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Bifunctional reagents in organic synthesis

Abstract

Developments in synthetic chemistry are increasingly driven by improvements in the selectivity and sustainability of transformations. Bifunctional reagents, either as dual coupling partners or as a coupling partner in combination with an activating species, offer an atom-economic approach to chemical complexity, while suppressing the formation of waste. These reagents are employed in organic synthesis thanks to their ability to form complex organic architectures and empower novel reaction pathways. This Review describes several key bifunctional reagents by showcasing selected cornerstone research areas and examples, including radical reactions, C–H functionalization, cross-coupling, organocatalysis and cyclization reactions.

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Fig. 1: Introduction to bifunctional reagents in organic synthesis.
Fig. 2: Photocatalytic atom transfer radical addition reactions.
Fig. 3: Catalytic carboamination reactions.
Fig. 4: Pyridinium salts as bifunctional reagents.
Fig. 5: Catalytic radical carbosulfation, silylation and aminofluorination reactions.
Fig. 6: C–H functionalization reactions.
Fig. 7: Hypervalent iodine reagents as bifunctional reagents.
Fig. 8: N,N-aminals and N,O-acetals as bifunctional reagents.
Fig. 9: Bifunctional reagents in cross-coupling reactions.
Fig. 10: Bifunctional reagents in organocatalysed reactions.
Fig. 11: Bifunctional reagents in cyclization reactions.

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Acknowledgements

This work was generously supported by the Alexander von Humboldt Foundation (H.-M.H.) and the Deutsche Forschungsgemeinschaft (Leibniz Award, SBF 858).

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H.-M.H. and P.B. equally contributed to the literature search and writing of the article, J.M. contributed to the preparation of figures, T.D. contributed to the editing of the manuscript and F.G. coordinated the project and supervised the writing of the manuscript.

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Correspondence to Frank Glorius.

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Glossary

Photoredox chemistry

Approaches that rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates.

Electrosynthesis

Synthesis of chemical compounds that exploits an electrochemical cell to facilitate redox processes.

Atom transfer radical addition

(ATRA). Reaction class that involves radical atom transfer over a multiple-bond system (e.g. alkene), yielding bifunctionalized species with high atom-economy.

Radical chain process

Chemical reaction that involves propagation of radical processes via the intermediacy of free radicals.

Energy transfer

Transfer of energy between one excited (the photosensitizer) and one ground state species, via either Dexter or Förster-type energy transfer.

Boron-dipyrromethene

(BODIPY). Heterocyclic organoboron class of compounds, investigated for its highly tunable optical properties.

Single-electron transfer

(SET). Step in a chemical reaction characterized by donation or removal of an electron.

Radical Truce–Smiles rearrangement

An intramolecular, nucleophilic ipso substitution on an aromatic ring system, activated by electron withdrawing group(s) at the ortho-position(s) and/or para-position(s) with respect to the reaction centre.

Hydrogen atom transfer

(HAT). Concerted transfer of a proton and an electron to result overall in the movement of a hydrogen atom.

1,5-Hydrogen atom transfer

Intramolecular abstraction of a hydrogen atom from a radical species located five atoms from the reactive centre to affect the overall migration of radicals along a chain.

Suzuki–Miyaura cross-coupling

Palladium-catalysed coupling reaction between a halide (often aryl or alkenyl) and an organoboron species (e.g. boronic acid, boronic ester) to forge a new C–C bond.

Heck reaction

Palladium-catalysed coupling reaction between a halide (often aryl or alkenyl) and an olefin to forge a new C–C bond.

Hypervalent iodine reagents

Species that contain an iodine atom either in its trivalent or in its pentavalent oxidation state; these species have found widespread application in oxidative processes and cross-coupling reactions.

Ullmann coupling

Coupling reaction between two aryl halide species to yield biaryls, usually catalysed by a copper salt.

Carbenoid

Reactive intermediate that possesses features resembling a carbene.

ipso Substitution

Substitution reaction occurring in aromatic systems at the carbon bearing the leaving group, usually via a nucleophilic aromatic displacement; less frequently, an electrophilic aromatic substitution at the ipso carbon can be observed.

Dearomatization

Process or elemental step that involves the loss of aromatic character.

Organocatalysis

Branch of catalysis featuring an organic molecule as catalyst.

N-heterocyclic carbene

(NHC). Molecular species featuring a ring structure and containing a divalent carbon atom bearing only six valence electrons, often used as ligand in transition-metal catalysis and organocatalysis.

Ireland–Coates–Claisen rearrangement

[3+3]-Sigmatropic rearrangement of a silyl ketene acetal of an allyl ester to give a γ-β unsaturated carboxylic acid.

Polymetallate species

Chemical species containing more than one metallic atom.

Sonogashira coupling

Palladium-catalysed cross-coupling reaction between a halide (often aryl or alkenyl) and a terminal alkyne. Involves the in situ formation of copper acetylides that undergo transmetallation.

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Huang, HM., Bellotti, P., Ma, J. et al. Bifunctional reagents in organic synthesis. Nat Rev Chem 5, 301–321 (2021). https://doi.org/10.1038/s41570-021-00266-5

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