Cross-coupling reaction

Short description: Chemical reaction in which two molecules are joined due to a metal catalyst

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−M+RA′X⟶R−RA′+MX

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]

## Contents

* 1 Mechanism
* 1.1 Catalysts
* 1.2 Leaving groups
* 2 Carbon–carbon cross-coupling
* 3 Carbon–heteroatom coupling
* 4 Miscellaneous reactions
* 5 Applications
* 6 Reviews
* 7 References

## 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.

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

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]

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.[15] 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

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 | sp2 | Cu |
Corey–House synthesis | 1967 | R2CuLi or RMgX | sp3 | R-X | sp2, sp3 | Cu  | Cu-catalyzed version by Kochi, 1971
Kumada coupling | 1972 | RMgBr | sp2, sp3 | R-X | sp2 | Pd or Ni or Fe |
Heck reaction | 1972 | alkene | sp2 | Ar-X | sp2 | Pd or Ni | requires base
Sonogashira coupling | 1975 | ArC≡CH | sp | R-X | sp3 sp2 | Pd and Cu | requires base
Negishi coupling | 1977 | R-Zn-X | sp3, sp2, sp | R-X | sp3 sp2 | Pd or Ni |
Stille cross coupling | 1978 | R-SnR3 | sp3, sp2, sp | R-X | sp3 sp2 | Pd or Ni |
Suzuki reaction | 1979 | R-B(OR)2 | sp2 | R-X | sp3 sp2 | Pd or Ni | requires base
Murahashi coupling[16] | 1979  | R-Li  | sp2, sp3 | R-X  | sp2 | Pd or Ru  |
Hiyama coupling | 1988 | R-SiR3 | sp2 | R-X | sp3 sp2 | Pd | requires base
Fukuyama coupling | 1998 | R-Zn-I | sp3 | RCO(SEt) | sp2 | Pd or Ni | see Liebeskind–Srogl coupling, gives ketones
Liebeskind–Srogl coupling | 2000 | R-B(OR)2 | sp3, sp2 | RCO(SEt) Ar-SMe | sp2 | Pd | requires CuTC, gives ketones
Cross dehydrogenative coupling | 2004 | R-H | sp, sp2, sp3 | R'-H | sp, sp2, sp3 | Cu, Fe, Pd etc. | requires oxidant or dehydrogenation
Decarboxylative cross-coupling | 2000s | R-CO2H | sp2 | R'-X | sp, sp2 | Cu, Pd | Requires little-to-no base

The restrictions on carbon atom geometry mainly inhibit β-hydride elimination when complexed to the catalyst.[17]

## Carbon–heteroatom coupling

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

The Buchwald–Hartwig reaction

|
|

(Eq.1)

Reaction | Year  | Reactant A  | Reactant B | Catalyst | Remark

|
|
|
|
|

Ullmann-type reaction | 1905  | ArO-MM, ArNH2,RS-M,NC-M | sp3 | Ar-X (X = OAr, N(H)Ar, SR, CN) | sp2 | Cu |
Buchwald–Hartwig reaction[18] | 1994 | R2N-H | sp3 | R-X | sp2 | Pd | N-C coupling,
second generation free amine
Chan–Lam coupling[19] | 1998 | Ar-B(OR)2 | sp2 | Ar-NH2 | sp2 | 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.[20]

## Applications

Cross-coupling reactions are important for the production of pharmaceuticals,[4] examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.[21] with Suzuki coupling being most widely used.[22] Some polymers and monomers are also prepared in this way.[23]

## Reviews

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

## References

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. 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. ↑ 4.0 4.1 King, A. O.; Yasuda, N. (2004). "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals". Organometallics in Process Chemistry. Topics in Organometallic Chemistry. 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. https://nobelprize.org/nobel_prizes/chemistry/laureates/2010/. 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. https://durham-repository.worktribe.com/output/1323930.
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. https://pubs.acs.org/cen/coverstory/83/8336chiral3.html. 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.
10. ↑ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
11. ↑ 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.
12. ↑ 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.
13. ↑ Cahiez, GéRard; Moyeux, Alban (2010). "Cobalt-Catalyzed Cross-Coupling Reactions". Chemical Reviews 110 (3): 1435–1462. doi:10.1021/cr9000786. PMID 20148539.
14. ↑ 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. PMID 21133429.
15. ↑ 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, https://books.google.com/books?id=JDR-nZpojeEC&printsec=frontcover
16. ↑ 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" (in en). The Journal of Organic Chemistry 44 (14): 2408–2417. doi:10.1021/jo01328a016. ISSN 0022-3263.
17. ↑ Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford UP: Oxford, U.K., 2012. pp. 1069-1102.
18. ↑ 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. PMID 27689804.
19. ↑ 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. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials. Wiley-VCH. pp. 315–361. doi:10.1002/9783527639328.ch6. ISBN 9783527639328.
20. ↑ 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. doi:10.1021/ja062509l. PMID 16819868. Bibcode: 2006JAChS.128.8754L.
21. ↑ 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 9783527328970.
22. ↑ 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.
23. ↑ Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ISBN 1-891389-53-X

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