An efficient synthesis of 2 H -1,4-benzoxazin-3(4 H )-ones via Smiles rearrangement

A novel and effective synthesis of substituted 1,4-benzoxazinones via Smiles rearrangement is described. Treatment of N -substituted 2-chloroacetamide, substituted 2-chlorophenols and cesium carbonate in refluxing DMF afforded the corresponding substituted 1,4-benzoxazinones in excellent yield.


Introduction
1,4-Oxazinones are very important structural motif, which has wide application in medicinal chemistry due to its pharmacological properties.1a-c The members of this family are used for treating Parkinson's disease, 1d-e ischemia reperfusion, 2 selective potassium channel openers, 3 antinociceptive, 4 antidepressant 5 and antifungal agent. 6In addition the fluorescent properties of 1,4-oxazinones are valuable as laser dyes 7 and coupling agent for oxidative hair dyes. 8Moreover, 1,4-oxazinones used as intermediates for the synthesis of aza sugars 9 and ambident cycloaddition reactions of these compounds were well established. 10Despite their importance from pharmacological, industrial, and synthetic point of view, comparatively few methods for their preparation were reported.Some of the methods reported in the literature for the synthesis of oxazine derivatives are McKillop cycloaddition, 11 N-and O-alkylation with dibromo compounds, 12 lithiation method, 13 use of chiral epoxides under phase transfer catalysts. 14owever, very few methods are available for the synthesis of 1,4-benzoxazinone or 1,4pyridooxazinone derivatives.They are usually prepared by direct cyclization of 2-haloacetyl halide or alkyl 2-halo propionates with 2-aminophenol or 2-amino-3-hydroxypyridine.This is the most straightforward method by using 2-aminophenol or 2-nitrophenol as starting materials to obtain 1,4-benzoxazinones and a similar approach is also applied for pyridine series.Recently Chaudhuri and coworkers reported the palladium catalyzed C-C bond formation for the construction of different heterocyclic compounds. 15Very recently Dai and his group described one-pot synthesis of 1,4-benzoxazinones under microwave condition. 16However, many of these procedures have major drawbacks such as low yields of the products, long reaction time, harsh reaction conditions, difficulties in work-up, and the use of stoichiometric amounts and/or relatively expensive reagents.The majority of the existing methods are not useful to synthesize the different substituted benzoxazinones.
Our interest in development of new methodologies 17 and experience in the synthesis of 1,4pyridooxazinones via Smiles rearrangement 18,19 resulted in identifying a new method for the synthesis of 1,4-benzoxazinone derivatives.Herein we report a simple and efficient synthesis of 1,4-benzoxazinones by using substituted 2-chlorophenols as readily available starting material.To the best of our knowledge this is the first method for the synthesis of 1,4-benzoxazinone derivatives from 2-chlorophenols which is useful to prepare a large number of substituted 1,4benzoxazinones.

Results and Discussion
Initially, 2-chloro-4-methylphenol 1a was treated with N-benzyl-2-chloroacetamide in the presence of potassium carbonate in acetonitrile.The substituted acetamide 2a thus obtained was cyclized with cesium carbonate in DMF to give the corresponding 1,4-benzoxazinones 3a in good yield via Smiles type of rearrangement (Scheme 1).It is interesting to note that acetamide 2a undergoes Smiles type of rearrangement to form 7-methyl-2H-1,4-benzoxazin-3(4H)-one (3a) instead of the 6-methyl substituted product 3a'.The formation of 3a was confirmed by the reaction of 5-methyl-2-amino phenol (4) with 2chloroacetyl chloride using known methods (Scheme 2).Thus 2-chloroacetyl chloride was reacted with 4 to afford the intermediate 5 which was further cyclized (to give 6) followed by treatment with benzyl chloride furnished the compound 3a.The two compounds obtained by different synthetic routes were compared using physical and spectral data which was found to be same.The above results encouraged us to prepare various 1,4-benzoxazinone derivatives (3a-j) from different substituted 2-chloro phenols by the Smiles rearrangement.Accordingly 2-chloro phenols having methyl, methoxy, chloro and nitro substitution 1a-j (entries 1 to 10, Table 1), were treated with N-benzyl-2-chloroacetamide in the presence of potassium carbonate in acetonitrile.The substituted acetamides 2a-j thus obtained were cyclized with cesium carbonate in DMF under refluxing conditions to give the corresponding 1,4-benzoxazinones 3a-j in good yields and the results are summarized in Table 1.
We also investigated the base and solvent effects on the synthesis of 3a and we found that K 2 CO 3 in CH 3 CN was the most effective system (90% yield).Whereas K 2 CO 3 in DMF, Cs 2 CO 3 in CH 3 CN and in DMF were found to be less effective.On the other hand, Cs 2 CO 3 in DMF was found to be more effective (66% yield) for the cyclization of 2a when compared with other bases such as Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , and Ag 2 CO 3.

Conclusions
In summary we have developed a novel and efficient method for the synthesis of a wide range of 1,4-benzoxazinone derivatives via Smiles rearrangement.Further work including the application, chemical transformation and biological activity is underway in our laboratory.

Experimental Section
General Procedures. 1 H and 13 C NMR spectra were recorded in CDCl 3 (400 MHz for 1 H and 100 MHz for 13 C, respectively) with TMS as the internal reference on Bruker Advance 400 FT spectrometer.Chemical shifts were reported in parts per million.Mass spectra (MS) were measured by the EI method.Melting points are uncorrected.Silica gel (70-230 mesh) was used for flash column chromatography.All the reactions were monitored by TLC using 0.25 mm silica gel plates (Merck 60F-254) with or without UV indicator.Acetonitrile was distilled from anhydrous calcium sulfate and N, N-dimethylformamide was distilled from anhydrous magnesium sulfate prior to use.All other reagents were commercially available (Acros, Aldrich) and were used without further purification.All microwave-assisted reactions were carried out on KMIC-1.5KWcreator from Korea Microwave Instrument Company.The microwave-assisted reaction time is the hold time at the final temperature.