Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) Novel synthesis of 3-monosubstituted furoxans Alexander N. Blinnikov and Nina N. Makhova* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: mnn@cacr.ioc.ac.ru The nitro group in 3-substituted 4-nitrofuroxans (4-nitro-1,2,5-oxadiazol 2-oxides) can be replaced by the hydride ion under the action of NaBH4 in EtOH, and this reaction is convenient for the preparation of 3-monosubstituted furoxans.Recently,1 we have proposed a general preparative synthesis of a-hydroxyalkyl(benzyl)furoxan and -furazan derivatives based on the reduction of acyl and ethoxycarbonyl substituents in these heterocycles with NaBH4 in EtOH. Acyl, methyl and amino groups were second substituents in the compounds studied. The reaction was completed within 10–30 min at 10–15 °C.The 4-amino groups in 4-amino-3-(a-hydroxymethyl- and ethyl)- furoxans 1a,b were oxidised to nitro groups to form corresponding 4-nitro-3-(a-hydroxymethyl- and ethyl)furoxans 2a,b (Scheme 1). In this work, we attempted to obtain nitroalcohol 2a by the reduction of a furoxan derivative containing a nitro group, 3-ethoxycarbonyl-4-nitrofuroxan 3,2 using the same reducting agent.Compound 3 was found to react with NaBH4 in EtOH under milder conditions (–10 °C, ~1 min); however, previously unknown 3-ethoxycarbonylfuroxan 4 was isolated (yield 51%) instead of expected 2a (Scheme 2). These conditions seem to be favourable to the nucleophilic substitution of the hydride ion for the nitro group in compound 3.It is likely that the ethoxycarbonyl group cannot be reduced to the hydroxymethyl group under mild conditions. The chemical shift of the hydrogen atom at C(4) in the 1H NMR spectrum of compound 4 is 8.2 ppm, and the chemical shift of the C(4) atom in the 13C NMR spectrum is 148.5 ppm. These values are consistent with the data published for the parent furoxan3 and 3-phenylfuroxan.4 The mass spectrum exhibits a peak of the molecular ion.The reactions of nitroaromatic compounds with NaBH4 can proceed via various pathways depending upon the reaction conditions and the type of substitution in the ring. For instance, azobenzenes, azoxybenzenes and anilines can be obtained by this reaction.5 Nitroaromatic compounds with electron-accepting substituents are reduced by NaBH4 to cyclohexene derivatives6 or form stable Meisenheimer complexes with hydride.7 The nucleophilic substitution of the hydride ion for the nitro group in aromatic compounds under the action of NaBH4 was also described.However, this reaction requires the presence of bulky substituents adjacent to the nitro group to prevent its conjugation with the ring and the presence of electron-withdrawing groups to activate the ring towards the hydride ion attack.8 In the oxadiazole series, this reaction was observed for the first time, and it could not be predicted in advance.Though the oxadiazole ring possesses a very high electron-withdrawing effect,9 only one substituent is adjacent to the nitro group in compound 3.Moreover, the nitro groups in both the 4- and 3-positions of the furoxan cycle are almost coplanar with the ring (16° in 3-methyl-4-nitrofuroxan10 and 11° in 3-nitro-4-phenylfuroxan11). 3-Monosubstituted furoxans in contrast to 4-monosubstituted ones are not easily accessible compounds. Only few examples of such structures have been described: 3-arylfuroxans 5 and 3-furazanylfuroxans 6 and isomeric furoxan-3-aldoximes 7a,b.These compounds were prepared by different methods. 3-Arylfuroxans 5 were synthesised by oxidation of the b-forms of corresponding monoarylglyoximes 8.12–15 3-Furazanylfuroxan 6 was obtained by dehydration of a-(furazanyl)nitrooxime 9.16 Furoxan-3-aldoximes 7a,b were synthesised as a mixture of isomers by transformation of a diacetyl derivative of nitromalonaldehyde 1017 (Scheme 3).In this connection, the replacement of the nitro group by the hydride ion in 3-R-4-nitrofuroxans can be useful for the preparation of 3-monosubstituted furoxans. To estimate the application field of this reaction, we studied the interaction of 3-alkyl-4-nitrofuroxans 11a,b and 3-phenyl-4- nitrofuroxan 12 with NaBH4 in EtOH.The following expected 3-monosubstituted furoxans were isolated in high yields in all cases: 3-methyl- and 3-ethylfuroxans 13a,b (which were unknown previously) and 3-phenylfuroxan 5a (Scheme 4).† Thus, the interaction of 3-substituted 4-nitrofuroxans with NaBH4 in EtOH is a new, general and convenient method for N O N R COR1 (O)n NaBH4 EtOH N O N R2 CH(OH)R3 (O)n N O N H2N CH(OH)R 90% H2O2/H2SO4 N O N O2N CH(OH)R O O a R = H b R = Me 1 2 Scheme 1 R = NH2, Me, COR1 R1 = Me, OEt, Ph R2 = NH2, Me, CH(OH)R3 R3 = H, Me, Ph n = 0, 1 N O N O2N CO2 Et O 3 i 2a i N O N H CO2 Et O 4 Scheme 2 Reagents and conditions: NaBH4 (2 mol), EtOH, –10 °C, 1 min, then HCl/H2O.HON Ar NOH H N O N Ar H O HNO3 (N2O4) a Ar = Ph 8 5 N O N H 9 NO2 H NOH N O N H N O N H O SOCl2 6 NOAc H NO2 K+ H NOAc N O N H 7a H N 10 i, H2O, 60–70 ºC ii, 0.1 M HCl O OH N O N H 7b H N O HO 2:1 Scheme 3Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) the synthesis of hitherto hardly accessible 3-monosubstituted furoxans, and the result of this reaction is independent of the second substituent (alkyl, aryl or alkoxycarbonyl). This work was supported by the NATO Linkage grant nos.DISRM LG961369 and CNS 970584. † All new compounds had satisfactory elemental analysis data, and their structures were confirmed by IR and NMR spectroscopy and mass spectrometry. IR spectra were recorded in KBr pellets. 1H, 13C and 15N NMR spectra (300, 75.5 and 30.4 MHz, respectively) were measured in CDCl3, internal standard SiMe4 for 1H and 13C and external standard MeNO2 for 15N.Preparation of 3-monosubstituted furoxans (general procedure). A solution of NaBH4 (5 mmol) in 50 ml of anhydrous ethanol was added to a solution of nitrofuroxan (2.5 mmol) at –10 °C, and the reaction mixture was stirred at corresponding temperatures (compound 3: –10 °C, 1 min; compounds 11a,b: 20 °C, 5–6 min; compound 12: 5–10 °C, 10 min).Next, the reaction system was cooled, 12 mmol of conc. HCl was added, EtOH was evaporated and 3-monosubstituted furoxans were purified by column chromatography on SiO2 (CHCl3–hexane eluent). 3-Ethoxycarbonylfuroxan 4: yield 53%, high-boiling liquid, Rf 0.62 (CHCl3). 1H NMR, d: 1.20 (t, 3H, Me, 3J 7.7 Hz), 4.17 (q, 2H, CH2, 3J 7.7 Hz), 8.20 (s, 1H, CH). 13C NMR ([2H6]acetone) d: 14.45 (q, Me, 1J 137 Hz), 83.47 (t, CH2, 1J 147 Hz), 109.18 (C-3 in furoxan ring, 2J 10.8 Hz), 148.05 (d, C-4 in furoxan ring, 1J 205 Hz), 158.80 (C=O). IR (n/cm–1): 1395, 1417, 1438, 1523, 1623 (furoxan ring), 1732, 1760 (CO), 2857, 2925, 2995 (CH in Et), 3145 (CH in furoxan ring). MS, m/z: 158 (M+). Phenylfuroxan 5a: yield 89%, mp 107–108 °C (lit.,10 108–109 °C). 3-Methylfuroxan 13a: yield 74%, bp 63–64 °C (2 Torr), Rf 0.2 (CHCl3– heptane, 1:4). 1H NMR, d: 2.18 (s, 3H, Me), 8.55 (s, 1H, CH). 13C NMR, d: 8.16 (dq, Me, 1J 132 Hz, 3J 6.0 Hz), 113.45 (m, C-3 in furoxan ring, 2J 6.0 Hz), 148.25 (dt, C-4 in furoxan ring, 1J 200 Hz, 3J 3.2 Hz). 15N NMR, d: –22.95 (N-2, 3JCH–N-2 4.0 Hz), –2.77 (N-5, 2J 11.8 Hz). IR (n/cm–1): 1380, 1495, 1620 (furoxan ring), 2930 (CH in Me), 3140 (CH in furoxan ring).MS, m/z: 100 (M+). 3-Ethylfuroxan 13b: yield 49%, bp 86–87 °C (2 Torr), Rf 0.29 (CHCl3– CCl4, 1:1). 1H NMR, d: 1.27 (t, 3H, Me, 3J 8.1 Hz), 2.54 (q, 2H, CH2, 3J 8.1 Hz), 8.14 (s, 1H, CH). 13C NMR, d: 10.49 (q, Me, 1J 121 Hz), 16.38 (t, CH2, 1J 141 Hz), 116.7 (m, C-3 in furoxan ring, 2J 11.4 Hz), 145.16 (d, C-4 in furoxan ring, 1J 182.7 Hz). 15N NMR, d: –23.19 (m, N-2, 3JCH–N-2 1.7 Hz), –1.56 (d, N-5, 2J 12.1 Hz). IR (n/cm–1): 1410, 1445, 1470, 1500, 1625 (furoxan ring), 2900, 2960, 2990 (CH in Et), 3135 (CH in furoxan ring). MS, m/z: 114 (M+). References 1 A. N. Blinnikov, A. S. Kulikov, N. N. Makhova and L. I. Khmel’nitskii, Izv. Akad. Nauk, Ser. Khim., 1996, 1782 (Russ. Chem. Bull., 1996, 45, 1692). 2 N. N. Makhova, V.G. Dubonos, A. N. Blinnikov, I. V. Ovchinnikov and L. I. Khmel’nitskii, Zh. Org. Khim., 1997, 33, 1216 (Russ. J. Org. Chem., 1997, 33, 1140). 3 T. I. Godovikova, S. P. Golova, Yu. A. Strelenko, M. Yu. Antipin, Yu. T. Struchkov and L. I. Khmel’nitskii, Mendeleev Commun., 1994, 7. 4 L. I. Khmel’nitskii, T. I. Godovikova, N. A. Ruleva, B. N. Khasapov and S. S. Novikov, Izv.Akad. Nauk SSSR, Ser. Khim., 1979, 2295 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1979, 28, 2118). 5 R. O. Hutchins, D. W. Lamson, L. Rua, C. Milewsky and B. Maryanoff, J. Org. Chem., 1971, 36, 803. 6 T. Severin, R. Schmitz and M. Adam, Chem. Ber., 1963, 96, 3076. 7 L. A. Kaplan and A. R. Siedle, J. Org. 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