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Thietane 1, 1-dioxide derivatives as potential analgetics of the methadone type Coates, James Everett 1972

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!IZ!3 THIETANE 1,1-DIOXIDE DERIVATIVES AS POTENTIAL ANALGETICS OF THE METHADONE TYPE by JAMES EVERETT COATES B.S.P., University of Bri t i s h Columbia, 1967 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Division of Medicinal Chemistry of the Faculty of Pharmaceutical Sciences We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA April , 1972 In presenting t h i s thes is 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 at the U n i v e r s i t y of B r i t i s h Columbia, I agree that 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 reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s thesis f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s representat ives . It i s understood that copying or p u b l i c a t i o n of t h i s thes is f o r f i n a n c i a l gain s h a l l not be allowed without my wri t ten permission. Bepartment - o f - /^a^^^/^Z, / ^ M ^ ^ ^ s W ^ ^ y f The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada Date y>1^ ?, /9<7*. DEDICATION To my parents. ABSTRACT Thietane 1,1-dioxide d e r i v a t i v e s were synthesized as p o t e n t i a l n a r c o t i c a n a l g e t i c s of the methadone type. Thietane 1,1-dioxides are con-f o r m a t i o n a l l y more r e s t r i c t e d than methadone and thus may be u s e f u l i n e l u c i d a t i n g the pharmacophoric conformation of methadone and r e l a t e d a n a l -g e t i c s . The r e a c t i o n of £-dimethylaminostyrene w i t h phenylmethanesulfony1 c h l o r i d e i n the presence of t r i e t h y l a m i n e gave a mixture of c i s - and t r a n s -2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide and the a c y c l i c isomer, b e n z y l 1-pheny1-2-dimethylaminoetheny1 s u l f o n e . Of the two c y c l i c isomers, the trans isomer was l e s s s t a b l e and decomposed when heated i n e t h a n o l . The nature of the decomposition products i n d i c a t e d that the c y c l i z a t i o n r e a c t i o n was r e v e r s i b l e . That the trans isomer formed to a greater extent than the more s t a b l e c i s isomer suggested that t h i e t a n e 1,1-dioxide r i n g formation was s u b j e c t to s t e r i c approach c o n t r o l . No apparent c o r r e l a t i o n was observed between s o l v e n t p o l a r i t y and the amount of a c y c l i c isomer formed. trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide could be isomerized to the c i s and a c y c l i c isomers i n the presence of t r i e t h y l a m i n e and t r i e t h y l a m i n e h y d r o c h l o r i d e . In the r e a c t i o n between p-dimethylaminostyrene and p_-chloropheny 1-methanesulfony1 c h l o r i d e i n the presence of t r i e t h y l a m i n e , evidence was obtained that only two c y c l i c isomers were formed. This i n d i c a t e d that the c o n f i g u r a t i o n of the enamine was maintained during c y c l i z a t i o n . Re-a c t i o n of the enamine w i t h the sulfene derived from p_-nitrophenylmethane-s u l f o n y l bromide afforded cis-2-(4-nitropheny1)-3-dimethy 1amino-4-pheny1-th i e t a n e 1,1-dioxide and benzyl l-(4-nitrophenyl)-2-dimethylaminoethenyl i v s u l f o n e . Submitting the 3-dimethylaminothietane 1,1-dioxides to the Cope e l i m i n a t i o n r e a c t i o n gave the corresponding t h i e t e 1,1-dioxides. Examina-t i o n of the isomeric t h i e t e 1,1-dioxides obtained from c i s - and trans-2-(4-chlorophenyl)-3-dimethylamino-4-phenylthietane 1,1-dioxide provided evidence supporting the c o n f i g u r a t i o n a l assignment of the c i s and trans isomers. With the p _ - n i t r o - s u b s t i t u t e d t h i e t a n e 1,1-dioxide, only one e l i m -i n a t i o n product was i s o l a t e d , which was i d e n t i f i e d as 2-(4-nitropheny1)-4-phenylthiete 1,1-dioxide. Thermolysis of 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide, 2-(4-chlorophenyl)-4-phenylthiete 1,1-dioxide and 2 - p h e n y l - 4 - ( 4 - c h l o r o p h e n y l ) - t h i e t e 1,1-di-oxide gave chalcone, benzylidene p_-chloroacetophenone and p_-chlorobenzy 1-idene acetophenone, r e s p e c t i v e l y . R e f l u x i n g 2 , 4 - d i p h e n y l t h i e t e 1,1-diox-ide i n aqueous THF a f f o r d e d l , 3 - d i p h e n y l p r o p e n e - 3 - s u l f o n i c a c i d . These r e s u l t s supported the proposal that t h i e t e 1,1-dioxides undergo r i n g open-in g on h e a t i n g to give s u l f e n e i n t e r m e d i a t e s . From the decomposition of 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide i n r e f l u x i n g e t h a n o l , a k e t o n i c s u l f o n e was i s o l a t e d and c h a r a c t e r i z e d as b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) s u l f o n e . M i c h a e l a d d i t i o n of hydrogen cyanide to the t h i e t e 1,1-dioxides f o l l o w e d by r e d u c t i o n to the primary amines and d i m e t h y l a t i o n gave the p o t e n t i a l a n a l g e t i c s , 2,4-diphenyl-3-dimethylaminomethylthietane 1,1-diox-ide , 2-(4-chloropheny1)-3-dimethylaminomethy1-4-pheny1thietane 1,1-dioxide and 2-(4-nitropheny1)-3-dimethylaminomethy 1-4-phenylthietane 1,1-dioxide. The f o u r t h compound, 2, 4 - d i p h e n y l - 3 - ( l - d i m e t h y l a m i n o e t h y l ) - t h i e t a n e 1,1-d i o x i d e , was prepared by a d d i t i o n of n i t r o e t h a n e to 2 , 4 - d i p h e n y l t h i e t e 1,1-d i o x i d e f o l l o w e d by r e d u c t i o n and d i m e t h y l a t i o n . C o n f i g u r a t i o n a l and con-f o r m a t i o n a l assignments f o r the four compounds were based on nmr evidence. V The mouse hot p l a t e , mouse phenylquinone w r i t h i n g and e l e c t r i -c a l l y s t i m u l a t e d guinea-pig ileum methods were used to measure a n a l g e t i c a c t i v i t y . When teste d by one or more of these methods, none of the four compounds showed s i g n i f i c a n t a c t i v i t y . Signatures of Examiners v i TABLE OF CONTENTS PAGE ABSTRACT i i i LIST OF TABLES x LIST OF FIGURES x i INTRODUCTION 1 THIETANE 1,1-DIOXIDE CHEMISTRY 10 DISCUSSION OF THE CHEMISTRY 38 Nmr Determination of the C o n f i g u r a t i o n and Conformation of c i s -and trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide . . . . 42 Examination of the R e l a t i v e S t a b i l i t i e s of c i s - and trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide 45 Benzyl 1-Pheny1-2-dimethylaminoetheny1 Sulfone 51 E f f e c t of Reaction Solvent on Isomer P r o p o r t i o n s 53 I n t e r p r e t a t i o n of the P r e f e r e n t i a l Formation of the Less S t a b l e Isomer, trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide . . 58 React i o n of § -Dimethylaminostyrene w i t h p_-Chlorophenylmethane-s u l f o n y l C h l o r i d e and p_-Nitrophenylmethanesulfonyl Bromide . . . . 60 Synthesis of Thie,te 1,1-dioxides 69 Thermolysis of Thiete 1,1-dioxides 76 B i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) Sulfone 82 Synthesis of 3-Cyanothietane 1,1-dioxides 87 Reduction of 3-Cyanothietane 1,1-dioxides 94 Dim e t h y l a t i o n of 3-Aminomethylthietane 1,1-dioxides 96 Synthesis of 2,4-Dipheny1-3-carboxythietane 1,1-dioxide and 2,4-Diphenyl-3-acetylthietane 1,1-dioxide 100 Synthesis of 2,4-Diphenyl-3-(l-dimethylaminoethyl)-thietane 1,1-dioxide 102 ANALYTICAL METHODS 109 v i i PAGE EXPERIMENTAL 110 1. Synthesis of p-Diraethylaminostyrene (131) 110 2. Synthesis of Phenylmethanesulfony1 Chloride (13) 110 3. Synthesis of p_-Chloropheny lmethanesulf ony 1 Chloride (129) . . . 112 4. Synthesis of p_-Nitrophenylmethanesulfony 1 Bromide (130) . . . . 112 5. Synthesis of c i s - and trans-2,4-Dipheny1-3-dimethylamino-thietane 1,1-dioxide (126a and b) 113 6. Benzyl 1-Pheny1-2-dimethylaminoetheny1 Sulfone (132) 116 7. Decomposition of c i s - and trans-2,4-Dipheny1-3-dimethy1-aminothietane 1,1-dioxide (126a and b) under R e c r y s t a l -l i z a t i o n Conditions 117 8. Decomposition of trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide (126b) i n Ethanol 118 9. Decomposition of cis-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide (126a) i n Ethanol 120 10. Isomerization of trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide (126b) 121 11. Preliminary Examination of the E f f e c t s of Water, Addition Time, and Reaction Temperature on the Synthesis of c i s -and trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide (126a and b) 122 12. Synthesis of Dimethylammonium Phenylmethanesulfonate (137) . . 123 13. Synthesis of Et h y l Phenylmethanesulfonate (138) 124 14. Synthesis of c i s - and trans-2-(4-Chloropheny1)-3-dimethylamino-4-phenylthietane 1,1-dioxide (127a and b) . . . . 125 15. Synthesis of 2-(4-Nitrophenyl)-3-dimethylamino-4-phenylthietane 1,1-dioxide (128) 129 16. Benzyl l-(4-Nitrophenyl)-2-dimethylaminoethenyl Sulfone (148) 131 17. Synthesis of 2,4-Diphenylthiete 1,1-dioxide (152) 132 18. Synthesis of 2-(4-Chlorophenyl)-4-phenylthiete 1,1-dioxide (153a) and 2-Pheny1-4-(4-chloropheny1)-thiete 1,1-dioxide (153b) 133 v i i i PAGE 19. I n v e s t i g a t i o n of the E f f e c t of S t a r t i n g M a t e r i a l C o n f i g u r a t i o n on the Isomer R a t i o of the Product i n the Synthesis of 2-(4-Chloropheny1)-4-phenylthiete 1,1-dioxide (153a) and 2-Phenyl-4-(4-chlorophenyl)-t h i e t e 1,1-dioxide (153b) . • 134 20. Synthesis of 2 - ( 4 - N i t r o p h e n y l ) - 4 - p h e n y l t h i e t e 1,1-d i o x i d e (155) 136 21. Decomposition of 2,4-Diphenylthiete 1,1-dioxide (152) i n Ethanol. B.is(l,3-diphenyl-3-oxopropyl) Sulfone (171) and trans-Chalcone (165a) 138 22. Synthesis of B i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) Sulfone (171) . . . 140 23. Decomposition of 2,4-Diphenylthiete 1,1-dioxide (152) i n Aqueous Tetrahydrofuran. l,3-Diphenylpropene-3-s u l f o n i c A c i d (170) 142 24. Thermolysis of 2,4-Diphenylthiete 1,1-dioxide (152) and B i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) Sulfone (171) 145 25. Synthesis of trans-p-Chlorobenzylidene Acetophenone (167) and trans-Benzylidene p_-Chloroacetophenone (166) . . . . 147 26. Thermolysis of 2-(4-Chlorophenyl)-4-phenylthiete 1,1-d i o x i d e (153a) and 2 - P h e n y l - 4 - ( 4 - c h l o r o p h e n y l ) - t h i e t e 1,1-dioxide (153b) 148 27. Synthesis of 2,4-Diphenyl-3-cyanothietane 1,1-dioxide (178) 149 28. Synthesis of 2-(4-Chlorophenyl)-3-cyano-4-phenylthietane 1,1-dioxide (180) 151 29. Synthesis of 2-(4-Nitropheny1)-3-cyano-4-phenylthietane 1,1-dioxide (181) 152 30. I s o l a t i o n of Two Unsaturated N i t r i l e s (182a and b) 153 31. Treatment of 2-(4-Nitrophenyl)-3-cyano-4-phenylthietane 1,1-dioxide (181) w i t h Base 155 32. Synthesis of 2,4-Dipheny1-3-aminomethylthietane 1,1-d i o x i d e (193) 156 33. Synthesis of 2-(4-Chloropheny1)-3-aminoraethy1-4-phenylthietane 1,1-dioxide (194) 158 34. Synthesis of 2,4-Dipheny1-3-dimethylaminomethylthietane 1,1-dioxide (9) 160 i x PAGE 35. Synthesis of 2-(4-Chloropheny1)-3-dimethylaminomethy1-4-phenylthietane 1,1-dioxide (124) 161 36. Synthesis of 2-(4-Nitrophenyl)-3-dimethylaminomethyl-4-phenylthietane 1,1-dioxide (125) 162 37. Synthesis of 2,4-Diphenyl-3-carboxythietane 1,1-d i o x i d e (196) 164 38. Synthesis of 2,4-Diphenyl-3-acetylthietane 1,1-d i o x i d e (197) . . 164 39. Synthesis of 2 , 4 - D i p h e n y l - 3 - ( l - n i t r o e t h y l ) - t h i e t a n e 1,1-dioxide (201) 167 40. Synthesis of 2,4-Diphenyl-3-(l-dimethylaminoethyl)-t h i e t a n e 1,1-dioxide (123) 169 PHARMACOLOGICAL TESTING 174 BIBLIOGRAPHY 178 X LIST OF TABLES TABLE PAGE I. E f f e c t of Reaction Solvent on the R a t i o of Isomers from the C y c l o a d d i t i o n of £-Dimethylaminostyrene to Phenylsulfene . . . 55 I I . Comparison of the Chemical S h i f t s of the B e n z y l i c Protons of the 3-Dimethylaminothietane 1,1-dioxides w i t h Those Reported for Related 3,3-Diethoxythietane 1,1-dioxides . . . . 68 I I I . Chemical S h i f t Values of the 3-Dimethylaminothietane 1,1-d i o x i d e s 98 IV. Chemical S h i f t Values of the 3-Dimethylaminomethylthietane 1,1-dioxides 99 x i LIST OF FIGURES FIGURE PAGE 1. Nmr spectrum of the crude product from the c y c l o a d d i t i o n ( i n CH^CN) of $-dimethylaminostyrene to phenylsulfene d i s s o l v e d i n CDCI3 54 2. Nmr spectrum of b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) s u l f o n e d i s s o l v e d i n CDCI3 84 ACKNOWLEDGEMENTS The author i s indebted to Dr. Frank S. Abbott f o r h i s guidance and encouragement throughout the course of t h i s work. F i n a n c i a l support from the M e d i c a l Research C o u n c i l i s g r a t e f u l l y acknowledged. INTRODUCTION The diphenylpropylamine c l a s s of n a r c o t i c a n a l g e t i c s , the f i r s t members of which were synthesized i n Germany during World War I I , has been e x t e n s i v e l y reviewed ( 1 , 2 ) . The prototype and c l i n i c a l l y most u s e f u l mem-ber of the group i s methadone ( 6-dimethylamino - 4 , 4-diphenyl - 3-heptanone, I). Methadone was the f i r s t s y n t h e t i c a n a l g e t i c which possessed only one asymmetric centre and was r e a d i l y r e s o l v e d i n t o i t s enantiomeric forms. A n a l g e t i c t e s t i n g of the enantiomers r e v e a l e d that the (-)-isomer was approximately twice as potent as the racemate, whereas the (+)-isomer was v i r t u a l l y i n a c t i v e . Subsequent i n v e s t i g a t i o n of the o p t i c a l isomers of other diphenylpropylamines, i n c l u d i n g the sulfone analogue of methadone 2 1 CH 3CH 2S C — CH 2CHN(CH 3) as w e l l as members of other c l a s s e s of s y n t h e t i c a n a l g e t i c s possessing an asymmetric centre common to that of I, i n d i c a t e d that the a n a l g e t i c a c t i v i t y and morphine-like s i d e e f f e c t s r e s i d e d predominantly i n one isomer of each enantiomeric p a i r . As w e l l , i t was o r i g i n a l l y found that the a c t i v e enan-tiomers were a l l c o n f i g u r a t i o n a l l y r e l a t e d to R - ( - ) - a l a n i n e . These obser-v a t i o n s provided stereochemical evidence f o r the exis t e n c e of an a n a l g e t i c r e c e p t o r ( 3 ) . I t was proposed by Beckett and Casy that the a n a l g e t i c receptor was a r i g i d e n t i t y whose topography was complementary to one of the surfaces of the c o n f o r m a t i o n a l l y immobile morphine molecule ( 3 ) . A p a r t i c u l a r arrangement of three b i n d i n g s i t e s on the receptor was considered to account f o r the observed s t e r e o s e l e c t i v i t y . An e f f o r t was made to show how members of a l l important c l a s s e s of n a r c o t i c a n a l g e t i c s could present s i m i l a r s t r u c t u r a l f e a t u r e s at these b i n d i n g s i t e s ( 4 ) . In the case of methadone, evidence was obtained f o r a p r e f e r r e d conformation which was thought to f a c i l i t a t e a s s o c i a t i o n w i t h the receptor ( 5 ) . The p r e f e r r e d conformation apparently arose from an i n t e r a c t i o n between the lone p a i r e l e c t r o n s of the n i t r o g e n atom and the e l e c t r o p o s i t i v e carbon of the carbonyl moiety. Since a s i m i l a r i n t r a m o l e c u l a r i n t e r a c t i o n was p o s s i b l e i n 2, i t was assumed that the s u l f o n e analogue possessed a p r e f e r r e d conformation s i m i l a r to that of I ( 5 ) . As r e s e a r c h progressed i n the a n a l g e t i c f i e l d , c e r t a i n observa-t i o n s were made which could not be r e a d i l y r a t i o n a l i z e d i n terms of the Beckett and Casy receptor hypothesis. Perhaps the most s i g n i f i c a n t of these, as pointed out by Portoghese ( 6 ) , was the dis c o v e r y that the more a c t i v e enantiomers of s y n t h e t i c a n a l g e t i c s possessing an asymmetric centre common to that of _1 were not a l l c o n f i g u r a t i o n a l l y r e l a t e d . For example, the c o n f i g u r a t i o n of the a c t i v e antipode of _3> a member of the b a s i c a n i l i d e c l a s s of n a r c o t i c a n a l g e t i c s , was found to be r e l a t e d to S-(+)- r a t h e r than to R - ( - ) - a l a n i n e ( 7 ) . Portoghese proposed that such an i n v e r s i o n i n receptor 0 II CCH.CH-A _ N CH 2CHN(CH 3) 2 CH 3 3 s t e r e o s e l e c t i v i t y could be explained i n terms of there being more than one mode of b i n d i n g of a n a l g e t i c s at the r e c e p t o r . I t was a l s o suggested that the receptor was f l e x i b l e r a t h e r than r i g i d , which would allow f o r the accommodation of a greater v a r i e t y of s t r u c t u r a l l y d i s s i m i l a r , y e t potent, n a r c o t i c a n a l g e t i c s (6). Casy has i n v e s t i g a t e d the p r e f e r r e d conformations of compounds 1 and 3 and found them to be s i g n i f i c a n t l y d i f f e r e n t (8,9). In support of Portoghese's concept he has proposed that i f i t i s assumed that these pre-f e r r e d conformations are the same as those adopted by the a n a l g e t i c s at the receptor s i t e , then i t i s probable that the mode of b i n d i n g of 1_ to the receptor d i f f e r s markedly from that of 3_. Again, i t was f e l t that d i f f e r -i n g b i n d i n g modes could account f o r the i n v e r s i o n of s t e r e o s e l e c t i v i t y shown by the receptor f o r the enantiomers of 1 and 3_ (9,10). R e c e n t l y , Portoghese has f u r t h e r elaborated the concept of d i f f e r -ing b i n d i n g modes to r a t i o n a l i z e the i n v e r s i o n s i n s t e r e o s e l e c t i v i t y seen when the more a c t i v e isomers of methadone (I), the methadols (4a) and the methadol acetates (4b) are compared (11). I t had been known f o r some time t h a t , l i k e the a c t i v e enantiomer of 1, the more a c t i v e diastereoisomers of 4 2 4a, R = H 4b, R = COCH3 4b possessed the (R) c o n f i g u r a t i o n at C-6, whereas the more a c t i v e isomers of 4a had a (6S) c o n f i g u r a t i o n . In an e f f o r t to e x p l a i n these o b s e r v a t i o n s , the absolute c o n f i g u r a t i o n of the isomers of 4a and 4b at C-3 were deter-mined. C o r r e l a t i o n of the a n a l g e t i c a c t i v i t i e s w i t h the absolute c o n f i g -u r a t i o n s at C-3 f o r the four diastereoisomers of 4a r e v e a l e d that the stereochemistry of t h i s centre had a greater i n f l u e n c e - on a c t i v i t y than that at C-6 and that the two more a c t i v e isomers both possessed the (S) c o n f i g u r a t i o n at C-3 and opposite c o n f i g u r a t i o n s at C-6. With the methadol acetate diastereoisomers (4b), the reverse was tr u e . The two more a c t i v e isomers of 4b possessed the (R) c o n f i g u r a t i o n at C-6 and opposite s t e r e o -chemistry at C-3. Portoghese has r a t i o n a l i z e d these r e s u l t s by assuming that there are s e v e r a l donor and acceptor hydrogen bonding d i p o l e s s i t u a t e d i n d i f f e r e n t l o c a t i o n s on the r e c e p t o r . In the case of methadone and the methadol a c e t a t e s , i n t e r a c t i o n of the carbonyl groups of these molecules w i t h donor hydrogen bonding d i p o l e s gives r i s e to a mode of b i n d i n g such that the c o n f i g u r a t i o n at C-6 i s important--the (R) c o n f i g u r a t i o n a l l o w i n g a more e f f e c t i v e i n t e r a c t i o n w i t h the receptor than the ( S ) . With the methadols, however, i n t e r a c t i o n of the a l c o h o l group w i t h an acceptor d i p o l e on the receptor leads to a b i n d i n g mode i n which the C-3 asymmetric centre i s o r i e n t a t e d i n a receptor environment that i s s t e r i c a l l y demanding, the isomers w i t h the (S) c o n f i g u r a t i o n at t h i s centre being more r e a d i l y accom-modated than the two w i t h the (R) c o n f i g u r a t i o n . In a d d i t i o n to the nature of i t s hydrogen bonding group, the conformation of an a n a l g e t i c molecule would determine w i t h which p a r t i c u l a r receptor d i p o l e hydrogen bonding occurred. Thus, methadone and the methadol acetates are not n e c e s s a r i l y i n t e r a c t i n g w i t h the same donor d i p o l e (11). I t has been proposed that methadone e x i s t s i n a p r e f e r r e d confor-mation when d i s s o l v e d i n aqueous s o l u t i o n (5,8,11). There i s a d i f f i c u l t y , however, i n a p p l y i n g t h i s p r e f e r r e d conformation to s t e r e o s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s t u d i e s because, as has been pointed out (12), the p r e f e r r e d conformation of a drug molecule i n s o l u t i o n i s not n e c e s s a r i l y the confor-mation of the molecule when bound to i t s receptor (pharmacophoric conforma-t i o n ) . The reason f o r t h i s i s that mutual i n t e r a c t i o n s between the drug molecule and receptor may q u i t e p o s s i b l y perturb the s o l u t i o n conformation (12). Thus, s t e r e o s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s t u d i e s employing meth-adone must c o n t a i n a c e r t a i n element of ambiguity which r e s u l t s from the assumption (as made by Casy (9)) that the p r e f e r r e d conformation resembles that adopted by the a n a l g e t i c at the receptor s i t e . I t i s p o s s i b l e that the use of c o n f o r m a t i o n a l l y r e s t r i c t e d and r i g i d analogues of methadone may provide an answer to t h i s problem. The concept of employing conformation-a l l y c o n s t r a i n e d d e r i v a t i v e s of f l e x i b l e pharmacological agents i n such s i t u a t i o n s has been reviewed (12). A few examples of c o n f o r m a t i o n a l ^ r e s t r i c t e d methadone analogues have appeared i n the l i t e r a t u r e (13). Constrainment of 1_ has i n v o l v e d e i t h e r b r i d g i n g the aromatic r i n g s , as i n 5, or c y c l i z i n g the p r o p i o n y l and b a s i c groups to form a p i p e r i d i n e r i n g , as i n 6. In g e n e r a l , such compounds CH 3 N ( C H 3 ) 2 CH 3 5 6 have possessed a low order of a n a l g e t i c a c t i v i t y or have been i n a c t i v e (13). The s u l f o n e analogue of methadone 2 has been found to be as a c t i v e as methadone and to possess the same enantiomeric potency r a t i o (1,3). A l s o , the proposal has been made that 2 i n t e r a c t s w i t h the a n a l g e t i c receptor i n a p r e f e r r e d conformation s i m i l a r to that of _1 ( 5 ) . I t was considered, t h e r e f o r e , that as an i n i t i a l approach to c o n s t r a i n e d d e r i v a t i v e s of diphen-ylpropylamine-type a n a l g e t i c s , the i n v e s t i g a t i o n of four-membered c y c l i c sulfone ( t h i e t a n e 1,1-dioxide) analogues of 2 would be of i n t e r e s t . A de-r i v a t i v e of 2 i n c o r p o r a t i n g the t h i e t a n e 1,1-dioxide r i n g (_7) would be con-f o r m a t i o n a l ly much more r e s t r i c t e d than 2 i t s e l f . Perhaps the most d e s i r -able of the t h i e t a n e 1,1-dioxide analogues was 8, which i s f o r m a l l y d e r i v e d <>. °2 7 8 7 from 2 by j o i n i n g C-2 to C-5. Attempts to syn t h e s i z e 8_, however, have been un s u c c e s s f u l (14). As an a l t e r n a t i v e to 8_, i t was proposed that compounds of the type 9_ be prepared and tested f o r a n a l g e t i c a c t i v i t y . Although not as s u i t a b l e 9 as 8_ because of the r e p o s i t i o n i n g of one of the aromatic groups on the h e t e r o c y c l i c r i n g (from C - l to C-4), the s y n t h e s i s of 9_ was considered to be worthwhile i n view of the suggestion that only one of the phenyl sub-s t i t u e n t s of diphenylpropylamine-type a n a l g e t i c s i s i n v o l v e d i n a s s o c i a t i o n at the receptor (2,3). By r e t a i n i n g the second phenyl r i n g i n 9_, i t was hoped that some semblance of the s o l u b i l i t y c h a r a c t e r i s t i c s of 2 would be maintained. Although 9_ lacked a methyl s u b s t i t u e n t a to the dimethylamino group, i t was f e l t that t h i s compound may s t i l l possess a n a l g e t i c a c t i v i t y s i n c e the methadone analogue without the methyl s u b s t i t u e n t (normethadone) i s known to be f a i r l y a c t i v e ( 2 ) . The s y n t h e s i s of the d e r i v a t i v e of 9 possessing the rx.-methy 1 group was undertaken w i t h the a n t i c i p a t i o n of observ-in g augmented a c t i v i t y . D e r i v a t i v e s of _9 having p a r a - s u b s t i t u e n t s on one of the aromatic r i n g s were a l s o sought, as there was the p o s s i b i l i t y that such s u b s t i t u e n t s might a f f e c t the a c t i v i t y of 9 as a r e s u l t of an i n f l u e n c e 8 on d i s t r i b u t i o n and drug-receptor i n t e r a c t i o n s . The work described i n t h i s t h e s i s was undertaken as p a r t of a p r o j e c t to explore t h i e t a n e 1,1-dioxide d e r i v a t i v e s and s i m i l a r novel h e t e r o c y c l e s for v a r i o u s types of pharmacological a c t i v i t y . Such compounds may serve as u s e f u l pharmacological t o o l s f o r expanding the knowledge of drug-receptor i n t e r a c t i o n s . The s y n t h e s i s of t h i e t a n e 1,1-dioxides and the chemical manipu-l a t i o n of compounds c o n t a i n i n g the t h i e t a n e 1,1-dioxide r i n g are r e l a t i v e l y new areas, a ready s y n t h e s i s of the h e t e r o c y c l e having become a v a i l a b l e only as l a t e as 1962. In the process of d e v i s i n g and e f f e c t i n g the synthe-s i s of the compounds described h e r e i n , i t was deemed app r o p r i a t e and bene-f i c i a l to e x p l o r e , where p o s s i b l e , the i n t r i c a c i e s of t h i e t a n e 1,1-dioxide chemistry i n order to provide a broader base f o r the s y n t h e s i s of other t h i e t a n e 1,1-dioxide compounds of p o t e n t i a l pharmacological i n t e r e s t . A l i m i t e d number of t h i e t a n e 1,1-dioxides have been i n v e s t i g a t e d f o r v a r i o u s types of b i o l o g i c a l a c t i v i t y . In a l l cases they represented the i n i t i a l cycloadducts from the r e a c t i o n of enamines w i t h s u l f e n e s and thus possessed a t e r t i a r y amino group attached d i r e c t l y to C-3 of the hetero-c y c l e . Compounds of the type _10 (NRR1 = dimethylamino, p y r r o l i d i n e , e t c . ) R R' 10 11 were prepared as p o t e n t i a l monoamine oxidase i n h i b i t o r s . A s i g n i f i c a n t l e v e l of i n h i b i t o r y a c t i v i t y was not observed (15). A s e r i e s of s p i r o - 5 -norbornene-2,2 1-thietane 1 1 1 - d i o x i d e s (11, NRR1 = p y r r o l i d i n o , p i p e r i d i n o , e t c . ) i s the subject of a patent. Members of the s e r i e s are apparently claimed f o r use as b a c t e r i o s t a t i c s , b a c t e r i c i d e s and v e t e r i n a r y s e datives (16). Screening a number of compounds based on s t r u c t u r e 1_2 (R = methyl, b e n z y l , e t c . ) revealed no s i g n i f i c a n t a n t i b a c t e r i a l , a n t i v i r a l , hypotensive or antiinflammatory a c t i v i t y (17). CH. L3 R 12 10 THIETANE 1,1-DIOXIDE CHEMISTRY The synthesis of 3-aminothietane 1,1-dioxides by the i n t e r a c t i o n of a l i p h a t i c s u l f o n y l c h l o r i d e s w i t h enamines i n the presence of t r i e t h y l -amine was f i r s t reported independently by two groups i n 1962 (18,19). For example, a d d i t i o n of phenylmethanesulfony1 c h l o r i d e (13) to a s o l u t i o n of the p y r r o l i d i n e enamine of isobutyraldehyde .14 and t r i e t h y l a m i n e gave 2,2-d i m e t h y l - 3 - p y r r o l i d i n o - 4 - p h e n y l t h i e t a n e 1,1-dioxide (15) i n 70 per cent 14 13 15 y i e l d (19). La t e r i n the same year a s i m i l a r r e a c t i o n was reporte d i n which a d d i t i o n of methanesulfony1 c h l o r i d e to a s o l u t i o n of ketene d i e t h y l a c e t a l (16) and t r i e t h y l a m i n e a f f o r d e d 3,3-diethoxythietane 1,1-dioxide (17) i n good EtO OEt \ / C II CH„ + CH SO C l 3 2 16 EtO OEt ( E t ) 3 N -HCl y i e l d (20). I t was soon discovered that the c y c l o a d d i t i o n occurred only w i t h s t r o n g l y n u c l e o p h i l i c o l e f i n s (20,21,22). Besides enamines and ketene acetals, ketene 0,N- and N,N-acetals (23,24) and ynamines (25,26) were subsequently found to yield four-membered cyclic sulfones. The aliphatic sulfonyl chlorides that are used for the synthe-sis of thietane 1,1-dioxides are those which possess a hydrogen atom OC to the sulfonyl group. It was postulated that formation of the heterocycle involved i n i t i a l dehydrochlorination of the sulfonyl chloride by tr i e t h y l -amine to give a sulfene JJ3, which then underwent cycloaddition to the ena-mine or ketene acetal (19,20,21,27). The existence of sulfene intermediates CH I R' so2ci + (Et) 3N SO, R' 18 •f (Et) N.HC1 3 was eventually demonstrated by the alcoholysis of aliphatic sulfonyl chlor-ides with deuterated alcohols in the presence of triethy1amine, which gave monodeuterated but no polydeuterated sulfonate esters (28,29,30,31). These experiments were followed by the isolation of mesylfulfene (19) as its stable trimethylamine adduct 20. The reactions of ^ 0 were the same as those brought 2 CH3S02C1 2(Et) 3N CH3CN,-40C CH SO — CH 3 2 19 SO, (Et) 3N CH3S02CHS02N(C2H5). (CH 3) 3N CH3S02CHS02N(CH3). 20 about by treating mesylmethanesulfonyl chloride with triethylamine (22). R e c e n t l y , the f i r s t d i r e c t o b servation of f r e e s u l f e n e was made by o b t a i n -ing i t s i n f r a r e d spectrum at -196° (32). The p o s s i b i l i t y that formation of 3-aminothietane 1,1-dioxides i n v o l v e d r e a c t i o n of the enamine w i t h the s u l f o n y l c h l o r i d e d i r e c t l y , r a t h e r than w i t h a sulfene intermediate, has been r u l e d out (22,27). I t i s not known w i t h c e r t a i n t y whether the c y c l o a d d i t i o n of s u l -fenes w i t h enamines i s a concerted r e a c t i o n (path a) or a two-step a d d i t i o n (path b) i n v o l v i n g a z w i t t e r i o n i c intermediate 21_- However, a two-step mechanism i s apparently g e n e r a l l y favored (22,33,34) and the intermediacy of a z w i t t e r i o n has been invoked by v a r i o u s workers (35,36,37,38,39,40). 21 23 In support of path b, i t has been pointed out that such a mechanism i s p r e f -e r a b l e on the b a s i s of the Woodward-Hoffmann s e l e c t i o n r u l e s (41), and that i t provides a b e t t e r e x p l a n a t i o n of the s i n g l e o r i e n t a t i o n ( d i a l k y l a m i n o group on C-3 as i n 2J2) and of the f a c t that only s t r o n g l y n u c l e o p h i l i c o l e f i n s are attacked by sulfenes (22). A l s o , the intermediate 21 allows f o r the formation of s u b s t i t u t i o n product 23 by prototropy (path c) (34). 13 The r e a c t i o n s of phenylsulfene w i t h 1-morpholinocyclohexene and 1-morpholinocyclopentene to give the corresponding t h i e t a n e 1,1-dioxides, 24 and 25_, were considered to be two-step processes i n v o l v i n g d i p o l a r i n t e r -mediates (37). When cycloadduct 24 was c r y s t a l l i z e d from e t h a n o l , N-b e n z y l s u l f o n y l morpholine (26) was obtained. R e f l u x i n g 25 i n ethanol a f f o r d e d f i r s t the s u b s t i t u t i o n product 27 and then the ketone 28. I t was 28 f e l t that these r e a c t i o n s e s t a b l i s h e d the r e v e r s i b i l i t y of both stages of the r e a c t i o n between su l f e n e s and enamines (37). 14 The i s o l a t i o n of an enamino su l f o n e 3_2 as w e l l as c y c l i c product 33 i n the r e a c t i o n between phenylsulfene (30) and 1,3-bis(dimethylamino)-propene (29) has been a t t r i b u t e d to the intermediacy of z w i t t e r i o n 31. I t was p o s t u l a t e d that the phenyl r i n g i n 3_1 s t a b i l i z e d the o c - s u l f o n y l car-banion component of the z w i t t e r i o n to an extent s u f f i c i e n t to permit N(CH 3) 2 H CH 9 I N(CH 3) 2 29 + CH = SO, N(CH 3) 2 II C H / \ :H2 : N(CH 3) 2 CH2 S0 2 —CH-31 30 (CH 3) 2N N ( C H 3 ) 2 33 - C H 2 = N ( C H 3 ) 2 <^ CHS0 2CH = CHN(CH 3) 2 ^ y V-CH 2 S 0 2CH = CHN(CH 3) 2 32 15 cleavage (path a) as a mechanistic a l t e r n a t i v e to c y c l o a d d i t i o n (path b). F u r t h e r , i t was proposed that such r e s u l t s s t r o n g l y suggested that s u l f e n e -enamine i n t e r a c t i o n s were nonconcerted, at l e a s t i n those cases where phenylsulfene (30) was i n v o l v e d (35). Re c e n t l y , i n the r e a c t i o n of s u l f e n e (35) w i t h the o p t i c a l l y a c t i v e enamine 34 prepared from ( R ) - ( - ) - 2 - m e t h y l p y r r o l i d i n e and propionalde-hyde, i t was observed that the cycloadduct 38_ was formed to a greater extent than i t s diastereoisomer 3_9 (42). Paquette has proposed that t h i s i s the H 3 16 consequence of the rate-determining t r a n s i t i o n state for thietane 1,1-dioxide r i n g formation being more product-like than r e a c t a n t - l i k e (product development c o n t r o l ) . He has formulated a t r a n s i t i o n state model in which the enamine and sulfene double bonds are orthogonally orientated with respect to each other. T r a n s i t i o n state complex 3^ was considered to be preferred, even though 35 approached from the more s t e r i c a l l y hindered surface of the enamine 34, since i t produced d i r e c t l y a cycloadduct 3_8 r e l a t i v e l y free of non-bonded i n t e r a c t i o n s . The corresponding complex 3_7 i n which 3_5 approached 3ift f r o m the least hindered side was less favored, since the diastereoisomer 39_ obtained d i r e c t l y possessed a serious methyl-methyl compression (as indicated) (42). l i k e thietane i t s e l f , was puckered, as i n 40 (35). He reasoned that i n t r o -duction of two oxygens on the s u l f u r atom of thietane could be expected to r e s u l t i n the generation of severe non-bonded i n t e r a c t i o n s which the oxidized species could best a l l e v i a t e by maintaining the puckered conformation. Sup-port for th i s assumption was f i r s t obtained from the observation that trans-* 2,4-diphenylthietane 1,1-dioxide (41), upon treatment with sodium methoxide i n methanol, gave the cis-isomer 40 to the extent of 96 per cent (35,43). In 1967 Paquette suggested that the thietane 1,1-dioxide r i n g , H 0 NaOCH. l3 H H H 0 H 0 41 40 17 Presumably, the ci s - i s o m e r was the more s t a b l e of the two because i t pos-sessed the phenyl groups i n pseudoequatorial p o s i t i o n s on the puckered h e t e r o c y c l i c r i n g (43). On the b a s i s of the e q u i l i b r i u m r e s u l t , i t has been proposed that 40 e x i s t s almost e x c l u s i v e l y i n the conformation de-p i c t e d (43) . In c e r t a i n i n s t a n c e s , a p p l i c a t i o n of the Karplus c o r r e l a t i o n (44a) has provided evidence f o r a puckered t h i e t a n e 1,1-dioxide r i n g . The v i c i n a l c o u p l i n g constant (10.0 Hz) observed f o r the r i n g protons of the s u l f o n e h e t e r o c y c l e i n 42 was r e a d i l y r a t i o n a l i z e d i n terms of a f o l d e d t h i e t a n e 42 43 1,1-dioxide r i n g on which the p y r r o l i d i n e and phenyl groups occupied trans pseudoequatorial p o s i t i o n s and the two protons i n question pos-sessed a d i h e d r a l angle of approximately 180° (45). In a s i m i l a r manner, a puckered conformation was assigned to 43 to e x p l a i n the v i c i n a l c o u p l i n g constant of 9.3 Hz. The a l t e r n a t e p o s s i b i l i t y , a planar t h i e t a n e 1,1-d i o x i d e r i n g i n which the d i h e d r a l angle was 0°, was considered u n l i k e l y because i t r e q u i r e d e c l i p s i n g of the bulky p i p e r i d i n o and carbethoxy groups (46). To o b t a i n f u r t h e r evidence f o r the trans pseudoequatorial d i s p o s i -t i o n of the p i p e r i d i n o and carbethoxy s u b s t i t u e n t s i n 43, the compound was exposed to sodium methoxide i n methanol. A f t e r prolonged treatment, no 18 e p i m e r i z a t i o n was apparent (46) I n v e s t i g a t i o n s of the angle of pucker (9 i n 44) have been c a r r i e d out f o r a few thie t a n e 1,1-dioxides. On the b a s i s of nmr data and c e r t a i n assumptions, 6 f o r 40 has been approximated to be 35° (43). C a l c u l a t i o n s C l H " C l 45 46 based on d i p o l e moment measurements gave a valu e of 15° f o r 6 i n compound 45 (47), and an angle of pucker of 25.1° has been obtained f o r 46 by X-ray c r y s t a l l o g r a p h y (48). I t i s p o s s i b l e that the nature of the s u b s t i t u e n t s on the t h i e t a n e r i n g has an e f f e c t on the degree of puckering (49). S e v e r a l other instances where a puckered conformation f o r thie t a n e 1,1-dioxides has been a l l u d e d to are found i n the recent l i t e r a t u r e (50,51,52,53,54). The s y n t h e s i s of th i e t a n e 1,1-dioxides by the c y c l o a d d i t i o n of sulf e n e s to e l e c t r o n - r i c h o l e f i n s has been e x t e n s i v e l y reviewed (22,33,55, 56,57,58). O p i t z ' s review (22) i s e s p e c i a l l y i n f o r m a t i v e . In the f o l l o w -i n g , some recent preparations of th i e t a n e 1,1-dioxides by t h i s method w i l l 19 be b r i e f l y considered, as w e l l as s e v e r a l t h i e t a n e 1,1-dioxide rearrangement r e a c t i o n s . Because of t h e i r s y n t h e t i c u t i l i t y , a b r i e f d i s c u s s i o n of t h i e t e 1,1-dioxides (the« $- u n s a t u r a t e d analogues of thiet a n e 1,1-dioxides) i s al s o warranted. Treatment of the p y r r o l i d i n e enamine 4_7 w i t h s u l f e n e generated i n s i t u i n c o l d t e t r a h y d r o f u r a n gave the thiet a n e 1,1-dioxide 48 i n 58% + CH 3S0 2C1 47 ( E t ) 3 N THF, 0 C 48 y i e l d (59). Compound 48 allowed f o r the p r e p a r a t i o n of a t h i e t e 1,1-dioxide fused <*, p to naphthalene. When the cycloadduct 49 from the a d d i t i o n of s u l f e n e to N,N,N',N'-tetramethyl-l-butene-1,3-diamine was resubmitted to the o r i g i n a l r e a c t i o n c o n d i t i o n s under which i t was formed, 5_0 was obtained. I t was proposed that under the r e a c t i o n c o n d i t i o n s , p r o t o n a t i o n of the ex.-dime thy laminoe thy 1 49 N ( C H 3 ) 2 (CH 3) 2N N S ' 0 2 CH CH (CH 3) 2NH N S ' 0, 3 C H = CHS0 2CH 2CH = N ( C H 3 ) 2 N ( C H 3 ) 2 HN(CH 3) 2 -H CH 3CH = C H S 0 2 C H = CHN(CH 3) 2 50 20 s u b s t i t u e n t at C-2 of 49 created an e l e c t r o n - d e f i c i e n t centre which permit-ted a f a c i l e r i n g cleavage w i t h the e j e c t i o n of dimethylamine (35,60). R e a c t i o n of the d i s u l f o n y l c h l o r i d e 51 w i t h ketene d i e t h y l a c e t a l (16) i n the presence of excess t r i e t h y l a m i n e afforded the monocycloadduct 52 r a t h e r than a b i t h i e t a n e t e t r o x i d e (61) . Compound 52 was apparently s o 2 c i I 3 ( E t ) 3 N CH 3CHCH 2S0 2C1 + 2 CH 2 = C ( 0 E t ) 2 »-THF, 0° 51 16 52 i d e n t i c a l to the th i e t a n e 1,1-dioxide prepared from _16 and a l l y l s u l f o n y l c h l o r i d e (21). I n t e r e s t i n g l y , whereas r e a c t i o n of phenylsulfene w i t h 1-morpholino-cyclohexene gave the expected cycloadduct 24, the c y c l o a d d i t i o n w i t h 1-p y r r o l i d i n o c y c l o h e x e n e under the same c o n d i t i o n s y i e l d e d the s u b s t i t u t i o n product 53 (37). Rapid column chromatography of the crude m a t e r i a l obtained by r e a c t i n g the dienamine 54 w i t h s u l f e n e gave, amongst other products, a low y i e l d of the unstable t h i e t a n e 1,1-dioxide 5_5 (38). Upon standing i n chloroform s o l u t i o n at room temperature, 5_5 was c l e a n l y converted to 5_6 by cleavage of the bond common to both r i n g s . A mechanism was suggested f o r t h i s t r a n s f o r m a t i o n (38). As part of an i n v e s t i g a t i o n i n t o the p o s s i b i l i t y of preparing a s t a b l e s u l f e n e , s u l f o n y l c h l o r i d e 5_7 was reacted w i t h 1 - i s o b u t e n y l p i p e r i d i n e (58) i n the presence of t r i e t h y l a m i n e to give the cycloadduct 43 i n good ( E t ) 3 N Et2O,-20° 57 58 22 COOEt y i e l d (46). When the r e a c t i o n was run under s i m i l a r c o n d i t i o n s using 1-b u t e n y l p i p e r i d i n e (59) r a t h e r than 58_, the s u b s t i t u t i o n product 60 was 57 + C — 59 ( E t ) 3 N * Et 2O,-10 c CH q EtOOC — CHS0 2—C 60 obtained i n 86% y i e l d . No attempt was made to r a t i o n a l i z e t h i s d i f f e r e n c e i n r e a c t i v i t y between 5_8 and 59 (46) . The simp l e s t 3 - d i a l k y l a m i n o t h i e t a n e 1,1-dioxide 6jL has been pre-pared d i r e c t l y i n 86% y i e l d by the c y c l o a d d i t i o n of N,N-dimethylvinylamine CH, 2 — CH — N ( C H 3 ) 2 + CH 3S0 2C1 ( E t ) 3 N > E t 2 0 , - 2 0 c N ( C H 3 ) 2 61 62 (61) to sulfene (62). Enamine 61 was synth e s i z e d by dehydrohalogenation 23 of N,N-dimethyl-N-@-chloroethylamine and was found to be s t a b l e below -20° (62). A d d i t i o n of methanesulfony1 c h l o r i d e to a d i e t h y l ether s o l u t i o n of l , 3 , 3 - t r i m e t h y l - 2 - m e t h y l e n e i n d o l i n e (63) and t r i e t h y l a m i n e a f f o r d e d a 2:1 mixture of the cycloadduct 64_ and the s u b s t i t u t i o n product 6_5 i n about CHg CH 3 H 64 65 507o y i e l d (36) . Prolonged exposure of 64 i n d i e t h y l ether to excess t r i -ethylamine and one molar e q u i v a l e n t of t r i e t h y l a m i n e h y d r o c h l o r i d e d i d not generate 6_5_, nor d i d t r e a t i n g 65 i n the same manner y i e l d 64. On t h i s b a s i s , i t was concluded that 6_4 and 6_5 were formed independently i n the r e a c t i o n of 63_ w i t h s u l f e n e , probably from a common intermediate z w i t t e r i o n . D e r i v -a t i v e s of 63 i n which the N-methyl group was r e p l a c e d w i t h other a l k y l and a r a l k y l groups have a l s o been s u c c e s s f u l l y cycloadded to s u l f e n e (17). The r e a c t i o n of methanedisulfony1 c h l o r i d e (66) w i t h ketene d i -e t h y l a c e t a l (16) and t r i e t h y l a m i n e gave a c r y s t a l l i n e substance which has 24 been formulated as the s p i r o b i t h i e t a n e t e t r o x i d e 67. I t was proposed that the formation of 6_7 proceeded through the intermediacy of d i s u l f e n e (0 2S = C = S0 2) (39). When 67_ was d i s s o l v e d i n c o l d ethanol and allowed to stand at -10 to -50°, a r i n g cleavage and proton t r a n s f e r occurred to gi v e 6_8, q u a n t i t a t i v e l y . This t r a n s f o r m a t i o n was considered to be due to 2 ( E t ) 3 N C1S0 2CH 2S0 2C1 + 2 CH 2 = C ( O C 2 H 5 ) 2 >-benzene,-5° 66 16 EtO OEt EtOH 10 to -50° EtO OEt S0 2CH. OEt 'OEt 6a s t r a i n inherent i n 67_ (39). A d d i t i o n of the morpholine enamine of acetophenone (69) to s u l f e n e gave 20 i n 46% y i e l d (63). This r e a c t i o n i s of i n t e r e s t because i t has been -(- CH 3S0 2C1 ( E t ) 3 N E t 2 0 , 0° 69 noted that <x-substitution of the enamine tends to favor the formation of s u b s t i t u t i o n product r a t h e r than cycloadduct (22). H y d r o l y s i s of 70 i n 25 aqueous base y i e l d e d the s u b s t i t u t i o n product 7_1. The para- c h l o r o analogue 70 NaOH/H20 >• MeOH A, 2 hr \ C = C H S 0 CH 2 3 71 of 70 was converted to the corresponding t h i e t e 1 , 1-dioxide and then reduced w i t h sodium borohydride to gi v e 72. A c o n t r a s t i n s u s c e p t i b i l i t y to base-induced h y d r o l y s i s was observed between 70 and 72. Warming _72 w i t h sodium deuteroxide i n deuterium oxide and dioxane, r a t h e r than r e s u l t i n g i n r i n g cleavage, gave the ( X-tetradeuterated s u l f o n e , 73» i n 887<, y i e l d (63). Na0D/D20 dioxane 40-50°, 24 hr 73 A novel t h i e t a n e 1 , 1-dioxide s y t h e s i s was performed by r e f l u x i n g a benzene s o l u t i o n of 1 - c h l o r o e t h a n e s u l f i n i c a c i d (24) w i t h excess enamine 14 i n the presence of t r i e t h y l a m i n e . The cycloadduct 75_ was obtained i n 167o y i e l d . I t was proposed that the r e q u i r e d i n t e r m e d i a t e , methylsulfene, was generated from _74 by a process that was the formal reverse of that whereby the same intermediate was der i v e d from ethanesulfony1 c h l o r i d e (64) 26 CH,CHSO,H I C l 74 + CH„ N I CH I! c / \ 14 CH, ( E t ) 3 N benzene CH-, CH. 75 Rea c t i o n of the (3-cyano-substituted ketene aminal 7_6 w i t h methane-s u l f o n y l c h l o r i d e and t r i e t h y l a m i n e under c o n d i t i o n s (22) conducive to the formation of mesylsulfene (19) gave the s u b s t i t u t i o n product 7_7 r a t h e r than the expected cycloadduct (65). Such a r e s u l t was perhaps p r e d i c t a b l e i n NC CH ^ N ( E t ) 2 :C + ^ N ( E t ) 2 CH 3S0 2CH: SO, CH 3CN •40c 76 19 NC-CH 3S0 2CH 2S0 2 N(Et), N(Et), 77 view of the r e p o r t that only the s u b s t i t u t i o n product 7_9 was obtained from the r e a c t i o n of ketene aminal 78 w i t h phenylsulfene (30). This was a t t r i -buted, i n p a r t , to s t e r i c crowding at the v i n y l i c carbon atom bear i n g the CH 0 . N ( E t ) 2 N ( E t ) 2 C H = SO, THF 78 30 27 o-H y N(Et) C = C / \ CH 2S0 2 N(Et), 79 gem-diethylamino groups which prevented r i n g c l o s u r e of the presumed z w i t -t e r i o n i c i n termediate (66). When the product SO from the c y c l o a d d i t i o n of ketene d i e t h y l a c e t a l to phenylsulfene was t r e a t e d w i t h concentrated h y d r o c h l o r i c a c i d , the e n o l i c d e r i v a t i v e 81_ and the t h i e t e 1,1-dioxide 82 were formed (67). An unsuccess-f u l attempt to convert 80 to 81 had p r e v i o u s l y been reported (68). EtO OEt cone. HCl >-18 hr OEt + 81 82 A d d i t i o n of the h i g h l y r e a c t i v e s u l f o n y l c h l o r i d e 83 to a dioxane 28 s o l u t i o n of j34 and t r i e t h y l a m i n e at 15° gave a 307o y i e l d of cycloadduct 85 (40). When the r e a c t i o n was repeated using 1-morpholinocyclopentene (86) i n place of 84, the s u b s t i t u t i o n product 90 was obtained i n 207o y i e l d . The presumption was made that the sul f e n e 87 der i v e d from 83 could add to 86 to give e i t h e r the z w i t t e r i o n 8_8 or the th i e t a n e 1,1-dioxide 8_9. Ring cleavage i n 89 or a p r o t o t r o p i c s h i f t i n 88_ would then y i e l d 90. Although 90 e a r l i e r work (69) i n d i c a t e d that the former pathway may have been i n v o l v e d , i t was considered that the h a l f - l i f e of 8_8 might be s u f f i c i e n t l y long, owing to resonance s t a b i l i z a t i o n of the negative charge, to permit the l a t t e r mech-anism(40). 29 Treatment of c i s - 2 , 4 - d i p h e n y l t h i e t a n e 1,1-dioxide (40) w i t h t e r t -butoxy magnesium bromide i n d i e t h y l ether at 35° a f f o r d e d the c y c l i c s u l f i n i c e s t e r 9_1 i n 707o y i e l d , s t e r e o s p e c i f i c a l l y . In a s i m i l a r manner, the t r a n s -isomer 4_1 gave a 41% y i e l d of 92 (72) . Heating e i t h e r 40 or 41 w i t h e t h y l magnesium bromide i n d i e t h y l ether - benzene y i e l d e d trans-1,2-diphenyl-c y c l o p r o p a n e s u l f i n i c a c i d (93) to the extent of 75 per cent (70). Mechan-isms have been proposed f o r both types of rearrangement (71). EtMgBr 40 or 41 E t 2 0 - benzene H A C,HC D D C 6 H 5 S 0 2 H 93 30 Exposure of 2-methylene-l,3-dioxolane (94) to chloromethanesulfony1 c h l o r i d e (95) and t r i e t h y l a m i n e i n t e t r a h y d r o f u r a n s o l u t i o n at room temper-ature gave 96 i n 67.57» y i e l d (54). The presence of an c x-chloroketal f u n c t i o n CH„ C \ 0' 94 + G1CH 2S0 2C1 95 (E t ) 3 N ) THF 230-250° 0 I! CH3C- 0 — CH 0CH r tCl 2 2 + SO. 97 i n 9_6 apparently f a c i l i t a t e d i t s thermal conversion to 2-chloroethy 1 acetate (97) i n high y i e l d . A p o s s i b l e mechanism f o r t h i s rearrangement was pre-sented (54) . Other r e p o r t s d e a l i n g w i t h the thermal decomposition of thie t a n e • 1,1-dioxides have appeared i n the recent l i t e r a t u r e . Thermal d e s u l f o n y l a -t i o n of t h i e t a n e 1,1-dioxide i t s e l f (7) at 960° gave a mixture of propene and cyclopropane, q u a n t i t a t i v e l y (67). When 2,2-dimethyl-3-thietanone 1,1-d i o x i d e (98) was thermolyzed at 940°, formation of is o b u t y l e n e occurred to the extent of 96.57, by l o s s of carbon monoxide and s u l f u r d i o x i d e . I t was S' 0, -SO, + 31 p o s t u l a t e d that e x t r u s i o n of one of the oxides followed by c o u p l i n g gave a three-membered r i n g from which the second oxide was l o s t to give the alkene CH, CH-0 II S °2 98 -SO , -CO 2 CH, CH„ CH (67). Thermolysis of the 3-hydroxy analogue of _7 gave a complex mixture of products, the formation of most of which has been r a t i o n a l i z e d i n terms of d e s u l f o n y l a t i o n , reverse c y c l o a d d i t i o n and dehydration (67). Heating -SO, 100 t h i e t a n e 1,1-dioxide 99 at 230° y i e l d e d a mixture of c i s - and t r a n s - 1 -phenyl-2-benzoylcyclopropane (100). S i m i l a r r e s u l t s were obtained when 99 •SO, 150 c 101 32 was photolyzed i n d i l u t e cyclohexane s o l u t i o n (72). Other p y r o l y s e s of t h i e t a n e 1,1-dioxides which afforded cyclopropane d e r i v a t i v e s have been recorded i n the l i t e r a t u r e (43,51). L a s t l y , thermal decomposition of 101 gave the pyrazole 102 i n 5270 y i e l d . A mechanism f o r t h i s t r a n s f o r m a t i o n has been proposed (73). The p r e p a r a t i o n of t h i e t e 1,1-dioxides has been b r i e f l y reviewed (57) and an i n c l u s i v e l i s t of references p e r t a i n i n g to the subject has been compiled to e a r l y 1968 (45). The most common approach to t h i e t e 1,1-dioxides i s through the corresponding 3 - d i a l k y l a m i n o t h i e t a n e 1,1-dioxides by the Hofmann (45,62,74) or Cope (45,50,59,63) e l i m i n a t i o n procedures. R e c e n t l y , a p p l i c a t i o n of the former method to 62 gave u n s u b s t i t u t e d t h i e t e 1,1-dioxide (103) i n good 62 103 y i e l d (62). 3 - D i a l k y l a m i n o t h i e t e 1,1-dioxides are obtained d i r e c t l y from the c y c l o a d d i t i o n of ketene 0,N-acetals to sulfenes as a consequence of spon-taneous e l i m i n a t i o n of an a l c o h o l from the i n i t i a l adduct. For example, r e a c t i o n of ketene 0,N-acetal 104 w i t h methanesulfonyl c h l o r i d e i n the presence of t r i e t h y l a m i n e gave 3-dimethylamino-4,4-dimethylthiete 1,1-dioxide (105) i n 697» y i e l d (23). S i m i l a r l y , the i n i t i a l cycloadducts from ketene N,N-acetals and sulfenes undergo spontaneous e l i m i n a t i o n of a d i a l k y l a m i n e 33 to give 3 - d i a l k y l a m i n o t h i e t e 1,1-dioxides (24,43). CH. OEt ( E t ) 3 N CH 3 N ( C H 3 ) 2 benzene -5 to 5° 104 N(CH 3) l3 -EtOH L3 105 Another route to 3 - d i a l k y l a m i n o t h i e t e 1,1-dioxides that has r e c e i v e d c o n s i d e r a b l e a t t e n t i o n r e c e n t l y i s the c y c l o a d d i t i o n of ynamines to sulfenes (25,26,37,50,75). For i n s t a n c e , r e a c t i o n of 1-diethylamino-2-phenylacetylene (106) w i t h phenylmethanesulfony1 c h l o r i d e (13) i n the pres-ence of t r i e t h y l a m i n e a f f o r d e d 107 i n 907» y i e l d (37). The c y c l o a d d i t i o n has been p o s t u l a t e d to occur through a d i p o l a r intermediate (26). + 106 13 Et Et 107 34 Thie t e 1,1-dioxides u n s u b s t i t u t e d at C-3 are u s e f u l f o r synthesiz-i n g t h i e t a n e 1,1-dioxide d e r i v a t i v e s as a r e s u l t of t h e i r p r o p e n s i t y to undergo M i c h a e l a d d i t i o n w i t h v a r i o u s n u c l e o p h i l e s (15,52,76,77) and to behave as d i e n o p h i l e s i n the D i e l s - A l d e r r e a c t i o n (52,77,78,79,80,81). R e f l u x i n g an absolute ethanol s o l u t i o n of t h i e t e 1,1-dioxide (103) w i t h thiophenol (108) and t r i e t h y l a m i n e gave the M i c h a e l adduct 109 i n 92.57Q + S' °2 103 ( E t ) 3 N 3 EtOH A 1.5 hr 108 y i e l d (77). Condensation of 4, 4 - d i m e t h y l t h i e t e 1,1-dioxide (110) w i t h 1,4-diphenyl-2,3-benzofuran (111) i n r e f l u x i n g xylene a f f o r d e d the D i e l s - A l d e r product 112 i n good y i e l d (79). Re c e n t l y , t h i e t e 1,1-dioxide has been shown CH. CHo + C,HP 6 5 CH„ C 6 H 5 110 111 112 to undergo 1 , 2 - c y c l o a d d i t i o n w i t h enamines to g i v e 2 - t h i a b i c y c l o [j2.2.d]-hexane d e r i v a t i v e s (82) and 1 , 3 - c y c l o a d d i t i o n w i t h d i a z o alkanes to y i e l d p y r a z o l i n e s (73). Reduction of t h i e t e 1,1-dioxides u n s u b s t i t u t e d at C-3 to give the 35 corresponding t h i e t a n e 1,1-dioxides i s apparently g e n e r a l l y s u c c e s s f u l by e i t h e r c a t a l y t i c hydrogenation u s i n g p a l l a d i u m on c h a r c o a l c a t a l y s t (52,63, 67,83,84) or by means of sodium borohydride (50,63,77). A d i e t h y l ether s o l u t i o n of 113 hydrogenated over 10% palladium on c h a r c o a l gave 114 i n greater than 9 0 % - y i e l d . At a lower hydrogen pressure and w i t h a shorter H 2, 10% Pd-C 50 p s i , 58 hr V J X s 0 113 114 hydrogenation time, the e x o c y c l i c double bond was s e l e c t i v e l y reduced (83). Reduction of t h i e t e 1,1-dioxides w i t h l i t h i u m aluminum hydride g e n e r a l l y r e s u l t s i n r i n g cleavage (63,77,79), although a few exceptions are known (79,85). An attempt to reduce the double bond of c e r t a i n 3-diethylamino-t h i e t e 1,1-dioxides w i t h sodium borohydride was u n s u c c e s s f u l (50). Ring cleavage occurs when t h i e t e 1,1-dioxides are t r e a t e d w i t h aqueous base (15,45,63,68,76,77). For example, h e a t i n g 2-phenylthiete 1, 1-dioxide (115) i n a mixture of aqueous sodium hydroxide'and methanol gave NaOH / -0, 115 116 benzyl methyl s u l f o n e (116)(15). The base-catalyzed r e a c t i o n has been l i k e n e d to a revers e a l d o l condensation (77). Thermal rearrangements of c e r t a i n t h i e t e 1,1-dioxides have 36 r e c e n t l y been i n v e s t i g a t e d (67,86,87). When t h i e t e 1,1-dioxide 117 was heated at 400° i n the presence of 9,10-dihydroanthracene, a c y c l i c s u l f i n i c 117 118 ester 118 was obtained i n good y i e l d . A mechanism accounting f o r t h i s t r a n s f o r m a t i o n has been proposed (87). A c i d h y d r o l y s i s of 3 - d i a l k y l a m i n o t h i e t e 1,1-dioxides a f f o r d s the corresponding 3-thietanone 1,1-dioxides (22,23,25,26). S t i r r i n g 119 i n 119 120 aqueous s o l u t i o n w i t h an a c i d i c i o n exchange r e s i n gave 120 i n 74% y i e l d . The k e t o n i c sulfone 120 possessed an a c i d i t y comparable to that of c a r b o x y l i c a c i d s (23). S i m i l a r l y , exposure of 121 to concentrated h y d r o c h l o r i c a c i d y i e l d e d the h y d r o l y s i s product 122, q u a n t i t a t i v e l y (26). 37 38 DISCUSSION OF THE CHEMISTRY The t h i e t a n e 1,1-dioxide d e r i v a t i v e s i n v e s t i g a t e d as p o t e n t i a l a n a l g e t i c s were 9_, 123, 124 and 125. Synthesis of these compounds was approached through the corresponding 3-dimethylaminothietane 1,1-dioxides 126, 127 and 128. The general s y n t h e t i c pathway employed i s o u t l i n e d i n Scheme I u s i n g the p r e p a r a t i o n of 9_ as an example. Replacement of phenyl-I, R l = R 2 = H 126, R l = H 123, R l = H i = 127, R l = C l 124, R l = C l ; R 2 = H 128, R l = N0 2 125, R l = N0 2; R 2 = H methanesulf ony 1 c h l o r i d e (13) w i t h p_-chloropheny lmethanesulf ony 1 c h l o r i d e (129) or £-nitrophenylmethanesulfony1 bromide (130) allowed f o r the synthe-s i s of 124 and 125, r e s p e c t i v e l y . A s i m i l a r scheme i n which hydrogen cya-nide was re p l a c e d by n i t r o e t h a n e was used to prepare compound 123. The f o l l o w i n g d i s c u s s i o n a l s o deals w i t h , i n t e r a l i a , c o n f i g u r a -t i o n a l and conformation aspects, as w e l l as the r e l a t i v e s t a b i l i t i e s , of the cycloadducts from the r e a c t i o n of e-dimethylaminostyrene w i t h phenyl-s u l f e n e . Data from a b r i e f study of the e f f e c t of r e a c t i o n solvent on t h i s c y c l i z a t i o n r e a c t i o n are considered. The p r e f e r e n t i a l formation of the 39 SCHEME 1. S y n t h e t i c Pathway f o r 2,4-Dipheny1-3-dimethylaminoraethylthietane 1,1-dioxide ( 9 ) . 40 l e s s s t a b l e t h i e t a n e 1,1-dioxide isomer i n the three s o l v e n t s i n v e s t i g a t e d i s i n t e r p r e t e d i n terms of a r e c e n t l y proposed t r a n s i t i o n s t a t e model f o r t h i e t a n e 1,1-dioxide r i n g formation. R e s u l t s from the c y c l i z a t i o n of P-dimethy laminos tyrene w i t h p_-chloro- and p_-nitropheny l s u l f ene are d e a l t w i t h i n l i g h t of the i n f o r m a t i o n obtained from the r e a c t i o n of t h i s enamine w i t h p h e n y l s u l f e n e . U t i l i z a t i o n of the 3-dimethylaminothietane 1,1-dioxides to prepare the corresponding t h i e t e 1,1-dioxides i s discussed w i t h r e f e r e n c e to p o s s i b l e mechanistic dichotomy. The t h i e t e 1,1-dioxides proved to be i n t e r e s t i n g i n respect to t h e i r s u s c e p t i b i l i t y to thermal rearrangement. £-Dimethylaminostyrene (131) i s a known compound (15,88). The nmr spectrum (CDCl^) of 131 i n d i c a t e d that i t e x i s t e d e x c l u s i v e l y i n one form at room temperature and showed the v i n y l protons as doublets at S6.73 and 5.13 w i t h J = 14 Hz. On the b a s i s of the magnitude of t h i s c o u p l i n g constant, 131 was assigned a t r a n s - c o n f i g u r a t i o n . The same assignment has been made by C a s e r i o and co-workers (88) . A t r a n s - c o n f i g u r a t i o n was a l s o i n d i c a t e d by the presence of a band at 935 cm ^ i n the i r spectrum. The nmr spectrum (neat, -10°) of a sample of 131 which had been s t o r e d at 0° f o r four months showed only the trans-isomer. Other a c y c l i c enamines that can be i s o l a t e d i n one c o n f i g u r a t i o n are known (74,90). For example, the enamine 205 d e r i v e d from propionaldehyde and methyl-«-phenethylamine was 131 205 41 apparently obtained only i n the trans-form ( J = 13.2 Hz) (74). Pheny lmethanesulf ony 1 c h l o r i d e (13) and p_-chlorophenylmethane-s u l f o n y l c h l o r i d e (129) are known compounds and t h e i r s y n t h e s i s i s des-c r i b e d i n the Experimental f o r the sake of completeness. I n t e r e s t i n g l y , upon c h l o r i n o l y s i s of the sodium t h i o s u l f a t e s a l t d e r i v e d from p_-nitro-b e nzyl bromide, only p_-nitropheny lmethanesulf ony 1 bromide (130) and no s u l f o n y l c h l o r i d e was i s o l a t e d . S i m i l a r r e s u l t s have been reporte d and are a t t r i b u t e d to the presence of sodium bromide i n the r e a c t i o n mixture (91). I n i t i a l l y , c o n s i d e r a t i o n was a l s o given to the p r e p a r a t i o n of p_-methoxyphenylmethanesulfony1 c h l o r i d e . However, two u n s u c c e s s f u l attempts 132 42 to prepare t h i s compound are recorded i n the l i t e r a t u r e (21,91) and, t h e r e f o r e , the matter was not f u r t h e r pursued. The r e a c t i o n of (3 -dimethy laminostyrene (131) w i t h phenylme thane-s u l f o n y l c h l o r i d e (13) i n the presence of t r i e t h y l a m i n e has been found (14, 15) to give two c y c l i c isomers, c i s - and tr_ans-2,4-dipheny1-3-dimethylamino-t h i e t a n e 1,1-dioxide (126a and b ) * . During the course of the present i n -v e s t i g a t i o n a t h i r d isomer, b e n z y l 1-pheny1-2-dimethylaminoetheny1 s u l f o n e (132), was i s o l a t e d and c h a r a c t e r i z e d . The three isomers could be separ-ated by c a r e f u l f r a c t i o n a l c r y s t a l l i z a t i o n of the crude product from hexane methyl e t h y l ketone. The c o n f i g u r a t i o n a l and conformational assignments f o r 126a and 126b were based on t h e i r nmr s p e c t r a . A determination of the r e l a t i v e s t a b i l i t i e s of the two c y c l i c isomers supported these assignments. Nmr Determination of the C o n f i g u r a t i o n and Conformation of c i s - and t r a n s - 2,4-Dipheny1-3-dimethylaminothietane-1,1-dioxide In the nmr spectrum of 126a the b e n z y l i c protons, Hfl and H^, appeared as a sharp doublet at S5.28 and were coupled to the remaining r i n g proton, H c, which was seen as a t r i p l e t at 83.68, J a c = = 9 Hz. A s i x -proton s i n g l e t a t S 2 . 1 0 was a t t r i b u t e d to the dimethylamino group. The equivalency of the b e n z y l i c protons i n d i c a t e d that the phenyl groups i n 126a were attached i n a c i s - c o n f i g u r a t i o n on the t h i e t a n e 1,1-dioxide r i n g . The magnitude of the v i c i n a l c o u p l i n g constant was e x p l i c a b l e i n terms of a puckered conformation i n which a l l three r i n g s u b s t i t u e n t s occupied pseudo-* The d e s i g n a t i o n s c i s and trans r e f e r to the c o n f i g u r a t i o n s of the aro-matic r i n g s w i t h respect to the plane of the h e t e r o c y c l i c r i n g . 43 e q u a t o r i a l p o s i t i o n s and the d i h e d r a l angle between each b e n z y l i c proton and H c approached 180°. In the 60 MHz spectrum of 126b, U& and H^ appeared as a d i f f u s e t r i p l e t a t S 5 . 4 3 and H Q was seen as a t r i p l e t atS 3.68. The protons of the dimethylamino group were revealed as a s i n g l e t a t S 1.93. The 100 MHz spec-trum of 126b showed H a as a doublet atS 5.494, ^ as a doublet at 5 5.304 and H c as a sharp t r i p l e t at<$3.648, w i t h J a c = JijQ = 9.4 Hz. The doublets were f u r t h e r s p l i t as a consequence of transannular c o u p l i n g , J a ^ = 1 Hz. The nonequivalency of protons H Q and H^ suggested a t r a n s - c o n f i g u r a t i o n f o r the phenyl groups on the h e t e r o c y c l i c r i n g . This assignment was supported by the u p f i e l d s h i f t of the N-methyl protons i n 126b when compared to the corresponding protons i n 126a. Such a s h i f t was a t t r i b u t a b l e to diamagnetic s h i e l d i n g of the N-methyl groups i n 126b by the phenyl group c i s to the dimethylamino s u b s t i t u e n t . A d e s h i e l d i n g e f f e c t by t h i s phenyl group ex-p l a i n e d the downfield s h i f t of Hfl (6 5.49) i n 126b compared to Hfl and H^ (55.28) i n 126a. A con f i d e n t assignment of a puckered conformation to 126b on the b a s i s of i t s nmr spectrum was not p o s s i b l e because of the equivalency of the v i c i n a l c o u p l i n g c o n s t a n t s , J a c and A puckered conformation f o r 126b p r e d i c t e d J a c > J b c - I t has been noted (92) that v i c i n a l c o u p l i n g constants f or r i n g protons on th i e t a n e d e r i v a t i v e s can, on occ a s i o n , be 133 44 d i f f i c u l t to i n t e r p r e t i n a nonambiguous f a s h i o n . A s i t u a t i o n s i m i l a r to that of 126b i n which c i s and trans v i c i n a l c o u p l i n g constants are i d e n t i -c a l has been reported (51) for 2 , 2 , 4 - t r i m e t h y l t h i e t a n e 1,1-dioxide (133) Qab = i a c = 9 ' 4 H z>-The absence of transannular c o u p l i n g i n 126a and i t s presence i n 126b has a precedent i n the recent l i t e r a t u r e (43) w i t h the t h i e t a n e 1-oxides 134a and b. For 134a, i n which the phenyl groups are c i s , no t r a n s -annular c o u p l i n g was observed, whereas f o r 134b, i n which the phenyls are t r a n s , J a D was found to be 1.12 Hz. As w i t h 126b, H i n 134b was s h i f t e d 134a 134b to lower f i e l d than H Q and H^ i n i t s c i s counterpart 134a, presumably as a r e s u l t of the d e s h i e l d i n g e f f e c t of the pseudoaxial phenyl group i n 134b. The puckered nature of the t h i e t a n e 1-oxide r i n g i n 134a and 134b has been e s t a b l i s h e d on the b a s i s of e q u i l i b r i u m , nmr and X-ray c r y s t a l -lography evidence (43). Before l e a v i n g t h i s d i s c u s s i o n of the nmr s p e c t r a of 126a and b, i t should be pointed out that 135, the 3-diethylamino analogue of 126a, has r e c e n t l y been prepared and i t s nmr spectrum i n t e r p r e t e d (50). 135 was s y n t h e s i z e d by the r e a c t i o n of P - d i e t h y l a m i n o s t y r e n e w i t h phenylmethanesul-45 f o n y l c h l o r i d e i n the presence of t r i e t h y l a m i n e and was the only isomer i s o l a t e d . The nmr spectrum of 135 showed eq u i v a l e n t b e n z y l i c protons coupled to the proton at C-3, J = 9.0 Hz. This was i n t e r p r e t e d i n terms of a d i h e d r a l angle of 12° w i t h a l l three protons on the same s i d e of the puckered four-membered r i n g . No e x p l a n a t i o n was given f o r e l i m i n a t i n g a more l i k e l y d i h e d r a l angle of approximately 180°. The assignment by these workers r e q u i r e d that a l l three s u b s t i t u e n t s be on the same side of the th i e t a n e 1,1-dioxide r i n g w i t h e i t h e r the diethylamino group or the two phenyl r i n g s o r i e n t a t e d p s e u d o a x i a l l y . The l a t t e r case seems very un-l i k e l y s i n c e severe 1 , 3 - d i a x i a l non-bonded i n t e r a c t i o n s would ensue. With the diethylamino group ps e u d o a x i a l , severe non-bonded i n t e r a c t i o n s are a l s o expected to occur as a consequence of the a x i a l l y p r o j e c t e d oxygen of the s u l f o n y l group. On t h i s b a s i s , i n t e r a l i a , i t seems that the o r i g -i n a l c o n f i g u r a t i o n a l assignment f o r 135 i s i n c o r r e c t and that 135 more l i k e l y possesses a c o n f i g u r a t i o n analogous to that of 126a. Examination of the R e l a t i v e S t a b i l i t i e s of c i s - and trans-2,4-Dipheny1-3- dimethy laminothietane 1,1-dioxide Dodson found that treatment of tra n s - 2 , 4 - d i p h e n y l t h i e t a n e 1,1-d i o x i d e (41) w i t h sodium methoxide i n methanol gave the cis - i s o m e r 40 a l -most q u a n t i t a t i v e l y and i n t e r p r e t e d t h i s r e s u l t as evidence f o r the puckered N(Et) 0 2 135 46 nature of the thie t a n e 1,1-dioxide r i n g . Of the two isomers, c i s - 2 , 4 -d i p h e n y l t h i e t a n e 1,1-dioxide was more s t a b l e because both phenyl groups presumably occupied pseudoequatorial p o s i t i o n s on the f o l d e d h e t e r o c y c l e (43). By analogy, i s o m e r i z a t i o n of 126b to 126a would have allowed a more c o n f i d e n t assignment of a puckered conformation to the two isomers. The c o n d i t i o n s used f o r the e q u i l i b r a t i o n of 126b were c o n s i d e r -ably milder than those reported by Dodson (43). A sample of crude product which was found by nmr a n a l y s i s to be e s s e n t i a l l y pure i n the three isomers N ( C H 3 ) 2 ( E t ) 3 N -H N ( C H 3 ) 2 126b 1 3 6 H N ( C H 3 ) 2 C = C H — N ( C H 3 ) 2 S 0 2 — CH 126a H 1 3 2 47 126a (19%), 126b (74%) and 132 (7%) was d i s s o l v e d i n a 2:1 mixture of ace-t o n i t r i l e and chloroform along w i t h an equimolar amount of t r i e t h y l a m i n e h y d r o c h l o r i d e . Two drops of t r i e t h y l a m i n e was added and the s o l u t i o n was allowed to s i t at room temperature u n t i l the 1630 cm * i r band of isomer 132 ceased to increase i n i n t e n s i t y (3 days, w i t h the g r e a t e s t increase during the f i r s t day). Nmr a n a l y s i s of the isomerized product (897, recov-ery) i n d i c a t e d that 927o of the m a t e r i a l was accounted f o r by the three o r i g i n a l isomers, of which 64% was 126a, 8% 126b and 28% 132. Thus, equi-l i b r a t i o n increased the percentages of 126a and 132 i n the mixture by ap-proximately 457„ and 217o, r e s p e c t i v e l y , at the expense of 126b, which de-creased from 74% to 8%. Presumably, e q u i l i b r a t i o n occurred v i a thefX-s u l f o n y l carbanion 136, which subsequently underwent e i t h e r r e p r o t o n a t i o n w i t h e p i m e r i z a t i o n to give the c o n f i g u r a t i o n a l l y more s t a b l e isomer 126a or r i n g cleavage and r e p r o t o n a t i o n to g i v e the a c y c l i c isomer 132. There are s e v e r a l r e p o r t s i n the l i t e r a t u r e of base-catalyzed r i n g opening of 3 - d i a l k y l a m i n o t h i e t a n e 1,1-dioxides (15,36,63). Rather than t r i e t h y l a m i n e , however, these cleavage r e a c t i o n s i n v o l v e d the use of a l k a l i hydroxides i n r e f l u x i n g aqueous methanol or e t h a n o l . For example, Nagarajan and Mehta have reporte d that whereas thie t a n e 1,1-dioxide £4 was 48 recovered unchanged a f t e r exposure to t r i e t h y l a m i n e i n d i e t h y l ether s o l u -t i o n for four days, i t was converted to the corresponding a c y c l i c isomer 65 to the extent of 227„ on being r e f l u x e d i n an aqueous ethanol s o l u t i o n of potassium hydroxide f o r s i x hours (36). The p o s s i b i l i t y of an a c y c l i c isomer a r i s i n g by r i n g opening of the cycloadduct i n i t i a l l y formed i n the r e a c t i o n of a sul f e n e w i t h an en-amine has been opposed by Paquette (35) . He has claimed that such a reac-t i o n i s m e c h a n i s t i c a l l y unprecedented, at l e a s t w i t h t r i e t h y l a m i n e as base. The tra n s f o r m a t i o n of 126b to 132, however, i n d i c a t e s that r i n g cleavage can indeed occur, p a r t i c u l a r l y i f the i n i t i a l cycloadduct i s s t e r i c a l l y u nfavorable. Presumably, r e l i e f of r i n g s t r a i n as w e l l as the r e s u l t a n t decrease i n non-bonded i n t e r a c t i o n s would provide the d r i v i n g f o r c e f o r the conversion of 126b to 132. The d i f f e r e n c e i n s u s c e p t i b i l i t y of 126b and 64 to base-catalyzed r i n g opening i s perhaps a t t r i b u t a b l e to the a c i d -i f y i n g e f f e c t of the pseudoaxial phenyl group i n 126b on the cX-proton. Upon c r y s t a l l i z a t i o n from hexane - ethanol of a sample of crude product from the c y c l i z a t i o n of 131 and J3, only 357o was recovered as a c r y s t a l l i n e s o l i d . Nmr a n a l y s i s of t h i s s o l i d and the o i l obtained by evaporation of the mother l i q u o r r evealed that approximately 957» of 126a i n i t i a l l y present i n the crude m a t e r i a l was accounted f o r , whereas a l l but 1870 of the trans-isomer 126b had decomposed. An apparent product of t h i s decomposition, dimethy1ammonium phenylmethanesulfonate (137) was subse-quently i s o l a t e d from the evaporated mother l i q u o r . These r e s u l t s prompted f u r t h e r study of the r e l a t i v e s t a b i l i t y of 126a and b. A f t e r r e f l u x i n g a sample of pure 126a i n ethanol 100 f o r one hour, nmr a n a l y s i s of the recovered s o l i d showed that 81% remained un-changed. Repeating the procedure w i t h a sample of pure 126b gave a y e l l o w , mobile o i l which possessed an odor s i m i l a r to that of (S-dimethylaminosty-49 rene. From the nmr spectrum of the o i l i t was observed that a l l of the trans-isomer had decomposed and that approximately 57% of the m a t e r i a l c o n s i s t e d of 131 (28%), 126a (11%) and e t h y l phenylmethanesulfonate (138) (617o). Another sample of pure 126b was r e f l u x e d i n ethanol 95 f o r 12 hours. Nmr a n a l y s i s of the water s o l u b l e f r a c t i o n i s o l a t e d from the de-composition products showed that 6770 of the trans-isomer had been converted to dimethy1ammoniurn phenylmethanesulfonate (137) . F i n a l l y , gas chromato-graphy of a f r e s h l y prepared ethanol 95 s o l u t i o n of 126b w i t h the i n j e c -t i o n port and column temperatures at 280° and 140°, r e s p e c t i v e l y , gave peaks having r e t e n t i o n times i d e n t i c a l to those of phenylacetaldehyde (139), f-dimethylaminostyrene (131) and e t h y l phenylmethanesulfonate (138). On the b a s i s of the e q u i l i b r a t i o n experiment and the r e s u l t s from r e f l u x i n g 126a and 126b i n e t h a n o l , i t was concluded that 126a was . d e f i n i t e l y more s t a b l e than 126b. Furthermore, the r e s u l t s obtained f o r 126b s t r o n g l y suggested that the formation of the trans-isomer was a r e v e r s i b l e process i n that p h e n y l s u l f ene (30) and (9-dimethy laminos tyrene (131) could be regenerated by heating 126b i n ethanol (Scheme II). Ob-s e r v a t i o n s w i t h c e r t a i n other t h i e t a n e 1,1-dioxides have i n d i c a t e d that the c y c l o a d d i t i o n r e a c t i o n between enamines and sulfenes i s a completely r e v e r s i b l e process (37). The phenylsulfene thus formed would be trapped e i t h e r by ethanol to give the ester 138 or by water present i n the ethanol to give phenylmethanesulfonic a c i d (140). The presence of the l a t t e r could a i d i n the h y d r o l y s i s of the enamine 131 to l i b e r a t e dimethylamine (141) which i n turn would lead to the formation of the s a l t 137. The r e l a t i v e l y h igh y i e l d (677») of 137 obtained from the 12-hour r e f l u x was perhaps due to h y d r o l y s i s of the e s t e r 138. The means by which some of the t r a n s -50 SCHEME I I . Decomposition of trans - 2,4-Diphenyl-3-dimethylaminothietane 1,1-dioxide (126b) i n Ethanol. H 20 — " x CH2CH0 ^ jj— CH — CHN(CH 3) 2 NH(CH 3) 2 + ^ ^ 131 141 139 + \\ / / ~ C H = : S 0 2 30 EtOH H 20 * W / / - C H 2 S 0 3 H 140 NH(CH 3) 2 Q -CH 2S0 3Et 138 v / / — CH S0„ NH (CH ) \\ / / 2 3 2 3 2 137 isomer 126b isomerized to the c i s - f o r m 126a was presumably through e i t h e r z w i t t e r i o n 142 or the anion 136. 126b CH CH = N ( C H 3 ) 2 S 0 2 CH-142 126a Although no a c y c l i c isomer 132 was observed i n the decomposition products from e i t h e r the 1-hour or the 12-hour r e f l u x of 126b i n e t h a n o l , i t cannot be r u l e d out that 132 d i d form but i n such an amount as to be undetectable at the concentrations used i n the nmr a n a l y s i s . Benzyl l-Phenyl-2-dimethylaminoetheny1 Sulfone A f t e r most of 126a and b had been removed by f r a c t i o n a l c r y s t a l -l i z a t i o n of the crude product from the c y c l i z a t i o n r e a c t i o n of 131 and phenylmethanesulfonyl c h l o r i d e , b e n z y l 1-pheny1-2-dimethylaminoetheny1 su l f o n e (132) was i s o l a t e d as a c r y s t a l l i n e s o l i d . That 132 was an a c y c l i c adduct was revealed by the presence of a strong enamine band at 1630 cm"^ i n the i r spectrum. The uv spectrum showed a maximum at 253 nm (€15,800) which agreed w i t h uv data reported f o r s i m i l a r compounds (15,35). Further proof f o r the s t r u c t u r e of 132 was obtained from the nmr spectrum i n which the v i n y l , b e nzyl and dimethylamino protons appeared as s i n g l e t s a t ? 7 . 0 0 , 4.05 and 2.60, r e s p e c t i v e l y . These data compared w e l l w i t h those given (35) f o r an analogous compound 143 i n which the v i n y l proton appeared as a s i n g l e t at $ 7.22 and the dimethylamino protons as a s i n g l e t a t S 2 . 5 9 . 52 CH 3CH 2 S 0 2 C = CH — N ( C H 3 ) 2 143 The c o n f i g u r a t i o n of 132 was not d i s c e r n i b l e from the s p e c t r o s c o p i c data. However, a recent r e p o r t (70) on the c o n f i g u r a t i o n a l preference of C<-benzyl-s u l f o n y l s t i l b e n e has provided a b a s i s f o r a s s i g n i n g a c o n f i g u r a t i o n to 132. R e f l u x i n g < X - b e n z y l s u l f o n y 1 - t r a n s - s t i l b e n e (144) i n e t h a n o l i c sodium hydroxide r e s u l t e d i n an almost q u a n t i t a t i v e conversion to the cis - i s o m e r 145 (70). Considering t h i s evidence, together w i t h the f a c t that enamino NaOH EtOH A 144 145 sulfones such as 132 possess an i n t r i n s i c a b i l i t y to isomerize to the more s t a b l e isomer ( 9 3 ) , suggested that a t r a n s - c o n f i g u r a t i o n f o r 132 was plaus-i b l e . N ( C H 3 ) 2 CH 2 — S0 2 132 53 E f f e c t of Reaction Solvent: on Isomer Prop o r t i o n s F o r t u i t o u s l y , the chemical s h i f t s f o r the N-methyl protons of 131 (52.70), 132 (52.60), 126a (52.10) and 126b (51.93) were adequately separated, which permitted determination by nmr a n a l y s i s of the propor-t i o n s of 126a, 126b and 132 i n crude products from the r e a c t i o n of phenyl-s u l f e n e w i t h t? -dimethylaminostyrene (Figure 1). Since a f a i r amount of 2,4-diphenyl-3-dimethylaminothietane 1,1-dioxide (126a and b) was r e q u i r e d f o r p r e p a r a t i o n of the corresponding t h i e t e 1,1-dioxide, the o p p o r t u n i t y was presented f o r i n v e s t i g a t i n g the e f f e c t of r e a c t i o n s o l v e n t s on the pro-p o r t i o n s of 126a, 126b and 132 formed. Such a study may have provided f u r t h e r i n s i g h t i n t o the mechanism of the c y c l o a d d i t i o n of sulfenes to en-amines . The three s o l v e n t s s t u d i e d were d i e t h y l ether - t e t r a h y d r o f u r a n , a c e t o n i t r i l e and chloroform. Reactions were run under i d e n t i c a l c o n d i t i o n s , except where noted, and i n v o l v e d the a d d i t i o n of a s o l u t i o n of phenylmeth-a n e s u l f o n y l c h l o r i d e (13) over a p e r i o d of one hour to a cooled s o l u t i o n of f? -dimethylaminostyrene (131) and an e q u i v a l e n t molar amount of t r i e t h y l -amine. At the end of the 15-hour r e a c t i o n p e r i o d , the s o l v e n t was removed by evaporation in vacuo w i t h the a i d of a lukewarm water-bath and the r e -s u l t i n g r e s i d u e was r e d i s s o l v e d i n chloroform and e x t r a c t e d w i t h water to remove the t r i e t h y l a m i n e h y d r o c h l o r i d e . Evaporation of the d r i e d organic l a y e r gave the crude product as a pale y e l l o w s o l i d . I t was on t h i s mater-i a l that the nmr a n a l y s i s was performed. The e f f e c t of water upon the isomer composition was a l s o s t u d i e d w i t h aqueous a c e t o n i t r i l e as s o l v e n t . The data obtained from these r e a c t i o n s are presented i n Table I . When the c y c l o a d d i t i o n s run i n d i e t h y l ether - t e t r a h y d r o f u r a n and a c e t o n i t r i l e were TABLE I E f f e c t of Reaction Solvent on the R a t i o of Isomers from the C y c l o a d d i t i o n  of P-Dimethylaminostyrene to Phenylsulfene Solvent A B 126a C 126b 132 Et 20-THF 96 7 96 15 82 3 CHCI3 99 1 100 19 74 7 CH 3CN 98 6 99 35 60 5 CH 3CN-H 20* 90 7 84 36 47 17 A. 7o y i e l d based on the weight of crude product i s o l a t e d . B. % of A accounted f o r by 126a, 126b and 132. C a l c u l a t e d from the nmr s p e c t r a by comparison of the sum of the i n t e g r a l s f o r the dimethylamino s i g n a l s of 126a, 126b and 132 w i t h the i n t e g r a l f o r the aromatic protons. C. °L c a l c u l a t e d by t a k i n g the sum of the i n t e g r a l s f o r the three dimethylamino peaks as 1007o. * r e a c t i o n s c a l e d down by a f a c t o r of two (0.0340 mole); 0.5 ml (0.03 mole) of d i s t i l l e d water added j u s t p r i o r to i n i t i a t i n g the a d d i t i o n of s u l f o n y l c h l o r i d e . 56 repeated, e s s e n t i a l l y i d e n t i c a l r e s u l t s were r e a l i z e d . I t i s u n c e r t a i n whether the c y c l o a d d i t i o n of enamines to sulfenes i s a two-step process i n v o l v i n g a z w i t t e r i o n i c intermediate or a concerted r e a c t i o n (22). The suggestion has been made that i f a two-step mechanism were o p e r a t i v e , then one might expect an increase i n the amount of s u b s t i -t u t i o n product r e l a t i v e to .cycloadduct upon using r e a c t i o n s o l v e n t s of higher p o l a r i t y (22). This reasoning i s based on the premise that i n more po l a r s o l v e n t s the l i f e t i m e of the z w i t t e r i o n i c intermediate would be i n -creased and thus there would be a greater p o s s i b i l i t y of a p r o t o t r o p i c s h i f t (or p r o t o n a t i o n followed by deprotonation) o c c u r r i n g to gi v e the sub-s t i t u t i o n product. However, there are apparently no examples reported i n the l i t e r a t u r e f o r enamine-sulfene r e a c t i o n s i n which the p o l a r i t y of the r e a c t i o n s o l v e n t has had a d i s t i n c t i n f l u e n c e on the amount of a c y c l i c isomer formed. I n s p e c t i o n of Table I , d i s r e g a r d i n g the c y c l o a d d i t i o n run i n the presence of water, r e v e a l s that the r e a c t i o n between 131 and phenyl-s u l f e n e i s not an exception. There i s no apparent c o r r e l a t i o n between the y i e l d of be n z y l l-phenyl-2-dimethylaminoethenyl s u l f o n e (132) and sol v e n t p o l a r i t y . I n t e r e s t i n g l y , i n a l l three s o l v e n t s more of the l e s s s t a b l e trans-isomer 126b was formed than c i s - i s o m e r 126a. In comparing the r a t i o s of 126a and 126b, however, there appears to be a d e f i n i t e increase i n the p r o p o r t i o n of the more s t a b l e cycloadduct 126a i n the most polar s o l v e n t , a c e t o n i t r i l e . A p o s s i b l e e x p l a n a t i o n f o r t h i s increase can be made i f i t i s assumed that phenylsulfene and 131 approach each other i n such a manner as to give a z w i t t e r i o n i c intermediate which subsequently undergoes e i t h e r d i r e c t r i n g c l o s u r e to give 126b or bond r o t a t i o n followed by r i n g c l o s u r e 57 to give 126a. I f t h i s i s the case, then one might expect that the longer l i f e t i m e of the z w i t t e r i o n i n a c e t o n i t r i l e as compared to that i n the two l e s s p o l a r s o l v e n t s would be r e f l e c t e d by a greater incidence of bond r o -t a t i o n and consequently by an increase i n the amount of the c i s - i s o m e r 126a. This e x p l a n a t i o n i s supported to some extent by the r e s u l t s obtained from the r e a c t i o n run i n a c e t o n i t r i l e w i t h water present. The s i g n i f i c a n t i n -crease i n the amount of s u b s t i t u t i o n product 132 i n t h i s r e a c t i o n (177Q) compared to that obtained from the r e a c t i o n without water (5%) may be i n -d i c a t i v e of t r a p p i n g of the presumed z w i t t e r i o n by the presence of a ready proton source. However, f u r t h e r evidence from r e a c t i o n s run i n other p o l a r and non-polar a p r o t i c s o l v e n t s i s necessary before t h i s matter can be more s e r i o u s l y considered. D e f i n i t i v e i n t e r p r e t a t i o n of the data i n Table I was complicated by the f a c t that the trans-isomer 126b i s unstable and s u s c e p t i b l e both to e p i m e r i z a t i o n and to r i n g cleavage. I t has been pointed out that c y c l o -a d d i t i o n and subsequent r i n g opening could be mistaken f o r d i r e c t forma-t i o n of s u b s t i t u t i o n products i n the r e a c t i o n of enamines w i t h sulfenes (22). A f u r t h e r c o m p l i c a t i o n was the v a r y i n g s o l u b i l i t y of the cycloadducts (126a and b) and the t r i e t h y l a m i n e h y d r o c h l o r i d e i n the three s o l v e n t s . In d i e t h y l ether - t e t r a h y d r o f u r a n most of the product p r e c i p i t a t e d from s o l u t i o n and the p r e c i p i t a t i o n of t r i e t h y l a m i n e h y d r o c h l o r i d e was almost q u a n t i t a t i v e . Chloroform represented the other extreme, a l l of the product and t r i e t h y l a m i n e s a l t remaining i n s o l u t i o n . In the case of a c e t o n i t r i l e , much of the s a l t appeared to p r e c i p i t a t e , whereas most of the product r e -mained d i s s o l v e d . I f spontaneous r i n g cleavage of 126b were the source of the sub-58 s t i t u t i o n product 132, then the amount of 132 formed would be time-depen-dent. Thus, examination of the crude product a f t e r r e a c t i o n periods s h o r t e r than 15 hours should r e v e a l a lower y i e l d of the a c y c l i c isomer. P r e l i m -i n a r y i n v e s t i g a t i o n i n d i c a t e d that a p e r i o d much shor t e r than 15 hours was s u f f i c i e n t to complete the r e a c t i o n between 131 and _13. U n f o r t u n a t e l y , other c o n d i t i o n s besides r e a c t i o n time were a l t e r e d i n these experiments and, t h e r e f o r e , the r e s u l t s i n terms of the amount of 132 formed were not comparable. I t i s a l s o p o s s i b l e that the a d d i t i o n time of the phenylmethane-s u l f o n y l c h l o r i d e (13) to the s o l u t i o n of 131 and t r i e t h y l a m i n e i s impor-t a n t . In those c y c l o a d d i t i o n s i n which 13_ i s added over a p e r i o d of one hour, t r i e t h y l a m i n e not yet consumed by r e a c t i o n w i t h 1_3 may c a t a l y z e r i n g opening of trans-isomer 126b already formed. I n t e r p r e t a t i o n of the P r e f e r e n t i a l Formation of the Less S t a b l e Isomer,  trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide In proposing h i s t r a n s i t i o n s t a t e model f o r the r e a c t i o n of en-amines w i t h s u l f e n e s , Paquette has i m p l i e d that product development con-t r o l i s o p e r a t i v e (42). The g e n e r a l i t y of product development c o n t r o l i n t h i e t a n e 1,1-dioxide r i n g formations would appear to be debatable, how-ever, i n l i g h t of the r e s u l t s l i s t e d i n Table I f o r the r e a c t i o n of & -dimethylaminostyrene (131) w i t h phenylsulfene (30). In a l l three s o l v e n t s , the thermodynamically l e s s s t a b l e cycloadduct 126b was formed to a greater extent than the more s t a b l e isomer 126a. Thus, t h i s r e a c t i o n apparently p r e f e r r e d to proceed through a t r a n s i t i o n s t a t e that was more r e a c t a n t -l i k e than p r o d u c t - l i k e ( s t e r i c approach c o n t r o l ) . In terms of s t e r i c 59 126a 126b approach c o n t r o l , the suggested orthogonal r e l a t i o n s h i p between the enamine and the s u l f e n e i n the t r a n s i t i o n s t a t e (42), can be used to accommodate the p r e f e r r e d formation of 126b. On s t e r i c grounds, i t can be reasonably argued that the r e a c t i v e complex 147 w i l l form i n preference to 146, s i n c e 60 molecular models i n d i c a t e that there i s a s e r i o u s non-bonded i n t e r a c t i o n engendered between the enamine dimethylamino group and the sul f e n e phenyl r i n g as 131 and 30 approach to form 146 which i s not present i n the forma-t i o n of 147. Reaction of ft -Dimethylaminostyrene w i t h p-Chlorophenylmethanesulfonyl  C h l o r i d e and p-Nitrophenylmethanesulfony1 Bromide The r e a c t i o n of Q-dimethylaminostyrene (131) w i t h p_-chloropheny 1-methanesulfony1 c h l o r i d e (129) i n the presence of t r i e t h y l a m i n e was s i m i l a r to the r e a c t i o n of 131 w i t h the u n s u b s t i t u t e d s u l f o n y l c h l o r i d e _13 i n that two c y c l i c isomers, 127a and b, were i s o l a t e d . S pectroscopic evidence was 127a 127b obtained f o r the presence of an a c y c l i c isomer analogous to 132. That the r e a c t i o n proceeded w i t h p r e c i p i t a t i o n of 127b as a w h i t e , c r y s t a l l i n e s o l i d , w h i l e 127a remained d i s s o l v e d i n the r e a c t i o n s o l v e n t along w i t h the acy-c l i c m a t e r i a l , g r e a t l y f a c i l i t a t e d s e p a r a t i o n of the two c y c l i c isomers. The presence of c h a r a c t e r i s t i c s u l f o n e bands and the absence of enamine ab s o r p t i o n i n the i r s p e c t r a of r e c r y s t a l l i z e d 127a and crude 127b i n d i c a -ted that both were cycloadducts. U n l i k e 127a, which could be r e c r y s t a l l i z e d r e a d i l y , 127b was q u i t e unstable and decomposed when d i s s o l u t i o n was a t -tempted i n hot s o l v e n t . By analogy to 126a and b i n regard to r e l a t i v e 61 s t a b i l i t y , 127a was assigned a c i s - c o n f i g u r a t i o n f or the aromatic groups on the h e t e r o c y c l i c r i n g , whereas 127b was considered to possess a t r a n s -arrangement. L i k e the u n s u b s t i t u t e d trans-isomer 126b, 127b was formed p r e f e r e n t i a l l y . With chloroform as the r e a c t i o n s o l v e n t , a 917, y i e l d of the three isomers was obtained, of which 707„ was 127b, 207, 127a and 107., the u n c h a r a c t e r i z e d a c y c l i c isomer. With a c e t o n i t r i l e as s o l v e n t , of the t o t a l crude product i s o l a t e d (977 0), 597» was 127b, 407., 127a and 17» a c y c l i c isomer. As the two r e a c t i o n s were run under d i s s i m i l a r c o n d i t i o n s , i t i s not known at t h i s time i f there i s any s i g n i f i c a n c e i n the d i f f e r e n t pro-p o r t i o n a t e y i e l d s of the three isomers obtained i n the two r e a c t i o n s . The f a c t that the trans-isomer 127b p r e c i p i t a t e s from the r e a c t i o n s o l v e n t may make t h i s a u s e f u l r e a c t i o n f o r mechanistic i n v e s t i g a t i o n s . That only two c y c l i c isomers were observed was i n agreement w i t h i n f o r m a t i o n i n the l i t -e r a t u r e to the e f f e c t that the c o n f i g u r a t i o n of trans-enamines i s maintained i n the s u l f e n e cycloadducts (42,74,90). I t f o l l o w e d , t h e r e f o r e , that the £-chloro-substituted phenyl r i n g i n 127b was c i s to the dimethylamino group. A more conv i n c i n g chemical argument for t h i s assignment i s reserved to a l a t e r d i s c u s s i o n of the t h i e t e 1,1-dioxides d e r i v e d from 127a and 127b. In the nmr spectrum (CDCl^) of 127a the protons at C-2 and C-4 appeared as a doublet of doubl e t s , one centred at 8 5.25 ( b e n z y l i c proton) and the other at 6 5.22 (p_-chlorobenzylie proton). The assignment of chem-i c a l s h i f t s to these two protons was made on the b a s i s of the r e p o r t (94) that the b e n z y l i c proton of 2-( 4 - c h l o r o p h e n y l ) - t h i e t a n e appears at higher f i e l d (287.5 Hz) than the corresponding proton i n 2-phenylthietane (291 Hz). The b e n z y l i c protons i n 127a were e q u a l l y coupled to the proton at C-3, which appeared as a t r i p l e t at 3.57 ( J = 9 Hz). The protons of the 62 dimethylamino group were observed as a s i n g l e t at S 2.08, a chemical s h i f t almost i d e n t i c a l to that f o r the same protons i n cis-2,4-dipheny1-3-dimeth-y l a m i n o t h i e t a n e 1,1-dioxide (126a) (S2.10). The low s o l u b i l i t y of 127b i n common nmr so l v e n t s prevented a s u i t a b l e spectrum from being obtained. However, the HCl s a l t of 127b was found to be s u f f i c i e n t l y s o l u b l e i n DMSO-dg. The spectrum of the s a l t showed the b e n z y l i c protons as w e l l separated d o u b l e t s , one at£6.69 and the other at S 6.15 . Both were e q u a l l y coupled to the C-3 proton, which appeared as a t r i p l e t atS 4.93 ( J = 10 Hz). A s i n g l e t at<$2.39 was a t t r i b u t e d to the protons of the dimethylamino group. In the DMSO-d^ spectrum of the HCl s a l t of 127a, the b e n z y l i c pro-tons appeared as a broad doublet at & 6.47 coupled to a one-proton t r i p l e t at 65.27 ( J = 9 Hz). The protons of the dimethylamino group were seen as a s i n g l e t at 6 2.66. As w i t h the nmr s p e c t r a of 126a and b, the d i f f e r e n c e s i n the s p e c t r a of the HCl s a l t s of 127a and b were r a t i o n a l i z e d i n terms of the c o n f i g u r a t i o n a l d i s p o s i t i o n of the aromatic groups w i t h respect to the h e t e r o c y c l i c r i n g . The u p f i e l d s h i f t of the protons of the dimethyl-amino group of 127b HCl r e l a t i v e to the s i g n a l f o r the same protons i n 127a HCl was a t t r i b u t e d to the s h i e l d i n g e f f e c t of the p_-chloropheny 1 r i n g c i s to the dimethylamino group i n 127b. Taking the puckered nature of the th i e t a n e 1,1-dioxide r i n g i n t o account, the downfield s h i f t of one of the b e n z y l i c protons r e l a t i v e to the other i n 127b HCl was thought to be due, i n p a r t , to d e s h i e l d i n g of t h i s proton by the pseudoaxial p_-chloropheny 1 r i n g . The c h a r a c t e r i s t i c chemical s h i f t s f o r the protons of the dimethyl-amino group i n the hy d r o c h l o r i d e s a l t s of 127a and 127b allowed q u a n t i t a -t i v e determination of these isomers i n mixtures. The i r spectrum of an o i l y r e s i d u e i s o l a t e d by washing crude 63 127a w i t h d i e t h y l ether and evaporating the washings, showed a strong band at 1625 cm which was i n d i c a t i v e of an enamine. The nmr spectrum of the o i l showed the presence of 127a as w e l l as s i g n a l s at 5 7.31 (doublet, a r -omatic protons, >9), 6.98 ( s i n g l e t , v i n y l i c proton, 1), 3.97 ( s i n g l e t , b e n z y l i c protons, 2 ) , and 2.60 ( s i n g l e t , dimethylamino protons, 6) which were a t t r i b u t a b l e to an a c y c l i c isomer analogous to 132. This m a t e r i a l was not i s o l a t e d or f u r t h e r c h a r a c t e r i z e d . I t was subsequently found, as i n the case of 126a and 126b, that a good y i e l d of the p_-chloro-substituted cycloadduct could be obtained a f t e r a r e a c t i o n p e r i o d s h o r t e r than the g e n e r a l l y employed 15 hours. For example, a r e a c t i o n run i n a c e t o n i t r i l e using 0.20 mole of each r e a c t a n t (131, 129 and (Et)-jN) was worked up 3 hours f o l l o w i n g a d d i t i o n of 129 to g i v e a 97% y i e l d of crude product, of which 40% was 127a, 59% 127b and 1% a c y c l i c isomer. I t should be mentioned that the nmr spectrum (CDCl-j) of the crude 127a f r a c t i o n r evealed a r e l a t i v e l y weak s i n g l e t at S l . 9 1 which was t e n t a t i v e l y assigned to the protons of the dimethylamino group of a r e s i d u a l amount (37a) of 127b. This chemical s h i f t was very s i m i l a r to that f o r the same protons i n 126b (SI.93). The r e a c t i o n of 131 w i t h p_-nitrophenylmethanesulfonyl bromide (130) i n the presence of t r i e t h y l a m i n e w i t h chloroform as s o l v e n t d i f f e r e d from the r e a c t i o n s of 131 w i t h 1_3 and 129 i n that only one c y c l i c isomer 128 was obtained, r a t h e r than two. In a d d i t i o n , the corresponding a c y c l i c isomer 148 was i s o l a t e d and c h a r a c t e r i z e d . A r e a c t i o n time of 3 hours f o l l o w i n g the a d d i t i o n of the s u l f o n y l bromide was found to be adequate. Removal of the t r i e t h y l a m i n e h y d r o c h l o r i d e by-product by aqueous e x t r a c t i o n f o l l o w e d by evaporation of the organic solvent gave a r e d d i s h - b l a c k o i l 64 which y i e l d e d the crude product 128 as a c r y s t a l l i n e p r e c i p i t a t e upon d i l u t i o n w i t h a mixture of benzene and d i e t h y l ether. Evaporation of the f i l t r a t e and treatment of the r e s u l t i n g o i l w i t h d i e t h y l ether gave a s o l i d from which pure 148 was i s o l a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n . In a t y p i c a l r e a c t i o n , an 87% y i e l d of crude product was r e a l i z e d , of which 85% was 128 and 15% was 148 as determined by nmr a n a l y s i s . A pure sample of 128 was obtained by c r y s t a l l i z a t i o n from hexane - methyl e t h y l ketone. During c r y s t a l l i z a t i o n , much decomposition occurred and i t became apparent that 128 was unstable to d i s s o l u t i o n i n hot s o l v e n t . That 128 was a c y c l o -adduct was r e v e a l e d by i t s i r spectrum, which showed strong s u l f o n e bands but no a b s o r p t i o n a t t r i b u t a b l e to an enamine. Besides s i g n a l s expected 2 128 ' 148 f o r an u n s u b s t i t u t e d and a p _ - n i t r o - s u b s t i t u t e d phenyl r i n g , the nmr spec-trum ( C D C I 3 ) d i s p l a y e d a sharp doublet a t S 5 . 3 6 ( b e n z y l i c protons, 2) J = 9 Hz, a t r i p l e t at S3.70 (proton on C-3, 1) J = 9 Hz, and a s i n g l e t at S2.14 (N-methyl protons, 6 ) . By comparing the chemical s h i f t of the l a s t s i g n a l (S2.14) w i t h the corresponding a b s o r p t i o n i n 126a (S2.10) and 127a (S2.08), 128 was t e n t a t i v e l y assigned a c i s - c o n f i g u r a t i o n f o r the aromatic groups. I f 128 possessed a t r a n s - c o n f i g u r a t i o n , presumably the dimethyl-amino protons would have then been s h i e l d e d by the aromatic r i n g c i s to 65 the dimethylamino group, and thus s h i f t e d to higher f i e l d as i n 126b and 127b. The equivalent nature of the b e n z y l i c protons was unexpected s i n c e they are f o r m a l l y nonequivalent as a consequence of the p_-nitro s u b s t i t u -ent on one of the aromatic r i n g s . Perhaps a solvent other than CDCl^ would have r e v e a l e d a d i f f e r e n c e i n chemical s h i f t s . Since no evidence of a t h i r d type of dimethylamino group was present i n the nmr s p e c t r a of any of the crude products obtained from the r e a c t i o n of 131 w i t h the s u l -fene d e r i v e d from 130, the assignment of a c i s - c o n f i g u r a t i o n to 128 seemed reasonable. The decreased s t a b i l i t y of the p_-chloro-substituted t r a n s -isomer 127b compared to the u n s u b s t i t u t e d trans - isomer 126b suggested that the presence of the electron-withdrawing c h l o r i n e atom had a d e l e t e r i o u s e f f e c t on the s t r u c t u r a l i n t e g r i t y of 127b. Thus, a f u r t h e r decrease i n s t a b i l i t y would have been expected f o r the trans-form of 128 because of the greater electron-withdrawing c a p a c i t y of the n i t r o group compared to the c h l o r i n e atom. Perhaps the trans-isomer was formed i n the r e a c t i o n of 131 w i t h 130, but because of the enhanced a c i d i t y of the p_-nitrobenzylie proton, i t underwent r a p i d e p i m e r i z a t i o n and r i n g cleavage i n the presence of t r i e t h y l a m i n e to g i v e 128 and 148. Compound 148 was obtained as b r i g h t y e l l o w needles upon c r y s t a l -l i z a t i o n from n-butanol. That i t was an a c y c l i c isomer was evident from the i r spectrum, which showed a strong enamine band at 1625 cm"'' and s u l -fone bands at 1297 and 1135 cm ^. Comparison of the asymmetrical s t r e t c h -i n g frequency of the s u l f o n e group i n 128 w i t h that i n 148 showed that a d e f i n i t e s h i f t to lower frequency had occurred w i t h the l a t t e r (Ay = 33 cm A s i m i l a r s h i f t (AV = 44 cm ') was observed when 126a was compared w i t h 132. Comparing the values s t a t e d i n the l i t e r a t u r e (15) f o r 149 and the corresponding a c y c l i c isomer 150 gave AV= 40 cm''. This decrease i n 66 frequency seen f o r the a c y c l i c isomers i s probably a t t r i b u t a b l e to conju-g a t i o n of the s u l f o n y l moiety w i t h the enamine double bond. The nmr spec-trum of 148 showed s i m i l a r i t i e s to that of 132. In a d d i t i o n to s i g n a l s N ( C H 3 ) 2 °2 149 assigned to the u n s u b s t i t u t e d and p _ - n i t r o - s u b s t i t u t e d phenyl r i n g s , i t r e -vealed a s i n g l e t at-S7.11 ( v i n y l proton, 1), a s i n g l e t at S 4.13 (benzyl protons, 2) and a s i n g l e t at <S 2.67 (N-methyl protons, 6 ) . The b r i g h t y e l -low colour of 148 suggested that the p_-nitro s u b s t i t u e n t was on the phenyl r i n g which was conjugated w i t h the enamine double bond and not on the aro-matic r i n g of the be n z y l s u l f o n y 1 group. This assignment was i n agreement w i t h the uv spectrum (CH^CN), which showed maxima at 250 and 271 nm, €18,700 and 19,700, r e s p e c t i v e l y . The uv spectrum (CH-jOH) of p_ - n i t r o s t y -rene has been reported to have a maximum at 303 nm, £ 14,500 (95) . Presum-abl y , s t e r i c e f f e c t s as w e l l as the nature of the s u b s t i t u e n t s on the double bond would account f o r the s h i f t ofX„„^ from 303 to 271 nm. As max i n d i c a t e d p r e v i o u s l y , a c y c l i c isomer 132 possessed a maximum i n the uv (CH-jCN) at 253 nm, € 15,800. A t r a n s - r e l a t i o n s h i p of the dimethylamino and a-benzylsulfony1 groups was assigned to 148 f o r the same reasons that 132 was considered to possess t h i s c o n f i g u r a t i o n . Because of the p o s i t i o n of the £-nitropheny1 r i n g i n 148, t h i s isomer must have a r i s e n by r i n g c l e a v -age of a c y c l i c intermediate 151. Cleavage of bond a i n 151 would give N(CH 3) ; CH 3S0 2 150 67 148, whereas cleavage of bond b would give the corresponding a c y c l i c i s o -mer, which was not observed. P o s s i b l y , a b s t r a c t i o n of the more a c i d i c p_-n i t r o b e n z y l i e proton i n i t i a t e s the cleavage to g i v e 148. When a sample of pure c y c l i c isomer 128 was d i s s o l v e d i n a c e t o n i t r i l e and allowed to s i t at room temperature, i t decomposed, causing the s o l u t i o n to turn a b r i g h t orange. Nmr a n a l y s i s of the r e s i d u e obtained by evaporating the s o l v e n t a f t e r 43 hours showed that 877<> of the m a t e r i a l was accounted f o r , of which 247o was 128 and 767= 148. The t e r t i a r y amino group of 128 may be s u f f i c i e n t -l y b a s i c to cause proton a b s t r a c t i o n at room temperature. A s e r i e s of t h i e t a n e 1,1-dioxides prepared by r e a c t i n g ketene d i e t h y l a c e t a l w i t h the sulfenes d e r i v e d from 13_, 129 and p_-nitropheny 1-methanesulfony1 c h l o r i d e has been report e d (21). A s i m i l a r trend was ob-served when the chemical s h i f t s of the benzyl protons of these adducts were compared to those of 126a, 127a and 128 (Table II). TABLE II Comparison of the Chemical S h i f t s of the B e n z y l i c Protons of the 3- Dimethylaminothietane 1,1-dioxides w i t h Those Reported f o r Related 3,3- D i e t h o x y t h i e t a n e 1,1-dioxides E X X X S(H d) * S(H a) CDC13 H 5.37 5.28 Cl 5.35 5.22 NOo ' 5.55 5.36 * Presumably the same s o l v e n t was used for a l l three compounds. Values are taken from reference 21. 69 Synthesis of Thiete 1,1-dioxides The s y n t h e s i s of 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide (152) had been p r e v i o u s l y accomplished (14) and has r e c e n t l y been reported i n the l i t e r -ature (50). For the sake of completeness and s i n c e more experimental de-t a i l s became a v a i l a b l e as a r e s u l t of the present i n v e s t i g a t i o n , the pre-p a r a t i o n of 152 was i n c l u d e d i n the Experimental. Treatment of 126a or a mixture of 126a and b w i t h 40% p e r a c e t i c a c i d at 0° gave 152 d i r e c t l y , w i t hout h e a t i n g . The crude product was obtained i n good y i e l d and found to be r e l a t i v e l y f r e e of contaminants by i r and nmr spectroscopy. Other syntheses of t h i e t e 1,1-dioxides by amine oxide e l i m i n a t i o n have been r e -ported (45,59), which proceeded spontaneously at room temperature without i s o l a t i o n of the N-oxide intermediate. These examples, a s w e l l a s the formation of 152, probably f i t i n t o that category of the amine oxide e l i m -i n a t i o n r e a c t i o n that has been described as a reversed M i c h a e l a d d i t i o n (96,97). The m e l t i n g p o i n t reported (50) f o r 152, 133-134° (CHCl-j), was low compared to that obtained i n the present work, 137-138° (hexane -benzene). This discrepancy was probably the r e s u l t of the d i f f i c u l t i e s encountered i n r e c r y s t a l l i z i n g the product. Decomposition occurred when 152 was heated i n s o l u t i o n . Of s e v e r a l s o l v e n t s systems i n v e s t i g a t e d , minimum decomposition appeared to occur i n hexane - benzene. Whereas an i n c o n c l u s i v e elemental a n a l y s i s has been recorded (50) f o r the carbon con-tent of 152, s a t i s f a c t o r y carbon and hydrogen analyses (±0.4% of theore-t i c a l ) were obtained f o r 152 prepared i n t h i s l a b o r a t o r y (14). The i r spectrum of 152 showed the absence of the dimethylamino group and a weak band at 1622 cm ^ which was a t t r i b u t e d to an o l e f i n double bond conjugated w i t h a phenyl r i n g (98a). The asymmetrical s t r e t c h i n g band of the s u l f o n y l 70 group appeared at 1303 cm"* as compared to 1320 cm ^ i n the s t a r t i n g mate-r i a l . This s h i f t to lower frequency was thought to be due to co n j u g a t i o n , as observed w i t h the enamino s u l f o n e s , 132 and 148. A maximum occurred i n the uv spectrum (CH-jCN) at 255 nm (6 19,600). A comparable spectrum (EtOH) has been reported f o r 1_15, A m a x 253 nm (€14,000) (15). Besides the °2 115 10 aromatic protons, the nmr spectrum ( C D C I 3 ) of 152 showed a doublet at £7.03 ( o l e f i n i c proton, 1) J = 2 Hz, and a doublet at 8 5.92 ( b e n z y l i c pro-ton, 1) J = 2 Hz. The two h e t e r o c y c l i c r i n g protons were r e a d i l y assigned by r e f e r r i n g to the nmr spectrum ( C D C I 3 ) of 115, i n which the o l e f i n i c pro-ton was reported to appear as a t r i p l e t atS 7.0, J = 2 Hz, and the methy-lene protons as a doublet a t S 4 . 5 4 , J = 2 Hz (15). On t h i s b a s i s , the nmr s p e c t r a l data given for 152 i n the l i t e r a t u r e (50) are apparently i n c o r r e c t i n that the assignments f or the o l e f i n i c and b e n z y l i c protons were r e v e r s e d . Treatment of c_is_-2-(4-chloropheny 1)-4-pheny 1-3-dimethy lamino-t h i e t a n e 1,1-dioxide (127a) as a s l u r r y i n g l a c i a l a c e t i c a c i d w i t h 40% p e r a c e t i c a c i d at 0° gave a mixture of two t h i e t e 1,1-dioxide isomers, 153a and b_, w i t h 153a as the major component. The two isomers were sepa-r a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n from ethanol 95. The i r s p e c t r a of 153a and b showed d i s t i n c t s i m i l a r i t i e s to each other and to that of the un s u b s t i t u t e d isomer 152. In the nmr spectrum (CDCl-j) of 153a, the o l e -f i n i c proton appeared as a doublet at S 7.02, J = 2 Hz, and the b e n z y l i c 71 C l 153b proton as a doublet at S5.91, J = 2 Hz. The corresponding protons i n the spectrum ( C D C I 3 ) of 153b appeared at 8 6.98 and 5.85, r e s p e c t i v e l y , w i t h J = 2 Hz. That the p_-chlorobenzylie proton of 153b appeared at higher f i e l d than the b e n z y l i c proton of 153a was i n accord w i t h the nmr spectrum ( C D C I 3 ) of 127a. The d i f f e r e n c e between the chemical s h i f t s f o r each of the two types of r i n g protons i n the two isomers were s u f f i c i e n t l y l a r g e i n the 100 MHz spectrum that i n t e g r a t i o n of these protons could be used to determine the pro p o r t i o n s of 153a and b i n mixtures. The assignment of the double bond p o s i t i o n s i n 153a and b was supported by comparison of the uv s p e c t r a . In the spectrum of 153a, maxima were apparent at 262 and 294 nm (^262 26,300, ^ 294 I J ^ O O) whereas i n that of 153b, maxima were seen at 230 and 256 nm (€ 230 2 0>300, ^256 2 2 > 6 0 0 ) - T h e maximum at longer wave-len g t h i n the spectrum of 153b was reminiscent of that observed f or the un s u b s t i t u t e d isomer 152, 255 nm (619,600). The bathochromic s h i f t ob-served i n the spectrum of 153a when compared to that of 153b was a t t r i b u t e d to the £-chlorophenyl group being conjugated w i t h the double bond i n 153a and not conjugated i n 153b. In support of t h i s assignment was the obser-v a t i o n that 153a was formed i n preference to 153b. Assuming that the c i s -c o n f i g u r a t i o n p r e v i o u s l y assigned to 127a was c o r r e c t , then i n terms of geometry, the two b e n z y l i c protons would show an equal p r o b a b i l i t y of being a b s t r a c t e d i n an e l i m i n a t i o n r e a c t i o n r e g a r d l e s s of whether or not the ab-s t r a c t i o n process was i n t e r m o l e c u l a r or i n t r a m o l e c u l a r (96). However, when the presumed r e l a t i v e a c i d i t i e s of the two protons are considered, as w e l l as the p r e d i c t e d r e l a t i v e s t a b i l i t i e s of the two products (153a and b ) , then i t seems reasonable that the formation of 153a should be favored over that of 153b. A r e a c t i o n which more c l e a r l y showed that 153a was the pre-f e r r e d product was run by adding 40% p e r a c e t i c a c i d to a d i l u t e s o l u t i o n of 127a i n t e t r a h y d r o f u r a n at room temperature. A 97% y i e l d of crude prod-uct was obtained, which was found by nmr a n a l y s i s to c o n s i s t of 65% 153a and 35% 153b. Further chemical evidence supporting the assignment of the double bond p o s i t i o n s i n 153a and 153b w i l l be presented l a t e r i n the d i s -c u s s i o n when the thermolysis of the t h i e t e 1,1-dioxides i s considered. The amine oxide e l i m i n a t i o n r e a c t i o n was a l s o c a r r i e d out u s i n g 127b, which had t e n t a t i v e l y been assigned a t r a n s - c o n f i g u r a t i o n w i t h the £-chlorophenyl group c i s to the dimethylamino group. I t had been hoped that t h i s r e a c t i o n would confir m the assignment, s i n c e i n t h i s c o n f i g u r a -t i o n only the b e n z y l i c proton of the u n s u b s t i t u t e d phenyl group was c i s to the dimethylamino group and thus, according to the p o s t u l a t e d i n t r a -molecular mechanism for amine oxide e l i m i n a t i o n (96), t h i e t e 1,1-dioxide isomer 153b should be obtained p r e f e r e n t i a l l y . However, when the r e a c t i o n was run by adding 40% p e r a c e t i c a c i d to a s l u r r y of 127b i n g l a c i a l a c e t i c at 0°, the crude product (89%) was found to c o n s i s t of 95% 153a and 5% 73 C l 407» HC03H 153a 153b 127b 153b. These r e s u l t s i n d i c a t e d that i f the i n t r a m o l e c u l a r e l i m i n a t i o n mech-anism were o p e r a t i v e , then the c o n f i g u r a t i o n assigned to 127b was probably i n c o r r e c t . However, when the r e a c t i o n was repeated by adding p e r a c e t i c a c i d to a d i l u t e s o l u t i o n of 127b i n t e t r a h y d r o f u r a n at room temperature, the r e s u l t was i n agreement w i t h that p r e d i c t e d by the i n t r a m o l e c u l a r mech-anism f o r the assigned t r a n s - c o n f i g u r a t i o n . The crude product (857=) was found by nmr a n a l y s i s to c o n s i s t of 827o 153b and 187=. 153a. The r e s u l t s from the two r e a c t i o n s suggested that i n d i l u t e THF s o l u t i o n the e l i m i n a -t i o n occurred by the proposed i n t r a m o l e c u l a r mechanism (96), whereas i n g l a c i a l a c e t i c a c i d an i n t e r m o l e c u l a r process (E2) e f f e c t i v e l y competed w i t h the i n t r a m o l e c u l a r mechanism. An i n t e r m o l e c u l a r mechanism which gave 153a p r e f e r e n t i a l l y from the amine oxide d e r i v a t i v e of 127b may be r a t i o n -C l 154 153a 74 a l i z e d by assuming that i n g l a c i a l a c e t i c a c i d the amine oxide intermediate e x i s t s i n e q u i l i b r i u m w i t h i t s protonated form 154. E l i m i n a t i o n then could be accomplished by n u c l e o p h i l i c a t t a c k by an acetate anion on the l e a s t s t e r i c a l l y hindered hydrogen @ to the N,N-dimethylhydroxylamine l e a v i n g group. C o n s i d e r a t i o n of the puckered conformation of 154 i n d i c a t e d that the p_-chlorobenzy l i e proton, which occupied a pseudoequator i a l p o s i t i o n , was much l e s s hindered than the pseudoaxial b e n z y l i c proton and, t h e r e f o r e , would be the most l i k e l y candidate f o r removal by a n u c l e o p h i l e . As w e l l , the p_-chlorobenzy l i e proton more c l o s e l y approximated the i d e a l trans -d i a x i a l c o n f i g u r a t i o n f or l e a v i n g groups than d i d the pseudoaxial b e n z y l i c proton. Because of the i n s t a b i l i t y of 128 to r e c r y s t a l l i z a t i o n , crude m a t e r i a l c o n t a i n i n g approximately 12% a c y c l i c isomer 148 was used i n the p r e p a r a t i o n of the corresponding t h i e t e 1,1-dioxide 155. The r e a c t i o n was run i n the same manner as f o r the sy n t h e s i s of 152. However, the e l i m i n a -t i o n was found to be r e l a t i v e l y r a p i d and, t h e r e f o r e , a sho r t e r r e a c t i o n p e r i o d was r e q u i r e d . Nmr a n a l y s i s of the crude product (96%, based on the c a l c u l a t e d amount of 128 i n the s t a r t i n g m a t e r i a l ) i n d i c a t e d that i t was fr e e of contaminants and that i t c o n s i s t e d of a s i n g l e isomer (155) • The crude m a t e r i a l was r e a d i l y c r y s t a l l i z e d from ethanol 95 to give 155 as pale 75 y e l l o w p l a t e s . The i r spectrum showed, besides c h a r a c t e r i s t i c n i t r o group a b s o r p t i o n , d i s t i n c t s i m i l a r i t i e s to that of 152. In a d d i t i o n to the 9 aromatic protons, the nmr spectrum (DMSO-d^) d i s p l a y e d doublets at S8.18 and 6.49 ( J = 2 Hz), which were a t t r i b u t e d to the o l e f i n i c and b e n z y l i c protons, r e s p e c t i v e l y . The chemical s h i f t s for the corresponding protons i n the spectrum (CDCl-j) of 152 were S 7 .03 and 5.92. D i s r e g a r d i n g p o s s i b l e e f f e c t s due to a d i f f e r e n c e i n s o l v e n t , the greater downfield s h i f t seen f o r the o l e f i n i c proton ( A S = -1.15) compared to that of the b e n z y l i c pro-ton (AS= -0.57) i n going from 152 to 155 suggested that the e l e c t r o n -withdrawing p_-nitropheny 1 group was conjugated w i t h the double bond i n 155. Comparison of the uv s p e c t r a (CH 3CN) of 152 ( A m a x 255 nm) and 155 (^ m a x 288 nm) r e v e a l e d a bathochromic s h i f t , which supported t h i s assignment. Presumably, the enhanced a c i d i t y of the p_-nitrobenzylie proton compared to that of the b e n z y l i c proton i n 128, together w i t h the expected greater s t a b i l i t y of isomer 155 compared to the isomer i n which the u n s u b s t i t u t e d phenyl group was conjugated w i t h the double bond, predisposed 128 to y i e l d only 155 upon amine oxide e l i m i n a t i o n . Base-catal'yzed i s o m e r i z a t i o n s of the t h i e t e 1,1-dioxides 153a, 153b and 155 might be u s e f u l s i n c e such experiments may provide more e v i -dence f o r the p o s i t i o n of the double bond i n these compounds. Base-cata-ly z e d i s o m e r i z a t i o n s of t h i e t e 1,1-dioxides are known (52,59,76). For example, treatment of 156 w i t h potassium hydroxide i n t e t r a h y d r o f u r a n at 156 157 76 room temperature gave a 90% y i e l d of the e n d o c y c l i c isomer (157) (76). I t was p o s t u l a t e d that formation of the more s t a b l e a l l y l i c carbanion was i n -volved i n the i s o m e r i z a t i o n (76). Thermolysis of Thiete 1,1-dioxides King and co-workers have r e c e n t l y reported that thermolysis of t h i e t e 1,1-dioxide (103) at 615° under high vacuum gave r i s e to a c y c l i c S 0 159 161 s u l f i n i c a c i d e s t e r ( s u l t i n e ) 158 i n 70%, y i e l d . When 103 was thermolyzed at 950°, a c r o l e i n (159) was obtained i n 857D y i e l d . They have i n t e r p r e t e d these r e s u l t s i n terms of an e l e c t r o c y c l i c r i n g opening of 103 to g i v e v i n y l s u l f e n e (160). This s p e c i e s , depending on the temperature, then un-derwent i n t r a m o l e c u l a r rearrangement to give 158 or the intermediate 161. Loss of s u l f u r monoxide ( d e s u l f i n y l a t i o n ) by 161 gave the «,£-unsaturated carbonyl compound 159. Evidence supporting t h i s mechanism was obtained by t r a p p i n g the proposed intermediate 160 by heating a s o l u t i o n of 103 i n benzene at 220° w i t h an excess of phenol, which gave the p r e d i c t e d s u l f o n -ate e s t e r 162 i n 15% y i e l d (67,86). When 115, the phenyl analogue of 103, 103 SO, 160 OH \\ / r o s o 2 162 was thermolyzed at 455° a mixture of s u l t i n e 163 and t X , ^ - u n s a t u r a t e d ketone 164 was obtained (67). When the thermolysis was c a r r i e d out at 950°, the \\ / 455 c + 115 163 0 164 y i e l d of J.64 was 85% (86). C o n s i d e r i n g the s t r u c t u r a l resemblance, s i m i l a r r e s u l t s might be expected from the thermolysis of 152. I t had been observed that at the me l t i n g point of 152 a vigorous e v o l u t i o n of gas bubbles occurred. The i r spectrum of the resi d u e remaining a f t e r the e v o l u t i o n of gas had sub-sided was almost i d e n t i c a l to that of trans-chalcone (165a). I t was sub-78 sequently found by g l c that a sample of 152 heated at 166° for 3 minutes gave 165a to the extent of 9270. A second, minor peak was present i n the 152 165a chromatogram, which was t e n t a t i v e l y i d e n t i f i e d as c i s - c h a l c o n e (165b). I t i s known (99) that exposure of a s o l u t i o n of 165a to s u n l i g h t r e a d i l y g i v e s r i s e to 165b. Glc of a CHC1.J s o l u t i o n of 165a before and a f t e r ex-posure to s u n l i g h t revealed that a second component was obtained, presum-ably 165b. The r e t e n t i o n time of t h i s component was i d e n t i c a l to that of CHC1 3 165a hv the minor c o n s t i t u e n t i n the thermolysate obtained from 152. Probably no s i g n i f i c a n c e can be attached to the o b s e r v a t i o n that mainly the t r a n s -isomer 165a was formed i n the thermolysis of 152, s i n c e i t i s known that chalcone i s s u s c e p t i b l e to thermal i s o m e r i z a t i o n (99). Although the ab-sence of peaks other than the two a t t r i b u t e d to 165a and b i n the chroma-togram of the thermolysate, as w e l l as the high y i e l d of 165a obtained, suggested that a s u l t i n e was not present, i t s formation cannot be r u l e d 79 out at the present time. The thermolysis of t h i e t e 1,1-dioxides to g i v e the corresponding -unsaturated carbonyl compounds was of s p e c i a l s i g n i f i c a n c e when the p_-chloropheny 1 isomers 153a and b_ were considered. I f the assigned s t r u c -tures were c o r r e c t , then according to the mechanism proposed by King and co-workers f o r the thermal conversion of t h i e t e 1,1-dioxide to a c r o l e i n (67,86), thermolysis of 153a should have given benzylidene p_-chloroaceto-phenone (166), whereas thermolysis of 153b should have y i e l d e d p_-chloro-. benzylidene acetophenone (167) . Indeed, these were the observed r e s u l t s . 0 C l 153b 167 Heating a sample of pure 153a at 164° f o r 3 minutes gave an 807o y i e l d of 166 and no 167, as determined by g l c . In the same manner, pure 153b gave an 857> y i e l d of 167 w i t h no 166 observed. The i r s p e c t r a of the thermol-ysates from 153a and 153b were almost i d e n t i c a l to those of a u t h e n t i c sam-pl e s of 166 and 167, r e s p e c t i v e l y . A s i m i l a r thermolysis performed on the p_-nitropheny 1 isomer 155 gave a product possessing strong bands i n the i r at 1663, 1592 and 1212 80 cm \ which were i n d i c a t i v e of an cx , f i-unsaturated ketone. One major peak was observed when the thermolysate was analyzed by g l c . However, an authen-t i c sample of the p r e d i c t e d benzylidene p_-nitroacetophenone (168) was not 0 155 168 prepared f o r r e f e r e n c e . According to the proposed mechanism whereby t h i e t e 1,1-dioxides may y i e l d c< ,f>-unsaturated carbonyl compounds (67,86), t r a n s f o r m a t i o n of 152 to 165a presumably i n v o l v e d l o s s of s u l f u r monoxide from the s u l f e n e SO H 3 170 intermediate 169. The s u c c e s s f u l t r a p p i n g of the analogous intermediate 160 d e r i v e d from t h i e t e 1,1-dioxide (103) prompted a s i m i l a r attempt u t i l -i z i n g 152. I t was a n t i c i p a t e d that formation of 169 i n the presence of 81 water would be detected by isolation of the corresponding sulfonic acid 170. That sulfenes readily react with water to yield sulfonic acids is known (22). The reaction was carried out by refluxing a sample of 152 in a mixture of tetrahydrofuran and water (4:1). During the reflux, the odor of hydrogen sulfide was apparent. This observation may be significant with respect to the proposed desulfinylation of sulfenes to give carbonyl com-pounds (67,86), since i t has been shown (in the gas phase) that sulfur monoxide (SO) is extremely reactive and disproportionates to give disulfur monoxide (S2O), which in the presence of water decomposes to form hydrogen sulfide (100). Work-up of the refluxed reaction gave a water soluble, acidic solid 170 in 717<, crude yield and 77» 165a. A ketonic sulfone 171 in 117o crude yield was also isolated. The nature of 171 w i l l be considered separately. The acidic material 170 displayed characteristic sulfonic acid bands in the i r and formed a crystalline salt with dimethylamine. Besides a multiplet attributable to 10 aromatic protons, the nmr spectrum (DMSO-dg) showed a doublet atS 6.61 («-styryl proton, 1) J = 7 Hz, a sin-glet at£6.56 which was superimposed on the upfield signal of the doublet (benzylic proton, 1) and a doublet at 54.57 (p-styryl proton, 1) J = 7 Hz. Apparently, the benzylic proton was orientated in such a manner with respect to the ft -styryl proton that no coupling between the two protons was observ-able at 60 MHz. The magnitude of the coupling between the styryl protons was indicative of a cis-configuration. Maxima in the uv spectrum (CH^cN) occurred at 253 (€ 21,600), 282.5 (shoulder) (e 2,740) and 292 nm (el,450). A definite similarity was observed between this spectrum and that reported (101) for 172, the carboxylic analogue of the structure proposed for 170, which showed maxima (EtOH) at 252 (6 22,490), 283.5 (£2,080) and 292.5 nm 82 (£ 1,320). The c o n f i g u r a t i o n of 172 was not s p e c i f i e d (101). The nmr C0 2H 172 spectrum (CDCl^) of the dimethylamine s a l t of 170 was i n t e r e s t i n g i n that i t r e v ealed c o u p l i n g between the b e n z y l i c and f ? - s t y r y l protons ( J = 2 Hz) as w e l l as a decrease i n the c o u p l i n g between the s t y r y l protons ( J = 5.5 Hz). The uv spectrum (H 20) of t h i s m a t e r i a l was almost i d e n t i c a l to that of the f r e e a c i d . On one occasion a sample of 170 being s t o r e d i n a des-i c c a t o r decomposed to g i v e an o i l . Washing the o i l w i t h water caused a s o l i d to separate which possessed strong a b s o r p t i o n i n the i r at 1358, 1190 and 1168 cm \ c h a r a c t e r i s t i c of a s u l f o n i c a c i d e s t e r . Although the matter was not f u r t h e r pursued, the proposed s t r u c t u r e of 170 i s such that i n t r a m o l e c u l a r s u l f o n a t i o n to give a ^ - s u l t o n e 173 may be p o s s i b l e (102). 170 173 The compound 173 i s known and has been reported to show s u l f o n i c e s t e r bands at 1344 and 1172 cm 1 i n the i r (53). Bis(1,3-dipheny1-3-oxopropy1) Sulfone As p r e v i o u s l y mentioned, c r y s t a l l i z a t i o n of 152 from hot so l v e n t s 83 caused some decomposition. This was e s p e c i a l l y n o t i c e a b l e when the s o l -vent was e t h a n o l . Examination of the evaporated mother l i q u o r from a c r y s t a l l i z a t i o n i n ethanol revealed the presence of trans-chalcone (165a) and a white s o l i d which was subsequently i d e n t i f i e d as bis(1,3-dipheny1-3-oxopropyl) s u l f o n e (171). To determine the extent to which 152 was con-0 0 0 171 v e r t e d to 171, a sample of the t h i e t e 1,1-dioxide was r e f l u x e d i n ethanol 95 f o r 2 hours. The y i e l d of crude 171 was 17%. C r y s t a l l i z a t i o n from hexane - methyl e t h y l ketone gave s h o r t , white needles, m.p. 184 - 185°. Besides s u l f o n e absorptions at 1307 and 1138 cm \ i r bands i n d i c a t i n g the presence of a benzoyl group occurred at 1683 and 1241 cm l. The nmr spec-trum (Figure 2) showed a m u l t i p l e t at 5 7.93 - 7.67 (protons ortho to car-bonyl groups, 4) and a second m u l t i p l e t at 6 7.53 - 7.23 (protons meta and para to carbonyl groups, 6, and phenyl protons, 10). An ABX p a t t e r n was present, w i t h the centre of the X quartet at 64.70 ( e q u i v a l e n t b e n z y l i c protons, 2) and the unsymmetrical AB o c t e t at&4.20 - 3.39 (two e q u i v a l e n t p a i r s of nonequivalent methylene protons, 4 ) . From the 100 MHz spectrum, the chemical s h i f t of protons A was c a l c u l a t e d (44b) to be 8 3.717 ( J = AX 2.8 Hz) and that of protons B to be S3.925 ( J D V = 10.2 Hz) w i t h J A n = 17.5 —BX —AB Hz. A maximum occurred i n the uv spectrum (CH^OH) at 244 nm (£ 25,000) which was compatible w i t h a molecule c o n t a i n i n g two benzoyl groups. For 84 85 example, the spectrum (EtOH) of acetophenone d i s p l a y s a maximum at 240 nm (£ 13,000) (98b). I f c r y s t a l l i z a t i o n s of 171 from ethanol or hexane - methyl e t h y l ketone were allowed to s i t f o r s e v e r a l days, a second c r y s t a l l i n e substance 174 was obtained as c o l o u r l e s s , transparent p l a t e s , m.p. 196 - 197°. The i r spectrum (KBr) of 174 was q u i t e s i m i l a r but not i d e n t i c a l to that of 171, whereas the nmr s p e c t r a were superimposable. The s t r u c t u r e proposed f o r 171 possesses two asymmetric centres and, t h e r e f o r e , presents the pos-s i b i l i t y of meso- and d1 - d i a s t e r e o i s o m e r i c forms. That 171 and 174 were e i t h e r diastereoisomers or merely polymorphs cannot be s t a t e d w i t h c e r -t a i n t y at the present time. Instances of meso- and d1-diastereoisomers possessing i d e n t i c a l nmr s p e c t r a have been reporte d (61). At i t s m e l t i n g p o i n t , 171 decomposed w i t h the vigorous e v o l u t i o n of a gas. Glc a n a l y s i s of the res i d u e remaining a f t e r heating a sample of 171 at 200° f o r 2 minutes r e v e a l e d a 4:1 mixture of t r a n s - and c i s -chalcone (165a and b ) . The i r and nmr s p e c t r a of the thermolysate were 0 175 165a, b very s i m i l a r to those of 165a. These r e s u l t s were r e a d i l y r a t i o n a l i z e d i n terms of s t r u c t u r e 171. Thermal d e s u l f o n y l a t i o n (103) of 171 would be expected to y i e l d a r a d i c a l intermediate 175 which, upon loss of a hydro-- SO, 171 86 gen atom, would g i v e the tx ,3-unsaturated ketones 165a and b. The s y n t h e t i c approach to 171 in v o l v e d the a d d i t i o n of $-mercapto - p-phenylpropiophenone (176) (104) to trans-chalcone (165a) under f r e e r a d i c a l generating c o n d i t i o n s to give b i s ( l , 3 - d i p h e n y l - 3 - o x o -p r o p y l ) s u l f i d e (177). Reactions of a s i m i l a r nature are known (105). The 165a + CCH2CH SH ( C 6 H 5 C 0 2 ) 2 176 C CH 2CH— S CHCH2C-CH CO H 3 3 . 171 177 s u l f i d e 177 was obtained as an o i l , which was not p u r i f i e d but was o x i d i z e d d i r e c t l y to gi v e the corresponding s u l f o n e . The c r y s t a l l i z e d product, m.p. 184 - 185°, was found to have i r , uv and nmr s p e c t r a i d e n t i c a l to those of 171. A mixture mel t i n g p o i n t w i t h 171 was not depressed. L i k e 171, the syn t h e s i z e d m a t e r i a l decomposed at i t s m e l t i n g p o i n t to give chalcone. S i m i l a r l y , a second c r y s t a l l i n e form, m.p. 196 - 197°, was obtained from the c r y s t a l l i z a t i o n s of the crude product which possessed an i r spectrum that was i d e n t i c a l to that of 174. Compound 171 i s f o r m a l l y derived from two molecules of 2,4-d i p h e n y l t h i e t e 1,1-dioxide (152) by the lo s s of one molecule of s u l f u r 87 monoxide and the a d d i t i o n of one molecule of water. Since chalcone was produced along w i t h 171 i n the decomposition of 152 i n hot e t h a n o l , and s i n c e 171 was obtained i n low y i e l d , i t i s tempting to invoke the<X,£-unsaturated ketone i n the formation of 171. However, i n the absence of a d d i t i o n a l experiments, f u r t h e r s p e c u l a t i o n as to the o r i g i n of 171 i s unwarranted. I t should be noted that a cursory examination of the residues obtained upon evaporation of the mother l i q u o r s from the c r y s t a l l i z a t i o n s i n ethanol 95 of the s u b s t i t u t e d t h i e t e 1,1-dioxides 153a, 153b and 155 d i d not r e v e a l species analogous to 171. Synthesis of 3-Cyanothietane 1,1-dioxides The a d d i t i o n of hydrogen cyanide to the double bond of t h i e t e 1,1-dioxides has apparently not been p r e v i o u s l y r e p o r t e d . Treatment of a chloroform - ethanol s o l u t i o n of 152 w i t h hydrogen cyanide i n the pres-CN 152 179 •>-178 88 ence of potassium cyanide gave the a d d i t i o n product 178 as a f i n e p r e c i p -i t a t e i n 777» y i e l d . Evaporation of the f i l t r a t e y i e l d e d an i n t r a c t a b l e b l a c k t a r . The p r e c i p i t a t e was poorly s o l u b l e i n common organic s o l v e n t s . C r y s t a l l i z a t i o n from n-butanol gave w h i t e , f e a t h e r - l i k e c r y s t a l s , m.p. 236 - 237°. The adduct was s t a b l e at the temperature of b o i l i n g n-butanol (118°) and d i d not appear to decompose at i t s m e l t i n g p o i n t . In the i r spectrum, c h a r a c t e r i s t i c n i t r i l e a b s o r p t i o n occurred at 2245 cm"', Besides a 10 proton m u l t i p l e t , the nmr spectrum (DMSO-dg) showed a doublet at S6.34 ( b e n z y l i c protons, 2) J = 10.5 Hz, and a t r i p l e t atS 4.77 (proton at C-3, 1) J = 10.5 Hz. The equivalency of the b e n z y l i c protons and the magnitude of the v i c i n a l c o u p l i n g constant i n d i c a t e d a c i s - c o n f i g u r a t i o n fo r the phenyl groups on the h e t e r o c y c l i c r i n g . C onsidering the r e l a t i v e s t a b i l i t i e s already noted f o r c i s - and trails-2,4-dipheny 1-3-dimethy lamino-t h i e t a n e 1,1-dioxide (126a and b ) , such a r e s u l t was not unexpected. The course of the r e a c t i o n may be r a t i o n a l i z e d by assuming that the cyanide i o n a t t a c k s from the l e a s t hindered s i d e of 152, i . e . , the si d e opposite the phenyl group at C-4, to generate the intermediate carbanion 179, which 2 may possess planar (sp ) geometry at the ca r b a n i o n i c carbon (52). Such a species could then undergo p r o t o n a t i o n to give p r e f e r e n t i a l l y the more s t a b l e c i s - i s o m e r 178. Even i f some trans-isomer were i n i t i a l l y formed, e p i m e r i z a t i o n to 178 could presumably occur under the b a s i c c o n d i t i o n s (KCN) of the r e a c t i o n . No r e a c t i o n was observed i n the absence of potas-sium cyanide. When the r e a c t i o n was repeated using a mixture of the £-chloro-s u b s t i t u t e d isomers, 153a and b, a 567» y i e l d of the a d d i t i o n product 180 was obtained and 147, of the s t a r t i n g m a t e r i a l was recovered. U n l i k e 178, 89 180 was reasonably s o l u b l e i n common organic s o l v e n t s and was r e a d i l y c r y s t a l l i z e d from ethanol 95 to give f i n e , white needles, m.p. 199 - 200°. N i t r i l e a b s o r p t i o n i n the i r spectrum occurred at 2280 cm *. That the product possessed a c i s - c o n f i g u r a t i o n was i n d i c a t e d by the nmr spectrum (DMSO-dg), which showed the b e n z y l i c protons as a doublet atS 6.39 ( J = 11 Hz) and the proton on C-3 as a t r i p l e t at 6 4.76 ( J = 11 Hz). C = N 180, X = C l 181, X = N0 2 With the p _ - n i t r o - s u b s t i t u t e d isomer 155 the chloroform - ethanol s o l v e n t mixture was r e p l a c e d by THF because of the i n s u f f i c i e n t s o l u b i l i t y of 155 i n chloroform. A d d i t i o n of potassium cyanide caused the s o l u t i o n to turn a dark orange. The colour was perhaps a t t r i b u t a b l e to the carbanion species analogous to 179, i n which the p_-nitro group would tend to s t a b i -l i z e the negative charge. U n l i k e the r e a c t i o n s w i t h 152 and 153a - b, the a d d i t i o n product 181 d i d not p r e c i p i t a t e from s o l u t i o n . The r e s i d u e ob-t a i n e d by evaporating the r e a c t i o n s o l v e n t was washed w i t h ethanol 95 to g i v e 181 as a pale yellow s o l i d i n 677, crude y i e l d . The product obtained by column chromatography of the evaporated washings r a i s e d the y i e l d to 757o. C r y s t a l l i z a t i o n from hexane - chloroform y i e l d e d pure 181 i n two polymorphic forms, one as f i n e , white needles (m.p. 164 - 165°) and the other as t h i c k , pale y e l l o w needles (m.p. 152 - 153°). The i r s p e c t r a 90 (KBr) of the two forms were e s s e n t i a l l y i d e n t i c a l and showed n i t r i l e ab-s o r p t i o n at 2275 cm *. The nmr s p e c t r a (DMSO-d^) were superimposable and, i n a d d i t i o n to the 9 aromatic protons, revealed a p a i r of p a r t i a l l y over-lapped d o u b l e t s , one at 8 6.56 (p_-nitrobenzylie proton, 1) J = 10.5 Hz, and the other at 8 6.48 ( b e n z y l i c proton, 1) J = 10.5 Hz, and a t r i p l e t at £4.92 (proton on C-3, 1) J = 10.5 Hz. By analogy to 178 and 280, 181 was assigned a c i s - c o n f i g u r a t i o n f o r the aromatic groups on the h e t e r o c y c l i c r i n g . That the two c r y s t a l l i n e forms of 181 were a c t u a l l y polymorphs was supported by the o b s e r v a t i o n that r e c r y s t a l l i z a t i o n of e i t h e r the high or low melt-ing form gave a mixture of the two c r y s t a l types upon c o o l i n g . The r e s i d u e obtained from the ethanol washings of crude 181 was subjected to column chromatography. F r a c t i o n a t i o n of t h i s m a t e r i a l was prompted by the appearance i n i t s i r spectrum of a medium i n t e n s i t y band at approximately 2220 cm ^, which was i n d i c a t i v e of a conjugated n i t r i l e , p a r t i c u l a r l y of the c i n n a m o n i t r i l e - t y p e (106) . The f r a c t i o n possessing the c h a r a c t e r i s t i c band was obtained as a y e l l o w s o l i d . I t became appar-ent from the behavior of t h i s substance on c r y s t a l l i z a t i o n that i t was a mixture of two components 182a and b which were subsequently separated. The i r s p e c t r a of 182a and b were s i m i l a r and showed n i t r o group and con-jugated n i t r i l e a b s o r p t i o n . Sulfone bands were absent. On the b a s i s of the i r data alone, i t appeared that 182a and b were base-catalyzed e l i m i -n a t i o n products d e r i v e d from 181. The presence of the cyano group i n 181 would be expected to enhance the a c i d i t y of the proton at C-3 and thus promote ( 3 - e l i m i n a t i o n of the s u l f o n y l group on exposure to base (107). A p o s s i b l e mechanism for t h i s e l i m i n a t i o n , assuming i t to be a stepwise process, i s o u t l i n e d i n Scheme I I I using s t r u c t u r e 183. A b s t r a c t i o n of SCHEME III 92 the C-3 proton i n 183 would give carbanion 184, which could presumably undergo r i n g opening to give e i t h e r 185 or 186 or both, depending on the nature of s u b s t i t u e n t s A and B. Loss of SO2 (103, 107) from 185 and 186 would then g i v e the corresponding a l l y l i c carbanions 187 and 188. Pro-t o n a t i o n by s o l v e n t would y i e l d the r e s p e c t i v e unsaturated n i t r i l e s , 189 and 190, each of which may e x i s t as a p a i r of geometric isomers. Consid-e r i n g 182a and b to be isomers of e i t h e r 189 or 190 where A = NO2 and B = H, gave C. ,rL oN.0 o as t h e i r molecular formula. The elemental a n a l y s i s 16 12 2 2 r e s u l t s f o r both compounds agreed s a t i s f a c t o r i l y w i t h the proposed formu-l a . I t can perhaps be argued that because of the i n d u c t i v e e f f e c t of the p_-nitro s u b s t i t u e n t , carbanion 188 (A = NC>2> B = H) would be p r e f e r r e d over the a l t e r n a t e resonance form 187. Thus, 182a and b might be the geo-m e t r i c isomers 191a and b. To some extent, the nmr s p e c t r a of 182a and 191a 191b b supported such an assignment and i n d i c a t e d that the s t r u c t u r e of 182a was perhaps as shown i n 191a and that of 182b was as shown i n 191b. The non-aromatic protons of 182a were seen as a s i n g l e t at S7.08 ( o l e f i n i c proton, 1) and as a s i n g l e t at S 3 .83 ( b e n z y l i c protons, 2 ) , whereas those of 182b appeared as a s i n g l e t at<S3.93 ( b e n z y l i c protons, 2 ) . Apparently, the o l e f i n i c proton i n 182b was s h i f t e d downfield r e l a t i v e to that i n 182a and was hidden under the aromatic envelope. As w e l l , the s i g n a l f o r the b e n z y l i c protons of 182b was s h i f t e d downfield compared to that of 182a. 93 Such downfield s h i f t s could be r a t i o n a l i z e d i n terms of s t r u c t u r e s 191a and 191b. In 19lb the o l e f i n i c proton i s adjacent to the cyano group and the b e n z y l i c protons are proximate to the u n s u b s t i t u t e d phenyl r i n g . As a consequence, these protons are subj e c t to a greater degree of d e s h i e l d -ing than are the corresponding protons i n 191a, which are f u r t h e r removed from the cyano and phenyl s u b s t i t u e n t s . A maximum occurred i n the uv spectrum (CH 3CN) of 182a at 278 nm (€26,700). In the spectrum (CH3CN) of 182b the maximum was seen at 269 nm (6 39,000). The uv spectrum (EtOH) of compound 192 has been reported (106) to show a maximum at 275 nm (€18,620). N = C H \ / C = C / NCCH 2CH 20CH 2 192 That 182a possessed a lower molar a b s o r p t i v i t y than 182b may be the r e s u l t of the former isomer having the c i n n a m o n i t r i l e chromophore i n a c i s - c o n -f i g u r a t i o n as i n 191a, whereas the l a t t e r isomer possesses t h i s e n t i t y i n a t r a n s - c o n f i g u r a t i o n as i n 191b. Presumably, the molar a b s o r p t i v i t y of 182b was approximately twice that of 192 because of the c o n t r i b u t i o n made by the p_-nitrophenyl group i n 182b. Obviously, i n the absence of s u i t a b l e r e f e r e n c e compounds, the s t r u c t u r e s assigned to 182a and b are e q u i v o c a l . Evidence that 181 i t s e l f , r a t h e r than a decomposition product of 155, was the source of 182a and b was obtained by t r e a t i n g a te t r a h y d r o -furan - ethanol s o l u t i o n of 181 w i t h aqueous sodium hydroxide at room tem-perature. A t r a n s i e n t magenta colour was observed during the a d d i t i o n of the base, which was perhaps due to a carbanion species such as 188 (A = N0 2, B = H). Nmr a n a l y s i s of the crude product r e v e a l e d a 2.4:1 mixture 94 of 182a and b, r e s p e c t i v e l y . A s i m i l a r r a t i o was i n d i c a t e d by g l c . That conjugated n i t r i l e s analogous to 182a and b were not detected i n the syntheses of the 3-cyanothietane 1,1-dioxide d e r i v a t i v e s 178 and 180 was perhaps due to the f a c t that under the c o n d i t i o n s of the a d d i t i o n r e a c t i o n both 178 and 180, u n l i k e 181, p r e c i p i t a t e d from s o l u t i o n . Since 181 remained d i s s o l v e d , i t was s u s c e p t i b l e to proton a b s t r a c t i o n . I t was a l s o p o s s i b l e that the p_-nitro s u b s t i t u e n t of 181 has an a c t i v a t i n g e f f e c t w i t h regard to °,-elimination of the s u l f o n y l group. U n f o r t u n a t e l y , s o l u -t i o n s of 178 and 180 were not subjected to base treatment. I f a conjugated n i t r i l e analogous to 182a and b could be generated from 178, i t may prove to be a very u s e f u l reference compound f o r a s s i g n i n g s t r u c t u r e s to 182a and b. Reduction of 3-Cyanothietane 1,1-dioxides Although W-2 Raney n i c k e l i s g e n e r a l l y employed i n the c a t a l y t i c r e d u c t i o n of n i t r i l e s to primary amines (108,109), the a b i l i t y of t h i s c a t a l y s t to cause d e s u l f u r a t i o n of sulfones (110) made i t s use i n the pres-ent instance u n d e s i r a b l e . A p o t e n t i a l s u b s t i t u t e appeared to be sponge n i c k e l c a t a l y s t , which had been reported (109) to c a t a l y z e the hydrogena-t i o n of n i t r i l e s under unusually m i l d c o n d i t i o n s (room temperature, 40 -55 p . s . i . hydrogen p r e s s u r e ) . There was the p o s s i b i l i t y that under such c o n d i t i o n s d e s u l f u r a t i o n would not be a ser i o u s problem. The hydrogenation of 178 was c a r r i e d out i n the presence of a lar g e excess of ammonia i n order to suppress secondary amine formation (108,109). The product, 2,4-dipheny1-3-aminomethylthietane 1,1-dioxide (193), was obtained as a white s o l i d i n 41% crude y i e l d . In the i r spec-95 trum of 193, c h a r a c t e r i s t i c primary amine bands were present at 3425 and 3365 cm , and strong sulfone a b s o r p t i o n was apparent. The nmr spectrum was i n agreement w i t h the proposed s t r u c t u r e . In view of the s u s c e p t i b i l -i t y of the p_-nitro analogue of 178 to base-catalyzed ( 3 - e l i m i n a t i o n , the r e l a t i v e l y low y i e l d of primary amine 193 was perhaps a t t r i b u t a b l e to l o s s of 178 by d e s u l f o n y l a t i o n i n the presence of ammonia. Products r e s u l t i n g from such a process may have gone undetected during the work-up of the hydrogenation. 178 193 -1 X X 178, 180, 181, X X X H C l N0 2 193, X X X H C l NO. 2 X 9, X = H 124, X = C l 125, X = N02 96 In an attempt to improve the y i e l d of 193, r e d u c t i o n of 178 by diborane was i n v e s t i g a t e d . I t has been reported that n i t r i l e s are r a p i d l y reduced by t h i s agent, whereas the s u l f o n y l group i s not a f f e c t e d (111). Reaction of 178 w i t h diborane i n te t r a h y d r o f u r a n at room temperature gave 193 i n 50% crude y i e l d . In a d d i t i o n to the primary amine, a white s o l i d was i s o l a t e d which was t e n t a t i v e l y i d e n t i f i e d as a borane d e r i v a t i v e of 193. Diborane r e d u c t i o n of 2 - ( 4-chloropheny1 ) - 3-cyano - 4-phenylthietane 1 , 1-dioxide (180) gave a 757o crude y i e l d of the corresponding primary amine 194. The low me l t i n g product showed a broad, weak band i n the N-H s t r e t c h -i n g r e g i o n and strong s u l f o n e a b s o r p t i o n . The nmr spectrum was i n accor-dance w i t h the proposed s t r u c t u r e . The diborane procedure appeared to be the method of choice f o r c o n v e r t i n g 2 - ( 4-nitrophenyl ) - 3-cyano - 4-phenylthietane 1 , 1-dioxide (181) to the primary amine 195 s i n c e the n i t r o group i s i n e r t to diborane under c o n d i t i o n s that allow n i t r i l e r e d u c t i o n (111). The m a t e r i a l obtained f o l -lowing treatment of 181 w i t h diborane was g r o s s l y p u r i f i e d by column chro-matography, which gave 195 as a pale y e l l o w o i l i n 667» y i e l d . Both the i r and nmr s p e c t r a of t h i s o i l agreed w i t h the proposed s t r u c t u r e . An elemental a n a l y s i s was not obtained f o r 195. D i m e t h y l a t i o n of 3-Aminomethylthietane 1 , 1-dioxides The primary amines, 193, 194 and 195, were converted to the cor-responding dimethylated d e r i v a t i v e s 9_, 124 and 125 by the E s c h w e i l e r - C l a r k e procedure (112), which i n v o l v e d warming the amines i n a mixture of formal-dehyde and formic a c i d . That the r e a c t i o n proceeded r e a d i l y i n a l l three cases was evidenced by the vigorous e v o l u t i o n of a gas, presumably carbon d i o x i d e (112). The crude products were obtained i n good y i e l d s and were found to be reasonably pure by nmr a n a l y s i s . S a t i s f a c t o r y elemental an-a l y s e s were obtained f o r 9 and 124. Attempts to prepare s u i t a b l e d e r i v a -t i v e s of 125 f o r elemental a n a l y s i s were u n s u c c e s s f u l and, t h e r e f o r e , the assignment of s t r u c t u r e to t h i s compound r e s t s on s p e c t r o s c o p i c data o n l y . In Table I I I are summarized the p e r t i n e n t chemical s h i f t data f o r the 3-dimethylaminothietane 1,1-dioxides, 126a, 127a and 128. The chemical s h i f t data f o r the corresponding 3-dimethylaminomethy1 homologues are entered i n Table IV. Comparison of the chemical s h i f t s of the h e t e r -o c y c l i c r i n g protons i n Table I I I w i t h those i n Table IV shows a d e f i n i t e u p f i e l d s h i f t f o r these protons i n going from the 3-dimethy1amino to the 3-dimethylaminomethy1 compounds, the s h i f t being greater f o r the C-3 pro-ton than f o r the protons at C-2 and C-4. Such an e f f e c t was to be expected as a consequence of the replacement of n i t r o g e n at C-3 f o r the l e s s e l e c -t r o n e g a t i v e methylene carbon (113). Of s p e c i a l i n t e r e s t were the chemical s h i f t s f o r the methylene protons l i s t e d i n Table IV. As p r e v i o u s l y mentioned, chemical and nmr evidence i n d i c a t e d that the c o n f i g u r a t i o n of 2,4-diphenyl-3-cyanothietane 1,1-dioxide (178) was such that the aromatic groups were c i s to each other and trans to the cyano s u b s t i t u e n t . Although, on the b a s i s of the same chemical evidence, the p_-substituted 3-cyano d e r i v a t i v e s 180 and 181 were assumed to possess the same c o n f i g u r a t i o n as 178, the nmr evidence was not as e x p l i c i t f o r these compounds as for 178 because of the f o r m a l l y non-e q u i v a l e n t nature of t h e i r b e n z y l i c protons. The data i n Table IV, how-ever, appear to co n f i r m that 178, 180 and 181 a l l possessed the same con-f i g u r a t i o n . The nmr spectrum of 9_, l i k e that of the corresponding 3-cyano compound 178, i n d i c a t e d a c i s - c o n f i g u r a t i o n f o r the phenyl groups. The TABLE III Chemical S h i f t Values of the 3-Dimethy.laminothietane 1,1-dioxides Compound X SH a SE c SN(CH 3) 126a H 5 .28 5 .28 3.68 2.10 127a C l 5.22 5 .25 3.57 2.08 128 N0 2 5.36 5.36 3.70 2.14 2 99 TABLE IV Chemical S h i f t Values of the 3-Dimethylaminomethylthietane 1,1-dioxides (CH 3) 2NCH 2 H c Compound X SH c S N ( C H 3 ) 2 8CH 2 9 H 5.13 5.13 3 .10 2.06 2.62 124 C l 5.09 5.13 3.06 2.06 2.60 125 N0 o 5.23 5.17 3.13 2.10 2.64 100 s i m i l a r i t y of the chemical s h i f t s of the methylene protons of 124 and 125 to that of these protons i n 9_ was strong evidence that the c o n f i g u r a t i o n s of a l l three 3-dimethylaminomethyl compounds were the same. An a l t e r n a t e arrangement f o r 124 or 125 i n which one of the aromatic r i n g s was c i s to the dimethylaminomethyl group would be expected to s i g n i f i c a n t l y s h i f t the methylene ab s o r p t i o n from the p o s i t i o n observed i n the spectrum of 9. The chemical manipulations whereby the 3-cyano compounds 178, 180 and 181 were converted to the 3-dimethylaminomethy1 d e r i v a t i v e s were such that e p i m e r i -z a t i o n at any of the carbons of the h e t e r o c y c l i c r i n g was u n l i k e l y . There-f o r e , i t followed that the c o n f i g u r a t i o n s of 180 and 181 were probably i d e n t i c a l to that of 178. Synthesis of 2,4-Dipheny1-3-carboxythietane 1,1-dioxide and 2,4-Dipheny1- 3 - a c e t y l t h i e t a n e 1,1-dioxide I n i t i a l l y , the s y n t h e s i s of 2,4-dipheny1-3-(1-dimethylaminoethyl) - t h i e t a n e 1,1-dioxide (123) was attempted through the 3-cyano d e r i v a t i v e 178. 2,4-Diphenyl-3-carboxythietane 1,1-dioxide (196) and 2,4-diphenyl-3 - a c e t y l t h i e t a n e 1,1-dioxide (197) were intermediates i n that approach. 2,4-Dipheny1-3-carboxythietane 1,1-dioxide (196) was prepared by r e f l u x i n g 178 i n a mixture of dimethyl s u l f o x i d e and 50 per cent aqueous s u l f u r i c a c i d . The d i m e t h y l s u l f o x i d e allowed for the formation of a ho-mogeneous mixture at r e f l u x temperature. Work-up of the h y d r o l y s a t e gave the crude c a r b o x y l i c a c i d as an o f f - w h i t e s o l i d i n high y i e l d . In the i r spectrum of 196, the presence of the c a r b o x y l group was evidenced by an 0 - H s t r e t c h i n g band at 3270 cm * and a strong carbonyl band at 1730 cm ^. The i n t e g r i t y of the t h i e t a n e 1,1-dioxide r i n g was revealed by the appear-ance of the C-2 and C-4 protons as a doublet at 8 5.90 ( J = 10 Hz) i n the 101 nmr spectrum. The a c i d was r e a d i l y s o l u b l e i n 5 per cent sodium hydroxide and caused the e v o l u t i o n of a gas, presumably carbon d i o x i d e , when added as a DMSO s o l u t i o n to 5 per cent sodium bic a r b o n a t e . Apparently, the only 3-carboxythietane 1,1-dioxide that has been reported i n the l i t e r a t u r e i s the parent compound, 198 (114). However, 198 was synthesized (115) by a route q u i t e d i f f e r e n t from that employed i n the p r e p a r a t i o n of 196. The i n f r a r e d spectrum published (114) for 198 showed d i s t i n c t s i m i l a r i t i e s to that of the 2,4-diphenyl d e r i v a t i v e . R e f l u x i n g 196 i n t h i o n y l c h l o r i d e gave the corresponding a c i d c h l o r i d e 199 as a cream-coloured s o l i d , q u a n t i t a t i v e l y . The a c i d c h l o r i d e SOC1 196 was used s h o r t l y a f t e r p r e p a r a t i o n without p u r i f i c a t i o n . A sample of 199 l e f t s i t t i n g i n the open f o r s e v e r a l days r e v e r t e d to the c a r b o x y l i c a c i d 196. Treatment of 199 w i t h an organocadmium reagent prepared from 102 methylmagnesiura bromide and anhydrous cadmium c h l o r i d e (116) gave 2,4-dipheny 1 - 3-acetylthietane 1 , 1-dioxide (197) as a white s o l i d i n 687» crude y i e l d . In a d d i t i o n , the c a r b o x y l i c a c i d 196 was recovered to the extent of 237o. The i n f r a r e d spectrum of 197 showed a strong ketone carbonyl band at 1715 cm ' as w e l l as sulfone a b s o r p t i o n . That 197 possessed the same c o n f i g u r a t i o n as the 3-cyano compound 178 was i n t e r p r e t e d from the equiv-alency of the b e n z y l i c protons and the magnitude of the v i c i n a l c o u p l i n g constant i n i t s nmr spectrum. The i s o l a t i o n of the c a r b o x y l i c a c i d 196 i n d i c a t e d that not a l l of the a c i d c h l o r i d e 199 underwent m e t h y l a t i o n . This was perhaps due e i t h e r to too short a r e a c t i o n p e r i o d (8 hours) or to l o s s of organocadmium reagent by m e t a l l a t i o n of 3-acetyl product already formed (116). Treatment of 197 w i t h hydroxylamine gave the corresponding oxime 200 i n good y i e l d . S ynthesis of 2 , 4-Diphenyl - 3-(l-dimethylaminoethyl)-thietane 1 , 1-dioxide While the work w i t h 196 and 197 was i n progress, a more e f f i c i e n t route to 123 was sought. An approach u t i l i z i n g the n i t r o e t h a n e adduct of 2 , 4 - d i p h e n y l t h i e t e 1 , 1-dioxide (152) appeared to be q u i t e a t t r a c t i v e and was attempted. The base-catalyzed a d d i t i o n of n i t r o a l k a n e s to v i n y l s u l -fones has been known f o r some time (117). However, the r e a c t i o n has ap-p a r e n t l y not p r e v i o u s l y been a p p l i e d to t h i e t e 1 , 1-dioxides. Treatment of a s o l u t i o n of 152 d i s s o l v e d i n a mixture of n i t r o e t h a n e and ethanol 95 w i t h a ni t r o e t h a n e - ethanol 95 s o l u t i o n of potassium hydroxide at room temperature y i e l d e d 2 , 4 - d i p h e n y l - 3 - ( l - n i t r o e t h y l ) - t h i e t a n e 1 , 1-dioxide (201) as a white s o l i d . C r y s t a l l i z a t i o n of the adduct from hexane - ben-zene gave f i n e , white needles i n 74 per cent y i e l d . The i r spectrum showed 103 strong n i t r o group abs o r p t i o n at 1554 and 1324 cm . The asymmetrical s t r e t c h i n g band of the s u l f o n y l group was c o i n c i d e n t a l w i t h the l a t t e r n i t r o group absorption and the symmetrical s t r e t c h i n g band appeared at 1147 cm \ In the nmr spectrum the b e n z y l i c protons ( a r b i t r a r i l y d e s i g -nated d and e) appeared as a t r i p l e t which was a t t r i b u t e d to two over-NO 152 201 lapping d o u b l e t s , one at 55.33 ( b e n z y l i c proton e, 1) = 10 Hz, and the other at 55.14 ( b e n z y l i c proton d, 1) = 11 Hz. A m u l t i p l e t was appar-ent at £4.83 (proton c, 1) J L ^ = 8 Hz, J c a = 7 Hz, a m u l t i p l e t centred at S3.50 (remaining r i n g proton b, 1) J^g = 10 Hz, = 11 Hz, J j ) c = 8 Hz, and a doublet at 51.33 (methyl protons a, 3) J a c = 7 Hz. The u p f i e l d s i g -n a l of the doublet at 65.14 overlapped the lowest f i e l d s i g n a l of the mul-t i p l e t at 8 4.83. I t was considered that the carbanion d e r i v e d from n i t r o -ethane would most l i k e l y a t t a c k 152 i n the same manner as proposed f o r the cyanide i o n , i . e . , from the l e a s t hindered s i d e , to give a t h i e t a n e 1,1-d i o x i d e adduct i n which the phenyl groups were c i s to each other and trans to the s u b s t i t u e n t at C-3. The nonequivalency of Hd and Hg was a t t r i b u t -able to the i n t r o d u c t i o n of an asymmetric centre by the a - n i t r o e t h y 1 group at C-3 r a t h e r than to a t r a n s - c o n f i g u r a t i o n f o r the phenyl groups. In view of the l a r g e r s t e r i c b u l k of t h e o c - n i t r o e t h y 1 group compared to that of the cyano group, a t r a n s - c o n f i g u r a t i o n of phenyls i n 201 seemed even 104 l e s s l i k e l y than such a c o n f i g u r a t i o n i n the 3-cyano d e r i v a t i v e 178, which was obtained only i n the ^ is-arrangement. A molecular model* i n d i c a t e d that w i t h the thie t a n e 1,1-dioxide r i n g of 201 i n a puckered conformation, non-bonded i n t e r a c t i o n s were p o s s i b l e between the pseudoaxial protons at C-2 and C-4 and the oxygens of the oC-nitroethy1 group. Presumably, such i n t e r a c t i o n s may have been great enough to r e s t r i c t r o t a t i o n about thecX-n i t r o e t h y l - C-3 bond and thus c o n t r i b u t e to the nonequivalency of the b e n z y l i c protons. U n f o r t u n a t e l y , the e f f e c t of elevated temperatures on the nmr spectrum of 201 was not i n v e s t i g a t e d . However, some evidence which at l e a s t supported the proposal that the phenyl groups were c i s to each other and trans to the n i t r o e t h y l s u b s t i t u e n t at C-3 was e v e n t u a l l y ob-tai n e d and w i l l be presented s h o r t l y . A sample of 201 which had been r e -c r y s t a l l i z e d s e v e r a l times from hexane - benzene was submitted f o r elemen-t a l a n a l y s i s and found to have a carbon content 3.2% greater than that c a l c u l a t e d on the b a s i s of i t s molecular formula. I t was subsequently found by nmr and g l c a n a l y s i s that 201 c o - c r y s t a l l i z e d w i t h benzene and that the r e s u l t i n g c r y s t a l s contained one molecule of benzene f o r every two molecules of 201. Although i t was then most d e s i r a b l e to f i n d a sub-s t i t u t e f o r benzene which would give c r y s t a l s f r e e of s o l v e n t , i n s u f f i c i -ent product was on hand by the time the anomaly was r e s o l v e d to permit such an undertaking. The elemental a n a l y s i s r e s u l t s f o r a l l elements present i n 201 were s a t i s f a c t o r y when compared to the values c a l c u l a t e d on the b a s i s of the one-to-two composition of the c r y s t a l s . Hydrogenation of a s o l u t i o n of 201 d i s s o l v e d i n t e t r a h y d r o f u r a n * Framework Molecular Models, P r e n t i c e - H a l l , I nc., Englewood C l i f f s , N.J., U.S.A. 105 and ethanol 100 i n the presence of sponge n i c k e l c a t a l y s t under mi l d con-d i t i o n s gave a mixture of primary amine 202 and oxime 200. The two com-ponents were r e a d i l y separated by d i s s o l v i n g the mixture i n chloroform and 200 e x t r a c t i n g 202 w i t h 4N h y d r o c h l o r i c a c i d . Work-up of the e x t r a c t gave crude 202 (60%) as a cream-coloured s o l i d . Only one spot was observed upon t i c a n a l y s i s . The i r spectrum revealed N - H s t r e t c h i n g a b s o r p t i o n , strong sulfone bands and the absence of n i t r o group a b s o r p t i o n . In the nmr spectrum were seen a p a i r of overlapped doublets, one at 8 5.26 (ben-z y l i c proton, 1) J = 10 Hz, and the other at 8 5.16 (remaining b e n z y l i c proton, 1) J = 10 Hz, a d i f f u s e m u l t i p l e t , S 3.50 - 2.65 (proton on C-3 and proton cx to amino group, 2 ) , a s i n g l e t at Si.22 (protons on N, 2 ) , and a doublet at SO.87 (methyl protons, 3) J = 6.5 Hz. The primary amine was dimethylated without f u r t h e r p u r i f i c a t i o n . Evaporation of the chloroform l a y e r f o l l o w i n g the e x t r a c t i o n of 106 202 gave a beige-coloured s o l i d (36%), which was found by t i c to c o n s i s t almost e n t i r e l y of one component possessing the same Rf value as the oxime 200 d e r i v e d from 2 , 4 - d i p h e n y l - 3 - a c e t y l t h i e t a n e 1,1-dioxide (197) . The i r and nmr s p e c t r a of the c r y s t a l l i z e d s o l i d were i d e n t i c a l to those of 200. 200 Presumably, the oxime was an intermediate i n the pathway whereby 201 was reduced to 202• The i n i t i a l product i n the hydrogenation of a n i t r o a l k a n e i s known to be the corresponding n i t r o s o a l k a n e , which rearranges to give an oxime i f the n i t r o s o group i s attached to a primary or secondary carbon atom (118). Oximes, i n t u r n , y i e l d primary amines upon c a t a l y t i c reduc-t i o n (108). Thus, i t seemed reasonable that 200 should be formed d u r i n g the hydrogenation of 201, presumably by rearrangement of the n i t r o s o spe-c i e s 203. The nmr spectrum of 200 showed that the protons on C-2 and C-4 possessed i d e n t i c a l chemical s h i f t s and were e q u a l l y coupled to the proton on C-3 ( J = 10 Hz). Thus, l i k e the 3 - a c e t y l compound 197 and i t s n i t r i l e 107 precursor 178, 200 was considered to possess a c o n f i g u r a t i o n i n which the phenyl s u b s t i t u e n t s were c i s to each other and trans to the group at C-3. I s o l a t i o n of 200 i n the c a t a l y t i c r e d u c t i o n of 201 was, t h e r e f o r e , impor-tant because i t provided evidence that 201 and 202 a l s o possessed such a c o n f i g u r a t i o n , even though i t was not d i s c e r n i b l e from t h e i r nmr s p e c t r a . Of course, such a c o n c l u s i o n was dependent on the assumption that no e p i -m e r i z a t i o n occurred during the hydrogenation. That the b e n z y l i c protons were e q u i v a l e n t i n 200 but not i n 201 and 202 was a t t r i b u t a b l e to the f a c t that the s u b s t i t u e n t on C-3 i n 200, u n l i k e the corresponding s u b s t i t u e n t s i n 201 and 202, d i d not possess an asymmetric centr e . As a consequence, even i f r o t a t i o n about the bond j o i n i n g the oximino group to C-3 i n 200 were r e s t r i c t e d , symmetry w i t h respect to the b e n z y l i c protons would s t i l l be a t t a i n e d . However, r e s t r i c t e d r o t a t i o n about t h i s bond i n 201 and 202 would render the protons on C-2 and C-4 nonequivalent. D i m e t h y l a t i o n of 202 using the E s c h w e i l e r - C l a r k e procedure (112) gave the t e r t i a r y amine 123 as a f a i r l y pure, p a l e beige-coloured s o l i d 202 123 (79%). C r y s t a l l i z a t i o n from hexane - ethanol a f f o r d e d f i n e , white needles. The i r spectrum revealed the presence of a dimethylamino group and strong s u l f o n y l a b s o r p t i o n . As w i t h the primary amine 202, the b e n z y l i c protons of 123 were nonequivalent i n the nmr spectrum and appeared as a rough quar-t e t , which was a t t r i b u t e d to a p a i r of d o u b l e t s , one at 5 5.26 ( b e n z y l i c 108 proton, 1) J = 9 Hz, and the other at 65.07 (remaining b e n z y l i c proton, 1) J = 9 Hz. Shoulders were apparent on each of the s i g n a l s of the quar-t e t . With the success of the n i t r o e t h a n e route to 123, the a l t e r n a t e , multi-stepped approach u t i l i z i n g 2 , 4 - d i p h e n y l - 3 - a c e t y l t h i e t a n e 1,1-dioxide (197) was examined only i n a p r e l i m i n a r y f a s h i o n . I t has been shown (119) that oximes are hydroborated to hydroxylamines. More r e c e n t l y , however, i t has been found that treatment of ketoxime acetates w i t h diborane gives amines (120,121). I t was, t h e r e f o r e , of i n t e r e s t to see i f such a proce-dure could be a p p l i e d to 2 , 4 - d i p h e n y l - 3 - a c e t y l t h i e t a n e 1,1-dioxide oxime (200). Reaction of 200 w i t h a c e t y l c h l o r i d e gave an o i l which, according to i t s i r spectrum, appeared to be the d e s i r e d acetate 204. The ester was not p u r i f i e d but was d i s s o l v e d i n dry t e t r a h y d r o f u r a n and t r e a t e d w i t h an 204 excess of diborane at room temperature. The crude product from the reduc-t i o n was reacted d i r e c t l y w i t h a mixture of formaldehyde and formic a c i d . Work-up gave a pale y e l l o w s o l i d (147»), the i r spectrum of which was super-imposable w i t h that of 123. F a i l u r e to r e f l u x the product from the dibo-rane r e d u c t i o n w i t h mineral a c i d may have been the cause for the low y i e l d 109 ANALYTICAL METHODS M e l t i n g p o i n t s were determined using a Thomas-Hoover C a p i l l a r y M e l t i n g P o i n t Apparatus. A l l m e l t i n g p o i n t s and b o i l i n g p o i n t s are r e -ported uncorrected. U l t r a v i o l e t s p e c t r a were obtained using a Bausch and Lomb Model 505 r e c o r d i n g spectrophotometer. Solvents are s p e c i f i e d . A Beckman IR-10 i n f r a r e d spectrophotometer was used to record the i n f r a r e d s p e c t r a . The nmr spectroscopy was performed by Miss P h y l l i s Watson of the Department of Chemistry, U.B.C., usin g a Va r i a n A-60, T-60 or XL-100 spec-trometer. The c o n c e n t r a t i o n of s o l u t i o n s was ca. 107o and t e t r a m e t h y l s i l a n e served as the i n t e r n a l standard. Solvents are s p e c i f i e d . Peak m u l t i p l i -c i t i e s are abbreviated as f o l l o w s : s ( s i n g l e t ) , d ( d o u b l e t ) , t ( t r i p l e t ) , q ( q u a r t e t ) and m ( m u l t i p l e t ) . G a s - l i q u i d chromatography ( g l c ) was c a r r i e d out usin g a M i c r o -Tek gas chromatograph Model MT-200 equipped w i t h a flame i o n i z a t i o n detec-t o r . Hydrogen and a i r flows (per flame) were 60 and 283 ml/min, respec-t i v e l y . The c a r r i e r gas was n i t r o g e n and the flow r a t e i s s p e c i f i e d . Column c h a r a c t e r i s t i c s and the temperatures of the i n j e c t i o n p o r t , oven, and detector are s p e c i f i e d . Peak areas were measured by means of a Disc I n t e g r a t o r Model 222. Microanalyses were performed by A l f r e d Bernhardt, M i k r o a n a l y t i s c h e s Laboratorium, 5251 Elbach iiber E n g e l s k i r c h e n , F r i t z - P r e g l - S t r a s s e 14-16, West Germany. 110 EXPERIMENTAL 1 . Synthesis of $ -Dimethylaminostyrene ( 1 3 1 ) . The p r e p a r a t i o n of (3-dimethylaminostyrene was c a r r i e d out ac-co r d i n g to a known procedure ( 1 5 , 5 5 ) . Anhydrous potassium carbonate was employed as the d r y i n g agent. Vacuum d i s t i l l a t i o n of the crude product gave a pale y e l l o w l i q u i d w i t h a c h a r a c t e r i s t i c odor, bp 63-65° at 0 . 3 mm ( l i t . (88) 75 -78° , 1 mm); nmr ( C D C l ^ S 7 . 3 0 - 6 . 9 0 (m, 5 , phenyl p r o t o n s ) , 6.73 (d, 1, J = 14 Hz; . X - s t y r y l p r o t o n ) , 5 .13 (d, 1 , J = 14 Hz, (3 - s t y r y l proton) and 2 .70 ( s , 6 , N-methyl protons) ( l i t . ( 8 8 ) S 7 . 1 , 6 . 6 5 , 5 . 1 1 , 2 . 6 3 ; J = 13.9 Hz). A 100 MHz spectrum (neat, -10°) of a sample of 131 which had been s t o r e d at 0° f o r 4 months i n d i c a t e d the presence of only one isomer and showed a m u l t i p l e t at S 7 . 2 4 - 6 . 7 6 , a doublet at 6 .49 ( J = 14 Hz), a doublet at 4 .99 ( J = 14 Hz) and a s i n g l e t at 2 . 3 2 . At no time was the sample allowed to warm above 0° before o b t a i n i n g the -10° spec-trum. Spectra run at -40° and +35° showed no change i n isomeric p u r i t y from that observed at - 1 0 ° . A n a l y s i s of a sample of f r e s h d i s t i l l a t e d i s -s o l v e d i n acetone by g l c on a 6 f t x 5/32 i n ( i . d . ) s t a i n l e s s s t e e l column packed w i t h 57» SE -30 on Chromport (70 -80 mesh) w i t h the i n j e c t i o n p o r t , oven, and detector at 255, 150 and 243°, r e s p e c t i v e l y , and the n i t r o g e n flow at 54 ml/min gave one peak, r e t e n t i o n time 2 . 5 min. The average y i e l d of d i s t i l l e d product from 14 r e a c t i o n s using 60 g ( 0 . 5 mole) of phenylacetaldehyde, 45 g ( 1 . 0 mole) of dimethylamine and 70 g ( 0 . 5 mole) of anhydrous potassium carbonate was 61 g (837o) . 2 . Synthesis of Phenylmethanesulfonyl C h l o r i d e ( 1 3 ) . The procedure was taken from a patent ( 1 2 2 ) . A more d e t a i l e d d e s c r i p t i o n of the patented procedure has appeared i n the l i t e r a t u r e ( 9 1 ) . I l l To a 1000 ml three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r and a r e f l u x condenser were added 75.6 g (0.60 mole) of benzyl c h l o r i d e ( F i s h e r S c i e n t i f i c , r e a . ) , 148.8 g (0.60 mole) of sodium t h i o s u l f a t e pentahydrate ( F i s h e r S c i e n t i f i c , A.C.S.), 150 ml of methanol and 150 ml of d i s t i l l e d water. The mixture was heated under r e f l u x , w i t h s t i r r i n g , f o r 4 hours to o b t a i n a homogeneous s o l u t i o n . The condenser was then attached to a s t i l l head and approximately 140 ml of s o l v e n t was d i s t i l l e d o f f . A f t e r the t r a n s l u c e n t l i q u i d remaining i n the f l a s k had cooled to room temper-a t u r e , 375 ml of g l a c i a l a c e t i c a c i d was added. The condenser was removed and the f l a s k was equipped w i t h a gas i n l e t and o u t l e t and a thermometer. The i n l e t tube was p o s i t i o n e d below the s o l u t i o n s u r f a c e . A f t e r c o o l i n g to 5° i n an ice-water bath, c h l o r i n e was passed i n at such a r a t e that the r e a c t i o n temperature remained at approximately 5 ° . The r e a c t i o n was exo-thermic and r e q u i r e d e f f i c i e n t s t i r r i n g and c a r e f u l r e g u l a t i o n of the gas flow. White p r e c i p i t a t e appeared almost immediately and a f t e r 3 hours a t h i c k suspension was present. C h l o r i n a t i o n was. stopped when the suspen-s i o n became l i g h t green and c h l o r i n e gas began to c o l l e c t i n the a i r space above the r e a c t i o n . The mixture was d i l u t e d w i t h 300 ml of d i s t i l l e d water and s t i r r e d f o r s e v e r a l minutes. S u c t i o n f i l t r a t i o n w i t h water washing, fo l l o w e d by d r y i n g i n a d e s i c c a t o r o v e r n i g h t , gave 90.3 g (797o) of white s o l i d 13_, mp 8 7 - 9 2 ° . C r y s t a l l i z a t i o n from pet. ether ( 8 0 - 1 0 0 ° ) - benzene y i e l d e d 87.6 g (777») of white needles, mp 8 9 - 9 2 ° ( l i t . (123) 9 1 - 9 2 ° , from benzene). The i r spectrum (KBr) was i d e n t i c a l to that of the crude mate-r i a l and showed strong s u l f o n e bands at 1370 and 1165 cm ^. I f c r y s t a l -l i z a t i o n s o l u t i o n s were brown, c h a r c o a l treatment was necessary i n order to prevent the c r y s t a l s from being d i s c o l o u r e d . Phenylmethanesulfony1 c h l o r i d e showed a tendency to sublime when warmed under vacuum. 112 3. Synthesis of p-Chlorophenylmethanesulfony1 C h l o r i d e (129). The procedure used was s i m i l a r to that d e s c r i b e d f o r the prep-a r a t i o n of _13. A mixture of 148.8 g (0.60 mole) sodium t h i o s u l f a t e penta-hydrate, 96.6 g (0.60 mole) p_-chlorobenzy 1 c h l o r i d e (Eastman, p r a c ) , 70 ml methanol and 70 ml d i s t i l l e d water was heated at r e f l u x f o r 30 min. During t h i s time a homogeneous system was momentarily obtained, which rap-i d l y gave r i s e to a copious white p r e c i p i t a t e . Upon c o o l i n g to room tem-perature, 900 ml of g l a c i a l a c e t i c a c i d was added and then the mixture was cooled to 5° and c h l o r i n a t e d . When the suspension became pale green, the c h l o r i n a t i o n was stopped and the contents of the f l a s k were d i l u t e d w i t h 1200 ml of c o l d , d i s t i l l e d water. The s o l i d was c o l l e c t e d by s u c t i o n f i l -t r a t i o n and washed w i t h water. A f t e r d r y i n g , the white m a t e r i a l weighed 120.4 g (897 0), mp 89-91°. C r y s t a l l i z a t i o n from hexane - benzene gave 129 as white needles, mp 92-93° ( l i t . (69) 93-94°). The i r spectrum (KBr) was i d e n t i c a l to that of the crude m a t e r i a l and showed the p a t t e r n c h a r a c t e r -i s t i c of a p a r a - s u b s t i t u t e d phenyl group i n the r e g i o n between 2000 and 1650 cm"'. Strong sulfone bands appeared at 1350 and 1140 cm"'. 4. Synthesis of p-Nitrophenylmethanesulfony1 Bromide (130). In the manner des c r i b e d f o r the p r e p a r a t i o n of 13 and 129, 115.3 g (0.53 mole) of p_-nitrobenzyl bromide ( A l d r i c h ) , 227.0 g (0.92 mole) of sodium t h i o s u l f a t e pentahydrate, 229 ml of methanol and 229 ml of d i s t i l l e d water were heated at r e f l u x f o r 35 min to g i v e a homogeneous s o l u t i o n . A f t e r d i s t i l l i n g o f f approximately 220 ml of s o l v e n t , the remaining mate-r i a l was allowed to c o o l to room temperature and then 572 ml of g l a c i a l a c e t i c a c i d was added. The mixture was cooled to 5° and c h l o r i n a t e d i n a manner p r e v i o u s l y described (experiment 2 ) . During the c h l o r i n a t i o n , an orange-brown c o l o u r , presumably due to bromine, was n o t i c e a b l e around the c h l o r i n e i n l e t . When t h i s colour was no longer produced, the r e a c t i o n began to turn green. Work-up w i t h 3 1. of water y i e l d e d a pale y e l l o w , amorphous s o l i d , mp 102-108°, a f t e r d r y i n g i n a d e s i c c a t o r under vacuum. C r y s t a l l i z a t i o n from hexane - benzene gave 108.8 g (73%) of 130 as pale y e l l o w needles, mp 109-110° w i t h decomposition; i r (KBr) 3120, 3090, 3015, 2965 (C-H s t r e t c h i n g ) , 1528 ( n i t r o group), 1360 ( n i t r o group and s u l f o n e ) , 1163 cm"* ( s u l f o n e ) . When the s y n t h e s i s was c a r r i e d out using p_-nitrobenzy 1 c h l o r i d e , r a t h e r than the bromide, the c r y s t a l l i z e d product (p_-nitrophenylmethane-s u l f o n y l c h l o r i d e ) had a mp of 91-92° ( l i t . (124) 92-93°); i r (KBr) 3120, 3090, 3000, 2928, 2875 (C-H s t r e t c h i n g ) , 1525, 1358 ( n i t r o group), 1374, 1171 cm * ( s u l f o n e ) . C r y s t a l l i z a t i o n from hexane - CHC l 3 of the s a l t ( ( E t ) 3 N • HBr) i s o l a t e d from the treatment of 130 w i t h t r i e t h y l a m i n e , gave white needles, mp 247-249° ( l i t . (125) 248°, from CHC1 3). A pale y e l l o w p r e c i p i t a t e , c h a r a c t e r i s t i c of bromide s a l t s , was obtained when an aqueous s o l u t i o n of t h i s s a l t was tr e a t e d w i t h 5% AgNC>3 s o l u t i o n . 5. Synthesis of c i s - and trans-2,4-Diphenyl-3-dimethylaminothietane 1,1- d i o x i d e (126a and b) . trans-2,4-Dipheny1-3-dimethylaminothietane 1,1-dioxide (126b) i s a known compound (15,55). The cis-isomer 126a was subsequently i s o -l a t e d (14). The procedure described below was adopted from reference 55. A dry, 250 ml three-necked f l a s k was f i t t e d w i t h a mechanical s t i r r e r , a dropping f u n n e l , a gas i n l e t and a d r y i n g tube. The gas i n -l e t was connected to a source of dry n i t r o g e n i n order to provide an an-114 hydrous atmosphere throughout the r e a c t i o n . To the f l a s k was added 100 ml of sodium-dried d i e t h y l ether followed by 10.00 g (0.0679 mole) of f r e s h l y d i s t i l l e d $-dimethylaminostyrene (131) and 6.87 g (0.0679 mole) of dry t r i e t h y l a m i n e . The pale y e l l o w s o l u t i o n was s t i r r e d and cooled i n an ice-water bath. Phenylmethanesulfony1 c h l o r i d e (13) , 12.95 g (0.0679 mole), d i s s o l v e d i n 63 ml of dry THF was d i l u t e d w i t h 63 ml of dry d i e t h y l ether and added dropwise over a p e r i o d of 1 hour w i t h e f f i c i e n t s t i r r i n g . A white p r e c i p i t a t e ( ( E t ) 3 N • HCl) appeared immediately. A f t e r the a d d i -t i o n of 1_3 was complete, the r e a c t i o n was s t i r r e d f o r 15 hours at i c e -water temperature. The s o l v e n t was then removed by evaporation under vac-uum to give a pale y e l l o w s o l i d . A lukewarm water bath was used to a i d the evaporation. The s o l i d was d i s s o l v e d i n 100 ml of CHC1 3 and e x t r a c t e d w i t h two 200 ml p o r t i o n s and one 100 ml p o r t i o n of d i s t i l l e d water to r e -move the (Et)3N • HCl. A f t e r d r y i n g over anhydrous Na2S0^, the y e l l o w CHCl s o l u t i o n was evaporated under reduced pressure to give 19.80 g (96.7%) of y e l l o w s o l i d . A n a l y s i s by nmr (CDCl^) i n d i c a t e d that 967o (19 g) of t h i s s o l i d was accounted f o r by three isomers. Of the 19 g, 8270 was trans-2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide (126b), 15% was the c i s - i s o m e r 126a and approximately 3% was benzyl 1-pheny1-2-dimethylaminoetheny1 s u l -fone (132) (see experiment 6). F r a c t i o n a l c r y s t a l l i z a t i o n of the crude product from hexane - methyl e t h y l ketone gave 126b as w h i t e , f l u f f y nee-d l e s . A f t e r two r e c r y s t a l l i z a t i o n s the mp was 114.5-115.5° w i t h decompo-s i t i o n ( l i t . (15) 109°, from hexane - e t h a n o l ) ; the i r spectrum (KBr) showed abs o r p t i o n bands i n the C-H s t r e t c h i n g r e g i o n that were i n d i c a t i v e of the N-CH3 group. Strong s u l f o n e bands appeared at 1320 and 1160 cm '. Other strong bands were seen at 1460 and 695 cm"'. A medium i n t e n s i t y a b s o r p t i o n which could be used to d i f f e r e n t i a t e between 126a and 126b 115 occurred at 760 cm *. The nmr spectrum (CDCl^) agreed w i t h that already r e p o r t e d (15): 5 7.68-7.22 (m, 10, phenyl p r o t o n s ) , 5.43 ( t ( d i f f u s e ) , 2, protons at C-2 and C-4), 3.68 ( t , 1, J = 9 Hz, proton at C-3) and 1.93 ( s , 6, N-methyl p r o t o n s ) . The t r i p l e t a t S 5 . 4 3 was r e s o l v e d by 100 MHz nmr as two 1 proton d o u b l e t s , one centred at 5 5.304 ( J = 9.4 Hz) and the other at 5.494 ( J ^ 9.4 Hz); the proton at C-3 appeared as a sharp t r i p -l e t , J = 9.4 Hz. Each peak of the two doublets was s p l i t , i n d i c a t i n g transannular c o u p l i n g between the C-2 and C-4 protons w i t h J approximately 1 Hz. Repeating the r e a c t i o n w i t h dry CH-jCN as the r e a c t i o n s o l v e n t gave 20.19 g (98.6%) of crude product. A n a l y s i s by nmr (CDCl-j) showed that 997o (20 g) of the crude m a t e r i a l was accounted f o r by the three i s o -mers, 126a, 126b and 132. Of t h i s , 60% was the trans-isomer 126b, 35% was 126a and approximately 5% was 132, the a c y c l i c isomer. The c i s - i s o m e r 126a was i s o l a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n from hexane - ethanol 100. Three r e c r y s t a l l i z a t i o n s from hexane - methyl e t h y l ketone gave transp a r -ent p l a t e s , mp 137.0-138.0° w i t h decomposition. The i r spectrum (KBr) was s i m i l a r i n o v e r a l l appearance to that of 126b. Strong bands were present at 1320, 1133 and 692 cm *. However, u n l i k e that of 126b, there was no a b s o r p t i on band at 760 cm ^"j nmr (CDCl^) S 7-70~7.23 (m, 10> phenyl pro~ t o n s ) , 5.28 (d, 2, J = 9 Hz, protons at C-2 and C-4), 3.68 ( t , 1, J = 9 Hz, proton at C-3) and 2.10 ( s , 6, N-methyl p r o t o n s ) . A n a l . C a l c d . f o r C 1 7 H 1 9 N 0 2 S : C, 67.74; H, 6.35; N, 4.65; mol. wt., 301.41. Found: C, 67.91; H, 6.46; N, 4.64. When the r e a c t i o n was repeated using dry CHCl-j (ethanol s t a b i l -i z e r removed by treatment w i t h cone. H^SO^) as the r e a c t i o n s o l v e n t , es-s e n t i a l l y a l l of the crude product was accounted f o r by the isomers, 126a, 116 126b and 132, according to the nmr spectrum. From the spectrum, 747, of the product was determined to be 126b, 197, 126a and 77, 132. 6. Benzyl 1-Pheny1-2-dimethylaminoetheny1 Sulfone (132). As mentioned i n experiment 5, the crude product from the c y c l o -a d d i t i o n r e a c t i o n c a r r i e d out i n CH^CN was c r y s t a l l i z e d from hexane -ethanol 100. C o o l i n g the mother l i q u o r from t h i s c r y s t a l l i z a t i o n i n a dry i c e box caused an o f f - w h i t e s o l i d to p r e c i p i t a t e . The i r spectrum of the s o l i d i n d i c a t e d that i t was a mixture of 126a and 132. Upon evaporation of the f i l t r a t e under vacuum, a v i s c o u s , brown o i l was obtained. The o i l was heated w i t h hexane on a steam bath and d i s s o l v e d w i t h a minimum amount of ethanol 100. C o o l i n g the s o l u t i o n i n a r e f r i g e r a t o r overnight gave c o l o u r l e s s c r y s t a l s . A f t e r c o l l e c t i n g the c r y s t a l s , the f i l t r a t e was evaporated and the r e s u l t i n g o i l was allowed to s i t f o r two weeks. During t h i s time c r y s t a l s appeared i n the o i l . The i r s p e c t r a of the two batches of c r y s t a l s (1 g, 57») showed that they were both benzyl 1-pheny 1-2-dimeth-ylaminoetheny 1 s u l f o n e (132). C r y s t a l l i z a t i o n from hexane - methyl e t h y l ketone gave transparent p l a t e s , mp 130-131°; i r (KBr) 1630 (enamine), 1276, t 1125 cm"1 ( s u l f o n e ) ; nmr (CDCl.j)S7.41 (d, 10, phenyl p r o t o n s ) , 7.00 ( s , 1, v i n y l i c p r o t o n ) , 4.05 ( s , 2, b e n z y l i c protons) and 2.60 ( s , 6, N-methyl p r o t o n s ) ; uv max (CH3CN) 253 nm (£ 15,800). A n a l . C a l c d . f o r C 1 7 H 1 9 N 0 2 S : C, 67.74; H, 6.35; N, 4.65; mol. wt., 301.41. Found: C, 67.78; H, 6.34; N, 4.76. Attempts to reduce the double bond of 132 by treatment w i t h f o r -mic a c i d (126) or by hydrogenation over 107, p a l l a d i u m on c h a r c o a l i n THF s o l u t i o n (35) were u n s u c c e s s f u l . 117 7. Decomposition of c i s - and trans-2,4-Dipheny1-3-dimethylaminothietane  1,1-dioxide (126a and b) under R e c r y s t a l l i z a t i o n C o n d i t i o n s Nmr a n a l y s i s of a mixture of crude products from s e v e r a l c y c l o -a d d i t i o n r e a c t i o n s i n d i c a t e d that i t was 917, pure i n the three isomers, 126a, 126b and 132. Of t h i s 91%, 55% was 126b, 40% 126a and 5% 132. C r y s t a l l i z a t i o n of 60 g of the m a t e r i a l from hexane - ethanol 100 gave 21 g (357o) of white c r y s t a l s , mp 124-138° w i t h decomposition. The i r spec-trum revealed a mixture of 126a and b. From the nmr spectrum ( C D C I 3 ) the composition was found to be 84%, 126a and 16% 126b w i t h no observable im-p u r i t y present. Upon c o o l i n g the mother l i q u o r i n a r e f r i g e r a t o r over-n i g h t , 3.4 g (6%,) of white s o l i d p r e c i p i t a t e d . The s o l i d was found to be a mixture of 126a and 132 by i r a n a l y s i s . Evaporation of the f i l t r a t e under vacuum gave a l i g h t brown, v i s c o u s o i l w i t h a c h a r a c t e r i s t i c , un-pleasant odor. The nmr spectrum ( C D C I 3 ) of the o i l r e v e a l e d a complex mixture of compounds. By comparison w i t h the nmr s p e c t r a of a u t h e n t i c samples, f i v e of the components were i d e n t i f i e d as (3-dimethylaminostyrene (131), benzyl 1-pheny1-2-dimethylaminoethenyl s u l f o n e (132), c i s - and trans-2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide (126a and b) and e t h y l phenylmethanesulfonate (138). The f i v e compounds accounted f o r ap-proximately 757» of the t o t a l m a t e r i a l i n the o i l . Of t h i s 75%,, 26% was 131, 17% 13_2, 13% 126a, 7% 126b and 37% 138. Thus, a t o t a l of 95% of 126a i n the 60 g of crude product s u r v i v e d the c r y s t a l l i z a t i o n from hexane -ethanol 100 (does not i n c l u d e the cis - i s o m e r that was forced out of the o r i g i n a l mother l i q u o r by c o o l i n g i n a r e f r i g e r a t o r ) . However, only a t o t a l of 18% of 126b remained a f t e r the c r y s t a l l i z a t i o n . The amount of 132 appeared to increase from 3 g i n the crude product to approximately 4.6 g i n the o i l from the mother l i q u o r . (As w e l l , there was an undeter-118 mined amount of 132 i n the p r e c i p i t a t e r e f e r r e d to above.) Upon s i t t i n g f o r one week at room temperature, the o i l thickened and took on a c r y s t a l -l i n e appearance. This m a t e r i a l was d i s s o l v e d i n 100 ml of CHCl^ and ex-t r a c t e d w i t h a 100 ml and a 50 ml p o r t i o n of d i s t i l l e d water. Evaporation of the pooled aqueous e x t r a c t s under vacuum gave a v i s c o u s y e l l o w o i l which c r y s t a l l i z e d on s i t t i n g . Three c r y s t a l l i z a t i o n s from acetone gave 2 g of white needles, mp 116-118°. The i r spectrum (KBr) of the c r y s t a l l i z e d m a t e r i a l was superimposable w i t h that of dimethy1ammonium phenylmethane-s u l f o n a t e (137) . A mixture m e l t i n g p o i n t w i t h an aut h e n t i c sample of 137 was not depressed. Evaporation _in vacuo of the CHCl-j layer d r i e d over an-hydrous Na^SO^ afforded a v i s c o u s brown o i l . Upon a l l o w i n g the o i l to s i t f o r a week, a c r y s t a l l i n e s o l i d formed which was c o l l e c t e d and i d e n t i f i e d as b e n z y l 1-pheny1-2-dimethylaminoetheny1 s u l f o n e (132). 8. Decomposition of trans-2,4-Diphenyl-3-dimethylaminothietane 1,1-dioxide  (126b) i n Ethanol. In a 100 ml b o i l i n g f l a s k f i t t e d w i t h a r e f l u x condenser were placed 233 mg of pure trans-2,4-dipheny1-3-dimethylaminothietane 1,1-diox-ide (126b) and 50 ml of ethanol 100. A f t e r heating f o r s e v e r a l minutes a s o l u t i o n was obtained, which was heated at r e f l u x f o r 1 hour. Evapora-t i o n of the s o l v e n t under vacuum gave 276 mg of y e l l o w , mobile o i l which had an odor s i m i l a r to that of (3-dimethylaminostyrene (131) . In the i r spectrum (neat) of the o i l a strong band at 1640 cm * supported the pres-ence of 131. Strong bands appeared at 1350, 1170 and 920 cm"*, which i n -d i c a t e d the presence of a s u l f o n i c a c i d e s t e r . In the nmr spectrum (CDCl^) s i g n a l s a t t r i b u t a b l e to 131, cis-2,4-dipheny1-3-dimethylaminothietane 1, 1-dioxide (126a) and e t h y l phenylmethanesulfonate (138) were present. No 119 absorptions due to the s t a r t i n g m a t e r i a l 126b were observed. According to the nmr spectrum, the three compounds 131, 126a and 138 accounted f o r approximately 57% of the o i l . Of t h i s 57%, 28% was 131, 11% 126a and 61% 138. A major peak at 6*2.28 i n the spectrum was unassigned. The o i l was d i s s o l v e d i n 20 ml of CHCl^ and e x t r a c t e d q u a n t i t a t i v e l y w i t h three 20 ml po r t i o n s of d i s t i l l e d water. Evaporation of the pooled aqueous e x t r a c t s under hig h vacuum gave 102 mg of gummy s o l i d . The i r spectrum (neat) of t h i s m a t e r i a l was s i m i l a r but not i d e n t i c a l to that of dimethy1ammonium phenylmethanesulfonate (137) . A f t e r d r y i n g over anhydrous MgSO^, the OHCl^ la y e r was evaporated under reduced pressure to give a yellowish-orange o i l which no longer had the odor of 131. A strong band at 1640 cm ^ was ab-sent i n the i r spectrum ( n e a t ) . Strong bands occurred at 1350, 1170 and 920 cm L, i n d i c a t i n g that 138 was present. In the nmr spectrum (CDCI3), a doublet at 5 5.27 (2 protons) and a s i n g l e t at 5 2.10 (6 protons) i n d i c a t e d the presence of cis-2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide (126a). The presence of the s u l f o n a t e e s t e r 138 was evident from a s i n g l e t at 57.40 (5 p r o t o n s ) , a s i n g l e t at 4.33 (2 pr o t o n s ) , a quartet at 4.10 (2 protons) and a t r i p l e t at 1.27 (3 p r o t o n s ) . The two compounds accounted f o r approximately 51% of the o i l . Of t h i s 51%, 21% was 126a and 79% 138. A s o l u t i o n of 467 mg (0.00155 mole) of pure 126b i n 100 ml of ethanol 95 was r e f l u x e d f o r 12 hours. Evaporation of the sol v e n t under vacuum gave a v i s c o u s , pale y e l l o w o i l w i t h an aldehydic odor. The o i l was d i s s o l v e d i n 30 ml of CHC1 and e x t r a c t e d w i t h three 20 ml p o r t i o n s 3 v of d i s t i l l e d water. Upon evaporation of the pooled aqueous e x t r a c t s i n vacuo, 300 mg of white, gummy s o l i d was obtained. From the nmr spectrum (CDCI3), t h i s m a t e r i a l was determined to be 757. dimethy1ammonium phenyl-methanesulfonate (137) (225 mg, 0.00104 mole). A d d i t i o n of D-0 to the nmr 120 sample caused the d i f f u s e band a t S 8.35-7.72 (protons on N, 2) to d i s a p -pear and the t r i p l e t atS 2.25 (N-methyl protons, 6) to c o l l a p s e to a s i n -g l e t . On the b a s i s of the c a l c u l a t e d amount of 137, 677» of 126b was con-v e r t e d to the s a l t . The presence of £-dimethylaminostyrene (131) and e t h y l pheny1-methanesulfonate ( 138) as decomposition products of tr_ans-2,4-dipheny1-3-dimethy laminothietane 1,1-dioxide (126b) i n hot ethanol was confirmed by g l c . A sample of pure 126b, f r e s h l y d i s s o l v e d i n ethanol 95, was analyzed on the column described i n experiment 1 w i t h the i n j e c t i o n p o r t , oven, and d e t e c t o r at 280, 140 and 250°, r e s p e c t i v e l y , and the n i t r o g e n flow at 55 ml/min. Four peaks e x c l u d i n g that of the s o l v e n t were observed. The f i r s t peak, r e t e n t i o n time 1.4 min, corresponded to phenylacetaldehyde; the second, 4.4 min, to 131; and the t h i r d , 7.8 min, to 138. The f o u r t h peak, 10.9 min, was not i d e n t i f i e d . When a sample of dimethylammonium phenyl-methanesulfonate (137) d i s s o l v e d i n ethanol 95 was a p p l i e d to the column, no peak was observed. 9. Decomposition of cis-2,4-Diphenyl-3-dimethylaminothietane 1,1-dioxide  (126a) i n Ethanol. Pure cis-2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide (126a) (229 mg) was t r e a t e d i n the same manner as d e s c r i b e d i n experiment 8 f o r the 1 hour r e f l u x of 126b i n ethanol 100. Evaporation of the s o l v e n t i n  vacuo gave a pale yellow s o l i d . The i r spectrum (KBr) of the s o l i d was i d e n t i c a l to that of 126a except f o r weak bands at 1640, 1400 and 920 cm *. The nmr spectrum (CDCl-j) i n d i c a t e d that the s o l i d was 817o 126a. The most intense i m p u r i t y s i g n a l occurred atS 2.76, which suggested the presence of £ -dimethylaminostyrene (131) . Weak s i g n a l s a t t r i b u t a b l e to e t h y l 121 phenylmethanesulfonate (138) were a l s o present. 10. I s o m e r i z a t i o n of trans-2, 4-Diphenyl-3-dimethylaminothietane 1,1- d i o x i d e (126b). Crude product from a c y c l o a d d i t i o n r e a c t i o n run i n CHCl-j was used (experiment 5 ) . The nmr spectrum of t h i s m a t e r i a l i n d i c a t e d that i t was e s s e n t i a l l y pure i n the three isomers, 126a (197»), 126b (747o) and 132 (77o). In a 100 ml r e a c t i o n f l a s k f i t t e d w i t h a mechanical s t i r r e r and a d r y i n g tube were placed 3.01 g (0.010 mole) of crude product, 1.38 g (0.010 mole) of t r i e t h y l a m i n e HCl, 20 ml of dry CH3CN and 10 ml of dry CHC1.J. S t i r r i n g the mixture at room temperature gave a pale y e l l o w s o l u -t i o n to which 2 drops of dry t r i e t h y l a m i n e was added. The i s o m e r i z a t i o n was f o l l o w e d by removing samples at i n t e r v a l s and observing the change i n the i n t e n s i t y of the band at 1630 cm 1 (enamine band of 132). Sodium c h l o r i d e c e l l s , 0.1 mm i n t h i c k n e s s , were used and samples were anlyzed d i r e c t l y ; 2:1 CH^CN - CHCl^ served as the r e f e r e n c e . A new tare l i n e was placed on the r e a c t i o n f l a s k a f t e r each sample was removed so that l o s s of s o l v e n t by evaporation could be adjusted f o r u s i n g 2:1 CH^CN - CHCl-j mixture. The greate s t increase i n i n t e n s i t y of the band at 1630 cm"' occurred d u r i n g the f i r s t day. A f t e r 3 days, the band i n t e n s i t y ceased to change. The s o l u t i o n was s t i r r e d f o r another day and then was evapo-r a t e d under vacuum to give a pale brown s e m i - s o l i d . This was d i s s o l v e d i n 20 ml of CHCl-j and e x t r a c t e d w i t h three 20 ml p o r t i o n s of d i s t i l l e d water. A f t e r d r y i n g over anhydrous N^SO^, the CHCl-j layer was evaporated i n vacuo to y i e l d 2.69 g (8970) of y e l l o w s o l i d . Approximately 0.1 g (37*) of the s t a r t i n g m a t e r i a l was l o s t as a r e s u l t of the sampling procedure. 122 From the nmr spectrum ( C D C I 3 ) , 92% of the m a t e r i a l was c a l c u l a t e d to con-s i s t of the three isomers and of the 92%, 64% was 126a, 8% 126b and 28% 132• Evaporation of the pooled aqueous e x t r a c t s under vacuum gave a y e l -low s e m i - s o l i d . Upon washing w i t h a small amount of acetone, 1.21 g (88%) of white needles separated. I n f r a r e d a n a l y s i s showed t h i s m a t e r i a l to be t r i e t h y l a m i n e HCl. Again, approximately 0.05 g (3%) had been l o s t due to sampling. Evaporation of the acetone washings gave 0.24 g of v i s c o u s y e l -low l i q u i d . The i r spectrum (neat) i n d i c a t e d a mixture of t r i e t h y l a m i n e HCl and a s u l f o n i c a c i d d e r i v a t i v e ( s t r o n g bands at 1200 and 1050 cm L ) . 11. P r e l i m i n a r y Examination of the E f f e c t s of Water, A d d i t i o n Time and Reaction Temperature on the Synthesis of c i s - and trans-2,4-Diphenyl- 3-dimethylaminothietane 1,1-dioxide (126a and b) . Under the c o n d i t i o n s d e s c r i b e d i n experiment 5, 6.48 g (0.0340 mole) of phenylmethanesulfonyl c h l o r i d e (13) d i s s o l v e d i n 42.5 ml of dry C H 3 C N was added to a s o l u t i o n of 5.00 g (0.0340 mole) of p-dimethylamino-styrene (131) and 3.44 g (0.0340 mole) of dry t r i e t h y l a m i n e i n 34 ml of CH^CN over a period of 15 min. Just before the a d d i t i o n of 1_3 was s t a r t e d , 0.5 ml (0.03 mole) of d i s t i l l e d water was added to the enamine s o l u t i o n . Upon work-up, 9.29 g (90.77») of crude, s o l i d product was obtained. The i r spectrum (KBr) of t h i s m a t e r i a l i n d i c a t e d a mixture of c i s - and tr a n s -2,4-dipheny1-3-dimethylaminothietane 1,1-dioxide (126a and b) and benzyl 1-pheny1-2-dimethylaminoetheny1 s u l f o n e (132) . From the nmr spectrum ( C D C I 3 ) , 847, of the product was c a l c u l a t e d to c o n s i s t of 126a, 126b and 132. Of the 84%, 36% was 126a, 47% 126b and 17% 132. When the r e a c t i o n was repeated u s i n g 2.0 ml of water, the nmr spectrum of the i s o l a t e d prod-uct i n d i c a t e d that 797» was accounted f o r by the three isomers. Of the 123 79%, 42% was 126a, 34% 126b and 24% 132. Phenylmethanesulfony1 c h l o r i d e (13), 6.48 g (0.0340 mole), i n 42.5 ml of dry CH^CN was reacted w i t h a s o l u t i o n of 5.00 g (0.0340 mole) of J J l . and 3.44 g (0.0340 mole) of t r iethylamine i n 34 ml of dry CH3CN under the c o n d i t i o n s described i n experiment 5, except that the s o l u t i o n of 1_3 was poured d i r e c t l y i n t o the enamine s o l u t i o n . A f t e r s t i r r i n g f o r 1 h r , the r e a c t i o n was worked up to give 8.83 g (867») of pale y e l l o w s o l i d . From the nmr spectrum, the crude product was c a l c u l a t e d to be 99% pure i n the three isomers. Of t h i s 99%, 36% was 126a, 57% 126b and 7% 132. Phenylmethanesulfony1 c h l o r i d e (13), 3.24 g (0.0170 mole), i n 21 ml of dry CH-jCN was reacted w i t h a s o l u t i o n of 2.50 g (0.0170 mole) of 131 and 1.72 g (0.0170 mole) of t r iethylamine i n 17 ml of dry CH-jCN under the c o n d i t i o n s described i n experiment 5, except that the r e a c t i o n was run at room temperature and the s o l u t i o n of 13 was poured d i r e c t l y i n t o the enamine s o l u t i o n . The temperature i n the f l a s k rose r a p i d l y from 26 to 41°. A f t e r 15 min, the temperature had returned to 26° and the r e a c t i o n was worked up to give 4.60 g (907o) of pale y e l l o w s o l i d . The nmr spectrum of the crude product i n d i c a t e d that i t was 95% pure i n the three isomers. Of t h i s 95%, 32% was 126a, 65% 126b and 3% 132. 12. Synthesis of Dimethy1ammonium Phenylmethanesulfonate (137). In a 250 ml b o i l i n g f l a s k f i t t e d w i t h a r e f l u x condenser were placed 2.0 g (0.011 mole) of phenylmethanesulfony1 c h l o r i d e (13) and 150 ml of d i s t i l l e d water. A f t e r r e f l u x i n g f o r about 10 min, a homogeneous s o l u t i o n was obtained. The s o l u t i o n was r e f l u x e d f o r another 20 min and then was allowed to c o o l to room temperature. Evaporation of the water under reduced pressure gave a v i s c o u s , pale y e l l o w o i l . The i r spectrum 124 (neat) showed strong bands at 1205 and 1055 cm - 1, which were i n d i c a t i v e of a s u l f o n i c a c i d . The o i l was d i s s o l v e d i n 30 ml of d i s t i l l e d water and dimethylamine gas was bubbled i n t o the s o l u t i o n f or about 30 sec. Evapo-r a t i o n in vacuo gave a v i s c o u s , pale y e l l o w o i l which s o l i d i f i e d when washed w i t h acetone. Three c r y s t a l l i z a t i o n s from hexane - acetone gave 1.2 g (50%) of 1_37 as transparent, f l a t needles, mp 116-118°; i r (KBr) 3180 - 2820, 2475 (ammonium band), 1210, 1052 cm"1 ( s u l f o n i c a c i d ) ; nmr (CDC1 3) & 8.37-7.72 (broad peak, 2, protons on N), 7.52-7.20 (m, 5, phenyl p r o t o n s ) , 4.05 ( s , 2, b e n z y l i c protons) and 2.26 ( t , 6, J = 5.5. Hz, N-methyl p r o t o n s ) . In the nmr spectrum, the peak i n t e n s i t i e s of the t r i p -l e t were i n the r a t i o of 1:2:1. A f t e r adding D2O, the broad peak at 68.37-7.72 disappeared and the t r i p l e t atS 2.26 c o l l a p s e d to a s i n g l e t . A n a l . C a l c d . f o r C 9H 1 5N0 3S: C, 49.75; H, 6.96; N, 6.45; mol'.wt., 217.28. Found: C, 49.68; H, 7.38; N, 6.39. 13. Synthesis of E t h y l Phenylmethanesulfonate (138). In a dry 250 ml three-necked f l a s k f i t t e d w i t h a dropping f u n n e l and a r e f l u x condenser and pr o t e c t e d from atmospheric moisture by a d r y i n g tube were placed 100 ml of ethanol 100 and 5.06 g (0.050 mole) of dry t r i -ethylamine. The s o l u t i o n was heated to r e f l u x and 9.53 g (0.050 mole) of phenylmethanesulfony1 c h l o r i d e (13) d i s s o l v e d i n 30 ml of dry CH^CN was added dropwise over a p e r i o d of 1 hour. A f t e r the a d d i t i o n of 1_3 was com-p l e t e , the r e a c t i o n was r e f l u x e d for another 2 hrs and allowed to c o o l to room temperature. Evaporation of the solvent under vacuum gave a y e l l o w o i l c o n t a i n i n g white c r y s t a l l i n e masses. The mixture was d i s s o l v e d i n 50 ml of CHC1 3 and e x t r a c t e d w i t h three 50 ml p o r t i o n s of d i s t i l l e d water. The CHCl-j l a y e r was d r i e d over anhydrous MgSO^ and evaporated in vacuo to 125 g i v e 4.29 g (50%) of pale y e l l o w , mobile o i l . The o i l was d i s t i l l e d twice u s i n g a s h o r t - p a t h vacuum d i s t i l l a t i o n apparatus to give e t h y l phenylmeth-anesulfonate (138), bp 87° at 0.02 mm; i r (neat) 3070, 3040, 2989, 2940 (C-H s t r e t c h i n g ) , 1350, 1170, 920 ( s u l f o n i c a c i d e s t e r ) , 1605, 1500, 1457, 695 cm" 1 (phenyl); nmr (CDCI3), S7.34 ( s , 5, phenyl p r o t o n s ) , 4.32 ( s , 2, b e n z y l i c p r o t o n s ) , 4.11 (q, 2, J = 7 Hz, methylene protons) and 1.25 ( t , 3, J = 7 Hz, methyl protons.). A n a l . C a l c d . f o r C 9 H 1 2 0 3 S : C, 53.98; H, 6.04; S, 16.01; mol. wt., 200.26. Found: C, 53.88; H, 6.15; S, 16.16. Approximately 1 g of 138 was heated on a steam bath w i t h 50 ml of 4 N HCl f o r 2 hours to o b t a i n a homogeneous s o l u t i o n . The s o l u t i o n was evaporated under hig h vacuum to give a c o l o u r l e s s s e m i - s o l i d . This mate-r i a l was d i s s o l v e d i n 10 ml of d i s t i l l e d water and t r e a t e d w i t h dimethyla-mine gas. Evaporation of the s o l u t i o n in vacuo y i e l d e d an o i l which so-l i d i f i e d upon sta n d i n g . C r y s t a l l i z a t i o n from hexane - acetone gave t r a n s -parent needles, mp 116-117.5°. The i r spectrum (KBr) was superimposable w i t h that of dimethy1ammonium phenylmethanesulfonate (137) . A mixture m e l t i n g p o i n t w i t h an a u t h e n t i c sample of 137 was not depressed. 14. Synthesis of c i s - and trans-2-(4-Chlorophenyl)-3-dimethylamino-4- phenylthietane 1,1-dioxide (127a and b ) . A. A c e t o n i t r i l e as Reaction S o l v e n t . The procedure was iden-t i c a l to that described i n experiment 5, except f o r m o d i f i c a t i o n s i n the work-up. £-Chlorophenylmethanesulfony1 c h l o r i d e (129), 16.88 g (0.0750 mole), i n 141 ml of dry CH-jCN was reacted w i t h 11.04 g (0.0750 mole) of f r e s h l y d i s t i l l e d B -dimethylaminostyrene (131) and 7.59 g (0.0750 mole) of dry t r i e t h y lamine i n 112 ml of dry CH-jCN. Much white p r e c i p i t a t e 126 formed, which was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h a s m a l l amount of CH^CN and a i r d r i e d . Evaporation under reduced pressure of the combined pale y e l l o w f i l t r a t e and washings gave a y e l l o w s o l i d . The white p r e c i p i t a t e was m a g n e t i c a l l y s t i r r e d w i t h 200 ml of d i s t i l l e d water to d i s s o l v e the t r i e t h y l a m i n e HCl, s u c t i o n f i l t e r e d , and d r i e d i n a d e s i c c a t o r under vacuum to give 13.55 g (53.8%) of w h i t e , c r y s t a l l i n e powder (127b). . Attempts to c r y s t a l l i z e 127b were un s u c c e s s f u l because of e x t e n s i v e decomposition. The compound was not s o l u b l e to an extent of 10% i n CHCl-j, benzene or DMSO at room temperature. A sample of 127b was p u r i f i e d by washing s e v e r a l times w i t h CHCl^. When placed i n a 150° bath, t h i s m a t e r i a l decomposed at 154° (heating r a t e was approximately 1° per min). The i r spectrum (KBr) showed bands i n the C-H s t r e t c h i n g r e g i o n at 3080, 3060, 3005, 2980, 2895, 2855 and 2805 cm"1. The l a t t e r two bands were more intense than the one at 2980 cm"*. Sulfone bands ap-peared at 1323 and 1164 cm \ A strong doublet occurred at 523 cm"*. The HCl s a l t of 127b was prepared by d i s s o l v i n g 1.0 g i n 100 ml of CHCl^ and t r e a t i n g the s o l u t i o n w i t h dry HCl gas. Removal of the s o l v e n t _in vacuo gave a white s o l i d , mp 130-131° w i t h decomposition. The s a l t decomposed when an attempt was made to c r y s t a l l i z e i t from acetone; i r (KBr) 2700 -2300 cm 1 (ammonium band); nmr (DMS0-d6) & 9.2-8.7 (band, 1, proton on N), 8.07-7.80 (m, 2, protons ortho to C l ) , 7.80-7.26 (m, 7, remaining aromatic p r o t o n s ) , 6.69 (d, 1, J = 10 Hz, b e n z y l i c p r o t o n ) , 6.15 (d, 1, J = 10 Hz, p_-chlorobenzylic p r o t o n ) , 4.93 ( t , 1, J = 10 Hz, proton at C-3), and 2.39 ( s , 6, N-methyl p r o t o n s ) . Isomer 127b was submitted f o r a n a l y s i s as the CHCl^-washed, crude product. A n a l . C a l c d . f o r C 1 7H 1 8C1N0 2S: C, 60.80; H, 5.40; N, 4.17; mol. wt., 335.85. Found: C, 60.63; H, 5.20; N, 4.18. 127 The y e l l o w s o l i d obtained from the work-up of the c y c l i z a t i o n r e a c t i o n was d i s s o l v e d i n 100 ml of CHCl^ and e x t r a c t e d w i t h four 50 ml p o r t i o n s of d i s t i l l e d water. Evaporation of the pooled aqueous e x t r a c t s f o l l o w e d by d r y i n g of the r e s i d u e i n a d e s i c c a t o r under vacuum gave 9.78 g (957o) of s o l i d , the i r spectrum of which was superimposable w i t h that of t r i ethylamine h y d r o c h l o r i d e . The CHCl-j l a y e r was d r i e d over anhydrous Na2S0^ and then evaporated under vacuum to give 11.27 g (44.77o) of y e l l o w s o l i d (127a). A weak band at 1625 cm 1 i n the i r spectrum (KBr) of the crude m a t e r i a l i n d i c a t e d that some a c y c l i c isomer may a l s o have been pres-ent (approximately 57o) . C r y s t a l l i z a t i o n from hexane - ethanol 100 gave 127a as white needles, mp 145-146° w i t h decomposition. The i r spectrum (KBr) of 127a was q u i t e s i m i l a r to that of 127b. In the C-H s t r e t c h i n g r e g i o n the band p o s i t i o n s were i d e n t i c a l ; however, the a b s o r p t i o n at 2980 cm - 1 was more intense than that at 2855 and 2805 cm - 1. The band due to asymmetrical s t r e t c h i n g of the s u l f o n y l moiety was 10 cm 1 higher than that of 127b. A s i n g l e sharp band appeared at 510 cm \ r a t h e r than the doublet seen at 523 cm 1 f o r 127b; nmr ( C D C l ^ S 7.63-7.26 (m, 9, aromatic p r o t o n s ) , 5.25 (d, 1, J = 9 Hz, b e n z y l i c p r o t o n ) , 5.22 (d, 1, J = 9 Hz, p_-chlorobenzylie p r o t o n ) , 3.57 ( t , 1, J = 9 Hz, proton at C-3), and 2.08 ( s , 6, N-methyl p r o t o n s ) . A n a l . C a l c d . f o r C,_H,QC1N0_S: C, 60.80; H, 5.40; N, 4.17; mol. wt., 335.85. Found: C, 60.88; H, 5.34; N, 4.20. Treatment of an anhydrous d i e t h y l ether s o l u t i o n of pure 127a w i t h dry HCl gas gave a white s o l i d , mp 166-167° w i t h decomposition; i r (KBr) 2700 - 2200 cm"1 (ammonium band); nmr (DMS0-d6) S 7.87-7.33 (m, 9, aromatic p r o t o n s ) , 6.47 (d (broad), 2, J = 9 Hz, protons at C-2 and C-3), 5.27 ( t , 1, J = 9 Hz, proton at C-3), and 2.66 ( s , 6, N-methyl p r o t o n s ) . 128 In a modified procedure, 45.00 g (0.20 mole) of 129 d i s s o l v e d i n 392 ml of dry CH-jCN was added to a cooled s o l u t i o n of 29.45 g (0.20 mole) of 131 and 20.24 g (0.20 mole) of t r iethylamine i n 270 ml of CH-jCN over a per i o d of 23 min w i t h vigorous s t i r r i n g . The r e a c t i o n was exother-mic and caused the temperature of the r e a c t i o n mixture to r i s e from 0 to 8°. Three hours f o l l o w i n g a d d i t i o n of the s u l f o n y l c h l o r i d e , the r e a c t i o n was worked up to give 37.68 g (56%) of 127b and 27.74 g (41%) of crude 127a. In the i r spectrum (KBr) of the l a t t e r , a weak band appeared at 1625 cm * due to the presence of a c y c l i c m a t e r i a l . The nmr spectrum (CDCl^) of the crude 127a f r a c t i o n showed s i n g l e t s a t $ 2.60, 2.08 and 1.91, which were a t t r i b u t e d to the a c y c l i c isomer, 127a and 127b, r e s p e c t i v e l y . These three components were c a l c u l a t e d to account f o r e s s e n t i a l l y a l l of the crude m a t e r i a l and of t h i s , 3% was the a c y c l i c isomer, 93% 127a and 3% 127b. Thus, of the t o t a l 65.42 g (97%) of product i s o l a t e d , 59% was 127b, 40% 127a and 17° a c y c l i c isomer. B. Chloroform as Reaction Solvent. Using a procedure s i m i l a r to that d e s c r i b e d f o r the r e a c t i o n run i n CrLjCN, 4.50 g (0.020 mole) of i 129 i n 38 ml of dry, e t h a n o l - f r e e CHCI3 was added to 2.94 g (0.020 mole) of j J l . and 2.02 g (0.020 mole) of t r i ethylamine i n 30 ml of C H C l ^ A f t e r s t i r r i n g f o r 8 hours, the r e a c t i o n was s u c t i o n f i l t e r e d to g i v e 3.79 g (56%) of 127b, which was i d e n t i f i e d by i t s i r spectrum. Evaporation of the pale y e l l o w f i l t r a t e in vacuo a f f o r d e d a s o l i d which was r e d i s s o l v e d i n 25 ml of CHCl^ and e x t r a c t e d w i t h four 10 ml p o r t i o n s of d i s t i l l e d water. A f t e r d r y i n g over anhydrous Na^SO^, the CHCl^ s o l u t i o n was evapo-r a t e d under reduced pressure to give a gummy, y e l l o w s o l i d . Washing w i t h anhydrous d i e t h y l ether gave a pale y e l l o w s o l i d (0.82 g, 12%), which was found to be a mixture of 127a and b by i r a n a l y s i s . In order to determine 129 the p r o p o r t i o n s of the two isomers, the mixture was t r e a t e d w i t h HCl gas to form the corresponding s a l t s as described above f o r 127b. From the i n t e g r a l s of the N-methyl proton s i g n a l s i n the nmr spectrum (DMSO-dg) the mixture was found to c o n s i s t of 65% (0.53 g) 127b and 35% (0.29 g) 127a. Evaporation of the f i l t r a t e pooled w i t h the ether washings y i e l d e d another gummy s o l i d from which 0.30 g (4%) of 127a was i s o l a t e d by washing w i t h anhydrous ether. The nmr spectrum (CDCl^) of the yel l o w v i s c o u s o i l (1.47 g) obtained by evaporating the ether washings showed the presence of two major components, one being 127a and the other, presumably, one of the p o s s i b l e £-chloro-substituted analogues of be n z y l 1-pheny1-2-dimethyl-aminoethenyl sulfone (132). The spectrum of the a c y c l i c isomer c o n s i s t e d of a doublet at 57.31 (aromatic protons) and s i n g l e t s at 66.98 ( v i n y l i c proton, 1), 3.97 ( b e n z y l i c protons, 2 ) , and 2.60 (N-methyl protons, 6 ) . The i n t e g r a l f o r the 9 aromatic protons was greater than expected on the b a s i s of the i n t e g r a l f o r the N-methyl protons because of other minor com-ponents i n the o i l absorbing i n the same r e g i o n . Cycloadduct 127a and the a c y c l i c isomer were c a l c u l a t e d to account f o r 837» (1.22 g) of the o i l . Of t h i s 83%, 50% (0.'61 g) was 127a and 50% (0.61 g) was the a c y c l i c mate-r i a l . Thus, 91% of the t h e o r e t i c a l y i e l d of product was accounted f o r by 127a, 127b and the a c y c l i c m a t e r i a l . Of t h i s 91%, 20% was 127a, 70% 127b and 107o the a c y c l i c adduct. This l a t t e r substance was not i s o l a t e d or f u r t h e r c h a r a c t e r i z e d . 15. Synthesis of 2-(4-Nitropheny1)-3-dimethylamino-4-phenylthietane 1,1- d i o x i d e (128). The procedure described i n experiment 5 was used w i t h s e v e r a l m o d i f i c a t i o n s . £-Nitrophenylmethanesulfony1 bromide (130), 21.4 g (0.076 1 3 0 mole), was mixed w i t h 2 5 0 ml of dry, e t h a n o l - f r e e CHCl^ i n a stoppered c o n i c a l f l a s k u n t i l most of the s o l i d had d i s s o l v e d . The s l u r r y was then t r a n s f e r r e d to a dropping funnel w i t h the a i d of 5 0 ml of CHCl^ and added dropwise over a per i o d of 2 hrs to a cooled s o l u t i o n of 1 2 . 7 g ( 0 . 0 8 7 mole) of 1_31 and 8 . 8 g ( 0 . 0 8 7 mole) of dry t r i e t h y lamine i n 1 2 8 ml of C H C 1 3 . The r e a c t i o n mixture r a p i d l y turned b r i g h t orange. When the a d d i t i o n of 1 3 0 was complete, the s o l u t i o n was s t i r r e d f o r another 3 hours and was then reduced to approximately 1 0 0 ml i n volume by evaporation _in vacuo. A lukewarm water bath was used to a i d the evaporation. The reddish-orange s o l u t i o n that remained was e x t r a c t e d w i t h one 2 0 0 ml p o r t i o n and two 1 0 0 ml p o r t i o n s of d i s t i l l e d water, d r i e d over anhydrous Na2S0^, and evaporated under reduced pressure to g i v e a r e d d i s h - b l a c k o i l . The o i l was d i s s o l v e d i n 3 0 ml of benzene and the r e s u l t i n g s o l u t i o n was d i l u t e d w i t h 4 5 0 ml of d i e t h y l ether to give a pale orange s o l u t i o n from which a cream-coloured, c r y s t a l l i n e s o l i d r a p i d l y p r e c i p i t a t e d . A f t e r s i t t i n g o v e r n i g h t , the s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n and washed w i t h ether. Upon d r y i n g , the m a t e r i a l weighed 2 1 . 2 g ( 8 0 . 6 % ) . Evaporation of the f i l t r a t e , pooled w i t h the ether washings, gave a re d d i s h - b l a c k o i l which y i e l d e d 1 . 7 g ( 6 . 5 7 o ) of greenish-yellow s o l i d when t r e a t e d w i t h ether. The i r s p e c t r a (KBr) of the two s o l i d s i n d i c a t e d that they were mixtures of the d e s i r e d c y c l i c product 1 2 8 and a c y c l i c m a t e r i a l 1 4 8 . From the nmr s p e c t r a (CDCl^), u s i n g the i n t e g r a l s of the N-methyl proton s i g n a l s as a b a s i s f o r c a l c u -l a t i o n , the composition of the f i r s t s o l i d was determined to be 8 9 7 « 1 2 8 and 1 1 7 » 1 4 8 and that of the second s o l i d , 3 6 % 1 2 8 and 6 1 % 1 4 8 . Thus, of the t o t a l y i e l d of 2 2 . 9 g ( 8 7 . 1 % ) of crude product, 8 5 % was 1 2 8 and 1 5 % 1 4 8 . C r y s t a l l i z a t i o n of the f i r s t s o l i d from hexane - methyl e t h y l ketone gave 1 2 8 as pale y e l l o w prisms, mp 1 3 0 - 1 3 1 ° w i t h decomposition; i r (KBr) 131 1524, 1354 (N02 group), 1336, 1324, 1160, 1138 cm"1 ( s u l f o n e ) ; nmr (CDCLj) 68.47-8.20 (m, 2, protons ortho to n i t r o group), 7.87-7.60 (m, 2, protons meta to n i t r o group), 7.60-7.33 (m, 5, phenyl p r o t o n s ) , 5.36 (d, 2, J = 9 Hz, protons at C-2 and C-4), 3.70 ( t , 1, J = 9 Hz, proton at C-3), and 2.14 ( s , 6, N-methyl p r o t o n s ) . R e c r y s t a l l i z a t i o n d i d not change the melt-i n g p o i n t and decomposition was apparent. A n a l . C a l c d . f o r C 1 7H 1 8N 2 0 4S: C, 58.95; H, 5.24; N, 8.09; mol. wt., 346.40. Found; C, 60.14; H, 5.12; N, 7.99. Although the a n a l y s i s was i n c o n c l u s i v e f o r carbon, the a n a l y s i s f o r the t h i e t e 1 , 1-dioxide analogue d e r i v e d from 128 was s a t i s f a c t o r y (see exper iment 20). A 100 mg sample of c r y s t a l l i z e d 128 was d i s s o l v e d i n 5 ml of CH^CN at room temperature. A f t e r s i t t i n g f o r 2 hours the s o l u t i o n had turned a b r i g h t orange. Evaporation in vacuo of a p o r t i o n of the s o l u t i o n a f t e r 22 hours gave an orange s o l i d . From the i r spectrum (KBr) of t h i s m a t e r i a l i t was apparent that a f a i r amount of 128 had rearranged to the a c y c l i c isomer 148. A f t e r 43 hours, the remainder of the s o l u t i o n was evaporated under reduced pressure to gi v e an orange o i l . Nmr a n a l y s i s (CDCl-j) i n d i c a t e d that 877o of the o i l was accounted f o r by the isomers 128 and 148. Of the 877„, 247o was s t a r t i n g m a t e r i a l (128) and 767o was the a c y c l i c isomer 148. 16. Benzyl l - ( 4-Nitrophenyl ) - 2-dimethylaminoethenyl Sulfone (148). C r y s t a l l i z a t i o n of the second s o l i d i s o l a t e d i n experiment 15 from hexane - ethanol gave 148 as y e l l o w , granular c r y s t a l s . Upon r e c r y s -t a l l i z a t i o n from n-butanol, b r i g h t y e l l o w , f l a t needles were obtained, mp 1 6 5 . 5 - 1 6 6 . 5 ° ; i r (KBr) 1625 (enamine), 1530, 1355 ( n i t r o group), 1297, 1135, 132 1115 cm - 1 ( s u l f o n e ) ; nmr (CDCl-j) S 8 .30-8 .03 (m, 2, protons ortho to n i t r o group), 7.60-7.30 (m, 7, protons meta to n i t r o group and phenyl p r o t o n s ) , 7.11 ( s , 1, v i n y l i c p r o t o n ) , 4.13 ( s , 2, b e n z y l i c p r o t o n s ) , and 2.67 ( s , 6, N-methyl p r o t o n s ) ; uv max (CH^CN) 250 (€ 18,700) and 271 nm (€ 19,700). A n a l . C a l c d . for C.^H l oN o0.S: C, 58.95; H, 5.24; N, 8.09; mol. wt., 1/ lo 2 4 346.40. Found: C, 58.99; H, 5.09; N, 8.22 17. Synthesis of 2,4-Diphenylthiete 1,1-dioxide (152). In a 100 ml r e a c t i o n f l a s k equipped w i t h a mechanical s t i r r e r and a dropping funnel were placed 14.5 g (0.048 mole) of c i s - 2 , 4 - d i p h e n y l -3-dimethylaminothietane 1,1-dioxide (126a) and 14.5 ml of g l a c i a l a c e t i c a c i d . The s t i r r e d mixture was cooled i n an ice-water bath and 43.5 ml of 407o p e r a c e t i c a c i d (FMC Corporation) was added dropwise over a pe r i o d of 45 min. When most of the p e r a c e t i c a c i d had been added, a pale y e l l o w so-l u t i o n was obtained. A f t e r s e v e r a l hours the s o l u t i o n became t r a n s l u c e n t and then p r o g r e s s i v e l y more opaque as the product (152) p r e c i p i t a t e d . The r e a c t i o n was run f o r 17 hours at i c e bath temperature. The contents of the f l a s k were t r a n s f e r r e d to a 1 l i t r e c o n i c a l f l a s k , cooled i n an i c e bath and then n e u t r a l i z e d w i t h a s a t u r a t e d , aqueous s o l u t i o n of Na2C0-j. The mixture was e x t r a c t e d w i t h 200, 100 and 50 ml p o r t i o n s of CHCl^. The pooled CHC1 3 e x t r a c t s were washed w i t h 370 ml of 107» HCl followed by 300 ml of d i s t i l l e d water. A f t e r d r y i n g over anhydrous MgSO^, the y e l l o w s o l u -t i o n was evaporated under vacuum w i t h the a i d of a lukewarm water bath to giv e 10.5 g (857,) of beige-coloured crude product. The i r and nmr sp e c t r a of t h i s m a t e r i a l were i d e n t i c a l to those of the c r y s t a l l i z e d product. C r y s t a l l i z a t i o n from hexane - benzene y i e l d e d 9.3 g (767,) of 152 as white, f l u f f y needles, mp 137-138° w i t h decomposition ( l i t . (50) 133-134°, from 133 CHC1 3); i r (KBr) 3082, 3050 (sh) (C-H s t r e t c h i n g ) , 1622 (double bond con-jugated w i t h phenyl group), 1303, 1150 cm 1 ( s u l f o n e ) ; uv max (CH^CN) 255 nm (6 19,600) ( l i t . (50) EtOH, 257 nm (£17,400)); nmr (CDCl ) 8 7.77-7.27 (m, 10, phenyl p r o t o n s ) , 7.03 (d, 1, J = 2 Hz, proton at C-3), and 5.92 (d, 1, J = 2 Hz, proton at C-4). R e c r y s t a l l i z a t i o n of 152 using ethanol r e s u l t e d i n decomposition and formation of trans-chalcone (165a) and b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) s u l f o n e (171) (experiment 21). 18. Synthesis of 2-(4-Chlorophenyl)-4-phenylthiete 1,1-dioxide (153a) and  2-Phe n y l - 4 - ( 4 - c h l o r o p h e n y l ) - t h i e t e 1,1-dioxide (153b). The procedure used was s i m i l a r to that d e s c r i b e d i n experiment 17. To a s t i r r e d mixture of 27.0 g (0.080 mole) of 127b and 27.0 ml o f g l a c i a l a c e t i c a c i d cooled i n an i c e bath was added 81.0 ml of 40% perace-t i c a c i d over a period of 30 min. A f t e r s t i r r i n g f o r 18 hours, the opaque, cream-coloured r e a c t i o n mixture was worked up to give a ye l l o w s o l i d . C r y s t a l l i z a t i o n from ethanol 95 gave 13.7 g (59%) of 153a as white needles, mp 128-129° w i t h decomposition; i r (KBr) 3095, 3080, 2970 (C-H s t r e t c h i n g ) , 1621 ( o l e f i n i c double bond conjugated w i t h aromatic group), 1302, 1160 cm ( s u l f o n e ) ; uv max (CH-jCN) 262 (£26,300) and 294 nm (sh) (£1,400); nmr (CDC1 3) S 7.67-7.25 (m, 9, aromatic p r o t o n s ) , 7.02 (d, 1, J = 2 Hz, proton at C-3) and 5.91 (d, 1, J = 2 Hz, b e n z y l i c p r oton). Anal • Ca l c d . f o r C ^ H ^ H ^ S : C, 61.96; H, 3.81; C l , 12.19; mol. wt., 290.77. Found: C, 61.93; H, 4.25; C l , 12.31. In the same manner, 35.4 g (0.105 mole) of 127a mixed w i t h 35 ml of g l a c i a l a c e t i c a c i d was reacted w i t h 106 ml of p e r a c e t i c a c i d . When approximately one-half of the p e r a c i d had been added, a pale y e l l o w s o l u -134 t i o n was obtained which p e r s i s t e d throughout the r e a c t i o n p e r i o d . A f t e r s t i r r i n g .for 18 hours, the r e a c t i o n was worked up to give a yel l o w s o l i d . C r y s t a l l i z a t i o n from ethanol 95 gave 13.2 g (43.2%) of white c r y s t a l s , mp 117-119°. I n f r a r e d a n a l y s i s of t h i s m a t e r i a l i n d i c a t e d the presence of 153a and another component (153b). Evaporation of the mother l i q u o r under reduced pressure and c r y s t a l l i z a t i o n of the r e s i d u e from ethanol 95 gave 4.1 g (13.4%) of white c r y s t a l s which appeared to be about a 50:50 mixture of 153a and 153b, according to the i r spectrum. Repeated r e c r y s t a l l i z a t i o n s of t h i s l a t t e r s o l i d from ethanol 95 e v e n t u a l l y gave pure 153b as w h i t e , shiny f l a k e s , mp 130-131° w i t h decomposition; i r (KBr) 3095, 3060, 2965 (C-H s t r e t c h i n g ) , 1622 ( o l e f i n i c double bond conjugated w i t h aromatic group), 1310, 1160 cm"1 ( s u l f o n e ) ; uv max (CH 3CN) 230 (£ 20,300), 256 (£22,600) and 290 nm (sh) (£800); nmr ( C D C I 3 ) <5 7.70-7.08 (m, 9, aromatic p r o t o n s ) , 6.98 (d, 1, J = 2 Hz, proton at C-3) and 5.85 (d, 1, J = 2 Hz, £-chlorobenzylie pro t o n ) . A n a l . C a l c d . f o r C ^ H j ^ C l C ^ S : C, 61.96; H, 3.81; C l , 12.19; mol. wt., 290.77. Found: C, 61.72; H, 4.12; C l , 12.10. A mixture m e l t i n g p o i n t of 153a and b was depressed to 117-119°. 19. I n v e s t i g a t i o n of the E f f e c t of S t a r t i n g M a t e r i a l C o n f i g u r a t i o n on the  Isomer R a t i o of the Product i n the Synthesis of 2- (4-Chloropheny1)- 4-phenylthiete 1,1-dioxide (153a) and 2-Pheny1 - 4 -(4-chloropheny1)- t h i e t e 1,1-dioxide (153b). A f t e r r e a c t i n g 1.90 g (0.0057 mole) of trans-2-(4-chloropheny1)-3-dimethylamino-4-phenylthietane 1,1-dioxide (127b) i n 2.0 ml of g l a c i a l a c e t i c a c i d w i t h 6.0 ml of 407o p e r a c e t i c a c i d at ice-water temperature for 20 hours (experiment 18), the r e a c t i o n was worked up by adding 20 ml of 135 d i s t i l l e d water - ethanol 95 (1:1) followed by 10 ml of water, and subse-quently c o l l e c t i n g the s o l i d by s u c t i o n f i l t r a t i o n . The product was washed w i t h more water and then d r i e d i n a d e s i c c a t o r under vacuum. Upon adding the washings to the f i l t r a t e , a second p r e c i p i t a t e formed which was c o l -l e c t e d by s u c t i o n f i l t r a t i o n , washed and d r i e d . The f i r s t s o l i d , 1.24 g (75.670) was found to be 153a by i r and nmr a n a l y s i s . The second s o l i d , 0.22 g (13.47«) was a mixture of 153a and b, according to the i r spectrum. From the appearance of the one-proton doublets i n the nmr spectrum, the pr o p o r t i o n s of 153a and b i n the mixture were estimated to be 2:1, r e s p e c t -i v e l y . Thus, of the 897o of the t h e o r e t i c a l amount of product i s o l a t e d , approximately 957» was 153a and 57o was 153b. In a 100 ml r e a c t i o n f l a s k f i t t e d w i t h a mechanical s t i r r e r and a thermometer were placed 0.50 g (0.0015 mole) of 127b and 45 ml of THF. S t i r r i n g gave an almost s a t u r a t e d , c o l o u r l e s s s o l u t i o n to which 3.0 ml of 407» p e r a c e t i c a c i d was added dropwise over a p e r i o d of 2 min from a p i p e t t e . When most of the p e r a c i d had been added, the r e a c t i o n temperature g r a d u a l l y rose from an i n i t i a l 27 to 28°. The temperature was maintained at 27± 1° by c o o l i n g the f l a s k i n an ice-water bath when necessary. The r e a c t i o n was monitored by uv a n a l y s i s . At v a r i o u s times 0.5 ml a l i q u o t s were r e -moved from the s o l u t i o n , d i l u t e d to 1 l i t r e w i t h ethanol 95 and the absorp-t i o n determined at 260 nm. Formation of product was e s s e n t i a l l y complete a f t e r 2.5 hours. A f t e r running f o r 5 hours, the volume of the r e a c t i o n s o l u t i o n was reduced to about 10 ml by evaporation under reduced pressure. Upon adding 40 ml of d i s t i l l e d water a white s o l i d p r e c i p i t a t e d . The mix-ture was c a r e f u l l y n e u t r a l i z e d w i t h a s a t u r a t e d , aqueous s o l u t i o n of Na^CO^ and the s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h water and d r i e d i n a d e s i c c a t o r . Neither a d d i t i o n of the washings to the f i l t r a t e nor f u r -136 ther d i l u t i o n w i t h water caused more p r e c i p i t a t e to form. A f t e r d r y i n g , the white crude product weighed 0.35 g, making the y i e l d 857o when the amount removed by sampling was taken i n t o c o n s i d e r a t i o n . The i r spectrum (KBr) of t h i s m a t e r i a l i n d i c a t e d that i t was f r e e of 127b and that i t con-s i s t e d mainly of 153b, w i t h a small p r o p o r t i o n of 153a. In the 100 MHz spectrum (CDCl-j) the a b s o r p t i o n due to the v i n y l i c proton of 153b appeared as a doublet at S 6.980 and that due to the p_-chlorobenzylie proton as a doublet at 5.858 ( J = 2 Hz). The corresponding absorptions f o r 153a were at ^7.017 and 5.904 ( J = 2 Hz). From the doublet i n t e g r a l s , the product was found to c o n s i s t of 827, 153b and 187, 153a. Thermolysis of a 30.0 mg sample of the product at 166° f o r 3 min and determination of the amounts of p_-chlorobenzylidene acetophenone (167) and benzylidene p_-chloroacetophe-none (166) i n the thermolysate by gl e gave the composition as 857, 153b and 157o 153a (see experiment 26). An i d e n t i c a l r e a c t i o n i n THF was run using 0.50 g (0.0015 mole) of 127a. Upon adding the f i r s t few drops of p e r a c i d , the temperature of the r e a c t i o n rose r a p i d l y to 30°. B r i e f l y c o o l i n g the f l a s k i n an i c e -water bath returned the temperature to 27°. Uv a n a l y s i s i n d i c a t e d that the r e a c t i o n was e s s e n t i a l l y complete w i t h i n the f i r s t 30 min f o l l o w i n g the a d d i t i o n of the p e r a c i d . Work-up, a f t e r running f o r 5 hours, gave 0.40 g (977o) of white s o l i d . The i r spectrum (KBr) of t h i s m a t e r i a l showed the presence of both t h i e t e 1,1-dioxide isomers w i t h no evidence of 127a. From the 100 MHz spectrum (CDCl^) the composition was determined to be 357» 153b and 657o 153a. The thermolysis procedure gave the composition as 3670 153b and 647, 153a. 20. Synthesis of 2-( 4 - N i t r o p h e n y l ) - 4 - p h e n y l t h i e t e 1,1-dioxide (155). 137 The procedure described i n experiment 17 was used. However, p r e l i m i n a r y experiments i n d i c a t e d that the e l i m i n a t i o n r e a c t i o n w i t h 128 was r e l a t i v e l y r a p i d and, t h e r e f o r e , a shorter r e a c t i o n p e r i o d was r e -q u i r e d . Because of the i n s t a b i l i t y of 128 to c r y s t a l l i z a t i o n , crude mate-r i a l c o n t a i n i n g approximately 12% 148 as impurity was employed. To a cooled, s t i r r e d suspension of 20.3 g of s t a r t i n g m a t e r i a l i n 20 ml of g l a c i a l a c e t i c a c i d was added 61 ml of 40% p e r a c e t i c a c i d over a period of 1 hour. A f t e r s t i r r i n g f o r another hour, the cream-coloured mixture was n e u t r a l i z e d w i t h a s a t u r a t e d aqueous s o l u t i o n of Na2C0 3 and e x t r a c t e d w i t h one 250 ml p o r t i o n and two 150 ml p o r t i o n s of CHCl-j. The pooled CHC1.J e x t r a c t s were washed w i t h 150 ml of 10% NaCl s o l u t i o n , d r i e d over anhydrous Na2S0^ and then evaporated under reduced pressure to g i v e 15.0 g (96%, based on the c a l c u l a t e d amount of 128 present i n the s t a r t i n g m a t e r i a l ) of cream-coloured s o l i d , mp 139-142° w i t h decomposition. The i r and nmr s p e c t r a of the crude product were i d e n t i c a l to those of the p u r i f i e d m a t e r i a l . C r y s t a l l i z a t i o n from ethanol 95 gave 155 as pale y e l -low, t h i n p l a t e s , mp 147-148° w i t h decomposition; i r (KBr) 3075, 2955, 2860 (C-H s t r e t c h i n g ) , 1615 ( o l e f i n i c double bond conjugated w i t h aromatic group), 1520, 1320 ( n i t r o group), 1300, 1155 cm" 1 ( s u l f o n e ) ; nmr (DMS0-d6) S8.57-8.30 (m, 2, protons ortho to n i t r o group), 8.18 (d, 1, J = 2 Hz, proton at C-3), 8.07-7.83 (m, 2, protons meta to n i t r o group), 7.50 ( s , 5, phenyl p r o t o n s ) , and 6.49 (d, 1, J = 2 Hz, b e n z y l i c p r o t o n ) ; uv max (CH 3CN) 288 nm (€ 19,000). A n a l . C a l c d . for C,rH NO,S: C, 59.79; H, 3.68; N, 4.65; mol. wt. , 301.32. 15 11 4 Found: C, 59.83; H, 3.75; N, 4.79. A sample of 155 was thermolyzed using the same c o n d i t i o n s as de s c r i b e d f o r the thermolysis of 152 i n experiment 24. The thermolysate, 138 a dark brown s o l i d , was d i s s o l v e d i n CHCl-j and analyzed by g l c using the same column and c o n d i t i o n s as i n experiment 23, except w i t h the oven at 240° and the n i t r o g e n flow at 80 ml/min. Only one major peak was observed i n the chromatogram, r e t e n t i o n time 4.0 min. The i r spectrum (KBr) of the thermolysate showed strong bands at 1663, 1592 and 1212 cm - 1, which sup-ported the presence of an cx ,£3-unsaturated, aromatic ketone. Strong n i t r o group bands were present at 1517 and 1338 cm L. 21. Decomposition of 2,4-Diphenylthiete 1,1-dioxide (152) i n E t h a n o l . Bis(1,3-dipheny1-3-oxopropy1) Sulfone (171) and trans-Chalcone (165a). In a 500 ml b o i l i n g f l a s k f i t t e d w i t h a r e f l u x condenser were placed 2.56 g (0.010 mole) of c r y s t a l l i n e 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide (152) and 250 ml of ethanol 95. Upon warming the mixture, a s o l u t i o n was obtained which was heated at r e f l u x f o r 2 hours. Evaporation of the s o l -vent under reduced pressure gave a v i s c o u s , y e l l o w o i l w i t h a c h a r a c t e r -i s t i c odor. The o i l was mixed w i t h 20 ml of ethanol 95 and heated to r e -f l u x temperature on a steam bath and then allowed to c o o l . Upon c o o l i n g , a white p r e c i p i t a t e formed. The s o l i d was c o l l e c t e d by s u c t i o n f i l t r a -t i o n , washed w i t h ethanol 95 and a i r d r i e d . The f i l t r a t e , pooled w i t h the washings, was evaporated i n vacuo and the r e s u l t i n g o i l was heated w i t h ethanol 95 to give a d d i t i o n a l p r e c i p i t a t e . Repeating the process two more times gave a t o t a l of 0.41 g (0.00084 mole, 17%) of 171. The i r spectrum of t h i s crude m a t e r i a l was i d e n t i c a l to that of the c r y s t a l -l i z e d compound. C r y s t a l l i z a t i o n from hexane - methyl e t h y l ketone gave b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) sulfone (171) as s h o r t , white needles, mp 184-185° w i t h decomposition; i r (KBr) 3065, 3040, 2925 (C-H s t r e t c h i n g ) , 1683, 1241 (benzoyl group), 1600, 1582, 1452, 765, 715, 702 (mono-substi-tuted phenyl), 1307, 1138 cm ( s u l f o n e ) ; nmr (CDC^) S 7 .93-7 .67 (m, 4, protons ortho to c a r b o n y l ) , 7.53-7.23 (m, 16, meta, para, and phenyl pro-t o n s ) , 4.70 (q, X p o r t i o n of ABX p a t t e r n , 2, b e n z y l i c protons) and 4.20-3.39 (m, AB p o r t i o n of ABX p a t t e r n , 4, methylene p r o t o n s ) . From the 100 MHz nmr spectrum of 171, the chemical s h i f t of protons A was c a l c u l a t e d (44b) to be 5 3.717 ( J ^ = 2.8 Hz) and that of protons B to be 3.925 ( J g x = 10.2 Hz) w i t h J^g = 17.5 Hz. The uv spectrum (CH^OH) showed a maximum at 244 nm (6 25,000) ( c o n t r i b u t i o n of two benzoyl groups). A n a l . Calcd. f o r C. nH o c0.S: C, 74.66; H, 5.43; 0, 13.26; S, 6.64; mol. 3U Zo H wt., 482.60. Found: C, 74.21; H, 5.66; 0, 13.62; S, 7.00. C r y s t a l l i z a t i o n s of crude 171 gave a second c r y s t a l l i n e sub-stance 174 as c o l o u r l e s s , transparent p l a t e s , mp 196-197° w i t h decomposi-t i o n . The i r sp e c t r a (KBr) of 171 and 174 were s i m i l a r , the main d i f f e r -ence being that the high frequency s u l f o n e band i n the spectrum of 174 was s p l i t w i t h one peak at 1310 cm"* and the other at 1292 cm *. The nmr s p e c t r a (CDCl^) were superimposable. Substance 174 was more slo w l y s o l u b l e i n CHCl-j and ethanol 95 than was 171. Evaporation of the f i n a l f i l t r a t e from the i s o l a t i o n of 171 gave a brownish-yellow o i l . In the i r spectrum (neat) strong bands occurred at 1665 and 1600 cm which suggested the presence of an *X unsaturated ketone. Vacuum d i s t i l l a t i o n of the o i l u s i n g a sho r t - p a t h apparatus gave 0.2 g (10%) of y e l l o w d i s t i l l a t e (165a), bp 120-130° at 0.1 mm ( l i t . (127) 208° at 25 mm). The d i s t i l l a t e s o l i d i f i e d soon a f t e r c o l l e c t i o n . A b l a c k , n o n d i s t i l l a b l e t a r remained i n the d i s t i l l i n g f l a s k C r y s t a l l i z a t i o n of the yel l o w s o l i d from pet. ether (bp 60-80°) affo r d e d pale y e l l o w prisms, mp 54-55° ( l i t . (127) 57-58°). Except for minor d i f -ferences i n some band s p l i t t i n g s , the i r spectrum (KBr) was superimposabl 140 w i t h that of an authentic sample of trans-chalcone (165a) (128). The nmr spectrum (CDCl^) appeared to be i d e n t i c a l to a published spectrum (129) except for minor impurity s i g n a l s a t S 3 . 5 0 , 1.77 and 0.97. The uv spec-trum (hexane) showed two maxima, one at 226 nm (log€ 4.06) and the other at 298 nm (log£4.36) ( l i t . (130) 226 (log£4.08) and 299 nm (log£4.38)). When an acetone s o l u t i o n of the c r y s t a l l i z e d m a t e r i a l was analyzed by g l c on the same column as described i n experiment 1, w i t h the i n j e c t i o n p o r t , oven, and det e c t o r at 282, 193 and 253°, r e s p e c t i v e l y , and the n i t r o g e n flow at 80 ml/min, one peak was observed w i t h a r e t e n t i o n time (5.1 min) i d e n t i c a l to that of an aut h e n t i c sample of 165a. 22. Synthesis of Bis(1,3-dipheny1-3-oxopropy1) Sulfone (171). £-Mercapto-^-phenylpropiophenone (176) was prepared u s i n g a method adopted from the l i t e r a t u r e (104). A s o l u t i o n of 16.0 g (0.077 mole) of trans-chalcone (165a) (128) and 8.0 g (0.079 mole) of dry t r i -ethylamine i n 480 ml of dry CHCl-j was cooled i n a dry ice-acetone bath and then placed i n a 1 l i t r e bomb of a Parr Pressure Reaction Apparatus No. 4511 (fume hood). Immediately, 80 ml of l i q u i d fl^S ( p r e v i o u s l y c o l -l e c t e d u s i n g a dry ice-acetone bath) was added and the bomb was se a l e d . The apparatus was heated at 40° f o r 21 hours and allowed to c o o l to room temperature over a period of 12.5 hours. The pressure was returned to atmospheric by ven t i n g the excess H^S i n t o an aqueous a l k a l i s o l u t i o n . The contents of the bomb were then t r a n s f e r r e d to a separatory funnel w i t h the a i d of a small amount of CHCl^ and e x t r a c t e d w i t h two 500 ml po r t i o n s of d i l u t e HCl followed by two 500 ml po r t i o n s of d i s t i l l e d water. A f t e r d r y i n g the orange-brown CHCl^ s o l u t i o n over anhydrous Na2S0^, i t was evaporated i n vacuo to give a l i g h t brown o i l , which r a p i d l y r e v e r t e d to 141 an o f f - w h i t e , c r y s t a l l i n e s o l i d upon s i t t i n g (18.0 g, 97%). C r y s t a l l i z a -t i o n from ethanol 100 gave 176 as s i l v e r y - w h i t e p l a t e s , mp 102-105° ( l i t . (104) 102-103°). The i r spectrum (KBr) was i d e n t i c a l to that of the crude m a t e r i a l and showed a strong carbonyl band at 1675 cm"1 and a weak S-H s t r e t c h i n g band at 2585 cm 176 darkened on exposure to l i g h t . A mixture of 2.08 g (0.010 mole) of 165a and 2.42 g (0.010 mole) of 176 was t r i t u r a t e d to form a f i n e powder, which was placed i n a 100 ml b o i l i n g f l a s k . A f t e r mixing i n 20 mg of benzoyl peroxide ( F i s h e r S c i e n t i -f i c , rea.) w i t h a s p a t u l a , the f l a s k was stoppered and heated on a steam bath. W i t h i n 10 min, a y e l l o w homogeneous l i q u i d was obtained, from which a s o l i d began to separate a f t e r 2 hours. A f t e r 3 hours, the r e a c t i o n mix-ture appeared as a y e l l o w , s o l i d mass. Heating was d i s c o n t i n u e d a f t e r 6 hours and the f l a s k was allowed to c o o l to room temperature. Washing the product w i t h anhydrous d i e t h y l ether gave a white s o l i d and a y e l l o w super-natant. The s o l i d (1.86 g) was s u c t i o n f i l t e r e d , washed f u r t h e r w i t h ether and allowed to dry. The i r spectrum (KBr) of the s o l i d showed an hydroxyl band at 3440 cm - 1 and a f a i r l y s t r ong a b s o r p t i o n at 1640 cm I t was apparent from t h i s spectrum that the s o l i d was not the d e s i r e d s u l -f i d e and i t was not f u r t h e r i n v e s t i g a t e d . Evaporation of the f i l t r a t e pooled w i t h the ether washings gave a y e l l o w o i l (2.67 g ) . A n a l y s i s of the o i l by t i c , using microscope s l i d e s coated w i t h s i l i c a g e l G, benzene as the developing s o l v e n t and c h a r r i n g as the v i s u a l i z a t i o n method, i n d i c a t e d the presence of one main component, presumably b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) s u l f i d e (177), as w e l l as r e l a -t i v e l y s m a l l amounts of 165a and 176. In the i r spectrum ( n e a t ) , no de-f i n i t e a bsorption due to S-H s t r e t c h i n g was observed; a strong band at 1680 cm * was a t t r i b u t e d to 177, w h i l e a shoulder at 1665 cm"* was appar-142 e n t l y due to 165a. The o i l was d i s s o l v e d i n 10 ml of CHCl^ and t r a n s -f e r r e d to a 50 ml r e a c t i o n f l a s k f i t t e d w i t h a mechanical s t i r r e r . G l a c i a l a c e t i c a c i d , 10 ml, was added and the r e s u l t i n g y e l l o w s o l u t i o n was cooled i n an ice-water bath. P e r a c e t i c a c i d (407o), 4.6 ml, was then added drop-wise over a p e r i o d of 5 min w i t h s t i r r i n g . A f t e r 20 hours, evaporation of the s o l u t i o n under reduced pressure to remove the CHCl-j caused the product (171) to p r e c i p i t a t e as a white s o l i d . The s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h d i e t h y l ether and d r i e d . The f i l t r a t e and ether washings were pooled and mixed w i t h CHCl^ and water. The organic l a y e r was separated, d r i e d over anhydrous ^ £ 5 0 ^ and evaporated to give a pale y e l l o w o i l , which on warming w i t h ethanol 95 a f f o r d e d a d d i t i o n a l s o l i d product. The t o t a l weight of product was 1.70 g (60% y i e l d , based on t a k i n g the crude s u l f i d e 177 to be pure). C r y s t a l l i z a t i o n from hexane -methyl e t h y l ketone gave short white needles, mp 184-185° w i t h decomposi-t i o n . The i r spectrum (KBr) was superimposable w i t h that of the k e t o n i c s u l f o n e 171 i s o l a t e d from the decomposition of 2 , 4 - d i p h e n y l t h i e t e 1,1-d i o x i d e (152) i n r e f l u x i n g e thanol. The nmr and uv s p e c t r a were a l s o i d e n t i c a l to those of 171. A mixture m e l t i n g p o i n t w i t h 171 was not de-pressed. As w i t h the c r y s t a l l i z a t i o n of crude 171, a second substance was obtained as transparent p l a t e s from the c r y s t a l l i z a t i o n of the crude product. The i r spectrum of the transparent p l a t e s was i d e n t i c a l to that of 174. 23. Decomposition of 2 , 4-Diphenylthiete 1 , 1-dioxide (152) i n Aqueous  Tetrahydrofuran , 1 , 3-Diphenylpropene - 3-sulfonic A c i d (170). A s o l u t i o n of 2.56 g (0.01 mole) of t h i e t e 1 , 1-dioxide 152 i n a mixture of 40 ml of THF and 10 ml of d i s t i l l e d water was r e f l u x e d f o r 143 41 hours. The temperature of the b o i l i n g s o l u t i o n was 66°. A f t e r r e f l u x -i n g f o r 12 hours, the odor of rL^S was n o t i c e a b l e at the open end of the condenser. A piece of f i l t e r paper wetted w i t h aqueous Pb(0Ac)2 s o l u t i o n was darkened when exposed to these fumes. Evaporation of the s o l v e n t under vacuum gave a v i s c o u s , y e l l o w o i l . The o i l was d i s s o l v e d i n 20 ml of CHCl^ and e x t r a c t e d w i t h a 20 ml p o r t i o n and two 10 ml p o r t i o n s of d i s t i l l e d water. The pooled, pale brown, aqueous e x t r a c t s had a pH of 1 when te s t e d w i t h i n d i c a t o r paper. The Pb(0Ac)2 t e s t for H^S was n e g a t i v e . Evapora-t i o n of the e x t r a c t s under high vacuum gave a y e l l o w o i l which c r y s t a l l i z e d upon s i t t i n g . A f t e r s t o r i n g i n a d e s i c c a t o r o v e r n i g h t , the s o l i d (170) weighed 1.95 g (71%). C r y s t a l l i z a t i o n from hexane - CHCI3 gave 1.0 g (37%) of l , 3 - d i p h e n y l p r o p e n e - 3 - s u l f o n i c a c i d (170) as f i n e , o f f - w h i t e needles, mp 97-102° w i t h decomposition; i r (KBr) 3700-2400, 1225, 1050 ( s u l f o n i c a c i d ) , 1600, 1500, 1460, 761, 705 cm - 1 (mono-substituted p h e n y l ) ; nmr (DMS0-d6) <5 7.64-7.10 (m, 10, phenyl p r o t o n s ) , 6.61 (d, 1, J = 7 Hz,tX-s t y r y l p r o t o n ) , 6.56 ( s , superimposed on u p f i e l d s i g n a l of doublet at 6.61, 1, b e n z y l i c p r o t o n ) , and 4.57 (d, 1, J = 7 Hz, ^ - s t y r y l p r o t o n ) ; uv max (H 20) 253 (€21,600), 282.5 (sh) (£2,740) and 292 nm (£1,450). The s u l f o n i c a c i d was unstable and decomposed when st o r e d f o r 1 week i n a d e s i c c a t o r i n the dark, at room temperature, to g i v e a w a t e r - i n s o l u b l e s o l i d . The i r spectrum (KBr) of the decomposition m a t e r i a l showed the absence of s u l -f o n i c a c i d bands. Strong absorptions occurred at 1358, 1190 and 1168 cm *, which suggested the presence of a s u l f o n i c a c i d e s t e r . The dimethylamine s a l t of 170 was prepared and found to be r e l a t i v e l y s t a b l e . C r y s t a l l i z a t i o n of t h i s s a l t from hexane - benzene gave s h o r t , white needles, mp 169-170°; i r (KBr) 3040, 2800, 2950, 2480 (ammonium band), 1250, 1225, 1160, 1027 cm"1 ( s u l f o n i c a c i d s a l t ) . The 144 nmr spectrum (CDCl-j) showed a complex m u l t i p l e t at S 7.91-7.10 (phenyl protons, 10, and protons on N, 2) an unsymmetrical t r i p l e t which was a t t r i b u t e d to a doublet at 6.70 ((X-styryl proton ( c ) , 1, J = 5.5 Hz), c a the u p f i e l d s i g n a l of which was superimposed on the u p f i e l d s i g n a l of a doublet at 6.67 ( b e n z y l i c proton ( b ) , 1, = 2 Hz), a quartet at 4.77 ( e - s t y r y l proton ( a ) , 1, J = 2 Hz, J =5.5 Hz), and a s i n g l e t at 2.24 (N-methyl protons, 6). Upon a d d i t i o n of D 2 O the i n t e g r a l f o r the m u l t i -p l e t atS 7.91-7.10 decreased and a d i f f u s e band appeared w i t h i t s centre at about 4.4. The dimethylamine s a l t of 170 was submitted f o r a n a l y s i s . A n a l . C a l c d . f o r C 1 7 H 2 1 N ° 3 S : C> 63.92; H, 6.63; mol. wt., 319.42. Found: C, 63.93; H, 6.53. The CHCl^ layer from the aqueous e x t r a c t i o n of the s u l f o n i c a c i d 170 was d r i e d over anhydrous Na 2S0^ and evaporated under reduced pressure to give 1.11 g of t r a n s l u c e n t , brown o i l . I n f r a r e d a n a l y s i s (neat) i n d i -cated the presence of b i s ( l , 3 - d i p h e n y l - 3 - o x o p r o p y l ) s u l f o n e (171) and t r a n s -chalcone (165a). Approximately 20 ml of hexane was added to the o i l and the mixture was heated on a steam bath to e x t r a c t 165a. A f t e r r e p e a t i n g the e x t r a c t i o n a second time, a yellowish-brown, v i s c o u s syrup remained. The syrup was warmed w i t h a small amount of ethanol 95 and 0.27 g (117o) of 171 was recovered upon c o o l i n g . The hexane e x t r a c t s were analyzed by g l c and the t o t a l amount of 165a was determined to be 0.15 g (77»). The a n a l y s i s was c a r r i e d out using a 6 f t x 5/32 i n ( i . d . ) s i l a n i z e d g l a s s column packed w i t h 6.4 g of 3% QF-1 on Gas-Chrom Q (100-120 mesh) w i t h the i n j e c t i o n p o r t , oven, and d e t e c t o r at 240, 170 and 270°, r e s p e c t i v e l y , and the n i t r o g e n flow at 67 ml/min. Under the described c o n d i t i o n s , 165a had a r e t e n t i o n time of 6.3 min. A s t r a i g h t - l i n e c a l i b r a t i o n curve was obtained by chromatographing hexane s o l u t i o n s of 165a of known concentra-145 t i o n (0.1, 0.3, and 0.5%) and p l o t t i n g the observed peak area a g a i n s t con-c e n t r a t i o n . Approximately 90% of the t h i e t e 1,1-dioxide 152 r e f l u x e d i n aqueous THF was accounted for by the decomposition products 165a, 170 and 171. 24. Thermolysis of 2,4-Diphenylthiete 1,1-dioxide (152) and B i s ( l , 3 - dipheny1-3-oxoprdpy1) Sulfone (171). A stoppered 8 x 70 mm t e s t tube c o n t a i n i n g 30.0 mg (0.000117 mole) of pure 152 was placed i n a 166° o i l bath f o r 3.0 min. During the f i r s t min the s o l i d melted and a gas was r a p i d l y evolved from the melt. A f t e r 2 min the e v o l u t i o n had almost ceased. Upon c o o l i n g , the brownish-y e l l o w r e s i d u e was d i s s o l v e d i n s u f f i c i e n t CHCI3 to give 10 ml of pale y e l l o w s o l u t i o n . The s o l u t i o n was analyzed f o r trans-chalcone (165a) by g l c u s i n g the same column and c o n d i t i o n s as des c r i b e d i n experiment 23. By r e f e r e n c e to a c a l i b r a t i o n curve, the t o t a l amount of 165a ( r e t e n t i o n time 6.3 min) i n the s o l u t i o n was determined to be 22 mg (92%). A second peak was present i n .the chromatogram at 3.2 min, which was a t t r i b u t e d to c i s - c h a l c o n e (165b) (see below). The area of t h i s l a t t e r peak was about 27» that of the peak at 6.3 min. The i r spectrum (neat) of a r e s i d u e ob-tai n e d from a s i m i l a r t h e rmolysis c l o s e l y resembled the spectrum (KBr) of 165a. The thermolysis of 171 was i n v e s t i g a t e d q u a l i t a t i v e l y . A stop-pered 8 x 70 mm t e s t tube c o n t a i n i n g a sample of 171 was placed i n a 160° o i l bath, which was then r a p i d l y heated to 200° by means of a Bunsen flame At the mp of the sample, there was a vigorous e v o l u t i o n of gas. A f t e r heating at 200° f o r 2 min, the e v o l u t i o n ceased and the tube was removed 146 from the bath. Upon removing the stopper, a harsh odor was n o t i c e a b l e . The thermolysate was a v i s c o u s , golden-yellow syrup. The i r and nmr s p e c t r a of t h i s m a t e r i a l were very s i m i l a r to those of 165a. A n a l y s i s by g l c of a C H C I 3 s o l u t i o n of the thermolysate using the same column and con-d i t i o n s as mentioned i n experiment 23 gave two peaks. The f i r s t , at 3.2 min, was a t t r i b u t e d to c i s - c h a l c o n e (165b) and the second, at 6.3 min, corresponded to trans-chalcone (165a). The area of the peak at 3.2 min was 23% that of the peak at 6.3 min. Is o m e r i z a t i o n i n s o l u t i o n of trans-chalcone to the ci s - i s o m e r upon exposure to s u n l i g h t i s a known process (99). When a f r e s h l y pre-pared 0.27» C H C I 3 s o l u t i o n of trans-chalcone (mp 57-58°) was analyzed by g l c , u s i n g the same column and c o n d i t i o n s as i n experiment 23, only one peak, r e t e n t i o n time 6.3 min, was observed. A f t e r s i t t i n g i n a Pyrex con-t a i n e r i n the open ( f l u o r e s c e n t l i g h t i n g ) f o r 3 hours, a second peak, r e -t e n t i o n time 3.2 min, was apparent. A f t e r p l a c i n g the container i n d i r e c t s u n l i g h t f o r 1 hour, the area of the peak at 3.2 min increased and that at 6.3 min decreased, such that the r a t i o of the two areas was approximately 1:1. Upon removing the f l a s k from d i r e c t s u n l i g h t , the peak at 3.2 min decreased and that at 6.3 min increased. On the b a s i s of these observa-t i o n s , the peak at 3.2 min was a t t r i b u t e d to c i s - c h a l c o n e (165b). Evapo-r a t i o n of a CHCl-j s o l u t i o n i n which the c i s to trans r a t i o was found to be 1.2:1 by g l c gave an orange-yellow l i q u i d . This agreed w i t h the l i t -e r a t u r e o b s e r v a t i o n that a mixture of c i s - c h a l c o n e , mp 45-46°, w i t h the trans-isomer l i q u i f i e d at room temperature (99). The i r spectrum (neat) was q u i t e s i m i l a r to the spectrum (KBr) of 165a. D i f f e r e n c e s i n the i n -t e n s i t i e s of some bands as w e l l as d i f f e r e n c e s i n some band s p l i t t i n g s between the two s p e c t r a may have been due to the d i f f e r e n c e i n sampling 147 technique, as w e l l as to the d i f f e r e n c e i n isomer c o n s t i t u t i o n . 25. Synthesis of trans-p-Chlorobenzylidene Acetophenone (167) and t r a n s - Benzylidene p-Chloroacetophenone (166). trans-p-Chlorobenzylidene acetophenone (167) was prepared using a procedure taken from the l i t e r a t u r e (137). To a 500 ml three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r and a thermometer were added 240 ml of ethanol 95, 20.08 g (0.142 mole) of p_-chlorobenzaldehyde (Eastman, prac.) and 17.16 g (0.143 mole) of acetophenone ( F i s h e r S c i e n t i f i c , r e a . ) . The mixture was s t i r r e d to give a c o l o u r l e s s s o l u t i o n and then 24 ml of 10% aqueous NaOH s o l u t i o n was added w i t h vigorous s t i r r i n g . The s o l u t i o n immediately turned y e l l o w and i t s temperature began to r i s e . The temper-ature was maintained at 2 4 - 2 5 ° by immersing the f l a s k i n an ice-water bath when necessary. Approximately 3 minutes a f t e r adding the base the s o l u t i o n became t r a n s l u c e n t and then much s o l i d r a p i d l y p r e c i p i t a t e d . The mixture was allowed to s i t f o r 15 min and then the s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h 1 l i t r e of d i s t i l l e d water followed by 100 ml of i c e - c o l d ethanol 100 and a i r d r i e d . The weight of the pale y e l l o w , amor-phous s o l i d a f t e r d r y i n g was 26.12 g (75%). C r y s t a l l i z a t i o n from hexane -ethanol 95 gave 167 as pale y e l l o w needles, mp 1 1 2 - 1 1 3 . 5 ° ( l i t . (137) 1 1 4 . 5 ° , from ethanol 95). Using a s i m i l a r procedure, 15.05 g (0.142 mole) of benzaldehyde was reacted w i t h 22.11 g (0.143 mole) of p_-chloroacetophenone (Eastman, white l a b e l ) i n 240 ml of ethanol 95 i n the presence of 24 ml of 107o aqueous NaOH. About 2 min a f t e r adding the base, s o l i d began to p r e c i p i t a t e , at a slower r a t e , however, than w i t h the s y n t h e s i s of 167. One hour a f t e r adding the base, the s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n and washed 148 w i t h water followed by c o l d e t h a n o l . Drying i n a d e s i c c a t o r y i e l d e d 22.64 g (657o) of pale y e l l o w s o l i d . C r y s t a l l i z a t i o n from hexane - ethanol 100 gave 166 as pale y e l l o w , f e a t h e r - l i k e c r y s t a l s , mp 96.5-98° ( l i t . (89) 94-96°). G a s - l i q u i d chromatography of f r e s h l y prepared 0.05, 0.10, 0.20 and 0.307o s o l u t i o n s of trans-p-chlorobenzylidene acetophenone (167) i n CHCl^, each c o n t a i n i n g 0.107o b e n z i l as i n t e r n a l standard, using the same column and c o n d i t i o n s as d e s c r i b e d i n experiment 23, except w i t h the oven at 200°, gave one peak f o r 167, r e t e n t i o n time 3.9 min, and one peak f o r b e n z i l at 1.5 min. P l o t t i n g the r a t i o of the height of the 167 peak to that of the b e n z i l peak against the c o n c e n t r a t i o n of 167 gave a s t r a i g h t -l i n e c a l i b r a t i o n curve. In a s i m i l a r manner, a s t r a i g h t - l i n e curve was obtained f o r trans-benzylidene- p-chloroacetophenone (166), r e t e n t i o n time 3.6 min. A f t e r a l l o w i n g CHCl^ s o l u t i o n s of 167 and 166 to s i t i n the open i n Pyrex c o n t a i n e r s f o r about a week, a second peak, r e t e n t i o n time 2.2 min, was observed i n the chromatogram of the 167 s o l u t i o n and a second, r e t e n t i o n time 1.9 min, i n that of the 166 s o l u t i o n . By analogy to s i m i -l a r observations made w i t h trans-chalcone (165a) (experiment 24), the two new peaks were assumed to be due to c i s - p - c h l o r o b e n z y l i d e n e acetophenone and c i s - b e n z y l i d e n e £-chloroacetophenone, r e s p e c t i v e l y . 26. Thermolysis of 2-(4-Chloropheny1)-4-phenylthiete 1,1-dioxide (153a)  and 2- P h e n y l - 4 - ( 4 - c h l o r o p h e n y l ) - t h i e t e 1,1-dioxide (153b). A stoppered 8 x 70 mm t e s t tube c o n t a i n i n g 30.0 mg (0.000103 mole) of pure 153b was placed i n a 164° o i l bath f o r 3 min. During the f i r s t min, the s o l i d melted and a vigorous e v o l u t i o n of gas from the melt 1 4 9 commenced. Production of gas bubbles ceased a f t e r about 2 min. Soon a f t e r removing the t e s t tube from the bath, the l i q u i d r e s i d u e r e v e r t e d to an orange s o l i d . A harsh odor was n o t i c e a b l e upon removal of the stop-per. When c o o l , the s o l i d was d i s s o l v e d i n s u f f i c i e n t CHCl^ along w i t h 1 ml of 1% b e n z i l s o l u t i o n to give 10 ml of f i n a l s o l u t i o n . Immediate g l c of t h i s s o l u t i o n using the column and c o n d i t i o n s r e f e r r e d to i n ex-periment 25 gave three peaks, the r e t e n t i o n times of which corresponded to those of trans - p - c h l o r o b e n z y l i d e n e acetophenone (167), presumed c i s -£-chlorobenzylidene acetophenone (see experiment 25) and b e n z i l . The area of the cis - i s o m e r peak was approximately 1% that of the 167 peak. From a c a l i b r a t i o n curve (experiment 25) the c o n c e n t r a t i o n of 167 was determined to be 0.21%, i n d i c a t i n g that 85% of the s t a r t i n g m a t e r i a l 153b had been converted to t h i s compound. The i r spectrum (KBr) of the s o l i d product obtained i n a s i m i l a r thermolysis of 153b showed only minor d i s c r e p a n c i e s from that of an authe n t i c sample of 167. An i d e n t i c a l t h e rmolysis was c a r r i e d out on 153a. Besides the peak due to the i n t e r n a l standard, two other peaks were present i n the chromatogram, one a t t r i b u t a b l e to 166 and the other to the presumed c i s -benzylidene £-chloroacetophenone (see experiment 25). The area of the l a t t e r peak was approximately 17o that of the former. From a c a l i b r a t i o n curve (experiment 25) the CHCI3 s o l u t i o n was found to c o n t a i n 0 . 2 0 7 o 166, which meant that 80% of the t h i e t e 1,1-dioxide 153a had been converted to 166. The i r spectrum (KBr) of a sample of s o l i d thermolysate was almost i d e n t i c a l to that of authe n t i c 166. 27. Synthesis of 2,4-Dipheny1-3-cyanothietane 1,1-dioxide (178). The e t h a n o l i c s o l u t i o n of hydrogen cyanide r e q u i r e d f o r t h i s procedure was prepared by mixing 80 ml of l i q u i f i e d HCN (131a) w i t h 2 150 l i t r e s of i c e - c o l d ethanol 100. The s y n t h e s i s of 178 was c a r r i e d out i n a fume hood. In a 2 l i t r e three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r were placed 10.0 g (0.039 mole) of c r y s t a l l i n e 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide (152) and 250 ml of reagent CHCI3. The mixture was s t i r r e d to give a s o l u t i o n and then 500 ml of ethanol 100 was g r a d u a l l y added, f o l l o w e d by 250 ml of e t h a n o l i c HCN s o l u t i o n . The reaction'was i n i t i a t e d by adding 575 mg of dry, f i n e l y powdered KCN, which caused the s o l u t i o n to t u r n a b r i g h t y e l l o w c o l o u r . The f l a s k was stoppered and s t i r r e d at a moderate r a t e f o r 18 hours, during which time a s o l i d p r e c i p i t a t e d . The s o l i d was c o l l e c t e d by s u c t i o n f i l -t r a t i o n and washed w i t h a s m a l l amount of ethanol 95. Evaporation of the f i l t r a t e pooled w i t h the ethanol washings gave an i n t r a c t a b l e , b l a c k t a r . The crude product was s t i r r e d i n 400 ml of d i s t i l l e d water f o r s e v e r a l minutes and then s u c t i o n f i l t e r e d . Upon d r y i n g o v e r n i g h t , the pale y e l l o w powder weighed 8.57 g (77.6%) and had a mp of 235-237°. The i r spectrum of the powder was i d e n t i c a l to that of the c r y s t a l l i z e d m a t e r i a l . Crys-t a l l i z a t i o n from n - b u t y l a l c o h o l gave 178 as heavy, white c r y s t a l s w i t h a f e a t h e r - l i k e appearance, which when washed w i t h ethanol 100 and d r i e d had a mp of 236-237°; i r (KBr) 3070, 2960 (C-H s t r e t c h i n g ) , 2245 ( n i t r i l e ) , 1338, 1178, 1138 cm"1 ( s u l f o n e ) ; nmr (DMS0-d &) S7.81-7.33 (m, 10, phenyl p r o t o n s ) , 6.34 (d, 2, J = 10.5 Hz, protons at C-2 and C-4), and 4.77 ( t , 1, J = 10.5 Hz, proton at C-3). A n a l . C a l c d . f o r C 1 6H 1 ; JN0 2S: C, 67.82; H, 4.63; N, 4.94; mol. wt., 283.35. Found; C, 67.80; H, 4.73; N, 4.84. Washing of the crude product w i t h water was necessary i n order to remove an i n o r g a n i c side-product. Evaporation of the aqueous washings gave a brown s o l i d . The i r spectrum (KBr) of t h i s m a t e r i a l (^SO^?) was 151 q u i t e s i m i l a r to that of N^SO^. Treatment of an a c i d i f i e d aqueous s o l u -t i o n of the i n o r g a n i c substance w i t h BaCNO^^ s o l u t i o n caused a white s o l i d to separate, which suggested the presence of the s u l f a t e anion. Crude t h i e t e 1,1-dioxide 152 could be used i n t h i s r e a c t i o n without a f f e c t i n g the y i e l d of 178. 28. Synthesis of 2-(4-Chlorophenyl)-3-cyano-4-phenylthietane 1,1-dioxide  (180). The r e a c t i o n procedure was i d e n t i c a l to that d e s c r i b e d i n ex-periment 27. The s t a r t i n g m a t e r i a l was a mixture of 2-(4-chlorophenyl)-4 - p h e n y l t h i e t e 1,1-dioxide (153a) and 2-pheny1-4-(4-chloropheny1)-thiete 1,1-dioxide (153b) . A f t e r r e a c t i n g 15.00 g (0.0516 mole) of isomer mix-ture o v e r n i g h t , a p r e c i p i t a t e was present, which was c o l l e c t e d by s u c t i o n f i l t r a t i o n and washed w i t h a s m a l l amount of ethanol 100. Upon d r y i n g , the white, c r y s t a l l i n e s o l i d (180) weighed 6.80 g (42.0%) and had a mp of 198-199°. Evaporation in vacuo of the yel l o w f i l t r a t e pooled w i t h the ethanol washings y i e l d e d a y e l l o w s o l i d . F r a c t i o n a l c r y s t a l l i z a t i o n of t h i s m a t e r i a l from ethanol 100 affo r d e d 2.26 g (14.0%) a d d i t i o n a l product and 2.07 g (13.8%,) of c r y s t a l l i n e s t a r t i n g m a t e r i a l . C r y s t a l l i z a t i o n from ethanol 95 gave 180 as w h i t e , f i n e needles, mp 199-200°; i r (KBr) 3070, 2968, 2940 (C-H s t r e t c h i n g ) , 2280 ( n i t r i l e ) , 1333, 1180, 1148 cm"1 ( s u l -f one); nmr (DMSO-d,) S 7.89-7.43 (m, 9, aromatic p r o t o n s ) , 6.39 (d, 2, J o — = 11 Hz, protons at C-2 and C-4), and 4.76 ( t , 1, J = 11 Hz, proton at C-3). A n a l . C a l c d . f o r C., H o C l N 0 o S : C, 60.47; H, 3.81; C l , 11.16; mol. wt., 16 12 2 317.79. Found: C, 60.26; H, 3.82; C l , 11.18. 152 29. Synthesis of 2-(4-Nitrophenyl)-3-cyano-4-phenylthietane 1,1-dioxide  (181). The procedure used was s i m i l a r to that described i n experiment 27 and was c a r r i e d out i n a fume hood. A mixture of 10.26 g (0.0341 mole) of 155 and 308 ml of THF i n a stoppered 1 l i t r e c o n i c a l f l a s k was magnet-i c a l l y s t i r r e d to give a pale y e l l o w s o l u t i o n . To the s o l u t i o n was added 256 ml of 1 M e t h a n o l i c HCN followed by 590 mg of powdered KCN. W i t h i n a few minutes the r e a c t i o n turned a t r a n s l u c e n t , orange-brown. A f t e r s t i r r i n g f o r 5 hours, the s o l v e n t was removed by evaporation under r e -duced pressure to g i v e an orange-brown o i l . Upon mixing the o i l w i t h 30 ml of ethanol 100, a pale y e l l o w s o l i d separated, which was c o l l e c t e d by s u c t i o n f i l t r a t i o n and washed w i t h a s m a l l amount of e t h a n o l . Evaporation of the f i l t r a t e pooled w i t h the washings gave an orange-brown syrup. Re-peating the treatment w i t h ethanol y i e l d e d more s o l i d . A f t e r washing w i t h 400 ml of d i s t i l l e d water and d r y i n g i n a d e s i c c a t o r , the pooled s o l i d s (181) weighed 7.52 g (677o) . Approximately 0.9 g more product was obtained when the o i l f o r the evaporation of the l a s t f i l t r a t e was subjected to column chromatography (see experiment 30). Thus, the t o t a l y i e l d of crude product was about 757o. The i r spectrum of t h i s m a t e r i a l was almost iden-t i c a l to that of the p u r i f i e d compound. C r y s t a l l i z a t i o n from hexane - CHC1 gave 18_1 as f i n e , white needles, mp 164-165°; i r (KBr) 3100, 2975 (C-H s t r e t c h i n g ) , 2275 ( n i t r i l e ) , 1530, 1353 ( n i t r o group), 1334, 1177, 1145 cm - 1 ( s u l f o n e ) ; nmr (DMS0-d&) <S8.57-8.28 (m, 2, protons ortho to n i t r o group), 8.15-7.91 (m, 2, protons meta to n i t r o group), 7.88-7.40 (m, 5, phenyl p r o t o n s ) , 6.56 (d, 1, J = 10.5 Hz, p _ - n i t r o b e n z y l i e p r o t o n ) , 6.48 (d, 1, J = 10.5 Hz, b e n z y l i c p r o t o n ) , 4.92 ( t , 1, J = 10.5 Hz, proton at 153 C-3). A second polymorphic form of 181 was obtained as pale y e l l o w nee-dles i n the form of r o s e t t e s , mp 152-153°. U s u a l l y , the higher m e l t i n g form came out of s o l u t i o n f i r s t , f ollowed by the lower m e l t i n g form. In one i n s t a n c e , when a mixture of the two forms was l e f t s i t t i n g i n super-natant at room temperature f o r s e v e r a l days, the f i n e white needles grad-u a l l y disappeared as more of the lower melting form appeared. The i r s p e c t r a (KBr) of the two polymorphs were e s s e n t i a l l y i d e n t i c a l and the nmr s p e c t r a (DMSO-d^) were superimposable. Compound 181 was submitted f o r a n a l y s i s as the low m e l t i n g polymorph. Anal. C a l c d . f o r C ,H_-No0.S: C, 58.53; H, 3.68; N, 8.53; mol. wt., lo 12 2 H 328.34. Found: C, 58.65; H, 3.75; N, 8.58. 30. I s o l a t i o n of Two Unsaturated N i t r i l e s (182a and b ) . Evaporation of the f i n a l f i l t r a t e from the work-up of the r e -a c t i o n i n experiment 29 gave 4.5 g of orange-brown o i l . The o i l was mixed w i t h 20 ml of benzene, b r i e f l y heated on a steam bath, and then s u c t i o n f i l t e r e d to remove a reddish-brown i n s o l u b l e s o l i d . The s o l i d was found to be almost completely water s o l u b l e . Evaporation of the benzene f i l t r a t e under reduced pressure gave 3.1 g of straw-coloured, viscous o i l . This was added to 1.8 g of o i l i s o l a t e d i n the same way from a r e a c t i o n run i n an i d e n t i c a l manner to that described i n experiment 29, but on a smaller s c a l e . The pooled o i l s were d i s s o l v e d i n 10 ml of benzene and a p p l i e d to the top of a 2.5 x 60 cm column prepared using 93 g of a c t i v a t e d s i l i c a g e l (60-200 mesh, Davison Chemicals). The column was developed w i t h ben-zene and four f r a c t i o n s were e l u t e d . Evaporation of the benzene from the f i r s t f r a c t i o n gave 2.6 g of y e l l o w s o l i d . The second f r a c t i o n y i e l d e d 0.1 g of orange-yellow s o l i d , which was not c h a r a c t e r i z e d . As the t h i r d f r a c t i o n was e l u t e d , a white c r y s t a l l i n e s o l i d appeared i n the e l u a t e , the 154 i r spectrum (KBr) of which was superimposable w i t h that of 2 - ( 4 - n i t r o -phenyl)-3-cyano-4-phenylthietane 1,1-dioxide (181) . A t o t a l of 1.4 g of pure 181 was obtained by evaporation of the supernatant. F r a c t i o n f o u r , 0.5 g, appeared to be a mixture of 181 and other u n i d e n t i f i e d substances, according to i t s i r spectrum. C r y s t a l l i z a t i o n of f r a c t i o n one from hex-ane - benzene gave a mixture of pale y e l l o w needles and p l a t e s , mp 88-100°. The two c r y s t a l forms were separated by hand. R e c r y s t a l l i z a t i o n of the p o r t i o n that was mainly p l a t e s , from hexane - benzene gave 182a as pale y e l l o w p l a t e s , mp 100-101°; i r (KBr) 2220 (medium i n t e n s i t y , cX , £ -unsaturated n i t r i l e ) , 1626 ( o l e f i n i c double bond conjugated w i t h aromatic r i n g ) , 1520, 1348 cm" 1 ( n i t r o group); nmr (CDCl-j) S 8 .37-8.07 (m, 2, pro-tons ortho to n i t r o group), 7.87-7.63 (m, 2, ortho protons of phenyl r i n g , presumably), 7.63-7.27 (m, 5, protons meta to n i t r o group and remaining protons on phenyl r i n g ) , 7.08 ( s , 1, v i n y l i c p r o t o n ) , and 3.83 ( s , 2, b e n z y l i c p r o t o n s ) ; uv max (CH3CN), 278 nm ( 6 26,700). A n a l . C a l c d . f o r C ^ H ^ N ^ : C, 72.72; H, 4.58; mol. wt., 264.28. Found: C, 72.58; H, 4.66. R e c r y s t a l l i z a t i o n of the p o r t i o n that c o n s i s t e d mainly of nee-d l e s gave 182b as pale y e l l o w needles i n the form of r o s e t t e s , mp 132-133°; i r (KBr) 2225 (medium i n t e n s i t y , CX ,f-unsaturated n i t r i l e ) , 1625 ( o l e f i n i c double bond conjugated w i t h aromatic group), 1516, 1348 cm" 1 ( n i t r o group); nmr (CDCl^)6 8.36-8.09 (m, 2, protons ortho to n i t r o group), 7.61-7.28 (m, 8, protons meta to n i t r o group, phenyl protons and v i n y l i c p r o t o n ) , and 3.93 ( s , 2,. b e n z y l i c p r o t o n s ) ; uv max (CH 3CN) 269 nm (£39,000). Anal . C a l c d . f o r C 1 6 H 1 2 N 2 0 2 : C, 72.72; H, 4.58; mol. wt., 264.28. Found: C, 72.53; H, 4.48. 155 31. Treatment of 2-(4-Nitrophenyl)-3-cyano-4-phenylthietane 1,1-dioxide  (181) w i t h Base. A s t i r r e d s o l u t i o n of 0.33 g (0.001 mole) of 18J. i n 10 ml of THF was d i l u t e d w i t h 50 ml of ethanol 95 and then t r e a t e d w i t h 2 ml of aqueous 1 N NaOH, which was added dropwise from a p i p e t t e . I n i t i a l l y , each drop of base caused the s o l u t i o n to turn a magenta colour and suf-f i c i e n t time was allowed between drops f o r most of the colour to d i s a p -pear. When approximately 1.75 ml of base had been added, the colour was no longer produced and the r e a c t i o n remained a t r a n s l u c e n t brown. A f t e r s t i r r i n g f o r 30 min f o l l o w i n g the a d d i t i o n of the base, 2 ml of g l a c i a l a c e t i c a c i d was added and the s o l u t i o n was evaporated under reduced pres-sure to g i v e an orange s o l i d . The s o l i d was d i s s o l v e d i n 10 ml of CHCl-j and e x t r a c t e d w i t h four 10 ml p o r t i o n s of d i s t i l l e d water. A f t e r d r y i n g over anhydrous Na2S0^, the CHCl-j layer was evaporated in vacuo to give 0.26 g of orange s o l i d . The i r spectrum (KBr) of t h i s m a t e r i a l was q u i t e s i m i l a r to that of 182a. No s u l f o n e a b s o r p t i o n was e v i d e n t . The nmr spectrum (CDCI3) showed a mixture of 182a and b and i n d i c a t e d that these two compounds accounted f o r about 90% of the crude product. By compari-son of the i n t e g r a l s of the b e n z y l i c protons, the r a t i o of 182a to 182b was found to be 2.4:1. S i g n a l s due to i m p u r i t i e s were present at 84.31, 2.40 and 1.25. A n a l y s i s of CHC1 3 s o l u t i o n s of pure 182a and 182b by g l c u s i n g the 3% QF-1 column des c r i b e d i n experiment 23 w i t h the oven, i n j e c -t i o n port and detector at 210, 243 and 270°, r e s p e c t i v e l y , and the n i t r o -gen flow at 67 ml/min gave one peak f o r 182a, r e t e n t i o n time 14.3 min, and one peak f o r 182b, r e t e n t i o n time 13.1 min. A n a l y s i s of a CHCl-j s o l u -t i o n of the crude product under the same c o n d i t i o n s gave two main peaks, the r e t e n t i o n times of which were i d e n t i c a l to those of 182a and 182b. 156 On the b a s i s of peak area, the r a t i o of 182a to 182b was 2.2:1. A t h i r d peak w i t h an area 57° that of 182a was a l s o present, r e t e n t i o n time 20.0 min. 32. Synthesis of 2,4-Diphenyl-3-aminomethylthietane 1,1-dioxide (193). 2,4-Diphenyl-3-aminomethylthietane 1,1-dioxide (193) was prepared from 2,4-diphenyl-3-cyanothietane 1,1-dioxide (178) by e i t h e r c a t a l y t i c hydrogenation or hydroboration. For the hydrogenation procedure, a Parr Pressure Reaction Appa-r a t u s No. 4511 w i t h a 1 l i t r e bomb was used. In the g l a s s l i n e r of the bomb were placed 5.0 g (0.018 mole) of f i n e l y powdered 178 and a s o l u t i o n prepared by bubbling dry ammonia i n t o 550 ml of dioxane u n t i l there was 1 g of NH3 per 100 ml of s o l v e n t . The dioxane had been p r e v i o u s l y p u r i -f i e d by r e f l u x i n g w i t h sodium f o r 12 hours and then d i s t i l l i n g . F i v e teaspoonsful of sponge n i c k e l c a t a l y s t (W.R. Grace & Co., No. 986) were s u c t i o n f i l t e r e d , washed w i t h a s m a l l amount of dioxane and added to the mixture. The c a t a l y s t was not allowed to dry at any time. The mixture was then sealed i n the pressure apparatus. A f t e r f l u s h i n g the bomb two times w i t h hydrogen, a pressure of 50 p s i was a p p l i e d and the r e a c t i o n was s t i r r e d f o r 21 hours. The c a t a l y s t was removed by s u c t i o n f i l t r a t i o n , washed w i t h dioxane and r a p i d l y covered w i t h water ( c a u t i o n : the c a t a l y s t i s h i g h l y pyrophoric i f allowed to dry a f t e r exposure to hydrogen). Evap-o r a t i o n of the f i l t r a t e pooled w i t h the washings, under vacuum, gave a pale green, v i s c o u s o i l . Upon adding a s m a l l amount of hexane - ethanol (50:50) and s c r a t c h i n g w i t h a g l a s s rod, 2.1 g (417.) of white s o l i d (193) separated. C r y s t a l l i z a t i o n from water - ethanol 95 gave large transparent prisms, mp 110-113° ( a f t e r d r y i n g under vacuum at 60° f o r 2 days); i r 157 (KBr) 3425, 3365 (N-H s t r e t c h i n g of 1° amine), 1310, 1165, 1150 cm" 1 ( s u l f o n e ) ; nmr (CDC1 3) S 7.61-7.23 (m, 10, phenyl p r o t o n s ) , 5.21 (d, 2, J = 10 Hz, protons at C-2 and C-4), 3.38-2.80 (m, 3, proton at C-3 and meth-ylene p r o t o n s ) , and 1.60-1.15 (band, 2, protons on N). A n a l . C a l c d . f o r C^H^NC^S: C, 66.87; H, 5.96; 0, 11.13; S, 11.16; mol. wt., 287.38. Found: C, 67.03; H, 6.32; 0, 11.32; S, 11.33. The p i c r a t e of 193 was prepared and c r y s t a l l i z e d from n - b u t y l a l c o h o l to give b r i g h t y e l l o w needles, mp 263° w i t h decomposition. For the hydroboration procedure, a s o l u t i o n of diborane i n THF, approximately 0.3 M, was prepared using a method from the l i t e r a t u r e (111, 132). A 500 ml three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r , a dropping funnel and a r e f l u x condenser p r o t e c t e d w i t h a d r y i n g tube was f l u s h e d w i t h dry n i t r o g e n and flame d r i e d . Upon c o o l i n g , 14.15 g (0.050 mole) of f i n e l y powdered 178 and 125 ml of dry THF were placed i n the f l a s k and the s t i r r e r was a c t i v a t e d . The dropping funnel was charged w i t h 250 ml of diborane s o l u t i o n (about 0.08 mole of B„H,), which was added dropwise L O over a p e r i o d of 1.5 hours. Three hours a f t e r the a d d i t i o n was completed, a c o l o u r l e s s s o l u t i o n was obtained. A f t e r s t i r r i n g f o r 13 hours, s u f f i -c i e n t ethanol 100 was added, i n p o r t i o n s , to decompose the excess diborane and the s o l u t i o n was heated at r e f l u x f o r 1 hour. Upon reducing the v o l -ume to about 100 ml by evaporation under reduced pressure, the s o l u t i o n was d i l u t e d w i t h 200 ml of anhydrous d i e t h y l ether and cooled i n an i c e -water bath. Treatment w i t h anhydrous HCl caused a white s o l i d to p r e c i p -i t a t e , which was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h d i e t h y l ether and s t o r e d i n a d e s i c c a t o r . A d d i t i o n of the ether washings to the f i l t r a t e caused more white s o l i d to separate, which was c o l l e c t e d and 158 t r e a t e d i n the same manner. A f t e r r e p e a t i n g t h i s process two more times, a t o t a l of 11.0 g of crude 193 was obtained as the HCl s a l t . When the s o l i d was shaken w i t h 200 ml of d i s t i l l e d water i n a separatory f u n n e l , not a l l the m a t e r i a l d i s s o l v e d . S u f f i c i e n t 18 N NaOH was added to gi v e a pH of 12 and the mixture was e x t r a c t e d w i t h two 100 ml p o r t i o n s and one 50 ml p o r t i o n of CHCl-j. The pooled CHCl^ e x t r a c t s were an opaque white and upon s u c t i o n f i l t e r i n g gave 1.1 g of white s o l i d and a transparent f i l t r a t e . A f t e r d r y i n g w i t h anhydrous Na2S0^, the f i l t r a t e was evaporated i n vacuo to give 7.20 g (507o) of 193. The white s o l i d f i l t e r e d from the CHCI3 e x t r a c t had a mp of 239-241° w i t h decomposition. In the i r spectrum (KBr) of the s o l i d no N-H s t r e t c h i n g a b s o r p t i o n was observed. Bands at 2510 and 1460 cm 1 were a t t r i b u t e d to B-H and B-N s t r e t c h i n g , r e s p e c t i v e l y (133a). A sample of the presumed aminoborane complex was r e f l u x e d f o r 10 min i n dioxane w i t h a few drops of cone. HCl. The re s i d u e obtained by evaporation of the solvent was d i s s o l v e d i n water, b a s i f i e d w i t h 5% NaOH, and e x t r a c t e d w i t h CHCl-j. Evaporation of the d r i e d e x t r a c t gave a l i g h t brown, v i s c o u s o i l . The i r spectrum (neat) of t h i s o i l was q u i t e s i m i l a r to that of 193 and showed N-H s t r e t c h i n g a b s o r p t i o n but no bands a t t r i b u t -able to a borane adduct. 33. Synthesis of 2-(4-Chlorophenyl)-3-aminomethyl-4-phenylthietane 1,1- d i o x i d e (194). The procedure was s i m i l a r to the diborane r e d u c t i o n d e s c r i b e d i n experiment 32, w i t h s e v e r a l m o d i f i c a t i o n s . To a s t i r r e d mixture of 12.9 g (0.041 mole) of 180 and 101 ml of dry THF was added 203 ml of 0.3 M diborane i n THF s o l u t i o n , dropwise, over a p e r i o d of 30 min. A f t e r s t i r r i n g f o r 22 hours, a s o l u t i o n was present to which 129 ml of ethanol 159 100 was added, i n p o r t i o n s , to decompose the excess diborane. A f t e r heat-in g at r e f l u x f o r 1 hour, the s o l u t i o n was allowed to c o o l and was t r e a t e d w i t h anhydrous HCl gas u n t i l i t turned a s l i g h t y e l l o w c o l o u r . Evaporation i n vacuo gave a pale y e l l o w syrup which was d i s s o l v e d i n 100 ml of d i s t i l l e d water. During the d i s s o l u t i o n step an i n s o l u b l e white s o l i d separated, which was c o l l e c t e d by s u c t i o n f i l t r a t i o n and d r i e d . The i r spectrum of t h i s m a t e r i a l , 0.9 g, corresponded n e i t h e r to that of 180 nor to that of the d e s i r e d product. The combined f i l t r a t e and water washings from the s o l i d were placed i n a separatory f u n n e l , b a s i f i e d w i t h 5 ml of 18 N NaOH and e x t r a c t e d w i t h two 100 ml p o r i t i o n s and one 50 ml p o r t i o n of CHCl-j. The pooled CHCl^ e x t r a c t s were washed w i t h two 100 ml p o r t i o n s of 107o NaCl so-l u t i o n and then d r i e d over anhydrous ^£80^. Evaporation under reduced pressure gave a white o i l which s o l i d i f i e d when placed under vacuum i n a d e s i c c a t o r f o r 6 hours. The white s o l i d (194) weighed 9.8 g (757») and had a mp of 39-45°; i r (KBr) 3500-3300 (N-H s t r e t c h i n g ) , 1320, 1150 cm" 1 ( s u l -f o n e ) ; nmr (CDCl.j) & 7.60-7.30 (m, 9, aromatic p r o t o n s ) , 5.23 (d, 1, J = 10 Hz, b e n z y l i c p r o t o n ) , 5.20 (d, 1, J = 10 Hz, p_-chlorobenzylie p r o t o n ) , 3.33-2.80 (m, 3, proton at C-3 and methylene p r o t o n s ) , and 1.18 ( s , 2, protons on N). The p i c r a t e of 194 was prepared by b r i e f l y warming a s o l u -t i o n of 0.76 g of the crude primary amine i n 5 ml of ethanol 95 w i t h 5 ml of a s a t u r a t e d , e t h a n o l i c s o l u t i o n of p i c r i c a c i d . The r e s u l t i n g y e l l o w p r e c i p i t a t e was c r y s t a l l i z e d from 107» aqueous a c e t i c a c i d to give s m a l l , f e a t h e r - l i k e y e l l o w c r y s t a l s , mp 249-250° w i t h decomposition. Compound 194 was submitted for a n a l y s i s as the p i c r a t e . A n a l . C a l c d . f o r C ^ H ^ C l N ^ S : C, 47.96; H, 3.48; N, 10.17; mol. wt., 550.93. Found: C, 48.31; H, 3.36; N, 10.03. 160 34. Synthesis of 2 , 4-Diphenyl - 3-dimethylaminomethylthietane 1 , 1-dioxide In a 50 ml round-bottom f l a s k f i t t e d w i t h a r e f l u x condenser were placed 1.77 g (0.0062 mole) of f i n e l y powdered 193, 3.2 g (0.06 mole) of 90.77o formic a c i d and 2.9 ml (0.04 mole) of 37% formaldehyde s o l u t i o n . A b o i l i n g stone was added and the mixture was heated at 90 ± 5° i n an o i l bath (134). W i t h i n 3 minutes a vigorous e v o l u t i o n of gas began and a pale y e l l o w s o l u t i o n was r a p i d l y obtained. A f t e r heating f o r 18 hours, the f l a s k was removed from the bath and allowed to c o o l to room temperature. The s o l u t i o n was mixed w i t h 6.5 ml of 4 N HCl and evaporated under vacuum to g ive a pal e y e l l o w , v i s c o u s o i l . The o i l was d i s s o l v e d i n 60 ml of d i s t i l l e d water and the r e s u l t i n g t u r b i d s o l u t i o n was t r a n s f e r r e d to a separatory f u n n e l , b a s i f i e d w i t h 2 ml of 18 N NaOH and e x t r a c t e d w i t h three 20 ml p o r t i o n s of CHCl-j. The CHCl-j e x t r a c t s were pooled, washed w i t h two 20 ml po r t i o n s of d i s t i l l e d water and d r i e d over anhydrous N a 2 S 0 ^ . Evap-o r a t i o n of the CHCl^ under reduced pressure gave 1.67 g (86%) of pale y e l -low s o l i d (9_). The i r spectrum of t h i s s o l i d was i d e n t i c a l to that of the c r y s t a l l i z e d m a t e r i a l . C r y s t a l l i z a t i o n from hexane - ethanol 100 w i t h c h a r c o a l treatment gave f i n e , white needles, mp 1 2 3 - 1 2 4 ° ; i r (KBr) 3085, 3060, 3005, 2970, 2880, 2840, 2810, 2790 (C-H s t r e t c h i n g ) , 1315, 1154 cm - 1 ( s u l f o n e ) ; nmr ( C D C I 3 ) S 7.63-7.27 (m, 10, phenyl p r o t o n s ) , 5.13 (d, 2, J = 10 Hz, protons at C-2 and C-4), 3.45-2.83 (m, 1, proton at C-3), 2.62 (d, 2, J = 6 Hz, methylene p r o t o n s ) , and 2.06 ( s , 6, N-methyl p r o t o n s ) . A n a l . C a l c d . f o r C l g H 2 1 N 0 2 S : C, 68.54; H, 6.71; N, 4.44; mol. wt., 315.44. Found: C, 68.74; H, 6.65; N, 4.58. The HCl s a l t of 9_ was prepared from pure f r e e base and i s o l a t e d as a pale cream-coloured s o l i d . Attempts to c r y s t a l l i z e the s a l t were 161 u n s u c c e s s f u l . Upon s i t t i n g i n the open, the d e r i v a t i v e l i q u i f i e d . 35. Synthesis of 2-(4-Chlorophenyl)-3-dimethylaminomethy 1-4-phenylthietane  1,1-dioxide (124). The procedure was s i m i l a r to that described i n experiment 34. To a 250 ml round-bottom f l a s k f i t t e d w i t h a condenser were added 9.0 g (0.028 mole) of crude _194, 40 ml of 90.7% formic a c i d and 36 ml of 37% formaldehyde s o l u t i o n . S e v e r a l b o i l i n g chips were added and the f l a s k was placed i n an o i l bath heated at 93 ± 1°. w i t h i n a few minutes a s o l u t i o n was obtained and a vigorous e v o l u t i o n of gas commenced. A f t e r heating f o r 19 hours, the f l a s k was allowed to c o o l to room temperature and 80 ml of 4 N HCl was added. Evaporation in vacuo gave a v i s c o u s , y e l l o w syrup, which was d i s s o l v e d i n 240 ml of d i s t i l l e d water, b a s i f i e d w i t h 25 ml of 18 N NaOH and e x t r a c t e d w i t h two 100 ml p o r t i o n s and one 50 ml p o r t i o n of CHCl-j. The pooled CHC1 3 e x t r a c t s were washed w i t h 100 ml of 10% NaCl so-l u t i o n , d r i e d over anhydrous Na^SO^, and evaporated under reduced pressure to give 9.6 g (98%) of pale y e l l o w s o l i d . The i r spectrum of the crude product was i d e n t i c a l to that of the p u r i f i e d m a t e r i a l . S e v e r a l c r y s t a l -l i z a t i o n s from hexane - ethanol 100 w i t h c h a r c o a l treatment gave 124 as s h o r t , white needles, mp 124-125°; i r (KBr) 3050, 2950, 2870, 2835, 2785 -1 (C-H s t r e t c h i n g ) , 1325, 1155 cm ( s u l f o n e ) ; nmr (CDC1 3) 67.48 ( s , 9, aro-matic p r o t o n s ) , 5.13 (d, 1, J = 10 Hz, b e n z y l i c p r o t o n ) , 5.09 (d, 1, J = 10 Hz, p_-chlorobenzylic p r o t o n ) , 3.39-2.75 (m, 1, proton at C-3), 2.60 (d, 2, J = 6 Hz, methylene p r o t o n s ) , and 2.06 ( s , 6, N-methyl p r o t o n s ) . A n a l . C a l c d . f o r C 1 8H 2 ( )C1N0 2S: C, 61.79; H, 5.76; N, 4.00; mol. wt., 349.88. Found: C, 61.64; H, 5.81; N, 3.91. 162 36. Synches i s of 2-(4-Nitropheny1)-3-dimethylaminomethy1-4-phenylthietane  1,1-dioxide (125). Using a procedure s i m i l a r to that described i n experiment 32, 9.0 g (0.027 mole) of 181, d i s s o l v e d i n 73 ml of dry THF, was reacted w i t h 146 ml of 0.3 M diborane i n THF for 21 hours at room temperature. A f t e r adding 90 ml of ethanol 100 i n p o r t i o n s to decompose the excess diborane, the pale y e l l o w s o l u t i o n was r e f l u x e d f o r 30 min and then evaporated i n vacuo to give a y e l l o w , v i s c o u s o i l . When the o i l was d i s s o l v e d i n CHCl^, a white s o l i d (0.4 g) separated which was removed by s u c t i o n f i l t r a t i o n . E vaporation of the f i l t r a t e under reduced pressure gave a y e l l o w syrup which was r e d i s s o l v e d i n 20 ml of CHCI3 - ethanol 100 (9:1) and chromato-graphed i n two equal p o r t i o n s on 60 x 2.5 cm s i l i c a g e l columns (60-200 mesh, 94 g per column), using CHCl-j - ethanol 100 (9:1) as the developing s o l v e n t . Two main f r a c t i o n s were obtained from each column. The second f r a c t i o n s were pooled and evaporated under vacuum to gi v e 5.9 g (66%) of pale y e l l o w , v i s c o u s o i l , which d i d not s o l i d i f y when t r i t u r a t e d w i t h v a r -ious s o l v e n t s . The o i l appeared to be the d e s i r e d r e d u c t i o n product 2-(4-nitropheny1)-3-aminomethy1-4-phenylthietane 1,1-dioxide (195), according to s p e c t r o s c o p i c evidence; i r (neat) 3400, 3340 (N-H s t r e t c h i n g ) , 1515, 1350 ( n i t r o group), 1310, 1150 cm" 1 ( s u l f o n e ) ; nmr (CDC1 3) * 8.41-8.13 (m, 2, protons ortho to n i t r o group), 7.85-7.55 (m, 2, protons meta to n i t r o group), 7.55-7.32 (m, 5, phenyl p r o t o n s ) , 5.37 (d, 1, J = 10 Hz, p_-nitro-b e n z y l i c p r o t o n ) , 5.31 (d, 1, J = 10 Hz, b e n z y l i c p r o t o n ) , 3.41-2.88 (m, 3, proton at C-3 and methylene p r o t o n s ) , and 1.20 ( s , 2, protons on N). Minor impurity s i g n a l s were observed i n the nmr spectrum at S 1.07 and 0.98. The d i m e t h y l a t i o n r e a c t i o n was c a r r i e d out as described i n exper-iment 34. A mixture of 4.8 g (0.015 mole) of crude primary amine 195, 23 163 ml of 90.1% formic a c i d and 20 ml of 377, formaldehyde s o l u t i o n was heated at 93 ± 1° f o r 11 hours. A d d i t i o n . o f 44 ml of 4 N HCl followed by evapo-r a t i o n in vacuo gave a reddish-orange, transparent syrup. The syrup was d i s s o l v e d i n 50 ml of d i s t i l l e d water, b a s i f i e d w i t h 3 ml of 18 N NaOH and e x t r a c t e d w i t h three 50 ml p o r t i o n s of CHCl-j. The pooled CHCl-j e x t r a c t s were washed w i t h 100 ml of 107« NaCl s o l u t i o n , d r i e d over anhydrous Na2SO^ and then evaporated under reduced pressure to give 3.5 g of straw-coloured syrup (125). The syrup was d i s s o l v e d i n 150 ml of anhydrous d i e t h y l e t h e r , t r e a t e d w i t h HCl gas, and the r e s u l t i n g white p r e c i p i t a t e was c o l l e c t e d by s u c t i o n f i l t r a t i o n i n a dry n i t r o g e n atmosphere. An attempt to c r y s -t a l l i z e the s a l t from anhydrous d i e t h y l ether - absolute ethanol was un-s u c c e s s f u l . A s o l u t i o n of the s a l t i n 50 ml of d i s t i l l e d water was n e u t r a l -i z e d w i t h a saturated aqueous s o l u t i o n of Na2C0 3, which caused the forma-t i o n of a copious white p r e c i p i t a t e . The s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h d i s t i l l e d water and placed i n a d e s i c c a t o r . W i t h i n an hour, the s o l i d darkened and r e v e r t e d to a straw-coloured syrup. While s i t t i n g f o r two weeks i n a d e s i c c a t o r , the syrup s o l i d i f i e d to give 125 as a g l a s s , mp 39-43°; i r (KBr) 3105, 3085, 3048, 2990, 2960, 2880, 2840, 2795 (C-H s t r e t c h i n g ) , 1520, 1350 ( n i t r o group), 1320, 1155 cm" 1 ( s u l f o n e ) ; nmr (CDCl^) & 8.44-8.19 (m, 2, protons ortho to n i t r o group), 7.87-7.58 (m, 2, protons meta to n i t r o group), 7.50 ( s , 5, phenyl p r o t o n s ) , 5.23 (d, 1, J = 10 Hz, £-nitrobenzylie pr o t o n ) , 5.17 (d, 1, J = 10 Hz, b e n z y l i c pro-t o n ) , 3.35-2.83 (m, 1, proton at C-3), 2.64 (d, 2, J = 6 Hz, methylene p r o t o n s ) , and 2.10 ( s , 6, N-methyl pr o t o n s ) . Only minor extraneous s i g -n a l s occurred atS 2.25 and 1.92 i n the nmr spectrum. The p i c r i c a c i d d e r i v a t i v e of 125 was obtained as a y e l l o w , amorphous s o l i d . However, attempts to c r y s t a l l i z e the p i c r a t e were u n s u c c e s s f u l . 164 37. Synthesis of 2,4-Dipheny1-3-carboxythietane 1,1-dioxide (196). In a 200 ml round-bottom f l a s k f i t t e d w i t h a r e f l u x condenser were placed 10.00 g (0.0353 mole) of 2,4-dipheny1-3-cyanothietane 1,1-d i o x i d e (178) and 70 ml of DMSO. A b o i l i n g stone was added and the mix-ture was heated to give a s o l u t i o n . To the s o l u t i o n was added 50 ml of 507» B^SO^ and the r e s u l t i n g mixture was heated at r e f l u x . A f t e r one hour, a transparent, beige-coloured s o l u t i o n was obtained, which was r e f l u x e d f o r another 2 hours and then was allowed to c o o l to room temperature. While c o o l i n g , the s o l u t i o n became t r a n s l u c e n t and a white s o l i d began to sepa-r a t e . The r e a c t i o n mixture was poured onto 200 g of crushed i c e w i t h s t i r -r i n g to give an o f f - w h i t e , f l u f f y s o l i d . This was f u r t h e r d i l u t e d w i t h about 500 ml of d i s t i l l e d water and the s o l i d was c o l l e c t e d by s u c t i o n f i l t r a t i o n , washed w i t h water and d r i e d i n a d e s i c c a t o r o v e r n ight. Crys-t a l l i z a t i o n from 1,2-dichloroethane gave 9.45 g (897») of 196 as w h i t e , f l u f f y needles, mp 223-224°; i r (KBr) 3270 ( c a r b o x y l OH), 1730 ( c a r b o x y l c a r b o n y l ) , 1305, 1172, 1130 cm"1 ( s u l f o n e ) ; nmr (DMSO-d,) S 7.83-7.33 (m, 6 10, phenyl p r o t o n s ) , 5.90 (d, 2, J = 10 Hz, protons at C-2 and C-4), and 4.15 ( t , 1, J = 10 Hz, proton at C-3). A n a l . C a l c d . f o r C 1 6 H 1 4 S 0 4 : C, 63.56; H, 4.67; S, 10.60; mol. wt., 302.35. Found: C, 63.40; H, 4.79; S, 10.54. 38. Synthesis of 2,4-Diphenyl-3-acetylthietane 1,1-dioxide (197). In a dry, 1 l i t r e round-bottom f l a s k f i t t e d w i t h a condenser which was p r o t e c t e d from atmospheric moisture by a d r y i n g tube were placed 40.00 g (0.132 mole) of 196 and 400 ml of f r e s h l y d i s t i l l e d t h i o n y l c h l o -r i d e (BDH, r e a . ) . The mixture was heated to r e f l u x temperature. A f t e r r e f l u x i n g f o r 1.5 hours, a pale orange s o l u t i o n was obtained. The reac-165 t i o n was r e f l u x e d for a t o t a l of 5 hours and allowed to c o o l to room temperature. Evaporation of the excess t h i o n y l c h l o r i d e under reduced pressure i n a fume hood gave a cream-coloured s o l i d (199), mp 140-141°; i r (KBr) 1780, 1740 (sh) ( a c i d c h l o r i d e c a r b o n y l ) , 1333, 1180, 1137 cm - 1 ( s u l f o n e ) . The r e a c t i o n was r e a d i l y f o l l o w e d by observing the decrease i n i n t e n s i t y of the c a r b o x y l i c a c i d bands at 3270 and 1730 cm 1 and the concomitant increase i n i n t e n s i t y of the a c i d c h l o r i d e band at 1780 cm 1 i n the i n f r a r e d s p e c t r a of samples removed at i n t e r v a l s . The a c i d c h l o -r i d e was s t o r e d i n a d e s i c c a t o r under vacuum u n t i l needed. A sample of 199 l e f t s i t t i n g i n the open for s e v e r a l days r e v e r t e d to the c a r b o x y l i c a c i d 196. The f o l l o w i n g procedure was adopted from the l i t e r a t u r e (131b). A 250 ml three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r , dropping f u n n e l , gas i n l e t and a F r i e d r i c h condenser and p r o t e c t e d from atmospheric moisture w i t h a d r y i n g tube was f l u s h e d w i t h dry n i t r o g e n and flame d r i e d . A dry n i t r o g e n atmosphere was provided throughout the r e a c t i o n . Upon c o o l i n g , 4.01 g (0.165 mole) of Mg turnings ( p r e v i o u s l y washed w i t h an-hydrous ether and oven d r i e d ) was placed i n the f l a s k , f o l l o w e d by 40 ml of dry THF and a small piece of i o d i n e . A s o l u t i o n of bromomethane (East-man, p r a c ) , 20.00 g (0.211 mole), i n 80 ml of dry THF was placed i n the dropping f u nnel and approximately 10 ml was drained i n t o the f l a s k w i t h s t i r r i n g . The f l a s k was g e n t l y warmed usin g a lukewarm water bath. Once the r e a c t i o n began, the bath was removed and the remainder of the s o l u -t i o n was added at such a r a t e as to maintain a moderate r e f l u x . A f t e r c o o l i n g to room temperature, the f l a s k c o n t a i n i n g the dark, almost b l a c k Grignard reagent was cooled i n an ice-water bath. Anhydrous CdCl2> 15.13 g (0.0825 mole), was added i n p o r t i o n s over a p e r i o d of 5 min w i t h e f f i -166 c i e n t s t i r r i n g to give a gray suspension. The bath was removed and the r e a c t i o n was heated to r e f l u x temperature, which caused the mixture to turn b l a c k . A f t e r r e f l u x i n g f o r 1 hour, a Gilman t e s t (131b) was performed on a sample from the r e a c t i o n and found to be negative. The f l a s k was allowed to c o o l to room temperature and then cooled i n an ice-water bath. The crude a c i d c h l o r i d e 199, 43 g (0.13 mole), was d i s s o l v e d i n 140 ml of dry THF and the yel l o w s o l u t i o n was placed i n the dropping funnel and drained i n t o the f l a s k over a pe r i o d of 3 min w i t h vigorous s t i r r i n g . When the a d d i t i o n was completed, the bath was removed and the r e a c t i o n was s t i r r e d at room temperature f o r 8 hours. Approximately 180 ml of THF was evaporated o f f under reduced pressure and 200 ml of CHCl-j was slow l y added. The gray mixture was poured, w i t h s t i r r i n g , onto a mixture of 200 g of crushed i c e and 100 ml of d i l u t e H^SO^. The r e s u l t i n g mixture was t r a n s f e r r e d to a separatory f u n n e l , the y e l l o w CHCl-j l a y e r was drained o f f and the c o l o u r l e s s aqueous l a y e r was e x t r a c t e d w i t h 100 and 50 ml p o r t i o n s of CHC1.J. The combined CHCl^ e x t r a c t s were d r i e d over anhydrous MgSO^ and evaporated _in vacuo to g i v e a v i s c o u s , beige syrup. I n f r a r e d a n a l y s i s (neat) i n d i c a t e d the presence of the c a r b o x y l i c a c i d 196 and a compound w i t h strong carbonyl a b s o r p t i o n at 1715 cm *. The syrup was d i s s o l v e d i n 150 ml of CHCl-j and 196 was removed by e x t r a c t i n g w i t h two 100 ml p o r t i o n s of 107o NaOH s o l u t i o n . A c i d i f i c a t i o n of the pooled b a s i c e x t r a c t s gave a 22.57» recovery of the c a r b o x y l i c a c i d . The CHCl^ l a y e r was washed w i t h two 100 ml p o r t i o n s of d i s t i l l e d water, d r i e d over anhydrous MgSO^, and then evaporated under reduced pressure to a f f o r d a pale y e l l o w , v i s c o u s syrup. Upon adding a few drops of absolute methanol to the syrup and s c r a t c h i n g the mixture w i t h a g l a s s rod, a white s o l i d (197), 27.03 g (68.47.), was obtained. Two c r y s t a l l i z a t i o n s from d i s t i l l e d water - ethanol 167 95 w i t h c h a r c o a l treatment gave 197 was wh i t e , f e a t h e r - l i k e c r y s t a l s , mp 124-125°. A t h i r d c r y s t a l l i z a t i o n from hexane - ethanol 100 gave shiny white l e a f l e t s , mp 125-126°; i r (KBr) 1715, 1364 (methyl ketone), 1330, 1172, 1140 cm"1 ( s u l f o n e ) ; nmr (CDC1 3) S7.64-7.32 (m, 10, phenyl p r o t o n s ) , 5.50 (d, 2, J = 10 Hz, protons at C-2 and C-4), 3.90 ( t , 1, J = 10 Hz, proton at C-3),. and 2.03 ( s , 3, methyl p r o t o n s ) . A n a l . C a l c d . f o r C 1-,H 1,0 oS: C, 67.98; H, 5.37; S, 10.67; mol. wt., 1/ l o 3 300.37. Found: C, 68.15; H, 5.33; S, 10.64. The oxime d e r i v a t i v e 200 of 2 , 4 - d i p h e n y l - 3 - a c e t y l t h i e t a n e 1,1-d i o x i d e was prepared using a method from the l i t e r a t u r e (135). C r y s t a l -l i z a t i o n from d i s t i l l e d water - ethanol 95 gave 200 as s m a l l white needles, mp 181-186° w i t h decomposition; i r (KBr) 3440 (0-H s t r e t c h i n g ) , 1315, 1170, 1135 cm" 1 ( s u l f o n e ) ; nmr (DMSO-d.)S 7.80-7.36 (m, 10, phenyl p r o t o n s ) , 6 5.81 (d, 2, J = 10 Hz, protons at C-2 and C-4), 4.08 ( t , 1, J = 10 Hz, proton at C-3), and 1.68 ( s , 3, methyl p r o t o n s ) . 39. Synthesis of 2 , 4 - D i p h e n y l - 3 - ( l - n i t r o e t h y l ) - t h i e t a n e 1,1-dioxide (201). The b a s i c s o l u t i o n r e f e r r e d to i n this procedure was prepared by d i s s o l v i n g 1.0 g of KOH i n 10 ml of ethanol 95 and adding 5 ml of n i t r o -ethane (M.C. & B., p r a c ) . The s o l u t i o n (approx. 1.2 N) was m a g n e t i c a l l y s t i r r e d f o r 15 min, during which time i t became a pale y e l l o w . In a 500 ml c o n i c a l f l a s k were placed 4.50 g (0.0176 mole) of 2, 4 - d i p h e n y l t h i e t e 1,1-dioxide (152) and 90 ml of n i t r o e t h a n e . The mix-ture was s t i r r e d m a g n e t i c a l l y to give a s o l u t i o n , which was then d i l u t e d w i t h 90 ml of ethanol 95. Upon adding 9.0 ml of b a s i c s o l u t i o n , the r e -a c t i o n turned a b r i g h t y e l l o w . The s o l u t i o n was s t i r r e d f o r 7 hours, dur-ing which time i t became somewhat t u r b i d . The a d d i t i o n of 9.0 ml of g l a c i a l 168 a c e t i c a c i d caused the mixture to turn almost c o l o u r l e s s . Removal of the so l v e n t under reduced pressure gave a white s o l i d , which was t r i t u r a t e d w i t h d i s t i l l e d water, s u c t i o n f i l t e r e d and d r i e d i n a d e s i c c a t o r . C r y s t a l -l i z a t i o n from hexane - benzene gave 4.79 g (73.57o) of 201 as f i n e , white needles, mp 1 8 1 - 1 8 2 ° ; i r (KBr) 1554 ( n i t r o group), 1324 ( n i t r o group and s u l f o n e ) , 1147 cm 1 ( s u l f o n e ) . The nmr spectrum (CDCl^) showed a doublet a t 5 7.48 (phenyl protons, 10), a t r i p l e t a t t r i b u t e d to two o v e r l a p p i n g d o u b l e t s , one at S5.33 ( b e n z y l i c proton e, 1, J ^  = 10 Hz) and the other at 5 5.14 ( b e n z y l i c proton d, 1, = 11 Hz), a m u l t i p l e t centred at 5 4.83 (proton c, X to n i t r o group, 1, J , = 8 Hz, J =7 Hz), a m u l t i p l e t cen-CD C d t r e d at S 3.50 (remaining r i n g proton b, 1, J ^ e = 10 Hz, = 11 Hz, = 8 Hz), and a doublet at $ 1.33 (methyl protons a, 3, J a c = 7 Hz). The high f i e l d s i g n a l of the doublet at 55.14 overlapped the low f i e l d s i g n a l of the m u l t i p l e t at 6 4.83. A s i n g l e t at 5 7.38 w i t h an i n t e g r a l e q u i v a l e n t to 3 protons was a t t r i b u t e d to benzene. The magnitude of the i n t e g r a l suggested that c r y s t a l l i z a t i o n of the product from hexane - benzene occurred w i t h the i n c l u s i o n of one molecule of benzene f o r every two molecules of 201 i n the c r y s t a l l a t t i c e . A n a l y s i s by g l c of a s o l u t i o n , prepared by d i s s o l v i n g 20.0 mg of c r y s t a l s i n 1.20 ml of anhydrous DMSO, on a 6 f t x 5/32 i n ( i . d . ) s i l a n i z e d g l a s s column packed w i t h 3% 0V-225 on Gas-Chrom Q (100-120 mesh) w i t h the i n j e c t i o n p o r t , oven and detector at 250, 35 and 2 7 2 ° , r e s p e c t i v e l y , and the n i t r o g e n flow at 32 ml/min, gave one peak w i t h a r e t e n t i o n time of 3.4 min, i d e n t i c a l to that obtained f or benzene when chromatographed under the same c o n d i t i o n s . The c a l c u l a t e d c o n c e n t r a t i o n of benzene i n the s o l u t i o n was 1.76 mg/ml, i f the e f f e c t of s o l u t e volume on s o l u t i o n volume was ignored ( c a l c u l a t i o n based on a 1 to 2 complex be-tween benzene and 201). The area of the peak obtained by i n j e c t i n g 1 ^ \ 169 of a refe r e n c e s o l u t i o n c o n t a i n i n g 1.76 mg/ml of benzene i n DMSO was i d e n t i c a l to that obtained by applying an equal volume of the sample s o l u t i o n . The r e t e n t i o n time of hexane under the described c o n d i t i o n s was 1.2 min. The s o l v e n t , DMSO, d i d not come o f f the column under these c o n d i t i o n s . The product 201 was submitted f or a n a l y s i s as the'benzene-c o n t a i n i n g c r y s t a l s . A n a l . C a l c d . f o r (C H NO.S) . C H : C, 64.85; H, 5.44; N, 3.78; 0, 17 17 H- 2 6 £> 17.28; S, 8.65; mol. wt., 740.89. Found; C, 65.04; H, 5.31; N, 3.96; 0, 17.33; S, 8.62. S c a l i n g the r e a c t i o n up by a f a c t o r of 3 or using crude 152 d i d not a f f e c t the percentage y i e l d of 201 s i g n i f i c a n t l y . 40. Synthesis of 2,4-Dipheny1-3-(1-dimethylaminoethyl)-thietane 1,1-dioxide  (123). Method A. Reduction of 2 , 4 - d i p h e n y l - 3 - ( l - n i t r o e t h y l ) - t h i e t a n e 1,1-dioxide (201) to the corresponding primary amine 202 and subsequent d i m e t h y l a t i o n . A s o l u t i o n prepared by d i s s o l v i n g 4.00 g (0.0121 mole) of 201 i n 30 ml of THF and . d i l u t i n g w i t h 50 ml of ethanol 100 was placed i n the b o t t l e of a Parr hydrogenator. To the s o l u t i o n was added 8 g of sponge n i c k e l c a t a l y s t (W.R. Grace & Co., No. 986), which had been p r e v i o u s l y s u c t i o n f i l t e r e d and washed w i t h ethanol 100. The b o t t l e was attached to the hydrogenator r e s e r v o i r and the system was purged 5 times w i t h hydro-gen. With the hydrogen pressure at 52 p s i , the shaker was a c t i v a t e d and the hydrogenation was c a r r i e d out f o r 7 hours. The c a t a l y s t was then c a u t i o u s l y removed by g r a v i t y f i l t r a t i o n , washed w i t h THF and placed under water. At no time was the c a t a l y s t allowed to go dry, as i t was h i g h l y pyrophoric. The pale y e l l o w f i l t r a t e was combined w i t h the THF washings 170 and evaporated under reduced pressure to give a v i s c o u s , pale y e l l o w syrup. A n a l y s i s by t i c using microscope s l i d e s coated w i t h s i l i c a g e l G, benzene -ethanol 100 (9:1) as developing s o l v e n t and c h a r r i n g as the v i s u a l i z a t i o n method, i n d i c a t e d the presence of two major components and the absence of 201. The syrup was d i s s o l v e d i n 20 ml of CHCl-j and e x t r a c t e d w i t h two 20 ml p o r t i o n s of 4 N HCl f o l l o w e d by one 20 ml p o r t i o n of d i s t i l l e d water. The pooled aqueous e x t r a c t s were evaporated in vacuo to give an almost c o l o u r l e s s , v i s c o u s o i l . The o i l was d i s s o l v e d i n 20 ml of d i s t i l l e d water, 3 ml of 18 N NaOH was added and the r e s u l t i n g white p r e c i p i t a t e was e x t r a c t e d w i t h two 20 ml p o r t i o n s and one 10 ml p o r t i o n of CHCl-j. The pooled CHCl-j e x t r a c t s were washed w i t h 107., NaCl s o l u t i o n , d r i e d over an-hydrous Na 2S0 4 and evaporated under reduced pressure to give 2.19 g (607») of 2,4-dipheny1-3-(1-aminoethy1)-thietane 1,1-dioxide (202) as a pale y e l -low s o l i d , mp 145-147°; i r (KBr) 3440-3360 (N-H s t r e t c h i n g ) , 1310, 1145 cm" 1 ( s u l f o n e ) ; nmr (CDCl-j) <S 7.67-7.30 (m, 10, phenyl p r o t o n s ) , 5.26 (d, 1, J = 10 Hz, b e n z y l i c p r o t o n ) , 5.16 (d, 1, J = 10 Hz, remaining b e n z y l i c p roton), 3.50-2.65 (m, 2, proton at C-3 and proton * to NH 2 group), 1.22 ( s , 2, protons on N), and 0.87 (d, 3, J = 6.5 Hz, methyl p r o t o n s ) . The primary amine was not submitted f o r elemental a n a l y s i s . The CHC1.J layer from the a c i d e x t r a c t i o n was washed w i t h d i s t i l l e d water, d r i e d over anhydrous Na 2S0 4 and then evaporated under reduced pres-sure to give a beige s o l i d (1.36 g, 3670) . This was the second main com-ponent observed by the t i c a n a l y s i s of the crude hydrogenation product. The i r and nmr s p e c t r a of the c r y s t a l l i z e d s o l i d (water - ethanol 95) were superimposable w i t h those of 2,4-dipheny1-3-acetylthietane 1,1-dioxide oxime (200). The primary amine 202 was dimethylated using a procedure s i m i l a r to that d e s c r i b e d i n experiment 34. Crude 202, 2.2 g (0.007 mole), was mixed w i t h 6.6 ml of 90.77» formic a c i d and 6.0 ml of 377o formaldehyde so-l u t i o n and heated at 93 ± 1° f o r 3 hours. A f t e r c o o l i n g to room temper-at u r e , 20 ml of 4 N HCl was added and the s o l u t i o n was evaporated i j i vacuo to g i v e a v i s c o u s syrup. The syrup was r e d i s s o l v e d i n 10 ml of d i s t i l l e d water, 3 ml of 18 N NaOH was added, and the r e s u l t i n g p r e c i p i t a t e was ex-t r a c t e d w i t h two 20 ml p o r t i o n s and one 10 ml p o r t i o n of CHCl^. The pooled CHC1 e x t r a c t s were washed w i t h 50 ml of 107o NaCl s o l u t i o n , d r i e d over an-3 hydrous Na 2S0^ and then evaporated under reduced pressure to g i v e 1.9 g (797») of pale beige s o l i d (123) . The i r spectrum of t h i s s o l i d was iden-t i c a l to that of the c r y s t a l l i z e d m a t e r i a l . C r y s t a l l i z a t i o n from hexane -ethanol 100 w i t h c h a r c o a l treatment gave 123 as white needles, mp 145-146°; i r (KBr) 3075, 3045, 2980, 2950, 2880 (C-H s t r e t c h i n g ) , 1310, 1150 cm" 1 ( s u l f o n e ) ; nmr (CDCl-j) S 7.70-7.31 (m, 10, phenyl p r o t o n s ) , 5.26 (d ( w i t h shoulder a b s o r p t i o n ) , 1, J = 9 Hz, b e n z y l i c p r o t o n ) , 5.07 (d ( w i t h s h o u l -der a b s o r p t i o n ) , 1, J = 9 Hz, remaining b e n z y l i c p r o t o n ) , 3.25-2.67 (m, 2, proton at C-3 and proton tX to N ( C H 3 ) 2 group), 1.97 ( s , 6, N-methyl pro-tons) and 0.75 (d, 3, J = 6 Hz, methyl p r o t o n s ) . A n a l . C a l c d . f o r C 1 9H 23N0 2S: C, 69.27; H, 7.04; N, 4.25; mol. wt., 329.46. Found: C, 69.17; H, 7.03; N, 4.43. Method B. Reduction of 2 , 4 - d i p h e n y l - 3 - a c e t y l t h i e t a n e 1,1-dioxide oxime (200) as i t s acetate e s t e r to the corresponding primary amine 202 and sub-sequent d i m e t h y l a t i o n . The acetate e s t e r of 200 was s y n t h e s i z e d u s i n g a method adopted from the l i t e r a t u r e (136). In a stoppered 250 ml c o n i c a l f l a s k were placed 2.24 g (0.0071 mole) of c r y s t a l l i n e ^00 and 25 ml of dry THF. A f t e r s t i r -r i n g the mixture m a g n e t i c a l l y to o b t a i n a c o l o u r l e s s s o l u t i o n , the f l a s k 172 was placed i n an ice-water bath and allowed to c o o l . Then 2.0 ml of a c e t y l c h l o r i d e was added and the r e a c t i o n was s t i r r e d f o r 1.5 hours. Evaporation of the s o l v e n t under reduced pressure gave a l i q u i d r e s i d u e , which was d i s s o l v e d i n 100 ml of d i e t h y l ether, washed w i t h 200 ml of 37. NaHCO-j s o l u t i o n and d r i e d over anhydrous Na2S0 4. Evaporation of the ether gave 2.35 g (947.) of pale y e l l o w , v i s c o u s o i l (204) . When a sample of the o i l was mixed w i t h hexane and rubbed w i t h a g l a s s rod on a watchglass, a white s o l i d separated, mp 55-65°; i r (KBr) 1762 (ester c a r b o n y l ) , 1325, 1175, 1137 ( s u l f o n e ) , 1206 cm 1 (ester band). Attempts to c r y s t a l l i z e the crude e s t e r from v a r i o u s s o l v e n t s were u n s u c c e s s f u l . Therefore, 204 was used i n the hydroboration step (120) without p u r i f i c a t i o n . In a dry 50 ml r e a c t i o n f l a s k f i t t e d w i t h a mechanical s t i r r e r , a dropping f u n n e l , a n i t r o g e n i n l e t and a r e f l u x condenser protected from atmospheric moisture by a d r y i n g tube were placed 1.2 g (0.003 mole) of 204 and 20 ml of dry THF. The mixture was s t i r r e d to give a pale y e l l o w s o l u t i o n . The drop-ping funnel was then charged w i t h 25 ml of 0.3 M diborane s o l u t i o n (exper-iment 32), which was added dropwise over a p e r i o d of 20 min. The f i r s t few drops of diborane s o l u t i o n d e c o l o u r i z e d the e s t e r s o l u t i o n . A f t e r the a d d i t i o n was complete, the r e a c t i o n was s t i r r e d f o r 16 hours. A dry n i t r o -gen atmosphere was provided throughout t h i s time. Upon adding 6 ml of d i s t i l l e d water dropwise to decompose the excess diborane, the c o l o u r l e s s s o l u t i o n was g e n t l y r e f l u x e d f o r one hour. Removal of the s o l v e n t i n  vacuo gave a white s o l i d . Although not i s o l a t e d , p a r t of t h i s s o l i d was considered to c o n s i s t of 2 , 4 - d i p h e n y l - 3 - ( l - a m i n o e t h y l ) - t h i e t a n e 1,1-dioxide (202) . The crude product was t r e a t e d w i t h 5 ml of 90.77, formic a c i d and 4.5 ml of 377. formaldehyde s o l u t i o n as described above f o r the p r e p a r a t i o n of 123. Work-up gave 0.16 g (147.) of l i g h t y e l l o w s o l i d (123) . The crude m a t e r i a l was c r y s t a l l i z e d from hexane - ethanol 100 to a f f o r d 123 as white needles, mp 144-145°. The i r spectrum (KBr) was superimposable w i t h that of the m a t e r i a l obtained by Method A. 174 PHARMACOLOGICAL TESTING To complete the o b j e c t i v e s of t h i s i n v e s t i g a t i o n , compounds 9^  123, 124 and 125 were test e d f o r a n a l g e t i c a c t i v i t y . Three t e s t procedures were employed: (A) the mouse hot p l a t e method as described by Janssen and Jageneau (138); (B) the phenylquinone w r i t h i n g method i n mice as o u t l i n e d by Blumberg, e_t al. (139); and (C) the e l e c t r i c a l l y s t i m u l a t e d guinea-pig ileum method as described by Cox and Weinstock (140). The use of proce-dure C i s based on the a b i l i t y of n a r c o t i c a n a l g e t i c s to depress the e l e c -t r i c a l l y induced c o n t r a c t i o n s of the guinea-pig ileum. Procedure C was modified somewhat from that o u t l i n e d by Cox and Weinstock (140). The arrangement for e l e c t r i c a l s t i m u l a t i o n of the ileum was more s i m i l a r to that o r i g i n a l l y d escribed by Paton (141). The g l a s s tubing to which the lower end of the gut was t i e d was of such a l e n g t h that i t s open end protruded approximately 1 cm above the bath s u r f a c e . Gut movements were recorded by a t t a c h i n g the polyethylene tubing c o v e r i n g the ileum e l e c t r o d e to a microdisplacement myograph transducer (E & M I n s t r u -ment Co.) which was connected to a type PMP-4A Physiograph (E & M I n s t r u -ment Co.). A f t e r a p p l y i n g a tension of 2 g, the l e n g t h of the ileum s t r i p was approximately 4 cm. The t i s s u e was s t i m u l a t e d by s i n g l e shocks w i t h a pulse w i d t h of 0.5 m i l l i s e c o n d s , d e l i v e r e d every 10 seconds from a Grass S8 s t i m u l a t o r . The v o l t a g e was adjusted i n i t i a l l y to give a maximal r e -sponse. The volume of the organ bath was 15 ml and compounds were added i n a volume of 0.1 ml. The contact time f o r t e s t and reference compounds was 3 minutes and the i n t e r v a l between a d d i t i o n s of agents to the bath was 25 - 30 minutes. Only 2,4-dipheny1-3-dimethylaminomethylthietane 1,1-dioxide (9) 175 was t e s t e d by a l l three methods. The known r e l a t i v e i n s e n s i t i v i t y of the hot p l a t e method (142) and the f a c t that compound 9 was found to be in a c -t i v e by t h i s assay procedure prompted the adoption of the phenylquinone w r i t h i n g method (method B). The l i m i t e d supply of 2 , 4 - d i p h e n y l - 3 - ( l - d i -methylaminoethyl)-thietane 1 , 1-dioxide (123) allowed f o r t e s t i n g of t h i s compound by method B only. . 2 - ( 4-Chlorophenyl ) - 3-dimethylaminomethyl - 4 -p h e n y l t h i e t a n e 1 , 1-dioxide (124) and 2 - ( 4-nitrophenyl ) - 3-dimethylamino-methy1 - 4-phenylthietane 1 , 1-dioxide (125) were examined by the s e n s i t i v e i s o l a t e d t i s s u e procedure, C. For t e s t i n g purposes, the h y d r o c h l o r i d e s a l t s of 9_, 123, 124 and 125 were prepared by t r e a t i n g anhydrous d i e t h y l ether s o l u t i o n s of the pur-i f i e d bases w i t h hydrogen c h l o r i d e gas and then c o l l e c t i n g the white pre-c i p i t a t e s by s u c t i o n f i l t r a t i o n . The s a l t s were st o r e d i n a d e s i c c a t o r u n t i l needed. During storage, the h y d r o c h l o r i d e s a l t of 125 changed to a ye l l o w o i l and was used i n t h i s form. Other drugs employed were morphine s u l f a t e ( B r i t i s h Drug Houses), methadone h y d r o c h l o r i d e (Pitman-Moore, 10 mg/ml i n j e c t i o n USP, w i t h 1.5% b e n z y l a l c o h o l ) and phenylquinone (phenyl-£-benzoquinone, Eastman). With the exception of phenylquinone, a l l s o l u t i o n s were prepared us i n g d i s t i l l e d water. The 0.027, pheny lquinone s o l u t i o n (140) was prepared d a i l y by d i s s o l v i n g 20 mg of the compound i n 5 ml of ethanol 100 and d i l u t -i n g to a volume of 100 ml w i t h d i s t i l l e d water. The s o l u t i o n was kept at 37° i n order to prevent p r e c i p i t a t i o n of the w r i t h i n g agent. S a l i n e s o l u -t i o n was 0.97o sodium c h l o r i d e i n d i s t i l l e d water. In procedure A, the i n -j e c t i o n volume f o r a l l compounds was 0.1 ml/10 g body weight. The same volume was used i n procedure B, except f or the w r i t h i n g agent, the dose of which was 0.25 ml/20 g. 1 7 6 The mice used i n procedures A and B were male, Swiss a l b i n o s (SPF-derived) weighing 2 0 - 3 0 g. In procedure C, male and female guinea-pigs ( H a r t l y s t r a i n ) weighing 3 5 0 - 5 0 0 g were employed. A l l animals were obtained from the Animal U n i t , F a c u l t y of Medicine, U n i v e r s i t y of B.C. The guinea-pigs were starved f o r 2 4 hours before s a c r i f i c e . When tested by method A, compound 9_ showed no a n a l g e t i c a c t i v -i t y at dose l e v e l s of 3 0 0 mg/kg or l e s s . No S t r a u b - t a i l was observed. The compound appeared to induce a h y p e r e x c i t a b l e s t a t e i n the mice, espe-c i a l l y at higher doses. At 6 0 0 mg/kg, 9_ produced a convulsant s e i z u r e which terminated i n death. By t e s t procedure A, a l l mice r e c e i v i n g meth-adone h y d r o c h l o r i d e or morphine s u l f a t e i n a dose of 1 5 mg/kg showed a p o s i t i v e response ten minutes a f t e r i n j e c t i o n . Using the phenylquinone w r i t h i n g method (method B ) , the e f f e c t of 9_ at dose l e v e l s of 2 5 , 5 0 , 7 5 and 1 0 0 mg/kg (as the f r e e base) was examined. F i v e mice were used at each dose l e v e l . From the r e s u l t i n g d ata, the E D ^ Q and 9 5 % confidence l i m i t s were determined by the method of L i t c h f i e l d and Wilcoxon ( 1 4 3 ) to be 5 4 . 0 ( 6 8 . 4 - 4 2 . 7 ) mg/kg. An E D 5 Q given i n the l i t e r a t u r e ( 1 4 4 ) f o r methadone h y d r o c h l o r i d e , obtained by the phenylquinone w r i t h i n g method, was 0 . 7 8 ( 0 . 5 7 - 1 . 0 9 ) mg/kg. Conversion to a value f o r methadone f r e e base gave 0 . 7 0 ( 0 . 5 1 - 0 . 9 7 ) mg/kg. Obser-v a t i o n s w i t h methadone h y d r o c h l o r i d e i n the mice used i n the present i n -v e s t i g a t i o n i n d i c a t e d that such an E D ^ Q was reasonable. From a comparison of E D ^ Q v a l u e s , compound 9_ appeared to be approximately 1 / 8 0 as potent as methadone. T e s t i n g of compound 1 2 3 by method B r e v e a l e d that i t was f a i r l y t o x i c . A n a l g e t i c a c t i v i t y was not observed below 5 0 mg/kg, a dose which caused c o n v u l s i o n s . 177 In method C, methadone hydr o c h l o r i d e was found to depress the e l e c t r i c a l l y induced c o n t r a c t i o n s of the ileum by 50% at a c o n c e n t r a t i o n of 0.08 nmole/ml. At concentrations somewhat greater than 800 times t h i s , 9^  124 and 125 caused no observable depression. That the t h i e t a n e 1,1-dioxides 9, 123, 124 and 125 lacked s i g -n i f i c a n t a n a l g e t i c a c t i v i t y i s perhaps a t t r i b u t a b l e to t h e i r c i s - 2 , 4 -d i a r y l s t r u c t u r e . The phenyl r i n g at C-4 c i s to the aromatic group at C-2 may be i n t e r f e r i n g w i t h e f f e c t i v e b i n d i n g of these compounds at the a n a l g e t i c r e c e p t o r . On t h i s b a s i s , an i n v e s t i g a t i o n of 2-pheny1-3-dimeth-ylaminomethylthietane 1,1-dioxide and other d e r i v a t i v e s not possessing an aromatic s u b s t i t u e n t at C-4 may be worthwhile. I t has been suggested that a c l o s e approach of the b a s i c group and oxygenated f u n c t i o n i n diphenylpropylamine-type a n a l g e t i c s such as methadone and i t s sulfone analogue i s necessary f o r high a c t i v i t y ( 5 ) . I f t h i s i s c o r r e c t , then the apparent pseudoequatorial d i s p o s i t i o n of the b a s i c side c h a i n i n j) , 123, 124 and 125, which tends to preclude i n t i m a t e i n t e r a c t i o n of the t e r t i a r y amino group w i t h the s u l f o n y l moiety, may a l s o account f o r the absence of s i g n i f i c a n t a c t i v i t y shown by these compounds. 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