Hydrazidic azides, synthesis

The first three steps show that the reaction sequence in Figure 14.45 actually provides a widely applicable approach to such a-aminophosphonic acids. The step leading to the acyl azide F, i.e., the nitrite oxidation of an acyl hydrazide (Formula C in Figure 14.45), is as commonly used for the preparation of an acyl azide synthesis as that shown in Figure 14.44. 

Hydrazides —> Azides. The acid azide method of peptide synthesis, for example of the protected dipeptide (3), has the advantage that no racemization of the peptide vomptments occurs. However, conversion of N-carbobenzoxy-S-benzyl-u-cysteine hydni/.lde (I) into the azide by reaction with nitrous acid under normal conditions (ITor ls considerable amide as by-product (Rt ONHNHNO — RCONH> + fiBaNHaOl. Amide formation can be lUDoraiiad hv onaratlna at hlah aoiditv and... 

Hydrazide— azide. In the synthesis of putrescine dihydrochloride, diethyl adipate is converted into the dihydrazide, which on reaction with nitrous acid affords... 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

Curtius rearrangement of a-oximino acid azides is reported as a new method of synthesis for 3-substituted 5-hydroxyoxadiazoles. In this method, the oxime of an a-ketoester is converted to the acid hydrazide, which in turn is converted to the azide by reaction with nitrous acid 115a). 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

Addition, of potassium cyanide to diethyl benzalmalonate, 30, 84 of sodium bisulfite, to cyclo-heptanone, 34, 25 to phenanthrenequmone, 34, 76 Adipyl azide, 36, 70 Adipyl hydrazide, 36, 69 Alanine, 33, 1 Aldehjde collidine, 30, 42 Aldehydes, stabilization against autoxidation, 37, 40 Aldehyde synthesis, 31, 92... 

A major side reaction in the synthesis of azides is the formation of amides. This was detected for the first time in the preparation of Z-Lys(Z)-N3 via the NaN02/HCl procedure where Z-Lys(Z)-NH2 was obtained as a side product. " Sinnilarly, in the case of Z-Cys(Bzl)-N3 the related amide is readily formed.b ] As this side reaction does not occur when the azide is prepared from the acid chloride and sodium azide, it was proposed that the mechanism involves cleavage of the nitrosated hydrazide as shown in Scheme 6.h l... 

The azide procedure adopted for the synthesis of apamin by CSPPS included the preparation of 4- [4-(bromomethyl)-3-nitrobenzoyl]amino)(phenyl)methylphenyl-copo-ly(styrene-l%-divinylbenzene) (BrCH2-Nbb-resin) 1 which was used for the generation of the protected hydrazide peptide (Scheme 1). The Kaiser oxime resin can also be used for generation of hydrazide peptides. 

The usual procedure of preparing acid azides, which involves treating an acid chloride with sodium azide, - 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. Synthesis of the azide by way of the ester and hydrazide 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 carboxyhc-carbonic anhydrides and sodium azide under very mild conditions. 

The third synthesis reported was not complete as it did not produce the optically active base. Propyllithium is condensed with 8-methoxy-quinoline, and the product is hydrolyzed and oxidized with nitric acid to 2-propyl-5,6-pyridinedicarboxylic acid. This acid is converted via the ethyl ester, the hydrazide, the azide, and urethan to 2-propyl-... 

The majority of 2-alkyl-5-aryl-l,3,4-oxadiazoles can easily be cleaved in mineral acid solution to give the corresponding diacid hydr azides. 2- (a-Bromoethyl) - 5-phenyl-1,3,4-oxadiazole is hydrolyzed so easily that even during the synthesis from 1 -a-bromopropionyl-2-benzoylhydrazine, on treating the reaction mixture with water, partial hydrolysis occurs to give the diacid hydrazide or even hydrazine. This can be eliminated in the synthesis by among other means the use of petrol ether in place of water. The 2-bromomethyl-5-aryl-... 

Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically 1,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides <04JCO312>. 

Carbonyl azides are usually obtained from the hydrazides, although in principle they can also be prepared directly from the carbonyl chlorides and sodium azide. They are frequently used as intermediates for synthesis of isocyanates, urethanes, ureas, amines, etc., and are often used in such work without isolation. 

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