Carboxylic acids amide formation

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

An alternative to the azlactone procedure for the preparation of short-chain dehydropeptides 19 is offered by the direct condensation of an a-oxo acid 17 on heating with one equivalent of a carboxylic acid amide or by the treatment of an a-oxo acid 17 with a nitrile in the presence of dry HC1 gas (Scheme 6). If the former reaction proceeds with the condensation of two molecules of amide per molecule of a-oxo acid, then the corresponding a,a-bis(acylamino) aliphatic acid 18 is formed, which on warming with acetic acid results in partial deamidation with formation of the corresponding dehydropeptide 19. 

Owing to the presence of many amine, carboxylic acid, amide, and other polar groups, wool and silk are hydrophilic in nature, wetted by water, and are dyed with either acid or basic dyes through the formation of ionic bonds (salt linkages). They may also be dyed with reactive dyes that form covalent bonds with available amino groups. 

The addition of alcohols to nitrilium salts gives rise to formation of alkoxymethyleneiminium salts, which react with bases to yield imido esters (231 Scheme 33). - By deprotonation of carboxylic acid amides ambident anions are formed, which can be alkylated in the presence of silver ions to give imido esters, e.g. (232). " Secondary amides react with trifluoroacetic acid anhydride or trifluorosulfonic acid anhydride to give mixed anhydrides of imidic acids (233). ... 

Heating of secondary carboxylic acid amides with HMPA gives rise to formation of A(-substituted V JV -dimethylamidines (310 Scheme 48). - In this procedure the secondary amide can be replaced by a ketoxime in which at least one substituent has to be an aromatic one. Similar methods were de-... 

With /J-amino carboxylic acid amides and formation of 4.5.6,7-... 

Cartx>nyldiimidazole 2 an activating reagent for carboxylic acids in formation of esters, amides, peptides, aldehydes and ketones via acylimidaroles 3 (see 1st edition). 

The presence of electron withdrawing groups at the a position (R3) of the acrylate derivative increases the reactivity of the reagent toward conjugate addition, while substituents in the ( position (R4) tend to provide steric constraints that hinder carbon-carbon bond formation (Scheme 3). Of the various acrylate derivatives employed in these reactions, the most frequently used have electron withdrawing functionality such as a carboxylic acid, amide, ester, or nitrile group or a combination of these. Direct pyridone formation can be achieved primarily through the use of either a,(J acetylenic esters or acrylate derivatives with P substituents (Y = SR, OR, NR2) that eliminate under the reaction conditions. 

The most frequently used approaches for derivatizing carboxylic acids are esterification with a variety of single-enantiomer alcohols, or formation of amides with single-enantiomer amines [234,252]. The formation of amide derivatives requires activation of the carboxylic acid by formation of the acid chloride with thionyl chloride, mixed anhydrides with chloroformates, N-acylimidazoles with 1,1 -carbonyldiimidazole or N-acylureas with dicyclohexylcarbodiimide. Esterification reactions generally re-... 

If an ortho-substituted benzene ring is attached to the nitrogen, the self-condensation is minimized due to steric hindrance and the yield of imidoyl chlorides increases in this order CH3 < Cl < Br ( ). Likewise, lowering of the basicity of the nitrogen prevents condensation. For example, N-sulfonimidoyl chlorides of aliphatic carboxylic acids are obtained in excellent yield ( ). The carboxylic acid amides of a,j8-unsaturated acids also do not undergo tautomerization, because the formation of allenes is not favored under mild conditions... 

Sulfur monochloride Partial formation of acylaminodisulfides from carboxylic acid amides in polar solvents... 

Wallach was the first (1874) to report on the transformation of carboxylic acid amides to amide chlorides by treatment with PCls various types of amides were converted by this reagent to chloromethyleneiminium chlorides (30 equation lg). - > Side reactions can include the a-chlorination of the amide chloride. If excess PCIs is used, the formation of iminium salts with complex ions (31) has been reported. The very labile bromomethyleneiminium bromides (32 equation 19) can be obtained by action of PBrs on tertiary amides. The iodomethyleneiminium salt (33) was prepared from DMF and diphosphorus tetraiodide in CS . ... 

Formation of anhydride succeeds with Ni catalysts even at lower temperatures (230 to 250 °C) than the synthesis of propionic acid from ethylene. Thiolcarboxylic acid esters are obtained analogously by addition of thiols instead of carboxylic acids (2). Olefins, carbon monoxide and amines react to give saturated carboxylic acid amides (3) and acid chlorides are formed from hydrogen chloride and carbon monoxide in the presence of noble metal catalysts of the 8th group of the periodic table of the elements (4). 

Aromatic isocyanates react with regular olefins only in the presence of metal catalysts. For example, reaction of ethylene with phenyl isocyanate in the presence of liganded nickel (o) catalysts under argon in THF at -20 °C affords a five-membered ring metalla-cycle, which on hydrolysis gives a Af-substituted carboxylic acid amide. Heating of the metallacycle causes jS-elimination with formation of Af-substituted acrylic acid amides Diolefines and allenes also undergo this reaction with phenyl isocyanate. From 1,1-bis-p-dimethylaminophenylethylene and p-nitrophenyl isocyanate a linear 1 1 adduct is obtained... 

The insertion of isocyanates into C-H bonds is also well known. Olefins, alkanes, aromatic and heteroaromatic compounds are known to react with isocyanates to give N-substituted carboxylic acid amides. Often the formation of the linear adduct is the result of a [2+2] cycloaddition reaction and subsequent rearrangement. Electron donating groups on the aromatic nucleus on the one side and electron withdrawing groups on the isocyanate enhance the reactivity of both components. Lewis acids, such as aluminum chloride, are supplied successfully as catalysts... 

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