Addition reaction of 2-iminocyclopentanedithiocarboxylic acid with Schiff's bases: a novel route to the synthesis of 1,3-thiazine derivatives

摘要

J.C.S. Perkin I Addition Reaction of 2-lminocyclopentanedithiocarboxylicAcid with Schiff's Bases : A Novel Route to the Synthesis of 1,3-Thiazine Derivatives By Naoaki Fukada, Masahide Kato, Hitoshi Seki, Masayuki Kawana, and Tatsuo Takeshima,' Department of Chemistry, Faculty of Science, Chiba University, Yayoi-Cho, Chiba City, Japan 2-lminocyclopentanedithiocarboxylic acid (1 ) reacted with Schiff's bases to give the adduct esters (2). The esters were easily converted into the corresponding thiazines (3a). (3e). and (3f) with accompanying elimination of anilines. In the case of cyclopentylideneanilines, the esters could not be isolated, instead the thiazine (4) was directly obtained. THEpresent investigation was directed towards exploring be due to the fact that these 1,S-thiazines are cyclic the addition reaction of (3-iminodithiocarboxylic acids p-iminodithiocarboxylic acid esters (see Table).The with Schiff's bases. 2-Iminocyclopentanedithiocarboxy-reaction of the acid (1) with cyclopentylideneanilines lic acid (1) was chosen as a model acid, because it is resulted in direct formation of the 1,3-thiazine (4),l easily accessible as a crystalline free acid.l Schiff's bases the intermediate adduct esters being not stable enough were prepared by the dehydration reaction of ketones and to be isolated (Scheme 3). anilines with potassium fluoride. The addition reaction The addition reaction was influenced by a steric effect. of the acid (1)with cyclohexylideneanilines proceeded as 2-Methylcyclohexylideneaniline and S-pentylidene-expected to give the adduct esters (2) (Scheme 1). aniline did not enter into the reaction, instead the imino- The esters (2),when heated in a solvent, easily under- group of the acid (1) was displaced by a phenylimino-went elimination of 1 mol equivalent of the aniline group (Scheme 4).Thus, the 1,3-thiazine (34 was made function to yield the 1,3-tliiazine derivatives (3a),I from the acid (1) and 2-methylcyclohexanone via the (3e), and (3f) (Scheme 2). The U.V. spectra of the 1,3-alternative route (Scheme 2). The 1,3-thiazines (3e) thiazines resembled those of the esters (2). This may and (3f) could also be obtained by this method. T. Takeshima, M. Yokoyama, T. Imamoto, M. Akano, and M. Muraoka, M. Yokoyama, K. Yamamoto, and T. Take-H.Asaba, J. Org. Chem., 1969, 34, 730. shima, Bull. Chem. SOC.Japan, 1970, 43, 2134. 1978 559 EXPERIMENTAL cyclopentylidene-p-chloroaniline,157-1 59 "C at 17 mmHg ; N-Aamp;ylideneanilines.-A lllixture of aniline (or p-N-cyclopentylidene-p-anisidine,162-166 at 18 mmHg ;OC substituted aniline) (0.1 mol) and ketone (0.12 mol) was N-3-pentylideneaniline, 102-105 "C at 17 mmHg. refluxed with anhydrous potassium fluoride (0.1 mol) for Addition Reaction of 2-Iminocyclopentanedithiocarboxylic 3-6 h. The potassium fluoride was filtered off and the Acid (1) with N-Cyclohexylideneani1ines.-A mixture of the filtrate was distilled under reduced pressure. The following acid (1) (0.4 g, 0.002 5 mol), N-cyclohexylideneaniline Schiff's bases with the b.p.s stated were obtained as oils in (0.011 mol), and ethanol (0.5-1 ml) was kept overnight in Adduct esters and 1.3-thiazines Found (yo) Required (yo)Yield M.p.AIna*./nm vrnax.1 (1 4 c' H*N S 7--(yo) cm-I Formula CHN SCompound ("C)111-114 64.7 7.25 8.3 19.1 65.0 7.3 8.4 19.25(24 71 235 (4.01) 3 290s Cl,HZ*N2S2336 (3.72) 3 150s 410 (4.26) C19H26N2S2 66.1 7.7 8.05 18.2 65.9 7.6 8.1 18.5236 (4.26) 336 (3.83) 3 150s 408 (4.36) 98-100 245 (4.10) 3 295s C18HZ3N2S2C1 60.0 6.3 7.8 17.4 58.9 6.3 7.6 17.5 338 (3.80) 3 150s 408 (4.32) 108-1 11 236 (4.08) 3 340vs C19H26N20S2 63.0 7.3 7.7 17.4 63.0 7.2 7.7 17.7 336 (3.76) 3 160vs 408 (4.30) 119-120 234 (4.12) 3 290s C19H26N2S2 65.8 7.7 8.1 18.9 65.9 7.6 8.1 18.5 337 (3.80) 3 150s 408 (4.33) (2f) 52 106-107 234 (4.16) 3 300s C19H26N2S2 65.8 7.5 8.4 18.3 65.9 7.6 8.1 18.6 337 (3.84) 3 170s 408 (4.35) 170 240sh (3.66) 3 19ovs 61.45 7.6 5.55 25.0 61.6 7.6 5.5 25.3C13H19NS2 337 (3.86) 407 (4.37) 147-149 240sh (3.52) 3 150s C13Hl9NSZ 61.5 7.5 5.45 25.1 61.6 7.6 5.5 25.3 336 (3.70) 408 (4.20) 192 245sh (3.64) 3 165s C13H19NS2 61.6 7.55 5.5 25.8 61.6 7.6 5.5 25.3 337 (3.81) 407 (4.33) a Rapid heating.In EtOH. NH stretching absorption. d From the ester (2). From the acid (1) and methylcyclohexanone. Rt NH R3 (1 1 (2 1 98-101 yields of ca. 20-50 ; N-cyclohexylideneaniline, 137-141 "C at 16 mmHg ; N-cyclohexylidene-p-toluidine,155-157 "C at 18 mmHg ; N-cyclohexylidene-p-chloroaniline, 167-168 "C at 15 mmHg ; N-cyclohexylidene-p-anisidine, 170-174 "C at 15 mmHg ; N-2-methylcyclohexylidene-aniline, 142-146 "C at 16 mmHg; N-3-methylcyclohexyl-ideneaniline, 137-141 "C at 15 mmHg; N-kmethyl-cyclohexylideneaniline, 135-140 "C at 15 mmHg ; N-cyclopentylideneaniline, 132-1 36 "C at 18 mmHg ; N-cyclopentylidene-p-toluidine,142-146 "C at 18 mmHg; N-a refrigerator.The solid product was collected, washed with ethanol, and dried. The following adduct esters were obtained : 1-anilinocyclohexyl (2a) , I-p-toluidinocyclohexyl (Zb), 1-p-chloroanilinocyclohexyl(2c), 1-p-anisidinocyclohexyl (2d), 1-anilino-3-methylcyclohexyl (Ze), and l-anilino-4-methylcyclohexyl (2f) 2-iminocyclopentanedithiocarboxylates (see Table).These esters were not recrystallised because they were easily converted into the corresponding stable 1,3-thiazines (3) when warmed in a solvent. lJ3-Thiazines (3).-(a) From the esters (2). The ester (2) (0.001 2 mol) was dissolved in ethanol (ca.10 ml) ancl the solution was reduced in volume at ca.80 "C by one half. The solid product was collected, washed with ethanol, and R3 J.C.S. Perkin I paste was collected, dissolved in acetone, and water was added to it. The orange solid product was collected, washed with ethanol-water, and recrystallised from methanol. SCHEME2 R =H, Me, CI, or OMe SCHEME 3 recrystallised from methanol or methanol-water. The 1,3-Thiazines (3e)and (8f) and 1,5,6,7-tetrahydro-2'-met/zyl-known 1,3-thiazine (3s) was obtained from (2a)-(2d).cyclopentacl1,3thiaziize-2-s~irocyclolzexane-4(2H)-thione The esters (2e) and (2f) afforded 1,5,6,7-tetralzydro-3'-(3 g) were obtained from corresponding methylcyclohex- methylcyclopentad1,3thinzine-2-s$~irocyclohexane-anones. 4(2H)-thione(3e) and 1,5,6,7-tetraJaydro-4'-metJ~ylcyclofientn-Renctiom of the Acid (1) witJL N-Cyclopentylideneani1ines.-dJ1,3thiazine-2-spiroc~yclohexane-4(2H)-tlzione(3f), respect- ively. Me Q -CS.SHi+ (5) SCHEME4 (b) From the acid (1) and methylcyclohexanones.2 To a solution of the acid (1) (1 g, 0.006 3 mol) in methanol (40 ml) were added nietliylcyclohexanone (1 g, 0.009 mol) and sulphuric acid (0.7 g), and the mixture was refluxed for 1-1.5 h.After reduction of the volume of the mixture by 5Oy0 in a rotary evaporator, water was added to it. The This reaction was carried out under the same conditions as those for the addition reaction described above. N-Cyclopentylideneaiiiline, iV-cyclopentylidene-p-toluidine, N-cyclopentylidene-fi-chloroaniline,and N-cyclopentyl-iclene-p-anisidine were used as Schiff's bases. In every case 1,5,6,7-tetrahyclrocylopentad1,3tliiazine-2-spirocyclo-pentane-4(2H)-thione (4) was obtained. 2-Phenylinzinocyclopentanedithiocarboxylic A cid (5).-A mixture of the acid (1) (0.4 g, 0.002 5 mol), N-2-methyl- cyclohexylideneaniline (or N-3-pentylideneaniline) (0.008 5 mol), and ethanol (1 nil) was kept overnight at room temperature. The orange-yellow solid product was col-lected, washed with ethanol, and dried (yield ca.20), n1.p. 69 "C; v,,,~~.(KBr) 2 450s (SH), 1604vs, 1 590vs, and 1 565vs cm-l (conj. C=N, aromatic C=C);A,,,. (EtOH) 251 (log E 4.02), 317 (3.84),and 418 nm (4.33) (Found: C, 61.2; H, 5.5; N, 6.0; S, 27.0. C,,H,,NS, requires C, 61.3; H, 5.6; N, 6.0; S, 27.2). The acid (5) produced a bluish green precipitate with Nirl ions. iWethylation of the Acid (5).-The acid (5) (0.4g, 0.001 7 mol) was dissolved in a mixture of 1N-sodium hydroxide (20 ml) and ethanol (30 ml). To the mixture was added gradually a solution of methyl iodide (0.4g, 0.0028 mol) in ethanol (20ml) with stirring. After being stirred for an additional 30 min, the reaction mixture was kept for 1 h in a refrigerator.The yellow solid product was collected and dried. Recrystallisation from methanol-water gave methyl 2-phenyliminocyclopentanedithiocarboxylate(yield ca. 0.3 g, 71), m.p. 69-70 "C; v,,,. (KBr) 2 850m (CH,), 1 602vs, 1 588s, and 1 570vs (conj. C=N, aromatic C=C); A,,,. (EtOH) 252 (log E 4.14),325 (4.10),and 412 nm (4.43) (Found: C, 62.8; H, 6.1; N, 5.5; S, 26.0. C,,H1,NS2 requiresc, 62.6; HI 6.1;N,5.6; S,25.7). Oxidation of the Acid (5).-To a solution of the acid (5) 561 (0.1 g, 0.000 43 mol) in ethanol (7 ml) was added gradually a solution of iodine (0.2g) in NN-dimethylformamide (2ml) with stirring. The dark red solid product was collected, washed with ethanol, and recrystallised from tetrahydro- furan-ethanol (yield ca. 0.05 g, 50). The oxidative dimer,, bis-(2-plzenylirninocyclopentylthiocarbonyl)disulphide had m.p. 155 "C (slow heating) and 177 "C (rapid heating) (Found: C, 61.6; H, 5.2; N, 5.9; S, 27.7. C,4H,,N2S, requires C, 61.5; H, 5.2;N,6.0; S,27.4). We thank Dr. M. Muraoka for discussions and support of this research. 7/1404 Received, 1st A itpst, 19771 T. Takeshima, N. Fukada, T. Ishii, and M. Muraoka, J.C.S. Perkin I, 1976, 1706.