Tetrazolo pyrimidines

When the azomethine group is part of an electron-deficient ring, such as pyridine, pyrimidine or thiazole, the compounds exist as tetrazoles in the solid state, and at equilibrium with the azido form in solution . The equilibrium constants depend on the solvent, the nature of the substituents and the temperature . 2-Azido-4,6-dimethylpyrimidine (288a) thus exists in equilibrium with tetrazolo-pyrimidine (288b). Its chemical behaviour is, however, in accord with the azide structure 288a, including dipolar addition reactions and nitrene reactions . 

Tetrazolo[l,5-c]pyrimidine, 8-amino-7-chloro-purine synthesis from, 5, 591 Tetrazolopyrimidines... 

Tetrazolo[l,5-(2]pyrimidine (/) exists in equilibrium with its valence isomer 2-azidopyrimidine (2). 

In all types of NMR spectra H, C, N), 2-azidopyrimidine (2) can be distinguished by the symmetry of its pyrimidine ring (chemical equivalence of 4-H and 6-H, C-4 and C-6, N-1 and N-3) from tetrazolo[l,5-a]pyrimidine ( ) because the number of signals is reduced by one. Hence the prediction in Table 30.1 can be made about the number of resonances for the -butyl derivative. 

Routes have been developed to furo[3,2-e][l,2,4]triazolo[4,3-c]pyriniidmes 67 and furo [3,2-e]tetrazolo[l,5-c]pyrimidines 68 which are shown in Scheme 10 <96JHC659>. 

The hydrazine 70 reacts with triethyl orthoformate, sodium nitrite in acetic acid, or pyruvic acid, to yield l,2,4-triazolo[4,3-c]-, tetrazolo[l,5-c]- and l,2,4-triazino[5,6-c]pyrano [4 ,3 4,5]pyrrolo[3,2-e]pyrimidine derivatives 71(X= CH), 71(X= N) and 72 respectively <95KGS700 96CA(124)176023>. 

A kinetic study of thermolysis reactions of TV-crotyl substituted 1,2,4-triazoles was performed at temperatures in the range of 260-350 CC <00JHC1135>. Thermolysis of tetrazolo[l, 5- >]pyridazines, tetrazolo[l,5-a]pyrimidines and tetrazolo[l,5-a]pyridines allowed easy ring contraction to a facile preparation of cyanopyrazole heterocycles . 

NMR investigations of some carbohydrate-substituted tetrazolo[l,5-h]pyrimidin-5(6//)ones as nucleotide analogues have been studied by Chu et al. <1997JOC7267>. The H and 13C chemical shifts of these derivatives are shown in Table 3. 

Table 3 1H and 13C chemical shifts of some carbohydrate-substituted tetrazolo[1,5-c]pyrimidin-5(6H)ones... 

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>. 

Thus, unsubstituted, 6-propyl- and 5,7-dimethyl tetrazolo[l,5-tf]pyrimidines 29, 30, and 31, respectively, as well as unsubstituted 6-methoxy- and 6-phcnyltctrazolo[ 1,5-/r]pyridazines 32-34, when heated at ambient temperature (close to their melting points), gave rise to the correspondingly substituted jV-cyanopyrazolcs 35-40 in medium to good yields. 

Irradiation of tetrazolo[l,5- ]pyrimidine 1 in benzene in the presence of trifluoroacetic acid was investigated by Takeuchi and Watanabe <1998JP0478> (Scheme 10). Formation of 2-anilinopyrimidine 57, 2-aminopyrimidine 58, and biphenyl was observed. The authors assumed that 57 was formed via a singlet nitrene, whereas formation of the other products may result from the triplet nitrene intermediate. In contrast to this early assumption, Hill and Platz <2003PCP1051> exclude the formation of a triplet nitrene upon spectroscopic evidence as discussed in Section 11.18.5.1. 

Ring opening of the oxo derivative of the tetrazolo[l,5- ]pyrimidine ring system has also been reported <1996JHC229>. Treatment of the 6-hydroxyethyl-7-methyl substituted compound 59 with triphenylphosphine gave the phosphinimine derivative 60 in nearly quantitative yield (Scheme 10). 

An intramolecular cyclization of a tetrazole-containing nucleoside 64 has been observed by Chu and co-workers <1997JOC7267> (cf. other properties of this compound in Table 3). These authors reported that the 3-OH group on the arabinofuranose ring participates in an addition reaction at position 7 of the tetrazolo[l,5-c]pyrimidine ring to form 65 which is a dihydro derivative of the parent heterocycle. The final structure elucidation has been carried out with the help of the tricyclic tandem mass spectrometry (MS/MS) fragment 66. 

The synthetic pathway to tetrazolo[l,5-tf]pyrimidines starting from 5-amino-tetrazoles has already been discussed in CHEC-II(1996) <1996CHEC-II(8)465>. During the recent period of time, several modifications of this approach have been described. The obtained products - among them some partly saturated derivatives - and the applied reagents as well as yields and references are summarized in Table 9. 

Table 9 Synthesis of tetrazolo[1,5-a]pyrimidines starting from 5-aminotetrazole...

Aus 5,7-Dimethyl- erhalt man durch Pyrolyse in 99% Ausbeute 1 -Cyan-2,4-dimethyl-imidazol 31 32. 

Reduction of tetrazolo[ 1,5- >]pyridazine (274) by sodium borohydride results in the partial reduction of the pyridazine moiety (tetrahydro compound 275 was formed) (76JHC835). The catalytic reduction of the substituted tetrazolo[ 1,5- >]pyrimidine (276) afforded the diaminopyrimidine derivative (277) (85MIP155606). 

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