NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes and the ligand effects on regioselectivity

Abstract

Alkene hydrocarbonation reactions have been developed to supplement traditional electrophile-nucleophile cross-coupling reactions. The branch-selective hydroalkylation method applied to a broad range of unactivated alkenes remains challenging. Herein, we report a NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines. A broad range of alkyl iodides and bromides with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant molecules. Under modified reaction conditions with NiCl₂(PPh₃)₂ as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined experimental and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.

Fig. 1. NiH-catalysed hydroalkylation of internal alkenes and their regioselectivities.

a NiH-catalysed linear-, α- or β-selective (migratory) hydroalkylation of internal alkenes. b Our strategy: directed NiH-catalysed proximal-selective hydroalkylation and migratory β-selective hydroalkylation. Bpin pinacol borate, diglyme 2-methoxyethyl ether, MEA ethanolamine.

Fig. 2. Scope of proximal-selective hydroalkylation.

Standard conditions A: alkene (0.20 mmol, 1.0 equiv), alkyl halide (0.40 mmol, 2.0 equiv), NiBr₂(diglyme) (0.02 mmol, 10 mol%), MEA (0.024 mmol, 12 mol%), DEMS (0.60 mmol, 3.0 equiv), KF (0.60 mmol, 3.0 equiv), DMAc (1.0 mL, 0.2 M), 25 °C, 12 h, isolated yield. r.r. was determined by GC or ¹H NMR analysis. r.r. refers to the regioisomeric ratio, that of the major product to the sum of all other isomers. Proximal-selective hydroalkylation product was obtained as the major regioisomer, and distal-selective hydroalkylation product as the minor regioisomer; other regioisomers could hardly be detected. ^aNaI (0.10 mmol, 0.5 equiv) was added. ^b40 °C. d.r. diastereomeric ratio, DG directing group.

Fig. 3. Synthetic applications.

a Late-stage functionalization of biorelevant molecules. b Gram-scale reaction and removal of the directing group. Standard conditions A: as shown in Fig. 2, 0.2 mmol scales. All yields refer to the isolated yield of purified products. Regioisomeric ratios and diastereomeric ratios were determined by GC or ¹H NMR analysis. tmhd 2,2,6,6-tetramethyl-3,5-heptanedionato.

Fig. 4. Mechanistic studies.

a Radical clock experiments. b Deuterium labelling experiments. c Effects of nitrogen-containing ligands. d Preliminary results of asymmetric synthesis. e Effects of phosphine-containing ligands. f Migratory β-selective hydroalkylation. Standard conditions A: as shown in Fig. 2, 0.2 mmol scales. Standard conditions B: determination of regioisomeric ratio was consistent with standard conditions A, 0.1 mmol scales. Standard conditions C: total yield for the mixture of all regioisomers. r.r. refers to the regioisomeric ratio, that of the major product to the sum of all other isomers. In most cases, a mixture of β- and γ-selective products was obtained; we could hardly observe other isomers. *¹H NMR yield with dibromomethane as an internal standard. ^†GC yield with triphenylmethane as an internal standard. ^¶Isolated yield in parentheses.

Fig. 5. Proposed mechanism and DFT calculation details.

a Proposed mechanism. b DFT calculations at the M06L-D3/6-311 + G(d,p)-SDD-SMD(DMA)//B3LYP-D3/6-31 G(d)-SMD(DMA) level of theory. Free energies are given in kcal/mol. c Optimized 3D structures of TS1, TS2, TS3 and TS4.