Reductive Cleavage of 1 , 2-Oxazines Promoted by Zinc and Ammonium Chloride ; Mild One Pot Preparation of γ-Hydroxy Ketones

A facile method for a mild single pot reductive cleavage of 1,2-oxazines to γ-hydroxy ketones was developed using zinc and aqueous ammonium chloride as the reagent in methanol. The reaction involves the reduction of N-O bond of the oxazine and the hydrolysis of the resulting 1,4-iminoalcohol.

[4+2] Cycloaddition of α-nitrosoolefins derived from acetophenone derivatives with various alkenes afforded the starting 5,6-dihydro-4H-1,2-oxazines.This procedure is based on Rai's method 23 .Typically, the reductions of the oxazines are carried out by heating a mixture of oxazines, zinc powder and ammonium chloride in methanol/water at 70 o C. In general γ-hydroxy ketones are thus obtained in good yield.

Experimental
All chemicals used were lab grade chemicals without further purification.All reactions were monitored by TLC, which was performed on Merck Alumafoil 60A° TLC plates with an UV indicator. 1H and 13 C NMR spectra were recorded using a 400 MHz Bruker Avance Ultrashield NMR spectrometer (400.23 and 100.64 MHz, respectively) and referenced to CDCl 3. Melting points are determined using a Campbell Electronics melting point apparatus.IR spectra were recorded using a JASCO FTIR-680 spectrophotometer.The elemental analysis of the compounds were carried out using Perkin Elmer 2400 series elemental analyzer and also by Orion ISE meter.General method for the reductive cleavage of oxazine

4-Hydroxy-4-phenyl-1-p-tolyl-butan-1-one (2b)
In a typical procedure, to a stirred solution of 6-phenyl-3-p-tolyl-5,6-dihydro-4H- [1,2]oxazine (1b), (0.9 g, 0.0036 moles) in methanol (25 mL) was added ammonium chloride (1.91 g, 0.036 moles) in water (7 mL).Zinc powder (0.70 g, 0.0108 moles) was then added to the reaction mixture and the solution heated to 70 o C for 3 h.The reaction monitored by TLC after 3 h showed the absence of starting material.The solution was filtered to remove zinc/zinc oxide mixture.The filtrate was then extracted into ethyl acetate followed by washings with water.The organic layer was evaporated to get crude compound.The crude compound was purified by column chromagraphy using hexane/ethylacetate (

Results and Discussion
The oxazines with various functional groups were prepared by the [4 +2] cycloaddition reaction of α-nitrosoolefins with alkenes, a method followed by Rai et al 23  The oxazines were reduced using zinc and ammonium chloride in methanol and water to corresponding γ-hydroxy ketones (Scheme 1).The reductive cleavage was accomplished using three moles of zinc and ten moles of ammonium chloride in methanol/water.The reaction stalled with lesser amounts of zinc and ammonium chloride.The reaction easily happened with 6-phenyl derivatives.With 6-methyl and 6-cyano methyl derivatives the reaction was sluggish.In these cases the reaction proceeded to completion at elevated temperatures.
Different reagents were tried for the conversion.Use of hydrogen/boric acid has been reported 24 .Our trials using hydrogen gas and boric acid lead to cleavage of N-O bonds but also resulted in the removal of some functional groups (eg: aromatic chloro group).Also there are some reports of the use of zinc/acetic acid/water 25,26 .for the cleavage but trials using the same for our substrates also resulted in the reduction of aromatic chloro groups in the system.Our screening of milder reagent for the preparation of γ-hydroxy ketones from 1, 2-oxazines led to the choice of the zinc and ammonium chloride which can accomplish the hydrogenolysis in a single pot.
The reactions were initiated at lower temperatures (50 o C and 60 o C) but took longer time for completion.This also resulted in more tar formation.The temperature of 70 o C was the optimum temperature for the conversion.All the compounds were purified by column chromatography using hexane/ ethyl acetate as eluent and characterized by 1 H and 13 C-NMR.The yields of γ-hydroxy ketones (after column purification) were in the range of 63-76%.The yield of compounds 2a and 2e are 72% and 75% respectively.The hydroxyl group in the γ-hydroxy ketones were characterized by 1 H-NMR (by deuterium exchange using D 2 O) and using IR-spectra.
The reductive cleavage using zinc and ammonium chloride reported here supersedes the other methods of reduction of 1, 2-oxazines in that it can be carried out without hydrogen gas, metals like Pd and Raney nickel and avoids expensive regents like LiAlH 4 , DIBAL-H.The other major advantage is that this reagent being milder, reduction can tolerate different functional groups like chloro, cyano and methoxy.The keto group in the product remained unaffected after the reaction.

Conclusion
In conclusion, using zinc and ammonium chloride in methanol/water, an economical and convenient method of cleavage of oxazines to γ-hydroxy ketones is established.The mild one pot procedure tolerates various functional groups.