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UBC Theses and Dissertations

Studies related to the preparation of 2-alkyl- and 2-alkenyl-1,3-cyclohexanediones ; An investigation… Grierson, John Rodney 1983

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I. STUDIES RELATED TO THE PREPARATION OF 2-ALKYL- AND 2-ALKENYL-1,3-CYCLOHEXANEDIONES II. AN INVESTIGATION INTO THE REGIOSELECTIVE FORMATION OF B-IODO a UNSATURATED KETONES FROM UNSYMMETRICAL 1,3-CYCLOHEXANEDIONES II I . STUDIES RELATED TO THE DIVINYLCYCLOPROPANE REARRANGEMENT by JOHN RODNEY GRIERSON B. Sc., Un i v e r s i t y of B r i t i s h Columbia, 1976 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA APRIL 1983 <g) John Rodney Grierson l<3^ > DOCTOR OF PHILOSOPHY i n In 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 of the requirements f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make 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 and study. I f u r t h e r agree 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 copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the head o f my department or by h i s or her r e p r e s e n t a t i v e s . I t i s understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n p e r m i s s i o n . Department of The U n i v e r s i t y of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 DE-6 (3/81) i i ABSTRACT The work described i n t h i s thesis i s devoted to three separate synthetic methods studies, which represent some past and current i n t e r e s t s i n our laboratory. In the f i r s t study, a preparation of 2 - a l k y l - and 2-alkenyl-l,3-cyclohexanediones (2) from l,5-dimethoxy-l,4-cyclohexadiene (14) i s described. Metalation of the diene (14) with t e r t - b u t y l l i t h i u m i n tetrahydrofuran solution at low temperature (-78°C) followed by addition of an a l k y l or alkenyl h a l i d e , i n the presence of hexamethylphosphoramide, resulted in a completely r e g i o s e l e c t i v e a l k y l a t i o n reaction a f f o r d i n g the correspond-ing 6 - a l k y l - or 6-alkenyl-l,5-dimethoxy-l,4-cyclohexadiene (16). The l a t t e r substances were is o l a t e d i n good to excellent y i e l d s . Simple aqueous hydrolysis of these materials i n the absence of a i r afforded the desired 2 - a l k y l - and 2-alkenyl-l,3-cyclohexanediones (2) i n good y i e l d s . In the second study, an i n v e s t i g a t i o n into the r e g i o s e l e c t i v e forma-tio n of g-iodo a, (^-unsaturated ketones (e.g., (64) and (65)) from unsym-metrical 1,3-cyclohexanediones (63) employing triphenylphosphine d i i o d i d e -triethylamine i n a c e t o n i t r i l e i s described. It has been found that when one of the carbonyl f u n c t i o n a l i t i e s of the substrate i s quite s t e r i c -a l l y hindered the reaction i s nearly completely r e g i o s e l e c t i v e . In the t h i r d study, the thermal (Cope) rearrangement of the b i c y c l i c dienes (136a), (136b-E), and (136b-2) and the t r i c y c l i c dienes (137a-d) i s described. In each case, thermolysis of the substrate at 240°C followed by hydrolysis of the intermediate product thus obtained afforded a b i c y c l o -[3.2.2]non-6-en-3-one, ketones (148), (149), (150) and (151a-d), respec-t i v e l y , i n f a i r to good o v e r a l l y i e l d (49-81%). i i i (136a) R = R' = H (136b-E) R = H,R' = CH 3 (136b-Z) R = CH3,R' = H (137a-d) (148) R = R' = H (149) R = H, R' = CH 3 (150) R = CH3, R' = H (d) n=7 (151a-d) i v TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i LIST OF FIGURES v i i i ACKNOWLEDGEMENTS i x PART I STUDIES RELATED TO THE PREPARATION OF 2-ALKYL- AND 2-ALKENYL-1,3-CYCLOHEXANEDIONES INTRODUCTION 1 DISCUSSION 6 EXPERIMENTAL 12 BIBLIOGRAPHY 24 PART II AN INVESTIGATION INTO THE REGIOSELECTIVE FORMATION OF g-IODO a,^-UNSATURATED KETONES FROM UNSYMMETRICAL 1,3-CYCLOHEXANEDIONES INTRODUCTION . 26 DISCUSSION 38 EXPERIMENTAL 52 BIBLIOGRAPHY , . 65 V PART III STUDIES RELATED TO THE DIVINYLCYCLOPROPANE REARRANGEMENT INTRODUCTION 68 DISCUSSION 1. Preparation of the cyclopropyl ketones 88 2. Preparation of the Cope rearrangement substrates . . . 92 3. Cope rearrangement studies a) Prelude 102 b) Cope rearrangement of the substituted b i c y c l i c compounds (136b) 109 c) Relative rate of rearrangement experiment f or the b i c y c l i c dienes (136b-E) and 136b-Z) 126 d) Cope rearrangement of the t r i c y c l i c diene s e r i e s . 132 EXPERIMENTAL 138 BIBLIOGRAPHY 159 v i LIST OF TABLES TABLE Page 1 A l k y l a t i o n of 1,5-dimethoxy-l,4-cyclohexadiene with a l k y l and alkenyl halides 8 2 Hydrolysis of compounds (16) 10 3 Selected i r , "^H nmr and uv s p e c t r a l properties for compounds (2a-g) 11 4 Reagents and molar quantities used i n the preparation of compounds (16a-g) 16 5 Reaction of c y c l i c g-diketones with triphenylphosphine d i c h l o r i d e and dibromide 33 6 Reaction of some selected c y c l i c g-diketones with triphenylphosphine d i i o d i d e i n benzene 35 7 Reaction of symmetrical g-diketones with t r i p h e n y l -phosphine diiodide-triethylamine 36 8 Reaction of unsymmetrical 1,3-cyclohexanediones with triphenylphosphine diiodide-triethylamine i n a c e t o n i t r i l e 43 9 Infrared and *H nmr data for g-iodo a,g-unsaturated ketones derived from unsymmetrical 1,3-cyclohexane-diones (63a-h) 47 10 Longest wavelength TT -> T T * u l t r a v i o l e t absorption bands of 6-iodo a,g-unsaturated ketones (methanol solution) 51 11 K i n e t i c data and products i n the Cope rearrangement of cis-1,2-dialkenylcyclopropanes 71 12 Preparation of the cyclopropyl ketones (134a-g) and some selected spectroscopic properties 90 v i i 13 Preparation of the O - t r i m e t h y l s i l y l enol ethers of the cyclopropyl ketones (134) 93 14 R e g i o s e l e c t i v i t i e s observed for the k i n e t i c deprotonation-s i l y l a t i o n of some selected c i s - and trans- 2 - v i n y l -cyclopropyl ketones 95 15 S t e r e o s e l e c t i v i t i e s observed for the k i n e t i c deprotonations of some selected e t h y l carbonyl compounds 98 16 *H nmr spe c t r a l and glc c o r r e l a t i o n s for the OTMS enol ethers (136b-E/Z) 99 17 Some in f r a r e d absorption frequencies f o r some selected cycloheptanoid ketones 106 18 Preparation of the b i c y c l i c and t r i c y c l i c ketones 135 v i i i LIST OF FIGURES FIGURE Page 1 The 400 MHz 1H nmr spectrum of the ketone (148) 107 2 Display of high f i e l d region of Figure 1 108 3 The 400 MHz 1H nmr spectrum of the ketone (149) 111 4 Display of high f i e l d region of Figure 3 112 5 High f i e l d methyl i r r a d i a t i o n of the ketone (149) 113 6 The 400 MHz 1H nmr spectrum of the ketone (150) 114 7 Display of the high f i e l d region of Figure 6 115 8 High f i e l d methyl i r r a d i a t i o n of the ketone (150) 116 9 The 400 MHz ''"H nmr spectrum of the i n i t i a l l y i s o l a t e d sample of ketone (150) 117 10 The 400 MHz "*"H nmr spectrum of the product obtained from the p a r t i a l thermolysis of the OTMS enol ethers (136b-E/Z) 118 i x ACKNOWLEDGEMENTS I wish to s i n c e r e l y thank Dr. Edward Piers for the opportunity to have studied under h i s very capable and personable d i r e c t i o n . His many valuable discussions and suggestions throughout t h i s period have surely served to guide my way towards a sound and meaningful approach to science. I also thank the many members of h i s group, both past and present, who have offered me t h e i r encouragement, c r i t i c i s m s , and fri e n d s h i p . Special thanks go to Mr. Max Burmeister, Mr. Ian Suckling, and Mr. Michael Chong for proofreading t h i s thesis. I would l i k e to g r a t e f u l l y acknowledge Dr. L.S. Weiler for the instrument time on his a n a l y t i c a l gas l i q u i d chromatograph. 1 STUDIES RELATED TO THE PREPARATION OF 2-ALKYL- AND 2-ALKENYL-1,3-CYCLOHEXANEDIONES INTRODUCTION In connection with another research problem i n our laboratory, we required a serie s of 2-alkyl- and 2-alkenyl-1,3-cyclohexanediones (2) (Scheme 1). The preparation of th i s type of compound by the d i r e c t a l k y l a t i o n of the parent 1,3-cyclohexanedione (1) i s reasonably e f f i c i e n t (1) (2 3) with reactive a l k y l a t i n g agents such as methyl iodide and a l l y l i c ' (2) or b e n z y l i c halides . However, with much less r e a c t i v e a l k y l a t i n g agents,reaction i s generally sluggish and i n e f f i c i e n t , due to frequent concurrent formation of both C and 0 a l k y l a t i o n products (Scheme 1, (2) and (3) respectively) as w e l l as products a r i s i n g from (3-diketone cleavage and (3) d i a l k y l a t i o n . For example, a l k y l a t i o n of (1) with 1-bromobutane and 4 - i o d o - l - b u t e n e ^ afforded the corresponding alkylated products (2) (R = -(CH 2) 3CH 3 and - ( C H ^ C H = CH 2 r e s p e c t i v e l y ) i n very poor y i e l d s (<11%) . Scheme 1 2 To further compound these d i f f i c u l t i e s , the i s o l a t i o n of the product i n pure form, e s p e c i a l l y i n some instances, i s hampered by rapid autoxidation of these materials when they contain even trace amounts of water ^ \ Numerous attempts have been made to improve the e f f i c i e n c y of the C - a l k y l a t i o n of g-dicarbonyl compounds. However these have met with l i m i t e d success Even methods reputed to provide e f f i c i e n t C - a l k y l a t i o n of a c y c l i c 6-dicarbonyl compounds f a i l when applied to the c y c l i c analogues. For example, a most promising i n i t i a l report by T a y l o r a d v o c a t e d the use of thallium (I) enolates of a c y c l i c g-dicarbonyl compounds as intermediates i n these a l k y l a t i o n reactions (e.g. (5), Scheme 2). These enolates when heated i n the presence of short chain a l k y l iodides provided e x c l u s i v e l y the products of C - a l k y l a t i o n i n excellent y i e l d . However, the a p p l i c a t i o n of t h i s method to the a l k y l a t i o n of 1,3-cyclohexanedione (1) and 1,3-cyclopentanedione (9) with methyl iodide, ethyl bromide and various a-bromoketones and esters resulted i n O-alkylation as the dominant mode of (9) r e a c t i o n (Scheme 3). Scheme 2 Y i e l d % (6), -R J^J^ T10CH 2CH 3 JJJjjJ, RX(neat) - 1 0 Q ? _ C R Pet. ether -A — 93 , -CH 2CH 3 (4) (5) R 91 , -CH(CH 3) 2 More recently however, the v a l i d i t y of t h i s method has been strongly (8) contested by Hooz 3 S cheme 3 (1) (7) RX= CH 3CH 2Br CH 3I V • a -R + 6 (2) . (8) (3) 0 : 0 : 100 51 : 27 : 22 %Conversion 15 90 (10) CH„I + ^ " 0 C H 3 ( i i ) (12) 95 %Conversion 98 Our approach to the preparation of 2-alkyl and 2-alkenyl-1,3-cyclo-hexanediones has not been based on the t r a d i t i o n a l a l k y l a t i o n scheme previously discussed but rather on the a l k y l a t i o n of a la t e n t precursor to 1,3-cyclohexanedione (1). In t h i s manner the inherent complexities associated with the g-diketone moiety with regard to i t s r e a c t i v i t y and ambident nature may be circumvented. Our choice of substrate to accomplish t h i s task was prompted by some (11) i n i t i a l reports by Birch which showed that m-dimethoxybenzene (13) (Scheme 4) may be reduced by sodium i n l i q u i d ammonia to produce 1,5-dimethoxy-l,4-cyclohexadiene (14), and that the l a t t e r material could be 4 alkylated r e g i o s e l e c t i v e l y with both reactive and non-reactive a l k y l a t i n g agents with equal e f f i c i e n c y . Thus, compound (16d) was obtained i n 46% y i e l d when the dienol ether (14) was treated with potassium amide i n l i q u i d ammonia and the anion thus produced quenched with 2-phenylethyl bromide (15). Furthermore, a l k y l a t i o n of the potassium anion of the dienol ether (14) with either bromide (17) (Scheme 5) or methyl iodide followed by hydrolysis of the intermediate products of these reactions, (18) and (16g) r e s p e c t i v e l y , afforded the diones (19) and (2g) i n moderate o v e r a l l y i e l d (46 and 43% y i e l d s r e s p e c t i v e l y ) . Scheme 4 /^)CH3 Na/NH3 /OCH3 1. KNH2/NH3 /OCH3 Q - ~Q -<>CH2CH2^g> \ ) C H 3 EtOH-Et^O \ ) C H 3 2- B r C H 2 C H 2 C 6 H 5 ^OCH3 (15) (13) (14) (16d) 46% Based on these encouraging r e s u l t s , a more thorough i n v e s t i g a t i o n of t h i s synthetic scheme seemed appropriate. S p e c i f i c a l l y i t was a n t i c i -pated that compound (14) could be deprotonated conveniently and regioselec-t i v e l y with a s u i t a b l e a l k y l l i t h i u m reagent (RLi, Scheme 6). Should the projected a l k y l a t i o n of the resultant intermediate species (20) be r e g i o s e l e c t i v e and a f f o r d only the corresponding 6-alkyl- or 6-alkenyl-1,5-dimethoxy-1,4-cyclohexadienes (16), then the l a t t e r could presumably be r e a d i l y transformed by hydrolysis to the desired 2-alkyl- and 2-alkenyl-1,3-cyclohexanediones (2). 5 Scheme 5 Scheme 6 6 DISCUSSION As previously mentioned, the preparation of the dienol ether (14) had been recorded i n the chemical l i t e r a t u r e a n d t h i s procedure afforded a s t a r t i n g point for our synthetic plan. Thus, a Birch reduction of m-dimethoxybenzene (13) was accomplished by the addition of a s o l u t i o n of t h i s substance i n ethanol-ether to a so l u t i o n of sodium metal i n anhydrous, s a l t - f r e e l i q u i d ammonia. This procedure afforded the dienol ether (14) i n 95% y i e l d . The "^H nmr spectrum of t h i s material was consistent with that expected for the symmetrical 1,5-dimethoxy-1,4-cyclohexadiene (14). The di e n o l ether (14) was converted into the corresponding organo-l i t h i u m d e r i v a t i v e by treatment with t e r t - b u t y l l i t h i u m i n tetrahydrofuran (THF) at -78°C. On the basis of competing inductive and resonance e f f e c t s associated with the two methoxy groups i n (14), one would expect the a l l y l i c protons at C-6 to be more a c i d i c than those at C-3. Furthermore, l i t h i a t i o n at C-6 would undoubtedly be f a c i l i t a t e d by i n i t i a l a s s o c i a t i o n of the lithium atom of t e r t - b u t y l l i t h i u m with the oxygen atoms of the two methoxy groups, and i t i s reasonable to propose that the l i t h i a t e d species can be conveniently represented by structure (20) (Scheme 7). In any case, successive addition of hexamethylphosphoramide (HMPA) ( s l i g h t l y more than 1 equiv.) and a l k y l a t i n g agent to the so l u t i o n of the l i t h i a t e d intermediate (13) (14) 7 resulted i n smooth and e f f i c i e n t formation of the alkylated product (16) (Table 1).* In nearly every case, the product obtained by simple extractive work up and d i s t i l l a t i o n gave s a t i s f a c t o r y combustion a n a l y s i s . Only the i s o l a t i o n of an a n a l y t i c a l l y pure sample of (16f) required chromatographic p u r i f i c a t i o n , to remove approximately 9% of s t a r t i n g material. In each case i t was clear from glc and sp e c t r a l analyses of the product that the a l k y l a t i o n was very highly r e g i o s e l e c t i v e since no isomeric products could be detected. Scheme 7 (14) (20) (16) yOCH 3 X 0 C H 3 (16 a) R = -(CH 2) 3CH 3 06b) R = -(CH )2CH. = CH 2 (16 c) R = -(CH 2) 4CH 3 (16 d) R = -CH 2CH 2C 6H 5 (16 e) R = -(CH 2) 2CH = C(CH 3) 0 6 f) R = -(CH 2) 3CH = C(CH 3) (16g) R = -CH 3 This type of i n t e r n a l chelation which provides for r e g i o s e l e c t i v e (12) metalation has been amply demonstrated i n aromatic substrates 8 Table 1 A l k y l a t i o n of 1,5-dimethoxy-1,4-cyclohexadiene with a l k y l and alkenyl h a l i d e s . Entry 1 2 3 4 5 6 7 Moreover, a survey of the AH nmr spectra of compounds (16) confirmed that a l k y l a t i o n had indeed occurred, as anticipated, at the C-6 p o s i t i o n . Thus, i n each case, the nmr spectrum exhibited a r e a d i l y observed two-proton o l e f i n i c resonance (6 4.6-4.7) appearing as a broad t r i p l e t (J~3Hz) as a r e s u l t of being coupled to two adjacent and equivalent a l l y l i c protons at C-3. In contrast to these observations, i f a l k y l a t i o n had occurred at C-3 rather than C-6, then the two equivalent o l e f i n i c protons would surely have been observed as a doublet as a r e s u l t of being coupled to a si n g l e methine proton at C-3. A number of d i f f e r e n t reagents and procedures were investigated i n connection with the conversion of the alkyl a t e d products (16) i n t o the corresponding 1,3-cyclohexanediones (2_). Eventually i t was found that t h i s hydrolysis could be conveniently and e f f e c t i v e l y accomplished by treatment of compounds (16) with d i l u t e hydrochloric acid (IN) i n acetone (Scheme 8, A l k y l a t i n g Agent CH ( C H ^ I CH 2=CH(CH 2) 2Br CH 3(CH 2) 4I C 6 H 5 C H 2 C H 2 B r (CH 3) 2C=CH(CH 2) 2Br (CH 3) 2C=CH(CH 2) 3I CH 3I Product ( y i e l d %) 16a (99) I6b (99) JL6c (96) 16d (99) J_6e (98) _16f (88) 16g (98) 9 Table 2). However, the reactions were clean and high y i e l d i n g only i f precautions were taken to exclude oxygen from the reaction mixture. Thus, p r i o r to use, both the acetone and d i l u t e hydrochloric acid were thoroughly purged with a stream of nitrogen and the hydrolyses were ca r r i e d out under an atmosphere of nitrogen. I f these precautions were not followed, the products obtained were se r i o u s l y discoloured and the y i e l d s were considerably diminished. This i s understandable i n view of the previously mentioned s u s c e p t i b i l i t y of 1,3-cyclohexanediones to rapid autoxidation by a i r . Scheme 8 (2a) R = -(CH 2) 3CH 3 Qb) R = -(CH 2) 2CH=CH 2 a c ) R = -(CH 2) 4CH 3 (2d) R = -CH 2CH 2C 6H 5 (2e) R = -(CH 2) 2CH=C(CH 3) (2f) R = -(CH 2) 3CH=C(CH 3) (2g) R = -CH 3 10 Product ( y i e l d %) 2a (96) 2b (95) 2c (95) 2d (93) 2e (93) 2f (94) 2g (65) In each case the product was i s o l a t e d as a white c r y s t a l l i n e material. Glc analysis of these materials (OV-17 and OV-210) showed them to be consistently >96% pure. Furthermore, the i n i t i a l l y formed products exhibited '''H nmr spectra which were e s s e n t i a l l y i d e n t i c a l with those of a n a l y t i c a l l y pure samples obtained by r e c r y s t a l l i z a t i o n from benzene-heptane. The i n f r a r e d spectra of these c y c l i c 6-diketones, i n so l u t i o n (CHCl^ or CH^CN), a l l showed the c h a r a c t e r i s t i c v(C=0), v (C=C) and v(0H) absorptions at t r i b u t e d to the g-diketone s t r u c t u r a l f e a t u r e ( T a b l e 3). The *H nmr spectra of compounds Q2a-f), i n deuterochloroforrn s o l u t i o n , a l l c h a r a c t e r i s t i -c a l l y exhibited a C-2 methine resonance of the diketone tautomer (6 3.4-3.5) as a t r i p l e t (J=5-7Hz) which t y p i c a l l y integrated f o r 0.2-0.5 H. The u l t r a v i o l e t absorption spectra f o r compounds (2), i n ethanol s o l u t i o n , a l l exhibited a TT->TT e l e c t r o n i c t r a n s i t i o n of the enol tautomer at 261-262 nm 4 (e 1.49-1.56x10 ) which was i n close agreement with those predicted (14) (Xmax (EtOH) 267 nm ) c l e a r l y supporting the presence of a C-2 C3. J. C a l k y l and C-3 hydroxy substituent on the parent 2-cyclonex-1-one system. Table 2 Hydrolysis of compounds (16) Entry Diene 1 _16a 2 16b 3 Jjjc 4 _16d 5 16e 6 JL6f 7 16g Table 3 Selected i r , H nmr and uv sp e c t r a l properties for 11 compounds (2a-g) Compound i r absorption (cm "*") "*~H nmr ( 5 ) uv (95%) EtOH) v(O-H) (enol) v(C=0,C=0) (diketone) v(C=0,C=C) (enol) H(C-2) diketone tautomer max(nm)(e) 2a 3700-3150 1735, 1710 1620 3.36 261(1.51xl0 4) 2b 3500-3000 1715, 1695 1615 3.45 262(1.56xl0 4) 2c 3600-3100 1730, 1700 1620 3.39 262(1.52xl0 4) 2d 3650-3040 1740, 1710 1620 3.38 262(1.49xl0 4) 2.e 3600-3000 1730, 1700 1620 3.38 262(1.55xl04) 2f 3600-3100 1730, 1700 1620 3.38 262(1.42xl0 4) *2g 3600-3000 1720, 1695 1620 - 262(1.49xl0 4) * Due to the inherent i n s o l u b i l i t y of dione (2g) i n d^-chloroform the """H nmr spectrum of t h i s material was obtained i n d^-acetone. In t h i s solvent the dione (2g) was completely enolized. In addition, a c e t o n i t r i l e was the solvent of choice for obtaining a solution i r spectrum of t h i s material. 12 EXPERIMENTAL General Information Melting points were determined using a Fisher-Johns melting point apparatus and are uncorrected. B o i l i n g points are also uncorrected and those designated as air-bath d i s t i l l a t i o n s r e f e r to short-path (Kugelrohr) d i s t i l l a t i o n s . Infrared ( i r ) spectra were recorded on Perkin-Elmer model 710 or model 710B spectrophotometers and were c a l i b r a t e d using the 1601 cm ^  absorption band of polystyrene f i l m . U l t r a v i o l e t (uv) spectra were taken of ethanol or methanol solutions (as designated) and recorded on a Carey 15 spectrophoto-meter. The proton magnetic resonance ('''H nmr) spectra were taken of deutero-chloroform (CDC1 3) solutions using tetramethylsilane (TMS) as an i n t e r n a l standard. These spectra were recorded on the following instruments. 80 MHz Bruker WP-80 100 MHz Varian HA-100, XL-100 270 MHz *Composite instrument 400 MHz Bruker WH-400 Signal p o s i t i o n s are given i n parts per m i l l i o n (6) downfield from TMS and the m u l t i p l i c i t y , coupling constants, integrated peak areas (where p o s s i b l e ) , and proton assignments (where p o s s i b l e ) , are indicated i n parentheses. 13 Carbon-13 nuclear magnetic resonance ( C) spectra were taken of deutero-chloroform solutions using TMS as an i n t e r n a l standard and were recorded This instrument was comprised of an Oxford Instruments 63.4 KG super-conducting magnet and a Ni c o l e t 16 K computer attached to a Bruker TT-23 console. 13 on a Varian CFT-20 spectrometer. Low res o l u t i o n mass spectra were recorded with a Varian/MAT CH4B mass spectrometer. High reso l u t i o n mass spectra were recorded with a Kratos/AEI MS 50 or MS 902 mass spectrometer. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, University of B r i t i s h Columbia. 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 HP 5832A Gas Chromatography u n i t connected to a HP 18850A GC terminal or a l t e r n a t i v e l y on a Hewlett Packard HP 5880A c a p i l l a r y glc unit. The following columns were used: (a) packed columns OV-210 (5% on Chromosorb W(HP) 80-100 mesh), 6 f t x 0.125 i n OV-17 (5% on Chromosorb W(HP) 80-100 mesh), 6 f t x 0.125 i n SE-30 (10% on Chromosorb W(HP) 80-100 mesh), 10 f t x 0.125 i n (b) c a p i l l a r y columns Carbowax 20M, 12m x 0.21mm i d (Hewlett Packard) 0V-101, 12m x 0.21mm i d (Hewlett Packard) Preparative gas l i q u i d chromatography was performed on a Varian Aerograph model 90-P gas chromatograph using a SE-30 (~10% on Chromosorb W(HP), 10 f t x 0.25 in) column. Thin layer chromatography ( t i c ) was car r i e d out on commercial s i l i c a gel plates (Eastman 13181 or E. Merck s i l i c a gel 25b s ^ e e t p l a t e s ) . Preparative thin layer chromatography was car r i e d out on 20x20 cm glass plates coated with 0.9 mm of s i l i c a gel (E. Merck, s i l i c a gel 60). Column chromatography was done using 70-230 mesh s i l i c a gel (E. Merck) and f l a s h chromatography was done using 230-400 mesh s i l i c a gel (E. Merck). 14 A l l reactions r e q u i r i n g anhydrous conditions were done using glassware which was flame-dried under a flow of nitrogen or argon. A l l reactions were done under an i n e r t atmosphere, unless stated otherwise. Solvents and Reagents Solutions of methyllithium-lithium bromide, n-butyllithium, and t e r t -b u t y l l i t h i u m were obtained from the A l d r i c h Chemical Company, Inc. and were standardized using Gilman's p r o c e d u r e ^ ^ ^ . Lithium diisopropylamide (LDA) was prepared by the addition of a hexane s o l u t i o n of n-butyllithium (1.0 equiv) to a solution of d i i s o p r o p y l -amine (1.1 equiv) i n dry tetrahydrofuran (THF) at -78°C under argon. 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 -78°C f o r 15 minutes and then warmed to 0°C f o r 5 minutes before being used. The solvents were dried and p u r i f i e d (when necessary) by the following procedures. Tetrahydrofuran (THF), d i e t h y l ether and 1,2-dimethoxyethane were d i s t i l l e d from sodium benzophenone k e t y l ^ ^ C ^ under nitrogen. Triethylamine and diisopropylamine were d i s t i l l e d from calcium hydride. Hexamethylphosphoramide (HMPA) was d i s t i l l e d from barium oxide and d stored over 4A molecular sieves. 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 and stored over o 4A molecular sieves. Anhydrous ethanol was obtained by d i s t i l l i n g absolute ethanol from magnesium ethoxide. Chlorotrimethylsilane was obtained by d i s t i l l i n g commercial grade chlorotrimethylsilane (Aldrich) from 5% N,N-dimethylaniline. 15 Petroleum ether r e f e r s to the f r a c t i o n b o i l i n g at 30-60°C. Preparation of 1,5-Dimethoxy-1,4-cyclohexadiene (.1.4) CH3 CH3 OCH3 OCH3 (13) (14) Compound (14) was prepared according to the procedure reported by Birch (11) Thus, ammonia (700 mL, f r e s h l y d i s t i l l e d from sodium metal) was c o l l e c t e d i n a three-necked IL f l a s k equipped with a dry-ice condenser, an 1.3 mol) was added over a period of about 30 minutes while the ammonia was an a d d i t i o n a l 30 minutes. A s o l u t i o n of m-dimethoxybenzene (32.7 g, 0.24 mol) i n a mixture of anhydrous ether (100 mL) and ethanol (62.5 g, 1.36 mol) was added slowly over a period of 2 h. The mixture was s t i r r e d f o r an a d d i t i o n a l 1.5 h. The reaction mixture was quenched by the c a r e f u l addition of 75 mL of 1:1 ethanol-water, followed by water u n t i l a colourless s o l u t i o n was obtained. The condenser and addition funnel were removed from the f l a s k and the ammonia was allowed to evaporate. The remaining mixture was d i l u t e d with brine (700 mL) and thoroughly extracted with a 1:1 mixture of ether and petroleum ether (b.p. 30-60°C). The combined extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure, followed by d i s t i l l a t i o n of the remaining o i l , afforded 31.5 g (95%) of 1,5-dimethoxy-1,4-cyclohexadiene (1_4) as a a l l glass mechanical s t i r r e r , and an addition funnel. Sodium metal (30.0 g, vigorously s t i r r e d , and the resultant dark blue s o l u t i o n was s t i r r e d for 16 clear colourless o i l : bp 56°C/0.55 Torr [ l i t bp 95°C/18 T o r r V J " i y ] ; i r (film) v : 3090, 3010, 2960, 2925, 2850, 1690, 1665, 1590, 1440, 1390, 1360, 1230, 1200, 1140, 1005, 920, 885, 760 cm"1; *H nmr (100 MHz) 6 2.66-2.86 (unresolved 4 H , a l l y l i c protons), 3.47 (s, 6H, methoxy protons), 4.58 (br t, J~3Hz, 2H, v i n y l protons). Anal, calcd. f o r C 0H.„0 : C 68.55, H 8.63; found: C 68.74, H 8.80. General procedure f o r the preparation of 6-Alkyl- and 6-Alkenyl-i ?5-dimethoxy- 1,4-cyclohexadienes (16a-g) 0 C H 3 (16) (2a) R = -(CH 2) 3CH 3 (2e) R = (2b) R = -(CH 2) 2CH=CH 2 (2f) R = (2c) R = -(CH 2) 4CH 3 (Jg) R = (_2d) R = -CH 2CH 2C 6H 5 '2'2 y 3 c '3'2 V 2 Table 4 Reagents and molar qu a n t i t i e s used i n the preparation of compounds (16 a-g) RLi (equiv) A l k y l a t i n g agent (equiv) HMPA (equiv) 1.07 CH 3(CH 2) 3I (1.30) 1.33 1.11 CH 2=CH(CH 2) 2Br (1.31) 1.17 1.09 CH 3(CH 2) 4I (1.09) 1.02 1. 11 C 6 H 5 C H 2 C H 2 B r (1.11) 1.33 1.09 (CH 3) 2C=CH(CH 2) 2Br (1.10) 1.04 1.08 (CH 3) 2C=CH(CH 2) 3I (1.04) 1.04 1.11 CH 3I (1.08) 1.08 17 To a s o l u t i o n of t e r t - b u t y l l i t h i u m (Table 4) i n cold (-78°C) anhydrous tetrahydrofuran (40 mL per 1.0 g of substrate), under an atmosphere of nitrogen, was added 1,5-dimethoxy-1,4-cyclohexadiene (14) (1.0 or 2.0 g s c a l e ) , and the resultant s o l u t i o n was s t i r r e d for an a d d i t i o n a l 1 h. Hexamethylphosphoramide (HMPA) was next added and s t i r r i n g was continued for an a d d i t i o n a l 10 minutes. Addition of the appropriate a l k y l or alkenyl h a l i d e to the cold s o l u t i o n resulted i n a rapid change i n colour of the reaction mixture (maroon to l i g h t brown). This mixture was allowed to warm to room temperature, followed by d i l u t i o n with brine (50 mL) and then extracted with pentane (3x50 mL). The combined pentane extracts were washed with brine and then dried over anhydrous magnesium s u l f a t e . Removal of the solvent from the combined extracts followed by d i s t i l l a t i o n of the resultant brown o i l afforded the corresponding 6-alkyl or 6-alkenyl-1,5-dimethoxy-1,4-cyclohexadiene (16). Only i n the case of compound (16f) was chromatographic p u r i f i c a t i o n ( s i l i c a g e l , pet. ether (30-60°C)/ether) necessary to obtain an a n a l y t i c a l l y pure sample. The following compounds were obtained by t h i s procedure: 6-Butyl-1,5-dimethoxy-1,4-cyclohexadiene (16a): (99% y i e l d ) : d i s t i l l a t i o n temperature ( a i r bath) 80-85°C/0.4 Torr; i r (film) v : 3060, r" max 2990, 2950, 2870, 2825, 1670, 1645, 1580, 1450, 1430, 1370, 1355, 1310, 1180, 1130, 1105, 1000, 930, 740 cm"1; *H nmr (100 MHz) 6: 0.80 ( t , J=7Hz, 3H, -(CH 2) 3CH 3), 1.00-1.38 (m, 4H), 1.48-1.76 (unresolved m, 2H), 2.60-2.90 (m, 3H, a l l y l i c protons), 3.46 (s, 6H, -0CH 3), 4.60 (broad t, J=3Hz, 2H, v i n y l protons); Exact mass calcd. for ^^2^20^2: 196.1463; found 196.1464; Anal, calcd. f o r C 1 2 H 2 0 ° 2 : C 7 3 ' 4 3 ' H 1 0- 2 7> found: C 73.16, H 10.27. 18 6-(3-Butenyl)-1,5-dimethoxy-l,4-cyclohexadiene (16b) : (99% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 55-60°C/0.1 Torr, i r ( f i l m ) v : 3090, max 3020, 2950, 2850, 1690, 1660, 1640, 1610, 1450, 1390, 1320, 1300, 1140, 1020, 985, 955, 900, 760 cm"1; *H nmr (100 MHz) 6: 1.70-2.02 (unresolved m, 4H, -CHJ^H„CH=CH 0), 2.66-3.04 (m, 3H, a l l y l i c r i n g protons), 3.50 (s, 6H, —I—z z -OCH^), 4.68 (t, J=4Hz, 2H, v i n y l r i n g protons), 4.76-5.06 (unresolved m, 2H, -(CH2)2CH=CH_2) , 5.56-6.02 (unresolved m, lH, - (CH 2) 2~CH=CH 2) ; Exact mass calcd. f o r C 1 0H 0 : 194.1306; found: 194.1306. Anal, calcd. f o r lz lo L C. oH l o0_: C 74.19, H 9.34; found: C 74.00, H 9.38. lz lo z 1,5-Dimethoxy-6-pentyl-1,4-cyclohexadiene (16c): (96% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 60-67°C/0.25 Torr; i r ( f i l m ) ~ : 3080, r max 3010, 2960, 2875, 2840, 1685, 1660, 1610, 1590, 1460, 1450, 1390, 1220, 1200, 1140, 1120, 1020, 950, 760 cm"1; *H nmr (100 MHz) 6: 0.83 ( t , J=6Hz, 3H, -(CH„).CH„), 1.10-1.35 (m, 6H), 1.55-1.80 (m, 2H), 2.64-2.94 (m, 3H, a l l y l i c 2 4—3 protons), 3.42 (s, 6H, -OCH^), 4.60 (br t, J~3Hz, 2H, v i n y l protons); Anal, calcd. f o r C 1 3 H 2 2 0 2 : C 7 4- 2 4> H 10.54; found: C 74.35, H 10.47. 1,5-Dimethoxy-6-(2-phenylethyl)-1,4-cyclohexadiene (166.)^^: (99% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 107-110°C/0.25 Torr [ l i t . b.p. 163-164°C/2 T o r r ( U ) ] ; i r ( f i l m ) v : 3090, 3050, 3030, 2960, 2840, 1690, max 1650, 1600, 1490, 1450, 1390, 1220, 1200, 1140, 1030, 950, 760, 730, 680 cm"1; *H nmr (100 MHz) 6: 1.92-2.20 (m, 2H), 2.38-2.58 (m, 2H), 2.68-2.86 (m, 2H), 2.90-3.12 (m, IH), 3.42 (s, 6H, -0CH_3), 4.62 (t, J=4Hz, 2H, v i n y l protons), 6.96-7.20 (unresolved m, 5H, aromatic protons); Anal, calcd. f o r Cj^H^O,,: C 78.65, H 8.25; found: C 78.59, H 8.03. 19 1,5-Dimethoxy-6-(4-methyl-3-pentenyl)-1,4-cyclohexadiene Q6e) : (98% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 60-65°C/0.25 Torr; i r ( f i l m ) v : 3080, 2950, 2875, 2850, 1685, 1655, 1590, 1445, 1385, 1280, 1220, 1140, max 1040, 1020, 950, 805, 760 cm"1; *H nmr (100 MHz) 6: 1.56, 1.65 (s, s, 6H, -CH=C(CH 3) 2), 1.70-1.90 (m, 4H), 2.70-3.00 (m, 3H, a l l y l i c r i n g protons), 3.53 (s, 6H, -0CH 3), 4.72 (t, J=3Hz, 2H, v i n y l r i n g protons), 5.02-5.22 (m, IH, -CH=C(CH 3) 2; Anal, calcd. for C 1 4 H 2 2 0 2 : C 7 5' 6 3> H 9 ' 9 7 ^ f°und: C 75.58, H 9.79. 1, 5-Dimethoxy-6- (5-methyl-4-hexenyl)- 1,4-cyclohexadiene (16f ) : (88% y i e l d ) ; i s o l a t e d from the reaction d i s t i l l a t e by column chromatography ( s i l i c a g e l , pet. ether (b.p. 30-60°C)/ether); d i s t i l l a t i o n temperature ( a i r bath) 65-70°C/0.08 Torr; i r ( f i l m ) v : 3075, 3000, 2950, 2860, 2840, ' max 1680, 1580, 1440, 1380, 1360, 1220, 1200, 1140, 750 cm"1; *H nmr (100 MHz) 6: 1.05-1.33 (m, 2H), 1.58, 1.68 (s, s, 6H, -CH=C (CHg^), 1.68-2.10 (m, 4H), 2.70-3.00 (m, 3H, a l l y l i c r i n g protons), 5.00-5.20 (unresolved m, IH, -CH=C(CH 3) 2); Anal, calcd. f o r C 1 5 H 2 4 ° 2 : c 76.23, H 10.24; found: C 76.15, H 10.14. 1,5-Dimethoxy-6-methyl-1,4-cyclohexadiene (16g): (98% y i e l d ) ; d i s t i l l a t i o n ( a i r bath) 40-45°C/0.2 Torr; i r ( f i l m ) v : 3060, 3000, 2950, max 2910, 2845, 1685, 1450, 1375, 1220, 1195, 1140, 1100, 1050, 950, 780, 685 cm"1; *H nmr (100 MHz) 6: 1.23 (d, J=6Hz, 3H, -CHg), 2.70-2.90 (m, 3H, a l l y l i c protons), 3.53 (s, 6H, -OCH^), 4.63 (brt, J~3Hz, 2H, v i n y l protons); Anal, calcd. for CgH^O^ C 70.10, H9.15; found: C 70.05, H. 9.00. 20 General procedure for the preparation of 2-alkyl- and 2-alkenyl-1,3- cyclohexanediones (2a-f) (2a) R = -(CH 2) 3CH 3 (2b) R = -(CH 2) 2CH=CH 2 (2c) R = -(CH 2) 4CH 3 (2d) R = -CH 2CH 2C 6H 5 (2e) R = -(CH 2) 2CH=C(CH 3) 2 (2f) R = -(CH 2) 3CH=C(CH 3) 2 To a so l u t i o n of the appropriate 6-alkyl- or 6-alkenyl-1,5-dimethoxy-1,4-cyclohexadiene (0.2 to 0.5 g) i n acetone (12 mL, spectrograde, previously purged with a stream of nitrogen f o r 15 min) was added, with vigorous s t i r r i n g , IN aqueous hydrochloric acid (4 mL, previously purged with a stream of nitrogen f o r 15 min). The resultant s o l u t i o n was s t i r r e d f or 1 h. The acetone was removed under reduced pressure, the residue was di l u t e d with brine (10 mL), and the mixture was then extracted with methylene chloride (4 x 10 mL). The combined extracts were dried over anhydrous magnesium s u l f a t e . Removal of the solvent afforded the corresponding 1,3-cyclohexanedione as a c r y s t a l l i n e s o l i d . These diones were shown by glc analysis (0V-17 or OV-210) to be consistently >96% pure, and exhibited i r and nmr spectra which were e s s e n t i a l l y i d e n t i c a l with those of a n a l y t i c a l samples obtained by r e c r y s t a l l i z a t i o n from benzene-heptane. 2-Butyl-1,3-cyclohexanedione (2a): (96% y i e l d ) ; mp 116-117°C; [ l i t . mp . .115-116°C ( 3' ), 112-113°C <- 1 7' ) ; d i s t i l l a t i o n temperature (air-bath) 165°C/0.05 Torr; uv (ethanol) X : 261 nm (e 1. 51 x 10 4); i r (CHC1„ soln) ; v : 3700-2800 (broad), 1735 max 3 max 1710, 1620, 1380, 1175, 1110, 910 cm"1; *H nmr (100 MHz) 6: 0.88 (t, J=6.5Hz, 21 3H, -CH 3), 1.16-1.55 (m, 4H), 1.55-2.80 (di f f u s e m, 8H), 3.36 ( t , J=6Hz, -0.5H, C-2 proton of diketone tautomer), 7.52-7.94 (diffuse s, ~0.5H, -OH of enol tautomer); Exact mass calcd. for C H O : 168.1150; found: 10 16 z 168.1142; Anal, calcd. for C 1.H 1.0 o: C 71.39, H 9.59; found: C 71.08, ' 10 16 2 H 9.59. 2- (3 -Butenyl)-l,3-cyclohexanedione (2b): (95% y i e l d ) ; mp 95-96°C mp [ l i t . 95-97.5°C ( 4 ), 92.5-93.5°C ( 1 7 )] ; d i s t i l l a t i o n temperature ( a i r bath) 140°C/0.5 Torr; uv(ethanol) X : 262 nm (e 1.56 x 10 4); i r ( C H C l . soln) max J v : 3570, 3500-3000 (broad), 1715, 1695, 1615, 1370, 1170, 1105 cm"1; max LH nmr (100 MHz) 6: 1.74-2.28 (m, 4H), 2.28-2.76 (m, 6H), 3.45 ( t , J~5Hz, -0.2H, C-2 proton of diketone tautomer), 4.84-5.16 (unresolved m, 2H, -CH=CHp; Exact mass calcd. f o r C 1 0 H 1 4 ° 2 : 166.0994; found: 166.0994. Anal, calcd. for C ^ ^ ^ C 72.26, H 8.45; found: C 72.27, H 8.49. 2-Pentyl-1,3-cyclohexanedione (2c): (95% y i e l d ) ; mp 91-95°C; uv(ethanol) X : 262 nm (e 1.52 x 10 4) ; i r ( C H C l 3 soln) v ^ : 3610, 3600-3100 (broad), 3075, 3050, 3000, 2940, 1730, 1700, 1620, 1460, 1420, 1380, 1260, 1170, 1105, 910 cm"1; *H nmr (100 MHz) 6: 0.75-1.00 (t, J=6Hz, 3H, -CH 3), 1.10-1.50 (m, 6H), 1.70-2.15 (m, 3H), 2.15-2.75 (m, 5H), 3.39 (t, J~7Hz,~0.2H, C-2 proton of diketone tautomer); Anal. calcd. for C H O : 11 l o z C 72.49, H 9.95; found: C 72.41, H.9.85. 2-(2--Phenylethyl)-l, 3-cy clohexanedione (2d) : (93% y i e l d ) ; mp 149-150°C [ l i t . mp 1 4 7 - 1 4 8 ° C ( 1 1 ) ] ; uv(ethanol) X : 262 nm (e 1.49 x 10 4); i r r max (CHC1 0 soln) v : 3650-3040 (broad), 3025, 2975, 1740, 1710, 1620, 1490, 3 max 22 1450, 1380, 1280, 1180, 1160, 1140, 1080, 1020, 910 cm x ; *H nmr (100 MHz) 6: 1.80-2.38 (m, 4H), 2.38-2.80 (m, 6H), 3.38 (t, J=6Hz, ~0.5H, C-2 proton of diketone tautomer), 7.10-7.30 (unresolved m, 5H, aromatic protons); Anal, calcd. for C-.H.-O,,: C 77.75, H 7.46; found: C 77.93, H 7.40. 14 16 I 2- (4-Methyl-3-pentenyl)-l, 3-cyclohexanedione (2_e) : (93% y i e l d ) : 4 — mp 117-120°C; uv(ethanol) A : 262 nm (e 1.55 x 10 ); ir(CHCl„ soln) v : max 3 max 3600-3000 (broad), 2950, 2875, 1730, 1700, 1620, 1440, 1380, 1170, 1150, 1130 cm"1; ^ nmr (100 MHz) 6: 1.58, 1.70 (s, s, 6H, -CH=C (CH >2>, 1.80-2.20 (m, 4H), 2.20-2.72 (m, 6H), 3.38 ( t , J=6Hz, ~0.6H, C-2 proton of diketone tautomer), 5.00-5.30 (unresolved m, IH, -CH=C(CH ) ^ ) , 7.36 (s, ~0.4H, -OH of enol tautomer); Anal, calcd. for C 1 oH. o0 : C 74.19, H 9.34; found: 1/ lo z C 74.20, H 9.47. 2- (5-Methyl-4-hexenyl)- 1, 3-cyclohexanedione (_2f) : (94% y i e l d ) : mp 87-89°C; uv(ethanol) X : 262 nm (e 1.42 x 10 4); i r ( C H C l 3 soln) v^^: 3600-3100 (broad), 2950, 1730, 1700, 1620, 1445, 1420, 1370, 1270, 1175, 1130, 1100, 1065 cm"1; XH nmr (100 MHz) 6: 1.58, 1.68 (s, s, 6H, -CH=C(CH 3) 2, 1.30-2.70 ( d i f f u s e m, 12H), 3.38 (t, J=6Hz, ~0.3H, C-2 proton of diketone tautomer), 5.00-5.25 (unresolved m, IH, -CH=C ( C H ^ ; Anal, calcd. f o r C 1 3 H 2 0 ° 2 : C 7 4 ' 9 6 ' H 9 , 6 8 ; found: C 74.90, H 9.56. 23 Preparation of 2-Methyl-l,3-cyclohexanedione (2g): (2g) The hydrolysis procedure employed i n the hydrolyses of compounds (2a-f) was used here (0.405 g (2g)) with the exception of the i s o l a t i o n procedure. Compound (2g) was i s o l a t e d i n s o l i d form a f t e r removal of the acetone, under reduced pressure, from the reaction s o l u t i o n . This s o l i d was washed with a minimum amount of i c e - c o l d water (4-6 mL) and then dried (0.2 Torr) f o r 12 h at room temperature a f f o r d i n g 0.217 g (65%) of 2-methy 1-1,3-cyclohexanedione (_2g) which exhibited: mp 205-208°C [ l i t . mp 208-210 C ( d e c ) ( 1 ) ] ; uv(ethanol) X : 261 nm (e 1.49 x 10 4); ir(CHCl_ soln) max 3 ~ : 3600-3000 (broad), 1695, 1620, 1185, 1090 cm"1; *H nmr (100 MHz, d 6 -max acetone) 6: 1.65 (s, 3H, -CH^ of enol tautomer), 1.98 ( m, C-5 methylene of enol tautomer), 2.36 ( t , J=6.5Hz, 4H, C-6 and C-4 methylenes of enol tautomer); Anal, calcd. f o r c 7 H 1 o ° 2 : C 6 6 ' 6 5 ' H 7 - 9 9 5 found: C 66.66, H 8.00. 24 REFERENCES 1. A.M. Mekler, S. Ramachandran, S. Swaminathan, and M.S. Newman, Org. Synth., 41, 56 (1961). 2. H. Stetter and W. Di e r i c h s , Chem. Ber., 94, 1061 (1961). 3. K. W. Rosenmund and H. Bach, Chem. Ber., 94_, 2394 (1961). 4. W.S. Johnson, W.H. Lunn, and K. F i t z i , J . Am. Chem. S o c , 86, 1972 (1964). 5. H. Stetter i n , Newer Methods of Preparative Organic Chemistry. Vol. 2, Edited by W. Foerst. Academic Press, New York, NY. 1963, p. 51. 6. H.O. House, Modern Synthetic Reactions, second e d i t i o n , W.A. Benjamin Inc., Menlo Park, C a l i f . , 1972, pp 520-530, and references c i t e d therein. 7. E.C. Taylor and A. McKillop, Acc. Chem. Res., J3, 330 (1970). 8. J . Hooz and J. Smith, J . Org. Chem., 37, 4200 (1972). 9. J.M. Mcintosh and P.M. Beaumier, Can. J . Chem., 51, 843 (1973). 10. E. Pi e r s and J.R. Grierson, J. Org. Chem., 42, 3755 (1977). 11. A.J. Birch, J. Chem. S o c , 102 (1947); i b i d , 1551 (1950); i b i d , 1882 (1951). 12. a) R.A. E l l i s o n and F.N. Kotsonis, J. Org. Chem., 24, 4192 (1973); b) M. Uemura, S. Tokuyama and T. Sakan, Chem. L e t t . , 1195 (1975); c) R.C. Ronald, Tet. L e t t . , 3973 (1975); d) F.E. Z e i g l e r and K.W. Fowler, J. Org. Chem., 41, 1564 (1976); e) L. Barsky, H.W. Gschwend, J . McKenna, and H.R. Rodriguez, J. Org. Chem., 41, 3651 (1976). 13. K. Nakanishi and P.H. Solomon, Infrared Absorption Spectroscopy, Holden-Day Inc., San Francisco, 1977, pp. 66-72. 25 14. D.J. Pasto and CR. Johnson, Organic Structure Determination, P r e n t i c e - H a l l , Englewood C l i f f s , N.J.,' 1969. 15. M. J u l i a , S. J u l i a , and R. Guegan, B u l l . Soc. Chim. Fr., 1072 (1960). 16. M.F. Anselland, S.S. Brown, J. Chem. S o c , 1789 (1957). 17. a) T. Fukuyama, L.V. Dunkerton, M. Aratani, and Y. K i s h i , J . Org.  Chem., 40, 2011, (1975); b) H. Gilman and F.K. Cartledge, J. Organometal. Chem., _2, 447 (1964); c) A.J. Gordon and R.A. Ford, "The Chemists Companion: A Handbook  of P r a c t i c a l Data, Techniques and References", J. Wiley and Sons, New York, (1972), p. 439. 26 AN INVESTIGATION INTO THE REGIOSELECTIVE FORMATION OF g-IODO a,B-UNSATURATED KETONES FROM UNSYMMETRICAL 1,3-CYCLOHEXANEDIONES GENERAL INTRODUCTION g-Halo a,|3-unsaturated ketones ((21)X =CI, Br, I, Scheme 9) are useful (18-44) intermediates i n organic synthesis . H i s t o r i c a l l y though, the use of t h i s class of compounds has been r e s t r i c t e d to the B-chloro a,6-unsaturated ketones ((21), X = CI) (g-chloro enones) which have been known for a long time and have served as u s e f u l intermediates i n the synthesis of a large (18) v a r i e t y of a l i p h a t i c and h e t e r o c y c l i c compounds . The main i n t e r e s t i n t h i s class of compounds has stemmed from the r e a c t i v i t y that the B-halo substituent confers upon the a,6-unsaturated enone system towards the conjugate addition of n u c l e o p h i l i c species. The products of these reactions were a,B-unsaturated ketones i n which the g-halo substituent had been displaced, i n an o v e r a l l sense, by the n u c l e o p h i l i c species employed. This s u b s t i t u -t i o n or displacement reaction i s thought to proceed v i a the i n i t i a l conjugate addition of the n u c l e o p h i l i c species to the g-halo enone system followed by the f a c i l e elimination of a h a l i d e ion from the r e s u l t i n g intermediate, providing the corresponding s u b s t i t u t i o n product (Scheme 9). Scheme 9 Nuc conjugate addition elimination 27 In t h i s regard, the synthetic u t i l i t y of g-chloro enones has been p a r t i c u l a r l y w e l l established since the chloro substituent has been displaced s u c c e s s f u l l y by a wide v a r i e t y of oxygen, nitrogen, s u l f u r and carbon (18-35) nucleophiles . U n t i l recently, however, the e f f i c i e n t s u b s t i t u t i o n of the chloro group by carbon nucleophiles had been accomplished only when the carbanions were r e l a t i v e l y highly s t a b i l i z e d (e.g. conjugate bases of malonic ester derivatives (24), g-keto esters (25), trimethylsulfoxonium chloride (26), e t c . ) . In addition, the incorporation of less highly functionalized s u b s t i -tuents at the g-carbon, such as with simple a l k y l and alkenyl groups, had been accomplished with d i a l k y l - and dialkenylcadmium reagents, although (18) the y i e l d s were generally poor to mediocre (Scheme 10). Scheme 10 CdR„ CH3C0CH=CHC1 (27) CH3C0CH=CHR (28) Y i e l d % (28), -R 18 18 50 -CH 3 -CH=CHCH, - i " c 5 H n 28 Lately, the synthetic i n t e r e s t i n the use of g-halo enones (21) (32 37-44) has been renewed ' . Recently, i t has been demonstrated that (3-halo enones are excellent acceptors i n the transfer of simple or func-t i o n a l i z e d organic substituents from l i t h i o ( p h e n y l t h i o ) c u p r a t e reagents ( i . e . , C^H^S(R)-CuLi, Scheme 11) r e s u l t i n g i n the net displacement* of a halogen for a carbon based substituent. Several aspects of t h i s reaction are p a r t i c u l a r l y noteworthy with regard to the g-halo enone employed, the type of R group that may be transferred, and the u t i l i t y of the products that may be derived by t h i s * The mechanism of the transfer of a l k y l groups from organocuprate reagents to the 3-position of conjugated ketones i s s t i l l uncertain. One suggestion i s that reaction takes place by one electron transfer from the organocopper(I) species to the ketone to form a r a d i c a l anion, followed by the transfer of an a l k y l r a d i c a l f r om the metal to the (45) 3-carbon atom . This o v e r a l l process has been shown to a f f o r d enolate anions of type (a). Thus, i t i s reasonable to presume that reaction of g-halo enones with organocuprate reagents might a f f o r d a s i m i l a r intermediate which would, a f t e r f a c i l e elimination of a halide ion from the r e s u l t i n g enolate anion (b), provide an enone r e s u l t i n g from the net displacement of halogen. 0 1 ll R R CuLi i I I R R CuLi 0 •A. + X e 29 Scheme 11 R= a l k y l alkenyl cyclopropyl 2-vinylcyclopropyl (21) (29) X= Cl,Br,I process. Although g-chloro enones have been investigated as p o t e n t i a l (37) substrates i n t h i s type of process , preliminary investigations indicated that the corresponding g-bromo and g-iodo enones were superior i n terms of (44) the e f f i c i e n c y with which the transfer reactions took place . These cuprate reactions have provided a generally e f f i c i e n t method v i a which even substituents such as t e r t - b u t y l and sec-butyl may be incorporated into (44) hindered substrates such as (30) and (31) (Scheme 12) Scheme 12 (30) C tH_S(tert-C.H.)CuLi 0 D 4 9 THF, 0 C, 2.5h (32) (31) C H S ( t e r t - C . H n ) C u L i o :> 4 9 r THF, 22°C, 2.5h (33) (30) C,H S(sec-C.H n)CuLi b i> — — 4 9 THF, -20 C, 2.5h (34) 30 Furthermore, amongst the groups that may be e f f i c i e n t l y transferred, the cyclopropane, and 2-vinylcyclopropane systems have been p a r t i c u l a r l y (38) u s e f u l i n that they have allowed f o r the d i r e c t formulation of f i v e (43) and seven membered r i n g systems i n projected natural product syntheses (Schemes 13 and 14 r e s p e c t i v e l y ) . Scheme 13 31 Previous studies related to the preparation of B-halo a,B-unsaturated  ketones from B-diketones and triphenylphosphine d i h a l i d e s The synthesis of B-chloro a,B-unsaturated ketones from B-diketones has been c a r r i e d out by the treatment of the l a t t e r substances with a d i v e r s i t y of reagents: phosphorus t r i c h l o r i d e (43) phosphorus oxychloride ( 4 4 ) ^ ^ ' " * 4 \ phosgene (45) , a c e t y l chloride (46) , triphenylphosphine d i c h l o r i d e (47) } o x a l y l chloride (48) ^ ' 4 ^ , and (59) triphenylphosphine-carbon tetrachloride(49) . Of these^he l a t t e r two appear to be the best i n terms of convenience and e f f i c i e n c y . reagents: PCI. P0C1 C0C1„ CH.C0C1 (C,H.).PC1 0 ( C 0 C 1 ) o (C,H ) P/CC1. 3 3 I 3 6 5 3 Z 2 6 5 3 4 (43) (44) (45) (46) (47) (48) (49) ( c o c i ) 2 Benzene (50) 91% R ( C 6 H 5 ) 3 P / C C 1 4 « • Y i e l d % 85 'R (a) R=H •Cl 0>) R=CH 3 81 (51) ( 4 ) Cl 81% (53) 32 Conversion of B-diketones into B-bromo enones has t r a d i t i o n a l l y been accomplished by t r e a t i n g the former substances with phosphorus tribromide (54)( 4^,53,60)^ although the y i e l d of the process does not appear to be very high. More recently, t h i s type of conversion has been accomplished (59) employing triphenylphosphine-carbon tetrabromide(55_) and t r i p h e n y l -(58) phosphine dibromide (56) REAGENT REAGENT Y i e l d % PBr 3(54) 43 (C 6H 5) 3P/CBr 4(55) 85 (50) / (57) (C 6H 5) 3PBr 2(56) 93 (58) (61) P r i o r to studies i n i t i a t e d and continued i n our laboratory, the d i r e c t conversion of B-diketones into B-iodo a,B-unsaturated ketones had not been accomplished. These studies, however, had resulted i n the development of an e f f i c i e n t method for the conversion of c y c l i c B-diketones into t h e i r corresponding B-chloro, B-bromo and B-iodo enones a l l based on a common reaction process (Scheme 15). Scheme 15 33 S p e c i f i c a l l y , when these B-diketones (Table 5) and triethylamine were added to suspensions of eit h e r f r e s h l y prepared triphenylphosphine d i c h l o r i d e or triphenylphosphine dibromide i n benzene and the resultant mixtures were s t i r r e d at room temperature ( t y p i c a l l y 1-7 h), uniformly excellent y i e l d s of the corresponding B-chloro or B-bromo enones, respectively could be obtained d i r e c t l y . Table 5 Reaction of c y c l i c B-diketones with triphenylphosphine d i c h l o r i d e and dibromide. B-Diketone Reagent A B Reaction time at r . t . Y i e l d of B-halo enone A B A B lh 3h 4h 4h l h 3h 91 97 97 96 94 93 (50) (59) 7h 4h 90 91 ( I D A B 4h 4h 92 93 Reagent A: (CfiH ) PC1 2; Reagent B: ( C g H ^ P B r ^ solvent = benzene 34 However, the extension of t h i s method to the preparation of the analogous B-iodo enones employing triphenylphosphine d i i o d i d e f a i l e d to produce any of the desired compounds. Indeed, monitoring of the course of the reaction by th i n layer chromatography ( t i c ) showed that, even though no s t a r t i n g material had remained, only trace quantities of the corresponding B-iodo enone had formed. Fortunately however, i t was l a t e r discovered that evaporation of the solvent, followed by heating of the r e s i d u a l material to 145-160°C under reduced pressure with d i r e c t d i s t i l l a t i o n of the product, gave the iodo enones i n f a i r y i e l d (Scheme 16, Table 6). Scheme 16 (58) 1. ( C 6 H 5 ) 3 P I 2 , Et 3N C,H, 20-24h, r . t . 6 6, 2. A , 145-165°C (10-12 Torr) X=I In e f f o r t s to improve t h i s s i t u a t i o n , the use of a more polar reaction medium was investigated. Indeed, i t was found that the reaction of various B-diketones with triphenylphosphine diiodide-triethylamine i n dry a c e t o n i t r i l e at room temperature produced d i r e c t l y improved y i e l d s of the corresponding B-iodo enones. However, even when th i s solvent system was used, the reactions at room temperature were very slow and, 35 (58" ) Table 6 : Reaction of some selected c y c l i c B-diketones with t r i p h e n y l - phosphine d i i o d i d e i n benzene. B-Diketone Reaction time at r . t . Y i e l d Of B-iodo.enone (1) 20h 46 (2s) 24h 60 (50) t y p i c a l l y , reaction times of four days were required for complete conversion of the s t a r t i n g materials into the desired products. Eventually, i t was found that the y i e l d s could be improved s t i l l further and the reaction times reduced to a matter of hours by carrying out the reactions at elevated temperatures ( r e f l u x i n g a c e t o n i t r i l e ) . Under these conditions i t was possible to obtain co n s i s t e n t l y good to excellent y i e l d s of the B-iodo enones and t h i s procedure, with few e x c e p t i o n s ' 1 ^ , i s the preferred one. A comparative summary of these r e s u l t s appears i n Table 7. Based on these observations a generalized mechanistic scheme for the formation of these B-halo enones was formulated. I t appeared l i k e l y that the conversion of these B-diketones occurred v i a the intervention of 36 Table Redaction of symmetrical B-diketones with triphenylphosphine di i o d i d e - t r i e t h y l a m i n e . g-Diketone Procedure Reaction time (h) Y i e l d of g-iodo enone (1) A B C 20 96 9 46 72 87 (2g) A B C 24 96 9 60 73 73 CH 2CH=CH 2 (60) 96 80 CH 2 CH 2 CH=CH 2 (2b) 86 (50) A B 24 96 62 83 (9) 85 ( I D A C 24 3 71 92 (a) Procedure A: benzene, r . t . , followed by concentration and d i s t i l l a t i o n of the residue (see text) Procedure B,C: a c e t o n i t r i l e , r . t . and r e f l u x , respectively 37 the phosphonium s a l t (61) (Scheme 17) , formed by the reaction of the enolate anion of the g-diketone with triphenylphosphine d i h a l i d e . Conjugate addition of halide ion to (61), followed by elimination of t r i p h e n y l -phosphine oxide from the r e s u l t i n g intermediate (62) would a f f o r d the desired products. Scheme 17 (21) (62) The Objective P r i o r to the work discussed i n t h i s t h e s i s , an i n v e s t i g a t i o n i n t o the r e g i o s e l e c t i v i t y of g-iodo a,g-unsaturated ketone formation from unsymmetrical c y c l i c g-diketones had not been reported. In f a c t , a l l recent studies r e l a t e d to the a p p l i c a t i o n of g-heterosubstituted a,g-unsaturated c y c l i c ketones have u t i l i z e d symmetrical precursors. In the i n t e r e s t of producing g-halo enones more highly substituted than those previously mentioned, that might be useful as p o t e n t i a l intermediates i n organic synthesis, a study into the r e g i o s e l e c t i v e formation of g-iodo 38 enones from unsymmetrical 1,3-cyclohexanediones with triphenylphosphine d i i o d i d e was undertaken, as outlined i n Scheme 18. Scheme 18 (67) (68) Furthermore, the choice to employ triphenylphosphine d i i o d i d e rather than the d i c h l o r i d e or dibromide was based on the premise that iodide, being the larges t of the three r e a d i l y a v a i l a b l e halides (CI, Br, I ) , would display the greatest r e g i o s e l e c t i v i t y towards 3-halo enone formation. DISCUSSION As outlined above, the reaction of triphenylphosphine d i i o d i d e with unsymmetrically substituted 1,3-cyclohexanediones i s the subject of the work described within t h i s section of the the s i s . The substrates (63 a-h) deemed necessary for t h i s i n v e s t i g a t i o n were prepared i n a straightforward manner. Entry into t h i s c l a s s of compounds was based on a report by Stork 39 demonstrating that the monoalkylation of the B-alkoxy a, (3-unsaturated ketone (69a) (Scheme 19) could be effected i n an e n t i r e l y r e g i o s e l e c t i v e manner affording enones of generalized type (70). These a l k y l a t i o n s were e s p e c i a l l y e f f i c i e n t with reactive ( a l l y l i c ) halides. It was thus a simple matter to next l i b e r a t e the desired g-diketones from these latent precursors by mild aqueous hydrolysis. (63) (a) R=H, R = CH„ » J (b) R=H, R = CH2CH=CH2 (c) R=H, R = CH_CH„CH_ t 2 z j (d) R=H, R = CH(CH 3) 2 (e) R=CH , R = CH (f) R=CH3, R = CH2CH=CH2 (g) R=CH3, R = CH 2CH 2CH 3 (h) R=CH3, R = CH(CH 3) 2 Thus, the k i n e t i c a l l y formed (lithium diisopropylamide (LDA), t e t r a -hydrofuran (THF), -78°C) enolate anions of the i s o b u t y l enol ethers (69a) and (69b) (Scheme 19) were alkyla t e d with methyl iodide, a l l y l bromide, and isopropyl iodide. Although the a l k y l a t i o n (THF solution) of the enolate anions with the former two a l k y l a t i n g agents proceeded i n excellent y i e l d s ((70a): 95%, (70b): 93%, (70e): 94%, (70f) : 95%), s i m i l a r reactions ( 62^ i n v o l v i n g isopropyl iodide gave, not unexpectedly , poor y i e l d s of the desired products (70d) (16%) and (70h) (13%), even when hexamethylphospho-ramide (HMPA) was used as a cosolvent - a substance known to promote rate enhancements i n a l k y l a t i o n s and related reactions. Nevertheless, quantities of (70d) and (70h) s u f f i c i e n t to carry out the present study could be obtained quite r e a d i l y by t h i s rather simple procedure. Hydrogenation of the a l l y l d e r i v a t i v e s (70b) and (70f) i n the presence of the homogeneous catalyst tris(triphenylphosphine)chlororhodium Scheme 19 ( 6 3 a - h ) (69) (a) R=H (70)(a) R=H, R = CH i 3 (b) R=CH3 (b) R=H, R = CH2CH=CH2 (c) R=H, R = CH 2CH 2CH 3 (d) R=H, R = CH(CH ) (e) R=CH,, R = CH 3 i J (f) R=CH3, R = CH2CH=CH2 (g) R=CH3, R = CH 2CH 2CH 3 (h) R=CH3, R = CH(CH 3) 2 afforded excellent y i e l d s of the corresponding n-propyl compounds (70c) and (70g) res p e c t i v e l y . Careful h y d r o l y s i s ^ ' x ^ of the enol ethers (70a-h) with IN hydro-c h l o r i c a c i d i n acetone provided very good y i e l d s of the required B-cyclo-hexanediones (63a-h). It i s pertinent to point out that t h i s hydrolysis should be done i n the absence of oxygen and the products should be stored under a dry i n e r t atmosphere. I t i s w e l l known, a s previously stated i n Chapter I, that 1,3-diones are quite prone to autoxidation by a i r , 41 p a r t i c u l a r l y when they are moist." Treatment of 4-methy1-1,3-cyclohexanedione (63a) with triphenylphosphine d i i o d i d e i n r e f l u x i n g a c e t o n i t r i l e i n the presence of triethylamine provided i n 92% y i e l d , a product which on the basis of analysis by glc and t i c appeared to consist of two components i n the r a t i o of about 70 : 30. Separation of these components was achieved by preparative t i c . The major component provided s p e c t r a l data consistent with that expected (vide i n f r a ) f o r 3-iodo-6-methyl-2-cyclohexen-1-one (64a) (Scheme 20), while the minor component was shown on the basis of the i n f r a r e d and XH nmr s p e c t r a l data to consist of a mixture of isomeric iodo ketones (65a) and (66a) i n the r a t i o of about 8 :3 r e s p e c t i v e l y . Apparently, under the reaction conditions, the a,3-unsaturated ketone (65a) was p a r t i a l l y isomerized to the corresponding 6,Y-unsaturated isomer (66a). Presumably the triethylamine hydrogen iodide, present within the r e a c t i o n medium, was the a c t i v e agent responsible for promoting t h i s process (Scheme 21). It i s quite possible that the observed r a t i o of these two isomers i s a r e f l e c t i o n of the thermodynamic s t a b i l i t i e s of the respective compounds. Since the separation of (65a) from (66a) could not be effected, these substances were not i n d i v i d u a l l y characterized. Reaction of triphenylphosphine d i i o d i d e with the unsymmetrical 1,3-cyclohexanediones (63b-h) under conditions i d e n t i c a l with those used for the dione (63a) produced r e s u l t s which are summarized i n Table 8. * (63) One report i n the l i t e r a t u r e states that the s t a b i l i t i e s of some substituted 1,3-cyclohexanediones i n a i r follows the i r r e g u l a r sequence: 5,5-dimethyl >> unsubstituted compound> 2-methyl>2,5,5-trimethyl>4-methyl. 42 Scheme 20 (63a) ( M a ) ( ^ a ) ( — a ) Scheme 21 (65) CH 3CN (66) It can be seen that a l l of these transformations are quite e f f i c i e n t and i n terms of r e g i o s e l e c t i v i t y of the reactions, the trends are not unexpected. For example, i f one considers the series of 4-alkyl-l,3-cyclohexanediones (63a-d), i t can be seen that as the a l k y l group adjacent to the C-3 carbonyl function becomes larger the r e g i o s e l e c t i v i t y of the reaction increases. That i s , i n the case of 4-methyl-l,3-cyclohexanedione (63a), the iodine atom becomes attached to carbon atoms 1 and 3 i n the r a t i o of 70 : 30 (Table 8, Entry 1), while i n the case of the corresponding isopropyl substrate (63d), the reaction i s nearly t o t a l l y r e g i o s e l e c t i v e (Table 8, Entry 4). When the C-4 substituent i s intermediate i n s i z e ( a l l y l , 43 Table 8 Reaction of unsymmetrical 1,3-cyclohexanediones with t r i p h e n y l -(a) phosphine diio d i d e - t r i e t h y l a m i n e i n a c e t o n i t r i l e . - A : (*3) (64) (65) (66) (a) R=H, R i i CH 3 (b) R=H, R i i CH2CH=CH2 (c) R=H, R = CH 2CH 2CH 3 (d) R=H, R i CH(CH 3) 2 (e) R=CH3, R » = CH 3 (f) R=CH3> R i = CH2CH=CH (g) R=CH3, R | = CH2CH2CH (h) R=CH3, R = CH(CH 3) 2 Entry 1 2 3 4 5 6 7 8 g-Diketone 63a 63b 63c 63d 63e 63f 63g 63h Products ( y i e l d %) 64a, 65a, 66a (92) .64b, 62b, 66b (76) 64c, 65c, (88) 64d, 65d, (85) 64e, j>5e, (91) 64f, 65f, (71) 64g, 65g, (78) 64h, 65h, (90) (b) Ratio (d) 70:22:8 83:14:3 89:11 >99 :<1 83:17 88:12 87:13 >98:<2 (c) (c) (a) (b) (c) (d) A l l reactions were ca r r i e d out i n r e f l u x i n g a c e t o n i t r i l e . Y i e l d of d i s t i l l e d products. Although i t was possible to separate (preparative t i c ) compounds (64a) and (64b) from the mixtures of (65a) + (66a) and (65b) + (66b), r e s p e c t i v e l y , we were not able to e f f e c t separation of the l a t t e r two pai r s of products. The r a t i o s (65a/66a) and (65b/66b) were determined by AH nmr spectroscopy and, i n each case, the two compounds were characterized as a mixture (see Table 9). Ratios were determined by glc and XH nmr spectroscopy. 44 n-propyl), the r e g i o s e l e c t i v i t y i s between these two extremes (Table 8, Entries 2 and 3). A very s i m i l a r trend i s observed with the 4-aIky1-2-methy1-1,3-cyclohexanediones (63e-h) (Table 8, Entries 5-8). (63) The observed r e g i o s e l e c t i v i t y i n these reactions i s presumably due to s t e r i c f a c t o r s . Thus, reaction of triphenylphosphine d i i o d i d e with the enolate anion (71) of the generalized 1,3-dione (63) would be expected to take place p r e f e r e n t i a l l y at the le s s hindered oxygen atom to provide mainly the phosphonium s a l t (72), with species (73) being the minor isomeric intermediate (Scheme 22). On t h i s b a s i s , i f the formation of (72) and (73) i s considered to be i r r e v e r s i b l e , then the r a t i o of the f i n a l products (64) and (65) would be a r e f l e c t i o n of the r e l a t i v e proportions of the intermediate phosphonium s a l t s (72) and (73). As R' becomes larger the r a t i o (72):(73) should increase, thus accounting for the observed trends. An a l t e r n a t i v e r a t i o n a l e i s p o s s i b l e . On the basis of the e a r l i e r d iscussion dealing with the generalized scheme f o r the synthesis of 3-halo enones from B-diketones employing triphenylphosphine d i h a l i d e s (see Scheme 17 and discussion thereof), i t appears that the conversion of the phosphonium s a l t s (72) and (73) i n t o iodo enones (64) and (65) i s the rate determining step i n the o v e r a l l transformation (63) ->• (64) + (65). Therefore i f under the reaction conditions the reaction (71) -> (72) and (73) were r e a d i l y 45 r e v e r s i b l e and r e l a t i v e l y f a st equilibrium between (72) and (73) (via (71)) would thus be established, the r a t i o of (72)/(73) would depend upon the r e l a t i v e rates of conversion of (72) and (73) (via (74) and (75)) into the f i n a l products. C l e a r l y , the attack of iodide ion on the less hindered (3 carbon of the enone system of (72) would be a more f a c i l e process than the corresponding reaction with intermediate (73). Furthermore, as R' becomes lar g e r , t h i s rate d i f f e r e n c e would be enhanced. In any case, whatever the course of events, the observed r e g i o s e l e c t i v i t i e s , e s p e c i a l l y i n those cases where one of the carbonyl groups i s quite hindered, should prove to be useful from a synthetic point of view. 46 Some selected Infrared and H nmr sp e c t r a l data for the iodo enones l i s t e d i n Table 8 are summarized i n Table 9. (6A) (65) (66) (a) R=H, R = CH (b) R=H, R = CH2CH=CH2 (c) R=H, R = CH 2CH 2CH 3 (d) R=H, R = CH(CH 3) 2 (e) R=CH , R = CH (f) R=CH3, R = CH2CH=CH2 (g) R=CH3, R = CH 2CH 2CH 3 (h) R=CH3, R = CH(CH 3) 2 The s t r u c t u r a l assignments for each of the isomeric p a i r s of compounds ( i . e . (64)/(65)) was based mainly on ^H nmr spectra and, therefore, i t i s appropriate to discuss b r i e f l y how these conclusions were drawn. F i r s t l y , i t was observed that i n the ^ H nmr spectra of a l l the 3-iodo-2-cyclohexen-1-ones which were prepared, the proton or protons at C-4 resonate at lower f i e l d (in the region of 6 2.75-3.15) than the other r i n g protons and, i n nearly a l l cases, the s i g n a l was quite r e a d i l y i d e n t i f i e d . Thus f o r example, i n the ^ H nmr spectrum of 3-iodo enone (64c), the C-4 methylene protons gave r i s e to a two proton multiplet at 6 2.78-2.98, while the C-4 proton of the isomeric compound (65c) produces a one proton mu l t i p l e t at 6 2.60-2.88. Similar comparisons can be made f o r other pa i r s of isomeric 3-iodo enones. Secondly, the C-2 o l e f i n i c protons of the g-iodo enones (64a-d), and (65a-c) ex h i b i t a l l y l i c coupling to the C-4 protons, while homoallylic coupling can be observed between the C-2 v i n y l methyl protons and the C-4 protons 47 Table 9 Infrared and H nmr data for g-iodo a, B-unsaturated ketones derived  from unsymmetrical 1,3-cyclohexariediones (63a-h). Compound (s) 64a (a) 65a + 66a (c) 64b 65b + 66b (c) 64c 65c 64d 64e 65e 64f _ . . . - l . ( b ) Infrared (cm ) 1680,1600 1730, 1680, 1595 1 1670, 1600 1720, 1670, 1595 1670, 1595 1670, 1590 1670, 1595 1670, 1610 1680, 1600 1670, 1600 H Nuclear magnetic resonance (6) 1.12(d, J=6.5Hz, 3H), 1.60-2.14(m, 3H), 2.16-2.54(m, IH), 2.76-3.04 (m, 2H), 6.70(t, J=2Hz, IH). 1.30(d, J=7.0Hz, secondary methyl of .65a), 1.70-2.50 (diffuse m), 2.54(broad s, v i n y l methyl of 66a), 2.64-3.00 (m), 3.38 (unresolved m, Wj^~6Hz, C-2 methylene of 66a) , 6.72 (d, J=2Hz, v i n y l proton of 65a). 1.62-2.72 (di f f u s e m, 5H), 2.78-3.00 (m, 2H), 4.88-5.16 (m, 2H), 5.48-5.94 (m, IH), 6.70 ( t , J=2Hz, IH). 1.72-2.94 (diffuse m), 3.09 (broad d, -CH2CH=CH2 of 66b), 3.46 (broad s, C-2 methylene of _66b), 5.02-5.32 (m), 5.58-6.04 (m), 6.84 (d, J=lHz, r i n g v i n y l proton of 65b). 0.90 ( t , J=6Hz, 3H), 1.16-1.58 (m, 4H), 1.60-2.40 (m, 3H), 2.78-2.98 (m, 2H), 6.68 ( t , J=2Hz, IH). 1.00 ( t , J=6Hz, 3H), 1.20-2.55 (diffuse m, 7H), 2.60-2.88 (m, IH), 6.79 (t, J=2Hz, IH). 0.84, 0.91 (d, d, J=7Hz, 6H), 1.70-2.48 (m, 4H), 2.76-2.98 (m, 2H), 6.67 ( t , J=2Hz, IH) . 1.11 (d, J=6Hz, 3H), 1.60-2.10 (m, 2H), 1.99 ( t , J=2Hz, 3H), 2.22-2.56 (m, IH), 2.90-3.14 (m, 2H). 1.36 (d, J=7Hz, 3H), 1.62-2.76 (diffuse m, 4H), 2.03 (d, J-1.5Hz, 3H), 2.80-3.12 (m, IH). 1.52-2.72 (di f f u s e m, 5H), 2.01 (t, J=2Hz, 3H), 2.88-3.12 (m, 2H), 4.86-5.14 (m, 2H), 5.49 (m, IH). Cont'd 48 65f 64g 658 64h 1670, 1600 1670, 1600 1670, 1600 1675, 1610 1.74-3.02 (di f f u s e m, 7H), 2.01 (d, J=1.5Hz, 3H), 4.96-5.22 (m, 2H), 5.52-5.96 (m, IH). 0.91 (t, J=6Hz, 3H), 1.14-2.14 (diffuse m, 7H), 2.00 ( t , J=2Hz, 3H), 2.16-2.46 (m, IH), 2.88-3.12 (m, 2H). 0.98 ( t , J=6.5Hz, 3H), 1.20-2.60 (diffuse m, 8H), 2.03 (d, J=1.5Hz, 3H), 2.70-2.98 (m, IH). 0.84, 0.91 (d, d, J=6.5 Hz, 6H), 1.62-2.48 (m, 4H), 1.99 ( t , J=2Hz, 3H), 2.84-3.10 (m, 2H). (a) A l l compounds were l i q u i d s at room temperature and a l l exhibited one peak on glc analysis and one spot by t i c analysis. (b) A l l i n f r a r e d spectra were taken of l i q u i d f i l m s . (c) We were unable to e f f e c t separation of 65a and 66a or of 65b and 66b. On the basis of c a r e f u l i n t e g r a t i o n of the areas under the XH nmr signals due to the C-2 v i n y l protons of 65a (6 6.72) and 65b (6 6.84) vs. the C-2 methylene protons of 66a (8 3.38) and 66b (6 3.46), the r a t i o s of the two pair s of compounds were e s t i -mated to be as follows 65a/66a ~8 : 3; 65b/66b ~4 : 1. 49 of the iodo enones (64e-h) and (65e-g). Thus for example, i n the H nmr spectra of the isomeric compounds (64c) and (65c), the C-2 o l e f i n i c protons give r i s e to a t r i p l e t (6 6.88, J ~2Hz) and a doublet (6 6.79, J~1.5Hz), resp e c t i v e l y , c l e a r l y showing that the C-4 of these two substances contains two protons and one proton, r e s p e c t i v e l y . S i m i l a r l y , the C-2 v i n y l methyl groups of the isomeric g-iodo enones (64g) and (65g) produce a t r i p l e t (<5 2.00, J ~2Hz) and a doublet (6 2.03, J=1.5Hz), r e s p e c t i v e l y . Analogous observations can be made for other 8-iodo enones. The s t r u c t u r a l assignment for the B-iodo g ,y-unsaturated enone (66a) was also based on in f r a r e d and nmr sp e c t r a l data. Although the enone (66a) could not be separated from the isomeric compound (65a), i t was evident from the i n f r a r e d spectrum of th i s mixture that both an unsaturated ketone (v(C=0) 1680 cm"1, v(C=C) 1595 cm"1) and a saturated ketone (v(C=0) 1730 cm"1) were present. In addition the nmr spectrum of t h i s mixture exhibited resonances at 6 3.38 (unresolved m) and 6 2.54 (broad s) a t t r i b u t e d to the C-2 methylene and the v i n y l methyl group of (66a), r e s p e c t i v e l y . Furthermore, 13 these proton assignments were supported by the C nmr sp e c t r a l data obtained on this mixture which exhibited carbon resonances at 6 53.5 ( t r i p l e t ) and <5 89.3 (singlet) a t t r i b u t e d to the C-2 and C-4 carbons of (66a), r e s p e c t i v e l y . In a s i m i l a r manner, the s t r u c t u r a l assignment f o r enone (66b) was also based on i n f r a r e d and nmr s p e c t r a l data. U l t r a v i o l e t s p e c t r a l c o r r e l a t i o n s (64—66) The w e l l established Woodward- Fieser rules have been employed very s u c c e s s f u l l y i n c o r r e l a t i n g e l e c t r o n i c t r a n s i t i o n s with s t r u c t u r a l patterns i n conjugated chromophores. For example, on the basis of the 50 s u b s t i t u t i o n pattern on the enone system of a,8-unsaturated ketones, i t i s possible to predict quite accurately the p o s i t i o n of the longest wave-* • (64-66) length TT-*"JT absorption band of these compounds . Since p r i o r to the (61) execution of the work ca r r i e d out in our laboratory e s s e n t i a l l y nothing had been reported concerning the e f f e c t of a 8-iodo substituent on the TT-*-7T absorption maxima of enones, the u l t r a v i o l e t spectra of methanol solutions of the 8-iodo enones prepared i n t h i s study were measured. In addition, the absorption maxima of these and other 8-iodo cycloalkenones, (58) previously prepared i n our laboratory and unreported i n the l i t e r a t u r e , were compared i n the hopes of e s t a b l i s h i n g the extent of the bathochromic s h i f t caused by the B-iodo group. These r e s u l t s are summarized i n Table 10. The most i n t e r e s t i n g observation that one can make regarding the data given i n Table 10 i s that, whether or not there i s an a l k y l substituent at C-2, the 7r->-rr absorption maxima of a l l the 3-iodo-2-cyclohexen-1-ones which were measured appear i n nearly the same place. Thus, the average of the X values of the 3-iodo-2-cyclohexen-1-ones i s 257 nm, with a range max of 256-261 nm. The analogous values for 3-iodo-2-alky1-2-cyclohexen-1-ones are 259 nm and 256-262 nm. Furthermore, i f one compared the u l t r a v i o l e t absorption maxima with those of the "parent" enones (2-cyclohexen-1-one, X 226 nm; 2-methy1-2-cyclohexen-1-one, X 234 nm), then the "increments" max max for the 3-iodo group should be ~32 nm for those cyclohexenones having a proton at C-2 and -25 nm f o r the corresponding substances possessing a C-2 , a l k y l substituent. 51 Table 10 Longest wavelength TT-HT* u l t r a v i o l e t absorption bands of g-iodo  a,g-unsaturated ketones (methanol s o l u t i o n ) . Compound A , .nm (e) , • ^ max 3-Iod o-2-cy clohexen-1-ones 257 (8430) 256 (8380) 257 (8700) 260 (8860) 259 (8680) 257 (8150) 261 (8330) 3-Iodo-2-alkyl-2-cyclohexen-1-ones 77 258 (9500) 78 259 (9440) 79 260 (9200) 64e 256 (8720) 64f 258 (8700) 64g 257 (9840) _64h 262 (7140) 65e 260 (9140) 65f 260 (8300) 65g 259 (8760) (a) R=H, R = CH (b) R=H, R = CH2CH=CH2 (c) R=H, R = CH 2CH 2CH 3 (d) R=H, R = CH(CH 3) 2 (e) R=CH,, R = CH, (f) R=CH , R = CH CH=CH (g) R=CH3, R = CH2CH2CH (h) R=CH3, R = CH(CH 3) 2 40 76 64a 64b 64c 14d 65c 6* " A " " A A r (40) (64) (65) (76) CjC £j£CH2CH=CH2 r ^ ^ C H 2 C H 2 C H = C H 2 (77) (78) (79) 52 EXPERIMENTAL General procedure for the a l k y l a t i o n of 3-isobutoxy-2-cyclohexen-l-6ne(6_9_a)  and 3-isobutoxy-2-methyl-2-cyclohexen-l-one (69a) with methyl iodide and i i i v -A (62) a l l y l bromide To a cold (-78°C) s t i r r e d s o l u t i o n of LDA (22 mmol) i n dry THF (80 mL) under an atmosphere of dry nitrogen was added 20 mmol of the ketone (69a) or (69b). The so l u t i o n was s t i r r e d for 1 h. The a l k y l a t i n g agent (methyl iodide or a l l y l bromide, 26 mmol) was added, the solu t i o n was slowly allowed to warm to room temperature, and s t i r r i n g was continued for 4 h. Brine (50 mL) was added and the r e s u l t i n g mixture was extracted with petroleum ether (bp 30-60°C). The combined extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the solvent, followed by bulb-to-bulb 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 under reduced pressure, afforded the desired product. The following compounds were prepared by means of t h i s procedure. (70) (a) R=H, R = CH (b) R=H , R = C H 2 C H = C H 2 (e) R = C H _ , R ' = CH (f) R=CH_, R = C H _ C H = C H , 53 3- Isobutoxy-6-methyl-2-cyclohexen-l-one (70a): 95% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 80-90°C/0.07 Torr; i r ( f i l m ) : 1690, 1610 cm • uv(methanol) X : 247 nm (e 17800); *H nmr 6: 0.98 (d, J=6Hz, 6H), 1.16 (d, max J=7Hz, 3H), 1.54-2.58 (di f f u s e m, 6H), 3.59 (d, J=6Hz, 2H), 5.33 (s, IH); Anal, calcd. f o r C,.H,o0.: C 72.49, H 9.95; found: C 72.70, H 9.97. 11 l o 2 6-Ally1-3-isobutoxy-2-cyclohexen-1-one (70b) : 93% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 95-100°C/0.4 Torr; mp 37-38°C [ l i t . mp 37-38°C ] : ir(CHCl_ s o l n ) : 1660, 1605 cm"1; uv(methanol) X : 247 nm (e 19600): *H j max nmr 6: 0.98 (d, J=6.5Hz, 6H), 1.46-2.78 (diffuse m, 8H), 3.60 (d, J=6Hz, 2H), 4.98-5.20 (m, 2H), 5.34 (s, lH), 5.61-6.05 (m, lH); Anal, calcd. f o r C 1 3 H 2 0 ° 2 : C 7 4 * 9 6 ' H 9 * 6 8 ' f o u n d : c 75.05, H 9.54. 3-Isobutoxy-2,6-dimethyl-2-cyclohexen-1-one (70e) : 94% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 100-110°C/0.2 Torr; i r ( f i l m ) : 1650, 1630 cm"1; uv(methanol) X : 265 nm (e 18800); LH nmr S: 0.96 (d, J=7Hz, max 6H), 1.11 (d, J=6.5Hz, 3H), 1.48-2.38 (diffuse m, 5H), 1.68 ( t , J=2Hz, 3H), 2.40-2.64 (m, lH), 3.71 (d, J=7Hz, 2H) ; Exact mass calcd. for C^H 0 ^ 196.1463; found 196.1470. 6-Allyl-3-isobutoxy-2-methy1-2-cyclohexen-1-one (70f): 95% y i e l d ; bp 110°C/0.35 Torr; i r ( f i l m ) : 1640, 1620 cm"1; uv(methanol) X : 265 nm r • ' max (e 18600); *H nmr 6: 1.00 (d, J=6.5Hz, 6H), 1.52-2.40 ( d i f f u s e m, 6H), 1.72 (t, J=1.5Hz, 3H), 3.77 (d, J=6.5Hz, 2H), 4.92-5.18 (m, 2H), 5.60-6.04 (m, IH); Exact mass calcd. for C u H 9 9 0 9 : 222.1620; found: 222.1606. 54 Hydrogenation of compounds (70b) and (70f). Preparation of 3-isobutoxy-6- n-propyl-2-cyclohexen-l-6ne (70c) and 3-i sob u t oxy-2-me thy1-6-n- p f op y1-2- cyclohexen- 1-one (70g). (70)(b) R=H, R = CH CH=CH i z 2 (f) R=CH3, R = CH2CH=CH2 i (70)(c) R=H, R = CH CH CH. t z z 3 (g) R=CH3, R = CH 2CH 2CH 3 To a solu t i o n of ketone (70b) or (70f) (15 mmol) i n 150 mL of dry benzene was added approximately 10% by weight of tris(triphenylphosphine)-chlororhodium. The resultant s o l u t i o n was s t i r r e d vigorously and subjected to an atmosphere of hydrogen at room temperature f o r 18 h. The solvent was removed under reduced pressure and the r e s i d u a l material was treated with 150 mL of petroleum ether (bp 30-60°C). The mixture was f i l t e r e d through C e l i t e . Removal of the solvent from the f i l t r a t e , 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 under reduced pressure gave the desired products. 3-Isobutoxy-6-n-propyl-2-cyclohexen-1-one (70c) : 95% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 95-105°C/0.1 Torr; mp 25-28°C; ir(CHCl„ s o l n ) : 1630, 1600 cm"1; uv(methanol) X : 247 nm (e 19400); -> max "'"H nmr 6: 0.82-1.06 (superimposed d, J=6.5Hz, and poorly resolved t, 9H) , 1.20-2.30 (di f f u s e m, 8H), 2.44 ( t , J=7Hz, 2H), 2.59 (d, J=6.5Hz, 2H), 5.30 (s, IH); Anal, calcd. f o r C ^ H ^ O ^ C 74.24, H 10.54; found: C 74.47, H 10.40. 3-Isobutoxy-2-methyl-6-xi-propyl-2- cy clohexen-1-one (70g) : 94% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 100-110°C/0.2 Torr; i r ( f i l m ) : 1645, 55 1625 cm""1"; uv(methanol) X : 265 nm (e 17500); AH nmr 6: 0.91 (t, J=7Hz, max 3H), 0.98 (d, J=6Hz, 6H), 1.14-2.24 (diffuse m, 8H), 1.68 (t, J=1.5Hz, 3H) , 2.40-2.66 (m, 2H), 3.72 (d, J=7Hz, 2H); Exact mass calcd. for C 1 4 H 2 4 ° 2 : 224.1776; found: 224.1786. Preparation of 3-isobutoxy-6-isopropyl-2-cyclohexen-l-one (70b) and  3-isobutoxy-6-isopropyl-2-methyl-2-cyclohexen-1-one (70d). (70)(b) R=H, R = CH(CH 3) 2 (d) R=CH3, R = CH(CH 3) 2 To a cold (-78°C) s t i r r e d s o l u t i o n of LDA (55 mmol) i n 60 mL of a 5 : 1 mixture of dry THF and dry HMPA was added 50 mmol of the ketone (69a) or (69b), and the so l u t i o n was s t i r r e d f o r 1 h. A s o l u t i o n of isopropyl iodide (9.35 g, 55 mmol) i n 10 mL of dry THF was added, the resultant mixture was allowed to warm to room temperature, and s t i r r i n g was continued fo r 16 h. Water (50 mL) was added and the resultant mixture was extracted thoroughly with petroleum ether (bp 30-60°C). The combined extracts were washed with b r i n e and dried over anhydrous magnesium s u l f a t e . Removal of the solvent produced an o i l which was subjected to column chromatography on s i l i c a gel (300 g). The eluant was a 7 : 3 mixture of n-hexane-ether. In addition to minor, u n i d e n t i f i e d products and a major amount of s t a r t i n g m aterial, the following desired products were obtained. 56 3-Isobutoxy-6-isopropyl-2-cyclohexen-1-one (70d): 16% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 70-90°C/0.2 Torr; mp 22.5-24°C; i r ( f i l m ) : 1650, 1605 cm"1; uv(methanol) X : 247 nm (e 12800); XH nmr max 6: 0.83 (d, J=6.5Hz, 3H), 0.94 (d, J=6.5Hz, 9H), 1.60-2.16 (m, 4H), 2.25-2.56 (m, 3H), 3.53 (d, J=6.5Hz, 2H), 5.26 (s, IH); Exact mass calcd. f o r C 1 3 H 2 2 ° 2 : 2 1 0 , 1 6 2 0 ' found: 210.1618. 3-Isobutoxy-3-isopropy1-2-methy1-2-cyclohexen-1-one (70h): 13% y i e l d : d i s t i l l a t i o n temperature ( a i r bath) 85-95°C/0.1 Torr; i r ( f i l m ) : 1640, 1620 cm \ uv(methanol) X 266 nm (e 18300); \ nmr 6: 0.84 (d, J=5Hz, 3H), 0.97 max (d, J=6Hz, 9H), 1.58 ( t , J=1.5Hz, 3H), 1.60-2.78 (diffuse m, 7H), 3.77 (d, J=6Hz, 2H) ; Exact mass calcd. f o r C H^O : 224.1770; found: 224.1780. General procedure f o r the hydrolysis of compounds (70a-h). Preparation of  the unsymmetrical 1,3-cyclohexanediones (63a-h). t (a) R=H, R = CH t 3 (b) R=H, R = CH2CH=CH2 (c) R=H, R ^ CH 2CH 2CH 3  R v V ^ V ^ R R-v/S^K (d) R=H, R = CH(CH 0)„ I 1 (70) I (") (f) R=CH3, R = CH2CH=CH2 (g) R=CH3, R = CH 2CH 2CH 3 (h) R=CH3, R = CH(CH 3) 2 To a solu t i o n of the g-isobutoxy a,g-unsaturated ketone (70a-h) (30 mmol) i n acetone (80 mL, spectro-grade, previously purged with a stream of nitrogen for 15 min) was added with vigorous s t i r r i n g 30 mL of IN hydro-c h l o r i c acid (previously purged with a stream of nitrogen f o r 15 min). 57 The resultant s o l u t i o n was s t i r r e d under an atmosphere of nitrogen for 6 h. Most of the acetone was removed under reduced pressure, the r e s i d u a l material was d i l u t e d with brine, and the resultant mixture was thoroughly extracted with dichloromethane. The combined extracts were dried over anhydrous magnesium s u l f a t e . Removal of the solvent, followed by p u r i f i c a t i o n of the r e s i d u a l material by d i s t i l l a t i o n under reduced pressure and/or r e c r y s t a l l i z a t i o n , gave the following desired products. 4-Methyl-l,3-cyclohexanedione (63a): 96% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 85-100°C/0.03 Torr; r e c r y s t a l l i z a t i o n from ether-petroleum ether (bp 30-60°C), mp 53-57°C; i r ( C H C l 3 soln): 3400-2400 (broad), 1700, 1610-1580 (broad) cm"1; 1H nmr 6: 1.16 (d, J=6Hz, 3H), 1.38-2.80 (di f f u s e m, 5H), 3.38 (s, IH, C-2 methylene of enol tautomer); Anal. calcd. for C ?H 0 : C 66.75, H 7.99; found: C 66.79, H 7.99. 4-Allyl-l,3-cyclohexanedione (63b): 90% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 90-100°C/0.08 Torr; mp 34-36°C; i r ( C H C l 3 soln): 3600-2400 (broad), 1720, 1710, 1640-1590 (broad)cm" 1; 1H nmr 6: 1.40-2.80 (di f f u s e m, 7H), 3.38 (s, ~1H, C-2 methylene of keto tautomer), 4.90-5.20 (m, 2H), 5.42 (s, ~0.5H, C-2 v i n y l proton of enol tautomer), 5.52-5.60 (m, IH); Exact mass calcd. for C 9 H 1 2 ° 2 : 1 5 2 - 0 8 3 8 5 found: 152.0845. 4-n.-Propyl-l,3-cyclohexanedione (63c) : 60% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 110-125°C/0.9 Torr; mp 69-71°C; i r ( C H C l 3 soln): 3500-2400 (broad), 1730, 1710, 1600 (broad) cm"1; 1H nmr 6: 0.91 ( t , J=7Hz, 3H), 1.16-2.72 (d i f f u s e m, 9H), 3.40 (s, -0.7H, C-2 methylene of keto tautomer), 5.40 (s, -0.7H, C-2 v i n y l proton of enol tautomer); Exact mass calcd. f or C 9 H 1 4 ° 2 : 1 5 4 - 0 9 9 4 ' f o u n d : 154.1005. 58 4-Isopropyl-l,3-cyclohexanedione (63d): 95% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 110-130°C/0.07 Torr; mp 106-107°C; i r ( C H C l 3 s o l n ) : 1730, 1710, 1615 cm"1; "1H nmr 6: 0.80-1.14 (series of overlapping d, 6H), 1.58-2.86 ( d i f f u s e m, 6H), 3.36 (s, -1.4H, C-2 methylene of keto tautomer), 5.42 (s, -0.3H, C-2 v i n y l proton of enol tautomer; Exact mass calcd. for C 9 H 1 4 ° 2 : 1 5 4 ' 0 9 9 4 ' f o u n d : 154.0992. 2,4-Dimethyl-l,3-cyclohexanedione (63e): 97% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 80-95°C/0.3 Torr; mp 108-110°C: i r ( C H C l 3 s o l n ) : 3650-2450 (broad), 1745, 1705, 1630 cm"1; 1H nmr 6: 1.10-1.34 (series of d), 1.34 ( d i f f u s e m), 1.72 (s, v i n y l methyl of enol tautomer), 3.38-3.68 (m, C-2 protons of diastereomeric keto tautomers). On the basis of the r e l a t i v e integrated areas of the l a t t e r two signals, the keto-enol r a t i o was ~1 : 1; Exact mass calcd. for C oH_„0 o: 140.0838; found: 140.0841. o 1/ Z 4-Allyl-2-methyl-l,3-cyclohexanedione (63f): 88% y i e l d ; d i s t i l l a t i o n temperature ( a i r bath) 110-120°C/0.3 Torr; mp 51-53°C; i r ( C H C l 3 soln): 3575, 3500-2600 (broad), 1735, 1705, 1615 (broad) cm"1; 1H nmr 6: 1.19, 1.21 (d, d, J=6.5Hz), 1.32-2.86 (di f f u s e m), 1.71 (s, v i n y l methyl of enol tautomer), 2.50 (q, J=6.5Hz, C-2 proton of keto tautomers), 4.90-5.20 (m, 2H), 5.52-6.00 (m, IH). On the basis of the r e l a t i v e integrated areas of the signals at 6 1.71 and 3.50; the keto-enol r a t i o was ~1 : 1; Exact mass calcd. f o r C l nH_.0„: 165.9994; found: 166.1007. 10 14 2 2-Methyl-4-n_-propyl^l, 3-cyclohexaned ione (63g) : 95% y i e l d ; d i s t i l l a -t i o n temperature ( a i r bath) 100-110°C/0.03 Torr; mp 67-69°C; i r ( C H C l 3 s o l n ) : 3650-2500 (broad), 1740, 1705, 1635 cm"1; 1H nmr 6: 0.82-1.04 (m, 3H), 59 1.18, 1.20 (d, d, J=6.5Hz), 1.24-2.76 (d i f f u s e m), 1.72 (s, v i n y l methyl of enol tautomer), 3.36-3.68 (m, C-2 protons of diastereomeric keto tauto-mers). The r e l a t i v e integrated areas of the l a t t e r two signals was ~4 : 1. Exact mass calcd. f o r C.nH..,0o: 168.1150; found: 168.1146. 10 l b 2 4-Isopropyl-2-methyl-l,3-cyclohexanedione (63h): 96% y i e l d ; sublimes at 95-100°C ( a i r bath)/0.01 Torr; mp 104-105°C; i r ( C H C l 3 s o l n ) : 3560, 3500-3000 (broad), 1735, 1700, 1625 (broad) cm"1; """H nmr 6: 0.80-1.26 (series of d), 1.26-2.90 ( d i f f u s e m), 1.70 (s, v i n y l methyl of enol'tautomer), 3.32-3.62 (m, C-2 protons of diastereomeric keto tautomers). The r e l a t i v e integrated areas of the l a t t e r two signals was ~2.5 : 1; Exact mass calcd. for C l oH 1,0 o: 168.1150; found: 168.1151. 10 16 z General procedure for the conversion of unsymmetrical 1,3-cyclohexanediones  into g-iodo a,g-unsaturated ketones To a s t i r r e d suspension of iodine (660 mg, 2.6 mmol) i n 15 mL of dry a c e t o n i t r i l e under an atmosphere of nitrogen was added 681 mg (2.6 mmol) of r e c r y s t a l l i z e d triphenylphosphine and the mixture was s t i r r e d for 30 min. To the resultant yellow suspension was added sucessively dry triethylamine (263 mg, 2.6 mmol) and 2.4 mmol of the appropriate 1,3-cyclohexanedione (63a-h). The dark solution was s t i r r e d at room temperature for 1 h and was then heated at r e f l u x temperature for 12 h. The solvent was removed under reduced pressure and the residue was extracted (decantation) with 6 x 25 mL of ether. Removal of the ether from the combined extracts produced a mixture of a s o l i d and an orange o i l . This material was washed with 3 x 15 mL of 7 : 1 n-pentane-ether and the combined washings were applied to a dry column cons i s t i n g of a mixture of 20 g of F l o r i s i l (100-6 0 120 mesh) and 10 g of alumina (neutral, a c t i v i t y I ) . The column was eluted with 7 : 1 n-pentane-ether and the f r a c t i o n s containing the desired products were combined. Removal of the solvent from the combined eluate, followed by bulb-to-bulb 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 , provided the desired product(s) (Table 8). In each case, the d i s t i l l e d material was subjected to analysis by glc (6 f t x 0.125 i n column containing 5% 0V-17 on 100-120 mesh HP Chromosorb W) and, where possible (see footnote C, Table 8 and 9), the products were separated by preparative t i c on s i l i c a gel (plates developed with 7 : 3 n-pentane-ether). The following compounds (or pair s of compounds) were obtained by means of t h i s procedure. ( 6 4 ) "ex: ( 6 5 ) ( 6 6 ) (a) R=H, R = CH (b) R=H, R = CH2CH=CH2 (c) R=H, R = CH 2CH 2CH 3 (d) R=H, R - CH(CH 3) 2 (e) R=CH,, R = CH (f) R=CH3, R = CH2CH=CH2 (g) R=CH3, R = CH 2CH 2CH 3 (h) R=CH3, R = CH(CH 3) 2 3-Iodo-6-methyl-2-cyclohexen-l-one (64a): d i s t i l l a t i o n temperature (ai r bath) 60-74°C/0.01 Torr; mp 27-28°C; i r ( f i l m ) : 1680, 1600 cm - 1; uv (methanol) A : 257 nm (e 8700); 1H nmr 6: 1.12 (d, J=3.5Hz, 3H, methyl TT13.X group), 1.60-2.14 (m, 2H, C-5 methylene), 2.16-2.54 (m, IH, C-6 t e r t i a r y proton), 2.76-3.04 (m, 2H, C-4 methylene), 6.70 ( t , J=2Hz, IH, C-2 v i n y l 13 proton); C nmr 6: 14.6 (q, J . =122Hz, C-6 methyl substituent), 32.0 (t, J„ „ =132Hz, C-5), 40.3 (overlapping d and t, Jr =130Hz and 136Hz, C-6 C — r i C — r i 61 and C-4 r e s p e c t i v e l y ) , 125.6 (s, C-3), 139.9 (d, J„ =172Hz, C-2), 197.4 C—H (s, C - l ) ; Exact mass calcd. f o r C 7H gOI: 235.9698; found: 235.9721. 3- Iodo-4-methyl-2-cyclohexen-l-one (65a) and 3-Iodo-4-methyl-3- cyclohexen-l-one (66a): d i s t i l l a t i o n temperature ( a i r bath) 60-74°C/0.10 Torr; i r ( f i l m ) : 1730, 1680, 1595 cm"1; """H nmr 6: 1.30 (d, J=7.0Hz, secondary methyl of 65a), 1.70-2.50 (di f f u s e m), 2.54 (broad s, v i n y l methyl of 66a), 2.64-3.00 (m), 3.38 (unresolved m, Wx ~6Hz, C-2 methylene of 66a), 6.72 -3 —~ (d, J=2Hz, v i n y l proton of 65a); 1 3 C nmr 6: 53.8 (t, J =138Hz, C-2 of 66a), C—H 89.3 (s, C-4 of 66a), 140.4 (d, J =176Hz, C-2 of 65a), 206.4 (s, C-l of C—n 66a); Exact mass calcd. for C 7H 01: 235.9698; found: 235.9711. 6-Allyl-3-iodo-2-cyclohexen-l-one (64b): d i s t i l l a t i o n temperature (ai r bath) 80-100°C/0.20 Torr, i r ( f i l m ) : 1670, 1600 cm"1; uv(methanol) X : max 260 nm (e 8860); 1H nmr 6: 1. 62-2.72 (di f f u s e m, 5H), 2.78-3.00 (m, 2H, C-2 methylene), 4.88-5.16 (m, 2H, -CH2CH=CH2), 5.48-5.94 (m, IH, -CH2-CH=CH2), 6.70 (t, J=2Hz, C-2 v i n y l proton); Exact mass calcd. for C H^OI: 261.9855; found: 261. 9869; Anal, calcd. for C.H^OI: C 41.26; H 4.21; found: 9 1 1 C 41.48; H 4.21. 4- Allyl-3-iodo-2-cyclohexen-l-one (65b) and 4-Allyl-3-iodo-3-cyclo- hexen-l-one (66b): d i s t i l l a t i o n temperature ( a i r bath) 80-100°C/0.20 Torr; i r ( f i l m ) : 1720, 1670, 1595 cm"1;' 1H nmr <5: 1.72-2.94 (d i f f u s e m), 3.09 (broad d, -CH2CH=CH2 of 66b), 3.46 (broad s, C-2 methylene of 66b), 5.02-5.32 (m), 5.58-6.04 (m), 6.84 (d, J=lHz, r i n g v i n y l proton of j65b); Exact  mass ca l c d . for C Q H ^ O I : 261.9855; found: 261.9842. 62 3-Iodo-6-propyl-2-cyclohexen-l-one (64c): d i s t i l l a t i o n temperature (ai r bath) 90-105°C/0.16 Torr; i r ( f i l m ) : 1670, 1595 cm"1; uv(methanol) X : max 259 nm (E 8680); 1H nmr 6: 0.90 ( t , J=6Hz, 3H, -CH 2CH 2CH 3), 1.16-1.58 (m, 4H), 1.60-2.40 (m, 3H), 2.78-2.98 (m, 2H, C-4 methylene), 6.68 ( t , J=2Hz, IH, C-2 v i n y l proton); Exact mass calcd. f o r C H 01: 264.0011; found: 9 I J 264.0022. 3-Iodo-6-isopropyl-2-cyclohexen-l-one (64d): d i s t i l l a t i o n temperature (air bath) 65-85°C/0.07 Torr; i r ( f i l m ) : 1670, 1595 cm - 1; uv(methanol)X : max 257 nm (e 8150), 1H nmr 6: 0.84, 0.91 (d, d, J=7Hz, 6H, -CH(CH_ 3) 2), 1.70-2.48 (m, 4H), 2.76-2.98 (m, 2H, C-4 methylene), 6.67 (t, J=2Hz, IH); Exact mass calcd. f o r C H^OI: 264.0011; found: 264.0005. 3-Iodo-2,6-dimethyl-2-cyclohexen-l-one (64e): d i s t i l l a t i o n tempera-ture ( a i r bath) 65-75°C/0.30 Torr; i r ( f i l m ) : 1670, 1610 cm - 1; uv(methanol) X : 256 nm (e 8720); 1H nmr 6: 1.11 (d, J=6Hz, 3H, C-6 methyl group), max 1.60-2.10 (m, 2H), 1.99 ( t , J=2Hz, 3H, C-2 v i n y l methyl), 2.22-2.56 (m, IH, C-6 t e r t i a r y proton), 2.90-3.14 (m, 2H, C-4 methylene); Exact mass calcd. for C 0rL 01: 249.9855; found: 249.9856; Anal, calcd. for C oH 1 10I: o 11 o 11 C 38.42, H 4.43; found: C 38.44, H 4.38. 3-Iodo-2,4-dimethyl-2-cyclohexen-l-one (65e): d i s t i l l a t i o n temperature ( a i r bath) 65-75°C/0.30 Torr; i r ( f i l m ) : 1680, 1600 cm"1; uv (methanol) X : 260 nm (e 9140); 1H nmr 6: 1.36 (d, J=7Hz, 3H, C-4 max methyl group), 1.62-2.76 ( d i f f u s e m, 4H), 2.03 (d, J=1.5Hz, 3H, C-2 v i n y l methyl), 2.80-3.12 (m, IH, C-4 t e r t i a r y proton); Exact mass calcd. f o r CDH n i : 249.9855; found: 249.9858; Anal, calcd. for C Q H ^ O I : C 38.42, o 11 o ±1 H 4.43; found: C 38.33, H 4.29. 63 6-Allyl-3-iodo-2-methyl-2-cyclohexen-l-one (64f ): d i s t i l l a t i o n temperature ( a i r bath) 85-100°C/0.35 Torr; i r ( f i l m ) : 1670, 1600 cm"1; uv(methanol) X : 258 nm (e 8700); 1H nmr 6: 1.52-2.72 ( d i f f u s e m, 5H), max ' ' 2.01 (d, J=2Hz, 3H, C-2 v i n y l methyl), 2.88-3.12 (m, 2H, C-4 methylene), 4.86-5.14 (m, 2H, -CH2CH=CH2), 5.49-5.92 (m, IH, -CH2-CH=CH2); Exact  mass calcd. f o r C H^OI: 276.0011; found: 276.0013; Anal, calcd. for C 1 0 H 1 3 ° I : C 4 3 * 5 0 ' H 4 ' 7 4 ' f o u n d : C 43.78, H 4.70. 4-Allyl-3-iodo-2-methyl-2-cyclohexen-l-one (65f): d i s t i l l a t i o n temperature ( a i r bath) 85-100°C/0.35 Torr; i r ( f i l m ) : 1670, 1600 cm"1 uv(methanol) X : 260 nm (e 8300); 1H nmr 6: 1.74-3.02 (d i f f u s e m, VH), max 2.01 (d, J=1.5Hz, 3H, C-2 v i n y l methyl), 4.96-5.22 (m, 2H, -CH2CH=CH2), 5.52-5.96 (m, IH, -CH2CH=CH2); Exact mass calcd. for C H^OI: 276.0011; found: 276.0024; Anal, calcd. f o r C^H^OI: C.43.50, H 4.74; found: C 43.80, H 4.66. 3-Iodo-2-methyl-6-propyl-2-cyclohexen-l-one (64g): d i s t i l l a t i o n temperature ( a i r bath) 90-100°C/0.11 Torr; i r ( f i l m ) : 1670, 1600 cm"1; uv (methanol) A : 257 nm (e 9840); 1H nmr 6: 0.91 (t, J=6Hz, 3H, -CH -CH -CH ), max z. z J 1.14-2.14 ( d i f f u s e m, 7H), 2.00 ( t , J=2Hz, 3H, C-2 v i n y l methyl), 2.16-2.46 (m, IH, C-6 t e r t i a r y proton), 2.88-3.12 (m, 2H, C-4 methylene); Exact  mass calcd. f o r C H^OI: 278.0167; found: 278.0167. 3-Iodo-2-methyl-4-propyl-2-cyclohexen-l-one (65g): d i s t i l l a t i o n temperature ( a i r bath) 90-100°C/0.11 Torr; i r ( f i l m ) : 1670, 1600 cm"1; uv(methanol) X :259nm (e 8760); \ nmr 6: 0.98 (t, J=6.5Hz, 3H, -CH -CH -CH ), max z. *- J 1.20-2.60 (d i f f u s e m, 8H), 2.03 (d, J=1.5Hz, 3H, C-2 v i n y l methyl), 2.70-64 2.98 (m, IH, C-4 t e r t i a r y proton); Exact mass calcd. f o r C.^H 01: 278.0167; found: 278.0167. 3-Iodo-6-isopropyl-2-methyl-2-cyclohexen-l-one (64h): d i s t i l l a t i o n temperature ( a i r bath) 65-80°C/0.07 Torr; i r ( f i l m ) : 1675, 1610'cm"1; uv(CH.OH) A : 262 nm (e 7140); 1H nmr 6: 0.84, 0.91, (d, d, J=6.5Hz, 3 max ' ' ' ' ' 6H), -CH(CH ) ), 1.62-2.48 (m, 4H), 1.99 (t, J=2Hz, 3H, C-2 v i n y l methyl), 2.84-3.10 (m, 2H, C-4 methylene); Exact mass ca l c d . for C H 01: 278.0167; found: 278.0163. 65 REFERENCES 18. 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Arbuzov, M.N. Kolosov, G.A. Shatenstein, V.V. Onoprienko and Yu. V. Monnova, J. Gen. Chem. U.S.S.R., _30 563 (I960). 56. W. Huckel and K. Thiele , Chem. Ber., 94, 96 (1961). 57. R.D. Clark and CH. Heathcock, Synthesis, 47 (1974). 58. E. Piers and I. Nagakura, Syn. Comm., 193 (1975). 59. L. Gruber, J. Tomoskozi and L. Radios, Synthesis, 708 (1975). 60. W.R. Benson and A.E. Pohland, J . Org. Chem., _30, 1129 (1965). 61. E. P i e r s , J.R. Grierson, C.L Lau and I. Nagakura, Can. J. Chem., 60, 210 (1982). 62. G. Stork and R.L. Danheiser, J. Org. Chem.. 38, 1775 (1973). 63. E.G. Meek, J.H. Turnball and W. Wilson, J . Chem. S o c , 811 (1953). 64. R.B. Woodward, J. Am. Chem. S o c , 63, 1123 (1941); _64, 76 (1942). 65. L.F. Fieser and M. Fiese r , Steroids, Reinhold Publishing Corp., New York, N.Y. 1959, pp 15-21. 66. A.I. Scott. Interpretation of the U l t r a v i o l e t Spectra of Natural  Products . The MacMillan Company, New York, N.Y. 1964, pp 55-73. 68 STUDIES RELATED TO THE DIVINYLCYCLOPROPANE REARRANGEMENT INTRODUCTION The thermal bond reorganization of 1,5-dienes by a [3,3]-sigmatropic process i s ref e r r e d to as the Cope rearrangement. A p a r t i c u l a r variant of t h i s reaction which involves the rearrangement of 1,2-divinylcyclopropane systems i s known as the divinylcyclopropane rearrangement (Scheme 23). Scheme 23 (23,39,40,43,67-80) Reports concerning the r e s u l t s of recent studxes have indicated that thermal (Cope) rearrangements of t h i s type could be of considerable synthetic u t i l i t y . In th i s respect, the divinylcyclopropane rearrangement has found increasing use as a method of generating natural products containing a seven membered carbocycle. F i r s t applied to the ' (81) synthesis of (±)- dictyoptrene C ( 8 2 ) — , more highly developed methods for the generation of fun c t i o n a l i z e d divinylcyclopropanes have recently allowed for the extension of the rearrangement to the synthesis of (±)~g-himachalene (83) , the pseudoguaianes (72) (±)-damsinic acid (84) and (±)-confertin (85) and, most recently, to an approach to the t e t r a c y c l i c diterpene phorbol (86) . 69 (82) (83) (84) (85) (86) The thermal rearrangement of cis-1,2-divinylcyclopropanes i s generally a f a c i l e process, a fa c t which i s a t t r i b u t e d to the r e l i e f of r i n g s t r a i n upon rearrangement. In f a c t , the parent cis-1,2-divinylcyclopropane (80a) has only recently been i s o l a t e d and reactions designed to produce i t have usually led to the formation of 1,4-cycloheptadiene (81a) by concomitant (82 rearrangement. For example, both the Hofmann degradation of compound (87) (83) and the addition of methylene to the ce n t r a l bond of hexatriene (88) led to the exclusive formation of 1,4-cycloheptadiene (Scheme 24). Scheme 24 H © © ^ C H 2 C H 2 N ( C H 3 ) 3 O H © © / ^ C H 2 C H 2 N ( C H 3 ) 3 OH H 80°C (87) c (83) H L H ~CH 2 N 2 CuCl,-40°C (80a) o (81a) 70 Moreover, cis-1,2-divinylcyclopropane has been shown to rearrange r a p i d l y to 1,4-cycloheptadiene above -20°C, with a h a l f - l i f e of approximately 90 seconds at 3 5 ° C ^ 4 \ More substituted cis-1,2-divinylcyclopropanes have been found to be more thermally stable and temperatures t y p i c a l l y i n the range of 15° to 110°C are required to carry out t h e i r rearrangement at a reasonable r a t e ( 8 5 ) (e.g. (89) and (90) (82)). Various studies i n the l i t e r a t u r e have attempted to c o r r e l a t e the s t r u c t u r a l features within some s p e c i f i c a l l y substituted cjLs-1,2-divinyl-cyclopropanes with t h e i r k i n e t i c data for rearrangement. A recent report (86) by Schneider and Rau i s most i l l u s t r a t i v e i n t h i s respect (Table 11) Of p a r t i c u l a r i n t e r e s t i n t h i s matter i s the contrasting k i n e t i c behavior of compound (80b) compared to (80d), both of which a f f o r d the same 1,4-cycloheptadiene (81b) and between (80c) and (80e) both of which must af f o r d , upon successful Cope rearrangement, compound (81c) (Table 11, Scheme 25). C l e a r l y , the configuration about the v i n y l group has a pronounced e f f e c t on the rate of rearrangement, with the Z-stereochemistry producing the largest impediment. In f a c t , i n the case of compound (80e) the ^-stereochemistry about the two double bonds precludes rearrangement and only c i s £ trans isomerization i s observed. Furthermore, comparison 71 (86) Scheme 25 fast cr •  slow (E)-(80b) (81b) (Z)-(80d) (E,E)-(80c) (81c) (Z,Z)-(80e) (91) Table 11 K i n e t i c data and products i n the Cope rearrangement of cis-1,2- diaIkenylcy clopropanes ' Reactant V i n y l configuration Product k r e l ( 4 0 ° C ) A H ^ 2 7 3 O K A S 273°K (Kcal/mol) (eu) ( 8 0 a ) 2 ^ J " 5 8 0 0 18-8 ± 0- 3 "9.4 ± 1 (E) (81 b) / = = = ? Sf^ 1500 19.7 ± 0.3 -8.5 ± 1 ( G O c J j ^ W> (81c)(3C (80e 1100 19.8 ± 0.5 -9.4 ± 1.5 21.9 ± 0.5 -13.2 ± 1.5 (Z/Z) no Cope rearrangement; only c i s - t r a n s isomerization 72 amongst compounds (80a), (80b) and (80c) reveals that although the v i n y l groups with E-stereochemistry do provide reductions i n K ^, t h e i r e f f e c t i n comparison to Z-substituents i s n e g l i g i b l e . The r e l a t i v e rates of these reactions may be r a t i o n a l i z e d by considering the proposed t r a n s i t i o n state geometry v i a which rearrangement i s thought to occur. Rearrangements of the type (80) •> (81) are generally believed to be concerted [ 2 + 2 + 2 ] processes i n v o l v i n g a c i s o i d or O S T r S T T S b o a t l i k e t r a n s i t i o n state geometry, a preference which i s contrasted with the transoid or c h a i r l i k e conformation shown to be favored i n a c v c l i c systems (Schemes 26 and 27). Scheme 26 A c y c l i c 1,5-dienes transoid (favored) c i s o i d (disfavored) With regard to the three possible t r a n s i t i o n state geometries depicted i n Scheme 27, i t i s reasonable to expect that only the endo-c i s o i d geometry would be r e a d i l y accessible. This i s r a t i o n a l i z e d based on the po s t u l a t i o n that, f o r each of the three t r a n s i t i o n states depicted, the associated free energy of a c t i v a t i o n for rearrangement from 73 Scheme 27 cis-dlvinylcyclopropanes (80a) ( endo,endo) (80a)(endo,exo) (80a)(exo,exo) •T.:. endo-cisoid (favored) transoid (disfavored) exo-cisoid (disfavored) — s r - ^ geometrically • rrzz^S allowed N (z,z) (81a) (93) (94) forbidden (E,Z) r forbidden (E,E) cis-1,2-divinylcyclopropane should be influenced, to some extent, by the relative s t a b i l i t y of the respective cycloheptadiene which is produced. In this respect, i t is easy to see that the endo-cisoid geometry must be the preferred one as (IE, 4Z)- and (IE, 4_E)-cycloheptadiene ((93) and (94), respectively) are molecules too strained to exist independently by virtue of the incorporation of a trans-double bond within a seven membered ring. Thus, during the divinylcyclopropane rearrangement the two vinyl groups are folded back over the cyclopropane ring and brought into close proximity before rearrangement can occur (Scheme 28). In this manner, steric factors hindering the formation of the required endo-cisoid conformation and/or the necessary interaction of the double bonds should destabilize the 74 t r a n s i t i o n state, which i n turn would be r e f l e c t e d i n the kinetic, data f o r rearrangement. In the t r a n s i t i o n state f o r (80b) -»• (81b) the major s t e r i c d i f f e r e n c e compared to (80a) •+ (81a) i s a methyl-hydrogen (MH) non-bonded i n t e r a c t i o n (Scheme 29, t r a n s i t i o n state B, i n t e r a c t i o n b ) . S i m i l a r l y , (80c) -*• (81c) has a methyl-methyl (MM) i n t e r a c t i o n ( t r a n s i t i o n state C_, i n t e r a c t i o n c) and (80d) (81b) one MH and one methyl-ring (MR) i n t e r a c t i o n ( t r a n s i t i o n state D, i n t e r a c t i o n d). On the assumption that the s t e r i c d e s t a b i l i z i n g i n t e r a c t i o n free energies for MH, MM, and MR remain constant within any s e r i e s , Schneider's r e l a t i v e rate data have been evaluated as follows: AAGHTH = 0.84 kcal/mole, AAG'MM = 1.03 kcal/mole and AAG'MR =4.55 kcal/mole ( a l l calculated at 40°C). For example, i f one considers t r a n s i t i o n states B and D i n Scheme 29 and assumes that the presence of a methyl-hydrogen (MH) i n t e r a c t i o n ( i n t e r a c t i o n b) contributes equally to the d e s t a b i l i z a t i o n of each of these t r a n s i t i o n states i t then follows that the observed diffe r e n c e i n the r e l a t i v e rates of rearrangement f o r compounds (80b) and (80d) (Table 11, k (80b): 1500; k r e j _ (80d):1) i s a d i r e c t r e s u l t of the presence of a methyl-ring (MR) i n t e r a c t i o n which i s present i n t r a n s i t i o n state I) ( i n t e r a c t i o n d) for the 75 Scheme 29 (80a) A no non-bonded i n t e r a c t i o n s (81a) C H -(80b) ^ C H 3 + C H 3 DEMH, A A G ^ H = 0.84 kcal/mol (8ib) C ^ 3 3 (80c) r^H3 + 9 H3 C H c^MM, A A G J M = 1 .03 kcal/mol ( 8 i c ) (80d) , C H 3 H i Jd=MR, A A G + R = 4.55 kcal/mol (81b) C H 3 C H (80e) H C H 3 f (81c) 76 rearrangement of compound (80d) but absent i n t r a n s i t i o n 13 for the rearrangement of compound (80b). With the values of AAG'MH, MM and MR i n mind i t i s not d i f f i c u l t to understand why compound (80e) does not rearrange to compound (81c) as the necessary t r a n s i t i o n state f o r t h i s transformation ( t r a n s i t i o n state _E) would possess one MM and two MR i n t e r a c t i o n s (AAG^  = 10.13 kcal/mole at 40°C) which would preclude the rearrangement, even at elevated temperatures (e.g. 165°C) . Two further examples of rearrangement being circumvented, presumably due to s t e r i c i n t e r a c t i o n s within the t r a n s i t i o n state, are with compounds (95) and (9_7)^ 9^ which should experience even more severe non-bonded i n t e r a c t i o n s than those previously mentioned. 77 The thermal behavior of trans-1,2-divinylcyclopropanes i s i n sharp contrast to the epimeric cis-compounds. Trans-1,2-divinylcyclopropane ( 9 9 ) ^ ^ ) i s a stable i s o l a b l e compound. However, at elevated temperatures t h i s substance also rearranges cleanly and e f f i c i e n t l y to 1,4-cyclohepta-diene (81a), a r e s u l t of considerable importance from a synthetic point of view. It i s postulated that the Cope rearrangement of t r a n s - 1 , 2 - d i v i n y l -cyclopropane proceeds v i a either of two mechanistic pathways: e i t h e r an i n i t i a l epimerization of the trans-compound to the cis-isomer which c y c l i z e s d i r e c t l y , or v i a a d i r a d i c a l intermediate which c y c l i z e s d i r e c t l y (Scheme 30). However, i n general, based on the high s t e r e o s p e c i f i c i t y that ( 9 1 ) t h i s o v e r a l l process exhibits (e.g. (100), (101) and (103) •> (81c) , (911 (92) (102) and (104) , r e s p e c t i v e l y ) i t i s thought that the reaction proceeds v i a an i n i t i a l s t e r e o s p e c i f i c isomerization (usually rate determining) a f f o r d i n g the corresponding cis-isomer followed by normal (88) concerted rearrangement Scheme 30 78 In addition to the conventional thermal isomerization, the photo-chemical complement has r a r e l y been applied. F i r s t applied to the (81^ synthesis of dictyopterene C (82) by Pickenhagen , a more recent (72) a p p l i c a t i o n by Wender has demonstrated that t h i s mode of isomerization has shown a d d i t i o n a l merit (see Schemes 31 and 32). For example, the thermolysis of the mixture of the compounds (106a) and (106b) (1:4, r e s p e c t i v e l y ) , under conditions which would have been s u f f i c i e n t to promote c i s - t r a n s isomerization (case 1, Scheme 32) was fru s t r a t e d by Scheme 31 Scheme 32 (107) (108) 1. >_ 140° C —= *- minor(<20%) major (106b) (108) the formation of the triene (108) along with only a minor amount of the desired product, compound (107). Thermolysis of t h i s same mixture under milder conditions (case 2) also afforded a disappointing r e s u l t . In both of these cases the amount of compound (107) formed was approximately equivalent to the amount of compound (106a) s t a r t i n g material (^20%). Thus, the Cope rearrangement of compound (106b) was precluded by an even more f a c i l e rearrangement of t h i s material to compound (108), v i a a [1,5]-sigmatropic hydrogen atom s h i f t , under the former thermolysis con-d i t i o n s . However, under milder conditions with simultaneous photolysis (case 3) the o v e r a l l rearrangement could be almost e x c l u s i v e l y diverted 80 i n favor of the desired product. In addition to these synthetic points, the e f f i c i e n t and stereo-s e l e c t i v e elaboration of substituted 1,2-divinylcyclopropanes, which could serve as possible precursors i n projected natural product syntheses, has recently been demonstrated by Marino^*^, P i e r s ^ 4 " ^ , and Wender^^. Most noteworthy i n t h i s area has been the elaboration and rearrangement of compounds such as (112) , (41) and (117) (Schemes 33, 34 and 35), which have been elaborated i n convergent synthetic schemes. Scheme 33 U (no) H Q / ^ H 3 O + C H 2 C H 3 (109) a ( H D OCH 2 CH 3 Scheme 34 Li C 6 H 5 SCu (40) (119) (41) (42) 81 Scheme 35 V.OCH3 ^"\>CH3 (114) (115) (116) spontaneous at r . t . The Objective The synthetic accomplishments described i n th i s chapter were prompted (93) by preliminary work car r i e d out i n our laboratory . These previous in v e s t i g a t i o n s had provided an e f f i c i e n t method i n which the l i t h i u m phenylthio(7-norcar-2-enyl)cuprate reagents (122a) and (122b) could be coupled with the B-iodo enones (40) and (127) (Schemes 36-39). Scheme 36 tert-BuLi o - Li (120) (121) C,HcSCu o 5 ^ > - C u S C 6 H 5 (122a)=exo-Cu (122b)=endo-Cu 82 Scheme 37 (122b) endo-Cu Scheme 38 (40) NaOCFL CH3OH (125) Li 0>~ c l u S C 6 H 5 (122a,b) 1:1 exo-Cu endo-Cu (40) 2. NaOCH. CH30H (IP (125) (126) r e f l u x i n g o-dichlorobenzene 40h (quant.) The products of these reactions were fu n c t i o n a l i z e d b i c y c l i c dienes which were shown to undergo Cope rearrangement. In the case of the reaction between the cuprate reagent (122a) and the g-iodo enone (40) i t was evident that the products of th i s reaction ( t r i c y c l i c enones (124) and (125)) were derived, not unexpectedly, from a f a c i l e divinylcyclopropane rearrangement of compound (123) under the conditions of i t s formation or attempted i s o l a t i o n . The presence of the conjugated t r i c y c l i c enone (125) was evidently 83 Scheme 39 ( ^ } > ^ C u S C 6 H 5 _ (128) Li I "A , 2 0 h ( 1 2 2 a , b ) 1 : 1 1 . ( 1 2 7 ) ( ^ ^ . . . f i ^ e x o - C u 'H e n d o - C u 2. NaOCH3/CH3OH ^ due to a thermodynamically favorable isomerization of the B,y-unsaturated t r i c y c l i c enone (124). In contrast the epimeric divinylcyclopropane (126), prepared i n a s i m i l a r manner (see Scheme 38), was a stable i s o l a b l e substance. However, thermolysis (178°C, 40 h) of t h i s compound (iso l a t e d by chromatography) afforded, i n nearly quantitative y i e l d , the t r i c y c l i c enone (125). Thus, i t was apparent that the elaboration of the t r i c y c l i c enone (125) did not require the use of the is o m e r i c a l l y pure cuprate reagent (122a). S i m i l a r l y i t was also shown that the t r i c y c l i c enone (128) could be obtained using the epimeric mixture of cuprate reagents (122a/b) and the B-iodo enone (127) (Scheme 39). Thus, i n an o v e r a l l sense,an e f f i c i e n t method for the elaboration of the s t r u c t u r a l l y i n t e r e s t i n g bicyclo[3.2.2] nona-2,6-diene system (130) was developed i n a convergent synthetic scheme which could u t i l i z e e i t h e r of the isomeric cyclopropyl bromides (Scheme 36, (122) exo and endo) towards 84 the same synthetic goal. (130) Although t h i s type of structure ( i . e . (130))has been synthesized (94) previously v i a the thermal rearrangement of the parent b i c y c l i c diene system of compounds (123), (126), and (129) ( i . e . (131/162))further i n v e s t i g a t i o n s towards the production of more highly f u n c t i o n a l i z e d and s t r u c t u r a l l y diverse derivatives by t h i s strategy have not been reported p r i o r to the preliminary work discussed or the i n i t i a t i o n of the studies reported here. ok © H (162) (132) As a possible extension to the synthetic methods accomplished i n our laboratory, i t was proposed to investigate the rearrangement of compounds of the generalized structures (136b) and (137) (Scheme 40). Since compounds (136b-E) and (137a-d) each have a substituent on the OTMS (O - t r i m e t h y l s i l y l ) 85 Scheme 40 €>C Q>-o™s ——>Q>° H (136b-E/Z) (153/154) (149/150) (137) n= 4-7 (155) (151) enol ether f u n c t i o n a l i t y which i s i n a c i s stereochemical r e l a t i o n s h i p with the cyclopropyl moiety i t was questioned whether or not these b i c y c l i c systems would mimic the thermal behavior of the previously discussed examples of s t e r i c a l l y encumbered trans- and cis-1,2-divinylcyclopropanes. (e.g. (80e), (95) and (97), Scheme 41). Should the Cope rearrangements of these b i c y c l i c dienes prove to be unsuccessful then presumably the combination of the non-bonded in t e r a c t i o n s associated with the t r a n s i t i o n state geometry shown i n Scheme 41 (interactions e and f) would be s u f f i c i e n t l y d e s t a b i l i z i n g to preclude the rearrangement of t h i s type of compound. However, should the Cope rearrangements prove to be s y n t h e t i c a l l y useful then hydrolysis of the intermediate enol ethers (153/154) and (155) thus produced would constitute an e f f i c i e n t synthesis of the f u n c t i o n a l i z e d and substituted bicyclo[3.2.2 ] non-6-ene systems of the generalized structures (149/150) and (151). In addition to these proposals the 86 Scheme 41 (156-E) (156-E) (136b-E) (136b-E) l ! ^ -OTMS = T M S O ^ (153) 87 independent Cope rearrangement of compounds (136b-Z) and (136b-E), i f successful, would provide valuable information into the s t e r e o s p e c i f i c i t y of the Cope rearrangement within these b i c y c l i c diene systems. Scheme 42 (136b-Z) (156-Z) (154) 88 DISCUSSION (1) Preparation of the cyclopropyl ketones As outlined above, the thermal rearrangement of the substituted b i c y c l i c and t r i c y c l i c dienes, compounds (136) and (137) (Table 13, Scheme 40), i s the subject of t h i s section of the t h e s i s . The preparation of t h i s s e r i e s of compounds required the p r i o r preparation of the corresponding cyclopropyl ketones (_13_4a-g) (Schemes 43 and 44) which, presumably, could be transformed r e a d i l y into the desired substrates according to standard synthetic methods. It i s w e l l known that the addition of a l k y l l i t h i u m reagents to l i t h i u m carboxylates i s a useful method for the preparation of unsymmetrical ( 9 5 ) ketones . Accordingly, the ketone (134a) was prepared, i n excellent y i e l d (95%), by the addition of methyllithium to the known b i c y c l i c acid ( 1 3 3 ) ( 9 6 ) under the condi tions outlined i n Scheme 43. Conversely, the Scheme 43 H C0 2 H H CH 3Li(2equiv) (133) DME-ether -78°C to r . t . H > - C 0 C H 3 (95%) H (134a) DME= 1,2-dimethoxyethane preparation of the ketones (134b-g) was conveniently accomplished by the addition of the cyclopropyllithiums (121) to the l i t h i u m carboxylates (135) under the conditions outlined i n Scheme 44. The y i e l d s of these reactions were quite good and the r e s u l t s along with some c h a r a c t e r i s t i c spectroscopic 89 data for these ketones are l i s t e d i n Table 12. Scheme 44 •COR (120) (121) (134b-g,exo/endo) (134b-g,exo) Experimental conditions 1. tert-BuLi (2.0 equiv), ether-pentane, -78"C (2.5 h). 2. RC0 2Li (135) ( 1.3 equiv), -78°C (1 h), room temperature (5 h). 3. THF-HOBut (5:1), K0But ( c a t a l y t i c ) , room temperature (3 h). (120) = (120a = exo-bromide; 120b = endo-bromide; 1:5.6) (121) = (121a = e x o - l i t h i o ; 121b = endo-lithio) (134), (135) (b) R = CH2CH3 (c) R = c y c l o - C ^ (d) R = cyclo-C^H^ (e) R = cyclo-C H 5 y (f) R = cyclo-C^H., 6 11 (g) R = cyclo-C^H^ 3 The method was p a r t i c u l a r l y a t t r a c t i v e i n view of the ready a v a i l a b l i l i t y of the 7-bromobicyc lo[ 4.1.0]hept-2-enes (120a and 120b), (93 ) previously prepared i n our laboratory , and the commercial a v a i l a b i l i t y of the prerequisite acids (conjugate acids of compounds 135b-g). However, i t i s pertinent to point out a few experimentally important aspects of the preparative scheme. 90 Table 12 Preparation of the cyclopropyl ketones CL34a-g) and some selected  spectroscopic properties Entry Ketone ( y i e l d % ) a Infrared ( c m - 1 ) b 1H nmr (&) C, C-7 cyclopropyl (C=0), (C=C) proton  2.20 d a b d 1 134a (95) 1695, 1640 2 134b (71) 1680, 1630 3 134c (74) 1665, 1625 4 134d (84) 1680, 1635 5 134e (73) 1680, 1635 6 134f (83) 1680, 1630 7 134g (83) 1680, 1630 2.20 (d of d, J=4.0Hz, J'=3.0Hz) 2.32 (d of d, J=J'=4.0Hz) 2.11 (d of d, J=4.5Hz, J'=3.1Hz) 2.22 (d of d, J=J'=4.0Hz) 2.24 (d of d, J=J'=3.8Hz) 2.19 (d of'd, J=J'=3.9Hz) Y i e l d of i s o l a t e d pure product. A l l i n f r a r e d spectra were taken of l i q u i d f i l m s . *H nmr spectra taken of samples i n d i l u t e CDCl^ s o l u t i o n . The m u l t i p l i c i t y of t h i s proton resonance was obscured by the resonance of the terminal methyl group wit h i n t h i s compound. H •COR H (134) (a) R = CH 3 (b) R = CH 2CH 3 (c) R = cyclo-C^H^. (d) R = cycl o - C 4 H 7 (e) R = cyclo-C 5H 9 (f) R = cyclo-CgH^ (g) R = cyclo-C 7H^ 3 During the i n i t i a l i n v e s t i g a t i o n s of t h i s method i t was noted that reproducible r e s u l t s were obtained only when the preliminary lithium-halogen exchange reaction (step 1, Scheme 44) was performed by the slow addition of 91 an ethereal so l u t i o n of the b i c y c l i c cyclopropyl bromides (120) to a s o l u t i o n of t e r t - b u t y l l i t h i u m (2.0 equiv) i n ether-pentane at -78°C. Furthermore, i t became apparent that the q u a l i t y of the t e r t - b u t y l l i t h i u m solutions used i n these preparations was also of importance, with solutions which contained only a l i m i t e d amount of alkoxide contaminant ( t y p i c a l l y <5%) providing the best and most consistent r e s u l t s . The assignment of stereochemistry to the cyclopropyl ketones (134b-g) obtained by t h i s o v e r a l l procedure (Scheme 44, steps 1-3) was based on nmr spe c t r a l data. In each case, the (C-7) cyclopropyl proton adjacent to the carbonyl group i n these ketones was quite r e a d i l y observed as a p a r t i a l l y or f u l l y overlapped doublet of doublets, e x h i b i t i n g coupling constants with the cyclopropyl protons on C - l and C-6 i n the range of 3.0-4.5Hz. (134) Since i t i s well established that, i n cyclopropane systems, the i c i n a l coupling constants J (4.0-9.6Hz) are generally lower than v b trans (97) (7.0-12.6Hz) , the exo*- stereochemical assignments f or the ketones cxs  The stereochemical descriptors c i s and trans are not applicable to the des c r i p t i o n of the stereochemical r e l a t i o n s h i p s within the b i c y c l i c and t r i c y c l i c structures shown above. By convention the descriptors endo (synonomous with syn) and exo (synonomous with anti) are used i n these instances. 92 (134b-g) i s amply j u s t i f i e d . Furthermore, i n each case, the exo-ketone was the anticipated product of the base catalyzed epimerization (step 3) of the i n i t i a l l y i s o l a t e d crude mixture of the endo- and exo- ketones, based on consideration of the r e l a t i v e thermodynamic s t a b i l i t i e s of the two epimeric substances. (2) Preparation of the Cope rearrangement substrates Conversion of the cyclopropyl ketones (134) into the 0 - t r i m e t h y l s i l y l enol ethers (OTMS enol ethers) (136) and (137) was performed r o u t i n e l y and e f f i c i e n t l y by the s i l y l a t i o n (chlorotrimethylsilane (TMSC1)) of the k i n e t i c a l l y formed enolate anions of the former substances (lithium d i i s o -propylamide (LDA), tetrahydrofuran (THF) so l u t i o n , - 7 8 ° C ) ^ 9 8 \ The y i e l d s of these reactions were quite good and the re s u l t s along with some character-i s t i c spectroscopic data of the products appears i n Table 13. In each case, i t was clear from the H^ nmr sp e c t r a l analysis of the product (s) of these reactions that the k i n e t i c deprotonation of the ketone and the subsequent s i l y l a t i o n of the enolate anion(s) thus produced were e n t i r e l y r e g i o s e l e c t i v e , since no regioisomeric products could be detected. Moreover, i n f r a r e d analysis of these substances showed no evidence for the presence of any -1 (99) methylene-cyclopropane systems (OTMS enol ether v (C=C) -1770 cm ) t which would have resulted from the undesirable deprotonation of the a-keto cyclopropyl proton of the parent ketones. The observed r e g i o s e l e c t i v i t i e s i n these OTMS enol ether preparations are i n accord with the r e s u l t s of previous studies undertaken i n our (74 laboratory, which employed other s t r u c t u r a l l y s i m i l a r cyclopropyl ketones ' (Scheme 45, Table 14). The high r e g i o s e l e c t i v i t i e s observed i n these 93 Table 13 Preparation of the O - t r i m e t h y l s i l y l enol ethers of the cyclopropyl ketones (134). H 1. LDA/THF,-78°C JH QTMS OTMS C 0 R ~ f > \(_R or H 2. TMSC1 -78°C to r . t . R (134) (a) R = CH 3 (b) R = CH 2CH 3 (d) R = cyclo-C 4H 7 (e) R = cyclo-C 5H 9 (f) R = cyclo-C^H^^ (g) R = c y c l o - C 7 H i 3 (136a) R = R' = H (137) (a) n = 4 (136b-E) R = H, R' = CH 3 (b) n = 5 (136b-Z) R = CH 3 > R' = H (c) n = 6 (d) n = 7 Ketone Product (s) ( y i e l d %) Infrared (cm"1) v(C=C) XH nmr (6) OTMS 134a 136a (89) 1635 0.21 134b 136b (94, E/Z; 1:1) 1680 0.16, 0.20 134d 137a (100) 1690 0.15 134e 137b (98) 1680 0.17 134f 137c (98) 1680 0.17 134g 137d (98) 1680 0.18 previous in v e s t i g a t i o n s for those cases i n which the trans- 2-vinylcyclo-propyl ketones were employed are i n sharp contrast with the r e s u l t s obtained for those cases where the corresponding cis-isomers were used as substrates. These previous observations were s u f f i c i e n t motivation to prompt us to invest i g a t e the rearrangement of only the ex o - b i c y c l i c and t r i c y c l i c dienes (136) and (137) i n the present study (Table 13). 94 Scheme 45 -V^  2. IMSCl J X ~ 0 T M S trans-ketones trans-1,2-divinylcyclopropanes cis-ketones c i s - 1 , 2 - d i v i n y l - methylene cyclopropanes cyclopropanes TMSC1= ( C H 3 ) 3 S i C l While the transformation of the ketone (134b) into the OTMS enol ethers (136b-E) and (136b-Z) ( b i c y c l i c dienes) was e f f i c i e n t and t o t a l l y r e g i o s e l e c t i v e the associated s t e r e o s e l e c t i v i t y exhibited i n t h i s process was non-existent (1:1 mixture). I t i s generally believed that the stereo-s e l e c t i v i t y observed i n t h i s type of transformation i s established upon the k i n e t i c deprotonation of the carbonyl compound involved. Thus, where there i s the p o s s i b i l i t y of obtaining diastereomeric products i n these reactions, the observed r a t i o of s i l y l enol ethers produced i s believed to be a d i r e c t r e f l e c t i o n of the r a t i o of the corresponding enolate anions present before s i l y l a t i o n . Furthermore, i t has been f a i r l y w e l l established 95 Tab l e 14 R e g i o s e l e c t i v i t i e s observed f o r the k i n e t i c deprotonation s i l y l a t i o n of some selected c i s - and trans-2-vinylcyclopropyl (74,100) ketones. Ketone Conditions R e g i o s e l e c t i v i t y (%) divinylcyclopropane methylene cyclopropane t_rans-2-Vinylcyclopropyl ketones rz^h' 1- LDA-THF, -78 C 2. TMSC1 (138) R= -(CH 2) 3CH 3 100 (139) R= -CH 2C(CH 3) 3 100 (140) R= y \ / 100 (141) R= <-\ 1 0 0 (142) R= l-( > 87 : 13 96 _cis-2-vinylcyclopropyl ketones R e g i o s e l e c t i v i t y (%) divinylcyclopropane methylene cyclopropane 1. LDA-THF, -78 C 2. TMSC1 (143) R •KD (144) R= -CH 2C(CH 3) 3 (145) R= 7.3 (146) R =K3 1.(a) LDA-THF, -78 C (b) LTMP-THF, -78°C (c) LiEt 2N-THF, -78°C 1 1 2.3 1 2.3 1 TMSC1 (a) LDA (li t h i u m diisopropylamide); LTMP (lithium 2,2,6,6-tetramethyl-piperidide) ;TMSCl(chlorotrimethylsilane) ; L i E t 2 N ( l i t h i u m d i e t h y l -amide) . 97 what factors control the enolate configuration i n these deprotonations. For example, Heathcock and co-workers have r e c e n t l y ^ 1 ^ ^ demonstrated that the deprotonation of an ethyl carbonyl compound (CH^CH^COR, where R = a l k y l or alkoxyl) i n which the other group, R, attached to the carbonyl i s small* gives predominantly the trans-enolate** (Table 15). As the R group becomes larger more cis-isomer i s produced. With very large R groups the c i s -enolate i s the overwhelming diastereomer produced. Thus, i f one compares the s t e r e o s e l e c t i v i t i e s shown i n Table 15 with that obtained f o r the transformation of ketone (134b) into the s i l y l enol ethers (136b-E) and (136b-Z) i t can be seen that the exo-7-bicyclo[4.1.0]hept-2-enyl moiety i s intermediate i n si z e between that of an ethyl and isopropyl group. The s t e r e o s t r u c t u r a l assignments for the two diastereomeric OTMS enol ethers (136b-E) and (136b-Z) appeared rather problematic since e s s e n t i a l l y equivalent amounts of these two substances were obtained. However, i t was fortunate that these two substances could be separated nearly completely The terms large and small require d e f i n i t i o n . What i s important i n these k i n e t i c deprotonations i s the s i z e of the group, R, r e l a t i v e to the s i z e of the methyl group of the e t h y l moiety. Thus, for example, i n propionate esters a l l alkoxy groups are small, since the methyl group of the e t h y l moiety only senses ( s t e r i c a l l y i n t e r a c t s with) the oxygen part of the alkoxy group i n the t r a n s i t i o n state for deprotonation. The configurational descriptors c i s - and trans- are used i n the context that the 0 or 0 M + group of the enolate i s always considered as the point of reference (see Table 15). 98 Table 15 S t e r e o s e l e c t i v i t i e s observed for the k i n e t i c deprotonations of some selected ethyl carbonyl compounds.^^l) J L , (ethyl carbonyl compound) LDA-THF o -78 C OLi trans-enolate cis- e n o l a t c S t e r e o s e l e c t i v i t y (%) trans c i s OCH3 0 ( C H 3 ) 3 CH 2CH 3 CH(CH 3) 2 C 6 H 5 C(CH 3) 3 97 97 70 44 0 0 3 3 30 56 100 100 -exo-bicyclo[4.1.0] hep-2-enyl 52 (or 48) 48 (or 52) H CH H exo-bicyclo[4.1.0]hep-2-enyl by preparative g l c . In t h i s manner the r e l a t i v e glc retention times of the two diastereomers present within the 1:1 mixture (OTMS enol ethers A and J3) could be correlated with t h e i r respective XH nmr resonances. A summary of these co r r e l a t i o n s appears i n Table 16. 99 Table 16 H nmr sp e c t r a l and glc co r r e l a t i o n s f o r the OTMS enol ethers  : (136b-E/Z) H O OK. H (134b) ,H OTMS H (136b-Z) .H OTMS o H / (136b-E) E/Z= 1:1 Compound OTMS enol ether A OTMS enol ether B Glc composition (%) , r e l a t i v e Rt* 48 long 52 short 1 ,,.c H nmr assignment (5) 0.21 (s, OTMS), 1.50 (d of d, i J=6.6Hz, J =0.7Hz, v i n y l methyl), 4.52 (q, J=6.6Hz, a c y c l i c v i n y l proton). 0.16 (s, OTMS), 1.62 (d, J=6.9Hz, v i n y l methyl), 4.63 (q , J=7.0Hz, a c y c l i c v i n y l proton) Glc analysis was performed on a 6' x 1/8" s t a i n l e s s s t e e l column packed with 10% by weight SE-30 stationary phase on Chromosorb W(HP) The terms short and long are used i n a q u a l i t a t i v e sense. The actual d i f f e r e n c e i n the retention times f o r these two substances (ARt . _ ) i n an isothermal run at 130°C (30 ml/min He) on the column described above was 0.4 minutes. '''H nmr sp e c t r a l data r e f e r to a d i l u t e CDCl^ s o l u t i o n . 100 With reference to Table 16 i t can be seen that, despite the rather subtle differences i n the chemical s h i f t s of the resonances l i s t e d f o r the isomers A and J3, the only d i s t i n g u i s h i n g spectroscopic feature these two diastereomers exhibit i s the presence or absence of a homoallylic coupling associated with the v i n y l methyl resonances (6 1.50, 6g 1.62 ppm). This observation i s consistent with the general s t e r e o s t r u c t u r a l properties exhibited by homoallylic couplings (^J). For example, d i f f e r e n t values are generally observed for "*J transoid and c i s o i d and the re l a t i o n s h i p "*J transoid > "*J c i s o i d i s quite general (A^J t y p i c a l l y 0.3Hz). Based on t h i s premise i t appears that isomer A exhibits a transoid homoallylic coupling of 0.7Hz while isomer B, presumably, exhibits a c i s o i d coupling too small to be resolved. Thus, the OTMS enol ethers A and _B were assigned structures (134b-2) and 134b-E), r e s p e c t i v e l y . A survey of the l i t e r a t u r e reveals that there also e x i s t s another precedent for these nmr spectroscopic assignments. House and co-workers This homoallylic coupling i s assigned to a coupling between the protons of the v i n y l methyl group and the (C-7) a l l y l i c cyclopropyl proton i n the generalized structure (136b). 5. H OTMS H ^ 3 (13Gb) (136b) 101 1. Have u t i l i z e d H nmr spectroscopy with moderate success for the stereo-s t r u c t u r a l assignment of stereoisomeric t r i m e t h y l s i l y l enol ethers, a l k y l enol ethers and enol acetates. It was pointed out that the 3-vinyl proton of an E-diastereomer (derived from ketones) generally resonates downfield of the corresponding proton i n the Z-diastereomer (A6 t y p i c a l l y 0.6 to 0.1 ppm). With reference to Table 16 i t then follows that isomer B should be once again assigned as structure (134b-E) while isomer A would be correspondingly assigned as structure (134b-Z). Thus, i t can be seen that, i n each case, consideration of the r e l a t i v e s i z e of the homoallylic coupling associated with the v i n y l methyl resonance and the r e l a t i v e p o s i t i o n of the chemical s h i f t of the 8-vinyl proton within these two diastereomers both r e s u l t i n the same s t e r e o s t r u c t u r a l assignments. It i s pertinent to point out at t h i s time that there have appeared i n the l i t e r a t u r e some noted objections to the use of the l a t t e r spectroscopic c r i t e r i a for t h i s type of s t e r e o s t r u c t u r a l assignment. For example, the B-vinyl proton resonances for compounds (147E) and 147Z) have been , „ -, • • (104) reported to be an exception to the House generalization . However, the diffe r e n c e i n the chemical s h i f t s f o r the B-vinyl protons i n these OTMS OTMS (147-Z) (147-E) diastereomers i s only the diffe r e n c e i n the 0.06 ppm. s h i f t s of It may be c r i t i c i z e d these protons may not that, i n t h i s case, be s i g n i f i c a n t and 102 thus, the ap p l i c a t i o n of the generalization may not be j u s t i f i e d . * In support of t h i s opinion i t can be seen i n House's o r i g i n a l papers describing t h i s method that a l l the examples c i t e d where the general i z a t i o n was v a l i d had involved differences i n the range of 0.6-0.1 ppm for the s h i f t s of these B-vinyl protons. With regard to the present case i t can be seen that the d i f f e r e n c e i n the s h i f t s of the a c y c l i c v i n y l protons i n the OTMS and ethers A and _B i s 0.11 ppm and thus i t i s reasonable to believe that the ste r e o s t r u c t u r a l assignments given to these two substances are correct. 3. Cope rearrangement studies (a) Prelude As mentioned previously i t i s the in t e n t i o n of t h i s section of the thesis to evaluate whether or not the Cope rearrangements of the b i c y c l i c diene (134b-E) and the t r i c y c l i c dienes (137a-d) are f e a s i b l e . If successful, these transformations would allow for the elaboration of the yet unknown s t r u c t u r a l l y i n t e r e s t i n g ketones shown i n Scheme 46. In order to carry out t h i s study, protocol required the p r i o r establishment of a r e l i a b l e set of spectroscopic data ( i r , XH nmr) which It i s indeed g r a t i f y i n g to discover that regardless of whether or not the diastereomeric p a i r of OTMS enol ethers (147E)/(147Z) are t r u l y an exception to the House genera l i z a t i o n that the st e r e o s t r u c t u r a l assignments for these two isomers may be c o r r e c t l y predicted on the basis of a reported homoallylic coupling, s i m i l a r to that previously discussed, which i s exhibited by the E-isomer but absent or too small to be resolved i n the spectrum of the Z-isomer. This fact was apparently overlooked i n House's o r i g i n a l a r t i c l e . 103 Scheme 46 H OTMS (136a) R = R' = H (I36b-E) R = H,R' = CH 3 (136b-Z) R = CH3,R' = H (148) R = R' = H (149) R = H, R' = CH 3 (150) R = CH3, R' = H OTMS (a) n=4 (b) n=5 (c) n=6 (d) n=7 (151a-d) would serve to i d e n t i f y the bicyclo[3.2.2]non-6-en-3-one system which i s the common s t r u c t u r a l feature of ketones (149/150) and (151). In this respect i t was f e l t that the spectroscopic characterization of ketone (148), the parent compound i n t h i s s e r i e s , would set a simple precedent. For example, i t was anticipated that the p o s i t i o n of the in f r a r e d carbonyl absorption maxima of ketone (148) would be c h a r a c t e r i s t i c of, or provide a point df reference f o r , the e n t i r e s e r i e s . The value of v(C=0) obtained for ketone (148) would also provide valuable information regarding the e f f e c t of incorporating a v i n y l bridge within a cycloheptanone structure (v(C=0) cycloheptanone : 1705 cm "*"), since nothing was known about this type of s t r u c t u r a l modification of a seven membered r i n g ketone. As ketone 104 (148) i s the parent compound i n t h i s s e r i e s i t was also a n t i c i c i p a t e d to provide a basic set of *H nmr chemical s h i f t and coupling data which might serve to i d e n t i f y the a-keto methylene (-CH^CO-), the saturated bridge methylenes (-CH-CH - ) , the bridgehead methines, and the o l e f i n i c protons — 2 — 2 within ketones (148-151). The Cope rearrangement of the b i c y c l i c diene (136a) was anticipated to proceed without complication as the parent hydrocarbon, compound (131) had been previously reported to undergo t h i s type of transformation (Scheme 47). There was also ample l i t e r a t u r e precedent to expect that the subsequent hydrolysis of the Cope rearrangement product thus obtained would also proceed without complication. Scheme 47 H 16 5° C H (131) (132) + (136a) (152) (148) Thus, thermolysis of a sample of the b i c y c l i c diene (136a) at 240°C for 6 h followed by simple hydrolysis (THF - IN HC1 ( c a t ) , r t , 10 min) of 105 the intermediate thermolysate thus obtained afforded a crude hydrolysate which by glc was shown to be a mixture of two components i n the r a t i o of 9:1. The major component* of t h i s mixture was i s o l a t e d by column chromatography on s i l i c a gel (66% y i e l d of the t h e o r e t i c a l f o r C 9 H 1 2 ° ^ ' A l t h o u g h t h i s substance provided s a t i s f a c t o r y combustion analysis f or C^H^O i t was shown by glc to be contaminated with about 3% of an u n i d e n t i f i e d substance. This contaminant could be conveniently removed by low temperature (-78°C) c r y s t a l l i z a t i o n of t h i s sample from petroleum ether (30-60°C). The nmr spectrum of t h i s i s o l a t e d substance appears i n Figures 1 and 2. I t was c l e a r from the examination of t h i s spectrum that an element of symmetry, a mirror plane, was present within the structure of t h i s substance, as shown by the r e l a t i v e i n t e g r a l s obtained for each of the resonances exhibited (see inset Figure 1). Thus, each resonance was a t t r i b u t e d to a p a i r of homotopic protons. Furthermore, the prominent spectral observation of an AB spin system (6 2.47 and 6 2.59 ppm, resonances C and D, respectively) with A B a major coupling constant (J.,,) of 16.8Hz was t y p i c a l of a p a i r of AB diastereotopic geminal protons adjacent to a carbonyl f u n c t i o n a l i t y ^^"^. Both these observations and the accompanying assignments located i n Figure 1 were consistent with the s t r u c t u r a l assignment of t h i s substance as ketone (148). Ketone (148) exhibited an i n f r a r e d carbonyl absorption at 1680 cm The value of v(C=0) obtained f o r t h i s b i c y c l i c ketone was unexpectedly low for an unconjugated cycloheptanone ( i . e . compare structures (159) and (148) i n Table 17). The reason for t h i s carbonyl absorbance being so low i s not The structure and o r i g i n of the minor component within the crude hydrolysate was not investigated. 106 c l e a r . Table 17 Some i n f r a r e d absorption frequencies f o r some selected cyclo-heptanoid ketones. (106,107,108) Entry Compound v (C=0) \> (C=C) — c max max (106) (157) f A 1705 cm 1 O (158) fi \ - 1660 cm 1 (159) O ( 1 0 7 ) 1700 cm 1 1600 cm 1 (108) (160) S\ \ _ 1710 cm 1 0>° (148) f i\ V - o 1680 cm X It i s not known whether the p o s i t i o n of v (C=C) i s coincident with max the carbonyl absorption or i s non-coincident and too weak to detect. Resonance Integral (relative) H nmr assignment (6) BJ C D E F 1 1 1 1 1.70-1.80(m,4H,-CH CH2-) 2.47(d of d,J=16.8Hz,J=3.6Hz,protons E2/H^) 2.59(d of d,J=16.8Hz,J=4.2Hz,protons H^/H^') 2.62-2.66(diffuse m,2H,protons H^H ) 6.31-6.36( m,2H, o l e f i n i c protons) (148) 11 I ED C A,B FIGURE 1. The 400 MHz H nmr spectrum of the ketone (148) r-1 o 109 (b) Cope rearrangement of the substituted b i c y c l i c compounds (136b) With the above set of spectroscopic properties f a i r l y w e l l established attention was then turned to the transformation of the b i c y c l i c dienes (136b-E) and (136b-Z) (1 : 1 mixture) i n t o the ketones (149) and (150). As was mentioned i n the introduction i t was hoped that the Cope rearrangement of both these stereoisomers would be successful and that the rearrangements would proceed i n a s t e r e o s p e c i f i c manner. In t h i s respect there seemed l i t t l e question as to the success of the Cope rearrangement of the Z-isomer, as the parent compound i n t h i s series had now been shown to undergo successful rearrangement. However, the fate of compound (136b-E) upon thermolysis at 240°C was uncertain. Thermolysis of the 1 : 1 mixture of the s i l y l enol ethers (136b-E) and (136b-Z) at 240°C for 6 h followed by hydrolysis of the intermediate thermolysate (vide supra) thus obtained and chromatographic p u r i f i c a t i o n ( s i l i c a gel) of the crude hydrolysate* afforded two epimeric ketones (vide i n f r a ) , ketone C_ and ketone D, as approximately a 1 : 1 mixture (72% y i e l d of the t h e o r e t i c a l based on C^QH.^0). Analysis by both t i c and glc indicated the presence of only two components within t h i s mixture. A second, more s e l e c t i v e chromatographic separation of the less polar component ( t i c ) from t h i s mixture provided an a n a l y t i c a l sample of ketone (2. However, the Although a number of products were detected by glc and t i c within the crude hydrolysate (at l e a s t s ix) i t was decided to i s o l a t e only the two major components within t h i s mixture, which comprised approximately 85% of the t o t a l integrated detector response ( g l c ) . 110 sample of ketone I) obtained from t h i s same separation, although apparently homogeneous by t i c and glc, was c l e a r l y a mixture of two substances, as r e a d i l y indicated by the combined i n f r a r e d and XH nmr analysis of t h i s sample. The i s o l a t e d sample of ketone I) exhibited two unequally intense carbonyl absorptions, v(C=0) 1730 cm 1 (weak) and v(C=0) D 1680 cm 1 (strong) while the XH nmr spectrum exhibited two high f i e l d methyl resonances [61.12 (d, J=7.3Hz) and 6^ 1.07 (d, J=7.0Hz)] and two o l e f i n i c resonance regions [6 5.83 (m) and 6^ 6.31-6.36 (m)] i n which both sets of resonances were i n the r a t i o of -1:9, r e s p e c t i v e l y . The observation of the i n f r a r e d carbonyl absorption at 1730 cm x i s a t t r i b u t e d to a cyclopentanone, the tentative i d e n t i t y and o r i g i n of which w i l l be discussed l a t e r . The i s o l a t i o n of a pure sample of ketone D by chromatographic techniques proved to be rather problematic. However, the i s o l a t i o n of a pure sample of t h i s substance was f i n a l l y achieved i n an i n d i r e c t manner v i a the base catalyzed epimerization (HOBu*" - THF (1.5), KOBu*" (cat), r t , 1 h) of a pure sample of ketone C (vide supra), which afforded a 1 : 1 mixture of ketones C and D which were separated by a subsequent column chromatography. Based on the i n f r a r e d analysis of ketones C_ and D_ (v(C=0) c 1680 cm \ v(C=0)p 1680 cm x ) i t appeared reasonable to assume that these two substances were the an t i c i p a t e d epimeric 2-methylbicyclo[3.2.2] non-6-en-3-ones, compounds (149) and (150) . The i s o l a t e d sample of ketone (3 provided the ^H nmr spectra shown i n Figures 3-5, while ketone _D provided those shown i n Figures 6-9. Examination of Figures 3 and 6 reveals that ketone p_ exhibits a greater d i f f e r e n c e i n the chemical s h i f t s of i t s o l e f i n i c protons (A6 ~0.11 ppm) than does ketone £ (A6 -0.06 ppm). FIGURE 5 High f i e l d methyl i r r a d i a t i o n of the ketone (149) FIGURE 6 The 400 MHz H nmr spectrum of the ketone (150) FIGURE 7 Display of the high f i e l d region of Figure i n t e n s i t y increase FIGURE 8 High f i e l d methyl i r r a d i a t i o n of the ketone (150) (150) Resonance 1Hnmr(6) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0.14(s) 0.16(B) 0.17(s) 0.18(s) 0.21(s) 0.21(s) 0.95(d,J=7.2 Hz) 1.01(d,J=7.1 Hz) 1.07(d,J=6.7 Hz) 1.15(d,J=7.1 Hz) 1.51(d of d,J=6.6 Hz,J'=0.7 Hz) 1.61(d,J=6.9 Hz) 4.52(d,J=6.6 Hz) 4.64(d,J=6.9 Hz) 5.12(d of d,J=9.0 Hz,J'=l.l Hz) 5.15(d,J=9.0 Hz) 12 FIGURE 10 The 400 MHz H nmr spectrum of the product obtained from the p a r t i a l thermolysis of the OTMS enol ethers (136b-E/Z) 119 Inspection of molecular models for both ketones (149) and (150) suggests that, regardless of the conformational preference e i t h e r of these two compounds would display i n s o l u t i o n , ketone (150) should exhibit a greater difference i n the chemical s h i f t s of i t s v i n y l protons than should ketone (149). This p r e d i c t i o n i s r a t i o n a l i z e d based on the average closer proximity of the methyl substituent to the proximal o l e f i n i c proton i n ketone (150) than that i n ketone (149). Thus, the closer proximity of the methyl substituent i n ketone (150) to t h i s o l e f i n i c proton should r e s u l t i n a greater dissymmetry of the two o l e f i n i c protons i n t h i s ketone compared to those i n ketone (149) . Based on the above comparative XH nmr s p e c t r a l observation and the above ratio n a l e , ketone J} was assigned to structure (150) while ketone C_ was correspondingly assigned to structure (149). (149) Ketone C The conformational preferences that these two ketones exhibit i n s o l u t i o n were established on examination of the v i c i n a l coupling constants (150) Ketone D 120 between and i n these two systems* (Schemes 48 and 49). For each of these two diastereomeric ketones the methine proton (H^) adjacent to the methyl substituent could be r e a d i l y i d e n t i f i e d v i a i r r a d i a t i o n of the unobscured high f i e l d methyl resonance. In t h i s manner the v i c i n a l coupling between the methine proton (H^) and the bridgehead proton (H^) could be c l e a r l y examined. Ketone (149) exhibited no measurable (~0Hz) coupling constant between H, and H 0 while ketone (150) correspondingly exhibited a It i s common p r a c t i c e i n discussions of stereochemical r e l a t i o n s h i p s , that reference to a s p e c i f i c proton (H^) within a p a r t i c u l a r structure, normally follows the numbering scheme used to describe the carbon skeleton. Thus, f o r example, i n ketone (149) the bridgehead proton proximal to the methyl substituent i s referred to as H^, which i s the same number used to describe the carbon atom which bears t h i s proton i n the 2-methyl bicyclo[3.2 .2]non-6-en-3-one system shown below. In the event that there e x i s t two protons on the same carbon atom the proton which i s proximal to the o l e f i n i c f u n c t i o n a l i t y w i l l be designated  here as the unprimed number (e.g. see H, and H,,). 121 coupling ( J R H ) of 3.8Hz (see Figures 3 and 8). Both of these values are consistent with the conformational assignments shown i n Schemes 48 and 49. Scheme 48 Stereochemistry and conformational preference f o r ketone (149) (conformational preference) E ( f a v o r e d ) I ( d i s f a v o r e d ) Conformer E_ Conformer F_ Newman proje c t i o n Newman pro j e c t i o n 122 Scheme 49 Stereochemistry and conformational preference f o r ketone (150) © = 1 (stereochemis try) (150) G_( favored ) (conformational preference)' H CH3 H_(disf avored) Conformer Newman proje c t i o n 0 -II <|> = 35 H 4 CH-Conformer H Newman proje c t i o n >H-J&I&-H; H4 \={p/ CH3 0 J c a l c o = +5.4 Hz 1 2 J H H C a l c 0 5 ° =-0-2 Hz 1 2 The values of J calc were calculated s o l e l y f o r comparison to H 1H 2 those recorded. The t h e o r e t i c a l values were determined according to (109) the following equations 2 J = 8.5 cos (b-0.28 J = 9.5 cos 6-0.28 0o«J><90° 90o<(t><180c With reference to the above discussion i t i s i n t e r e s t i n g to note that the observed coupling constant between protons H<- and H^, for ketone (149) i s 5.5Hz while that calculated for t h i s same coupling constant i n conformer E of ketone (149) v i a the Karplus equation (see footnote at the bottom of Scheme 49) for a dihedral angle (<j>) of 35° (as measured from the model) i s 5.4Hz. Thus, i t appears that the Karplus r e l a t i o n s h i p may be r e l i a b l y used to estimate the v i c i n a l dihedral angles within these systems. Based on t h i s premise, i t i s concluded that ketone (149) e x i s t s e x c l u s i v e l y as conformer _E. S i m i l a r l y , i t can be shown* that the r e l a t i v e populations of conformers G and H of ketone (150) are approximately 7 : 3 , r e s p e c t i v e l y . With the s t e r e o s t r u c t u r a l assignments of ketones (149) and (150) f a i r l y well established i t appeared that the previously discussed tentative s t e r e o s t r u c t u r a l assignments for the OTMS enol ethers A and B might be reinforced v i a an independent approach. As i t was a simple matter to e f f e c t a near complete separation of a small sample of either of these two substances i t was proposed that the thermolysis of either of these substances followed by the hydrolysis of the rearrangement product thus obtained, under k i n e t i -c a l l y c o n t r o l l e d conditions, would allow for the d i r e c t comparison of the ketone obtained with the ketones (149) and (150), previously characterized. * The measured coupling constant between and of ketone (150) i s 3.8Hz while that calculated for conformer G_ i s +5.4Hz and the corre-sponding value for conformer H i s -0.2Hz. A simple weighted average of these two values [ (1-X) (5.4) + (X) (-0.2) = 3.8.*. X = 0.28] reveals that the population of conformer G of ketone (150) i s approximately 70%. 124 If i n either case the s t e r e o s p e c i f i c i t y of the rearrangement(^5,110) be assumed then the stereochemistry of the ketone obtained could be correlated with a s p e c i f i c stereochemistry (E or Z) of the respective OTMS enol ether (A or 15) used. Thus, i f one makes the reasonable assumption (see Schemes 50 and 51) that the rearrangement of eit h e r of the OTMS enol ethers (136b-Z) or (136b-E) proceeds v i a a one-centered e p i m e r i z a t i o n ^ 1 1 1 ^ followed by normal Cope rearrangement of the resultant endo-bicyclic diene (compounds (156-Z) and (156-E), respectively) v i a a bo a t - l i k e t r a n s i t i o n s t a t e ^ ^ \ then compound (136b-Z) could be correlated with compound (154) while compound (136b-E) could be correlated with compound (153) . It then Scheme 50 H OTMS L > - > ^ (136b-Z) 'H III T M S O ^ CH3 T M S O - ^ A (156-Z) C H 3 H T M S 0 - TMSO (T^ -OTMS (154) Ij /V-OTMS (154) H 30 + (150) 125 Scheme 51 (153) (149) follows that the hydrolysis of the rearrangement product thus obtained, under k i n e t i c a l l y c o n t r o l l e d conditions, would allow for the c o r r e l a t i o n of the ketone obtained with the OTMS enol ether that had been thermalized. I s o l a t i o n of the le s s v o l a t i l e component (OTMS enol ether A) from the 1 : 1 mixture of the b i c y c l i c dienes (136b-Z) and (136b-E), by preparative g l c , as a 90 : 10 mixture of isomers, followed by the thermolysis of t h i s sample at 240°C for 6 h (neat) afforded a four component mixture as detected by g l c . The major component of t h i s mixture comprised 126 approximately 77% of the t o t a l integrated response. Simple hydrolysis (THF - IN HCl (cat), r t , 10 min) of the thermolysate correspondingly afforded a four component mixture i n which the major component comprised approximately 80% of the t o t a l integrated response. The major component of t h i s mixture exhibited a glc retention time and t i c mobility i d e n t i c a l with those of ketone (150). Since i t had already been established that the thermodynamic r a t i o of ketones (149) and (150) was 1 : 1 (vide supra) i t was clear from the above r e s u l t that the hydrolysis of the rearrangement products had been performed under k i n e t i c a l l y c o n t r o l l e d conditions. Thus, i t was reasonable to assume from these r e s u l t s that the OTMS enol ether A could be i d e n t i f i e d as the b i c y c l i c diene (136b-Z) while, correspondingly, the OTMS enol ether J3 could be assigned the structure (136b-E). (c) Relative rate of rearrangement experiment for the b i c y c l i c dienes (136b-E) and (136b-Z). In an attempt to e s t a b l i s h the r e l a t i v e rates of Cope rearrangement of the two stereoisomeric b i c y c l i c dienes (136b-E) and (136b-Z) a p a r t i a l thermolysis of the 1 : 1 mixture of these substances was performed. Thermolysis of t h i s mixture at 240°C for approximately 40 minutes resulted i n about a 26% conversion of these substances into thermolysis products. Examination of the XH nmr spectrum of the thermolysate (Figure 10) revealed that the The Cope products, compounds (153) and (154) (Schemes 50 and 51) which are derived from the OTMS enol ethers A and j5 can be resolved i n this g l c analysis as was shown from the previous preparation of the ketones C and D. 127 Z-isomer was approximately two times more thermally l a b i l e than the E-isomer. Inspection of the OTMS region of th i s spectrum revealed the presence of s i x components within this mixture,two of which were the b i c y c l i c dienes (136b-E/Z). Of the remaining four components within t h i s mixture two were nec e s s a r i l y a t t r i b u t e d to the Cope rearrangement products, compounds (153) and (154). These two components were i n the approximate r a t i o of OTMS O < Q/-0TMS H / (136b-E) (153) 1 : 1.5 and were present to n e a r l y the same extent to which the b i c y c l i c dienes (136b-E) and (136b-Z) had undergone tr a n s f o r m a t i o n , r e s p e c t i v e l y . For the former two substances there was observed, i n each case, a ' methyl resonance (8 1.01 and 1.15) and an o l e f i n i c resonance (6 5.15 and 5.12, r e s p e c t i v e l y ) which were a t t r i b u t e d to the protons which are i n d i c a t e d The approximate (±10% of quoted value) proportions of the s i x observed components within the thermolysate, as determined by nmr were: 42, 32, 14, 10, 1 and 1%. The f i r s t two of these values correspond to the proportions of the b i c y c l i c dienes (136b-E) and (136b-Z) which had not undergone transformation. The next two values (14 and 10%) ne c e s s a r i l y correspond to the proportions of the two Cope rearrangement products. The remaining two proportions (1% each) correspond to two un i d e n t i f i e d substances. , H OTMS w -H (136b-Z) (154) 128 (c i r c l e d ) i n the generalized structure (153/154). (136b-E/Z) > i s r C H 3 H (153/154) f H /V-OTMS The remaining two minor components within the thermolysate ( 1% each) each exhibited complementary resonances (6 0.95 (d, J=7.2Hz), <5 1.07 (d, J=6.7Hz)) s i m i l a r to the methyl resonances observed for compounds (153) and (154) (1.01 (d, J=7.lHz) and 1.15 (d, J=7.lHz)). The chemical i d e n t i t y and o r i g i n of the two substances responsible for these resonances i s unknown. Scheme 52 H .H H H (99%) (131) (161) (162) (132) CO ™ (163) 1 2 9 Recently, Schneider and Csacsko (94) have demonstrated that the b i c y c l i c diene (131) (parent system to compounds (136b-E) and (136b-Z)) (Scheme 52). The process by which t h i s substance was produced was at t r i b u t e d to the intermediacy of a d i r a d i c a l intermediate (structure (161)) i n the epimerization of compound (131) to compound (162). With t h i s i n mind i t was reasonable to speculate that a s i m i l a r process might be active during the rearrangement of the b i c y c l i c dienes (136b-E) and (136b-Z). I f such a process were act i v e during the rearrange-ment of these dienes then compounds (165) and (166) would be present within the f i n a l product mixture (Scheme 53). Furthermore i t then follows that Scheme 53 underwent Cope rearrangement with concurrent formation of compound (163) .H (164-Z) OTMS H (136b-Z) OTMS (154) (153) .H OTMS (136b-E) (164-E) (165) (166) the hydrolysis of t h i s mixture would afford four ketonic products (Scheme 54). Thus, i t i s appropriate to re-examine the previous discussions 130 Scheme 54 IU-0TMS I II (154) (149) (150) ^ - O T M S O >0TMS 05=0 0 > (165J (166) (167) (168) concerning the spectroscopic r e s u l t s reported f o r the thermolysate obtained from the p a r t i a l thermolysis of the b i c y c l i c dienes (136b-E/Z) and of the hydrolysate obtained i n the preparation of the ketones (149) and (150) (ketones A and B) from these dienes. With reference to Figure 10 i t can be seen that the XH nmr resonances 7 and 9 bear a d i s t i n c t s i m i l a r i t y to those resonances, 8 and 10, which are exhibited by compounds (153) and (154). I t thus seems reasonable that the former two resonances are derived from the same type of s t r u c t u r a l feature as those responsible for the l a t t e r two resonances, namely of the a l l y l i c methyl groups of compounds (153) and (154) (see structure o v e r l e a f ) . These spectroscopic observations are consistent with (but by no means i d e n t i f y ) the structures (165) and (166) proposed i n Scheme 54. It was also previously mentioned that there was observed an u n i d e n t i f i e d ketonic product 131 >CH3 OTMS (153/154) i s o l a t e d i n conjunction with ketone (150) which could not be separated chromatographically but which could be detected by i n f r a r e d and AH nmr sp e c t r a l observations. It was observed that the in f r a r e d carbonyl absorption of t h i s unknown ketonic product was at 1730 cm 1 which i s c h a r a c t e r i s t i c of a cyclopentanone (v(C=0) cyclopentanone 1735 cm x ) . Furthermore, i t was noticed that t h i s ketone exhibited a s i m i l a r type of XH nmr resonance to that exhibited by the methyl groups of ketones (149) and (150) . Thus, s i m i l a r to the above argument, i t seemed reasonable that t h i s ketone possessed a si m i l a r s t r u c t u r a l feature to that present i n ketones (149) and (150) (see structure (149/150) below) but which was most l i k e l y not incorporated into a seven membered r i n g but a f i v e membered r i n g as shown i n structure (169). In addition, i t was also noted that t h i s unknown ketone c l e a r l y exhibited some type of XH nmr o l e f i n i c resonance. These i n f r a r e d and '''H nmr spe c t r a l (149/150) (169) 132 observations were consistent with e i t h e r of the proposed structures, (167) and (168), shown i n Scheme 54. Although each of the proposed structures i n Schemes 53 and 54 are purely speculative the i n t e r n a l consistency of the discussed spectral observations strongly supports these precedented proposals. (d) Cope rearrangement of the t r i c y c l i c diene ser i e s The successful transformation of the OTMS enol ether (136b-E) into ketone (149), under the conditions outlined above, set a strong precedent for the successful Cope rearrangement * of the t r i c y c l i c dienes (137a-d) and ultimate conversion of these substances into the ketones (151a-d) shown i n Scheme 55. Thermolysis of each of the t r i c y c l i c dienes at 240°C f or 12 h Scheme 55 (a) n=4 ( b ) n=5 ( c ) n=6 ( d ) n=7 (137) (155) (151) followed by hydrolysis of the resultant thermolysate and chromatographic p u r i f i c a t i o n of the crude hydrolysate afforded a ketonic product. In each case, the i s o l a t e d ketone exhibited an in f r a r e d carbonyl absorption at 1680 cm 1 and provided s a t i s f a c t o r y combustion analysis f o r the anticipated structure. The nmr analysis of these substances revealed that each of 1 the ketones c h a r a c t e r i s t i c a l l y exhibited an AB spin system which was at t r i b u t e d to an a-keto methylene s i m i l a r to that observed from ketone (148). Based on these observations, i t did not seem presumptuous to conclude that, i n each case, the Cope rearrangement of the t r i c y c l i c diene had taken place as proposed and that these ketones were those shown i n Scheme 55. With these s t r u c t u r a l assignments at hand a general survey of the XH nmr spectra of the ketones derived from both the b i c y c l i c and t r i c y c l i c dienes revealed that, with the exception of ketone (151c), there i s observed a c l e a r d i s t i n c t i o n i n the chemical s h i f t s of the two bridgehead protons and H,.. In each case where th i s d i s t i n c t i o n i s observed, the bridgehead , , The numbering scheme used here to designate the positions of the various carbon atoms i n the t r i c y c l i c ketone series i s shown i n the structure below. (151) (151) In the following discussion the protons attached to these carbon atoms w i l l be designated with the same number that the carbon atom bears. In the event that there ex i s t s two protons on the same carbon atom then they w i l l be designated as indicated i n structure (151). 134 protons (H^) adjacent to the substituted a-keto methylene i s the more resolved m u l t i p l e t and, with the exception of ketone (151a), i t i s found to resonate at higher f i e l d than the bridghead proton (R\.) adjacent to the unsubstituted a-keto methylene. In each of these cases, the proton i s exhibited as a broadened doublet of doublets ( J , J' ~6-7Hz) due to strong v i c i n a l coupling with the adjacent v i n y l proton and, presumably, the proton H O I. In contrast, proton H i s exhibited as a d i f f u s e or unresolved 8 5 multiplet due to v i c i n a l couplings with the analogous protons mentioned and the unsubstituted a-keto methylene. The y i e l d s obtained for the transformation of the t r i c y c l i c dienes i n t o the ketones (151a-d) are f a i r to good (Table 18) and thus i t appears that the preparation of t h i s type of ketone v i a the Cope rearrangement of either the b i c y c l i c or t r i c y c l i c dienes described here i s a useful synthetic method. There appears to be no appropriate r a t i o n a l e why the e f f i c i e n c y of this o v e r a l l process i s b e t t e r i n some cases than i n others. It i s not known at t h i s time whether or not the a p p l i c a t i o n of more sophisticated thermolysis techniques ( i . e . gas phase thermolysis) would provide d i r e c t l y improved y i e l d s for these ketones. For example, i t i s not unreasonable to expect that during the prolonged periods (6-12 h) at 240°C required i n order to carry out these transformations,that the low y i e l d s i n It was e m p i r i c a l l y determined that these rearrangements should be performed at 240°C. At temperatures lower than t h i s (e.g. 220°C) the rearrangements were quite slow ( 24 h f o r completion) while at moderately higher temperatures (e.g. 260°G) quite noticeable reductions i n the y i e l d s of the i s o l a t e d thermolysates were noted. 135 Table 18 Preparation of the b i c y c l i c and t r i c y c l i c ketones H .OTMS (136a) R = R' = H (136b-E) R = H, R' = CH, (148) R = R' = H (149) R = H, R' = CH, (136b-Z) R = CH 3, R' = H (150) R = CH 3, R* = H (a) n=4 ( b ) n=5 ( c ) n=6 (d) n=7 (151) ,a Thermolysis time (h) at 240°C Ketone ( y i e l d %) 136a 6 148 (66) 136b-E/Z (1 : 1) 6 149+ 150 137a 12 151a (80) 137b 12 151b (61) 137c 12 151c (81) 137d 12 151d (49) Overal l y i e l d of d i s t i l l e d product a f t e r chromatographic p u r i f i c a t i o n . A l l the ketones except ketones 148 and 149/150 were i s o l a t e d pure. This ketone was i s o l a t e d contaminated with approximately 3% of an impurity which could be removed by low temperature (-78°C) r e c r y s t a l l i z a t i o n of t h i s material from pentane. These ketones were i s o l a t e d contaminated with approximately 5% of an unknown material (however see Schemes 53 and 54 and re l a t e d discussions). 136 some instances may be a d i r e c t r e s u l t of the thermal i n s t a b i l i t y of the products and/or reactants towards a l t e r n a t i v e modes of reaction. For instance, the rearrangement of the t r i c y c l i c dienes (137b) and (137d) both afforded s i g n i f i c a n t amounts of n o n - d i s t i l l a b l e residue upon i s o l a t i o n of the intermediate thermolysate (19 and 13% r e s p e c t i v e l y ) . Furthermore, a l l of the above transformations afforded varying proportions (11-29%) as of yet u n i d e n t i f i e d by-products, which i n some cases proved to be d i f f i c u l t to remove. A case i n point was the rather i n e f f i c i e n t chroma-tographic i s o l a t i o n of ketone (151d). (79) A recent and related report to the present study which appeared i n the midst of the investigations reported here suggests that there i s good reason to believe that the e f f i c i e n c y of these rearrangements may be d i r e c t l y improved by the a p p l i c a t i o n of more sophisticated thermol-y s i s techniques. In t h i s respect i t was shown that dramatically d i f f e r -ent product r a t i o s may be obtained for the thermolysis of compound (170) (Scheme 56), depending on the temperature employed. For example, r e -arrangement of compound (170) i n r e f l u x i n g benzene for 48 h afforded a mixture of 20% of compound (171), the Cope rearrangement product, and 80% of a not f u l l y characterized triene believed to be 1-(3-cyclopentenyl)-3-methyl-l,3-butadiene (172). In contrast, when the rearrangement of compound (170) was c a r r i e d out at 350°C and 15 Torr, the sole product was compound (171), obtained i n a quantitative y i e l d . Scheme 56 138 EXPERIMENTAL Preparation of the b i c y c l i c esters (173) and (174) .H • C 0 2 C 2 H 5 ' C 0 2 C 2 H 5 H (173) (174) Hubert A s l i g h t l y modified version of the general procedure developed by 113) was followed i n th i s preparation. Thus, a s o l u t i o n of ethyl diazoacetate (28.0 g, 0.25 mol) i n pentane (75 mL) was slowly added, over a 30 h period, to a s o l u t i o n of anhydrous rhodium(II) acetate (190 mg, 0.43 mmol, diazoacetate : c a t a l y s t = 580 : 1) i n 1,3-cyclohexadiene (100 g, 1.25 mol, diene : diazoacetate = 5 : 1 ) at room temperature, under argon. A f t e r a short induction period, the reaction proceeded throughout the addition procedure, as evidenced by the c h a r a c t e r i s t i c evolution of nitrogen from the emerald green s o l u t i o n . The mixture was f r a c t i o n a l l y d i s t i l l e d at atmospheric pressure to recover as much of the 1,3-diene as possible (44 g, 49% recovery). The r e s i d u a l v o l a t i l e materials were removed (aspirator) and the residue was d i s t i l l e d d i r e c t l y ( a i r bath temperature) 40-60°C/0.3 Torr l i t . bp 72-76°C/15 T o r r ( U 3 ) ) to a f f o r d 36.1 g (90% y i e l d based on diazo-acetate) of a mixture of the epimeric esters (173) and (174) as a clear c o l o r l e s s o i l . Glc analysis (OV-17) of t h i s material showed i t to be composed of two components which were present i n the r a t i o of approximately 1 : ^ ((174) and (173) respectively) . No d i e t h y l fumarate or maleate could be detected. The H^ nmr spectrum of th i s material was i d e n t i c a l with that 139 previously reported^ 1 ; <5 1.21 and 1.24 (overlapping t r i p l e t s , J=7.5Hz and J=7.5Hz, 3H, -COCH2CH3 of (173) and (174), r e s p e c t i v e l y ) , 5.35-6.25 (unresolved m u l t i p l e t s , 2H, v i n y l protons). Preparation of the b i c y c l i c acids (175) and (133) H .H C0 2 H f^b~C02H H H (133) (175) (176) A s l i g h t l y modified and improved version of the preparation reported by Berson^1'''4^ was employed. Thus, a mixture of the b i c y c l i c esters (173) and (174) was saponified, at r e f l u x for 1 h, i n a mixture of 10% aqueous sodium hydroxide (300 mL) and ethanol (500 mL). A f t e r the mixture had been concentrated under reduced pressure (aspirator, 600 mL d i s t i l l a t e ) the residue was d i l u t e d with 1.4 L of water and then a c i d i f i e d (~pH 2) with s o l i d potassium hydrogen s u l f a t e (-80 g), which caused p r e c i p i t a t i o n of the epimeric acids. The suspended acids were reconverted into soluble s a l t s by the addition of potassium carbonate (35 g) and sodium bicarbonate (30 g). To t h i s solution was added, v i a burette, a s o l u t i o n of KI/I^ (113.1 mL, aq. 2.400 M i n K l and 0.700 M i n 1^) to an end point, which was indicated by a p e r s i s t e n t yellow-brown suspension. This mixture was extracted with dichloro-methane (3 x 200 mL), the organic extracts were washed with water (2 x 100 mL), and the aqueous phases were combined. S u f f i c i e n t potassium hydrogen s u l f a t e (-155 g) was added to p r e c i p i t a t e the b i c y c l i c acid (133) 140 from the aqueous s o l u t i o n . The suspension was extracted with d i c h l o r o -methane (4x200 mL) , the extract was washed with water (100 mL), dried and the solvent was removed affor d i n g the crude b i c y c l i c a c i d (133) as a l i g h t tan s o l i d . This material was dried ( r t , 0.3 Torr) overnight to a constant weight (32.9 g). The crude acid obtained was p u r i f i e d by d i s s o l v i n g i t i n b o i l i n g methylcyclohexane (150 mL), t r e a t i n g the s o l u t i o n with activated c h a r c o a l - c e l i t e and f i l t e r i n g while hot. The f i l t r a t e was concentrated and the residue dried ( r t , 0.3 Torr) for 1.5 h affording the b i c y c l i c acid (133) (32.3 g) as a white c r y s t a l l i n e material, which was pure and exhibited mp 85-86°C ( l i t 8 5 - 8 6 ° C ) ; i r (1% i n KBr) v :3600-3250 (broad OH), 3055, 3025, 3000, 2900, 2825, 1710, 1680, 1490, max 1445, 695 cm"1; ^ nmr 6: 1.50-2.3 (diffuse m, 7H), 5.40-5.70 (m, IH), 5.85-6.10 (m, IH) , 12.25 (s, IH, -C0_H); Anal, calcd. for C oH i n0 o: Z— o 10 z C 69.55, H 7.30; found: C 69.62, H 7.29. The iodo lactone (176) of the b i c y c l i c acid (175) was i s o l a t e d from the organic extract obtained i n the iodo l a c t o n i z a t i o n procedure employed above. Thus, the dried (MgSO^) dichloromethane extract was concentrated to dryness affo r d i n g a l i g h t brown s o l i d residue (20.2 g) which was dissolved i n b o i l i n g 1 : 1 chloroform-methylcyclohexane (60 mL). Activated charcoal-c e l i t e treatment of t h i s s o l u t i o n followed by hot f i l t r a t i o n and washing of the f i l t e r cake (3 x 50 mL of hot chloroform) afforded a clear c o l o r l e s s s o l u t i o n . Concentration of the f i l t r a t e and drying of the residue ( r t , 0.3 Torr) overnight afforded a white c r y s t a l l i n e material (19.8 g) (mp 124-125°C (dec), l i t . mp 129-131°C (dec) ( 1 1 5 ) , 134-136°C ( d e c ) ( 1 1 4 ) ) . Repeated r e c r y s t a l l i z a t i o n , as above, did not r a i s e the melting point of t h i s material. This material exhibited t i c ( s i l i c a g e l , 1 : 2 e t h y l acetate/pet. ether (30-60°C), Rf 0.4; ir(CHCL Q)v : 1755, 1320, 1155, 995, 980 cm"1; 3 max 141 XH nmr (.400 MHz) 6: 1.57 (broadened d of d of d, J=9.0Hz, J'=7.6Hz, J"=1.4Hz, IH, cyclopropyl proton), 1.75-1.83 (m, IH), 1.83-2.20 (m, 2H), 2.08 (d of d, J=9.0Hz, J'=6.3Hz, lH, a-carboxy cyclopropyl proton), 2.23-2.33 (m, IH), 2.63 (d of d of d, J=7.6Hz, J'=6.4Hz, J"=6.3Hz, IH, cyclopropyl proton), 4.28 (d of t, J=7.6Hz, J'=3.7Hz, lH), 4.99 (d of d, J=6.lHz, J'=3.7Hz, lH); Anal, calcd. f o r C.H 10: C 36.39, H 3.44; found: C 36.45, H 3.34. o y The b i c y c l i c a c i d (175) was regenerated from the iodo lactone (176) when activated zinc d u s t ^ 1 1 ^ (5.1 g, 85 mmol, 4 equiv) was added to a s t i r r e d suspension of the iodolactone (6.1 g, 23 mmol), at room temperature, i n a mixture of ether (200 mL) and g l a c i a l a c e t i c acid (3.0 mL, 48 mmol, 2 equiv). This reaction was monitored by t i c and showed no conversion of the iodo lactone u n t i l , a f t e r a 7 minute induction period, a mild exothermic reaction was i n i t i a t e d , 10 minutes a f t e r which the reaction was complete. The mixture was f i l t e r e d and the remaining zinc was washed with ether (100 mL). The f i l t r a t e was c o l o r l e s s but r a p i d l y developed a l i g h t brown col o r a t i o n within 5 minutes. The f i l t r a t e was extracted with brine (2 x 50 mL) contain-ing a few c r y s t a l s of sodium t h i o s u l f a t e which removed t h i s c o l o r immediately. The organic phase was dried (MgSO^), concentrated, and the residue was evacuated (0.3 Torr, 1 h) which afforded the crude b i c y c l i c a c i d (175) (3.15 g, 100%) as a white s o l i d . An a n a l y t i c a l sample of t h i s material -could be obtained v i a the c h a r c o a l - c e l i t e treatment employed for the b i c y c l i c acid (133). The p u r i f i e d b i c y c l i c acid exhibited mp 92.5-93.5°C ( l i t mp 83-8 4 P c ( 1 1 4 ) ir(cHCl„) v : 3150-3050 (broad), 2920, 1700, 1195, 1120, J max 890 cm"1; 1H nmr 5: 1.6-2.2 (diffuse m, 9H), 5.6-6.0 (unresolved m u l t i p l e t s , 2H, v i n y l protons), 11.45 (broad s, IH, -CO^H); Anal, calcd. for C gH 1 C )0 2: C 69.55, H 7.30; found: C 69.44, H 7.46. 142 Preparation of the cyclopropyl ketone (134a) (134a) To a s t i r r e d s o l u t i o n of the b i c y c l i c acid (133) (10.0 g, 72.4 mmol) i n dry 1,2-dimethoxyethane (300 mL), at -78°C under an argon atmosphere, was added dropwise over a period of 15 minutes an ethereal solution of methyllithium-lithium bromide complex (126 mL, 148 mmol, 2.05 equiv). The mixture was s t i r r e d at t h i s temperature f o r 15 minutes, was warmed to room temperature and then was s t i r r e d for an a d d i t i o n a l 1 h. In order to destroy any excess methyllithium, anhydrous sodium acetate (^ 5 g) was added and s t i r r i n g was continued f o r a further 1 h. The mixture was then poured into water (500 mL) which resulted i n a two phase system. The upper organic phase was washed to n e u t r a l i t y with brine (2 x 100 mL). The combined aqueous phases were extracted with pet. ether (30-60°C, 5 x 100 mL) and the combined organic extracts were washed with brine (2 x 50 mL), dried (MgSO^), and concentrated. The residue was twice f l a s h d i s t i l l e d (0.3 Torr, -78°C trap, a i r bath temperature 50°C) a f f o r d i n g a c l e a r c o l o r l e s s o i l (9.35 g, 95%) for which s a t i s f a c t o r y combustion analysis could be obtained. T i c ( s i l i c a gel, 9 : 1 pet. ether (30-60°C)/ether, R f 0.18) and glc (0V-17) analysis indicated the presence of a s i n g l e component. This material exhibited i r ( f i l m ) v : r o r max 3050, 2950, 2860, 1695, 1360, 1300, 1180 cm"1; XH nmr 6: 2.20 (overlapping s i g n a l s , 4H, -C0CH 3 and -CHCOCH^), 5.40-5.70 (m, IH), 5.83-6.13 (m, IH); Anal, calcd. for C gH 1 20: C 79.37, H 8.88; found: C 79.15, H 8.75. 143 Preparation of the cyclopropyl bromides (120a) and (120b) H .H .H H Br Br •••Br ir VI (177) (120b) (120a) A modified version of the procedure used by Lau (93) was employed i n thi s procedure. Thus, a 500 mL fl a s k equipped with an addition funnel and re f l u x condenser was charged with 1,3-cyclohexadiene (22.5 g, 280 mmol), ethanol (1.1 mL), bromoform (71.1 g, 280 mmol) and benzyltriethylammonium chloride (550 mg, 1 mol % ) . To this r a p i d l y s t i r r e d mixture was added a sol u t i o n of 50% aqueous sodium hydroxide (140 mL) over a period of 10-15 minutes. A f t e r a b r i e f induction period (~15 min) a mildly exothermic reaction was noted, accompanied by a steady darkening of the reaction mixture to a dark brown color and a pronounced thickening of the s l u r r y . This mixture was then d i l u t e d with dichloromethane (100 mL) which ensured a s u f f i c i e n t l y mobile medium. The reaction mixture was allowed to s t i r f o r a further 1.5 h a f t e r which i t was poured i n t o dichloromethane (700 mL). This mixture was gently swirled and the lower aqueous phase was removed. The aqueous phase was extracted with dichloromethane (3x 100 mL), the organic extracts were combined, washed with water (3 x 500 mL), dried (MgSO^) and concentrated, aff o r d i n g a deep red-brown heavy o i l . When t h i s material was added dropwise, with rapid s t i r r i n g , to a large volume of pet. ether (800 mL), a f i n e brown s o l i d p r e c i p i t a t e d . To t h i s suspension was added successively C e l i t e (10 g) and F l o r i s i l (30 g) and the mixture was then f i l t e r e d through a short column of F l o r i s i l (15 x 5 cm). The column was 144 eluted with pet. ether (3 x 100 mL). The combined eluate was concentrated and the r e s i d u a l v o l a t i l e materials were removed ( r t , 0.3 Torr) overnight a f f o r d i n g the crude b i c y c l i c dibromide (177) (57.1 g, 79%) as a l i g h t amber o i l . Infrared analysis of t h i s material showed no bromoform to be present. To a cold (0°C) s o l u t i o n of the crude dibromide i n anhydrous ether (600 mL) and g l a c i a l a c e t i c a c i d (60 mL, 476 mmol, 4 equiv) was added, with rapid s t i r r i n g , an anhydrous ethereal (.200 mL) s l u r r y of f r e s h l y activated commercial zinc d u s t ^ x ± ^ (160 g, 1.2 mol, 11 equiv). The reaction was allowed to proceed while being p e r i o d i c a l l y monitored by glc (OV-17) and was found to be complete af t e r 2 h. While at 0°C the r a p i d l y s t i r r e d mixture was treated with N,N,N',N'-tetramethylethylenediamine (TMEDA, 100 mL), which quickly i n i t i a t e d an agglutination of the remaining s o l i d materials. The mixture was s t i r r e d manually u n t i l the mass became granular and magnetic s t i r r i n g was s u f f i c i e n t to maintain a suspension. The suspension was f i l t e r e d and the s o l i d residues were washed with ether (2 x 100 mL) a f f o r d i n g a clear c o l o r l e s s f i l t r a t e . This s o l u t i o n was extracted with half-saturated aqueous copper s u l f a t e s o l u t i o n (3 x 100 mL) and the aqueous washings were extracted with pet. ether (2 x 100 mL). The combined organic extracts were washed with 10% aqueous sodium hydroxide (2 x 50 mL) and brine (2 x 50 mL) and dried (MgSO^) and concentrated. Flash d i s t i l l a t i o n (.0.1 Torr, -78 PC trap, water bath temperature 50-60°C) of the residue afforded the cyclopropyl bromides (120a) and (120b) (27.9 g, 57% o v e r a l l y i e l d ) as a c o l o r l e s s o i l . Examination of t h i s mixture both by XH nmr and The term half-saturated i s used here i n the context that saturated aqueous copper s u l f a t e s o l u t i o n was d i l u t e d with an equal volume of water. 145 glc (OV-17) revealed i t to be composed of a 5.6:1 mixture of (120b) and * .1 . (120a), r e s p e c t i v e l y . This material exhibited spectra ( H nmr, i r ) (93) i d e n t i c a l with those reported previously i n our laboratory These cyclopropyl bromides could be stored conveniently at -20°C under argon for extended periods (1-2 months) without noticeable deterio-r a t i o n . However storage at room temperature f o r periods of 1-2 days resulted i n s u b s t a n t i a l decomposition. In th i s event, these compounds could be recovered i n pure form by the following simple procedure. The impure bromides are taken up into pet. ether, the solu t i o n i s extracted successively with portions of 6N aqueous sodium hydroxide u n t i l a c o l o r l e s s aqueous phase r e s u l t s , the organic phase i s washed free of base and the solu t i o n i s dried (MgSO^) and concentrated. F r a c t i o n a l d i s t i l l a t i o n of the residue (15 cm Vigreux column) affords the pure cyclopropyl bromides (bp 57-55°C/5 Torr) . General procedure for the preparation of the l i t h i u m carboxylates (135b-g) RC0 2Li (b) R = CH 2CH 3 (135) (c) R = cyclo-C^H^ (d) R = cyc l o - C A H 7 (e) R = cyclo-C <.Hg (f) R = c y c l o - C 6 H 1 1 (g) R = cyc l o - C 7 H ^ 3 Depending on the age of the zinc dust and e f f i c i e n c y of a c t i v a t i o n the r a t i o of the two cyclopropyl bromides w i l l vary to a moderate extent, with a t y p i c a l range of 5.6 to 9 : 1. 146 Approximately 10-20 g of the appropriate carboxylic acid was dissolved i n an aqueous l i t h i u m hydroxide s o l u t i o n (30 mL/g acid, 1.01 equiv of l i t h i u m hydroxide). The resultant s o l u t i o n was frozen (-78°C) and the s o l i d mass was freeze-dried (0.1 Torr, r t ) to a s o l i d white residue. The s o l i d material was ground to a fi n e powder and dried (0;.l Torr) f o r a further 14 h at room temperature. In t h i s manner t y p i c a l l y 95-100% y i e l d s of the ^corresponding l i t h i u m carboxylate was obtained. General procedure for the preparation of the cy c l o p r o p y l ketones (134b-g) .H -COR H (134) (b) R = CH 2CH 3 (c) R = cyc l o - C 3 H 5 (d) R = cyclo-C H (e) R = c y c l o - C ^ (f) R = cyclo-C 6H i : L (g) R = c y c l o - C 7 H 1 3 To a cold (-78°C) s t i r r e d , s o l u t i o n of t e r t - b u t y l l i t h i u m (2.03 M i n pentane, 2.0 equiv, 5.7 mL, 11.6 mmol) i n anhydrous ether (20 mL) was added slowly, over a period of 30-45 minutes, a solu t i o n of the cyclopropyl bromides (120a) and (120b) (as a mixture i n the approximate r a t i o of 5.6 : 1, respectively, 1.00 g, 5.78 mmol, 1.0 equiv) i n ether under argon. The lithium-halogen exchange reaction was allowed to proceed for 2.5 h a f t e r which time the appropriate anhydrous l i t h i u m carboxylate (~1.3 equiv) was added i n one portion. The s l u r r y was s t i r r e d f o r an a d d i t i o n a l 5 h. The mixture was poured into a ra p i d l y s t i r r e d mixture of saturated aqueous ammonium chloride (100 mL) and pet. ether (100 mL). The aqueous phase was 147 extracted with pet. ether (2 x 50 mL) and the combined organic extracts (~200 mL) were washed with water (30 mL) and brine (30 mL) and then were dried (MgSO^) and concentrated. The residue was quickly passed through a short column ( 6 x 4 cm) of s i l i c a gel. The column was eluted with ether (250 mL). Concentration of the eluate followed by d i s t i l l a t i o n of the residue afforded the crude ketone (mixture of endo and exo epimers) as a co l o r l e s s o i l . The d i s t i l l a t e was taken up i n anhydrous tetrahydrofuran (25 mL) and mixed, at room temperature under an argon atmosphere, with a sol u t i o n of tert-butanol (5 mL) containing a c a t a l y t i c quantity of potassium tert-butoxide (25 mg) followed by s t i r r i n g of the resultant orange colored s o l u t i o n f o r 3 h. The reaction mixture was treated with saturated aqueous ammonium chloride (6 mL) which quickly d i s s i p a t e d the orange color and pr e c i p i t a t e d a white s o l i d . The l i q u i d phase was removed by decantation and the s o l i d residue was extracted, with decantation, with pet. ether (3x20 mL). The solvent was removed from the combined solutions and the residue (2 phases) was d i l u t e d with pet. ether (250 mL) and dried (MgSO^). The s o l u t i o n was f i l t e r e d through a short column ( 6 x 4 cm) of s i l i c a g e l . The column was eluted with ether (200 mL). The eluant was concentrated and the residue was d i s t i l l e d to af f o r d the exo-cyclopropyl ketone. Both t i c ( s i l i c a gel, 9 : 1, pet. ether/ether) and glc (12 m Carbowax-20M c a p i l l a r y column) showed, that i n each case, the exo-cyclopropyl ketone was i s o l a t e d pure. The following ketones were prepared by the procedure described above. Ketone (134b): (71% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 45-50°C/0.13 Torr; R, 0.26; i r ( f i l m ) v : 3010, 2950, 2910, 2835, t max ' ' ' 148 1680, 1630, 1410, 1350, 1280, 1130, 1050, 800, 700 cm -"; lH nmr <5: 1.07 (t, J=7.5Hz, 3H, -C0CH 2CH 3), 1.61-1.73 (m, IH), 1.75-1.90 (m, 2H), 1.93-2.10 (m, 3H), 2.20 (d of d, J=4.0Hz, J'=3.0Hz, IH, C-7 cyclopropyl proton), 2.54 (q, J=7.5Hz, 2H, -COCH^CH^), 5.56 (d of d of d, J=9.0Hz, J'=7.0Hz, j"= 2.0Hz, IH, v i n y l proton), 5.98 (d of d of d, J=9.0Hz, J'=5.5Hz, J"=3.5Hz, IH, v i n y l proton); Anal, calcd. f o r C^H^O: C 79.96, H 9.39; found: C 80.20, H 9.39. Ketone (134c): (74% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 60-65°C/0.07 Torr; Rr 0.29; i r ( f i l m ) v : 3000, 2980, 2900, 2820, r max 1665, 1625, 1435, 1375, 1280, 1105, 895, 795 cm"1; XH nmr 6: 0.84-0.94 and 1.00-1.10 (multiplets, 2H and 2H, cyclopropyl methylenes), 1.62-1.72 (unresolved m, IH), 1.78-1.93 (m, 2H), 1.95-2.13 (m, 4H), 2.32 (d of d, J=J'=4.0Hz, IH, C-7 cyclopropyl proton), 5.59 (d of d of d, J=9.0Hz, J*=7.0 Hz, J"=2.0Hz, IH, v i n y l proton), 6.00 (d of d of d, J=9.0Hz, J'=5.5Hz, J"=3.5Hz, 1H, v i n y l proton); Anal, calcd. for C^^0'- c 81.44, H 8.70; found: C 81.59, H 8.91. Ketone (134d): (84% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 6O-70°C/0.07 Torr; R £ 0.29; i r ( f i l m ) v : 3010, 2960, 2910, 2840, f max 1680, 1635, 1420, 1380, 1130, 1020, 800, 700 cm"1; *H nmr 6: 1.62-1.79 (m, IH), 1.80-1.87 (diffuse m, 3H), 1.90-2.07 (di f f u s e m, 4H), 2.11 (d of d, J=4.5Hz, J'=3.lHz, IH, C-7 cyclopropyl proton), 2.12-2.29 (diffuse m, 4H), 3.27-3.37 (symmetrical 8 l i n e m u l t iplet, IH, a- ketone proton of cyclobutane r i n g ) , 5.55 (d of d of d, J=9.9Hz, J'=6.5Hz, J"=2.2Hz, IH, v i n y l proton), 5.97 (d of d of d, J=9.9Hz, J'=5.2Hz, J"=2.9Hz, IH, v i n y l proton); Anal, calcd. for C l OH 1 t0: C 81.78, H 9.15; found: C 81.63, H 9.12. 149 Ketone (134e): (73% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature (air bath) 85-95°C/0.10 Torr: R. 0.38; i r ( f i l m ) v : 3020, 2930, 2850, r max 1680, 1635, 1420, 1290, 1120, 1080, 1050, 800 cm"1; lE nmr 6: 1.60-1.78 (dif f u s e m, 5H), 1.78-1.92 (di f f u s e m, 6H), 1.92-2.10 (m, 3H), 2.22 (d of d, J=J'=4.0Hz, IH, C-7 cyclopropyl proton), 2.96 (symmetrical m, IH, a-keto proton of cyclopentane r i n g ) , 5.55 (d of d of d, J=9.8Hz, J'=6.6Hz, J"=2.2Hz, IH, v i n y l proton), 5.98 (d of d of d, J=9.8Hz, J'=5.3Hz, J"=3.0Hz, IH, v i n y l proton); Anal, calcd. f o r C^H^O: C 82.06, H 9.50; found: C 82.32, H 9.50. Ketone (134f): (83% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 95-105°C/0.07 Torr; mn 21.5-23.0°C; R r 0.32; i r ( f i l m ) ~v : 3020, - f max 2900, 2840, 1680, 1630, 1445, 1410, 1295, 1150, 1100, 1020, 800 cm"1; lE nmr 6: 1.15-1.40 (di f f u s e m, 5H), 1.62-1.74 (m, 2H), 1.74-2.10 (di f f u s e m, 9H), 2.24 (d of d, J=J'=3.8Hz, IH, C-7 cyclopropyl proton), 2.40-2.50 (unresolved m, IH, a-keto proton of cyclohexane r i n g ) , 5.55 (d of d of d, J=9.8Hz, J'=6.6Hz, J"=2.1Hz, IH, v i n y l proton), 5.97 (d of d of d, J=9.8Hz, J'=5.2Hz, J"=2.9Hz, IH, v i n y l proton); Anal, calcd. f o r C 0: c 82.30 H 9.87; found: C 82.40, H 9.85. Ketone (134g): (83% o v e r a l l y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 105-110°C/0.07 Torr; mp 28.0-29.0°C; R 0.32; i r ( f i l m ) ~ : 3010, i max 2900, 2830, 1680, 1630, 1455, 1405, 1290, 1100, 800, 690 cm"1; XH nmr 6: 1.40-2.10 (diffuse m, 18H), 2.19 (d of d, J=J'=3.9Hz, IH, C-7 cyclopropyl proton), 2.58-2.67 (m, IH, a-keto proton of cycloheptane r i n g ) , 5.79 (d of d of d, J=9.9Hz, J'=6.6Hz, J"=2.2Hz, IH, v i n y l proton), 6.21 (d of d of d, 150 J=9.9Hz, J'=5.2Hz, J"=2.8Hz, IH, v i n y l proton); Anal, calcd. f o r C 1 5 H 2 2 ° : C 82.52, H 10.16; found: C 82.33, H 10.35. General procedure f o r the preparation of the b i c y c l i c and t r i c y c l i c dienes  (OTMS enol ethers) ( 136a), (136b-E), (136b-Z) and (137a-d). ^OTMS ^J* ,0TMS (136a) R = R' = H (b) n = 5 (136b-E) R = H, R' = CH 3 (c) n = 6 (136b-Z) R = CH 3, R' = H (d) n = 7 An adaption of the procedure used by F l e m i n g ^ 9 ^ was used i n these preparations. Thus, to a cold (-78°C) s t i r r e d s o l u t i o n of l i t h i u m d i i s o -propylamide (7.08 mmol, 1.1 equiv) i n anhydrous tetrahydrofuran (10 mL) under argon, was added slowly, over a period of 15-20 minutes, a s o l u t i o n of the appropriate exo-cyclopropyl ketone (6.44 mmol) i n tetrahydrofuran (15 mL), The re a c t i o n mixture was allowed to s t i r at t h i s temperature f o r 45 minutes a f t e r which time i t was warmed to 0°C for 15 minutes. The solution was recooled to -78°C and chlorotrimethylsilane (0.98 mL, 7.3 mmol, 1.2 equiv) was added i n one portion. The mixture was maintained at t h i s temperature for 20 minutes, was warmed to room temperature and s t i r r e d f o r an a d d i t i o n a l 1 h. The s o l u t i o n was concentrated (aspirator) to a white residue, which was treated with dry pet. ether (100 mL) and the s o l i d was removed by f i l t r a t i o n . The f i l t r a t e was concentrated and the residue, a l i g h t brown l i q u i d , was taken up i n pet. ether (10-20 mL). The r e s u l t i n g s o l u t i o n was chromatographed r a p i d l y through a short column of alumina 151 (20 g, neutral a c t i v i t y I I I , triethylamine deactivated ) followed by e l u t i o n with pet. ether (125 mL). The eluate was concentrated and the residue, a co l o r l e s s o i l , d i s t i l l e d (0.1-0.3 Torr) a f f o r d i n g the 0 - t r i m e t h y l s i l y l enol ether as a c o l o r l e s s o i l . The materials obtained by t h i s procedure were shown by glc (SE-30 and OV-101) and '''H nmr to be pure. In each case, a s a t i s f a c t o r y combustion I analysis or a high r e s o l u t i o n mass spectrometric measurement could be obtained d i r e c t l y . The following 0 - t r i m e t h y l s i l y l enol ethers were obtained by t h i s procedure. Compound (136a): (89% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 40-50°C/ 0.05 Torr; i r ( f i l m ) v : 3100, 3010, 2940, 2900, 2830, 1635, 1330, max 1300, 1250, 1050, 1030, 1010, 890, 855, 845, 800 cm"1; XH nmr 6: 0.21 (s, 9H, OTMS), 1.42-1.51 (unresolved m, IH), 1.51-1.68 (m, 3H), 1.72-1.86 (unresolved m, IH), 1.93-2.06 (diffuse m, 2H), 3.99 and 4.08 (d and d, J~lHz, 2H, terminal v i n y l protons), 5.47 (m, 2H, v i n y l proton), 6.13 (m, IH, v i n y l proton); Exact mass calcd. for C ^ H ^ O S i : 208.1283; found: 208.1281. Compound (136b-E) and (136b-Z): (94% y i e l d , 1 : 1 mixture); d i s t i l l a t i o n temperature ( a i r bath) 50-60°C/0.15 Torr; i r ( f i l m ) v" : 3020, 2940, 2900, max 2840, 1650, 1250, 1230, 1110, 1050, 900, 845 cm"1; XH nmr 6: 0.16 and 0.2 1 (s and s, 9H, OTMS of (136b-E) and (136b-Z), r e s p e c t i v e l y ) , 1.29-1.34 (m, The alumina was deactivated by allowing a s o l u t i o n of triethylamine (2 mL/ 10 mL pet. ether) to pass down the column to be used followed by e l u t i o n with pet. ether (100 mL) to remove a l l but the l a s t traces of the amine from the column. 152 (0.5H), 1.50 (d of d, J=6.6Hz, J'=0.7Hz, v i n y l methyl group of (136b-Z)), 1.62 (d, J=6.9Hz, v i n y l methyl group of (136b-E)), 1.42 (diffuse m) , 1.70-1.90 (di f f u s e m), 1.90-2.70 (d i f f u s e m), 4.52 (q, J=6.6Hz, 0.5H, a c y c l i c v i n y l proton of (136b-Z)), 4.63 (q, J=7.0Hz, 0.5H, a c y c l i c v i n y l proton of (136b-E)), 5.43-5.50 (overlapping m u l t i p l e t s , IH, v i n y l protons), 5.98-6.07 (overlapping m u l t i p l e t s , IH, v i n y l protons); Anal, calcd. f o r C -^2^22^^: C 70.21, H 9.97; found: C 69.95, H 9.95. Compound (137a): (100% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 75-85°C/0.10 Torr; i r ( f i l m ) v : 3010, 2930, 2900, 2830, 1690, 1630, 1270, max 1250, 1120, 1050, 1040, 910, 880, 850 cm"1; 1H nmr 6: 0.15 (s, 9H, OTMS), 1.34-1.41 (m, IH), 1.50-1.63 (m, 3H), 1.73-1.85 (m, IH), 1.85-2.00 (m, 4H), 2.59-2.73 (m, 4H), 5.44 (d of d of d, J=9.9Hz, J'=6.8Hz, J"=2.2Hz, IH, v i n y l proton), 6.03 (d of d of d, J=9.9Hz, J'=5.2Hz, J"=2.9Hz,lH, v i n y l proton); Anal, calcd. for C ^ H ^ O S i : C 72.51, H 9.74; found: C 72.66, H 9.88. Compound (137b): (98% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 80-90°C/0.10 Torr; i r ( f i l m ) v~ : 3020, 2950, 2850, 1680, 1640, 1440, 1270, max 1260, 1180, 1170, 1050, 890, 860 cm"1; XH nmr 6: 0.17 (s, 9H, OTMS), 1.36-1.42 (m, IH), 1.55-1.67 (m, 6H), 1.70-1.73 (m, IH), 1.79-1.84 (m, IH), 1.93-2.03 (m, 2H), 2.18-2.29 (m, 4H), 5.45 (d of d of d, J=9.9Hz, J'=6.6Hz, J"=2.lHz, IH, v i n y l proton), 6.05 (d of d of d, J=9.9Hz, J'=5.3Hz, J"=2.9Hz, lH, v i n y l proton); Anal, calcd. f o r C.,H o.0Si: C 73.22, H 9.98; found: C 73.19, 16 26 H 10.00. Compound (137c): (98% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 110-120°C/0.12 Torr; i r ( f i l m ) v : 3000, 2930, 2900, 2820, 1680, 1650, 1630, 153 1440, 1250, 1045, 920, 880, 840 cm_J"; XH nmr 6: 0.17 (s, 9H, OTMS), 1.33-1.38 (m, IH), 1.42-1.54 (diffuse m, 7H), 1.54-1.64 (m, IH), 1.72 (overlapping d of d, J=J'=4.4Hz, IH), 1.75-1.85 (m, IH), 1.96-1.99 (m, 2H), 2.00-2.19 (m, 4H), 5.46 (d of d of d, J=9.9Hz, J'=6.4Hz, J"=2.1Hz, IH, v i n y l proton), 6.07 (d of d of d,J=9.9Hz, J'=5.2Hz, J"=2.9Hz, lH, v i n y l proton); Anal, calcd. for C ^ H ^ O S i : C 73.85, H 10.21; found: C 74.00, H 10.37. Compound (137d): (98% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 100-110°C/0.15 Torr, i r ( f i l m ) v : 3000, 2900, 2820, 1630, 1440, 1245, max 1210, 1180, 1160, 1050, 910, 875, 850, 840, 750 cm"1; !H nmr 6: 0.18 (s, 9H, OTMS), 1.34-1.40 (d of d of d, J=8.0Hz, J'=4.0Hz, J"=3.0Hz, IH), 1.44-1.65 (d i f f u s e m, 10H), 1.72-1.77 (d of d, J=J'=4.0Hz, IH), 1.77-1.88 (m, IH), 1.94-2.00 (m, 2H), 2.20-2.29 (m, 4H) , 5.43-5.49 (d of d of d, J=10Hz, J'=7Hz, J"=2Hz, IH, v i n y l proton), 6.04-6.10 (d of d of d, J=10Hz, J'=5Hz, J"=3Hz, IH, v i n y l proton); Anal, calcd. f o r C ^ H ^ O S i ; C 74.42, H 10.41; found: C 74.62, H 10.33. General procedure f o r the preparation of ketones (148-151) (148) (149) (150) (151) (a) Sample tube conditioning The sample tubes (30 cm x 9.5 mm o.d. heavy walled tubing, 2 mm wall) were cleaned by soaking i n potassium hydroxide saturated isopropanol f o r 154 10-15 minutes with u l t r a s o n i c a t i o n . Each tube was rinsed thoroughly with d i s t i l l e d water and dried (130-140°C) for 4-6 h. Conditioning was achieved by taking the hot tubes, f i l l i n g each with hexamethyldisilazane and l e t t i n g them stand u n t i l cool. The emptied tubes were evacuated (0.1 Torr) with heating (80-100°C) for 10 minutes. Each cooled tube was capped with a rubber septum and stored u n t i l used. (b) Sample preparation A 0.5 to 1.0 g sample of the appropriate b i c y c l i c or t r i c y c l i c diene was placed within a sample tube, evacuated (0.1-0.3 To r r ) , heated (hot a i r gun) b r i e f l y u n t i l the f i r s t sign of d i s t i l l a t i o n and then sealed. (c) Thermolysis of the b i c y c l i c and t r i c y c l i c dienes and subsequent  hydrolysis to the b i c y c l i c and t r i c y c l i c ketones. A prepared sample tube containing the neat b i c y c l i c or t r i c y c l i c diene was placed i n a thermostated a i r bath and maintained at 240° ± 2°C (uncorrected) for 6 h i n the case of the b i c y c l i c dienes (136a), (136b-E) and (136b-Z), or 12 h i n the case of the t r i c y c l i c dienes (137a-d). The cooled tube was opened, the thermolysate was d i l u t e d with pet. ether (10-20 mL) and the resultant s o l u t i o n was chromatographed ra p i d l y on a short column of alumina (20 g, neutral a c t i v i t y I I I , Et^N deactivated). The column was eluted with pet. ether (100 mL) . The column eluate was concentrated and the residue was d i s t i l l e d (0.1-0.3 Torr) a f f o r d i n g a clear c o l o r l e s s o i l . A tetrahydrofuran solution (50 mL) of the d i s t i l l e d material was mixed with IN hydrochloric acid (1 mL) and the resultant s o l u t i o n was s t i r r e d at room temperature f o r 10 minutes. The hyd r o l y s i s mixture was concentrated, 155 the residue (2 phases) was mixed with pet. ether (100 mL) and the mixture was dried (MgSO^). The s o l u t i o n was f i l t e r e d r a p i d l y through a short column of s i l i c a gel ( 6 x 4 cm) and the column was eluted with 9 : 1 pet. ether/ ether (200 mL). The eluate was concentrated and the residue was subjected to f l a s h chromatography^ 1 1 7^ ( s i l i c a gel, 230-400 mesh, 7" x 5 cm column). The column was eluted with 9 : 1 pet. ether/ether (~1.5 L ) . The appropriate f r a c t i o n s of the eluate containing the desired ketone were selected, combined, concentrated and the residue was d i s t i l l e d (0.1-0.3 Torr) a f f o r d i n g the ketone as a c o l o r l e s s o i l . The ketones (148) and (151a-d) obtained by t h i s procedure were analyzed by spectroscopic ( i r , 1H nmr) and p h y s i c a l methods ( t i c , glc (OV-101, 12M c a p i l l a r y column)), a l l of which indicated that, i n each case, the ketone was obtained e i t h e r pure or nearly pure (>97%). However, thermolysis of the 1 : 1 mixture of the b i c y c l i c dienes (136b-E) and (136b-Z) and subsequent hydrolysis of the thermolysate, by t h i s procedure, provided an approximately 1 : 1 mixture of the epimeric ketones (149) and (150). Although an a n a l y t i c a l sample of ketone (149) could be obtained conveniently by column chromatography of t h i s mixture, ketone (150) could not be A completely p u r i f i e d by t h i s method. However an a n a l y t i c a l sample of ketone (150) was obtained by epimerization (as i n the procedure used i n the Examination of the sample of ketone (150), obtained by the s e l e c t i v e chromatography described above, both by t i c and glc indicated the presence of only one component. However, the 1H nmr and i r s p e c t r a l properties of t h i s sample of ketone (150) revealed i t to be contaminated with approximately 10% of an u n i d e n t i f i e d ketonic material (see discussion). 156 preparation of the ketones (134b-g)) of a pure sample of ketone (149) followed by column chromatography. Ketones (148-150) and (151a-d) which were obtained by these procedures exhibited the following properties: Ketone (148): (66% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 65-75°C/0.10 Torr; mp 95.0-96.0°C; sublimes at 30-40°C (0.2 T o r r ) ; R 0.15; ir(CHCl„) v : 2990, 2920, 2855, 1680 cm"1; Hi nmr 6: 1.70-1.80 (m, 4H, 3 max -CH2-CH - ) , 2.47 (broadened d of d, J=16.8Hz, J'=3.6Hz, 2H, protons endo to v i n y l bridge on C-2 and C-4), 2.59 (d of d, J=16.8Hz, J'=4.2Hz, 2H, protons exo to v i n y l bridge on C-2 and C-4), 2.62-2.66 (unresolved m, 2H, bridgehead protons), 6.31-6.36 (m, 2H, v i n y l protons); Anal. calcd. for CgH^O: C 79.37, H 8.88; found: C 79.50, H 9.00. Ketone (149): ( i s o l a t e d from a 1 : 1 mixture of (149) and (150) obtained i n 72% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 40-50°C/0.2 Torr; R, 0.27; i r ( f i l m ) v : 3010, 2910, 2850, 1680, 1460, 1370, 1200, 1145, f max 1050, 910, 730 cm"1; XH nmr 6: 1.13 (d, J=6.9Hz, 3H, -CH ), 1.49-1.84 (diffuse m, 4H, -Cj^CH - ) , 2.32 (broadened d of d, J=J'~6.4Hz, IH, bridgehead proton on C - l ) , 2.37-2.46 (overlapping d and unresolved m, J=16.9Hz, 2H, proton endo to v i n y l bridge on C-4 and C-2 methine, r e s p e c t i v e l y ) , 2.56-2.64 (overlapping d of d and unresolved m, J=16.9Hz, J'=5.5Hz, 2H, proton exo to v i n y l bridge on C-4 and C-5 bridgehead proton, r e s p e c t i v e l y ) , 6.36-6.45 (m, 2H, v i n y l protons); Anal, calcd. f o r C 1 0 H 1 4 ° : C 7 9 , 9 6 > H 9 - 3 9 5 found: C 79.87, H 9.39. Ketone (150): (obtained from the base catalyzed epimerization of (149)) : d i s t i l l a t i o n temperature ( a i r bath) 40-50°C/0.2 Torr; 'R 0.18; 157 i r ( f i l m ) v : 3010, 2900, 2840, 1680, 1450, 1410, 1370, 1205, 1120, 1100, max 930, 800, 710 cm"1; *H nmr 5 : 1,07 (d, J=7.3Hz, 3H, -CHg), 1.62-1.89 (diffuse m, 4H, -CH^CT^-), 2.45-2.52 (overlapping signals, 3H, C-l bridgehead proton, C-4 methylene), 2.58 (q of d, J=7.2Hz, J=3.8Hz, lH, C-2 methine), 2.65 (unresolved m, lH, C-5 bridgehead proton), 6.26 (overlapping d of d, J=J'= 8Hz, IH, v i n y l proton), 6.33 (overlapping d of d, J=J' ~8Hz, IH, v i n y l proton); Exact mass calcd. for c 1 0 H i 4 ° : 150.1045; found: 150.1045. Ketone (151a): (80% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 60-70°C/0.10 Torr; R £ 0.32; i r ( f i l m ) v : 3025, 2970, 2900, 2850, 1680, f max 1480, 1340, 1200, 1160, 1020, 850, 800, 740, 700 cm"1; LH nmr 5 : 1.58-1.69 (d i f f u s e m, 5H), 1.84-1.97 (d i f f u s e m, 4H), 2.45 (d of d of d, J=16.1Hz, J'=3.1Hz, J"=1.3Hz, IH), 2.51 (d of d, J=16.lHz, J'=4.8Hz, lH), 2.57-2.62 (unresolved m, lH, C-5 bridgehead proton), 2.67-2.77 (overlapping broadened d of d and m, J=J' ~6.5Hz, 2H, C - l bridgehead proton), 6.32-6.38 (symmetrical m, 2H, v i n y l protons); Anal, calcd. f o r C 1 0H .0: C 81.77, H 9.15; found: 1/ 16 C 82.00, H 9.20. Ketone (15 lb) : (61% y i e l d ) : d i s t i l l a t i o n temperature ( a i r bath) 65-75°C/0.1 Torr, R £ 0.25; i r ( f i l m ) v : 3010, 2900, 2895, 2845, 1680, f max 1640, 1460, 1440, 1200, 1140, 900, 800, 700 cm"1; lE nmr 6: 1.27-1.35 (d of d of d, J=13.1Hz, J'=8.5Hz, J"=5.8Hz, IH), 1.48-1.83 (diffuse m, 10H), 2.30 (broadened d of d, J=J' ~6Hz, IH, C-l bridgehead proton), 2.33-2.40 (d of d of d, J=13.3Hz, J'=8.5Hz, J"=6.2Hz, IH), 2.51 (d of d of d, J=16.0Hz, J'=3.1Hz, J"=1.3Hz, IH, C-4 methylene proton), 2.55 (d of d, J=16.0Hz, J'=5.0 Hz, IH, C-4 methylene proton), 2.59-2.64 (unresolved m, IH, C-5 bridgehead 158 proton), 6.29-6.40 (m, 2H, v i n y l protons); Anal, calcd. f o r C 1 3 H 1 8 0 : C 82.06, H 9.53; found: C 82.23, H 9.65. Ketone (151c): (81% y i e l d ) : d i s t i l l a t i o n temperature ( a i r bath) 70-75°C/0.05 Torr; IU 0.31; i r ( f i l m ) v : 3010, 2910, 2840, 1680, 1455, r max 1440, 1200, 1190, 1135, 1115, 700 cm"1; *H nmr 6: 1.20-1.72 (diffuse m, 12H), 1.72-1.83 (m, IH), 1.94-2.04 (m, IH), 2.45 (d of d, J=14.6Hz, J'=5.9Hz, IH, C-4 methylene proton), 2.50-2.65 (m, 2H, bridgehead protons), 2.55 (d of d, J=14.6Hz, J'=2.2Hz, lH, C-4 methylene proton), 6.26 (d of d, J=J'~ 8.1Hz, IH, v i n y l proton), 6.39 (d of d, J=J' ~8.2Hz, IH, v i n y l proton); Anal, calcd. f o r C n /H 0: C 82.30, H 9.98; found: C 82.55, H 9.88. 1-4 ZU Ketone (151d): (49% y i e l d ) ; d i s t i l l a t i o n temperature ( a i r bath) 110-120°C/0.35 Torr; R r 0.34; i r ( f i l m ) v : 3010, 2900, 2825, 1680, 1455, f max 1440, 1195, 1150, 1120, 970, 815, 730, 690 cm"1; lE nmr 8: 1.35-1.57 (diffuse m, 12H), 1.59-1.66 (m, IH), 1.72-1.78 (m, IH), 1.81-1.89 (m, IH), 2.25 (d of d, J=14.5Hz, J'=9.7Hz, IH), 2.37 (d of d, J=J' ~6.6Hz, IH, C - l bridgehead proton), 2.48 (d of d, J=16.lHz, J'=5.8Hz, IH, C-4 methylene proton), 2.56-2.60 (overlapping s i g n a l s , 2H, C-4 methylene proton and C-5 bridgehead proton), 6.24-6.35 (m, 2H, v i n y l protons); Anal, calcd. for C 1 5 H 2 2 ° : C 8 2 > 5 2 ' H 1 0 - 1 6 ; found: C 82.57, H 10.26. 159 REFERENCES 67. 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