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Review
. 2022 Aug 1;51(15):6738-6756.
doi: 10.1039/d2cs00012a.

C-H bond activation and sequential addition to two different coupling partners: a versatile approach to molecular complexity

Daniel S Brandes  1 , Jonathan A Ellman  1
Affiliations
Review

C-H bond activation and sequential addition to two different coupling partners: a versatile approach to molecular complexity

Daniel S Brandes et al. Chem Soc Rev. .

Abstract

Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C-H bonds are typically added across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two σ-bonds in a single reaction sequence. Many sequential C-H bond addition reactions have been developed to date, including additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C-H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Given the large number of possible combinations of coupling partners, there are enormous opportunities for the discovery of new sequential C-H bond addition reactions.

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Conflict of interest statement

Conflicts of interest

There are no conflicts to declare.

Figures

Scheme 1.
Scheme 1.
General depiction of C–H bond addition to one or two coupling partners
Scheme 2.
Scheme 2.
Development of sequential C–H bond additions to enones and aldehydes
Scheme 3.
Scheme 3.
Applications and mechanism of sequential C–H bond additions to enones and aldehydes
Scheme 4.
Scheme 4.
Enantio- and diastereoselective C–H bond addition to enones and aldehydes
Scheme 5.
Scheme 5.
Bimetallic C–H bond addition to enones/enals and TEMPO
Scheme 6.
Scheme 6.
Additions of C–H bonds to substituted butadienes and aldehydes
Scheme 7.
Scheme 7.
Additional examples of C–H bond additions to dienes and aldehydes
Scheme 8.
Scheme 8.
Additions of C–H bonds to internally substituted dienes and aldehydes
Scheme 9.
Scheme 9.
Sequential C–H bond addition to 1-arylbutadienes and amidating reagents
Scheme 10.
Scheme 10.
Regio- and enantioselective 1,2-carboamidation of dienes
Scheme 11.
Scheme 11.
Sequential C–H bond addition to dienes and a cyanating reagent
Scheme 12.
Scheme 12.
Synthesis of allenyl alcohols from enyne coupling partners
Scheme 13.
Scheme 13.
Sequential C–H bond addition to prepare alkenyl halides
Scheme 14.
Scheme 14.
Sequential C–H bond addition to alkenes and electrophilic aminating reagents for the synthesis of α-branched amines
Scheme 15.
Scheme 15.
Mechanistic rationale for 1,1-carboamidation
Scheme 16.
Scheme 16.
Three- and four-component carboamidation employing a readily diversifiable hydrazone directing group
Scheme 17.
Scheme 17.
Three-component carboamidation of bridged bicyclic alkenes
Scheme 18.
Scheme 18.
Mechanistic rationale for 1,2-carboamidations of bridged bicyclic alkenes
Scheme 19.
Scheme 19.
Sequential C–H bond addition to bicyclobutanes and ethyl glyoxylate
Scheme 20.
Scheme 20.
Meta-selective, Ru-catalysed multicomponent addition operating by a reverse addition mechanism
Scheme 21.
Scheme 21.
Reverse addition mechanism for multicomponent alkylation
Scheme 22.
Scheme 22.
Co(I)-catalysed coupling of ethylene and alkynes via a metallacyclopentene intermediate
Scheme 23.
Scheme 23.
Sequential addition of C–H bond to diazo compounds and a peroxide
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