Heterocyclic Hydrazoic acid

The seemingly complex imidazolone (78-3) is in fact obtained in a single step by reaction of the amino-ester (78-1) with the iminoether (78-2) derived from capro-nitrile. The relatively acidic proton on the heterocyclic ring is next removed by reaction with sodium hydride. This anion is then alkylated with the same biphenyl-methyl bromide (77-2) that was used to prepare losartan to afford (78-4). The nitrile group is in this case converted to the tetrazole by means of tributyltin azide, a reagent that involves milder conditions than the traditional acidic medium used to generate hydrazoic acid. Thus, treatment of (78-4) with the tin reagent affords irbesartan (75-5) [82]. 

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

Analogously, Bognar and coworkers45-46 prepared the same thiourea derivative 33, and synthesized some other N-glycosyl heterocyclic derivatives, such as thiazole 36, 1,3,4-thiadiazole 38, and 1,2,3,4-thiatriazole 39, using as the starting material isothiocyanate 2, or its ureido (34) or semicar-bazide (37) analogs. It is noteworthy that treatment of semicarbazide 37 with a nitroso acid at 0° afforded the 1,2,3,4-thiatriazole derivative 39 by addition and cyclization. The same 1,2,3,4-thiatriazole derivative 39 was obtained by treatment of isothiocyanate 2 with hydrazoic acid. 

In the series of stable five-membered nitrogen-containing heterocycles, tetrazole possesses extreme characteristics that are inferior only to those of pentazole (cf. Section 6.07.4.3). Attention should be paid to the obvious fact that, in contrast to the hypothetical pentazole, tetrazole is a thermodynamically stable compound. This heterocycle surpasses the simple azide and hydrazoic acid by a number of key tests. However, tetrazoles are thermodynamically stable in the condensed phase, relatively weakly sensitive to impact and friction, and not very toxic, unlike HN3 which is notorious for its high sensitivity to impact, friction, thermal and electric impulses, and toxicity <1999THS(3)467>. 

Unstable azido compounds which have been obtained by addition of hydrazoic acid to enamines such as 181 are also thought to arise from an Adf processAlthough catalysis of an Adj reaction by protonation of the heterocyclic nitrogen atom in 181 is possible, and in fact the salt (182) was isolated from the reaction, the position of the azido group in the products (183-185) indicates that an electrophilic addition on the unprotonated enamine is the rate-limiting step. Conjugation of the nitrogen lone-pair with the diene chain could provide sufficient activation for such an addition. 

Additions of hydrazoic acid to carbon-sulphur double bonds may conceivably be of the general type outlined in equation (88) but do not constitute a synthetic route to azides. Recent corrections to the earlier literature relating to this field are, however, noteworthy. It was originally suggested that thiocarbamoyl azides " (193) were obtained from organic isothiocyanates and hydrazoic acid. The spectroscopic studies of Lieber and co-workers " have now established that the products are in fact thiatriazoles (194). The reactions of sodium azide with isothiocyanates , and carbon disulphide , which were also previously considered to furnish organic azides, have now been shown to produce the heterocyclic compounds 195 and 196 respectively. 

Helerocycles. The review cited summarizes reactions of hydrazoic acid leading to heterocycles containing several ring nitrogens. 

Heterocycles Acetylacetone. N-Aminophthalimide. Boron trichloride. Dichloro-formoxime. Oicyanodiamide. Dicyclohexylcarbodiimide. Dietboxymethyl acetate. Diethyl oxalate. Diketene. Dimethylformaniide diethylacetal. Diphenyldiazomethene. Ethyl ethoxy-methylenecyanoacetate. Formaldehyde. Formamide. Formamidine acetate. Formic acid. Glyoxal. Hydrazine. Hydrazoic acid. Hydroxylamine. Hydroxylamine-O-sulfonic acid. Methyl vinyl ketone. o-Phenylenediamine. Phenylhydrazine. Phosphorus pentasullide. Piperidine. Folyphosphoric acid. Potassium diazomethanedisulfonate. Sodium ethoxide. Sodium nitrite. Sodium thiocyanate. Tetracyanoethylene. Thiosemicarbozide. Thiourea. Triethyl orthoformate. Tris-formaminomethane. Trityl perchlorate. Urea. Vinyl triphenyl-phosphonium bromide. 

Coned. H2SO4 added dropwise during 0.5 hr. with vigorous stirring at 40° to a soln. of ra 5 -dibenzoylstilbene and hydrazoic acid in chloroform, and the product isolated when Ng-evolution has ceased -> 4-benzoyl-2,3"diphenylquinoline. Y 53%. R. E. Pratt, W. J. Welstead, Jr., and R. E. Lutz, J. Heterocyclic Chem. 7, 1051 (1970). 

The authors proposed a mechanism that starts with the generation of a (trifluoroaceto>q )iodo benzene radical and an azide radical (Scheme 5.26). The azide radical abstracts a hydrogen atom from the cyclic alkane and the resulting hydrazoic acid reacts with a second FIFA molecule with release of trifluoroacetic acid that protonates the heterocycle and activates it for the addition of the allq l radical. The resulting heterocyclic radical cation is oxidized into the corresponding product by the (trifluoroaceto>y)iodo benzene radical. 

During the last 15 years, in the course of the development of nucleophilic planar chiral A-heterocycles as orga-nocatalyst, Fu and co-workers published a succession of papers dealing with the asymmetric protonation of ketene (Scheme 31.22). Indeed, by use of various protic nucleophiles such as alcohols, phenols, amines, enolysable aldehydes, or hydrazoic acid, they developed straightforward accesses to enantioenrichied esters,amides, " and amines. " ... 

And last, but not least, Fu et al. [21] reported that the planar-chiral heterocycle 45d catalyzed the enantioselective addition of hydrazoic acid to ketenes. This result in the formation of an acyl azide intermediate, which then can be subjected to Curtius rearrangement to supply a straightforward stereoselective access to chiral amines. As can be seen from Scheme 3.26, amine derivatives 56 were obtained in... 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

From To — Akanes CycJoaikanes Akenes Akynes Aryls Halogen compounds Alcohols Phenols Ethers, Quinones B, 5 and Si compounds P and BI compounds Nttro. Nitroso, Azo. Azoxy, Hydrazo Azides Amines Organometahic compounds Adehydes Ketones Acids. AnHyd rides. Esters Amides, Amidines. Nitriles Hydroxy-aldehydes or -ketones. Sugars. Hydroxy acids Ammo acids. Peptides Heterocycles Nucleosides Miscellaneous, including heterocycles... 

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