Classical protocols for carbonyl allylation, propargylation and vinylation typically rely upon the use of preformed allyl metal, allenyl metal and vinyl metal reagents, respectively, mandating stoichiometric generation of metallic byproducts. Through transfer hydrogenative C-C coupling, carbonyl addition may be achieved from the aldehyde or alcohol oxidation level in the absence of stoichiometric organometallic reagents or metallic reductants. Here, we review transfer hydrogenative methods for carbonyl addition, which encompass the first cataltyic protocols enabling direct C–H functionalization of alcohols.

We report byproduct-free carbonyl reverse prenylation, crotylation, and allylation from the alcohol oxidation state via alcohol−allene hydrogen autotransfer. Specifically, exposure of alcohols 1a−6a to 1,1-dimethylallene, methylallene, and allene in the presence of [Ir(cod)(BIPHEP)]BARF (5−7.5 mol %) delivers reverse prenylation products 1c−6c, crotylation products 1d−3d, and allylation product 1e. Similarly, under the conditions of transfer hydrogenation employing isopropanol as terminal reductant, aldehydes 1b−6b are converted to the very same adducts 1c−6c, 1d−3d, and 1e. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH). The ability to achieve carbonyl addition directly from the alcohol oxidation level circumvents the redox manipulations so often required to convert alcohols to aldehydes. Further, through hydrogen autotransfer, there resides the potential to develop myriad byproduct-free carbonyl additions wherein alcohols and π-unsaturated compounds are exploited as coupling partners.

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to benzylic and aliphatic alcohols 1a–1i to furnish allylic alcohols 2a–2i, constituting a direct C-H vinylation of alcohols employing alkynes as vinyl donors. Under related transfer hydrogenation conditions employing formic acid as terminal reductant, 2-butyne couples to aldehydes 4a, 4b, and 4e to furnish identical products of carbonyl vinylation 2a, 2b, and 2e. Thus, carbonyl vinylation is achieved from the alcohol or the aldehyde oxidation level in the absence of any stoichiometric metallic reagents. Nonsymmetric alkynes 6a–6c couple efficiently to aldehyde 4b to provide allylic alcohols 2m–2o as single regioisomers. Acetylenic aldehyde 7a engages in efficient intramolecular coupling to deliver cyclic allylic alcohol 8a.

Under hydrogen auto-transfer conditions employing a catalyst derived from [Ir(cod)Cl] 2 and BIPHEP, 1,3-cyclohexadiene (CHD) couples to benzylic alcohols 1a-9a to furnish carbonyl addition products 1c-9c, which appear as single diastereomers with variable quantities of regioisomeric adducts 1d-9d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, identical carbonyl adducts 1c-9c are obtained from the aldehyde oxidation level. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).As part of a broad program aimed at the development of methods for byproduct-free carbonyl and imine addition, 1,2 we recently reported that carbonyl allylation may be achieved by simply hydrogenating allenes in the presence of aldehydes. 2h Though effective for reverse prenylation, attempted crotylations and allylations using gaseous hydrogen as the terminal reductant suffered from over-reduction of the olefinic adduct. To address this limitation, allene-aldehyde reductive coupling was performed under the conditions of mkrische@mail.utexas.edu . Supporting Information Available. Experimental procedures and spectral data for all new compounds ( 1 H NMR, 13 C NMR, IR, HRMS). This material is available free of charge via the internet at http://pubs.acs.org. transfer hydrogenation using isopropanol as the terminal reductant. 2i In the course of these studies, it was found that carbonyl allylation could be achieved directly from the alcohol oxidation level by way of allene-alcohol transfer hydrogenation, 2i constituting a novel variant of hydrogen auto-transfer processes wherein hydrogen exchange between reactants is used to generate nucleophile-electrophile pairs (Scheme 1). 2i, 3,4,5,6,7 Through hydrogen auto-transfer, there exists the potential to develop a broad new family of byproduct-free catalytic C-C bond formations wherein alcohols and diverse π-unsaturated compounds are exploited as coupling partners. Motivated by this prospect, diene-aldehyde hydrogen auto-transfer was explored. Catalytic diene-aldehyde reductive coupling has been accomplished in both intra-and intermolecular settings. 8,9,10 Recently, the first examples of asymmetric diene-aldehyde intermolecular coupling were reported.9k,l Here, we disclose that 1,3-cyclohexadiene and aromatic alcohols 1a-9a engage in C-C coupling under the conditions of iridium catalyzed hydrogen auto-transfer. Additionally, we report the coupling of 1,3-cyclohexadiene to an analogous set of aldehydes 1b-9b under related transfer hydrogenation conditions employing isopropanol as the terminal reductant. NIH Public AccessInitial studies focused upon the coupling of benzyl alcohol 1a to 1,3-cyclohexadiene (CHD) under the conditions of iridium catalysis. It was found that a catalyst derived from commercially available [Ir(cod)Cl] 2 and BIPHEP delivers homoallylic alcohol 1c as a mixture of diastereomers, along with significant amounts of the regioisomeric product 1...

Over the past half century, numerous protocols for carbonyl propargylation using allenylmetal reagents have been developed.[1] Allenic Grignard reagents were used by Prévost et al.[2a] in carbonyl additions to furnish mixtures of β-acetylenic and α-allenic carbinols, which led to them to coin the term "propargylic transposition." [2a,b] Subsequent studies by Chodkiewicz and co-workers[2c] demonstrated relative stereocontrol in such additions. Shortly thereafter, Lequam and Guillerm[2d] reported that isolable allenic stannanes provide products of carbonyl propargylation upon exposure to chloral. Later, Mukaiyama and Harada[2e] demonstrated that stannanes generated in situ from propargyl iodides and stannous chloride reacted with aldehydes to provide mixtures of β-acetylenic and α-allenic carbinols. Related propargylations employing allenylboron reagents were first reported by Favre and Gaudemar,[2f] and propargylations employing allenylsilicon reagents were first reported by Danheiser and Carini.[2g] Asymmetric variants followed (Scheme 1). Allenylboron reagents chirally modified at the boron center engage in asymmetric propargylation, as was first reported by Yamamoto and coworkers[2h] and Corey et al.[2i] Allenylstannanes chirally modified at the tin center also induce asymmetric carbonyl propargylation, as was first reported by Minowa and Mukaiyama.[2j] Axially chiral allenylstannanes, allenylsilanes, and allenylboron reagents propargylate aldehydes enantiospecifically, as was first described by Marshall et al.,[2k,l] and Hayashi and coworkers,[2m] respectively. Finally, asymmetric aldehyde propargylation using allenylmetal reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as was first reported by Keck et al.,[2n] and Denmark and Wynn,[2o] respectively.Here, we report a new approach to carbonyl propargylation based on ruthenium-catalyzed C-C bond-forming transfer hydrogenation. [3][4][5] Specifically, upon exposure of 1,3-enynes 1a-1g to alcohols 2a-2o in the presence of [RuHCl(CO)(PPh 3 ) 3 ]/dppf (dppf =1,1′-bis (diphenylphosphino)ferrocene), hydrogen shuffling between reactants occurs to generate nucleophile-electrophile pairs that regioselectively combine to furnish products of carbonyl