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Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls

Alejandro Cervantes-Reyes, Aaron C. Smith*, Gary M. Chinigo, David C. Blakemore, and Michal Szostak*

*Medicine Design, Pfizer, Inc., Groton, Connecticut 06340; Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States, Email: Aaron.Smith2pfizer.com, michal.szostakrutgers.edu

A. Cervantes-Reyes, A. C. Smith, G. M. Chinigo, D. C. Blakemore, M. Szostak, Org. Lett., 2022, 24, 1662-1667.

DOI: 10.1021/acs.orglett.2c00267


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Abstract

A Pd-catalyzed decarbonylative Suzuki cross-coupling of widely available heterocyclic carboxylic acids with arylboronic acids enabled the straightforward preparation of >45 heterobiaryl products using pyridines, pyrimidines, pyrazines, and quinolines in very good yields.


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General Procedure for Decarbonylative Suzuki-Miyaura Cross-Coupling of Heterocyclic Carboxylic Acids

An oven-dried vial equipped with a stir bar was successively charged with carboxylic acid (0.2 mmol, 1.0 equiv), (hetero)arylboronic acid (0.4 mmol, 2.0 equiv), pivalic anhydride (0.4 mmol, 2.0 equiv), H3BO3 (0.4 mmol, 2.0 equiv), ligand (0.02 mmol, 10 mol%), Pd(OAc)2 (0.01 mmol, 5 mol%), anhydrous dioxane (1 mL, 0.20 M with regard to carboxylic acid) and Et3N (0.35 mmol, 1.75 equiv), under open air conditions. The vial was sealed and placed under a positive pressure of argon by three evacuation/backfilling cycles under high vacuum. The reaction mixture was placed in a preheated oil bath (160 C) and stirred for 15 h. After the indicated time, the reaction mixture was cooled down to room temperature and concentrated. A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, selectivity and yield using internal standard and comparison with authentic samples. Purification by chromatography on silica gel (EtOAc/hexanes: 2:8) afforded the title product.


Key Words

Pyridines, Quinolines


ID: J54-Y2022