Ryan L. Patman

Catalytic Carbonyl Addition through Transfer Hydrogenation: A Departure from Preformed Organometallic Reagents

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, however, 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 catalytic protocols enabling direct C-H functionalization of alcohols.

Direct vinylation of alcohols or aldehydes employing alkynes as vinyl donors: a ruthenium catalyzed C-C bond-forming transfer hydrogenation.

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to benzylic and aliphatic alcohols 1a-1l to furnish allylic alcohols 2a-2l, 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.

Iridium Catalyzed C-C Coupling via Transfer Hydrogenation: Carbonyl Addition from the Alcohol or Aldehyde Oxidation Level Employing 1,3-Cyclohexadiene

Under hydrogen autotransfer 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).

Carbonyl propargylation from the alcohol or aldehyde oxidation level employing 1,3-enynes as surrogates to preformed allenylmetal reagents: a ruthenium-catalyzed C-C bond-forming transfer hydrogenation.

Over the past half century, numerous protocols for carbonyl propargylation using allenylmetal reagents have been developed.[1] Allenic Grignard reagents were used by Prevost 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 co-workers[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. Scheme 1 Chirally modified allenylmetal reagents for carbonyl propargylation. Tf =trifluoromethanesulfonyl, Ts =para-toluenesulfonyl. Here, we report a new approach to carbonyl propargylation based on ruthenium-catalyzed C–C bond-forming transfer hydrogenation.[3–5] Specifically, upon exposure of 1,3-enynes 1a–1g to alcohols 2a–2o in the presence of [RuHCl(CO)(PPh3)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 propargylation.[6] Under related transfer hydrogenation conditions and employing isopropanol as the terminal reductant, 1,3-enynes couple to aldehydes to furnish identical products of carbonyl propargylation. The observed regiochemistry is unique with respect to related enyne–carbonyl reductive coupling reactions that are catalyzed by rhodium[5,7] and nickel complexes, [8,9,10] which favor coupling at the acetylenic terminus of the enyne. Significantly, this protocol enables carbonyl propargylation from the alcohol or aldehyde oxidation level in the absence of preformed allenylmetal reagents (Scheme 2). Scheme 2 Divergent regioselectivity observed in metal-catalyzed enyne–carbonyl coupling. In connection with our efforts to exploit catalytic hydrogenation in C–C coupling reactions beyond hydroformylation,[5] we recently demonstrated that C–C bond formation may be achieved under the conditions of iridium- and ruthenium-catalyzed transfer hydrogenation.[11] These processes enable direct carbonyl allylation from the alcohol or aldehyde oxidation level by using commercially available allenes or dienes as allyl donors. Seeking to develop corresponding carbonyl propargylations, diverse iridium and ruthenium complexes were assayed for their ability to catalyze the coupling of enyne 1a and alcohol 2a. Gratifyingly, both [{Ir(cod)Cl}2]/biphep (biphep =diphenylphosphine, cod =cycloocta-l,5-diene) and [RuHCl(CO)(PPh3)3]/dppf catalyze the desired coupling. The ruthenium-based catalyst was most effective and, under optimized conditions, enyne 1a coupled to benzylic, allylic, and aliphatic alcohols 2a–2o to form homopropargyl alcohols 3a–3o in good to excellent yields (Table 1). To probe the scope of the enyne coupling partner, enynes 1b–1g were coupled to benzyl alcohol 2b under standard reaction conditions. Good to excellent yields of propargylation products 3p–3u were observed (Table 2). Substitution at the olefinic terminus of the enyne was found to diminish conversion to product. Finally, carbonyl allylation can also be achieved from the aldehyde oxidation level by employing isopropanol as the terminal reductant. Under standard reaction conditions, aldehydes 4a–4c couple to enyne 1a to provide the products of carbonyl propargylation 3a–3c, respectively, in good to excellent yield. Thus, carbonyl propargylation may be achieved from either the alcohol or aldehyde oxidation level (Table 3). The coupling products 3a–3u are remarkably resistant to over-oxidation to form the corresponding β,γ-acetylenic ketones. However, such over-oxidation is observed if cationic ruthenium complexes are employed as catalysts. This result suggests that, for the neutral ruthenium complexes employed in this study, the alkyne moiety of the coupling product blocks a coordination site required for β hydride elimination of the carbinol C–H bond. Other aspects of the catalytic mechanism, including determination of the structural and interactive features of the ruthenium complex that influence relative and absolute stereocontrol, are currently under investigation. Table 1 Carbonyl propargylation from the alcohol oxidation level by ruthenium-catalyzed transfer hydrogenation.a Table 2 Coupling of enynes 1b–1g to benzyl alcohol 2b by ruthenium-catalyzed transfer hydrogenation.a Table 3 Carbonyl propargylation from the aldehyde oxidation level by ruthenium-catalyzed transfer hydrogenation.a A general catalytic mechanism is likely to involve the following steps:[11] a) alcohol dehydrogenation to generate a ruthenium hydride is followed by b) enyne hydrometalation to generate an allenyl metal–aldehyde/nucleophile–electrophile pair, which undergoes c) carbonyl addition with propargylic transposition. Consistent with this interpretation, the coupling of enyne 1a to [D]-2b under standard reaction conditions provides [D]-3b, in which deuterium is incorporated at the benzylic position (>95%), the allylic methyl group (56%), and the allylic methine position (24%), thus suggesting reversible olefin-hydrometalation [Eq. (1)]. (1) Our collective studies on hydrogenative and transfer hydrogenative C–C coupling define a departure from the use of preformed organometallic reagents in carbonyl addition chemistry.[5,11] For such transfer hydrogenative coupling reactions, hydrogen embedded within isopropanol or an alcohol substrate is redistributed among reactants to generate nucleophile–electrophile pairs, thus enabling carbonyl addition from the aldehyde or alcohol oxidation level. In this way, carbonyl additions that transcend the boundaries of oxidation level are devised. In the present study, we have demonstrated that 1,3-enynes serve as allenylmetal equivalents under the conditions of transfer hydrogenative coupling, thus also enabling carbonyl propargylation from the alcohol or aldehyde oxidation level. These studies contribute to a growing body of catalytic methods for the direct functionalization of carbinol C–H bonds.[11,12] Future studies will focus on the development of related alcohol–unsaturate C–C coupling processes.

Divergent Regioselectivity in the Synthesis of Trisubstituted Allylic Alcohols by Nickel‐ and Ruthenium‐Catalyzed Alkyne Hydrohydroxymethylation with Formaldehyde

Trisubstituted allylic alcohols are ubiquitous in natural products and are readily converted into diverse chiral building blocks by enantioselective epoxidation, cyclopropanation, hydrogenation, and allylic substitution. Among methods for the regioand stereoselective synthesis of trisubstituted primary allylic alcohols, alkyne hydrometalation or carbometalation mediated by stoichiometric organometallic reagents has found broad use. For example, in seminal studies by Corey et al. (1967), the regioand stereoselective hydroalumination of propargyl alcohols was used to construct vinyl iodides, which were converted into trisubstituted allylic alcohols upon exposure to lithium dialkyl cuprates. Similarly, alkyne hydromagnesiation and carbomagnesiation with Grignard reagents delivered trisubstituted allylic alcohols regioand stereoselectively. Although alkyne functionalization through hydrometalation and carbometalation remains at the forefront of research, the development of equivalent transformations that avoid stoichiometric metal reagents is clearly desirable. Conversely, whereas related nickel-catalyzed alkyne–carbonyl reductive couplings can be highly regioselective, such processes require terminal reductants that are metallic, pyrophoric, or highly mass intensive (e.g. ZnR2, BEt3, HSiR3; Scheme 1), [8–10] although nickel-catalyzed alcoholmediated alkyne–enone couplings were recently disclosed. Hence, the discovery of alkyne–carbonyl (or alkyne– imine) reductive couplings under hydrogenation conditions is significant. 13] More recently, an alkyne–carbonyl reductive coupling by ruthenium-catalyzed transfer hydrogenation was developed; however, regioselectivity in such processes remains largely unexplored. 15] Herein, we report the regioand stereoselective synthesis of trisubstituted primary allylic alcohols from alkynes in the absence of stoichiometric metallic reagents. In this reaction, paraformaldehyde is used as a C1 feedstock and, more remarkably, as a reductant under conditions of transfer hydrogenation with nickel and ruthenium catalysts, which exhibit complementary regioselectivity (Scheme 2). In response to the lack of efficient methods for diene hydroformylation, we recently developed a process for diene hydrohydroxymethylation under the conditions of ruthenium-catalyzed transfer hydrogenation using paraformaldehyde as a C1 feedstock; paraformaldehyde was itself prepared from synthesis gas (via methanol). As the development of efficient catalysts for alkyne hydroformylation remains an unmet challenge, we undertook the current investigation into alkyne–paraformaldehyde reductive coupling. Initial studies focused on the reductive coupling of 1phenylpropyne (1a) with paraformaldehyde. We explored the nickel-catalyzed reductive coupling of 1a with paraformaldehyde in the absence of a reducing agent. Remarkably, conditions were identified under which the nickel catalyst produced adduct 3a as a single regioand stereoisomer, as determined by H NMR spectroscopic analysis. Previously determined conditions for ruthenium-catalyzed alkyne–carbonyl coupling with higher aldehydes were further evaluated and meticulously adapted for the use of paraformaldehyde to enable formation of the isomeric primary trisubstituted allylic alcohol 2a in 85 % yield as a single regioand Scheme 1. Previously developed approaches requiring a stoichiometric amount of a reducing agent, and the approach investigated in the current study without exogenous reductants.

Enantioselective carbonyl allylation, crotylation, and tert-prenylation of furan methanols and furfurals via iridium-catalyzed transfer hydrogenation.

5-Substituted-2-furan methanols 1a-c are subject to enantioselective carbonyl allylation, crotylation and tert-prenylation upon exposure to allyl acetate, alpha-methyl allyl acetate, or 1,1-dimethylallene in the presence of an ortho-cyclometalated iridium catalyst modified by (R)-Cl,MeO-BIPHEP, (R)-C3-TUNEPHOS, and (R)-C3-SEGPHOS, respectively. In the presence of 2-propanol, but under otherwise identical conditions, the corresponding substituted furfurals 2a-c are converted to identical products of allylation, crotylation, and tert-prenylation. Optically enriched products of carbonyl allylation, crotylation, and reverse prenylation 3b, 4b, and 5b were subjected to Achmatowicz rearrangement to furnish the corresponding gamma-hydroxy-beta-pyrones 6a-c, respectively, with negligible erosion of enantiomeric excess.

Alkyne–Aldehyde Reductive CC Coupling through Ruthenium‐Catalyzed Transfer Hydrogenation: Direct Regio‐ and Stereoselective Carbonyl Vinylation to Form Trisubstituted Allylic Alcohols in the Absence of Premetallated Reagents

Nonsymmetric 1,2-disubstituted alkynes engage in reductive coupling to a variety of aldehydes under the conditions of ruthenium-catalyzed transfer hydrogenation by employing formic acid as the terminal reductant and delivering the products of carbonyl vinylation with good to excellent levels of regioselectivity and with complete control of olefin stereochemistry. As revealed in an assessment of the ruthenium counterion, iodide plays an essential role in directing the regioselectivity of C-C bond formation. Isotopic labeling studies corroborate reversible catalytic propargyl C-H oxidative addition in advance of the C-C coupling, and demonstrate that the C-C coupling products do not experience reversible dehydrogenation by way of enone intermediates. This transfer hydrogenation protocol enables carbonyl vinylation in the absence of stoichiometric metallic reagents.