Cycloaddition of 3-Amino-5-chloro-2(1H)-pyrazinones and Olefins:  Ring Transformation into 3-Amino- or 6-Cyano-Substituted 2-Pyridinone Systems

Abstract

The cycloadducts formed from the Diels−Alder reaction of 3-amino-5-chloro-2(1H)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-1,2-dihydro-2-oxo-4-pyridinecarboxylates, e.g. 12a,b (loss of amine substituent), or the corresponding 3-amino-6-cyano-1,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates, e.g. 15a,b. From the latter compounds, 3-amino-2-pyridinones can be generated through subsequent loss of HCN. A mechanism accounting for the loss or retention of the amine substituent is based on (1) the effects observed for each reaction mode when varying the substituents in both reaction partners and (2) the exclusive retention of the amine substituent when replacing toluene with the basic solvent pyridine.

Domino Reaction Sequence for the Synthesis of [2.2.2]Diazabicycloalkenes and Base-Promoted Cycloreversion to 2-Pyridone Alkaloids

“…9 The cycloreversion of the intermediate [2.2.2]diazabicycloadducts derived from these chlorinated pyrazinone precursors has two primary limitations: (1) extrusion of cyanide or cyanate derivatives requires high temperatures 10 (at or above 140 °C), and (2) extrusion is often nonselective and gives mixtures of both pyridine and pyridone products. 9 …”

“…Cascade pericyclic processes such as merged cycloaddition/cycloreversion strategies, particularly those employing 1,2,3- and 1,2,4-triazines, are a valuable synthetic complement to traditional and more contemporary condensation methods . In comparison, merged cycloaddition/cycloreversion approaches for the direct synthesis of 2-pyridones are not common; however, Hoornaert and co-workers validated the possibility of this approach using cycloaddition of chlorinated pyrazinone intermediates . The cycloreversion of the intermediate [2.2.2]­diazabicycloadducts derived from these chlorinated pyrazinone precursors has two primary limitations: (1) extrusion of cyanide or cyanate derivatives requires high temperatures (at or above 140 °C), and (2) extrusion is often nonselective and gives mixtures of both pyridine and pyridone products …”

A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones

“…When compared with reported cyclizations under classical conditions, the microwave approach gave improved or at least similar isolated yields (Table 2). 8, [23][24][25] Proteases are involved in many pathological conditions, and consequently, these enzymes are also important drug targets. The natural substrates of proteases are generally assumed to adopt an extended conformation prior to binding the enzymes (Chart 1, I), and 2(1H)-pyrazinones substituted by an RNH group in the C-3 position and with an amino acid C-terminal incorporated in the N-1, are known b-strand conformation inducers (Chart 1, II).…”

Expanding the substitution pattern of 2(1H)-pyrazinones via Suzuki and Heck reactions

“…17,18 4.1. Synthesis of 3-(hetero)aryl, 3-alkenyl-2(1H)-pyrazinones 7a-e via Suzuki-coupling reaction General procedure.…”