Synthesis of Acyl Azides

Dehydration. This reagent is useful for synthesis of acyl azides from carboxylic acids, NaCN, and pyridine, with tetrabutylammomum bromide as catalyst (75-95% yield). In combination with pyridine, it effects dehydration of oximes to nitriles in 80-90% yield, P-Lactams can be prepared directly in 40-75 )t yield from carboxylic acids and imines with the reagent (1 equiv,) and triethylamine (excess). In general, a mixture of cis- and rra/j5-azetidinones is formed. 

Dehydration.1 This reagent is useful for synthesis of acyl azides from carboxylic acids, NaCN, and pyridine, with tetrabutylammonium bromide as catalyst (75-95% yield). In combination with pyridine, it effects dehydration of oximes to nitriles in 80-90% yield. 

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. ... 

Sridhar, R., Perumal, P. T. Synthesis of acyl azides using the Vilsmeier complex. Synth. Commun. 2003, 33, 607-611. 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

Bandgar et al. reported a general route for the synthesis of acyl azides from aryl, heteroaryl, alkylaryl and alkyl acids with cyanuric chloride (297) in the presence of sodium azide and (V-methylmorpholine. Acid activation can also be achieved using triphosgene. In fact, aromatic and aliphatic carboxylic acids react with triphosgene in the presence of sodium azide and triethylamine giving acyl azides in good yield (e.g. synthesis of 301). 

Formation of mixed anhydrides also provides the basis for the synthesis of acyl azides (eq I ) and hence amines via the Curtius rearrangement. The azide ion is usually delivered to the most electrophilic carbonyl, but steric considerations may be important. The method is applicable even to strained cyclopropyl- and cyclobutylcarboxylic acids. Diisopropylethy-kunine (Hiinig s base) has been mooted as a superior base for the formation of mixed anhydrides. ... 

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. 

The use of acyl azides in the preparation of amines by the Curtius rearrangement has been discussed previously (Section 23-12E). Alkyl azides can be reduced readily by lithium aluminum hydride to amines and, if a pure primary amine is desired, the sequence halide — azide — amine may give as good or better results than does the Gabriel synthesis (Section 23-9D). 

Irradiation of acyl azides also has proved useful in organic chemical synthesis. Thus irradiation of Formula 466 gives Formula 467 (25%), the... 

HONZL - RUDINGER PepWe Synthasis Peptide synthesis by coupling of acyl azides with ammo esters... 

The preparation of acyl azides has received considerable attention due to the value of these compounds as synthetic intermediates. In the Gurtius rearrangement for example, acyl azides arc converted into isocyanates, urethans, ureas and amines and this aspect of the chemistry of acyl azides is considered in detail in a later chapter. The use of acyl azides in peptide synthesis has increased the scope of general... 

Preparation of acyl azides by the nitrosation method has been used to advantage in the synthesis of peptides " (cf. section III.B.3) and is particularly valuable since it is the only procedure for peptide chain lengthening which does not cause racemization of the peptide components The use of acyl azides as protecting... 

We anticipated that a similar strategy would be applicable to the synthesis of l,3-oxazine-2,4-diones, involving the in situ formation of isocyanates by thermal Curtius rearrangement of acyl azides under the same conditions of the Wolff rearrangement. Indeed, tenperature-regulated microwave irradiation of a 1 1 mixture of a 2-diazo-1,3-diketone and an acyl azide afforded the desired l,3-oxazine-2,4-dione products 33 (Scheme 3.281. This sequence nicely illustrates the utilization of microwave activation for the selective one-pot thermal rearrangements of azido and diazo compounds. 

Activation of the carboxylic acid as the acyl chloride permits direct reaction with azide anion to form the acyl azide substrates for Curtius rearrangement. Sodium azide is commonly used, and the reaction has been used on the process chemistry scale for the synthesis of benzyl-A-vinyl carbamate. Acryloyl chloride was combined with sodium azide in a biphasic system with phase-transfer catalysis (PTC), providing acyl azide 25. Upon heating, Curtius rearrangement provided vinyl isocyanate, which was distilled directly into benzyl alcohol containing phenothiazine (27) to inhibit polymerization of 26 and triethylamine to catalyze addition of the alcohol to the isocyanate. The vinyl carbamate product 28 was isolated by crystallization. As the autiior clearly pointed out, preparation and reaction of acyl azides, particularly on large scales, require appropriate safety precautions. 

Castelhano et al. described the solid-phase synthesis of quinazoline-2,4-diones 313 based on the chemistry of acyl azides. Phthalic acid was immobilized on a PEG4-PS resin and converted into acyl azide 310 with DPPA and triethylamine in toluene. Curtius rearrangement, followed by reaction with a primary amine and subsequent cyclocleavage with K2CO3 gave quinazoline-2,4-diones 313 in good yield (Scheme 3.48). 

Diazotization of acylhydrazines is one route to acyl azides. In fact, the diazotization of bis-hydrazide 318 can be accomplished by treattnent with NaNOa under acidic conditions giving the corresponding bis-acyl azide 319 in 90% yield. A similar procedure can be applied to the synthesis of nicotinoyl azide 321 (Scheme 3.50). ... 

Moreover, Bols et al. developed another methodology for the synthesis of carbamoyl azides from aldehydes by treatment with iodine azide at reflux in acetonitrile [41]. The carbamoyl azides are obtained in 70-97 % yield from the aliphatic and aromatic aldehydes (Scheme 5.4). When the reaction of phenyl-propanal with IN3 at 25 °C was performed in the presence of the radical trap, no acyl azide was observed, which was taken as support for a radical reaction mechanism. The mechanism shown in Scheme 5.6 is proposed for the reaction. Iodine radicals are formed by homolysis of the weak iodine-azide bond, abstracting the aldehyde hydrogen atom. The resulting carbon-centered radical reacts with iodine azide to produce an acyl azide. The following Cuitius rearrangement provides carbamoyl azides. 

In 2003, Bols and co-workers described that the reagent IN3 can easily transform the aldehydes into the acyl azides under mild conditions (Scheme 6.22a) [76]. Furthermore, they demonstrated that the synthesis of carbamoyl azides could be realized at reflux by combining the aldehyde C-H bond azidation and flie Cuilius rearrangement in a one-pot protocol (Scheme 6.22b). A possible radical mechanism were proposed for this transformation (Scheme 6.22c). The weak I-N3 bond homolysis can initiate the chain reaction. The generated iodine radical abstracts an aldehyde hydrogen atom from the substrates to produce the acyl radical A. The acyl radical A reacts with IN3 to afford the acyl azides and iodine radical, thereby sustaining the radical chain. 

Acyl azides may loose N2 on heating and rearrange to isocyanates (Curtius rearrangement), which may be solvolyzed. Some of the possibilities of classical carboxyl conversions are exemplified in the schemes below, which are taken from a triquinacene synthesis (R. Russo, 1971 C. Merder, 1973) and the ergotamine synthesis of A. Hofmann (1963). 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

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