Synthesis and reactivity of 3-methylisoxazolo4,5-cpyridines

摘要

2190 J.C.S. Perkin ISynthesis and Reactivity of 3-Methylisoxazolo4,5-c pyridinesBy Giorgio Adembri,* Alfredo Camparini, and Fabio Ponticelli, lstituto di Chirnica Organica dell'llniversith,Siena, ItalyPiero Tedeschi, Centro di studio del C.N.R. sulla chirnica e la struttura dei composti eterociclici e loroapplicazioni, presso I'lstituto di Chirnica Organica dell'llniversith, Firenze, ItalyThe preparation of 3-methylisoxazolo 4,5-cpyridine and some derivatives is described. As expected, the 4-position of this system i s the most reactive towards nucleophiles.OF the four possible 1,2-benzisoxazole analogues with anitrogen atom in the benzene ring, only derivatives ofisoxazolo 5,4-bpyridine are kn0wn.l We report herea synthesis of 3-methylisoxazolo4,5-cpyridine (XIV)and the reactions of some of its derivatives.In this system, the presence of the isoxazole ringshould result in reactions with nucleophiles (Nu) beingfaster than those of the pyridine system, owing to-81 BIincreased stabilisation of negative charge over a seven-atom system. This stabilisation should be most effectivewas prepared from ethyl 5-ch1oro-3-methy1isoxazo1e-4-carboxylate (I); this was treated with diethyl sodio-malonate to give the isoxazolylmalonate (11), which, onhydrolysis (20 NaOH) , gave the isoxazol-5-ylaceticacid (111).The diester (IV), obtained by the action ofdiazomethane, reacted with concentrated aqueousammonia to give compound (V), whereas reaction withmethylamine afforded the methyl derivative (VI).Compound (V) can be obtained in a single step by theaction of concentrated aqueous ammonia on the malonateCompound (V) can exist in numerous tautomericforms. In the solid state a hydroxy-oxo-form (vco1 660 cm-l) is present; signals attributable to CH andCH, in the n.m.r.spectrum (CD,),SO (Table) show theexistence of an equilibrium mixture of tautomers. Themethyl derivative (VI) exists in the dioxo-form in thesolid state (vco 1690 and 1715 cm-l) and in CDC1,solution (CH, singlet in the n.m.r. spectrum), whereas in(CD,),SO a signal assignable to CH is also detectable.By heating compound (V) with phenylphosphonicdichloride, 4,6-dichloro-3-methylisoxazolo4,5-cpyridine(11) *when the leaving group (Le) is a t the 4-position, becausethe 4-substituted transition state, when written as (A),is expected to be more extensively conjugated than the6-analogue (B).6-Hydroxy-3-methylisoxazolo4,5-cpyridin-4( SH)-one(a) K.Bowden, G. Crank, and W. J. Ross, J . Chem. SOC.( C ) , 1968, 172; (b) U.S.P. 3,381,016 (Chem. Abs., 1968, 69,62122k); (c) Fr. P. 1,613,038 (Chem. Abs., 1969, 70, 106502a);(d) G.P. 2,216,087 (Chem. Abs., 1973, 78, 4 2 3 6 ~ ) ; (e) G.P.2,213,077 (Chem. Abs., 1973, 78, 4236q); (A T. Denzel and H.Hohn, Arch. Pharm., 1972, 305, 833; (g) G.P. 2,213,076 (Chem.Abs., 1973, 78, 16162a); (h) G.P. 2,237,765 (Chem. Abs., 1973,78, 136281k); ( 2 ) G.P. 2,301,267 (Chem. Abs., 1973, 79, 92212~);( j ) A. Sammour, A. Raouf, M. Elkasaby. M. Hassan, J. prakt.Chem., 1973, 315, 1176; ( k ) G.P.2,329,809 (Chem. Abs., 1974,80, 82964f).(VII) was obtained, along with a small amount of themonochloro-derivative (VIII). As predicted, compoundC I CI(VII) reacted with most nucleophiles to yield the cor-responding disubstituted products. The most reactivehalogen is that at the 4-position. The difference inreactivity is so great that the reaction can alwaysG. Adembri and P. Tedeschi, Boll. sci. Fac. Chim. ind.Bologna. 1965, 23, 2031975 2191be stopped at the monosubstitution stage. Thus, by theaction of hydrazine hydrate in dioxan at room tem-perature, we obtained the 4-hydrazino-derivative (IX),the tosyl derivative (X) of which decomposed underalkaline conditions to give the monochloroisoxazolo-4,5-cpyridine (XI), Indeed, vigorous conditions areusually necessary to obtain disubstituted products.state (vco 1 670 cm-l) and in methanolic solution, inwhich it shows an U.V.spectrum nearly identical withthat of compound (XVIII), obtained along with the 0-methyl isomer (XV), by treatment of the chloro-deriv-ative (XVII) with diazomethane. On the other hand,the isomeric chloro-derivative (VIII) exists always in thehydroxy-form; in the i.r. spectrum bands at 3 050 cm-lFormation of the dihydrazine (XII) needed anhydroushydrazine and brief heating.The structure of compound (XI) followed from itsn.m.r. spectrum. The position of the protons was con-firmed from the coupling constant, whose value is inagreement with J2,5 for pyridine3 and with J4,, for 3-methylisoxazolo4,5-~pyridine (XIV), obtained from thebistosylhydrazine (XIII) by alkaline degradation.Analogously, when compound (VII) was treated for 3h with sodium methoxide (4.5 mol.equiv), only themonomethoxy-derivative (XV) was isolated. The di-methoxyisoxazolo4,5-cpyridine (XVI) was prepared byprolonged heating of the dichloro-derivative (VII) witha larger excess of methoxide.The structure of compound (XV) was deduced fromits n.m.r. spectrum: the position of the ring protonsignal is shifted by 0.4 p.p.m., in comparison with thecorresponding proton of compounds (XI) and (XIV), inagreement with the presence of a $ara-metho~y-group.~Demethylation by acid of compound (XV) gives the 6-chloro-compound (XVII). The isomer (VIII) musttherefore be the 4-chloro-compound,Compound (XVII) exists in the oxo-form in the solidL.M. Jackman and S. Sternhell, in ' Applications of NuclearMagnetic Resonance Spectroscopy in Organic Chemistry,'Pergamon, Oxford, 1969, p. 307.(CH) and 3 560 cm-l (non-bonded OH) are present.The strong band at 1 630 cm-l must be assigned to a ringvibration mode because it appears at lower frequencies00 / iin the spectra of solutions of carbon tetrachloride. Then.m.r. spectrum shows a CH signal unaffected by D20:therefore there is no appreciable conversion into the-CH2-CO- form. The U.V. spectrum is very similar tothat of the O-methyl derivative (XIX), which was pre-pared along with (XX) by treatment of compound(VIII) with diazomethane.The structures (XVIII)and (XX) were supported by conversion into the dione(VI) by hydrolysis.The assignment of structure (XIX) led us to theconclusion that compound (V), when treated withdiazomethane (1.3 mol. equiv.), gave the 6-methoxy-derivative (XXI), almost exclusively, since this wasH. L. Retcofsky and F. R. McDonald, Tetrahedron Letters,1968, 25762192 J.C.S. Perkin IN.m.r. data (60 MHz) (J in Hz; internaltetramethylsilane as reference)62.34s4.1 Obr,s a6.66s a11.20br,s a2.40s3.20brJs *4.30brJs a6.80br,s all170br,s a2.49s3.22s4.04s 02.66s8.08s2.72s7.44s2.67s6.74s c2.62s12.00br,s a8.97d7.92d) J4*7 o*82.62s8.70d7.46d) J4*72.62s8.95d2.62s4.03s7.49s2.59s4.00s7.06s2.47s3.91s, 4.01s6.63s2.63s3 .9 6 ~ ~ 4.06s6.31s2.49s6.99s2.60s3.94s7.08s2.67s4.01s6.67s2.64s3.77s6.26s2.63s3.63s6.62s2.40s3.88s6.14s2.42s3.31s3.97s6.28s2.67s3.46s3.98s6.85s12.75br,s a11.90br,sAssignment3-Me7-Ha7-H6- or 4-OH and NH3-MeNMe7-H,7-H6-OH3-MeNMe3-Me3-Me3-Me7-Ha7-H7-H7-H6-OH4-H7-H4-H7-H4-H7-H6-H4-H7-H6-H3-Me3-Me3-Me3-Me3-Me4-OMe3-Me4-OMe3-Me7-H7-H4-, 6-OMe7-H3-Me4-, 6-OMe3-Me4-OH and NH3-Me6-OMe3-Me6-OMe3-MeNMe3-MeNMe3-Me6-OMe4-OH and NH3-MeNMe6-OMe3-MeNMe6-OMe7-H7-H7-H7-H7-H7-H7-H7-H7-Ha Signal disappears on deuteriation. b The broad signalappears as a sharp singlet a t about 60 "C; on deuteriation twosignals appear at 3.07 and 3.22 which coalesce at temperaturesnear 60 "C and appear as a sharp singlet at ca.80 "C. C Signaldoes not disappear on deuteriation after 5 h.converted into compound (XIX) by phenylphosphonicdichloride.With an excess of diazomethane compound (V)afforded a mixture of 00- and NO-dimethyl derivatives,(XVI) and (XXII). Compound (XXII) was also pre-pared from the chloro-derivative (XVIII) with sodiummethoxide.EXPERIMENTAL1.r. spectra were recorded on a Perkin-Elmer 457 spectro-meter for KBr discs, unless otherwise stated. 1H N.m.r.spectra were recorded with a Hitachi-Perkin-Elmer R20 Binstrument. U.V. spectra were measured for solutions inmethanol with a Cary 14 spectrophotometer.Silica gelplates (Merck F,,3 were used for analytical and preparativet.1.c.Diethyl (4-Ethoxycarbonyl-3-methylisoxazol-5-yl)malonate(II).-To a suspension of diethyl sodiomalonate (0.793 mol)in dry benzene, prepared from diethyl malonate (127 g)and sodium hydride (18.9 g) in benzene (850 ml), a solutionof ethyl 5-chloro-3-methylisoxazole-4-carboxylate (50 g,0.265 mol) in benzene (50 ml) was added. The mixture wasrefluxed for 15 h, then evaporated and the residue wasdissolved in water. The solution, after extraction withether, was acidified to pH 4 with concentrated hydrochloricacid and again extracted with ether. The ethereal solutionwas washed with water, dried (N+SO,), and evaporated.The residual liquid was distilled yielding an oil (75 g, go),b.p.134-136' at 0.16 mmHg (Found: C, 53.6; H, 6.15;N, 4.5.Methyl (4-EthoxycarbonyZ-3-methylisoxazoE5-yl)acetate(IV).-The ester (11) (40 g, 0.128 mol) was refluxed for 2 hin aqueous 15 sodium hydroxide (635ml) to give the diacid(111) (19.8 g, 84). A sample crystallised from water hadm.p. 195-196O (decomp.) (Found: C, 45.5; H, 3.8; N,7.8. C,H,NO, requires C, 45.4; H, 3.8; N, 7.6). To asuspension of the diacid (111) (19.8 g, 0.107 mol) in ether(1 80 ml) , ethereal diazomethane (0.32 1 mol) was added.The solvent was removed and the residue distilled to give aliquid (18.85 g, 82.5y0), b.p. 89-92" a t 0.05 mmHg (Found:C, 50.95; H, 5.2; N, 6.65. C,H,,NO, requires C, 50.7;H, 5.2; N, 6.6); vex; (film) 1745 and 1725 cm-1 (CO).6-Hydroxy-3-MethyZzsoxazolo 4,5-cpyridin-4( 5H) -one(V).-A suspension of the ester (11) (50 g, 0.16 mol) inaqueous 32 ammonium hydroxide (300 ml) was kept atroom temperature for 12 h and then refluxed for 6 h.Theresulting solution was cooled and acidified to pH 3 withconcentrated hydrochloric acid to give compound (V) , whichwas filtered off, washed with ether, and dried (yield 14 g,53). A sample crystallised from ethanol had m.p.227-228' (decomp.) (Found: C, 50.7; H, 3.7; N, 16.7.C7H,N,03 requires C, 50.6; H, 3.6; N, 16.9); v max3 300-2 400br (NH and OH) and 1660 cm-l (CO); A,,265sh and 285 nm (log E 3.93 and 4.11). This compoundwas also prepared (82) from the diester (IV) in an analo-gous way.3,5-DimethylisoxazoZo4,6-c~yvidirre-4,6( 7H)-dione (VI) .-(a) A suspension of the diester (IV) (5 g, 0.0235 mol) inaqueous 36 methylammonium hydroxide (75 ml) wasrefluxed for 5 h.The resulting solution was acidified (pH3) with concentrated hydrochloric acid and kept overnightin the refrigerator to give the N-methyl derivative (VI),which was recrystallised from water and dried a t 90'C,,H,,NO, requires C, 53.7; H, 6.1; N, 4.5)1975(yield 2 g, 47); m.p. 136-137" (Found: C, 53.45; H,4.5; N, 15.85. C,H,N,O, requires C, 53.3; H, 4.5; N,15.55); vmx. 1715 and 1690 cm-l (CO); A,, 208, 250,and 289 nm (log E 4.21, 3.51, and 3.87).(b) A suspension of the chloro-derivative (XX) (0.2 g,0.001 mol) in N-sodium hydroxide (7 ml) was heated a t50 "C for 5 min.The resulting solution was acidified topH 3 with concentrated hydrochloric acid to give com-pound (VI) (0.15 g, 82.5). The product (VI) was alsoobtained (25) from the chloro-derivative (XVIII) in N-sodium hydroxide a t 80-100 "C (1 h).4,6-DichZoro- 3-methyl (VII) and 4-Chloro- 6-hydroxy-3-methyZisoxazoZo4,5-~~yridine (VIII) .-A mixture of com-pound (V) (7.6 g, 0.046 mol) and phenylphosphonic di-chloride (16.5 ml, 0.116 mol) was heated a t 160 "C for 3 hand,after cooling, poured into ice-water (330 ml). Afterdecomposition of the excess of phenylphosphonic dichloride,the solid was filtered off, washed with water, and treatedwith 0.5~-sodium hydroxide (170 ml) ; the insolubledichloro-derivative (VII) was collected, washed with water,dried, and sublimed a t 60" and 0.02 mmHg (yield 6.44 g,69.4); m.p.91-92" (Found: C, 41.4; H, 1.9; C1, 34.8;N, 13.7. C,H,Cl,N,O requires C, 41.4; H, 2.0; C1, 35.0; N,13.8); vmx. 3 080 cm-l (CH); LX. 213, 240sh, 248, 254,and 264sh nm (log E 4.41, 3.83, 3.94, 3.96, and 3.73).The mother liquors were acidified to pH 3 with concen-trated hydrochloric acid to afford the monochloro-derivative(VIII) (1.75 g, 21), which, after sublimation a t 110" and0.02 mmHg, melted a t 243" (decomp.) (Found: C, 45.3;H, 2.6; C1, 19.2; N, 15.2. C7H,C1N,02requires C, 45.55;H, 2.7; C1, 19.2; N, 15.2); vmX. 3 080 (CH) and 3 300-3 200br cm-1 (OH) ; 216, 247sh, 253,268sh, and 275 nm(log E 4.36, 3.68, 3.78, 3.77, and 3.78).(IX).-To a solution of the dichloro-derivative (VII) (2 g,0.009 85 mol) in dioxan (5 ml), hydrazine hydrate (1.90 ml,0.0395 mol) was added slowly with stirring.The resultantmixture was kept a t room temperature for 12 h. Thewhite precipitate provided compound (IX) (1.55 g). Treat-ment of the mother liquors with water afforded a secondcrop (0.25 g) of the same product (total yield 92). Crystal-lisation from benzene gave pure monohydrazino-derivative(IX), n1.p. 200-201 (decomp.) (Found: C, 42.25; H,3.35; C1, 17.85; N, 28.2. C,H,C1N40 requires C, 42.3;H, 3.55; C1, 17.85; N, 28.2); vmx 3 320, 3 240, and3 200-2 500br cm-l (NH, and NH) ; h,, 221, 286, and296sh nm (log E 4.30, 4.23, and 4.19).4,6-Dihydrazino-3-methyZisoxazoZo4,5-cpyridine (XII) .-To the dichloro-derivative (VII) ( 5 g, 0.0246 mol), anhy-drous hydrszine (15 ml) was added dropwise with cooling(ice-water bath).The mixture was then heated at 100-110 "C for 15 min, cooled, and diluted with water (30 ml).The precipitate was filtered off, washed with cold methanol,and recrystallised from methanol to give compound (XII)(4.3 g, goyo), m.p. 227-228" (decomp.) (Found: C, 43.4;H, 5.2; N, 43.1. C,H,,N,O requires C, 43.3; H, 5.2; N,43.3); v,,,,,. 3 360-2 700br cm-l (NH, and NH); A,,,232 and 295 nm (log E 4.29 and 4.14).The Tosylhydrazino-derivatives (X) and (XIII) .-To asuspension of the hydrazino-derivative (IX) or (XII) (0.01mol) in anhydrous pyridine (15 ml), cooled in ice, tosylchloride (1.2 mol. equiv. for each NH-NH, group) wasadded.After 12 h the solution was poured onto crushed ice.The oily product was washed with cold water and solidifiedon rubbing to a brown mass.6-Chloro-4-hydrazino-3-methyZisoxazoZo 4,5-cpyridine6- ChZoro-3-methyl-4-tosyZhydrazinoisoxazoZo a, 5-clpyridine(X) (75) was obtained after three crystallisations fromethanol; m.p. 175-176" (decomp.) (Found: C, 47.8; H,3.7; C1, 10.05; N, 16,O; S, 9.0. C14H13C1N,03S requires C,47.7; H, 3.7; C1, 10.05; N, 15.9; S, 9.1); , 220, 267,and 285 nm (log E 4.40, 3.96, and 3.88).(XIII) (75) was obtained by two crystallisations frombenzene-ethanol (1 : 4) (charcoal) and two further crystallis-ations from ethanol; m.p. 186-187" (decomp.) (Found :C, 50.4; H, 4.45; N, 16.8; S, 12.7. C21H22NB06S2 requiresC, 50.2; H, 4.4; N, 16.7; S, 12.8); A,, 227 and 285 nm(log E 4.64 and 4.16).Alkaline Decomposition of the Tosylhydrazines (X) and(XIII).-The hydrazine (X) or (XIII) (0.008 mol) andethylene glycol (16 ml) was heated to 160 "C.To the hotsolution anhydrous sodium carbonate (2.5 mol. equiv. foreach NHoNHTs group) was added. Heating was continuedfor an additional 60-120 s and the solution was thenrapidly cooled to about 100 "C and diluted with hot water(160 ml). The mixture was extracted with ether and theextracts were dried (Na,SO,) and evaporated. The crystal-line residue was purified by sublimation a t 60' and 0.05mmHg.6-ChZoro-3-methyZisoxazolo4,5-c~yridine (XI) melted a t106-108" (yield 68.6) (Found: C, 49.7; H, 3.0; C1,21.2; N, 16.4.C,H,C1N20 requires C, 49.9; H, 3.0;C1, 21.0; N, 16.6); vm, 3 100 and 3 090 cm-l (CH);3-Methylisoxuzolo4,6-c~yridine (XIV) melted a t 11 lo(yield 40) (Found C, 62.9; H, 4.55; N, 20.7. C,H,N,Orequires C, 62.7; H, 4.5; N, 20.9); v,, 3 075 cm-l(CH); Am= 232 and 265sh nm (log E 3.82 and 2.93).Reaction of the Dichloro-derivative (VII) with SodiumMethoxide.-The dichloro-derivative (VII) (2 g, 0.009 85mol) was added to a solution of sodium (1 g, 0.043 5 g atom)in dry methanol (200 ml). The mixture was refluxed for3.6 h and was evaporated to dryness in vacuo. The residue,treated with water, collected by filtration, and dried, yieldedchromatographically pure 6-chZoro-4-methoxy-3-methyZisox-azoZo4,5-cpyridine (XV) (1.85 g, 94.6).A sampleobtained by sublimation a t 60" and 0.02 mmHg had m.p.90-91" (Found: C, 48.6; H, 3.6; C1, 17.65; N, 14.1.C8H,C1N202 requires C, 48.4; H, 3.55; C1, 17.9; N, 14.1) ;v,, 3 110 cm-l (CH); Am, 211, 248sh, 252.5, 267, and273sh nm (log E 4.34, 4.02, 4.04, 3.84, and 3.78).The above reaction, carried out with more sodium (5.66 g,0.246 g atom) in methanol (100 ml) a t reflux temperaturefor 16 h, gave 4,6-dinzethoxy-3-methyZisoxazoZo4,5-cpyridine (XVI) (1.76 g, 92) as the only product (t.1.c.).This compound, after crystallisation from light petroleum(b.p. 75-120"), melted a t 96-97" (Found: C, 55.5; H,5.1; N, 14.2. C,H1,N,03 requires C, 55.7; H, 5.2; N,14.4) ; vmx. 3 115 cm-l (CH) ; Amx. 212 and 265 nm (log E4.33 and 4.15).(XVII).-A suspension of compound (XV) (1 g, 0.005 mol)in concentrated hydrochloric acid (85 ml) was refluxed for2 h and poured into water (200 ml). A crystalline whiteprecipitate was collected which yielded the chlovo-derivative(XVII) (0.6 g, 65y0), m.p.293" (decomp.) (from ethanol)(Found: C, 45.5; H, 2.8; C1, 19.2; N, 15.1. C7H5C1N,0,requires C, 45.5; H, 2.7; C1, 19.2; N, 15.2); vma, 3 100(CH), 3 000-2 lOObr (NH) and 1 670 cm-l (CO) ; A,, 208,253, and 290 nm (log E 4.12, 3.83, and 3.95).3-Methyl-4,6-bistosyZhydrazinoisoxazolo4,5-cpyridine210 and 241 nm (log E 4.40 and 3.89).6-ChZoro- 3-methyZisoxazoZo 4,5-cpyridin-4 (5H) -onJ.C.S. Perkin I6-Methoxy-3-methyZisoxazoZo4,5-c~yridin-4( 5H) -one(XXI) .-Ethereal diazomethane (0.008 mol) was added to asuspension of compound (V) (1 g, 0.006 mol) in ether (25 ml).After 12 h the solid was filtered off t.l.c.of the etherealsolution showed the presence of small amounts of com-pounds (XVI) and (XXII) and recrystallised from ethanol(charcoal) to give the methoxy-derivative (XXI) (0.8 g, 74y0),m.p. 250" (decomp.) (Found: C, 53.5; H, 4.5; N, 15.45.C,H,N,O, requires C, 53,3; H, 4.5; N, 15.55); vmk 3 135(CH), 3 050-2 300br (NH) and 1 665 cm-l (CO); Lk 257and 282 nm (log E 3.99 and 4.07).(XIX).-A mixture of the methoxy-derivative (XXI) (0.5 g,0.0028 mol) and phenylphosphonic dichloride (0.51 ml,0.003 58 mol) was heated at 160 "C for 3 h and, after cooling,poured into ice-water (30 ml). After decomposition of theexcess of phenylphosphonic dichloride, the solid was filteredoff, washed with aqueous 5 sodium hydrogen carbonateand then with water, dried, and sublimed at 50" and 0.03mmHg to give the chloro-derivative (XIX) (0.36 g, 64.8y0),m.p.117-118" (Found: C, 48.6; H, 3.5; C1, 17.9; N,14.1. C8H,C1N,O, requires C, 48.4; H, 3.55; C1, 17.9; N,14.1); vmx. 3 110 cm-l (CH); A,, 216, 247sh, 254,258sh, and 277 nm (log E 4.43, 3.77, 3.85, 3.83, and 3.83).Treatment of the Methoxy-derivative (XXI) with Diazo-methane.-Ethereal diazomethane (0.0347 mol) was addedto a solution of the methoxy-derivative (XXI) (2.5 g,0.0139 mol) in methanol (80 ml). After 12 h the solutionwas evaporated and the residue (2.4 g) separated into twocomponents by preparative layer chromatography withlight petroleum (b.p.30-50")-chloroform (2 : 1 v/v) asdeveloper. The fastest running band gave the dimethoxy-derivative (XVI) (1 g, 37.1y0), identical (m.p. and i.r.spectrum) with the material described above. The secondband yielded 6-methoxy-3,5-dimethyZisoxazoZo4,5-c~yridin-4(6H)-one (XXII) (0.9 g, 33.4y0), m.p. 163-164" fromlight petroleum (b.p. 75-120°) (Found: C, 55.5; H,5.15; N, 14.4. CgH1,N,O, requires C, 55.7; H, 5.2; N,14.4y0); vmX 3 090 (CH) and 1 690 cm-l (CO); A,, 204,4-Chloro-6-methoxy- 3-methylisoxazoZo4,5-c~yridine257, and 283 nm (log E 4.22, 3.93, and 4.06). This product(20) was also obtained from the chloro-derivative (XVIII)(0.001 mol) and sodium methoxide (0.004 mol) in methanol(10 ml) at reflux temperature (10 h).Treatment of the Chloro-derivative (VIII) with Diazo-methane.-Ethereal diazomethane (0.007 58 mol) was addedto a suspension of the chloro-derivative (VIII) (0.7 g,0.0038 mol) in ether (20 ml).After 12 h the solid wasfiltered off, washed with a small amount of ether, andrecrystallised from carbon tetrachloride to give 4-chZoro-3,5-dimethyZisoxazoZo4.5-cpyridin-6(5H)-o~e (XX) (0.2g, 26.3), m.p. 223-224" (decomp.) (Found: C, 48.4;H, 3.4; C1, 18.1; N, 14.0. C,H,C1N202 requires C, 48.4;H, 3.5; C1, 17.9; N, 14.1); v,, 3 060 (CH) and 1 67Ocm-1(CO): A,, 225, 257sh, 263, and 336 nm (log E 4.45, 3.56,3.63, and 3.76). The mother liquors were evaporated andthe resulting solid sublimed to give the methoxy-derivative(XIX) (0.450 g, 59.6y0), identical (m.p. and i.r. spectrum)with the material described above.Treatment of the Chloro-derivative (XVII) with Diazo-methane.-Ethereal diazomethane (0.0065 mol) was addedto a suspension of the chloro-derivative (XVII) (0.6 g,0.003 25 mol) in ether (20 ml). After 12 h the solid wasfiltered off and crystallised from light petroleum (b.p.75-120") to give 6-chZoro-3,5-dimethyZisoxuzoZo4,5-cpyri-din-4(5H)-one (XVIII) (0.2 g, 31y0), m.p. 162-163"(Found: C, 48.2; H, 3.5; C1, 18.0; N, 14.2. C,H,ClN,O,requires C, 48.4; H, 3.5; C1, 17.9; N, 14.1); v,, 3 080(CH) and 1 675 cm-l (CO) ; hx 212, 252, and 295 nm (log E4.1, 3.74, and 3.98). The mother liquors were evaporatedto give a mixture which was sublimed at 50" and 0.05 mmHgto afford the methoxy-derivative (XV) (0.20 g, 31). Theresidue (0.17 g, 26) was compound (XVIII).This work was supported by a grant from the ConsiglioNazionale delle Ricerche, Rome. We are grateful to Dr.L. J. Mazza for the analytical data and to Dr. E. Belgoderefor the U.V. spectra.5/298 Received, 13th February, 1975