Electrochemical Reduction of 1-Aryl-4-nitroazoles

Transcription

1 Polish J.Chem., 74, (2000) Electrochemical Reduction of 1-Aryl-4-nitroazoles by A. Tallec 1, R. azard 1, J. Suwiñski 2* and P. Wagner 2 1 Laboratoire d Electrochimie, Université de Rennes 1, Campus de Beaulieu, Rennes Cedex, France 2 Institute of Organic Chemistry and Technology, Silesian University of Technology, Krzywoustego 4, Gliwice, Poland, * suwinski@polsl.gliwice.pl (Received March 20th, 2000) Electrochemical reduction of the nitro group in 1-aryl-4-nitroazoles occurs in slightly acidic medium as a typical four-electron process leading to hydroxylamine group formation. The forming 1-aryl-4-hydroxylaminoazoles undergo further reactions. Stability of the hydroxylamines depends on the heteroring (imidazole or pyrazole) and on C-substituents. More stable derivatives condense with the nitroso intermediates to yield azoxycompounds. Less stable hydroxylamines undergo rearrangements, azole ring reduction and decomposition. Some products of these transformations, following the electrochemical reduction, were isolated and their structures were fully characterized by standard methods. Key words: nitroazoles, electroreduction, mechanisms Reduction of nitroazoles is important because of their activity in biological systems. Moreover, metabolic reduction of the nitro group is responsible for the toxicity of nitro compounds [1]. Many studies have reported on radiosensitizing efficiency of nitroazoles in cancer therapy related to their high reduction potentials [2]. It is known that nitroazoles follow the general pattern of other aromatic nitro compounds reduction. Therefore, the nitro group is reduced to the amino group via the nitroso and hydroxylamine groups. Electrochemical (polarographic or voltammetric) reduction of the nitro group occurs in slightly acidic medium as a four-electron process, leading to the hydroxylamine group formation (wave 1). A possible condensation of the nitroso and hydroxylamino derivatives yields azoxycompounds that can be further reduced. Moreover, in an acidic medium the protonated hydroxylamino group can undergo a two-electron reduction, leading to a formation of the amino group (wave 2) [3]. Several hydroxylamino- and aminoazoles are unstable and decompose in the reaction media to ring opening products [4]. Thus, products of 4-nitroazoles electrochemical reduction have been isolated in a few cases only. umerous papers concern the electroreduction of 1-alkyl-4-nitroazoles [5], none of them describing the electrochemical behavior of 4-nitroazoles with -aryl substituent yet. This paper intends to fill this gap. For a long time 1-aryl-4-nitroazoles, particularly 1-phenyl-4-nitroimidazoles have not been available. Recently, we have * Author for correspondence

2 1178 A. Tallec et al. elaborated a very efficient method for their synthesis. It involves a treatment of 1,4-dinitroimidazoles with aniline or its C-substituted derivatives in aqueous-methanol solution at room temperature [6]. Some 1-aryl-4-nitroimidazoles have been tested as radiosensitizers of hypoxic tumor cells, showing a higher efficiency as compared with the corresponding 1-alkyl derivatives [7]. Since biological toxicity and radiosensitizing efficiency of nitro compounds involve their reduction and depend on their reduction potentials, we have studied the polarographic and voltammetric behaviors of some 4-nitro-1-phenylazoles. EXPERIMETAL Synthesis of 4-nitroazoles: Starting 1-aryl-4-nitroimidazoles 1a c were obtained according to [6]. Properties of the compounds were in accordance with those reported there. Synthesis of 5-cyano-2-methyl-4-nitro and of 5-carbamoyl-2-methyl-4-nitro (1d e) we also described earlier [11]. 1-Benzyl-4-nitroimidazole (1f, m.p C) we obtained by alkylation of 4(5)-nitroimidazole with benzyl bromide using a known method [13]. 1-enyl-4-nitropyrazole (1f, m.p C) was prepared according to [6]. Polarographic and voltammetric measurements: Polarograms were recorded at a dropping mercury electrode (dropping time = 2 s) using a three-electrode PAR 362 potentiostat coupled with a XY Kipp & Zonen recorder. The starting material concentration in a mixture of aqueous supporting electrolyte and ethanol (1:1) was 10 3 mole/dm 3. The compositions of three supporting electrolytes were: sulfuric acid (0.5 mole/dm 3 ), acetate buffer (acetic acid 0.5 mole/dm 3, sodium acetate 0.5 mole/dm 3 )or hydrochloric acid (3 mole/dm 3 ). Voltammetric curves were recorded at a Metrohm MDE with the same apparatus as above at a scan rate of 0.2 or 0.5 Vs 1. Preparative electrolyses: Preparative electrolyses were carried out at a mercury pool electrode in the cell described in [15]. The working potential was imposed by a Tacussel PRT potentiostat, while the reference electrode was a saturated calomel electrode (SCE). An amount of electricity was measured with Tacussel IG5 coulometer. For a typical run, the starting material (10 2 mole) was dissolved in 120 cm 3 of the catolyte (aqueous supporting electrolyte and ethanol 1:1); electrolysis was then performed under continuous nitrogen flow. The post-reaction mixtures were neutralized with a saturated sodium bicarbonate solution. Ethanol was evaporated then under diminished pressure at ca. 50 C. Possible precipitations were collected and the filtrate extracted three times with methylene chloride. The extracts were dried by anhydrous magnesium sulfate(vi) and the solvent was evaporated under diminished pressure at 50 C. The residue and precipitations were combined and recrystallized from suitable solvents as indicated below. Characteristic of the isolated products: 4-Imino-1-phenyl-5-imidazolidinone yield 66%; m.p. (ethanol-water) C; 1 MR (ppm, chloroform-d 1 ): (m, 5, Ar), 5.46 (br. s, 2, 2 ), 5.27 (s, 2, C 2 ); 13 C MR (ppm, chloroform-d 1 ): , , , , , , 69.12; RMS 70 ev for C O requires: , found: ; MS 70 ev (m/e, %) M + : 175 (49.52), 119 (2.50), 104 (5.14), 77 (9.90), 56 (100.00). 4-Imino-1-benzyl-5-imidazolidinone yield 54%; m.p. (ethanol-water) C; 1 MR (ppm, chloroform-d 1 ): (m, 5, Ar), 5.17 (br. s, 2, 2 ), 4.58 (s, 2, C 2 ), 4.50 (s, 2, C 2 ); 13 C MR (ppm, chloroform-d 1 ): , , , , , , 68.38, 46.06; MS 70 ev (m/e, %) M + : 189 (90.9), 106 (46.4), 91 (100.0), 57 (78.3); Found for C O: C 63.70; 5.72, 22, requires: 13C 63.48, 5.86, ,4 -Azoxy-5,5 -dicyano-2,2 -dimethyl-1,1 -diphenyl-imidazole yield 93%; m.p. (ethanol) 265 C dec.; 1 MR (ppm, chloroform-d 1 ): (m, 10, Ar), 1.93 (s, 6, C 3 ); MS 70 ev (m/e, %) M + : 408 (11.7), 364 (44.9), 363 (72.9), 223 (46.9), 155 (25.6), 118 (67.2), 77 (100.0), 52 (30.0); Found for C O: C 64.70, 3.95, 27, requires: 44C 64.70, 3.95, Cyano-4-hydroxylamino-2-methyl yield 40%; m.p. (methanol-water) 152 C dec.; 1 MR (ppm, DMSO-d 6 ): 8.43 (s, 2, O), (m, 5, Ar), 1.67 (s, 3, C 3 );

3 Electrochemical reduction of 1-aryl-4-nitroazoles 1179 MS 70eV (m/e, %) M + : 214 (32.8), 198 (90.5), 156 (67.7), 129 (37.0), 77 (100.0), 52 (58.2); Found for C O: C 61.97, 4.63, 26, requires: 28C 61.67, 4.71, Imino-2-methyl-1-phenylimidazolo[4,5-d]isoxazolinone yield 4.3%; m.p. (ethanol) C; 1 MR (ppm, DMSO-d 6 ): (br. s, 1, ), (s, 1, ), (m, 5, Ar), 2.28 (s, 3, C 3 ); 13 C MR (ppm, DMSO-d 6 ): , , , , , , , 20.84; Found for C O: C 61.61, 4.84, 26.15, requires: C 61.67, 4.71, Amino-5-chloro-1-phenylpyrazole yield 23%; m.p. (petroleum ether) C; 1 MR (ppm, chloroform-d 1 ): (m, 6, Ar + C); RMS 70 ev for C Cl requires: , found: ; MS 70 ev (m/e, %) M + : 193 (99.06), 166 (10.12), 131 (25.91), 104 (100.00), 77 (63.39), 51 (27.30). 4,4 -Azoxy-1,1 -diphenylpyrazole yield 60% [10]. 4,4 -Azoxy-5,5 -dicyano-1,1,3,3 -tetramethylpyrazole yield 67% [10]. 4-Acetylamino-5-hydroxy-1-phenylpyrazole yield 27%; m.p. (ethanol-water) C; 1 MR (ppm, DMSO-d 6 ): (br. s, 1, ), 9.92 (br. s, 1, O), (m, 6, Ar + C), 2.04 (s, 3, C 3 ); 13 C MR (ppm, DMSO-d 6 ): , , , , , 22.20; RMS 70 ev for C O 2 requires: found: ; MS 70 ev (m/e, %) M + : 217 (100.00), 199 (32.81), 175 (55.15), 120 (37.42), 77 (64.90), 43 (64.67). RESULTS AD DISCUSSIO Electrochemical investigations: Polarographic four-electron reduction potentials (E 1/2, wave 1) for the compounds mentioned were measured in the acetate buffer of p = 4.8 (Table). The reduction potentials measured are rather unexpectedly low, considering high toxicity and sensibilizing efficiency of the compounds. Moreover, E 1/2 for 1-benzyl-4-nitroimidazole is much lower ( = 0.12 V) than that of 4-nitro-. As it should be expected, a reduction potential increases with the increase in electron withdrawing character of substituents. Electron releasing effect of the methyl group on the reduction potential is stronger at C5 (1c) than at C2 (1b) position. We have not found E 1/2 polarographic potentials for the corresponding 1-methyl-4-nitroazoles in the acetate buffer of p = 4.8. Possible extrapolation of E 1/2 values, measured under different conditions, could have affected the comparison between 1-alkyl and 1-aryl derivatives. Cyclic voltammetric experiments have proved that 1-aryl-4-nitroimidazoles (1a e), in the acetate buffer - ethanol solution, are reduced indeed to the corresponding hydroxylamines (2a e) (Scheme 1, Figure). R' O 2 R Scheme 1 +4e O R' O 1 2 a: R=R =; b: R=C 3,R =; c: R=, R =C 3 ; d: R=C 3,R =C; e: R=C 3,R =CO 2 R

4 1180 A. Tallec et al. Table. Polarographic E 1/2 potentials for the four-electron reduction of 4-nitro-1-phenylazoles and of 1-benzyl-4-nitroimidazole in the acetate buffer-ethanol solution of p = 4.8. o. 4-nitroazole E 1/2 [V] o. 4-nitroazole E 1/2 [V] 1a 4-nitro d 5-cyano-2-methyl nitro 1b 2-methyl-4-nitro e 5-carbamoyl-2-methyl-4-nitro c 5-methyl-4-nitro f 1-benzyl-4-nitroimidazole nitro-1-phenylpyrazole 0.53 Figure. Cyclic voltammograms recorded for 10 3 M solutions of 1d, 1a, 1b, 1c in 0.5 M acetate buffer + EtO 1:1 by volume. Sweep scan: 200 mvs 1. owever, stability of 2 depends on C-substituents at the imidazole ring and decreases in the order 2d > 2a, 2f > 2b > 2c (see Fig.). Then, the most stable hydroxylamine is 2d, containing the electron withdrawing cyano group at C5 (the reversible system nitroso hydroxylamine is clearly observed at 0.2 Vs 1 ), while the least stable one is 2c (slight appearance of the nitroso hydroxylamine system only at 0.5 Vs 1 ). Electrochemical reduction of 4-nitroimidazoles: Chemical reduction of 1-aryl- -4-nitroimidazoles can be achieved in few ways: by hydrogenation on a metal catalyst [8], by a treatment with iron in carboxylic acid [9] or by the hydride reduction, e.g. with sodium borohydride [10]. In the first two reactions unstable 4-amino-1-arylimidazoles can be isolated only as -acyl derivatives. 4-Amino-5-cyano-2-methyl-

5 Electrochemical reduction of 1-aryl-4-nitroazoles 1181 Scheme 2 C O C 3 [O] C O C 3 2d 5d - 2 O C O C 3 7d 3 C C C O 6d C 3 can be separated as a free base [11]. The hydride reduction leads to 1-aryl-4-oximinoimidazolines; thus, the imidazole ring also undergoes reduction. In contrast to that, the hydride reduction of 1-aryl-4-nitropyrazoles yields azoxycompounds [8]. Those results show that 4-amino- and 4-hydroxylaminoimidazoles, not containing electron-withdrawing substituents at C5, are less stable than isomeric pyrazoles. Therefore, it is not surprising that our attempts of preparative electrochemical reduction of 4-nitros were only partly successful, while 4-nitro-1-phenylpyrazole (3) gave a corresponding azoxycompound in a good yield. Electroreduction of 1d in acetic buffer leads to the relatively stable hydroxylamine 2d; the latter, when left in solution under nitrogen for twelve hours, gives, besides some starting material, a mixture of the azoxy derivative 6d and the iminoisoxazolinone 7d (Scheme 2). The compound 7d probably arises from an intramolecular addition of the -hydroxy group to the neighbouring cyano substituent. The electroreduction of 1e leads to the corresponding hydroxylamine 2e, stable only when kept under nitrogen; nevertheless, it can be reduced at more negative potential into the corresponding amine already obtained by chemical reduction [11]. Moderately stable hydroxylamine 2a prepared in the acetate buffer underwent Gattermann-Bamberger rearrangement to yield 66% of 4-imino-1-phenyl-5- -imidazolidinone (8a). We observed a similar behavior for 2f obtained from 1f and rearranging to 1-benzyl-4-imino-5-imidazolidinone in 54% yield. Thus, the presence of an aryl substituent at 1 is not critical for stability of 4-hydroxylaminoimidazoles since 1-benzyl- and 1-phenyl- derivatives gave products of the same type (Scheme 3). At least, as expected from voltammetric investigations, no significant results have been obtained from electroreduction of compounds 1b and 1c.

6 1182 A. Tallec et al. Scheme 3 rear. O O O 2a 2 8a We also carried out the electrochemical reduction of 4-nitros in dilute sulfuric or hydrochloric acid. It led to the imidazole ring decomposition products with formation of aniline. Electrochemical reduction of 4-nitro-1-phenylpyrazole: Compound 3 was reduced in the acetate buffer to the corresponding hydroxylamine 4 that, when partly oxidized to the nitroso derivative, gave 1,1 -diphenyl-4,4 -azoxypyrazole in 60% yield. ydroxylamine 4, when left overnight in the reaction medium, underwent a partial transformation into 4-acetylamino-5-hydroxypyrazole (9). The mechanism of the transformation is not clear. A similar transformation has been reported for a benzene derivative [12]. One can assume that the acetate anion attacks a protonated molecule of 4 at C5. The attack is accompanied by a departure of the water molecule from the protonated hydroxylamino group. An unstable non-aromatic intermediate transforms into the final product through tautomerization and intramolecular transfer of the acetyl group from the oxygen to the exocyclic imine nitrogen atom (Scheme 4). Scheme 4 +4e + 4 O 2 3 O 4 2 O 3 CCOO 3 COO - 2 O O 2 O- 3 CO 9 4-itro-1-phenylpyrazole (3) reduced in 3 M hydrochloric acid yields 23% of 4-amino-5-chloro-1-phenylpyrazole (10) as the only isolated product. The formation of 10 can be rationalized as follows. A nucleophilic attack of the chloride anion on the protonated hydroxylamine 4, accompanied by departure of a molecule of water, leads to the formation of a non-aromatic intermediate. Tautomerization of the latter yields 10 (Scheme 5). The transformations of 4 in the acetate buffer and in hydrochloric acid seem to be alike in principle, though they yield different products.

7 Electrochemical reduction of 1-aryl-4-nitroazoles 1183 Scheme 5 Cl - 2 O Cl Cl 2 O 2 10 COCLUSIOS Concluding the results obtained we can say that a course of the four-electron electrochemical reduction of 4-nitroazoles in slightly acidic solution does not depend on a ring (imidazole or pyrazole) and on substituents at it. These structural factors affect only the stability of the corresponding hydroxylamines and therefore the structures of the products. This conclusion agrees with conclusions drawn by us from the results of chemical reduction of nitroazoles. REFERECES 1. oss M.B, Panicucci R., McClelland. R.A and Rauth A.M., Biochem.armacol., 37, 2585 (1988). 2. Adams G.E., Flockhart I.R., Smithen C.E.,Stratford I., Wardman P. and Watts M.E., Radiat. Res., 67, 9 (1976). 3. Lund. and Baizer M., Organic Electrochemistry, Marcel Dekker., Y, Katritzky A.R., Rees C.W. and Scriven E.F.V., Comprehensive eterocyclic Chemistry, Pergamon, Exeter, Dumanovic D., Jovanovic J., Suznjevic D., Erceg M. and Zuman P., Electroanalysis, 4, 871 (1992), and references cited therein. 6. Salwiñska E. and Suwiñski J., Polish J. Chem., 64, 813 (1990). 7. Suwiñski J., Szczepankiewicz W. and Wide³ M., Archiv. arm. (Weinheim, Germany), 325, 949 (1990). 8. Walczak K. and Suwiñski J., Polish J. Chem., 67, 691 (1993). 9. Suwiñski J. and Wagner P., unpublished results. 10. Suwiñski J., Wagner P. and olt E.M., Tetrahedron, 52, 9541 (1996). 11. Suwiñski J., Walczak K. and Wagner P., Polish J. Appl. Chem., 38, 499 (1994). 12. Le Guyeder M., Bull. Soc. Chim. Fr., 1867 (1966). 13. Cosar C., Crisan C., orclois R., Jacob R.M., Robert J., Tchelitcheff S. and Vaupre R., Arzn. Forsch., 16, 23 (1966). 14. Finer I.L. and urloch R.J., J. Chem. Soc., 3021 (1957). 15. Moinet C. and Peltier D., Bull. Soc. Chim. Fr., 690 (1969).