A One-Pot, Three-Component Synthesis of β,γ-Unsaturated α-Aminonitriles Using TMSCN as the Cyanide Source

We thank Prof. Zheng Li of Northwestern Normal University (China) for his support and celebrate his 60^th birthday.

Abstract

An efficient method for synthesizing β,γ-unsaturated α-aminonitriles via a one-pot procedure using cinnamaldehydes, anilines and trimethylsilyl cyanide (TMSCN) as starting materials under catalyst-free conditions is reported. This one-pot, three-component reaction proceeds efficiently with a broad range of substrates and tolerates a wide variety of functional groups. Notably, the process features a simple work-up procedure and does not require transition-metal catalysts. Additionally, the reaction can be performed on gram scale without loss of efficiency.

Key words

α-aminonitriles - trimethylsilyl cyanide - cyanide source - catalyst-free - cinnamaldehyde

Publication History

Received: 14 November 2024

Accepted after revision: 27 January 2025

Accepted Manuscript online:
27 January 2025

Article published online:
12 March 2025

• References and Notes

• 1a Bhalla TC, Miura A, Wakamoto A, Ohba Y, Furuhashi K. Appl. Microbiol. Biotechnol. 1992; 37: 184
• 1b Duthaler RO. Tetrahedron 1994; 50: 1539
• 2a Matier WL, Owens DA, Comer WT, Deitchman D, Ferguson HC, Seidehamel RJ, Young JR. J. Med. Chem. 1973; 16: 901
• 2b Weinstok LM, Davis P, Handelsman B, Tull R. J. Org. Chem. 1967; 32: 2823
• 3a Lee CH, Francesco F, Angiolillo DJ. Expert Opin. Drug Metab. Toxicol. 2020; 16: 1079
• 3b Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J. Med. Chem. 1991; 34: 2202
• 3c Tantry U, Singh S, Bliden K, Gurbel P, Ashley W. Expert Rev. Neurother. 2024; 24: 139
• 3d Fukuyama T, Yang L, Ajeck KL, Sachleben RA. J. Am. Chem. Soc. 1990; 112: 3712
• 3e Namba K, Shinada T, Teramoto T, Ohfune Y. J. Am. Chem. Soc. 2000; 122: 10708
• 4 Ramalingam B, Seayad AM, Li CZ, Garland M, Yoshinaga K, Wadamoto M, Nagata T, Chai CL. L. Adv. Synth. Catal. 2010; 352: 2153
• 5a El-Ahl AS. Synth. Commun. 2003; 33: 989
• 5b Rafiee E, Azad A. Synth. Commun. 2007; 37: 1127
• 6 Shah S, Singh B. Tetrahedron Lett. 2012; 53: 151
• 7 Nakamura S, Sato N, Sugimoto M, Toru T. Tetrahedron: Asymmetry 2004; 15: 1513
• 8a Vachal P, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 10012
• 8b Xie ZF, Li GL, Zhao G, Wang JD. Synthesis 2009; 2035
• 9a Pathare SP, Akamanchi KG. Tetrahedron Lett. 2012; 53: 871
• 9b Dekamin MG, Mokhtari Z. Tetrahedron 2012; 68: 922
• 9c Nasreen A. Tetrahedron Lett. 2013; 54: 3797
• 9d Saberi D, Cheraghi S, Mahdudi S, Akbari J, Heydari A. Tetrahedron Lett. 2013; 54: 6403
• 9e Yadav JS, Reddy BV. S, Eeshwaraiah B, Srinivas M. Tetrahedron 2004; 60: 1767
• 9f Yadav JS, Reddy BV. S, Eshwaraiah B, Srinivas M, Vishnumurthy P. New J. Chem. 2003; 27: 462
• 9g Enders D, Gottfried K, Raabe G. Adv. Synth. Catal. 2010; 352: 3147
• 9h Surendra K, Krishnaveni NS, Mahesh A, Rao KR. J. Org. Chem. 2006; 71: 2532
• 9i Kumar MA, Babu MF. S, Srinivasulu K, Kiran YB, Reddy CS. J. Mol. Catal. A: Chem. 2007; 265: 268
• 10a Kobayashi S, Ishitani H, Ueno M. Synlett 1997; 115
• 10b De SK, Gibbs RA. Synth. Commun. 2005; 35: 951
• 10c Paraskar S, Sudalai A. Tetrahedron Lett 2006; 47: 5759
• 10d Heydari A, Fatemi P, Alizadesh AA. Tetrahedron Lett. 1998; 39: 3049
• 10e De SK, Gibbs RA. Tetrahedron Lett. 2004; 45: 7407
• 10f De SK. J. Mol. Catal. A: Chem. 2005; 225: 169
• 10g De SK. Synth. Commun. 2005; 35: 653
• 10h Pasha MA, Nanjundaswamy HM, Jayashankara VP. Synth. Commun. 2007; 37: 4371
• 10i Banu BC, Dev SS, Hajri A. Tetrahedron 2002; 58: 2529
• 10j Shen ZL, Ji SJ, Loh TP. Tetrahedron 2008; 64: 8159
• 10k Majhi A, Kim SS, Kadam ST. Tetrahedron 2008; 64: 5509
• 10l Narasimhulu M, Reddy TS, Mahesh KC, Reddy SM, Reddy AV, Venkateswarlu Y. J. Mol. Catal. A: Chem. 2007; 264: 288
• 10m Royer L, De SK, Gibbs RA. Tetrahedron Lett. 2005; 46: 4595
• 10n Das B, Ramu R, Ravikanth B, Reddy KR. Synthesis 2006; 1419
• 11a Li Z, Ma Y, Xu J, Shi J, Cai H. Tetrahedron Lett. 2010; 51: 3922
• 11b Zhao Z, Li Z. J. Braz. Chem. Soc. 2011; 22: 148
• 11c Hu X, Ma Y, Li Z. J. Organomet. Chem. 2012; 705: 70
• 11d Li Z, Zhang Y, Wen F, Yin J, Zheng H, Li H, Yang J. J. Chem. Res. 2013; 37: 601
• 11e Li Z, Wen F, Yang J. Chin. J. Chem. 2014; 32: 1251
• 11f Zhang Y, Hu X, Li Z. Chem. Pap. 2015; 64: 596
• 11g Li Z, Wen F, Yang J. J. Chem. Sci. 2016; 128: 1849
• 11h Song G, Li Z. Eur. J. Org. Chem. 2018; 1326
• 11i Lu H, Li Z. Adv. Synth. Catal. 2019; 361: 4474
• 12 β,γ-Unsaturated α-Aminonitriles 3; General Procedure A reaction tube (15 mL) containing a magnetic stir bar was charged with cinnamaldehyde 1 (1.0 mmol), aniline 2 (1.0 mmol), TMSCN (1.2 mmol) and EtOH (5 mL) under air. The reaction mixture was stirred at room temperature for 24 h. Upon completion the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc as eluent) to give the target product 3.
• 13 (E)-4-Phenyl-2-(o-tolylamino)but-3-enenitrile (3b) ¹H NMR (600 MHz, CDCl₃): δ = 7.44 (d, J = 7.2 Hz, 2 H), 7.37 (t, J = 7.0 Hz, 2 H), 7.32 (t, J = 7.1 Hz, 1 H), 7.20 (t, J = 7.3 Hz, 1 H), 7.12 (d, J = 7.4 Hz, 1 H), 7.06 (dd, J = 15.9, 1.3 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 6.31 (dd, J = 15.9, 5.2 Hz, 1 H), 5.06 (dd, J = 5.2, 1.3 Hz, 1 H), 3.75 (s, 1 H), 2.18 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 142.5, 135.1, 135.0, 130.8, 129.0, 128.9, 127.4, 127.0, 123.7, 121.2, 120.0, 117.8, 111.7, 47.6, 17.5. HRMS (ESI): m/z [M – H]⁺ calcd for C₁₇H₁₅N₂: 247.12407; found: 247.12410.