Metal-catalyzed reductive coupling of olefin-derived nucleophiles: Reinventing carbonyl addition

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Science  21 Oct 2016:
Vol. 354, Issue 6310, aah5133
DOI: 10.1126/science.aah5133

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How to turn olefins into nucleophiles

The Grignard reaction has a storied place in the development of organic chemistry. Recognized by the Nobel Prize more than a century ago, this coupling of organomagnesium halides with carbonyl compounds remains a widely used route to carbon-carbon bonds. Nguyen et al. review an emerging alternative protocol that replaces the sensitive magnesium reagent with a catalytically activated olefin and a reductant such as hydrogen or an alcohol. In addition to safety and efficiency considerations, this class of reactions benefits from the high abundance and low cost of the olefins.

Science, this issue p. 300

Structured Abstract


Since the discovery of the Grignard reaction more than a century ago, carbonyl addition mediated by premetalated reagents has played a central role in synthetic chemistry. Metal-catalyzed reductive coupling of π-unsaturated reactants with carbonyl compounds has emerged as an alternative to classical carbonyl addition. Although such processes bypass stoichiometric organometallic reagents and the issues of safety, selectivity, and waste associated with their use, in many cases the requisite terminal reductants are just as problematic as the organometallic reagents they replace. Catalytic reductive coupling via hydrogenation or transfer hydrogenation represents a more ideal strategy for carbonyl addition as relatively safe, inexpensive reductants with low molecular weights may be used (H2 or 2-propanol). Carbonyl addition via hydrogen autotransfer is most ideal. In such processes, hydrogen embedded within a reactant alcohol mediates reductive coupling. By allowing alcohols to serve dually as reductant and proelectrophile (carbonyl precursor), this strategy completely bypasses the use of exogenous reductants, enabling byproduct-free carbonyl addition from the alcohol oxidation level—that is, the direct conversion of lower alcohols to higher alcohols. Alcohols are typically cheaper and more tractable than the corresponding carbonyl compounds, which is a further benefit of this approach. Ethylene (H2C=CH2) and α-olefins are the simplest π-unsaturated reactants and are manufactured on a vast scale at production volumes exceeded only by alkanes. Hence, the discovery and development of catalytic methods that exploit olefin-derived nucleophiles in byproduct-free carbonyl reductive coupling represents an especially important goal of chemical research.


Methods for the metal-catalyzed reductive coupling of π-unsaturated reactants with carbonyl partners have expanded considerably in recent years. A broad palette of catalysts comprising diverse metals, ligands, and terminal reductants offers access to a surprising array of transformations. In addition to providing catalytic variants of classical carbonyl additions, the mechanisms availed by transition metal catalysts have unlocked broad, new capabilities and access to hitherto unavailable volumes of chemical space. Despite these advances, intermolecular catalytic reductive coupling of simple linear α-olefins with unactivated carbonyl partners remains an unmet and multifaceted challenge. Beyond defining active catalysts, the use of such abundant reactants mandates an additional consideration: the identification of terminal reductants that are equally inexpensive. Additionally, to avoid waste generation (a major issue in the context of large-volume chemical manufacture), byproduct-free methods for reductive coupling are highly preferred. Hence, processes mediated by elemental hydrogen or hydrogen autotransfer processes that exploit hydrogen embedded in the alcohol reactant itself are especially attractive. This latter class of catalytic C–C bond–forming processes was only recently discovered.


The prototypical metal-catalyzed reductive C–C bond formation and largest-volume application of homogenous catalysis is hydroformylation (>10 million metric tons/year), which transforms olefins into aldehydes through reaction with carbon monoxide and hydrogen. Despite longstanding use of this chemistry, the concept of hydrogen-mediated reductive coupling underlying hydroformylation lay dormant for decades. Systematic efforts to exploit hydrogenation and transfer hydrogenation in reductive couplings to carbonyl compounds have only begun to emerge. The impact is clear: Reactions that traditionally have used organometallic reagents may now be conducted catalytically in the absence of premetalated reagents or stoichiometric byproducts. Among the numerous possibilities for growth in this area, the development of catalytic systems for the intermolecular reductive coupling of ethylene and simple linear α-olefins with unactivated carbonyl partners remains an important, elusive objective. Reactions conducted from the alcohol oxidation level via hydrogen autotransfer offer a promising approach to catalytic processes of this type.

Evolution of carbonyl addition chemistry.

The progression from (top) premetalated reagents, to (top middle) reductive couplings mediated by external reductants, and last, (bottom middle) byproduct-free reductive couplings powered by hydrogen autotransfer. (Bottom) Departure from preformed organometallic reagents in carbonyl addition.


α-Olefins are the most abundant petrochemical feedstock beyond alkanes, yet their use in commodity chemical manufacture is largely focused on polymerization and hydroformylation. The development of byproduct-free catalytic C–C bond–forming reactions that convert olefins to value-added products remains an important objective. Here, we review catalytic intermolecular reductive couplings of unactivated and activated olefin-derived nucleophiles with carbonyl partners. These processes represent an alternative to the longstanding use of stoichiometric organometallic reagents in carbonyl addition.

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