Acyl azides mixed anhydrides

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. ... 

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... 

The acylation of formamidoxime should lead to oxadiazoles unsubstituted in the 3-position. While benzoylation with benzoyl chloride is reported to give dibenzhydroxamic acid 45), 0-acylated formamidoxime could be prepared in good yields with acetic anhydride, the mixed anhydride of acetic and ethyl carbonic acid, benzoic anhydride and benzoyl azide. The cyclization of these esters of formamidoxime into 5-substituted oxadiazoles has been accomplished by heating in an aqueous medium. 

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]). 

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... 

Despite the relatively high reactivity of the serine hydroxy group, serine esters and serine-containing peptides with free hydroxy groups have been used as amine components in solution synthesis. Syntheses with free serine hydroxy groups can be performed with azides, without the risk of 0-acylation.b l Mixed anhydrides, active esters, and carbodiimides have also been successfully used for the coupling reactions. Therefore, for this couphng reaction, any over activation has to be avoided. 

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... 

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. ... 

Other activated acrylate derivatives have been used more successfully to minimize formation of 60 with concommitant increase in reaction yield.28 The corresponding anhydride (X = H2C=CHC02-), mixed anhydride (X = EtOC02-), azide (formed by treatment of acrylic acid with (PhO)2P(0)N3 (DPPA)), and the acyl imidazole all enhanced the aza-annulation process. In general, substitution at the a-position had minimal effect on the outcome of the reaction, but was accompanied by variations in the ratio of 61 to 62. However, when the crotyl derivative was used (R3 = Me) the aza-annulation process was significantly slower, and when compared to the acrylic acid reagents (R3 = H), the amount of 60 was increased relative to the amounts of 61 and 62... 

A variety of preactivated acyl derivatives has been developed for peptide bond formation. These include acyl halides [chlorides [66], fluorides [67,68]], acyl azides [69,70], active esters [e.g., pentafluorophenyl (OPfp) [71], o-nitrophenyl (ONp) [72], 3,4-dihydro-4-oxo-l,2,3-benzotriazin-3-yl (ODhbt) [73]], mixed anhydrides [3], and symmetrical anydrides [74,75]. 

Acyl azides can also be used much as mixed anhydrides are in small peptide synthesis. In this case, the azido group can be introduced via reaction of an amino-protected add chloride with sodium azide, as well as by hydrazinolysis. There is also a reagent, diphenylphosphoryl azide, that converts carboxyl groups directly to the azide... 

Another synthetic approach to acyl azides was reported by Weinstock one decade earlier. In this methodology, acyl azides are prepared via carboxylic-carbonic anhydrides. Generally, carboxylic acids are treated with ethyl chloroformate, generating mixed anhydrides which are trapped in situ by sodium azide. This sinple strategy was applied recently in the synthesis of ( )-spisulosine fScheme 4.21 After only 5 min in the presence of ethyl chloroformate, the appropriate carboxylic acid 58 was next treated with sodium azide. The intermediate ene-isocyanate 59 was obtained after heating, and this latter is finally hydrolyzed by water. The corresponding methyl ketone 60 was isolated in 40% overall yield. 

The acyl azides required for Curtius rearrangement can be prepared under mild conditions via mixed carboxylic-carbonic anhydrides. The original 1961 report detailed preparation of racemic c/5-2-phenylcyclopropylamine. Treatment of carboxylic acid 58 with ethyl chloroformate and base in aqueous acetone provided the mixed anhydride, which was treated in situ with sodium azide. The crude acyl azide was isolated by extractive workup and underwent Curtius rearrangement, followed by acid hydrolysis. After raising the pH, the free base 59 was obtained in good overall yield. 

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