Synthesis Of 3, 4-dihydro-2H-pyrido[3, 2-b][1, 4] Oxazines And Its Analogs

3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazines are important nitrogen- containing heterocycles in organic and medicinal chemistry. 3,4-Dihydro-2H-benzo[1,4]oxazines as its analogs have been studied extensively due to a wide range of biological activities, such as anticancer, antibacterial and antithrombotic effects. However, the synthetic methods of 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazines in literature are limited in applications.In this dissertation, an effective methodology for the synthesis of 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazines and its analogs has been described. The key of this method involves two successive nucleophilic substitution reactions ofβ-aminoalcohols to pyridine or benzene ring with two leaving groups.Initially, commercially available 2-chloro-3-nitropyridine and D-prolinol was selected to investigate the reaction conditions. The results showed that in presence of triethylamine, the chloro atom on the pyridine ring could be substituted selectively by nitrogen atom of D-prolinol in refluxing acetonitrile to give 2-(3-nitropyridin-2- ylamino)ethanol in good yield. Strong base potassium hydroxide in DMSO promoted an intramolecular nucleophilic substitution reaction of nitro group by the hydroxyl to yield the desired annulated product in 75% yield.On the basis of the above optimal conditions, another 14 amino alcohols were selected to react with 2-chloro-3-nitropyridine. As a result, 14 intermediates were obtained over 60% yields. In the next intramolecular substitution, 8 of the 14 intermediates were successfully converted into pyridoxazines with moderate to good yields.From the above experiments, it could be found that the substituent on the nitrogen atom of the amino alcohols played an important role in the intramolecular cyclization. No desired pyridoxazines could be obtained when there was no substituent or only a benzyl group on the nitrogen atom of the amino alcohols, while the existence of bulky alkyl substituents could increase the yield of the product.To extend the scope of the above method, the benzene ring system was applied. In similar fashions, 1-fluoro-2-nitrobenzene, 3,4-difluorobenzonitrile and 4-fluoro-3-nitrobenzonitrile were treated with various amino alcohols. As a result, 17 intermediates were obtained over 65% yields. In the next intramolecular substitution, 14 of the 17 intermediates were successfully converted into benzoxazines, and 10 of them in yields more than 75%.The above strategy for the synthesis of pyridoxazines or benzoxazines has two advantages. Firstly, various substituents could be introduced into the desired molecules from commercially available amino alcohols or amino acids; Secondly, the chirality of amino alcohols could be kept in pyridoxazines or benzoxazines.In conclusion, an efficient method for the construction of oxazine ring has been developed and a series of 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazines and 3,4-dihydro-2H-benzo[1,4]oxazines are prepared. The key to this strategy is through two successive nucleophilic substitution reactions by differentiating the nucleophilic ability of the amino and hydroxyl groups.