Carboxylic acids, azides preparation

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

Very few imidazo[4,5-b] pyrazines have been reported in the literature1-3 and no good general method has been available for preparing compounds in this most interesting heterocyclic class. We have found that the Curtius reaction of a 3-aminopyrazine-2-carboxylic acid azide (Scheme I) proceeds with intramolecular cyclization to provide, in good yield, a wide variety of the subject compounds. We will report here only the 6-substituted 5-chloro-l, 3-dihydro-2tf-... 

Carboxylic acid azides give rise to three different reactions under different conditions. Azide coupling (equation 9) was the earliest method in peptide synthesis and is still one of the most important in fragment condensation and preparation of cyclic peptides due to its almost complete lack of racemization. At elevated temperatures a frequent side reaction is the Curtius rearrangement. Trapping of the intermediate isocyanate with amines (equation 10) gives urea derivatives and with carboxylic acids rearranged amides are obtained (equation 11). ... 

Carboxylic acid azides are prepared from carboxylic acid halides or from amino acid/peptide esters via hydrazides, followed by nitrosylation with nitrous acid in water or with alkyl nitrites in organic solvents.Also, the aforementioned diphenylphosphorazidate cf. Section 2.3.1.1.2.2.ii.e) is often used in this preparation method starting from carboxylic acids. 

Bromo-5-imino-3-pyrazolidinones are synthesized by Curtius rearrangement of the azides of 4-bromo-5-oxo-3-pyrazolin-3-carboxylic acids.697 4-Nitroso-5-imino-3-pyrazolidinones are believed to exist as the oximino tautomers.337 They are usually prepared by direct nitro-sation with nitrous acid.644-1339 1649 A Curtius rearrangement of 4-oximino-5-oxo-2-pyrazolin-3-carboxylic acid azide has also been used.337... 

Only one example was found where this class of amino acids was produced. Oxidation of 7.246 gave a ketone and treatment with boron trifluoride led to the conjugated ketone, 7.247.132 Conjugate addition of azide, reduction to the amine and cyclization gave diastereomeric methyl 9-(3-hexyl-2-aziridino)nonanoic acid (J.248 and 7.249). The final step in that sequence proceeded in only 37% yield. If the alkenyl moiety was converted to an epoxide moiety, aziridine carboxylic acids were prepared in good yield, via the azide.132... 

General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis, " and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids and o-aryl carboxylic acids direct preparation of thiol esters from carboxylic acids and thiols the stereospecific preparation of alkyl azides and the phosphorylation of alcohols and amines The application of DPPA in a modified Curtius reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source, and can undergo 1,3-dipolar cycloaddition reactions. The Curtius degradation of carboxylic acids in the presence of f-butanol gives the Boc-protected amine directly (eq 1). 

Early attempts to prepare 5-amino- and 5-acylaminobenzofuroxans by hypochlorite oxidation of the corresponding o-nitroanilines met with failure. Pyrolysis of the appropriate azide, however, gives 5-dimetliylamino- and 5-acetamidobenzofuroxan, whereas urethans of type (33) are produced by Curtius degradation of the 5-carboxylic acid. Controlled hydrolysis of the acetamido compound and the... 

The acyl azide intermediates are prepared either by reaction of sodium azide with a reactive acylating agent or by diazotization of an acyl hydrazide. An especially convenient version of the former process is treatment of the carboxylic acid with ethyl chloroformate to form a mixed anhydride, which then reacts with azide ion.265... 

The usual procedure of preparing acid azides, which involves treating an acid chloride with sodium azide,8,9 suffers from the disadvantage that it is often difficult to obtain pure acid chlorides in good yields from acids which either decompose or undergo isomerization in the presence of mineral acids.7 Synthesis of the azide by way of the ester and hydrazide10 has been used to circumvent this difficulty but is much less convenient. The present procedure permits ready formation of acid azides in excellent yields from mixed carboxylic-carbonic anhydrides and sodium azide under very mild conditions. 

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

Carboxylic acids show most of the standard reactions of benzoic acid. Amides, esters, hydrazides, azides and nitriles can be prepared by standard methods. Thiophenes form stable acid chlorides, furans unstable ones, and A-unsubstituted pyrroles do not form them. 

The (aminomethyl)thiophene-2-carboxylic acid isomers were prepared from the corresponding methylthiophene-2-carboxylic acid esters, as exemplified for the 3-(aminomethyl) isomer 79 (Scheme 22))66 The 4-(aminomethyl) isomer was prepared in the same way, but with a low yield for the bromination step (7%))66,111 For the 5-(aminomethyl) isomer the bromomethyl compound was reacted with sodium azide, followed by catalytic reduction)74 The corresponding furan and pyridine analogues were prepared similarly. 

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