Carboxylic acids amides

Synthesis.—Af-Phenylamides can be prepared from carboxylic acids by first esteri-fying the acid with 2-fluoro-1,3,5-trinitrobenzene followed by displacement of the ester group with aniline.This mild method is successful for a good range of acids, giving consistently high yields of the amide. A direct, high-yield conversion of esters into AW-disubstituted amides is by reaction with dimethylaluminium amides, which similarly convert lactones into hydroxyamides.  

A further report has appeared on the use of polymer-supported tertiary phosphines in conjunction with carbon tetrachloride for the formation of peptide amide bonds,and hexachloroethane has been suggested as an alternative to carbon tetrachloride in this type of reaction.The well-known azide coupling method for the formation of amides gives cleaner and higher yields if two equivalents of the 

Kotake, K. Inomata, H. Kinoshita, K. Tanabe, and O. Miyano, Chem. Letters, 1977, 647. 

The condensation of ketoximes with 2-fluoropyridinium salts leads to salts (157), which on aqueous hydrolysis undergo a Beckmann rearrangement, giving amides (158) in high yields.  

A seemingly simple method for the coupling of acid chlorides to acetylenes which avoids the use of copper acetylides employs mixtures of copper(i) iodide, tri-phenylphosphine, and palladium(ll) chloride as catalysts. By treating terminal acetylenes with dimethylcarbamoyl chloride under these conditions, high yields of 2-alkynamides (159) may be obtained.  

Carboxamides substituted in the 2-position by eleetron-donor groups (299 X = Me, OMe, OH) react easily with chlorosulfonic acid (three equivalents) at 50-70 °C for between 30 minutes and 2 hours to give excellent yields (85-98%) of the corresponding 5-sulfonyl chlorides 300 (Equation 93).  

The yields obtained were substantially lower than those achieved in the chlorosulfonation of phenoxyacetamide, probably because steric interaction from the 2-substituent reduces the mesomeric activation of the aromatic nucleus by the phenoxy group. Phenylmethylacetamide 305 reacted sequentially with chlorosulfonic acid and ammonia to give a low yield of the p-sulfonamide 306 (Equation 96)288 

The latter compound is reported to possess antidiabetic properties. N-Benzylcarboxamides are chlorosulfonated by chlorosulfonic acid. For instance, A -benzyl / -chlorobenzamide 307 reacted with excess chlorosulfonic acid (12 equivalents) in boiling chloroform (3 hours) to give an excellent yield (84%) of the p-sulfonyl chloride 308 (Equation 97).  

In the 7V-benzylthiophene derivative 311, in contrast to the iV-benzylbenzamides 307 and 309, selective monochlorosulfonation was not observed indicating that the aromatic rings A and B in compound 311 must be of comparable reactivity towards sulfonation. 

Muraki and T. Mizoguchi, Chem. and Pharm. Bull. Japan ), 1970,18, 217. 

Mukaiyama, K. Goto, R. Matsueda, and M. Ueki, Tetrahedron Letters, 1970,5293. 

Use of the triphenylphosphine-carbon tetrachloride reagent, with or without the addition of triethylamine, provides an efficient peptide coupling procedure, both methods involving the intermediate phosphonium ester salt (94) the presence of triethylamine obviates the use of two equivalents of reacting amine. 

The activation of acids by oxidation or dehydration of their derivatives has been studied by a German school. Oxidation of an acid diphenylhydrazide by JV-bromosuccinimide yields the azonium ion (96), which functions as a highly activated acid derivative, azobenzene being eliminated on nucleophilic attack. A related activation by oxidation has been performed in the solid phase by production of the polymer-bound azo-compound (97), nitrogen being expelled on amide-bond formation. Dehydrative activation is exemplified by conversion of the ester (98), prepared from the acid and 1,1-diphenylethylene glycol, into the enol ester (99). The generation of azo-compounds by anodic oxidation of hydrazides has been reported. All of these procedures have been utilized successfully in peptide synthesis. 

In the dicyclohexylcarbodi-imide method of peptide-bond formation, the problems of racemization and rearrangement to A-acylureas can be avoided by interception of the intermediate activated ester with 1-hydroxybenzo-triazole. The ester so produced functions efficiently in amide-bond formation similar beneficial properties have already been noted with iV-hydroxy-succinimide. 

Uncatalysed aminolysis of esters by primary amines usually requires temperatures of 200°C or more such reactions can however be 

The known but little used reaction between carboxylic acids and 

Subsequent condensations with aldehydes and ketones generally 434 

Aminolyses of nitriles (505) are catalysed by many ruthenium species, most notably Rul (PPh-j), to give amides (506) in excellent 

Double deprotonation of a-keto-amides (517) gives rise to the 

Hollitzer, A. Seewald, and W. Steglich, Angew. Chem. Internal. Edn. 1976, 15, 444. 

An interesting new route to amides starting from either acyl chlorides or Grignard 

Reactions.—A-Alkylation of acetanilides has been achieved using a two-phase system of water and benzene with sodium hydroxide as base and triethylbenzylam-monium chloride yields are better than 80%. An efficient two-step process for the A-methylation of unsubstituted amides, lactams, and ureas has been described which involves initial formation of the corresponding methylol, by treatment with formaldehyde, followed by reduction with either triethylsilane and trifluoroacetic acid or with hydrogen over palladium in TFA. A method for the methylthiomethy-lation of both amides and lactanes has appeared.  

Yamashita, Y. Watanabe, T. Mitsudo, and Y. Takegami, Tetrahedron Letters, 1976, 1585. 

Normant and co-workers have shown that carbanions generated from NN-disubstituted amides and lactams can be alkylated in excellent yields. 

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Hofmann s amine synthesis can be applied to both aliphatic and aromatic carboxylic acid amides, benzamide, C HsCONH, thus giving aniline, C4H5NH,. 

Amino groups bound to sulfur can be replaced by fluorine via diazotization. In contrast to carboxylic acid amides, fluorodediazoniation of aromatic sulfonamides IS readily accomplished to give sulfonyl fluorides in high yields [52, 7S (equation 16) Tetrazotization-fluorination of sulfanilamide can also be effected to give a 38% yield of p-fluorobenzenesulfonyl fluoride [52],... 

Bond-Huper [69JCS(C)2453] synthesis, no traces of the described high-melting dark red substance were found. Only tolane-2-carboxylic acid amide (yield 65%) was obtained—the white crystals with a melting temperature of 156-157°C— which coincided with the results of Castro et al. (66JOC4071). Thus, in conditions of acetylide synthesis, o-iodobenzamide forms no bicyclic product. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

TABLE XXVn. l-Methyl-l,6-dihydropyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of Vicinal 4-(Alkyn- l-yl)pyrazole-5-carboxylic Acid Amides [90IZV2089]. 

Anhydrides are reduced with relative ease. McAlees and McCrindle 20) established the following increasing order of difficulty for various carbonyls acid chlorides > aldehydes, ketones > anhydrides > esters > carboxylic acids > amides. Reduction may proceed by 1,2-addilion of hydrogen or by cleavage of an oxygen-carbonyl bond. If 1,2-addition to the carbonyl occurs, as in the presence of strong protic acids over palladium, 1,1-diesters are formed by acylation 26). 

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. 

The tertiary amines 303 and the acid chlorides 304 (X = Cl) initially formed acylammonium salts 305, which underwent a von Braun type degradation by an attack of the nucleophilic chloride ion at the allyl system to give allyl chlorides 306/307 and carboxylic acid amide functions. 

Some pairs of functional groups such as alcohol, ester carboxylic acid, ester amine, amide and carboxylic acid, amide can be interconverted by simple reactions. When a member of these groups is the desired product or starting material, the other member should also be consulted in the text. 

Section 315 (Carboxylic Acid - Amide). Section 344 (Amide - Ester). 

Hydroxylation of long-chain carboxylic acids, amides, and alcohols—but not the esters or the corresponding alkanes—at the w-l, (0-2, and (o-3 positions by a soluble enzyme system from Bacillus megaterium (Miura and Fulco 1975 Narhi and Fulco 1986,1987). 

Alkylation of Aldehydes, Esters, Carboxylic Acids, Amides, and Nitriles... 

Cleavage of all the linkers described above provide a functional group (carboxylic acid, amide, amine, etc) at the anchoring position. Silyl-based handles 71,72, and 73 as well as germanium-based handle 74 insert a C-H bond at the anchoring position and are referred to as traceless (Fig. 15) [82-... 

In contrast to the reaction of benzamide and other carboxylic acid amides with lead tetraacetate, which has been said to proceed via an acyl nitrene intermediate 46>, methanesulphonamide and 2-biphenylsulphon-amide are completely inert towards this reagent 42>. 

The Alper group [163] reported on a highly efficient double carbohydroamination for the preparation of a-amino carboxylic acid amides 6/1-345, starting from aryl iodides and a primary amine 6/1-344, in usually high yield (Scheme 6/1.88) both, aryl iodides with electron-donating and electron-withdrawing groups can be used. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Isocyanates are quite reactive and they react with compounds which contain active hydrogen such as hydroxy, amine, carboxylic acids, amide, urea, etc. They can also undergo addition reaction ... 

Addition of HCN to acetone to form the cyanohydrin is still the main route to methyl methacrylate. Hydrocyanins can be converted to amino acids as well. The nitrile group can be easily converted to amines, carboxylic acids, amides, etc. Addition to aldehydes and activated alkenes can be done with simple base, but addition to unactivated alkenes requires a transition metal catalyst. The methods of HCN addition have been discussed by Brown [2],... 

CHIREX 3022 [N-l-[(l-naphthyl)ethyl]amido]indoline-2-carboxylic acid amide 179... 

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