摘要:
1977 97 1Thermally Induced lsomerisation of Isoxazol-5-ylhydrazinesBy Giorgio Adembri,' Alfred0 Camparini, and Fabio Ponticelli, lstituto di Chimica Organica dell'Universith,Piero Tedeschi, Centro di studio del C.N.R. sulla chimica e la struttura dei composti eterociclici e loro appli-The thermal isomerisation of isoxazol-5-ylhydrazines (I) led to 1 -aminopyrazolin-5-ones (11). 4-aminopyrazolin-5-ones (111). and 1.2.4-triazin-6-ones (IV), in ratios depending on the nature of the substituents and the solventsused. A reaction mechanism involving a bicyclic intermediate. is suggested on the basis of the behaviour ofisoxazolyl hydrazines methylated on the hydrazine moiety towards heating. Heating the methylated isoxazolyl-hydrazines ( I X g and h) afforded the corresponding azirinecarbohydrazides ( X I I ) .Siena, Italycazioni, presso I'lstituto di Chimica Organica dell'Universit8, Firenze, ItalyRECENTLY 1 we reported the thermally induced isomeris-ation of isoxazol-5-ylhydrazines (I), in hydrazine, to givel-amino- (11) and 4-amino-pyrazolin-5-ones (111). Onthe basis of previous work we suggested a mechanisminvolving a diradical intermediate.We now reportstudies on substituted isoxazol-5-ylhydrazines in varioussolvents or in the molten state carried out in order todiscover whether the rearrangement involved hydrazine,and whether other products expected on the basis of theproposed reaction path could be isolated. We alsohoped to obtain support for the suggested pathway.Thermal cleavage reactions of isoxazoles are now.G. Adembri, F. Ponticelli, and P. Tedeschi, J. HeterocyclicChem., 1972, 9, 1219.(a) I. Adachi, K. Harada, and H. Kanij,, Tetrahedron Lettevs,1969, 4875; (b) T. Nishiwaki, T. Kitamura, and A. Nakano,Tetrahedron, 1970, 26, 463; (c) T. Nishiwaki, A. Nakano, and H.Matsuoka, J . Cbem. Soc. ( C ) , 1970, 1826.assumed to occur along a reaction co-ordinate involvingin-plane stretching of the N-0 bond, which is intrinsic-ally the weakest link of the ~ystern.~As expected: attempts to obtain evidence for thepresence of a radical intermediate failed: no n.m.r.signal attributable to CIDNP, nor e.s.r. signal wasdetected during the reaction. However in the presenceof peroxides the reaction was quicker and, occurred atlower temperature, whereas it was unaffected by smallamounts of water and organic acids.The rate wasstrongly dependent on the purity of the starting material.As well as in anhydrous hydrazine, we studied theA. Padwa, E. Chen, and A. Ku, J. Amer. Chem. Soc., 1976,97, 46484.(a) N. M. Atherton, in Electron Spin Resonance,' EllisHorwood, Chichester-Halsted -, 1973, p. 182; (b) A. R.Lepley and G. L. Closs, in Chemically Induced MagneticPolarization,' Wiley, New York, 1973, p. 130972 J.C.S. Perkin Ireaction in benzene, toluene, xylene, and dimethyl substituents on the nature and relative yields of productssulphoxide. From reactions in these solvents we wereable to isolate also 1,2,4-triazin-6-ones (IV), expected on The disappearance of the isoxazolylhydrazines and thewas also marked (see later).( I ):N )r=( ,c=oNH1NHZ 1k $ O H INH2(a: 1I4IH('1111SCHEME 1HIHHon the basis of the proposed path,l moreover the triazin-one was sometimes the major product.The effect ofR 2 R ' R 3 N H - N H R( = a - c 1 ( 1 )N H2-N M e 2 1R' .-R 2( m a - c 1appearance of the products was followed by t.1.c. and byn.m.r. spectroscopy. Besides the main products (11)-(IV), minor compounds were detected; among these thepyrazolin-5-ones (V) were almost always present.The thermal rearrangement can be rationalised interms of an equilibration of a transient diradical inter-mediate with a ZH-azirine, which subsequently re-arranges as shown in Scheme 1. Support for this sug-gestion was provided by the thermal isomerisation ofisoxazolylhydrazines methylated on the hydrazinemoiety.The hydrazines (Ia-i) were conveniently preparedfrom 5-chloroisoxazoles (VI) and the appropriate hydra-zines (Scheme 2).Reactions with methylhydrazine ledonly to a single product (Id-f) in high yield, whereasthose with 1,l-dimethylhydrazine afforded a mixture ofthe hydrazine (Id-f) and 5-dimethylaminoisoxazole(VIIa-c). The hydrazines (IX) were obtained from thecorresponding formyl derivatives (VIII) ; treatment ofthe hydrazines (I) with formic acid gave the 2-formylderivatives only, and borane solutions reduced the CHOgroup to Me, without affecting the isoxazole ring. Thedimethylhydrazine (XI) was achieved analogously byreduction of compound (X), obtainable by two proced-ures, the more convenient being the treatment of theformylhydrazine (VIIIa) with diazomethane.Thestructures of above compounds were assigned on thebasis of spectral data.Heating the hydrazines (IXg and h) gave the azirine1977 973(XIIg and h) in high yield (Scheme 4). The i.r. spectra The methyl ether (XV) was also prepared from 1-of the azirines were characterised by a medium intensity amino-5-methoxypyrazole (XVI) by reductive methyl-band at 1 740 cm-l, due to C=N stretching 5 and a strong ation with formaldehyde and sodium borohydride,carbonyl band at ca. 1640 cm-1, U.V. spectra (solvent formylation of the N-methyl derivative (XVII) to giveR 3(m aJg,h\ f r o m ( m a Y2 \ P h ,-. MeSCHEME 3MeCHOmethanol) were almost identical with that of 2,3-di-phenylazirinecarboxamide.6 The n.m.r.spectra showedthree NMe signals, two of which coalesced on heating.The isolation of the azirines (XII) can be considered todemonstrate that the azirines are intermediates in therearrangement of compound (I). We believe that ringexpansion to the triazinones could occur by intramolec-ular attack of the hydrazine moiety with formation of abicyclic aziridine by analogy with the mechanism proposedfor the reaction of hydrazine with azirinecarboxamides.6This interpretation i s supported by the thermal iso-merisation of the hydrazines (Id-f and g-i). Heatingthe hydrazines (Id-f) gave 4-amino-l-methylpyrazol-ones (IIId-f) and/or l-methyltriazinones (IVd-f) .7In agreement with the formation of a bicyclic intermedi-ate, the hydrazines (Ig-i) yielded lJ2,5,6-tetrahydro-triazin-6-ones (XIII) .7In all cases, the methyl group (R3) prevented therearrangement to l-aminopyrazolones (11).In contrast,introducing two methyl groups onto the terminal nitro-gen atom of the hydrazino-group, only the rearrangementto l-aminopyrazolones (11) was still possible. Thus, onheating the isoxazolylhydrazine (XI) in 1 ,l-dimethyl-hydrazine, we obtained a mixture of l-dimethylamino-pyrazolone (XIV) and the corresponding deaminatedpyrazolone, which were easily separated by preparativet.1.c. of the methyl ethers (made by treatment withdiazomethane) .G. Smolinsky, J . Org. Chem., 1962, 27, 3557.T.Nishiwaki and T. Saito, J. Chem. SOC. (C), 1971, 2648.compound (XVIII), and reduction of this with diboranesolution.The formation of the pyrazolone (Va) must be attribu-ted to the decomposition of the l-dimethylaminopyrazo-lone (XIV) , since l-aminopyrazolones (11), when heated,are deaminated to pyrazolones and, as expected, this tend-ency is more pronounced in the N-methyl derivatives.These results are also indicative of the position that thenitrogen atoms of the starting material assume in theproducts. Thus we can infer that the isoxazole ringnitrogen atom is that at the 4-position in the triazinones,and the amino-group nitrogen in the 4-aminopyrazol-ones ; the amino-group nitrogen atom of l-aminopyrazol-ones is the terminal nitrogen atom of the hydrazinemoiety in the isoxazolylhydrazines.Ph Ph Me - ‘ g O HN---N( X I 1 - N,NINMe2( X T Y 1H( Y a 1C H 2 N 2 1PhI NMe2 H(xY1SCHEME 5Thermal conrotatory opening of the aziridine ring inthe bicyclic intermediate is not permitted by theA.Celli, A. Camparini, F. Ponticelli, and P. Tedeschi,Chimica c? Tndustria, 1976, 58, 221974 J.C.S. Perkin Igeometry of the system.8 However, thermally disallowed position with formation of 4-aminopyrazolones (111) orvalence isomerisation has been reported for other closely triazinones (IV), respectively.SCHEME 6related system^.^ It was suggested that the drivingforce for the process is provided by the relief of ring strainPh, .Me$6/MekF-o H NISCHEME 7in the bicyclic intermediate and the gain in resonanceenergy of the dipolar intermediates.(XX) NHMeR 3H\When the 2-methylisoxazolylhydrazine (IXa) re-arranged in benzene, we obtained the pyrazolone (XIX),whereas in methylhydrazine a mixture of the l-methyl-aminopyrazolone (XX) and its deamination product(Va) was isolated; the products were identified as methylethers. The formation of compound (XIX) suggeststhat the pyrazolone (V), often present in these reactionmixtures, can be formed by decomposition of the bicyclicintermediate as well as by deamination of the l-amino-pyrazolones (11).The nature and position of the substituents exert aconsiderable influence on the relative yields of products.Although the number of compounds studied is not large,it is clear that in hydrocarbon solvents the l-methylisox.azolylhydrazines (ld-f) give higher yields [especially of4-aminopyrazolones (111)] than the unsubstituted com-pounds (Table 1).As regards substituents on the isox-A \BSCHEME 8Rearrangement of the bicyclic intermediate can beachieved by either C-N or C-C bond cleavage of theazole ring, a methyl group increased the yield of 4-amino-pyrazolones (111), whereas two phenyl groups increasedring by a hydrogen shift from the 2- 9 (a) J. W. and K. Matsumoto, J . Org. Chem., 1971, 86,8 R. Huisgen and H. Mader, Angew. Chem. Internat. Edn., 1406; [b) P. E. Hansen, and K. Undheim, J.C.S. Perkin I , 1976,1969, 8, 604. 3061977 975that of the triazinone (IV). Two paths (a and b) forrearrangement of the bicyclic intermediate, involving abond cleavage to give a dipolar intermediate A and/orB, are possible.Stabilisation of intermediate A by twophenyl groups (C-C bond cleavage) is competitive withthat of intermediate B (C-N bond cleavage), favoured byTABLE 1Rearrangement products (yo yields) ofisoxazol-5-ylhydrazines in various solventsIsoxazol-5-yl-hydrazine Solvent 7 (11) (111) (TV)6347 230 {ia 14 32 4 236834.6 5Trace 7043 12Trace 1521.2 22 CC 90C 25 70C 60 26(14(Ib) {k C(Tc) {G a(Id)(14(If)t A, hydrazine; B, di-n-butylamine; C, aromatic hydro-carbons; D, toluene-triethylamine (12 : 1 v/v).Ref. 1.the higher electronegativity of the nitrogen atom. Theisomerisation to the triazinones (IV) is completed by thehydrogen shift from N-2 to C-5.When the N-2 hydrogenatom is substituted by a methyl group the formation ofthe pyrazolones (111) and triazinones (IV) is disallowed;the only allowed path is that to the ylide A, followed bymigration of the hydrogen atom from position 6 to C-5with formation of triazinones (XIII).The major production of l-aminopyrazolones (11) inthe presence of bases can be interpreted as an effect of thebase on the azirine hydrazide intermediate. Thus theknown mobility of hydrazide hydrogen atoms makespossible the formation of an anion, which promotesnucleophilic attack on the nitrene obtained by ringopening of the azirine.1°SCHEME 9It has been suggested that bases stabilise the nitreneintermediate.ll The same behaviour, to a lesser extent,is shown by basic solvents, or hydrocarbon solvents towhich a base has been added.Variation of substituents on the isoxazole ring has aconsiderable effect on the amounts of l-aminopyrazol-ones (11).* For details of Supplementary Publications see Notice to10 (a) T.Nishiwaki, J.C.S. Chem. Comm., 1972, 565: (b) A.Authors No. 7, J.C.S. Perkin I, 1976, Index issue.Padwa and P. H. J . Carlsen, J . Org. Chem., 1976, 41, 180.EXPERIMENTAL1.r. spectra were recorded with a Perkin-Elmer 357spectrometer for Nujol mulls, unless otherwise stated. l HN.m.r. spectra (60 MHz) were recorded with a Hitachi-Perkin-Elmer R20 B instrument (Me,Si as internal standard).U.V. spectra were measured for solution in methanol with aPerkin-Elmer 124 spectrophotometer.Spectroscopic datafor compounds ( l b and d-i), (VIIIa, g, and h), (IXa, g, andh), and (X) and (XI) are available as SupplementaryPublication No. SUP 21967 (3 pp.).* Silica gel plates(Merck F,,,) were used for analytical and preparative t.1.c.5-Chloro-3,4-diphenylisoxazole (VIb) .-To a stirred mix-ture of 3,4-diphenylisoxazolin-5-one (17 g, 0.071 7 mol) andphosphoryl chloride (52 ml, 0.568 rnol), triethylamine(10.3 ml, 0.073 3 mol) was added dropwise with cooling (ice-water bath). The mixture was then heated a t 120 "C for2 h and the excess of phosphoryl chloride removed in vacuo.The residue was poured into ice-water, and the solid wasfiltered off, washed with water, dried, and extracted withboiling light petroleum (b.p.40-70"). The extract wasevaporated to give compound (VIb) (15 g , 81.9%). Asample obtained by two sublimations a t 60 "C and 0.02mmHg melted at 87-88' (Found: C, 70.5; H, 3.95; C1,14.0; N, 5.6. Cl,Hl,CINO requires C, 70.45; H, 3.95; C1,13.9; N, 5.5%) ; A,,,. 230sh nm (log E 4.02).Preparation of Isoxazol-5-ylhydrazines (Ib and d-i) .-Amixture of 5-chloroisoxazole and the appropriate hydrazinewas heated as indicated in Table 2. The resulting solutionwas poured into ice-water and the crystalline productfiltered off, washed with water, and purified as appropriate.Compound (Ig) was recovered by evaporation (to remove1,2-dirnethylhydrazine), treatment with 3~-hydrochloricacid, and extraction with light petroleum (b.p.30-50 "C)(to remove starting material). Neutralisation of the aque-ous layer, extraction with ether, and evaporation of thedried (Na,SO,) extracts gave an oil which was dissolved inboiling light petroleum (b.p. 30-50 "C). The solution, atroom temperature, deposited a solid which was filtered off;the mother liquor was concentrated in vacuo and cooled a t- 10 "C to give compound (Ig) .Reaction of 5-Chloroisoxazoles (VIa-c) with 1,l-Dimethyl-hydrazine. General Procedure.-5-Chloroisoxazole (0.0 10 3mol) and 1,l-dimethylhydrazine (10 ml, 0.131 6 mol) wereheated in a sealed tube a t 105-120 "C for 3 h. The resultingsolution was evaporated in vacuo and the oily residuetreated with water and extracted with ether. The etherealsolution was dried (Na,SO,) and evaporated.(i) 5-Chloro-4-methyl-3-phenylisoxazole (VIa) a t 120 "Cafforded a mixture which was dissolved in light petroleum(b.p.30-50 "C) and extracted first with 3~-hydrochloricacid and then with 6~-hydrochloric acid. Evaporation ofthe light petroleum layer yielded unchanged chloroisoxazole(VIa) (40%). Neutralisation of the S~-hydrochloric acidsolution, extraction with ether, and evaporation of theorganic solvent afforded the isoxazolylmethylhydrazine (Id)(12%), identical (m.p. and i.r. spectrum) with the materialalready obtained. Analogous treatment of the 6~-hydro-chloric acid solution yielded the 5-dimethylaminoisoxazole(VIIa) l2 (15%).(ii) 5-Chloro-3,4-diphenylisoxazole (VIb) a t 105 "Cl1 M. Komatsu, S.Ichijima, Y. Ohshiro, and T. Agawa, J. Org.12 G. Adembri, E. Belgodere, G. Speroni, and P. Tedeschi,Chem., 1973, 38, 4341.Boll. sci. Fac. Chim. ind. Bologna, 1965, 23, 255976 J.C.S. Perkin Iafforded a mixture which was separated into two compon-ents by preparative layer chromatography with ether asdeveloper. The fastest running band yielded B-dimethyl-amino-3,4-diphenylisoxazole (VIIb) (62%) , m.p. 72-74'(from ethanol-water) (Found: C, 77.4; H, 6.15; N, 10.8.C1,H1,N,O requires C, 77.25; H, 6.1; N, 10.6%); Am%231 and 280 nm (log E 4.24 and 3.95) ; 6 (CDCl,) 2.80 (NMe,)and 7.15-7.22 (m, 2Ph). This product (yield 90%) wasalso obtained from the chloroisoxazole (VIb) and an excessof dimethylamine in benzene a t 80 'C for 3 h.The second band yielded the isoxazolylmethylhydrazine(Ie) (7%), identical (m.p.and i.r. spectrum) with thematerial already described.a t room temperature for 24 h and the excess of hydridedestroyed with ethanol (6 ml) . The solvents were removedi n vacuo, concentrated hydrochloric acid (15 ml) was addedslowly to the residue, and the solution was kept at ambienttemperature for 18 h and neutralised with aqueous 25%sodium hydroxide. If the product was precipitated as asolid, i t was collected by filtration. In the cases where theproduct was not precipitated, it was extracted with dichloro-methane; the organic layer was washed with water, dried(Na,SO,), and evaporated. The crude compound waspurified as described below.(i) l-Methyl-2-( 4-methyl-3-pheny2isoxazol-5-yl) hydrazine(IXa), The crude product was collected by filtration (yieldTABLE 2Preparation of isoxazol-5-ylhydrazines (I)Molar ratioof Found (yo) Required (% ) BenzYlideIlechloroisoxazole Temp. Time Yield M.p.(--, ,-&.-, deriv.Compound to hydrazine ("C) (min) (%) ( "C) Formula C H N C H N m.p. ("C)1 : 30 96 6 68 160-1620 Cl,Hl,N,O 71.9 6.0 16.5 71.7 5.2 16.7 135-137 h(decomp .)(Ib)(Id)(Ie)(If)(Id(Ih)(Ii)1 : 15 105O 60 88.5 70 CllHl,N,O 65.2 6.6 20.75 65.0 6.45 20.7 97 i1 : 25 Reflux 20 96.6 1276 Cl,Hl,N,O 72.6 5.85 16.7 72.45 5.7 15.85 174-176 f1:8 100" 360 55' 34-36a C1,H1,N,O 66.25 6.7 19.35 66.35 6.95 19.351:6 100" 90 97.1 93-95* C17H,,N,O 73.1 6.1 15.16 73.1 6.16 15.051:8 100" 120 74.3 89-90d C,,Hl,N,O 66.25 6.96 19.35 66.35 6.95 19.351 : 25 Reflux 20 96 82 f CllHl,N,O 65.1 6.25 20.65 65.0 6.45 20.7 70(I In a sealed tube.b Based on starting material consumed. After recrystallisation from ethanol and from benzene. AfterAfter recrystallisation from ethanol-water (1 : 1 v/v) and from light petroleum (b.p.After recrystallisation from lighttwo recrystallisations from cyclohexane.60-80 "C).petroleum (b.p. 30-50 "C).f After recrystallisation from benzene-light petroleum (b.p. 40-70 "C) (1 : 2 v/v). * From ethanol. From light petroleum (b.p. 75-120 "C).TABLE 3N'-( Isoxazol-5-yl) formohydrazidesFound (%) Required (%)Crys t . M.p. Yield r-- \ Compound solvent t ("C) (%I Formula C H N' ' C H N(VIIIa) A 161 69.7 Cl1Hl1N,O, 60.9 5.2 19.3 60.8 5.1 19.35(VIIIh)B 75-76 79.9 C13H1,N3O2 63.65 6.1 17.3 63.65 6.16 17.15(X) C 96-98 54.1 C1,Hl,N,O, 62.5 5.7 18.2 62.35 5.65 18.15A 130-131 96.3 C1,H17N,0, 70.5 5.5 13.6 70.35 5.6 13.7(VIIIg)t A, ethanol; B, light petroleum (b.p.40-70 "C); C, benzene-light petroleum (b.p. 40-70 "C) (1 : 1 v/v).(iii) 5-Chloro-3-methyl-4-phenylisoxazole (VIc) a t 110 'Cafforded a mixture which was chromatographed on silicagel. 5-Dimethylamino-3-methyl-4-phenylisoxazole (VIIc) l2(yield 62%) was eluted with light petroleum (b.p. 30-50 'C)-ether (9 : 1 v/v). Further elution with the same solventsgave the isoxazolylmethylhydrazine (If) (yield 21 yo),identical (m.p. and i.r. spectrum) with the material alreadyobtained .Preparation of the Formyl Derivatives (VIIIa, g, and h) and(X) .-A mixture of the appropriate isoxazol-5-ylhydrazine(0.01 mol) and formic acid (10 ml) was heated a t 85-90 "Cfor 30 min, cooled, and diluted with water to afford theformyl derivative which was purified as reported in Table 3.Compound (X) was also obtained from the formyl deriv-ative (VIIIa) (0.032 mol) in methanol (70 ml) and etherealdiazomethane (0.083 mol).The crude product was chro-matographed over silica gel. Elution with ether gave asmall amount of material which was discarded. Furtherelution with the same solvent afforded the formyl derivative(X) (yield 40%).Reduction of the Formyl Derivatives (VIIIa, g, and h) and(X) .-To the appropriate formyl derivative (0.01 mol)1M-borane in tetrahydrofuran (20 ml) was added dropwisewith stirring at 0 "C under nitrogen.The mixture was left60%). The hydrochloride of (IXa), obtained by treatingwith gaseous hydrogen chloride a solution of (IXa) in dryether, was crystallised from dry ethanol-ether, suspendedin ether, and neutralised with N-sodium hydroxide to givethe isoxazolylmethylhydrazine (IXa) , which was recoveredfrom ethereal solution. A sample obtained by crystallis-ation from cyclohexane melted a t 95-98' (Found: C,64.9; H, 6.3; N, 20.5. C11H13N30 requires C, 65.0; H,6.45; N, 20.7%).(ii) 1,1,2-Trimethyl-2- (4-methyl-3-phenylisoxazol-5-yl)hy-drazine (IXg). This compound was collected as an oil(yield 57%), which was dissolved in dry ether and treatedwith gaseous hydrogen chloride to give the hydrochloride,m.p. 121-122' (from dry ethanol-ether) (Found: C, 58.2;H, 6.8; C1, 13.3; N, 15.8.Cl,Hl,CIN,O requires C, 58.3;H, 6.8; C1, 13.25; N, 15.7%).(iii) 1-( 3,4-Diphenylisoxazol-5-yl) - 1 , 2,2-trimethylhydrazine(IXh). This compound was collected by extraction and,after two crystallisations from ethanol-water (1 : 1 v/v),melted a t 98.5-100" (yield 65%) (Found: C, 73.95; H,6.8; N, 14.5. Cl,Hl,N30 requires C, 73.7; H, 6.5; N,14.3%).(iv) l,l-Dimethyl-2-(4-rnethyl-3-phenylisoxazol-5-yl) hy-drazine (XI). This compound was collected by filtratio1977 977(yield 71%). A sample obtained by crystallisation firstfrom ethanol-water ( 1 : 1 v/v) and then from cyclohexane,melted a t 116-119' (Found: C, 66.4; H, 6.9; N, 19.15.Cl,Hl,N,O requires C, 66.35; H, 6.95; N, 19.35%).(XVII) .-A solution of l-amino-5-methoxy-4-methyl-3-phenylpyrazole (XVI) 1 (0.609 g, 0.003 mol) and aqueousformaldehyde (35% ; 3 ml) in methanol (10 ml) was refluxedfor 1 h.After cooling, sodium borohydride (0.4 g, 0.010 6mol) was added slowly; the solution was kept a t roomtemperature for 12 h, then evaporated in vacuo. Theresidue was extracted with dichloromethane ; evaporationyielded l-methylaminopyrazole (XVII) (0.55 g, 84.4%). Asample obtained by crystallisation from cyclohexane hadm.p. 83-85" (Found: C, 66.6; H, 6.95; N, 19.35. C1,H1,-N,O requires C, 66.35; H, 6.95; N, 19.35%); v,,,. 3 255cm-l (NH); Am. 249 nm (log E 4.15); 6 (CDC1,) 2.10 (s, Me),2.91 (s, NMe), 3.96 (s, OMe), 4.69br (exch., NH), and 7.25-7.71 (m, Ph).5-Methoxy-4-methyl- 1- (N-methylformamido) - 3-phenylfiyra-zole (XVIII) .-A solution of the l-methylaminopyrazole(XVII) (0.5 g, 0.002 3 mol) in formic acid (5 ml) was heatedat 90-95 "C for 40 min and neutralised with 2~-potassiumcarbonate, yielding the formyl derivative (XVIII) (0.45 g,80y0), which was collected by filtration and purified bysublimation a t 65 'C and 0.01 mmHg; m.p. 73-75' (Found:C, 63.6; H, 6.2; N, 17.35.C1,Hl,N,O, requires C, 63.65;H, 6.15; N, 17.1%); v,,,. 1 690 cm-l (CO); Am,. 244 nm(log E 4.18).(XV).-To a solution of the formyl derivative (XVIII)(0.8 g, 0.003 3 mol) in dry dichloromethane (10 ml), tetra-butylammonium boronate l3 [0.006 6 mol in dichloromethane(5 ml)] was added with stirring at 0 "C under nitrogen.Methyl iodide (0.82 ml, 0.013 mol) was added dropwise, andthe solution was refluxed (2 h) and then kept a t roomtemperature overnight.Ethanol (1.5 ml) was added andthe solvents were evaporated off in vacuo. The residue wasdissolved in concentrated hydrochloric acid (8 ml) ; thesolution was filtered and neutralised with 25% sodiumhydroxide to yield the 1-dimethylaminoyrazole (XV)(0.65 g, 86.2y0), which was sublimed at 40 "C and 0.02mmHg; m.p. 49-51' (Found: C, 67.75; H, 7.5; N, 18.3C,,H,,N,O requires C, 67.5; H, 7.4; N, 18.2%) ; Ama, 248nm (log E 4.06); 6 (CDCl,) 2.10 (s, Me), 2.89 (s, NMe,),3.96 (s, OMe), and 7.25-7.71 (m, Ph).Rearrangements of Isoxazol- 5-ylhydrazines .-Conditionsof reactions are reported in Table 4.The reaction mixtureswere worked up as described below.(a) 4-Methyl-3-~henylisoxazoZ-5-ylhydrazine (Ia) . (i) I ntoluene. After cooling, the solid was filtered off, dissolved inthe minimum of N-sodium hydroxide, and acidified to pH 6with concentrated hydrochloric acid to give (overnight inthe refrigerator) l-amino-4-methyl-3-phenylpyrazolin-5-one(IIa) (0.06 g). Extraction of the mother liquors withchloroform afforded a second crop (0.01 g) of the sameproduct (total 14%). The toluene solution was evaporatedto dryness in vacuo, and the residue dissolved in chloroformand extracted with 1.5~-hydrochloric acid (3 x 10 ml).The combined acidic extracts were neutralised with 25%sodium hydroxide, cooled in the refrigerator, filtered , andextracted with chloroform.Evaporation of this extractafforded a residue which, on trituration with light petroleum(b.p. 30-50 "C) , yielded 4-amino-4-methyl-3-phenylpyrazol-in-5-one (IIIa) (0.15 g, 30%). A sample obtained by5-Methoxy- 4-methyl- l-methylamino- 3-phenylpyrazole1-Dimethylamino-5-methoxy-4-methyl-3-fihenylfiyrazolecrystallisation from benzene melted a t 127-129" (Found :C, 63.4; H, 6.0; N, 22.3. Cl,HllN,O requires C, 63.5;H, 5.85; N, 22.2%); vmx. (CHC1,) 3 430 and 3 880br (NHand/or NH,) , and 1 725 cm-l (CO) ; Am,. 216 and 290 nm(log E 3.97 and 4.13); 6 (CDCl,) 1.46 (s, Me), 1.85br (exch.,NH,), 7.28-7.43 and 7.98-8.13 (m, Ph), and 9.45brTABLE 4Conditions of rearrangement ofisoxazol- 5- ylhydrazinesCompound Solvent (ml) 4PhMe (12)Xylene (16)BunSNH (12)PhMe (16)Xylene (12)PhMe (20)MeNH*NH, (7.5)NoneNoneMeaN*NHa (5.5)Temp.("C)100100 bReflux11711780100RefluxRefluxReflux140RefluxRefluxRefluxReflux82132150102 b*cTime (h)2.52.52.51 .o2.52.01.56.01.53.01 .o10.07.02.01.82.51.81 .o5.0* For 0.5 g of isoxazol-5-ylhydrazine. Under nitrogen.C In a sealed tube.(exch., NH). No 4,5-dihydro-5-methyl-3-phenyl-1,2,4-tri-azin-6(1H)-one (IVa) was obtained. T.1.c. of the rest ofthe reaction mixture [chloroform-methanol (9 : 1 v/v)]showed the presence of a small amount of 4-methyl-3-phenylpyrazolin-5-one (VIa) .The above rearrangement, carried out in the presence oftriethylamine (1 ml) under the same conditions, gave the1-aminopyrazolin-5-one (IIa) (yield 0.1 15 g , 23%) and the4-aminopyrazolin-5-one (IIIa) (yield 0.160 g, 32%).After cooling, the mixture wastreated as above, yielding the l-aminopyrazolin-5-one (IIa)(0.235 g, 47%) and the 4-aminopyrazolin-&one (IIIa)(i) I n hydra-zine.The solvent was removed in vucuo and the residuetreated with 3~-sodium hydroxide to give a solid (0.025 g)which consisted largely of 5-amino-3,4-diphenylisoxazole l4(t.1.c.). The mother liquors were acidified to pH 6 withconcentrated hydrochloric acid, cooled in a refrigerator, andfiltered, to afford l-amino- 3,4-diphenylpyrazolin- &one ( IIb)(yield 0.340 g, 68%), contaminated (t.1.c.) by a smallamount of 3,4-diphenylpyrazolin-5-one (Vb) .A sample ofthe former crystallised from ethanol melted a t 184-1 86'(decomp.) (Found: C, 71.8; H, 5.2; N, 16.8. Cl,Hl,N,Orequires C, 71.7; H, 5.2; N, 16.7%); vmax. 3 335 and 3 185(NH,) and 2 650br cm-' (OH) ; A,,,. 240sh nm (log E 4.14) ;6 [(CD,),SO] 6.5br (exch., NH, and OH/NH) and 7.18-7.42 (m, 2 Ph). The aqueous mother liquors of (IIb) wereextracted with chloroform, and the solvent was evaporatedoff t o give a residue which, after repeated crystal-lisations from benzene, yielded 4-amino-3,4-diphenylpyraz-olin-5-one (IIIb) (0.02 g, 4%), m.p. 196-197' (Found: C.(ii) I n di-n-butylamine.(0.01 g, 2%).(b) 3,4-Diphenylisoxazol-5-ylhydrazine (Ib).l3 A. Brandstrom, U. Junggren, and B. Lamm, Tetrahedronl4 R. Walter and P.G. Schickler, J . prakt. Chew., 1897,55, 305.Letters, 1972, 3173978 J.C.S. Perkin I71.5; H, 5.2; N, 16.9. C1,H13N,0 requires C, 71.7; H,5.2; N, 16.7%); vnlax. (CHCl,) 3 445, 3 385, and 3 300 (NHand/or NH,), and 1 730 cm-l (CO) ; Amax. 294 nm (log E 4.13) ;6 [(CD,),SO] 2.88 (s, exch., NH,), 7.21-7.81 (m, 2 Ph), and11.50 (s, exch., NH).After cooling, the solid was filtered off(yield 0.35 g, 70%) and identified (i.r.) as 4,5-dihydro-3,5-diphenyl-1,2,4-triazin-6(lH)-one (IVb).s T.1.c. of themother liquors showed the presence of small amounts of the4-aminopyrazolin-5-one (IIIb) and the pyrazolin-5-oneThe mixture was kept a t roomtemperature (12 h) to afford a precipitate which was filteredoff and dissolved in the minimum of N-sodium hydroxide(charcoal). Acidification to pH 6 with concentratedhydrochloric acid gave the 1-aminopyrazolin-&one (IIb)(0.14 g).The di-n-butylamine solution was evaporated todryness in vacuo, and the residue was treated with N-sodiumhydroxide (5 ml) and extracted with ether. Acidification(pH 6) of the alkaline solution afforded a second crop (0.033g) of the same product (total 34.6%), contaminated (t.1.c.)by a small amount of 3,4-diphenylpyrazolin-5-one (Vb) .The ethereal solution was evaporated in vacuo and theresidue, crystallised from benzene, afforded the 1,2,4-triazin-6-one (IVb) (0.025 g, 5%).(c) 3-Methyl-4-phenyZisoxazoZ-5-yZhydrazine (Ic) . (i) Intoluene. The mixture was kept at room temperature (6 h)t o afford a precipitate which was filtered off (0.230 g).T.1.c.analysis [chloroform-methanol (9 : 1 v/v)] showed thepresence of the 1,2,4-triazin-6-one (IVc) ,7 the 4-aminopyraz-olin-&one (IIIc),~ and the pyrazolin-&one (Vc) .The ratios of products [(IVc) : (IIIc) : (Vc)] were determinedby n.m.r. as 3 : 2.25 : 1. The toluene solution was extractedwith 10% sodium hydroxide; the alkaline solution wasneutralised and extracted with chloroform to afford, afterevaporation and crystallisation from benzene, a second crop(0.023 g) of compound (IIIc) (total 21.2%).The solution was evaporated invacuo and the residue, in ether ( 5 ml), yielded the 1,2,4-tri-azin-&one (IVc) (0.075 g, 15%). No l-aminopyrazolin-5-one (IIc) was obtained, and t.1.c. of the rest of the mixtureshowed the presence of small amounts of the 4-aminopyr-azolin-&one (IIIc) and the pyrazolin-&one (Vc) , and anumber of unidentified products.(d) 1 -Methyl- 1 - (4-methyl- 3-phenyZisoxazoZ-5-yZ) hydrazine(Id).The solution was evaporated to dryness in vacuo andthe residue, on trituration with light petroleum (b.p. 30-50 "C) , yielded 4-amino- 1,4-dimethyZ-3-~henyZPyrazolin-5-one(IIId) (0.45 g, 90%). A sample crystallised from cyclo-hexane melted at 118-119" (Found: C, 65.2; H, 6.4; N,20.55. CllHl,N,O requires C, 65.0; H, 6.45; N, 20.7%);v- 3 350 and 3 285 (NH,), and 1 705 cm-l (CO) ; A,, 218and 300 nm (log E 4.01 and 4.13); 6 [(CD,),SO] 1.32 (s, Me),2.50br (exch., NH,), 3.29 (s, NMe), 7.37-7.53 and 8.02-8.20 (m, Ph). No 4,5-dihydro-1,5-dimethyl-3-phenyl- 1,2,4-triazin-6(1H)-one (IVd) 7 was found by t.1.c.of the rest ofthe reaction mixture.(e) I-Methyl- 1-(3,4-di~henyZisoxazol-5-yZ)hydrazine (Ie) .The solution was evaporated in vacuo and the residueseparated into two components by preparative layerchromatography with ether as developer. The fastestrunning band gave 4-amino-l-methyZ-3,4-diphenyZ~yrazolin-5-one (IIIe) (0.125 g, 25y0), which, sublimed at 100 "C and0.06 mmHg and crystallised from ethanol-water, melted at149-150" (Found: C, 72.6; HI 5.8; N, 15.85. C,,H15N,0(ii) In xylene.(Vb) *(iii) In di-n-butylamine.(ii) In di-n-butylamine.requires C, 72.4; H, 5.7; N, 15.85%) ; vmx. 3 365 and 3 300(NH,) and 1 710 cm-l (CO); Amx. 220sh and 304 nm (log c4.09 and 4.08); 6 (CDCl,) 2.11br (exch., NH,), 3.38 (s, NMe),and 7.16-7.80 (m, Ph).The second band yielded the1,2,4-triazin-6-one (IVe) (0.35 g, 70%).(f) 1-MethyZ- 1-( 3-methyZ-4-phenylisoxazoZ-5-yZ)hydrazine(If). The mixture was worked out as aboveyielding the 4-aminopyrazolin-5-one (IIIf) (0.3 g, 60%)and the 1,2,4-triazin-6-one (IVf)(ii) In hexadeuteriodimethyl sdphoxide. The reaction wasmonitored by n.m.r. spectroscopy. The ratios of products[(IIIf) : (IVf) : (If)] were determined as 12 : 6 : 1. Whenthe above rearrangement was carried out in the same sol-vent at 120 "C in the presence of a small amount of benzoylperoxide, the ratios of products [(IIIf) : (IVf) : (If)] weredetermined, after 40 min, as 4.7 : 1 : 8.6. No products wereobserved under the same conditions .in hexadeuterio-dimethyl sulphoxide alone or in the presence of smallamounts of water and of benzoic acid.(g) 1,2-DimethyZ-l- (4-methyl-3-~henyZisoxazoZ-5-yZ) hy-drazine (Ig). The solvent was evaporated off in vacuo andthe residue separated into five components by preparativelayer chromatography with ether as developer. The fastestrunning band gave 1-methyl-2-methylene- 1-(4-methyZ-3-PhenyZisoxazoZ-5-yZ) hydrazine (0.035 g, 7%), which waspurified by crystallisation from light petroleum (b.p. 30-50"C) and sublimation at 40 "C and 0.02 mmHg; m.p. 48-49'(Found: C, 66.8; H, 6.1; N, 19.5. C1,H,,N30 requiresC, 66.95; H, 6.1; N, 19.5%); A,,,. 228 and 284 nm (log E4.12 and 4.19); 6 (CDCl,) 2.13 (s, Me), 3.34 (s, NMe), 6.41(AB system, J 10 Hz, CH,), and 7.33-7.63 (m, Ph).Thiscompound was also obtained (yield 60%) by refluxing theisoxazolylhydrazine (Id) (0.609 g, 0.003 mol) with aqueousformaldehyde (35%; 3 ml) for 30 min. The second bandgave starting material (0.025 g, 5%). The third band gave2-methyZ-3-~henyl-2H-azirine-2-N-methyZcarboxamide (0.095g, 22y0), after sublimation at 50 "C and 0.01 mmHg, m.p.63-65' (Found: C , 70.0; H, 6.5; N, 14.8. C1,H1,N,Orequires C, 70.2; H, 6.4; N, 14.9%) ; v, (KBr) 3 280 (NH),1 740 (C=N), and 1 635 cm-I (CO) ; A,,,. 247 nm (log E 4.10) ;6 (CDC1,) 1.52 (s, Me), 2.64 (d, J 6.5 Hz, s with D,O, NHMe),5.60br (exch., NH), and 7.32-7.84 (m, Ph). The fourthband yielded the 1,2,4-triazin-6-one (XIIIg) (0.075 g, 15%)as an oil.The fifth band (0.165 g) was still a mixture[t.l.c. with chloroform-methanol (9 : 1 v/v)] and was notfurther examinated.(h) 1-(3,4-DiphenyZisoxazol-5-yZ)- 1,2-dimethylhydrazine(Ih). The solvent was evaporated off in vacuo and theresidue treated with ether t o give the 1,2,4-triazin-6-one(XIIIh) 7 (0.300 g). A second crop (0.115 g, total 83%) wasrecovered from the mother liquors.(i) 1- (3-MethyZ-4-phenyZisoxazoZ-5-yZ) - 1,2-dimethylhydraz-ine (Ii). The solution was evaporated in vacuo, and theoily residue was chromatographed on silica gel. Startingmaterial (0.25 g, 50%) was eluted with ether. Furtherelution with ethanol gave the 1,2,4-triazin-6-one (XIIIi)as an oil (0.20 g, 40%).(j) l-MethyZ-2-(4-methyZ-3-~henyZisoxazoZ-5-yZ) hydrazine(IXa) .The solvent was evaporated off andthe residue chromatographed on silica gel. Elution of thecolumn with ether gave 4-methyZ-5-methyZazo-3-phenyZisox-azoZe (0.113 g, 22.8y0), which was sublimed at 60 "C and0.02 mmHg; m.p. 79-81O (Found: C, 65.8; H, 5.4; N,20.9. Cl1H,,N,O requires C, 65.65; H, 5.5; N, 20.9%);A,, 225 and 278 nm (log E 4.12 and 4.09); 6 (CDCl,) 2.40(i) In xylene.(0.13 g, 26%).(i) In benzene1977 979(s, Me), 4.11 (s, NMe), and 7.37-7.78 (m, Ph). The sameproduct (m.p. and i.r. spectrum) was also obtained (55%) byadding to a solution of the isoxazol-5-ylhydrazine (IXa) indioxan an excess of hydrogen peroxide (30%).Further elution of the column with the same solvent gave1,4-dimethyl-5-phenylpyrazolin-3-one (XIX) (0.12 g, 26%).Further elution with ethanol gave 4-methyl-3-phenylpyraz-olin-5-one (Va) (0.115 g, 26.9%).The solvent was evaporated offin vacuo and the residue treated with N-sodium hydroxide(6 ml) and extracted with ether.The extract was con-centrated and chromatographed on silica gel. Elution ofthe column with ether gave l-methyZene-2-(4-methyZ-3-phenyZisoxazoZ-5-y2)hydrazine (0.069 g, 13.9%). A sampleobtained by crystallisation from cyclohexane, melted a t130-133' (Found: C, 65.5; H, 5.6; N, 20.9. CllHllNsOrequires C, 65.65; H, 6.5; N, 20.9%) ; vm, 3 200 cm-1 (NH) ;A,, 228 and 285 nm (log E 4.16 and 4.15); 6 (CDCl,) 2.09(s, Me), 6.68 (AB system, JAB 11 Hz, CH,), 7.34-7.64 (m,Ph), and 8.10br (exch., NH). The same product (m.p. andi.r.spectrum) was also obtained (yield 80%) from the isox-azol-5-ylhydrazine (Ia) (0.003 mol) and aqueous formalde-hyde (35%; 3 ml) in methanol a t reflux temperature for30 min.Further elution of the column with ether gave startingmaterial (0.032 g, 6.4%).The alkaline solution was acidified (pH 6) with concen-trated hydrochloric acid and extracted with chloroform.The extract was evaporated and the residue (0.175 g) shownby t.1.c. to contain the pyrazolones (XX) and (Va), in aratio determined by n.m.r. analysis as 3 : 1. Etherealdiazomethane (0.126 g, 0.003 mol) was added to a suspensionof the above mixture in ether (10 ml). After 12 h the solu-tion was evaporated and the residue separated into twocomponents by preparative layer chromatography withchloroform-ether (3: 1 v/v) as developer.The fasterrunning band gave the B-methoxy- l-methylaminopyrazole(XVII) identical (m.p. and i.r. spectrum) with the materialdescribed above. The second band yielded 5-methoxy-4-methyl-3-phenylpyrazole.(b) 1, 1,2-TrimethyZ-2-(4-rnethyZ-3-~henyZisoxazoZ-5-yZ) hy-* The two signals coalesced near 60 "C and gave a sharp singlet(ii) In methylhydrazine.at ca. 80 OC.drazine (IXg). The mixture, treated with ether, depositedbrown material, which was filtered off. Evaporationafforded 2-methyZ-3-~henyL2H-azirine-2-trimethyZcarbohy-drazide (XIIg) (0.25 g, 50%) which, after sublimation a t70 OC and 0.02 mmHg, melted at 119-121' (Found: C,67.3; H,7.4; N, 18.1. C,,H,,N,OrequiresC, 67.6; H, 7.4;N, 18.2%); v,, (KBr) 1750 (C=N) and 1 635 cm-l (CO);A- 241 nm (log E 4.12); 6 (CDCl,) 1.68 (s, Me), 2.00s and2.10s (NMe,),* 2.80 (s, NMe), and 7.46-7.90 (m, Ph).(1) 1-(3,4-Di~henyZisoxazoZ-5-yZ)-l,2,2-t~imethyZhy~razine(IXh). The mixture, treated with a small amount of ether,yielded 2,3-dif~henyZ-2H-azirine-2-tvimethyZcarbohydrazide(XIIh) (0.355 g, 71%). A sample obtained by crystallis-ation from cyclohexane melted a t 13 1-1 33' (Found :C, 73.7; H, 6.5; N, 14.35. Cl,H,,NsO requires C, 73.7;H, 6.5; N, 14.3%); vmx. 1 740 (C=N) and 1 630 cm-1 (CO);& 218sh and 245 nm (log c 4.21 and 4.24) ; 6 [(CD,),SO]2.00s and 2.19s (NMe,),t 2.81 (s, NMe), 7.25 (s, Ph), and7.65-8.00 (m, Ph).(m) l,l-DimethyZ-2-(4-methyZ-3-~hertyZisoxazoZ-5-yZ)hydra-zine (XI). The solvent was evaporated off in an atmosphereof nitrogen; the residue, treated with N-sodium hydroxide,afforded starting material (0.116 g, 23.2%) which wasfiltered off. The alkaline solution was acidified (pH 6) withconcentrated hydrochloric acid and extracted with chloro-form. The extract was evaporated and the residue, dis-solved in methanol-ether (1 : 1 v/v) (30 ml), treated withethereal diazomethane (0.18 g, 0.004 3 mol). After 12 h thesolution was evaporated and the residue separated into twocomponents by preparative layer chromatography withchloroform as developer. The faster running band gavel-dimethylamino-5-methoxypyrazole (XV) (0.096 g, 18%)identical (m.p. and i.r. spectrum) with the material describedabove. The second band yielded 5-methoxy-4-methyl-3-phenylpyrazole (0.052 g, 12%).This work was supported by a grant from the ConsiglioNazionale delle Ricerche, Rome. We thank Dr. L. R.Lampariello for the U.V. spectra.[6/1602 Received, 2nd August, 19761t The two signals coalesced near 70 "C and gave a sharp singletat ca. 90 OC
ISSN:1472-7781
DOI:10.1039/P19770000971
出版商:RSC
年代:1977
数据来源: RSC