Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) New approaches to the preparation of azoxyfuroxans Alexander N. Blinnikov, Nina N. Makhova* and Lenor I. Khmel’nitskii 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 A new convenient method for the synthesis of 4,4'-azoxyfuroxans by reductive condensation of 4-nitrofuroxans (4-nitro-1,2,5- oxadiazole 2-oxides) has been developed; the title compounds can also be synthesised by oxidation of 4-amino- and 4,4'-azofuroxans, and a general method for the synthesis of isomeric azofuroxans is suggested.The first representatives of azoxyfuroxans (4,4'-azoxy-3,3'-diphenyl- and -3,3'-dimethylfuroxans 1a,b) were synthesised by the oxidation of 4-trioctylphosphinimino-3-phenyl(methyl)furoxans under the action of MCPBA.1 However, this method is inconvenient, because the latter needs to be specially prepared.However, azoxy derivatives of the aromatic and heteroaromatic series exhibit various biological activities (antibacterial, anticancer, antituberculous, and nematocidal).2 Therefore, it was reasonable to search for new, more convenient approaches to the preparation of azoxyfuroxans with various substituents.The synthesis of aromatic azoxy derivatives is normally based on the transformation of amino-, azo-, or nitro-substituted derivatives using various oxidising or reducing agents. Until recently, it has been impossible to perform similar reactions in the furoxan series, because the corresponding starting furoxan derivatives were lacking.We have recently developed convenient methods for the synthesis of amino- and nitrofuroxans.3–7 In this work, we studied the possibility of preparing azoxyfuroxans 1† by the oxidative condensation of aminofuroxans, by oxidation of azofuroxans, and by reductive condensation of nitrofuroxans.It seemed probable that the first two reactions would be efficient, since similar transformations with aminoand azo-furazans proceed successfully.8,9 The possibility of reductive condensation of nitrofuroxans seemed less probable, because of the sensitivity of the furoxan ring towards reducing agents.10 The oxidation of 4- and 3-aminofuroxans 4 and 5 by KMnO4 in the presence of HCl (Scheme 1) was used to obtain the starting isomeric 4,4'- and 3,3'-azofuroxans 2 and 3.‡ The synthesis of compounds 2 and 3 is of independent interest, because only a few representatives of these structures are described in the literature.11,12 This reaction was established to apply to both 4- and 3-aminofuroxans 4 and 5 and to be almost independent of the second substituent in the aminofuroxan.The possibility of direct oxidation of aminofuroxans to azoxyfuroxans was studied using 4-aminofuroxans 4 only, since it is known11 that 3-aminofuroxans 5 give a mixture of compounds by the action of oxidants of the peroxide type, which are those usually used for these transformations in the furazan series.8 A mixture of hydrogen peroxide and H2SO4 was used as the oxidant.The studies showed that electron-withdrawing substituents in position 3 of the furoxan ring (for example, CON3, compound 4f) prevent the formation of azoxy derivatives. The oxidation † 4,4'-Azoxy-3,3'-diphenylfuroxan 1a: yield 52%, mp 190–192 °C (MeOH), (lit.,1 190–192 °C). 4,4'-Azoxy-3,3'-dimethylfuroxan 1b: yield 58%, mp 187–189 °C (CHCl3), (lit.,1 187–189 °C). 4,4'-Azoxy-3,3'-dihydroxymethylfuroxan 1g: yield 27%, mp 103–104 °C, Rf 0.45 (CHCl3:PriOH, 9:1). 1H NMR (CDCl3) d: 4.75 (d, 2H, CH2), 4.96 (d, 2H, CH2), 5.05 d (1H, OH), 5.07 d (1H, OH). 13C NMR (CDCl3) d: 54.04 and 54.72 (CH2), 111.42 and 111.59 (C-3 in furoxan ring), 156.12 and 159.48 (C-4 in furoxan ring). 14N NMR (CDCl3, internal standard MeNO2) d: –68.0 [N=N(O)]. IR (n/cm–1): 1315 [N=N(O)], 1600 (furoxan ring), 2800, 2920 (CH), 3320 (OH). 4,4'-Azoxy-3,3'-diethylfuroxan 1h: yield 49%, mp 129–130 °C (CHCl3), Rf 0.47 (hexane:CH2Cl2, 1:2). 1H NMR (CDCl3) d: 1.21 and 1.24 (t, Me), 2.63 and 2.96 (q, CH2). IR (n/cm–1): 1185 [N=N(O)], 1536, 1650 (furoxan ring). MS, m/z: 270 (M+). 4,4'-Azoxy-3,3'-bis(2-methoxyethyl)furoxan 1i: yield 17%, mp 72.5– 73 °C, Rf 0.11 (benzene:EtOAc, 20:1). 1H NMR (CDCl3) d: 2.99 and 3.27 (t, CH2), 3.28 and 3.29 (s, Me), 3.70 and 3.77 (t, CH2O). 13C NMR (CDCl3) d: 24.33 and 25.22 (Me), 58.76 (2CH2), 67.81 and 68.12 (CH2O), 110.77 and 110.94 (C-3 in furoxan ring), 156.90 and 160.18 (C-4 in furoxan ring). IR (n/cm–1): 1323 [N=N(O)], 1630 (furoxan ring); MS, m/z: 330 (M+). ‡ 4,4'-Azo-3,3'-diphenylfuroxan 2a: yield 96%, mp 160–162 °C, Rf 0.45 (CCl4:CHCl3, 1:1). 1H NMR ([2H6]DMSO) d: 7.5 (m, 3H, m- and p-CH in Ar), 7.65 (m, 2H, o-CH in Ar). IR (n/cm–1): 1330, 1465, 1610 (furoxan ring). UV (EtOH, lmax/nm): 227, 270. MS, m/z: 350 (M+). 4,4'-Azo-3,3'-dimethylfuroxan 2b: yield 96%, mp 156–158 °C, Rf 0.4 (CHCl3:CH2Cl2, 1:1). 1H NMR (CDCl3) d: 2.45 (s, Me). IR (n/cm–1): 1400, 1540, 1655 (furoxan ring). UV (EtOH, lmax/nm): 263, 352.MS, m/z: 226 (M+). 4,4'-Azo-3,3'-diethoxycarbonylfuroxan 2c: yield 68%, mp 128–129 °C, Rf 0.51 (CHCl3). 1H NMR ([2H6]acetone) d: 1.26 (t, Me, 3J 7.2 Hz), 4.40 (q, CH2, 3J 7.2 Hz). 13C NMR ([2H6]acetone) d: 14.17 (Me), 64.39 (CH2), 103.82 (C-3 in furoxan ring), 155.89 (C-4 in furoxan ring), 162.29 (C=O). IR (n/cm–1): 1620, 1630 (furoxan ring), 1720 (C=O), 2960 (CH); 3,3'-Diacetyl-4,4'-azofuroxan 2d: yield 22.5%, mp 123–125 °C, Rf 0.64 (benzene:methanol, 10:0.3). 1H NMR ([2H6]DMSO) d: 2.63 (s). IR (n/cm–1): 1330, 1370, 1500, 1630 (furoxan ring), 1650 (CO), 2940 (CH). UV (EtOH, lmax/nm): 261, 342. MS, m/z: 282 (M+). 4,4'-Azo-3,3'-bis(2-methoxyethyl)furoxan 2i: yield 7%, mp 89.5–91 °C, Rf 0.18 (benzene:EtOAc, 20:1). 1H NMR (CDCl3) d: 3.46 (t, CH2), 3.63 (s, Me), 4.02 (t, CH2O). 13C NMR (CDCl3) d: 25.24 (CH2), 58.54 (Me), 66.31 (CH2O), 107.72 (C-3 in furoxan ring), 165.3 (C-4 in furoxan ring). IR (n/cm–1): 1118, 1622 (furoxan ring), 2840, 2870, 2915, 2950, 3000 (CH). MS, m/z: 314 (M+). 3,3'-Azo-4,4'-diphenylfuroxan 3a: yield 96%, mp 196–197 °C, Rf 0.65 (hexane:ethylacetate, 3:1). 1H NMR ([2H6]DMSO) d: 7.65 (m, 3H, mand p-CH), 8.05 (m, 2H, o-CH).IR (n/cm–1): 1335, 1475, 1570 (furoxan ring). UV (EtOH, lmax/nm): 216, 252, 349. MS, m/z: 350 (M+). 3,3'-Azo-4,4'-dibenzoylfuroxan 3e: yield 67%, mp 143–144 °C, Rf 0.57 (acetone). 1H NMR ([2H6]DMSO) d: 7.42 (m, 2H, m-H in Ar), 7.7 (m, 1H, p-H in Ar), 7.9 (m, 2H, o-H in Ar). 13C NMR ([2H6]DMSO) d: 124.0 (C-3 in furoxan ring), 128.5, 129.2, 130.1, 132.8 (Ar), 148.5 (C-4 in furoxan ring), 167.3 (C=O).IR (n/cm–1): 1325, 1390, 1460, 1500, 1600, 1630 (furoxan ring), 1680, 1700 (C=O). UV (EtOH, lmax/nm): 263, 293, 380. 3-Hydroxymethyl-4-nitrofuroxan 6g: yield 16%, oil, IR and NMR spectral data are identical with those of 6g in ref. 17. N R O N NH2 O N R O N N O N R O N N O i N R O N NH2 N R O N N N R O N N i O O O 4a–d 2a–d 5a,e 3a,e aR = Ph b R = Me c R = CO2Et d R = COMe e R = COPh Scheme 1 Reagents and conditions: i, KMnO4 (1.5–2 mol), HCl/H2O/ CH2Cl2, 20 °C, then HOOC–COOH.Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) was carried out using hydrogen peroxide of different concentrations. With dilute hydrogen peroxide, the starting compound 4f is unchanged, while an increase in the concentration of hydrogen peroxide leads to the formation of 4-nitrofuroxan 6f.The oxidation of 4-aminofuroxans with electron-donating substituents 4b,g gives a mixture of azoxy derivatives 1b,g (predominantly) and nitrofuroxans 6b,g (Scheme 2). A peroxide type oxidant (peracetic acid) was also used for the oxidation of isomeric azofuroxans 2 and 3. The isomeric diphenylazofuroxans 2a and 3a were studied. It was found that only 4,4'-azo-3,3'-diphenylfuroxan 2a formed an azoxy derivative 1a (Scheme 3).The isomer 3a was not affected by the oxidant. Evidently, this transformation is sterically hindered by the N-oxide groups. An appropriate reducing agent should be chosen for the synthesis of compounds 1 by the reductive condensation of 4-nitrofuroxans. Various reagents (aldehydes, hydrazines, Mg and Zn metals, and SnII salts) are used in the aromatic series for this purpose.13 The reactions are usually carried out in an alkaline medium, but the reactions of compounds with electronwithdrawing substituents are performed in neutral or weakly acidic media.Since the furoxan ring possesses a strong electronwithdrawing effect,14 we used zinc dust in acetic acid for the transformation of 4-nitrofuroxans into 4,4'-azoxyfuroxans.Although this reagent can reduce the furoxan ring,15,16 it can be expected that, due to an increase in the reactivity of the nitro group under the action of the ring, its transformation will occur rapidly under very mild conditions, and the ring itself be untouched. First, the reaction was studied using 4-nitro-3-methylfuroxan 6b.It was carried out at low temperature with a small excess of the reducing agent. The reaction afforded a mixture of the expected 4,4'-azoxy-3,3'-dimethylfuroxan 1b (predominantly) and its azo analogue 2b. The mixture was separated by column chromatography on SiO2. The reduction of the azoxy fragment in compound 1b is the most probable reason for the production of 2b.To prevent this process and to obtain almost pure 1b, a 1:1 acetic acid–water mixture was used as the solvent. In this mixture the starting nitrofuroxan 6b is only slightly soluble, and the azoxy compound 1b is virtually insoluble. It precipitates and does not react further. The other azoxyfuroxans were synthesised under similar conditions in high yields (Scheme 4).§ In all cases, the AcOH:H2O ratio was selected according to the solubility of the starting and final compounds.Pure azoxyfuroxans 1 were obtained after recrystallisation from appropriate solvents. Only in the case of 3-methoxyethyl-4-nitrofuroxan 6i, the formation of the azo derivative was not avoided. Clearly, the MeOCH2CH2 group increases the solubility of 1i in the AcOH/H2O mixture, resulting in its partial reduction to 2i. 3-Nitrofuroxans 7a,b (4-methyl-3-nitro- and 3-nitro-4-phenylfuroxans were studied) do not form the expected 3,3'-azoxy derivatives with zinc dust in AcOH; they decompose under the reaction conditions. Thus, the reductive condensation of 4-nitrofuroxans 6 is a new and convenient method for the preparation of 4,4'-azoxyfuroxans 1. It is noteworthy that nitrofurazans (methyl- and phenylnitrofurazans were studied) do not form azoxy derivatives under the action of the Zn/AcOH mixture. This reaction is specific for 4-nitrofuroxans only.All new compounds had satisfactory elemental analysis data and their structures were confirmed by IR, NMR and mass spectroscopy.†,‡ This work was supported by the NATO Linkage grant nos. DISRM LG961369 and CNS 970584.References 1 O. A. Rakitin, O. G. Vlasova, A. N. Blinnikov, N. N. Makhova and L. I. Khmel’nitskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 523 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1991, 40, 455). 2 S. G. Zlotin and O. A. Luk’yanov, Usp. Khim., 1993, 62, 157 (Russ. Chem. Rev., 1993, 62, 143). 3 N. N. Makhova, A. N. Blinnikov and L. I. Khmel’nitskii, Mendeleev Commun., 1995, 56. 4 I. V. Ovchinnikov, A. N. Blinnikov, N. N. Makhova and L. I. Khmel’nitskii, Mendeleev Commun., 1995, 58. 5 V. G. Dubonos, I. V. Ovchinnikov, N. N. Makhova and L. I. Khmel’nitskii, Mendeleev Commun., 1992, 120. 6 N. N. Makhova and T. I. Godovikova, Ross. Khim. Zh., 1997, 41, 54 (in Russian). 7 N. N. Makhova, V. G. Dubonos, A. N. Blinnikov and L. I. Khmel’nitskii, Zh. Org.Khim., 1997, 33, 1216 (Russ. J. Org. Chem., 1997, 33, 1140). 8 T. S. Novikova, T. M. Mel’nikova, O. V. Kharitonova, V. O. Kulagina, N. S. Alexandrova, A. B. Sheremetev, T. S. Pivina, L. I. Khmel’nitskii and S. S. Novikov, Mendeleev Commun., 1994, 138. 9 M. A. Epishina, N. N. Makhova, L. V. Batog, L. S. Konstantinova and L. I. Khmel’nitskii, Mendeleev Commun., 1994, 102. 10 L. I.Khmel’nitskii, S. S. Novikov and T. I. Godovikova, Khimiya furoksanov: reaktsii i primenenie (Chemistry of Furoxans: Reactions and Application), 2nd edn., Nauka, Moscow, 1996, p. 51 (in Russian). 11 N. N.Makhova, I. V. Ovchinnikov, B. N. Khasapov and L. I. Khmel’nitskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1982, 646 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1982, 31, 573). 12 I. V.Ovchinnikov, N. N. Makhova, L. I. Khmel’nitskii, L. N. Akimova and V. I. Pepekin, Dokl. Ross. Akad. Nauk, 1998, 359, 499 [Dokl. Chem. (Engl. Transl.), 1998, 359, 67]. 13 K. H. Schundenhulte, Aromatic Azoxycompounds, in Metoden der Organischen Chemie, Houben-Weyl, 1965, 10/3, 745. 14 E. Sedano, C. Sarasola, J. M. Ugalde, I. X. Irarabalbetia and A. G. Guerrero, J. Phys. Chem., 1988, 92, 5094. 15 A. R. Gagneux and R. Meier, Helv. Chim. Acta, 1970, 53, 1883. § Synthesis of 4,4'-azoxyfuroxans 1 by reductive condensation of 4-nitrofuroxans 6 (general procedure). 4-Nitrofuroxan (10 mmol) was added to a mixture of AcOH/water (6a, 20:15 ml and 15 ml of MeOH; 6b, 15:15 ml; 6h, 15:30 ml; 6i, 10:15 ml). The reaction mixture was cooled to 0–2 °C and Zn dust (1.5–2.5 mmol) was added at this temperature over 2–4 h.The mixture was then warmed to 20 °C and stirred at this temperature for 1 h; the product obtained was filtered off and crystallised. N R O N NH2 O N R O N N O N R O N N O i N R O N NO2 O O + b R =Me f R = CON3 g R = CH2OH 1b 33% 1f 0% 1g 27% 6b 12% 6f 65% 6g 16% Scheme 2 Reagents and conditions: i. H2O2 (85%) (2.5 mol)/conc. H2SO4, 20 °C, 30 min, then 30 °C, 30 min and 65 °C, 30 min. 4b,f,g N Ph O N N O N Ph O N N O O N Ph O N N O N Ph O N N O i 2a 1a Scheme 3 Reagents and conditions: i, 30% H2O2 (24 mol), AcOH (170 mol), Ac2O (110 mol), 80–90 °C, 7 h, then reflux with addition of H2O2 until colourless. N R O N N O N R O N N O i N R O N NO2 O O 6a,b,h,i 1a,b,h,i + 2 (only 2i) i N R O N NO2 7a,b O decomposition a R = Ph b R =Me h R = Et i R = CH2CH2OMe Scheme 4 Reagents and conditions: i, Zn dust (1.5–2.5 mol), AcOH/H2O.Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) 16 G. Alimenti, M. Grifantini, F. Gualtieri and M. L. Stein, Tetrahedron, 1968, 24, 395. 17 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). Received: Moscow, 3rd June 1998 Cambridge, 17th July 1998; Com. 8/04734K