Synthesis of Chiral α-CF₃-Substituted Benzhydryls via Cross-Coupling Reaction of Aryltitanates

Abstract

We describe a highly efficient approach toward α-CF3-substituted benzhydryls thanks to the employment of organotitanium­(IV) based nucleophiles. The use of commercially available anesthetic halothane as a cheap fluorinated building block in a sequential one-pot nickel-catalyzed enantioselective cross-coupling reaction of aryl titanates allowed for the synthesis of chiral α-CF3-substituted benzhydryls in good yields and excellent enantioselectivities. Alternatively, α-CF3-benzyl bromides could be employed under similar conditions to obtain the same family of compounds in higher yields and excellent selectivities. A benzhydryl moiety is a common motif in many biologically active compounds, and their enantioenriched fluorinated analogs should be of great interest in the search for novel drugs and agrochemicals.

Synthesis of Trifluoromethylated Dithiocarbamates via Photocatalyzed Substitution Reaction: Pentafluoropyridine as Activating Reagent

“…The proposed mechanism is shown in Scheme 3. The light activated catalyst reduces substrate 3 to generate radical anion, which eliminates the stabilized alkoxide anion to give the CF 3 ‐substituted benzyl radical [15] . The radical is trapped by a copper species formed between copper cyanide and dithiocarbamate anion, and the copper(II) intermediate is oxidized by cationic form of the photocatalyst leading to a copper(III) species with subsequent reductive elimination.…”

Catalytic Asymmetric Construction of CF3-Substituted Chiral sp3 Carbon Centers

“…Scheme 11 Pd-catalyzed, ligand-controlled regiodivergent asymmetric -allylation of -CF 3 ketones Aryltitanates 36 could also be employed in a similar Nicatalyzed enantioconvergent cross-coupling reaction of compounds 33 (Scheme 14a). 36 A feature of the titanatebased process is the applicability of less reactive but stable and cheap benzylic chlorides as well as bromides. The successful conversion of the benzylic chloride allowed 1-bromo-1-chloro-2,2,2-trifluoroethane (37), a readily available anesthetic, to be adopted in one-pot sequential cross-coupling reactions with two different aryltitanates, directly giving products 35 in good yields (Scheme 14b).…”

Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

“…[ 3 ] However, while drug chirality has seen its importance and thus emerged as one major theme in drug research and development in the past decades, the utility of chiral fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped due to lack of feasible methods for enantioselective syntheses of such chiral molecules. Moreover, the precedented protocols for asymmetric construction of trifluoromethylated stereogenic carbon centers usually relies on skeletal divergence at bond‐ forming site, resulting in positioning of this CF 3 ‐substituted carbon at specific spots [ 8,13 ] like benzyl, [ 4,6,11 ] allylic, [ 12 ] or ɑ‐position of heteroatoms, [ 5,9‐10 ] etc . [ 7 ] A general, highly efficient and enantioselective strategy for diverse synthesis of enantiopure alkanes featuring trifluoromethyl‐substituted stereocenters remains elusive but extremely desired.…”