Efficient Synthesis of Secondary Alkyl Fluorides via Suzuki Cross-Coupling Reaction of 1-Halo-1-fluoroalkanes

Abstract

Organofluorine compounds have found extensive applications in various areas of science. Consequently, the development of new efficient and selective methods for their synthesis is an important goal in organic chemistry. Here, we present the first Suzuki cross-coupling reaction which utilizes dihalo compounds for the preparation of secondary alkyl fluorides. Namely, an unprecedented use of simple 1-halo-1-fluoroalkanes as electrophiles in C(sp(3))-C(sp(3)) and C(sp(3))-C(sp(2)) cross-couplings allows for the formal site-selective incorporation of F-group in the alkyl chain with no adjacent activating functional groups. Highly effective approach to the electrophilic substrates, 1-halo-1-fluoroalkanes, via iododecarboxylation of the corresponding α-fluorocarboxylic acids is also presented. The conceptually new route to organofluorides was used for the facile preparation of biomedically valuable compounds. In addition, we demonstrated that an asymmetric version of the developed reaction for the stereoconvergent synthesis of chiral secondary alkyl fluorides is feasible.

Nickel‐Catalyzed Carbofluoroalkylation of 1,3‐Enynes to Access Structurally Diverse Fluoroalkylated Allenes

“…Over the past few decades,agreat number of fluorinating and fluoroalkylating agents have been successfully developed, enabling facile synthesis of different kinds of fluorinecontaining molecules, [6] whereas the general approaches to access each fluoroalkylating building blocks typically require multistep syntheses.While such fluoroalkylating agents could only work in specific fluoroalkylation reactions,the development of efficient fluoroalkylation reactions,w hich are compatible with ab road array of fluorine-containing functional groups,w ill evidently offer ap erfect tactic for batch production of fluorinated products in medicinal chemistry. As part of our continuous efforts on nickel-catalyzed fluoroalkylation, [7] we envisioned that the addition of various in situ generated radicals from fluoroalkyl halides [6d] to 1,3enynes [8] would give allenyl radicals for nickel-catalyzed cross-coupling, [9] affording the allenes with structurally different fluorine-containing groups.I ndeed, such ar adical relay strategy was first used for 1,2-carbofluoroalkylation of alkenes by the group of Zhang,a nd then further illustrated by the group of Chu (Scheme 1). [10] However,a lkenes with chelating groups were essential for both transformations, possibly because of the unique catalytic reactivity of the nickel complex.…”

Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel‐Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides

“…Inspired by the pioneering work from Fu and co-workers on nickel-catalyzed asymmetric couplings of secondary alkyl halides with avariety of nucleophiles, [9][10][11][12] we envisaged that if an ickel-catalyzed asymmetric cross-coupling of racemic trifluoromethoxy-substituteds econdary alkyl bromides such as compound 1 could be developed [Eq. (1)],ageneral method for the formation of trifluoromethoxy-substituted stereogenic carbon centers could be provided.…”

“…[18] Indeed, the reaction of 1a with this lithium organoborate in THF proceeded smoothly with full conversion after 5.0 ha t08 8Ct og ive the corresponding coupling product 2ain 81 %yield with 93:7 e.r. Further optimization in term of the reaction temperature and stoichiometry of the reagents disclosed that reactions conducted at 0 8 8Cw ith 1.5 equiv of the lithium organoborate gave the desired product in high yield with good enantioselectivity (entries [8][9][10][11][12]. Ther eaction was much less effective in terms of the yield and enantioselectivity in other ethereal solvents,s uch as DME, dioxane,d iglyme,o rt riglyme (entries 2-5).…”

Nickel‐Catalyzed Monofluoromethylation of Aryl Boronic Acids

“…[3] Although av ariety of methods for the transition-metalcatalyzed trifluoromethylation [4] and difluoromethylation [3b, 5] of arenes have been developedinthe past several decades,the incorporation of methyl groups containing as ingle fluorine (CH 2 F) into arenes has been studied to al esser extent and remains ac hallenge. [9][10][11] We commenced our study with phenylboronic acid (1a)as the pilot substrate and PhSO 2 CFHI [8] (2)a st he coupling partner in the presence of ac atalytic amount of [Ni(acac) 2 ] (5 mol %) in dichloromethane at 100 8 8C. [7] Therein, astoichiometric amount of palladium and alarge excess of the boronic ester (40 equiv) were required, and the yield was modest (57 %, Scheme 1).…”

“…[6] Theo nly example of ap alladiummediated direct monofluoromethylation of pinacol phenylboronate was reported by the Suzuki group in 2009. [9][10][11] We commenced our study with phenylboronic acid (1a)as the pilot substrate and PhSO 2 CFHI [8] (2)a st he coupling partner in the presence of ac atalytic amount of [Ni(acac) 2 ] (5 mol %) in dichloromethane at 100 8 8C. More recently,u sing fluoromethyl 2-pyridyl sulfone reagents,H ua nd co-workers reported ac opper-mediated monofluoromethylsulfonylation of aryl iodides.…”