1.2.4- Triazine 3-methoxy-, reaction with nucleophiles

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). 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

Another example of a nucleophilic addition at C-3 is provided by the reaction of the quaternary salt 20 with sodium methoxide yielding the relatively stable adduct 33, (Scheme 24) (74BSF999). The C-3 adducts 35 and 36 have been suggested as intermediates in the conversion of 2-meth-yl-3-methylthio-l,2,4-triazin-5-ones 34 into the corresponding 3-methoxy derivatives however, no spectroscopic evidence for adduct formation has been presented (Scheme 24) (72BSF1511). 

Trifluoro-l,2,4-triazine (106) behaves similarly to the trichloro compound toward nucleophilic reagents, but is more reactive. When treated with methanol at room temperature it gives a mixture of 5,6-di-methoxy-3-fluoro-l,2,4-triazine (109) and 3,5-dimethoxy-6-fluoro-l,2,4-triazine (110) in the ratio 2 1 (82JCS(P1)1251). Reactions of 106 with di-... 

The preference of the C-5 position for nucleophilic substitution is further supported by the results of reactions of 1,2,4-triazines that posess groups with better leaving abilities at C-3 and/or C-6 than at C-5. For instance, substitution of the methoxy group at C-5, but not of halogen... 

Nucleophilic substitution of hydrogen Sn can also be combined with the displacement of a good leaving group as illustrated by the reaction of 3-phenyl-5-methoxy-l,2,4-triazine with resorcinol, proceeding via the intermediate o -adduct and affording benzofuro[2,3-e]-l,2,4-triazine according to the tandem Sn -Sn cyclization protocol (Scheme 57) [175]. 

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