2006, 2006, 1351–1354. 143. Taniguchi, N. Convenient synthesis of unsymmetrical organochalcogenides using organoboronic acids with dichalcogenides via cleavage of the S−S, Se−Se, or Te−Te bond by a copper catalyst. J. Org. Chem. 2007, 72, 1241–1245. 144. Luo, P.-S.; Wang, F.; Li, J.-H.; Tang, R.-Y.; Zhong, P. Copper-catalyzed selective S-arylation of 1,2-bis(O-amino-1H-pyrazolyl) disulfides with arylboronic acids. Synthesis 2009, 2009, 921–928. 145. Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L. An improved Cu-based catalyst system for the reactions of alcohols with aryl halides. J. Org. Chem. 2007, 73, 284–286. 146. Xu, H.-J.; Zhao, Y.-Q.; Feng, T.; Feng, Y.-S. Chan–Lam-type S-arylation of thiols with boronic acids at room temperature. J. Org. Chem 2012, 77, 2878–2884. 147. Roy, S.; Sarma, M. J.; Kashyap, B.; Phukan, P. A quick Chan-Lam C-N and C-S cross coupling at room temperature in the presence of square pyramidal [Cu(DMAP)4I]I as a catalyst. Chem. Commun. 2016, 52, 1170–1173. 148. Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang, X.; Qing, F.-L. Copper-catalyzed oxidative trifluoromethylthiolation of aryl boronic acids with TMSCF3 and elemental sulfur. Angew. Chem., Int. Ed. 2012, 124, 2542–2545. 149. Helton, M. E.; Chen, P.; Paul, P. P.; Tyeklár, Z.; Sommer, R. D.; Zakharov, L. N.; Rheingold, A. L.; Solomon, E. I.; Karlin, K. D. Reaction of elemental sulfur with a copper(I) complex forming a trans-μ-1,2 end-on disulfide complex: New directions in copper−sulfur chemistry. J. Am. Chem. Soc. 2003, 125, 1160–1161. 150. Yu, J.-T.; Guo, H.; Yi, Y.; Fei, H.; Jiang, Y. The Chan–Lam reaction of chalcogen elements leading to aryl chalcogenides. Adv. Synth. Catal. 2014, 356, 749–752. 355 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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151. Shao, X.; Liu, T.; Lu, L.; Shen, Q. Copper-catalyzed trifluoromethylthiolation of primary and secondary alkylboronic acids. Org. Lett. 2014, 16, 4738–4741.

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Chapter 11

Introduction, Interconversion and Removal of Boron Protecting Groups Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch011

Quentin I. Churches and Craig A. Hutton* School of Chemistry, Bio21 Institute Building, The University of Melbourne, 30 Flemington Rd, Parkville, Victoria 3010, Australia *E-mail: [email protected]

Boronic acid protecting groups have revolutionized the use of organoborons in synthetic chemistry, enabling organoboron functional groups to be carried through multistep protocols, no longer limited to introduction of boron at a late stage or subject to immediate transformation. The development of novel B-protecting groups and methods for their orthogonal introduction and deprotection has enabled chemoselective transformations of organoboron compounds, including those with multiple organoboron functional groups. The arsenal of B-protecting groups and methods for their introduction, interconversion and removal is outlined in this chapter.

Introduction The utility of organoboron compounds in organic synthesis has flourished in recent years (1), particularly through developments in the Suzuki–Miyaura coupling reaction (2). Boronic acids are also extremely valuable substrates for the Petasis reaction (3, 4) and Chan-Evans-Lam coupling reaction (5, 6). Free boronic acids are often unstable, difficult to handle, or are prone to dehydration to give the corresponding boroxine. As such, organoboronic acids and esters have typically been installed as late as possible in a synthetic sequence, rather than carried through multiple steps, to avoid decomposition or protodeboronation. Bulky boronate esters such as pinacol boronates have been used extensively as ‘blocking groups that are resistant to hydrolysis through steric effects and improve the ease of handling of such organoboron reagents. In some cases these groups can be selectively removed to unveil the boronic acid, © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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but such transformations are not general. In most cases the boronate esters are reactive in metal-catalyzed cross-couplings and the generated organoboronates are transformed through such processes soon after they are formed. In the past decade a number of true ‘protecting’ groups for boronic acids have been introduced that enable organoboron functional groups to be carried through multistep transformations. To function as true protecting groups, such systems must be able to be introduced and removed under mild conditions, preferably in an orthogonal manner, and be stable to a broad range of reaction conditions experienced in standard synthetic procedures. In addition to facilitating the carriage of organoborons through multi-step synthetic sequences, the development of modern boronic acid protecting groups has also enabled chemoselective reactions of di- and tri-boronated compounds, which ultimately enables iterative cross-coupling protocols to build complex molecules through straightforward and efficient processes. Several boronic acid protecting groups have been developed (Figure 1). The most commonly used of these are the N-methyliminodiacetyl (MIDA) and diaminonaphthalenyl (DAN) B-protecting groups. Burke developed the MIDA group as a boronic acid protecting group that abolishes the reactivity of an organoboron toward metal-catalyzed cross-couplings or degradation (7, 8). Suginome developed the DAN group that similarly renders the organoboron unreactive toward cross-coupling reactions (9). Both the DAN and MIDA B-protecting groups require removal to regenerate the boronic acid in order to re-establish reactivity of the organoboron in cross-coupling reactions. Other N- and O-based protecting groups have also been developed, including the anthranilamide (AAM) (10) and 2-(pyrazol-5-yl)aniline (PZA) (11) groups, which act as both directing and protecting groups.

Figure 1. Common organoboron protecting groups. Organotrifluoroborates have also been employed as ‘protected’ boronic acids (12, 13). Organotrifluoroborates are generally easily handled, stable crystalline solids. In the absence of protic solvents they have limited reactivity, though they are readily hydrolyzed to the boronic acid in the presence of water (14). In this chapter, the preparation of protected boronic acids will be described, focusing on methods for the introduction and removal of the boronic acid protecting groups and their interconversion to activate or deactivate organoboron 358 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

reactivity. Transformation of the C–B bond to C–C or C–heteroatom bonds is covered in detail elsewhere in this book.

Boronate Esters as B-Protecting Groups

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While a large number of boronate esters have been employed in organoboron chemistry, cyclic boronate esters are most commonly used due to their stability towards hydrolysis (2). Such boronate esters are easily prepared from the parent boronic acid by addition of a diol, typically a 1,2- or 1,3-diol (1). Examples include boronate esters derived from pinacol, neopentylglycol, pinanediol and hexylene glycol. Introduction of Boronate Esters Boronate esters are perhaps the most commonly generated organoborons, usually through Miyaura borylation of the an organohalide (15, 16), or direct borylation of arenes (17), with a diboron or borane reagent. For example, pinacol boronate esters are readily derived from aryl halides by treatment with bispinacolatodiboron (Pin–BPin) (Scheme 1).

Scheme 1. Miyaura borylation to generate boronate esters. Boronate esters can be easily prepared from the parent boronic acid by treatment with a diol to generate a stable cyclic boronate ester. This form of ‘protection’ of a boronic acid is not commonly employed, as the boronic acid and boronate ester tend to have similar reactivity profiles. One exception is the preparation of pinanediol boronate esters 2, which are used extensively in Matteson asymmetric chloromethylation reactions to generate functionalized alkylboronic acids in a stereoselective manner (Scheme 2) (18).

Scheme 2. Pinanediol boronate esters for Matteson chloromethylation. Though usually used as a stable organoboron reagent for cross-coupling procedures, the pinacol boronate has been shown act as a ‘protecting’ group in some circumstances. For example, the bromination of an arylboronate 3 proceeded when ‘protected’ as a pinacol boronate ester, whereas no reaction of 359 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

the corresponding boronic acid occurred (19). The BDAN protected version similarly did not react, whereas the corresponding BMIDA and BF3K compounds gave a complex mixture of products (Scheme 3).

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Scheme 3. BPin as a B-protecting group. Whiting has shown that the hexyleneglycol boronate ester group acts as a ‘protecting group’ against Suzuki–Miyaura cross couplings, promoting selective Heck reactions of vinylboronates 5 to give styrenylboronates 6 (Scheme 4) (20).

Scheme 4. Vinyl hexylene glycol boronate for Heck-selective processes. Deprotection of Boronate Esters The utility of the pinacol boronate ester is due to it’s resistance to hydrolysis, and as such hydrolytic cleavage of pinacol boronate esters to generate the boronic acid is rarely performed. Nonetheless, for systems that require the free boronic acid, deprotection of pinacol boronate esters can be performed through oxidative cleavage with periodate (21, 22), or through transesterification in the presence of an excess of a sacrificial boronic acid (23) or solid-supported boronic acid (Scheme 5) (24).

Scheme 5. Deprotection of BPin by oxidative cleavage or transesterification. Neopentylglycol boronate esters are more readily hydrolyzed to the boronic acid than the corresponding pinacol boronates. Accordingly, Miyaura borylation with the corresponding diboron reagent 7, followed by deprotection through aqueous hydrolysis, can be used to generate an aryl boronic acid 9 where the boronate ester 8 is not suitable for subsequent reactions (e.g., Scheme 6) (25). 360 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Scheme 6. Hydrolysis of neopentylglycol boronate ester.

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Overall hydrolysis of pinacol boronate esters to boronic acids has also been achieved through conversion to the intermediate trifluoroborate and subsequent treatment with TMS-Cl/H2O (Scheme 7) (26).

Scheme 7. Conversion of BPin to boronic acid through BF3K intermediate. Interconversion of Boronate Esters Deprotection of chiral diol boronate esters has been achieved through initial conversion to a triol boronate species, which is subsequently hydrolyzed to give the boronic acid (Scheme 8) (27). Pinanediol boronate esters have also been deprotected through initial conversion to the corresponding trifluoroborate, followed treatment with TMS-Cl and pinacol to generate the pinacol boronate ester (28). Both of these processes can be followed by (trans)esterification with the antipode of the initial chiral diol for subsequent asymmetric chloromethylation reactions with inverted stereochemistry (Scheme 8).

Scheme 8. Interconversion of chiral diol boronate esters to their antipodes, via triol boronates or trifluoroborates. Triol Boronate Complexes Triol boronate complexes 12 are generated as stable, activated forms of boronic acids that do not require addition of base to facilitate cross-coupling reactions (27, 29). These species can be generated directly from organolithium reagents by treatment with a trialkylborate (30). More commonly, triol boronate derivatives are prepared by reaction of the boronic acid with a triol under 361 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Dean–Stark conditions to generate a diol boronate intermediate 11, which is then treated with base to generate the tetracoordinate ate-complex 12 (Scheme 9) (31). The most common triol used in this process is trimethylolethane (TME, 10). TME-ate complexes 12 have been shown to be more reactive than boronic acids, boronate esters and trifluoroborates in cross-coupling reactions (32, 33). Further, they have been used to prepare stable derivatives of 2-heteroaryl boronic acids (e.g. 2-pyridyl, 2-furyl) and methylboronic acid, which are unstable as the free boronic acids (34–36).

Scheme 9. Conversion of boronic acids to diol esters to triol boronates.

scyllo-Inositol 13 is a hexol that has been employed in the preparation of bis-triolboronates 14. Interestingly, scyllo-inositol bis-boronates are less reactive than the corresponding boronic acids toward cross coupling, which enables chemoselective Suzuki–Miyaura reactions of these species with arylboronic acids to generate biaryl boronic acids, e.g. 15 (Scheme 10) (37).

Scheme 10. sycllo-Inositol bis(triolboronate) complexes.

Triolboronates are not usually deprotected as they are normally used directly in cross coupling reactions. However, triolboronates have been prepared as intermediates in the deprotection of pinanediol boronates, with final hydrolysis under aqueous acidic conditions (see Scheme 8) (27).

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The MIDA B-Protecting Group MIDA-protected boronic acids (38) are inert to cross-coupling reactions due to their overall neutral charge and tetracoordinate nature, which prevents transmetallation (8). MIDA boronates have been employed as one of the first examples of true protecting groups for boronic acids, where the BMIDA species remains intact and inert in cross-coupling reactions of other organoboron derivatives. Chemoselective cross-couplings of BMIDA derivatives are detailed elsewhere in this book. BMIDA compounds uniformly possess a highly unusual binary affinity for silica gel with certain eluents. This binary elution profile has enabled the development of a ‘catch-and-release’ protocol that simplifies the purification of MIDA boronates and has enabled automation of iterative cross-couplings (39).

Introduction of the MIDA B-Protecting Group The MIDA B-protecting group is commonly introduced by treatment of the boronic acid with MIDA under Dean–Stark conditions (Scheme 11) (8). High temperatures are normally required, which can result in protodeboronation of electron-rich arylboronic acids during this process (40). The use of 4Å molecular sieves has been shown to promote BMIDA formation with suppression of protodeboronation, allowing preparation of BMIDA derivatives of such systems (Scheme 12) (40).

Scheme 11. Conversion of boronic acids to BMIDA boronates under Dean-Stark conditions.

Scheme 12. Preparation of electron rich aryl-BMIDA compounds.

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BMIDA derivatives have been prepared by direct transesterification of the corresponding BPin boronate esters by treatment with MIDA, but this process is generally inefficient, requiring multiple cycles to generate the BMIDA derivative in good yield (e.g., 17→18, Scheme 13) (41).

Scheme 13. A BMIDA boronate from the BPin boronate ester.

BMIDA derivatives can be prepared from the corresponding dibromoborane by treatment with MIDA or its sodium salt (42–44). They can similarly be prepared from the corresponding trifluoroborate by treatment with MIDA and a fluorophile (TMS-Cl or silica) (Scheme 14) (45, 46). BMIDA derivatives can also be prepared from trialkoxyborates by treatment with MIDA at elevated temperature (47).

Scheme 14. BMIDA boronates from dibromoboranes or trifluoroborates.

Deprotection of MIDA B-Protecting Groups Deprotection of BMIDA derivatives to the corresponding boronic acids is readily achieved by treatment with aqueous base (Scheme 15) (8, 39). However, being susceptible to reaction with hard nucleophiles, the BMIDA group is incompatible with LiAlH4, DIBAL, TBAF and some metal alkoxides (48).

Scheme 15. Deprotection of BMIDA derivatives by basic hydrolysis.

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The slow hydrolysis of BMIDA derivatives under protic conditions has been exploited in the ‘slow release’ of the reactive boronic acid for cross coupling reactions of otherwise unstable or hard to handle boronic acids (Scheme 16) (49).

Scheme 16. Slow release–cross-coupling of BMIDAs.

Interconversion of MIDA B-Protecting Groups MIDA-protected boronic acids have been converted to BPin boronates by treatment with NaHCO3 in the presence of pinacol (Scheme 17) (50, 51).

Scheme 17. Conversion of BMIDA boronates to BPin boronates.

Watson has developed a procedure for the controlled speciation of BMIDA boronates to BPin boronates in cross-couplings of organo–BPin compounds (39, 52–55). First, chemoselective Suzuki–Miyaura cross-coupling of an aryl–BPin with a MIDA-protected borono-arylhalide generates the cross-coupled biaryl adduct 19 containing the BMIDA group. Under protic conditions, the HO–BPin byproduct can hydrolyze to generate pinacol and the BMIDA compound 19 can hydrolyze to the boronic acid 20. Recombination of boronic acid 20 and pinacol ultimately generates the cross-coupled biaryl–BPin 21 under finely tuned equilibrium conditions (Scheme 18). Under this protocol the initial MIDA-protected biaryl adduct 19 is converted to a reactive BPin ester 21 in one pot with no need for a separate deprotection event. Moreover, subsequent addition of a second aryl bromide results in a second Suzuki–Miyaura coupling to generate a triaryl product in one pot.

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Scheme 18. Controlled speciation of BMIDA–BPin protecting groups.

Burke has developed the N-isopinocampheyl equivalent of the MIDA protecting group, known as PIDA. This BPIDA group not only acts as a protecting group, preventing oxidation of the C–B bond, but also as a chiral auxiliary in the asymmetric epoxidation of vinyl boronates such as 22 (Scheme 19). Meinwald rearrangement then generates α-boryl aldehyde 24 (39, 56). Further transformations can include transesterification of the BPIDA group with pinacol in MeOH to generate the corresponding BPin derivative, which can then undergo cross-coupling reactions.

Scheme 19. BPIDA as a protecting group and chiral auxiliary.

BMIDA compounds are only very slowly converted to the corresponding trifluoroborates derivatives under standard condition (KHF2, MeOH, room temp.), with more forcing conditions required for efficient transformation (e.g. 25→26, Scheme 20) (46). The reduced reactivity of BMIDA compounds to fluorolysis enables chemoselective formation of trifluoroborates from differentially protected diboron compounds. For example, the aryl-BMIDA/BPin compound 27 is selectively converted to the BMIDA/BF3K derivative 28 under standard conditions (Scheme 20).

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Scheme 20. Conversion of BMIDA boronates to trifluoroborates.

The DAN B-Protecting Group After the MIDA protecting group, the next most common group used to attenuate reactivity of organoborons in cross-couplings is the DAN B-protecting group. The BDAN group contains a tricoordinate boron, but possesses reduced reactivity in cross-coupling reactions due to donation of electron density toward the Lewis acidic boron from the Lewis basic nitrogen atoms, thus reducing the Lewis acidity of the boron and the reactivity of the C–B bond (9). DAN-protected organoborons have been used in iterative couplings through cross-coupling–deprotection sequences (9, 57), similar to iterative processes enabled by MIDA-protected organoborons.

Introduction of the DAN B-Protecting Group Aryl–BDAN derivatives can be prepared through Miyaura borylation of organohalides with the mixed diboron reagent PinB–BDAN (Scheme 21) (58). Vinyl–BDAN derivatives can be prepared through metal-catalyzed borylation of alkynes with H–BDAN (57) or PinB–BDAN (Scheme 22) (59, 60). Hydroboration of alkynes with H–BDAN in the presence of an iridium catalyst generates predominantly the trans-vinylboronate 29. The use of the mixed diboron reagent PinB–BDAN under similar conditions results in diboration to give the PinB/BDAN-disubstituted vinyl bis-boron adduct 30. The NHC-Cu(I)-catalyzed reaction with PinB–BDAN generates the 1,1-disubstituted vinyl–BDAN adduct 31.

Scheme 21. Miyaura borylation with PinB–BDAN generates aryl–BDAN.

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Scheme 22. Hydroboration or diboration of alkynes to generate vinyl–BDANs. The DAN B-protecting group can be installed onto boronic acids by treatment with diaminonaphthalene under Dean–Stark conditions (Scheme 23), similar to the introduction of the MIDA B-protecting group (9). This reaction has also been reported to proceed under ball milling of the solid reagents at 0 °C (61).

Scheme 23. Protection of boronic acids as BDAN derivatives. BDAN derivatives have also been prepared from trifluoroborates through treatment with TMS-Cl/diaminonaphthalene (46).

Deprotection of DAN B-Protecting Groups DAN B-protecting groups are stable to basic, neutral and weakly acidic conditions but are cleaved through hydrolysis with strong aqueous acid (Scheme 24) (9, 62). The DAN B-protecting group is therefore orthogonal to the MIDA B-protecting group, which is stable to acid but is cleaved with aqueous base.

Scheme 24. Hydrolysis of BDAN derivatives to boronic acids. This simple deprotection method allows for iterative couplings or aryl and vinyl–BDAN derivatives through sequential coupling–deprotection processes incorporating BDAN-protected halo-organoboronates (9, 55, 57). 368 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Interconversion of DAN B-Protecting Groups

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Organo–BDAN derivatives have been converted to the corresponding BPin derivatives through treatment with pinacol under acidic conditions (Scheme 25) (63).

Scheme 25. Transesterification of an alkyl–BDAN to an alkyl–BPin.

The DAN B-protecting group is one of the most stable boronic acid protecting groups; for example, it is unreactive to conditions that convert other organoboron derivatives to the corresponding trifluoroborate (KHF2, MeOH, H2O, rt). This property has been used in the chemoselective conversion of BPin/BDAN bis-boron compounds to the corresponding BF3/BDAN analogues (Scheme 26) (46, 63).

Scheme 26. Selective conversion of BDAN–BPin bisboronates to BDAN–BF3K.

Trifluoroborates as B-Protecting Groups Organotrifluoroborates are commonly employed as bench stable, crystalline forms of organoborons where the corresponding boronic acid is unstable or difficult to handle (12, 13). While most anionic tetracoordinate boron reagents are activated towards transmetalation and are therefore reactive in cross-couplings, trifluoroborates are not due to the high electronegativity of fluorine. Thus, hydrolysis of trifluoroborates to the boronic acid is required for cross-coupling processes (14). This property enables trifluoroborates to act as slow release reagents of the reactive boronic acid, which reduces flux through unproductive routes such as homocoupling and protodeboronation. The trifluoroborate group is protected against various oxidation processes, such as epoxidation and dihydroxylation, which would otherwise oxidize aryl- or vinylboronic acids and esters (Scheme 27). 369 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Scheme 27. Oxidative functionalization in the presence of trifluoroborate.

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Preparation of Trifluoroborates Organotrifluoroborates are routinely prepared from boronic acids or boronate esters by treatment with KHF2 (Scheme 28) (64, 65). They can also be prepared from dibromo- or difluoroboranes by treatment with KF (Scheme 29) (13).

Scheme 28. Conversion of boronic acids/boronate esters to trifluoroborates.

Scheme 29. Conversion of dihaloboranes to trifluoroborates.

Organotrifluoroborates can be prepared from BMIDA derivatives under slightly more forcing conditions (46). The reduced susceptibility of BMIDA compounds to the standard fluorolysis conditions enables selective formation of trifluoroborates in bis-boron compounds (see Scheme 20).

Hydrolysis of Trifluoroborates to Boronic Acids In the presence of water and a fluorophile, trifluoroborates are readily hydrolyzed to the corresponding boronic acids (Scheme 30). Examples of fluorophiles employed to facilitate this process include TMS-Cl (26, 66), silica gel (67), alumina (68) and FeCl3 (69).

Scheme 30. Hydrolysis of trifluoroborates to boronic acids. 370 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Interconversion of Trifluoroborates with Other B-Protecting Groups

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Analogous to the hydrolysis of trifluoroborates in the presence of a fluorophile and water, treatment of trifluoroborates with a fluorophile and the appropriate bis-nucleophile effects the interconversion of trifluoroborates with virtually any other boronic acid protecting group (Scheme 31 (46). For example, treatment of trifluoroborates with TMS-Cl, a base and a diol generates the corresponding boronate ester (70). Use of silica as the fluorophile (67) or the diol bis-silyl ether in place of the diol (71, 72) obviates the need for addition of base. Treatment with MIDA or DAN in place of the diol generates the BMIDA or BDAN compounds, respectively (45, 46).

Scheme 31. Conversion of trifluoroborates to a wide range of other B-protecting groups.

Miscellaneous Boron Protecting Groups Anthranilamide (AAM) (10) and 2-(pyrazol-5-yl)aniline (PZA) (11) B-protecting groups have recently been developed. AAM and PZA B-protected compounds are similar to DAN B-protected compounds in that they possess a tri-coordinate boron with two nitrogen atoms attached. However, they are much more labile than the BDAN group due to less efficient donation of the nitrogen lone pair electrons to the B-atom, due to conjugation through the carbonyl group and nitrogen aromaticity, respectively. These groups act as ortho-directing groups in addition to boron protecting groups. The B-protecting groups are introduced by treatment of the boronic acid with the corresponding bis-nucleophile under Dean-Stark conditions. Use of 2-pyrazol-5-ylaniline generates the aryl-BPZA 32 (Scheme 32) (11). The PZA group directs ortho-silylation in the presence of Et3SiH and a Ru-catalyst to generate 33. Removal of the PZA group is achieved under acidic conditions; aqueous acid generates the boronic acid 34 whereas treatment with pinacol and TsOH generates the pinacol boronate 35. Both 34 and 35 can then be used in subsequent Suzuki–Miyaura reactions. 371 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 32. PZA as a dual B-protecting group and ortho-directing group. The use of anthranilamide generates the aryl–BAAM boronate in a similar manner to preparation of Ar–BPZA (Scheme 33) (10). Removal of the AAM group is again achieved under aqueous acidic conditions to generate the boronic acid, or by treatment with pinacol and TsOH to generate the pinacol boronate ester (Scheme 33).

Scheme 33. Introduction and removal of the BAAM protecting group. The utility of the AAM group as both a B-protecting group and ortho-directing group is highlighted in Scheme 34. AAM-protected m-bromobenzeneboronic acid 36 undergoes a chemoselective Suzuki–Miyaura reaction with tolueneboronic acid to generate the biaryl–BAAM 37. Subsequent ortho-directed silylation generates the silyl arylboronate 38 (10).

Scheme 34. AAM as a B-protecting group and an ortho-directing group.

Conclusion True boronic acid protecting groups have revolutionized the use of organoborons in synthetic chemistry, enabling organoboron functional groups to be carried through multistep protocols, no longer limited to introduction of boron 372 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

at a late stage or subject to immediate transformation. B-Protecting groups enable chemoselective transformations of systems with multiple organoboron functional groups, which has facilitated the development of iterative coupling–deprotection sequences to build up complex molecules in a straightforward manner.

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45. Burke, S. J.; Gamrat, J. M.; Santhouse, J. R.; Tomares, D. T.; Tomsho, J. W. Potassium Haloalkyltrifluoroborate Salts: Synthesis, Application, and Reversible Ligand Replacement with MIDA. Tetrahedron Lett. 2015, 56, 5500–5503. 46. Churches, Q. I.; Hooper, J. F.; Hutton, C. A. A General Method for Interconversion of Boronic Acid Protecting Groups: Trifluoroborates as Common Intermediates. J. Org. Chem. 2015, 80, 5428–5435. 47. Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. General Method for Synthesis of 2-Heterocyclic N-Methyliminodiacetic Acid Boronates. Org. Lett. 2010, 12, 2314–2317. 48. Gillis, E. P.; Burke, M. D. Multistep Synthesis of Complex Boronic Acids From Simple MIDA Boronates. J. Am. Chem. Soc. 2008, 130, 14084–14085. 49. Knapp, D. M.; Gillis, E. P.; Burke, M. D. A General Solution for Unstable Boronic Acids: Slow-Release Cross-Coupling From Air-Stable MIDA Boronates. J. Am. Chem. Soc. 2009, 131, 6961–6963. 50. Fujii, S.; Chang, S. Y.; Burke, M. D. Total Synthesis of Synechoxanthin Through Iterative Cross-Coupling. Angew. Chem., Int. Ed. 2011, 50, 7862–7864. 51. Woerly, E. M.; Roy, J.; Burke, M. D. Synthesis of Most Polyene Natural Productmotifs Using Just 12 Building Blocks and One Coupling Reaction. Nat. Chem. 2014, 6, 484–491. 52. Fyfe, J.; Watson, A. Strategies Towards Chemoselective Suzuki–Miyaura Cross-Coupling. Synlett 2015, 26, 1139–1144. 53. Seath, C. P.; Fyfe, J. W. B.; Molloy, J. J.; Watson, A. J. B. Tandem Chemoselective Suzuki-Miyaura Cross-Coupling Enabled by Nucleophile Speciation Control. Angew. Chem. 2015, 127, 10114–10117. 54. Fyfe, J. W. B.; Seath, C. P.; Watson, A. J. B. Chemoselective Boronic Ester Synthesis by Controlled Speciation. Angew. Chem., Int. Ed. 2014, 53, 12077–12080. 55. Xu, L.; Zhang, S.; Li, P. Boron-Selective Reactions as Powerful Tools for Modular Synthesis of Diverse Complex Molecules. Chem. Soc. Rev. 2015, 44, 8848–8858. 56. Li, J.; Burke, M. D. Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks. J. Am. Chem. Soc. 2011, 35, 13774–13777. 57. Iwadate, N.; Suginome, M. Synthesis of B-Protected Β-Styrylboronic Acids via Iridium-Catalyzed Hydroboration of Alkynes with 1,8-Naphthalenediaminatoborane Leading to Iterative Synthesis of Oligo(Phenylenevinylene)S. Org. Lett. 2009, 11, 1899–1902. 58. Xu, L.; Li, P. Direct Introduction of a Naphthalene-1,8-Diamino Boryl [B(Dan)] Group by a Pd-Catalysed Selective Boryl Transfer Reaction. Chem. Commun. 2015, 51, 5656–5659. 59. Yoshida, H.; Takemoto, Y.; Takaki, K. A Masked Diboron in Cu-Catalysed Borylation Reaction: Highly Regioselective Formal Hydroboration of Alkynes for Synthesis of Branched Alkenylborons. Chem. Commun. 2014, 50, 8299–8302. 376 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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60. Iwadate, N.; Suginome, M. Differentially Protected Diboron for Regioselective Diboration of Alkynes: Internal-Selective Cross-Coupling of 1-Alkene-1,2-Diboronic Acid Derivatives. J. Am. Chem. Soc. 2010, 132, 2548–2549. 61. Kaupp, G.; Naimi-Jamal, M. R.; Stepanenko, V. Waste-Free and Facile Solid-State Protection of Diamines, Anthranilic Acid, Diols, and Polyols with Phenylboronic Acid. Chem. Eur. J. 2003, 9, 4156–4161. 62. Noguchi, H.; Shioda, T.; Chou, C.-M.; Suginome, M. Differentially Protected Benzenediboronic Acids: Divalent Cross-Coupling Modules for the Efficient Synthesis of Boron-Substituted Oligoarenes. Org. Lett. 2008, 10, 377–380. 63. Lee, J. C. H.; Mcdonald, R.; Hall, D. G. Enantioselective Preparation and Chemoselective Cross-Coupling of 1,1-Diboron Compounds. Nat. Chem. 2011, 3, 894–899. 64. Vedejs, E.; Chapman, R.; Fields, S.; Lin, S.; Schrimpf, M. Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates - Convenient Precursors of Arylboron Difluoride Lewis-Acids. J. Org. Chem. 1995, 60, 3020–3027. 65. Bagutski, V.; Ros, A.; Aggarwal, V. K. Improved Method for the Conversion of Pinacolboronic Esters into Trifluoroborate Salts: Facile Synthesis of Chiral Secondary and Tertiary Trifluoroborates. Tetrahedron 2009, 65, 9956–9960. 66. Inglis, S. R.; Woon, E. C. Y.; Thompson, A. L.; Schofield, C. J. Observations on the Deprotection of Pinanediol and Pinacol Boronate Esters via Fluorinated Intermediates. J. Org. Chem. 2010, 75, 468–471. 67. Molander, G. A.; Cavalcanti, L. N.; Canturk, B.; Pan, P.-S.; Kennedy, L. E. Efficient Hydrolysis of Organotrifluoroborates via Silica Gel and Water. J. Org. Chem. 2009, 74, 7364–7369. 68. Kabalka, G. W.; Coltuclu, V. Thermal and Microwave Hydrolysis of Organotrifluoroborates Mediated by Alumina. Tetrahedron Lett. 2009, 50, 6271–6272. 69. Blevins, D. W.; Yao, M.-L.; Yong, L.; Kabalka, G. W. Iron Trichloride Promoted Hydrolysis of Potassium Organotrifluoroborates. Tetrahedron Lett. 2011, 52, 6534–6536. 70. Hohn, E.; Paleček, J.; Pietruszka, J.; Frey, W. Enantiomerically Pure Vinylcyclopropylboronic Esters. Eur. J. Org. Chem. 2009, 3765–3782. 71. Touchet, S.; Carreaux, F.; Molander, G. A.; Carboni, B.; Bouillon, A. Iridium-Catalyzed Allylic Amination Route to α-Aminoboronates: Illustration of the Decisive Role of Boron Substituents. Adv. Synth. Catal. 2011, 353, 3391–3396. 72. Yamamoto, Y.; Hattori, K.; Ishii, J.-I.; Nishiyama, H. Synthesis of Arylboronates Via Cp*Rucl-Catalyzed Cycloaddition of Alkynylboronates. Tetrahedron 2006, 62, 4294–4305.

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Chapter 12

B-Protected Boronic Acids: Methodology Development and Strategic Application Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch012

John J. Molloy and Allan J. B. Watson* Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom *E-mail: [email protected]

Boron reagents are among the most heavily used and studied class of synthetic components throughout the chemical sciences, with essential roles in organic synthesis, sensing, drug design, and materials. Historically, in synthetic chemistry, the use of an organoboron unit generally quickly followed its installation, due to the perceived reactivity of these functional groups to the reaction conditions associated with common transformations. This lack of flexibility over when an organoboron residue is used in a synthetic route has inspired the development of several protecting group strategies. These methods have now enabled the practitioner to carry a boronic acid derivative through synthetic sequences, and releasing it for use when desired. This chapter will discuss several ‘gold standard’ B-protecting groups (BMIDA, BDAN, and BF3K) with a focus on their use in methodological development and target molecule synthesis.

Introduction The chemoselective manipulation of two (or more) ostensibly equivalent functional groups or those with unfavorable reactivity gradients is often encountered within synthetic chemistry. To ensure selectivity, protecting group strategies are often employed to render one group unreactive under the prevailing reaction conditions (1). Functionalisation can then take place without concern over chemoselectivity and the protecting group can then be removed. Careful selection of a protecting group for a particular functionality is therefore crucial: © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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this must be straightforward to install, inert under the planned reaction conditions, and facile to remove. In the context of organoboron compounds, many boron functionalities can be intolerant of the reaction conditions associated with routine organic transformations. As such, organoboron residues have typically been used as soon as possible after installation to avoid potential unwanted degradation, limiting synthetic flexibility. Indeed, prior to the advent of B-protecting groups, carrying a boronic acid through a multi-step synthetic sequence was relatively rare (2–4). Organoboron reactivity is principally driven by the interaction of a nucleophilic species with the Lewis acidic empty p-orbital of boron (5). Accordingly, in order to inhibit the reactivity of an organoboron residue, the Lewis acidity of this orbital must be tempered. This has been the focus of numerous investigations over the last 30 years leading to a series of strategically designed reagents and methods that render organoboron species inert to potential nucleophiles. This now allows protected organoboron residues to be tolerant of a broad range of standard organic chemistry transformations and thereby provides the synthetic chemist the ability to choose the stage at which an installed organoboron functionality is manipulated. Based on their widespread use and accessibility, several of these protecting group methods have now become ‘gold standard’ (Figure 1). These include: N-methyliminodiacetic acid (MIDA) boronic esters, often called MIDA boronates (BMIDA, 1) (6); diaminoboranes, often called boronamides, derived from 1,8-diaminonaphthalene (BDAN, 2) (7); and potassium trifluoroborates (BF3K, 3) (8, 9). As the most prolific protecting groups throughout this area, these three protecting groups will be the basis for the following discussion.

Figure 1. Common organoboron protecting groups.

Preparation and General Information General details for the preparation of BMIDA, BDAN, and BF3K species are provided here; however, for a more detailed discussion of the interconversion of organoboron species, see the chapter by Hutton and co-workers. Boronic Acid N-Methyliminodiacetic Acid (BMIDA) Esters The BMIDA protecting group was initially discovered by Contreras and Mancilla in 1986 (10). This protecting group is derived from Nmethyliminodiacetic (MIDA) acid to which the boron forms two B-O bonds. A strong dative interaction of the ligand’s tertiary amine backbone with the boron p-orbital renders boron sp3 hybridized and provides a hindered tetrahedral structure. It is this occupation of the p-orbital that provides the stability of this 380 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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motif, rendering it inert to many common organic transformations. After synthetic manipulations of other functionalities are complete, the BMIDA unit can be easily hydrolyzed under aqueous basic conditions to reveal the boronic acid (6, 11). BMIDA reagents can be easily synthesized from the parent boronic acids by heating with MIDA acid with extrusion of water (Scheme 1) (6, 11). In addition, BMIDA reagents can also be synthesized from other organoboron species such as pinacol esters (12) and potassium organotrifluoroborates (13).

Scheme 1. General Preparation and Deprotection of BMIDA Species. Boronic Acid Diaminonaphthalene (BDAN) Boronamides Over the past decade, the BDAN motif, pioneered by Suginome, has emerged as a robust boronic acid protecting group (7, 14). 1,8-Diaminonaphthalene forms two strong B-N bonds, but unlike other B-protecting groups, the boron remains neutral and sp2 hybridized: donation of electron density from the lone pairs of the adjacent N atoms is sufficient to lower the reactivity of the boron p-orbital, providing ample protection towards many common reagents. In contrast to BMIDA, BDAN tolerates aqueous basic reaction conditions and is deprotected using aqueous acidic conditions. Similar to BMIDA, BDAN reagents can be readily synthesized through condensation reactions: the boronic acid and 1,8-diaminonaphthalene are heated in toluene with azeotropic removal of water (Scheme 2) (7). BDAN motifs can also be installed using transition metal-catalyzed borylation of aryl halides (15).

Scheme 2. General Preparation and Deprotection of BDAN Species. Potassium Trifluoroborates (BF3K) Potassium organotrifluoroborates (BF3Ks) were first isolated in the 1960s by Chambers (16). However, application of these groups as B-protected boronic acids did not follow until the 1990s. BF3Ks exist as a negatively charged tetrahedral trifluoroborate with an associated potassium countercation and can demonstrate stability in the presence of largely anhydrous basic, acidic, and neutral reaction conditions (8, 9). 381 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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BF3Ks can be prepared using a variety of approaches but perhaps the most notable of these methods is Vedejs’ direct formation of BF3Ks from their boronic acid counterparts using KHF2 (Scheme 3) (17). Treating a boronic acid with a saturated aqueous solution of KHF2 will usually provide good yields of the corresponding BF3K adduct, which are generally isolated by precipitation (8, 9). BF3Ks are readily hydrolyzed using aqueous base to yield the parent boronic acid. However, if the BF3K group is unintentionally hydrolyzed during a reaction, the BF3K group can be restored using KHF2 in the work up procedure (18).

Scheme 3. General Preparation and Deprotection of BF3K Species.

The BMIDA Protecting Group Following their initial discovery in 1986 (10), the BMIDA protecting group received little attention until pioneering studies by Burke and coworkers beginning in the late 2000s (19). Burke has shown that the inert nature of the BMIDA group allows tolerance of an array of standard organic transformations, in particular its retention through cross-coupling processes, allowing for so-called ‘iterative’ cross-coupling (6, 11). BMIDA compounds are typically bench stable solids that can be purified by column chromatography or precipitation (6, 11). While tolerant of relatively mild reaction conditions, they are generally intolerant of relatively hard nucleophiles (organometallics) or high pH media (bases), especially at elevated temperatures (6, 11, 20). However, this property can also be beneficial, permitting in situ cleavage to the latent boronic acid to allow reaction of this residue. Accordingly, BMIDA reagents have two main applications: those that retain the BMIDA unit and those that use the BMIDA unit via in situ hydrolysis.

Synthetic Utility of BMIDAs: Retaining the BMIDA Unit In 2008, Burke demonstrated the stability of aryl BMIDAs to a range of common organic transformations (Scheme 4) (21). Benzylalcohol BMIDA 4 was shown to be resistant to Swern and Jones oxidations, silyl protection and deprotection, and Appel reaction conditions (21). Similarly, the benzaldehyde BMIDA 5 was shown to be tolerant of mild reductive conditions using NaBH4, olefination reactions (Takai and Horner-Wadsworth-Emmons), reductive amination, and Evans aldol processes (21). Besides the reaction conditions themselves, the BMIDA withstood the associated work-up and purification procedures involving brine, aq. HCl, aq. NH4Cl, and aq. NaHCO3 as well as column chromatography (21). 382 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 4. BMIDA Tolerance of Standard Organic Transformations. In addition to their stability towards standard organic transformations, Burke demonstrated the stability of aryl BMIDAs towards Suzuki-Miyaura cross-coupling (under controlled basic conditions) and, in so doing, established a platform for iterative cross-coupling (Scheme 5) (6, 11, 19). Cross-coupling of boronic acid 6 and haloaryl BMIDA 7 delivered biaryl BMIDA 8. Hydrolysis using aq. NaOH revealed the latent boronic acid 9, primed for further cross-coupling. Burke has used this iterative cross-coupling strategy to effect the rapid synthesis of a series of structurally diverse natural products (vide infra). In addition, haloaryl BMIDA species, such as 7, can undergo Miyaura borylation to provide diboryl aryls (13). For a more detailed discussion of the preparation and utility of diboron compounds, see the chapter by Li and co-workers. While aryl boronic acids and esters are readily available, vinyl and ethynyl boronic acids can be unstable and are therefore not generally commercially accessible. However, the corresponding BMIDA reagents are considerably more inert. These are readily prepared allowing a collection of vinyl (22) (eq 1, 10) and ethynyl (23) (eq 2, 11) BMIDA to become commercialized (Scheme 6). 383 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 5. Haloaryl BMIDA Within Iterative Cross-Coupling Reactions.

Scheme 6. Preparation of Vinyl and Ethynyl BMIDA. Similar to the aryl BMIDA counterparts, Burke has shown that bromovinyl BMIDA 12 is a competent electrophile within cross-coupling reactions. Under controlled reactions conditions, 12 efficiently underwent Heck, Stille, SuzukiMiyaura, Sonagashira, and Negishi cross-couplings (Scheme 7) (24).

Scheme 7. Pd-catalyzed Cross-Couplings of Bromovinyl BMIDA 12. 384 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In addition, vinyl BMIDA 10 can participate in a further series of transformations without disruption of the BMIDA unit (Scheme 8). BMIDA 10 is a competent olefin for Heck and oxidative Heck reactions, whilst cyclopropanation and epoxidations of the pendant olefin are also readily achieved (22). Similarly, the olefinic unit participates readily in cross-metathesis reactions (22) and can take part in radical addition reactions (25).

Scheme 8. Functionalization of Vinyl BMIDA 10. In the context of epoxidation, Burke has developed a chiral derivative of MIDA with pinene replacing the N-methyl group (26). This chiral auxiliary, termed PIDA (13), is able to direct diastereoselective epoxidation as well as being viable as a protecting group with properties similar to MIDA (Equation 1).

Alkynyl BMIDA 11 has been shown to be a competent alkyne for Sonogashira cross-coupling (Scheme 9a) (23). In addition, Toste has shown the generated aryl alkynyl BMIDA products to be compatible with Au-catalyzed heterocycle syntheses to deliver indoles, benzofurans, and phthalans (Scheme 9b) (27). Similar to the vinyl BMIDA 10, alkynyl BMIDA 11 has been shown to be tolerant of a range of reaction conditions (Scheme 10) (23). Specifically, 11 can undergo hydroboration and partial or complete reduction via hydrogenolysis (23). Radical hydrostannylation and Diels-Alder chemistries can also be applied to 11 (23). Glorius also reported a Rh-catalyzed C-H activation and annulation protocol using alkynyl BMIDAs to allow the synthesis of borylated heterocycles (28). 385 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 9. Sonogashira Cross-Coupling of 11 and Heterocycle Formation.

Scheme 10. Further Transformations of Alkynyl BMIDA 11. Accordingly, alkenyl and alkynyl BMIDA species are not only robust protected organoboron reagents but the BMIDA unit is still capable of undergoing a broad range of olefin-based transformations. These reagents therefore provide powerful and synthetically flexible units for the installation of organoboron residues. Building on developments by Burke, Yudin has demonstrated the utility of sp3-hybridized BMIDA systems towards the construction of borylated peptides via the Ugi reaction (Scheme 11a) (29) and heterocycles via a series of condensation reactions (Scheme 11b) (30). Yudin has also shown that α–BMIDA aldehydes are a key intermediate that can participate in a diverse series of synthetic 386 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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transformations including olefinations, nucleophilic additions, enolizations, and Tsuji-Trost processes, amongst others (31). In addition to building useful frameworks, these applications further demonstrate the resilience of the BMIDA unit towards synthetic manipulations.

Scheme 11. sp3-Hybridized BMIDA: Access to Borylated Peptides and Heterocycles.

Synthetic Utility of BMIDAs: Using the BMIDA Unit Many boronic acids are known to have issues with stability (5, 32). This primarily manifests in problems associated with protodeboronation and is common to, for example, 2-heterocyclic (5, 33, 34) and alkenyl/alkynyl boronic acids (5, 35). As noted above, alkenyl and alkynyl BMIDAs are significantly more stable than the parent boronic acid. This not only provides a useful method for introducing a boron motif but also provides a method for stabilizing a potentially unstable organoboron compound. With a suitable in situ release strategy, hydrolysis of the BMIDA to reveal the parent boronic acid may then enable more effective control over protodeboronation-prone substrates. In this regard, in 2009 Burke developed a general solution to the problem of using unstable boronic acids in the Suzuki-Miyaura reaction (33, 34). By using a carefully designed slow-release strategy using a mild aqueous base, hydrolysis of BMIDA reagents was effected in situ to provide the parent boronic acid, which underwent Suzuki-Miyaura cross-coupling with substantially improved efficiency than conventionally achieved using the corresponding boronic acid (Scheme 12a) (33). Alkynyl boronic acids can be harnessed using this approach (Scheme 12b) (23) as well as sp3-hybridized species (Scheme 12c) (36). Lipshutz has also shown that in situ hydrolysis of aryl BMIDA can be used to enable Suzuki-Miyaura reactions in aqueous media (37). 387 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 12. In Situ Hydrolysis of BMIDA During Suzuki-Miyaura Cross-Coupling. However, in situ hydrolysis and use of the BMIDA motif is not limited to the Suzuki-Miyaura cross-coupling reaction. In 2010, Ellman developed a Rhcatalyzed asymmetric 1,2-addition of BMIDAs to N-tert-butylsulfinyl aldimines (Ellman imines, Equation 2) (38).

Beyond the transition metal catalysis arena, Bode has developed acyl BMIDA species that are capable of amidation under very mild reaction conditions and in the absence of any additional promoter (Equation 3) (39). A similar process is achievable from acyl BF3Ks, the precursor from which the acyl BMIDAs are accessed (40).

The application of BMIDA via in situ hydrolysis to release the parent boronic acid usually results in the formation of a new C-C bond and loss of the boron residue. However, recent developments by Watson and coworkers have shown that boron speciation can be controlled in situ during the Suzuki-Miyaura cross-coupling (41). Pd-catalyzed reaction of BPin species with haloaryl BMIDA 388 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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allowed formation of a new BPin in a formal homologation process (Scheme 13a) (41). This protocol also works effectively for boronic acids (Scheme 13b) (42).

Scheme 13. Formal Homologation of Organoboron Compounds via Controlled Boron Speciation. The Watson group subsequently demonstrated how this protocol could be leveraged to enable tandem chemoselective Suzuki-Miyaura cross-coupling in one-pot (Equation 4) (43). Combining chemoselective oxidative addition based on known reactivity profiles (44) with their speciation transfer process allowed two consecutive Suzuki-Miyaura reactions with control over the nucleophile-electrophile combinations.

In summary, the BMIDA protecting group enables effective protection of a boronic acid through many common transformations and in various reaction media. The robustness of this motif combined with facile cleavage under aqueous basic conditions has enabled the development of synthetically powerful processes for the generation of both borylated final products (retention of the BMIDA unit), for the effective use of sensitive boronic acids (via controlled release), and for the selective and sequential formation of multiple bonds (use of the BMIDA unit). One of the most powerful applications of the BMIDA protecting group has been its strategic application within iterative synthesis, leading to rapid syntheses of complex, highly functionalized natural products, as discussed below (6, 11, 35). Synthetic Utility of BMIDAs: Strategic Application In 2007, Burke demonstrated the utility of BMIDAs via an iterative Suzuki-Miyaura cross-coupling strategy towards the total synthesis of ratanhine (Scheme 14) (19). A series of simple building blocks were fused together through a sequence of Suzuki-Miyaura cross-coupling and deprotection to complete a short synthesis of the natural product. 389 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 14. Iterative Total Synthesis of Ratanhine.

In 2011, Burke vastly increased the complexity of the total synthesis target by application of a similar approach to synechoxanthin (Scheme 15) (45). Here, a convergent approach was used to assemble the symmetrical polyene from a single tetraene BMIDA intermediate. Burke and coworkers have further advanced the iterative synthesis approach to complex molecule synthesis by developing a robotic system capable of carrying out automated iterative synthesis at “the touch of a button” (46). The engineered system permits deprotection, cross-coupling, and purification of bifunctional haloaryl/haloalkenyl BMIDAs in a highly ordered process. For example, the synthesis of the core structure of citreofuran was accomplished using this system (Scheme 16). Based on the applicability and stability of the BMIDA unit throughout preparative chemistry processes, their ease of synthesis and commercial availability, their utility in iterative cross-coupling, and that these reagents are compatible within automated synthesis, BMIDA represents one of the most powerful and flexible organoboron protecting groups.

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Scheme 15. Iterative Total Synthesis of Synechoxanthin.

Scheme 16. Automated Iterative Approach Towards the Synthesis of Citreofuran.

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The BDAN Protecting Group Aminoboranes have classically been studied within inorganic and main group chemistry (47). However, Suginome and others have exploited the unique protection afforded to boron functional groups by conversion to the corresponding aminoboranes. In particular, aminoboranes derived from 1,8-diaminonaphthalene (DAN) have been developed allowing the direct installation of protected boron functional groups as well as manipulation of boron-bearing molecules without adversely affecting the boron unit. As previously described, the lack of reactivity of the BDAN residue arises from deactivation of the Lewis acidic boron p-orbital achieved via partial delocalization of the adjacent N lone pairs (7, 20). In contrast to other B-protecting groups, BDANs are unique as they are neutral and they also exhibit an increased stability to basic reaction conditions, in contrast to BMIDA and BF3K. This is potentially advantageous in the context of cross-coupling since the majority of, for example, Pd-catalyzed processes are carried out in basic media. BDAN functional groups can be removed by mild acidic conditions to reveal the latent boronic acid. This step is commonly carried out during aqueous work up of a particular reaction (7). This is, again, in contrast to the relative stability of BMIDA and BF3K in acidic media. Accordingly, there is a useful orthogonality to BDAN and BMIDA/BF3K making it possible to select the preferred protecting group based on the anticipated reaction conditions of a planned synthetic sequence.

Synthetic Utility of BDANs: Retaining the BDAN Unit

In 2007, in parallel with the development of BMIDA by Burke, Suginome and co-workers demonstrated the utility of the BDAN protecting group to enable selective Suzuki-Miyaura cross-coupling of diboron systems to generate a new BDAN product (Scheme 17a) (7). Cross-coupling was followed by hydrolysis of the BDAN unit to reveal the parent boronic acid that was primed for further catalytic C-C bond formation. As discussed above, since BDAN are stable towards aqueous basic reaction conditions, Suzuki-Miyaura reactions could be conducted in more routine reaction media using co-solvent levels of H2O (7), unlike the BMIDA processes that are usually performed anhydrously to avoid premature hydrolysis (41). Similarly, symmetrical BDAN-protected diboron compounds can be prepared by exhaustive cross-coupling (Scheme 17b) (48). The BDAN protecting group is more robust than BMIDA under certain reaction conditions, especially in the presence of harder nucleophilic reagents. Consequently, BDAN protection allows extension of the range of reactions in which a protected organoboron can participate, widening the scope of organoboron products that can be accessed. 392 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 17. Selective Suzuki-Miyaura Cross-coupling Using BDAN. For example, the formation of aryne intermediates often involves the presence of hard nucleophilic species. However, in 2013, Akai and Ikawa successfully demonstrated a fluoride-mediated aryne formation in the presence of a BDAN unit followed by in situ nucleophilic amination to access substituted borylanilines (Equation 5) (49). Notably, the group also demonstrated the poor tolerance of other boron species (BPin, BMIDA) towards this protocol, identifying BDAN as the only viable boron functional group.

Similarly, Miura and Hirano exploited the base-stability of BDAN to allow Cu-catalyzed asymmetric hydroamination for the synthesis of chiral α-amino BDAN products (Equation 6) (50). Despite exposure to an excess of LiOt-Bu, the BDAN unit remains intact. This methodology generates a new C-B stereocentre but without relying on conventional approaches via, for example, hydroboration (51).

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Hayashi also exploited alkenyl BDAN to generate chiral BDAN-containing products via Rh-catalyzed asymmetric addition of arylboroxines (Equation 7) (52). Products were isolated as the alcohol following conversion to the pinacol derivative and subsequent oxidation.

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Synthetic Utility of BDANs: Using the BDAN Unit Despite numerous examples of reactions retaining the BDAN functionality, direct reaction of the BDAN group is limited. Direct reaction of the BDAN unit would require an in situ deprotection via hydrolysis to access the latent boronic acid. BDAN requires mild acidic conditions for complete deprotection which limits in situ transformations since the majority of boronic acid-based reactions involve basic reaction conditions. Consequently, the properties that engender BDAN reagents with increased stability to basic media preclude their in situ hydrolysis and use. As a result, BDANs are typically manipulated and deprotected before reaction of the liberated boronic acid (7). Having said this, Hosoya and coworkers reported a synthesis of dibenzoxaborins via chemoselective Suzuki-Miyaura cross-coupling and a subsequent deprotection/cyclization cascade (Equation 8) (53). Following the cross-coupling step, the proximity of the newly installed phenol leads to deprotection and cyclization to furnish the desired dibenzoxaborin.

Synthetic Utility of BDANs: Strategic Application The main strategic application of the BDAN protecting group has been through the development of methods to access diboron compounds. Several examples of this are provided below; for a more detailed discussion of the preparation and utility of diboron systems, see the chapter by Li and co-workers. Similar to the equivalent BMIDA compounds, haloaryl BDAN compounds can be borylated to provide access to useful orthogonally reactive diboron compounds (Scheme 18). This application has been well-explored for BDAN systems with Pd- (a) (48), Ni- (b) (54), and Rh-catalyzed (55) (c) methods all available and applicable to the borylation of a series of haloaryl BDANs.

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Scheme 18. Preparation of Diboron Compounds by Borylation of Aryl BDANs.

Suginome developed an Ir-catalyzed regioselective alkyne diboration using an unsymmetrical diboron reagent (Scheme 19) (56). The resulting diboryl alkene products could then be chemoselectively cross-coupled at the BPin unit. The alkenyl BDAN was then shown to withstand hydrogenation to deliver an alkyl BDAN, which was hydrolyzed and oxidized to deliver alcohol products.

Scheme 19. Ir-Catalyzed Diboration of Alkynes and Subsequent Chemoselective Manipulation of the Resulting Diboryl Alkyne.

Hall and coworkers employed a Cu-catalyzed asymmetric conjugate addition protocol to generate geminal diboryl alkyl compounds with high levels of enantioselectivity (Scheme 20) (51). The resulting diboron compounds contained a reactive BPin and protected BDAN moiety allowing selective functionalization of the geminal diboryl carbon via stereoretentive Suzuki-Miyaura cross-coupling of the BF3K derivative.

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Scheme 20. Regioselective Asymmetric Hydroboration and Chemoselective Suzuki-Miyaura. In summary, the BDAN functionality provides a very stable B-protected boronic acid which can be manipulated under basic or neutral conditions. Its stability to basic media presents some advantages as well as disadvantages over base-labile protecting groups such as BMIDA and BF3K. Importantly, the greater stability of BDAN serves to expand the potential scope of application of protected boronic acids, allowing boron residues to be taken through multiple transformations allowing useful C-C and C-X bond formation on borylated compounds.

The BF3K Protecting Group Organotrifluoroborates were initially described in the 1940’s by Fowler and Kraus who prepared tetramethyl- and tetrabutylammonium (TBA) salts (57). However, isolation and characterization of the potassium trifluoroborate (BF3K) species did not follow until some 20 years later by Chambers (16). Since then, BF3Ks have grown exponentially in popularity, becoming one of the most widely used organoboron reagents within synthetic chemistry. A wide variety of BF3Ks are commercially available – many more than BMIDA and BDAN. In addition, the applications of BF3Ks have been and continue to be thoroughly investigated. As described above, the BF3K functional group serves as a B-protected boronic acid through formation of a tetracoordinate boronate in which the reactive p-orbital is occupied by a fluoride ligand. Unlike BMIDAs, BF3Ks are salts and are therefore incompatible with column chromatography; purification/isolation is typically achieved by precipitation or crystallization (8, 9). The stability of BF3Ks is one of their most attractive features – they are usually bench (i.e., air and moisture) stable at room temperature, and therefore provide a convenient solution for the storage of unstable boronic acids. Similar to BMIDAs, BF3Ks are base labile, allowing for similar reactions based on in situ hydrolysis. Synthetic Utility of BF3Ks: Retaining the BF3K Unit In 2006, the Molander group successfully demonstrated the stability of potassium and tetra-n-butylammonium (TBA) trifluoroborates under oxidative 396 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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conditions (58). The oxidation of hydroxy-substituted TBA trifluoroborates proceeded in excellent yields under TPAP, Swern, and Dess-Martin conditions with complete retention of the trifluoroborate salt (Scheme 21a). Oxidation of non-benzylic alcohols was also shown to be viable using TPAP (Scheme 21b).

Scheme 21. Alcohol Oxidation in the Presence of BF3K. BF3Ks were also shown to tolerate Upjohn dihydroxylation using catalytic OsO4 and NMO, ensuring the integrity of the B-protected boronic acid under otherwise incompatible reaction conditions (Equation 9) (59).

The BF3K group is also generally tolerant of mild olefination processes including Wittig (Scheme 22a), stabilized Wittig (Scheme 22b), and Horner-Wadsworth-Emmons (Scheme 22c) reactions (60).

Scheme 22. Olefination of Aryl and Heteroaryl BF3Ks. 397 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Perhaps more impressively in the context of protecting group robustness, Molander demonstrated the stability of the BF3K unit towards lithium-halogen exchange (Scheme 23) (18). Lithiation of haloaryl BF3K 13 using n-BuLi at -78 °C generated the expected aryl lithium reagent 14, which could react with a selection of electrophiles. It is important to note that KHF2 was used in the quench of these reactions to ensure quantitative BF3K recovery, in the event of any unwanted hydrolysis.

Scheme 23. Lithiation and Subsequent Electrophile Trapping of Haloaryl BF3Ks. While the above examples showcase how BF3Ks can be used to protect the latent boronic acid, the primary application of BF3Ks is to provide a bench stable reservoir of boronic acid. This is especially important in the context of unstable boronic acid derivatives and enables the effective use of species which are otherwise difficult to handle/use. The section below describes several applications where the BF3K is used in situ. Synthetic Utility of BF3Ks: Using the BF3K Unit Batey demonstrated that allyl and crotyl BF3K species perform effectively in nucleophilic 1,2-addition processes to give the expected products with the anticipated diastereoselectivity (Equation 10) (61).

Batey also showed that Rh-catalysis enables nucleophilic 1,2- and 1,4-addition processes, using aryl BF3Ks as the requisite nucleophile, with both aldehydes (Scheme 24a) and α,β-unsaturated carbonyl compounds (Scheme 24b), respectively (62). 398 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 24. Rh-Catalyzed 1,2- and 1,4-Addition of RBF3K. Metal catalysis is typically required to enable nucleophilic addition of RBF3Ks based on activation of the nucleophile (i.e., the BF3K). However, MacMillan has shown that aryl and vinyl BF3Ks are sufficiently nucleophilic to participate in asymmetric bond forming reactions using organocatalysis. Here, the electrophile substrate is activated, with iminium catalysis facilitating Friedel-Crafts alkylations of aryl BF3Ks (Scheme 25a) (63). and singly occupied molecular orbital (SOMO) catalysis generating a platform for vinylation of aldehydes (Scheme 25b) (64).

Scheme 25. Organocatalytic Nucleophilic Addition of RBF3K. Perhaps the most widely known use and function of BF3Ks are as a source of boronic acid for Suzuki-Miyaura cross-coupling – an area championed primarily by Molander (8, 9). The advantages described in the previous sections have led to BF3Ks being one of the most broadly used nucleophiles for Pd-catalyzed C-C bond formation. The classic use of the Suzuki-Miyaura reaction to forge sp2-sp2 C-C bonds is readily achievable using BF3Ks as the nucleophile. This accommodates aryl (Scheme 26a) (65, 66), vinyl (Scheme 26b) (67), and, 399 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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notably, notoriously unstable heteroaryl nucleophiles (Scheme 26c) (68). This latter use is complementary to the use of BMIDA reagents to facilitate the same type of difficult C-C bond formation while avoiding side reactions (primarily protodeboronation) as much as possible.

Scheme 26. Use of sp2-Hybridized BF3Ks for Suzuki-Miyaura Cross-Coupling. BF3K nucleophiles have also been developed for use within sp2-sp3 cross-coupling. Primary BF3Ks are cross-coupled with good efficiency (Scheme 27a) (69) and while secondary nucleophiles presented issues with the generation of mixtures of branched and linear products (Scheme 27b) (70), this has seen improvement with the use of unprotected boronic acids (71). Biscoe has also developed robust reaction conditions that inhibit β-hydride elimination of secondary BF3Ks, allowing for significantly improved branched:linear product distributions (72).

Scheme 27. Use of Primary BF3Ks in sp2-sp3 Suzuki-Miyaura Cross-Coupling. A particularly useful application of BF3K Suzuki-Miyaura reactions is that heteroatom-substituted nucleophiles (i.e., carbenoids) are readily prepared and accommodated allowing for the direct installation of methylamino (73) (Scheme 28a) and methylalcohol (74) (Scheme 28b) functional groups. 400 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 28. Suzuki-Miyaura Cross-Coupling of Carbenoid BF3K Nucleophiles.

Based on the success of BF3K nucleophiles within sp2-sp3 cross-coupling, the natural step to enantioselective variants was prosecuted using chiral non-racemic BF3Ks. Molander developed reaction conditions that allowed stereoretentive sp2-sp3 cross-coupling (Scheme 29a) (75). Here, the stereochemistry from the BF3K nucleophile is relayed with high fidelity to the product. Stereoretentive cross-coupling of BF3Ks was also observed in reactions of diboron compounds developed by Hall (see Scheme 20) (51). Conversely, using their conditions developed to inhibit β-hydride elimination, Biscoe and coworkers developed a stereoinvertive Suzuki-Miyaura cross-coupling of secondary BF3K nucleophiles (Scheme 29b) (72). The stereochemical information is, once again, relayed effectively to the product but in this case with inversion. From these observations and other studies (76–82), the stereochemical course of similar sp2-sp3 cross-couplings appears to be dependent on both the substrate and reaction conditions.

Scheme 29. Use of Chiral Non-Racemic BF3Ks in sp2-sp3 Suzuki-Miyaura Cross-Coupling Reactions.

Moving beyond Pd catalysis, in 2015 Molander and co-workers designed and developed a cooperative Ir/Ni catalysis process for sp2-sp3 cross-coupling of alkyl BF3Ks (Scheme 30). Molander has shown this process to be effective for primary BF3Ks (Scheme 30a) (83), secondary BF3Ks (Scheme 30b) (84), and carbenoid BF3Ks (Scheme 30c) (85). In addition, use of a suitable ligand for the Ni catalyst permits enantioselective C-C bond formation from racemic BF3Ks, albeit with moderate levels of enantioinduction (Scheme 30d) (83). 401 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 30. Ir/Ni-Catalyzed Chemoselective sp2-sp3 Cross-Coupling.

Lastly, BF3Ks can be employed within Cu-catalyzed C-X bond forming reactions. Specifically, broadly similar to the use of boronic acids, Batey has shown that BF3Ks are effective reaction partners within Chan-Evans-Lam-type C-N (Scheme 31a and b) (86, 87) and C-O (Scheme 31c and d) (88, 89) bond formation.

Synthetic Utility of BF3Ks: Strategic Application BF3Ks have seen widespread uptake and use throughout the synthetic chemistry arena. As such, a full account of their use is beyond the scope of this chapter. However, several notable examples of the strategic use of BF3Ks are given below. For a more complete discussion of the use of BF3Ks, see current reviews (8, 9). As discussed above, BF3Ks are competent nucleophiles for allylation. Batey employed 3-methyl-2-butenyl BF3K for a diastereoselective nucleophilic allylation en route to the depsipeptides kitastatin and respirantin (Scheme 32) (90). 402 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 31. Use of BF3Ks in Cu-Catalyzed C-X Bond Formation.

Scheme 32. Diastereoselective Nucleophilic Allylation Using a BF3K Reagent.

In 2007, MacMillan used an aryl BF3K as the nucleophile for an iminiumcatalyzed enantioselective Friedel-Crafts reaction to facilitate a rapid synthesis of frondosin (Scheme 33) (91). 403 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 33. Iminium-catalyzed Friedel-Crafts Reaction of BF3K.

Similar to BMIDAs and BDANs, BF3Ks have been used to allow the installation of a second, more reactive boron functional group and thereby enable chemoselective cross-coupling. Molander and co-workers developed a sequential hydroboration/chemoselective Suzuki-Miyaura cross-coupling protocol. 4-Styrenyl BF3K underwent hydroboration with 9-BBN and, following addition of Pd catalyst, ligand, base, and electrophile, a subsequent cross-coupling of the newly installed trialkyl boron unit (Scheme 34a) (92). In this way the BF3K motif was retained, and could then be used for further bond formation. The natural extension of this process followed, allowing one-pot tandem chemoselective cross-coupling: hydroboration, trialkyl boron cross-coupling with an electrophile and then addition of a second catalyst and electrophile allowed cross-coupling of the aryl BF3K (Scheme 34b) (92). It is important to note that the integrity of the BF3K unit during the first cross-coupling step was ensured by inhibiting hydrolysis through use of KF as the base in an aprotic solvent. The second step employed an inorganic base (K2CO3) in MeOH to assist BF3K hydrolysis, which is required for effective cross-coupling. Building on his recently established platform, Molander has shown that reactive BPin units are tolerated within the Ir/Ni cooperative catalysis sp2-sp3 cross-coupling platform (Scheme 35) (93). This allows a sequential chemoselective Ir/Ni-catalyzed sp2-sp3 cross-coupling of the BF3K, which, without purification, is followed by treatment with a Pd catalyst and electrophile to allow a conventional Suzuki-Miyaura sp2-sp2 cross-coupling of the remaining BPin unit. The remaining electrophilic site can then undergo Buchwald-Hartwigtype amination to deliver a highly functionalized product. Accordingly, this Ir/Ni approach effectively reverses the observed chemoselectivity established in the above (Scheme 34) hydroboration/cross-coupling process.

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Scheme 34. One-pot Hydroboration and Chemoselective Suzuki-Miyaura Cross-Coupling of BF3Ks.

Scheme 35. Chemoselective Sequential sp2-sp3 and sp2-sp2 Cross-Coupling.

BF3K-based Suzuki-Miyaura cross-coupling has also been strategically applied in the total synthesis of bioactive compounds and natural products. For example, vinyl BF3K was used for a late stage cross-coupling in the synthesis of a Raf kinase inhibitor (Scheme 36) (94). Here, the use of vinyl BF3K provides some advantages over alternative methods: vinyl boronic acid is unstable and other competent nucleophiles, such as vinyl stannanes, have greater health and safety issues.

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Scheme 36. Application of Vinyl BF3K Within the Synthesis of a Raf Kinase Inhibitor. An alkenyl BF3K was also pivotal within Molander’s synthesis of oximidine II where an intramolecular Suzuki-Miyaura cross-coupling generated the macrocyclic framework (Equation 11) (95).

In summary, BF3Ks are a broadly useful class of B-protected boronic acid. Their ease of synthesis and commercial availability has rendered these reagents the most widely used class of protected organoboron reagents. Similar to BMIDA, the base lability of this species allows for in situ deprotection and use of the latent boronic acid – providing a method for the stabilization of otherwise unstable boronic acids has been the primary use of this protecting group. While its use as a protecting group has been demonstrated in a series of elegant applications, the base lability of this motif means that precautions must be taken to avoid premature hydrolysis in specific reaction media; however, this can be easily mitigated by use of KF as the requisite base reagent and/or use of a KHF2 work-up procedure to restore the BF3K unit.

Conclusion In conclusion, the organoboron functional group underpins some of the most important and widely practiced chemical reactions. The ability to ensure the integrity of an installed organoboron unit through several steps of a particular synthesis provides the practitioner with increased flexibility, potentially allowing an increase in synthetic efficiency of a chosen route or diversity at a late stage in a target molecule synthesis. Of the classes discussed above, the BF3K unit 406 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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is the most widely employed, but its uses are typically as a reservoir of boronic acid rather than a protecting group to ensure a boronic acid survives a particular transformation. BMIDA has emerged as a viable protecting group that can both guard against boronic acid decomposition as well as enable powerful iterative synthesis approaches to complex molecule synthesis. Both BF3K and BMIDA are base labile and so precautions must be taken to ensure premature hydrolysis is avoided. However, this base-lability can be advantageous by enabling in situ deprotection and subsequent bond formations using the liberated boronic acid. Although less used, the BDAN protecting group is more robust towards basic media. This ensures that the protected boronic acid can survive reaction conditions that would be incompatible with BF3K and BMIDA, and therefore extends the potential applications of B-protecting group strategies. The orthogonality of these three B-protecting groups is important as it provides the user with options – a practitioner can now choose the desired properties of the protecting group that would best serve their planned synthesis.

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88. Quach, T. D.; Batey, R. A. Copper(II)-catalyzed ether synthesis from aliphatic alcohols and potassium organotrifluoroborate salts. Org. Lett. 2003, 5, 1381–1384. 89. Huang, F.; Quach, T. D.; Batey, R. A. Copper-catalyzed nondecarboxylative cross-coupling of alkenyltrifluoroborate salts with carboxylic acids or carboxylates: Synthesis of enol esters. Org. Lett. 2013, 15, 3150–3153. 90. Beveridge, R. E.; Batey, R. A. An Organotrifluoroborate-based convergent total synthesis of the potent cancer cell growth inhibitory depsipeptides kitastatin and respirantin. Org. Lett. 2014, 16, 2322–2325. 91. Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D. W. C. The organocatalytic three-step total synthesis of (+)-frondosin B. Chem. Sci. 2010, 1, 37–42. 92. Molander, G. A.; Sandrock, D. L. Orthogonal reactivity in boryl-substituted organotrifluoroborates. J. Am. Chem. Soc. 2008, 130, 15792–15793. 93. Yamashita, Y.; Tellis, J. C.; Molander, G. A. Protecting group-free, selective cross-coupling of alkyltrifluoroborates with borylated aryl bromides via photoredox/nickel dual catalysis. Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 12026–12029. 94. Oikawa, N.; Mizuguchi, E.; Morikami, K.; Shimma, N.; Ishii, N.; Tsukaguchi, T.; Ozawa, S. Heteroarylphenylurea derivative. WO 2005080330, 2005. 95. Molander, G. A.; Dehmel, F. Formal total synthesis of oximidine ii via a suzuki-type cross-coupling macrocyclization employing potassium organotrifluoroborates. J. Am. Chem Soc. 2004, 126, 10313–10318.

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Chapter 13

Di- and Polyboron Compounds: Preparation and Chemoselective Transformations Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch013

Liang Xu,1,2 Shuai Zhang,1 and Pengfei Li1,* 1Center

for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi, 710054 China 2School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang, 832003 China *E-mail: [email protected]

Boron-selective chemical transformations of di- and polyboron compounds have emerged as a useful strategy for modular assembly of complex molecules. There has been great progress in this type of approach in the last decade based on the development and discriminate utilization of various boron species. These advances have encouraged modular construction of molecular diversity and complexity from easily-prepared or commercially available building blocks, as well as led to simplifying synthetic design and experimental operations. For this reason, this chapter will survey and present an overview of representative advances in this emerging field.

Introduction The biosynthesis of complex molecules, such as polypeptides, generally involves modular assembly processes based on simple di- and/or polyfunctionalized building blocks, such as amino acids. With nature as the model, modular synthesis of complex molecules from simple building blocks might provide an opportunity to simplify some daunting organic synthesis. Thus, increasing attention has been paid to the development and utilization of effective building blocks and the corresponding assembly methodologies. Modular synthesis generally involves consecutive chemoselective transformations, which are critical to the precise construction of molecular © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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diversity and complexity. Among them, boron-selective transformations (1) based on functionally different boronyl groups are of particular importance since boronyl species are generally easily-prepared, shelf-stable, environment-friendly and compatible with diverse functional groups. Generally, boron-selective reactions refer to the chemical transformations in which the reactivity of two or more boronyl groups can be discriminated. Under certain reaction conditions, certain boronyl groups can be distinguished by promoting the conversion of the more reactive boronyl group and leaving the relatively inert boronyl group intact. The remaining boronyl group can usually be utilized and converted to other functional groups under different reaction conditions, therefore providing flexible and consecutive synthetic approaches to complex molecules. The key to realizing a boron-selective reaction is to differentiate the boronyl groups under the same reaction conditions. The different reactivity of boronyl groups sometimes derives from the different steric and/or electronic environment of the carbon atoms bearing the boron groups. In other cases, a proper combination of different masking groups on boron atoms plays a critical role. In 2007, Suginome (2) and Burke (3) independently realized the masking group-based boron-selective Suzuki–Miyaura coupling (SMC) reactions. These achievements supply a general solution for the difficulties in the preparation of functionalized organoboron reagents and inspired the following exploration in this field. This strategy has been developed rapidly and significant progress has been made in the last decade not only in SMC reactions but also in some other (catalyzed) transformations, contributing greatly to the prosperity of boron-selective transformations and providing efficient modular and even automated routes to synthesize natural products and organic materials (4). Boron-selective reactions may be classified into two categories based on the involved organoboron starting materials: one involves the utilization of two competitive organoboron reagents (Scheme 1, A), and the other utilizes di- or polyboron reagents (Scheme 1, B). This review will focus on the latter type of transformations and introduce the representative advances in this field, including the preparation (5) and chemoselective transformations of di- and polyboron compounds. Through multiple functionalizations of the C–B bonds, the boronyl groups on di- or polyboron building blocks are differentiated in successive reactions, and diverse structures will be achieved by making full use of each boronyl group. The following section will discuss the boron-selective reactions where boronyl groups of di- or polyboron reagents are reacted chemoselectively. Detailed discussion will be categorized according to the reaction type and starting materials used. The development and utilization of the former type of reactions (Scheme 1, A), specifically innovative examples in iterative coupling reactions (6), will not be discussed here but can be found in another separate chapter (by Dr. Watson). There is also a specific chapter (by Drs. Churches and Hutton) discussing the preparation and deprotection of protected boronic acid species. We would like to refer readers to these discussions when necessary.

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Scheme 1. Boron-Selective Chemical Transformations.

Boron-Selective SMC Reactions Since the inception of Suzuki-Miyaura coupling (SMC) reaction in 1979, it has become one of the most powerful and reliable methods for C–C bond construction (Scheme 2, A) (7). Along with this development, in order to synthesize more complicated molecules, synthetic chemists have also made great efforts to realize successive SMC reactions using multifunctionalized reagents. Electrophile-selective SMC reactions (Scheme 2, B), based on the discrimination of various electrophilic sites with leaving groups such as (pseudo)halogens, have been well developed to achieve this goal. In contrast, nucleophile-selective SMC reactions (Scheme 2, C) based on the discrimination of different boron sites on the same reagent have been far less explored, largely due to the difficulties in the preparation of di- or polyboron reagents.

Scheme 2. SMC Reactions and Strategies towards Successive SMC Reactions.

417 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

In the last decade, thanks to the discovery of feasible (catalytic) methods for preparing di- and polyboron reagents and utilization of several powerful boron-masking groups, boron-selective SMC reactions have also gained great development (8). We would like to highlight the representative examples in which boronyl groups of di- or polyboron reagents are well differentiated.

1,1-Diborylalkanes

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1,1-Diborylalkanes with Two Identical Boronyl Groups In 2009, Shibata and coworkers reported a Rh-catalyzed method towards the preparation of 1,1-diborylalkanes via sequential regioselective hydroboration of terminal alkynes at room temperature (Scheme 3, A) (9).

Scheme 3. Chemoselective SMC Reactions of 1,1-Diborylalkanes.

Later, the same group realized the chemoselective SMC of 1,1-diborylalkanes for the first time (10). Generally, the palladium-catalyzed SMC reactions of alkyl boronates suffer from slow transmetalation, hence harsh conditions and/or excess alkyl boronates are usually necessary to achieve high yield for such transformations. However, Shibata’s group demonstrated that gem-bis-B(pin)-substituted alkanes were competent in chemoselective SMC 418 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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reactions and two pinacol boronates on the same C(sp3) atom could be well differentiated at room temperature (Scheme 3, B). At elevated temperature, side reactions such as protodeboronation occurred whereas it could be prevented at room temperature. Aryl iodides and bromides were both suitable electrophiles in these SMC reactions and extensive screening revealed that the utilization of strong bases such as LiOH, NaOH or KOH was necessary for successful transformations. A gem-boryl-assisted transmetalation process via a monoborate intermediate was proposed to be the key to the success of this chemoselective coupling reaction. In contrast, this type of transmetalation could not be achieved with common C(sp3)–B(pin) groups under mild conditions. After the first catalytic coupling, a common C(sp3)–B(pin) group without an adjacent B(pin) moiety was formed, which was reluctant to become a borate intermediate hence would not react further in SMC reactions under the same reaction conditions. This reactivity is seen with the competing reaction between reagents 1 and 2 (Scheme 3, C). As shown in Table 1, further exploration towards the chemoselective SMC reactions of diborylmethane revealed that an equimolar amount of KOH with diborylmethane, which ensured the predominant generation of monoborate intermediates and prevented the generation of detrimental diborate intermediates, was necessary for efficient conversion (11). This method could be used in preparing various benzylboronate derivatives.

Table 1. Chemoselective SMC Reactions of Diborylmethane.

Shibata’s group also disclosed a one-pot synthetic method towards various symmetrical and unsymmetrical diarylmethanes from diborylmethane via sequential SMC reactions (12). By adjusting the reaction temperature and the amount of base used, the reaction could be well controlled to achieve high yields of unsymmetrical diarylmethanes (Scheme 4, A). 419 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 4. Sequential Chemoselective SMC Reactions of 1,1-Diborylalkanes.

In 2014, a new and convenient synthetic approach towards 1,1-diborylalkanes which proceeded via gem-diborylation of N-tosylhydrazones under transitionmetal-free conditions, was developed by the Wang group (13). They also explored the stepwise couplings of 1,1-diborylalkanes with two aryl halides, which afforded diarylalkane derivatives in moderate yields (Scheme 4, B). The same group also developed an efficient synthetic method for preparing 9H-fluorenederivatives via sequential SMC reactions of 1,1-diborylalkanes with and 2,2′-dibromobiphenyls (Scheme 4, C) (14).

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When vinyl bromides were treated with 1,1-diborylalkanes, boron-selective SMC reactions were also feasible, affording allylboron intermediates which could be isolated in moderate yield when 2,2-disubstituted vinyl bromides were used as the electrophiles. However, when 2-monosubstituted vinyl bromides and 1,1-dibromoalkenes were used as starting materials, 1,4-dienes and allenes were ultimately generated respectively via allylboron intermediates (Scheme 5) (15).

Scheme 5. SMC Reactions of 1,1-Diborylalkanes with Vinyl Bromides.

Recently, taking advantage of a suitable combination of chiral ligands and palladium precursors, asymmetric boron-selective SMC reactions of 1,1-diborylalkanes with aryl/vinyl halides have been developed by Morken and coworkers, enabling the efficient construction of nonracemic chiralbenzylboronates (16) from aryl iodides or bromides and γ,γ-disubstituted allylboronates (17) from 2,2-disubstituted vinyl bromides. For the construction of C(sp3)–C(sp3) bonds, Shibata’s group discovered that the palladium-catalyzed coupling reactions between diborylmethane and allyl halides or benzyl halides proceeded efficiently at room temperature, providing various homoallylboronates and alkylboronates with excellent chemoselectivity (Scheme 6, A) (18).

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Scheme 6. Three Types of Reactions for C(sp3)–C(sp3) Bond Construction from 1,1-Diborylalkanes

Nonactivated primary alkyl electrophiles, which had not been utilized in palladium-catalyzed SMC reactions with 1,1-diborylalkanes, were found to be competent in similar copper-catalyzed/promoted transformations (19). By virtue of the chemoselective construction of C(sp3)–C(sp3) bonds, this method provided a new strategy for the preparation of alkylboronates. Generally, when more hindered 1,1-diborylalkaneswere utilized in such transformations, more copper salt is necessary to achieve efficient conversion and high yield (Scheme 6, B). In 2014, Morken’s group discovered that alkoxide-promoted selective deborylative alkylation of 1,1-diborylalkanes could be achieved under catalyst-free conditions (Scheme 6, C) (20). A boron-stabilized carbanion could be generated via alkoxide-induced deborylation, which was then trapped by alkyl halides, affording a simple and reliable access to alkylboronates. They conducted the deborylative alkylation reaction of 1,1-diborylethane with benzyl chloride under nitrogen, affording > 6g of product in 87% yield. In the three types of reactions mentioned above, when allyl(pseudo)halides were treated with diborylalkanes, SN2-selective alkylation products were always obtained, affording linear alkylboronates. More recently, Cho’s group realized copper-catalyzed SN2′-selective alkylation reactions of diborylalkanes with allylchlorides, affording branched alkylboronates (21). For examples, under the catalysis of CuI, diborylmethane could couple efficiently with cinnamyl phosphate in an SN2-selective version to obtain linear alkylboronate 3 (Scheme 7, A). However, when catalyst and electrophile were changed to Cu(IMes)Cl and cinnamyl chloride, respectively, the branched product 4 was formed in 78% yield under proper conditions (Scheme 7, B).

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Scheme 7. SN2-Selective vs SN2′-Selective Alkylation of Diborylmethane.

1,1-Diborylalkanes with Two Different Boronyl Groups By virtue of proper combinations of copper precursors and chiral ligands, enantiomerically enriched gem-B(pin)/B(dan) compounds could be prepared via regio- and enantioselective hydroboration of B(dan)-substituted alkenes with B2(pin)2, as reported by Hall’s (22) and Yun’s (23) groups, respectively (dan = 1,8-diaminonaphthalene). The newly-incorporated B(pin) moiety could be converted to corresponding BF3K group, which was then applied in chemoselective and stereoselective SMC reactions with various organic electrophiles, affording enantioenriched benzylic or allylic boronates. The reserved B(dan) moiety could be deprotected under acidic conditions and then utilized in the following SMC reactions (Scheme 8).

1,2-Diborylalkanes Formal asymmetric carbohydroxylation of alkenes was realized by Morken’s group by virtue of a tandem one-pot asymmetric diboration/boron-selective SMC/ oxidation sequence in 2004 (24). In this process, Rh-catalyzed enantioselective diboration of terminal aliphatic alkenes with B2(cat)2 afforded chiral 1,2-diborylalkane intermediates, which could in situ participate in boron-selective coupling with aryl halides and aryl triflates. More accessible primary C–B(cat) bonds reacted faster, leaving the secondary C–B(cat) bonds intact that were then oxidized to hydroxyl groups (Scheme 9). This one-pot transformation provided a concise method for preparing versatile optically active intermediates from simple alkenes.

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Scheme 8. Synthesis and Application of gem-B(pin)/B(dan) Compounds.

Scheme 9. Formal Asymmetric Carbohydroxylation of Alkenes.

Later, the same group described a tandem one-pot diboration/hydroboration/ boron-selective SMC/oxidation sequence, facilitating the enantioselective synthesis of chiral aromatic and alkenyl diols (25). Pd-catalyzed enantioselective diboration of prochiral allenes afforded chiral allyl vinyl boronates, which went through hydroboration with 9-BBN to form triboron intermediates. Then, by simply adding aryl/vinylhalides and Cs2CO3, boron-selective SMC reactions occurred efficiently and diastereoselectively without an additional palladium catalyst or ligand. The least hindered C–B bonds reacted selectively and the two inert boronyl groups were oxidized to hydroxyl groups to generate diols products (Scheme 10).

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Scheme 10. The Synthesis and Application of Triboron Intermediates.

In 2008, Molander’s group described that organotrifluoroborates containing alkene moiety could undergo hydroboration with 9-BBN to prepare diverse diboron products (26), including the 1,2-diborylethane (27). Chemoselective SMC reactions between the resulting trialkylboranes and aryl/vinyl halides could be realized, affording organotrifluoroborates which could be isolated or exposed to the following coupling reactions in a one-pot version (Scheme 11). The 1,2-diborylethane thus could function as a 1,2-dianion equivalent to link two different electrophiles via palladium-catalyzed sequential SMC reactions.

Scheme 11. The Synthesis and Application of 1,2-Diborylethane.

Taking advantage of a chiral imidazolinium salt, Hoveyda’s group realized a Cu-catalyzed enantioselective tandem double-hydroboration of terminal alkynes, (28), furnishing enantiomerically enriched 1,2-diborylalkanes such as product 5 (Scheme 12). A following boron-selective SMC reaction was also feasible with the terminal primary C–B bond reacting with β-bromoenone 6 chemoselectively.

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Scheme 12. Cu-Catalyzed Double Hydroboration of Alkynes and SMC Reaction.

In 2014, Morken’s group realized Pt-catalyzed asymmetric diboration of terminal alkenes with B2(pin)2 (29). The obtained 1,2-diborylalkanes were also compatible with boron-selective SMC reactions. They also demonstrated that the presence of a β-B(pin) could greatly accelerate the transmetalation of the less hindered primary B(pin) group. Since the boronyl groups could function as versatile functional group precursors, the previously unreacted secondary B(pin) groups were readily transformed to afford a broad array of chiral compounds. Thus, the enantioselective diboration/selective cross-coupling (DCC) strategy, combined with further conversion of boronyl groups, provided a reliable and flexible platform that could convert readily available terminal alkenes into complex chiral compounds. As shown in Scheme 13, for the synthesis of the pharmaceutical agent Lyrica (pregabalin), by virtue of the DCC strategy, chiral secondary boronic ester 7 was prepared conveniently from two simple alkenyl substrates in excellent yield. Subsequently, the stereospecific boronates homologation, amination and protection sequence afforded intermediate 8, which was then oxidized and deprotected to complete the synthesis, affording the aimed product in an overall 36% yield from 7. In the above-mentioned examples, when 1,2-diborylalkanes were exposed to SMC reactions, the less hindered C–B bonds usually reacted preferentially. Very recently, Morken’s group developed a novel β-hydroxyl-directed regioselective coupling reactions of 1,2-diborylalkanes to inverse such selectivity, enabling boron-selective SMC reactions of the inherently less reactive secondary C–B bonds preferentially (Scheme 14) (30).

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Scheme 13. DCC Strategy and Its Application.

Scheme 14. Hydroxyl-Directed Selective SMC Reactions.

This hydroxyl-directed selective SMC reaction merged seamlessly with hydroxyl-directed metal-free diboration and thus allowed for rapid functionalization of homoallylic alcohol derivatives. Importantly, the reaction was compatible with various electrophiles such as (hetero)aryl and alkenyl halides/triflates. Not only terminal alkenes, but also internal olefins and trisubstituted alkenes were suitable starting material for such transformations. This achievement might inspire the development of other novel innovative strategies to overcome the inherent electronic and/or steric limitations in boron-selective SMC reactions.

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Di- and Polyborylalkenes The selective SMC reactions of di- and polyborylalkenes which bear two similar boronyl groups have been well-documented, enabling the stereocontrolled preparation of polysubstituted olefins that are important structural motifs in natural products and functional materials. This strategy was explored as early as 1996 and revealed by Miyaura’s group (31). They realized the synthesis of (E)-1,2-bis(boryl)-1-hexene via the platinum-catalyzed diboration of 1-hexyne with B2(pin)2. Then regioselective SMC reaction occurred between this diborylalkene and aryl, vinyl, benzyl and allyl halides, providing the corresponding (E)-(1-butyl-1-alkenyl)boronic esters in good yields. The less hindered terminal C–B bond reacted preferentially (Scheme 15).

Scheme 15. Boron-Selective SMC Reactions of 1,2-Diborylalkenes. More recently, Sawamura’s group developed phosphine-catalyzed anti-selective vicinal diboration of the triple bond in alkynoates to prepare α,β-diborylacrylates (32) such as compound 9. The two boronyl groups of the diborylacrylates could be differentiated and transformed in sequential SMC reactions, affording a diversity of unsymmetrical tetrasubstituted alkenes. The first SMC reaction occurred selectively at the α-boron site to give alkenylboronate 10 without the formation of the diarylation product (Scheme 16). Such selectivity is probably due to the presence of the ester group whose electron-withdrawing resonance effect might render the β-carbon less nucleophilic.

Scheme 16. Boron-Selective SMC Reactions of α,β-Diboryl Acrylates. 428 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In 2001, Hiyama and Shimizu developed a strategy to prepare 1,1diborylalkenes such as compound 12 via gem-diborylation of 1,1-dibromoalkenes with B2(pin)2 (33). They also demonstrated the feasibility of stepwise SMC reactions for such products. An allylation/phenylation sequence afforded double coupling product 13 in a high overall yield (Scheme 17).

Scheme 17. Preparation and Application of 1,1-Diborylalkenes.

Later, Hiyama and Shimizu realized the stereoselective SMC reactions of 1,1-diboryl-2-arylalkenes (34). Perfect discrimination of two geminal alkenyl boryl groups could be achieved and the coupling reaction with aryl/vinyl iodides took place exclusively with the boryl moiety trans to the aryl groups. In combination with the subsequent SMC reactions of previously inert boronyl groups, the whole stepwise SMC approach provided an efficient and stereocontrolled access to triarylated alkenes. Sequential SMC reactions could also be accomplished as a one-pot version (Scheme 18).

Scheme 18. Stereoselective Couplings of 1,1-Diborylalkenes with Electrophiles. 429 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In 2013, Nishihara’s group reported that Pd(OAc)2/tOctNC catalyzed regio- and stereoselective silaboration of alkynylboronates could afford 1,1diborylalkenes (35). They also realized the preparation of 1,2-diborylalkenes via Pt-catalyzed diboration of alkynylsilanes (36). The obtained trimetalated products could also go through boron-selective SMC reactions with the boryl moiety trans to the aryl groups reacting preferentially. More recently, by virtue of an iridium complex supported by a SiNN pincer ligand, Ozerov’s group successfully converted terminal alkynes into triborylalkenes via sequential C–H borylation of alkynes and dehydrogenative diboration of alkynylboronates with HB(pin). The obtained triborylalkenes were demonstrated to be compatible with stereoselective SMC reactions, affording trans-1,2-diborylalkenes (37). As illustrated in examples below, among the three boronyl groups, the one trans to the aryl group coupled with electrophiles preferentially (Scheme 19, A).

Scheme 19. Two Newly Developed Methods for the Synthesis of 1,1-Diborylalkenes. Sawamura’s group also developed a new synthetic method for the preparation of 1,1-diborylalkenes (38) via a Brønsted base catalyzed reaction between terminal alkynes and B2(pin)2. Various terminal alkynes which were conjugated with carbon-oxygen/nitrogen double bonds including propiolates, propiolamides, and 2-ethynylazoles were compatible with this transformation. The two geminal boronyl groups of the 1,1-diborylalkenes could be differentiated and reacted in 430 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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stepwise SMC reactions. The first coupling reaction occurred selectively at the boron site trans to the ester group (Scheme 19, B). In the above-mentioned cases, the starting materials contained two or more identical boronyl groups. However, some synthetic requirements could not be met using such substrates. For example, it was difficult to reverse the preferential reactivity of terminal and internal alkenyl boronyl groups without directing groups. Along with the development of boronyl-protecting groups (refer to the chapter of Drs. Churches and Hutton), di- and polyboron alkenes containing two or more different masked boronyl groups were prepared and utilized to solve such problems. Burke’s group (3) developed an efficient masking group for boronic acids, i.e., N-methyl iminodiacetic acid (MIDA) in 2007. Since then, they have prepared a library of building blocks based on the inert reactivity of MIDA boronates to build a synthetic platform for iterative and even automated synthesis of complex molecules (4) (refer to the chapter of Dr. Watson). Among such building blocks, the diborylalkenes can function as precursors for halo-B(MIDA) building blocks or linchpins to connect two different electrophiles by virtue of boron-selective reactions (39), which leave the B(MIDA) moiety intact (Scheme 20, A).

Scheme 20. Di- and Polyborylalkenes with Different Boronyl Functionalities. 431 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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An unsymmetrical diboron reagent, B(pin)–B(dan), could be applied in diboration of alkynes, affording 1,2-diborylalkenes, as disclosed by Suginome’s group. The B(dan) groups were incorporated to the terminal carbon atoms regioselectively. As a result of the inertness of B(dan) groups, selective SMC reactions were then realized with internal C–B bonds reacting preferentially (Scheme 20, B) (40). This was in sharp contrast to the above-mentioned reactivity of 1,2-di(pinacolatoboronic ester)alkenes. Thus, these two protocols are complementary to each other. By virtue of Pt-catalyzed diboration of alkynyl MIDA boronates, Nishihara’s group realized the synthesis of 1,1,2-triborylalkenes which contained two different boronyl functionalities in 2014. Three C–B bonds on the obtained products could be well discriminated in the following SMC reactions, consuming the internal B(pin) groups and affording 1,1-diborylalkenes selectively (Scheme 20, C) (41). Di- and Polyborylarenes Generally, when two or more identical boronyl groups are on the same building block, it is difficult to realize selective SMC reactions among these boronyl groups (42). However, via careful control of the reaction conditions, especially the ratio of nucleophiles and electrophiles, a few cases of selective SMC reactions have been disclosed, affording aim products in moderate yields (43). If such reactions commence with differently protected di- or polyborylarenes, they may become more convenient and efficient. In fact, differentiated diborylarenes have been used as double nucleophilic linkers to converge various electrophilic building blocks. In 2007, Suginome’s group developed an efficient masking group for boronic acids, i.e., 1,8-diaminonaphthalene (dan). The dan-protected boronyl group was found to be inert in most SMC reaction conditions, therefore they have applied haloaryl-B(dan) in iterative synthesis of polyarenes via sequential boron-selective SMC/deprotection iteration (refer to the chapter of Dr. Watson). To make best use of the inertness of the B(dan) moiety, they also prepared diborylarenes containing both B(dan) and B(pin) via Miyaura borylation of haloaryl-B(dan) compounds. The differently protected diborylarenes then underwent cross-coupling with aryl/ vinyl halides at the B(pin) moiety exclusively, leaving the B(dan) moiety intact (Scheme 21, A) (44). For the synthesis of differentiated diborylarenes, direct C–H borylation of the readily available aryl MIDA boronates would be a more convenient choice, as reported by Li’s group (45). They successfully obtained a broad range of di- and triborylarenes from simple monoboron compounds via a one-step transformation. The newly-incorporated B(pin) moiety could be selectively consumed in the following chemoselective SMC reactions. The thus obtained MIDA boronates could be utilized directly in the following SMC reactions via the slow-release strategy, providing multi-substituted arenes (Scheme 21, B). More recently, Li’s group also realized a boron-selective SMC reaction to differentiate aryl B(dan) and B(MIDA) with the B(dan) moiety remaining intact (Scheme 21, C), based on the different stability of these two groups in aqueous basic conditions (46). 432 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 21. Diborylarenes for Boron-Selective SMC Reactions.

Selective Allylboration Reaction of Di- and Polyboron Reagents The addition of allylic boronyl groups to polar unsaturated bonds, such as carbonyl groups in aldehydes and ketones, is known as allylboration reaction, which is able to deliver new functional groups and construct C–C bonds in a onepot version. Generally, the reaction is considered to occur via a closed chair-like six-membered transition state. The carbonyl groups are activated by the Lewis acidic boron atom. This transition state enables the transformation to occur in a diastereoselective fashion. By virtue of chiral boronyl groups or asymmetric catalysts, enantioenriched homoallylic alcohols may be reliably prepared (47). In the past decades, along with the development of the allylboration reaction, a series of diboron compounds have also been applied in such transformations. Generally, these compounds contain a reactive boronyl group at allyl position and a second temporarily inert boronyl group is connected at a different position. The former type of boronyl groups can be selectively used in the boron-selective allylboration reactions. Exploiting the versatile reactivity of the latter inert boronyl groups, a variety of complex functionalized intermediates become accessible. 433 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Single Selective Allylboration Reaction

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This strategy was explored as early as 1995 and disclosed by Brown’s group (48). Optically active [(E)-γ-(boronic ester)allyl]diisopinocampheylborane 15 could be prepared via hydroboration of allenyl boronates with (dIpc)2BH. Then the allyl Ipc-borane unit of such diboron reagent could react preferentially with aldehydes, affording allylboration product 16 with a newly generated allyl boronate moiety. A following stereo-retentive oxidation afforded anti-1,2-diols in high diastereo- and enantioselective fashion (Scheme 22).

Scheme 22. The First Example of Boron-Selective Allylboration.

By virtue of the combination of Pd2(dba)3 and a chiral phosphoramidite ligand, Morken’s group realized a regioselective and enantioselective diboration reaction of allenes with B2(pin)2. The obtained diboration products contained an allyl and alkenyl B(pin) group, respectively. The allyl B(pin) groups were then utilized in allylboration of aldehydes (49) and imines (50), affording vinylboronate intermediates that were readily utilized in the following transformations, such as oxidation and SMC reactions (Scheme 23). The same group also realized the Pt-catalyzed enantioselective 1,4-diboration (51) and 1,2-diboration (52) of 1,3-dienes. In both cases, the obtained allylboronyl groups were transformed selectively in the allylboration step. After oxidation, synthetically useful chiral 2-buten-1,4-diols or 2-buten-1,5-diols were ultimately obtained (Scheme 24).

434 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 23. Diboration of Allenes and the Following Allylboration Reactions.

Scheme 24. Diboration of 1,3-Dienes and the Following Allylboration Reactions.

435 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Double Allylboration Reactions

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In 2002, Roush’s group applied the allylic boronyl group of intermediate 16 which was formed after the initial allylboration step of the Brown strategy into a further allylboration reaction (53). by modification of the reaction temperature, this double allylboration reaction could be realized consecutively in a one-pot version with two different aldehydes, producing (E)-1,5-anti-diols in excellent stereoselectivity (Scheme 25, A). This type of products were formally linked by the carbon skeleton of the diboron compounds. Interestingly, when the allenylboronic ester contained a bulky diol unit, via the hydroboration/double allylboration sequence, (Z)-syn-1,5-diols could be obtained in high yield and high level of enantioselectivity (Scheme 25, B).

Scheme 25. Double Allylboration Sequence. Kinetically controlled hydroboration of monosubstituted allenes with 10-TMS-9-BBD-H (9-BBD = 9-borabicyclo[3.3.2]decane) afforded (Z)-γborylallylboranes, which were then utilized in the following double allylboration reactions, affording (Z)-anti-1,5-diols (Scheme 25, C) (54). In 2009, Soderquist and co-workers successfully prepared a novel double-allylating reagent with two different borane components. Hydroboration of allenyl 10-TMS-9-BBD with 10-Ph-9-BBD-H afforded two regioisomeric trans-1,3-diborylpropenes through a series of 1,3-borotropic shifts. Such mixtures could be utilized directly in the following selective asymmetric allylboration of 436 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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ketones and/or ketimines. It was noted that the 10-Ph-9-BBD moiety was more reactive than its 10-TMS counterparts. The first allylboration was followed by a sterically driven 1,3-borotropic rearrangement, affording new allyl boranes that could not react with ketones (or ketimines) further. The second allylboration was triggered by the addition of an aldehyde (or aldimine). Thus, the sequential addition of ketones (or ketimines) and aldehydes (or aldimines) would generate three stereogenic centers in a one-step procedure (Scheme 26) (55).

Scheme 26. Double Allylboration of Ketones and Aldehydes.

For the synthesis of 2-methyl-1,5-anti-pentenediols, Roush’s group recently disclosed an efficient synthetic route via kinetically controlled hydroboration and double allylboration sequence (56). Double allylboration of the kinetic product, (Z)-17, afforded (Z)-2-methyl-1,5-anti-pentenediols. In the second allylboration step, BF3•OEt2 catalysis was necessary to reach high enantioselectivity. (Z)-17 could isomerize to (E)-17 at 65 °C, which could go through double allylboration reactions to synthesize (E)-2-methyl-1,5-anti-pentenediols. In this case, good yield and high enantioselectivity could be achieved without the assistance of BF3•OEt2 (Scheme 27). 437 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 27. Kinetically Controlled Stereoselective Double Allylboration.

Scheme 28. The Synthesis of N-Acetyl Dihydrotetrafibricin Using Three Double Allylboration Reagents.

In view of the powerful capacity for stereospecific construction of diverse diols structure, the double allylboration also gained application in natural product synthesis. Morken’s group has applied this strategy in the construction of highly substituted and stereochemically complex cyclohexanols via cascade allylborations of diboron compounds with dicarbonyls (57). Recently, Roush and Nuhant completed the diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester, which involved three-fold double 438 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

allylboration processes to construct stereocenters and assemble synthetic fragments convergently (Scheme 28) (58). This work spectacularly exemplifies how chemoselective double allylboration reactions can be used in the modular synthesis of complex molecules.

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Conclusion Based on the extensive research about the synthesis and reactivity of organoboron compounds, the boron-selective reactions have gained great advance and productive application in the last decade in particular. This selectivity has encouraged the preparation and utilization of a variety of bifunctional building blocks, such as organic halides containing masked boronyl groups and di- and polyboron compounds. These versatile molecules can provide modular and flexible platform to construct molecular diversity and complexity via consecutive boron-selective transformations. The synthetic value of reactivity-differentiated di- and polyboron compounds has been validated by the convergent assembly of various pre-functionalized fragments. The research towards their preparation and utilization has undergone significant advancement in recent years. However, compared with the diverse transformations of common boronyl groups, reaction types of reported boron-selective transformations are relatively limited to Suzuki–Miyaura coupling or the allylboration reactions although sporadic examples of other types of reactions have been disclosed. For examples, 1,1-diborylalkanes could react with carbonyl groups of ketones to generate tetrasubstituted alkenyl boronates with one boronyl group eliminated selectively (59); the terminal B(pin) moieties of (Z)-1,2-diborylalkenes would participate in Borono−Mannich reactions selectively to generate boronated amino esters (60). It appears that if yet more organoboron-involved reaction types could be realized in boron-selective version then a great number of diverse structures may be readily synthesized from the present building block library. Therefore, further exploration in this area, especially the development of more convenient synthetic methods towards di- and polyboron building blocks and methodologies to discriminate and make best use of the each boronyl group, will consolidate the existing synthetic platform for modular synthesis of complex molecules, thus benefiting the scientific community of organic synthesis, biochemistry, medical research and material science which are usually perplexed by tedious syntheses of their targeted products.

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59. Endo, K.; Hirokami, M.; Shibata, T. Stereoselective synthesis of tetrasubstituted alkenylboronates via 1,1-organodiboronates. J. Org. Chem. 2010, 75, 3469–3472. 60. Sridhar, T.; Berree, F.; Sharma, G. V.; Carboni, B. Regio- and stereocontrolled access to γ-boronated unsaturated amino esters and derivatives from (Z)-alkenyl1,2-bis(boronates). J. Org. Chem. 2014, 79, 783–789.

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Chapter 14

Acylation Reactions of Organoborons

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Manoj Mondal1 and Utpal Bora*,2 1Department

of Chemistry, Dibrugarh University, Dibrugarh 786004, Assam, India 2Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India *E-mail: [email protected]

Organoborons are structurally diverse, relatively stable, readily prepared and environmentally benign with the potential to undergo rapid transmetalation with transition metal complexes. These characteristics have made them the most versatile organometallic species for frequent use in numerous well known cross-coupling reactions. The Ullmann and Suzuki-Miyaura couplings are prominent examples of such approaches, which have played decisive roles just over half a century, in many of chemistry’s most complex synthetic approaches. During the last quarter of the 20th century, acylation reactions have undergone tremendous development, largely driven by the implementations of organometalic reagents. Among them, the strategy involving couplings of organoborons in the presence of palladium catalysts are the most prominent. In this chapter, highlights of a number of important strategies are discussed.

Introduction Ketones are ubiquitous structural motifs found across various natural products, pharmaceuticals and agrochemicals (1–3). For example, as shown in Figure 1, (S)-ketoprofen is an anti-inflammatory drug with approximately 160 times the potency of aspirin (4). Rottlerin (ROT) is commonly used as an inhibitor of protein kinase C-delta (5). Sofalcone, a chalcone derivative, is used as an anti-ulcer drug with mucosa protective effect and commonly isolated from the root of the Chinese medicinal plant Sophora subprostrata (6). Sulisobenzone is used as a UV absorber in various sunscreens (1). © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 1. Examples of Representative Diaryl Ketones. Apart from this, ketones also represent a wide range of ideal starting material for the synthesis of cyanohydrins, oximes, hydrazones, carbazones, acetals, pinacols, etc. The synthetic and pharmaceutical significances of ketone derivatives have attracted substantial interest from the scientific community for the development of industrial processes under simple, safe, economical and environmentally benign conditions. Traditionally, one potential approach to introduce acyl functionalities is the Friedel-Crafts acylation of aromatic compounds with acyl halides (Equation 1) (7, 8).

However, the reaction is incompatible with many functional groups (9), and delivers limited para-regioselectivity, and a large amount of by-products. Organometallic species, such as organotin (10), zinc (11), Grignard and organolithium reagents also promote the synthesis of ketones from acid chlorides or esters (12–15), but strong affinity of these reagents towards the ketone product produces tertiary alcohols as side-products (16). Recently, the strategy involving the use of organoboron based cross-coupling reactions for the introduction of acyl functionality have received widespread application due to their non-toxicity, thermal and air stability (17–20).

446 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch014

The chemical stability of boron compounds in water and alcohols makes them highly attractive compared to other organometallic counterparts. This unique property was previously considered insignificant for synthetic approaches. However, recently organoborons have been utilized in Green Chemistry approaches, as one can easily use them in the presence of water without any special care. Organoborons are structurally diverse, relatively stable, readily prepared and generally environmentally benign with the ability to undergo rapid transmetalation with palladium complexes. These characteristics have made them the most versatile organometallic species and have seen frequent use in numerous well known cross-coupling reactions. During the last four decades tremendous developments have been made in the application of organoborons for complex molecular synthesis under exceptionally mild and functional group tolerant reaction conditions. The outer shell in the neutral boron atom is sp2 hybridized in which the p-orbital is devoid of any electron. Thus, organoborons are trivalent boron-containing organic compounds with a trigonal planar geometry and a non-bonding vacant p-orbital orthogonal to the plane. This low-energy empty p-orbital is responsible for the chemical and physical characteristics of all neutral boron compounds and makes them reactive towards electron donating Lewis bases. The use of widely functionalized and diverse organoboron reagents allows the selective introduction of the acyl function into complex and unique structures under mild and efficient reaction conditions. In general there are two significant methods that have been developed to introduce acyl functionality onto a specific organoboron substrate with high regioselectivity. The first of them includes an extraordinarily useful transformation involving the palladium-catalyzed coupling of organic electrophiles, such as aryl halides with organoboron compounds in presence of carbon monoxide (21), a process known today as the carbonylative Suzuki-Miyaura Coupling reaction (Scheme 1). First published in 1986 by Kojima et al. (22) this coupling reaction relies on a palladium-based catalyst and a base to effect part of the catalytic transformation. Further efforts from the group of Suzuki (23) and other have modified this method into versatile and efficient protocols (24). The palladium-catalyzed cross-coupling of carboxylic acid derivatives with arylboronic acid under mild reaction conditions represent another powerful synthetic tool to prepare biaryl ketones (Scheme 1) (25, 26). Considering the cleavage of the C-O bond of the carboxylic acid derivative in the presence of a palladium catalyst, Bumagin introduced this imperative method for the synthesis of biaryl ketones in 1997 (25, 26). This method is superior to the previous one in terms of environmental significance, reaction conditions, efficiency, and functional group tolerance. Predominant advancements include numerous modifications, primarily involving homogeneous Pd(II)- or Pd(0)-based catalysts, and use of both conventional organic and biphasic media (21).

447 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch014

Scheme 1. Synthetic Methods for Ketones

Carbonylation of Organoborons with Aryl Halides and Carbon Monoxide Conventionally, the introduction of acyl functionalities is achieved by the transition-metal-based, three-component, catalytic carbonylative cross-coupling reaction between aryl-X (X=Br, I, OTf, N2+), organometalic reagent and carbon monoxide. Numerous organometallic reagents including silicon (27), magnesium (28), tin (29–31) and aluminum (32) reagents have been reported. However, many of these methods suffer the drawback of the formation of biaryl side products without carbon monoxide insertion, particularly when electron-withdrawing groups are present on the aryl ring. Electron-deficient aryl halide accelerate the rate of transmetalation to form the aryl-Pd-aryl intermediate and block the insertion of carbon monoxide into the aryl-Pd-X species. In 1986, Kojima and co-workers reported a potent methodology for the synthesis of alkyl aryl ketones using palladium-catalyzed cross-coupling of aryl iodides or benzyl halides with organoboranes under a carbon monoxide atmosphere (Scheme 2) (22). This was the first report of the use organoboranes in carbonylative coupling reactions. The reaction relies on the use of 1.1 equivalents 448 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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of Zn(acac)2, which assist in the formation of the RCOPdII(acac) species for the transmetalation in the absence of base.

Scheme 2. First Pd-catalyzed Carbonylative Coupling of 9-borabicyclo-[3.3.1] nonane Thereafter, in 1991, Suzuki and co-workers developed another protocol for the Pd(PPh3)4-catalyzed carbonylative coupling of organoboranes with vinyl halides to synthesize vinyl ketones in benzene/dioxane and using K3PO4 as the base (Scheme 3) (33). However, the chemoselectivity of the reaction decreased when iodoalkenes bearing electron withdrawing substituents were used, and a mixture of both carbonylated and non-carbonylated products were observed.

Scheme 3. Pd-catalyzed carbonylative coupling of 9-borabicyclo-[3.3.1] nonane with vinyl halides. In 1993, Suzuki and Miyaura reported the synthesis of biaryl ketones using palladium-mediated cross-coupling of aryl iodides and benzyl bromide with arylboronic acids under a carbon monoxide atmosphere (Scheme 4) (23). Arylboronic acids have wide functionality, high selectivity, stability and non-toxicity, which make them a favorite candidate in coupling reactions. However, there are certain side-reactions associated with arylboronic acids that arise during the course of a palladium-based reaction (34–37). Hence, the proper 449 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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choice of catalyst, base and solvent is essential to obtain the desired ketones without by-products.

Scheme 4. Pd-catalyzed Carbonylative Coupling of Aryl and Benzyl Halides with Arylboronic Acids. The general mechanism for this carbonylative coupling reaction is analogous to the direct cross-coupling except the insertion of carbon monoxide, which takes place after the oxidative addition step and prior to the transmetalation step (Scheme 5).

Scheme 5. Mechanism for Carbonylative Cross-Coupling The method was further developed by employing various aryl electrophiles (Ar-I, Ar-Br and Ar-OTf) in the presence of a palladium catalyst and K2CO3 450 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch014

under an atmosphere of carbon monoxide (38). Although, PdCl2(PPh3)2 (3 mol %) provides efficient yields with aryl iodides, the use of the dppf ligand for the palladium catalyst and KI or NaI (3 equiv) are requisite to achieve selective coupling for aryl bromides or triflates. Moreover, the rate of carbon monoxide insertion and the selectivity of the ketone synthesis increases in the order of dppe