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Thietane 1, 1-dioxides as potential analgetics of the methadone type Leung, Chun-Cheung 1978

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THIETANE 1,1-DIOXIDES AS POTENTIAL ANALGETICS OP THE METHADONE TYPE 7-hj Chun-Cheung Leung B.Sc.(Pharm), National Taiwan U n i v e r s i t y , 1969 M.Sc, Dalhousie U n i v e r s i t y , 1971 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS 1 FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the D i v i s i o n of Medicinal Chemistry of the Faculty of Pharmaceutical Sciences We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1978 (§) Chun-Cheung jteung, 1978 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l m a k e i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s m a y b e g r a n t e d b y t h e H e a d o f my D e p a r t m e n t o r b y h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t b e a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . P h a r m a c e u t i c a l S c i e n c e s D e p a r t m e n t o f ' T h e U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 D a t e 1 7 J u l y 1 9 7 8 i i ABSTRACT Thietane d e r i v a t i v e s containing phenyl and d i -me thylaminomethyl substituents were synthesized as poten-t i a l n a r c o t i c analgetics of the methadone type. These com-pounds which are s t r u c t u r a l l y derived from the sulfone an-alogue of methadone "by j o i n i n g 0-2 to C - 5 , are conforma-t i o n a l ^ more r e s t r i c t e d than methadone and thus may he u s e f u l i n e l u c i d a t i n g the conformation of methadone when bound to i t s receptor (pharmacophoric conformation). The photocycloaddition r e a c t i o n of thiobenzo-phenone and an appropiate o l e f i n i c n i t r i l e provided 2,2-diphenyl-3-cy'anothietane, cis-2.2-diphenyl-3-cyano-4-methylthietane and trans-2.2-diphenyl-3-cyano-4-methyl-thietane, cis-2,2-diphenyl-3-methyl-4-cyanothietane and trans-2.2-diphenyl-3-methyl-4-cyanothietane. Treatment of the f i r s t three thietane d e r i v a t i v e s with m-chloroper-oxybenzoic a c i d gave 2,2-diphenyl-3-cyanothietane 1,1-dioxide, cis-2,2-diphenyl-3-cyano-4-niethylthietane 1-oxide, cis-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide and trans-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide. Submitting the cyanothietane 1,1-dioxides to hydroboration reduction gave the corresponding p r i -mary amines which were c a t a l y t i c a l l y dimethylated with formaldehyde at room temperature to give 2,2-diphenyl-3-dimethylaminomethylthietane 1,1-dioxide, c i s - 2 , 2 - d i -i i i phenyl-3-dime thylaminome thyl-4-me t h y l t h i e tane 1,1-dioxi de a n < ^ trans-2,2-diphenyl-3-dime thylaminome thyl-4-me t h y l -thietane 1,1-dioxide. Two attempts to synthesize the precursors of thietane d e r i v a t i v e s containing a dimethylaminomethyl side chain attached to the carbon °< to the s u l f o n y l group gave unexpected r e s u l t s . The r e a c t i o n of (5-chloroethane-s u l f o n y l chloride and dime t h y l amino styrene generated an a c y c l i c sulfone, o(-(vinylsulfonyl)-£>-dimethylaminostyrene, instead of the expected c y c l i c adduct, 2-phenyl-3-dimethyl-amino-4-chloromethylthietane 1,1-dioxide. The reported r e a c t i o n of methoxyallene and thiobenzophenone to give 2,2-diphenyl-3-methoxy-4-methylenethietane was found to pro-ceed i n a d i f f e r e n t course. The re a c t i o n was proved to occur thermally as opposed to a photochemical react i o n . During the course of the studies, several reac-tions were performed on, 2,4-diphenylthiete 1,1-dioxide with a hope of generating 2,4-diphenylthietan-3-one 1,1-dioxide f o r antiinflammatory studies: Treating 2,4-diphenylthiete 1,1-dioxide with sodium hydroxide r e s u l t e d i n the cleavage of the thietane r i n g and formation of dibenzyl sulfone. The expected product, 2,2-diphenyl-3-hydroxythietane 1,1-dioxide was l i k e l y formed hut r a p i d l y underwent r i n g cleavage to give dibenzyl sulfone. The r e a c t i o n of 2,2-diphenylthiete 1,1-dioxide with concentrated s u l f u r i c a c i d r e s u l t e d i n formation of two rare compounds, 3,c_-5-diphenyl-l,r-2-oxathiacyclo-penta-3-ene 2-oxide and 3,j;-5-diphenyl-l,r-2-oxathiacyclo-penta-3-ene 2-oxide. This r e a c t i o n did not occur with 2-phenylthiete 1,1-dioxide and 2-phenyl-4-methylthiete -1,1-dioxide. Hone of three compounds tested showed s i g n i f i c a n t analgesic a c t i v i t y i n an i n v i t r o experiment based on the i n h i b i t i o n of the contractions of e l e c t r i c a l l y stimulated guinea-pig ileum by nar c o t i c analgetics. In an i n vivo experiment, the compounds were also unable to modify the pain threshold of a rabbit towards e l e c t r i c a l stimulation on tooth-pulp. The r e s u l t s i n d i c a t e the exacting r e q u i r e -ment f o r binding of methadone to the n a r c o t i c receptor. Signature of Supervisor V TABLE OF CONTENTS PAGE ABSTRACT . i i i LIST OF TABLES . x LIST OF FIGURES .. . x i INTRODUCTION 1 THIETANE CHEMISTRY 2 6 SYNTHETIC APPROACH 60 DISCUSSION 63 1. Synthesis of cyanothietanes by photo-c y c l o a d d i t i o n of thiobenzophenone with o l e f i n i c n i t r i l e s 63 2. Synthesis of cyanothietane 1,1-dioxides ... 76 3. Synthesis of 3-aminomethylthietane 1,1-dioxides 84 4« Synthesis of 3-dimethylaminomethylthi-etane 1,1-dioxides 92 5« Synthesis of 2,2-diphenyl-3-dimethyl-aminome thylthietane 100 6.. Attempted synthesis of thietane deriva-t i v e s with °<-dime thylaminome t h y l side chain 105 7. Chemical reactions of ,2,4-diphenylthiete 1,1-dioxide and attempted synthesis of 2,4-diphenylthietan-3-one 1,1-dioxide 118 PHARMACOLOGICAL TESTING 143 PARTITION STUDIES 150 STRUCTURE-ACTIVITY CONSIDERATIONS 159 ANALYTICAL METHODS 1 6 6 EXPERIMENTAL ... ' 1^7 1. Synthesis of thiobenzophenone (9^) 167 v i PAGE 2. Synthesis of 2,2-diphenyl-3-cyano-thietane (155) 1 6 7 3. Synthesis of 2,2-diphenyl-3-cyano-thietane 1,1-dioxide (l60) 169 4 . Synthesis of 2,2-diphenyl-3-ainino-methy1thietane 1,1-dioxide ( l 6 l ) 170 5. Synthesis of 2,2-diphenyl-3-dimethyl- . aminomethylthietane 1,1-dioxide (J32) .. 174 6. Separation of c i s - "and trans-2-butenenitriles 177 7. Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthietane (156) and cis-2,2-diphenyl-3-methyl-4-cyano-thietane (158) 178 8. Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthietane 1,1-di-oxide (174) .'. . 179 9. Synthesis of c i s-2.2-diphenyl-3-cyano-4-methylthietane 1-oxide (178) .. 180 10. Synthesis of cis-2.2-diphenyl-3-amino-methyl-4-methyl-thietane 1,1-di-oxide. (179) 181 11. Synthesis of c i s-2,2-diphenyl-3-di-me thylaminome thyl-4-me t h y l t h i e tane , 1,1-dioxide (33) 183 12. Synthesis of trans-2,2-diphenyl-3-cyano-4-methylthietane (157) and trans-2,2-diphenyl-3-methyl-4-cyano-thietane (li9_) 185 13. Synthesis of trans-2,2-diphenyl-3-cyano-4-methylthietane 1,1-di-. oxide (176) 186 14. Synthesis of trans-2,2-diphenyl-3-aminome thyl-4-methylthi e tane 1,1-di-oxide (180) 187 15. Synthesis of trans-2,2-diphenyl-3-di- 1 methylaminomethyl-4-methylthietane 1,1-dioxide (34) ..........>.' 190 v i i PAGE 16. Synthesis of 2,2-diphenyl-3-di-me thylaminome t h y l thie tane (19,1) 191 17. Synthesis of ¥,N-dimethylallylamine (200) 194 18. Attempted photocycloaddition of t h i o -benzophenone (95) to N,N-dimethyl-allylamine (200) 195 19. Synthesis of P—chloroethanesulfonyl chloride (212) .... 196 20. Reaction of (a-chloroe thane s u l f o n y l chloride (212) and (5-dimethylamino-styrene (2117 197 21. Synthesis of methyl propargyl ether (218) 199 22. Synthesis of methoxyallene (113) 199 23. Synthesis of 2,2-diphenyl-3-meth-oxy-4-methylenethietane (114) 200 24. Attempted hydroxylation of 2,4-di-phenylthiete 1,1-dioxide (22J) with sodium hydroxide. I s o l a t i o n of d i -benzyl sulfone (234) 202 25. Reaction of 2,4-diphenylthiete 1,1-dioxide- (227) with s u l f u r i c a c i d . Iso-l a t i o n Of 3,5-diphenyl-l,2-oxathiacyc-lopenta-3-ene 2-oxide (243, 244) 203 2 6 . Attempted hydrohoration of 2,4-di-phenylthiete 1,1-dioxide (227) 2 0 6 27. Synthesis of 2,2-dichlorophenyl-a c e t y l chloride. (282), 2 0 7 28. ' Synthesis of M,N-diethyl-2.2-di-chlorophenylacetamide (283; 207 29. Synthesis of N,N-diethyl-<*,/5-di-chloro-/l-styrylamine (284) 208 30. Synthesis of N,N-diethylphenyl-v i i i PAGE ethynylamine (285) 208 31. Synthesis of 2,4-diphenyl-3-diethyl-aminothiete 1,1-dioxide (231) 209 32. Attempted h y d r o l y s i s of 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (231) 210 BIBLIOGRAPHY .. 212 X X LIST OF TABLES TABLE PAGE I. Analgesic a c t i v i t i e s of methadone and i t s sulfone analogue i n mice 12 I I . V i c i n a l coupling'constants J(Ha-Hb) of 2,2-diphenylthietane d e r i v a t i v e s 97 I I I . V i c i n a l coupling constants of t h i - qo etane d e r i v a t i v e s IV. Chemical s h i f t s of s u l f o n y l en-amines ' I l l V. Chemical s h i f t s of s u l t i n e s 135 VI. Rm values of thietane 1,1-di-oxides at Qffo methyl ethyl ketone cal c u l a t e d from regression l i n e s 153 LIST OF FIGURES FIGURE PAGE I. Analgesic receptor surface proposed by-Beckett and Casy 17 I I . Pmr spectrum of cis-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide dissolved i n GD.C13 79 I I I . I n h i b i t i o n of contractions of e l e c t r i -c a l l y stimulated guinea-pig ileum by methadone .and thietane 1,1-dioxides 148 17. E f f e c t of methadone, thietane l ? l - d i -oxides and naloxone on guinea-pig ileum contractions 149 x i ACKNOWLEDGEMENTS The author i s indebted to Dr. Frank S. Abbott f o r h i s guidance, encouragement and understanding through-out the course of t h i s work. F i n a n c i a l support from the Medical Research Council i s g r a t e f u l l y acknowledged. x i i DEDICATION To my wife, Li-Tchou INTRODUCTION Thousands of morphine-like compounds have appeared i n the l i t e r a t u r e . To date, the majority of synthetic anal-gesics which are as active as morphine i n r e l i e v i n g pain are a l l associated with tolerance and addiction. Extensive e f f o r t s of medicinal chemists are needed to design an analgesic mole-cule without these undesirable properties. 1 2 Morphine (1) i s a der i v a t i v e of phenanthrene (2) bridged by oxygen and nitrogen across the 4, 5 and 9, 13 pos i t i o n s r e s p e c t i v e l y . The natural morphine, i s o l a t e d from opium, occurs as a levo isomer. The p i p e r i d i n e r i n g D adopts * 3" OH 2 a c h a i r conformation, while the cyclohexene r i n g G i s i n a boat form with a C/D r i n g junction trans, rings G and B being cis -fused. The phenolic r i n g A i s connected to r i n g D by an a x i a l C-13 bond and an a x i a l C-9 methylene bridge. Expanding the phenanthrene unit of morphine leads to a s e r i e s of potent analgesics. The best known example i s etorphine (7,8-.di- . hydro-7- (l-(R)r-hydroxy-l-methylbutyl) -O^-methyl-6,14-endo-ethenomorphine (J3)) which i s 8600 times the a c t i v i t y 3 of morphine i n guinea pigs a f t e r subcutaneous administration (1-3)• Unfortunately, as the analgesic a c t i v i t y increases, the p h y s i c a l dependence l i a b i l i t y and other side e f f e c t s of the compound r i s e commensurately. I t has been generally accepted that the properly oriented p i p e r i d i n e r i n g and the properly situated phenolic nucleus are the most c r i t i c a l components to analgesic a c t i v i t y i n the structure of morphine. The 4-phenylpiperidine system of morphine affo r d s a t e r t i a r y amino group separated by 3 carbons(C-13, C-15 and G-l6) from a hydrophobic aromatic nucleus. Almost a l l the strong narcotic analgesics which are used c l i n i c a l l y have these s t r u c t u r a l l y s i m i l a r features (4,5). 3 Removing the ether bridge of morphine gives a ser i e s of potent analgesics c a l l e d morphinans. The best known example i s levorphanol (3-hydroxy-N-methylmorphinan (A)) which i s used c l i n i c a l l y i n t h i s country and i s more 4 potent and longer a c t i n g than morphine. Levorphanol and other morphinan d e r i v a t i v e s have the main skeleton of the morphine structure, l a c k i n g only a hydrofuran r i n g and an a l l y l i c hydroxy system i n r i n g G. Apparently, neither the hydrofuran r i n g , nor the o l e f i n i c a lcohol system i s necessary f o r the analgesic a c t i v i t y . The r i n g junctions i n levorphanol are also i d e n t i c a l to those i n the natural morphine, C/D and G/B r i n g junctions being trans- and c i s - fused r e s p e c t i v e l y . The orien-t a t i o n of r i n g G i s also not important i n the analgesic a c t i v -i t y v N-methylisomorphinan ( 3-hydroxy-N-methylisomorphinan ( 5 ) ) , an isomer of levorphanol with r i n g C and D being c i s -fused, r e t a i n s good analgesic a c t i v i t y ( 6 ) . A free phenolic hydroxy group, however, i s required f o r high analgesic potency 4 5 i n morphinan d e r i v a t i v e s , as i t i s i n morphine (7). That r i n g C of morphine i s not important f o r the analgesic a c t i v i t y can be r e a l i z e d from 6,7-benzomorphan de r i v a t i v e s . In t h i s c l a s s of analgesics, the r i n g C of the morphinan structure i s replaced by two a l k y l substituents at po s i t i o n s now r e f e r r e d to as C-5 and C-9 of 6,7-benzomorphan (£>). A simple example i s 2'-hydroxy-2-methyl-5,9-dimethyl-6,7-benzomorphan (7,8). Isomers having 5,9-dimethyl s u b s t i -= a l k y l or H = H or a l k y l '=• a l k y l 6 5 7 ( J3 isomer) 8 (d isomer) tuents i n a c i s ( p isomer) or trans (^isomer) r e l a t i o n s h i p with respect to the p i p e r i d i n e r i n g have been i s o l a t e d . A potent analgesic a c t i v i t y i s found i n both / ( * ) and p(±) racemates. In animals the d racemate i s as active as morphine while the p racemate i s even more potent. Like the s i t u a t i o n s i n morphine and morphinan, the analgesic a c t i v i t y resides l a r g e l y i n the levo antipodes of «/ and p diastereoisomers (8). The cL isomer i s r e l a t e d s t e r i c a l l y to morphine and morphinans and the p isomer to isomorphinan ( _ 5 ) . In monkey i t has been shown that complete d i s s o c i a t i o n of the undesired dependence l i a b i l i t y from analgesia can be obtained i n 6,7-benzomorphan de r i v a t i v e s . Unfortunately, t h i s h i g hly a t t r a c t i v e property can not be observed i n humans (9). Nevertheless, e f f e c t i v e analgesics having l e s s side e f f e c t s than morphine have been obtained i n the 6,7-benzomorphan s e r i e s . Phenazocine (oC-21-hydroxy-2-phenethyl-5,9-dimethyl-6 ,7-benzomorphan (_9), f o r example, i s about three times as potent as morphine and causes l e s s c i r c u l a t o r y depression and other side e f f e c t s . The devel-opment of tolerence i s slower and the ad d i c t i o n l i a b i l i t y i s 6 H (—CH 3 GH 3 OH 9 l e s s although the p o t e n t i a l f o r the abuse s t i l l e x i s t s (10). The hydroaromatic r i n g B i n morphine, morphinan, and benzomorphan d e r i v a t i v e s serves to lock the 4-phenylpiperidine system i n t o a r i g i d u n i t so that the p i p e r i d i n e r i n g i s con-strained to a c h a i r conformation and the phenyl r i n g to an a x i a l o r i e n t a t i o n with the aromatic plane passing through G-2 and G-4 of the p i p e r i d i n e r i n g . This axial-phenyl-chair con-formation of the 4-phenylpiperidine moiety, however, does not seem to be absolutely required f o r analgesic a c t i v i t y . Non-r i g i d c y c l i c d e r i v a t i v e s i n which the phenyl r i n g can not be constrained to an a x i a l orientation/, r e t a i n the analgesic ac-t i v i t y and the undesired t o x i c i t y of morphine. The best known examples are meperidine (10)..and </-prodine (11). These two H 10 11 0 7 simple p i p e r i d i n e d e r i v a t i v e s possess an equatorial phenyl ch a i r conformation. Meperidine has about one f i f t h the poten-cy of morphine. In /-prodine a propionoxy ; function replaces the ethoxycarbonyl group of JLO and r e s u l t s i n potency r i s e . </-Prodine, which i s about two times as a c t i v e as morphine, i s one of the two racemic diastereoisomers of prodine. I t has a trans 3-methyl /4-phenyl configuration and i s about 3 times l e s s a c t i v e than the second form, (5-prodine (12), which has a cis- 3-methyl/4-phenyl configuration (11). In other potent pro< dine d e r i v a t i v e s such as ^-promedol, the phenyl group resides I I 0 p r e f e r e n t i a l l y i n the a x i a l conformation (19). M o d i f i c a t i o n of the meperidine structure has gener-ated a potent analgesic, fentanyl (13), i n which the phenyl 1 3 and the a c y l groups are separated from the p i p e r i d i n e r i n g by a nitrogen atom. In man fentanyl i s a powerful analgesic, about 100 times more potent than morphine (11). Although the 4-phenylpiperidine moiety appears to be the most fundamental component of morphine, morphinan, benzomorphan, meperidine and t h e i r d e r i v a t i v e s , the p i p e r i -dine r i n g i s not contained i n the structures of a seri e s of a c y c l i c analgesics represented by methadone (14), diampromide (15.), dextromoramide (JL6) and dextropropoxyphene (17). These 1 6 17 9 a c y c l i c compounds are s t r u c t u r a l l y r e l a t e d and possess good analgesic a c t i v i t y . The potency of diampromide approaches that of morphine i n r a t s (12). Dextromoramide possesses a po-tency tha tt. a dose of 5 mg i s equivalent to 10 mg of morphine f o r the treatment of post-operative pain (13)- Dextropropoxy-phene has been used extensively f o r the treatment of mild to moderate pain although i t s potency i n man f a l l s between a s p i r -i n and codeine (14). The potency of methadone i s twice that of morphine and 10 times that of meperidine but i t s t o x i c i t y i s 3 to 10 times greater than that of morphine (11). The </-methyl isomer of methadone, isomethadone (18), and the nor-methyl d e r i v a t i v e , normethadone (19), are also e f f e c t i v e anal-gesics although l e s s potent than methadone (14). The carbonyl group of methadone has been converted to the alcohol and i t s a c e t y l ester. The alcohol d e r i v a t i v e , methadol (20), i s l e s s potent while the a c e t y l d e r i v a t i v e , acetylmethadol (21), i s more potent and longer ac t i n g than methadone (15). Replace-ment of the propionyl group of methadone by hydrogen, hydroxy, 1 0 acetoxy or propionoxy has re s u l t e d i n a decrease or a lack of analgesic a c t i v i t y (11). I t has been proposed that an ele c -t r o n i c i n t e r a c t i o n between the amino nitrogen and the carbonyl carbon e x i s t s and locks the methadone molecule i n a p i p e r i -d i n e - l i k e conformation (22) that: may account f o r the'analgesic 2 W i i3 3 / \ CH^ CH^ 22 a c t i v i t y ( 1 6 , 17). The two phenyl groups i n methadone are also important and removal of one of them causes a sharp decrease i n analgesic potency (18). I t i s possible that second phenyl residue helps to maintain the propionyl group of methadone i n 1 1 a p o s i t i o n to simulate the a l i c y c l i c r i n g of morphine (11). Replacement of the carbonyl group of methadone with a s u l f o n y l function has l e d to an analgesic sulfone. This sulfone analogue of methadone (23) i s as active as methadone 23 and c a r r i e s the resemblance to the l a t t e r i n that the analge-s i c a c t i v i t y mainly resides i n the R-isomer. Like methadone, the R-isomer of the sulfone analogue possesses a potency 18 times that of the S-antipode (Table I ) . A preferred conforma-t i o n s i m i l a r to that of methadone was also proposed to account f o r the analgesic a c t i v i t y of _23 ( 1 6 ) . I t has been widely accepted that narcotic analgesics i n t e r a c t with some s p e c i f i c receptors i n the OTS to t r i g g e r the analgesic e f f e c t s . A number of attempts have been made to l o c a l i z e the s i t e s of a c t i o n of narcotic analgesics within the GNS. The techniques that have been employed involve microin-j e c t i o n of n a r c o t i c agonists or antagonists i n t o various brain areas, and observation of the i n h i b i t i o n of nociceptive reac-t i o n s of agonists or examination of the a c t i o n of antagonists Table I Analgesic a c t i v i t i e s of methadone and i t s sulfone analogue _23_ i n mice (19) Isomer Configuration A c t i v i t y a Methadone + R 180 - S 10 Sulfone analogue of + R 180 methadone (23) - S 10 a (i)-methadone = 100 13 against the e f f e c t s of systemic administration of agonists. Studies of p r e c i p i t a t i o n of the withdrawal syndrome i n mor-phine-dependent animals or autoradiographic studies of the d i s t r i b u t i o n of r a d i o a c t i v e analgesics i n the GNS have also been employed. The s i t e s of a c t i o n of opiates have been found to occur with very considerable r e g i o n a l v a r i a t i o n s , and the r e s u l t s presented from d i f f e r e n t l a b o r a t o r i e s are not i n agreement. The l o c a l i z a t i o n of these c e n t r a l s i t e s has been ascribed to the a n t e r i o r thalamus (20), p o s t e r i o r hypothalamus (21), p e r i v e n t r i c u l a r - p e r i a q u e d u c t a l region of midbrain (22, 23), and the area surrounding the t h i r d v e n t r i c l e (24). He-ports from a group represented by Herz and Teschemacher, how-ever, have presented disparate r e s u l t s . They showed that the structures e a s i l y reached from the 4th v e n t r i c l e (medulla, pons and lower part of midbrain) were the main s i t e s of a c t i o n of analgesics (25-27). The discrepancies i n the c e n t r a l l o c a l -i z a t i o n of opiate receptors obviously needs to be resolved. Unfortunately, the i n v i t r o binding studies with n a r c o t i c agonists or antagonists have not provided an unambiguous ans-3 wer. Regional study of s t e r e o s p e c i f i c binding of H -naloxone to b r a i n homogenate obtained from d i f f e r e n t areas of rat b r a i n revealed that the greatest amount of s t e r e o s p e c i f i c binding was found i n the corpus striatum. The midbrain and the b r a i n stem exhibited only one-quarter and one-eighth r e s p e c t i v e l y as much s t e r e o s p e c i f i c binding (28). This pattern of stereospecif-i c binding was also generally observed i n monkey and human brains by using H -dihydromorphine (29). The greatest amount 14 of s t e r e o s p e c i f i c binding was observed i n amygdala, periaque-ductal area of midbrain, hypothalamus, thalamus and caudate nucleus. The binding was found to be very low i n the area surrounding the 4th v e n t r i c l e , i n contrast to the r e s u l t s of Hertz et a l . (25-27). On the other hand, Goldstein and h i s coworkers (30) demonstrated a set of s t e r e o s p e c i f i c binding of 3 H -levorphanol i n mice which occurred predominantly i n the b r a i n stem, e s p e c i a l l y i n medulla-pons area. This set of s t e r e o s p e c i f i c binding was shown to possess properties d i f f e r -ent from those of naloxone binding (28). I t was argued that two groups of workers were dealing with d i f f e r e n t sets of opiate binding receptors which were r e l a t e d but d i f f e r e n t somewhat i n structure and function (30). The s i t u a t i o n can not be c l a r i f i e d u n t i l the various opiate receptors are separated and studied i n d i v i d u a l l y . Nevertheless, there has been a common f i n d i n g i n that the opiate receptor bindings are associated with neuronal membranes, mainly with microsomal and crude mitochondrial f r a c t i o n s (28, 29, 30-32). An H-^-etorphine-macromolecule complex has been r e c e n t l y i s o l a t e d when the membrane f r a c t i o n prepared from rat b r a i n homogenate was t r e a t -3 ed with H -etorphine. I t was shown that t h i s i s o l a t e d bound macromolecule may represent the pharmacological receptor (33). The existence of opiate receptors has been supported by the recent i s o l a t i o n of some endogenous substances with opiate a c t i v i t i e s (34-39). Hughes (40, 41) i d e n t i f i e d a sub-stance i n the brains of pigs, cows, guinea pigs, r a t s , r a b b i t s and mice, that mimicked the e f f e c t of morphine to i n h i b i t con-15 t r a c t i o n s of guinea p i g ileum. This substance which i s c a l l e d enkephalin and has a molecular weight of 1000 was found to be a .mixture.-o'f two clos e l y : related..pentapepti.des having the- " following sequence: Tyr-Gly-Gly-Phe-Met (Methionine-Enkephalin) Tyr-Gly-Gly-Phe-Leu (Leucine-Enkephalin) S i m i l a r peptides were also i s o l a t e d by Snyder and Ternius ( 3 4 , 35, 3 9 , 42, 4 3 ) - Goldstein i d e n t i f i e d another peptide from p i t u i t a r y gland, having a molecular weight of 1800. He thought that t h i s peptide may be the precursor of enkephalin (44, 45)• I t i s i n t e r e s t i n g to note that enkephalin has a tyramine moie-ty (tyrosine minus G00H group) i n the terminal portion, which i s a common feature of many opiate agonists and antagonists ( 4 6 , 47). The conformation of met-enkephalin has been proposed on the basis of s t r u c t u r a l s i m i l a r i t i e s with morphine and r e -l a t e d analgesics ( 6 4 - 6 7 ) . Opiate receptors are also located i n the peripheral nervous t i s s u e s of c e r t a i n animal species. The transmission from the myenteric plexus to the l o n g i t u d i n a l muscle i s de-pressed by morphine i n guinea pigs (48, 49). The transmission from vagal nerve to s i n o a t r i a l node i s morphine s e n s i t i v e i n r a t s and r a b b i t s (50). As f a r as adrenergic autonomic junc-ti o n s are concerned, the n i c t i a t i n g membrane of cats and the vas deferens of mice are morphine s e n s i t i v e (24, 5 1 - 5 3 ) . . The depressant actions of nar c o t i c analgesics on the guinea p i g ileum have been i n t e n s i v e l y investigated i n recent years (28, 48, 49, 54-62). Morphine and other potent na r c o t i c s 1 6 s t e r e o s p e c i f i c a l l y produce depressant e f f e c t s on the e l e c t r i -c a l l y evoked contractions of guinea p i g ileum i n the concen-—R — Q t r a t i o n range of 10" to 10"^ M (49). The potencies of narco^ t i c agonists and antagonists i n the i n h i b i t i o n of contractions have been demonstrated to predict accurately the analgesic potencies of these drugs i n animals and i n man ( 6 3 ) . Tolerance to actions of nar c o t i c analgesics and withdrawal e x c i t a t i o n s p r e c i p i t a t e d by using n a r c o t i c antagonists such as naloxone have also been demonstrated i n t h i s t i s s u e (49, 6 l ) . I t has now been widely accepted that guinea p i g ileum i s a r e l i a b l e model f o r analgesic studies. I t s uses i n the i n v e s t i g a t i o n of narc o t i c analgesics have c e r t a i n advantages. E f f e c t s of abr-:/_ sorption, d i s t r i b u t i o n , biotransformation and excretion of the drugs are l i m i t e d or almost completely excluded. In the stud-i e s of 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 of nar c o t i c analgesics i n whole animals, serious d i f f i c u l t i e s i n the i n t e r p r e t a t i o n of r e s u l t s have a r i s e n due to the considerable v a r i a t i o n i n the l i p o p h i l i c i t y of nar c o t i c analgesic drugs and therefore i n t h e i r a b i l i t y to penetrate the blood b r a i n b a r r i e r . I t has been known that, i n whole animals, r e l a t i v e l y h y d r o p h i l i c nar-c o t i c s such as morphine are more ac t i v e a f t e r i n t r a v e n t r i c u l a r than intravenous administration, while no s i g n i f i c a n t d i f f e r -ence i s found f o r more l i p o p h i l i c compounds ( 2 6 , 6 8 , 6 9 ) . The nature of opiate receptors has been demonstrated to be p r o t e i n (33, 70), phospholipid (71, 72) and p r o t e o l i p i d (73, 74). I t i s l i k e l y that the opiate receptors are membrane bound complexes whose s t e r e o s p e c i f i c binding i s dependent on 17 the i n t e g r i t y of hoth proteins and phospholipids {13). The shape of the opiate receptor has "been proposed by Beckett and Gasy (17) according to the common s t r u c t u r a l features of nar-c o t i c analgesics and studies of 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 -ships on these drugs. A receptor surface was formulated and l a t e r modified (19) to .accommodate the r i g i d skeleton of natu-r a l morphine and other c y c l i c and a c y c l i c analgesics (Figure I ) . The receptor was proposed to consist of three e s s e n t i a l Figure I Analgesic receptor surface proposed by Beckett and Gasy (17, 19). s i t e s : a f l a t surface which allows binding with the phenolic or aromatic nucleus of the analgesic molecule, an anionic s i t e 18 which associates with the p o s i t i v e l y charged ammonium group of the drug molecule, and a c a v i t y which accommodates .the p r o j e c t -ing C(15)-C,(l6) portion of p i p e r i d i n e r i n g i n morphine and other analgesic molecules. The stereochemical requirements f o r the analgesic a c t i v i t i e s of morphine, morphinan, 6,7-benz— omorphan and t h e i r d e r i v a t i v e s have been a t t r i b u t e d to the s p a c i a l constraint of the binding s i t e s on the r i g i d receptor surface. In the explanation of analgesic a c t i v i t i e s of c e r t a i n a c y c l i c compounds such as methadone, methadol, acetylmethadol and diampromide etc., Portoghese has postulated that more than one binding mode can occur i n the i n t e r a c t i o n of these f l e x i -ble drugs with the same analgesic receptor (75, 76). Recently, the opiate receptor has been proposed (5) to e x i s t i n two i n t e r c o n v e r t i b l e states which are responsible f o r t r i g g e r i n g the a g o n i s t i c and antagonistic a c t i v i t y respec-t i v e l y . Sodium i o n i s thought to modulate the interconversion of the two states by a c t i n g on the a l l o s t e r i c s i t e of the r e -ceptor. Under the p r e v a i l i n g sodium concentration i n the b r a i n , the opiate receptor i s considered to e x i s t predominantly i n the antagonistic state. As mentioned previously,'the analgesic a c t i v i t y of methadone was a t t r i b u t e d to the p i p e r i d i n e - l i k e conformation r e s u l t i n g from an intramolecular i n t e r a c t i o n between the n i -trogen atom and the carbonyl carbon (16). This e l e c t r o n i c i n t e r a c t i o n appears to be present i n the c r y s t a l 'structure of o methadone free base. A short distance of 2.91 A between the two atoms was observed by Bye (77). In s o l u t i o n , the magnitude 19 Methadone of t h i s i n t e r a c t i o n i s considerably weaker than what i s gener-a l l y believed. Studies by c i r c u l a r dichroism and proton mag-ne t i c resonance (78) ind i c a t e d that N...CO i n t e r a c t i o n of meth done i s l i k e l y present i n the molecule so that i n CDCl^ so l u t i o n three possible conformers, 14a, 14b and 14c were 14a 14b 14c present i n approximately 1:1:2 r a t i o . The N...CO i n t e r n a l a s s o c i a t i o n i s possible i n the conformers 14a and 14c, but i t c e r t a i n l y did not predominate to the exclusion of the unasso-ciat e d rotamer 14b. In CD^OD sol u t i o n a conformeric d i s t r i b u -t i o n of approximately 1:4:5 (14a:14b:14c) occurred. The per-20 sistence of 14b i n both solvents i s s u r p r i s i n g i n l i g h t of considerable s t e r i c i n t e r a c t i o n s . I t s presence was explained by the s o l v a t i o n e f f e c t of polar solvents, which tend to dimin-i s h the magnitude of intramolecular a s s o c i a t i o n (78). In a more recent study of 5-methylmethadone i t i s believed that one of the pharmacophoric conformations of diphenylpropylamine analgesics possesses an a n t i p e r i p l a n a r - l i k e d i s p o s i t i o n of the Ph 2CC(0)Et and ~N(CEj)2 as represented by 14b (79). At p h y s i o l o g i c a l pH, methadone appears as the proton-ated form, which i s expected to be the species that i n t e r a c t s with the n a r c o t i c receptor. According to Beckett and Gasy, an e l e c t r o n i c a t t r a c t i o n between the p o s i t i v e ammonium group and the carbonyl oxygen i s s t i l l possible and the p i p e r i d i n e - l i k e Methadone, protonated conformation that f i t s the hypothetical receptor s t i l l e x i s t s ( 1 6 ) . This e l e c t r o n i c i n t e r a c t i o n , however, was not observed i n the c r y s t a l l i n e structure of methadone hydrobromide which was found to e x i s t i n an a n t i p e r i p l a n a r conformation (80). 21 0 2 An t i p e r i p l a n a r conformation of methadone hydrobromide Measurements by using c i r c u l a r dichroism and proton magnetic resonance methods also i n d i c a t e d that the presence of such an extended form could not be excluded (78). A preferred a n t i p e r -i p l a n a r conformation was also observed f o r isomethadone (18) and normethadone (19) i n organic solutions (78, 81). Although methadone may exi s t i n c e r t a i n preferred conformations i n p h y s i o l o g i c a l f l u i d , whether or not such preferred conformations can be r e l a t e d to the analgesic a c t i v -i t i e s of methadone i s questionable. I t has been now f a i r l y well accepted that both the receptor macromolecule and the 22 drug molecule can influence the conformation of each other. The preferred conformation of methadone may he perturbed by the i n t e r a c t i o n forces e x i s t i n g between the drug and the r e -ceptor. Thus the preferred conformation of methadone i n solu-t i o n may not be the pharmacological conformation, the conformation that f i t s the perturbed receptor macromolecule. To in v e s t i g a t e the nature of i n t e r a c t i o n between the analgesic receptor and the s t r u c t u r a l l y f l e x i b l e methadone molecule, conformationally r e s t r i c t e d analogues of methadone seems to be better suited. A few conformationally r i g i d methadone analo-gues, such as 2A and _25_ have been studied. In general, such GH 3 24 25 Methadone s t r u c t u r a l modifications of methadone re s u l t e d i n l e s s a c t i v e or i n a c t i v e compounds (82). I t i s possible that the stereo-chemistry of these r i g i d analogues of methadone does not sat-i s f y the requirements demanded by the opiate receptor. Thietane 1,1-dioxides such as 2G are considered to be s t r u c t u r a l l y s i m i l a r to the sulfone analogue of methadone 23 (23) which i s believed, as mentioned i n page 11, to inter-act with opiate receptor i n the same manner as that of 22. CH-, V GH. IT-CH-CH-s o , CH^ / CH-IT-CH. CH-> -SO, 2 6 23 (sulfone analogue of methadone) Studies of these r e l a t i v e l y new and l e s s i nvestigated c y c l i c sulfones may lead to development of new potent diphenylpropylamine type analgesics containing a s i g n i f -i c a n t degree of conformational r i g i d i t y . The present project continues previous i n v e s t i g a -t i o n s , i n our laboratory, of thietane 1,1-dioxides f o r medi-c a l uses ( 8 3 - 8 6 ) . Because of the synthetic d i f f i c u l t y en-countered i n the synthesis of £ 6 , Coates and Haya ( 8 4 , 8 5 ) , on the basis of c e r t a i n assumptions and proposals, synthe-sized 2,4-diphenyl-3-dimethylaminomethylthietane 1,1-dioxid-es (27-29) and 2-phenyl-3-dimethylaminomethylthietane 1,1-dioxides (J30, ,3_1) as an approach to apply the semirigid t h i — etanes to the studies of methadone-receptor i n t e r a c t i o n . A l l these compounds were found to be devoid of analgesic a c t i v i -ty. In comparison with the structure of _ 2 6 ^ 27-31 lacks a phenyl group o n C ( 2 ) . I t i s possible that t h i s missing phenyl group, rather than the one already placed on 24 27 R 1 = H, R 2 = H _3_0 R = H 28 R 1 = H, R 2 = Gl or N0 2 31 R = CH 3 29 R 1 = CH^, R 2 = H the.C(2) carbon of thietane r i n g , has the required o r i e n t a t i o n to bind with the f l a t surface of the analgesic receptor (Fig-ure I ) . I t was considered, therefore, that synthesis of com-pounds 32-36, with two phenyl groups on the G(2) carbon, would be of i n t e r e s t . The high s i m i l a r i t y of these compounds to the sulfone analogue of methadone (23) reasonably suggested that they would be potent analgesics. The synthesis of J35 and _36 was desirable to explore the suggestion by previous workers CH 3 32 R = H 35 c i s 33 R = GH^ c i s 36 trans 34 R = CH- trans ( 8 4 , 8 5 ) that a close approximation of amino side chain to sulfone group may be necessary f o r the achievement.of ahalg s i c a l l y a c t i v e thietane d e r i v a t i v e s . THIETANE CHEMISTRY 2 6 Two review a r t i c l e s on thietane chemistry have ap-peared i n the l i t e r a t u r e (87, 88). Surveys on the same subject i n c l u d i n g the l i t e r a t u r e to 1973 are found i n two d i s s e r t a t i o n s (84, 85). The material presented i n t h i s section i s a b r i e f summary of pu b l i c a t i o n s that have not been previously covered, with emphasis on the chemistry relevant to the research prob-lem of the present project. Thietane d e r i v a t i v e s have been known to possess non-planar structures. The r i n g puckering v i b r a t i o n of the thietane r i n g was observed i n i r (89), f a r i r (90), and pmr (91) spec-t r a . The determination of molecular structure of thietane (37) by electron d i f f r a c t i o n , showed that the bond lengths of C-S, o C-C, and C-H were 1.84, 1.55 and 1.10 A r e s p e c t i v e l y and that the bond angles of C-S-C and H-C-H were 76.8 and 112° respec-t i v e l y . The angle of puckering defined by C2-S-C4 plane and C2-C3-C4 plane was 2 6 ° (92). In substituted thietanes, the non-3 7 \ bonded i n t e r a c t i o n s of the substituents would p a r t i c u l a r l y fa> vour a puckered structure. Infrared studies showed that 3-chlorothietane possessed a bent r i n g with the chlorine atom being equatorial (93). The x-ray crystallography showed that 27 (p-chlorobenzenesulfonamido )-|5-propiothiolactone was pucker-ed "by about 13° (94). Puckering of the r i n g has also been ob-served i n the thietane 1-oxide d e r i v a t i v e s . The c r y s t a l struc-ture of cis-2,4-diphenylthietane trans-l-dxi.de (38), determin-ed by x-ray crystallography, possessed a puckered thietane r i n g to accommodate two equatorial phenyl groups. The bond distances and the bond angles were s i m i l a r to those of unsub-s t i t u t e d thietane, the bond lengths of S-C and G-G being 1.85 and 1.57 A r e s p e c t i v e l y ; and the bond angles of G-S-G, S-C-G and C-C-C being 76.5, 86.9 and 93.9° r e s p e c t i v e l y (95). The angle of puckering was found to be 41.9°. The s u l f i n y l oxygen was shown to have equatorial o r i e n t a t i o n (95). The equatorial o r i e n t a t i o n of s u l f i n y l oxygen was also observed i n both c i s -and trans-3-(p-bromophenyl)thietane 1-oxide ( 9 6 ) . Thietane 1,1-dioxide d e r i v a t i v e s also possess a nonplanar thietane r i n g . Z i e g l e r e_t a l . studied the molecular structure of 2,2-dimethylthietane 1,1-dioxide (39) by x-ray methods. They show-ed that the thietane r i n g was puckered by 23° (97). A n d r e t t i et a l . reported that the thietane r i n g of cis-2-chloro-3-mor-38 o 28 0 39 pholino-4,4-dimethylthietane 1,1-dioxide was puckered by 2 6 . 6 ° (98). The x-ray studies of cis-2.2-diphenyl-3.4-dichloro-thietane and i t s oxidation product, _cis-2,2-diphenyl-3,4-di-chlorothietane 1,1-dioxide showed an i n t e r e s t i n g r e s u l t (99, 100). The thietane rings i n both compounds were puckered, by angles of 29 and 31.3° r e s p e c t i v e l y . The conformations of C-Gl bonds were 3-equatorial and 4-axial with respect to the t h i e -tane r i n g i n the former compound (40). The oxidation of t h i e -tane _40 to sulfone _41 re s u l t e d i n 3-axial and 4-equatorial 40 41 conformations of two C-Cl bonds i n the thietane 1,1-dioxide. 29 The r i n g puckering and the preferred a x i a l o r i e n t a t i o n of the 3-substituents were also reported by Gistaro _et a l . i n t h e i r pmr study of 3-substituted thietane 1,1-dioxides (101). Thietanes are re a c t i v e compounds probably because of the high s t r a i n of the four-membered r i n g and the a v a i l a b i l i t y of nonbonded electrons on s u l f u r . In the presence of a c i d , thietanes r e a d i l y undergo polymerization. Ring cleavage reac-tions take place when thietanes are treated with base or elec -MH2CH2CH2GH2SH. t r o p h i l i c reagents. The e l e c t r o p h i l i c reagents such as methyl iodide probably form a sulfonium s a l t with thietane leading to the r i n g opening (87, 88). + GH 3I S ® I © I CH 3 ICrI 2CH 2CH 2SCH 3 Thietanes can be r e a d i l y oxidized to sulfoxides or sulfones. Unlike the thietanes, the oxidized analogues are more stable and u s u a l l y appear as c r y s t a l l i n e products. Thie-S • SO 1 — s o 2 30 tane 1,1-dioxides are thus frequently prepared as d e r i v a t i v e s of thietanes f o r easy handling. Certain thietanes which can not he obtained d i r e c t l y have been obtained by reduction of the corresponding thietane 1,1-dioxides with l i t h i u m aluminum hydride. - s o 2 An e f f i c i e n t route to thietane 1,1-dioxides i s the cyc l o a d d i t i o n of strongly n u c l e o p h i l i c o l e f i n s (e.g. enamines, ynamines, v i n y l ethers, ketene acetals and ketene aminals) with an appropiate sulfene generated i n s i t u by the reac t i o n of s u l f o n y l chloride and triethylamine. These cy c l o a d d i t i o n . c = c ; RCH=S0, E t 3 N RCH 2S0 2C1 H -R -SO, reactions have been extensively reviewed (84, 85, 102-107). A b r i e f summary i s presented here. The s u l f o n y l c h l o r i d e s used i n the cyc l o a d d i t i o n r e -actions are unsubstituted or substituted methanesulfonyl chlorides. With methanesulf onyl- . c h l o r i d e , the cyc l o a d d i t i o n r e a c t i o n r e s u l t s i n formation of 3-substituted or 2,3-substi-tuted thietane 1,1-dioxide. Treating methanesulf onyl'. chloride 31 (42) with substituted N-methyl-N-phenylvinylamines (43), f o r example, was reported to generate 2,3-substituted thietane 1,1-dioxides (44) (108). With substituted methanesulfonyl ? H3 </\\-TT-C=CHR2 43 CH 3S0 2C1 42 Et 2 > \ 1 SO, 4 4 R 1 = H, CH. R^ = CH. or R XR 2 = ( 0 H 2 ) 4 chlorides the cycl o a d d i t i o n leads to the formation of 2,3- or 2,3,4-substituted thietane 1,1-dioxides. The rea c t i o n of mor-pholino enamines (45) with substituted 2-halomethanesulfonyl R 1 „2 R 4 , , . / R T Et„N 0 N-C=C^ , + X-CH-S09C1 > R RJ VTT X 1 1 r 45 R 1 = H, C^H^ R 2 = R 3 = CH, or R 2 = H, R 3 = CH Q R 4 .R4 + R l J r z -SO, !2 R^ R 4 = H, CH, X = CI, Br, I 4 7 3 R- -S0, R£ 48 32 chlorides ( 4 6 ) « i n the presence of triethylamine, was reported to give substituted 2-halo-3-morpholinothietane 1 , 1 - d i o x i d e s as a mixture of c i s and trans isomers ( 4 7 , 4 8 ) ( 1 0 9 ) . The be-havior of these thietane 1 , 1 - d i o x i d e products towards the treatment of base was studied ( 1 1 0 ) . The r i n g substituents and t h e i r stereochemistry were shown to determine the r e a c t i o n paths. The 4,4-dimethyl d e r i v a t i v e s ( 4 9 , 5 0 ) underwent halogen halide e l i m i n a t i o n to give a t h i e t e 1 , 1 - d i o x i d e j j l upon t r e a t -ing with aqueous a l c o h o l i c NaOH. I t was proposed that trans hydrogen halide elimination was the main process and that pre-isomerization of the trans isomer to the c i s form occurred be-fore the dehalogenation. In the case of 2,4,4-trimethyl-3-mor-33 pholinothietane 1 , 1 - d i o x i d e ( 5 2 ) , the c i s isomer was r e a d i l y dehalogenated to give j?3 while the trans isomer was unreactive 0 H--Ir CI ! r r~"CH-CH, -SO, CH 3 £ 2 OH © *0> SET-" CH, 0H 3 -SO, CH 3 53 towards the hase probably because the isomerization was not possible i n the trans isomer. In those d e r i v a t i v e s bearing the 3 , 3 - d i s u b s t i t u e n t s ( 5 4 ) , the hydrogen halide elimination was s t r u c t u r a l l y prevented. Ring cleavage was the preferred reac-t i o n leading to formation of 5 - p h e n y l - 2 H - l , 3 - o x a t h i o l e 3 , 3 -dioxide ( 5 6 ) and other a c y c l i c fragments through an enamine intermediate ( 5 5 ) • Upon r e f l u x i n g an ethanolic s o l u t i o n of 0 // W \Rr CI RB -H -SO, E t 3N H 20 H R <^~^-C=C-S0 2CH 2Cl o ^ o ^ R = H, CH^ 5 4 55 34 R <^ r"Vc=C-S0 oGH oGl 0 0 0 R ^ S ^ c i s - or trans-2-chloro-3-morpholino-3-phenyl-4-me t h y l thietane 1,1-dioxide (.54., R=CH-3), the sulfonylenamine ( 5 5 . , R=CH3) form-ed underwent intermolecular rearrangement to give 3-(2-(2-chloroethoxy)ethyl)-5-methyl-4-phenyl- A^-thiazoline 1,1-diox-i d e (58) v i a the formation of a quaternary ammonium interme-diate (57) (111). The c y c l o a d d i t i o n of an enamine intermediate with sulfene was proposed "by Chen and Ghow (112) f o r the formation 35 of substituted thietane 1,1-dioxides (6l) i n the re a c t i o n of o^-aminoketoximes (59) with phenylmethanesul.fonyl chloride (60) i n the presence of pyridine. The amino group of the ketox-OH 59 60 n = 1 or 2 H CH 9(CH 9) CN m d d d n N— I---H H- -SO, 61 . ime (59) was s t r a t e g i c a l l y placed at a p o s i t i o n to f a c i l i t a t e r i n g cleavage. The possible enamine intermediate (62) was formed and reacted with phenylsulfene. I t was proposed that the bulky groups (phenyl, p i p e r i d i n o and a l k y l ) , during the cyclo a d d i t i o n process, staggered themselves around the r i n g to 36 (GH 2) n 6 2 -C=N <^)-CH=S0 2 H CH 0(CH 0)CN | » 2 2 n H--H -SO, 6 1 avoid undue s t e r i c crowding, so that a l l the substituents on the thietane r i n g assumed a trans r e l a t i o n s h i p . I t i s not known whether the cyc l o a d d i t i o n of s u l -fenes with enamines i s a concerted process (path 1) or a two-step r e a c t i o n i n v o l v i n g formation of zwit t e r i o n (63) (path 2). A two-step a d d i t i o n process has been chosen by various workers i n explaining the nature of product formation (103, 112-117)• 3 7 In a study of cyc l o a d d i t i o n reactions of a number of TT,N-di-substituted 2-methyl-l-propenylamines ( 6 4 ) with substituted methanesulfonyl chlorides (§3), Truce _et a l . (118) reported that the reactions l e d to a mixture of c i s and trans s u b s t i -tuted thietane 1,1-dioxides (66, 6jO. The c i s products i n which the amino moiety and the sulfene substituent assume E ^CH^ 6 4 RJ R 2^CHS0 2C1 6 5 R \ / N CH T 3 CH. -SO, 6 6 ( c i s ) H-\/ N CH T R1-R< 3 •CH. -SO, 6 7 (trans) CH. CH. \ / — \ Pr IT, 0 IT, / \ — / p r ^ R c = Halogen, CH, CH 3 > Pr, C ^ , CH 3-C 6H 4, N0 2C 6H 4 > COC 6H 5, COEt H, CH 3 a l e s s thermodynamically stable c i s r e l a t i o n s h i p , were found to be predominant i n many reactions p a r t i c u l a r l y when the s u l -38 fenes used were derived from methanesulfonyl chloride contain-in g an /-phenyl, 06-halo or o^-tolyl substituent, or from ethane-s u l f o n y l chloride bearing an o^-chloro, or oC-cjano moiety. The s t e r i c f a c t o r s appeared not to determine the s t e r e o s e l e c t i v i t y i n the formation of c i s products. A r a t i o n a l e f o r t h i s observed s t e r e o s e l e c t i v i t y was postulated on the basis that the r e a c t i o n was a two-step process and proceeded v i a the formation of a zwit t e r i o n intermediate. The e l e c t r o s t a t i c a t t r a c t i o n between the p o s i t i v e and the negative charges of the d i p o l a r zwitterion intermediate (68), which can be d e l o c a l i z e d by the amino and GH 3\-GH 3SL 3 H :c=c; ,CH, •CH-GH 3 \ 68 v H CH, CH 3 ^ CH. N — G ^ ® ^ c ; GH 3 -CH, -SO, H ,CH 3 C^H, 39 the phenyl moieties r e s p e c t i v e l y was suggested to favour the c i s geometry of products. This explanation was supported by . the data that c i s preference was not observed f o r products de-ri v e d from the sulfenes bearing substituents without apprecia-bly negative character. The cy c l o a d d i t i o n of v i n y l s u l f e n e ( 6 9 ) with morpho-l i n o or pip e r i d i n o enamine (70) was reported (119) to proceed with no s t e r e o s e l e c t i v i t y , g i v i n g a 1:1 mixture of c i s and trans thietane 1,1-dioxide products (_71, 12). Whether the post-isomerization of the c i s isomer to the trans form occurred was not known. I t was reported that 71 isomerized to 72 when the former was treated with butyl l i t h i u m . CH2=CHCH2S02C1 Et 3 N CH2=CHCH=S02 69 .OH H ^ T!H 70 R CH. R CH. H H \ -CH. I CH=CH SO, H-CH2=CH--CH. -SO, H 71 72 40 Thietane 1,1-dioxides are not the only type of pro-ducts formed i n the re a c t i o n of sulfenes with enamines. In c e r t a i n conditions, sulfenes react with enamines to form acy-c l i c s u b s t i t u t i o n products. The r e a c t i o n of phenyl s u l f o n y l c hloride (60) with 1-pyrrolidinocyclohexene (73) was reported to give an a c y c l i c sulfone 74 (120). Reaction of s u l f o n y l c hloride 75 with enamine 76 i n the presence of triethylamine afforded a c y c l i c product 77 i n 86% y i e l d (121). In the reac-0H 3 EtOOCCHS0201 IS E-tr 76 CH-Et 3 N Et00CCHS0oC=CH C. I Et II t i o n of enamine 78 with cyanomethanesulfonyl chloride (79) an a c y c l i c intermediate 80 was also proposed to account f o r the i s o l a t i o n of benzoylmethyl cyanomethyl sulfone (81) (85). Cer-t a i n ^-cyanothietanes 1,1-dioxides (82) (122) can be 41 C=CH2 + CTGH2S02C1 78 0> •IK" CN R H-1 R c 82 -H -SO, 7 9 R 1 = R 2 R 1R 2 ~ CH 3; -> X .G=CHS02GH2G1 80 0 ^"^-C-OHgSOgCHgCU 81 generated by t h i s method depending on the e l e c t r o n i c nature >: and the bulkiness of the r i n g substituents. The r e a c t i o n of j[9_ with enamine 8_3_ gave only a c y c l i c product 8_5_. I t was pointed out that thietane 8_4. may be formed before rearrangement to 85 (117 )• In c e r t a i n reactions the formation of a c y c l i c s u b s t i t u -( G H 2 ) n J 83 Et.N NCCH 2S0 2C1 *—> 7 9 (CH 0) CN 2'n S ° 2 84 ^ G H2^n ^S0 oCH oCN _ _ 2 2 n = 1, 2 85 42 t i o n products may be a t t r i b u t e d to the s t e r i c and e l e c t r o n i c f a c t o r s that were unfavorable f o r the intermolecular c y c l i z a -t i o n of the zw i t t e r i o n intermediate 6_3 and thus allowed f o r the formation of a c y c l i c products as an alternate route. Although c e r t a i n thietanes can be e f f i c i e n t l y pre-pared by reducing the corresponding thietane 1,1-dioxides, i n the s i t u a t i o n s where the synthesis of thietane 1,1-dioxide by cycl o a d d i t i o n i s not possible or thietane 1,1-dioxide i s de-composed by the reducing conditions employed, d i r e c t synthesis of thietane may be an alternate approach. The c l a s s i c method of synthesis of thietanes involves the generation of a t h i o -l a t e anion containing a good leaving group separated by three carbons from the s u l f u r atom. Intramolecular c y c l i z a t i o n of t h i s t h i o l a t e anion r e s u l t s i n formation of 2-substituted or 43 3-substituted thietanes. Synthesis of 2-substituted thietanes by t h i s method generally r e s u l t s i n low y i e l d s probably due to the s t e r i c hindrance of the c y c l i z a t i o n process by the s u b s t i -tuents (122). -C-C-C-R se R = OCN o , halogen, O-S-^^-GR^ et c. 0 Dubs .et a l . (123) reported a method to prepare a series of substituted 2-thietanols J37 i n 16-84% y i e l d s by tr e a t i n g U,(5-unsaturated aldehydes 86 with hydrogen s u l f i d e i n R \ ^ R 2^ CHO H 2S R 86 R = H, GH3, CH(GH 3) 2, Et R 1 = H, CR~3, Pr, Et R = H or GH 3 E t 3 N R-RJ -OH -S R 2 82 the presence of triethylamine. I t was assumed that the t h i o -l a t e i o n was formed and underwent intramolecular c y c l i z a t i o n 44 to give the products. Mayer (124) developed a method of synthesis of 2,2-dime t h y l thietane (89). He treated l,3-dichloro-3-methylbutane (88) with hydrogen s u l f i d e i n the presence of a c a t a l y t i c amount of aluminum chloride and i s o l a t e d 2,2-dimethylthietane CI CI CH.—C—CH0—CH0 j i d d CH A1C1. H 2S CH 3 88 3 CH, 89 (89) i n 90% y i e l d . I t was proposed that the re a c t i o n proceeded v i a the formation of intermediate 90 or 91. The aluminum chlo-r i d e might a c t i v a t e the double bond to f a c i l i t a t e the attack of hydrogen sulfide., A l C l . A1C1, (CH 3) 2C=CHCH 2C1 CH2=:CCH2CH2C1 CH 3 45 Capanovich e_t a l . discovered a method of c y c l i z i n g the bromomethylthioester .92 to 3,3-diphenylthietan-2-one (94)» The carbanion 33 was probably the intermediate of the c y c l i z a -t i o n process (125). 92 93 14 A r e l a t i v e l y new and very u s e f u l method of preparing thietanes i s the photocycloaddition of thiocarbonyl compounds with o l e f i n s bearing a v a r i e t y of substituents. This method has l e d to the synthesis of many substituted thietanes which can not be generated by the c l a s s i c a l intramolecular c y c l i z a -t i o n of t h i o l a t e or c y c l o a d d i t i o n of sulfenes with o l e f i n s . .' The formation of thietane intermediates upon i r r a d i a t i n g a mixture of thiobenzophenone and o l e f i n s was f i r s t proposed by Kaiser and Wulfers ( 1 2 6 ) . The i s o l a t i o n of thietanes was sub-sequently demonstrated by the Japanese photochemists i n 19695 Ohno e_t a l . showed that i r r a d i a t i n g a mixture of thiobenzophen-one . (95) and c e r t a i n o l e f i n s (.96), with 366 nm l i g h t or 589 nm l i g h t , generated thietanes (97) i n good y i e l d s (127-129). The c y c l o a d d i t i o n r e a c t i o n was found to be s t e r e o s p e c i f i c . The photocycloaddition of c i s - and trans- dichloroethylene (96, 1 2 R =R =G1), f o r example, gave e x c l u s i v e l y cis-3,4-dichloro-2,2-4 6 9 5 9 6 97 R 1 = CI, CH3COO, CH3OGO, CN R 2 = H, CI, CH"3 diphenylthietane (97, R1=R2=C1) and trans-3.4-dichloro-2,2-1 2 diphenylthietane (97, R =R =C1) re s p e c t i v e l y . In add i t i o n to the generation of thietanes (1:1 thiobenzophenone/olefin ad-ducts), the formation of 1,3- or 1,4- dithianes (2:1 thiobenz-ophenone/olefin adducts) has also been observed i n some pho-tocycloaddition of thiobenzophenone with olefins.. The photo-chemical r e a c t i o n of thiobenzophenone with styrene (98). f o r example, afforded both 1,4-dithiane _99 and thietane 100 with y i e l d s depending on the concentrations of _95_ and '98 (127). S 99 100 47 On the basis of the r e s u l t s obtained from reactions of thiobenzophenone and o l e f i n s bearing various substituents, Ohno and h i s coworkers (127-129) concluded that o l e f i n s bear-ing electron-withdrawing groups (eg. CN, C00CH3, G l , 0C0CH 3 etc.) upon r e a c t i n g with thiobenzophenone excited by 366 nm l i g h t gave thietanes, and that o l e f i n s bearing e l e c t r o n - r e l e a s -ing substituents (eg. a l k y l , alkoxy, phenyl etc.) upon react-ing with thiobenzophenone excited by 366 or 589 nm l i g h t , gen-aerated thietanes or dithianes depending on the nature of the o l e f i n s . The f a c t o r s that governed the course of photocyclo-ad d i t i o n reactions appeared to be both s t e r i c and e l e c t r o n i c . The r e a c t i v e species i n the reactions was suggested to be the l i g h t - e x c i t e d thiobenzophenone since the o l e f i n s used i n the photochemical reactions were transparent i n the wavelength r e -gions employed (127, 132). The i r r a d i a t i o n was proposed to cause two types of e l e c t r o n i c t r a n s i t i o n of thiobenzophenone, depending on the wavelength of l i g h t used (127). The i r r a d i a -t i o n at long wavelength (589 nm) produced t r a n s i t i o n of an electron from non-bonding o r b i t a l (n) to pi-antibonding o r b i -t a l ( T C ) of the thiocarbonyl group of thiobenzophenone. The r e s u l t i n g excited state 0**3t) possessed an energy 40-43 Kcal higher than the ground state of thiobenzophenone and has been suggested to be a t r i p l e t , the spin of the excited electron i n the 7C o r b i t a l being unpaired with that of the unexcited e l e c -tron i n the n o r b i t a l . The i r r a d i a t i o n at short wavelength (366 nm) induced t r a n s i t i o n of an electron from p i - o r b i t a l (Jt) to pi-antibonding o r b i t a l . The r e s u l t i n g excited state ( * : - » JC ; ©c-48 cupied an energy l e v e l about 50 Kcal higher than the n-4jc state and has been suggested to be a s i n g l e t , two electrons i n each o r b i t a l being paired (127, 130, 131). Ohno et a l . suggested * that the n-»Jt t r i p l e t state of thiobenzophenone behaved l i k e a t h i y l r a d i c a l while"the K^TL s i n g l e t state behaved l i k e a t h i o -l a t e anion (RS~). Two kinds of mechanism were thus postulated f o r the photochemical reactions of thiobenzophenone with o l e -f i n s (127). With electron d e f i c i e n t o l e f i n s , 'the 7i-*Jt species of thiobenzophenone formed a charge-transfer complex leading to the formation of thietanes. The energy of n-*7t species of t h i o -benzophenone was considered to be too low to tr a n s f e r to the o l e f i n s . However, with el e c t r o n r i c h o l e f i n s , the n-*7i species of thiobenzophenone reacted through a d i r a d i c a l mechanism. The s u l f u r atom of thiobenzophenone attacked the o l e f i n leading to the formation of:'diradical 101 which e i t h e r intramolecularly c y c l i z e d to form thietane or reacted with a second molecule of thiobenzophenone r e s u l t i n g i n generation of 1,3- or 1,4- d i -thiane (102, 103). The f a c t o r s that determined the r e a c t i o n 4 9 path were suggested to be the concentration of thiobenzo-phenone and the s t e r i c environment of the d i r a d i c a l . n -> X 5 8 9 nm n?c : c = c : I - G 6 H 5 • G 6 H 5 101 s I D 5 >f ^ G - G 6 H 5 ^ \ S ^ G — G 6 H 5 G 6 H 5 ' J G 6 H 5 ' G 6 H 5 Y 3 ^ 102 G 6 H 5 " G 6 H 5 • G 6 H 5 G 6 H 5 or G 6 H 5 " G 6 H 5 G 6 H 5 G 6 H 5 G 6 H 5 G 6 H 5 G 6 H 5 G 6 H 5 103 The ea r l y work on the photocycloaddition of t h i o -50 benzophenone with o l e f i n s has been reviewed. (130, 132). ,; Recent studies of the photocycloaddition reactions using various substituted o l e f i n s have l e d to the generation of many new substituted thietanes. A summary of these new fi n d i n g s i s presented i n the remainder of t h i s section. When a mixture of a thione (105, 107) and a pen-tadiene (104, 109) was i r r a d i a t e d under 589 nm l i g h t (n-»rc. band), the corresponding thietane (106, 108, 110, 111) was i s o l a t e d (133). An a c y c l i c rearranged adduct (112) was a l -so i s o l a t e d i n the reactions of 104 with 105. 104 107 108 51 The photocycloaddition of methoxyallene (113) with thiobenzophenone (95) at 589 nm was reported to give thietane 114 together with a benzothiane 115» I t was assum-* ed that the t r i p l e t thiobenzophenone attacked methoxy-allene at the c e n t r a l carbon atom r e s u l t i n g i n formation of a b i r a d i c a l which then c y c l i z e d to y i e l d thietane and ben-zothiane. With xanthene-9-thione (107) the photocycloaddi-t i o n of methoxyallene (113) gave only thietane 1 1 6 . No ben-zothiane was detected (134a). 52 53 Gotthardt and L i s t l e (135), by i r r a d i a t i n g mix-tures of thiocarbonates (117, 123) and substituted o l e f i n s (118-121) with n-m band l i g h t (328 nm), i s o l a t e d the cor-responding thietanes (122, 124)» When they i r r a d i a t e d mix-117 R R CH. R RJ 3 328 nm 3 R< 118: R 1=R 2=R 3=CH 3  119: R-^R^CH^ R3=H 120: R 1=CH ?; R 2R 3=:C / C H 3  J V C H 3 121: R 1=C(CH 3):GH 2; R2=R3=H R 122 RJ GH; .R' :c=c; V h-v 328 nm' 123 118-120 124 54 tures of thiophosgene (125) and o l e f i n s (118-120), the ex-pected thietane products (126) were also obtained (136). Cl-C-Cl 125 C-G . o CH^ NR^ 118-120 hi> 455 nm' R 1 Gl GH R Gl R-126 With o l e f i n s 119 and 120 the photocycloaddition of t h i o -phosgene also generated a c y c l i c adducts 127 and 128 re s -p e c t i v e l y . The 2,2-dichlorothietanes (126 ) i s o l a t e d rapid-C l CI R 2 R 1 ^CH-S-C-C=CH0 i R-^  127: R1=R2=CH3; R3=H 128: R ^ C H ^ R 2=R 3=C(CH 3) 2 l y underwent dechlorination, upon chromatography on s i l i c a g e l , to give the corresponding thietanones (129-131) • I t CH GH; CH; CH 3 129 CH GH, CH; 3 0 130 CH, CH; 0 G H 3 ~ C ^ 3 131 55 was suggested that the r e a c t i v e thiophosgene was the n-*jt t r i p l e t species. The photocycloaddition of O-methyl or O-ethyl thiobenzoate (132) with substituted o l e f i n s (133, s u b s t i -tuents are H, benzyl, methyl, e t h y l , propyl) afforded 2-OR 132 133 134 phenyl-2-alkoxythietane d e r i v a t i v e s (134)» The r e a c t i o n was a t t r i b u t e d to the formation of n-»x t r i p l e t species of thiobenzoate (137 )• When a mixture of diarylthioketone (135) and v i -n y l ethyl ether (136) was i r r a d i a t e d under 589 nm l i g h t , the r e a c t i o n r e s u l t e d i n the formation of thietane (138) or dithiane (139) depending on the concentration of t h i o -ketone used (135 )• A b i r a d i c a l intermediate was suggested f o r the product formation. At a low concentration of t h i o -ketone, the b i r a d i c a l intermediate (137) underwent i n t r a -molecular c y c l i z a t i o n to form the thietane 138. At a high concentration of thioketone, the b i r a d i c a l intermediate (137) was trapped by a second molecule of thioketone lead-ing to the formation of dithiane 139. The photocycloaddi-56 R-C-R + C 2 H 5 O C H = C H 2 135 136 TJR, HC-G 2H 50' 137 2 5 N ,R, 138 S 11 R-C-R - S \ R, R, C 2 H 5 0 139 R = - < ^ ) ; H ( ^ ) - C H 3 ; - 0 - < ^ ) - C H 3 t i o n of thioketone with e l e c t r o n - d e f i c i e n t o l e f i n s l e d to more i n t e r e s t i n g r e s u l t s (135). With methyl acrylate (140), the r e a c t i o n of x-*x species of thiobenzophenone res u l t e d i n the formation of thietane 141 and the reac t i o n of n->3t species of thiobenzophenone afforded a 2:3 mixture of t h i e -tane 141 and benzothiane 142. Apparently the formation of thietane 141 was not governed by the wavelength used. I t was observed that the benzothiane 142 was generated ther-mally by heating a mixture of thiobenzophenone and methyl acrylate at 40-50°. The photocycloaddition of thione 143 with a c r y l o n i t r i l e (144) or methyl acrylate (140) at 589 nm 57 (40%) 142 (60%) y i e l d e d thietane 145• This again showed that the Jt-»3t ex-c i t a t i o n of the thiocarbonyl compounds was not neccessary f o r thietane formation from electron d e f i c i e n t o l e f i n s , i n 1 4 3 1 4 4 R = 0 N 1 4 5 1 4 0 R=C00CH, contrast to the r e s u l t reported by Ohno and h i s coworkers (138). The photocycloaddition of xanthione with methyl acr y l a t e also supported the argument. I r r a d i a t i n g a mix-58 ture of xanthene-9-thione (107) and methyl acrylate (140) at e i t h e r 589 nm (n-»7t e x c i t a t i o n ) or 405-408 nm (n-iic ex-c i t a t i o n ) r e s u l t e d i n the formation of spirothietane 146. The photocycloaddition of nitrogenous thiocarbon-y l compounds with o l e f i n was reported by Fourrey et a l . (139). The expected spirothietanes 149 and 151 were obtain-ed when a s o l u t i o n of 4 - t h i o u r a c i l d e r i v a t i v e s (147, 150) and m e t h a c r y l o n i t r i l e (148) was i r r a d i a t e d . R .CH-0 ^ F I CH R = H or CH. H2C=C ^ CN hv CH 3-F 3^>^CH-0 ^ N CH-147 148 149 S CH-N I CH-CN CHo N4-OH3 —IT 150 148. 15i 5 9 The photocycloaddition of thioparabanate (152) with various o l e f i n s (153) also generated the correspond-ing spirothietanes 154 (140). R I RJ 3 + R > G = % 5 152 153 R< -> R~ R RJ 0 R-•S Ll 154 0 R X= GH- R = H, CH^ R 3= G00GH3, 0C 2H 5, GH^ R = H, GH^ R 5= H or R 4R 5= =C(GH 3) 2 SYNTHETIC APPROACH 6 0 The thietane d e r i v a t i v e s investigated as poten-t i a l analgesics were compounds 32-36. The synthesis of these compounds was approached through the corresponding CH 3 > C H 9 CH 3 / 2 N R •SO, 32 R=H 33 R=CH3, c i s 34 R=CH3, trans CH-\ CH- •SO, NCH, CH-35 c i s 36 trans cyanothietanes 155-159 which were prepared according to the photochemical method described by Ohno and h i s cowork-ers (138). The general synthetic pathway established f o r 155 R=H 158 c i s 156 R=CH3, c i s 159 trans 157 R=CH,, trans the synthesis of 32 i s outlined i n Scheme I : 61 Scheme I Synthetic route to 2,2-diphenyl-3-dimethylaminomethylthie- tane 1,1-dioxide Q2.) H 155 Replacing p r o p e n e n i t r i l e (144) with c i s - and trans- 2-hutenenitrile (162, 163) allowed the synthesis of 6 2 CH 3 ^ CH 3 \ H C=C C=C H 162 163 thietanes 156-159 which were the precursors of thietane 1,1-dioxides 33-36 r e s p e c t i v e l y . Generally, the synthesis of the desired products (32-36) was approached through 4 steps: 1. Preparation of the cyanothietanes by photocy-c l o a d d i t i o n of thiobenzophenone with appro-p r i a t e o l e f i n i c n i t r i l e 2. Preparation of cyanothietane 1,1-dioxides 3. Synthesis of aminomethylthietane 1,1-dioxides 4 . Synthesis of N,N-dimethylaminomethylthietane 1,1-dioxides During the course of synthesis of above thietane products, many r e l a t e d chemical reactions were performed i n an attempt to solve the synthetic problems which were encountered, and to develop the present project. These w i l l be described under the following a d d i t i o n a l t i t l e s : 5. Synthesis of 2,2-diphenyl-3-dimethylamino- .  methylthietane. 6. Attempted synthesis of thietane d e r i v a t i v e s with the <<-dime thylaminome t h y l side chain 7. Chemical reactions of 2,4-diphenylthiete 1,1-dioxide and attempted synthesis of 2,4-diphen-ylthietan-3-one 1,1-dioxide 63 DISCUSSION 1. Synthesis of cyanothietanes by photocycloaddition of  thiobenzophenone with o l e f i n i c n i t r i l e s Thiobenzophenone (95) i s a blue c r y s t a l l i n e ma-t e r i a l which i s very s e n s i t i v e to atmospheric oxygen and e a s i l y undergoes polymerization at room temperature. I t was prepared from benzophenone (164). i n an amount as r e -quired, by a modification of the method of Grofton and Braude (141). Benzophenone (164) was treated with hydrogen s u l f i d e i n the presence of hydrogen chloride. The product was immediately p u r i f i e d by repeated r e c r y s t a l l i z a t i o n 0 S 164 95 from n-pentane which was found to be a better solvent than the petroleum ether used by Grofton and Braude. With n-pentane, c r y s t a l l i z a t i o n occured i n a shorter time and the p u r i f i e d thiobenzophenone was recovered i n a better y i e l d . Pure thiobenzophenone obtained a f t e r r e c r y s t a l l i z a t i o n f o r three or four times was stable i n the freezer f o r a few months i f the material was kept under nitrogen or carbon dioxide atmosphere. In most of the photocycloaddition r e -actions, f r e s h l y prepared thiobenzophenone was used. When 64 the stored thiobenzophenone was employed, i t was f u r t h e r r e c r y s t a l l i z e d three or four times. The o l e f i n i c n i t r i l e s were commercially supplied. P r o p e n e n i t r i l e (144) was obtained as a c o l o r l e s s l i q u i d a f t e r f r a c t i o n a t i o n through a Vigreaux column. Upon i r r a -d i a t i o n with u n f i l t e r e d u l t r a v i o l e t l i g h t generated from a medium pressure mercury arc, p r o p e n e n i t r i l e r a p i d l y r e -acted with thiobenzophenone (95) to produce a white, un-i d e n t i f i e d polymer which was not soluble i n common organic solvents. The 2-butenenitrile was obtained as a mixture of c i s and trans isomers (162, 163) known commercially as c r o t o n o n i t r i l e . The a n a l y s i s of t h i s mixture by using gas l i q u i d chromatography (glc) i n d i c a t e d that i t contained f.. 60-70% ci s - 2 - b u t e n e n i t r i l e (162) and 30-40% jtrans-2-butene-n i t r i l e (163) depending on the commercial sources. The b o i l i n g points (162: 108°, 163: 121°) of these two isomers were so close that they were not separated by f r a c t i o n a t i o n through a 5 f t Vigreaux column. The systematically repeated f r a c t i o n a t i o n (142) using a 2 f t column packed with glass h e l i c e s also f a i l e d to separate the two isomers. The c a l -c u l a t i o n based on the b o i l i n g point difference showed that a d i s t i l l a t i o n column of at l e a s t 20 t h e o r e t i c a l p l a t e s was required to achieve a 95% separation of two isomers (142). This meant that a column packed with 1/4 i n x 1/4 i n glass tubing and measuring at l e a s t 6 f t was needed f o r 95% sep-arat i o n . In order to obtain the separation of each isomer i n a pure form, a column of higher e f f i c i e n c y was required. A Spinning-Band-Column d i s t i l l a t i o n apparatus, kind l y made av a i l a b l e by Mr. L. T. Muenster of the Chemistry depart-ment, The U n i v e r s i t y of B r i t i s h Columbia, was selected f o r the separation of 1 6 2 and 1 6 3 . The c r o t o n o n i t r i l e was r e -peatedly d i s t i l l e d u n t i l pure c i s - 2 - b u t e n e n i t r i l e and pure t r a n s - 2 - b u t e n e n i t r i l e were obtained. The p u r i t y of the sep-arated isomers was confirmed by g l c . I r r a d i a t i n g a cyclohexane s o l u t i o n of thiobenzo-phenone ( 9 5 ) and pr o p e n e n i t r i l e ( 1 4 4 ) with u l t r a v i o l e t l i g h t at the wavelength of 3 6 6 nm, generated a crude pro-duct which was p u r i f i e d by column chromatography to give pure 2,2-diphenyl-3-cyanothietane 1 5 5 as a white s o l i d i n •S 95 1 1 4 155 a y i e l d of 41%. The i r spectrum of 155 displays the absorp-t i o n (2235 cm""^ ) f o r the cyano group i n additi o n to the signals f o r two phenyl substituents. The pmr spectrum of 155 i s i n agreement with the thietane structure. The two methylene protons (H , H, ) are magnetically nonequivalent being displayed as two symmetrical, p a r t l y overlapping . quartets centered at 3.32 and 3«47 ppm r e s p e c t i v e l y . The methine proton (H c) appears as a t r i p l e t at 4.99 ppm due 66 to two p a r t l y superimposing doublets. The geminal and the v i c i n a l coupling constants (J(H a-Hb), J(H a-H c), J(Hh-H c)) are a l l equal to 9 Hz i n comparison with the reported JCHa-H^) value of 10 Hz i n compound l6_5_ (139). The ten Hb CH 3 155 165 aromatic protons are displayed as a m u l t i p l e t at 7.10-7.70 ppm. The conformation of 155 w i l l be considered l a t e r . The 41% y i e l d of 155 was not the r e s u l t of l o s s due to the p u r i f i c a t i o n process. Analysis by g l c and t h i n l a y e r chromatography methods i n d i c a t e d that crude product contained only 50% of 155 and at l e a s t four other compo-nents. Pure 155 was not soluble i n n-pentane whereas about 40% of the crude mixture was soluble i n t h i s solvent. The n-pentane s o l u t i o n of the soluble components gradually be-came blue i n colour suggesting the l i b e r a t i o n of _9_5_ from some unstable products. Evaporating t h i s blue s o l u t i o n gave a greenish gummy substance with the c h a r a c t e r i s t i c odour of s u l f i d e . Attempts were made to improve the y i e l d of 155 by using acid-base washed 144, employing a new l i g h t f i l t e r , narrowing the band width of the i s o l a t e d 67 li g h t by using an additional l i g h t f i l t e r , shortening the irradiation time and using different proportions of 35. to 144- No significant improvement i n the yield of 155 was observed. When the cyclohexane was replaced by anhydrous ether as solvent, the work-up was easier, due to the vola-t i l i t y of ether, and the crude reaction product obtained was a solid instead of a gummy substance, but the yiel d of 155 was comparable. Ohno and his coworkers (138) i n 1969 claimed that irradiating a mixture of 144 and 9^ at 366 nm for four days resulted i n a 93% yield of product. They did not specify whether this yield referred to the total crude product or the pure thietane 155» The photocycloaddition °f 144 with _95_ was re-examined by de Mayo and Shizuka (131) i n 1973* Their data showed that the quantum yield i n the formation of 155 was low and did not change with the i r r a -diation time i n the I n i t i a l stage of reaction. The quantum yield for a substance under consideration i s defined as the number of molecules that react or are formed i n a photo-chemical process per number of photons absorbed i n a unit of time. I f every photon absorbed can i n i t i a t e a molecule to undergo a certain chemical reaction',; the quantum yield i s unity. I f other processes compete with the one under consideration, the quantum yield i s much lower. The low quantum yield i n the generation of thietane 155 implied that more than one single process occurred i n the reaction of 35 with 144. In fact, i t was discovered by de Mayo and 6 8 Schizuka (131) that thietane 1 5 5 was not the firs t - f o r m e d product but was derived from the thermal decomposition of an intermediate, 1,3-dithiane 1 6 6 which was i s o l a t e d as a white s o l i d i n a 6 5 % y i e l d a f t e r i r r a d i a t i n g a mixture of 9 5 and 144 at - 7 8 ° (131). The dithiane 1 6 6 was r e l a t i v e l y S 155 15 stable at low temperature. At 3 7 ° one mole of 1 6 6 l i b e r a t -ed one mole of thietane 1 5 5 and one mole of 35. within a period of two days ( 1 3 1 ) . Ohno and h i s coworkers (138) r e -ported that the re a c t i o n of _95_ and 144 d i d not occur at a longer wavelength ( 5 8 9 nm). On the contrary, de Mayo and Nicholson ( 1 3 0 ) i s o l a t e d , i n ad d i t i o n to thietane 155% 1,4-dithiane 1 6 7 , benzothiane l 6 8 y and a d i s u l f i d e deriva-t i v e 1 6 9 a f t e r i r r a d i a t i n g a mixture of 9_5_ and 144 at wavelengths longer than 5 0 0 nm. Considering that so many photocycloaddition products were i s o l a t e d and that the 69 8% 15_5_ 26% 167 r YG 6 V 2 95 + 144 y i e l d of dithiane 166 i n the re a c t i o n at 366 nm was only 65%, the reason of higher y i e l d (93%) claimed "by Ohno and h i s coworkers (138) f o r the photocycloaddition r e a c t i o n of 95 with 144 i s not c l e a r . The 41% y i e l d of 155 i n our ex-periment supports the f i n d i n g of de Mayo et a l . that the thietane 155 was not the only product of the photochemical reacti o n . The other u n i d e n t i f i e d by-products were probably i d e n t i c a l or s i m i l a r to 167, 168 and 169. I t was observed 70 that prolonged i r r a d i a t i o n beyond the end point r e s u l t e d i n a poor y i e l d of 155• This i n d i c a t e d that 155 was a c t i -vated to undergo secondary photochemical reactions. Thus the 4-1% y i e l d i n the generation of 155 and the formation of other side-products a f t e r a long period of i r r a d i a t i o n (about four days) i s not s u r p r i s i n g . Products such as 169 may be derived from the decomposition and further r e a c t i o n 2-butenenitrile ( 1 6 2 ) at 3 6 6 nm f o r 152 hours generated a mixture of cis-2,2-diphenyl-3-cyano-4-methylthietane ( 1 5 6 ) and cis-2,2-diphenyl-3-methyl-4-cyanothietane (158) i n a of 155. I r r a d i a t i n g a mixture of _9_5_ and excess pure c i s -S CH •3 \ H ^ + 3 6 6 nm H 95 1 6 2 1 5 6 158 2.5 1 r a t i o of 2.5:1, cal c u l a t e d on the basis of r e l a t i v e i n t e n -s i t i e s of the two methyl signals i n the pmr spectrum of 71 the r e a c t i o n mixture. Analyzing the recovered excess bu-t e n e n i t r i l e by g l c in d i c a t e d that no isomerization of 162 to trans - 2-butenenitrile (163) occurred during 152 hours of i r r a d i a t i o n . Only 162 was recovered from the photochem-i c a l r e a c t i o n and no appreciable amount of trans-isomer (163) was detected. The pmr spectrum of the re a c t i o n pro-duct showed two sets of signals that agreed with the data reported by Ohno e_t a l . (138) f o r thietanes 156 and 158. The f i r s t set of signals was a t t r i b u t e d to the thietane 156 : The three methyl protons and H a were displayed as two doublets at 1.54 and 5*00 ppm r e s p e c t i v e l y . The H"b proton, coupling with i t s adjacent methyl protons and H a, was located as a m u l t i p l e t centered at 3-80 ppm. Prom the signals of methyl protons and H a the coupling constants, J(Ha-H-b) and JtCH^-H-fc,) were measured to be 8 and 7 Hz res-p e c t i v e l y i n agreement with the corresponding coupling constants extracted from the Hb m u l t i p l e t . The 10 phenyl protons appeared as a m u l t i p l e t at 7.10-7.75 ppm. The se-cond set of signals agreed with the structure of 158. The doublets which were a t t r i b u t e d to the methyl protons and t the Hk were located at 1.07 and 4-25 ppm r e s p e c t i v e l y . The t t t coupling constants, J(H a-Hk) and J(CH 3-H a), were also 8 t and 7 Hz r e s p e c t i v e l y . S i m i l a r l y , H a coupling with the ad-jacent methyl protons and H^ ,, appeared as a m u l t i p l e t cen-tered at 4.20 ppm. When a mixture of trans - 2-butenenitrile (163) and 35. was i r r a d i a t e d at 3 6 6 nm, a mixture of trans-2,2-diphenyl-3-cyano-4-methylthietane (157) and trans-2,2-di-phenyl-3-methyl-4-cyanothietane (15'9) was obtained i n a r a t i o of 2.8:1, calcul a t e d on the basis of the r e l a t i v e i n t e n s i t i e s of two methyl signals i n the pmr spectrum. No isomerization of 1 6 3 to 1 6 2 during the re a c t i o n was ob-served. The pmr spectrum of the mixture showed two sets of signals that were compatible with the pmr data reported f ° r 157 and 159 by Ohno and h i s coworkers (138). The f i r s t set of signals was a t t r i b u t e d to the thietane 157: The three methyl protons and H a were displayed as two doublets at 1.45 and 4 - 3 6 ppm r e s p e c t i v e l y . The Hb proton, coupling with i t s adjacent methyl protons and H a, was located as a 7 3 m u l t i p l e t centered at 3 - 8 6 ppm. The 1 0 phenyl protons ap-peared as a m u l t i p l e t at 6 . 8 - 7 - 8 ppm. The second set of signals agreed with the structure 1 5 9 ; The doublets which were a t t r i b u t e d to the methyl protons and H"b were located i at 0 . 8 3 and 3 . 6 6 ppm r e s p e c t i v e l y . The H a proton coupling t with the adjacent methyl protons and Hb, appeared as a mu l t i p l e t centered at 3 - 8 6 ppm and overlapping with the signals of H^ i n 157. The 1 0 aromatic protons were found i n the region of 6 . 8 - 7 * 8 ppm. The coupling constants of corresponding protons i n 157 were i d e n t i c a l to those i n 15 9. J(CH 3-H) and J(H-H) being 6 and 1 0 Hz r e s p e c t i v e l y . The photocycloaddition of with o l e f i n s has been reported to be s t e r e o s p e c i f i c (138). The configura-?, t i o n i n the o l e f i n s was retained i n the thietane products. Of the 2 - b u t e n e n i t r i l e s ( 1 6 2 , 163), the c i s - and trans-isomers generated e x c l u s i v e l y the c i s - and trans- t h i e -tanes ( 1 5 6 - 1 5 9 ) r e s p e c t i v e l y . The mechanism of the photo-cy c l o a d d i t i o n r e a c t i o n was proposed to involve the nucleo-p h i l i c attack of the electron d e f i c i e n t o l e f i n s by the jc-7t s i n g l e t species of _95_. In the r e a c t i o n of propeneni-t r i l e (144), the s u l f u r atom of S>5_ attacked the p-end of the double bond, r e s u l t i n g i n formation of p-cyanothietane 155 while i n the reactions of c i s - and trans- 2-buteneni-t r i l e s , the s u l f u r atom attacked both the o<- and <a- car^. bons of the o l e f i n s ( l 6 2 , 1 6 3 ) to produce a mixture of <*-cyano- and p-cyano- thietanes ( 1 5 6 - 1 5 9 ) . The l a t t e r reac-74 tions were explained on the basis that electron d e f i c i e n c y at the (3-carbons of 162 and 163 was somewhat weakened by the e l e c t r o n - r e l e a s i n g a b i l i t y of the methyl group, and as a r e s u l t , the o r i e n t a t i o n of photocycloaddition observed i n the re a c t i o n with p r o p e n e n i t r i l e (144) no .longer held i n that with 2-butenenitriles (l6_2, 163) (138). de Mayo and Shizuka (131) showed that the forma-t i o n of thietane 155 was derived from the thermal decompo-s i t i o n of the fir s t - f o r m e d product 1,3-dithiane 166. The rea c t i o n between the^-^Tt s i n g l e t species of 35 and 144 166 was described to involve the generation of a zwitt e r i o n 170 which, upon formation, immediately associated with an ad d i t i o n a l molecule of 35 r e s u l t i n g i n the formation of 75 15 I i i 155 15 1,3-dithiane which l i b e r a t e s one molecule of each of thie tane and thiobenzophenone at room temperature. I t i s not known whether the formation of thietanes from 1 6 2 and 1 6 3 also involved the thermal decomposition of s i m i l a r i n t e r -mediates (171, 172). Attempts to separate the o<-cyanothietanes (158, 159) and the (3-cyanothietanes (156 , 157) from t h e i r i s o -meric mixtures were c a r r i e d out by c r y s t a l l i z a t i o n and chromatography methods but without sucess. The isomeric mixtures of o(- and p- cyanothietanes were then oxidized with the hope that separation of the o<- and the (b- cyano isomers could be achieved at t h e i r sulfone stage. Thietane 1-oxides and thietane 1,1-dioxides are u s u a l l y more stable 76 and of higher melting point than the parent compounds. 2 . Synthesis of cyanothietane 1,1-dioxides When thietane 155 was treated with m-chloroperox-ybenzQic a c i d (173), the expected product, 2 , 2 - d i p h e n y l -3-cyanothietane 1,1-dioxide (160), was obtained. The i r 155 173 160 spectrum of 1 6 0 showed the absorptions of sulfone (1143 and 1 3 2 5 cm~^) and n i t r i l e ( 2 2 6 5 cm""'"). In the pmr spec-trum of l 6 0 , the two methylene protons and the methine proton appeared as a m u l t i p l e t centered at 4 . 6 3 ppm, and the ten phenyl protons appeared as a m u l t i p l e t at 7 « 4 3 ppm. The coupling constants could not be measured because of the complexity of the spectrum. Sim i l a r treatment of a 2 . 5 : 1 mixture of 1 5 6 and 158 with 173 gave a 6 8 . 4 % y i e l d of c i s - 2 , 2 - d i p h e n y l - 3 - c y a n -0\r- 4-me t h y l thie tane 1 , 1 - d i o x i d e (174)« The <<-cyano isomer, 175, was not detected i n the re a c t i o n mixture, i n d i c a t i n g that thietane 158 or sulfone 175 did not survive the o x i -dation reac t i o n . The structure of 174 was assigned accord-ing to the spectroscopic data and elemental a n a l y s i s , and 77 (156, 158) + 173 175 was supported by the y i e l d of 174 i n the oxidation reac-t i o n . The i r spectrum of 174 showed stretchings of sulfone (1155 and 1330 cm"1) and n i t r i l e (2260 cm"1) :.in, a d d i t i o n to the phenyl and carbon-hydrogen v i b r a t i o n a l absorptions. The 60 mHz pmr spectrum of 174 displayed signals f o r three methyl protons (1.63 ppm), a m u l t i p l e t f o r the r i n g methine protons H a and H^ , (4.40-4.80 ppm) as well as absorptions f o r 10 phenyl protons (7.20-7.60 ppm). High-order s p l i t t i n g was observed:, i n the m u l t i p l e t of H a and Hb due to small d i f -ference . i n the chemical s h i f t s of these two protons and t h e i r coupling with the. .methyl protons. The high-order coup-l i n g 1 , e f f e c t was also observed i n the methyl absorptions which appeared as an abnormal t r i p l e t with the middle peak 78 shorter than the outer peaks by a h a l f of t h e i r i n t e n s i -t i e s (Figure I I ) . In the 100 mHz pmr spectrum, t h i s abnor-mal t r i p l e t tended to become a doublet and the mu l t i p l e t of H a and H"h was composed of more peaks than i n the 60 mHz spectrum. In order to measure the v i c i n a l coupling cons-tant, J(H a-Eb), spin-decoupling was employed. When the me-thy l signal at I . 6 3 ppm was i r r a d i a t e d , the mu l t i p l e t at 4.40-4-80 ppm collapsed to form an AB quartet centered at 4.57 ppm. The v i c i n a l coupling constant, J(Ha-H-b), and the chemical s h i f t d i f f e r e n c e , &v(Ha-H-b) were found to be 9 Hz and 4-6 Hz r e s p e c t i v e l y . The small A V / J r a t i o thus was the cause of the complexity of the methyl signal and the mul-t i p l e t of two r i n g methine protons. V i r t u a l coupling be-tween the. methyl.-protons and H a occurred (143).. The y i e l d of sulfone i n the oxidation of the isomeric mixture of thietanes 156 and 158 excluded the p o s s i b i l i t y that the product formed was sulfone 175- I f the oxidation product i s o l a t e d had been the sulfone 175, the y i e l d of product would have been only 59% of the quan-t i t y of the pure sulfone 174 a c t u a l l y i s o l a t e d , according to the c a l c u l a t i o n of a 100% y i e l d of sulfone 175 on the basis of a 2.5:1 mixture of thietanes 156 and 158 used i n the oxidation r e a c t i o n . The y i e l d of the i s o l a t e d sulfone exceeded the possible maximum y i e l d of sulfone 175 i n a quantity of 41%. When a 2.8:1 mixture of trans isomeric thietanes Figure II Pmr spectrum of cis-2.2-diphenyl-3-cyano-4-methylthietane 1,1-. dioxide (174) dissolved i n CDCl. 80 157 and 159 was oxidized by peracid 173, trans-2,2-diphen-yl-3-cyano-4-methylthietane 1,1-dioxide (176) was i s o l a t e d i n 58.7% y i e l d . The p<-cyano isomer, trans-2,2-diphenyl-3-methyl-4-cyanothietane 1,1-dioxide (177), unfortunately v. was not detected i n the r e a c t i o n mixture, i n d i c a t i n g that thietane 159 or sulfone 177 did not survive the oxidation reaction. The structure of sulfone 176 was assigned ac-cording to the spectroscopic data and the elemental analy-s i s , and was supported by the y i e l d of 176 i s o l a t e d from the oxidation react i o n . The i r spectrum of sulfone 176 showed absorptions of sulfone (1148 and 1318 cm""1") and n i t r i l e (2260 cm~^). The pmr spectrum of sulfone 176» u n ~ 81 l i k e that of sulfone 174, showed a f i r s t - o r d e r spectrum f o r the methyl and the r i n g methine protons. The 10 phenyl protons were displayed as a m u l t i p l e t at 7-42 ppm. The proton H-5, coupling with the methyl protons and H a, ap-peared as two p a r t l y overlapping quartets centered at 4'83 and 5-01 ppm r e s p e c t i v e l y . The proton H a and the methyl protons were displayed as two doublets at 3.78 and 1.63 ppm r e s p e c t i v e l y . The v i c i n a l coupling constants, JCCH^-Hb) and J(Ha-Ht>), were equal to 7 Hz and 10 Hz respective-l y -The y i e l d of sulfone i n the oxidation of the ' isomeric mixture of thietanes 157 and 159 excluded the p o s s i b i l i t y that the product formed was sulfone 177• I f the oxidation product i s o l a t e d had been the sulfone 177, the y i e l d of product would have been 5 0 % of the quantity of the pure sulfone 176 a c t u a l l y obtained according to the c a l c u l a t i o n of a 100% y i e l d of sulfone 177, on the basis of a 2.8:1 mixture of thietanes 157 and 159 used i n the oxidation r e a c t i o n . The y i e l d of the i s o l a t e d sulfone ex-ceeded the possible maximum y i e l d of 177 i n a quantity of 50%. The oxidation of cis-o(-cyanothietane 158 and trans-o<-cyanothietane 159 did not produce the expected sulfones. As previously mentioned i n the Thietane Chemis-tr y section, the e l e c t r o n i c nature and the bulkiness of substituents on the thietane r i n g determine whether the p<-82 cyanothietane 1,1-dioxide can he formed. The presence of two bulky phenyl groups and the lack of a 4-methyl s u b s t i -tuent that can compensate f o r the electron-withdrawing e f f e c t of the sulfone function may lead to breakdown of sulfone 175 i f i t was formed. One of the possible paths of degradation i s the reversed process of c y c l i z a t i o n of s u l -fene and o l e f i n . 175 In the oxidation of thietanes 155-157 to s u l -fone s l60, 174 and 176, chloroform or methylene chloride was used as solvent. When anhydrous ether was used as s o l -vent i n the oxidation of a mixture of c i s thietanes 156 and 158, p r e c i p i t a t i o n of a white s o l i d soon occurred af-t e r the a d d i t i o n of peracid 173« The white s o l i d was 156 178 83 i d e n t i f i e d as cijs-2,2-diphenyl-3-cyano-4-me t h y l thietane 1-oxide (178) according to i t s spectroscopic data and subse-quent oxidation to 174* Obviously, the formation of s u l f -oxide 178 was due to i t s low s o l u b i l i t y i n ether. There-fore further oxidation to sulfone 174 was prevented by im-mediate p r e c i p i t a t i o n of the sulfoxide upon i t s formation. When a mixture of trans thietanes 157 and 159 was oxidized i n an i d e n t i c a l condition, the p r e c i p i t a t i o n of the expected trans thietane 1-oxide did not occur. The s o l u b i l i t y of trans-2,2-diphenyl-3-cyano-4-methylthietane 1-oxide might be higher i n ether so that the oxidation c a r r i e d on u n t i l the sulfone stage was reached. I t was also possible that the rate of r e a c t i o n i n oxidation of c i s sulfoxide to c i s sulfone was slower than that of the trans isomer, probably because of the s t e r i c e f f e c t of the r i n g substituents. The oxidation of thietanes to thietane 1,1-dioxides i n f a c t proceeded very f a s t i n chloroform. S t i r r i n g a chloroform s o l u t i o n of peracid 173 and a t h i e -tane mixture of 156 and 158 or of 157 and 159 generated 174 or 176 i n the expected good y i e l d within one or'two hours. In the i r spectrum of 178, the c h a r a c t e r i s t i c sulfoxide and n i t r i l e absorptions appeared at 1080 and 2260 cm"1 r e s p e c t i v e l y , and no sulfone band was observed. The pmr spectrum of 178 showed a m u l t i p l e t f o r 10 phenyl protons (7*40 ppm), a doublet f o r proton H a (4.71 ppm), 84 two overlapping quartets of a doublet f o r proton Hb (3-41 ppm), and a doublet f o r three methyl protons (1.67 ppm). The v i c i n a l coupling constants, J(H a-Hb) and JCCH^-H-h) were 10 and 7 Hz re s p e c t i v e l y . 3. Synthesis of 3-aminomethylthietane 1,1-dioxides In consideration of the inherent nature of t h i e -tane d e r i v a t i v e s to undergo r i n g opening reactions, only l i m i t e d methods were considered suitable to convert the cyano-thietane 1,1-dioxides 160, 174 and 1 7 6 to the cor-responding aminomethyl d e r i v a t i v e s ( l 6 l , 179, 180). I t had 1 6 0 R=H 1 6 1 R=H 174 R=GH3 c i s 179 R=GH3 c i s 176 R=CH-3 trans 180 R=CH-, trans been reported from our laboratory (84) that sponge n i c k e l c a t a l y s t under mild conditions (room temperature, 50 p s i H^) catalyzed the conversion of 2,4-diphenyl-3-cyanothie-tane 1,1-dioxide (181) to the corresponding 2,4-diphenyl-3-aminomethylthietane 1,1-dioxide. Attempts to hydrogenate l 6 0 by t h i s method, however, re s u l t e d i n recovery of un-reacted s t a r t i n g material. When the hydrogenation was per-85 NC •SO, H, Sponge Ni NH 2CH 2 -SO, 181 182 formed under r e l a t i v e l y vigorous conditions by using Raney n i c k e l , co-catalysts (sodium acetate and ace t i c anhydride), higher temperature (90°), and 50 p s i H 2, desulfonation of the sulfone l60 occurred. • s o , H 2 , Raney Ni NH 2CH 2 90°,Co-catalysts -SO, 160 1 6 1 The reduction of n i t r i l e s 160, 174 and 176 was achieved by using diborane. Conversion of 3-cyanothietane 1,1-dioxides (183) to the corresponding 3-aminomethylthie-tane 1,1-dioxides (184) by using t h i s mild, a c i d i c , reduc-ing agent had been reported from our laboratory (84, 85). The method involved the hydroboration, f o r one day, by using excess diborane (144), and the subsequent hydroly-s i s of the intermediate formed. The l a t t e r step was accom-86 pl i s h e d by t r e a t i n g the r e a c t i o n mixture with ethanol f o l -lowed by r e f l u x i n g the r e s u l t i n g s o l u t i o n f o r one hour. I t had been reported that diborane reduced a v a r i e t y of func-t i o n a l groups but did not react with s u l f i d e or sulfone (144)• The mechanism of diborane reduction of n i t r i l e i n -volves the formation of a borane-nitrogen bond and the tra n s f e r of hydride i o n (145). The preliminary r e a c t i o n product i s therefore a borane adduct such as N,N,N-tri-alkylborazine (185) (144)- The i s o l a t i o n of primary amine RON • + H-B. > R-C=N-B^ ^-4 H H H R-4-K I H ^ B ; - H •H •H H H , R - C - N H 0 •7 I 2 H consequently requires h y d r o l y s i s of the borane interme-87 diate. Some of the borane-nitro'gen complexes are quite stable and must be subjected to strong a c i d i c h y d r o l y s i s . HB' BH RON + 3BH 3 ^ GHgR H 185 For instance, borane-trimethylamine complex i n water-gly-co l s o l u t i o n containing 1M HC1 required a period of s i x hours f o r complete h y d r o l y s i s (146). above described diborane method, l60 was treated with d i -borane, the excess hydride was destroyed by adding ethanol, and the r e s u l t i n g ethanolic s o l u t i o n was hydrolyzed by r e -f l u x i n g on a steam bath f o r one hour. Work-up of the reac-t i o n mixture afforded a gummy substance of which the i r spectrum showed the l o s s of c h a r a c t e r i s t i c absorptions of n i t r i l e and sulfone groups, i n d i c a t i n g that the CN group was s u c c e s s f u l l y reduced, but with apparent s a c r i f i c e of the thietane r i n g . When the diborane reduction was simi^:' l a r l y repeated but the r e f l u x i n g step omitted to prevent thermal desulfonation of the expected product, the i r spec-trum of the crude reduction product confirmed the absence of the CN group, and displayed strong absorptions f o r S0 ? In an attempt to reduce n i t r i l e 160 by using the 88 and BH groups. These r e s u l t s i n d i c a t e d that the borane adduct was formed i n the reac t i o n , and that h y d r o l y s i s was necessary to generate the amine under conditions which would not destroy product. The l i b e r a t i o n of primary amine from the borane adduct without destruction of thietane r i n g was found to be successful by hydrolyzing the borane adduct i n aqueous hydrochloric a c i d at room temperature f o r two days. The hydroboration with f r e s h l y generated diborane generally gave a good y i e l d of the expected primary amine a f t e r the acid-catalysed h y d r o l y s i s process. The use of stored solu-tions of diborane i n tetrahydrofuran, however, resu l t e d i n high y i e l d s of borane adduct but low y i e l d s of primary amine, probably due to the formation of more stable borane complexes which were more r e s i s t a n t to the mild h y d r o l y s i s process used. Schematically, the conversion of n i t r i l e 160, 174 and 176 i s shown as follows: 160 R=H 174 R=CH3, c i s 176 R=CH,, trans 89 l 6 l R=H 179 R=GH3, c i s 180 R=CH,, trans The diborane reduction of l60 gave the expected primary amine l 6 l . The i r spectrum of l 6 l showed absorptions f o r NH 2 (3300 and 3360 cm"1) and S0 2 (1135 and 1310 cm" 1). Treating l 6 l ,:with a c e t i c anhydride gave the corresponding amide, 2,2-diphenyl-3-(acetamidomethyl) thietane 1,1-dioxide (186), as needle-like c r y s t a l s . The i r and pmr spectra agreed with the structure 186. The mono-substituted amide absorption appeared at 3425 (N-H) and 1 6 7 5 (G=0) cm"1 161 186 whereas strong sulfone bands occurred at 1145 and 1300 cm"1. The pmr spectrum of 186 displayed a s i n g l e t f o r 90 three methyl protons, a m u l t i p l e t (2.72 - 4 .28 ppm) f o r 3 r i n g protons (H a, H-^ ) together with two methylene protons adjacent to the amide function, a broad t r i p l e t (5-70-6.10 ppm) f o r the EH proton and a m u l t i p l e t (7-10-7- 6 5 ppm) f o r the ten phenyl protons. The complexity of the spectrum precluded the measurement of the coupling constants- Treat-ing l 6 l with p i c r i c a c i d gave a p i c r a t e s a l t of l 6 l . The i r and pmr spectra agreed with the structure. The diborane reduction of n i t r i l e 174 gave the expected primary amine 179 as needle-like c r y s t a l s . The i r spectrum of 179 showed the absorption f o r lEf^ (3325 and 3385 cm"1) and S0 2 (1140, 1155 and 1300 cm"1) groups. The 179 pmr spectrum of 179 displayed a broad, D2Q-exchangeable si n g l e t f o r the amino protons (0.98 ppm), a doublet f o r .. three methyl protons (1.53 ppm) and a broad d i s t o r t e d doublet f o r two N-methylene protons (2.89 ppm). Protons H a (3-50 ppm), H-fc (4-53 ppm) and 10 phenyl protons (7-42 ppm) were displayed as 3 sets of m u l t i p l e t s . The coupling constants were: J(H a-H b)=9 Hz; JtCH.-Hft)=7 Hz and J(CH 9-91 H a)=7 Hz. Treating the primary amine 179 with p i c r i c a c i d generated a yellow p i c r a t e salt-. The i r and pmr spectra were i n accord with the structure expected. The diborane reduction of n i t r i l e 176 generated the expected primary amine 180. The i r spectrum of 180 showed the absorptions f o r NHg (3320 and 3380 cm - 1) and SO^ (1145 and 1303 cm""1) groups. Treating 180 with a c e t i c anhydride gave the corresponding N-acetyl d e r i v a t i v e 187> The i r spectrum of 187 showed the mono-substituted amide 187 absorptions (1650 and 3330 cm"1) i n additi o n to the strong sulfone bands (1145 and 1300 cm - 1). The pmr spectrum of . 187 displayed a doublet f o r three r i n g methyl protons (1.52 ppm), a s i n g l e t f o r three methyl protons adjacent to the carbonyl group (1.83 ppm), a m u l t i p l e t f o r two N-me-thylene protons together with proton H a (2.93-3.37 ppm), a m u l t i p l e t f o r proton H-^  (4*40 ppm), a broad t r i p l e t f o r HH proton (5*40 ppm) and a strong signal f o r 10 phenyl protons (7-38 ppm). The coupling constants were: JtCH^-Hb)=7 Hz; J(Ha-H-h)=9 Hz. Treating the primary amine 187 with p i c r i c 92 acid generated the corresponding p i c r a t e s a l t with pmr da-ta i n agreement with the expected structure. 4 . Synthesis of 3-dImethylaminomethylthietane 1 , 1 - d i o x i d e s I t has been reported that 3-aminomethylthietane 1,1-dioxides (184) could be dimethylated using the Eschwei-l e r - C l a r k procedure which involved heating the amines i n a mixture of formaldehyde and formic acid (84, 85). The rea c t i o n probably proceeds through the formation of an amine alcohol or an imine which i s subsequently reduced by formic acid. The f i r s t step can be affec t e d by such cata-v, 1 " H 2 ° / A REH 2 + )C=0 — > RHH-C-OH ^ * RN=C"x HCOOH > RNHCHX R 1 R^v^ I R 1 I R 2 ^ m + > = ° 1 R 2 ^ N - f - ° H HCOOH > RC*-\-E 93 l y s t s as pyridine, ammonia, and urea, whereas the second step, the reduction of amine alcohol or S c h i f f f s base, has been found, i n some reactions, to be a f f e c t e d more by heat than by other means. Methylation of ammonia to tri m e t h y l -amine, f o r example, proceeded i n a good y i e l d by heating the formaldehyde and ammonia without a d d i t i o n of formic ac i d (147). When 2,2-diphenyl-3-aminomethylthietane 1,1-di-oxide ( l 6 l ) was heated i n a mixture of formic a c i d and formaldehyde (30%) at 90°, desulfonation occurred as i n d i -cated by the lack of sulfone absorptions i n the i r spec-trum of the r e a c t i o n product. The heating was believed to be the cause of desulfonation during the dimethylation process. 1 6 1 32 Among other mild methods of M-dialkylation, ca-t a l y t i c a l l y reductive a l k y l a t i o n was found to be the most suitable method to synthesize the expected dimethylamines 32-34 from t h e i r corresponding primary amines l 6 l , 179 and 180. The method involves the c a t a l y t i c hydrogenation of a 94 NH 2GH 2 R 1 6 1 R=H •SO, 179 R=OH3, c i s 180 R=GH^, trans CH GH 3 \ 1. GH20 SO, 2. H 2, 10% Pd/G, HAc R. 32 R=H 1 3 R=CH3, c i s 3 4 R=CH3, trans mixture of amine and carbonyl compound and has been well documented f o r preparing secondary or t e r t i a r y amines (147). The re a c t i o n intermediate i s also believed to be the amine alcohol or the inline which i s c a t a l y t i c a l l y hy-RHH, C=0 RN=C^  Catalyst •> RNHCH RJ R 0 m + ; c = o -2^" / V R R< 1 H, N-C-OH RJ NCH Catalyst I drogenated, r e s u l t i n g i n the formation of the secondary or t e r t i a r y amine. By using formaldehyde, f o r example, the a l k y l a t i o n of a primary amine may lead to N-methylation or N,N-dimethylation, depending on the quantity of formalde-hyde used. The e f f i c i e n c y of the a l k y l a t i o n depends on the H, RNH2 + H2C=0 -} REH-C-OH -> RFHCH. 95 RNHCH3 + H2C=0 > m-^CE3 — ^ m ^ 3 ease with, which aldehyde or ketone reacts with amine to form a reducible intermediate. The b a s i c i t y of the amine group i s thus a f a c t o r . When two amino groups are present i n the same molecule, the more basic one i s expected to undergo p r e f e r e n t i a l a l k y l a t i o n . Various d i f f e r e n t kinds of c a t a l y s t have been used f o r the reduction. Raney n i c k e l and palladium are two of the most common c a t a l y s t s used. In consideration of the a b i l i t y of the Raney n i c k e l to cause desulfonation of s u l -fone s and the capacity of palladium to catalyze low-pre-ssure hydrogenation at room temperature, palladium on char-coal was considered to be the best choice f o r the dimethyl-a t i o n of 3-aminomethylthietanes l 6 l , 179 and 180. I t i s known that the amine i t s e l f may have a poisonous e f f e c t on the c a t a l y s t . Addition of an equivalent amount of weak acid such as a c e t i c to the hydrogenation mixture has been sug,-gested to n e u t r a l i z e the e f f e c t of base and thus f a c i l i t a t e the low pressure reductive a l k y l a t i o n (147). The reductive dimethylation of primary amines l 6 l , 179 and 180 gave the desired products 32-34. The i r spectra showed t y p i c a l absorptions f o r the sulfone group i n the range of 1135-1300 cm - 1 and the lack of M-H stretching, confirming the presence of t e r t i a r y amino structure. The 96 pmr data were i n accord with the structures of 32-34, N-dimethylamino group absorption appearing i n the range of 2.1-2.2 ppm. The products were further characterized as pi c r a t e s a l t s . The hydrochloride s a l t of 33 was not stable i n chloroform s o l u t i o n . When a sample of 33 was dissolved i n chloroform, an i n s o l u b l e material r a p i d l y c r y s t a l l i z e d out from the s o l u t i o n i n one or two minutes. This u n i d e n t i f i e d c r y s t a l l i n e substance, d i f f e r e n t from the o r i g i n a l materi-a l , was i n s o l u b l e i n common laboratory solvents. I r spec-trum showed the".absorptions., f o r .sulfone- and ammonium groups. The configurations of.33 and 31 were assigned i n terms of those of t h e i r n i t r i l e precursors since neither diborane reduction nor reductive a l k y l a t i o n would be ex-pected to produce any isomerization of the r i n g s u b s t i -tuents. I t i s not possible to apply Karplus c o r r e l a t i o n (148, 149) to assign conformations f o r .33 and 34 since both c i s and trans v i c i n a l coupling of r i n g protons of j these compounds and t h e i r precursors are not discrimina-tory i n magnitude (Table I I ) . This r;esult was not unex-pected considering the reported values f o r c i s and trans coupling i n thietane d e r i v a t i v e s (138, 150). Inspection of the v i c i n a l coupling constants l i s t e d i n Table I I I reveals that J(2ax-3eq) and J(2eq-3ax) i n the c i s and J(2ax-3ax) In the trans coupling have s i m i l a r and l a r g e r values where-as J(2eq-3eq) i n the trans coupling i s d i s c e r n i b l y smaller. 97 Table I I V i c i n a l coupling constants, J(H a-Hb), of 2,2-diphenylthie-tane d e r i v a t i v e s CH-H a Hb SR 1 Compound R 2 i ( H a - H b ) , 156 - c i s CH 8 157 - trans CH 10 178 0 c i s CH 10 174 °2 c i s CH 9 176 °2 trans CH 10 179 °2 c i s CH 2HH 2 9 188 °2 c i s CH 2HH 2 p i c r a t e 9 189 °2 trans CH^HH0 p i c r a t e 9 187 °2 trans CH^HHCCH. li 3 9 11 0 177 °2 c i s CH 2H(CH 3) 2 9 190 °2 c i s CH 2H(CH 3) 2 9 pi c r a t e 34 °2 trans CH^H(CH.)^ 10 Table I I I V i c i n a l coupling constants (Hz) of thietane d e r i v a t i v e s ( 1 5 0 ) J ( c i s ) J( trans) J ( 2 a x - 3 e q ) J ( 2 e q - 3 a x ) J ( 2 a x - 3 a x ) J ( 2 e q - 3 e q ) Thietane 1 , 1-dioxide 1 0 . 3 4 6 . 3 3 Thietane 1-oxide 1 0 . 6 3 7.49 1 2 . 5 3 1 . 8 3 Trans - 2 , 4-diphenylthie-tane 1-oxide 10.24 8 . 7 9 1 1 . 9 0 3 . 1 6 Cis - 2 , 4-diphenylthietane 1-oxide 9 . 5 3 - 1 2 . 6 2 Trans - 2 , 4-diphenylthie-tane 1 , 1-dioxide 9-17 - 1 1 . 1 2 3-Substituted thietane 1 , 1-dioxides 7 - 5 - 8 . 3 - - 3 - 2 - 3 - 9 Thietane 3-carboxylic ac i d 1-oxide 1 0 . 8 4 - - 3 - 4 6 Thietane 3-carboxylic acid - 8 . 0 4 9 - 3 8 3-chlorothietane - 7 . 6 7 9 . 3 4 99 The large J(H a-Hh) values of 9-10 Hz (Table I I ) i n trans-2,2-diphenyl-4-methylthietane d e r i v a t i v e s .34, 157, 176, 187 and 189 thus suggested that both the 3-substituent and the 4-methyl group possessed an equatorial o r i e n t a t i o n so that a trans 2,3-diaxial coupling occurred. For 2,2-di-phenyl-3-cyanothietane (155), the value of 9 Hz found f o r 157 176 R=;CF 189 R= CH 2NH 2 p i c r a t e 187 R= GHoNHC0Ho 2 II 3 0 34 R= GH 2N(CH 3) 2 both c i s and trans v i c i n a l coupling suggested, on the same basis , an equatorial o r i e n t a t i o n of the 3-cyano group. The other possible conformation having an a x i a l cyano group 100 o r i e n t a t i o n , can be expected to r e s u l t i n a large J(2ax-3eq) but a small J(2eq-3eq) value. In the cis-2,2-diphenyl-4-methylthietane.derivatives (33, 156, 174, 178, 179, 188 and 190), the magnitude of J(Ha-H-h) values could not be r e -l a t e d to t h e i r stereochemistry since both J(2ax-3eq) and J(2eq-3ax) can be expected to have s i m i l a r values (Table I I I ) . I t i s , nevertheless, reasonable to consider that both 32 and 33 possess equatorial o r i e n t a t i o n of the amino subs-t i t u e n t since non-bonding i n t e r a c t i o n s are expected to be l e s s i n such a conformation. 32 33 5. Synthesis of 2,2-diphenyl-3-dimethylaminomethylthietane  (191) Since the synthetic route to 2,2-diphenyl-3-dime-thylaminomethylthietane 1,1-dioxides (32-34) from t h e i r 3-cyano precursors (155-157) had been established, i t was considered that preparation of 2,2-diphenyl-3-dimethylami-nome t h y l thie tane (191) from t h e i r 3-cyanothietane deriva-t i v e (155), by employing the same method might be of i n -101 H CH 3. H GH 3 S S 155 191 terest i n consideration that the sulfone group i n the com-pounds 32-34 might cause s t e r i c hindrance to t h e i r binding to the analgesic receptor. Although the sulfone analogue of methadone (23) was found ( 1 6 ) to be as active as methadone (14), the sulfone group i n the semi-rigid thietane deriva-t i v e s 32-34 was not expected to have the same f l e x i b i l i t y as that i n 23. The r e s t r i c t e d sulfone group thus might a-f f e c t the binding of compounds 32-34 to the receptor and consequently r e s u l t i n the l o s s of analgesic a c t i v i t y . The removal of two oxygen atoms from the s u l f i n y l s u l f u r may r e s u l t i n compounds with s i g n i f i c a n t change i n l i p o p h i l i c i -ty. Whether t h i s change w i l l a f f e c t the analgesic a c t i v i t y of the new compounds i s also an i n t e r e s t i n g problem. When 3-cyanothietane d e r i v a t i v e s 155 was reduced with borane dimethyl s u l f i d e complex, the primary amines 193 was generated. C a t a l y t i c reductive dimethylation of 193 9 s 155 193 102 1. CH20 /\ 2. H 2, 10% Pd/C HAc 191 using formaldehyde did not a f f o r d the expected dimethyl-amine 191» An alternate route to 191 was c a r r i e d out by using repeated formylation and reduction (151 )• The method involved the preparation of a formamide, which was subse-quently reduced by using l i t h i u m aluminum hydride. When primary amine 155 was formylated with formic-acetic anhy-dride, a formamide (195) was obtained as evidenced by the c h a r a c t e r i s t i c absorptions of 0=0 (1675 cm"1) and I-H (3300 cm"1) i n the i r spectrum of the product. Treating t h i s f o r -mamide (195) with l i t h i u m aluminum hydride at 0° yi e l d e d a secondary amine (196) f o r which the i r spectrum confirmed the reduction of the carbonyl group and showed an absorp-t i o n f o r H-H stretching (3310 cm" 1). When s i m i l a r formyla-t i o n and reduction procedures were performed on 196, the dimethylated product 191 was generated. Treating the t e r -103 198 191 t i a r y amine 191 with HG1 gave a crude hydrochloride s a l t (197) of 191, which displayed c h a r a c t e r i s t i c ammonium ab-sorptions i n i t s i r spectrum. The pmr spectrum of 197 show-ed a s i n g l e t f o r s i x N-methyl protons (2.73 ppm), a m u l t i -p l e t (2.35-3*40 ppm) f o r two TJ-methylene protons and two r i n g ^-methylene protons, a m u l t i p l e t ( 4 . 1 0 p^.pm')'forf; one-me-thine proton and a s i n g l e t f o r ten phenyl protons (7-33 ppm). The ammonium proton was displayed as a DgO exchange-able broad s i n g l e t at 5-88 ppm. I t had been reported that o l e f i n s which were sub-s t i t u t e d by electron r e l e a s i n g groups (e.g. 136, 202, 204), on i r r a d i a t i o n with e i t h e r 366 nm or 589 nm l i g h t , reacted with thiobenzophenone (.95) to form e i t h e r dithiane (e.g. 104 201) or thietane d e r i v a t i v e s (e.g. 203, 205) depending on the s t e r i c f a c t o r (138). An attempt to generate 191 using CHo=CH-0CoH[- + 95 2 2 5 — M. 366 c r 589 nm 4 C 2H 50 G 6 H 5 C 6 H 5 6 H5 136 201 t h i s simple procedure "by i r r a d i a t i n g a mixture of d i -me thylallylamine (200) and thiobenzophenone (.95) was with-out success. H2C=0H-CH2HH2 H 2 C O, A H O OOH > H 2 C = C H - 0 H 2 < ^ 199 200 105 hv ( 3 6 6 nm) 95 GH. H w // -s 1 9 1 6. Attempted synthesis of thietane d e r i v a t i v e s with o(-di- methylaminomethyl side chain As mentioned previously, methadone existed i n a preferred conformation i n which a close approach of the t e r t i a r y amine group to the oxygenated function was observ-ed. In two studies (84, 85) of thietane d e r i v a t i v e s as po-tent analgesics, i t was suggested that an o<-dimethylamino-methyl side chain might be required f o r the analgesic a c t i -v i t y . A close approximation between amino group and sulfone function might be achieved (84, 85) i n compounds 35, 36 and 206-208• The precise l o c a t i o n of the amino group and 206 35 c i s 36 trans 106 3 ~ SO, CH "NCHr 3 \ SO, NCH, CH 3 CH. 207 208 the o r i e n t a t i o n of the unbonded electron p a i r of nitrogen i n n a r c o t i c analgesics have been reported to be important to t h e i r analgesic a c t i v i t y . ' Compounds 35". 36 and 206-208 thus might be valuable i n the study of structure-a c t i v i t y r e l a t i o n s h i p s with comparisons i n p a r t i c u l a r to the thietane d e r i v a t i v e s having a /3-amino side chain (32-34 etc. ). Haya (85) had attempted the synthesis of 206 by reactin g s u l f o n y l chloride 79 with enamine 209 but i s o l a t -ed an a c y c l i c sulfone instead of the desired c y c l i c product 210. R 2K 0 :C=CHS C=GH 2 + NCCH 2S0 2C1 E t 3 N • 209 R= morpholino or p y r r o l i d i n o 3 \ NCH 79 CH2CN NC -SO, SO, 210 CH 3 206 107 Since attempts to prepare c i s - and trans- 2,2-di-ph eny1-3-me thyl-4-dimethylaminome t h y l t h i etane 1,1-dioxide (35, 36) were f r u s t r a t e d by d i f f i c u l t i e s encountered i n the synthesis of the precursors, 175 and 177, the synthesis of compounds 207 and 208 was considered and approached accord-ing to the following scheme: H0CH2CH2SH 211 01 2, H 20 J G10H 20H 2S0 2C1 212 ( E t ) 3 N C 6H 5-CH=0HM(0H 3) 2 213 GH 3 CH„C1 GH 3 X y d SO, 214 ^GH2C1 SO, 215 ,CH2N /C H 3 •CH. •SO, 2 1 6 ,CH2isrN -SO, 2 0 7 •CH. G^H. CH=CCH 90H ) CH=CCH90CH., d ( C H 3 ) 2 S 0 4 d * NaOBu 217 108 CH2=C=CH-0CH3 hv 95 CHo0 3 v GH 113 114 GH^ 208 The cy c l o a d d i t i o n of electron r i c h o l e f i n s with sulfenes generated from s u l f o n y l chlorides has "been des-cribed i n the in t r o d u c t i o n section. I t was expected that the r e a c t i o n between the (5-chloroethanesulfonyl chloride (212) and (5-dimethylaminostyrene (213) i n the presence of triethylamine would generate the cycloadduct 214 which could then be converted to the f i n a l product 207-The s u l f o n y l chloride 212 was prepared, accord-ing to a method taken from a patent (152), by reacting (5-mercaptoethanol (211) with chlorine and water. The ^ - d i -me th y l amino styrene (213) was prepared according to the procedure described by Coates (84a) from phenylacetalde-hyde and dimethylamine. 109 When a mixture of 213 and triethylamine i n an equimolar amount was treated with 212, the product i s o l a t -ed was not the expected c y c l i c adduct 214 hut a mixture of an a c y c l i c compound, vinylsulfonyl)-(b-dimethylaminosty-rene (218), and triethylamine hydrochloride. The t r i e t h y l -214 amine hydrochloride formed was quantitative (0.03 mole) when the amount of s u l f o n y l chloride (212), enamine (213) and triethylamine used were 0.015, 0.015 and 0.03 moles re s p e c t i v e l y , i n d i c a t i n g that the two chlorine atoms i n 212 were removed by two molecules of triethylamine and that generation of compound 214 containing a chloromethyl group (A to the s u l f o n y l function was not possible i n t h i s r e a c t i o n . The i r spectrum of 218 showed strong absorptions of enamine ( 1 6 2 0 cm" 1), sulfone (1120, 1135 and 1300 cm"1) 110 and v i n y l i c C-N (1185 and 1258 cm - 1) fun c t i o n a l groups. The pmr spectrum of 218 displayed a sharp s i n g l e t f o r s i x dimethylamino protons (group a, 2.68 ppm), an ABX m u l t i -p l e t f o r three v i n y l i c protons (group b, 5.50-6.80 ppm) and two s i n g l e t s f o r f i v e phenyl protons (7-33 ppm) and one enamine proton H c (7-37 ppm). These data are compared well with those reported f o r the analogous compounds 222, 223 (153) and 221 (84). The same v i n y l enamino s u l -fone 218 was also i s o l a t e d by Paquette and Rosen i n a y i e l d of only 6% upon t r e a t i n g thietane 219 with methane-su l f o n y l chloride and triethylamine (153). The pmr signals CH 3 \ CH-/ G H 3 CH2H CH 3 s o 2 219 CH 3S0 2C1, E t 3 N 218 of 218, however, were not c o r r e c t l y assigned. A value of 5.94 ppm was reported by these workers f o r the chemical s h i f t of the =CHW proton and was not consistent with those £-values reported f o r compounds 221-223 (Table IV). A si n g l e t at 6.00 ppm was indeed present i n the pmr spectrum of 218 but was part of the ABX mul t i p l e t of the three CH2=CHS protons. I t has been known that reactions of sulfenes and Table IV Chemical s h i f t s (ppm) of sulfonyl enamines (84, 153) G6 H5- G= NCH= 1 ( C H 3 ) 2 CH2=CHS C 6H 5-CH 2-S0 2-C=CHN(CH 3) 2 (221) 7-41 7-22 2.60 CH2=CH-S02-CH=CHN(CH3)2 (222) 7.18 2.92 5.73(d) 6.10(d) 6.68(q) C 6 H 5 CH 3-CH 2-S0 2-C=CHN(CH 3) 2 (223) 7-22 7-14 2.59 C 6 H 5 CH2=CH-S02-C=CHM(CH3)2 (218) 7-33 7-37 2.68 5.5-6.8(m) d: d o u b l e t , q: q u a r t e t , m: m u l t i p l e t 112 enamines can give e i t h e r thietanes or a c y c l i c s u b s t i t u t i o n products depending on the nature of reactants. A two-step mechanism (Page 36) i s generally favored (112-117) on the basis of Woodward-Hoffman s e l e c t i o n r u l e s (154), the ste-r e o s e l e c t i v i t y i n the formation of products and the nu-c l e o p h i l i c nature of o l e f i n s used (106). I t appears that the nature of the product was governed by e l e c t r o n i c and s t e r -i c f a c t o r s that influence the Zwitterion j33. Any e l e c t r o -n i c e f f e c t which s t a b i l i z e s 6j3 or any s t e r i c hindrance which obstructs the intramolecular c y c l i z a t i o n of 6^ w i l l f a c i l i t a t e the formation of a c y c l i c product. The i s o l a t i o n of a c y c l i c product 218 i n the attempted cycl o a d d i t i o n r e -action was probably due to the intramolecular dehalogena-t i o n of the Zwitterion 224» The absence of c y c l i c product i n t h i s case a t t e s t s to the f a c i l e nature of the dehalo-genation. t!=S0o + CH2=CH-S02 CH 218 CH P C1CH 2 224 214 113 As the desired product, 214, could not be pre-pared by t h i s route, synthesis of 207 was abandoned, and the attempt to prepare an analogous compound, 208, was considered. I t was expected that 208 could be derived from 2,2-diphenyl-3-methoxy-4-methylenethietane (114) and d i -CH2=C=CH-0CH3 CH 30 x GH, /0H 9 s o , 115 114 208 methylamine. Paquette et a l . (155) had shown that dime-thylamine could be added to the double bonds of 2-methyl-ene-4-phenyl-2H-thiete 1,1-dioxide (225) to give a dime-thylamino d e r i v a t i v e 219 i n 4 6 % y i e l d . -SO, HN^ OH. OH. CH. CH. 225 /CH CH„N J  d X C H 3 s o 2 219 114 The synthesis of 114 was claimed by Bos and h i s coworkers (134a). They reported that i r r a d i a t i n g a mixture of thiobenzophenone (95) and methoxyallene (113) f o r twen-ty minutes, under uv l i g h t generated from a mercury lamp and f i l t e r e d through a potassium dichromate solution, gave a mixture of 114 and 115, both i n a y i e l d of 15-20%. A l -though the y i e l d of 114 was low, a suitable quantity f o r generating the f i n a l product, 208, could be e a s i l y obtain-ed by repeating the simple photochemical process. The me-thoxyallene (113) was a known compound (156) and was pre-pared, according to the procedures taken from l i t e r a t u r e , from methyl propargyl ether (217) which was obtained (157) by methylating propargyl a l c o h o l . Treating 217 with dimethyl su l f a t e i n the pre-sence of base gave 218 as a c o l o r l e s s l i q u i d . The pmr spectrum of 218 showed a t r i p l e t ( 2 . 6 2 ppm) f o r one ace-t y l e n i c proton, a s i n g l e t (3*33 ppm) f o r three methyl pro-tons, a doublet (4.14 ppm) f o r two methylene protons. The doublet and the t r i p l e t r e s u l t e d from a long range coupl-ing between the acetylenic proton and the methylene pro-tons (J=2.5 Hz). An anisotropic sh i e l d i n g of the t r i p l e bond caused the high f i e l d absorptions of the acetylenic proton. Treating 218 with sodium butoxide generated 113 as a c o l o r l e s s l i q u i d . The pmr spectrum of 113 showed a sing-l e t ( 2 . 9 3 ppm) f o r three methyl protons and a t r i p l e t (6.30 ppm) f o r one methine proton. Again, long range coup-115 l i n g occurred between the methane and the methylene pro-tons, J=5'5 Hz. When the re a c t i o n of thiobenzophenone (95) with methoxyallene (113) was performed, r e s u l t s obtained were not i n agreement with those claimed by Bos et a l . (134a). Bos and h i s coworkers claimed that the re a c t i o n was photo-chemical but the present fi n d i n g s proved that the re a c t i o n was thermal. When 113 and a benzene s o l u t i o n of 9_5_ was mixed thoroughly under nitrogen, the blue color of _95_ gra-dually faded and completely disappeared within 1% hours, without r e q u i r i n g the i r r a d i a t i o n procedure that Bos est a l . used. To prove that the re a c t i o n was not caused by the laboratory fluorescent l i g h t , two p a r a l l e l experiments were c a r r i e d out simultaneously. In one experiment, the rea c t i o n of 95. and 113 was allowed to proceed i n the dark while i n the second experiment, the mixture of 95 and 113 was exposed to uv l i g h t f i l t e r e d through a sol u t i o n of po-tassium dichromate. Both reactions were found to be com-plete within 1-g- hours, the same reac t i o n time found from the r e a c t i o n occurring under laboratory fluorescent l i g h t s . The blue color of 95. remained very intense a f t e r twenty minutes of i r r a d i a t i o n , while Bos et a l . claimed that the re a c t i o n completed a f t e r twenty minutes of i r r a d i a t i o n . The reason f o r t h i s discrepancy i s not known at the present time Analysis by t h i n l a y e r chromatography showed that the three reactions performed under d i f f e r e n t conditions 1 1 6 (laboratory' fluorescent l i g h t ; i n the dark; and exposure to uv l i g h t f i l t e r e d through potassium dichromate solution) r e s u l t e d i n the formation of the same products i n about the same y i e l d s . Bos et a l . (134a) reported that 114 and 115 were both formed i n 15-20% y i e l d s a f t e r twenty minutes of uv exposure and probably r e f e r r e d to the composition of 114 and 115 i n the crude rea c t i o n mixture before i s o l a t i o n . The rea c t i o n mixtures obtained from above three experiments performed under three d i f f e r e n t conditions were a l l pale yellow i n colour. A f t e r exposing to the a i r , the colour of the solutions gradually became red, i n d i c a t i n g the presence of c e r t a i n unstable products. When the re a c t i o n mixtures were worked up, 115 was e a s i l y i s o l a t e d as a pale yellow s o l i d i n a y i e l d greater than 50% (cf. 15-20% reported by Bos _et a l . ) - The pmr spectrum of 115 showed signals compa-t i b l e with those reported by Bos et a l . (134a). Attempts to i s o l a t e 114 however, encountered d i f f i c u l t i e s . When a r e -action mixture of 114 and 115 was eluted through a s i l i c a gel or neutral alumina columns, only u n i d e n t i f i e d degraded substances were recovered as a red mixture. I t was report-ed that ' dry column chromatography a f f o r t e d a better e f f i -ciency of separation than l i q u i d column chromatography, and a good r e s o l u t i o n comparable with that of t h i n l a y e r chro-matography (158). When one gram of a mixture of 114 and 115 was treated twice by using dry column chromatography' , 115 was found to be completely decomposed but a small quantity (20 mg) of grossly p u r i f i e d 114 was obtained. The pmr spec-117 trum of t h i s sample showed signals i n agreement with those presented by Bos ejfc a l . f o r 114- More than ten phenyl pro-tons were found at 6.8-8.0 ppm, probably due to the pre-sence of a compound having a structure s i m i l a r to 2 2 6 which was also i s o l a t e d by Bos according to a private com-munication (134b). Bos ejb a l . reported that 114 was an unstable red o i l which oxidized r e a d i l y i n a i r (134b). Inspection of the structure of 114, however, ind i c a t e d that the compound does not contain a highly conjugated system and should not have colour. The red colour was probably due to the conta-minants derived from the decomposition of 114 and 115• Spontaneous evaporation of about 10 mg of 115 dissolved i n 1 ml of chloroform, res u l t e d i n a red o i l containing at l e a s t two major components which were d i f f e r e n t from 115 as revealed by t i c an a l y s i s . The i n s t a b i l i t y of 114 and the unexpected d i f f i -c u l t y encountered i n i t s i s o l a t i o n precluded the approach to synthesize 208 through 114. The work was not pursued further. 118 7. Chemical reactions of 2,4-diphenylthiete 1,1-dioxide and  attempted synthesis of 2,4-diphenylthietan-3-one 1,1-di- oxide In connection with our i n t e r e s t s i n the chemistry and the b i o l o g i c a l a c t i v i t y of thietane d e r i v a t i v e s , 2,4-diphenylthiete 1,1-dioxide (227) was submitted to various chemical reactions with the hope to produce 2 , 4 - d i p h e n y l -thietan-3-one 1 , 1 - d i o x i d e (228) f o r study as an a n t i i n f l a m -matory agent. The study of the chemical r e a c t i v i t y of 227 was considered to be i n t e r e s t i n g with respect to the sus-c e p t i b i l i t y of the o l e f i n i c bond of thiete 1 , 1 - d i o x i d e s to n u c l e o p h i l i c attack ( 8 4 , 8 5 ) , i n addi t i o n to chemical r e -arrangement reactions ( 1 5 9 - 1 6 1 ) of 4-membered c y c l i c s u l -fones. I t has been r e c e n t l y reported that 2-aryl-3-amino-thiete 1 , 1 - d i o x i d e s ( 2 2 9 ) ( 1 6 2 , 163) and 2-phenylbenzo-(b)-thiophen-2H-3-one 1 , 1 - d i o x i d e ( 2 3 0 ) ( 1 6 4 ) possessed a n t i -inflammatory a c t i v i t y . The s t r u c t u r a l s i m i l a r i t y of 228 to 229 and 2 3 0 suggested that 228 may likewise prove i n t e r e s t -ing'.as an antiinflammatory agent. Attempts to convert 227 119 0 Am RJ SO, R = Halogenated phenyl or h e t e r o c y c l i c a r y l 2 R = H, a l k y l , or a r y l Am= T e r t i a r y amino group 229 0^ ^ 0 230 to 228 were thus considered to be worthwhile with respect to the pharmacological a c t i v i t y of the expected product and the chemical nature of the s t a r t i n g material. The synthetic routes designed to generate the expected product 228 involved n u c l e o p h i l i c addition, hy-dration, hydroboration as well as h y d r o l y s i s of an ena-mine, 231, as shown i n Scheme I I . The addi t i o n of HON to the double bond of thiete 1,1-dioxides (232) has been reported (84, 85). I t was sug-gested that the r e a c t i o n occurred through the formation of R SO, 232 R 233 R= H, CH 3, <^> H-R -SO, 183 120 Scheme II Attempted synthesis of 2,4-diphenvlthietan-3-one 1,1-di-oxide (228) o -CH=CH-N -CH. • CH. 213 1. <^^-CH 2S0 2Cl, E t 3 N 2. Oxidative deamination NaOH, H o0 SO, — ) or H 2S0 4, or 1. BgHg 2 . H 2Cr0 4 HO SO, 227 Et Et' IT SO, 0 - s o , 231 228 121 a carbanion (233) which picked up a proton to give the product 183• I t appeared that the strong electron-with-drawing sulfone group activated the double bond toward the; n u c l e o p h i l i c addition. Other strong n u c l e o p h i l i c reagents such as 0H~ were expected to attack the double bond i n a s i m i l a r manner. Treating 2,4-diphenylthiete 1,1-dioxide (227) with aqueous sodium hydroxide s o l u t i o n , however, re-sulted i n the i s o l a t i o n of dibenzylsulfone (.234)• Wo appre-c i a b l e amount of the desired product 235 was detected. I t was l i k e l y that 235 was formed i n the r e a c t i o n but, under the basic r e a c t i o n conditions, r a p i d l y underwent r i n g c l e a -vage to give 234* This type of reverse A l d o l condensation has been known to occur with 2-phenylthiete 1,1-dioxide 0 235 122 OH e H-Ov H H -SO, OH© H 20 227 235 H 0 H Q-rl-f-O H 0 H y H -HCOO (236) and 2-phenyl-3-hydroxythietane 1,1-dioxide (237) which, upon heating i n an aqueous sodium hydroxide solu-t i o n , gave the same product, benzyl methyl sulfone (238). 236 237 238 123 I t was thought that an alternate route to 228 could be achieved through the e l e c t r o p h i l i c addition of borane to 227• O l e f i n s are well known to undergo e l e c t r o -p h i l i c addition. Although the sulfone group i n 227 would be expected to deactivate the double bond, the phenyl sub-st i t u e n t attached to C-2 might lessen t h i s e f f e c t to a c e r t a i n extent by dispersing the p o s i t i v e charge of the tran-s i t i o n .state.- The addition of borane to alkene has been >CH 2 0 H \ \ • , 2 2 -/C=CH 2 + BH 3 ) ^CH0H2-BN H o 0 r 0 ^ 2^"4 GH-0\ ' ^ 0 known to generate a borane adduct which y i e l d s an alcohol or ketone a f t e r oxidation. Because of the e l e c t r o n i c na-ture of the borane, the r e a c t i o n occurs i n an anti-Markow-n i k o f f manner. I t was therefore expected that borane might ^ = CH 2 + ^B—H ^ /0^-0H 2 > /CHCH 2B N H ^ - H H attack 0-3 of 227 and the desired product could be obtain-ed a f t e r o x i d i z i n g the borane intermediate 240« Treating 227 stepwise with diborane and chromic a c i d , however, f a i l -ed to give 228 and re s u l t e d only i n the recovery of un-changed s t a r t i n g material. The resistance of 227 to borane 124 240 228 addition implies that deactivating e f f e c t s of the sulfone group on the double bond and inductive e f f e c t s of the sub-s t i t u e n t are s u f f i c i e n t to prevent substantial formation of the t r a n s i t i o n state 239« That the o l e f i n i c bond of 227 was not sen s i t i v e to e l e c t r o p h i l i c a d d i t i o n reactions was once again demon-strated by means of t r e a t i n g 227 with, concentrated s u l f u r i c acid. O l e f i n s have been known to react with concentrated s u l f u r i c a c i d to form an a l k y l hydrogen s u l f a t e which can be e a s i l y hydrolyzed, with water, to an alcohol. The addi-t i o n of s u l f u r i c a c i d to the double bond involves the ele c -125 >=C N 0 + HO-S-OH 0 0 II -CH-C-OSOH I I 0 H 20 -CH-C-OH + H 2S0 4 t r o p h i l i c attack of hydrogen, leading to the formation of a carbonium ion. The o r i e n t a t i o n of additi o n depends on the s t a b i l i t y of the carbonium ion formed (I.e. benzylic carbonium >J5° carbonium > 2° carbonium > 1° carbonium .on). © i -> -CH-C-OSO-H | | ^ ) -CH-C-OS03H Inspection of the possible o r i e n t a t i o n of the additio n of s u l f u r i c a c i d to 227 i n d i c a t e s two possible carbonium ions, 241 and 242. In consideration of the de-ll H H H SO, H H w / s o , 241 242 1 2 6 s t a b i l i z a t i o n of the benzylic carbonium i o n 241 by the ad-jacent sulfone group and s t e r i c f a c t o r s involved during the subsequent n u c l e o p h i l i c a d d i t i o n of the b i s u l f a t e ion, i t would appear that carbonium i o n 242 would be preferred and 235 might be obtained as product. 235 When 227 was dissolved i n cooled concentrated s u l f u r i c a c id, a brown so l u t i o n was obtained. D i l u t i n g t h i s brown s o l u t i o n with water r e s u l t e d i n i s o l a t i o n of two i s o -meric c y c l i c s u l f i n a t e s , 3,c-5-diphenyl-l,r-2-oxathiacyclo-penta-3-ene 2-oxide (243) and 3,t-5-diphenyl-l,r-2-oxathia-cyclopenta-3-ene 2-oxide (£44), as a 3:2 (243:244) mixture Hone of the desired product 235 was detected. 127 235 C y c l i c s u l f i n a t e s ( s u l t i n e s ( l 6 l ) ) are rare com-pounds and only ten sul t i n e s had "been reported i n the l i -terature at the time when the present work was performed; f i v e (245-249) v i a thermal isomerization of thietane 1,1-dioxides at 300-400° (159, 160, 1 6 5 , l 6 l ) , one (250) by synthesis through chlorine oxidation' of benzothiadiazine 245 £46 217 24J3 249 128 ( l 6 l ) , two (251, 252) by the action of j;-butoxymagnesium bromide on 2,4-diphenylthietane 1,1-dioxides (159, 166 ) and two unsubstituted four- and f i v e - membered s u l t i n e s (255 and 2 5 6) v i a d e s u l f u r i z a t i o n of thiosulfonates (253, 254) by aminophosphine (257) ( 1 6 7 ) . More recently, several un-L - S ^ O 253 n=l 254 n=2 + P ( N E t 2 ) 3 257 ( C H 2 ) n P ( N E t 2 ) 3 :0 255 n=l 256 n=2 stable four-membered s u l t i n e s (259) were claimed (168) to be the intermediates i n the formation of o l e f i n s (260) from ^-hydroxy sulfoxide (258), an analogous rea c t i o n of 129 0 II H R-SGHR1CR2R3 258 so2ci2 0 OH 11 1' 2 3 R-a-CHR-LGR^RJ 01 WC1 0 CR 2R 3 RS——OHR II© @ 0 'CI -RC1 2 3 0 CR R 0=S CHR 259 " S 0 2 ) R1CH=CR2R3 260 R R 2 R 3 H H H H G H 3 H H H H H CH 3 H H H C 6 H 5 H CH 3 H CH 3 H CH 3 H C 6 H 5 H H H H CH 3 the W i t t i g o l e f i n synthesis. These four-membered s u l t i n e s were found to have only l i m i t e d thermal s t a b i l i t y . They r e a d i l y l o s t S0 2 within a few minutes at room temperature to give o l e f i n s . Sultine 2 6 l was found to be r e l a t i v e l y stable and was the only s u l t i n e f o r which the pmr data was H H W A H 0 S=0 261 1 3 0 provided. During the l a s t two years, only one more s u l t i n e ( 2 6 2 ) was added to the l i t e r a t u r e ( 1 6 9 ) . The conversion of unsaturated four-membered cy-c l i c sulfones to t h e i r corresponding r - s u l t i n e s was report-ed only from two l a b o r a t o r i e s ( 1 5 9 - 1 6 1 , 1 & 5 ) . Dittmer e_fc a l . ( 1 6 0 ) reported the i s o l a t i o n of s u l t i n e 248 upon pyro-l y s i s of a naphthothiete sulfone ( 2 6 3) i n the presence of 9 , 1 0-dihydroanthracene. The p y r o l y s i s of 263 without using 9 , 1 0-dihydroanthracene was found to take a complete d i f f e r -ent r e a c t i o n course and give d i f f e r e n t products. The au-131 thors suggested that the p y r o l y s i s of thiete sulfone 263 involves i n i t i a l s c i s s i o n of the sulfur-carbon bond to give a d i r a d i c a l intermediate which c y c l i z e s to y i e l d sul f i n a t e 248 hy formation of an 0-C "bond. The r o l e of 9,10-248 dihydroanthracene i n the r e a c t i o n was uncertain. The au-thors suggested that i t inte r a c t e d with the intermediates formed or with s u l t i n e 248 to prevent extensive rearrange-ment . Thermolysis of thi e t e 1,1-dioxide ( 2 6 4 ) and 2-phenylthiete 1,1-dioxide ( 2 6 5) gave the corresponding 5H-1,2-oxathiolene 2-oxides (245. 2 4 6 ) ( l 6 l ) . The r e a c t i o n 132 was also explained i n terms of the formation of sulfene ( 2 6 6) by e l e c t r o c y c l i c opening of the thiete r i n g . 0 R- A R. A R-264 R= H 245 R= H 265 R= 266 246 R= Q The rearrangement of a 4-membered c y c l i c sulfone to s u l t i n e by using chemical reagents has been described from only one laboratory (159, 165). Dodson et a l . (159) reported that t r e a t i n g 2,4-diphenylthietane 1,1-dioxides ( 2 6 6) with jfc-butoxymagnesium bromide gave 3,5-diphenyl-1,2-oxathiolane 2-oxides (267). The rearrangement was sug-+ t-BuOMgBr 266 267 gested to be catalyzed by base and an i o n i c mechanism was proposed as described i n the following scheme: 1 3 3 H H BuOH ^MgBr H The c o n s t i t u t i o n of s u l t i n e s 243 and 244 was es-tablished as follows: Elemental analysis proved the mole-cular formula to be C^H-^O^S. Mass spectrum displayed an intense peak (m/e 208) a t t r i b u t e d to (M +-S0), i n agreement with the f i n d i n g of Dittmer et a l . ( 1 6 0 ) that a (M+-S0) peak was observed i n the mass spectrum of 248. The i r spec-t r a of 243 and 244 showed the absence of sulfone and the presence of a s u l f i n a t e band (160, 168, 170) at 1125 cm"1. The pmr spectra of 243 and 244 confirmed t h e i r structures. The chemical s h i f t s (243: 6.73 ppm; 244: 6.80 ppm) of the o l e f i n i c protons (H^) agreed with the values of 6.70 and 6.81 ppm f o r the corresponding o l e f i n i c protons i n 245 and 246 (Table V). The pronounced difference (0.51 ppm) i n the chemical s h i f t values of proton H a i n 243 (6.39 ppm) and that i n 244 (6.90 ppm) i s i n accordance with the observa-t i o n (159, 160, 1 6 1 , 171) that the s u l f i n y l bond ( S = 0 ) 6 ( p p m ) H a 243  244 6.39 6.90 6.73 6.80 7-48 7.50 caused a downfield s h i f t to those protons which were c i s to the s u l f i n y l bond. This e f f e c t i s i l l u s t r a t e d by the S-values of proton Hb i n compounds 245-248 (Table V). Larger 6-values f o r proton H a i n s u l t i n e s 243 (6.39 ppm) and 244 (6.90 ppm) as compared to the parent sulfone 227 (5.92 ppm) i n d i c a t e that the benzylic proton i n 243 and 244 i s indeed contained i n a -S-0-CH- str u c t u -0 r a l configuration. The other possible p o s i t i o n a l isomers containing the configuration -0-S-CH- as i n 268 would be H 0 expected to disp l a y the benzylic proton at lower s values. Protons v i c i n a l to a sulfone group are shielded l e s s than i f adjacent to a s u l f i n a t e group. For instance the two me-Table V Chemical S h i f t s of s u l t i n e s H a H a 249 8 (ppm) 248 H a Hb H c Hd 245 ( 1 6 1 ) 5 . 0 6 5 . 4 1 6 . 7 0 6 . 9 0 246 ( 1 6 1 ) 5.32 5.72 6.81 -248 ( 1 6 0 ) 5.31 5 - 9 8 - -249 ( 1 6 1 ) 5 - 4 2 5 - 7 8 - -136 thylene protons i n s u l f i n a t e 2 6 l (168) possess a smaller 8-value than the corresponding ^-methylene protons i n s u l -fone 2 6 9 (171-173). The C-3 proton i n s u l t i n e s 251 and 252 I L H H<* 0— s = o 2 6 1 Ho<- -SO, Ho<= 3.7 ppm(m) Hp= 5.3 ppm(m) Hoc 269 H*= 4.34 ppm(m) has a smaller &-value than the Ru proton i n thietanes 270 and 271 whereas the C-5 proton i n 251 and 252 has a l a r g e r 6-value than the Ho< proton i n 270 and 271 (159, 174). The s u l f i n y l oxygen i n s u l t i n e s 243 and 244 was considered to most l i k e l y assume an equatorial o r i e n t a t i o n since a 1,3-d i a x i a l i n t e r a c t i o n would he expected to occur between an a x i a l s u l f i n y l oxygen and the C-5 a x i a l group. 137 H H—^ H H --C7Hr H \} G 6 H 5 ^ °6 H5 0 251 H G 6 H 5 H u 252 HV--" G 6 H 5 " G6 H5 I G( 270 •SO, d 5 SO, G 6 H 5 H« 271 C 3-H 5 251 4-29 ppm 252 4-34 ppm 5.58 ppm 6.17 ppm H«<= 5-58 ppm H0<= 5.36 ppm The reac t i o n of concentrated s u l f u r i c acid with 2,4-diphenylthiete 1,1-dioxide may be r a t i o n a l i z e d i n terms of i n i t i a l s c i s s i o n of the sulfur-carbon bond to generate a benzylic carbonium ion which then gives s u l t i n e s 243 and 244 by formation of an oxygen-carbon bond. The formation 243, 244 138 of a benzylic carbonium i o n intermediate was supported by the f a c t that the r e a c t i o n did not occur with 2-phenyl-thiete 1,1-dioxide (272) and 2-phenyl-4-methylthiete 1,1-dioxide (273)» The primary and secondary carbonium ions derived from 272 and 273 r e s p e c t i v e l y would not be expect-ed to be as stable as the benzylic carbonium i o n generated from 227-H H H H SO, H - s o , 272 273 Rosen (175) and Truce et a l . (176) reported that 3-aminothiete 1,1-dioxides (274. 275. 277, 278) were con-verted i n t o t h e i r corresponding ketones (276) or enols (279) upon r e a c t i o n with hydrochloric acid or treatment with an ion-exchange r e s i n . I t was f e l t that t h i s r e a c t i o n would be a f a c i l e route f o r preparation of 2,4-diphenyl-Et. N Et CH. 0 Et' or SO, SO, Ion exchange. r e s i n s o , CH. CH. 274 275 276 Et' 'Ms GH, -SO, or 277 278 279 thietan-3-one 1,1-dioxide (228) from a known enamine, 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (231). The thiete E t ^ ^ •SO, 0 SO, 231 228 could be synthesized by the r e a c t i o n of benzylsulfonyl . chloride (60) and 1,1-diethylphenylethynylamine (285) de-r i v e d from phenylacetyl chloride (281) (177-179)- The pre-paration of ynamine 285 was s t r a i g h t forward, according to 0 \A AfCHp^CCl 281 PCl r C-CC1 I CI 282 CI Q HNEt 9 f=\ I — ^ CI 283 -Et Et 140 231 published methods (178, 179), and i t s structure was con-firmed by spectroscopic data which had not previously been reported. The i r spectrum displayed a c h a r a c t e r i s t i c ace-tylene peak at 2210 cm"1. The pmr spectrum showed a t r i p l e t ( 1 . 1 6 ppm) f o r six methyl protons, a quartet (2.82 ppm) f o r four methylene protons and a m u l t i p l e t (6.98-7-45 ppm) f o r f i v e phenyl protons. The c y c l o a d d i t i o n r e a c t i o n of ynamines with s u l f o n y l chlorides has been extensively reviewed (102-107). In the presence of triethylamine, sulfene 286 i s ge-nerated and attacks the ynamine through an i n i t i a l Zwitter-i o n 287 which undergoes intramolecular c y c l i z a t i o n to y i e l d 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (£31). The structure of 231 was confirmed by the spectroscopic data. The i r spectrum showed c h a r a c t e r i s t i c absorptions of s u l -141 CH=S02 + 285. 286 287 fone (1165 and 1300 cm" ) and enamine ( 1 6 2 5 cm" ). The pmr spectrum displayed a t r i p l e t (0.85 ppm) and a quartet (3.03 ppm) f o r six methyl and four methylene protons respective-l y , a s i n g l e t (5-73 ppm) f o r one benzylic proton and a mul-t i p l e t (7.15-7 . 6 5 ppm) f o r ten phenyl protons. When enamine 231 was treated with ion-exchange r e s i n s (BIO-RAD AG50W-X8 and Amberlite 120) according to Rosen's method f o r conversion of 3-aminothiete 1,1-dioxides (£74, 275) to the corresponding thietan-3-one 1,1-dioxide (276) , unchanged s t a r t i n g material (231) was recovered. In concentrated hydrochloric acid, 231 was also found r e s i s -tant to expected h y d r o l y s i s . Truce et a l . (176) reported that 2-phenyl-3-diethylamino-4-methylthiete 1,1-dioxide (277) was stable i n d i l u t e aqueous HC1, but i n benzene so-l u t i o n and i n /the presence of trace hydrochloric acid, was r e a d i l y transformed in t o 2-phenyl-3-hydroxy-4-methylthiete 1,1-dioxide (279). Treating an acetone s o l u t i o n of 231 with concentrated hydrochloric acid f o r one week or r e f l u x i n g a sol u t i o n of 231 i n a HGl-acetone mixture f o r three hours, 142 also r e s u l t e d i n recovery of the unchanged s t a r t i n g mater-i a l , 231. Inspection of the structure of 231 showed that the molecule contains a highly conjugated system. The reso-nance s t a b i l i z a t i o n as described by 288 may account f o r the resistance of 231 to acid h y d r o l y s i s . Further e f f o r t s to hydrolyze 231 were abandoned and the attempted synthesis of-228 was not continued at t h i s time. Et Et PHARMACOLOGICAL TESTING 143 2,2-Diphenyl-3-dimethylaminomethylthietane 1,1-dioxide (32), c i s-2,2-diphenyl-3-dimethylaminomethyl-4-methylthietane 1,1-dioxide (3.3) and trans-2,2-diphenyl-3-dimethylaminomethyl-4-methylthietane 1,1-dioxide (34) were tested f o r t h e i r analgesic a c t i v i t y . The method used was s i m i l a r to that described by Cox and Weinstock 32 33 34 (56) and was based on the a b i l i t y of nar c o t i c analgesics to produce a block of contractions of the e l e c t r i c a l l y stimulated ileum. Male guinea pigs (300-500 gm) were starved overnight and k i l l e d by a blow on t h e i r heads. The ileum was immediately i s o l a t e d and kept i n Krebs s o l u t i o n at 37°, oxygenated with 95% 0 2 and 5% COg.- A length of ileum (2-3 cm) was removed and set up i n a 15-ml organ bath containing oxygenated Krebs s o l u t i o n at 37°. The lower end of the gut was threaded to a glass anchor positioned at the bottom of the organ bath. The upper end of the gut was t i e d to a l e v e r which recorded 144 the gut movements on a kymograph. Both ends of the ileum were l e f t open. The t e n s i o n (about 2-3 gm) on the gut was adjusted so that a l e v e l b a s e l i n e was obtained. Two platinum s t i m u l a t i n g electrodes were used, one being i n s e r t e d i n t o the i n t r a l u m i n a l space and the other being placed i n the bath s o l u t i o n . The t i s s u e was stimulated by s i n g l e square wave pulses (0.5 msec) d e l i v e r e d every 7 seconds from a Grass SD9 s t i m u l a t o r . The voltage was adjusted i n i t i a l l y to give about 80% maximum response ( 30.-35 v o l t s ) . The t e s t e d compounds were d i s s o l v e d i n ethanol and were added i n a volume of 0.02 5 ml. Methadone hydrochloride which was used as a reference n a r c o t i c was d i s s o l v e d i n water and added i n a volume of 0.1 ml. Nal-oxone h y d r o c h l o r i d e , a n a r c o t i c antagonist, was a l s o d i s -solved i n water and added i n a volume of 0.1 ml. The drugs were l e f t i n contact w i t h the t i s s u e f o r 2-5 min. ' and a f t e r washing out . , the ileum was allowed to r e t u r n to i t s c o n t r o l height before the next dose or next drug was added. Ethanol was used as solvent f o r the t e s t com-pounds because of the s o l u b i l i t y problem. At a volume of 0.025 ml ethanol d i d not produce any detectable depression on the e l e c t r i c a l l y induced gut c o n t r a c t i o n s . The depress-ion by methadone of the gut c o n t r a c t i o n s was not a f f e c t e d by the presence of 0.025 ml of ethanol as w e l l . A s o l u -— 8 t i o n of methadone hydrochloride i n ethanol (1.1 x 10 M) produced the same percentage of depression as an aqueous 145 so l u t i o n of methadone hydrochloride and the" depress-i o n was e f f e c t i v e l y reversed by naloxone hydrochloride (2 x 10" 8 M). Methadone hydrochloride was found to depress the e l e c t r i c a l l y induced contractions of ileum by 44% and 83% at concentrations of 1.1 x 10" M and 1.1 x _7 10 M r e s p e c t i v e l y . The depressions were immediately r e -versed by the a d d i t i o n of naloxone hydrochloride at a con-centration of 2 x 10~ 8 M (Fig. IV). The a b i l i t y of three tested compounds to depress the response of ileum to e l e c t r i c a l stimulation i s shown i n Figures I I I and IV. I t i s obvious that the compounds block the contractions at concentrations much higher than those of methadone. At these high concentrations the com-pounds are believed to act by nonspecific mechanisms. To determine whether or not the block of con-t r a c t i o n s by the tested compounds was a r e a l n a r c o t i c —8 e f f e c t , . naloxone hydrochloride (2 x 10" M) was added to the organ bath a f t e r the gut contractions had been depressed by the compounds (3*3 x 10 M). I t was observed that naloxone was incapable of reversing the de-pressive a c t i o n of a l l three compounds. This r e s u l t shows that the compounds i n h i b i t e d the e l e c t r i c a l contractions by a mechanism d i f f e r e n t from that of the blockade induc-ed by narcotic analgesics such as morphine and methadone etc. i n d i c a t i n g that the compounds are devoid of narcotic an al ge si c a c t i v i t y . In order to determine whether the compounds possessed n a r c o t i c a n t a g o n i s t i c a c t i v i t y , the ileum was _ j t r e a t e d with methadone hydrochloride (1.1 x 10 M, 2 minutes), followed by the t e s t e d compound at a concen--7 . . t r a t i o n of 3 x 10 M. The i n h i b i t o r y a c t i o n of methadone was found not to be reversed by the compounds but immediat-e l y antagonized by a subsequent dose of naloxone hydro-— 8 c h l o r i d e (2 x 10 .M). In an a l t e r n a t e procedure the _ 7 ileum was pret r e a t e d with the tes t e d compound.. (3 x 10 M) followed by methadone (1.1 x 10 ). None of the te s t e d compounds prevented or reduced the b l o c k i n g a c t i o n of methadone on the ileum c o n t r a c t i o n s . . In a d d i t i o n t o the guinea-pig ileum t e s t , the abse ce of s i g n i f i c a n t a c t i v i t y of three t e s t e d compounds was f u r t h e r supported by the r e s u l t obtained from determina-t i o n of the pain t h r e s h o l d of one r a b b i t to the e l e c t r i c a l s t i m u l a t i o n i n i t s tooth-pulp. The animal and the set-up were k i n d l y s u p p l i e d by Dr. John G. S i n c l a i r , F a culty of Pharmaceutical Sciences, The U n i v e r s i t y of B.C., and the t e s t was performed by Mrs. Majorie F. Chaplin. The t e s t e d compounds were d i s s o l v e d i n ethanol and i n j e c t e d i n t o the l a t e r a l v e n t r i c l e (180) of the r a b b i t (2.3 Kg). The to o t h -pulp of the animal was stimulated by s i n g l e pulses (10 msec 3 Hz) d e l i v e r e d from a Grass S8 s t i m u l a t o r . The voltage at 147 which the animal l i c k e d i t s l i p s or chewed i t s teeth was considered as threshold voltage. The threshold voltage of the tested r a b b i t given e i t h e r a r t i f i c i a l C. S. F. or 0.05 ml of ethanol i n t r a v e n t r i c u l a r l y was 13-13-5 "V. At a dose of 300 jjig ( i n 0.05 ml of ethanolic s o l u t i o n ) , com-pounds _3_2, 22 and 2A did not s i g n i f i c a n t l y change the threshold voltage which was observed every 5 minutes f o r 30 minutes a f t e r administration of the drugs. Observa-t i o n was extended to 75 minutes f o r compound 34 and no analgesic a c t i v i t y was detected. Compound 22 given at double dose (600 jxg, 0.1 ml) also produce no analgesic a c t i v i t y . Morphine s u l f a t e at dose of 50 jug r a i s e d the pain threshold to 30 V at 15 minutes a f t e r i n t r a v e n t r i -c u l a r administration. FIGURE III I n h i b i t i o n of contractions of e l e c t r i c a l l y stimulated guinea-pig Ileum by methadone (•), compounds _32 (>'), 33 (O) and 34. (Y)* Each point represents the average of two determinations on two ileum preparations. % I n h i b i t i o n 100 80 L 60 L 40 L 30 0 ^8 -7 ,-6 v-5 10 ^ 10 1 10 " 10 J 10 Molar concentrations of test compounds •4 149 Figure IV Effect of methadone, thietane 1,1-dioxides and naloxone (2 x 10" M) on guinea-pig ileum contractions. 150 PARTITION STUDIES I t i s expected that n a r c o t i c drug molecules t r a v e l through many membrane b a r r i e r s before they reach t h e i r locus of a c t i o n . The r e l a t i o n s h i p s between the an-a l g e s i c a c t i v i t y of n a r c o t i c s and t h e i r p a r t i t i o n c o e f f -c i e n t s (P) have been w e l l documented: Casy and Wright (181) have r e l a t e d the high a n a l g e s i c potency of benzimidazole d e r i v a t i v e s t o t h e i r higher p a r t i t i o n c o e f f i c i e n t s than that of morphine. In the work of Kutter et. a l . (182) the ana l g e s i c potency of morphine and r e l a t e d s y n t h e t i c a n a l -gesics have been shown to depend p a r t l y on t h e i r l o g P values. The high a n a l g e s i c a c t i v i t y of nonpolar n a r c o t i c s f o l l o w i n g intravenous a d m i n i s t r a t i o n was explained by a good pen e t r a t i o n of these compounds through the blood b r a i n b a r r i e r . The analgesic potency of etorphine (3800 times the a c t i v i t y of dihydromorphine a f t e r intravenous i n j e c t i o n ) has been considered to a r i s e i n large part from i t s high l i p o p h i l i c i t y (183). In an i n v i t r o study of binding of n a r c o t i c analgesics to cerebroside s u l f a t e , the binding was shown to c o r r e l a t e with the heptane, s o l u b i l i t y of the compounds (184). I t was of i n t e r e s t to see i f th i e t a n e compounds had any unusual p a r t i t i o n p r o p e r t i e s that may account f o r the r e s u l t s of the an a l g e s i c t e s t s . Compounds with r e s t r i c t e d conformation have been known to have d i s s i m i l a r l i p o p h i l i c i t i e s as compared.to the extended analogs. 151 The present study was undertaken with a view to making a preliminary assessment of the physico-chemical influence of the thietanes on t h e i r analgesic a c t i v i t y by using a simple p a r t i t i o n method. Direct determination of p a r t i t i o n c o e f f i c i e n t s of compounds 32-34 presented prac-t i c a l d i f f i c u l t i e s because l i m i t e d quantities of the tes t compounds were av a i l a b l e and the compounds were poorly soluble i n ei t h e r water or nonpolar phases such as 1-octa-n o l , p a r a f f i n , heptane and corn o i l . The problem of measur-ing low concentrations of solute by s p e c i f i c quantitative a n a l y t i c a l methods was also foreseen. The reversed-phase thi n l a y e r chromatography method was thus chosen to com-pare the l i p o p h i l i c i t y of the compounds to that of metha-done. This method was based on the t h e o r e t i c a l r e l a t i o n -ship between the p a r t i t i o n c o e f f i c i e n t and the value deduced by Martin (186): P = K ( J= 1 ) (equation 1) R f Where K i s the constant f o r the system. Bate-Smith and Westall (187) introduced the term R , where R = log m' m ( ~- - l ). I t i s therefore possible i n p r i n c i p l e to cor-R f r e l a t e the l i p o p h i l i c property of substances with t h e i r R m values (equation 2). The v a l i d i t y of t h i s theory has log P = R + k (equation 2) been established by a number of workers (188-191). The p a r t i t i o n c e f f i c i e n t s determined with d i f f e r e n t solvent systems f o r twelve n a r c o t i c analgesics extending from the h y d r o p h i l i c N-methylmorphine to the l i p o p h i l i c metha-152 done has been shown p a r a l l e l to the R F values determined by t h i n l a y e r chromatography ( 2 6 ) . In a serie s of para-substituted a c e t a n i l i d e s , the analgesic a c t i v i t y was shown to c o r r e l a t e better with the chromatographic sub-st i t u e n t constant AR^ than with the Hansch's hydrophobic substituent constantn derived from the p a r t i t i o n c o e f f i -c i e n t . I t was also observed that better c o r r e l a t i o n of A R M and analgesic a c t i v i t y was obtained when the l i p o p h i -l i c phase was 1-octanol than when i t was l i q u i d p a r a f f i n (189). The procedure used was i n general s i m i l a r to that described by Bi a g i et a l . (192). Chromatography was c a r r i e d out on commercially a v a i l a b l e c e l l u l o s e sheets which were impregnated with 1-octanol by dipping i n t o a so l u t i o n of 5% 1-octanol i n hexane. The mobile phase was a s o l u t i o n of 0-20% (v/v) methyl ethyl ketone i n water. The chromatogram was v i s u a l i z e d by spraying with Dragen-d o r f f reagent plus 0.01 N s u l f u r i c a c i d i f necessary. The R^ values of the pink spots that appeared were measured and transformed i n t o R values which were pl o t t e d against m the ketone concentrations i n the mobile phase. The R M values at 0% ketone (Table VI) were calcula t e d by extra-p o l a t i o n from the regression l i n e s . The R^ values charac-t e r i z e the migration of the compounds with the polar phase. The greater the R F values, the smaller the R M values and the more hy d r o p h i l i c the compounds appear to be. Table YI shows the calcula t e d R_ values f o r m Table VI Rm values at 0% methyl ethyl ketone calcul a t e d from regression l i n e s (CH3)2NCH2 X Eh H " j V s s o „ 289 (CH 3) 21TCH^ GEl , G6 H5 SO, 34 (GH3)2NGH2, OH HI 3 " / G6 H5 ^ C 6 H 5 SO, 33 Methadone ( C H 3 ) 2 M 2 > E \ * H H " V 6 H 5 OH, s o , 290 Rm(l-octanol) 1.70 1.43 1.32 0.89 0.70 154 compounds .33, .34, 289 and 290 as well as methadone as r e -ference. Compound 290 has a smaller R value ( l e s s l i p o -m p h i l i c ) than methadone as expected, probably due to the f a c t that the former compound lacks a l i p o p h i l i c C-2-phenyl sub-st i t u e n t and has a s u l f o n y l group which i n nature i s more hyd r o p h i l i c than the carbonyl function (193)- The higher l i p o p h i l i c i t y of compounds 3J3, 34 and 289 than methadone suggests that the two C-2-phenyl substituents exert s i g -n i f i c a n t s t e r i c e f f e c t s on the hy d r o p h i l i c nature of the su l f o n y l group. The sh i e l d i n g of the lone p a i r electrons of two s u l f o n y l oxygen atoms i s expected to produce s i g -n i f i c a n t increases i n R m values (185). In 289 the presen-ce of a l i p o p h i l i c chlorine substituent also contributes to the l a r g e s t R m value (193)• In Table VII are presented the log P and R^ values f o r a number of nar c o t i c agonists and antagonists calcul a t e d from the p a r t i t i o n c o e f f i c i e n t data (1-octanol-water system, pH = 7»4, 20°) determined by Kaufman e_t a l . (183) and the R^ values determined from a s i m i l a r revers-ed-phase p a r t i t i o n chromatographic method (mobile phase: water containing 10% ammonium formate, stationary phase: paper impregnated with 20% 2-octanol i n acetone) by Gen-est and Parmilo (194). Comparison of the R m data shown i n Table VII with those of "thietane 1,1-dioxides determined i n the present study (Table VI) suggests that the l i p o -p h i l i c i t i e s of the thietane 1,1-dioxides 33, 3JL a n d 289 l i e 155 Table VII Log P(1-octanol) and Rm(2-octanol) values of narcotic  agonists and antagonists calcu l a t e d from l i t e r a t u r e da- ta (183, 194) Compounds Log P ( l - o c t a n o l ) a Rm(2-octanol) Oxymorphone -0.33 -0.60 Morphine 0.07 0 . 5 5 Codeine 0.23 -0.58 Levorphanol 0.63 -Naltrexone O . 6 4 -Cyclazocine 0.89 -Naloxone 1.12 -Nalorphine 1.27 -Meperidine 1.37 -0.18 Pentazocine 1.60 -Methadone 1.64 +0.43 MR1256BS0 2.13 -MR1029BSd 2 . 5 6 -<K-Acetylmethadol 2 . 6 9 +1.28 Myrophine - +2.00 a Logarithms of p a r t i t i o n c o e f f i c i e n t s determined by Kaufman _et a l . (183) (1-octanol-water system at 20° pH = 7.4) b R values calcu l a t e d from R~ data determined by Gen-m f . J est and Farmilo (194) (mobile phase; : water containing 10% ammonium formate; stationary phase: paper impreg-nated with 2-octanol) c Pure n a r c o t i c antagonist (183) d Mixed na r c o t i c agonist-antagonist 156 b e t w e e n t h o s e o f m e t h a d o n e a n d m y r o p h i n e w h i c h i s a p o t e n t n a r c o t i c a n a l g e s i c . T h e o r e t i c a l m a t h e m a t i c t r a n s f o r m a t i o n o f t h e R m ( 2 - o c t a n o l ) v a l u e o f m y r o p h i n e ( T a b l e V I ) i n t o t h e R m ( l - o c t a n o l ) v a - ] - u e o f " f c l i e p a r t i t i o n s y s t e m u s e d i n t h e p r e s e n t s t u d y g i v e s a R m ( i _ o c - t a n o l ) v a l u e e c l u a l o r l a r g e r t h a n 2 . 1 5 , i n d i c a t i n g t h a t t h e l i p i d s o l u b i l i t y o f m y r o -* A l i n e a r r e l a t i o n s h i p b e t w e e n t h e R v a l u e s f o u n d i n o n e s o l v e n t s y s t e m a n d t h o s e f o u n d i n a s e c o n d c a n b e d e r i v e d f r o m H a n s e n 1 s ( 1 8 5 ) s o l v e n t r e g r e s s i o n e q u a -t i o n ( e q u a t i o n 3 ) a n d e q u a t i o n 2 w h e r e a , b a n d c a r e l 0 § P ( s o l v e n t ) = a l Q S P ( l - o c t a n o l ) + b ( e q u a t i o n 3 ) R m ( s o l v e n t ) = a R m ( l - o c t a n o l ) + c ( e q u a t i o n 4 ) c o n s t a n t s . I n H a n s c h ' s e x c e l l e n t review o f p a r t i t i o n c o e f f i c i e n t s ( 1 8 5 ) t h e c o n s t a n t a h a s b e e n s h o w n t o b e a m e a s u r e o f a s o l v e n t s y s t e m ' s s e n s i t i v i t y t o c h a n g e s i n t h e l i p o p h i l i c ! t y o f s o l u t e . I n a n u m b e r o f a l c o h o l -s o l v e n t s y s t e m s , t h e c o n s t a n t a v a r i e s f r o m 0 . 6 9 5 t o 1 . 0 0 . A m a x i m u m s e n s i t i v i t y i s r e a c h e d a t 1 - o c t a n o l a n d o l e y l a l c o h o l w i t h c o n s t a n t a b e i n g 1 . S u b s t i t u t i n g i n -t o e q u a t i o n 4 t h e k n o w n t e r m s : a = 0 . 6 9 5 t o 1 . 0 0 ; R / -, , N = R / „ , -, \ = 0 . 4 3 2 f o r m e t h a d o n e f o u n d m ( s o l v e n t ) m ( 2 - o c t a n o l ) i n t h e r e v e r s e d - p h a s e p a r t i t i o n s y s t e m o f G e n e s t a n d P a r m i l o ( T a b l e V I I ) a n d R / n , -, >, = 0 . 8 9 f o r m e t h a -m ( l - o c t a n o l ) d o n e f o u n d i n t h e p r e s e n t s t u d y ( T a b l e V I ) , t h e c o n s t -a n t c i s c a l c u l a t e d t o b e i n t h e r a n g e b e t w e e n - 0 . 1 4 6 a n d - 0 . 4 5 8 . S u b s t i t u t i n g R m ( g 0 - L v e n t ) = 2 . 0 0 f o r m y r o -p h i n e ( T a b l e V I I ) i n t o e q u a t i o n 4 r e s u l t s R . -, % m ( l - o c t a n o l ) ^ 2 . 1 5 . 157 phine i s higher than that of thietane 1,1-dioxides (Table VI I I ) , The c a l c u l a t i o n of log P ( i _ o c t a n o l ) values of t h i e -tane - 1,1-dioxides .33, .34, 289 and 290 by using equation 2 also gives f i g u r e s i n d i c a t i n g that the l i p o p h i l i c i t i e s of 33, 34 and 289 (Table VIII) l i e between those of methadone and o(-acetylmethadol which i s a potent and long acting nar-c o t i c analgesic. I t follows therefore that the lack of an-al g e s i c a c t i v i t y i n compounds 32-34 does not appear to re s t with the nature of t h e i r l i p o p h i l i c i t y . The choice of an j_n v i t r o guinea-pig ileum method to test the compounds excludes many e f f e c t s of absorption and d i s t r i b u t i o n on the r e s u l t s . In the rab b i t tooth pulp test the intraven-t r i c u l a r administration of compounds also circumvents many penetration f a c t o r s . k i s calcula t e d by using methadone as a standard: l o § P ( l - o c t a n o l ) = 1 ' 6 3 5 a n d Rm(l-octanol) = ° ' 4 3 (Table V I I ) . 158 Table VIII Comparison of cal c u l a t e d Rm(l-octanol) and log P(l-octan-o l ) values of thietane 1,1-dioxides with l i t e r a t u r e data of n a r c o t i c agonists and antagonists (183, 194)' Compounds Rm(l-octanol) c log P ( l - o c t a n o l ) e 290 0.70 . 1.45 d '; Methadone 0.89 1.64 33 1.32 2.07 d MR1256BS a - 2.13 34 1.34 2.18 d 289 1.70 2.45 d MR1029BS b - 2.56 t(-Ac e t ylme thadol - 2.69 Myrophine 2 . 1 5 d — a Pure narcotic antagonist (183) b Mixed nar c o t i c agonist-antagonist (183) c Experimental data determined from present p a r t i t i o n study d Calculated values. See text e Logarithms of p a r t i t i o n c o e f f i c i e n t s determined by Kaufman et a l . (183) (1-octanol-water system at 2 0 ° , pH = 7.4) 159 S T R U C T U R E - A C T I V I T Y C O N S I D E R A T I O N S I n t w o p r e v i o u s s t u d i e s ( 8 4 a , 8 5 a ) o f n a r c o t i c a n a l g e s i c a c t i v i t y o f t h i e t a n e 1 , 1 - d i o x i d e s ( 2 7 - 3 1 ) c o n -t a i n i n g a s i n g l e p h e n y l r i n g a t C - 2 , t h e l a c k o f a c t i v i t y o f t h e t e s t e d c o m p o u n d s w a s a t t r i b u t e d t o i m p r o p e r o r i e n -t a t i o n o f t h e e q u a t o r i a l p h e n y l r i n g . I n 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 s ( 2 7 - 2 9 ) , t h e e q u a t o r i a l p h e n y l r i n g a t C-4 w a s t h o u g h t ( 8 4 a ) t o i n t e r f e r e w i t h t h e e f f e c t i v e b i n d -i n g o f t h e c o m p o u n d s a t t h e a n a l g e s i c r e c e p t o r . I n t h e p r e -s e n t s t u d y , t h e f a c t t h a t 2 , 2 - 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 s 3 2 - 3 4 c o n t a i n i n g b o t h e q u a t o r i a l a n d a x i a l p h e n y l r i n g s a t C - 2 l a c k e d s i g n i f i c a n t a n a l g e s i c a c t i v i t y i n d i c a t e s t h a t t h e i n a c t i v i t y o f t h i e t a n e 1 , 1 - d i o x i d e s i n t h e t w o p r e v i o u s s t u d i e s w a s n o t m a i n l y d u e t o t h e e q u a t o r i a l p h e n y l r i n g . O t h e r c r i t i c a l s t e r e o c h e m i c a l f e a t u r e s h a d t o p l a y a n i m -p o r t a n t r o l e . F o r i n s t a n c e , t h e r e s t r i c t e d b u l k y s u l f o n e g r o u p m a y i n t e r f e r e w i t h t h e r e c e p t o r b i n d i n g , t h e d i m e -t h y l a m i n o m e t h y l g r o u p m a y n o t a s s u m e t h e p r o p e r o r i e n t a t i o n t o i n t e r a c t w i t h t h e a n i o n i c s i t e o f t h e a n a l g e s i c r e c e p t o r s u r f a c e , o r e v e n t h e C - 4 a n d t h e s u b s t i t u e n t a t t a c h e d t o i t m a y n o t b e c o m p a t i b l e w i t h t h e s t e r e o c h e m i c a l l y d e m a n d i n g o p i a t e r e c e p t o r . T h e l a c k o f a n a l g e s i c a c t i v i t y i n c o m p o u n d s 3 2 - 3 4 s u p p o r t s t h e t h e o r y t h a t m e t h a d o n e a n d i t s s u l f o n e a n a l o g u e a s s u m e a c e r t a i n p h a r m a c o p h o r i c c o n f o r m a t i o n a t t h e r e c e p -160 t o r l e v e l . T h e f l e x i b l e o p e n c h a i n a p p e a r s t o b e n e c e s -s a r y t o r e n d e r t h e m e t h a d o n e m o l e c u l e e n o u g h f r e e d o m t o a d o p t a c o n f o r m a t i o n s o t h a t t h e a r o m a t i c r i n g s , t h e a m i n o g r o u p , a n d t h e r e m a i n i n g p a r t o f t h e m o l e c u l e c a n b e p l a c e d p r e c i s e l y o n t h e t o p o g r a p h i c a l r e c e p t o r s i t e s . R e s t r i c t i o n o f t h e f l e x i b i l i t y o f t h e m o l e c u l e s o t h a t t h e p h a r m a c o p h o r i c c o n f o r m a t i o n c a n n o l o n g e r b e a c h i e v e d m a y t h u s l e a d t o t h e c o m p l e t e l o s s o f n a r c o t i c a n a l g e s i c a c -t i v i t y . T h e p i p e r i d i n e a n a l o g u e ( 2 5 . ) o f m e t h a d o n e , i n w h i c h t h e C - 2 a n d t h e n i t r o g e n a t o m o f m e t h a d o n e w e r e j o i n e d t o g e t h e r w i t h d e p r i v a t i o n o f o n e T T - m e t h y l g r o u p d i d n o t s h o w a n a l g e s i c a c t i v i t y ( 1 9 5 ) a l t h o u g h i t s s t r u c -t u r e a p p e a r s t o b e g e n e r a l l y c l o s e t o t h e p r o p o s e d c y c l i c s t r u c t u r e o f m e t h a d o n e (22) ( P a g e 1 0 ) . T h e e x p l a n a t i o n m a y b e t h a t t h e o r i e n t a t i o n o f t h e r e s t r i c t e d p r o p i o n y l c o m p o n e n t i n 23 m a y n o t i n d e e d m i r r o r t h a t o f t h e c o r r e s -p o n d i n g p a r t i n t h e p h a r m a c o p h o r i c c o n f o r m a t i o n o f m e t h a -d o n e a n d t h u s r e s u l t i n h i n d e r i n g r e c e p t o r b i n d i n g . R e s -1 6 1 t r i c t i o n o f t h e r o t a t i o n a l f r e e d o m o f t h e t w o a r o m a t i c r i n g s h a s l e d t o s e v e r a l m e t h a d o n e a n a l o g u e s (24_, 291-295) w i t h d i m i n i s h e d o r i n s i g n i f i c a n t a n a l g e s i c a c t i v i t y X J E t B CH," ;N U  3 / \ CH^  CH3 R N CH^  CH-^  291 24 X=CH2CH2 R=CH 292 X=CH2 R=CH 293 X=0, S R=H 294 X=CH2CH2 R=H 295 (82). I t w a s c o n c l u d e d t h a t t h e p h e n y l r i n g s i n t h e s e c o m p o u n d s f a i l e d t o m a i n t a i n t h e r e q u i r e d c o n f o r m a t i o n f o r r e c e p t o r b i n d i n g . I n c o m p o u n d 3J3 a n d m o s t • l i k e l y i n 32 a n d 34 a s w e l l , t h e d i m e t h y l a m i n o m e t h y l s u b s t i t u e n t p o s s e s s e s a n e q u a t o r i a l o r i e n t a t i o n a s r e p r e s e n t e d b y 296. E x a m i n a -t i o n o f t h e N e w m a n p r o j e c t i o n o f t h e s t a g g e r e d c o n f o ' r m a -162 0 H CH 3 0 CH 3 0 296 t i o n of 296 about the C3-CHQE' bond shows that the dimethyl-araino group most l i k e l y adopts a s y n c l i n a l r e l a t i o n s h i p with respect to C-4 as represented by 297• The staggered con-formation of 296 about C2-C3 bond as represented by 298 shows that the t o r s i o n angle i s l e s s than 60 and the d i -me thylaminome t h y l group adopts a pseudo-antiperiplanar r e -l a t i o n s h i p with respect to the sulfone group. The orien-t a t i o n of the two phenyl rings and the amino group i n con-formations represented by 297 and 298 do not appear to show ,-N(CH 3) 2 297 298 163 s i m i l a r s p a c i a l arrangements to that of the corresponding groups i n the pharmacophoric conformation 299 proposed by Portoghese and h i s coworkers f o r methadone (75, 78). In 2 CH 3 299 299 the dimethylamino group and the C-4 group were des-cribed to assume a s y n c l i n a l r e l a t i o n s h i p as represented by 300 while the dimethylaminomethyl group and one of the two phenyl rings assume an an t i p e r i p l a n a r o r i e n t a t i o n (301). 2 0 300 301 164 A folded conformation of 296 as represented by 302 and 303 i n which the dimethylamino group i s placed on top of the thietane r i n g , a favorable conformation to the i n t e r a c t i o n between the s u l f o n y l and the amino groups, seems highly u n l i k e l y because of too many nonbonded i n t e r -actions. Nevertheless the two phenyl rings i n 302 and 303 do not appear to have the same o r i e n t a t i o n as that i n 300 and 301• The CH^CHSO^ component of the thietane r i n g i n 302 and 3 0 3 may even hinder the binding of these conformers to the narcotic receptor. Thus the change of sp a c i a l d i s p o s i -t i o n of the phenyl rings and the amino group i n 296 as com-pared to 299 may account f o r the lack of analgesic a c t i v i -ty i n compounds 32-34» The present r e s u l t and the previous studies (82, 195) of r i g i d analogues of methadone such as 25 indeed r e f l e c t the exacting requirement f o r binding of methadone to the narcotic receptor. A small change i n the conformation of methadone thus r e s u l t s i n complete l o s s 302 303 of n a r c o t i c analgesic a c t i v i t y . 166 ANALYTICAL METHODS Melting points were determined using a Thomas-Hoover C a p i l l a r y Melting Point Apparatus. A l l melting points are reported uncorrected. U l t r a v i o l e t spectra were obtained using a Bausch and Lomb Model 505 recording spectrophotometer. 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 spectra. The pmr spectroscopy was performed by the De-partment of Chemistry, U. B. C. , using a "Varian A-60, T-60 or XL-100 spectrometer. The concentration of solutions was .ca. 10% and tetramethylsilane 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 follows: s ( s i n g l e t ) , d (doublet), t ( t r i -p l e t ) , q (quartet) and m ( m u l t i p l e t ) . Mass spectra and gc/mass spectral data were ob-tained using a Varian MAT-111 mass spectrophotometer. Gas-liquid chromatography (glc) was c a r r i e d out using a MicroTek gas chromatograph Model MT-200 equipped with a flame i o n i z a t i o n detector and a Disc Integrator Model 222. The c a r r i e r gas was nitrogen. A l l other con-d i t i o n s and column types are s p e c i f i e d . Microanalyses were performed by A l f r e d Bern-hardt, Mikroanalytisches Labora t o r i urn, 5251 Elbach iiber Engelskirchen, P r i t z - P r e g l - S t r a s s e 14-16, West Germany. EXPERIMENTAL 16? 1. Synthesis of thiobenzophenone (95). Thiobenzophenone was prepared according to a method taken from the l i t e r a t u r e (141) with modifications. Into a s t i r r e d and cooled ( i c e - s a l t bath) s o l u t i o n of ben-zophenone (25 gm, 0.14 mole) i n 125 ml of 95% ethanol, hy-drogen s u l f i d e and hydrogen chloride were simultaneously passed. A f t e r 3 hours the hydrogen chloride was disconnect-ed. The blue s o l u t i o n was s t i r r e d i n the i c e - s a l t bath f o r a f u r t h e r 24 hours under a stream of hydrogen s u l f i d e . The blue product was f i l t e r e d through a Buchner funnel sur-rounded with dry i c e , washed twice with 30 ml of cooled 95% ethanol and immediately r e c r y s t a l l i z e d from n-pentane i n a glove box under nitrogen. Thiobenzophenone was obtain-ed as blue needle-like c r y s t a l s (19 gm, 73%), mp 54° ( l i t . (141) 53-54°, 66-77%). 2. Synthesis of 2,2-diphenyl-3-cyanothietane (155)• 2,2-Diphenyl-3-cyanothietane Was prepared by photocycloaddition of thiobenzophenone (.95) to propene-n i t r i l e (144) at 3 6 6 nm (138). In a nitrogen glove box f r e s h l y r e c r y s t a l l i z e d 9J5 (21.2 gm, 0.106 mole) and r e -d i s t i l l e d 144 (160 gm, 3.01 mole) were dissolved i n a s u f f i c i e n t amount of r e d i s t i l l e d cyclohexane to a volume of one l i t e r . The bright blue s o l u t i o n was divided and transferred i n t o 50-ml pyrex tubes. Five tubes were used 168 at one time and mounted d i r e c t l y i n front of a f i l t e r window (Corning CS7-60 glass f i l t e r , 4-5 x 165 x 165 mm). The solutions and the window were ai r - c o o l e d with two j e t s of compressed a i r . About two inches behind the f i l t e r was a medium-pressure mercury arc (Hanovia 679A36, 450 W) placed i n a water-cooled quartz vessel. The apparatus was e n t i r e l y enclosed i n a dark hood and exposed only to the l i g h t through the window. I r r a d i a t i o n was performed u n t i l the blue c o l o r of the s o l u t i o n completely disappeared (about 4 days) and a pale yellow s o l u t i o n was obtained. A f t e r i r r a d i a t i o n the content of each tube was f i l t e r e d and evaporated to a viscous l i q u i d (1.34 gm). P u r i f i c a t i o n of t h i s crude material by column chromato-graphy ( s i l i c a g e l , 48 ml i n 50-ml buret; benzene/petro-leum ether 30-60°, 5:3) gave a white s o l i d (155) (0.6l gm, 41%). R e c r y s t a l l i z a t i o n of t h i s s o l i d from a mixture of n-pentane and ether yielded a c o l o r l e s s c r y s t a l l i n e subs-tance (155) (0.4 gm, 31%), mp 84-85.5° ( l i t . (138) 84°, 93%); i r (KBr) 708, 752, 775, 1400, 1478 (phenyl) and 2234 ( n i t r i l e ) cm"1; pmr (CDC1 3)S3.40 (m, 2, SCH 2), 4-99 ( t , 1, CNCH, s p l i t t i n g = 9 Hz) and 7.10-7-70 (m, 10, phenyl) ppm. Attempts to improve the y i e l d of the product were unsuccessful. Repeating the experiment by using p u r i -f i e d p r o p e n e n i t r i l e , re p l a c i n g cyclohexane with anhydrous ether or employing combined f i l t e r s (Corning CS7-60 and 169 CS52) did not s i g n i f i c a n t l y improve the y i e l d . I t was ob-served that using aged solutions of 95 or prolonged i r -r a d i a t i o n u s u a l l y r e s u l t e d i n a poor y i e l d . 3 . Synthesis of 2,2-diphenyl - 3-cyanothietane 1,1-dioxide (160). To a s t i r r e d and cooled s o l u t i o n of 2,2-diphen-yl - 3-cyanothietane (155) (3-0 gm, 0.012 mole) i n chloro-form (50 ml) was added a s o l u t i o n of m-chloroperoxybenzoic aci d (85%, 5.0 gm, 0.024 mole) i n 100 ml of chloroform at such a speed that the temperature of the thietane s o l u t i o n was maintained at 15-20°. A f t e r the additi o n of the per-aci d , the r e s u l t i n g s o l u t i o n was s t i r r e d at room tempera-ture f o r 1 day. One hundred m i l l i l i t e r s of anhydrous ether was added to dissolve the p r e c i p i t a t e that separated and the s t i r r i n g was continued f o r 4 more days. Cautious con-centration of the so l u t i o n at room temperature to about 80 ml r e s u l t e d i n the formation of a white p r e c i p i t a t e which was c o l l e c t e d by f i l t r a t i o n and was treated a f t e r the work-up of the f i l t r a t e . The f i l t r a t e was washed succes-s i v e l y with 20% sodium s u l f i t e s o l ution, saturated sodium carbonate and saturated sodium chloride solutions, dried P r o p e n e n i t r i l e was washed successively with 10% s u l -f u r i c a c i d , 10% sodium carbonate s o l u t i o n and a satu-rated s o l u t i o n of sodium s u l f a t e . A f t e r drying over calcium chloride i t was d i s t i l l e d at atmospheric preS' sure and f i n a l l y d i s t i l l e d at room temperature i n va-cuo. 170 (anhydrous sodium su l f a t e ) and evaporated to give the crude l 6 0 as a white powder (2 . 6 2 gm), mp 129-143°. The p r e c i p i t a t e previously obtained was s t i r r e d i n 50 ml of saturated sodium carbonate solu t i o n . F i f t y m i l l i l i t e r s of chloroform was added to dissolve the i n -soluble substance. The chloroform s o l u t i o n was separat-ed, washed, dried and evaporated as above to give more white s o l i d product (0 . 3 gm) mp 155-160°. The i s o l a t e d product was combined (2.92 gm, 86%) and r e c r y s t a l l i z e d once from a mixture of chloroform and ether to y i e l d a co-l o r l e s s c r y s t a l l i n e substance (l60) (2 . 3 gm, 70%) mp 156 . 5 -160° ( l i t . (138) 157-158.5°); i r (KBr) 540, 710, 788, 1450, 1498, 3040, 3065 (phenyl), 1143, 1172, 1325 (S0 2(172)) and 2265' ( n i t r i l e ) cm"1; pmr (CDCl^) S4 - 6 3 (m, 3, CNCH and SCH^) and 7-43 (m, 10, phenyl) ppm. Using peracetic acid i n place of m-chloroper-oxybenzoic acid i n a s i m i l a r experiment res u l t e d i n a low-er y i e l d (67%) of crude 1 6 0 . 4 . Synthesis of 2,2-diphenyl - 3-aminomethylthietane 1,1-dioxide ( l 6 l ) . The r e a c t i o n was performed i n a 250-ml three-necked f l a s k which was equipped with a magnetic s t i r r e r and a sintered glass dispersion tube connected to a d i -borane generation apparatus. The out l e t of the three-necked f l a s k was connected to an i n a c t i v a t i o n trap. The 171 i n a c t i v a t i o n trap was a mercury bubbler i n which some mercury was l a i d at the bottom. Above the mercury was a laye r of acetone which served to destroy the diborane escaping from the r e a c t i o n f l a s k . The diborane generator was a dry 500-ml three necked f l a s k equipped with a mag-ne t i c s t i r r e r , a pressure-equalizing add i t i o n funnel and a diborane out l e t which was connected to a dry trap (ser-ving as a r e s e r v o i r i n case of back flow of the so l u t i o n from the r e a c t i o n f l a s k to the generator) and then to the gas dispersion tube dipped i n the re a c t i o n f l a s k . The top of the additi o n funnel served as an i n l e t f o r the dried nitrogen. Under a stream of dried nitrogen, the genera-t i o n r e a c t i o n u n i t was thoroughly dried with an open flame. The system was then allowed to cool to room tem-perature with the dried nitrogen being passed slowly through the system. The r e a c t i o n f l a s k was f i l l e d with 100 ml of dried tetrahydrofuran to cover the sintered glass of the dispersion tube. 2,2-Diphenyl-3-cyanothietane 1,1-dioxide (160) (2.3 gm, 0.008 mole) was added and the r e s u l t i n g s o l u t i o n was s t i r r e d and cooled i n an i c e bath. In the generator were placed 20 ml of diglyme * Tetrahydrofuran was f r e s h l y d i s t i l l e d over l i t h i u m aluminum hydride. ** Diglyme was p u r i f i e d by drying over calcium hydride and then d i s t i l l e d over l i t h i u m aluminum hydride. 172 and 23 ml of p u r i f i e d boron t r i f l u o r i d e etherate (25-5 gm, 0.18 mole, 50% excess). The addition funnel was f i l l -ed with a s o l u t i o n of sodium borohydride (3*4 gm, 0.09 mole, 20% excess) i n p u r i f i e d diglyme (about 300 ml). D i -borane (0.0375 mole) was generated by slow addition of the sodium borohydride solu t i o n to the boron t r i f l u o r i d e etherate and was forced to pass in t o the s o l u t i o n of l60 by a s l i g h t flow of dried nitrogen. A f t e r the addi t i o n of sodium borohydride s o l u t i o n , the generator was heated f o r 1 hour at 70-80° to ensure the complete transfer of the diborane to the n i t r i l e s o l u t i o n . The reac t i n g solu-t i o n was then r a i s e d above the i c e bath and allowed to return to room temperature. The i n l e t and the outlet were disconnected, the f l a s k was t i g h t l y stoppered and the s o l u t i o n was then s t i r r e d at room temperature f o r two days. The excess diborane was destroyed i n an i c e bath by care-f u l a d d i t i o n of 10 ml of water. The borane adduct was hy-drolyzed by s t i r r i n g the c o l o r l e s s s o l u t i o n with 20 ml of 10% hydrochloric acid at room temperature f o r three days. The s o l u t i o n was b a s i f i e d with a cooled s o l u t i o n of 3 gm of sodium hydroxide i n 30 ml of water. The mixture was evaporated at room temperature i n a rotary evaporator to * Boron t r i f l u o r i d e d i e t h y l etherate, 100 ml, was p u r i -f i e d by adding 2 ml of anhydrous ether and d i s t i l l -i ng under reduced pressure from 2 gm of granular c a l -cium hydride. 173 remove post of the tetrahydrofuran. The r e s i d u a l aqueous mixture was extracted with chloroform. The combined chlo-roform s o l u t i o n was dried and evaporated at room tempera-ture to a viscous l i q u i d ( l 6 l ) (2.40 gm, q u a n t i t a t i v e l y ) ; i r (neat) 705, 760, 1448, 1495, 3020, 3050 (phenyl), 1135, 1310 (sulfone), 1598, 3300 and 3360 (primary amine) cm"1. The acetamide d e r i v a t i v e was prepared by d i s -solving 0.2 gm (0.007 mole) of the crude l 6 l i n 2.5 ml of a c e t i c anhydride. When the exothermic r e a c t i o n ceased, the so l u t i o n was d i l u t e d with 15 ml of i c e water. The o i l y de-p o s i t was separated by decantation of the aqueous superna-te and s o l i d i f i e d by t r i t u r a t i o n i n d i s t i l l e d water with a glass rod. The white p r e c i p i t a t e , 2,2-diphenyl-3-acet-amidomethylthietane 1,1-dioxide (186) was c o l l e c t e d by f i l t r a t i o n and washed with d i s t i l l e d water, weighing 0.17 gm (74%). R e c r y s t a l l i z a t i o n of the product from toluene and subsequently from a mixture of benzene and n-hexane gave needle-like c r y s t a l s mp 160-170°; i r (KBr) 710, 770, 1450, 1498, 3020, 3065 (phenyl), 1145, 1300 (sulfone), 1675 (amide carbonyl) and 3425 (secondary amide) cm"1; pmr (CDC1 3) 81.85 (s, 3 , GH^), 2.72-4-28 (m, 5, SCH 2 and CHCH2N), 5.70-6.10 ( t , broad, 1, MH) and 7-10-7.65 (m, 10, phenyl) ppm. Attempts to r e c r y s t a l l i z e the product from a mixture of ethanol and water r e s u l t e d i n desulfonation. The p i c r a t e s a l t was prepared by d i s s o l v i n g the 174 crude l 6 l (0.2 gm, 0.0007 mole) i n a minimum amount of 95% methanol (about 1 ml). A f t e r f i l t r a t i o n , 2 ml of saturated s o l u t i o n of p i c r i c a c i d i n 9 5 % ethanol was added. The yellow s o l u t i o n was evaporated to a yellow l i q u i d which was redissolved i n 5 ml of absolute methanol. The r e -s u l t i n g yellow s o l u t i o n was f i l t e r e d and the f i l t r a t e was cooled i n the freezer f o r a long period u n t i l the c r y s t a l -l i n e p i c r a t e s a l t appeared. The yellow s o l i d (lOOmg, 24%) was c a r e f u l l y f i l t e r e d and washed thoroughly with 9 5 % me-thanol; mp 160.5-164.5°, i r (KBr) 705, 753, 778, 799, 1615 (phenyl), 1142, 1260-1365 (sulfone and n i t r o ) and 2050-3300 (ammonium and carbon-rhydrogen stretching) cm"1; pmr (DMS0-d6) 5 2.73-4-20 (m, overlapping with solvent im-p u r i t y peaks, 3, CHCiyO , 4-50 (d, broad, 2, SCHg, s p l i t -t i n g =7.5 Hz), 7.42 (s, broad, 10, phenyl), 7-97 (m, bro-ad, 3, NH-j) and 8 . 6 5 (s, 2, t r i n i t r o p h e n y l ) ppm. Attempts to r e c r y s t a l l i z e the p i c r a t e r e s u l t e d i n degradation. 5. Synthesis of 2,2-diphenyl-3-dimethylaminomethylthie-tane 1,1-dioxide (32). Crude 2,2-diphenyl-3-aminomethylthietane 1,1-dioxide ( 1 6 1 ) (1.9 gm, 0.0063 mole) and 3 ml of 3 6 . 4 % formaldehyde s o l u t i o n were dissolved i n 95% ethanol (100 ml). The r e s u l t i n g s o l u t i o n was s t i r r e d at room tempera-ture f o r 9 hours and then f i l t e r e d . The f i l t r a t e was 175 transferred i n t o a 400-ml Parr b o t t l e . Seven hundred m i l l i -grams of 10% palladium on charcoal was added. The b o t t l e was then placed on a Parr hydrogenation apparatus. The former and the tank were evacuated and f i l l e d with hydro-gen f o r 10 times and f i n a l l y f i l l e d with hydrogen to 50 p s i . The shaker was started and the methylation was allowed to proceed f o r 12 hours. A f t e r venting the hydrogen from the b o t t l e s a f e l y , the ethanol s o l u t i o n was f i l t e r e d with the ai d of " C e l i t e " and the c a t a l y s t was washed c a r e f u l l y with ethanol. The f i l t r a t e was evaporated at room temperature i n a rotary evaporator. The o i l y residue was mixed with 50 ml of water, b a s i f i e d with a cooled sodium hydroxide s o l u t i o n and extracted with chloroform. The combined chlo-roform s o l u t i o n was washed with a saturated s o l u t i o n of sodium chl o r i d e , dried over anhydrous sodium sul f a t e and evaporated to give a viscous l i q u i d (1.86 gm). This o i l y m aterial was redissolved i n anhydrous ether and the ether-eal s o l u t i o n was cooled i n a fr e e z i n g mixture of acetone and dry i c e . The s o l i d product which p r e c i p i t a t e d from -ether was c o l l e c t e d by f i l t r a t i o n . Repeated concentration and cooling of the f i l t r a t e gave a t o t a l of 0.81 gm (41%) of crude 32, mp 141-152°; i r (KBr) 705, 760, 1445, 1495, 3020, 3050 (phenyl), 1140, 1300 (sulfone) and absence of NH st r e t c h i n g ; pmr (CDC1 3) 2.18 (s, 6, N(CH 3) 2), 2.17 (d, 2, 0H2N, J = 8 Hz), 3-20-3.83 (m, 1, CHOHgS), 3-93-4 . 3 5 (m, 2, CH 2S) and 7-05-7.60 (m, 10, phenyl) ppm. 176 Attempts to further p u r i f y the product by co-lumn chromatography (neutral alumina/benzene-chloroform-methanol) re s u l t e d i n u n i d e n t i f i e d degraded substances. The p i c r a t e s a l t was prepared by d i s s o l v i n g 32 (0.1 gm) i n a minimum amount of absolute methanol. The so-l u t i o n was f i l t e r e d . A s u f f i c i e n t amount of ethanolic solu-t i o n of p i c r i c a c i d was added u n t i l the formation of tur-b i d i t y had ceased. Upon standing without disturbance, the s o l u t i o n y i e l d e d yellow needle-like c r y s t a l s . The solvent was c a r e f u l l y withdrawn and the c r y s t a l l i n e substance was thoroughly washed several times with 60% aqueous methanol. F i n a l l y the bright yellow p i c r a t e s a l t (0.1 gm) was c o l -l e c t e d by f i l t r a t i o n and dried, mp >184.5° (decomp.); i r (KBr) 709, 750, 1 4 6 0 , 1490, 1525, 1544, 1565, 3010, 3040, 3070, 3090 (phenyl and n i t r o ) , 1135, 1310, 1360 (sulfone and n i t r o ) and 2050-2850 (ammonium) cm"1; pmr (DMSO-dg)S 2.85 (s, 6, F ( C H 3 ) 2 ) , 3.03-3.35 (m, 2, ECH 2), 3-50-4.20 (m, 1, CH pCH), 4.35-4-87 (m, 2, SCH ?), 7-38 (m, 10, phen-+ y l ) , 8.57 (s, 2, t r i n i t r o p h e n y l ) and 9-47 (broad, 1, EH) ppm. Anal - Calcd. f o r C ^ H ^ N ^ S : C, 52.89; H, 4-44; E, 10.37-Found: C, 52.82; H, 4-43; E, 10.18. The free base 32 was regenerated as white s o l i d by a l k a l i z a t i o n of the p i c r a t e and extraction of the l i b e r a t e d amine by chloroform. Attempted dimethylation of l 6 l by using Eschwei-177 l e r - C l a r k procedure (196) was unsuccessful: A s o l u t i o n of crude l 6 l (0,177 gm, 0.00062 mole), 3-2 gm of 90.7% formic acid (0.06 mole) and 0.1ml of 37% formaldehyde so-l u t i o n (0.0013 mole) was s t i r r e d and heated at 68° f o r 24 hours. The s o l u t i o n was evaporated to a residue which was b a s i f i e d with sodium carbonate and extracted with chloro-form. The chloroform s o l u t i o n was separated and evaporated to remove the solvent. The remaining material was d i s s o l v -ed i n 10% hydrochloric acid. A f t e r f i l t r a t i o n , the acid f i l t r a t e was b a s i f i e d (sodium carbonate) and extracted with chloroform. Evaporation of the dried chloroform s o l u t i o n gave a s o l i d , i r (KBr) 710, 760, 925, 1025, 1450, 1490, 2960, 3020 and 3060 cm"1. The i r data obviously i n d i c a t e s the l o s s of a sulfone group. 6. Separation of c i s - 2 - b u t e n e n i t r i l e ( 1 6 2 ) and trans-2-butenenitrile ( 1 6 3 ) . The commercial 2-butenenitrile ( c r o t o n o n i t r i l e ) contained a mixture of c i s - (60-70%) and trans- (30-40%) isomers. The two components were separated by repeated d i s t i l l a t i o n through a Spinning-Band-Column d i s t i l l a t i o n apparatus (motor speed 7 6 O O RPM). The p u r i t y of the se-parated isomers (bp: c i s , 108°; trans,' 121°) were deter-mined by glc (1/8 i n x 6 f t s t a i n l e s s s t e e l column pack-ed with 3-2 gm of 15% GE SE-30 on 90 to 100 mesh Anakrom ABS, column temperature 60°). 178 7. Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthie-tane (156 ) and cis-2,2-diphenyl-3-methyl-4-cyano-thietane (158). Freshly r e c r y s t a l l i z e d thiobenzophenone (95) (2.4 gm, 0.0121 mole), pure c i s - 2 - b u t e n e n i t r i l e ( 1 6 2 ) (7.0 gm, 0.105 mole) and r e d i s t i l l e d cyclohexane (10 ml) were mixed under a carbon dioxide atmosphere. The solu-t i o n was t i g h t l y sealed and i r r a d i a t e d at 366 nm, a pro-cedure described i n the synthesis of 155 (experiment 2). A f t e r 152 hours of i r r a d i a t i o n the yellow solu t i o n obtain-ed was f i l t e r e d and d i s t i l l e d at room temperature in. va cuo to give a viscous l i q u i d (3.6 gm). The d i s t i l l a t e con-t a i n i n g a mixture of cyclohexane and excess 2-buteneni-t r i l e was trapped i n a f l a s k cooled i n a dry ice-acetone mixture. Analysis by glc showed that the recovered 2-bu-t e n e n i t r i l e was e n t i r e l y cis-isomer ( 1 6 2 ) . This revealed that no isomerization of 1 6 2 occurred during the photo-chemical process. Analysis of the pmr spectrum (CDCl^) of the v i s -cous l i q u i d obtained above ind i c a t e d the presence of a 2.5 : 1 mixture of 156 and 158; pmr (CCl^) 156 : £1.54 (d, 3, CKy, J = 7 Hz), 3.80 (m, 1, SCH), 5-00 (d, 1, CHCT, J = 8 Hz) and 7.10-7-75 (m, 10, phenyl) ppm; 158: Sl-07 (d, 3, 0H 3, J = 7 Hz), 4-20 (m, 1, CH^CH), 4-25 (d, 1, SCH, J = 8 Hz) and 7-10-7-75 (m, 10, phenyl) ppm. Attempts to separate these two isomers by cry-179 s t a l l i z a t i o n and chromatography methods were unsuccess-f u l . 8 . Synthesis of cis - 2 , 2-diphenyl - 3-cyano-4-methylthie-tane 1 , 1-dioxide (174). The viscous mixture ( 3 . 6 gm) of c i s - 2 , 2 - d i p h e n y l -3-cyano - 4-methylthietane ( 1 5 6) and i t s isomer, c i s - 2 , 2 - d l -phenyl - 3-methyl - 4-cyanothietane (158) prepared by the pho-tocycloaddition of thiobenzophenone (.95) ( 2 . 4 gm, 0 . 0 1 2 mole) to c i s - 2 - b u t e n e n i t r i l e ( 1 6 2 ) (7 . 0 gm, 0 . 1 0 5 mole) was dissolved i n methylene chloride ( 5 0 m l ) . The r e s u l t i n g s o l u t i o n was s t i r r e d i n a cold water bath and treated with a s o l u t i o n of m-chloroperoxybenzoic ac i d ( 8 5 % , 4 - 5 8 gm, 0 . 0 2 6 mole) i n 1 5 0 ml of methylene c h l o r i d e . A f t e r s t i r -r i n g at room temperature f o r 5 days the oxidation mix-ture was c a r e f u l l y concentrated under reduced pressure to about 1 0 0 ml. The m-chlorobenzoic ac i d that p r e c i p i t a t e d was removed by f i l t r a t i o n . The f i l t r a t e was washed succes-s i v e l y with 10% sodium s u l f i t e s o l u t i o n , saturated sodium carbonate s o l u t i o n and water. A f t e r drying over anhydrous sodium s u l f a t e , the s o l u t i o n was concentrated again to about 10 ml. Anhydrous ether ( 1 0 ml) was added to the r e -sidue and the mixture was shaken. The c o l o r l e s s c r y s t a l -l i n e substance that appeared was c o l l e c t e d by f i l t r a t i o n and washed with a minimum amount of anhydrous ether. The pmr spectrum of t h i s product showed that i t was pure 174. 180 The y i e l d was 1.75 gm ( 6 8 . 4 % ) . The material was fur t h e r p u r i f i e d by r e c r y s t a l -l i z a t i o n at room temperature from a mixture of chloroform and n-pentane or from a mixture of methylene chloride and ether to give c o l o r l e s s l e a f l e t c r y s t a l s , mp 184-186 . 5 ° ; i r (KBr) 705,760, 1450, 1496, 1600, 3025, 3060 (phenyl), 1155, 1330 (sulfone), 2260 ( n i t r i l e ) cm"1; pmr (CDCl^) 8 1.63 (m, 3, 0H 3), 4.40-4-80 (m, 2, CHCN and SCH) and 7-20-7.60 (m, 10, phenyl) ppm. Anal. Oalcd. f o r C 1 7H 1 5NS0 2: C, 68.66; H, 5-08; ET, 4-71. Pound: C, 68.69; H, 5-09; N, 4-76. The ethereal mother l i q u i d from which 174 was i s o l a t e d , was evaporated to an o i l . The pmr spectrum of t h i s o i l y substance i n d i c a t e d that no appreciable amount of cis-2,2-diphenyl-3-methyl-4-cyanothietane 1,1-dioxide (175) existed. 9. Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthie-tane 1-oxide (178). A crude l i q u i d (7.3 gm) of cis-2,2-diphenyl-3-cyano-4-methylthietane (156) prepared by the photocyclo-ad d i t i o n r e a c t i o n i n experiment 7 was dissolved i n a mini-mum amount of anhydrous ether and a soluti o n of m-chloro-peroxybenzoic a c i d (9-7 gm) i n 20 ml of anhydrous ether was added with s t i r r i n g . A f t e r the addition of peracid p r e c i -p i t a t i o n occurred. The r e s u l t i n g mixture was placed aside 181 overnight and f i l t e r e d to give a white powder (178) (3-03 gm), mp 135-136°; i r (KBr) 708, 762, 1450, 1500, 1600, 3040, 3070 (phenyl), 1080 (S=0 (172)), and 2260 (cyano) cm"1; pmr (CDC1 3)6 1.67 (d, 3 , CH 3, J = 7 Hz), 3-41 (two overlapping doublets centered at 199.5 and 210.1 Hz r e s -p e c t i v e l y , 1, SOH, J(CH-CH) = 10 Hz, J(CH 3-CH) = 7 Hz), 4-71 (d, 1, CNCH, J = 10 Hz) and 7-40 (m, 10, phenyl) ppm. Oxidation of the sulfoxide 178 i n chloroform with excess m-chloroperoxybenzoic acid gave corresponding sulfone 174-10. Synthesis of cis-2,2-diphenyl-3-aminomethyl-4-methyl-thietane 1,1-dioxide (179). The procedure described i n the experiment 4 was used. A stream of diborane (0.0375 mole) generated by ad-d i t i o n of sodium borohydride (3.4 gm, 0.09 mole) to boron t r i f l u o r i d e etherate (25.5 gm, 0.18 mole) was slowly pass-ed i n t o a s t i r r e d and cooled s o l u t i o n of 174 (3.3 gm, 0.01 mole) i n 200 ml of dried tetrahydrofuran. The c o l o r l e s s s o l u t i o n was s t i r r e d at room temperature f o r 48 hours. The excess diborane was destroyed with 10 ml of water, 27 ml of 20% aqueous hydrochloric acid was added and the r e s u l -t i n g s o l u t i o n was s t i r r e d f o r 40 hours. A f t e r a l k a l i z a t i o n to pH 12 with sodium hydroxide solution, the aqueous mix-ture was evaporated at room temperature to remove the te-trahydrofuran. The remaining aqueous mixture was extract-182 ed with chloroform. The chloroform extract was washed with saturated sodium chloride s o l u t i o n and dried over anhydrous sodium s u l f a t e . The crude 179 (2.84 gm, 86%) was obtained as a gummy substance a f t e r evaporation of the solvent and drying i n vacuo. A sample of t h i s gummy material was grossly p u r i f i e d by d i s s o l v i n g i n a mix-ture of methanol and n-pentane and allowing the so l u t i o n to be concentrated spontaneously at room temperature to give c o l o r l e s s needle-like c r y s t a l s (179), mp 136-143°; i r (KBr) 710, 7 6 3 , 780, 1450, 1495, 3030, 3060 (phenyl), 1140, 1155, 1300, 1320 (sulfone), 3325 and 3385 (primary amine) cm - 1; pmr (0001^)8 0.98 (s, broad, 2, NH2, exchang-ed by D 20), 1.53 (d, 3, CEyJ = 7 Hz), 2.89 (d, broad, 2, CH^T, J = 7 Hz), 3.50 (m, 1, NCH2CH, J(CH 2-CH) = 7 Hz, J(CH-CH) = 9 Hz), 4-53 (m, 1, SCH, J(CH 3-CH) = 7 Hz, J(CH-OH) = 9 Hz) and 7-42 (m, 10, phenyl) ppm. The p i c r a t e s a l t was prepared by d i s s o l v i n g the crude 179 i n a minimum amount of 95% ethanol. Addition of an ethanolic s o l u t i o n of p i c r i c a c i d gave the yellow cry-s t a l l i n e p i c r a t e which was r e c r y s t a l l i z e d several times from a mixture of 95% ethanol and 10% a c e t i c acid, mp 198-201°; i r (KBr) 715, 755 (phenyl), 1495, 1530, 1555, l 6 l 0 , 1630 (phenyl and n i t r o ) , 1210-1400 (sulfone and n i t r o ) and 2150-3420 (ammonium) cm"1; pmr (DMSO-dg)S 1.51 (d, 3, CH 3, J = 7 Hz), 2.95 (d, broad, 2, OE^, J = 7 Hz), 3.82-4-35 (m, 1, NCH2CH), 4.40-5.15 (m, 1, SCH), 7-43 (s, 10, phenyl 183 + ), 7-87 (s, broad, 3, NH^) and 8.72 (s, 2, t r i n i t r o p h e n -y l ) ppm. Anal. Calcd.for C 2 3H 2 2N 4SO g: C, 52.07; H, 4-18; N, 10.56. Found: C, 52.29; H, 4-21; N, 10.6 9 . 11. Synthesis of cis-2,2-diphenyl-3-dimethylaminomethyl-4-methylthietane 1,1-dioxide (33)• A mixture of crude 2,2-diphenyl-3-aminomethyl-4-methylthietane 1,1-dioxide (179) (2.5 gm, 0.0083 mole), formaldehyde s o l u t i o n (3: ml of 3 6 . 4 % ) and 95% ethanol ( 100 ml) was s t i r r e d at room temperature f o r 9 hours and then f i l t e r e d . To the f i l t r a t e were added 0.49 ml of g l a -c i a l a c e t i c a c i d and 0.7 gm of 10% palladium on charcoal. The r e s u l t i n g mixture was immediately shaken at 50 p s i of hydrogen, a procedure described i n experiment 5- A f t e r 11 hours of methylation the dark mixture was f i l t e r e d with the a i d of " C e l i t e " . The solvent and the excess form-aldehyde were removed at room temperature by vacuum eva-poration. The residue was b a s i f i e d with sodium hydroxide s o l u t i o n and extracted with ether. The pooled ether ex-tr a c t was washed with saturated sodium chloride solution, f i l t e r e d and dried. Crude J33_ was obtained as a viscous l i q u i d (3-0 gm) a f t e r evaporation of the ether i n a ro-tary evaporator. The i r spectrum of t h i s crude product showed the absence of N-H stretching of the primary amino group. White hydrochloride p r e c i p i t a t e (mp 120-150°) was 184 obtained when a sample of the crude t e r t i a r y amine d i s s o l v -ed i n ether was treated with an ethereal s o l u t i o n of hydro-gen chloride. This hydrochloride s a l t deteriorated r a p i d l y i n chloroform. A sample of 0.02 gm of the hydrochloride was very soluble i n about 0.4 ml of CDCl^ but an i n s o l u b l e ma-t e r i a l r a p i d l y c r y s t a l l i z e d out from the chloroform solu-t i o n i n one or two minutes. This c r y s t a l l i n e material, d i f -ferent from the o r i g i n a l material, was i n s o l u b l e i n most common laboratory solvents. The i r spectrum showed that ;. t h i s material was a hydrochloride and sulfone but was d i f -ferent from the o r i g i n a l hydrochloride. The crude 33 (0.50 gm) was p u r i f i e d by using co-lumn chromatography (neutral alumina/benzene). The i s o l a t -ed pure product was s o l i d i f i e d upon addition of n-pentane. A white s o l i d (33) was obtained, mp 132-135°; ir(KBr) 702, 715, 752, 1 4 4 5 , 1 4 5 6 , 1 4 9 5 , 1596, 3020, 3050 (phenyl), 1135 and 1300 (sulfone) cm"1; pmr(CDCl 3) Si.53 (d, 3 , 0H 3, J = 7 Hz), 2.20 (s, 6 , N(GH 3) 2), 1.83-2.77 (m, 2, NCH 2), 3.18-3-92 (m, 1, FCH 2CH), 4-20-4.83 (two overlapping quartets centered at 2 6 5 .0 and 274-5 Hz r e s p e c t i v e l y , 1, SCH, J(CH-CH) = 9 Hz) and 7-38 (m, 10, phenyl protons) ppm. The p i c r a t e s a l t was prepared by d i s s o l v i n g 33_ i n a. minimum amount of methanol. Addition of ethanolic solu-t i o n of p i c r i c a c i d yielded a yellow p r e c i p i t a t e which was c o l l e c t e d and r e c r y s t a l l i z e d from a mixture of methanol and acetone to give f i n e , needle-like c r y s t a l s , mp 212-214°; i r 185 (KBr) 705, 752 (phenyl), 1150, 1210-1385 (sulfone and n i -t r o ) , 1490, 1560, 1615 ( n i t r o and phenyl), and 2100-3100 (ammonium) cm"1; pmr (DMSO-dg) 51.52 (d, 3, CH^, J = 7 Hz), 2.90 (s, broad, 6, tfCCH^), 3.00-3-30 (broad band, 2, NCH 2), 3-80-4-40 (m, 1, TTCHpCH), 4-50-5-10 (m, 1, SOH), 7-45 (m, 10, phenyl protons), 8 . 6 3 (s, 2, t r i n i t r o p h e n y l protons), and 9.37 (broad band, KH) ppm. Anal. Calcd. f o r C^H^CT^SOg: C, 53-76; H, 4-69; N, 10.03-Pound: C, 53-79; H, 4-82; H, 10.23-12. Synthesis of trans-2,2-diphenyl-3-cyano-4-methylthie-tane (157) and trans-2,2-diphenyl-3-methyl-4-cyanothie-tane (159). Freshly r e c r y s t a l l i z e d thiobenzophenone ('95) (1.1 gm, O.OO56 mole), glc-pure trans-2-butenenitrile ( 1 6 3 ) (3«l6 gm, 0.0471 mole), and r e d i s t i l l e d cyclohexane (4-5 ml) were mixed under a carbon dioxide atmosphere. The solu-t i o n was t i g h t l y stoppered and i r r a d i a t e d at 366 nm, a pro-cedure described i n the synthesis of 2,2-diphenyl-3-cyano-thietane (155) - The r e s u l t i n g yellow solu t i o n was f i l t e r e d and evaporated i n vacuo to give a viscous l i q u i d (1.7 gm). The solvent and the excess 2-butenenitrile were recovered i n a cold trap. Analysis by g l c indicated that no isomeri-zation of 1 6 3 occurred i n the photochemical process and only 1 6 3 was recovered. Analysis of the pmr spectrum of the viscous l i -186 quid i n d i c a t e d the existence of an isomeric mixture of trans-2,2-diphenyl-3-cyano-4-methylthietane (157) and trans-2,2-diphenyl - 3-methyl-4-cyanothietane (159) i n a r a -t i o of 2.8:1; pmr (CCl^) 157: S i . 4 5 (d, 3 , GH^, J = 6 Hz), 3.86 (m, 1, CH^CH), 4 - 3 6 (d, 1, CNCH, J = 10 Hz), and 6.80-7.80 (m, 10, phenyl protons) ppm; 159: SO.83 (d, 3 , CH 3, J = 6 Hz), 3.66 (d, 1, CNCH, J = 10 Hz), 3-86 (m, 1, CH^CH) and 6.80-7-80 (m, 10, phenyl protons) ppm. Attempts to separate the two isomers by chroma-tography or by c r y s t a l l i z a t i o n were unsuccessful. 13- Synthesis of trans-2,2-diphenyl - 3-cyano-4-methylthie-tane 1,1-dioxide (176) • The crude mixture (1.7 gm) of trans-2,2-diphenyl-3-cyano-4-methylthietane (157) and trans-2,2-diphenyl-3-methyl-4-cyanothietane (159) prepared by the photocyclo-addit i o n of thiobenzophenone (.95) (1.1 gm, 0.0056 mole) to trans-2-butenenitrile ( 1 6 3) (3-l6 gm, 0.0471 mole) was d i s -solved i n methylene chloride (50 ml). The sol u t i o n was s t i r r e d i n a cold water bath and treated with a sol u t i o n of m-chloroperoxybenzoic a c i d (2.13 gm, 0.0123 mole) i n me-thylene chloride (150 ml). The reac t i o n mixture was s t i r r e d f o r 5 days. The excess m-chloroperoxybenzoic a c i d and i t s product m-chlorobenzoic a c i d were removed by washing suc-c e s s i v e l y with 10% sodium s u l f i t e , saturated sodium carbo-nate, and saturated sodium chloride solutions. The organic 187 sol u t i o n was then dried over anhydrous sodium sul f a t e and evaporated under reduced pressure. The residue obtained was chromatographed on s i l i c a gel (benzene) to give trans-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide (176) as a white s o l i d (0.88 gm, 52'i-.8%). No appreciable amount of other isomer, trans-2,2-diphenyl-3-methyl-4-cyanothietane 1,1-dioxide (177) was detected. The i s o l a t e d product was r e c r y s t a l l i z e d three times from a mixture of chloroform and n-pentane to give a c o l o r l e s s c r y s t a l l i n e substance (176), mp 167-2-171°; i r (KBr) 710, 7 3 5 , 7 5 5 , 774, 1450, 1498, 1600, 3030, 3060 (phenyl), 1148, 1318 (sulfone), and 2260 ( n i t r i l e ) cm"1; pmr (CDC1 3) S i . 6 3 (d, 3 , CH"3, J = 6.6 Hz), 3-78 (d, 1, CNCH, J = 10 Hz), 4-92 (two overlapping quartets centered at 290.0 and 300.8 Hz r e s p e c t i v e l y , 1, SCH, J(CHCH) = 10 Hz, J(CH 3CH) = 7 Hz) and 7-42 (m, 10, phenyl protons) ppm. Anal. Calcd. f o r C-^H^NSO^ C, 68.66 ; H, 5-08; N, 4-71. Pound: C, 68 - 5 7 ; H, 5-20; N, 4-84-14- Synthesis of trans-2,2-diphenyl - 3-aminomethyl-4-methyl-thietane 1,1-dioxide (180). A stream of diborane (0.0375 mole) generated by add i t i o n of sodium borohydride (3-4 gm, 0.09 mole) to boron t r i f l u o r i d e etherate (25-5 gm, 0.18 mole) was slowly passed int o a s t i r r e d and ice-cooled s o l u t i o n of trans-2,2-diphen-yl-3-cyano-4-methylthietane 1,1-dioxide (176 ) (1.37 gm, 188 0.004& mole) i n 100ml of dried tetrahydrofuran. The react-ing mixture was s t i r r e d at room temperature f o r 2 days, 10 ml of water was added to i n a c t i v a t e the excess di"borane, 20 ml of 10% hydrochloric acid followed and the r e s u l t i n g mixture was s t i r r e d f o r 3 days to hydrolyze the borane adduct. Then a cold s o l u t i o n of 3 gm of sodium hydroxide i n 30 ml of water was added. The r e s u l t i n g basic mixture was evaporated at room temperature to remove most of the tetrahydrofuran. The product was extracted from the remain-ing aqueous mixture with chloroform. The chloroform solu-t i o n was washed with saturated sodium chloride s o l u t i o n and dried. Removal of the solvent from the chloroform extract gave trans-2,2-diphenyl-3-aminomethyl-4-methylthietane 1,1-dioxide (180) as a gummy substance ( 1 . 6 9 gm); i r (neat) 710, 738, 760, 1450, 1500, 3030, 3060 (phenyl), 1145, 1303 (sulfone), 3320 and 3380 (primary amine) cm"1. The p i c r a t e s a l t was prepared by addition of an ethanolic s o l u t i o n of p i c r i c a c i d to a methanolic s o l u t i o n of 180 (0.1 gm). Upon standing the r e s u l t i n g s o l u t i o n f o r one hour without disturbance, the yellow c r y s t a l l i n e p i -crate that appeared was c o l l e c t e d by f i l t r a t i o n and washed thoroughly with 50% aqueous methanol. A f t e r drying, the p i c r a t e s a l t (0.1 gm) was pure enough f o r elemental analy-s i s , mp 168.5-170.5°; i r (KBr) 710, 733, 752 (phenyl), 1150, 1200-1400 ( n i t r o and sulfone), 1400-1650 (n i t r o and phenyl) and 2100-3300 (ammonium and C-H) cm"1; pmr (DMS0-dg) 81.50 (d, 3,, C H V J = 7 Hz), 2.70-4.0 (m, HCH?, OH CH and 189 solvent i m p u r i t i e s ) , 4 . 8 5 (qd, 1 , SCH, J(CH 3CH) = 7 Hz, J (CHCH) = 9 Hz), 7 . 0 - 7 - 7 (m, 1 0 , phenyl protons), 8 . 6 0 (s, 2 , t r i n i t r o p h e n y l protons) ppm. Anal. Calcd. f o r C 2 3 H 2 ? N 4 S 0 g ; C, 52 . 0 7 ; H, 4-18; N, 1 0 . 5 6 . Pound: C, 52.18; H, 4 - 4 2 ; I, 1 0 . 6 l . -R e c r y s t a l l i z a t i o n of the pi c r a t e from a mixture of acetone and methanol r e s u l t e d i n a depressed melting point and the appearance of carbonyl absorption i n the i r spectrum. The 1-acetyl d e r i v a t i v e was prepared by reacting 180 ( 0 . 1 5 gm) with a c e t i c anhydride ( 0 . 5 ml) f o r 15 minutes. The gummy substance that appeared upon d i l u t i n g the anhy-dride s o l u t i o n with 10 ml of cooled water, was separated by decantation of the aqueous so l u t i o n and then p u r i f i e d by using a s i l i c a gel column ( 3 0 gm, eluted successively with chloroform and methanol). The acetamide which was i s o -l a t e d as a c o l o r l e s s s o l i d was then r e c r y s t a l l i z e d several times from benzene to give the c o l o r l e s s c r y s t a l l i n e trans-2 , 2-diphenyl - 3-acetamidomethyl - 4-methylthietane 1 , 1-dioxide, mp 182-185°; i r (KBr) 7 1 0 , 7 3 8 , 7 5 8 , 1448, 1 5 0 0 , 1 5 4 0 , 3060 (phenyl), 1 1 4 5 , 1 3 0 0 (sulfone), 1 6 5 0 (amide carbonyl) and 3 3 3 0 (secondary amide) cm"1; pmr (CDCl^) Si. 5 2 (d, 3 , CHCH3, J = 7 Hz), 1 . 8 3 (s, 3 , C 0 C H 3 ) , 2 . 9 3 - 3 - 3 7 (m, 3 , CHCH2H), 4 - 1 0 - 4 - 6 0 (m, 1 , SCH), 5 - 4 0 ( t , broad, EH), and 7 - 3 8 (s, 1 0 , phenyl protons) ppm. 190 15- Synthesis of trans-2,2-diphenyl-3-dimethylaminomethyl-4-methylthietane 1,1-dioxide (34)• The crude trans-2,2-diphenyl-3-aminomethyl-4-me-thylthietane 1,1-dioxide (180) (1.49 gm, 0.00428 mole) prepared i n the previous experiment was dissolved i n 2.5 ml of 36.4/0 formaldehyde s o l u t i o n and 80 ml of 95% ethanol. The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 10 hours and then f i l t e r e d . To the f i l t r a t e were added 0.4 ml of g l a c i a l ace-t i c a c i d and 0.5 gm of 10% palladium on charcoal. The r e -s u l t i n g mixture was shaken i n a Parr hydrogenation b o t t l e at 50 p s i of hydrogen f o r 11 hours, and then c a r e f u l l y f i l -tered. The f i l t r a t e was b a s i f i e d , the solvent was evaporat-ed and the residue was extracted with chloroform. The chlo-roform s o l u t i o n was washed with saturated sodium chloride s o l u t i o n , dried over anhydrous sodium sul f a t e and evaporat-ed at room temperature to an o i l to which was added a small amount of anhydrous ether to p r e c i p i t a t e the crude product. A f t e r f i l t r a t i o n , J34 was obtained as a white s o l i d (0.92 gm, 6 5 % ) which was r a p i d l y chromatographed on neutral a l u -mina (chloroform) to give a gummy substance which was s o l i -d i f i e d by t r i t u r a t i o n i n a small amount of methanol and r e c r y s t a l l i z e d at room temperature as follows: The material (34) was dissolved i n methylene chl o r i d e , the s o l u t i o n was c a r e f u l l y concentrated to a very small volume i n a rotary evaporator, a small amount of methanol was added, and the so l u t i o n was set aside f o r several hours. A c r y s t a l l i n e 191 substance which appeared during t h i s period was c o l l e c t e d and treated by repeating the above procedure. Consequently 34 was obtained as c o l o r l e s s c r y s t a l s , rap 125•5-130,5°; i r (KBr) 702, 712, 760, 1447, 1500, 1600, 3030, 3050, 3065 (phenyl), 1143, 1153 and 1293 (sulfone) cm - 1; pmr (CDCl^) Si .58 (d, 3, CH 3, J = 7 Hz), 2.06 (obscured doublet, 2, WCH2), 2.14 (s, 6, N(CH 3) 2), 2.74-3-33 (m, 1, MCH2CH), 4-38 (two overlapping quartets centered at 257-50 and 268.25 Hz r e s p e c t i v e l y , 1, SCH, J(CHCH) = 10 Hz, J(CHCH 3) = 7 Hz) and 7-37 (m, 10, phenyl protons) ppm. Anal. Calcd. f o r C i gH 2 3NS0 2: C, 69-27; H, 7-04; IT, 4-25-Pound: C, 68.97; H, 6.77; IT, 4-10. The p i c r a t e s a l t was prepared by reacting a so-l u t i o n of 34 (0.1 gm) i n a minimum amount of methanol with p i c r i c a c i d (0.3 ml of saturated ethanolic s o l u t i o n ) . The c r y s t a l l i n e p i c r a t e was c o l l e c t e d and washed with methanol, mp 184-188°. 16. Synthesis of 2,2-diphenyl-3-dimethylaminomethylthie- tane (191). To a s t i r r e d s o l u t i o n of 2,2-diphenyl-3-cyano-thietane (l_5_5) (2.0 gm, 0.008 mole) i n 60 ml of dried te-trahydrofuran was added 0.025 mole of borane-methyl-sul-f i d e complex (2'ml, neat l i q u i d , containing about 5% methyl s u l f i d e ) . The reacting mixture was s t i r r e d f o r 24 hours and then hydrolyzed f o r 20 hours by s t i r r i n g the solu t i o n 192 i n a mixture of 10 ml each of water and concentrated hy-d r o c h l o r i c acid. A f t e r evaporating most of the tetrahydro-furan, the remaining aqueous mixture was extracted with chloroform. The hydrochloride i n the chloroform s o l u t i o n was converted i n t o free amine by shaking the s o l u t i o n with sodium carbonate sol u t i o n . The chloroform s o l u t i o n was then washed with saturated sodium chloride solution, dried, and evaporated to a pale yellow l i q u i d (2.3 gm), i r (neat) 710, 760, 775, 1450, 1493, 3025, 3060 (phenyl), 1600, 3300 and 3360 (primary amine) cm-"'". The crude amine was dissolved i n anhydrous ether. The s o l u t i o n was f i l t e r e d . To the f i l t r a t e was added a suf-f i c i e n t amount of ethereal s o l u t i o n of hydrogen chloride to p r e c i p i t a t e the crude hydrochloride s a l t , which was then c o l l e c t e d and dried, weighing 0.9 gm, mp >149° (decomp.); i r (KBr) 710, 755, 780, 1448, 1495 (phenyl), 1 6 0 0 and 2100-3300 (ammonium) cm"1; pmr (CDCl^) $7-15 (phenyl protons) + and 8.15 (NHrj, exchanged by D^0) ppm. Attempted c a t a l y t i c methylation of the hydrochlo-r i d e by using formaldehyde, 10% palladium on charcoal and 50 p s i of hydrogen was unsuccessful. The crude hydrochloride was methylated by repeat-ed formylation and reduction method (151). The hydrochlo-r i d e (0.8 gm) was dissolved i n 2 ml of formic a c i d and a minimum amount of ether. The s o l u t i o n was cooled i n an i c e bath, a cooled s o l u t i o n of formic-acetic anhydride prepared 193 from dried formic acid (5-1 ml) and ace t i c anhydride (10 gm) (197) was added and the r e s u l t i n g mixture s t i r r e d at room temperature overnight. A f t e r evaporating the ether, the anhydride s o l u t i o n was added dropwise into an i c e -water mixture. A gummy deposit which appeared was extract-ed with chloroform. The chloroform solu t i o n was washed with water, dried and then evaporated to a viscous l i q u i d (0.65 gm); i r (neat) 710, 765, 1450, 1498, 3010, 3060 (phenyl), 1675 (amide carbonyl), 1600 and 3300 (secondary amide) cm-"'". The i r data in d i c a t e d that the product was a secondary amide. An ice-cOoled solu t i o n of t h i s amide (O.65 gm) i n tetrahydrofuran was reduced by addition of l i t h i u m aluminum hydride (0.4 gm). The mixture was s t i r r e d at i c e temperature f o r 6 hours. The solvent was evaporated, the l i t h i u m aluminum hydride was i n a c t i v a t e d by sodium s u l -fate s o l u t i o n and the r e s u l t i n g mixture was then extracted with chloroform. Subsequent washing, drying, and evapora-t i o n of the chloroform s o l u t i o n r e s u l t e d i n a pale yellow l i q u i d (0.5 gm); i r (neat) 710, 760, 1450, 1495, 3025, 3060 (phenyl), 1600, and 3310 (secondary amine) cm""1. The i r data in d i c a t e d that the secondary amide was reduced to a secondary ¥-methyl amine. This secondary amine was f o r -mylated by using the same method to give a t e r t i a r y forma-mide (0.4 gm); i r (neat) 710, 760, 1450, 1495, 3020, 3060 (phenyl) and 1670 (amide carbonyl) cm"1. Subsequent reduc-t i o n of the t e r t i a r y amide with l i t h i u m aluminum hydride 194 by employing the above method gave a crude N,N-dimethyl-amine as a pale yellow l i q u i d (0.3 gm); i r (neat) 710, 760, 1450, 1498, 1600, 3030, 3060 and 3090 (phenyl) cm"1. The absence of the carbonyl absorption in d i c a t e d that the formamide was reduced. The crude t e r t i a r y amine was gross-l y p u r i f i e d by column chromatography (neutral alumina/ chloroform). The i s o l a t e d l i q u i d substance (0.2 gm) was dissolved i n dried ether and treated with a dried ethereal s o l u t i o n of hydrogen chloride. The hydrochloride p r e c i p i -tate formed was c o l l e c t e d , weighing 0.1 gm a f t e r drying i n vacuo; m p > 7 0 ° ; i r (KBr) 740, 760, 1498, 1505, 1600, 3040, 3060 (phenyl), and 2200-2800 (NH) cm"1; pmr (CDC1 3)S2.73 (s, 6, N(CH 3) 2), 2.35-3-40 (m, 4 , HCH2 and SCH"2), 4.10 (m, + 1, SCH2CH), 5-88 (s, broad, 1, KH, exchanged with D 20) and 7-33 (s, broad, 10, phenyl).ppm. The spectroscopic data in d i c a t e d that the i s o l a t e d hydrochloride s a l t was a crude material of 2,2-diphenyl-3-dimethylaminomethylthietane hy-drochloride (191) • Attempts to further p u r i f y t h i s mater-i a l by c r y s t a l l i z a t i o n were unsuccessful. 17. Synthesis of N,N-dimethylallylamine (200). A s t i r r e d mixture of allylamine (25.2 gm, 0.30 mole), 90% formic ac i d (66.8 gm, 1 . 2 6 mole) and 37% form-aldehyde s o l u t i o n (86 ml, 1.2 mole) was heated at 90° f o r 24 hours. T h i r t y m i l l i l i t e r s of concentrated hydrochloric a c i d was added. The mixture was concentrated under reduced 195 pressure to 150 ml, then b a s i f i e d with sodium carbonate, and extracted with chloroform. The chloroform s o l u t i o n was dried over anhydrous sodium s u l f a t e , bubbled with hydrogen chloride to convert the free amine i n t o i t s s a l t and f i n a l -l y stripped o f f the chloroform by evaporation. The r e s i d u a l l i q u i d (31.2 gm) was cooled (-9°) and b a s i f i e d with a cool s o l u t i o n of 12 gm of sodium hydroxide i n 12 ml of water. The t e r t i a r y amine ( 1 6 . 6 gm) was then grossly d i s t i l l e d i n  vacuo and trapped i n a f l a s k cooled i n a dry Ice-acetone mixture. A f t e r repeated r e d i s t i l l a t i o n at atmospheric pres-sure, N,N-dimethylallylamine (200) was obtained as a c o l o r -l e s s l i q u i d (13.5 gm, 40%), bp 6 5 - 6 6 ° ( l i t . (198) 6 4 ° (743 mm)); pmr (neat) £ 2 . 2 0 (s, 6 , N(CH 3) 2), 2.80-3-08 (m, 2, NCH 2), 4-95-5-40 (m, 2, =CH2) and 5 - 5 6 - 6.30 (m, 1, =CH) ppm. The uv spectrum of t h i s amine did not show absorption at 366 nm, the wavelength employed to prepare the thietane d e r i v a t i v e s by photocycloaddition of thiobenzophenone to o l e f i n s . 18. Attempted photocycloaddition of thiobenzophenone (.9^ ) to N.N-dimethvlallylamine (200). A mixture of N,N-dimethylallylamine (200) (8 . 6 gm, 0.077 mole), f r e s h l y r e c r y s t a l l i z e d thiobenzophenone (95) (4-80 gm, 0.024 mole) and 250 ml of anhydrous ether was i r r a d i a t e d at 366 nm f o r 211 hours, a procedure being described i n the synthesis of 2,2-diphenyl-3-cyanothietane 196 (155) • A sample of the decolorized s o l u t i o n ( 5 0 ml) was evaporated to an o i l (1.48 gm). Analysis by thi n l a y e r chromatography (neutral alumina, chloroform) in d i c a t e d the presence of at l e a s t seven components. Attempts to prepare a p i c r a t e d e r i v a t i v e or to separate the d i f f e r e n t compo-nents by using column chromatography method were unsuc-c e s s f u l . A white s o l i d was obtained when HGl-ether was added to an ethereal s o l u t i o n of the above crude o i l , mp > 9 1 ° (decomp.). The pmr spectrum showed that the material was not the expected product. Oxidation of the crude pho-toaddition products with m-chloroperoxybenzoic acid gave a crude mixture e x h i b i t i n g carbonyl and s u l f o n y l absorption In the i r spectrum. 19• Synthesis of ft-chloroethane s u l f o n y l chloride (212). The method used was taken from a patent (152). Thirty-one m i l l i l i t e r s (47 gm) of chlorine was c o l l e c t e d i n a graduated c y l i n d e r cooled at -80°. The yellow chlo-r i n e l i q u i d was slowly b o i l e d at about -30°, and the chlo-r i n e vapor was passed in t o a s t i r r e d and ice-cooled solu-t i o n of |3-mercaptoethanol ( 1 6 . 6 gm, 0.213 mole) i n 1,2-dichloroethane (30 gm). A f t e r 13 ml of chlorine had been passed in t o the t h i o l s o l u t i o n , 4 ml of water was added dropwise to the reacti n g mixture simultaneously. When the trans f e r of the remaining chlorine was completed, the ex-cessive halogen i n the reacti n g mixture was expelled with 197 a stream of nitrogen. A small amount of l i q u i d (ca. 2 ml) that separated from the mother l i q u i d was removed. The mo-ther s o l u t i o n was dried over anhydrous sodium s u l f a t e , . f i l t e r e d and evaporated. The r e s u l t i n g residue was d i s t i l l -ed to give 29.2 gm (84%) of /5-chloroethane s u l f o n y l chloride (212). bp 52-54° (0.2 mm) ( l i t . ( 1 5 2 ) 80° (1-2 mm); 94%). R e d i s t i l l a t i o n of the product (29 gm) gave a c o l o r l e s s l i -quid (212) (21 gm) bp 40.5° (0.01 mm), i r (neat) 670, 710 (chloro), I I 6 5 and 1370 ( s u l f o n y l ) cm"1; pmr (neat) 8 3-75-4.40 (m, CH 2CH 2S) ppm. 20. Reaction of /3-chloroethanesulfonyl chloride (212) and @-dimethylaminostyrene (213)-. A mixture of /a-dime t h y l amino styrene (213) (2.21 gm, 0.015 mole), p u r i f i e d triethylamine (3.02 gm, 0.03 mole) and 20 ml of dried ether v;as s t i r r e d and cooled i n a dry ice-acetone bath at -80°, a s o l u t i o n of 2-45 gm (0,015 mole) of /8-chloroethanesulfonyl chloride (212) i n 20 ml of dried ether was added dropwise and the r e a c t i o n was allowed to proceed f o r l i hours during which a white p r e c i p i t a t e appeared. The r e s u l t i n g mixture was allowed to return to room temperature and f i l t e r e d to give a white s o l i d material which was i d e n t i f i e d as triethylamine hy-drochloride. The f i l t r a t e was evaporated to a brownish yellow mass, 10 ml of dried ether was added and the ether-eal s o l u t i o n was c h i l l e d y i e l d i n g 1.1 gm of s o l i d . The 198 pmr spectrum showed that i t contained mainly o 7/-(vinyl s u l -fonyl )-$-dimethylamino styrene (218) and a l i t t l e amount of triethylamine hydrochloride. The f i l t r a t e was evaporat-ed to a "brownish yellow semi-solid (1.44 gm). Infrared an-a l y s i s i n d i c a t e d that t h i s material contained mainly 218. The c a l c u l a t e d y i e l d of the t o t a l triethylamine hydrochlo-r i d e obtained was quantitative (0.03 mole). This i n d i c a t -ed that one mole of (5-chloro ethane s u l f o n y l chloride was dechlorinated "by two moles of triethylamine and the expect-ed c y c l i c product was not produced. The crude 218 was dissolved i n ether, the ether-eal s o l u t i o n was washed successively with sodium carbonate s o l u t i o n and water. The solvent was evaporated and the r e -sidue was r e c r y s t a l l i z e d four times from anhydrous ether to give the pure 218 as c o l o r l e s s l e a f l e t c r y s t a l s , mp 102-105°; i r (KBr) 722, 740, 1448, 1500 (phenyl), 1185, 1258 ( v i n y l GE"), 855, 958, 970, 990, 1 6 2 0 , 3035, 3065 (dou-ble bond), 1120, 1135.and 1300 (sulfone) cm"1; pmr (CDCl^) S2.68 (s, 6, E ( G H 3 ) 2 ) , 5.50-6.80 (m, 3, CHCHg), 7-33 (s, 5, phenyl) and 7-37 (s, 1, ECH) ppm. Anal. Calcd. f o r Cj-2-H15N02S: C, 60.73; H, 6.37; E, 5-90. Found: C, 60.73; H, 6.29; E, 5-86. The sodium fusion test f o r the presence of chlo-r i n e was negative. Repeating the experiment by using an equimolar amount of triethylamine at temperature of -80, 0, or 25° 199 also r e s u l t e d i n the i s o l a t i o n of 218. No appreciable amount of c y c l i z a t i o n product was observed. Addition of a mixture of triethylamine and 213 to the so l u t i o n of 212, a reversed a d d i t i o n procedure, also gave same r e s u l t s . 21. Synthesis of methyl propargyl ether (217)• Methyl propargyl ether was synthesized according to a method taken from l i t e r a t u r e (157). A mixture of r e -d i s t i l l e d propargyl alcohol (89 gm, 1.59 mole), 71 ml of water and 176 gm of 50% (w/v) aqueous sodium hydroxide so-l u t i o n was heated at 40°. The soluti o n was s t i r r e d and 120 gm of dimethyl su l f a t e (120 gm, 0.95 mole) was added i n slowly so that the temperature of the soluti o n was main-tained below 60°. The mixture was heated at 50-60° f o r 2 hours, and then d i s t i l l e d at atmospheric pressure to give 57-9 gm ( 6 1 % ) of methyl propargyl ether (217). bp 6 0 - 6 1 . 5 ° ; pmr (neat)8 2 . 6 2 ( t , 1, CH, J = 2.5 Hz), 3-33 (s, 3, CH 3), and 4.14 (d, 2, CH 2, J = 2.5 Hz) ppm. 22. Synthesis.of methoxyallene (113). Methoxyallene (113) was prepared according to the method described by Hoff et a l . (156). A mixture of methyl propargyl ether (217) (52 gm, 0.866 mole) and potas-sium t-butoxide (7-15 gm, prepared by r e f l u x i n g t-butyl a l -cohol and potassium and evaporating the excessive alcohol i n vacuo) was heated at 70° f o r two hours. The mixture was 200 d i s t i l l e d at atmospheric pressure to give 32.5 gm (63%) of methoxyallene (113), hp 50.8-51.5°; pmr (neat) £2.93 (s, 3, CH 3), 5-00 (d, 2, CH 2, J = 5.5 Hz), and 6.30 ( t , 1, GH, J = 5.5 Hz) ppm. 23. Synthesis of 2,2-diphenyl-3-methoxy-4-methylenethie-tane (114)• A very b r i e f note taken from l i t e r a t u r e (134a) was used as a reference. Freshly r e c r y s t a l l i z e d thiobenzo-phenone (95) (5 gm, 0.025 mole) and p u r i f i e d methoxyallene (113) (7.2 gm, 0.1 mole) were dissolved In 280 ml of anhy-drous ether reagent. The blue color of thiobenzophenone completely disappeared within 3^ - hours at room temperature. The solvent was removed by evaporation. To the o i l y r e s i -due was added about 100 ml of ether-n-pentane s o l u t i o n (2: 3) and the r e s u l t i n g p r e c i p i t a t e s was f i l t e r e d to give 2-methoxymethylene-6-phenyl-benzo(d)thiane (115 ) as a pale yellow s o l i d (>3-5 gm, ^>50%) ( l i t . (134a) 15-20%): pmr (CDC1 3) S3-42 (s, 2, CH 2), 3.60 (s, 3, 0CH 3), 5-31 (s, 1, CHS), 6.15 (s, 1, CH0) and 7-1-7.6 (m, 9, phenyl protons) ppm. The pmr data was i d e n t i c a l to that reported i n the l i t e r a t u r e . The f i l t r a t e was evaporated to a semi-solid. Ana-l y s i s by using t h i n layer chromatography method (neutral alumina; GCl^) in d i c a t e d the presence of two major compo-nents and some impurities. One major component was benzo-201 thiane 115, another was 2,2-diphenyl-3-methoxy-4-methylene-thietane (114)• The prar spectrum (CDCl^) of t h i s mixture showed that i n addi t i o n to the signals accounted f o r "by 115 and other impurities, signals at 8 3*33 ( s ) , 4«98 ( t , s p l i t -t i n g = 2.5) and 5 • 38 (m) ppm were comparable to the l i t e r a -ture pmr data of 114 ( l i t . (134) (CCl^) 3-21 ( s ) , 4-91 ( t , J = 2.3 Hz), 5-24 ( t , J = 2.3 Hz), and 5-35 ( t , J = 2.2 Hz) ppm). An experiment was c a r r i e d out to prove that the rea c t i o n of 113 and 95 was a thermal r e a c t i o n : A 50-ml so-l u t i o n of 95. (0.1 M) i n dried and thiophene-free benzene was t i g h t l y sealed with a rubber septum, wrapped i n alumi-num f o i l and placed i n a dark place to protect the solu t i o n from l i g h t . Methoxyallene (113) (1.44 gm, 0.02 mole) mea-sured i n a syringe was i n j e c t e d i n t o the s o l u t i o n which was then shaked thoroughly. The blue color disappeared within 1-g- hours and the s o l u t i o n became yellow. Tic analysis I n d i -cated that the products were the same as obtained above. In another experiment, two pyrex f l a s k s each con-ta i n i n g 100-ml of a s o l u t i o n of 95. (0.1 M) i n thiophene-free benzene were sealed with rubber septa and placed i n a dark hood. A f t e r a d d i t i o n of 113 (2.88 gm, 0.01 mole), the solutions were immediately i r r a d i a t e d with uv l i g h t gene-rated from a medium pressure mercury arc (450 W) f i l t e r e d through a 3% potassium dichromate solu t i o n . The blue color of the react i n g mixture remained very intense a f t e r 20 mi-202 nutes of i r r a d i a t i o n , but completely disappeared by 1-g-hours. This was incompatible wi-th the report that the r e -action was complete during 20 minutes of i r r a d i a t i o n (134a). Analysis by using t h i n l a y e r chromatography indicated the presence of the same products and work up gave comparable y i e l d s of benzothiane 115 and thietane 114. The i s o l a t e d benzothiane 115 was not stable at room temperature. T i c analysis indicated that 115 was com-p l e t e l y decomposed upon evaporating a s o l u t i o n of 115 (about 10 mg) i n chloroform (1 ml) during a period of 24 hours. Attempts to p u r i f y 115 by using column chromatogra-phy (neutral alumina or s i l i c a gel) r e s u l t e d i n the i s o l a -t i o n of several unidentifed materials. Wo appreciable amount of 115 could be recovered. Attempts to i s o l a t e 2,2-diphenyl-3-methoxy-4-me-thylenethietane (114) by using l i q u i d column chromatogra-phy was also unsuccessful. Repeated chromatography of 1 gm of mixture containing 114 by employing Dry Column Chroma-tography method (158) (neutral alumina containing 4-5% wa-ter; benzene or CCl^ used as solvent) r e s u l t e d i n i s o l a t i o n of only a small amount of crude 114 (about 20 mg). The i n -s t a b i l i t y of both 114 and 115 caused the d i f f i c u l t y i n the i s o l a t i o n of the former. 24- Attempted hydroxylation of 2,4-diphenylthiete 1,1-dioxide (227) with sodium hydroxide. I s o l a t i o n of 203 dibenzylsulfone (234)• To a s t i r r e d mixture of 2,4-diphenylthiete 1,1-dioxide (227) (0 . 5 gm, 0.002 mole) (84), 3 ml of ¥/ater and 10 ml of dimethylsulfoxide, was added a s o l u t i o n of 1 gm of sodium hydroxide i n 20 ml of 50% aqueous dimethylsulf-oxide s o l u t i o n . The r e s u l t i n g greenish s o l u t i o n was s t i r -red at room temperature f o r 5 hours and then cooled i n the r e f r i g e r a t o r f o r 3 days i n an attempt to induce c r y s t a l l i -z ation of the desired 2,4-diphenyl - 3-hydroxythietane 1,1-dioxide ( £ 3 5 ) . When s o l i d f a i l e d to separate, the s o l u t i o n was then d i l u t e d with 75 ml of water and extracted with ether (150 ml). The ethereal s o l u t i o n was separated, dried over anhydrous sodium sul f a t e and f i n a l l y evaporated to give a yellow s o l i d ( 0 . 4 gm). R e c r y s t a l l i z a t i o n from a . mixture of ether and n-pentane gave c o l o r l e s s needle-like c r y s t a l s , mp 148-152°; i r (KBr) 706, 7 1 6 , 738, 770, 1458, 1498, 1604, 3028, 3058 (phenyl), 1135 and 1308 (sulfone) cm"1; pmr (CDC1 3)5 4-10 (s, 4, CH 2) :and 7 - 4 (s, 10, phen-y l ) ppm. The i r and mp data were i n accord with the l i t e -rature data (198, 199) of dibenzylsulfone ( £ 3 1 ) . The y i e l d was 81%. Repeating the experiment at room temperature f o r 16 hours without r e f r i g e r a t i o n r e s u l t e d i n the i s o l a t i o n of the same product. 25. Reaction of 2,4-diphenyl thiete, 1,1-di-r-204 o x i d e (227 ) w i t h " s u l f u r i c a c i d . I s o l a t i o n o f 3,5-di p h e n y l - 1 , 2 - r O x a t h i a c y c l o p e n t a - 3 - e n e 2 - o x i d e (.243, 244). 2,4-Diphenylthiete 1 , 1 - d i o x i d e (£27) (1.0 g m , 0.0039 m o l e ) w a s d i s s o l v e d i n 15 m l o f s t i r r e d a n d c o o l e d (-5°) c o n c e n t r a t e d s u l f u r i c a c i d . The r e s u l t i n g "brown s o -l u t i o n w a s a d d e d d r o p w i s e i n t o 150 m l of w a t e r w h i l e s t i r -red a n d c o o l e d i n an i c e h a t h . The white p r e c i p i t a t e t h a t a p p e a r e d u p o n d i l u t i o n o f t h e a c i d w a s s e p a r a t e d b y d e c a n -t a t i o n . The d e c a n t e d s u p e r n a t a n t w a s e x t r a c t e d w i t h e t h e r a n d the e t h e r e a l e x t r a c t was r e t u r n e d to t h e p r e c i p i t a t e . More e t h e r was a d d e d t o d i s s o l v e t h e p r e c i p i t a t e c o m p l e t e -l y . The e t h e r e a l s o l u t i o n w a s t h e n d r i e d o v e r a n h y d r o u s s o d i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a s o l i d m a t e r i a l (1 g m , 100%). The i r , p m r a n d t i c d a t a i n d i c a t e d t h a t t h i s m a t e r i a l was a m i x t u r e o f t w o •• i s o m e r i c s u l f i n a t e s , 3 , £ - 5 - d i p h e n y l - l , r - 2 - o x a t h i a c y c l o p e n -t a - 3 - e n e 2 - o x i d e (243) (59-6%) a n d 3 , t - 5 - d i p h e n y l - l , r - 2 -o x a t h i a c y c l o p e n t a - 3 - e n e 2 - o x i d e (244) ( 4 0.4%). The p e r c e n -t a g e w a s d e t e r m i n e d o n t h e b a s i s o f t h e s i g n a l s a t t r i b u t e d t o t h e b e n z y l i c p r o t o n s i n t h e p m r s p e c t r a . These t w o c o m -p o n e n t s w e r e s e p a r a t e d b y u s i n g c o l u m n c h r o m a t o g r a p h y ( s i -l i c a g e l , c h l o r o f o r m ) a n d r e c r y s t a l l i z e d f r o m a n h y d r o u s e t h e r : 3 , c s - 5 - d i p h e n y l - l , r - 2 - o x a t h i a c y c l o p e n t a - 3 - e n e 2-o x i d e (243): mp 129-131°; i r (KBr) 710, 748, 768, 1450, 1495, 1600 ( p h e n y l ) , 1630, 3035, 3060, 3070 (C=C) a n d 1125 ( s u l f i n a t e ) c m " 1 ; p m r (CDC1.J 5 6.39 (d, 1, S-0-CH, J = 2 205 H z ) , 6 . 7 3 (d, 1 , = C H ; J = 2 H z ) , 7 - 4 8 ( m , 1 0 , p h e n y l ) p p m ; + m a s s s p e c t . m / e 2 0 8 ( M - S O ) . A n a l . C a l c d . f o r ^ 1 ^ ? 0 2 S : C , 7 0 . 2 8 ; H , 4 - 7 2 ; S , 1 2 . 5 0 , P o u n d : C , 7 0 . 1 2 ; H , 4 - 6 4 ; S, 1 2 - 5 1 -3 , _ t - 5 . - D i p h e n y l - l , r - 2 - o x a t h i a c y c l o p e n t a - 3 - e n e 2 -o x i d e ( 2 4 4 ) : mp 1 3 0 - 1 3 2 ° ; i r ( K B r ) 7 0 5 , 7 3 5 , 7 4 5 , 7 7 0 , 1 4 5 0 , 1 4 9 5 , 1 6 0 0 ( p h e n y l ' ) , 1 6 3 0 , 3 0 3 0 , 3 0 6 0 ( C = C ) , 1 1 2 5 ( s u l f i n a t e ) c m " 1 ; p m r ( C D C l ^ ) S 6 , 8 0 ( d , 1 , = C H , J = 2 H z ) , 6 . 9 0 ( s , 1 , S - O - C H , J = 2 H z ) , 7 - 5 0 ( m , 1 0 , p h e n y l ) p p m ; + m a s s s p e c t , m / e 2 0 8 ( M - S O ) . A n a l . C a l c d . f o r C 1 5 H 1 2 0 2 S : C , 7 0 , 2 8 ; H , 4 - 7 2 ; S , 1 2 . 5 0 . P o u n d : C , 7 0 . 1 7 ; H , 4 - 7 8 ; S , 1 2 . 5 1 -I n t w o s i m i l a r e x p e r i m e n t s , 2 2 7 w a s r e a c t e d w i t h c o n c e n t r a t e d s u l f u r i c a c i d a t 0 ° a n d a t r o o m t e m p e r a t u r e . I n " b o t h c a s e s t h e s a m e i s o m e r i c s u l f i n a t e s w e r e o b t a i n e d . I n o n e e x p e r i m e n t , a b s o l u t e e t h a n o l w a s u s e d a s d i l u e n t . A s o l u t i o n o f 0 . 2 gm ( 0 . 0 0 0 7 8 m o l e ) of 2 2 7 d i s -s o l v e d i n c o n c e n t r a t e d s u l f u r i c a c i d ( 2 m l ) w a s c o o l e d t o - 7 ° C a n d d i l u t e d w i t h 1 5 m l o f a b s o l u t e e t h a n o l . T h e s l i g h t l y b r o w n s o l u t i o n w a s n e u t r a l i z e d w i t h s o d i u m b i c a r -b o n a t e . T h e m i x t u r e w a s t h e n f i l t e r e d , t h e y e l l o w f i l t r a t e e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e a n d t h e r e s i d u e d r i e d i n  v a c u o . I n f r a r e d s p e c t r a s h o w e d t h a t t h i s r e s i d u e w a s a m i x t u r e o f t h e s a m e s u l f i n a t e s . T h e c o n c e n t r a t i o n o f s u l f u r i c a c i d r e q u i r e d f o r t h e r e a c t i o n w a s i n v e s t i g a t e d . 2 , 4 - D i p h e n y l t h i e t e 1 , 1 - d i -206 oxide (£27) was soluble i n the concentrated but not the d i l u t e s u l f u r i c acid. Therefore a suspension was used. S t i r r i n g a suspension of (227) i n 70% (w/w) s u l f u r i c a c i d f o r 22 hours or heating the mixture at 50° f o r one hour re s u l t e d i n the recovery of the s t a r t i n g material. Again no r e a c t i o n was observed when 227 was dissolved i n a mix-ture containing organic solvent (acetone or benzene) and 60% or 70% aqueous s u l f u r i c acid. No re a c t i o n was observed when 2-phenylthiete 1,1-dioxide (272) (85) or 2-phenyl-4-methylthiete 1,1-dioxide (273) (85) was treated with concentrated s u l f u r i c acid. Heating a mixture of concentrated s u l f u r i c acid and 272 at 5 0 - 6 0 ° f o r ^ hour also r e s u l t e d i n recovery of un-changed s t a r t i n g material. 2 6 . Attempted hydroboration of 2,4-diphenylthiete 1,1-dioxide (227). A s o l u t i o n of 222 (0.5 gm, 0.002 mole) i n 25 ml of dried tetrahydrofuran was cooled i n an i c e bath, swept with dried nitrogen and treated with 0.012 mole of d i -borane i n 20 ml of dried tetrahydrofuran. The r e s u l t i n g mixture was swept with dried nitrogen, stoppered and then s t i r r e d overnight. The excess diborane was c a r e f u l l y des-troyed by adding 5 ml of water and 3 ml of chromic a c i d (prepared by d i s s o l v i n g 5-5 gm of sodium dichromate. i n a mixture of 4-2 ml concentrated s u l f u r i c acid and 24 ml of 207 water) was added i n . The r e a c t i o n mixture was refluxed on a steam bath f o r ^ hour and the solvent was removed by eva-poration. The residue was extracted with chloroform. The chloroform s o l u t i o n was washed with water, dried over an-hydrous sodium s u l f a t e and evaporated to give 0.4 gm of l i q u i d . A small amount of ether was added and the s o l i d (0.15 gm, 73%) that appeared was c o l l e c t e d by f i l t r a t i o n . The i r spectrum i n d i c a t e d that I t was unchanged 227• The ethereal f i l t r a t e was evaporated to an o i l y l i q u i d . T i c and i r data showed that i t was a crude mixture of several components, containing unreacted 227 and other substances. ¥ 0 desired product was detected. 27- Synthesis of 2,2-dichlorophenylacetyl chloride (282). 2,2-Dichlorophenylacetyl chloride was prepared according to a method adopted from the l i t e r a t u r e (117). A mixture of phosphorous pentachloride ( 5 6 7 gm, 2.72 mole) and phenylacetyl chloride (209 gm, I . 3 6 mole) was refluxed at 140° f o r 3.6 hours. The r e s u l t i n g mixture was d i s t i l l e d at 73 - 7 6 ° to give 311 gm of phosphorous t r i c h l o r i d e , a r e -action by-product. The r e s i d u a l l i q u i d was then d i s t i l l e d i n vacuo to y i e l d 262 gm (85%) of 282, bp 110-115° ( 8 mm) ( l i t . (117) 102-105° (6.5-7 mm); 90%). 28. Synthesis of E,N-diethyl-2,2-dichlorophenylacetamide (283). N,N-diethyl-2,2-dichlorophenylacetamide (283) 208 was synthesized according to a known method (117). To a s t i r r e d and ice-cooled s o l u t i o n of 2,2-dichlorophenyl-acetyl chloride (254 gm, 1.14 mole) i n one l i t e r of dried benzene, diethylamine (170 gm, 2.36 mole) was introduced dropwise from a pressure-equalizing addition funnel. A f t e r s t i r r i n g at i c e temperature overnight, the s o l u t i o n was f i l t e r e d and evaporated to give a yellow l i q u i d which was d i s t i l l e d i n vacuo to y i e l d 2 5 1 gm (85%) of 283, bp 120° (0.05 mm) ( l i t . (117) 142-144° (1-3 mm); 50%); i r (neat) 1 6 6 5 (carbonyl) cm - 1. 29. Synthesis of N,E-die t h y l - fi-dichloro-fi-styrylamine  (284). The method was adopted from the l i t e r a t u r e (117). A mixture of N,N-diethyl-2,2-dichlorophenylacetamide (283) (52 gm, 0.2 mole) and tri-n-butylphosphine ( 4 1 gm, 0.2 . mole), under a stream of dried nitrogen, was heated on a steam bath f o r one hour. The s l i g h t l y brown l i q u i d was d i s t i l l e d i n vacuo. The f r a c t i o n b o i l i n g at 103-106° ( 0.04 mm) was c o l l e c t e d . R e d i s t i l l a t i o n of t h i s crude pro-duct gave a c o l o r l e s s product (284) bp 81-83° (0.03 mm) ( l i t . (117) 90-92° (0.1 mm)); i r (neat) absence of car-bonyl absorption. 30. Synthesis of N,E"-diethylphenylethynylamine (285). The preparation of the t i t l e compound was c a r r i e d out according to a known procedure (179). Butyl 209 l i t h i u m (0.14 mole) In 82 ml of dried benzene was s t i r r e d under a stream of dried nitrogen and cooled to -10°. A so-l u t i o n of E,N-diethyl-o(,P-dichloro-/i-styrylamine (284) (30 gm, 0.125 mole) i n 18 ml of dried benzene was added drop-wise from a stoppered pressure-equalizing dropping funnel, the temperature of the reac t i n g mixture being maintained at -10". A f t er the addition had been completed, the reac t -ing mixture was placed at room temperature and s t i r r e d f o r one more hour. The brown turbid mixture was centrifuged, the supernatant was separated with the aid of more benzene and the s o l u t i o n was evaporated under reduced pressure to a brown l i q u i d . P u r i f i c a t i o n by vacuum d i s t i l l a t i o n y i e l d -ed 13-3 gm (72%) of pure 285, bp 78° (0.03 mm) ( l i t . (179) 7 5 ° (0.2 mm), 85%); i r (neat) 698, 765,1440,1580, 3050 (phenyl) and 2210 (acetylene) cm""1"; pmr (neat) 8 1 . 1 6 ( t , 6, CH 3, J = 7 Hz), 2.82 (q, 4, CH 2, J = 7 Hz) and 6.98-7-45 (m, 5, phenyl protons) ppm. 31. Synthesis of 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (231). This compound was prepared according to a proce-dure taken from the l i t e r a t u r e (200). A s o l u t i o n of benzyl-su l f o n y l chloride (0.57 gm, 0.003 mole) i n 10 ml of dried a c e t o n i t r i l e was added dropwise to a s t i r r e d and i c e - c o o l -ed mixture of triethylamine (0.39 gm, 0.003 mole), l , N - d i -e thylphenyle thynyl amine (0.51 gm, 0.003 mole) and 30 ml of 210 dried a c e t o n i t r i l e . The r e s u l t i n g s o l u t i o n was s t i r r e d i n the i c e bath f o r 18 hours, f i l t e r e d and evaporated to a residue which was redissolved i n tetrahydrofuran. The i n -soluble hydrochloride was removed by f i l t r a t i o n . The f i l -t rate was evaporated to give 0.55 gm (56%) of s o l i d pro-duct which was r e c r y s t a l l i z e d from ethyl acetate to y i e l d 0.4 gm of c r y s t a l l i n e 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (231), mp 142-144° ( l i t . (185) 143-144°); i r (KBr) 720, 780, 790, 1470, 1505, 3070 (phenyl), 1165, 1130 (sulfone), 1625 (enamine) cm"1; pmr (CDCl^)8 0.85 ( t , 6, CH 3, J = 7 Hz), 3.03 (q, 4, 0H 2, J = 7 Hz), 5-73 (s, 1, SCH), and 7-15-7.65 (m, 10, phenyl) ppm. 32. Attempted h y d r o l y s i s of 2,4-diphenyl-3-diethylamino-thiete 1,1-dioxide (231). A suspension of water-insoluble 2,4-diphenyl-3-diethylaminothiete 1,1-dioxide (.231.), 5 ml of water and 2.5 gm of s u l f o n i c acid r e s i n (BI0-RAD AG50W-X8) was s t i r -red f o r 3 hours. The r e s u l t i n g aqueous mixture was ex-tracted with chloroform. Evaporation of the chloroform so-l u t i o n r e s u l t e d i n quantitative recovery of the unchanged 231. 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