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Reductive Cross-Coupling: From Humble Beginnings to a Dynamic Revival

Image depicts young man in a lab, peering at the contents of a tube
Christopher DeAngelis
Graduate Student, Department of Chemistry
University of Georgia
iSTEM-2 Building, Room 1218
Organic Seminar

Conventional cross-coupling reactions typically involve the union of a nucleophilic and electrophilic coupling partner. In contrast, reductive (or cross-electrophile) coupling has recently emerged as an alternative approach in which two electrophilic partners can be coupled together. However, achieving cross-selectivity is an ongoing challenge for it necessitates chemoselective activation of one electrophile over the other.

Three recently reported complementary approaches to reductive coupling will be discussed. The first will focus on the application of Ni-catalyzed, enantioselective variants for the synthesis of medicinally relevant motifs.[1] The second describes the union between Ni-catalyzed strategies alongside photoredox catalysis to afford cross-coupled products from inexpensive, bench-stable electrophiles without invoking the use of terminal reductants such as Zn or Mn.[2] The final report introduces a convenient electrochemical strategy for coupling two aliphatic electrophiles, a strategy that remains an on-going challenge in conventional cross-coupling.[3]

Together, these three reports serve as valuable approaches alongside early pioneering examples.[4] With ongoing efforts to address chemoselectivity, reductive cross-coupling has attracted considerable attention in recent years and will likely continue to serve as a useful compliment alongside conventional cross-coupling as another powerful approach to carbon–carbon bond formation. 

Illustration: examples of conventional cross-coupling and reductive cross-coupling


[1]       T. J. DeLano, S. E. Dibrell, C. R. Lacker, A. R. Pancoast, K. E. Poremba, L. Cleary, M. S. Sigman, S. E. Reisman, Chem. Sci. 2021, 12, 7758–7762.

[2]       H. A. Sakai, W. Liu, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2020, 142, 11691–11697.

[3]       W. Zhang, L. Lu, W. Zhang, Y. Wang, S. D. Ware, J. Mondragon, J. Rein, N. Strotman, D. Lehnherr, K. A. See, S. Lin, Nature 2022, 604, 292–297.

[4]       D. A. Everson, R. Shrestha, D. J. Weix, J. Am. Chem. Soc. 2010, 132, 920–921.


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