REVIEW SUMMARY◥

ORGANIC CHEMISTRY

Metal-catalyzed reductive couplingof olefin-derived nucleophiles:Reinventing carbonyl additionKhoa D. Nguyen, Boyoung Y. Park, Tom Luong, Hiroki Sato,Victoria J. Garza, Michael J. Krische*

BACKGROUND: Since the discovery of theGrignard reaction more than a century ago,carbonyl addition mediated by premetalatedreagents has played a central role in syntheticchemistry. Metal-catalyzed reductive couplingof p-unsaturated reactants with carbonyl com-pounds has emerged as an alternative to clas-sical carbonyl addition. Although suchprocesses bypass stoichiometric organo-metallic reagents and the issues of safety,selectivity, and waste associated withtheir use, in many cases the requisiteterminal reductants are just as prob-lematic as the organometallic reagentsthey replace. Catalytic reductive couplingvia hydrogenation or transfer hydro-genation represents a more ideal strat-egy for carbonyl addition as relativelysafe, inexpensive reductants with lowmolecular weightsmay be used (H2 or 2-propanol). Carbonyl addition via hydro-gen autotransfer is most ideal. In suchprocesses, hydrogen embedded withina reactant alcohol mediates reductivecoupling. By allowing alcohols to servedually as reductant and proelectrophile(carbonyl precursor), this strategy com-pletely bypasses the use of exogenousreductants, enabling byproduct-free car-bonyl addition from the alcohol oxida-tion level—that is, the direct conversionof lower alcohols to higher alcohols. Al-cohols are typically cheaper and moretractable than the corresponding carbo-nyl compounds, which is a further bene-fit of this approach. Ethylene (H2C=CH2)anda-olefinsarethesimplestp-unsaturatedreactants and are manufactured on avast scale at productionvolumes exceededonly by alkanes. Hence, the discoveryand development of catalytic methodsthat exploit olefin-derived nucleophiles

in byproduct-free carbonyl reductive couplingrepresents an especially important goal ofchemical research.

ADVANCES: Methods for the metal-catalyzedreductive coupling of p-unsaturated reactantswith carbonyl partners have expanded consid-

erably in recent years. A broad palette of cat-alysts comprising diverse metals, ligands, andterminal reductants offers access to a surpris-ing array of transformations. In addition toproviding catalytic variants of classical carbonyladditions, the mechanisms availed by transi-tion metal catalysts have unlocked broad, newcapabilities and access to hitherto unavailablevolumes of chemical space. Despite theseadvances, intermolecular catalytic reductive

coupling of simple lineara-olefinswith unactivatedcarbonyl partners remainsanunmetandmultifacetedchallenge. Beyond definingactive catalysts, the use ofsuch abundant reactants

mandates an additional consideration: the id-entification of terminal reductants that are eq-ually inexpensive. Additionally, to avoid wastegeneration (a major issue in the context oflarge-volume chemicalmanufacture), byproduct-free methods for reductive coupling are highly

preferred. Hence, processes mediatedby elemental hydrogen or hydrogenautotransfer processes that exploithydrogen embedded in the alcoholreactant itself are especially attract-ive. This latter class of catalytic C–Cbond–forming processes was only re-cently discovered.

OUTLOOK: The prototypical metal-catalyzed reductive C–C bond forma-tion and largest-volume applicationof homogenous catalysis is hydrofor-mylation (>10 million metric tons/year), which transforms olefins intoaldehydes through reactionwith car-bonmonoxide and hydrogen. Despitelongstanding use of this chemistry,the concept of hydrogen-mediated re-ductive coupling underlying hydro-formylation lay dormant for decades.Systematic efforts to exploit hydro-genation and transfer hydrogena-tion in reductive couplings to carbonylcompounds have only begun to em-erge. The impact is clear: Reactionsthat traditionally have used organo-metallic reagents may now be con-ducted catalytically in the absence ofpremetalated reagents or stoichiomet-ric byproducts. Among the numerouspossibilities for growth in this area, thedevelopment of catalytic systems forthe intermolecular reductive couplingof ethylene and simple linear a-olefinswith unactivated carbonyl partners re-mains an important, elusive objective.Reactions conducted from the alcoholoxidation level viahydrogenautotrans-fer offer a promising approach tocatalytic processes of this type.▪

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The list of author affiliations is available in the fullarticle online.*Corresponding author. Email: mkrische@mail.utexas.eduCite this article as K. D. Nguyen et al., Science 354,aah5133 (2016). DOI: 10.1126/science.aah5133

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Read the full articleat http://dx.doi.org/10.1126/science.aah5133..................................................

Classical C=O addition - Stoichiometric metals

Metal catalyzed C=O reductive coupling

Redox-triggered C=O coupling via H2 transfer

no cat/cat

Then H2O

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ZnEt2then H2O

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H2 embeddedin alcohol

(Metal salts)

PyrophoricHigh mass, $$$Optimal

Steps

Olefinfeedstocks

VS

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2-PrOH, H2

R3SiH

Evolution of carbonyl addition chemistry. The progressionfrom (top) premetalated reagents, to (topmiddle) reductive cou-plings mediated by external reductants, and last, (bottom middle)byproduct-free reductive couplings powered by hydrogen auto-transfer. (Bottom) Departure from preformed organometallic re-agents in carbonyl addition.

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REVIEW◥

ORGANIC CHEMISTRY

Metal-catalyzed reductive couplingof olefin-derived nucleophiles:Reinventing carbonyl additionKhoa D. Nguyen, Boyoung Y. Park, Tom Luong, Hiroki Sato,Victoria J. Garza, Michael J. Krische*

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

Byproduct-free catalytic C–C bond–formingreactions of a-olefins are of great commer-cial interest. Hydroformylation (1, 2) andsingle-site alkene polymerization (3) arenow among the largest-volume applications

of homogenous metal catalysis. Carbonyl com-pounds represent another abundant class of chem-ical feedstock that are derived from a-olefins viahydroformylation (oxo-products) (1, 2) orWackeroxidation (4). Despite the availability of a-olefinsand carbonyl compounds, there is a striking paucityof catalytic processes for the coupling of theseorthogonal feedstocks.Here,we reviewdirectmeth-

ods for the metal-catalyzed reductive couplingof olefins with carbonyl compounds. Transforma-tions are cataloged according to their use of(i) unactivated or less activated olefins (a-olefinsand styrenes), (ii) conjugated olefins (1,3-dienes,1,3-enynes), and (iii) highly activated olefins (en-ones, acrylates, and vinyl azines) (Fig. 1). Multi-component reactions, reductive couplings ofallenes, reductive carboxylation, and carbonyladditions in which olefins are reduced in situto form stoichiometric quantities of premetalatedreagent—for example, through hydroborationor hydrozirconation—are not covered.

a-Olefins and styrenesIntermolecular catalytic reductive coupling ofsimple linear a-olefins with unactivated carbonyl

partners remains an unmet challenge. Titanocene-catalyzed silane-mediated reductive cyclizationsof 1,5-enones and enals were reported byKablaouiand Buchwald (5, 6) and Crowe and Rachita (7)in 1995; however, intermolecular variants remainelusive. The concept of transfer hydrogenativecarbonyl addition introduced by our laboratory(8–10) provides an important inroad to this prob-lem. Through the use of ruthenium(0) catalysts,vicinally oxygenated secondary alcohols serve du-ally as reductants and carbonyl precursors (Fig. 2)(11, 12). Ethylene, propylene, 1-octene, styrene, anda host of other terminal olefins were found toengage in highly regio- and diastereoselectiveC–C couplingwith 3-hydroxy-2-oxindoles to formthe corresponding tertiary alcohols (11). The scopeof this process was extended through the use ofrelated osmium(0) catalysts (12), which promotethe C–C couplings of ethylene and 1-octene withdiols, a-ketols, or a-hydroxy esters by way of vic-inal dicarbonyl intermediates. The collective datacorroborate a catalytic mechanism involving oxa-metalacyclopentane formation via olefin-carbonyloxidative coupling. Transfer hydrogenolysis of themetalacycle mediated by the reactant alcohol re-leases the product and regenerates the requisitecarbonyl partner. As indicated in the general cat-alytic mechanism, carboxylic acid cocatalysts dra-matically enhance rate and conversion in theseprocesses (Fig. 2), an effect thatmay be attributedto intervention of 6-centered transition structuresfor both protonolytic cleavage of the metalacycleand substitution of the carboxylate ligand by the

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Department of Chemistry, University of Texas at Austin,Austin, TX 78712, USA.*Corresponding author. Email: mkrische@mail.utexas.edu

Fig. 2. Metal-catalyzed reductive coupling of a-olefins with carbonyl partners. AdCO2H refers to 1-adamantane carboxylic acid. X-Phos, 2-dicyclohexylphosphino-2’,4′,6′-triisopropylbiphenyl.

Fig. 1. Metal-catalyzed reductive coupling ofunactivated and activated olefin-derived nu-cleophiles with carbonyl compounds.

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reactant alcohol at the metal center. Related C–Ccouplings of vinyl carboxylates with activatedsecondary alcohols result inmetalacycle fragmen-tation to form products of vinyl transfer (13).Anhydrides represent an alternate class of car-

bonyl electrophile that have proven effective incatalytic reductive couplings with styrenes andcertain a-olefins (Fig. 3). After initial observationsby Kokubo et al. (14), we reported a highly regio-selective rhodium-catalyzed olefin-anhydride re-ductive couplingmediated by elemental hydrogen(15). Subsequently, an enantioselective variantof this process involving copper catalysts wasdeveloped by Bandar et al. (16). Oxidative coupling-metalacycle fragmentationpathways are proposedfor the hydrogen-mediated processes, whereasthe copper-catalyzed reactions are postulated tooperate via olefin hydrometalation to forms-benzylcopper intermediates. Whereas hydroacylationsusing aldehydes as acyl donors require chelatinggroups to suppress conversion of the transientacyl metal intermediates to catalytically inactivecarbonyl complexes, the present anhydride reduc-tive couplings overcome this limitation (17).Recently, an iron-catalyzed Prins-Meerwein-

Ponndorf-Verley–type olefin-aldehyde reductivecoupling mediated by 2-propanol was reported byZheng et al. (Fig. 4) (18). Deuterium-labeling studiescorroborate a catalytic mechanism in which con-densation of the aldehyde with 2-propanol trig-gers nucleophilic attack by the olefin. The nascentcation is reduced via internal hydride transfer. Asanticipated on the basis of this nonconcerted orasynchronous oxonia-ene mechanism, olefins thatbest stabilize the developing cation are the mostefficient reactants. The use of unactivated a-olefinsin these couplings would represent amajor advance.

Dienes and enynes

Butadiene (12 × 106 metric tons/year), isoprene(0.8 × 106 metric tons/year), and myrcene (30 ×103 metric tons/year) are important chemical feed-

stocks. The first intermolecular metal-catalyzedreductive coupling of dienes with carbonyl com-pounds, a process mediated by triethylborane,was reported by Kimura et al. in 1998 (Fig. 5)(19, 20). Diverse dienes may be converted to therespective homoallylation products in good yieldsand excellent levels of anti-1,3-diastereoselectivity.Regioselectivity in favor of coupling to the moresubstituted olefin moiety is observed. A mech-anism involving diene-carbonyl oxidative couplingto form transient oxo-nickelacycles is postulated(19, 20). Corresponding ketone homoallylations

were developed by using diethylzinc as the ter-minal reductant (21). Asymmetric variants of thenickel-catalyzed diene-aldehyde reductive cou-plings are limited to 1,4-diaryl-butadienes (22, 23).Whereas rhodium-catalyzed diene-carbonyl re-ductive couplingmediated by elemental hydrogenrequires use of a-ketoaldehydes (24), rutheniumcatalysts promote the reductive coupling of di-verse dienes to unactivated aldehydes via transferhydrogenation (25); 2-propanol or formic acidmay serve as terminal reductant, or remarkably,the reactant itself may serve dually as reductant

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Fig. 4. Iron-catalyzed Prins-Meerwein-Ponndorf-Verley–type olefin-aldehyde reductive coupling.

Fig. 5. Metal-catalyzed diene-carbonyl reductive coupling. dppf, 1,1-bis(diphenylphosphino)ferrocene; (R)-DM-SEGPHOS, (R)-(+)-5,5′−bis[di(3,5-xylyl)phosphino]-4,4′-bi-1,3-benzodioxole; (S)-SEGPHOS, (S)-(-)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole; acac, acetylacetonate.

Fig. 3. Metal-catalyzed reductive coupling of olefins with anhydrides. (S,S)-Ph-BPE, 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane; DMMS, dimethoxymethylsilane.

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and carbonyl precursor. Enantioselective variantsof the ruthenium-catalyzed reductive couplingshave been developed (26–29). Whereas initialstudies relied on the use of 2-silyl–substituteddienes to direct syn-diastereo and enantioselec-tivity (26), chiral phosphate counterions (28) en-able access to either the anti- or syn-diastereomerswith good control of enantioselectivity (27, 28, 30).The collective data are consistent with a catalyticmechanism in which alcohol dehydrogenationtriggers diene hydrometalation (Fig. 5).Ruthenium complexes that embody cationic

character catalyze the reductive coupling of 2-substituted dienes to form all-carbon quaternarycenters, as illustrated in 2-propanol–mediated re-ductive couplings with paraformaldehyde (Fig. 6)(31, 32); a vacant or labile coordination site at themetal center facilitates reversible diene hydro-metalation, enabling conversion of the kineticp-allylruthenium isomer to the thermodynami-cally more stable, terminally disubstituted p-allylspecies. Related hydrohydroxymethylations thatdirectly use methanol (36 × 106 metric tons/year) as a coupling partner were reported for thefirst time by using an iridium catalyst and 1,1-disubstituted allenes as pronucleophiles (33). In-deed, iridiumcomplexes also catalyze the reactionof dienes with carbonyl compounds to form sec-ondary homoallylic alcohols (33, 34). Cyclohex-adiene (34) and butadiene (35) engage in either2-propanol–mediated reductive coupling or, asshown, direct primary alcohol C–C coupling viahydrogen autotransfer (Fig. 6).Ruthenium(0) catalysis enables reductive cou-

pling of dienes with activated ketones from thesecondary alcohol oxidation level via hydrogenautotransfer (Fig. 7) (36–38). Mechanistic studiescorroborate a catalyticmechanism involvingdiene-carbonyl oxidative coupling to form an oxaruthe-nacycle. Hydrogen transfer from the secondaryalcohol reactant mediates metalacycle hydrogen-olysis, releasing the products of C–C coupling andregenerating the activated ketone to close thecatalytic cycle. The regioselectivity of C–C couplingat the diene C4-position is distinct among diene-carbonyl reductive couplings. Beyond a-hydroxyesters (36), this process applies to 3-hydroxy-2-oxindoles (37) and heteroaryl-substituted sec-ondary alcohols (38). In the latter case, theoxaruthenacycle intermediate was isolated andcharacterized, and reversible metalacycle forma-tion was established through experiments involv-ing diene exchange.The reductive coupling of conjugated enynes

with carbonyl compounds to form homopropar-gylic alcohols was first reported in 2008 (Fig. 8)(39). Through the use of the ruthenium catalystderived in situ from HClRu(CO)(PPh3)3 and 1,1'-bis(diphenylphosphino)ferrocene (dppf), hydrogenis transferred from primary alcohols to 1,3-enynesto form aldehyde-allenylruthenium pairs thatcombine to deliver the products of C–C couplingas single regioisomers in the absence of stoichi-ometric byproducts. In corresponding 2-propanol–mediated reductive couplings of aldehydes with2-propoxy–substituted enynes, good levels of anti-diastereoselectivity are achieved (40). The 2-propoxy

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Fig. 6. Alternate regioselectivity and use of cyclic dienes in metal-catalyzed carbonyl reductivecoupling. dppb, bis(diphenylphosphino)butane; biphep, 2,2′-bis(diphenylphosphino)-1,1′-biphenyl.

Fig. 8. Metal catalyzed enyne-carbonyl reductive coupling. DMMS, dimethoxymethylsilane; (R)-BINAP,(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.

Fig. 7. Ruthenium(0)-catalyzed diene-ketone reductive coupling via hydrogen auto-transfer.PCy3, tricyclohexylphosphine.

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group of the product readily eliminates acetoneupon exposure to aqueous sodium hydroxide toreveal the terminal alkyne. More recently, by usingthe chiral ruthenium complex derived in situ from(TFA)2Ru(CO)(PPh3)2 and (R)-BINAP [(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl], the enan-tioselective C–C couplings of diverse primaryalcohols with the commercially available 1,3-enyne,TMSC≡CC(Me)=CH2, were reported (41). Metalsother than ruthenium catalyze enyne-carbonyl re-ductive coupling. For example, an iridium catalystwith (R)-SEGPHOS [(R)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole] or (R)-DM-SEGPHOSligands catalyzes highly enantioselective enyne-carbonyl reductive coupling from the alcohol oraldehyde oxidation level (42). In the latter case,formic acid serves as terminal reductant. Last,copper complexes recently were found to catalyzethe silane-mediated reductive coupling of 1,3-enyneswith diverse ketoneswith excellent control of syn-diastereo- and enantioselectivity (Fig. 8) (43).

Acrylates, enones, and vinyl azines

The use of a,b-unsaturated carbonyl compoundsas pronucleophiles in reductive couplings with car-bonyl compounds is known as the “reductive aldolreaction” (44). After seminal studies by Revis andHilty in 1987 on the rhodium-catalyzed reductivealdol reaction of acrylates with aldehydes and ke-tones mediated by silane (45), numerous processesof this type were developed by using differentmetal catalysts. We focus here on enantioselec-tive intermolecular reductive aldol reactions (Fig.9). Catalytic carbonyl reductive couplings ofa,b-unsaturated carbonyl compounds that occurat the b-position are not covered (46).The first enantioselective reductive aldol reac-

tion was reported by Taylor et al. in 2000 (47).This reductive coupling of acrylic esters withaldehydes was catalyzed by a rhodium-BINAPcatalyst by using Et2MeSiH as the terminal reduc-tant. High levels of enantioselectivity were accom-panied by modest levels of syn-diastereoselectivity(Fig. 9). Mechanistic studies implicate hydrometal-ative pathways en route to rhodiumenolates.Usingan Ir(pybox) catalyst, improved syn-diastereo- andenantioselectivitieswere observed; however, induc-tively activated aldehydes are required (48). Aremarkably general Rh(phebox) catalyst for asym-metric reductive aldol addition was subsequentlyreported by Nishiyama et al. (49). Uniformly highlevels of anti-diastereoselectivity and enantiose-lectivity were observed across a diverse range ofsubstrates, including additions to ketones (50).Ketone electrophiles are also accommodated bycopper catalysts (51). The preceding examples ofasymmetric reductive aldol coupling pair acry-late pronucleophiles with hydrosilane as terminalreductant. Vinyl ketones serve as pronucleophiles,with rhodium catalysts and H2 as reductant (52).Substituting deuterium as the reductant leads totransfer of a single deuterium atom to the formerenone b-position, which is consistent with a cat-alytic mechanism involving oxidative couplingfollowed by hydrogenolysis of the resulting me-talacycle via s-bond metathesis. Hydrometala-tive pathways cannot be excluded on the basis of

these results; however, reversiblehydrometalation–b-hydride elimination would be anticipated to dim-inish the extent of deuterium incorporation.Vinyl azines are isostructural with respect to

a,b-unsaturated carbonyl compounds and, asdescribed in the review literature (53), displayanalogous reactivity. However, their use as pro-nucleophiles in catalytic reductive coupling hasonly recently begun to be explored. In 2008, thefirst example of vinyl azine reductive couplingto a p-electrophile was achieved via rhodium-catalyzed hydrogenation of vinyl azines in thepresence of imines (Fig. 10) (54). Good levels ofsyn-diastereoselectivity were observed. The Lamlaboratory subsequently reporteda copper-catalyzedcoupling of vinyl azines to ketone electrophileswith good levels of syn-diastereoselectivity andexcellent enantioselectivity (55). For both pro-cesses, optimal results are obtained by using vinylazines in which both positions adjacent to ni-trogen are substituted.

Conclusion and outlook

Intermolecular catalytic reductive coupling ofsimple linear a-olefins with unactivated carbonylpartners remains an important unmet challengein chemical synthesis. For such abundant feed-stocks, an additional consideration resides in id-entifying terminal reductants that are equallyinexpensive and minimize or eliminate byproductformation. Hence, byproduct-free processes med-

iated by elemental hydrogen or transfer hydro-genative C–C couplings of alcohol reactants areespecially attractive. Conversely, processes medi-ated by reductants that are pyrophoric (ZnEt2 andBEt3) or those that are costly and mass-intensive(R3SiH) can only be viewed as interim solutions.Despite themany unrequited challenges, progressmade in the area of metal-catalyzed reductivecoupling clearly shows that classical methodsfor carbonyl addition that traditionally have ex-ploited stoichiometric organometallic reagentsmay be replaced with catalytic processes thatbypass premetalated reagents (Fig. 11). It is ourhope that this Review will inspire and guidefuture research aimed at unlocking carbonyl-addition chemistry beyond stoichiometric metals.

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Fig. 9. Enantioselective metal-catalyzed reductive aldol reactions. The structures of indane-pybox, phebox, taniaphos, and AbbasPhos-I are provided in the cited references.

Fig. 11. A departure from preformed organo-metallic reagents in carbonyl addition.

Fig. 10. Metal-catalyzed reductive coupling of vinyl azines.

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24. H.-Y. Jang, R. R. Huddleston, M. J. Krische, A New catalytic C–Cbond-forming hydrogenation: Reductive coupling of dienes andglyoxals under catalytic hydrogenation conditions. Angew. Chem.Int. Ed. Engl. 42, 4074–4077 (2003). doi: 10.1002/anie.200351986; pmid: 12973774

25. F. Shibahara, J. F. Bower, M. J. Krische, Ruthenium-catalyzedC-C bond forming transfer hydrogenation: Carbonyl allylationfrom the alcohol or aldehyde oxidation level employing acyclic1,3-dienes as surrogates to preformed allyl metal reagents. J.Am. Chem. Soc. 130, 6338–6339 (2008). doi: 10.1021/ja801213x; pmid: 18444617

26. J. R. Zbieg, J. Moran, M. J. Krische, Diastereo- and enantioselectiveruthenium-catalyzed hydrohydroxyalkylation of 2-silyl-butadienes:Carbonyl syn-crotylation from the alcohol oxidation level. J. Am.Chem. Soc. 133, 10582–10586 (2011). doi: 10.1021/ja2046028;pmid: 21627316

27. J. R. Zbieg, E. Yamaguchi, E. L. McInturff, M. J. Krische,Enantioselective C–H crotylation of primary alcohols viahydrohydroxyalkylation of butadiene. Science 336, 324–327(2012). doi: 10.1126/science.1219274; pmid: 22442385

28. E. L. McInturff, E. Yamaguchi, M. J. Krische, Chiral-anion-dependent inversion of diastereo- and enantioselectivity incarbonyl crotylation via ruthenium-catalyzed butadienehydrohydroxyalkylation. J. Am. Chem. Soc. 134, 20628–20631(2012). doi: 10.1021/ja311208a; pmid: 23234459

29. V. Komanduri, M. J. Krische, Enantioselective reductive couplingof 1,3-enynes to heterocyclic aromatic aldehydes and ketonesvia rhodium-catalyzed asymmetric hydrogenation: Mechanisticinsight into the role of Brønsted acid additives. J. Am. Chem.Soc. 128, 16448–16449 (2006). doi: 10.1021/ja0673027;pmid: 17177363

30. M. N. Grayson, M. J. Krische, K. N. Houk, Ruthenium-catalyzedasymmetric hydrohydroxyalkylation of butadiene: The role ofthe formyl hydrogen bond in stereochemical control. J. Am.Chem. Soc. 137, 8838–8850 (2015). doi: 10.1021/jacs.5b04844; pmid: 26107070

31. T. Smejkal, H. Han, B. Breit, M. J. Krische, All-carbon quaternarycenters via ruthenium-catalyzed hydroxymethylation of 2-substituted butadienes mediated by formaldehyde: Beyondhydroformylation. J. Am. Chem. Soc. 131, 10366–10367 (2009).doi: 10.1021/ja904124b; pmid: 19594163

32. B. Sam, B. Breit, M. J. Krische, Paraformaldehyde andmethanol as C1 feedstocks in metal-catalyzed C–C couplings ofπ-unsaturated reactants: Beyond hydroformylation. Angew.Chem. Int. Ed. Engl. 54, 3267–3274 (2015). doi: 10.1002/anie.201407888; pmid: 25430585

33. J. Moran, A. Preetz, R. A. Mesch, M. J. Krische, Iridium-catalyseddirect C–C coupling of methanol and allenes. Nat. Chem.3, 287–290 (2011). doi: 10.1038/nchem.1001; pmid: 21430686

34. J. F. Bower, R. L. Patman, M. J. Krische, Iridium-catalyzed C–Ccoupling via transfer hydrogenation: Carbonyl addition fromthe alcohol or aldehyde oxidation level employing 1,3-cyclohexadiene. Org. Lett. 10, 1033–1035 (2008). doi: 10.1021/ol800159w; pmid: 18254642

35. J. R. Zbieg, T. Fukuzumi, M. J. Krische, Iridium catalyzedhydro-hydroxyalkylation of butadiene: carbonyl crotylation.Adv. Synth. Catal. 352, 2416–2420 (2010). doi: 10.1002/adsc.201000599; pmid: 21165157

36. J. C. Leung, L. M. Geary, T.-Y. Chen, J. R. Zbieg, M. J. Krische,Direct, redox-neutral prenylation and geranylation of secondarycarbinol C–H bonds: C4-regioselectivity in ruthenium-catalyzedC–C couplings of dienes to a-hydroxy esters. J. Am. Chem. Soc.134, 15700–15703 (2012). doi: 10.1021/ja3075049;pmid: 22985393

37. T.-Y. Chen, M. J. Krische, Regioselective rutheniumcatalyzed hydrohydroxyalkylation of dienes with 3-hydroxy-2-oxindoles: Prenylation, geranylation, and beyond. Org.Lett. 15, 2994–2997 (2013). doi: 10.1021/ol401184k;pmid: 23721207

38. B. Y. Park, T. P. Montgomery, V. J. Garza, M. J. Krische, Rutheniumcatalyzed hydrohydroxyalkylation of isoprene with heteroaromaticsecondary alcohols: Isolation and reversible formation of theputative metallacycle intermediate. J. Am. Chem. Soc. 135,16320–16323 (2013). doi: 10.1021/ja4087193; pmid: 24156560

39. R. L. Patman, V. M. Williams, J. F. Bower, M. J. Krische,Carbonyl propargylation from the alcohol or aldehyde oxidationlevel employing 1,3-enynes as surrogates to preformedallenylmetal reagents: A ruthenium-catalyzed C–C bond-forming transfer hydrogenation. Angew. Chem. Int. Ed. Engl.47, 5220–5223 (2008). doi: 10.1002/anie.200801359;pmid: 18528831

40. L. M. Geary, J. C. Leung, M. J. Krische, Ruthenium-catalyzedreductive coupling of 1,3-enynes and aldehydes by transferhydrogenation: Anti-diastereoselective carbonyl propargylation.Chemistry 18, 16823–16827 (2012). doi: 10.1002/chem.201202446; pmid: 23147989

41. K. D. Nguyen, D. Herkommer, M. J. Krische, Ruthenium-BINAPcatalyzed alcohol C–H tert-prenylation via 1,3-enyne transferhydrogenation: Beyond stoichiometric carbanions inenantioselective carbonyl propargylation. J. Am. Chem.Soc. 138, 5238–5241 (2016). doi: 10.1021/jacs.6b02279;pmid: 27079149

42. L. M. Geary, S. K. Woo, J. C. Leung, M. J. Krische,Diastereo- and enantioselective iridium-catalyzed carbonylpropargylation from the alcohol or aldehyde oxidationlevel: 1,3-enynes as allenylmetal equivalents. Angew. Chem. Int.Ed. Engl. 51, 2972–2976 (2012). doi: 10.1002/anie.201200239;pmid: 22337340

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52. C. Bee, S. B. Han, A. Hassan, H. Iida, M. J. Krische,Diastereo- and enantioselective hydrogenative aldolcoupling of vinyl ketones: Design of effective monodentateTADDOL-like phosphonite ligands. J. Am. Chem. Soc.130, 2746–2747 (2008). doi: 10.1021/ja710862u;pmid: 18266373

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ACKNOWLEDGMENTS

The Robert A. Welch Foundation (grant F-0038) andNIH–National Institute of General Medical Sciences(grant RO1-GM069445) are acknowledged for financialsupport. H.S. gratefully acknowledges a Japan Student ServicesOrganization graduate student exchange fellowship.

10.1126/science.aah5133

SCIENCE sciencemag.org 21 OCTOBER 2016 • VOL 354 ISSUE 6310 aah5133-5

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additionMetal-catalyzed reductive coupling of olefin-derived nucleophiles: Reinventing carbonyl

Khoa D. Nguyen, Boyoung Y. Park, Tom Luong, Hiroki Sato, Victoria J. Garza and Michael J. Krische

DOI: 10.1126/science.aah5133 (6310), aah5133.354Science 

, this issue p. 300Sciencesafety and efficiency considerations, this class of reactions benefits from the high abundance and low cost of the olefins.magnesium reagent with a catalytically activated olefin and a reductant such as hydrogen or an alcohol. In addition to

review an emerging alternative protocol that replaces the sensitiveet al.used route to carbon-carbon bonds. Nguyen Prize more than a century ago, this coupling of organomagnesium halides with carbonyl compounds remains a widely

The Grignard reaction has a storied place in the development of organic chemistry. Recognized by the NobelHow to turn olefins into nucleophiles

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