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Nickel-Catalyzed Diaryl Ketone Synthesis by N-C Cleavage: Direct Negishi Cross-Coupling of Primary Amides by Site-Selective N,N-Di-Boc Activation

Shicheng Shi and Michal Szostak*

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

S. Shi, M. Szostak, Org. Lett., 2016, 18, 5872-5875.

DOI: 10.1021/acs.orglett.6b02952


Abstract

Nickel catalysis and a site-selective N,N-di-Boc activation enable a general Negishi acylation of primary amides. The reaction is promoted by a bench-stable, inexpensive Ni catalyst and shows excellent functional group compatibility.

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Preparation of ZnCl2 Solution (1.0 M in THF)

A Schlenk flask equipped with a stir bar was flame-dried under vacuum and allowed to cool down to room temperature. Following backfilling/evacuation cycles with argon (3x), ZnCl2 (4.08 g, 30.0 mmol) was added, the flask was placed under vacuum and heated in an oil-bath at 150 °C for 12 h. After the indicated time, the flask was cooled to room temperature, evacuated/backfilled with argon (3x), and THF (anhydrous, 30.0 mL) was added. The mixture was vigorously stirred until all ZnCl2 dissolved.

Preparation of Arylzinc Reagents

A flame-dried Schlenk flask equipped with a stir bar was charged with a solution of aryl bromide (5.0 mmol) in THF (5.0 mL). The reaction mixture was cooled down to -78 °C and n-BuLi (2.2 mL, 5.5 mmol, 1.1 equiv, 2.5 M, hexanes) was added dropwise over 5 min. A precipitate formed immediately, the reaction mixture was stirred for 60 min at the indicated temperature. After the indicated time, a THF solution of ZnCl2 (5.5 mL, 5.5 mmol, 1.1 equiv) was added dropwise, the reaction mixture was allowed to warm to room temperature, and stirred for an additional 30 min at room temperature. Arylzinc reagents were titrated according to a method reported by Knochel and co-workers. The concentration of arylzinc reagents prepared by this method is from 0.33 M to 0.58 M.

General Procedure for Negishi Cross-Coupling of Amides

An oven-dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv) and Ni(PPh3)2Cl2 (0.10 equiv), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under vacuum. Diethyl ether (0.20 M) was added with vigorous stirring at room temperature and the reaction was stirred at room temperature for 5 min. A solution of arylzinc reagent (THF solution, 1.5 equiv) was added with vigorous stirring and the reaction mixture was stirred for the indicated time at 23 °C. After the indicated time, the reaction mixture was diluted with HCl (0.1 N, 10 mL), the aqueous layer was extracted with EtOAc (3 x 20 mL), organic layers were combined, dried, filtered and concentrated. The sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. Purification by chromatography on silica gel (hexanes/ethyl acetate) afforded the title product.


Key Words

aryl ketones


ID: J54-Y2016