1208 J.C.S. Perkin I Dithiols. Part 292 Syntheses of cis-and trans-2-Phenyliminoperhydro-I ,3-benzodithiole By Richard C. Forster and Leonard N. Owen,' Department of Chemistry, Imperial College, London SW7 2AY Reaction of trans-2-(phenylthiocarbamoylthio)cyclohexyl acetate and of rrans-2-(acetylthio) (phenylimino) -methy It h i03 c y c I oh ex y I acetate with pot assiu m h yd rox id e in e tha noI g ives trans-2-p h enyI iminoper h ydro-1,3-be n zo-dithiole. Overall retention of configuration is explained by the formation of an intermediate thiiranium ion. The same product, and the cis-isomer, are obtained when rrans-perhydro-l.3-benzodithiole-2-thione and its cis-isomer, respectively, are successively treated with methyl iodide, aniline, and aqueous sodium hydroxide.(7) by analogyIN a previous PartJ2 the selective reaction of phenyl phenyliminoperhydro-lJ3-benzodithiole isothiocyanate with the thiol function in trans-2-with the conversion of the mono(pheny1thiourethane) (1) mercaptocyclohexanol was described. Treatment of the of trans-cyclopentane-1 ,Z-diol into cis-Z-phenylimino-product trans-2-(phenylthiocarbamoylthio)cyclohexanol perhydrocyclopenta-lJ3-oxathiole(2)J3 but instead only (3),with thionyl chloride was expected to give cis-2- the monothio-compound (6) was obtained; this was also 1 Part 28, R. C. Forster and L. 3. Owen, J.C.S. Perkin I, 1978, the product when an attempt was made to prepare the 822. 2 M. E. Ali, N. G. Kardouche, and L. N. Owen, J.C.S. Perkin I, L. Goodman, A.Benitez, C. D. Anderson, and B. R. Baker, 1975, 748. J. Amer. Chem. SOC.,1958, 80, 6582. O-toluene-9-sulphonate of the dithiourethane (3). The projected stereospecific synthesis of a cis-dithiol was thus thwarted. A modified approach to this objective has now been made by use of the acetate (4), since an acetoxy function S*CS. NHPh under acidic conditions, to the corresponding dithiol- uO*CS.NHPh ao,o.,,carbonate. Surprisingly, this was identical to the C=NPh known trans-perliydro-l,3-benzodithiol-2-one(11), indi-Srsquo;lsquo;OH cating that the cyclisation had proceeded with retention 1209 eneaniline (9) and quite different from that of methyl N-methyl-N-phenyldithiocarbamate (10).6 Further-more, the i.r. spectrum contained a strong band at 1580 cm-l (cf.1 570 cm-l reported for 2-phenylimino-1,3- dithiolan). The product was therefore hydrolysed, (1 1 (2) (3) R=H (4)R=Ac MeS bsol; .,c=s MeS lsquo; MeNPh fbsol;S-C-NHPh (11) x=o (12) x=s (13) X=NPh (15) R=H (16) R = AC is known to be susceptible to intramolecular attack by thiolate anion.4 It seemed possible that the desired cyclised product (7) could be formed by treatment of the acetate with base under mild conditions, though it was recognised that attack by the nitrogen atom, rather than the thione sulphur, might OCCU~,~~~ to give the isomeric thiazolidinethione (8). In the event, reaction of the acetate (4) or the diacetyl compound (5) with ethanolic potassium hydroxide yielded a crystalline product which had the required molecular formula C,,H,,NS2, and it was encouraging to find that the U.V.spectrum was similar to that illustrated for N-bismethylthiomethyl- L. W. C. Miles and L. N. Owen, J. Chem. SOC.,1952, 817; J. S. Harding and L. N. Owen, ibid., 1954, 1528, 1536; M. Kyaw andL. N. Owen, ibid., 1964, 6252. 6 Cf. B. R. Baker, K. Hewson, L. Goodman, and A. Benitez, J. Amer. Chem. SOC.,1958, 80, 6577; F. L. Scott, R. E. Glick, and S. Winstein, Experientia, 1957, 18,183. of configuration to give the trans-product (13),a disap- pointing stereochemical result. This can be explained by displacement of the acetoxy group in the acetate (4) by the vicinal sulphide group, rather than by the thione function, to give the episulphonium intermediate (14), from which the trans-compound (13) would be derived by the depicted rearrangement.The yellow colour of the diacetyl compound (5)was immediately discharged on treatment with the basic reagent, indicating very rapid loss of the S-acetyl func- tion to give the monoacetate (4), thus accounting for the similar yields of cyclised product obtained from both starting materials. Cyclisation of the acetate (4) was further investigated under a variety of conditions, but when it occurred, for example by heating in dimethyl sulphoxide, the product was still the trans-compound (13). It was now of obvious interest to study the reactions of the amp;-analogues of the acetates (4) and (5). Base-catalysed reaction of cis-2-mercaptocyclohexanol with phenyl isothiocyanate (I mol) gave the dithiourethane (15) which with an excess of acetic anhydride gave the diacetyl derivative (17) ; the use of less anhydride gave the monoacetate (16) which was also obtained by selec- tive deacetylation of the diacetyl compound.No cyclic dithiolan derivative could be obtained by treatment of either the mono- or the di-acetyl compound with ethanol- ic potassium hydroxide; the main products isolated in each case were the parent alcohol (15) and O-ethyl N-phenylthiocarbamate, formed by simple solvolysis. This result supports the mechanism proposed for the formation of the cyclised product from the trans-acetate (4), since the cis-isomer cannot undergo a neighbouring group reaction to give an intermediate thiiranium ion.To provide further evidence for the constitution and stereochemistry of the phenylimino compound (13), both this and the cis-isomer (7) were synthesised by an adapt- ation of the method used for the conversion of 1,3-di- thiolan-2-thione into 2-phenylimino-l ,3-di thiolan. Re-action of tmns-perhydro-lI3-benzodithiole-2-thione(12) with methyl iodide gave a crystalline salt (IS) which con- tained almost four extra moles of methyl iodide not readily removed under high vacuum ; subsequent treat- ment with aniline, followed by aqueous sodium hydroxide, 6 A. D. Ainley, W. H. Davies, H. Gudgeon, J. C. Harland, and W. A. Sexton, J. Chem. SOC.,1944, 150. 7 Y. Ueno, T. Nakai, and M. Okawara, Bull.Chem. SOC. Japan, 1970, 43, 162. 8 T. J. Adley, A. K. M. Anisuzzaman, andL. N. Owen, J, Chem. SOC.(C), 1967, 807. 8 R. Mayer and K. Schafer, J. prakt. Chem., 1964, 26, 279. gave the trans-phenylimino-compound (13), identical with that obtained by the cyclisation process. The cis-isomer (7)was prepared by a similar series of reactions on cis-perhydro-1,3-benzodithiole-Z-thione(the intermediate salt again contained an excess of methyl iodide), and also by reaction of cis-cyclohexane-l,2-dithiolwith phenyl isothiocyanate under the conditions described lofor con-version of ethane-1,2-dithiol into Z-phenylimino-1,3-dithiolan. The mass spectra of the phenylimino compounds were generally similar to one another, but the cis-compound (7)showed a strong peak at m/e 146 (C,H,,S,) which was insignificant in that of the trans-isomer (13),whilst the latter showed a strong peak at m/e 114 (C,H,,S) which was very weak in that of the cis-isomer.There were also characteristic differences in the i.r. spectra in the region 900-1 000 cm-l. EXPERIMENTAL 1.r. spectra were recorded for solutions in chloroform, U.V. spectra for solutions in ethanol, and lH n.m.r. spectra for solutions in deuteriochloroform (Varian T60 instrument). Mass spectra were recorded with a Perkin-Elmer 270 instru- ment. The adsorbent for t.1.c. was Kieselgel GF,,, (Merck), the developing solvent being dichloromethane unless other- wise specified. Extracts were dried over magnesium sul- phate.Petroleum refers to the solvent of b.p. 40-60 "C. trans-2-Phenyliminoperhydro-1,3-benzodithiole( 13) .-(i) M-Potassium hydroxide in ethanol (2.2 ml) was added to a warm solution of trans-2-(phenylthiocarbamoylthio)cyclo-hexyl acetate (0.63 g) in ethanol (9 ml), and the mixture was left at ambient temperature overnight. Water (7 ml) was then added, and the precipitated solid was collected and recrystallised from aqueous methanol to give the phenyl- imino compound (13) (0.27 g), m.p. 110", vmxa 1580, 1485, 1445,960, and 940 cm-l, Am, 238 (11 000) and 280 nm (E 6 000), 7 2.4-3.2 (5 H, m), 6.4 (2 H, m), and 7.4-8.8 (8 H, m), m/e 249 (M+,70), 167 (PhNCS,, lo), 135 (PhNCS, 94), 114 (C6HloS, 31), 81 (C,H,, loo), 80 (C6H8, 66), and 77 (Ph, 34) (Found: C, 62.7; H, 6.1; N, 5.35; S 25.35.C1,H15NS, requiresc, 62.6; H, 6.1; N, 5.6; S, 25.7). Anadditional quantity (57 mg) was isolated from the mother liquors by t.1.c. (ii) Similar treatment of trans-2-(acetylthio) (phenyl- imino)methylthiocyclohexyl acetate (0.36 g) in ethanol (6 ml) with M-potassium hydroxide (1.5 ml) gave the same product (13) (0.165 g), m.p. 105--107". (iii) A solution of trans- 2- (phenylthiocarbamoylthio)-cyclohexyl acetate (68 mg) in dry dimethyl sulphoxide (0.5 ml) was kept at ca. 95 "C for 80 h. T.1.c. then gave some starting material and the phenylimino compound ( 19 mg), m.p. 110" (purified by sublimation). Hydrolysis.-A solution of the phenylimino compound (13) (100 mg) in a mixture of acetic acid (12 ml) and concen- trated hydrochloric acid (2.7 ml) was heated on a steam- bath for 70 h, then cooled, diluted with water (20 ml), and extracted with dichloromethane.Evaporation of the dried extract gave trans-perhydro- 1,3-benzodithiol-2-one ( 1 1) (58 mg), m.p. 109-110" not depressed on admixture with an authentic sample,8 m.p. 109-1 10". lo A. Donche and C. Thibault, F. P. 1516855/1968; (Chem.Abs., 1969, 70, 115148). l1 E. Fromm, Ber., 1909, 42, 1945. J.C.S. Perkin I cis-2-(Phenylthiocarbamoylthio)cyclohexanol (15).-A solu-tion of phenyl isothiocyanate (1.05 g) in dry benzene (3 ml) was slowly added (10 min) to a stirred mixture of cis-2-mercaptocyclohexanol (1.O g), triethylamine (0.1 g), and dry benzene (6 ml) . After 12 h at ambient temperature the solution was concentrated to an oil which solidified on storage under benzene-petroleum at 0 "C.The product was washed with petroleum and recrystallised from carbon tetrachloride to give the dithiourethane (15) (1.2 g), m.p. 135-137", vmaX.(paraffinmull) 3 370 (OH), 3 200 (NH), 1 600, 1 330, and 1046 cm-l, 7 0.42br (1 H, NH, exchanged), 2.4 (5 H, m, aryl), 5.6 (2 H, m), 7.6br (1 H, OH, exchanged), and 7.7-8.8 (8H, m) (Found: C, 58.6; H, 6.7; N, 5.2; S 24.2. Cl,Hl,NOS2 requires C, 58.4; H, 6.4; N, 5.2; S, 24.0). cis-2-(Acetylthio)(phenylimino)methylthiocyclohexyl Ace-tate (1 7) .-A mixture of cis-2-(phenylthiocarbamoylthio)-cyclohexanol (1.0 g), pyridine ( 1.1 g), and acetic anhydride (2.0 g) was heated on a steam-bath for 10 min and then left overnight at ambient temperature.Addition of petroleum precipitated the diacetyl compound (17) (0.75g), which after t.1.c. and recrystallisation from ether-petroleum had m.p. 115-117", v,,,. 1 726 (OAC), 1 702 (SAC), 1 600, 1 495, 1 233, 1 163, and 1081 cm-l, 72.3-2.9 (5H, m, aryl), 4.6 (1 H,m), 5.8 (1 H, m), 7.88 (3 H, s, SAC), 7.93 (3 H, s, OAc), and 7.7- 8.7 (8 H, m) (Found: C, 57.8; H, 5.9; N, 4.0; S, 18.6. Cl,H,lN0,S2 requires C, 58.1; H, 6.0; N, 4.0; S, 1 8.25 yo). cis-2-(PhenylthiocarbamoyZthio)cycZohexylAcetate (1 6) .-(i) A mixture of acetic anhydride (45 mg) and pyridine (1.0ml) was gradually added (4 h) to a stirred solution of cis-2- (phenylthiocarbamoy1thio)cyclohexanol(0.23g) in pyridine (0.8 ml).After storage overnight the solution was diluted with water (20 ml) and extracted with dichloromethane to give an oil, which by t.1.c. was separated into starting material (90 mg) and the acetate (16) (61 mg), m.p. 108-111" (from carbon tetrachloride), vmax. 3 355 (NH), 1 730 (OAc), 1 600, 1 505, 1 245, and 1 040 cm-l, 7 1.05br (1 H, NH), 2.55 (5H, m, aryl), 4.7 (1 H, m), 5.7 (1 H, m), 7.95 (3 H, s, OAc), and 7.7-8.7 (8 H, m) (Found: C, 58.3; H, 6.1; N, 4.4; S, 20.5. Cl,Hl,N02S2 requires C, 58.2; H, 6.2; N, 4.5; S, 20.7). (ii) A solution of cis-2-(acetylthio) (pheny1imino)methyl- thiocyclohexyl acetate (0.51 g) in chloroform (5 ml) was shaken with 3~-hydrochloric acid (8 ml) until the deep yellow colour had faded to pale yellow (30 min).The chloroform layer was washed with aqueous sodium hydro- gencarbonate, then dried, and evaporated to give the acetate (16) (0.30 g), identical to that described in the preceding paragraph. Reaction of ci~-2-(PhenyZthiocarbamoylthio)cyclohexylAce-tate with Base.-M-Potassium hydroxide in ethanol (0.5ml) was added to a warm solution of the acetate (115 mg) in ethanol (2 ml) and the mixture was set aside overnight, then diluted with water and extracted with dichloromethane. Concentration of the extract gave a residue which by t.1.c. was separated into O-ethyl N-phenylthiocarbamate (25 mg), m.p. 67-69' (lit.,ll 68-69'), and ci~-2-(phenylthiocarba- moylthio)cyclohexanol(46mg), m.p. 130-132", both identi- fied by their i.r.and lH n.m.r. spectra. Reaction of cis-2-(Acetylthio)(phenylimino)methyZthio-cyclohexyl Acetate with Base.-The diacetyl compound (214 mg) in warm ethanol (4 nil), treated with M-potassium hy- droxide in ethanol (1.5 ml) by the procedure described for the monoacetate, gave O-ethyl N-phenylthiocarbamate (76 mg), m.p. 68-69", and cis-2-(phenylthiocarbamoylthio)-cyclohexanol ( 16 mg), identified spectroscopically. trans-Perhydro-1,3-benzodithiole-2-thioneMethiodide (18). -A mixture of trans-perhydro- 1,3-benzodithiole-2-thione (0.5g), methyl iodide (0.75 g), and dichloromethane (6 ml) was set aside for 7 days. The dark red crystals which had been formed were collected, washed with benzene, and dried under high vacuum to give the methiodide (18) (0.30 g), m.p.123-125", which contained trapped methyl iodide (Found : C, 16.3;' H, 2.2; I, 66.6. Calc. for C8H131S3,4CH31: C, 16.0; H, 2.8; I, 70.5). Reaction with Aniline.-A mixture of the methiodide (62 mg), aniline (40 mg), and methanol (1.5 ml) was left for 3 days and then diluted with ether (3ml). The solution was shaken with 2~-sodium hydroxide (8 ml), and the ether layer was isolated, dried, and concentrated to a residue which was purified by t.1.c. to give trans-2-phenylimino- perhydro-1,3-benzodithiole(8.5mg), m.p. 110-1 1 lo, (ix. and mass spectra identical with those recorded earlier), and trans-perhydro-1,3-benzodithiol-2-one (6.2 mg), identified from the i.r. spectrum. cis-Perhydro-1,3-benzodithiole-2-thione Methiodide .-Pre- pared from cis-perhydro- 1,3-benzodithioIe-2-thione (0.24 g) as described for the trans-compound, the methiodide (0.10 g)formed dark red crystals, m.p. 86-88O, containing trapped methyl iodide (Found: C, 21.3; H, 2.9; S, 21.9. Calc.for C8H131S3, 1.SCH31: c, 20.9; H, 3.2; s, 17.6). cis- 2-Phenylimino$~erhydro- 1,3-benzodithiole (7)*-(i)Treatment of the cis-methiodide (43 mg) with aniline (50 mg) and methanol (1.0 ml) as described for the trans-methiodide gave, after t.l.c., the phenylimino compound (7) (19 mg), m.p. 102-103" (depressed to 70-74" on admixture with the trans-isomer) ,vwx. 1 585,1 490, 1 450,and 955 cm-l, ~2.4-3.3(5H,m,aryl),6.0(2H,m),and7.7-8.7(8H,m), m/e 249 (M+,35), 194 (ll),146 (C,Hl,S2, 27), 135 (PhNCS, 24), 81 (C,H,, loo), 80 (C,H,, ll),and 77 (Ph, 38) (Found: C, 62.9; H, 6.0; N, 5.6; S, 25.4. Cl3HISNS, requires C, 62.6; H, 6.1; N, 5.6; S, 25.7). (ii) cis-Cyclohexane-l,2-dithiol (240 mg) and phenyl isothiocyanate (400 mg) were heated together at 150 "C for 30 min and then allowed to cool. The product was purified by t.1.c. to give the phenylimino compound (7) (30 mg), re- crystallised from aqueous methanol, m.p. and mixed m.p. 100-102", and cis-perhydro-1,3-benzodithiole-2-thione(1 6 mg), recrystallised from ether-petroleum, m.p. and mixed m.p. 99-100". We thank the S.R.C. for a Research Studentship (to R. C. F.). 7/2159 Received, 8th December, 19771
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