Nickel-catalyzed alkyl-arylation of 3,3,3-trifluoropropene

Abstract

Owing to the versatile synthetic utility of its carbon-carbon double bond, low-cost industrial chemical 3,3,3-trifluoropropene (TFP) represents one of the most straightforward and cost-efficient precursors to prepare trifluoromethylated compounds. However, only limited methods for the efficient transformations of TFP have been reported so far. Here, we report a nickel-catalyzed dicarbofunctionalization of TFP. The reaction uses inexpensive NiCl₂·6H₂O as the catalyst and 4,4'-biMeO-bpy and PCy₂Ph as the ligands, allowing the alkyl-arylation of TFP with a variety of tertiary alkyl iodides and arylzinc reagents in high efficiency. This nickel-catalyzed process overcomes the previous challenges by suppressing β-H and β-F eliminations from TFP, rendering this strategy effective for the transformations of TFP into medicinal interest trifluoromethylated compounds.

Fig. 1. Transformations of 3,3,3-trifluoropropene.

a Traditional transformations of TFP. b Previous work, metal-catalyzed transformation of TFP. c This work, Ni-catalyzed dicarbofunctionalization of TFP.

Fig. 2. Scope of the Nickel-catalyzed alkyl-arylation of TFP.

^aReaction conditions (unless otherwise specified): 1 (0.8 mmol, 2.0 equiv), 2 (0.4 mmol, 1.0 equiv), 3 (1.5 equiv in THF), and DMA (2 mL). Isolated yields are given. The phosphine ligands used for the substrates were enclosed in the parentheses. ^bReaction was conducted at 0 °C. ^cReaction was conducted without L3 and phosphine ligand, and 5 mol% NiCl₂·DME was used. a Substrate scope of arylzinc reagents with 2a. b Substrate scope of alkyl iodides.

Fig. 3. Synthetic applications.

a Synthesis of pyrroloindoline derivative. b Gram-scale synthesis of 4a. c Transformations of compound 4a.

Fig. 4. Mechanistic studies.

a Radical inhibition experiments with 1,4-dinitrobenzene and TEMPO. b Synthesis of arylnickel(II) complex B1. c Stoichiometric reactions of B1 with TFP and 2a. d Catalytic reaction using L2 as the ligand. e Standard reaction catalyzed by complex B1.

Fig. 5. Proposed reaction mechanisms.

a Proposed mechanism for the formation of 4c from the reaction of B1 with 1 and 2a. b Proposed mechanism for the reaction.