The Blaise Reaction allows the synthesis of β-enamino esters or β-keto esters (depending on the work-up conditions) via the zinc-mediated reaction of nitriles with α-haloesters.
Mechanism of the Blaise Reaction
Formation of an organozinc compound from the α-haloester is followed by addition to the nitrile, yielding the Blaise intermediate.
The Blaise intermediates can either be hydrolyzed to β-enamino esters or β-keto esters. Work-up with 50% aq. K2CO3 delivers β-enamino esters in the organic phase. An additional acidification of the product phase with 1 M aq. HCl hydrolyzes the β-enamino esters to give β-keto esters.
Further derivatization of the Blaise intermediate is possible, although rarely described. Some examples can be found in the recent literature section.
Drawbacks of the originally reported Blaise Reaction, such as low yield, narrow scope and competing side reactions such as self-condensation of the α-haloesters, are overcome by some recent modifications:
Use of activated zinc, tetrahydrofuran as solvent and an excess of α-haloester, added over 30 - 60 min, substantially improve the yield:
For the work-up, it is important that the reaction mixture is diluted with THF until a total volume of 3 mL for each mmol of α-haloester is reached and then 1/3 mL of 50% aqueous K2CO3 should be added with vigorous stirring. Rapid stirring for 30 minutes gives two cleanly separated layers. It's important to follow this protocol exactly; otherwise, emulsions will form, making the work-up tedious and decreasing the yield. The organic layer can be worked up using column chromatography on solvent-wetted silica gel to isolate the pure enamino ester. For the isolation of β-keto esters, the organic phase is first treated with 1 M aq. HCl at room temperature for 30 min.
The use of ultrasound allows a more convenient, one-step synthesis using zinc powders without specific activation. The amount of self-condensation side product is also lowered, as exemplified by the use of only a slight excess of bromoacetate:
Some more reactions can also be found in the recent literature section, making the Blaise Reaction a potentially useful method for the synthesis of β-enamino esters, β-keto esters and related compounds.
One-Pot Synthesis of 2-Pyridones via Chemo- and Regioselective Tandem Blaise Reaction of Nitriles with Propiolates
Y. S. Chun, K. Y. Ryu, Y. O. Ko, J. Y. Hong, J. Hong, H. Shin, S.-g. Lee, J. Org. Chem., 2009, 74, 7556-7558.
A tandem sequential reaction 2-bromoarylnitriles with a Reformatsky reagent (Blaise reaction), followed by Pd-catalyzed intramolecular aminocarbonylation with carbon monoxide at 1 atm pressure provides (Z)-3-methyleneisoindolin-1-ones. The conformational flexibility of the bisphophine ligand is of great importance to the success of this tandem aminocarbonylation reaction.
Z. Xuan, D. J. Jung, H. J. Jeon, S.-g. Lee, J. Org. Chem., 2016, 81, 10094-10098.