Acyl azides anhydrides

Method 2 addition of the amine nucleophile to one of the activated forms of the acid (activated ester, acyl azide, anhydrides, etc.) to which it is to be combined. 

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaN3 and ZnCl2 in 82 ° or by treating tertiary alcohols with NaN3 and CF3-COOH or with HN3 andTiCl4 or BF3. Acyl azides, which can be used in the Curtius reaction (18-14), can be similarly prepared from acyl halides, anhydrides, " esters, or other acyl derivatives. ° Acyl azides can also be prepared... 

Carboxylic acids can also be activated by the formation of mixed anhydrides with various phosphoric acid derivatives. Diphenyl phosphoryl azide, for example, is an effective reagent for conversion of amines to amides.140 The proposed mechanism involves formation of the acyl azide as a reactive intermediate. 

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... 

Section A of Scheme 10.15 contains a number of examples of Curtius rearrangements. Entry 1 is an example carried out in a nonnucleophilic solvent, permitting isolation of the isocyanate. Entries 2 and 3 involve isolation of the amine after hydrolysis of the isocyanate. In Entry 2, the dihydrazide intermediate is isolated as a solid and diazotized in aqueous solution, from which the amine is isolated as the dihydrochloride. Entry 3 is an example of the mixed anhydride procedure (see p. 948). The first stage of the reaction is carried out in acetone and the thermolysis of the acyl azide is done in refluxing toluene. The crude isocyanate is then hydrolyzed in acidic water. Entry 4 is a reaction that demonstrates the retention of configuration during rearrangement. 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

The traditional method for preparing activated esters of A -protected dipeptides is combination of the A-protected amino acid with the amino acid ester (Figure 7.16). The latter is obtained by A-deprotection of the diprotected amino acid in an acidic milieu. Coupling is achievable using the carbodiimide, mixed-anhydride, and acyl-azide methods. Success with this approach indicates that the esterified residues react preferentially with the other derivatives and not among themselves. The chain cannot be extended to the protected tripeptide ester because the dipeptide ester cyclizes too... 

Anhydride 150 and trimethylsilyl azide in dioxane yielded an acyl azide, which by thermolysis, and Curtius degradation spontaneously furnished the isocyanate 151 (72CB3958 74CB3533). Anhydride 152 was formed by silyl ester cleavage on hydrolysis [73MI2 90JCS(P1)375]. 

Curtius degradation of the acyl azide and subsequent transesterification with tert-butanol and hydrolysis resulted in the A/-BOC amino acid 156. Compound 156 was readily cyclized with thionyl chloride, resulting in anhydride 157 diendo, R = H, Me diexo, R = H) in one step. In the cyclization step, acid chlorides were formed first and thereafter an intramolecular cyclization took place with loss of hydrogen chloride (93BSB227,93T1985). 

Curtius rearrangement of the acyl azide of Ac-Phe-OH 31, at rt in dilute HC1, provided Ac-Phe-NH2-HC1 32 in up to 65% yield. Coupling of Z-Phe-OH with 32 using the mixed anhydride method afforded Ac-Pheip[NHCO]Phe-Z 33 as a single diastereomer in 55% yield. Reaction of 33 after hydrogenation with HCOCH(iPr)C02Me provides 34. Compound 34 was hydrogenated to afford the reduced-retro pseudotripeptide 35 in 65% yield for the two steps. 

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. 

Other less commonly used coupling reagents include EEDQ (formation of mixed carboxylic carbonic anhydrides), Bop-Cl (formation of mixed carboxylic phosphinic anhydrides [52,53]), DPPA (formation of acyl azides), DECP (formation of acyl cyanides), MSNT (formation of mixed carboxylic sulfonic anhydrides), and benzisoxazo-lium salts (generation of phenyl esters [54]). 

Pyridopyrimidine systems may also be accessed by in situ generation of pyridylisocyanates <2003TL2745>. Treatment of 2,3-pyridinccarboxylic anhydride with methanol leads to the formation of 2-(methoxycarbonyl)nicotinic acid that undergoes Curtius rearrangement on conversion to the 3-acyl azide with sodium azide and ethyl chloro-formate. Condensation of the resulting isocyanate with a series of amino acids leads to the synthesis of pyrido[3,2- T pyrimidines in good to excellent yield (Scheme 19). 

Fig. 14.44. A one-pot diastereoselective degradation of a carboxylic acid to a Boc-protected amine via a Curtius rearrangement Boc refers to tert-butoxylcarbonyl. The mixed anhydride B is formed by a condensation of the phosphorus ) reagent with the carboxyl group. The anhydride B acylates the concomitantly generated azide ion forming the acyl azide A. A Curtius degradation converts A to C, and the latter reacts subse-guently with tert-butanol to the Boc-protected amine.

Other organo-phosphorous reagents are based on the mixed carboxylic-phosphoric or phosphinic anhydrides. Initially used to convert carboxylic acids into acyl azides, DPPA 12 has been introduced as a one-pot coupling reagent for peptide chemistry (32), and it was adapted later to solid-phase chemistry (81). The driving force of these reactions is the formation of the phosphoric or phosphinic acids and their salts. Later DPP-Cl 49 (82) and FDPP 50 were introduced. FDPP 50 has been used successfully in macro cyclizations (83). Examples of... 

In the case of halophosphonium reagents, as demonstrated for PyCloP, the acyloxyphosphonium intermediate (Scheme 10) reacts to give a mixture of anhydride 30 and oxazolone 31 (Scheme 11) which are aminolyzed. In the case of the azido reagent 13, an acyl azide is the aminolyzed compound. ... 

In the first transformation, the carboxylic acid moieties are converted to the corresponding isocyanates employing a Curtius rearrangement. This transformation starts with the formation of mixed anhydride 33 which is subsequently attacked by the azide anion to give acyl azide 34. Then, acyl azide 34 rearranges with the formation of isocyanate 35 and nitrogen. As isocyanate 35 is unstable to hydrolysis... 

It should be mentioned at this stage that instead of acyl chlorides, mixed anhydrides may also be used for the synthesis of acyl azides. From carboxylic acids and chloroformates/triethylamine, mixed anhydrides are formed, which can directly react with azide ions. Sterically hindered acids fail in this procedure (equation 31)." " The similar synthesis of /-butyl azidoformate by reaction of /-butylcarbonic diethylphosphoric anhydride with KN3 is described in Organic Syntheses. ... 

Trimethylsilyl azide (TMS-A) in the presence of catalytic amounts of pyridine turned out to be very useful in the preparation of acyl azides, as this reagent will not only transform acyl chlorides and mixed anhydrides into azides, but also works with reactive esters and lactones (Scheme 40). 2 - 4S Many of these reactions have, however, been run under conditions which will lead to the Curtius rearrangement of the azide intermediates. Pyridine as a catalyst can be replaced by the combination KNa/18-crown-6. Diazidodiphenylsilane, which was investigated as well, will probably not become a standard reagent. 

Mixed carboxylic-carbonic anhydrides, prepared from carboxylic acids and alkyl chloioformates in the presence of base, are easily converted to acyl azides by the action of sodium azide. Since the reaction sequence from carboxylic acids to acyl azides proceeds under mild conditions, it has a broad applica-... 

The Curtius rearrangement has been extensively utilized for the synthesis of numerous cyclo-propylamines 4 from cyclopropanecarboxylic acids 1. The necessary acyl azides 2 are most conveniently obtained by reaction of sodium azide with the mixed anhydride of the cyclopropanecarboxylic acid and ethyl chloroformate. ... 

A-Acyl-benzotriazoles, which are stable and easily handled (cf. acid chlorides or anhydrides) and can be prepared from a large variety of acids, including A-protected a-amino acids, have been widely used as N-, 0-, S- and C-acylating agents, for example to make acyl azides. ° The benzotriazole derivatives of A-protected-a-amino acids have been extensively developed as agents for peptide coupling. ... 

The major classes of carbonyl compounds include aldehydes, ketones, carboxamides, esters, carboxylic acids and anhydrides, and carbonyl halides (acyl halides). These groups differ in the identity of the substituent X on the carbonyl group. At this point we concentrate on these examples, but a number of other carbonyl derivatives have important roles in synthetic and/or biological reactions. These other compounds include acyl cyanides, acyl azides, A-acylimidazoles, 0-aryl esters, and thioesters. The carbonyl compounds are arranged below in the order of the increasing reactivity toward nucleophilic addition. 

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