What Is the Blaise Reaction?
The Blaise reaction involves the addition of an organozinc reagent formed by an α-halo ester and zinc to a nitrile, and then generates a β-keto ester via an enamine ester (vinyl carbamate) [1].
Similar to the Reformatsky reaction, the Blaise reaction involves the reaction of a zinc enolate of an α-halo ester with a carbonyl compound to produce β-hydroxy esters. However, the Blaise reaction faces challenges such as low yields and competing side reactions in organic synthesis. Recent advancements in organometallic chemistry have reignited interest in exploring the potential of the Blaise reaction as a valuable tool for synthetic organic chemists. The attractiveness of this reaction lies in the ease of preparation or availability of starting materials like 2-bromoacetates and nitriles, as well as the versatility of the β-keto ester functional group in the resulting product for further modifications.
Fig 1. The formula of the Blaise reaction.
Mechanism of Blaise Conversions
The proposed mechanism for the Blaise reaction is depicted in Scheme 1. Initially, an a-bromoacetate 1 reacts with activated zinc(0) to form the zinc enolate, which then adds to the nitrile to produce the zinc imino ester 3. Upon acid hydrolysis of the zinc imino ester 3, the β-keto ester 2 is obtained through intermediates 4 and 5. Conversely, base hydrolysis of intermediate 4 results in the formation of β-amino-a,β-unsaturated esters.
Approximately 60 years after the discovery of the Blaise reaction, Cason and colleagues discovered that employing excess zinc (1.5 equiv) and α-bromoacetate (1.5 equiv) could increase the yield of b-keto esters up to 58% under reflux conditions in benzene with a catalytic amount of copper(II) bromide. For instance, the condensation of isobutyl α-bromopropionate 7 with hexanenitrile 6 yielded isobutyl 2-methyl-3-oxooctanoate 8 in 57% yield (Scheme 2).
Fig 2. The mechanism and development of the Blaise reaction. [2]
Application Examples of Blaise Reaction
In recent years, the Blaise reaction has become an essential carbon–carbon bond-forming reaction in synthetic organic chemistry, largely due to advancements in utilizing activated zinc. This reaction is particularly valuable for converting nitriles into β-keto esters or enamino esters with diverse structures, allowing for a two-carbon homologation. By incorporating further modifications to functional groups, a wide array of molecules can be produced. Additionally, the Blaise reaction can accommodate a wide range of functional groups and strained rings.
- Example 1: Kishi found that the use of activated zinc and tetrahydrofuran as solvents could improve the reaction yield and reduce side reactions, and used the improved steps to synthesize key intermediates of the marine toxin saxitoxin [3].
- Example 2: By using zinc-silver alloy and ultrasound, Meyers successfully carried out an intramolecular Blaise reaction under mild conditions (25-40°C), thereby completing the asymmetric synthesis of the alkaloids (-)-corynantheidol and (-)-dihydrocorynantheol [4].
- Example 3: The Blaise reaction was also successfully used to synthesize the starting materials of quinolone antibiotics [5] and to construct the lactone ring of the natural product Jerangolid D with antifungal activity [6].
Fig 3. Synthetic examples via Blaise reaction.
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References
- Blaise, E. E., Hebd, C., R., Seances Acad. Sci. 1901, 132, 478-978.
- Rao, H. et al. Tetrahedron, 2008, 64(35), 8037-8043.
- Hannick, S. M., Kishi, Y., J. Org. Chem. 1983, 48, 3833–3835.
- Beard, Richard L., and A. I. Meyers. The Journal of Organic Chemistry, 1991, 56(6), 2091-2096.
- Choi, B. S., Chang, J. H., Choi, H. W. Org. Process Res. Dev. 2005, 9, 311.
- Pospíšil, Jiří, and István E. Markó. Journal of the American Chemical Society, 2007, 129(12), 3516-3517.
