Unexpected Synthesis of Three Components from the Reaction of 4-Chloro-3-Formylcoumarin with Hydroxylamine Hydrochloride

A mild and simple oximation reaction of 4-chloro-3-formylcoumarin with hydroxylamine hydrochloride in basic medium gave unexpected three components via oxime.Those compounds were separatedin good yields by preparative TLC and by chemical means using differentreaction conditions. IR, 1H NMR, 13C NMR and mass spectral data confirmed the structure of the separated compounds. key words: 4H-coumarin[3,4-d]isoxazol-4-one; ethyl-5-(2-hydroxyphenyl)-isoxazole-4 -formate; methyl-5-(2-hydroxyphenyl)-isoxazole-4-formate;4-chloro-3-cyano-coumarin.

In this study we have investigatedthe reaction of 4-chloro-3-for mylcoumarin with hydroxylamine hydrochlorideatdifferent conditions to see if the reaction will have the same behavior as previouslydescribed in literature 3 .

RESULTS ANd dISCUSSION
The literature survey revealed some debate about the assignment of the structure of the reaction products of coumarin derivatives with hydroxylamine.
Structures of12a and 12b were confirmed on the basis of spectral analysis.Compound 10was obtained directly when the reaction was carried out under stirring 5 minutes by using 3eq hydroxylamine/3eq sodium acetate in ethanol as a solvent (Scheme 3).
It was found that the spectral data of 10were in agreement with literature results [7](m.p.199-200 o C).These compounds 10-12 were separated and purified by chromatographyusinghexane/ethyl acetate (8:2) as eluent.
Concerning the mechanism10 was formed by elimination of water from oxime (9); 11was formed by elimination of HCl to ring closure.Finally, the ethylesterisoxazole12a was obtained via ring opening of coumarin (lactone)by the action of ethanol.
In order to study the effect of solvent, we have repeated the reaction in methanol instead of ethanol to give methylesterisoxazole12b (Scheme2).A possible route for the multi-step mechanism is outlined in (Scheme 4).
We suggest that the hydroxylamine in basic medium conver ts 8 i n t o t h e key intermediate compound 9 which then undergoes further recyclizationby eliminationof HClto afford coumarino [3,4-d]isoxazole11.Ethanol or methanol makes the ring opening of the lactone part to form compounds 12a,b.

Experimental Section general Procedures.
Melting points were determined by using the kofler melting point apparatus, and were uncorrected.IR (kBr, cm -1 ) spectra were recorded on a Pye-Unicam SP3-100 instrument at Taif University. 1 H NMR spectra were obtained on a Varian (400 MHz) EM 390 USA instrument at king Abdel-Aziz University. 13C NMR spectra were recorded on a JNM-LA spectrometer (100 MHz) at king Abdel-Aziz University, Saudi Arabia.For both 1 H and 13 C -NMR, DMSO d 6 was used.Spectra were internally referenced to TMS.Peaks are reported in ppm downfield of TMS.Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q).Mass spectra were recorded on ISQ Thermo Scientific GC-MS.GC column TG-SQC, Trace GC ultra at TaifUniversitykSA.Purity of the compounds b) [9]  was checked by thin layer chromatography (TLC) using silica gel plates.Column chromatography was carried out on 0.04"0.063mm(Merck) silica gel, thin layer chromatography was carried out on aluminum backed silica plates by Merck and plates were revealed using a UV 254 light.

4-Chloro-3-coumarincarbaldehyde (8)
C o m p o u n d 8 w a s p r e p a r e d a s previously describe by sabitaeet.alwith a little bit modification 8 .
To a stirred mixture of 4-hydroxycoumarin 7 (9.72 g, 0.06mol) in anhydrous DMF (46.2 mL, 0.6 mol) were added dropwise POCl3 (27.6 g, 0.18 mol) at -10° to -5 °C.The reaction mixture was then stirred for 1 hr at room temperature after that heated and stirred for 5 hrs.at 80 °C.The reaction mixture was poured onto crushed ice (300 g) under vigorous stirring.The reaction mixture was kept overnight at 0°C.The pale yellow solid was collected by filtrationand recrystallized from acetone to give 10.To a mixture of NH 2 OH.HCl (1 eq.) and anhydrous sodium acetate (1 eq.)in ethanol, or methanol a solution of compound 8 (1 eq.) in ethanol was added.The reaction mixture was refluxed for 3hrs.After the reaction completed, the reaction mixture was poured onto crushed ice (300 g) under vigorous stirring.The pale yellow solid was collected by filtration and further purified by silica gel column chromatography using a mixture of hexane/ethyl acetate (8:2) as eluent to afford the desired three compounds10, 11 and 12a,b.

Notes
Compound 10 was prepared by using 3eq of NH 2 OH.HCl/ 3eq anhydrous sodium acetate and 1eq of compound 8 in ethanol.The reaction mixture was stirred for 5 minute to give compound 10 as yellow crystal m.p. 198-200°C (Lit, 199-200 °C)

Fur
therrecyclization and reduction o f c o m p o u n d 4 l e d t o t h e f o r m a t i o n o f 3-(diaminomethylene) chroman-2,4-dione 6.