Open AccessReaction Scope of Methyl 1,2,3-Triazine-5-carboxylate with Amidines and the Impact of C4/C6 Substitution
Author(s) -
Ryan E. Quiñones,
Zhi-Chen Wu,
Dale L. Boger
Publication year - 2021
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.1c01553
Subject(s) - substitution (logic) , scope (computer science) , carboxylate , chemistry , triazine , substitution reaction , medicinal chemistry , stereochemistry , organic chemistry , philosophy , computer science , linguistics , programming language
A comprehensive study of the reaction scope of methyl 1,2,3-triazine-5-carboxylate ( 3a ) with alkyl and aryl amidines is disclosed, reacting at room temperature at remarkable rates (<5 min, 0.1 M in CH 3 CN) nearly 10000-fold faster than that of unsubstituted 1,2,3-triazine and providing the product pyrimidines in high yields. C4 Methyl substitution of the 1,2,3-triazine ( 3b ) had little effect on the rate of the reaction, whereas C4/C6 dimethyl substitution ( 3c ) slowed the room-temperature reaction (<24 h, 0.25 M) but displayed an unaltered scope, providing the product pyrimidines in similarly high yields. Measured second-order rate constants of the reaction of 3a-c , the corresponding nitriles 3e and 3f , and 1,2,3-triazine itself ( 3d ) with benzamidine and substituted derivatives quantitated the remarkable reactivity of 3a and 3e , verified the inverse electron demand nature of the reaction (Hammett ρ = -1.50 for substituted amidines, ρ = +7.9 for 5-substituted 1,2,3-triazine), and provided a quantitative measure of the impact of 4-methyl and 4,6-dimethyl substitution on the reactivity of the methyl 1,2,3-triazine-5-carboxylate and 5-cyano-1,2,3-triazine core heterocycles.