Organic Chemistry Portal

Abstracts

Search:

Practical and Regioselective Synthesis of C-4-Alkylated Pyridines

Jin Choi, Gabriele Laudadio, Edouard Godineau and Phil S. Baran*

*Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States, Email: pbaranscripps.edu

J. Choi, G. Laudadio, E. Godineau, P. S. Baran, J. Am. Chem. Soc., 2021, 143, 11927-11933.

DOI: 10.1021/jacs.1c05278 (free Supporting Information)



see article for more reactions

Abstract

A simple maleate-derived blocking group for pyridines enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to a broad range of valuable building blocks. The method is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion.

see article for more examples

Mock Medicinal and Process Chemistry Synthesis



General Procedure: Minisci Reaction

To a 15 mL culture tube equipped with Teflon septum screw cap and containing a stir bar pyridinium salt (0.5 mmol, 1 equiv), carboxylic acid (1.0 mmol, 2 equiv), (NH4)2S2O8 (228 mg, 1.0 mmol, 2 equiv) and AgNO3 (16.7 mg, 0.1 mmol, 20 mol%) were added, together with dichloroethane (2.5 mL) and H2O (2.5 mL). The biphasic mixture was stirred at 50 C for 2 hours. The reaction and ist regioselectivity were monitored by NMR or LCMS. Upon completion, the reaction was diluted with dichloromethane (1 mL). The aqueous phase was extracted with dichloromethane (3 x 3 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was used next step without further purification.

General Procedure: Base-promoted Deprotection Reaction

To the crude alkylated product was added DBU (225 L, 1.5 mmol, 3 equiv) in dichloromethane (5 mL, 0.1 M). and the reaction mixture was stirred at room temperature for 30 min. Upon the reaction completion, the reaction mixture was transferred to a separatory funnel containing 1 N NaOH (3 mL) for adjusting pH >10 [Note: In case of base sensitive substrate, aq. NaOH could be changed by aq. NaHCO3]. The aqueous phase was extracted with dichloromethane (3 x 3 mL) and combined organic phase was washed with brine. The resulting combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to yield the desired product.


Key Words

 pyridines, ammonium peroxydisulfate


ID: J48-Y2021