Ethyl azide, preparation

Treatment of ethyl 2-(l-isoquinolylaminomethylene)cyanoacetate (238) with aluminum azide, prepared in situ from aluminum chloride and sodium azide, in boiling tetrahydrofuran gave 3-(l//-tetrazol-5-yl)-4//-pyrimido-[2,l-a]isoquinolin-4-one (239) (78USP4127720). The 8,9,10,11-tetrahydro derivative of compound 239 was similarly prepared (80USP4209620). 

A general synthesis of c-fused pyridines under neutral conditions involves the thermolysis of vinyl azides, prepared from aromatic aldehydes that bear an ortho methyl group and ethyl azidoacetate. Thus thermolysis of the vinyl azide (151) from mesitaldehyde (150) gives the isoquinoline (152) in 45—50% yield (Scheme... 

The resulting 2-benzylthioethylamine could be debenzylated by treatment with sodium in liquid ammonia. However, when 2-benzylthioethylamine was treated with carbobenzyloxy-P-alanine azide (prepared from carbobenzyloxy-P-alanylhydrazide by nitrosation), 2-benzylthio-7V-(carbobenzyloxy-P-alanyl)ethyl-amine formed. Reduction with sodium in liquid ammonia was sufficient to remove both the benzyl and carbobenzyloxy protecting groups and, as noted above, reaction with pantolactone yielded pantetheine. Phosphorylation to the mono- and diphosphates of pantetheine has been effected with the corresponding dibenzylphospho-nates (vide supra, ATP). 

The synthesis of 4,5-difluoroimidazole has also been described by Kirk using a photochemical Schiemann reaction (Scheme 59) [74]. Curtius rearrangement of the acyl azide, prepared in two steps from ethyl 4-fluoroimidazole-5-carboxylate via hydrazide, afforded the key intermediate Boc-protected 5-fluoroimidazol-4-carboxylate. In situ Boc deprotection followed by diazotization of the amine and photolysis of the diazonium tetrafluoroborate afforded 4,5-difluoroimidazole. 

The easiest organic azide and smallest member of azidomethanes, CH3N3, was first prepared by O. Dimroth in 1905 by simple methylation of sodium azide with dimethyl sulfate. Methyl azide has been proven to be more explosive than originally reported (same accounts for ethyl azide). The much more hazardous diazidomethane, CH2(N3)2 and triazidomethane, CH(N3)3, are accessible by rather time-consuming slow reactions of dichloro/dibromomethane and tribromomethane with a polymeric ammonium azide reagent. Several reports on the potential risk when working with azides in dichlorometh-ane exist, and are attributed to the potential formation of diazidomethane (please see appropriate references cited in ref. °). 

Burns and Smith more recently [3] reported an explosion during their preparation of 20 gm ethyl azide following their precautions cited above for methyl azide [2]. The explosion took place just after approximately 0.5 ml of additional indicator solution was added. They postulated that either the acidic indicator or exposure to the ground glass joint initiated the detonation. The force of the detonation of this 20 gm ethyl azide left a 1-cm deep depression in their 16-gauge stainless steel hood floor and shattered the safety glass around the hood s fluorescent lamp. 

The Curtius rearrangement in acetic anhydride of the azide (8) prepared from 4-carboxythiazole yields 4-acetamidothiazole (Scheme 8) (47). The same reaction starting with ethyl-2-methyl-4-thiazolyl carboxy-late, failed to give the 4-aminothiazole (48). Heterocyclizations are more convenient synthetic methods (Chapter II. Table 40). 

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

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... 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

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 title compounds were prepared safely by a diazo-transfer reaction onto f3-oxosulfones by treatment with l-ethyl-2-chloropyridinium tetrafluoroborate and sodium azide in presence of sodium acetate. 

This method can be extended to the preparation of alkenylcopper compounds. Thus, treatment of the iodoalkenyl azide 10 with nBuLi at —100 °C (Scheme 2.3), followed by transmetalation with Znl2 in THF and then by a second transmetalation with CuCN-2LiCl, produces the copper species 11. This then effects a cis-selective carbocupration of ethyl propiolate to furnish the ( , ) diene 12 in 81% yield. 

Another method was developed for the synthesis of 5,8-methano-3,l-benzoxazine-2,4-diones 157. The A-BOC amino acid 156 was prepared from the half ester 155 without purification of the intermediates. Thus, 155 was treated with ethyl chloroformate, and subsequently with sodium azide. 

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