Frustrated Lewis-Pair-Meditated Selective Single Fluoride Substitution in Trifluoromethyl Groups

Abstract

Single fluoride substitution in trifluoromethylarenes is an ongoing synthetic challenge that often leads to "overreaction", where multiple fluorides are replaced. Development of this reaction would allow simple access to a vast range of difluoromethyl derivatives of current interest to pharmaceutical, agrochemistry, and materials sciences. Using a catalytic frustrated Lewis pair approach, we have developed a generic protocol that allows a single substitution of one fluoride in trifluoromethyl groups with neutral phosphine and pyridine bases. The resulting phosphonium and pyridinium salts can be further functionalized via nucleophilic substitution, photoredox coupling, and electrophilic transfer reactions allowing the generation of a vast array of difluoromethyl products.

Iron‐Catalyzed Halogen Exchange of Trifluoromethyl Arenes**

“…Conversion to ArCF2X (2a-k) was quantified by 19 F NMR, relative to 4-fluorotoluene (-119.5 ppm). † 3 , 2e 4 , 2f 5 all matched their respective reported 19 F NMR chemical shifts. GC-MS analysis was also performed to verify the identity of these products, using the following method.…”

“…[2] A prominent example, the trifluoromethyl group (CF3) is present in 24% of drugs globally approved in 2019. [3] The selective conversion of C-F bonds to C-H or C-C bonds in polyfluorinated molecules has enjoyed increased focus as a strategy to access challenging fluorination patterns. [4] A related transformation is the conversion to higher halide C-X bonds (X = Cl, Br, I), through halogen-exchange (halex) reactions.…”

“…HPLC (method A) R.T. = 13.8 min. 1 H NMR (CDCl3, 700MHz): δ 7.88 (d, 1H, J = 8.4 Hz), 7.75 (d, 1H, J = 2.4 Hz), 7.26 (dd, 1H, J = 8.4, 2.4 Hz) ppm.13 C NMR (CDCl3, 176MHz): δ 143.9 (CH), 141.1 (C, t, 2 JCF = 23.1 Hz), 135.3 (CH), 128.9 (CH, t,3 JCF = 8.6 Hz), 122.5 (C), 115.9 (C, t, 1 JCF = 305.5 Hz), 89.6 (C, t, 3 JCF = 2.7 Hz) ppm 19. F NMR (CDCl3, 376MHz): δ -46.4 (s, 2F) ppm.…”

C-F bond activation under transition-metal-free conditions

“…Activation of the allylic C-F bond could be accomplished through treatment with a Lewis acid (Scheme 35), which was demonstrated by Ichikawa's group [97]. In the presence of stoichiometric EtAlCl 2 , the (trifluoromethyl)alkenes readily eliminated F − and underwent cationic substitution with arenes to produce 3,3-difluoroallylated arenes (197)(198)(199)(200)(201)(202) in good yields. The silyl ether 202 was isolated after the quenching procedure.…”

Selective C–F Bond Allylation of Trifluoromethylalkenes

“…[3] Nevertheless, the fact that -CF 2 -unit finds a wide occurrence in pharmaceutically and agrochemically relevant molecules [4] evokes considerable interest from the synthetic community regarding selective C À F bond functionalization of CF 3 group. [5] In this area, the past several years have witnessed significant progress with respect to aryl-CF 3 [6][7][8][9][10] and carbonyl-CF 3 , [11] however, the alkenyl counterparts remain comparatively far less explored. Due to the competing interference of highly activated alkenyl moiety, the vast majority of reported protocols only led to g-selective defluorinative functionalization for gem-difluoroalkene synthesis.…”