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. 2019 Jan 14;38(1):3-35.
doi: 10.1021/acs.organomet.8b00720. Epub 2018 Nov 27.

Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future

Louis-Charles Campeau  1 , Nilay Hazari  2
Affiliations

Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future

Louis-Charles Campeau et al. Organometallics. .

Abstract

Cross-coupling reactions, which were discovered almost 50 years ago, are widely used in both industry and academia. Even though cross-coupling reactions now represent mature technology, there is still a significant amount of research in this area that aims to improve the scope of these reactions, develop more efficient catalysts, and make reactions more practical. In this tutorial, a brief background to cross-coupling reactions is provided, and then the major advances in cross-coupling research over the last 20 years are described. These include the development of improved ligands and precatalysts for cross-coupling and the extension of cross-coupling reactions to a much wider range of electrophiles. For example, cross-coupling reactions are now common with sp3-hybridized electrophiles as well as ester, amide, ether, and aziridine substrates. For many of these more modern substrates, traditional palladium-based catalysts are less efficient than systems based on first-row transition metals such as nickel. Conventional cross-coupling reactions have also inspired the development of a range of related reactions, such as cross-electrophile and decarboxylative couplings as well as couplings based on metallaphotoredox chemistry. The development of these new reactions is probably at the same stage as traditional cross-coupling reactions 30 years ago, and this tutorial highlights how many of the same strategies used to improve cross-coupling reactions may also be applicable to making the new reactions more practical.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(a) Depiction of a generic cross-coupling reaction. (b) Depiction of the Suzuki-Miyaura reaction used in the synthesis of losartan.
Figure 2.
Figure 2.
Proposed mechanism for traditional palladium-catalyzed cross-coupling reactions.
Figure 3.
Figure 3.
Examples of selected challenges in cross-coupling: (a) protodeborylation of boronic acids; (b) generation of tetra-ortho-substituted biaryl products.
Figure 4.
Figure 4.
(a) Generic advantages and design principles of Buchwald-type dialkylbiarylphosphine ligands. (b) Specific examples of common dialkylbiarylphosphine ligands.
Figure 5.
Figure 5.
Examples of NHC ligands that are commonly used in cross-coupling reactions.
Figure 6.
Figure 6.
Selected examples of commercially available bench-stable palladium(II) precatalysts for cross-coupling.
Figure 7.
Figure 7.
Flow cross-coupling of fluorinated aromatics and heteroaromatics.
Figure 8.
Figure 8.
Competition between β-hydride elimination and transmetalation in cross-coupling with sp3-hybridized substrates. After oxidative addition, β-hydride elimination is an undesired side reaction when alkyl substrates are used. If the nucleophile contains a β-hydride, reductive elimination is also in competition with β-hydride elimination (not shown in the figure).
Figure 9.
Figure 9.
Selected examples of stereoconvergent (a) Negishi and (b) Suzuki-Miyaura reactions using racemic alkyl electrophiles.
Figure 10.
Figure 10.
Phenol derivatives that are used as electrophiles in cross-coupling.
Figure 11.
Figure 11.
Generic representations of the different types of cross-coupling reactions involving aryl ester electrophiles.
Figure 12.
Figure 12.
Examples of (a) Suzuki-Miyaura and (b) Buchwald-Hartwig reactions involving cleavage of the C(acyl)-O bond in phenyl esters.
Figure 13.
Figure 13.
General scheme for nickel-catalyzed Kumada-Corriu couplings involving aryl ethers.
Figure 14.
Figure 14.
Selected examples of stereospecific Kumada-Corriu couplings involving secondary benzylic ethers.
Figure 15.
Figure 15.
(a) Generic example of a nickel-catalyzed conversion of an amide and alcohol into an ester and (b) proposed mechanism.
Figure 16.
Figure 16.
Examples of nickel-catalyzed Negishi reactions involving (a) 2-styrenylaziridines and (b) 2-alkylaziridines.
Figure 17.
Figure 17.
Examples of palladium-catalyzed Suzuki-Miyaura reactions involving (a) 2-alkylaziridines and (b) 2-arylaziridines.
Figure 18.
Figure 18.
(a) Cross-electrophile coupling reactions between alkyl halides and acyl electrophiles and (b, c) mechanisms proposed by (b) Gong and (c) Weix.
Figure 19.
Figure 19.
Examples of asymmetric nickel-catalyzed cross-electrophile coupling reactions.
Figure 20.
Figure 20.
General reaction and functional group tolerance of nickel-catalyzed cross-electrophile coupling reactions between aryl and heteroaryl halides and alkyl bromides.
Figure 21.
Figure 21.
(a) Examples of other electrophiles successfully used in nickel-catalyzed cross-electrophile coupling reactions with aryl and/or heteroaryl halides. (b) Sequential Prins cyclization and cross-electrophile coupling to generate a cyclopropane.
Figure 22.
Figure 22.
New bidentate ligands for challenging cross-electrophile coupling reactions identified through screening of the Pfizer library.
Figure 23.
Figure 23.
(a) Generic reaction scheme and (b) proposed catalytic cycle for metallaphotoredox-catalyzed trifluoromethylation of boronic acids.
Figure 24.
Figure 24.
Examples of arylations mediated by nickel metallaphotoredox catalysis with (a) tetrafluoroborates and (b) carboxylic acids.
Figure 25.
Figure 25.
Examples of arylative functionalization mediated by gold metallaphotoredox catalysis with (a) homoallylic alcohols and (b) allylic cyclobutanols.
Figure 26.
Figure 26.
Mechanistic probe for nickel metallaphotoredox chemistry involving C–O coupling.
Figure 27.
Figure 27.
(a) Generic scheme, (b) seminal example, and (c) proposed mechanism for conjunctive cross-coupling.
Figure 28.
Figure 28.
Generic depiction of decarboxylative cross-coupling, including the proposed metal intermediates that facilitate decarboxylation.
Figure 29.
Figure 29.
(a) Generic scheme for the preparation of N-hydroxyphthalimide esters. (b) Generic example of Ni-catalyzed Negishi reactions involving N-hydroxyphthalimide esters. (c) Proposed mechanism.
Figure 30.
Figure 30.
General disconnections in direct arylation reactions.
Figure 31.
Figure 31.
Proposed mechanisms for the C–H “activation” step in palladium-catalyzed direct arylation. reactions.
Figure 32.
Figure 32.
Proposed mechanism for arylation of benzoic and phenylacetic acids with arylboron reagents.
Figure 33.
Figure 33.
Direct arylation of cyclopropyl carboxylic acids using aryl iodides.
Figure 34.
Figure 34.
Greaney’s “on-water” direct arylation of heterocycles.
Figure 35.
Figure 35.
Divergent arylation of indoles using aryl iodonium salts.
Figure 36.
Figure 36.
Proposed mode of action of the pivalic acid cocatalyst in the direct arylation of benzene.
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