Amide formation ethyl formate

FIGURE 20 6 Mechanism of amide formation in the reac tion of a secondary amine with an ethyl ester... 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

A mixture of 105.7 g. (0.55 mole) of ethyl benzoylacetate and 46.6 g. (0.5 mole) of aniline (Note 1) is placed in the dropping funnel D (Fig. 1) at the top of the continuous reactor (Notes 2 and 3) after the column has been heated to 135° (transformer set at 80 volts) (Notes 4 and 5). The reactants are then admitted to the column during about 15 minutes (this corresponds to a rate of amide formation of 396-400 g. per hour). Alcohol distils (Note 5) noticeably from the column during the addition and collects in flask G. At the completion of the reaction,... 

Amide formation, from a carboxylic acid and urea, 37, 50 from 2-amino-5-nitroanisole and ethyl benzoylacetate, 37, 4 from aniline and ethyl benzoylacetate, 37, 3... 

Peptides. A new amide or peptide synthesis is based on the formation of iminophosphoranes, R N=PR3, from the reaction of azides with a tertiary phosphine. These phosphoranes react with carboxylic acids to form amides.1 Ethyl diphenylphosphinite is more useful than a triarylphosphine because the by-product is hydrolyzed to diphenylphosphinic acid, which can be readily removed. The iminophosphorane 2, derived from 1 and ethyl azidoacetate, reacts with CboGly-L-Phe-OH to give optically pure 3 in 70% yield.2... 

When catalyst poisoning occurs, it is due to amide formation by reaction of the amine with the ester group of ethyl cyanoacetate. The HMS catalysts are generally slightly less active when compared directly, but their ability to function well in toluene, and the much higher loadings achievable (2.5 mmol g-1 vs. 1.0 mmol g-1) means that under optimum conditions they can match the silica catalysts in terms of rate. Their turnover numbers are typically higher by a factor of 4-5. 

Another approach based on the introduction of amine groups onto chitosan was also proposed. Ghosn et al. investigated the introduction of secondary and tertiary amines to improve the transfection efficiency of chitosan [46]. This one-step synthesis was based on the grafting of a carboxylic acid-bearing imidazole onto chitosan by amide formation, mediated by l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and was simple and reproducible and improved the solubility and the buffering capacity of the chitosan derivatives. 

The same method was also used for the synthesis of the anti-malarial compound mefloquine. Heterocyclization of 2-trifluoromethylaniline with trifluoroacetic acid ethyl ester provides 2,8-6w-(trifluoromethyl)-4-hydroxyquinoline. Bromination with phosphorous tribromide, followed a carbon monoxide introduction, affords 2,7-trifluoromethyl-4-carboxylic acid quinoline. Amide formation and pyridine reduction completes the synthesis providing mefloquine in high yields. ... 

An isomiinchnone-based strategy has also been deployed to gain access to a new class of 5-functionalized adenosines [158]. Elaboration of the 5 -aminoadenosine 201 employing amine protection, amide formation with methyl malonyl chloride and the usual diazotransfer reaction led to the a-di-azoimide 202. The Rli2(pfbm)4-catalyzed reaction of the diazoimide 202 in the presence of ethyl vinyl ether yielded the endo-selective cycloadducts 203a... 

From Enamines and Mercaptocarboxylic Acids. In the course of their wider study of the reaction between enamines and thiol adds, Klemmensen et have described a smooth condensation of enamines (312) derived from ethyl acetoacetate and ammonia or methylamine (/.e. ethyl j8-amino-crotonates) with a-mercaptocarboxylic acids (311) to thiazolidinones (313). The cyclization involves the addition of the thiol group, of (311), to the double bond, and amide formation between the amine and acid. ... 

Alkaloids with polycyclic skdetal frameworks are, when it comes to their synthesis, excellent candidates for RCM. Illustrative are the indolizidines rhynchophylline (43) and its C(7)-epimer ixo-rhynchophylhne (44), both isolated from the plant Uncaria rhynchophytta (Rubiaceae) [26]. Deiters total synthesis of 43 and 44 started with the efficient construction of diallylamine 39 via amide formation between indole-3-acetic acid (38) and diallylamine (Scheme 2.10). One-pot RCM-carbomagnesation of 39 was smoothly achieved with only 1 mol% of [Ruj-I catalyst and 4 equiv. of EtMgCl to afford the 2-ethyl-3-butene-amine derivative in 71% yield. It appeared that the electron-withdrawing carbonyl moiety was critical to the success of the RCM-carbomagnesation steps. Amide reduction and subsequent treatment with acryloyl chloride dehvered the second metathesis precursor 40. Cyclization with [Ruj-I (5 mol%) then furnished the a,j8-unsaturated lactam 41 in a high yield of 91%. Continuation of the total synthesis of alkaloids 43 and 44 included a Bischler-Napieralski cychzation (42) and subsequent rearrangement into the oxindole framework. 

Ethyl oxalate is the only liquid ester which gives this rapid separation of the amide, which is therefore characteristic. Methyl and ethyl formate react rapidly with ammonia, but the soluble formamide does not separate methyl succinate gives crystalline succinamide after about I hour s standing, other esters only after a much longer time. The solid esters, other than methyl oxalate, are either soluble in water and remain so when treated with ammonia, or alternatively are insoluble in water and hence clearly not methyl oxalate. 

Even though form amide was synthesized as early as 1863 by W. A. Hoffmann from ethyl formate [109-94-4] and ammonia, it only became accessible on a large scale, and thus iadustrially important, after development of high pressure production technology. In the 1990s, form amide is mainly manufactured either by direct synthesis from carbon monoxide and ammonia, or more importandy ia a two-stage process by reaction of methyl formate (from carbon monoxide and methanol) with ammonia. 

In a number of cases the intermediate oxime has been isolated in the reaction of hydroxylamine and /3-keto esters. The reaction of ethyl acetoacetate with hydroxylamine generated an oxime which cyclized on base treatment (Scheme 144) (70MI41600). Likewise, treatment of an analogous amide with hydroxylamine generated a ring opened material which cyclized on treatment with HCl (Scheme 144) (67T831). The presence of a minor contaminant in the standard reaction of ethyl acetoacetate with hydroxylamine was discovered and identified as an isomeric isoxazolin-3-one. The mechanism of product formation has been discussed (70BSF2685). 

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