Enantioselective Palladium-Catalyzed Oxidative b , b-Fluoroarylation of a , b-Unsaturated Carbonyl Derivatives

Content Provider	Semantic Scholar
Author	Mirý, Javier Pozo, Carlos Domingo Del Toste, F. Dean Fustero, Santos
Copyright Year	2016
Abstract	The site-selective palladium-catalyzed three-component coupling of deactivated alkenes, arylboronic acids, and N-fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and stepeconomical approach to the stereoselective b-fluorination of a,b-unsaturated systems. Fluorine plays a decisive role in medicinal chemistry, having led to remarkable breakthroughs in the field. Despite its widespread distribution in nature, the presence of fluorine in natural organic molecules is scarce, and most of the fluorinecontaining organic molecules are synthetic. Given this perspective, the development of new methodologies which gain access to new fluorinated derivatives is always in great demand, particularly those enabling selective fluorination on specified positions of an organic framework. Among current strategies for the asymmetric construction of C(sp3)¢F bonds, a-fluorination of carbonyl derivatives is the strategy most commonly exploited. Distinct approaches, including organocatalysis, chiral anion phase-transfer catalysis, ring-opening of strained heterocycles, and transitionmetal-catalyzed fluorinations have been devised. In the last case, C¢F reductive elimination is usually accomplished from high-valent electron-deficient species, since fluoride, as a hard base, is well suited for stabilizing highly oxidized metal centers. While great progress has been made in the assembly of C¢F bonds adjacent to an electron-withdrawing group, just a few protocols incorporating fluorine at the b-position of a carbonyl derivative have been reported, and most of them are racemic. Seminal contributions entailed prior installation of a functional group, for example, alcohols, halides, sulfonates, or boronates, and further conversion into the corresponding b-fluorinated carbonyl compounds using either nucleophilic or electrophilic fluorinating reagents (Figure 1a). The enantioselective variant has recently been achieved through a fluorinative semipinacol rearrangement (Figure 1b). Recently reported methods explored selective C¢H (Figure 1c) and C¢C (Figure 1 d) activation as a means to guide C(sp) fluorination. On the basis of the limited reported oxidative transitionmetal-catalyzed fluorinations 15] and inspired by the latest examples on palladium-catalyzed 1,1-difunctionalizations, 16] we envisioned access b-fluorinated carbonyl derivatives by a single-step three-component Heck arylation/oxidative fluorination cascade reaction (Figure 1e). Under this scenario, we decided to test our hypothesis by examining the fluoroarylation of ethyl acrylate (1a) with 4-tolylboronic acid (2a) as a model reaction, under reaction conditions similar to those previously employed in the 1,2fluoroarylation of styrenes (Table 1). Thus, 1a was initially treated with 2a (2 equiv), Pd(OAc)2 (15 mol%), 1,10-phenanthroline (15 mol %), and 4-tBu-catechol (4 mol%) in DCM/H2O using Selectfluor as the electrophilic fluorine source. However, after 20 hours only trace amounts of the ester 3a were detected, with the major product resulting from the undesired competing oxidative Heck reaction (entry 1). Pleasantly, switching the (N¢F)+ source to NFSI had a dramatic effect, thus giving rise to the exclusive formation of 3a Figure 1. Strategies to access to b-fluorocarbonyl-derived systems. DG= directing group, EWG= electron-withdrawing group, FG = functional group, Tf = trifluoromethanesulfonyl. [*] J. Mirü, Dr. C. del Pozo, Prof. S. Fustero Departamento de Qu†mica Org‚nica, Universidad de Valencia 46100 Burjassot (Spain) E-mail: carlos.pozo@uv.es santos.fustero@uv.es
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Alternate Webpage(s)	http://www.cchem.berkeley.edu/toste/publications/ACIE_2016_55_9045.pdf
Language	English
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Resource Type	Article