Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Abstract

Chiral aliphatic amine and alcohol derivatives are ubiquitous in pharmaceuticals, pesticides, natural products and fine chemicals, yet difficult to access due to the challenge to differentiate between the spatially and electronically similar alkyl groups. Herein, we report a nickel-catalyzed enantioselective hydroalkylation of acyl enamines and enol esters with alkyl halides to afford enantioenriched α-branched aliphatic acyl amines and esters in good yields with excellent levels of enantioselectivity. The operationally simple protocol provides a straightforward access to chiral secondary alkyl-substituted amine and secondary alkyl-substituted alcohol derivatives from simple starting materials with great functional group tolerance.

Fig. 1. Impetus for the development of the reaction.

a Representative molecules containing chiral secondary alkyl-substituted amines and alcohols. b Representative ways to access chiral secondary alkyl-substituted amines and alcohols. c Ni-catalyzed hydroalkylation of acyl enamines and enol esters.

Fig. 2. Scope for alkyl iodides of tertiary acyl enamines and internal acyl enamines.

For reaction conditions, see Table 1, entry 19 unless otherwise stated. ^aBenzyl bromide was used. ^bThe reaction was conducted using 1 (0.2 mmol), 2 (0.6 mmol) at 45 °C for 16 h.

Fig. 3. Scope for secondary acyl enamines.

The reaction was run on 0.2 mmol of acyl enamine and 0.4 mmol of alkyl iodide using DEMS (0.6 mmol) under indicated conditions unless otherwise stated. ^aDMMS was used instead of DEMS. ^bL4 was used as the ligand.

Fig. 4. Scope for alkyl iodides with secondary acyl enamines.

The reaction was conducted on 0.2 mmol of acyl enamine and 0.4 mmol of alkyl iodide (2.0 equiv.) under indicated conditions.

Fig. 5. Scope for the hydroalkylation of enol esters.

The reaction was conducted on 0.2 mmol of enol ester (1.0 equiv.) and alkyl iodide (2.0 equiv.) using potassium phosphate monohydrate (3.0 equiv.) as base in Et₂O/DMF = 3:1 (0.1 M) at room temperature for 12 h unless otherwise stated. ^a5.0 equiv. of RI was used. ^b3.0 equiv. of RI was used. ^cThe reaction was conducted using alkyl iodide (3.0 equiv.) and potassium carbonate (3.0 equiv.) as base in Et₂O/NMP = 3:1 (0.2 M) at 45 °C for 16 h. ^dThe reaction was conducted using alkyl iodide (3.0 equiv.) and potassium carbonate (3.0 equiv.) as base in the presence of tert-butanol (4.0 equiv.) in Et₂O/NMP = 3:1 (0.2 M) at 45 °C for 16 h. NMP = N-methyl pyrrolidone.

Fig. 6. Mechanistic probe for the reaction.

a Hydroalkylation of terminal acyl enamine with Ph₂SiD₂. b Hydroalkylation of internal acyl enamine with Ph₂SiD₂.

Fig. 7. Proposed mechanism for the reaction.

Ligand is omitted for clarity. a Ni(I)–H pathway. b Ni(II)–H pathway.