Blaise Reaction refers to the reaction between a nitrile and an α-bromoester in the presence of zinc to form β-enamino esters or β-keto esters. It was first reported by Edmond Blaise in 1901 and is named after him.

The Blaise reaction has certain drawbacks, such as a narrow substrate scope and competing side reactions. However, due to the ready availability of starting materials and the synthetic utility of the β-keto ester products—common intermediates in organic synthesis—the reaction remains valuable. Furthermore, Blaise reaction intermediates can act as nucleophiles and react with various electrophiles to generate more complex structures, including heterocycles. Ongoing research and optimization of reaction conditions have significantly improved product yields.

Reagents: Zinc, hydrochloric acid, potassium carbonate, etc.
Reactants: Nitrile, α-bromoester
Products: β-Enamino ester or β-keto ester
Reaction type: Coupling reaction

Experimental Tips:

• During the workup step, using 50% aqueous potassium carbonate yields the β-enamino ester product. However, if the desired product is a β-keto ester, hydrolyze the β-enamino ester with 1 M hydrochloric acid to afford the final β-keto ester.

• Activated zinc is crucial for achieving high yields. Common activation methods include ultrasonic treatment and acid washing.

Reaction Mechanism

Original Reference:
Edmond E. Blaise. Compt. Rend. 1901, 132, 478.

Popular Citations:

• An improved procedure for the Blaise reaction: a short, practical route to the key intermediates of the saxitoxin synthesis. J. Org. Chem. 1983, 48(21), 3833–3835.

• A simple and highly efficient synthesis of β-amino-α,β-unsaturated ester via sonochemical Blaise reaction. Tetrahedron Letters. 1997, 3(20), 443–446.

• Reformatsky and Blaise reactions in flow as a tool for drug discovery. One-pot diversity-oriented synthesis of valuable intermediates and heterocycles. Green Chem. 2017, 19, 1420–1424.