Photoinduced, Copper-Catalyzed Alkylation of Amides with Unactivated Secondary Alkyl Halides at Room Temperature

  • 10.1021/ja4126609
  • Journal of the American Chemical Society
  • p 2162-2167, Volume 136, Issue 5,
  • journal-article
The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for S N 2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C–N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper–amidate complex, followed by electron transfer to form an alkyl radical.

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Coupling N-alkylation of Amides with Secondary Alkyl Halides

Yapin Wang


1) Reaction of Standard Condition
Using photo-induced (hn 254), copper- catalyzed (10% CuI), two ratio base(LiOt-Bu), CH3CN/DMF as solvents and
stirring for 24 hrs at room temperature, Amides react with inactivated second alkyl...