Nitriles Blaise reaction

The reaction of a nitrile with a Reformatsky reagent is known as the Blaise reaction and when applied to (9-trimethylsilyl cyanohydrins leads to the formation of tetronic acids with high ee [79]. By working-up the Blaise reaction with ammonium chloride it is possible to isolate... 

Allylic zinc reagents are highly reactive and add to acid chlorides and anhydrides. A double addition of the allylic moiety usually occurs, leading to tertiary alcohols . The double addition can be avoided by using a nitrile as substrate (Blaise reaction). By... 

Usually, after hydrolysis, the alcohol is the product, but sometimes (especially with aryl aldehydes) elimination follows directly and the product is an olefin. By the use of Bu,P along with Zn, the olefin can be made the main product,454 making this an alternative to the Wittig reaction (6-47). Since Grignard reagents cannot be formed from a-halo esters, the method is quite useful, though there are competing reactions and yields are sometimes low. A similar reaction (called the Blaise reaction) has been carried out on nitriles 455... 

Reformatsky first introduced electron-withdrawing substituents on the a-carbon of an organozinc halide, leading to the more reactive and thermally stable a-(alkoxycarbonyl)alkylzinc halides (123).107 Typically these reagents react with aldehydes or ketones to afford 3-hydroxy esters while nitriles afford 3-keto esters (Blaise reaction),l07b>c but 1,4-conjugate additions to select a,3 unsaturated ketones are precedented (Section 1.2.2.2.2). 

Blaise reaction. Formation of (i-oxocsters by treatment of a-bromocarboxylic esters with zinc in the presence of nitriles. The intermediate organo-zinc compound reacts with the nitrile, and the complex is hydrolyzed with 30% potassium hydroxide. 

This chapter summarizes studies on the nature of the Reformatsky reagent as well as other, related, zinc enolates and outlines the synthetic aspects of the reaction with aldehydes and ketones. In addition, reactions of the Reformatsky reagent with imines and nitriles (the Blaise reaction) are described. 

An improved Blaise reaction provides a simple access to enaminones 34. Treatment of nitriles 32 with three to five molar equivalents of a-bromo esters 33 and activated zinc dust in refluxing THF gives the enaminones in high yield, Scheme 10. The value of the method was demonstrated by the conversion of the nitrile 35 to the pyrrolidine derivative 36, a key intermediate in the synthesis of the alkaloid saxitontn (83JOC3833). 

A-tosylhydrazones (equation 2) [52]. The reaction can also be executed in one pot from arylhalide, aldehyde, and tosyl hydrazine. A novel 2-arylindole synthesis that was discovered by Rashinkar entails the Pd-catalyzed reaction of o-nitrobenzyl cyanides with arylboronic acids (equation 3) [53]. Tobisu and Chatani accomplished the direct Pd-catalyzed alkynylation of anihdes leading to indoles (equation 4) [54], Lee and colleagues induced nitriles into becoming indole-3-carboxylates through the Blaise reaction (equation 5) [55]. 

Some papers mention the improvement of the Reformatsky reaction applied to nitriles (the Blaise reaction) by sonication. The presence of a chemical activator for zinc seems useful. This can be zinc oxide or silver. In the latter example, a cyclization between a bromoester moiety and a nitrile group was used in the synthesis of corynantheidol (Eq. 76). 2... 

A tandem one-pot method for the construction of highly substituted pyridine derivatives from nitriles, Reformatsky reagents, and 1,3-enynes was developed by Lee and coworkers in 2011 [64], The reaction sequential consisted of the reaction of nitrile with a Reformatsky reagent and then selective addition of the Blaise reaction intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatiza-tion cascade to give the final pyridines in moderate to excellent yields. 

A novel use of a wide range of nitriles as mediator has enabled the regioselective inter-molecular addition of unstabilized zinc ester enolates to 1-alkynes and l.S-enynes. " This reaction was made possible by a reversible addition of enolates to a nitrile (Blaise reaction), generating a zinc aza-enolate that, unlike zinc ester enolates, can add inter-molecularly to 1-alkynes and 1,3-enynes. Subsequent removal of the nitrile through a retro-Blaise reaction has generated the targeted addition product. 

Non-stabilized zinc ester enolates (463) (Reformatsky enolates) have been reported to add to terminal alkynes (465) in the presence of nitriles RC=N, affording (467). The reaction is initiated by the Blaise reaction of (463) with the nitrile, which generates the zinc chelate (464). The latter species then adds to the alkyne (465) in a Markovnikov manner, and the resulting intermediate (466) undergoes a retro-Blaise fragmentation to afford the zinc enolate (467) and the original nitrile. When combined with aDiels-Alder reaction partner and subsequent oxidative aromatization, this sequence can serve as a one-pot de novo construction of a-arylated alkanoates. " ... 

Synthesis of 2-pyridone-5-carboxylates from nitriles and propiolates by Blaise reaction Chun, Y.S., Ryu, K.Y., Ko, Y.O.,... 

REACTION WITH ACYLATING AGENTS /. 83.1 Reaction with Esters and Acid Chlorides 1.832 Reaction with Nitriles, the Blaise Reaction... 

Solid zinc activation has been used with success for the formation of stable organozinc compounds from functionalized benzylic bromides [8] and has been applied to the condensation of activated halides with nitriles [9] (Blaise reaction) or carbonyl compounds (10] (Reformatsky reaction). In this case, solid zinc is activated by catalytic generated zinc formed by electroreduction of anhydrous ZnBr2 solution in acetonitrile as solvent. Results and practical approaches have been reported [llj. 

Tetronic acids (Scheme 18) are of great interest because their derivatives are widespread in nature. The Blaise reaction (addition of the zinc derivative of an a-bromo ester to a nitrile) has been applied to optically active 0-protected cyanohydrins. Isolation of the tetronic acids was achieved, in moderate yields, by acid hydrolysis and cyclization of the intermediate imines [94]. Better results were obtained in an optimized reaction sequence [141] (Scheme 18). 

Reaction between nitriles, zinc, and a-halo esters (Blaise)... 

The most successful acylations of Reformatsky reagents have been obtained with nitriles. This reaction, first reported in 1901 by Blaise, was little used until Kagan and Suen reported that slow addition of a benzene solution of a-bromo esters to a refluxing mixture of zinc and the nitrile gave good yields (70-83%) of a,a-disubstituted 3-keto esters. Hannick and Kishl reported that a similar proce-... 

Zn-Barbier Reactions with Nitriles. The reaction of allylic halides with zinc in the presence of nitriles, was first studied by Blaise [102] in 1901. Later investigations showed that much better yields of the jS-unsaturated ketones could be obtained if benzene was employed as the solvent and when a zinc-silver couple was used [103, 104] (prepared from zinc and 0.1% silver acetate in methanoic acid). 

The Blaise reaction56 involves the condensation of an a-bromoester and a nitrile, in the presence of zinc metal, to give p-keto esters. The fundamental reaction is illustrated by the reaction of 4.126 to give 4.128, via a zinc iminium salt 4.127). 

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