Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds Haining Wang † , Xi-Jie Dai † and Chao-Jun Li * Nucleophilic addition reactions of organometallic reagents to carbonyl compounds for carbon–carbon bond construction have played a pivotal role in modern chemistry. However, this reaction’s reliance on petroleum-derived chemical feedstocks and a stoichiometric quantity of metal have prompted the development of many carbanion equivalents and catalytic metal alternatives. Here, we show that naturally occurring carbonyls can be used as latent alkyl carbanion equivalents for additions to carbonyl compounds, via reductive polarity reversal. Such ‘umpolung’ reactivity is facilitated by a ruthenium catalyst and diphosphine ligand under mild conditions, delivering synthetically valuable secondary and tertiary alcohols in up to 98% yield. The unique chemoselectivity exhibited by carbonyl-derived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility. Enantioenriched tertiary alcohols can also be accessed with the aid of chiral ligands, albeit with moderate stereocontrol. Such carbonyl-derived carbanion equivalents are anticipated to find broad utility in chemical bond formation. T he nucleophilic addition of organometallic reagents to carbo- nyl compounds, to form new carbon–carbon bonds, is a funda- mental process in contemporary organic synthesis 1–3 . This simple alkylation process, complementary to the reduction of carbonyl com- pounds, provides a reliable method for generating a wide array of alcohol products. These alcohols are frequently encountered as key building blocks in the synthesis of complex pharmaceutical drugs and biologically active molecules. The discovery of Grignard reagents as car- banion equivalents 4 and their subsequent additions to carbonyl com- pounds marked a milestone in synthetic chemistry, enabling facile access to a diverse range of alcohols using preformed organomagnesium reagents with high generality, reactivity and easy manipulation 5–8 . Since then, other organometallic reagents 9 , such as those based on zinc 10 , alu- minium 11 , copper 12 and titanium 13 , have been sought and used to achieve better selectivity. However, the preparation of these robust orga- nometallic reagents requires stoichiometric quantities of metal (Fig. 1a). Despite considerable advances, and the abundance of organo- metallic reagents developed for additions to carbonyl compounds, three key challenges have endured. First, the dependence on stoichiometric, pre-formed organometallic reagents in carbonyl addition reactions produces copious metal waste. This is particularly problematic for large-scale synthesis, as it complicates synthetic operations and raises environmental concerns. In addition, petroleum-derived chemical feedstocks (that is, organic halides) are typically used to prepare organometallic reagents. Their paucity in nature 14 constrains the types of nucleophiles accessible to perform carbonyl addition reactions without prior functionalization. Furthermore, the high nucleophilicity and basicity of most organo- metallic reagents generally result in poor selectivity, making these reagents inferior candidates in late-stage chemical transformations where highly functionalized molecules are present. To address these challenges, much effort has been devoted to developing original catalytic and asymmetric methods to produce enantioenriched alcohols, whereby π-unsaturated hydrocarbons (alkenes or alkynes) are masked as carbanion equivalents (Fig. 1b). Krische and co-workers have pioneered stereoselective coupling reactions between diverse π-unsaturated reactants and aldehydes under hydrogenative conditions catalysed by late transition metals 15,16 . Hoveyda and colleagues have successfully developed copper-catalysed borylative enantioselective additions to carbonyl compounds using olefin-derived nucleophiles 17,18 . Montgomery, Jamison and co-workers have designed nickel-based catalysts for stereoselective aldehyde additions, in which alkynes are employed as carbanion equivalents 19–21 . To synthesize more sterically encumbered tertiary alcohols, Buchwald, Liu and colleagues have devised enantioenriched alkyl copper intermediates, synthesized from olefins, for additions to ketones 22 . The catalytic generation of carbanion equivalents from either alkenes or alkynes, elegantly exem- plified in these reports, has successfully addressed some of the long- standing challenges facing organometallic reagents. Nevertheless, as the chemical industry shifts from using petrochemicals to renewable feedstocks, the synthetic community is increasingly giving attention to more sustainable and efficient chemical syntheses 23,24 . In this context, the development of carbanion equivalents that originate from naturally occurring chemical feedstocks, require only a catalytic quantity of metal, have improved compatibility towards benign protic solvents and various functional groups, and generate innocuous by-products would be highly desirable for additions to carbonyl compounds. Here, we report such alkyl carbanion equivalents, derived from the naturally prevalent carbo- nyls with umpolung reactivity 25–29 , for carbonyl addition reactions (Fig. 1c). Very recently, we have pioneered a ruthenium-catalysed redox system 30 for direct primary alcohol deoxygenation 31 . This practical deoxygenation chemistry evolved from our initial iridium-based system 32 and proved to be highly chemo- and regio- selective in complex molecules such as alkaloids and steroids. The proposed mechanism involves the in situ generation of a ruthe- nium-coordinated hydrazone intermediate A, followed by a ruthe- nium-assisted Wolff–Kishner (WK) reduction under relatively low-temperature conditions (Fig. 2a). Intriguingly, when benzylic alcohols were subjected to the same catalytic reaction conditions, a trace amount of reductive C-C coupling product—the carbonyl addition product—was observed. On the basis of this serendipitous discovery, we hypothesized that the coordinately unsaturated ruthe- nium complex in A might rapidly metallate another carbonyl com- pound and subsequently rearrange to give intermediate C, via Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada. † These authors contributed equally to this work. *e-mail: cj.li@mcgill.ca ARTICLES PUBLISHED ONLINE: 5 DECEMBER 2016 | DOI: 10.1038/NCHEM.2677 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 1 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.