Advances in Organic Synthesis: Volume 10 [10] 9781681087443

Table of contents :
Cover
Advances in Organic Synthesis: Volume 10
Copyright
End User License Agreement
Contents
Preface
List of Contributors
1. Organocatalytic α-hydroxylation or α-aminoxylation of Carbonyl Compounds
Abstract
Introduction
Functionalisation of Aldehydes and Ketones
α-Aminoxylation Reactions with Nitrosobenzene or Derivatives
First Publications: the “Classical Method”
Generalities
α-Aminoxylation Reactions in Aqueous Media
α-Aminoxylation Reactions in Ionic Liquids
α-Aminoxylation Reactions in Continuous Flow Systems
Oxidative α-C-H N,O-ketalization of Ketone
α-Oxybenzoylation Reactions
α-Aminoxylation Reactions with TEMPO
First Publications: the “Classical Method”
TEMPO α-aminoxylation Reactions Without Metal
Electrochemical Oxidation
Organophotocatalysis
Singlet Oxygen
Α-Functionalisation of 1,3-dicarbonyl Compounds
Conclusion
Consent for Publication
Conflict of Interest
Acknowledgements
References
2. Achmatowicz Rearrangement Derived Synthons, and their Relevant Bioinspired Chemistry
Abstract
Introduction
Natural Products Containing Six-Membered Oxygen Ring Substructures
Furyl Carbinols and Their Rearrangements
Achmatowicz Rearrangement; Reagents, Conditions, and Procedures
Some Synthetically Useful Transformations of Pyranosuloses Generated via AR
Applications of the Achmatowicz Rearrangement to Total Syntheses of Natural Products
MONOSACCHARIDES
Non-Carbohydrate Natural Products
AR-Derived Pyranosuloses as Versatile Glycosylation and Glycoconjugation Synthons
Conclusion
Consent for Publication
Conflict of Interest
Acknowledgements
Abbreviations
References
3. Recent Advances in the Synthesis of N-Glycosyl Compounds
Abstract
Introduction
Free Glycosylamines and their N-alkyl and N-aryl Glycosyl Compounds
N-Glycosylhydroxylamines and Alkoxyamines
N-Glycosylamino Acids
N-Glycosylamides
N-Glycosylsulfonamides, -sulfamides and -sulfinamides
N-Glycosylhydrazines
N-Glycosylphosphoramidates and -phosphonamidates
N-Glycosylimines and -imides
Concluding Remarks
Consent for Publication
Conflict of Interest
Acknowledgements
References
4. Acidic and Basic Functionalized Ionic Liquid Systems for Advanced Synthesis of Five and Six Membered Nitrogenates Heterocycles
Abstract
Introduction on Ionic Liquid Systems
Different Classification of Ionic Liquids
1. Based on Number of Cation
2. Based on Type of Anion
3. Based on Acidity
4. Based on Physical Properties
Sustainable Organic Synthesis and Functionalized Ionic Liquids
Advantages of One-Pot Protocol in Organic Reactions
Use of Functionalized Ionic Liquids in One-Pot Synthesis of Five Membered N- Heterocycles
Pyrroles
Pyrazoles
Imidazoles
Use of Functionalized Ionic Liquids in One-Pot Synthesis of Six Membered N-Heterocycles
Pyridines
Quinolines
Acridines
Pyrimidines
Conclusion and Future Scopes
Consent for Publication
Conflict of Interest
Acknowledgements
References
5. Mesoporous SBA-15: A Superior Heterogeneous Catalytic Support for Multicomponent Organic Synthesis
Abstract
Introduction
Surface Modifications of Mesoporous Silica Materials
Grafting Methods
Grafting with Passive Surface Groups
Grafting with Reactive Surface Groups
Site-selective Grafting
Co-condensation Reactions
Mesoporous SBA-15 as Support or Host
Encapsulation of Nanoparticles on Mesoporous SBA-15 Support for Catalytic Application
Immobilization of Transition Metal Complexes/Salts and Organic Species on Functionalized Mesoporous SBA-15 Support for Catalytic Application
Immobilization of Heteropolyacids on Functionalized Mesoporous SBA-15 Support for Catalytic Application
Multicomponent Reactions
Three Component Coupling
A3 Coupling Reaction
Biginelli Reaction
Mannich Reaction
Some Other Three Component Coupling Reactions
Four Component Reaction/Pseudo Four Component Reaction
Conclusion
Conflict of Interest
Conflict of Interest
Acknowledgements
References
Subject Index
Cover back

Citation preview

Advances in Organic Synthesis (Volume 10)

Edited by

Atta-ur-Rahman, FRS

Honorary Life Fellow, Kings College,University of Cambridge,Cambridge, UK

Advances in Organic Synthesis Volume # 10 Editor: Atta-ur-Rahman ISSN (Online): 2212-408X ISSN (Print): 1574-0870 ISBN (Online): 978-1-68108-743-6 ISBN (Print): 978-1-68108-744-3 ©2018, Bentham eBooks imprint. Published by Bentham Science Publishers – Sharjah, UAE. All Rights Reserved. First published in 2018.

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CONTENTS PREFACE ................................................................................................................................................ i LIST OF CONTRIBUTORS .................................................................................................................. ii CHAPTER 1 ORGANOCATALYTIC Α-HYDROXYLATION OR Α-AMINOXYLATION OF CARBONYL COMPOUNDS ................................................................................................................. Armando Talavera-Alemán, Rosa E. del Río, Christine Thomassigny and Christine Greck INTRODUCTION .......................................................................................................................... FUNCTIONALISATION OF ALDEHYDES AND KETONES ................................................ α-Aminoxylation Reactions with Nitrosobenzene or Derivatives .......................................... First Publications: the “Classical Method” ................................................................. Generalities ................................................................................................................... α-Aminoxylation Reactions in Aqueous Media ............................................................. α-Aminoxylation Reactions in Ionic Liquids ................................................................. α-Aminoxylation Reactions in Continuous Flow Systems ............................................. Oxidative α-C-H N,O-ketalization of Ketone ................................................................ α-Oxybenzoylation Reactions ................................................................................................. α-Aminoxylation Reactions with TEMPO ............................................................................. First Publications: the “Classical Method” ................................................................. TEMPO α-aminoxylation Reactions Without Metal ..................................................... Electrochemical Oxidation ............................................................................................ Organophotocatalysis ................................................................................................... Singlet Oxygen ........................................................................................................................ Α-FUNCTIONALISATION OF 1,3-DICARBONYL COMPOUNDS ...................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 2 ACHMATOWICZ REARRANGEMENT DERIVED SYNTHONS, AND THEIR RELEVANT BIOINSPIRED CHEMISTRY ........................................................................................ Grzegorz Grynkiewicz INTRODUCTION .......................................................................................................................... NATURAL PRODUCTS CONTAINING SIX-MEMBERED OXYGEN RING SUBSTRUCTURES ............................................................................................................................... FURYL CARBINOLS AND THEIR REARRANGEMENTS ................................................... ACHMATOWICZ REARRANGEMENT; REAGENTS, CONDITIONS, AND PROCEDURES ............................................................................................................................... SOME SYNTHETICALLY USEFUL TRANSFORMATIONS OF PYRANOSULOSES GENERATED VIA AR .................................................................................................................. APPLICATIONS OF THE ACHMATOWICZ REARRANGEMENT TO TOTAL SYNTHESES OF NATURAL PRODUCTS ................................................................................ MONOSACCHARIDES ......................................................................................................... NON-CARBOHYDRATE NATURAL PRODUCTS .................................................................. AR-DERIVED PYRANOSULOSES AS VERSATILE GLYCOSYLATION AND GLYCOCONJUGATION SYNTHONS ..................................................................................................... CONCLUSIONS ............................................................................................................................. CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTERESTS .......................................................................................................

1 1 2 2 2 3 7 7 9 11 13 15 15 19 20 21 25 29 34 34 35 35 35 41 42 44 52 57 61 64 64 71 76 79 81 81

ACKNOWLEDGEMENT ............................................................................................................. 81 ABBREVIATIONS ......................................................................................................................... 81 REFERENCES ............................................................................................................................... 83 CHAPTER 3 RECENT ADVANCES IN THE SYNTHESIS OF N-GLYCOSYL COMPOUNDS Nuno M. Xavier and Rafael Nunes INTRODUCTION .......................................................................................................................... Free Glycosylamines and their N-alkyl and N-aryl Glycosyl Compounds ............................ N-Glycosylhydroxylamines and Alkoxyamines ..................................................................... N-Glycosylamino Acids .......................................................................................................... N-Glycosylamides ................................................................................................................... N-Glycosylsulfonamides, -sulfamides and -sulfinamides ...................................................... N-Glycosylhydrazines ............................................................................................................. N-Glycosylphosphoramidates and -phosphonamidates .......................................................... N-Glycosylimines and -imides ............................................................................................... CONCLUDING REMARKS ......................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 4 ACIDIC AND BASIC FUNCTIONALIZED IONIC LIQUID SYSTEMS FOR ADVANCED SYNTHESIS OF FIVE AND SIX MEMBERED NITROGENATES HETEROCYCLES .................................................................................................................................. Pinky Gogoi, Susmita Saikia, Arup Kumar Dutta and Ruli Borah INTRODUCTION ON IONIC LIQUID SYSTEMS ................................................................... Different Classification of Ionic Liquids ................................................................................ 1. Based on Number of Cation ...................................................................................... 2. Based on Type of Anion ............................................................................................. 3. Based on Acidity ........................................................................................................ 4. Based on Physical Properties ................................................................................... SUSTAINABLE ORGANIC SYNTHESIS AND FUNCTIONALIZED IONIC LIQUIDS .... ADVANTAGES OF ONE-POT PROTOCOL IN ORGANIC REACTIONS .......................... USE OF FUNCTIONALIZED IONIC LIQUIDS IN ONE-POT SYNTHESIS OF FIVE MEMBERED N- HETEROCYCLES ........................................................................................... Pyrroles ................................................................................................................................... Pyrazoles ................................................................................................................................. Imidazoles ............................................................................................................................... USE OF FUNCTIONALIZED IONIC LIQUIDS IN ONE-POT SYNTHESIS OF SIX MEMBERED N-HETEROCYCLES ............................................................................................ Pyridines ................................................................................................................................. Quinolines ............................................................................................................................... Acridines ................................................................................................................................. Pyrimidines ............................................................................................................................. CONCLUSION AND FUTURE SCOPES .................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

99 99 102 104 105 109 112 116 117 120 124 125 125 125 125

139 139 141 141 142 143 143 144 145 146 146 149 156 159 159 161 165 171 179 179 179 179 179

CHAPTER 5 MESOPOROUS SBA-15: A SUPERIOR HETEROGENEOUS CATALYTIC SUPPORT FOR MULTICOMPONENT ORGANIC SYNTHESIS .................................................. 197

Diganta Bhuyan, Mrinal Saikia, Pallab Kumar Saikia and Lakshi Saikia INTRODUCTION .......................................................................................................................... SURFACE MODIFICATIONS OF MESOPOROUS SILICA MATERIALS ......................... Grafting Methods .................................................................................................................... Grafting with Passive Surface Groups .......................................................................... Grafting with Reactive Surface Groups ........................................................................ Site-selective Grafting ................................................................................................... Co-condensation Reactions ........................................................................................... MESOPOROUS SBA-15 AS SUPPORT OR HOST ................................................................... Encapsulation of Nanoparticles on Mesoporous SBA-15 Support for Catalytic Application Immobilization of Transition Metal Complexes/Salts and Organic Species on Functionalized Mesoporous SBA-15 Support for Catalytic Application ............................... Immobilization of Heteropolyacids on Functionalized Mesoporous SBA-15 Support for Catalytic Application .............................................................................................................. MULTICOMPONENT REACTIONS .......................................................................................... Three Component Coupling .................................................................................................... A3 Coupling Reaction ................................................................................................... Biginelli Reaction .......................................................................................................... Mannich Reaction ......................................................................................................... Some Other Three Component Coupling Reactions ..................................................... Four Component Reaction/Pseudo Four Component Reaction .............................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ...............................................................................................................................

198 199 200 200 200 202 202 203 203 205 207 208 208 208 210 214 215 226 231 231 231 231 231

SUBJECT INDEX .................................................................................................................................... 248

i

PREFACE This volume of Advances in Organic Synthesis presents recent exciting developments in synthetic organic chemistry. It covers a range of topics including important researches on novel approaches to the construction of complex organic compounds. The chapters are written by authorities in the field and are mainly focused on organocatalytic α-hydroxylation and αaminoxylation of carbonyl compounds, Achmatowicz rearrangement derived synthons, synthesis of N-Glycosyl compounds, five and six membered nitrogenates heterocycles and mesoporous SBA-15. The book should prove to be a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information on recent important developments in synthetic organic chemistry.I hope that the readers will find these reviews valuable and thought-provoking. I am thankful to the efficient team of Bentham Science Publishers especially Dr. Faryal Sami (Assistant Manager), Mr. Shehzad Iqbal Naqvi (Senior Manager) and Mr. Mahmood Alam (Director Publications).

Atta-ur-Rahman, FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UK

ii

List of Contributors Armando TalaveraAlemán

Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia, Michoacán, 58030, Mexico

Arup Kumar Dutta

Department of Chemistry, Pandit Deen Dayal Upadhyaya Adarsha Mahavidalaya, Behali, Jinjia-784184, Assam, India

Christine Greck

Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035 Versailles, France

Christine Thomassigny

Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035 Versailles, France

Diganta Bhuyan

Materials Sciences & Technology Division, CSIR-North East Institute of Science and Technology Jorhat–785006, Assam, India

Grzegorz Grynkiewicz

Pharmaceutical Research Institute, Warsaw, Poland

Lakshi Saikia

Materials Sciences & Technology Division, CSIR-North East Institute of Science and Technology Jorhat–785006, Assam, India Academy of Scientific and Innovative Research, India

Mrinal Saikia

Materials Sciences & Technology Division, CSIR-North East Institute of Science and Technology Jorhat–785006, Assam, India Academy of Scientific and Innovative Research, India

Nuno M. Xavier

Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

Pallab Kumar Saikia

Materials Sciences & Technology Division, CSIR-North East Institute of Science and Technology Jorhat–785006, Assam, India

Pinky Gogoi

Department of Chemical Sciences, Tezpur University, Napaam-784028, Tezpur, Assam, India

Rafael Nunes

Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal BioISI – Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

Rosa E. del Río

Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia, Michoacán, 58030, Mexico

Susmita Saikia

Department of Chemical Sciences, Tezpur University, Napaam-784028, Tezpur, Assam, India

Ruli Borah

Department of Chemical Sciences, Tezpur University, Napaam-784028, Tezpur, Assam, India

Advances in Organic Synthesis, 2018, Vol. 10, 1-40

1

CHAPTER 1

Organocatalytic α-hydroxylation aminoxylation of Carbonyl Compounds

or

α-

Armando Talavera-Alemán1, Rosa E. del Río1, Christine Thomassigny*, 2 and Christine Greck2 Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia, Michoacán, 58030, Mexico 2 Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035Versailles, France 1

Abstract: α-Hydroxylation or α-aminoxylation of carbonyl compounds in the presence of an organocatalyst has become a significant method for the creation of asymmetric C-O bonds. From the first studies with the classical proline-type or Cinchona-derived organocatalysts, methods have evolved to more efficient systems. Phase-transfer organocatalysts, flow chemistry, ionic liquids, electrochemistry or photo-oxidation permit the reaction with a large range of substrate. While originally aldehydes and ketones were used in these reactions, it is now possible to extend the scope to amides or dicarbonyl compounds such as β-keto ester and β-keto amide. The present review aims to present a general overview of the evolution of these systems.

Keywords: Benzoyl peroxide, Carbonyl, Cinchona-based catalyst, Dicarbonyl, Flow chemistry, Ionic liquid, Nitrosobenzene, Organocatalysis, Organophotocatalysis, Phase-transfer, Photo-oxidation, Proline, Singlet oxygen, TEMPO, α-aminoxylation, α-hydroxylation, β-keto amide, β-keto ester, αoxidation, α-oxybenzoylation. INTRODUCTION Chiral α-hydroxylated carbonyl compounds belong to a very important class of compounds in organic synthesis as intermediates for natural products or bioactive compounds. Their synthesis is of great interest, and the development of new methodologies to obtain them is still of significance. Organocatalysis represents a very attractive pathway from the point of view of Green Chemistry. Many methods are known today for the α-hydroxylation of * Corresponding author Christine Thomassigny: Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035, Versailles, France; Tel: +33 139254424; Fax +33 139254452; E-mail: [email protected]

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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carbonyl or dicarbonyl compounds, and these have been very well reviewed in 2010 by the group of Vilaivan [1] and in 2012 by the group of Momiyama [2]. The present review does not aim to make another systematic review of all these methods, but proposes an overview of recent advances, as most of the processes have evolved in the last decade. The first part of the review is articulated around the four most widely used reagents for the asymmetric organocatalyzed α-oxidation of carbonyls, namely nitrosobenzene, benzoyl peroxide, TEMPO and O2. Other electrophiles have been used such as oxaziridines, H2O2, NaClO, meta-chloroperbenzoic acid, oxone or even 3O2, but will not be reviewed here, as they remain marginal methods. For the four most commonly used reagents, methods have greatly evolved as the “classical” protocol has given way to more modern or greener ones. Ionic or aqueous media, flow chemistry and photo-oxidation for instance have led to more powerful systems, and larger substrate scopes. The evolution of the use of these four oxidizing reagents will be detailed below, from their classical uses and facts about the reaction mechanism, up to the more modern protocols. The second part is focused on the α-oxidation of 1,3-dicarbonyl compounds. FUNCTIONALISATION OF ALDEHYDES AND KETONES α-Aminoxylation Reactions with Nitrosobenzene or Derivatives First Publications: the “Classical Method” The organocatalytic α-aminoxylation of aldehydes and ketones in the presence of nitrosobenzene (PhNO) has been one of the most studied reactions. The reasons for this are the accessibility of the reagents, the ease of following the reaction (the reaction mixture generally turns from light blue to blue-green then to yelloworange when the reaction is finished), and the ease with which an alcohol can be obtained from an aminoxyl function. In 2003, the groups of Hayashi [3], MacMillan [4] and Zhong [5] independently published the first publications on the asymmetric aminoxylation of aldehydes 1 in the presence of the catalyst L-proline and PhNO as the electrophilic agent, giving 2 that was reduced in situ to the corresponding primary alcohol 3 (Scheme 1). The three proposed systems lead to the expected products with good yields and ee. Hayashi and co-workers preferred reactions in acetonitrile at low temperatures (0 °C or -20 °C) to avoid side reactions such as the dimerization of PhNO or the self-aldol reaction of the aldehyde, known respectively to proceed at 0 °C and 4 °C. They needed to introduce an excess of aldehyde (3 equiv.). The group of MacMillan preferred reactions at 4 °C in chloroform and managed to decrease the catalyst loading to 0.5 mol% for the α-oxidation of propionaldehyde. Zhong and

Organocatalytic α-hydroxylation or α-aminoxylation

Advances in Organic Synthesis, Vol. 10 3

co-workers worked at room temperature in DMSO, which allowed them to decrease the ratio of aldehyde/PhNO to 1.2/1.

Scheme 1. Asymmetric α-aminoxylation of aldehydes in the presence of proline.

In parallel, the reactivity of ketones 4 for the formation of the mono-adducts 5 briefly reported at that time by Hayashi and co-workers [3], was thoroughly studied the next year by the same group [6] and by the one of Córdova (Scheme 2) [7]. They demonstrated particularly the importance of the speed of addition of the PhNO reagent or the aldehyde to avoid α,α’-di-aminooxylation.

Scheme 2. Asymmetric α-aminoxylation of ketones in the presence of proline.

Generalities Several models have been proposed for the catalytic cycle of the reaction with proline, but the consensus today is for a “standard” cycle passing through an enamine transition state, accompanied by a possible autocatalytic route (Scheme 3) [8 - 11].

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Scheme 3. a) Catalytic cycle and b) transition state for the α-oxyamination of aldehydes with PhNO.

A proline-saturated solution would have a concentration inferior to 0.005 M in a nonpolar, aprotic solvent. The first step would be the slow formation of the (E)-anti-enamine B via the oxazolidinone A. Then the addition of the electrophile PhNO leads to the iminium C: this step is the key-point for both heteroatom selectivity and stereoselectivity. Indeed, the formation of the C-O bond in favor of the C-N one could be explained by the higher basicity of the nitrogen atom compared to the oxygen atom. In the presence of a catalyst which could form a hydrogen bond (e.g. proline: the hydrogen of the carboxylic function), this basicity induces a preferential protonation of the nitrogen, allowing the oxygen to become electrophilic and leading to the formation of the C-O bond. Consequently, a catalyst acting without a hydrogen bond should favor C-N bond formation. The hydrogen bond explains the stereoselectivity, as the approach of the PhNO would be on the same face as the carboxyl function. The corresponding transition state is represented in Scheme 3.b. Lastly, the hydrolysis of the iminium C gives the expected product E and proline that can be reused in a new cycle.

Organocatalytic α-hydroxylation or α-aminoxylation

Advances in Organic Synthesis, Vol. 10 5

The autocatalytic route described by Blackmond and co-workers [8] is based on hydrogen bonds between the carboxylic oxygen atom of the catalyst and the NH of the product, giving the complex D from C. The lone pair of the proline nitrogen atom would then be accessible for the attack of a new substrate, giving B and an equivalent of the product E. Taking into account the autocatalytic way and the studies of Seebach et al. [12] over the role of the oxazolidinone intermediate A for the formation of the enamine B, McQuade and coworkers in 2009 described the utility of introducing an urea co-catalyst in the reaction medium [13]. The bifunctional urea 6 (Fig. 1a) easily prepared from phenylisocyanate and N,N-dimethylethylenediamine has been tested for the α-aminoxylation of hexanal in the presence of 5 mol% of proline at 0 °C. The reaction rate was considerably accelerated, allowing the use of more eco-friendly solvents than normally used, namely ethyl acetate instead of chloroform. Substrate screening (Scheme 1: 5 mol% of both proline and 6) led to the expected products 2 with yields of 55-97% and ee of 98-99% (7 examples). The rate enhancement with conservation of the enantioselectivity led the authors to propose the formation of stabilizing hydrogen bonds between the urea and the oxazolidinone intermediate A (Fig. 1b). The corresponding enamine B would then be formed much faster.

Fig. (1). a) Bifunctional urea 6 and b) proposed interactions with the oxazolidinone intermediate A.

After the firsts reports in 2003 of the α-aminoxylation of aldehydes or ketones, few developments have been reported to extend the system. Several modifications of the substrate or catalyst, including proline derivatives and non-proline catalysts, or studies of the mechanism have been reported [1, 14 - 20]. The development of sequences including this reaction leads to compounds with two consecutive stereogenic centers. As examples, chiral 1,2-diols have been obtained by O-nitrosoaldol/Grignard addition [21] or chiral 1,2,3-triols by a αhydroxylation of protected β-hydroxyaldehydes/reduction process [22]. Today, the organocatalyzed α-aminoxylation of carbonyls is used in total

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synthesis as a key-step for the formation of a stereocontrolled C-O bond. The protocol is generally based on the use of nitrosobenzene or nitrosotoluene in the presence of a proline catalyst. Numerous examples have been cited in the both reviews of the groups of Vilaivan in 2010 [1] and of Kumar for the synthesis of biologically active compounds in 2012 [23]. More recent total syntheses led to the targets represented in Fig. (2): (-)-cleistenolide 7 [24], (+)-trans cognac lactone 8 and analogues [25], oxylipids 9 [26], xyolide 10 [27], (+)-duryne 11 [28], hydroxylated piperidines 12 or 3-hydroxypipecolic acid 13 [29], and vinyl sulfone derivatives 14 [30].

Fig. (2). Target molecules obtained via α-aminoxylation of carbonyls.

Even if the method using PhNO has been studied in depth, some problems remain with its use. The first concerns the generally large quantities of carbonyl substrate needed, generating evident limitations for multistep syntheses. Effectively, the syntheses generally used this reaction as a key-step when it can be introduced at the very beginning of the synthesis. A second inconvenience is the nonecofriendly solvent usually encountered in the protocols: acetonitrile, chloroform, dichloromethane, dimethylformamide or dimethylsulfoxide. Finally, another problem is the possibility of oxyamination in parallel to the expected aminoxylation. This point was particularly significant in the case of α-branched aldehydes. These facts explain the development of supplementary methods for the oxidation of carbonyls with PhNO. Performing the reaction in water, the introduction of ionic liquids or the use of continuous flow techniques are some of

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the modifications that have been explored, and will be discussed below. α-Aminoxylation Reactions in Aqueous Media The advantages of the use of water in organocatalysis are well described now, namely acceleration of the reaction rates and enhancement of the stereoselectivity. Zhong demonstrated the possibility of running the reaction in aqueous medium by using L-thiaproline and tetrabutyl ammonium bromide as a phase-transfer catalyst (Scheme 4) [31]. The reaction with aldehydes led to the expected products with good yields (74-88%) and ee (93-99%). Replacing PhNO by nitrosotoluene (pTolNO) in the optimized conditions for propanal led to the corresponding product in a good yield of 83% and enantioselectivity of 97%.

Scheme 4. α-Aminoxylation reaction in aqueous media.

α-Aminoxylation Reactions in Ionic Liquids As catalyst recycling is an important aspect of Green Chemistry, ionic liquids represent a good solution as the mixture of catalyst/ionic liquid can be recovered easily. The first examples with 1-butyl-3-methyl imidazolium tetrafluoroborate [bmim][BF4], known to be a room temperature ionic liquid (RTIL) and used as a solvent, were reported independently by the groups of Huang [32] and Guo [33] in 2006. The system for the direct α-aminoxylation in the presence of PhNO and 20 mol% of proline was efficient for aldehydes or ketones 15 (Scheme 5). Huang and coworkers noted short reaction times (10-30 min) giving high yields after in situ reduction of 17 (68-94%) and ee (95-99%), whereas the team of Guo noted similar values with longer times (3-4 h) to obtain the compound 16. Recycling was possible taking advantage of the solubility of each partner, as the catalyst was retained by the RTIL after extraction of the product with diethyl ether. The proline/RTIL mixture could then be reused. Huang described little or no decrease in yield and ee after 6 batches with propanal or cyclohexanone as substrates. Guo remarked good yields from cyclohexanone for 4 batches (74-73%) then a drastic

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decrease for the fifth one (50%), pointing perhaps to a failure in the system.

Scheme 5. L-Proline catalyzed α-aminoxylation of carbonyls in [bmim][BF4].

The first polymer-supported catalyst for the α-aminoxylation of ketones was made possible by fixing 4-trans-hydroxyproline onto Merrifield-type resins through click chemistry [34]. The resulting resin 18 (Fig. 3) remained very enantioselective for ketones and aldehydes. A very slow introduction of PhNO (3 h) to a mixture of carbonyl/catalyst in DMF provided the desired product with modest to good yields (ketones, 5 ex: 43-60%; aldehydes, 8 ex: 35-86%) and excellent ee (ketones: 97-99%; aldehydes: 96-99%).

Fig. (3). Polymer supported organocatalyst 18.

The imidazolium ion-tagged 19 has been prepared in 3 steps from protected proline by Cheng and co-workers [35]. They then studied the α-oxyamination of aldehydes or ketones 20 in the presence of PhNO in ionic liquid medium (Scheme 6). The catalyst loading (5-20 mol%) had no significant effect on enantioselectivity as the corresponding products 21 (ketones) or 22 (reduction of the aldehydes) were always obtained with an ee of 99%. The authors assumed a synergistic effect of the catalyst and the ionic liquid media ([bmim][BF4]) that would stabilize the enamine intermediate.

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Scheme 6. Imidazolium ion-tagged proline catalyzed α-aminoxylation of carbonyls in ionic liquid.

The proline or lysine derivatives tagged with several triazolium or guanidinium salts 23-28 in [bmim][BF4] (Fig. 4) were efficient catalysts for the aminoxylation of cyclohexanone with PhNO in short times (15-35 min) [36]. The protocol was extended to isobutyraldehyde and 3-phenylpropionaldehyde with 23a, giving the corresponding products with good yields (83 and 89% respectively) and ee (96 and 98% respectively). Recycling of 23a lead to a notable decrease of enantioselectivity and yield in each cycle, linked to a need to increase the reaction time to complete the reaction. Based on the observation that the oxazolidinone 29 (detected by HPLC-MS) was present in equilibrium with the enamine 30 in the reaction with cyclohexanone, the authors assumed that the addition of a small amount of water favors catalyst recycling by facilitating the hydrolysis of 29 or 30 (Fig. 5). α-Aminoxylation Reactions in Continuous Flow Systems The main problem for α-aminoxylation under flow chemistry is the use of a catalyst that is known to only partially or slowly dissolve in the reaction medium, such as the proline catalyst. One answer to override this problem would be to limit the solubility of the catalyst by immobilizing it on a resin or polymer. This was the solution envisaged by Pericàs and co-workers [37] in 2011 who used a combination of flow chemistry and the polymer-supported catalyst 18 linked to 1,4-divinylbenzene (DVB) with various degrees of functionalization. The system with low cross-linked polystyrene (18a: 1% DVB; functionalization f = 0.48 mmol.g-1) was described as a microporous system giving a gel that could ensure contact of the reactants, showing high activity. Another system (18b: 8% DVB; f = 0.74 mmol.g-1) had behavior between a micro- and macroporous system. Both catalysts have been tested for the α-aminoxylation of aldehydes 31 with PhNO followed by reduction to the corresponding alcohol 32 (Scheme 7).

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Excellent enantioselectivities were obtained by both catalysts in 1 h. In terms of activities, the catalyst 18a was more efficient than 18b and was not dependent on chain length, as opposed to 18b that worked better with propanal than with longer-chain or branched aldehydes.

Fig. (4). Catalysts 23-28 used for the α-aminoxylation of cyclohexanone with PhNO.

Fig. (5). Equilibrium between oxazolidinone 29 and enamine 30.

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Scheme 7. Continuous flow α-aminoxylation of aldehydes with immobilized catalysts.

The same year, McQuade and co-workers [38] proposed a system where a mixture of aldehyde 33/thiourea 34 was passed through a packed-bed of solid proline before reacting with the PhNO reagent (Scheme 8). They particularly demonstrated that one of the more important parameters was the temperature of both the column and coil. Their adjustment allowed good yields and enantioselectivities from hexanal, 3-phenylpropionaldehyde or isovaleraldehyde.

Scheme 8. Continuous flow α-aminoxylation of aldehydes with thiourea 34.

Oxidative α-C-H N,O-ketalization of Ketone As a last example, the α-oxidation reaction of carbonyls by a primary amine catalyst has been described recently [39]. The group of Luo demonstrated that the action of N-hydroxycarbamate on β-keto esters or ketones led to a duality for C-N and C-O bond formation, introducing both bonds in the α,α’-position. Several cyclic ketones 36 were tested for α,α’-bis-functionalization in the presence of the catalyst 37 (20 mol%), the chiral additive 38 (20 mol%) and CuCl (15 mol%) (Scheme 9). The corresponding N,O-ketals 39 were obtained with yields and ee up to 78%, although the determination of their absolute configuration was not possible. Five or seven membered-ring, or acyclic ketones were unreactive under these conditions.

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Scheme 9. Oxidative α-C-H N,O-ketalization of ketones.

The proposed catalytic cycle from a β-keto ester 40 assumed the formation of the enamine 41 after reaction with 37 (Scheme 10). Addition to the nitroso derivative 42 led to the intermediate 43, that can easily lose a molecule of water due to the strong acidity of the H-N. The corresponding compound 44 can react with another equivalent of the N-hydroxycarbamate to produce the intermediate 45, whose hydrolysis gave the product 46 and the catalyst 37.

Scheme 10. Catalytic cycle for the oxidative α-C-H N,O-ketalization of a ketone.

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α-Oxybenzoylation Reactions Benzoyl peroxide (BPO) has long been known as a readily available oxidative reagent. In 2009, the groups of Hayashi [40], Maruoka [41] and Tomkinson [42] simultaneously used this reagent for the organocatalyzed α-oxybenzoylation of several aldehydes 47 (Scheme 11). Bulky catalysts need to be introduced in the reaction to avoid the reaction of BPO with the secondary amine, that would lead to N-benzoyloxy or amide side-products. The three authors used respectively the prolinol derivative 50, 51 and the imidazolidinone 52. Hydroquinone may be used as a radical scavenger to increase the yield. In all cases, the aldehyde 48 or the corresponding alcohol 49 were obtained with medium to acceptable yields and good enantioselectivities.

Scheme 11. α-Oxybenzoylation of aldehydes.

The authors agree on two plausible mechanisms as represented in Scheme 12 with the catalyst 52. The first one would be the direct approach of BPO to the enamine 53 formed by the condensation of aldehyde 47 (R = Me) with 52, leading to the iminium 54 (path A). The second would concern a N-oxybenzoylation of the enamine 53 followed by a [3, 3]-sigmatropic rearrangement of the intermediate 55, giving 54. The hydrolysis of this last would give the product 48 and recovery of the catalyst 52.

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Scheme 12. Proposed mechanisms for the α-oxybenzoylation of aldehydes.

The α-oxybenzoylation of cyclic ketones was described in 2011 by List and coworkers [43], becoming the first example of the use of a primary amine as a catalyst for the α-oxidation of carbonyl compounds (Scheme 13). With the aim to avoid the decomposition of the secondary amine used as catalyst with aldehydes as substrates, the authors used the Cinchona derivative 56 in the presence of an acid and 2,6-di-tert-butyl-4-methylphenol (BHT). The reaction was possible with diversely substituted and functionalized cyclohexanones 57 including acetal, olefin and carbamate, and can be extended to cyclohepta- and cyclooctanones. Larger rings or acyclic ketones were not reactive enough under these reaction conditions.

Scheme 13. α-Oxybenzoylation of ketones.

The group of Bencivenni described three years later a similar system, composed of 9-amino-(9-deoxy)epi-dihydroquinidine 59 and salicylic acid in the presence of a base [44]. The scope of cyclic ketones used was fairly large, giving the products with yields of up to 96% and ee up to 99% (13 examples). In particular, the reaction was extended to 1-indanones 60 and showed low to good yields (3082%) with ee from 40 to 89% (Scheme 14).

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Scheme 14. α-Oxybenzoylation of 1-indanones.

The benzoylation of 3-aryloxindole 62 in the presence of several chiral phosphoric acids has been tested [45]. In particular, 63 was very efficient to obtain 64 with a yield of 81% and an ee of 99% when used in ether at 5 mol% (Scheme 15). Interestingly, the use of DCM as solvent induced a reverse in selectivity (yield 56%; ee (-)-64 36%). A systematic study of the salts of 63 allowed a decrease in catalytic charge to 2.5 mol% to reach a yield of 83% and an ee of 99% when the catalyst was used as its calcium salt.

Scheme 15. α-Oxybenzoylation of 3-aryloxindoles.

α-Aminoxylation Reactions with TEMPO First Publications: the “Classical Method” The introduction of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) reagent represented a significant improvement for the asymmetric α-oxidation of carbonyls. If the first attempts needed the presence of a metallic co-species, more recent methods now completely avoid the use of such pollutants. We present here the general evolution of the use of this reagent. Its first use as an alternative method for the organocatalysed α-oxyamination of aldehydes was described in 2007 by Sibi and Hasegawa [46]. In the presence of the single electron transfer reagent (SET) FeCl3, the co-oxidant NaNO2, O2 and the tetrafluoroborate salt of imidazolidinone 52 (20 mol%), several aldehydes 65

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reacted with TEMPO (Scheme 16). The corresponding α-aminoxy alcohols 66 were obtained after in situ reduction with ee of up to 90%. In particular the effect of temperature was studied and it was shown that working at -10 °C allowed better ee than at room temperature, but with much longer reaction times (RT: 2h; -10 °C: 24h) and similar or generally lower yields.

Scheme 16. First α-aminoxylation of aldehydes with TEMPO and FeCl3.

A complete study of the reaction by the group of MacMillan proved the mechanism goes through an enamine catalysis pathway where a TEMPO/FeCl3 complex would be one of the key-intermediates of the reaction (Scheme 17) [47]. Effectively, the solvation of FeCl3 in DMF is known to induce the formation of less oxidizing salt [Fe(DMF)3Cl2][FeCl4], which coordinates with the TEMPO ligand. The complex then would combine with the enamine 67, giving the enantioenriched iminium 68. Its hydrolysis would liberate the expected αaminooxylated 69. In this pathway, the co-oxidant NaNO2/O2 recommended by Sibi is in fact not required for the reaction.

Scheme 17. Proposed mechanism for the α-aminoxylation with TEMPO and FeCl3.

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Based on this mechanistic study, the group of MacMillan in 2012 replaced FeCl3 by CuCl2, that formed a more stable complex with TEMPO [48]. The system catalyst 72/CuCl2 in a proportion of 2/1 was efficient in a wide structural variety of aldehydes 70, leading to the α-substituted products 71 with good yields (7790%) and ee (89-95%) (Scheme 18).

Scheme 18. α-Aminoxylation of aldehydes with TEMPO and CuCl2.

The anti-73 and syn-74 derivatives were obtained from each enantiomer of citronellal respectively with dr of >20/1 and 15/1 (Fig. 6). These results were in favor of stereocontrol induced by the catalyst, in preference to a substrate-directed 1,2-asymetric induction.

Fig. (6). Structures of anti-73 and syn-74.

This methodology has been used in the asymmetric total synthesis of several natural products or derivatives. As a first example, the same group capitalized on one of the products obtained, namely 2-OTMP-3-benzyloxypropionaldehyde 75, as a reactive to obtain pentose derivatives 76 [49] (Scheme 19). More recently, Chen and co-workers developed a method for the preparation of several oxylipins [50]. They took advantage of the possibility to reach anti-diols with the sequence α-oxyamination/nucleophilic attack of a lithiated species without loss of enantioselectivity (Scheme 20). The oxidation of decanal 77 with TEMPO and CuCl2 gave the product 78 with a yield of 79% and an ee of 72%. The addition of the organolithium 79 led to the anti-diol 80. Further transformations gave a natural oxylipin 81 and two derivatives 82 and 83.

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Scheme 19. Enantioselective synthesis of pentose derivatives 76.

Scheme 20. Total syntheses of a natural oxylipin 81 and two derivatives 82 and 83.

In 2013, Song, Li and co-workers used a combined system of Cu/Fe and TEMPO for the α-aminoxylation of ketones [51] (Scheme 21). An optimization of the reaction conditions between 2-phenoxy-1-phenylethanone, TEMPO and several catalysts showed that the yield was enhanced with the increased purity of the copper powders, and with the decreased purity of the iron catalyst. The system Cu/Fe in acetonitrile was the most efficient. Even if this system is not designed for stereoselectivity, it could open the way to new stereoselective systems for the α-aminoxylation of ketones.

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Scheme 21. α-Aminoxylation of ketones with TEMPO and Cu/Fe.

TEMPO α-aminoxylation Reactions Without Metal The group of Maruoka carried out the first organocatalyzed α-aminoxylation of aldehydes in the absence of metal by using the system TEMPO/BPO [52]. In order to obtain good enantioselectivities, they synthesized the binaphthyl-based catalyst 86 containing bulky substituents. Effectively, 86 allowed the oxidation of 3-phenylpropanal with an ee of 94%, when its dihydroxy equivalent or other bulky pyrrolidine-type catalysts gave lower ee of 30 to 44% in the same conditions (Scheme 22). The reaction was extended to several alkyl or unsaturated aldehydes 87, giving the products 88 with good yields (75-99%) and ee (91-99%). Plausible mechanisms and transition-state models have been advanced by the authors, while they remain unclear, the formation of an oxoammonium salt from TEMPO and BPO has been confirmed.

Scheme 22. α-Aminoxylation of aldehydes with TEMPO/BPO.

Using the fact that TEMPO can serve both as oxidation catalyst and aminoxylating reagent, the same authors introduced the system in a sequential one-pot oxidation/aminoxylation/reduction of 3-phenylpropanol 89 (Scheme 23), giving the corresponding alcohol 90 with a yield of 53% in three steps, and an ee of 97%.

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Scheme 23. One-pot oxidation/aminoxylation of alcohol with TEMPO/BPO.

This method can be compared to the one-pot three-step sequence that has been developed for the asymmetric synthesis of O-benzoyloxy alcohol 92 from the corresponding primary alcohol 91 (Scheme 24) [53]. In this protocol, the quantity of TEMPO remained catalytic for both steps, leaving the benzoyl peroxide reagent acting as oxidant at the α-position of the aldehyde.

Scheme 24. One-pot oxidation/benzoyloxylation of alcohol with TEMPO/BPO.

Studer and co-workers developed a method for the α-oxidation of ketones [54], based on his previous work on the aminoxylation of α,β-unsaturated ketones via the formation of an enolate [55]. The extension of this method to ketones 94 was possible using the mixture TEMPO/chlorocatecholborane (CatBCl) in the presence of a bulky base, namely 2,6-di-tert-butylpyridine (Scheme 25). After a study of the aminoxylation reaction of cyclohexanone, the scope was extended to numerous examples (52-99% yield). Particularly, good to complete stereoselectivities were obtained for 96, 97 and 98. Electrochemical Oxidation Anodic oxidation of aldehydes in the presence of TEMPO radical and several chiral amines has been tested [56]. In the presence of 50 mol% of the prolinolderived catalyst 93 and tetrabutylammonium perchlorate (TBAP, 0.1 M) as the electrolyte, the product was obtained with low yields (23-57%) and medium ee (60-70%) in 9-10 h (Scheme 26).

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Scheme 25. α-Aminoxylation of ketones with TEMPO/chlorocatecholborane.

Scheme 26. Electrochemical oxidation of aldehydes with TEMPO.

Organophotocatalysis Until recently, photochemical processes were limited to substrates that absorb light and could be stimulated by absorption of UV, visible or IR radiation. Photocatalysis then emerged, using different modes of activation including enamines radical processes, and allowing access to many more reactions. Today photocatalysis can lead to synthetically difficult compounds, especially in terms of asymmetric synthesis. Furthermore, photoredox-catalyzed reactions require relatively small catalytic loading of photoredox compounds (5-0.5 mol%) compared to “classical” enamine radical processes involving a large excess of chemical oxidants. In endeavors to reach the best system, the α-aminoxylation reaction has been the subject of research in this field. The first photoinduced oxyamination of aldehydes and enamines with TEMPO was described in 2009 [57], and the first asymmetric reaction appeared in 2011 [58]. Koike and Akita effectively described the use of a tris(bipyridyl) ruthenium(II) complex [Ru(bpy)3]2+, known to act as an oxidizing reagent after

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being irradiated with visible light. The reaction was not stereoselective, but the authors demonstrated the importance of the formation of an enamine as an intermediate. Several aldehydes 101 were converted to their corresponding products 102 (Scheme 27a) whereas cyclohexanecarboxaldehyde and cyclohexanone were unreactive. Interestingly, the 4-(1-cyclohexenyl) morpholine 104 gave the expected 105 with a yield of 81% (Scheme 27b). This experiment was in favor of the formation of an enamine during the catalytic cycle.

Scheme 27. Photoinduced catalytic aminoxylation with TEMPO a) of aldehydes; b) of 4-(-cyclohexenyl)morpholine.

The oxidation of aldehydes 106 with TEMPO in the presence of TiO2 catalyst and 20 mol% of organocatalyst with a mercury lamp (UV light) led to the products 107 [58] (Scheme 28). Proline derivatives and imidazolidinone-based catalysts have been tested, and particularly 93 and 108 led to the products 107 with low to moderate yields (9-88%) and ee (14-78%).

Scheme 28. Photoinduced catalytic aminoxylation of aldehydes with TEMPO and TiO2.

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The proposed mechanism for this reaction is in favor of the formation of the enamine 109 from the aldehyde 106 and the organocatalyst (Scheme 29). The results were more in favor of the oxidation of this enamine by TiO2 than by TEMPO. This main route would then lead to the radical 110, whose addition to TEMPO would give 111 followed by hydrolysis to obtain the product 107. The oxidation of TEMPO to 112 then subsequent addition to the enamine 109 is not excluded, giving a secondary pathway via the same iminium 111.

Scheme 29. Catalytic pathway via an enamine radical.

A tandem Michael addition/oxyamination reaction in the presence of the photosensitizer N719 dye and using a TiO2/TEMPO based system for the second step was particularly efficient [59]. The reaction concerned the one-pot Michael addition of malonates to α,β-unsaturated aldehydes 113 followed by the αoxyamination of the resulting β-substituted aldehydes (Scheme 30). The yields observed were up to 80%, with ee up to 99% and de of 95% in all cases. The proposed catalytic cycle involves a tandem iminium catalysis/photoinduced SOMO process (Scheme 31). The iminium intermediate 115, obtained from the secondary amine catalyst 93 and the aldehyde 113, would react with the malonate to give the enamine intermediate 116. This can undergo hydrolysis to form the βsubstituted aldehyde 117, or photo-oxidation with the photoexcited Ru(II) dye to form the enamine radical 118. An addition of TEMPO to this last followed by hydrolysis afforded 114.

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Scheme 30. Tandem Michael addition/oxyamination reaction.

Scheme 31. Catalytic cycle for the tandem Michael/oxyamination reaction.

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A very recent paper described the photoorganocatalytic α-oxyamination of aldehydes 120 with TEMPO, morpholine and methylene blue, giving 121 (Scheme 32) [60]. If the conditions used did not induce stereoselectivity, the authors open the possibility to such reactions with other organic dyes.

Scheme 32. Photoorganocatalytic α-oxyamination of aldehydes with TEMPO and morpholine.

Interestingly, 2-hexenal led to the corresponding α,β-unsaturated product 122 with a low yield of 20%, but opens the way to the possibility of dienamine catalysis of the reaction (Scheme 33).

Scheme 33. Photoorganocatalytic α-oxyamination of 2-hexenal with TEMPO and morpholine.

Singlet Oxygen The direct catalytic hydroxylation of carbonyls with O2 remains a challenge. The more commonly encountered complications concern the limited scope of substrates, low selectivities, and the frequent formation of by-products resulting from C-C cleavage. A transition metal, a base or a phosphine additive also need to be used in the reaction. The challenge of the reaction is even more complex when there is a need for diastereoselectivity. Córdova and co-workers studied the use of oxygen for the α-oxydation of ketones [61] and aldehydes [62, 63]. Treatment under UV irradiation in the presence of

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several amino acids and TPP gave the corresponding products. Cyclic ketones 123 in the presence of alanine or valine led to 124 with good yields (61-93%) and enantioselectivities (52-72%) (Scheme 34). An example with an acyclic ketone, namely octan-2-one, led to the hydroxyketone with a comparable yield of 50%, but a low ee (28%).

Scheme 34. Direct catalytic asymmetric oxidation of ketones with O2.

Both L-alanine and L-valine gave the same configuration (S)-124, whereas Lproline gave the corresponding enantiomer. The authors proposed a plausible enamine mechanism with proton abstraction by molecular 1O2 from the carboxyl group of the acyclic amino acids. The addition would then be at the Re face of the enamine (Scheme 35.a). Conversely, the cyclic proline would favor addition at the Si face, giving the opposite configuration (Scheme 35.b).

Scheme 35. Proposed enamine conformations and approach of 1O2, for a) an acyclic amino acid; b) proline.

The oxidation of aldehydes 125 under similar conditions in the presence of proline, α-methyl proline [62] or in the presence of the bulky catalyst 93 [63] led to 126 after reduction (Scheme 36).

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Scheme 36. Direct catalytic asymmetric oxidation of aldehydes with O2.

A system using a chiral phase-transfer catalyst in the presence of triethyl phosphite has been developed for the hydroxylation of oxindoles with O2 [64]. The oxidation of 127 in air led to the formation of tertiary alcohols 128 with excellent yields and ee when using the cinchonidine derivative 129 (Scheme 37).

Scheme 37. Catalytic asymmetric oxidation of oxindoles with O2 and a phase-transfer catalyst.

The use of TEMPO as described above opened the way to photooxygenation of aldehydes via enamine catalysis. Similar reactions using O2 as the oxidant have been proposed much more recently [65]. The group of Gryko in 2015 answered the apparent contradiction of the reaction of a secondary amine or enamine with singlet oxygen giving different products depending on the conditions. Effectively, secondary amines and enamines are known to lead to the corresponding imines or amides when reacting with O2 and tetraphenylporphyrin (TPP) under irradiation. Under photooxidative conditions in the reactions of carbonyls with proline-type catalysts, the enamine intermediate led to no such products of degradation or decomposition. The 3-phenylpropane-1, 2-diol 131 was obtained from 3-phenylpropanal 130 in a 2-step sequence by αoxidation with O2 in the presence of an organic catalyst, followed by reduction (Scheme 38). In particular the catalyst 132 gave the (R)-131 (ee 74%) whilst the catalyst 52 gave the (S)-enantiomer (ee 80%).

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Scheme 38. Photooxygenation of aldehydes with O2.

Calculations demonstrated the three most important factors affecting the stereochemistry of the product, namely the E-configuration of the enamine double bond, the conformation (s-cis/s-trans) of the C-N single bond between the pyrrolidine ring and the double bond, and the steric hindrance imposed by the phenyl substituent and the amide or benzyl ring of the catalyst. With the catalyst 132, the enamine-O2 complex has the lowest energy with the s-cis conformation (Scheme 39.a). Consequently, the proton attached to the phenyl ring of the substrate interacts with the amide oxygen atom, shielding the Si face and giving the (R)-enantiomer 131. In the other case (catalyst 52), the preferred s-trans conformation led to the (S)-enantiomer 131 (Scheme 39.b).

Scheme 39. Explanation for the stereochemistry of the reaction a) with catalyst 132; b) with catalyst 52.

The proposed mechanism, represented in Scheme 40 with the catalyst 52, was based on the formation of the enamine 133, formed from the aldehyde and the catalyst. A reaction with singlet oxygen led to the zwitterionic imine-peroxide 134, whose hydrolysis released the hydroperoxyaldehyde 135, precursor of the product (R)-131. An alternative way would be the degradation of 134 by formation of the dioxetane 137 leading to the formylamide 138.

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Scheme 40. Proposed mechanism with catalyst 52.

Α-FUNCTIONALISATION OF 1,3-DICARBONYL COMPOUNDS Enantioselective organocatalytic α-hydroxylation of 1,3-dicarbonyl compounds has been slow to develop. The main problem consists of the supplementary challenge of the formation of a quaternary center. The discovery of new methodologies for aldehydes and ketones has allowed access to the reaction with such substrates. The first attempts consisted in the search for the best catalyst/oxidant system for the α-oxidation of β-keto esters. This area was reviewed recently by Russo et al. [66]. Jorgensen and coworkers in 2004 used a system with dihydroquinine 139 as catalyst and cumyl hydroperoxide (CHP) as oxidant for the enantioselective reaction of the β-keto esters 140, giving 141 (Scheme 41) [67]. The group of Lattanzi in 2013 extended this method to the use of the catalyst 139 in the presence of tert-butyl hydroperoxide (TBHP) as oxidant for the α-oxidation of βketoamides [68]. Other catalyst/oxidant systems have been proposed, such as the phosphoric acid 142/pCl-PhNO [69], the alkaloid lappaconitine 143/tBuOOH [70], (S)-timolol

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144/tBuOOH [71] or the chiral guanidine 145/oxaziridine 146 [72] (Scheme 42). In general, these systems are not very active in the absence of the benzene ring, and cyclopentanones (n=1) are much more active than cyclohexanones (n=2).

Scheme 41. Enantioselective hydroxylation of β-keto esters with a Cinchona alkaloid.

Scheme 42. Enantioselective hydroxylation of β-keto esters.

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Chiral quaternary ammonium salts have been developed for their use as phasetransfer catalysts. Meng and co-workers [73, 74] in 2010 described a system using the Cinchona-derived 149 in the presence of K2HPO4 (50 mol%), resulting in the formation of 148 with low to moderate ee (Scheme 43). An improvement of the system by modifying both the hydroxyl group and the quaternary nitrogen group of the catalyst led to 150. Its use as catalyst allowed an increase in the ee of 148 to 90%.

Scheme 43. Phase-transfer enantioselective hydroxylation of β-keto esters with Cinchona derivatives.

More recently Nagasawa and co-workers proposed the α-hydroxylation of tetralone-derived β-keto esters 152 in the presence of a guanidinium-urea catalyst 151 and cumene hydroperoxide (CHP) as oxidant [75]. The corresponding αhydroxylated compounds 153 were obtained with yields up to 99% and ee up to 95% (Scheme 44). A study on the origin of the stereocontrol from the reaction by DFT calculations led to a transition-state model where the role of the three functional groups of the catalyst 151 was underlined [76]. This last coordinated with the β-keto ester mainly through hydrogen bonds between the guanidinium and urea groups of 151, and the two carbonyl groups of the enolate of 152. The results led the authors to propose an oxidative kinetic resolution of racemic β- or γ-substituted tetralones 154, giving selectively the corresponding alcohol 153 or the unreacted diastereomer 154 (Scheme 45).

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Scheme 44. Phase-transfer enantioselective hydroxylation of β-keto esters with guanidine-urea catalyst.

Scheme 45. Oxidative kinetic resolution of racemic β-or γ-substituted tetralones.

Photo-organocatalytic α-oxygenation of β-keto esters and β-keto amides with oxygen represents the last advance of the reaction, developed by Gao and coworkers [77 - 79]. In the presence of the phase-transfer catalyst 157 and tetraphenylporphine (TPP) as photosensitizer, the hydroxylation of 155 led to 156 with good yields (81-93%). However, the enantioselectivity in some cases was very low or non-existent, depending on the nature and position of the aromatic substituents (Scheme 46). Much more recently, the same team developed a series of Cinchona-derived catalysts in order to run an important study of the structure/activity relation in the reaction of α-hydroxylation of 1-indanone keto esters 155 (Alk = 1-adamantyl; R’ = H; n = 1) [78, 79]. Particularly, the authors showed that a good stereoselectivity depends on the modifications of the quinoline ring, respectively at the N- or at the C-2’ positions, leading to the design of the new catalysts 158 and 159. The

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substrate study of 158 demonstrated a very useful system that can be reused 6 times without loss of reactivity (from 96 to 91%) and enantioselectivity (ee from 81 to 78%). In parallel, the Cinchona derivative 159 led to the corresponding products 156 with excellent yields up to 99% and ee up to 90%. The stereoselectivity was influenced by the size of the ester substituent, as a bulky group led to better ee.

Scheme 46. Phase-transfer enantioselective photo-oxidation of β-keto esters.

Interestingly, the two catalysts were also active for the α-hydroxylation of β-keto amides 160 to obtain 161 with good yields but moderate enantioselectivities (Scheme 47).

Scheme 47. Phase-transfer enantioselective photo-oxidation of β-keto amides.

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The proposed mechanism for these photo-organocatalytic α-hydroxylations of βdicarbonyl compounds 162 is represented in Scheme 48. The enolate formed by the action of the base could interact with the phase-transfer catalyst (PTC). The complex 163 could then react with singlet molecular oxygen, giving 164, precursor of 165.

Scheme 48. Proposed mechanism for the phase-transfer enantioselective photo-oxidation of β-dicarbonyls.

CONCLUSION The formation of an asymmetric C-O bond at the α-position of a carbonyl compound by organocatalysis is now a well-established methodology. The classical process, consisting of the introduction of an organocatalyst such as proline-derived or Cinchona-derived organocatalysts, is particularly efficient with the oxidants nitrosobenzene, TEMPO, benzoyl peroxide or even the non polluant singlet oxygen under irradiation. Furthermore, the design of new catalysts including phase-transfer agents or the use of flow chemistry, electrochemistry and photo-oxidation has widened the substrate scope of the reaction, particularly to amides, β-keto esters and β-keto amides. If some effort is still needed for successful asymmetric organophotocatalysis, this method remains particularly attractive as demonstrated by the quantity of articles that have appeared on this subject over the last years. CONSENT FOR PUBLICATION Not applicable.

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CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. ACKNOWLEDGEMENTS We thank CIC-UMSNH for financial assistance, and CONACYT-Mexico for scholarship 398462. Special thanks to Karen Wright for editing corrections. REFERENCES [1]

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CHAPTER 2

Achmatowicz Rearrangement Derived Synthons, and their Relevant Bioinspired Chemistry Grzegorz Grynkiewicz* Pharmaceutical Research Institute, Warsaw, Poland Abstract: Among enormous wealth of natural product structural diversity, those containing pyran rings are quite common, since they abound in a pool of primary metabolites as well as among products of sugar transfer biocatalytic processes, which lead to glycosides and glycoconjugates classified as secondary metabolites. Additionally, practically every major biogenetic pathway allows, and often promotes, formation of oxygen heterocycles from polyketides or multiply hydroxylated chain intermediates, by way of 1,5-diol dehydration, lactonization, intramolecular hydroxyl group Michael addition, or an intramolecular epoxide ring opening. A variety of the resulting structures among natural products, which are of interest as prospective leads for medicinal compounds, elicit problems with the substance availability and call for efficient synthetic methods of their preparation. The chapter focuses on a particular rearrangement, featuring ring enlargement of 2-furyl carbinols into pyran-2,3-en- 4uloses [2H-pyran-3(6H)-ones], known as Achmatowicz rearrangement (Achmatowicz reaction; AR), presenting examples of its scope, utility and efficiency, including remarkable capability for enantioselection in chemo- and biocatalytic preparative procedures. The rearrangement can constitute the key transformation in stepwise syntheses of a variety of O- and N- heterocyclic natural products and their mimics, while its primary products – the unsaturated pyranosuloses, provide versatile glycosylation synthons which practically do not require protecting groups and secure easy access to simple and structurally modified mono- and oligo-saccharides with chosen functions and configurations.

Keywords: 2-Furylcarbinols, Achmatowicz rearrangement, Chemistry, Dihydropyrans, Enantioselective syntheses of substituted pyrans, Furan oxidative ring enlargement, Oxygen heterocycles, Palladium catalyzed glycosylation, Pyranoses, Pyranosuloses, Pyrans, Pyran containing natural products, Structurally modified saccharides, Tetrahydropyrans, Total synthesis of naturally occurring pyrans, Unsaturated pyranoses. Corresponding author Grzegorz Grynkiewicz: Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland; Tel: 48-22-4563885; Fax: 48-22-4563838; E-mail: [email protected]

*

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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INTRODUCTION This chapter concerns a particular synthetic transformation (Achmatowicz rearrangement, or Achmatowicz reaction = AR ; Sch. 1 and 6; Fig. 1 and 7), historically connected to the massive effort of total synthesis of carbohydrates from non-chiral materials continued since the beginning of synthetic organic chemistry [1 - 8], by which various derivatives of pyran can be prepared conveniently and efficiently [1 - 4]. This transformation stemmed from observation that known 2,5-dimethoxyfuran derivatives constitute 1,4-dicarbonyl synthons, which could serve as a convenient entry to a stepwise total synthetic approach towards pyranoses and pyranosides. The idea of sugar synthesis based on oxidation of furan derivatives could be perceived as an intentional reversal of monosaccharide dehydration process, known since 19th century from Döbereiner study [3]. Recognition of AR as viable synthetic tool for sugars as well as noncarbohydrate pyran ring containing targets has been developing rather slowly at first, but gained considerable appreciation in the recent years along with availability of new ways for controlling stereoselectivity, and its multiple applications amassed an impressive number of citations (“Achmatowicz reaction” entry gets 3040 hits on Google Scholar, and “Achmatowicz rearrangement” fetches 1550 responses [Google Scholar; June 15th, 2017]; selected important reviews dedicated to the name reaction are listed in the opening part of the references list [9 - 20]). Thus, the interest evoked by AR over decades deserve some general, as well as specific comments. Sugars are encountered mostly as pyranoid structures, so it would be unreasonable to claim that pyran-containing materials are in short supply, globally. On the contrary, out of all renewable biomass, estimated at 1.8 x 1011 tons per annum production, carbohydrates constitute ca. 75%. Although most of it is cellulose – a polymer somewhat difficult to handle as a chemical raw material, even in case of simple sugars (e.g.: sucrose, D-glucose) manufacturing output is comparable in quantity (million ton scale) to basic petrochemicals, such as propylene or acetone [21 - 23]. Despite this practically unlimited supply of carbohydrates from biomass, the subject of chemical synthesis of sugars remained of vivid interest, from the time of the first synthesis of D-glucose, marked with Nobel Prize for Emil Fischer in 1902 [24], throughout the century, to the W.S. Knowles, R. Noyori, and B.K. Sharpless, Nobel Prize (2002) for efficient enantioselective catalysis based on transition metal chemistry, documented among other by preparation of all eight enatiomers of natural hexopyranoses [25]. Several extensive reviews covered the progress in total chemical synthesis of sugars, based on traditional methods of C-C and C-O bond formation, consequently resulting in racemic mixtures of the target products [3 - 8]. While in the second half of the century, the focus on the chirality issue led to increase in the use of chiral pool substrates and/or in application of enzymatic catalysis for racemate resolution. At the end of that period enantioselective

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catalysis took over completely, becoming the golden standard of total synthesis in the field of natural products and secondary metabolites of pharmacological interest [25 - 30]. Selective chemical transformations, performed as a rule in enantio-enriched homogenous catalytic manner, such as asymmetric hydrogenation (AH) [31], asymmetric epoxidation (AE) [25] and asymmetric dihydroxylation (AD) [25], along with stereocontrolled biocatalytic aldol condensation (BAC) [8] and hetero Diels-Alder cyclization (HDA) [5], became versatile tools for synthesis, soon supplemented by additional powerful catalytic reactions of C-C bond formation: olefin metathesis and a variety of metal assisted coupling reactions, introduced by Trost, Stille, Suzuki, Negishi, and others [25 30]. Combination of these preparative procedures formed new and powerful armamentarium of total organic synthesis, which stands up as a competitive method, when it comes to supply of a complex secondary metabolite or its analog, in an amount needed for pharmaceutical process development or clinical trial batch preparation. Consequently, standards of an outstanding academic achievement have also changed significantly. For example, in the carbohydrate field, for a meaningful achievement classified as de novo synthesis, no less than demonstration of all L-hexoses attainability (at least formal) is expected, as a test of suitability for a newly described method. Meanwhile, a wave of new, oxygen heterocyclic structures of natural products surfaced from various sources, featuring so unexpected structural assemblies, that they at first resisted classical strategies elaborated by the old masters of classical period of total synthesis. The new secondary metabolites, which as a rule came out of the marine environment, featured distinct biological activity but were extremely hard to collect in a reasonable quantity, capable of securing pharmacological studies. Newer accounts on the recent advances of stereocontrolled total synthesis are elegantly and comprehensively described, how new strategies were designed, tested and validated, until extremely complicated targets like maitotoxin, brevitoxins, and palytoxin became achievable as synthetic samples in chemist laboratories [32, 33]. Obviously, new and dedicated tools had to be created in the process, and the methods developed in parallel, on other fields of natural product syntheses were also diligently adapted for targeting complex secondary metabolites containing repeatable and often condensed oxygen containing heterocycles (Fig. 5). In this connection, a development of Achmatowicz rearrangement [1, 2] as a part of larger project designed and carried out in the Institute of Organic Chemistry, Polish Academy of Sciences in Warsaw in 1970s (Fig. 1) is outlined and discussed as the primary impact for further achievements. Indeed, from a method initially set on preparation of regular and modified pyranoses and pyranosides, with a proof of principle delivered at first on simple racemic deoxyhexoses, convincing demonstration of its role as a versatile tool in enantioselective total synthesis has emerged, securing access to a great variety of structures featuring

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diverse heterocyclic scaffolds. Large number of pyran, dihydropyran and tetrahydropyran structures, as well as nitrogen heterocycles present in Nature, and also represented among medicinally useful compounds, well justify such interest in novel methods for their preparation, since their natural sources have usually very limited capacity.

Fig. (1). The two approaches to total synthesis of carbohydrates pursued in Warsaw in early 1970s..

NATURAL PRODUCTS CONTAINING SIX-MEMBERED OXYGEN RING SUB-STRUCTURES The term: pyran derivatives, used in this Chapter (Fig. 2), applies to the sixmembered one oxygen ring compounds (oxanes), with either two double bonds (2H- pyrans and 4H- pyrans), one C=C double bond (dihydropyrans), or no double bond (tetrahydropyrans). Six-membered lactones (α-pyrones ; δ-lactones) are particularly abundant, and consequently have been occasionally reviewed separately [34 - 36] as justified by distinct methods of their preparation [37 - 42].

Fig. (2). The main types of pyran ring structures encountered in natural products.

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There is a great deal of confusion in qualifying natural products as derivatives of pyran. Therefore in many reviews, macrolides, aminoglycoside, antracycline, or polyene antibiotics are qualified as such, based upon the presence of pyranose moieties linked to the core molecule through glycosidic bond. Such practice of including naturally occurring glycosides, which have separate chemical and biological characteristics, would result in complete dilution of pyran derivatives category. Thus glycosides, such as macrolide antibiotics or saponins are not discussed in this account. Some other, rather numerous classes of pyran ring containing compounds of natural origin, traditionally recognized as coumarins, flavones or pyrylium ion derivatives, commonly encountered among plant flowering pigments are also not included in this review. In recent years considerable increase in new chemical entities of natural origin is observed due to more intensive exploration of aquatic environment. New structures of marine natural products are reviewed regularly and added on a pace of approximately thousand per annum [43 - 46]. In keeping with previous observations a fair proportion of this number contain pyran ring within a molecule, while structural versatility of newly discovered compounds does not increase significantly. In keeping with practice observed in chemical literature, monosaccharide nomenclature, and consequently sugar atom numbering system is often employed for single ring pyrans, containing typical carbohydrate substituents. Thus, typical AR product pictured on Scheme 1 (R=CH2OH) is named either 6-hydroxy-2Hpyran-3(6H)-one or hex-2,3-dideoxy-2-ene-DL-pyranos-4-ulose, with tendency to favor the second choice, particularly in case of defined (enantiomeric) stereochemical configuration. Among oxygen heterocycles which are widespread in Nature, carbohydrates which constitute by far the largest part of the planet biomass, are composed mainly of pyranoid, and to a lesser extend of furanoid scaffolds. Formation of oxygen ring componds and their turnover constitute the essential steps of plant biochemistry, following photosynthetic fixation of atmospheric carbon, and giving rise to basic building blocks of structural polymers as well as to innumerable secondary metabolites. In a distant past, some considerable proportion of biomass entered geological transformation processes, which deposited coal, oil and natural gas – materials on which entire contemporary industrial complex supporting technical civilization is based. Since fossils and therefore petrochemicals are exhaustible, and have to be inevitably replaced by a biomass derived platform chemicals, the role and significance of new catalytic processes for fine chemicals, green chemistry and atom economy in industrial chemistry is steadily growing. Obviously, conversion of biomass into fine chemicals involve more constitutive oxygen than cracking of petrochemicals, therefore a new chemistry of oxygenated molecules is of great interest. Furan and its derivatives, such as furfural, hydroxymethylfurfural (HMF) and dihydroxymethylfuran are typical, thermodynamically favored, products of

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biomass conversion which involves polysaccharide and hemicellulose degradation, followed by monosaccharide dehydration reactions, and became commodity chemicals, for which some novel applications should be designed [21 - 23].

Fig. (3). Schematic summary of hydrolytic and dehydrative processes in which plant cellulose is converted into 5-hydroxymethyl furfural.

In this respect, five membered oxygen ring expansion of furan derivatives (which may be perceived as a formal reversion of well known transformation depicted in Fig. 3) is of great interest for development of novel processes, since their pyran congeners are not directly accessible (neither from petrochemical sources, nor from biomass transformation). Our overview, which is focused on chemically synthesized pyranosuloses as versatile synthons [1, 2], starts from some chemistry of their precursors – substituted furans, in particular furylcarbinols. This topic also tackles the problem of paramount importance in life sciences – molecular diversity oriented synthesis and applicability of novel chemical glycosylation methods for preparation of overwhelmingly present natural glycoconjugates, and their mimics, which are recognized as physiologically and medicinally important compounds [47 - 49]. Although pyranose containing secondary metabolites characterized by the presence of a glycosidic bond are very common in nature, one should also be aware of existence of a large number of natural products, which contain pyrane rings of different, that is non-carbohydrate origin. Polyketides, which originate by biogenetic pathways similar to fatty acids, tend to contain multiple hydroxyl groups, which can form heterocyclic oxygen rings by dehydration, ketalization, and variety of intramolecular cyclizations, radical or ionic in character. In such ways, multifunctional aliphatic compounds acquire, under influence of various biocatalysts, partially heterocyclic, condensed and aromatic character. Additionally, shikimic acid biogenetic pathways, abundant in plant physiology, produce phenylpropanoid and chromone scaffolds, which add such large natural products categories like flavonoids and their glycosides. Thus, naturally occurring pyran derivatives exhibit extraordinary variety of structures

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with unsaturated lactone motif and trans-fused tetrahydropyran scaffolds playing predominant roles, as exemplified on Fig. (4), which represents structure of brevetoxin-B, phytoplankton derived marine poison responsible for “red tide” phenomenon, one of most challenging structures in the history of the total syntheses [32] (Structures of maitotoxin and palytoxin are somewhat similar in composition, but larger and even more complex). Brevetoxin molecule comprise 11 rings (marked A – K starting from the unsaturated lactone side on the left), three C=C double bonds and 22 stereogenic carbon atoms.

Fig. (4). Structural formula of brevetoxin B.

Fig. (5) (5a – 5c) presents a handful of natural product structures, comprising compounds isolated from natural sources such as plants, microbial metabolites and marine organisms, which feature examples of structural variety from as simple molecules as maltol and rose oxide to polycyclic structures as okadaic acid, which represent even more complicated secondary metabolites from marine toxin group (brevitoxins, maitotoxin, palytoxin). Well known classes of oxygen heterocycles constituting pyran derivatives found in Nature, such as saponins, flavonoids, coumarins, iridoids, tocopherols, are easily recognized as separate structural categories, repeatedly dealt with in dedicated monographs, and were therefore omitted from Fig. (5). One more point, concerning choice of exemplary structures for Fig. (5a-c) should be explained – glycosides, which are plentiful in all categories of natural products, were not included, on the ground that glycosylation constitutes subsequent and secondary derivatization in respect to the action of gene clusters involved in an aglycone biosynthesis, moreover, glycosidations are biologically as well as chemically reversible under conditions in which aglycon integrity remains preserved. All discussed compounds play distinct and important biological roles in environment, species communication and allelopathy, but are also frequently recognized as valuable materials for human use, either as food additive, cosmetic, or medicine. Availability of the materials isolated from natural sources constitute a formidable problem, more

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often than not. Marine metabolites, which became a focus in search for new chemical entities can serve as an example. The ocean, which covers nearly 70% of the planet surface is most likely to harbor over two million species (less than 10% identified thus far), different from these encountered within terrestrial ecosystems, offering a great range of previously unexplored biodiversity. Also in terms of biomass amount, the marine biosphere is likely to contain 1012 tons of the bacterial weight alone. However, the most interesting new compounds of marine origin were usually obtained only in minute amounts, barely satisfying the demand for analytical examination and structural elucidation. Eventually many of them became available as a result of successful, multistep total synthesis effort. Even in the case of easier available terrestrial plant material, the role organic synthesis in providing samples for biological activity studies, not to mention clinical trials, is paramount. All presented compounds were selected from recent reviews, which are focused on natural products containing pyran scaffolds, and tackle the issues of their isolation, availability, biological activity and methods of synthesis [50 54]. In many of these syntheses, the heterocyclic ring formation constitute a crucial step, in which control of stereochemistry should be performed. Methods of preparation evolve in direction of green chemistry, by application of sophisticated catalytic systems, and are constantly evaluated for efficiency, regarding formation of synthetic targets in particular categories, including new compounds designated for medicinal chemistry [55, 56]. Out of the collection of pyran ring containing natural products and derivatives, some are known as valuable research tools (molecular probes; e.g.: forskolin), while other became successful medicines, including notorious global sales leader lovastatin (mevinolin), an inhibitor of HMG reductase (the rate limiting enzyme in cholesterol biosynthesis) and the prototype lead of other best selling cholesterol lowering drugs, which belong to the statins category. In this respect, one compound from the collection (5a – 5c) particularly deserves mentioning. Eribulin (5b), is a simplified synthetic analog of marine toxin halichondrin B, which retains inhibitory activity of microtubule polymerization, characteristic for larger structure of the parent compound. Eribulin mesilate (E7389) was approved by FDA in 2010 as metastatic breast cancer treatment, based on the totally synthetic active compound [57, 58]. Considering total synthesis as a viable method of supply for compounds known as pyran substructure containing natural products, such as these presented below, it would be impossible to ignore AR as a practical approach, which in turn inevitably leads to furan chemistry and issue of availability of substrates for the rearrangement, which features a furan ring enlargement step as the key transformation.

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Fig.  cont.....

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Fig.  cont.....

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Fig. (5). (in three parts: 5a; 5b; 5c – compounds arranged in alphabetical order). Some non-carbohydrate secondary metabolites of various origin containing pyran ring fragments.

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There is a vivid interest in synthesis of the natural products which contain pyran ring of various degree of saturation and different pattern of side chain substitution or ring condensation. In recent decades, thousands of pyran natural product syntheses have been reported, using various methodologies, many quite sophisticated in terms of stereoselectivity and application of catalysis. Among the most effective methods of cyclizations leading to pyran ring formation, following procedures should be mentioned: Williamson alkylation, hetero Diels-Alder reaction, Prins cyclization, pyrylium cation cycloaddition, lactonization, addition of alcohols to olefins, particularly oxa-Michael addition, intramolecular epoxide ring opening, ring closing olefin methatesis [37, 41, 51, 59]. Out of this abundance one particular synthetic transformation has been selected to discuss in some detail – the oxidative enlargement of the five membered ring of 2furylalkylcarbinols (AR). FURYL CARBINOLS AND THEIR REARRANGEMENTS Chemical conversion of biomass, which largely consists of cellulose, and hemicelluloses, gives through dehydration of its C6 and C5 monomers – glucopyranose, fructofuranose, and pentoses like xylose, hydroxymetylfurfural (HMF), and furfural (FUR), which therefore can be considered as practically inexhaustible platform chemicals of the post-fossil era and the same applies for a dozen of other furan derivatives, considered commodity chemicals [60, 61]. Furan itself is an electron-rich, reactive ring system, susceptible to a variety of electrophilic substitution, metalation and heteroatom exchange reactions, as well as cycloaddition reactions, such as Diels-Alder reaction or dipolar additions, which sums up to a very extensive collection of chemical transformations [62 64]. It is often perceived as a disubstituted C4 synthon, e.g. 1,4-dicarbonyl equivalent, which makes it a perceivable precursor of furanoses. In furan derivatives bearing a C-2 substituent, the oxygen heterocycle nucleus is also sometimes considered a C1 synthon - masked carboxylic function, which can be recovered by action of strong oxidants [65, 66]. Furan is prone to action of various oxidants which generate hydroxyl radicals, affording maleic anhydride, or under similar conditions, a variety of other 1,4-dicarbonyl compounds, either olefinic or saturated. One of the characteristic transformations of the furan ring consists of 2,5-conjugate addition reactions (e.g. oxidation with hydrogen peroxide, peroxyacids or their salts), which can be conducted under variety of conditions. For example, single oxygen adds easily to furan derivatives and similar reactions are observed with peroxyacids, halogens and pseudohalogens. In 1948 Clauson-Kaas observed facile 2,5-dialkoxylation of furans (preferably in methanol as the reagent and solvent), in the presence of bromine, or as a result of electrochemical oxidation [67 - 69]. Stable mixed acetals and ketals obtained in such way, were easily applied in variety of transformations as equivalents to

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parent 1,4-dicarbonyl compounds (e.g. beforehand inaccessible maleic aldehyde), readily affording heterocyclic systems on condensation with amines and other nitrogen nucleophilic reagents [67, 70]. In a larger project devoted to the total synthesis of monosaccharides from simple achiral synthons, which commenced in Warsaw towards the end of 1960-ties (1960s), the five-membered mixed acetalketal products, obtained from furylcarbinols, were taken up as substrates, at first for testing the double bond oxidation, and later for a ring expansion and intended follow-up functionalization to pentoses and hexoses in their pyranoid ring form [1, 2]. This transformation, later frequently performed as a one pot / one step preparative process, became subsequently known as Achmatowicz rearrangement (AR ; Achmatowicz reaction has the same meaning).

Scheme 1. Achmatowicz rearrangement carried out as a stepwise process.

It is obvious that such approach to de novo synthesis of pyranoses ofers ample opportunity for structural modification of each and every ring carbon atom, with radically simpler procedures than tedious traditional sugar chemistry, which abounds in repetitive protection – deprotection steps. In particular, the task of synthesis of natural but rare deoxysugars, which are constituents of numerous antibiotics, with application of new intermediates - an enulose synthons looked very appealing. Among 2-substituted furans, furylcarbinols deserve a special attention as synthons which provide ways to other compounds, carbocyclic and heterocyclic, through skeletal rearrangements induced by variety of catalysts [69 73]. Thus, protic acids, as well as some Lewis acids, can convert furyl carbinols into cyclopentenones through tandem of mechanistically complex processes, which can be summarized as a simple transformation, named Piancatelli rearrangement [74, 75], presented below (Fig. 6).

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Fig. (6). Piancatelli rearrangement (R = alkyl or aryl); carbonium and oxonium intermediates shown in brackets.

The reaction presented on Fig. (6), has undergone extensive studies, which led to its application in steroid chemistry, synthesis of prostaglandins and variety of condensed cyclic systems which include cyclopentane ring. Some particular variants of this rearrangement, which involve 2,5-disubstituted furans with hydroxyl substituents suitably placed in the side chains afford easy access to spiroethers, while in an aza-version they are often utilized for synthesis of azasugars and alkaloids [75]. 2-Substituted furans containing hydroxyl group in the α- position of an aliphatic chain can be easily obtained by a variety of generally applicable synthetic methods. Furfural easily adds metaloorganic reagents, such as Grignard compounds, to afford secondary carbinols. Furans readily undergo Friedel-Crafts type acylation to furyl analogs of acetophenones, which can be reduced to similar carbinols, and enantioselective versions of such transformation (chemocatalytic or biocatalytic) are of particular interest. 2-Metalated furans react with carbonyl compounds and the same effect can be achieved with unsubstituted furans, under controlled conditions, when aldehydes are used as carbonyl substrates [76, 77]. Other synthetic approaches, based on catalytic couplings of suitably substituted alkyl reagents to activated aromatic substrates [68, 78, 79] (Suzuki, Stille, Sonogashira protocols) are also conceivable. The excerpts from furan chemistry quoted on Scheme 2 have been supplemented in recent decades, among others, by metal-catalyzed propargyl and allene derivatives chemistry, in which furans with various patterns of ring substitution can be obtained by cyclization of suitably designed open chain precursors [60, 68, 77]. Therefore an access to furylcarbinols can be based on wide selection of procedures, which can be ranked according to modern validation criteria,

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including environmental, technical and economic compatibility factors [78, 79]. It should be stressed, that in view of the further synthetic target requirement, stereochemistry of furylcarbinols as starting materials is essential, thus focus on methods securing access to homochiral reagents in the following part of the presentation.

Scheme 2. Synthetic approaches to 2-furylcarbinols (2-hydroxyalkylfurans).

Scheme 3. Asymmetric addition of diethylzinc to furfural, catalysed by bornane derivative (-)-MIB.

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It should be stressed, that apart from classical catalyst-induced additions of metaloorganic reagents to carbonyl group, depicted on Scheme 3, a great deal of a novel chemistry appeared recently, based on redistribution of hydrogen atoms in the presence of ruthenium or iridium catalysts. These transformations can lead, in the presence of suitable chiral ligands, to a catalytic, enantioselective C-H functionalization of alcohols, and/or carbon – carbon coupling in case of reacting carbonyl group substrates with allyl esters or their analogs, as illustrated on the Scheme 4 [80 - 84]. This advancement in stereocontrolled coupling of nucleophilic olefinic substrates with substrates containing the polarized C-O bonds in carbonyl compouns and corresponding alcohols was summarized by authors of the discovery as “reinventing carbonyl addition” [85].

Scheme 4. General synthesis of homoallyl alcohols by enantioselective catalysis (applicable for furfural and furyl carbinol).

In connection with reaction depicted on Fig. (2), as a bulk technical process of hexose dehydration, it should be mentioned that successful attempts have been made at segmentation of the process, resulting in furan ethandiol (or ethanol) obtained in good yield, with C-5 chiral center of the starting hexose retaining its integrity [75, 79]. This transformation performed initially on deprotected glycals, can also be applied to suitably protected pseudoglycals, obtainable by Ferrier rearrangement [86, 87]. In summary, efficient ways to the enantiopure furylcarbinols, include: application of chiral pool substrate for pathways b) and d) of the side chain introduction procedures (Fig. 2) or use of enantioselective transformation of prochiral elements in already existing C-2 substituents (carbonyl group reduction or C=C double bond functionalization). Needless to say, efficient enantioselective chemical catalysis or scalable biocatalysis would be preferred for such functionalization. Examples of such desirable reactions, featuring high level of atom economy in installing chirality centers, are presented in the following parts of the Chapter. A ring expansion rearrangement of furyl carbinols (AR) was devised and described as a general and versatile approach to pyranosides and pyran containing heterocycles, via pyranosuloses [1, 2]. Initial design of pyranosulose syntheses as

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a stepwise process was based on the reasonable assumption of limited stability of ketals under acidic conditions, but initially chosen substrates from 2,5-dialkoxy-2, 5-dihydrofuran group, subjected to such environment seemed surprisingly recalcitrant to hydrolysis at first, as judged on TLC monitoring of the reaction mixtures. Cross-examination of the crude products by spectroscopic methods revealed that expected pyranosyl compounds are indeed formed by aqueous hydrolysis, as assumed by formulae shown (Schemes 1 and 5, Fig. 7). Apparently the cyclic mixed ketals generated in the two-step AR (Scheme 1) can easily withstand the presence of bromine, resisting the double bond addition. Liberation of unsaturated dicarbonyl compounds during hydrolysis renders the opportunity of Z – E double bond isomerization, but pyranoid hemiacetal ring closure is apparently privileged transformation (unlike hemiketal formation in case of 2,5-dialkyl furan substrates). As recorded on numerous examples, furan oxidative ring cleavage/ring expansion transformations proceed without affecting chiral centers present in an alkyl side chain, which can be illustrated on example of NBS promoted AR by sequence of bond reorganization pictured on Fig. (7).

Fig. (7). Stereochemical account of the Achmatowicz rearrangement catalyzed by positive bromine ion.

Accordingly, use of AR as synthetic pathway to stereoselectively functionalized pyrans, such as carbohydrates, calls for homochiral furyl carbinols at the start. Presently, there are several ways to achieve such goal by efficient separation of racemates (biocatalytic or chemical) [88], as well as enantiocatalytic formation of the alpha hydroxyl position in the furan side chain, through Friedel-Crafts alkylation [89, 90] addition to the furfural or acetylfuran carbonyl group [91], or olefin functionalization (e.g. from easily accessible vinylfuran), such as Sharpless epoxidation [91 - 93]. ACHMATOWICZ REARRANGEMENT; REAGENTS, CONDITIONS, AND PROCEDURES Just as furan chemistry, which is already quite substantial in its classical textbook version, is undergoing continuous vigorous developments, its new extensions such as AR are prone to improvements which result in leaps towards new technological openings. The ring enlargement reaction of furylkarbinols discussed in this chapter, belongs to the class of ring-cleaving transformations evoked by action of

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electrophilic (oxidative) reagents upon an electron-rich, aromatic-like heterocyclic nucleus, which nevertheless exhibit some characteristics of a conjugated 1,3-diene system prone to 1,4-addition (or cycloaddition) reactions. That chemistry, which generally leads at first to 1,4-dicarbonyl derivatives is best covered in a comprehensive review by Merino [76], composed for a series of Organic Reactions, and providing representative collection of experimental procedures. Historically, at the outset of the Achmatowicz team commencement, furylcarbinols intended for the ring-enlargement rearrangement, were converted to the corresponding 2,5-dimethoxy- derivatives, first electrochemically and subsequently by action of bromine in methanol, the products were isolated and purified, as a matter of diligence, and carefully subjected to chemical hydrolysis, under variety of conditions. Some initial overreliance on TLC, which at the period served as an universal test of the reaction result control somewhat delayed recognition of the expected conversion, since RF values of substrates and products of intended transformation notoriously overlapped. Finally, engagement of UV and IR spectroscopy revealed that very mild conditions of protic acid aqueous catalysis is sufficient for completion of a five-membered ketal into six-membered enulose transformation [1]. While the initial effort was focused on structure, spectral properties and chemical reactivity of the AR products, follow up research soon started in many centers around the world demonstrated that the new compounds feature interesting biological activity [93, 94, 96 - 98], which promoted more research on their synthesis [75, 95, 97 - 107]. While fair proportion of new reports dealt with detailed chemistry and improvements in efficiency of the established procedures, some radical innovations, following green chemistry rules and aiming at environmentally friendly scalable processes were also announced [106 - 110]. These included incremental or radical elimination of organic solvents, reducing amount of oxidants such as bromine to a catalytic quantities, introducing photooxidation as the key step of AR and replacement of chemical promoters of the transformation with biocatalysis by specific enzymes, as laccases or peroxidases [111 - 113]. The key dimethoxydihydrofuran intermediates for the two-step alkoxylation - hydrolysis procedure, were gradually omitted, in favor of alternate oxidants applications, which promoted one-pot transformation [98, 99, 104]. As the result, collections of unsaturated, deoxy and modified pyranosides could be obtained, by stepwise selective functionalization of primary AR products, at first in form of racemic mixtures. Further syntheses were set at enantiomerically pure sugars, regular or modified by functional groups introduction or chain elongation, which allowed successful targeting a number of rare carbohydrates, particularly from antibiotic sugars collection. Over the years, as the use of AR method spread over to a large number of laboratories, the list of oxidants for one step transformation has grown

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longer, and presently include: N-bromosuccinimide (NBS); m-chloroperoxybenzoic acid (PCBA) or other peroxyacids andtheir salts; tert-butyl hydroperoxide (tBHP); hydrogen peroxide in the presence of metal salts, pyridinium chlorochromate (PCC), various forms of activated oxygen; cerric ammonium nitrate (CAN); dimethyldioxirane (DMDO); iodoxybenzene (IOX); lead tetraacetate (LTA) etc. [75, 112]. A recent observation reported that 2,5bishydroxymetylfuran (BHMF) undergoes AR without an oxidant, under influence of Amberlyst 15, in water at 700C [106]. Finally, it has been demonstrated that AR can be carried out biocatalitically, by chloroperoxidase (CPO) – an enzyme from cytochrome family or laccase – fungal multicopper oxidase (E. C. 1.10.3.2.) [13, 15, 113].

Scheme 5. Oxidative rearangement of furylcarbinols under influence of various oxidative agents R1 ; R2 = alkyl, substituted alkyl, aryl, etc.

Among dozens of publications on the subject, a few made an attempt to evaluate critically a method of choice from the point of view of technical viability and environmental safety. Georgiadis compared a couple of bromine using procedures, with the methods using NBS as the oxidant, indicating advantage of the later [106]. Tong opted for Oxone® (the triple salt: 2KHSO5 / KHSO4 / K2SO4) as an environment-friendly and highly efficient catalyst, when applied in the presence of catalytic (5 mol %) amount of KBr [107]. The two latter procedures can be considered as validated methods for a laboratory scale and prospective candidates for a scale-up. Naturally, recent discoveries in area of biocatalytic AR, promoted by oxidative enzymes are very promising as an inspiration for future biotechnology [110] but are likely to need more time to get ripe for application than new chemical reactions. Photooxidation can serve as an example of chemical reaction which has in principle a chance to be accepted as the process suitable from economical as well as environmental point of view for prospective postpetrochemical chemical industry. Such reaction conditions are valued for tolerance of aqueous conditions and the presence of wide variety of functional groups. Fairly recently, a series of papers appeared, dealing with various apects of photocatalytic AR, based on the singlet oxygen chemistry [111 - 121]. It has also been demonstrated that AR reaction can be coupled to a photoredox cycle. Thus, tris(bipyridine) ruthenium (II) complexes {e.g. [Ru(bpy)3Cl2]} in combination with sodium persulfate can carry out a stoichiometric photoinduced oxidation of

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furyl carbinols in aqueous solutions containing organic solvents, under irradiation with visible light or its components Aqueous solution AR based photochemical generation of reactive intermediates is presently suggested as a viable method for bioconjugation [118, 121]. Although availability of enantiomerically pure furyl carbinols based on stoichiometric reactions appears to be quite good, an issue of catalytic enantioenrichment continued to be hot topic, until satisfactory preparative solutions were found. Presently efficient procedures exist for a catalytic conversion of prochiral furan derivatives (furfural, 2-acetylfuran and 2-vinyl furan being representative substrate examples) for which efficient asymmetric functionalization is feasible [123 - 127]. In particular, O’Doherty has published validated procedure in which 2-acetylfuran was converted into either enantiomer of 1-(2-furyl)ethanols by action of Noyori catalyst used in 5 mole % amount [121, 122]. Similar successes were achieved with ADH and AEP reactions using olefinic substrates [93, 94] (Scheme 6).

Scheme 6. O'Doherty protocols for asymmetric syntheses of chiral 2-furyl alcohols.

Apart from simple racemate resolutions applied earlier, contemporary and more efficient studies on consequences of enantiomeric equilibration should be mentioned here. Dynamic kinetic resolution (DKR) based on chemo- and/or biocatalysis has already found wide application in the synthesis of bioactive compounds [120, 121]. Some interesting examples from applications of DKR for AR practical synthetic solutions are presented below. Scheme 7 shows facile resolution of racemic furylcarbinols upon action of the Sharpless epoxidation reagent, during which only one epimer is converted into pyranosulose, greatly facilitating their separation [91 - 93]. As an another example dynamic kinetic isomerisation of an anomeric mixture of pyranosuloses to the homochiral isomeric lactone, completed under influence of a meticulously selected iridium catalyst [120, 121]. Next paragraph illustration (Scheme 9) illustrate diastereoselective acylation of enulose hemiacetals driven by chiral catalyst – an invention of

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practical value in application of pyranosuloses as glycosyl donors [128 - 132].

Scheme 7. Kinetic resolution of racemic furylcarbinols upon action of Sharpless epoxidation reagent.

A radically different concept of enantiocontrol within pyranosulose chemistry, based on AR, was presented by Liebeskind [122 - 124]. This organometallic complex topology based side differentiation, is based on application of a chiral auxillary at the step of intermediate enulose glycoside, followed by chromatographic separation of diastereoisomers, but it offers easy access to sizable (and scalable) portions of reactive, yet stable materials, which can serve as advanced intermediates for synthesis of various pyran structures (Scheme 8).

Scheme 8. Preparation of chiral oxopyranyl scaffolds; involves use of chiral auxilliary and chromatographic separation. Reagents: i) m-CPBA ; ii) Ac2O/Et3N , ct. DMAP; PhCH(OH)Pr, cat ZnCl2; iii) Mo(CO)3(DMF)3, then KTp [potassium tris(pyrazolyl)borohydride].

SOME SYNTHETICALLY USEFUL TRANSFORMATIONS PYRANOSULOSES GENERATED VIA AR

OF

At the initial period of the AR study concern over selectivity of planned transformations was practically limited to the issue of diastereoselection. Over the years, with advancement of synthetic and analytical methodologies, the question of enantiomeric purity of the products of total synthesis became crucial. Achmatowicz rearrangement of furylcarbinols affords pyran derivatives, which are densly functionalized, featuring apart from the ring oxygen: hemiacetal (or optionally - a hemiketal) anomeric center (C-1) and conjugated (2,3-) unsaturated 4-ketone, with adjacent (C-5) center of chirality, where the alkyl substituent of the furylcarbinols substrate ends up. Integrity of the furyl carbinols center stereochemistry (becoming pyranosulose C-5) is secured throughout AR, (Fig. 7) thus, chirality can be fixed at either step: before or after, and even during the rearrangement, as demonstrated in examples presented in previous section [123126]. It should be reminded at this point that hexenuloses have also a record of chemical transformation investigations which stem from study of unsaturated

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sugars of natural origin [80, 126-130]. Homochiral furyl substrates usually produce during AR a pair of C-1 epimeric 1-OH products, which are capable of equilibrating. Control of the anomeric center stereochemistry is relatively easy, as the hemiacetal hydroxyl group can undergo both: kinetically or thermodynamically controlled functionalization, e.g. enzymatic or chemically catalyzed esterification, which greatly facilitate preparation of a single anomer products. Recently, a novel concept in biocatalysis - a N-heterocyclic carbene catalyzed (NHC) dynamic kinetic resolution (DKR) of racemates have been applied to selective esterification of pyranosuloses with a considerable success [130 - 132]. It appears that the anomeric hydroxyl group (also described as hemiacetal or lactol) can be esterified selectively in the presence of such catalysts as drug substance tetramisol or levamisol, although diastereoselectivities are not higher than 20:1. Further progress in stereoselectivity of NHC – DKR lactol functionalization is important in view of efficiency of follow-up palladium catalyzed glycosylations, which proceed with retention of configuration [53, 54].

Scheme 9. Diastereoselective esterification catalyzed by chiral benzotetramizoles (BMT).

Another, extremely important finding for efficient control of stereochemistry in the primary AR products concerns its susceptibility for the iridium catalyzed isomerization. After AR step of a homochiral furylcarbinols the diastereomeric ratio is close to 3: 1, in favor of the cis- isomer. Tang and co-workers have found that treatment of such mixture with a catalytic amount of a selected iridium complex {[Ir(cod)Cl]2} results in the formation of a single lactone product [14] (Scheme 10). Some other transformations of the AR generated pyranosulose scaffolds, which found wide application in syntheses of pyran containing natural products, also involve the oxygen ring adjacent carbon-hydroxyl function, named either anomeric, hemiacetal (hemiketal) or lactol, depending on synthetic target and its relation to natural products, like carbohydrates or isoprenoids. The anomeric

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group removal can be achieved by action of triethylsilane in the presence of a Lewis acid, known as Kishi reduction. Intramolecular dehydration between the anomeric and a side chain hydroxyl groups leads to bicyclic systems which are very handy for control of subsequent transformations into non-carbohydrate targets. Base catalysed elimination of an anomeric good leaving substituent affords pyrylium ion intermediates, which are prone to polar [5 + 2] cycloaddition reactions with unsaturated substrates [16, 133, 134] (Scheme 11).

Scheme 10. Isomerization of pyranosulose lactols and lactons.

Scheme 11. An example of generation of pyrylium ion and its [5 + 2] cycloaddition reaction.

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Scheme 12. Reaction of AR products with 1,3-dicarbonyl compounds: catalyst governed chemo- and regioselectivity.

Primary AR products feature conjugated unsaturated carbonyl functionality, which is considered a reactive Michael-type acceptor. This was confirmed experimentally in early period of AR connected chemistry research [135] and had an interesting continuation which demonstrated great potential of biocatalysis for regio- and diastereoselection in reactions involving Michael type addition of carbanionic nucleophiles (Scheme 12) and other reactions with polar nucleophilic reagents [136 - 139]. APPLICATIONS OF THE ACHMATOWICZ REARRANGEMENT TO TOTAL SYNTHESES OF NATURAL PRODUCTS MONOSACCHARIDES The first synthesis of the title pyranosyl hemiacetal, on the way to the total synthesis of racemic pentopyranosyl glycosides, was performed by hydrolysis of diastereoisomeric mixture of 2,5-dihydo-2,5-dimethoxy-2-hydroxymethyl furan, obtained from furfural via Clauson-Kaas procedure [69, 70], with diluted aqueous sulfuric acid. Although chemical yield of this procedure is quite good, it has to be remembered that the product is quite sensitive to excessive pH as well as action of various chemicals, exceptionally nucleophilic. The product is water soluble, which presents some problems with its isolation. In original preparation, immediate conversion to a mixture of methyl glycosides was advocated, for easier handling [1, 140 - 144]. Gradually, the initially adopted stepwise process of furylcarbinols conversion, involving isolation of intermediate mixed methyl ketals, gave way to one step procedures, for which a variety of oxidizing promoters have been designed [96, 99, 106]. Leaving bromine as the oxidant, but omitting methanol as the reacting solvent, proved effective for clean one-step furylcarbinol to pyranone lactal transformation. Reactions run stoichiometrically, in 9:1 acetonirile – water solution at 0oC, afforded very good yield of products, which were isolated after neutralization, in a standard way [106]. Methyl glycosides were deliberately selected for studying thus obtained 2,3-en4-ulose properties – physicochemical and spectral, as well as chemical reactivity

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[145 - 158]. It was also reasoned that prospective targets of further syntheses: deoxy- pyranoses, modified monosaccharides, antibiotic sugars and regular primary metabolic sugars, as well as their enantiomers, were as a rule characterized in form of methyl glycosides as the first choice. After some experiments with traditional procedures of glycosylation, including alkylation with alkyl halides under mildly basic conditions, the reaction of AR derived hemiacetals with trimethyl orthoformate in the presence of catalytic amount of boron trifluoride etherate was selected as preferred procedure for lower aliphatic aglycones [1, 140, 144, 145]. Later on, this procedure was supplemented by more universal two step exchange of an anomeric ester, in reaction with a hydroxylic substrate in the presence of catalytic amount of tin tetrachloride, which secured access to wide variety of pyranosulose glycosides. It has not been overlooked that such simple anomeric exchange reactions can be conveniently carried out with properly protected complex and multifunctional alcohols, including sugars. In this way precursors of disaccharides bearing D- or L- sugar moieties in the nonreducing unit have been obtained [159 - 161]. Methyl enulosides, usually easily separable by column chromatography, readily underwent carbonyl group reduction, affording C-4 epimeric secondary alcohols, with preference for the pseudoequatorial product [143]. Less abundant reduction product could be easily supplemented by application of configuration inverting procedures, such as Mitsunobu reaction. As a result, four pairs of racemic methyl pyranosides became available, featuring allyl alcohol function, suitable for stereocontrolled further functionalization, like mono-, di- hydroxylation or epoxidation [144 - 147, 151 153].

Scheme 13. Principal transformations of the AR products as intermediates for stepwise conversion to racemic methyl pentopyranosides, 6-deocyhexopyransides and hexopyranosidec; i)HC(OMe)3, BF3 (cat.), MC, rt.; ii)LAH, ether, rt. Chemical steps were foollowed by chormatographic separation of the isomeric products.

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Hexenoses presented on Scheme 13 bear close resemblance to 2,6-dideoxy-, 3,6dideoxy and 2,3,6-trideoxy-L-hexoses, which are frequent constituents of some medicinally important antibiotics. Accordingly, cinerulose and amicetose were among the first natural carbohydrate targets reached after successful completion of the AR furylcarbinol ring enlargement [140]. Naturally, with carbohydrates as the ultimate targets of the AR in mind, first the correlation of chirality between substrates and products was needed, as well as an easy acess to 2-furylcarbinols of suitable absolute configuration. Scheme 14 presents solution of both issues by referring to unsaturated sugar chemistry and classical Friedel-Crafts chemistry, which became available in enantioselective catalytic version [89].

Scheme 14. Chemistry for configuration correlation at the initial period of AR application; i) pTsA, MC; ii) LAH, diethylether; iii) standard conditions for tri-O-acetyl D-glucal preparation and deprotection; iv) protic acid catalysis, aqueous solution.

Further work included synthesis of ketoses, and variety of higher monosaccharides (heptoses, octoses), including 6-aminooctose constituting sugar part of antibiotic lincomycin [149, 151, 152, 154]. The next figure (Fig. 8) presents some selection of pyranosides obtained by the Achmatowicz group during initial period of their involvement in de novo prepared pyranosulose chemistry [143 - 153]. In keeping with the results accumulated by Achmatowicz group [162, 163], it appeared reasonable to use at first chiral pool derived synthons to assemble chosen sugar target synthesis, as demonstrated in (+)-KDO preparation, completed in 1989, based on 2-FL alkylation [164]. 2-FL was first subjected to highly diastereoselective addition to isopropylidene-D-glyceraldehyde, then hydroxyl protected product was lithiated again and alkylated with chloromethyl benzylether, to complete assembling all skeletal carbon atoms required. Direct C5 carboxylation of the furyl precursor was naturally considered as the first choice, but unexpectedly the intermediate thus obtained could not be transformed to required pyranosulose, under any of the standard AR conditions. Eventually, the AR step was completed by treatment of the 5-benzyloxymethyl furylcarbinol intermediate with t-BuOOH in the presence of VO(acac)2, while protecting

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glycosidation of the rearrangement product was achieved by methyl iodide action in the presence of silver oxide. Although installation of the required pyranosyl hydroxyl substituent was not straightforward, the key iodo carbonate intermediate obtained in multistep transformation of the primary AR product was smoothly converted into desired 3-deoxy-D-manno-2-octulosonic acid [164] (Scheme 15). KDO is an extremely important molecule; being the key component of Gram negative glycolipid component of bacterial cell walls it serves as a model target for design of new antibacterial therapeutics [165]. Admittedly, in this particular case, many synthetic methods of its synthesis have been elaborated, some of which are considerably more efficient that AR approach [166, 167].

Fig. (8). Examples of some monosaccharide methyl glycosides and some disaccharide precursors prepared via AR in an early period of its application.

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Scheme 15. Synthesis of (+) -KDO.

Recently, O’Doherty introduced a distinction between “de novo” and “de novo – asymmetric” routes in the total synthesis of carbohydrates, which has not only over a century long history, but it is full of original, illuminating and successful approaches: Sharpless and Masamune (AE, asymm. epoxidation); Sharpless and Wong (AH); Johnson (ER); Hudlicky, Banwell (EO); and finally Danishefsky, Vogel (hetero DA; furan DA), to name a few [2 - 8]. The term – de novo asymmetric, implies a catalytic process in which chirality centers are installed, which in turn has important consequences in terms of the product availability. This can be easily observed on example of AR as an useful synthetic method, for which the scope in the carbohydrate field was readily outlined, based on diastereoselectivity drawn from the chiral pool, in a few years after discovery. Only after ca. 20 years of relatively subdued existence, AR started its presently blossoming life, which apparently thrives on the power of asymmetric catalysis, which is capable of providing practically unlimited supply of the crucial raw materials – non-racemic furylcarbinols [30, 67, 76]. Among chemical enantiocatalytic approaches to homochiral furylcarbinols additions of diethylzinc to 2-furylaldehydes, catalyzed by chiral amines and aminoalcohols should be mentioned, because of high anomeric excess (up to 97%) were achieved [90 - 93]. Later paper advocated employment of (-)-MIB catalyst { (-)-3-exo(morpholino)isoborneol } for addition of dimethyzinc to furfural [99], which at 4 mol % level secured efficient conversion (97% yield; 98% ee) to (S)-methylfuryl carbinol methylzinc derivative, convertible in situ into pyranosulose, with use of

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either stoichiometric NBS or excess of hydrogen peroxide in the presence of a catalytic amount of vanadyl complex VO(acac)2. Since this procedure affords only one enantiomer of furylcarbinol, application of Noyori catalyst for asymmetric hydrogen transfer in reaction with 2-acylfurans, by which both enantiomeric alcohols can be obtained in excellent yield and with very high ee values, gained more popularity [9, 19, 26, 76]. Another de novo asymmetric oxidation approach to prochiral 2-furylolefins was developed independently in Ogasawara and O’Doherty laboratories. 2-Vinylfuran in situ solutions, easily prepared from furfural, were subjected to asymmetric dihydroxylation, in the presence of AD mix of choice, to obtain either 2-(R)- or 2-(S)- diol, in over 90% ee. Next, AR was carried out, by action of mCPPA or NBS [76, 119]. As could be expected, facile access to homochiral AR synthons greatly enhanced efforts towards carbohydrate targets, which was reflected by increase in total syntheses in L-hexoses and similar molecules, previously difficult to come by [167 - 176]. Deoxyhexoses presented on Scheme 16, which are constituents of various antibiotics, were also obtained by total synthesis through AR, with application of chiral furyl alcohols as substrates [9, 17, 177 - 179].

Scheme 16. Syntheses of antibiotic L-deoxypyranoses following iridium isomerization of 2-en-4-uloses.

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As already mentioned earlier, obtained enuloses can be subjected to intramolecular dehydration, an thus converted to bicyclic epimeric levoglucosenones. Following stepwise reduction-hydroxylation functionalization, easily afford hexopyranoses of manno-, talo- and gulo- configurations [9, 17, 179] (Scheme 17).

Scheme 17. Synthesis of both enantiomers of levoglucosenone via asymmetric dihydroxylation of 2vinylfuran. Final enulose isomerizaton involves epoxidation followed by action of hydrazine acetate and MnO2 oxidation.

Enantiomericaly pure D-hexopiranoses, with 2,3-cis arrangement of hydroxyl functions, selectively esterified at the anomeric center, were obtained via AR, as shown on Scheme 18 [17].

Scheme 18. Synthesis of D-pyranose 1-O-benzoates of manno- gulo- talo- configrations via cishydroxylation of intermediate hex-2 enoses.

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It can be concluded, that primary products of AR require immediate protection of the hemiacetal function in the form of alkyl glycoside or a carboxylic acid ester. However, different strategies emerged, based on iridium catalyzed kinetic isomerization, convert enuloses into lactones. Due to initial isomerization of anomers a single product is formed in this transformation, which resolves problems of stereocontrol at two chirality centers (C-1 and C-4) at the same time [14]. NON-CARBOHYDRATE NATURAL PRODUCTS As already mentioned, natural products whose structures are, at least in part pyran ring containing, are plentiful and well-covered in chemical literature [180 - 189]. Consequenly, methods for assembling tetrahydropyrans, particularly in polycondensed systems, are of great interest, even at the level of pharmaceutical process chemistry [189 - 192] One of the simplest examples is Prelog-Djerassi lactone (PDL), first isolated as a degradation product of narbomycin and later identified as substructure of other macrolide antibiotics. This compound is presently recognized as a chiral synthon of industrial significance, and there are dozens of its total syntheses published. The one which uses Evans’ oxazolidinone as the source and exploits AR as the key transformation, is presented in the Scheme 19 below [193, 194].

Scheme 19. Synthesis of Prelog-Djerassi lactone. i) Bu2BOTf/Et3N; H2O2; ii) K2CO3/MeOH ; iii) Br2/MeOH; H2SO4aq/THF; iv) ethyl vinyl ether/PPTS; v) LiCuMe2, Me3SiCl; vi) Pd (OAc)2 ; vii) Ph3P=CH2; viii)H2/PdC; ix) H2CrO6/acetone.

Styryl lactones, which are secondary metabolites of Asian plant genus Goniothalamus, (ca. 160 species) were reported to exhibit antiproliferative activities specifically against cancer cells, in which they tend to induce apoptosis. This group of natural products, numbering ca. 90 compounds, underwent a SAR study in search for a drug lead [195 - 197]. Two exemplary syntheses of styryllactones: altholactone and goniotriol, with the use of AR are presented on

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Schemes 20 and 21.

Scheme 20. Synthesis of altholactone. The key steps involve: 2-vinylfuran asymmetric dihydroxylation; AR; primary OH oxidation; Witting olefination; epoxidation, cyclization and inversion of configration by triflate displacement.

Scheme 21. Synthesis of goniotriol using D-glyceraldehyde as a chiral precursor.

Exploration of marine environment brought to light plethora of new structures, many in combination with promising biological activities. Among others, marine toxins should be mentioned, as a milestone in both: structural complexity and toxic efficiency. Maitotoxin, isolated from dinoflagellate Gambierdiscus toxicus has molecular composition C164H256O68S2Na2 which corresponds to a molecular weight 3422 daltons; apparently the largest non-polymeric secondary metabolite ever discovered. Degree of its structural complication is daunting – it constitutes 32 rings (28 tetrahydropyrans!) and 99 elements of stereochemistry (98 chirality centers + 1 trisubstituted double bond; a number of possible stereoisomers of this molecule equals 6.3 x 1028). The fused rings are composed into segments linked by hydroxyalkyl chains or even sigle bonds. These segments are marked as follows: A-F ; G-K, L-M, N-O, P-V and the last molecular fragment of ten rings from W to Z and from A’ to F’. Soon after solving BTX-B structure in 1981, attempts started of total syntheses of its subunits, chiefly in K. C. Nicolaou group at Scripps Institute. Remarkably, this extensive and long lasting synthetic effort, reported in several recent papers [167 - 170] involved repeated application of AR

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transformation for construction of particular tetrahydropyran rings. It usually started with acylation of furan (or protected 2-hydroxymethylfuran) with a suitable reagent, followed by Noyori reduction, AR, and removal of the lactol functionality by Kishi protocol. In such way precursors of particular rings, with proper groups for further assembly, assigned with the alphabet letters according to the target structure, were prepared. Some of this chemistry is shown on the following schemes (Schemes 22-24).

Scheme 22. Synthesis of the ring A building block for MTX-B i) n-BuLi ; ii) PivCl/Et3N; iii) Noyori reduction; iv) oxolane deprotection; v) BnBr; vi) HClaq; vii) Et3N, n-Bu2BOTf; viii) m-CPBA; ix) Et3SiH/BF3OEt2.

Scheme 23. Synthesis of ring D intermediate i)n-BuLi; ii)CSAcat; iii) PivCl/TEA; iv) Noyori reduction; v) m-CPBA; vi) Et3SiH/BF3; vii) MeMgBr, TMSOTf; viii) i-amyl2BH/H2O2; ix) PMBOC(=NH)CCl3.

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Scheme 24. An example of preparation QRS ring assembly of MTX-B i) n-BuLi ; ii) acylation ; iii) Noyori reduction; iv) AR - NBS/H2O; v) (MeO)3CH/BF3.OEt2; vi) Me2Zn/BF3.OEt2; vii) (MeO)3CH/BF3.OEt2; viii) TBSCl/Imidazol/DMF.

Other synthetic motifs prevail in the next examples of syntheses illustrating usefulness of the AR intermediacy in approach to pyran containing natural products. These represent preparation of engelrin A [198, 199]; brevisamide [200] and papulacandin D [201 - 204] as illustrated on Schemes 25 – 27.

Scheme 25. Synthesis of englerin A: i) POCl3/DMF; ii) iPrMgCl; iii) mCPBA; iv) MsCl/iPr3N; for multistep transformations of oxabicyclo intermediate into product see Ref.

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Scheme 26. Crucial steps in the synthesis of (+) - brevisamide.

Scheme 27. Papulacandin D; synthesis of its tricyclic spiroketal nucleus.

There are many other cases of AR application during total synthesis of pyran containing natural products, reported in literature. It often takes ca. 30 linear steps to reach the target, which results in the yield below 1%, but earlier syntheses

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which did not utilized AR are even longer. As a rule, homochiral furyl substrates are applied for AR step. The furylcarbinol ring enlargement is usually carried out with NBS, less frequent with mCPBA. The most frequent transformations performed on the primary AR products, are: Luche reduction of the ulose function, Kishi reduction of the hemiacetal function, or spiroketalization. Among examples published after 2000, are: ambruticin S [205], attenol B [206], brownin F [207], FCRR toxin [208], halichondrins [209], musellarins [210], phomopsolides [211], phostriecin [212], pseudomonic acids [213], psoracorylifols [214], rasfonin [215], spliceostatin A [216], and uprolide G [217]. As evident from the Scheme 1, in principle there are no restrictions, which limit class of Z substituents vicinal to the furan ring to oxygen only and analogs bearing other elements which can form nucleophilic substituents in this position should perform similarly. Indeed, properly protected amine analogs of 2furylcarbinols undergo a transformation analogous to AR, leading to dihydropyridine derivatives, which has been named aza-Achmatowicz rearrangement [12, 217]. This version of AR also became very popular recently, mainly because its great utility for preparation of condensed heterocyclic systems and applications in the total syntheses of alkaloids [218 - 221]. AR-DERIVED PYRANOSULOSES AS VERSATILE GLYCOSYLATION AND GLYCO-CONJUGATION SYNTHONS It has been generally accepted that natural products continue to provide valuable inspiration for establishing new drug leads [222, 223]. It is also agreed that pyrans, pyranosides, pyranoses and their analogs, featuring multitude of chirality centers, are important carriers of structural information and therefore can be included into a pool of privileged structures from the point of view of medicinal chemistry. Thus, the importance of sugars in processes of molecular recognition is best illustrated by lectins example, and is supplemented by abundance of cases from current studies in glycobiology. These studies require not only the native glycans, but a variety of model glycoconjugate molecules, designed de novo, according to the medicinal chemistry principles, hence the need for reliable and efficient chemical glycosylation methods. Contemporary sugar chemistry is, to a large extend, still involved in coping with traditional problems: a choice of anomeric substituent and its conversion into effective leaving group, control of anomeric stereochemistry and the other hydroxyl groups protection-deprotection efficiency. An interesting line of research which stems from unsaturated pyranosides chemistry, initiated and developed by Ferrier, for a change focuses on a C-3 substituent chemistry in glycals (hex-1-enitols) as a source of 2,3unsaturated glycosides, to which “missing” functionalities can be easily added by dihydroxylation or epoxidation. Esters of glycals easily undergo chemoselecive

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activation at C-3 by a variety of Lewis (and protic) acids, which facilitates a nucleophilic substitution reaction at C-1. However, in a palladium catalyzed allylic substitution reactions, there is a general preference for a C-1 substituent exchange in hex-2-enoses, over a C-3 ester group in hex-1-enitols. This points out directly to the prospective role of AR-derived pyranosuloses as glycosylating synthons of wide application, in accord with earlier observations based on a Lewis acid activation of the anomeric substituent. According to O’Doherty, the Pd(0) catalyzed glycosylation of pyranosulose anomeric esters (preferably 1-O tbutoxycarbonate), is both: general and stereospecific [17], as shown on the following scheme (Scheme 28).

Scheme 28. Stereoselective palladium catalyzed glycosylations with pyranosulose 1-O-carbonates.

Obviously, this approach has great potential also for oligosaccharide synthesis, with easy control of anomeric configuration, facile activation for anomeric exchange and no need for protection of the ring-connected functionalities. The proof of principle has been delivered in the form of 1,6-L- trisacharide syntheses: 2,3-eno, 2,3-dideoxy and 1,6-manno- trisacharide, as a result of the easily obtainable tri-enulose treatment with NaBH4, followed by either diimide double bond reduction or the osmium tetroxide catalyzed dihydroxylation [17] (Scheme 29). The same strategy was applied for the synthesis of a variety oligosaccharides: anthrax tetrasaccharide, cleistetrosides, and mezzettiasides [17]. Combination of AR with other cyclization methods is also feasible; for example pyranosulose glycosides which contain terminal acetylenes and 5-hydroxyl group in the same chain, can undergo tungsten catalyzed cycloisomerization affording disaccharide glycal. Such synthons can be easily functionalized at both ends: enulose can be extended into oligosaccharide chain and the glycal functionality secures facile glycosylation even complex and multifunctional aglycones (Scheme 30).

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Scheme 29. Synthesis of L-trisacharide enulose precursor.

Scheme 30. Synthesis of trisaccharide synthon by sequential AR - glycosylation - cycloisomerization reactions.

Besides, various pharmacologically important aglycons, like macrocyclic lactones, flavonoids and anthracyclines, were glycosidated with AR derived 2,3en4-uloses bearing ester (preferably carbonate) groups at the anomeric position. O’Doherty has also demonstrated usefulness of the stereoselective, palladium promoted glycosidation with AR derived synthons, in an extensive research program aimed at establishing of a structure-activity relationship (SAR) in a series of natural and synthetic glycosides of digitoxygenin [17]. The results of a sugar moiety combinatorial approach in search for new biological properties, natural steroidal saponins with Na/K ATP-ase activity, is a good example of using the potential of AR-derived synthons generated in a

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stereocontrolled manner. Obviously, the needs for new, structure-driven and function-targeted pyran derivatives as prospective drug leads are much wider. This has been convincingly demonstrated recently by rise of new type of antidiabetic therapeutics with function of sodium dependent glucose transporter inhibitors, (SGLT-1 and SGLT-2) named generically gliflozins. They originated from an early observation that natural chalcone glycoside: phlorizin is binding to sodium-dependent-glucose-transporting-protein with significantly higher affinity than the native ligand – glucose [224]. Phlorizin has been first isolated from apple tree bark and subsequently shown to occur in apples, its peels and pulp, as well as in apple juices and ciders, and it was known to cause glycosuria in experimental animals. An initial examination of a synthetic phlorizin analog (T-1095) in Japan confirmed, that it increased urinary glucose excretion and reduced glucose and glycohemoglobin blood levels. These results prompted search for other inhibitors of SGLT co-transporters and rise of new generation of synthetic C-glycoside antidiabetic drugs, presented on Scheme 31 [225, 226]. Gliflozins have been initially prepared from benzylated D-glucono-lactone, by addition of a suitable aryllithium derivative, followed by reductive removal of the anomeric hydroxyl function, but eventually the use of silylated glucono-lactone derivative prevailed, for technological and economical reasons [227]. This turn in the medicinal chemistry research and pharmaceutical industry strategies towards one of the most serious challenges to the contemporary global human healthcare, indicating that total synthetic approaches to novel, pyran containing biologically active small molecules (and therefore AR as well), have a bright future ahead. CONCLUSIONS It is generally accepted that the principal mission of chemical synthesis is in delivery of new materials with conceptually designed properties and functions. Drug candidates are particular category of such sought after innovative materials, often discovered from Nature, but also designed de novo from biological inspirations. There is no doubt that low molecular weight carbohydrates and to certain extent also their structural analogs like acetogenin derived pyran secondary metabolites, belong to a category of privileged structures in terms of inherent affinity to macromolecular targets and resulting potential of biological activity [227, 228]. Consequently, they evoked an interest as drug leads [229, 230] or drug delivery auxiliaries [231, 232] and many recent new drug launches are based on pyran/pyranoside scaffold structures. Classical carbohydrate chemistry can in principle provide an oligosaccharide or a glycoconjugate molecule of any complexity, but at a considerable expense in time, labor and materials, because it is based on a repetitive protection-deprotection strategy. The transformation of achiral furan derived raw materials described in this Chapter (AR), belongs to entirely different methodology, which operates on unsaturated

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and low-oxygenated pyran synthons, having only minimal requirements in terms of the functional groups protection, thus corresponding well with Green Chemistry principles. Besides, chirality management during entire synthesis can easily be carried out based on the principle of efficient enantioselective catalysis. Overall, AR fits well currently advocated formats of searches for new drugs: structure driven design, diversity oriented synthesis, design of analog libraries and function oriented synthesis [233, 234].

Scheme 31. Syntheses of C-glycosyl inhibitors of sodium-dependent glucose transporters.

In recent decades convincing evidence has been accumulated, that AR gained a prominent significance among general approaches to assembly of six-membered oxygen and nitrogen heterocycles. Some leading examples of this transformation

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utility towards efficient preparation of the pyran ring containing molecular targets, spanning from simple sugars, through modified pyranoses and their oligosaccharides, to polycyclic segments of higher molecular weight marine toxins, were presented in this chapter. Pyranosulose synthons, which are readily available by AR from furan or its derivatives in a stereocontrolled manner, found already many applications in total synthesis of natural products and their potential as glycosylating and glycoconjugating reagents, although already well documented, is likely to reach yet new dimensions, owing to admirable preparational simplicity and good tolerance for an acceptor complexity. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTERESTS The author declares no conflict of interests concerning this publication. ACKNOWLEDGEMENT The author gratefully acknowledges support from the Pharmaceutical Research Institute. ABBREVIATIONS 2-LF

2-lithiofuran;

ADMET

adsorbtion, distribution, metabolism, excretion, toxicity;

AD-mix-α

a reagent system for catalytic asymmetric dihydroxylation of alkene;

ADH

asymmetric dihydroxylation;

AEP

asymmetric epoxidation;

AHD

asymmetric hydrogenation;

AR

Achmatowicz rearrangement;

Boc2O

ditert-butyl dicarbonate;

cat. Pd(PPh3)2

Palladium bistriphenylphosphine (the catalytic intermediate in Pd(0/II) cross coupling reactions;

DBU

1,8-diazabicycloundec-7-ene;

DCC

N,N'- dicyclohexylcarbodiimide;

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone;

DEAD

diethyl azodicarboxylate;

DHAP

3-hydroxy-2-oxopropyl phosphate;

DIBAL-H

diisobutylaluminum hydride;

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hydrazide/triethylamine; (+)-DIPT

(+)-diisopropyltartrate;

DMAP

4-dimethylaminopyridine;

DMP

2,2-dimethoxypropane;

HWE-olefination

Horner–Wadsworth–Emmons olefination reaction;

IBX

2-iodoxybenzoic acid;

KDO

3-deoxy-D-manno-oct-2-ulosonic acid;

LAH

lithium aluminium hydride;

Luche reduction

selective NaBH4 reduction of ketones to alcohols with lanthanoid chlorides;

m-CPBA

m-chloroperoxybenzoic acid;

MIB

(-)-3-exo-(morpholino)isoborneol;

MTT

dimethyl thiazolyl diphenyl tetrazolium salt, a type of tetrazole;

Mukaiyama aldol condensation

a Lewis acid catalyzed aldol reaction;

NBS

N-bromosuccinimide;

NMO

N-methylmorpholine N-oxide;

Noyori catalysts

(R,R)-Noyori, (R)-Ru(η6-mesitylene)-(R,R)-TsDPEN;

(S,S)-Noyori

(S)-Ru(η6-mesitylene)-(S,S)-TsDPEN;

Pd2(dba)3

Tris(dibenzylideneacetone)dipalladium(0);

Petersen olefination

the conversion of aldehydes and ketones to alkenes via a beta-hydroxy silane;

PMB

p-methoxybenzyl;

PMBOH

p-methoxybenzyl alcohol;

RedAl

sodium bis(2-methoxyethoxy)aluminum hydride;

SAR

structure-activity relationship;

Sharpless asymmetric epoxidation (SAE)

condition for the asymmetric epoxidation of allylic alcohols;

TBAF

tetra-n-butylammonium fluoride;

TBS

tert-butyldimethylsilyl;

TBSCI

tert-butyldimethylsilyl chloride;

TFA

trifluoroacetic acid;

THF

tetrahydrofuran;

TMEDA

tetramethylethylenediamine;

TMS

trimethylsilyl;

TMSOTF

trimethylsilyl trifluoromethanesulfonate;

TPP

triphenylphosphine;

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oxidation of alkenes to a vicinal diols with catalytic OsO4 and NMO.

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[http://dx.doi.org/10.1021/acs.chemrev.6b00475] [PMID: 28121130] [227] Bernhardson, D.; Brandt, T.A.; Hulford, C.A.; Lehner, R.S.; Preston, B.R.; Price, K.; Sagal, J.F.; St. Pierre, M.J.; Thompson, P.H.; Thuma, B. Development of an early-phase bulk enabling route to sodium-dependent glucose cotransporter 2 inhibitor ertugliflozin. Org. Process Res. Dev., 2014, 18, 57-65. [http://dx.doi.org/10.1021/op400289z] [228] Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol., 2010, 14(3), 347-361. [http://dx.doi.org/10.1016/j.cbpa.2010.02.018] [PMID: 20303320] [229] Costantino, L.; Barlocco, D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem., 2006, 13(1), 65-85. [http://dx.doi.org/10.2174/092986706775197999] [PMID: 16457640] [230] Jimenez-Barbero, J.; Canada, F.J.; Martin-Santamaria, S., Eds. Carbohydrates in Drug Design and Discovery. RSC Drug Discovery Series No. 43; RSC Cambridge UK 2015. [231] Jain, K.; Kesharwani, P.; Gupta, U.; Jain, N.K. A review of glycosylated carriers for drug delivery. Biomaterials, 2012, 33(16), 4166-4186. [http://dx.doi.org/10.1016/j.biomaterials.2012.02.033] [PMID: 22398205] [232] Wender, P.A.; Verma, V.A.; Paxton, T.J.; Pillow, T.H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res., 2008, 41(1), 40-49. [http://dx.doi.org/10.1021/ar700155p] [PMID: 18159936] [233] DeCorte, B.L. Underexplored opportunities for natural products in drug discovery. J. Med. Chem., 2016, 59(20), 9295-9304. [http://dx.doi.org/10.1021/acs.jmedchem.6b00473] [PMID: 27331414] [234] Bebbington, M.W.P. Natural product analogues: towards a blueprint for analogue-focused synthesis. Chem. Soc. Rev., 2017, 46(16), 5059-5109. [http://dx.doi.org/10.1039/C6CS00842A] [PMID: 28675202]

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CHAPTER 3

Recent Advances in the Synthesis of N-Glycosyl Compounds Nuno M. Xavier1,2,* and Rafael Nunes1,2,3 Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal 2 Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal 3 BioISI – Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal 1

Abstract: N-Glycosyl compounds, analogs of glycosides possessing an N-glycosidic linkage, have attracted much attention as synthetic targets in medicinal chemistry, due to their biological activities. In this chapter, the synthesis of non-nucleosidic Nglycosyl compounds is reviewed. The groups of molecules covered herein include Nglycosylamines/amides, sulfonamides, hydrazines, phosphoramidates and Nglycosylamino acids, among other related derivatives. Methods for their access, based on the literature from the last 20 years, as well as their relevance as bioactive substances, are focused.

Keywords: Biological activity, Glycals, Glycosyl azides, N-Glycosylation, NGlycosylamines, N-Glycosylhydroxylamines, N-Glycosylalkoxyamines, NGlycosylamino acids, N-Glycosylamides, N-Glycosyl trichloroacetamides, NGlycosylsulfonamides, N-Glycosylhydrazines, N-Glycosylphosphoramidates, NGlycosylimines, N-Glycosyl succinimides, O-Glycoside mimetics, Staudinger ligation, Staudinger-type reactions. INTRODUCTION The knowledge on the roles of carbohydrates in essential biological processes in health and in disease progress, as well as the bioactivity exhibited by numerous carbohydrate derivatives, has motivated the development of carbohydrate-like molecules, known as glycomimetics, for potential use in therapeutics. These types of compounds may interfere in biological pathways in which carbohydrates play key roles and are associated or contribute to pathological disorders. Among these * Corresponding author Nuno M. Xavier: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal; Tel: +351 21 7500853; E-mail: [email protected]

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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events are cell-cell recognition or cell adhesion, which trigger processes such as inflammation, pathogen-host interaction leading to infection or signal transduction and are mediated by carbohydrate-carbohydrate interactions [1, 2] or by carbohydrate-protein interactions [1 - 8]. The search for carbohydrate mimetics able to inhibit carbohydrate-lectin interactions has especially been a focus of research in various groups, and has led to promising molecules against bacterial and viral infections [9 - 11]. Glycosylation and carbohydrate-processing pathways are also targeted by glycomimetics as potential therapeutic strategies for diseases such as cancer or diabetes [12, 13]. In these cases, such compounds are frequently intended to inhibit carbohydrate-acting enzymes such as glycosidases [14], whose abnormal activity contributes to the modifications in the glycosylation patterns observed in cancer cells and to the increase on the levels of glucose in diabetic patients. Among the glycomimetic structures, carbohydrate heteroanalogs in which an oxygen atom has been replaced by another atom, namely nitrogen, sulfur or carbon, are the most studied. Mimetics arising from endocyclic replacement include imino sugars [15 - 18], thio sugars [19, 20] or carba sugars [21, 22]. Concerning the structures resulting from the replacement of exocyclic oxygen atoms of a sugar ring, the most interesting molecules from the biological/therapeutic point of view are those in which such alteration occurs at the anomeric oxygen. This structural change has been particularly relevant for the access to potential mimetics of O-glycosides, in the search of new bioactive substances. Besides having propensity to inhibit glycoside-acting enzymes, namely glycosidases, the development of such mimetics may open new therapeutic opportunities, due to the broad biological profile of many naturallyoccurring O-glycosides [23], which include saponins [24, 25], flavonoid glycosides [26], or glycoside antibiotics [27]. The replacement of the anomeric oxygen atom in a glycoside is also a strategy to increase the stability of the molecules under physiological conditions, since an O-glycosidic bond is rather susceptible to enzymatic hydrolysis. Included in the most relevant heteroanalogs of O-glycosides are the thioglycosides, the selenoglycosides, the C-glycosyl and the N-glycosyl derivatives. The S- and Se-glycosides are mostly used as synthetic intermediates in Oglycoside synthesis, acting as glycosyl donors [28 - 30]. These types of compounds scarcely occur in nature. The most representative group of bioactive molecules having an S-glycosidic bond are the glucosinolates [31], while there are few examples of synthetic Se-glycosides showing biological properties of interest,

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namely as lectin binders [32]. The C- and N-analogs are often named as C- or N-glycosides, although the use of these terms is discouraged by IUPAC [33]. C-Glycosyl compounds are the most stable O-glycoside mimetics due to their non-cleavable C-C bond linking the sugar and aglycon moieties, making them resistant in vivo. Such molecules frequently display interesting biological properties, sometimes higher than the corresponding O-glycosides [34 - 36]. The challenge of connecting a molecule to a sugar by a C-C bond at the anomeric position makes the development of synthetic methodologies towards C-glycosyl derivatives a continuously relevant topic of research [35 - 41]. In this chapter, emphasis is given on N-glycosyl compounds (also named glycosylamines), which have especially become important target molecules in medicinal chemistry, due to the broad range of biological activities exhibited by natural and synthetic derivatives. The most notorious groups of compounds of this class are nucleosides and nucleotides, which play key roles in fundamental biological processes, including signaling pathways, cell division and as part of nucleic acids. Such pathways are overactivated in diseases such as cancer or viral infections and therefore the development of synthetic analogs to interfere with these events is a relevant strategy in anticancer and antiviral drug research. This rationale has led to numerous molecules which ended up in clinics as anticancer or antiviral drugs [42, 43]. Other relevant bioactivities reported for nucleoside analogs include antimicrobial [44, 45] and anticholinesterasic properties [46, 47]. The synthesis and therapeutic potential of natural/synthetic nucleosides and nucleotides have been extensively covered in various excellent reviews [43, 48 - 51] and therefore, these topics are not discussed. Naturally-occurring non-nucleosidic N-glycosyl derivatives include the Nglycosyl indoles akashines A, B, C [52], staurosporine [53 - 55] or rebeccamycin [56], which possess anticancer properties, and the ansacarbamitocin antibiotics [57]. N-Glycosyl units are also found in a number of glycopeptides possessing relevant biological roles [58, 59], being N-glycosylation an important post-translational modification of proteins [60]. Previously published survey papers on N-glycosyl compounds were dedicated to the synthesis of N-glycosyl ureas [61], N-glycosylhydrazines [62, 63] and oxyamines [63], N-aryl glycosylamines [64] and to the synthesis and potential use

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in medicinal chemistry of N-glycosyl amides, triazoles [65], and Nglycosylsulfonamides [66]. Therefore, these groups of compounds, although mentioned and included in this chapter as part of specific sections, are not included in this discussion. Instead, recent findings are highlighted. Concerning other most significant synthetic N-glycosyl derivatives, namely N-alkyl/aryl glycosylamines, N-glycosyl amino acids, N-glycosylphosphoramidates or Nglycosylimines/imides, the methodologies developed in the last 20 years towards their access are compiled, as well as their bioactivities, when relevant. Free Glycosylamines and their N-alkyl and N-aryl Glycosyl Compounds Early methods for the synthesis of free glycosylamines include the treatment of unprotected monosaccharides with methanolic ammonium chloride [67], or with ammonium bicarbonate, a protocol that is also effective for disaccharides [68], and the reduction of glycosyl azides [69, 70]. The later precursors are frequently prepared by treating 1-O-acetyl sugar derivatives with trimethylsilyl azide (TMSN3) in the presence of a Lewis acid or from glycosyl halides via nucleophilic displacement with an azide-based nucleophile, such as TMSN3 or LiN3 [69]. NAryl glycosylamines (2) can be synthesized by a simple condensation between an arylamine derivative and an unprotected free sugar (1) in the presence of a catalytic amount of a protic or a Lewis acid in a polar solvent (Scheme 1) [64, 71]. D-Configured monosaccharides give preferentially N-β-glycosyl derivatives, due to their stabilization by the exo-anomeric effect, an orbital interaction based on the donation of electron density from the nitrogen lone pair to the endocyclic C1–O bond (nN1→σ*C1–O5) [72]. ArNH2

O HO OH 1

cat. acid (CH3COOH, HCl or NH4Cl or Lewis acid)

O HO NHAr 2

Scheme 1. Synthesis of N-aryl glycosylamines from unprotected free monosaccharides.

N-Alkylamines are more reactive than aromatic ones and therefore the condensation reaction can be successfully conducted without catalyst. N-Alkylβ-D-glucosylamines were synthesized in good to excellent yields using this methodology and some of them, particularly those containing a long N-alkyl chain, displayed antifungal effects [73]. A greener version of the direct coupling of an unprotected sugar with an Nsubstituted amine, based on a mecanosynthetic protocol, by employing high speed ball milling (HSBM) under solventless conditions, was reported [74]. In the

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presence of SiO2 as grinding-aid agent, various monosaccharides were reacted with alkyl/arylamines, alkyldiamines or aminoalcohols and were converted into the corresponding N-glycosylamines in excellent yields, after a reaction time of 1.5 h in most of the cases. The method also allowed the complete conversion of D-maltose to N-dodecyl D-maltosylamine. 2-Nitroglycals can be used as glycosyl donors for the glycosylation of secondary amines. The reaction does not require catalyst or promotor and affords stereoselectively β-N-glycosylamines in very good yields. The methodology was also effective for cyclic amines [75]. δ-Hydroxy nitriles constitute another type of suitable precursors for Nglycosylamines [76]. These acyclic derivatives (3, Scheme 2) can be accessed by reaction of free monosaccharides with hydroxylamine and further dehydration of the resulting oximes by treatment with triphenylphosphine and CBr4 [77]. When subjected to sodium borohydride in ethanol, these compounds were shown to undergo reductive cyclization to the target hemiaminals (4) in moderate to good yields and stereoselectivity to β-anomers. The methodology worked well for Dglucose-, D-mannose-, D-galactose- and N-acetyl-D-glucosamine-derived δhydroxynitriles (3) as well for a maltonitrile derivative. BnO BnO

OBn OH CN R

NaBH4

BnO BnO

EtOH

3 R = OBn (D-gluco, D-manno, D-galacto)

OBn O R

NH2

4  as major or sole stereoisomers

R = NHAc (D-gluco)

Scheme 2. Synthesis of glycosylamines by reductive cyclization of δ-hydroxy nitriles.

Glycosyl trichoroacetimidates are amongst the most commonly used glycosyl donors and can be easily prepared by reaction of free sugars with trichloroacetonitrile in basic medium. In the presence of a Lewis acid, without an active glycosyl acceptor these compounds are prone to rearrange into Ntrichloroacetyl glycosylamines. Taking advantage of this tendency for rearrangement, a practical and high yielding method for the access to glycosylamines was developed, which involves the reduction of the rearranged products to the corresponding glycosylamines (Scheme 3) [78]. Hence, conversion of tetra-O-benzyl glycosyl trichloroacetimidates (5) into 1-Ntrichloroacetyl derivatives (6) was accomplished within one hour using a catalytic amount of trimethylsilyl triflate (TMSOTf). The treatment of 6 with sodium borohydride allowed the removal the trichloroacetyl group, affording the target

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glycosylamines 7. This methodology was also successfully applied for the access to an N-maltosylamine counterpart. BnO BnO

OBn O OBn O

NH CCl3

TMSOTf CH2Cl2

OBn O

BnO BnO

OBn N H

5

NaBH4

O CCl3

EtOH

6

BnO BnO

OBn O OBn NH2 7

D-gluco, D-manno

Scheme 3. Synthesis of glycosylamines by rearrangement of glycosyl trichloroacetimidates and subsequent reduction.

N-Glycosylhydroxylamines and Alkoxyamines The condensation of hydroxylamines or alkoxyamines with free sugars is the commonly used method to obtain N-glycosylhydroxy- or alkoxyamines. The treatment of an aldose with hydroxylamine hydrochloride provides anomeric hydroxylamines [79] that have the tendency to isomerize via equilibrium with their acyclic oximes. Using N-alkylhydroxylamines, the cyclic product is formed exclusively (Scheme 4). The first published report on the synthesis of N-alkyl-Nglycosylhydroxylamines (9) dealt with N-benzyl derivatives [80]. The condensation of various O-protected free monosaccharides (8) with Nbenzylhydroxylamine (R' = Bn) was shown to occur with complete conversion when conducted with a Lewis acid as promoter, namely zinc chloride, in the presence of MgSO4. Starting from O-benzyl protected D-ribo- and D-xyloconfigured derivatives only β-anomers were obtained, while derivatives of Dglucose and D-galactose afforded anomeric mixtures. A diacetonide derivative of D-manofuranose led solely to the α-N-glycosyl compound. R' RO O

OH n

8

N H

OH

R' N

RO O

n = 1, 2

OH

n

9

Scheme 4. Synthesis of N-alkyl N-glycosylhydroxylamines by reaction of free monosaccharides with Nsubstituted hydroxylamines.

Modifications of this protocol resulted in considerable improvement in the method. A solventless procedure applied to free tri-O-benzyl-glycofuranoses, based on heating the sugar with N-benzylhydroxylamine at high temperature, proved to be very efficient, leading to compounds of type 9 (R, R' = Bn) in very good yields and short reaction time (30 min) [81]. Other reported procedure

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consists on the treatment of compounds of type 8, comprising benzyl or isopropylidene O-protecting groups, with N-benzylhydroxylamine hydrochloride in dry pyridine at room temperature [82, 83]. The method was also effective when using N-methylhydroxylamine hydrochloride. The stereochemical outcome of the reaction is influenced by the orientation of the substituent at C-2 in the sugar ring. The products (9) were obtained as anomeric mixtures, in which the more thermodynamically stable anomer dominates, or as sole anomers. In the case of N,O-disubstituted hydroxylamines, the condensation can be performed with unprotected free sugars (1), under mild acidic conditions, generally in aqueous buffers at pH 4 or in polar organic solvents containing acetic acid (Scheme 5) [84, 85]. Starting from glucose, only N,O-dialkyl-Nglycosyloxyamines (10) having β-anomeric configuration are obtained. When the N-alkyl group is non-benzylic, galactose gives only β-anomers, while mannose leads to α-configured N-glycosyl derivatives [84]. β-N-Galactofuran/pyranosyl derivatives and anomeric mixtures of N-mannopyranosyl derivatives along with α-N-mannofuranosyl compounds are obtained when galactose or mannose are reacted with N-benzyloxyamines [85]. R1 O HO

N H

OR2 O HO

OR2 N aq. buffer, pH 4 or 1 10 R1 AcOH/solv. Scheme 5. Synthesis of N,O-dialkyl-N-glycosyloxyamines by reaction of unprotected free monosaccharides with N,O-disubstituted hydroxylamines. OH

The alkoxyamine glycosylation has been used to form new types of glycoconjugate analogs or mimetics in which the oxyamino fragment replaces the interglycosidic oxygen atom, namely glycopeptide mimetics [84, 86], methoxyamino-linked di- and trisaccharide analogs [87]. Alkoxyamine-based glycosylation is also generally termed “neoglycosylation”. This reaction has served as a strategy to access analogs of natural glycosides with improved biological properties. The approach consists in the functionalization of the aglycon part of a bioactive O-glycoside with an oxyamine moiety and further Nglycosylation with a range of natural and unnatural reducing sugars [88]. Various neoglycosides were shown to display a significantly better bioactivity profile than that of the parent natural compound, from which cardiac neoglycosides can be highlighted [85, 89, 90]. N-Glycosylamino Acids N-Glycosylamino acids represent a particularly relevant class of N-glycosyl

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compounds, owing to their utility as building blocks for the chemical/enzymatic synthesis of N-linked glycopeptides which participate in numerous biological processes [58 - 60]. Hence, glycoconjugates of this type can also be exploited as chemical probes for studying biochemical mechanisms, such as protein Nglycosylation, or towards the design of potentially bioactive glycopeptidomimetics. Furthermore, glycosylation can be employed as an efficient strategy to modulate the pharmacological properties of therapeutic peptides, namely their bioavailability or biomembrane permeability, as highlighted recently in the literature [91]. Natural glycoprotein systems feature a diversity of glycosidic linkages, most frequently involving N-acetyl-D-glucosamine (GlcNAc) units either β-N-linked to the carboxamide side chain of L-asparagine residues, or β-O-linked to a hydroxy group from L-serine or L-threonine, amongst other existing glycan-protein linkages [59]. The development of synthetic strategies towards glycosidic linkages of the former type, namely N-glycosylamino acids, has been covered in previous reviews [59, 65, 92, 93] and, therefore, only a selection of recent findings are discussed in this section. Related molecular entities encompass also anomeric sugar-amino acids and their spirocyclic derivatives, embodying both the amine and carboxylate functionalities bound to the anomeric position of the sugar, have also been described [65]. In earlier reports, preparation of N-glycosylamino acids, namely β-N-(GlcNAc-asparagine derivatives, relied on the condensation between glycosylamines and protected L-aspartate derivatives using conventional coupling reagents (e.g. carbodiimides) to promote in situ activation of the amino acid carboxylate moiety towards amide bond formation, followed by selective deprotection and peptide chain elongation to produce the corresponding N-linked glycopeptides [92]. However, the propensity of glycosylamines to undergo anomerization typically compromises the stereoselectivity of the reaction leading to anomeric mixtures of N-glycopeptides. In alternative, other methods have been developed taking advantage of glycosyl isothiocyanates, sulfoxides or pentenyl glycosides as glycosyl donors or their precursors [93]. The application of Staudinger ligation reactions to access N-glycosylamino acids has provided a significant contribution to this field. Several methods have been described based on the reaction of glycosyl azides with phosphine derivatives suitably functionalized with acylating agents in order to deliver the amino acid moiety to the intermediate iminophosphoranes by intramolecular transacylation. Hence, the synthesis of β-N-glycosyl asparagine derivatives (12) has been undertaken by means of Staudinger ligation between acetyl- or benzyl-protected glycosyl azides (11) and phosphinothioesters bearing alkyl or phenyl substituents

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(Scheme 6), in moderate yields [94]. The series of glycosyl azides tested further included an azido disaccharide. In all cases, transformations proceeded with βstereoselectivity regardless of the sugar protecting groups or anomeric configuration, suggesting that iminophosphorane α- to β-anomerization followed by transacylation is the preferred pathway involved. R = Et, Bu, Ph O

OR1 1

R O R1O

O

R2 P

R2 N3 11

NHBoc

S DMF, r.t.

CO2Bn

OR1 1

R O R1 O

O R 12

H N

2

CO2Bn O

NHBoc

R1 = Bn, Ac R2 = OBn, OAc, NHAc

Scheme 6. Synthesis of β-N-glycosylamino acid derivatives of asparagine by Staudinger ligation of protected glycosyl azides with phosphinothioesters.

The use of unprotected glycosyl azides as starting materials for the preparation of β-N-glycosylated asparagines, through conventional three-component Staudinger ligation with L-aspartic acid derivatives in the presence of tributyl phosphine and N,N’-dicyclohexylcarbodiimide (DCC), has been subsequently described [95]. Alternative methods for the stereoselective synthesis of N-glycosylamino acids from unprotected anomeric azides that take advantage of Staudinger ligation with functionalized phosphanes have also been optimized. Indeed, ligation of α- or β-D-glucosyl azides (13) with 2-(diphenylphosphanyl)-4-fluorophenyl esters in N,N-dimethylacetamide (DMA)/DMPU (98:2) leads to the corresponding Nglycosylated amino acids (14) with retention of configuration, as illustrated in Scheme 7 for asparagine (n=1) and glutamine (n=2) derivatives [96]. Noteworthy, this stereoconservative protocol provides an efficient route towards unusual αconfigured N-glycopeptide mimetics. Transformations were successfully extended to β-D-galacto-/β-L-fucopyranosyl azides and the less reactive N-acetyl-β-Dglucosamine analogue, as well as to phosphane precursors incorporating other amino acids, namely glycine, proline or β-alanine. α-Furanosyl by-products, resulting from ring contraction of the intermediate iminophosphoranes, are produced in only trace amounts in most cases. In comparison with previous work, where both protected and unprotected glycosyl azides along with non-fluorinated phosphanes were explored as precursors for the stereodivergent synthesis of Nglycosylamino acids/amides [97, 98], substantial improvements were achieved regarding conversion efficiency and stereocontrol. This type of methodology has also been applied to the stereoselective synthesis of related N-glycofuranosyl compounds [99, 100], including α-N-ribosy-asparagine/glutamine derivatives (16, Scheme 7) [101]. These compounds are

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important building blocks for the preparation of adenosine diphosphate (ADP)ribosylated oligopeptides, which can be valuable probes for studying posttranslational ADP-ribosylation of proteins in biological systems. Access to target compounds (16) required protection of the 5-hydroxy group of β-D-ribofuranosyl azide as a tert-butyldiphenylsilyl ether (15) to avoid the concomitant formation of β-pyranosyl products arising from ring-expansion. The reaction proceeded with inversion of configuration to afford isomerically pure α-anomers. These structures have also been obtained by other approaches, namely through condensation of a glycosylamines with carboxylic acids [102] or by stereoselective N-glycosylation of carboxamides with ribofuranosyl N-phenyltrifluoroacetimidates [103]. PPh2 n

O OH HO HO

F

O HO 13

O

CO2Me O

HO HO

a) DMA/DMPU b) H2O

N3

OH

NHCbz

HO 14

O N H

NHCbz CO2Me

n

n = 1, 2 PPh2

n

O TBDPSO O

N3

HO OH 15

F

O

CO2Me

NHCbz

a) DMA/DMPU b) H2O

TBDPSO O

HO OH 16

O NHCbz

N H n

CO2Bn

n = 1, 2

Scheme 7. Synthesis of N-glycosylamino acid derivatives of asparagine or glutamine by Staudinger ligation of unprotected glycosyl azides with 2-(diphenylphosphanyl)-4-fluorophenyl amino acyl esters.

Traditionally, N-linked glycopeptides can be assessed through a sequential approach involving the preparation of N-glycosylamino acid precursors as described above and subsequent selective deprotection for their incorporation into growing peptide chains, using solid-phase peptide synthesis (SPPS). This type of iterative process is most commonly not suitable to access larger N-glycopeptide sequences, for which the overall efficiency of the stepwise procedure is compromised. In alternative, a convergent strategy, the so-called Lansbury aspartylation, is often employed for N-glycopeptide or N-glycoprotein synthesis [104, 105]. In this case, a glycosylamine is condensed with the unprotected carboxylate side chain of an aspartate residue within a peptide sequence, typically after complete peptide assembling, in the presence of standard coupling reagents. The major drawback of this methodology concerns the concomitant formation of cyclic aspartimides and other by-products. Indeed, several reports have focused on the development of protocols attempting to improve the efficiency of this process by circumventing aspartimide formation, either in solution or in the solid-phase [106]. More recently, an efficient reaction has been developed that enables the convergent synthesis of N-linked glycopeptides (18), through direct aminolysis of

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p-nitrophenyl thioester-activated peptides using unprotected mono-, di- or oligosaccharide-based glycosylamines (17) in solution (Scheme 8) [107]. This high-yielding procedure further benefits from being compatible with unprotected carboxylate groups either at the C-terminal of the peptide substrates or in the sialic acid moiety of a sialyloligosaccharide. P1, P2 = Peptide sequences O2N S

NH2 NHAc

DIPEA, DMSO, r.t.

2H

O

18

H N NHAc O

Bo

c-

17

OH RO HO

P1 -C O

O

p-

OH RO HO

P2 -A s

O Boc P2 Asp P1 CO2H

R = H, GlcNAc, sialyloligosaccharide

Scheme 8. Synthesis of N-glycosylamino acids by aminolysis of p-nitrophenyl thioester peptides.

N-Glycosylamides In addition to N-glycosylamino acids, related N-glycosyl compounds have been described that also exhibit a carboxamide functionality linked to the anomeric carbon, generically referred to as N-glycosylamides or N-acyl-N-glycosylamines. The chemical space and bioactivity of this type of structures has been vastly explored [65]. Examples include immunomodulatory glycolipid analogs [108 110], inhibitors of glycogen phosphorylase [111, 112], sodium ion voltage-gated channels inhibitors [113], or cytotoxic substances [114], amongst others [65]. Synthetic methods developed for the preparation of N-glycosylamino acids, as described above, are also most typically convenient to access N-glycosylamides. Therefore, the use of glycosyl azides in Staudinger-type reactions or ligations [97 - 100, 111, 115 - 118], along with strategies based on direct N-acylation of glycosylamines [108, 109, 112], are frequently reported. Nevertheless, methodological improvements as well as more unconventional routes towards this type of compounds have also been conceived. BnO BnO

OBn O BnO 19

NH2COR AgOTf, ACN, r.t.

Cl

BnO BnO

OBn O BnO

O N H

R

20

Scheme 9. Synthesis of N-glycosylamides by direct N-glycosylation of primary and secondary amides with perbenzylated glycosyl chlorides.

A solvent-free approach for the coupling between protected glycosylamines and long acyl chain-containing p-nitrophenol activated esters has been described

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[110]. For the preparation of N-(2-deoxyglucosyl)amides, in turn, direct iodoamidation of D-glucal in the presence of trimethylsilyl amides and Niodosuccinimide (NIS) in propionitrile at low temperature, followed by radical reduction, can be employed [113]. More recently, a novel procedure has been optimized to enable direct coupling between amides and protected glycosyl chlorides simply by reacting them in the presence of silver triflate in acetonitrile, affording N-glycosylamides and ureas in good yields [114]. The reactivity of several amides, such as acetamide, benzamide, a lactam and a D-glucuronamide derivative, was investigated (Scheme 9). N-Glycosylation using perbenzylated D-gluco- and D-galacto-configured glycosyl chlorides (19) typically afforded anomeric mixtures (α/β = 1:1) of the target N-acyl-N-glycosyl compounds (20), except for the reactions involving the D-glucuronamide derivative or the lactam, which proceeded with β-stereoselectivity. 0.5 mol % Pd(CH3CN)4(BF4)2

2.5 mol % Pd(PhCN)2Cl2

21

CCl3 O

OR O

2.5 mol % TTMPP 10 mol % salicylaldehyde

RO

H

HN 22

O

O NH

O

2 mol % salicylaldehyde

OR Cl3C

OR

2 mol % Ni(dppe)(OTf2)

O O 24

CCl3 NH

H N

H 23

CCl3

O

O

RO

HN

CCl3

25 O

Scheme 10. Synthesis of N-glycosyl trichloroacetamides by Pd(II)-catalyzed rearrangement of glycal trichloroacetimidates or by Ni(II)-catalyzed conversion of glycosyl trichloroacetimidates.

N-Glycosyl trichloroacetamides can be obtained by means of Lewis acidcatalysed rearrangement of glycosyl trichloroacetimidates in the absence of a glycosyl acceptor, as noted previously (see Scheme 3) [78]. Additionally, transition metal-catalysed stereoselective approaches to this type of procedure have also been developed. Palladium(II)-catalysed rearrangement of nonanomeric glycal trichloroacetimidates (21) yields 2,3-unsaturated N-glycosyl trichloroacetamides with different stereoselectivity depending on the nature of catalytic system (Scheme 10). Indeed, while the use of a cationic palladium– salicylaldehyde complex promotes the formation of α-anomers (22), the neutral complex bearing a tris(trimethoxyphenyl)phosphine (TTMPP) resulted in βstereoselectivity (23) [119, 120]. The use of other metal catalysts, namely the cationic nickel(II) complex [Ni(dppe)(OTf)2] (dppe=1,2-bis(diphenylphosphino) ethane), was shown to be suitable for the stereoselective conversion of mono- and

Synthesis of N-Glycosyl Compounds

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oligosaccharide trichloroacetimidates (24) into the corresponding α-N-glycosyl trichloroacetamides (25, Scheme 10) [120, 121], which are useful precursors of N-glycosyl ureas after treatment with an appropriate amine in the presence of cesium carbonate [119 - 121]. O

OAc O

AcO AcO

AcHN 26

NO2

H N S O O

HS

OAc R

CsCO3, DMF

AcO AcO

O

H N

R

AcHN

NO2

27

O

R = CH3, C6H5

Scheme 11. Synthesis of N-glucosylamides by N-glucosylsulfonamide acylation with thioacids.

The transformation of N-glycosylsulfonamide substrates into N-glycosylamides has been described. Indeed, treatment of peracetylated β-N-glycosyl-24-dinitrobenzenesulfonamide (26), derived from GlcNAc, with either thioacetic or thiobenzoic acid in the presence of cesium carbonate affords N-glycosylamides 27 in good yields with retention of β-configuration (Scheme 11) [122]. This procedure could be successfully extended to the amidation of a thioacid analog of L-aspartate, affording a β-N-glycosylasparagine derivative. Further investigation involved the optimization of the reaction when using perbenzoylated N-glycosy-2,4-dinitrobenzenesulfonamide substrates derived from different sugars, including disaccharides [123]. OAc AcO AcO Se0

b) ClCOR

28 OAc

O

a) LiEt3BH, THF R

O

SeLi

50 ºC

N3

OAc AcO AcO

O AcO 29

H N

R

O

Scheme 12. Synthesis of N-glycosylamides by reaction of glycosyl azides with in situ generated lithium selenocarboxylates.

Very recently, a new synthetic route has been reported relying on the use of lithium selenocarboxylates as traceless reagents for the formation of Nglycosylamides, as well as other non-anomeric sugar amides, from the corresponding azides [124]. Reduction of elemental selenium using lithium triethylborohydride generates lithium selenide that reacts in situ with acyl chlorides (or carboxylic acids), yielding highly activated lithium selenocarboxylates. Treatment of the mixture, without further manipulation, with an appropriate protected glycosyl azide (28), affords N-glycosylcarboxamides (29) with retention of configuration (Scheme 12), through a cycloaddition-type reaction and

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subsequent decomposition of the selenotriazoline intermediate. An advantageous aspect of this procedure concerns to the fact that gaseous nitrogen and elemental selenium are the only by-products formed. N-Glycosylamides are widely known for their high stability under both acidic and basic conditions, being also mostly unreactive towards oxidation or hydrogenation. Nonetheless, the development of efficient methodology for their cleavage as anomeric protecting groups and subsequent activation as glycosyl donors, using mild conditions, has been undertaken [125, 126]. Hence, treatment of per-O-pivaloylated β-D-galactosylamides (30) with triphenylphosphine and tetrabromomethane triggers a retro-Ritter reaction yielding an unstable imidoyl bromide intermediate, whose decomposition produces an α-glycosyl bromide with concomitant elimination of acetonitrile. Addition of oxygen or nitrogen nucleophiles produces O-glycosides or N-glycosyl compounds (31), respectively, in the presence of silver triflate (Scheme 13). Noteworthy, the substituent on the amide substrate has a significant impact on the overall reactivity since considerably higher yields are obtained when using the p-methoxyphenyl amide compared to those obtained with the analog acetamide. PivO

OPiv a) PPh3, CBr4

O PivO

H N OPiv

R b) R'XH, AgOTf

PivO

O

XR' OPiv

PivO

O

30 R = CH3, p-methoxyphenyl

OPiv

31 X = O, NR''

Scheme 13. Synthesis of O-glycosides and N-glycosyl compounds by one-pot deprotection and activation of N-glycosyl amides.

N-Glycosylsulfonamides, -sulfamides and -sulfinamides The relevance of the sulfonamide moiety in medicinal chemistry [127] has prompted its connection to carbohydrates and particularly the N-anomericallylinked derivatives have attracted much attention, namely for their abilities to inhibit therapeutically relevant enzymes and to display anticancer properties. Moreover, N-glycosylsulfonamides are among the most stable N-glycosyl derivatives towards hydrolysis. The synthetic methodologies towards this group of compounds, as well as for their S-linked analogs, were reviewed in 2012 [66]. Nevertheless, in order to give a general account, in this section, a brief compilation of the methods already covered therein is given as well as the routes reported afterwards are surveyed. Glycals, methyl glycosides, per-O-acetylated sugars or free monosacharides have been the precursors used for the access to N-glycosylsulfonamides via N-

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glycosylation. Glycals (32, Scheme 14) can be converted to N-2-iodoglycosylsulfonamides by treatment with iodonium di-sym-collidine perchlorate in 10-30 min, which affords stereoselectively trans-diaxial-1,2-iodosulfonamides (33) [128]. It was shown that their C1-epimerization to 34 can occur easily, by increasing the reaction time to 1 h, by the presence of acid or even during purification on silica [129]. N-2-Deoxyglycosylsulfonamides (35) can be prepared by reaction of per-O-benzylated glycals (32) with primary or secondary sulfonamides using triphenylphosphine hydrobromide (PPh3.HBr) as catalyst [130]. Two compounds having S-benzyl and S-tolyl groups showed cytotoxic effects on human hepatocellular carcinoma cell lines (HepG2). Starting from trior tetra-O-acetyl glycals (36) in the presence of catalysts such as boron trifluoride etherate (BF3Et2O), silica-supported perchloric or tetrafluoroboric acid, the Nglycosylation with a sulfonamide occurs with concomitant Ferrier rearrangement and α-stereoselectivity, affording 2,3-unsaturated N-glycosyl derivatives (37) in very good yields [131, 132]. N-(2-O-Acetyl-D-erythro-hex-2-enopyranosyl) sulfonamides (37, R = OAc) comprising tolyl and ethyl R2 groups displayed antitumor activities towards HepG2 and human lung adenocarcinoma (A549) cell lines. I

I O RO

PhSO2NH2 (sym-Collidine)2ClO4

NHSO2Ph 33

for R = Bn R2SO2NHR1 PPh3.HBr O 35

NR1SO2R2

AcO AcO

NHSO2Ph

RO

RO

32

RO

O

O

OAc O

R2SO2NHR1 AcO

R 36

BF3Et2O

34

OAc O R NR1SO2R2 37

R = H, OAc

Scheme 14. Synthesis of N-glycosylsulfonamides from glycals.

Few reports have also showed the possibility of performing the N-glycosylation of primary and secondary sulfonamides with methyl glycosides. The reactions involving O-benzylated methyl riboside and 2-deoxyriboside (38) and methyl 2deoxyhexopyranosides (40) were shown to be effective when using boron trifluoride etherate or silica-supported perchloric acid as promoters (Scheme 15) [133, 134]. While the N-glycosylations with furanosides conducted to anomeric mixtures of N-glycosyl sulfonamides (39), those with 2-deoxy pyranosides led solely to β-pyranosyl derivatives (41). The N-glycosylation of sulfonamides can be efficiently achieved using per-Oacetylated glycosyl donors in the presence of BF3Et2O. D-Glucose, D-galactose, D-mannose and L-arabinose derivatives gave only N-glycosyl derivatives

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comprising the sulfonamide moiety in an equatorial orientation, even for the mannosyl derivative despite the presence of a 2-O-acetyl participating group, which is a consequence of the exo-anomeric effect [135]. BnO

BnO

R2SO2NHR1

O BnO R

OMe

38

NR1SO2R2

O

BF3Et2O or HClO4-SiO2

BnO R 39

R = OBn, H

OBn

BnO

O

BnO

OMe 40

R2SO2NHR1

BnO BnO

OBn O

NR1SO2R2

BF3Et2O or HClO4-SiO2

41

Scheme 15. Synthesis of N –glycosylsulfonamides from methyl glycosides.

The BF3.Et2O-promoted N-glycosylation of methanesulfonamide with peracetylated N-substituted D-glucuronamides (42) was shown to occur with modest yields, which reflects the relatively low reactivity of glucuronamide-base glycosyl donors (Scheme 16) [136]. In these cases, α-configured N-glycosyl compounds (43) were also obtained due to the remote participation of the amide group at C-5. O AcO AcO

NHR O OAc OAc

O CH3SO2NH2

AcO AcO

BF3Et2O

42

NHR O OAc NHSO2CH3 43

Scheme 16. Synthesis of D-glucuronamide-based N-glycosylsulfonamides.

The sulfonylation of glycosylamines is another method for accessing Nglycosylsulfonamides [122, 137, 138]. The reduction of per-O-acetylated β- Dglycosyl azides (44), including mono and disaccharide derivatives, and further treatment of the resulting glycosylamines with methanesulfonyl chloride in the presence of trimethylamine or with chloromethanesulfonyl chloride in pyridine, led to N-glycosylsulfonamides (45) in good overall yields and β-stereoselectivity (Scheme 17) [138].

Synthesis of N-Glycosyl Compounds

O AcO 44

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a) H2, Pd/c

N3

O

NHSO2CH2R

AcO b) CH3SO2Cl, NEt3 or ClCH2SO2Cl, py

45 R = H, Cl

Scheme 17. Synthesis of N-glycosylsulfonamides by a two-step procedure involving reduction of glycosyl azides and subsequent sulfonylation of the intermediate glycosylamines.

Per-O-benzylated free furan/pyranoses (such as 46) can also act as glycosyl donors for the N-glycosylation of S-alkyl or S-arylsulfonamides in the presence of a Lewis acid, namely TMSOTf (Scheme 18) [139, 140]. In the case of D-arabino-configured N-glycosyl derivatives (such as 47), after removal of the O-benzyl groups, the fully deprotected derivatives have the tendency to isomerize into the more stable pyranosyl forms adopting a 1C4 conformation and having the N-aglycon oriented in an equatorial position (48), which is a consequence of the exo-anomeric effect [140]. BnO

OBn O OH

CH3SO2NH2

BnO

OBn O NHSO2CH3

H2, Pd/C

O

TMSOTf HO

BnO

BnO 46

47

NHSO2CH3 OH

OH 48

Scheme 18. Synthesis of a N-glycosylsulfonamide from a O-benzyl protected free monosaccharide and further deprotection with concomitant isomerization to the pyranose form.

Compounds related to N-glycosylsulfonamides, namely sulfamides, which comprise another S-linked amino group, instead of an alkyl or an aryl group, or sulfinamides, which contain a sulfinyl function (SO), have been synthesized. Methods developed for the N-glycosylation of sulfonamides were reported to be also effective for sulfamides. Hence, sulfamides react with per-O-acetylated monosaccharides and methyl glycosides in the presence of BF3Et2O, affording the corresponding N-glycosylsulfamides, while their treatment with glycals in the presence of PPh3.HBr or BF3.Et2O gives N-β-2-deoxyglycosyl derivatives or products of Ferrier rearrangement, i.e. 2,3-unsaturated N-glycosylsulfamides, respectively [141 - 143]. The coupling of hydroxysulfamide derivatives with various glycals using nitrosonium tetrafluoroborate as catalyst was reported. The Ferrier rearrangement also commanded the reaction outcome in these cases [144, 145]. Some of the compounds of these types revealed their ability to inhibit various carbonic anhydrase (CA) isoforms, which are therapeutic targets for cancer (CA IX and XII) and for glaucoma (CA II).

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The synthesis of N-glycosylsulfinamides (such as 49), through N-glycosylation of (R)-N-tert-butanesulfinamide with free furanoses (such as 46) and pyranoses using titanium ethoxide, which was the most effective reaction promoter, among a variety of Lewis acids tested, was described (Scheme 19). These molecules proved to be useful precursors for the synthesis of iminosugar-based C-glycosyl derivatives, due to their capability to undergo addition of organometallic reagents in a diastereoselective manner [146]. O S BnO

OBn O OH

NH2

Ti(OEt)4

BnO 46

O OBn S O N H

BnO

BnO 49

Scheme 19. Synthesis of N-(glycosyl)-tert-butanesulfinamides by N-glycosylation of a sulfinamide with an O-protected free furanose.

N-Glycosylhydrazines N-Glycosylhydrazines and derivatives can be accessed by reaction of free carbohydrates with a hydrazine under mild acid conditions. While reactions with a hydrazine leads frequently to mixtures of α/β anomers of furanosyl/pyranosyl derivatives along with the acyclic hydrazone, N-acyl and N-sulfonyl derivatives afford mainly β-pyranosyl compounds. Comprehensive reviews on these topics have been published and therefore in this chapter only recent reports are mentioned [62, 63]. A series of antifungal N-glycosyl hydrazides were obtained by treatment of various monosaccharides with 5-substituted phenyl-2-furoyl hydrazides in the presence of acetic acid as catalyst. The compounds showed broad activity against plant and fruit pathogenic fungi and some of them displayed cytotoxicity against cancer cells [147]. N-Glycosylsulfonohydrazides are of particular interest among hydrazine derivatives, due to their higher stability towards hydrolysis [63]. This is also the trend observed for N-glycosylamine derivatives, whose hydrolytic stability is increased with the electron-withdrawing character of the N-linked group, following the order (N-glycosylsulfonamides > N-glycosylamides > N-glycosylamines). The synthesis of N-glycosylsulfonohydrazides was firstly reported by the reaction of O-acyl or O-benzyl gluco-, manno- and galacto-configured monosaccharides having a free anomeric hydroxyl group with N-tosylhydrazide in acetonitrile or toluene, using a catalytic amount of acetic acid [148]. The methodology proved also to be effective with fully unprotected reducing monosaccharides, namely glucose, galactose, mannose, xylose, N-acetylglucosamine (1) as well as with the disaccharide lactose [149, 150], affording only N-β-glycosyl derivatives in yields higher than 80% (50, Scheme 20).

Synthesis of N-Glycosyl Compounds

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O HO

O

O N H

S

O

AcOH / DMF

OH

HO

H N

O O S N H

50

1

Scheme 20. Synthesis of N-glycosylsulfonohydrazides from unprotected free monosaccharides.

Ribose lead quantitatively to the N-ribosylsulfonohydrazide adopting a 1C4 conformation [151]. Glucuronic acid (51) and N-substituted glucuronamide derivatives also underwent direct conversion into the corresponding anomeric sulfonohydrazides by this method, although in modest yields [151]. The tosylhydrazinyl glucopyranuronic acid derivative 52 proved to be an effective inhibitor of carbonic anhydrase II, which is a therapeutic target for glaucoma. Acetylation of this compound followed by the treatment with N-propargylamine afforded the bicyclic glucuronolactam-based sulfonohydrazide 53 (Scheme 21). O O

OH

HO HO

O OH 51

H2N

OH

O

O N H

S

AcOH / DMF

O HO HO

O

OH O OH 52

H N

O O S N H

a) Ac2O/py b) H2N

OAc O

HN N

O S

OAc OAc 53

Scheme 21. Synthesis of 1-(2-tosylhydrazin-1-yl)-β-D-glucopyranuronic acid and further acetylation leading to a 1,6-glucuronolactam-based sulfonohydrazide.

The condensation of O-benzylated monosaccharides comprising a free anomeric hydroxyl group with tosylhydrazide was also reported to occur in high yields using TMSOTf as promoter [139]. N-Glycosylsulfonohydrazides have demonstrated its usefulness as glycosyl donors for the synthesis of O-glycosides, glycosyl azides or glycosyl phosphates with the advantage of allowing a direct glycosylation reaction without the need for previous protection of the carbohydrate hydroxyl groups [149, 150, 152]. N-Glycosylphosphoramidates and -phosphonamidates N-Glycosylphosphoramidates (also named glycosyl amidophosphates) represent a relatively unexplored type of N-glycosyl derivatives. These compounds are also mimetics of glycosyl phosphates and therefore have the potential to exhibit a variety of biological activities. Their synthesis is typically accomplished through the Staudinger-phosphite reaction of anomeric azides with phosphites, as early reported for the preparation of dimethyl β-N-D-pentopyranosylphosphoramidate derivatives (such as 55), which can be obtained from the corresponding per-Oacetylated β-D-ribo- or lyxo-configured glycosyl azides (54) by the reaction with

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trimethyl phosphite in dioxane (Scheme 22) [153]. A similar procedure has been employed for the synthesis of N-(D-glycero-D-manno-heptosyl)phosphoramidates as potential inhibitors of heptose synthetase, an important enzyme involved in the biosynthesis of bacterial lipopolysaccharide [154]. Reaction of per-O-benzylated heptosyl azides (56, 57) with tribenzyl- or tributyl phosphite afforded Nglycosylphosphoramidates (58, 59), which were subsequently deprotected by reduction with Na/NH3 to give the α-N-heptosylphosphoramidate 60 or its dibutyl-substituted β-analogue 61, respectively. O

AcO AcO

OAc

N3

P(OMe)3,

O

AcO

dioxane

AcO

54

OAc 55

H N P(OMe)2 O

D-ribo D-lyxo

BnO

BnO BnO BnO BnO

OBn O R

R

1

2

56 R1 = H; R2 = N3 57 R1 = N3; R2 = H

P(OBn)3 or P(OBu)3, dioxane

BnO BnO BnO

HO OBn O

R1

Na/NH3

R2 58 R1 = H; R2 = NHPO(OBn)2 59 R1 = NHPO(OBu)2; R2 = H

HO HO HO

OH O R

R1 2

60 R1 = H; R2 = NHPO(OH)2 61 R1 = NHPO(OBu)2; R2 = H

Scheme 22. Synthesis of N-glycosylphosphoramidates from pentopyranosyl- or heptosyl azides.

The synthesis of N-linked dimethylphosphoramidate derivatives of β-D-glucose, N-acetyl-β-D-glucosamine and β-D-galactose as isosteres of glycosyl phosphates has also been pursued, following a similar procedure starting from the corresponding peracetylated glycopyranosyl azides [155]. The deprotected β-D-gluco derivative was later shown to be a competitive inhibitor of rabbit muscle glycogen phosphorylase b (GPb), a known therapeutic target for type 2 diabetes [156]. Related compounds have been described as inhibitors of kinases involved in cancer pathogenesis, namely protein kinase B (PKB/Akt). They include dialkyl N-glycosylphosphoramidate analogs of phosphatidylinositol 3phosphate based on β-D-glucoronyl [157] or sulfoquinovose (6-deoxy-6-sulfo-Dglucose) [158] scaffolds. Recently, the synthesis and antiproliferative activity of dimethyl N-glycosylphosphoramidates based on peracetylated D-glucuronamides bearing N-alkyl substituents at the carboxamide group (62) was also reported. These derivatives are obtained from the corresponding azides by Staudingerphosphite reaction, after TMSN3-promoted azidation of anomeric acetates (42) under microwave irradiation (Scheme 23) [136]. N-Phosphoramidate-linked glycopeptide mimetics have been accessed by solidphase synthesis, involving the reaction of peracetylated glycosyl azides with an immobilized dimethyl phosphite-containing peptide, followed by deprotection.

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The new glycoconjugates synthetized were shown to present excellent hydrolytic stability under both acidic and neutral conditions [159]. O AcO AcO

NHR O

a) TMSN3, TMSOTf, MW irradiation

OAc OAc

b) P(OMe)3,CH2Cl2

O AcO AcO

NHR O OAc N H 62

42

O P(OMe)2

Scheme 23. Synthesis of D-glucuronamide-based N-glycosylphosphoramidates.

The synthesis of N-(2-deoxy-2-iodoglycosyl)phosphoramidates (64, 65), starting from acetyl-, benzyl- and methoxymethyl-protected hexo- or pentopyranosyl Dglycals (63), was also early reported (Scheme 24) [160]. In this case, addition of iodoazide to the glycals produces intermediate 2-deoxy-2-iodoglycosyl azides having 1,2-trans configuration, which are subsequently reacted with trimethyl phosphite in dichloromethane. The reaction stereoselectivity is dependent on the configuration and protecting groups of the starting glycal. These compounds, as well as related structures, were later shown to be suitable precursors of 1,2-transconfigured 2-phosphoramino- and 2-acetamido-2-deoxyglycosides, acting as glycosyl donors in the glycosylation of a variety of alcohols under basic conditions, which proceeds with migration of the phosphoramidate group from C1 to C-2 of the sugar and concomitant inversion of configuration at both positions [161]. R2

O

R1O 63 D-gluco D-galacto D-xylo

a) N3I, MeCN or AcOEt b) P(OMe)3, CH2Cl2

R2 I

R2 O

+

R1O

I

HN 64

P(OMe)2 O

O

R1O 65

H N

P(OMe)2 O

Scheme 24. Synthesis of N-glycosylphosphoramidates via conversion of glycals into intermediate 2-deoxy2-iodoglycosyl azides followed by Staudinger-phosphite reaction.

N-Glycosylphosphonamidates are compounds structurally related to phosphoramidates but featuring an alkyl substituent linked to phosphorous instead of an alkoxy group. This type of glycosyl phosphate mimetics, which have been relatively neglected in the literature, can be accessed by treating glycosylamines with alkyl alkylphosphonochloridates under basic conditions. As shown in Scheme 25, reaction of glycosylamines (such as 66) with ethyl benzylphosphonochloridate in pyridine leads to N-glycosylphosphonamidate esters (67), which can be subsequently dealkylated with bromotrimethylsilane and further depro-

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tected by methanolysis to afford fully deprotected derivatives type 68 as sodium salts, or otherwise deacetylated with ammonia in methanol to afford the related ethyl esters, both being conceived as transition-state analogs of glycopeptidases and hence potential inhibitors of those enzymes [162]. OAc AcO AcO

O OAc

NH2

O P OEt Bn Cl AcO AcO pyridine

66

a) TMSBr, CH2Cl2

OAc O

H N

b) NaOMe/ MeOH

Bn P OEt or NH / OAc 3 O MeOH 67

OH HO HO

O OH 68

H N

Bn P R O

R = O-Na+ or OEt

Scheme 25. Synthesis of N-glycosylphosphonamidates from glycosylamines followed by dealkylation and deacetylation.

N-Glycosylimines and -imides The chemistry of sugar derivatives comprising an imine functionality (Schiff bases), or the less common imide group, N-linked to the anomeric center, has also been investigated, both types of compounds finding relevant synthetic utility mostly as precursors for a diversity of N-glycosyl heterocycles. Related structures include also N-glycosylenamines, which have been covered by previous literature surveys [163] and therefore will not be further reviewed herein. Initial reports concerning N-glycosylimines were focused on bromoimino derivatives, whose C=N bond involves the anomeric carbon and a bromine atom is linked to the imine nitrogen atom. These compounds can be readily prepared by treatment of protected glycosyl azides with N-bromosuccinimide (NBS) in refluxing carbon tetrachloride under free radical-generating conditions (Scheme 26). Indeed, transformation of fully protected β-D-mannofuranosyl- (69) or β-Dglucopyranosyl azides (28) into the corresponding N-bromo-N-glycosylimines (70,71) was shown proceed nearly quantitatively upon irradiation [164, 165], or when using catalytic benzoyl peroxide [164] or azobisisobutyronitrile (AIBN) [166] as free radical initiators. Although such compounds are typically characterized by presenting only moderate thermal and chemical stabilities, their conversion into open-chain aldonitriles by reductive elimination was shown to be possible upon reaction with Zn/Ag- or C8K-graphite in THF [166], highlighting their utility as synthetic intermediates as well. The reactivity of an extended set of α- and β-D-glycosyl azides, differing in sugar configuration and protecting group pattern, towards N-bromo-N-glycosylimine formation, was assessed [165]. It was shown that while the α- and β-anomeric furanosyl azides are both susceptible to transformation into the corresponding sugar bromoimines, in the case of pyranosyl azides the α-anomer is less reactive when compared to its βstereoisomer. This distinct reactivity is considerably more pronounced in the case

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of gluco-configured azides. The results support a mechanistic interpretation involving homolysis of the activated C−H bond at the anomeric center, which leads to the formation of the more stable (Z)-configured sugar bromoimines, as supported by X-ray crystallography. O O

O O O N3 O

NBS, CCl4

O O O

O

Br N

hv 70

69 OAc

OAc NBS, CCl4

O

AcO AcO

N3

AcO

hv

O

AcO AcO

AcO

28

N

Br

71

Scheme 26. Synthesis of N-bromo-N-glycosylimines from glycosyl azides.

N-Alkylidene- and N-arylidene-N-glycosylimines, in which the imine carbon atom is exocyclic, have also been described. Hence, a variety of hexo- and pentopyranosyl aldimines (73) have been synthetized directly from per-Oacylated glycosylamines (type 72) [167 - 176], including polymer-immobilized derivatives [170], by means of condensation with aldehydes and typically in the presence of catalytic (protic) acid, depending of the reactivity of the amine/aldehyde system (Scheme 27). These reactions have been reported to proceed with selectivity for 1,2-trans-linked N-glycosyl compounds, probably resulting from participation of the pivaloyl or acetyl group at C-2 of the sugar moiety, while concerning the imine double bond stereochemistry, (E)-isomers are favored. R2 R O

OR

R2

R3CHO

O

1

1

NH2

(cat. acid)

R1O

72

O

N

R3

N

R

OR1 73

-gluco

-galacto -arabino

AcO

OAc O

AcO AcO N3 74

a) PMe3, CH2Cl2 b) RCHO

AcO

OAc O

AcO AcO 75

 as major or sole stereoisomers

Scheme 27. Synthesis of N-alkylidene or N-arylidene-N-glycosylimines from per-O-acylated glycosylamines or glycosyl azides.

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Alternatively, peracetylated glycosyl azides (74) can also be employed as starting materials for the preparation of N-glycosylimines (75) (Scheme 27) [115]. The procedure involves an initial Staudinger reaction between the anomeric azide and trimethylphosphine to produce intermediate N-glycosylphosphinimide derivatives (also known as N-glycosyliminophosphoranes), which are subsequently converted into the target N-glycosylimines through in situ aza-Wittig reaction with an appropriate aldehyde. Transformation of D-gluco- and D-galactopyranosyl azides exhibiting either α- or β-anomeric configuration was show to feature similar stereoselectivity for β-N-glycosylimines. Thus, α-phosphinimide intermediates typically undergo anomerization to the thermodynamically more stable βcounterparts, although α-stereoselectivity could be achieved when the reaction was performed with tribromoacetaldehyde, comprising a strong electrowithdrawing substituent. N-Glycosyl aldimines have found noteworthy application as chiral auxiliaries in synthetic chemistry, namely in the asymmetric synthesis of structurally varied amino acids [167, 175, 176], or in the stereoselective preparation of N-glycosyl heterocycles such as piperidinone derivatives which are precursors of natural alkaloids [168 - 171]. Further derivatization of compounds of this type has also been explored as a strategy for building N-glycosylated monocyclic β-lactams exhibiting antimicrobial properties [172, 173]. Regarding N-glycosylimides, i.e. sugar derivatives comprising an anomericallylinked exocyclic nitrogen atom bonded to two carbonyl groups, only a few reports have been dedicated to this type of compounds, which have been mainly investigated as precursors of sugar-fused heterocycles or N-glycosylated heterocycles. The synthesis of α-N-(2-deoxyglucopyranosyl)succinimides (77) has been reported. These compounds are readily obtained by the addition of Niodosuccinimide (NIS) to silylated, methylated or benzylated glycals exhibiting D-gluco or D-xylo configuration (76), followed by the reduction of the intermediate N-(2-deoxy-2-iodoglycosyl)succinimides (Scheme 28) [177 - 179]. This is a highly efficient procedure, since in the absence of other nucleophiles the initial N-glycosylation reaction is stereoselective towards the α-anomers, whereas the subsequent dehalogenation reaction is typically quantitative. The photochemical transformations of the resulting N-succinimido sugars, into highly functionalized bi- and tricyclic sugar-annelated heterocyclic systems, namely oxalactams, have been extensively exploited. Indeed, photolysis of Nglycosylsuccinimides 77 in solution results in the conversion of such compounds into enantiomerically pure 2,5-azepanediones or heterotricyclic undecanamides, by stereoselective intramolecular alkylation, the regiochemical outcome

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depending on both the sugar configuration and protecting groups. More recently, the transformation of this type of compounds into N-pyrrol-containing sugaralkaloid conjugates has also been investigated [179]. R2 R1 O R1O

a) NIS

O

R1O R1O

b) Bu3SnH/AIBN

R2 O O 77 N

76

O

D-gluco D-xylo

Scheme 28. Synthesis of N-(2-deoxyglycosyl)succinimides from protected glycals.

Related N-gluco- and N-mannopyranosyl succinimides, bearing α- and βanomeric configuration (80), have been synthetized from the corresponding per-O-silylated glycosylamines (78) by the reaction with succinic anhydride to produce intermediate N-glycosyl succinamidic acids (79), which are subsequently subjected to intramolecular cyclization by treatment with acetic anhydride and pyridine (Scheme 29) [180]. The reactivities of the resulting hexopyranosyl succinimide diastereoisomers, upon irradiation by UV light, was also investigated. These studies have been further extended to non-anomeric imido sugar derivatives whose photochemical activation also leads to enantiopure heterocyclic compounds [181 - 184]. O O OTBS TBSO TBSO

O TBSO NH2 78

OTBS O DIPEA

TBSO TBSO

O TBSO N H 79

OTBS Ac2O

O

OH pyridine O

TBSO TBSO

O

O

TBSO N 80 O

Scheme 29. Synthesis of N-glycosyl succinimides by reaction of per-O-silylated glycosylamines with succinic anhydride and subsequent intramolecular cyclization.

The synthesis of other N-linked five- or six-membered sugar imides, namely Nglucosyl 3-hydroxysuccinimide derivatives (85) or an N-glucosyl 5,6dihydropyrimidine (88), respectively, has also been described (Scheme 30). These compounds have been accessed by different synthetic approaches both starting from per-O-acylated β-D-glucosylamines (81, 66) and involving the key basepromoted intramolecular condensation of β-N-glycosylated L-malic, L-citramalic acid or L-isoserine derivatives protected with an hexafluoroacetone (HFA) group, which acts as an activator of the α-carbonyl group. N-Acylation of glucosylamines with acyl chlorides 82 or 83, derived from L-malic or L-citramalic acid, respectively, produces β-N-glucosylated α-hydroxy acid derivatives (84), which

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after treatment with pyridine in boiling chloroform are converted into 3hydroxysuccinimido sugars (85) by means of a cyclocondensation reaction, in high yield [185]. In contrast, the reaction of the acetyl-protected glucosylamine 66 with isocyanate 86 leads to the β-Ν−glucosylated L-isoserine derivative 87, comprising an urea linkage between the sugar and the α-hydroxy-β-amino acid moiety. Intramolecular cyclization of the N-glucosyl urea affords the sugar-linked six-membered 5-hydroxy-2,4-dioxo-5,6-dihydropyrimidine derivative 88 as an isomerically pure compound [186, 187]. OR O

RO RO

OR 82 or 83 NH2

O

RO RO

pyridine CH2Cl2

RO

H N

R' O

RO O

81 R = Bz 66 R = Ac

O

84

CHCl3

O

AcO AcO

CH2Cl2, 0 ºC

O

O

85

H N

AcO

H N

O O

87

R' O O

O

OH

OAc O F3C

O

O

N

RO

OAc

O

O

RO RO

F3C CF3

86

Cl

OH R'

OR O pyridine

O

pyridine CF3

CHCl3

O

AcO AcO

N

AcO

NH

O 88

O C

N

F3C CF3 82 R' = H 83 R' = CH3

O

O

F3C CF3 86

Scheme 30. Synthesis of N-glycosylimides by base-promoted intramolecular cyclocondensation of hexafluoroacetone-protected N-glycosylated malic acid or isoserine derivatives.

CONCLUDING REMARKS The biological relevance of naturally occurring/physiological N-glycosyl derivatives, glycoconjugates comprising N-glycosidically-linked moieties as well as the interest of developing analogs of O-glycosides, has been the driving force for the access to novel types of N-glycosyl compounds. Various types of Nglycosyl derivatives have been reported in the last 20 years and efficient methodologies, some of them straightforward, have been developed for their synthesis. Many of them include the direct condensation of a primary or secondary amine derivative with a carbohydrate derivative containing a free anomeric hydroxyl group. Other N-glycosylation methodologies, involving glycosyl donors such as 1-O-acetyl derivatives, glycals or methyl glycosides have been implemented with success. Glycosyl azides are also suitable precursors for N-glycosyl derivatives, since these compounds can be easily reduced to glycosylamines and functionalized further, or directly converted into

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functionalized derivatives, such as N-glycosylphosphoramidates by Staudingertype reactions. The biological properties exhibited by various groups of compounds, including N-glycosyl alkoxyamines, sulfonamides, sulfonohydrazides as well as the usefulness of some types of N-glycosyl derivatives as precursors for other glycoderivatives, will surely continue to motivate the research on the design and synthesis of new types of N-glycosidic structures as well as the exploitation of their applications for medicinal chemistry purposes. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors confirm that there are no conflicts of interest to declare for this publication. ACKNOWLEDGEMENTS The authors thank ‘Fundação para a Ciência e Tecnologia’ (FCT) for funding through the FCT Investigator Program (IF/01488/2013), the exploratory project IF/01488/2013/CP1159/CT0006, the strategic project UID/MULTI/00612/2013 and for the PhD grant SFRH/BD/116614/2016. REFERENCES [1]

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CHAPTER 4

Acidic and Basic Functionalized Ionic Liquid Systems for Advanced Synthesis of Five and Six Membered Nitrogenates Heterocycles Pinky Gogoi1, Susmita Saikia1, Arup Kumar Dutta2 and Ruli Borah*, 1 Department of Chemical Sciences, Tezpur University, Napaam-784028, Tezpur, Assam, India Department of Chemistry, Pandit Deen Dayal Upadhyaya Adarsha Mahavidalaya, Behali, Jinjia-784184, Assam, India 1 2

Abstract: This book chapter describes a brief introduction on acidic and basic functional group tethered ionic liquid systems with various ion-pairs and their utilization as recyclable catalyst/medium in designing sustainable advanced synthetic methods of selected five and six membered nitrogenated heterocycles via one-pot approach.

Keywords: Acidic ionic liquids, Basic ionic liquids, Multicomponent, NHeterocycles, One-pot reaction, Reusable catalysts, Sustainable method. INTRODUCTION ON IONIC LIQUID SYSTEMS The development of target oriented functionalized ionic liquids (FILs) with unique physicochemical properties has received major recognition in different research fields with diversified applications in catalysis [1], such as reaction medium for organic reactions [2], biocatalysis [3], biomass treatment and processing [4], electrochemistry [5], analytical chemistry [6, 7], coordination chemistry [8], polymer chemistry [9], fluorine chemistry [10], nanotechnology [11], material science [12] and other miscellaneous uses [13]. The various types of ionic liquids (ILs) are represented in Fig. (1) which can be extended to cover new families and generations of ionic liquids with target oriented properties. Corresponding author Ruli Borah: Department of Chemical Sciences, Tezpur University, Napaam-784028, Tezpur, Assam, India; Tel: +91 3712265057; Fax: +91 3712-267005; E-mail: [email protected]

*

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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This chapter covers a brief description of target-oriented acidic/basic character ionic liquids of different ion pairs and also their modification with support material as recyclable catalyst/medium for advanced synthetic routes of some five and six membered nitrogen heterocycles. The first review on room temperature ionic liquids was published by Welton in 1999 and from then onwards ionic liquids have grown as a major research area in the last 18 years [1, 14, 15]. Ionic liquids include a wide variety of molten organic salts comprising organic cations and inorganic or organic anions having variable physicochemical properties based on the nature of constituent ion pairs. The inherent properties of ionic liquids can be considered as a function of ionic interaction of the corresponding ion-pairs and coexistence of distinct structural environment of the component ions [16]. These ionic interactions can be varied by tethering appropriate functional groups or atoms either in the cation or anion of the ionic liquid.

Fig. (1). Representation of IL generations.

They show low vapor pressures, wide range of thermal stability and high boiling points owing to their strong secondary ionic interactions. The term “designer liquids” is also used to express their environment-friendly behavior in chemical reactions as medium or catalyst and as electrolyte in electrochemistry with specific physical and chemical properties. They are known to be ideal replacement of volatile organic solvents in reaction due to their advantageous non-volatile, nonflammable, recyclable and outstanding solvating properties. Furthermore, the study of molecular mechanism of reaction in ionic liquid environment suggested faster rate of reaction as compared to conventional process [17 - 19].

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Ionic liquids that contain aromatic heterocyclic cations tend to have lower melting points than those containing aliphatic ammonium salts. More electronegative nature of the anion decreases the melting point of ionic liquid. Structural modification of the cations or anions of ionic liquids can result in unique phase transition from liquid to solid state that dramatically influences the strategies of IL catalyzed reactions either in homogeneous or heterogeneous conditions. Davis et al. in 2004 [20] introduced the term “task specific ionic liquid” in a brief review presented on target-oriented ionic liquids for organic synthesis. He also utilized thiazolium based organic ionic liquids as dual functionalized solvent / catalyst system for benzoin condensation [21]. These target-oriented Functionalized Ionic Liquids (FILs) are the latest generation of ionic liquids where a functional group is covalently attached with either the cation or anion (or both) of the organic salt as per requirement of a particular use. The incorporation of this functionality should imbue the ionic liquid with a capacity to behave not only as reaction medium but also as a reagent or catalyst in some reactions or processes. The functionalization of cation or anion of ionic liquids allows amazing tunability of ionic-liquid properties, including acidity, basicity, melting point, phase transition, conductivity, viscosity, density and solubility of diverse solutes, and miscibility/immiscibility with a wide range of solvents [22]. Most of the functionalized ILs possess imidazolium, ammonium and pyridinium ions as organic cations [23]. Few examples are found with functionalized phosphonium cation [24]. The incorporation of specific functionality facilitates the ionic liquid with a capacity to behave not only as reaction medium but also as a reagent or catalyst in some reactions or processes [25, 26]. From the economic and ecological reasons, they are very attractive in organic synthesis and some of them have even been applied to the chemical industry. The types of FILs mainly include acidic ionic liquids, basic ionic liquids, metal–containing ionic liquids, chiral ionic liquids, and polymer-anchored acidic/basic/neutral ionic moieties bearing one or more number of organic cations. Different Classification of Ionic Liquids Ionic liquids can be categorized into different groups based on various factors such as number of cation, nature of anion, acidity, basicity and other physical properties [1, 27]. 1. Based on Number of Cation Ionic liquids can be sub-grouped as mono-, di-, tri- or tetra-cationic ionic liquids depending on the number of cationic moieties present in the ionic liquid. Fig. (2A)

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represents some of the examples of this kind of IL: N MeN Cl

HO N

OH HO

N

Cl

-

Br

Cl N N

N

N (CH2)n N

N Cl

Br

N

OH N

R N

R N

N

N O N

R

O

O

O

OO

4X-

N

O X = Cl-

N R

X = NTf2Fig. (2A). Examples of mono-, di-, tri- and tetra-cationic ionic liquids.

2. Based on Type of Anion Ionic liquids are divided into four generations depending on the nature of anions with unique physicochemical properties. First generation ionic liquids are composed of derivatives of organic cations like dialkylimidazolium, alkylpyridinium and dialkylammonium derivatives in association with complex metal halide anionic species such as AlCl4-, Al2Cl7-, FeCl4-, NiCl42-, etc. (Fig. 2B). They witness variation in hygroscopic character and thermal stability. The resulting halometallate ionic salt can also remain in solid or semi-solid phase at room temperature. Ionic liquids with discrete anions like Cl-, Br-, I-, BF4-, [N(CN)2]- are termed as second generation ionic liquids. Their anions are stable to air and oxygen as compared to the first generation. They possess superior solvating properties, viscosities, and low melting points and have different solubility in classical organic solvents. Third generation ionic liquids contain more hydrophobic and stable anions such as (CF3SO2)2N-, sugars, amino or organic acids, alkylsulfates, alkylphosphates and cations such as choline. These ionic liquids are biodegradable and have lower toxicities. The fourth generation represents deep eutectic solvent possessing choline chloride and uncharged hydrogen bond donors such as amide, amine, alcohol, urea, carboxylic acid or glycerol, etc. They are liquid at room temperature with very low vapor pressure, although their individual components (donor and hydrogen bond donors) are usually solid at room temperature [28].

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Some common cations of 1st and 2nd geneartion ionic liquids: N

N

R1

R2 N R

R1

R2

Example of 3rd generation cation:

R, R1, R2= Alkyl group 1st generation anions: AlCl4-, Al2Cl7-, FeCl4-, NiCl422nd geneartion anions: Cl-, Br-, I-, BF4,- [N(CN)2]-

H

Some 3rd generation anions: (CF3SO2)2N-,

CH3

H3C

H N

O

O

N O

OH

NH2

CH3 [Ch]

O

+

[Gly]-

O S O

OMe

MeO

P

O

OMe

[MeSO4]-

[Me2PO4]-

Some 4th generation ionic liquids/deep eutectic solvents: Salt: H3C

CH3 N

Cl-

Cl-

N

N

OH

Cl-

CH3 Tetrabutylammonium chloride (Bu4NCl)

Triethylbenzylammonium chloride (Et3BzNCl)

Choline chloride (ChCl) Hydrogen bond donors:

O

O

OH OH O

HO

H2N

H

NH2

NH2

OH D-xylose (Xyl)

Urea (U)

Formamide (F)

Fig. (2B). Structures of some 1st, 2nd, 3rd and 4th generation ionic liquids.

3. Based on Acidity Depending on the presence of acidic or basic functional groups incorporated into the anion or cation, the ionic liquids can be sub-divided as neutral, Brönsted acidic or basic and Lewis acidic or basic. Ionic liquids with discrete anions such as BF4-, SCN-, TsO-, NTf2- etc. are neutral or very weakly basic (Fig. 2C). Protonated as well as –SO3H functionalized ammonium, pyridinium and imidazolium salts have been classified as Brönsted acidic, Lewis acidic and Brönsted–Lewis acidic ILs. Lewis acidic ionic liquids can be synthesized by varying the mole fraction of metal halide in the ionic liquid [15]. Basic ionic liquid forming anions include lactate, formate, carboxylate, dicyanamide etc. The ionic liquids possess amphoteric nature if the cations are pair up with anions such as [HSO4]-, [H2PO4]-, [HCO3]- having the ability to donate or accept protons based on the nature of other substrate present. 4. Based on Physical Properties Ionic liquids can also be classified against their tunable physical properties including conductivity, viscosity, density, thermal stability. The literature search

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reveals potential uses of several derivatives of imidazolium, ammonium, and pyridinium based ionic liquids as non-aqueous electrolytes in electrochemical studies [29]. Their conductivity and electrochemical stability are the most important physical properties. In addition their negligible vapour pressure and non-flammable nature appear to be ideal electrolytes for electrochemical applications. The wide electrochemical window of some ionic liquids is a measure of their electrochemical stability against oxidation and reduction processes. The ionic liquids with highest conductivities showed lower electrochemical stabilities as compared to comparable small conductivities ionic liquids. The later types of ionic liquids are good electrolyte for use in batteries, fuel cells, metal deposits. The presence of both conductivity and electrochemical stability of ionic liquids are the material of choice for uses as electrolyte in super capacitors or sensors. Brönsted acidic:

Brönsted-Lewis acidic: SO3H

N

N SO3H Cl

[msim][Cl]

NH [HSO4] [Et3NH][HSO4]

Lewis acidic:

N

N [Zn2Cl5]

[bmim][Zn2Cl5]

N [HSO ] 4 H [HPy][HSO4]

N

[SO3H-bmim][Zn2Cl5]

Basic: N N [AlCl4] [emim][AlCl4]

N

N[Zn Cl ] 2 5

N [CH3COO]

[bmim][CH3COO]

Neutral: N [BF4]

[bmPy][BF4]

Fig. (2C). Examples of some ionic liquids based on their acidity or basicity.

SUSTAINABLE ORGANIC SYNTHESIS AND FUNCTIONALIZED IONIC LIQUIDS The exploration of target oriented FILs for sustainable development of new synthetic route of organic reactions has been studied widely as environmentally benign dual solvent-catalyst system [30]. They have some unconventional solvent characteristics such as ability to dissolve both organic and inorganic compounds, polar nature, thermal stability, capability of promoting organic reaction to form selective product, non-volatility, non-flammability, availability of raw materials for their preparation, safe handling, simple separation and reusability. As reaction media they become too expensive for use, some of them are water sensitive and the work-up step requires volatile organic solvents for extraction of desired products from the ILs phase [31].

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The designing of FILs with suitable functional groups into the cation or anion or both ions provides addition of unique characteristic to the ionic liquid systems which include variation of acidity and basicity as well as paramagnetic, semiconductor and fluorescent properties in case of metal tethered ionic liquids. Acidic ionic liquids were employed as solvent-catalyst systems in esterification [32], Friedel-Crafts alkylation or acylation [33], condensation [34] and also heterocycle synthesis under anhydrous condition [35]. The use of such IL is also not favorable to the organic reaction in which water is one of the reactant or product. Some air stable Lewis acidic ILs are known, still they could not participate in the organic reaction in presence of water [36, 37]. But, the uses of Brӧnsted acidic ionic liquids are possible in organic reactions [38] in which water is one of the by-products and their range of applications are broader than that of the Lewis acidic ionic liquids. The preparation method doesn’t require anhydrous conditions. With these merits, they have gained a prominent position as potential acidic catalysts in organic reactions as alternative of strong mineral acids than Lewis acidic ionic liquids. Two or more acidic sites can be attached with the cation or anion (or both) of Brӧnsted acidic ionic liquids in the form of –SO3H, COOH functional group. The Brӧnsted-Lewis acidic ionic liquids are obtained from ion-pair of Brӧnsted acidic organic cation and complex halometallate anion in definite molar ratio. The presence of one or more basic functional groups in cation or anion of ionic liquid provides strong basic character and they can easily replace toxic and corrosive alkali metal hydroxide in organic reactions. Asymmetric synthesis can be performed with the use of chiral ionic liquids obtained from incorporation of chiral center either in organic cations or organic anions. Some of these functionalized ionic liquid systems require further treatment to improve their physical properties such as thermal and water stability for successful applications as reusable catalyst in organic synthesis. The immobilization of ILs on to a solid support makes a simple way for reducing the amount of IL required for a given application, accordingly reduces the associated cost which simplifies their handling and separation process from the reaction mixture, and finally, greatly reduces the potential leaching to the environment [39]. Thus the resulting materials present the advantages associated to ILs and will overcome the above mentioned drawbacks currently limiting many technological applications of bulk ILs. ADVANTAGES OF ONE-POT PROTOCOL IN ORGANIC REACTIONS One pot organic synthesis is an attractive sustainable route for preparation of complex library of products involving two or more components of substrates in one vessel with or without use of any catalyst [40 - 42]. This approach reduces

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large number of steps for multistep organic synthesis and thus generates less waste material to the environment [43 - 45]. A multicomponent (MCR) one pot reaction avoids isolation of unstable reaction intermediates form in various steps and increases the rate of reaction through formation of selective product with high yields and formation of fewer side products. The simple isolation procedure of product and minimum use of organic solvents make the synthetic protocol more efficient [46 - 48]. The 5-6 membered N-heterocycles are of exceptional interest in the pharmaceutical industry, as they appear in the core structure of several drugs molecules [49, 50]. As material they have wide range of applications as dyes, polymer, fluorescent material etc. [51, 52]. The next section discusses utilization of some functionalized ionic liquids in development of synthetic strategies for available five and six membered N-heterocycles via one-pot approach. USE OF FUNCTIONALIZED IONIC LIQUIDS IN ONE-POT SYNTHESIS OF FIVE MEMBERED N- HETEROCYCLES Pyrroles Pyrrole possesses a five membered primary structure with one N atom and it is present in many bioactive natural products such as heme, chlorophyll and vitamin B12 [53 - 55] and also in drug molecules (Fig. 3a and 3b). This compound was first discovered in 1857 during bone pyrolysis [51]. Br

Br

N Br O H Pentabromopseudilin

HN Br

N H H N

Cl

Pylouteorin

Cl HN

O N H

N H

OH O

NH2 Br

Cl

OH

Br

Br

N OH O Cl

N

Cl O

OH

COOH

N H O Nakamuric acid

Cl

X

Marinopyrrole A (X= H) Marinopyrrole B (X= Br)

Fig. (3a). Some pyrrole containing bioactive natural products.

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O N H

H3C COOH N O

CH3

N

F

CH3

CH3 OH

Tolmetin

Atorvastatin

OH COOH

Fig. (3b). Some drugs containing pyrrole subunit.

They are important as versatile reaction intermediates for conversion to other heterocycles [56] and also semiconductor material [57, 58]. Some of the common one-pot preparation of pyrroles have been developed based on condensation reactions of 1,3-dicarbonyl compounds such as Hantzsch pyrrole synthesis [59], reactions involving enamines formation [60], MCRs for the synthesis of isonitrile [61]. The other known reactions are Paal-Knorr type cyclization reactions [62], 1,3-dipolar cycloaddition with variety of double and triple-bond dipolarophiles [63] and condensation reactions of 1,4-dicarbonyl reactants [64, 65]. Some of the above mentioned methodologies have been studied with a variety of acidic and basic catalysts such as H2SO4, P2O5, p-TSA and Montmorillonite KSF and basic reagents including TsCl/DBU, alumina, and zirconium phosphate/zirconium sulfophenyl phosphate [66 - 71]. The use of ionic liquids was also investigated for the one-pot preparation of pyrroles (Fig. 4). For example, Yadav et al. [72] and Wang et al. [73] used several imidazolium based non-functionalized ILs as reaction medium for condensation reaction of 1,4-dicarbonyl compound with primary amine during 1.5-3h reaction to get good to excellent yield of pyrrole derivatives (Scheme 1).

N

X N

Cl N

X = BF4, I, OH, HSO4, PF6

N

[pmim][Cl]

N

PF6 [bPy][PF6]

[bmim][X]

N

N

HSO4 / H2PO4 / PhSO3

[hmim][HSO4]/ [hmim][H2PO4]/ [hmim]PhSO3]

Fig. (4). Structure of ionic liquids used for synthesis of pyrrole derivatives.

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Yaveri et al. (2008) employed, 1-butyl-3-methylimidazolium hydroxide ([bmim][OH]) as basic ionic liquid for three-component condensation of acid chlorides, amino acids, and dialkylacetylenedicarboxylates in aqueous media to afford functionalized pyrroles in 84-96% yields (Scheme 2) [74]. The author observed that non basic ionic liquids [Et-Py][BF4] and [bmim][BF4] were found to be less effective for the same reaction with phenylalanine. O IL, rt R NH2 O

N

1.5-3h

R (86-99% yield) IL= [bmim][BF4], [bmim][I], [pmim][Cl,] [bmim][PF6], [bdim][PF6], [bPy][PF6], [hmim][PhSO3] R= Alkyl or aryl Scheme 1. Paal-Knorr synthesis of pyrrole derivatives in ionic liquid medium. O 1

R

COOR3

O R2

Cl

O

N

O OR3

3

OH NH2

1

OH N

RO COOR3

Aqueous media

R = Ar R2= Ph, Bn, i-Bu R3= Me, Et

R2

1

R N H (84-96%)

Scheme 2. Synthesis of functionalized pyrrole using [bmim][OH].

He et al. (2011) designed one 1,4-diketonic condensation with aniline (or ethylenediamine) in 1-butyl-3-methyl-imidazolium hydrogen sulfate, [bmim] [HSO4] as acidic medium to form polysubstituted pyrroles (Scheme 3) [75]. This method utilized a wide range of aliphatic, aromatic, heteroaromatic and carboxylic 1,4-diketones and provided a new approach to monoester pyrroles from 1,4-diketo-2,3-dicarboxylic acid esters via sequential decarboxylation/PaalKnorr pyrrole condensation. Aydogan et al. (2013) prepared pyrrole derivatives using microwave irradiation through Clauson-Kaas reaction of 2,5-dimethoxytetrahydrofuran and amine using acidic 1-hexyl-3-methylimidazolium hydrogen sulfate ([hmim][HSO4]) with higher activity as compared to other catalysts such as acetic acid, [bmim][BF4], and [hmim][H2PO4] (Scheme 4) [76].

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Advances in Organic Synthesis, Vol. 10 149 Ph

Ph R4

N

1

R

R1

R4

N

R3

R2

5-12%

75-86%

R2 = COOEt, H ; R3 = COOEt R2 = COOEt, H ; R3 = H [bmim][HSO4]

150oC, 3h

NH2

Ph R4

N

R1

R3

R2

[bmim][HSO4]

R3

O

150oC, 3h

NH2

R4 R1

2

R2

O

NH2CH2CH2NH2, 100oC, 24h Ph

N

[bmim][HSO4]

Ph R5

85-97%

74% and 89%

R1= R2= R3=Ar or HetAr

R5 = H, Ph

R4 = H

Scheme 3. Synthesis of polysubstituted pyrroles reported by He et al. IL, MW (90W) H3CO

O

RNH2

OCH3

N

3-25 min

a-i

R

IL= [hmim][HSO4]

69-91%

R = Chiral or achiral substituted alkyl or pyrimidinyl group

NH2 Ph a (S)

Ph

NH2

f (1R, 2S)

Ph g (1S, 2S)

HO

HO d (S)

c (S)

HO

NH2

NH2

COOMe

COOMe b (R)

NH2 HO

NH2

NH2

N

OH

e (S)

H2N

NH2

N h

i

Scheme 4. Synthesis of N-alkylsubstituted pyrroles using [hmim][HSO4].

Pyrazoles Ludwig Knorr in 1883 coined ‘Pyrazole’ term to represent the five membered aromatic heterocycle of two nitrogen atoms. Various pyrazoles are well known for their versatile biological activities including anti-microbial, anti-fungal, antitubercular, anti-inflammatory, anticancer, anti-viral, angiotensin converting enzyme (ACE) inhibitor, neuroprotective, cholecystokinin-1 receptor antagonist, estrogen receptor (ER) ligand, etc. [77]. Among the vast field of medicinal drugs or agrochemicals, there are many pyrazoles which have greater value in drug industry (Fig. 5).

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Cl Cl N N

N

N

O Rimonabant

Cl H3COC

H N N N O

N

O

N

Isolan N

N

H3COC Epirizole N N N

N

N H HOOC

N

F Fezolamn

N

O

H2N

S

Lonazolac Cl

F

N

F

N

O Celecoxib

Fig. (5). Some drugs containing pyrazole moiety.

The general synthesis of pyrazoles includes method using reaction of hydrazines with 1,3-dicarbonyl compound, reaction of α,β-unsaturated carbonyl compounds and β-(dimethylamino)enones [78 - 84]. The synthesis of pyrazoles using [3+2] atom fragments has been extensively studied. Generally, β-diketones or their derivatives (as three atom fragment), are condensed with hydrazine and its derivatives (as two atom fragment) to close the five-membered ring [85]. Initially, ionic liquids were examined as reaction medium at different temperature for preparation of variety of pyrazoles starting from two or multicomponent reactions in presence of additional acid catalyst or without it [86 - 88]. Martin et al. employed [bmim][BF4] ionic liquid as reaction medium at 80°C for the synthesis of 4,5-dihydro-1H-1-carboxy amide pyrazoles for the first time (Scheme 5) [86]. O

[bmim][BF4], 80oC OR

X3C

R1

O

R1 H2N

HO X3C

NHNH2.HCl

N

N

1h H2N

O

1

R= Me, Et; R = H, Me, Ph; X= F, Cl

Scheme 5. Synthesis of 4, 5-dihydropyrazoles in [bmim][BF4].

(73-86%)

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Similarly another three-component reaction was conducted by Bazgir et al. (2009) starting from a mixture of phthalhydrazide, aromatic aldehydes and malononitrile or ethyl cyanoacetate for synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives in 1-butyl-3-methylimidazolium bromide at 100°C using p-toluenesulfonic acid as catalyst (Scheme 6) [87]. O

O CN

p-TSA, [bmim][Br] 100oC ArCHO 2.2-5h

NH NH

Y

NH2 N N Ar

O O

Y

(78-95%)

Y= CN,CO2Et Ar= Aryl Scheme 6. Synthesis of pyrazole derivatives using [bmim][Br].

Frizzo et al. (2009) utilized two functionalized ionic liquids, basic [bmim][OH] and acidic [hmim][HSO4] as reaction medium for cyclocondensation reaction between β- dimethylaminovinyl ketones and tert-butylhydrazine hydrochloride to synthesize N-t-butyl-pyrazoles at 80oC along with several other neutral imidazolium based ionic liquids (Scheme 7) [89].

N

X N

m(C)

X= BF4, Br, PF6, SCN, CF3CO2 m= 4, 6 and 8 numbers of carbon O R

N

t-Bu-NHNH2 HCl

IL, 80oC R

N

N

R= Aryl/ heteroaryl groups

Scheme 7. Synthesis of N- tert-butylpyrazoles reported by Fizzo et al.

Moreira et al. (2010) synthesized bis-pyrazoles in [bmim][BF4] with addition of co-catalyst HCl (or BF3.OEt2) using a two-component reaction of β-enamino ketone with hydroxylamine or hydrazines or amidines at 90°C for 0.5-2h to get good yield of products (Scheme 8) [90]. They also studied the effect of other two functionalized basic [bmim][OH] and acidic [hmim][HSO4] ionic liquids for this reaction. The reaction in basic IL [bmim][OH] afforded lower yields as compared to the other two IL.

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O CH3

CH3

N +

N

CH3

H3C

RNHNH2

Reaction condition (i) or (ii) or (iii)

R N N N N

O

R

R = H (a), Ph (b), 4-NO2-C6H5 (c), 2,4-(NO2)2-C6H4 (d), C6F5 (e), COOMe (f), CONH2 (g), CH2CH2OH(h), t-Bu (i) Reaction condition (i) = H2SO4(cat.) for (a) only (ii) = [bmim][BF4]/HCl and [hmim][HSO4], 90oC, 0.5-1.5h for (b) to (g) (78-88% yield) (iii)= [bmim][BF4]/BF3.OEt2, 70oC, 2h for (g) (70% yield)

Scheme 8. Synthesis of bis-pyrazoles using ionic liquids.

Safaei et al. (2013) employed Lewis acidic ionic liquid [bmim][InCl4] catalyzed multicomponent and regioselective synthesis of fully substituted pyrazoles and pyrazole-fused cyclohexanones from aldehydes, arylhydrazines, and acyclic or cyclic 1,3-diketones (Scheme 9) after optimizing the reaction condition with different ionic liquids along with various metal salt catalysts [91]. This method is simple, affording the corresponding products in good to high yields (61-90%). O R

O

O

O

O

R

O

O

2

R

R2

N N

R (i)

H

R1NHNH2

R= Alkyl or aryl

1

R 1

R = Ph, 4-Cl-Ph, 4-Me-Ph, 4-Meo-Ph R2= H, Ph

N (i)

N R1

Reaction condition: (i) = [bmim][InCl4], 140 oC 60-120 min

Scheme 9. Synthesis of fully substituted pyrazoles and pyrazole-fused cyclohexanones.

Shaterian and coworkers (2013) utilized one weak basic ionic liquid catalyst, 1,8diazabicyclo[5.4.0]-undec-7-en-8-ium acetate ([DBU][Ac]) for four-component preparation of 6-amino-4-aryl-5-cyano-3-methyl-1,4-dihydropyrano[2,3-c] pyrazole derivatives (Scheme 10(a)) [92]. They performed the reaction by mixing equal amount (1 mmol) of each reactant at room temperature using 10 mol% of [DBU][Ac]. Srivastava et al. in the same year demonstrated another threecomponent synthesis of highly functionalized pyrazoles under grinding method at ambient temperature using 20 mol% of basic [bmim][OH] and 1 mL of water taking an equal mixture (1 mmol) of aromatic aldehyde, malononitrile and phenyl hydrazine within 10-30 min [Scheme 10b) [93].

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(a) CH3 CHO NH2NH2.H2O

CH3COCH2COOEt

CH2(CN)2

O

N H

H2N

H N [CH3COO] [DBU][Ac] =

N

solvent free

R

R= EWG or EDG

(b)

NC

[DBU][Ac]

(87-98%)

N

H [bmim][OH], rt, grinding Ph

NH

N N

CH2(CN)2

NH2

NH2

R1

R3 R2

1

R

3

R

R1= H, Cl, OH R2= H, NO2, OCH3 R3= H, Cl, CN, F, OCH3 , NO2, N(CH3)2, CH3

R2

CN

(80-97%)

Scheme 10. Synthesis of (a) 6-amino- 4-aryl-5-cyano-3-methyl-1, 4-dihydropyrano [2,3-c] pyrazole derivatives, (b) 5,3 substituted 1-phenyl-1H-pyrazole-4-carbonitrile.

Zolfigol and his group (2015) successfully utilized the first task specific nano ionic liquid 1-methylimidazolium trinitromethanide ([hmim][C(NO2)3]) as reusable catalyst for multicomponent synthesis of 5-amino-pyrazole-4-carbonitrile derivatives (Scheme 11a) and 1,4-dihydropyrano-[2,3-c]-pyrazoles (Scheme 11b) within half an hour at room temperature stirring without any solvent [94]. They also proposed that the buffer ability of nanoionic liquid probably plays dual catalytic role in the described reactions. H2N R

CHO

CH(CN)2

PhNHNH2

N Solvent free, r.t.

R= Aryl

O

[hmim][C(NO2)3], 0.5 mol% H3C

Solvent free, r.t.

R

91-97%

N CN

N (a)

OEt

H3C

N

H C(NO2)3

[hmim][C(NO2)3] (Nano ionic liquid)

N Ph

Ph

O

R

N

CN

[hmim][C(NO2)3], 0.5 mol%

O NH2 (b) 89-95%

Scheme 11. Synthesis of (a) 5-amino-pyrazole-4-carbonitrile and (b) 1, 4-dihydropyrano-[2, 3-c]-pyrazoles.

Liu and his group (2017) synthesized five basic ionic liquids containing DABCO as parent cation with varying substituent and different anions (Fig. 6) [95]. They examined their catalytic activities with a model four-component route (Scheme

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12a) of dihydropyrano[2,3-c]pyrazole synthesis under mild condition. Out of the five catalysts, the highest activity was observed for 10 mol% of [dabco][AcO] IL in acetonitrile which can be accounted for basic nature of acetate anion in combination with DABCO cation. This protocol was also applicable to aliphatic ketones, isatin, acenaphthene quinone and ninhydrin (Scheme 12b, c & d). R4

R3

R1

Catalyst [dabco-H][AcO], 10 mol% CH3CN

CN N N

O

R2

NH2

N H Isatin

O

R2

OEt

N

O

O

N

H N NH2

N

Acenaphthenequinone

(b)

R2

R4= F, Cl, Br

O

O R1

CN

NH2

(c)

O

N

O

O

(a)

R1

N R2

R4

R3= Aryl or alkyl

Aliphatic ketones

O CN

N O

R3 CHO Aromatic/aliphatic aldehyde

NH

R1

(d) R1= Me (a), Ph R2= H, Ph (a)

O

NH2

R1 O

(e)

O Ninhydrin

R1 O

O CN

N N R2

O

NH2

O CN

N N

O

NH2

R2

Scheme 12. Synthesis of various substituted pyrazoles.

N N

X

[dabco][X] X= AcO, HSO4, Cl,

N N

Cl

[dabco-C4]Cl

N N

OH Cl

[dabco-C3OH]Cl

Fig. (6). Structures of some DABCO-based ionic liquids.

Mamaghani et al. (2015) employed Brӧnsted-acidic ionic liquid 1,2–dimethyl-Nbutane sulfonic acid imidazolium hydrogen sulfate ([dmbsi][HSO4]) as recyclable catalyst for the above four component synthesis of pyrano[2,3-c]pyrazoles

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(Scheme 12a) in neat condition at 60oC within 10-20 min to afford excellent yields of product (85-96%) [96]. The same method was also efficiently extended with 1,2-diketone for preparation of spiro conjugated pyrano[2,3-c] pyrazoles (Scheme 13). R2 O 1-3 min R1COCH2COOEt

NH2 N N H

[dmbsi][HSO4]

O

O

R1

R2CH2CN

H2NNH2.H2O

O

1

O

R = CH3, C3H7, Ph R2 = CN, CO2Et

or

O

O

86-96%

O

Cl O

H3C

O

N H

SO3H

N H

HSO4

CH3

[dmbsi][HSO4]

Scheme 13. Synthesis of spiro-conjugated pyrano[2,3-c].

A crown ether based acidic IL [crown ether mim][HSO4] was introduced by Dayanand et al. (2015) and examined as recyclable catalyst for cyclocondensation of various substituted β-enaminones with hydrazine hydrate or phenyl hydrazine to obtain a series of functional pyrazoles under thermal solvent-free condition within 10-35 min (Scheme 14) [97]. O N N H

88% O N

O CH3

O

N H

O 79%

N

O

CH3 N

O

R1 NH NH2.H2O or R1 NH NH2

CH3

HSO4

N

O N

CH3

O CH3

O

O O

O N

O O IL = [crown ether mim][HSO4]

R CH3

R

R= H, Cl, F, Br, NO2, OCH3 R1= H, Ph

i = IL (20 mol%), 50oC Solvent free

N

CH3

R

1

Reaction condition

N

CH3

O

89%

N H

Scheme 14. Synthesis of pyrazole derivatives using [crown ether MIm][HSO4].

(84-92%)

N

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Imidazoles Imidazole (1,3-diaza-2,4-cyclopentadiene) is a planar five-member ring system with 3C and 2N atom in 1 and 3 positions. Various one pot approaches are available for preparation of substituted imidazole derivatives. Some of them are three component reactions of benzil (or benzoin), aromatic aldehyde in ammonia (Scheme 15) [98, 99], synthesis from α-halo ketones [100], from aminonitrile and aldehyde [101], condensation of 1,2-diaminobenzene with carboxylic acid [102] etc. H

O

N

O 2NH3

N H

O

Scheme 15. Synthesis of trisubstituted imidazole.

O O S O O H

O N

O HSO4 N H2

H

H3C

N-methyl-2-pyrrolidonium hydrogen sulphate

Morpholinium hydrogen sulphate

O O

PPh3 O

S

S

O

SO3H

H3C

N

O

N HSO4

OH [(CH2)4SO3hmim][HSO4]

Triphenyl (propyl-3-sulphonyl) phosphoniumtoluenesulfonate

N

N

N

O

N

2HSO4

nO

PEG1000-DAIL

Fig. (7). Structures of some ionic liquids used in the synthesis of substituted imidazole derivatives.

The three-component reactions of benzil, aldehydes and ammonium acetate are widely studied in presence of various traditional acidic/basic catalysts such as pTSA [103], DABCO [104], I2 [105], InF3 [106], BF3.SiO2 [107] etc. Some of them have several disadvantages like low yields, longer reaction times, use of hazardous, expensive and moisture-sensitive catalyst, and excess amount of

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reagents, harsh reaction conditions, complex workup procedure and reusability of the catalysts. These limitations were minimized by performing the reaction in [hbim][BF4] [108], [hemim][BF4], [hemim][Br], [hmim][Cl] and [bbim][PF6] [109] ionic liquids and also with catalytic amount of neutral tetrabutylammoniumbromide in isopropanol under reflux temperature [110]. Few acidic or basic ionic liquid catalyzed reactions were also reported using [emim][AcO] [111], [Et3NH][HSO4] [112], [(CH2)4SO3hmim][HSO4] [113], Nmethyl-2-pyrrolidonium hydrogen sulfate [114] and triphenyl(propyl-3-sulphonyl) phosphoniumtoluenesulfonate [115], morpholinium hydrogen sulphate (Fig. 7) [116]. Fang et al. (2011) employed polyethylene glycol based acidic dicationic ionic liquids PEG1000-DAIL for the synthesis of 2,4,5-trisubstituted imdazoles (Scheme 16) as recyclable catalyst involving homogeneous reaction and heterogeneous separation procedure [117]. Jourshari et al. (2013) developed supported ionic liquid like phase (SILLP) catalyzed synthesis of 2,4,5-trisubstituted imidazoles using benzoin or 9,10-phenanthrenequinone, aldehyde and ammonium acetate in ethanol at 50oC or ultrasonic irradiation (Scheme 16) [118]. SO3H

Toluene

P S O

O

reflux, 12h

SO3 P

SO3H

H2SO4 P

80-150OC, 12h

HSO4

O

1, 4-butane sultone

HO3S

SO3H Ionic Liquid [(4-SB)T(4-SPh)P][HSO4]

Scheme 16. Synthesis of (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogen sulfate.

Banothu et al. (2017) utilized a simple, recyclable and efficient Brӧnsted acidic ILs, (4-sulfobutyl)tris(4-sulfophenyl) phosphonium hydrogen sulphate [(4-SB)T (4-SPh)P][HSO4] (Scheme 16) for the preparation of 2,4,5-trisubstituted-1Himidazoles under solvent-free conditions (Scheme 17) [119]. Shaterian et al. explored N-methyl-2-pyrrolidone hydrogen sulfate ionic liquid [NMP]+[HSO4]- as catalyst for 1,2,4,5-tetrasubstituted imidazole synthesis using the common procedure involving benzil or benzoin (1 mmol), aldehyde (1 mmol), amine (1 mmol), and ammonium acetate (1 mmol) at 100 oC (Scheme 18) [121]. Also this procedure involved other functionalized ionic liquid systems such as [dsim][HSO4] [120], 1-methyl-3-(3-trimethoxysilylpropyl) imidazolium chloride

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immobilized super paramagnetic nanoparticle (IL-MNP) [121] and [bmim]3 [GdCl6] as catalyst to synthesize tetra-substituted imidazoles. O

O

RCHO

H N

Benzil or Benzoin N R

R N

IL, EtOH, 500C )))

83-97%

NH4OAc

R: Substituted aromatic aldehydes Cl IL =

N H

IL , heat, solvent-free )))

90-98%

CH3

N

N

CH3

Scheme 17. Synthesis of 2, 4, 5-trisubstituted imidazoles.

O R1CHO

NH4OAc

R2NH2

[NMP]+[HSO4](cat.)

O

N R1 N R2

R1: Substituted aromatic aldehydes R2: Benzyl, phenyl, cyclohexyl, ethyl etc.

N Me

O H [HSO4]

[NMP]+[HSO4]-

Scheme 18. Synthesis of 1,2,4,5-tetrasubstituted imidazole.

The preparation of pharmacologically important benzimidazole derivatives proceeds through coupling of o-phenylenediamines with carboxylic acids or their derivatives [122 - 125] and also condensation between o-phenylenediamine and aldehydes followed by oxidative cyclo-dehydrogenation [126]. All the reported catalytic procedures used various toxic solvents such as MeCN or DMF, high reaction temperature and suffered from difficulty in product isolation. A number of ionic liquid mediated methods were studied for the synthesis of substituted benzimidazole derivatives utilizing [bmim][BF4] [127], [pmim][BF4] [122], [pro][NO3] [128], 3-hydroxyethyl-(1-methylimidazolium)-tetrafluoroborate [129], [dabco][diAC] [130] as reaction medium for the condensation of o-phenylenediammines with aldehydes and acid scaffolds (Scheme 19).

Nitrogenates Heterocycles

Advances in Organic Synthesis, Vol. 10 159 NH2 R1

NH2

1

R : H, NO2, CO2H, OCH3

IL r.t./reflux

R2

R2 N H R2: Ar/HetAr

R1

ILs:.[bmim][BF4] [pmim][BF4] [pro][NO3] [dabco][diAC] N

N

N R1

R2CHO/R3COOH

N

R3

or

1

R R2

N H R3: Ar

Scheme 19. Synthesis of benzimidazole derivatives using ionic liquid.

USE OF FUNCTIONALIZED IONIC LIQUIDS IN ONE-POT SYNTHESIS OF SIX MEMBERED N-HETEROCYCLES Pyridines Pyridine derivatives abundantly exist in nature and occupy a prominent position in the field of heterocyclic chemistry [131]. These derivatives are important as industrial, pharmaceutical and agricultural chemicals. They show moderate to excellent activities against number of biological targets depending on the nature of substituted pyridine nucleus [132 - 137]. 1,4-Dihydropyrimidines (DHPs) are partially hydrogenated N-heteroaromatics compounds containing various substituent at positions 2,6-, 3,5-, and 1,4- (Fig. 8) with diverse biological and pharmacological actions [138 - 140]. They act as important groups of calcium-channel modulating agents with structurally diverse compounds and have gained lots of use in the treatment of cardiovascular disease viz antihypertensive, antianginal, vasodilator and cardiac depressants activities [141]. The function of 1,4-dihydropyridines are identical to their structural analogy 1,4-dihydronicotinamide in terms of radical scavenging and antioxidant properties [141, 142]. The 1,4 dihydropyridines can be obtained from Hantzsch type cyclic condensation reactions (Scheme 20) by refluxing a mixture of aldehyde, β-ketoester, and aqueous ammonium hydroxide in ethanol [143]. Domino synthesis of the Hantzsch method was reported by Penieres et al. and Cotterill et al. using ammonium nitrate as a source of ammonia and oxidizing species under microwave irradiation [144, 145]. Researchers have been following this general method with a number of catalysts like triphenylphosphine, silica gel,

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silica NPs supported Fe(III) etc. [146 - 149]. Nia et al. (2014) demonstrated a protocol for the synthesis of 4-aryl-l,4-dihydropyridines by a rapid and efficient one-pot four-component approach, using 1,2-dimethyl-3-butanesulfonyl imidazolium bisulfate ([dmbsi][HSO4]) ionic liquid under solvent-free conditions in high to excellent yields (Scheme 21) [150]. Keeping attention to the wide range of biological activities exhibited by pyridine derivatives and obvious shortcomings appeared from the reported procedures, various methods have been developed based on the advantages of ionic liquids as catalyst or medium to limit those flaws. Various ionic liquids were studied as medium or catalyst to develop efficient synthetic route of the pyridines for several years. Among them very known ionic liquids as solvent and catalyst used in the process are [bmim][BF4], [bmim][PF6] [151], [bmim][Cl] [152], [hmim][Tfa] [153], 1,1,3,3-N,N,N´,N´tetramethylguanidinium trifluoroacetate (TMGT) [154] [bmim][Br] [155], and [C4C1im] [(MeO)2PO2] (Fig. 9) [156]. Besides these studies, Ranu et al. employed basic ionic liquid [bmim][OH] in three-component condensation of aldehydes, malononitrile, and thiophenols to produce highly substituted pyridines in high yields at room temperature within 0.5-1.5h (Scheme 22) [157]. Again Davoodina et al. reported a simple, efficient, and green method for synthesis of 2,4,6triarylpyridines by one-pot reaction from a mixture of acetophenones, aryl aldehydes, and ammonium acetate using a Brӧnsted acidic ionic liquid 3-methyl1-(4-sulfonylbutyl)imidazolium hydrogen sulfate as an effective and reusable catalyst under solvent-free conditions (Scheme 23) [158]. Thus different functionalized ionic liquids played major role as catalyst or media for various procedures involved in the preparation of pyridine derivatives. Cl Cl COOEt

MeOOC Me

N H

N O N COOCHMe2

MeOOC Me

Me

Felodipine

N H

Me

Isradipine

NO2 OCHF2 MeOOC Me

COOMe N H

O MeOOC

Me

Foridone

Fig. (8). Structures of some DHPs used as Ca2+ antagonist.

Me

O N H

Me

Barnidipine

N

Nitrogenates Heterocycles

Advances in Organic Synthesis, Vol. 10 161 R

O

Catalyst

2 EtOOC

EtOOC

COOEt

AcONH4

RCHO

Solvent

N H

R= Alkyl or aryl bearing EWG or EDG

Scheme 20. Hantzsch synthesis of 1,4-dihydropyridine. Ar

O

O

NH4OAc [dmbsi][HSO4]

R ArCHO

CO2Et

MeCOCH2CO2Et

R

R

60oC

O

N H

R

Me

Ar = Aryl/ heteroaryl R = H, Me

Scheme 21. Synthesis of 4-aryl-l,4-dihydropyridines.

CF3COO

NH2 H3C

CH3

N

N

CH3 CH3 TMGT Cations

MeN

NBu

MeN

N N

NMe

Me3N

OH

N

Anion O P

OMe

HO OMe

[C4C1im] [(MeO)2PO2]

Fig. (9). Structures of some ionic liquids used in the synthesis of pyridine derivatives.

Ar

O Ar

CN H

2

[bmim][OH]/ EtOH RSH

CN

rt, 0.5-1.5h

NC H2N

Ar= Aryl or heteroaryl R= Aryl or Benzyl Scheme 22. Synthesis of highly substituted pyridines using [bmim][OH] by Ranu et al.

CN N

SH

62-92%

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O

O

[HO3S(CH2)4mim][HSO4] R2

R1

H

NH4OAc

Solvent free, 120oC R2

N

R2

1

R = H, 4-Br R2= EWG or EDG

82-93%

Scheme 23. Synthesis of 2,4,6-triarylpyridines.

Quinolines The core structure of quinoline derivatives can be made by Skraup [159, 160], Doebner-Miller [161, 162], Friedländer [163], Combes [164], Conrad-Limpach [165] and Pfitzinger [166] syntheses. These reactions involve a cyclocondensation of aniline or aniline derivatives with carbonyl compound, followed by aromatization reactions. Only in the Skraup reaction, glycerol is used as one of the starting materials for in situ generation of acrolein through dehydration reaction. The classical methods suffer from various limitations including use of stoichiometric amounts of catalysts, harsh reaction condition resulting lack of environmental safety, longer reaction time and formation of undesirable products which lead to difficulty in product purification step [167, 168]. To eliminate few drawbacks of those methods, two reports were found regarding microwave assisted synthesis of quinolines in [bmim][BF4] ionic liquid for the Skraup synthesis in presence of concentrated acid at high temperature [169] and also the reaction of aniline derivatives and phenyl acetaldehydes with lower atom economy due to formation of side products [170]. Sarma et al. explored synthesis of 2,4-disubstituted quinolines from o-amino acetophenones and nitriles in recyclable [hmim][PF6] ionic liquid with 1 mol% of Zn(OTf)2 as catalyst within short time [171]. The function of ionic liquid in Friedländer annulation was studied as reaction media, promoter or catalyst [172, 173] which is an acid or base catalyzed condensation of 2-aminoaryl ketone with aldehyde or ketone containing α-methylene functionality followed by cyclodehydration [174]. Palimkar and his co-workers (2003) [175] explored N-protonated [hbim][BF4] ionic liquid as recyclable medium for this heteroannulation at 100°C without any added catalyst during 3-6 h reaction to generate variety of biologically active substituted quinolines and fused polycyclic quinolones (Scheme 24).

Nitrogenates Heterocycles

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R1

O O

R

R1 NH2

R3

R2

[hbim][BF4] R 3-6 h, 100°C 90-98%

R2 N

R3

R = H, Cl R2, R3 = open chain/cyclic keto ester R1 = CH3, Ph Scheme 24. Synthesis of quinoline derivatives using [hbim][BF4].

The same reaction was performed at room temperature by Perumal et al. (2004) [176] in 1:2 mixture of [bmim][Cl] and ZnCl2 melt for 24 h that can act both as solvent and Lewis acid catalyst to get 55-92% yields of product. The same catalyst was also utilized by Palimkar et al. to conduct one-pot reaction of 2amino-3-acyl benzofuran and ethylacetoacetate to yield the corresponding quinoline at 80°C (Scheme 25) [177]. O

O O

O

O

[bmim][Cl]:ZnCl2 (1:2) OEt

NH2

OEt

80 °C, 24 h

O N 55% yield

Scheme 25. Synthesis of quinoline using [bmim][Cl]:ZnCl2.

A water stable -SO3H functionalized task-specific ionic liquid catalyst (TSIL) was introduced by Akbari et al. (2010) [178] for one-pot domino approach quinoline synthesis (Scheme 26) in aqueous medium at 70°C for 1-8h to get 85-98% yields. The product can be separated from the aqueous IL solution by filtration and the catalyst could be easily recycled for five times without any pre-treatment. R2

O R1

R4

R2 NH2

O

R3

TSIL (5 mol%) R1 H2O, 70°C

R4 N

R3

R1 = H, Cl R2 = Ph, CH3 R3, R4 = acyclic/ cyclic ketone TSIL :

N

N

Scheme 26. Quinoline synthesis using TSIL.

SO3H CF3SO3

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The ultrasound assisted Friedländer annulations was also performed in [hbim] [BF4] as solvent containing MeOH as co-solvent at ambient temperature without any other catalyst within 10-35 min (Scheme 27) [179]. R2

O R1

R4

R2

[hbim][BF4]

R1

R4

MeOH )))) r. t. 10-35 min R1 = H, Cl, NO2; R2 = Ph, CH3 R3/ R4 = Cyclic or acyclic ketone NH2

O

R3

R3

N

Scheme 27. Ultrasound assisted Friedländer annulation.

Prola et al. (2012) [180] synthesized 3-haloacetyl-4-methylquinoline derivatives under microwave irradiation from the reaction of 4-alkoxy-3-alken-2-ones and 2aminoacetophenone (Scheme 28) in combination of reusable Brӧnsted acidic ionic liquid 1H-methylimidazolium toluene sulfonate [hmim][TsO] and TsOH in 10-20 min time (10-20 min). O O R1

OCH3 R2

[hmim][TsO], CH3 TsOH, MW

NH2

CH3 O R1 N

R2

R1 = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 R2 = Alkyl Scheme 28. Synthesis of quinoline derivatives using IL [hmim][TsO].

An acidic ionic liquid supported catalyst was utilized by dispersing protic nbutanesulfonic acid pyridinium hydrogensulfate [bspy][HSO4] (Fig. 10) on the surface of MCM-41 nanoparticles by Alibeik and his group (2012) [181] in the Friedländer synthesis of quinolines at 100°C in neat condition.

N

HSO4-

CH2(CH2)2CH2SO3H Fig. (10). Structure of [bspy][HSO4] IL.

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Due to less acidic character of 1-butyl-3-methylimidazolium hydrogen sulfate [bmim][HSO4], Tajik et al. [182] used 50 mol% of this IL for the reaction of 2aminobenzophenones and ethylacetoacetate or ketones at 70°C under solvent-free medium. This method produced 75-95% yields of product within 25 min to 10 h reaction. A Lewis acidic deep eutectic solvent [Choline chloride-ZnCl2] was employed as solvent and catalyst for the Friedländer annulation under mild conditions by Wang et al. (2009) [183]. The -N-SO3H functionalized acidic ionic liquid 1,3-disulfonic acid imidazolium hydrogen sulfate (DSIMHS) was studied by Shirini et al. (2014) [184] and presented a convenient, highly versatile and eco-friendly protocol for the Friedländer annulation with 25 mol% of this IL as reusable catalyst at 70°C (Fig. 11). A variety of ketones afforded the substituted quinolines in excellent yields (88-94%) during relatively short reaction times (5-45 min).

DSIMHS =

HO3S

N

N

SO3H

HSO4

Fig. (11). Structure of ionic liquid DSIMHS.

In 2015 Sarma et al. employed another -N-SO3H functionalized imidazolium IL 3-methyl-1-sulfoimidazoliumtrichloroacetate ([msim][OOCCCl3]) (Fig. 12) for the same reaction at 100°C in neat condition as medium and catalyst to get excellent yield of single product [185].

N

N SO H [OOCCCl3] 3 [msim][OOCCCl3]

Fig. (12). Structure of [msim][OOCCCl3].

Acridines Acridine derivatives are weak bases and show the characteristic properties of alkaloids. Acridines and their fused derivatives are known to possess various pharmacological activities, including anticancer, antitumor, antiviral,

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antimicrobial, antimalarial, analgesic and anti-inflammatory, which stimulate synthesis and further studies of new compounds of this series (Fig. 13) [186 188]. During the World War II, the discovery of quinacrine or mepacrine as antimalarial drug was observed in place of quinine [189]. At present, a number of acridine based medicines are marketed for various clinical purposes (Fig. 14) [190, 191]. R

O

O

R

N R'

R

O

N R'

N R'

N

Where R & R'= H, alkyl, aryl etc. Fig. (13). Structure of acridines. (H3CH2C)2N

(H3C)2N NH

HN O

H2N

N H Cl

NO2

NH2 Cl

Proflavin (antimicrobial)

N Quinacrine (antimalarial)

N Nitracrine (Antitumor)

Fig. (14). Some acridine derivatives in clinical uses.

The 1,8-dioxodecahydroacridinones were investigated for their potential as laser dyes, photochemical/physical properties, electrochemical properties, and interactions with DNA [192 - 194]. Similarly polyhydrodibenzoacridines have characteristic luminescent properties [195, 196]. The common synthetic strategies of acridine nucleus include Ullmann reaction [197, 198], Bernthsen synthesis [199], Friedlander annulations [200], Pfitzinger’s and Goldberg methods [201]. The one-pot approach of acridines have been studied in a number of environmentally benign methods for simplification of reaction procedure in concern to easy work-up step, selective formation of one product, generation of complex library of molecules, incorporation of mild reaction condition, use of recyclable catalysts, shorter reaction period and minimum side products [202].

Nitrogenates Heterocycles

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The general construction of acridine nucleus in 1,8-dioxodecahydroacridines is studied from acid catalyzed three-component condensation of 1,3-cyclohexanones, aldehydes and various nitrogen sources such as ammonium acetate or primary amines (Scheme 29) in solution or neat condition at different temperature [203 - 205]. These conventional acid catalyzed methods have several limitations like longer reaction period, drastic reaction condition, expensive cost, use of toxic non-recyclable catalyst or solvent, lower yield of product and complex purification steps in comparison to IL catalyzed or mediated methods. O Urea/NH4OAc Catalyst

O

R

O

N H

+ RCHO

2 O

R=alkyl, aryl, H R'= alkyl, aryl

O

R

O

R'NH2 Catalyst N R'

Scheme 29. Classical/general route for acridine synthesis.

The first preparation of IL mediated reaction was reported by Yu-Linget et al. in [bmim][BF4] using aromatic aldehydes, dimedone and NH4OAc as nitrogen source. The use of IL attributed high yields in milder reaction conditions and simplifies the work-up procedure [206]. One report utilized CeCl3.7H2O catalyst in [bmim][BF4] reaction medium for preparation of other polyhydroacridinones at 55-100 °C [207]. Vahdat and his co-workers (2011) performed the same synthesis at mild condition in presence of 1 mol% of multi–SO3H groups containing triphenylphosphinium based ionic liquid (Scheme 17) as catalyst (Scheme 29) in water for 5-21 min with excellent yields [208]. They also employed another acidic ionic systems of heteropolyanion bearing solid ionic salts [mimps]3[PW12O40] and [teaps]3[PW12O40] (Fig. 15) as excellent catalysts to complete the reaction within one hour in water at room temperature [209]. A Brӧnsted acidic 1-methylimidazolium trifluoroacetate ([Hmim][TFA]) ionic liquid was used by Dabiri et al. (2008) as catalyst for the preparation of 9,10diaryl-1,8-dioxo-decahydroacridines at 80°C using 0.1 g of that IL [210]. This

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weaker acidic IL mediated reaction required 4-7 h reaction to yield 78-89% of product and it was reused for four runs without loss of activity.

3SO3H PW12O40

N

N

N

3-

SO3H PW12O40 3

3

[mimps]3[PW12O40]

[Pyps]3[PW12O40] C2H5 C2H5

N

SO3H PW O 312 40

C2H5

3

[teaps]3[PW12O40] Fig. (15). Ionic liquids containing heteropolyacidic anion.

In 2009 Yu and his group developed two Brӧnsted acidic imidazolium salts containing perfluoroalkyl tails (Fig. 16) as Brӧnsted acid-surfactant combined catalyst for the synthesis of 9,10-diaryl-1,8-dioxo-decahydroacridine derivatives with good yields (79-91%) in water under reflux condition for 4h. The method provides several advantages such as low catalyst loading (1-1.5 mol %), recycling of the catalyst and simple work procedure [211].

C8F17

N

C8H17

N

N

SO3H

C8F17

N

N

SO3H

SO3H

N

SO3

2

SO3

Fig. (16). Brӧnsted acidic imidazolium based ionic liquid containing perfluoroalkyl tails.

Many of the published work required varied amountof acidic ionic liquids to catalyze the reactions depending on their acidic strength. For instance, 30 mol% of 3-(carboxymethyl)-1-methyl-1H-imidazol-3-ium-trifluoroacetate [cmim] [CF3COO] worked well in 50% aqueous ethanol in homogeneous phases at 80 °C during 1-1.5 h time to produce 81-90% yield of 9-aryl-1,8-dioxodecahydroacridine derivatives (Scheme 30) [212].

Nitrogenates Heterocycles

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[CF3COO] N

N + ClCH COOH Acetone 2 Reflux, 5-7 h

N

COOH CF3COOH N rt, -HCl Cl

COOH

N

N

Scheme 30. Synthesis of 3-(carboxymethyl)-1-methyl-1H-imidazol-3-ium-trifluoroacetate.

On the other hand, Alinezhad et al. (2013) performed the preparation of 9,10diaryl substituted 1,8-dioxo-acridines in water within 7-20 min using 1 mol % of [2-mPyH][OTf] at room temperature to form 91-98% yields of the corresponding products (Scheme 31) [213]. R' O

CHO

NH2

O

O

[2-mPyH][OTf] (1 mol%) R R

+ O

+ R'

R R

Water(2mL)/rt R''

R= Me, H R'= H, EWG/EDG R''=H, 4-Me, 4-OMe, 4-Cl [2-mPyH][OTf]

N

R R

R''

NH CF3SO3

Scheme 31. Synthesis of 9,10-diaryl substituted 1,8-dioxo-acridines.

Dutta et al. [214] (2014) synthesized three –SO3H functionalized acidic 1,3disulfoimidazolium carboxylate ionic liquids [dsim][X] where X= [CH3COO]-, [CCl3COO]-, [CF3COO]-) as viscous liquids (Scheme 32). The more acidic ILs [dism][CCl3COO] and [dsim][CF3COO] were efficiently utilized as recyclable catalysts for three-component synthesis of 1,8-dioxo-acridines using a mixture of dimedone, aromatic aldehydes and ammonium chloride in neat condition at 80100°C during 10-20 min reaction (Scheme 33). The above two ILs also effectively worked as catalysts for the synthesis of 1, 8-dioxo-decahydroacridine in water at the same temperature. Besides the above mentioned acid catalyzed synthesis of 1,8-dioxo-acridines, some tetrahydrobenzo[a] acridine-1-one derivatives were also developed via three component reactions of 1 or 2-naphthylamine, aromatic aldehydes and dimedone in organic solvent or neat condition at different temperature with or without any catalyst (Scheme 34) [215, 216].

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HN

HO3S

N

N

Gogoi et al.

ClSO3H rt, 30min

HO3S

N

N SO3H Cl CX3COOH 50 OC, 1h X= H Cl F

N SO3H Cl

HO3S

N

N SO3H [CX3COO]-

[dsim][CH3COO] [dsim][CCl3COO] [dsim][CF3COO]

Scheme 32. Synthesis of 1,3-disulfonic acid imidazolium carboxylate ILs.

[dsim][CCl3COO] or [dsim][CF3COO]

O

+ RCHO + NH4Cl O

2

O

R

O

(25 mol %) N H

heat

Where R = Aryl

Scheme 33. Acidic IL catalyzed preparation of 1,8-dioxo-decahydroacridines.

RCHO +

O

O

NH2

Heat +

O

O NH2 + O

N H

solution or neat

O

RCHO +

R

R

Heat solution or neat

N H

R= alkyl, aryl & heteroaryl group

Scheme 34. Polyhydrobenzo[a]acridines synthesized from 1-or 2- naphthylamine.

But the first ionic liquid catalyzed formation of tetrabenzo[a]acridinones was conducted with a four-component reaction of 2-naphthol as one of the starting material instead of 2-naphthylamine under solvent-free thermal method in presence of 5 mol% of two acidic ionic liquids [dstmg][CF3COO] and [dstmg][CCl3COO] (Scheme 35) [217]. The tetramethylguanidinium based ionic liquids were synthesized according to reaction described in Scheme (36).

Nitrogenates Heterocycles

Advances in Organic Synthesis, Vol. 10 171 NH4Cl (1 mmol)

O

R

O

Neat / 75-85oC

OH RCHO

5 mol% of IL

O

10-18 min R = Aryl

IL = [dstmg][CCl3COO], [dstmg][CF3COO]

N H 85-94%

Scheme 35. Synthesis of tetrahydrobenzo[a]acridinone derivatives.

NH N

HO3S

dry hexane/ClSO3H

N

SO3H N

r.t., 45-60 min

N

Cl N

[dstmg][Cl] CX3COOH 60 °C/ 1h

SO3H

HO3S

X= H, [dstmg][CH3COO] Cl, [dstmg][CCl3COO] F, [dstmg][CF3COO]

N N

[CX3COO] N

Scheme 36. Synthetic route of TMG-based –SO3H functionalized ILs.

The only reported preparation of 14-aryl-7-(N-phenyl)-14H-dibenzo[a.j]acridines was conducted by Dutta et al. in 2017 under solvent-free condition at 100°C using two recyclable heterogeneous Brӧnsted-Lewis acidic diethyl-disulfoammoniumchlorometallates [dedsa][FeCl4] and [dedsa]2[Zn2Cl6] catalysts for the first (Scheme 37) [218]. H N

OH +

+ (1 mmol)

(1 mmol)

Ph RCHO (1 mmol)

10 mol % of IL 100 °C / Neat

R

45-55 min

N Ph

R= Alkyl or aryl

IL =

HO3S

C2H5 SO3H FeCl4 N C2H5

[dedsa][FeCl4]

77-81 %

HO3S

C2H5 SO3H N C2H5

Zn2Cl622

[dedsa]2[Zn2Cl6]

Scheme 37. Synthesis of 14-aryl-7-(N-phenyl)-14H-dibenzo[a.j]acridines.

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Pyrimidines Pyrimidine is a six membered cyclic aromatic compound with two N-atoms at 1 and 3 positions. This compound has wide occurrence in nature as substituted and ring fused compounds and derivatives including the nucleotides, thiamine (vitamin B1) and alloxan [219]. The ring system is found in many synthetic drugs (Fig. 17) such as barbiturates thiopental sodium (Pentothal), HIV drug zidovudine. Some diaminopyrimidines, such as pyrimethamine or trimethoprim are potential antimalarial drugs. Minoxidil can act as powerful antihypertensive. O O HN O

HO N H

NH2 N

N O

O

C2H5

NH2

N

N3

Pentobarbital

H3CO

O

Cl

CH3

HN

pyrimethamine

Zidovudine

OCH3 OCH3

N

NH2

N

N N

H2N

N

NH2

NH2 Minoxidil

trimethoprim

Fig. (17). Structures of synthetic drugs containing pyrimidine moiety.

The unique nature of ILs as promoter and reaction medium was also investigated for preparation of variety of substituted pyrimidines in different one-pot synthetic strategies with or without catalysts [220 - 222]. The reported methods mostly used 1,3-dialkylimidazolium or alkylpyridinium based ionic liquids which include [bmim][BF4], [emim][BF4] or [bPy][BF4], [bmim][Br], [bmim][PF6] etc. [223 225]. Few reports were found on one pot reactions with functionalized acidic or basic ILs as dual solvent/catalyst systems [226, 227]. R1 CN

NH

R1CHO CN

H2N

NH2.HCl

[bmim]OH MW, 100W, 60oC 2-3 min

R1= Ar, HetAr

CN

N H2N

N

NH2

87-96%

Scheme 38. Synthesis of 2,4-diamino-5-pyrimidine carbonitrile catalyzed/mediated by [bmim][OH].

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The first example of basic IL, [bmim][OH] was employed as dual solvent/catalyst system for three-component synthesis of 2,4-diamino-5-pyrimidine carbonitrile under controlled microwave irradiation at 60°C within 2-3 min (Scheme 38) [226]. This FIL catalyzed protocol of pyrimidines exhibited various advantages such as excellent yield, easy work up procedure, lesser reaction time etc. Me N

SO3H

N HSO4-

[mim(CH2)4SO3H][HSO4]

SO3H

Et3N HSO4-

[Et3N(CH2)4SO3H][HSO4]

IL 1

IL 2

O R1 N

R1

NH2 N Ar

NH2

R2C(OEt)3

Brönsted acidic ILs Solvent-free 80oC

O NH

N N Ar

N

R2

80-93%

R1=H, Me R2=H, Me, Et Ar= Ph, 2,4-(NO2)2-C6H3 Scheme 39. Synthesis of pyrazolo[3,4-d]pyrimidin-4-ones catalyzed by Brönsted acidic ILs.

The acidic FILs were successfully applied as reusable solvent/catalysts systems for construction of pyrazolo[3,4-d]pyrimidin-4-ones [227], pyrido[2,3-d] pyrimidines [228], pyrano[2,3-d] pyrimidines [229], 5H-thiazolo[3,2-a] pyrimidines [230] starting from two component or MCRs reaction mixtures. The presence of Brönsted acidic IL worked as reusable catalyst for heterocyclization of 5-amino1H-pyrazole-4-carboxamides and triethylorthoesters to pyrazolo[3,4-d]pyrimidin-4-ones in neat conditions at 80°C (Scheme 39). Two acidic ILs 3-methyl1-(4-sulfonic acid)butylimidazolium hydrogen sulfate [mim(CH2)4SO3H] [HSO4] (IL 1) and N-(4-sulfonic acid)butyl triethylammoniumhydrogen sulfate [Et3N (CH2)4SO3H][HSO4] (IL 2) were used for this purpose [227]. A three component mixture of 6-amino-2-(methylthio)pyrimidin-4(3H)-one, substituted aromatic/heteroaromatic aldehydes and ethylcyanoacetate or Meldrum’s acid was used for the preparation of pyrido[2,3-d]pyrimidines in presence of 1,2–dimethyl-N-butanesulfonic acid imidazolium hydrogen sulfate ([dmbsi][HSO4]) as reusable solvent/catalyst system under solvent-free medium at 80 °C (Scheme 40) [228].

174 Advances in Organic Synthesis, Vol. 10

Gogoi et al.

SO3H.HSO4

H3C

N

N CH3 [dmbsi][HSO4]

O

O [dmbsi][HSO4]

CN

HN

ArCHO SMe

N

NH2

COOEt

80oC