Sodium azide reaction scheme

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

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... 

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>. 

Reaction between 2,8-dichloro derivative 115 and sodium azide in DMSO does not lead to 3,9-diazido derivative 116 expected by direct displacement. Instead, the reaction gives isomeric 3,9-diazide 117, presumably by an addition-elimination sequence <1995JOC6110, 1995HAC391>. Compound 116 is available by treatment of tetra-nitro derivative 90 (z-TACOT) with LiN3 in DMSO (Scheme 11) <1967JA2626>. 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

Reaction of 2,3-dichloroquinoxaline 367 with sodium azide in ethanol has been used to synthesize bistetrazolo-[l,5- 5, l -c]quinoxaline 368 in 65% yield (Scheme 28) <1997JOC4082>. Similarly, reaction of 2,3-dichloroquinoxaline 367 with thiosemicarbazide 366 has been used to generate l,6-diamino-bis-l,2,4-triazolo[4,3- 3,4-f]quinoxaline 365 in 67% yield <2002AP389>. Condensation of cyclopropanecarboxylic acid hydrazide 369 meanwhile gives rise to the cyclopropyl-substituted tetracycle 370 in 93% yield in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base (Scheme 28) <2005JOC2878>. 

Azolo[l,8]naphthyridines. The reactions of the chloronaphthyridine 229 with o-phenylenediamine at 200 °C and with sodium azide in acetic acid give the fused-ring products 230 and 231, respectively (Scheme 54) <2003IJB192>. Amino acid-substituted naphthyridines can be cyclized to the fused imidazolones 232 upon treatment with phosphorus oxychloride and under microwave irradiation (Equation 62) <2002SC857>. Acylation of 2-hydrazino-naphthyridines followed by heating gives W-acyl compounds which are cyclized intramolecularly to the [l,2,4]tri-azolo[4,3- ][l,8]naphthyridines 233 (Scheme 55) <1996IJB106>. The same compounds may also be obtained from... 

Pyranopyridines. The chlorobenzopyranoquinolone 325 reacts with hydrazides to give a triazole-fused ring system, such as in compound 326. Likewise, reaction with sodium azide gives the tetrazolo-fused product 327 (Scheme 79) <2003IJB2567>. 

A way to introduce the primary amino group directly onto the selenophene ring is via the azido compound, obtained by nucleophilic substitution of the bromo derivative with sodium azide. Useful transformations of the azido group are shown in Scheme 12.117 The amino aldehyde (109) is a suitable starting material for the preparation of selenolo[3,2-b]pyridine (110) by the Friedlander reaction.138 Not only can the azido be reduced to an amino... 

A rather complex microwave-assisted ring-opening of chiral difluorinated epoxy-cyclooctenones has been studied by Percy and coworkers (Scheme 6.131) [265]. The epoxide resisted conventional hydrolysis, but reacted smoothly in basic aqueous media (ammonia or N-methylimidazole) under microwave irradiation at 100 °C for 10 min to afford unique hemiacetals and hemiaminals in good yields. Other nitrogen nucleophiles, such as sodium azide or imidazole, failed to trigger the reaction. The reaction with sodium hydroxide led to much poorer conversion of the starting material. 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

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>. 

Azide 367 is prepared from 4-r -butyl-2-nitroaniline in 76% yield by its diazotization followed by treatment with sodium azide. In a 1,3-dipolar cycloaddition with cyanoacetamide, azide 367 is converted to triazole 368 that without separation is directly subjected to Dimroth rearrangement to give derivative 369 in 46% yield. Reduction of the nitro group provides ortfc-phenylenediamine 371 in 91% yield <2000EJM715>. Cyclocondensation of diamine 371 with phosgene furnishes benzimidazol-2-one 370 in 39% yield, whereas its reaction with sodium nitrite in 18% HC1 leads to benzotriazole derivative 372, which is isolated in 66% yield (Scheme 59). Products 370 and 372 exhibit potassium channel activating ability <2001FA841>. 

An example of asymmetric synthesis involving cycloaddition of an azide to dimethyl acetylenedicarboxylate is depicted in Scheme 172. Thus, asymmetric auxiliary 1042 reacts with styrene and sodium azide to generate azide 1043 in 90% yield and 94% diastereomeric purity. The following reaction (Scheme 172) with dimethyl acetylenedicarboxylate converts azide 1043 into triazole 1044 in 75% yield. Finally, the bond with selenium is cleaved by treatment with triphenyltin hydride and AIBN to furnish triazole 1045 in 80% yield and preserved optical purity (94%) <2003AGE3131>. 

Azides 1253 obtained from propargyl halides or sulfonates 1252 undergo sigmatropic rearrangement to azidoal-lenes 1254, which subsequently undergo cyclization to triazafulvenes 1255. Under the reaction conditions, species 1255 react with another molecule of sodium azide to furnish triazoles 1256. Products 1256 are isolated in 65-97% yield (Scheme 209) <2005S1514>. 

Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

The conversion of acyl isothiocyanates 47 with sodium azide leads to thiol-functionalized tetrazole derivatives such as 48 (Scheme 9) <1995PJC1022>. The reaction of 48 with chloro acetonitrile leads to an intermediate 49 that reacts in... 

Tandem nucleophilic substitution-[2+3] cycloaddition reaction of 4-bromo- and 4-toluenesulfonyloxy aldehydes 77 with sodium azide in DMF at 50 °C affords excellent yields (>80%) of substituted pyrrolo[.2.3.4]oxatriazoles 78 (Scheme 8) <2002HAC307>. 

The reaction of sodium azide with N-aryl chloroimines, obtained from benzanilides and thionyl chloride, to form 1,5-disubstituted tetrazoles is catalysed by tetra-n-butyl-ammonium bromide (Scheme 5.26, Table 5.40) [18] in variable yields, but generally <85%. 5-Butyl-2,3-diphenyltetrazolium salts have also been used as catalysts [18, 19]. 1,5-Disubstituted tetrazoles are also obtained from a one-pot sequential reaction of carbodimides with sodium azide and an aroyl chloride in the presence of tetra-n-butylammonium chloride [20]. 5-Chlorotetrazoles are obtained from the catalysed reaction of aryldichloroisocyanides with sodium azide (Scheme 5.26) [21],... 

Thus, sodium azide and a,p-dinitrocumene do not react unless subjected to the action of light (48 h control period). In contrast to sodium azide, the lithium salt of 2-nitropropane reacts with a,p-dinitrocumene in the dark for 3 h, giving the product of a-substitution in 87% yield. When a,p-dinitrocumene (1 mol) is treated with sodium azide (2 mol) in the presence of the lithium salt of 2-nitropropane (only 0.1 mol), the initial a,p-dinitrocumene quantitatively converts into p-nitrocumyl azide for 3 h. The product is extremely pure, and the reaction requires no UV irradiation (Kornblum et al. 1970) (Scheme 5.6). 

Azidoformic esters such as 342 react with Cgg in a [2-tl] addition (Scheme 4.70), if the temperature is high enough to induce the loss of nitrogen prior to addition, otherwise a [3-1-2] addition can be observed (Section 4.3.2) [172, 395, 397]. Typical conditions include heating of the mixture in solvents such as tetrachloroethane [395, 397, 398], chloronaphfhalene [397] or toluene [396] at 110-160 °C. These conditions also afford multiple addition products [172]. To avoid potential hazard during purification of the azido formiates, they were also generated in situ in one pot by the reaction of chloro-formic ester with sodium azide [396]. 

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