Palladium-Catalyzed α-Arylation of Boc-Protected Lactams Using 2,2,6,6-Tetramethylpiperidine·ZnCl·LiCl

Abstract

We report general conditions for the palladium-catalyzed α-arylation of Boc-protected lactams using TMP·ZnCl·LiCl as a base, eliminating the need for preformed zinc amide enolates. The method is compatible with various 5- and 6-membered lactams and a broad range of aryl bromides. These operationally simple conditions enable efficient access to α-arylated lactams, streamlining SAR exploration in medicinal chemistry.

Keywords

Lactams - Amides - Arylation - Palladium - Catalysis - α-Arylation

Publication History

Received: 18 November 2025

Accepted after revision: 12 December 2025

Accepted Manuscript online:
12 December 2025

Article published online:
24 December 2025

• References

• 1a Caruano J, Muccioli GG, Robiette R. Org Biomol Chem 2016; 14 (43) 10134-10156
• 1b Saldivar-Gonzalez FI, Lenci E, Trabocchi A, Medina-Franco JL. RSC Adv 2019; 9 (46) 27105-27116
• 1c Lima LM, Silva B, Barbosa G, Barreiro EJ. Eur J Med Chem 2020; 208: 112829
• 2 Leit S, Greenwood JR, Mondal S. et al. Bioorg Med Chem Lett 2022; 73: 128891
• 3 Hu Z, Sitkoff D, Glunz PW. et al. Bioorg Med Chem Lett 2023; 88: 129304
• 4 Humphries PS, Bersot R, Kincaid J. et al. Bioorg Med Chem Lett 2018; 28 (03) 293-297
• 5 Micheli F, Pasquarello A, Tedesco G. et al. Bioorg Med Chem Lett 2006; 16 (15) 3906-3912
• 6 deSolms SJ, Ciccarone TM, MacTough SC. et al. J Med Chem 2003; 46 (14) 2973-2984
• 7a Bellina F, Rossi R. Chem Rev 2010; 110 (02) 1082-1146
• 7b Swathy KJ, Saranya PV, Anilkumar G. Appl Organomet Chem 2024; 38 (07)
• 8a Hama T, Culkin DA, Hartwig JF. J Am Chem Soc 2006; 128 (15) 4976-4985
• 8b de Filippis A, Gomez Pardo D, Cossy J. Tetrahedron 2004; 60 (43) 9757-9767
• 8c Cossy J, de Filippis A, Gomez Pardo D. Synlett 2003; 14: 2171-2174
• 9a Mai CK, Sammons MF, Sammakia T. Org Lett 2010; 12 (10) 2306-2309
• 9b Durbin MJ, Willis MC. Org Lett 2008; 10 (07) 1413-1415
• 10 Mosrin M, Knochel P. Org Lett 2009; 11 (08) 1837-1840
• 11a Rene O, Fauber BP, Malhotra S, Yajima H. Org Lett 2014; 16 (13) 3468-3471
• 11b Knauber T, Tucker J. J Org Chem 2016; 81 (13) 5636-5648
• 12 Sotnik SO, Mishchenko AM, Rusanov EB. et al. Molecules 2021; 26 (12)
• 13 Milne JE, Buchwald SL. J Am Chem Soc 2004; 126 (40) 13028-13032
• 14a Hicks JD, Hyde AM, Cuezva AM, Buchwald SL. J Am Chem Soc 2009; 131 (46) 16720-16734
• 14b Ruiz-Castillo P, Buchwald SL. Chem Rev 2016; 116 (19) 12564-12649
• 15 Huang X, Anderson KW, Zim D, Jiang L, Klapars A, Buchwald SL. J Am Chem Soc 2003; 125 (22) 6653-6655
• 16 Fors BP, Buchwald SL. J Am Chem Soc 2009; 131 (36) 12898-12899
• 17 Fors BP, Watson DA, Biscoe MR, Buchwald SL. J Am Chem Soc 2008; 130 (41) 13552-13554
• 18 Kurihara M, Ozutsumi K, Kawashima T. J Chem Soc Dalton 1993; 22: 3379-3382
• 19 Yin J, Buchwald SL. Org Lett 2000; 2 (08) 1101-1104