4 + 2Cycloaddition of monocyclic imidazole derivatives with electron-deficient acetylenes

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1990 3085 4 + 2lCycloaddition of Monocyclic lmidazole Derivatives with Electron- deficient Acetylenes Chiji Yamazaki," Kikumi Katayama and Kieko Suzuki Department of Chemistry, School of Hygienic Sciences, Kitasato University, Kitasato, Sagamihara, Kanagawa 228, Japan 1 -Alkylidene- and 1-arylmethylene-amino-4-aryl-2-mercapto-lH-imidazole derivatives 2-1 1 react with dimethyl acetylenedicarboxylate (DMAD) in hot chlorobenzene to give the corresponding retro- Diels-Alder products 1 -alkylidene- and 1-arylmethylene-amino-2-mercapto-lH-pyrrole-3,4-dicarboxylate derivatives 19-26 and benzonitriles 27 in high yield. No intermediate Diels-Alder adducts could be isolated from these substrates. 1 -Amino-2-methylthio-4-phenyl-l H-imidazole 1 gives dimethyl 1-I,2-bis(methoxycarbonyl)vinylamino -2-methylthio-4-phenyl-1H-lr3-diazepine-5,6 -dicarboxylate 28 in addition to dimet hyl 1-amino-2-methylt hio- 1H-pyrrole- 3,4-dicar boxylate 18, with the ratio 18:28 ranging from 2:l to 3:l under the same reaction conditions.At lower temperature, however, the former cycloadduct is obtained as the sole product in acetonitrile. No cycloaddition to these imidazole derivatives is observed with ethyl propiolate or with bis(trimethylsilyl)acetylene even under forced conditions. Any changes in the substituents or their positions on the imidazoles 2-11 that otherwise successfully give rise to the cycloaddition decidedly inhibited the reaction. Among a number of di-and tri-substituted imidazole derivatives employed as substrates, only a limited number bearing an amino or alkylidene- or arylmethylene- amino, a substituted mercapto, and an aryl group at the I-, 2-and 4-position, respectively, can produce the corresponding pyrroledicarboxylates through the retro- Diels-Alder reaction.In the course of our studies on the cyclization of amino-imidazoles to obtain new ring systems, it was found that 1- amino-2-methylthio-4-phenyl-1H-imidazole 1gave a 1:2 cyclo- adduct, dimethyl 1-1,2-bis(methoxycarbonyl)vinylarnino1-2-methylthio-4-phenyl-1H-1,3-diazepine-5,6-dicarboxylate28 and a retro-Diels-Alder product 18 rather than the expected imidazopyridazine derivative upon treatment with DMAD. 4 + 2lCycloaddition of monocyclic imidazole derivatives t has not been investigated as extensively as in the case of their oxygen analogues, oxazoles.2 As in furan, the strongly electronegative oxygen in the oxazole ring may poorly contribute to the aromaticity of the five-membered ring so that the remaining two double bonds might behave as a 1,3-diene system.Although a few reports3 concerning treatment of an imidazole derivative with a dienophile have been published, none of these papers describe 1,4-~ycloaddition across the imidazole ring. Thus we now report the 4 + 2)cycloaddition of certain imidazole derivatives and the effect of the substitution pattern and the nature of the substitutents on the substrate on the cycloaddition across the imidazole ring. Results and Discussion The cycloaddition reaction of 1-amino-2-methylthio-4-phenyl-1 H-imidazole 1was performed by heating the imidazole 1and a slight excess of DMAD in acetonitrile at 80deg;C (Scheme 1).Chromatographic separation gave a 1:2 cycloadduct 28 and no 1:1 adduct 30 or 31 was found in the reaction mixture, regardless of the ratio of aminoimidazole 1 to DMAD em- ployed. The maximum yield (45) of cycloadduct 28 was obtained when the molar ratio of DMAD to imidazole was 2: 1. On the other hand, when the aminoimidazole was heated with a slight excess of DMAD at a higher temperature (145-150 "C)in chlorobenzene, a retro-Diels-Alder product dimethyl 1-amino- 2-methylthio- 1 H-pyrrole-3,4-dicarboxylate18 was produced in addition to the diazepine 28, with the ratio 18:28 ranging from Compd.R' RZ R3 R4 1 NHZ SMe Ph H 2 MeCH=N SMe Ph H 3 PhCH=N SMe Ph H 4 PhCH=N SMe 4-MeOC6H4 H 5 PhCH=N SMe 4-OzNC6H4 H 6 4-MeOC6H4CH=N SMe Ph H 7 4-MeOC6H4CH=N SCH,CH=CH, Ph H 8 4-MeOC6H4CH=N SCH,Ph Ph H 9 2,6-C1,C6H ,CH=N SMe Ph H 10 PhCH=N SCD, Ph H 11 Ph(Me)C=N SMe Ph H 12 PhCH=N SMe H Ph 13 4-MeOC6H4CH=N SMe Me H 14 AcNH SMe Ph H 15 PhCH=N NHZ Ph H 16 PhCH=N NHAc Ph H 17 Ac H Ph H 2: 1 to 3: 1. A probable Michael adduct 29 could not be detected in the reaction mixture. The first step of this reaction at higher temperature may thus be 1,4-cycloaddition to form an inter- mediate 1 :1 cycloadduct 30 rather than nucleophilic addition of the amino group to the triple bond of DMAD to form an enamine 31.The cycloadduct 30 should then rapidly lose a nitrile 27 to produce the pyrrole product 18. At lower t The 1,4-cycloaddition of DMAD across a condensed imidazole ring was suggested by Abe et al.,' in their work on imidazo2,1-bthiazole systems. Compd. R5 R6 18 NH, SMe 19 MeCH=N SMe 20 PhCH=N SMe 21 PhCH=N SCD, 22 4-MeOC,H,CH=N SMe 23 4-MeOC,H4CH=N SCH,CH=CH ,24 4-MeOC6H4CH=N SCH,Ph 25 2,6-CI,C,H,CH=N SMe 26 Ph(Me)GN SMe 27 R3CN Ph. .. SMe N'k"NNH, + DMAD MeS4' Ph NHC=CHE I (11 E (28) (18) + (28) Scheme 1. Conditions: i, 80deg;C, MeCN, ii, 145-15OoC, PhCl. E = C0,Me. E SMe E temperatures, however, 2 + 2lcycloaddition to the 4,5-bond of the imidazole 1 followed by ring expansion as reported by Troxler et aLJbwith nucleophilic addition of the amino group can predominate to form 1,3-diazepine-5,6-dicarboxylate28 probably due to kinetic control.2 + 2)Cycloaddition involving the 2,3-bond is unlikely to occur because compound 28 exhibits the NMR signal for the phenyl group as a singlet (6, 7.39), suggesting vicinal s~bstitution.~Compound 28 was highly stable thermally and remained intact after exposure of its solution in chlorobenzene to temperatures of 145-150 "C (bath temperature) for 4 h. To assist structural elucidation, reduction of compound 28 with zinc dust in acetic acid or catalytic hydrogenation was attempted; however, these gave a complex mixture and no information on the structure.1-Alkylideneamino-and 1-arylmethyleneamino-imidazole *The resonance of C-2 of this compound could unambiguously be assigned by its exceptionallyweak intensity. J. CHEM. SOC. PERKIN TRANS. 1 1990 derivatives 2-1 1 successfully gave the corresponding pyrrole-dicarboxylates 19-26 upon treating with DMAD in chloro-benzene at 145-1 50 "C (Scheme 2). N'x NR1 + DMAD i E26NR5 + R3CN E--R3 'wl (1) -(11) Scheme 2. Conditions: i, 145-150 OC, PhCl. The driving force of the conversion of an imidazole into a pyrrole derivative through the retro-Diels-Alder reaction might be the formation of two aromatic molecules, a pyrrole derivative stabilized by the dicarboxylate structure and an aromatic nitrile.Comparison of imidazoles 3 and 6 with the 5-phenyl isomer 12 and the 4-methyl analogue 13, respectively, which are unreactive to cycloaddition with DMAD, leads to the con-clusion that conjugation is an essential factor between the substituent at the 4-position and N(3) in the imidazole ring for the present 4 + 2)cycloaddition. As expected, introduction of an electron-withdrawing group into the substituent R3on the imidazole 3 significantly retarded the rate of reaction and lowered the yield of the corresponding pyrrole 20. Similarly, acetylation of aminoimidazole 1 to form compound 14 resulted in complete inhibition of the reactivity of the aminoimidazoleas a diene. Use of an electron-rich alkyne, such as bis(trimethy1-sily1)acetylene or methyl propiolate, in place of DMAD resulted in the total recovery of the imidazole 3.These observations suggest that the reactions of 1,2,4-trisubstitutedimidazoles 1-1 1 with DMAD may be LUMO (dienophi1e)-HOMO (diene) controlled. A further structural requirement that makes it possible to bring about the 1,Ccycloaddition of imidazoles with DMAD may be the presence of a sulphur atom bonded to the 2-position. None of imidazoles 15, 16 and 17, which lack a sulphur-containing group at the 2-position, gave the corresponding pyrrole derivatives; instead, reaction resulted in either a highly darkened mixture containing unchanged starting imidazole 16 or formation of tar 15 and 17-J.It seems that the effect of the sulphur atom on the pyrrole formation through 1,4-cycloaddi-tion with DMAD may be steric rather than electronic.The bulky sulphur atom should serve to push out the nitrile 27 from the highly crowded transition state, thereby leaving the corresponding pyrroledicarboxylate. The resonances of the four ring carbons in the l-amino-pyrrole 18 appeared at 6, 111.77 as a doublet ('JCH 5.4 Hz), 221.21 as a doublet (3JCH 6.1 Hz), 6c 126.97 as a multiplet, and 6, 128.29 as a doublet ('JCH 194.6 Hz) and could easily be assigned to C-4, C-3, C-2 and C-5, respectively. Because tri-deuteriomethylthio compound 21 showed the C-2 resonance* (6, 127.24) as a doublet with 3JcH6.6 Hz, the three-bond coupling along the pyrrole ring in the pyrroledicarboxylates might generally have a coupling constant -6 Hz.The assign-ment of the resonancesfor C-3 and C-4 of the pyrrole ring could thus be made on the basis of the magnitude of their coupling constant with the proton at the 5-position. The resonances of the four ring carbons of other pyrroles 19-26 ranged from 6, 113.28-114.79 for C-4, 117.82-123.10 for C-5, iSC 121.28-123.43for C-3 and 6c 124.07-128.72 for C-2, with large coupling constants (lJCH 192-194 Hz) being observed for the C-5 doublets. An attempt to convert compound 20 into the known dimethyl pyrrole-3,4-dicarboxylate 34 ' by reductive cleavage gave instead dimethyl 2-methylthio-lH-pyrrole-3,4-dicarboxylate32 and N-benzylacetamide 33 (Scheme 3). J. CHEM. SOC. PERKIN TRANS.1 1990 SMe SMe I I -~-amp;N-N=CHPh i EcNH + AcNHCH2Ph ED" Scheme 3. Reagents: i, Zn, AcOH, Ac,O. Experimental Microanalyses were performed with a Perkin-Elmer 240D elemental analyser at the Microanalytical Laboratory of Kitasato University. IR, UV and mass spectra were recorded on Perkin-Elmer 983, JASCO UVIDEC 610 and JMS-DX100 instruments, respectively. 'H and I3C NMR spectra were obtained with a JNM-FX90Q spectrometer operating at 89.55 and 22.50 MHz, respectively. Preparative high-pressure liquid chromatography (HPLC) was carried out on a Kusano Kagaku KHLC-201 instrument with a 300 x 22 or a 300 x 15 mm glass column packed with silica gel. Di-and Tri-substituted Imidazoles.-Most of the imidazoles employed are known compounds and were prepared according to the literature method.6 New compounds are as follows: Compound 11 (20), pale yellow prisms, m.p.105-106deg;C from benzene-hexane (1 :4) (Found: C, 70.15; H, 5.6; N, 13.6. C18H17N3Srequires C, 70.3; H, 5.6; N, 13.7); 6, 2.33 (3 H, s, CMe), 2.60 (3 H, s, SMe), 7.24 (1 H, s, 5-H), 7.40 (6 H, m, ArH) and 7.82 (4 H, m, ArH); m/z 307 (M+, 67), 189 (46) and 118 (100). Compounds 2 and 9 were obtained by an alternative procedure as follows. Preparation of 1-Ethylideneamino-2-methylthio-4-phenyl-1H-imidazole 2.-A mixture of l-amino-2-methylthio-4-phenyl-1H-imidazole 1 (1.0 g, 4.9 mmol), 90 acetaldehyde (10 ml, 0.18 mol) and ethanol (5 ml) was heated at 50 "C for 3 h and evapor-ated. The residual oil was subjected to column chromatography on silica gel (Wakogel C-300,50 g) with benzene*thano1(98:2 v/v) as eluant.Fractions containing the desired imidazole were collected and evaporated to give the imidazole as an oil (0.67 g, 59) which gradually crystallized upon storage. Recrystal-lization from hexane gave the title compound 2 as needles, m.p. 77-78 "C (Found: C, 62.4; H, 5.6; N, 18.1. C12H13N3Srequires C, 62.3; H, 5.7; N, 18.2); GH(cDCl3)2.18 (3 H, d, J 5.4 Hz, =CHMe), 2.71 (3 H, s, SMe), 7.33 (3 H, m, ArH), 7.53 (1 H, s, 5-H), 7.76 (2 H, m, ArH) and 7.78 (1 H, q, J 5.4 Hz, =CHMe); m/z 231 (M', 100) and 189 (71). 1-(2,6-Dichlorobenzylideneamino)-2-methylthio-4-phenyl-1H-imidazole 9.-This was prepared when a mixture of 2,6-dichlorobenzaldehyde (0.4 g, 2.3 mmol), 1-amino-2-methylthio-4-phenyl-lH-imidazole (0.4g, 2.0 mmol), acetic acid (0.1 ml) and benzene-thanol (1 :1 v/v, 10 ml) was heated under reflux for 24 h.The desired imidazole (9) crystallized out of the hot reaction mixture as analytically pure, fluorescent yellow prisms (0.53 g, 71), m.p. 172-173 "C (Found: C, 56.4; H, 3.6; N, 11.5. Cl7Hl3C1,N3Srequires C, 56.4; H, 3.6; N, 11.6); GH(CDC13) 2.71 (3 H, s, SMe), 7.35 (6 H, m, C12C6H3and ArH), 7.74 (1 H, s, 5-H), 7.83 (2 H, m, ArH) and 8.51 (1 H, s, N=CH); m/z 363 (M' + 2,27), 361 (M+, 37), 253 (29) and 189 (100). Imidazoles 14 and 16 were obtained by acetylation of the corresponding aminoimidazoles 1 and 15,7 respectively. 3087 Compound 14 (55) was obtained as fibre-like crystals, m.p.157-159 "C (from benzene) (Found: C, 58.4; H, 5.3; N, 17.15. C12H13N30Srequires C, 58.3; H, 5.3; N, 17.0); v,,,(KBr) 3176 (NH) and 1712 cm-' (C=O); 6~(cD,),So 2.10 (3 H, S, COMe),2.64(3 H,s,SMe),7.26(1 H,s,5-H),7.29(3 H,m, ArH), 7.76 (2 H, m, ArH) and 8.47 (1 H, br s, NH); m/z 247 (M+,100) and 189 (22). Compound 16 (75) was obtained as yellow needles, m.p. 167-169deg;C (from benzene) (Found: C, 71.1; H, 5.4; N, 18.2. C18H16N40requires C, 71.0; H, 5.3; N, 18.4);v,,,(KBr) 3391 (NH) and 1704 cm-' (C=O); 6,(CDC13) 2.61 (3 H, s, Me), 7.55 (7 H, m, ArH and 5-H), 7.84 (4 H, m, ArH), 8.20 (1 H, br s, NH) and 8.26 (1 H, s, NXH); m/z 304 (M', 91), 262 (32) and 158 (100). Deuteriation of the Aminoimidazole 1.-A solution of the imidazole 1(1.0g) in MeOD (5 ml) was boiled under argon with protection from atmospheric moisture for 1 h and was then evaporated.The residue was again subjected to this procedure to achieve ca. 100 deuteriation. The product 1-(N,N-dideuter-ioamino)-2-methylthio-4-phenyl-1H-imidazole (1; R' = ND,) thus obtained was immediately used for the preparation of the monodeuteriated derivative of compound 28. The Reaction of Imidazoles with DMAD.-Formation of dimethyl 1-benzylideneamino-2-methylthiopyrrole-3,4-dicar-boxylate 20 (generalprocedurefor conversion of imidazoles into pyrroledicarboxylates through retro-Diels-Alder reaction). A mixture of l-benzylideneamino-2-methylthio-4-phenyl-1H-imidazole 3 (0.29 g, 1 mmol), DMAD (0.17 g, 1.2 mmol) and chlorobenzene (5 ml) was heated at 140-145deg;C (bath temperature) for 6 h.An additional amount of DMAD (0.04 g, total amount 1.5 mmol) was added and the mixture was heated for a further period of 4 h. After evaporation of the solvent under reduced pressure, the residue was subjected to preparative HPLC on silica gel with chloroform4ichloromethane (2: 1 v/v) as eluant. Further chromatographic purification of the impure compound thus obtained on silica gel with dichloromethane-hexane (1 :1 v/v) gave the desired product 20 (0.29 g, 87) as needles, m.p. 105 "C from benzene-hexane (9: 1 v/v)J (Found: C, 57.8; H, 4.7; N, 8.3. CI6Hl6N,O4S requires C, 57.8; H, 4.85; N, 8.4); h,,,(EtOH) 215,260 and 309 nm (E 23 080,19 200 and 21 700 dm3 mol-I cm-'); v,,,(CCl,) 1732 cm-' (C=O); 6,(CDC13) 2.44 (3 H, s, SMe), 3.83 (3 H, s, OMe), 3.93 (3 H, s, OMe), 7.54 (3 H, m, ArH), 7.74 (1 H, s, 5-H), 7.87 (2 H, m, ArH) and 8.50 (1 H, S, NSH); Gc(CDC13) 19.60 (4, lJCH141.3 Hz, SMe), 51.49 (9, 'JCH146.8 Hz, OMe), 52.08 (9, 'JCH146.8 Hz, OMe), 114.33(d, 2JcH5.0 Hz, C-4), 118.47(d, 'JCH193.0Hz, C-5), 122.00 (d, 3JcH6.6 Hz, C-3), 127.36 (m, C-2), 128.70, 129.07, 132.14 and 132.60 (Ph), 155.49 (dt, 'JCH161.6, 3Jc~4.9 Hz, NXH), 163.11 (dq, 3J~~ 1.6 Hz, 3-C02) and 165.043.8, 4J~~ (dq, 3JcH3.8 and 1.6 Hz, 4-C0,); m/z 332 (M', 9473, 301 (32), (196 (58) and 118 (100).This compound was also obtained by similar treatment of imidazoles 4 and 5 with DMAD in 75 and 47 yield, respectively.Trideuterio analogue 21 was similarly prepared from the corresponding imidazole 10 which, in turn, was obtained from S-(trideuteriomethy1)isothiosemicarbazone * according to the literature method.6 The following new pyrroles were similarly obtained. Compound 19 (68), prisms, m.p. 1 16-1 17 "C from hexane-benzene (9: 1)J (Found: C, 48.8; H, 5.2; N, 10.3. C11H14N204S requires C, 48.9; H, 5.2; N, 10.4);h,,,(EtOH) 208 and 246 nm (E 20 300 and 16 400 dm3 mol-' cm-'); v,,,(CC14) 1732 cm-' (Ca); G~(cDc13)2.24 (3 H, d, J 5.4 Hz, CHMe), 2.37 (3 H, s, SMe), 3.79 (3 H, s, OMe), 3.90 (3 H, s, OMe), 7.53 (1 H, s, 5-H) and 8.01 (1 H, q, J 5.4 Hz, CHMe); GC(CDC13)18.94 (dq, 'JCH 129.2, 'JCH9 Hz, CHMe), 19.67 (9, 'JCH140.8 Hz, SMe), 51.51 (9, 'JCH 146.8 Hz, OMe), 52.15 (9, 'JcH147.3 Hz, OMe), 113.55 (d, 'JcH 4.9 Hz, C-4), 118.99 (d, 'JCH192.4 Hz, C-5), 121.60 (d, 3JCH 6.0 Hz, C-3), 125.89 (m, C-2), 159.03 (dq, 'JCH 161.1, 'JCH 7.7 HZ, CHMe), 163.11 (dq, 3JCH 3.8, 4JCH 1.6 HZ, 3-C02Me), and 165.13 (dq, 3JcH3.8 and 1.6 Hz, 4-C02Me); m/z 270 (M', loo), 239 (33), 223 (39) and 196 (37).Compound 22 (81), light yellow needles, m.p. 98 "C from benzene-hexane (1: l) (Found: C, 56.4; H, 5.1; N, 7.8. C17H18N205S requires C, 56.35; H, 5.0 N, 7.7); h,,,(EtOH) 205,227,276sh and 323 nm (E 18 800,19 400,14 000 and 26 200 dm3 mol-' cm-'); vma,(CC14) 1 733 cm-' (M);G~(cDc13)2.43 (3 H,s,SMe),3.82(3 H,s,OMe),3.88(3 H,s,OMe),3.92(3 H,s, OMe), 6.98 (2 H, d, J8.8 Hz, ArH), 7.69 (1 H, s, 5-H), 7.80 (2 H, d, J 8.8 Hz, ArH) and 8.42 (1 H, s, NSH); Gc(CDC13) 19.52 (q, 'JCH 140.8 Hz, SMe), 51.42 (9, 'JCH146.8 Hz, OMe), 52.00 (q, 'JCH 146.8 Hz, OMe), 55.52 (9, 'JCH144.6 Hz, OMe), 114.04 (d, 3JcH 4.9 Hz, c-4), 114.77, 125.28, 130.55 and 163.21 (aryl), 118.87 (d, 'JCH192.4 HZ, C-5), 121.82 (d, 3J~~6.0 Hz, C-3), 126.90 (9, 3Jc~ 4.9 HZ, 7.1 HZ, C-2), 155.93 (dt, 'JCH160.5, 3Jc~ NSH), 163.21 (dq, 3JcH3.8, 4JcH1.6 Hz, 3-C02Me), and 165.11 (dq, 3JcH3.8 and 1.6 Hz, 4-C02Me); m/z 362 (M', loo), 331 (14), 196 (18) and 148 (48).Compound 23 (87), light yellow needles, m.p. 96 "C from benzene-hexane (1: l) (Found: C, 58.7; H, 5.2; N, 7.2. C19HZON205Srequires C, 58.8; H, 5.2; N, 7.2); h,,,(EtOH) 202,225,276sh and 323 nm (E 28 OOO, 27 500,19 300 and 31 500 dm3 mol-' cm-'); v,,,(CC14) 1732 cm-' (M);GH(CDCI3) 3.49 (2 H, d, J7.1 Hz, SCH,), 3.82 (3 H, s, OMe), 3.88 (3 H, s, OMe), J.CHEM. SOC. PERKIN TRANS. I 1990 (E 25600, 27200, 16000 and 12800 dm3 mol-' cm-'); V,,,(CCI4) 1734 cm-' (C--O);amp;(CDCl3) 2.44 (3 H, S, SMe), 3.84 (3 H, s, OMe), 3.93 (3 H, s, OMe), 7.40 (3 H, m, ArH), 7.81 (1 H, S, 5-H) and 8.81 (1 H, S, N=CH); Gc(CDC13) 19.77 (9, 'JCH141.3 Hz, SMe), 51.71 (4, 'JCH 146.8 Hz, OMe), 52.29 (9, 'JcH146.8 Hz, OMe), 114.79 (d, ,J,-H 4.4 Hz, C-4), 117.82 (d, 'JCH 193.5 Hz, C-5), 122.43 (d, 3J~~6.0 Hz, C-3), 128.72 (m, C-2), 127.87,129.21, 131.65 and 135.60 (aryl), 150.29 (d, 'JCH168.2, N=CH), 162.98 (dq, 3JC.j 3.8, 4JCH 1.1 HZ, 3-C02Me) and 164.93 (dq, 3JCH 3.8 and 1.1 Hz, 4-C02Me); m/z 402 (M' + 2,61), 400 (M', loo), 365 (49,333 (86) and 166 (34).Compound 26 (75), light yellow plates, m.p. 132-134 "C from benzene-hexane (1 :9) (Found: C, 59.0 H, 5.2; N, 8.0. C17H18N204S requires C, 58.95; H, 5.2; N, 8.1); hmax(EtOH) 212 and 252 nm (E 25200 and 23500 dm3 mol-' cm-'); VmaX(CCI4) G~(cDc13)1730 cm-' (M); 2.24 (3 H, S, CMe), 2.30 (3 H, s, SMe), 3.80 (3 H, s, OMe), 3.92 (3 H, s, OMe), 7.25 (1 H, s, 5-H), 7.52 (3 H, m, Ph) and 7.95 (2 H, m, Ph); Gc(CDC13) 16.94 (q, 'JCH 129.8 Hz, CMe), 19.42 (4, 'JCH 141.3 Hz, SMe), 51.47 (9, 'JcH146.3 Hz, OMe), 52.17 (9,'JcH146.8 Hz, OMe), 113.28 (d, ,JcH 5.5 Hz, C-4), 121.28 (d, 3Jc~ 6.0 Hz, C-3), 123.10 (d, 'JCH 194.1 Hz, C-5), 124.07 (m, C-2), 127.58, 128.79, 132.07 and 135.65 (Ph), 163.30(dq, 3J~~ 1.1 HZ, 3-C02Me), 165.32 3.8, 4Jc~ (dq, 3JCH 3.8 and 1.0 Hz, 4-C02Me) and 176.41 (m, N=CMe); m/z 346 (M', 3779, 196 (lo), 132(24), 118 (100) and 77 (79).Reaction of l-Amino-2-methylthio-4-phenyl-1 H-imidazole 1 with DMAD. Formation of (1:2) CycZoadduct 28.-l-Amino-2- 3.92 (3 H, s, OMe), 4.86 and 5.01 (each 1 H, m, together =CH,), methylthio-4-phenyl- 1H-imidazole 1 (0.5 g, 2.44 mmol) was 5.6@-5.98(1 H,m,CH2CH=),7.02(2H,d,J8.8Hz,ArH),7.68(1dissolved in hot acetonitrile (5 ml). To the solution was added H, s, 5-H), 7.85 (2 H, d, J8.8 Hz, ArH) and 8.42 (1 H, s, N=CH); Gc(CDCl3) 39.39 (t,* 'JCH 142.9 Hz, SCH,), 51.54 (t, 'JcH146.8 Hz,OMe), 52.13 (t, 'JCH 146.8 Hz, OMe), 55.49 (t, 'JCH 144.6 Hz, OMe), 113.64 (d, ,JCH4.9 Hz, C-4), 117.77 (t,* 'JCH 156.3 Hz, =CH2), 1 18.77 (d, 'JCH 192.4 Hz, C-5), 123.21 (d, 3JcH 6.0 Hz, C-3), 124.58 (m, c-2), 133.60 (d,*'JcH 154.5 Hz, CH,CH=), 114.62, 125.07, 130.50 and 163.15 (aryl), 155.71 (dt, 'JCH160.0, 3JCH 4.9 HZ, N=CH), 163.01 (dq, 3J~~4.0, 4Ja 1.6 HZ, 3- CO,Me), and 165.1 1 (dq, 3JcH4.4 and 1.6 Hz, 4-C0,Me); m/z 388 (M', 16), 356 (23), 214 (19), 174 (100) and 134 (39).Compound24 (8673, needles, m.p. 109-1 10 "C from benzene- hexane (1:9) (Found: C, 62.8; H, 5.0; N, 6.4. C23H22N205S requires C, 63.0; H, 5.1; N, 6.4); h,,,(EtOH) 204,223,275 and 320 nm (E 27 800,27 200, 16 400 and 23 800 dm3 mol-' cm-I); v,,,(cc1~) 1730 cm-' (Ca); amp;(CDC13) 3.80 (3 H, S, OMe), 3.87 (6 H, s, 2 x OMe),4.00 (2 H, s, SCH2), 6.96 (2 H,d,J8.9 Hz,~-M~OC~H~),7.08 (5 H, S, Ph), 7.56 (1 H, S, 5-H), 7.67 (2 H, d, J 8.9 Hz, p-MeOC,H4), and 8.08 (1 H, s, N=CH); Gc(CDC13) 41.34 (t, 'JCH 142.9 Hz, SCH,), 51.54 (9, 'JCH 146.8 Hz, OMe), 52.15 (q, 'JCH146.8 Hz, OMe), 55.49 (4, 'JCH144.0 Hz, OMe), 113.62 (d, 2JcH4.9 Hz, C-4), 119.06 (d, 'JCH192.4 Hz, C-5), 123.43 (d, 3J~~5.5 HZ C-3), 124.28 (m, C-2), 114.47, 125.01, 130.55, and 162.94 (MeOC,H,), 127.09, 128.23, 128.94 and 137.49 (Ph), 156.08 (dt, 'JCH160.5, 3JcH 4.4 Hz, N=CH), 162.94 (dq, 3JcH4.2, 4JcH1.1 Hz, 3-C0,Me) and 165.13 (dq, 3JcH 3.8 and 1.1 Hz, 4-C02Me); m/z 438 (M', 4), 224 (95) and 91 (100).Compound 25 (9579, prisms, m.p. 124-125 "C (from benzene) (Found: C, 47.9; H, 3.5; N, 7.0.Cl6H14C12N2o4S requires c, 47.9; H, 3.5; N, 7.0); h,,,(EtOH) 205, 218, 259 and 289 nm * Each component splits into a multiplet. t Irradiation of the NH signal (at irradiation frequency 54.8802 kHz) changed the doublet into a sharp singlet. $ This compound showed the NH band (3235 cm-') rather than the expected ND band due to hydrogen exchange during work-up. Its C-D stretching band appeared at 2309 cm-'. DMAD (0.69 g, 4.88 mmol) and the mixture was heated under reflux for 4 h. The solvent was removed under reduced pressure and the residual oil was subjected to column chromatography on silica gel (Wakogel C-300,70 g)with benzene+thanol(98:2) as eluant. An oil (0.53 g) from the cycloadduct-rich fractions was extracted several times with hot hexane and the crystals (0.38 g, 45) which separated out from the extracts were collected and recrystallized from benzene-hexane (1 :9) to give compound 28 as yellow needles, m.p.1131 14 "C (Found: C, 53.85; H, 4.6; N, 8.5. C22H23N308S requires C, 54.0; H, 4.7; N, 8.6); h,,,(EtOH) 205,228sh, 272 and 357 nm (E 29 200,21 OOO, 20 900 and 14 900 dm3 mol-' cm-'); vma,(CC14) 3236br (NH), 1742vs and 1698 cm-' (M);GH(CDC13) 2.50 (3 H, s, SMe), 3.22,3.80, 3.92 and 3.98 (each 3 H, OMe), 5.42 (1 H, s,=CHCO,Me), 6.79 (1 H, d,f JO.77 Hz, 7-H), 7.39 (5 H, s, Ph) and 11.28 (1 H, br s, NH); Gc(CDC13) 19.17 (4, 'Jm 142.4 Hz, SMe), 51.30 (4, 'JCH 146.2 Hz, OMe), 52.17 (9, 'JCH 147.9 Hz, OMe), 52.39 (9, 'JCH 147.3 Hz, OMe), 97.12 (dd, 'JCH 169.9, 3JcH 2.2 Hz, =CHC02Me), 105.78 (dd, 'JCH 185.8, 3JCH 2.2 Hz, c-7), 119.22 (s, HNC=), 127.87, 128.82, 129.31 and 135.56 (Ph), 136.04 (m, C-4), 138.09 (dq, 3Ja 4.9, 4Jc~1.6 Hz, C-2), 142.44 (s, C-6), 145.36 (S, c-5), 161.67 (9,3J~~3.8 HZ, 5-CO,Me), 162.84 (9, 3Jc~ 3.8 Hz, =CHCO,Me), 164.30 (dq, 3JcH 4.4 and 3.8 Hz, NHCC0,Me) and 167.89 (q, 3JcH3.8 Hz, 6-C02Me); m/z 489 (M', 36), 259 (47), 246 (loo), 227 (56), 118 (27) and 103 (37).Deuteriated analogues of the aminoimidazole 1 at the amino moiety or the 5-position were similarly treated with DMAD to give the corresponding deuteriated cycloadducts, which served to assist us in our assignment of the 'H and 13C NMR spectra of compound 28. The monodeuteriated compound $ on the ethylenic carbon of the fumarate moiety obtained from l-(N,N-dideuterio)amino-2-methylthio-4-phenyl-1 H-imidazole (1;R' = ND,) lacked the SH5.42 and 6c 97.12 resonances.On the other hand, the 7-deuteriocycloadduct was produced from the 5-deuteriated derivative of aminoimidazole (1; R4 = D) and showed no 8H6.79 or tic 105.78 resonances. It also showed a simple quartet for C-2 at 6, 138.09 (jJCH 4.9 Hz). J. CHEM. SOC. PERKIN TRANS. I 1990 Formation of Dimethyf 1 -Amino-2-methyfthio- 1 H-pyrrofe-3,4- dicarboxyfate 18.-When the above reaction was performed at 145-1 50 "C in chlorobenzene, starting with the 1-aminoimid- azole 1(0.21 g, 1 mmol) and DMAD (0.21 g, 1.5 mmol), followed by work-up according to the general procedure, the pyrrole 18 was prepared as a light yellow oil (0.13 g, 53); h,,,(EtOH) 212 and 259 nm (E 19 900 and 7 200 dm3 mol-' cm-'); v,,,(CCl,) 3354, 3295 and 3225 (NH,) and 1722 cm-' (M);GH(CDC13) 2.37 (3 H, s, SMe), 3.78 and 3.89 (each 3 H, s, OMe) and 7.41 (1 H, s, 5-H); Gc(CDC13) 20.23 (9, JcH141.3 Hz, SMe), 51.44 (q, 'JCH146.8 Hz, OMe), 52.13 (4, 'JCH147.3 Hz, OMe), 111.77 (d, ,JCH5.5 HZ, C-4), 121.21 (d, 3J~~6.0 Hz, C-3), 126.97 (m, C-2), 128.29 (d, 'JCH 3.8,194.6 HZ, C-5), 163.37 (dq, 3J~~ 1.1 HZ, 3-C02Me) and 165.32 (dq, 3JcH3.8 and 1.6 Hz,4-C02Me).This product 18 was identified by its reaction with anisaldehyde to convert it into the p-methoxybenzylidene derivative 22. In this reaction, cycloadduct 28 (0.08 g, 16) was also isolated from a fraction preceding that of the first pyrrole. Reductive Cleavage of Dimethyf 1-Benzyfideneamino-2-methylthio-lH-pyrrofe-3,4-dicarboxyfate 20.-A mixture of the pyrrole 20 (0.1 g), zinc dust (3.0 g), acetic acid (10 ml) and acetic anhydride (4 ml) was stirred at room temperature for 2 h, and then evaporated under reduced pressure.The residue was extracted with chloroform (10 ml) and the extract was washed with 5 aq. sodium carbonate. After evaporation of the solvent, the residue was subject to preparative HPLC on silica gel with chloroform as eluant to give a homogeneous fraction containing * Decoupling of the NH resonance at an irradiation frequency of 54.6818 kHz gave the 5-H signal as a singlet at BH 7.31. 3089 dimethyl 2-methylthio-lH-pyrrole-3,4-dicarboxylate 32.Recrystallization from benzene gave the pyrrole 32(46 mg, 67) as prisms, m.p. 91-92deg;C (Found C, 47.3; H, 4.85; N, 6.05. C9H1 ,NO$ requires C, 47.1 5; H, 4.8; N, 6.1); v,,,(CCl,) 3459 (free) and 3287br (bonded) (NH) and 1730 cm-' (M); GH(CDC1,) 2.43 (3 H, s, SMe), 3.80 (3 H, s, OMe), 3.89 (3 H, s, OMe), 7.3 1 (1 H, d, J 3.1 Hz, 5-H) and 9.04 (1 H, br, NH); * m/z 229 (M+, 4579,198 (52), 197 (100) and 166 (78). References 1 N. Ah, T. Nishiwaki and N. Komoto, Bull. Chem. SOC.Jpn., 1980,53, 3308. 2 R. Grigg, R. Hayes and J. L. Jackson, Chem. Commun., 1969,1167;R. Grigg and J. L. Jackson, J. Chem. SOC.C, 1970,552;S. R. Ohlsen and S. Turner, J. Chem. SOC.C, 1971, 1632; J. J. K. Novak, Collect. Czech. Chem. Commun., 1975,40, 2855; T. Jaworski and T. Mizerski, Rocz. Chem., 1976,50,359. 3 (a) T. Novinson, D. E. OBrien and R. K. Robins, J. Heteracycl. Chem., 1974,11,873;(b) F. Troxler, H. P. Weber, A. Jaunin and H. R. Loosli, Helv. Chim. Acra, 1974,57,750 (c) H. P. Weber, J. J. Petcher, A. Jaunin, and F. Troxler, Helu. Chim. Acta, 1975,58,552. 4 L. G. Tensmeyer and C. Ainsworth, J. Org. Chem., 1966,31,1878. 5 R. M. Acheson and J. M. Vernon, J. Chem.SOC.,1961,457. 6 C. Yamazaki, Bull. Chem. SOC.Jpn., 1978,51, 1846. 7 H. Beyer, A. Hetzheim, H. Honeck, D. Ling and T. Pyl, Chem. Ber., 1968,101,3151. 8 C. Yamazaki, Bull. Chem.SOC.Jpn., 1981,54,1767. Paper 0/02882G Received 26th June 1990 Accepted 5th July 1990