Copper-Catalyzed γ-Cyanation of Aza-Baylis–Hillman Adducts Using Trimethylsilyl Cyanide

Abstract

A copper-catalyzed γ-cyanation of aza-Baylis–Hillman adducts via iminium ion formation adjacent to benzylic tertiary amines has been developed using tert-butyl hydroperoxide (TBHP) as the external oxidant. The protocol involves in situ formation of 4π-conjugated iminium ion intermediates that undergo nucleophilic attack by cyanide to provide valuable γ-cyanated α,β-unsaturated amines.

Key words

benzylic amines - Baylis–Hillman adducts - copper catalysis - cyanides - electron transfer - Michael addition

• References and Notes


For recent articles, see:
• 1a Li C.-J, Li Z. Pure Appl. Chem. 2006; 78: 935
• 1b Li C.-J. Acc. Chem. Res. 2009; 42: 335
• 1c Shu X.-Z, Xia X.-F, Yang Y.-F, Ji K.-G, Liu X.-Y, Liang Y.-M. J. Org. Chem. 2009; 74: 7464
• 1d Scheuermann CJ. Chem. Asian J. 2010; 5: 436
• 1e Yeung CS, Dong VM. Chem. Rev. 2011; 111: 1215
• 1f Sun C.-L, Li B.-J, Shi Z.-J. Chem. Rev. 2011; 111: 1293
• 1g Hirano K, Miura M. Chem. Commun. 2012; 48: 10704
• 1h Kozhushkov SI, Ackermann L. Chem. Sci. 2013; 4: 886
• 1i Dev ML, Dey SS, Bento I, Barros MT, Maycock CD. Angew. Chem. Int. Ed. 2013; 52: 9791
• 1j Liu D, Liu C, Li H, Lei A. Chem. Commun. 2014; 50: 3623
• 1k Wu XF, Gong J.-L, Qi X. Org. Biomol. Chem. 2014; 12: 5807
• 1l Muramatsu W, Nakano K. Tetrahedron Lett. 2015; 56: 437
• 1m Shang X.-J, Liu Z.-Q. Tetrahedron Lett. 2015; 56: 482

For selected examples, see:
• 2a Li Z, Li C.-J. J. Am. Chem. Soc. 2004; 126: 11810
• 2b Li Z, Li C.-J. J. Am. Chem. Soc. 2005; 127: 6968
• 2c Li Z, Li C.-J. J. Am. Chem. Soc. 2005; 127: 3672
• 2d Zhang Y, Li C.-J. J. Am. Chem. Soc. 2006; 128: 4242
• 2e Li Z, Bohle DS, Li C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 8928
• 2f Li Z, Li H, Guo X, Cao L, Yu R, Li H, Pan S. Org. Lett. 2008; 10: 803
• 2g Shen Y, Li M, Wang S, Zhan T, Tan Z, Guo C.-C. Chem. Commun. 2009; 953
• 2h Sugiishi T, Nakamura H. J. Am. Chem. Soc. 2012; 134: 2504
• 2i Zhang G, Ma Y, Cheng G, Liu D, Wang R. Org. Lett. 2014; 16: 656
• 3a Srivastava VP, Yadav AK, Yadav LD. S. Tetrahedron Lett. 2014; 55: 1788
• 3b Yadav AK, Yadav LD. S. Tetrahedron Lett. 2015; 56: 686

For selected articles on Baylis–Hillman reaction, see:
• 4a Basavaiah D, Rao PD, Hyma RS. Tetrahedron 1996; 52: 8001
• 4b Kotti SR. S. S, Xu X, Li G, Headley AD. Tetrahedron Lett. 2004; 45: 1427
• 4c Yadav JS, Gupta MK, Pandey SK, Reddy BV. S, Sharma AV. S. Tetrahedron Lett. 2005; 46: 2761
• 4d Basavaiah D, Kalapala Rao V, Reddy RJ. Chem. Soc. Rev. 2007; 36: 1581
• 4e Singh V, Pathak R, Batra S. Catal. Commun. 2007; 8: 2048
• 4f Shi Y.-L, Shi M. Eur. J. Org. Chem. 2007; 2905
• 4g Singh V, Batra S. Tetrahedron 2008; 64: 4511
• 4h Ma G.-N, Jiang J.-J, Shi M, Wei Y. Chem. Commun. 2009; 5496
• 4i Basavaiah D, Reddy BS, Badsara SS. Chem. Rev. 2010; 110: 5447
• 4j Basavaiah D, Veeraraghavaiah G. Chem. Soc. Rev. 2012; 41: 68
• 5a Yadav LD. S, Patel R, Srivastava VP. Synlett 2008; 1789
• 5b Yadav LD. S, Srivastava VP, Patel R. Tetrahedron Lett. 2008; 49: 3142
• 5c Yadav LD. S, Patel R, Srivastava VP. Tetrahedron Lett. 2009; 50: 1335
• 5d Yadav LD. S, Rai VK, Singh S. Synlett 2009; 1423
• 5e Yadav LD. S, Awasthi C. Tetrahedron Lett. 2009; 50: 3801
• 5f Patel R, Srivastava VP, Yadav LD. S. Synlett 2011; 1261
• 6a Srivastava VP, Yadav AK, Yadav LD. S. Synlett 2013; 24: 465
• 6b Yadav AK, Yadav LD. S. RSC Adv. 2014; 4: 34764
• 6c Yadav AK, Yadav LD. S. Org. Biomol. Chem. 2015; 13: 2606

For recent developments in nitrogen radical cation chemistry, see:
• 7a Condie AG, González-Gómez JC, Stephenson CR. J. J. Am. Chem. Soc. 2010; 132: 1464
• 7b Rueping M, Leonori D, Poisson T. Chem. Commun. 2011; 47: 9615
• 7c Rueping M, Zhu S, Kόnigs RM. Chem. Commun. 2011; 47: 12709
• 7d Xuan J, Cheng Y, An J, Lu L.-Q, Zhang X.-X, Xiao W.-J. Chem. Commun. 2011; 47: 8337
• 7e Pan Y, Wang S, Kee CW, Dubuisson E, Yang Y, Loh KP, Tan C.-H. Green Chem. 2011; 13: 3341
• 7f Rueping M, Zhu S, Koenigs RM. Chem. Commun. 2011; 47: 8679
• 7g Zhao G, Yang C, Guo L, Sun H, Chen C, Xia W. Chem. Commun. 2012; 48: 2337
• 7h Fu W, Guo W, Zou G, Xu C. J. Fluorine Chem. 2012; 140: 88
• 7i Freeman DB, Furst L, Condie AG, Stephenson CR. J. Org. Lett. 2012; 14: 94
• 7j DiRocco DA, Rovis T. J. Am. Chem. Soc. 2012; 134: 8094
• 7k Rueping M, Koenigs RM, Poscharny K, Fabry DC, Leonori D, Vila C. Chem. Eur. J. 2012; 18: 5170
• 7l Zhu S, Rueping M. Chem. Commun. 2012; 48: 11960
• 7m Mathis CL, Gist BM, Frederickson CK, Midkiff KM, Marvin CC. Tetrahedron Lett. 2013; 54: 2101
• 7n Feng Z.-J, Xuan J, Xia X.-D, Ding W, Guo W, Chen J.-R, Zou Y.-Q, Lu L.-Q, Xiao W.-J. Org. Biomol. Chem. 2014; 12: 2037
• 8 Nobuta T, Tada N, Fujiya A, Kariya A, Miura T, Itoh A. Org. Lett. 2013; 15: 574
• 9 Allen JM, Lambert TH. J. Am. Chem. Soc. 2011; 133: 1260

For selected articles on electrochemical cyanation of amines, see:
• 10a Andreades S, Zahnow E.-W. J. Am. Chem. Soc. 1969; 91: 4181
• 10b Le Gall E, Hurvois J.-P, Sinbanbhit S. Eur. J. Org. Chem. 1999; 2645
• 10c Le E, Malassene G, Toupet RL, Hurvois J.-P, Moinet C. Synlett 1999; 1383
• 10d Tajima T. Nakajima A. 2008; 130: 10496
• 10e Libendi SS, Demizu Y, Onomura O. Org. Biomol. Chem. 2009; 7: 351
• 10f Louafi F, Hurvois J.-P, Chibani A, Roisnel T. J. Org. Chem. 2010; 75: 5721
• 11 General Procedure for the Copper-Catalyzed γ-Cyanation of Aza-Baylis–Hillman Adducts (Table 3) A round-bottom flask was charged with aza-Baylis–Hillman adduct 1 (1.0 mmol), MeCN (3 mL), CuI (10 mol%), TBHP (2.0 equiv), and TMSCN (1.5 equiv). The flask was stoppered, and the reaction mixture was stirred at r.t. for 6–12 h (Table 3). After completion of the reaction (as monitored by TLC), H₂O (5 mL) was added, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried over MgSO₄, filtered, and evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography using a gradient mixture of hexane–EtOAc as eluent to afford an analytically pure sample of 2. All the compounds were characterized by NMR, IR, and MS analysis. The characterization data of representative compounds 2a, 2h, and 2k are given below. Compound 2a: yellow oily liquid. IR (neat liquid): ν_max = 3053, 3021, 2235, 2950, 2925, 2850, 2710, 1962, 1727, 1624, 1575, 1492, 1435, 1378, 1260, 1013, 767, 705 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.26 (m, 5 H), 3.76 (s, 3 H), 3.07 (s, 2 H), 2.35–2.33 (m, 4 H), 1.36–1.34 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.1, 156.2, 133.4, 128.3, 127.1, 126.9, 116.2, 95.9, 54.1, 52.3, 26.5, 13.1. HRMS (EI): m/z calcd for C₁₆H₁₈N₂O₂: 270.1368; found: 270.1365. Compound 2h: yellow oily liquid. IR (neat liquid): ν_max = 3023, 3067, 3023, 2957, 2923, 2858, 2713, 2232, 1693, 1632, 1572, 1497, 1437, 1379, 1264, 1197, 1148, 1013, 753, 715 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.56 (s, 1 H), 7.27–7.14 (m, 4 H), 7.08–6.76 (m, 5 H), 3.17 (t, J = 6.4 Hz, 2 H), 3.08 (t, J = 6.4 Hz, 2 H), 3.05 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.7, 168.4, 144.1, 138.0, 134.3, 129.1, 127.6, 127.0, 125.3, 120.7, 118.8, 116.3, 109.2, 74.5, 51.7, 27.6, 12.3. HRMS (EI): m/z calcd for C₁₉H₁₆N₂O: 288.1263; found: 288.1261. Compound 2k: yellow oily liquid. IR (neat liquid): ν_max = 3107, 3064, 3020, 2963, 2920, 2854, 2713, 2237, 1722, 1621, 1572, 1495, 1434, 1370, 1263, 1197, 1148, 1012, 762, 711 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.24 (m, 4 H), 7.12–6.69 (m, 5 H), 3.66 (s, 3 H), 3.19 (t, J = 6.4 Hz, 2 H), 3.03 (t, J = 6.4 Hz, 2 H), 2.93 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.5, 144.3, 137.6, 133.7, 126.2, 125.0, 124.7, 120.3, 118.3, 117.5, 115.2, 72.5, 52.3, 50.3, 42.7, 27.1, 24.5, 12.9. HRMS (EI): m/z calcd for C₂₀H₁₈N₂O₂: 318.1368; found: 318.1370.
• 12a Lee KY, Kim TH, Kim JN. Bull. Korean Chem. Soc. 2004; 25: 1966
• 12b Kim SJ, Lee HS, Kim JM, Kim JN. Bull. Korean Chem. Soc. 2008; 29: 265