Decarboxylative amidation

Trichloroacetic acid K = 0.2159) is as strong an acid as hydrochloric acid. Esters and amides are readily formed. Trichloroacetic acid undergoes decarboxylation when heated with caustic or amines to yield chloroform. The decomposition of trichloroacetic acid in acetone with a variety of aUphatic and aromatic amines has been studied (37). As with dichloroacetic acid, trichloroacetic acid can be converted to chloroacetic acid by the action of hydrogen and palladium on carbon (17). 

Biosynthesis. Two closely related genes encode the three mammalian tachykinins. The preprotachykinin A gene encodes both substance P and substance K, while the preprotachykinin B gene encodes neuromedin K (45—47). The active sequences are flanked by the usual double-basic amino acid residues, and the carboxy-terrninal amino acid is a glycine residue which is decarboxylated to an amide. As with most neuropeptide precursors, intermediates in peptide processing can be detected, but their biological activities are not clear (ca 1994). 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Carboxylic Acid Group. Reactions of the carboxyl group include decarboxylation, reduction to alcohols, and the formation of salts, acyl hahdes, amides, and esters. 

Pyridazinecarboxylic acids can also be prepared by hydrolysis of esters, nitriles and amides in the presence of acids or alkali. Another interesting method is partial decarboxylation of... 

Esters undergo hydrolysis and conversion to amides under the usual conditions, and amide side chains have also been formed from the acid and amine with DCCI. Acids have been formed from the corresponding spirohydantoins via ureido derivatives (Section 2.15.15.6.1), and undergo decarboxylation in the usual manner. 

The method described is a modification of the procedure used by Ghosez to synthesize cinnamonitrile. 3-(2-Furyl)acrylo-nitrile has been prepared by catalytic condensation of furfural with acetonitrile in the vapor phase at 320°, by dehydration of the corresponding amide over phosphorus pentachloride, and by decarboxylation of 3-(2-furyl)-2-cyanoacrylic acid. ... 

Hydroxycinchoninic acid of this purity is adequate for decarboxylation. A sample recrystallized from dimethylform-amide or SiV hydrochloric acid decomposes at 224° when observed as described before. 

Triazole has been prepared by the oxidation of substituted 1,2,4-triazoles, by the treatment of urazole with phosphorus pentasulfide, by heating equimolar quantities of formyl-hydrazine and formamide, by removal of the amino function of 4-amino-l,2,4-triazole, by oxidation of l,2,4-triazole-3(5)-thiol with hydrogen peroxide, by decarboxylation of 1,2,4-triazole-3(5)-carboxylic acid, by heating hydrazine salts with form-amide,by rapidly distilling hydrazine hydrate mixed with two molar equivalents of formamide, i by heating N,N -diformyl-hydrazine with excess ammonia in an autoclave at 200° for 24 hours, and by the reaction of 1,3,5-triazine and hydrazine monohydrochloride. ... 

It has been shown that 2,3-thiophenedicarboxylic acid is preferentially esterified in the 2-position and the dimethyl ester is preferentially hydrolyzed in this position. The structure proof was difficult to achieve as rearrangements occurred. Thus both isomeric amides (195) and (196) were decarboxylized to the N-methylanilide of 3-thiophenecarboxylic acid (197). The same carbomethoxy benzoyl-thiophene, proved to be 2-carbomethoxy-3-benzoylthiophene (198),... 

In cases where decarboxylation is anticipated, the quinazolinone could be obtained by heating ammonium o-formamidobenzoate or o-forra ami do benz amide for several hours. This ring closure could be effected more conveniently by boiling the o-formamidobenzamide with 3% aqueous sodium hydroxide for a few minutes, o-Amino-benzamides have also been converted to quinazolinones by refluxing with ethyl orthoformate alone or preferably in the presence of acetic anhydride. ... 

Application of the Bischler-Napieralski reaction to amides of tryptophan has been investigated. The cyclodehydration of acetyltrypto-phan under conventional conditions proved unsuccessful. Attempted ring closure of acetyltryptophan or its ethyl ester was accompanied by decarboxylation and aromatization, yielding... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Initialiy, 4-bromobenzyl-cyanide is reacted with sodium amide and 2-chloropyridine to give bromophenyl-pyridyl acetonitrile. This is then reacted with sodium amide then dimethyi amino ethyl chloride to give 4.bromophenyl-dimethylamlnoethyl-pyrldyi acetonitrlie. This intermediate is then hydrolyzed and decarboxylated to bromphenirame using 80% H2SO4 at 140°-150°C for 24 hours. The brompheniramine maieate may be made by reaction with maleic acid in ethanol followed by recrystallization from pentanoi. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

The cationic pathway allows the conversion of carboxylic acids into ethers, acetals or amides. From a-aminoacids versatile chiral building blocks are accessible. The eliminative decarboxylation of vicinal diacids or P-silyl carboxylic acids, combined with cycloaddition reactions, allows the efficient construction of cyclobutenes or cyclohexadienes. The induction of cationic rearrangements or fragmentations is a potent way to specifically substituted cyclopentanoids and ring extensions by one-or four carbons. In view of these favorable qualities of Kolbe electrolysis, numerous useful applications of this old reaction can be expected in the future. 

The published synthesis does the Michael addition first to give (19) which is not isolated but combined immediately with symmetrical (18). Amide formation to give (17) and condensation to give (16) occur under the same conditions and decarboxylation is carried out in the usual way,... 

Figure 17-5. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an amide link to a lysine residue of the transacetylase component of the enzyme complex. It forms a long flexible arm, allowing the lipoic acid prosthetic group to rotate sequentially between the active sites of each of the enzymes of the complex. (NAD nicotinamide adenine dinucleotide FAD, flavin adenine dinucleotide TDP, thiamin diphosphate.)...

Co-adsorption experiments show a complex role of the nature and concentration of chemisorbed ammonia species. Ammonia is not only one of the reactants for the synthesis of acrylonitrile, but also reaction with Br()>nsted sites inhibits their reactivity. In particular, IR experiments show that two pathways of reaction are possible from chemisorbed propylene (i) to acetone via isopropoxylate intermediate or (ii) to acrolein via allyl alcoholate intermediate. The first reaction occurs preferentially at lower temperatures and in the presence of hydroxyl groups. When their reactivity is blocked by the faster reaction with ammonia, the second pathway of reaction becomes preferential. The first pathway of reaction is responsible for a degradative pathway, because acetone further transform to an acetate species with carbon chain breakage. Ammonia as NH4 reacts faster with acrylate species (formed by transformation of the acrolein intermediate) to give an acrylamide intermediate. At higher temperatures the amide may be transformed to acrylonitrile, but when Brreform ammonia and free, weakly bonded, acrylic acid. The latter easily decarboxylate forming carbon oxides. 

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

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