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

The development of a mild and general
method for the alkylation of amides with relatively unreactive alkyl
halides (i.e., poor substrates for SN2 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.