Carboxylic acid derivatives synthesis hydrochloride

A -methoxy-A -methyl-a-enaminoketoesters were employed as synthetic precursors for the regioselective condensations with hydrazines in a microwave-assisted synthesis of ethyl 1,5-disubstituted-4-pyrazole carboxylate derivatives <06OL3219>. Protected Af(r)-substituted (S)-3-(4-methoxycarbonyl-l//-pyrazol-5-yl)alanines were prepared by acid-catalyzed cyclocondensations of chiral enaminone, available from L-aspartic acid, with hydrazine hydrochlorides <06S2376>. 

Pyrrole-based anthranilic acid derivatives have been prepared utilizing a four step sequence starting from arylacetonitriles 4 <04T2267>. Condensation of the latter with ethyl formate followed by treatment with diethylaminomalonate hydrochloride (DEAM-HCl) led to enamine 6. Cyclization and transesterification then gave 3-aminopyrrole-2-carboxylate 7. The acid-mediated cyclocondensation of methylaminoacetaldehyde dimethyl acetal with malonitrile provided a novel synthesis of 2-amino-3-cyanopyrroles, useful building blocks for the preparation ofpyrrolo[2,3- f]pyrimidines <04OL2857>. 

Variations in the 5-substituent of chiral oxazolines cause considerable fluctuations in the degree of asymmetrical alkylation of these substrates, showing that steric as well as chelation factors are important in this method of obtaining chiral carboxylic acids. An impressive example of asymmetric induction is the synthesis of 3-substituted-3-phenylpropionic acids (5) of ca. 99% optical purity, from the 1,4-oxazepine (4) (derived from a-ethoxycarbonylcinnamic acid and /-ephedrine hydrochloride), by Michael addition of Grignard reagents in the presence of nickel chloride, followed by hydrolysis and decarboxylation."... 

The hydrochloride salt of procaine is marketed under the trade name Novocaine. We will show how to complete the synthesis of procaine when we study the derivatives of carboxylic acids in Chapter 18. 

A particular application of the synthesis of 4-ylidenebutenolides via acetylenic precursors is shown in Scheme 8 for the case of derivatives of the fungal metabolite patulin (10). Reaction between the acetylenic Grignard reagent (114) and keto-acetal (115) led first to (116) which by Wittig condensation with methoxycarbonylmethylenetriphenylphospho-rane was converted into a mixture of Z- and iE -isomers of ester (117). Saponification of the mixture of isomers then led to an isomeric mixture of the corresponding carboxylic acids, one of which, the Z-isomer (118) was cyclized to the butenolide (119). Acidic hydrolysis of (119) in the presence of hydroxylamine hydrochloride then gave the oxime derivative (120) of natural patulin 110). 

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