Synthesis of some novel α-cyanoketeneS,S-acetals and their use in heterocyclic synthesis

摘要

J. Chem. Soc. Perkin Trans. 1 1997 3285 Synthesis of some novel ·-cyanoketene S,S-acetals and their use in heterocyclic synthesis Galal H. Elgemeie,*,a Ahmed H. Elghandour,b Ali M. Elzanate b and Sayed A. Ahmed b a Chemistry Department Faculty of Science Helwan University Helwan Cairo Egypt b Chemistry Department Faculty of Science Cairo University Beni suef branch Beni suef Egypt A variety of novel ·-cyanoketene S,S-acetals readily prepared by the reaction of cyanoacetanilides or cyanothioacetamide with carbon disulfide followed by alkylation react smoothly with nucleophiles to afford variously substituted methylthio derivatives of pyrrole pyrazole pyridine and pyrimidine. The synthesis and reactions of ketene S,S-acetals versatile starting materials for the synthesis of a wide variety of fused heterocycles,1 have attracted much attention.2–4 As a part of our program directed towards the development of new simple and efficient procedures for the synthesis of mercaptopurine analogues and other antimetabolites 5–9 we have recently reported successful syntheses of mercaptopurine and thioguanine analogues by reactions of ketene dithioacetals with amino- and oxo-substituted azoles.10 In an extension to this work we now report a novel synthesis of functionalized pyrimidines pyridines and other antimetabolite analogues by the reaction of ketene dithioacetals with amidine and active methylene derivatives.Thus it has been found that reaction of substituted acetanilide derivatives 1 with carbon disulfide in the presence of sodium ethoxide followed by the alkylation with methyl iodide gives the novel ketene dithioacetals 2 the structures of which have been established on the basis of their elemental analysis and spectral data.Thus structure 2b is supported by its mass spectrum which showed a molecular formula C12H12N2OS2 (M1 278) and 1H NMR spectral results dH 2.64 and 2.66 (2 s 2 × SCH3) 7.10– 7.31 (m ArH) and 7.94 (br s NH). The 13C NMR spectrum had signals at dC 25.69 and 25.90 (2 × SCH3). Reaction of compounds 2 with hydrazine in refluxing ethanol containing catalytic amounts of piperidine gave the pyrazole derivatives 3 the structures of which were established on the basis of spectral evidence compound 3b showed the absence of a CN absorption in its IR spectrum whilst its mass spectrum was compatible with the molecular formula C12H14N4OS (M1 262); its 1H NMR spectrum had signals at dH 2.51 (SCH3) 5.98 (br s NH2) and 9.31 and 12.61 (both br s endocyclic and exocyclic NH).The 13C NMR spectrum of 3f was characterized by signals at dC 20.00 (SCH3) and 162.00 (CO). Compounds 2 reacted with formamide in refluxing ethanol containing catalytic amounts of piperidine to afford the corresponding 5-methylthiopyrrol-2- one derivatives 4 the structures of which were established on the basis of elemental analysis and spectral data the mass spectrum of 4a was compatible with the molecular formula C12H11N3O2S (M1 262) and its 1H NMR spectrum showed signals at dH 2.51 (s SCH3) and 5.51 and 9.68 (both br s NH2 and NH). Compounds 2 bearing latent functional substituents were used to synthesize pyrimidines pyridines and their fusedring derivatives.Thus compounds 2 reacted with cyanoacetohydrazide in refluxing ethanol containing catalytic amounts of piperidine to give the corresponding 4-methylthio-1- aminopyridones 7 in good yields structure 7d was supported by its mass (M1 349) which agreed with its molecular formula C14H12ClN5O2S; its 1H NMR spectrum displayed signals at d 2.46 (s SCH3) and 3.35 8.30 and 13.21 (three br s for NNH2 NH2 and NH). The formation of 7 from the reaction of 2 and cyanoacetohydrazide is assumed to proceed via intermediacy of the acyclic Michael adducts 5 which cyclized to yield the final 1-amino-2-pyridone derivatives 7. Compounds 7 reacted smoothly with hydrazine to yield the pyrazolo4,3-cpyridin-2- one derivatives 10 the structures of which were established and confirmed on the basis of their elemental analysis and spectral data (MS IR and 1H NMR).Thus a CN absorption was absent from the IR spectrum of 10d whilst the mass spectrum was compatible with the molecular formula C13H12ClN7O2 (M1 334); the 1H NMR spectrum showed signals at dH 3.49 6.14 and 9.24 (NNH2 and 2 × NH2) and 9.25 and 12.28 (br s ring NH and anilide NH). The reaction of ketene dithioacetals 2 with thiosemicarbazide in sodium isopropoxide gave the interesting 6-methylthio-1-aminopyrimidine-2-thione derivatives 8 the structures of which were established on the basis of mass IR and 1H NMR spectral evidence. There was no CN absorption in the IR spectrum of compound 8d and its 1H NMR spectra showed broad signals at dH 3.51 and 8.26 (NNH2 and NH2) and 13.21 (br s NH). Treatment of the ketene dithioacetals 2 with cyanothioacetamide in refluxing ethanol containing catalytic amounts of piperidine gave the 4-methylthiopyridine- 2(1H)-thione derivatives 9 a reaction which was assumed to proceed via intermediacy of the acyclic Michael adducts 6.The structures of 9 were established on the basis of their elemental analysis and spectral evidence (MS IR and 1H NMR). Thus the IR spectrum for 9b showed a CN absorption at 2222 cm21 and its 1H NMR showed signals dH 2.47 (SCH3) and 7.64 and 13.24 (both br s NH2 and NH). Compounds 9 reacted with hydrazine to yield the corresponding pyrazolo4,3-cpyridin-2- one derivatives 11 the structures of which were established and confirmed on the basis of their elemental analysis and spectral data. Thus a CN absorption was absent in the IR spectra for 11b whilst its mass spectrum was compatible with the molecular formula C13H11ClN6OS (M1 334).Similarly it has been found that reaction of cyanothioacetamide with carbon disulfide in the presence of sodium ethoxide followed by alkylation with methyl iodide gave the novel ketene dithioacetals 12 the structures of which were established on the basis of elemental analysis and spectral evidence. Reaction of compound 12 with hydrazine and formamide gave the 3-methylthiopyrazole 13 and 5-methylthiopyrrol-2-one 14 respectively. The structure of compound 13 was established on the basis of elemental analysis and spectral evidence. Thus its mass spectrum was compatible with the molecular formula C5H8N4S2 (M1 188). Compound 12 bearing a latent functional substituent was used for the synthesis of pyridine pyrimidine and their fused-ring compounds.Thus compound 12 reacted 3286 J. Chem. Soc. Perkin Trans. 1 1997 with cyanoacetohydrazide and ethyl cyanoacetate in refluxing ethanol containing catalytic amounts of piperidine to give the 4-methylthio-1-aminopyridone 17 and methylthiopyridine- 2(1H)-thiones 19 respectively. The structures of 19 were established and confirmed on the basis of elemental analysis and spectral evidence. The reaction of ketene dithioacetal 12 with thiosemicarbazide in sodium isopropoxide gave the 6-methylthio- 1-aminopyrimidine-2-thione 18 the structure of which was established and confirmed on the basis of its elemental analysis and spectral data. Thus the mass spectrum was compatible with the molecular formula C6H9N5S3 (M1 247) whilst its 1H NMR spectrum showed signals at dH 2.52 (SCH3) and 3.37 5.25 and 8.11 (3 × br s NH2).NC NAr O MeS NAr O CN MeS N N H2N R SMe ArN O H H H N MeS NH2 ArN O H O i ii iii 1a–d 2a–d 3a–h 4a–d C N N ArN O SMe S CN H H H •• C HN N SMe O CN •• 2 v vi 6a–b 5a–d ArN O NH2 H NH SMe S CN 9a–b ArN O H H2N N N NH2 S 8a–d ArN O H MeS N SMe O CN ArN O H H2N NH2 NH2 7a–d vii viii ix NH HN S 11a–b ArN O H H2N NH2 N N HN O 10a–d ArN O H H2N NH2 N x NH2 iv 1,2,4 abc d Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 3 abc d Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 R1 HHHH 3 ef gh Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 R1 Ph Ph Ph Ph Scheme 1 Reagents and conditions i CS2 EtONa; ii MeI EtONa; iii RNHNH2 EtOH PiP heat; iv H2NCHO EtOH PiP heat; v NCCH2C(S)NH2 EtOH PiP heat; vi NCCH2C(O)NHNH2 EtOH PiP heat; vii EtOH PiP heat; viii H2NHNC(S)NH2 NaOPri PriOH heat; ix NH2NH2 EtOH PiP heat; x NH2NH2 EtOH PiP heat In summary by the reaction of ketene dithioacetals with nucleophiles we have achieved a regiospecific synthesis of antimetabolites compounds which have both chemical and biological potential.Experimental All mps are uncorrected. The IR spectra were obtained (KBr disk) on a Perkin-Elmer/1650 FT-IR instrument. The 1H NMR spectra were measured on a Varian 400 MHz spectrometer for solutions in (CD3)2SO with SiMe4 as an internal standard. Mass spectra were recorded on a Varian MAT 112 spectrometer. Analytical data were obtained from the Microanalytical Data Center at Cairo University. N-Substituted bis(methylthiomethylene)(cyano)acetamides 2a–e A mixture of sodium ethoxide (0.02 mol) and the cyanoacetamide 1a–e (0.01 mol) was heated for 20 min and then cooled and diluted with carbon disulfide (0.01 mol).The reaction mixture was warmed for 20 min after which it was cooled and treated with methyl iodide (0.02 mol). The mixture was poured onto ice–water and neutralized with dilute hydrochloric acid. Scheme 2 Reagents and conditions i CS2 EtONa; ii MeI EtOH; iii RNHNH2 EtOH PiP heat; iv H2NCHO EtOH PiP heat; v NCCH2C(O)OEt EtOH PiP heat; vi NCCH2C(O)NHNH2 EtOH PiP heat; vii EtOH PiP heat; viii H2NNHC(S)NH2 NaOPri PriOH heat; ix NH2NH2 EtOH PiP heat NC NH2 S MeS NH2 S CN MeS N N H2N R SMe H2N O N MeS NH2 H2N S O i ii iii 12 13 R 14 C N SMe S CN H H •• C HN N SMe O CN •• 12 v vi 16 15 H2N S NH2 NH SMe S CN 19 NC HO N N NH2 S 18 H2N S MeS N SMe O CN H2N S H2N NH2 NH2 17 vii viii N HN O 20 H2N S H2N NH2 N ix a H b Ph iv NC EtO O NH2 J.Chem. Soc. Perkin Trans. 1 1997 3287 The precipitated product was filtered off and recrystallized from ethanol. Compound 2a. Yellow crystals (80) mp 145 8C; nmax/cm21 (KBr) 3216 and 3165 (NH) 2200 (CN) and 1652 (CO); dH(CD3)2SO 2.64 (s 3H SCH3) 2.66 (s 3H SCH3) 7.00–7.51 (m 5H C6H5) and 7.89 (s br 1H NH) (Found C 54.2; H 4.3; N 10.8. Calc. for C12H12N2OS2 C 54.5; H 4.5; N 10.6). Compound 2b. Yellow crystals (85) mp 170 8C; nmax/cm21 (KBr) 3214 and 3100 (NH) 2200 (CN) and 1659 (CO); dH(CD3)2SO 2.37 (s 3H CH3) 2.64 (s 3H SCH3) 2.66 (s 3H SCH3) 7.33 (m 4H C6H4) and 7.95 (s br 1H NH); dC 20.04 (CH3) 25.69 (SCH3) 25.90 (SCH3) 118.17 (CN) 124.81 (aromatic CH) 130.39 ( CCH3) 134.75 (aromatic CH) 136.91 ( CNH) 142.54 (H3CSC C) 168.48 (C CCN) and 175.66 (C O); m/z 278 (Found C 56.3; H 5.2; N 10.4.Calc. for C12H12N2OS2 C 56.1; H 5.0; N 10.0). Compound 2c. Yellow crystals (75) mp 160 8C; nmax/cm21 (KBr) 3232 (NH) 2202 (CN) and 1653 (CO) (Found C 53.4; H 4.9; N 9.2. Calc. for C13H14N2O2S2 C 53.0; H 4.7; N 9.5). Compound 2d. Yellow crystals (80) mp 198 8C; nmax/cm21 (KBr) 3243 (NH) 2203 (CN) and 1657 (CO); dH(CD3)2SO 2.52 (s 3H SCH3) 2.55 (s 3H SCH3) 7.10–7.61 (m 4H C6H4) and 13.22 (s br 1H NH) (Found C 48.5; H 3.8; N 9.5. Calc. for C12H11ClN2OS2 C 48.2; H 3.68; N 9.38). 5-Amino-3-methylthiopyrazoles 3a–j General procedure. A mixture of compounds 2a–e (0.01 mol) and hydrazine hydrate or phenylhydrazine (0.01 mol) was refluxed in ethanol (20 ml) containing a catalytic amount of piperidine for 6 h.After cooling of the reaction mixture the solid product was filtered off and recrystallized from ethanol. Compound 3a. Pale yellow crystals (45) mp 160 8C nmax/ cm21 (KBr) 3452 3347 and 3271 (NH2 NH) 1648 (CO) and 1549 (C N); m/z 248 (Found C 53.2; H 4.6; N 22.9. Calc. for C11H12N4OS C 53.4; H 4.8; N 22.6). Compound 3b. Colourless crystals (50) mp 165 8C; nmax/ cm21 (KBr) 3460 3340 and 3271 (NH2 NH) 1652 (CO) and 1608 (C N); dH(CD3)2SO 2.33 (s 3H CH3) 2.51 (s 3H SCH3) 5.89 (s 2H NH2) 7.1–7.4 (m 4H C6H4) 9.31 (s br 1H ring NH) and 12.61 (s br 1H NH); m/z 262 (Found C 54.6; H 5.6; N 21.5. Calc. for C12H14N4OS C 54.96; H 5.3; N 21.3). Compound 3c. Pale yellow crystals (45) mp 150 8C; nmax/ cm21 (KBr) 3444 3334 and 3295 (NH2 NH) 1656 (CO) and 1547 (C N); dH(CD3)2SO 2.51 (s 3H SCH3) 3.81 (s 3H OCH3) 6.62 (s 2H NH2) 7.21–7.45 (m 4H C6H4) and 8.22 (s br 1H ring NH); m/z 280 (Found C 51.6; H 5.3; N 20.5.Calc. for C12H14N4O2S C 51.8; H 5.0; N 20.1). Compound 3d. Colourless crystals (50) mp 280 8C; nmax/ cm21 (KBr) 3458 3389 and 3349 (NH2 NH) and 1650 (CO) (Found C 46.5; H 4.1; N 19.6. Calc. for C11H11ClN4OS C 46.7; H 3.8; N 19.8). Compound 3e. Colourless crystals (60) mp 200 8C; nmax/ cm21 (KBr) 3270 3207 and 3144 (NH2 NH) 1669 (CO) and 1561 (C N) (Found C 62.7; H 4.5; N 17.1. Calc. for C17H16N4OS C 62.9; H 4.9; N 17.28). Compound 3f. Colourless crystals (65) mp 145 8C; nmax/ cm21 (KBr) 3426 3376 and 3321 (NH2 NH) 1661 (CO) and 1536 (C N); dH(CD3)2SO 2.42 (s 3H CH3) 2.61 (s 3H SCH3) 6.61 (s 2H NH2) 7.1–7.5 (m 9H C6H4 and C6H5) and 9.10 (s br 1H NH); dC 15.10 (CH3) 20.00 (SCH3) 162.00 (C-6) 150.00 (C-5) 145.22 (C-3) 138.12 (C-4) and 120.00–137.11 (2 phenyl C) (Found C 63.5; H 5.6; N 16.2.Calc. for C18H18N4OS C 63.9; H 5.3; N 16.56). Compound 3g. Pale yellow crystals (55) mp 168 8C; nmax/ cm21 (KBr) 3443 3340 and 3198 (NH2 NH) and 1660 (CO) (Found C 61.4; H 5.4; N 15.5. Calc. for C18H18N4O2S2 C 61.0; H 5.1; N 15.8). Compound 3h. Colourless crystals (70) mp 160 8C; nmax/ cm21 (KBr) 3427 3376 and 3321 (NH2 NH) 1662 (CO) and 1535 (C N) (Found C 56.6; H 4.4; N 15.3. Calc. for C17H15ClN4OS C 56.9; H 4.2; N 15.62). 3-Amino-5-methylthiopyrrol-2-ones 4a–e General procedure. A mixture of compounds 2a–e (0.01 mol) and formamide (0.01 mol) was heated in ethanol (20 ml) containing a catalytic amount of piperidine for 3 h.After this the product was collected and recrystallized from the appropriate solvent. Compound 4a. Brown crystals (75) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3325 and 3161 (NH2 NH) and 1662 (CO); dH(CD3)2SO 2.51 (s 3H SCH3) 5.51 (s 2H NH2) 7.21–7.50 (m 5H C6H5) and 9.68 (s br 1H NH); m/z 262 (Found C 55.6; H 4.5; N 15.8. Calc. for C12H11N3O2S C 55.1; H 4.2; N 16.0). Compound 4b. Brown crystals (70) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3330 and 3154 (NH2 NH) and 1658 (CO) (Found C 56.2; H 4.5; N 15.6. Calc. for C13H13N3O2S C 56.7; H 4.7; N 15.3). Compound 4c. Brown crystals (74) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3326 and 3154 (NH2 NH) and 1656 (CO) (Found C 53.4; H 4.6; N 14.1. Calc. for C13H13N3O3S C 53.6; H 4.5; N 14.4). Compound 4d. Brown crystals (65) from EtOH mp >300 8C; nmax/cm21 (KBr) 3329 and 3156 (NH2 NH) and 1660 (CO) (Found C 51.41; H 3.23; N 15.41.Calc. for C12H10ClN3OS C 51.61; H 3.58; N 15.05). 6-Amino-3-cyano-4-methylthiopyridin-2-ones 7a–e General procedure. A mixture of equivalent amounts (0.01 mol) of compound 2a–e and cyanoacetohydrazide was refluxed in ethanol containing a catalytic amount of piperidine for 6 h. After cooling of the reaction mixture the product was filtered off and recrystallized from ethanol. Compound 7a. Yellow crystals (75) mp 182 8C; nmax/cm21 (KBr) 3269 3207 and 3144 (NH2 NH) 2200 (CN) and 1669 (CO); dH(CD3)2SO 2.26 (s 3H SCH3) 3.42 (s 2H NH2) 3.89 (s 2H NH2) 7.10–7.41 (m 5H C6H5) and 10.25 (s br 1H NH) (Found C 53.1; H 4.5; N 22.5. Calc. for C14H13N5O2S C 53.3; H 4.1; N 22.2).Compound 7b. Yellow crystals (70) mp 148 8C; nmax/cm21 (KBr) 3271 and 3204 (NH2 NH) 2174 (CN) and 1664 (CO) (Found C 54.5; H 4.2; N 21.6. Calc. for C15H15N5O2S C 54.7; H 4.5; N 21.3). Compound 7c. Yellow crystals (65) mp 165 8C; nmax/cm21 (KBr) 3250 and 3019 (NH2 NH) 2188 (CN) and 1708 (CO) (Found C 52.4; H 4.6; N 20.1. Calc. for C15H15N5O3S C 52.2; H 4.3; N 20.3). Compound 7d. Yellow crystals (80) mp 202 8C; nmax/cm21 (KBr) 3240 and 3077 (NH2 NH) 2200 (CN) and 1660 (CO); dH(CD3)2SO 2.46 (s 3H SCH3) 3.35 (s 2H NH2) 7.31–7.6 (m 4H C6H4) 8.24 (s 2H NH2) and 13.21 (s br 1H NH); m/z 349 (Found C 48.2; H 3.6; N 20.2. Calc. for C14H12Cl- N5O2S C 48.0; H 3.4; N 20.0). Pyrazolo4,3-cpyridin-2-ones 10a–d General procedure. A mixture of equivalent amounts (0.01 mol) of 7a–d and hydrazine hydrate was heated in ethanol containing a catalytic amount of piperidine for 6 h.The product was filtered off and recrystallized from the appropriate solvent. Compound 10a. Brown crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3300 3245 and 3023 (NH2 NH) and 1654 (CO); dH(CD3)2SO 3.41 (s 2H NH2) 3.41 (s 2H NH2) 6.16 (s 2H NH2) 7.31–7.62 (m 5H C6H5) 7.78 (s 2H NH2) 9.26 (s br 1H ring NH) and 12.30 (s br 1H NH) (Found C 52.5; H 4.5; N 32.3. Calc. for C13H13N7O2 C 52.2; H 4.3; N 32.8). Compound 10b. Yellow crystals (55) from EtOH–DMF mp >183 8C; nmax/cm21 (KBr) 3404 3317 and 3200 (NH2 NH) and 1659 (CO) (Found C 53.2; H 4.5; N 31.6. Calc. for C14H15N7O2 C 53.6; H 4.8; N 31.3). 3288 J. Chem. Soc. Perkin Trans. 1 1997 Compound 10c. Yellow crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3320 and 3197 (NH2 NH) 1660 (CO) and 1544 (C N) (Found C 51.5; H 4.4; N 29.5.Calc. for C14H15N7O3 C 51.1; H 4.5; N 29.8). Compound 10d. Yellow crystals (60) from EtOH–DMF mp 300 8C; nmax/cm21 (KBr) 3409 3310 and 3112 (NH2 NH) 1653 (CO) and 1603 (C N); dH(CD3)2SO 3.36 (s 2H NH2) 3.47 (s 2H NH2) 6.14 (2H NH2) 7.32–7.56 (m 4H C6H4) 7.65 (s 2H NH2) 9.24 (s br 1H ring NH) and 12.28 (s br 1H NH) m/z 334 (Found C 46.5; H 3.9; N 29.8. Calc. for C13H12ClN7O2 C 46.8; H 3.6; N 29.4). 1,4-Diamino-6-methylthiopyrimidine-2-thiones 8a–d General procedure. To a solution of sodium isopropoxide (0.01 mol) equimolar amounts of compounds 2a–e (0.01 mol) and thiosemicarbazide (0.01 mol) were added. The reaction mixture was refluxed for 3 h and then neutralized with dilute hydrochloric acid.The resulting precipitate was filtered off and recrystallized from the appropriate solvent. Compound 8a. Brown crystals (52) from DMF mp >300 8C; nmax/cm21 (KBr) 3860 and 3139 (NH2 NH) 1690 (CO) and 1539 (C N) (Found C 47.4; H 3.5; N 22.4. Calc. for C12H12N5OS2 C 47.0; H 3.9; N 22.9). Compound 8b. Brown crystals (51) from DMF mp >300 8C; nmax/cm21 (KBr) 3750 and 3220 (NH2 NH) 1648 (CO) and 1548 (C N); dH(CD3)2SO 2.25 (s 3H CH3) 2.51 (s 3H SCH3) 3.89 (s 2H NH2) 7.15–7.50 (m 4H C6H4) 8.24 (s 2H NH2) and 13.00 (s br 1H NH) (Found C 48.1; H 4.2; N 22.1. Calc. for C13H15N5OS2 C 48.6; H 4.8; N 21.8). Compound 8c. Pale yellow crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3444 3377 and 3116 (NH2 NH) 1647 (CO) and 1536 (C N) (Found C 46.5; H 4.2; N 20.4.Calc. for C13H15N5O2S2 C 46.29; H 4.4; N 20.8). Compound 8d. Brown crystals (53) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3190 and 3092 (NH2 NH) 1676 (CO) and 1558 (C N); dH(CD3)2SO 2.51 (s 3H SCH3) 3.51 (s 2H NH2) 7.31–7.62 (m 4H C6H4) 8.26 (s 2H NH2) and 13.21 (s br 1H NH); m/z 342 (Found C 42.5; H 3.1; N 20.1. Calc. for C12H12ClN5OS2 C 42.2; H 3.5; N 20.5). 6-Amino-3-cyano-4-methylthiopyridin-2-ones 9a–b General procedure. A mixture of an equivalent amount (0.01 mol) of compounds 2a–e and cyanothioacetamide was refluxed in ethanol containing a catalytic amount of piperidine for 6 h. After cooling of the reaction mixture the product was filtered off and then recrystallized from ethanol. Compound 9a. Yellow crystals (65) from EtOH mp 170 8C; nmax/cm21 (KBr) 3406 3267 and 3203 (NH2 NH) 2220 (CN) and 1687 (CO) (Found C 54.7; H 4.5; N 16.5.Calc. for C15H14N4OS2 C 54.5; H 4.2; N 16.9). Compound 9b. Yellow crystals (70) from EtOH mp 165 8C; nmax/cm21 (KBr) 3270 3187 and 3056 (NH2 NH) 2222 (CN) and 1669 (CO); dH(CD3)2SO 2.47 (s 3H SCH3) 7.31–7.59 (m 4H C6H4) 7.64 (s 2H NH2) 8.30 (s br 1H ring NH) and 13.24 (s br 1H NH) (Found C 48.3; H 3.5; N 15.8. Calc. for C14H11ClN4OS2 C 48.0; H 3.1; N 16.0). Pyrazolo4,3-cpyridin-2-ones 11a–b General procedure. A mixture of equivalent amounts (0.01 mol) of 9a–b and hydrazine hydrate was heated in ethanol containing a catalytic amount of piperidine for 6 h. The product was filtered off and recrystallized from EtOH–DMF solvent. Compound 11a. Brown crystals (54) mp >300 8C; nmax/ cm21 (KBr) 3270 3207 and 3144 (NH2 NH) 1688 (CO) and 1560 (C N) (Found C 53.7; H 4.6; N 26.5.Calc. for C14H14N6OS C 53.5; H 4.4; N 26.8). Compound 11b. Brown crystals (60) mp >300 8C; nmax/ cm21 (KBr); 3440 and 3196 (NH2 NH) and 1652 (CO); dH(CD3)2SO 7.02 (s 2H NH2) 7.22–7.51 (m 4H C6H4) 8.86 (s 2H NH2) and 10.6 (s br 1H NH); m/z 334 (Found C 46.2; H 3.7; N 24.7. Calc. for C13H11ClN6OS C 46.6; H 3.3; N 25.0). Bis(methylthiomethylene)cyanoacetamide 12 General procedure. A mixture of sodium ethoxide (0.02 mol) and cyanothioacetamide (0.01 mol) was heated for 20 min after which it was cooled and treated with carbon disulfide (0.01 mol). The reaction mixture was warmed for 20 min and after cooling was treated with methyl iodide (0.02 mol). It was then poured onto ice–water and neutralized with dilute hydrochloric acid.The precipitated product was filtered off and recrystallized from ethanol. Compound 12. Brown crystals (70) mp 185 8C; nmax/cm21 (KBr) 3218 3215 and 3048 (NH2 NH) and 2218 (CN); dH(CD3)2SO 2.59 (s 3H SCH3) 2.61 (s 3H SCH3) 3.44 (s 2H NH2) and 12.00 (s br 1H NH); m/z 204 (Found C 35.6; H 3.5; N 13.4. Calc. for C6H8N2S3 C 35.3; H 3.9; N 13.7). 5-Amino-3-methylthiopyrazole 13a–b General procedure. A mixture of compound 12 (0.01 mol) and hydrazine hydrate or phenylhydrazine (0.01 mol) was refluxed in ethanol (20 ml) for 6 h. After cooling of the reaction mixture the solid product was filtered off and recrystallized. Compound 13a. Red crystals (55) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3400 3296 and 3174 (NH2 NH) and 1579 (C N); dH(CD3)2SO 2.52 (s 3H SCH3) 5.51 (s 2H NH2) and 7.81 (s br 1H NH); m/z 188 (Found C 31.4; H 4.6; N 29.4.Calc. for C5H8N4S2 C 31.9; H 4.2; N 29.7). Compound 13b. Brown crystals (70) from EtOH mp >300 8C; nmax/cm21 (KBr) 3370 and 3158 (NH2 NH) (Found C 50.3; H 4.1; N 21.7. Calc. for C11H12N4S2 C 50.0; H 4.5; N 21.2). 3-Amino-5-methylthiopyrrol-2-one 14 A mixture of compound 12 (0.01 mol) and formamide (0.01 mol) was heated in ethanol (20 ml) containing a catalytic amount of piperidine for 3 h. After this the product was collected and recrystallized from EtOH. Compound 14. Brown crystals (70) mp 240 8C; nmax/cm21 (KBr) 3330 and 3142 (NH2 NH) and 1653 (CO) (Found C 35.5; H 3.6; N 20.6. Calc. for C6H7N3OS2 C 35.8; H 3.4; N 20.9). 6-Amino-3-cyano-4-methylthiopyridin-2-one 17 A mixture of compound 12 (0.01 mol) and cyanoacetohydrazide (0.01 mol) was refluxed in ethanol containing a catalytic amount of piperidine for 6 h.After cooling of the reaction mixture the final product was filtered off and recrystallized from EtOH–DMF to give brown crystals (60) mp >300 8C; nmax/cm21 (KBr) 3385 3228 and 3082 (NH2 NH) 2200 (CN) and 1658 (CO); m/z 256 (Found C 54.5; H 3.7; N 27.6. Calc. for C8H9N5OS2 C 37.6; H 3.5; N 27.5). Pyrazolo4,3-cpyridin-2-one 20 A mixture of 17 (0.01 mol) and hydrazine hydrate (0.01 mol) was heated in ethanol containing a catalytic amount of piperidine for 6 h. The product was filtered off and recrystallized from EtOH to afford brown crystals (70) mp >300 8C; nmax/ cm21 (KBr) 3132 and 3043 (NH2 NH) 1680 (CO) and 1591 (C N) (Found C 35.5; H 3.5; N 41.3.Calc. for C7H9N7OS C 35.1; H 3.8; N 41.0). 1,4-Diamino-5-aminothiocarbonyl-6-(methylthio)pyrimidine-2- thione 18 To a solution of sodium isopropoxide (0.01 mol) compound 12 (0.01 mol) and thiosemicarbazide (0.01 mol) were added. The reaction mixture was refluxed for 3 h after which it was neutralized with dilute hydrochloric acid and the product then filtered off and recrystallized from EtOH–DMF to give brown crystals (55) mp >300 8C; nmax/cm21 (KBr) 3384 3343 3228 and 3138 (NH2 NH) and 1556 (C N); dH(CD3)2SO 2.52 (s 3H, J. Chem. Soc. Perkin Trans. 1 1997 3289 SCH3) 3.21 (s 2H NH2) 3.24 (s 2H NH2) and 3.37 (s 2H NH2); m/z 247 (Found C 29.4; H 3.4; N 28.6. Calc. for C6H9N5S3 C 29.1; H 3.6; N 28.3). 3-Cyano-4-methylthiopyridine-2-ones 19 Equivalent amounts (0.01 mol) of 12 and ethyl cyanoacetate were refluxed in ethanol (20 ml) containing a few drops of piperidine for 6 h.After this the product was filtered off and recrystallized from ethanol to give yellow crystals (70) mp 190 8C; nmax/cm21 (KBr) 3200 and 3093 (NH2 NH) 2174 (CN) and 1660 (CO); dH(CD3)2SO 2.52 (s 3H SCH3) 9.42 (s br H NH) and 12.89 (s br 1H OH) (Found C 60.1; H 4.3; N 19.3. Calc. for C15H12N4OS C 60.4; H 4.0; N 18.9). References 1 G. E. H. Elgemeie H. A. Ali and A. M. Elzanaty J. Chem. Res. (S) 1996 340. 2 H. Junjappa H. Ila and C. V. Asokar Tetrahedron 1990 46 5423. 3 Y. Matsude M. Yamashita K. Takahashi S. Ide K. Torisu and K. Furuno Heterocycles 1992 33 295. 4 A. Hsomi Y. Miyashiro R. Yoshida Y. Tominaga T. Yamagi and M. Hojo J. Org.Chem. 1990 55 5308. 5 G. E. H. Elgemeie and B. A. W. Hussain Tetrahedron 1994 50 199. 6 G. E. H. Elgemeie A. M. Attia and N. M. Fathy Liebigs Ann. Chem. 1994 955. 7 G. E. H. Elgemeie and A. M. Atia Carbohydr. Res. 1995 268 295. 8 G. E. H. Elgemeie A. M. Elzanaty and A. K. Mansour J. Chem. Soc. Perkin Trans. 1 1992 1037. 9 G. E. H. Elgemeie A. M. Attia D. S. Farag and S. M. Sherif J. Chem. Soc. Perkin Trans. 1 1994 1285. 10 G. E. H. Elgemeie S. E. Elezbawy H. A. Ali and A. K. Mansour Bull. Chem. Soc. Jpn. 1994 67 738. Paper 7/02343J Received 7th April 1997 Accepted 8th July 1997 © Copyright 1997 by the Royal Society of Chemistry J. Chem. Soc. Perkin Trans. 1 1997 3285 Synthesis of some novel ·-cyanoketene S,S-acetals and their use in heterocyclic synthesis Galal H. Elgemeie,*,a Ahmed H.Elghandour,b Ali M. Elzanate b and Sayed A. Ahmed b a Chemistry Department Faculty of Science Helwan University Helwan Cairo Egypt b Chemistry Department Faculty of Science Cairo University Beni suef branch Beni suef Egypt A variety of novel ·-cyanoketene S,S-acetals readily prepared by the reaction of cyanoacetanilides or cyanothioacetamide with carbon disulfide followed by alkylation react smoothly with nucleophiles to afford variously substituted methylthio derivatives of pyrrole pyrazole pyridine and pyrimidine. The synthesis and reactions of ketene S,S-acetals versatile starting materials for the synthesis of a wide variety of fused heterocycles,1 have attracted much attention.2–4 As a part of our program directed towards the development of new simple and efficient procedures for the synthesis of mercaptopurine analogues and other antimetabolites 5–9 we have recently reported successful syntheses of mercaptopurine and thioguanine analogues by reactions of ketene dithioacetals with amino- and oxo-substituted azoles.10 In an extension to this work we now report a novel synthesis of functionalized pyrimidines pyridines and other antimetabolite analogues by the reaction of ketene dithioacetals with amidine and active methylene derivatives.Thus it has been found that reaction of substituted acetanilide derivatives 1 with carbon disulfide in the presence of sodium ethoxide followed by the alkylation with methyl iodide gives the novel ketene dithioacetals 2 the structures of which have been established on the basis of their elemental analysis and spectral data.Thus structure 2b is supported by its mass spectrum which showed a molecular formula C12H12N2OS2 (M1 278) and 1H NMR spectral results dH 2.64 and 2.66 (2 s 2 × SCH3) 7.10– 7.31 (m ArH) and 7.94 (br s NH). The 13C NMR spectrum had signals at dC 25.69 and 25.90 (2 × SCH3). Reaction of compounds 2 with hydrazine in refluxing ethanol containing catalytic amounts of piperidine gave the pyrazole derivatives 3 the structures of which were established on the basis of spectral evidence compound 3b showed the absence of a CN absorption in its IR spectrum whilst its mass spectrum was compatible with the molecular formula C12H14N4OS (M1 262); its 1H NMR spectrum had signals at dH 2.51 (SCH3) 5.98 (br s NH2) and 9.31 and 12.61 (both br s endocyclic and exocyclic NH). The 13C NMR spectrum of 3f was characterized by signals at dC 20.00 (SCH3) and 162.00 (CO).Compounds 2 reacted with formamide in refluxing ethanol containing catalytic amounts of piperidine to afford the corresponding 5-methylthiopyrrol-2- one derivatives 4 the structures of which were established on the basis of elemental analysis and spectral data the mass spectrum of 4a was compatible with the molecular formula C12H11N3O2S (M1 262) and its 1H NMR spectrum showed signals at dH 2.51 (s SCH3) and 5.51 and 9.68 (both br s NH2 and NH). Compounds 2 bearing latent functional substituents were used to synthesize pyrimidines pyridines and their fusedring derivatives. Thus compounds 2 reacted with cyanoacetohydrazide in refluxing ethanol containing catalytic amounts of piperidine to give the corresponding 4-methylthio-1- aminopyridones 7 in good yields structure 7d was supported by its mass (M1 349) which agreed with its molecular formula C14H12ClN5O2S; its 1H NMR spectrum displayed signals at d 2.46 (s SCH3) and 3.35 8.30 and 13.21 (three br s for NNH2 NH2 and NH).The formation of 7 from the reaction of 2 and cyanoacetohydrazide is assumed to proceed via intermediacy of the acyclic Michael adducts 5 which cyclized to yield the final 1-amino-2-pyridone derivatives 7. Compounds 7 reacted smoothly with hydrazine to yield the pyrazolo4,3-cpyridin-2- one derivatives 10 the structures of which were established and confirmed on the basis of their elemental analysis and spectral data (MS IR and 1H NMR). Thus a CN absorption was absent from the IR spectrum of 10d whilst the mass spectrum was compatible with the molecular formula C13H12ClN7O2 (M1 334); the 1H NMR spectrum showed signals at dH 3.49 6.14 and 9.24 (NNH2 and 2 × NH2) and 9.25 and 12.28 (br s ring NH and anilide NH).The reaction of ketene dithioacetals 2 with thiosemicarbazide in sodium isopropoxide gave the interesting 6-methylthio-1-aminopyrimidine-2-thione derivatives 8 the structures of which were established on the basis of mass IR and 1H NMR spectral evidence. There was no CN absorption in the IR spectrum of compound 8d and its 1H NMR spectra showed broad signals at dH 3.51 and 8.26 (NNH2 and NH2) and 13.21 (br s NH). Treatment of the ketene dithioacetals 2 with cyanothioacetamide in refluxing ethanol containing catalytic amounts of piperidine gave the 4-methylthiopyridine- 2(1H)-thione derivatives 9 a reaction which was assumed to proceed via intermediacy of the acyclic Michael adducts 6.The structures of 9 were established on the basis of their elemental analysis and spectral evidence (MS IR and 1H NMR). Thus the IR spectrum for 9b showed a CN absorption at 2222 cm21 and its 1H NMR showed signals dH 2.47 (SCH3) and 7.64 and 13.24 (both br s NH2 and NH). Compounds 9 reacted with hydrazine to yield the corresponding pyrazolo4,3-cpyridin-2- one derivatives 11 the structures of which were established and confirmed on the basis of their elemental analysis and spectral data. Thus a CN absorption was absent in the IR spectra for 11b whilst its mass spectrum was compatible with the molecular formula C13H11ClN6OS (M1 334). Similarly it has been found that reaction of cyanothioacetamide with carbon disulfide in the presence of sodium ethoxide followed by alkylation with methyl iodide gave the novel ketene dithioacetals 12 the structures of which were established on the basis of elemental analysis and spectral evidence.Reaction of compound 12 with hydrazine and formamide gave the 3-methylthiopyrazole 13 and 5-methylthiopyrrol-2-one 14 respectively. The structure of compound 13 was established on the basis of elemental analysis and spectral evidence. Thus its mass spectrum was compatible with the molecular formula C5H8N4S2 (M1 188). Compound 12 bearing a latent functional substituent was used for the synthesis of pyridine pyrimidine and their fused-ring compounds. Thus compound 12 reacted 3286 J. Chem. Soc. Perkin Trans. 1 1997 with cyanoacetohydrazide and ethyl cyanoacetate in refluxing ethanol containing catalytic amounts of piperidine to give the 4-methylthio-1-aminopyridone 17 and methylthiopyridine- 2(1H)-thiones 19 respectively.The structures of 19 were established and confirmed on the basis of elemental analysis and spectral evidence. The reaction of ketene dithioacetal 12 with thiosemicarbazide in sodium isopropoxide gave the 6-methylthio- 1-aminopyrimidine-2-thione 18 the structure of which was established and confirmed on the basis of its elemental analysis and spectral data. Thus the mass spectrum was compatible with the molecular formula C6H9N5S3 (M1 247) whilst its 1H NMR spectrum showed signals at dH 2.52 (SCH3) and 3.37 5.25 and 8.11 (3 × br s NH2). NC NAr O MeS NAr O CN MeS N N H2N R SMe ArN O H H H N MeS NH2 ArN O H O i ii iii 1a–d 2a–d 3a–h 4a–d C N N ArN O SMe S CN H H H •• C HN N SMe O CN •• 2 v vi 6a–b 5a–d ArN O NH2 H NH SMe S CN 9a–b ArN O H H2N N N NH2 S 8a–d ArN O H MeS N SMe O CN ArN O H H2N NH2 NH2 7a–d vii viii ix NH HN S 11a–b ArN O H H2N NH2 N N HN O 10a–d ArN O H H2N NH2 N x NH2 iv 1,2,4 abc d Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 3 abc d Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 R1 HHHH 3 ef gh Ar Ph C6H4Me-4 C6H4Me-4 C6H4Cl-4 R1 Ph Ph Ph Ph Scheme 1 Reagents and conditions i CS2 EtONa; ii MeI EtONa; iii RNHNH2 EtOH PiP heat; iv H2NCHO EtOH PiP heat; v NCCH2C(S)NH2 EtOH PiP heat; vi NCCH2C(O)NHNH2 EtOH PiP heat; vii EtOH PiP heat; viii H2NHNC(S)NH2 NaOPri PriOH heat; ix NH2NH2 EtOH PiP heat; x NH2NH2 EtOH PiP heat In summary by the reaction of ketene dithioacetals with nucleophiles we have achieved a regiospecific synthesis of antimetabolites compounds which have both chemical and biological potential.Experimental All mps are uncorrected. The IR spectra were obtained (KBr disk) on a Perkin-Elmer/1650 FT-IR instrument. The 1H NMR spectra were measured on a Varian 400 MHz spectrometer for solutions in (CD3)2SO with SiMe4 as an internal standard. Mass spectra were recorded on a Varian MAT 112 spectrometer. Analytical data were obtained from the Microanalytical Data Center at Cairo University. N-Substituted bis(methylthiomethylene)(cyano)acetamides 2a–e A mixture of sodium ethoxide (0.02 mol) and the cyanoacetamide 1a–e (0.01 mol) was heated for 20 min and then cooled and diluted with carbon disulfide (0.01 mol). The reaction mixture was warmed for 20 min after which it was cooled and treated with methyl iodide (0.02 mol).The mixture was poured onto ice–water and neutralized with dilute hydrochloric acid. Scheme 2 Reagents and conditions i CS2 EtONa; ii MeI EtOH; iii RNHNH2 EtOH PiP heat; iv H2NCHO EtOH PiP heat; v NCCH2C(O)OEt EtOH PiP heat; vi NCCH2C(O)NHNH2 EtOH PiP heat; vii EtOH PiP heat; viii H2NNHC(S)NH2 NaOPri PriOH heat; ix NH2NH2 EtOH PiP heat NC NH2 S MeS NH2 S CN MeS N N H2N R SMe H2N O N MeS NH2 H2N S O i ii iii 12 13 R 14 C N SMe S CN H H •• C HN N SMe O CN •• 12 v vi 16 15 H2N S NH2 NH SMe S CN 19 NC HO N N NH2 S 18 H2N S MeS N SMe O CN H2N S H2N NH2 NH2 17 vii viii N HN O 20 H2N S H2N NH2 N ix a H b Ph iv NC EtO O NH2 J. Chem. Soc. Perkin Trans. 1 1997 3287 The precipitated product was filtered off and recrystallized from ethanol.Compound 2a. Yellow crystals (80) mp 145 8C; nmax/cm21 (KBr) 3216 and 3165 (NH) 2200 (CN) and 1652 (CO); dH(CD3)2SO 2.64 (s 3H SCH3) 2.66 (s 3H SCH3) 7.00–7.51 (m 5H C6H5) and 7.89 (s br 1H NH) (Found C 54.2; H 4.3; N 10.8. Calc. for C12H12N2OS2 C 54.5; H 4.5; N 10.6). Compound 2b. Yellow crystals (85) mp 170 8C; nmax/cm21 (KBr) 3214 and 3100 (NH) 2200 (CN) and 1659 (CO); dH(CD3)2SO 2.37 (s 3H CH3) 2.64 (s 3H SCH3) 2.66 (s 3H SCH3) 7.33 (m 4H C6H4) and 7.95 (s br 1H NH); dC 20.04 (CH3) 25.69 (SCH3) 25.90 (SCH3) 118.17 (CN) 124.81 (aromatic CH) 130.39 ( CCH3) 134.75 (aromatic CH) 136.91 ( CNH) 142.54 (H3CSC C) 168.48 (C CCN) and 175.66 (C O); m/z 278 (Found C 56.3; H 5.2; N 10.4. Calc. for C12H12N2OS2 C 56.1; H 5.0; N 10.0). Compound 2c. Yellow crystals (75) mp 160 8C; nmax/cm21 (KBr) 3232 (NH) 2202 (CN) and 1653 (CO) (Found C 53.4; H 4.9; N 9.2.Calc. for C13H14N2O2S2 C 53.0; H 4.7; N 9.5). Compound 2d. Yellow crystals (80) mp 198 8C; nmax/cm21 (KBr) 3243 (NH) 2203 (CN) and 1657 (CO); dH(CD3)2SO 2.52 (s 3H SCH3) 2.55 (s 3H SCH3) 7.10–7.61 (m 4H C6H4) and 13.22 (s br 1H NH) (Found C 48.5; H 3.8; N 9.5. Calc. for C12H11ClN2OS2 C 48.2; H 3.68; N 9.38). 5-Amino-3-methylthiopyrazoles 3a–j General procedure. A mixture of compounds 2a–e (0.01 mol) and hydrazine hydrate or phenylhydrazine (0.01 mol) was refluxed in ethanol (20 ml) containing a catalytic amount of piperidine for 6 h. After cooling of the reaction mixture the solid product was filtered off and recrystallized from ethanol. Compound 3a. Pale yellow crystals (45) mp 160 8C nmax/ cm21 (KBr) 3452 3347 and 3271 (NH2 NH) 1648 (CO) and 1549 (C N); m/z 248 (Found C 53.2; H 4.6; N 22.9.Calc. for C11H12N4OS C 53.4; H 4.8; N 22.6). Compound 3b. Colourless crystals (50) mp 165 8C; nmax/ cm21 (KBr) 3460 3340 and 3271 (NH2 NH) 1652 (CO) and 1608 (C N); dH(CD3)2SO 2.33 (s 3H CH3) 2.51 (s 3H SCH3) 5.89 (s 2H NH2) 7.1–7.4 (m 4H C6H4) 9.31 (s br 1H ring NH) and 12.61 (s br 1H NH); m/z 262 (Found C 54.6; H 5.6; N 21.5. Calc. for C12H14N4OS C 54.96; H 5.3; N 21.3). Compound 3c. Pale yellow crystals (45) mp 150 8C; nmax/ cm21 (KBr) 3444 3334 and 3295 (NH2 NH) 1656 (CO) and 1547 (C N); dH(CD3)2SO 2.51 (s 3H SCH3) 3.81 (s 3H OCH3) 6.62 (s 2H NH2) 7.21–7.45 (m 4H C6H4) and 8.22 (s br 1H ring NH); m/z 280 (Found C 51.6; H 5.3; N 20.5. Calc. for C12H14N4O2S C 51.8; H 5.0; N 20.1).Compound 3d. Colourless crystals (50) mp 280 8C; nmax/ cm21 (KBr) 3458 3389 and 3349 (NH2 NH) and 1650 (CO) (Found C 46.5; H 4.1; N 19.6. Calc. for C11H11ClN4OS C 46.7; H 3.8; N 19.8). Compound 3e. Colourless crystals (60) mp 200 8C; nmax/ cm21 (KBr) 3270 3207 and 3144 (NH2 NH) 1669 (CO) and 1561 (C N) (Found C 62.7; H 4.5; N 17.1. Calc. for C17H16N4OS C 62.9; H 4.9; N 17.28). Compound 3f. Colourless crystals (65) mp 145 8C; nmax/ cm21 (KBr) 3426 3376 and 3321 (NH2 NH) 1661 (CO) and 1536 (C N); dH(CD3)2SO 2.42 (s 3H CH3) 2.61 (s 3H SCH3) 6.61 (s 2H NH2) 7.1–7.5 (m 9H C6H4 and C6H5) and 9.10 (s br 1H NH); dC 15.10 (CH3) 20.00 (SCH3) 162.00 (C-6) 150.00 (C-5) 145.22 (C-3) 138.12 (C-4) and 120.00–137.11 (2 phenyl C) (Found C 63.5; H 5.6; N 16.2.Calc. for C18H18N4OS C 63.9; H 5.3; N 16.56). Compound 3g. Pale yellow crystals (55) mp 168 8C; nmax/ cm21 (KBr) 3443 3340 and 3198 (NH2 NH) and 1660 (CO) (Found C 61.4; H 5.4; N 15.5. Calc. for C18H18N4O2S2 C 61.0; H 5.1; N 15.8). Compound 3h. Colourless crystals (70) mp 160 8C; nmax/ cm21 (KBr) 3427 3376 and 3321 (NH2 NH) 1662 (CO) and 1535 (C N) (Found C 56.6; H 4.4; N 15.3. Calc. for C17H15ClN4OS C 56.9; H 4.2; N 15.62). 3-Amino-5-methylthiopyrrol-2-ones 4a–e General procedure. A mixture of compounds 2a–e (0.01 mol) and formamide (0.01 mol) was heated in ethanol (20 ml) containing a catalytic amount of piperidine for 3 h. After this the product was collected and recrystallized from the appropriate solvent. Compound 4a. Brown crystals (75) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3325 and 3161 (NH2 NH) and 1662 (CO); dH(CD3)2SO 2.51 (s 3H SCH3) 5.51 (s 2H NH2) 7.21–7.50 (m 5H C6H5) and 9.68 (s br 1H NH); m/z 262 (Found C 55.6; H 4.5; N 15.8.Calc. for C12H11N3O2S C 55.1; H 4.2; N 16.0). Compound 4b. Brown crystals (70) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3330 and 3154 (NH2 NH) and 1658 (CO) (Found C 56.2; H 4.5; N 15.6. Calc. for C13H13N3O2S C 56.7; H 4.7; N 15.3). Compound 4c. Brown crystals (74) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3326 and 3154 (NH2 NH) and 1656 (CO) (Found C 53.4; H 4.6; N 14.1. Calc. for C13H13N3O3S C 53.6; H 4.5; N 14.4). Compound 4d. Brown crystals (65) from EtOH mp >300 8C; nmax/cm21 (KBr) 3329 and 3156 (NH2 NH) and 1660 (CO) (Found C 51.41; H 3.23; N 15.41. Calc. for C12H10ClN3OS C 51.61; H 3.58; N 15.05).6-Amino-3-cyano-4-methylthiopyridin-2-ones 7a–e General procedure. A mixture of equivalent amounts (0.01 mol) of compound 2a–e and cyanoacetohydrazide was refluxed in ethanol containing a catalytic amount of piperidine for 6 h. After cooling of the reaction mixture the product was filtered off and recrystallized from ethanol. Compound 7a. Yellow crystals (75) mp 182 8C; nmax/cm21 (KBr) 3269 3207 and 3144 (NH2 NH) 2200 (CN) and 1669 (CO); dH(CD3)2SO 2.26 (s 3H SCH3) 3.42 (s 2H NH2) 3.89 (s 2H NH2) 7.10–7.41 (m 5H C6H5) and 10.25 (s br 1H NH) (Found C 53.1; H 4.5; N 22.5. Calc. for C14H13N5O2S C 53.3; H 4.1; N 22.2). Compound 7b. Yellow crystals (70) mp 148 8C; nmax/cm21 (KBr) 3271 and 3204 (NH2 NH) 2174 (CN) and 1664 (CO) (Found C 54.5; H 4.2; N 21.6.Calc. for C15H15N5O2S C 54.7; H 4.5; N 21.3). Compound 7c. Yellow crystals (65) mp 165 8C; nmax/cm21 (KBr) 3250 and 3019 (NH2 NH) 2188 (CN) and 1708 (CO) (Found C 52.4; H 4.6; N 20.1. Calc. for C15H15N5O3S C 52.2; H 4.3; N 20.3). Compound 7d. Yellow crystals (80) mp 202 8C; nmax/cm21 (KBr) 3240 and 3077 (NH2 NH) 2200 (CN) and 1660 (CO); dH(CD3)2SO 2.46 (s 3H SCH3) 3.35 (s 2H NH2) 7.31–7.6 (m 4H C6H4) 8.24 (s 2H NH2) and 13.21 (s br 1H NH); m/z 349 (Found C 48.2; H 3.6; N 20.2. Calc. for C14H12Cl- N5O2S C 48.0; H 3.4; N 20.0). Pyrazolo4,3-cpyridin-2-ones 10a–d General procedure. A mixture of equivalent amounts (0.01 mol) of 7a–d and hydrazine hydrate was heated in ethanol containing a catalytic amount of piperidine for 6 h. The product was filtered off and recrystallized from the appropriate solvent.Compound 10a. Brown crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3300 3245 and 3023 (NH2 NH) and 1654 (CO); dH(CD3)2SO 3.41 (s 2H NH2) 3.41 (s 2H NH2) 6.16 (s 2H NH2) 7.31–7.62 (m 5H C6H5) 7.78 (s 2H NH2) 9.26 (s br 1H ring NH) and 12.30 (s br 1H NH) (Found C 52.5; H 4.5; N 32.3. Calc. for C13H13N7O2 C 52.2; H 4.3; N 32.8). Compound 10b. Yellow crystals (55) from EtOH–DMF mp >183 8C; nmax/cm21 (KBr) 3404 3317 and 3200 (NH2 NH) and 1659 (CO) (Found C 53.2; H 4.5; N 31.6. Calc. for C14H15N7O2 C 53.6; H 4.8; N 31.3). 3288 J. Chem. Soc. Perkin Trans. 1 1997 Compound 10c. Yellow crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3320 and 3197 (NH2 NH) 1660 (CO) and 1544 (C N) (Found C 51.5; H 4.4; N 29.5. Calc. for C14H15N7O3 C 51.1; H 4.5; N 29.8).Compound 10d. Yellow crystals (60) from EtOH–DMF mp 300 8C; nmax/cm21 (KBr) 3409 3310 and 3112 (NH2 NH) 1653 (CO) and 1603 (C N); dH(CD3)2SO 3.36 (s 2H NH2) 3.47 (s 2H NH2) 6.14 (2H NH2) 7.32–7.56 (m 4H C6H4) 7.65 (s 2H NH2) 9.24 (s br 1H ring NH) and 12.28 (s br 1H NH) m/z 334 (Found C 46.5; H 3.9; N 29.8. Calc. for C13H12ClN7O2 C 46.8; H 3.6; N 29.4). 1,4-Diamino-6-methylthiopyrimidine-2-thiones 8a–d General procedure. To a solution of sodium isopropoxide (0.01 mol) equimolar amounts of compounds 2a–e (0.01 mol) and thiosemicarbazide (0.01 mol) were added. The reaction mixture was refluxed for 3 h and then neutralized with dilute hydrochloric acid. The resulting precipitate was filtered off and recrystallized from the appropriate solvent. Compound 8a.Brown crystals (52) from DMF mp >300 8C; nmax/cm21 (KBr) 3860 and 3139 (NH2 NH) 1690 (CO) and 1539 (C N) (Found C 47.4; H 3.5; N 22.4. Calc. for C12H12N5OS2 C 47.0; H 3.9; N 22.9). Compound 8b. Brown crystals (51) from DMF mp >300 8C; nmax/cm21 (KBr) 3750 and 3220 (NH2 NH) 1648 (CO) and 1548 (C N); dH(CD3)2SO 2.25 (s 3H CH3) 2.51 (s 3H SCH3) 3.89 (s 2H NH2) 7.15–7.50 (m 4H C6H4) 8.24 (s 2H NH2) and 13.00 (s br 1H NH) (Found C 48.1; H 4.2; N 22.1. Calc. for C13H15N5OS2 C 48.6; H 4.8; N 21.8). Compound 8c. Pale yellow crystals (52) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3444 3377 and 3116 (NH2 NH) 1647 (CO) and 1536 (C N) (Found C 46.5; H 4.2; N 20.4. Calc. for C13H15N5O2S2 C 46.29; H 4.4; N 20.8). Compound 8d. Brown crystals (53) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3190 and 3092 (NH2 NH) 1676 (CO) and 1558 (C N); dH(CD3)2SO 2.51 (s 3H SCH3) 3.51 (s 2H NH2) 7.31–7.62 (m 4H C6H4) 8.26 (s 2H NH2) and 13.21 (s br 1H NH); m/z 342 (Found C 42.5; H 3.1; N 20.1.Calc. for C12H12ClN5OS2 C 42.2; H 3.5; N 20.5). 6-Amino-3-cyano-4-methylthiopyridin-2-ones 9a–b General procedure. A mixture of an equivalent amount (0.01 mol) of compounds 2a–e and cyanothioacetamide was refluxed in ethanol containing a catalytic amount of piperidine for 6 h. After cooling of the reaction mixture the product was filtered off and then recrystallized from ethanol. Compound 9a. Yellow crystals (65) from EtOH mp 170 8C; nmax/cm21 (KBr) 3406 3267 and 3203 (NH2 NH) 2220 (CN) and 1687 (CO) (Found C 54.7; H 4.5; N 16.5. Calc. for C15H14N4OS2 C 54.5; H 4.2; N 16.9).Compound 9b. Yellow crystals (70) from EtOH mp 165 8C; nmax/cm21 (KBr) 3270 3187 and 3056 (NH2 NH) 2222 (CN) and 1669 (CO); dH(CD3)2SO 2.47 (s 3H SCH3) 7.31–7.59 (m 4H C6H4) 7.64 (s 2H NH2) 8.30 (s br 1H ring NH) and 13.24 (s br 1H NH) (Found C 48.3; H 3.5; N 15.8. Calc. for C14H11ClN4OS2 C 48.0; H 3.1; N 16.0). Pyrazolo4,3-cpyridin-2-ones 11a–b General procedure. A mixture of equivalent amounts (0.01 mol) of 9a–b and hydrazine hydrate was heated in ethanol containing a catalytic amount of piperidine for 6 h. The product was filtered off and recrystallized from EtOH–DMF solvent. Compound 11a. Brown crystals (54) mp >300 8C; nmax/ cm21 (KBr) 3270 3207 and 3144 (NH2 NH) 1688 (CO) and 1560 (C N) (Found C 53.7; H 4.6; N 26.5. Calc. for C14H14N6OS C 53.5; H 4.4; N 26.8).Compound 11b. Brown crystals (60) mp >300 8C; nmax/ cm21 (KBr); 3440 and 3196 (NH2 NH) and 1652 (CO); dH(CD3)2SO 7.02 (s 2H NH2) 7.22–7.51 (m 4H C6H4) 8.86 (s 2H NH2) and 10.6 (s br 1H NH); m/z 334 (Found C 46.2; H 3.7; N 24.7. Calc. for C13H11ClN6OS C 46.6; H 3.3; N 25.0). Bis(methylthiomethylene)cyanoacetamide 12 General procedure. A mixture of sodium ethoxide (0.02 mol) and cyanothioacetamide (0.01 mol) was heated for 20 min after which it was cooled and treated with carbon disulfide (0.01 mol). The reaction mixture was warmed for 20 min and after cooling was treated with methyl iodide (0.02 mol). It was then poured onto ice–water and neutralized with dilute hydrochloric acid. The precipitated product was filtered off and recrystallized from ethanol. Compound 12.Brown crystals (70) mp 185 8C; nmax/cm21 (KBr) 3218 3215 and 3048 (NH2 NH) and 2218 (CN); dH(CD3)2SO 2.59 (s 3H SCH3) 2.61 (s 3H SCH3) 3.44 (s 2H NH2) and 12.00 (s br 1H NH); m/z 204 (Found C 35.6; H 3.5; N 13.4. Calc. for C6H8N2S3 C 35.3; H 3.9; N 13.7). 5-Amino-3-methylthiopyrazole 13a–b General procedure. A mixture of compound 12 (0.01 mol) and hydrazine hydrate or phenylhydrazine (0.01 mol) was refluxed in ethanol (20 ml) for 6 h. After cooling of the reaction mixture the solid product was filtered off and recrystallized. Compound 13a. Red crystals (55) from EtOH–DMF mp >300 8C; nmax/cm21 (KBr) 3400 3296 and 3174 (NH2 NH) and 1579 (C N); dH(CD3)2SO 2.52 (s 3H SCH3) 5.51 (s 2H NH2) and 7.81 (s br 1H NH); m/z 188 (Found C 31.4; H 4.6; N 29.4. Calc. for C5H8N4S2 C 31.9; H 4.2; N 29.7).Compound 13b. Brown crystals (70) from EtOH mp >300 8C; nmax/cm21 (KBr) 3370 and 3158 (NH2 NH) (Found C 50.3; H 4.1; N 21.7. Calc. for C11H12N4S2 C 50.0; H 4.5; N 21.2). 3-Amino-5-methylthiopyrrol-2-one 14 A mixture of compound 12 (0.01 mol) and formamide (0.01 mol) was heated in ethanol (20 ml) containing a catalytic amount of piperidine for 3 h. After this the product was collected and recrystallized from EtOH. Compound 14. Brown crystals (70) mp 240 8C; nmax/cm21 (KBr) 3330 and 3142 (NH2 NH) and 1653 (CO) (Found C 35.5; H 3.6; N 20.6. Calc. for C6H7N3OS2 C 35.8; H 3.4; N 20.9). 6-Amino-3-cyano-4-methylthiopyridin-2-one 17 A mixture of compound 12 (0.01 mol) and cyanoacetohydrazide (0.01 mol) was refluxed in ethanol containing a catalytic amount of piperidine for 6 h.After cooling of the reaction mixture the final product was filtered off and recrystallized from EtOH–DMF to give brown crystals (60) mp >300 8C; nmax/cm21 (KBr) 3385 3228 and 3082 (NH2 NH) 2200 (CN) and 1658 (CO); m/z 256 (Found C 54.5; H 3.7; N 27.6. Calc. for C8H9N5OS2 C 37.6; H 3.5; N 27.5). Pyrazolo4,3-cpyridin-2-one 20 A mixture of 17 (0.01 mol) and hydrazine hydrate (0.01 mol) was heated in ethanol containing a catalytic amount of piperidine for 6 h. The product was filtered off and recrystallized from EtOH to afford brown crystals (70) mp >300 8C; nmax/ cm21 (KBr) 3132 and 3043 (NH2 NH) 1680 (CO) and 1591 (C N) (Found C 35.5; H 3.5; N 41.3. Calc. for C7H9N7OS C 35.1; H 3.8; N 41.0). 1,4-Diamino-5-aminothiocarbonyl-6-(methylthio)pyrimidine-2- thione 18 To a solution of sodium isopropoxide (0.01 mol) compound 12 (0.01 mol) and thiosemicarbazide (0.01 mol) were added.The reaction mixture was refluxed for 3 h after which it was neutralized with dilute hydrochloric acid and the product then filtered off and recrystallized from EtOH–DMF to give brown crystals (55) mp >300 8C; nmax/cm21 (KBr) 3384 3343 3228 and 3138 (NH2 NH) and 1556 (C N); dH(CD3)2SO 2.52 (s 3H, J. Chem. Soc. Perkin Trans. 1 1997 3289 SCH3) 3.21 (s 2H NH2) 3.24 (s 2H NH2) and 3.37 (s 2H NH2); m/z 247 (Found C 29.4; H 3.4; N 28.6. Calc. for C6H9N5S3 C 29.1; H 3.6; N 28.3). 3-Cyano-4-methylthiopyridine-2-ones 19 Equivalent amounts (0.01 mol) of 12 and ethyl cyanoacetate were refluxed in ethanol (20 ml) containing a few drops of piperidine for 6 h.After this the product was filtered off and recrystallized from ethanol to give yellow crystals (70) mp 190 8C; nmax/cm21 (KBr) 3200 and 3093 (NH2 NH) 2174 (CN) and 1660 (CO); dH(CD3)2SO 2.52 (s 3H SCH3) 9.42 (s br H NH) and 12.89 (s br 1H OH) (Found C 60.1; H 4.3; N 19.3. Calc. for C15H12N4OS C 60.4; H 4.0; N 18.9). References 1 G. E. H. Elgemeie H. A. Ali and A. M. Elzanaty J. Chem. Res. (S) 1996 340. 2 H. Junjappa H. Ila and C. V. Asokar Tetrahedron 1990 46 5423. 3 Y. Matsude M. Yamashita K. Takahashi S. Ide K. Torisu and K. Furuno Heterocycles 1992 33 295. 4 A. Hsomi Y. Miyashiro R. Yoshida Y. Tominaga T. Yamagi and M. Hojo J. Org. Chem. 1990 55 5308. 5 G. E. H. Elgemeie and B. A. W. Hussain Tetrahedron 1994 50 199. 6 G. E. H. Elgemeie A. M. Attia and N. M. Fathy Liebigs Ann.Chem. 1994 955. 7 G. E. H. Elgemeie and A. M. Atia Carbohydr. Res. 1995 268 295. 8 G. E. H. Elgemeie A. M. Elzanaty and A. K. Mansour J. Chem. Soc. Perkin Trans. 1 1992 1037. 9 G. E. H. Elgemeie A. M. Attia D. S. Farag and S. M. Sherif J. Chem. Soc. Perkin Trans. 1 1994 1285. 10 G. E. H. Elgemeie S. E. Elezbawy H. A. Ali and A. K. Mansour Bull. Chem. Soc. Jpn. 1994 67 738. Paper 7/02343J Received 7th April 1997 Accepted 8th July 1997 © Copyright 1997 by the Royal Society of Chemistry