Conversion to azides

Stepwise degradation of polypeptides involving benzoylation, conversion to azides and treatment of the azides with benzyl alcohol this treatment yields, via rearrangement to isocyanates, carbobenzoxy compounds which undergo catalytic hydrogenation and hydrolysis to the amide of the degraded peptide ... 

The reaction mixture is then passed through a basic alumina column to remove the catalyst, allowed to concentrate in a vacuum, and the polymer (P3-II) is recovered by precipitation in methanol and drying in vacuum at 60°C. For conversion to azide end-functionality, NaN3 (10 equiv) is added to DMF solution (0.01 M) of the above ATRP polymer containing bromide end group and the reaction mixture is stirred for 20 h at room temperature. The heterotelechelic polystyrene (P3-III) thus formed is recovered by precipitation in methanol and is dried in vacuum at 60°C. 

A lactone-based synthesis converted keto-alkyne 6.245 to carboxylic acid 6.246 in four steps. Formation of lactone 6.247 was followed by conversion to azide 6.248. Reaction with butylamine and hydrogenation gave N-butyl 5-amino-6-cycIohexyI-2-isopropylhexanamide, 6.249. This amino acid product is considered to an hydroxy-ethylene dipeptide isostere. 115,143 jn the case of 6.249, the term isostere essentially refers to replacing one group in a molecule with another that will give similar chemical or physiological properties. 

Tetrazole is insensitive (or much less sensitive than azide) to light, so more prolonged irradiation or conversion to azide form by heating or aeidifying is demanded for photochemical decomposition of tetrazole form. 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

Iodine azide, generated in situ from an excess of sodium azide and iodine monochloride in acetonitrile, adds to ethyl l//-azepine-l-carboxylate at the C4 — C5 and C2 —C3 positions to yield a 10 1 mixture of the rw-diazidodihydro-l//-azepines 1 and 2, respectively.278 The as stereochemistry of the products is thought to be the result of initial trans addition of the iodine azide followed by an SN2 azido-deiodination. The diazides were isolated and their stereochemistry determined by conversion to their bis-l,3-dipolar cycloadducts with dimethyl acetylene-dicarboxylate. 

Whereas currently most studies deal with azides, a similar effort devoted to other metal salts such as nitrates and chlorates would be an important step toward understanding electrical initiation of pyrotechnics, and conversely to making possible safe, non-expl igniters. For instance, a study by Maycock (Ref 4) shows that those azides, perchlorates, and nitrates in which the solid state shows absorption on the long wavelength side of the anionic excitation band in soln, are the most unstable members of the respective series. Consequently, there is a direct relationship between the absorption spectra of pyrotechnic oxidizers and their respective sensitivities... 

Among the experiments that have been cited for the viewpoint that borderline behavior results from simultaneous SnI and Sn2 mechanisms is the behavior of 4-methoxybenzyl chloride in 70% aqueous acetone. In this solvent, hydrolysis (i.e., conversion to 4-methoxybenzyl alcohol) occurs by an SnI mechanism. When azide ions are added, the alcohol is still a product, but now 4-methoxybenzyl azide is another product. Addition of azide ions increases the rate of ionization (by the salt effect) but decreases the rate of hydrolysis. If more carbocations are produced but fewer go to the alcohol, then some azide must he formed by reaction with carbocations—an SnI process. However, the rate of ionization is always less than the total rate of reaction, so some azide must also form by an Sn2 mechanism. Thus, the conclusion is that SnI and Sn2 mechanisms operate simultaneously. ... 

With alkyl aryl ketones, it is the aryl group that generally migrates to the nitrogen, except when the alkyl group is bulky. The reaction has been applied to a few aldehydes, but rarely. With aldehydes the product is usually the nitrile (16-21). Even with ketones, conversion to the nitrile is often a side reaction, especially with the type of ketone that gives 17-31. A useful variation of the Schmidt reaction treats a cyclic ketone with an alkyl azide (RN3) in the presence of TiCU, generating a... 

Diphenylphosphoryl azide also gives good conversion of primary alkyl and secondary benzylic alcohols to azides in the presence of the strong organic base diazabicyc-loundecane (DBU). These reactions proceed by O-phosphorylation followed by Sw2 displacement.78... 

With a common intermediate from the Medicinal Chemistry synthesis now in hand in enantiomerically upgraded form, optimization of the conversion to the amine was addressed, with particular emphasis on safety evaluation of the azide displacement step (Scheme 9.7). Hence, alcohol 6 was reacted with methanesul-fonyl chloride in the presence of triethylamine to afford a 95% yield of the desired mesylate as an oil. Displacement of the mesylate using sodium azide in DMF afforded azide 7 in around 85% assay yield. However, a major by-product of the reaction was found to be alkene 17, formed from an elimination pathway with concomitant formation of the hazardous hydrazoic acid. To evaluate this potential safety hazard for process scale-up, online FTIR was used to monitor the presence of hydrazoic acid in the head-space, confirming that this was indeed formed during the reaction [7]. It was also observed that the amount of hydrazoic acid in the headspace could be completely suppressed by the addition of an organic base such as diisopropylethylamine to the reaction, with the use of inorganic bases such as... 

Reduction of azides is a classical approach to primary amine synthesis. Treatment of 17 with sodium azide in DMF or in THF/H2O mixtures in the presence of phase transfer catalysts effects a quantitative conversion to the corresponding polymeric azide, 27. Recently the reduction of azides to primary amines via hydrolysis of iminophosphoranes produced by interaction of the azide with triethyl phosphite was reported.30 Application of this technique to the azidomethyl polymer, 27, as shown below, failed to produce a soluble polyamine. 

In general, azides are more easily available than nitro compounds by SN2 reaction of the corresponding halides. Thus, the direct conversion of an azide into a nitro group is useful for the synthesis of nitro compounds. Corey and coworkers have reported the easy conversion of azides to nitro compounds via ozonolysis of phosphine imines (Eq. 2.70).139... 

Esters of 1,2,3-triazolecarboxylic acids are the most common derivatives of triazole (Section 5.01.9) therefore, their conversions to other, more useful, functionalities are of great importance. In an example given in Scheme 48, 4-triazolecarbocylic ester 317, obtained from a reaction of (3-ketoester 316 with 4-chloro-2-nitrophenyl azide, is hydrolyzed to free acid 318 (82% yield) by 4% KOH. Heated to reflux in DMF for 3 h, acid 318 undergoes decarboxylation to triazole derivative 319 with 81% isolated yield <2004FA397>. 

Conversion of aromatic amines to azides was studied by Scechter et al. <2002TL8421> and these studies lead to the recognition of a new approach to tetrazolo[l,5- ]pyridine. Thus, reaction of 2-aminopyridine 142 with butyl-lithium followed by treatment with azidotris(diethylamino)phosphonium bromide gave rise to tetrazolo[l,5- ]pyr-idine 1 in 80% yield. The first intermediate is obviously the azide 7. 

The portion of azide which was not used for conversion to cyanate (about 2 g.) is boiled for half an hour under reflux condenser with 5 c.c. of absolute alcohol.1 On concentrating the solution, phenylurethane likewise separates. Melting point 52°. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

The aminopuromycin analog 1076 was prepared in a similar manner to that developed for 9-(3-amino-2-hydroxypropyl)adenine (78CCC3444). The starting 4-benzyloxymethyl-2-oxo-l,3-dioxalane (1071) was condensed with 1072 to give 1073, which was benzoylated and then debenzylated to give 1074. Conversion to the azide 1075 followed by reduction gave... 

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