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Accelerated SuFEx Click Chemistry for Modular Synthesis

preprint
submitted on 21.01.2021, 22:20 and posted on 25.01.2021, 05:49 by Christopher J. Smedley, Timothy Gialelis, John Moses
Click chemistry is a method for the rapid synthesis of functional molecules with desirable properties. We report the development of accelerated SuFEx, a powerful click reaction for the efficient coupling of aryl and alkyl alcohols directly with SuFExable hubs catalyzed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, Barton's base). The new method circumvents the need to synthesize silyl ether substrates while allowing the use of sub-stoichiometric catalyst loadings. This is made possible through a synergistic effect between BTMG and hexamethyldisilazane (HMDS) additive. The powerful combination drives the in situ formation of reactive TMS-ether intermediates while exploiting the silicon-fluoride bond formation's thermodynamic driving force. Comparatively, the required BTMG base's catalyst loading is generally low (1.0–20 mol%) compared to the dominant SuFEx catalyst, DBU (10–30 mol%). In line with click chemistry principles, the scalable reaction only requires simple evaporation of the volatile side products (NH3, Me3Si-F, TMS-OH, BTMG) under reduced pressure instead of extensive purification. The new SuFEx protocol is tolerant of a wide selection of functional groups and meets all the demands of a click reaction, thereby dramatically shortening reaction times and delivering products in excellent yield.

Funding

NCI Cancer Center Support Grant 5P30CA045508

History

Email Address of Submitting Author

moses@cshl.edu

Institution

Cold Spring Harbor Laboratory

Country

United States

ORCID For Submitting Author

0000-0003-2162-3234

Declaration of Conflict of Interest

No conflict of interest

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ChemRxiv

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