Formation of C–C Bonds via Iridium-Catalyzed Hydrogenation and Transfer Hydrogenation

Abstract

The formation of C–C bonds via catalytic hydrogenation and transfer hydrogenation enables carbonyl and imine addition in the absence of stoichiometric organometallic reagents. In this review, iridium-catalyzed C–C bond-forming hydrogenations and transfer hydrogenations are surveyed. These processes encompass selective, atom-economic methods for the vinylation and allylation of carbonyl compounds and imines. Notably, under transfer hydrogenation conditions, alcohol dehydrogenation drives reductive generation of organoiridium nucleophiles, enabling carbonyl addition from the aldehyde or alcohol oxidation level. In the latter case, hydrogen exchange between alcohols and π-unsaturated reactants generates electrophile–nucleophile pairs en route to products of hydro-hydroxyalkylation, representing a direct method for the functionalization of carbinol C–H bonds.

1 Introduction

The majority of chemical commodities (plastics, foams, pharmaceuticals, agrochemicals) are made from rapidly depleting petrochemical feedstocks. Consequently, there is a growing need to develop catalytic methods for the direct manufacture of chemical products from abundant renewable resources in the absence of stoichiometric byproducts [1]. In the specific case of carbonyl and imine addition, a departure from the use of premetallated nucleophiles represents a particularly important focus. Progress in this area will depend largely upon the discovery of new chemical reactivity.

Catalytic hydrogenation is the cleanest and most cost-effective method available for the reduction of organic molecules. Accordingly, chemical processes such as the Haber–Bosch reaction¹ [2, 3], alkene hydroformylation² [4–7], and enantioselective hydrogenation³ [8–10], all of which provide materials essential to humanity, are practiced on a vast scale. The industrialization of these processes is assisted by the fact that such hydrogen-mediated transformations do not generate stoichiometric byproducts, which facilitate product purification and waste stream management. Interestingly, although catalytic hydrogenation and the Grignard reaction are both reductive transformations, a union between catalytic hydrogenation and carbonyl addition chemistry failed to materialize after the emergence of alkene hydroformylation, which may be viewed as the prototypical C–C bond-forming hydrogenation.

The collective studies from our laboratory establish metal-catalyzed hydrogenation and transfer hydrogenation as general methods for C–C bond formation.⁴,⁵,⁶ These processes exploit π-unsaturated reactants as surrogates to moisture sensitive organometallic reagents, enabling carbonyl and imine addition under essentially neutral conditions in the absence of stoichiometric organometallic reagents and resulting metallic byproducts. Remarkably, under transfer hydrogenation conditions, hydrogen exchange between alcohols and π-unsaturated reactants generates electrophile–nucleophile pairs en route to products of hydro-hydroxyalkylation, representing a direct method for the functionalization of carbinol C–H bonds.⁷,⁸,⁹ For such “carbonyl additions from the alcohol oxidation level,” preactivation is not required as both the nucleophile and electrophile are generated catalytically from simple and stable precursors (Scheme 1). In this review, iridium-catalyzed C–C bond-forming hydrogenations and transfer hydrogenations are surveyed. Related hydrogen-mediated C–C couplings employing rhodium and ruthenium catalysts are not covered in this account but are described in several recent monographs (see footnote ⁴, [11–17]).

Scheme 1.

Catalytic C–C coupling via hydrogenation and transfer hydrogenation (X=O, NR₂)

2 Iridium-Catalyzed Hydrogenation for C–C Bond Formation

2.1 Alkynes as Vinylmetal Surrogates via Iridium-Catalyzed Hydrogenation

Allylic alcohols and allylic amines are highly versatile building blocks for organic synthesis, and methods for their preparation in enantiomerically enriched form are the subject of intensive investigation.¹⁰,¹¹ The majority of established protocols rely upon metal-catalyzed allylic substitution employing O- and N-nucleophiles (For reviews on metal catalyzed allylic amination and alkoxylation, see: [37–43]). An alternative approach to allylic alcohols and allylic amines involves the catalytic enantioselective vinylation of aldehydes and imines. Based upon the seminal studies of Oguni [44] and Noyori [45] on the enantioselective addition of dialkylzinc reagents to aldehydes (For reviews encompassing catalytic enantioselective addition of organozinc reagents to carbonyl compounds, see: [46–51]), Oppolzer (see footnote ¹², [52]) devised the first catalytic enantioselective aldehyde vinylations.¹²,¹³ In this process, vinylzinc reagents are generated in situ by alkyne hydroboration followed by transmetallation from boron to zinc using ZnMe₂. A conceptually related approach was developed subsequently by Wipf, in which hydrozirconation-transmetallation is used to generate the vinylzinc reagent (see footnote ¹², [55]). These studies, along with catalytic enantioselective alkyl- and aryl-zinc-mediated ketone additions described by Yus [73, 74] and Fu [75], set the stage for catalytic enantioselective ketone vinylations, as described by Walsh (For catalytic enantioselective ketone vinylation using organozinc reagents, see: [76–78]). Catalytic methods for carbonyl vinylation continue to emerge, as demonstrated by recent reports on rhodium-catalyzed aldehyde additions employing vinylboron reagents [79].

Enantioselective vinylzinc-mediated imine additions reveal additional challenges (For reviews encompassing the catalytic enantioselective addition of organozinc reagents to imines, see: [80–84]). After the seminal report of Soai [85], several enantioselective catalysts for the addition of organozinc reagents to imines were developed. However, highly activated N-acyl and N-(diphenylphosphinoyl) imines are required (For enantioselective catalytic addition of organozinc reagents to imines, see: [85–96]). To address the issue of reactivity, Tomioka (see footnote ¹⁴, [97]) disclosed an enantioselective copper catalyst for organozinc-mediated imine addition.¹⁴ In addition to late transition metals (Cu, Rh) (see footnote ¹⁴) [117, 118], early transition metal catalysts (Ti, Zr, Hf) (For enantioselective zirconium, titanium and hafnium catalyzed addition of organozinc reagents to imines, see: [119–124]) are found to promote the highly enantioselective addition of organozinc reagents to imines. The enantioselective addition of organolithium reagents to imines promoted or catalyzed by chiral chelating agents also has been described (For reviews encompassing catalytic enantioselective addition of organolithium reagents to carbonyl compounds and imines, see: [125–132]). Finally, under the conditions of rhodium catalysis, organotin, organotitanium, and organoboron reagents participate in catalytic asymmetric imine addition (For enantioselective rhodium catalyzed addition of organometallic reagents to imines, see: Organotin reagents [133–134], Organotitanium reagents [135] and Organoboron reagents [136]). Despite these efforts, highly enantioselective imine additions employing vinylmetal reagents remain elusive (Catalyzed addition of vinylzirconocenes to imines is known, but enantioselective variants have not been developed: [147, 148]).¹⁵

The direct metal-catalyzed reductive coupling of alkynes to carbonyl compounds or imines provides an alternative to the use of discrete vinylmetal reagents (For a compilation of reviews on the subject of metal catalyzed reductive C–C coupling, see: [150]).¹⁶ Catalytic intramolecular carbonyl vinylation was first reported by Ojima (1994), who employed a rhodium catalyst in combination with a silane as the terminal reductant [159]. Related cyclizations using titanium or nickel catalysts later were reported by Crowe [160] (For an aligned study, see: [161]) and Montgomery [162–167], respectively. Finally, in an adaptation of Montgomery’s cyclization protocol, intermolecular nickel-catalyzed alkyne–aldehyde reductive couplings were reported by Jamison [168–171]. Subsequently, improved nickel catalysts for this process were devised by Takai [172] and Montgomery [165]. However, while direct alkyne–carbonyl reductive couplings circumvent the use of discrete vinylmetal reagents, they nevertheless employ terminal reductants such as hydrosilanes, hydrostannanes, organozinc reagents, organoboron reagents or chromium(II) chloride, which generate stoichiometric quantities of byproduct.

Under the conditions of iridium-catalyzed hydrogenation, alkyne–carbonyl and alkyne–imine reductive coupling occurs in the absence of stoichiometric byproducts. For example, iridium-catalyzed hydrogenation of nonconjugated alkynes in the presence of α-ketoesters delivers the corresponding α-hydroxy esters in excellent yield [173]. Notably, nonsymmetric alkynes engage in highly regioselective reductive coupling (Scheme 2).

Scheme 2.

Iridium-catalyzed hydrogenation of alkynes in the presence of α-ketoesters to furnish α-hydroxy esters

Deuterium labeling studies are consistent with a mechanism involving alkyne–carbonyl oxidative coupling to furnish iridacycle A followed by Brønsted acid-assisted hydrogenolysis of this species to deliver the product. Deuterium at oxygen is removed through exchange in the course of chromatographic isolation but is observed via EI–MS analysis of reaction mixtures. Although mechanisms involving alkyne hydrometallation cannot be excluded on the basis of deuterium labeling studies alone, regioselectivity trends observed in response to variation of the steric features of both the alkyne and carbonyl partners strongly suggest that oxidative coupling pathways are operative (Scheme 3).

Scheme 3.

Alkyne-carbonyl reductive coupling via iridium-catalyzed hydrogenation under a deuterium atmosphere

Cationic rhodium complexes also catalyze alkyne–carbonyl and alkyne–imine reductive coupling under hydrogenation conditions [174–178]. The rhodium-catalyzed processes are applicable to the reductive coupling of conjugated alkynes (1,3-enynes, 1,3-diynes) to activated ketones [174], aldehydes [175–177], or imines [178]. The rhodium-catalyzed reductive coupling of acetylene to carbonyl compounds or imines also is described [179–182]. For reactions of conjugated alkynes, the observed trends in substrate scope suggest π-backbonding at the stage of the metal–alkyne complex facilitates alkyne-C=X (X=O, NR) oxidative coupling [183–185]. As rhodium is a relatively weak π-donor, conjugated alkynes and activated carbonyl and imine partners, which embody lower lying LUMOs, are required for oxidative coupling. Due to relativistic effects, iridium is a stronger π-donor than rhodium [186–189] and, therefore, can promote oxidative coupling of nonconjugated alkynes, which have higher lying LUMOs (Scheme 4).¹⁷

Scheme 4.

Significance of π-backbonding at the stage of the alkyne–metal complex

Regarding the role of the Brønsted acid cocatalyst, computational studies by Musashi and Sakaki suggest that carboxylic acid additives accelerate coupling by circumventing highly energetic four-centered transition structures for hydrogenolysis of metallacyclic intermediates A [195]. In the presence of carboxylic acid, protonolysis of oxa-iridacyclic intermediates A provide iridium carboxylates, which engage in hydrogenolysis through lower energy six-centered transition structures C. Protonolysis itself may occur through six-centered transition structures B. This interpretation is consistent with recently reported ESI–MS and DFT studies on the rhodium-catalyzed reductive coupling of acetylene to carbonyl and imine partners under hydrogenation conditions (Fig. 1) [182].

Fig. 1.

Carboxylic acid-assisted hydrogenolysis of oxa-iridacyclic intermediates that arise via alkyne–carbonyl oxidative coupling

Cationic iridium complexes modified by chiral phosphine ligands promote highly enantioselective alkyne–imine reductive coupling under hydrogenation conditions to furnish trisubstituted allylic amines as single geometrical isomers [196, 197]. Carboxylic acid cocatalysts are required to enforce high levels of conversion. Additionally, Na₂SO₄ facilitates coupling by serving as a desiccant, thus mitigating imine hydrolysis by adventitious water. A remarkable feature of these transformations involves high levels of contrasteric regioselectivity observed in reductive couplings of nonsymmetric alkynes (Scheme 5).

Scheme 5.

Enantioselective iridium-catalyzed hydrogenation of alkynes in the presence of N-arylsulfonyl imines to furnish trisubstituted allylic amines

As corroborated by deuterium labeling, the observed contrasteric regiocontrol appears to be a consequence of the oxidative coupling pathway. Specifically, formation of aza-iridacycle A via alkyne–imine oxidative coupling occurs such that nonbonded interactions between the large alkyne substituent and the sterically demanding iridium center are minimized. Carboxylic acid-assisted hydrogenolysis (via B and C) delivers the allylic amine. Formation of the iridacyclic intermediate A is the enantiodetermining event. Here, square planar iridium(I) binds the alkyne and imine at adjacent coordination sites. In accordance with the Dewar–Chatt–Duncanson model [183–185], the bound alkyne exhibits iridacyclopropene character (Alkyne complexation by iridium(I) results in substantial deviation from linearity, as revealed by single crystal X-ray diffraction analysis: (see footnote ¹⁷) [190–194]). Bidentate coordination of the N-arylsulfonyl imine to the iridium center is anticipated¹⁸ [198]. Insertion of the imine into the iridium–carbon bond of the iridacyclopropene then delivers the indicated aza-iridacyclopentene A. Minimization of nonbonded interactions between the N-arylsulfonyl group and the phenylphosphino moieties accounts for the observed sense of stereoinduction (Scheme 6).

Scheme 6.

Proposed mechanism for hydrogenative imine vinylation and proposed enantiodetermining transition states

2.2 Allenes as Allylmetal Surrogates via Hydrogenation

Enantioselective carbonyl allylation is one of the most broadly utilized transformations in synthetic organic chemistry (For reviews on enantioselective carbonyl allylation, see: [199–204]). Shortly after the first reports of carbonyl allylation employing isolable allylboron and allylsilicon reagents by Mikhailov and Bubnov [205] and Hosomi and Sakurai [206], respectively, enantioselective carbonyl allylations were reported by Hoffmann (see footnote ¹⁹, [207]). While the design of increasingly effective chiral allylmetal reagents continues¹⁹ 207–220], this approach only can be viewed as an interim solution as the use of stoichiometric chiral-inducing elements invariably leads to molar quantities of byproduct, diminishing prospects for large-volume applications (Fig. 2).

Fig. 2.

Selected examples of chiral allylmetal reagents for enantioselective carbonyl allylation

This limitation is addressed, in part, by the groundbreaking work of Yamamoto [221] and subsequent studies by Umani-Ronchi [222] and Keck [223] on chiral Lewis acid catalysts for enantioselective carbonyl allylation. Chiral Lewis base-catalyzed enantioselective carbonyl allylations soon followed, as reported by Denmark [224].²⁰ Although these methods avoid the stoichiometric use of chiral modifiers, they employ molar quantities of allylmetal reagent and, consequently, generate stoichiometric quantities of metallic byproducts. Furthermore, preparation of the allylmetal reagent itself is often beset by excessive waste production. For example, allylstannanes employed in the Umani-Ronchi–Keck process are prepared from the corresponding organomagnesium reagents, which, in turn, are prepared from the allylic halides [222, 223]. Thus, preactivation in the form of three stoichiometric operations is required in advance of C–C coupling (Scheme 7).

Scheme 7.

Preactivation often accompanies the use of stoichiometric organometallic reagents

The reductive generation of transient allylmetal species from allylic alcohols, allylic carboxylates,²¹,²² or allylic halides²³,²⁴ represents an approach to carbonyl allylation that avoids discrete allylmetal reagents. However, with a few exceptions, (see footnote ²¹, [235–238]) such processes require stoichiometric quantities of metallic reductants, such as SmI₂, SnCl₂, and Et₂Zn. Finally, the carbonyl–ene reaction enables carbonyl allylation in the absence of stoichiometric byproducts by employing simple olefins as allyl donors; however, enantioselective variants are limited to highly activated electrophiles, and general protocols remain a distant goal.²⁵,²⁶

Carbonyl allylation in the absence of metallic reagents is achieved under the conditions of iridium-catalyzed hydrogenation or transfer hydrogenation employing 1,2-dienes, 1,3-dienes, or allyl acetates as precursors to transient allylmetal species (see footnote ⁴, [16]). Here, hydrogen or isopropanol may serve as reductant. For transfer hydrogenative processes, isopropanol dehydrogenation drives reductive generation of allylmetal nucleophiles from unsaturates. Of greater significance is the fact that hydrogen exchange between reactant alcohols and π-unsaturated partners occurs to generate electrophile–nucleophile pairs en route to products of C–C coupling. In this way, carbonyl allylation is achieved directly from the alcohol oxidation level, availing a method for the hydro-hydroxyalkylation of unsaturates via functionalization of carbinol C–H bonds (Scheme 8) (see footnotes (⁷, ⁸, ⁹), [22–31]).

Scheme 8.

Carbonyl allylation via hydrogenation and transfer hydrogenation

Hydrogen-mediated carbonyl allylation was first demonstrated under the conditions of iridium-catalyzed hydrogenation in studies of allene–carbonyl reductive coupling [269]. Using a cationic iridium catalyst, hydrogenation of commercially available 1,1-dimethylallene in the presence of carbonyl electrophiles delivers products of carbonyl tert-prenylation as single regioisomers in good to excellent yield. Note that functional groups typically considered “hydrogen-labile,” such as aryl halides, benzylic ethers, alkenes, and nitroarenes, are tolerated under these conditions. Unlike conventional allylation protocols, all reactant atoms, including hydrogen, are incorporated into the product and so no stoichiometric byproducts are generated (Scheme 9).

Scheme 9.

Catalytic carbonyl addition via iridium-catalyzed hydrogenative coupling of dimethylallene

Reductive coupling of 1,1-dimethylallene and 5-nitro-2-furancarboxaldehyde under a deuterium atmosphere provides the product of tert-prenylation incorporating deuterium at the interior vinylic position (80% ²H). This result is consistent with a mechanism involving allene–aldehyde oxidative coupling. However, alternate pathways involving allene hydrometallation to furnish allyliridium species cannot be excluded on the basis of these data (Scheme 10).

Scheme 10.

Iridium-catalyzed reductive coupling of 1,1-dimethylallene to an aldehyde under an atmosphere of deuterium

3 Iridium-Catalyzed Transfer Hydrogenation for C–C Bond Formation

3.1 Allenes as Allylmetal Surrogates via Transfer Hydrogenation

Although carbonyl tert-prenylation occurs efficiently upon iridium-catalyzed hydrogenation of 1,1-dimethylallene in the presence of aldehydes, attempted crotylations and allylations employing methylallene or allene gas, respectively, suffer from competing conventional hydrogenation of the olefinic C–C coupling product. Corresponding iridium-catalyzed transfer hydrogenations overcome this limitation [270]. Under nearly identical conditions, by simply substituting isopropanol (200 mol%) for hydrogen as the terminal reductant, 1,1-dimethylallene reductively couples to aldehydes to furnish products of tert-prenylation in good to excellent yield across a broad range of substrates. Remarkably, it was found that alcohol reactants serve dually as reductants and aldehyde precursors, enabling formation of identical products. Thus, carbonyl addition occurs with equal facility from the aldehyde or alcohol oxidation levels. This chemistry is also applicable to carbonyl crotylation and allylation employing methylallene or allene gas, respectively. However, the volatility of these reagents contributes to diminished efficiencies (Scheme 11).

Scheme 11.

Carbonyl tert-prenylation, crotylation, and allylation from the aldehyde or alcohol oxidation level under the conditions or iridium-catalyzed transfer hydrogenation

The coupling of 1,1-dimethylallene to benzaldehyde employing d₈-isopropanol as reductant delivers the product of tert-prenylation, incorporating deuterium primarily at the internal vinylic position (85% ²H). Similar results are obtained when the reaction is conducted from the alcohol oxidation level employing d₂-benzyl alcohol. Further mechanistic insight comes from crossover experiments in which 1,1-dimethylallene is exposed to equimolar quantities of p-nitrobenzyl alcohol and benzaldehyde. The p-nitrophenyl- and phenyl-containing adducts are obtained in a 4:1 ratio, respectively. An identical product distribution is obtained upon exposure of 1,1-dimethylallene to equimolar quantities of p-nitrobenzaldehyde and benzyl alcohol under otherwise identical conditions. These data are consistent with fast and reversible alcohol dehydrogenation to form nonmetal-bound aldehyde in advance of C–C coupling (Scheme 12).

Scheme 12.

Isotopic labeling and crossover experiments in iridium-catalyzed couplings of 1,1-dimethylallene under transfer hydrogenation conditions

Highly enantioselective variants of these processes employ a cyclometallated iridium C,O-benzoate derived from allyl acetate, m-nitrobenzoic acid, and (S)-SEGPHOS [271, 272]. Using this complex as a precatalyst, transfer hydrogenation of 1,1-dimethylallene in the presence of diverse aldehydes mediated by isopropanol delivers products of tert-prenylation in good to excellent yield and with excellent levels of enantioselectivity. In the absence of isopropanol, enantioselective carbonyl reverse prenylation is achieved directly from the alcohol oxidation level to furnish an equivalent set of adducts. Notably, enantioselective tert-prenylation is achieved under mild conditions (30–50°C) in the absence of stoichiometric metallic reagents. Indeed, for reactions conducted from the alcohol oxidation level, stoichiometric byproducts are completely absent (Scheme 13).

Scheme 13.

Enantioselective carbonyl tert-prenylation from the alcohol or aldehyde oxidation level via iridium-catalyzed C–C bond-forming transfer hydrogenation

Our collective mechanistic studies are consistent with the indicated catalytic cycle. Notably, the catalyst engages primary alcohols in rapid and reversible dehydrogenation, yet the coupling products, which are homoallylic alcohols, are not subject to oxidation as coordination of the homoallylic olefin to the catalyst provides a hexa-coordinate 18-electron complex lacking an open coordination site for β-hydride elimination (Scheme 14).

Scheme 14.

Proposed catalytic mechanism for carbonyl tert-prenylation from the alcohol oxidation level via iridium-catalyzed C-C bond-forming transfer hydrogenation

3.2 Dienes as Allylmetal Surrogates via Transfer Hydrogenation

Under the conditions of iridium-catalyzed transfer hydrogenation employing isopropanol as reductant, 1,3-cyclohexadiene couples to aryl aldehydes to provide products of carbonyl cyclohexenylation in good to excellent yield and with high levels of diastereocontrol. Under nearly identical conditions, but in the absence of isopropanol, corresponding alcohols couple directly to 1,3-cyclohexadiene to furnish identical products of carbonyl cyclohexenylation (Scheme 15) [273].

Scheme 15.

Iridium-catalyzed couplings of 1,3-cyclohexadiene under transfer hydrogenation conditions (ratio refers to 1,4-olefinic versus 1,5-olefinic alcohols)

More recently, using the cyclometallated iridium C,O-benzoate derived from allyl acetate, 4-methoxy-3-nitrobenzoic acid and BIPHEP, catalytic carbonyl crotylation employing 1,3-butadiene from the aldehyde, or alcohol oxidation was achieved under transfer hydrogenation conditions [274]. Carbonyl addition occurs with roughly equal facility from the alcohol or aldehyde oxidation level. However, products are obtained as diastereomeric mixtures. Stereoselective variants of these processes are under development. It should be noted that under the conditions of ruthenium-catalyzed transfer hydrogenation, conjugated dienes, including butadiene, couple to alcohols or aldehydes to provide either products of carbonyl crotylation or β,γ-enones (Scheme 16) [275, 276].

Scheme 16.

Iridium-catalyzed C–C couplings of 1,3-butadiene under transfer hydrogenation conditions

3.3 Alkynes as Allylmetal Surrogates via Transfer Hydrogenation

As demonstrated in recent work by Obora and Ishii, alkynes serve as allyl donors in carbonyl allylations from the alcohol oxidation level [277]. Specifically, upon exposure to an iridium catalyst generated in situ from [Ir(OH)(cod)]₂ and P(n-Oct)₃, 1-aryl-2-methylalkynes couple to primary alcohols to furnish homoallylic alcohols with complete branched regioselectivity and excellent levels of diastereoselectivity (Scheme 17).

Scheme 17.

Carbonyl arylallylation from the alcohol oxidation level via iridium-catalyzed transfer hydrogenation employing alkynes as allyl donors

For alkyne-mediated allylation, alcohol dehydrogenation generates an iridium hydride that hydrometallates the alkyne to form a vinylmetal species, which, in turn, isomerizes to generate the primary σ-allyliridium intermediate. Carbonyl addition through a closed six-centered transition state accounts for the observed anti-diastereoselectivity (Scheme 18). Interestingly, under the conditions of ruthenium-catalyzed transfer hydrogenation, alkynes couple to alcohols or aldehydes to provide products of carbonyl vinylation [278]. Here, isomerization of the vinyl-ruthenium intermediate to the σ-allylruthenium intermediate is not observed.

Scheme 18.

Plausible stereochemical model for anti-diastereoselective iridium-catalyzed allylation of alcohols employing alkynes as allyl donors

3.4 Allylic Acetates as Allylmetal Surrogates via Transfer Hydrogenation

Using allyl acetate as the allyl donor, enantioselective variants of the parent carbonyl allylation process are achieved under the conditions of iridium-catalyzed transfer hydrogenation employing the cyclometallated iridium C,O-benzoate derived from allyl acetate, 3-nitrobenzoic acid, and a chiral bis-phosphine ligand, which is generated in situ [279, 280]. Allyl acetate couples to diverse alcohols to furnish products of carbonyl allylation with exceptional levels of enantioselectivity. Identical products of carbonyl allylation are produced from the corresponding aldehydes upon use of isopropanol as terminal reductant. Thus, enantioselective carbonyl allylation is achieved from the alcohol or aldehyde oxidation level in the absence of metallic reagents or metallic reductants. The reactivity embodied by these processes is remarkable in light of the fact that iridium-catalyzed allylic substitution (O-allylation) employing alcohol nucleophiles is a well-established mode of reactivity (Scheme 19) [281–283].²⁷

Scheme 19.

Enantioselective carbonyl allylation from the alcohol or aldehyde oxidation level via iridium-catalyzed C–C bond-forming transfer hydrogenation

The results of deuterium labeling are consistent with intervention of a symmetric iridium π-allyl intermediate or rapid interconversion of σ-allyl haptomers through the agency of a symmetric π-allyl (Scheme 20) [280]. Competition experiments akin to those previously described (see Scheme 12) again demonstrate rapid and reversible dehydrogenation of the carbonyl partner in advance of C–C coupling.

Scheme 20.

Carbonyl allylation from the alcohol oxidation level employing isotopically labeled allyl acetate [R = p-(CO₂Me)C₆H₄]

The BINAP derivative of the ortho-cyclometallated iridium catalyst has been characterized by single crystal X-ray diffraction analysis [280]. Remarkably, although the reaction sequence depends upon oxidation of either the reactant alcohol or isopropanol, the enantiomeric purity of the homoallylic alcohol product is not subject to erosion through reversible dehydrogenation as the pendant alkene of the product prevents dehydrogenation by occupying the single remaining vacant coordination site on iridium, as required for β-hydride elimination (Scheme 21).

Scheme 21.

Proposed catalytic mechanism for carbonyl allylation from the alcohol oxidation level via iridium-catalyzed C–C bond-forming transfer hydrogenation

A model accounting for the observed sense of absolute stereoinduction is based upon the coordination mode revealed in the crystal structure of the cyclometallated C,O-benzoate complex [280]. It is postulated that aldehyde binding by the σ-allyl haptomer occurs such that the allyl moiety is placed between the naphthyl and phenyl moieties of the ligand, allowing the aldehyde to reside in a more open environment. In the favored mode of addition, the aldehyde C–H bond projects into the π-face of a phenyl moiety of the ligand, potentially resulting in a weakly attractive aldehyde C–H–π interaction. The disfavored mode of addition requires the aldehyde substituent to project into the π-face of the ligand phenyl moiety, resulting in a severe nonbonded interaction (Fig. 3).

Fig. 3.

Proposed stereochemical model accounting for the observed sense of absolute stereoinduction (chiral ligand = (S)-Cl,MeO-BIPHEP)

Direct asymmetric carbonyl allylation from the alcohol oxidation level potentially streamlines synthesis by circumventing discrete alcohol oxidation as well as enabling carbonyl allylation processes that are unattainable using conventional allylmetal reagents. For example, two-directional chain elongation via double allylation of 1,3-dialdehydes has not been achieved due to the instability of the requisite 1,3-dicarbonyl precursors (For a review on two-directional chain synthesis, see: [285]). However, propane-1,3-diol and related glycols are highly tractable and participate in bidirectional allylation via sequential generation and capture of transient monoaldehydes to provide C₂-symmetric adducts in good yield [286]. In these processes, the minor enantiomer of the monoallylated intermediate is transformed to the meso-stereoisomer of the product, thus amplifying the level of enantiomeric enrichment (Scheme 22) (This mechanism for enantiomeric enrichment is documented by Eliel and Midland: [287, 288]).

Scheme 22.

1,n-Glycols as dialdehyde equivalents in iridium-catalyzed enantioselective carbonyl allylation from the alcohol oxidation level

Iterative two-directional chain elongation enables rapid construction of 1,3-polyols (Scheme 23). For example, the polyol substructure that appears in the oxopolyene macrolide (+)-roxaticin is available in nine steps from propane-1,3-diol upon three iterations of double carbonyl allylation [286]. Notably, high levels of catalyst-directed stereoselectivity are observed (For selected examples of catalyst directed diastereoselectivity, see: [289–296]). Analogous 1,3-polyol syntheses via iterative homologation in one direction also are reported [297].

Scheme 23.

Synthesis of the 1,3-polyol substructure of the polyene macrolide (+)-roxaticin

This carbonyl allylation strategy is extended to crotylation through the use of α-methyl allyl acetate as a crotylmetal surrogate [298]. Here, after screening several ortho-cyclometallated C,O-benzoates, the iridium complex derived from 4-cyano-3-nitrobenzoic acid and (S)-SEGPHOS [272] was found to provide good levels of anti-diastereoselectivity accompanied by uniformly high levels of enantioselectivity across a broad range of substrates. Notably, complete branch-regioselectivity is observed in all cases. The observed regio- and anti-diastereoselectivity suggest that aldehyde addition occurs from the primary (E)-σ-allyliridium haptomer. As before, carbonyl crotylation is achieved with equal facility from the aldehyde or alcohol oxidation level (Scheme 24).

Scheme 24.

Enantioselective carbonyl crotylation from the alcohol or aldehyde oxidation level via iridium-catalyzed C–C bond-forming transfer hydrogenation

Allylic gem-dibenzoates derived from acrolein serve as (alkoxy)allylmetal surrogates under the conditions of iridium-catalyzed transfer hydrogenation [299]. In this case, generation of the catalytic complex in situ failed to provide the desired products in good yield, requiring use of the isolated complex prepared from [Ir(cod) Cl]₂, 4-cyano-3-nitrobenzoic acid, allyl acetate, and the chiral phosphine ligand (R)-SEGPHOS [272]. To achieve high levels of anti-diastereoselectivity, efficient partitioning of transient (E)- and (Z)-σ-allyliridium intermediates is required. It was found that the allylic gem-dibenzoate derived from acrolein is unique in its ability to combine high levels of anti-diastereoselectivity and favorable reactivity. Under the reported conditions, iridium-catalyzed aldehyde anti-(hydroxy)allylation occurs under transfer hydrogenation conditions to provide anti-1-ene-3,4-diols with excellent relative and absolute stereocontrol. Corresponding carbonyl additions from the alcohol oxidation level are currently under development (Scheme 25).

Scheme 25.

Diastereo- and enantioselective anti-(hydroxy)allylation employing allylic gem-dicarboxylates as allyl donors via iridium-catalyzed transfer hydrogenation

New catalytic allylation methodologies continue to emerge. For example, iridium-catalyzed transfer hydrogenation of α-(trimethylsilyl)allyl acetate in the presence of aldehydes mediated by isopropanol and employing the iridium catalyst modified by (R)-SEGPHOS [272] delivers products of (trimethylsilyl)allylation in good isolated yields and with exceptional levels of anti-diastereo and enantiocontrol [300]. In the absence of isopropanol, carbonyl (trimethylsilyl)allylation is achieved directly from the alcohol oxidation level to furnish an equivalent set of adducts (Scheme 26, top). Similarly, using the enantiomeric iridium complex, the indicated cyclic carbonate engages in carbonyl (hydroxymethyl)allylation from the alcohol or aldehyde oxidation level with good anti-diastereoselectivities and exceptional levels of enantiocontrol [301]. Notably, stereoselective (hydroxymethyl) allylation protocols employing conventional allylmetal reagents are unknown (Scheme 26, bottom).²⁸,²⁹,³⁰

Scheme 26.

Enantioselective carbonyl (trimethylsilyl)allylation and (hydroxymethyl)allylation from the alcohol or aldehyde oxidation level via iridium-catalyzed C–C bond-forming transfer hydrogenation

Enantioselective ketone addition is one of the many challenging extensions in scope that remains. In a preliminary step toward this goal, the allylation, crotylation, and tert-prenylation of substituted isatins was examined using the cyclometallated iridium C,O-benzoate generated in situ from [Ir(cod)Cl]₂, 4-chloro-3-nitrobenzoic acid and CTH-(R)-P-PHOS [309]. Isopropanol-mediated transfer hydrogenation of allyl acetate, α-methyl allyl acetate or 1,1,-dimethylallene as allyl donors, in the presence of the substituted isatins delivered the anticipated products of allylation, crotylation, and tert-prenylation, respectively, in highly enantiomerically enriched form. Notably, highly enantioselective allylation, crotylation, and reverse prenylation of isatins employing conventional allylmetal reagents have not been reported (Scheme 27) (For enantioselective catalytic allylation of isatins, see: [310]).

Scheme 27.

Enantioselective allylation, crotylation, and tert-prenylation of substituted isatins via iridium-catalyzed transfer hydrogenation

4 Conclusion

Organic molecules are defined as compounds of carbon and hydrogen. Hence, the formation of C–C bonds under the conditions catalytic hydrogenation and transfer hydrogenation is a natural endpoint in the evolution of strategies for the synthesis of organic molecules. The use of unsaturates as surrogates to premetallated nucleophiles under hydrogenation conditions represents a departure from the use of stoichiometric organometallic reagents in carbonyl and imine addition that circumvents generation of stoichiometric byproducts. This concept is extended further via C–C bond-forming transfer hydrogenation – processes in which alcohol reactants serve dually as hydrogen donors and carbonyl precursors, enabling carbonyl addition directly from the alcohol oxidation level in the absence of stoichiometric byproducts and premetallated nucleophiles.

As highlighted in this review, iridium complexes are especially versatile catalysts for C–C bond-forming hydrogenation and transfer hydrogenation. And now, based on these studies, many aspirational transformations are placed within reach (Scheme 28). However, to fully realize the potential of hydrogen-mediated C–C coupling, alternate metal catalysts should be developed and applied to processes beyond those described herein. This challenge will ultimately evoke catalytic methods for the sustainable manufacture of pharmaceutical ingredients, bulk chemicals, and fuels from renewable feedstocks.

Scheme 28.

Examples of two aspirational processes: byproduct-free couplings of α-olefins to (renewable) alcohols and amines with linear or branch regiocontrol