Cu-Catalyzed Hydroboration of Benzylidenecyclopropanes: Reaction Optimization, (Hetero)Aryl Scope, and Origins of Pathway Selectivity

Abstract

The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via β-carbon elimination. Computational studies provide insight into how the rigidity and steric environment of these different bis-phosphine ligands influence the relative activation energies of β-carbon elimination versus protodecupration from the key benzylcopper intermediate. The method tolerates a wide variety of heterocycles prevalent in clinical and pre-clinical drug development, giving access to valuable synthetic intermediates. The versatility of the tertiary cyclopropylboronic ester products is demonstrated through several derivatization reactions.

Keywords: Copper catalysis; benzylidenecyclopropanes; cyclopropylboronic esters; heterocycles; hydroborations; β-carbon elimination.

Figure 1.

Overview of Proposed Approach to Preparation of Cyclopropylboronic Esters.

Figure 2.

Origin of ligand effects on β-carbon elimination and protodecupration barriers.

Scheme 1.. Hydroboration of BCPs with substituted arenes

^aReaction conditions: 1 (0.2 mmol), CuCl (10 mol%), rac-BINAP (10 mol%), B₂pin₂ (0.3 mmol), NaOt-Bu (0.2 mmol), MeOH (0.2 mmol) in THF (0.5 mL) at room temperature. Percentages refer to the isolated yields. ^bThe values in parentheses correspond to NMR yields with (C₆F₅)₃P as ligand in place of rac-BINAP

Scheme 2.. Hydroboration of BCPs with heterocycles

^aReaction conditions: 1 (0.2 mmol), CuCl (10 mol%), rac-BINAP (10 mol%), B₂pin₂ (0.3 mmol), NaOt-Bu (0.2 mmol), MeOH (0.2 mmol) in THF (0.5 mL) at room temperature. Percentages refer to the isolated yields. ^b The values in parentheses correspond to NMR yields with (C₆F₅)₃P as ligand in place of rac-BINAP. ^cYield determined by ¹H NMR. The product was isolated as the corresponding BF₃K salt in 51% yield over two steps.

Scheme 3.. Synthesis of alkenyl boronates via β-C elimination

^aReaction conditions: 1 (0.2 mmol), CuCl (10 mol%), dppe (10 mol%), B₂pin₂ (0.3 mmol), NaOt-Bu (0.2 mmol), MeOH (0.2 mmol) in THF (0.5 mL) at room temperature. Percentages refer to the isolated yields.

Scheme 4.

Select derivatization reactions with tertiary boronic ester 3a

Scheme 5.

Enabling Suzuki–Miyaura couplings with tertiary trifluoroborate 8

Scheme 6.

Activation energies of the selectivity-determining steps.