Cross-coupling reaction

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 + R'−X → R−R' + MX (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.^[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 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	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:

(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". 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.
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.
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

^ 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.
^ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
^ New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5
^ ^a ^b 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.
^ "The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06.
^ 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.
^ Sun, Chang-Liang; Shi, Zhang-Jie (2014). "Transition-Metal-Free Coupling Reactions". Chemical Reviews. 114 (18): 9219–9280. doi:10.1021/cr400274j. PMID 25184859.
^ Thayer, Ann (2005-09-05). "Removing Impurities". Chemical & Engineering News. Retrieved 2015-12-11.
^ 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.
^ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
^ 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.
^ 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.
^ Cahiez, GéRard; Moyeux, Alban (2010). "Cobalt-Catalyzed Cross-Coupling Reactions". Chemical Reviews. 110 (3): 1435–1462. doi:10.1021/cr9000786. PMID 20148539.
^ 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.
^ 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
^ 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.
^ Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford UP: Oxford, U.K., 2012. pp. 1069-1102.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ISBN 1-891389-53-X

[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

[Pharma-4] 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] 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. PMC 3055945. 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

[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". 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. PMC 5070552. 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 (ed.). 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. CiteSeerX 10.1.1.631.607. doi:10.1021/ja062509l. PMID 16819868.

[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.

[JFH-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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Cross-coupling reaction

Mechanism

Catalysts

Leaving groups

Carbon–carbon cross-coupling

Carbon–heteroatom coupling

Miscellaneous reactions

Applications

Reviews

References

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