Cross-coupling reaction explained

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 MgX; 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

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.In such cases, the mechanism generally involves reductive elimination of R-R' from L_nMR(R') (L = spectator ligand). This intermediate L_nMR(R') is formed in a two step process from a low valence precursor L_nM. The oxidative addition of an organic halide (RX) to L_nM gives L_nMR(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

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]

Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds.^{[10] [11]}

Iron-,^[12] cobalt-,^[13] and nickel-based^[14] catalysts have been investigated.

Leaving groups

The leaving group X in the organic partner is usually a halide, although triflate, tosylate, pivalate esters, and other pseudohalides have been used. 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 usually is an electropositive element such as tin, zinc, silicon, or boron.

Carbon–carbon cross-coupling

Many cross-couplings entail forming carbon–carbon bonds.

Reaction	Year	Reactant A		Reactant B		Catalyst	Remark
Cadiot–Chodkiewicz coupling	1957	RC≡CH	sp	RC≡CX	sp	Cu	requires base
Castro–Stephens coupling	1963	RC≡CH	sp	Ar-X	sp^2	Cu
Corey–House synthesis	1967	R2CuLi or RMgX	sp^3	R-X	sp^2, sp^3	Cu	Cu-catalyzed version by Kochi, 1971
Kumada coupling	1972	RMgBr	sp^2, sp^3	R-X	sp^2	Pd or Ni or Fe
Heck reaction	1972	alkene	sp^2	Ar-X	sp^2	Pd or Ni	requires base
Sonogashira coupling	1975	ArC≡CH	sp	R-X	sp^3 sp^2	Pd and Cu	requires base
Negishi coupling	1977	R-Zn-X	sp^3, sp^2, sp	R-X	sp^3 sp^2	Pd or Ni
Stille cross coupling	1978	R-SnR3	sp^3, sp^2, sp	R-X	sp^3 sp^2	Pd or Ni
Suzuki reaction	1979	R-B(OR)2	sp^2	R-X	sp^3 sp^2	Pd or Ni	requires base
Murahashi coupling^[15]	1979	R-Li	sp^2, sp^3	R-X	sp^2	Pd or Ru
Hiyama coupling	1988	R-SiR3	sp^2	R-X	sp^3 sp^2	Pd	requires base
Fukuyama coupling	1998	R-Zn-I	sp^3	RCO(SEt)	sp^2	Pd or Ni	see Liebeskind–Srogl coupling, gives ketones
Liebeskind–Srogl coupling	2000	R-B(OR)2	sp^3, sp^2	RCO(SEt) Ar-SMe	sp^2	Pd	requires CuTC, gives ketones
Cross dehydrogenative coupling	2004	R-H	sp, sp^2, sp^3	R'-H	sp, sp^2, sp^3	Cu, Fe, Pd etc.	requires oxidant or dehydrogenation
Decarboxylative cross-coupling	2000s	R-CO2H	sp^2	R'-X	sp, sp^2	Cu, Pd	Requires little-to-no base

The restrictions on carbon atom geometry mainly inhibit β-hydride elimination when complexed to the catalyst.^[16]

Carbon–heteroatom coupling

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

Reaction	Year	Reactant A		Reactant B		Catalyst	Remark
Ullmann-type reaction	1905	ArO-MM, ArNH2,RS-M,NC-M	sp^3	Ar-X (X = OAr, N(H)Ar, SR, CN)	sp^2	Cu
Buchwald–Hartwig reaction^[17]	1994	R2N-H	sp^3	R-X	sp^2	Pd	N-C coupling, second generation free amine
Chan–Lam coupling^[18]	1998	Ar-B(OR)2	sp^2	Ar-NH2	sp^2	Cu

Miscellaneous reactions

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.^[19]

Applications

Cross-coupling reactions are important for the production of pharmaceuticals,^[4] examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.^[20] with Suzuki coupling being most widely used.^[21] Some polymers and monomers are also prepared in this way.^[22]

Reviews

• N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union. Chemical Society Reviews. 40. 10. 5151–69. 10.1039/c1cs15088j. 21731956. en. George C.. Fortman. Steven P.. Nolan. 2011.
• 10.1021/cr0505674. 17212474. Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts. Chemical Reviews. 107. 1. 133–173. 2007. Yin. Liebscher. Jürgen. 36974481.
• 10.1021/cr100327p. 21319862. 3075866. Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners. Chemical Reviews. 111. 3. 1417–1492. 2011. Jana. Ranjan. Pathak. Tejas P.. Sigman. Matthew S..
• 10.1021/cr100355b. 21391571. Efficient, Selective, and Recyclable Palladium Catalysts in Carbon−Carbon Coupling Reactions. Chemical Reviews. 111. 3. 2251–2320. 2011. Molnár. Árpád.
• 10.1021/cr00039a007. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews. 95. 7. 2457–2483. 1995. Norio Miyaura . Akira Suzuki (chemist). Miyaura. Norio. Suzuki. Akira. 10.1.1.735.7660.
• 10.1021/cr0509861. 17091930. Diazonium Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions. Chemical Reviews. 106. 11. 4622–4643. 2006. Roglans. Anna. Pla-Quintana. Anna. Moreno-Mañas. Marcial. 8128630.
• 10.1021/acs.chemrev.8b00628. Cross-Coupling of Heteroatomic Electrophiles . 2019 . Korch . Katerina M. . Watson . Donald A. . Chemical Reviews . 119 . 13 . 8192–8228 . 31184483 . 6620169 .
• 10.1021/cr9000786. Cobalt-Catalyzed Cross-Coupling Reactions . 2010 . Cahiez . Gérard . Moyeux . Alban . Chemical Reviews . 110 . 3 . 1435–1462 . 20148539 .
• 10.1021/acs.chemrev.6b00620. Recent Advances in Radical C–H Activation/Radical Cross-Coupling . 2017 . Yi . Hong . Zhang . Guoting . Wang . Huamin . Huang . Zhiyuan . Wang . Jue . Singh . Atul K. . Lei . Aiwen . Chemical Reviews . 117 . 13 . 9016–9085 . 28639787 .

Notes and References

1. 10.1021/acs.chemrev.8b00628 . Cross-Coupling of Heteroatomic Electrophiles . 2019 . Korch . Katerina M. . Watson . Donald A. . Chemical Reviews . 119 . 13 . 8192–8228 . 31184483 . 6620169 .
2. 10.1021/cr0505268 . Selected Patented Cross-Coupling Reaction Technologies . 2006 . Corbet . Jean-Pierre . Mignani . Gérard . Chemical Reviews . 106 . 7 . 2651–2710 . 16836296 .
3. New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014
4. Book: King, A. O.. Yasuda, N.. Organometallics in Process Chemistry. 6. 205–245 . Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. 10.1007/b94551. Springer. Heidelberg. Topics in Organometallic Chemistry. 2004. 978-3-540-01603-8.
5. Web site: The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki . NobelPrize.org . 2010-10-06 . 2010-10-06.
6. 10.1002/anie.201107017. 22573393. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angewandte Chemie International Edition. 51. 21. 5062–5085. 2012. Johansson Seechurn. Carin C. C.. Kitching. Matthew O.. Colacot. Thomas J.. Snieckus. Victor. 20582425.
7. 10.1021/cr400274j. Transition-Metal-Free Coupling Reactions . 2014 . Sun . Chang-Liang . Shi . Zhang-Jie . Chemical Reviews . 114 . 18 . 9219–9280 . 25184859 .
8. Removing Impurities . Thayer . Ann . 2005-09-05 . Chemical & Engineering News . 2015-12-11 .
9. Yin, L.. Liebscher, J.. 36974481. Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts. Chemical Reviews. 2007. 107. 1. 133–173. 10.1021/cr0505674. 17212474.
10. 10.1021/cr0505268. 16836296. Selected Patented Cross-Coupling Reaction Technologies. Chemical Reviews. 106. 7. 2651–2710. 2006. Corbet. Jean-Pierre. Mignani. Gérard.
11. 10.1021/cr8002505. 18698737. Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis. Chemical Reviews. 108. 8. 3054–3131. 2008. Evano. Gwilherm. Blanchard. Nicolas. Toumi. Mathieu.
12. How Low Does Iron Go? Chasing the Active Species in Fe-Catalyzed Cross-Coupling Reactions. Robin B. Bedford. Acc. Chem. Res.. 2015. 48. 5. 1485–1493. 10.1021/acs.accounts.5b00042. 25916260.
13. 10.1021/cr9000786. 20148539. Cobalt-Catalyzed Cross-Coupling Reactions. Chemical Reviews. 110. 3. 1435–1462. 2010. Cahiez. GéRard. Moyeux. Alban.
14. 10.1021/cr100259t. 21133429. 3055945. Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen Bonds. Chemical Reviews. 111. 3. 1346–1416. 2011. Rosen. Brad M.. Quasdorf. Kyle W.. Wilson. Daniella A.. Zhang. Na. Resmerita. Ana-Maria. Garg. Neil K.. Percec. Virgil.
15. 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. en. 44. 14. 2408–2417. 10.1021/jo01328a016. 0022-3263.
16. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford UP: Oxford, U.K., 2012. pp. 1069-1102.
17. Ruiz-Castillo, P.. Buchwald, S. L.. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions . Chemical Reviews . 2016. 116. 19 . 12564–12649. 10.1021/acs.chemrev.6b00512. 27689804 . 5070552.
18. Book: Recent Advances in Chan–Lam Coupling Reaction: Copper-Promoted C–Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives. Jennifer X. Qiao. Patrick Y.S. Lam. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials. 315–361. Dennis G. Hall. 2011. Wiley-VCH. 10.1002/9783527639328.ch6. 9783527639328.
19. M. Lafrance . C. N. Rowley . T. K. Woo . K. Fagnou . Catalytic Intermolecular Direct Arylation of Perfluorobenzenes . 2006 . . 128 . 27 . 8754–8756 . 10.1021/ja062509l . 16819868. 10.1.1.631.607 .
20. Book: 10.1002/9783527651733.ch2. Hydroformylation. Applied Homogeneous Catalysis with Organometallic Compounds. 2017. Cornils. Boy. Börner. Armin. Franke. Robert. Zhang. Baoxin. Wiebus. Ernst. Schmid. Klaus. 23–90. 9783527328970.
21. 10.1021/jm200187y. The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. 2011. Roughley. Stephen D.. Jordan. Allan M.. Journal of Medicinal Chemistry. 54. 10. 3451–3479. 21504168.
22. Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010.