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Alkyl Carbanion Derived from Carbonyl Umpolung for Nucleophilic Additions

Honored Contributor
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Contributed by Xijie Dai, M.Sc., Ph.D. candidate; Haining Wang; and Chao-Jun Li, Ph.D.; McGill University

scheme1-mcgill.pngSecondary and tertiary alcohols, especially chiral ones, are important chemical building blocks found in various biologically active complex molecules, natural products and fine chemicals. The traditionally most well-established approaches toward such alcohols rely mainly on the use of highly nucleophilic and basic organometallic reagents (i.e., organolithium and organomagnesium reagents) (Scheme 1, a). Such an approach requires excessive amounts of metal (magnesium, lithium, zinc, etc.) and pre-synthesized organohalides to produce alcohols. The stoichiometry of organometallic reagents raises concerns as it implies inefficiency and stoichiometric waste. Organohalides, on the other hand, are mostly manufactured from small petrochemicals despite their commercial availability and broad utilization in the synthetic community. Furthermore, the often high reactivity of the organometallic reagents renders them incompatible with water and many functional groups (alcohol, halides, esters, acids, amines, amides, nitrile, nitro, etc.), necessitating “protection” and “deprotection.”

Recently, researchers from McGill University in Canada have made a breakthrough that serves as an alternative to the classical, organometallic reagent-based, nucleophilic carbonyl addition reactions (e.g., the Grignard reaction) for alcohol synthesis. This novel reaction – that appeared in Nature Chemistry – highlights an efficient alkylation process based on two different carbonyl compounds that form new carbon-carbon bonds: Naturally prevailing (or readily available) carbonyl compounds were used as surrogates for alkyl carbanions to react with other carbonyl compounds in this reaction to produce a wide range of alcohols with great efficiency. This transformation is mediated by hydrazine and is catalyzed by a ruthenium catalyst under mild conditions (45 degrees Celsius), producing water and N2 as its stoichiometric waste (Scheme 1, b).

The most innovative aspect of this reaction lies in the formal umpolung reactivity of carbonyl functionalities, meaning that the polarity of the carbon in the carbonyl functionality is inverted from electrophilic (natural chemical reactivity) to nucleophilic. This was done by the formation of hydrazones from carbonyl compounds. Using a phosphine-bound, ruthenium-based catalyst; a base; and a reaction additive, hydrazones (preformed or generated in situ from aldehyde and hydrazine) can react with a broad spectrum of carbonyl compounds to produce secondary or tertiary alcohols in moderate to excellent yields. By simply switching the racemic phosphine ligand to the chiral ones, this reaction could yield enantioenriched tertiary alcohols. The weak base potassium phosphate and the additive cesium fluoride are also key ingredients to maximize efficiency.

One striking feature of this carbonyl-derived carbanion is its excellent chemoselectivity when present alongside other functional groups in the same molecule. This is distinct from classical organometallic reagents, which often find themselves incompatible with basic labile functionalities. In fact, it is extremely important for carbanion equivalents to have good chemoselectivity so that structurally complex alcohols can be obtained via carbonyl addition reactions. There are two reasons for this: (1) a shortened synthetic route could be designed for more efficient CC bond formations by stitching together larger pieces of carbonyl-containing molecules; (2) complex molecules bearing previously indistinguishable functional groups (e.g., esters, nitriles, alcohols, etc.) could be selectively alkylated on carbonyl functionalities at a later stage.

As it stands, certain aspects of this reaction – such as the safety and toxicity issues with hydrazine as well as the rarity and relatively high cost concerns associated with precious metal catalyst ruthenium – preclude it from being ideal in green chemistry and render the opportunity for further improvement. Nevertheless, it does open an avenue for converting naturally occurring carbonyl functionalities to carbanion equivalents, which is a stepping-stone toward more sustainable carbon-carbon bond-forming processes. Indeed, we believe that some of the aforementioned concerns can be addressed via further modification of the metal catalyst (by, for instance, using earth-abundant metals and via catalyst immobilizations) or the reducing reagent. Unlike copious metal waste generated in other organometallic addition reactions, this reaction’s production of only innocuous by-products (e.g. N2 and H2O), its relatively mild reaction conditions, and its tolerance toward a wide range of functional groups (as well as air and water), makes it attractive to researchers across academia and industry.

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