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).     

Ruthenium-catalyzed C-C bond forming transfer hydrogenation: carbonyl allylation from the alcohol or aldehyde oxidation level employing acyclic 1,3-dienes as surrogates to preformed allyl metal reagents

Under the conditions of ruthenium-catalyzed transfer hydrogenation, commercially available acyclic 1,3-dienes, butadiene, isoprene, and 2,3-dimethylbutadiene, couple to benzylic alcohols 1a-6a to furnish products of carbonyl crotylation 1b-6b, carbonyl isoprenylation 1c-6c, and carbonyl reverse 2-methyl prenylation 1d-6d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, isoprene couples to aldehydes 7a-9a to furnish identical products of carbonyl isoprenylation 1c-3c. Thus, carbonyl allylation is achieved from the alcohol or the aldehyde oxidation level in the absence of preformed allyl metal reagents. Coupling to aliphatic alcohols (isoprene to 1-nonanol, 65% isolated yield) and allylic alcohols (isoprene to geraniol, 75% isolated yield) also is demonstrated. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).     

Diene hydroacylation from the alcohol or aldehyde oxidation level via ruthenium-catalyzed C-C bond-forming transfer hydrogenation: synthesis of beta,gamma-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.     

Branch-selective reductive coupling of 2-vinyl pyridines and imines via rhodium catalyzed C-C bond forming hydrogenation

Hydrogenation of 2-vinyl azines 1a-1e in the presence of N-arylsulfonyl imines 2a-2l at ambient temperature and pressure employing cationic rhodium catalysts ligated by tri-2-furylphosphine results in regioselective reductive coupling to furnish branched products of imine addition 3a-3v, which embody modest to high levels of syn-diastereoselectivity. Catalytic coupling of 6-bromo-2-vinylpyridine 1a to imine 2l under an atmosphere of elemental deuterium provides deuterio-3l, with deuterium exclusively at the former beta-position of the vinyl moiety. These data are consistent with a catalytic mechanism involving oxidative coupling of the vinyl azine and imine partners to furnish a cationic aza-rhodacyclopentane, which upon deuteriolytic cleavage releases the adduct and regenerates cationic rhodium(I) to close the catalytic cycle. These studies represent the first metal catalyzed reductive C-C couplings of vinyl azines.     

Ruthenium catalyzed C-C bond formation via transfer hydrogenation: branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes

Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes 1a- h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohols 2a- h. Under identical transfer hydrogenation conditions, 1,1-disubstituted allenes engage in reductive coupling to aldehydes 3a- f to furnish homoallylic alcohols 4a- n. In all cases, reductive coupling occurs with branched regioselectivity to deliver homoallylic alcohols bearing all-carbon quaternary centers.     

Alkynylation of benzonitriles via nickel catalyzed C-C bond activation

The scope of synthetically useful nickel catalyzed cross coupling reactions of benzonitriles has now been expanded to allow alkynylation. Thus, the cross coupling of benzonitriles with alkynylzinc reagents occurs readily in the presence of Ni/PMe₃ based catalysts to afford the respective aryl alkynes in high yields.     

New C2-symmetrical ferrocenyl diamines as ligands for ruthenium catalyzed transfer hydrogenation

The new C₂-symmetrical ferrocenyl diamines 5–7 and 13 proved to be good ligands for the ruthenium catalyzed enantioselective transfer hydrogenation of unsymmetrical ketones. The stereocontrolled and highly flexible synthetic route to the new diamines made it possible to vary the ligand structure in an efficient manner. A short trial and error process led to a very active catalytic system with diamine 6a as the ligand, which is capable of reducing ketones even at −30°C using 2-propanol as a hydrogen source. Enantioselectivities up to 90% were reached in the reduction of 1′-acetonaphthone.     

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.     

Total synthesis of (+)-roxaticin via C-C bond forming transfer hydrogenation: a departure from stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles in polyketide construction

A total synthesis of the oxo-polyene macrolide (+)-roxaticin is achieved in 20 steps from 1,3-propanediol. In this approach, 9 of 10 C-C bonds formed in the longest linear sequence are made via metal catalysis, including 7 C-C bonds formed by iridium catalyzed alcohol C-C coupling. Notably, the present synthesis, which represents the most concise preparation of any oxo-polyene macrolide reported to date, is achieved in the absence of chiral reagents and chiral auxiliaries with minimal use of premetalated C-nucleophiles.     

Binuclear ruthenium(II) pyridazine complex catalyzed transfer hydrogenation of ketones

A convenient and general method of synthesis of binuclear ruthenium(II) pyridazine complex was reported. The synthesized complex was characterized by analytical and spectral methods. The structure of the complex was confirmed by X-ray diffraction technique and was found to be an efficient catalyst for the transfer hydrogenation of ketones with excellent conversions in the presence of isopropanol/KOH at 82 °C. The effect of solvents, bases, and different catalyst/substrate ratio for the reaction was also investigated.     

Efficient asymmetric transfer hydrogenation of activated olefins catalyzed by ruthenium amido complexes

The asymmetric transfer hydrogenation of activated olefins with chiral ruthenium amido complexes (Noyori catalyst) using formic acid-triethylamine azeotrope as hydrogen source resulted in excellent yields and high enantioselectivities (up to 88.5%).     

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.     

Recyclable gold nanoparticle catalyst for the aerobic alcohol oxidation and C-C bond forming reaction between primary alcohols and ketones under ambient conditions

A recyclable gold catalyst is synthesized from readily available reagents by immobilizing gold nanoparticles in aluminum oxyhydroxide support through a simple sol-gel method. The catalyst showed the high activity even at room temperature in the aerobic oxidation of various alcohols and in the coupling reaction between primary alcohols and ketones.     

Transfer hydrogenation via generation of hydride intermediate and base-free alcohol oxidation activity studies on designed ruthenium complexes derived from NNN pincer type ligands

Ruthenium complexes( 1 – 3 ) have been synthesized using pincer-type ligands L¹ = (E)-2-((2-phenyl-2-(pyridin-2-yl)hydrazono)methyl)pyridine, L² = (E)-2-(1-phenyl-2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)pyridine, L³ = (E)-2-(phenyl(2-phenyl-2-(pyridin-2-yl)hydrazono) methyl)pyridine. The molecular structures of all the complexes 1 , 2 and 3 were determined by using single crystal X-ray diffraction. These complexes showed excellent catalytic activities such as transfer hydrogenation and alcohol oxidation. Theoretical calculations have been performed to understand the electronic properties of all the complexes using B3LYP as a function and LANL2DZ as a basis set.     

Hydrogen-mediated reductive coupling of conjugated alkynes with ethyl (N-Sulfinyl)iminoacetates: synthesis of unnatural alpha-amino acids via rhodium-catalyzed C-C bond forming hydrogenation

Rhodium-catalyzed hydrogenation of 1,3-enynes 1a-8a and 1,3-diynes 9a-13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated alpha-amino acid esters 1b-13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing alpha-amino acid esters 1b-8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the beta,gamma-unsaturated alpha-amino acid esters 1c-8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b-16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the alpha-amino acid esters 14d-16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon-carbon bond formation.