Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

Summary α,α-Difluoro-substituted organozinc reagents generated from conventional organozinc compounds and difluorocarbene couple with 1-bromoalkynes affording gem-difluorinated alkynes. The cross-coupling proceeds in the presence of catalytic amounts of copper iodide in dimethylformamide under ligand-free conditions.

Typically, the difluoromethylene fragment is created by deoxyfluorination, which requires harsh or hazardous conditions [10,11]. Alternatively, functional group manipulations starting from available CF 2 -containing building blocks can be considered, but multistep sequences render this approach laborious [12][13][14]. Difluoro-substituted cyclopropanes and cyclopropenes constitute a specific class of compounds accessible by difluorocarbene addition to multiple bonds [15].

Results and Discussion
Organozinc compound 2a generated from benzylzinc bromide was first evaluated in a reaction with haloalkynes derived from phenylacetylene (Table 1). First, most reactive iodo-substituted alkyne 3a-I (X = I) was evaluated in the presence of copper iodide (10 mol %). Expected product 4a was formed in 12% yield, but its yield was tripled simply by adding 2 equiv of DMF additive (Table 1, entries 1 and 2). However, in these experiments, the reaction mixtures contained about 40% of (2,2-difluoro-2-iodoethyl)benzene (PhCH 2 CF 2 I) arising from zinc/ iodine exchange between 2a and the iodoalkyne. Chloroalkyne 3a-Cl was markedly less reactive, likely because of the strong carbon-chlorine bond. Fortunately, bromoalkyne 3a-Br provided the best results, with the optimal conditions involving the use of DMF as a solvent and only 5 mol % of copper iodide at 0 °C to room temperature, which afforded the coupling product in 79% isolated yield (Table 1, entry 5). The addition of various ligands, as well as the use of other copper salts, did not had a beneficial effect.
Under the optimized conditions, a series of organozinc compounds 2 were coupled with bromoalkynes 3 (Table 2). Good yields of coupling products 4 were typically achieved. The reaction tolerates ester groups or TBS-protected hydroxy groups. Aromatic iodide also remains unaffected (Table 2, entry 2).
As for the mechanism, we believe that the reaction starts with the zinc/copper exchange resulting in the formation of fluorinated organocopper species 5 (Scheme 2). Compound 5 inter-

Conclusion
In summary, a method for the copper-catalyzed coupling of α,α-difluoro-substituted organozinc compounds with 1-bromoalkynes has been developed. The reaction is performed under mild conditions affording gem-difluoro-substituted alkynes in good yields.

Supporting Information
Supporting Information File 1 Full experimental details, compound characterization, and copies of NMR spectra.