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:

$\mathrm{R}-\mathrm{M}+\mathrm{R}{\phantom{A}}^{\prime }\mathrm{X}⟶\mathrm{R}-\mathrm{R}{\phantom{A}}^{\prime }+\mathrm{M}\mathrm{X}$

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. 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.

Mechanism

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

File:Katalysezyklus-Kumada-Kupplung.png

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

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

File:Sonogashira coupling mechanism.png

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. Heterogeneous catalysts based on Pd are also well-developed.

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

Iron-, cobalt-, and nickel-based 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 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	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.

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	1994	R2N-H	sp3	R-X	sp2	Pd	N-C coupling, second generation free amine
Chan–Lam coupling	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.

Applications

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