Pd-catalyzed asymmetric Suzuki-Miyaura coupling reactions for the synthesis of chiral biaryl compounds with a large steric substituent at the 2-position

Abstract

Pd-catalyzed asymmetric Suzuki-Miyaura couplings of 3-methyl-2-bromophenylamides, 3-methyl-2-bromo-1-nitrobenzene and 1-naphthaleneboronic acids have been successfully developed and the corresponding axially chiral biaryl compounds were obtained in very high yields (up to 99%) with good enantioselectivities (up to 88% ee) under mild conditions. The chiral-bridged biphenyl monophosphine ligands developed by our group exhibit significant superiority to the naphthyl counterpart MOP in both reactivity and enantioselectivity control. The large steric hindrance from π-conjugated ortho-substituents of the bromobenzene substrates and the Pd···O interaction between carbonyl and palladium seem essential to achieve high enantioselectivity.

Keywords: Suzuki–Miyaura couplings; asymmetric catalysis; biaryls; monophosphine ligand; palladium catalyst.

Figure 1

(R)-MeO-MOP and our ligands.

Scheme 1

Asymmetric Suzuki–Miyaura coupling. Reaction conditions: 1 equiv N-aryl-bromoaryl compounds, 2 equiv arylboronic acids, 5 mol % Pd, 6 mol % ligand, 3 equiv of K₃PO₄, 2 mL THF, 50 ⁰C, 72 h; Yields are combined isolated values; ee values were determined by HPLC with chiral columns.

Scheme 2

Asymmetric Suzuki–Miyaura coupling. Reaction conditions: 1 equiv of bromoaryl compounds, 2 equiv of arylboronic acids, 5 mol % Pd, 6 mol % of ligand, 3 equiv of K₃PO₄, 2 mL THF, 50 ⁰C, 72 h; Yields are combined isolated values; ee values were determined by HPLC.

Scheme 3

Gram-scale reaction.

Scheme 4

Based on our analysis and speculation, a possible intermediate structure is proposed [–66].

Scheme 5

Method A for the synthesis of amide substrates.

Scheme 6

Method B for the synthesis of amide substrates.