2632 J . Org. Chem., Vol. 44, No. 15, 1979
Lambeth and Swank
247-248 "C); NMR (CDCl,) 2.38 (s, ring CH,), 2.98 (9) ppm. Tetramethyl-l,4-benzenedithiol. The above S,S'-diester (11 g, 0.032 mol) was refluxed with 60 mL of pyridine, 11mL, of water, 60 mL of methanol, and 20 g (0.3 mol) of potassium hydroxide for 6.5 h under nitrogen with stirring. The volume was then reduced under nitrogen, the solution was diluted with water, and hydrochloric acid was added until precipitation of the dithiol was complete. The dithiol was filtered off, air-dried, and recrystallized from dichloromethane to give 5.8 g (91%) in two crops: mp 195-198.5 "C; NMR (CDClJ 2.37 (9, CHJ, 3.12 (s, SH) ppm; NMR (C6D6) 2.17 (S, CHJ 2.84 (5, SH) ppm. Anal. Calcd for C1$lI4S2: C, 60.56; H, 7.11; S,32.33. Found C, 60.88; H, 7.25; S, 32.50. 2,5-Dimethoxy-1,4-benzenedithiol.2,5-Dimethoxy-1,4benzenedisulfonyl chloride15 (40 g, 0.12 mol), 650 mL of ethanol, 200 g (2.9 mol) of 95% zinc dust, and 240 mL (2.86 mol) of hydrochloric acid were stirred and refluxed for 30 min. The mixture was poured into 2 L of water, and the product and excess zinc were filtered off. The air-dried mixture was extracted with cyclohexane, and the dithiol was crystallized from the cyclohexane t,o give 16.5 g (68%), m p 124-126 "C (lit.16 mp 122 "C, prepared by another route). 1,4-Benzenedithiol. This dithiol was prepared by the hydrolysis of p-phenylene S,S'-bis(dimethy1thiocarbamate)llb as (15) Manecke, G.; Beyer, H. J. Makromol. Chem. 1968, 116, 26. (16) Ariyan, 2. S.; Martin, R. L. J . Chem. Soc., Perkin Trans. 1 1972, 1687.
described for the tetrafluoro derivative.
Acknowledgments. I am indebted to W. A. Sheppard and L. R. Melby for helpful discussions, t o G. S. R e d d y for calculation of the conformation energy barrier for 4, to L. J. Guggenberger for the X-ray examination of 4, to N. E. Schlichter and E. W. M a t t h e w s for IR, UV, and Raman spectra interpretations, and t o P. J. Krusic for the ESR experiment. Registry No. 4, 70470-78-9; 4 N,N-dimethyldihydrophenazine complex (l:l), 70470-79-0; 4 1,3-diphenylisobenzofurancomplex (1:4), 70470-80-3;tetrafluorc-p-phenylene 0,O-bis(dimethylthiocarbamate), 70470-81-4;tetrafluorohydrcquinone, 771-63-1;dimethylthiocarbamoyl chloride, 16420-13-6; tetrafluoro-p-phenylene S,S-bis(dimethy13467-7&5; thiocarbamate), 70470-82-5;tetrafluoro-l,4-benzenedithiol, N,N'-dimethyldihydrophenazine,15546-75-5; 1,3-diphenylisobenzofuran, 5471-63-6; tetrachloro-p-phenylene 0,O-bis(dimethy1thiocarbamate), 70470-83-6;tetrachlorohydroquinone, 87-87-6;tetrachloro-p-phenylene S,S'-bis(dimethylthiocarbamate),70470-84-7; tetrachloro-l,4-benzenedithiol,67341-48-4;tetramethyl-p-phenylene 0,O-bis(dimethylthiocarbamate), 13522-73-1; tetramethylhydroquinone, 527-18-4;tetramethyl-p-phenylene S,S'-bis(dimethy1thio70470-85-8; carbamate), 13512-07-7;tetramethyl-l,4-benzenedithiol, 2,5-dimethoxy-1,4-benzenedithiol, 30079-16-4; 2,5-dimethoxy-1,4benzenedisulfonyl chloride, 19116-92-8;l,Cbenzenedithiol, 624-39-5; p-phenylene-S,S'-bis(dimethylthiocarbamate), 13512-06-6;2,3,5,6tetrachloro-1,4-benzenedithiolhomopolymer, 70470-87-0; poly[dithio(2,3,5,6-tetrachloro-1,4-phenylene)], 70470-88-1.
Oxidative Cyclization of 3-(Amino)thioethers t o Form S-Substituted Isothiazolidinium Salts' David
0. L a m b e t h * and Darrell W. S w a n k
Department of Biochemistry, School of Medicine, The University of North Dakota, Grand Forks, North Dakota 58202 Received M a y 23, 1978
The reaction in which methionine is cyclized to form dehydromethionine (S-methylisothiazolidinium-3carboxylate) by iodinic oxidation at neutral pH3 has now been shown to be a general one for compounds possessing an amine group y to a thioether function. Thus, the reaction provides a convenient route to the preparation of N-protonated, cyclic sulfilimines. The S-substituted isothiazolidinium salts from ethionine, S-phenylhomocysteine, S-benzylhomocysteine, and 3-(methy1thio)propylaminewere prepared and characterized by elemental analyses and NMR spectra. Cyclization of L-methionine was shown to produce a mixture of diastereomers which are chiral a t positions 1 (sulfur) and 3. Evidence was obtained that hydrolysis of each diastereomer to form the sulfoxide proceeds with inversion of configuration. Oxidative cyclization of 3-(amino)thioethers was found to also be induced by a variety of N-halo derivatives and by lead tetraacetate. S u b s t a n c e s containing an isothiazolidine ring unsubto form methionine.: Evidence has also been presented s t i t u t e d at sulfur a r e unknown, presumably because of that a sulfurane intermediate is on the p a t h w a y to det h e i r instability. The only previous example of an Shydromethionine when methionine is oxidized b y iodine.8 s u b s t i t u t e d isothiazolidine is d e h y d r o m e t h i o n i n e (SIn this paper, we report our findings regarding the scope methylisothiazolidinium-3-carboxylate)which was isolated of t h e reaction resulting i n formation of S-substituted isothiazolidinium salts. W e find that iodine and several b y Lavine as a stable intermediate on the pathway to sulfoxide when methionine was oxidized b y iodine in N-halo derivatives will induce ring closure of substances proposed s t r u c t u r e for n e u t r a l s o l u t i ~ n . ~ - Lavine's ~ containing a 3-(amino)thioether moiety. M a n y of the dehydromethionine was confirmed b y X-ray d i f f r a ~ t i o n . ~ substances cyclized b y u s are a m i n o acid derivatives and Additional studies of dehydromethionine have been the carboxyl group neither prevents nor interferes with the concerned with reversibility of the formation reaction and cyclization reaction. Ring closure introduces a chiral center hydrolysis to the sulfoxide6 and with reduction b y thiols at sulfur and the mixture of diastereomers resulting from L- and/or D-amino acids is separated b y chromatography. The S-substituted isothiazolidinium salts m a y be viewed (1)This work was supported by USPHS Grants GM 21539 and 25252. as the conjugate acids of cyclic sulfilimines. The sulflimine The work was initiated while D.O.L. was a member of the faculty of the Department of Chemistry, University of South Florida, Tampa, Fla. class has been the subject of a recent reviewg and i n (2) T. F. Lavine, J . B i d . Chem., 151, 281 (1943). (3) T. F. Lavine, Fed. Proc., Fed. Am. Soc. E x p . Biol., 4, 96 (1945). (4) T. F. Lavine, U S . Patent No. 2465461 (March 29, 1949). (7) D. 0. Lambeth, J . Am. Chem. Soc., 100, 4808 (1978). (5) R. S. Glass and J. R. Duchek, J . Am. Chem. Soc., 98, 965 (1976). (8) P. R. Young and L.-S. Hsieh, J. Am. Chem. Soc., 100,7121 (1978). (6) K.-H. Gensch and T. Higuchi, J . Pharm. Sci., 56, 177 (1967). (9) T. L. Gilchrist and C. J. Moody, Chem. Reu., 77, 409 (1977). 0022-326317911944-2632$01.00/0
0 1979 American Chemical Society
Synthesis of S-Substituted Isothiazolidinium Salts Scheme I
J . Org. Chem., Vol. 44, No. 15, 1979 2633
stances are stable for at least several weeks when stored desiccated at 0 "C. Characterization of Compounds 1-5. In analogy with sulfonium salts, the products of the cyclization reaction were expected to be chiral a t sulfur. Since the parent compounds for 1-4 are amino acids with a chiral center R R1 at carbon 2, cyclization of each should result in a mixture of diastereomers. The product mixtures containing 1-4 compd R, RZ each gave two well-resolved spots on thin-layer chromal CH, cootograms which showed the properties of isothiazolidinium 2 CZH, coosalts. The faster moving spots always contained 2-3 times 3 C,H, coo4 C,H,CH, COOmore material than the slower spot. 5 CH, H The diastereomers of 1 were prepared from L-methionine, and elemental analyses of each indicated their comparison with previously reported sulfilimines, the empirical formulas were identical. The chemical shifts and S-substituted isothiazolidinium salts reported here are integrated intensities of the proton NMR spectra of the unique. They are N-protonated sulfilimines which are diastereomers were consistent with an S-alkylisothiazofairly stable in aqueous solution at neutral pH, even when lidine structure. The proton resonance of the S-methyl both carbon substituents of sulfur are alkyl groups. In substitutent of 1 appeared as a singlet which was shifted contrast, most of the previously reported sulfilimines have downfield relative to methionine by 0.7 ppm which is the strong electron-withdrawing groups adjacent to the sulapproximate shift observed for methionine sulfoxide and filimine linkageag The increased stability of the S-subS-methylmethionine sulfonium chloride. The remaining stituted isothiazolidinium salts may be due to their cyclic proton resonances of the diastereomers of 1 gave a complex structure since enhanced stability of labile functional and not easily interpreted spectrum which is to be expected groups has often been observed for ring systems. for a ring system in which none of the ring hydrogens are equivalent. Results and Discussion The diastereomeric relationship of the chromatoSynthesis of S-Substituted Isothiazolidinium Salts. graphically separable components of 1 was further indiScheme I shows the general procedure for the synthesis cated by comparing the I3C NMR spectrum of the faster of S-substituted isothiazolidinium salts and the structures migrating component with that of an approximately of five members of this group isolated in sufficient quantity equimolar mixture of the diastereomers. The resonance to permit characterization by elemental analyses and NMR of each carbon of the mixture was clearly resolved, and the spectroscopy. The numbering system for the ring is also signals of the corresponding carbons were closely paired shown. as expected for diastereomers. The cyclization reactions take place in high yield. Data from the proton NMR spectra for 2-5 and the 13C Purification of product mixtures was facilitated by using NMR spectra of 2 and 5 are listed in the Experimental exactly stoichiometric amounts of reactants and by taking Section. In each case, these data together with elemental care to minimize side reactions. The latter was accomanalyses are consistent with the S-substituted isothiazoplished by slowly adding iodine and sodium hydroxide to lidinium structure. the thioether, by efficiently stirring the reaction mixture, On the basis of the following arguments, the absolute and by working rapidly through the purification procedure. configurations of the diastereomers of 1 are tentatively Our procedure for preparing 1 and 2 differs from preassigned. In more than 10 crystallization attempts using vious procedures for 1 in that we used ion-retardation resin the vapor-diffusion technique of Glass and D ~ c h e konly ,~ to remove NaI from the zwitterionic products. Our method the faster migrating diastereomer (Rf 0.39) crystallized. is also more suitable for large quantities since it avoids the Since Glass and Duchek used DL-methionine as the starting use of expensive silver oxide3 and the inconvenience of material for the synthesis of 1,we believe the crystal they working with sodium methoxide in strictly nonaqueous chose for X-ray diffraction contained one or both of the solvent^.^ enantiomers which would show an Rf of 0.39 in our The reactions of S-phenyl- and S-benzylhomocysteine thin-layer chromatography system. The structure depicted with iodine to form 3 and 4 were comparatively sluggish in their paper5 shows the crystal originated from Dand were forced to completion by precipitating the iodide methionine and has the 3(R),S(S)configuration. However, as the silver salt. Purification of 2-4 and separation of the their packing diagram for the crystal shows both the 3diastereomeric mixtures were accomplished by column (S),S(R) and 3(R),S(S) enantiomers. Regardless, since our chromatography on silica columns, using methanol as the synthesis started with L-methionine, we assign our cryseluent. tallizable isomer the 3(S),S(R) configuration. The other Crystallization of dehydromethionine, 1, had previously diastereomer derived from L-methionine (R 0.27) is asbeen induced by permitting ether to diffuse through the signed the 3(S),S(S) configuration. This diastereomer vapor phase into a methanol solution of the ~ u b s t a n c e . ~ precipitated from methanol as a seemingly amorphous Using this technique, we found that only one of the two solid regardless of the rate at which ether was added. diastereomers derived from L-methionine (see below) Hydrolysis of each diastereomer of 1 in 1 N HC1 was formed crystals, and attempts to use the vapor-diffusion found by TLC to give methionine sulfoxide. The sulfoxide technique for crystallization of 2-4 were unsuccessful. resulting from the isomer of 1 assigned the 3(S),S(R) Substance 5 was easily purified as the nitrate salt by configuration showed an optical rotation, [ ( u ] ~of~ +126.5'. ~, crystallization from ethanol. This rotation is in good agreement wit,h the values of +127 Once purified, products 1-5 are white compounds which and +131" reported for L-methionine d-sulfoxide,'O,"which are very soluble in methanol and water to give colorless has been shown to have the B(S),S(S)Configuration." The solutions. They hydrolyze slowly to give sulfoxides in neutral aqueous solution, but hydrolysis occurs within (10) T. F. Lavine, J . B i d . Chem., 169, 477 (1947). (11) B. W. Christensen and A. Kjaer, Chem. Commun., 225 (1965). minutes in either 0.1 M HC1 or 0.1 M NaOH. The subs,
Lambeth and Swank
2634 J. Org. ChPm., Vol. 44, No. 15, 1979 Table I. Reactions of 34 Amino)thioethers and Related Compounds with Iodine" __ reacn time,b % reversicompd min bilityC ___.____
