ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 10–13. © Pleiades Publishing, Ltd., 2015. Original Russian Text © I.B. Krylov, A.O. Terent’ev, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 1, pp. 17–20.
Oxidative C–O Coupling of Benzylmalononitrile with 3-(Hydroxyimino)pentane-2,4-dione I. B. Krylov and A. O. Terent’ev Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia e-mail:
[email protected] Received October 6, 2014
Abstract—Oxidative C–O coupling of benzylmalononitrile with 3-(hydroxyimino)pentane-2,4-dione has been accomplished. This reaction is the first example of oxidative C–O coupling of a malononitrile with an oxime. The best yield (65%) of the coupling product, 2-benzyl-2-[(2,4-dioxopent-3-ylidene)aminooxy]malononitrile, has been achieved with the use of Cu(ClO4)2 · 6 H2O as oxidant. It is believed that the reaction involves intermediate formation of oxygen-centered aminoxyl radical.
DOI: 10.1134/S1070428015010029 During the past decade increased attention has been given to oxidative cross-coupling reactions [1–13] that lead to formation of new bonds with a high atom efficiency and do not require additional steps for the introduction of functional groups necessary in other cross-coupling versions (Hlg, OTf, BR2, SnR3, SiR3, ZnHlg, MgHlg). Oxidative C–C cross-coupling has been studied most thoroughly, whereas C–N, C–P, and C–O coupling methods have been developed to a much lesser extent. Selective oxidative C–O coupling is a difficult task due to readily occurring side oxidation and fragmentation processes, e.g., formation of alcohols and carbonyl compounds. Oxidative C–O coupling of oximes with various CH reagents could give rise to compounds containing an important pharmacophoric fragment, R2C=NOR. This fragment is present in molecules exhibiting various biological activities. For instance, O-substituted oximes were found to possess antidepressant [14], anticarcinogenic [15, 16], anti-inflammatory [17], antiviral [18–20], antibacterial [21, 22], fungicidal [21–24], insecticidal [24, 25], and antihelminthic activity [25]. O-Substituted oximes, including those containing cyano groups [26–28], are used as means for
plant and crop protection [23–28]. The R 2 C=NOR fragment is a structural unit of the insecticide flucycloxuron, antimicrobial drugs ceftazidime and roxithromycin, and fungicide trifloxystrobin. Oxidative coupling with oximes as OH reagents is complicated by the fact that the R2 C=NOH group readily decomposes under the action of oxidants to form the corresponding carbonyl compounds R2C=O [29]. Only a few examples of successful oxidative C–O coupling with oximes have been reported, in particular coupling of oximes with isochromans [30], 1-phenylpropene derivatives [31], and β-dicarbonyl compounds [32]. It was presumed that the first two reactions [30, 31] involve generation of carbocations from CH reagents and subsequent nucleophilic attack by oxime with formation of coupling products. The third reaction follows a different mechanism, according to which oxime is converted into aminoxyl radical [32]. The scope of synthetic applications of such aminoxyl radicals has long been limited to reactions of stable (t-Bu)2C=N–O · radical [33], namely oxidation of amines to imines [34], oxidative addition to phenols [35], and allylic substitution of hydrogen in cyclohexene [36]. As a rule, aminoxyl radicals are unstable,
Scheme 1. O
O
CN +
Ph
Me
Me
CN HO 1
Oxidant
N
NC Ph
Me
CN N
O
Me
2
3
10
O O
OXIDATIVE C–O COUPLING OF BENZYLMALONONITRILE
11
Scheme 2. O
O
Me
O Me
HO
N
Cu(II) –Cu(I)
O
Me
Me N
·O
2
NC Ph
A CN
Ph
Cu(II) CN
1
R2 R3
–Cu(I) CN
R1 Cu
N
O
Me
O O
3
·
N
Me
CN
Ph B
and they undergo dimerization via formation of N–N, N–O, or O–C bond to give a complex mixture of products [37]. First selective processes with participation of unstable aminoxyl radicals generated in situ have recently been reported: intramolecular abstraction of hydrogen atom with subsequent cyclization [38] and intramolecular addition to C=C double bond [39, 40]. The present work continues our studies on oxidative C–O coupling of β-dicarbonyl compounds [12, 32, 41, 42] and their hetero analogs [12, 42, 43] (CH reagents) with OH reagents (tert-butyl hydroperoxide [12, 41, 43], oximes [12, 32], N-hydroxyamides, and N-hydroxyimides [12, 42]). A common feature of the examined C–O coupling reactions is generation of oxygen-centered radicals from OH reagents and oneelectron oxidation of CH reagents [12, 32, 41–43]. These reactions are the only examples of oxidative C–O coupling with malononitriles and cyanoacetic acid esters [42, 43]. We set ourselves the task of performing for the first time oxidative coupling of malononitrile with an oxime. It was found previously that oxidative couplings of 2-substituted malononitriles and cyanoacetic esters with N-oxyl radicals generated from N-hydroxyimides and N-hydroxyamides occur with difficulty [42]. We used as reactants benzylmalononitrile (1) and 3-(hydroxyimino)pentane-2,4-dione (2); the oxidants were Cu(ClO4)2, Cu(NO3)2, Fe(ClO4)3, Mn(OAc)3, and KMnO4, and the reactions were carried out in acetonitrile and acetic acid (Scheme 1; see table); these oxidants and solvents ensured the best results in analogous oxidative C–O coupling of oximes with β-dicarbonyl compounds [32]. Copper(II) perchlorate turned out to be the best oxidant; in this case, compound 3 was obtained in 65% yield. Such salts as Fe(ClO4)3, KMnO4, and Mn(OAc)3 were low efficient as oxidants; the yield of 3 in the
presence of Cu(NO3)2 was 35%. The high efficiency of Cu(ClO4)2 in the examined reaction was unexpected since Fe(ClO4)3, KMnO4, and Mn(OAc)3 were more efficient than Cu(ClO4)2 in the oxidative coupling of oximes with β-diketones and β-ketoesters [32]. On the basis of our results and published data we presumed that the high efficiency of Cu(ClO4)2 in oxidative C‒O coupling is related to its ability to form reactive complexes with malononitrile [43, 44] (Scheme 2). According to the proposed mechanism, copper ion reacts with oxime 2 to generate aminoxyl radical A and also forms complex B with dinitrile 1. Radical A reacts with complex B, yielding coupling product 3. The formation of radical A from oxime 2 under the action of Cu(ClO4)2 in acetonitrile was proved previously using ESR spectroscopy [32]. Our results led us to presume that copper(II) salts, especially copper(II) perchlorate, are promising as reagents or catalysts for CH-activation and oxidative functionalization of malononitriles. EXPERIMENTAL The 1 H and 13 C NMR spectra were recorded on a Bruker AM 300 spectrometer from solutions in CDCl 3 . The IR spectra were obtained on a Bruker Alpha spectrometer with Fourier transform. Glacial acetic acid was used without additional purification. Oxidative coupling of benzylmalononitrile (1) with oxime 2 Oxidant (mol per mole of 1)
Solvent
Yield of 3, %
Cu(ClO4)2 · 6 H2O (2.5)
MeCN
65
Cu(NO3)2 · 2.5 H2O (2.5)
MeCN
35
Fe(ClO4)3 · 8 H2O (2)
MeCN
00
Mn(OAc)3 · 2 H2O (2)
AcOH
25
KMnO4 (0.4)
AcOH
10
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Acetonitrile was distilled over P2O5. The other reagents and solvents were commercial products (from Acros Organics). General procedure for oxidative coupling of benzylmalonitrile (1) with 3-(hydroxyimino)pentane-2,4-dione (2). A mixture of 200 mg (1.28 mmol) of dinitrile 1 and 165 mg (1.28 mmol) of oxime 2 in 5 mL of acetonitrile or acetic acid was heated to 78– 80°C, 0.512–3.20 mmol (80.9–1276 mg) of the corresponding oxidant (0.4–2.5 mol per mole of 1) was added under stirring over a period of 5–10 s, and the mixture was stirred for 10 min at 78–80°C. The mixture was cooled to room temperature, 10 mL of chloroform and 20 mL of water were added, the mixture was shaken up, the organic layer was separated, and the aqueous layer was extracted with chloroform (2 × 10 mL). The extracts were combined with the organic phase, washed with a solution of 200 mg of Na2S2O4 in 20 mL of water and with 20 mL of water, and dried over MgSO 4 , the solvent was removed on a rotary evaporator under reduced pressure (10–14 mm), and the residue was subjected to silica gel column chromatography using methylene chloride‒ethyl acetate (0 to 4 vol % of the latter) as eluent. 2-Benzyl-2-[(2,4-dioxopent-3-ylidene)aminooxy]propanedinitrile (3). White crystals, mp 108–109°C. IR spectrum (KBr), ν, cm–1: 3074, 3036, 2988, 2947, 2251 (CN), 1728 (C=O), 1697 (C=O), 1362, 1288, 1241, 1028, 933, 917, 706. 1 H NMR spectrum (300.13 MHz), δ, ppm: 2.25 s (3H, CH3), 2.49 s (3H, CH 3 ), 3.57 s (2H, CH 2 ), 7.52–7.29 m (5H, Ph). 13 C NMR spectrum (75.47 MHz), δC, ppm: 26.3 and 30.6 (CH 3 ), 43.3 (CH 2 ), 73.0 (CON), 112.2 (CN); 129.0, 129.3, 129.5, 130.8 (Ph); 159.1 (C=NO), 192.8 and 195.0 (C=O). Found, %: C 63.62; H 4.61; N 14.78. C15H13N3O3. Calculated, %: C 63.60; H 4.63; N 14.83. This study was performed under financial support by the Russian Scientific Foundation (project no. 14-23-00 150). REFERENCES 1. Li, C.-J. and Li, Z., Pure Appl. Chem., 2006, vol. 78, no. 5, p. 935. doi: 10.1351/pac200678050935 2. Beccalli, E.M., Broggini, G., Martinelli, M., and Sottocornola, S., Chem. Rev., 2007, vol. 107, no. 11, p. 5318. doi: 10.1021/cr068006f 3. Yeung, C.S. and Dong, V.M., Chem. Rev., 2011, vol. 111, no. 3, p. 1215. doi: 10.1021/cr100280d 4. Yoo, W.-J. and Li, C.-J., Top. Curr. Chem., 2010, vol. 292, p. 281. doi: 10.1007/128_2009_17
5. Li, C.-J., Acc. Chem. Res., 2009, vol. 42, no. 2, p. 335. doi: 10.1021/ar800164n 6. Li, Z., Bohle, D.S., and Li, C.-J., Proc. Natl. Acad. Sci. USA, 2006, vol. 103, no. 24, p. 8928. doi: 10.1073/ pnas.0601687103 7. Cho, S.H., Kim, J.Y., Kwak, J., and Chang, S., Chem. Soc. Rev., 2011, vol. 40, no. 10, p. 5068. doi: 10.1039/ c1cs15082k 8. Scheuermann, C.J., Chem. Asian J., 2010, vol. 5, no. 3, p. 436. doi: 10.1002/asia.200900487 9. Zhang, C., Tang, C., and Jiao, N., Chem. Soc. Rev., 2012, vol. 41, no. 9, p. 3464. doi: 10.1039/ C2CS15323H 10. Samanta, R., Matcha, K., and Antonchick, A.P., Eur. J. Org. Chem., 2013, vol. 26, p. 5769. doi: 10.1002/ ejoc.201300286 11. Girard, S.A., Knauber, T., and Li, C.-J., Angew. Chem., Int. Ed., 2014, vol. 53, no. 1, p. 74. doi: 10.1002/ anie.201304268 12. Ananikov, V.P., Khemchyan, L.L., Ivanova, Yu.V., Bukhtiyarov, V.I., Sorokin, A.M., Prosvirin, I.P., Vatsadze, S.Z., Medved’ko, A.V., Nuriev, V.N., Dilman, A.D., Levin, V.V., Koptyug, I.V., Kovtunov, K.V., Zhivonitko, V.V., Likholobov, V.A., Romanenko, A.V., Simonov, P.A., Nenajdenko, V.G., Shmatova, O.I., Muzalevskiy, V.M., Nechaev, M.S., Asachenko, A.F., Morozov, O.S., Dzhevakov, P.B., Osipov, S.N., Vorobyeva, D.V., Topchiy, M.A., Zotova, M.A., Ponomarenko, S.A., Borshchev, O.V., Luponosov, Y.N., Rempel, A.A., Valeeva, A.A., Stakheev, A.Yu., Turova, O.V., Mashkovsky, I.S., Sysolyatin, S.V., Malykhin, V.V., Bukhtiyarova, G.A., Terent’ev, A.O., and Krylov, I.B., Rus. Chem. Rev., 2014, vol. 83, no. 10, p. 885. doi: 10.1070/RC2014v083n10ABEH004471 13. Gulzar, N., Schweitzer-Chaput, B., and Klussmann, M., Catal. Sci. Technol., 2014, vol. 4, no. 9, p. 2778. doi: 10.1039/C4CY00544A 14. Welle, H.B.A. and Claassen, V., US Patent no. 4 085 225, 1978. 15. Parthiban, P., Pallela, R., Kim, S.-K., Park, D.H., and Jeong, Y.T., Bioorg. Med. Chem. Lett., 2011, vol. 21, no. 22, p. 6678. doi: 10.1016/j.bmcl.2011.09.063 16. Wang, C., Barluenga, S., Koripelly, G.K., Fontaine, J.-G., Chen, R., Yu, J.-C., Shen, X., Chabala, J.C., Heck, J.V., Rubenstein, A., and Winssinger, N., Bioorg. Med. Chem. Lett., 2009, vol. 19, no. 14, p. 3836. doi: 10.1016/j.bmcl.2009.04.030 17. Crichlow, G.V., Cheng, K.F., Dabideen, D., Ochani, M., Aljabari, B., Pavlov, V.A., Miller, E.J., Lolis, E., and Al Abed, Y., J. Biol. Chem., 2007, vol. 282, no. 32, p. 23 089. doi: 10.1074/jbc.M701825200 18. Ouyang, G., Cai, X.-J., Chen, Z., Song, B.-A., Bhadury, P.S., Yang, S., Jin, L.-H., Xue, W., Hu, D.-Y., and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015
OXIDATIVE C–O COUPLING OF BENZYLMALONONITRILE
19.
20.
21. 22.
23.
24. 25. 26. 27. 28. 29. 30.
31.
32.
Zeng, S., J. Agric. Food Chem., 2008, vol. 56, no. 21, p. 10 160. doi: 10.1021/jf802489e Watson, K.G., Brown, R.N., Cameron, R., Chalmers, D.K., Hamilton, S., Jin, B., Krippner, G.Y., Luttick, A., McConnell, D.B., Reece, P.A., Ryan, J., Stanislawski, P.C., Tucker, S.P., Wu, W.-Y., Barnard, D.L., and Sidwell, R.W., J. Med. Chem., 2003, vol. 46, no. 15, p. 3181. doi: 10.1021/jm0202876 Chern, J.-H., Lee, C.-C., Chang, C.-S., Lee, Y.-C., Tai, C.-L., Lin, Y.-T., Shia, K.-S., Lee, C.-Y., and Shih, S.-R., Bioorg. Med. Chem. Lett., 2004, vol. 14, no. 20, p. 5051. doi: 10.1016/j.bmcl.2004.07.084 Narayanan, K., Shanmugam, M., Jothivel, S., and Kabilan, S., Bioorg. Med. Chem. Lett., 2012, vol. 22, no. 21, p. 6602. doi: 10.1016/j.bmcl.2012.09.002 Parthiban, P., Aridoss, G., Rathika, P., Ramkumar, V., and Kabilan, S., Bioorg. Med. Chem. Lett., 2009, vol. 19, no. 11, p. 2981. doi: 10.1016/ j.bmcl.2009.04.038 Cristau, P., Rahn, N., Tsuchiya, T., WachendorffNeumann, U., Voerste, A., and Benting, J., Int. Patent no. WO 2010066353, 2010. Hugo, Z., US Patent no. 6 319 925, 2001. Zambach, W., Hall, R.G., Renold, P., and Trah, S., US Patent no. 7 569 727, 2009. Martin, H., US Patent no. 4 152 137, 1979. Martin, H., US Patent no. 4 456 468, 1984. Martin, H., US Patent no. 4 472 317, 1984. Corsaro, A., Chiacchio, U., and Pistarà, V., Synthesis, 2001, no. 13, p. 1903. doi: 10.1055/s-2001-17700 He, H.-F., Wang, K., Xing, B., Sheng, G., Ma, T., and Bao, W., Synlett, 2013, vol. 24, no. 2, p. 211. doi: 10.1055/s-0032-1317960 Jin, J., Li, Y., Wang, Z.-J., Qian, W.-X., and Bao, W.-L., Eur. J. Org. Chem., 2010, no. 7, p. 1235. doi: 10.1002/ ejoc.200901321 Krylov, I.B., Terent’ev, A.O., Timofeev, V.P., Shelimov, B.N., Novikov, R.A., Merkulova, V.M., and Nikishin, G.I., Adv. Synth. Catal., 2014, vol. 356, no. 10, p. 2266. doi: 10.1002/adsc.201400143
13
33. Brokenshire, J.L., Mendenhall, G.D., and Ingold, K.U., J. Am. Chem. Soc., 1971, vol. 93, no. 20, p. 5278. doi: 10.1021/ja00749a064 34. Cornejo, J.J., Larson, K.D., and Mendenhall, G.D., J. Org. Chem., 1985, vol. 50, no. 25, p. 5382. doi: 10.1021/jo00225a078 35. Ngo, M., Larson, K.R., and Mendenhall, G.D., J. Org. Chem., 1986, vol. 51, no. 26, p. 5390. doi: 10.1021/ jo00376a061 36. Eisenhauer, B.M., Wang, M., Labaziewicz, H., Ngo, M., and Mendenhall, G.D., J. Org. Chem., 1997, vol. 62, no. 7, p. 2050. doi: 10.1021/jo962136e 37. Brokenshire, J.L., Robert, J.R., and Ingold, K.U., J. Am. Chem. Soc., 1972, vol. 94, no. 20, p. 7040. doi: 10.1021/ ja00775a030 38. Zhu, X., Wang, Y.-F., Ren, W., Zhang, F.-L., and Chiba, S., Org. Lett., 2013, vol. 15, no. 13, p. 3214. doi: 10.1021/ol4014969 39. Han, B., Yang, X.-L., Fang, R., Yu, W., Wang, C., Duan, X.-Y., and Liu, S., Angew. Chem., Int. Ed., 2012, vol. 51, no. 35, p. 8816. doi: 10.1002/anie.201203799 40. Peng, X.-X., Deng, Y.-J., Yang, X.-L., Zhang, L., Yu, W., and Han, B., Org. Lett., 2014, vol. 16, no. 17, p. 4650. doi: 10.1021/ol502258n 41. Terent’ev, A.O., Borisov, D.A., Yaremenko, I.A., Chernyshev, V.V., and Nikishin, G.I., J. Org. Chem., 2010, vol. 75, no. 15, p. 5065. doi: 10.1021/jo100793j 42. Terent’ev, A.O., Krylov, I.B., Timofeev, V.P., Starikova, Z.A., Merkulova, V.M., Ilovaisky, A.I., and Nikishin, G.I., Adv. Synth. Catal., 2013, vol. 355, nos. 11–12, p. 2375. doi: 10.1002/adsc.201300341 43. Terent’ev, A.O., Borisov, D.A., Semenov, V.V., Chernyshev, V.V., Dembitsky, V.M., and Nikishin, G.I., Synthesis, 2011, no. 13, p. 2091. doi: 10.1055/s-00301260027 44. Kremer, C., Melián, C., Torres, J., Juanicó, M.P., Lamas, C., Pezaroglo, H., Manta, E., Schumann, H., Pickardt, J., Girgsdies, F., Ventura, O.N., and Lloret, F., Inorg. Chim. Acta, 2001, vol. 314, nos. 1–2, p. 83. doi: 10.1016/S0020-1693(00)00389-3
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