Enantiospecific Trifluoromethyl‐Radical‐Induced Three‐Component Coupling of Boronic Esters with Furans

Abstract

In the presence of trifluoromethylsulfonium reagents,b oronate complexes derived from 2-lithio furan and non-racemic secondary and tertiary alkyloraryl boronic esters undergo deborylative three-component coupling to give the corresponding 2,5-disubstituted furans with excellent levels of enantiospecificity.T he process proceeds via the reaction of boronate complexes with at rifluoromethyl radical, which triggers 1,2-metallate rearrangement upon single-electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar threecomponent coupling reactions.Transition-metal-catalyzed stereoselective sp 2 -sp 3 cross-coupling reactions of secondary alkyl organoboron reagents with aryl halides attract considerable interest owing to the importance of populating drug-discovery libraries with molecules containing 3D structural motifs.[1] However,t he slow rates of both the transmetalation and the reductive elimination steps associated with these types of cross-coupling reactions have hindered progress.Although several advances have been charted in this challenging area, [2] we recently developed ac onceptually different, transition-metal-free cross-coupling reaction, [3] which enables the stereospecific coupling of non-racemic secondary and tertiary alkylboronic esters [4,5] with aw ide range of aryl lithium reagents (Scheme 1A). Ther eaction involves initial formation of aryl boronate I through Li-B exchange of an aryl lithium and an alkylboronic ester.[6] Subsequent addition of an electrophilic halogenating agent (NBS = N-bromosuccinimide) to I forms oxocarbenium II (structure drawn for clarity although aconcerted mechanism has been proposed), [3b] which promotes a1 ,2-metallate rearrangement giving the neutral boronic ester III.F inally,r earomatization-driven elimination of the halide and the boronic ester group generates the substituted aryl product. We reasoned that this useful methodology could be substantially expanded by using carbon-based electrophiles in place of halogenating agents,asthen the intermediate akin to boronic ester III (boronic ester V,S cheme 1B) would not undergo elimination, thus enabling not one,b ut two CÀCb onds to be formed in the process.S ubsequent oxidative rearomatization would lead to high-value aromatic products derived from three components.We initially considered using trifluoromethyl-based electrophiles because this group has found widespread utility in pharmaceuticals,e ndowing molecules with more attractive levels of bioavailability and membrane permeability relative to the hydrocarbon-based parent compounds.[7] Indeed, new methods to introduce the trifluoromethyl group have received considerable attention in recent years. [8] We recognized the potential application of electrophilic trifluoromethylation [9] in our proposed three-component coupling reaction, which would provide access to enantioenriched trifluoromethylated furans,amotif that has been incorporated into potential drug candidates targeting the treat...

Catalytic Enantioselective Synthesis of β-Allenyl Boronic Esters by Conjunctive Cross-Coupling with Propargylic Carbonates

“…In contrast to the reaction of four-coordinate ate complex 1, treatment of PhB(pin) (6) with methanol did not lead to any detectable ligand exchange (Scheme 2, eq 2); as expected, treatment of PhB(OCH 3 ) 2 (7) with pinacol led to quantitative formation of PhB(pin) (Scheme 2, eq 3). Collectively, these experiments show that the four-coordinate boronic esterderived "ate" complexes do not follow the well-known preference for three-coordinate boronic esters to bind pinacol in place mono-ols.…”

Synthesis of Chiral N-Heterocyclic Allylboronates via the Enantioselective Borylative Dearomatization of Pyrroles

“…The development of new methods for the synthesis of other N-heterocyclic allylic boronates (e.g., five-membered rings) is also highly desirable for providing an attractive route for the rapid construction of complex saturated N-heterocycles via stereospecific, boronbased functionalization processes. 1,2,4 Our group has been interested in applying a copper(I)catalyzed nucleophilic borylation protocol to the synthesis of chiral N-heterocyclic organoboronates. 5a,6 We have previously reported an enantioselective borylative dearomatization reaction of indole-2-carboxylate derivatives using a copper(I) catalyst to furnish the corresponding optically active 3-borylindolines.…”

Lewis Acid Catalyzed Stereoselective Dearomative Coupling of Indolylboron Ate Complexes with Donor–Acceptor Cyclopropanes and Alkyl Halides

“…Aggarwal and co-workers recently described an elegant coupling of 2-lithiofuran with various boronic esters as induced by trifluoromethyl radical addition (Scheme 1A). [5] Morken and co-workers, [6] Aggarwal and co-workers, [7b] and our group [7a] successfully explored the reactivity of vinylboron ate complexes in three-component coupling processes either through palladium catalysis or electron catalysis.…”