Mendeleev Communications Electronic Version, Issue 4, 2000 (pp. 125–166) N,C-Cross-coupling of trimethylsilyl derivatives of azoles with N,N-bis(silyloxy)enamines Igor V. Bliznets,a Alexey V. Lesiv,b Lyudmila M. Makarenkova,c Yuri A. Strelenko,c Sema L. Ioffe*c and Vladimir A. Tartakovskiic a Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation. Fax: +7 095 135 8860 b Moscow Chemical Lyceum, 109033 Moscow, Russian Federation.Fax: +7 095 362 3440 c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328 10.1070/MC2000v010n04ABEH001293 N-Trimethylsilyl derivatives of di- and triazoles smoothly undergo N,C-cross-coupling reactions with terminal and internal N,N-bis(silyloxy)enamines to give a-azolyl-substituted oximes.Bis(trialkylsilyloxy)enamines1 (BSENA) are convenient reagents for organic synthesis.2 BSENA, as formal b-carbon electrophiles, smoothly undergo C,C-cross-coupling reactions with a-nitro carbanions3 or trimethylsilyl derivatives of aliphatic nitro compounds.4 They also enter into N,C-cross-coupling with trimethylsilyl derivatives of N-nitramines5 and primary6 or secondary1 amines.The main products of these processes are a-substituted oximes, and the main side reaction is the rearrangement of BSENA into trimethylsilyl derivatives of 2-trimethylsilyloxy-substituted oximes, which is catalysed by Lewis or Brönsted acids1,7 and amines.6 It was found3 that at least some of the above reactions can proceed via a-nitroso alkenes as key intermediates.It is interesting that N,C-cross-coupling reactions of BSENA with alkyl-Nnitroamines, which are N–H acids, can be performed using trimethylsilyl derivatives of N-nitramines; however, N-trimethylsilyl derivatives of amines do not react with BSENA. Therefore, it is very interesting to examine the N,C-cross-coupling reaction of azoles with BSENA since the N–H acidity of azoles and N-nitroamines is almost the same,8 whereas the basicity of azoles is close to that of amines.9 We found that trimethylsilyl derivatives of azoles 1 containing at least two nitrogen atoms react smoothly with model terminal and internal BSENA 2† without a solvent at room temperature to give derivatives of oximes 3,‡ which could be transformed into free a-azolyl-substituted oximes 4§ after alcoholysis (Scheme 1).The target products can be purified by fractionation in vacuo (for 3) and by crystallization (for 4). The reactions between 1 and 2 afforded derivatives 3 in good yields only when BSENA were dried by azeotropic evaporation of water with benzene followed by distillation before the N,C-cross-coupling reaction.The structure of compounds 3 and 4 was confirmed by 1H and 13C NMR data and additionally by elemental analysis for oximes 4 (the error was no higher than 0.19% for carbon or 0.35% for hydrogen). The (E)-configuration of an oximino fragment for oximes 4a,c,e and their derivatives 3a,c,e was found using the published rules.3,5,6 Oximes 4b,d,f and their derivatives 3b,d,f represent mixtures of (Z)- and (E)-isomers.¶ The reactions of 1,2,4-triazole 1c with BSENA 2 are not regioselective (Scheme 2). However, only pure 1-substituted triazoles 3e,f and 4e,f were isolated from the reaction mixture by distillation in vacuo or by crystallization. † A solution of BSENA 2 (1 mmol) in dry hexane (3 ml) was added dropwise to the TMS derivative of azole 1 (1 mmol) at 20 °C in an inert atmosphere.The mixture was stirred at 20 °C for 30 min, evaporated at 20 °C (10 Torr), then stirred for 24 h. Finally, the residue was dried in vacuo at 20 °C (0.1 Torr) to constant weight. Target derivative 3 was isolated by distillation of the residue in vacuo. ‡ NMR spectra were recorded on a Bruker AM 300 spectrometer at 300.31 MHz and 75.47 MHz for 1H and 13C, respectively; TMS as an internal standard. 3a: yield 95%, bp 53 °C (0.06 Torr). 1H NMR (CDCl3) d: 0.19 (s, 9H, SiMe3), 1.57 (s, 3H, Me), 4.80 (s, 2H, CH2), 6.25 (t, 1H, 4-H, 3JH,H 2 Hz), 7.33 and 7.47 (d, 2H, 3-H and 5-H, 3JH,H 2 Hz). 13C NMR (CDCl3) d: –0.75 (SiMe3), 11.91 (Me), 55.89 (CH2), 106.38 (4-C), 128.99 and 139.44 (3-C and 5-C), 157.44 (C=N). 3b: yield 78%, bp 44 °C (0.08 Torr). 3c: yield 88%, bp 65 °C (0.08 Torr). 3d: yield 97%, bp 73 °C (0.09 Torr). E/Z ª 6:1. 1H NMR (CDCl3) d: (E)-isomer: 0.20 (s, 9H, SiMe3), 1.65 (d, 3H, Me, 3JH,H 7 Hz), 4.90 (m, 1H, CH, 3JH,H 7 Hz), 6.90 and 7.05 (br. s, 2H, 4-H and 5-H), 7.51 (d, 1H, CH=N, 3JH,H 7 Hz), 7.67 (s, 1H, 2-H); (Z)-isomer: 0.19 (s, 9H, SiMe3), 1.63 (d, 3H, Me, 3JH,H 7 Hz), 5.50 (m, 1H, CH, 3JH,H 7 Hz), 6.90 and 7.05 (br.s, 2H, 4-H and 5-H), 7.43 (d, 1H, CH=N, 3JH,H 7 Hz), 7.67 (s, 1H, 2-H). 13C NMR (CDCl3) d: (E)-isomer: –0.90 (SiMe3), 19.00 (Me), 52.31 (CH), 117.14 and 129.76 (4-C and 5-C), 135.55 (2-C), 153.18 (C=N); (Z)-isomer: –0.90 (SiMe3), 18.00 (Me), 47.63 (CH), 117.30 and 129.76 (4-C and 5-C), 135.55 (2-C), 153.91 (C=N). 3e: yield ~100%, bp 60 °C (0.08 Torr). 3d: yield 95%, bp 64 °C (0.08 Torr).§ 4a: yield 91%, mp 94–95 °C (from H2O). 4b: yield ~100%, oil. E/Z ª 5:2. 1H NMR (CDCl3) d: (E)-isomer: 1.65 (d, 3H, Me, 3JH,H 6.6 Hz), 5.10 (m, 1H, CH, 3JH,H 6.6 Hz), 6.24 (d, 1H, 4-H, 3JH,H 2 Hz), 7.42 and 7.53 (d, 2H, 3-H and 5-H, 3JH,H 2 Hz), 7.58 (d, 1H, CH=N, 3JH,H 6.6 Hz), 9.36 (br. s, 1H, OH); (Z)-isomer: 1.66 (d, 3H, Me, 3JH,H 6.6 Hz), 5.72 (m, 1H, CH, 3JH,H 6.6 Hz), 6.24 (d, 1H, 4-H, 3JH,H 2 Hz), 6.95 (d, 1H, CH=N, 3JH,H 6.6 Hz), 7.45 and 7.55 (d, 2H, 3-H, 5-H, 3JH,H 2 Hz), 9.36 (br.s, 1H, OH). 13C NMR (CDCl3) d: (E)-isomer: 18.54 (Me), 56.71 (CH), 105.95 (4-C), 128.00 and 139.59 (3-C and 5-C), 149.58 (C=N); (Z)-isomer: 17.69 (Me); 52.15 (CH); 105.59 (4-C), 128.57 and 139.83 (3-C and 5-C), 150.30 (C=N). 4c: yield ~100%, mp 162–167 °C (from H2O). 1HNMR ([2H6]DMSO) d: 1.63 (s, 3H, Me), 4.66 (s, 2H, CH2), 6.88 and 7.08 (br. s, 2H, 4-H and 5-H), 7.61 (s, 1H, 2-H), 10.92 (s, 1H, OH). 13C NMR ([2H6]DMSO) d: 11.37 (Me), 49.87 (CH2), 119.56 and 128.55 (4-C and 5-C), 137.64 (2-C), 151.58 (C=N). 4d: yield 95%, mp 109–112 °C (from H2O). 4e: yield ~100%, mp 149–151 °C (from EtOH). 4f: yield ~100%, mp 109–113 °C (from H2O).¶ A mixture of two regio isomers (see Scheme 2). Y N X SiMe 3 R' R N(OSiMe 3)2 Y N X R' R NOSiMe 3 i Y N X R' R NOH ii 1a–c 2a,b 3a–f 4a–f 1: a X = N, Y = CH b X = CH, Y = N c X = Y = N 2: a R = H, R' = Me b R = Me, R' = H 3,4: a X = N, Y = CH, R = H, R' = Me b X = N, Y = CH, R = Me, R' = H c X = CH, Y = N, R = H, R' = Me d X = CH, Y = N, R = Me, R' = H e¶ X = Y = N, R = H, R' = Me f¶ X = Y = N, R = Me, R' = H Scheme 1 Reagents and conditions: i, molar ratio 1:2 = 1:1, without a solvent, room temperature, 24 h; ii, an excess of EtOH, room temperature, 20 h.Mendeleev Communications Electronic Version, Issue 4, 2000 (pp. 125–166) The interaction of BSENA with free azoles was studied using a model reaction of enamine 2a with pyrazole. This process is not chemoselective and includes a rearrangement of 2a into 5†† catalysed by pyrazole (Scheme 3).We can conclude that the reactivity of azoles in the N,C-crosscoupling reactions with BSENA is similar to the reactivity of N-nitramines in analogous reactions.5 Thus, a convenient preparative method for synthesis of 2-azolylsubstituted oximes from available aliphatic nitro compounds and azoles was developed. Oximes 4 are promising synthetic building blocks for drug and plant protection research.10,11 This work was performed at the Scientific Educational Centre for Young Scientists and supported by the Russian Foundation for Basic Research (grant nos. 99-03-32015 and 00-15-97455) and by the Federal Programme ‘Integration’ (grant no. A0082). References 1 H. Feger and G.Simchen, Liebigs Ann. Chem., 1986, 1456. 2 A. D. Dilman, A. A. Tishkov, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and V. A. Tartakovsky, Synthesis, 1998, 181. 3 A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and V. A. Tartakovsky, Synthesis, 1999, 1767. 4 A. D. Dilman, I. M. Lyapkalo, Yu. A. Strelenko, S. L. Ioffe and V. A. Tartakovskii, Mendeleev Commun., 1997, 133. 5 S. L. Ioffe, L. M. Makarenkova, Yu. A. Strelenko, I. V. Bliznets and V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim., 1998, 2045 (Russ. Chem. Bull., 1998, 47, 1989). 6 L. M.Makarenkova, I. V. Bliznets, S. L. Ioffe, Yu. A. Strelenko and V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim., 2000, 1265 (in Russian). 7 H. Feger and G. Simchen, Liebigs Ann. Chem., 1986, 428. 8 H.Feuer, The Chemistry of the Nitro and Nitroso Groups, New York, 1969, vol. 1, p. 470. 9 T. L. Gilchrist and W. Stretch, J. Chem. Soc., Perkin Trans. 1, 1987, 2235. 10 J. G. Keay, E. F. V. Scriven and N. Shobana, Heterocycles, 1994, 37, 1951. 11 T. L. Gilchrist, D. A. Lingham and T. G. Roberts, J. Chem. Soc., Chem. Commun., 1979, 1089. †† 5: E/Z ª 4:1 (ref. 7). 13C NMR (CDCl3) d: (E)-isomer: –0.68 and –0.45 (2SiMe3), 11.54 (Me), 64.86 (CH2), 160.82 (C=N); (Z)-isomer: –0.45 and –0.17 (2SiMe3), 16.50 (Me), 58.72 (CH2), 163.4 (C=N). N N N SiMe 3 R' R N(OSiMe 3)2 N N N R' R NOSiMe 3 1c 2a,b 3e,f i N N N R' R NOSiMe 3 3e',f' Molar ratio 3e:3e' ~ 6:1; 3f:3f' ~ 2:1 Scheme 2 Reagents and conditions: i, molar ratio 1:2 = 1:1, without a solvent, room temperature, 20 h. NH N N(OSiMe 3)2 N N NOSiMe 3 i 2a Me3SiO NOSiMe 3 3a (30%) 5 (60%) Scheme 3 Reagents and conditions: i, molar ratio pyrazole:2a = 1:1, without a solvent, room temperature, 20 h. Received: 1st March 2000; Com. 00/1619