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Thietanes as potential MAO inhibitors and analgetics Haya, Katsuji 1973

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c! THIETANES AS POTENTIAL MAO INHIBITORS ni'X'Z) AND ANALGETICS BY KATSUJI HAYA B.S.P., University of B r i t i s h Columbia, 1967 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS 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 thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1973 In presenting th i s thesis i n p a r t i a l fulfilment of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t freely available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of P h a r m a c e u t i c a l S c i e n c e s The University of B r i t i s h Columbia Vancouver 8, Canada Date August 7, 1973 - i i i -ABSTRACT Thietane derivatives were synthesized as p o t e n t i a l monoamine oxidase (MAO) i n h i b i t o r s . These derivatives were useful i n studying the e l e c t r o n i c and s t e r i c requirements of the tranylcypromine type of MAO i n h i b i t o r s i n drug-receptor i n t e r a c t i o n s . The synthesis of these thietanes also gave further information on the physical and chemical properties of thietanes and t h e i r dioxides. The reaction of 3-chloro-l-phenylpropylene oxide-1,2 with, sodium sulfhydride gave 3--hydroxy-2-phenylthietane. In order to provide a basis for the chemical manipulations that can be performed without r i n g cleavage, a number of reactions were performed on t h i s thietane. The thietane could be oxidized to the corresponding thietane 1,1-dioxide with m-chloroperben-zoic acid, then converted to 2-phenylthiete 1,1-dioxide through the treatment of the sulfonate ester with triethylamine. Treatment of the thietane 1,1-dioxide with base gave benzyl methyl sulfone whereas treatment with concentrated acid gave benzyl methyl ketone. Preliminary experiments were performed, which indicated that the 3-hydroxyl could be replaced to give 3-amino-2-phenylthietane, the thietane analogue of tranylcypromine desired for MAO i n h i b i t i o n studies. During the course of the studies the synthesis of 2-benzyl-3-hydroxythietane was sought. This led to the synthesis of l-chloro-4-phenylbutylene oxide-1,2 which was reacted with sodium sulfhydride to give 3-hydroxy-2-- i v -phenylthiolane. This r e s u l t i s discussed i n r e l a t i o n to a proposed mechanism, whereby nuc l e o p h i l i c attack of the sulfhydride ion occurs at the most electron d e f i c i e n t carbon of the epoxide. As a possible route to 3-amino-2-phenoxythietane, several enamines prepared from phenoxyacetaldehyde were subjected to a cycloaddition reaction with methyl sulfene. A number of a c y c l i c s u b s t i t u t i o n products were obtained. These r e s u l t s are discussed i n r e l a t i o n to the mechanism of the cycloaddition reaction. Cycloaddition of l-dimethyl-3-phenylpropene with methyl sulfene gave 2-benzyl-3-dimethyl-aminothietane 1,1-dioxide, which was reduced with LiAlH^ to 2-benzyl-3-dimethylaminothietane. Exposure of 2-benzyl-3-dimethylaminothietane 1,1-dioxide to the amine oxide elimination procedure gave 2-benzylthiete 1,1-dioxide. A number of thietane derivatives were of s u f f i c i e n t s i m i l a r i t y to tranylcypromine to warrant i n v i t r o studies for MAO i n h i b i t i o n . A r a d i o i s o t o p i c assay method using r a t 14 l i v e r homogenates as the enzyme source and C-tyramme as the substrate was employed. 2-Benzyl-3-dimethylaminothietane was also tested for i n vivo MAO i n h i b i t i o n by a dopamine potentiation procedure. The r e s u l t s of these studies are discussed i n r e l a t i o n to structure a c t i v i t y r e l a t i o n s h i p s . The high i n v i t r o a c t i v i t y of 2-benzyl-3-dimethylamino-thietane was taken as evidence to support the hypothesis that the e l e c t r o n i c and s t e r i c properties i n the cyclopropyl - v -ri n g of tranylcypromine, i n the ground state, i s important i n the attachment of tranylcypromine to MAO. A number of thietane derivatives were prepared as p o t e n t i a l narcotic analgetics of the methadone type. These derivatives are conformationally more r e s t r i c t e d than methadone and thus may be useful i n el u c i d a t i n g the pharmacophoric conformation of methadone and related analgetics. Cycloaddition of an appropriate enamine and sulfene gave the synthesis of 3-dimethylamino-2-phenylthietane 1,1-dioxide, 3-dimethylamino-4-methyl-2-phenylthietane 1,1-dioxide,. 4-methyl-3-morpholino-2-phenylthietane 1,1-dioxide, and r - 2, c - 3, t - 4 - and r-2,t-3,c-4- 3-dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-dioxide. Treatment of the f i r s t three of these compounds i n the amine oxide elimination procedure gave 2-phenylthiete 1,1-dioxide and 4-methyl-2-phenylthiete 1,1-dioxide. Addition of HCN i n the presence of c a t a l y t i c amounts of KCN to the thietes gave 3-cyano-2-phenylthietane 1,1-dioxide and 3-cyano-4-methyl-2-phenylthietane 1,1-dioxide. Reduction of these n i t r i l e s with diborane gave the corresponding primary amines which were dimethylated with HC02H and HCHO to give trans-3-dimethylaminomethyl-2-phenylthietane 1,1-dioxide and t_-3-dimethylaminomethyl-c-4-methyl-r-2-phenylthietane 1,1-dioxide. The reaction of several a-alkylstyrenes with cyanosulfene gave the corresponding a c y c l i c s u b s t i t u t i o n products, which - v i -were r a t i o n a l i z e d on the basis of a 2-step cycloaddition mechanism of sulfenes to enamines. None of the compounds tested showed s i g n i f i c a n t analgetic a c t i v i t y i n an i n v i t r o t e s t based on the i n h i b i t i o n of the contractions of an e l e c t r i c a l l y stimulated guinea pig ileum. Included i n t h i s d i s s e r t a t i o n are discussions on the e l u c i d a t i o n of the configuration of the synthesized thietanes from t h e i r nmr spectra. The mass spectral c h a r a c t e r i s t i c s of thietanes and thietane 1,1-dioxides are discussed i n some d e t a i l . Signature of Supervisor - v i i -TABLE OF CONTENTS Page ABSTRACT i i i LIST OF TABLES x i LIST OF FIGURES x i i INTRODUCTION 1 1. Monoamine Oxidase Studies 2 A. Monoamine Oxidase 2 B. Monoamine Oxidase Inhibitors 9 C. Thietane Derivatives as Pot e n t i a l MAO Inhib i t o r s 17 2. Analgetic Studies 1 9 THIETANE CHEMISTRY . .. . 2 8 DISCUSSION OF THE CHEMISTRY 5 9 1. Synthesis of Thietanes for MAO Studies 60 Phenoxythietanes for MAO Studies 101 Benzylthietanes for MAO Studies 107 Synthesis of 3-Hydroxy-2-phenylthiolane (203) 119 2. Synthesis of Thietane 1,1-Dioxides for Analgetic Studies 124 3. Mass Spectra of Thietane 1,1-Dioxides 151 ANALYTICAL METHODS 162 EXPERIMENTAL 164 1. Synthesis of 3-Chloro-l-phenylpropylene Oxide-1,2 (116) 164 2. Synthesis of 3-Hydroxy-2-phenylthietane (117) 165 - v i i i -Page 3. Synthesis of 3-Hydroxy-2-phenylthietane 1,1-Dioxide (127) 166 4. Synthesis of 3-Dimethylamino-2-phenyl-thietane 1,1-Dioxide (144) 168 5. Synthesis of 2-Phenylthiete 1,1-Dioxide (142) from 3-Dimethylamino-2-phenylthietane 1,1-Dioxide (144) 169 6. Synthesis of 2-Phenylthiete 1,1-Dioxide (142) from 3-Hydroxy-2-phenylthietane 1,1-Dioxide (127) 171 7. Synthesis of 3-Ethoxy-2-phenylthieta.ne 1,1-Dioxide (133) 173 8. Synthesis of Benzyl Methyl Sulfone (130).. . 173 9. Attempted Synthesis of 3-Chloro-2-phenyl-thietane (145) 174 10. Synthesis of 3-Amino-2-phenylthietane 1,1-Dioxide (165) 175 11. Attempted Synthesis of 3-Amino-2-phenyl-thietane (5_) 176 12. Synthesis of 3-Phenoxy 1,2-propanediol (170) 179 13. Synthesis of 3-Phenoxyacetaldehyde (171) .. 180 14. Synthesis of Enamines from Phenoxy-acetaldehyde (171) 181 (a) l-Dimethylamino-2-phenoxyethene (172).. 181 (b) 2-Phenoxy-l-pyrrolidinoethene (173).... 182 15. Attempted Synthesis of 2-Phenoxy Substituted Thietane 1,1-Dioxides 182 (a) Attempted Synthesis of 3-Dimethylamino-2-phenoxythietane 1,1-Dioxide (174).. . . 182 (b) Attempted Synthesis of 2-Phenoxy-3-pyrrolidinothietane 1,1-Dioxide (175).. 184 16. Synthesis of l-Dimethylamino-3-phenyl-propene (183) 185 - i x -Page 17. Synthesis of 2-Benzyl-3-dimethylamino-thietane 1,1-Dioxide (184) 186 18. Synthesis of 2-Benzylthiete 1,1-Dioxide (186) 188 19. Synthesis of 2-Benzyl-3-dimethylaminothietane (8) 189 20. Synthesis of Ethyl-4-phenyl-3-buten 0ate (193) 191 21. Synthesis of Ethyl-4-phenyl-2-butenoate (195) 192 22. Synthesis of 4-Phenyl-3-buten-l-ol (200) ... 194 23. Synthesis' of 4-Phenyl-2-buten-l-ol (196) .. 195 24. Synthesis of l-Chloro-4-phenyl-3-butene (201) 196 25. Synthesis of l-Chloro-4-phenyl-2-butene (197) . 197 26. Synthesis of l-Chloro-4-phenylbutylene Oxide-3,4 (202) 197 27. Synthesis of 3-Hydroxy-2-phenylthiolane (203) 199 28. Synthesis of 3-Hydroxy-2-phenylthiolane 1,1-Dioxide (205) 199 29. Synthesis of 2-Phenyl-2-thiolene 1,1-Dioxide (207) 200 30. Synthesis of 1-Morpholinopropene (222) .... 201 31. Synthesis of a-Morpholinostyrene (239) and a-Pyrrolidinostyrene (240) 202 32. Synthesis of l-Dimethylamino-2,2-diphenyl-ethene (210) 203 33. Attempted C y c l i z a t i o n of 1-Dimethylamino-2,2-diphenylethene (210) and some Substituted Sulfonyl Chlorides 204 34. Synthesis of 3-Dimethylamino-4-methyl-2-phenylthietane 1,1-Dioxide (226) 205 35. Synthesis of 4-Methyl-3-rr.orpholino-2-phenylthietane 1,1-Dioxide (227) 206 36. Synthesis of 4-Methyl-2-phenylthiete 1,1-Dioxide (229) 208 - x -Page 37. Synthesis of 3-Cyano-2-phenylthietane 1,1-Dioxide (217) 208 38. Synthesis of 3~Cyano-4-methyl-2-phenyl-thietane 1,1-Dioxide (230) 210 39. Synthesis of 3-Aminomethyl-2-phenylthietane 1,1-Dioxide (218) 210 40. Synthesis of 3-Aminomethyl-4-methyl-2-phenylthietane 1,1-Dioxide (231) 212 41. Synthesis of 3-Dimethylaminomethyl-2-phenylthietane 1,1-Dioxide (214) 213 42. Synthesis of 3-Dimethylaminomethyl-4-methyl-2-phenylthietane 1,1-Dioxide (215) 214 43. Attempted Synthesis of 4-Cyano-3-dimethylamino-2-phenylthietane 1,1-Dioxide (245). I s o l a t i o n of Cyanomethyl 2-Dimethylamino-l-phenylethenyl Sulfone (246) 215 44. Attempted Synthesis of 4-Cyano-3-phenyl Substituted Thietane 1,1-Dioxides. I s o l a t i o n of Benzoylmethyl Cyanomethyl Sulfone (244) 217 45. Synthesis of 1,3-Bis(dimethyland no)propene (76) 218 46. Synthesis of 3-Dimethylamino-4-dimethyl-amincmethyl-2-phenylthietane 1,1-Dioxide (80) 218 47. Attempted Synthesis of 4-Dimethylaminomethyl-2-phenylthiete 1,1-Dioxide (255) .. 220 (a) Demethylation of the Quaternary Ammonium Salt 220 (b) Selective Hoffman Elimination 221 (c) Selective Dimethylation 222 PHARMACOLOGICAL TESTING 223 1. Monoamine Oxidase I n h i b i t i o n Studies 223 2. Analgetic Studies 232 BIBLIOGRAPHY 237 - x i -LIST OF TABLES Table Page 1. Chemical S h i f t s i n the NMR Spectra of the Isomers of 3-Dimethylamino-4-dimethylamino-methyl-2-phenylthietane 1,1-Dioxide 146 2. Results i n In V i t r o Studies for MAO I n h i b i t i o n 228 - x i i -LIST OF FIGURES Figure Page 1. Postulated Interaction of Substrates and Drugs with MAO 16 2. Proposed Preferred Conformation of Methadone 21 3. Possible Configurations of 3-Dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-Dioxide 146 4. Thietanes Tested for MAO I n h i b i t i o n 224 5. I n h i b i t i o n of MAO i n Rat Liver Homogenates by Tranylcypromine and Thietane Derivatives 229 6. Thietanes Tested for Narcotic Analgetic A c t i v i t y 233 - x i i i -ACKNOWLEDGEMENTS The author i s indebted to Dr. Frank S. Abbott for his guidance and encouragement which has made t h i s work possible. F i n a n c i a l support from the Medical Research Council and the University of B r i t i s h Columbia i s g r a t e f u l l y acknowledged. - x i v -DEDICATION To my wife, Jane - 1 -INTRODUCTION The work which i s described i n t h i s thesis was undertaken as part of a project to explore the p o t e n t i a l pharmacological a c t i v i t y of thietane d e r i v a t i v e s . The der i v a t i v e s were designed to serve as pharmacological t o o l s i n expanding the knowledge of drug-receptor i n t e r a c t i o n s . The chemistry of these four membered c y c l i c systems containing a su l f u r atom i s r e l a t i v e l y a new area of study. Thus the synthesis of these compounds would also provide more information on the physical and chemical properties of thietane d e r i v a t i v e s . In c e r t a i n cases i t was deemed appropriate and b e n e f i c i a l to explore the i n t r i c a c i e s of thietane syntheses and the chemical manipulations of compounds containing the thietane system to provide a broader base f o r the preparation of other thietane derivatives of p o t e n t i a l pharmacological i n t e r e s t . The discussion which follows w i l l be divided into two major sections. F i r s t , the considerations which led to thietane derivatives used i n the study of drug-receptor in t e r a c t i o n s between monoamine oxidase (MAO) and the cyclopropylamine class of MAO i n h i b i t o r s . Second, the considerations which led to the thietane derivatives used i n the study of the - 2 -drug-receptor interactions related to the diphenylpropylamine class of synthetic analgetics. 1. Monoamine Oxidase Studies A. Properties of monoamine oxidase The enzyme, MAO, (monoamine: O2 oxidoreductase (deaminat-ing), E.C. 1.4.3.4) belongs to a class of amine oxidases which are characterized by t h e i r a b i l i t y to o x i d a t i v e l y deaminate amines with the stoichiometric formation of one molecule each of aldehyde, ammonia, and hydrogen peroxide. RCH2NH2 + 0 2 + H 20 — RCHO + NH^ +  E 2 ° 2 MAO has recently been reviewed (1,2). One of these reviews i s very comprehensive, containing sections written by most of the leading workers i n the biochemistry and pharmacology of MAO (1). Published i n early 1972, i t covers most of the work published to date. A b r i e f summary of the current knowledge of MAO w i l l be presented with a greater emphasis on the discoveries that have occurred since the p u b l i c a t i o n of the review a r t i c l e . MAO has been found i n a l l classes of vertebrates, as well as i n some invertebrates and plants. MAO i s found i n many d i f f e r e n t tissues but p a r t i c u l a r l y i n glands, p l a i n muscle and nervous t i s s u e . In man the parotid and submaxillary glands seem to be the r i c h e s t sources. In a l l vertebrates - 3 -high a c t i v i t y i s always found i n the l i v e r , brain and kidney. MAO i s f i r m l y bound to the outer membrane of mitochondria. I t i s generally accepted that MAO i s synthesized on the cytoribosomes and transported to the mitochondria and i s incorporated only at s p e c i f i c s i t e s within the supramolecular f a b r i c of the mitochondria. There appears to be a precursor-pool r e l a t i o n s h i p between MAO i n the microsomes and that l o c a l i z e d i n the mitochondria. MAO has not yet been i s o l a t e d as a pure c r y s t a l l i n e product. The molecular weight has been estimated to be approximately 300,000 or 150,000 by gel f i l t r a t i o n or u l t r a -c e n t r i f ugation r e s p e c t i v e l y . I t i s possible that dimerization of the enzyme occurs upon gel f i l t r a t i o n . By equating moles of f l a v i n to grams of enzyme a molecular weight more consistent with 150,000 mu i s indicated. The pH optimum for a c t i v i t y i s usually about 7.4, but can fluctuate depending on the experimental conditions, the buffer system used, substrate tested, and the temperature. The substrates for MAO are primary amines, long chain diamines and secondary or t e r t i a r y amines where the s u b s t i -tuents on the nitrogen are methyl(s). A hydrogen on the carbon a to the amine function i s required. The rate of oxidation of secondary amines i s very high sometimes even higher than that of primary amines, but the t e r t i a r y amines are oxidized slowly. The substrates of p a r t i c u l a r importance are the so-called biogenic amines and includes tyramine, - 4 -serotonin, tryptamine, norepinephrine, epinephrine and dopamine. There i s an increasing i n d i c a t i o n that MAO i s a series of isoenzymes or a group of homologous enzymes. The m u l t i p l i c i t y of MAO i s indicated by the differences i n pH a c t i v i t y curves, thermostability, substrate s p e c i f i c i t y , and s u s c e p t i b i l i t y to i n h i b i t o r s i n v i t r o and i n vivo by MAO i s o l a t e d from d i f f e r e n t tissues or from d i f f e r e n t species. M u l t i p l i c i t y has also been indicated for MAO obtained from the same organ, as shown by the appearance of several bands upon electrophoresis of p u r i f i e d solutions of MAO from rat and pig l i v e r . A number of explanations have been proposed for the m u l t i p l i c i t y of MAO. Some of these explanations state that the m u l t i p l i c i t y of MAO could be a r t i f a c t s of the p u r i f i c a t i o n procedures. For example, since MAO i s f i r m l y bound to the outer membrane of mitochondria, p u r i f i c a t i o n usually involves d r a s t i c techniques, which i n i t s e l f could lead to s t r u c t u r a l changes i n the enzyme. S o l u b i l i z e r s have to be used, which cannot be completely removed l a t e r . The extraction of d i f f e r e n t amounts of phospholipids can account for d i f f e r e n t m o b i l i t i e s upon electrophoresis. Recently i t has been shown that differences i n thermo-s t a b i l i t y does not necessarily mean that d i f f e r e n t forms of MAO have been i s o l a t e d (3). Because of the differences i n net charge, MAO may be bound d i f f e r e n t l y to the outer membrane in mitochondria of d i f f e r e n t c e l l s and such a difference i n - 5 -binding may account for the observed v a r i a t i o n s i n c a t a l y t i c a c t i v i t y . The m u l t i p l i c i t y of MAO could also be the r e s u l t of the i s o l a t i o n of various conformers of MAO. Each amine substrate, i n in t e r a c t i n g with the enzyme can cause a small, but not r e a d i l y r e v e r s i b l e change i n conformation, with a corresponding a l t e r a t i o n of s p e c i f i c a c t i v i t y , but not a f f i n i t y of the substrate to the enzyme. This type of i n t e r -action could occur either during the f o l d i n g of the poly-peptide chain or perhaps during the c a t a l y t i c procedure i t s e l f . Using immunological procedures i t has been shown that the various separable forms of beef l i v e r MAO are a n t i g e n i c a l l y i d e n t i c a l . The bulk (80%) of beef brain MAO i s a n t i g e n i c a l l y i d e n t i c a l to l i v e r MAO. Recently the remaining 20% of brain MAO was i s o l a t e d and found to be a n t i g e n i c a l l y unrelated to l i v e r MAO and found to have d i f f e r e n t substrate and i n h i b i t o r s p e c i f i c i t i e s (4) . These immunological studies could support the postulate that the various separable forms of MAO are conformational isomers. Some recent reports indicate that m u l t i p l i c i t y of MAO i s a r e a l i t y . In vivo studies with human brain (5), r a t and human l i v e r (6), and various tissues from rats and mice (7) were performed. The humans were pretreated with MAO i n h i b i t o r s and the various tissues were i s o l a t e d shortly a f t e r death. The animals were s a c r i f i c e d a f t e r s u f f i c i e n t pretreatment with MAO i n h i b i t o r s . The various multiple forms i s o l a t e d from these sources were not i n h i b i t e d to the same - 6 -extent by any of the i n h i b i t o r s used. This might be explained on the basis of multiple MAO enzymes or by the differences i n the d i s t r i b u t i o n of the i n h i b i t o r s to the various tissues. Strong evidence for the m u l t i p l i c i t y of MAO was obtained by a series of d i s s o c i a t i o n and reassociation experiments with r a t l i v e r MAO (8). P u r i f i e d r a t l i v e r MAO can be separated into f i v e bands by polyacrylamide gel electrophoresis. I s o l a t i o n and storage of the i n d i v i d u a l bands at 4° resulted i n less than 15% loss of enzyme a c t i v i t y and they d i d not interconvert or change into the other forms ( i . e . they remained e l e c t r o p h o r e t i c a l l y pure). This suggests the presence of a free energy b a r r i e r between the various forms, and could r e s u l t from a r e d i s t r i b u t i o n of solvent molecules, s t r u c t u r a l d i s t o r t i o n s or hydrogen bond breakages. The molecular weights of a l l the bands were nearly equal, thus could not be the r e s u l t of polymerized or dimerized enzyme. Disso c i a t i o n of each band followed by reassociation yielded with the exception of one band, the o r i g i n a l electrophoretic pattern. This suggests that m u l t i p l i c i t y of MAO could occur as differences i n ligand binding or as the r e s u l t of conforma-t i o n a l isomers. Treatment of highly p u r i f i e d preparations of MAO (from r a t and beef l i v e r and beef brain) with o x i d i z i n g agents (11^ 02/ Cu under aerobic conditions, and oxidized o l e i c , and ergosterol peroxide) brought about a decrease i n the rate of - 7 -e n z y m i c d e a m i n a t i o n o f m o n oamines. A t t h e same t i m e t h i s t r e a t m e n t e n g e n d e r e d a q u a l i t a t i v e l y new p r o p e r t y o f d e a m i n a t i n g d i a m i n e s , h i s t a m i n e a n d some o t h e r n i t r o g e n compounds, w h i c h a r e n o t n o r m a l l y s u b s t r a t e s o f MAO, b u t o f d i a m i n e o x i d a s e (DAO). T h i s c h a n g e was a c c o m p a n i e d b y a d e c r e a s e i n t h e f r e e s u l f h y d r y l c o n t e n t o f MAO. T r e a t m e n t o f DAO o r o x i d i z e d MAO w i t h r e d u c i n g a g e n t s (H^S, NaBH^, s o d i u m a r s e n a t e ) p a r t i a l l y r e s t o r e d t h e s u l f h y d r y l c o n t e n t a n d a t t h e same t i m e t h e a b i l i t y t o d e a m i n a t e monoamines ( 9 ) . S e v e n s u l f h y d r y l g r o u p s p e r m o l e c u l e o f f l a v i n a d e n i n e d i n u c l e o t i d e (FAD) w e r e i n d i c a t e d b y t i t r a t i o n w i t h m e t h y l m e r c u r i c c h l o r i d e . A f t e r p r e t r e a t m e n t o f MAO w i t h MAO i n h i b i t o r s o n l y f i v e s u l f h y d r y l g r o u p s p e r m o l e c u l e o f FAD r e a c t e d w i t h t h e s u l f h y d r y l r e a g e n t . T h e s e s u l f h y d r y l g r o u p s w e r e t a k e n t o be p r e d o m i n a n t l y due t o c y s t e i n e r e s i d u e s . I t was t h e n p r o p o s e d t h a t t h e l o w e s t s u b u n i t o f MAO c o n t a i n e d a h y d r o p h o b i c a c t i v e s i t e c o n t a i n i n g a c o v a l e n t l y b o u n d m o l e c u l e o f FAD. The a c t i v e s i t e c o n t a i n s two c y s t e i n e r e s i d u e s , w h i c h a r e p r o t e c t e d f r o m r e a c t i n g w i t h t h e s u l f -h y d r y l r e a g e n t s when p r e t r e a t e d w i t h MAO i n h i b i t o r s . The o t h e r f i v e c y s t e i n e r e s i d u e s a r e p r e s u m a b l y o n t h e s u r f a c e o f t h e enzyme a n d may be r e q u i r e d f o r c o n f o r m a t i o n a l s t a b i l i t y . I t h a s b e e n s u g g e s t e d f o r some t i m e t h a t c o v a l e n t l y b o u n d FAD i s t h e p r o s t h e t i c g r o u p r e q u i r e d by MAO. R e c e n t l y i t h a s b e e n shown t h a t FAD i s c o v a l e n t l y b o u n d t o t h e enzyme t h r o u g h t h e 8ct-CHU g r o u p o f r i b o f l a v i n (10) , t h r o u g h a s u l f i d e - 8 -bond to cysteine (11). A pure pentapeptide f l a v i n was is o l a t e d from beef l i v e r MAO and i d e n t i f i e d as ser-gly-gly-c y s ( - t y r ) - f l a v i n (12,13). In a d i f f e r e n t laboratory 8a-(S - c y s t e i n y l ) r i b o f l a v i n (1) was synthesized and found to have an esr and fluorescence spectra i d e n t i c a l to a sample of 1 obtained from the natural source (14). COOH 0 1 A previously proposed mechanism for the deamination of amines by MAO involving FAD would now seem correct. The reaction can be divided into an anaerobic and an aerobic phase. Anaerobic phase E-FAD + RCH2NH2 + H 20 — E-FADH2 + NH^ + RCHO Aerobic phase E-FADH2 + 0 2 E-FAD + ^2°2 The exact p h y s i o l o g i c a l r o l e of MAO i s unknown, however, there are several functions of MAO that appear to be important. 9 -One function may be to i n a c t i v a t e t o x i c amines produced endogenously or ingested. MAO may play a major r o l e i n the metabolism of transmitter amines that d i f f u s e from the neuronal amine storage v e s i c l e s into the neuroplasm. MAO may also be important i n maintaining a steady-state l e v e l of biogenic amines i n the brain and thus maintaining a healthy mental state. A low l e v e l of biogenic amines, e s p e c i a l l y 5-hydroxytryptamine has been associated with mental depression. B. Monoamine Oxidase I n h i b i t o r s MAO i n h i b i t o r s have been extensively reviewed (15-18). MAO i n h i b i t o r s are a group of compounds with a wide v a r i e t y of chemical structure, but a l l possess the a b i l i t y to i n h i b i t the oxidative deamination of some biogenic amines by MAO. In vitro,MAO i n h i b i t o r s and the substrates of MAO generally compete for the enzyme as long as the i n h i b i t i o n of the enzyme i s not complete (19). Once t h i s i n h i b i t i o n has been established, i t becomes noncompetitive and almost i r r e v e r s i b l e . Tranylcypromine seems to be an exception because i t may induce competitive or noncompetitive i n h i b i t i o n depending on the substrate. The i r r e v e r s i b i l i t y of these compounds i s r e f l e c t e d i n t h e i r in_ vivo action. They are long l a s t i n g and t h e i r e f f e c t s are noticeable even a f t e r the drug has disappeared from the body. The e f f e c t s of the i r r e v e r s i b l e i n h i b i t i o n are r e l i e v e d only by the synthesis of new enzyme. A l l types of MAO i n h i b i t i o n cause some t y p i c a l e f f e c t s i n vivo. There i s an increase i n the endogenous and exogenous monoamines, development of antagonism toward monoamine releasers (e.g. reserpine), and a change i n the excretion pattern of monoamines and t h e i r metabolites. There i s no absolute p a r a l l e l i s m between MAO i n h i b i t i o n and monoamine increase. The enzyme has to be i n h i b i t e d at l e a s t by 85% before the monoamine content of the brain and possibly of other tissues r i s e s . Furthermore, the monoamine accumulation i s of shorter duration than the MAO i n h i b i t i o n . Other e f f e c t s noted include CNS stimulation ( f i r s t a depressive action followed by stimulation), sympatholytic action, changes i n the EEG a l e r t pattern, production of catalepsy, s e l e c t i v e blockade of the conditioned escape response i n r a t s , possible blockage or depression of ganglionic transmission, and a cardiostimulatory action s i m i l a r to that of ephedrine has been indicated (15). Some of these actions may not be the r e s u l t of MAO i n h i b i t i o n . The i n t e n s i t y , onset and duration of action depend on the species, t i s s u e , amine, mode of administration and chemistry of the drug. MAO i n h i b i t o r s are used as antidepressants, hypotensive agents and i n the treatment of angina p e c t o r i s . A casual r e l a t i o n between the pharmacological e f f e c t s and MAO i n h i b i -t i o n has not been f u l l y established but i s l i k e l y for the - 11 -following reasons. Only hydrazine derivatives exerting marked MAO i n h i b i t i o n i n vivo have a psychostimulant, hypotensive, and anginal action; chemically related hydrazines which do not influence the enzyme are generally devoid of these e f f e c t s . Long l a s t i n g MAO i n h i b i t o r s not belonging to the hydrazine class also cause psychostimulation and hypo-tension. In general, the MAO i n h i b i t i o n and the pharmacologic action have a s i m i l a r time course. Both appear only slowly a f t e r repeated therapeutic doses of MAO i n h i b i t o r s , but p e r s i s t for some time a f t e r the discontinuation of the drugs. Structure a c t i v i t y r e l a t i o n s h i p s (SAR) A complete l i s t of the MAO i n h i b i t o r s i s probably greater for MAO, than the i n h i b i t o r s for any other enzyme. Since t h i s project i s concerned with the drug-receptor in t e r a c t i o n s of the cyclopropylamine class of MAO i n h i b i t o r s , namely tranylcypromine (2), t h i s discussion w i l l be l i m i t e d to the SAR of cyclopropylamines. 3 2 - 12 -(a) Stereoisomerism No generalization can be drawn regarding the e f f e c t of geometrical or o p t i c a l isomerism upon MAO i n h i b i t o r y a c t i v i t y . (+)-trans-2 i s 2 or 3 times more potent than (+)-cis-2. With 2-phenoxycyclopropylamine the c i s isomer i s 2.5 times more potent than the trans isomer with r a t l i v e r MAO. With the 2-phenylthio- or the 2-benzylcyclopropylamine the trans isomer i s the more ac t i v e . (+)-trans-2 i s about 4 times more active than the (-)-trans-2. There were no s t r i k i n g differences i n the a c t i v i t i e s of (+) or (-) isomers of trans-2-cyclohexyloxyeyelopropylamine. (b) Size of the a l i c y c l i c r i n g A c t i v i t y decreases sharply when the cyclopropyl r i n g i s enlarged. Cis-2-phenylcyclobutylamine i s 1,000 times less active than 2. Trans-2-phenylcyclobutylamine, or larger r i n g systems are v i r t u a l l y i n a c t i v e , with the exception of cis-2-phenylcyclohexylamine. (c) Substituents on the benzene r i n g In general, the substituents on the benzene r i n g of 2_ have l i t t l e e f f e c t on, or decrease MAO i n h i b i t o r y a c t i v i t y . Para-substituted derivatives are usually more e f f e c t i v e than the corresponding meta or ortho de r i v a t i v e s which are approximately equipotent. A l l the para-substituted derivatives r e t a i n at l e a s t 40% of the a c t i v i t y of 2. Bulky substituents - 13 -i n the ortho or meta p o s i t i o n of the benzene r i n g may prevent t h i s portion of the molecule from l y i n g f l a t on the enzyme surface and thus prevent optimal i n t e r a c t i o n between the enzyme and the i n h i b i t o r . (d) Substitutions on the cyclopropyl r i n g Replacement of the phenyl group by other r i n g systems or by a l i p h a t i c groups reduces or v i r t u a l l y abolishes a c t i v i t y . Unsubstituted cyclopropylamine i s i n a c t i v e . There are some exceptions to t h i s generality. Separation of the benzene r i n g of 2_ from the cyclopropane r i n g by an 0, S, or group affords compounds with s i g n i f i c a n t a c t i v i t y . Cis-2-phenoxy- and trans-2-phenylthio-cyclopropylamine are as active as 2_. The 2-benzyl d e r i v a t i v e has 1/10 the a c t i v i t y of 2_. Separation of the benzene r i n g by groups larger than methylene r e s u l t s i n i n a c t i v e compounds. Replace-ment of the benzene group with cyclohexyloxy (20) or imidazole (21) r e s u l t s i n compounds with s i g n i f i c a n t a c t i v i t y . Substitution of the 1-position of 2_ with a methyl group has l i t t l e e f f e c t on the MAO a c t i v i t y . Any other changes or substitutions on 2, markedly decrease the a c t i v i t y . (e) N-substitution Mono- or di-methylation of the amino group of 2_ decreases MAO i n h i b i t o r y a c t i v i t y only s l i g h t l y . A l k y l a t i o n or a r y l -- 14 -a l k y l a t i o n by larger groups r e s u l t s i n considerable loss of a c t i v i t y . Acylation decreases a c t i v i t y unless the compound can be metabolized to 2_ in_ vivo. Separation of the amino group from the cyclopropane r i n g by a methylene group r e s u l t s i n the complete loss of a c t i v i t y . Drug receptor interactions A l l the speculations concerning the d e t a i l e d mode of action of 2-substituted cyclopropylamines must be tempered by the uncertainty whether these compounds a c t u a l l y block the active s i t e ( s ) of MAO enzymes by excellent f i t and thereby cause t h e i r long l a s t i n g i n h i b i t i o n , or whether they complex with the enzyme at a secondary s i t e and thereby disturb the conformation of the primary active s i t e ( s ) at which the most e f f e c t i v e substrates are thought to f i t . At present, most of the evidence points to a probable d i r e c t interference by 2-phenylcyclopropylamines with various substrates at the active s i t e , regardless of t h e i r mechanism of action (15,17). Presumably the substrates are attached to the active s i t e of the enzyme through the amino group of these compounds. Binding might r e s u l t from the e l e c t r o s t a t i c i n t e r a c t i o n between the p o s i t i v e l y charged ammonium form of the amine and a negative group, probably a carboxylate ion, on the enzyme (18). Belleau and Moran suggested binding of the free amino group to an e l e c t r o p h i l i c center of the enzyme may occur through the unshared electrons on the nitrogen (22). Recently a study r e l a t i n g pH to pK m (K Michaelis constant) indicated that the substrates of MAO i n t e r a c t with the enzyme i n the nonprotonated form (23). From a series of k i n e t i c studies using various deuter-ated substrates, Belleau and Moran have shown that the rate c o n t r o l l i n g step i n the MAO catalyzed oxidation of amines involves breaking of an a-carbon hydrogen bond and that the two hydrogens on the a-carbon are not equivalent for the enzyme. They proposed a multipoint attachment between the substrate and the enzyme (Fig. 1). The a,3-carbon-carbon bond of the substrate acquired double bond character i n the process with the a- and the g-carbon atoms approaching the t r i g o n a l state. In the process the TT electrons generated between the a,3-carbon-carbon bond of the substrate may contribute greatly to the binding energy i n the t r a n s i t i o n state. Consequently they proposed that the e l e c t r o n i c and s t e r i c properties of the cyclopropane plays a dominant r o l e i n the attachment of tranylcypromine (2) to MAO. The high a f f i n i t y of 2_ for the enzyme may be due to the f a c t that i n the ground state t h i s amine resembles, e l e c t r o n i c a l l y and s t e r i c a l l y , the postulated t r a n s i t i o n state of the substrate. A s i m i l a r type of binding has been postulated to explain the MAO i n h i b i t o r y a c t i v i t y of c e r t a i n mesoionic compounds as 4_ (24) . After the i n i t i a l combination of the i n h i b i t o r s with MAO, the long acting i n h i b i t o r s conceivably could undergo gure 1: P o s t u l a t e d i n t e r a c t i o n of s u b s t r a t e s and drugs w i t h MAO. P o s t u l a t e d t r a n s i t i o n s t a t e f o r s u b s t r a t e o x i d a t i o n P o s t u l a t e d i n t e r a c t i o n of 2 w i t h MAO P o s t u l a t e d i n t e r a c t i o n of 5 w i t h MAO - 17 -further reactions r e s u l t i n g i n i r r e v e r s i b l e chemical changes near the active s i t e . This postulate i s supported by the fa c t that 2-phenylcyclobutylamine (3_) has 1/1, 000 the a c t i v i t y of 2_ i n v i t r o studies. Presumably the decrease i n a c t i v i t y i s due to the loss i n electron density i n going from the cyclopropyl to the cyclobutyl r i n g . NH 2 Ar 0 3 4 C. Thietane Derivatives Considered for MAO Studies 5 6 - 18 -N.(CH_) S 7 8 I t was f e l t that the synthesis of 3-amino-2-phenyl-thietane (5_) , by v i r t u e of the s u l f u r atom would r e t a i n some of the electron density l o s t i n going from the cyclopropyl to the cyclobutyl r i n g while maintaining s t e r i c properties more l i k e the cyclobutyl r i n g . The thietane d e r i v a t i v e , 5_ can i n t e r a c t i n a s i m i l a r manner with the enzyme as 2_ (Fig. 1). In t h i s case the s u l f u r atom i s shown to increase the electron density of the whole r i n g system, however, an equally possible mechanism i s where the s u l f u r atom i s d i r e c t l y involved i n binding through i t s lone p a i r of electrons. Regardless of which mode of i n t e r a c t i o n r e s u l t s , 5_ would s t i l l serve as a pharmacological t o o l to study the v a l i d i t y of Belleau and Moran 1s hypothesis. Synthetic d i f f i c u l t i e s precluded the synthesis of 5_. From the consideration of the SAR of cyclopropylamines the synthesis of 3-amino-2-phenoxy-thietane (6) and 3-amino-2-benzylthietane (1) were attempted. These studies eventually led to the synthesis and b i o l o g i c a l t e s t i n g of 3-dimethylamino-2-phenylthietane (8_) as a p o t e n t i a l MAO i n h i b i t o r . - 19 -2. Analgetic Studies Narcotic analgetics have been systematically investigated from a three-dimensional point of view i n an e f f o r t to elucidate the optimal s t r u c t u r a l requirements for analgetic a c t i v i t y . Methadone (6-dimethylamino-4,4-diphenyl-3-heptanone, 9_) , the prototype for the diphenylpropylamine class 2 of analgetics, was the f i r s t synthetic analgetic to be studied from an absolute configurational approach. The diphenylpropylamine class of analgetics has been reviewed (25,26). Methadone contains only one asymmetric center (*) and was r e a d i l y resolved into i t s enantiomers. I t was found that (-)-methadone was approximately twice as active as the racemate and that (+)-methadone was v i r t u a l l y i n a c t i v e . Subsequent investigations indicated that i n a l l the highly active synthetic analgetics the active enantiomer - 20 -was related to the absolute configuration of R-(-)-alanine. On the basis of these early stereochemical studies and s t r u c t u r a l features common to analgetics, Beckett and Casy proposed a "three point" association between the drug molecule and the receptor (27). They pictured the receptor s i t e as a r i g i d e n t i t y containing: (a) a f l a t surface which allows for binding with the aromatic r i n g , (b) an anionic s i t e which associates with the p o s i t i v e l y charged basic center of the drug molecule, (c) a cavit y suitably oriented to accommodate a projecting hydrophobic group. I t was considered that association of drug donor groups with the s i t e s (a) and (b) represented the primary s i t e of analgetic action, whereas correct alignment of a projecting hydrocarbon residue with the cavity i n one of the enantiomers enhances the drug-receptor contact and consequently the analgetic a c t i v i t y . In the opposite enantiomer the projecting group would impair the drug-receptor contact. An attempt has been made to show how a l l classes of narcotic analgetics could acquire a conformation compli-mentary to the proposed receptor (28). In the case of methadone, i t was suggested that a mutual i n t e r a c t i o n between the unprotonated amino-nitrogen and the carbonyl-carbon atom a s s i s t s i n the formation of a favorable conformation (Fig. 2). By such an i n t e r a c t i o n the f l e x i b l e methadone molecule could approximate the desired conformation (similar to the conformation of morphine) and thus f a c i l i t a t e i t s association with the receptor. Figure 2: Proposed Preferred Conformation of Methadone Subsequent studies led to active compounds whose a c t i v i t i e s could net be e a s i l y r a t i o n a l i z e d by the hypothesis of Beckett and Casy. The f i r s t of these was the observation by Portoghese, that with the a n i l i d e 10, the active \ / r- C H 2CH 2 CC 2H 5 10 enantiomer was co n f i g u r a t i o n a l l y related to S-(+)-alanine (29). It was suggested that d i f f e r e n t s i t e s on the same receptor have a p o t e n t i a l for binding some common features of s t r u c t u r a l l y s i m i l a r analgetics or i f more than one species of receptor having d i s s i m i l a r s t r u c t u r a l requirements are i n t e r a c t i n g with the analgetic molecule, then the - 22 -observed configurational s e l e c t i v i t y w i l l represent an average value rather than a single type of analgetic-receptor i n t e r a c t i o n (30). Such differences i n the mode of binding of o p t i c a l l y active narcotic analgetics i n cer t a i n cases may involve an apparent inversion i n the configurational s e l e c t i v i t y of the receptor. The anionic s i t e was envisaged as a p i v o t a l point around which various modes of binding may occur. OR CH3CH2CH- C CH 2CHN(CH 3) 2 CH. 11 R = H 12 R = COCH. Portoghese has elaborated on thi s concept from the follow-ing observations (31). In methadol (11) the more active enantiomer has the (3S) configuration, and the configuration of the 6-methyl group plays only a minor r o l e i n determin-ing the potency of 11. Acetylation of the alcohol to give 12 r e s u l t s i n a change from (6S) to (6R) receptor stereo-s p e c i f i c i t y , with the configuration at c-3 playing only a - 23 -minor r o l e . The more active enantiomer of 1_2 i s related to the active enantiomer of methadone (9), whereas the more active enantiomer of 1_1 i s rela t e d to the inactive enantiomer of 9_. This phenomenon was explained by assuming that there are several donor and acceptor hydrogen bonding dipoles situated i n d i f f e r e n t locations on the receptor. In the case of methadone and the methadol acetates, i n t e r a c t i o n of the carbonyl groups of these molecules with donor hydrogen bonding dipoles gives r i s e to a mode of binding such that the configuration at C-6 i s important (the (R) configuration allowing a more e f f e c t i v e i n t e r a c t i o n with the receptor than the (S)). With the methadols i n t e r a c t i o n of the alcohol group with an acceptor dipole on the receptor leads to a binding mode i n which the C-3 asymmetric center i s oriented i n a receptor environment that i s s t e r i c a l l y demanding, the enantiomers with the (S) configuration being more r e a d i l y accommodated than the two with the (R) configuration. In addition to the nature of i t s hydrogen bonding group, the conformation of an analgetic molecule would determine with which p a r t i c u l a r receptor dipole hydrogen bonding occurred. Thus, methadone and the methadol acetates are not necessarily reacting with the same donor dipole. Similar studies with 4-phenylpiperidine analgetics have been summarized and support the p o s s i b i l i t y of d i f f e r e n t modes of analgetic-receptor i n t e r a c t i o n (32). Recent studies have indicated that the configuration about c h i r a l • - 24 -centers w i l l a f f e c t the mode of i n t e r a c t i o n (33-35). I t was also stated that configuration and conformation are inseparable features i n analyzing SAR of analgetics. The concept that there are several distinguishable independent categories of receptors which induce analgesia has been used to explain agonist and antagonist actions of analgetic drugs (36) . The term "receptor dualism" has been coined for t h i s hypothesis. The primary d i f f i c u l t y i n attempting to deduce SAR through conformational analysis i s that v i r t u a l l y nothing i s known about the mutual conformational changes that occur i n the drug molecule and the receptor i n the course of the drug-receptor i n t e r a c t i o n (37). At one extreme both the preferred and pharmacophoric conformation may be i d e n t i c a l , and. at the other extreme the receptor may place c e r t a i n s t e r i c demands on the drug so that i t i s bound i n an unfavorable conformation. Thus the SAR studies employing methadone must contain a c e r t a i n element of ambiguity which r e s u l t s from the assumption that the preferred conformation resembles that adopted by the analgetic at the receptor s i t e . I t i s possible, that the use of conformationally r e s t r i c t e d and r i g i d analogues of methadone may provide an answer to t h i s problem. A few examples of conformationally r e s t r i c t e d methadone analogues have appeared i n the l i t e r a t u r e (38). Constrainment of methadone (9) has involved e i t h e r bridging the aromatic - 25 -rings, as i n 13_, or c y c l i z i n g the propionyl and basic groups to form a p i p e r i d i n e r i n g as i n 14_. In general, such compounds have possessed a low order of analgetic a c t i v i t y or have been i n a c t i v e . 15 16 - 26 -The sulfone analogue (15) of 9^  has the same enantiomeric potency as 9^  (26,27). I t i s as active and i n t e r a c t s with the receptor with a conformation s i m i l a r to 9_. I t was considered that a conformationally restrained d e r i v a t i v e of 15 could be obtained by the synthesis of the thietane 1,1-dioxide 1_6, which i s formally derived from 15_ by j o i n i n g C-2 to C-5. °2 17_ R = H, C l , N0 2 A previous study with 2,4-diarylthietane 1,1-dioxides (17) has been done i n t h i s laboratory (39). At concentrations 1,000 times that of methadone, 17_ d i d not show a high order of a c t i v i t y . I t was indicated that one of the phenyls may i n t e r f e r e with a close approximation of 17_ to the receptor. I t has also been suggested that only one of the phenyls i n 9_ i s involved i n the association of 9_ with the receptor (26,27). Thus as an a l t e r n a t i v e to 1_6 the monophenyl analogues 1_8 were prepared. Although the a-methyl group i s lacking i n 18_, i t was f e l t that these compounds may s t i l l possess analgetic a c t i v i t y since the methadone analogue 27 -without the a-methyl substituent (normethadone) i s known to be f a i r l y active (26). I t was previously indicated that the active conformer of 9_ was suggested to have a mutual i n t e r a c t i o n between the amino-nitrogen and the carbonyl-carbon. In compounds of the type 1_7, the dimethylaminomethyl group was indicated to be i n a pseudoequatorial p o s i t i o n . In such a conformation an i n t e r a c t i o n between the amino-nitrogen and the sulfone may not have been possible. To check t h i s p o s s i b i l i t y the synthesis of thietane 1,1-dioxides with the dimethylamino-methyl group on the carbon a to the sulfone were attempted. CH 2N(CH 3) 2 18, R = H, CH 3 - 28 -THIETANE CHEMISTRY The chemistry of thietanes has been reviewed (40,41). At the time of these early review a r t i c l e s the general consensus was that the thietane r i n g was a planar structure. Since t h i s time many workers have shown that the thietane r i n g system and i t s oxides are puckered and have preferred conformations. Although the r i n g s t r a i n would tend to make the r i n g planar, non-bonded interactions of the substituents would favor a puckered arrangement through twisting of carbon-carbon bonds. In the ground state the equilibrium between the two forces r e s u l t s i n a puckered r i n g (42). Several groups determined the bond angles from X-ray cr y s t a l l o g r a p h i c studies (43,44). They found the sum of the bond angles to be less than 360°, i n d i c a t i n g a puckered r i n g system. Arbuzov et aJL. studied the dipole moments of 3-chloro substituted thietane, thietane 1-oxide and thietane 1,1-dioxide and concluded the rings were puckered by 37° (45). In a s i m i l a r series of 3-substituted thietanes, they found the angle of pucker to range from 30-40° and the degree of pucker was found to decrease i n the order s u l f i d e , sulfoxide, sulfone (46). The e l e c t r o n i c spectrum of thietane showed the - 29 -rin g to be puckered by 30 (42). Dodson et al_. oxidized 2,4-diphenylthietane (19) to i t s 1,1-dioxide (20) (47). Treatment of 2_0 with sodium methoxide gave 21_ i n 96% y i e l d . He reasoned from the nmr data that the r e s u l t s were explainable only i n terms of a puckered conformation. Treatment with the weak base resulted H (O) 19 H H NaOMe 0 0 20 21 - 30 -i n epimerization to the more stable configuration 21, with the phenyl substituents i n a pseudoequatorial p o s i t i o n where non-bonded interactions are minimal. In f a c t X-ray c r y s t a l l o -graphic studies showed 19 to be puckered by 37.7° and 21 by 35°. C 6 H 5 H 22, R = C l , CN 23_, R = C l , OH, OCOMe Dipole moment studies on the 2,2-diphenylthietanes, 22, have shown that these rings have preferred conformations i n which the R groups tend to favor pseudoequatorial positions (48). With 3,3-dimethylthietane and i t s oxides, however, nmr studies showed a rapid equilibrium existed between the possible conformers (49). In the case of the 3-substituted thietane 1,1-dioxides (23), R was found to be i n an a x i a l p o s i t i o n by X-ray crystallography (50). There may be a polar i n t e r a c t i o n between the sulfone and the 3-substituent to favor the a x i a l position, such as hydrogen bonding between the hydroxyl and the pseudoaxial oxygen of the sulfone i n 23, R = OH. The four bonded coupling constants of these compounds were also studied and the large J e e (4 Hz) could only be explained by a puckered conformation. The bond lengths of the C-C and C-S bonds i n 2-chloro-3-morpholino-2,4,4-trimethylthietane 1,1-dioxide were found to be s i g n i f i c a n t l y longer than i n a single C-C or C-S bond (44). The r o t a t i o n a l angles of the bonds were found to be 18.9° and 16°, respectively. I t seems apparent from these studies of thietanes, that the degree of puckering and bond ro t a t i o n and the length of the bonds vary depending on the. oxidation state of the s u l f u r as well as the p o s i t i o n and nature of the substituents on the r i n g . Review a r t i c l e s (40,41) have covered the synthesis and reactions of thietanes extensively to 1963 and p a r t l y to 1964. The material presented, then, w i l l be a b r i e f summary of new aspects i n the synthesis and r e a c t i v i t y of thietanes and thietane 1,1-dioxides since 1964 with emphasis on the chemistry pertinent to the research problem of t h i s project. Reduction of thietane 1,1-dioxides with lithiu m aluminum hydride has been a s y n t h e t i c a l l y useful method. However, the most common method of preparation of thietanes involves the formation of a sulfhydride ion containing a suitably I i I — C — C — C — X I I I SR R = H, CN, C0CH-; X - 32 -positioned leaving group. These methods usually give good y i e l d s i n the preparation of 3-substituted thietanes. Preparation of 2-substituted thietanes r e s u l t s i n lower y i e l d s due to the s t e r i c hindrance of the substituents to the intramolecular c y c l i z a t i o n process. Paquette prepared pure S-(-)-2-methylthietane (25) from R-(-)-4-methyl-l,3-dioxan-2-one (24) and KSCN at 170-180° (51). The o v e r a l l stereochemical conversion of 2_4 to 2_5 substantiates the previously proposed mechanism and p a r a l l e l s that found i n the analogous reaction of the thiocyanate ion with 1,3-dioxol-2-ones to give e p i s u l f i d e s . The requirement that a Walden inversion at C-4 i n 2_4 accompanies the s u b s t i t u t i o n of oxygen by s u l f u r can be a t t r i b u t e d to the operation of a process at t h i s s i t e . The intramolecular displacement - 33 -of the cyanate ion by sulfhydride ion i s the p r i n c i p l e stereochemical step i n t h i s example. The y i e l d s of thietanes by condensations of c y c l i c carbonates, however, are low. NCS 26 NaH triglyme OH R H R CH, NCS ONa R = H, CH. R 2 = H, CH. 27 Trost et a l . developed a modification of the i n t r a -molecular c y c l i z a t i o n reactions i n the synthesis of thietane to give a l k y l substituted thietanes (27_) i n 70% y i e l d (52) . Treatment of the hydroxythiocyanate (26) with sodium hydride, followed by p y r o l y s i s , generated the thietanes 2_7 with the elimination of sodium cyanate. Raash has developed a method of preparing hexfluoro-isopropylidenethietanes (28) (53,54). He found that t h i o -ketenes w i l l react with c e r t a i n o l e f i n s (methyleneadamantane, styrenes, ketene and methylketene are operable as well as the electron r i c h unsaturates comprising v i n y l ethers, s u l f i d e s - 34 -S R 3 R = H, CH 3 R2, R 3 = H, a l k y l , Ph, OR, or 0 (thietanone) R 2 R 1 28 and e s t e r s ) to g i v e t h i e t a n e s . The d i r e c t i o n o f the c y c l o -a d d i t i o n i s such t h a t the s u l f u r atom becomes a t t a c h e d to the carbon atom b e a r i n g the s u b s t i t u e n t ( s ) . For example, b i s ( t r i f l u o r o m e t h y l ) t h i o k e t e n e (29) r e a c t e d w i t h p-methoxy-s t y r e n e (30_) t o g i v e the t h i e t a n e , 3JL, i n 69% y i e l d . The scope, o f t h i s type o f c y c l o a d d i t i o n appears to be g r e a t e r (CF 3) 2C — C r r S 29 + 31 30 - 35 -than that reported by Middleton (55), where he reacted hexa-fluorothioacetone with v i n y l i c ethers and thioethers to give thietanes. Treatment of ketones v/ith t h i o n y l chloride i n the presence of c a t a l y t i c amounts of pyridine at room temperature resulted i n the formation of unsaturated thietanones (35) (56). 34 35 I t was assumed that the s u l f e n y l chloride 3_2 was formed and i t s enol form 3_3 was captured by either addition of the s u l f e n y l chloride groups to the carbon-carbon double bond or n u c l e o p h i l i c attack of the terminal methylene carbon atom upon s u l f u r to give r i s e to the thietanone 3_4. Elimination of hydrogen chloride would then give r i s e to the unsaturated thietanone 3_5. The pyridine present, may be involved i n a s s i s t i n g the e n o l i z a t i o n process or the elimination of hydrogen chloride. - 36 -hv R' 1 3660 A 36 37 R 2 38 Photochemical addition of thiobenzophenone (3_7) to c e r t a i n types of o l e f i n s has led to 2,2-diphenyl substituted thietanes (38) i n good y i e l d . The i r r a d i a t i o n of 37 with o l e f i n s activated with electron withdrawing groups (36) at 3660 A i n a CO^ atmosphere lead to the formation of 38_ i n an excess of 80% y i e l d (57). This cycloaddition probably involves the TT-TT s i n g l e t state of 3_7 and i s s t e r e o s p e c i f i c . For example c i s or trans dichloroethylene resulted i n exclusively cis-3,4-dichloro or trans-3,4-dichloro analogues of 38, respectively. With o l e f i n s containing electron donating groups (styrene and substituted styrenes) and 37, i r r a d i a t i o n at 5890 A was required i n order to obtain cycloaddition (58). In t h i s case the n-ir t r i p l e t state of 3_7 i s involved and the o r i e n t a t i o n of the products resulted from an intermediate which would give r i s e to the most stable d i r a d i c a l . For example, trans-g-methylstyrene (3_9) gave trans-3-methyl-2, 4, 4-triphenylthietane (£0) i n 63% y i e l d . Other examples of thietane formation by photochemical technique have been reported (59,60), but t h e i r synthetic usefulness i s questionable o * o * - 37 -CH. + (C 6H 5) 2C=S hv C6H5 CP 5890 A 39 37 40 since they resulted from the fragmentation of larger molecules and w i l l not be discussed here. + (Et 2N) 3P S S 41 42_ 43 R = H, C 6H 5, a l k y l Harpp et a l . reported a method of preparing thietanes by a d e s u l f u r i z a t i o n technique (61). Treatment of dithiolanes (41_) with t r i (diethylamine)phosphine (42) resulted i n the formation of the thietanes 4_3. The same procedure was used to desulfurize 1,2-dithiolane-3,5-diones (45) with triphenylphosphine to t h e i r corresponding thietane 2,4-diones 4_6 (62). Treatment of the pyridinium s a l t s of the b i s t h i o acids (44) with t r i f l u o r o a c e t i c anhydride gave 46 i n high y i e l d s . Heating the dithiolanes (41 or 45) - 38 -p y r i d i n e , t r i f l u o r o a c e t i c anhydride R = Me, Et r e s u l t s i n thietanes but the y i e l d s are usually very low. The method was modified by s e l e c t i v e l y o x i d i z i n g one of the s u l f i d e s to a sulfone, which serves as a better leaving group (63). For example, 47 was oxidized to 4 8 with 49 50 - 3 9 -m-chloroperbenzoic acid, then refluxed i n benzene to y i e l d 25% of £ 9 and 3 8 % of 5 0 _ . Treatment of 4_7 by the method of Harpp gave 4 9 i n 6 0 % y i e l d . 5 1 5 2 53_ The addition of s u l f u r d i c h l o r i d e to norbornadiene ( 5 1 ) gave the fused thietane system 5_3 ( 6 4 ) . Due to the s p e c i f i c nature of t h i s reaction, i t does not appear to be useful as a general synthetic method. The reaction i s of i n t e r e s t from the stand point of being an unusual synthesis of thietanes. The high s e l e c t i v i t y suggested the p o s s i b i l i t y of an episulfonium intermediate ( 5 _ 2 ) . The existence of 5_2_ was shown by the treatment of 5_3 with BBr^ or Zn/HOAc which resulted i n the replacement of the chlorines by bromines or acetates, respectively. Thietanes appear to be reactive compounds l a r g e l y because of the ease at which they undergo r i n g opening to give addition or polymerization products. In general the r i n g remains i n t a c t i n the addition reactions at the free electron pair of s u l f u r . An example i s the formation of sulfonium s a l t s with mercuric d i c h l o r i d e . Thietanes are s t a b i l i z e d by base but undergo polymerization i n the presence of acid. - 40 -Treatment with Raney n i c k e l r e s u l t s i n d e s u l f u r i z a t i o n . E l e c t r o p h i l i c addition usually r e s u l t s i n r i n g cleavage. For example, thietane (54) gave the addition product 55 on treatment with ammonia. Other examples of r i n g opening reactions are given by the review a r t i c l e s (40,41). Organo lithiums are suspected to react by carbanion attack at the su l f u r rather than the adjacent carbon atom. Experimental evidence f o r t h i s was found by Morton (65). Reacting CH- + E t L i > CH_CH_SCHCH_CH_Li J 3 2 | 2 2 CH 3 56 57 58 2-methylthietane (5_6) with ethyl l i t h i u m (57_) at -7 8° yielded products which would be expected from an attack of a carbanion at the s u l f u r atom and subsequent r i n g opening with the formation of a new carbanion species, 58_. At warmer temperatures or with an excess of 56 polymerization resulted. - 41 -0 0 C^HrCHO NaOH S CHC^H 59 60 An unusual thietane product, 6_0, was obtained by the reaction of 3-thietanone (59) with benzaldehyde i n base (56) . The 2- and 4-positions of 5_9_ are p a r t i c u l a r l y susceptible to the a l d o l condensation, followed by dehydration, due to the p o s s i b i l i t y of the p a r t i c i p a t i o n by sulfur as well as the carbonyl i n the reaction mechanism. Recently trans-2,4-diphenylthietane (19) was treated with potassium t-butoxide i n dimethylformamide to give a mixture of 9 compounds (66) . Four of the compounds (61, 62, 63, 64) have been i d e n t i f i e d and t h e i r formation explained on the basis of an intermediate sulfanion. - 42 -C ^ H 6 5 19 C 6 H 5 K(t-BuO) D M F C 6 H 5 C 6 H 5 61 T6H5 C 6 H 5 C 6 H 5 62 0 II 6 5 2 2 6 5 63 64 Refluxing 3-chlorothietane with triphenylphosphine or triphenylphosphite i n xylene for 70 hours resulted i n de s u l f u r i z a t i o n to give 3-chloropropene (67) . U l t r a v i o l e t i r r a d i a t i o n i n 95% ethanol of 65_ also led to the desulfurized product 66^  (68) . I t i s i n t e r e s t i n g to note that the sulfone analogue of 6_5 resulted i n the cyclopropane d e r i v a t i v e 6_7 upon heating or u l t r a v i o l e t i r r a d i a t i o n . - 43 -C^E^C—O 6 5 95% hEtOH > C 6 H 5 f r C H _ C H C 6 H 5 + (CH2=S) x 65 66 C 6 H 5 0 6 5 67 Unlike the thietanes the sulfone analogues are characterized by t h e i r s t a b i l i t y and can usually be obtained as c r y s t a l l i n e products. Thietane 1,1-dioxides are frequently prepared by o x i d i z i n g the corresponding thietanes with peracid. Dittmer oxidized 3-thietanol (6_8) with hydrogen peroxide and g l a c i a l a c e t i c acid to the corresponding sulfone 69 i n 56% yield. (69). A more e f f i c i e n t and v e r s a t i l e route - 44 -to thietane 1,1-dioxides i s from the much studied cyclo-addition of sulfenes with o l e f i n s containing strong electron donating groups such as enamines, ynamines, v i n y l ethers, ketene acetals, and ketene aminals. These reactions have been extensively reviewed (70-74). Sulfene reaction with ketene has also led to thietane 1,1-dioxides (75). Only the cycloaddition of enamines with sulfenes w i l l be discussed because of i t s relevance to the material i n t h i s d i s s e r t a t i o n . 70 71 72 The formation of thietane 1,1-dioxides from the cyclo-addition of sulfenes and enamines was independently discovered by Stork and Borowitz (76) and by Opitz and Adolph (77) . Opitz prepared 7_2 from the enamine 7_0 and the s u l f o n y l chloride 7_1 by the i n s i t u formation of phenyl-sulfene. A number of thietane 1,1-dioxides s i m i l a r to 7_2 were prepared by Optiz u t i l i z i n g t h i s method. It i s unknown whether these c y c l i c sulfones form as a r e s u l t of a one-step multicenter reaction (path a) or from a two-step addition (path b). The two-step mechanism - 45 -involves the i n i t i a l formation of an intermediate zwitterion. The zwitterion can undergo intramolecular c y c l i z a t i o n (path b 2) or undergo a prototropic s h i f t to give a s u b s t i t u t i o n product (path c ) . Path b i s the preferred route by Woodward-Hoffman rules (78). This route provides a better explanation of the single orienta-t i o n (dialkylamino group on C-3 of the thietane 1,1-dioxide) and of the fact that only strongly n u c l e o p h i l i c o l e f i n s are attacked by sulfenes (70). Additi o n a l evidence for the z w i t t e r i o n i c intermediate came from the i s o l a t i o n of a c y c l i c products (path c) (79-82). However, the expected solvent dependence for the r e l a t i v e r a t i o of products i s lacking (70). Although i t has been postulated that the a c y c l i c material could be derived from an i n i t i a l l y c y c l i z e d - 46 -thietane product (81) and that the c y c l i z a t i o n process i s reve r s i b l e (80), there i s some recent evidence to show that the a c y c l i c material could not a r i s e from the breakdown of the thietane 1,1-dioxide under the reaction conditions used for the c y c l i z a t i o n (83,84). For example, when Fischer's base (7_3) was reacted with sulfene, 7_4 and 7_5_ were obtained i n 50% y i e l d i n a r a t i o of 2:1 respectively. 75 Reexposure of 7_4 to the reaction conditions did not r e s u l t i n the formation of 7_5 (83) . I t has also been determined that increasing the size of the substituents on the a-carbon of the su l f o n y l chloride or enamine increases the r e l a t i v e amount of a c y c l i c product formed (85). I t was f e l t that the - 47 -a substituent s t e r i c a l l y i n h i b i t e d the intramolecular c y c l i z a t i o n of the zwi t t e r i o n i c intermediate, thus r e s u l t i n g i n a greater amount of a c y c l i c product. The reaction of phenylsulfene (77) with 1,3-bis(dimethyl-amino)-propene (76) gave only a 30% y i e l d of the c y c l i c (CH3) 2NCH2CH —CHN (CH3) 2 + 76 \ / r ~ c h = s o 2 77 (CH ) 2NCH 2CH—C N(CH3) 2 78 •CH^=rN(CH3)2 CHSO«CH=CHN(CH_) 3' 2 H CH 2 S 0 2CH=CHN (CH,) 3' 2 (CH 3) 2NCH 2-N(CH 3) 2 2 80 79 - 48 -product 8_0 and the enamino sulfone 7_9_ was also i s o l a t e d (86) . Paquette r a t i o n a l i z e d the formation of 19_ as a r e s u l t of the s t a b i l i z i n g e f f e c t of the phenyl on the a sulf o n y l carbanion component of the intermediate zwitterion 78. He f e l t that t h i s increased l i f e t i m e of the zwitterion can be diagnosed by v i r t u e of the fact that a mechanistic a l t e r n a t i v e other than c y c l i z a t i o n i s avail a b l e to the system, strongly suggesting the non-concertedness of the sulfene-enamine i n t e r a c t i o n s . I t has been shown that the cycloaddition i s stereo-s p e c i f i c with respect to the o l e f i n (87). The reaction of the c i s o l e f i n 82 with mesylsulfene (81) afforded 86% of the Et OBu 82 83 c i s cycloadduct 83_. Also trans 82 with 81_ gave the trans cycloadduct i n 80% y i e l d . Although the reaction of sulfene with cis-l-morpholinopropene gave a mixture of c i s and trans (49:51), the trans enamine gave exclusively the trans adduct. The discrepancy with the c i s enamine probably arises - 49 -from the isomerization of the enamine i t s e l f rather than as a r e s u l t of the c y c l i z a t i o n step. Support for the stereo-s p e c i f i c i t y of the c y c l i z a t i o n came when the trans enamine 84 was reacted with sulfene to give only trans 85 (88). In t h i s case a c e r t a i n amount of asymmetric induction was also found to take place. H CH 3 84 85 Paquette has r a t i o n a l i z e d the inductive e f f e c t by proposing that the rate determining t r a n s i t i o n state i s more product l i k e than reactant l i k e , and a marked s e n s i t i v i t y to s t e r i c interactions i n product formation w i l l be encountered (89). To i l l u s t r a t e t h i s point he reacted the enamine from R-(-)-2-methylpyrrolidine and propionaldehyde (86) with sulfene {81) . He obtained the cycloadduct 90_ to a greater extent than 9_1. The sulfene can approach the o l e f i n orthogonally from eit h e r side. If anything, attack from the backside as i n 88^  should be more hindered than that of the frontside attack as i n 89. Since the preferred - 50 -90 91 p r o d u c t 90 i s f r e e o f non-bonded m e t h y l - m e t h y l i n t e r a c t i o n s , the i n h e r e n t a s s u m p t i o n i s t h a t a t t a c k from t h e more s t e r i c a l l y s h i e l d e d s u r f a c e o f t h e enamine i s more t h a n compensated a t t h e t r a n s i t i o n s t a t e by t h e m i n i m i z a t i o n o f c o m p r e s s i v e m e t h y l - m e t h y l i n t e r a c t i o n s i n t h e d e v e l o p i n g f o u r membered r i n g . 93 94 When g - d i m e t h y l a m i n o s t y r e n e (9_2) was r e a c t e d w i t h p h e n y l s u l f e n e (77) t h e l e s s s t a b l e c y c l o a d d u c t 94_ was formed t o a g r e a t e r e x t e n t t h a n the more s t a b l e i s o m e r 9K3 (90) . The p r e f e r e n t i a l f o r m a t i o n o f 9_4 was r a t i o n a l i z e d u s i n g t h e same t r a n s i t i o n s t a t e model p r o p o s e d by P a q u e t t e . However t h e f o r m a t i o n o f p r o d u c t s was pr o p o s e d t o be a - 52 -result of a s t e r i c approach control mechanism, i n contrast to the product development control mechanism implied by Paquette. An i n t e r e s t i n g cycloaddition reaction occurred when the enamine 9_6 was reacted with bromomethanesulfonyl chloride (95) i n benzene (91) . As well as the expected thietanes 9_9 and 100 (27% yield) , the bromide s a l t s 97_ and 98_ were i s o l a t e d as a 50:50 mixture i n 29% y i e l d . The products were believed to r e s u l t from the normal a c y c l i c enamine product which underwent an intramolecular displacement by the t e r t i a r y nitrogen on the bromomethylsulfonyl group. In 96 99 100 - 53 -contrast, when 9_6_ was reacted with chloromethanesulfonyl chloride, only the chloro substituted analogues of 9_9 and 100 were i s o l a t e d . As previously mentioned trans-2,4-diphenylthietane 1,1-dioxide (2_0) isomerized to the c i s analogue 2_1_ i n base. Dodson et a l . did further studies with these isomers. C 102 They found that t r e a t i n g 20_ or 21_ with e t h y l magnesium bromide resulted i n the cyclopropane d e r i v a t i v e 101 (92). However, treatment of 2_0 with the bromide of magnesium t-butoxide resulted i n the formation of the c y c l i c s u l f i n a t e ester 102 (21 gave the c i s analogue of 102) (93). The stereoselective rearrangement with ethyl magnesium bromide i s thought to r e s u l t from the rapid formation of an a-sulfonyl carbanion which rearranges to give the s u l f i n i c a c i d . The s u l f i n i c acid can s t a b i l i z e the charge better than the - 54 -carbanion and eventually picks up a proton. The formation of the s u l f i n a t e ester 102 i s st e r e o s p e c i f i c with respect to the phenyl substituents and stereoselective with respect to the oxygen (axial oxygen i s preferred). The intermediate i s suspected to be an anion d i r a d i c a l i n a solvent cage which leads to the s t e r e o s p e c i f i c c y c l i z a t i o n (94). N(CH 3) 2 103 104 Submitting 3-dialkylamino substituted thietane 1,1-dioxides to the Hoffman elimination (69) or the Cope elimination (82) reactions r e s u l t s i n deamination to give substituted t h i e t e 1,1-dioxides. For example, when 3-dimethylaminothietane 1,1-dioxide (103) was treated with methyl iodide, then s i l v e r oxide i n water a good y i e l d of thiete 1,1-dioxide (104) was obtained (69). With 2-methyl-3-piperidinothietane 1,1-dioxide (105) there e x i s t s the p o s s i -b i l i t y of the formation of two isomers. The exposure of 105 to the Hoffman reaction i n aqueous media gave the formation of 106 exclusively. If the elimination was c a r r i e d out under non-aqueous conditions, with the addition of calcium sul f a t e , the isomeric th i e t e 107 i s formed (less than 7% of - 55 -CH 3 o 106 CH 3 105 107 106 as shown by nmr studies) (51). Conversion of 3-hydroxy substituted thietane 1,1-dioxides to t h e i r chlorides (69) or t h e i r sulfonate ester (95) followed by treatment with triethylamine has led to thi e t e 1,1-dioxides i n good y i e l d . Cycloaddition of sulfenes with ynamines (80,96,97) or with ketene 0,N or N,N acetals (98,99) r e s u l t s i n 3-amino substituted t h i e t e 1,1-dioxides. Thiete 1,1-dioxides w i l l undergo Michael addition with nucleophiles to give 3-substituted compounds (100,101). For example, thiete 1,1-dioxide (104) can be converted back to 103 by allowing a solution of 104 and dimethylamine i n ethanol to stand for several days. Treatment of thi e t e 1,1-dioxides with base can lead to a reverse A l d o l type reaction followed by a base catalyzed cleavage of B-hydroxy sulfones - 56 -104 CH 3S0 2CH 2CHO 5> CH 3S0 2CH 3 + HCO 108 (82,100). For example, 104 i s converted into dimethyl sulfone (108). These c y c l i c o l e f i n s also undergo Diels Alder type reactions quite r e a d i l y (100-103). An in t e r e s t i n g cycloaddition reaction r e s u l t s i n the formation of a b i c y c l i c system 110, when 104 i s refluxed with the enamine 109 i n benzene (104) . 104 109 110 Reduction of the double bond o f t h i e t e 1,1-dioxides to the corresponding thietane 1,1-dioxides can be accomplished with sodium borohydride (96,100,105) or by c a t a l y t i c hydrogenation (101,105). Reduction with lithiu m aluminum hydride usually r e s u l t s i n r i n g cleavage (100,105). R R LiAlH CH3CHCH2SH S R = H, a l k y l , Ph Although the t h i e t e 1,1-dioxides are highly reactive compounds, they can usually be obtained as stable c r y s t a l l i n e material. The s u l f i d e analogues, however, are highly unstable and have been rather e l u s i v e . Two thietes i n which the double bond i s part of a fused aromatic r i n g system have been prepared (106). There has been evidence of a thiete fused to a cyclohexane r i n g (107) . Thiete' (112) has been prepared by a modified Hoffmann procedure (108). By t r e a t i n g 111 with potassium t-butoxide, 112 was i s o l a t e d i n I Kt-BuO 111 112 - 58 -20-30% y i e l d s . Thiete i s a colourless l i q u i d which slowly decomposes at room temperature. Recently the same procedure was employed to prepare thietes of the general structure 113 (109). A l l the compounds were l i q u i d s and 113, R ,R = H, a l k y l somewhat thermally unstable. The compound 113 (R = R = (CR^)4) was the most unstable, and could be stored at -10° for several weeks, but at room temperature decomposed explosively. A l l the thietes could be oxidized to t h e i r corresponding sulfones. - 59 -DISCUSSION OF THE CHEMISTRY The synthetic work of t h i s project involved the preparation of thietanes as p o t e n t i a l MAO i n h i b i t o r s and of thietane 1,1-dioxides as p o t e n t i a l narcotic analgetics. Although there i s considerable overlap i n the chemistry involved i n the preparation of these compounds, the discussion of the synthetic methods used w i l l be divided into two main categories: 1. Synthesis of thietanes for MAO studies 2. Synthesis of thietane 1,1-dioxides for analgetic studies. During the course of these studies a number of thietane 1,1-dioxides were prepared and i d e n t i f i e d with the aid of mass spectroscopy. Since no general discussion of the mass spectral c h a r a c t e r i s t i c s of thietane 1,1-dioxides has appeared i n the l i t e r a t u r e , the fragmentation patterns of the thietane 1,1-dioxides w i l l be discussed i n a separate section. - 60 -1. Synthesis of Thietanes for MAO Studies The thietane analogue of tranylcypromine required for pharmacological studies was 3-amino-2-phenylthietane (5_) . Although 5_ appears to be a r e l a t i v e l y simple compound, the available methods of synthesis are l i m i t e d . Treatment of epoxides with hydrogen s u l f i d e i n base has been reported to give 3-thietanols (69,110). For example, Dittmer and OH Christy prepared 3-thietanol (68) by the exposure of 3-chloropropylene oxide-1,2 (114) to hydrogen s u l f i d e and barium hydroxide i n 39% y i e l d (69). I t was f e l t that t h i s procedure would be a f a c i l e method of preparing 2-phenyl-3>-substituted thietanes (by converting the 3-hydroxyl to other functional groups) and was used i n the attempted preparation of 5_ (Scheme 1) . Commercially a v a i l a b l e 3-chloropropenylbenzene (115) showed a coupling constant of 16 Hz for the o l e f i n i c protons (H and H, ), i n d i c a t i n g a trans configuration (111) . There a D was no i n d i c a t i o n of the c i s isomer being present. Thus epoxidation of 115 with monoperphthalic acid gave pure trans-3-chloro-l-phenylpropylene oxide-1,2 (116) (110). - 61 -Scheme 1. Proposed Synthetic Route to 3-Amino-2-phenyl-thietane (5). 117 5 This configurational assignment was supported by the nmr data for the r i n g protons(H a and H^) which had a coupling constant of 2 Hz, and i s the expected value for trans substituted epoxides (111). Hydrogen s u l f i d e i n the basic conditions of the reaction would probably e x i s t as sodium sulfhydride. Reaction of the sulfhydride ion with the epoxide (116) can lead to two possible end products depending on the i n i t i a l p o s i t i o n of attack on the epoxide r i n g (Scheme 2). A nuc l e o p h i l i c attack of the sulfhydride ion on the a-carbon atom w i l l lead to an intermediate (118) which can undergo intramolecular - 62 -Scheme 2. Proposed Mechanism for the Reaction of Epoxide with Sulfhydride Ion. 117 120 - 63 -c y c l i z a t i o n by a further n u c l e o p h i l i c attack of the s u l f i d e ion on the y c a r b o n with the expulsion of the chloride ion to give the thietane 117. The chloride ion p r e c i p i t a t e s from the s o l u t i o n as sodium chloride and thus promoting the completion of the reaction. Similar intermediates have been proposed for thietane r i n g formation under basic conditions (40,41). For example, the treatment of 1,3-dihalides (121) with sodium s u l f i d e , forms an intermediate s u l f i d e ion (122) which undergoes intramolecular c y c l i z a t i o n to form the thietane (123) (40). R - a l k y l ; X = halogen Although the a-carbon i n 116 i s probably more electron d e f i c i e n t , due to the electron withdrawing e f f e c t of the phenyl, the sulfhydride ion could also attack the 3-carbon, to go through a s i m i l a r intermediate 119 to give 2-(a-hydroxybenzyl)thiirane (120). Treatment of 6-halomercaptans with base i s a method used for the synthesis of t h i i r a n e s (112). By analogy to a s i m i l a r system the sulfhydride ion could i n i t i a l l y replace the chloro group of 116 by an SN 9 121 122 123 - 64 -mechanism (113). Then under the basic conditions of the reaction the s u l f i d e ion can cleave the epoxide by nu c l e o p h i l i c attack on the a- or 3-carbon to give 117 or 120• OH 126 The reaction of 3-chloro-2-phenylpropylene oxide-1,2 (124) i n a basic solution saturated with hydrogen s u l f i d e followed by heating at 80° gave the thietane 125 (110). At temperatures of 50° or less the main product was the a c y c l i c material 126. Heating the t h i o l 126 i n ethanolic sodium ethoxide at r e f l u x temperatures gave 125. These r e s u l t s , e s p e c i a l l y the i s o l a t i o n of 126 would tend to support the mechanism involving the i n i t i a l attack of the - 65 -sulfhydride ion on the carbons of the epoxide r i n g . These res u l t s also point out that the sulfhydride ion does not necessarily attack the most electron d e f i c i e n t carbon of the epoxide. In t h i s case i t appears to attack the l e a s t s t e r i c a l l y hindered carbon of the epoxide. Work up of the reaction of the epoxide 116 with a basic solution of hydrogen s u l f i d e gave a crude o i l . Scratching the o i l with a glass rod resulted i n the formation of a thick gum, which was extracted with hot portions of hexane. Cooling the pooled hexane extracts gave white needle-like c r y s t a l s which melted at 56.5-57.5° upon further r e c r y s t a l l i z a t i o n . This material was highly unstable, but could be stored at -15° under nitrogen without any detect-able decomposition. The i r spectrum showed absorptions at 1065, 3220, and 3310 cm i n d i c a t i v e of an alcohol. Further spectroscopic studies indicated that the material i s o l a t e d was the thietane 117. In t h i s case, then, the sulfhydride ion favored attack of the most electron d e f i c i e n t carbon of the epoxide since the s t e r i c factors on both carbons of the epoxide are s i m i l a r . The nmr spectrum was consistent with the structure of 117. A broad s i n g l e t at 6 2.68 disappeared on the addition of D 20 and was a t t r i b u t e d to the hydroxyl proton. A doublet of doublets at 6 3.17 was a t t r i b u t e d to the H and H-, c d protons and a m u l t i p l e t at <5 4.62 was assigned to the H and H, protons. The aromatic protons appeared as a - 66 -m u l t i p l e t at <S 7.34. A comparison of the chemical s h i f t of the H c and protons to s i m i l a r methylene protons, H a and H, of 2-benzyl-3-dimethylaminothietane (8) would favor N(CH3) 2 8 the thietane 117 as the product i s o l a t e d . The H a and protons of 8_ appear at 6 3. 08 which i s s i m i l a r to the chemical s h i f t (6 3.17) of the H c and protons of the material i s o l a t e d . The t h i i r a n e 120 could show a s i m i l a r s p l i t t i n g pattern as the thietane 117, but the H c and protons of 120 would probably show up at a higher f i e l d due to the greater r i n g s t r a i n i n the three membered r i n g (111). Since the epoxide 116 was of the trans configuration, i t follows from the proposed mechanism the configuration of 117 w i l l be such that the phenyl and the hydroxyl w i l l be i n a trans r e l a t i o n s h i p and probably both i n the pseudo-equatorial p o s i t i o n on the puckered r i n g . The nmr data could not be used to support t h i s trans configuration since H and H, had s i m i l a r chemical s h i f t s and as a r e s u l t t h e i r a b peaks were overlapped. Accurate coupling constants for these protons were not determined. - 67 -The s u l f i d e 117 was oxidized to the corresponding sulfone, 3-hydroxy--2-phenylthietane 1,1-dioxide (127) using m-chloroperbenzoic acid i n 85% y i e l d . I t was of i n t e r e s t to see what e f f e c t o x i d i z i n g the s u l f i d e to the sulfone H 117 127 would have on the nmr spectrum. Oxidation of thietanes to th e i r dioxides with ^ 2 ° 2 ^ n <3^ ac^- a^- acetic a c i d has been used by many workers (40,41) and l a t e l y i t was reported that explosions have resulted from the concentration of the reaction mixture under vacuum (114). I t has been suggested that concentration of the reaction mixture be done at atmospheric pressure with the a i d of a steam bath u n t i l a yellow colouration develops and then allowing the solvents to evaporate at room temperature. Attempts to use t h i s procedure with 117 resulted i n low y i e l d s (30-50%) and required approximately one week to concentrate the reaction mixture. The low y i e l d s were thought to be due to the high water s o l u b i l i t y of 127, which decreased the e f f i c i e n c y of extraction procedures and the d i f f i c u l t y i n r e c r y s t a l l i z a t i o n - 68 -of 127 as a r e s u l t of r e s i d u a l amounts of acetic acid present i n the crude s o l i d . However, by u t i l i z i n g m-chloroperbenzoic acid i n chloroform or dichloromethane 127 can be recovered safely and e f f i c i e n t l y by extracting the crude residue with water a f t e r the removal of the reaction solvent under vacuum. Since the m-chlorobenzoic acid formed i n the reaction i s e s s e n t i a l l y insoluble i n water, 127 can be obtained with a high degree of pu r i t y . The material could also be r e c r y s t a l l i z e d with ease from ether-petroleum ether (30-60°). The nmr spectrum of 127 showed that oxidation of the s u l f i d e 117 to the sulfone 127 resulted i n a paramagnetic s h i f t of the H^ proton by 0.6 8 6 units, which appears as a doublet and a s i m i l a r s h i f t of 0.68 6 units for the H c and H^ protons. This paramagnetic s h i f t provided evidence that the i n i t i a l c y c l i z e d product was indeed the thietane 117. If the compound was the t h i i r a n e 120 a paramagnetic s h i f t would have occurred with the H^, H c and H^ protons also, but the H^ protons would appear as a multip l e t i n t h i s case. The nmr data also indicated that 127 had a trans configura-t i o n of the phenyl and hydroxyl and both i n a pseudoequatorial p o s i t i o n . The coupling constant f o r H^H^ was 6.5 Hz. If the protons were i n a c i s r e l a t i o n s h i p , then the coupling constant would be expected to be small, since the dihedral angle would be near 90° i n the puckered r i n g . This i s - 69 -Scheme 3. Fragmentation Pattern of 3-Hydroxy-2-phenylthietane (117) i n the Mass Spectrum. 117 supported by the coupling constants observed for the H and H, which were 2.5 Hz for H H, (cis) and 7.0 Hz for d a d H H (trans pseudodiaxial r e l a t i o n s h i p ) . The Karplus cl C ————— c o r r e l a t i o n has been shown to be r e l i a b l e i n thietane 1,1-dioxides (115) . The mass spectrum of the material i s o l a t e d from the treatment of 116 with sodium sulfhydride confirmed the material to be 117. The two major routes for the fragmenta-ti o n of 117 i n the mass spectrum are as proposed i n Scheme 3. Path (a) i s probably the preferred route of fragmentation, sincethe peaks at m/e 122, 121, and 91 are dominant, with the peak at m/e 122 being the base peak. A l l other peaks are less than 30% of the base peak. An analogous pattern has been evoked for 3-methylthietane (116). If the material i s o l a t e d had been the t h i i r a n e 120, then strong peaks at m/e 105 and 106 due to (C gH 5CO) + and (CgHgCHOjt would be expected. These are r e l a t i v e l y stable ions and should form r e a d i l y from 120. At t h i s point a number of experiments were performed to investigate some of the chemical properties of thietanes. The knowledge obtained from these studies were to provide some in s i g h t into the r e a c t i v i t y of the 3-hydroxyl group and the type of chemical manipulations that can be performed, while keeping the thietane r i n g i n t a c t . The eventual aim was to devise a scheme whereby the synthesis of 3-amino-2-phenylthietane (5) could be accomplished. Chemical evidence - 71 -which established the structure of 117 was also obtained i n the course of t h i s work. Although the mass spectroscopic data was rather conclusive, routine use of a mass spectro-meter was not avail a b l e u n t i l the work on t h i s .phase of the project was complete. When 127 was refluxed i n 2% sodium hydroxide solution and cooled a 70% y i e l d of benzyl methyl sulfone (130) pr e c i p i t a t e d from the reaction mixture. The i r spectrum of the material i s o l a t e d was superimposable with the i r spectrum of 130 given i n Sadtler (117), and the melting point agreeed with l i t e r a t u r e values (82,117). This type of r i n g cleavage i n base i s well known for thiete 1,1-dioxides. OH ONa+ 129 130 The mechanism proposed involved a reverse Aldol condensation, proceeding through an intermediate analogous to 128, - 72 -followed by a base catalyzed hydrolysis of the 8-hydroxy-sulfone, which proceeds through the intermediate 12 9 to give 130. The i s o l a t i o n of 130 from the base treatment of 127 may be interpreted as supporting t h i s mechanism proposed for the base catalyzed hydrolysis of t h i e t e 1,1-dioxides. OCH„CH_ i 2. J C H 3 S 0 ; J <^ \ 2H—> CH 3S0 2CH 2S0 2CH 3 + CH^CH^OH S °2 131 132 I t has also been shown that 3-alkoxy compounds undergo the same type of r i n g cleavage i n base (118). For example, 3-ethoxy-2-methylsulfonylthietane 1,1-dioxide (131) on treatment with base gave methylsulfonylmethyl methyl sulfone (132). To investigate the r e a c t i v i t y of the 3-hydroxyl group, 117 and 127 were subjected to ethoxylation procedures. In a l l cases studied the alcohol appeared r e s i s t a n t to e t h e r i f i c a t i o n . For example, when 127 was treated with triethyloxonium tetrafluoroborate i n dichloromethane (119), work up of the reaction resulted i n the i s o l a t i o n of s t a r t i n g material only. When 117 was reacted with sodium metal, i t appeared to form the sodium s a l t . However, addition of ethyl bromide and work up of the reaction, did not give the desired ethoxide compound 134 and the s t a r t i n g - 73 ~ OCH2CH3, 117 134 alcohol 117 was the only i d e n t i f i a b l e material i s o l a t e d . Attempted dehydration of 127 with 85% phosphoric acid or concentrated s u l f u r i c acid i n g l a c i a l acetic acid resulted i n the i s o l a t i o n of benzyl methyl ketone (138). This was i d e n t i f i e d from the b o i l i n g point, nmr and i r data given i n Sadtler (117). The acid catalyzed d e s u l f u r i z a t i o n and ring cleavage could proceed by the mechanism outlined i n Scheme 4. Protonation of the alcohol r e s u l t s i n the expulsion of su l f u r dioxide and water to give the carbonium ion 135, which rearranges with the loss of a proton to give phenylallene (136). Under a c i d i c conditions allenes are known to undergo Markovnikov addition of water (120). The r e s u l t i n g enol 137 tautomerizes to benzyl methyl ketone (138) .. - 74 -Scheme 4, Proposed Mechanism for the Acid Catalyzed Cleavage of 3-Hydroxy-2-phenylthietane 1,1-Dioxide. CH 3 137 138 The i n i t i a l r i n g cleavage depicted i n the mechanism i s not without precedent. Paquette has postulated a si m i l a r mechanism i n a fused r i n g system containing a 3-hydroxy sulfone (139) (121). In t h i s case a stable conjugated product 140 i s formed from'the carbonium ion r e s u l t i n g from the expulsion of s u l f u r dioxide. - 75 -OH CH 140 King and De Mayo reported a method of dehydrating 3-hydroxythietane 1,1-dioxide u t i l i z i n g benzylsulfonyl chloride and triethylamine (95). This method was applied to 127. An anhydrous tetrahydrofuran s o l u t i o n of 127 was reacted with molar quantities of benzylsulfonyl chloride and triethylamine. The solvent was removed under vacuum to give a white waxy residue of the sulfonate ester 141, which had a wide melting point range (115-122° dec). This material was unstable and attempts to p u r i f y i t by r e c r y s t a l l i z a -t i o n from ethanol or ethanol-hexane resulted i n further decomposition. Thus the sulfonate ester 141 was used as the crude product i n subsequent reactions. Spectroscopic - 76 -evidence was consistent with the structure of 141. The i r spectrum showed the loss of the alcohol band present i n 127 and the appearance of bands at 1200 and 1360 cm ^ i n d i c a t i v e of a sulfonate ester. An nmr spectrum could not be obtained due to the insoluble nature of 141 i n common nmr solvents. A mass spectrum of 141 did not show a molecular ion, however, i t complied with the spectrum expected for 141. 143 144 - 77 -When a molar quantity of triethylamine was added to a benzene solution of 141, a p r e c i p i t a t i o n of triethylammonium benzylsulfonate occurred. Removal of the benzene l e f t 2- phenylthiete 1,1-dioxide (142) as white flaky c r y s t a l s . The material was r e c r y s t a l l i z e d from hexane-ethanol to give 142 i n 45% y i e l d as white p l a t e - l i k e c r y s t a l s . This i s a known compound and has been prepared by an alternate route (82). 3-Dimethylaminostyrene (143) was reacted with methanesulfonyl chloride and triethylamine i n a c e t o n i t r i l e to give 3-dimethylamino-2-phenylthietane 1,1-dioxide (144). Exposure of 144 to the amine oxide elimination procedure gave the thie t e 142. The products i s o l a t e d from both synthetic routes were determined to be i d e n t i c a l by virtue of superimposable i r spectra and by t h e i r mixed melting point . From these preliminary experiments a number of synthetic schemes were considered as methods of converting the 3- hydroxyl of 117 to a primary amine without causing r i n g cleavage. The synthetic schemes considered involve c h l o r i n a t i o n at C-3 or oxidation to the 3-thietanone or through the sulfonate ester. These methods w i l l e n t a i l the discussion that follows. When 117 was treated with thion y l chloride i n dry chloroform (122), the expected 3-chloro-2-phenylthietane (145) was not i s o l a t e d . D i s t i l l a t i o n of the crude product gave a yellow l i q u i d , which was i d e n t i f i e d as 3-chloro-- 78 -Cl 115 propenylbenzene (115). The b o i l i n g point, i r spectrum and nmr spectrum were i d e n t i c a l to a commercially a v a i l a b l e sample of 115. Dittmer and Christy reported good y i e l d s i n the conversion of 3-hydroxythietane 1,1-dioxide (69) to 3-chlorothietane 1,1-dioxide (146) with t h i o n y l chloride and 2,4,6-collidine (69). When t h i s procedure was applied to 117 only polymerized material was obtained. I t was reported that lower y i e l d s were obtained i n the c h l o r i n a t i o n of 6_9 i f pyridine were used instead of 2,4,6-collidine, due to a greater amount of dehydrohalogenation that occurred as a r e s u l t of pyridine's greater b a s i c i t y . This was supported by the ease at which 146 could be dehydrohalogenated to thiete 1,1-dioxide (104). In the attempted c h l o r i n a t i o n - 79 -OH C l 69 146 104 of 117, i t i s possible that 145 was formed, but the 2,4,6-c o l l i d i n e i n t h i s case was s u f f i c i e n t l y basic to cause dehydrohalogenation to 2-phenylthiete. Since thietes are known to be unstable compounds (107,108) and spontaneously polymerize, t h i s may explain the i s o l a t i o n of polymeric material i n the attempted c h l o r i n a t i o n of 117. I t was then of i n t e r e s t to see i f the c h l o r i n a t i o n of the sulfone analogue of 117, 127 using the method of Dittmer and Christy would give the corresponding thiete 1,1-dioxide. However, work up of the reaction gave unreacted 127 as the only i d e n t i f i a b l e material. Cyanuric chloride (148) has been reported as a convenient c h l o r i n a t i n g reagent for alcohols giving no isomerization and possessing the advantage that i t requires no added base such as sodium alkoxide or pyridine (123) . For example, 2-pentanol (147) was converted with 148 to give only 2-chloropentane (149), that i s , no isomerization occurred. When 117 was treated with cyanuric c h l o r i d e , 3-chloropropenylbenzene (115) and polymerized material were - 80 -obtained. OH 3 CH 3CH 2CH 2CHCH 3 147 C l 3 CH 3CH 2CH 2CHCH 3 149 + C l N N C l ^ N ^ C l 148 OH N HO N OH 150 The i s o l a t i o n of 115 from these experiments may be explained by analogy to some s i m i l a r r e s u l t s obtained by Dittmer and Kotin (67). They reported that treatment of 3-chlorothietane (151) with triphenylphosphine re s u l t e d C l 151 S 152 C l A Ph_P CH2C1 - >- CH2=CHCH2C1 + Ph 3PS 153 154 - 81 -i n d e s u l f u r i z a t i o n to a l l y l chloride (154) . It was proposed that 151 rearranged through the sulfonium ion 152 to chloromethylthiirane (153) , followed by d e s u l f u r i z a t i o n with triphenylphosphine. Thus i n the attempted c h l o r i n a t i o n of 117, i t i s possible that the c h l o r i n a t i o n to 145 occurred, then 145 rearranged through a s i m i l a r mechanism to 2-chloromethyl-l-phenylthiirane (155), but was s u f f i c i e n t l y unstable to spontaneously d e s u l f u r i z e to the o l e f i n 115. Aromatically substituted t h i i r a n e s are known to r e a d i l y lose elemental s u l f u r and to be converted to the corresponding o l e f i n (112) . Electron withdrawing groups such as CO, COOR or C l also promote the loss of s u l f u r . Thus i t does not seem unreasonable that 155 w i l l spontaneously desulfurize without the aid of triphenylphosphine. Attempted oxidation of 117 to 2-phenyl-3-thietanone (156) using the Oppenauer oxidation, Moffatt oxidation or the use of other hydrogen abstractors were without success. The use of hydrogen abstractors, diethylazodicarboxylate (124,125) or 1-chlorobenzotriazole (126) appeared to be a mild method of o x i d i z i n g alcohols to ketones i n good y i e l d . When 117 was allowed to react with diethylazodicarboxylate S 155 - 82 -OH 0 [0] S S 117 156 for several weeks the orange color due to the o x i d i z i n g agent disappeared, however, work up of the reaction f a i l e d to indicate the presence of 156. S i m i l a r l y the treatment of a benzene solution of 117 with 1-chlorobenzotriazole gave a mixture of products, none of which were indicated to be 156. I t i s . i n t e r e s t i n g to note that attempted oxidation of the sulfone analogue of 117 also f a i l e d to give the corresponding thietanone. The Oppenauer oxidation procedure has been described as a method of o x i d i z i n g secondary alcohols to the corresponding ketones with aluminum alkoxides i n the presence of a large excess of acetone under mild conditions (127). Oxidation i s accomplished by the transfer of hydride ion from the alcohol carbon to the carbonyl carbon of acetone. Using the conditions described, 117 was refluxed with aluminum isopropoxide and acetone i n dry benzene for 12 hours. Work up of the reaction gave only unreacted alcohol 117. Increasing the r e f l u x time resulted i n only a greater amount of decomposition to u n i d e n t i f i e d products. - 83 -The Moffatt oxidation procedure has been described as a mild method which i s p a r t i c u l a r l y useful with s t e r i c a l l y hindered alcohols. Oxidation of the alcohol i s accomplished with DMSO and dicyclohexylcarbodiimide (DCC) i n the presence of a suitable acid (128) or with DMSO and ace t i c anhydride (129). Using the methods described f a i l e d to give the i s o l a t i o n of 156 from the r e s u l t i n g dark reaction mixtures. Preparative t i c resulted i n the separation of 5 bands. None of the fractio n s appeared to contain appreciable amounts of a compound possessing a carbonyl function i n the i r spectrum and attempts to i d e n t i f y the reaction products were not performed. During the course of t h i s work 3-hydroxy-2-phenylthiolane (157) was prepared. I t was of i n t e r e s t to subject 157 to the Moffatt oxidation to see i f t h i s s u l f u r r i n g system with a 3-hydroxyl group could be oxidized to the B-keto compound 158. The method employed was that described by Pfi t z n e r and Moffatt (128), using t r i f l u o r o a c e t i c acid as the suitable acid and benzene as the solvent. An o i l was - 84 -i s o l a t e d upon work up and was indicated to contain mostly 158 by the i r spectrum of the crude product, which showed a carbonyl band at 1725 cm (dicyclohexyl urea, the side product from the reaction has a carbonyl band at 1685 cm . The nmr spectrum of the crude o i l showed peaks which could be a t t r i b u t e d to the structure of 158 (a m u l t i p l e t at 6 7.35 was a t t r i b u t e d to the aromatic protons, a s i n g l e t at 6 4.55 to the benzylic proton and a m u l t i p l e t at 6 2.95 accounted for the rest of the protons). When the crude o i l was subjected to preparative t i c or column chromatography using s i l i c a gel or vacuum d i s t i l l a t i o n a pure sample of 15G was not obtained. However the r e s u l t s indicated that a f3-hydroxysulfide can be oxidized to the corresponding g-ketosulfide. Thus 117 should have undergone oxidation to 156, but probably due to the greater r i n g s t r a i n and thus the greater tendency of thietanes to undergo rin g cleavage, 117 may have decomposed rather than being oxidized to the thietanone. The conditions of the Moffatt oxidation may have been a c i d i c enough to cause ri n g cleavage of the thietane but not the thiolane. F l e i c h e r et al_. reported that alcohols could be converted to the primary amines, s t e r e o s p e c i f i c a l l y , i n good y i e l d s through an azide (130). In general the alcohol i s converted to the benzene sulfonate, which i s heated at ROH > ROSO„C^H c > RN-, > RNH~ 2 6 5 3 2 - 85 -135 i n diethylene g l y c o l with sodium azide for 16 hours, r e s u l t i n g i n n u c l e o p h i l i c displacement of the sulfonate by the azide ion. The r e s u l t i n g azide was reduced with lithiu m aluminum hydride to the primary amine. Using these conditions an attempted conversion of 117 to 3-azido-2-phenylthietane (160) resulted i n decomposition and the conditions were modified to minimize the degradation of the thietane. At each step of the reaction a small sample was dissolved i n methanol and analyzed by gc/mass spectro-metry. 160 5 - 86 -To a tetrahydrofuran solution of 117 and benzylsulfonyl chloride at -40°, a molar equivalent of triethylamine was slowly added. The p r e c i p i t a t e d triethylamine hydrochloride was removed by f i l t r a t i o n a f t e r 1 hour. The f i l t r a t e was concentrated under vacuum, using a cold water bath, to leave a gummy residue of 2-phenyl-3-thietanyl benzylsulfonate (159). If benzenesulfonyl chloride was used the corresponding benzenesulfonate ester was not formed. This indicated that the sulfonate ester formation occurred through the formation of a sulfene intermediate, since a sulfene cannot be formed from benzenesulfonyl chloride. The i r spectrum of the crude material did not have an alcohol band at 3320 and 3310 cm as seen i n the i r spectrum of 117, and had strong absorptions at 1185 and 1365 cm ^ i n d i c a t i v e of a sulfonate ester. The crude material was found to consist mainly of 159 by gc/mass spectroscopic analysis. The mass spectrum of 159 (Scheme 5) showed a base peak at m/e 105, which could be explained by a fragmentation pattern involving the formation of an epoxide, accompanied by d e s u l f u r i z a t i o n . This process must occur very r e a d i l y since no molecular ion i s observed. The fragments at m/e 13 3, 106 and 77 are the other intense peaks and are accounted for i n the pattern presented. The configuration of 159 was assumed to have the phenyl and the ester group i n a trans r e l a t i o n s h i p from the configuration of 117, since formation of the sulfonate ester should not a f f e c t the configuration of the substituents - 87 -Scheme 5. Fragmentation Pattern of 2-Phenyl-3-thietanyl Benzylsulfonate (159) . m/e 105 m/e 77 on the r i n g . The nmr spectrum of 159 was not obtained due to i t s lack of s o l u b i l i t y i n common nmr solvents. Since 159 appeared to be an unstable compound, attempts to pu r i f y the crude product by r e c r y s t a l l i z a t i o n were not done, and the i s o l a t e d crude product was used immediately i n the substitution reaction with sodium azide. Crude 159 was s t i r r e d with a suspension of sodium azide i n hexamethylphosphoramide (HMPA) at room temperature - 88 -for 24 hours under a nitrogen atmosphere. Work up of the reaction mixture resulted i n the i s o l a t i o n of 3-azido-2-phenylthietane (160) as an orange o i l . The i r spectrum of the o i l no longer had strong absorptions at 1185 and 1365 cm due to a sulfonate ester, but had a strong absorption at 2120 cm ^ i n d i c a t i v e of the azide function. The gc/mass spectrum indicated a 50:50 mixture of 2 componments, which were assumed to be the c i s and trans isomers of 160. This seems to dispute the s t e r e o s p e c i f i c nature of the reaction claimed by F l e i s c h e r (130). In t h i s case the reaction may not proceed by a pure SN 2 mechanism alone. A p o s s i b i l i t y of a neighbouring group p a r t i c i p a t i o n , to give an intermediate phenonium or sulfonium ion could give the trans product. The mass spectral data was used to i d e n t i f y the isomers. The fragmentation patterns are explained on the basis of a z i r i d i n e intermediates (Schemes 6 and 7). Cis-160 had a shorter retention time i n the gc and neither isomer showed a molecular ion i n the mass spectrum. I t was assumed that the formation of the a z i r i d i n e occurs through a trans mechanism of elimination. Thus, cis-160 would require the elimination of a hydrogen r a d i c a l and trans-160 the elimina-t i o n of a sul f u r r a d i c a l . This mechanism provides an explanation for the difference of 1 mass unit for the base peaks at m/e 130 for trans-160 and m/e 129 for c i s -160, as well as the strong m/e 116 peak i n the spectrum of trans-160, which i s absent i n the spectrum of cis-160. The - 89 -Scheme 6. Fragmentation Pattern of cis-3-Azido-2-phenyl-thietane (160) . m/e 77 Scheme 7. Fragmentation Pattern of trans-3-Azido-2-phenyl-thietane (160). H m/e 13 0 m/e 103 m/e 116 m/e 129 fragment of cis-160 cannot r e a d i l y lose a methylene r a d i c a l to give a corresponding m/e 115 peak. In f a c t the m/e 129 fragment appears to be a f a i r l y stable ion, possibly due to the conjugation of the double bonds and r e s i s t s - 91 -further cleavage. This i s evidenced by the r e l a t i v e small abundance of the m/e 77 fragment i n cis-160 as compared to the base peak, than i n a s i m i l a r comparison of the m/e 77 peak and the base peak i n trans-160. A secondary fragmentation pattern involving the loss of a methylene s u l f i d e also supports the assignment of configuration to the isomers. In cis-160 the loss of methylene s u l f i d e i s followed by a trans elimina-t i o n of HN^ to give the m/e 102 fragment. With trans-160 a trans elimination of HN^ i s not possible and the loss of methylene s u l f i d e i s followed by the loss of N 2 or to give the m/e 116 and 103 fragments respectively. I t i s i n t e r e s t i n g to note that i n the mass spectra of the sulfonate ester, 159, and the azido compound, 16 0, the su b s t i t u t i o n at C-3 of the thietane played a major r o l e i n the fragmentation of the molecule and the formation of a stable thiobenzaldehyde ion does not r e s u l t as i n the fragmentation of the 3-hydroxyl compound, 117 (Scheme 3). The absence of the thiobenzaldehyde ion also indicates the preference of the epoxide or the a z i r i d i n e to form at the benzyl carbon atom and not at the methylene carbon (C-4) of the thietane, a route which should r e a d i l y r e s u l t i n the formation of a thiobenzaldehyde ion. Because of the unstable nature of azides, and t h e i r p o t e n t i a l hazardous properties (130), no attempts were made to p u r i f y the crude product or to i s o l a t e the isomers. The crude o i l was used immediately i n the reduction reaction. A tetrahydrofuran solution of crude 160 was reduced with lithium aluminum hydride at room temperature for 12 hours. Work up of the reaction resulted i n the i s o l a t i o n of a dark o i l . Gc/mass spectroscopic analysis of the crude product indicated the presence of three main f r a c t i o n s . C a l c u l a t i o n of the peak areas indicated the r e l a t i v e amount of f r a c t i o n 1 to be 40%, of f r a c t i o n 2 to be 40% and of f r a c t i o n 3 to be 20%. Fraction 1 was not i d e n t i f i e d . The mass spectrum of f r a c t i o n 1 showed major peaks at m/e 134, 133, 107, 105 (base peak), 92, 79 and 77. The p o s s i b i l i t y of t h i s f r a c t i o n being the desired product, 3-amino-2-phenylthietane (5_) was ruled out due to the base peak at m/e 105, an ion that cannot be r e a d i l y r a t i o n a l i z e d from the structure of 5_. Fraction 2 was not p o s i t i v e l y i d e n t i f i e d . However extraction of the crude product with 10% hydrochloride solution led to the i s o l a t i o n of an o i l which had an i d e n t i c a l mass spectrum as f r a c t i o n 2, possessing major peaks at m/e 135, 118, 117 (base peak), 92, 91, 77 and 65. There was a p o s s i b i l i t y that t h i s could be the r i n g opened product, 2-amino-l-phenylpropanthiol (161). A fragmentation pattern could be r a t i o n a l i z e d to explain most of the major ions i n the mass spectrum (Scheme 8). The i r spectrum of t h i s material showed the p o s s i b i l i t y of a primary amine, but an expected t h i o l absorption at 2600-2550 cm was not present (131). The nmr spectrum appeared to be consistent - 93 -Scheme 8. F r a g m e n t a t i o n P a t t e r n o f 2 - A m i n o - l - p h e n y l -p r o p a n t h i o l ( 1 6 1 ) , F r a c t i o n 2. H /~NH 1 c— c CH. a---e, - • SH -e,-NH "SH H 161 3; H \ // -CH. H -•CH. H H + C C = NH, m/e 119 -H- o r 2«H C H = C = = N H 2 m/e 118 + CH C ^ N H m/e 135 -C 2H 2S + m/e 117 -CN' m/e 77 m/e 91 - 94 -heme 9. Fragmentation P a t t e r n of 2-Amino-2-phenyl-t h i e t a n e (5), F r a c t i o n 3. - 95 -with the structure of 161, however, treatment with D^O f a i l e d to indicate the presence of any replaceable protons. The protons of the primary amine and of the t h i o l would be expected to exchange protons r e a d i l y . The data i s then inconclusive as to the nature of f r a c t i o n 2. The mass spectrum of f r a c t i o n 3 could be r a t i o n a l i z e d on the basis of the structure of 5_. The fragmentation pattern proposed, shows the formation of a cyclopropenyl ion and has been previously reported i n explaining the mass spectrum of thietes (108,109). A molecular ion peak at m/e 165 was also present. Attempts to obtain a pure sample of f r a c t i o n 3 by column chromatography, or a c i d i c extraction procedures, or by preparation of the hydrochloride s a l t from an ethereal solution were without success. Although the preparation of 5_ by t h i s route may be possible by refinement of the experimental conditions, for example, the use of a le s s basic reducing agent than l i t h i u m aluminum hydride, the preparation of 5_ was not pursued. These experi-ments were run near the end of the present studies and the time required to prepare s u f f i c i e n t amounts of the s t a r t i n g materials was considered to be too lengthy to warrant further studies at t h i s time. Dittmer et al_. have prepared 3-thietanyltrimethylammonium tosylate (162) from 3-hydroxythietane (68) (109). The method used involved reacting 6_8 with trimethylamine and p_-toluenesulfonyl chloride i n a c e t o n i t r i l e for 4 hours at - 96 -OH S 68 N(CH 3); OTS S 162 -20 , to give a 31% y i e l d of 162. Pinkus et a l . have rep l a c e d t o s y l a t e s w i t h anhydrous ammonia i n a s t e e l bomb at e l e v a t e d temperatures to the corresponding ammonium t o s y l a t e s (132). The primary amine was recovered by a s e r i e s of a c i d and base e x t r a c t i o n procedures. In an attempt to prepare 2-phenyl-3-thietanylammonium b e n z y l -s u l f o n a t e (163) from 3-hydroxy-2-phenylthietane (117) a 0S0oCHoC,H.-2 2 6 5 CH3CN OSO^CH^C^H,. 2 2 6 5 159 163 procedure was adapted from these methods. Thus the sulfonate ester 159 was prepared and i s o l a t e d i n the crude form and dissolved i n dry a c e t o n i t r i l e . This solution was added to an excess of ammonia i n . a c e t o n i t r i l e and s t i r r e d at -20° for 15 hours. A p r e c i p i t a t e which formed during t h i s time - 97 -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 showed strong peaks at 1050 and 1190 cm ^ i n d i c a t i v e of a sulfonate group and a t y p i c a l ammonium s a l t absorption at 2950-3300 cm ^. The i r spectrum was almost i d e n t i c a l to the i r spectrum of triethylammonium benzylsulfonate i n the 300-1500 cm ^ region. On t h i s basis the p r e c i p i t a t e from the reaction was taken to be ammonium benzylsulfonate. When the f i l t r a t e of the reaction mixture was concentrated under vacuum at room temperature only polymeric material could be i s o l a t e d . The i r spectrum of t h i s material indicated the presence of some unreacted 159. Previously i t was shown that 2-phenyl-thiete 1,1-dioxide (142) was formed from the treatment of the corresponding sulfonate ester (141) with triethylamine. I t i s possible that a s i m i l a r reaction occurred here to give 2-phenylthiete, which spontaneously polymerized. An alternate route to 3-amino-2-phenylthietane (5_) involving reduction of the corresponding sulfone, 3-amino-2-phenylthietane 1,1-dioxide (165) was considered. A solution of 142 i n a 50:50 chloroform:ethanol solution was added to an ammonia solut i o n i n the same solvent system and s t i r r e d at room temperature for 4 hours. Dimethylamine has been added to thiete 1,1-dioxides by the same procedure (82,101). Work up of the reaction using an acid extraction procedure gave 165 as a white amorphous s o l i d i n 50% y i e l d . The i r spectrum showed absorptions at 3330 and 3400 cm - 1 i n d i c a t i v e of the primary amine. The nmr spectrum appears - 98 -165 5 to indicate that a mixture of c i s and trans-165 were formed. The benzylic proton appears to be a pair of overlapped doublets at 5 5.33 with coupling constants of 5.5 and 8.5 Hz. The observed coupling constants are probably due to a pseudoaxial-pseudoequatorial i n t e r a c t i o n of the protons as would be the case i n cis-165 and a pseudoaxial-pseudo-a x i a l i n t e r a c t i o n of the protons i n trans-165 (50,47,57). The addition of ammonia probably involves n u c l e o p h i l i c attack by ammonia at C-3 to give an intermediate carbanion 164. This carbanion i s more stable due to the electron withdrawing e f f e c t s of the sulfone and the phenyl, than the carbanion formed at C-3 by the addition of ammonia at the benzylic carbon. This e f f e c t probably controls the p o s i t i o n of the addition. The a - s u l f o n y l carbanion 164 has e f f e c t i v e l y a planar (sp ) geometry at the carbon (133) and should presumably protonate to give the trans isomer, which has less s t e r i c i n t e r a c t i o n s and thus a more stable structure. Since both c i s and trans 165 was indicated by the nmr spectrum, there does not appear to be such a product control mechanism i n operation, but a non-stereo-s e l e c t i v e addition of a proton to either side of the planar carbanion. Attempted reductions of 165 with l i t h i u m aluminum hydride were c a r r i e d out i n a soxlet apparatus and refluxed for at l e a s t 43 hours. Basic work up of the reaction resulted i n the i s o l a t i o n of a yellow o i l . An i r spectrum of t h i s crude product contained strong sulfone bands at 1135 and 1305 cm ^ and primary amine bands at 3380 and 34 80 cm ^ and a medium absorption at 1645 cm \ A sample of the crude o i l was subjected to preparative t i c to give the separation of at l e a s t 6 components. An i r spectrum of the o r i g i n appeared to indicate the presence of unreacted 165. A l l the other f r a c t i o n s appeared to have l o s t the amine function and two of the fract i o n s had l o s t the sulfone functions as indicated by the i r spectra. The sulfone 166 has been found to be unreactive towards reduction by lithiu m aluminum hydride, and t h i s lack of - 100 -166 • 167 R = morpholino reduction was at t r i b u t e d to s t e r i c hindrance or the resistance of the aluminohydride complex to further attack by the reducing agent (134). The loss of the 3-amino functions has been detected i n the reduction of other thietane 1,1-dioxides with l i t h i u m aluminum hydride (109). Attempted reduction of 144 and 167 has also led to deamination and r i n g cleavage to a number of u n i d e n t i f i e d products (82). Many substituted thietane 1,1-dioxides have been reduced with l i t h i u m aluminum hydride to the corres-ponding thietanes (e.g., 79, 100, 105, 107, 109, 135). In a l l these cases the protons on the a-sulfonyl carbons are not as a c i d i c as i n 144, 165 or 167. The a c i d i c nature of these protons could be involved i n the formation of ri n g opened products, perhaps by hydrogenolysis. - 101 -Phenoxythietanes for MAO Studies NH NH 2 2 o o o o 168 6 2-Phenoxycyclopropylamine (168) i s equipotent with tranylcypromine as a MAO i n h i b i t o r . I t was considered that the synthesis of 3-amino-2-phenoxythietane (6_) would be an e f f e c t i v e a l t e r n a t i v e to 3-amino-2-phenylthietane (5_) . It was hoped that i f the sulfone analogue of 6_ could be synthesized i t would undergo reduction with l i t h i u m aluminum hydride without ri n g cleavage. The synthetic scheme considered involved the cycloaddition of a phenoxy-enamine with sulfene. The use of t h i s unique enamine should also provide some information on the nature of the cycloaddition reaction. The reaction of monochlorohydrin (169) with sodium phenolate gave 3-phenoxy-l,2-propandiol (170) as a waxy s o l i d (136). T r i t u r a t i o n of t h i s s o l i d with ether afforded 170 as c r y s t a l l i n e material i n 52% y i e l d . The i r spectrum had strong absorptions at 1065 and 3310 cm ^ i n d i c a t i v e of the alcohol function and 1260 cm i n d i c a t i v e of the ether function. The nmr spectrum was consistent - 102 -C1CH2CH(0H)CH20H p ^ g g x > 169 u // OCH2CH(OH)CH2OH 170 Pb(OAc) OCH2CHO HNR, 171 \ // CH SO C l OCH — C H N R „ - - > Et 3N 172 R = CH 3 173 R = p y r r o l i d i n e 174 R = CH 3 175 R = p y r r o l i d i n o with the structure of 170 and treatment with D 20 showed the presence of 2 a c i d i c protons. Oxidations of 1,2-glycols with lead tetraacetate r e s u l t i n g i n the cleavage of carbon-carbon bonds to form alkoxyacetaldehydes has been reported (136,137). A s l u r r y of lead tetraacetate i n benzene was slowly added to a benzene solution of 170, while c o n t r o l l i n g the temperature of the exothermic reaction between 25-30°. It was f e l t that an excess of lead tetraacetate decreased the y i e l d s and the addition of o x i d i z i n g agent to 170 avoided even a - 103 -temporary excess of lead tetraacetate. Vacuum d i s t i l l a t i o n of the crude product gave the colourless phenoxyacetaldehyde (171) (136,137) i n 63% y i e l d . The i r spectrum showed absorptions at 1735 and 2730 cm i n d i c a t i v e of an aldehyde function and 1250 cm ^ i n d i c a t i v e of the ether function. The nmr spectrum was consistent with that expected for 171. The aldehyde was found to polymerize r e a d i l y and was used immediately upon preparation i n the enamine reaction. Phenoxy-acetaldehyde (171) was also prepared by the oxidation of 2-phenoxyethanol with lead tetraacetate, but because of the low y i e l d s , t h i s method was discarded i n favor of the g l y c o l oxidation method. The enamines 172 and 173 were prepared by reacting 171 with dimethylamine or p y r r o l i d i n e r e s p e c t i v e l y i n anhydrous ether at 0 - 5 ° , u t i l i z i n g potassium carbonate to remove the water which i s formed from t h i s condensation reaction. In the case of 172, i t was i s o l a t e d as a white s o l i d which decomposed quickly into an o i l . The crude product could not be p u r i f i e d without further decomposition. The i r spectrum indicated the presence of an enamine by the absorptions at 875, 910 and 1600 cm ^, and the ether function by the absorption at 1245 cm \ There was no i n d i c a t i o n of unreacted aldehyde 171 i n the i r spectrum of the crude product. The nmr spectrum showed 2 singlets at ^ 2.26 and- 2.52 i n d i c a t i n g that c i s and trans 172 were formed. With cis-172 s h i e l d i n g of the N-methyl protons by the phenoxy group caused a diamag-netic s h i f t of 0.26 6 units. The presence of 2 o l e f i n i c peaks - 104 -a t 875 and 910 cm i n the i r spectrum c o u l d a l s o be the r e s u l t of the presence o f 2 isomers. In the p r e p a r a t i o n o f 173 a dark o i l was o b t a i n e d . Attempted vacuum d i s t i l l a t i o n o f the o r e s u l t e d i n decomposition, however, a s m a l l sample was f o r c e d over. The i r spectrum had peaks a t 890 and 1600 cm ^ i n d i c a t i v e of the enamine s t r u c t u r e and 1245 cm ^ i n d i c a t i v e of the et h e r f u n c t i o n . The nmr spectrum was c o n s i s t e n t w i t h the s t r u c t u r e of 173. In t h i s case because of the m u l t i p l i c i t y o f the s p l i t t i n g p a t t e r n no c o n c l u s i o n s about the isomer content i n the prod u c t c o u l d be made. The un s t a b l e nature o f 172 and 173 r e q u i r e d t h e i r immediate use i n the c y c l o a d d i t i o n r e a c t i o n upon p r e p a r a t i o n and i s o l a t i o n of the crude product. "A t e t r a h y d r o f u r a n o r a c e t o n i t r i l e s o l u t i o n of 172 and t r i e t h y l a m i n e was r e a c t e d w i t h methanesulfonyl c h l o r i d e a t 0-5°. C o n c e n t r a t i o n o f the brown r e a c t i o n mixture a f t e r the removal of t r i e t h y l a m i n e h y d r o c h l o r i d e r e s u l t e d i n a dark o i l . A t i c a n a l y s i s on s i l i c a g e l i n d i c a t e d the p o s s i b i l i t y o f 7 components. A s m a l l sample was s u b j e c t e d to column chromatography and f o u r f r a c t i o n s were o b t a i n e d . F r a c t i o n 3 had an i d e n t i c a l i r spectrum to t h a t o f the enamine 172 when i t decomposed t o an o i l . F r a c t i o n 4 was found t o be the aldehyde 171 from i t s i r spectrum which was superimposable w i t h t h a t o f an a u t h e n t i c sample. F r a c t i o n 2 was suspected to be the a c y c l i c product 178 by the i r spectrum which possessed s t r o n g enamine bands a t 965 and 1590 cm ^ and s u l f o n e bands a t 1145 and 1325 cm ^. When a sample - 105 -of the crude product was vacuum d i s t i l l e d , a clear l i q u i d was c o l l e c t e d which had an i d e n t i c a l i r spectrum to that of f r a c t i o n 2 obtained from column chromatography. The suspicion that f r a c t i o n 2 was the enamino sulfone 178 was confirmed by the nmr spectrum. The N-methyl protons and the a-sulfonylmethyl protons appeared as the expected si n g l e t s at 5 2.82 and 2.73 respectively. The o l e f i n i c proton was masked by the aromatic protons. The configuration NR 2 S CH °2 H 176 R = CH 3 178 R = CH 3 177 R = p y r r o l i d i n o 179 R = p y r r o l i d i n o SCH 3 180 - 106 -about the double bond i s not known. Fraction 1 was suspected to be the hydrolysis product 180. This was supported by the i r spectrum which indicated the presence of a sulfone by the peaks at 1150, 1170, 1300, 1330 and 1370 cm ^ and the peaks at 1650 and 2740 cm i n d i c a t i v e of an aldehyde function. I t was not c e r t a i n whether 180 was formed during the reaction or as a r e s u l t of the work up procedure. Similar r e s u l t s were obtained when the enamine 17 3 was reacted with sulfene. The products obtained were indicated to be the enamine 179 and i t s hydrolysis product 180. The i r and nmr spectrum of the crude product could be r a t i o n a l i z e d as a mixture of the 2 compounds. The attempted cycloaddition probably resulted i n the formation of the z w i t t e r i o n i c intermediates 176 and 177 (70). Any e l e c t r o n i c e f f e c t s which s t a b i l i z e the intermediate zwitterion (86) or s t e r i c hindrance to c y c l i z a t i o n by large substituents on the a-carbon of the enamine or the s u l f o n y l chloride w i l l promote the formation of a c y c l i c products. Since R-dimethylaminostyrene prefers to undergo cycloaddition, the phenoxyenamines (which are s t e r i c a l l y s i m i l a r to R-dimethylaminostyrene) may s t a b i l i z e the intermediate zwitterion and i n e f f e c t increase i t s l i f e span to allow greater time for a prototropic s h i f t to occur or the proton a to the ether oxygen i s very a c i d i c and i s r e a d i l y l o s t . E i ther of these e f f e c t s would r e s u l t i n a preference for a c y c l i c product. I t appeared that the - 107 -desired 2-phenoxythietane system could not be achieved by t h i s route and i t s preparation was abandoned. Benzylthietanes for MAO Studies 181 7 The i n s e r t i o n of a methylene bridge between the phenyl and the cyclopropane of tranylcypromine (2_) to give 2-benzylcyclopropylamine (181) does.not s i g n i f i c a n t l y a l t e r the MAO i n h i b i t o r y properties (15,16). I t was considered that synthesis of 3-amino-2-benzylthietane (7_) would be an e f f e c t i v e a l t e r n a t i v e to 3~amino-2-phenylthietane (5_) for MAO i n h i b i t i o n studies. I t was thought that the preparation of the sulfone analogue of 1_ would prove to be a productive route. The protons on the a-sulfonyl carbons are not as a c i d i c as i n the 2-phenylthietane 1,1-dioxides and thus reaction with l i t h i u m aluminum hydride should give 1_ with a minimum amount of degradation of the c y c l i c system. In order to prepare the desired system hydrocinnamin-aldehyde (182) was reacted with dimethylamine at 0-5° using potassium carbonate to remove the water formed from t h i s - 108 -2 8 condensation reaction. D i s t i l l a t i o n of the crude product gave an 81% y i e l d of l-dimethylamino-3-phenylpropene (183) as a colourless l i q u i d . A f t e r storage of 183 i n the - 109 -r e f r i g e r a t o r for several days, i t became a pale yellow colour, but no detectable changes i n the i r or nmr spectra was evident. The structure of 183 was confirmed by the i r and nmr spectra and indicated to be the pure trans isomer. The i r spectrum showed peaks at 950 and 1650 cm i n d i c a t i v e of a trans enamine. The nmr spectrum showed the N-methyl protons as a sharp s i n g l e t at 6 2.56 which indicated i t was free of the shielding e f f e c t s of the phenyl. The v i c i n a l coupling constant for the o l e f i n i c protons was 13.5 Hz which i s i n d i c a t i v e of a trans configuration (111). Synthesis of 2-benzyl-3-dimethylaminothietane 1,1-dioxide (184) was accomplished by reacting an a c e t o n i t r i l e solution of 183 and triethylamine with methanesulfonyl chloride at 0-5°. The crude gum obtained from the work up of the reaction could be r e c r y s t a l l i z e d from hexane to give 184 as white needle-like c r y s t a l s i n 36% y i e l d . I t i s i n t e r e s t i n g to note that attempted r e c r y s t a l l i z a t i o n from ethyl methyl ketone resulted i n decomposition to an un i d e n t i f i e d s u l f o n i c acid s a l t , which melted at 190°. No other i d e n t i f i a b l e products were i s o l a t e d from the reaction. The i r spectrum showed sulfone bands at 1135, 1195 and 1315 cm The nmr spectrum showed one s i n g l e t due to the N-methyl protons at <5 2.16 and the i s o l a t i o n of only one geometric isomer was assumed. The nmr and mass spectral data were not conclusive as to which geometric isomer was i s o l a t e d . However, i t has been shown that the cycloaddition - n o -reaction i s s t e r e o s p e c i f i c with respect to the enamine (87) and thus the trans configuration of 184 was assumed. A solution of 184 i n anhydrous ether was slowly added to a suspension of lithiu m aluminum hydride i n anhydrous ether and the mixture was refluxed for 12 hours. Basic work up of the reaction gave 2-benzyl-3-dimethylaminothietane {8) as a yellow o i l . Vacuum d i s t i l l a t i o n resulted i n a 47% y i e l d of 8 as a clear l i q u i d . The trans configuration was assumed from that of 184. The methyl iodide s a l t of 8_ was prepared and r e c r y s t a l -l i z e d from ethanol. A mass spectrum of t h i s s a l t was obtained using the s o l i d probe technique. No molecular ion was observed and the fragmentation could occur by 2 major routes (Scheme 10). The m/e 71 peak i s the base peak and the m/e 58 peak has an abundance value of 67%. I t i s i n t e r e s t i n g to note that a thioaldehyde ion has been postulated as being formed, but does not appear i n the spectrum. I t probably fragments very quickly to the more stable tropylium ion. In t h i s fragmentation pattern i t appears as i f the ammonium substituent i s the primary factor i n d i r e c t i n g the route of fragmentation. Successful reduction of 184 to 8_ provided reassuring evidence that 187 could be reduced with l i t h i u m aluminum hydride to 3-amino-2-benzylthietane (7_) . With the intention of synthesizing 3-amino-2-benzyl-thietane 1,1-dioxide (187), 184 was subjected to the amine - I l l -10. Fragmentation Pattern of the Methyl Iodide S a l t of 2-Benzyl-3-dimethylaminothietane (8). V ° / Y C H3 \ ^CU2—H / — C H 2 C H + + HQ —N (CH_ ) „ i J 2. •CH, 1 CHS m/e 91 l2 m/e 71 CH 2-=N(CH 3) 2 m/e 58 + ( -s Y^-CH 2CH--rr.CHTrr:CH 2 m/e 131 -CH, CH -2 -H + • CH=C=CHCH, m/e 115 m/e 129 - 112 -186 187 oxide elimination procedure. A solution of 184 i n g l a c i a l a c e t ic acid was treated with 30% hydrogen peroxide solution at room temperature for 12 hours. Upon n e u t r a l i z a t i o n with base a p r e c i p i t a t e of the intermediate N-oxide (185) formed. Heating the mixture under vacuum at 60° for 1 hour gave a colourless o i l which could be s o l i d i f i e d by scratching with a glass rod. The crude material was r e c r y s t a l l i z e d from hexane-ethanol to give a 45% y i e l d of 2-benzylthiete 1,1-dioxide (186) as white needle-like c r y s t a l s which melted at 60-62°. Elemental and spectroscopic data were consistent with the structure of 186. I t i s - 113 -i n t e r e s t i n g to note that i n the nmr spectrum of 186 the benzylic protons did not appear as the expected s i n g l e t , but these protons were nonequivalent and appear as a multiplet. The reason for t h i s nonequivalency does not appear to be e a s i l y explainable. The p o s s i b i l i t y that the isomer 188 could be the product was ruled out because of the aqueous conditions of the reaction (51) and the presence of only one o l e f i n i c proton i n the nmr spectrum was determined by the integration of the peaks. Refluxing 186 i n d i l u t e base resulted i n the expected r e t r o - A l d o l condensation to give phenethyl methyl sulfone (189), which was characterized by i r 188 189 and nmr spectra. A small sample of the p r e c i p i t a t e upon ne u t r a l i z a t i o n of the elimination reaction with base was taken and found to melt at 84-87°. This was assumed by the i r spectrum to be the N-oxide 185 due to the strong absorption at 1320 cm ^. Attempted p u r i f i c a t i o n of 185 by r e c r y s t a l l i z a t i o n from hexane-ethanol resulted i n elimination to the thiete 186. In an attempt to increase the y i e l d of the product, 184 was subjected to the Hoffman elimination procedure. An i d e n t i c a l product (186) was obtained, but - 114 -the y i e l d s were consistently lower. Attempts to aminate 186 to 3-amino-2-benzylthietane 1,1-dioxide (187) were without success. An ethanol or a 50:50 ethanol:chloroform solu t i o n of 186 and ammonia were allowed to s i t at room temperature for 65 hours i n a closed system. Evaporation of the solvent gave only unreacted 186. Due to the r e l a t i v e ease at which t h i s reaction was found to take place with 2-phenylthiete 1,1-dioxide (142) and s i m i l a r t h i e t e s , as well as the propensity of th i e t e 1,1-dioxides to add other nucleophiles (e.g., 82,100,101,103,138), the reason for the unreactive nature of 186 i s not known at the present time. Brown has reported that a s t e r e o s p e c i f i c conversion of hindered and unhindered o l e f i n s to primary amines could be achieved by a hydroboration technique (139). For example, treatment of a diglyme solution of 1-phenylcyclopentene (190) with diborane and hydroxylamine-O-sulfonic acid at 100° f o r 3 hours afforded trans-2-phenylcyclopentylamine (191) i n 47% y i e l d . Treatment of 186 by a s i m i l a r procedure resulted i n the recovery of only unreacted 186. OO ^Sr 00 t 190 191 - 115 -An alternate route to 1_ through the preparation of 2-benzyl-3-hydroxythietane (199) was now considered (Scheme 11). Since the aromatic r i n g i s no longer d i r e c t l y attached to the thietane r i n g as i n 3-hydroxy-2-phenylthietane (117), i t was of i n t e r e s t to see i f 1_ could be prepared from 199 by the methods used i n the attempted amination of 117. Direct s u b s t i t u t i o n of a phenyl a to the s u l f u r appears to make the thietane r i n g more prone to r i n g cleavage. The following discussion w i l l then be concerned with the attempted preparation of 199. When a sodium ethoxide solution was added to an ethanolic solution of ethylacetotriphenylphosphonium chloride (192) and phenylacetaldehyde a p r e c i p i t a t i o n of triphenylphosphine oxide occurred almost immediately. Work up of the reaction a f t e r 16 hours gave a colourless l i q u i d . Spectroscopic data indicated that the compound was ethyl-4-phenyl-3-butenoate (193) and not the expected 2-butenoate derivative (195) (140). The mechanism of the Wittig reaction requires that the carbonyl group be replaced s p e c i f i c a l l y by a carbon-carbon double bond without the formation of isomeric o l e f i n s (141). I t can be assumed that 195 was formed, but under the basic conditions of the reaction 195 completely isomerized to 193 (142). The basic conditions could be avoided by the i s o l a t i o n of carboethoxymethylenetriphenyl phosphorane (194). Thus 192 was treated with 1 N sodium hydroxide solution u n t i l the aqueous solution became basic to phenolphthalein indicator. - 116 -Scheme 11. Proposed Route to 3-Amino-2-benzylthietane (7_) . C l + 0 0 (C^H_) _PCH„COCH„CH_ b D J 2 2 6 PhCH2CHO NaOEt •CH = CHCH2COCH2CH3 192 193 NaOH 0 (C gH 5) 3P=rCHCOCH2CH3 PhCH2CHO 0 I I CH2CH =CHCOCH 2CH 3 194 195 LiAlH EtOH -CH„CH-=CHCH„OH cyanuric chloride 196 Vv ^-CH 2CH=CHCH 2C1 P e r a c l d > ^ / > — CH 2 O IX CH2C1 197 198 OH H2S,NaOEt NH, -CH; 199 7 - 117 -The r e s u l t i n g gummy p r e c i p i t a t e was r e c r y s t a l l i z e d from ethyl acetate to give 194 as white amorphous c r y s t a l s . Phenylacetaldehyde was added to a benzene solut i o n of 194 and s t i r r e d at room temperature for 4 8 hours. Work up of the reaction resulted i n the i s o l a t i o n of a yellow o i l . The i r spectrum indicated the presence of an a,B-unsaturated ester by the strong absorption at 1715 cm ^ as opposed to a strong absorption at 1735 cm i n the i r spectrum of 193. The nmr spectrum confirmed the structure of 195 and showed a 30% contamination with triphenylphosphine oxide. A v i c i n a l coupling constant of 16 Hz for the o l e f i n i c protons indicated a trans configuration. This i s consistent with the findings that the trans isomer i s always formed predomin-antly or excl u s i v e l y i f resonance s t a b i l i z e d alkylidene phosphoranes are used i n the Wittig reaction (141). Vacuum d i s t i l l a t i o n gave pure trans-195 i n 64% y i e l d . However, during the f i n a l stages of the d i s t i l l a t i o n , isomerization occurred to give a f r a c t i o n which was shown to contain 59.5% of 195 and 4 0.5% of 193 by nmr ana l y s i s . Apparently heating of 195 also caused isomerization of the double bond to give 193, since the presence of 193 was not indicated i n the nmr spectrum of the crude product. It was next necessary to reduce the conjugated ester 195 to the primary a l l y l i c alcohol, 4-phenyl-2-buten-l-ol (196). Lithium aluminum hydride could not be used since conjugated o l e f i n s are reduced by t h i s reagent. A method - 118 -employing the i n s i t u formation of lithiu m aluminum mono-ethoxy hydride was reported as being an e f f e c t i v e method of reducing conjugated esters to the corresponding a l l y l i c alcohols (143). To an ethereal solution of f r e s h l y prepared lithium aluminum monoethoxy hydride, an ethereal solution of 195 was slowly added. Work up of the reaction a f t e r 4 8 hours resulted i n the i s o l a t i o n of a dark o i l . Vacuum d i s t i l l a t i o n of t h i s o i l gave a 27% y i e l d of 196. The configuration about the double bond was not conclusively determined as the peaks due to the o l e f i n i c protons were overlapped and v i c i n a l coupling constants could not be determined. I t was recently reported that commercially avail a b l e sodium bis-(2-methoxy)aluminum hydride (Redal ) s e l e c t i v e l y reduces conjugated a,3-unsaturated carbonyls to a l l y l i c alcohols (144). However, the use of Redal i n the reduction of 195 gave only minimal y i e l d s of 196. Conversion of a l l y l i c alcohols to a l l y l i c chlorides requires the use of thio n y l chloride and base (145) or the use of methanesulfonyl chloride and a mixture of l i t h i u m chloride, dimethylformamide and c o l l i d i n e (146) to prevent a l l y l i c rearrangements from occurring. Employing eith e r f of these methods to the conversion of 196 to l-chloro-4-phenyl-2-butene (197) resulted i n low y i e l d s of product. On the other hand, when 196 was treated with cyanuric chloride (148) at 100° for 2 hours, vacuum d i s t i l l a t i o n of the crude product gave a 65% y i e l d of 197. - 119 -The low y i e l d obtained i n the reduction of the ester 195 was suspected to be the r e s u l t of the p u r i f i c a t i o n step, since the d i s t i l l a t i o n of the crude alcohol, 196, could not be accomplished without the use of very high temperatures. However, when the crude alcohol 196 was treated with 148, the y i e l d s of the c h l o r i d e , 197 obtained were very small. Due to the consistent low y i e l d s obtained i n the preparation of the alcohol, 196, the preparation of 199 by t h i s route was abandoned. Synthesis of 3-Hydroxy-2-phenylthiolane (203) I t was previously found that the chloromethyl epoxide system of 3-chloro-l-phenylpropylene oxide-1,2 (116) formed a 3-hydroxythietane upon treatment of hydrogen s u l f i d e i n sodium ethoxide. Since a chloroethyl epoxide system could be r e a d i l y obtained from 193, i t was of i n t e r e s t to see i f a s i m i l a r treatment of l-chloro-4-phenylbutylene oxide-3,4 (202) would lead to a 3-hydroxythiolane. This reaction may give further i n s i g h t into the e l e c t r o n i c and s t e r i c e f f e c t s of the sulfhydride ion attack on the epoxide. Reduction o f trans-193 with l i t h i u m aluminum hydride i n anhydrous ether gave trans-4-phenyl-3-buten-l-ol (200) (147, 148), i n 77% y i e l d . None of the c i s isomer was detected. Chlorination of 200 with cyanuric chloride at 100° gave l-chloro-4-phenyl-3-butene (201) i n 72% y i e l d . The i r spectrum of 201 showed a strong absorption at 975 cm ^ and - 120 -204 i n the nmr spectrum a v i c i n a l coupling constant of 16 Hz for the o l e f i n i c protons; both these spectra were i n d i c a t i v e of a trans configuration for the o l e f i n 201• Epoxidation of 201 with monoperphthalic acid gave a mixture of c i s - and trans-l-chloro-4-phenyIbutylene oxide-3,4 - 121 -(202). A gc analysis of the crude product indicated that the trans isomer was present to the extent of 70%. A pure sample of the c i s isomer, by preparative gc and a pure sample of the trans isomer by f r a c t i o n a l d i s t i l l a t i o n were obtained. The nmr spectrum of the trans isomer showed a v i c i n a l coupling constant of 2.5 Hz for the epoxide protons, which i s i n the range expected for trans epoxides (111). In the nmr spectrum of the second isomer the peaks due to the epoxide protons were overlapped and assumed to be that of the c i s isomer. Exposure of trans-202 to a saturated solution of hydrogen s u l f i d e i n a sodium ethoxide solution i n ethanol gave a colourless l i q u i d . The reaction could proceed to give either 3-hydroxy-2-phenylthiolane (203) or 2-(a-hydroxybenzyl)-thietane (204) by mechanisms which have previously been discussed. Spectroscopic data were consistent with either structure. The material i s o l a t e d was confirmed to be 203 by a series of reactions as shown i n Scheme 12 and by the p o s i t i v e i d e n t i f i c a t i o n of 2-phenyl-2-thiolene 1,1-dioxide (207) . Oxidation of 203 with m-chloroperbenzoic acid (m-CPBA) i n chloroform at room temperature for 12 hours gave the corresponding sulfone, 3-hydroxy-2-phenylthiolane 1,1-dioxide (205) as a gummy s o l i d . R e c r y s t a l l i z a t i o n from hexane-ethanol gave 205 as white c r y s t a l s . The nmr spectrum of 205 indicated a trans r e l a t i o n s h i p between the hydroxyl and phenyl, the coupling constant J . of 9.0 Hz being i n d i c a t i v e - 122 -Scheme 12. Sequence of Reactions Used i n the I d e n t i f i c a t i o n of 3-Hydroxy-2-phenylthiolane (203) . H 206 207 of a pseudoaxial-pseudoaxial i n t e r a c t i o n of the protons i n a 5-membered r i n g (111). Treatment of 205 with a t e t r a -hydrofuran solution of benzylsulfonyl chloride and triethylamine i n molar quantities gave a 75% y i e l d of 1,l-dioxy-2-phenyl-3-thiolanyl benzylsulfonate (206) as a waxy residue. Attempted r e c r y s t a l l i z a t i o n of 206 resulted i n further decomposition, thus 206 was used as the crude product i n the subsequent elimination reaction. Treatment of a benzene solution of 206 with t r i e t h y l -amine resulted i n elimination of the sulfonate to give 2-phenyl-2-thiolene 1,1-dioxide (207) . R e c r y s t a l l i z a t i o n from - 123 -benzene-petroleum ether (30-60 ) gave white c r y s t a l s of 207 i n a 46% y i e l d . The nmr spectrum of t h i s product showed the o l e f i n i c proton as a t r i p l e t at 6 6.70 as expected for 207. Had the o r i g i n a l material been 204, the f i n a l product from the above treatment would have given the o l e f i n 208. The nmr spectrum of the o l e f i n 208 would be expected to show the o l e f i n i c proton as a s i n g l e t or as part of the aromatic multiplet. OH 204 208 In the reaction of sodium sulfhydride with the epoxide 202, the attack of the sulfhydride ion appears to be s o l e l y under the influence of the e l e c t r o n i c properties of the epoxide. Thus the sulfhydride ion attacked the more electron d e f i c i e n t carbon of the epoxide, although t h i s carbon would appear to be the more s t e r i c a l l y hindered carbon of the epoxide. A s i m i l a r r e s u l t was obtained with 3-chloro-l-phenylpropylene oxide-1,2 (116). Therefore, i t can be stated that i n general n u c l e o p h i l i c attack of a sulfhydride ion on an epoxide i s stereoselective and w i l l occur at the most electron d e f i c i e n t carbon unless there i s severe s t e r i c hindrance. - 124 -2. synthesis of Thietane 1,1-Dioxides for Analgetic Studies The thietane 1,1-dioxide required for analgetic studies was 3-(1 1-dimethylamino)ethyl-2,2-diphenylthietane 1,1-dioxide (16). The synthetic scheme considered involved the formation of the thietane 1,1-dioxide system by the cycloaddition of an enamine to a sulfene. 211 16 Diphenylacetaldehyde (209) was added to an ethereal solution of dimethylamine containing a suspension of potassium carbonate and cooled to 0-5°. Work up of the reaction a f t e r - 125 -12 hours gave a white s o l i d which was r e c r y s t a l l i z e d from petroleum ether (30-60°) to give the enamine 210 i n 34% y i e l d as needle-like c r y s t a l s . The i r spectrum showed absorptions at 895, 950 and 1625 cm i n d i c a t i v e of the enamine structure. The nmr spectrum v/as consistent with the structure of 210, the o l e f i n i c and dimethylamino protons occurring as s i n g l e t s . Heating a small sample of 210 with d i l u t e acid, followed by the treatment of the hydrolysis product with 2,4-dinitrophenylhydrazine gave the 2,4-dinitro-phenylhydrazone der i v a t i v e of 209. The enamine 210 could be stored under nitrogen at -15° for several months, but decomposed r e a d i l y at room temperature. Attempted cycloaddition of 210 with ethanesulfonyl chloride and triethylamine to 3-dimethylamino-2,2-diphenyl-thietane 1,1-dioxide (211) was without success. The reaction became a purple colour and work up of the reaction gave a yellow s o l i d residue. The i r spectrum indicated that t h i s residue was mostly a mixture of 209 and 210. R e c r y s t a l l i z a t i o n of t h i s residue with ethanol gave only 210. Repeating the reaction using methanesulfonyl chloride or benzylsulfonyl chloride gave s i m i l a r r e s u l t s . In the cycloaddition of enamines with sulfenes a two step mechanism involving the formation of a z w i t t e r i o n i c intermediate i s the preferred mechanism (70). The formation of the purple colour i n the reaction could be due to the formation of a z w i t t e r i o n i c intermediate (212) or to the - 126 -N(CH3) 2 + N ( C H 3 ) 2 c C C - c + H \ H S 0 CHCH 3 S 0 2 2 212 213 formation of excess methyl sulfene. Two possible e f f e c t s may be operative i n preventing c y c l i z a t i o n . If the purple colour i s due to the formation of excess sulfene, then the bulky nature of the phenyls may s t e r i c a l l y r e s i s t the formation of 212. I n i t i a l attack of the methyl sulfene on the enamine 210 should occur, since 210 would be 2 expected to be close to a sp configuration at the o l e f i n i c carbons and thus possess no s t e r i c hindrance to the attack of the sulfene from above or below the planar system. However, s t e r i c repulsion from the 2 phenyls may prevent the i n i t i a l addition product from forming the zwitte r i o n i c intermediate 212. Even i f the zw i t t e r i o n i c intermediate 212 were formed and thus the cause of the purple colour of the reaction, the diphenyls may s t e r i c a l l y i n h i b i t the c y c l i z a t i o n through non-bonded in t e r a c t i o n s between one of - 127 -the phenyls and the dimethylamino group as shown i n the resonance form of the zwitterion (213). Formation of 213 may be e s s e n t i a l for c y c l i z a t i o n . Formation of the alt e r n a -t i v e a c y c l i c product would involve the loss of a phenyl cation or the loss of methylsulfene. The loss of methyl sulfene would r e s u l t i n the formation of the i n i t i a l enamine 210 and i s probably preferred, due to the more stable nature of the sulfene. A build-up of excess sulfene would eventually dimerize or polymerize. It has been suggested that only one of the aromatic groups of methadone i s involved i n i t s binding to the analgetic receptor (25,27). Previous studies with 2,4-diaryl-3-dimethylaminomethylthietane 1,1-dioxides (17) lead 17 214 R = H 215 R = CH 3 to compounds without a high degree of a c t i v i t y (39). I t was suggested that one of the aromatic groups s t e r i c a l l y i n t e r f e r e d with the close approach of the molecule to the analgetic receptor. Only those compounds i n which the aromatic groups were i n a c i s configuration to each other - 128 -were prepared. These observations led to the synthesis of the monophenyl analogues 214 and 215 as p o t e n t i a l analgetics. The synthetic pathway employed i n the preparation of these compounds i s outlined i n Scheme 13 using the preparation of 214 as the example. The experimental techniques used i n the synthetic scheme have been previously determined (39). The following w i l l then be a b r i e f discussion of the synthetic steps i n the preparation of 214 and 215. Addition of phenylacetaldehyde (216) to a suspension of potassium carbonate i n dimethylamine at 0-5° afforded trans-g-dimethylaminostyrene (143) (39,82,149). A s i m i l a r treatment of propionaldehyde (219) and morpholine (221) gave 1-morpholinopropene (222). A mixture of c i s and trans isomers of 222 was indicated by i r and nmr spectra. The 1 2 K 2 C 0 3 1 2 R xCH 2CHO + HNR 2 — ^-^ ITCHrzCHNR* 216 R 1 = Ph 220 R 2 = CH 3 143_ R 1 = Ph,R 2 = CH 3 219 R 1 = CH 221 R 2 = morpholino 2_22 R 1 = CH ,R 2 = morpho-l i n o i r spectrum showed absorptions at 875 cm ^ i n d i c a t i n g a c i s o l e f i n and 950 cm i n d i c a t i n g a trans o l e f i n as well as an enamine band at 1665 cm \ In the nmr spectrum the g-o l e f i n i c protons of the two isomers were overlapped and the complex was centered at 6 5.7. The v i c i n a l coupling constants were determined to be 12 and 16 Hz, but the - 129 -Scheme 13. Synthetic Pathway for 3-Dimethylaminomethyl-2-phenylthietane 1,1-Dioxide (214). 218 214 - 130 -isomer r a t i o was not calculated due to the spectrum. complexity of the 1 2 3 E t 3 N R CH=rCHNR2 + R CH 2S0 2C1 >-143 R 1 = Ph, R 2 = CH 3 223_ R 3 = H 222 R 1 = CH , R 2 = morpho- 2_2_4 R 3 = CH l i n o 225 RJ = Ph When an a c e t o n i t r i l e solution of 143 and methanesulfonyl chloride (223) was treated with triethylamine at 0-5° for 12 hours, work up of the reaction gave 3-dimethylamino-2-phenylthietane 1,1-dioxide (144) (82) i n 84% y i e l d . The material i s o l a t e d was suspected to be pure trans-144 (the phenyl and dimethylamino are i n a trans r e l a t i o n s h i p , both i n a pseudoequatorial p o s i t i o n ) , since.trans-143 was the s t a r t i n g o l e f i n . The cycloaddition of sulfenes to enamines has been shown to be s t e r e o s p e c i f i c with respect - 131 -to the o l e f i n (87,88). The magnitude of the v i c i n a l coupling constant, J = 8.0 Hz, would support a pseudoaxial-pseudoaxial i n t e r a c t i o n between H & and H^ corresponding to a dihydral angle which approaches 180°. This would necessitate that the phenyl and dimethylamino are both pseudoequatorial and trans to each other. When ethanesulfonyl chloride (224) was used, the cycloaddition reaction gave 3-dimethylamino-4-methyl-2-phenylthietane 1,1-dioxide (226) i n 16% y i e l d . The nmr spectrum indicated that only 1 geometric isomer was present, by the sharp s i n g l e t for the dimethylamino protons at 6 2.18. I f a mixture of geometric isomers were present, the N-methyl proton s i n g l e t s of the isomers would be expected to have d i f f e r e n t chemical s h i f t s (39,90). The nmr spectrum indicated that the isomer of 226 obtained had the r-2,t-3,c-4 configuration (as shown). The coupling constant for H H, and H.H were equivalent and had a a b b e ^ magnitude of 8.0 Hz. If i t i s assumed that the reaction i s s t e r e o s p e c i f i c with respect to the enamine, the other isomer of 226 possible would have a r-2,t-3,t-4 configuration. In t h i s configuration J ^ would be expected to be d i f f e r e n t from J^c' since the dihedral angle for HaH^ would approach 180° and for would approach 90°. I t was also noticed that and J ^ c i n 226 was equivalent to J ^ i n 144, and the chemical s h i f t values of H a, H^, and the dimethyl-amino protons i n 144 and 226 were almost i d e n t i c a l . In the - 132 -r-2,t-3,t-4 isomer of 226 these protons would be expected to have d i f f e r e n t chemical s h i f t values to those of 144, due to a d i f f e r e n t chemical environment of the protons. The low y i e l d obtained i n the preparation of 226 prompted the use of 222 and benzylsulfonyl chloride (225) i n the cycloaddition reaction i n an attempt to increase the y i e l d of c y c l i z e d product. A 25% y i e l d of 4-methyl-3-morpholino- . 2-phenylthietane (227) was obtained. The nmr spectrum indicated that J ^ = = 8.0 Hz, and using the s i m i l a r arguments as above, the material i s o l a t e d was taken to be r-2,t-3,c-4-227. Since the enamine 222 had been indicated to be a mixture of the c i s and trans isomers, r-2,t-3,t-4-227 was also expected, but was not i s o l a t e d from the reaction. Morpholino benzylsulfonamide (228) was also i s o l a t e d from the reaction. This material was i d e n t i c a l with an authentic sample of 228 prepared by the reaction of 225 and 221 i n ether. I s o l a t i o n of dimethylamino benzylsulfonamide has been reported i n the cycloaddition of an enamine with phenyl-sulfene and was reported to r e s u l t from an intermediate i n the c y c l i z a t i o n step (86). Since the nmr spectrum of the enamine 222 used i n the reaction indicated contamination with 225 221 228 - 133 -221, the formation of the sulfonamide 228 i n t h i s case was taken to be the r e s u l t of the reaction of 225 with the contaminating 221 and not as a r e s u l t of some property i n the c y c l i z a t i o n step. This side reaction probably accounted for the low y i e l d of 227 obtained. Treatment of 144 i n the amine oxide elimination reaction (82,150) gave 2-phenylthiete 1,1-dioxide (142) (82) i n 89% y i e l d . Exposure of 226 or 227 to a s i m i l a r procedure gave 4-methyl-2-phenylthiete 1,1-dioxide (229) (101) i n good y i e l d s . - 134 -During the r e c r y s t a l l i z a t i o n of 142 from hexane-ethanol d i l u t i o n of the mother liqu o r with hexane resulted i n the formation of f l u f f y white c r y s t a l s . The nmr and i r spectra indicated the compound to be 3-ethoxy-2-phenyl-thietane 1,1-dioxide (133). The nmr spectrum showed a t y p i c a l t r i p l e t and quartet of an ethoxy function. The formation of 133 was suspected to r e s u l t from the base catalyzed Michael addition of ethanol, the base being r e s i d u a l amounts of sodium carbonate present from the work up of the elimination reaction. This was supported by the formation of 133 y when an ethanolic solution of 142 and potassium hydroxide was allowed to s i t at room temperature for 2 hours. Treatment of an ethanolic solution of 142 with hydrogen cyanide and a c a t a l y t i c amount of potassium cyanide gave trans-3-cyano-2-phenylthietane 1,1-dioxide (217). I t has been suggested that Michael addition of hydrogen cyanide to thiete 1,1-dioxides involves formation of an intermediate H c H R KCN HCN CN 142 R = H 217 R = H 229 R = CH 3 230 R = CH 3 - 135 -carbanion which picks up a proton to give the p r e f e r e n t i a l l y more stable product (39). The i s o l a t i o n of trans-217 was also supported by the nmr spectrum which showed the coupling constant to be 9.0 Hz, i n d i c a t i n g the protons to be trans-pseudodiaxial. A s i m i l a r treatment of 229 with hydrogen cyanide gave 3-cyano-4-methyl-2-phenylthietane 1,1-dioxide (230) i n 54% y i e l d . The nmr spectrum of 230 indicated a r-2,t-3,c-4 configuration. The coupling constants of ^H^ and H^H of 230 were 11 and 10 Hz respectively. The trans r e l a t i o n s h i p between the methyl and n i t r i l e i s probably the r e s u l t of the attack of the cyanide ion from the l e a s t s t e r i c a l l y hindered side of the t h i e t e . Both 217 and 230 were highly c r y s t a l l i n e materials with unusually high melting points. 2 217 R = H 218 R = H 230 R = CH 3 231. R = CH 3 The reduction of the n i t r i l e i n 217 and 230 was accomplished by diborane i n tetrahydrofuran to give 3-amino-methyl-2-phenylthietane 1,1-dioxide (218) and 3-aminomethyl-4-methyl-2-phenylthietane 1,1-dioxide (231) respe c t i v e l y . Both 218 and 231 were viscous l i q u i d s which could not be vacuum d i s t i l l e d without r e s u l t i n g i n decomposition. The - 136 -work up of the reaction involved an a c i d i c extraction procedure which resulted i n the i s o l a t i o n of 218 and 231 as almost pure e n t i t i e s . The v i c i n a l coupling constant, J k = 9.0 Hz for 218 i n the nmr spectrum supported the trans r e l a t i o n s h i p between the n i t r i l e and the phenyl. The nmr spectrum of 218 confirmed that the use of v i c i n a l coupling constants i n these thietane 1,1-dioxides to assign configuration was j u s t i f i e d . The C-4 protons appeared as a doublet of doublets at 6 3.93. The coupling constants were calculated to be 2.5 and 8.5 Hz, which are probably due to a pseudoaxial-pseudoequatorial and a dipseudoaxial i n t e r a c t i o n respectively. A compound possessing a c i s -r e l a t i o n s h i p between the phenyl and the n i t r i l e would then be expected to have a small coupling constant (>2.5 Hz) since a pseudoaxial-pseudoequatorial i n t e r a c t i o n of H and Hj^  would be involved. The nmr spectrum of 231 showed the coupling constants, J ^ = 10 Hz and J ^ c = 9.0 Hz i n d i c a t i n g , a r-2,t-3,c-4 configuration for 231. The configurations of 218 and 231 are as expected, since the reduction of the n i t r i l e by diborane should not a f f e c t the configuration of the thietane system. The primary amines 218 and 231 were converted to the dimethylated analogues 214 and 215 by the Eschweiler-Clark procedure (39,151). The method involving warming of 218 or 231 i n a sol u t i o n of formic acid and formaldehyde. Work up of the reaction gave 214 i n 61% y i e l d and 215 i n 54% y i e l d - 137 -as c r y s t a l l i n e material. The nmr spectrum of 214 showed the coupling constant J ^ = 8.0 Hz and of 215 showed the coupling constants, J ^  = = 9.0 Hz. This data supported CH 2NH 2 S 0, -R HC0oH 0 V  2 ^ HCHO CH 2N(CH 3) 2 218 R = H 214 R = H 231 R = CH. 215 R = CH. the configurations to be trans-214 and r-2,t-3,c-4-215 (as shown). These configurations were expected, since the ac i d i c conditions of the dimethylation reaction should not cause any epimerizations. I t has been suggested that a close approach of the basic group and the oxygenated function of the diphenyl-propylamine class of analgetics i s necessary for high a c t i v i t y (152). In the 2,4-diaryl thietane 1,1-dioxides studied (17), i t was suggested that the pseudoequatorial p o s i t i o n of the basic group precluded intimate i n t e r a c t i o n of the t e r t i a r y amine with the sulfone and may have accounted for the absence of s i g n i f i c a n t a c t i v i t y i n these compounds (39). With regard to these points the synthesis of 232 and - 138 -233 were attempted. By having the dimethylamino a to the sulfone, the close approximation of these groups to each other which i s necessary for analgetic a c t i v i t y could perhaps be achieved. A possible synthetic route to these compounds was considered to be cycloaddition of cyanosulfene and an CNCH2S02C1 234 + \ / — \ C=CH N 0 / v_y CH 3 235 - 139 -enamine. Sammes e_t a l . have recently prepared cyanomethane-sulf o n y l chloride (234) and reacted i t with several enamines i n the presence of base (153). For example, when 234 was reacted with 2-methyl-l-morpholinopropene (235) i n dioxane i n the presence of triethylamine a 21% y i e l d of 4-cyano-2,2-dimethyl-3-morpholinothietane 1,1-dioxide (236) was obtained. The enamines ct-morpholinostyrene (239) and a - p y r r o l i -dinostyrene (240) were prepared by r e f l u x i n g acetophenone (237) with morpholine (221) or p y r r o l i d i n e (238) respectively i n toluene. Vacuum d i s t i l l a t i o n gave 239 and 240 as clear l i q u i d s which showed strong enamine bands i n the i r spectra at 1603 and 1605 cm ^ r e s p e c t i v e l y . When 239 or 240 were reacted with 234 and triethylamine the expected c y c l i c product (242) was not obtained. Both reactionsresulted i n an i d e n t i c a l semi-solid which could not be r e c r y s t a l l i z e d from common laboratory solvents. I t was suspected, since the same product was obtained from the reaction of e i t h e r enamine, that the a c y c l i c compound 243 was formed, which spontaneously hydrolyzed to benzoyl-methyl cyanomethyl sulfone (244) i n the reaction or work up of the reaction. That the material i s o l a t e d was 244 was supported by the i r spectrum. Absorptions were present at 1680 cm ^ i n d i c a t i v e of an a r y l ketone, 2190 and 2270 cm ^ i n d i c a t i v e of a n i t r i l e as well as the presence of strong sulfone bands. The nmr spectrum also supported the structure of 244, the methylene protons appearing as 2 - 140 -O CCH. HNR, R2N \ C — C H , 237 221 R = morpho- / < l i n o 238 R = pyrro- \ /) l i d i n o X X / CNCH2S02C1 E t 3 N > 239 R = morpholino 240 R = p y r r o l i d i n o + NR, H 0C C-2 i ii 7 -S CHCN °2 241 242 R2N \ .C=CHS0 2CH 2CN 243 0 CCH 2S0 2CH 2CN 244 - 141 -si n g l e t s at 6 2.54 and 3.63. Upon inspection of the reactants i t i s apparent that the factors which promote a c y c l i c products rather than cycloadducts are present. The phenyl substituent on the a-carbon of the enamine would s t e r i c a l l y i n h i b i t the intramolecular c y c l i z a t i o n process available to the intermediate zwitterion (241) . In addition the h a l f - l i f e of the zwitterion may be s u f f i c i e n t l y prolonged by resonance s t a b i l i z a t i o n of the negative charge by the a-cyano, which would promote a c y c l i c product by allowing greater time for a prototropic s h i f t to occur. N(CH 3) 2 c— C / \ CNCH202S H 246 - 142 -In an attempt to prepare 234, R-dimethylaminostyrene (143) was reacted with 234 and triethylamine i n dioxane. When the residue from the reaction was r e c r y s t a l l i z e d from ethanol, the cyclo-adduct 245 was not obtained. The i r spectrum showed a strong band at 1615 cm ^ i n d i c a t i v e of an enamine structure and the nmr spectrum showed 3 s i n g l e t s as well as an aromatic m u l t i p l e t . Thus the material i s o l a t e d was assumed to be the a c y c l i c product 246, and was obtained i n a 33% y i e l d . Since 143 re a d i l y undergoes cyclo-addition with other sulfenes, the resonance s t a b i l i z a t i o n of the intermediate zwitterion by the a-cyano must be s u f f i c i e n t enough to promote the formation of only the a c y c l i c product. Sammes has attr i b u t e d the i s o l a t i o n of the a c y c l i c product 248 from the reaction of the enamine 247 and cyanosulfene to s i m i l a r e f f e c t s (153). 247 248 It was thought that an alternate route to 233 could be achieved through the preparation of 3-dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-dioxide (80) and by s e l e c t i v e l y removing the dimethylamino group at C-3. - 143 -(CH3) 2NCH2CH = CHN (CH3) 2 N(CH_) + 76 CH 2S0 2C1 CH 2N(CH 3) 2 80 225 The enamine 76_ was prepared by a method subject to a patent (154) . The nmr spectrum of 7_6 showed a v i c i n a l coupling constant for the o l e f i n i c protons of 13 Hz. This i s i n d i c a t i v e of a trans-configuration about the double bond (111). The o l e f i n band i n the i r spectrum appeared at 945 cm \ which also supports a trans structure. Paquette has previously prepared 80^  by the reaction of 76 and benzylsulfonyl chloride (225) i n the presence of triethylamine (86). He obtained 80 as a white c r y s t a l l i n e N(CH ) 2 CH 2N(CH 3) 249 80 - 144 -material which melted at 95-96°. When 8_0 was prepared by a si m i l a r method, r e c r y s t a l l i z a t i o n of the crude product from hexane resulted i n the f r a c t i o n a l c r y s t a l l i z a t i o n of 2 products. One of the compounds melted at 94-97° and had spectral c h a r a c t e r i s t i c s i d e n t i c a l to those reported by Paquette for 80_. The other compound melted at 78-80° which i s s i m i l a r to that of an isomer of 80_ obtained by Paquette from the addition of dimethylamine to 2-methylene-4-phenyl-2H-thiete 1,1-dioxide (249) (101). This isomer melted at 76-78 and at 84-85 upon further p u r i f i c a t i o n . The i r and nmr spectra of the low melting isomer obtained from the f r a c t i o n a l r e c r y s t a l l i z a t i o n , however, was not i d e n t i c a l to the spectral data reported for the low melting isomer obtained by Paquette, and was taken to be a t h i r d geometric isomer of 80. Paquette did not assign configurations to the 2 isomers he i s o l a t e d owing to the unresolvable complexities of cer t a i n nmr absorptions and the lack of appropriate model compounds. I s o l a t i o n of the t h i r d isomer has provided further information and the configurational assignment of the three isomers can be made from a comparison of the nmr data. The possible geometric isomers of 8_0 are given i n Figure 3 i n t h e i r probable preferred conformations. I f the assumption i s made that the cycloaddition reaction i s stereo-s p e c i f i c as to the nature of the enamine (87,88,155), then the only 2 geometric isomers of 80_ possible from the cycloaddition of 225 and trans-76 are r-2,t-3,c-4-80_ (250) and r-2 ,c-3,t-4-80_ (251) . The t h i r d isomer obtained from the addition of dimethylamine to 249 must then have the substituents at C-3 and C-4 i n a c i s r e l a t i o n s h i p and would then be r-2,c-3,c-4-80 (252) or r-2,t-3,t-4-80 (253). The v i c i n a l coupling constants of the r i n g protons exhibited i n the nmr spectra of the three isomers does not provide conclusive configurational assignment. A comparison of the chemical s h i f t data (Table 1), however, does provide s u f f i c i e n t evidence to assign configurations to the three isomers. A s i m i l a r analysis has been used i n the assignment of configuration to c e r t a i n 2,4-diaryl-3-dimethylaminothietane 1,1-dioxides (39) . The high melting isomer obtained from the cycloaddition reaction was assigned the configuration of 250 and the low melting isomer the configuration of 251.-The t h i r d isomer was assigned the configuration of 253. The following arguments were used i n the assignment of configuration to the geometric isomers. The H c proton of 251 should appear at a higher f i e l d than the H c proton of 250 due to the diamagnetic shielding e f f e c t of the phenyl i n 251 on the H c proton. The chemical s h i f t s of the and protons can then be assigned i n a manner which i s consistent with the configurations. The protons i n 251 would appear at a higher f i e l d than the protons i n 250 due to the greater s h i e l d i n g e f f e c t the phenyl has on the H, protons - 146 -Figure 3. Possible Isomers of 3-Dimethylamino-4-dimethyl-aminomethyl-2-phenylthietane 1,1-Dioxide (80). H - C ^ e ^ ^ f N ( C H 3 } 2 d 250 CH 2 eN(CH 3) 2 f N ( C H 3 ) 2 d 251 H -CH 2 eN(CH 3) 2 f N ( C H 3 ) 2 d CH 2 eN(CH 3) 2 f N ( C H 3 ) 2 d 252 253 Table 1. Chemical S h i f t s i n the NMR Spectra of the Isomers of 3-Dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-Dioxide Compound Chemical S h i f t (6) H H H. H 250 251 253 5.12 5.10 5.18 3.57 4.41 4.25 4.25 2.29 2.12 2.17 3.10 1.92 2.27 2.40 - 147 -i n a pseucloaxial-pseudoequatorial i n t e r a c t i o n i n 251 than i n a pseudoequatorial-pseudoequatorial i n t e r a c t i o n i n 250, the phenyl being closer to the protons i n 251 than i n 250. Thus, the protons i n 250 would be the s i n g l e t at 6 2.29 and i n 251 the s i n g l e t at 6 2.12. This would require the H f protons for 250 to be the s i n g l e t at 6 1.92 and f o r 251 to be the s i n g l e t at 6 2.27. In 250 the protons could approach the proximity of the phenyl and thus r e s u l t i n g i n a greater shielding e f f e c t of the phenyl on the H^-protons i n 250 than i n 251. If the t h i r d isomer had the configuration of 252 then the protons would be expected to have a s i m i l a r chemical s h i f t to the protons of 250. The appearance of the and the at 6* 2.4 0 and 2.17 r e s p e c t i v e l y would indicate that the large s h i e l d i n g e f f e c t of the phenyl on the protons i n 250 i s absent i n the t h i r d isomer. This would by elimination give the t h i r d isomer the configuration of 253. The chemical s h i f t of the protons would probably be the s i n g l e t at 6 2.17, which i s intermediary between the chemical s h i f t of the protons i n 250 and 251. The e f f e c t of the diamagnetic sh i e l d i n g of the phenyl on the protons i n 253 i s the same as that i n 250, but the shielding e f f e c t of the dimethylaminomethyl on the protons i n 253 r e s u l t s i n a greater o v e r a l l diamagnetic s h i f t of the H d protons i n 253 than i n 250. However, t h i s i s s t i l l smaller than the diamagnetic s h i f t of the H, protons i n 251. - 148 -That the t h i r d isomer has the configuration of 253 i s also i n agreement with the stereochemistry of the Michael addition of nucleophiles to 2-phenylthiete 1,1-dioxides observed i n t h i s project and i n previous studies (39). The addition of a nucleophile r e s u l t s i n an i n t e r -mediate carbanion, which protonates to form the p r e f e r e n t i a l l y more stable compound. Thus a trans r e l a t i o n s h i p i s expected for the phenyl and the dimethylamino at C-3. Addition of dimethylamine to the exocyclic double bond i n 249 probably r e s u l t s i n a s i m i l a r preference. In the present case i t gives the pseudoaxial substituent at C-4, and i s probably a r e f l e c t i o n of the greater non-bonded interactions e x i s t i n g between the C-2 phenyl and the C-4 pseudoequatorial dimethyl-aminomethyl than between the C-4 pseudoaxial dimethylamino-methyl and the C-3 pseudoequatorial dimethylamino. Firm conclusions, however, cannot be drawn on the mechanisms involved i n t h i s reaction, since i t i s unknown to which double bond dimethylamine adds f i r s t . The reaction of 0^_ i n the Hoffman elimination procedure gave the methyliodide s a l t 254 (150) . Shamma et a_l. have reported on a method of N-demethylation of quaternary ammonium compounds by the use of thiophenoxide ion i n r e f l u x -ing 2-butanone (155). A v a r i e t y of N-methyl quaternary al k a l o i d s or a l k a l o i d d e r i a t i v e s were demethylated and appeared to be a mild method. This method involved conversion of the iodide to a chloride with s i l v e r chloride - 149 -S CH 2 -5>-s CH 2 + 80 254 I 1. AgCl 2. 3. PhS Na A + CH 2N(CH 3) 2 255 i n methanol. The chloride s a l t was then treated with sodium thiophenoxide, which r e s u l t s i n the attack by r e f l u x i n g i n 2-butanone. Treatment of 254 by t h i s procedure did not give the desired product 255. The i r spectrum of the crude residue appeared to be a mixture of 2-butanone and an u n i d e n t i f i e d sulfone product. In an attempt to perform a s e l e c t i v e Hoffman elimination reaction, 80_ was reacted with a molar amount of methyl iodide i n methanol for 48 hours. The desired product 255 was not i s o l a t e d . Concentration of the reaction mixture gave a material which was indicated to be the a c y c l i c break-down product 256 (150). A strong enamine band at 1615 cm ^ was present i n the i r spectrum. - 150 -I C 2 H 4 N ( C H 3 ) 3 1 mole / 2 ^ (CH 3) 2NCH C N ( C H J 3' 2 80 256 Paquette has prepared 249 by an amine oxide elimination procedure on 80_ (150) . In a series of experiments with 249, i t was indicated that the exocyclic double bond was more reactive than the endocyclic double bond. For example, 249 could be s e l e c t i v e l y reduced by c a t a l y t i c hydrogenation at atmospheric pressure to 229. At higher pressures (450 psi) both double bonds were reduced. The exposure of 249 to the D i e l s Alder reaction, resulted i n Atm. Pr.' 0 2 249 229 cycloaddition to the exocyclic double bond only. Using the methods outlined by Paquette, 249 was prepared and p u r i f i e d (150). I t was hoped that the enhanced r e a c t i v i t y of the - 151 -exocyclic double bond would permit the p r e f e r e n t i a l addition of nucleophiles to the exocyclic double bond. Treatment of 249 with a molar amount of dimethylamine i n ethanol did not give the desired product 255. Only unreacted 249 and polymeric material could be i s o l a t e d . Attempted amination with diborane and hydroxylamine-O-sulfonic acid (139) f a i l e d to give the desired primary amine 257. Only u n i d e n t i f i e d products were i s o l a t e d , none of which appeared to show the presence of a primary amine function i n the i r spectrum. The d i f f i c u l t y and the low y i e l d obtained i n the preparation of 80_ and 249 precluded any further studies at t h i s time. 0 2 249 257 3. Mass Spectra of Thietane 1,1-Dioxides 3 2' OH, OEt, CN 0 2 258 The mass spectra of the thietane 1,1-dioxides studied were of the generalized structure 258. A s i m i l a r fragmentation pattern could be envoked to explain most of the major peaks observed i n the mass spectra (Scheme 14). A l l the compounds had l a b i l e groups on C-3, which i n many cases directed a second major route of fragmentation. In general a l l the compounds studied involved the i n i t i a l loss of s u l f u r dioxide to give the fragment 259. This i s probably a very f a c i l e process, as indicated by the very small or non-existence of a molecular ion peak. This i s usually followed by the ready loss of a R^ r a d i c a l to give the fragment 260, which usually represents the f i r s t ion seen for t h i s route of fragmentation. The 261, 263, and 264 fragments were usually among the more intense peaks observed. The following discussion w i l l be concerned with the exceptions to or a d d i t i o n a l formation of ions to the generalized pattern of fragmentation. The cases where these secondary routes appear to become an important method of fragmentation w i l l be mentioned. Ions which are formed with low p r o b a b i l i t y , giving r i s e to very small peaks w i l l not be mentioned since these fragmentations may not be very c h a r a c t e r i s t i c of the structure (156). The ions may have been formed by a complex process involving the rupture of a number of bonds. - 153 -Scheme 14. Generalized Fragmentation Pattern for Thietane 1/1-Dioxides i n the Mass Spectrometer. ,1 -e 258 (x = 0) R l RJ CH / \ 2 CH CH—R or ,CH \ + so. •so. + . 9 CH CH CH—R^ CH N,CH—R o2s--.RJ 259 261 (m/e 115) I 262 263 (m/e 77) 264 (m/e 91) - 154 -267 (m/e 142) 268 (m/e 129) Where R = CN, the f i r s t major ion observed i s not fragment 260, but i s fragment 265 (same as 259 where B?~ = CN), which can lose a hydrogen r a d i c a l to give the 266 ion. The 266 ion then fragments to 2 ad d i t i o n a l ions 267 and 268 as well as ions corresponding to 261 and 262 fragments. The 267 fragment may also lead to the 261 ion by loss of a CN r a d i c a l . 269 270 271 - 155 -1 3 Where R = CH2NR2 the 259 fragment forms the 260 fragment through the loss of a quaternary ammonium ion (270) which appears as the base peak. This type of fragmentation could occur before the formation of 259. The molecular ion formed could be 269 which could r e s u l t from the loss of an electron from the lone p a i r on nitrogen. Loss of 270 from 269 would give the r a d i c a l 271. The ion of 271 can then form 259 by the loss of s u l f u r dioxide. CH R 2 + - C 6 H 5 ( C H 2 > x C H NR CHCHR + 3 2 2 272 273 276 Where R = NR2 (R 2 = H, CH^, morpholino) formation of a 1 3 quaternary ammonium ion from 272 (same as 259 where R = N R 2 ^ involves the loss of carbons- that were part of the thietane r i n g . Formation of these quaternary ammonium ions could also occur from a molecular ion species i n which an electron i s l o s t from the lone p a i r on nitrogen. The 273 ion i s usually the base peak and the 275 and 276 ions are present i n varying amounts. H H 279 (m/e 133) 280 (m/e 106) Where R = R = H ad d i t i o n a l strong peaks are observed for the fragments 279 and 280. This can be r a t i o n a l i z e d by 1 2 the c y c l i z a t i o n of 277 (same as 259 where R = NH2, R = H) to an azir i d i n i u m ion 278. The fragment 278 could lose a hydrogen r a d i c a l to give 279 and then an ethylene r a d i c a l to give the 280 ion. - 157 -H 283 (m/e 106) 2_8_4 (m/e 105) A s i m i l a r c y c l i z a t i o n sequence where R = OH, OEt; R = H can account for the strong peaks observed for fragments 283 and 284. For example, the 281 fragment (same as 259 where B?~ = OEt) appears as a weak ion. This can then c y c l i z e with the loss of an ethyl r a d i c a l to give the 282 ion, which w i l l eventually give the 284 ion. The 284 fragment could also r e s u l t from the formation of a s u l f i n a t e ester. Such an intermediate has been proposed to explain the fragmentation of several thietes (138,150). The formation of a s u l f i n a t e ester intermediate was supported by the f a c t that such a species has been i s o l a t e d i n the p y r o l y s i s of thiete 1,1-dioxides (138,157). If a s u l f i n a t e ester i s used to explain - 158 -OH OH 285 (m/e 133) 284 (m/e 105) the fragmentation of 127 (same as 258 where R = OH, R = H, X = O) the 285 ion could be attributed to an oxetane fragment which forms the 284 ion by the loss of an ethylene and hydrogen r a d i c a l . E i ther mechanism i s possible and no preference can be stated without further evidence (metastable peaks were not detected i n the mass spectra of the compounds) . Although i n the case where R^" = OEt the detection of the 281 fragment, even though i t i s a weak peak cannot be e a s i l y r a t i o n a l i z e d by the formation of a s u l f i n a t e ester and would probably mean that i n t h i s case fragmentation through the epoxide route i s preferred. 286 (m/e 132) 284_ (m/e 105) The formation of a s u l f i n a t e ester does appear to be involved i n the fragmentation of 2-phenylthiete 1,1-dioxide (142). Only by such a mechanism could the 286 and 284 fragments be r a t i o n a l i z e d . I t should be mentioned that t h i s i s not the primary route for the fragmentation of 142 and 2-benzylthiete 1,1-dioxide (186), but the fragmentation i s s i m i l a r to the major route proposed for the thietane 1,1-dioxides (Scheme 14), the only difference being the formation of fragment 260 on the - 160 -288 (m/e 180) loss of s u l f u r dioxide. I t i s i n t e r e s t i n g to note that the sulfonate ester 141 forms an ion equivalent to the • molecular ion of 142. This i s apparent by the appearance of fragment 288 and a mass spectrum i d e n t i c a l to that of 142 except for peaks which can be a t t r i b u t e d to the fragmentation of the benzylsulfonate species (287). 2 80 - 161 -As expected 8_0 has a very complex mass spectrum, but the fragmentation pattern can be r a t i o n a l i z e d by the formation of various quaternary ammonium ions. I t should also be noted that f a i r l y strong peaks appear at m/e 106 and 105 and could indicate the involvement of a s u l f i n a t e ester i n the mechanism of fragmentation. H CH=CCH 2SCy CH = CS0 2t 290 (m/e 102) 291_ (m/e 89) A minor fragmentation pattern i n the t h i e t e 1,1-dioxides and i n 258 (R 1 = CN, X = 0) appears to involve the formation of the 290 and 291 ions. The cyano compounds could f i r s t form th i e t e 1,1-dioxides and proceed i n a si m i l a r manner to 289 to give these ions. These are low p r o b a b i l i t y fragments and are probably not very c h a r a c t e r i s t i c , but are i n t e r e s t -ing i n that they appear to be the only ions formed which retained the sulfone group. - 162 -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 and b o i l i n g points are uncorrected. A Beckman IR-10 i n f r a r e d spectrophotometer was used to record a l l i n f r a r e d spectra. A l l the nmr spectroscopy was performed by Miss P h y l l i s Watson of the Department of Chemistry, U.B.C., using a Varian A-60, T-60 or XL-100 spectrophotometer. The concentration of the solutions was ca. 10% and trimeth y l -silane served as the i n t e r n a l standard. U l t r a v i o l e t spectra were obtained using a Bausch and Lomb Model 505 recording spectrophotometer. Solvents are s p e c i f i e d . Mass spectra and gc/mass spectral data were obtained using a Varian MAT-111 mass spectrophotometer. A l l samples were introduced by a s o l i d probe unless otherwise s p e c i f i e d . 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. - 163 -The c a r r i e r gas was nitrogen. A l l other conditions and column types are s p e c i f i e d . Preparative glc was c a r r i e d out with a Beckman Model GC-2 gas chromatography equipped with a thermoconductivity detector. A l l other conditions are s p e c i f i e d . Micro analyses were performed by A l f r e d Bernhardt, Microanalytisches Laboratorium, 5251 Elbach liber Engelskirchen, F r i t z - P r e g l - S t r a s s e 14-16, West Germany. - 164 -EXPERIMENTAL 1. Synthesis of 3-Chloro-l-phenylpropylene Oxide-1,2 (116) Freshly d i s t i l l e d 3-chloropropenylbenzene (115) (60.84 g, 0.4 moi) was added to a 500 ml ether solution of * monoperphthalic acid (105 g, 0.58 moi) (158) i n a 1,000 ml erlenmeyer f l a s k and covered with a watch glass. The solution was placed i n a fumehood and allowed to stand at room temperature for 6 days. During t h i s time phthalic acid p r e c i p i t a t e d on the walls of the f l a s k . The solution was f i l t e r e d into a 1,000 ml separatory funnel and washed with a 150 ml portion of saturated Na 2C0 3 solution u n t i l the washings remained basic to litmus paper. The ether portion was washed with 100 ml of d i s t i l l e d H^O, dried with anhydrous Na^O^ and concentrated under vacuum. The r e s u l t i n g yellow o i l was d i s t i l l e d under vacuum u t i l i z i n g a Vigreaux s t i l l h e a d to give 47 g (70%) of a colourless l i q u i d : bp 69° (0.5 mm) ( l i t . (110) bp 67°, 0.3 mm); i r (neat) 890, 940, 1275 cm"1 (epoxide r i n g ) ; nmr (CDC13) 6 3.22 (dt, 1, J = 2, 5 Hz, CHCH2), 3.64 (d, 2, J = 5 Hz, CH 2C1), 3.77 (d, 1, J = 2 Hz, ArCH), and 7.30 (m, 5, Ar). _ The solution was prepared and standardized as described and then concentrated to approximately 500 ml. - 165 -2. Synthesis of 3-Hydroxy-2-phenylthietane (117) A 500 ml three-necked round bottom f l a s k was f i t t e d with a gas i n l e t and o u t l e t , 125 ml dropping funnel, drying tube and a mechanical s t i r r e r i n a fumehood. The f l a s k was charged with 250 ml of ethanol (100), the s t i r r e r activated and sodium metal (6.13 g, 0.266 g at) was added cautiously i n small fragments. When the sodium had completely reacted the solution was cooled to 0-5° with an i c e - s a l t water bath and saturated with H 2S (Matheson) by bubbling the H 2S through the cooled solution for 1 hour. Then, 3-chloro-l-phenyl-propylene oxide-1,2 (116) (22.27 g, 0.132 moi) was added dropwise to the solu t i o n over a period of 1 hour, at which time the H2S was shut o f f . A white p r e c i p i t a t e began to form almost immediately. The reaction was s t i r r e d at 0-5° for a further 12 hours, f i l t e r e d and concentrated under vacuum at room temperature to approximately 1/4 the o r i g i n a l volume. The residue was d i l u t e d with 200 ml of d i s t i l l e d H 20 and extracted with 3 x 150 ml of CHC13. The CHC13 f r a c t i o n s were pooled and washed with 150 ml of d i s t i l l e d H20, dried with anhydrous Na2SO^ and concentrated under vacuum. The yellow o i l which remained was s o l i d i f i e d by scratching with a glass rod. Immediately, the s o l i d residue was extracted with portions of hot hexane. This process was repeated u n t i l a yellow insoluble gum remained. Upon cooling the combined hexane f r a c t i o n s , 13.77 g (62.5%) of white needle l i k e c r y s t a l s p r e c i p i t a t e d : mp 52-54° (56.5-- 166 -57.5 upon further r e c r y s t a l l i z a t i o n from hexane); i r (KBr) 1065, 3220, 3310 cm - 1 (alcohol); nmr (CDC13) 6 2.68 (s, 1, OH, disappeared on addition of D 20), 3.17 (dd, 2, J = 1.5, 6 Hz, SCH 2), 4.62 (m, 2, ArCHCHOH), 7.34 (m, 5, Ar); mass spectrum m/e 166 (molecular ion), 122 ((CgHj-CHS)* base peak), 121 ((C gH 5CS) +), 91 ( ( C ? H 7 ) + ) , 77 ( ( C g H 5 ) + ) . Anal. Calcd. for C gH 1 ( )OS: C, 65.02; H, 6.06; S, 19.29; m wt 166.25. Found: C, 64.86; H, 5.92; S, 19.19. If the c r y s t a l s were l e f t at room temperature i n contact with the atmosphere, the c r y s t a l s completely decomposed into a yellow gum within a few days. Storage i n a t i g h t l y capped container at -15° showed l i t t l e decomposition a f t e r 1 year. 3. Synthesis of 3-Hydroxy-2-phenylthietane 1,1-dioxide (127) A solution of 3-hydroxy-2-phenylthietane (117) (5 g, 0.03 moi) i n 50 ml of CHCl^ was added slowly over a period of 2 hours by means of a dropping funnel into a 2 50 ml three-necked round bottom f l a s k f i t t e d with a mechanical s t i r r e r and containing a s t i r r e d solution of m-chloroper-benzoic acid (16.25 g of 80% p u r i t y , 0.08 moi) i n 150 ml of CHCl^. There was a s l i g h t exothermic reaction during the addition of the s u l f i d e , 117 and the cl e a r solution became pale yellow. The solution was s t i r r e d for a further 10 hours at room temperature during which time some m-chlorobenzoic acid p r e c i p i t a t e d . The p r e c i p i t a t e was removed by suction - 167 -f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum u n t i l a s o l i d residue remained. The residue was t r i t u r a t e d with 3 x 150 ml of d i s t i l l e d H 20. The H 20 insoluble material was c o l l e c t e d by suction f i l t r a t i o n and the U^O removed under vacuum to give 5.1 g (85%) of a white s o l i d , mp 75-77°. Infrared analysis indicated a small amount of contamina-t i o n with m-chlorobenzoic acid, 1700 cm R e c r y s t a l l i z a t i o n from ether-petroleum ether (30-60°) gave 4.39 g (71.5%) of white p l a t e - l i k e c r y s t a l s : mp 76.2-78°; i r (KBr) 1070 and 3500 (alcohol), 1140, 1185 and 1285 cm" 1(sulfone); nmr (CDC13) 6 3.35 (broad s, 1, OH, disappeared on addition of D 20), 4.05 (dd, 2, J = 2.5, 7 Hz, SCH_2) , 4.70 (m, 1, CHOH), 5.30 (d, 1, J = 6.5 Hz, ArCH), 7.35 (m, 5, Ar); mass spectrum m/e 198 (weak molecular ion), 134 ((C 6H 5CHCHOHCH 2) +), 116 ( (C6H5CHCHCH)+) , 105 ( (C^CO) +) , 91 ( (C.^) + base peak), 77 ( ( C 6 H 5 ) + ) . Anal. Calcd. for C gH 1 ( )0 3S: C, 54.53; H, 5.08; S, 16.17, m wt, 198.25. Found: C, 54.62; H, 4.96; S, 16.29. A sample of 127 (1.5 g, 7.6 mmol) was refluxed i n 10 ml of 85% H 3P0 4 (or Ac0H/H 2S0 4) for 25 minutes. The dark solution was allowed to cool to room temperature and extracted with CHC13. The CHC13 was concentrated under vacuum and the remaining o i l was vacuum d i s t i l l e d . No accurate bp was recorded since the product was forced over with a flame (approx. 101°, 13 mm). The material i s o l a t e d (0.5 g, 49.5%) was found to be benzyl methyl ketone - 168 -(138), i r and nmr spectra were superimposable with the reported spectra i n Sadtler (117). A crude sample of the 2,4-dinitrophenylhydrazine der i v a t i v e had a mp of 140-142° ( l i t . (127b) 153°). Refluxing of a sample of 127 i n xylene for 48 hours did not cause any decomposition. 4. Synthesis of 3-Dimethylamino-2-phenylthietane 1,1-Dioxide (144) A 1,000 ml three-necked round bottom f l a s k was f i t t e d with a dropping funnel, mechanical s t i r r e r , and gas i n l e t and o u t l e t v i a a drying tube charged with CaCl,,. While flushing the system with dry N 2, the apparatus was flame dried with a bunsen burner and cooled. The N 2 atmosphere was maintained throughout the reaction. B-Dimethylamino-styrene (143) (65.1 g, 0.44 moi) (82,39) and 500 ml of dry CH3CN (freshly d i s t i l l e d from p 2 ° 5 ^ w a s P o u r e d into the round bottom f l a s k and cooled to 0-5° with an i c e - s a l t water bath. A solution of methanesulfonyl chloride (48.2 g, 0.42 moi) i n 10C ml of dry CH3CN was added slowly from the dropp-ing funnel over a period of 1 hour. Et-jN-HCl began to pr e c i p i t a t e immediately. The reaction was s t i r r e d for a further 12 hours allowing the system to gradually warm to room temperature. The Et-jN-HCl was removed by suction f i l t r a -t i o n and the f i l t r a t e was concentrated under vacuum to give 84.11 g (89%) of a buff coloured o i l y s o l i d . This residue was suspended i n a cold mixture of 400 ml of hexane and 30 ml - 169 -of ethanol, f i l t e r e d and washed with cold hexane to give 78 g (83.5%) of a s l i g h t l y yellow s o l i d , mp 118-120°. . The s o l i d could be r e c r y s t a l l i z e d from hexane-ethanol to give white needle-like c r y s t a l s : mp 121-123° ( l i t . (82) 116-117°); i r (KBr) 1135, 1190, 1320 and 1335 (sulfone), 2790 and 2835 cm - 1 (dimethyl ami no) ; nmr (CDC13) 6 2.16 (s, 6, N(CH_ 3) 2), 3.33 (m, 1, CHN) , 4.05 (m, 2, CH_2S) , 5.28 (d, 1, J = 8 Hz, ArCH), 7.44 (m, 5, Ar); mass spectrum m/e 225 (molecular ion), 117 ( (CgH5CHCHCH2):!") , 115 ( (CgH^HCCH) +) , 91 ((C^)"*"), 71 ( (CH2CHN(CH3) ) t base peak), 56 ( ( C ^ N ) +) . When anhydrous ether (Na dried) was used as the solvent an i d e n t i c a l product was obtained. The product p r e c i p i t a t e d with the Et 3N*HCl and could be separated by washing the mixture with H 20 and c o l l e c t i n g the product by suction f i l t r a t i o n . A small f r a c t i o n of the product remained i n the anhydrous ether. However the best y i e l d obtained was 65%. 5. Synthesis of 2-Phenylthiete 1,1-Dioxide (142) from  3-Dimethylamino-2-phenylthietane 1,1-Dioxide (144) A solution of 144 (39 g, 0.173 moi) i n 85 ml of g l a c i a l acetic acid and 85 ml of ac e t i c anhydride was mechanically s t i r r e d i n a 500 ml three-necked f l a s k and cooled to 0-5° with an i c e - s a l t water bath. An addition of 30% H 20 2 (40 g) was monitored through a dropping funnel at such a rate that the temperature of the reaction d i d not exceed 15°. After the addition was complete the reaction was s t i r r e d for - 170 -12 hours at room temperature. A second reaction was run simultaneously and the colourless solutions from both reactions were combined i n a 2 l i t r e erlenmeyer f l a s k and cooled to 0-5° i n an i c e - s a l t water bath. The excess peroxide was cautiously neutralized with saturated ^2^3^ solution with constant s t i r r i n g to keep the foaming that resulted at a minimum. A white p r e c i p i t a t e formed, which was c o l l e c t e d by suction f i l t r a t i o n . The material was allowed to a i r dry and gave 55.48 g (89%) of a white powder, mp 92-95°. If crude 144 was used there was no appreciable change i n the y i e l d , however, the product was a yellow colour. The material could be r e c r y s t a l l i z e d from hexane-ethanol to give shiny white p l a t e - l i k e c r y s t a l s : mp 94.2-95.5° ( l i t . (82) mp 96°); i r (KBr) 1140, 1180, 1300, 1310 cm"1 (sulfone); nmr (CDC13) 5 4. 52 (d, 2, J = 2 Hz, SCH_2) , 7.02 (t, 1, J = 2 Hz, CCH), 7.46 (m, 5, Ar); mass spectrum m/e 180 (weak molecular ion), 116 ((CgHgCCHCHj) *) , 115 ( (C 6H 5CCCH 2) + base peak), 105 ((C gH 5CO) +), 89 ( (SC^CCH) *) , 77 ( ( C g H 5 ) + ) . D i l u t i o n of the mother l i q u o r from the r e c r y s t a l l i z a t i o n of the crude product with hexane caused f l u f f y white c r y s t a l s to p r e c i p i t a t e . Further r e c r y s t a l l i z a t i o n from hexane-ethanol gave f l u f f y white needle-like c r y s t a l s , mp 107-108°. Spectroscopic data and mixed melting point indicated the compound to be 3-ethoxy-2-phenylthietane 1,1-dioxide (133) (see Experiment 7). - 171 -Treatment of 14 2 i n H^PO^ using the same procedure as outlined i n experiment 3 gave a black semisolid on concentra-t i o n of the organic extract. This residue was treated with hot hexane and the hexane was decanted from the insoluble material. The s t a r t i n g material, 14 2, p r e c i p i t a t e d from the combined hexane extracts upon cooling. The insoluble l i g h t brown scaly material was r e c r y s t a l l i z e d from hexane-ethanol to give white c r y s t a l s : mp 187-188°; i r (KBr) 705 and 760 (phenyl), 985 ( o l e f i n ) , 1135, 1270 and 1320 (sulfone), 1685 cm ^ (carbonyl). This data seems to indicate that phenyl v i n y l ketone was i s o l a t e d . 6. Synthesis of 2-Phenylthiete 1,1-Dioxide (142) from  3-Hydroxy-2-Phenylthietane 1,1-Dioxide (127) A solution of 127 (390 mg, 1.97 mmol), benzylsulfonyl chloride (410 mg, 2.16 mmol) and 30 ml of fre s h l y d i s t i l l e d THF (from LiAlH^) i n a 100 ml round bottom f l a s k was s t i r r e d with a magnetic s t i r r e r . Dropwise addition of Et^N (240 mg, 2.4 2 mmol) with a Pasteur pipet over a period of 5 minutes was exothermic with almost immediate p r e c i p i t a t i o n of Et^N'HCl. The mixture was s t i r r e d at room temperature for another 4 5 minutes. Removal of the p r e c i p i t a t e by suction f i l t r a t i o n and concentration of the f i l t r a t e under vacuum l e f t a s o l i d residue. The crude residue was dissolved i n 50 ml of CP^C^ and washed with 3 x 25 ml of F^O to remove any res i d u a l Et^N-HCl. The organic f r a c t i o n was dried with anhydrous MgSO., - 172 f i l t e r e d and concentrated under vacuum to give 380 mg (60%) of a l i g h t brown scaly residue: mp 115-122° dec; i r (KBr) 1145, 1175 and 1320 (sulfone), 1200, 1360 cm - 1 (sulfonate). The absorptions at 1070, 3500 cm ^ (alcohol) i n 127 were absent. Mass spectrum (no molecular ion) m/e 116 ( (C6H5CCHCH2) t) , H 5 ( (C 6H 5CCCH 2) +) , 105 ( (CgHgCO)+) , 91 ((C^H^) + base peak). From t h i s data the compound i s o l a t e d was presumed to be 1,l-dioxy-2-phenyl-3-thietanyl benzyl-sulfonate (141). A solution of 141 (380 mg, 1.18 mmol) i n 15 ml of benzene was magnetically s t i r r e d i n a 50 ml round bottom f l a s k . A dropwise addition of a solution of Et^N (1.01 g, 10 mmol) in 3 ml of benzene from a Pasteur pipet produced a white p r e c i p i t a t e of Et^N-HOS02CH2CgHr.. After s t i r r i n g at room temperature for 45 minutes, the p r e c i p i t a t e was removed by f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum to give a s o l i d residue. The residue was dissolved i n 50 ml of ether and washed with 3 x 25 ml of H 20. The ether layer was dried with anhydrous MgSO^, f i l t e r e d and concentrated under vacuum to give a white s o l i d . The s o l i d was r e c r y s t a l l -ized from hexane-ethanol to give 95 mg (45%) of white p l a t e -l i k e c r y s t a l s , mp 94-95°. A mixed melting point (94-96°) and a superimposable i r spectrum with that of 142 prepared as i n Experiment 5 showed that the two compounds were i d e n t i c a l . - 173 -7. S y n t h e s i s o f 3 - E t h o x y - 2 - p h e n y l t h i e t a n e 1 , 1 - D i o x i d e (133) A s o l u t i o n o f 2 - p h e n y l t h i e t e 1 , 1 - d i o x i d e (142) i n 15 ml o f e t h a n o l was m a g n e t i c a l l y s t i r r e d i n a 50 ml e r l e n m e y e r f l a s k . A 1 ml p o r t i o n o f a KOH s o l u t i o n (1 g KOH, 5 ml I^O, 5 ml e t h a n o l ) was added t o g i v e a t r a n s p a r e n t p a l e y e l l o w s o l u t i o n . The s o l u t i o n was s t i r r e d a t room tempera-t u r e f o r 1 hour and t h e n a l l o w e d t o s i t f o r a n o t h e r hour. D u r i n g t h i s t i me a w h i t e p r e c i p i t a t e formed w h i c h was c o l l e c t e d by s u c t i o n f i l t r a t i o n and r e c r y s t a l l i z a t i o n from h e x a n e - e t h a n o l t o g i v e f l u f f y w h i t e c r y s t a l l i n e m a t e r i a l : mp 107-108°; i r (KBr) 1105, 1210 and 1330 ( s u l f o n e ) , 1080 and 1160 c m - 1 (ethoxy e t h e r ) ; (nmr (CDC1 3) 6 1.15 ( t , 3, J = 7 Hz, CH 3) , 3.43 (q, 2, J = 7 Hz, OCH_2) , 3.95-4.68 (m, 3, OCHCH 2S), 5.38 (d, 1, J = 6 Hz, ArCH), 7.41 (m, 5, A r ) ; mass spe c t r u m (no m o l e c u l a r i o n ) , m/e 133 (C-HP.CHCHO/CH_) *) , C D Z 115 ( (C 6H 5CHCCH) +) , 105 ( ( C g H 5 C O ) + base p e a k ) , 91 ( ( C ? H 7 ) + ) , 90 ( ( C ? H 6 ) + ) . A n a l . C a l c d . f o r C 1 1 H 1 4 ° 3 S : c> 58.38; H, 6.24; S, 14.17; m wt 226.30. Found: C, 58.61; H, 6.03; S, 14.22. 8. S y n t h e s i s o f B e n z y l M e t h y l S u l f o n e (130) Treatment o f e i t h e r 2 - p h e n y l t h i e t e 1 , 1 - d i o x i d e (142) o r 3 - h y d r o x y - 2 - p h e n y l t h i e t a n e 1 , 1 - d i o x i d e (127) w i t h base gave 130. A s o l u t i o n o f 142 (2 g, 0.111 moi) i n 25 ml o f methanol - 174 -and 25 ml of E^O was poured into a 100 ml b o i l i n g f l a s k equipped with a F r i e d l i c h condenser. A b o i l i n g stone and NaOH (1 g) was added and the r e s u l t i n g solution was refluxed for 12 hours. After cooling, the methanol was removed under vacuum. A p r e c i p i t a t e formed i n the remaining solution and was c o l l e c t e d by suction f i l t r a t i o n , then r e c r y s t a l l i z e d from hexane-ethanol to give 1.1 g (58%) of 130: mp 124-126° ( l i t . (117) mp 124-125.5°); i r (KBr) 1120, 1160, 1305, 1330 cm 1 (sulfone) agrees with i r given i n Sadtler (117); nmr (CDC13) 6 2.76 (s, 3, CH_3) , 4.25 (s, 2, CH_2) , 7.48 (m, 5, Ar) . A solution of 127 (500 mg, 2.53 mmol) i n 50 ml of 2% aqueous NaOH was refluxed for 12 hours i n a 100 ml b o i l i n g f l a s k f i t t e d with a F r i e d l i c h condenser. Upon cooling a white p r e c i p i t a t e (305 mg, 70.5%) was c o l l e c t e d by suction f i l t r a t i o n . R e c r y s t a l l i z a t i o n from hexane-ethanol gave 266 mg (62%) of 13_0, mp 124. 5-126.5°. A mixed melting point (124-126°) and a superimposable i r spectra of the two products showed that they were i d e n t i c a l . 9. Attempted Synthesis of 3-Chloro-2-phenylthietane (145) A solution of 3-hydroxy-2-phenylthietane (117) (5 g, C.03 moi) i n 15 ml of fre s h l y d i s t i l l e d dry CHC13 was poured into 50 ml miniware reaction f l a s k f i t t e d with a mechanical s t i r r e r , dropping funnel and drying tube charged with CaCl,,. Freshly d i s t i l l e d SOC1, (3.72 g, 0.0316 moi) was dissolved - 175 -i n 10 ml of dry CHCl^ and added dropwise over a period of 2 hours. The mixture was s t i r r e d vigorously for 20 hours and became dark yellow. The CHCl^ was removed under vacuum to leave a thick orange o i l . The o i l was vacuum d i s t i l l e d i n a short path d i s t i l l a t i o n apparatus to give 2.2 g of a pale yellow l i q u i d , bp 55-60° (0.7 mm). The i r and nmr spectra were found to be superimposable with that of 3-chloro-propenyl benzene (115) (Aldrich). This represented 48% conversion of 117 to 115. When c h l o r i n a t i o n was attempted using SOC^ with pyridine (69) only polymeric material was i s o l a t e d . A method f o r conversion of alcohol to chloride using cyanuric chloride (123) gave polymer and 115. (For method see Experiment 24). 10. Synthesis of 3-Amino-2-phenylthietane 1,1-Dioxide (165) A 1,000 ml three-necked round bottom f l a s k containing 400, ml of 50:50 CHC1 3:ethanol (100) was f i t t e d with a mechanical s t i r r e r , drying tube charged with C a C l 2 , and a 250 ml dropping funnel. In a graduated cy l i n d e r , which was cooled to -78° i n a dry ice-acetone bath, 28 ml of NH3 (19.7 g, 1.11 moi) was c o l l e c t e d and quickly poured into the solvent mixture. A solution of 2-phenylthiete 1,1-dioxide (142) (10 g, 0.555 moi) i n 200 ml of the 50:50 CHC1 3:ethanol was added dropwise over a period of 2 hours. The mixture was s t i r r e d for another 2 hours at room temperature and the clear solution was concentrated under vacuum to leave a s o l i d residue. The residue was dissolved i n CHCl^ and extracted with several portions of 10% HCl solution. The pooled aqueous fr a c t i o n s were neutralized with saturated Na^O^ solution, and extracted with several portions of CHCl^. The CHCl^ extracts were pooled and dried over anhydrous MgSC>4, and concentrated to give 5.5 g (50.3%) of a white amorphous s o l i d , mp 81-83° (HCl s a l t mp 210-211° dec); i r (KBr) 3330 and 3400 (NH 2), 1150, 1210 and 1300 cm"1 (sulfone) nmr (DMSO-dg) 6 3.2 (NH_2 masked by H20) , 4. 05 (m, 3, NCHCH_2) , 5.32 (perturbed d, 1, ArCH), 7.42 (m, 5, Ar); mass spectrum m/e 197 (weak molecular ion), 133 ((C6H5CHCHNHCH2)*) 115 ( (CcHr.CHCCH)+) , 106 ( (C^HC HNH) t) , 91 ((C_H_) +), 43 6 b 6 b / / ( (CH 2CHNH 2)t base peak). Anal. Calcd. for CgH^NOjS: C, 54. 80; H, 5.62; N, 7.10; S, 16.26; m wt 197.26. Found: C, 54.84; H, 5.71; N, 6.93; S, 16.22. 11. Attempted Synthesis of 3-Amino-2-phenylthietane (5_) A solution of 3-hydroxy-2-phenylthietane (117) (4.6 g, 27.7 mmol) and benzylsulfonyl chloride (5.3 g, 27.8 mmol) in 120 ml of freshly d i s t i l l e d THF (from LiAlH^) was magnetically s t i r r e d i n a 250 ml round bottom f l a s k . The reaction mixture was cooled to -4 0° i n a dry ice-acetone bath and Et^N (3.03 g, 30 mmol) dissolved i n 30 ml of THF was added slowly from a 50 ml dropping funnel over a period of 1 hour. A p r e c i p i t a t e of Et^N'HCl appeared almost immediately. After s t i r r i n g at -40° for another 2 hours, the p r e c i p i t a t e was removed by suction f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum i n a cold water bath. A white gummy residue of 2-phenyl-3-thietanyl benzyl-s u l f onate (159) remained: i r (neat) 1185, 1365 cm ^ (sulfonate); gc-mass spectrum (SE-30 column, oven at 110°, methanol solvent, the same conditions were used throughout t h i s experiment): retention time, 6.4 minutes; m/e (no t V + ' , + molecular ion) 133 ( (C6H5CHCHOCH2) •) , 106 ( (CgHgCHO) *) , 105 ((C gH 5CO) + base peak), 77 ( ( C 6 H 5 ) + ) , 51 ( ( C 4 H 3 ) + ) . The residue 159 was dissolved i n 50 ml of fr e s h l y d i s t i l l e d hexamethylphosphoramide i n a 100 ml round bottom f l a s k . NaN^ (3 g, 4.62 mmol) was added and the suspension was s t i r r e d at room temperature i n an N 2 atmosphere f o r 24 hours. During t h i s time the NaN^ disappeared and the solution became orange. The solution was added to 200 ml of H 20 and extracted with 3 x 50 ml of CHC13. The CHC13 . extracts were pooled and washed with 50 ml of H 20, dried with anhydrous MgSO^, and concentrated under vacuum to give crude 2-phenyl-3-thietanyl azide (16 0) as an orange o i l : i r (neat) 2120 (azide), 710 and 760 cm - 1 (phenyl); i n the gc-mass spectrum two components were separated, which appeared to be the c i s and trans isomer of 160; c i s , 50%, retention time 13.2 minutes, m/e (no molecular ion), 129 ((C 9H ?N)t base peak), 102 ((CgHg)»), 77 ( ( C g H 5 ) + ) ; trans - 178 50%, retention time 22.7 minutes, m/e (no molecular ion), 130 ((CgHgNjt base peak), 116 ((CgHgNjt), 103 ( ( C g H 7 ) t ) , 77 ( ( C g H 5 ) + ) . A 250 ml three-necked f l a s k f i t t e d with a mechanical s t i r r e r , F r i e d l i c h condenser, 125 ml dropping funnel and drying tube was flame dried with a bunsen burner. A solution of the crude azide 160 i n 50 ml of THF was added dropwise over a period of 30 minutes to a s t i r r e d suspension of L i A l H 4 (1.25 g, 3 3 mmol) i n 100 ml of THF. The mixture was s t i r r e d at room temperature of another 12 hours. The excess LiAlH^ was destroyed with 1.25 ml of H 20, 1.25 ml of 20% NaOH, and 3.75 ml of H 20. The lit h i u m s a l t s were removed by suction f i l t r a t i o n and the organic layer was separated from the f i l t r a t e , d r ied with anhydrous Na2SG"4, and concentrated under vacuum u n t i l a dark o i l remained. A gc-mass spectrum analysis of the o i l indicated the presence of 3 main f r a c t i o n s : (a) 40%, retention time 7 minutes, u n i d e n t i f i e d , m/e 134, 133, 107, 105 (base peak), 92, 79, 77; (b) 40%, retention time 11.7 minutes, u n i d e n t i f i e d , m/e 135, 118, 117 (base peak), 92, 91, 77, 65; (c) 20%, retention time 27.3 minutes, possibly the desired product 5_ m/e 165 (molecular ion), 117 ((C^H^CCNH-)t base peak), 115 ((C 6H 5CHCCH) +), 91 ( ( C ? H 7 ) + ) , 77 ( ( C g H 5 ) + ) . The crude o i l was dissolved i n CHC13, extracted with 10% HCl. The aqueous f r a c t i o n was c o l l e c t e d and neutralized with 10% NaOH and extracted with CHCl^. The organic layer - 179 -was dried with anhydrous MgSO^, and concentrated under vacuum to give the basic material as a yellow o i l : i r 715, 760 cm 1 (phenyl), 3300, 3360 cm 1 (possible amine); gc-mass spectrum was the same as f r a c t i o n (b); the nmr (CDCl^) 6 1.20 (m, 1), 1.80 (m, 2), 2.6 (d, 3), 3.7 (m, 2), 7.3 (m, 5, Ar). Attempts to p u r i f y on a column using alumina f a i l e d to separate any appreciable amount of i d e n t i f i a b l e products. 12. Synthesis of 3-Phenoxy-l,2-propanediol (170) A 500 ml three-necked round bottom f l a s k was equipped with a 125 ml dropping funnel and a mechanical s t i r r e r and a solution of phenol (80 g, 0.85 moi) i n 100 g of 30% NaOH solution was added. Monochlorhydrin (Eastman) (92 g, 0.825 moi) was added to the s t i r r e d solution over a period of 1.5 hours. The reaction mixture was s t i r r e d for 24 hours at room temperature during which time the solution became dark brown with the p r e c i p i t a t i o n of NaCl. The pr e c i p i t a t e was removed by f i l t r a t i o n through glass wool and the f i l t r a t e was extracted with 3 x 100 ml of CHCl^. The yellow CHCl-j extract was washed with 3 x 50 ml of ^ 0 , dried over anhydrous MgSO^ and concentrated under vacuum to give a pale yellow thick l i q u i d . The l i q u i d was placed i n a vacuum oven at 40° for 24 hours to give a semisolid material which became a white s o l i d on t r i t u r a t i o n with cold ether. The suspension was suction f i l t e r e d and a waxy s o l i d - 180 -which could not be r e c r y s t a l l i z e d from common laboratory solvents was co l l e c t e d . By placing t h i s waxy s o l i d i n a 250 ml round bottom flask and heating under vacuum a small amount of a l i q u i d was d i s t i l l e d . The residue which remained i n the f l a s k was again t r i t u r a t e d with ether and the suspension f i l t e r e d to give 63.31 g (52.5%) of a white c r y s t a l l i n e s o l i d : mp 48-52° ( l i t . (136) 48-53°); i r (KBr) 705 and 765 (phenyl), 1065 and 3310 (alcohol), 1260 cm"1 (ether); nmr (CDC13) 6 3.57 (s, 2, OH), 3.71 (d, 2, J = 3 Hz, CH_2OH) , 3.97 (m, 3, OCH_2CH) , 7.05 (m, 5, Ar) . 13. Synthesis of Phenoxyacetaldehyde (171) A solution of 3-phenoxy-l,2-propanediol (170) (38.6 g, 0.23 moi) i n 300 ml of benzene (Na dried) was s t i r r e d i n a 1000 ml three-necked f l a s k equipped with a mechanical s t i r r e r and a thermometer. A s l u r r y of Pb(OAc) 4 (159a) (102 g, 0.23 moi) i n 200 ml of benzene was added slowly with a Pasteur pipet. The temperature of the exothermic reaction mixture was kept between 25-30° by regulation of the addition of Pb(OAc) 4 and cooling with an i c e - s a l t water bath. After about 1 hour the solution became dark red and further addition of Pb(OAc) 4 caused the p r e c i p i t a t i o n of probably Pb(OAc) 2. The addition of Pb(OAc) 4 took about 2 hours and the reaction mixture was s t i r r e d for another 2 hours at room temperature. The p r e c i p i t a t e was removed by suction f i l t r a t i o n and washed with benzene. The combined f i l t r a t e s - 181 -were washed with 200 ml of H^O, 3 x 200 ml of 10% Na 2C0 3 solution and 2 x 100 ml of H^ O to remove the a c e t i c acid. If a p r e c i p i t a t e formed during the washing with H 20 i t was removed by f i l t r a t i o n followed by washing with benzene. The combined organic f r a c t i o n s were dried with anhydrous MgSO^ and concentrated under vacuum to give a dark o i l . The o i l was d i s t i l l e d under vacuum with a Vigreaux s t i l l h e a d to give a yellow forerun followed by 19.84 g (63.5%) of a colourless l i q u i d : bp 75-77° (2.0 mm) ( l i t . (137) 82-83°, 4-5 mm); i r (neat) 695 and 760 (phenyl), 1250 (ether), 1735 and 2730 cm"1 (aldehyde); nmr (CDC13)<5 4. 52 (d, 2, J = 1.5 Hz, CH 2), 7.12 (m, 5, Ar). The aldehyde 171 was found to polymerize and could not be stored for any length of time and was prepared immediately before use. 1.4. Synthesis of Enamines from Phenoxyacetaldehyde (171) (a) l-Dimethylamino-2-phenoxyethene (172) The general conditions for enamine synthesis as outlined i n Experiment 16 were followed. To a s t i r r e d suspension of dimethylamine (9.6 g, 0.29 moi) i n 100 ml of anhydrous ether and of K 2C0 3 (20 g, 0.145 moi), f r e s h l y prepared phenoxy-acetaldehyde (171) (19.8 g, 0.14 5 moi) was slowly added at 0-5°. After s t i r r i n g for 12 hours at 0-5°, the hydrated K 2C0 3 was removed by f i l t r a t i o n and the f i l t r a t e was concen-trated under vacuum. A white s o l i d remained, but r e a d i l y decomposed into an o i l on standing. The s o l i d also appeared to adsorb a l o t of ether solvent and could not be e f f e c t i v e l y - 182 -dried or p u r i f i e d without decomposition, thus no mp or ca l c u l a t i o n of the y i e l d could be accurately determined: i r (KBr) 700 and 760 (phenyl), 875, 910 and 1600 (enamine), 1245 (ether), 2795 and 2860 cm"1 (dimethylamino); nmr (DMSO-dg) (can be interpreted as a mixture of c i s and trans isomers) 6 2. 26 and 2.52 (2s, 6, N(CH_ 3) 2), 6.75-7.5 (m, 7, ArOCHCH) . Since the material decomposed r e a d i l y , 172 was prepared immediately before use and was not p u r i f i e d further. (b) 2-Phenoxy-l-pyrrolidinoethene (173) The same procedure as outlined above was used. A suspension of p y r r o l i d i n e (14.4 g, 0.2 moi) i n 200 ml of anhydrous ether and of K 2 C 0 3 (18.8 g, 0.133 moi) was reacted with phenoxyacetaldehyde (18 g, 0.133 moi). Workup gave a dark o i l , which could not be vacuum d i s t i l l e d without a large amount of decomposition. The material boiled well i n the pot but would not d i s t i l l and 1.1 g of a yellow o i l was forced over with a flame: i r (neat) 700 and 760 (phenyl), 890 and 1600 (enamine), 1245 cm - 1 (ether); nmr (CDC13) 6' 1.75 (m, 4, CH_2CH2) , 2.88 (m, 4, CH2NCH_2) , 6.65-7. 35 (m, 7, ArOCHCH). 15. Attempted Synthesis of 2-Phenoxy Substituted Thietane  1,1-Dioxides (a) Attempted synthesis of 3-dimethylamino-2-phenoxy- thietane 1,1-dioxide (174) - 183 -The general conditions of Experiment 4 were followed. A solut i o n of l-dimethylamino-2-phenoxyethene (172) (14.5 g, crude) and Et^N (8.99 g, 0.089 moi) i n 200 ml of CH^CN was reacted with a solution of methanesulfonyl chloride (10.19 g, 0.089 moi) i n 100 ml of CH3CN at 0-5° for 12 hours. The reaction mixture became a brown colour and was concentrated under vacuum, the r e s u l t i n g residue was dissolved i n CHC13. The CHC13 solution was extracted with several portions of H 20 to remove the Et 3N*HCl and was dried with anhydrous MgSO^, then concentrated under vacuum to give a dark brown o i l . A t i c on s i l i c a gel with a 9:1 benzene:ethanol and using E^SO^ to develop the spots showed a p o s s i b i l i t y that 7 compounds were present i n the crude o i l . Approximately 2 g of the crude material was subjected to column chromatography using s i l i c a gel with a 9:1 benzene:ethanol solution as the eluent. Four f r a c t i o n s were separated. Fraction (a): i r (neat) 695 and 755 (phenyl), 1150, 1170, 1300, 1330 and 1370 (sulfone), 1220 (ether), 1650 and 2740 cm"1 (aldehyde). Fraction (b): i r (neat) 680, 700 and 780 . (phenyl), 965 and 1590 (enamine), 1145 and 1325 (sulfone) and 1240 cm"1 (ether). Fraction (c): the i r was i d e n t i c a l with that of decomposed 172. Fraction (d) : the i r was superimposable with that of phenoxyacetaldehyde (171). A small f r a c t i o n of the crude o i l was vacuum d i s t i l l e d using a short path d i s t i l l a t i o n apparatus. A clear l i q u i d was c o l l e c t e d : i r was i d e n t i c a l with that of f r a c t i o n - 184 -(b) from the column. The material was suspected to be the a c y c l i c product, 2-dimethylamino-l-phenoxyethenyl methyl sulfone (178). This appears to be supported by the nmr spectrum, (CDClg) 6 2. 73 (s, 3, SCH_3) , 2.82 (s, 6, N(CH_ 3) 2), 6.17-7.36 (m, 6, ArOCCH). In t h i s respect f r a c t i o n (a) was suspected to be 2-methylsulfonylphenoxyacetaldehyde (180). Similar r e s u l t s were obtained when THF was used as the solvent. (b) Attempted synthesis of 2-phenoxy-3-pyrrolidino- thietane 1,1-dioxide (175) The same procedure as above was repeated using 2-phenoxy-l-pyrrolidinoethene (173) (1.1 g, 5.8 mmol), Et 3N (0.59 g, crude) i n 20 ml of CH3CN and methanesulfonyl chloride (0.67 g, 5.8 mmol) i n 10 ml of CH3CN. Workup and d i s t i l l a -t i o n of the crude product i n a short path vacuum d i s t i l l a t i o n apparatus using a flame gave a l i q u i d which appears to be a mixture of the a c y c l i c product, l-phenoxy-2-pyrrolidino-ethenyl methyl sulfone (179) and the aldehyde derived from i t , 180: i r (neat) 875, 980 and 1600 (enamine), 1155, 1180, 1335 and 1375. (sulfone), 1650 and 2740 cm - 1 (aldehyde); nmr (CDC13) 6 1.90 (m, 4, CH 2 C-2 ) ' 2 , 8 0 ( s ' l r s c ^ ' 3 - 3 2 (m, 4, CH 2NCH 2), 6.70-7.48 (m, 6, ArOCCH), and 3.12 (s, 3, SCH.J , 4.89 (s, 1, CHCO) , 6. 70-7.48 (m, 5, Ar) , - 185 -16. Synthesis of l-Dimethylamino-3-phenylpropene (183) A three-necked 250 ml round bottom f l a s k , tared at the 66 ml l e v e l was set up i n a fumehood with a mechanical s t i r r e r , gas i n l e t and a dry ice-acetone condenser f i t t e d with a drying tube charged with CaCl,,. While passing N 2 through the system the apparatus was flame dried with a bunsen burner. The round bottom f l a s k was cooled below -10° and the condenser was cooled to -78° with dry ice acetone. The N 2 was exchanged with dimethylamine (Matheson) which was added u n t i l 66 ml (45 g, 1 moi) had condensed i n the reaction f l a s k . The gas i n l e t was exchanged with a dry 125 ml dropping funnel and anhydrous K^CO^ (70 g, 0.5 moi, dried at 150° for 2 hours i n an oven and cooled i n a dessicator) was introduced into the reaction f l a s k and the s t i r r e r activated. Freshly d i s t i l l e d hydrocinnamaldehyde (182) (bp 50-55°, 0.3 mm) was added dropwise over a period of 1 hour. The dry ice-acetone bath was exchanged for an i c e - s a l t water bath. The mixture was s t i r r e d for 12 hours, gradually allowing the system to warm to room temperature and the excess dimethylamine to escape. The K^CO^ was removed by suction f i l t r a t i o n and washed with anhydrous ether (Na d r i e d ) . The washings were combined with the o r i g i n a l f i l t r a t e and concentrated under vacuum to give a c l e a r yellow l i q u i d . The l i q u i d was vacuum d i s t i l l e d with a Vigreaux s t i l l h e a d to give 65.7 g (81.5%) of a colourless l i q u i d with an odour c h a r a c t e r i s t i c of enamines, bp 72° - 186 -(1.0 mm). The enamine 183 became pale yellow within several days storage i n the r e f r i g e r a t o r , but no detectable change i n the i r or nmr spectra was noticed. Ir (neat) 950 and 1650 (trans enamine), 2800, 2850 cm - 1 (dimethylamino); nmr (CDC13) <5 2.56 (s, 6, N-(CH_3) 2) , 3.30 (d, 2, J = 7 Hz, ArCH 2), 4.35 (dt, 1, J = 13.5, 7 Hz, CH2CH), 6.00 (d, 1, J = 13.5 Hz, CHN), 7.24 (m, 5, Ar). 17. Synthesis of 2-Benzyl-3-dimethylaminothietane 1,1- Dioxide (184) The general conditions outlined i n Experiment 4 were used. A so l u t i o n of methanesulfonyl chloride (52 g, 0.456 moi) i n 100 ml of dry CH3CN was added dropwise to a solution of l-dimethylaminq-3-phenylpropene (183) (75 g, 0.466 moi) and Et-jN (46.1 g, 0. 456 moi) i n 500 ml of dry CH3CN. After s t i r r i n g the mixture for 12 hours at 0-5° the Et 3N-HCl was removed from the orange solu t i o n by suction f i l t r a t i o n and the CH3CN was removed under vacuum. A dark o i l remained which was dissolved i n CHC13 and extracted with 10% HCl s o l u t i o n . The aqueous extract was neutralized with 10% Na 2C0 3 solution and extracted with CHC13. The organic layer was dried with anhydrous MgSO^, f i l t e r e d and concentrated under vacuum to leave a yellow gum. The gum was r e c r y s t a l l i z e d from hexane by decanting the hot solution from the insoluble material. Upon cooling the pooled hexane extracts, 39.7 g (36.4%) of white needle-like c r y s t a l s p r e c i p i t a t e d : mp 70-. 72°; i r (KBr) 1135, 1195 and 1315 (sulfone), 2790 and - 187 -and 2840 cm"1 (dimethylamino); nmr (CDC13) 6 2.16 (s, 6, N(CH_3) 2 ) , 2.60-3.75 (m, 3, CHN, ArCH_2) , 3.98 (m, 2, SCH_2) , 4.45 (m, 1, SCH) , 7.30 (m, 5, Ar); mass spectrum m/e 239 (weak molecular ion), 160 ( (C-Hj-CHCHCHN (CH_) „) •") , 115 fa J 6 2. ((C 6H 5CHCCH) +), 91 ( ( C 7 H ? ) + ) , 84 ((CH2CHCHN(CH3) ) t ) , 71 ((CH 2CHN(CH 3) 2)t base peak). Anal. Calcd. for C 1 2H 1 7N0 2S: C, 60.22; H, 7.16; N, 5.85; S, 13.40; m wt 239.34. Found: C, 60.14; H, 7.05; N, 5.74; S, 13.55. No other i d e n t i f i a b l e compounds could be i s o l a t e d . When the crude product, obtained from the removal of the CH3CN, was r e c r y s t a l l i z e d with hexane or hexane-ethanol lower y i e l d s (< 30%) of c y c l i z e d product were obtained. R e c r y s t a l l i z a t i o n from methyl ethyl ketone resulted i n decomposition to an u n i d e n t i f i e d s u l f o n i c acid s a l t : mp 190°; i r (KBr) 1035, 1170, 1195 and 1310 (sulfonate), 2490, 2680, 2740 and 2780 cm"1. The methyl iodide s a l t was prepared by d i s s o l v i n g 184 (5 g, 0.22 moi) i n 15 ml of CH 3I i n a 125 ml erleymeyer f l a s k . Warming the solution on a steam bath gave the immediate formation of a p r e c i p i t a t e . The mixture was l e f t i n the dark for 1.5 hours, 75 ml of ethanol was added and the mixture warmed. The gummy material changed to a white p r e c i p i t a t e , cooling and f i l t r a t i o n gave 7.3 g (90.5%) of white c r y s t a l s of 2-benzyl-3-(NNN)trimethylammoniumthietane 1,1-dioxide iodide: mp 185°; i r (KBr) 1140, 1150, 1215, 1335 cm 1 (sulfone). - 188 -18. Synthesis of 2-Benzylthiete 1,1-Dioxide (186) A solution of 2-benzyl-3-dimethylaminothietane 1,1-dioxide (184) (10 g, 41.9 mmol) in 10 ml of g l a c i a l a c e t i c acid was mechanically s t i r r e d i n a 100 ml miniware reaction f l a s k at 0-5°. Peracetic acid (40%, 30 ml) was added dropwise through a 25 ml dropping funnel over a period of 1 hour. The solution was s t i r r e d at room temperature for 12 hours and poured into a 250 ml suction f l a s k and cooled to 0-5°. The excess peracid was cautiously neutralized with saturated Na2C03 solution, during which time a white p r e c i p i -tate formed. The mixture was heated under vacuum i n a 6 0° water bath for 30 minutes. An o i l separated and the mixture was cooled and extracted with CHCl^. The CHCl^ extracts were pooled and dried with anhydrous Na2SO^. Concentration under vacuum l e f t a cl e a r colourless o i l which was s o l i d i f i e d by scratching with a glass rod. R e c r y s t a l l i z a t i o n of the s o l i d from hexane-ethanol gave 3.67 g (45.2%) of white needle-like c r y s t a l s : mp 60-62°; i r (KBr) 1145, 1220 and 1300 (sulfone), 865 and 975 cm"1 ( o l e f i n ) ; nmr (CDC13) 6 3. 70 (m, 2, ArCH_2) , 4.34 (m, 2, SCH_2) , 6.50 (m, 1, CCHCI^) , 7.35 (m, 5, Ar); mass spectrum m/e 194 (molecular ion), 129 ( (C 6H 5CH 2CCCH 2) + base peak), 115 ( (CgH^CH^CC)+) , 102 ( (SC^CCCH^)*) , 91 (.(C 7H 7) +). Anal. Calcd. for C 1 0 H 1 0 ° 2 S : C / 6 1 , 8 3 ; H ' 5- 1 9'* s/ 16.51; m wt 194.26. Found: C, 61.76; H, 5.13; S, 16.67. A sample of the white p r e c i p i t a t e a f t e r the n e u t r a l i z a t i o n - 189 -with Na 2C0 3 was taken and had a mp 84-87°; i r (KBr) 1145, 1220 and 1300 (sulfone), 1320 cm - 1 (N-oxide). R e c r y s t a l l i z a -t i o n of t h i s N-oxide from hexane-ethanol resulted i n the elimination of the amine with the p r e c i p i t a t i o n of only the thiet e 186 upon cooling the solvent. In a 100 ml round bottom f l a s k f i t t e d with a F r i e d l i c h condenser, a solution of 186 (1.6 g, 8.35 mmol) and NaOH (1.2 g) i n 60 ml of 50:50 methanol:water was refluxed for 12 hours. The methanol was recovered under vacuum. The pr e c i p i t a t e which formed was c o l l e c t e d by suction f i l t r a t i o n and r e c r y s t a l l i z e d from H 20 to give 95 mg (62%) of white c r y s t a l s of phenethy 1 methyl sulfone (189): mp 87-88°; i r (KBr) 1125, 1145, 1265, 1290 and 1300 cm - 1 (sulfone); nmr (CDC13) 6 2.8 (s, 3, CH3) , 3.22 (m, 4, CH^CH_2) , 7.28 (m, 5, Ar) . 19. Synthesis of 2-Benzyl-3-dimethylaminothietane (8) A 3,000 ml three-necked flask was f i t t e d with a drying tube containing C a C l 2 , F r e i d l i c h condenser, mechanical s t i r r e r and a dropping funnel i n a fumehood. The system was flame dried with a bunsen burner, while flushing with N 2-After the apparatus had cooled to room temperature f i n e l y powdered LiAlH^ (1.6 g, 0.2 moi) was suspended i n 900 ml of anhydrous ether (Na dried) and the s t i r r e r activated. A solution of 2-benzyl-3-dimethylaminothietane 1,1-dioxide (184) i n 700 ml of anhydrous ether was slowly added through the dropping funnel over a period of 2 hours, while gently - 190 -r e f l u x i n g over a steam bath. The re f l u x i n g was continued for 12 hours and the reaction was cooled to room temperature. The excess LiAlH^ was destroyed by c a r e f u l l y adding 32 ml of H 20, 24 ml of 20% NaOH and 115 ml of li 0. The li t h i u m s a l t s were removed by suction f i l t r a t i o n , washed with ether and the ether portion separated from the aqueous f r a c t i o n . The water layer was extracted with 2 x 50 ml of ether. The combined ether portions were dried with anhydrous Na^SO^, f i l t e r e d and concentrated under vacuum to give a yellow o i l . The o i l was vacuum d i s t i l l e d with a Claisen s t i l l h e a d to give 7.35 g (47.2%) of a clea r l i q u i d : bp 127-128° (0.75 mm); i r (neat) 2780 and 2820 (dimethylamino), 705 and 755 (mono-substituted phenyl), 1050 and 1455 cm"1; nmr (CDC13) 6 2.20 (s, 6, CH_3) , 2.63-3.62 (m, 5, ArCH2CHCHCH_2) , 3.84-4.24 (m, 1, SCH), 7.04 (m, 5, Ar). The methyl iodide of 8^  was prepared by d i s s o l v i n g 8^  (1.15 g, 5.55 mmol) i n three ml of methyl iodide. An exo-thermic reaction was immediately observed with the simultaneous p r e c i p i t a t i o n of a white s o l i d , which was r e c r y s t a l l i z e d from ethanol to give 1.59 g (82%) of white amorphous c r y s t a l s : mp 189-192°; i r (KBr) 705 and 750 (monosubstituted . phenyl), 860, 960, 1475 and 3010 cm - 1; mass spectrum (no molecular ion) m/e 129 ( (C^H^CHCCHCH^) t) , H 5 ( (r HCCHCCH) *) , b 3 2. b J 91 ( ( C ? H 7 ) + ) , 71 ((CH 2CHN(CH 3) 2)t base peak), 58 ((CH 2N(CH 3) 2) +) . The HC104 s a l t was prepared (160) by d i s s o l v i n g 8_ (0.3 g, 1.45 mmol) i n 5 ml of ethanol and added to 3 ml of a - 191 -HC104 solution (1.44 g, of 70% HC104 i n 5 ml of ethanol). Afte r allowing the solution to stand for 1 hour at room temperature, 20 ml of ether was added and the solution was cooled i n an ice-water bath. The HC104 s a l t of 8_ p r e c i p i t a t e d as large, white, needle-like c r y s t a l s , which could be further p u r i f i e d by r e c r y s t a l l i z i n g from ethanol-ether: mp 141.5-142.8°; i r (KBr) 1100 (chlorate), 2470, 2660 and 3430 cm 1 (trimethylammonium). Anal. Calcd. for C 1 2H l gClN0 4S: C, 46.82; H, 5.89; C l , 1152; N, 4.55; S, 10.42; m wt 307.81. Found: C, 46.65; H, 5.92; C l , 11.50; N, 4.51; S, 10.45. 20. Synthesis of Ethyl-4-phenyl-3-butenoate (193) A 1,000 ml three-necked f l a s k f i t t e d with a mechanical s t i r r e r , 250 ml dropping funnel and drying tube was flame dried. A solution of ethylacetotriphenylphosphonium chloride (192) (84 g, 0.218 moi) (159b) and fr e s h l y d i s t i l l e d phenyl-acetaldehyde (25.8 g, 0.218 moi) i n 300 ml of super dry ethanol (127c) was s t i r r e d at room temperature. A 150 ml solution of NaOEt (0.24 moi; Na, 5.52 g i n 150 ml of ethanol) was added slowly from a dropping funnel over a period of 2 hours. A p r e c i p i t a t e began to form almost immediately and the reaction mixture was s t i r r e d at room temperature for another 16 hours. The p r e c i p i t a t e was removed by suction f i l t r a t i o n and the f i l t r a t e concentrated under vacuum to approximately 1/4 of the o r i g i n a l volume and 300 ml of H„0 - 192 -added to the residue. The yellow mixture was extracted with 3 x 200 ml of benzene, which was pooled and dried with anhydrous MgSO^ and concentrated under vacuum to give a yellow s o l i d . The s o l i d was suspended i n 3 x 200 ml of hexane, the insoluble triphenylphosphine oxide was removed by suction f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum leaving a yellow l i q u i d . The l i q u i d was vacuum d i s t i l l e d using a Vigreaux s t i l l h e a d to give 28-. 96 g (70%) of a colourless l i q u i d : bp 117-120° (1.5 mm) ( l i t . (140) bp 135-137°, 2.0 mm); i r (neat) 970 ( o l e f i n ) , 1170 and 1735 cm"1 (ester); nmr (CS 2) <5 1.20 (t, 3, J = 7 Hz, CH_3) , 3.10 (d, 2, J = 6 Hz, CH_2CO) , 4.03 (q, 2, J = 7 Hz, CH_2CH3) , 6.24 (m, 2, ArCHCH), 7.23 (m, 5, Ar), ( l i t . (140) (CDC13) 6 3.17 (d, 2, J = 6 Hz, CH_2CO) , 6.32 (obscured t, 1, J = 6 Hz, ArCHCH), 6.4 (s, 1, ArCH), a s i m i l a r pattern could be r a t i o n a l i z e d for the o l e f i n i c proton's multi p l e t centered at 6 6.24). 21. Synthesis of Ethyl-4-phenyl-2-butenoate (195) A solution of ethylacetotriphenylphosphonium chloride (192) (20 g, 0.052 moi) i n 1,000 ml of H 20 was s t i r r e d i n a 2,000 ml three-necked f l a s k f i t t e d with a 500 ml dropping funnel. A 1 N NaOH solution was added dropwise u n t i l the reaction became basic to phenolphthalein. During the addition of base a gummy white p r e c i p i t a t e coated the sides of the fl a s k . The water was decanted o f f and the residue was dissolved i n hot ethyl acetate. D i l u t i o n of the hot ethyl acetate with petroleum ether (30-60°) and cooling resulted i n amorphous white c r y s t a l s of carboethoxy-methylenetriphenyl phosphorane (194): 8.95 g (49%), mp 110-114° ( l i t . (161) 116-117°), i r (KBr) 705 and 765 (phenyl), 1110, 1125, 1605 cm 1 (ester). When the reaction was scaled up there was a decrease i n the y i e l d and an increase i n the amount of triphenylphosphine oxide formed. A solution of 194 (73 g, 0.21 moi) i n 700 ml of benzene was s t i r r e d i n a 2,000 ml three-necked f l a s k at room temperature. A dropwise addition of phenylacetaldehyde (22.8 g, 0.19 moi) i n 120 ml of benzene over a period of 1 hour was accomplished through a dropping funnel. The reaction mixture was s t i r r e d at room temperature for 4 8 hours and the benzene was concentrated under vacuum. The slu r r y which remained was extracted with 2 x 200 ml of petroleum ether (30-60°). The combined petroleum ether fr a c t i o n s were concentrated under vacuum and 4 5.25 g of a yellow l i q u i d remained: i r (neat) 705 and 755 (phenyl), 995 ( o l e f i n ) , 1170 and 1715 cm"1 (ester); nmr (CDC13) 6 1.25 (t, 3, J = 7 Hz, CH3) , 3.48 (dd, 2, J = 1.5, 7 Hz, ArCH_2) , 4.16 (q, 2, J = 7 Hz, CH_2CH3) , 5.78 (dt, 1, J = 1.5, 16 Hz, ArCH 2CH), 7.23 (m, 6, Ar, CHCHCO), a 30% contamination with triphenylphosphine oxide was calculated from the nmr. The projected y i e l d was then calculated to be 31 g (86%). The mixture was vacuum d i s t i l l e d using a Claisen s t i l l h e a d - 194 -to give 22.9 g (63.5%) of pure 19J5: bp 110-117° (1.0 mm), the i r and the nmr was the same as that of the crude material and the nmr agreed with that reported by Gerkin and Rickborn (140). During the d i s t i l l a t i o n the material i n the pot began to re f l u x much faster and a second f r a c t i o n was col l e c t e d , 6.1 g. This material was found to be a mixture of 195 and ethyl-4-phenyl-3-butenoate (193): i r (neat) 970 and 990 ( o l e f i n ) , 1710-1740 cm - 1 (wide ester band); nmr analysis showed that there was 59.5% of 195 and 40.5% of 193. 22. Synthesis of 4-Phenyl-3-buten-l-ol (200) F i n e l y powdered LiAlH^ (5.7 g, 0.15 moi) was magnetically s t i r r e d i n 300 ml of anhydrous ether (Na dried) i n a 500 ml round bottom flask f i t t e d with a drying tube and a condenser. The suspension was s t i r r e d for 24 hours and f i l t e r e d i n a dry box f i l l e d with N 2 to give a translucent s o l u t i o n of LiAlH^. A 2,000 ml three-necked f l a s k was f i t t e d with a drying tube, 500 ml dropping funnel, F r i e d l i c h condenser and a mechanical s t i r r e r and the apparatus was flame d r i e d . The LiAlH^ solution was added through the dropping funnel to a s t i r r e d solution of ethyl-4-phenyl-3-butenoate (193) (48.3 g, 0.254 moi) i n 300 ml of anhydrous ether at such a rate as to maintain a gentle r e f l u x of the ether. Afte r the addition was complete, the mixture was refluxed for another 2 hours and cooled. The excess LiAlH^ was destroyed with 5.7 ml of H 00, 5.7 ml of 20% NaOH, 18.1 ml of H o0. The - 195 -lith i u m s a l t s were removed by suction f i l t r a t i o n and washed with ether. The ether f r a c t i o n was separated and dried with anhydrous MgSO^, and concentrated under vacuum. The yellow o i l which remained was vacuum d i s t i l l e d with a Vigreaux s t i l l h e a d to give 28.46 g (77%) of a colourless l i q u i d : bp 105-108° (0.8 mm) ( l i t . (147) 137-138°, 12 mm); i r (neat) 970 ( o l e f i n ) , 1050 and 3340 cm - 1 (alcohol); nmr (CDC13) 6 2.05 (s, 1, OH, disappears on addition of D 20), 2.39 (q, 2, J = 6 Hz, CHCH_2) , 3.67 (t, 2, J = 6 Hz, CH_2OH) , 6.15 (dt, 1, J = 16.6 Hz, CHCH2), 6.48 (d, 1, J = 16 Hz, ArCH), 7.26 (m, 5, Ar). A l l the data complied, with that of the trans isomer of 200 (147,148) and was the only isomer i s o l a t e d . 23. Synthesis of 4-Phenyl-2-buten-l-ol (196) Fin e l y powdered LiAlH^ (8.8 g, 0.232 moi) was magnetically s t i r r e d i n 100 ml of anhydrous ether for 48 hours i n a 1,000 ml round bottom flask equipped with a drying tube and a condenser. Super dry ethanol (10.64 g, 0.242 moi) was added slowly to the s t i r r e d suspension and f i l t e r e d i n a dry box to give a translucent solution of mainly LiAlH 3OCH 2CH 3 (143). A 1,000 ml three-necked f l a s k was equipped with a mechanical s t i r r e r , 500 ml dropping funnel, condenser and drying tube and flame dried. A solution of ethyl-4-phenyl-2-butenoate (195) (36.3 g, 0.191 moi) i n 200 ml of anhydrous ether was added and the - 196 -s t i r r e r activated. The LiAlH^OCH^CH^ solution was added through the dropping funnel over a period of 4 hours and the reaction mixture was s t i r r e d at room temperature for 48 hours. The excess LiAlH^OC^CH^ was destroyed by c a r e f u l addition of H 20 and the l i t h i u m s a l t s were removed by suction f i l t r a t i o n and washed with ether. The ether was separated from the f i l t r a t e and dried with anhydrous MgSO^ and concentrated under vacuum. The remaining dark o i l was vacuum d i s t i l l e d with a Vigreaux s t i l l h e a d . No accurate bp was obtained because the d i s t i l l a t e was forced over with a bunsen burner. There was a large amount of u n d i s t i l l a b l e residue and 7.56 g (27%) of a yellow l i q u i d was c o l l e c t e d : i r (neat) 980 ( o l e f i n ) , 1050 and 3350 cm - 1 (alcohol); nmr (CDC13) 6 1.75 (s, 1, OH), 3.32 (d, 2, J = 5 Hz, ArCH_2) , 4.04 (d, 2, J = 3 Hz, CH2OH), 5.75 (m, 2, CHCH), 7.22 (m, 5, Ar) . 24. Synthesis of l-Chloro-4-phenyl-3-butene (201) (123) A 50 ml miniware round bottom f l a s k containing 4-phenyl-3-buten-l-ol (200) (28.46 g, 0.192 moi) was f i t t e d with a condenser and placed i n a fumehood. The alcohol, 200, was heated to 100° i n an o i l bath and f i n e l y powdered cyanuric chloride (148) (Aldrich, 20 g, 0.108 moi) was added i n small portions with a spatula over a period of 30 minutes. During the addition of 148 a gas was evolved. The suspension was heated for another 2 hours during which time a considerable - 197 -amount o f c y a n u r i c a c i d p r e c i p i t a t e d . The s u s p e n s i o n was a l l o w e d t o c o o l t o room t e m p e r a t u r e a n d t h e p r e c i p i t a t e was r e m o v e d by s u c t i o n f i l t r a t i o n . The y e l l o w f i l t r a t e was vacuum d i s t i l l e d w i t h a V i g r e a u x s t i l l h e a d a n d 23 g (72%) o f t h e c l e a r c o l o u r l e s s f r a c t i o n , bp 9 8 - 1 0 4° (0.65 mm) was c o l l e c t e d : uv max ( e t h a n o l 95) 251 nm (e 1 0 , 4 9 0 ) ; i r ( n e a t ) 705 a n d 755 ( p h e n y l ) , 975 a n d 3035 c m- 1 ( o l e f i n ) ; nmr (C D C l g ) 6 2. 67 ( q , 2, J = 7 H z , CHCH_2) , 3.62 ( t , 2, J = 7 H z , CH_2C1) , 6.24 ( d t , 1, J = 7, 16 H z , C H C H 2 ) , 6.54 ( d , 1, J = 16 H z , A r C H ) , 7.32 (m, 5, A r ) . 2 5 . S y n t h e s i s o f l - C h l o r o - 4 - p h e n y l - 2 - b u t e n e (1_97) The same p r o c e d u r e a s E x p e r i m e n t 24 was u s e d . I n a 10 m l m i n i w a r e r o u n d b o t t o m f l a s k 4 - p h e n y l - 2 - b u t e n - l - o l (196) (3 g , 0.0201 moi) was h e a t e d a t 1 0 0° w i t h c y a n u r i c c h l o r i d e (148) i n t h e f u m e h o o d . Upon w o r k u p a n d vacuum d i s t i l l a t i o n w i t h a s h o r t p a t h d i s t i l l a t i o n a p p a r a t u s g a v e 2.2 g (65%) o f a c o l o u r l e s s l i q u i d : bp 6 5 - 7 0° (0.4 mm); i r ( n e a t ) 9 7 5 , 3015 ( o l e f i n ) , 7 0 5 , 750 c m- 1 ( p h e n y l ) ; nmr (CDC1 3) 6 3.37 ( d , 2 , J = 5 H z , A r C H 2 ) , 4.04 ( d , 2 , J = 6 H z , CH_2C1) , 5.8 (m, 2 , CHCH)-, 7.25 (m, 5, A r ) . 2 6 . S y n t h e s i s o f l - C h l o r o - 4 - p h e n y l b u t y l e n e O x i d e - 3 , 4 (202) The same g e n e r a l p r o c e d u r e a s i n E x p e r i m e n t 1 was u s e d . A s o l u t i o n o f l - c h l o r o - 4 - p h e n y l - 3 - b u t e n e (201) (23 g , 0.138 moi) a n d m o n o p e r p h t h a l i c a c i d (34.6 g , 0.19 moi) i n - 198 -approximately 250 ml of ether was reacted i n a 500 ml Erlenmeyer f l a s k . The reaction was worked up i n 8 days. Vacuum d i s t i l l a t i o n of the crude o i l u t i l i z i n g a Vigreaux s t i l l h e a d gave 2 f r a c t i o n s : (a) bp 96-105° (0.8 mm); (b) bp 105-108° (0.8 mm). Both fr a c t i o n s were analyzed by gc (column, chromoport-SE 30 5%; oven temperature, 125°; i n l e t and detector temperature, 240°; c a r r i e r gas, N^', 4.5 l./min; flame i o n i z a t i o n detector) from which i t was determined that: (a) was a 3 0% and 60% mixture of compounds with 4 and 6 minute retention times respectively; (b) was a 20% and 80% mixture of compounds with 6 and 11 minute retention times, respe c t i v e l y . Preparative gc on a sample of (a) using a Carbowax column gave the compound with the 6 minute retention time i n 90% pur i t y , but a pure sample of the other was not obtained. F r a c t i o n a l d i s t i l l a t i o n of (b) gave almost pure material with the 6 minute retention time. This f r a c t i o n was thought to be the c i s isomer of 202: bp 85-87° (0.45 mm), i r (neat) 710 and 750 (phenyl), 1040 and 1315 cm"1 (epoxide); nmr (CDC13) 6 1.76 (dt, 2, J = 2, 7 Hz, CHCH_2) , 2.60 (m, 2, CHCH), 3.54 (disturbed t, 2, J = 7 Hz, CH 2C1), 7.2 (m, 5, Ar). A f r a c t i o n corresponding to the 11 minute retention time was i s o l a t e d i n 100% puri t y and was found to be the trans isomer of 202: i r (neat) 710 and 760 (phenyl), 895, 950, 1040 and 1300 cm"1 (epoxide); nmr (CDC13) 6 2.12 (m, 2, CHCH_2) , 3.09 (dt, 1, J = 2.5, 5 Hz, CHCH2) , 3.66 (t, 2, J =. 5.5 Hz, CH„C1), 3.68 (obscured d, 1, J = 2.5 Hz, ArCH), 7.26 (m, 5, Ar). - 199 -Fraction (a) and (b) represented 21.67 g (86%) y i e l d of 202. In subsequent reactions gc analysis of the crude product indicated 70% of the product consisted of the trans isomer. 27. Synthesis of 3-Hydroxy-2-phenylthiolane (203) The same general procedure as outlined i n Experiment 2 was used. A NaOEt solution (1.26 g, 55 mmol of Na i n 65 ml of ethanol) was reacted with l-chloro-4-phenylbutylene oxide-3,4 (202) (5 g, 27.4 mmol) for 12 hours at 0-5°. The same workup procedure gave a buff coloured CHCl^ extract. Drying with anhydrous Na^O^ and concentration under vacuum l e f t a dark o i l which was vacuum d i s t i l l e d using a short path d i s t i l l a t i o n apparatus to give 2.6 g (53%) of a colourless l i q u i d : bp 110-114° (0.1 mm); i r (neat) 705 and 750 (phenyl), 1065 and 3400 cm - 1 (alcohol); nmr (CDC13) <5 2.10 (m, 2, CHCH_2) , 2.36 (s, 1, OH), 3.02 (m, 2, SCH 2), 4.23 (m, 2, ArCHCH), 7.35 (m, 5, Ar). 28. Synthesis of 3-Hydroxy-2-phenylthiolane 1,1-Dioxide (205) The general conditions as outlined i n Experiment 3 was used. A solution of 3-hydroxy-2-phenylthiolane (203) (5 g, 27.8 mmol) i n 50 ml of CHCl^ was reacted with m-chloroper-benzoic acid (16.25 g of 85% pure, 80 mmol) for 12 hours at room temperature. During the reaction, m-chlorobenzoic acid p r e c i p i t a t e d and was removed by suction f i l t r a t i o n . The f i l t r a t e was extracted with saturated Na„CO_ solution u n t i l the aqueous washings were basic to litmus paper. The organic layer was washed with 25 ml of H 20, dried with anhydrous MgSO^ and concentrated under vacuum to leave a gummy residue which was r e c r y s t a l l i z e d from hexane-ether to give 1.61 g (27.3%) of white c r y s t a l s : mp 95-96.4°; i r (KBr) 705 and 750 (phenyl), 1075 and 3410 (alcohol), 1130 and 1305 cm - 1 (sulfone); nmr (CDCl 3) 6 1.8-2.9 (m, 2, CH_2CH) , 2.38 (s, 1, OH), 3.25 (m, 2, SCH_2) , 4.00 (d, 1, J = 9 Hz, ArCH), 4.58 (dt, 1, J = 6, 9 Hz, CHOH), 7.39 (m, 5, Ar) . Anal. Calcd. for C 1 ( )H 1 20 3S: C, 56.58; H, 5.70; S, 15.11; m wt 212.27. Found: C, 56.65; H, 5.70; S, 14.95. 29. Synthesis of 2-Phenyl-2-thiolene 1,1-Dioxide (207) The same procedure as outlined i n Experiment 6 was used. A s o l u t i o n of 3-hydroxy-2-phenylthiolane 1,1-dioxide (205) (1 g, 4.72 mmol) and benzylsulfonyl chloride (0.95 g, 5 mmol) i n 30 ml of f r e s h l y d i s t i l l e d THF was reacted with a solution of Et 3N (0.585 g, 5.3 mmol) i n 10 ml of THF for 1 hour at room temperature. The p r e c i p i t a t e d Et 3N*HCl was removed by suction f i l t r a t i o n and the TEF was removed under vacuum. The gummy residue was dissolved i n 30 ml of CHC13, extracted with 3 x 10 ml of H 20, dried with anhydrous MgSO^ and concentrated under vacuum to give 1.2 5 g (75%) of a waxy residue: mp 120-130° dec, i r (KBr) 1130, 1290 and 1320 (sulfone), 1183 and 1365 cm - 1 (sulfonate). This data - 201 -indicated that the material i s o l a t e d was 1,l-dioxy-2-phenyl-3-thiolanyl benzylsulfonate (206). A sol u t i o n of 206 (0.8 g, 2.4 mmol) i n 30 ml of benzene was reacted with a solution of Et^N (1.43 g, 14 mmol) i n 6 ml of benzene at 50° for 4 hours, then 12 hours at room temperature. During t h i s time Et^N• HOSC^CI^CgH,-pr e c i p i t a t e d ( i r (KBr) 1035, 1055, 1195 and 1210 (sulfonate), 2500, 2670 and 2730 cm - 1 (3° amine s a l t ) ) and was removed by suction f i l t r a t i o n . The f i l t r a t e was concentrated under vacuum to leave a s o l i d residue which was t r i t u r a t e d with 3 x 60 ml of ether. The insoluble material (Et 3N-HOS0 2CH 2C 6H 5) was removed by suction f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum to give a s o l i d residue. The s o l i d was r e c r y s t a l l i z e d from benzene-petroleum ether (30-60°) to give 0.2 g (46%) of white c r y s t a l s of 207: mp 113.5-116°; i r (KBr) 695 and 760 (phenyl), 1130, 1200 and 1280 cm"1 (sulfone); nmr (CDC13) 6 2. 88 (m, 2, CHCH_2) , 3.37 (m, 2, SCH 2), 6.70 (t, 1, J = 2.5 Hz, CCH), 7.47 (m, 5, A r ) . Anal. Calcd. for C 1 0 H 1 0 ° 2 S : C ' 6 1 - 8 3 ; H ' 5- 1 9'" S ' 16.51; m wt 194.26. Found: C, 62.00; H, 5.08; S, 16.48. 30. Synthesis of 1-Morpholinopropene (222) The general conditions as outlined i n Experiment 16 were used. Propionaldehyde (52 g, 1 moi) was added slowly to a s t i r r e d suspension of morpholine (43.5 g, 0.5 moi) and K_CO_ (70 g, 0.5 moi) at 0-5°. A f t e r s t i r r i n g for 12 hours - 202 -at room temperature the hydrated K^CO^ was removed by suction f i l t r a t i o n and the excess propionaldehyde was removed under vacuum. The residue was vacuum d i s t i l l e d using a Vigreaux s t i l l h e a d . It was noted that d i s t i l l a t i o n at 5-6 mm (bp 59-65°) gave considerable decomposition i n the pot. To cut down on the decomposition, the material was d i s t i l l e d at 1.5 mm (bp 35-50°), however the bp range was wider and there was a greater contamination of the product with morpholine. A colourless l i q u i d was c o l l e c t e d : 27.5 g (45%); i r (neat) 875, 950 and 1665 (enamine), 1130 cm 1 (ether); nmr (CDCl^) <5 1.63 (2 dd, superimposed, 3, J = 1.5, 6 Hz, CH_3) , 2.71 (m, 4, CH2NCH_2) , 3.65 (m, 4, CH 2OCH 2), 4.43 (m, 1, CHCH 3), 5.7 (1 dd, 1, J = 12, 15 Hz, NCH). I t appears as i f the c i s and trans isomers were i s o l a t e d . 31. Synthesis of g-Morpholinostyrene (239) and a-Pyrr o l i d i n o - styrene (240) A solution of acetophenone (60 g, 0.5 moi), f r e s h l y d i s t i l l e d morpholine (52 g, 0.6 moi) and a pinch of benzylsulfonic acid i n 200 ml of benzene was poured into a 500 ml round bottom flask. The f l a s k was f i t t e d with a drying tube charged with C a C l 2 , F r i e d l i c h condenser and a Dean-Stark trap. The reaction mixture was refluxed for 48 hours during which time 10 ml of H 20 c o l l e c t e d i n the trap and the solution became yellow. The s o l u t i o n was cooled - 203 -and the benzene was removed under vacuum and the residue was vacuum d i s t i l l e d using a Vigreaux s t i l l h e a d . A colour-less f r a c t i o n of 239 was c o l l e c t e d : 31.42 g (33%); bp 98-102° (0.3 mm) ( l i t . (105) bp 85°, 0.08 mm); i r (neat) 715 and 785 (phenyl), 998 and 1603 (enamine), 1130 cm"1 (ether). Repeating the synthesis using p y r r o l i d i n e (42.6 g, 0.6 moi) instead of the morpholine and r e f l u x i n g for 4 days resulted i n only 4.6 g (5.3%) of 240 as a yellow l i q u i d : bp 98-102° (0.7 mm); i r (neat) 705 and 775 (phenyl), 965 and 1605 cm 1 (enamine). 32. Synthesis of l-Dimethylamino-2,2-diphenylethene (210) The general conditions of enamine synthesis as outlined i n Experiment 16 was used. A solution of dimethylamine (15 ml, 0.227 moi) i n 25 ml of anhydrous ether and K 2C0 3 (7.5 g) was s t i r r e d at 0-5°. Diphenylacetaldehyde (9.8 g, 0.05 moi) was added dropwise over a period of 1 hour and the reaction mixture was s t i r r e d at 0-5° for 12 hours. The hydrated K 2C0 3 was removed by f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum to give 6.43 g (57.5%) of a white s o l i d which could be r e c r y s t a l l i z e d from petroleum ether (30-60°) to give 3.78 (33.9%) of needle-like c r y s t a l s : mp 79.5-84.5°; i r (nujol) 705 and 765 (phenyl), 895, 950 and 1625 cm"1 (enamine); nmr (CDC13) 6 2.57 (s, 6, N(CH ) 2)., 6.34 (s, 1, CH), 7.18 (m, 5, Ar). Treatment of a small sample of 210 with d i l u t e HCl on a steam bath, and extraction with CHC13 and concentration of the CHCI3 extracts under vacuum l e f t an - 204 -o i l . The residue was dissolved i n methanol and treated with 2,4-dinitrophenylhydrazine sol u t i o n . The r e s u l t i n g orange p r e c i p i t a t e was r e c r y s t a l l i z e d from ethanol to give yellow c r y s t a l s , mp 154-155°. This material was i d e n t i c a l to the 2,4-dinitrophenylhydrazine d e r i v a t i v e prepared from commercially available diphenylacetaldehyde. The enamine 210 i s very unstable, but can be stored i n a N 2 atmosphere at -15° for several months without appreciable decomposition. 33. Attempted C y c l i z a t i o n of l-Dimethylamino-2,2-diphenyl- ethene (210) with Some Substituted Sulfonyl Chlorides The general conditions for synthesis of thietane 1,1-dioxides as outlined i n Experiment 4 were followed. A solution of 210 (2.33 g, 0.01 moi), Et^N (1.01 g, 0.01 moi) in 35 ml of anhydrous ether was s t i r r e d at 0-5° i n an N 2 atmosphere. A solution of ethanesulfonyl chloride (1.28 g, 0.01 moi) i n 10 ml of anhydrous ether was added dropwise. The reaction r e a d i l y became purple i n colour and a p r e c i p i t a t e formed. The reaction mixture was concentrated under vacuum and the r e s u l t i n g residue was dissolved i n 50 ml of CHCl^. The solution was washed with several portions of H 20, dried with anhydrous Na 2S0 4, and concentrated under vacuum to give a yellow s o l i d residue. An i r spectrum (KBr) of the residue indicated the product to be mostly the s t a r t i n g enamine 210 and perhaps some breakdown to diphenylacet-aldehyde. When the reaction was repeated with methanesulfonyl - 205 -chloride or benzylsulfonyl chloride i n molar r a t i o the same r e s u l t s were obtained. 34. Synthesis of 3-Dimethylamino-4-methyl-2-phenylthietane  1,1-Dioxide (226) The general reaction conditions outlined i n Experiment 4 were used. A solution of 3-dimethylaminostyrene (143) (64 g, 0.435 moi) and Et^N (44 g, 0.4 moi) i n 125 ml of CH^CK at 0-5°. Et^N-HCl began to p r e c i p i t a t e immediately and the solution became a yellow colour at f i r s t then turned purple. The reaction was s t i r r e d at 0-5° for 1.5 hours a f t e r the addition of ethanesulfonyl chloride. The Et^N'HCl was removed by suction f i l t r a t i o n and the f i l t r a t e was concen-trated under vacuum to give a black o i l . This residue was dissolved i n 300 ml of CHCl^ and extracted with 100 ml of H 20 and 3 x 500 ml of 10% HCl solution. The combined yellow a c i d i c extracts were b a s i f i e d with saturated Na 2C0 3 soluton and extracted with 3 x 150 ml of CHC13. The organic layer was concentrated under vacuum to give 50 g of a gummy material which could be r e c r y s t a l l i z e d from benzene-hexane to give 15.5 g (16.2%) of f l u f f y white needle-like c r y s t a l s : mp 138-139.5°; i r (KBr) 720 and 750 (phenyl), 1145, 1183, 1203 and 1317 (sulfone), 2790 and 2840 cm"1 (dimethylamino); nmr (CDC13) 6 1.60 (d, 3, J = 8 Hz, CHCH_3) , 2.18 (s, 6, N(CH_ 3) 2), 3.38 (dd, 1, J = 8, 10 Hz, CHN) , 4.18 (dq, 1, J = 8, 8 Hz, CHCH3), 5.18 (d, 1, J = 10 Hz, ArCH), - 206 -7.43 (m, 5, Ar); mass spectrum m/e 239 (v ; weak molecular ion), 147 ( (C,HCCHCHN(CH.)_)t) , 131 ((CrHcCHCHCHCH-)+) , b D 3 2. b o j 115 ((C gH 5CHCCH) +) , 91 ( ( C 7 H ? ) + ) , 85 ( (CH^CHCHN(CH^)2) * (base peak), 70 ( (CH 2CN(CH 3) 2) +). Anal. Calcd. for C 1 2H 1 7N0 2S: C, 60.22; H, 7.16; N, 5.85; S, 13.40; m wt 239.33. Found: C, 60.34; H, 7.05; N, 5.71; S, 13.40. No other i d e n t i f i a b l e products were i s o l a t e d . The i r spectrum of the crude product showed a strong enamine band at 1625 cm 1 which could have been a c y c l i c product. C y c l i z a t i o n using anhydrous ether as the solvent or reacting for 12 hours at 0-5° did not increase the y i e l d . 35. Synthesis of 4-Methyl-3-morpholino-2-phenylthietane  1,1-Dioxide (227) The general reaction conditions of Experiment 4 were used. A solution of 1-morpholinopropene (222) (27.52 g, 0.215 moi) and Et^N (22 g, 0.218 moi) i n 300 ml of dry CH3CN was reacted with benzylsulfonyl chloride (225) (41 g, 0.215 moi) i n 200 ml of CH3CN at 0-5° for 12 hours, during which time the reaction took on a buff colour. After removal of the Et^N'HCl, the CH3CN was removed under vacuum to give a buff coloured s o l i d residue. The residue was dissolved i n 200 ml of CHC13 and extracted with 10% HCl solution. The CHC13 layer was washed with 2 x 50 ml of H20, dried and concentrated under vacuum to give a white s o l i d residue. - 207 -The residue was r e c r y s t a l l i z e d from benzene-petroleum ether(80-100°) to give white c r y s t a l s of morpholinobenzyl-sulfonamide (228): mp 170-174°; i r (KBr) 710 and 755 (phenyl), 1115, 1155, 1320 and 1345 (sulfonamide), 1260 and 950 cm - 1 (ether); nmr (CDClg) <5 3. 08 (m, 4, CH NCH_2) , 3.54 (m, 4, CH2OCH2) , 4.18 (s, 2, ArCH_2) , 7.35 (m, 5, Ar) . A mixed mp with a sample of 228 prepared by reacting morpholine with 225 i n anhydrous ether was not depressed and the i r spectra were superimposable. The acid extract was worked up as i n Experiment 34 to give a buff coloured s o l i d . R e c r y s t a l l i z a t i o n from n-butanol-hexane gave 15 g (24.5%) shiny white s c a l e - l i k e c r y s t a l s of 227: mp 155.5-158°; i r (KBr) 715 and 755 (phenyl), 1130, 1210, 1300 and 1328 (sulfone), 885 and 1285 cm - 1 (ether); nmr (CDC13) "6 1.57 (d, 3, J = 7 Hz, CHCH_3) , 2.30 (m, 4, CH2NCH_2) , 2.87 (dd, 1, J = 8, 8 Hz, CHN) , 3.60 (m, 4, CH_2OCH_2) , 4.20 (dq, 1 J = 7, 8 Hz, CHCH3), 5.17 (d, 1, J = 8 Hz, ArCH), 7.40 (m, 5, Ar); mass spectrum (no molecular ion) m/e 131 ((CgH^CHCH-+ 1 1 + , CHCH3) ), 127 ((CH 3CHCHNC 2H 4OC 2H 4)• base peak), 115 ((C 6H 5CHCCH) +), 112 ((CH 2CNC 2H 4OC 2H 4) +), 91 ( ( C ? H 7 ) + ) . Anal. Calcd. for C..H1nNO.S: C, 59.76; H, 6.81; N, 4.9 14 i y 3 S, 11.40; m wt 281.38. Found: C, 59.70; H, 6.85; N, 4.80; S, 11.34. - 208 -36. Synthesis of 4-Methyl~2-phenylthiete 1,1-Dioxide (229) The same procedure outlined i n Experiment 5 was followed. Starting with eith e r 3-dimethylamino-4-methyl-2-phenylthi.etane 1,1-dioxide (226) or 4-methyl-3-morpholino-2-phenylthietane 1,1-dioxide (227) gave the same product i n approximately the same y i e l d . Thus a solution of 227 (13.1 g, 46.6 mmol) in 31.5 ml of AcOH and 31.5 ml of Ac 20 was reacted with 30% H2°2 " z 9) a t r o o m temperature for 12 hours. I n i t i a l l y a p r e c i p i t a t e of probably the AcOH s a l t of 227 formed but disappeared on the addition of ^2G2 t o 9 l v e a colourless solution. Neutralization with saturated Na 2C0 3 solution caused the formation of a white p r e c i p i t a t e . The p r e c i p i t a t e was c o l l e c t e d by suction f i l t r a t i o n and r e c r y s t a l l i z e d from n-butanol-hexane to give 8.9 g (94%) of white c r y s t a l l i n e material: mp 111-112.8° ( l i t . (101) 111-112°); i r (KBr) 710, 748 and 782 (phenyl), 1143, 1190, 1295 and 1315 cm"1 (sulfone); nmr (CDC13) 6 1.57 (d, 3, J = 7 Hz, CE^), 4.84 (dq, 1, J = 2, 7 Hz, CHCH3), 6.90 (d, 1, J = 2 Hz, CCH), 7.45 (m, 5, Ar). 37. Synthesis of 3-Cyano-2-phenylthietane 1,1-Dioxide (217) L i q u i f i e d HCN (127d) was c o l l e c t e d , weighed and d i l u t e d with ethanol to give a 1 molar solu t i o n . A solution of 2-phenylthiete 1,1-dioxide (142) (7.5 g, 41.7 moi) i n 250 ml of ethanol and 300 ml of 1 molar HCN solution was s t i r r e d i n a 1,000 ml three-necked f l a s k i n a fumehood. To - 209 -i n i t i a t e the reaction KCN (0.6 g) was added and the flask stoppered to give a closed system. The reaction mixture became pale yellow af t e r 1 hour and was s t i r r e d at room temperature for 4 8 hours during which time a white p r e c i p i t a t e formed. The solution was cooled i n the r e f r i g e r a t o r and the p r e c i p i t a t e was c o l l e c t e d by suction f i l t r a t i o n i n the fumehood. The p r e c i p i t a t e was thoroughly washed with H^ O to remove any inorganic s a l t s and a i r dried to give 5.88 g (68%) of a white powder, which was r e c r y s t a l l i z e d from hexane-ethanol r e s u l t i n g i n f l u f f y white needle-like c r y s t a l s : mp 196.8-197.5°; i r (KBr) 705, 719 and 755 (phenyl), 1150, 1215 and 1335 (sulfone), 2265 cm"1 ( n i t r i l e ) ; nmr (DMSO-dg) <S 4.03-4.91 (m, 3, CHCH_2) , 6.30 (d, 1, J = 7 Hz, ArCH ), 7.55 (m, 5, Ar); mass spectrum (no molecular ion) m/e 143 ( (C^Hj-CHCH (CN) CH„) +) , 116 ( (CgHgCHCHCH) •") , 115 ( (CgH^HCCH) + base peak), 91 ( ( C ? H 7 ) + ) , 89 ((CHCS0 2) +). Anal. Calcd. for C^HgNC^S: C, 57.95; H, 4.38; N, 6.76; S, 15.47; m wt 207.26. Found: C, 57.86; H, 4.36; N, 6.63; S, 15.29. Concentration of the f i l t r a t e from the reaction resulted i n a gummy residue which was r e c r y s t a l l i z e d from hexane-ethanol to give unreacted s t a r t i n g material 142. - 210 -38. Synthesis of 3-Cyano-4-methyl-2-phenylthietane  1,1-Dioxide (230) The same procedure as outlined i n Experiment 37 was used. A solution of 4-methyl-2-phenylthiete 1,1-dioxide (229) (15.95 g, 82.3 mmol) and KCN (1 g) i n 500 ml of ethanol was reacted with 600 ml of 1 molar HCN solut i o n . The reaction was s t i r r e d for 4 8 hours at room temperature, 250 ml of 1 molar KCN solution added and the reaction mixture was s t i r r e d for another 24 hours. The cooled yellow suspension was suction f i l t e r e d and the p r e c i p i t a t e was c o l l e c t e d . R e c r y s t a l l i z a t i o n from ethanol gave 9.72 g (53.5%) of f l u f f y white c r y s t a l s : mp 197.5-199°; i r (KBr) 705, 733, 795 (phenyl), 1145, 1200, 1300, 1333 (sulfone), 2265 cm"1 ( n i t r i l e ) ; nmr (DMSO-dg) 6 1.51 (d, 3, J = 7 Hz, CH_3) , 3.99 (dd, 1, J = 10, 11 Hz, CHCN), 5.03 (dq, 1, J = 7, 10 Hz, CHCH3), 6.20 (d, 1, J = 11 Hz, ArCH), 7.53 (m, 5, Ar); -(. mass spectrum (no molecular ion) m/e 156 ((C_HCCHC(CN)CHCH_) ), b -> 3 142 ((C 6H 5CHC(CN)CH 2)t), 129 ((C 6H 5CHCCCH 3) + base peak), 91 ( ( C 7 H ? ) + ) . Anal. Calcd. for C^H^NC^S: C, 59.71; H, 5.01; N, 6.33; S, 14.49; m wt 221.28. Found: C, 59.80; H, 5.03; N, 6.27; S, 14.29. 39. Synthesis of 3-Aminomethyl-2-phenylthietane 1,1-Dioxide (218) A 500 ml three-necked f l a s k was f i t t e d with a drying tube, F r i e d l i c h condenser, mechanical s t i r r e r and a 250 ml - 211 -dropping funnel and flame dried while flushing the system with dry N 2. Upon cooling, a suspension of 3-cyano-2-phenylthietane 1,1-dioxide (217) (10.35 g, 50 mmol) and 125 ml of dry THF was s t i r r e d at room temperature while 250 ml of 0.08 molar solution of B 2H g i n THF. (162,163) was added dropwise over a period of 1 hour. The reaction mixture was s t i r r e d at room temperature for 12 hours during which time a colourless solution resulted. The excess B 2H g was destroyed by c a r e f u l addition of 100 ml of ethanol and r e f l u x i n g the r e s u l t i n g solution for 1 hour. Upon cooling, HCl gas was bubbled into the s o l u t i o n u n t i l the solution started to take on a yellow colour. There was also the formation of some white p r e c i p i t a t e . The solvent was removed under vacuum and the r e s u l t i n g residue was dissolved i n 100 ml of H 20. The aqueous solut i o n was made basic with the addition of 5 ml of 18 N NaOH solution and extracted with 3 x 100 ml of CHC13. The combined CHC13 extracts were washed with 2 x 50 ml of H 20, dried with anhydrous MgSO^ and concentrated under vacuum to leave 7.71 g (73%) of a viscous, c l e a r , colourless l i q u i d : i r (neat) 710 and 763 (phenyl), 1145, 1205 and 1315 (sulfone), 3320 and 3390 cm"1 (NH2) ; nmr (CDC13) <5 1.50 (s, 2, NH_2, disappeared on addition of D20) , 2.49-3. 07 (m, 3, CHCH_2N) , 3.93 (dd, 2, J = 2.5, 8.5 Hz, SCH 2), 5.18 (d, 1, J = 9 Hz, ArCH), 7.42 (m, 5, A r ) . There was no detectable amount of impurities i n these spectra and no further p u r i f i c a t i o n was done, as i t - 212 -was discovered that polymerization occurred while attempting to do a vacuum d i s t i l l a t i o n . The HCl s a l t was prepared by bubbling HCl gas into an ethereal solution of 218, c o l l e c t i n g the p r e c i p i t a t e by suction f i l t r a t i o n and r e c r y s t a l l i z i n g the p r e c i p i t a t e from ethanol-ether, with charcoal treatment. White needle-like c r y s t a l s with a mp of 213-215° dec were obtained. Anal. Calcd. for C^H-^CINC^S: C, 48.48; H, 5.70; C l , 14.31; N, 5.65; S, 12.94; m wt 247.75. Found: C, 48.36; H, 5.63; C l , 14.25; N, 5.75; S, 12.95. 40. Synthesis of 3-Aminomethyl-4-methyl-2-phenylthietane  1,1-Dioxide (231) The same procedure as outlined inExperiment 39 was used. A suspension of 3-cyano-4-methyl-2-phenylthietane 1,1-dioxide (230) (12.5 g, 55 mmol) i n 125 ml of dry THF was reacted with 275 ml of 0.08 molar B0H^ sol u t i o n i n THF. 2 6 The excess B-H,. was destroyed with 100 ml of ethanol and 2. o the reaction worked up to give 11.92 g (86.2%) of a cl e a r colourless viscous o i l : i r (neat) 705 and 760 (phenyl), 1140 and 1305 (sulfone), 3310 and 3380 cm"1 (1° amine); nmr (CDCl^) 1.15 (s, 2, NFL,, disappeared on addition of D20) , 1.48 (d, 3, J = 7 Hz, CH_3) , 2.32 (m, 1, CHCH2N) , 2.87 (d, 2, J = 6 Hz, CH 2N), 4.07 (dq, 1, J = 7, 9 Hz, CHCH3), 5.05 (d, 1, J = 10 Hz, ArCH), 7.38 (m, 5, Ar). There were no detectable impurities i n these spectra and further - 213 -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 was not attempted. The HCl s a l t was prepared and r e c r y s t a l l i z e d from ethanol-ether to give white needle-like c r y s t a l s , mp 218.5-220.5° dec. Anal. Calcd. for C, ,H.,rClNO„S: C, 50.47; H, 6.16; C l , 1 1 1 6 2 13.55; N, 5.35; S, 12.25; m wt 261.78. Found: C, 50.55; H, 6.21; C l , 13.43; N, 5.36; S, 12.26. 41. Synthesis of 3-Dimethylaminomethyl-2-phenylthietane  1,1-Dioxide (214) A solution of 3-aminomethyl-2-phenylthietane 1,1-dioxide (218) (6.4 g, 0.0304 moi), 90.7% formic acid (15.5 g, 0.3 moi) and 37% formaldehyde (14.2 ml, 0.2 moi) i n a 100 ml miniware round bottom f l a s k f i t t e d with a condenser was set up i n a fumehood and magnetically s t i r r e d . The reaction was immersed i n an o i l bath and heated at 90° (+ 5°). Almost immediately there was a vigorous evolution of a gas which soon stopped and the solut i o n became a pale yellow colour. The heating was continued for 18 hours and the solution was allowed to cool to room temperature. A portion of 4 N HCl (31.8 ml) was added and the r e s u l t i n g mixture was concentrated under vacuum. The r e s u l t i n g o i l y residue was dissolved i n 300 ml of H2O and poured into a separatory funnel. The a c i d i c s o l u t i o n was neutralized with 18 N NaOH (10 ml) and the r e s u l t i n g suspension was extracted with 3 x 100 ml of C H C 1 3 . The combined CHC1-, extracts were washed with 3 x 100 ml of H 00, - 214 -dried with anhydrous MgSO^ and concentrated under vacuum to give 5.3 g (73%) of crude product. R e c r y s t a l l i z a t i o n from hexane by decanting the hot hexane from the insoluble material gave 4.4 g (60.8%) of f l u f f y white c r y s t a l s : mp 101.5-103°; i r (KBr) 708 and 768 (phenyl), 1145, 1155, 1185 and 1323 (sulfone), 2770 and 2820 cm"1 (dimethylamino); nmr (CDC13) 6 2.18 (s, 6, N(CH_ 3) 2), 2.40-3.10 (m, 3, CHCH_2N) , 3.99 (m, 2, SCH 2), 6.08 (d, 1, J = 8 Hz, ArCH), 7.42 (m, 5, Ar); mass spectrum m/e 239 (weak molecular i o n ) , 117 ( (C 6H 5CHCHCH 2) +) , 115 ( (CgHgCHCCH)+) , 91 ( ( C ? H 7 ) + ) , 58 ( (CH2N(CH3) 2 ) + base peak). Anal. Calcd. for C 1 2H 1 7N0 2S: C, 60.22; H, 7.16; N, 5.85; S, 13.40; m wt 239.34. Found: C, 60.10; H, 7.24; N, 5.78; S, 13.40. The HCl s a l t was prepared and r e c r y s t a l l i z e d from ethanol-ether to give f l u f f y white needle-like c r y s t a l s , mp 208.5-210° dec. 42. Synthesis of 3-Dimethylaminomethyl-4-methyl-2- phenylthietane 1,1-Dioxide (215) The same procedure as outlined i n Experiment 41 was used. A solution of 3-aminomethyl-4-methyl-2-phenylthietane 1,1-dioxide (231) (10 g, 0.0445 moi), 90.7% formic acid (22.8 g, 0.445 moi) and 37% formaldehyde (25 ml, 0.355 moi) was heated for 18 hours at 90° (+ 5°). Work up of the reaction gave a thick o i l which was taken up i n hexane-ethanol - 215 -and cooled to give 6 g (53.5%) of yellow amorphous c r y s t a l s : mp 80-84.8°; i r (thin film) 715 and 765 (phenyl), 1150, 1180, 1285 and 1315 (sulfone), 2790 and 2830 cm"1 (dimethyl-ami no) ; nmr (CDC13) 6 1.60 (d, 3, J = 7 Hz, CHCH_3) , 2.18 (s, 6, N(CH_ 3) 2), 2.54 (obscured m, 1, CHCH2N), 2.55 (d, 2, J = 1.5 Hz, CH_2N) , 4.08 (dq, 1, J = 7, 9 Hz, CHCH3) , 4.99 (d, 1, J = 9 Hz, ArCH), 7.43 (m, 5, Ar); mass spectrum m/e 253 (molecular ion) , 129 ((C,HCCHCCCH,)+) , 115 ( (C^HCCHCCH)+) , D D O D O 91 ( ( C ? H 7 ) + ) , 58 ((CH 2N(CH 3) 2) + base peak). The crude product was not p u r i f i e d further because of the low e f f i c i e n c y of the r e c r y s t a l l i z a t i o n procedure. The preparation of the HCl s a l t resulted i n a fin e powder which adsorbed a large amount of ether. This powder was a i r dried and r e c r y s t a l l i z e d from ethanol-ether to give f l u f f y white needle-like c r y s t a l s , mp 211-213° dec. Anal. Calcd. for C 1 3H 2 0ClNO 2S: C, 53.88; H, 6.96; C l , 12.23; N, 4.83; 0, 11.04; S, 11.06; m wt 289.82. Found: C, 53.81; H, 6.75; C l , 12.09; N, 4.98; S, 10.99. 43. Attempted Synthesis of 4-Cyano-3-dimethylamino-2-phenylthietane 1,1-Dioxide (245), I s o l a t i o n of Cyanomethyl  2-Dimethylamino-l-phenylethenyl Sulfone (246) The general conditions outlined i n Experiment 4 were followed. A solut i o n of fre s h l y prepared cyanomethane-sulf o n y l chloride (234) (153) (3.5 g, 25 mmol) i n 25 ml of dioxane was reacted with a solut i o n of B-dimethylaminostyrene - 216 -(143) (3.68 g, 25 mmol) and Et^N (2.52 g, 25 mmol) i n 25 ml of dioxane a t 15° f o r 2 hours. A dark s o l u t i o n r e s u l t e d q u i c k l y as w e l l as the p r e c i p i t a t i o n o f Et^N-HCl. Removal of the p r e c i p i t a t e by s u c t i o n f i l t r a t i o n and c o n c e n t r a t i o n o f the f i l t r a t e under vacuum l e f t a dark o i l . The i r spectrum showed a s t r o n g enamine band a t 1640 cm The r e s i d u e was taken up i n an equal volume of hot e t h a n o l and allowed t o c o o l . The y e l l o w c r y s t a l s which p r e c i p i t a t e d were r e c r y s t a l l i z e d s e v e r a l times from e t h a n o l t o g i v e s h i n y , s c a l e - l i k e c r y s t a l s (1.95 g ) : mp 118-120° dec; i r (KBr) 715 and 740 (phenyl), 1110, 1130, 1175, 1240 and 1305 ( s u l f o n e ) , 1615 (enamine), 2270 cm" 1 ( n i t r i l e ) ; nmr (CDC1 3) 6 2.78 (s, 6, N ( C H 3 ) 2 ) , 3.44 (s, 2, CH_2S) , 7.42 (m, 5, Ar) , 7.50 (s, 1, CHN) . The data i n d i c a t e d t h a t the m a t e r i a l i s o l a t e d was the a c y c l i c p r o d u c t , 246. On t h i s b a s i s the m a t e r i a l i s o l a t e d r e p r e s e n t e d a 33% y i e l d . A n a l . C a l c d . f o r C 1 2 H 1 4 N 2 ° 2 S : C ' 5 7 * 5 8 ; H ' 5- 6 4'* N ' 11.19; S, 12.81; m wt 250.13. Found: C, 57.83; H, 5.52; N, 11.06; S, 12.63. Repeating the experiment i n dry CH 3CN a t 0-5° o r adding the E t 3 N to a s o l u t i o n o f 143 and 234 d i d not r e s u l t i n the i s o l a t i o n o f the d e s i r e d c y c l i c p r oduct, 245. - 217 -44. A t t e m p t e d S y n t h e s i s o f 4-Cyano-3-phenyl S u b s t i t u t e d  T h i e t a n e 1 , 1 - D i o x i d e s . I s o l a t i o n o f B e n z o y l m e t h y l  Cyanomethyl S u l f o n e (244) The g e n e r a l c o n d i t i o n s f o r enamine c y c l i z a t i o n as o u t l i n e d i n Ex p e r i m e n t 4 were f o l l o w e d . A s o l u t i o n o f c y a n o m e t h a n e s u l f o n y l c h l o r i d e (5.6 g, 0.04 moi) i n 50 ml o f anhydrous e t h e r was r e a c t e d w i t h a s o l u t i o n o f a - m o r p h o l i n o -s t y r e n e (239) (7.55 g, 0.04 moi) and Et^N (4.04 g, 0.04 moi) i n 100 ml o f anhydrous e t h e r a t 0-5° f o r 3 h o u r s . The s o l u t i o n became brown c o l o u r e d and was accompanied by t h e p r e c i p i t a t i o n o f E t ^ N - H C l . The p r e c i p i t a t e was removed by s u c t i o n f i l t r a t i o n and t h e f i l t r a t e was c o n c e n t r a t e d under vacuum t o g i v e a d a r k v i s c o u s o i l . Upon s t a n d i n g t h e m a t e r i a l became a s e m i s o l i d , b u t c o u l d n o t be r e c r y s t a l l i z e d from common l a b o r a t o r y s o l v e n t s . The i r and nmr spectrum i n d i c a t e d t h a t t h e m a t e r i a l i s o l a t e d was 24j4: i r (neat) 705 and 765 ( p h e n y l ) , 1125, 1275, 1300 and 1330 ( s u l f o n e ) , 1680 ( a r y l k e t o n e ) , 2190 and 2270 ( n i t r i l e ) ; nmr (CDC1 3) 6 2.54 ( s , 2, CH_2CN) , 3.63 ( s , 2, OCCH_2) , 7.17-8.03 (m, 5, Ar) . A t t e m p t s t o e x t r a c t a CHC1 3 s o l u t i o n o f t h e crud e m a t e r i a l w i t h 10% HCl s o l u t i o n f a i l e d t o i s o l a t e any c y c l i z e d p r o d u c t . I f a - p y r r o l i d i n o s t y r e n e (240) was used i n molar r a t i o as above i n s t e a d o f 239 and i d e n t i c a l p r o d u c t was o b t a i n e d . T h i s p r o v i d e d a d d i t i o n a l e v i d e n c e t h a t an a c y c l i c enamine was formed and s u b s e q u e n t l y h y d r o l y z e d t o 244. - 218 -45. Synthesis of 1,3-Bis(dimethylamino)-propene (76) A suspension of dimethylamine (15.2 ml, 2.3 moi) and anhydrous MgSO^ (120 g, 1 moi) i n 200 ml of anhydrous ether (Na dried) was s t i r r e d i n a 1,000 ml three-necked fl a s k f i t t e d with a drying tube, mechanical s t i r r e r and a 250 ml dropping funnel. The system was cooled to 0-5° i n a i c e - s a l t water bath and a solution of a c r o l e i n (56 g, 1 moi) i n 150 ml of ether was added dropwise over a period of 2 hours. The reaction mixture was s t i r r e d at room temperature for 24 hours. The hydrated MgS04 was removed by suction f i l t r a t i o n , washed with anhydrous ether and the f i l t r a t e was concentrated under vacuum to give a yellow o i l . The residue was vacuum d i s t i l l e d with a Claisen s t i l l h e a d to give 88.81 g (69%) of a colourless l i q u i d : bp 59-61° (12-14 mm) ( l i t . (154) 37-43°, 5 mm); i r (neat) 945 and 1655 (enamine), 2770, 2850 cm 1 (dimethylamino); nmr (neat) 6 2.13 (s, 6, CH 2N(CH 3) 2), 2.56 (s, 6, CHN(CH_3)2), 2.78 (d, 2, J = 7 Hz, CHCH2), 4.17 (dt, 1, J = 7, 13 Hz, CH2CH), 5.93 (d, 1, J = 13 Hz, NCH). 46. Synthesis of 3-Dimethylamino-4-dimethylaminomethyl-2- phenylthietane 1,1-Dioxide (80) The general conditions outlined i n Experiment 5 were used. A solution of 1,3-bis(dimethylamino)-propene (76) (30 g, 0.234 moi) and Et 3N (24.7 g, 0.245 moi) i n 250 ml of anhydrous ether was s t i r r e d at 0-5°. A solution of benzylsulfonyl chloride (44.55 g, 0.234 moi) i n 300 ml of 50:50 THF:ether was added dropwise over a period of 2 hours at 0-5°, during which time the solution became buff coloured. The Et-jN-HCl p r e c i p i t a t e was removed by suction f i l t r a t i o n and the f i l t r a t e was concentrated under vacuum to leave a dark semisolid. This material could be r e c r y s t a l l i z e d from hexane by decanting the hot hexane from the insoluble material to give 12.8 g of white needle-like c r y s t a l s : mp 94-97° ( l i t . (86) 95-96° from ether-hexane), 112-114° dec (HCl s a l t ) ; i r (KBr) 705, 735 and 800 (phenyl), 1128, 1143, 1160, 1178, 1230, 1313 and 1345 (sulfone), 2785 and 2835 cm"1 (dimethylamino) ; nmr (CDClg) <5 1.92 (s, 6, CH 2N(CH_ 3) 2), 2.29 (s, 6, CHN(CH3) 2 ) , 2. 43-3.38 (m, 3, CHN, CH_2N) , 4.41 (dt, 1, J = 3, 9 Hz, CHCH2), 5.12 (dd, 1, J = 1, 9 Hz, ArCH), 7.38 (m, 5, Ar); mass spectrum m/e 282 (v. weak molecular ion), 148 ( (C 6H 5CH 2CHN(CH 3) 2 ) + ) , 105 ( (CgHgCO) +) , 91 ( ( C ? H 7 ) + ) , 84 ( (CH 2CHCHN(CH 3) 2) +) , 77 ( ( C g H 5 ) + ) , 58 ( (CH2N(CH3) 2 ) + base peak). Upon further standing of the mother l i q u o r from the r e c r y s t a l l i z a t i o n procedure a further 4.17 g of white needle-l i k e c r y s t a l s p r e c i p i t a t e d : mp 78-80°, 144-146° (HCl s a l t ) ; i r (KBr) 708, 735 and 798 (phenyl), 1138, 1155, 1185, 1275, 1300 and 1325 (sulfone), 2790 and 2840 cm - 1 (dimethylamino); nmr (CDC13) <5 2.12 (s, 6, CHN(CH_3)2), 2.27 (s, 6, CH 2N(CH_ 3) 2), 2.45-3.35 (m, 3, CHN, CH 2N), 4.25 (dt, 1, J = 4, 9 Hz, CHCH.J , 5.10 (d, 1, J = 9 Hz, ArCH), 7.34 (m, 5, Ar). - 220 -Anal. Calcd. for C 1 4H 2 4C1 2N 20 2S: C, 47.32; H, 6.18; C l , 19.95; N, 7.88; S, 9.02; m wt 355.32. Found: C, 47.32; H, 7.07; C l , 19.85; N, 7.72; S, 9.05. The data indicated that 2 isomers of 8_0 were i s o l a t e d having a r-2, t-3, c-4 and a r-2, c-3, t-4 configuration, the higher melting isomer being the compound with the r-2, t-3, c-4 configuration. A t o t a l of 16.97 g (26%) of c y c l i z e d product was obtained. No other products were is o l a t e d , although an i r spectrum (neat) of the crude product showed enamine bands at 970 and 1630 cm 1 which could be i n d i c a t i v e of an a c y c l i c product. 47. Attempted Syntheses of 4-Dimethylaminomethyl-2- phenylthiete 1,1-Dioxide (255) (a) Demethylation of the quaternary ammonium s a l t (155) A s o l u t i o n of 4-dimethylaminomethyl-2-phenylthiete I, 1-dioxide methyl iodide (254) (150) (242 mg, 0.645 mmol) i n 250 ml of methanol was magnetically s t i r r e d at room temperature f o r 18 hours with f r e s h l y prepared AgCl (372 mg, 2.6 mmol). The reaction mixture was f i l t e r e d and the f i l t r a t e was concentrated under vacuum. The residue was dissolved i n 20 ml of ethanol and sodium thiophenoxide (159c) (175 mg, 1.32 mmol) i n 20 ml of ethanol was added and the mixture was s t i r r e d for 4 8 hours. During t h i s time a small amount of a p r e c i p i t a t e , presumably NaCl, appeared and was removed by f i l t r a t i o n . The f i l t r a t e was concentrated under vacuum and the remaining residue was dissolved i n 30 ml of 2-butanone and refluxed for 18 hours under N 2 atmosphere. The solvent was removed under vacuum and the residue was dissolved i n 30 ml of CHCl.^. The solution was extracted with 20 ml of H 20 and 3 x 20 ml of 10% HCl solution. The a c i d i c extracts were combined, neutralized with saturated Na 2C0 3 solution and extracted with 3 x 20 ml of CHCl^. The organic layer was dried with anhydrous MgSO^ and concentrated under vacuum to give a few drops of an o i l . The i r and nmr spectra appeared to be a mixture of 2-butanone and an un i d e n t i f i e d material with a sulfone function (1120 and 1310 cm i n the i r spectrum. (b) Selective Hoffman elimination A solution of 3-dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-dioxide (80) (1 g, 3.55 mmol) i n 50 ml of methanol was reacted with methyl iodide (0.505 g, 3.55 mmol) at room temperature for 48 hours i n a 125 ml erlenmeyer f l a s k . During t h i s period a p r e c i p i t a t formed, and was removed by f i l t r a t i o n . The f i l t r a t e was concentrated under vacuum to give a residue which was indicated to be the a c y c l i c breakdown product, 2-dimethylamino-l-phenyl-l-ethenyl 2'-dimethylamino-1'-ethanyl sulfone methyl iodide (256) (150); i r (KBr) 845, 905 and 1615 (enamine), 1115, 1130, 1300 and 1320 cm"1 (sulfone). - 222 -(c) Selective dimethylation A solution of 4-methylene-2-phenylthiete (249) (150) (100 mg, 0.52 mmol) i n 10 ml of ethanol was reacted with 0.0735 ml of dimethylamine per ml of ethanol solution (1.1 ml, 0.52 mmol of dimethylamine) i n a stoppered 25 ml erlenmeyer flask at room temperature for 96 hours. The solution was concentrated under vacuum and analysis of the residue indicated that the material i s o l a t e d was unreacted s t a r t i n g material, 249. - 223 -PHARMACOLOGICAL TESTING 1. Monoamine Oxidase I n h i b i t i o n Studies 2 5 Although the compound, 3-amino-2-phenylthietane (5_) , desired as the exact s t r u c t u r a l analogue of tranylcypromine (2_) was not synthesized, several of the compounds prepared were of s u f f i c i e n t s i m i l a r i t y to 2_ to warrant study (Figure 4). S p e c i f i c a l l y , 2-benzyl-3-dimethylaminothietane (8), 3-amino-2-phenylthietane 1,1-dioxide (165) and 2-benzyl-3-dimethylaminothietane 1,1-dioxide (184) were tested for MAO i n h i b i t i o n a c t i v i t y . I t has been reported (15) that the aromatic r i n g i n 2_ can be separated from the cyclopropyl r i n g by a methylene bridge and that the amine function could be dimethylated without s i g n i f i c a n t loss of i n h i b i t o r y a c t i v i t y . Thus 8 should give a v a l i d assessment of the - 224 -Figure 4. Thietanes Tested for MAO I n h i b i t i o n . H H 2 165 involvement of the electron density of the cyclopropyl r i n g of 2_ i n drug-receptor i n t e r a c t i o n s . In a study of several other thietane 1,1-dioxides (144) was shown to have 1/5 0 -2 the a c t i v i t y (91% i n h i b i t i o n at 2 x 10 molar concentration) of i p r o n i a z i d on rat l i v e r homogenates. Since 165 has the primary amine function instead of the dimethylamino and thus more l i k e 2_, i t was of i n t e r e s t to see what e f f e c t t h i s change on MAO a c t i v i t y would be.Thietane 1,1-dioxides have d i f f e r e n t s t e r i c and e l e c t r o n i c properties from the thietanes - 225 -144 and thus a comparative study between the thietane 1,1-dioxide, 184 and the thietane, j8 should provide some in s i g h t as to these e f f e c t s on MAO i n h i b i t o r y properties. The r a d i o i s o t o p i c assay used for the i n v i t r o MAO i n h i b i t i o n determinations was adapted from the methods reported by Wurtman and Axelrod ( 1 6 4 ) , Otuska and Kobayashi (165) and recently reviewed by Kapeller-Alder ( 2 ) . The method involves preincubation of a rat l i v e r homogenate (enzyme source) with the MAO i n h i b i t o r i n a phosphate buffer o 14 at 37 for 3 0 minutes. The substrate C-tyramine, i s added and the homogenate i s incubated at 3 7° for 1 hour. 14 14 The C-tyramine i s metabolized to C-4-hydroxyphenylacet-aldehyde which i s extracted and the r a d i o a c t i v i t y of the extract i s determined. A decrease i n the r a d i o a c t i v i t y extracted as compared to the control with no i n h i b i t o r ( 0 % i n h i b i t i o n ) represents the degree of i n h i b i t i o n of the enzyme. Tranylcypromine (2_) was used as the standard MAO i n h i b i t o r . A l l the reagents used were of a n a l y t i c a l grade. The C-tyramine (HCl salt) was obtained from Amersham-Searle, and a stock solution containing 80 nmol/ml, 0.3 3 uC/ml i n 0.1 molar phosphate buffer (Na-K phosphate buffer, pH 7.4,. -3 containing 10 molar EDTA) was prepared. Tranylcypromine sulfate was obtained from Smith Kline and French and the test solutions were made with d i s t i l l e d water. The r a t l i v e r homogenate was made by s a c r i f i c i n g a rat (Wister strain) and removing the l i v e r . The l i v e r was homogenized i n cold 0.1 molar phosphate buffer with a motor driven homogenizer such that a 2 mg/ml homogenate was obtained. The homogenate was kept i n an i c e bath and was used as quickly as possible. The HCl s a l t s of the t e s t compounds were prepared by bubbling HCl gas through an anhydrous ether solution and r e c r y s t a l l i z i n g the p r e c i p i t a t e from ethanol-ether. The s a l t s were dried and stored i n a dessicator u n t i l required. The t e s t solutions were prepared with d i s t i l l e d water j u s t p r i o r to use. The r a d i o a c t i v i t y of the samples were determined with a Nuclear Chicago Spectrophotometer, Model ISOCAP-300. The s c i n t i l l a t i o n solution used contained 0.4% 2,5-diphenyloxazole (PPO) and 0.05% 1,4-di-(2,5-phenyloxazole)benzene (POPOP) i n toluene base. A l l the samples were counted for 10 minutes and for 3 cycles. A l l data were corrected for quenching and for background. The general procedure involved incubation of 0.5 ml of the enzyme preparation, 1.3 ml of 0.1 molar phosphate buffer and 0.1 ml of i n h i b i t o r solution i n a 15 ml test tube at 37° - 227 -for 30 min. A 0.1 ml portion of C-tyramine solution ( f i n a l concentration 8 nmol/ml, 33 uC/ml) was added and the preparation was incubated for 1 hour at 37°. The a c t i v i t y of the enzyme was terminated with 0.4 ml of 2 molar c i t r i c acid solution. A f t e r 6 ml of ethyl acetate were added, the mixture was vigorously shaken and allowed to separate for 2 hours. A 4 ml portion of the ethyl acetate layer was added to 10 ml of the s c i n t i l l a t i o n s olution and the radio-a c t i v i t y determined. A control assay containing 0.5 ml of the enzyme preparation, 1.4 ml of 0.1 molar phosphate buffer and 0.1 ml of substrate was performed simultaneously. A blank assay containing 0.5 ml of boiled enzyme preparation ( i n a c t i v e ) , 0.1 ml of the most concentrated i n h i b i t o r solution, 0.1 ml of substrate and 1.3 ml of 0.1 molar phosphate buffer was performed. The blank assay corrected 14 for unmetabolized C-tyramine extracted by the ethyl acetate and for the background a c t i v i t y . The r e s u l t s obtained are shown i n Figure 5. The concentrations of the i n h i b i t o r reported are those of the drug i n the f i n a l incubation mixture. The 1^^ and the r e l a t i v e a c t i v i t i e s as compared to tranylcypromine (2_) are l i s t e d i n Table 2. The i n v i t r o r e s u l t s appear to support the hypothesis of Belleau and Moran (22), that the e l e c t r o n i c and s t e r i c properties of the cyclopropyl r i n g of tranylcypromine (2_) plays a dominant r o l e i n the attachment of 2_ to MAO. Since 2-benzyl-3-dimethylaminothietane (8) was found to be 3 5 times - 228 -Table 2. Results of In V i t r o Studies on MAO I n h i b i t i o n . Compound I 5 0 (mol/1) Relative A c t i v i t y 2 7.0 x 10~ 8 1.0 8 2.0 x 10~ 6 3.5 x 10~ 2 165 2.0 x 10~ 3 3.5 x 10~ 5 184 5.5 x 10~ 3 1.3 x 10~ 5 3 1.0 x 10~ 3 (15) more potent than the reported 1^^ of 2-phenylcyclobutylamine (3_) and 1/29 times the a c t i v i t y of 2_, i t can be assumed that the thietane r i n g has retained some of the e l e c t r o n i c properties absent i n the cyclobutyl r i n g that i s required for MAO i n h i b i t o r y a c t i v i t y . The sulfone analogue, 184 showed only a weak i n h i b i t i o n of MAO. Presumably the larger bulk of the system and i t s more polar nature has abolished any advantage the thietane r i n g had i n providing i n h i b i t i o n of MAO properties of the molecule. Comparison of 144 and 165 a c t i v i t i e s can be used to demonstrate the e f f e c t of dimethylating the primary amine. The reported value for -4 < 144 (110) at 5 x 10 i s 5% i n h i b i t i o n of the enzyme a c t i v i t y whereas the value for 165 i s 22% i n h i b i t i o n of the enzyme a c t i v i t y at the same concentration as calculated from the graph i n Figure 5. The difference i n a c t i v i t y i s small compared to the e f f e c t on MAO a c t i v i t y by increasing the - 229 -Figure 5. I n h i b i t i o n of MAO i n Rat Li v e r Homogenates by Tranylcypromine and Thietane Derivatives Key: x—X Tranylcypromine (2.) 0—o 2-Benzyl-3-dimethylaminothietane {8) a - 0 3-Amino-2-phenylthietane 1,1-dioxide (165) & 2-Benzyl-3-dimethylaminothietane 1,1-dioxide (184) - 230 -size of the ri n g i n 2_. The e f f e c t of the methylene bridge on a c t i v i t y can be seen by comparing the percent i n h i b i t i o n -4 values for 184 and 144 at 5 x 10 molar. There seems to be a three-fold decrease i n i n h i b i t o r y a c t i v i t y due to the in s e r t i o n of a methylene group between the phenyl group and the r i n g . Again t h i s appears to be a r e l a t i v e l y small change i n i n h i b i t o r y a c t i v i t y . I t should be noted that although the a c t i v i t i e s of 184 and 165 are low, the st r u c t u r a l changes correspond to known SAR and thus a r e l a t i v e comparison of the compounds seems to be j u s t i f i e d . Although 5_ was not synthesized, by app l i c a t i o n of these SAR considera-tions to S_T i t i s possible to predict the i n h i b i t o r y a c t i v i t y of 5_ that would be expected. The potency of 5_. would be at leas t 1/2 the potency of 2_. These preliminary r e s u l t s seem to support the hypothesis of Belleau and Moran. The good i n v i t r o i n h i b i t i o n of MAO by 8_ prompted a dopamine potentiation t e s t (166) to see i f 8^  had any i n vivo a c t i v i t y . The mice (White Swiss s t r a i n , 25-30 g) were pretreated with aqueous solutions of 2_ and 8_ by i n t e r -peritoneal i n j e c t i o n s . L-Dopa (100 mg/kg) was then in j e c t e d interperitoneally and the spontaneous a c t i v i t i e s of the mice were recorded i n an a c t i v i t y chamber. Readings were taken for 10 minutes every 30 minutes for 2 hours. At leas t 3 mice per dose were tested. A 2-hour pre treatment with 2_ (30 mg/kg) produced a four - f o l d increase i n the spontaneous a c t i v i t y of the mice a f t e r 30 minutes of the i n j e c t i o n of L-dopa. P i l o e r e c t i o n and defensive behaviour were also noticed. A 2-hour pre-treatment with £ (50-200 mg/kg) or a 24-hour pretreatment with 8^  (300 mg/kg) did not produce any increase i n spontaneous a c t i v i t y a f t e r L-dopa. I t was observed that a 50 mg/kg dose of 8^  produced no noticeable a f f e c t s . At doses of 100 and 200 mg/kg there was a progression towards a depression of spontaneous a c t i v i t y , loss of defensive behaviour and the production of catalepsy. These e f f e c t s have been associated with MAO i n h i b i t i o n (15). There was also some i n d i c a t i o n of a Straub t a i l . At doses of 300 mg/kg of 8^  there developed an extreme depression of spontaneous a c t i v i t y (2.5 minutes a f t e r injection) followed by a severe convulsive state (5 minutes a f t e r injection) which lasted for 10-15 minutes. The mice appeared to recover completely from the convulsions and to return to the depressed state. After 2 days they seemed to be normal. I t i s possible that the doses of £ required f o r the i n h i b i t i o n of MAO i n vivo were within the range of high doses which produced convulsions, or that the depression of the spontaneous a c t i v i t y by 8^  was such that i t masked any e f f e c t of the L-dopa potentiation. The sulfone analogue, 184, did not show any e f f e c t u n t i l a dose of 200 mg/kg and at 300 mg/kg there was a d e f i n i t e depression i n the spontaneous a c t i v i t y , defensive behaviour was l o s t and catalepsy developed. There were some movements which suggested convul-- 232 -sions might occur but these did not f u l l y develop. 2. Analgetic Studies As a sequel to the investigations by Coates (39), trans-3-dimethylaminomethyl-2-phenylthietane 1,1-dioxide (214) , t-3-dimethylaminomethyl-c-4-methyl-r-2-phenylthietane 1,1-dioxide (215), trans-2-benzyl-3-dimethylaminothietane (J3) , trans-2-benzyl-3-dimethy lamino thietane 1,1-dioxide (184) , and r-2,c-3,t-4- and r-2,t-3,c-4- 3-dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-dioxide (251) and (250) (Figure 6) were tested for t h e i r analgetic a c t i v i t y . The compounds were tested by the method of Paton (167), and l a t e r refined by Cox and Weinstock (168) . In t h i s method the contractions of an e l e c t r i c a l l y stimulated guinea pig ileum i s depressed by narcotic analgetics, and i s correlated to the i n h i b i t i o n of the release of acetylcholine upon e l e c t r i c a l stimulation. Methadone hydrochloride (Pitman Moore, 10 mg/ml i n j e c t i o n USP, with 1.5% benzyl alcohol) was used as the standard narcotic analgetic. A l l the test compounds were employed as t h e i r hydrochloride s a l t s and the t e s t solutions were made just p r i o r to use. The general procedure involved s a c r i f i c i n g a guinea pig (Hartly strain) , immediately removing the entir e i n t e s t i n e and pla c i n g i t i n Krebs solution (169) at 3 7 ° . A length of ileum (3-4 cm) i n which the food residues were - 233 -Figure 6. Thietanes Tested f o r N a r c o t i c A n a l g e t i c A c t i v i t y . H H 251 - 234 -minimal, was removed and set up i n a 15 ml organ bath containing Krebs solution at 37° and oxygenated with 95% oxygen and 5% carbon dioxide. The arrangement of the ileum and the electrodes was s i m i l a r to that described by Cox and Weinstock (168). Gut movements were recorded by attaching the polyethylene tubing covering the ileum electrode to a microdisplacement myograph transducer (E & M Instrument Co.) which was connected to a type PMA-4A Physiograph (E & M Instrument Co.). After applying a 2 g tension the tissue was allowed to e q u i l i b r a t e for 1 hour af t e r which i t was stimulated by single e l e c t r i c a l shocks with a pulse width of 0.5 milliseconds, delivered every 10 seconds from a Grass S8 stimulator. The voltage was adjusted i n i t i a l l y to give a maximum response (30-35 V). The drugs were added i n a volume of 0.1 ml, with a contact time of 3 minutes. The ileum was allowed to return to i t s control height before the next drug was added (usually 30-35 minutes). Methadone hydrochloride at a concentration of 50 pmol/ml produced a 50% depression of the e l e c t r i c a l l y stimulated contractions of the guinea pig ileum. Compounds 184, 214, 215, 250, and 251 at concentrations up to 67 nmol/ml (approximately 1300 times greater than that of methadone) had no observable e f f e c t on the contractions of the ileum. The i n a c t i v i t y of 184, 214 and 215 may have been the r e s u l t of having the wrong configuration of the phenyl and the basic group. That i s a c i s configuration may be required - 235 -so that the binding groups are i n a proper o r i e n t a t i o n to the receptor. Also a close approximation of the t e r t i a r y amine to the sulfone, which has been indicated as being necessary for narcotic analgetic a c t i v i t y may not be possible i n these compounds. This would require a conformation i n which a l l the substituents on the thietane r i n g are i n a pseudo-a x i a l p o s i t i o n and thus d i f f i c u l t to achieve. Although t h i s type of i n t e r a c t i o n i s possible i n 250 and 251 by vi r t u e of a 4-dimethylaminomethyl, the e f f e c t of having two basic groups i n the molecule may be deleterious to the analgetic receptor by s t e r i c as well as e l e c t r o n i c e f f e c t s . The d i s t r i b u t i o n of the compounds would grossly be alte r e d as w e l l . They may be expected to bind n o n s p e c i f i c a l l y to other protein l i k e material. As opposed to the i n a c t i v i t y of the thietane 1,1-dioxides, the thietane d e r i v a t i v e £ was found to depress the contractions of the e l e c t r i c a l l y stimulated guinea pig ileum by 50% at concentrations of 50 nmol/ml. To determine whether or not t h i s was a r e a l narcotic analgetic e f f e c t the ileum was pretreated with nalorphine, using doses at which nalorphine does not cause depression of the contractions. Cox and Weinstock have shown that narcotic antagonists s p e c i f i c a l l y reversed the e f f e c t of narcotic analgetics on the ileum (168). Pretreatment of the ileum with a 2 pmol/ml dose of nalorphine ( C E . Frosst & Co., 5 mg/ml i n j e c t i o n , 0.2% NaHSCO i n h i b i t e d the e f f e c t of methadone - 236 -(50 pmol/ml) , but did not a l t e r the e f f e c t of 8_ (50 nmol/ml) . This indicated that 8_ did not have narcotic analgetic a c t i v i t y . Although £ was found to be an e f f e c t i v e MAO i n h i b i t o r i n v i t r o , i t was f e l t that the e f f e c t of 8_ on the guinea pig ileum was probably not due to the i n h i b i t i o n of MAO because of the immediate response of the ileum. Such a rapid b u i l d up of amines due to the i n h i b i t i o n of MAO would not occur. Cox and Weinstock have shown that at a concentration of 10 pmol/ml, L-epinephrine depressed the contractions of the e l e c t r i c a l l y stimulated guinea pig ileum by 5 0% (168). Thus £ may be acting by some adrenergic mechanism. For example, £ could cause the release of epinephrine from the nerve endings or i t could act d i r e c t l y , i n a manner s i m i l a r to epinephrine or by a non-specific depressant action on the i n t e s t i n a l smooth muscle. - 237 -BIBLIOGRAPHY 1. "Monoamine Oxidases - New Vist a s " , i n Advances i n Biochemical Psychopharmacology, Costa, E. and Sandler, M. ed., Raven Press, New York, 1972. 2. "Amine Oxidases and Methods for Their Study", Kapeller-Adler, K., Wiley-Interscience, New York, 1970. 3. Oreland, L., and Ekstedt, B., Biochem. Pharmacol., 21, 2479 (1972) . 4. Hartman, B.K. , B i o l . Psychiatry, 4_, 147 (1972). 5. Youdim, M.B.H., C o l l i n s , G.G.S., Sandler, M. Bevan Jones, A.B., Pare, C.M.B., and Nicholson, W.J., Nature, 236, 225 (1972). 6. C o l l i n s , G.G.S., Youdim, M.B.H., and Sandler, M., Biochem. Pharmacol., 21_, 1995 (1972). 7. F u l l e r , R.W., and Roush, B.W., Arch. Int. Pharmacodyn., 198, 270 (1972). 8. Youdim, M.B.H., and C o l l i n s , G.G.S., Eur. J . Biochem., 18, 73 (1971). 9. Gorkin, V.Z., Akopyan, Z . I. , Veryovkina, I.V., Stesina, L.N., and Abdel, M.M. , Proc. Biochem. S o c , i n Biochem. J., 121, 31p (1971). 10. Kearney, E.B., Salach, J . I . , Walker, W.H., Seng, R., and Singer, T.P., Biochem. Biophys. Res. Commun., 42, 490 (1971). 11. Walker, W.H., Kearney, E.B., Seng., R., and Singer., T.P. Biochem. Biophys. Res. Commun., 4_4, 287 (1971). 12. Kearney, E.B., Salach, J . I . , Walker, W.H., Seng, R., Kenney, W., Zeszotek, E., and Singer, T.P., Eur. J . Biochem., 2_4, 321 (1971). 13. Walker, W.H., Kearney, E.B., Seng, R., and Singer, T.P., Eur. J. Biochem., 24_, 328 (1971) 14. Ghisla, S., and Hemmerich, P., FEBS Letters, 1_6, 229 (1971). 15. Z i r k l e , C.L., and Kaiser, C , i n "Psychopharmacological Agents", Maxwell Gordon, ed., Academic Press., New York, 1964, p. 445. - 238 -16. B i e l , J.H.,-in "Drugs A f f e c t i n g the Central Nervous System", Medicinal Research Series, Burger, A., ed., Marcel Dekker, Inc., New York, 1968, p. 61. 17. Burger, A. Drug Research, 15, 227 (1971). 18. Ho, B.T., J. Pharm. S c i . , 61, 821 (1972). 19. Pletscher, A., Pharmacol. Rev., 1_8, 121 (1966). 20. F i n k e l s t e i n , J . , Chiang, E., Vane, F.M., and Lee, J . , J. Med. Chem., 9_, 319 (1966). 21. Burger, A., Bernabe, N., and C o l l i n s , P.W.,'J. Med. Chem., 13, 33 (1970). 22. Belleau, B. , and Moran, J . , J . Med. Pharm. Chem., 5_, 215 (1962). 23. Huszti, Z., Molec. Pharmacol., 8^, 385 (1972). 24. Wiseman, E.H., and Cameron, D.P., J. Med. Chem., 12, 586 (1969). 25. Hardy, R.A., J r . , and Howell, M.G., i n "Analgetics", de Stevens, G., ed., Academic Press, New York, 1965, p. 222. 26. Janssen, P.A.J., "Synthetic Analgesics" Part 1; Diphenylpropylamines, Pergamon Press, London, 1960. 27. Beckett, A.H. , and Casy, A.F., J. Pharm. Pharmacol., 6_, 986 (1954). 28. Beckett, A.H., and Casey, A.F., Prog. Med. Chem., 4_, 171 (1965). 29. Portoghese, P.S., and Larson, D.L., J . Pharm. S c i . , 53, 302 (1964). 30. Portoghese, P.S., J. Med. Chem., 8_, 609 (1965). 31. Portoghese, P.S., and Williams, D.A., J . Med. Chem., 12, 839 (1969). 32. Casey, A.F., Prog. Med. Chem., 7, 229 (1970). 33. Larson, D.L., and Portoghese, P.S., J. Med. Chem., 16, 195 (1973). 34. Portoghese, P.S., Gomaa Z.S.D., and Larson, D.L., J . Med. Chem., 16, 195 (1973) . - 239 -35. B e l l , K.H., and Portoghese, P.S., J. Med. Chem., 1_6, 203 (1973). 36. K o s t e r l i t z , H.W., C o l l i e r , H.O.J, and V i l l a r r e a l , J.E., "Agonist and Antagonist Actions of Narcotic Analgesic Drugs", University Park Press, Baltimore, 1973. 37. Portoghese, P.S., Ann. Rev. Pharmacol., 10_, 51 (1970). 38. Horning, D.E., and Muchowski, J.M., Can. J. Chem., 49, 485 (1971). 39. Coates, J.E., Di s s e r t a t i o n , University of B.C., Van. B.C., (1972). 40. Snader, M., Chem. Rev., 66/ 341 (1966). 41. Etienne, Y., Soulas, R., and Lumbroso, H., "Heterocyclic Compounds with Three and Four Membered Rings", Weissberger, A., ed., Part 2, 1964, p. 647. 42. Whiteside, J.A. B, and Warsop, P.A., J . Molec. Spectr., 2_9, 1 (1969) . 43. Allenmark, S., Ark. Kimi., 26_, 73 (1967). 44. Andreetti, G.D., Cavalca, L., and Sgarabotto, P., Chim. I t a l . , 101, 440 (1971). 45. Arbuzov, B.A., Nuretdinova, O.N. and Vereshchagin, A.N., Dokl. Akad. Nauk. SSSR, 172, 591 (1967), through Chem. Abstr. 6_6, 89337y (1967) . 46. Arbuzov, B.A., Samitov, Y.Y., Vereshchagin, A.N.,Nuetdinova, O.N., and Kostyliva, T.A., Vop. Stercokhim, 1,14 (1971), through Chem. Abstr. 7_8, 3577q (1973). 47. Dodson, R.M., Jancis, E.H., and Klose, G., J. Org. Chem., 35_, 2520 (1970) . 48. Kumakura, S., Shimozawa, T., Ohnishi, Y., and Ohno A., Tetrahedron, 27, 767 (1971). 49. S i e g l , W.O., and Johnson, C.R., Tetrahedron, 2_7_, 341 (1971) . 50. Citaro, C , Fronza, G. , Mondelli, R. , Bradamante, S. and Pagani, G., Tetrahedron Lett., 189 (1973). 51. Paquette, L.A., and Freeman, J.P., J. Org. Chem., 35, 2249 (1970). 52. Trost, B.M., Schinski, W.L., Chen, F. , and Mantz, I.B., J. Amer. Chem. S o c , 93, 676 (1970). - 240 -53. Raasch, M.S., J. Org. Chem., 3_5, 3471 (1970). 54. Raasch, M.S., U.S. 3,468,908 (du Pont de Nemours, E.I., and Co.), Sept. 23, 1969, through Chem. Abstr., 71, 112794J (1969) . 55. Middleton, W.J., Howard, E.G., and Sharkey, W.H., J . Org. Chem., 30_, 1395 (1965) . 56. Krubsack, A.J., Higa, T., and Slack, W.E., J. Amer. Chem. S o c , 92_, 5258 (1970). 57. Ohno, A., Ohnishi, Y., and Tsuchihashi, G., Tetrahedron Lett., 161 (1969) . 58. Ohno, A., Ohnishi, Y., and Tsuchihashi, G., Tetrahedron Lett., 283 (1969). 59. Ohno, A., Koizumi, T., and Akazaki, Y., Tetrahedron Lett., 4993 (1972) . 60. . Johnson, P.Y., and Berchtold, G.A., J. Org. Chem., 35, 584 (1970). 61. Harpp, D.N., and Gleason, J.G., J . Org. Chem., 35, 3259 (1970). 62. Schauble, J.H., and Williams, J.D., J. Org. Chem., 37, 2514 (1972) . 63. Sander, M., U.S. 3,297,718 (Mobil O i l Corp.), Jan. 10, 1967, through Chem. Abstr., 6_6, 55367t (1967). 64. Ziman, S.D., and Trost, B.M., J. Org. Chem., 38_, 649 (1973) . 65. Morton, M. , and Kammereck, R.F., J. Amer. Chem. S o c , 92, 3217 (1970). 66. Dodson, R.M., and Fan, J.Y., J. Org. Chem., 36, 2708 (1971). 67. Dittmer, D.C., and Kotin, S.M., J. Org. Chem., 3_2, 2009 (1967). 68. Padwa, A., and Gruber, R. , J. Org. Chem., 3_5, 1781 (1970) 69. Dittmer, D.C., and Christy, M.E., J. Org. Chem., 26, 1324 (1961). 70. Opitz, G., Angew. Chem. Inter. Ed., 6, 107 (1967). - 241 -71. Truce, W.E., and L i u , L.K., Mech. of React. Sulfur Compd., 4, 145 (1969). 72. Wallace, T.J., Quart. Rev. (London), 2_0, 67 (1966). 73. Muller, L.L., and Hamer, J . , "1,2-Cycloaddition Reactions", Interscience, New York, 1967, p. 206. 74. U l i c h , H., "Cycloaddition Reactions of Heterocumulenes", Academic Press, New York, 1967, p. 286. 75. Nagai, T., Tanaka, M., and Tokura, N., Tetrahedron Lett., 6293 (1968). 76. Stork, G. , and Borowitz, I.J., J. Amer. Chem. S o c , 84, 313 (1962). 77. Opitz, G., and Adolph, H., Angew. Chem. Inter. Ed., 1, 113 (1962). 78. Truce, W.E., and Campbell, R.W. , J. Amer. Chem. S o c , 88^ , 3599 (1966). 79. Opitz, G., Schempp, H. and Adolph, H., Ann. Chem., 684, 92 (1965). 80. •Hamid, A.M., and Trippett, S., J . Chem. S o c , C, 1612 (1968). # 81. Looker, J . J . , J. Org. Chem., 31, 2973 (1966). 82. Wells, J.N., and Abbott, F.S., J. Med. Chem., 9, 489 (1966). 83. Nagarajan, K., and Mehta, S.R., J. Org. Chem., 35, 4248 (1970). 84. Bradamante, S., Maiorana, S., and Pagani, G., J. Chem. S o c , Perkin I, 282 (1972). 85. Tsugi, 0., Iwanami, S., and Hagio, S., B u l l . Chem. S o c Jap., 45, 237 (1972). 86. Paquette, L.A., and Rosen, M. , J. Amer. Chem. S o c , 89, 4102 (1967). 87. Opitz, G., Angew. Chem. Inter. Ed., 7, 646 (1968). 88. Paquette, L.A. , and Freeman, J.P., J . Amer. Chem. S o c , 91, 7548 (1969). 89. Paquette, L.A., Freeman, J.P., and Maiorana, S., Tetrahedron, 27, 2599 (1971). - 242 -90. Abbott, F.S., Coates, J.E., and Haya, K., to be published. 91. Goralski, C.T., and Evans, T.E., J. Org. Chem., _37, 2080 (1972) . 92. Dodson, R.M., Hammen, P.D., and Klose, G. , J . Org. Chem. , 36_, 2698 (1971) . 93. Dodson, R.M., Hammen, P.D., and Davis, R.A., J. Org. Chem., 36, 2693 (1971). 94. Dodson, R.M., Hammen, P.D. and Fan, J.Y., J. Org. Chem. , 36., 2703 (1971) . 95. King, J.F., de Mayo, P., Mcintosh, C.L., Pier s , M.K., and Smith, D.J.H., Can. J. Chem., 4_8, 3704 (1970). 96. Eckroth, D.R., and Love, G.M., J . Org. Chem., 34, 1136 (1969) . 97. Truce, W.E., Bavry, R.H., and Ba i l y , P.S., J r . , Tetrahedron Lett., 5651 (1968). 98. Hasek, R.H., Gott, P.G., Meen, R.H., and Martin, J.C.,. j . Org. Chem., 2£, 2496 (1963). 99. Truce, W.E., Abraham, D.J., and Son, P., J . Org. Chem., 3_2, 990 (1967) . 100. Dittmer, D.C., and Christy, M.E., J . Amer. Chem. S o c , 84_, 399 (1962) . 101. Paquette, L.A. and Rosen, M. , J . Org. Chem., 33_, 3027 (1967). 102. Dittmer, D.C., Ikura, K., Balquist, J.M., and Takashina, N. , J. Org. Chem., 3_7, 225 (1972). 103. Dittmer, D.C., and Glassman, R., J . Org. Chem., 35, 999 (1970). 104. Paquette, L.A., Houser, R.W., and Rosen, M., J. Org. Chem. , 3_5, 905 (1970) . 105. S i e g l , W.O., and Johnson, C.R., J. Org. Chem., 35, 3657 (1970). 106. Paquette, L.A., J. Org. Chem., 30, 629 (1965).. 107. Dittmer, D.C., and Davis, F.A., J. Amer. Chem. S o c , 87, 2064 (1965). - 243 -108. Dittmer, D.C., Takahaski, K. , and Davis, F.A., Tetrahedron Lett., 4061 (1967). 109. Dittmer, D.C., Chang, P. L-F., Davis, F.A., Iwanani, M., Stamos, I.K., and Takahashi, K., J . Org. Chem., 37, 1111 (1972). 110. A b b o t t , F.S., Dissertation, Purdue University, Lafayette, Indiana, 1966. 111. Bible, R.H., J r . , "Interpretation of NMR Spectra", Plenum Press, New York, 1965. 112. Sander, M. , Chem. Rev., 6(5, 297 (1966). 113. Apler, H., and Keung, E.C.H., J . Org. Chem., 37, 1464 (1972) . 114. Dittmer, D.C., Christy, M.E., Takashina, N., Heinion, R.S., and Balquist, J.M., J . Org. Chem., 3_6, 1324 (1971) 115. Paquette, L.A. , J. Org. Chem., 2_9, 2854 (1964). 116. Porter, Q.N. , and Balds, J . , "Mas.s Spectrometry of Heterocyclic Compounds, Wiley, New York, 1971, p. 229. 117. Sadtler - Standard Molecular Spectra, Sadtler Research Laboratories, Inc., Philadelphia, U.S.A. 118. Opitz, G., Rieth, K., and Walz, G., Tetrahedron Lett., 5269 (1966), through Chem. Abstr., 66, 46266g (1967). 119. Paquette, L.A., J. Amer. Chem. S o c , 86_, 4096 (1964). 120. Roberts, J.D., and Caserio, M.C., "Basic P r i n c i p l e s of Organic Chemistry", W.A. Benjamin, Inc., New York, 1965, p. 275. 121. Paquette, L.A., and P h i l l i p s , T.R., J. Org. Chem., 3_0, 3883 (1965). 122. Kirner, W.R., and Windus, W., "Organic Syntheses", C o l l e c t i v e Vol. I I , John Wiley and Sons, Inc., 1943, p. 136. 123. Sandler, S.R., J. Org. Chem., 35_, 3967 (1970). 124. Yoneda, F., Suzuki, K., and N i t t a , Y., J. Amer. Chem. S o c , 88, 2328 (1966). - 244 -125. Yoneda, F. , et a l . J . Org. Chem., 3_2, 727 (1967). 126. Rees, C.W., and Storr, R.C, Chem. Commun., 1305 (1968). 127. Vogel, A.I., "A Textbook of P r a c t i c a l Organic Chemistry", Third E d i t i o n , Longmans, Green and Co. Ltd., London, 1956, (a) p. 886, (b) p. 743, (c) p. 167, (d) p. 182. 128. P f i t z n e r , K.E., and Moffatt, J. G. , J. Amer. Chem. S o c , 87_, 5670 (1965). 129. Al b r i g h t , J.D., and Goldman, L. , J. Amer. Chem. S o c , 89, 2416 (1967). 130. F l e i s c h e r , E.B., Gebala, A.E., Levey, A., and Tasker, P.A., J. Org. Chem., 3_6, 3042 (1971). 131. Rao, C.N.R., "Chemical Applications of Infrared Spectroscopy", Academic Press, New York, 1963. 132. Pinkus, J.L., Pinkus, G., and Cohen, T., J. Org. Chem., 27, 4356 (1962). 133. Paquette, L.A., Freeman, J.P., and Wyvratt, M.J., J. Amer. Chem. S o c , 93_, 3216 (1971). 134. Dittmer, D.C., and Balquist, J.M., J. Org. Chem., 33, 1364 (1968). * 135. Chang, P. L.-F., and Dittmer, D.C, J. Org. Chem., 3_4, 2791 (1969). 136. Hatch, L.F. and Nesbitt, S.S., J. Amer. Chem. S o c , 67, 39 (1945) . 137. Speer, R.J., and Makler, H.R., J . Amer. Chem. S o c , 71, 1133 (1949). 138. Dittmer, D.C, and Davis, F.A., J . Org. Chem., 32_, 3872 (1967) . 139. Brown, H.C, and Vijaya, V., J. Amer. Chem. S o c , 88, 2870 (1966) . 140. Gerkin, R.M., and Rickborn, B. , J. Amer. Chem. S o c , 89, 5850 (1967). 141. Maercker, A. , Organic Reactions, 14_, 270 (1965) . 142. MacKenzie, K., "The Chemistry of Alkenes", S. Patai, Ed., Interscience, New York, 1964, p. 428. - 245 -143. Davidson, R.S., Gunther, W.H.H., Waddington-Feather, S.M., and Lythgoe, B. , J. Chem. S o c , C, 4907 (1964). 144. Bazant, V., Capka, M., Cerny, M., Chvalovsky, V., Kochloefl, K., Kraus, M., and Malek, J . , Tetrahedron Lett. , 3303 (1968) . 145. Roberts, J.D., and Caserio, M.C., "Basic P r i n c i p l e s of Organic Chemistry", W.A. Benjamin, Inc., New York, 1965, p. 394. 146. Collington, E.W., and Meyers, A.I., J. Org. Chem., 36, 3044 (1971). 147. Hands, A.R., and Mercer, A.J.H., J. Chem. S o c , C, 2448 (1968). 148. Breuer, E. , and Sarel, S., Tetrahedron, 2_4, 6339 (1968). 149. Caserio, M.C., Pratt, R.E., and Holland, R.J., J. Amer. Chem. S o c , 88 # 5747 (1966). 150. Paquette, L.A., Rosen, M., and Stuki, H., J . Org. Chem., 33_, 3020 (1968). 151. Moore, M.L., Organic Reactions, 5_, 301 (1949). 152. Beckett, A.H., J . Pharm. Pharmacol., 8, 848 (1956). * 153. Sammes, M.P., Wylie, CM., and Hoggett, J.G., J . Chem. Soc., C, 2151 (1971). 154. Doss, R.C, and Schnetzer, A.M., U.S. 2,800,509, July 23, 1957, through Chem. Abstr., 51, 17979 (1957). 155. Shama, M. Deno, N.C, and Remar, J.F., Tetrahedron Lett., 1375 (1966). 156. Biemann, K., "Mass Spectrometry Organic Chemical Applications", McGraw-Hill, Inc., New York, 1962. 157. Dittmer, D.C, Henion, R.S., and Takashina, N. , J. Org. Chem., 34, 1310 (1969). 158. Bohme, H., "Organic Syntheses", C o l l e c t i v e Vol. I l l , John Wiley, and Sons, Inc., New York, 1955, p. 619. 159. Fieser, L.F., and Fieser, M., "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1967, (a) p. 537, (b) p. 1238, (c) p. 1106. - 246 -160. Stephen, J.F., and Marcus, E., J. Org. Chem., 34, 2535 (1969). 161. Von 0. I s l e r , H.G., Montavon, M., Ruegg, R., Ryser, G., and Z e l l e r , P., Helv. Chem. Acta, 40_, 1242 (1957). 162. Brown, H.C., and Subba Rao, B.C., J. Amer. Chem. S o c , 82_, 681 (1960) . 163. Brown, H.C., and Tierney, P.A., J. Amer. Chem. S o c , 8£, 1552 (1958). 164. Wurtman, R.J., and Axelrod, J . , Biochem. Pharmacol., 12, 1439 (1963). 165. Otsuka, S., and Kobayashi, Y., Biochem. Pharmacol., 13, 995 (1964). 166. M i l l s , J . , Kattau, R., Sl a t e r , I.H., and F u l l e r , R.W., J. Med. Chem., 11, 95 (1968). 167. Paton, W.D.M., J. Phsyiol. (London), 127, 40P (1955). 168. Cox, B.M., and Weinstock, M., B r i t . J. Pharmacol. Chemother., 27_, 81 (1966). 169. Lawrence, D.R., and Bacharach, A.L. , ."Evaluation of Drug A c t i v i t i e s : Pharmacometrics", Vol. 2, Academic Press) London, 1964, p. 892. 

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