Borrowing Hydrogen for Organic Synthesis

Abstract

Borrowing hydrogen is a process that is used to diversify the synthetic utility of commodity alcohols. A catalyst first oxidizes an alcohol by removing hydrogen to form a reactive carbonyl compound. This intermediate can undergo a diverse range of subsequent transformations before the catalyst returns the "borrowed" hydrogen to liberate the product and regenerate the catalyst. In this way, alcohols may be used as alkylating agents whereby the sole byproduct of this one-pot reaction is water. In recent decades, significant advances have been made in this area, demonstrating many effective methods to access valuable products. This outlook highlights the diversity of metal and biocatalysts that are available for this approach, as well as the various transformations that can be performed, focusing on a selection of the most significant and recent advances. By succinctly describing and conveying the versatility of borrowing hydrogen chemistry, we anticipate its uptake will increase across a wider scientific audience, expanding opportunities for further development.

Scheme 1. Generalized Transition-Metal-Catalyzed Borrowing Hydrogen Reaction

Scheme 2. Selected Approaches for the Catalytic Synthesis of N-Benzylaniline via Borrowing Hydrogen

Figure 1

Examples showcasing product diversity.

Scheme 3. Routes Toward API Synthesis with Borrowing Hydrogen

Scheme 4. Diastereoselective N-Alkylation of Sulfinamides

Scheme 5. Enantioselective Alkylation of Amines

Scheme 6. Biocatalytic Borrowing Hydrogen with Primary Amines

Scheme 7. Enantioselective Hydroamination of Racemic Secondary Allylic Alcohols

Scheme 8. Selective Mono-N-Methylation of Anilines

Scheme 9. Amine Cross-Coupling Using Borrowing Hydrogen

Scheme 10. Selected Approaches for the Catalytic Synthesis of Dihydrochalcone via Borrowing Hydrogen

Figure 2

Functional group tolerance and natural product modification in the α-alkylation of ketones.

Scheme 11. α-Alkylation of Esters and Amides

Scheme 12. α-Alkylation of Ketones with Secondary Alcohols, with Second Stage Derivatization of Products

Scheme 13. α-Alkylation of Ketones with Diols

Scheme 14. α-Methylation of Ketones

Scheme 15. Enantioselective β-Alkylation of Alcohols

Scheme 16. Upgrading of Ethanol to n-Butanol

Scheme 17. Dual-Catalytic System Combining Borrowing Hydrogen Activation and Enantioselective Organocatalysis

Scheme 18. Dual-Catalytic Transition-Metal System to Access Enantioenriched γ-Aryl Alcohols from Allylic Alcohols

Scheme 19. Ruthenium-Catalyzed Redox Coupling of α-Hydroxyesters and Dienes

Scheme 20. Deuteration of Alcohols