Reactions of thiazolidine-2,5-dithiones with amino nucleophiles. Synthesis of midazolidine-2,4-dithiones, lmidazo5,1-a-imidazole, -pyrimidine, -perimidine, -2,1-b1,3,4thiadiazines and pyrrole-3(2H)-thiones

摘要

J. CHEM.SOC. PERKIN TRANS. I 1990 Reactions of Thiazolidine-2,5-dithiones with Amino Nucleophiles. Synthesis of Imidazolidine-2,4-dithiones, Imidazo5,1 -a-imidazole, -pyrimidine, -perimidine, -Z,l -b I ,3,4thiadiazines and Pyrrole-3(2H)-thiones Tatsuo Yamamoto, Masumi T. Imagawa, Yumiko T. Yabe, Eriko M. Suwabe and Motomu Muraokardquo; Department of Chemistry, Faculty of Science, Josai University, 7 -I, Keyaki- Dai, Sakado, Saitama 350-02, Japan Reactions of 4,4 -d isu bst it u ted th iazo Iidine-2,5 -dit h iones with various am ino-co n taining nu c Ieo p h iles gave 1 -substituted imidazolidine-2,4-dithiones 3 and 11. The diamines, in these reactions, produced fused N-containing heterocycles 7a,b and 10. Imidazo2,1-6 1,3,4thiadiazines 14 were synthesized by further reaction of compounds 11 with a-bromoacetophenones. Enamino nitriles reacted as carbanions to give pyrrole-3(2H) -thiones 16.1,3-Thiazine-2,6-dithionesbearing an electron-withdrawing group, in particular an alkyl- or aryl-sulphonyl or cyano group, at the 5-position were previously shown to react with various nucleophiles and amino-containing nucleophiles to give fused heterocycles, such as pyrimidines, thiadiazines, thiopyridones, reductively alkylated thiazinethiones and dithiocinnamic acid derivatives by ring-opening reactions of thiazinedithiones. A series of thiazolidine-2,5-dithiones corresponding to the ring-contracted compounds of 173-thiazine-2,6-dithioneswere initially synthesized.2 Abnormal methylation reactions and marked susceptibility to oxidation to give bis(dihydrothiazo1- 5-yl) disulphides also occurred in the case of thiazolidinedi- thiones having a hydrogen at the 4-position.MNDO molecular orbital calculations adequately explained these methylations and oxidations of 4-monosubstituted thiazolidinedithiones.2 No reports appear to be available on the reactions of thiazolidine-2,5-dithiones with electrophiles and nucleophiles. The present study was conducted in order to examine the reactions of thiazolidine-2,5-dithiones with amino-containing nucleophiles such as amines, diamines, hydrazines, enamino nitriles and thiourea, leading to the formation of imidazolidine- 2,4-dithiones, imidazo-5,1-aimidazole, -pyrimidine, -perimi- dine, -2,l-b 1,3,4thiadiazines and pyrrole-3(2H)-thiones.The reaction mechanisms involved are briefly discussed based on the results of reactions of 4,4-disubstituted thiazolidinedi- thiones with the nucleophiles used. 4-Methyl-4-phenylthia~olidine-2~5-dithionela when added to an excess of a primary amine in 50 ethanol followed by warming to obtain a clear solution and then storage at room temperature, gave 3-substituted 5-methyl-5-phenyl-imidazolidine-2,4-dithiones 3 in moderate to high yield except for 3g (45) produced by reaction with aniline. Only methylamine, when used in large excess, yielded the l-methyl-5- methyliminoimidazolidine-2-thione4 as the major product along with compound 3a. The latter was obtained as the sole product in quantitative yield when normal excess of methylamine (2.5 mol equiv.) reacted with the reactant under the same reaction conditions.Compounds 3 were also synthesized in quantitative yields on treatment of 2-alkylthiothiazol-5(4H)-thiones 2 with alkyl- amines in EtOH. Compounds 2 were easily produced by reaction of thiazolidinedithiones with alkyl iodides (Scheme 1). The structural isomer of compound 4, 3-methyl-2-methyl-iminothiazolidine-4-thione 5 or its tautomer, could not be obtained. The structure of compound 4 was easily determined from its 13C NMR spectrum and from that of thiazolidinedi- H H a; Rrsquo; = Ph, R3 = Me 9; Rrsquo; = R2 = Ph b; Rrsquo; = Ph, R3 = Et h; Rlsquo;= Ph, R2 = H c ; Rrsquo; = p-Tolyl, R3 = Me i; Rrsquo; = p-TOIYI,R~ = H H H Ph MeN eNbsol;Me (4) (5) Scheme 1.Reagents: R31, NEt,; ii, Rrsquo;NH,. thione (see Experimental section). Amines higher than methylamine failed to give compounds homologous to compound 4, whereas 1, a-alkylene diamines and naphthalene- 1,g-diamine reacted quite smoothly with thiazolidinedithiones to form fused N-containing heterocycles 7 and 10, corresponding to compound 4, in good yield (Scheme 2). The intermediate, the 3-(2-aminoethyl)imidazolidine-2,4-dithione6, was isolated after a short reaction period. o-Phenylenediamine also gave intermediate compounds 8a-c in high yield. However, in no case could these intermediates 8a-be converted into fused N-containing heterocycles corresponding to compounds 7/10. The strain of a 6.5.5 product, together with the lower nucleophilicity of the o-amino group in structures 6/8 may possibly have been the reason for this.In addition, from thiosemicarbazide, only the imidazolidine- 3004 J. CHEM. SOC. PERKIN TRANS. I 1990 (8) a; Rlsquo; = Ph, R2 = Et b; Arsquo; = p-Tolyl, Ff = Me C; Rlsquo; = 2-naphthy1, R2= Me (6) n = 1 (7) a; n = 1 b; n=2 Scheme 2. Rrsquo; R2 R3 R4 Rlsquo; R2 R3 R4 (11)a; Ph Me H H g; Ph Et H H b; Ph Ph H H h; Ph Et MeH c; p-Tolyl Me H H i; p-Tolyl Me Me H d; 2-naphthyl Me H H j; p -Tolyl Me Me Me e; Ph Me MeH k;p-Tolyl Me Ph H f; Ph Me Ph H I; Ph Ph MeH H I R3rsquo; dithione derivative 9 could be obtained, even under drastic reaction conditions. The cyclisation of compound 9 may not have occurred due to ring strain in the 5.5 product and the low nucleophilicity of the thioamide NH,.group. This is in striking contrast to the reaction of 1,3-thiazine-2,6-dithioneswith thiosemicarbazide to give fused heterocycles, 1,2,4 tri- azolo1,5-upyrimidine-2,7-dithiones,in moderate yields.rsquo; Hydrazines were particularly reactive toward thiazolidine- dithiones to form l-amino-, -alkylamino- and -aniline-imidazo-lidine-2,4-dithiones 11 in quantitative yield.The possibility of 1,2,4-triazine-3,6-dithiones12 instead of compounds 11 being formed was ruled out since imidazoC2, l-b1,3,4 thiadiazine derivatives 14 were produced on treatment of compounds lla-d with a-bromoacetophenones. The intermediate compounds 13 were isolated under alkaline reaction conditions and were converted into compounds 14 by ring-closure under acidic conditions (Scheme 3).Molina et aL3 found l-amino-2-thioxo- 1,2-dihydropyridines to react with a-bromocarbonyl com-pounds to give 1,3,4-thiadiazino3,2-uJpyridiniumsalts by a reaction similar to that for the formation of compounds 14. Compounds 3h and 3i, simpler imidazolidines with no substituent on N-3 of the ring, were produced in rather low yield by reactions of thiazolidinedithiones with thiourea in the presence of a strong base in a polar aprotic solvent. Methylthiourea in this reaction merely afforded compound 3h in very low yield (2) and it thus follows that thiourea itself does not react directly with the thiazolidinedithiones but with ammonia generated by the decomposition of thiourea under basic reaction conditions to give compounds 3h,i.Aq.ammonia also reacted with 4-methyl-4-phenylthiazolidinedithioneso that compound 3h was obtained in 56 yield. Enamino nitriles, different from the above amino-containing nucleophiles, reacted as carbanions to give pyrrole-3(2H)- thiones 16. In this case, a strong base such as t-alkoxide was required to promote the reaction (Scheme 4). The most active positions for nucleophiles for the reactions with thiazolidinedi thiones and with 1,3-thiazine-2,6-di thiones were different; the nucleophiles attack the thiocarbonyl carbon at the 5-position in thiazolidine-2,5-dithiones, while 1,3-thia- zine-2,6-dithiones react with the same nucleophiles at the Rrsquo; $ R3 Rrsquo; R2 R3 (13)a; Ph Me H (14)a; Ph Me H b; Ph Ph H b; Ph Ph H C; Ph Ph Br c; p-Tolyl Me H d; p-Tolyl Me H d; 2-naphthyl Me H e; p-Tolyl Me Br e; 2-naphthyl Me Br f; 2- naphthyl Me H g; 2 -naphthyl Me Br Scheme 3. Reagent and conditions: i, NEt,, room temp.J. CHEM.SOC. PERKIN TRANS. I 1990 U Me H2N*CHCNR2 (1) a; R1 = Ph (15) a; R2 =Me b; R' = p-MeCamp; b; F? = p -MeC6H4 Ii t (16) a; R'=Ph, R2=Me b; R' = Ph, F? = p-Tolyl c; R1= Ff=p-Tolyl Scheme 4. Reagent and conditions: i, Bu'OK, reflux. 2-position. Abnormal methylation of 4-phenylthiazolidine-2,5-dithione was noted in the previous study but results of calculations for the heat of formation and the contribution of the HOMO to two tautomers, the enethiolic and dithione form of this thiazolidinethione, showed that this methylation was in fact reasonable.The present data show the thiocarbonyl carbon at the 5-position in thiazolidinedithiones to be exclusive to the reactive site likely to be initially attacked by a nucleophile. The 4-position as well as the thiocarbonyl carbon at the 2-position in thiazinedithiones may be the two most reactive centres in these molecules. However, sterically, the 2-position of thiazinedithiones is much more advantageous than the 4-position for any nucleophile and all reactions gave products corresponding to those whose formation was initiated by the attack of a nucleophile at this position. ' Elemental analyses and IR, NMR and some electronic and mass spectra showed good agreement with the proposed structures for compounds 2-16 (see Experimental section).Experimental M.p.s were measured on a Yanagimoto micro melting point apparatus and are uncorrected. NMR spectra were determined with a JNM-GX270-FT-NMR spectrometer at 270 MHz with tetramethylsilane as internal standard. IR spectra were determined with a JASCO A-302 spectrophotometer. Electronic spectra were obtained on a Hitachi 557 double-wavelength double-beam spectrophotometer. Starting Materials.-4,4-Disu bstituted thiazolidine-2,5-di-thiones were prepared by our previous method of synthesk2 4,4-Disubstituted 2-Alkylthiothiazole-5(4H)-thiones 2a-c.-For example, a solution of 4-methyl-4-phenylthiazolidine-2,5-dithione la (10.76 g, 45 mmol), methyl iodide (9.58 g, 67.5 mmol) and triethylamine (5.01 g, 49.5 mmol) in tetrahydrofuran (THF) was kept at room temperature for 1 h.Water (80 ml) was added to the reaction mixture and the resulting mixture was extracted with diethyl ether (100 ml x 3). The combined extract was dried over MgS04 and evaporated to dryness to give a red oil, which was distilled in vacuo to give 4-methyl-2-methylthio-4-phenylthiazole-5(4H)-thione2a as a red oil (9.88 g, 87); b.p. 126 OC/O.2 mmHg; m.p. 41.5-42 "C; vmax(KBr) 2960, 2920, 1580,1563s, 1490,1442,1420,1359,1303,1206,1162,1100,1076, 3005 1025,983s, 951 and 913 cm-'; h,,,(EtOH) 280 (log E 3.72), 317 (3.91), 487 (1.55) and 509 nm (1.47); G,(CDC13) 7.3 (5 H, m, Ph), 2.68 (3 H, s, SMe) and 1.94 (3 H, s, Me); Gc(CDCl,) 246.67, 161.92, 140.37, 128.41, 128.01, 125.48, 98.98, 28.72 and 14.74 (Found: C, 52.1; H, 4.2; N, 5.5; S, 37.9.C,lH11NS3 requires C, 52.1; H, 4.4; N, 5.5; S, 38.0). 2-Ethylthio-4-methyl-4-phenylthiazole-5(4H)-thione2b. Yield 75, b.p. 155 "C/0.2 mmHg; v,,,(neat) 2960, 2930, 2860, 1580, 1563,1493,1442,1370,1360,1264,1169,1100, 1071,1028,959s and 920 cm-'; h,,,(EtOH) 278 (3.80), 316 (4.00), 487 (1.55) and 509 nm (1.47); G,(CDCl,) 7.3 (5H, m, Ph), 3.28 (2 H, q, J7.3 Hz, SCH2), 1.91 (3 H, s, Me) and 1.47 (3 H, t, J 7.3 Hz, CH2Me) (Found: C, 53.9; H, 4.8; N, 5.2; S, 35.8. C12H13NS3 requires C, 53.9; H, 4.9; N, 5.2; S, 36.0). 4-Methyl-2-methylthio-4-(p-toly~thiazole-5(4H)-thione 2c.Yield 85, b.p. 136-137 "C/0.065 mmHg; v,,,(neat) 2975,2920, 1563s, 1506, 1441, 1407, 1358, 1309, 1186, 1167, llOOs, 1058, 1019, 983s, 953s and 916 cm-'; h,,,(EtOH) 278 (3.77), 317.5 (3.94), 478 (1.76) and 510 nm (1.76); GH(CDC13) 7.25 and 7.12 (each 2 H, each d, Jeach 8.3 Hz, C6H4), 2.68 (3 H, s, SMe), 2.31 (3 H, s, C,H4Me), 1.93 (3 H, s, Me) (Found: C, 53.8; H, 4.8; N, 5.3; S, 35.9. C12H13NS3 requires C, 53.9; H, 4.9; N, 5.2; S, 36.0). Preparation of 5,5-Disubstituted Imidazolidine-2,4-dithiones 3a-i.-Method A: From the thiazolidinedithiones and Amines. General procedure. To a suspension of a thiazolidine-2,5-dithione (2 mmol) in 50 ethanol (7 ml) was added an amine (5 mmol). The mixture was warmed to 70 OC to obtain a clear solution, which was kept at room temperature* and then filtered to remove a small quantity of insoluble matter.The filtrate was treated under reduced pressure to remove EtOH, and the yellow crystals which were separated were collected, and washed with water. Yields, m.p.s, solvent for recrystal- lization and IR spectra of compounds 3a-i are shown in Table 1. NMR data are given in footnotes to Table 1. Method B. A mixture of 4-methyl-2-methylthio-4-phenyl-thiazole-5(4H)-thione 2a (0.506 g, 2 mmol), an amine (5 mmol) and ethanol (7 ml) was warmed to 70deg;C for a short time to obtain a clear solution and then the solution was kept at room temperature for 1-2 h. Water (7 ml) was added to the reaction mixture, and EtOH in the aq.solution was removed under reduced pressure; yellow crystals of a compound 3 separated out. The crystals were collected, washed with water and dried. A small amount of compound 3 was also obtained from the acidified filtrate (pH 1). Reaction time and yields by method B are listed in Table 1. 5-Methyl-5-phenylimidazolidine-2,4-dithione3h. A mixture of 4-methyl-4-phenylthiazolidine-2,5-dithionela (0.24 g, 1 mmol) lS~-amrnonia water (1.7 ml, 2.5 mmol) and 50 EtOH (5 ml) was warmed at 70 "C for a very short time. The mixture turned into a clear solution, which was kept for 48 h. The reaction mixture was filtered, and EtOH in the filtrate was removed under reduced pressure to give yellow crystals. 5-Methyl-5-(p- tolyl )imidazolidine-2,4-dith ione 3i.A solution of methyl-(p-tolyl)thiazolidine-2,5-dithione1b (1.01 g, 4 mmol), thiourea (0.76 g, 10 mmol) and sodium 1,l-dimethyl- propanolate (0.90 g, 4.2 mmol) in N,N-dimethylformamide (25 ml) was warmed at 85 "C for 1 h. Water (20 ml) was added to the cooled reaction mixture and the resulting aq. solution was washed twice with diethyl ether. The aq. layer, from which any remaining ether was removed under reduced pressure, was acidified with ~M-HC~ (pH 1) and was then extracted with diethyl ether. The extract was washed six times with water, dried (MgS04) and evaporated to dryness to afford a red oil. Yellow * In this method, the time of storage needed (1-24 h) depended upon the amine employed. 3006 J.CHEM. SOC. PERKIN TRANS. 1 1990 Table 1. 3,5,5-Trisubstituted imidazolidine-2,4-dithiones3. vm,x(KBr)Reaction Yield M.P.~ Compd" R' R2 time (h) () ("C) NH hetero ring 3a Ph Me 1 99 134.5-135 3150 1520 1 97' (aq. EtOH) 3bf Ph Et 3 91" 125.5-1 26 3160 1513 1 97" (aq. EtOH) 3c Ph Pr 20 83 72.5-73 3140 1516 1 99 (C6H14)3de Ph Pr 1 97 1 72-1 72.5 3140 1513 (aq. EtOH) 3e Ph Bu 24 91 78-78.5 3110 1520 2 96 (C6H 14) 3f Ph 1 1 98 185-185.5 3130 1525 (C6H6)3g Ph Ph 20 45 166.5-168.5 3110 1525 (EtOH)3hk Ph H 48 56 179.5-180.5 3100 1533 0.5 36' (c6H6x6H14)3i p-T01y1 H 1 38' 21 3.5-21 6 3140 1535 (c6 6 6 14) " All the compounds gave satisfactory microanalyses. Solvent for recrystallization in parentheses. GH(CDC13)8.89(1 H, br s, NH), 7.40 (5 H, m, Ph), 3.56 (3 H, s, NMe) and 1.97 (3 H, s, Me); Gc(CDC13) 207.2, 182.0, 139.1, 128.7, 125.5, 125.0, 75.7, 32.6 and 27.5.Method A. Method B. 'GH(CDC13)7.3 (5 H, m, Ph), 3.30 (2 H, q, J 6.5Hz, NCH2), 1.96(3 H, s, Me)and 1.47(3 H, t, CH2Me). GH(CD3SOCD,) 11.46(1 H, br s, NH),7.35 (5 H, m, Ph), 5.42(1 H, sept, J 6.4 Hz, NCH) and 1.57 and 1.53 (total 6 H, each d, each J 6.4 Hz, CHMe,); G,(CD,SOCD,) 207.4 (br).180.8(br), 139.9, 128.5, 128.1, 125.4, 74.6,49.2, 26.2 and 17.5(br). I, ~H(CD~COCD~)11.98(1 H, br s, NH), 9.88(1 H,br s, NH), 7.40(5 H, m,Ph) and 1.93(3 H, s, Me); Gc(CD3SOCD3) 210.8, 181.5, 140.5, 129.3, 129.0, 78.4 and 26.9. From the reaction with ammonia. j From the reaction with thiourea. crystals were obtained by treatment of this red oil with hexane and the product was recrystallized from hot benzene-hexane to give yellow crystals of compound 3i.1,4-Dimethyl-5-methylimino-4-phenylimidazolidine-2-thione4.-A solution of 4-methyl-4-phenylthiazolidine-2,5-dithionela (0.48g, 2 mmol) and aq. methylamine (40; 4.66 g, 60mmol) in 50 EtOH (3ml) was refluxed at 70deg;C for 2 h. EtOH was removed from the reaction mixture under reduced pressure, and pale yellow crystals separated out and were collected. The mother liquor was acidified with ~M-HC~ (pH 1)to give a second crop of yellow crystals. Both sets of crystals were column chromatographed on silica gel with benzene as eluant to give compound 4 (0.246g, 53).Recrystallization from hot benzene- hexane gave pure compound4as long plates, m.p.184.5-186"C; v,,,(KBr) 3140s, 2910, 1688s,1498s, 1441, 1388,1372, 1320s, 1232,1183,1125,1092, 1043, 1028 and 947 cm-'; h,,,(EtOH) 261 nm (4.50);8H(CDCI,) 7.54 (1 H, br s, NH), 7.3 (5 H, m, Ph), 3.31 (3H, s, NMe), 2.92 (3 H, s, =NMe) and 1.94 (3 H, s, Me); Gc(CDC13) 181.1,160.1, 137.9, 129.2,128.9,126.0,64.4,35.8and 29.0;m/z(70eV) 233 (M', loo), 218 (M+ -CH,, 13), 162 Ph(Me)C=N--IC=S+, 151,145 Ph(Me)G+NMe+, 131 and 119Ph(Me)CNH+,351(Found: C, 61.9;H, 6.6;N, 17.9;S, 13.9. C,2H15N3S requires C, 61.8;H, 6.5;N, 18.0;S, 13.7). 3-(2-Aminoethyl)-5-methyl-5-(p-tolyl)imidazolidine-2,4-di-thione 6.-A solution of 4-methyl-4-(p-tolyl)thiazolidine-2,5-dithione lb (1.01g, 4mmol) and ethylenediamine (0.721g, 12 1061and 1003cm-'; h,,,(EtOH) 228 (4.03)and 304nm (4.32);m/z(70 eV) 279 (M+, 373, 262 (M+ -NH3, 15), 237 (M+ -CH,CH=NH, 43), 203 (M+-NH3 -HNCS, 40),176 C7H7(Me)ENCS+, 211, 162 C,H,(Me)GC=S+, 241 and 43(CH2=CHNH2,100)(Found: C, 56.1;H, 6.0; N, 15.3;S, 23.1.C13H17N3S2requires C, 55.9;H, 6.1;N, 15.0;S, 23.0).Reactionof o-Phenylenediamine with 4,4-Disubstituted Thia-zolidine-2,5-dithiones.Formationof 5,5-Disubstituted3-(2-Am-inophenyl)imidazolidine-2,4-dithiones8a-c.-A solution of a 4,4-disubstituted thiazolidine-2,5-dithione (4 mmol) and 0-phenylenediamine (0.864 g, 8 mmol) in EtOH (12ml) was warmed for 3 h at 70"C. ~M-HC~( 8 ml) was added dropwise to the cooled reaction mixture under reduced pressure. To the acidified mixture was added water (20ml) and the mixture was kept for 24h.The solid which separated out was collected and washed with 20 EtOH. 3-(2-Aminophenyl)-5-ethyl-5-phenylimidazolidine-2,4-di-thione 8a. Yield 83, m.p. 271-272deg;C (rapid heating), 263-263.5 "C (slow heating) (from hot EtOH-hexane); v,,,(KBr) 3450, 3360, 3120, 2960, 1617, 1520s, 1459, 1442, 1381, 1310, 1287s,1212sand 1192scm-'; h,,,(EtOH) 301 (4.34) and 410nm (2.00);m/z(70 eV) 327 (M', 58), 294 (M' -SH, loo),235 (M+ -C,H,NH,, 19) and 161 MeCH=C(Ph)CS+, 53) (Found: C, 62.2;H, 5.4;N, 12.8;S, 19.6.Cl7HI7N3S2requires C, 62.4;H, 5.2;N, 12.8;S, 19.6). 3-(2-Aminophenyl)-5-methyl-5-(p-tolyl)imidazolidine-2,4-dithione 8b. Yield 87, m.p. 183.5-184.5"C (rapid heating), mmol) in ethanol (12ml) was warmed for 3 h at 70"C.~M-HC~ 180.5-181"C (slow heating) (from hot EtOH-hexane);1450,1381,1363,was added (pH 2)to the cooled reaction mixture to give a small v,,,(KBr) 3400,3320,3200,2970,1610,1500s, amount of solid, which was collected. The mother liquor was made alkaline (pH 9)with ~M-N~OH under reduced pressure; a pale yellow solid separated out, which was collected and washed with 20 EtOH. Both solids were combined and recrystallized from hot isopropyl alcohol to give the tide compound 6 as pale yellow crystals (0.9g, 70, m.p. 245-245.5"C; v,,,(KBr) 3340, 3260,3100,2920,1550,1509,1427,1345,1283,1178,1143,1099, 1293s,1202, 1147, 1130 and 1104cm-'; h,,,(EtOH) 301 (4.35) and 410 nm (2.00);m/z(70 eV) 327.088 (M+. M requires327.087, 18), 294.105 (M+ -SH.M -SH requires 294.107, 22),235.025(kf+-C6H4NH2. M -C6H6N requires 235.037, 7)and 161.040CH2=C(C7H,)CS+. Cl,H,S requires 161.043, 16) (Found: C, 62.3;H, 5.4;N, 12.6;S, 19.7.C17H17N,S, requires C, 62.4;H, 5.2;N, 12.8;S, 19.6). J. CHEM. SOC. PERKIN TRANS. 1 1990 3-(2-Aminophenyl)-5-methyl-5-(2-naphthyl)imidazolidine-2,4-dithione amp;. Yield 93, m.p. 232.5-233 "C (from hot EtOH- hexane); v,,,(KBr) 3430, 3360, 3100, 2970, 1617, 1520s, 1502s, 1459,1377,1350,1290s, 1228s, 1208,1188,1150,1131 and 11 18 cm-'; h,,,(EtOH) 294 (4.39) and 410 nm (2.21); m/z (70 eV) 363 (M', 52), 330 (M' -SH, 100), 304 (M+ -HNCS, lo), 271 (M' -C6H4NH2, 35) and 197 CH2=C(C,0H7)CS', 161 (Found C, 65.9; H, 4.6; N, 11.5; S, 17.6.C20H1 7N3S2 requires C, 66.1; H, 4.7; N, 11.6; S, 17.6). Compounds 8a-c were never converted into corresponding benzimidazolethiones on refluxing for 5 h in EtOH. 5-Methyl-3-thioureido-5-(p-tolyl)imidazolidine-2,4-dithione !amp;--To a mixture of 4-methyl-4-(p-tolyl)thiazolidine-2,5-dithione lb (0.253 g, 1 mmol), potassium hydroxide (0.112 g, 2 mmol) and EtOH (7 ml) was added a solution of thiosemi-carbazide hydrochloride (0.256 g, 2 mmol) in water (4 ml). The mixture was warmed for 3 h at 70deg;C and then cooled. The reaction mixture was filtered and the filtrate was diluted with water (10 ml) and acidified with ~M-HC~ (pH 1) to give a yellow solid, which was collected, washed with water and recrystallized from xylenes-ethanol-hexane to give compound 9 as yellow crystals (0.184 g, 5973, m.p.21 3-3 14 "C (rapid heating), 207.5- 208 "C (slow heating); v,,,(KBr) 3300, 3240, 3130, 1608, 1508, 1440,1402,1350,1300,121 1,1102,1060 and 1013 cm-' (Found: C, 46.6; H, 4.5; N, 17.8. C12H13N3S2 requires C, 46.3; H, 4.55; N, 18.05). 2,3,6,7-Tetrahydro-7-methyl-7-(p-tolyl)-5H-imidazo5,l-a-imidazole-5-thione 7a.-A solution of 4-methyl-4-(p-tolyl)-thiazolidine-2,5-dithione(2.02 g, 8 mmol) and ethylenediamine (1.44 g, 24 mmol) in EtOH (25 ml) was warmed for 24 h at 70 "C. The hot reaction mixture was filtered and then cooled to room temperature to give lustrous crystals on prolonged storage, which were collected and washed three times with carbon disulphide.Recrystallization from hot ethanol gave the title compound 7a as crystals (0.70 g, 71), m.p. 247 "C; v,,,(KBr) 3190, 2930, 2760, 1677s, 1503s, 1425, 135Os, 1276, 1224, 1180, 1142, 1105, 1082, 1070, 1019, 983 and 964 cm-'; h,,,(EtOH) 263 nm (4.26); 6H(C5D5N) 8.71 (1 H, br s, NH), 7.3 (4 H, m, CsH4), 4.60 (2 H, t, J 6.8 Hz, =NCH2), 3.28 (2 H, t, J 6.8 Hz, NCH,), 2.18 (3 H, s, C6H4Me) and 2.02 (3 H, s, Me) (Found: C, 63.6; H, 6.3; N, 17.0. C,,H,,N,S requires C, 63.7; H, 6.2; N, 17.1). 3,4,7,8-Tetrahydro-8-methyl-8-(p-tolyl)-2H,6H-imidazo5,1-a pyrimidine-6-thione 7b.-A solution of 4-methyl-4-@-tolyl)-thiazolidine-2,5-dithione lb (1.01 g, 4 mmol) and trimethyl- enediamine (0.89 g, 12 mmol) in EtOH (13 ml) was warmed for 3 h at 70 "C and then cooled to -12 "C.The resulting white solid was collected, washed with a mixed solvent of EtOH and hexane (4:6), and recrystallized from hot ethanol to give compound 7b as crystals (0.78 g, 7579, m.p. 235 "C; v,,,(KBr) 3110, 2950, 2930, 167Os, 1492s, 1438, 1409, 1359, 1340, 1328, 1300s, 1260, 1238, 1200, 1107, 1038, 1020 and 952 cm-'; h,,,(EtOH) 261 nm (4.42); 6,(CDC13) 7.61 (1 H, br s, NH), 7.32 and 7.1 8 (each 2 H, each d, J 8 Hz, C6H4), 3.82 (2 H, t, J 6.8 Hz, =NCH2), 3.44 (2 H, t, J6.8 Hz, NCH2), 2.33 (3 H, S, C6H4Me), 1.94 (2 H, m, CH,CH,CH,) and 1.82 (3 H, s, Me); G,-(C,D,N) 179.6, 158.0, 138.6, 136.8, 128.8, 125.2, 64.2, 43.8, 26.3, 20.5 and 19.3; m/z (70 eV) 259 (M', 100) and 244 (M+ -CH,, 3) (Found: C, 64.8; H, 6.6; N, 16.1; S, 12.6.Cl,H17N3S requires C, 64.8; H, 6.6; N, 16.2; S,12.35). 8,9-Dihydro-8-methyl-8-(p-tolyl)imidazo1,Salperimidine-10-thione 10.-A solution of 4-methyl-4-(p-tolyl)thiazolidine-2,Sdithione 1b (1.01 g, 4 mmol) and naphthalene-l,8-diamine (1.90 g, 12 mmol) in EtOH (12 ml) was warmed for 3 h at 70 "C and then cooled. The reaction mixture was acidified with 2M-HCl pH 2) followed by the addition of water (5 ml) to give yellow crystals. Recrystallization from hot isopropyl alcohol gave compound 10 as yellow crystals (1.34 g, 97), m.p. 215.5- 216 "C; v,,,(KBr) 3380, 1664s, 1595, 1590, 1512, 1473s, 1402s, 1372,1339,1258s, 1228,1210, 1175, 1162,1108 and 1077 cm-'; h,,,(EtOH) 225 (4.48, 233 (4.47), 291 (4.08), 334 (4.06), 348 (4.03), 380 (3.83), 398 (3.83) and 420 nm (3.50) (Found: C, 73.1; H, 5.3; N, 11.9; S, 9.6.CzlHI7N,S requires C, 73.4; H, 5.0 N, 12.2; s,9.3). Preparation of 5,5-Disubstituted 3-Amino- and -Alkylamino-imidazolidine-2,4-dithiones11a-1.-General procedure. To a stirred solution of a 4,4-disubstituted thiazolidine-2,5-dithione (2 mmol) in EtOH (12 ml) was added dropwise a hydrazine NH,NR3R4 (4 mmol). The mixture was kept for 3 h at room temperature. Water (15 ml) was added to the reaction mixture and this aq. solution was acidified with ~M-HCI (pH 1); an oil separated out, and solidified within a few min. The solid was collected, washed with water, dried and recrystallized. Yields, m.p.s and v,,,(KBr) values are given in Table 2. Reaction of Compounds 11 with 4'-Substituted a-Bromo-acetophenones.Isolation of Intermediates, 5,5-Disubstituted 3-Amino-2-(benzoylmethylthio)imidazole-4(5H)-thiones13.-General procedure. A mixture of a compound 11 (2 mmol), phenacyl bromide or 4'-bromophenacyl bromide (2 mmol), triethylamine (4 mmol) and dry benzene (17 ml) was refluxed for 2.5 h. Triethylammonium bromide which separated out and filtered off, and the filtrate was condensed to give yellow crystals, which were collected, washed with hexane and recrystallized from hot EtOH-water to give yellow crystals of compounds 13. Yields, m.p.s and v,,,(KBr) are shown in Table 3. Imidazo2,1-b 1,3,4thiadiazines 14. For example, conc. sulphuric acid (0.055 g, 1 mmol) was added to a solution of compound lla (0.355 g, 1 mmol) in EtOH (5 ml) and the solution was warmed for 1 h at 78 "C and cooled.Water (10 ml) was added to the solution and the aq. solution was then extracted with diethyl ether (20 ml x 2). The combined extract was dried over MgSO, and evaporated to give an oil, which was dissolved in benzene (5 ml). Addition of hexane to this solution caused a crystalline solid to separate out (0.304 g, 90), which was recrystallized from hot EtOH-water to give yellow crystals of 7-methyl-3,7-diphenyl-2H,7H-irnidazo2,1-b 1,3,4 thiadia- zine-6-thione 14a. Compounds 14b-e were also obtained by a similar reaction. Yields, m.p.s, solvent for recrystallization and spectral data of compounds 14a-e are shown in Table 3. Direct Synthesis of Compounds 14 from Compounds 11.For example, a solution of compound 6a (0.475 g, 2 mmol) and phenacyl bromide (0.398 g, 2 mmol) in benzene (20 ml) was refluxed for 2 h. Hydrobromide of compound 14a separated from the solution. Triethylamine (0.405 g, 4 mmol) was added to the reaction mixture without filtration and then the resulting mixture was stirred for 0.5 h. The reaction mixture was filtered to remove triethylammonium bromide to obtain benzene soh-tion, which was concentrated and followed by the addition of hexane. Yellow solid which separated was collected, washed with hexane and recrystallized from hot EtOH-water to give pure compound 14a. IR spectrum and m.p. were identical with those of the compound obtained by conversion of compound 13a.Reaction with Enamino Nitriles. Formation of Pyrrole-3(2H)-thiones 16.-General procedure. A mixture of a 4-aryl-4-methylthiazolidine-2,5-dithione(2 mmol), an enamino nitrile (2.5 mmol), potassium t-butoxide (0.696 g, 5.7 mmol) in THF (30 ml) was refluxed for 23 h and then water (30 ml) was added to the cooled reaction mixture. The aq. solution was washed 3008 J. CHEM. SOC. PERKIN TRANS. I 1990 Table 2.3-Aminoimidazolidine-2,4-dithiones11. ~~ vm,x(KBr)Yield M.pb Compd" R' R2 R3 R4 () ("C) NH, hetero ring Ila' Ph Me H H 67 145-1 46.5 3260, 1510 (C6H6-C6H 14) 3 140 llbd Ph Ph H H 93 220.5-222 3270, 1508 (as. EtOH) 3160 Ilc' p-Tolyl Me H H 92 137-138 3280, 1518 (C6H6-C6H14) 3140 1ld 2-Naphthyl Me H H 94 154155 3370, 1510 (aq.THF) 3150 1le Ph Me Me H 81 128.5-129 3200 1510 (C6H6-C6H1 4) llf Ph Me Ph H 99 175.5-1 76 3210 1518 (aq. EtOH) llgf Ph Et H H 94 118.5-1 19 3350, 1515 (aq. EtOH) 3155 llh Ph Et Me H 99 129.5-1 30 3160 1522 (Et0H-C6H14)1li p-Tolyl Me Me H 94 141.5-142.5 3200 1512 (aq. EtOH) Ilje p-Tolyl Me Me Me 92 182-1 84 3140 1492 (C6H6-C6H14)Ilk p-Tolyl Me Ph H 98 2 1 3.5-2 14.5 3360, 1510 (C6H6-C6H14) 3240 111 Ph Ph Me H 81 164.5-165.5 3160 1510 (aq. EtOH) " All the compounds gave satisfactory micronalyses. 'Solvent for recrystallization in parentheses. 6,(CD3COCD3) 10.29 (1 H, br s, NH), 7.4 ( 5 H, m, Ph), 5.99 (2 H, br s, NH,) and 1.94 (3 H, s, Me). ~H(CD~COCD~)10.24 (1 H, br s, NH), 7.4 (5 H, m, Ph), 6.02 (2 H, br s, NH,), 2.48 and 2.37 (each 1 H, each d, q, each J 13 and 7 Hz, CH,Me) and 0.84 (3 H, t, J 7 Hz, CH2Me).~H(CD~COCD~) 10.68 (1 H, br s, NH), 7.40 (10 H, m, Ph x 2) and 6.13 (2 H, br s, NH,). G,(CD,SOCD,) 11.57 (1 H, br s, NH), 7.20 (4 H, s, C6H4), 6.02 (2 H, br s, NH,), 2.28 (3 H, s, C6H4Me) and 1.78 (3 H, s, Me); G,(CD,SOCD,) 197.3, 177.5, 137.6, 136.3, 129.0, 125.4, 73.4, 26.0 and 20.4. 86H(CD3COCD,) 10.26 (1 H, br s, NH), 8.07 (2 H, br s, NH,), 7.0 (9 H, S, c6H4 + PhNH), 2.32 (3 H, S, C6H4Me) and 2.01 (3 H,s, Me). Table 3.5,5-Disubstituted 3-amino-2-(benzoylmethylthio)-3,5-dihydro-4H-imidazole-4-thiones13and imidazo2,1-b 1,3,4thiadiazines 14. ~ 13a Ph Me H 100 156.61 57.5 3310, 1683 1610 (aq. EtOH) 325 1 13b' Ph Ph H 88 15 1.5-1 52 3280, 1677 1587 (aq.EtOH) 3250 13C Ph Ph Br 97 168.5-1 69.5 3300, 1680 1623 (CH2C12-C6H12) 3200 13d pTolyl Me H 99 153-154 33 15, 1685 1610 (CH2C1246Hl 2) 3250 1 P-Tolyl Me Br 100 164.5-1 65.5 3300, 1682 1583 (CH2C12-C6H12) 3200 13f 2-Naphthyl Me H 93 160.5- 16 1.5 3300, 1685 1618 (aq. EtOH) 3180 13s 2-Naphthyl Me Br 100 132-1 34 3300, 1688 1588 (aq. EtOH) 3200 14a Ph Me H 94 149 1600 (aq. EtOH) 14bd Ph Ph H 93 180.5-1 8 1.5 1599 (aq. EtOH) 14C P-Tolyl Me H 96 16U-160.5 1591 (CH2C12-C6H12)14d 2-Naphthyl Me H 100 213-215 1595 (C6H6) 14e 2-Naphthyl Me Br 49 1 32- 1 34 1595 (EtOH-C,H 12) All the compounds gave satisfactory microanalyses. 'Solvent for recrystallization in parentheses. GH(CD3COCD,) 7.5 (15 H, m, Ph x 3), 5.46 (2 H, s, NH,) and 4.92 (2 H, s, CH,).G,(CD,COCD,) 7.5 (15 H, m, Ph x 3) and 4.46 (2 H, s, CH,). J. CHEM. SOC. PERKIN TRANS. 1 1990 with diethyl ether and treated under reduced pressure to remove any remaining ether. Acidification (pH 4) with ~M-HC~ gave a yellow solid, which was collected, washed with water, dried and recrystallized to give the corresponding pyrrole-3-(2H)-thione 16. 4-Cyano-2,5-dimethyl-2-phenylpyrrole-3(2H)-thione16a.* Yield 68, m.p. 203 "C (from acetone-water); v,,,(KBr) 3220, 3009 8.8; S, 10.8. CI~H~~N~S requires C, 75.0; H, 5.3; N, 9.2; S, 10.5). 4-Cyano-2-methyl-2,5-di-(p-tolyl)pyrrole-3(2H)-thione 16c.$: Yield 58; m.p. 236-239 "C (from acetone-water); vmax(KBr) 3200,2220,1610,1550,1500,1467,1328,1320,1306,1280,1252, 1187, 1157, 1104, 1073 and 1012 cm-'; Gc(CD,SOCD3) 11.65 (1 H, br s, NH), 8.00 and 7.54 (each 2 H, each d, J 8.5 Hz, 5-2210,1600,1550,1500,1480,1450,1432,1370,1354,1317,1260,C6H4), 7.21 and 7.17 (each 2 H, each d, J 8 Hz, 2-C6H4), 2.45 1159, 1082 and 1030 cm-'; h,,,(EtOH) 264 (3.90) and 370 nm (3 H, S, 5-Camp;Me), 2.28 (3 H, S, 2-C,H,Me), 1.84 (3 H, S, 2-Me); (4.31); GH(CD3COCD3) 10.30 (1 H, br s, NH), 7.34 (5 H, m, Ph), GC(CD3SOCD3) 223.3, 171.8, 144.7, 137.3, 135.9, 129.9, 129.0, 2.59 (3 H, s, 5-Me) and 1.81 (3 H, s, 2-Me); Gc(CD3COCD3) 128.4, 125.5, 123.7, 116.7,98.4, 80.0,26.2,21.2 and 20.5 (Found: 223.7, 178.0, 177.9, 139.6, 129.2, 128.8, 126.5, 115.9, 103.0, 81.7, C, 75.2; H, 5.65; N, 8.5;S, 10.1.C20H18N2S requires C, 75.4; H, 26.9and15.1(Found:C,68.4;H,5.4;N,12.0;S,14.0.C,3Hl2N2S5.7; N, 8.8;S, 10.1).requires C, 68.4; H, 5.3; N, 12.3; S, 14.0). 4-Cyano-2-methyl-2-phenyl-5-(p-tolyl)pyrrole-3(2H)-thione 16b.t Yield 38; m.p. 280-281 "C (from acetone-water); v,,,(KBr) 3200,2220,1610,1555,1502,1465,1432,1370,1354, 1317, 1305, 1255, 1212, 1186, 1155, 1076, 1055 and 1026 cm-'; h,,,(EtOH) 276 (4.44) and 398 nm (4.28); GH(CD,SOCD3) 1 1.70 (1 H, br s, NH), 8.00 and 7.54 (each 2 H, each d, J 8.5 Hz, C6H4), 7.35 (5 H, -s, Ph), 2.46 (3 H, s, C6H4Me), 1.84 (3 H, s, 2-Me); G,-(CD3SOCD3) 223.1, 172.0, 144.7, 138.7, 129.9, 128.5, 125.6, 123.7, 116.6,98.5,80.2,26.2 and 21.2 (Found: C, 74.9; H, 5.4; N, * Systematic name: 4,5-dihydro-2,5-dimethyl-5-phenyl-4-thioxopyr-role-3-carbonit rile. t Systematic name: 4,S-dihydro-5-methyl-5-phenyl-2-(p-tolyl)pyrrole-3-carboni trile. 1Systematic name: 4,5-dihydro-5-methyl-2,5-di-(p-tolyl)pyrrole-3-carbonit rile. References 1 T.Yamamoto, M. Muraoka and T. Takeshima, J. Chem. Res. (S), 1979, 384; J. Chem. Res. (S), 1980, 148; (M),1980, 2059; T. Yamamoto and M. Muraoka, J. Chem. Res. (S), 1982, 274; (M),1982,2816;T.Yamamoto and M. Muraoka, J. Chem. Res. (S), 1984, 266;M. Muraoka and T. Yamamoto, J. Heterocycl. Chem., 1984,21, 1445; M. Muraoka, A. Yamada, T. Yamamoto, J. Heterocycl. Chem., p. 953;T. Yamamoto and M. Muraoka, J. Heterocycl. Chem., 1988, 25,835. 2 T. Yamamoto, M. Itoh, N. U. Saitoh and M. Muraoka, J. Chem. Soc., Perkin Trans. I, in the press (0/0067J/PlP). 3 P. Molina, A. Arques and A. Ferao, Synthesis, 1982,645. Paper O/O1297A Received 26th March 1990 Accepted 3rd July 1990