1.5- Disubstituted tetrazole

Theoretical and spectroscopic studies of the protonation of tetrazoles have been discussed in Sections 4.17.2.2 and 4.17.3. Protonation of 5-substituted tetrazoles, 1,5-disubstituted tetrazoles and 2,5-disubstituted tetrazoles in aqueous H2SO4 at H2SO4 concentrations up to 96% occurs at N-4 <82KGS142l>. The tetrazoles are weak bases with basic pAl values of about —3 to —4 <87AHC(4i)i87>. A basic pXj value of —3.0 has been measured for tetrazole in aqueous H2SO4. Hammett relationships have been reported for the basic pX values of 5-substituted tetrazoles... 

However, in some cases carboxylic acid-derived groups can participate in ring fission-reclosure reactions. Thus photolysis of 1,5-disubstituted tetrazole (399) gives nitrogen and appears to involve the amino-nitrene intermediate (400), which reacts further to give (401) (77AHC(21)323). 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

Besides addition reactions, azides or hydrazoic acid can also yield tetrazoles through displacement reactions. Thus, halide displacement in imide chloride (78) yields 1,5-disubstituted tetrazoles (79), and in 2-chloro-pyridine (80), yields tetrazolopyridine (81) (Eq. 16a,b).141 143 Vinylogous... 

Disubstituted tetrazoles are conveniently prepared from acyl hydrazines (98) and diazonium salts.166 The reaction proceeds through the intermediate tetrazenes (99) followed by cyclization to the tetrazole (100) (Scheme 13). The intermediate can be isolated under mildly basic conditions. Symmetrically 1,2-diacylated hydrazines yield 1-substituted tetrazoles through the elimination of one of the acyl groups.166 - 168 Diformyl-hydrazine is a very convenient starting material for 1-substituted tetrazoles.166, Unsymmetrically 1,2-diacylated hydrazine usually results in mixtures.169... 

Benson et al. 177 first reported the synthesis of tetrazolium salts by the alkylation of disubstituted tetrazoles. While selectivity is a major problem, alkylation can still be considered a viable method for the preparation of 1,3,5- and 1,4,5-trisubstituted as well as 1,5 and 2,5-disubstituted tetrazolium salts. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

Novel applications of benzotriazole methodology in organic synthesis include regiospecific preparation of 1,4,5-trisubstituted pyrazoles <2007ARK(i)9>, efficient synthesis of 1,5-disubstituted tetrazoles <2007SL1204>,... 

Substituted tetrazoles reacting in the mass spectrometer with acyl ions afforded 2,5-disubstituted 1,3,4-oxadiazoles with nitrogen loss. Tandem mass spectrometry allowed for the collision-induced dissociation of the products. Chemical ionization was the better method to make the transformation. A scheme for the transformation of 5-substituted tetrazoles into 2,5-disubstituted 1,3,4-oxadiazoles was proposed (Scheme 1) <2001JMP1069>. The fragmentation patterns of monocyclic l,3,4-oxadiazolium-2-thiolates have been proposed by Ollis and Ramsden <1974J(P1)645>. 

The reaction of sodium azide with N-aryl chloroimines, obtained from benzanilides and thionyl chloride, to form 1,5-disubstituted tetrazoles is catalysed by tetra-n-butyl-ammonium bromide (Scheme 5.26, Table 5.40) [18] in variable yields, but generally <85%. 5-Butyl-2,3-diphenyltetrazolium salts have also been used as catalysts [18, 19]. 1,5-Disubstituted tetrazoles are also obtained from a one-pot sequential reaction of carbodimides with sodium azide and an aroyl chloride in the presence of tetra-n-butylammonium chloride [20]. 5-Chlorotetrazoles are obtained from the catalysed reaction of aryldichloroisocyanides with sodium azide (Scheme 5.26) [21],... 

Thermolysis of tetrazole oximes (478) in a suitable hydrocarbon solvent, or pyrolysis without it, produces 3,5-disubstituted 1,2,4-oxadiazoles (480) (Scheme 75) (81BSB193 87BSB675 91MIP137367). in the case of 5-unsubstituted tetrazoles (478 R = H), the reaction goes by two concomitant pathways, which imply elimination of hydrazoic acid or nitrogen. 

N-Unsubstituted and 1,5-disubstituted tetrazoles fragmentations to nitrenes and carbenes... 

The tetrazole ring exhibits only weak end absorptions at 200-220 nm in the ultraviolet and only tetrazoles with conjugated auxochromic groups give normal ultraviolet spectra. Absorption maxima are controlled by the conjugation which is usually more extensive in 2,5-disubstituted derivatives relative to the 1,5-disubstituted isomers. Thus 2,5-disubstituted tetrazoles have higher as seen from the following examples 1-Me,5-Ph, 232 nm, 2-Me,5-Ph, A ax 240 nm 1-Ph,5-H, A ax 236... 

Ultraviolet and infrared absorptions have been reported for an extensive series of l-aryl-5-(2 -dialkylaminovinyl)-lTf-tetrazoles. The 5-vinyl C=C stretch appears at 1624-1641 cm and the ultraviolet A ax (MeCN) was at ca. 300 50 nm depending on substituents <88JPR963>. In some 1,5-disubstituted derivatives the conjugated substituent may be twisted significantly out of the tetrazole... 

---