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
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 µL, 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.