Diels-Alder Cycloaddition of 4,6-Dimethyl-1,2,3-triazine with Enamines, or their Precursors, under Microwave Irradiation

Abstract

4,6-Dimethyl-1,2,3-triazine undergoes Diels−Alder cycloaddition with enamines, derived from cyclic ketones, under microwave irradiation within 20 min. This methodology represents a dramatic improvement on the classical method and allows fused pyridine systems to be obtained, in some cases, in good yields. 1,2,3-Triazines are useful compounds that have been shown to participate in cycloaddition reactions. 1 These compounds behave as π-deficient dienes and undergo inverse-demand Diels−Alder cycloadditions with electronrich dienophiles. Thus, several reactions of 1,2,3-triazine and its 4-or 5-methyl derivatives with electron-rich dienophiles have been reported to afford pyridines and pyridazines. 2 This approach has been successfully employed with 4-methyl-1,2,3-triazine to prepare alkaloid derivatives. 3 We believe that cycloaddition reactions between dialkyltriazines and enamines derived from cyclic ketones represent a useful process to prepare a wide range of heterocyclic derivatives and natural products (see Scheme). SchemeHowever, the presence of alkyl substituents in the triazine ring diminishes the electron deficiency of the ring and increases the steric hindrance experienced in the cycloaddition. For these reasons, cycloaddition reactions of 4,6-dimethyl-1,2,3-triazine (1), especially with enamines, 4 are scarce and reaction conditions are very energetic and yields very poor. 5 Likewise, Diels−Alder reactions of 4,5,6-trimethyl-1,2,3-triazine have not been reported. 4Microwave irradiation in solvent-free conditions is an energy source that is well suited to performing chemical transformations and has demonstrated its utility when a reaction requires energetic conditions or unstable reagents and/or products are involved. 6In the course of our investigations into Diels−Alder reactions of heterocyclic derivatives that act as dienes, 7 we have studied the cycloaddition reactions of 4,6-dimethyl-1,2,3-triazine (1) with enamines derived from cyclic ketones. The reactions were performed under microwave irradiation, which provides milder reaction conditions than those required by classical heating. The enamine can be prepared 'in situ' from pyrrolidine and the cyclic ketone, and the process can be envisaged as a tandem condensation cycloaddition reaction.Dialkyltriazine 1 reacts with enamines derived from cyclic ketones under microwave irradiation in solvent-free conditions at atmospheric pressure within 20 min to afford the corresponding heterocyclic product 8−13 in 21−71% yield (see Table). 8 The modest yields obtained in some cases are due to the poor thermal stability of the reagents employed (1,2,3-triazines and enamines). The products were characterized by their spectroscopic and analytical data. 9Under classical heating, the reported yields for compounds 8−11 are in the range 0−27%. 4 Moreover, the microwave procedure and the absence of solvent avoids the necessity of performing reactions in a sealed tube (dry chloroform, 100−120 ºC, 2 h) or the removal of high boiling solvents (dry o-dichlorobenzene, 200...

Recent Advances in Microwave-Assisted Synthesis of Heterocyclic Compounds

“…Microwave irradiation is an alternative energy source, well suited to chemical transformations which otherwise require vigorous heating. As such, the microwaveassisted cycloaddition reaction of dialkyltriazenes with enamines has been reported [138]. This transformation is represented in Fig.…”

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…4,6-Dimethyl-1,2,3-triazine (20) also reacts as diene with enamines under microwave irradiation [129,130] (Scheme 20.24). The presence of alkyl substituents in the triazine ring diminishes the electron deficiency of the ring and increases the steric hindrance experienced in the cycloaddition.…”

Microwaves in Cycloadditions

“…DÌaz-Ortiz described the cycloaddition of 4,6-dimethyl-1,2,3-triazine (105) with enamines to give condensed pyridine systems [82]. These reactions were performed in a monomode reactor at a power of 270 W for 20 min at 15 8C.…”