Hydrogen auto-transfer

Hydrogen auto-transfer, also known as borrowing hydrogen, is the activation of a chemical reaction by temporary transfer of two hydrogen atoms from the reactant to a catalyst and return of those hydrogen atoms back to a reaction intermediate to form the final product.^[1][2][3][4] Two major classes of borrowing hydrogen reactions exist: (a) those that result in hydroxyl substitution,^[1][2] and (b) those that result in carbonyl addition.^[3][4] In the former case, alcohol dehydrogenation generates a transient carbonyl compound that is subject to condensation followed by the return of hydrogen. In the latter case, alcohol dehydrogenation is followed by reductive generation of a nucleophile, which triggers carbonyl addition. As borrowing hydrogen processes avoid manipulations otherwise required for discrete alcohol oxidation and the use of stoichiometric organometallic reagents, they typically display high levels of atom-economy and, hence, are viewed as examples of Green chemistry.

Mechanism of the hydroxyl substitution hydrogen auto-transfer reaction.^[1][2]

Mechanism of one type of carbonyl addition hydrogen auto-transfer reaction involving hydrometalation (step 2).^[3]

History

The Guerbet reaction, reported in 1899,^[5] is an early example of a hydrogen auto-transfer process. The Guerbet reaction converts primary alcohols to β-alkylated dimers via alcohol dehydrogenation followed by aldol condensation and reduction of the resulting enones. Application of the Guerbet reaction to the development of ethanol-to-butanol processes has garnered interest as a method for the production of renewable fuels.^[6] In 1932 using heterogeneous nickel-catalysts Adkins reported the first alcohol aminations that occur through alcohol dehydrogenation-reductive amination.^[7] Homogenous catalysts for alcohol amination based on rhodium and ruthenium were developed by Grigg^[8] and Watanabe^[9] in 1981. The first hydrogen auto-transfer processes that convert primary alcohols to products of carbonyl addition were reported by Michael J. Krische in 2007-2008 using homogenous iridium and ruthenium catalysts.^[10][11][12]

Hydroxyl substitution

Alcohol aminations are among the most commonly utilized borrowing hydrogen processes.^[13][14][15] In reactions of this type, alcohol dehydrogenation is followed by reductive amination of the resulting carbonyl compound. This represents an alternative to two-step processes involving conversion of the alcohol to a halide or sulfonate ester followed by nucleophilic substitution

As shown below, alcohol amination has been used on kilogram scale by Pfizer for the synthesis of advanced pharmaceutical intermediates.^[16] Additionally, AstraZeneca has used methanol as an alternative to conventional genotoxic methylating agents such as methyl iodide or dimethyl sulfate.^[17] Nitroaromatics can also participate as amine precursors in borrowing hydrogen-type alcohol aminations.^[18]

The formation of carbon–carbon bonds have been achieved through borrowing hydrogen-type indirect Wittig,^[19] aldol,^[20] Knoevenagel condensations ^[21] and also through various carbon nucleophiles.^[22][23] Related to the Guerbet reaction, Donohoe and coworkers have developed enantioselective borrowing hydrogen-type enolate alkylations.^[24]

Carbonyl addition

As exemplified by the Krische allylation, dehydrogenation of alcohol reactants can be balanced by reduction of allenes, dienes or allyl acetate to generate allylmetal-carbonyl pairs that combine to give products of carbonyl addition.^[3][4] In this way, lower alcohols are directly transformed to higher alcohols in a manner that significantly decreases waste.^[25]

In 2008, borrowing hydrogen reactions of 1,3-enynes with alcohols to form products of carbonyl propargylation was discovered.^[26] An enantioselective variant of this method was recently used in the total synthesis of leiodermatolide A.^[27]