Carboxylic esters with amines

The rate of reaction of carboxylic esters with amines can often be increased by using as acylating agents esters that exchange their alcohol residues with particular ease. With this in mind Schwyzer781 recommends the use of cyano-methyl esters, RCOOCH2CN. The cyanomethyl esters of N-protected amino acids react readily even at room temperature with amino esters and are thus particularly suitable for peptide synthesis. Also, phenyl trifluoroacetate has been recommended for trifluoroacetylation of amino acids and peptides.782 The possibilities offered by such activated esters for peptide synthesis are reviewed in the monograph by Schroder and Liibke.783... 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Although, the enzymatic reaction of esters with amines or ammonia have been well documented, the corresponding aminolysis with carboxylic acids are rarer, because of the tendency of the reactants to form unreactive salts. For this reason some different strategies have been used to avoid this problem. Normally, this reaction has been used for the preparation of amides of industrial interest, for instance, one of the most important amides used in the polymer industry like oleamide has been produced by enzymatic amidation of oleic acid with ammonia and CALB in different organic solvents [10]. 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

Reactions of 2,3-dioxo-l,2,3,5,6,7-hexahydropyrido[l,2,3-carboxylic acids and the homologous acetic and propionic acids, prepared by basic hydrolysis of the corresponding ester, with amines, 28% NH4OH, and hydroxylamine derivatives in the presence of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and hydroxybenztria-zole <1995BML1527>, 1995BML1533>, and in the presence of NEt3 and A, A -bis(2-oxo-3-oxazolidinyl)phosphinic... 

Amides can be obtained from acyl halides, carboxylic anhydrides, or esters with amines or ammonia. The mechanisms of these reactions are very similar to the corresponding reactions of alcohols ... 

Antimony(m) ethoxide (Sb(OEt)3) promotes the intermolecular amidation of esters and carboxylic acids with amines under azeotropic conditions.47,48 When tetramino esters are used, the antimony(in)-templated intramolecular macrolactamization provides macrocyclic spermine alkaloids in good yields (Equation (14)). Under the same... 

Carboxamides of the tricyclic compounds 244 (n = 1, R = CONH2) and 389 (w = 1, R = CONH2) were obtained from the appropriate esters or from carboxylic acids with ammonia, via mixed anhydrides. N-Substi-tuted carboxamides of the pyrido[l,2-fl]quinazolinones 211 (R = CONHR ) were prepared directly from the corresponding acids with amines in the presence of diphenylphosphoryl azide and triethylamine in dimethyl-formamide at — S C " or were obtained from esters with amines. ... 

The only way to realize an enantioselective Biginelli reaction is to conduct it intramolecularly where the enantiopure urea and aldehyde portions are tethered. This reaction was the key step in L.E. Overman s total synthesis of guanidine alkaloid 13,14,15-lsocrambescidin 800. An optically active guanidine aminal was reacted with an enantiopure (3-keto ester in trifluoroethanol to afford 1-iminohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester with a 7 1 trans selectivity between CIO and Cl3 positions. 

PhjSbO mediates the dehydrative condensation of carboxylic acids with amines via Ph3Sb(OCOR)2 as reactive intermediates [146]. This catalytic system has been applied to dipeptide synthesis (Scheme 14.73) [147]. Treatment of olefins with a mixture of AcOH and P4S10 in the presence of Ph jSbO affords alkylthio esters [148]. 

Reaction of a free acid or a carboxylic ester with an amine with KOH/K2CO3 and a phenylphosphonate coupling agent. 

Acylation of nitrogen compounds by carboxylic esters. The action of carboxylic esters on ammonia or primary or secondary amines generally leads to carboxamides under relatively mild conditions, and the analogous treatment of carboxylic esters with hydrazine and hydroxylamine provides the most important methods of preparing simple carboxhydrazides and carbohydrox-amic acids. 

Reaction of carboxylic esters with hydrazines is generally easier than that with amines. Simple aliphatic esters often give the corresponding hydrazide exothermally at room temperature, though it is advisable to warm the mixture on the water-bath for a short time thereafter. In such reactions the formation of 1,2-diacylated hydrazines rarely proves troublesome although it is a frequent side reaction when acid chlorides or anhydrides are used. The following details exemplify the technique ... 

The reactions of enolized keto carboxylic esters with ammonia and amines are described on page 507, and those of a-amino alcohols, cyanohydrins, and a-hydroxy sulfonic acids on pages 516-520. 

Substitution reactions of RCO2H require a leaving group OH". The of water is about 15, so acids should be about as electrophilic as esters. Esters react well with ammonia to give amides. However, if we try to react carboxylic acids with amines to give amides no substitution occurs an ammonium salt is formed because the amines themselves are basic and remove the acidic proton from the acid. 

When the base is hydroxide and the reaction is done in water, as in the preparation of 189, this reaction is known as the Schotten-Baumann reaction, after Carl Schotten (Germany 1853-1910) and Eugen Baumann (Germany 1846-1896). Just as amides are prepared from the reaction of carboxylic acid esters with amines or ammonia, so sulfonamides are prepared from sulfonate esters. An example is the reaction of ethyl butanesulfonate (190) with ammonia to give butanesulfonamide, 191. 

N-Substituted amides are produced in small amounts by heating carboxylic acids with amines. They are formed relatively easily from fatty acids or their esters (such as triacylglycerols) and amines. The reactivity of esters of fatty acids is greater than the reactivity of free fatty acids. At temperatures above 150 °C, amino acids also... 

Dehydrative Condensation of Carboxylic Acids with Amines and Alcohols. In the presence of a mercuric catalyst, (1) causes dehydrative condensation of carboxylic acids with H-acidic materials such as amines and alcohols to give the corresponding amides, esters, lactones, and peptides in high yields. ... 

Typical nonsieve, polar adsorbents are siUca gel and activated alumina. Kquilihrium data have been pubUshed on many systems (11—16,46,47). The order of affinity for various chemical species is saturated hydrocarbons < aromatic hydrocarbons = halogenated hydrocarbons < ethers = esters = ketones < amines = alcohols < carboxylic acids. In general, the selectivities are parallel to those obtained by the use of selective polar solvents in hydrocarbon systems, even the magnitudes are similar. Consequendy, the commercial use of these adsorbents must compete with solvent-extraction techniques. 

The aminolysis of esters of pyrimidine occurs normally to yield amides. The reagent is commonly alcoholic ammonia or alcoholic amine, usually at room temperature for 20-24 hours, but occasionally under refiux aqueous amine or even undiluted amine are used sometimes. The process is exemplified in the conversion of methyl pyrimidine-5-carboxylate (193 R = Me) or its 4-isomer by methanolic ammonia at 25 °C into the amide (196) or pyrimidine-4-carboxamide, respectively (60MI21300), and in the butylaminolysis of butyl ttracil-6-carboxylate (butyl orotate) by ethanolic butylamine to give A-butyluracil-5-carboxamide (187) (60JOC1950). Hydrazides are made similarly from esters with ethanolic hydrazine hydrate. 

If there is no phenyl substituent in the 3-position the amination ability decreases. The acyloxaziridine (104) yields only 11% of a semicarbazide derivative with piperidine. In the presence of strong bases an intramolecular amination competes. Compound (104) reacts with methoxide within a couple of seconds to give phenylhydrazine carboxylic ester (106), and with cyclohexylamine to give the substituted semicarbazide (107). A diaziridinone (105) is assumed to be the common intermediate, formed by an intramolecular reaction from deprotonated (104) (67CB2600). 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

It was anticipated that fragments 147 and 214 could be united through an amide bond linking the nitrogen atom of the latter with C-8 of the former. Indeed, the active ester formed by treatment of carboxylic acid 147 with 1,3-diisopropylcarbodiimide and 1-hydro-xybenzotriazole reacts efficiently with amine 214 to afford dihydroxy amide 215 in 95 % yield. This convergent union creates a molecule that possesses all but two carbon atoms of the natural product. 

Since 3-methylenecyclobutane-l,2-dicarboxylic anhydride is easily converted to 3-methyl-2-cydobutene-l,2-dicarboxylic acid, it is an intermediate to a variety of cyclobutenes. The dimethyl ester of 3-methylenecyclobutane-l,2-dicarboxylic acid is also a versatile compound on pyrolysis it gives the substituted allene, methyl butadienoate, and on treatment with amines it gives a cyclobutene, dimethyl 3-methyl-2-cyclobutene-l,2-di-carboxylate. ... 

When a carbonyl group is bonded to a substituent group that can potentially depart as a Lewis base, addition of a nucleophile to the carbonyl carbon leads to elimination and the regeneration of a carbon-oxygen double bond. Esters undergo hydrolysis with alkali hydroxides to form alkali metal salts of carboxylic acids and alcohols. Amides undergo hydrolysis with mineral acids to form carboxylic acids and amine salts. Carbamates undergo alkaline hydrolysis to form amines, carbon dioxide, and alcohols. 

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