Azides, acyl preparation

Employing this method, enantioenriched phenol esters 68, amides 69, and carbamates 70 (after Curtius rearrangement of the intermediate acyl azide) were prepared in yields often greater than 90% with ee-values reaching up to 97% (generally 80-95%, see Fig. 37). 

Acyl azides. These azides are prepared in almost quantitative yield by reaction of a carboxylic acid or the potassium salt with phcii/l dichlorophosphate, pyridine, sodium azide, and a catalytic amount of tetrabutylammonium bromide in CH,C1, at 25°. 

Modified Curtius rearrangement. Acyl azides, preferably prepared in situ under phase-transfer conditions by reaction of acid chlorides and NaN, are converted to tri-fluoroacetamides by reaction with CF,COOH in refluxing CH CI, solution. These products are cleaved to primary amines under mild conditions (equation I). ... 

Tributylstannyl azide (51), prepared from tributylstannyl chloride and sodium azide, is also useful for the direct conversion of acyl chlorides to isocyanates (equation 32). In addition, succinic anhydride... 

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. 

In the early literature, including the pioneering studies of Curtius himself, acyl azides were prepared from carboxylic acids via treatment of the derived acid hydrazides with nitrous acid. This method is less commonly used in contemporary synthesis but still appears occasionally in the literature. Examples were shown for compounds 1, 7, 17, and 21 in the earlier sections above. 

A slightly milder reagent that has been used to prepare acid chlorides is oxalyl chloride, 15.14. This also has the advantage that the by-products are gaseous. The reaction can be catalyzed by a trace of dimethylformamide. The reaction and some examples of use in synthesis are shown in Figure 15.32. In the second example, an unusual acyl azide was prepared the ability of azide to displace chloride should not be surprising, as it was also an excellent nucleophile... 

In these cases the acyl azides formed have been used to prepare amines via Curtius rearrangement. The acyl chloride or azide intermediates can. however, also be reacted with amines or alcohols to form amides or esters. 

A third approach to 3-amino-/3-lactams is by Curtius rearrangement of the corresponding acyl azides. These are readily prepared from r-butyl carbazides, available via photochemical ring contraction of 3-diazopyrrolidine-2,4-diones in the presence of f-butyl carbazate (c/. Section 5.09.3.3.2). Thus treatment of (201) with trifluoroacetic acid followed by diazotiz-ation gives the acyl azide (202) which, in thermolysis in benzene and subsequent interception of the resulting isocyanate with r-butanol, yields the protected 3-amino-/3-lactam (203) (73JCS(P1)2907). 

This derivative, prepared from an amino acid and the acyl azide, is selectively cleaved in 80% yield by chymotrypsin. ... 

The Cunius degradation of acyl azides prepared either by treatment of acyl halides with sodium azide or trimethylsilyl azide [47] or by treatment of acyl hydrazides with nitrous acid [f J yields pnmarily alkyl isocyanates, which can be isolated when the reaction is earned out in aptotic solvents If alcohols are used as solvents, urethanes are formed Hydrolysis of the isocyanates and the urethanes yields primary amines. 

Attempts in this laboratory to prepare the analogous 1,2,3,4-selenatriazoles have so far been unsuccessful. Acyl azides show no tendency to cyclize to 1,2,3,4-oxatriazoles. ... 

The required acyl azide 1 can be prepared from the corresponding acyl chloride... 

The Curtius rearrangement can be catalyzed by Lewis acids or protic acids, but good yields are often obtained also without a catalyst. From reaction in an inert solvent (e.g. benzene, chloroform) in the absence of water, the isocyanate can be isolated, while in aqueous solution the amine is formed. Highly reactive acyl azides may suffer loss of nitrogen and rearrange already during preparation in aqueous solution. The isocyanate then cannot be isolated because it immediately reacts with water to yield the corresponding amine. 

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

CAUTION All azides, particularly low molecular weight acyl and alkyl azides, are explosive, and great care should be taken while preparing and handling these materials. In addition, hydrazoic acid, which is liberated from unbuffered aqueous solutions of sodium azide, is highly toxic and all operations involving its use should be carried out in an efficient fume hood. 

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... 

The triazoles previously obtained from jS-keto-ylides and acyl azides or ethyl azidoformate are the 2-acyltriazoles (80) formed by isomerization under the basic conditions of the initially formed 1-substituted triazoles (79). The latter can be isolated in some cases if the reactions are interrupted. Aryl mono- and bis-azides have also been used in the preparation of the triazolcs (81). 

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... 

A violent explosion occurred during vacuum distillation of 4-chlorophenyl isocyanate, prepared by Curtius reaction from the azide. It was found by IR spectroscopy that this isocyanate (as well as others prepared analogously) contained some unchanged azide, to which the explosion was attributed. The use of IR spectroscopy to check for absence of azides in isocyanates is recommended before distillation [1], Subsequently, the explosion was attributed to free hydrogen azide, produced by hydrolysis of the unchanged acyl azide [2],... 

The acyl-azide method of coupling (Figure 2.13) has been available for about a century, but it is not attractive for routine use because it involves four distinct steps that include two stable intermediates that require purification. In addition, aminolysis of the azide is slow. The first step involves preparation of the ester (see Section 3.17), which can be methyl, ethyl, or benzyl. The ester is converted to the hydrazide by reaction in alcohol with excess hydrazine at ambient or higher... 

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... 

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