Although the alkylation of an amine by an alkyl halide serves as a "textbook example" of a nucleophilic substitution reaction, the selective mono-alkylation of aliphatic amines by unactivated, hindered halides persists as a largely unsolved challenge in organic synthesis. We report herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (-10 °C), displays good functional-group compatibility, and employs commercially available catalyst components. A trapping experiment with TEMPO is consistent with C-N bond formation via an alkyl radical in an out-of-cage process.
Although the alkylation of an amine by ann class="Chemical">alkyl halide serves as a "textbook example" of a nucleophilic substitution reaction, the selective mono-alkylation of aliphatic amines by unactivated, hindered halides persists as a largely unsolved challenge in organic synthesis. We report herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (-10 °C), displays good functional-group compatibility, and employs commercially available catalyst components. A trapping experiment with TEMPO is consistent with C-N bond formation via an alkyl radical in an out-of-cage process.
Authors: Daniel T Ziegler; Junwon Choi; José María Muñoz-Molina; Alex C Bissember; Jonas C Peters; Gregory C Fu Journal: J Am Chem Soc Date: 2013-08-22 Impact factor: 15.419
Authors: David C Miller; Jacob M Ganley; Andrew J Musacchio; Trevor C Sherwood; William R Ewing; Robert R Knowles Journal: J Am Chem Soc Date: 2019-10-14 Impact factor: 15.419
Authors: Jesus Rodrigalvarez; Manuel Nappi; Hiroki Azuma; Nils J Flodén; Matthew E Burns; Matthew J Gaunt Journal: Nat Chem Date: 2019-12-20 Impact factor: 24.427
Authors: Ranjeet A Dhokale; Frederick J Seidl; Anand H Shinde; Joel T Mague; Shyam Sathyamoorthi Journal: J Org Chem Date: 2021-06-15 Impact factor: 4.354
Authors: Timothy J Fazekas; Jill W Alty; Eliza K Neidhart; Austin S Miller; Frank A Leibfarth; Erik J Alexanian Journal: Science Date: 2022-02-03 Impact factor: 63.714
Authors: Seth M Barrett; Bethany M Stratakes; Matthew B Chambers; Daniel A Kurtz; Catherine L Pitman; Jillian L Dempsey; Alexander J M Miller Journal: Chem Sci Date: 2020-03-06 Impact factor: 9.825