Ethyl benzimidates

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

Pankova and Tichy prepared all four stereoisomeric 4-rerr-butyl-2-aminomethyl-l-cyclohexanols and cyclized them with ethyl benzimidate to hexahydro-l,3-benzoxazines 158-161 (74CCC1447). From the A-acyl O-mesylate derivatives 162 and 163 on thermal cyclization or thionyl chloride treatment, ring closure occurred with inversion and resulted in 158 and 159 (74CCC1447). 

Because some of the compounds with general structure 316 have noteworthy pharmacological activities, a number of alternative methods have been developed for the synthesis of the 2-substituted and 2,3-disubstituted derivatives 316. 2-Substituted derivatives of 316 cis, n = 1, 2, 3, 4 trans, n = 2, 3, 4) were prepared (77GEP2643384 80AUP507798) from 312-315 with ethyl benzimidates. The attempted ring closure of trans-2-amino-l-cyclopentanecarboxylic acid to rra/w-fused derivatives failed. In this reac-... 

Benzimidazoles and their derivatives possess varied pharmacological activities59 60 and have therefore been targets of intense synthetic efforts using both solution- and solid-phase methods. In one of the pioneering studies on the assembly of benzofused heterocycles via SvAr reactions of o-fluoro-ni-troarenes, Phillips and Wei reported a solid-phase synthesis of benzimidazoles from 3-fluoro-4-nitrophenol, amines, and ethyl benzimidates (Scheme 13).61... 

The benzimidoyl thiocarbodihydrazide (237) was cyclized by Soviet chemists to yield 3-phenyl-l,4-dihydro-l,2,4,5-triazine-6(5//)-thione (238). But since (237) was prepared by reaction of ethyl benzimidate and thiocarbodihydrazide this reaction can also be classified as a synthesis by a [5 + 1] atom fragment method (77KGS564). When the perfluoroalkyl hydrazidines (239) were heated with anhydrous iron(III) chloride, cyclization occurred with... 

The tetrahydropyridopyrimidinone 348 is produced from the enediamine 346 and ethyl benzimidate (347) in the presence of catalytic amounts of polyphosphoric acid (equation 141)171. 

A solution of ethyl benzimidate hydrochloride (496.9 mmol) in 300.0 ml methyl alcohol was cooled to 0°C, then treated with a solution of aminoacetaldehyde dimethyl acetal (670.9 mmol) in 75 ml methyl alcohol at such a rate that the temperature was kept below 5°C. The solution was stirred 3 days at or below 5°C, then concentrated, and an yellow oil isolated. The residue was dissolved in 750 ml 1M NaOH, then extracted four times with 250 ml CH2C12, dried with MgS04, concentrated, and 108.13 g of crude /V-(2,2-dimethoxyethyl)benzamidine was isolated as an yellow oil. It was used without further purification. 

Imidic esters are easily hydrolyzed in aqueous solution, but some are stable enough for a polarographic investigation in a cold solution. Reduction at a lead cathode in cold 1 M sulfuric acid of ethyl benzimidate gave benzylamine in 76% yield [43]. The reduction can probably be described by ... 

The pA a and log-on for the dissociation of the conjugate acid and hydroxide ion catalysed elimination from substituted ethyl benzimidate esters obey the Hammett correlations ... 

Scheme 1 Map of p values for hydroxide ion catalysed elimination of substituted ethyl benzimidate esters. Note that K/ is not the same as the dissociation constant for the conjugate acid ArClNH fOC H )... 

The phenyl thiazoline is formed from an amino thiol upon reaction with ethyl benzimidate hydrochloride in 87% yield. It is cleaved by heating to reflux with 6 N HCl. ... 

The reaction of ethyl acetimidate with 3-aminopyridine-4-carboxylic acid yields 2-methylpyri-do[3,4-d]pyrimidin-4(3//)-one (12, R = Me).471 Whereas other isomeric aminopyridinecar-boxylic acids are not cyclized by this reagent, the application of ethyl benzimidate has proved to be successful in all cases studied. 

A great number of 2-substituted pyrimidinones 108 have been synthetized by reaction of the corresponding P-amino acid 107 (R=OH) or its derivatives (R=OEt, NHR) with ethyl benzimidates, or by reaction of orthoesters with carboxamide 107 (R=NH2). Of this set of compounds, the racemic 2-(/n-chlorophenyl)-3,4a,5,6,7,7a-hexahydrocyclopenta [d]pyrimidin-4(3/f)-one (CHINOIN 143) displayed excellent antiinflammatory activity [44, 46, 120,121]. 

Hydrazino alcohols 296 react with ethyl benzimidate to form pyrrolo[l,2-r4[l,3,4]oxadiazine 298a or pyrido[l,2-4 -... 

Triazoles. Ethyl benzimidate hydrochloride and semicarbazide hydrochloride refluxed 1 hr. in pyridine 3-hydroxy-5-phenyl-l,2,4-triazole. Y 83%. F. e., also from nitriles in place of iminoesters, and methods s. H. Weidinger and J. Kranz, B. 96, 1064 (1963) f. heterocyclics s. B. 96, 1049, 1059. 

Just enough anhydrous disodium phosphate added with stirring and ice-cooling to a mixture of ethyl benzimidate hydrochloride and aq. 50%-cyanamide soln. to bring the pH to 5.5, and the product isolated after 2 hrs. ethyl N-cyano-benzimidate. Y 65%. F. e. s. W. Lwowski, Synthesis 1971, 263. 

Ethyl benzimidate warmed 1 hr. at 60° with a catalytic quantity of dry Na-ethoxide in abs. ethanol benzonitrile. Y 95%. - Through this reaction, prim, amides can be dehydrated under non-acidic conditions in excellent yield. F. e. s. R. F. Borch, Tetrah. Let. 1968, 61. 

---