Fused tetrazole

Nucleophilic substitution of the chloropyridazine 166 with sodium azide in DMF is followed by cyclization to give the fused tetrazole 167 (Equation 41) <1997JHC39>. 

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 . A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 200 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 201, with sodium azide afforded aryl tetrazoles 202 . 

Simoni et al. described <2000TL2699> that some fused tetrazoles readily participate in thermolytic ring contraction reactions which result in the formation of cyanopyrroles (Scheme 5). Thus, heating of tetrazolo[l,5- ]pyridine derivatives 14 at 150-170 °C yields the corresponding 2-cyanopyrrole 16. The process is believed to proceed via a nitrene intermediate 15. 

Extension of these studies to benzologues of tetrazolo[l,5- ]pyridine, that is, for tetrazolo[l,5- ]quinoline 21 and tetrazolo[5,l- ]isoquinoline 22, led to interesting results <2003JOC1470> as shown in Scheme 7. Both of these fused tetrazoles resulted in formation of a nitrene 23 and 24, respectively, which could be interconverted via formation of the fused cyclic carbodiimide derivative 25. Isoquinolylnitrene 24, furthermore, was found to undergo subsequent reactions ring opening afforded the vinylnitrene 26, which was transformed to o-cyanophe-nylacetonitrile 27 by a 1,2-H shift and to 4-cyanoindole 28 by an intramolecular cyclization in 40% and 25% yields, respectively. 

The fact that tetrazolo[l,5- ]pyridine reacts with phosphines - via ring opening to the valence bond isomer azide -to give a phosphorane has been long recognized. Some novel applications of this transformation have been published during the recent period. The fused tetrazoles subjected to this reaction, the resulting phosphoranes, and the literature sources are summarized in Table 4. 

As discussed in CHEC-II(1996) <1996CHEC-II(8)412>, the most widely established synthetic pathway to fused tetrazoles involves the synthesis of a 2-azidoazine participating in the equilibrium with the fused tetrazole. This equilibrium is - in most cases - shifted to the tetrazole form. The easiest way to the 2-azides is either a nucleophilic... 

Reaction of hydrazinoazines with nitric acid has also proved to be suitable route to form azido moieties to complement the nucleophilic exchange reaction of a halide for an azide. This approach has also been applied recently for the synthesis of fused tetrazoles, and these transformations are shown in Scheme 24. 

Dipolar cycloaddition between azides and nitriles is also a well-established route to tetrazoles. If these two functional groups are closely located within one molecule, intramolecular cyclization can occur to yield fused tetrazoles. The present survey of the recent literature shows that this approach has also been successfully applied in some cases and led to the synthesis of novel ring systems belonging to this chapter. These results are depicted in Scheme 25. 

A substantial amount of research has been carried out in the field of tetrazole-fused sugars (rhamnose, mannose, and glucose derivatives) - mostly because of the biological importance of these derivatives. In many of these cases synthesis of the fused tetrazole moieties has been perfected by intramolecular 1,3-cycloaddition reactions with participation of a cyano and azido group. Some of these results are shown in Schemes 26 and 27. 

Quantum-chemical calculations (AMI, PM3) have been carried out in order to investigate the thermodynamic behavior of the possible equilibrium between variously substituted 6-azidotetrazolo[l,5-A pyridazine 11 and the bis-tetrazole 12 <2005JST65> (Scheme 2). From the calculated heat of formation, the authors concluded that this value is consistently lower for the azide tautomers 11 than for the corresponding tetrazoles 12 on average by 20kcalmol 1 and, thus, the azide isomers- in full accordance with the experimental observations - are more stable than the ring-closed fused tetrazoles. 

Wentrup and co-workers have carried out systematic flash vacuum thermolysis studies with a series of fused tetrazoles. Investigations of the isomeric tetrazolo[l,5- ]pyrazine 17 and tetrazolo[l,5-f]pyrimidine 20 showed that, in both cases, ring contraction takes place to afford imidazoles in high yields, but isotope labeling experiments revealed that the mechanisms of the openings of the two ring systems are different <2002JOC8538>. 

Ring contraction of fused tetrazoles to iV-cyanopyrazoles under thermal conditions has been elaborated by Simoni et al. <2000TL2699>. The results are compiled in Table 4. 

Ring opening of the five-membered tetrazole ring has also been observed in several cases. The most trivial conversion is the equilibrium between the fused tetrazole and azidodiazine which, in principle, could take place with every fused tetrazole compound described in this chapter, and, therefore, no special comment on this type of ring opening needs to be discussed. 

The majority of the syntheses of fused tetrazoles have been realized by using the well-documented azide-tetrazole equilibrium, which has been discussed in detail in CHEC-II(1996) <1996CHEC-II(8)465>. Among these synthetic routes, differentiation can be achieved according to the various modes of accessing of the azidoheterocycles. Basically, two general routes are applied. 

Table 7 Synthesis of fused tetrazoles starting from hidrazinodiazines...

Qu6guiner and co-workers found that some diazinylazides suitable for formation of fused tetrazoles can be obtained via metallation of the diazine ring as shown in Scheme 19 <1996S838>. 

Thus, the substituted tetrazoles 113 upon oxidation with lead tetraacetate gave rise to the fused tetrazoles 114, in most cases in high yields. Tetrazole derivatives 115, bearing an anisidine side chain, also underwent oxidative cyclization and afforded 10-methoxycarbonylmethyltetrazolo[l,5- ]quinoxaline 116 in good yield. This compound was obtained as a mixture of tautomers (with participation of the methylene hydrogen atoms) and the depicted tautomeric form 116 proved to be dominant. 

Ring closure to the 5//-tetrazolo[5,l-t][l,3]oxazine skeleton has been reported by Hoornaert and co-workers <1996T8813>. These authors treated variously substituted 2,4-dichloro[l,4]oxazin-2-ones 133 with sodium azide. The fused tetrazoles 135 obtained were formed via the formation of their azide valence bond isomer intermediate 134. A similar approach proved to be suitable for the benzologues of these compounds. Thus, the benzoxazinone compounds 136 gave the tricyclic ring-closed tetrazoles 137. Both reactions yielding 135 and 137 proceeded in high yields (80-90%). 

The fused tetrazoles 10 containing various aryl groups in position 6 were boiled in acetic acid in the presence of either triphenylphosphine or copper and gave rise to the amino-substituted triazines 12. The reaction proceeds obviously via valence bond isomerization of 10 to the azide 11 and is regarded as a useful synthetic route to the diamino compounds 12. 

The tetramethylammonium triazine-olate 55 was treated with sodium azide, whereupon nucleophilic exchange of the trinitromethyl substituent took place to give the azide intermediate 56, which spontaneously underwent valence bond isomerization to the fused tetrazole 57. 

Density functional theory methods using the hybrid B3LYP functionals have been performed to study geometries and energetics of several intramolecular [2+3] dipolar cycloadditions of azides to nitriles (Section 11.06.6.1) toward fused tetrazole formation, including tetrazoles 14 and 15 <2003JOC9076>. 

The reaction of the -C(Hal)=N-function with azide ion or hydrazoic acid is known to give the tetrazole system. As part of a mechanistic study of the one-pot synthesis of an azadibenzoporphyrine in 84% isolated yield from reaction of a 1-bromobenzopyrromethene hydrobromide 74 with sodium azide at 140 °C, 74 was treated with azide at lower temperature (60 °C) in an attempt to isolate the proposed azide mechanistic intermediate 75 however, the fused tetrazole 76 was isolated in 47% yield (identified by X-ray analysis) (Equation 4) <1999MI530>. Upon heating a dimethyl formamide (DMF) solution of tetrazole 76 to 140°C for 1 h, the desired porphyrin was indeed obtained in 14% yield, consistent with the temperature-dependent equilibrium between tetrazole and azide that has been observed with some fused tetrazoles. 

Umkehrer et al. developed the synthesis of tetrazolopiperazine building blocks 178 via Ugi five-center-four-component reaction (U-5C-4CR) of primary amines 179, aldehydes 180, trimethylsilylazide 181, and 2-isocyanoethyltosylate 182 [54]. The in situ generated secondary amine finally gets alkylated by the toluenesulfo-nate, leading to the expected fused tetrazoles 178 (Scheme 31). The primary amines and the aldehydes can be varied broadly, which allows to produce products with two potential diversity points. 

Scheme 33 Synthesis of fused tetrazole-ketopiperazines 187 and two representative 3D conformations of 187A (blue) and 187B (cyan)...

A library of fused tetrazole-ketopiperazines 187 was obtained by Nixey et al. via Ugi four-component reaction in the solution phase [56]. The reaction of an oxo component 188, primary amine 189, methyl isocyanoacetate 190, and trimethylsi-lylazide 181 in methanol at reflux affords bicyclic tetrazole-ketopiperazines 187 in good yield (Scheme 33). The cyclization to afford the tetrazole-ketopiperazines is performed spontaneously under the reaction conditions. 

Nixey T, Kelly M, Huhne C (2000) The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Lett 41(45) 8729-8733... 

TABLE I Fused Tetrazoles Prepared According to Scheme 6... 

The fused tetrazole 422 (Scheme 19) was originally assumed307" to be nitrated on the thiazole ring, but recent NMR studies have shown that a p-nitrophenyl derivative is formed.1836 Since 422 (and 424) display azide tetrazole tautomerism (Section IV,B,1), the exact structure of the reacting species is unknown, but the product exists predominantly as the azide. 

Compounds of type (104) are readily available by intramolecular dehydrogenation of appropriate triazenopyrazoles (82AG(E)698, 87CB1375). Fused tetrazoles with three unsubstituted nitrogens arise by cyclizations of azides see Sections 2.2.5.4, 2.4.5.3.2, 3.4.1.2.3 and 3.2.3.6.4. 

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