Tetrazoles, 1-substituted, lithiation

Substituted 1,2,3-triazoles, 1,2,4-triazoles and tetrazoles are metallated by n-butyllithium at low temperature at the 5-position. At room temperature 5-lithium derivatives tend to undergo ring opening. No direct lithiation of a 2-substituted 1,2,3-triazole has been reported. 

The difference in physical and chemical properties between 1- and 2-substituted tetrazoles can be large. The preparation of pure 2-methyltetrazole via alkylation (below) and the lithiation properties described later in this section, nicely demonstrate this differential reactivity, which can be put to good preparative use. 

C-Lithiation of 1-substituted tetrazoles occurs readily and the resulting lithio derivatives can be trapped with electrophiles, but there is a strong tendency for decomposition of the lithio compounds, which depends on the 1-substituent. 5-Lithiated 2-substituted tetrazoles appear to be significantly more stable than the 1-isomers, as shown below, by a comparison of the two A -benzyloxymethyl (BOM)-protected isomers. p-Methoxybenzyl can be removed finally by hydrogenation or oxidation with cerium(lV) ammonium nitrate. 

Alkyl groups in 1-substituted tetrazoles can be lithiated but in a 5-alky 1-2-methyltetrazole it is the A-methyl which is metallated but 5-methyl-2-trityltetrazole... 

Tetrazole can be lithiated on the 5-position however, attempts to carry out substitution reactions sometimes fail because the intermediates are easily cleaved and eliminate nitrogen above -50 A series of 1,5-disubstituted tetrazoles were synthesized from a Pd/Cu catalyzed direct arylation of 1-substituted tetrazoles in the presence of tris(2-furyl)phosphine (TFP) and cesium carbonate. ... 

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