Wikipedia

Cross-coupling reaction

(Redirected from Cross-coupling)

In organic chemistry, a cross-coupling reaction is a reaction where two different fragments are joined. Cross-couplings are a subset of the more general coupling reactions. Often cross-coupling reactions require metal catalysts. One important reaction type is this:

R, R' = organic fragments, usually aryl;
M = main group center such as Li or Mg;
X = halide

These reactions are used to form carbon–carbon bonds but also carbon-heteroatom bonds.[1][2][3][4] Cross-coupling reaction are a subset of coupling reactions.

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed coupling reactions.[5][6]

Mechanism

edit

Many mechanisms exist reflecting the myriad types of cross-couplings, including those that do not require metal catalysts.[7] Often, however, cross-coupling refers to a metal-catalyzed reaction of a nucleophilic partner with an electrophilic partner.

Mechanism proposed for Kumada coupling (L = Ligand, Ar = Aryl).

In such cases, the mechanism generally involves reductive elimination of R-R' from LnMR(R') (L = spectator ligand). This intermediate LnMR(R') is formed in a two-step process from a low valence precursor LnM. The oxidative addition of an organic halide (RX) to LnM gives LnMR(X). Subsequently, the second partner undergoes transmetallation with a source of R'−. The final step is reductive elimination of the two coupling fragments to regenerate the catalyst and give the organic product. Unsaturated substrates, such as C(sp)−X and C(sp2)−X bonds, couple more easily, in part because they add readily to the catalyst.

Catalysts

edit
Mechanism proposed for the Sonogashira coupling.

Catalysts are often based on palladium, which is frequently selected due to high functional group tolerance. Organopalladium compounds are generally stable towards water and air. Palladium catalysts can be problematic for the pharmaceutical industry, which faces extensive regulation regarding heavy metals. Many pharmaceutical chemists attempt to use coupling reactions early in production to minimize metal traces in the product.[8] Heterogeneous catalysts based on Pd are also well-developed.[9]

Alternatives to palladium cross-couplings became prevalent in the 2000s, with interest in non-precious and less toxic metals.[10] Copper-based catalysts are especially useful for coupling involving heteroatom-C bonds.[11][12] Iron-[13] and cobalt-catalysis have also been investigated.[14] The use of nickel-based catalysis has become more widespread.[15][16][17][18][19]

Leaving groups

edit

The leaving group X in the organic partner is usually a halide, although triflate, tosylate, pivalate esters,[20] carbamates,[21][22] and other pseudohalides have been used.[15][23] Chloride is an ideal group due to the low cost of organochlorine compounds. Frequently, however, C–Cl bonds are too inert, and bromide or iodide leaving groups are required for acceptable rates. The main group metal in the organometallic partner is usually an electropositive element such as tin, zinc, silicon, or boron.

Carbon–carbon cross-coupling

edit

Many cross-couplings entail forming carbon–carbon bonds.

ReactionYear Reactant A Reactant BCatalystRemark
Cadiot–Chodkiewicz coupling1957RC≡CHspRC≡CXspCurequires base
Castro–Stephens coupling1963RC≡CHspAr-Xsp2Cu
Corey–House synthesis1967R2CuLi or RMgXsp3 R-Xsp2, sp3 Cu Cu-catalyzed version by Kochi, 1971
Kumada coupling1972RMgBrsp2, sp3R-Xsp2Pd or Ni or Fe
Heck reaction1972alkenesp2Ar-Xsp2Pd or Nirequires base
Sonogashira coupling1975ArC≡CHspR-Xsp3 sp2Pd and Curequires base
Negishi coupling1977R-Zn-Xsp3, sp2, spR-Xsp3 sp2Pd or Ni
Stille cross coupling1978R-SnR3sp3, sp2, spR-Xsp3 sp2Pd or Ni
Suzuki reaction1979R-B(OR)2sp2R-Xsp3 sp2Pd or Nirequires base
Murahashi coupling[24] 1979 R-Li sp2, sp3 R-X sp2 Pd or Ru
Hiyama coupling1988R-SiR3sp2R-Xsp3 sp2Pdrequires base
Fukuyama coupling1998R-Zn-Isp3RCO(SEt)sp2Pd or Nisee Liebeskind–Srogl coupling, gives ketones
Liebeskind–Srogl coupling2000R-B(OR)2sp3, sp2RCO(SEt) Ar-SMesp2Pdrequires CuTC, gives ketones
Cross dehydrogenative coupling2004R-Hsp, sp2, sp3R'-Hsp, sp2, sp3Cu, Fe, Pd etc.requires oxidant or dehydrogenation
Decarboxylative cross-coupling2000sR-CO2Hsp2R'-Xsp, sp2Cu, PdRequires little-to-no base

The restrictions on carbon atom geometry mainly inhibit β-hydride elimination when complexed to the catalyst.[25]

Carbon–heteroatom coupling

edit

Many cross-couplings entail forming carbon–heteroatom bonds (heteroatom = S, N, O). A popular method is the Buchwald–Hartwig reaction:

ReactionYear Reactant A Reactant BCatalystRemark
Ullmann-type reaction1905 ArO-MM, ArNH2,RS-M,NC-Msp3Ar-X (X = OAr, N(H)Ar, SR, CN)sp2Cu
Buchwald–Hartwig reaction[26]1994R2N-Hsp3R-Xsp2PdN-C coupling,
second generation free amine
Chan–Lam coupling[27]1998Ar-B(OR)2sp2Ar-NH2sp2Cu

Miscellaneous reactions

edit

Palladium-catalyzes the cross-coupling of aryl halides with fluorinated arene. The process is unusual in that it involves C–H functionalisation at an electron deficient arene.[28]

A new class of cross-couplings was discovered in 2015 by the research teams of Neil Garg and Ken Houk involving amides as coupling partners.[29] Nickel catalysis breaks the typical strong C-N bonds of amides through oxidative addition.[30] Using nickel or palladium, transformations of amides can be achieved, including esterification, transamidation, hydrolysis, Suzuki-Miyaura couplings,[31] and asymmetric Heck reactions.[32][33][34]

Applications

edit

Cross-coupling reactions are important for the production of pharmaceuticals,[4] examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.[35] with Suzuki coupling being most widely used.[36] Some polymers and monomers are also prepared in this way.[37]

See also

edit

Reviews

edit

References

edit
  1. ↑ Korch, Katerina M.; Watson, Donald A. (2019). "Cross-Coupling of Heteroatomic Electrophiles". Chemical Reviews. 119 (13): 8192–8228. doi:10.1021/acs.chemrev.8b00628. PMC 6620169. PMID 31184483.
  2. ↑ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
  3. ↑ New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5
  4. 1 2 King, A. O.; Yasuda, N. (2004). "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals". Organometallics in Process Chemistry. Topics in Organometallic Chemistry. Vol. 6. Heidelberg: Springer. pp. 205–245. doi:10.1007/b94551. ISBN 978-3-540-01603-8.
  5. ↑ "The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06.
  6. ↑ Johansson Seechurn, Carin C. C.; Kitching, Matthew O.; Colacot, Thomas J.; Snieckus, Victor (2012). "Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize". Angewandte Chemie International Edition. 51 (21): 5062–5085. doi:10.1002/anie.201107017. PMID 22573393. S2CID 20582425.
  7. ↑ Sun, Chang-Liang; Shi, Zhang-Jie (2014). "Transition-Metal-Free Coupling Reactions". Chemical Reviews. 114 (18): 9219–9280. doi:10.1021/cr400274j. PMID 25184859.
  8. ↑ Thayer, Ann (2005-09-05). "Removing Impurities". Chemical & Engineering News. Retrieved 2015-12-11.
  9. ↑ Yin, L.; Liebscher, J. (2007). "Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts". Chemical Reviews. 107 (1): 133–173. doi:10.1021/cr0505674. PMID 17212474. S2CID 36974481.
  10. ↑ Boit, T.; Bulger, A.; Dander, J.; Garg, N. "Activation of C–O and C–N Bonds Using Non-Precious-Metal Catalysis". pubs.acs.org. doi:10.1021/acscatal.0c03334. PMC 8049354. PMID 33868770. Retrieved 2026-04-14.
  11. ↑ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
  12. ↑ Evano, Gwilherm; Blanchard, Nicolas; Toumi, Mathieu (2008). "Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis". Chemical Reviews. 108 (8): 3054–3131. doi:10.1021/cr8002505. PMID 18698737.
  13. ↑ Robin B. Bedford (2015). "How Low Does Iron Go? Chasing the Active Species in Fe-Catalyzed Cross-Coupling Reactions". Acc. Chem. Res. 48 (5): 1485–1493. doi:10.1021/acs.accounts.5b00042. PMID 25916260.
  14. ↑ Cahiez, GéRard; Moyeux, Alban (2010). "Cobalt-Catalyzed Cross-Coupling Reactions". Chemical Reviews. 110 (3): 1435–1462. doi:10.1021/cr9000786. PMID 20148539.
  15. 1 2 Rosen, Brad M.; Quasdorf, Kyle W.; Wilson, Daniella A.; Zhang, Na; Resmerita, Ana-Maria; Garg, Neil K.; Percec, Virgil (2011). "Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen Bonds". Chemical Reviews. 111 (3): 1346–1416. doi:10.1021/cr100259t. PMC 3055945. PMID 21133429.
  16. ↑ Tasker, Sarah Z.; Standley, Eric A.; Jamison, Timothy F. (May 2014). "Recent advances in homogeneous nickel catalysis". Nature. 509 (7500): 299–309. doi:10.1038/nature13274. ISSN 1476-4687. PMC 4344729.
  17. ↑ Baviskar, Bhushan A.; Ajmire, Prashant V.; Chumbhale, Deshraj S.; Khan, Mohammad Sadat; Kuchake, Vitthal G.; Singupuram, Madhavi; Laddha, Purushottam R. (2023-05-01). "Recent advances in nickel catalyzed Suzuki-Miyaura cross coupling reaction via C-O& C-N bond activation". Sustainable Chemistry and Pharmacy. 32 100953. doi:10.1016/j.scp.2022.100953. ISSN 2352-5541.
  18. ↑ "Process-Ready Nickel-Catalyzed Suzuki–Miyaura Coupling Enabled by tri-ProPhos". pubs.acs.org. doi:10.1021/acscatal.5c07157. PMC 12645473. PMID 41307039. Retrieved 2026-04-14.
  19. ↑ "Nickel-Catalyzed Suzuki–Miyaura Couplings in Green Solvents". pubs.acs.org. doi:10.1021/ol401727y. PMC 3768281. PMID 23879392. Retrieved 2026-04-14.
  20. ↑ Quasdorf, Kyle W.; Tian, Xia; Garg, Neil K. (2008-11-05). "Cross-Coupling Reactions of Aryl Pivalates with Boronic Acids". Journal of the American Chemical Society. 130 (44): 14422–14423. doi:10.1021/ja806244b. ISSN 0002-7863.
  21. ↑ Quasdorf, Kyle; Riener, Michelle; Petrova, Krastina; Garg, Neil. "Suzuki−Miyaura Coupling of Aryl Carbamates, Carbonates, and Sulfamates". J. Am. Chem. Soc. 131 (49): 17748 – via American Chemical Society.
  22. ↑ Mesganaw, Tehetena; Silberstein, Amanda L.; Ramgren, Stephen D.; Nathel, Noah F. Fine; Hong, Xin; Liu, Peng; Garg, Neil K. (2011-08-08). "Nickel-catalyzed amination of aryl carbamates and sequential site-selective cross-couplings". Chemical Science. 2 (9): 1766–1771. doi:10.1039/C1SC00230A. ISSN 2041-6539. PMC 6520651.
  23. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 792, ISBN 978-0-471-72091-1
  24. ↑ Murahashi, Shunichi; Yamamura, Masaaki; Yanagisawa, Kenichi; Mita, Nobuaki; Kondo, Kaoru (1979). "Stereoselective synthesis of alkenes and alkenyl sulfides from alkenyl halides using palladium and ruthenium catalysts". The Journal of Organic Chemistry. 44 (14): 2408–2417. doi:10.1021/jo01328a016. ISSN 0022-3263.
  25. ↑ Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford UP: Oxford, U.K., 2012. pp. 1069-1102.
  26. ↑ Ruiz-Castillo, P.; Buchwald, S. L. (2016). "Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions". Chemical Reviews. 116 (19): 12564–12649. doi:10.1021/acs.chemrev.6b00512. PMC 5070552. PMID 27689804.
  27. ↑ Jennifer X. Qiao; Patrick Y.S. Lam (2011). "Recent Advances in Chan–Lam Coupling Reaction: Copper-Promoted C–Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives". In Dennis G. Hall (ed.). Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials. Wiley-VCH. pp. 315–361. doi:10.1002/9783527639328.ch6. ISBN 978-3-527-63932-8.
  28. ↑ M. Lafrance; C. N. Rowley; T. K. Woo; K. Fagnou (2006). "Catalytic Intermolecular Direct Arylation of Perfluorobenzenes". J. Am. Chem. Soc. 128 (27): 8754–8756. Bibcode:2006JAChS.128.8754L. CiteSeerX 10.1.1.631.607. doi:10.1021/ja062509l. PMID 16819868.
  29. ↑ Hie, Liana; Fine Nathel, Noah F.; Shah, Tejas K.; Baker, Emma L.; Hong, Xin; Yang, Yun-Fang; Liu, Peng; Houk, K. N.; Garg, Neil K. "Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds". Nature. 524 (7563): 79–83. doi:10.1038/nature14615. ISSN 1476-4687. PMC 4529356.
  30. ↑ Boit, Timothy B.; Bulger, Ana S.; Dander, Jacob E.; Garg, Neil K. (2020-10-16). "Activation of C–O and C–N Bonds Using Non-Precious-Metal Catalysis". ACS Catalysis. 10 (20): 12109–12126. doi:10.1021/acscatal.0c03334. PMC 8049354. PMID 33868770.
  31. ↑ Weires, Nicholas A.; Baker, Emma L.; Garg, Neil K. "Nickel-catalysed Suzuki–Miyaura coupling of amides". Nature Chemistry. 8 (1): 75–79. doi:10.1038/nchem.2388. ISSN 1755-4349.
  32. ↑ Bulger, Ana S.; Nasrallah, Daniel J.; Meza, Arismel Tena; Garg, Neil K. (2024-02-14). "Enantioselective nickel-catalyzed Mizoroki–Heck cyclizations of amide electrophiles". Chemical Science. 15 (7): 2593–2600. doi:10.1039/D3SC05797F. ISSN 2041-6539.
  33. ↑ Dander, J.; Garg, N. "Breaking Amides Using Nickel Catalysis". pubs.acs.org. doi:10.1021/acscatal.6b03277. PMC 5473294. PMID 28626599. Retrieved 2026-05-20.
  34. ↑ Meng, Guangrong; Szostak, Michal (2016-06-15). "Palladium-catalyzed Suzuki–Miyaura coupling of amides by carbon–nitrogen cleavage: general strategy for amide N–C bond activation". Organic & Biomolecular Chemistry. 14 (24): 5690–5707. doi:10.1039/C6OB00084C. ISSN 1477-0539.
  35. ↑ Cornils, Boy; Börner, Armin; Franke, Robert; Zhang, Baoxin; Wiebus, Ernst; Schmid, Klaus (2017). "Hydroformylation". Applied Homogeneous Catalysis with Organometallic Compounds. pp. 23–90. doi:10.1002/9783527651733.ch2. ISBN 978-3-527-32897-0.
  36. ↑ Roughley, Stephen D.; Jordan, Allan M. (2011). "The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates". Journal of Medicinal Chemistry. 54 (10): 3451–3479. doi:10.1021/jm200187y. PMID 21504168.
  37. ↑ Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ISBN 1-891389-53-X
Retrieved from "https://en.wikipedia.org/w/index.php?title=Cross-coupling_reaction&oldid=1355986109"