134 Heterocycles with More than Two Heteroatoms: Higher Azoles (5-Membered) and Higher Azines (6-Membered)
1,2,4-Triazoles alkylate very predominantly on one of the two adjacent nitrogens and the minor regioisomer (on the
lone nitrogen) is eliminated during a simple isolation. (Note: The 1- and 2-nitrogens of the parent heterocycle are
equivalent before alkylation.) Selective alkylation on the lone (4-) nitrogen requires a more complex method: selective
acylation at N-1 allows the product to be quaternised selectively at N-4. Easy hydrolysis of the acyl group during work-
up permits isolation of the pure 4-alkyl derivative. However, this method has limited scope, as only a few highly reactive
alkylating agents can quaternise triazoles.
Copper-catalysed N-arylation is also known: 1,2,3-triazole reacts at N-1; 1,3,4-triazole is arylated, as for alkylation, at
one of the adjacent nitrogens.
The regioselectivity of N-alkylation of tetrazoles is also affected by the steric and polar properties of the 5-substituent, thus
electron-withdrawing or bulky groups at C-5 favour 2-alkylation, as exemplifi ed by N-methylation of 5-phenyltetrazole,
as shown below.
The reaction of 5-cyanotetrazole with iodomethane also proceeds selectively, 85:15, N-2:N-1, despite the low steric
requirements of the cyano group.
As mentioned previously, the reactivity of ‘fi xed’ tautomers can be very different and this is nicely demonstrated by the
further transformations of the mixture of methyl cyanotetrazoles shown above. 1-Methyltetrazole-5-carboxylic acid
decarboxylates spontaneously at room temperature, whereas its 2-methyl isomer requires heating to 200 °C to achieve
the same result. Thus hydrolysis of the mixture of nitriles gives a mixture of 1-methyltetrazole and 2-methyltetrazole-
5-carboxylic acid, which can be easily separated; decarboxylation of the 2-methyl-5-acid at 200 °C then gives pure
2-methyltetrazole.
Selective 1-alkylation of some tetrazoles can be achieved by a two step method similar to that used for the 4-alkylation
of 1,2,4-triazole shown above, but again it is limited by the availability of suffi ciently reactive alkylating agents.