Ruthenium-Catalyzed Transfer Hydrogenation for C-C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs

Abstract

Merging the chemistry of transfer hydrogenation and carbonyl or imine addition, a broad new family of redox-neutral or reductive hydrohydroxyalkylations and hydroaminomethylations have been developed. In these processes, hydrogen redistribution between alcohols and π-unsaturated reactants is accompanied by C-C bond formation, enabling direct conversion of lower alcohols to higher alcohols. Similarly, hydrogen redistribution between amines to π-unsaturated reactants results in direct conversion of lower amines to higher amines. Alternatively, equivalent products of hydrohydroxyalkylation and hydroaminomethylation may be generated through the reaction of carbonyl compounds or imines with π-unsaturated reactants under the conditions of 2-propanol-mediated reductive coupling. Finally, using vicinally dioxygenated reactants, that is, diol, ketols, or diones, successive transfer hydrogenative coupling occurs to generate 2 C-C bonds, resulting in products of formal [4+2] cycloaddition.

Keywords: Borrowing Hydrogen; C-C Bond Formation; Enantioselective; Ruthenium; Transfer Hydrogenation.

Scheme 1

Selected milestones in homogeneous ruthenium catalyzed hydrogenation and transfer hydrogenation.^{a a}BINAP = 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene. TsDPEN = N-p-Tosyl-1,2-diphenylethylenediamine.

Scheme 2

Ruthenium catalyzed C-C coupling of primary alcohols with 1,3-dienes to form homoallylic alcohols or β,γ-enones.^a Yields are of material isolated by flash chromatography on silica gel. ^aLigand = (p-MeOPh)₃P, ^bLigand = rac-BINAP, 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene. ^c120 °C.

Scheme 3

Diastereo- and enantioselective alcohol mediated hydrohydroxyalkylation of butadienes.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. DM-SEGPHOS = 5,5′−bis-[di(3,5-xylyl)phosphino]-4,4′-bi-1,3-benzodioxole. dppf = 1,1-bis-(diphenylphosphino)ferrocene. SEGPHOS = 5,5′-bis-(diphenylphosphino)-4,4′-bi-1,3-benzodioxole

Scheme 4

Divergent regioselectivity in 2-propanol mediated reductive couplings of dienes with paraformaldehyde and redox neutral couplings of ethanol.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. dppb = bis-(diphenylphosphino)butane.

Scheme 5

Divergent regioselectivity in the hydrohydroxyalkylation of 2-substituted dienes.

Scheme 6

Alcohol-mediated hydrohydroxyalkylation of allenes.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. dippf = bis-(diisopropylphosphino)ferrocene

Scheme 7

Alkynes as latent allenes in alcohol-mediated hydrohydroxyalkylation to form linear or branched homoallylic alcohols.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. SL-J009-1 = (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. Ar = 2,4,6-triisopropylphenyl.

Scheme 8

anti-Diastereo- and enantioselective siloxy-crotylation in the transfer hydrogenative coupling of primary alcohols with alkynes via hydride-shift enabled π-allyl formation.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. SL-J009-1 = (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine.

Scheme 9

Transfer hydrogenative couplings of 2-butyne to form allylic alcohols and conjugated enones.^{a a}Yields are of material isolated by flash chromatography on silica gel.

Scheme 10

Carbonyl propargylation via 1,3-enyne hydrohydroxyalkylation.^{a a}Yields are of material isolated by flash chromatography on silica gel. Diastereoselectivity was determined through ¹H NMR analysis of crude reaction mixtures. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. dppb = bis-(diphenylphosphino)butane. dppf = 1,1-bis-(diphenylphosphino)ferrocene. BINAP = 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene.

Scheme 11

Conversion of secondary to tertiary alcohols via ruthenium(0) catalyzed C-C bond forming transfer hydrogenation with conjugated dienes.^{a a}Yields are of material isolated by flash chromatography on silica gel. PCy₃ = tricyclohexylphosphine.

Scheme 12

Ruthenium(0) catalyzed C-C coupling of diols with alkynes via transfer hydrogenation.^{a a}Yields are of material isolated by flash chromatography on silica gel. C₁₀H₁₅CO₂H = 1-adamantanecarboxylic acid. PCy₃ = tricyclohexylphosphine.

Scheme 13

Ruthenium(0) catalyzed C-C coupling of diols with α-olefins via transfer hydrogenation.^{a a}Yields are of material isolated by flash chromatography on silica gel. C₁₀H₁₅CO₂H = 1-adamantanecarboxylic acid. PCy₃ = tricyclohexylphosphine.

Scheme 14

Ruthenium(0) catalyzed C-C coupling of acrylic esters with diols and α-hydroxycarbonyl compounds via transfer hydrogenation.^{a a}Yields are of material isolated by flash chromatography on silica gel. C₁₀H₁₅CO₂H = 1-adamantanecarboxylic acid. dppp = bis-(diphenylphosphino)propane.

Scheme 15

Redox level-independent cycloaddition to form a γ-lactone.^{a a}Yields are of material isolated by flash chromatography on silica gel. C₁₀H₁₅CO₂H = 1-adamantanecarboxylic acid. dppp = bis-(diphenylphosphino)propane.

Scheme 16

Transfer hydrogenative diene-diol [4+2] cycloaddition.^{a a}Yields are of material isolated by flash chromatography on silica gel. dppp = bis-(diphenylphosphino)propane. BINAP = 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene. dppPh = bis-(1,2-diphenylphosphino)benzene.

Scheme 17

Transfer hydrogenative cycloaddition of α-ketols with benzannulated 1,5-diynes or ortho-acetylenic benzaldehydes.^{a a}Yields are of material isolated by flash chromatography on silica gel.

Scheme 18

Transfer hydrogenative imine addition and hydroaminoalkylation.^{a a}Yields are of material isolated by flash chromatography on silica gel. FcCO₂H = ferrocene carboxylic acid. dCypp = bis-(dicyclohexylphosphino)propane.

Scheme 19

Regioselective hydroaminomethylation of allenes and dienes via 2-propanol mediated reductive coupling with formaldimines.^{a a}Yields are of material isolated by flash chromatography on silica gel. dCypm = bis-(dicyclohexylphosphino)methane. dCype = bis-(dicyclohexylphosphino)ethane.

Scheme 20

Regioselective ruthenium(0) catalyzed hydroaminoalkylation of isoprene with hydantoins.^{a a}Yields are of material isolated by flash chromatography on silica gel. triphos = bis-(diphenylphosphinoethyl)phenylphosphine.