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Chemoselective Ketone Synthesis by the Addition of Organometallics to N-Acylazetidines

Chengwei Liu, Marcel Achtenhagen and Michal Szostak*

*Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States, Email:

C. Liu, M. Achtenhagen, M. Szostak, Org. Lett., 2016, 18, 2375-2378.

DOI: 10.1021/acs.orglett.6b00842

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N-acylazetidines are bench-stable, readily available amide acylating reagents, in which the reactivity is controlled by amide pyramidalization and strain of the four-membered ring. A general and highly chemoselective synthesis of ketones by the addition of organometallics to N-acylazetidines via stable tetrahedral intermediates offers wide substrate scope and exquisite selectivity for the ketone products.

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General Procedure for Ketone Synthesis from Azetidinyl Amides

An oven-dried vial equipped with a stir bar was charged with an N-acylazetidine substrate (typically, 0.50 mmol, 1.0 equiv), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles. Tetrahydrofuran (typically, 5.0 mL, 0.10 M) was added, the reaction mixture was cooled to 0 C or -78 C, followed by dropwise addition of an organometallic reagent (typically, 3.0 equiv) with vigorous stirring. After the indicated time, the reaction was quenched by slow addition of HCl (1.0 N, 5 mL), extracted with Et2O (2 x 30 mL), organic layers were combined, dried, filtered and concentrated. The sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain selectivity, conversion and yield using internal standard and comparison with authentic samples. Purification by chromatography on silica gel afforded the title product.

Note: For reactions that were run at -78 C, the reaction was quenched with HCl (1.0 N, 5 mL) at -78 C and then allowed to reach room temperature. All other reactions were quenched with HCl (1.0 N, 5 mL) at room temperature. For the addition of the reactive organometallic reagents, the rate of addition was about 1 drop every 3 seconds (MeLi, n-BuLi, t-BuLi). For the less reactive organometallic reagents, the rate of addition was about 1 drop every second.

Key Words

ketones, aryl ketones

ID: J54-Y2016