Morita–Baylis–Hillman Reaction Strategies in Organic Synthesis

The Morita–Baylis–Hillman reaction represents a powerful carbon–carbon bond‐forming transformation that couples activated alkenes with electrophilic carbonyl compounds under the influence of a nucleophilic promoter. Central to its appeal is the formation of densely functionalised allylic alcohol motifs in a single step, enabling rapid assembly of complex frameworks. Over the past decade, strategic advances have encompassed the design of bifunctional organocatalysts to achieve high enantioselectivity, the extension to aza–Morita–Baylis–Hillman variants for imine substrates, and the exploration of cascade sequences that integrate MBH adducts into multi‐step processes. Sustainable methodologies have emerged, including solvent‐free mechanochemical protocols and the use of deep eutectic solvents or photoredox systems to broaden substrate scope beyond electron‐deficient olefins. Mechanistic insights, often supported by spectroscopic or computational studies, have refined our understanding of key zwitterionic intermediates and transition‐state geometries. Collectively, these strategies have cemented the MBH reaction as a versatile tool for constructing building blocks in medicinal chemistry, agrochemicals and advanced materials, while aligning with green‐chemistry imperatives.

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Technical terms

Morita–Baylis–Hillman reaction: A nucleophile-mediated coupling of activated alkenes with carbonyl or imine electrophiles to form allylic alcohols or amines.

Michael acceptor: An electron-deficient alkene (e.g., acrylates, acrylonitrile) that undergoes conjugate addition with a nucleophile.

Organocatalysis: Catalysis by small organic molecules, often tertiary amines or bifunctional catalysts, rather than metal complexes.

Enantioselectivity: The preference for formation of one enantiomer over its mirror image in a chiral transformation.

Photoredox catalysis: Activation of substrates via single-electron transfer processes initiated by visible‐light‐absorbing catalysts.

Deep eutectic solvent: A low‐melting mixture of hydrogen‐bond donors and acceptors that serves as a green reaction medium.

References

1. Choline Chloride–Urea Deep Eutectic Solvent/Cu–Mn Iminodiacetate Coordination Polymer as an Efficient Catalytic System for Synthesis of Morita–Baylis–Hillman Adducts with Antimicrobial Activity. ACS Omega (2024).
2. The Morita–Baylis–Hillman reaction for non-electron-deficient olefins enabled by photoredox catalysis. Chemical Science (2022).
3. Expedient Organocatalytic Aza-Morita–Baylis–Hillman Reaction through Ball-Milling. ACS Sustainable Chemistry & Engineering (2020).