Fukuyama Coupling refers to the reaction between organozinc compounds and thioesters under palladium catalysis to produce ketones. This reaction was discovered by Tohru Fukuyama and colleagues in 1998 and is named after him.

Fukuyama Coupling has attracted widespread attention for its mild reaction conditions and high functional group compatibility, making it particularly suitable for the synthesis of complex molecules requiring high tolerance toward sensitive groups. Compared to traditional acylation methods, it avoids the use of strong bases or acids, thereby improving the selectivity and efficiency of the reaction. Since the resulting ketones are key structural units in many natural products, pharmaceuticals, and functional materials, Fukuyama Coupling holds significant value in organic synthesis.

• Reagents: Palladium catalyst, solvent

• Reactants: Organozinc compound, thioester

• Product: Ketone

• Reaction Type: Coupling reaction

Experimental Tips:

1. Organozinc reagents are sensitive to water and oxygen and should be handled under an inert atmosphere (e.g., nitrogen or argon). Solvents must be rigorously dried.

2. The reaction commonly uses Pd(0) catalysts such as Pd(PPh₃)₄, and sometimes Pd₂(dba)₃ in combination with ligands (e.g., PPh₃, XPhos).

3. In addition to palladium systems, nickel can also catalyze Fukuyama coupling reactions, with Ni(acac)₂ performing better than other nickel catalysts [1].

4. Thioesters bearing S-benzyl (S–Bn) or S-ethyl (S–Et) groups tend to be more reactive and give better results. Thioesters can be conveniently synthesized from carboxylic acids and the corresponding thiols.

Reaction Mechanism:

Mechanism of the Fukuyama Coupling Reaction

Original Publication:
Tokuyama, Hidetoshi; Yokoshima, Satoshi; Yamashita, Tohru; Fukuyama, Tohru. Tetrahedron Letters, 1998, 39 (20), 3189–3192.

Key References:

• Fukuyama Cross-Coupling Approach to Isoprekinamycin: Discovery of the Highly Active and Bench-Stable Palladium Precatalyst POxAP, Org. Lett., 2019, 21 (3), 1779–1794.

• Enantioconvergent Fukuyama Cross-Coupling of Racemic Benzylic Organozinc Reagents, Angew. Chem. Int. Ed., 2016, 128 (14), 4663–4666.

• A Practical Synthesis of Multifunctional Ketones through the Fukuyama Coupling Reaction, Advanced Synthesis and Catalysis, 2007, 349 (11–12), 2027–2038.