Cyano-esters enolates

Cyano-esters can also be condensed with other nitriles, as in the reaction of methyl a-cyano acetate and a-amino acetonitrile to give 4.6. Initial condensation of the cyano-ester enolate with the "other" nitrile moiety gave an iminium salt. Subsequent reaction with aqueous acid led to an imine, which isometizes to the... 

Whereas reaction of the cyano-substituted indolizine 251 with a base results in the tf-fused product (Equation 34), the diester 255 reacts to give only the Afused product 256 <1987CL2043> (Equation 37). Similarly, when the acylindolizines 257 are prepared (Equation 38), very small amounts of the thienoindolizines are found in the product mixture. When such indolizines are substituted with both cyano and keto groups, treatment with a base gives a mixture of products resulting from reaction of the ester enolate with either of these electrophiles <1989BCJ119> (Equation 39). 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Cyclic derivatives having the A -acylenamines or N-acylimines structure can be prepared starting from the cyano esters as well as from the enol forms of / -ketonitriles. 

With the 1,4-dimethoxynaphthalene ligand, cyano-stabilized anions (including cyanohydrin acetal anions) and ester enolates equilibrate even at low temperature and strongly favor addition at the a-position (C-5). The kinetic site of addition is also generally C-a. However, the 2-lithio-l,3-dithiane anion and phenyllithium do not equilibrate over the temperature range -78 to 0°C. The sulfur-stabilized anions favor addition at C-/3 (equation 119) 134,190 phenyllithium... 

The nature of the base can profoundly influence the regiochemistry of the reaction. f-BuOK favors kinetic control in the reaction shown in eq 16 and the product derived from cyclization of the enolate having a /3-amino group is obtained. However, when EtONa/EtOH is employed, the more stable /3-keto ester enolate resulting from thermodynamic control is obtained. In addition to diesters, dinitriles, e-keto esters, e-cyano esters, e-sulfinyl esters, and -phosphonium esters may participate in these reactions. 

Other C-arylation reactions have been accomphshed with vinylogues of P dicarbonyls [93], malonic acid derivatives [94], a-cyano esters and malonitriles [95]. The a-arylation of ketone enolates/enamines and nitroalkanes has also been achieved [96-98]. 

Predominant formation of the C-benzylated product can be understood by considering the soft carbon nucleophile attacking the benzyl carbon of the oxosulfonium trilluoromethane sulfonate, with diphenyl sulfoxide acting as a soft leaving group. The reaction also proceeds smoothly with various other substituted benzyl alcohols with moderate to good yields. Sodium enolates derived from esters, a-cyano esters, a-aromatic and aliphatic ketones can also be benzylated with consistent high yields. 

As applied to an amino acid synthesis, the ester enolate must react with another molecule that contains a nitrogen moiety. In one example, methyl 2-methylpropan-oate was treated with lithium diisopropylamide and then with 4-bromobutanenitrile to give 4.68. Catalytic hydrogenation of the cyano group gave methyl 6-amino-2,2-dimethylhexanoate (4.dP).35a in this case, the nitrile was the amine surrogate and the ester was the acid precursor. 

Unlike the chiral, neutral N-F reagents, the [N-F] ammonium salts of cinchona alkaloids are employed for the fluorination of a number of substrates ketone and ester enolates, (3-keto esters, a-cyano esters, a-nitro esters, a-amino esters, silyl enol ethers, enol acetates, nitrile anions, and... 

It is believed (54IZV47 72JPR353) that in the first stage the intermediate 282 is formed due to the addition of the CH acid to the enamine moiety with subsequent elimination of amine. The enol form of the intermediate 282 undergoes cyclization in two fashions, depending on the nature of substituent X. In the case of the ester (X = OMe) the attack is directed to the cyano group to form substituted 3-methoxycarbonyl-I//-pyridin-2-one (283) or its tautomer (2-hydroxy-3-methoxycarbonylpyridine). With the amide (X = NH2) intramolecular condensation leads to 3-cyano-l//-pyridin-2-one and its hydroxy tautomer (284). 

With respect to the olefinic substrate, various functional groups are tolerated, e.g. ester, ether, carboxy or cyano groups. Primary and secondary allylic alcohols, e.g. 14, react with concomitant migration of the double bond, to give an enol derivative, which then tautomerizes to the corresponding aldehyde (e.g. 15) or ketone ... 

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