The carbon–carbon (C–C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, β-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C–C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C–C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor–acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

Cobalt­(II) halides in combination with phenoxyimine (FI) ligands generated efficient precatalysts in situ for the C­(sp2)–C­(sp3) Suzuki–Miyaura cross-coupling between alkyl bromides and neopentylglycol (hetero)­arylboronic esters. The protocol enabled efficient C–C bond formation with a host of nucleophiles and electrophiles (36 examples, 34–95%) with precatalyst loadings of 5 mol %. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI–cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to those of diamine-type ligands. Studies of the phenoxyimine–cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well-defined, air-stable mono-FI–cobalt­(II) precatalyst structure.

Herein, we report a Ni-catalyzed reductive coupling for the synthesis of benzonitriles from aryl (pseudo)halides and an electrophilic cyanating reagent, 2methyl-2-phenyl malononitrile (MPMN). MPMN is a bench-stable, carbon-bound electrophilic CN reagent that does not release cyanide under the reaction conditions. A variety of medicinally relevant benzonitriles can be made in good yields. Addition of NaBr to the reaction mixture allows for the use of more challenging aryl electrophiles such as aryl chlorides, tosylates, and triflates. Mechanistic investigations suggest that NaBr plays a role in facilitating oxidative addition with these substrates.

The ability to understand and predict reactivity is essential for the development of new reactions. In the context of Ni-catalyzed C­(sp3)–O functionalization, we have developed a unique strategy employing activated cyclopropanols to aid the design and optimization of a redox-active leaving group for C­(sp3)–O arylation. In this chemistry, the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar (2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate that the optimal leaving group is redox-active and are consistent with a Ni­(I)/Ni­(III) catalytic cycle. The optimized reaction conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.

Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of β-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy.

Metal homoenolates are valuable synthetic intermediates which provide access to β-functionalized ketones. In this report, we disclose a Ni-catalyzed β-alkylation reaction of cyclopropanol-derived homoenolates using redox-active N-hydroxyphthalimide (NHPI) esters as the alkylating reagents. The reaction is compatible with 1°, 2°, and 3°NHPI esters. Mechanistic studies imply radical activation of the NHPI ester and 2e β-carbon elimination occurring on the cyclopropanol.

Homoenolates are unique synthetic intermediates which display umpolung reactivity. Homoenolates and homoenolate equivalents like cyclopropanols have seen a recent surge in popularity due to their particular utility for accessing β‐functionalized carbonyl derivatives. This popularity has been enabled by the development of protocols for facile access to cyclopropanols and homoenolates from a variety of readily available starting materials. This microreview will highlight common strategies for generating cyclopropanols and metal homoenolates, as well as procedures for homoenolate functionalization, with a particular emphasis on protocols that have appeared after 2003. As an amphoteric molecule, two main reactivity modes have been established: the homoenolate reacts as a carbon nucleophile for β‐functionalization reactions and/or as a carbonyl electrophile, a strategy which has only emerged in the past few years. This microreview will highlight the use of homoenolates as convenient intermediates for accessing especially challenging motifs. The use of homoenolate chemistry in the context of natural product and pharmaceutical synthesis will also be presented.

The mechanism of phenoxyimine (FI)−cobalt-catalyzed C(sp 2 )−C(sp 3 ) Suzuki−Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CF 3 PhFI)CoBr] 2 , [(4-OMePhFI)CoBr] 2 , and [(2,6-di i PrPhFI)CoBr] 2 , were isolated and characterized by 1 H and 19 F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CF 3 PhFI)CoBr] 2 , was explored as a single-component precatalyst for C(sp 2 )−C(sp 3 ) Suzuki−Miyaura cross-coupling. Addition of potassium methoxide to [(4-CF 3 PhFI)CoBr] 2 generated the corresponding (FI)cobalt(II) methoxide complex as determined by 1 H and 19 F NMR and EPR spectroscopies. These spectroscopic signatures were used to identify this compound as the resting state during catalytic C(sp 2 )− C(sp 3 ) coupling. Variable time normalization analysis (VTNA) of in situ catalytic 19 F NMR spectroscopic data was used to establish an experimental rate law that was first-order in a (FI)cobalt(II) precatalyst, zeroth-order in the alkyl halide, and first-order in an activated potassium methoxide−aryl boronate complex. These findings are consistent with turnover-limiting transmetalation that occurs prior to activation of the alkyl bromide electrophile. The involvement of boronate intermediates in transmetalation was corroborated by Hammett studies of electronically differentiated aryl boronic esters. Together, a cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a "boronate"-type mechanism.