Cross electrophile coupling

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Cross electrophile coupling (XEC or sometimes CEC) [1] is a type of cross-coupling reaction that occurs between two electrophiles. It is often catalyzed by transition metal catalyst(s). Unlike conventional cross-coupling reactions of an electrophile with an organometallic reagent, [2] the coupling partners in cross electrophile coupling reactions are both electrophiles. [3] Generally, additional reductant to regenerate active catalyst is needed in this reaction.

Contents

Cross selectivity

Reductive dimerization of electrophiles has long been known (Wurtz reaction, Ullman reaction, etc.), [4] [5] Few methods exist for achieving cross selectivity.

Using excess of one reagent

Using excess amount of one reagent can provide synthetically useful yields of cross-coupled product when the starting reagents have similar reactivity. (e.g. coupling between two alkyl halides). This strategy has been used with a Ni catalyst and zinc as reductant. [6] Dimerization of the more reactive alkyl halide was the major byproduct.

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Alkyl-alkyl (Csp3-Csp3) cross electrophile coupling using metallaphotoredox catalysis has also been achieved. [7] In this case, small alkyl electrophiles were used excess amount. Tris(trimethylsilyl)silanol can be employed as a halogen abstractor in combination with photoredox and Ni catalysis.

Sp3sp3scheme.png

Sequential oxidative addition

In cases where two electrophiles have disparate reactivity, this difference can be used to achieve high selectivity for cross product.

Sp2sp3scheme.png

For example, aryl halide and alkyl halide can be differentiated by the reactivity trends of two electrophiles whether it prefers heterolytic or homolytic pathway. [8] [9] Through detailed mechanistic studies, the origin of high selectivity was revealed : Aryl halides do faster oxidative addition to Ni(0) center than alkyl halides, however, alkyl halides form radicals when it react with nickel center. The catalysis begins with oxidative addition of an aryl halide to Ni(0). The resulting Ni(II) species reacts with an alkyl radical generated from alkyl halides to form diorganonickel(III) intermediate which can undergo reductive elimination of the cross coupled product. Reduction of Ni(II) to Ni(0) by Mn closes the catalytic cycle.

Sp2sp3mech.png

Reductive cross coupling of two different aryl (pseudo)halide was achieved.  Use of two different metals (Ni and Pd) was essential for the observed cross-selectivity of chemically similar two reactants. Aryl triflates generally prefer oxidative addition to the electron-rich Pd(0) catalyst whereas Ni(0) selectively reacts with aryl bromides. [10]  

Sp2sp2scheme.png

Transmetallation of the aryl-nickel(II) onto the Aryl-palladium(II) forms a Pd(II)Ar1Ar2 species followed by reductive elimination to give product. Finally, reduction of Ni(II) by additive zinc regenerates Ni(0). 

Sp2sp2mech.png

References

  1. ↑ Ehehalt, Lauren E.; Beleh, Omar M.; Priest, Isabella C.; Mouat, Julianna M.; Olszewski, Alyssa K.; Ahern, Benjamin N.; Cruz, Alexandro R.; Chi, Benjamin K.; Castro, Anthony J.; Kang, Kai; Wang, Jiang; Weix, Daniel J. (2024-12-11). "Cross-Electrophile Coupling: Principles, Methods, and Applications in Synthesis". Chemical Reviews. 124 (23): 13397–13569. doi:10.1021/acs.chemrev.4c00524. ISSN   0009-2665. PMC   11638928 . PMID   39591522.
  2. ↑ Hartwig JF (2010). Organotransition metal chemistry : from bonding to catalysis. University Science Books. ISBN   9781891389535. OCLC   781082054.
  3. ↑ Everson DA, Weix DJ (June 2014). "Cross-electrophile coupling: principles of reactivity and selectivity". The Journal of Organic Chemistry. 79 (11): 4793–8. doi:10.1021/jo500507s. PMC   4049235 . PMID   24820397.
  4. ↑ Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M (2002). "Aryl−Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction". Chemical Reviews. 102 (5): 1369–1469. doi:10.1021/cr000664r. PMID   11996540.
  5. ↑ Wurtz A (1855). "Ueber eine neue Klasse organischer Radicale". Justus Liebigs Annalen der Chemie. 96 (3): 364–375. doi:10.1002/jlac.18550960310. ISSN   1099-0690.
  6. ↑ Yu X, Yang T, Wang S, Xu H, Gong H (April 2011). "Nickel-catalyzed reductive cross-coupling of unactivated alkyl halides". Organic Letters. 13 (8): 2138–41. doi:10.1021/ol200617f. PMID   21434609.
  7. ↑ Smith RT, Zhang X, Rincón JA, Agejas J, Mateos C, Barberis M, García-Cerrada S, de Frutos O, MacMillan DW (December 2018). "3 Coupling of Aliphatic Bromides". Journal of the American Chemical Society. 140 (50): 17433–17438. doi:10.1021/jacs.8b12025. PMC   6697083 . PMID   30516995.
  8. ↑ Everson DA, Jones BA, Weix DJ (April 2012). "Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides". Journal of the American Chemical Society. 134 (14): 6146–59. Bibcode:2012JAChS.134.6146E. doi:10.1021/ja301769r. PMC   3324882 . PMID   22463689.
  9. ↑ Biswas S, Weix DJ (October 2013). "Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides". Journal of the American Chemical Society. 135 (43): 16192–7. Bibcode:2013JAChS.13516192B. doi:10.1021/ja407589e. PMC   3946589 . PMID   23952217.
  10. ↑ Ackerman LK, Lovell MM, Weix DJ (August 2015). "Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates". Nature. 524 (7566): 454–7. Bibcode:2015Natur.524..454A. doi:10.1038/nature14676. PMC   4552586 . PMID   26280337.
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