Bis(acetoxy)iodobenzene-Mediated Direct Transformation of α-Amino Acids into Nitriles

Abstract

A novel bis(acetoxy)iodobenzene (PIDA)–mediated decarboxylative cyanation of α-amino acids to nitriles was developed using aqueous ammonia. Optimized conditions (CH₃CN/aqueous ammonia = 10/1, 2.5 equiv PIDA) afforded model compound 4-methylphenylacetonitrile in 87% yield. The method demonstrates broad substrate scope for both natural and unnatural amino acids bearing electronically diverse substituents (electron-donating and -withdrawing groups), yielding products in up to 92% yield with insensitivity to electronic effects. Gram-scale synthesis of 4-methylphenylacetonitrile (85% yield) confirmed the method’s scalability.

Keywords

Hypervalent iodine - Amino acids - Decarboxylation - Nitrile

Publication History

Received: 02 August 2025

Accepted after revision: 18 August 2025

Article published online:
09 September 2025

• References

• 1 Kumar Singaravel D, Sharma S, Kumar P, Patel PR. Polym-Plast Tech Mater 1998; 2023: 62
• 2a Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. J Med Chem 2010; 53: 7902
• 2b Ravula AR, Yenugu S. Crit Rev Toxicol 2021; 51: 117
• 3 Brijesh K, Jareer M, Sagar GL. et al. J Phys Chem C 2025; 129: 11221
• 4 Larock RC. Comprehensive Organic Transformations: A Guide to Functional Group Preparations. New York: Wiley-VCH; 1989
• 5 Cui F, García-López V, Wang Z. et al. Chem Rev 2025; 125: 445
• 6a Zhou S, Junge K, Addis D, Das S, Beller M. Org Lett 2009; 11: 2461
• 6b Sueoka S, Mitsudome T, Mizugaki T, Jitsukawa K, Kaneda K. Chem Commun 2010; 46: 8243
• 7a Yamaguchi K, Fujiwara H, Ogasawara Y, Kotani M, Mizuno N. Angew Chem, Int Ed 2007; 46: 3922
• 7b Yu L, Li H, Zhang X. et al. Org Lett 2014; 16: 1346
• 8a Zhou W, Zhang L, Jiao N. Angew Chem, Int Ed 2009; 48: 7094
• 8b Guo S, Wan G, Sun S, Jiang Y, Yu J-T, Cheng J. Chem Commun 2015; 51: 5085
• 8c Liu J, Zheng H-X, Yao C-Z, Sun B-F, Kang Y-B. J Am Chem Soc 2016; 138: 3294
• 9a Kim J, Chang S. J Am Chem Soc 2010; 132: 10272
• 9b Dong Y, Yang P, Zhao S, Li Y. Nat Commun 2020; 11: 4096
• 10a Utsugi M, Ozawa H, Toyofuku E, Hatsuda M. Org Process Res Dev 2014; 18: 693
• 10b Wen Q, Jin J, Zhang L, Luo Y, Lu P, Wang Y. Tetrahedron Lett 2014; 55: 1271
• 10c Chandra P, Choudhary N, Lahiri GK, Maiti D, Mobin SM, Asian J. Org Chem 1897; 2021: 10
• 11a Laval G, Golding BT. Synlett 2003; 542
• 11b Gowda BT, Mahadevappa DS. J Chem Soc Perkin Trans 1983; 2: 323
• 12a Takeda T, Yamauchi S, Fujiwara T. Synthesis 1996; 600
• 12b Hiegal G, Lewis J, Bae J. Synth Commun 2004; 34: 3449
• 13 Telvekar VK, Sasane KA. Synlett 2010; 2778
• 14 Brägger Y, Paschke AK, Nasiri N, Botlik BB, Felician F, Morandi B. Science 2025; 387: 1108
• 15 General procedure for the synthesis of 2: A 10 mL reaction tube equipped with a stir was charged subsequently with 1 (0.3 mmol, 1.0 equiv), NH₃ ^.H₂O (25% aqueous solution, 0.2 mL), and MeCN (2 mL, 0.15 M). PIDA (241.6 mg, 0.75 mmol, 2.5 equiv) was added to the reaction system, and the reaction mixture continued to stir at room temperature for 2 h. The resulting mixture was treated with water (3 mL) and extracted with ethyl acetate (3 mL). Then, the organic phase was evaporated under reduced pressure to remove all the solvent. The residual was purified by the mixed solvent (PE/EA = 10/1 to 2/1) to give nitriles 2
• 16 2a was purified by flash column chromatography on silica gel using a PE/EA (10/1) mixture as the eluent. 34.3 mg, 87% yield, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29–7.19 (m, 4H), 3.73 (s, 2H), 2.41 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 137.8, 129.8, 127.8, 126.9, 118.2, 23.2, 21.1.