Chan-Lam Coupling
The Chan-Lam coupling is the cross-coupling reaction between an aryl boronic acid and an amine or alcohol to generate the corresponding secondary aryl amine or ether.
General features:
1. In contrast to other cross-coupling reactions such as the Suzuki coupling or the Buchwald-Hartwig reaction, which are catalyzed by palladium, in the Chan-Lam coupling, a catalytic or stoichiometric amount of copper is often used. 2. The reaction can be conducted in air and at room temperature. 3. The Chan-Lam coupling resembles the Ullmann-type reaction, which is a sort of copper-catalyzed nucleophilic aromatic substitution between nucleophiles such as amines with aryl halides. However, to some extent, the Ullmann coupling sometimes requires harsh reaction conditions such as high temperature or the use of strong bases. 4. While the Ullmann reaction follows the characteristic transition metal-catalyzed nucleophile/electrophile coupling, the Chan-Lam amination is unique, coupling two nucleophiles, an aryl organoboron compound, and an amine. 5. The utility of the Chan-Lam amination is often hampered by significant problems with by-product formation. Some by-products include the oxidation product, the protodeboronation product, or the homocoupling of the organoboron component.
Chan-Lam Coupling
Reaction Mechanism
The mechanism of the amination is complex, but some experiments indicate that one of the roles of the base in the Chan-Lam amination is to sequester the acid generated and that the resulting salt provides the necessary protons to promote the oxidation of the Cu(I) species generated during the process. The use of molecular sieves is also beneficial to lower the production of the oxidation by-products. Among other reasons, the presence of atmospheric oxygen is necessary to reoxidize the catalyst upon reductive elimination.
Example
Experimental Procedure
To a stirred solution of the boronic ester (10.9 mmol, 1.0 eq) in CH2Cl2/MeOH (1:1, 109 mL) at room temperature was added 4Ã… molecular sieves (activated, 6.0 g), Cu(OAc)2 (1.0 eq) and DMAP (2.0 eq). The resulting mixture was stirred for 8 h before it was filtered through a pad of silica gel, eluted with EtOAc, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography to afford the desired product (60% yield).
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