Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating Substituents: Robust Pyrimidine Synthesis

Abstract

The examination of the cycloaddition reactions of 1,2,3-triazines 17–19, bearing electron-donating substituents at C5, are described. Despite the noncomplementary 1,2,3-triazine C5 substituents, amidines were found to undergo a powerful cycloaddition to provide 2,5-disubstituted pyrimidines in excellent yields (42–99%; EDG = SMe > OMe > NHAc). Even select ynamines and enamines were capable of cycloadditions with 17, but not 18 or 19, to provide trisubstituted pyridines in modest yields (37–40% and 33% respectively).

Catalysis of Heterocyclic Azadiene Cycloaddition Reactions by Solvent Hydrogen Bonding: Concise Total Synthesis of Methoxatin

“…Although this is in line with expectations based on our studies with 4 , 12c it is notable that 4 bears two electron-withdrawing groups (−CO 2 Et) placed at non-complementary sites that enhance the intrinsic reactivity of the 1,2,3-triazine without altering its mode of enamine cycloaddition. 12,19 …”

“…11 Herein, we report a remarkably concise total synthesis of methoxatin that emerged as a consequence of our development of the inverse electron demand Diels–Alder reactions of 1,2,3-triazines. 12 Its development permits the use of a series of complementary heterocyclic azadiene cycloaddition reactions 13 for the late stage divergent 14 synthesis of analogues containing replacements of the fused pyridine or its substituents. Its success rested on the discovery of a powerful hydrogen bonding activation of the heterocyclic azadiene cycloaddition, and its completion resulted in the discovery of a solution to the previously unsuccessful direct single-step pyrroloquinoline oxidation to an o-quinone.…”

“…16 With enamine 3 in hand, the key intermolecular cycloaddition reaction was initially examined under conditions reported for the use of 4 15 (2 equiv, 0.1 M CHCl 3 , 60 °C, 5 h). 12c These conditions afforded a complex mixture of products, containing a disappointing 8% yield of the desired cycloadduct 5 . We initiated optimization studies, examining the reaction solvent, temperature, stoichiometry, additives, and concentration (see Supporting Information).…”

“…This included not only a series of 1,2,3-triazines 4, 16–21 that we recently introduced, 12 but also the isomeric 1,3,5-triazine ( 22 ) 20 and 1,2,4-triazine ( 23 ). 21 In each case and without deliberate optimization efforts (run at 60, 90 or 120 °C, 24 h), the cycloadditions were more effective in HFIP, including many (e.g.…”

Recent Approaches to the Synthesis of Pyrimidine Derivatives

“…The use of electron-donating substituents such as methylthio (19, X = SMe), methoxy (19, X = OMe), and acetamido (19, X = NHAc) groups did decrease the reaction rates but did not prevent the cycloaddition from occurring, as might have been expected (Scheme 20). [27] Despite the need for long reaction times and increased temperatures, the pyrimidines were still obtained in outstanding yields. The reactivity hierarchy between the three electron-rich triazines was well defined (SMe > OMe > NHAc).…”