Expeditive Access to 2-Substituted 4H-Pyrido[1,3]oxazin-4-ones via an Intramolecular O-Arylation

Abstract

Unreported 2-substituted 4H-pyrido[e][1,3]oxazin-4-ones are synthesized via an unprecedented intramolecular O-arylation of N-aroyl- and N-heteroaroyl-(iso)nicotinamides under microwave irradiations, in good to excellent yields. The broad applicability was demonstrated by 24 examples with a variety of substituents at the 2-position of the final compounds and 3 possible positions for the nitrogen atom of the pyridine ring. In addition, transformation of one of these compounds into 2-hydroxypyridyl-substituted 1,2,4-triazole and 1,2,4-oxazinone was realized. This approach opens a rapid access to a new bicyclic heteroaromatic chemical series with high potential in medicinal chemistry.

Preparation of Halogen‐Containing 4H‐Pyrido[e][1,3]oxazin‐4‐ones and Their Transformation into 2‐Hydroxypyridinyl‐Substituted 1,2,4‐Oxadiazoles and 1,2,4‐Triazoles

“…Bearing in mind the wide range of potential applications of 1,2,4-oxadiazole [7,13] and 1,2,4-triazole [6,14] derivatives, ad-In general, the imide sodium salts (i.e., 4, 7, and 9) were isolated in good yields by precipitation (Table 1). [11] The methylated examples were used as monosubstituted aryl reference compounds for comparison with their halogenated analogues. Next, we studied the influence of the methylated and halogenated aryl substituent on the efficiency of the intramolecular O-arylation ( Table 1).…”

“…In our preliminary report, [11] we described the one-step transformation of pyrido-oxazinone 5a into the corresponding 4-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-ol (12a) and also into the corresponding 4-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)pyridin-3-ol (13a) (Scheme 1). In our preliminary report, [11] we described the one-step transformation of pyrido-oxazinone 5a into the corresponding 4-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-ol (12a) and also into the corresponding 4-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)pyridin-3-ol (13a) (Scheme 1).…”

“…We faced the synthetic challenge represented by these new scaffolds, and developed the first synthesis of the 4H-pyrido[e] [1,3]oxazin-4-ones, which used an unprecedented intramolecular O-arylation, and proceeded in good to excellent yields. [11] We also demonstrated the transformation of the pyridooxazinone ring into various hydroxypyridyl-substituted 1,3,5-triazines, [12] and into only one example (R = Ph) of a hydroxypyridyl-substituted 1,2,4-oxadiazole or 1,2,4-triazole in 78 % yield (Scheme 1). [11] Since an halogen substituent is certainly one of the most useful groups for structural modifications, we wish to report here a complete study on the synthesis of halogen-containing 4H-pyrido[e] [1,3]oxazin-4-ones.…”

“…[11] We also demonstrated the transformation of the pyridooxazinone ring into various hydroxypyridyl-substituted 1,3,5-triazines, [12] and into only one example (R = Ph) of a hydroxypyridyl-substituted 1,2,4-oxadiazole or 1,2,4-triazole in 78 % yield (Scheme 1). [11] Since an halogen substituent is certainly one of the most useful groups for structural modifications, we wish to report here a complete study on the synthesis of halogen-containing 4H-pyrido[e] [1,3]oxazin-4-ones. These compounds were prepared by the established method starting from precursors of imide sodium salts bearing an halogen atom either on the pyridine ring or on the C-2 aryl substituent (R).…”

“…The intramolecular Oarylation must take place under microwave irradiation and at a relatively high dilution to avoid the formation of degradation products and a significant decrease in the yield. [11] The methylated examples were used as monosubstituted aryl reference compounds for comparison with their halogenated analogues. The 94 % yield obtained for the Oarylation step leading to para-methoxylated compound 8i is the best yield obtained to date, and so serves as a benchmark.…”