1.2.4- Triazines vicarious nucleophilic substitution

Scheme 39 Vicarious nucleophilic substitution in triazine iV-oxides...

The reaction of 3-methoxy-1,2,4-triazine 1-oxide 20 with the carbanion generated from chloromethyl phenyl sulfone proceeds as the vicarious nucleophilic substitution (VNS) of hydrogen (Scheme 1, path B) via addition of the carbanion at position 5 of the heterocycle. Following base-induced elimination of HCl and protonation, 3-methoxy-5-phenylsulfonyl-1,2,4-triazine 4-oxides 65 result (88LA627). 

Deoxygenative v.s vicarious nucleophilic substitution of hydrogen in reactions of 1,2,4-triazine-4-oxides with a-halocarbanions has been described <02EJO1412>. Tandem vicarious nucleophilic substitution of hydrogen/intramolecular Diels-Alder reaction of 1,2,4-triazine (19) into functionalized cycloalkenopyridines 21 has been reported <02CPB463>. 

Another method to introduce a substituent into the 1,2,4-triazine system is vicarious nucleophilic substitution. Here, a carbanion with a leaving group at the carbanionic center reacts with a 1,2,4-triazine replacing protons in the 5-, 3- and 6-position with the carbanionic moiety. The reactivity of the various positions decreases in the order 5 > 3 > 6. This reactivity differs from that toward Grignard reagents. Thus, substitution of the 5-position occurs in the 1,2,4-triazine to afford 15 which undergoes elimination to 16 followed by protonation to yield 17 275,276 Carbanions of the following compounds were used in this reaction nitrones, chloromethyl phenyl sulfones, chloromethanesulfonamides and acetonitriles.274-378... 

Autoaromatization can also be facilitated by an auxiliary group which is present in a nucleophile (Scheme 44, route c). This approach is commonly known as the vicarious nucleophilic substitution of hydrogen (VNS), and it is illustrated by several examples of the displacement of hydrogen at C-5 of the 1,2,4-triazine ring by action of chloromethyl arylsulfones as C-nucleophiles <1992PJC3, 19%RCB491, 2004CRV2631>. 

Kozhevnikov et al. (02EJO1412) have investigated the vicarious nucleophilic substitution reactions of l,2,4-triazine-4-oxides 53. They have shown that, although mixtures are often formed, by tuning the conditions the reaction can be biased to favour either the deoxygenated (59) or dehalogenated product (60). For a representative example, see Scheme 20. 

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