Tetrazoles halogenation

Alkyl groups and halogen atoms in tetrazoles are not highly activated unless the ring is quaternized. 

Halogen atoms at the 5-position of tetrazoles are reactive and easily replaced by nucleophiles. 5-Bromo-l-methyltetrazole is significantly more reactive than the 2-methyl isomer (77AHC(21)323). 

Halogen atoms at the tetrazole-5-position are readily displaced by better nucleophiles because of the electron-depleted character of the ring. The nucleophilic displacement was much more rapid with l-substituted-5-bromotetrazoles than with the 2-substituted isomers <84CHEC-I(5)791>. These reactions are often best carried out by warming the halotetrazole in the neat amine or hydrazine when these are liquid. Synthetic uses of the reaction are shown in Schemes 6 and 10. New routes to 5-halotetrazole derivatives have been found <95J06468>... 

Preparation of 5-halogenated tetrazoles from the diazonium salts is well known [47CRV1 77AHC(21)323]. 

Treatment of tetrazolium salts (154) with mercuric acetate gives the bistetrazolium mercury salts (155) which represent essentially a metal-carbene trapping of the tetrazolium ylide species. Replacement of the mercury atom of (155) is readily achieved with halogens to give the 5-halotetrazolium compounds (156) (93CB1149). These electrophilic reactions at the tetrazole C-5 arise from the lability of the 5-CH proton and they show the necessity of generating carbanionic character at C-5 before electrophilic attack can occur on this strongly ir-deficient azole. 

Gallacher, T. C. et al., J. Chem. Soc., Chem. Comm., 1979, 420 Thermal decomposition is vigorous, and was explosive on one occasion. See other N-HALOGEN COMPOUNDS, TETRAZOLES... 

Nucleophilic substitution of the terminal halogen in the alkyl groups at G-5 atom is a simple but efficient approach to modification of tetrazole derivatives. Treatment of 1-phenyl-5-chloromethyltetrazole with imidazole or pyrazole (DMSO, NaOH) gave the corresponding products of the halogen /3-substitution 338 and 339 <2002JOC8230>. 

Growing attention is directed to intramolecular reactions involving alkyls attached to position 5 of the tetrazole ring. The synthesis of 4,5-dihydrotetrazolo[l,5- ]quinoxalines 347 from 5-substituted tetrazoles 346 via the intramolecular. KNAr substitution of the halogen in the ortho-position of the iV1-aryl substituent is an example of such a reaction (Equation 64) <2006TL2041>. 

The replacement of the halogen in the imidoyl chloride by an azide group with subsequent cyclization of the intermediate imidoyl azide 150 into 1,5-disubstituted tetrazole 5 can be performed under PTC conditions < 1996S 1428>. This procedure avoids contact with HN3 solutions and also removes the problem of the low solubility of HN3 salts in organic solvents. It is important that in this procedure the losses due to hydrolysis of imidoyl chlorides... 

The substitution of the halogen in the cyclic imidoyl chloride, like 2-chloropyridine, with azide leads to the intermediate formation of an imidoyl azide 497 that further undergoes cyclization into a fused tetrazole 14 (Scheme 61) <2004SOS(13)861>. 

Electroreduction of l-(4-fluorophenyl)-5-(2-halogenophenyl)tetrazoles (89), when the halogen substituent is Cl, Br or I, leads to cleavage of the carbon-halogen bond to give a phenyl radical (equation 52). Competition then follows between intramolecular radical substitution giving 7-fluorotetrazolo[l,5-f]phenanthridine (90). Further reduction of the... 

Because of the deactivated ir-deficient nature of the ring, nucleophilic attack can readily occur on tetrazoles. Nucleophilic replacement of halogens at the C-5 position has been widely used for the synthesis of disubstituted tetrazoles, e.g. (56). Kinetic studies of the reaction between 5-bromo-l-methyltetrazole and the 2-methyl isomer with piperidine have shown the 1-methyl compound to be considerably more reactive. Comparison of these kinetics with similar reactions for a series of azoles has suggested that two to three deactivating doubly bound nitrogens (—N=) are required to overcome the electron release from one pyrrole-type nitrogen atom in these systems <67JCS(B)64l>. 

The essential reaction of halogen substituents at the tetrazole carbon atom is that of nucleophilic displacement. This readily occurs because of the tt-deficient deactivated nature... 

Substituted tetrazoles 40 (X = halogen, N3, NHj, OH) liberate nitrogen on heating at 110-200 °C without solvent, or in an aromatic solvent, and furnish acetylenes in 16-81% yields, depending on and R (equation 118). A FBW-type of rearrangement might be involved. ... 

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