Methyl ketones, acylation condensation with aldehydes

Dimethyl-188 and 2,6-dimethylpyrazine react very similarly to methylpyrazine. Thus, 2,6-dimethylpyrazine can be converted into a monoanion with sodamide in liquid ammonia which can be condensed with aldehydes and ketones,179 acylated with esters,181 and alkylated with alkyl halides181 to give the corresponding 2-methyl-6-substituted pyrazines. Acylation under suitable conditions also yields diacylated derivatives. Thus, when 2,6-dimethylpyrazine, sodamide, and ethyl benzoate are reacted in 1 3 2 molecular proportion, 38% 2,6-diphen-acylpyrazine (35) and 25% 2-methyl-6-phenacylpyrazine (36) is obtained. From the preparative point of view it is better to form the diacyl derivative by the further acylation of the monoacyl derivative rather than by direct diacylation.187... 

There are a number of variations of the condensation reaction of acid derivatives. The reaction between a cyclic ketone having a pendant alkynyl ester unit and tetra-butylammonium fluoride leads to cyclization to a bicyclic alcohol with an exocyclic allene moiety. A chain-extension reaction culminates in acyl addition of an ester enolate. The reaction of a p-keto ester, such as methyl 3-oxobutanote and EtZnCH2k leads to chain extension via a carbenoid-like insertion reaction (p. 803), which reacts with an aldehyde in a second step to give a methyl 3-oxopentanoate derivative with a —CH(OH)R group at C-2 relative to the ester carbonyl. ... 

According to Carlin et al. (1986), the exact mechanism of oxazole formation is not known, despite the previous schemes proposed by Vitzthum and Werkhoff (1974a,b) and by Ohloff and Flament (1978). Formation pathways were proposed by Baltes and Bochmann (1987d) and Mottram (1991). For Vitzthum and Werkhoff (1974b), one pathway could be the decarboxylation of serine or threonine into ethanolamine or methylethanolamine condensation with an aldehydic compound into an oxazolidine, then oxidation into an oxazole unsubstituted or methylated on position 5 and bearing an alkyl or an acyl radical on position 2. Another pathway could be the condensation of amino acids with a-dicarbonyl compounds, followed by a Strecker degradation, formation of an a-amino ketone which, after acylation... 

Several other methods for the synthesis of N-acyl A -amino acid derivatives have been described. These include the condensation of aldehydes or ketones with isocyanoacetates followed by transformation of the resultant iV-formyl derivatives, 7V-chlorination of A -acyl amino acid esters followed by elimination of HCl using DBU, reaction of a-oxo carboxylic acids with amides or methyl carbamates and enzymatic dehydrogenation of A -acyl amino acid amides ". With the exception of the last, these methods have not been reported so far in isotope chemistry. 

The Woodward synthetic route was initiated with a Diels-Alder reaction between 1,4-benzoquinone (14) and diene 15. The cycloadduct 16 formed in this way underwent Meerwein-Pondorff-Verley reduction to afford tricyclic lactone 17 which was converted to bromoether 18. Treatment of this substance with methoxide gave the methyl ether 19. Conversion of 19 to its halohydrin followed by chromium oxidation provided the a-bromo ketone 20 which upon treatment with zinc in glacial acetic acid afforded the bicyclic enone 21. This substance was transformed to the aldehyde-acid 23 by an osmylation-periodate cleavage sequence. The acid function in 23 was es-terified and the aldehyde moiety was condensed with 6-methoxytryptamine. The Schiff base intermediate obtained in this fashion was reduced to give an amine which provided the lactam 24 upon intramolecular acylation. Bischler-Napieralski cyclization of 24 gave the pentacyclic intermediate 25 in which... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

Lithium salts of t-butylhydrazones of aldehydes have been shown to be useful acyl anion equiv-alents. Treatment of an aldehyde r-butylhydrazone with an alkyllithium reagent or LDA gives the am-bident nucleophile (95), which reacts with both aldehydes and ketones to give carbon-substituted products as shown in equation (35). The condensation works best with nonenolizable carbonyl derivatives. Extension of this chemistry to the reaction of (95) with a,3-unsaturated carbonyl compounds met with mixed success. While good yields of Michael products were seen in the addition of (95) to methyl crotonate, other a,p-unsaturated electrophiles such as methyl acrylate, acrylonitrile and methyl P,p-di-methylacrylate gave negligible yields of carbon-substituted products. 

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