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Synthesis of 4-alkyl-1, 4-dihydropyridines and related compounds ; Synthesis and thermolysis of β-cyclopropyl-⍺,… Lau, Cheuk Kun 1978

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SYNTHESIS OF 4-ALKYL-l,4-DIHYDROPYRIDINES AND RELATED COMPOUNDS. SYNTHESIS AND THERMOLYSIS OF 3-CYCLOPROPYL-a,3-UNSATURATED KETONES AND RELATED COMPOUNDS. CHEUK KUN|LAU B . S c , McMaster U n i v e r s i t y , 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept t h i s thes i s as conforming to the required standard by i n THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 1978 CHEUK KUN/LAU, 1978 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l m a k e i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may b e g r a n t e d b y t h e H e a d o f my D e p a r t m e n t o r b y h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t b e a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f C h e m i s t r y T h e U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 - i i -ABSTRACT This thesis i s composed of three separate parts. Part I describes the synthesis of a series of l-carbomethoxy-4-alkyl(aryl)-l,4-dihydro-pyridines by the reaction of pyridine with l i t h i u m phenylthio(alkyl or aryl)cuprate reagents i n the presence of methyl chloroformate. In general, the y i e l d s of the reactions were reasonably good and the reactions were very regioselective. The e f f i c i e n c y of l i t h i u m phenylthio(alkyl or a r y l ) -cuprate reagents i n the preparation of 4-alkyl-l,4-dihydropyridine d e r i -vatives was compared with that of l i t h i u m d i a l k y l ( a r y l ) c u p r a t e s . I t was found that, i n most cases, the former reagents offered no advantages over the l a t t e r reagents. The use of electrophiles other than methyl chloro-formate was also investigated. Acetyl bromide gave reasonable y i e l d s of the corresponding 4-alkyl-l,4-dihydropyridine derivatives but when chlorotrimethylsilane and diethylphosphorochloridate were employed, the yi e l d s of the corresponding 4-alkyl-l,4-dihydropyridine derivatives were f a i r l y poor. F i n a l l y , the l-carbomethoxy-4-alkyl-l,4-dihydropyridines prepared as outlined above were transformed i n good y i e l d s into the corresponding 4-alkylpyridines by treatment of the former with methyl-l i t h i u m , followed by oxidation of the r e s u l t i n g 1-lithio-l,4-dihydropyridine derivatives with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone. The synthesis of l-carbomethoxy-4-alkyl(aryl)-l,4-dihydropyridinesand t h e i r subsequent conversion into the corresponding 4-alkylpyridines introduces a new and f a i r l y e f f i c i e n t way of synthesizing these compounds. Part I I describes the synthesis and thermal rearrangement of a number of B-cyclopropyl-a,B-unsaturated ketones and i n certain cases, t h e i r trimethyl-- i i i -s i l y l enol ether d e r i v a t i v e s . The g -cyc lopropyl -a ,g -unsaturated ketones were prepared i n good y i e l d s from the corresponding g-iodo enones by t r e a t i n g the l a t t e r with l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) -cuprate . The g-iodo enones were obtained i n good y i e l d s by the r e a c t i o n of the corresponding g-diketones 'and a-hydroxymethylenecycloalkanones with tr iphenylphosphine d i i o d i d e . When the c y c l i c g - c y c l o p r o p y l - a , g -unsaturated ketones were thermolyzed, they underwent the expected v inylcyc lopropane-cyc lopentene rearrangement, g iv ing the corresponding annelated cyclopentenes i n reasonable y i e l d s . In the case of a - c y c l o -propylmethylenecycloalkanones, p y r o l y s i s of the corresponding tr imethyl -s i l y l enol ethers gave bet ter y i e l d s of the corresponding spiroannelated cyclopentenes than d id p y r o l y s i s of the parent enones. This new s p i r o cyclopentene annelat ion r e a c t i o n was appl ied to the preparat ion of the sp iro ketone 198, a key intermediate for the synthesis of a number of sp irovet ivane sesquiterpenes . The key steps i n the synthesis of the sp iro ketone 198 involved the preparat ion and thermolysis of the t r i m e t h y l s i l y l enol ether 200. Copper cata lysed conjugate a d d i t i o n of methyl magnesium iod ide to 2-cyclohexen- l -one , fol lowed by trapping of the r e s u l t i n g enolate anion with cyclopropanecarboxaldehyde gave the g-hydroxyketone 203 i n 9^8% y i e l d . O v e r a l l dehydration of 203, v i a base-promoted e l i m i n a t i o n of a c e t i c a c i d from the corresponding acetate 211 gave a 78% y i e l d of a mixture of the g -cyc lopropyl enones 155 and 156, i n a r a t i o of 13:1, r e s p e c t i v e l y . Treatment of the l a t t e r mixture with l i t h i u m d i i sopropylamide , fol lowed by trapping the r e s u l t i n g enolates with c h l o r o t r i m e t h y l s i l a n e gave the enol s i l y l ethers 200 i n 9^5% y i e l d . P y r o l y s i s of 200, fol lowed by h y d r o l y s i s of the crude product , gave a 57% y i e l d of a - i v -mixture of the spiro enone 212 and 213, i n the r a t i o of 2.5:1, respectively. The desired isomer 212 was isola t e d from the mixture and was subsequently transformed into the spiro ketone 198 v i a a straightforward, four-step sequence of reactions. Part I I I describes the synthesis and thermal rearrangement of the t r i c y c l i c enones _39 and related compounds. Reaction of l i t h i u m phenylthio(syn-7-norcar-2-enyl)cuprate (38) with 3-iodo-2-cyclohexen-l-one and 3-iodo-2-cyclopenten-l-one gave the t r i c y c l i c enones 55_ and 56, respectively. I t was thus clear that the i n i t i a l l y formed enones 39 underwent f a c i l e Cope rearrangement to give the t r i c y c l i c enones _55 or 56 during work-up and/or p u r i f i c a t i o n . Reaction of a 1:1 mixture of syn and a n t i l i t h i u m phenylthio(7-norcar-2-enyl)cuprates with 3-iodo-2-cyclohexen-l-one gave a 1:1 mixture of the t r i c y c l i c enones _5_5 and 57. S i m i l a r l y , reaction of the same cuprate reagent mixture with 3-iodo-2-cyclopenten-l-one gave a 1:1 mixture of the enones _56_ and _58. When o-dichlorobenzene solutions of the enones _57_ and _58_ were refluxed, these compounds r e a d i l y rearranged to the t r i c y c l i c enones _5_5 and 56, respectively. TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES v i i ACKNOWLEDGEMENTS v i i i PART I. SYNTHESIS OF 4-ALKYL-l,4-DIHYDROPYRIDINES AND RELATED COMPOUNDS INTRODUCTION 1 I. General 1 I I . Structure 2 I I I . Synthesis of Dihydropyridines 4 IV. Oxidation of Dihydropyridines 25 DISCUSSION 27 I. General 27 I I . Reaction of Lithium Phenylthio(alkyl or a r y l ) - 28 cuprates with Pyridine i n the Presence of Methyl Chlorofonnate I I I . Comparison of Lithium D i a l k y l ( o r diaryl)cuprates 33 with Lithium Phenylthio(alkyl or aryl)cuprates i n the Synthesis of l-Carbomethoxy-4-alkyl(or aryl)-l,4-dihydropyridines IV. Reaction of Lithium Dialkylcuprates with Pyridine 37 i n the Presence of Acetyl Bromide V. Comparison of Different Electrophiles i n the 40 Synthesis of 4-Alkyi-l,4-dihydropyridine Derivatives from the Reaction of Lithium Dialkylcuprates with Pyridine i n the Presence of the Electrophiles VI. Mechanistic Considerations 45 VII. Conversion of l-Carbomethoxy-4-alkyl-l,4-dihydropyri- 49 dines to the Corresponding 4-Alkylpyridines EXPERIMENTAL 54 BIBLIOGRAPHY 72 - v i -Page PART I I . SYNTHESIS AND THERMOLYSIS OF g-CYCLOPROPYL-a,g-UNSATURATED KETONES AND RELATED COMPOUNDS INTRODUCTION 81 I. General 81 I I . Vinylcyclopropane-Cyclopentene Rearrangement 82 I I I . Mechanistic Considerations i n the Thermal Vinylcyclopropane-Cyclopentene Rearrangement 92 IV. The Problem 95 DISCUSSION 97 I. Synthesis of C y c l i c B-Iodo-a,8-Unsaturated Ketones 97 I I . Conversion of g-Iodo-a,B-Unsaturated Ketones into 111 the Corresponding B-Cyclopropyl-a,B-Unsaturated Ketones I I I . Thermolysis of B-Cyclopropyl-a,g-Unsaturated Ketones 117 IV. Application of Thermal Vinylcyclopropane-Cyclopentene 136 Rearrangement to Spirovetivane Synthesis EXPERIMENTAL 153 BIBLIOGRAPHY 189 PART I I I . REACTION OF LITHIUM PHENYLTHIO(7-NORCAR-2-ENYL)CUPRATES WITH CYCLIC g-IODO-a,g-UNSATURATED KETONES AND RELATED REACTIONS INTRODUCTION 199 I. General 199 I I . 1,2-Divinylcyclopropane Rearrangements 199 I I I . The Objective 205 DISCUSSION 206 I. General 206 I I . Reaction of C y c l i c g-Iodo-a,B-Unsaturated Ketones 207 with Lithium Phenylthio(7-norcar-2-enyl)cuprate Reagent EXPERIMENTAL 217 BIBLIOGRAPHY 224 - v i i -LIST OF TABLES PART I Table 0  Page I. Reaction of Lithium Phenylthio(alkyl or aryl)cuprates with 31 Pyridine i n the Presence of Methyl Chloroformate. I I . Comparison of the Use of Lithium Dialkyl(diary1)cuprates with 35 the Use of Lithium Phenylthio(alkyl or aryl) cuprates i n the Synthesis of l-Carbomethoxy-4-alkyl(or aryl)-1,4-dihydropyridines. I I I . Reaction of Lithium Dialkylcuprates with Pyridine i n 39 the Presence of Acetyl Bromide. IV. Comparison of Different Electrophiles i n the Synthesis 44 of 4-Alkyl-l,4-dihydropyridine Derivatives from the Reaction of Pyridine with Lithium Di-n-butylcuprate. V. Conversion of l-Carbomethoxy-4-alkyl(aryl)-l,4- 53 dihydropyridines to the corresponding 4 - A l k y l ( a r y l ) -pyridines. PART I I Table I. Conversion of C y c l i c g-Diketones and a-Hydroxymethylenecyclo- 101 alkanones to the Corresponding g-Iodo-a,g-Unsaturated Ketones. I I . The uv Absorption Maxima ( X m a x ) of Some g-Halo Enones and 106 th e i r Parent g-Unsubstituted Enones. I I I . Conversion of g-Iodo-a,g-Unsaturated Ketones into 115 g-Cyclopropyl-a,g-Unsaturated Ketones. IV. Thermal Rearrangement of g-Cyclopropyl-a,g-Unsaturated Ketones and Related Compounds. 126 - v i i i -ACKNOWLEDGEMENT I wish to express my gratitude to Dr. Edward Piers for his excellent guidance throughout the course of my research. I t has been a very rewarding experience to work under his d i r e c t i o n . My thanks and best wishes are extended to Dr. Isao Nagakura whose collaboration on many problems helped to stimulate the present work. In addition, I wish to thank the other members of our research group for many h e l p f u l discussions. The able typing of t h i s thesis by Mrs. Anna Wong i s appreciated. Also I wish to thank Mr. Dave Herbert, Mr. Pat Jamieson, Mr. Howard Morton, Miss May Lee and Miss Josephine Yeung for proof reading the thesis. The f i n a n c i a l support from the National Research Council of Canada (1975-1978) i s g r a t e f u l l y acknowledged. - 1 -PART I Synthesis of 4 - A l k y l - l , 4 - d i h y d r o p y r i d i n e s and Related Compounds INTRODUCTION I . General Dihydropyridines have been known s ince 1882 when Hantzsch publ ished the synthes is of the f i r s t representat ives of th i s c lass of compounds.^* Dihydropyridines are of considerable i n t e r e s t because of t h e i r p h y s i o l o g i c a l proper t i e s and because of the r o l e they play i n b i o l o g i c a l systems. The 1 ,4-dihydronicot inamide moiety appears i n the reduced forms of nicot inamide adenine d inuc leo t ide (NADH) 1_ and nicot inamide adenine d inuc leo t ide phosphate (NADPH), which 2 are very important hydrogen transfer reagents in b i o l o g i c a l systems. 1 Dihydropyrid ines e x h i b i t a wide v a r i e t y of p h y s i o l o g i c a l a c t i v i t i e s . For example, severa l analogs of 3 , 5 - d i e t h o x y c a r b o n y l - l , 4 - d i h y d r o - 2 , 4 , 6 -3 t r i m e t h y l p y r i d i n e _2 were found to have porphyria inducing a c t i v i t y . Other p h y s i o l o g i c a l proper t i e s of d ihydropyr id ines inc lude antitumor a c t i v i t y , ^ c o r o n a r y d i l a t i n g p r o p e r t i e s , ^ hypertensive a c t i v i t y , ^ 9 a n a l g e s i c , spasmolytic and l o c a l anesthet ic a c t i v i t y . Some d i h y d r o -pyr id ines have found use as herb ic ides and d e f o l i a n t s -2-Dihydropyridines are important intermediates i n c e r t a i n reactions 11 12 of pyridines, for example, nucleophilic s u b s t i t u t i o n s , reductions, 13 and acylations i n the presence of pyridine. Dihydropyridines which are read i l y convertible to pyridines also serve as important precursors of 14 the l a t t e r . Studies directed towards understanding the nature of the hydrogen transfer mechanism of the coenzyme NADH (or NADPH) have stimulated the synthesis of a wide v a r i e t y of model dihydropyridines, e s p e c i a l l y , 1,4-dihydropyridines. A large number of highly substituted dihydropyridines have been synthesized by the Hantzsch and related r i n g closure methods and by the reduction of the pyridine r i n g by complex hydrides."''"' Grignard reagents and organolithium reagents react with simple pyridines to give dihydropyridines i n which the 1,2 isomer i s always the major product."'""' U n t i l recently, i t has been quite d i f f i c u l t to synthesize simply substituted 1,4-dihydropyridines. I I . Structure Theoretically, dihydropyridines can ex i s t i n f i v e isomeric forms, (3_-7) , but almost a l l known dihydropyridines have either the 1,2- or the 1,4-dihydrostructure (3 and h_, respectively) ."''"' This can be explained by the p a r t i c i p a t i o n of the unshared pair of electrons on nitrogen i n the IT electron system of these two isomers. The isomers 3_ and 4_ have 2 the highest number of sp -hybridized centers. 4 H ' N' I H -3-•N- -N-1 A I A 1 The structure of dihydropyridines has been the subject of much research and controversy. The incorrect s t r u c t u r a l assignment of the 1,4-dihydropyridine derivative 2_ obtained from the reaction of ethyl acetoacetate, acetaldehyde, and ammonia as a 2,3-dihydropyridine derivative by Hantzsch^ resulted i n a l o t of confusion i n subsequent studies concerning the structure of dihydropyridines, p a r t i c u l a r l y with regard to the d i s t i n c t i o n between 1,2 and 1,4 isomers. This was p a r t i c u l a r l y serious i n the case of the coenzyme NADH, 1_, which was erroneously i d e n t i f i e d as a 1,2-dihydropyridine^ u n t i l i t s structure 17 18 was unambiguously established by deuterium l a b e l l i n g . ' Now, modern spectroscopic methods can r e a d i l y d i s t i n g u i s h between the two types of isomers and unambiguous assignment of structure i s r e l a t i v e l y s t r a i g h t -forward . The r e l a t i v e s t a b i l i t i e s of 1,2- and 1,4-dihydropyridines appears s t i l l to be somewhat open to question. HMO calculations on the ir systems of the dihydropyridine r i n g systems indicate that the 1,2 isomer i s more 19 20 stable. However, studies on hydrogen-transfer reactions and e q u i l i -19 21 bration ' indicate that the 1,4-dihydropyridines are thermodynamically more stable than the corresponding 1,2 isomers. Dihydropyridines are, i n general, very reactive compounds. They 22 23 are very susceptible to oxidation by a i r ' and most of them decompose 24 readily when l e f t i n contact with a i r . For example, the dihydropyridine derivative 8_ was a i r - o x i d i z e d to the substituted pyridine 9^  i n ca. 20h - 4 -( e q . l ) . 23 When e lec tron-wi thdrawing subs t i tuents capable of resonance R R'. J N H ca.20h a i r N (1) 8 9 i n t e r a c t i o n (COR, CO2R, CN, M ^ ) are present on the 3 and 5 p o s i t i o n s , the d i h y d r o p y r i d i n e system i s cons iderab ly more s tab le than the un-s u b s t i t u t e d case . On the other hand, e l ec t ron-donat ing subs t i tuent s at 25 these p o s i t i o n s d e s t a b i l i z e these compounds. A l k y l s u b s t i t u t i o n on n i t rogen has a mi ld s t a b i l i z i n g e f f e c t , whi le a g l y c o s y l subs t i tuent on n i t r o g e n appears to have a remarkable s t a b i l i z i n g e f f e c t . For example, d i h y d r o p y r i d i n e 10_ can be r e c r y s t a l l i z e d from a c e t i c a c i d -26 water i n the form of pale ye l low needles . Highly s u b s t i t u t e d d i h y d r o -p y r i d i n e s seem to be l ess r e a c t i v e than those that are unsubs t i tu ted ; t h i s may be due, at l e a s t i n p a r t , to s t e r i c reasons. I I I . Synthesis of D ihydropyr id ines There are two b a s i c methodologies for prepar ing d i h y d r o p y r i d i n e s ; one i n v o l v i n g the a d d i t i o n of var ious reagents to a p y r i d i n e r i n g and Ph 10 -5-the other involving d i r e c t formation from a l i p h a t i c reagents, as i n the Hantzsch and related syntheses. A. Hantzsch Synthesis and Related Condensations The o r i g i n a l Hantzsch synthesis of dihydropyridines involved the condensation of ethyl acetoacetate with an aldehyde i n the presence of ammonia. The product of th i s reaction was the highly substituted 1,4-dihydropyridine 11, as shown i n eq.2.^ This method has been widely used 27-29 for the preparation of the dihydropyridines 1_1, where R i s an a l i p h a t i c , 30-32 30 31 33 aromatic or heterocyclic residue. ' ' P ri o o \y O E t O ^ N ^ , / N ) E r ^ E t O - ^ Y | f ^ O E t ( 2 ) 11 (a) R=CH3; (b) R=C6H4N02; (c) R=H; (d) R=C6H5; (e) R=CH2CN The Hantzsch synthesis, as o r i g i n a l l y devised, has been modified i n a great variety of ways. The aldehyde component has been replaced , , „ 34,35 . . . . ,36,37 , ... . , 38 by ketones, g l y o x y l i c acid and p r o p i o l i c acid. Ammonium 25 39 40 41 42 43 acetate, formamide, hexamethylenetetramine, ' primary amines ' 44 45 and hydrazine ' have been used as substitutes for ammonia as the source of nitrogen. F i n a l l y , the active methylene component has been modified most extensively. The o r i g i n a l l y employed ethyl acetoacetate 46 47 25 has been substituted by 1,3-diketones ,' and w-cyanoacetophenone to give 3,5-diacyl-l,4-dihydropyridines 12_ and 2,6-diphenyl-3,5-dicyano-l,4-dihydropyridines 13, respectively, as shown i n eq.3 and 4. S i m i l a r l y , the phenylthioether 2A_ reacts with benzaldehyde and ammonium acetate to give -6-dihydropyridine 15 (eq.5) 25 A R H NH, O t / O ! H 12 (3) NC-P h -Y NH4OAc , HOAc R H N'C\ X /CN P h ' 13 (4) PhS P h / ^ 14 NH,OAc 4 HOAc O-'SPh -Ph H Ph P h S ^ J X l ^ S P h X X I H 15 (5) Enamines can also be used to replace ethyl acetoacetate. For example, enamines of general structure 1_6_ react with aldehydes to give 9 31 48 the dihydropyridines 17_ (eq.6). ' ' 1,5-Diketones preformed from the reaction of an aldehyde with an active methylene compound provide another v a r i a t i o n on the Hantzsch synthesis. For example, diketone 18, derived from condensation of ethyl acetoacetate and formaldehyde, reacts 49 with ammonia to give the dihydropyridine 11c. In a s i m i l a r fashion, the bis-enamine 19_ formed from the reaction of 3-aminocrotononitrile with an aromatic aldehyde was cycliz e d to the dihydropyridine 20 (eq.8).~^ Aldehydes can also condense with active methylene compounds to give a, 8 -unsaturated ketones such as 21. These l a t t e r compounds can react with an enamine or with a ketone and ammonia, to give the unsymmetrical 1,4 •dihydropyridines 22 (eq.9).^^ + RCHO -NH, R' - 2 16 H y R r ! AM> \ r 1 H 17 17(a) R=aryl, R ^ a l k y l , X=CC>2Et; (b) R^CHg, X=CN; (c) R^Ar, X=CN EUMH ^ CH3COCH2C02Et + HCHO --2 i? NH3 Et OEt 18 11c -8-B. Preparation from Pyridine Derivatives 1. Reduction with Complex Hydrides A number of dihydropyridine derivatives have been prepared by reduction of the corresponding pyridines or pyridinium s a l t s with complex metal hydrides. Sodium borohydride reduces pyridine and pyridinium s a l t s , usually 12 52 to an isomeric mixture of 1,2-, 1,4- and/or 1,6-dihydropyridines. ' Depending on the conditions of the reactions and on the type of sub-stituents present on the pyridine r i n g , the dihydropyridines formed by the i n i t i a l attack of the hydride ion may undergo further reduction to tetrahydropyridines or may be isolated without further reduction. For example, the pyridinium s a l t 23_ was reduced by sodium borohydride i n methanolic sodium hydroxide to the corresponding mixture of 1,2- and 1,6-dihydropyridines, which were isolat e d as stable tricarbonyl chromium 53 complexes 24_ and 25, respectively (eq.10). In a more recent study, i t was reported that the pyridinium s a l t Z3 could be reduced by sodium borohydride i n a two phase system (ethyl ether, aqueous methanol containing sodium hydroxide) to the corresponding 1,2-dihydropyridine only, and i n good 54 y i e l d . In contrast, reduction of the pyridinium s a l t 26^  by sodium borohydride gave a mixture of the corresponding tetrahydropyridine 27 and the piperidine 28_ ( e q . l l ) . ^ ^ 1. NaBH4,CH3OH,NaOH > 2. (CH 3CN) 3Cr(CO) 3 Cr(CO)3 + Cr(CO)3 (10) 25 -9-26 27 28 Pyridine i t s e l f can also be reduced by sodium borohydride i n the presence of an ele c t r o p h i l e to give N-substituted dihydropyridines. ' Thus, reduction of pyridine by sodium borohydride i n the presence of methyl chloroformate afforded a mixture of the 1.4- and 1,2-dihydropyridi 29 and 30 (eq.12), 5 6 C£C0„Me (12) C02Me CO,Me 29 30 3-Cyanopyridine 31_, when reduced by sodium borohydride i n an aprotic solvent (for example, diglyme), produced the corresponding 1,4-dihydro-5 8 pyridine 32_. In pr o t i c solvents (for example, ethanol) further reduction 58 to the tetrahydropyridine 33_ occurred. S i m i l a r l y , the 3-cyanopyridinium s a l t 34a was reduced by sodium borohydride i n methanol to a mixture of the corresponding d i - and tetrahydropyridines 36a and 37a, respectively.^»61 In a l k a l i n e sodium borohydride, the corresponding 1,2- and 1,6-dihydropyridines 35a and 36a, respectively,were formed i n s t e a d . ^ > ^ j n contrast, the p y r i -dinium s a l t 34b was reduced by sodium borohydride i n methanol to the corresponding dihydropyridines 35b and 36b without being further reduced to tetrahydropyridines.^ Reduction of the nicotinamide derivatives 34c and 34d by sodium borohydride afforded mainly the corresponding 1,6-dihydro-pyridines 36c and 36d, respectively. 65 -10-31 CN NaBH, diglyme • CN NaBH, •N-A 32 EtOH -> CN 33 (13) NaBH, -N R 34 I R 35 I R 36 (14) R 37 34 (a) R=CH3, Y=I, X=CN; (b) R=2,6-Cl 2C 6H 3CH 2, Y=Br, X=CN; (c) R=CH3, Y=MeOS03 X=C0NH2; (d) R=n-Pr, Y=I, X=C0NH2 Pyridines and pyridinium s a l t s having electron-withdrawing substituents on both the 3 and 5 positions, can be reduced re a d i l y by sodium borohydride to the corresponding dihydropyridines. These l a t t e r compounds are less susceptible to further reduction than the i r monosubstituted or unsubstituted counterparts. Thus, the disubstituted pyridines 38a, 38b, 3 8 c 5 2 > 6 ^ ^ 8 and the pyridinium s a l t 4 1 6 9 were reduced by sodium borohydride to the corresponding mixtures of dihydro-pyridines as shown i n eq. 15 and 16. X> NaBH, 38 X 4 40 (15) 38(a) X=CN; (b) X=C02Me; (c) X=C02Et, (d) X=C0CH3 -11-The r a t i o of 1,4 to 1,2 isomers formed i n the reduction reactions was found to be highly solvent dependent, ranging from 87:13 i n pyridine 52 to 37:63 i n a c e t o n i t r i l e for the diester 38c. In contrast, sodium cyanoborohydride reduced 38b, 38c and 38d to the corresponding pure 52 1,4-dihydropyridines. The r e g i o s e l e c t i v i t y of the reduction also depends on the position of a l k y l substituents on the r i n g . Thus, sodium borohydride reduction of 3,5-dicyano-4-methylpyridine 44 and 3,5-dicyano-2, 6-dimethylpyridine 46_ afforded only the dihydropyridines 45_ and 47_ respec--] 67,70 txvely. (17) H 44 45 (18) Occasionally, reduction of functional groups present on the substituents by sodium borohydride may become a serious problem. For example, the diester 48_ was reduced mainly to the monoester 4 9 ^ and the diketone _50_ was reduced mainly to the d i o l 5_1. In each case only small amounts of the corresponding dihydropyridine was formed. -12-0 O NT 50 (19) 51 Lithium aluminum hydride, a very strong reducing agent, reduces pyridine or i t s a l k y l derivatives less s e l e c t i v e l y than the milder reducing agent, sodium borohydride. For example, a-picoline 5_2 was reduced by lith i u m aluminum hydride to a mixture of the tetrahydropyridine 53 and the piperidine 5_4.71 S i m i l a r l y , 1,3-dimethylpyridinium iodide 26_ 72 was reduced exclusively to the tetrahydropyridine 27 . 52 LiAlH, 53 54 (20) (21) 26 27 Very often, when lith i u m aluminum hydride i s employed, functional groups present on the substituents are reduced more readily than the 12 aromatic r i n g . For example, methyl nicotinate underwent reaction with lit h i u m aluminum hydride with exclusive reduction of the ester function 73 (eq.22). The only preparatively useful reaction i s that of 3,5-dicyanopyridine i n which the ring i s reduced more readily than the n i t r i l e -13-groups (eq.23). 67 _ r n .. LiA£H. 55 •N 56 CH2OH (22) LLAHH N N I H 40a (23) 2. Addition of Organometallic Reagents Certain organometallic compounds react with pyridine, pyridinium s a l t s and pyridine oxides to form dihydropyridines. A l k y l l i t h i u m or a r y l l i t h i u m reagents react with pyridine and a l k y l pyridines to give 2-substituted l - l i t h i o - l , 2 - d i h y d r o p y r i d i n e s which can be hydrolysed to the corresponding 1,2-dihydropyridines (eq.24) 74-79 or react with an el e c t r o p h i l e to give N-substituted 1,2-dihydropyridines (eq.25) , 7 8 R'Li (24) -14-Pyr id in ium s a l t s and t h e i r a l k y l d e r i v a t i v e s react with a l k y l -or a r y l l i t h i u m reagents and with Grignard reagents to give mainly the corresponding 1 ,2 -d ihydropyr id ines For example, the pyr id in ium s a l t 80 60 reacts wi th pheny l l i th ium to give the d ihydropyr id ine 61_ and . j . . , „ 81 , ,82-84 . , ,85 ,86 . . „ . pyridmxum s a l t s j)2_, 64_ and bo_ react with Grignard reagents to give the 2 -subst i tuted 1 ,2 -d ihydropyr id ines 63, 65 and 67, respectively. I x -Mc P h L i -> I H Me Ph (26) 60 61 62 RMgBr R=Et, Ph PhCH2MgX -> CHjPh (27) (28) 65 R'MgX -> COjEt 67 (29) Reaction of p y r i d y l ketones 68_ with Grignard reagents a f fords the -15-87 88 corresponding 1,4-dihydropyridines 69_. ' However, quaternary s a l t s of n i c o t i n i c esters or n i t r i l e s 70_ react with Grignard reagents to give mainly the corresponding 1,6-dihydropyridines _7_1, accompanied 89 90 by minor amounts of the 1,2-dihydro isomers 7_2. ' , C 0R 1) PhMgBr -> 2) H20 H Ph I H COR (30) 68 69 (31) 70 71 J_2 70 (a) Y=C00R2 ; (b) Y=CN Normally, Grignard reagents react with pyridine molecules containing electron-withdrawing groups at the 3 and 5 positions to give a mixture of 1,2- and 1,4-dihydropyridines. For example the disubstituted pyridines 38a, 38b and 38c react with methyl magnesium iodide to afford a mixture 27 37 68 of the corresponding dihydropyridines 73 and 74, respectively (eq.32) ' ' ' (32) 38(a) X=CN; (b) X=C02Me; (c) X=C02Et; (d) X=C0CH3 -16-In some cases, the Grignard reagent attacks the substituents rather than the r i n g moiety. In the case of 38d, for example, the major product of the reaction i s the d i o l formed by attack of the Grignard reagent on the carbonyl group. Recently, i t was found that organocadmium reagents, formed from the reaction of cadmium chloride with Grignard reagents, give good yie l d s of r i n g addition without concommitant addition to the carbonyl substituents on the pyridine 86 ri n g . For example, the pyridinium s a l t 75 reacts with phenyl magnesium bromide to give the corresponding dihydropyridines _76 and 77 together with a f a i r amount of the diphenyl-3-pyridylcarbinol 78. With the phenyl cadmium reagent, none of the py r i d y l c a r b i n o l was i s o l a t e d (33) COPh COPh COPh 75 7_6 _77 78 M = MgBr 13% 49% 15% M = Cd 19% 61% 0% 3. Addition of Other Nucleophiles Pyridine and pyridinium s a l t s also react with a wide v a r i e t y of other nucleophiles to give dihydropyridine derivatives. For example, 94 sodium hydrazide reacts with 2,6-lutidine to give the adduct J9_ and sodium methoxide reacts with 4-methoxy-3,5-dinitropyridine to give the 95 compound ^0_. S i m i l a r l y , pyridinium s a l t s react with a wide range of nucleophiles such as carbanions derived from ketones, d i e t h y l malonate, -17-malononitrile, cyanoacetic esters and nitromethane to give 1,4-96—99 dihydropyridine derivatives. For example, the pyridinium s a l t 81 reacts with acetone i n the presence of strong base to give the 1,4-dihydropyridine 82_ (eq.36) and pyridinium s a l t 8^3 reacts with the enolate anion derived from d i e t h y l malonate to give the dihydropyridine 99 84, which was then cy c l i z e d to the dihydropyridine 235. (eq.37). 'N' OMe NaNHNH, NaOMe -> yNHNH2 (34) (35) CX=CHAr 81 CH3COCH3 OH H CH2COMe CXnCHAr 82 (36) + X H CH(C02Et)2  C 0 N H 2 -CH(C0^Et)2>yCONH2 -EtOH 83 CH2R 8 4 C H 2 R (37) Di t h i o n i t e reduction of pyridinium s a l t s to dihydropyridines also proceeds by nucleophilic attack to form the intermediate sodium s u l f i n a t e derivative (for example 87) which then decomposes i n acid to the corres-ponding dihydropyridine ( e q . 3 8 ) . ' A number of 3-substituted and -18-3,5-disubstituted dihydropyridines have been prepared this way. 24,89,102-105 R 86 Rl II „-K s - 0 .CONH-) r R 87 H R ' V ' ^H CONH, 88 V Li) •N I R 89 t SO, (38) Cyanide ion, which has a lower n u c l e o p h i l i c i t y than the reagents discussed above, reacts only with the more electron-deficient pyridinium s a l t s , preferably those that have electron-withdrawing substituents on the 3 and 5 positions, to give the corresponding 1,4-dihydropyri-21,75,106-109 . - j . • , dines. For example,pyridinium s a l t 90_ reacts with cyanide ion i n dimethyl sulfoxide to give the adduct 91, which was isolated. 7"' However, the formation of the 1,4-dihydro n i t r i l e adduct i s usually reversible"*""^ and the adducts are usually very unstable. For example, the cyanide adducts 92, which have been detected spectroscopically, were not i s o l a t e d but were readily transformed to cyanopyridines 93 (eq.40).^"^ .CONH2 -CN I l -Me DMSO H CN CONH, (39) 90 91 H CN I OR 92 93 COX (40) -19-4. Other Methods Dihydropyridines can also be prepared by reduction of pyridines or pyridinium salts with metals. Thus, reduction of 4-alkylpyridines 94 by zinc in either acetic anhydride or an acid chloride gave the corres-112 ponding 1,4-dihydropyridines 95_. With unsubstituted pyridine, the A- Q r r A • * A H3-115 dimer 96 was formed instead. Zn, R*COC£ COR' (41) Zn,(RCO)20 ROC —N N—COR (42) Electrolytic reduction of the pyridinium salt 90_ at controlled potentials allowed the isolation of either the dihydropyridine 97_ or ,. n Q 116,117 the dimer 98. ' HjNOC N Me CONH2 <— N I Me -1.2V 98 ^CONHo „ - + N Me 90 -1.8V N Me 97 ,CONH2 (43) Catalytic hydrogenation can also be used to prepare dihydropyridines. For example, hydrogenation of the disubstituted pyridines 38a, 38b, 38c -20-and 38d yielded i n each case a mixture of the corresponding 1,2- and 1,4-dihydropyridines, with the 1,2 isomer p r e d o m i n a t i n g . 1 1 8 ' 1 1 9 1 mole of Hr Pd 38 ^ N -I H 39 (44) I H 40 X = CN, C02Me, C0 2Et, C0CH3 C a t a l y t i c s i l y l a t i o n of pyridine by trimethylsilane gave a complex 22 120 mixture from which the dihydropyridines 100 and 101 were i s o l a t e d . ' Methanolysis of 101 lib e r a t e d the parent, 1,4-dihydropyridines 105 (eq.46) Me3SiH/Pd I Si Me. 102 5.8% + N-I SiMe3 12% 99 I SiMea <25% 100 N I SiMe, 35% 101 SiMe3 + Me«5i-N •f Si Me. 103 0.2% 25% 104 N—SiMe, (45) 101 Si Me* CH30H H 105 + CH 3OSiMe, 121 Alkylpyridines have been reduced by li t h i u m i n ammonia. In the presence of an elect r o p h i l e (for example, an a l k y l h a l i d e ) , the N-substituted 1,4-dihydropyridine 107 was isolated (eq.47). (46) -21-1. Li.'NH ,EtOH N 106 R = H,CH„ 2. R 1X (47) R =CH3, Et, n-Pr Diborane reduces the diester 38c to the corresponding mixture of 52 1,4-and 1,2-dihydropyridines (eq.48). The reduction i s solvent dependent. In pyridine, the 1,4 isomer i s the major product while i n tetrahydrofuran, the 1,2 isomer predominates. Cycloaddition reactions have also been applied to the preparation of dihydropyridines. Thus, dimethyl acetylenedicarboxylate 108 reacts with the Schiff base 109 to give the 1,2-dihydropyridine 110 (eq.49). 1' Similarly,l-dimethylamino-3-methyl-2-azabutadiene 111 reacts with the 123 diester 112 to give the 1,4-dihydropyridine 113. Me02CECC02Me + C6H5CH=NR 108 109 Q 2Me MeOjC C0 2Me H (49) R 110 -22-+ -C02Me — - > (50) CQ2Me NMe« 111 112 113 Dihydropyridines have also been prepared from other heterocyclic compounds. For example, pyrolysis of the homoazepine 114 afforded l-ethoxycarbonyl-2-vinyl-l,2-dihydropyridine 115 (eq.51) 124 Pyro l y s i s of d i e t h y l 2-azo-2-benzyloxycarbonyl-l,3-dimethylbicyclo [3.1.0]-hex-3-ene-4,6-dicarboxylate 116 gave the 1,2-dihydropyridine 117 125 Hydrogen halides react with the 4H-azepine 118 to give the dihydropyridine 119 (eq.53)." 126 Oxidation of the t r i c y c l i c compound 120, followed by spontaneous nitrogen extrusion from the intermediate 121,afforded the 127 N-substituted 1,4-dihydropyridine 122 (eq.54). 114 A (51) E t ° 2 \ /" I C02CH2Ph 116 / \ E , ° 2 C N' COjEt 117 (52) -23-(54) R 120 121 122 R = C 6H 5S0 2 ; C 6H 5 ; Me ; C ^ C ^ C H . C. Regioselective Synthesis of Simply Substituted 1,4-Dihydropyridines. Objectives of the Work Described i n this Thesis. Of the variety of methods which can be employed i n the synthesis of dihydropyridines, the Hantzsch type synthesis has been the most productive. Indeed, hundreds of substituted dihydropyridines have been prepared v i a this method. However, r e l a t i v e l y few simple dihydropyridines have been prepared, since the Hantzsch synthesis works best for the preparation of dihydropyridines that have electron-withdrawing substituents on both the 3 and 5 positions. Furthermore, reduction of pyridinium s a l t s by sodium borohydride i s successful only i f strongly electron-withdrawing groups are present on the pyridine r i n g . Almost no success has been achieved with the reduction of the free base. The major d i f f i c u l t i e s l i e i n the ease with which the p a r t i a l l y reduced pyridines are further reduced to tetrahydropyridines and piperidines, and the readiness with which the dihydropyridines isomerize, oxidize and polymerize. Addition of organo-m e t a l l i c reagents to pyridines gives mainly 1,2-dihydropyridines which are not very useful as model compounds for probing the mode of action of enzymes that bear a 1,4-dihydropyridine structure. Addition of other nucleophiles to pyridine also leads to highly substituted dihydropyridines. In view of these f a c t s , i t appeared that there was s t i l l a need for better methods of making simply substituted 1,4-dihydropyridines. C a t a l y t i c -24-s i l y l a t i o n of pyridine or a l k y l pyridines does give simple 1,4-dihydro-pyridines, but a complex mixture of side products always accompanies the desired product. In 1974, our research group had developed a new, regioselective method for synthesizing 4-substituted 1,4-dihydropyridines by reacting pyridine with l i t h i u m dialkylcuprates i n the presence of chlorof ormate." Thus,addition of methyl chloroformate to a solution of pyridine and the d i a l k y l (or aryl) cuprate reagent i n ether, afforded i n good y i e l d a mixture of the corresponding 1,4- and 1,2-dihydropyridines, i n which the 1,4 isomer predominated (> 89% of the product)(eq.55). The present section of th i s thesis i s concerned with results obtained from a continuation 128 N-R 2CuLi C£C02CH3 + (55) C0 2Me 123 I C0 2Me 124 R= (a) CH3; (b) CH3CH2; (c) n-Bu; (d) ^-Bu; (e) i - P r ; (f) C ^ ; (g) v i n y l 128 of that work. In the e a r l i e r work,"""'"" i t was found that l i t h i u m dialkylcuprate reagents are quite e f f i c i e n t i n transferring a primary a l k y l group to the 4-position of the pyridine r i n g . However, the reaction was not very e f f e c t i v e i n the case of cuprate reagents containing secondary and t e r t i a r y a l k y l groups. In work described i n this thesis, mixed cuprates [lithium phenylthio(alkyl or aryl)cuprates] were investigated and compared with l i t h i u m dialkylcuprates i n the aforementioned type of reaction. -25-Electrophiles other than chloroformate were also investigated. F i n a l l y , the 4-substituted 1,4-dihydropyridines synthesized were converted to the corresponding 4-substituted pyridines. Thus, this work provided a new synthesis of simple 4-alkyl and 4-aryl pyridines. IV. Oxidation of Dihydropyridines According to one author, "the most important reaction of dihydro-14 pyridines i s t h e i r oxidation to the corresponding pyridines." This i s understandable i n view of the important role of NADH i n hydrogen transfer processes i n b i o l o g i c a l systems and the role dihydropyridines play as intermediates i n the reactions of pyridines. Dihydropyridines can be oxidized by a wide va r i e t y of reagents. The oldest and s t i l l most commonly used reagents are nitrous or d i l u t e n i t r i c ., 1,44,48 , , 129,130 _ . . ... , ... acids, and chromic acid. For example,the dihydropyridine 125 was oxidized to the corresponding pyridine 126 by 20% n i t r i c acid (eq.56).^ High potential quinones such as c h l o r a n i l ^ 7 or dichloro-131 dicyanoquinone are also quite commonly used. For example, dihydropyridine 127 was oxidized by c h l o r a n i l i n r e f l u x i n g benzene to give the corresponding pyridine derivative 128 (eq.57).^ 7 S i l v e r nitrate 8"*"'"*"^ 2 and i o d i n e " ^ 2 have also been employed (for example, eq.58). Sulfur i s often used because i t 28 29 i s least l i k e l y to give side reactions. ' C a t a l y t i c dehydrogenation 133 13^ 133 by platinum and palladium ' have also been employed. Other reagents include p_-nitrosodimethylaniline,^ hydrogen peroxide, 137 138 diisoamyl d i s u l f i d e , mercuric acetate, and iron or n i c k e l carbonyls."^ 7 Oxygen or a i r have been employed i n a number of instances , , 1 23,132,139 (example, eq.1,58) R H2C 0, N' 1 2 CH R or I or AgNO 2 R]H2C (58) 129 CH2R 130 -27-DISCUSSION I . General In studying the react ions of l i t h i u m d i a l k y l c u p r a t e s with p y r i d i n e i n the presence of methyl chloroformate, i t was found that when the l i t h i u m d i - s^buty lcuprate reagent was employed, the reac t ion was not always r e p r o d u c i b l e . This l ack of r e p r o d u c i b i l i t y might be a t t r i b u t e d to the low thermal s t a b i l i t y of sec-alkylcuprat'es i n g e n e r a l , a 141 c h a r a c t e r i s t i c which was recognized by Posner e_t a l . In an attempt to circumvent th i s l i m i t a t i o n , Posner e_t al_.synthesized a ser i e s of he tero (a lky l ) cuprate reagents [Het(R)CuLi (Het=t-BuO,PhO,t-BuS,PhS,Et 2 N)] and compared them with other organocopper reagents for t h e i r s e l e c t i v i t y and e f f i c i e n c y i n t r a n s f e r r i n g an a l k y l group to severa l d iverse types of 141 organic substrates . I t was found that l i t h i u m pheny l th io (a lky l )cuprates PhS(R)CuLi were super ior to other he tero (a lky l )cuprate reagents and l i t h i u m d i a l k y l c u p r a t e s i n t r a n s f e r r i n g secondary a l k y l groups i n s u b s t i t u t i o n and conjugate a d d i t i o n reactions". For example, i i - o c t y l iodide undergoes replacement of iod ide by a js-butyl group when treated with two equivalents of l i t h i u m pheny l th io ( s -buty l ) cuprate to give a 67% y i e l d of the corresponding alkane 131. With l i t h i u m _t-butoxy ( s -buty l ) cuprate , the y i e l d of the coupl ing product 131 was 52%. However, only 7% of 131 was i s o l a t e d when f ive e q u i -141 va lents of l i t h i u m di-s_-butylcuprate were employed (eq.59) . R(s-Bu)CuLi n - C g H 1 7 I > B - C 8 H 1 7 - ± - B u ( 5 9 ) solvent 131 R Y i e l d (a) PhS 67% (b) t-BuO 52% (c) s-Bu 7% -28-These observations triggered our investigation of the reaction of lithium phenylthio(alkyl or aryl)cuprates with pyridine i n the presence of methyl chloroformate. I I . Reaction of Lithium Phenylthio(alkyl or aryl)cuprates with Pyridine i n the Presence of Methyl Chloroformate. Our i n i t i a l studies were carried out with lithium phenylthio-128 (n-butyl)cuprate 132c. Following the procedure of Piers and Soucy, a four f o l d excess of methyl chloroformate was added to a solution of pyridine (one equivalent) and the cuprate reagent (1.4 equivalents) i n tetrahydrofuran at -78°C. After the reaction mixture had been s t i r r e d for 3h at -78°C, a small amount of methanol was added. The d i s t i l l e d product obtained after work-up was analysed by gas-liquid chromatography (glc) and proton magnetic resonance ("*"Hnmr) spectroscopy. I t was found that the major product of the reaction was methyl phenylthioformate 133, along with some of the expected l-carbomethoxy-4-n-butyl-l,4-dihydropyridine 128 123c (eq.60). An a n a l y t i c a l sample of each of the two products was obtained by preparative glc. The "Hlnmr spectrum of 133 was i d e n t i c a l with that of an authentic sample of the same material obtained by the reaction of thiophenol and methyl chloroformate i n the presence of aqueous sodium hydroxide. However, when the amount of methyl chloroformate used i n the above reaction was reduced from four equivalents to one equivalent, the desired product, l-carbomethoxy-4-n-butyl-l,4-dihydropyridine 123c was obtained i n ^65% y i e l d . Under these conditions, the amount of side product, methyl phenylthioformate 133,was reduced to VL4% of the product mixture. No trace -29-of the corresponding 1,2-dihydropyridine derivative was found. R ClC0„CHo I + PhS(R)CuLi + PhSC02Me 132 C0 2Me 123 133 132(a) R=CH ; (b) R=Et; (c) R=n-Bu; (d) R=s-Bu; (e) R=_t-Bu; (f) R=Ph Compound 123c exhibited the c h a r a c t e r i s t i c 1,4-dihydropyridine "Slnmr pattern. The protons at C-2 and C-6 resonated as a two-proton doublet centred at T3.20, with coupling constant J=8 Hz. The protons at C-3 and C-5 gave r i s e to a two-proton doublet of doublets centred at T5.13 (J=8 Hz, J'=2 Hz). F i n a l l y , the proton at C-4 produced a one-proton multip l e t centred at x7.05 and the protons of the carbomethoxy group appeared as a three-proton s i n g l e t at T6.20. The i r spectrum of 123c showed a strong carbonyl absorption at 1730 cm and two other absorption peaks at 1633 and 1690 cm \ In a s i m i l a r fashion, the aforementioned procedure was extended to include the use of other l i t h i u m phenylthio(alkyl or aryl)cuprate reagents. Some of the results obtained are summarized i n Table 1. A l l of the dihydropyridine derivatives l i s t e d i n Table 1 exhibited 'Hnmr and i r spectra which were s i m i l a r to that of compound 123c and a l l gave sat i s f a c t o r y molecular weight determination (high resolution mass spectrometry). I t was found that when l i t h i u m phenylthio(methyl)cuprate was employed, the y i e l d of the desired product, l-carbomethoxy-4-methyl-l,4-dihydropyridine -30-123a,was merely 52% (entry 1, Table 1). Attempts to improve the y i e l d by r a i s i n g the temperature of the reaction mixture from -78°C to 0°C led to the formation of methyl phenylthioformate 133 as the major product. Even at -50°C a considerable amount of 133 was formed as a side product. I t was also found that, regardless of the temperature of the reaction mixture, a considerable amount of high b o i l i n g residue remained a f t e r d i s t i l l a t i o n of the i n i t i a l l y i s o l a t e d crude product. Spectral evidence ("hlnmr) indicated that the major component of this residual material might be the dimer 134. However, attempts to i s o l a t e a pure sample of this material f a i l e d , since i t decomposed extensively 123a 134 when the d i s t i l l a t i o n residue was subjected to column chromatography on s i l i c a g e l . I t i s important to note that compound 123a was quite unstable i n a i r . In fact, a freshly d i s t i l l e d colorless sample of 123a turned green nearly immediately upon contact with a i r . Indeed, a l l of the 1-carbomethoxy-4-alkyl(or aryl)-l,4-dihydropyridines which were synthesized during the course of our work were found to be unstable i n a i r , although they were stable for a few weeks i f c a r e f u l l y kept under an atmosphere of argon i n the freezer. An a n a l y t i c a l sample of each of the dihydropyridine derivatives was obtained from each of the reaction product mixtures by means of preparative -31-Table 1. Reaction of l i t h i u m phenylthio(alkyl or aryl)cuprates with pyridine i n the presence of methyl chloroformate. PhS(R)CuLi + 132 Entry Cuprate(R) Y i e l d 3 ( % ) of 123 Ratio of 123:133 1 CH3- 52 >99:1 2 C 2H 5- 70 88:11 3 CH 3(CH 2) 3- 65 86:14 4 CH3CH2CHCH3 80 89:11 5 (CH 3) 3C- 26 50:50 b 6 C6 H5 24C >99:1 (a) The y i e l d i s based on the t o t a l material recovered m u l t i p l i e d by the percentage purity as determined by g l c . (b) The r a t i o here i s act u a l l y 50% 123 to 50% of side product which was a mixture of 133 plus methyl 2,2-dimethylpropanoate (135). (c) The major product was biphenyl. R COzMe 123 133 -32-gl c . They were characterized by i r , 'Hnmr, and mass spectral analysis as soon as they were i s o l a t e d . When the procedure described above was carried out employing l i t h i u m phenylthio(ethyl)cuprate and the corresponding s^butyl reagent, the reactions proceeded smoothly and the products were quite clean. Thus, the corresponding products, l-carbomethoxy-4-ethyl-l,4-dihydropyridine 123b and l-carbomethoxy-4-s-butyl-l,4-dihydropyridine 123d, were formed i n y i e l d s of 70% and 80%, respectively (see Table 1, entries 2 and 4). However, when l i t h i u m phenylthio(_t-butyl)cuprate was used under a variety of reaction conditions, the major products formed appeared to be a mixture of methyl phenylthioformate 133 and methyl 2,2-dimethylpropanoate 135 (eq.61). These two compounds were not separable by preparative glc but the ''"Hnmr spectrum of the mixture was almost i d e n t i c a l with an authentic 1:1 mixture of the same two materials. The best reaction conditions found gave a y i e l d of approximately 26% (glc yi e l d ) of the desired product, l-carbomethoxy-4-t_-butyl-l,4-dihydropyridine 123e. Approximately equal amounts of the side products 133 and 135 were also formed i n the reaction (entry 5, Table 1). In the case of l i t h i u m phenylthio(phenyl)cuprate (entry 6, Table 1), the major product formed appeared to be biphenyl 136. The l a t t e r , along t-Bu (61) COzMe 123e 133 135 -33-with some other minor impurities, were separated from the desired product 123f by f r a c t i o n a l d i s t i l l a t i o n . Comparison of the %nmr spectrum of the former material with that of an authentic sample of biphenyl showed that this material was mainly biphenyl. The presence of biphenyl i n the reaction product was further confirmed by a glc coinjection analysis involving an authentic sample of biphenyl and this mixture. The desired product l-carbomethoxy-4-phenyl-l,4-dihydro-pyridine 123f was formed i n only 24% y i e l d (eq.62). + Ph-Ph ( 6 2) 12 3 f F i n a l l y , when lithium phenylthio(vinyl)cuprate was employed, no trace of the expected product l-carbomethoxy-4-vinyl-l,4-dihydropyridine 123g was found. A small amount of methyl phenylthioformate 133 was isolated together with a considerable amount of a high b o i l i n g , unidentified residue. I l l . Comparison of Lithium Dialkyl(or diaryl)cuprates with Lithium Phenylthio(alkyl or aryl)cuprates i n the Synthesis of 1-Carbomethoxy- 4-alkyl(or aryl)-1,4-dihydropyridines. Since one of the objectives of the work described i n this part of the thesis was to investigate the e f f i c i e n c y of lithium phenylthio(alkyl or aryl) cuprates i n transferring an a l k y l ( o r aryl) group to pyridine i n the formation of 1,4-dihydropyridines, i t i s appropriate to make a comparison -34-of the results obtained by using l i t h i u m d i a l k y l ( o r diaryl)cuprates with those obtained by employing l i t h i u m phenylthio(alkyl or aryl)cuprates. A summary of both sets of res u l t s i s tabulated i n Table 2. A perusal of the results summarized i n Table 2 c l e a r l y shows that l i t h i u m phenylthio(s_-butyl)cuprate 132d was superior to l i t h i u m di-s_-butylcuprate i n y i e l d i n g l-carbomethoxy-4-s-butyl-l,4-dihydropyridine (entry 4, Table 2). The li t h i u m di-s_-butylcuprate reagent reacted with pyridine i n the presence of methyl chloroformate to y i e l d 56% of a mixture of l-carbomethoxy-4-s_-butyl-l, 4-dihydropyridine 123d and l-carbomethoxy-2-s_-butyl-l, 2-dihydro-pyridine 124d i n a r a t i o of 89:11 respectively (eq.63). When l i t h i u m phenylthio(s_-butyl)cuprate was employed, a mixture of the 1,4-dihydro-R o —> o c x I I COzMe COzMe 123 ( 124 (a) R=CH3; (b) R=Et; (c) R=n-Bu; (d) R=s-Bu; (e) R=_t-Bu; (f) R=Ph pyridine 123d and methyl phenylthioformate 133 (i n a r a t i o of 89:11, respectively) was obtained, i n which the y i e l d of dihydropyridine 123d was approximately 80%. When the a l k y l group i n the cuprate reagent was methyl or primary a l k y l , l i t h i u m phenylthio(alkyl)cuprates were no better than the corresponding dialkylcuprates. For example, the reaction of li t h i u m dimethylcuprate with pyridine i n the presence of methyl chloroformate gave i n 81% y i e l d a mixture of the corresponding dihydropyridine Table 2. Comparison of the use of l i t h i u m d i a l k y l ( d i a r y l ) c u p r a t e s with the use of l i t h i u m phenylthio(alkyl or aryl)cuprates i n the synthesis of l-carbomethoxy-4-alkyl(or aryl)-1,4-dihydropyridines R2CuLi PhSCu(R)Li Entry R= Ratio Product Y i e l d a ( % ) 123:124 Y i e l d of 123(%) 1 CH3- 81° 98:2 52 2 CH3CH2 67 C 96:4 70 3 CH 3(CH 2) 3- 86° 98:2 65 4 t CH3CH2CHCH3 56C 98:11 80 5 (CH 3) 3C- 26 6 C6 H5 7 0 c , d 88 e 90:10 84:16 24 7 CH2=CH- 67 f 60 C' g 51:46 72:28 <1 a) The y i e l d here i s based on t o t a l material recovered. b) Same as footnote a), Table 1. c) Data obtained from E.Piers et a l . " d) Cul was used to prepare the cuprate reagent. e) CuBr was used to prepare the cuprate reagent. f) Dimethylsulfide complex of CuBr was used to make the cuprate reagent. g) Tri-n-butylphosphine complex of Cul was used to prepare the cuprate reagent. -36-d e r i v a t i v e s , i n which the r a t i o of the 1,4-isomer 123a to the 1,2-isomer 124a was 98:2 r e s p e c t i v e l y (entry 1, Table 2) . When l i t h i u m phenylthio(methyl)cuprate was employed, the y i e l d of 1-carbomethoxy-4 - m e t h y l - l , 4 - d i h y d r o p y r i d i n e 123a was only 50%. When the incoming group was phenyl , i t i s c l ear that l i t h i u m phenylthio(phenyl)cuprate was d e f i n i t e l y i n f e r i o r to the d i p h e n y l -cuprate (entry 7, Table 2) . Li th ium phenylthio(phenyl)cuprate reacted with p y r i d i n e i n the presence of methyl chloroformate to give only a 24% y i e l d of the des ired product , l - carbomethoxy-4 -pheny l - l , 4 -d ihydro-p y r i d i n e 123f. When l i t h i u m diphenylcuprate (prepared from the r e a c t i o n of pheny l l i th ium and cuprous iodide) was employed, the y i e l d of the corresponding mixture of d ihydropyr id ine d e r i v a t i v e s was 70% and the r a t i o of the 1,4- to 1,2-isomer (123f and 124f, r e s p e c t i v e l y ) was 90:10. However, i t was found that the r e a c t i o n of l i t h i u m diphenylcuprate with p y r i d i n e i n the presence of methyl chloroformate was not always reproduc ib l e . 140 G.M. Whiteside et_ a l reported that they had d i f f i c u l t i e s i n preparing s table so lut ions of l i t h i u m diphenylcuprates from the r e a c t i o n of phenyl-l i t h i u m with cuprous i o d i d e . However, they a lso reported that the 140 problem was solved by s u b s t i t u t i n g cuprous bromide for cuprous i o d i d e . When th i s method for preparing l i t h i u m diphenylcuprate was followed and the r e s u l t a n t reagent was allowed to react with pyr id ine i n the presence of methyl chloroformate i n the usual manner, there was obtained an 88% y i e l d of a mixture of l - carbomethoxy-4 -pheny l - l , 4 -d ihydropyr id ine 123f and l - carbomethoxy-2 -pheny l - l , 2 -d ihydropyr id ine 124f i n a r a t i o of 84:16. Although l i t h i u m p h e n y l t h i o ( a l k y l or ary l ) cuprate s produced no 1 ,2 -d ihydropyr id ine der ivat ives react ions with these reagents were not -37-problem free. In most cases, a side product, methyl phenylthioformate 133,was formed i n approximately 10% y i e l d and, i n the case where the a l k y l group was _t-butyl, this side product was formed i n >25% y i e l d . Thus, the use of l i t h i u m phenylthiol(alkyl)cuprates i n the reaction with pyridine and methyl chloroformate i s complementary to the use of lith i u m d i a l k y l ( o r diaryl)cuprates but cannot take i t s place i n the synthesis of l-carbomethoxy-4-alkyl(or aryl)-l,4-dihydropyridines. IV. Reaction of Lithium Dialkylcuprates with Pyridine i n the Presence  of Acetyl Bromide The work described above cl e a r l y showed that methyl chloroformate served quite w e l l as an electrophile i n promoting the reaction of pyridine with various cuprate reagents. Furthermore, the products (N-carbomethoxy dihydropyridines) were s u f f i c i e n t l y stable to allow for i s o l a t i o n and characterization. Nevertheless, i t was of interest to study the p o s s i b i l i t y of using alternate electrophiles, not only to determine whether or not the reaction would be e f f i c i e n t , but also i n order to prepare simple dihydro-pyridine compounds containing a substituent on nitrogen other than a carbomethoxy group. The f i r s t alternate we t r i e d was acetyl bromide. The procedure used was e s s e n t i a l l y the same as with methyl chloroformate. For example, a four f o l d excess of acetyl bromide i n ether was added to a solution of pyridine (1 equivalent) and lit h i u m di-n-butylcuprate (1.2 equivalents) at -78°C. The re s u l t i n g mixture was s t i r r e d at -78°C for 30 min, warmed to 0°C and s t i r r e d for an additional 30 min. After work-up, the d i s t i l l e d product (^73% yield) was analysed by glc and i t was found to be pure -38-1-acety1-4-n-buty1-1,4-dihydropyridine 137c (eq.64). Although the "''Hnmr of this material was s l i g h t l y d i f f e r e n t from i t s N-carbomethoxy counterpart, the 1,4-dihydropyridine structure was c l e a r l y present. The protons at C-2 and C-6 of 137c appeared as a pair of doublets (J=9 Hz i n each case) centered at x2.83 and 3.46. The protons at C-3 and C-5, on the other hand, resonated as a two-proton multiplet centered at x5.05. F i n a l l y , the proton at C-4 appeared as a multiplet centred at x7.05 and the methyl group on the acyl group resonated as a s i n g l e t at x7.83. The i r spectrum of th i s material showed a strong carbonyl absorption at 1675 cm ^ and another f a i r l y strong absorption at 1623 cm "'". PhS(R)CuLi J] (64) CH3COBr ^ COMe 137 137(a) R=CH3; (b) R=Et; (c) R=n-Bu; (d) R=Ph Similar r e s u l t s were obtained when l i t h i u m dimethylcuprate and l i t h i u m diethylcuprate were employed,and the spectral data (}Hnmr, i r ) of the corresponding products, l-acetyl-4-methyl-l,4-dihydropyridine 137a, and l-acetyl-4-ethyl-l,4-dihydropyridine 137b respectively,were quite s i m i l a r to those of 1-acetyl-4-n-buty1-1,4-dihydropyridine 137c described above. The resu l t s are summarized i n Table 3. In general, the y i e l d s of 1,4-dihydropyridine derivatives were not bad and, somewhat s u r p r i s i n g l y , no trace of the corresponding 1,2-dihydropyridine derivatives were found. Again, l i t h i u m diphenylcuprate posed the same problem as had been encountered e a r l i e r . Using cuprous iodide to make the diphenylcuprate, -39-Table 3. Reaction of l i t h i u m dialkylcuprates with pyridine i n the presence of acetyl bromide R 2CuLi N' CH3COBr r CO Me 137 Entry Cuprates(R) Product y i e l d ( % ) 1 CH3- 59 2 CH3CH2- 50 3 CH 3(CH 2) 3- 73 -40-the reaction gave a complex mixture of products. When cuprous bromide was employed to make the cuprate reagent , the reaction was cleaner, and the spectral data (^Hnmr) of the crude product indicated that the desired product, l-acetyl-4-phenyl-l,4-dihydropyridine 137d, was present i n the product mixture, along with a considerable amount of unknown impurities. The reaction was not investigated further. When the use of l i t h i u m di-s_-butylcuprate was investigated, again, a s y n t h e t i c a l l y useless complex mixture of products resulted. C l e a r l y , the above r e s u l t s showed that acetyl bromide did not give r e s u l t s superior to those obtained from methyl chloroformate. Therefore the reaction with acetyl bromide acting as an electrophile for the synthesis of 1,4-dihydropyridine derivatives was not investigated further. V. Comparison of Different Electrophiles i n the Synthesis of 4-A l k y l - l , 4 -dihydropyridine Derivatives from the Reaction of Lithium Dialkylcuprates  with Pyridine i n the Presence of the Electrophiles. Methyl chloroformate and acetyl bromide are both f a i r l y strong e l e c t r o p h i l e s . They both r e a d i l y react with pyridine to form pyridinium s a l t s . The l a t t e r , probably mainly due to the positive charge on the nitrogen atom and to the electron-withdrawing group (COOMe or COMe) attached to the nitrogen, are apparently quite susceptible to reaction with electron transfer reagents such as cuprates. I t was of int e r e s t to investigate i f weaker e l e c t r o p h i l i c reagents could serve the same purpose. In this connection, the reaction of pyridine with l i t h i u m di-n-butylcuprate i n the presence of chlorotrimethylsilane was investigated f i r s t . Under reaction conditions very s i m i l a r to those used i n the case -41-of methyl chloroformate, the expected l - t r i m e t h y l s i l y l - 4 - _ n - b u t y l - l , 4 -dihydropyridine 138 was obtained. However, i t seemed that this compound was very unstable. Indeed, the ^Hnmr spectrum of the crude product showed that i t contained a considerable amount of 4-n-butylpyridine. The presence of 4-n-butylpyridine was confirmed by comparing the "4lnmr spectra of the crude product mixture with that of a pure sample of 4-n-butylpyridine. The "*"Hnmr spectrum of the crude product was interpreted as follows. A p a i r of doublets (J=5 Hz, J'=2 Hz) centered at xl.52, was assigned to the protons at C-2 and C-6 of 4-n-butylpyridine, while the pair of doublets (J=5 Hz, J"=2 Hz) at x2.89, was due to the C-3 and C-5 protons of 4-n-butylpyridine. A t r i p l e t (J=7 Hz) centered at x3.40, was assigned to the two methylene protons on the n-butyl group adjacent to C-4 of the r i n g of 4-n-butylpyridine. A doublet, (J=8 Hz), which appeared at x4.07 was assigned to the protons at C-2 and C-6 of the dihydropyridines 138. Another pair of doublets (J=8 Hz, J'=3.5 Hz) centered at x5.57, was assigned to the C-3 and C-5 protons of the dihydropyridine 138. F i n a l l y , a m u l t i p l e t centered at x3.00 was assigned to the proton at C-4 of the dihydropyridine 138. Since the l-trimethylsily-4-ri-butyl-l,4-dihydropyridine 138 was quite unstable, i t was not i s o l a t e d i n pure form for characterization. Instead, the crude product mixture obtained from the reaction described above was treated f i r s t with methanolic potassium hydroxide ( i n order to cleave the N - t r i m e t h y l s i l y l group) and then with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone ( i n order to oxidize the resultant 1,4-dihydro-pyridine) . This procedure afforded a 33% isol a t e d y i e l d of 4-n-butyl-pyridine (eq.65). -42-n-Bo n-Bo l)n-Bu 0CuLi 1) KOH/MeOH (65) -> 2)ClSiMe 3 2) DDQ Si Me. 138 ' Next, the use of diethylphosphorochloridate as an ele c t r o p h i l e was investigated. When the reaction was attempted under the usual reaction conditions (addition of diethylphosphorochloridate to a solution of pyridine and l i t h i u m di-n-butylcuprate), none of the expected product, 1,4-dihydropyridine derivative 139 was is o l a t e d . However, addition of a solution of diethylphosphorochloridate i n excess pyridine to a solution of l i t h i u m di-n-butylcuprate i n ether at -78°C did give the expected product, although the y i e l d was very low (^17%) (eq.66). The d i s t i l l e d product of the reaction was analysed by t i c and was shown to be the pure dihydropyridine 139. The "'"Hnmr of this material showed the c h a r a c t e r i s t i c 1,4-dihydropyridine structure. A two proton mu l t i p l e t between T3.56 and 3.93 was assigned to the protons at C-2 and C-6 while the protons at C-3 and C-5 were found to resonate at x5.10-5.46 as a two-proton mu l t i p l e t . The C-4 proton resonated as a one-proton multip l e t at x6.90-7.23. This material also showed strong absorption at 1680, 1620, 1290 and 1270 cm \ i n the i r spectrum. n-Bu O + (66) O ^ P — OEt 139 Although the l a s t two electrophiles t r i e d did give the corresponding -43-dihydropyridine derivatives, methyl chloroformate and acetyl bromide were d e f i n i t e l y better choices i n terms of giving better y i e l d s and cleaner crude products. Table 4 summarizes and compares the r e s u l t s of the four electrophiles i n the reaction of l i t h i u m di-n-butylcuprate with pyridine. In the presence of methyl chloroformate, pyridine reacts with l i t h i u m di-n-butylcuprate reagent to give an 86% y i e l d of a mixture of the corresponding 1,4 and 1,2-dihydropyridine, 123c and 124c, i n a r a t i o of 98:2 respectively (entry 2, Table 4). With acetyl bromide, the y i e l d of the corresponding 1,4-dihydropyridine 137c was 73% and no trace of the corresponding 1,2-dihydropyridine was detected (entry 1, Table 4). When diethylphosphorochloridate was employed, the y i e l d of the cor-responding 4-n-butyl-l,4-dihydropyridine derivative 139 was a mere 17% (entry 3, Table 4). With chlorotrimethylsilane, the crude product was a mixture of the expected l-trimethylsilyl-4-n-butyl-l,4-dihydropyridine 138 and the corresponding oxidized product., 4—n-butylpyridine (entry 4, Table 4). Although the study j u s t described was very b r i e f , i t appeared that the use of chlorotrimethylsilane and diethylphosphorochloridate as electrophiles was of l i m i t e d synthetic value i n the reaction of pyridine with l i t h i u m dialkylcuprates. Therefore the use of these reagents was not investigated further. -44-Table 4. Comparison of d i f f e r e n t electrophiles i n the synthesis of 4-alkyl-l,4-dihydropyridine derivatives from the reaction of pyridine with l i t h i u m di-n-butylcuprate. n-Bo I E Entry E l e c t r o p h i l e Product y i e l d ( % ) 1 CH3COBr 73 2 CJcC02CH3 86 a 3 C£PO(OC 2H 5) 2 17 4 C£Si(CH 3) 3 >33b (a) The product was a mixture of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine and l-carbomethoxy-2-n-buty1-1,4-dihydro-pyridine i n the r a t i o of 98:2. (b) The product was a mixture of l - t r i m e t h y l s i l y l - 4 - n - b u t y l -1,4-dihydropyridine and 4-ri-butylpyridine. -45-VI. Mechanistic Considerations Although we have not done any mechanistic studies on the reactions of organocuprate reagents with pyridine i n the presence of methyl chloroformate, separate control experiments showed that the cuprate 128 reagents did not react with pyridine d i r e c t l y . For example, when a solution of pyridine and l i t h i u m dimethylcuprate i n ether was s t i r r e d at 0°C for l h and was then worked up without addition of methyl chloroformate, 128 pyridine could be recovered i n greater than 80% y i e l d . These r e s u l t s indicated that the products were probably formed by reaction of the cuprate reagent with the i n i t i a l l y formed pyridinium s a l t 140. c r COoMe 140 As was already mentioned e a r l i e r , pyridine and alkylpyridines undergo nucleophilic attack by a l k y l l i t h i u m or a r y l l i t h i u m reagents to give 2-74-79 su b s t i t u t e d - l - l i t h i o - l , 2 - d i h y d r o p y r i d i n e s . 1-Carbomethoxypyridinium chloride reacts with Grignard reagents to afford mainly l-carbomethoxy-2-85 86 alky1-1,2-dihydropyridine (eq.29). ' The high r e g i o s e l e c t i v i t y involved i n the conjugate addition of cuprate reagents to pyridine i n the presence of methyl chloroformate indicated that t h i s reaction probably goes v i a a -46-mechanism different from that involved i n the reactions employing Grignard or alkyllithium reagent. Conjugate addition of 142-145 cuprate reagents to a,g-unsaturated enones are well documented. The N-carbomethoxypyridinium s a l t system 140 can be considered as an analogue equivalent of an a,B-unsaturated ketone i n which the nitrogen atom replaces the oxygen atom i n the enone system, as shown below. The carbon-COjMe 140 141 nitrogen double bond C=N+ i s sim i l a r to the carbonyl fu n c t i o n a l i t y (JX=0) and the other double bond on the pyridinium ring i s analogous to the double bond conjugated to the carbonyl function i n the enone system. Although the mechanism of conjugate addition of organocuprate reagents to a,3-unsaturated enones i s s t i l l open to question, the electron transfer hypothesis proposed by H. 0. House e_t a l . i s currently 144 145 the most well accepted. ' The limited s t r u c t ural information 145 146 presently available ' suggests that the lithium dialkylcuprate reagents probably ex i s t as dimers (R^C^L^) i n ether solution with a c y c l i c structure having approximately D0 symmetry - structure 142. The charge transfer mechanism suggests an i n i t i a l transfer of an electron from the cuprate reagent to the unsaturated substrate 143 to form r a d i c a l anion 144 (Scheme 1). Subsequent transfer of an organic r a d i c a l from a transient species l i k e 145 would complete the addition sequence. -47-R—Li —R I J | | e l e c t r o n • + ? " I | <}" Y - C - C - C - , [ R 4 C u 2 L i 2 J - + - C = C - C - coupling _ > R—Li—R transfer 143 144 142 R—Li —R I Cu Li + RCu 7 N ° u * \ L I i l l r -,+ L i + <jfc-C-C = C - > R - C - C = C - + [ R 3 C u 2 L i 2 ] , R-Li-R + ^ 4^12 145 SCHEME I Observations i n d i c a t i n g that there i s a rela t i o n s h i p between the reduction potentials of various unsaturated carbonyl compounds and the i r a b i l i t y to react with cuprate reagents has lent support to 144 the mechanism proposed. Such a co r r e l a t i o n also allows a f a i r l y r e l i a b l e prediction to be made as to whether or not an unsaturated substrate w i l l undergo conjugate addition. Various other studies directed towards the elucidation of the mechanism of conjugate addition of cuprate reagents to unsaturated carbonyl compounds have shown that i n most cases, an anion-radical i s indeed an intermediate 144 i n these reactions. Analogously, a s i m i l a r mechanism can be postulated for the formation of 4-alkyl-l,4-dihydropyridine derivatives from the reaction of pyridine with cuprate reagents i n the presence of an el e c t r o p h i l e . Thus i t can be proposed that the cuprate reagent transfers an electron to the pyridinium ri n g to form an electron-transfer complex 146 which then couples with the cuprate reagent to form a transient intermediate 147. Subsequent transfer of an a l k y l group from the copper atom of the intermediate to the dihydropyridine r i n g would give the corresponding product (Scheme 2). R4Cu2Li2 -48-j^^X. electron transfer * [ W a J ( M l 146 coupling R—Li—R I Cu R—Li —R + [ R 3Cu 2Li 2] H Li++ RCu + 2 R 4 C U2 L I2 SCHEME 2 Reactions involving electron transfer to pyridine are not new. Certain metals (for example, sodium) transfer one electron to pyridine to form the radi c a l anion 148 which dimerizes readily to tetrahydrobipyridyl 149 (eq.67). 1 4 7 Na N' 148 * HO~OH 149 (67) Charge-transfer complexes of pyridinium sa l t s were known as early as 1955. E.M. Kosower et a l .investigated the spectra of substituted 1-methylpyridinium iodides i n aqueous solution and obtained evidence for the presence of a charge-transfer complex, the pr i n c i p a l contributing 148 forms of which may be depicted as 150 and 151 that Kosower also found V Me 150 Me 151 nucleophiles which form charge-transfer complexes e a s i l y , or which might be expected to do so, add to the pyridinium s a l t at the 4-position, while -49-those nucleophiles which probably do not form complexes' or do so only 149 to a very l i m i t e d extent, add at the 2-position. These l a t t e r findings are i n perfect accord with our mechanistic proposal. The mechanism suggested above i s very tentative and based only on analogy. We, have no experimental basis to substantiate our postulation. Therefore, more work should be done i n this area i f the nature of the reaction i s to be understood more f u l l y . VII. Conversion of l-Carbomethoxy-4-alkyl-l,4-dihydropyridiries to the  Corresponding 4-Alkylpyridines. As has been mentioned previously, one of the most important reactions of dihydropyridine derivatives i s the i r oxidation to the corresponding pyridine compounds. By o x i d i z i n g the. l-carbomethoxy-4-alkyl-l,4-dihydro-pyridines synthesized v i a the reaction of pyridine with organocuprate reagents i n the presence of methyl chloroformate, we have provided a new route to the synthesis of simple 4-alkylpyridines. Synthesis of 4-alkylpyridines from pyridine i t s e l f has been a f a i r l y d i f f i c u l t task. Most available methods y i e l d a mixture of 4-alkylpyridines and 2-alkylpyridines. For example, the thermal rearrangement of the pyridinium s a l t s 152 i n the Ladenburg rearrangement reaction gave i n each case a mixture of the corresponding 2- and 4-alkyl (or aryl)pyridines (eq.68).150,151 C a t a l y t i c a l k y l a t i o n of pyridine by the reaction of the l a t t e r with an a l i p h a t i c acid i n the presence of the corresponding lead s a l t and a ca t a l y s t also affords a mixture of 2- and 4-alkylpyridines, 152 together with dialkylated product (eq.69). When pyridine i s heated with a d i a c y l peroxide i n the presence of the corresponding a l i p h a t i c carboxylic a c i d , a mixture of the corresponding 2- and 4-alkylpyridine i s -50-4-Alkylpyridines can be synthesized d i r e c t l y from pyridine by the Wibaut-Arens a l k y l a t i o n . The o v e r a l l synthesis involves the reaction of pyridine with an acid anhydride i n the presence of zinc (Dimroth reaction), thermal rearrangement of the resultant dimeric product 96^ to a 1,4-diacyl-l,4-dihydropyridine 153 and f i n a l l y , reduction of the l a t t e r to a 4-alkylpyridine (eq.71).1^4,155 153 -51-A more e f f i c i e n t synthesis of 4-alkylpyridines uses 4-picoline s t a r t i n g material. 4-Picoline i s f i r s t treated with sodium or potassi amide and the resultant anion i s allowed to react with various a l k y l halides to give the corresponding 4-alkylpyridines (eq.72). 1"^ (72) As had been mentioned previously, dihydropyridines serve as important intermediates i n several reactions of pyridine. In fa c t , a large number of pyridine derivatives may be obtained by oxidizing the corresponding dihydropyridine derivatives synthesized by the Hantzsch and related syntheses. By oxidizing the l-carbomethoxy-4-alkyl-l,4-dihydropyridines synthesized from the reaction of pyridine with cuprate reagents i n the presence of methyl chloroformate, we have developed a f a i r l y e f f i c i e n t method for synthesizing simple 4-alkyl pyridines. Our i n i t i a l studies were carried out with l-carbomethoxy-4-n-butyl-1,4-dihydropyridine. In general, the dihydropyridine derivative was f i r s t treated with three equivalents of methyllithium i n order to remove the N-carbomethoxy group,and the resulting lithium piperidide derivative was then oxidized i n s i t u by addition of an appropriate oxid i z i n g agent (eq.73). p_-Benzoquinone was the f i r s t reagent t r i e d i n -52-the oxidation step,but a disappointingly low y i e l d (48%) of 4-n-butyl-pyridine was obtained. When tetrachloro-1,4-benzoquinone was employed, the y i e l d of 4-n-butylpyridine improved to 65%. F i n a l l y , i t was found that 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) gave the most satisfactory y i e l d (73%) of 4-n-butylpyridine. This type of procedure was extended to include other 1,4-dihydropyridine derivatives and the results are summarized i n Table 5. In general, 4-alkylpyridines obtained from the oxidation were es s e n t i a l l y pure after d i s t i l l a t i o n from the crude products. In each case, the product was analyzed by glc and characterized by i r and "*Hnmr spectroscopy. The spectral data ( i r , "^ Hnmr) of each product was compared with those of an authentic sample available commercially or with those reported i n the l i t e r a t u r e . As can be seen from the results summarized i n Table 5, the yields of 4-alkyl(aryl)pyridines were f a i r l y good. For example, the y i e l d of 4-ethylpyridine was 89% and the y i e l d of 4-s-butylpyridine was 79% (entry 2 and 4 respectively, Table 5). The only exception was 1-carbomethoxy-4-methyl-l,4-dihydropyridine which gave only a 58% y i e l d of 4-picoline (entry 1, Table 5). The low y i e l d of the l a t t e r product may be attributed to mechanical loss owing to i t s v o l a t i l i t y . Compared with most other methods for synthesizing simple 4-alkyl-pyridines, the combined synthesis of l-carbomethoxy-4-alkyl(aryl)-l, 4-dihydropyridines and their subsequent conversion to the corresponding 4-alkylpyridines opens a new, clean and f a i r l y e f f i c i e n t way of synthesizing these compounds. -53-Table 5. Conversion of l-carbomethoxy-4-alkyl(aryl)-l,4-dihydropyridines to the corresponding 4-alkyl(aryl)pyridines Entry 0 Yield(%) of 4-alkyl(or aryl)pyridines I C09CH^ p-benzoquinone tetrachloro-1,4-benzoquinone  DDQ 1 2 3 4 5 R = CH3-CH3CH2-CH 3(CH 2) 3-CH3CH2CHCH3 C 6 H 5 55 48 65 58 89 73 79 73 -54-EXPERIMENTAL General Information Mel t ing p o i n t s , determined with a Fisher-Johns mel t ing point apparatus, and b o i l i n g points are uncorrected. U l t r a v i o l e t (uv) spectra were obtained with a Cary 15 spectrophotometer i n methanol s o l u t i o n . Infrared ( i r ) spectra were obtained with a Perkin-Elmer 710 i n f r a r e d spectrophotometer, as l i q u i d f i lms or i n chloroform s o l u t i o n . Nuclear magnetic resonance ("Hlnmr) spectra were obtained with V a r i a n T-60, HA-100 and/or XL-100 spectrometers, i n deuterochloroform s o l u t i o n , with te tramethyls i lane as i n t e r n a l s tandard. Low r e s o l u t i o n mass spectra were recorded with a Varian/MAT CH4B mass spectrometer. High r e s o l u t i o n mass spectra were recorded with a Kratos /AEI MS50 mass spectrometer. Microanalyses were performed by M.P. Borda, M i c r o a n a l y t i c a l Laboratory , U n i v e r s i t y of B r i t i s h Columbia, Vancouver. A n a l y t i c a l gas l i q u i d chromatography (glc) was performed on a Hewlett Packard HP5830A Gas Chromatography un i t connected to a HP18850A GC termina l . The fo l lowing columns were used: (A) 6 f t x 0.125 i n . , 5% OV-210 on HP chromosorb w (80-100 mesh); (B) 6 f t x 0.125 i n . , 5% OV-17 on HP chromosorb w (80-100 mesh). Preparat ive gas l i q u i d chromatography was performed on a Var ian Aerograph Model 90-P gas chromatograph, using the fo l l owing columns: (C) 10 f t x 0.25 i n . , 10% OV-210 on chromosorb w (60-80 mesh); (D) 10 f t x 0.25 i n . , 10% 0V-17 on chromosorb w (60-80 mesh); (E) 10 f t x 0.25 i n . , 15% Versamide 900 on chromosorb w (60-80 mesh) . A l l reac t ions i n v o l v i n g organocopper reagents were performed i n -55-three-necked round-bottomed flasks equipped with a serum stopper, an argon i n l e t tube, and a glass-covered magnetic s t i r r i n g bar. P r i o r < to the introduction of solvent or any reagent, the apparatus was dried with a bunsen flame while being evacuated and was then f i l l e d with argon. A s l i g h t p o s i t i v e pressure of argon was maintained throughout the reaction. Starting Materials and Reagents Solutions of methyllithium i n ether, e t h y l l i t h i u m i n benzene, n-butyllithium i n hexane, s^butyllithium i n cyclohexane, _t-butyllithium i n pentane and phenyllithium i n benzene were obtained from A l f a Inorganics Inc., and were standardized by the procedure of Gilman et al\^ V i n y l -l i t h i u m , which i s no longer commercially a v a i l a b l e , was prepared as 158 159 follow. To a s t i r r e d s olution of t e t r a v i n y l t i n (6.8 g, 30 mmol) i n pentane (150 ml) i n a flame-dried 500 ml three-necked f l a s k equipped with a mechanical s t i r r e r and an argon i n l e t tube was added v i a a syringe a solution of ri-butyllithium i n hexane (2.1M, 28.6 ml, 60 mmol) over a period of 10 min. The solut i o n was concentrated by blowing a rapid stream of argon across the surface of the solution for 40 min. The pre-c i p i t a t e d v i n y l l i t h i u m was f i l t e r e d under argon, washed twice with pentane and dissolved i n 80 ml of anhydrous ether. The solution was then standardized by the procedure of Gilman et al."*"^ 7 Commercial samples of cuprous iodide and cuprous bromide were p u r i f i e d by d i s s o l v i n g them i n a saturated aqueous solu t i o n of the appropriate halide (potassium iodide or potassium bromide, respectively) followed by treatment of the solution with charcoal, f i l t r a t i o n and d i l u t i o n with water to repre-c i p i t a t e the copper(I)halide.'''^ Phenylthiocopper was prepared by re f l u x i n g a mixture of cuprous oxide (9g, 60 mmol) and thiophenol (16g, 136 mmol) i n -56-absolute ethanol (500ml) for seven days.1""1" The bright yellow s o l i d phenylthiocopper obtained by f i l t r a t i o n of the resultant mixture was washed thoroughly with ethanol and then dried under vacuum. The y i e l d was e s s e n t i a l l y quantitative. Anhydrous ether, obtained from Mallinckodt Ltd., was used from freshly opened 1 lb cans without further treatment. Tetrahydrofuran was d i s t i l l e d from lithium aluminum hydride immediately prior to use. Pyridine and triethylamine were d i s t i l l e d from potassium hydroxide and stored over potassium hydroxide. A c e t o n i t r i l e was d i s t i l l e d from phosphorous pentoxide. 162 General Procedure for the Preparation of Lithium Dialkylcuprates To a slurry of cuprous iodide (572 mg, 3 mmol) i n cold (temperature varies with different cuprates) dry ether (25 ml) was added a solution of the appropriate commercial a l k y l l i t h i u m reagent (6 mmol). The resulting mixture was s t i r r e d at the appropriate temperature for 30 to 60 min (temperature and time vary with different cuprates, see ref. 162 for d e t a i l s ) . A solution containing 3 mmol of the appropriate li t h i u m dialkylcuprate resulted. General Procedure for the Preparation of Lithium Phenylthio(alkyl or 161 aryljcuprates To a suspension of phenylthiocopper (726 mg, 4.2 mmol) i n cold (-20°C) tetrahydrofuran (25 ml) was added a solution of the appropriate a l k y l - or a r y l l i t h i u m reagent (4.2 mmol). The mixture was s t i r r e d at -20°C (0°C when methyllithium was used) for 30 min. A solution containing 4.2 mmol of the appropriate li t h i u m phenylthio(alkyl or aryl)cuprate resulted. -57-General Procedure for the Reaction of Lithium Phe n y l t h i o l a l k y l ( o r  aryl)cuprates with Pyridine i n the Presence of Methyl Chloroformate. To a cold (-78°C) s t i r r e d solution of the appropriate l i t h i u m phenylthio(alkyl or aryl)cuprate (4.2 mmol) i n about 30 ml of t e t r a -hydrof uran (under argon) was added 3 mmol (237 mg) of pyridine. A solution of methyl chloroformate (3 mmol) i n tetrahydrofuran (25 ml) was added dropwise over a period of 15 min. The re s u l t i n g mixture was s t i r r e d at -78°C for the appropriate time, warmed to an appropriate temperature and s t i r r e d for an additional length of time. Methanol (3 ml) and ether (15 ml) was added to the reaction mixture, the l a t t e r was s t i r r e d for a few seconds, and then f i l t e r e d through a short column (4 cm diameter) of f l o r i s i l (35 g, 60-80 mesh). The column was eluted with an additional 350 ml of ether. Evaporation of the ether, followed by d i s t i l l a t i o n of the residual o i l ( a i r bath) gave the f i n a l products. Reaction of Lithium Phenylthio(methyl)cuprate with Pyridine i n the  Presence of Methyl Chloroformate. Following the general procedure outlined above, 4.2 mmol of li t h i u m phenylthio(methyl)cuprate was allowed to react with 3 mmol of pyridine and 3 mmol of methyl chloroformate at -78°C for l h , and at 0°C for an additional 2h. Normal work-up followed by d i s t i l l a t i o n (air-bath temperature V50°C, 0.1 Torr) of the crude product afforded 241 mg (52%) of l-carbomethoxy-4-methyl-l,4-dihydropyridine 123a. This material was pure by glc analysis (column A, 90°C) and exhibited i r (film) v m a x 1730, 1690, 1630 cm"1; "Shimr, x3.25 (d,2H, =CH-N-CH=, J=8Hz), 5.17 (d of d, 2H, =CH-CH(CH3)-CH=, J=8Hz, J'=3.5 Hz), 6.20 (s, 3H, -C0 2CH 3), 7.00 (m, IH, -CH(CH 3)), 8.93 (d, 3H, -CH(CH3), J=7 Hz). Mol. Wt. Calcd. for -58-CgH^NO^: 153.0789. Found (high resolution mass spectrometry): 153.0760. A f a i r amount of high b o i l i n g o i l remained after a l l the 1-carbomethoxy-4-methyl-l,4-dihydropyridine had been d i s t i l l e d . The "hinmr of this material indicated that a major component of t h i s material could be 163 the dimer 134, but this material was not investigated further. Reaction of Lithium Phenylthio(ethyl)cuprate with Pyridine i n the  Presence of Methyl Chloroformate. Following the general procedure outlined above, 4.2 mmol of l i t h i u m phenylthio(ethyl)cuprate was allowed to react with pyridine (3 mmol) and methyl chloroformate (3 mmol) at -78°C for 3h. The reaction was then quenched with methanol. Normal work-up followed by d i s t i l l a t i o n (air-bath temperature V50°C, 0.2 Torr) of the crude o i l afforded 400 mg of a colorless o i l . A glc analysis of this material (column A, 90°C) showed the presence of one major component (88%) and a minor one (11%). The major component was shown to be l-carbomethoxy-4-ethyl-l,4-dihydropyridine 123b (70% y i e l d ) . An a n a l y t i c a l sample of the l a t t e r , obtained by pre-parative glc (column C, 110°C), exhibited i r (film) v 1727, 1690, max - 1 1 ' 1636 cm ; Hnmr, x3.20 (d, 2H, =CH-N-CH=, J=8 Hz), 5.17 (d of d, 2H, =CH-CH(CH3)-CH)=, J=8 Hz, J'=3.5 Hz), 6.20 (s, 3H, -C0 2CH 3), 7.13 (m, IH, -CH(CH 2CH 3)), 8.75 (m, 2H, -CH 2CH 3), 9.14 ( t , 3H, J=7.0 Hz). Mol. Wt. Calcd. for CgH^3N02: 167.0946. Found (high resolution mass spectrometry) :167.0909. An a n a l y t i c a l sample of the minor component was also obtained by preparative glc (column C, 110°C) and was shown to be methyl phenylthio-formate 133. An authentic sample of t h i s compound was prepared by the -59-reactionof thiophenol and methyl chloroformate i n the presence of aqueous sodium hydroxide. Comparison of the ^"Hnmr spectra of the authentic material with that of the same material isolated from the reaction mixture and a glc coinjection analysis of the authentic material with the same material isolated from the reaction mixture confirmed the id e n t i t y of the minor component. Reaction of Lithium Phenylthio(n-butyl)cuprate with Pyridine i n the  Presence of Methyl Chloroformate. Following the general procedure outlined above, 4.2 mmol of lithium phenylthio(n-butyl)cuprate was allowed to react with pyridine (3 mmol) and methyl chloroformate (3 mmol) at -78°C for 3h. Normal work-up followed by d i s t i l l a t i o n (air-bath temperature ^80°C, 0.2 Torr) of the crude o i l afforded 444 mg of colorless o i l . A glc analysis of this material (column A, 110°C) indicated that i t was a mixture of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine 123c (86%) and methyl phenylthioformate (14%). An a n a l y t i c a l sample of the former, obtained by preparative glc (column C, 110°C), exhibited -1 1 ' i r (film) v 1730, 1693, 1633 cm ; Hnmr, T3.20 (d, 2H, =CH-N-CK=,J=8 Hz), max — 5.13 (dof d,2H, =CH-CH(n-Bu)-CH=, J=8 Hz, J'=3.5 Hz), 6.20 (s, 3H, -C0 2CH 3), i t 7.05 (m, IH, -CH(n-Bu), 8.68 (unresolved m, 6H, -CH-CH2CH2CH2-), 9.12 (unresolved m, 3H, -CH2-CH3); y i e l d , 65%. Mol. Wt. Calcd. for C^H^NO^ 195.1253. Found (high resolution mass spectrometry): 195.1259. Reaction of Lithium Phenylthio(s-butyl)cuprate with Pyridine i n the Presence  of Methyl Chloroformate. Following the general procedure outlined above, lithium phenylthio(s-butyl)cuprate (4.2 mmol) was allowed to react with pyridine (3 mmol) and -60-methyl chlorofornate (3 mmol) at -78°C for l h , and at 0°C for an additional 2h. Normal work-up followed by d i s t i l l a t i o n (air-bath temperature ^75°C, 0.1 Torr) of the crude o i l afforded 519 mg of a colorless o i l . A glc analysis (column C, 155°C) of this material indicated that i t was a mixture of l-carbomethoxy-4-s_-butyl-l ,4-dihydropyridine 123d (89%) and methyl phenylthioformate (11%). An a n a l y t i c a l sample of the former, obtained by preparative glc (column C, 155°C), exhibited i r (film) v 1730, 1690, 1632 cm^^Hnmr, T3.15 max (d, 2H, =CH-N-CH=, J=8 Hz), 5.22 (dofd,2H, =CH-CH(srBu)-CH=, J=8 Hz, J'=3.5 Hz), 6.20(s, 3H, -C02CH_3), 7.02 (m, IH, -CH(s_-Bu)). The y i e l d of 123d was 80%. Mol. Wt. Calcd. for C^H^NCy 195.1255. Found (high resolution mass spectrometry): 195.1250. Reaction of Lithium Phenylthio(t-butyl)cuprate with Pyridine i n the  Presence of Methyl Chloroformate Following the general procedure outlined above, l i t h i u m phenylthio (_t-butyl)cuprate (4.2 mmol) was allowed to react with pyridine (3 mmol) and methyl chloroformate (3 mmol) at -78°C for l h , warmed to -20°C and s t i r r e d for an additional l h . Normal work-up followed by d i s t i l l a t i o n (air-bath temperature ^80°C, 0.2 Torr) of the crude o i l afforded 273 mg of colorless o i l . A glc analysis (column A, 110°C) of th i s material showed the presence of two components i n the r a t i o of approximately 1:1. An a n a l y t i c a l sample of each component was obtained by preparative glc (column C, 150°C). One of the components was shown to be l-carbomethoxy-4-_t-butyl-l,4-dihydro-pyridine 123e (^26% yi e l d ) and i t exhibited i r (film) v 1730, 1690, max 1635 cm - 1; -"-Hnrnr, T3.22 (d, 2H, =CH-N-CH=, J=8 Hz), 5.12 (d ofd,2H, =CH-CH-CH=, -61-i J=8 Hz, J'-4 Hz), 6.26 (s, 3H, -C0 2CH 3), 7.40 (m, IH, -CH(t-Bu)), 9.18 (s, 9H, -C(CH 3) 3). The 'Hnmr data obtained from the other component indicated that i t could be a mixture of methyl phenylthioformate 133 and methyl 2,2-dimethylpropionate 135, but th i s material was not investigated further. Reaction of Lithium Phenylthio(phenyl)cuprate with Pyridine i n the  Presence of Methyl Chloroformate. Following the general procedure outlined above, l i t h i u m phenylthio-(phenyl)cuprate (4.2 mmol) was allowed to react with pyridine (3 mmol) and methyl chloroformate (3 mmol) at -20°C for 30 min, and at room temperature for an addit i o n a l 20h. Normal work-up, followed by f r a c t i o n a l d i s t i l l a t i o n of the crude o i l gave two f r a c t i o n s . Fraction one (air-bath temperature up to 95°C, 0.1 Torr) contained a complex mixture of hydro-carbons (250 mg). There was no carbonyl nor C-N absorption i n the i r spectrum of this material. Comparison of the "4lnmr spectra of th i s material with that of an authentic sample of biphenyl showed that the major constituent of this material could be biphenyl. This was confirmed by a glc coinjection analysis involving a pure sample of biphenyl and the above mixture. This material was not investigated further. Fraction two (a i r bath temperature M.20°C, 0.1 Torr) was pure l-carbomethoxy-4-phenyl-1,4-dihydropyridine 123f (152 mg, 24% y i e l d ) . This material exhibited i r (film) v 1725, 1690, 1632 cm - 1; 1Hnmr, T2.79 (m, 5H, phenyl), 3.12 (d, 2H, =CH-N-CH=, J=8 Hz), 5.07 (d of d, 2H, =CH-CH(phenyl)CH=, J=8 Hz, J'=3.5 Hz), 5.90 (m, IH, -CH-phenyl), 6.22 (s, 3H, -C0 2CH 3). Mol. Wt. Calcd. for C 1 3H 1 3N0 2: 215.0943. Found (high resolution mass spectrometry): 215.0931. -62-Preparation of Lithium Divinylcuprate-Dimethyl Sufide Complex  ((jg^^CuLi'Me^S)"'"^^ and i t s Reaction with Pyridine i n the Presence  of Methyl Chloroformate. To a cold (-50°C) solution of Me,,S*CuBr (615 mg, 3 mmol) i n ether (5 ml) and dimethyl su l f i d e (4 ml) was added a solution of v i n y l l i t h i u m i n ether (10 ml, 0.6 M, 6 mmol). The resu l t i n g solution was s t i r r e d at -50°C for 15 min. To this solution was added 2.5 mmol (198 mg) of pyridine followed by the dropwise addition of a solution of methyl chloroformate (15 mmol) i n ether (10 ml) over a period of 15 min. The resulting black solution was s t i r r e d at -50°C for 2h, warmed to 0°C and s t i r r e d for an additional 30 min. This solution was then f i l t e r e d through a short column of f l o r i s i l (35 g, 60-80 mesh). The column was eluted with an additional 300 ml of ether. Evaporation of solvent and d i s t i l l a t i o n ( a i r -bath temperature ^50°C, 0.1 Torr) of the residual o i l afforded 253 mg (61%) of a colorless o i l . A glc analysis (column A, 100°C) of this material indicated that i t was a mixture of l-carbomethoxy-4-vinyl-l,4-dihydro-pyridine 123g and l-carbomethoxy-2-vinyl-l,2-dihydropyridine 124g i n the ra t i o of ca. 1:1. An a n a l y t i c a l sample of each compound was obtained by preparative glc (column C, 130°C). The former exhibited i r (film) v max 1730, 1690, 1635 cm - 1; 1Hnmr, T3.19 (d, 2H, =CH-N-CH=, J=8 Hz) 3.9-4.40 (m, IH, ^ = ^ ) , 4.84-5.26 (diffuse, 4H, =CH-CH(vinyl)CH= and § ^ = C H ) > 6.20 (s, 3H, -C0 2CH3 1, 6.42 (m, IH, =CH-CH-CH=). Mol. Wt. Calcd. for C9H11N02:165.0790. Found (high resolution mass spectrometry): 165.0790. The l a t t e r exhibited i r (film) v 1720, 1645, 1585 cm"1; 1Hnmr max T3.27 (d, IH, =CH-N-, J=7 Hz), 3.91-4.99 (diffuse, 7H), 6.21 (s, 3H, -CO^R^l Mol. Wt. Calcd. for CgH^NO^. 165.0790. Found (high resolution mass spectrometry): 165.0790. -63-Reaction of Lithium Diphenylcuprate with Pyridine i n the Presence of Methyl Chloroformate. To a solution of l i t h i u m diphenylcuprate (6 mmol prepared from 140 cuprous bromide and phenyllithium ) i n anhydrous ether (25 ml) at -78°C under an atmosphere of argon was added 5 mmol of pyridine. A solution of methyl chloroformate (20 mmol) i n ether (25 ml) was added dropwise over a period of 15 min. The re s u l t i n g mixture was s t i r r e d at -78°C for l h , warmed to 0°C and then s t i r r e d for an addit i o n a l 1.25h. F l o r i s i l (3 g) was added to the reaction mixture, the l a t t e r was s t i r r e d for a few seconds, and then f i l t e r e d through a short column of f l o r i s i l (35 g). The column was eluted with an additional 350 ml of ether. Evaporation of the ether, followed by f r a c t i o n a l d i s t i l l a t i o n (air-bath) of the residual o i l gave two fra c t i o n s . The f i r s t f r a c t i o n (air-bath temperature up to 110°C, 0.2 Torr) was a complex mixture. "''Hnmr of th i s material showed that the major component i n this mixture was probably biphenyl, but this was not investigated further. The second f r a c t i o n (air-bath temperature VL25°C, 0.2 Torr; 897 mg, 89% yiel d ) was shown by glc analysis (column C, 170°C), to be a mixture of 1-carbomethoxy-4-phenyl-l,4-dihydropyridine 123f and l-carbomethoxy-2-phenyl-l,2-dihydropyridine 124f i n the r a t i o of 84:16. A n a l y t i c a l samples of each compound was obtained by preparative glc (column C, 180°C). Spectral data ('''Hnmr, i r ) of the former was i d e n t i c a l with that of authentic 128 material prepared e a r l i e r by M. Soucy. The very small amount of the l a t t e r obtained exhibited i r (film) v 1720, 1645, 1590 cm"1; max ' • ' "''Hnmr, T2. 30-3.00 (5H, m, phenyl), 3.0-3.37 (m, IH,), 4.0-4.94 (m, 4H), 6.28 (s, 3H, -C0 2CH 3). -64-Reaction of Lithium Dialkylcuprates with Pyridine i n the Presence  of Acetyl Bromide. General Procedure To a solution of the appropriate l i t h i u m dialkylcuprate (6 mmol) i n dry ether (25 ml) at -78°C under an atmosphere of argon was added 5 mmol of pyridine. A solution of acetyl bromide (20 mmol) i n dry ether (25 ml) was added dropwise over a period of 15 min. The r e s u l t i n g mixture was s t i r r e d at -78°C for 30 min, warmed to 0°C and then s t i r r e d for an additional 30 min. F l o r i s i l (3 g) was added to the reaction mixture. The l a t t e r was s t i r r e d for a few seconds, and then f i l t e r e d through a short column of f l o r i s i l (35 g). The column was eluted with an additional 350 ml of ether. Evaporation of the ether, followed by d i s t i l l a t i o n of the residual o i l gave the corresponding l - a c e t y l - 4 - a l k y l -1,4-dihydropyridine. Reaction of Lithium Dimethylcuprate with Pyridine i n the Presence of  Acetyl Bromide. Following the general procedure outlined above, 6 mmol of li t h i u m dimethylcuprate was allowed to react with 5 mmol of pyridine and 20 mmol of acetyl bromide. Normal work-up followed by d i s t i l l a t i o n ( a i r bath temperature ^65°C, 0.1 Torr) of the crude o i l afforded 404 mg (59%) of a colorless o i l . A glc analysis (column C, 140°C) of th i s material showed that i t was pure l-acetyl-4-methyl-l,4-dihydropyridine 137a and i t exhibited i r (film) v 1680, 1637 cm"1; 1Hnmr, x2.90 (d, IH, max » t i =CH-N-, J=9 Hz), 3.52 (d, IH, =CH-N-, J=9 Hz), 5.10 (m, 2H, =CH-CH-CH=), Mol. Wt. Calcd. for CSH, ,N0: 137.0840. Found (high resolution mass 7.00 (m, IH, -CH(CH 3)), 7.85 (s, 3H, (d, 3H, -CH-CH3, J=7 Hz). -65-spectrometry): 137.0836. None of the corresponding 1,2-dihydropyridine derivative was detected. Reaction of Lithium Diethylcuprate with Pyridine i n the Presence of  Acetyl Bromide. Following the general procedure outlined before, 6 mmol of l i t h i u m diethylcuprate was allowed to react with 5 mmol of pyridine i n the presence of 20 mmol of acetyl bromide. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^85°C, 0.2 Torr) of the crude o i l gave 386 mg (51%) of a colorless l i q u i d . A glc analysis (column C, 145°C) of this material showed that i t was pure l-acetyl-4-ethy1-1,4-dihydropyridine and i t exhibited i r (film) v 1670, 1625 cm "*"Hnmr, x2.87 (d, IH, =CH-N-, J=9 Hz), 3.48 (d, IH, =CH-N-, J=9 Hz), 5.13 (m, 2H, =CH-CH-CH=Q, 7.13 (m, IH, -CH(CH 2CH 3)), 7.99 (s, 3H, -C0CH_3) , 8.37-8.77 (m, 2H, -CH(CH 2CH 3)), 9.16 ( t , 3H, -CH(CH 2CH 3)). Mol. Wt.Calcd. for C gH 1 3N0: 151.0997. Found (high resolution mass spectrometry): 151.0993. None of the corresponding 1,2-dihydropyridine derivative was detected. Reaction of Lithium Di-n-butylcuprate with Pyridine i n the Presence of  Acetyl Bromide. Following the general procedure outlined above, 6 mmol of l i t h i u m di-ri-butylcuprate was allowed to react with 5 mmol of pyridine i n the presence of 20 mmol of acetyl bromide. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature M.10°C, 0.1 Torr) of the crude o i l gave 653 mg (73%) of a colorless l i q u i d . A glc analysis (column C, 140°C) of t h i s material showed that i t was pure 1-acety1-4-n-buty1-1,4-dihydro-pyridine and i t exhibited i r (film) v 1675, 1632 cm"1; 1Hnmr, T2.83 max ' f i «• (d, IH, =CH-N-, J=9 Hz), 3.46 (d, IH, -N-CH=, J=9 Hz), 5.05 (m, 2H, =CH-CH-CH -66-7.05 (m, IH, -CH(n-Bu)), 7.83 (s, 3H, -COCH^), 8.45-8.90 ( d i f f u s e , 6H, -CH(CH 2CH 2CH 2CH 3)), 9.10 ( t , 3H, -(CH^CH^, J=7 Hz). Mol. Wt. Calcd. for C^H^NO: 179.1309. Found (high resolution mass spectrometry): 179.1307. None of the corresponding 1,2-dihydropyridine d e r i v a t i v e was detected. Synthesis of l-Trimethylsilyl-4-n-butyl-l,4-dihydropyridine and i t s Conversion into 4-n-Butylpyridine To a cold solution of lith i u m di-n-butylcuprate (6 mmol) i n dry ether (25 ml) at -78°C under an atmosphere of argon was added 5 mmol of pyridine. A solution of chlorotrimethylsilane (702 mg, 6.5 mmol) i n ether (25 ml) was added dropwise over a period of 15 min. The r e s u l t i n g mixture was s t i r r e d at -78°C for 2h, warmed to 0°C and then s t i r r e d f o r an additional 30 min. F l o r i s i l (3 g) was added to the reaction mixture, the l a t t e r was s t i r r e d f o r a few seconds, and then f i l t e r e d through a short column of f l o r i s i l (35 g). The column was eluted with an ad d i t i o n a l 350 ml of ether. Evaporation of the ether afforded 520 mg of crude product. A glc analysis (column A, 110°C) of this material indicated the presence of two components i n the r a t i o of ca. 1:1 "^Hnmr indicated that t h i s material was a mixture of l-trimethylsily-4-n-butyl-l,4-dihydropyridine 138 and 4-n-butyl-pyridine. The presence of 4-n-butylpyridine i n the mixture was confirmed by comparing the "'"Hnmr spectrum of the mixture with the ''"Hnmr of an authentic sample of 4-n-butylpyridine. The "'"Hnmr spectrum of the product mixture was interpreted as follows: xl.52 (d of d, J=5 Hz, J'=2Hz, protons at C-2 and C-6 of 4-n-butylpyridine), 2.89 (d of d, J=5 Hz, J'=2 Hz, protons at C-3 and C-5 of 4-n-butylpyridine), 7.40 ( t , J=7 Hz, CH 2(CH 2)CH 3 > -67-4-n-butylpyridine), 4.07 (d, J=8 Hz, protons at C-2 and C-6 of the dihydropyridine 138), 5.57 (d of d, J=8 Hz, J'=3.5 Hz, protons at C-3, C-5 of the dihydropyridine 138), 3.00 (m, proton at C-4 of the dihydropyridine 138). Because of the i n s t a b i l i t y of the dihydropyridine 138, t h i s material was not isolated for characterization. Instead, the crude product mixture obtained above was subjected to oxidation. The crude mixture was dissolved i n 20 ml of dry ether. This solution was cooled to -78°C under an atmosphere of argon. A solution of 0.1% potassium hydroxide i n methanol (1.5 ml) was added. The mixture was s t i r r e d for 10 min, and a solution of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (1.25 g, 5.5 mmol) i n tetrahydrofuran (25 ml) was added dropwise over a period of 10 min. The resulting mixture was warmed to 0°C, s t i r r e d for 2h at that temperature, warmed to room temperature and then s t i r r e d for an additional l h . The product mixture was poured into an aqueous solution of sodium hydroxide (10%, 60 ml). The aqueous layer was extracted thoroughly with ether. The combined ether extracts were dried over anhydrous magnesium sulfate. Removal of solvent followed by d i s t i l l a t i o n (air-bath temperature ^95°C, 16 Torr) of the residual o i l afforded 233 mg (33%) of pure 4-n-butylpyridine, [ l i t . bp. 84°C, 8 T o r r ] . 1 5 4 ' 1 5 5 ' 1 6 6 This material exhibited i r (film) v 1602 cm 1; ^Hnmr, tl.52 (d of d,2H, max =CH-N=CH, J=5 Hz, J'=2 Hz), 2.89 (d of d,2H, =CH-C=CH, J=5 Hz, J'=2 Hz), 7.40 ( t , 2H, =C-CH2(CH2)2CH3, J=7 Hz), 8.00-9.30 (diffuse, 7H) . Conversion of l-Carbomethoxy-4-alkyl(or aryl)-l,4-dihydropyridines to the  Corresponding 4-Alkyl(or aryl)pyridines. A. Using p-Benzoquinone as Oxidant Conversion of l-Carbomethoxy-4-roethyl-l,4-dihydropyridine to 4-Methylpyridine -68-To a cold (-5°C) solution of l-carbomethoxy-4-methyl-l,4-dihydropyridine (306 mg, 2 mmol) i n dry ether (10 ml) under an atmosphere of argon was added dropwise a solution of methyllithium (6 mmol) i n ether over a period of 10 min. The r e s u l t i n g mixture was s t i r r e d for 15 min, and a solution of p-benzoquinone (216 mg, 2 mmol) i n ether (10 ml) was added dropwise over a period of 10 min. The r e s u l t i n g mixture was s t i r r e d at 0°G for l h and then poured into an ice-cold 50% aqueous solution of ammonium hydroxide (50 ml). The aqueous solution was extracted thoroughly with ether and the combined ether extracts were dried over anhydrous magnesium s u l f a t e . Evaporation of the ether, followed by d i s t i l l a t i o n of the residual o i l (air-bath temperature ^65°C, 16 Torr) afforded 102 mg (55%) of pure 4-methylpyridine. A glc analysis (column E, 110°C) of th i s material, by coinjection with an authentic sample obtained commercially, and comparison of spectral data with that of the authentic sample confirmed the i d e n t i t y of th i s material. Conversion of l-Carbomethoxy-4-n-butyl-l,4-dihydropyridine to 4-n-Butyl-pyridine. Following a procedure i d e n t i c a l with that described above for 1-carbomethoxy-4-methyl-l,4-dihydropyridine, a solution of 390 mg (2 mmol) of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine i n 10 ml of dry benzene was treated f i r s t with methyllithium (6 mmol) and then with p-benzoquinone (2 mmol). Normal work-up, followed by d i s t i l l a t i o n ( a i r bath temperature ^90°C, 16 Torr) of the crude product afforded 126 mg (48%) of 4-n-butylpyridine. A glc analysis (column E, 130°C) of this material show that i t was 95% pure. Spectral data (ir^Hnmr) of this material was i d e n t i c a l with the authentic material prepared e a r l i e r . -69-B. Using Tetrachloro-l,4-benzoquinone as Oxidant Conversion of l-Carbomethoxy-4-n,-butyl-l,4-dihydropyridine to  4-ji-Butylpyridine To a cold (-5°C) solution of l-carbomethoxy-4-n-butyl-l,4-dihydro-pyridine (195 mg, 1 mmol) i n dry benzene (10 ml) was added a solution of methyllithium (3 mmol) i n ether. The re s u l t i n g mixture was s t i r r e d for 15 min. A solution of tetrachloro-l,4-benzoquinone (246 mg, 1 mmol) i n benzene (20 ml) was added dropwise over a period of 15 min. The res u l t i n g mixture was refluxed for 3.5h, cooled to room temperature and then poured into an ice-cold 50% aqueous solution of ammonium hydroxide (80 ml). The aqueous solution was extracted thoroughly with benzene and the combined benzene extracts were dried over anhydrous magnesium su l f a t e . Evaporation of the benzene, followed by d i s t i l l a t i o n (air-bath temperature ^90°C, 16 Torr) of the residual o i l afforded 87.7 mg (65%) of pure 4-n-butylpyridine. C. Using 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) as Oxidant. General Procedure To a cold (-78°C) solution of the appropriate l-carbomethoxy-4-a l k y l ( o r aryl)-1,4-dihydropyridine (2 mmol) i n tetrahydrofuran (10 ml) under an atmosphere of argon was added dropwise a solution of methyllithium (6 mmol) i n ether over a period of 10 min. The r e s u l t i n g mixture was allowed to s t i r at -78°C for 45 min. A solution of DDQ (500 mg, 2.2 mmol) i n t e t r a -hydrofuran (10 ml) was added dropwise over a period of 10 min. The r e s u l t i n g mixture was s t i r r e d at -78°C for 2h, warmed to room temperature and then s t i r r e d for an additional l h . The .reaction mixture was poured into an ice -70-cold 10% aqueous solution of sodium hydroxide (60 ml). The aqueous solution was extracted thoroughly with ether. The combined ether extracts were dried over anhydrous magnesium s u l f a t e . Evaporation of the solvent followed by d i s t i l l a t i o n (air-bath, 16 Torr) of the residual o i l gave the corresponding 4-alkyl(or a r y l ) p y r i d i n e . Conversion of l-Carbomethoxy-4-methyl-l,4-dihydropyridine to 4-Methylpyridine Following the general procedure outlined above, 306 mg (2 mmol) of l-carbomethoxy-4-methyl-l,4-dihydropyridine was allowed to react f i r s t with 6 mmol of methyllithium and then with 2.2 mmol of DDQ. Normal work-up,, followed by d i s t i l l a t i o n (air-bath temperature ^65°C, 16 Torr) of the crude o i l gave 108 mg (58%) of pure 4-methylpyridine. Conversion of l-Carbomethoxy-4-ethyl-l,4-dihydropyridine to 4-Ethylpyridine Following the general procedure outlined above, 334 mg (2 mmol) of l-carbomethoxy-4-ethyl-l,4-dihydropyridine was allowed to react f i r s t with 6 mmol of methyllithium and then with 2.2 mmol of DDQ. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature MJ5°C, 16 Torr) of the residual o i l afforded 190 mg (89%) of 4-ethylpyridine. Comparison of the spectral data obtained from the product with that of the commercially available authentic sample and a coinjection experiment involving glc (column E, 100°C) confirmed the i d e n t i t y . Conversion of l-Carbomethbxy-4-ri-buty 1-1,4-dihydropyridine to 4-ii-Butylpyridine Following the general procedure outlined above,390 mg (2 mmol) of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine was allowed to react f i r s t with 6 mmol of methyllithium and then with 2.2 mmol of DDQ. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^90°C, 16 mm) of the residual -71-i o i l afforded 197 mg (73%) of pure 4-n-butylpyridine. Conversion of l-Carbomethoxy-4-s.-butyl-l ,4-dihydropyridirie to 4-s- Butylpyridine Following the general procedure outlined above, 390 mg (2 mmol) of l-carbomethoxy-4-s_-butyl-l,4-dihydropyridine was allowed to react f i r s t with 6 mmol of methyllithium and then with 2.2 mmol of DDQ. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^70°C, 36 Torr) afforded 214 mg (79%) of 4-s rbutylpyridine [ l i t . bp 197°C, 765 T o r r ] . 1 6 6 - 1 1 This material exhibited i r (film) v 1601 cm : Hnmr xl.50 (d of d, 2H, max ' =CH-N=CH-, J=5 Hz, J'=2 Hz), 2.92 (d of d, 2H, =CH-C=CH-, J=5 Hz, J'=2 Hz), 7.10-7.77 (m, IH, =C-CH(C 2H 5)), 7.83-9.00 (m, 2H, -CHCH2CH3), 8.77 (d, 3H, i CH3-CH-, J=7 Hz), 9.18 ( t , 3H, -CH2-CH3, J=7 Hz). Conversion of l-Carbomethoxy-4-phenyl-l,4-dihydrbpyridine to 4-Pheriylpyridine Following the general procedure outlined above, 430 mg (2 mmol) of l-carbomethoxy-4-phenyl-l,4-dihydropyridine was allowed to react f i r s t with 6 mmol of methyllithium and then with 2.2 mmol of DDQ. Normal work^up followed by d i s t i l l a t i o n of the residual o i l ( a i r bath temperature M.3Q°C, 0.5 Torr) afforded 220 mg (71%) of pure 4-phenylpyridine, mp 70-72°C [ l i t . mp. 69-73°C]. The spectral data ( i r , "Si nmr) of t h i s material were i d e n t i c a l with those obtained from a commercially available authentic sample. -72-BIBLIOGRAPHY 1. A. Hantzsch. Ann. 215, 1 (1882). 2. Reviews on the structure, synthesis, stereochemistry and hydrogen transfer reactions of the pyridine nucleotides are given i n the following: (a) T.P. Singer and E.B. Kearney. Advan. Enzymol. 15, 79 (1954); (b) N.O. Kaplan. Rec. Chem. Progr. 16, 177 (1962); (c) H. Sund, K. Diekmann, and K. Wallenfels. Advan. Enzymol. 26, 115 (1964); (d) F.H. Westheimer. Advan. Enzymol. 24, 469 (1962); (e) S.P. Colowick, J. van Eys, and J.H. Park. Compr. Biochem. 14, 1 (1966); (f) S. Chaykin. Annu. Rev. Biochem. 36, 149 (1967). 3. G.S. Marks, E.G. Hunter, V.K. Terner, and D. Schneck. Biochem. Pharmacol. 14, 1077 (1965). 4. S.R. Humphreys, T.M. Vendetti, C.J. C i o t t i , J . Kline, A. Goldine, and N.O. Kaplan. Cancer Res. 22, 483 (1962). 5. W.C.J. Ross. J. Chem. Soc. C, 1816 (1966). 6. F. Bossert and W. Vater (Farbenfabriken Bayer A.-G.), German Patent 1,813,436 (Oct. 29, 1970); Chem. Abstr. 7_4, 22702k (1971). 7. B. Loev and E. Ralph. S. African Patent 6,800,370, 21 June, 1968; Chem. Abstra. 71, 49786r (1969). 8. B. Loev and J.W. Wilson, U.S. Patent 3,455,939, 15 July 1969; Chem. Abstr. 71, 91319r (1969). 9. The Welcome Foundation Ltd., B r i t i s h Patent, 582,254 (November 11, 1946); Chem. Abstr. 41, 1715 (1947). 10. W.E. Kramer, U.S. Patent 3,118,891, 21 Jan., 1964; Chem. Abstr. 60, 9255(1964). 11. R.A. Abramovitch and J.G. Saba. Advan. Heterocycl. Chem. b, 224 (1966). 12. R.E. Lyle and P.S. Anderson, i b i d . _6, 45 (1966). 13. W. Von Doering and W.E. McEwen. J. Am. Chem. Soc. 73, 2104 (1951). -73-14 (a)R.A. Barns. In "Pyridine and Its Derivatives Part I",Edited by E. Klingsberg. Interscience Press, New York, N.Y., I960 (b) E.N. Shaw, i b i d . Part I I , 1961. 15. U. Eisner and J. Kuthan. Chem. Rev. 72, 1 (1972). 16. P. Karrer. Festschr. Prof. Dr. Arthur S t o l l Siebzigsten Geburtstag, 294 (1957). 17. M.E. Pullman, A. San Pi e t r o , and S.P. Colowick. J. Bio. Chem. 206, 129 (1954). 18. G.W. Rafter and S.W. Colowick. i b i d . 209, 773 (1954). 19. F.W. Fowler. J. Chem. Soc. Chem. Comm. 5926 (1973). 20. P.T. Lansbury and J.O. Peterson. J. Am. Chem. Soc. 85, 2236 (1963). 21. R.E. Lyle and G.J. Gauthier. Tetrahedron Lett. 4615 (1965). 22. N.C. Cook and J.E. Lyons. J. Am. Chem. Soc. 87, 3283 (1965). 23. A. Pelter and K.J. Gould. J. Chem. Soc. Chem. Comm. 347 (1974). 24. D.J. Norris, R. Stewart. Can. J. Chem. 55, 1687 (1977). 25. W. Zecher and F. Krbhnke. Chem. Ber. 94, 707 (1961). 26. N. Sugiyama, G. Inoue, and K. Ito. B u l l . Chem. Soc. Jap. 35, 927 (1962). 27. P.J. B r i g n e l l , U. Eisner, and P.G. F a r r e l l . J. Chem. Soc. B, 1083 (1966). 28. P.J. B r i g n e l l , E. Bullock, U. Eisner, B. Gregory, A.W. Johnson, and H. Williams. J. Chem. Soc. 4819 (1963). 29. E.H. Huntress and E.N. Shaw. J. Org. Chem. 13, 674 (1948). 30. A.H. Cook, I.M. Heilbron and L. Steger, J. Chem. Soc. 413 (1943). 31. A.P. P h i l l i p s . J. Am. Chem. Soc. 71, 4003 (1949). 32. A.P. P h i l l i p s , i b i d . 73, 3522 (1951). 33. R.H. Wiley and J.S. Ridgeway. J. Org. Chem. 26, 295 (1961). -74-34. E. Meyer. J. Prakt. Chem. [2] 92, 174 (1915). 35. G.B. G i l l , D.J. Harper and A.W. Johnson. J. Chem. Soc. C , 1675 (1968). 36. J.F. Biellmann and H.J. C a l l o t . J. Chem. Soc. Chem. Comm. 140 (1969). 37. J.F. Biellmann and H.J. C a l l o t . Tetrahedron. 26, 4799 (1970). 38. G. S c h r o l l , S.P. Nygaard, S.O. Lawesson, A.M. D u f f i e l d , and C. Djerassi. Ark. Kemi. 29, 525 (1968). 39. N. Sugimoto. J. Pharm. Soc. Jap. 64, 192 (1944); Chem. Abstr. 45, 2862 (1951). 40. P. Griess and G. Harrow. Ber. 21, 2740 (1888). 41. M. Jonescu and V.N. Georgescu. B u l l . Soc. Chim. France. [4] 41, 692 (1927). 42. A. Hantzsch. Ber. 18, 2580 (1885). 43. J.G. Erickson. J . Am. Chem. Soc. 67, 1382 (1945). 44. A. Baeyer, J. Piccard, and W. Gruber, Ann. 407, 332 (1915). 45. K.W. Merz and H. Richter. Arch. Pharm. (Weinheim) 275, 294 (1937); Chem. Abstr. 31, 7059 (1937). 46. C.A.C. Haley and P. Maitland. J. Chem. Soc. 3155 (1951). 47. A.P. P h i l l i p s , J. Am. Chem. Soc. 73, 2248 (1951). 48. T. Chennat and U. Eisner. J. Chem. Soc. Perkin I , 926 (1975). 49. A. Singer and S.M. McElvain. Org. Syn. 14, 30 (1934). 50. E. Mohr. J.Prakt. Chem. 5o\> 124 (1897). 51. C. Beyer. Ber. 24, 1662 (1891). 52. E. Booker and U. Eisner. J. Chem. Soc. Perkin I, 929 (1975). 53. C.A. Bear, W.R. Cullen, J.P. Kutney, V.E. Ridaura, J. Trotter, and A. Zanarotti. J . Am. Chem. Soc. 95, 3058 (1973). -75-54. J.P. Kutney, R. Greenhouse, and V.E. Ridaura. J. Am. Chem. Soc. 96, 7364 (1974). 55. M. Ferles. Collect. Czech. Chem. Commun. 23, 479 (1958). 56. F.W. Fowler. J. Org. Chem. 37, 1321 (1972). 57. E.E. Knaus and K. Redda. Can. J. Chem. 55, 1788 (1977). 58. S. Yamada, M. Kuramoto, and Y. Kikugawa. Tetrahedron Lett. 3101 (1969) . 59. N. Kinoshita and T. Kawasaki. Yakugaku Zasshi, 83, 123 (1963); Chem. Abstr. 59, 5126 (1963). 60. K. Schenker and J. Druey. Helv. Chim. Acta, 42, 1960 (1959). 61. R.M. Acheson and G. P a g l i e t t i . J. Chem. Soc. Perkin I, 45 (1976). 62. D.L. Coffen. J. Org. Chem. 33, 137 (1968). 63. K. Wallenfels, H. Schuly, and D. Hofmann. Ann. 621, 106 (1959). 64. K. Wallenfels and M. G e l l r i c h , i b i d . 621, 198 (1959). 65. R. Segal and G. Stein, J. Chem. Soc. 5254 (1960). 66. P. Rarer, G. Schwarzenbach, and C.E. Utzinger. Helv. Chim. Acta, 20, 72 (1937). 67. J. Kuthan and E. Janeckova. Collect. Czech. Chem. Commun. 29, 1654 (1964). 68. J. Palecek, L. Ptackova, and J. Kuthan. i b i d . 34, 427 (1969). 69. W. Hanstein and K. Wallenfels. Tetrahedron, Z3,585 (1967). 70. S. Yamada and Y. Kikugawa. Chem. Ind. (London),2169 (1966). 71. M. Ferles. Sb. Vysoke Skoly Chem. Technol. Praze Oddil Fak. Anorg. Org. Techno1. 519 (1960); Chem. Abstr. 55, 24740 (1961). 72. M. Ferles. Chem. L i s t y 52, 674 (1958); Chem. Abstr. 52_, 13724 (1958). 73. F. Bohlmann and M. Bohlmann. Ber, 86, 1419 (1953). -76-74. G. Fraenkel and J.C. Cooper. Tetrahedron Le t t. 1825 (1968). 75. R. Foster and C.A. Fyfe. Tetrahedron, 25, 1489 (1969). 76. G.S. Giam and J.L. Stout. J. Chem. Soc. Chem. Comm. 142 (1969). 77. G.S. Giam and J.L. Stout, ibid.478 (1970). 78. G.S. Giam and E.E. Knaus. Tetrahedron Lett. 4961 (1971). 79. R.F. Francis, W. Davis, and J.T. Wisener. J. Org. Chem. 39, 59 (1974), 80. R. Grashey and R. Huisgen. Chem. Ber. 92, 2641 (1959). 81. L.M. Thiessen, J.A. Lepoivre, and F.C. Alderweireldt. Tetrahedron  Lett. 59 (1974). 82. R. Grewe and A. Mondon. Chem. Ber. 81, 279 (1948). 83. 0. Schnider and A. Griisser. Helv. Chim. Acta, 32, 821 (1949). 84. E.L. May and E.M. Fry. J . Org. Chem. 22, 1366 (1957). 85. G. Fraenkel, J.W. Cooper, and CM. Fink. Angew. Chem. Int. Ed. Engl. £, 523 (1970). 86. R.E. Lyle, J.L. Marshall, and D.L. Comins, Tetrahedron Lett. 1015 (1977). 87. R.C. Fuson and J . J . M i l l e r . J. Am. Chem. Soc. 79, 3477 (1957). 88. R.E. Lyle and D.A. Nelson. J. Org. Chem. 28, 169 (1963). 89. R.E. Lyle and S.E. Mallet. Ann. N.Y. Acad. S c i . 145, 83 (1967). 90. R.E. Lyle and E. White. J. Org. Chem. 36, 772 (1971). 91. R. Lukes and J. Kuthan. Angew. Chem. 72, 919 (1960). 92. R. Lukes and J. Kuthan. C o l l e c t . Czech. Chem. Commun. 26, 1422 (1961), 93. R. Lukes and J. Kuthan. i b i d . 26, 1845 (1961). 94. T. Kauffmann and H. Hacker. Chem. Ber. 95, 2485 (1962). 95. P. Bemporad, G. I l l u m i n a t i , and F. Stegel. J. Am. Chem. Soc. 91, 6742 (1969). -77-96. H. Abrecht and F. Krohnke. Ann. 717, 96 (1968). 97. H. Abrecht and F. Krohnke. i b i d . 704, 133 (1967). 98. F.Krohnke, K. Ellegast, and E. Betram. i b i d . 600, 176 (1956). 99. M.N. Palfreyman, K.R.H. Wooldridge. J. Chem. Soc. Perkin I, 57 (1974). 100. J.F. Biellmann and H.J. Ca l l o t . B u l l . Soc. Chim. France, 1299 (1969). 101. W.S. Caughey and K.A. Schellenberg. J. Org. Chem. 31, 1978 (1966). 102. W. Traber and P. Karrer. Helv. Chim. Acta, 41, 2066 (1958). 103. P.R. Brock and P. Karrer. Ann. 605, 1 (1957). 104. A.F.E. Sims and P.W.G. Smith. Proc. Chem. Soc. 282 (1958). 105. A. Stook and F. Otting. Tetrahedron Lett. 4017 (1968). 106. T.O. Kamoto, M. Kirobe, C. Mizuskin, and A. Osawa. Chem. Pharm. B u l l . Jap. 11, 780 (1963); Chem. Abstr. 59, 9752 (1963). 107. R.E. Lyle. Chem. Eng. News, 72 (Jan. 10, 1966). 108. H. Diekmann, G. Englert, and K. Wallenfels. Tetrahedron, 20, 281 (1964). 109. R.N. Lindquist and E.H. Cordes, J. Am. Chem. Soc. 90, 1269 (1968). 110. K. Wallenfels and H. Diekmann. Ann. 621, 166 (1959). 111. K. Wallenfels and H. Schuly. Angew. Chem. 70, 471 (1958). 112. P.M. A t l a n t i and J.F. Biellmann. Tetrahedron Lett. 4829 (1969). 113. 0. Dimroth and F. F r i s t e r . Ber. 55, 1223 (1922). 114. A.T. Nielson, D.W. Moore, G.M. Muha, and K.H. Berry. J. Org. Chem. 29, 2175 (1964). 115. J.E. Colchester (Imperial Chemical Industries), B r i t i s h Patent 1189084 (1970); Chem. Abstr. 73, 253156 (1970). 116. H.H. Fox, J. I . Lewis, and W. Wenner. J. Org. Chem. 16, 1259 (1951). -78-117. S.J. Leach, J.H. Baxendale and M.G. Evans. Aust. J. Chem. 395 (1953). 118. 0. Mumm. Ann. 529, 115 (1937). 119. U. Eisner. J. Chem. Soc. Chem. Comm. 1348 (1969). 120. N.C. Cook and J.E. Lyons. J. Am. Chem. Soc. 88, 3396 (1966). 121. A.J. Birch and E.A. Karakhanov. J. Chem. Soc. Chem. Comm. 480 (1975). 122. R. Huisgen and K. Herbig. Ann. 688, 98 (1965). 123. A. Demoulin, H. Gorissen, A-M. Hesbain-Frisque, and L. Ghosez. J. Am. Chem. Soc. 97_, 4409 (1975). 124. W.H. Okamura. Tetrahedron Lett. 4717 (1969). 125. J.F. Biellmann and M.P. Goeldner. Tetrahedron, 2_7, 2957 (1971). 126. M. Anderson and A.W. Johnson. J. Chem. Soc. 2411 (1965). 127. D.M. Stout, T. Takaya, and A.I. Meyers. J. Org. Chem. 40, 563 (1975). 128. E. Piers and M. Soucy. Can. J. Chem. 52, 3563 (1974). 129. S. Skraup. Ann. 231, 1 (1919). 130. A. Courts and V. Petrow. J . Chem. Soc. 1 (1952). 131. L.G. Duquette and F. Johnson. Tetrahedron, 23, 4517 (1967). 132. N.R. Davis and R.A. Anwar. J. Am. Chem. Soc. 92, 3778 (1970). 133. D. Craig, L. Schaefgen, and W.D. Tyler. J . Am. Chem. Soc. 70, 1624 (1948). 134. A. Kamal, M. Ahmad, N. Mohd, and A.M. Hamid. B u l l . Soc. Chem. Jap. 37, 610 (1964). 135. E.J. Moriconi and R.E. Misner. J. Org. Chem. 34, 3672 (1969). 136. G. Vanags and E.I. Stankevich. Zh. Obshch. Khim. 30, 3287 (1960); Chem. Abstr. 55, 21119 (1961). 137. A.I. Meyers and J.J. R i t t e r . J. Org. Chem. 23, 1918 (1958). 138. T. Kametani, K. Ogasawara, and A. Kozuka, J. Pharm. Soc. Jap. 86, 815 (1966). -79-139. A.I. Meyer and S. Singh. Tetrahedron, 25, 4161 (1969). 140. G.M. Whiteside, W.F. Fischer, J r . , J. San F i l i p p o , J r . R.W. Bashe, and H.O. House. J. Am. Chem. Soc. 91, 4871 (1969). 141. G.H. Posner, C.E. Whitten and J.J. Ster l i n g . J . Am. Chem. Soc. 95, 7788 (1973). 142. J.F. Normant. Synthesis, 63 (1972). 143. G.H. Posner. Organic Reactions, 19, 1 (1972). 144. H.C. House and M.J. Umen. J. Org. Chem. 38, 3893 (1973). 145. H.O. House. Acc. Chem. Res. % 59 (1976) and the references cited therein. 146. R.G. Peason, and CD. Gregory. J. Am. Chem. Soc. 98, 4098 (1976). 147. B. Emmert. Ber. 50, 31 (1917). 148. E.M. Kosower and P.E. Klinedinst, J r . J. Am. Chem. Soc. 78, 3493 (1956) 149. E.M. Kosower. J. Am. Chem. Soc. 78, 3497 (1956). 150. A. Ladenburg. Ber. 16, 2059 (1883). 151. A. Ladenburg. Ann. 247, 1 (1888). 152. W.H. Rieger, U.S. Patent 2,502,174, Mar. 28, (1950); Chem. Abstr. 44, 5396g (1950). See also reference 14b. 153. S. Goldschmidt and M. Minsinger. Chem. Ber. 87, 956 (1954). 154. J.P. Wibaut and J.F. Arens. Rec. trav. Chim. 60, 119 (1941). 155. J.F. Arens and J.P. Wibaut, Rec. trav. Chim. 61, 59 (1942). 156. A.E. Chichibabin. B u l l . Soc. Chim. [5] 3_, 1607 (1936). 157. H. Gilman and F.K. Cartledge, J. Organometal. Chem. 2, 447 (1964). 158. D. Seyferth and M.L. Weiner, J. Am. Chem. Soc. 83, 3583 (1961). 159. Te t r a v i n y l t i n i s commercially available, but this compound was prepared i n our laboratory from the reaction of v i n y l magnesium bromide and stannic chloride, following the procedure of G.J.M. Van der Kerk. Organic Synthesis Collective Vol. 4_, 881 (1963). -80-160. G.B. Kauffman and L.A. Teter. Inorg. Synth. 7_, 9 (1963). 161. G.H. Posner, D.J. Brunelle and L. Sinoway. Synthesis, 662 (1974). 162. C.R. Johnson and G.A. Dutra. J. Am. Chem. Soc. 95, 7777 (1973). 163. P.M. A t l a n t i and J.F. Biellman. C.R. Acad. S c i . Ser. C, 271, 688 (1970). 164. Farbenfabriken Bayer A-G. Neth. Appl. 6,408,287 ( C l . C07C), Jan. 21, 1965. Chem. Abstr. 63, 11440 (1970). 165. H.O. House, C.Y. Chu, J.M. Wilkins and M.J. Umen. J. Org. Chem. 40, 1460 (1975). 166. C.T. Kyte, G.H. Jeffery and A.I. Vogel, J. Chem. Soc. 4454 (1960). -81-PART I I Synthesis and Thermal Rearrangement of B-Cyclopropyl-a,B-unsaturated Ketones and Related Compounds INTRODUCTION I. General The occurrence of five-membered rings i n an increasing number of natural products of b i o l o g i c a l importance has recently stimulated the development of a wide variety of new synthetic methods for the preparation of cyclopentane rings. For example, the a n t i b i o t i c sesquiterpenes h i r s u t i c 1 2 3 acid 1 and c o r i o l i n 2 , the l i p o p h i l i c a n t i b i o t i c pentalenolactone 3^  , 4 the sesterterpene retigeranic acid 4^  , the t r i c y c l i c sesquiterpenes capnellane 5^ and zizaene 6^, a l l contain two or more fused cyclopentane rings. Most of the more recently developed methods for constructing cyclopentane rings are based on intramolecular ring closure of acyclic 7-15 . , - . . . . . , . 16-18 precursors. A few novel methods that involve ring contraction and ring expansion^"9 ^ of c y c l i c compounds have been reported. Cyclo-21—26 addition reactions have also been employed. I t was not u n t i l quite recently that the well established vinylcyclopropane-cyclopentene rearrange-27-30 ment has received considerable attention as a viable and synthetically -82-valuable method for cyclopentane ring synthesis, II. Vinylcyclopropane-Cyclopentene Rearrangement The thermal rearrangement of vinylcyclopropane to cyclopentene 31 was f i r s t reported by Overberger and Borchert in 1960 (eq.l). Since then, this process has received considerable attention. A wide variety of substituted vinylcyclopropanes having the general structure 1_ have been thermally rearranged to cyclopentenes of tne general structure 8^  (eq. 1). a) b) c) d ) e) f) g) h) 32,33 34 35 36,37 36 37-39 38,39 40 R1=R2=Me R2=Et R3-C-C3H5 R l=CH 3, R 3 = X ^ > R2=CH3, R3=X-^Q-R2 , R3=C-C3H5 R.=CH„ 4 3 (1) P) q) r) s) 47 48 48 48 3 , R^ , Rg—C£ Rc, R,=C£ 5 6 R5=CH0 R5=R6=C02Et R2=C02Me, R5 or R6=C02Me R =R.=CH 3 4 3' R5' R5 or R 6=N(CH 3) 2 Rc or R =0CH_ j o J R4=0CH3 R5 or Rg=Ph In general, the yields of isolable cyclopentene products in these reactions are f a i r l y high,except when the cyclopropyl group is cis to a -83-methyl group across the double bond. For example,the rate of thermolysis of compound 7_f was comparable to that of the other members of ]_, but only a small amount of cyclopentene product 8f_ was obtained along with a large amount of polymer. It was also found that substitution i n the v i n y l -cyclopropane system, both on the ring and around the double bond, exerts considerable influence on the rate of the reaction and plays a role i n 2 determining the course of the thermal rearrangement into a cyclopentene. These substitution effects w i l l be discussed i n more d e t a i l l a t e r on when the mechanism of the rearrangement i s considered. Stepwise vinylcyclopropane rearrangements occur i n compounds 9 and 12 which give, i n addition to the monocyclized products ]_0 and L3, the dic y c l i z e d products 11_ and L4, respectively (eq. 2 and 3 ) . " ^ ' ^ In these examples, the incorporation of a portion of the vinylcyclopropyl moiety into a c y c l i c structure does not interfere with the reaction. In f a c t , these transformations represent the f i r s t examples of cyclopentene annelation v i a vinylcyclopropane rearrangement. The idea of using the rearrangement of vinylcyclopropanes as a method for f i v e membered ring annelation has been expanded recently by Stork^ 9, -84-Trost^^'^ 1, Corey"^ and Monti"^. By incorporating appropriate substituents on the cyclopropane ring or on the v i n y l i c double bond, the newly con-structed ring may contain a f a i r l y wide variety of functional groups. For example, compound 1_5_ rearranges smoothly at 360°C to the annelated 49 cyclopentene 16_ (eq.4). The siloxyvinylcyclopropanes _20, which were prepared from the cycloalkanones 17_ v i a the oxaspiropentanes 18^ , undergo thermal rearrangement to give the enol s i l y l ethers 21 i n over 90% y i e l d . Hydrolysis of the enol s i l y l ethers 21 unmasked the carbonyl groups to give the corresponding cyclopentanones _22 (Scheme 1). The enol s i l y l ethers 21_ may also be transformed into a spec i f i c enolate , which may then be alkylated to introduce further a l k y l groups. For example, treatment of 2lb with methyllithium followed by methyl iodide gave the perhydroazulene derivative 23 (eq.5)."^ 50 (4) 16 I^^Y© [>-SPh2 BF4-17_ a) n=0 b) n=2 c) n=l KOH (CH2)n 18 i N ( i - p r ) , _ > (CHJ, 2yn OLi 19 Me 3SiCJl <CH2)n OSiMe3 OSiMe3 H (CH2)n -85-OSiMe3 CH^Li CH 3I (5) 21b Although this procedure was found to work quite well with saturated cycloalkanones, i t f a i l e d with a,3-unsaturated cycloalkenones. Furthermore, with cyclohexanone, the y i e l d of the siloxyvinylcyclopropane from the corresponding oxaspiropentane was f a i r l y poor. However, these l i m i t a t i o n s could be overcome by substituting the siloxy group with a phenythio group. Tne vinyicyclopropylphenyl s u l f i d e 26_ could be prepared by the addition of 1-lithiocyclopropylphenyl s u l f i d e to 4-_t-butylcyclohexanone 2h_, followed by dehydrat ion of the resulting alcohol 25. Pyrolysis of the vin y i c y c l o -propylphenyl s u l f i d e J26_ gave the enol thioether 27_ which could be hydrolysed to the corresponding cyclopentanone 28^ or desulfurized to give the cyclo-pentene 29_ (Scheme 2) S i m i l a r l y , addition of 1-lithiocyclopropylphenyl su l f i d e to the a,8-unsaturated ketone _30^ , followed by dehydration of the l a t t e r gave the cyclopropylphenyl s u l f i d e 31. Pyrolysis of this compound, followed by hydrolysis of the resulting enol thio ether _32 afforded the cyclopentenone 33. ™ S A \ / SPh SOC£2,pyridin 24 25 26 -86-Th e l a s t few examples mentioned above demonstrated that the thermal rearrangement of vinylcyclopropane systems which incorporate the carbon-carbon double bond i n a r i n g afford s y n t h e t i c a l l y useful y i e l d s of the corresponding cyclopentane derivatives (annelation products). Similar re s u l t s have been obtained when the cyclopropane rin g i s fused to another c y c l i c structure. For example, pyrolysis of the enol s i l y l ethers 3>4_, followed by hydrolysis of the rearranged products, gave the cyclopentenones _3_5 and 3_6_, along with considerable 53 amounts of 37_ (eq.6). However, pyrolysis of the enol s i l y l ethers 38, followed by hydrolysis of the r e s u l t i n g products, afforded i n good y i e l d s 53 the annelated cyclopentanones 39_ as the only isol a t e d products (eq.7). In a s i m i l a r fashion, compound 40 rearranged upon heating to afford the -87-OSiMe, 38 a) n=0 b) n=l c) n=2 2. H 30 + <cCC) 39 Yield 21% 99% 85% (7) ketone 41_. The l a t t e r was transformed into the aldehyde 4^ 3, which served as an intermediate i n the synthesis of 11-deoxyprostaglandin 52 E2 — (Scheme 4) . I t i s interesting to note that compound 45_, the deoxo derivative of compound 4^), undergoes a f a c i l e intramolecular "ene" reaction rather than the normal vinylcyclopropane rearrangement. Thus pyrolysis of compound 4_5 afforded the o l e f i n 48_ as the major product 52a along with a small amount of the annelated cyclopentene 4 7 (ecj.8). Presumably, isomerization of 4_5 to 4j5 occurred, prior to the rearrangement to 48. OMe HO 600'C H ---s. H 40 41 H 42 CHO 43 -88-The thermal rearrangement of vinylcyclopropane systems i s unsuccessful i f the product that would be produced i s ex t r a o r d i n a r i l y strained. For example, i t was found that 1-vinylnortricyclene 49_ was recovered unchanged upon heating at 475°C for 25 min."*4 I f a normal vinylcyclopropane rearrangement had occurred, the r e s u l t i n g product (50) 55 would have been i n v i o l a t ion of Bredt's r u l e . 49 50 Normal vinylcyclopropane rearrangement can take place even i f the entire vinylcyclopropane moiety i s incorporated into a c y c l i c framework, provided that there i s no excessive ri n g s t r a i n present i n the rearranged product and that there i s no competitive reaction taking place. For example, at 250°C, 8-thujene _51 rearranged to afford a mixture of 52. and _53_ while at 300°C, 53 was the only observed product (eq.10).^^ The succes: of t h i s rearrangement might suggest that higher homologs would rearrange i n a s i m i l a r way. However, pyr o l y s i s of 7-carbomethoxynorcar-2-ene 54 gave a complex mixture i n which ethylene and carbomethoxycyclopentadiene 56^were present. Presumably, the l a t t e r were formed v i a the intermediate 55 ( e q . l l ) . 5 7 -89-51 250°C 52 300°C (10) 53 Me0 2 C 5 5 Me02C- + CH=CH2 (11) 56 Pyrolysis of bicyclo[3.1.0]hex-r2-ene 57a, bicyclo[5.1.0] oct-2-ene 57b and bicyclo[6.1.0]non-2-ene 57c resulted i n transannular hydrogen migration to give the dienes 58a, 58b and 58c respectively, rather than 58 59 undergoing the vinylcyclopropane-type rearrangement (eq.12). ' The ease of transannular hydrogen migration i n the bicyclo[6.1.0]nonene system could be diminished by incorporating additional unsaturation into the system. When this was done, the vinylcyclopropane-type rearrangement took place. For example, pyrolysis of the bicyclo[6.1.0Jnonatrienes _59 gave the corresponding dihydroindenes j>0 (eq.13).^ S i m i l a r l y , pyrolysis of the b i c y c l i c unsaturated ketone 61_ gave the cyclopentanone bl_ as the 65 major product (eq.14). (a) n=0; (b) n=2; (c) n=3 59 ( C H 2 ) N (a) R=H; (b) R=C£; (c) R=C02Et; (d) R=CH20H 60 (12) (13) -90-O (14) Vinylcyclopropane-Cyclopentene rearrangements may also be effected by means other than heat. Photolysis of the vinylcyclopropane derivative 64 gave the cyclopentene 65_ as the major product (eq.15). 6 6 Irradiation of the bicycloheptene 67 in the presence of a sensitizer gave 66% of the 67 bicyclo[3.2.0]heptene j68 and 13% of i t s isomer ^9 (eq.16). S i m i l a r l y , i r r a d i a t i o n of the b i c y c l i c compound 7_1 and 7_3 gave the corresponding 68 bicyclo [3.3. 0]octenes 12_ and 74_ respectively (eq.17 and 18). -91-h v 60% v y CD (18) r H 73 74 Treatment of l,l-dibromo-2-vinylcyclopropane 75a with methyllithium gave 86% of the cyclopentadiene 76a and 14% of the penta-l,2,4-triene, while l,l-dibromo-2-methyl-2-isopropenylcyclopropane 75b gave 95% of a mixture of the dimethylcyclopentadienes 76b (eq.19). 69 R-Br-CH 3Li \ (19) Br 75 76 (a) R=H; (b) R=CH, Transition metals have also been used to catalyse the v i n y l c y c l o -propane-cyclopentene rearrangement. Thus, a stoichiometric rhodium(I) complex of the vinylcyclopropane 7_7 rearranges readily to the rhodium (I) complex of bicyclo[3.3.0]octa-2,6-diene ( e q . 2 0 ) . 7 1 However, i n the absence of the catalyst, the same vinylcyclopropane 7_7 gave the bicyclo-72 [3.2.1]octa-2,6-diene _79 v i a a [3,3] sigmatropic rearrangement (eq.21). (20) (21) 21 79 -92-Sim i l a r l y the bicyclo[6.1.0]nona-2,4,6-triene jH) rearranged readily and quantitatively i n the presence of dicarbonylrhodium(I) chloride diraer into the corresponding bicyclo[4.3.0]nonatriene 81 (eq.22). 7 3 .CI * (CO) 2Rh^ c^Rh(CO) 2 (22) I H R 80 81 I I I . Mechanistic Considerations i n the Thermal Vinylcyclopropane- Cyclopentene Rearrangement. The mechanism of the thermal vinylcyclopropane-cyclopentene 27 28 30 rearrangement has long been a subject of controversy. ' ' Most of the arguments have focused on the degree to which the process i s concerted or stepwise. The vinylcyclopropane rearrangement can be thought to occur v i a a mechanism i n which the rate-determining step i s the opening of the 74 75 cyclopropyl ring to form the d i r a d i c a l 82, ' followed by ring closure as a result of intramolecular coupling of the d i r a d i c a l . On the other hand, i t can also be envisaged to proceed v i a a concerted mechanism involving a Cope-type t r a n s i t i o n state such as 83 (Scheme 5 ) # ^ » ^ » ^ -93-Scheme 5 Kinetic data has indicated that the rearrangement i s a unimolecular 33 76 process with an activation energy of cii. 50 kcal/mol. ' The activation energy i s about 14 kcal/mol lower than that of ordinary cyclopropane ring cleavage. The difference corresponds quite well to the a l l y l i c resonance energy and has been interpreted i n terms of a resonance s t a b i l i z e d b i r a d i c a l intermediate. Current sentiment seems to favor the intermediacy of a d i r a d i c a l rather than a concerted process. Theoretical molecular o r b i t a l calculations, based on the MINDO/3 (Modified Intermediate Neglect of D i f f e r e n t i a l Overlap) semiempirical SCF-MO (Self-Consistent F i e l d Molecular Orbital theory) method, 80 predicted that the rearrangement i s a "forbidden" b i r a d i c a l o i d process. Wilcott and Cargle were able to conclude, from nmr investigations, that i n the thermolysis of monodeuteriovinylcyclopropane, the loss of stereo-s p e c i f i c i t y at the deuterium-labeled s i t e i n the cyclopropyl ri n g i s at least f i v e times as fast as the conversion to cyclopentene, thus substantiating 81 the d i r a d i c a l mechanism (Scheme 6). More recently, the same authors have Scheme 6 -94-studied the degenerate rearrangement of 1-(2-deuteriovinyl)-trans,trans-2,3-dideuteriocyclopropane 84a by nmr and have obtained additional evidence supporting the intermediacy of a d i r a d i c a l (Scheme 7). 82 84b 84a \ / i i 4 1 Scheme 7 (84b+84c):84d=2:l Comparative k i n e t i c studies have shown that substitutions on C-2 of vinylcyclopropane with chloro^ 2, methoxyl^, phenyl^ 8, or a 47 dimethylamino group (85a, 85b, 85c, 85d respectively) considerably enhances the rate of rearrangement to the corresponding cyclopentene. Also, the products formed are exclusively the 4-substituted cyclopentenes 86 rather than the 3-substituted isomers 87_ (eq.23). The f a c i l i t y with which these reactions take place and the stereoselectivity of the process have been explained by invoking a d i r a d i c a l intermediate. > \ 87 (23) 85 86 (a) R=R -CA; (b) R or R^OCI^; (c) R or R^Ph; (e) R or R1=NMe2 It i s of interest to note that when an a l k y l group i s located c i s to the cyclopropyl ring i n these vinylcylopropane systems (for example, -95-as i n compounds 90_, 91_ and 93) , the rate of thermal rearrangement i s s t r i k i n g l y reduced and the products formed are usually polymers or 37 49 83 s t r u c t u r a l l y rearranged o l e f i n s (eq.24-26). ' ' In contrast, when the a l k y l group i s situated trans to the cyclopropyl r i n g , i t has no 37 83 diminishing effect on the rates of rearrangement. ' This observation has been explained i n terms of s t e r i c interactions. The c i s a l k y l groups prevent the r i g i d a l l y l i c r a d i c a l from remaining planar i n the t r a n s i t i o n state, thereby lowering i t s a l l y l i c resonance energy, r a i s i n g the energy b a r r i e r to r i n g closure and hence making the reaction pathway towards isomerization to o l e f i n s an energetically more favourable process, 450°C polymer (24) 360°C Me *~ CHzCOjR 92 300°C cis-trans (25) isomerization 390°C s> (26) 93 IV. The Problem Recently, our laboratory has developed an e f f i c i e n t method for the preparation of c y c l i c 8-halo-ot,6-unsaturated ketones from the reaction of -96-84 c y c l i c g-diketones 96_ with triphenylphosphine dihalides. These g-halo enones have been converted into a variety of g-alkyl-a,B-unsaturated ketones i n good y i e l d by treating the former with various cuprate 85 reagents. Thus, o v e r a l l , previous work i n our laboratory had established an e f f i c i e n t synthetic route for transforming a c y c l i c g-diketone of the general structure 96_ to the corresponding c y c l i c g-alkyl-a,g-unsaturated ketones of the general structure 98_, as shown i n the scheme below. P h 3 p x 2 o o 96 97. 98 The f i r s t objective of the work described i n this section of t h i s thesis was to investigate the p o s s i b i l i t y of extending this methodology to include the synthesis of c y c l i c g-cyclopropyl-a,g-unsaturated ketones of the general structure 99. I t can readily be seen that the l a t t e r compounds incorporate into their structures the vinylcyclopropane moiety, with the v i n y l portion of this functionality being part of the a,g-unsaturated ketone moiety. Thus, the second objective of this work was to investigate the thermolysis of these compounds, to determine whether or not they could serve as precursors for an e f f i c i e n t cyclopentane annelation method. F i n a l l y , the p o s s i b i l i t y of applying this methodology to the t o t a l synthesis of natural products was also considered worthy of investigation. -97-DISCUSSION I. Synthesis of Cyclic B-Iodo-a,B-Unsaturated Ketones The conversion of B-diketones into the corresponding B-chloro-ot,B-unsaturated ketones has been achieved by treating the former with a wide variety of reagents: phosphorous t r i c h l o r i d e , phosphorus oxychloride, 86 phosgene, acetyl chloride and oxalyl chloride. However, prior to recent work done i n our laboratory, the transformation of B-diketones into the corresponding B-iodo-a,B-unsaturated ketones by use of analogous reagents had not been accomplished. In f a c t , reports concerning the preparation of this class of compounds had been very scarce. 3-Iodo-2-cyclohexen-l-one 101 had been prepared by refluxing 3-chloro-2-cyclohexen-l-one 100 with 87 sodium iodide i n acetone for 24h (eq.27). However, the product of t h i s reaction was a mixture of B-iodo and B-chloro enones, and the B-iodo compound obtained was not f u l l y characterized. (27) 100 A24h Recently, Piers and Nagakura"^ reported an e f f i c i e n t conversion of c y c l i c B-diketones into the corresponding B-halo-a,B-unsaturated ketones by treating the former with triphenylphosphine dihalides i n the presence of triethylamine. I t was found that the halide could be chloride, bromide, or iodide (eq.28). This represented the f i r s t direct conversion of B-diketones into the corresponding B-iodo-a,B-unsaturated ketones, and, i n f a c t , represented the f i r s t general synthesis of the l a t t e r type of compound. -98-Ph 3PX 2 solvent 103 X = CI, Br, I (28) In studying the reaction of these 6-halo enones with various cuprate reagents, i t was found that the B-iodo enones were superior to the corresponding bromo or chloro derivatives i n y i e l d i n g the 85 corresponding B-alkyl-a,B-unsaturated ketones. Therefore, the B-iodo enones were chosen to be the s t a r t i n g materials to investigate the synthesis of the corresponding B-cyclopropyl-a,B-unsaturated ketones. The o r i g i n a l procedure reported for the conversion of B-diketones into the corresponding B-iodo enones was rather tedious. For example, when 1,3-cyclohexanedione 104 was treated with triphenylphosphine diiodide i n a c e t o n i t r i l e i n the presence of triethylamine at room temperature, i t took four days for complete conversion of the dione into 3-iodo-2-cyclohexen-84 1-one 101 (eq.29). During the course of the work described i n t h i s t h e s i s , the procedure has been s i m p l i f i e d and the y i e l d s of the reaction products have been improved considerably. Thus, the dione 104 was converted into the corresponding B-iodo enone 101 i n 87% y i e l d by re f l u x i n g the former with 1.1 equivalents of triphenylphosphine diiodide i n a c e t o n i t r i l e i n the presence of 1.1 equivalents of triethylamine for 9h. The B-iodo enone 101 was found to be a low melting s o l i d : mp 15-16°C. I t exhibited a strong absorption i n the uv spectrum at 258 nm, with e=9000(ir->-ir* t r a n s i t i o n of a,B-unsaturated ketone). Two strong absorption bands at 1675 and 1595 cm i n the i r spectrum of t h i s compound also indicated the presence of an a,B-unsaturated carbonyl f u n c t i o n a l i t y . The o l e f i n i c proton of t h i s compound gave r i s e to a one-proton t r i p l e t at T3.20 (J=2HZ) i n the "hlnmr spectrum. -99-The structure of the enone 101 was further Confirmed by a s a t i s f a c t o r y elemental analysis. 112 n=l, R=H 116 n=2 114 113 n=l, R=CH3 Similar transformations were carried using the g-diketones 105-108, i n c l u s i v e , and the hydroxymethylenecycloalkanones 109 and 110 as s t a r t i n g materials. The re s u l t s are summarized i n Table 1. In each case, the product exhibited spectral data ( i r , ^ Hnmr) i n f u l l accord with the assigned P h 3 P I 2 .-0 Et3N,CH3CN 104 r . t . 4 days (29) 101 structure, and gave a s a t i s f a c t o r y elemental analysis and/or a molecular -100-weight determination (high resolution mass spectrometry). Although the data summarized i n Table 1 are r e l a t i v e l y s t r a i g h t -forward, i t i s appropriate to make a few comments. I t was found that the conversion of cyclopentanediones 106 and 107 into the corresponding 3-iodo enones 112 and 113, respectively, required a shorter reaction time (3h) than did t h e i r six-membered ring counterparts 104 and 105 (entries 3 and 4 vs entries 1 and 2, Table 1). I t i s of interest to note that attempted conversion of the dione 108 (prepared from a Diels-Alder reaction between 1,3-cyclopentadiene and 1,3-cyclopentenedione) into the corresponding 0-iodo enone 114 under reaction conditions i d e n t i c a l with those used for other cyclopentanediones gave only a 30% y i e l d of the desired product 114. Attempts to improve the y i e l d of the reaction by extending the reaction time to 72h gave the same re s u l t . Addition of hexamethylphosphoramide as cosolvent, i n the hope that a more polar solvent might improve the reaction, showed no e f f e c t . Previous studies i n our laboratory by Dr. I. Nagakura had shown that the conversion of 2-hydroxymethylenecyclohexanone 110 into the corresponding 8-iodo enone 116 under conditions i d e n t i c a l with those employed for the c y c l i c 8-diketones (reflux i n a c e t o n i t r i l e ) gave a very low y i e l d of the desired product. I t was suspected that the 8-iodo enone which was formed i n t h i s reaction might not be stable enough to survive the high temperature of the reaction mixture. Previous studies had also shown that the conversions of 8-diketones into the corresponding 8-iodo enones were more e f f i c i e n t when the reactions were carried out i n a c e t o n i t r i l e rather 84 than i n benzene,a less polar solvent. Thus i t was hoped that by the addition of hexamethylphosphoramide, a very polar solvent, to a c e t o n i t r i l e as cosolvent, might improve the e f f i c i e n c y of the conversions of the -101-Table 1. Conversion of c y c l i c 6-diketones and a-hydroxymethylenecycloalkanones to the corresponding 8-iodo-a,g-unsaturated ketones Entry Starting material (1,3-dicarbonyl compounds) Reaction 3 Condition 8-Iodo enone produ c t ( y i e l d ) b 1. 104 B 101 (87%) 2. 105 B 111 (73%) 3. 106 A 112 (85%) 4. 107 A 113 (92%) 5. 108 A 114 (31%) 6. 109 C 115 (73%) 7. 110 C 116 (94%) Reaction condition A: 1.1 equiv. of Ph^P^ was used with a c e t o n i t r i l e as solvent. Time of r e f l u x was 3h"; B: a c e t o n i t r i l e was the solvent; time of r e f l u x was 9h; C: acetonitrile/HMPA i n the r a t i o of 6:1 was the solvent, reaction was carried out at r . t . for 15h. The y i e l d was based on d i s t i l l e d pure products. -102-a-hydroxymethylenecycloalkanones into the corresponding 0-iodo enones. This was indeed found to be the case. The conversions of the a-hydroxymethylenecycloalkanones 109 and 110 into the corresponding 3-iodo enones 115 and 116, respectively, were carried out i n a manner similar to that used for the 8-diketones, except that a 6:1 mixture of a c e t o n i t r i l e and hexamethylphosphoramide was used as solvent, and the reactions were carried out at room temperature for 15h (entries 6 and 7, Table 1). Both of the reactions were highly regio-selective and stereoselective, since, i n each case, only a single 8-iodo enone was formed. On the basis of "4lnmr spectral data (see below), i t appeared that i n both of the products the iodine atom was trans to the carbonyl group. The general p r i n c i p l e used i n assigning the stereochemistry of the a-halomethylenecycloalkanones 117 and 118 was based on the empirical observations that, i n the ^ Hnmr spectrum, the 8 - o l e f i n i c protons c i s to the carbonyl group i n enones of this type resonate downfield from their 88 89 trans counterparts. ' For example, the 8 - o l e f i n i c proton of compound 119 gives r i s e to a signal at T3.55, whereas the corresponding proton i n 89 the isomer 120 resonates at T2.65. However, since our reactions were completely stereoselective, we had only one of the two possible isomers available, and therefore, a direct comparison could not be made. 117 118 119 120 115 -103-Our assignments are based on the following arguments. The 88 protons a to the heteroatom i n v i n y l chloride 121 and v i n y l iodide 90 122 resonate at T3.72 and T3.52, respectively. The difference i n chemical s h i f t s of the two protons caused by changing the a-substituent on the ethylene derivatives from chloro to iodo (AT) was 0.2. Comparison of the AT value of the B - o l e f i n i c protons of compounds 120 and 115 (AT=0.26) with that of 119 and 115 (AT=1.16) indicates that compound 115 should have the same stereochemistry as compound 120, since the AT value, of t h e i r B - o l e f i n i c protons (AT=0.26) i s closer to that between v i n y l chloride and v i n y l iodide (AT=0.2) than the AT value between compound 119 and 115. Furthermore, both compounds 115 and 120 have si m i l a r molecular structures, and the chemical s h i f t s of t h e i r B - o l e f i n i c protons are quite s i m i l a r . More evidence comes from the observation that the c i s and trans B - o l e f i n i c protons i n 2-methylenecyclohexanone 123 89 resonate at T4.28 andT4.96 respectively. The difference i n chemical s h i f t s between the c i s and trans B - o l e f i n i c proton (AT) i n 123 was 0.68. Thus, taking into account the AT value caused by the change of a-substituent on the methylene group from chloro to iodo (0.2T u n i t s ) , the difference i n chemical s h i f t of the B - o l e f i n i c protons of 119 and 115 would be expected to be close to 0.9T u n i t s . The observed difference was 1.16, thus providing excellent evidence for the stereochemistry of 115 as assigned. The same type of argumentation can be applied to the B-iodo enone 116. -104-Heathcock e_t a l . reported that the """Hnmr spectrum of the 8-chloro enone 88 124 showed a 8 - o l e f i n i c proton resonance at T3.0 which d i f f e r s from that of the 8-iodo enone 116 by 0.7x unit. The difference would appear to be too large for the two compounds to have the same stereochemistry. Furthermore, the chemical s h i f t of the B-olefinic proton of enone 116 (T2.30) i s quite close to those of compounds 115 (T2.39) and 120 (T2.65). By analogy, i t i s clear that compound 116 should possess the stereochemistry as shown. It has been well established that the conjugation of a double bond with a carbonyl group leads to intense absorption i n the u l t r a v i o l e t 91 spectrum (TT-MT* transition). I t i s also well known that there i s a regular and s i g n i f i c a n t v a r i a t i o n i n the wavelength at which the absorption maximum (A ) occurs, depending upon the substitution pattern on the max chromophore. The magnitude of these s h i f t s can be predicted by a set of 92 93 rules f i r s t formulated by Woodward and l a t e r modified by Fieser and 91 by Scott. For example, according to the Woodward rules, an a-alkyl substituent causes a bathochromic s h i f t (a s h i f t of the absorption maximum towards higher wavelength) of ^10 nm. S i m i l a r l y , a 8-chloro substituent causes an increment of ^12 nm and a B-bromo substituent i s supposed to 91 cause an increment of "^ 30 nm. However, since no c y c l i c B-iodo-a,B-unsaturated ketones had been f u l l y characterized prior to our investigation, nothing was known about the effect of a B-lodo substituent on the position of the TT-HT* absorption maximum of an a,B-unsaturated ketone. Based on the uv data of the limited number of 3-iodo-2-cycloalken-l-ones and a-iodomethy-lenecycloalkanones prepared i n t h i s laboratory, i t was hoped that the extent of the bathochromic s h i f t caused by a 8-iodo substituent could be established. -105-Table 2 l i s t s the TT->TT* absorption maxima of a number of parent 2-cycloalken-l-ones and 2-methylenecycloalkanones, along with those of some of the corresponding B-halo compounds. The differences between the absorption maxima of the B-halo enones and that of th e i r parent unsubstituted enones are also l i s t e d i n Table 2. Cl e a r l y , the data summarized i n the table showed that the uv absorption maxima of the B-chloro-a,B-unsaturated ketones 130-132 follow the Woodward rules f a i r l y c losely (entries 7-9, Table 2). For example, 3-chloro-5,5-dimethyl-2-99 cyclohexen-l-one 130 showed an absorption maxima at 238 nm which was 12 nm higher than that of the parent 2-cyclohexen-l-one 125 (entries 1 and 7, Table 2). The magnitude of t h i s increment was as expected, since the Woodward rules predicted a ^12 nm bathochromic s h i f t caused by a 91 B-chloro substituent. S i m i l a r l y , 3-chloro-2,5,5-trimethyl-2-cyclohexen-1-one 131 had an absorption maximum at 244 nm''^  which was 10 nm higher than that of 2-methyl-2-cyclohexen-l-one (entries 2 and 8, Table 2). The difference i n X between the B-chloro enones 131 and 130 was 6 nm, which max was close to that predicted by the Woodward rules for the effect of an a- a l k y l substituent. I t was quite unexpected to fi n d that the positions of the uv absorption maxima of the three B-bromo enones 133-135 shown i n Table 2 did not agree with those predicted by the Woodward rules (entries 10-12). A l l three compounds showed absorption maxima much lower than those calculated by the Woodward rules. Compared with the corresponding a, 8-unsaturated ketones, a l l of them showed a bathochromic s h i f t . However, the magnitude of the s h i f t f e l l quite short of the 30 nm expected for a B-bromo substituent. For example, 3-bromo-2-methyl-2-cyclohexen-l-one 134 T a b l e 2 . T h e u v a b s o r p t i o n m a x i m a (X ) o f s o m e 8 - h a l o e n o n e s a n d t h e i r p a r e n t B - u n s u b s t i t u t e d e n o n e s a , B - U n s a t u r a t e d D i f f e r e n c e i n X m a x b e t w e e n E n t r y K e t o n e s O b s e r v e d X ^ t n m ) ( e ) C a l c u l a t e d * m a ^ l n m ) B - h a l o e n o n e s a n d t h e i r R e f e r e n c e p a r e n t B - u n s u b s t i t u t e d 1 2 5 1 2 6 6 1 2 7 & 1 2 8 1 2 3 2 2 6 ( 1 0 4 0 0 ) 2 3 4 2 1 3 ( 9 5 0 0 ) 2 2 6 ( 8 5 5 0 ) 2 3 1 ( 7 5 5 0 ) 6 \_J 2 3 0 (740°) 1 2 9 e n o n e s |[ 2 3 8 ( 1 1 3 5 0 0 ) 2 3 8 1 3 0 9 4 9 5 9 6 9 7 9 8 9 8 12 99 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 2 4 4 ( 1 3 0 0 ) 2 4 1 ( 1 6 0 0 0 ) 2 4 6 ( 1 3 4 0 0 ) 2 4 6 ( 1 3 0 6 0 ) 2 4 3 ( 1 2 3 0 2 ) 2 5 8 ( 9 0 0 0 ) 2 5 8 ( 9 5 0 4 ) 2 5 6 ( 8 3 7 7 ) 2 6 0 2 4 6 1 0 1 0 0 2 3 8 1 5 1 0 1 2 5 6 2 0 9 9 , 1 0 2 2 6 4 1 2 1 0 3 2 5 6 1 7 1 0 4 c i 3 2 1 0 5 2 4 1 0 5 3 2 1 0 3 2 6 1 0 6 1 7 1 8 1 1 2 1 1 3 s ' 2 4 9 ( 1 1 3 5 3 ) 2 4 8 ( 1 1 5 2 0 ) 3 1 2 2 1 0 5 1 0 5 1 9 1 1 4 1 2 5 3 ( 9 9 0 0 ) 3 5 1 0 5 2 0 1 1 6 . 2 6 5 ( 7 1 9 8 ) 3 4 1 0 5 2 1 2 2 2 3 1 3 8 1 3 9 6^ 1 1 5 2 6 1 ( 7 1 1 0 ) 2 5 7 ( 6 6 8 1 ) 2 7 6 ( 9 1 7 0 ) 2 6 3 ( s h o u l d e r ) 3 0 2 6 4 5 3 3 1 0 5 1 0 5 1 0 5 o oo i T h e X ( c a l c . ) w a s c a l c u l a t e d u s i n g t h e W o o d w a r d r u l e s : f o r a n a - a l k y l s u b s t i t u e n t , a d d 1 0 nm t o t h e p a r e n t m a x u n s u b s t i t u t e d e n o n e , f o r a 8 - c h l o r o s u b s t i t u e n t a d d 1 2 nm a n d f o r a 8 - b r o m o s u b s t i t u e n t a d d 3 0 nm t o t h e p a r e n t e n o n e . F o r e x a m p l e , t h e ^ m 3 J C ( c a l c . ) f o r 8 - b r o m o e n o n e 1 3 3 w o u l d b e 2 2 6 nm ( p a r e n t e n o n e 1 2 5 ) + 3 0 nm ( 6 - b r o m o s u b s t i t u e n t ) = 2 5 6 n m , w h e r e a s t h e X ( c a l c . ) o f 8 - b r o m o e n o n e 1 3 4 w o u l d b e 2 3 4 nm ( p a r e n t e n o n e 1 2 6 ) ' m a x r  + 3 0 nm ( 8 - b r o m o s u b s t i t u e n t ) = 2 6 4 n m . -109-had a A at 246 nm. On the basis of Woodward's r u l e s , the X for max max t h i s compound should be around 264 nm. Another s i g n i f i c a n t deviation from the Woodward rules was the observation that the absorption maxima of both 3-bromo-5,5-dimethyl-2-cyclohexen-l-one 133 and 3-bromo-2-methyl-2-cyclohexen-l-one 134 were i d e n t i c a l (entries 10 and 11, Table 2). They were predicted to have a difference i n absorption maximum by ^10 nm due to the presence of an extra a - a l k y l substituent on enone 134. This anomaly was also found i n the 3-iodo analogs. For example, 3-iodo-2-cyclohexen-l-one 101 and 3-iodo-2-methyl-2-cyclohexen-l-one 111 were shown to have the same absorption maximum at 258 nm (entries 13 and 14, Table 2). Also, the absorption maxima of 3-iodo-2-cyclopenten-l-one 112 and 3-iodo-2-methyl-2-cyclopenten-l-one 113 occurred at nearly the same wavelength (entries 17 and 18, Table 2). I t i s unfortunate that very l i t t l e uv data regarding c y c l i c g-bromo-a,B-unsaturated ketones have been reported i n the l i t e r a t u r e . Because of t h i s lack of data, i t i s not certain whether or not there i s a general trend for the abnormal behaviour described above. In any case, i t i s clear that one has to be careful when applying the Woodward rules i n predicting the absorption maxima of B-bromo-a,B-unsaturated ketones. Concerning the bathochromic effect of a B-iodo substituent, a perusal of the uv data obtained from the B-iodo enones l i s t e d i n Table 2 showed that there was no regular pattern i n the bathochromic s h i f t s . Owing to these i r r e g u l a r i t i e s and to the l i m i t e d data av a i l a b l e , i t i s not possible at t h i s moment to estab l i s h a discrete value for the bathochromic s h i f t caused by a B-iodo substituent. In general, the preparation of c y c l i c B-iodo-a,8-unsaturated ketones -110-from the corresponding 1,3-dicarbonyl compounds could be carried out i n a simple manner. Furthermore, the products obtained were clean and the y i e l d s of products were good. The 8-iodo enones were found to be stable and easy to handle. The a-iodomethylenecycloalkanones, though not as stable as the endocyclic analogs, could be stored under an atmosphere of argon i n a freezer for a few months without substantial decomposition. However, i f exposed to a i r at room temperature, these compounds darken i n color and decompose f a i r l y r apidly ( i n a day or two). I t i s also i n t e r e s t i n g to note that the a-iodomethylenecycloalkanones are apparently considerably more stable than t h e i r chloro counterparts. For example, 2-chloromethylenecyclohexanone 140 has been reported to undergo decom-po s i t i o n even at -20°C under n i t r o g e n . 1 ^ 7 The 8-iodo enones, i n general, are easier to prepare than t h e i r chloro and bromo counterparts. This i s mainly because, i n the preparation of the triphenylphosphine dihal i d e reagents, iodine c r y s t a l s are much easier to handle than noxious chlorine gas or the l i q u i d bromine. The 8-iodo enones are also easier to handle (higher molecular weight, less v o l a t i l e ) and are more reactive i n certain reactions (for example, 8 5 reaction with cuprate reagents ) than the corresponding chloro or bromo compounds. g-chloro-a,B-unsaturated carbonyl compounds have i n the past become 86 increasingly useful as intermediates i n organic synthesis. Since i t now appears that the corresponding 8-iodo enones can be r e a d i l y prepared and 140 -111-since these iodo enones are easier to handle and are more reactive i n certain reactions, i t i s clear that t h i s new class of compounds might also f i n d increasing use as intermediates i n organic synthesis. I I . Conversion of g-Iodo-a,g-Unsaturated Ketones into the Corresponding  g-Cyclopropyl-a,g-Unsaturated Ketones. Although a wide variety of functionalized vinylcyclopropanes have been synthesized, g-cyclopropyl-a,g-unsaturated ketones have ra r e l y been prepared. 3-Cyclopropyl-2-cyclohexen-l-one 142 has been prepared by the Michael addition of the enamine 141 to methyl v i n y l ketone, followed by intramolecular 108 c y c l i z a t i o n of the r e s u l t i n g intermediate (eq.30). (30) Recently, the addition of a l l y l - y l i d e s of a,B-unsaturated ketones to Michael acceptors has provided an e f f i c i e n t route to g-cyclopropyl-a,g-unsaturated ketones (eq. 31) . \ 0 II 0 II (31) X=SMe2, SMe2, SMe(NMe2); E=CN, COR, CHO, C02R, N0 2 For example, the y l i d e 143 reacted cleanly with methyl v i n y l ketone to give the vinylcyclopropane 144 i n 75% y i e l d ( e q.32). 1 1 0 -112-r . t . 75% (32) 113 More recently, Marino et al_ t u t i l i z e d the conjugate addition reactions of lithium dicyclopropylcuprate to B-halo, B-alkoxy and B-acetoxy enones i n preparing B-cyclopropyl-a,8-unsaturated ketones. For example, the B-chloro enone 100 reacted with lithium dicyclopropyl-cuprate to give the corresponding B-cyclopropyl enone 142 i n 80% y i e l d (eq.32a). (c^-C 3H 5) 2CuLi 80% (32a) 100 142 The conjugate addition of lithium dicyclopropylcuprate to acetylenic carbonyl compounds to give B-cyclopropyl-a,B-unsaturated ketones also has been reported 113 For example, treatment of the acetylenic ketone 146 with lithium dicyclopropylcuprate gave the corresponding B-cyclopropyl enone 147, i n >95% y i e l d (eq.33a). THPO-CH 2-CHC-G0Me + (c - C H 5 > C u L l 146 -78°C THPO-:CHCOMe (33a) 0.5h >95% 147 THP=Tetrahydropyran In e a r l i e r work i n our laboratory, i t had been found that c y c l i c B-halo-a,B-unsaturated ketones reacted with various cuprate reagents to produce the corresponding B-alkyl-a,B-unsaturated ketones i n high y i e l d 85 -113-The 3-halo enones can be prepared e a s i l y from the reaction of the 84 corresponding c y c l i c g-diketones with triphenylphosphine dihalides (described e a r l i e r i n t h i s t h e s i s ) . I t was therefore of int e r e s t to investigate whether or not t h i s procedure could be applied to the preparation of c y c l i c g-cyclopropyl-a,B-unsaturated ketones. As a r e s u l t , a series of c y c l i c B-cyciopropyl-a,B-unsaturated ketones were prepared by the reaction of B-iodo-a,B-unsaturated ketones with l i t h i u m phenylthio(cyclopropyl)cuprate (eq.33 and 34). Some of the r e s u l t s are summarized i n Table 3. R PhS(c-C 3H 5)CuLi ^ y-" ( 3 3 ) " (CH2)n-I, THF 101 n=2, R=H 142 n=2, R=H 111 n=2, R=CH_ 146 n=2, R=CH 112 n=l, R=H 147 n-1, R=H 113 n=l, R=CH 148 n-1, R=CH PhS(c-C,H )CuLi (34) 115 n-1 l i b n=2 150 n=2 A t y p i c a l procedure for the conversion of B-iodo-a,B-unsaturated ketones into the corresponding B-cyclopropyl enones follows. To a solution of li t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) i n t e t r a -hydrofuran at -78°C was added a solution of 3-iodo-2-cyclohexen-l-one 101 (3 mmol) i n tetrahydrofuran. The r e s u l t i n g mixture was s t i r r e d at -78°C for 2.5h. Methanol was added to quench the reaction and the reaction -114-mixture was f i l t e r e d through a short column of f l o r i s i l . Evaporation of the solvent, followed by d i s t i l l a t i o n of the r e s i d u a l o i l gave 335 mg (82%) of pure 3-cyclopropyl-2-cyclohexen-l-one 142. The spectral data 90 of t h i s material were i d e n t i c a l with those reported i n the l i t e r a t u r e . S i m i l a r l y , the fcS-iodo enones 111-116 were transformed into the corres-ponding 8-cyclopropyl enones 146-150, respectively. The r e s u l t s are summarized i n Table 3. A l l of the products l i s t e d i n Table 3 exhibited spectral data i n f u l l accord with the assigned structures. Each of the new compounds also gave a s a t i s f a c t o r y elemental analysis and/or molecular weight determination (high resolution mass spectrometry). Although the data summarized i n the table are l a r g e l y s e l f -explanatory, there are a few minor points that need to be discussed i n more d e t a i l . For simpler 8-iodo enones, l i k e 3-iodo-2-cyclohexen-l-one 101 and 3-iodo-2-cyclopenten-l-one 112, complete conversion into the corres-ponding 8-iodo enones needed only 1.5 equivalents of cuprate reagent, and the reaction was carried out at -78°C for 2.5h (entries 1 and 3, Table 3). However, for 8-iodo enones 111 and 113, which contained a methyl group at the a-position, a higher reaction temperature (0°) and more cuprate reagent (2 equivalents) were required to effect complete conversion of the s t a r t i n g material i n a reasonable time (entries 2 and 4, Table 3). Apparently, the a-methyl group caused a c e r t a i n amount of s t e r i c congestion, thus impeding the conjugate addition of the cuprate reagent to the g-position. S i m i l a r l y , for 2-iodomethylenecycloalkanones 115 and 116, higher temperatures (-20°C and 0°C respectively) than those needed for enones 101 and 112 were required for complete conversion of the s t a r t i n g material -115-Table 3. Conversion of 8-iodo-a,B-unsaturated ketones into B-cyclopropyl-a,B-unsaturated ketones. B-iodo Reaction B-cyclopropyl Entry enones Condition 3 enones (Yield %) 1. 101 A 142 (82%) 2. 111 C 146 (88%) 3. 112 A 147 (97%) 4. 113 C 148 (84%) 5. b 115 D 149 (65%) 6. 116 B 150 (82%) Reaction condition A: 1.5 eq. of PhS(c_-C.jH^)CuLi was used at -78°C for 2.5h; B: 1.5 eq. of PhS(c-C.jH,-)CuLi was used at 0°C for 2.5h; C: 2 eq. of PhS(c_-C.jH,.)CuLi was used at 0°C for 2.5h; D: 1.5 eq. of PhS(c-C 3H 5)CuLi was used at -78°C for l h , at -20°C for 2h. Reaction was performed by Dr. I. Nagakura. -116-i n a reasonable time (entries 5 and 6, Table 3). A careful analysis of the reaction products obtained from these reactions showed that, i n each case, transformation of the 2-iodomethylenecycloalkanone into the corresponding 8-cyclopropyl enone was highly stereoselective. E s s e n t i a l l y , only one product was obtained from each reaction. The stereochemistry of the products 149 and 150 could readily be assigned as shown on the basis of the "Sinmr spectra. The argument employed here was s i m i l a r to that used i n determining the stereochemistry of 2-iodomethylenecyclohexanone (described e a r l i e r ) and was based on the empirical observation that i n the "Slnmr spectra, the f i - o l e f i n i c protons c i s to the carbonyl group of certain a-alkylmethylenecyclo-89 hexanones resonate downfield from t h e i r trans counterparts. For example, for 2-methylenecyclohexanone 123, 152 153 154 155 the proton c i s to the carbonyl group resonated at x4.28 while the proton 89 trans to the carbonyl group gave r i s e to a signal at T4.96. Also, the 8- o l e f i n i c proton of compound 151 resonated at x3.53-3.55 whereas the 8' analogous proton of i t s isomer 152 gave r i s e to a signal at x4.30-4.35. -117-In a related study described i n a subsequent part of t h i s thesis we were able to i s o l a t e the two pairs of isomers 153 + 154 and 155 + 156. The B - o l e f i n i c protons of compounds 153 arid 155 resonated at x3.92 and 4.02, respectively. On the other hand, the analogous protons of the isomeric pair of compounds (154, 156) gave r i s e to signals at T5.08 and 5.16. Since compounds 153 and 155 had the B - o l e f i n i c proton resonances downfield from t h e i r isomeric counterparts (154, 156), they should have the structure as assigned. As for compounds 149 and 150, we had only one of the two possible isomers av a i l a b l e , and therefore, a direct comparison with t h e i r isomeric counterparts could not be made. However, a comparison of the chemical s h i f t s of the B - o l e f i n i c proton resonances of these two compounds with those of compounds 153 and 155, c l e a r l y indicates that 149 and 150, possess the stereochemistry shown. In general, the transformation of B-iodo enones into the corresponding B-cyclopropyl enones i s a very clean process and the yie l d s are high. Further-more, i n no case were we able to detect a product r e s u l t i n g from conjugate addition of a second cyclopropyl group. F i n a l l y , a l l the products obtained by the aforementioned procedure were stable and could be stored i n d e f i n i t e l y i f they were kept under argon i n a freezer. I I I . Thermolysis of B-Cyclopropyl-a , B-Unsaturated Ketones As already mentioned, c y c l i c 3-cyclopropyl-2-cycloalken-l-ones and 2-cyclopropylmethylenecycloalkanones are b a s i c a l l y vinylcyclopropane derivatives. I t was therefore of interest to determine whether or not thermolysis of these compounds would r e s u l t i n a cyclopentene-type annelation processes, as depicted by the following schemes. -118-A -> ( CH 2) i rW A Two general procedures (A and B) were employed i n the investigation of the thermal rearrangement of the aforementioned type of compounds. A detailed description of the general procedure A follows. A pyrex tube, 1.2 (i.d.)x32 cm, f i l l e d with glass helices ( i . d . 4.76 nm) was washed successively with water, acetone and n-hexane. The column was conditioned by placing i t i n a furnace and heating i t at ^ 450"C for 3h. During t h i s period of time, the column was thoroughly purged with a stream of nitrogen. A n-hexane solution of the appropriate g-cyclopropyl enone (200 mg i n 20 ml of n-hexane) was added dropwise over a period of 1.5h to the top of the v e r t i c a l l y held, heated tube (^450°C). During t h i s period of time, the stream of nitrogen was discontinued. The pyrolysate from the bottom of the column was cooled by having i t pass through a water condenser connected to the bottom of the pyrolysis tube, and was collected i n a two-necked fl a s k , equipped with a drying tube and immersed i n a cold (-78°C) bath (see diagram 1) After addition of the solution was complete, the hot column was washed with a further 30 ml of n-hexane. Removal of the hexane from the pyrolysate, followed by d i s t i l l a t i o n (air-bath) of the residual o i l , gave the thermolysis product . Thermolysis of 3-cyclopropyl-2-cyclopenten-l-one 147 under the conditions described above (.procedure A), gave an 80% y i e l d of a colorless o i l . A glc analysis of this material showed the presence of four major components -119-lc e -one bath Diagram 1 N, stopcock glass wool glass helices - furnace pyrex-tube(1.2x32cm) water i n l e t drying tube Diagram 2 Argon needle valve f heating tape asbestos glass helices pyrex-tube (1.2x100cm) drying tube dry ice acetone bath -120-together with small amounts of minor impurities (^2% ) which were not i d e n t i f i e d . The major components were shown to De the ketone 157 (^46%), the enone 158 (M.4%), the dienone 159 (^20%) and the dienone 160 (M.8%)(eq.34). (34) An a n a l y t i c a l sample of each major component was obtained by preparative glc. The structures assigned to the thermolysis products 157-160 were supported by spectroscopic data. The uv spectrum of enone 158 (^ m a x 237 nm, e=ll,370) agreed well with that expected (Woodward's rules) for a compound possessing this structure. The i r spectrum also indicated the presence of a conjugated ketone system ( v m a x 1690, 1630 cm 1) F i n a l l y , the ''"Hnmr spectrum of 158 showed only a complex multiplet at T7.10-7.80, thus c l e a r l y indicating the absence of o l e f i n i c protons. The i r spectrum of ketone 157 indicated that the compound was a saturated five-membered ring ketone (v 1740 cm ^ ) . The only o l e f i n i c max J proton present appeared as a one-proton multiplet at T4.58 i n the 1Hnmr spectrum. The l a t t e r also showed a one-proton multiplet between T6.57 and 6.88, which could readily be attributed to the t e r t i a r y bridgehead proton adjacent to the carbonyl group. When compound 157 was passed through a short column of basic alumina, i t isomerized quantitatively to the enone 158. The observed absorption maximum (268 nm, e=18,630) i n the uv spectrum -121-of the conjugated dienone 160 agreed w e l l with that expected for a compound possessing t h i s structure. The i r spectrum exhibited the expected absorp-tions at 1640 and 1570 cm 1. In the ^ Hnmr spectrum of compound 160, the o l e f i n i c proton a to the carbonyl group produced a signal at x4.09 as a broad, one-proton s i n g l e t . One of the two o l e f i n i c protons on the propenyl side chain appeared as a one-proton doublet (J=16 Hz) at x3.44, whereas the other (a to the terminal methyl group) appeared as a one-proton doublet of quartets (J=16 Hz, J'=6 Hz) at x3.7U. The large coupling constant between the two o l e f i n i c protons c l e a r l y indicated that they are trans to each other. The terminal methyl group of the side chain gave r i s e to a three-proton doublet (J=6 Hz) at x8.10. Both the uv absorption maximum (226 nm, e=14,090) of the dienone 159 and the infrared spectrum (v 1705, 1610 cm ^) of t h i s compound indicated max the presence of a conjugated cyclopentenone system. The "Slnmr spectrum of 159 exhibited a two-proton multiplet between x4.70 and 5.10, re a d i l y a t t r i b u t a b l e to the terminal o l e f i n i c protons of the v i n y l group, and a two-proton multiplet between x3.92 and 4.40, which could be assigned to the other two o l e f i n i c protons i n the molecule. The methylene group of the a l l y l side chain appeared as a two-proton doublet (J=6.5 Hz) at x6.88. Isomerization of the dienone 159 to the isomeric compound 160 was effected by passing the former through a short column of basic alumina. The spectral data obtained from the isomerized product were i d e n t i c a l with that of the dienone 160 obtained e a r l i e r . Thermolysis of 3-cyclopropyl-2-cyclohexen-l-one 142 under conditions very s i m i l a r to those described above (procedure A), afforded a 78% y i e l d of a colorless o i l . A glc analysis of t h i s material indicated that i t was -122-a mixture of the ketone 161 (^3%), the enone 162 (M34%) and the dienone 163 (^11%), along with a number of minor, uni d e n t i f i e d impurities (^2%). An a n a l y t i c a l sample of each of the three thermolysis products was obtained by preparative g l c , and each compound was characterized by i r and "'"Hnmr spectroscopy. Enone 162 exhibited the c h a r a c t e r i s t i c six-membered rin g O • O o - + (35) 142 161 162 163 a,B-unsaturated carbonyl absorptions i n the i r spectrum ( v m a x 1660, 1630 cm "*"). The "'"Hnmr spectrum of t h i s compound exhibited only a complex multipl e t between T7.2 and 8.3. The melting point [252°C (dec)] of the 2,4-dinitrophenyl-hydrazone derivative of t h i s material agreed very w e l l with that reported 114 i n the l i t e r a t u r e (251.5°C). The i r spectrum of ketone 161 indicated that the compound was a saturated six-membered rin g ketone ( v 1718 cm "'"). The only o l e f i n i c max proton present appeared as a broad one-proton s i n g l e t at T4.57. This material also showed a one-proton multiplet centered at x6.63, which could r e a d i l y be attributed to the t e r t i a r y bridgehead proton adjacent to the carbonyl group. When compound 161 was passed through a short column of basic alumina, i t isomerized to the enone 162. The i r spectrum of the dienone 163 also indicated the presence of an a,B-unsaturated carbonyl f u n c t i o n a l i t y ( v m a x 1670, 1642, 1590 cm ^ ) . The single o l e f i n i c proton a to the carbonyl group gave r i s e to a si n g l e t at T4.16 i n the "''Hnmr spectrum, while the two o l e f i n i c protons on the side chain appeared as a multiplet at T3.82. The terminal methyl group gave r i s e to a three-proton doublet (J=5 Hz) at x8.14. These spectral data were i d e n t i c a l with those previously reported for t h i s compound."'"'''"' -123-Although the thermolysis of 3-cyclopropyl-2-cyclohexen-l-one 142 at ^450°C gave a s a t i s f a c t o r y y i e l d of the annelated products 161 and 162, pyrolysis of 3-cyclopropyl-2-cyclopenten—1-one 147 gave s i g n i f i c a n t amounts of the dienones 159 and 160. Since i t was desirable to minimize the formation of these undesired side products, i t was decided to investigate d i f f e r e n t thermolysis conditions. I t was hoped that by lowering the thermolysis temperature and increasing the contact time (by increasing the length of the thermolysis tube), the thermolysis reaction might be improved and the formation of open-chain dienones might be reduced. A new pyrolysis apparatus with a longer pyrolysis tube was constructed (as shown i n diagram 2). A general experimental procedure (procedure B) employing t h i s set-up follows. A pyrex tube (1.2x100 cm) f i l l e d with glass helices (.i.d. 4.76 mm) was washed successively with saturated aqueous sodium bicarbonate so l u t i o n , water, acetone and n-hexane. By means of a heating tape which had been wrapped around i t , the column was heated to the desired thermolysis temperature and was kept at t h i s temperature for at least 3h. During t h i s time, the column was thoroughly purged with a rapid flow of argon. A n-hexane solution of the appropriate 8-cyclopropyl enone (200 mg i n 20 ml n-hexane) was added dropwise, over a period of 1.5h, to the top of the v e r t i c a l l y held column. During t h i s period, a very slow flow of argon (^ 5 ml/min) was passed through the column. The pyrolysate from the bottom of the column was cooled by allowing i t to pass through a water condenser attached to the bottom of the pyrolysis tube, and was collected i n a two-necked f l a s k which was equipped with a drying tube and was immersed i n a cold (-78°C) bath. After the addition of the solution was complete, the hot column was washed with a further 30 ml of ri-hexane. The combined hexane solution was concentrated and the residual o i l was d i s t i l l e d to give the pyrolysis product. -124-3-Cyclopropyl-2-cyclbhexen-l-one 142 was chosen as the substrate to study the new thermolysis conditions i n some d e t a i l . Pyrolysis of t h i s material at ^ 425°C (procedure B) gave a 98% y i e l d of a colorless o i l . A glc analysis of t h i s material showed that i t was a mixture of the ketone 161 (^31%) and the enone 162 (^67%), along with very small amounts of unidentified impurities (^2%). This material was passed through a short column of basic alumina. The column was eluted with ether. Removal of the ether and analysis of the residual o i l by glc and i r showed that the ketone 161 had isomerized completely to enone 162. The above procedure was repeated at 322°C, 400°C and 450°C. The resul t s are summarized i n Table 4 (entries 2b-e). At 322°C, no reaction had taken place. At 400°C, some rearrangement occurred, although a considerable amount of s t a r t i n g material was recovered (V37%). At 450°C, the annelated cyclopentenes constituted ^96% of the product and no s t a r t i n g material was recovered. However, the y i e l d was considerably lower than that obtained from thermolysis at 425°C and i t thus appeared that the l a t t e r pyrolysis temperature was the preferred one. In no case was there any of the dienone 163 detected. In comparison with the old procedure (procedure A), t h i s new procedure (B) showed a dramatic improvement i n terms of giving better y i e l d s and less undesired side-products. The use of t h i s new procedure was extended to include the thermolysis of other B-cyclopropyl-a,B-unsaturated ketones. Some of these r e s u l t s are summarized i n Table 4 and w i l l be discussed i n more d e t a i l l a t e r . A l l of the products l i s t e d i n Table 4 exhibited spectral-data i n f u l l accord with the assigned structures, and a l l new compounds gave sa t i s f a c t o r y elemental analysis and/or molecular weight determinations (high resolution mass spectrometry). -125-A preliminary study, performed by Dr. I. Nagakura of our laboratory, showed that thermolysis of 2-methyl-3-cyclopropyl-2-cyclohexen-l-one 146 (procedure A) gave the dienones 165 and 166 as the major products. Only a very small amount of the desired annelated cyclopentene 164 was formed (eq.36). (36) 146 164 165 166 ^10% M.8.4% ^50% These res u l t s were not t o t a l l y unexpected. We had mentioned e a r l i e r i n the introduction, that when an a l k y l group i s placed c i s to the cyclopropyl rin g across the double bond on a vinylcyclopropane system (as i n compound 146), the rate of thermal rearrangement i s usually much lower than the rate of rearrangement of unsubstituted cases, and the products formed are 37 49 83 usually polymers or s t r u c t u r a l l y rearranged o l e f i n s . ' ' In a related study described i n a subsequent part of t h i s t h e s i s , i t was found that the thermal rearrangement of the t r i m e t h y s i l y l enol ether derivatives of 2-cyclopropylmethylenecycloalkanones gave better y i e l d s of the corresponding spiroannelated products than did the corresponding parent enones (eq.37). I t was hoped that pyrolysis of the t r i m e t h y s i l y l enol ether derivative of (37) enone 146 might also give a better y i e l d of the annelated product 164'. Thus, Table 4. Thermal rearrangement of 8-cyclopropy1-a,B-unsaturated ketones and related compounds Entry Substrate Reaction Condition 3 Products and Products R a t i o ( % ) b Y i e l d C 1. 147 ^450°C(A) 157 ^46% 158 ^14% 159 160 ^20% M.8% Unidentified impurities ^2% 80% 2. a. b. c. d. e. 142 ^450°C(A) ^322°C(B) ^400°C(B) ^425°C(B) ^450°C(B) 161 V3% V37% ^31% ^5% 162 ^84% -V15Z ^67% ^91% 163 142 ^11% ^100% ^37% ^2% *11% ^2% ^5% 78% 100% 100% 98% 71% 3. 171 ^425°C(C) ^76% ^24% 67% 4. 167 ^425°C(B) 170(^75%) ^25% 50% 5. 172 -v450°C(A) 173(^75%) 174(^16%) ^9% 30% 6. 150 ^450°(A) 175 ^44% 176 ^9% 177 ^38% 74% 7. a. b. 184 ^450°(A) ^425°(B) 185 ^74% ^84% 186 VL2% VL6% 74% 85% 8- d a. b. 149 ^450°(A) ^425°(B) 187 ^39% ^33% 188 «V31% ^50% 189 190 ^9% M5% 149 ^9% ^6% ^8% 90% 85% 9. 191 ^425°(C) ^94% A-6% 56% I Pyrolysis was carried out i n a v e r t i c a l pyrex tube (1.2x32 cm) using procedure A (see t e x t ) . Pyrolysis was carried out i n a v e r t i c a l pyrex tube (1.2 cm x 1 m) under a very slow flow of argon (procedure B) (see te x t ) . Pyrolysis was carried out i n the same way as (B), the crude pyrolysis product was hydrolysed by 1:1 methanol and 1 N aq. HC1. ^Product r a t i o was based on glc analysis of d i s t i l l e d pyrolysate. c Y i e l d i s based on the t o t a l weight of d i s t i l l e d pyrolysate recovered. ^This data was obtained from Dr. I. Nagakura of our laboratory. -128-the t r i m e t h y l s i l y l enol ether 167 was prepared, by treatment of the enone 146 with lithium diisopropylamide i n 1,2-dimethoxyethane, followed by trapping of the resultant enolate anion with chlorotrimethylsilane i n the presence of triethylamine (eq.38). The structure of the s i l y l enol ether 167 was supported by the "'"Hnmr spectrum of the compound l.i-pr 2NLi,DME 2. Et3N,C£SiMe3 OSiMej (38) which showed a t r i m e t h y s i l y l group at T9.91 as a nine-proton sin g l e t . The o l e f i n i c proton gave r i s e to a signal at T 5.20 i n the form of a t r i p l e t , while the v i n y l methyl group appeared as a broad singlet at T8.20. The i r spectrum of this material showed two weak bands at 1650 and 1600 cm \ When the s i l y l ether 167 was pyrolysed (procedure B), the major product formed was _o-cyclopropyltoluene 170 (entry 4, Table 4). Pre-sumably, the s i l y l encl ether 167 had undergone two successive [1,5] sigmatropic hydrogen migrations to give the intermediate 169. Elimination of (CH 3) 3Si0H from 169 could then give O-cyclopropyltoluene 170 (eq.39). 167 Si Me, 168 169 (39) 170 -129-In contrast, pyrolysis (procedure B) of the t r i m e t h y l s i l y l enol ether of 3-cyclopropyl-2-cyclohexen-l-one 171, followed by hydrolysis and work-up, gave a 67% y i e l d of a mixture of the annelated cyclopentene 162 0W6%) and a number of unidentified impurities (^24%)(entry 3, Table 4) (40) The only a c y c l i c 8-cyelopropyl-a,B-unsaturated ketone investigated during the course of the work described i n t h i s thesis was compound 172. Thermolysis of t h i s compound at ^450°C (procedure A) gave a mixture of the ketone 173 (^75%) and m-xylene 174 (vL6%) i n a t o t a l y i e l d of ^30% (eq.41, entry 5, Table 4). 450c 30% + (41) 172 173 75% 174 16% The i n i t i a l studies involving thermal rearrangement of 2-cyclopropyl-methylenecycloalkanones were performed on the short thermolysis column, using the old procedure (procedure A). Thermolysis of 2-cyclopropyl-methylenecyclohexanone 150 at ^450°C gave a 74% y i e l d of a mixture of the spiroketone 175 (^44%), the dienone 176 (^9%) and t e t r a l i n 177 (^38%), along with a small amount (^9%) of minor impurities which were not i d e n t i f i e d (entry 6, Table 4). -130-(42) 150 175 176 177 The spiroketone 175 exhibited an int e r e s t i n g """Hnmr spectrum. From a s t r u c t u r a l point of view, the two o l e f i n i c protons were c l e a r l y non-equivalent and were expected to have d i f f e r e n t chemical s h i f t s . I t was therefore surprising to f i n d that these two protons appeared as a sharp two-proton singlet at T4.24. The rest of the protons showed up as a five-proton multiplet at T7.40-7.82 and a seven-proton m u l t i p l e t at T7.97-8.60. In order to determine whether or not i t was possible to disti n g u i s h between the two o l e f i n i c protons by ''"Hnmr, the spectrum of 175 was reinvestigated i n the presence of a s h i f t reagent: Eu(FOD) . ^ 2 7 • Under these conditions, the o l e f i n i c protons appeared as two sets of doublets of t r i p l e t s at T3.58 and 3.94. Each set had coupling constants, J=6 Hz and J'=2 Hz. Furthermore, the o r i g i n a l five-proton multiplet at T7.40-7.80 was transformed into a three-proton multiplet at x6.44-6.84 and a two-proton multipl e t at x7.14-7.50. The o r i g i n a l seven-proton multiplet was shift e d to x7.62-8.12. In a decoupling experiment ( i n the presence of the s h i f t reagent), i r r a d i a t i o n at x7.29 (the signal due to the two protons a to the double bond) caused the two doublets of t r i p l e t s at x3.58 and 3.94 to collapse to an AB pair of doublets (J=5.6 Hz), as would be expected. To further confirm the posi t i o n of the double bond i n the spiro compound 175, the "''Hnmr spectrum of the isomeric spiroketone 178 (kindly supplied by Dr. R. D. Sands of Alf r e d University, A l f r e d , New York"'"'"^ ) was compared with that of compound 175. As expected, the two o l e f i n i c -131-protons of compound 178, which were s t r u c t u r a l l y equivalent, appeared as a s i n g l e t . However, the chemical s h i f t of these protons (T4.50) was s l i g h t l y d i f f e r e n t from that of the o l e f i n i c protons i n compound 175. 178 Further evidence for the structure of the spiro enone 175 was 13 supplied by the Cnmr spectrum (proton decoupled) of th i s compound. The spectrum showed the presence of two nonequivalent o l e f i n i c carbon atoms at <5(ppm) 132.4b and 133.35, a carbonyl carbon atom at 211.48 and a quaternary carbon atom at 64.06. The rest of the carbon centers appeared at 6(ppm) 22.96, 27.67, 31.28, 32.29, and 39.89 (2 carbons). F i n a l l y , i n order to confirm the spiro carbon skeleton of ketone 175, t h i s material was hydrogenated (10% Pd/C i n methanol) to the saturated spiroketone 179. The spectral data ( i r , "4frimr) of the l a t t e r were i d e n t i c a l with those of an authentic sample of 179 prepared from 117 the p i n a c d rearrangement of the d i o l 180. The d i o l 180 was prepared from the dimerization of cyclopentanone using aluminum and mercuric 101 chloride. 179 180 The Hnmr spectrum of the dienone 176 indicated that i t was a mixture of c i s and trans isomers. The terminal methyl groups of the isomers resonated at x8.99 and 9.02. Exhausive hydrogenation of the -132-mixture gave a single product, 2-n-butylcyclohexanone. Spectral data ( i r , "^Hnmr) of the l a t t e r were i d e n t i c a l to those reported i n the Sadtler Index. The formation of t e t r a l i n 177 may be r a t i o n a l i z e d as follows. Homolysis of the cyclopropane ri n g would give the d i r a d i c a l 181. Ring closure to give the b i c y c l i c . d i r a d i c a l intermediate 182, followed by hydrogen migration would afford the dienol 183. Dehydration of the l a t t e r would then give t e t r a l i n 177 (Scheme 8). 150 181 182 1,4 hydrogen s h i f t 177 183 Scheme 8 Although the thermolysis of 2-cyclopropylmethylenecylohexanone 150 did give the expected spiro ketone 175, a considerable amount of the undesired t e t r a l i n 177 was also formed. Since, as postulated above, the formation of t e t r a l i n probably involved the carbonyl f u n c t i o n a l i t y , i t seemed reasonable to postulate that masking the carbonyl group would eliminate the formation of t e t r a l i n . Thus, the t r i m e t h y l s i l y l enol ether of enone 150 was prepared. The t r i m e t h y l s i l y l enol ether 184 was obtained b y f i r s t treating the enone 150 with l i t h i u m diisopropylamide i n 1,2-dimethoxyethane, followed by the addition of chlorotrimethylsilane -133-i n the presence of triethylamine (eq.43). The structure of the enol ether 184 was supported by spectral data. In the ''"Hnmr spectrum, the o l e f i n i c proton on the exocyclic cyclopropylmethylene group resonated as a doublet at x4.92, with coupling constant = 9.5 Hz. The other o l e f i n i c proton on the six-membered ring gave r i s e to a t r i p l e t at T5.04 with J=4.5 Hz. A nine-proton singlet due to the t r i m e t h y l s i l y l group appeared at T9.87. The i r spectrum showed two weak absorption bands at 1680 and 1660 cm "*". trans-l-phenyl-l-butene 186 (^14%), and small amounts of unidentified minor impurities (^12%). No t e t r a l i n was detected (eq.44, entry 7a, Table 4). An analytical sample of each of the two major components war-obtained by preparative glc and their structures were confirmed by the spectral data. The ''"Hnmr spectrum of compound 185 exhibited a one-proton t r i p l e t (J=4 Hz) at T5.28, readily attributable to the o l e f i n i c proton of the enol s i l y l ether group. A one-proton multiplet between T4.24 and 4.37 and another one-proton multiplet between T4.45 and 4.60 -134-could be assigned to the other two o l e f i n i c protons in the molecule. The t r i m e t h y l s i l y l group gave r i s e to a nine-proton s i n g l e t at x9.93. The i r spectrum of t h i s material showed a strong absorption at 1655 cm \ In the "4lnmr spectrum of compound 186, a five-proton m u l t i p l e t at T2.60-3.00 indicated the presence of a monosubstituted benzene r i n g . The two o l e f i n i c protons gave r i s e to a multiplet between x3.55 and 4.00. The two a l l y l i c methylene protons appeared as a multiplet at x7.64-8.00, whereas the terminal methyl group showed up as a three-proton t r i p l e t at x8.95 with J=7 Hz. These data were e s s e n t i a l l y the same as those 118 reported i n the l i t e r a t u r e . I t was thus quite clear that i n terms of the y i e l d of spiroannelation product, the thermolysis of the t r i m e t h y l s i l y l enol ether 184 showed con-siderable improvement over the thermal rearrangement of the parent enone 150. The thermolysis (procedure A) of the enol ether 184 was repeated on a larger scale (l.Og). The crude thermolysis product was hydrolyzed i n a 1:1 mixture of methanol and IN aqueous hydrochloric acid and the hydrolyzed product was subjected to column chromatography. A 50% o v e r a l l y i e l d of the pure spiro ketone 175 was is o l a t e d . The thermolysis of the t r i m e t h y l s i l y l enol ether 184 was l a t e r improved further by employing the new procedure (procedure B) using the long pyrolysis column. Thus pyrolysis of the enol ether 184 at ^425UC gave an 85% y i e l d of one major product, the spiro enol ether 185 (^84%), along with a small amount of minor impurities (^16%) which were not i d e n t i f i e d (entry 7b, Table 4). No trans-l-phenyl-l-butene was detected. A preliminary study by Dr. I. Nagakura of our laboratory showed that thermolysis of 2-cyclopropylmethylenecyclopentanone 149 at ^450°C \ -135-(procedure A) gave a f a i r l y low y i e l d of the desired product, the spiro ketone 187. A considerable amount of the undesired dienones 188, 189 and indane 190 was also formed (eq.45, entry 8a, Table 4). In an attempt to improve t h i s reaction, the cyclopropyl enone 149 was pyrolysed at ^ 425°C under the new procedure (procedure B)(entry 8b, Table 4). Although the reaction product was somewhat cleaner, the y i e l d of the spiro ketone 187 had not been improved. (45) 191 F i n a l l y , the t r i m e t h y l s i l y l enol ether 191 was prepared v i a a procedure i d e n t i c a l with that employed for the enol ether 184. Thermolysis of the enol ether 191 at ^ 425°C (procedure B) followed by hydrolysis of the crude pyrolysis product gave a 56% y i e l d of a colorless o i l . A glc analysis of thi s material showed the presence of e s s e n t i a l l y one product (^94%), the spiro ketone 187 (entry 9, Table 4). However, the i r spectrum of t h i s material showed the presence of both saturated and a,g-unsaturated carbonyl compounds. Therefore, t h i s material was subjected to column chromatography. Eventually, a 38% o v e r a l l y i e l d of the spiro ketone 187 was i s o l a t e d . The low y i e l d of the l a t t e r may be attributed p a r t l y to i t s v o l a t i l i t y and to mechanical losses. The structure of spiro ketone was confirmed by spectral analysis. Tne i r spectrum showed the presence of a five-membered rin g ketone ^Vmax c m ^ ' * n t* i e ^Hnmr spectrum, the two o l e f i n i c protons gave r i s e to two sets of multiplets at x4.10 and 4.55--136-In general, the thermolysis of the c y c l i c 8-cyclopropyl-a,6-unsaturated ketones described so far gave reasonable y i e l d s of the expected annelated cyclopentenes. Since the reactions were simple to perform and the desired products were f a i r l y easy to i s o l a t e , t h i s procedure should f i n d more applications i n the future as a synthetic method for cyclopentene annelation. Of p a r t i c u l a r interest i s the spiroannelation reaction involving the thermolysis of 2-cyclopropyl-methylenecycloalkanones or the corresponding enol s i l y l ethers. For example, the thermolysis of 2-cyclopropylmethylenecyclohexanone 150 or i t s t r i m e t h y l s i l y l e n o l ether derivative afforded a spiro[4.5]decane system and i t i s thus clear that t h i s reaction could serve as a key step i n the synthesis of a wide variety of nat u r a l l y occuring spiro[4.5]decane sesquiterpenes, for example, the spirovetivanes. The p o s s i b i l i t y of applying t h i s spiroannelation method to the synthesis of spirovetivanes was investigated and constitutes the next portion of t h i s thesis. IV. Application of Thermal Vinylcyclopropane-Cyclopentene Rearrangement  to Spirovetivane Synthesis The rapidly increasing number of known spirovetivane-type sesquiter-penoids have i n common the s t r u c t u r a l l y i n t e r e s t i n g carbon skeleton 192. Representatives of the spirovetivanes include 8-vetivone 193, a-vetispirene 119 194, g-vetispirene 195, hinesol 196, and anhydro-8-rotunol 197. -137-The interest i n the spirovetivane class of sesquiterpenoids as constituents of essential o i l s , as stress metabolites, and as proposed intermediates i n terpene biogenesis has stimulated considerable synthetic 121-132 effo r t s directed towaras the preparation of these compounds. The 120 f i r s t efforts i n this area were reported by Marshall and coworkers , who had e a r l i e r shown that 8-vetivone i s a member of this group rather than a hydroazulene derivative as o r i g i n a l l y reported. Due i n part to the widely variant oxidation state at carbons 1,2,6,7,8,11,12 and 14 throughout the series, e a r l i e r synthetic efforts had concentrated on the 121—128 construction of s p e c i f i c spirovetivanes- Recently, the emphasis has shifted toward the construction of one or more intermediates which could serve as a synthetic precursor of a number of natural products 129-132 belonging to th i s class of sesquiterpenes. Among the few syntheses 129-l'-i2 that employed this approach , i t i s of interest to note that those 129 132 reported by Caine anc Buchi have involved the use ot the spiro o l e f i n i c ketone 198 as a key intermediate. So f a r , the l a t t e r has been 129 132 converted into (±)-a-vetispirene 194 , (i ) - B-vetivone 193 , and (±)-132 hinesoi acetate 199. Here we report a convenient alternative preparation of the synthetic intermediate 198 based on the new thermal spiroannelation method developed e a r l i e r , as described i n the previous section of th i s thesis, O 199 As described previously, the spiro enone 175 could be prepared i n good y i e l d by the thermal rearrangement of the enol s i l y l ether 184, followed by the hydrolysis of the i n i t i a l l y formed product 185 (Scheme 9). -138-Th e success of these e a r l i e r efforts encouraged us to investigate the p o s s i b i l i t y of applying this methodology to the synthesis of spirovetivanes. Scheme 9 Since the synthetic intermediate 198 employed by C a i n e X Z y and Buchi"1""^ had the potential of serving as a synthetic precursor of a f a i r l y large number of spirovetivanes, i t was decided to make th i s compound our synthetic goal. The key step to compound 198 would then be to synthesize a spiroL4.5]decane system that contained both a methyl group at carbon 10 and a suitable f u n c t i o n a l i t y on the f i v e membered ring which subsequently could be readily converted to a carbonyl group at carbon 2. One possible candidate was the spiro enol s i l y l ether 201, which on the basis of the previous work, should be obtainable by thermal rearrangement of the enol s i l y l ether 200 (eq.46). Hopefully, mainly for s t e r i c reasons, the methyl group on the six-membered ring of 200 would, during the thermolytic rearrangement, direct bond formation i n the required manner so that the spiro compound 201 would be produced stereoselectively. Thus, the i n i t i a l synthetic objective was to prepare the enol s i l y l ether 200 and to carry out the thermal rearrangement of this compound. (46) 200 201 -139-The conjugate addition of l i t h i u m diorganocuprate reagents to a,8-unsaturated carbonyl compounds produces, p r i o r to hydrolysis,an 133 intermediate with the properties of a metal enolate. This reaction intermediate reacts with a va r i e t y of e l e c t r o p h i l i c reagents, such as 134 carbonyl compounds, to give a l d o l products , Michael addition acceptors 135 to form Michael adducts , and reactive a l k y l halides to form alkylated 136 ketones. Thus, i t was expected that the addition of l i t h i u m dimethyl-cuprate to 2-cyclohexen-l-one, followed by trapping the r e s u l t i n g enolate with cyclopropanecarboxaldehyde, would give the ke t o l 203 re g i o s e l e c t i v e l y , Dehydration of the keto l 203 would then give the desired 6-cyclopropyl enone 155 and/or 156 (scheme 10). CTM+ Me 2CuLi N^.c-C 3H 5CH0 202 Scheme 10 Cyclopropanecarboxaldehyde, which i s not commerically a v a i l a b l e , can be prepared by a wide variety of methods, including reduction of N,N-dimethyl-137 cyclopropylcarboxamide with diethoxyaluminohydride and oxidation of cyclo-138 propylcarbinol by pyridinium chlorochromate , chromium t r i o x i d e and s u l f u r i c 139 140 acid i n dimethylformamide , N-chlorosuccinimide and dimethylsulfide , or 141 manganese dioxide i n pentane. A l l of these methods were t r i e d , but none of them gave sat i s f a c t o r y i s o l a t e d y i e l d s of the pure aldehyde. F i n a l l y , i t was found that the method which gave the most s a t i s f a c t o r y r e s u l t s (71% i s o l a t e d y i e l d of pure cyclopropanecarboxaldehyde) involved eerie ammonium n i t r a t e 142 oxidation of cyclopropylcarbinol. The l a t t e r , though commercially a v a i l a b l e , was prepared from cyclopropanecarboxylic acid. E s t e r i f i c a t i o n of the acid with -140-ethanol i n refluxing benzene containing a c a t a l y t i c amount of s u l f u r i c 143 acid , followed by lithium aluminum hydride reduction of the resulting 144 ester, gave a 55% ov e r a l l y i e l d of the cyclopropylcarbinol (Scheme 11). It was found that direct reduction of cyclopropanecarboxylic acid by diborane i n tetrahydrofuran f a i l e d to give an acceptable y i e l d of cyclo-propylcarbinol. 1 4"' EtOH, Bz ^ LiA£H, . 2 ( N H 4 } 2 C e (N(V 6 COjH -> H 2 S 0 4 A DjB ^ Ether Scheme 11 HjOH >-CHO H20 Addition of 2-cyclohexen-l-one to a cold (0°C) ether solution of lithium dimethylcuprate, followed by trapping of the resulting enolate anion with one equivalent of cyclopropanecarboxaldehyde gave a 60% y i e l d of a colorless o i l . A glc analysis of th i s material showed the presence of a major component (^70%) and two minor compounds (VL4% and 7% respectively). An a n a l y t i c a l sample of each component was obtained by preparative g l c . The major component was i d e n t i f i e d as the enone 153, the regioisomer of the expected product 155. The structural assignment of enone 153 was based on spectral analysis. The 6-olefinic proton of enone 153 exhibited a doublet of t r i p l e t s ( J=ll Hz, J'=2 Hz) at T3.92 i n the "4inmr spectrum rather than a doublet of doublets as would be expected from the desired regioisomer 155. One of the minor components (^7%) was i d e n t i f i e d as the geometrical isomer 154 of the enone 153. The ^ Hnmr spectrum of the enone 154 also exhibited a doublet of t r i p l e t s (J=ll Hz, J'=2 Hz) for the B-ol e f i n i c proton, the chemical s h i f t of which was at T 5 . 0 8 . The assignment of stereo-chemistry to the two isomers, 153 and 154 had been discussed e a r l i e r i n this -141-thesis and w i l l not be repeated here. l.Me 2CuLi L^ JJ 2.C-C H-CHO * 153 154 F i n a l l y , the other minor isomer (^14%) was found to be 3-methyl-cyclohexanone by comparing the ^Hnmr spectrum of this material with that of an authentic sample obtained commercially. In order to show conclusively that the major component obtained from the cuprate reaction was indeed compound 153 and not 155, a s p e c i f i c syn-thesis of compound 153 was carried out. Thus, addition of 3-methylcyclo-hexanone to an ethereal solution of lithium diisopropylamide, k i n e t i c a l l y 146 generated enolate anion 204. Trapping this enolate anion with cyclo-propanecarboxaldehyde, followed by dehydration of the intermediate k e t o l , gave a 23% y i e l d of 2-cyclopropylmethylene-5-methylcyclohexanone 153 (eq.48). The spectral data obtained from this material were i d e n t i c a l with those of the major component obtained from the cuprate reaction described above. It was apparent that, i n the cuprate addition reaction to 2-cyclohexen-l-one, e q u i l i b r a t i o n and isomerization of the intermediate enolate anion must have occurred prior to the condensation with the aldehyde giving enones 153 and 154 as the resulting products. The condensation of the s p e c i f i c enolate 202 with ethyl formate was also investigated. Ethyl formate was chosen because the resulting 2-hydroxy--142-methylene-3-methylcyclohexanone 205, i f formed, could be r e a d i l y trans-formed into 2-cyciopropylmethylene-3-methylcyclohexanone 155 v i a the corresponding g-iodo enone 139 as described e a r l i e r i n t h i s thesis for 2-hydroxymethylenecyclohexanone 110 (Scheme 12). Scheme 12 The condensation reaction of ethyl formate with the s p e c i f i c enolate generated by the cuprate addition to 2-cyclohexen-l-one would also give r i s e to an ethoxide anion (Scheme 13). The l a t t e r could abstract a proton from the i n i t i a l l y formed product 205 to form ethanol. The ethanol could then serve as a source of protons to allow the k i n e t i c a l l y generated enolate 202 to e q u i l i b r a t e . 202 205 Scheme 13 I t was therefore proposed to add potassium hydride to the reaction mixture so that a s i g n i f i c a n t concentration of ethanol could be avoided. In t h i s way, i t was hoped that, i n absence of s i g n i f i c a n t amounts of a proton source, e q u i l i b r a t i o n of the intermediate enolate anion would be neg l i g i b l e and hence the reaction might be regioselective. This idea was t r i e d out as follows. To a cold solution (0°C) of li t h i u m dimethylcuprate -143-(1.5 eq.) i n ether was added one equivalent of 2-cyclohexen-l-one. Then two equivalents of potassium hydride were added, followed by the addition of two equivalents of ethyl formate. The r e s u l t i n g solution was s t i r r e d at 0°C for l h . After work-up, a 41% y i e l d of a 1:1 mixture of 2-hydroxy-methylene-3-methylcyclohexanone 205 and 2-hydroxymethylene-5-methylcyclo-hexanone 206 was obtained (eq.49). The '''Hnmr of t h i s mixture showed the (49) 205 206 presence of two o l e f i n i c protons at xl.30 and 1.36 i n the r a t i o of ^ 1:1, corresponding to the two B - o l e f i n i c protons on the a-hydroxymethylene groups of the two compounds 205 and 206. Although i t was clear that the above reaction was not r e g i o s e l e c t i v e , as had been hoped, i t was nevertheless decided to transform the two compounds, 205 and 206 into the corresponding B-cyclopropyl enones, so that the l a t t e r could be compared with the B-cyclopropyl enones obtained e a r l i e r by conden-sation of 202 with cyclopropanecarboxaldehyde. Thus, treatment of the mixture of 205 and 206 with triphenylphosphine diiodide i n acetonitrile-hexamethyl-phosphoramide i n the presence of triethylamine gave an 82% y i e l d of a 1:1 mixture of the corresponding B-iodo enones 139 and 138, respectively (eq.50). An a n a l y t i c a l sample of each of the products 138 and 139 was obtained by preparative g l c . -144-H( + >3PI2 206 205 CH3CN-HMPA, Et 3N (50) -6r 138 139 1:1 In each case, the assigned structure was supported by spectral data. The i r of iodo enone 138 showed the presence of an a,B-unsaturated ketone (v 1690, 1570 cm ^ ) . The "Sinmr spectrum showed the presence max r of only one o l e f i n i c proton which resonated at T2.30 as a t r i p l e t (J=2 Hz). The methyl group gave r i s e to a signal at x8.97 i n the form of a doublet (J=5.5 Hz). Compound 139 exhibited similar spectral data. The i r spectrum of compound 139 showed two strong bands at 1685 and 1565 cm \ The single o l e f i n i c proton showed up as a singlet at x2.51 i n the "4inmr spectrum. The methyl group gave r i s e to a doublet at x8.94 with J=7 Hz. The a l l y l i c proton at C-3 showed up as a multiplet at x6.64-7.02. The mixture of iodo enones 138 and 139 was converted into a mixture of the corresponding B-cyclopropyl enones by treating the former with lithium phenylthio(cyclopropyl)cuprate. A 75% y i e l d of a mixture of the B-cyclopropyl enones 153, 155 and 156 i n a r a t i o of 2:1:1, respectively, was obtained (eq.51). Ananalytical sample of each compound was obtained by preparative glc. The spectral data obtained from compound 153 was i d e n t i c a l with those "TJ-138 rV' yVS k ^ A ^ P h S (£-C3H5 ) CuLi 139 + 153 (51) of the same compound obtained as described e a r l i e r . In the 1Hnmr spectrum of the enone 1_55, the B - o l e f i n i c proton appeared as a doublet of doublets (J=ll Hz, J'=l Hz) at X4.02. The analogous proton of the isomeric compound -145-156 gave r i s e to a doublet of doublets (J=10.5 Hz, J'=2 Hz) at x5.16. The assignment of stereochemistry to the two isomers, 155 and 156 had been discussed e a r l i e r . On the basis of results obtained from the experiments described above,it was clear that addition of lithium dimethylcuprate to 2-cyclo-hexen-l-one, followed by trapping of the r e s u l t i n g enolate anion with cyclopropanecarboxaldehyde, did not give the desired product 155. Furthermore, although the alternative procedure involving ethyl formate as trapping agent, did eventually produce some of the desired material, t h i s methodology also f a i l e d to give the desired isomer 205 regioselectively.-Therefore, other methods were investigated. 147 Mukaiyama et_ a l had reported that s i l y l enol ethers, prepared from various carbonyl compounds, reacted with aldehydes and ketones i n the presence of titanium tetrachloride under mild conditions to give cross-a l d o l condensation products i n good yi e l d s . The enol s i l y l ether 207 was obtained from the 1,4-addition of lithium dimethylcuprate to 2-cyclohexen-l-one, followed by trapping the resulting enolate anion with chlorotrimethyl-148 silane (eq.52). When the Mukaiyama procedure was applied to the trimethyl-s i l y l enol ether 207 and cyclopropanecarboxaldehyde, however, no condensation product was obtained. Only 3-methylcyclohexanone was recovered. Me 2CuLi c-C3H5CHO TiC£, -X » (52) 207 203 It i s well known that s p e c i f i c enolates generated by the reaction of methyllithium with s i l y l enol ethers of various carbonyl compounds may be -146-alkylated regioselectively, for example, eq. 5 3 . 1 4 I t was therefore decided SiMe3 1. CH 3Li 2. RX (53) 6 208 209 to attempt a si m i l a r reaction using cyclopropanecarboxaldehyde as the e l e c t r o p h i l i c trapping reagent. I f t h i s reaction had been successful, i t should have produced the ketol 203. Unfortunately, when the enol ether 207 was treated with methyllithium, followed by the addition of cyclopropanecarboxaldehyde, only the enone 153 was obtained after work-up. Presumably, eq u i l i b r a t i o n of the intermediate lithiumenolate anion had occurred faster than condensation. In view of e a r l i e r results obtained from attempts to trap the s p e c i f i c enolate generated d i r e c t l y by cuprate addition to 2-cyclohexen-l-one, t h i s result was perhaps not surprising. F i n a l l y i t was found that the s p e c i f i c enolate anion generated by copper catalysed conjugate addition of methyl magnesium iodide to 2-cyclo-hexen-l-one could be trapped by cyclopropanecarboxaldehyde regioselectively to give the ketol 203 as a mixture of diastereomers i n ^97% y i e l d (Scheme 14). I t i s important to note that when cyclopropanecarboxaldehyde was added to the ether solution of the s p e c i f i c enolate anion, a thick greyish white precipitate formed immediately and remained undissolved throughout the reaction. The r e g i o s e l e c t i v i t y of the reaction may thus be attributed to the i n s o l u b i l i t y of this intermediate alkoxide anion 210. M a * MeMgl £-C3H5CHO > > Cul 210 Scheme 14 203 -147-The structure of the k e t o l 203 was supported by i t s i r spectrum which showed the presence of a saturated six-membered r i n g ketone (v max 1700 cm and an alcohol f u n c t i o n a l i t y (v 3470 cm V A t i c analysis max 3 of t h i s material snowed the presence of two components i n approximately equal amounts (spots of equal i n t e n s i t y ) . This material underwent p a r t i a l dehydration and r e t r o a l d o l reaction upon d i s t i l l a t i o n . Because of i t s i n s t a b i l i t y , i t was not p u r i f i e d further but was used d i r e c t l y i n the next step. Dehydration of k e t o l 203 by treatment of t h i s material with P_-toluenesulfonic acid i n r e f l u x i n g benzene gave a 6:1 mixture of the enones 155 and 156, respectively, i n ^50% o v e r a l l y i e l d from 2-cyclohexen-l-one (eq.54). A considerable amount of 3-methylcyclohexanone was also i s o l a t e d . Apparently, extensive r e t r o a l d o l reaction occurred under these reaction conditions. The y i e l d of the mixture of enones 155 and 156 was improved considerably + (54) 203 155 156 by f i r s t converting the k e t o l 203 into the corresponding acetate 211 (acetic anhydride, pyridine). The '''Hnmr spectrum of the l a t t e r showed that i t was a mixture of diastereomers. Elimination of acetic acid from the acetate 211, accomplished by treatment of the l a t t e r with l,5-diazabicyclo[4.3.0]non-5-ene (DBN) i n refluxing benzene, gave an o v e r a l l 787, y i e l d of a 13:1 mixture of enones 155 and 156, respectively, from the ketol 203 (.eq.55). -148-(55) 203 211 155 156 13 : 1 Conversion of the mixture of enones 155 and 156 into the corresponding t r i m e t h y s i l y l enol ethers 200 was carried out by the standard procedure (lithium diisopropylamide, glyme, 0°C; chlorotrimethyl-s i l a n e , triethylamine) as described previously for other enones of s i m i l a r structure. The formation of enol s i l y l ether 200 was confirmed by the "hhimr spectrum of t h i s material, which showed the presence of the o l e f i n i c proton at C-6 as a one-proton t r i p l e t (J=3 Hz) at T5.11. The i r spectrum of t h i s material also showed that the carbonyl f u n c t i o n a l i t y was absent. Thermolysis of the enol s i l y l ether 200 at ^380°C under argon (procedure B), followed by hydrolysis (1:1 mixture of IN aqueous hydrochloric acid and methanol) of the r e s u l t i n g crude product afforded a mixture (^57% y i e l d from 155 and 156) of the spiro enones 212 and 213 i n a r a t i o of about 2.5:1 respectively (eq. 56). The two products were separated by column chromato-graphy of the mixture on s i l i c a gel. The assignment of structure and (56) stereochemistry to compounds 212 and 213 were supported by spectral data and by subsequent transformation of 212 into compounds of known structure and stereochemistry. -149-The spiro enone 212 was a crystalline solid (m.p. 35-38°C). The i r spectrum showed the presence of a saturated six-membered ring ketone (v 1705 cm The two olefinic protons gave rise to a multiplet at max T4.02-4.38 in the ^"Hnmr spectrum. The methyl group gave rise to a doublet (J=6 Hz; at T9.10. The rest of the protons produced a multiplet at x7.16-8.60. The enone 213 also showed a saturated carbonyl absorption at 1705 cm ^  in the i r spectrum. The ''"Hnmr of this material showed a two-proton multiplet at x4.02-4.40 (olefinic protons), a three-proton doublet (J=6 Hz) at T9.14 (secondary methyl group), a four-proton multiplet between x7.42 and 7.80 and a seven proton multiplet between x7.80-8.60. There was no apparent relationship between the stereochemistry of the reactant 200 and that of the products (2l2 and 213) in the thermolysis reaction. The same ratio of products was obtained when different samples of 200 containing varying amounts of the two geometric isomers were pyrolysed. Although the stereoselectivity associated with this step was not as high as had been hoped, the minor isomer 213, which had the "wrong" stereochemistry, is not necessarily useless from a synthetic point of view, since i t is also a potential intermediate for spirovetivane synthesis. Treatment of the enone 212 with methyllithium in ether at 0°C afforded a 78% yield of a mixture of the alcohols 214 and 215, in a ratio of ^ 4.6:1 (eq. 57). The two isomers were separated by column chromatography on s i l i c a gel. OH (57) 214 215 4.6 : 1 -150-Compound 214 showed the presence of an alcohol functionality i n the i r spectrum (v 3500 cm 1) and, i n the "4lnmr spectrum, an "extra" max methyl group (singlet at x8.78). This material was i d e n t i c a l with an authentic sample of the same material previously prepared and kindly 132 supplied by Buchi and coworkers. The minor isomer 215 exhibited spectral data very similar to those of compound 214. A strong absorption band at 3490 cm 1 i n the i r spectrum indicated the presence of an alcohol fu n c t i o n a l i t y . In the ''"Hnmr spectrum, a three-proton singlet at T8.96 was assigned to the methyl group a to the alcohol fu n c t i o n a l i t y . The other methyl group remained as a three proton doublet (J=6.5 Hz) at T9.25. Each of the two o l e f i n i c protons gave r i s e to a doublet of t r i p l e t s (T4.19 and 4.48). Each signal had the same coupling constants (J=6 Hz, J'=2 Hz). Hydroboration of the o l e f i n i c alcohol 214 with disiamylborane i n tetrahydrofuran ( r . t . , 21h), followed by oxidation of the resulting trialkylborane with alkaline hydrogen peroxide gave a single d i o l 216 i n 77% y i e l d (eq.58). Diol 216 was a c r y s t a l l i n e s o l i d (m.p. 153-155°C). The'ir spectrum showed two alcohol bands at 3480 and 3640 cm 1. No o l e f i n i c protons were observed i n the "4lnmr spectrum of t h i s material. A one-proton multiplet at x 5.55-5.95 was assigned to the proton next to the newly acquired alcohol f u n c t i o n a l i t y . OH Me 2- H2°2' ° H 214 216 -151-The stereochemical assignment of compound 216 was based on s t e r i c arguments. In the more stable conformation of compound 214, one of the methyl groups and the hydroxyl group should be equatorial. Since the methyl group i s bulkier than the f l e x i b l e hydroxy group, and since the large hydroborating agent should p r e f e r e n t i a l l y attack from the less hindered side of the carbon-carbon double bond, one would expect the d i o l 216 to be the only (or at least the predominant) product. Oxidation of the d i o l 216 with pyridinium chlorochromate i n methylene chloride ( r . t . lh) afforded the ketol 217 i n 88% y i e l d (eq. 59). The structure of t h i s material (mp. 51-52°C) was supported by spectral data. The i r spectrum showed the presence of both an alcohol and a saturated carbonyl f u n c t i o n a l i t y ( v m a x 3500, 3660, 1730 cm "*"). The nmr spectrum showed the presence of an AB pair of doublets at T7.36 and 7.84 (J =19 Hz), which integrated for two protons. These were assigned to the two protons at C - l , a to the carbonyl f u n c t i o n a l i t y . (59) Dehydration of 217 i n r e f l u x i n g benzene containing a c a t a l y t i c amount of jj-toluenesulfonic a c i d , followed by e q u i l i b r a t i o n of the i n i t i a l l y formed dehydration products under the same conditions, afforded a 90% y i e l d of the spiro enones 198 and 218 i n a r a t i o of 9:1 respectively (eq.60). The enone 198 was isolated from the isomeric mixture by preparative t i c . The i r spectrum of t h i s material showed the presence of a five-membered rin g saturated carbonyl group at 1740 cm The o l e f i n i c proton gave r i s e to a -152-multiplet between T4.49 and 4.66 i n the '''Hnmr spectrum. The methyl group on the double bond showed up as a three proton singlet at T7.76. This material was i d e n t i c a l with a sample of the same material previously 132 129 prepared by Buchi and Caine. We are grateful for the i r assistance i n supplying spectral data and an authentic sample of this material. pTsOH A 217 Bz 90% 198 218 (60) Following a sequence similar to that outlined above, hydroboration of the alcohol 215 with disiamylborane i n tetrahydrofuran, followed by oxidation of the resulting d i o l (not purified) by pyridinium chlorochromate i n methylene chloride, afforded (38% o v e r a l l y i e l d from 215) the ketol 219 (Scheme 15). The i r spectrum of this material showed the presence of both an alcohol and a carbonyl fu n c t i o n a l i t y ( v 3500, 1730 cm \ respectively). The t e r t i a r y methyl group at C-6 gave r i s e to a three-proton singlet at T8.84 i n the ''"Hnmr spectrum. The secondary methyl group at C-10 appeared as a doublet (J=6.5 Hz) at x9.16. This material was i d e n t i c a l with a 129 sample of the same material previously prepared by Caine. We are grateful to Professor Caine for his assistance i n supplying spectral data of t h i s material. Ketol 219 had previously been converted into the spiro enone 129 198. 2. H202,Na0H 215 C5H5NCr03HC£ Scheme 15 219 198 -153-EXPERIMENTAL For general information, see the experimental part of Part I of thi s thesis. Reagents and Starting Materials. Cyclohexane-1,3-dione, cyclopentane-1, 3-dione, and 2-methylcyclopentane-l,3-dione were obtained from Aldrich Chemical Company Inc. and were used without further p u r i f i c a t i o n . 2-Methylcyclohexane-1,3-dione was prepared from cyclohexane-1,3-dione by alk y l a t i n g the l a t t e r with methyl iodide i n aqueous dioxane containing sodium hydroxide.^® The preparation of the t r i c y c l i c 8-diketone 108, involving a Diels-Alder reaction between cyclopentadiene and cyclopentane-1,3-dlone, was carried out i n our laboratory by Dr. I. Nagakura. 2-Hydroxy-methylenecyclohexanone and 2-hydroxymethylenecyclopentanone were prepared by the formylation of cyclohexanone and cyclopentanone, r e s p e c t i v e l y . 1 ^ 1 152 Cyclopropyllithium was prepared by the method of D. Seyferth. To a s t i r r e d suspension of 1.5 g (214 mmol) of lithium wire (or ribbon, washed with dry benzene) i n 80 ml of cold (0°C) anhydrous ether under an atmosphere of argon was added, dropwise, a solution of cyclopropyl bromide (12.1 g, 100 mmol). The mixture was s t i r r e d at 0°C for 1.5h. The resulting solution of cyclopropyllithium containing one equivalent of lithium bromide 153 was standardized by Gilman's procedure and used as such. T r i - n - b u t y l t i n Hydride was prepared by reduction of t r i - n - b u t y l t i n chloride with lithium aluminum hydride i n ether. I. Synthesis of B-Iodo-a,B-Unsaturated Ketones General Procedure A. - To a solution of triphenylphosphine (2.88 g, 11 mmol) i n dried a c e t o n i t r i l e (50 ml) was added 2.79 g (11 mmol) of iodine c r y s t a l s . The mixture was s t i r r e d at room temperature for 20 min. To the resulting yellow suspension of triphenylphosphine diiodide was added successively -154-triethylamine (1.1 g, 11 mmol) and the appropriate c y c l i c B-diketone (10 mmol). The r e s u l t i n g solution was refluxed for 3h. A c e t o n i t r i l e was removed under reduced pressure. The residual o i l was extracted by s t i r r i n g and decantation with f i v e 30 ml portions of ether. The combined ether extracts were concentrated to about 25 ml and the r e s u l t i n g solution was f i l t e r e d through a short column of f l o r i s i l (25 g, 80-100 mesh). The column was eluted with a further 75 ml of ether. Removal of solvent from the combined eluants and d i s t i l l a t i o n of the residual o i l gave the corresponding B-iodo-a,B-unsaturated ketone. General Procedure B. - The general procedure B was e s s e n t i a l l y the same as procedure A except that the reaction mixture was refluxed for 9h instead of for 3h. General Procedure C. - To a solution of triphenylphosphine (2.88 g, 11 mmol) i n a mixture of dried a c e t o n i t r i l e (50 ml) and hexamethylphosphor-amide (8 ml, freshly d i s t i l l e d from l i t h i u m aluminum hydride) was added 2.79 g (11 mmol) of iodine c r y s t a l s . The mixture was s t i r r e d at room temperature for 20 min. To the re s u l t i n g yellow suspension of tr i p h e n y l -phosphine diiodide was added successively triethylamine (1.1 g, 11 mmol) and the appropriate c y c l i c B-diketone (10 mmol) or a-hydroxymethylenecyclo-alkanone (10 mmol). The re s u l t i n g red solution was s t i r r e d at room temperature for 15h. A c e t o n i t r i l e was removed under reduced pressure. The remaining hexamethylphosphoramide solution was extracted by s t i r r i n g and decantation with f i v e 50 ml portions of pentane. The combined pentane extracts were washed with three 30 ml portions of water and dried over anhydrous magnesium s u l f a t e . Removal of solvent and d i s t i l l a t i o n of the residual o i l gave the corresponding B-iodo-a,B-unsaturated ketone. -155-Synthesls of 3-Iodo-2-Cyclohexen-l-one JJ11. - Following the general procedure B outlined above, a mixture of cyclohexane-l,3-dione (1.12 g, 10 mmol), triethylamine (1.1 g, 11 mmol) and triphenylphosphine diiodide (11 mmol) i n a c e t o n i t r i l e (50 ml) was refluxed for 9h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 75-85°C, 1 Torr) of the crude o i l , afforded 1.92 g (87%) of pure 3-iodo-2-cyclohexen-l-one 101 as a colorless o i l . This material c r y s t a l l i z e d i n a r e f r i g e r a t o r and exhibited mp vL5-16°C; uv A 258nm(e=9000);ir (film) v 1675 cm"1 max max (OO), 1595 cm"1 (C-C); 1Hnmr, x3.20 ( t , 1H.-C-C-H, J=2 Hz), 6.90-7.23 (m, 2H, CH - C ( I ) - ) , 7.40-8.27 (m, 4H). Anal. Calcd f o r C,H..I0:C, 32.45; H, 3.17. Found: C, 32.66; H, 3.25. Synthesis of 2-Methyl-3-iodo-2-cyclohexen-l-one ILL. - Following the general procedure B outlined above, a mixture of 2-methylcyclohexane-l,3-dione (1.26 g, 10 mmol), triethylamine (1.1 g, 11 mmol) and triphenylphosphine diiodide (11 mmol) i n a c e t o n i t r i l e (50 ml) was refluxed for 9h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 112-118°C, 11 Torr) of the crude o i l , afforded 1.72 g (73%) of pure c r y s t a l l i n e 2-methyl-3-iodo-2-cyclohexen-l-one 111. This material exhibited mp 57-59°C; uv X 258 nm max (e=9500); i r (CHC10) v 1670, 1605 cm - 1; 1Hnmr, T6.80-7.20 (m, 2H, -CH„-3 max —2 C(I)= ), 7.36-7.70 (m, 2H, -C0CH2~ ), 7.80-8.33 (m, 2H, -CH2-CH2-CH2-), 7.97(t, 3H, =C-CH3, J=2 Hz). Anal. Calcd f o r 0-^10: C, 36.04; H, 3.87. Found: C, 36.23; H, 4.00. Synthesis of 3-Iodo-2-cyclopenten-l-one 117. - Following the generalprocedure A outline above, cyclopentane-l,3-dione (981 mg, 10 mmol) was allowed to react with triphenylphosphine di i o d i d e (11 mmol) and triethylamine (1.1 g, 11 mmol) i n a c e t o n i t r i l e (50 ml). Normal work-up, followed by d i s t i l l a t i o n (air-bath -156-temperature ^80°C, 0.2 Torr) of the crude o i l , afforded 1.77 g (85%) of pure c r y s t a l l i n e 3-iodo-2-cyclopenten-l-one 112. This material ex-hib i t e d mp 67-68°C; uv X 249 nm (£=11350); ir(CHCl 0)v 1710, max J max 1570 cm"1; ^Ttamr, T3.36 ( t , 1H,-C=C-H, J=1.8 Hz), 6.84-7.10 (m, 2H), 7.44-7.66 (m, 2H). Anal. Calcd for C ^ I O : C, 28.88; H, 2.42. Found: C, 28.98; H, 2.40. Synthesis of 2-Methyl-3-iodo-2-cyclopenten-l-one 1 1 ^ . - Following the general procedure A, a mixture of 2-methylcyclopentane-l,3-dione (1.12 g, 10 mmol), triethylamine (1.1 g, 11 mmol) and triphenylphosphine diiodide (11 mmol) i n a c e t o n i t r i l e (50 ml) was refluxed for 3h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^50°C, 0.2 Torr) of the crude o i l , afforded 2.03 g (92%) of pure, c r y s t a l l i n e 2-methyl-3-iodo-2-cyclopenten-l-one 113. This material exhibited mp 52-53°C; uv X 248 nm J r max (e=11520), shoulder at 210 nm (£=4655); ir(CHCl-) v 1701, 1620 cm"1; j max 1Hnmr, T6.84-7.20 (m, 2H, -CH_2-C(I)= ), 7.32-7.60 (m, 2H, -C0CH_2- ), 8.17 ( t , 3H, -C=C-CH3, J=2 Hz). Anal, Calcd for Cg^IO: C, 32.43; H, 3.15. Found C, 32.36; H, 3.30. Synthesis of the B-Iodo Enone 1_14_. - Following the general procedure A, a mixture of the c y c l i c 8-diketone 108 (1.62 g, 10 mmol), triethylamine (1.1 g, 11 mmol) and triphenylphosphine diiodide (11 mmol) i n a c e t o n i t r i l e (50 ml) was refluxed for 3h. Normal work-up, followed by d i s t i l l a t i o n ( a i r -bath temperature VL20°C, 0.2 Torr) of the crude o i l , afforded 0.83 g (V31%) of the pure, c r y s t a l l i n e iodo enone 114. This material exhibited mp 78-80°C; uv X 253 nm (£=9900); i r (CHCl-Jv 1698, 1561 cm"1; 1Hnmr, x3.61 max 3 max (s, IH, -CH=C(I)-), 3.88-4.20 (m, 2H, H-C=C-H), 6.27-6.45 (m, IH), 6.60-6.80 (m, IH), 6.85-7.20 (m, 2H), 8.10-8.50 (m, 2H). -157-Anal. Calcd. for C^Hg'IO: C, 44.145; H, 3.333. Found: C, 44.15; H, 3.48. 103 Synthesis of 2-Iodomethylenecyclopentanone 115. Following the general procedure C, 2-hydroxymethylenecyclopentanone (1.02 g, 10 mmol) was allowed to react with triphenylphosphine diiodide (11 mmol) and triethylamine (1.1 g, 11 mmol) i n a mixture of a c e t o n i t r i l e (50 ml) and hexamethyl-phosphoramide (8 ml) at room temperature for 3 days. Normal work-up, followed by d i s t i l l a t i o n of the crude o i l , afforded 1.62 g (73%) of a pale yellow c r y s t a l l i n e material. This material was r e c r y s t a l l i z e d from ether and was shown to be 2-iodomethylenecyclopentanone 115. A r e c r y s t a l l i z e d sample of 115 exhibited mp 31.5°C; uv X m a x 276 nm (e=9170), 263 nm (shoulder); i r (CHCl-)v 1720, 1608 cm"1; "Slnmr, T2.39 ( t , IH, -C=C(I)-H, J=1.8 Hz), 3 max v > > — ' ' 7.0-8.3 (m, 6H). Mol.Wt. Calcd. for 0^10:221.9543. Found (high resolution mass spectrometry): 221.9544. Synthesis of 2-Iodomethylenecyclohexanone 116- - Following the general procedure C,2-hydroxymethylenecyclohexanone (1.26 g, 10 mmol) was allowed to react with triphenylphosphine d i i o d i d e (11 mmol) and triethylamine (1.1 g, 11 mmol) i n a mixture of a c e t o n i t r i l e (50 ml) and hexamethyl-phosphoramide (8 ml) at room temperature for 15h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^65°C, 0.4 Torr) of the crude o i l afforded 2.22 g (94%) of pure 2-iodomethylenecyclohexanone 116 as a colorless o i l . This material c r y s t a l l i z e d i n a r e f r i g e r a t o r and exhibited mp vL5°C; uv X 265 nm (e=7200); i r ( f i l m ) v 1695, 1570 cm - 1; 1Hnmr, T2.30 ( t , IH, -C=C(I)H, J=2 Hz) x7.32-7.70 (m, 4H), x7.96-8.42 (m, 4H). Anal. Calcd. for C 7H qI0: C, 35.62; H 3.84. Found: C, 35.65; H, 3.76. -158-Preparatlon of a 1:1 Mixture of 2-Hydroxymethylene-3-methylcyclohexanone  205 and 2-Hydroxymethylene-5-methylcyclohexanone 206 and the Conversion  of the Mixture to the Corresponding g-Iodo Enones 139 and 138. Respectively. -To a cold (0°C) solution of l i t h i u m dimethylcuprate (16.5 mmol, prepared from cuprous iodide and methyllithium) i n ether (75 ml) was added 1.44 g (15 mmol) of 2-cyclohexen-l-one under an atmosphere of argon. This was followed immediately by the addition of potassium hydride (1.2 g, 30 mmol) and ethyl formate (2.20 g, 30 mmol). The r e s u l t i n g mixture was s t i r r e d at 0°C for l h . Water and ice were added, and the r e s u l t i n g mixture was f i l t e r e d . The ether layer of the f i l t r a t e was extracted with a further 100 ml of 3% aqueous sodium hydroxide. The combined aqueous extracts were a c i d i f i e d and extracted with ether. The combined ether extracts were washed with brine and water and dried over anhydrous sodium su l f a t e . Removal of the solvent, followed by d i s t i l l a t i o n (air-bath temperature 95-110°C, 10 Torr) of the residual o i l , afforded 863 mg (41%) of a 1:1 mixture of the hydroxymethylenecyclohexanones 205 and 206. The mixture exhibited "''Hnmr, xl.30 (s, a-hydroxymethylene proton), 1.36 (s, a-hydroxy-methylene proton), T8.90 (d, methyl group), 8.93 (d, methyl group). The above mixture of the hydroxymethylene derivatives 205 and 206 was converted into the corresponding 6-iodo enones as follow. Following the general procedure C, the mixture of 205 and 206 (700 mg, 5 mmol) was allowed to react with triphenylphosphine diiodide (5.5 mmol) and t r i e t h y -lamine (0.55 g, 5.5 mmol) i n a mixture of a c e t o n i t r i l e (25 ml) and hexa-methylphosphoramide (4 ml) at room temperature for 15h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^ 50°C, 0.1 Torr) of the crude o i l , afforded 2.05 g (82%) of a colorless o i l . A glc analysis -159-(column A, 120°C) of t h i s material showed that i t consisted of a mixture of 2-iodomethylene-3-methylcyclohexanone 139 and 2-iodomethylene-5-methylcyclohexanone 138 i n the r a t i o of approximately 1:1. An a n a l y t i c a l sample of each of the products 138 and 139 was obtained by preparative glc (column C, 150°C). The pure iodo enone 139 exhibited uv X 257 nm max (e=6681); i r ( f i l m ) v 1685, 1565 cm - 1; 1Hnmr, T2.51(S,1H,-C=C(I)H), max — 6.64-7.02 (m, IH, -C(CH 3)H), 7.50-7.78 (m, 2H,-CH2-C0-), 7.80-8.50 (m, 4H), 8.94 (d, 3H, -CH(CH3), J=7 Hz). Mol.Wt. Calcd. for CgH.^10: 249.9856. Found (high resolution mass spectrometry): 249.9852. The pure iodo enone 138 exhibited uv X 261 nm (E=7110); i r ( f i l m ) v max max 1690, 1570 cm"1; """Hnmr, T2.30 ( t , IH,-C=C(I)H, J=2 Hz), 7.04-8.90 (unresolved m, 7H), 8.97 (d, 3H, -CH(CH_3), J=5.5 Hz). Mol.Wt. Calcd. for CgH^IO: 249.9856. Found (high resolution mass spectrometry) :249.9857. I I . Synthesis of B-Cyclopropyl-a,g-Unsaturated Ketones from B-Iodo-a,g- Unsaturated Ketones. General Procedure A. - To a cold (-78°C) sl u r r y of phenylthiocopper (779 mg, 4.5 mmol) i n dry tetrahydrofuran.(30 ml) under an atmosphere of argon was added a solution of freshly prepared cyclopropyllithium (containing l i t h i u m bromide; 4.5 mmol) i n ether. The r e s u l t i n g mixture was warmed to -20°C and s t i r r e d for 20 min. A c l e a r , l i g h t brown solution of l i t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) resulted. The solution was cooled to -78°C. To t h i s solution was added a solution of the appropriate B-iodo-a,B-unsaturated ketone (3 mmol) i n dry tetrahydrofuran (6 ml). The r e s u l t i n g mixture was s t i r r e d at -78°C for 2.5h. Methanol (2 ml) and ether -160-(20 ml) were added and the re s u l t i n g mixture was warmed to room temperature and then f i l t e r e d through a short column of f l o r i s i l (30 g, 80-100 mesh). The column was eluted with a further 300 ml of ether. Removal of solvent from the combined eluants and d i s t i l l a t i o n of the residual o i l gave the corresponding B-cyclopropyl-a,8-unsaturated ketone. General Procedure B. - Procedure B was e s s e n t i a l l y the same as procedure A except that the reaction of the B-iodo enone with the cuprate reagent was carried out at 0°C instead of at -78°C. General Procedure C. - Procedure C was e s s e n t i a l l y the same as procedure B except that 2 equivalents (6 mmol) of cuprate reagent was used instead of 1.5 equivalents. Synthesis of 3-Cyclopropyl-2-Cyclohexen-l-one 142.. - Following the general procedure A outlined above, 3-iodo-2-cyclohexen-l-one 101 (666 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) i n tetrahydrofuran at -78°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 62-75°C, 0.3 Torr) of the crude o i l afforded 335 mg (82%) of pure 3-cyclopropyl-2-cyclohexen-l-one 142 as a colorless o i l . This material exhibited uv A 254 nm (e=17100); i r ( f i l m ) v 1660, 1625, 1610 max max cm"1; """Hnmr, T4.19 (S, IH, C0C=C-H), 7.50-9.34 (m, 11H). These spectral 144 108 data were i d e n t i c a l with those reported i n l i t e r a t u r e . ' Synthesis of 2-Methyl-3-cyclopropyl-2-cyclohexen-l-one 1 4 6 . - Following the general procedure C, 2-methyl-3-iodo-2-cyclohexen-l-one 111 (708 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl)cuprate (6 mmol) i n tetrahydrofuran at 0°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n of the residual o i l (air-bath temperature 65-85°C, 0.35 Torr), afforded 396 mg (88%) of pure 2-methyl-3-cyclopropyl-2-cyclohexen-l-one 146 as a colorless -161-o i l . This material c r y s t a l l i z e d i n a r e f r i g e r a t o r and could be recry-s t a l l i z e d from an ether-hexane mixture. A r e c r y s t a l l i z e d sample of 146 exhibited mp 36-37°C; uv X 262 nm (£=14950); i r ( f i l m ) v 1660, r max max 1600 cm"1; "hfamr, T8.10 (S, 3H, -C0C(CH3)=CH-), 7.40-8.30 (m, 6H), 9.0-9.30 (m, 5H). Mol.Wt. Calcd. for C^H^O: 150.1044. Found (high resolution mass spectrometry): 150.1032. Synthesis of 3-Cyclopropyl-2-cyclopenten-l-one l&L. - Following the general procedure A, 3-iodo-2-cyclopenten-l-one 112 (624 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) i n tetrahydro-furan at -78°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n ( a i r -bath temperature ^65°C, 0.2 Torr) of the crude o i l , afforded 355 mg (97%) of c r y s t a l l i n e 3-cyclopropyl-2-cyclopenten-l-one 147. This material ex-hibite d mp 31-33°C; uv X 244 nm (e=16270); ir(CHCl 0)v 1700, 1670, max J max 1600 cm"1; 1Hnmr, x4.12 ( t , IH, -C0C=C-H, J=1.8 Hz), 7.40-7.74 (m, 4H) , 8.00-8.32 (m, IH), 8.78-9.26 (m, 4H). Mol.Wt. Calcd. for CgH^O: 122.0731. Found (high resolution mass spectrometry): 122.0733. Synthesis of 2-Methyl-3-cyclopropyl-2-cyclopenten-l-one - Following the general procedure C, 2-methyl-3-iodo-2-cyclopenten-l-one 113 (666 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl)cuprate (6 mmol) i n tetrahydrofuran at 0°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 5^0°'C, 0.1 Torr) of the crude o i l , afforded 343 mg (84%) of pure 2-methyl-3-cyclopropyl-2-cyclopenten-l-one 148 as a colorless o i l . This material exhibited uv X 254 nm (e=18580); max i r ( f i l m ) v 1698, 1637 cm"1; 1Hnmr, T7.6-8.1 (unresolved m, 4H), 8.23 max ( t , 3H, C=C-CH3, J-1.2 Hz), 8.85-9.20 (m, 5H). Mol.Wt. Calcd. f o r CgH^O: 136.0887. Found (high resolution mass spectrometry): 136.0888. -162-Synthesis of. 2-Cyclopropylmethylenecyclohexanone 15.0.. - Following the general procedure B outlined above, 2-iodomethylenecyclohexanone 116 (708 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl) cuprate (4.5 mmol) at 0°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^80°C, 0.2 Torr) of the crude o i l , afforded 369 mg (82%) of a colorless o i l . A glc analysis (column B, 120°C) of t h i s material showed that i t was approximately 96% pure. An a n a l y t i c a l sample of compound 150, obtained by preparative glc (column D, 150°C), exhibited mp ^15°C; uv X 265 nm (£=11750); i r ( f i l m ) v 1680, 1600 cm - 1; 1Hnmr, T3.96 (d of max max t , IH, -C=CH(c-C3H5), J = l l Hz, J'=2 Hz), 7.24-7.74 (m, 4H), 7.97-8.82 (m, 5H), 8.90-9.51 (m, 4H). Anal. Calcd. for C 1 ( )H 1 40: C, 79.96; H, 9.39. Found: C, 79.69; H, 9.35. 103 Synthesis of 2-Cyclopropylmethylenecyclopentanone 149. - Following the general procedure A outlined above, 2-iodomethylenecyclopentanone 115 (666 mg, 3 mmol) was allowed to react with l i t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) i n tetrahydrofuran at -78°C for l h , and at -20°C for another 2.5h. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^95°C, 0.35 Torr) of the crude o i l , afforded 265 mg (65%) of a colorless l i q u i d . A glc analysis (column A, 120°C) of t h i s material showed that i t was approxi-mately 94% pure. An a n a l y t i c a l sample of 149 was obtained by preparative glc (column C, 150°C) and i t exhibited mp VL8°C; uv X 267 nm (£=14820); max i r ( f i l m ) v 1706, 1640 cm - 1; 1Hnmr, T4.05 (d of t , IH, -C=C-H, J = l l Hz, J»=2.8 Hz), 7.15-9.50 (unresolved m, IH). Mol.Wt. Calcd. for Cg\20: 136.0887. Found (high resolution mass spectrometry): 136.0902. Reaction of Lithium Phenylthio(cyclopropyl)cuprate with a 1:1 Mixture of the  Iodo Enones 122. and 123.. - Following the general procedure B, a 1:1 mixture -163-of the iodo enones 138 and 139 (750 mg, 3 mmol) was allowed to react with lithium phenylthio(cyclopropyl)cuprate (4.5 mmol) i n tetrahydrofuran at 0°C for 2.5h. Normal work-up, followed by d i s t i l l a t i o n (air-bath tem-perature ^73°C, 0.2 Torr) of the crude o i l , afforded 369 mg (75%) of a s l i g h t l y yellow l i q u i d . A glc analysis (column A, 120°C) of th i s material showed that i t was composed of a mixture of the 0-cyclopropyl enones 156, 155 and 153 i n the r a t i o of approx. 1:1:2, together with some minor impurities (<5%). An a n a l y t i c a l sample of each of the compounds 156, 155 and 153 was obtained by preparative glc (column C, 145°C). The pure enone 156 exhibited uv X 263 nm (e=11720); i r ( f i l m ) v 1685, 1610 max max cm"1; "''Hnmr, x5.16 (d of d, IH, -C=C-H, J=10.5 Hz, J'=2 Hz), 8.96 (d, 3H, -CH(CH_3), J=7 Hz), 7.30-9.80 (unresolved m, 12H). Mol.Wt. Calcd. for ^11^16^: 164*1201. Found (high resolution mass spectrometry): 164.1206. The pure B-cyclopropyl enone 155 exhibited uv ^ m a x 265 nm (e=11420); i r ( f i l m ) v 1680, 1600 cm"1; "'"Hnmr, T4.02 (d of d, IH, -C=C-H, J = l l Hz, max — J'=l Hz), 6.58-6.98 (m, IH), 7.48-9.50 (m, 11H), 8.96 (d, 3H, -CH(CH3), J=7 Hz). Mol. Wt. Calcd. for C^H^O: 164.1201. Found (high resolution mass spectrometry): 164.1205. The pure enone 153 exhibited mp 54-56°C; uv X 265 nm (E=9810); max i r ( f i l m ) v 1680, 1602 cm"1; 1Hnmr, T3.92 (d of t , IH, -C=C-H, J = l l Hz, max — J'=2 Hz), 6.90-9.50 (unresolved m, 12H), 8.98 (d, 3H, -CH(CH3), J=6 Hz). Anal. Calcd. for C,1H.,,0: C, 80.44; H, 9.82. Found: C, 80.06; H9.77. 11 l b I I I . Regioselective Synthesis of 2-Cyclopropylmethylene-5-methylcyclo- hexanone _15_3 and 2-Cyclopropylmethylene-3-methylcyclbhexanones (155 + 156). A. Preparation of Cyclopropanecarboxaldehyde 1. E s t e r i f i c a t i o n of Cyclopropanecarboxylic Acid. - To 10 g (0.116 mol) of -164-cyclopropanecarboxylic acid was added 10 g of ethanol, 15 ml of benzene, and 0.1 ml of cone, s u l f u r i c acid. The r e s u l t i n g mixture was refluxed for 4.5h. The ethanol-benzene-water azeotrope was then d i s t i l l e d o f f . The residual o i l was d i l u t e d with ether, and washed with d i l u t e sodium bicarbonate solution. The ether solution was dried over anhydrous magnesium sulfate. After removal of the ether, the r e s i d u a l o i l was f r a c t i o n a l l y d i s t i l l e d to give 10 g (73%) of ethyl cyclopropanecarboxylate (bp 130-132°C; 143 l i t . reported bp 133-133.5°C ). This material exhibited i r ( f i l m ) v max 1723 cm"1; ^nmr, T5.91 (q, 2H, -CH_2CH3, J=7 Hz), 8.73 ( t , 3H, -CH2CH_3, J=7 Hz), 8.2-9.6 (m, 5H). 144 2. Lithium Aluminum Hydride Reduction of Ethyl Cyclopropanecarboxylate. To a cold (0°C) s l u r r y of l i t h i u m aluminum hydride (6.81 g, 0.18 mol) i n 300 ml of anhydrous ether, i n a dried three-neck f l a s k equipped with a water condenser, a dropping funnel and a nitrogen gas i n l e t , was added dropwise a solution of ethyl cyclopropanecarboxylate (18.55 g, 0.163 mol) i n ether (50 ml), through the dropping funnel. The r e s u l t i n g mixture was warmed to room temperature, and was then refluxed for 17h. Normal work-up, followed by f r a c t i o n a l d i s t i l l a t i o n , afforded 8.85 g (75%) of cyclo-propylcarbinol (bp 120-122°C, l i t . reported bp 123-124°C ). This material exhibited i r ( f i l m ) v 3350 cm - 1; 1Hnmr, T6.60 (d, 2H, -CH-OH, J=7 Hz), max —z. 7.13 (br s IH, -CH20H), 8.60-9.90 (m, 5H). 3. Oxidation of Cyclopropylcarbinol with Ceric Ammonium Ni t r a t e . - To a solution of c e r i c ammonium n i t r a t e (114.3 g, 0.21 mol) i n water (200 ml) was added 7.15 g (0.1 mol) of cyclopropylcarbinol. The r e s u l t i n g red solution was heated on a steam bath, with constant s w i r l i n g , u n t i l the red color discharged completely. Ice-cold saturated sodium chloride solution -165-(200 ml) was added to the r e s u l t i n g colorless solution. The r e s u l t i n g mixture was extracted with f i v e 80 ml portions of methylene chloride. The combined methylene chloride extracts were dried over anhydrous magnesium sulfate and sodium bicarbonate. The methylene chloride was removed by f r a c t i o n a l d i s t i l l a t i o n and the residual o i l was f r a c t i o n a l l y d i s t i l l e d to give 5.07 g (71%) of cyclopropanecarboxaldehyde (b.p. 98°-1 42 100°C, l i t . reported bp 9 7 - 9 9 ° C ) . This material exhibited i r ( f i l m ) v 1710 cm"1; """Hnmr, T1.09 (d, IH, -CHO, J=6 Hz), 8.95 (d, 4H, -<jji , J=6 Hz), T8.0-8.34 (m, IH, -CH-CHO). B. Synthesis of 2-Cyclopropylmethylene-5-methylcyclohexanone 1 ^ . - To a cold (0°C) solution of l i t h i u m dimethylcuprate (3.3 mmol) i n anhydrous ether (18 ml) under an atmosphere of argon was added a solution of 2-cyclohexen-l-one (288 mg, 3 mmol) i n ether (1 ml). The r e s u l t i n g mixture was s t i r r e d for 10 min at 0°C. Cyclopropanecarboxaldehyde (210 mg, 3 mmol) was added. The r e s u l t i n g yellow suspension was s t i r r e d at 0°C for l h . Saturated ammonium chloride solution (15 ml) was added and the r e s u l t i n g mixture was s t i r r e d vigorously for a few min. The two layers were separated and the aqueous phase was further extracted with three 50 ml portions of ether. The combined ether extracts were dried over anhydrous sodium s u l f a t e . Removal of solvent, followed by d i s t i l l a t i o n of the residual o i l ( a i r -bath temperature 115-150°C, 15 Torr), afforded 293 mg (60%) of a colorless l i q u i d . A glc analysis of t h i s material showed the presence of one major component A 0WO%) arid two minor components B and C (^14% and ^ 7% re s p e c t i v e l y ) , together with small amounts of minor impurities Ov-9%). An a n a l y t i c a l sample of the major component A was obtained by preparative glc (column D, 160°C) and was shown to be 2-cyclopropylmethylene-5-methylcyclohexanone 153. The -166-spectraldata (xHnmr, i r ) of t h i s material were i d e n t i c a l with those of the same material prepared e a r l i e r by the reaction of l i t h i u m phenylthio-(cyclopropyl)cuprate with the corresponding iodomethylenecyclohexanone. Small amounts of components B and C were also obtained by preparative glc (column 160°C). Spectral data ("^ Hnmr) showed that component B was 3-methylcyclohexanone, while component C was probably compound 154, the geometric isomer of the cyclopropyl enone 153. Component C exhibited 1Hnmr, x5.08 (d of t , IH, o l e f i n i c , J = l l Hz, J'=2 Hz), 8.98 (d, 3H, -CH(CH3), J=6 Hz). C. Synthesis of 2-Cyclopropylmethylene-3-methylcyclohexanone 1_55_. 1. Synthesis of 2-(1-Cyclopropyl-l-hydroxymethy1)-3-methylcyclohexanone  202.. - A 100 ml three-neck f l a s k equipped with an overhead mechanical s t i r r e r and an argon i n l e t tube, and containing 437 mg (18 mmol) of magnesium turnings, was flame-dried under a steady flow of argon. The fl a s k was cooled to 0°C and dry ether (25 ml) was added. To the r e s u l t i n g s t i r r e d suspension of magnesium i n ether was added, dropwise, 2.56 g (18 mmol) of methyl iodide. The r e s u l t i n g mixture was s t i r r e d at 0°C for 10 min. Cuprous iodide (60 mg, 0.3 mmol) was added to t h i s s o l u t i o n of methyl magnesium iodide and s t i r r i n g was continued for 5 min at 0°C. After addition of 2-cyclohexen-l-one (1.44 g, 15 mmol), the reaction mixture was s t i r r e d at 0°C for 30 min and was then cooled to -78°C. Cyclopropane-carboxaldehyde (1.05 g, 15 mmol) was added dropwise with vigorous s t i r r i n g . A gummy pre c i p i t a t e formed immediately. The re s u l t i n g mixture was warmed to 0°C, s t i r r e d for 30 min, warmed to room temperature and f i n a l l y s t i r r e d for an addit i o n a l 30 min. Saturated aqueous ammonium chloride (30 ml) was added and the re s u l t i n g mixture was s t i r r e d for 5 min. The aqueous layer -167-was separated and thoroughly extracted with four 30 ml portions of ether. The combined ether extracts were washed twice with brine and dried over anhydrous magnesium s u l f a t e . Removal of solvent, gave 2.65 g (97%) of the B-hydroxyketone 203. This material exhibited i r (film)v 3470, 3110, 1700 cm"1. A t i c analysis (elution with 1:1 max ether-hexane of t h i s material showed the presence of two spots (Rf = 0.3, 0.35) of approximately equal i n t e n s i t y . This material underwent p a r t i a l dehydration and r e t r o a l d o l reaction upon d i s t i l l a t i o n as shown by t i c analysis (5 spots) and by the i r spectrum of the d i s t i l l e d product, which showed absorptions due to the presence of both saturated and a,B-unsaturated carbonyl groups, as w e l l as absorption due to a hydroxy group ( i r ( f i l m ) v 3480, 1700, 1680, 1602 cm" 1). Because of the fact that ° max the ke t o l 203 was quite unstable, i t was not p u r i f i e d further but was used d i r e c t l y i n the next step. 2. Dehydration of 2-(l-Cyclopropyl-l-hydroxymethyl)-3-methylcyclohexanone 203.. -a. By Refluxing i n Benzene i n the Presence of a C a t a l y t i c Amount of _p_- Toluenesulfonic Acid. - The crude B-hydroxyketone 203 (2.65 g, 14.6 mmol), obtained as described above, was dissolved i n benzene (60 ml) containing a c a t a l y t i c amount of oj-toluenesulf onic acid (33 mg) , and the r e s u l t i n g solution was refluxed. A Dean Stark apparatus was used to trap the water. The progress of the dehydration reaction was followed by t i c analysis of aliquots taken from the reaction mixture. I t was found that, one of the two compounds (Rf=0.35) present i n the s t a r t i n g B-hydroxyketone mixture dehydrated completely within 3h to give two new compounds, while the other (Rf=0.3) dehydrated much more slowly and was completely transformed to the -168-products only after 18h. The benzene solution was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. Removal of solvent, and f r a c t i o n a l d i s t i l l a t i o n of the residual o i l , gave two fractions. The f i r s t f r a c tion (air-bath temperature up to ^50°C, 0.3 Torr) was a l i g h t colorless o i l (426 mg) and was shown ( i r , glc retention time on column A, 120°C) to be 3-methylcyclohexanone (25% y i e l d ) . A glc analysis (column A, 120°C) of the second fr a c t i o n (air-bath temperature ^80°C, 0.4 Torr; 1.40 g, 57% yield) showed the presence of two components i n a r a t i o of 1:6. An a n a l y t i c a l sample of each was obtained by preparative glc (column C, 150°C). The major component was shown to be 8-cyclopropyl enone 155 and the minor component was shown to be the enone 156, the geometric isomer of the enone 155 (see page 163). b. Via Base-Promoted Elimination of Acetic Acid from the Corresponding Acetate. (211). - To a solution of the g-hydroxyketone 203 (1.1 g, 6 mmol) in pyridine (20 ml) was added 6 ml of acetic anhydride. The resu l t i n g mixture was s t i r r e d at room temperature for 17h under an atmosphere of argon. Ether (200 ml) and water (30 ml) were added. The resu l t i n g mixture was s t i r r e d for 5 min. The ethereal layer was separated and washed successively with three 20 ml portions of IN hydrochloric acid, 20 ml of brine, two 30 ml portions of saturated sodium bicarbonate and f i n a l l y 20 ml of brine. After drying over anhydrous sodium su l f a t e , the solvent was removed and the crude acetate 211 was dried under reduced pressure (vacuum pump) for 2h. The yi e l d of the crude acetate 211 was 1.3 g (98%). This material exhibited i r ( f i l m ) v 1730 cm 1. The ^Hnrnr indicated the presence of at least two max isomers (acetate methyl groups at x7.96 and 7.98) although t i c analysis (elution with 1:1 ether-hexane) showed only one spot. -169-To a solution of the crude acetate 211 (1.12 g, 5.0 mmol) i n benzene (80 ml) was added 930 mg (0.75 mmol) of l,5-diazabicyclo[4.3.0] non-5-ene (DBN). The re s u l t i n g mixture was refluxed for 17h. Ether (250 ml) was added and the r e s u l t i n g solution was washed with ice-cold d i l u t e hydrochloric acid (IN, 30 ml) and then dried over anhydrous magnesium s u l f a t e . Removal of solvent, followed by d i s t i l l a t i o n of the residual o i l , afforded 640 mg (78%) of a colorless o i l . A glc analysis (column A, 120°C) of t h i s material showed that i t was composed of enones 155 and 156 i n a r a t i o of 13:1, respectively, together with small amounts (<6%) of minor impurities. IV. Preparation of Tr i m e t h y l s i l y l Enol Ethers of g-Cyclopropyl-a,g- Unsaturated Ketones. General P r o c e d u r e . 1 ^ 3 - An ethereal solution containing 4.0 mmol of methyllithium was concentrated under reduced pressure and the residual organolithium reagent was dissolved i n 4 ml of dry 1,2-dimethoxyethane. The r e s u l t i n g solution was cooled to 0°C and was treated with 404 mg (4 mmol) of diisopropylamine. To the resultant, s t i r r e d solution of lit h i u m diisopropylamide was added, dropwise, 3 mmol of the appropriate g-cyclopropyl-a,g-unsaturated ketone. Meanwhile a quenching s o l u t i o n , prepared from 2 ml of 1,2-dimethoxyethane, 0.2 ml (^ 2 mmol) of triethylamine and 0.6 ml (5.1 mmol) of chlorotrimethylsilane (freshly d i s t i l l e d from N,N-dimethylaniline) was centrifuged to remove any of the insoluble t r i e t h y l -amine hydrochloride. By use of a syringe, t h i s chlorotrimethylsilane solution was added rapidly with s t i r r i n g to the cold (0°C) solut i o n of the l i t h i u m enolate. After addition was complete, a white s o l i d began to separate. The re s u l t i n g mixture was s t i r r e d at 0°C for 15 min. Saturated -170-aqueous sodium bicarbonate (10 ml) and pentane (30 ml) were added. The aqueous solution was separated and extracted further with three 30 ml portions of pentane. The combined pentane extracts were dried over anhydrous magnesium sulfate. Removal of the pentane, followed by d i s t i l l a t i o n of the residual o i l gave the corresponding t r i m e t h y l s i l y l enol ether. Preparacion of the TrimethylsilylEnol Ether of 3-Cyclopropyl-2-Cyclohexen-1-one. - Following the general procedure outlined above, 3-cyclopropyl-2-cyclohexen-l-one 142 (408 mg, 3 mmol) was f i r s t treated with lithium diisopropylamide (4 mmol) and the resultant enolate anion was quenched with chlorotrimethylsilane (5 mmol). Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^80°C, 0.1 Torr) of the crude product, afforded 550 mg of the corresponding t r i m e t h y l s i l y l enol ether 171. A glc analysis (column A, 120°C) of this material showed that i t was 91% pure, indicating that the y i e l d of compound 171 was approximately 80%. This material exhibited , 0SiMe 3 i r ( f i l m ) v 1650, 1610 cm ; Hnmr, T4.54 (broad s, IH, -C=CE-C=C- ), max — 5.26 (m, IH, CH2-CH=C-0Si(CH3)3)9.86 (broad s, 9H, Si-(CH_ 3) 3. Due to the i n t r i n s i c i n s t a b i l i t y of this material, i t was pyrolysed without further p u r i f i c a t i o n or characterization. Preparation of the Trimethylsilyl Enol Ether of 2-Methyl-3-cyclopropyl-2- cyclohexen-l-one. - Following the general procedure outlined above, 2-methyl-3-cyclopropyl-2-cyclohexen-l-one 146 (450 mg, 3 mmol) was f i r s t treated with lithium diisopropylamide (4 mmol) and the resultant enolate anion was quenched with chlorotrimethylsilane (5 mmol). Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^60°C, 0.05 Torr) of the crude product, afforded 612 mg (88%) of the corresponding t r i m e t h y l s i l y l enol -171-ether 167 as a colorless o i l . A glc analysis (column A, 150°C) of t h i s material showed that i t was ^96% pure. This material exhibited i r ( f i l m ) v 1650, 1600 cm"1; 1Hnmr, T5.20 ( t , IH, -C=CH, J=5 Hz), 8.20 (broad max — s, 3H, -C=C-CH3), 9.91 (broad s, 9H, S i ( C H 3 ) 3 ) . Due to the i n t r i n s i c i n s t a b i l i t y of t h i s material, i t waspyrolysed without further p u r i f i c a t i o n or characterization. Preparation of the T r i m e t h y l s i l y l Enol Ether of 2-Cyclopropylmethylenecyclo- hexanone. - Following the general procedure outlined above, 2-cyclopropyl-methylene-cyclohexanone 150 (450 mg, 3 mmol) was f i r s t treated with l i t h i u m diisopropylamide (4 mmol) and the resultant enolate anion was quenched with chlorotrimethylsilane (5 mmol). Normal work-up, followed by d i s t i l l -ation (air-bath temperature ^125°C, 16 Torr) of the crude o i l , afforded 666 mg of the corresponding t r i m e t h y l s i l y l enol ether 184. A glc analysis (column B, 120°C) of t h i s material showed that i t was 91% pure, ind i c a t i n g that the y i e l d of the enol ether 184 was about 91%. This material exhibited ir(film)\> 1680 (w) , 1660 cm"1 (w); 1Hnmr, T4.92 (d, IH, -OCH^-C-HJ , max J _> J=9.5 Hz), 5.04 ( t , IH, CH2-CH=C-OSiMe3, J=4.5 Hz), 7.40-7.64 (m, IH, ), 7.72-7.96 (m, 2H, -C=CH-CH2- ), 8.20-8.64 (m, 4H), 8.95-9.44 (m, 2H), 9.52-9.74 (m, 2H) , 9.87 (broad s, 9H, S i ( C H 3 ) 3 ) . Mol.Wt. Calcd. for C^H^OSi: 222.1439 . Found (high resolution mass spectrometry: 222.1438 . Preparation of the Trimethylsily Enol Ether of 2-Cyclopropylmethylene-3- methyl-cyclohexanone. - Following the general procedure outlined above, a 1:6 isomeric mixture of the B-cyclopropyl enones 156 and 155, respectively, (492 mg, 3 mmol) was f i r s t treated with l i t h i u m diisopropylamide (4 mmol) and the resultant enolate anions were quenched with chlorotrimethylsilane (5 mmol). Normal work-up, followed by d i s t i l l a t i o n of the crude o i l , -172-afforded 710 mg of the corresponding t r i m e t h y l s i l y l enol ethers. A glc analysis (column B, 120°C) of t h i s material showed that i t was 94% pure. On this basis, the y i e l d of the enol ether 200 was about 95%. This material exhibited i r ( f i l m ) v 1650 (w), 1625 (w) cm-1; "Slnmr, max T4.98 (d, IH, -C=CH(c-C3H5), J=10 Hz), 5.11 ( t , IH, CH2-CH=C-0Si(CH3) , J=3 Hz), 8.97 (d, 3H, -CH(CH_3), J=7 Hz), 6.76-7.12 (m, IH). Due to the i n s t a b i l i t y of this material, i t was pyrolysed without further p u r i f i c a t i o n or characterization. Preparation of the T r i m e t h y l s i l y l Enol Ether of 2-Cyclopropylmethylenecyclo- pentanone. - Following the general procedure outlined above, 2-cyclopropyl-methylenecyclopentanone 149 (408 mg, 3 mmol) was treated with lithium d i i s o -propylamide (4 mmol) and the resultant enolate anion was quenched with chlorotrimethylsilane (5 mmol). Normal work-up, followed by d i s t i l l a t i o n of the residual o i l , afforded 562 mg (90%) of the corresponding t r i m e t h y l s i l y l enol ether 191. A glc analysis (column B, 120°C) showed that this material was pure. It exhibited i r ( f i l m ) v 1615 cm _ 1(s). 1Hnmr x4.90-5.32 (m, 2H, max o l e f i n i c ) , 9.86 (broad s, 9H, S i ( C H 3 ) 3 ) . Due to the i n s t a b i l i t y of t h i s material, i t was pyrolysed without further p u r i f i c a t i o n or characterization. V. Thermal Rearrangement Reactions of B-Cyclopropyl-a,B-Unsaturated  Ketones and their T r i m e t h y l s i l y l Enol Ether Derivatives General Procedure A. - A pyrex tube 1.2(i.d.)x32 cm, f i l l e d with glass helices ( i . d . 4.76 mm) was washed successively with water, acetone and n-hexane. The column was conditioned by placing i t i n a furnace and heating i t at ^ 450°C for 3h. During t h i s period of time, the column was thoroughly purged with a stream of nitrogen. A n-hexane solution of the appropriate 8-cyclopropyl-a,B-unsaturated ketone (or the corresponding t r i m e t h y l s i l y l enol ether) (200 mg in 20 ml of n-hexane) to be pyrolysed was added dropwise over a -173-period of 1.5h to the top of the v e r t i c a l l y held heated column (^450°C). During t h i s period of time, the stream of nitrogen was discontinued. The effluent from the bottom of the column was cooled by having i t pass through a water condenser connected to the bottom of the pyrolysis tube, and was collected i n a two-necked f l a s k , equipped with a drying tube and immersed i n a cold (-78°C) bath (see diagram 1). After addition of the solution was complete, the hot column was washed with a further 30 ml of n-hexane. Removal of the hexane, followed by d i s t i l l a t i o n of the residual o i l , gave the rearranged products. General Procedure B. - A pyrex tube (1.2 x 100 cm) f i l l e d with glass helices ( i . d . 4.76 mm) was washed successively with saturated aqueous sodium bicarbonate so l u t i o n , water, acetone and n-hexane. By means of a heating tape which had been wrapped around i t , the column was heated to the desired thermolysis temperature and was kept at t h i s temperature for at least 3h. During t h i s time, the column was thoroughly purged with a rapid flow of argon. A n-hexane solution of the g-cyclopropyl enone (or the corresponding t r i m e t h y l s i l y l enol ether)(200 mg i n 20 ml n-hexane) to be pyrolysed was added dropwise, over a period of 1.5h, to the top of the v e r t i c a l l y held column. During t h i s period of time, a very slow flow of argon (^ 5 ml/min) was passed through the column. The effluent from the bottom of the column was cooled by allowing i t to pass through a water condenser attached to the bottom of the pyrolysis tube, and was collected i n a two-neck f l a s k which was equipped with a drying tube and was immersed i n a cold (-78°C) bath (see diagram 2). After addition of the solution was complete, the hot column was washed with a further 30 ml of n-hexane. Removal of hexane, followed by d i s t i l l a t i o n of the residual o i l gave the -174-rearranged products. General Procedure C. - Procedure C was e s s e n t i a l l y the same as procedure B except that the crude mixture of pyrolysis products was not d i s t i l l e d but was subjected d i r e c t l y to hydrolysis. Thus, after the hexane had been removed from the pyrolysate, the residual o i l was taken up i n a 1:1 mixture (5 ml) of methanol and d i l u t e hydrochloric acid (IN) and the r e s u l t i n g solution was s t i r r e d for 30 min at room temperature. The solution was thoroughly extracted with pentane and the combined pentane extracts were dried over anhydrous magnesium sulfate. Removal of solvent and d i s t i l l a t i o n of the r e s i d u a l o i l gave the f i n a l product(s). Pyrolysis of 3-Cyclopropyl-2-cyclohexen-l-one 142.. A. At ^450°C, Procedure A. - Following the general procedure A outlined above, a solution of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n i i -hexane (20 ml) was pyrolysed at ^A50°C. Normal work-up, followed by d i s t i l l a t i o n ( a i r bath temperature ^110°C, 16 Torr) of the crude o i l , afforded 156 mg (78%) of a colorless o i l . A glc analysis (column B, 130°C) of t h i s material indicated that i t was a mixture of the ketone 161 (^3%), the enone 162 (^84%) and the dienone 163 Ov-11%), along with a number of minor unidentified impurities (^2%). An a n a l y t i c a l sample of each of the three major components was obtained by preparative glc (column D, 130°C). The pure enone 162 exhibited i r ( f i l m ) v 1660, 1630 cm"1; 1Hnmr, r7.2-8.3(m). max The 2,4-dinitrophenylhydrazone derivative exhibited mp 252°C (dec)(lit.mp 251.5°C). 1 1 4 Anal. (2,4-DNP derivative) Calcd. for C ^ ^ O ^ C, 56.96; H, 5.10; N, 17.71. Found: C, 57.09; H, 5.07; N, 17.58. -175-The pure ketone 161 exhibited i r ( f i l m ) y 1718, 1665 cm -1 1. Hnmr, max T4.57 (broad s, IH, -C=C-H), 6.63(m, IH, -CO-CH-). This material was passed through a short column of basic alumina and the column was eluted with ether. Evaporation of the ether from the eluant, followed by analysis of the residual o i l by i r , "''Hnmr and glc showed that the ketone 161 had B. At 322°C, Procedure B. - Following the general procedure B outlined above, a solution of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n n-hexane (20 ml) was pyrolysed at 322°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^110°C, 16 Torr) of the crude o i l afforded 200 mg (100%) of a colorless o i l . The infrared spectrum and a glc analysis (column B, 130°C) of t h i s material showed that i t was pure st a r t i n g material, the cyclopropyl enone 142. C At 400°C, Procedure B. - Following the general procedure B outlined above, a solution of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n n-hexane (20 ml) was pyrolysed at 400°C. Normal work-up, followed by d i s t i l l a t i o n of the crude o i l , afforded 200 mg (100%) of a colorless o i l . A glc analysis (column B, 130°C) of th i s material showed that i t was composed of the ketone 161 (^37%), the enone 162 (^15%) and the s t a r t i n g cyclopropyl enone 142 (^37%), along with a number of minor unidentified impurities (^11%). An a n a l y t i c a l sample of each of the three major components isomerized completely to the a,B-unsaturated enone 162. The pure dienone 163 exhibited i r ( f i l m ) v 1670, 1642, 1590 cm ; max -176-was obtained by preparative glc (column D, 130°C). In each case, the id e n t i t y of the compound was confirmed by spectral data ( i r , ^ Hnmr). D. At 425°C, Procedure B. - Following the general procedure B outlined above, a solution of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n n-hexane (20 ml) was pyrolysed at 425°C. Normal work-up, followed by d i s t i l l a t i o n of the crude o i l , afforded 196 mg (98%) of a colorless o i l . A glc analysis (column B, 120°C) of t h i s material showed that i t was a mixture of the ketone 161 (^31%) and the enone 162 (^67%), along with very small amounts of unidentified impurities (^2%). This material was passed through a short column of basic alumina. The column was eluted with ether. Removal of the ether and analysis of the residual o i l by glc (column B, 130°C) and i r showed that the ketone 161 had isomerized completely to the enone 162. E. At 450°C, Procedure B. - Following the general procedure B, a solution of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n n-hexane (20 ml) was pyrolysed at 450°C. Normal work-up, followed by d i s t i l l a t i o n of the crude o i l , afforded 142 mg (71%) of a colorless o i l . A glc analysis (column B, 130°C) of t h i s material showed that i t was composed of the ketone 161 (^5%) and the enone 162 (^91%), along with very small amounts of unidentified impurities (^4%). The i d e n t i t i e s of the major products 161 and 162 were confirmed by a coinjection experiment involving g l c . Pyrolysis of the Tri m e t h y l s i l y l E n o l Ether of 3-Cyclopropyl-2-cyclohexen- 1-one 221« - Following the general procedure C outlined above, a solution of the enol ether 171 (200 mg, 91% pure) i n ji-hexane (20 ml) was pyrolysed -177-at 425°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^110°C, 16 Torr) of the crude hydrolysed product, afforded 88 mg of a colorless o i l . A glc analysis of t h i s material (column A, 110°C) showed the presence of only one major product (76%) together with a number of minor impurities (24%). An a n a l y t i c a l sample of the major product was obtained by preparative glc (column C, 110°C) and was shown ( i r , ''"Hnmr) to be the enone 162. The number of minor components present i n the product mixture were not i d e n t i f i e d . Pyrolysis of the T r i m e t h y l s i l y l Enol Ether of 2-Methyl-3-cyclopropyl-2- cyclohexen-l-one 167. - Following the general procedure C outlined above, a solution of the enol ether 167 (200 mg, 96% pure) i n n-hexane (20 ml) was pyrolysed at 425°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 80-115°C, 16 Torr) of the hydrolysed product afforded 67 mg of a colorless o i l . A glc analysis (column B, 110°C) of t h i s material showed the presence of one major component (75%) and a number of minor impurities which were not i d e n t i f i e d . An a n a l y t i c a l sample of the major component was obtained by preparative glc (column D, 115°C) and was shown to be o_-cyclopropyltoluene. This material exhibited "''Hnmr T3.01 (broad s, 4H, aromatic), 7.60 (s, 3H, -CH 3), 7.93-8.40 (m, IH, £><- ), 8.95-9.50 (m, 4H, cyclopropyl). Pyrolysis of 3-Cyclopropyl-2-cyclopenten-l-one. JL4J. - Following the general procedure A outlined above, a solution of 3-cyclopropyl-2-cyclopenten-l-one 147 (200 mg) i n n-hexane (20 ml) was pyrolysed at ^450°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature 100-120°C, 16 Torr) of the crude o i l afforded 160 mg (80%) of a colorless o i l . A glc analysis (column -178-A, 100°C) of t h i s material showed the presence of four major components together with small amounts of minor impurities (^2%) which were not i d e n t i f i e d . The major components were shown to be the ketone 157 Cv46%), the enone 158 (^14%), the dienone 159 (>20%) and the dienone 160 (>18%). An a n a l y t i c a l sample of each major component was obtained by preparative glc (column B, 120°C). The pure enone 158 exhibited uv v 237 nm (E=11370); i r ( f i l m ) v 1690, 1630 cm"1; 1Hnmr, x7.10-7.80 max max (m). Mol.Wt. Calcd. for CgH^g 0: 122.0731. Found (high resolution mass spectrometry): 122.0734. The ketone 157 exhibited i r ( f i l m ) v 1740, 1660 cm 1; "'"Hnmr, x4.40-max 4.58 (m, IH, o l e f i n i c H), 6.57-6.88 (m, IH, -C0CH-), 7.16-8.43 (m, 8H). The ketone 157 was isomerized to the enone 158 by passing the former through a short column of basic alumina. The dienone 160 exhibited uv X 268 nm (£=18630); i r ( f i l m ) v 1640, max max 1570 cm"1; """Hnrnr, x3.44 (d, IH, -C=C-CH=C- , J=16 Hz), 3.70 (d of q, 1H,-C=C(H)CH3 J=16 Hz, J'=6 Hz), x4.09 (broad s, IH, C0CH=C), 7.12-7.90 (m, 4H), 8.10 (d, 3H,-C=C-CH_, J=6 Hz). Mol.Wt. Calcd. for CoHir,0: 122.0731. — j o 1U Found (high resolution mass spectrometry): 122.0732. The dienone 159 exhibited uv v 226 nm (E=14090); i r ( f i l m ) v 1705, max max 1610 cm"1; """Hnmr, x3.92-4.40 (m, 2H, o l e f i n i c H), 4.70-5.10 (m, 2H, o l e f i n i c H), 6.88 (d, 2H =C-CH_2-C=, J=6.5 Hz), 7.20-7.95 (m, 4H). The dienone 159 was subjected to isomerization by passing i t through a short column of basic alumina. The spectral data obtained from the isomerized product were i d e n t i c a l with those of the dienone 160. Pyrolysis of the g-Cyclopropyl Enone 1J2.. - Following the general procedure 103 A outlined above, a solution of the 8-cyclopropyl enone 172 (200 mg) i n -179-n-hexane (20 ml) was pyrolysed at ^450°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^75°C, 25 Torr) of the crude o i l , afforded 60 mg (^30%) of a colorless o i l . A glc analysis (column B, 80°C) of t h i s material showed that i t was composed of the ketone 173 (^90%), m-xylene 174 (^8%) and small amounts of unidentified minor impurities. The i d e n t i t y of m-xylene 174 was confirmed by a coninjection experiment with an authentic sample involving glc and by ^Hnmr of the mixture. An a n a l y t i c a l sample of the ketone 173, obtained by preparative glc (column D,90°C), exhibited i r ( f i l m ) v 3070, 1705, 1655 cm"1; 1Hnmr, max T4.41 (m, IH, o l e f i n i c H), 6.60 (m, IH, CH3C0CH-), 7.91 (s, 3H, -C0CH_3) , i i 8.30 (broad s, 3H, -C=C-CH_3). These data were i d e n t i c a l with those of the same material reported i n l i t e r a t u r e . Pyrolysis of the T r i m e t h y l s i l y l Enol Ether of 2-Cyclopropylmethylenecyclo- pentanone 191. - Following the general procedure C outlined above, a solution of the t r i m e t h y l s i l y l enol ether 191 (200 mg) i n n-hexane (20 ml) was pyrolysed at 425°C. Normal work-up, followed by d i s t i l l a t i o n of the crude hydrolysed product, afforded two f r a c t i o n s . Fraction one (air-bath temperature up to ^90°C, 16 Torr) weighed 87 mg (56%). A glc analysis of t h i s material showed the presence of only one major compound (94%), along with a number of unidentified minor impurities (^6%). The second f r a c t i o n (air-bath temperature up to ^110°C, 16 Torr) weighed 49 mg (18%). A glc analysis of t h i s material showed the presence of the same compound as i n f r a c t i o n one, along with a large amount of higher b o i l i n g impurities. Both fra c t i o n s showed the presence of saturated and a,8-unsaturated carbonyl compounds i n the i r spectra. The two fractions were combined and subjected to column chromatography on s i l i c a gel (10 g). The column was eluted with 10% ether -180-i n hexane. The major component was isolated (52 mg, 38%) and was shown to be the spiroketone 187. The l a t t e r exhibited i r ( f i l m ) v 3050, 1742 max cm "4lnmr, T4.10 (m, IH, o l e f i n i c H), 4.55 (m, IH, o l e f i n i c H), 7.30-8.70 (m, 10H). Mol.Wt. Calcd. for CgH^O: 136.0887. Found (high resolution mass spectrometry): 136.0925. Pyrolysis of 2-Cyclopropylmethylenecyclohexanone 150. - Following the general procedure A outlined above, a solution of 2-cyclopropylmethylene-cyclohexanone 150 (200 mg) i n n-hexane (20 ml) was pyrolysed at ^450°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^110°C, 16 Torr) of the crude o i l afforded 148 mg (^74%) of a colorless o i l . A glc analysis (column A, 100°C) of this material showed the presence of three major components along with small amounts 0^9%) of minor impurities which were not i d e n t i f i e d . A n a l y t i c a l samples of each of the three major components were obtained by preparative glc (column C, 100°C). These compounds were shown to be t e t r a l i n 177 (^38%), the dienone 176 (^9%) and the spiroketone 175 (^44%). An a n a l y t i c a l sample of t e t r a l i n 177 exhibited ''"Hnmr t2.98 (S, 4H, aromatic), 7.20-7.50 (m, 4H), 8.10-8.40 (m, 4H). The i r and 1Hnmr spectra of 177 were i d e n t i c a l with those of commercially available t e t r a l i n . The dienone 176 exhibited uv X 209 nm (e=10800), X 263 nm (e=3450); max max i r ( f i l m ) v 3040, 1678, 1610 cm \ The "''Hnmr showed the presence of two max r terminal methyl groups at T8.99 (t,-CH2CH_3, J=7 Hz), and 9.02 ( t , -CH2CH3, 3-1 Hz) of approximately equal in t e n s i t y , indicating the presence of a mixture of c i s and trans isomers. This material was subjected to hydro-genation (10% paladium on carbon as catalyst, methanol as solvent) and the hydrogenated product was i d e n t i f i e d ( i r , ^Hnmr) as 2-n-butylcyclohexanone. -181-An a n a l y t i c a l sample of the spiroketone 175 exhibited i r ( f i l m ) v J r r max 3080, 1710 cm"1; 1Hnmr T4.24 (narrow m, w, =2 Hz, 2H, o l e f i n i c H), 7.40-7.82 (m, 5H), 7.97-8.60 (m, 7H); 1Hnmr (after addition of 20 mg of the s h i f t reagent Eu(F0D) 3d 2 7) T3.58 (d of t , IH, o l e f i n i c H, J=6 Hz, J'= 2 Hz), 3.94 (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 6.44-6.84 (m, 3H), 7.14-7.50 (m, 2H), 7.62-8.12 (m, 7H). In a decoupling experiment, i r r a d i a t i o n at x7.29 caused the two doublet of t r i p l e t s at x3.58 and 3.94 13 to collapse to an AB pair of doublets with J=5.6 Hz; Cnmr (protons decoupled) 6(ppm) 22.96, 27.67, 31.28, 32.29, 39.89 (2 carbons), 64.06 (quaternary carbon), 132.46 ( o l e f i n i c carbon), 133.35 ( o l e f i n i c carbon), 211.48 (carbonyl carbon). Mol.Wt. Calcd for C^gH^O: 150.1044. Found (high resolution mass spectro-metry): 150.1027. The spiroketone 175 was hydrogenated (10% Pd/C i n methanol) to the corresponding saturated spiroketone 179, which exhibited i r (film)v 1700 cm ^; ° max 1Hnmr, x7.50-7.76 (m, 2H), 7.76-8.78 (m, 14H). These spectral data were i d e n t i c a l with those of an authetic sample of 179 prepared from the pinacol rearrangement of the d i o l 180. 1 1 7 The d i o l 180 was prepared from the reductive dimerization of cyclopentanone by aluminum and mercuric chloride. Pyrolysis of the Trimethylsily Enol Ether of 2-Cyclopropylmethylenecyclo- hexanone 184. A. At ^450°C, Procedure A. - Following the general procedure A outlined above, a solution of the t r i m e t h y l s i l y l enol ether 184 (200 mg, 91% pure) i n ii-hexane (20 ml) was pyrolysed at ^ Ab^Z. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^105°C, 56 Torr) of the crude o i l , afforded 148 mg of a colorless o i l . A glc analysis of th i s material -182-(column B, 120°C) showed the presence of two major components and a number of minor impurities (^12%) which were not i d e n t i f i e d . The two major components were isolat e d by preparative glc (column D, 125°C) and were shown to be the spiro enol ether 185 (^74%) and trans-l-phenyl-1-butene 186 (M.4%). An a n a l y t i c a l sample of the spiro enol ether 185 exhibited i r ( f i l m ) v max 3060, 1655 cm - 1; 1Hnmr, x4.24-4.37 (m, IH, o l e f i n i c H), 4.45-4.60 (m, IH, o l e f i n i c H), 5.28 ( t , IH, -CH=C-0SiMe3, J=4 Hz), 7.58-7.90 (m, 2H), 7.90-8.17 (m, 2H), 8.34-8.62 (m, 6H), 9.93 (s, 9H, - S i ( C H 3 ) 3 ) . Mol.Wt. Calcd. for C^ 3H220Si: 222.1440. Found (high resolution mass spectrometry): 222.1443. The spiro enol ether 185 was subjected to hydrolysis by s t i r r i n g i t i n 1:1 methanol - d i l u t e hydrochloric acid (IN) for 15 min. After work-up, the pure spiroketone 175 was obtained, the spectral properties ( i r , ^Hnmr) of which were i d e n t i c a l with those of the same material prepared as described previously. An a n a l y t i c a l sample of trans-l-phenyl-l-butene 186 exhibited i r ( f i l m ) v 3050, 1595, 955, 730, 680 cm"1, 1Hnmr, x2.60-3.00 (m, 5H, aromatic H), max 3.55-4.00 (m, 2H, o l e f i n i c H), 7.64-8.00 (m, 2H), 8.95 ( t , 3H, -CH3, J=7 Hz). The spectral data l i s t e d above were e s s e n t i a l l y the same as those reported 118 i n the l i t e r a t u r e . B. • At rv-450°C Procedure C (Preparative Scale) - Following the general procedure C outlined above, a solution of the t r i m e t h y l s i l y l enol ether 184 (1.0 g, ^90% pure) i n n-hexane (100 ml) was pyrolysed at ^ 450°C. After work-up, the crude hydrolysed product was subjected to column chromatography on s i l i c a gel (50 g, 70-270 mesh). The column was eluted -183-with pentane and 303 mg (^50%) of pure d i s t i l l e d spiro ketone 175 was iso l a t e d . I t s i d e n t i t y was confirmed by i r and '''Hnmr data. C. At 425°C, Procedure B. - Following the general procedure B outlined above, a solution of the t r i m e t h y l s i l y l enol ether 184 (200 mg, ^90% pure) i n n-hexane (20 ml) was pyrolysed at ^ 425°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^105°C, 56 Torr) of the crude o i l afforded 170 mg (^85%) of a colorless o i l . A glc analysis (column B, 120°C) of t h i s material showed that i t was composed of the spiro s i l y l enol ether 185 (^84%) and a number of unidentified minor impurities (^16%). The i d e n t i t y of enol ether 185 was confirmed by the i r and "'"Hnmr spectra of t h i s material. Pyrolysis of the Trim e t h y s i l y l Enol Ether of 2-Cyclopropylmethylene-3- methylcyclohexanone 200. A. At ^ 380°C, Small Scale. - Following the general procedure C outlined above, a solution of the t r i m e t h y l s i l y enol ether 200 (200 mg, ^90% pure) i n n-hexane (20 ml) was pyrolysed at V380°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^70°C, 0.4 Torr) of the hydrolysed crude product afforded 119 mg of a col o r l e s s o i l . A glc analysis of t h i s material showed that i t was composed of the spi r o -ketone 212 (^60%), the spiroketone 213 (^25%) and a number of unid e n t i f i e d minor impurities (^15%). An a n a l y t i c a l sample of each of the major products was obtained by preparative glc (column C, 110°C). The spiroketone 212 exhibited mp 35-38°C; uv X max 295 nm (e=237); i r (CHC1J v 3080, 1705 3 max -1 1. Hnmr, x4.02-4.38 (m, 2H, o l e f i n i c H), 7.16-8.60 (m, 11H), 9.10 cm (d, 3H, -CH3, J=6 Hz). Mol.Wt. Calcd. for C u H 1 6 0 : 164.1201. Found: (high resolution mass spectrometry): 164.1212. -184-An a n a l y t i c a l sample of the spiroketone 213 exhibited uv A 287 max (e=400); i r ( f i l m ) v 3090, 1705 cm"1; ""-Hnmr T4.02-4.40 (m, 2H, o l e f i n i c IUcLX H), 7.42-7.80 (m, 4H) , 7.80-8.60 (m, 7H), 9.14 (d, 3H, -CH_3, J=6 Hz). Mol.Wt. Calcd. for C T J ^ O 0 2 164.1201. Found (high resolution mass spectrometry): 164.1195. B. At ^ 380°C, Preparative Scale. Following the general procedure C outlined above, a solution of the t r i m e t h y l s i l y l enol ether 200 (8.44 g, 0.036 mol, ^ 90% pure) i n n-hexane (200 ml) was pyrolysed at ^ 380°C. After work-up, the crude hydrolysed product was subjected to column chromatography on s i l i c a gel (350 g) and the column was eluted with 10% ether i n hexane. A t o t a l of 3.35 g (0.021 mol, 57%) of the spiro-ketones 212 and 213 were isolat e d after d i s t i l l a t i o n (air-bath temperature ^50°C, 0.2 Torr). P a r t i a l separation of the two isomeric spiroketones 212 and 213 was obtained. Of the t o t a l 3.35 g isolat e d products, 2.03 g was pure spiroketone 212, 0.85 g was pure ketone 213 and the rest (0.47 g) was a mixture of 212 and 213 VI. Synthesis of the Spiroketone 193. - A Key Synthetic Intermediate for  the Synthesis of a Variety of Spirovetivane-type Sesquiterpenoids. Reaction of the Spiroketone 211 with Methyllithium. - To a cold (0°C) solution of the spiroketone 212 (492 mg, 3 mmol) i n dry ether (25 ml) was added dropwise a solution of methyllithium (4.5 mmol) i n ether. The r e s u l t i n g mixture was s t i r r e d at 0°C for l h , warmed to room temperature and s t i r r e d for an additional l h . Saturated brine (20 ml) was added. The ether solution was separated from the aqueous layer and the l a t t e r was extracted with three 30 ml portions of ether. The combined ether extracts were dried -185-over anhydrous magnesium sulfate. Removal of the ether, followed by d i s t i l l a t i o n (air-bath temperature rv75°C, 0.4 Torr) of the residual o i l afforded 513 mg (95%) of a colorless o i l . A glc analysis of t h i s material showed the presence of two components i n the r a t i o of 78:22. This material was subjected to column chromatography on s i l i c a gel (50 g). The column was eluted with 15% ether i n hexane. The major component (286.2 mg, 53%) was shown to be the spiroalcohol 214 and i t exhibited i r ( f i l m ) v 3060, 3500 cm"1; 1Hnmr T3.93 (d of t , IH, o l e f i n i c max H, J=6 Hz, J'=2 Hz), 4.28 (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 7.52-8.02 (m, 3H), 8.10-9.90 (m, 9H), 8.78 (s, 3H, -C(0H)CH 3), 9.42 (d, 3H, -CHCH3, J=6 Hz). Mol.Wt. Calcd. for C^H^O: 180.1515. Found (high resolution mass spectrometry): 180.1556. The spectral data of alcohol 214 l i s t e d above were i d e n t i c a l with those of the authentic material kindly supplied by Dr. G. Buchi of the Massachusetts I n s t i t u t e of Technology. The minor component (62.1 mg, 11.5% yie l d ) was shown to be the spiro-129 -1 1 alcohol 215 and i t exhibited i r ( f i l m ) v 3070, 3490 cm ; Hnmr x4.19 ' max (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 4.48 (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 7.54-8.66 (m, 12H), 8.96 (s, 3H, -C(0H)CH_3), 9.25 (d, 3H, -CHCH3, J=6.5 Hz). Mol.Wt. Calcd. for C 1 2H 2 Q0: 180.1515. Found (high resolution mass spectrometry): 180.1515. Another 78.3 mg (<^14.5%) of a mixture of 214 and 215 was also isolated from the column chromatography. 118 Hydroboration of the O l e f i n i c alcohol.214. with Disiamylborane. To a cold (0°C) solution of borane-tetrahydrofuran (10 mmol, 1M solution i n tetrahydro-furan) under an atmosphere of argon was added dropwise 1.4 g (20 mmol) of 2-methyl-2-butene. The solution was s t i r r e d at 0°C for 2h. To this solution of disiamylborane was added the o l e f i n i c alcohol 214 (180 mg, 1 mmol). The -186-r e s u l t i n g mixture was s t i r r e d at 0°C for l h , warmed to room temperature and s t i r r e d for 21h. I t was then cooled to 0°C. Ethanol (1 ml), aqueous sodium hydroxide (3N, 7ml) and 30% aqueous hydrogen peroxide s o l u t i o n (4 ml) were added and the r e s u l t i n g mixture was refluxed for 2h. Brine (5 ml) was added and the re s u l t i n g mixture was extracted with ether. The combined ether extracts were washed with brine and dried over anhydrous magnesium su l f a t e . Removal of the ether gave the d i o l 216 as a yellow s o l i d . The crude d i o l was r e c r y s t a l l i z e d to give 153 mg (77%) of pure white c r y s t a l s which exhibited mp 153-155°C; i r (CHCl 0)v 3480, 3640 J max - 1 1 i l cm ; Hnmr, T8.82 (S, 3H, -C(0H)CH3) 9.07 (d, 3H, -CHCH_3, J=6 Hz), 5.55-5.95 (m, IH, -CHOH). Anal. Calcd. for C 1 2H 2 20 2: C, 72.68; H, 11.18. Found: C, 72.54; H, 11.10. Oxidation of the D i o l 216. to the Keto Alcohol 2JL7_. - To a s l u r r y of pyridinium chlorochromate (324 mg, 1.5 mmol) i n methylene chloride (3 ml) was added a solution of the d i o l 216 (198 mg, 1 mmol) i n methylene chloride (10 ml). The r e s u l t i n g red solution was s t i r r e d at room temperature for l h . Ether (20 ml) was added. The mixture was f i l t e r e d through a short column of f l o r i s i l (10 g, 80-100 mesh). The column was eluted with a further 50 ml of ether. Removal of the solvent, followed by d i s t i l l a t i o n (air-bath temperature ^120°C, 0.2 Torr) of the residual o i l , afforded 176 mg (88%) of the keto alcohol 217 as a colorless o i l . A glc analysis of t h i s material (column A, 150°C) indicated the presence of only one component. This material could be r e c r y s t a l l i z e d from hexane-ether to give white c r y s t a l s , mp 51-52°C; ir(CHCl,)v 3660, 3500, 1730 cm - 1; """Hnmr, T7.36, 7.84 (AB system, 2H, -i-CH 2-C0-, J ^ - 19 Hz), 8.72 (s, 3H, -C(0H)CH 3), 9.18 (d, 3H, -CHCH3> J=6.5 HZ). -187-Anal. Calcd. for ^ ^ l o P l ' C, 73.43; H, 10.27. Found: C, 73.53; H, 10.17. Conversion of the O l e f i n i c Alcohol ? 1 S into the Keto Alcohol 219 -The o l e f i n i c alcohol 215 (72 mg) was hydroborated under conditions i d e n t i c a l with those used for the o l e f i n i c alcohol 214 as described above. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature up to 135°C, 0.4 Torr) afforded 92 mg of a colorless o i l . A glc analysis (column A, 150°C) of t h i s material showed that i t was composed of s t a r t i n g material 215 (^32%), hydroborated product (^58%), along with a number of unidentified minor impurities (10%). Fractional d i s t i l l a t i o n separated the s t a r t i n g material 214 together with some minor impurities from the hydroborated product. The l a t t e r was oxidized by treatment with pyridinium chlorochromate under conditions i d e n t i c a l with those used for the oxidation of the d i o l 216 as described above. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^120°C, 1 Torr) of the crude product, afforded 30 mg of a colorless o i l . A glc analysis of t h i s material (column A, 150°C) showed the presence of only one major component (^93%) and a number of minor impurities which were not i d e n t i f i e d . The major component, the keto alcohol 219, exhibited i r ( f i l m ) v 3500, 1730 cm"1; 1Hnmr, x8.84 max (s, 3H, -C(0H)CH 3), 9.16 (d, 3H, -CHCH_3, J=6.5 Hz). The spectral data l i s t e d above were i d e n t i c a l with those of an authentic sample of the same material provided by Dr. D. Caine of the Georgia I n s t i t u t e of 129 Technology. The o v e r a l l y i e l d of 219 from 215 was 38%. Dehydration of the Keto Alcohol 217_- - To a solution of the keto alcohol 217 (118 mg, 0.6 mmol) i n benzene (20 ml) was added 15 mg of p_-toluenesulfonic acid. The r e s u l t i n g solution was refluxed for 87h. The s o l u t i o n was cooled, -188-successively washed with 5 ml of saturated sodium bicarbonate solution and 5 ml of brine and dried over anhydrous magnesium sulfate. Removal of the solvent and d i s t i l l a t i o n (air-bath temperature 60-65°C, 0.2 Torr) of the residual o i l gave 96 mg (90%) of a colorless o i l . A glc analysis (column A, 120°C) of t h i s material showed the presence of only one peak (99%). However the "'"Hnmr of t h i s material indicated that i t was a 9:1 mixture of the isomeric keto o l e f i n s 198 and 218 respectively. An a n a l y t i c a l sample of the keto o l e f i n 198, obtained by preparative t i c (elut ion with 1:5 ether—hexane), exhibited i r ( f i l m ) \ J 2980, 1740 cm ; max 1H nmr T4.49-4.66 (m, IH, o l e f i n i c H), 7.76 (s, 3H, -C=C-CH3), 9.12 (d, 3H, -CHCH3, J=6.5 Hz). Mol.Wt. Calcd. for C^H^O: 178.1358. Found (high resolution mass spectrometry): 178.1360. The i r , "''Hnmr data of the keto o l e f i n 198 l i s t e d above were i d e n t i c a l with those of authentic samples of the same material kindly supplied by Dr. G. Buchi of the 132 Massachusetts I n s t i t u t e of Technology and by Dr. D. Caine of the 129 Georgia I n s t i t u t e of Technology. -189-BIBLIOGRAPHY 1. F. W. Comer, F. McCapra, I. H. Qureshi, and A. I. Scott. Tetrahedron, 23., 4761 (1967). 2. S. Takahashl, H. Naganawa, H. Iinuma, and T. Takita. Tetrahedron  Let t. 1955 (1971). 3. D. G. Martin, G. Slomp, S. Mizsak, D. J. Duchamp, and C. G. Childester. Tetrahedron Lett. 4901 (1970). 4. M. Kaneda, R. Takahashi, Y. I i t a k a , and S. Shibata. Tetrahedron Lett. 4609 (1972). 5. M. K a i s i n , Y. M. Sheikh, L. J. Durham, C. Djerassi, D. Tursch, D. Daloze, J . C. Braekman, D. Losman, and R. Karlsson. Tetrahedron  Lett. 2239 (1974). 6. I. C. Nigam, H. Komae, G. A. N e v i l l e , C. Radecka and S. K. Paknikar. Tetrahedron Lett. 2497 (1968). 7. M. E. Jung. Tetrahedron, 32, 3 (1976). 8. R. A. E i l i s o n . Synthesis, 397 (1973). 9. J. M. Conia and P. Le Perchec. Synthesis, 1 (1975). 10. P. T. Lansbury. Acc. Chem. Res. 5, 311 (1972). 11. J . E. McMurry, J. Melton. J . Am. Chem. Soc. 93, 5309 (1971). 12. R. E. Eaton, R. H. Mueller J r . J . Am. Chem. Soc. 94, 1014 (1972). 13. W. S. Johnson, M. B. Gravestork, R. J. Parry, R. F. Myers, T. A. Bryson, and D. H. Miles. J . Am. Chem. Soc. 93, 4330 (1971). 14. S. Danishefsky, J . Dynak, E. Hatch and M. Yamamoto. J. Am. Chem. Soc. 96, 1256 (1974). 15. R. F. Romanet and R. H. Schlessinger. J. Am. Chem. Soc. 96, 3701 (1974). 16. T. A. Spencer, A. L. H a l l , and C. F. von Reyn. J. Org. Chem. 33, 3369 (1968). -190-G. Buchi, U. Hochstrasser, and W. Pawlak. J . Org. Chem. 28, 4348 (1973). G. Buchi and B. Egger. J. Org. Chem. 36, 2021 (1971). W. F. Berkowitz and A. A. Ozorio. J . Org. Chem. 38, 3787 (1971). P. L. Fuchs. J. Am. Chem. Soc. 96, 1607 (1974). R. Noyori, K. Yokoyama, S. Makino, and Y. Hayakawa. J. Am. Chem. Soc. 94, 1772 (1972). R. Noyori, K. Yokoyama, and Y. Hayakawa. J. Am. Chem. Soc. 95, 2722 (1973) . J. P. Marino, and Wm. B. Mesbergen. J. Am. Chem. Soc. 96, 4050 (1974). T. Hiyama, M. Tsukanaka, and H. Nozaki. J. Am. Chem. Soc. 96, 3713 (1974) . H. C. Brown. Acc. Chem. Res. 2^, 65 (1969). B. M. Trost, and S. L. Melvin J r . , Tetrahedron Lett. 2675 (1975). C. D. Gutsche, and D. Redmore. "Advances i n A l i c y c l i c Chemistry", Supplement 1, Academic Press, New York, N.Y., 1968, Chapter 9. H. M. Frey. Advan. Phys. Org. Chem. 4_, 147 (1966). Houben-Weyl. "Methoden Der Organischen Chemie", Band IV/3, "Carbocyclische Dreiring-Verbindungen", p.597. S. Sarel, J. Y o r e l l and M. Sarel-Imber. Angew Chem. Int. Ed. ]_, 577 (1968). C. G. Overberger and A. E. Borchert. J . Am. Chem. Soc. 82, 1007 (1960). C. A. Wellington. J . Phys. Chem. 66, 1671 (1962). M. C. Flowers and H. M. Frey. J . Chem. Soc. 3547 (1961). C. S. E l l i o t and H. M. Frey. J . Chem. Soc. 345 (1965). R. J. E l l i s and H. M. Frey. J . Chem. Soc. 4188 (1964). A. D. Ketley. Tetrahedron Lett. 1687 (1964). -191-37. A. J. B e r l i n , L. P. Fisher and A. D. Ketley. Chem. and Ind. 509 (1965). 38. A. D. Ketley and J. L. McClanahan. J . Org. Chem. 30, 942 (1965). 39. A. D. Ketley, A. J. B e r l i n and L. P. Fisher. J . Org. Chem. 31, 2648 (1966). 40. A. D. Ketley, J . L. McClanahan, and L. P. Fisher. J . Org. Chem. 30, 1659 (1965). 41. R. J . E l l i s and H. M. Frey. J . Chem. Soc. 959 (1964). 42. A. D. Ketley, A. J. B e r l i n , E. Gorman, and L. P. Fisher. J. Org. Chem. 31, 305 (1966). 43. E. Vogel and R. Erb, quoted i n Angew. Chem. Int. Ed. 2_, 1 (1963). 44. G. H. Schmid and A. W. Wolkoff. J . Org. Chem. 32, 254 (1967). 45. J. R. Neff, R. R. Gruetzmacher, and J. E. Nordlander. J . Org. Chem. 39., 3814 (1974). 46. E. J. Corey and S. W. Walinsky. J . Am. Chem. Soc. 94, 8932 (1972) •. 47. H. G. Richey, J r . and D. W. Shu l l . Tetrahedron Lett. 575 (1976). 48. J . M. Simpson and H. G. Richey, J r . Tetrahedron Lett. 2545 (1973). 49. G. Stork. Lecture at the 19th National Organic Chemistry Symposium, Am. Chem. S o c , Phoenix, Arizona, 1965. 50. B. M. Trost and M. J. Bogdanowicz. J. Am. Chem. Soc. 95, 5311 (1973). 51. B. M. Trost and D. E. Keeley. J . Am. Chem. Soc. 98, 248 (1976). 52. E. J. Corey and R. H. Wollenberg. J . Org. Chem. 40, 2265 (1975). 52a. M. Schneider and I. Merz. Tetrahedron Lett. 1995 (1974). 53. S. A. Monti, F. G. Cowherd, and T. W. McAninch. J. Org. Chem. 40, 858 (1975). 54. J . A. Berson and M. R. W i l l c o t t . J. Org. Chem. 30, 3569 (1965). -192-55. F. S. Fawcett. Chem. Rev. 47, 219 (1950). 56. W. von E. Doering and J. B. Lambert. Tetrahedron 19, 1989 (1963). 57. J. A. Berson and E. S. Hand. J. Am. Chem. Soc. 86, 1978 (1964). 58. W. von E. Doering and W. Grimme, quoted i n re f . 29. 59. W. von E. Doering and W. Grimme. cit e d i n Angew. Chem. Int. Ed. 2_, 115 (1963). 60. E. Vogel and H. Kiefer. Angew. Chem. 73, 548 (1961). 61. K. F. Bangert and V. Bockelheide. J . Am. Chem. Soc. 86, 905 (1964). 62. E. Vogel. W. Wiedemann, H. Kie f e r , and W. F. Harrison. Tetrahedron  Lett. 673 (1963). 63. G. F. Fonken and W. Moran. Chem. and Ind. 1841 (1963). 64. T. L. Burkoth. J. Org. Chem. 31, 4259 (1966). 65. L. A. Paquette, R. P. Henzel and R. F. Eizember. J . Org. Chem. 38, 3257 (1973). 66. M. J. Jorgenson. J . Am. Chem. Soc. 91, 6432 (1969). 67. P. J. Kropp. J. Am. Chem. Soc. 89, 1126 (1967). 68. L. A. Paquette, G. V. Meehan, R. P. Henzel, and R. F. Eizember. J. Org. Chem. 38, 3251 (1973). 69. L. Skattebol. Chem. and Ind. 2146 (1962). 70. V. A r i s , J . M. Brown, and B. T. Golding. J . Chem. Soc. Chem. Comm. 1206 (1972). 71. V. A r i s , J . M. Brown, J. A.Conneely, B. T. Golding, and D. H. Williamson. J . Chem. Soc. Perkin Trans.II, 4 (1975). 72. J . M. Brown. J. Chem. Soc. Chem. Comm. 226 (1965). 73. R. Grigg, R. Hayes, and A. Sweeney. J. Chem. Soc. Chem. Comm. 1249 (1971). 74. B. S. Rabinovitch, E. W. Schlag and K. B. Wiberg. J. Chem. Phys. 28, 504 (1958) -193-75. D. W. Sester and B. S. Rabinovitch. J. Am. Chem. Soc. 86, 564 (1964). 76. H. M. Frey and D. C. Marshall. J. Chem. Soc. 3981 (1962). 77. B. Grzybowska, J. H. Know, and A. F. Trotman-Dickenson. J. Chem. Soc. 4402 (1961). 78. H. M. Frey. Trans. Faraday Soc. 58, I, 516 (1962). 79. K. W. Egger, D. M. Golden, and S. W. Benson. J. Am. Chem. Soc. 86, 5420 (1964). 80. M. J. S. Dewar, G. J. Fonken, S. Kirschner, and D. E. Minter. J . Am. Chem. Soc. 97, 6750 (1975). 81. M. R. Wllcott and V. H. Cargle. J. Am. Chem. Soc. 89, 723 (1967). 82. M. R. Wilcott and V. H. Cargle. J. Am. Chem. Soc. 91, 4310 (1969). 83. M. Sarel-Imber, as quoted i n Angew. Chem. Int. Ed. Engl. _7, 577 (1968). 84. E. Piers and I. Nagakura. Synth. Commun. _5, 193 (1975). 85. E. Piers and I. Nagakura. J. Org. Chem. 40, 2695 (1975). 86a. For a review of g-chloro-a,g-unsaturated ketones see A. E. Pohland and W. R. Benson. Chem. Rev. 66, 161 (1966). b. See also references 7-18 cited i n reference 84 above. 87. D. A. Archer and B. W. Singer. J. Chem. Soc. Perkin I, 2484 (1976). 88. R. D. Clark and C. H. Heathcock. J. Org. Chem. 41, 636 (1976). 89. L. M. Jackman and S. Sternhall, "Application of Nuclear Magnetic Resonance Spectroscopy i n Organic Chemistry", Pergamon Press, Elmsford, N.Y., 1969, p.223. 90. U. E. Matter, C. Pascual, E. Pretsch, A. Pross, W. Simon and S. Sternhell. Tetrahedron, 25, 2023 (1969). 91. A. I. Scott, "Interpretation of the U l t r a v i o l e t Spectra of Natural Products", Pergamon Press, N.Y., 1964. -194-92. R. B. Woodward. J. Am. Chem. Soc. 64, 72 (1942). 93. L. F. Fieser and M. Fieser. "Steroids", Reinhold, N.Y., 1959 , p.15-24. 94. W. F. Gannon and H. 0. House. Org. Syn. 40, 14 (1960). 95. E. W. Warnhoff, D. G. Martin and W. S. Johnson. Org. Syn. C o l l  Vol. j4, 162 (1963). 96. W. M. Schubert and W. A. Sweeney. J. Am. Chem. Soc. 77, 2297 (1955). 97. H. N. A. A l - J a l l o , E. S. Waight. J. Chem. Soc. (B), 73 (1966). 98. R. L. Erskin and E. S. Waight. J. Chem. Soc. 3425 (1960). 99. W. R. Benson and A. E. Pohland. J. Org. Chem. 30, 1129 (1965). 100. C. M. French and N. Singer. J . Chem. Soc. 2431 (1956). 101. C. Binet du Jasonneix. B u l l . Soc. Chim. Fr. 758 (1975). 102. I. J. Borowitz, K. C. Kirby J r . and Virkhaus. J . Org. Chem. 31, 4031 (1966). 103. This material was prepared by Dr. I. Nagakura of our laboratory. 104. A. J. Fry, J . J. 0'Dea. J. Org. Chem. 40, 3625 (1975). 105. This material was prepared by the author; uv data unpublished. 106. This material was prepared by J. Grierson of our laboratory. 107. J. Wolinsky, D. Chan and R. Novak. Chem.and Ind., 720 (1965). 108. R. C. Hahn, G. W. Jones. J. Am. Chem. Soc. 93, 4232 (1971). 109. J. P. Marino and T. Kaneko. Tetrahedron Lett. 3971 (1973). 110. J. P. Marino and T. Kaneko. J. Org. Chem. 39, 3175 (1974). 111. Y. Tamura, T. Miyamoto, T. Nikishima and Y.. K i t a . Tetrahedron Le t t. 2351 (1973). 112. J . R. Neff, R. R. Gruetzmacher and J. E. Nordlander. J. Org. Chem. 39, 3814 (1974). -195-113. J . P. Marino and L . J . Browne. J . Org. Chem. 41, 3629 (1976). 114. R. T. Conley and B. E . Nowak. J . Org. Chem. 2_6, 692 (1961). 115. A. F . Kluge and C. P. L i l l y a . J . Org. Chem. 36, 1977 (1971). 116. R. D. Sands. J . Org. Chem. 32, 3682 (1967). 117. P. A. Naro and J . A. Dixon. J . Am. Chem. Soc. 81, 1681 (1959). 118. Y. Fujiwara , I . M o r i t a n i , S. Danno, R. Asano and S. T e r a n i s k i . J . Am. Chem. Soc. 91, 7166 (1969). 119. For a review on the sp irove t ivanes , see J . A. M a r s h a l l , S. F . Brady, and N. H. Anderson. F o r t s c h r . Chem. Org. Naturs t . 31, 238 (1974). Recent repor t s : A. S t o e s s l , J . B. Stothers and E . W. B. Ward. J . Chem. Soc. Chem. Comm. 431 (1975); A. S t o e s s l , J . B. Stothers , and E . W. B. Ward. Can. J . Chem. 53, 3351 (1975); N. K a t s u i , H. K i t a h a r a , F . Y a g i h a s h i , A. Matsunaga, and T. Masamune. Chem. L e t t . 861 (1976); G. I . Burnbaum, C. P. Huber, M. L . Post , J . B. Stothers , J . R. Robinson. A . S t o e s s l and E . W. Ward. J . Chem. Soc. Chem. Comm. 330 (1976); R. C. Anderson, D. M. Gum, J . Murray-Rust , P. Murray-Rust , and J . S. Roberts . J . Chem. Soc. Chem. Comm. 27 (1977). 120. J . A. M a r s h a l l , N. H. Anderson, and P. C. Johnson. J . Am. Chem. Soc. 89, 2748 (1967); J . A. M a r s h a l l and P. C. Johnson. J . Am. Chem. Soc. 89, 2750 (1967); J . A. M a r s h a l l , N. H. Anderson and P. C. Johnson, J . Org. Chem. 34, 186 (1969). 121. J . A. M a r s h a l l , P. C. Johnson. J . Chem. Soc. Chem. Comm. 391 (1968); J . Org. Chem. _3_5, 192 (1970); J . A. M a r s h a l l and S. F . Brady. Tetrahedron L e t t . 1387 (1969); J . Org. Chem. 35, 4068 (1970). 122. M. Mongrain , J . La Fonta ine , A. Belanger and P. Deslongchamps. Can. J . Chem. 48, 3273 (1970). -196-123. P. M. McCurry, J r . , R. K. Singh and S. Link. Tetrahedron Lett. 1155 (1973); P. M. McCurry, J r . and R. K. Singh. Tetrahedron Lett. 3325 (1973). 124. G. Stork, R. L. Danheiser and B. Ganem. J. Am. Chem. Soc. 95, 3414 (1973). 125. G. Bozzato, J . P. Bachmann and M. Pesaro, J . Chem. Soc. Chem. Comm. 1005 (1974). 126. M. Deighton, C. R. Huges, and R. Ramage. J. Chem. Soc. Chem. Comm. 662 (1975). 127. D. Buddhsukh and P. Magnus. J. Chem. Soc. Chem. Comm. 952 (1975). 128. E. Wenkert, B. L. Buckwalter, A. A. Craveiro, E. L. Sanchez, and S. S. Sathe. J . Am. Chem. Soc. 100, 1267 (1978). 129. D. Caine, A. A. Boncugnani, S. T. Chao, J . B. Dawson, and P. F. Ingwalson. J . Org. Chem. 41, 1539 (1976); D. Caine, A. A. Boncugnani, and W. R. Pennington. J. Org. Chem. 41, 3632 (1976). 130. K. Yamada, H. Nagase, Y. Hayakawa, K. Aoki, and Y. Hirata. Tetrahedron  Lett. 4963 (1973); K. Yamada, K. Aoki, H. Nagase, Y. Hayakawa, and Y. Hirata. Tetrahedron Lett. 4967 (1973). 131. W. G. Dauben and D. J. Hart. J . Am. Chem. Soc. 9_7, 1622 (1975). 132. G. Buchi, D. Berthet, R. Decorzant, A. Grieder, and A. Hauser. J. Org. Chem. 41, 3208 (1976). 133. G. H. Posner, Org. React., 19, 1 (1972). 134a. G. Stork and M. Isobe. J. Am. Chem. Soc. 97, 6260 (1975); (b) F. Naf. R. Decorzant, and W. Thommen. Helv. Chim. Acta., 58, 1808 (1975); (c) K. K. Heng and R. A. J. Smith, Tetrahedron Le t t. 589 (1975). 135. R. K. Boeckman, J r . , J . Am. Chem. Soc. 95, 6867 (1973); 96, 6179(1974). -197-136a. G. H. Posner, J . J. S t e r l i n g , C. E. Whitten, C. M. Lentz, and D. J. Brunelle. J. Am. Chem. Soc. 97, 107 (1975). (b) R. K. Boeckman, J r . , J. Org. Chem. 38, 4450 (1973); (c) R. M. Coates, and L. 0. Sandefur, i b i d , 39, 275 (1974); (d) J. W. Patterson, J r . and J. H. Fried, i b i d . 39, 2506 (1974). 137. H. C. Brown and A. Tsukamoto. J. Am. Chem. Soc. 86, 1089 (1964). 138. E. J. Corey and J. W. Sugga. Tetrahedron Lett. 2647 (1975). 139. P. Worster, Ph.D. Thesis p.198, 280. Univ. of B.C., Vancouver, B.C.,Canada. 140. E. J. Corey, C. U. Kim. J. Am. Chem. Soc. 94, 7586 (1972). 141. L. Crombie and J. Crossley. J. Chem. Soc. 4983 (1963). 142. L. B. Young and W. S. Trahanovsky. J. Org. Chem. 32, 2349 (1967). 143. J. D. Roberts. J. Am. Chem. Soc. _7_3, 2959 (1951). 144. M. J u l i a , S. J u l i a , and B. Bemont, B u l l Soc. Chim. France, 304 (1960). 145. N. M. Yoon, C. S. Pak, H. C. Brown, S. Krishnamurthy, and T. P. Stocky. J. Org. Chem. 38, 2786 (1973). 146a. H. 0. House, M. G a l l and H. D. Olmstead. J. Org. Chem. 36, 2361 (1971). b. W. A. Kleschick, C. T. Buse, C. H. Heathcock. J. Am. Chem. Soc. 99, 247 (1977). 147. T. Mukaiyama, K. Banno, K. Narasaka. J. Am. Chem. Soc. 96, 7503 (1974). 148. R. D. Clark and C. H. Heathcock, J. Org. Chem. 41, 1396 (1976). 149. H. 0. House, D. S. Crumrine, A. Y. Teranishi and H. 0. Olmstead. J. Am. Chem. Soc. 95, 3310 (1973). 150. A. B. Mekler, S. Ramachandran, S. Swaminathanan, and M. S. Newman, Org. Syn. 41, 56 (1961). -198-151. W. S. Johnson and H. Posvic. J . Am. Chem. Soc. 69, 1361 (1947). 152. D. Seyferth and H. M. Cohen. J. Organometal. Chem. 1, 15 (1963). 153. H. Gilman and F. K. Cartledge. J. Organometal. Chem. 2, 447 (1964). 154. G. J. M. Van der Kerk, J. G. Noltes, and J. G. A. L u i j t e n . J .  Appl. Chem. _7, 366 (1957). 155. C. L. Bumgardner, J. Am. Chem. Soc. 83, 4423 (1961). -199-PART I I I Reaction of Lithium Phenylthio(7-norcar-2-enyl) cuprate with Cyclic 8-Iodo-a,6-unsaturated Ketones INTRODUCTION I. General The f a c i l e thermal Cope rearrangement of 1,2-divinylcyclopropane systems to the corresponding cycloheptadienes has been the subject of 1 2 extensive study. ' However, most of these studies have been primarily concerned with a delineation of the mechanism of the reaction. L i t t l e e f f o r t has been spent on the investigation of the a p p l i c a b i l i t y of t h i s transformation to synthesis. The increasing number of s t r u c t u r a l l y interesting and b i o l o g i c a l l y active natural products bearing a seven-membered ring (for example, the sesquiterpenes jaeschkeanadiol 1_, 6 -3 4 himachalene 2^, carolenin _3, c o r d i l i n h_ and cyclocolorenone 5) ' , has prompted recent investigations regarding the p o s s i b i l i t y of applying th i s type of transformation to the synthesis of these natural products. 1 2 1 1 1 I I . 1,2-Divinylcyclopropane Rearrangements The thermal rearrangement of cis-1,2-divinylcyclopropane compounds to the corresponding cycloheptadiene systems i s a very f a c i l e process, presumably largely due to the attendant r e l i e f of rin g s t r a i n . In fa c t , cis-1,2-divinylcyclopropane i t s e l f (6) has been isolated only very recent stable at -20°C, i t rearranges to 1,4-cycloheptadiene 7_ with a half l i f e 90 sec at 35°C.^ In reactions where cis-1,2-divinylcyclopropane would be the expected product, the compound actually isolated has always been 1,4--200-cycloheptadiene. For example, pyrolysis of the diquaternary hydroxide 8, yields only the diene 1_ ( e q . l ) . Even the reaction of diazomethane with cis-hexatriene i n the presence of cuprous chloride at -40°C yielded the diene _7 rather than the cyclopropane 6_ (eq.2). 7 < ^ ^ C H 2 N ( C H 3 } J O H 8 0 o c >isv^<:H2N(CH3)30H * 8 (1) 9 CH 2N 2 CuC£ -40°C (2) Some derivatives of cis-1,2-divinylcyclopropane are stable enough to be isolate d under ordinary conditions of work-up while others have been detected only as transient intermediates. For example, the b i c y c l i c derivative 1_0 has been isolated, but i t rearranges re a d i l y at room temperature to the b i c y c l i c compound 11. The ketene 13_ was presumed to be the i n t e r -mediate to account for the photolytic decomposition of the diazoketone 1_2 to the b i c y c l i c ketone 14_ (eq. 4). The l a b i l e ketene 17_ has been detected i n the low temperature (-190°C) i r r a d i a t i o n of the methoxyketones 16 or 18 (eq. 5)."^ On warming to -70°C, the ketene spontaneously isomerizes i n a Cope process to give an equilibrium mixture of methoxyketones i n which the more stable isomer 1_8 predominates 10 r. t. (3) 10 11 -201-hv THF in s e r t i o n Wolff rearrangement 15 o = c = Cope rearrangement (4) MeO o LI H 16 hv -70 c o - c hv H ,9 -78< (5) The cis,cis-divinylcyclopropane derivative 1_9_ has been is o l a t e d and i t rearranges readily to the corresponding cycloheptadiene 20 at 75°C; the more l a b i l e cis,trans isomer 21_ rearranges i n the process of preparation and work-up (eq.6). 1 1 The s t a b i l i t y of the cis,cis-isomer, i n contrast to that of the cis,trans-isomer or of cis-divinylcyclopropane i t s e l f , has been explained by the s t e r i c i n t e r a c t i o n of the n-butyl group with the cis-methylene hydrogen of the ring., which raises the energy requirement of the boatlike orientation necessary for a concerted re-arrangement. R W w 75c 19 <15°C (6) Trans-1,2-divinylcyclopropane has been prepared and i s o l a t e d . 1 2 As expected, i t i s much more stable than the corresponding c i s compound. -202-However, thermolysis of t h i s compound also gives 1,4-cycloheptadiene as the major product (eq.7) 12 Presumably, the cyclopropane ring undergoes homolysis and recombination to give the c i s compound which then rearranges to 1,4-cycloheptadiene _7_ been suggested. 1 4 13 A b i r a d i c a l intermediate l i k e 22 has also (7) S i m i l a r l y , the trans-divinylcyclopropane derivatives 23a and 23b have been isolated and thermally rearranged to the corresponding cyclo-heptadienes 24a and 24b respectively ( e q . 8 ) . 1 1 ' 1 ^ - cr 24 (a) R=n-Bu; (b) R=>=-<:2H5 (8) Incorporating a portion of the divinylcyclopropane moiety into another c y c l i c structure does not negate the p o s s i b i l i t y of rearrangement . For example,the b i c y c l i c compound 25_ rearranges to the b i c y c l i c compound 26 at 60°C within l h (eq.9). 1 6 60°C -> l h (9) -203-Although the conversion of the 1,2-divinylcyclopropane systems to cycloheptadienes has long been established, the transformation has rarely been applied to synthesis. Recently, Marino and Kaneko reported the use of thermal rearrangement of substituted 3-(2-vinylcyclopropyl)-2-cyclohexen-l-one 27a and 2-methyl-3-(2-vinylcyclopropyl)-2-cyclopenten-l-one 27b for the preparation of the r i n g fused cycloheptadiene derivatives 28a and 28b respectively (eq. 1 0 ) . 1 7 ' ^ (CH 2) n (10) 27 28 (a) n=l, R=H, R 1=C0 2Et; (b) n=o, R=CH3> R^CX^Et However, the synthesis of the compounds _27_ involved rather tedious procedures. For example, compound 27b was prepared from 3-chloro-2-methyl-2-cyclopentenone 29_. Treatment of the l a t t e r with dimethylsulfoxonium methylide gave the sulfoxonium y l i d e 30_. Reaction of the a l l y l y l i d e 30_ with acrolein gave the v i n y l cyclopropane _31. Treatment of compound 3_1 with the Wittig reagent _32_ gave a mixture of the trans-divinylcyclopropane 27b and the rearranged product 28b (scheme 1) 17 CH2=CHCH0 C02EtCH=PPh3 \ if XHO 32 COzEt ^ ^ C O j E t trans 27b 28b Scheme 1 -204-More recently, Marino and Wender independently reported an improved synthesis of 27_, by the 1,2-addition of the 2-vinylcyclopropyl-lithium derivatives 33 to 3-alkoxy-2-cycloalken-l-ones 34 (eq. 11). IrfcCHR2 (11) 34(a) n=o, R=Me,R =Me, (b) n=o, R=Me, R^Et, (c) n=l, 28 R=Me, R =Et, 33(a) R2=H, (b) R2=SPh ~ At about the same time, a complementary method involving the synthesis and rearrangement of the b i c y c l i c systems l i k e 27_ was reported by Piers and 21 Nagakura. Reaction of B-iodo-a,B-unsaturated ketones of general structure 35 and 216 with lithium phenylthio(2-vinylcyclopropyl)cuprate, followed by thermal rearrangement of the resu l t i n g B-(2-vinylcyclopropyl)-a,B-unsaturated ketones gave the corresponding cycloheptadienes 8^_ and _3_7 respectively, i n good y i e l d (eq. 12 and 1 3 ) . 2 1 (12) (a) n=l, R=H; (b) n=o, R=H (c) n=lR=CH (13) 36 37 (a) n=l; (b) n=o -205-I I I . The Objective The aforementioned e f f i c i e n t cycloheptadiene annelation reaction developed i n our laboratory stimulated our investigations of the reaction of B-iodo-a,B-unsaturated ketones with l i t h i u m phenylthio(endo-7-norcar-2-enyl)cuprate _38. I t was of special interest to investigate i f thermolysis of the r e s u l t i n g B-alkyl-a,8-unsaturated ketones 39 would give the s t r u c t u r a l l y i n t e r e s t i n g t r i c y c l i c enones 4-0_ as represented i n the following scheme: 35 38 39 40 -206-DISCUSSION I. General Divinylcyclopropane derivatives, with part of the d i v i n y l c y c l o -propane moiety incorporated into another c y c l i c structure or structures, have been shown to be capable of undergoing ordinary Cope type rearrange-ments. For example, compounds 10_ and 13 rearranged r e a d i l y to the b i c y c l i 8 9 compounds 11 and 1_4_ respectively (eq. 3 and 4). ' The thermal rearrange-ment of compound 41_ to compound 43_ was interpreted as a Cope rearrangement of 4T to 4_2, which was subsequently s t a b i l i z e d i n a thermally allowed 1,5-homodienyl hydrogen s h i f t with regeneration of the aromatic system to give 43_ (eq.14). 2 1 The objective of the work described i n t h i s part of the thesis was to synthesize the divinylcyclopropane derivatives of the general structure 39 and to investigate whether or not these compounds would undergo normal Cope -207-type rearrangement to the corresponding t r i c y c l i c compounds of general (15) (a) n=l ; (b) n=2 I I . Reaction of Cy c l i c g-Iodo-ct,g-Unsaturated Ketones with Lithium  Phenylthio(7-norcar-2-enyl)cuprate Reagent. To synthesize the divinylcyclopropane derivative 39_, the previously described methodology involving the transformation of g-iodo-a,g-unsaturated ketones to the corresponding g-cyclopropyl enones was employed. I t was expected that i f the l i t h i u m phenylthio (7-norcar-2-enyl) cuprate reagent 3o\ could be prepared, i t would react with c y c l i c g-iodo enones i n a manner analogous to l i t h i u m phenylthio (cyclopropyl)cuprate, and thus produce the desired b i c y c l i c system 39_ (eq.16). Thus, the f i r s t objective was to prepare the cuprate reagent 38. (16) 38 35 39 (a) n=l ; (b) n=2 7,7-Dibromonorcar-2-ene 44_ was obtained i n 71% y i e l d from 1,3-cyclo-hexadiene by s t i r r i n g the l a t t e r with bromoform i n 50% aqueous sodium -208-hydroxide i n the presence of a phase transfer catalyst, t r i e t h y l b e n z y l -22 ammonium chloride (TEBA) (eq.17). This material exhibited bp 82-85°C 22 (15 T o r r ) [ l i t bp 68-70°C (8 Torr)] , and i t s spectral data were i d e n t i c a l 22 with those reported i n the l i t e r a t u r e . Br (17) Preliminary studies by Dr. I. Nagakura of our laboratory had shown that 7,7-dibromonorcar-2-ene could be reduced by tri-n-butyltinhydride to a 1:1 mixture of syn and anti-7-bromonorcar-2-ene 45 and 4j5, respectively (eq.18). However, only the syn compound 4_5 was useful i n preparing the (18) M 45 46 1 : 1 cuprate reagent _38. Therefore, methods for preparing syn-7-bromonorcar-2-ene 4_5 stereoselectively were investigated. It had been reported that sodium cyanoborohydride reduction of 7,7-dibromonorcarane 47_ gave a mixture of syn- and anti-7-bromonorcarane 48 and 4j), i n a r a t i o of 77:21 respectively -209-(eq.19). However, when t h i s procedure was employed i n an attempted reduction of 7,7-dibromonorcar-2-ene 44, no monobromonorcar-2-ene was obtained. (19) 47 48 49 77 . : 21 Osborn et a l had reported that 9,9-dibromobicyclo[6.1.Ojnonane 50 could be reduced by zinc i n acetic acid to give a mixture of syn- and anti-9-bromobicyclo [6.1.0] nonane, 51 and 52_, i n a r a t i o of 24 9:1 respectively (eq.20). When t h i s method was employed i n the reduction of 7,7-dibromonorcar-2-ene 44_, a mixture of syn and a n t i -(20) 50 51 52 9 : 1 7-bromonorcar-2-ene 4_5 and 46, i n a r a t i o of ^9:1, respectively was obtained i n 61% y i e l d . The assignment of stereochemistry to compound 45 and 46 was based on -210-the ''"Hnmr spectral data. The proton at C-7 of the syn-monobromo compound 45 gave r i s e to a t r i p l e t at x6.63 with J=7 Hz while that of the a n t i compound 6^_ produced a t r i p l e t at x7.13 with J=3 Hz. I t has been w e l l established that, i n cyclopropane systems, the v i c i n a l . c o u p l i n g constants 25 J , i n general, are lower than J . . I t was thus clear that the trans c i s three protons on the cyclopropane ri n g of( compound 4^5 were i n a c i s re l a t i o n s h i p , whereas i n compound 46, the proton adjacent to the bromine atom was trans to the other two cyclopropyl protons. Compounds 4_5 and j+6 were quite unstable i n a i r . At room temperature, the mixture turned dark brown within a couple of days. 1,3,5-Cycloheptat-riene _53_ was found i n the "decomposed" material. Presumably, dehydro-bromination occurred with ring opening (eq.21). Attempts to separate 45 (21) and 46_ by subjecting a mixture of the two isomers to column chromatography on s i l i c a gel (eluted with hexane) resulted i n extensive decomposition to the triene 5_3, with very poor separation of the surviving desired compounds. Eventually, i t was found that pure syn-7-bromonorcar-2-ene 45 could be isolated from the mixture of isomers by c a r e f u l l y subjecting the mixture to column chromatography on 150 times i t s weight of f l o r i s i l (120 mesh, elution with hexane). The pure isomer 45_ was employed i n preparing the cuprate reagent 38. Treatment of the monobromo compound. 4_5 with two equivalents of t - b u t y l l i t h i u m -211-i n pentane at -78°C for 2h generated the syn-lithlum intermediate 5_4 st e r e o s p e c i f i c a l l y . Addition of tetrahydrofuran and phenylthiocopper to the solution of the lithium intermediate _54_ at -20°C gave a clear brown solution of the cuprate reagent 38_ (scheme 2). Scheme 2 The cuprate reagent _38 thus prepared was allowed to react with 3-iodo-2-cyclohexen-l-one 35b (2h at -20°C, 2h at 0°C). Examination of the crude product by i r spectroscopy showed that i t was composed of a mixture of saturated and a,B-unsaturated carbonyl compounds. A glc analysis of this material showed that i t was composed of two major components (^50% and^/25% respectively) and a number of minor impurities (^25%) . Treatment of t h i s material with sodium methoxide i n methanol caused the disappearance of the saturated carbonyl absorption i n the i r spectrum , and a single major component (^80%) resulted (as shown by glc analysis). The l a t t e r material was subjected to column chromatography and the major component was isolated and i d e n t i f i e d as the t r i c y c l i c enone _55 (72% y i e l d s t a r t i n g from the B-iodo enone 35b). The enone 5_5 was a white c r y s t a l l i n e s o l i d (mp 59-60°C). Its structure was supported by spectral evidence. A strong absorption band at 251 nm (e=7556) i n the uv spectrum and two strong bands at 1620 and 1660 cm 1 i n the i r spectrum indicated the presence of an a,B-unsaturated ketone. The ^Hnmr spectrum showed the presence of two o l e f i n i c protons, as a symmetrical multiplet at x3.54-3.98. The doubly a l l y l i c proton at one of the bridgehead -212-positions gave r i s e to a m u l t i p l e t at T6.19. The rest of the protons appeared as a thirteen-proton multiplet spreading from x7.32 to 8.40. It was quite clear from these re s u l t s that l i t h i u m phenylthio(7-norcar-2-enyl) cuprate 3_8 had indeed reacted with 3-iodo-2-cyclohexen-1-one 35b, to give the expected product 39b, which underwent f a c i l e Cope rearrangement to give the t r i c y c l i c ketone 40b. The l a t t e r isomerized p a r t i a l l y under the reaction conditions (or during work-up) to the enone _55. Treatment of the mixture with sodium methoxide i n methanol completed the isomerization of 40b to compound 55 (Scheme 3). _i MeOH 72% y i e l d Scheme 3 In s i m i l a r fashion, reaction of 3-iodo-2-cyclopenten-l-one 35a with the l i t h i u m phenylthio(7-norcar-2-enyl)cuprate reagent _38 gave the t r i c y c l i enone 56 i n 52% y i e l d (eq.22). The spectral data of t h i s material agreed w e l l with the structure assigned. The i r showed the presence of an a,3--213-(22) unsaturated ketone ( v 1635, 1685 cm "*") . A strong absorption band at max 243 nm (e=8005) i n the uv spectrum was i n agreement with that expected for a compound of this structure. The ^Hnmr showed the presence of two v i c i n a l o l e f i n i c protons, each of which gave r i s e to a doublet of doublets (T3.67 and 3 . 9 8 ) . Each set of signals exhibited the same coupling constants, J=9 Hz, J'=7 Hz. A broad one-proton doublet at T6.77 with J=7 Hz was assigned to the doubly a l l y l i c proton at one of the bridgehead positions. It was found l a t e r that the anti-7-bromonorcar-2-ene 46 was also useful i n preparing the t r i c y c l i c enones 55_ and 56. A 1:1 mixture of syn- and anti-7-bromonorcar-2-ene (obtained from the tri-n-butyltinhydride reduction of the dibromo compound 44) was used to prepare a mixture of the cuprate reagents 38_ and 38a i n a procedure similar to that used i n the case of the pure monobromo compound _5_5. (Scheme 4). Reaction of t h i s mixture of cuprate reagents with 3-iodo-2-cyclohexen-1-one, followed by treatment of the crude product with sodium methoxide i n methanol, gave a mixture of the t r i c y c l i c enones 5J5 and _5_7 i n a r a t i o of ^1:1 (Scheme 4). _ ' .1 1 Scheme 4 -214-The two compounds were separated by means of column chromatography of the mixture on s i l i c a g e l . The isolat e d y i e l d of each component was ^45%. The enone _57_ was a white c r y s t a l l i n e s o l i d with mp 53-54°C. I t s structure was confirmed by spectral data. The uv spectrum of t h i s material showed a very strong absorption at 260 nm (e=19159). The i r spectrum showed the presence of an a,B-unsaturated ketone (v 1655, max 1600 cm "S . Two one-proton multiplets at x3.94 and 4.43 i n the "'"Hnmr spectrum were assigned to the two o l e f i n i c protons on the isolat e d double bond. A one-proton broad singlet was assigned to the a-proton of the a,B-unsaturated ketone f u n c t i o n a l i t y . The rest of the protons appeared as a thirteen-proton multiplet at T7.52-8.52. When a solution of the enone _57_ i n _o-dichlorobenzene was refluxed for 40h, compound _57 rearranged smoothly to the enone 55, i n nearly quantitative y i e l d (Scheme 5). Presumably, an exo -* endo isomerization had occurred giving the endocyclic intermediate 39b which then rearranged to the t r i c y c l i c enone 5_5 (Scheme 5). 57 39b 55 Scheme 5 In a s i m i l a r fashion, reaction of 3-iodo-2-cyclopenten-l-one with a mixture of the li t h i u m phenylthio(7-norcar-2-enyl)cuprate reagents (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-2-ene), gave a mixture of the t r i c y c l i c enone 56_ (28% isolat e d y i e l d ) and the enone _58 (^30% isolat e d -215-yield)(eq.23). The two compounds were separated by means of column chromatography of the mixture on s i l i c a gel. The enone _58_ was a white s o l i d , mp 78-79°C. It showed a very strong uv absorption at 269 nm (e=17176). The two bands at 1695, 1595 cm 1 i n the i r spectrum indicated the presence of an a, 6-unsaturated carbonyl f u n c t i o n a l i t y . Two one-proton multiplets at T3.83 and 4.39 i n the ^Hnmr spectrum were assigned to the two o l e f i n i c protons on the isolated double bond. A one-proton broad singl e t at T4.13 was assigned to the a-proton of the a,8-unsaturated ketone moiety. When an ^-dichlorobenzene solution of the enone _58 was refluxed for 24h, compound 5_8 rearranged to the t r i c y c l i c enone _56_. The l a t t e r could be isolated i n 96% y i e l d . On the basis of the results obtained from the experiments j u s t described, i t was clear that the conversion of the 3-iodo-2-cyclohexen-l-one and 3-iodo-2-cyclopenten-l-one into the t r i c y c l i c enones _55 and 5^6^  respectively, did not require the use of isomerically pure cuprate reagent _38. Thus, the rather tedious p u r i f i c a t i o n of endo-7-bromonorcar-2-ene described e a r l i e r was unnecessary. In practice, the o v e r a l l conversions could be carried out most e f f i c i e n t l y by the following sequence of reactions: (a) reduction of 7,7-dibromonorcar-2-ene with tri- n - b u t y l t i n h y d r i d e to give a mixture of the -216-endo and exo monobromo derivatives; (b) conversion of the l a t t e r mixture into a mixture of the corresponding cuprate reagents (38 + 38a); (c) reaction of 2(8 + 38a with the iodo enones; (d) thermal rearrangement of resultant mixtures of products into the t r i c y c l i c enones _55_ and 56. -217-EXPERIMENTAL For general information, see the beginning of the experimental part of Part I i n this thesis. 22 Synthesis of 7,7-Dibromonorcar-2-ene 44. - To a s t i r r e d mixture of bromoform (12.6 g, 50 mmol), 1,3-cyclohexadiene (4.0 g, 50 mmol),triethyl-benzylammonium chloride (0.1 g) and ethanol (0.2 ml) was added, dropwise, 25 ml of 50% aqueous sodium hydroxide solution. The resulting mixture was s t i r r e d at room temperature for 2.5h. Water (50 ml) and pentane (50 ml) were added and the two phases were separated. The aqueous solution was extracted with three 30 ml portions of pentane. The combined pentane ex-tracts were washed twice with 15 ml of water and dried over anhydrous magnesium sulfate. Removal of the solvent and d i s t i l l a t i o n of the residual o i l gave 9.02 g (71%) of 7,7-dibromonorcar-2-ene 44_. This material exhibited bp 82-85°C (15 T o r r ) [ l i t . bp 68-70°C (8 T o r r ) ] 2 6 ; 1Hnmr, T4.08 (broad s, 2H, o l e f i n i c H), 7.70-8.35 (m, 6H). 2 6 24 Reduction of 7,7-Dibromonorcar-2-ene by Zinc i n Acetic Acid. - To a solution of 7,7-dibromonorcar-2-ene 44 (12 g, 47.6 mmol) i n g l a c i a l acetic acid (80 ml) was added, with s t i r r i n g , 18.56 g (280 mmol) of zinc dust i n small portions over a period of two hours at room temperature. After the l a s t portion of zinc dust had been added, the reaction mixture was s t i r r e d for another 30 min. Then 50 ml of brine was added and the s o l i d residue i n the reaction mixture was removed by f i l t r a t i o n . The aqueous f i l t r a t e was extracted s i x times with 75 ml portions of pentane. The combined pentane extracts were washed thrice with 15 ml portions of 10% aqueous sodium hydroxide solution, once with brine and dried over anhydrous magnesium sulfate. Removal of the solvent and d i s t i l l a t i o n of the residual o i l gave 5g (61%) of a colorless l i q u i d : bp -218-80-83°C (50 Torr). A glc analysis of th i s material (column B, 100°C) showed that i t was composed of a mixture of syn- and anti-7-bromonorcar-2-ene (^91%), 4_5 and 46^  i n r a t i o of 9:1, respectively, along with some minor impurities (M3%). A pure sample of each of compounds h5_ and 4_6 was obtained by column chromatography of 2g of the mixture on 300 g of 120 mesh f l o r i s i l (elution with hexane). An a n a l y t i c a l sample of 45 exhibited i r ( f i l m ) v — max 1640 cm"1; """Hnmr, T4.20 (m, 2H, o l e f i n i c H) , 6.63 ( t , IH, -CHBr, J=7 Hz), 7.40-8.65 (m, 6H). Pure compound 46 exhibited i r ( f i l m ) v 1640 cm "; "''Hnmr, — max T 3.90 (m, IH, o l e f i n i c H), 4.44 (m, IH, o l e f i n i c H), 7.13 ( t , IH, -CHBr, J=3 Hz), 7.50-8.90 (m, 6H). Compounds 45 and 46^  were quite unstable, no elemental analysis was obtained for these compounds. 27 Reduction of 7,7-Dibromonorcar-2-ene by Tri-n-butyltinhydride. - To 3.53 g (14 mmol) of 7,7-dibromonorcar-2-ene 44 was added, dropwise, 4.06 g (14 mmol) of tri-n-butyltinhydride over a period of l h . The r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature for 3h and then d i s t i l l e d (air-bath temperature 60-80°, 10 Torr) to give 1.26 g (52%) of a colorless o i l . Analysis of t h i s ^ material by glc (column B, 100°C) showed that i t was composed of a mixture of syn- and anti-7-bromonorcar-2-ene (^91%) 45_ and 46^ , i n a r a t i o of ^1:1, along with minor, unidentified impurities (^9%). General Procedure for the Preparation of Lithium Phenylthio(7-norcar-2-enyl)  cuprates. - A flame dried 50-ml three-necked f l a s k , equipped with a bent side-arm tube containing 258 mg (1.5 mmol) of phenylthiocopper, was evacuated (vacuum pump) and f i l l e d with argon. A solution of syn- or anti-7-bromonorcar-2-ene (or a mixture of the two compounds)(259 mg, 1.5 mmol) i n 2 ml of anhy-drous ether was transferred to the f l a s k . The solution was cooled to -78°C -219-and a solution of t- b u t y l l i t h i u m i n pentane (2M, 1.5 ml, 3 mmol) was added dropwise. The r e s u l t i n g solution was s t i r r e d for 2h at -78°C. Tetrahydrofuran (10 ml, freshly d i s t i l l e d from l i t h i u m aluminum hydride) was added. The phenylthiocopper i n the side arm was transferred to the reaction vessel by rotating the bent tube. The mixture was warmed to -20°C and s t i r r e d at that temperature for 30 min. A clear brown solution containing 1.5 mmol of the appropriate l i t h i u m phenylthio(7-norcar-2-enyl)cuprate resulted and was ready for use. General Procedure for Reaction of Lithium Phenylthio(7-nbrcar-2-enyl)- cuprates with B-Iodo-q.B-Unsaturated Ketones. - To a cold (-78°C) solution of the appropriate l i t h i u m phenylthio(7-norcar-2-enyl)cuprate (1.5 mmol) i n 14 ml of ether-tetrahydrofuran-pentane (under argon) was added a solution of the appropriate 8-iodo enone (1.0 mmol) i n 2 ml of dry tetrahydrofuran. The dark red solution which formed was warmed to -20°C and s t i r r e d at that temperature for 2h and then at 0°C for another 2h. Methanol (2 ml) was added to quench the reaction. The reaction mixture was allowed to warm to room temperature and 15 ml of ether was added. The r e s u l t i n g mixture was f i l t e r e d through a short column of f l o r i s i l (15 g, 80-100 mesh). The column was eluted with another 150 ml of ether. Crude products were isolat e d by evaporation of solvent under reduced pressure. Reaction of 3-Iodo-2-Cyclohexen-l-one with the Cuprate Reagent Derived from  syjl-7-Bromonorcar-2-ene. - Following the general procedure outlined above, 1.5 mmol of li t h i u m phenylthio(7-norcar-2-enyl)cuprate (derived from pure syn-7-bromonorcar-2-ene) was allowed to react with 222 mg (1 mmol) of 3-iodo-2-cyclohexen-l-one. Normal work-up gave 173 mg of crude product. The -220-i r spectrum of th i s material indicated the presence of a mixture of saturated and a,S-unsaturated carbonyl compounds. A glc analysis of th i s material showed that i t was composed of two major components (^50% and 25% respectively) and a number minor impurities (^25%). The crude mixture was dissolved i n 15 ml of methanol and a c a t a l y t i c amount of sodium methoxide was added. The r e s u l t i n g solution was s t i r r e d at room temperature for l h and the methanol was then removed under reduced pressure. To the residue was added 30 ml of brine and the re s u l t i n g mixture was extracted with three 50 ml portions of ether. The combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. The yellow o i l which remained showed no trace of saturated carbonyl absorption i n the i r spectrum. A glc analysis of t h i s material showed that i t was composed of a single major component (^80%), together with a number of minor un-i d e n t i f i e d impurities. This material was subjected to column chromatography (25 g s i l i c a g e l , elution with 25% ether i n hexane), and 134 mg (72%) of the major component was isolat e d and i d e n t i f i e d as the t r i c y c l i c enone 55. The l a t t e r material was r e c r y s t a l l i z e d from hexane to give white needles which exhibited mp 59-60°C; uv X 251 nm (e=7556); ir(CHCl 0)v 1620, max 3 max 1660 cm"1; 3"Hnmr, T3.54-3.98 (m, 2H, o l e f i n i c H), 6.19 (m, IH, -C=C-CH-C=C-), 7.32-8.40 (m, 13H). Anal. Calcd. for C--Hn,0: C, 82.94; H, 8.57. Found: C, 82.94; H, 8.46. Reaction of 3-Iodo-2-cyclohexen-l-one with the Cuprate Reagents Derived  from a 1:1 Mixture of syn and anti-7-Bromonorcar-2-ene. - Following the general procedure, 1.5 mmol of li t h i u m phenylthio(7-norcar-2-enyl)cuprate (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-2-ene) was allowed to react with 222 mg (1 mmol) of 3-iodo-2-cyclohexen-l-one. Normal work-up -221-followed by sodium methoxide treatment and column chromatography of the crude product on 25 g of s i l i c a gel (elution with 25% ether i n hexane) afforded 86 mg (45%) of the pure t r i c y c l i c enone _55_ and 85 mg (45%) of the pure enone 57_. The enone 57_ was i n i t i a l l y obtained as a colorless viscous o i l . However, this material could be r e c r y s t a l l i z e d (from hexane) to give a white c r y s t a l l i n e s o l i d . The l a t t e r exhibited mp 53-54°C; uv A 260 nm (e=19159); i r ( f i l m ) v 1655, 1600 cm"1; 1Hnmr x3.94 max max (m, IH, o l e f i n i c H), 4.21 (broad s, IH, -C0CH=C-), 4.43 (m, IH, o l e f i n i c H), 7.52-8.52 (m, 13H). Anal. Calcd. for C^H^O: C, 82.94; H, 8.57. Found: C, 82.76; H, 8.65. Reaction of 3-Iodo-2-cyclopenten-l-one with the Cuprate Reagent Derived from svn-7-Bromonorcar-2-ene. - Following the general procedure outlined above, 1.5 mmol of lithium phenylthio(7-norcar-2-enyl)cuprate (derived from pure syn-7-bromonorcar-2-ene) was allowed to react with 208 mg (1 mmol) of 3-iodo-2-cyclopenten-l-one. A different work-up procedure was used i n this reaction. After the reaction was complete, methanol (1 ml), ether (20 ml) and water (10 ml) was added to the reaction mixture. The s o l i d material that formed was removed by f i l t r a t i o n and the f i l t r a t e was extracted thoroughly with ether. The combined ether extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a yellow o i l . This material was subjected to column chromatography on 25 g of s i l i c a gel. Elution of the column with 25% ether i n hexane afforded 90 mg (52%) of the pure t r i c y c l i c enone 56_. The l a t t e r was r e c r y s t a l l i z e d from hexane, y i e l d i n g white f l a k e - l i k e crystals which exhibited mp 70-72°C; uv A 243 nm (e=8005); ir(CHCl 0)v 1685, 1635 cm"1; 1Hnmr, T3.67 (d of d, max 3 max IH, o l e f i n i c H, J=9 Hz, J'=7 Hz), 3.98 (d of d, IH, o l e f i n i c H, J=9 Hz, J'=7 Hz), 6.77 (broad d, IH, J=7 Hz, -C=C-CH-C=C-), 7.40 (m, IH), 7.50 (m, 2H), -222-7.72 (broad s, 4H), 8.05-9.40 (m, 4H). Anal. Calcd. for C^rL^O: C, 82.72; H, 8.10. Found: C, 82.93; H, 8.12. Reaction of 3-Iodo-2-cyclopenten-l-one with the Cuprate Reagents Derived from a 1:1 Mixture of syn- and anti-7-Bromonorcar-2-ene. - Following the general procedure outlined above, 1.5 mmol of l i t h i u m phenylthio(7-norcar-2-enyl)cuprate (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-2-ene) was allowed to react with 208 mg (1 mmol) of 3-iodo-2-cyclopenten-l-one. Normal work-up, followed by column chromatography of the crude product on 25 g of s i l i c a gel (elution with 25% ether i n hexane) afforded 49 mg (28%) of the pure t r i c y c l i c enone _56_ and 53 mg (31%) of the pure enone 58. The enone ^8_, which was i n i t i a l l y obtained as a colorless viscous o i l , could be r e c r y s t a l l i z e d from hexane to give white needles. The l a t t e r exhibited mp 78-79°C; uv X 269 nm (e=17176); i r ( f i l m ) v 1695, 1595 max max cm - 1; 1Hnmr, T3.83 (m, IH, o l e f i n i c H), 4.39 (m, IH, o l e f i n i c H), 4.13 (broad s, IH, -C=CH-C=0), 7.10-8.60 (m, 1 1 H ) . i Anal.Calcd. for C^H^O: C, 82.72; H, 8.10. Found: C, 82.74; H, 8.00. Thermal Rearrangement of the Enone 5J_. - A solut ion of the enone 57 (72 mg) i n o-dichlorobenzene (3 ml) was refluxed for 40h. Removal of solvent under reduced pressure (vacuum pump) and d i s t i l l a t i o n (air-bath temperature vL05°C, 0.4 Torr) of the residual o i l gave 68 mg (94%) of a colorless o i l . Analysis of t h i s material by glc (column B, 200°C) showed that i t was composed of the enone 5_5 (^92%) and small amount of minor impurities (^8%). This material was subejcted to r e c r y s t a l l i z a t i o n (hexane), and pure enone 55 was isolated as white c r y s t a l s . The spectral data of the l a t t e r were i d e n t i c a l with those of the same material obtained e a r l i e r . -223-Thermal Rearrangement of the Enone J58_. - A solution of the enone _58 (40 mg) i n o-dichlorobenzene (1.5 ml) was refluxed for 24h. Removal of solvent and d i s t i l l a t i o n (air-bath temperature 'vl05°C, 0.2 Torr) of the residual o i l gave 38 mg (96%) of the pure c r y s t a l l i n e t r i c y c l i c enone 56. A glc analysis (column B, 200°C) of t h i s material showed that i t was pure. -224-BIBLIOGRAPHY S. J. Rhoads and N. R. Raulins. Org. Reactions,22, 54 (1975). H. M. Frey. Advan. Phys. Org. Chem. 4_, 163 (1966). R. W. M i l l s and T. Money, "Terpenoids and Steroids," Vol. 4, Special P e r i o d i c a l Reports. The Chemical Society, London, 1974, Chapter 2. S. M. Kupchan, M. A. Eakin, and A. M. Thomas. J. Med. Chem. 14, 1147 (1971). J . M. Brown, B. T. Golding and J. J. Stofko. J. Chem. Soc. Chem. Comm. 319 (1973). E. Vogel, K. H. Ott and K. Gajek. Ann. 644, 172 (1961). W. von E. Doering and W. R. Roth. Tetrahedron, 18, 67 (1962). J. M. Brown, J. Chem. Soc. Chem. Comm. 226 (1965). P. K. Freeman and D. G. Kuper. Chem.Ind. 424 (1965). 0. L. Chapman and J. D. L a s s i l a . J . Am. Chem. Soc. 90, 2449 (1968). G. Ohloff and Pickenhagen. Helv. Chim. Acta. 52, 880 (1969). E. Vogel. Angew Chem. 74, 829 (1962). B. S. Rabinovitch, E. W. Schlag and Wiberg. J. Chem. Phys. 28, 504 (1958). W. von E. Doering and W. R. Roth. Tetrahedron,19, 715 (1963). A. A l l , D. Sarantakis, and B. Weinstein. J . Chem. Soc. Chem. Comm. 940 (1971). M. S. Baird and C. B. Reese. J . Chem. Soc. Chem. Comm. 1519 (1970). J. P. Marino and T. Kaneko. J. Org. Chem. 39, 3175 (1974). J. P. Marino and T. Kaneko. Tetrahedron Lett. 3975 (1973). J. P. Marino and L. J. Browne. Tetrahedron Lett. 3245 (1976). P. A. Wender and M. P. F i l o s a . J . Org. Chem. 41, 3490 (1976). -225-21. G. Maas and M. Regitz. Angew Chem. Int. Ed. Engl. 16, 711 (1977). 22. M. Makoza, and M. Fedorynski. Synth. Commun. _3, 305 (1973). 23. R. 0. Hutchins, D. Kadasamy, C. A. Maryanoff, D. Masilamarii and B. E. Maryanoff, J. Org. Chem. 42, 82 (1977). 24. C. L. Osborn, T. C. Shields, B. A. Shoulders, J. F. Krause, H. V. Cortez, and P. D. Gardner. J. Am. Chem. Soc. 87, 3158 (1965). 25. D. H. Williams, I. Fleming. "Spectroscopic Methods i n Organic Chemistry." McGraw-Hill Book Company (UK) Limited, 1973, p.106. 26. D. G. Lindsay and C. B. Reese. Tetrahedron,21, 1673 (1965). 27. H. G. K u i v i l a . Synthesis, 499 (1970). 

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