gem‐Difluoroallylation of Aryl Halides and Pseudo Halides with Difluoroallylboron Reagents in High Regioselectivity

Abstract

We report the palladium-catalyzed gem-difluoroallylation of aryl halides and pseudo halides with 3,3-difluoroallyl boronates in high yield with high regioselectivity, and we report the preparation of the 3,3-difluoroallyl boronate reactants by a copper-catalyzed defluorinative borylation of inexpensive gaseous 3,3,3-trifluoropropene with bis(pinacolato)diboron. The gem-difluoroallylation of aryl and heteroaryl bromides proceeds with low catalyst loading (0.1 mol % [Pd]) and tolerates a wide range of functional groups, including primary alcohols, secondary amines, ethers, ketones, esters, amides, aldehydes, nitriles, halides, and nitro groups. This protocol extends to aryl iodides, chlorides, and triflates, as well as substituted difluoroallyl boronates, providing a versatile synthesis of gem-difluoroallyl arenes that we show to be valuable intermediates to a series of fluorinated building blocks.The difluoromethylene (CF 2 ) unit can be used to fine-tune the physical, chemical, and biological properties of pharmaceuticals, agrochemicals, and materials. [1] This unit can serve as a bioisostere for an ether linkage or a keto group in pharmaceuticals, [2] and, when positioned at a benzylic site, it can block metabolic oxidation at otherwise labile benzylic CÀH bonds. [2] Difluoromethylene groups also have been used to alter the lipophilicity and ground-state conformation of organic molecules. [2] Compounds containing difluoromethylene groups even serve as valuable reactants, for example undergoing CÀF bond activation during reactions that form alkyl fluorides. [3] However, the installation of a difluoromethylene group poses synthetic challenges. Classical approaches to access 1,1difluoroalkanes, such as the deoxyfluorination of ketones with DAST or Deoxo-Fluor , [4] the fluorodesulfurzation of dithianes, [5] and the hydrofluorination of alkynes, [6,7] typically proceed in low yield and exhibit poor functional group tolerance. Recently, difluoroalkylations catalyzed by transition-metal complexes have provided an alternative, convergent route to access compounds containing the difluoro-methylene group. [8] Among these, difluoroallylations are notable for their ability to simultaneously install a difluoromethylene group and a versatile alkene functional group. In 2014, Zhang et al. reported the palladium-catalyzed coupling of arylboron reagents 1 and 3-bromo-3,3-difluoropropene (2) to provide synthetically versatile gem-difluoroallyl arenes 3 (Scheme 1 a). [9] Similarly, Feng et al. demonstrated that aryl boronic acids 4 undergo cross-coupling with 2-aryl difluoroallyl quaternary ammonium salts 5 to provide 2-aryl difluoroallyl arenes 6 (Scheme 1 b). [10] However, the arylboron reagents used in these reactions as the source of the aryl group are much less available than aryl halides and the 3bromo-3,3-difluoropropene reagent used as the source of the difluoroallyl group in one protocol is expensive; [11] it is prepared from dibromodifluoromethane and ethylene by Scheme 1. Background on the difluoroallylation of a...

Palladium-Catalyzed gem-Difluoroallylation Reaction between Aryltributyltin and Bromodifluoromethylated Alkenes

“…1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (s, 1H), 7.94−7.86 (m, 3H), 7.60−7.52 (m, 3H), 6.33−6.18 (m, 1H), 5.64 (dt, J = 17.3, 2.8 Hz, 1H), 5.54 (d, J = 10.9 Hz, 1H). 13 C{ 1 H} NMR (101 MHz, CDCl 3 ): δ 133.9 (C−F, t, 2 J C−F = 30.2 Hz), 133.6 (C−F, t, 2 J C−F = 27. 6 Hz),132.7,128.8,128.6,127.9,127.3,126.8,125.4 The title compound was isolated by flash column chromatography on silica gel (eluent: petroleum ether) as a colorless oil in 52% yield (22.0 mg).…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 7.67−7.55 (m, 6H), 7.47 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 6.27−6.13 (m, 1H), 5.63 (dt, J = 17.3, 2.7 Hz, 1H), 5.52 (d, J = 10.9 Hz, 1H). 13 1-Bromo-4-(1,1-difluoroallyl)benzene (3f). 7a The title compound was isolated by flash column chromatography on silica gel (eluent: petroleum ether) as a colorless oil in 86% yield (40.1 mg).…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (dd, J = 8.1, 0.6 Hz, 2H), 7.83−7.78 (m, 2H), 7.66−7.59 (m, 3H), 7.53−7.47 (m, 2H), 6.25−6.11 (m, 1H), 5.62 (dt, J = 17.6, 2.8 Hz, 1H), 5.54 (dd, J = 10.9, 0.5 Hz, 1H). 13 Methyl 4-(1,1-Difluoroallyl)benzoate (3m). The reaction was conducted at 110 °C.…”

“…6 Hz,2H),7.57 (d,J = 8.6 Hz,2H),1H),5.57 (dt,J = 17.2,2.8 Hz,1H),5.51 (d,J = 10.9 Hz, 1H), 3.93 (s, 3H). 13 6N-(4-(1,1-Difluoroallyl)phenyl)-2,2,2-trifluoroacetamide (3n). The title compound was isolated by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 40:1) as a colorless solid in 81% yield (43.0 mg).…”

“…12 During the preparation of this manuscript, the Hartwig group reported a palladium-catalyzed gem- difluoroallylation of aryl halides with difluoroallylboron reagents, leading to the convenient synthesis of gemdifluoromethylated compounds. 13 In view of the significance of 3-aryl-3,3-difluoropropenes as well as the cheap, stable, easily accessible organostannanes and also with the ongoing program on the development of pharmaceutically useful fluorinated intermediates in our lab, 14 we decided to optimize the Stille reaction between BDFP and aryl tributylstannanes, which was initially reported by Kirihara and Nemoto 11 α-substitution other than defluorinated γ-substitution or their mixture, thus allowing us for the convenient synthesis of various substituted 3-aryl-3,3-gem-difluoropropenes (Scheme 1d).…”