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.
Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.
Hien-Quang
HQ
Do
Shoshana
S
Bachman
Alex C
AC
Bissember
Jonas C
JC
Peters
Gregory C
GC
Fu
D000478:Alkylation; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D006846:Hydrocarbons, Halogenated / Q000737:chemistry*; D015394:Molecular Structure; D055668:Photochemical Processes; D013696:Temperature
D000577:Amides; D006846:Hydrocarbons, Halogenated; D003300:Copper