Carboxylation Carboxylic acid azides

Phcnylcyclopentylamine, by hydrolysis of phenylcyclo-pentyl isocyanate, 51, 49 Phenylcyclopentyl isocyanate, by thermolysis of phenyl-cyclopentane-carboxylic acid azide, 51, 49... 

Cyclobutanecarboxylic acid azides react in a similar manner. The azides were either made from the acid chloride and sodium azide44,45 or directly from the acid by reaction with diphenylphos-phoryl azide.37,46,47 The carboxylic acid azides rearrange via the isocyanates. An example is the reaction of (+ )-ra-2-acetoxycyclobutanecarboxylic acid with diphenylphosphoryl azide to give 4 in quantitative yield.37... 

Diehloro-isonicotinyl Azide. See 2,6 Di-chloropyridine-4-carboxylic Acid Azide in this vol... 

Dichloropicolinyl Azide. See 4,6-rDichloro-pyridine-4-carboxylic Acid Azide... 

Dichloropyridine-2-carboxylic Acid Azide or 4,6-D ich loro-pi coliny I Azide,... 

Fig. 14.45. Transformation of an a-phosphonylcarboxylic acid ester (B) via the related carboxylic acid azide F and its Curtius degradation in ethanol to furnish an ethoxycarbonyl-protected a-aminophosphonic acid ester E. The N- and 0-bound protective groups of the latter compounds are cleaved off under acidic conditions. In this manner a-aminophosphonic acids are synthesized. They are interesting analogs of the biologically important a-amino carboxylic acids.

The thermal Curtius reaction of a 3-aminopyrazine-2-carboxylic acid azide proceeds with intramolecular cyclization to provide a versatile synthetic route to a wide variety of 1,3-dihydro-2tf-imidazo[4,5-i]-pyrazin-2-ones. Many compounds in this series are potent hypotensive agents in animals they are also inhibitors of the enyzme cyclic AMP phosphodiesterase in vitro. 

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-... 

More than a decade ago, Yamada and coworkers [70] developed two efficient reagents, diphenylphosphoryl azide (DPPA) and diethyl phosphorocyanidate (DEPC), for peptide done construction. The exact mechanism still remains speculative. For example, in the case of DPPA, the intermediacy of the carboxylic acid azide is tentative, but it seems attractive to consider a concerted process as shown in Figure 2 [70 a]. 

Peptide synthesis. In the above-mentioned synthesis of urethanes the carboxylic acid azide may be the intermediate, and this possibility prompted the Japanese chemists to investigate the usefulness of diphcnylphosphoryl azide in peptide synthesis. Indeed the reagent allows coupling of acylamino acids or peptides with amino acid esters or peptide esters in the presence of a base in high yield and with practically no racemiza-tion. The new method is compatible with various functional groups. 

Carboxylic acid azides have been analysed and again, the characteristic asymmetric stretching frequency is 2140 cm . Substitution alpha to the carbonyl group has little effect d . A review of the infrared characteristics of carbamoyl azides has appeared which cites 2150 cm as the characteristic frequency for the azido group. 

Infrared measurements of the complex between boron trifluoride (or trichloride) and carboxylic acid azides conclusively demonstrate that complexing occurred through the carbonyl oxygen rather than one of the nitrogens since the usual absorption is present . 

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. 

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