Michael J. Krische

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

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.

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.

Enantioselective C-H Crotylation of Primary Alcohols via Hydrohydroxyalkylation of Butadiene

Bonded at the Source Asymmetric catalysis is a relatively mature field in the laboratory, with a diverse array of techniques available for the selective transformation of organic compounds. However, scaling up these techniques for industrial application remains challenging, in part because many catalysts act best on reagents that have been expensively modified, although this process often generates copious waste. Zbieg et al. (p. 324, published online 22 March) combat this challenge with a ruthenium-based catalyst that couples an unmodified bulk commodity feedstock (butadiene) with alcohols, forming carbon-carbon bonds to generate complex products with high selectivity. A catalyst facilitates complex carbon-carbon bond formation using a bulk commodity feedstock compound. The direct, by-product–free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 × 106 metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products.

Enantioselective Iridium Catalyzed Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level via Transfer Hydrogenative Coupling of Allyl Acetate: Departure from Chirally Modified Allyl Metal Reagents in Carbonyl Addition

Under the conditions of transfer hydrogenation employing an iridium catalyst generated in situ from [Ir(cod)Cl]2, chiral phosphine ligand (R)-BINAP or (R)-Cl,MeO-BIPHEP, and m-nitrobenzoic acid, allyl acetate couples to allylic alcohols 1a-c, aliphatic alcohols 1d-l, and benzylic alcohols 1m-u to furnish products of carbonyl allylation 3a-u with exceptional levels of asymmetric induction. The very same set of optically enriched carbonyl allylation products 3a-u are accessible from enals 2a-c, aliphatic aldehydes 2d-l, and aryl aldehydes 2m-u, using iridium catalysts ligated by (-)-TMBTP or (R)-Cl,MeO-BIPHEP under identical conditions, but employing isopropanol as a hydrogen donor. A catalytically active cyclometallated complex V, which arises upon ortho-C-H insertion of iridium onto m-nitrobenzoic acid, was characterized by single-crystal X-ray diffraction. The results of isotopic labeling are consistent with intervention of symmetric iridium pi-allyl intermediates or rapid interconversion of sigma-allyl haptomers through the agency of a symmetric pi-allyl. Competition experiments demonstrate rapid and reversible hydrogenation-dehydrogenation of the carbonyl partner in advance of C-C coupling. However, the coupling products, which are homoallylic alcohols, experience very little erosion of optical purity by way of redox equilibration under the coupling conditions, although isopropanol, a secondary alcohol, may serve as terminal reductant. A plausible catalytic mechanism accounting for these observations is proposed, along with a stereochemical model that accounts for the observed sense of absolute stereoinduction. This protocol for asymmetric carbonyl allylation transcends the barriers imposed by oxidation level and the use of preformed allyl metal reagents.

Catalytic enantioselective C-H functionalization of alcohols by redox-triggered carbonyl addition: borrowing hydrogen, returning carbon.

The use of alcohols and unsaturated reactants for the redox-triggered generation of nucleophile-electrophile pairs represents a broad, new approach to carbonyl addition chemistry. Discrete redox manipulations that are often required for the generation of carbonyl electrophiles and premetalated carbon-centered nucleophiles are thus avoided. Based on this concept, a broad, new family of enantioselective C-C coupling reactions that are catalyzed by iridium or ruthenium complexes have been developed, which are summarized in this Minireview.

Enantioselective Iridium-Catalyzed Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level Using Allyl Acetate as an Allyl Metal Surrogate

Protocols for highly enantioselective carbonyl allylation from the alcohol or aldehyde oxidation level are described based upon transfer hydrogenative C-C coupling. Exposure of allyl acetate to benzylic alcohols 1a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (R)-BINAP delivers products of C-allylation 2a-i. Employing isopropanol as terminal reductant, exposure of allyl acetate to aryl aldehydes 3a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (-)-TMBTP delivers identical products of C-allylation 2a-i. In all cases examined, exception levels of enantioselectivity are observed. Thus, enantioselective carbonyl allylation is achieved from the alcohol or aldehyde oxidation level in the absence of any preformed allylmetal reagents. These studies define a departure from preformed organometallic reagents in carbonyl additions that transcend the boundaries of oxidation level.

Diene Hydroacylation from the Alcohol or Aldehyde Oxidation Level via Ruthenium-Catalyzed C−C Bond-Forming Transfer Hydrogenation: Synthesis of β,γ-Unsaturated Ketones

Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a-g to deliver beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form beta,gamma-unsaturated ketones. In all cases, complete branch regioselectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product (homoallyl alcohol or beta,gamma-unsaturated ketone) are accessible.

The Utilization of Persistent H-Bonding Motifs in the Self-Assembly of Supramolecular Architectures

The present account describes some selected examples of the generation of supramolecular architectures by recognition-directed self-assembly of components containing complementary arrays of hydrogen-bonding sites. Specific groups yield one-, two- or three-dimensional motifs. Supramolecular materials such as polymeric arrays and liquid crystals may be obtained.

Enantioselective allylation, crotylation, and reverse prenylation of substituted isatins: iridium-catalyzed C-C bond-forming transfer hydrogenation.

3-Substituted-3-hydroxy-oxindoles appear as substructures within a fascinating array of natural products, including the convulutamydines,[1a,b] maremycins,[1c,d] donaxaridines,[1e,f] dioxibrassinins,[1g,h,i] celogentin K,[1j] hydroxyglucoisatisins[1k] and TMC-95A–D (Figure 1).[1l] While catalytic asymmetric additions to isatins are known,[2–6] highly enantioselective catalytic allylation, crotylation and reverse prenylation of isatins has remained elusive. In the course developing hydrogen-mediated C-C couplings beyond hydroformylation,[7–15] chiral ortho-cyclometallated iridium C,O-benzoates were found to catalyze highly enantioselective carbonyl allylation,[14a,b] crotylation[14c] and reverse prenylation[12d] under transfer hydrogenation conditions. In contrast to classical allylation procedures that employ stoichiometric organometallic reagents,[16] transfer hydrogenation protocols exploit allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respectively.[12,14a–c] To further evaluate the scope of this emergent methodology, catalytic enantioselective additions to ketones were explored.[17,18] In this account, we report that activated ketones in the form of substituted isatins are subject to highly enantioselective carbonyl allylation, crotylation and reverse prenylation, constituting a convenient synthesis of optically enriched 3-substituted-3-hydroxy-oxindoles. Figure 1 Examples of naturally occurring 3-substituted-3-hydroxy-oxindoles. Our initial studies focused on the asymmetric allylation of N-benzyl isatin 1a. Using the cyclometallated C,O-benzoate generated in situ from [Ir(cod)Cl]2, BIPHEP and 4-chloro-3-nitrobenzoic acid,[14b] the coupling of allyl acetate (1000 mol%) to 1a at 100 °C in THF (0.2 M) delivered the tertiary homoallyl alcohol 2a in 42% isolated yield. Under otherwise identical conditions, but with a lower loading of allyl acetate (200 mol%) and optimization of reaction temperature, reaction time, and concentration, the isolated yield of homoallyl alcohol 2a was increased to 77%. An assay of chelating chiral phosphine ligands was undertaken, which revealed dramatic enhancement in the level of asymmetric induction at lower reaction temperatures. However, lower temperatures also diminished conversion. This impasse was resolved by increasing the loading of isopropanol from 200 mol% to 400 mol%, which enabled conversion of N-benzyl isatin 1a to homoallyl alcohol 2a in 73% isolated yield and 91% enantiomeric excess using CTH-(R)-P-PHOS as ligand. Notably, under analogous conditions employing our initially disclosed iridium catalyst modified by 3-nitrobenzoic acid,[14a,b] 2a is obtained in 61% isolated yield and 90% enantiomeric excess. These data further illustrate how catalyst performance is enhanced through structural variation of the C,O-benzoate moiety. Data pertaining to the optimization of the catalytic enantioselective allylation of N-benzyl isatin 1a is tabulated in the supporting information. Optimal conditions identified for the conversion of N-benzyl isatin 1a to the hydroxy-oxindole 2a were applied to substituted isatins 1a–1g (Table 1). To our delight, the products of ketone allylation 2a–2g were produced in moderate to excellent isolated yield (65–92% yield) with uniformly high levels of optical enrichment (91–96% ee). The absolute stereochemical assignment of adducts 2a–2g are based upon that determined for the 5-bromo-dervative 2b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Table 1 Catalytic enantioselective allylation N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. Given these favorable results, the crotylation of substituted isatins 1a–1g was attempted under identical conditions employing α-methyl allyl acetate as the crotyl donor (Table 2). The products of ketone crotylation 3a–3g were produced in moderate to excellent isolated yield (64–87% yield) with moderate to excellent levels of optical enrichment (80–92% ee). In general, crotylation required longer reaction times (Table 2, entries 1, 2, 5–7). Additionally, it was found that lower loadings of Cs2CO3 increased conversion in certain cases. The absolute stereochemical assignment of adducts 3a–3g are based upon that determined for the 5-bromo-dervative 3b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Table 2 Catalytic enantioselective crotylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. Finally, the reverse prenylation of substituted isatins 1a–1g was attempted (Table 3). To our delight, adducts 4a–4g were generated in uniformly high isolated yields (70–90% yield) and levels of optical enrichment (90–96 % ee) under mild conditions. Notably, this transformation enables creation of two contiguous quaternary carbon centers. The absolute stereochemical assignment of adducts 4a–4g are based upon that determined for the 5-bromo-dervative 4b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Here, the enantiofacial selectivity of carbonyl addition is opposite to that observed in the case of allylation and crotylation. Table 3 Catalytic enantioselective prenylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. The inversion in absolute stereochemistry observed in isatin reverse prenylation merits further explanation. The catalytic mechanism for carbonyl prenylation employing 1,1-dimethylallene is analogous to that previously reported for corresponding allylations and crotylations (Scheme 1, left).14b,c Assuming isatin crotylation occurs through a chair-like transition structure and an (E)-σ-crotyl iridium intermediate, previously proposed absolute stereochemical models agrees with the observed π-facial selectivity with respect to the crotyl partner.14c The latter observation suggests that isatin crotylation occurs by way of transition structure A, whereas isatin prenylation occurs by way of transition structures B. The basis of this partitioning may arise from non-bonded interactions of the axial methyl group of the σ-prenyl iridium intermediate with the amide π-bond of isatin, which is presumably more destabilizing than non-bonded interactions of the axial methyl group with the electron-deficient rim of the arene (Scheme 1, right). Scheme 1 A simplified catalytic mechanism depicting isatin prenylation via transfer hydrogenation (left) and a plausible stereochemical model accounting for the observed inversion in absolute stereochemistry in the prenylation of isatins (right).a In summary, we report the first enantioselective allylations, crotylations and prenylations of isatin, which are achieved via isopropanol-mediated transfer hydrogenation. Unlike conventional allylation methodologies that employ stoichiometric quantities of allylmetal reagents, the present method exploits allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respetively.[12,14a–c] To our knowledge, these studies represent the first examples of catalytic enantioselective ketone allylation, crotylation and prenylation in the absence of stoichiometric allylmetal reagents. Future studies will focus on the development of related C-C bond forming transfer hydrogenations and synthetic applications of the methods reported herein.

Iridium-catalysed direct C–C coupling of methanol and allenes

Methanol is an abundant (35 million metric tons per year), renewable chemical feedstock, yet its use as a one-carbon building block in fine chemical synthesis is highly underdeveloped. Using a homogeneous iridium catalyst developed in our laboratory, methanol engages in a direct C–C coupling with allenes to furnish higher alcohols that incorporate all-carbon quaternary centres, free of stoichiometric by-products. A catalytic mechanism that involves turnover-limiting methanol oxidation, a consequence of the high energetic demand of methanol dehydrogenation, is corroborated through a series of competition kinetics experiments. This process represents the first catalytic C–C coupling of methanol to provide discrete products of hydrohydroxymethylation. Methanol is an abundant, renewable chemical feedstock. Here, a homogenous iridium catalyst enables a byproduct-free C–C coupling of methanol and allenes, producing higher alcohols that incorporate all-carbon quaternary centres. This process represents the first catalytic C–C coupling of methanol to provide discrete products of hydrohydroxymethylation.