Condensations introducing potential isoprene units

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ProQuest Number: 10102143

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The writer wishes to express his grateful appreciation to Professor Charles D. Hurd for his supervision, encouragement, and advice throughout this investigation, and to Northwestern University for the University Fellowships which made the work possible.

TABLE OF CONTENTS page I. HISTORICAL................................... 1 Carotenoids* ......................... 1 2 Structure of Vitamin A ..................... Approaches to the Syhthesis of Vitamin A • • 2 Citral in the Synthesis of Vitamin A • • • . 5 P-Methylerotonaldehyde Approach* • • • • • • 6 Methyl Ether of Vitamin A ..................... 10 Use of Acetylene and Vinylacetylene. • • • • 10 Higher Homologs of Vitamin A . * * . * * * * 11 II. PLANS OF APPROACH AND THE RESULTS OBTAINED* . 14 The Plan of Investigation..................... 14 Condensation of Chloroacetone and Various Esters....................................... 15 tf-Chloro-p-hydroxyisovaleronitrile ........ 19 Ethyl X-Chloro-p-hydroxyisovalerate. . . . . 20 Ethyl tf-Chloro-p-methylcrotonate.............20 Ethyl tf-Iodo-p-methylcrotonate ............ 21 (39tf-Dibromoisovaleronitrile................... 23 Reformatzsky Reaction of Ethyl X'-IodorPmethylcrotonate with Benzaldehyde and with Cyclo...................... 24 hexanone. Condensation of p-Ionylideneacetaldehyde with Ethyl ff-lodo-^-methylcrotonate • ...........25 Experiments with tf-Ethynyl-tf-valerolactone . 25 cxf-Benzal- tf-ethynyl- ^-valerolac tone . . . . . 27 &-Acetyl-i?-valerolactone. . ................ 28 III. EXPERIMENTAL. ........................... 31 1. Synthesis of Ethyl tf-Iodo-P-methylcrotonate 31 l-Chloro-3-bromo-2-methyl-2-propanol . . . 31 3-Chloro-2-methyl-1,2-epoxypropane. ... 31 tf-Chloro-/3-hydroxyisovaleronitrile . . . . 32 Ethyl y-Chloro-P-hydroxyisovalerate. . . . 35 Ethyl S-Chloro-P-methylcrotonate ........ 36 Ethyl if-Iodo-P-methylcrotonate.............37 Condensation of Ethyl Bromoacetate with Chloroacetone.............................. 38 Condensation of Ethyl Cyanoacetate with Chloroacetone........................... 39 P-Methylallyl C y a n i d e ...................... 40 .. • 41 Attempted Alcoholysis of -Dibromoisovaleronitrile ........................... 41 2. Reformatzsky Condensations of Ethyl tf-Iodop-methylcrotonate .......... • • • Condensation with Benzaldehyde.......... Condensation with Cyclohexanone • • . • • Condensation with f3-ionylideneacetaldehyde

42 42 44 45

3* Investigations with 5'-Ethynyl-6'-valerolactone • 48 Preparation of 4-Benzal-tf-ethynyl-tf-valerolactone............. 49 tf-Acetyl-f-valerolactone.................. • • 50 Attempted Preparation of Ethyl f-Ethynyltf-hydroxyvalerate. • • • 52 Reaction of tf-Ethynyl-^-valerolactone and Methyl Sulfate. .......... •• ........... 54 IV.

SUMMARY............................................. 55


VITA................................................ 59

CONDENSATIONS INTRODUCING POTENTIAL ISOPRENE UNITS HISTORICAL The carotenoids are a class of polyene pigments which, like the terpenes, may be regarded as constructed of "isoprene units 11 because the most widely distributed members of the class possess molecular formulas in which carbon is some multiple of five.

They occur widely distributed in

both plant and animal structures, and are essentially long chains of carbon atoms arranged in a sequence of conjugated double bonds.

The carotenoids have received considerable

attention not only because of their widespread occurrence in nature as the products of the living cell, but also because several of them have been recognized as progenitors of vitamin A. Carotene, the first to be discovered, is the most abundant in nature and the best known member of the class. 1

It was first isolated by Wackenroder

in 1831 from the root

of the cultivated carrot, and is now known to be a mixture of isomers of which

,6 -carotene is the dominant form.

has been shown to be a provitamin A 5


it is transformed in

the animal body into vitamin A, probably by hydrolysis. CH 3

CH^ y CH 3

, CH 3

+ 2H20 I®-Carotene (1) Gilman, "Organic Chemistry", Vol. II, John Wiley and Sons, New York, 1938, p. 1139.


ch 3

C E \ / CH3

ch 3

-ch=ch-c=chch=ch-c=chch2 oh ~ch3 vitamin A The problem of the synthesis of vitamin A will be discussed since the reactions involved include most of the synthetical approaches to the introduction of isoprene units in a conjugated sequence and, as yet, it may be considered unsolved*

Ho natural

carotenoid has been synthesized although the methods have led 2

to perhydrolycopene,



and to related compounds

containing isoprene units not in a conjugated sequence, such 4

as squalene,




and perhydrovitamin A*


In 1931 Karrer

and his co-workers assigned a structure 6

to vitamin A which was definitely proven in 1933

by the

synthesis of perhydrovitamin A, shown to be identical with the product obtained by hydrogenation of natural vitamin A concen­ trates.

This structure elucidation led to numerous attempts

to synthesize the pure vitamin, one of the first of which was 8

that of Karrer, Salomon, Morf and Walker* the cases,

As in a majority of

^-ionone was chosen as the starting point for the

following series of reactions, in which C 9Hi 5 represents the 2

,6 ,6 -trimethyl-l-cyclohexenyl group,

(2) (3) (4) (5) (6 ) (7) (8 )

Karrer, Helfenstein and Widmer, Helv.Chim.Acta, 11. 1201 (1928) Karrer, Benz and Stoll, ibid., 16, 297 (1933) Karrer and Helfenstein, ibid., 14. 78 (1931) Fischer and Ldwenberg, Ann., 475. 183 (1929) Karrer and Morf, Helv.Chim.Acta, 16, 625 (1933) Karrer, Morf and Schdpp, ibid., 14, 1434 (1931) Karrer, Salomon, Morf and Walker, ibid., 1^., 878 (1932)


CH 3

\ /

CE 3

/ CX ce 2 x cce 2

jC-CH3 un 3 CHS


BrCH2 CpOCaH 5 >

c 9 H 1 5 CH=CH-C=CHC00C3 H 5

reauctl^ '

|?-ionone Ma C 9E 1 7 CE 2 CE 2 CECE2 C00C2 E 5


o 2 Jl5 Un

C 9 H 1 7 CH 2 CH2 CHCH2 CH2Br

C 9 H 1 7 CH2 CH2 CHCE2 CH2 0H

C 9E 1 7 CH2 CE2 CECE2 CE2MgBr

CHS c 9 h 1 7 ce 2 ch2 chch2 ch 2 ch2 och3


CH 3 + (C 9E 1 7 CE 2 CH2 CHCH2 CE 2 ) 2

In the last step of the series the main product resulted from bimolecular condensation and only a small amount of the desired ether was formed* One of the closer approaches to the synthesis of vitamin A 9

was that of Heilbron

and his associates who prepared


ideneacetaldehyde by distilling under low pressure a mixture of barium

fl-ionylideneacetate with barium formate* CH 3 ce3 (C9 H 1 5 CH=CH-C=CHCOO)2Ba + (EC00)2Ba — C 9H 1 5 CE=CHC=CHCE0 + 2 BaC0 3

Reduction of the aldehyde by the action of aluminum isopropoxide gave the corresponding alcohol, a lower homolog of vitamin A which was found to be devoid of vitamin A activity. By the Reformatzsky reaction,


was condensed with ethyl bromoacetate*

Dehydration of the

?h3 C 9H 1 5 CE=CE-C=CECEO + BrCE2 C00C2 E 5 + Zn

CE 3 C 9 H 1 5 CH=CH-C=CHCH-CH2 OE I COOC2 E 5 (9) Davies,Eeilbron,Jones and Lowe, J *Chem.Soc*,1935,584*


hydroxy ester under mild conditions was not possible, and distillation of the barium salt of the corresponding hydroxy acid with barium formate caused a cleavage of the carbon chain, resulting in the formation of


The next step in the series was the condensation of the aldehyde with acetone in the presence of piperidine* GH 3 C 9 Hi 5 CH=CHC=CHCH0 + CH 3 COCH3 ch 3 C 9H i&CH=CHC=CHCHCH2 C0CH 3 OH Dehydration of the hydroxy ketone proved difficult but was 10


accomplished by means of anhydrous oxalic acid*



C 9Hi 5 ch=ch- 6 =chch=ciicoch3

The resulting ketone was condensed with ethyl bromoacetate yielding the difficultly distillable unsaturated ester* CH 3 C 9 H leCH=CHC=CHCH=GHC0 CH 3 + BrCH2 C00C2 H 5 + Zn

CH 3 CHs C 9 H i5 ch=chc=chch=chc=chcooc2 h 5 The ester was hydrolyzed but the resulting acid could not be obtained pure since on attempted recrystallization it was partly converted into an alkali insoluble material* The hydroxy ketone was then condensed with ethyl bromo­ acetate and hydrolyzed to the hydroxy acid*

On pyrolysis of

the barium salt of the acid with barium formate the hydroxy

(10) Heilbron, Jones, Lowe and Wright, J.Chem.Soc•,1936, 561

5. aldehyde was obtained, ch 3 ch 3 (C9H 1 5 CH=CHC=CHCHCH3 C=CHC00)2Ba + (HC00)2Ba OH CH 3 ch 3 2 C 9 H l5 CH=CHC=CHCHCH2 (i=CHCHO + 2 BaC0 3 OH n It has been suggested that the lack of dehydration during the pyrolysis may be due to the existence of the hydroxy aldehyde in the cyclic hemiacetal modification: CH 3

CH 3




This series of reactions Indicate the peculiarities often encountered in the synthesis of conjugated systems related to vitamin A. More recently Heilbron and his co-workers have turned their attention to condensations with citral, believing that this method offers a simpler approach than synthesis of vitamin A.

/?-ionone to the

Citral was found to condense readily

with crotonaldehyde or ^-methylcrotonaldehyde using sodamide 12 ,13 as the catalyst. Two products were obtained with croton­ aldehyde, one the expected citrylidenecrotonaldehyde and the other an isomeric aldehyde which, on the basis of spectroscopic data and microhydrogenation, was shown to be cyclic and to have only three ethylenic linkages.

Likewise, with f3 -methy1-

(11) Abernethy, Ph.D. Dissertation, Northwestern University, August, 1940, p.6 . (12) Heilbron and Jones, Chem. and Ind., 55, 813 (1936) (13) Barraclough, Batty, Heilbron ggd Jones, J.Chem.Soc., 1939. 1549


crotonaldehyde two isomeric aldehydes, pseudo-ionylideneacetaldehydes a and b, were formed hut, in this case, neither were cyclic structures. (CH3 )gC=CHCH2 CH2 C=CHCH0

+ (CHS )2 C=CHCH0


citral CHS CHs (CHs)2C=CHCH2 CH 2 C=CHCH=CHC=CHCH0 pseudo-ionylideneacetaldehyde 14


of the semicarbazones of the two pseudo-

ionylideneacetaldehydes with phosphoric acid gave hexahydronaphthaldehyde derivatives, the products suggesting that the two forms were derived from cis and trans citral.


since di-cyclization occurred, the results were of little interest in the problem of vitamin A synthesis. 15

Zalkind, Zonis and Blokhin

have condensed

/3-ionone with

the magnesium derivative of vinylacetylene to give the tertiary alcohol. C 9Hi 5 CH=CHC0CH3 + XMgC=CCH=CH2


Reduction produced the saturated carbinol whose constitution was established by oxidation to tetrahydroionone and butyric acid.

Biological tests with the unsaturated alcohol showed

that it was not a vitamin. 16 ,17 Several workers have investigated the condensation

(14) Batty, Heilbron and Jones, J.Chem.Soc., 1939. 1556 (15) Zalkind,Zonis and Blokhin, Compt.rend.Acad.Sci.U.R.S.S., 2, 57 (1935); C.A.,-22, 5819 (1935) (16) Beanhauer, Irrgang, Adler, Mattauch, Mttller, and Reiser, Ann ^95 43 Tl936'i (17) Fisher~and Hultzsch, Ber., 6 8 , 1726 (1935)

7. I I !of ^-methylcrotonaldehyde in the hopes of obtaining 3,7-diimethyl-2 .4,6 -octatrienal# (CH3 )2 C=CHCH0 + (CHs )sC=CHCH0

-H 0


;However, efforts to obtain the pure octatrienal were unsuc­ cessful, the products were invariably complex mixtures pro­ duced by further condensations.

These investigators hoped

,to condense the octatrienal with citral, cyclize the result­ ing aldehyde and then reduce it to vitamin A. CHs CH3 (CH3 )2 C=CHCH2 CH 2 C=CHCHO + (CH3 )2 C=CHCH=CHC=CHCH0 citral QK3 CH3 (ch3 )2 c=chch2 ch2 (C=CHCH=CH)2 C=CHCHO


c 9h 1 5 ch=chc=chch=ch§=chcho CIi3 CHs C 9 H 1 5 ch=chc=chch=chc=chch2 oh vitamin A Fuson and Christ 1 8 utilized a similar scheme in their condensation of one mdfe of

/5-cyclocitral with two moles of

j?-methylcrotonaldehyde followed by reduction of the aldehydic product with aluminum isopropoxide. C 9H 1 5 CH0 + (CH3 )2 C=CHCH0 + CCH3)2 C =CIiCHO j^-cyclocitral c 9 h 1 5 ch=chc=chch=ch6 =chcko qii3 ch3 C 9 Hi5 CH=CHC=CHCH=CH6=CHCH2 0H vitamin A The resulting reaction mixture gave a blue color with antimony trichloride in chloroform and an ultra-violet absorption spectrum with a maximum in the vicinity of 328



,Heilbron and Jones 12 have pointed out that in all of their (18) Fuson and Christ, Science, 84, 294 (1936)

8. condensations of citral, crotonaldehyde and


aldehyde considerable quantities of complex materials giving a blue color with antimony trichloride were obtained. was especially true with /3-methylcrotonaldehyde.



it is to be expected that the products of such reactions would have an absorption maximum in the neighborhood of 328 m ^ , and in view of these facts, the authors believe that bio­ logical tests alone would determine the presence of vitamin A in the mixture of Fuson and Christ. 19,20

In 1937 Kuhn and Morris

reported the synthesis of

impure vitamin A by condensing (3 -methylcrotonaldehyde with ^-ionylideneacetaldehyde. C 9H 1 5 CH=CHCOCH3 f3-ionone Q-CH3 C 6 H4KHMgI

The following steps were involved.

BrCHaC0 0 C3 H 5

?h 3 C 9Hi5 CH=CHC=CHCOKHC 7H 7

CHs C 9 Hi 5 ch=chc=chcci=nc 7 h 7 h8 0

CHS c 9h 1 5 ch=chc=chcooc2 h 5


CHs ^ c 9h 15 ch=chc=chch=hc7 h.

CH 3 (CH3 )aC=CHCH0 c 9h 1 5 ch=ch-c=chcho Piperidine + HOAc (3-ionylideneacetaldehyde