Methylation of aminopyridazines

摘要

1424 J.C.S. Perkin IMethylation of AminopyridazinesBy Gordon B. Barlin, Medical Chemistry Group, John Curtin School of Medical Research, Australian NationalQuaternisations of mono- and di-aminopyridazines with methyl iodide in methanol have been examined and theproducts identified. 3- and 4-Aminopyridazine and 3,5-diaminopyridazine gave both 1 - and 2-methyl derivatives.3.4-, 3,6-, and 4.5-Diaminopyridazines each gave a single product, which in the first case was tentatively identifiedas 3.4-diamino-1 -methylpyridazinium iodide. No ammonio-compounds were detected in these reactions.Ionization constants, U.V. and l H n.m.r. spectra are recorded and discussed.University, Canberra, Australia 2600QUATERNISATIONS of pyridazines (I) have been examinedon a number of occasions.l-6 With regard to aminopyr-i I) (Dlidazines, Lund and Lundel have studied by n.m.r.spectroscopy the mixtures obtained from the reactions ofsome 3-aminopyridazines with methyl iodide in aceto-nitrile, and observed signals due to 1- and 2-methylderivatives ; and 3,6-bis(dimethylamino)pyridazine aloneunderwent quaternisation in part at the exocyclic nitro-gen atom, to give 6-dimethylaminopyridazin-3-yltri-methylammonium iodide (11), and in part at the ringnitrogen atom.We describe here the reactions of the simple mono-amino- and diamino-pyridazines with methyl iodide inmethanol to give in most cases both 1- and 2-methylatedproducts.The isomers formed have been separated byH. Lund and P. Lunde, Acta Chem. Scand., 1967, 21, 1067.G. B.Barlinand A. C. Young, J . Chem. Soc. (B), 1971,1261.G. F. Duffin and J. D. Kendall, J . Chem. Soc., 1959, 3789.4 N. K. Basu and F. L. Rose, J . Chem. Soc., 1963, 5660.t.1.c. and identified by lH n.m.r. spectroscopy and/orhydrolysis to known compounds. There was no evidenceaf formation of ammonio-compounds in the methylationsexamined.The aminopyridazines required were prepared byliterature procedures except for 3,6-diaminopyridazine.This could not be prepared from 3-amino-6-chloropyr-idazine by treatment with ammonia,' nor from 3-aniino-6-methylsulphonylpyridazine with ammonia or hy-drazine; it was prepared by reduction of 3,6-dihy-drazinopyridazine .Methylation of 3-aminopyridazine with methyl iodidein methanol at 20 "C gave both 1- and 2-methyl deriv-atives (as distinct from the trimethylammonio-com-pound) as shown by the lH n.m.r.spectra of the individualproducts and by hydrolysis of 3-amino-2-methylpyr-idazinium iodide to the known 2-methylpyridazin-3-one.34-Aminopyridazine likewise gave the two nuclearN-methyl isomers, and 4-amino-l-methylpyridaziniumiodide was hydrolysed to the known l-methylpyridazin-M. S. Bale, A. B. Simmonds, and W. F. Trager, J . Chem.G. F. Duffin, Adv. Heterocyclic Chem., 1964, 3, 1.T. V. Gortinskaya and M. N. Shchukina, J . Gen. Chem.Soc. (B), 1966, 867.(U.S.S.R.), 1960, 30, 15311976P yridazineUnsubstituted3-NHa4-NH23,4-(NH2), '4,5-(NH,)z3-NHz-6-C16-COSH-3-OH3-OH-4,5-H2-6-hIe4-NH2-2-Me-3=05-NH2-2-Me-3=04-NHz-3,6-C1,3,4-(NH,) ,-6-C15-NHz-6-Cl-2-Me-3=04-CI-3,6-( OH) 84-C1-6-OH-2-Me-3=05-C1-6-OH-2-Me-3=05, 6-CI2-2-Me-3=0Pyridazinium iodide3-NH2-1-Me 33-NH2-2-Me J4-NH,-1-Me 34-NH2-2-Me J3,4-(NHZ),-l-Me J3,5-(NH,) 2- l-Me J3,5-(NHZ),-2-hIe j3,6- (NH,) 2- l-Me f4,5-(NH2),-1-Me fTABLE 1pK, Values and U.V.spectraIonization (in water at 20 "C)*Species 5 pK,0 i + 0 +2+0 +2 f0 +2+0 + 0 + 02-00 +0 +0 +2+0--0 + 0+0 + 02-000---+ + 0 + + 0 + + + + +2.335.196.69 37.640.027.846.72- 1.826.743.532.7510.55-0.280.408.966.828.491.324.49-0.304.7012.595.144.1914 it:10k14k1311 k1313.5913.68Spread(=I=)0.030.050.040.020.040.020.050.050.030.040.070.060.030.040.030.030.050.020.050.050.020.050.04Concn. Analvt:(M)0.000 10.000 150.000 10.000 10.000 020.000 060.000 20.000 20.000 20.000 010.000 020.000 50.000 50.000 30.000 0250.000 070.000 040.000 30.000 070.000 30.0010.000 030.000 03h/namp; 63003502802 80273315250255260283260265305315257305295345345350320310Spectroscopy (in water) cr- A231, 294227, 289249, 2809272214, 254, 291226, 299226, 299218, 257, 278225, 277235, 326233, 332229, 296214, 281219, 286, 314(213,) 239, 312213, 232, 301247, 281237, 285253, 295241287, 292, 309222, 226, 235,276220, 259, 263,281259, 295227232, 285210, 214, 238,2 89218, 236, 305217, 256, 292222, 281208, 221, 259,297204, 232, 275,302282223, 287211, 232, 308223, 241, 337241, 341211, 230, 314222, 340214, 312221, 240, 339217, 235, 303311(213), 243, 320228, 289287277(212), 260, 312317(204), 229, 305229, 300226, 278231, 331224, 290, 319log E3.86, 3.313.76, 3.424.07, 3.574.124.13, 3.72, 3.774.06, 3.983.97, 3.934.49, 3.54, 3.544.46, 3.744.06, 3.294.26, 3.274.10, 3.344.38, 3.944.24, 3.79, 3.97(3.67), 3.76, 2.954.07, 3.68, 2.993.87, 3.384.06, 3.553.804.035, 4.045, 3.713.84, 3.273.88.3.93, 3.72,4.243.784.14, 3.82, 3.84,3.873.91, 3.564.364.36, 3.754.20, 4.22, 3.15,3.474.26, 3.48, 3.514.12, 3.96, 3.663.96, 4.104.27, 4.15, 3.75,3.764.29, 4.00, 3.77,3.983.734.18, 3.854.31, 3.62, 3.474.30, 3.87, 3.393.87, 3.504.29, 3.66, 3.564.28, 3.484.22, 3.363.69, 3.21, 2.894.45, 3.67, 3.41(4.26), 3.82, 3.313.63, 3.454.214.18(4.22), 3.98, 3.564.13(4.15), 3.91, 4.054.57, 3.574.45, 3.784.23, 3.324.39, 3.79, 4.02pH 4 .8.02.010.05.0-2.1010.05.59.02.0- 3.99.04.06.01 .o0.56.012.55.04.0-2.354.0- 2.3511.07.94.06.011.05.0-1.07.02.04.0-2.352.08.014.73.08.02.07.05.010.08.014.711.010.015.07 .O9.07.07.07.02 - .dianion. Analvtical wavelength for sDectroscoDic determination a 0.neutral species : -/- , cation : 2 + , dication: - , anion :of pK,.which Hammett acidity functions (cf. M. A. Paul and F. A. Long, Chenz. Rev., 1957, 57, 1) were assigned.and J. Phillips, J. Chem. Soc., 1948, 2240. f A. Albert, Chem. SOC. Sfiecial Publ. No. 3, 1955, p. 124.Soc., 1960, 219.potentiometric titration.c Shohders. and inflections in italics.. pH Values below 0 obtained b solutions of"hydrochoric or h p h u r i c acid to6 A. Albert, R. Goldacre,V S. F. Mason, J. Chm.a Determined byf For the determination of the spectra the reference cell was compensated with potassium iodide.h As the picrate; reference cell compensated with picric acid for the determination of spectra.Relative instability in solutions of high pH precluded determination of the pK, value14264-one.2 3,4-Diaminopyridazine with methyl iodide inmethanol gave one product only, which with N-sodiumhydroxide gave no 4-amin0-2-methylpyridazin-3-one.~3,5-Diaminopyridazine gave two nuclear N-methylderivatives whose orientation was established by hydro-lysis of the 3,5-diamino-2-methylpyridazinium iodide to5-amino-2-methylpyridazin-3-one.8 Methylation of 3,6-diaminopyridazine with methyl iodide in methanol gave3 , 6-diamino-1 -met h ylp yridazinium iodide only , whichwas hydrolysed in N-sodium hydroxide at 100 "C to6-amino-2-methylpyridazin-3-one ; and 4,5-diamino-pyridazine with methyl iodide in methanol at 20 "C gavethe only possible nuclear methiodide.J.C.S.Perkin Isubstituent , 5-chloro-6-hydroxy-2-methylpyridazin-3-one is a stronger acid by 0.95 pH units than its 4-chloro-isomer.All the iminopyridazines are strong bases.Comparison of the U.V.spectra of the aminopyridazinecations with their N-methyl derivatives revealed that3-aminopyridazine cation resembled its 2-methyl de-rivative and 4-aminopyridazine cation its l-methylderivative; hence protonation involves N-2 and N-1 ,respectively.Inspection of the spectra of the cations from the sym-metrical 3,6- and 4,Ci-diaminopyridazines and of 3,5-di-aminopyridazine revealed a close similarity with theirTABLE 21H N.m.r. spectra (6 values) *CompoundPyridine methiodide Solvent2-NHz 6 D,O(CDA2SO3-NHZ DZO4-NHz * DZO3-"Hz-1-MeI DZO3-NH2-2-Mel DZO4-NH2- 1-Me1 DZO4-NH2-2-MeI DZO(CD3)(CD3)ZSOPyri d a z i n e(CD3)(CDJ ,SO(CDJ2SO3,4-(NH,),-l-hfeI (CD,),SO3,5-(NH2),-1-MeI D,O3,5- (NH,) ,-2-MeI D,O3,6- (NH,),- 1-Me1 (CD,) ,SO4,5-(NH,) ,-1-Me1 (CD,) ,SO(CD,),SO(CD3)2S01-Me3.813.804.174.163.933.864.244.194.074.043.914.094.043.614.132-Me NH2 2-H 3-H7.018.18 7.017.916.50 7.987.85 6.777.88 8.06 6.737.683.923.81 5.228.476.99, 7.784.336.90(3), 7.19(5)3.76 - ..3.74 7.54(5), 7.78(3)6.60(6), 7.98(3)6.50(4), 7.39(5)8.428.408.778.054-H7.767.937.557.557.447.517.587.526.286.146.166.117.146-H6.786.727.557.656.776.737.837.867.527.446.967.028.556.707.146-H7.767.937.917.987.858.068.609.008.258.218.428.657.148.328.208.217.767.808.16Sodium 3-trimethylsilylpropane-l-sulphonate and tetramethylsilane were used as internal standards.b P. Karrer, T. Ishii,C T. J. Batterham, D. J. Brown, and M. N. Paddon-Row,B. M. Anderson, C. J. Ciotti, and N. 0. Kaplan, J. Biol. Chem., 1959,F. W. Kahnt, and J. van Bergen, Helv. Chim. Acta, 1938, 21, 1174.J. Chem. SOC. (B), 1967, 171, also record this spectrum.234, 1219. E. J. Poziomek, J. Ovg. CJaern., 1963, 28, 590.Ionization Constants and Ultraviolet S@ectra (Table I) .-The diaminopyridazines have their first basic pKa valuesin the range 6.72-7.84 and are 0.09-1.53 units strongerbases than the most basic relevant monoaminopyrid-azines.The difference between the first and secondbasic pKa values is 7.62 and 8.54 units for 3,P and 3,6-diaminopyridazines, respectively; cf. 7.01 and 8.65 in thediamin~pyridines.~Base weakening by chloro-substituents at the 3- and6-positions varied from 1.66 in 3-amino-6-chloropyrid-azine to 5.33 units in 4-amino-3,6-dichloropyridazine.Ei-Amino-2-methylpyridazin-3-one is a stronger basethan 4-amino-2-methylpyridazin-3-one by 0.68 units ;this may be due to O-protonation to give a cation of type(111) which is stabilised by resonance, a situation notshared by the 4-amino-compound.H2NPH N;NMe - Hfl+PoH bsol;"NMe(rn)Because of the nearness of the electron-withdrawingmethiodides but there was some divergence between thecation of 3,4-diaminopyridazine and its methiodide.As expected, 3-amino-6-chloropyridazine on proton-ation showed spectral changes similar to S-aminopyrid-azine, also indicating protonation at N-2 ; 3,4-diamino-6-chloropyridazine behaved like 3,4-diaminopyridazine ;and 4-amino-3,6-dichloropyridazine like 4-aminopyrid-azine.A close similarity existed between the neutralspecies (and monoanions) from 4-chlor0-3~6-dihydroxy-pyridazine and its 2-methyl derivative; but there was asignificant divergence in intensity in the spectra of theiranions from that of the anion of 5-chloro-6-hydroxy-2-methylpyridazin-3-one.N.m.y. Spectra (Table 2) .-These were determinedwhere possible in D,O and (CD,),SO for the aminopyrid-azine methiodides and aminopyridine methiodides (forcomparison).The data are consistent with the structures establishedby conversions into known compounds.On the evidenceT. Nakagone, A. Misaki, and T. Komatsu, Chem. andPharm. Bull. (Japan), 1966, 14, 1082.S G. B. Barlin, J. Chem. SOC., 1964, 21501976 1427of the signals due to the methyl group and H-6 from 3,5-and 4,5-diaminopyridazine methiodides, 3,4-diamino-pyridazine methiodide appears to be the l-methyl COM-pound.EXPERIMENTALAll compounds were examined for the presence of isomersand impurities by paper chromatography on Whatmanno. 1 paper with (a) aqueous 3 ammonium chloride, and(b) butan-l-o1--5~-acetic acid (7 : 3) as solvents, t.l.c., andlH n.m.r. spectroscopy, and were recrystallised to constantm.p. Analyses were performed by the Australian NationalUniversity Analytical Services Unit.Solids for analysiswere dried a t 100 "C unless otherwise stated and each m.p.was taken in a Pyrex capillary. 1H N.m.r. spectra wererecorded a t 60 MHz and 35 "C with a Varian T-60A spectro-meter. Where required, portions of the spectra wereexpanded, and all signals were integrated. Ionization con-stants were generally determined spectroscopically lo but inone case by potentiometric titration by I. Hawkins. U.V.spectra were measured with a Perkin-Elmer 450 recordingspectrophotometer and A,,,. and E values were checked withan Optica CF4 manual instrument (by D. T. Light).3-A minopyridazine Methiodides.-A mixture of 3-amino-pyridazine l1 (0.5 g), methyl iodide (1.0 ml), and methanol(5.0 ml) was kept at 20 "C overnight.The precipitate (0.55g) was filtered off and the filtrate evaporated to give a yellowsolid (0.7 g). N.m.r. spectroscopy (solvent D,O) of theyellow solid showed methyl signals a t 6 4.24 and 3.92 ofapproximately equal intensity, but the precipitate showedone only, a t 6 4.24.) The precipitate was recrystallisedfrom ethanol to give 3-amino-l-methylpyridaziniu.wz iodide,m.p. 182-183" (Found: C, 25.8; H, 3.9; N, 17.7. C,H,IN,requires C, 25.3; H, 3.4; N, 17.7). The picrate, preparedin and recrystallised from isopropyl alcohol, had m.p. 162-163" (Found: C, 39.15; H, 3.05; N, 25.1. Cl,HloN,O,requires C, 39.1; H, 3.1; N, 24.85). The yellow solid(0.7 g) was subjected to t.1.c. (silica; acetone) and gave,after recrystallisation from isopropyl alcohol, 3-amino-2-nzethylpyridazinium iodide (0.15 g), m.p.223-224" (Found:C , 25.65; H, 3.65; N, 18.1y0). Thepicrate, preparedinandrecrystallised from water, had m.p. 231-232" (Found: C,38.8; H, 3.5; N, 24.5. C,,H,,N,O, requires C , 39.1; H,3.0; N, 24.85).Hydrolysis of 3-Amino-2-methyl$yridaziniunz Iodide.-Amixture of 3-amino-2-methylpyridazinium iodide (0.010 g)and O.lN-sodium hydroxide (5 ml) was kept a t 20 "C for 14days. The product, extracted with chloroform, was iden-tical (paper chromatography, t.l.c., and U.V. spectrum) withauthentic 2-methylpyridazin-3-0ne.~4-A minopyridazine Methiodides.-A mixture of 4-amino-pyridazine 12*13 (0.5 g ) and methyl iodide (1.0 ml) in methanol(2 ml) was kept a t 20 "C for 12 h.The mixture was thenevaporated to dryness and the residue recrystallised fromisopropyl alcohol to give a crystalline solid (1.04 g) . The1H n.m.r. spectrum of this product in D,O showed methylsignals at 6 4.33 and 4.07 (ca. 1 : Z). A portion (0.94 g) wassubjected to t.1.c. (alumina; ethanol) and gave in the upperband 4-arnino-l-methylpyridazinium iodide (0.358 g), m.p.10 A. Albert and E. P. Serjeant, 'The Determination ofIonization Constants,' Chapman and Hall, London, 1971, 2ndedn.11 E. A. Steck, R. P. Brundage, and L. T. Fletcher, J . Amer.Chem. SOC., 1954, 78, 3225.12 T. Kuraishi, Pharm. Bull. (Japan), 1956, 4, 497.123-124" (from isopropyl alcohol-benzene) (Found : C,25.65; H, 3.6; N, 17.4. C,H,IN,requiresC, 25.3; H, 3.4;N , 17.7 ), and in the lower band 4-amino-2-methyZpyrid-azinium iodide (0.060 g), m.p.186-187" (from isopropylalcohol) (Found: C, 25.5; H, 3.5; N, 18.0).Hydrolysis of 4-Amino-l-methylpyridaziniuwz Iodide.-4-Amino-l-methylpyridazinium iodide (0.050 g) in N-sodiumhydroxide (5 ml) was kept a t 20 "C for 22 h. The mixturewas then extracted with chloroform, and the extract dried(Na,SO,) and evaporated to leave an oil which solidified.This product was identical (paper chromatography, t.l.c.,and U.V. spectrum) with authentic 1-methylpyridazin-6one.23,4-Diaminopyridazine monohydrochloride was preparedfrom 6-chlor0-3~4-diaminopyridazine 14 as described byGuither et aZ.15 The $icrate, prepared in and recrystallisedfrom water, had m.p.253-254" (Found: C, 35.7; H, 2.6;N, 29.4. C,H,N,,C,H,N,O, requires C, 35.4; H, 2.7; N28.9).3,4-Diaminopyridazine Methiodide.-A mixture of 3 , 6diaminopyridazine (liberated from 0.50 g of its bishydro-chloride with alkali in methanol), methyl iodide (3.0 ml),and methanol (10 ml) was kept a t 20 "C for 3 days. (Paperchromatography indicated that the reaction was complete in2.5 h.) The mixture was evaporated to dryness and theproduct recrystallised from isopropyl alcohol with concen-tration to give 3,4-diamino-l-rnethyZpyridazinium iodide(0.627 g), m.p. 213-214" (Found: C, 24.0; H, 3.8; N, 21.8.C5H,IN, requires C , 23.9; H, 3.6; N, 22.2).3 , 5-Diarninopyridazine Hydrochloride .-5-Amino-4-chloro-3-hydrazinopyridazine 1, was reduced to 4-chloro-3,5-diaminopyridazine l5 and 3,5-diaminopyridazine hydro-chloride.15 The picrate (of the latter), prepared in and re-crystallised from water, had m.p.303-305" (Found: C,35.3; H, 2.7; N, 28.7. C,H,N,,C,H,N,O, requires C, 35.4;H, 2.7; N, 28.9).3,5-Diaminopyridazine Methiodides.-A mixture of 3,5-diaminopyridazine (liberated from 0.5 g of its monohydro-chloride 15 with alkali) , methyl iodide (5.0 ml), and methanol(10 ml) was kept a t 20 "C for 4 days. The mixture was thenevaporated to dryness and the product recrystallised fromt-butyl alcohol-methanol to give a crystalline solid (0.645 g),which after further crystallisations from t-butyl alcohol-methanol gave 3,5-diamino-l-methylpyridazinium iodide(0.254 g), m.p.208-210" (Found: C, 24.0; H, 3.8; N, 21.8.C5H,IN4 requires C, 23.9; H, 3.6; N, 22.2). The$icrute,prepared in and recrystallised from water, had m.p. 205",depressed on admixture with the picrate of m.p. 228"(Found: C, 37.5; H, 3.4; N, 27.7. Cl1HllN,O7 requiresC, 37.4; H, 3.1; N, 27.8).The filtrates from recrystallisation of the isomer describedabove were evaporated and the product was dissolved inmethanol and applied to three alumina plates (20 x 40 cm).These were developed with ethanol and the upper portion ofthe dark band was removed and extracted with boilingethanol. The product was recrystallised from t-butylalcohol-methanol to give 3,5diamino-2-methylpyridaziniumiodide (0.014 g) , m.p. 254-256", characterised as its Picrate(prepared in and recrystallised from water), m.p.228",13 T. L. Chan and J. Miller, Austral. J . Chem., 1967, 20, 1695.14 G. A. Gerhardt and R. N. Castle, J. Heterocyclic Chew.,15 W. D. Guither, D. G. Clark, and R. N. Castle, J . Hekrocyclicl6 T. Kuraishi and R. N. Castle, J . Heterocyclic Cbm., 1964,1964, 1, 247.Chem., 1965, 2, 67.1, 421428 J.C.S. Perkin Idepressed on admixture with the picrate of m.p. 205" (Found :C, 37.9; H, 3.4; N, 27.6. Cl1HllN7O7 requires C, 37.4;H, 3.1; N, 27.8).A ttempted Hydrolysis of 3,5-Diamino-l-methyl~yyridazin-ium Iodide with N-Sodium Hydroxide.-3,5-Diamino-l-methylpyridazinium iodide (0.006 g) and N-sodium hy-droxide (1.0 ml) were kept at room temperature for 4 days.Paper chromatography showed that some reaction had takenplace after 3 days but the product was not 5-amino-2-methylpyridazin-3-one.8 The mixture was adjusted to pH8 and extracted with chloroform, and the aqueous solutionwas evaporated to dryness and the residue extracted withboiling ethyl acetate, but neither extract gave a significantproduct.Hydrolysis of a Mixture of 3,5-Diamino-l- and -2methyl-Pyridazinium Iodides with N-Sodium Hydroxide.-A mixtureof 3,5-diamino-l-(and 2-)methylpyridazinium iodide (0.050g ; 1H n.m.r.evidence) and N-sodium hydroxide (3.0 ml)were heated on a steam bath for 1 h. The mixture wasadjusted to pH 9.0 and evaporated to dryness, and theresidue was extracted with boiling ethyl acetate. Thisextract was subjected to t.1.c. (alumina; isopropyl alcohol)and gave a small quantity of 5-amino-2-methylpyridazin-3-one, identical (paper chromatography and t.1.c.) with anauthentic specimen.3,6-Diaminopyridazine .- 3,6-Dihydrazinopyridazine 17* l8(4.0 g) in water (150 ml) was shaken with hydrogen andRaney nickel a t atmospheric pressure for 5 h.The catalystwas filtered off and washed with water, and the combinedfiltrates were evaporated to dryness. The residue crystal-lised from ethanol to give 3,6-diaminopyridazine (2.1 g),m.p. 235-237" (lit.,7 235") (Found: C, 43.9; H, 5.8; N,51.1. Calc. for C,H,N4: C, 43.6; H, 5.5; N, 50.9);picrate (from ethanol), m.p. 277-279" (Found: C, 35.5; H.3.1; N, 28.7. CloHgN@7 requires C, 35.4; H, 2.7; N,28.9).3,6-Diamino- 1 -methylpyridazinium Iodide .-3,6-Diamino-pyridazine (0.2 g), methyl iodide (0.5 ml), and methanol(8 ml) were kept standing a t room temperature for 2 days.The solvent was then removed and the residue recrystallisedfrom isopropyl alcohol-methanol to give 3,6-diamino-l-methylpyridazinium iodide (0.28 g), m.p.271-272" (Found:C, 24.1; H, 3.9; N, 21.8. C,HgIN, requires C, 23.9; H,3.6; N, 22.2). The picrate, prepared in and recrystallisedfrom water, had m.p. 215-216" (Found: C, 37.75; H, 3.4;N, 27.95. CllHllN707 requires C, 37.4; H, 3.1; N, 27.8).Hydrolysis of 3,6-Diaminopyridazine Methiodide. 3,6-Diaminopyridazine methiodide (0.025 g) and N-sodiumhydroxide (2.0 ml) were heated on a steam-bath for 1 h.The mixture was adjusted to pH 9-10 and extracted withchloroform, and the product was recrystallised from ethylacetate t o give 6-amino-2-methylpyridazin-3-one, m.p.222-224", not depressed on admixture with an authenticspecimen.84-Amino-5-chloro~yridazine.-A mixture of 4-amino-5-chloro-3-hydrazino- and 5-amino-4-chloro-3-hydrazino-pyr-idazines (2.87 g), copper(I1) sulphate (10 g ) , and water (170ml) was refluxed for 1.5 h as described by Kuraishi andCastle l6 for the reaction of 6-amino-4-chloro-3-hydrazino-pyridazine.The product was isolated by recrystallisationfrom benzene to give crystals (0.9 g), m.p. 120-122" (lit.,1670-73") (Found, for material dried a t 20" and 20 mmHg for2 h: C, 37.6; H, 3.3; N, 32.2. C4H,C1N, requires C, 37.1 ;H, 3.1; N, 32.4), M+ 129 and 131.4,5-Diamino- l-methylpyridazinium Iodide.-4,5-Diamino-pyridazine hydrochloride l5 0.2 g ; picrate (from water),m.p.240-241" (Found: C, 36.6; H, 2.9; N, 29.0. C,,H,-N707 requires C, 35.4; H, 2.7; N, 28.9) was added tosodium methoxide (from 0.04 g of sodium) in methanol (5 ml)and the mixture was evaporated to dryness. To the residuewere added methanol (4 ml) and methyl iodide (2 ml), andthe mixture was kept a t room temperature for 5 days to givea crystalline solid. The mixture was evaporated to drynessand the product recrystallised from isopropyl alcohol-methanol to yield 4,bdiamino- 1-metlzyl~yridazinium iodide,ni-p. 229-231" (Found: C, 24.1; H, 3.75; N, 21.8.C,H,IN, requires C, 23.9; H, 3.6; N, 22.2). The picrate,prepared in and recrystallised from water, had m.p.225-226" (Found: C, 37.3; H, 3.2; N, 27.5. Cl1HllN7O7 re-quires C, 37.4; H, 3.1; N, 27.8).5-Chloro-6-laydro,zy-2-methyl~yridazin-3-one and 4-ChlOYO-6-lzydroxy-2-methylpyridazin-3-one.-These compoundswere prepared from chloromaleic anhydride and methylhy-drazine sulphate,8 but the more soluble and lower melting4-chloro-6-hydroxy-2-methylpyridazin-3-one was purifiedby column chromatography in acetone over silica (14 in) andrecrystallised from a small volume of water, acetone, orbutyl acetate. It had m.p. 193-196" (lit.,8 185-186')(Found: C , 37.8; H, 3.1; N, 17.4. Calc. for C5H5C1N,0,:C, 37.4; H, 3.1; N, 17.45).5-Amino-2-methyl~yridazin-3-one.-This compound 8 wasrecrystallised from ethyl acetate and had m.p. 194-196"(lit.,8 193.5-194.5").4-Amino-2-methylpyridazin-3-one.-This compound 8 wasrecrystallised from ethyl acetate and had m.p.173-175'(lit.,8 175-176").3-Amino-6-methyZthiopyridazine.-A mixture of 3-amino-6-chloropyridazine 11 (2.0 g) and aqueous sodium methane-thiolate (prepared from 2 g of sodium hydroxide in 20 ml ofwater) was heated in a sealed tube a t 120 "C for 12 h. Theproduct, extracted into chloroform and recrystallised frombenzene, gave 3-amino-6-methylthiopyridazine (1.7 12 g),m.p. 117-118" (Found: C, 42.7; H, 5.0; N, 30.1; S, 22.8.C,H7N3S requires C, 42.5; H, 5.0; N, 29.8; S, 22.7).3-Amino-6-methylsul~honylpyridazine.-A solution ofpotassium permanganate (1.0 g) in water (15 ml) was addedt o a stirred solution of 3-amino-6-methylthiopyridazine (0.5g) in 8N-acetic acid (15 ml) a t room temperature over 30min, and stirring was continued for 10 min.The mixturewas then decolourised by passing sulphur dioxide, andadjusted to pH 8 by addition of aqueous ammonia. Theproduct was then extracted repeatedly into chloroform, andrecrystallised from ethanol to give 3-amino-6-methylsul-fihonylpyridazine (0.224 g), m.p. 183-185" (Found: C, 35.1;H, 4.5; N, 23.8. C,H,N,O,S requires C, 34.7; H, 4.1; N,24.3). The picrate, prepared in ethanol, had m.p. 2 0 6206" (Found: C, 33.1; H, 2.6; N, 20.8; S, 8.1. Cl,HloN807requires C, 32.8; H, 2.5; N, 20.9; S, 8.0).Reaction of 3-Amino-6-chloropyridazine with Benzylamine.-3-Amino-6-chIoropyridazine l1 (1 .0 g) and benzylamine(20 ml) were refluxed for 3 h and the excess of benzylaminewas removed under reduced pressure. The residue wasextracted with hot ethyl acetate and the extract was filteredand chromatographed over alumina (6 in) in ethyl acetate togive 3-benzylamino-6-chloro~yridazine (0.196 g), m.p. 163-164" (from benzene) (Found: C, 60.4; H, 4.5; N, 19.1.CllHl,CIN, requires C, 60.1; H, 4.6; N, 19.1). Elution17 J. A. Elvidge and J. A. Pickett, J.C.S. Perkin I , 1972, 1483.18 J. Druey, K. Meier, and K. Eichenberger, Helv. Chim. Ada,1964, 37, 1211976 1429of the column with ethanol gave unchanged 3-amino-6-chloropyridazine (0.458 g ) ,When the reaction mixture was refluxed for 63 h, therewas obtained 3,6-bisbenzyZumino~yriduz~ne picrate (0.3 g),m.p. 218-220" (Found: N, 18.9. C,H,,N,O, requires N,18.9). 5/2506 Received, 22nd December, 19751I thank Dr. D. J. Brown for discussion, Dr. M. D. Fennfor assistance in the interpretation and Mr. S. E. Brown formeasurement of the lH n.m.r. spectra, and Miss V. J.Richardson for technical assistance