What Is Buchwald-Hartwig Coupling?
The Buchwald-Hartwig reaction is a vital transformation in synthetic organic chemistry that allows for the formation of C-N bonds through a palladium-mediated cross-coupling of aryl halides with amines or amine derivatives. Among them, the amine can be a primary amine or a secondary amine, and the phenol ester of the pseudo-aryl halide trifluoromethanesulfonic acid (ArOTf) can also be used. This reaction, named after its pioneers Stephen L. Buchwald and John F. Hartwig, has revolutionized the field by providing an efficient and practical method for constructing aromatic amines, thereby enhancing the synthesis of various compounds crucial in medicinal and chemical research.
Fig 1. Buchwald-Hartwig reaction and its mechanism. [1]
Mechanism of Buchwald-Hartwig Reaction
Early investigations conducted by Hartwig revealed the fundamental mechanism employing P(Ar)3-type ligands. The process involves the oxidative insertion of the Pd(0) species I into the aryl halide substrate, resulting in the formation of a dimeric species of type II. Subsequent coordination of the amine enhances its acidity, enabling deprotonation through the use of a hindered base such as tBuONa or LiHMDS. This step leads to the formation of the palladium amide complex IV, which subsequently undergoes reductive elimination to yield the arylated amine product alongside the restored Pd(0) catalyst I.
Application Examples of Buchwald-Hartwig Reaction
- Example 1: Various industrial processes using C-N coupling technology on a kilogram scale have been reported. In 2004, a study reported the synthesis of a significant intermediate for a 5-HT receptor antagonist on a massive scale. Employing racemic BINAP as the ligand, cesium carbonate as the base, and anisole as the solvent facilitated a cost-effective and rapid reaction, resulting in the production of 24 kg of the desired intermediate within a 6-hour timeframe. [1]
- Example 2: The Buchwald-Hartwig cross-coupling reaction is widely used in the synthesis of natural products and physiologically active compounds and fluorescent emitter molecules. For example, Amos B. Smith reported the construction of an indole ring system by a sequential Stille cross-coupling/Buchwald-Hartwig binding/cyclization strategy). This method laid the foundation for the second-generation synthetic strategy of complex alkaloids (+)-nodulisporic acids A and B. [2]
Fig 2. Synthetic examples via Buchwald-Hartwig reaction.
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References
- Forero-Cortés, Paola A., et al. Organic Process Research & Development, 2019, 23(8), 1478-1483.
- Smith, Amos B., et al. The Journal of Organic Chemistry, 2007, 72(13), 4611-4620.
