Enantioselective synthesis of axially chiral biaryls by the Pd-catalyzed Suzuki-Miyaura reaction: substrate scope and quantum mechanical investigations

Abstract

We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80-92%, and with enantioselectivity in the range 88-94% ee employing an asymmetric Suzuki-Miyaura process with Pd(OAc)(2) and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051-12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H..O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C-C coupling.

Figure 1

Ligands and biologically active natural products containing the axially chiral biaryl structural motif.

Figure 2

The reaction of Pd(KenPhos) with (1-chloro-2-naphthyl)diisopropylphosphine oxide and subsequent reaction of the oxidative addition complex with o-tolylboronic acid.

Figure 3

Crystallographic structures for the (a) oxidative addition complex of Pd(KenPhos) with (1-chloro-2-naphthyl)diisopropylphosphine oxide. (Hydrogen atoms have been omitted and atoms belonging to the KenPhos ligand have been faded for clarity.) (b) coupled biaryl product from the reaction of (1-chloro-2-naphthyl)diisopropylphosphine oxide and o-tolylboronic acid.

Figure 4

Acid-catalyzed deprotection of a cumylamide.

Figure 5

The Pd(KenPhos)-catalyzed reaction of dimethyl-(1-bromo-2-naphthyl)phosphonate with o-tolylboronic acid.

Figure 6

Transition structures and relative free energies of activation in kcal/mol for reductive elimination of biaryl phosphines from Pd(KenPhos) complexes formed after transmetalation. Atoms participating in H-bonding interactions are highlighted in green. The stereochemistry of the product formed after reductive elimination is denoted in brackets. Relevant O-H bond distances in Å are shown on the pictures; H-O-P bond angles in degrees are shown in parentheses. Chemdraw representations of the transition structures are shown below the pictures; the KenPhos ligand in these drawings has been replaced by the symbol P and the naphthylphosphonate addend has been truncated for clarity. Transition structures and relative free energies of activation in kcal/mol for reductive elimination of biaryl phosphines from Pd(KenPhos) complexes formed after transmetalation. Atoms participating in H-bonding interactions are highlighted in green. The stereochemistry of the product formed after reductive elimination is denoted in brackets. Relevant O-H bond distances in Å are shown on the pictures; H-O-P bond angles in degrees are shown in parentheses. Chemdraw representations of the transition structures are shown below the pictures; the KenPhos ligand in these drawings has been replaced by the symbol P and the naphthylphosphonate addend has been truncated for clarity.

Figure 6

Transition structures and relative free energies of activation in kcal/mol for reductive elimination of biaryl phosphines from Pd(KenPhos) complexes formed after transmetalation. Atoms participating in H-bonding interactions are highlighted in green. The stereochemistry of the product formed after reductive elimination is denoted in brackets. Relevant O-H bond distances in Å are shown on the pictures; H-O-P bond angles in degrees are shown in parentheses. Chemdraw representations of the transition structures are shown below the pictures; the KenPhos ligand in these drawings has been replaced by the symbol P and the naphthylphosphonate addend has been truncated for clarity. Transition structures and relative free energies of activation in kcal/mol for reductive elimination of biaryl phosphines from Pd(KenPhos) complexes formed after transmetalation. Atoms participating in H-bonding interactions are highlighted in green. The stereochemistry of the product formed after reductive elimination is denoted in brackets. Relevant O-H bond distances in Å are shown on the pictures; H-O-P bond angles in degrees are shown in parentheses. Chemdraw representations of the transition structures are shown below the pictures; the KenPhos ligand in these drawings has been replaced by the symbol P and the naphthylphosphonate addend has been truncated for clarity.

Figure 7

Comparison of the lowest energy transition structure with the “twisted” tolyl; addend analogue. Atoms participating in H-bonding interactions are highlighted in green. The stereochemistry of the product formed after reductive elimination is denoted in brackets.

Scheme 1

Synthesis of enantioenriched biaryl phosphonates by Suzuki-Miyaura coupling

Scheme 2

Synthesis of chiral biaryl compounds containing esters and phosphonate

Scheme 3

Synthesis of axially chiral aromatic compounds.

Scheme 4

Possible orientations of addends in transition state geometries for reductive elimination. (Some atoms have been omitted and atoms belonging to the KenPhos ligand have been faded for clarity.)

Scheme 5

Determination of the stereochemistry of coupled biaryl products based on transition state geometries.