Sodium azide pathway

The two reaction pathways studied involve a route from the carboxylic acid to the isocyanate via the acyl chloride and azide (Sodium Azide Pathway, Pathway A), Figure 4 and a route from the carboxylic acid to the isocyanate via the hydrazide (Hydrazide Pathway, Pathway B), Figure 5. The reactions were monitored by isolating the intermediate reaction products and characterizing them by melting points, elemental composition, or IR spectroscopy. 

The sodium azide pathway (Pathway A), Figure 4, begins with a thionylchloride treatment of the free acid to form the acyl chloride. Subsequent treatment with sodium azide may involve a non-aqueous environment (1,2-dimethoxy ethane, "dry method"), or an aqueous medium ("wet method"). The organic azide is recovered from the reaction mixture and converted into the isocyanate by the Curtius rearrangement. This may be accomplished in solid form ("dry method"), or in a non-aqueous solvent like dioxane or DMF ("solution method"). 

Figure 4. Reaction scheme of the sodium azide pathway.

Model Type C, the isoeugenol-maleic anhydride copolymer, forms an organic azide and isocyanate by the sodium azide pathway as is indicated by the IR spectra (A and B) of Figure 7. However, overall isocyanate yields remain low. 

SODIUM AZIDE PATHWAY - MODEL TYPE C (R = CH3CO) - ACID... 

Sodium Azide Pathway The free carboxyl group-containing compound was dissolved in thionyl-chloride and refluxed for 10 hours, followed by vacuum evaporation. To a solution of acyl chloride in 1,2-dimethoxyethane was added, under stirring, an excess of freshly activated sodium azide in solid form ("dry method"), or in aqueous solution ("wet method"). In the dry method, the mixture was refluxed overnight, filtered, and evaporated to dryness. In the wet method, the mixture was stirred for 20 minutes and precipitated by the addition of water (10 times its original volume). The precipitate was filtered, washed, and freeze-dried. The organic azide was either heated for 1 hour to 100-120°C (oil bath) as a dry powder ("dry method"), or refluxed for 1 hour in dioxane- or DMF-solution ("solution method"), which was followed by vacuum evaporation. 

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... 

A ring-closure reaction to the bicyclic triazolopyridine system implying intramolecular 1,3-dipolar cycloaddition was published by Couty et al. <2004TL3725>. The reaction pathway started from an /V-propargylaruinoalcohol 398, which was treated first with thionyl chloride followed by sodium azide to give the intermediate 399, which underwent the desired cyclization to afford the final product 400. Although in other related cases (cf. Chapter 11.15 for tetrazolopyrazines) the yields were acceptable, this nitrogen positional derivative was obtained only in 20% yield. 

TAT liposomes remain intact within one hour of translocation and slowly migrate through the cell, bypassing the endocytic pathway, to the perinuclear zone where they disintegrate (95). The mechanism utilized by TAT to migrate across the membrane was thought to be energy independent because it operates at similar rates at both 4°C and 37°C (95,96). Cell entry by TAT is also unhindered by metabolic inhibitors such as sodium azide or iodoacetamide (97). Peptides constructed of both the d and l amino acids of Antp can be detected intracellularly, the inference of which is that no specific receptor was required because both isomers had equal potential (98,99). 

Azides are easily prepared by nucleophilic substitution of alkylhalogenides with sodium azide and the yields of azide additions to CgQ are generally sufficient. Thus the functionalization of CgQ via this pathway leads to a broad range of products. Some examples are shown in Table 4.6. 

Methyl 6-amino-6-deoxy-a-D-glucopyranoside derivatives 2c were synthesized in our laboratory by a somewhat different procedure [31]. 6-0-Sulfonyl or 6-bromo-6-deoxy derivatives of methyl a-o-glucopyranoside were substituted at C-6 by sodium azide. The 6-azido-6-deoxy intermediate was then treated by acyl chlorides in the presence of triphenylphosphine (Staudinger reaction) to afford amido derivatives which were finally de-O-acetylated to give 2c. The same reaction pathway allowed the preparation of 6-alkylamido-6-deoxy-D-glucopy-ranose derivatives, starting from o-glucose [31]. 

The use of the toxic and hazardous hydrazoic acid is avoided by generating it in situ by adding sodium azide gradually to the carboxylic acid in the presence of concentrated sulphuric acid and chloroform (eg.. 3,5-dinitroaniline, Expt 6.54). The reaction involves the hydrolysis of an intermediate isocyanate (RNCO), which is formed by a mechanistic pathway analogous to that involved in the Hofmann reaction. 

Surprisingly, when the cyclic sulfamidate derived from iV-acetyl-D-allosamine 126 was treated with different nucleophiles, three types of products were formed by nucleophilic displacement of sulfamide at C-3 and proton abstraction at C-2 or C-4 (Scheme 18) <1997T5863>. Potassium acetate and sodium azide effectively provide regioselective ring opening to afford thio and azido derivatives 127. When oxy-anions were used as nucleophiles, elimination was the main pathway (sugars 128 and 129). 

Many inhibitors of catabolic pathways cause a decrease in cellular heat dissipation. They are therefore valuable tools to indicate the sources of the dissipation and give clues to the relative importance of each pathway in overall metabolic activity (see reviews by Kemp, 1987, 1993 Monti, 1987, 1991). To give a few examples from these reviews, sodium fluoride is a classical inhibitor of glycolysis and it has been shown to substantially reduce heat dissipation by human erythrocytes, lymphocytes, neutrophils, and murine macrophages, indicating the contribution of this pathway to metabolic activity. Cyanide inhibits oxidative phosphorylation by mitochondria at the cytochrome c oxidase complex (site 3) and studies revealed that it decreased heat production in a mouse LS-L929 fibroblast cell line but had no effect on human erythrocytes and neutrophils and murine macrophages, all of which lack mitochondria. Sodium azide inhibits at the same site and so it should come as no surprise that it had no effect on human neutrophils and lymphocytes, but it did reduce heat production by lymphocyte hybridoma cells, which contain... 

On pyrolysis of methyl-i V-(2,4-diniIrophenyl)carbamate 5-nitro-2,l,3-benzoxadi-azole (5-nitrobenzofurazan) was isolated in a yield of 35% (Scheme 2.83) [519], The key product in this process is or/Zm-nitrozophenylnitrcnc from which ben-zofurazan is formed later. The reaction of 2-chloro-5-nitronitrozobenzene with sodium azide in an aqueous acetone medium is likely to follow a similar pathway. In this case the yield of 5-nitrobenzofurazan reaches 73% (Scheme 2.84) [520],... 

The enthalpy of formation of the azide radical is 467 SkJmoR. The spin-allowed dissociation to N( D) and N2(X 1 +) is endoergic by 225kJmol, the dissociation enthalpy to N( S) - -N2(X i +) is 0.5 IkJmol. The azide radical is only stable because this spin-forbidden decomposition pathway has an appreciable energy barrier. In aqueous solution, it primarily exists as a monomer, in contrast to other halide or pseudohaUde radicals that exist as the less reactive dimers (e. g. Brs (SCN)2 ). Reaction ofthe azide radical with halogen atoms or other small molecules hke O2, NO, CO, and CO2 produces molecules in electronically excited states because of propensity rules, which can be used for chemically pumped lasers. The azide ion is also formed during high-pressure photolysis of sodium azide. 

Model Type A, vanillic acid and its acetylated or methylated derivative, generated the expected isocyanate without major problems either via the sodium azide or the hydrazide pathway. 

Figure 6. Infrared spectra of isocyanate formation of model Type A (R = CH,) via the sodium azide and the hydrazide pathways.

We now return to the attempts to solvolyze primary S-coupled TTF salts. Reasoning that the solvolysis might be triggered in an Sn2 manner with more powerful nucleophiles, the salt 2a was treated with sodium azide [20]. Although TTF was produced, this did not result from a simple substitution reaction, as the other product was the Z-alkene 69. This can be rationalized as resulting from attack by azide at the peripheral alkene bond followed by fragmentation of the heterocycle however it is not clear why only the Z-isomer is detected. No other product was isolated from this reaction, but, to rationalize the formation of TTF, the thio-ketenedithioacetal 70 was proposed as an intermediate. Fragmentation of the azide adduct could occur by either of two possible pathways, as shown in Scheme 12. 

Other 2,3-epimino derivatives based on o-lyxose were also opened by sodium azide (R = CH2NHBz, R = CH2NHCbz, R = H ), and the same regioselectivity was observed. Formation of the C-3 regioisomer corresponds to a cleavage pathway having minimum activation energy as documented by ab initio calculations. ... 

In 1956, Hattori and co-workers estabUshed that aluminum azide adds to alkyl isocyanates or acid chlorides in tetrahydrofuran to afford l-aUcyl-A -tetrazoline-5-ones in excellent yields [ 101 ]. Three years later, Horwitz and coworkers reported on the synthesis of l-aryl-A -tetrazoline-5-ones by reaction of aryl isocyanates with a mixture of sodium azide and aluminum chloride in tetrahydrofiuan at reflux temperature [102]. The in situ produced aluminum azide adds to the N=C-bond of the corresponding isocyanate 122 and yields the 1-substituted A -tetrazoHne-5-one 124. According to this method, different 1-substituted A -tetrazoUne-5-ones 124 were synthesized by reaction of phenyl isocyanate and further 1-p-substituted phenyl isocyanates with aluminum azide. In addition, acyl halides 123, like acetyl chloride and benzoyl chloride, were converted to 1-methyl and 1-phenyl-A -tetrazoline-5-one with aluminum azide under the same conditions (Scheme 28A). It is assumed that in the initial step of the reaction, aluminum azide is able to coordinate to the aryl isocyanate by foiu pathways, forming an aluminum salt 129. The first two possibilities (Scheme 28B 125 and 126) require the separation of an azide ion from the complex, recombination at the electrophihc carbon atom followed... 

Sharpless et al. showed that nitriles, which are attached to heteroatoms react with sodium azide to form the corresponding IH-tetrazoles at lower temperatures than carbon-bound nitriles (Scheme 59, Z = O, S, NR) [208]. The range of the azidonitrile moiety is broad so the formed tetrazoles can be fused to five- or six-membered rings which can be saturated or imsaturated, and the heteroatom can be an oxygen, nitrogen or a sulfur. The reaction pathway involves imidoyl azide 297, which spontaneously cyclizes to the tetrazole 298 (Scheme 60). 

---