Conspectus
Transition metal-catalyzed carbonylation reactions
represent a
direct and atom-economical approach to introduce oxygen functionality
into organic compounds, with CO acting as an inexpensive and readily
available C1 feedstock. Despite the long history of carbonylation
catalysis, including many processes that have been industrialized
at bulk scale, there remain several challenges to tackle. For example,
noble metals such as Pd, Rh, and Ir are typically used as catalysts
for carbonylation reactions, rather than earth-abundant alternatives.
Additionally, while carbonylation of C(sp2)-hybridized
substrates (e.g., aryl halides) is well-known, carbonylation of unactivated
alkyl electrophiles, especially where β-hydride elimination
can compete with desired CO migratory insertion at the catalyst site,
remains challenging for many systems. Recently, base metal catalysis
based on Mn, Co, and other metals has enabled advances in carbonylative
coupling of alkyl electrophiles, though the nucleophiles are often
limited to alcohols or amines to generate esters or amides as products.
Thus, we have targeted base metal-catalyzed carbonylative C–C
and C–E (E = N, H, Si, B) coupling reactions as a method for
approaching diverse carbonyl compounds of synthetic importance.
Initially, we designed a heterobimetallic catalyst platform for
carbonylative C–C coupling of alkyl halides with arylboronic
esters (i.e., carbonylative Suzuki–Miyaura coupling) to generate
aryl alkyl ketones. Subsequently, we developed multicomponent carbonylation
reactions of alkyl halides using NHC-Cu catalysts (NHC = N-heterocyclic
carbene). These reactions operate by radical mechanisms, converting
alkyl halides into either acyl radical or acyl halide intermediates
that undergo subsequent C–C or C–E coupling at the Cu
site. This mechanistic paradigm is relatively novel in the metal-catalyzed
carbonylation area, allowing us to discover a previously unexplored
chemical space in carbonylative coupling catalysis. We have successfully
developed the following reactions: (a) hydrocarbonylative coupling
of alkynes with alkyl halides; (b) borocarbonylative coupling of alkynes
with alkyl halides; (c) reductive aminocarbonylation of alkyl halides
with nitroarenes; (d) reductive carbonylation of alkyl halides; (e)
carbonylative silylation of alkyl halides; (f) carbonylative borylation
of alkyl halides. These reactions provide a broad range of valuable
products including ketones, allylic alcohols, β-borylenones,
amides, alcohols, acylsilanes, and acylborons in an efficient manner.
Notably, the preparation of some of these products has previously
required multistep syntheses, harsh conditions, or specialized reagents.
By contrast, the multicomponent coupling platform that we have developed
requires only readily available building blocks and rapidly increases
molecular complexity in a single synthetic manipulation.