Synthesis of Fused-Oxazines from Cyclic Ketoximes Via a-Nitrosoalkenes

Cyclic ketoximes having a a-methylene group on reaction with chloramine-T followed by treatment with triethylamine generate a-nitrosoalkenes via a-chloronitroso intermediates, which are further treated with alkenes to give fused-oxazines.


INTRODUCTION
1,2-Oxazine and their fused counterparts received interest in these years due to their diverse synthetic and pharmacological importance.1,2-Oxazine derivatives are useful synthetic building blocks in heterocyclic chemistry.In our preceding report 1 , we have disclosed the method to obtain a-nitrosoalkenes from ketoximes having a-methylene group and their cycloaddition with olefinic compounds to 1,2-oxazines.a-Nitrosoalkenes behave like dienes (4П-elecron component) in Hetero-Diels-Alder reaction.Further to our research on oxazines and their counterparts, we are reporting the synthesis of a-nitrosoalkenes from cyclic ketoximes bearing a a-methylene group and their cycloaddition with dienophiles to yield fused-oxazines, which are having huge synthetic applications 2,3 and biological use as therapeutic agents [4][5][6][7] .Generation of a-nitrosoalkenes is quite difficult.Usually they are reactive intermediates and unstable, hence they are only generated in situ 2 .
In our prior work chloramine-T was used extensively for the synthesis of a-nitrosoolefins 1 , azoalkenes [8][9] , nitrile oxides 10 , nitrile imines 11 etc., which undergo cycloaddition with active dienes yield bioactive heterocycles.During the studies, cyclohexanone oxime was reacted with chloramine-T formed a blue colour indicates the formation of chloro-nitroso intermediate, which produces 1-nitroso-cyclohexene on treatment with a base.With this achievement, we are now reporting a new method for the conversion of cyclic ketoximes heaving an active methylene group into a-chloronitroso intermediates, which are appropriate for in situ formation of a-nitrosoalkenes which acts as dienes and undergo [4+2] cycloaddition with dienophiles.

RESULTS AND DISCUSSIONS
Cyclic ketoximes having a a-hydrogen atom on treatment with chloramine-T followed by treatment with a base are oxidized to a-nitroso alkenes which undergo Hetero-Diels-Alder reaction with olefinic compounds to produce fused-oxazines in good yield.Typically, the reaction was performed by boiling an equimolar mixture of cyclic ketoxime and chloramine-T in ethyl alcohol followed by addition of a base and an alkene.Overall fused-1,2-oxazines are synthesized in good yield as indicated in the scheme 1.
1 HNMR, 13 CNMR, Mass spectral analyses and elemental analyses established the structure of the fused-oxazines synthesized.The cycloaddition reaction was regioselective.Proton NMR spectrum of fused-oxazine 4 (when X=H) showed dd around d 3.6-4.4ppm which is due to H 3 and triplet in the region d 1.70-1.90ppm is the signal for H 4 .Where as in fused-oxazine 4 (when X=CH 3 ), no signal observed for H 3 in the above said region, while a new signal was appeared at d 1.69 ppm designates methyl group and H 4 observed in the region d 1.70-1.90ppm as doublet.
13 C NMR spectrum of all fused-oxazines gave expected signals for the newly formed ring carbons.For instance, in fused-oxazine 4 (when X=H) the peak due to C 3 observed around d 54-67 ppm while 4 (when X=CH 3 ) seen around d 62-69 ppm and a new signal was observed around d 23-26 ppm indicative of the methyl group.The signal in oxazine 4c at d 119 ppm is indicative of the CN group.The stable molecular ion peaks were seen in the Mass spectrum which supports the structure of the newly formed oxazines.The product formation further confirmed by elemental analyses.1,2-Oxazines and their fused counterparts are potentially very useful heterocycles in synthetic chemistry, and act as useful building blocks for the construction of complex and new heterocyclic compounds.
In summary we have established that fusedoxazines can be produced by the reaction of cyclic ketoximes having a a-methylene group with olefinic compounds in the presence of chloramines-T and a base in good yield.
EXPERIMENTAL 1 H NMR and 13 C NMR spectra were taken at 400 MHz and 100 MHz respectively on Bruker Avance 400 spectrometer using DMSO-d 6 or CDCl 3 as solvents and TMS as internal standard.The chemical shifts are stated in d ppm downfield shift from TMS. Mass spectrum was recorded on a Finnigan 4021 mass spectrometer using ionizing energy of 35 ev.Elemental analyses were performed using Vario-EL elemental analyzer.Reactions were checked for the completion by thin layer chromatography (TLC) on precoated silica gel plates using chloroform-ethyl acetate (7:3) as eluent.

Representative process for the preparation of 3-Phenyl-4,4a,5,6,7,8-hexahydro-3H-benzo[c] [1,2]oxazine 4a
A mixture of cyclohexanone oxime 1 (1.0 g, 8.85 mmol) and chloramine-T.3H 2 0 (2.51 g, 8.93 mmol) in ethyl alcohol (6 ml) were boiled for 1 hour.The reaction mass was cooled to rt. and triethylamine (1 ml) was added.The reaction mixture was further stirred for 30 minutes at rt. 3a (0.94 g, 9.03 mmol) dissolved in ethyl alcohol (3 ml) was then added to the above reaction mass and was further boiled 2 hr.After the completion of the reaction, ethyl alcohol Scheme 1 was removed under vacuum and the residue left behind was extracted with chloroform (2 X 20 ml).The combined chloroform extract was washed with H 2 0 (15 ml), with dilute NaOH solution (210 ml) and dried over anhydrous magnesium sulfate.Chloroform was removed under vacuum and the oily mass left behind was purified by column chromatography (CHCl 3 :EtOAc, 8:2) to give 4a as a pale yellow oily product to yield 1.25 g (66%);

CONCLUSION
We have established a simple and effective method for the synthesis of fused-oxazines from cyclic ketoximes by Heter-Diels-Alder cycloaddition of in situ generated a-nitroso olefins with various alkenes.