Fundamental Studies and Development of Nickel-Catalyzed Trifluoromethylthiolation of Aryl Chlorides: Active Catalytic Species and Key Roles of Ligand and Traceless MeCN Additive Revealed

A catalytic protocol
to convert aryl and heteroaryl chlorides to
the corresponding trifluoromethyl sulfides is reported herein. It
relies on a relatively inexpensive Ni­(cod)2/dppf (cod =
1,5-cyclooctadiene; dppf = 1,1′-bis­(diphenylphosphino)­ferrocene)
catalyst system and the readily accessible coupling reagent (Me4N)­SCF3. Our computational and experimental mechanistic
data are consistent with a Ni(0)/Ni(II) cycle
and inconsistent with Ni(I) as the reactive species. The
relevant intermediates were prepared, characterized by X-ray crystallography,
and tested for their catalytic competence. This revealed that a monomeric
tricoordinate Ni(I) complex is favored for dppf and Cl
whose role was unambiguously assigned as being an off-cycle catalyst
deactivation product. Only bidentate ligands with wide bite angles
(e.g., dppf) are effective. These bulky ligands render the catalyst
resting state as [(P–P)­Ni­(cod)]. The latter is more reactive
than Ni­(P–P)2, which was found to be the resting
state for ligands with smaller bite angles and suffers from an initial
high-energy dissociation of one ligand prior to oxidative addition,
rendering the system unreactive. The key to effective catalysis is
hence the presence of a labile auxiliary ligand in the catalyst resting
state. For more challenging substrates, high conversions were achieved
via the employment of MeCN as a traceless additive. Mechanistic data
suggest that its beneficial role lies in decreasing the energetic
span, therefore accelerating product formation. Finally, the methodology
has been applied to synthetic targets of pharmaceutical relevance.