Cross-coupling reaction

A cross-coupling reaction in organic chemistry is a reaction where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M = main group center) reacts with an organic halide of the type R'-X with formation of a new carbon–carbon bond in the product R-R'.[1][2][3] Cross-coupling reaction are a subset of coupling reactions. It is often used in arylations.

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross coupling reactions.[4][5]

Mechanism

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

The mechanism generally involves reductive elimination of the organic substituents R and R' on a metal complex of the type L_nMR(R') (where L is some arbitrary spectator ligand). The crucial intermediate L_nMR(R') is formed in a two step process from a low valence precursor L_n. 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 organic groups couple more easily in part because they add readily. The intermediates are also less prone to beta-hydride elimination.[6]

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.[7] Heterogeneous catalysts based on Pd are also well developed.[8]

Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds.[9][10]

Iron-,[11] cobalt-,[12] and nickel-based nickel.[13] catalysts have been investigated.

Leaving groups

The leaving group X in the organic partner is usually a halide, although triflate, tosylate and other pseudohalide 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	Ar-MgBr	sp^2, sp^3	Ar-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	RC≡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[14]	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

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		ArO-MM, ArNH2,RS-M,NC-M	sp^3	Ar-X (X = OAr, N(H)Ar, SR, CN)	sp^2	Cu
Chan–Lam coupling[15]		Ar-B(OR)2	sp^2	Ar-NH2	sp^2	Cu
Buchwald–Hartwig reaction[16]	1994	R2N-H	sp^3	R-X	sp^2	Pd	N-C coupling, second generation free amine

Miscellaneous reactions

One method for palladium-catalyzed cross-coupling reactions of aryl halides with fluorinated arenes was reported by Keith Fagnou and co-workers. It is unusual in that it involves C–H functionalisation at an electron deficient arene.[17]

Fluoroarene coupling

Applications

Cross-coupling reactions are important for the production of pharmaceuticals,[3] examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.[18] Some polymers and monomers are also prepared in this way.[6]

Reviews

• Fortman, George C.; Nolan, Steven P. (2011). "N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union". 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. S2CID 36974481.
• 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. PMC 3075866. 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. CiteSeerX 10.1.1.735.7660. 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. S2CID 8128630.

References

1. Organic Synthesis using Transition Metals Rod Bates ISBN 978-1-84127-107-1
2. New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5
3. 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.
4. "The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06.
5. 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.
6. Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ISBN 1-891389-53-X
7. Thayer, Ann (2005-09-05). "Removing Impurities". Chemical & Engineering News. Retrieved 2015-12-11.
8. 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.
9. Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
10. 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.
11. 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.
12. Cahiez, GéRard; Moyeux, Alban (2010). "Cobalt-Catalyzed Cross-Coupling Reactions". Chemical Reviews. 110 (3): 1435–1462. doi:10.1021/cr9000786. PMID 20148539.
13. 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.
14. 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.
15. 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 9783527639328.
16. 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.
17. 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. CiteSeerX 10.1.1.631.607. doi:10.1021/ja062509l. PMID 16819868.
18. 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.