Mendeleev Communications Electronic Version, Issue 2, 2002 1 Interaction of diazoimidazoles and their diazonium salts with primary and secondary amines Elena V. Sadtchikova* and Vladimir S. Mokrushin Department of Technology of Organic Synthesis, Urals State Technical University, 620002 Ekaterinburg, Russian Federation. Fax: +7 3432 74 0458; e-mail: seb@htf.ustu.ru 10.1070/MC2002v012n02ABEH001570 A number of 2- and 5-triazenoimidazoles were prepared by the coupling of diazo compounds with aliphatic amines; however, 4,5-dicyanoimidazole- 2-diazonium chloride was transformed into 2-amino-1-methylimidazole-4,5-dicarbonitrile. It is well known that dacarbazine [5-(3,3-dimethyl-1-triazeno)- imidazole-5-carboxamide, DTIC] is one of the most active anticancer drugs for the treatment of malignant melanomas and Hodgkin tumors.1 In in vivo experiments, dacarbazine generates the corresponding monomethyltriazene derivative, which undergoes proteolytic decomposition into 5-aminoimidazole-4-carboxamide (AIC) and a reactive methanediazonium species.The cytotoxic effect of the latter is due to the methylation of guanine residues in DNA.2 Here, we report on the interaction of diazotised 2- and 5-aminoimidazoles3–5 with primary and secondary amines, which was carried out to prepare more stable structural analogues of dacarbazine and its N-demethylated derivative. 5-(3,3-Dialkyl- 1-triazeno)imidazoles bearing nitro, cyano, aminocarbonyl and ethoxy groups at the 4-position were prepared earlier.4–7 We applied a similar procedure to obtain dialkyltriazenoimidazoles 3a–c and 4a–d† on the basis of 4,5-dicyanoimidazole-2-diazonium chloride3 1a, 5-diazoimidazol-4-morpholylcarboxamide 2a, 5-diazoimidazol-4-N-(p-tolyl)carboxamide 2b and its diazonium salt as diazo components.8 The reactions of diazo imidazoles with primary amines are of considerable interest.Since it is well known that monoalkyltriazeno derivatives are photosensitive and unstable substances, their reactions were carried out in the dark at low temperature. Monomethyltriazenoimidazoles 4e,f† were obtained by the reactions of 5-diazoimidazol-4-morpholylcarboxamide 2a and 5-diazoimidazol-4-N-methylcarboxamide 2c with methylamine.Similar conversions of diazo compound 2b and its diazonium salt allowed us to obtain 3-p-tolyl-3,7-dihydroimidazo[4,5-d]- [1,2,3]triazine-4-one 5a in almost quantitative yield as the only product, thus indicating that the intramolecular coupling reaction proceeds faster than the intermolecular one.Ethyl 5-diazoimidazole- 4-carboxylate 2d reacted with methylamine in a similar way to give imidazotriazinone derivative 5b. Unexpectedly, the reaction of diazonium salt 1a with methylamine resulted in the formation of 2-amino-1-methylimidazole- 4,5-dicarbonitrile 6 in 78% yield.We believe that unstable triazene 3d initially formed under the reaction conditions affords diazomethane. It generates a carbene species, which is capable of alkylating at NH of the imidazole ring. The structure of amine 6 was confirmed by 1H NMR spectroscopy, as well as by chemical conversions.‡ Thus, under diazotization conditions (NaNO2/HCl) compound 6 is transformed into 4,5-dicyano- 1-methylimidazole-2-diazonium chloride 1b, which affords N N COR N N R1 N N COR N2 H N N N N HN O R2 MeNH2 HR1 2a–c 2d 4a–f 2a– d 5a, b 2a R = morpholyl 2b R = NHC6H4-Me-p 2c R = NHMe 2d R = OEt 5a R2 = C6H4-Me-p 5b R2 = Me 4a R = morpholyl, R1 = NMe2 4b R = morpholyl, R1 = piperidinyl 4c R = NHC6H4-Me-p, R1 = piperidinyl 4d R = NHC6H4-Me-p, R1 = morpholyl 4e R = R1 = NHMe 4f R = morpholyl, R1 = NHMe Scheme 1 † All melting points are uncorrected.IR spectra were recorded on a Specord M-75 instrument in KBr pellets. 1H NMR spectra were recorded on a Bruker WR-250 instrument (250 MHz) in ([2H6]DMSO + CCl4) using TMS as an internal standard. General procedure for the synthesis of the triazeneimidazoles 3a–c and 4a–f. To a mixture of 1 mmol of 2- or 5-diazoimidazole (1a or 2a–d) in 3 ml of dry acetonitrile was added 10 mmol of a corresponding amine at –5 to 0 °C.The reaction mixture was kept in the dark at low temperature until the diazo compound disappeared (10–30 min). Crude products were collected by filtration. The precipitates were either crystallised from ethanol–chloroform or washed with diethyl ether. 3a: yield 62%, mp 136 °C. 1H NMR, d: 13.26 (br. s, 1H, NH), 3.64 (s, 3H, Me), 3.28 (s, 3H, Me). IR, n/cm–1: 3400, 2970, 2925, 2245, 1570. Found (%): C, 44.15; H, 3.77; N, 51.91. Calc. for C7H7N7 (%): C, 44.44; H, 3.73; N, 51.83. 3b: yield 98%, mp 143 °C. 1H NMR, d: 13.44 (br. s, 1H, NH), 3.67 (m, 2H, CH2), 3.05 (m, 2H, CH2), 1.70 (m, 6H, 3CH2).IR, n/cm–1: 3450, 2970, 2945, 2860, 2210, 1610. Found (%): C, 52.28; H, 4.79; N, 42.83. Calc. for C10H11N7 (%): C, 52.39; H, 4.84; N, 42.77. 3c: yield 96%, mp 157 °C. 1H NMR, d: 13.28 (br. s, 1H, NH), 3.73 (m, 6H, 2CH + 2CH2), 3.11 (m, 2H, 2CH). IR, n/cm–1: 3470, 2990, 2915, 2870, 2210, 1625. Found (%): C, 46.66; H, 3.88; N, 42.47. Calc. for C9H9N7O (%): C, 46.75; H, 3.92; N, 42.40. 4a: yield 74%, mp 152 °C. 1H NMR, d: 12.32 (br. s, 1H, NH), 7.45 (s, 1H, 2-H), 3.57 (s, 3H, Me), 3.53 (s, 3H, Me), 3.43 (m, 6H, 2CH + 2CH2), 3.16 (m, 2H, 2CH). IR, n/cm–1: 3415, 2955, 2900, 2860, 1610. Found (%): C, 47.64; H, 6.41; N, 33.21. Calc. for C10H16N6O2 (%): C, 47.61; H, 6.39; N, 33.31. 4b: yield 89%, mp 114 °C. 1H NMR, d: 12.17 (br. s, 1H, NH), 7.38 (s, 1H, 2-H), 3.73 (m, 4H, 2CH2), 3.57 (m, 8H, 4CH2), 1.69 (m, 6H, 3CH2).IR, n/cm–1: 3390, 2965, 2935, 2910, 2850, 1590. Found (%): C, 53.35; H, 6.93; N, 28.67. Calc. for C13H20N6O2 (%): C, 53.41; H, 6.90; N, 28.75. 4c: yield 85%, mp 216 °C. 1H NMR, d: 12.29 (br. s, 1H, NH), 7.84 (s, 1H, 2-H), 7.38 (d, 2H, 2',6'-H, J 8.24 Hz), 7.31 (d, 2H, 3',5'-H, J 8.24 Hz), 3.01 (m, 4H, 2CH2), 2.39 (s, 3H, Me), 1.63 (m, 6H, 3CH2).IR, n/cm–1: 3435, 3350, 2985, 2940, 2925, 2860, 1690, 1620. Found (%): C, 61.44; H, 6.45; N, 26.93. Calc. for C16H20N6O (%): C, 61.52; H, 6.45; N, 26.90. 4d: yield 83%, mp 237 °C. 1H NMR, d: 12.42 (br. s, 1H, NH), 8.03 (s, 1H, 2-H), 7.41 (d, 2H, 2',6'-H, J 8.24 Hz), 7.33 (d, 2H, 3',5'-H, J 8.24 Hz), 3.65 (m, 4H, 2CH2), 2.93 (m, 4H, 2CH2), 2.40 (s, 3H, Me).IR, n/cm–1: 3430, 3350, 3075, 2980, 2930, 2875, 1680, 1615. Found (%): C, 57.22; H, 5.74; N, 26.46. Calc. for C15H18N6O2 (%): C, 57.31; H, 5.77; N, 26.73. 4e: yield 55%, mp 168 °C. 1H NMR, d: 12.65 (br. s, 1H, NH), 10.70 (q, 1H, NHMe, J 3.66 Hz), 7.78 (q, 1H, CONHMe, J 4.58 Hz), 7.52 (s, 1H, 2-H), 3.03 (d, 3H, NHMe, J 3.66 Hz), 2.85 (d, 1H, CONHMe, J 4.58 Hz).IR, n/cm–1: 3290, 3090, 1640, 1570. Found (%): C, 39.67; H, 5.42; N, 46.22. Calc. for C6H10N6O (%): C, 39.56; H, 5.53; N, 46.13. 4f: yield 61%, mp 139 °C. 1H NMR, d: 12.24 (br. s, 1H, NH), 10.45 (m, 1H, NHMe), 7.34 (s, 1H, 2-H), 3.59 (m, 8H, 4CH2), 3.01 (d, 3H, J 3.60 Hz, NHMe). IR, n/cm–1: 3320, 3070, 2955, 2900, 2860, 1585. Found (%): C, 45.34; H, 5.84; N, 35.23. Calc. for C9H14N6O2 (%): C, 45.37; H, 5.92; N, 35.27.‡ 2-Amino-1-methylimidazole-4,5-dicarbonitrile 6. To a solution of 0.2 g (1.11 mmol) of diazonium salt 1a in 5 ml of acetonitrile a solution of 0.05 ml (1.11 mmol) of methylamine in 5 ml of acetonitrile was added at 0 °C. The mixture was kept in the dark for 5 min. The removal of the solvent under a reduced pressure gave amine 6, which was crystallised from ethanol (0.12 g, 75%).Mp 165 °C. 1H NMR, d: 6.83 (br. s, 2H, NH2), 3.46 (s, 3H, Me). IR (KBr, nmax/cm–1): 3250, 3170, 2910, 2240, 2220, 1630, 1580. Found (%): C, 49.04; H, 3.42; N, 47.69. Calc. for C6H5N5 (%): C, 48.98; H, 3.43; N, 47.60.Mendeleev Communications Electronic Version, Issue 2, 2002 2 2-(4-dimethylaminophenylazo)-1-methylimidazole-4,5-dicarbonitrile 7§ upon coupling with N,N-dimethylaniline. Thus, we found that the reactions of diazoimidazoles with aliphatic amines result in a variety of compounds, one of which is N-methylated imidazole derivative 6.This work was supported by the Russian Foundation for Basic Research (grant no. 01-03-96433a) and the US Civilian Research and Development Foundation (project no. RC1-2393-EK-02).References 1 Registr lekarstvennykh sredstv Rossii. Entsiklopediya lekarstv (Register of Medicinal Means of Russia. Encyclopædia of Medicine), 8th edn., ed. Yu. F. Krylov, Registr Lekarstvennykh Sredstv, Moscow, 2001, p. 251 (in Russian). 2 B. J. Denny, R. T. Wheelhouse, M. F. G. Stevens, L. L. H. Tsang and J. A. Slack, Biochemistry, 1994, 33, 9045. 3 W. A. Sheppard and O.W. Webster, J. Am. Chem. Soc., 1973, 95, 2695. 4 V. S. Mokrushin, I. S. Selezneva, T. A. Pospelova, V. K. Usova, S. M. Malinskaya, G. M. Anoshina and Z. V. Pushkareva, Khim.-Farm. Zh., 1982, 3, 303 (in Russian). 5 Y. E. Shealy, C. A. Krauth and J. A. Montgomery, J. Org. Chem., 1962, 27, 2150. 6 Y. E. Shealy, J. Pharm. Sci., 1970, 59, 1533. 7 T. A. Pospelova, Yu. M. Shafran, V. S.Mokrushin, Z. V. Pushkareva and G. M. Anoshina, Khim.-Farm. Zh., 1982, 5, 543 (in Russian). 8 E. V. Sadtchikova and V. S. Mokrushin, Khim. Geterotsikl. Soedin., in press. § 2-(4-Dimethylaminophenylazo)-1-methylimidazole-4,5-dicarbonitrile 7. A suspension of 0.1 g (0.68 mmol) of amine 6 in 5 ml of 2 N HCl was cooled to –5 °C with stirring. Then, 0.06 g (0.82 mmol) of sodium nitrite in 1 ml of water was added dropwise to the reaction mixture. The resulting mixture was stirred for 15 min. After diazotization, 0.1 ml (0.82 mmol) of N,N-dimethylaniline was added. The resulting suspension was filtered, and the product was recrystallised from ethanol (0.15 g, 79%). Mp 202 °C. 1HNMR, d: 7.82 (d, 2H, 2',6'-H, J 9.16 Hz), 6.83 (d, 2H, 3',5'-H, J 9.16 Hz), 3.42 (s, 3H, Me), 3.17 (s, 6H, 2Me). IR (KBr, nmax/cm–1): 3160, 3050, 2910, 2230, 2220, 1595. Found (%): C, 60.13; H, 4.61; N, 35.19. Calc. for C14H13N7 (%): C, 60.20; H, 4.69; N, 35.10. N N NC NC H N N R1 3a–c N N NC NC H N2Cl 1a R1–H MeNH2 N N NC NC H N N NH 3d Me N N NC NC NH2 6 Me N N NC NC N2Cl 1b Me N N NC NC N 7 Me PhNMe2 N NMe2 3a R1 = NMe2 3b R1 = piperidinyl 3c R1 = morpholyl Scheme 2 Received: 28th February 2002; Com. 02/1896