Pyrimidines. Part 53. Novel ring transformation induced by the substituent effect of the phenyl group. Reaction of 5-bromo-6-methyl-1-phenyluracil derivatives with amines and hydrazine to give hydantoins and pyrazolones

摘要

J. CHEM. SOC. PERKIN TRANS. I 1985 Pyrimidines. Part 53.lsquo;Novel Ring Transformation induced by the Substituent Effect of the Phenyl Group. Reaction of 5-Bromo-6-methyl-I -phenyluracil Derivatives with Amines and Hydrazine to give Hydantoins and Pyrazolones2 Kosaku Hirota,rsquo; Kazuo Banno, Yoshihiro Yamada, and Shigeo Senda Gifu Pharmaceutical University, Mitahora -higashi, Gifu 502, Japan Reaction of 5-bromo-6-methyluracil derivatives (1), possessing a phenyl or para-substituted phenyl group at the 1-position of the uracil ring, with methylamine and hydrazine hydrate causes novel ring transformations to give 1-arylhydantoins (2) and 4-ureidopyrazol-3-ones (9), respectively. The latter conversion into the pyrazolone (9) is a double ring transformation via a hydantoin intermediate (IV).The chemical properties of 6-unsubstituted 5-halogenouracil derivatives, which show interesting behaviour towards soft nucleophiles such as SO3rsquo;-and CN-, have been well in- ~estigated,~whereas little work has appeared on the reactivity of 5-halogeno-6-methyluracil derivatives4 Previously, we investigated the reaction of 5-bromo-6-methyluracils (I) with a variety of amines in order to prepare analgesic uracil deriva- tives, and reported that the reaction of the uracils (I) with arylamines caused an abnormal nucleophilic substitution on the 6-methyl group to give the corresponding 6-(arylaminomethy1)- uracils (111) although the reaction with dialkylamines afforded the corresponding 5-(dialky1amino)uracils (11) (Scheme 1).Our continuing interest in the properties of 5-bromo-6- methyiuracils has prompted us to undertake a study of the reaction with other nucleophiles such as primary alkylamines and hydrazines. When l-aryl-5-bromo-6-methyluracil deriva-tives (1) were used as starting materials, we found that a new type of ring transformation of the uracil occurred to give hydantoin and pyrazolone ring systems. Results and Discussion Reaction with Primary Aminex-Treatment of 5-bromo-3,6-dimethyl- 1-phenyluracil (la) with 30 aqueous methyl- amine in dimethylformamide (DMF) using a sealed tube at 100 ldquo;C for 18 h resulted in the formation of a ring-contraction product, 3-methyl- 1-phenylhydantoin (2a) (30), and a normal substitution product, 3,6-dimethyl-5-(methylamino)-l-phenyl-0 I -R a; Me b Me c; Me d; Et (rn) Scheme 1.Reagents: i, R3R4NH; ii, ArNH, uracil (3a)(21). The structure ofcompound (2a) was confirmed by direct comparison with an authentic sample7 prepared by methylation of 1 -phenylhydantoin (4) according to the modified method of Biltz and S10tta.~ Similar reaction of 5-bromo-6-methyluracils (lb-e), bearing a phenyl or para-substituted phenyl group at the 1-position, with methylamine gave the corresponding hydantoin derivatives (2b-e) in 19-36 yield X x X Hc1 OMe H e; CH,CH=CH, H f; Bu H Reagents: i, MeNH, I I IPh Ptl Ph (4) (51 (6) together with the uracils (3b)and (3c)as shown in Table 1. Other 5-(methy1amino)uracils (3d) and (3e) were detected in the respective crude products by U.V.and n.m.r. spectra but could not be isolated in pure form. Their structures were established by microanalytical and spectral data (Table 2). When the 5-bromouracil (la) was treated with ethylamine instead of methylamine, the same product (2a) was formed though its yield was low. The reaction with ammonia, how- ever, afforded the corresponding 5-aminouracil (5) and the reaction with tertiary amines such as triethylamine resulted in recovery of the starting material. In the latter two re-actions we were unable to detect the hydantoin (2a) in the reaction mixture. Upon treatment of the 5-bromouracil (la) with dialkylamines and aromatic amines, no ring contraction occurred but, instead, alternative reactions gave 5-(dialkyl- amino)uracils (11) and 6-(arylaminomethy1)uracils(IIX), respec-tively, as reported previously 5*6 Substituent effects at the 1-, 3-, 5-, and 6-position were examined.The uracil (6), having a 5-chloro group, was allowed to react with methylamine under the same conditions, and afforded the hydantoin (2e) (84) as the sole product. This result indicates that the ring contraction occurs in preference to Table 1. The reaction of 5-halogenouracils with amines 5-Halogenouracil Amine Product MeNH, MeNH, MeNH, MeNH, MeNH, MeNH, EtNH, NH3 MeNH, MeNH, MeNH, " Lit.7 185 "C. Light petroleum (boiling range 75-120 "C). Lit.,7 194 "C. J. CHEM. SOC. PERKlN TRANS. I 1985 the formation of the 5-(methy1amino)uracil (3e) because a chloro group is generally less active towards nucleophilic substitution by amines than is a bromo group.On the other hand, the 5-bromo- 1-phenyluracil derivatives (7a) and (7b), lacking either a 3-substituent or 6-methyl group respectively, and the 5-bromo-3-phenyluracil derivative (7c) reacted with methylamine to give normal displacement products, 5-(methyl- amino)uracils (8a-c), respectively. These results suggest that a 1 -phenyl substituent facilitates cleavage of the 1,6-bond, leading to ring contraction, and the lack of the 6-methyl group accelerates the replacement by the amine at the 5-position because of reduced steric hindrance. On the basis of the above facts, a plausible reaction mechan- ism for the ring transformation to the hydantoin ring system is shown in Scheme 2.Initial nucleophilic addition of methyl- amine to the 5,6-double bond and subsequent cleavage of the 1,6-bond are followed by ring closure to afford a hydantoin intermediate (IV). A tautomer (V) of the intermediate (IV) is subjected to aminolysis to give the final product (2). The possibility of hydrolysis instead of such an aminolysis was ruled out on the basis of the following experimental result. The reaction of compound (la) with methylamine under anhydrous conditions was attempted since we expected to isolate the intermediate (IV; R = Me, X = H), but this could not be obtained and compounds (2a) and (3a) were formed. This fact indicates that there is no participation of water in the reaction.Reaction with Hydrazine Hydrate.-When the 5-bromouracil (la) and excess of hydrazine hydrate in propan-2-01 were heated under reflux for 24 h, another ring transformation occurred to M.p. ("C) Recrystallization solvent Yield () 192" MeOH 30 124 b 21 172 b 36 158 b 22 198 AcOEt 36 164 MeOH-water 4 149 AcOEt 23 124 b 19 124 b 84 192 MeOH 16 25 1 MeOH 33 236 Benzene 17 163 EtOH 67 152 water 34 Table 2. Spectral and analytical data of hydantoins (2) Compound vma,./cm-'(C=O) ~Inax.(EtOH)/nm(.5/dm3 mol-' cm-') 6,(5-H,) Formula I Found (Requires) C H N 1 (24 (2b) (2c) (24 (2e 1770 1705 1 765 1700 1 760 1 705 1 760 1 705 1770 233sh (8 300), 247 (11 OOO) 272sh (2 200), 281 (1 200) 282sh (1 600),291 (900) 238 (10 500), 252 (10 200) 288sh (2 700), 299sh (1 600) 233sh (8 500), 247 (11 OOO) 272sh (2400), 281 (1 300) 232sh (9 800), 246 (12 600) ,252 (16 600) 4.26 4.27 4.30 4.33 4.29 C,,Hl,N,O, Cl,H12N,0, C,,H,,N,O, Cl2H1,N,O2 C,,H,ClO, 63.35 (63.15 53.3 (53.45 60.1 (60.0 64.6 (64.7 66.75 5.55 5.3 3.95 4.05 5.4 5.5 6.0 6.0 5.55 14.7 14.75) 12.6 12.45) 12.7 12.7) 13.7 13.7) 12.9 1710 273sh (2 300), 280 (I 400) (66.65 5.6 12.95) a CDCI, solution.Calculated values for known compound, J. CHEM. SOC. PERKIN TRANS. I 1985 0 with sodium borohydride in pyridine to give amines and formamides. Accordingly, compound (9a) was subjected to reduction with sodium borohydride--pyridine and was converted into the 4-anilinopyrazolone (lo), which was identical with the authentic sample obtained above. R' The ring transformation of the uraciI (la) to the pyrazolone (9a) was applicable to other 5-bromo-6-methyluracils (lc-f)(7) bearing a phenyl or para-substituted phenyl group at the 1- R' RZ R3 position.Treatment of the uracils (lc-f) with hydrazinea; Ph H Me hydrate under the same conditions gave the corresponding b Ph Me H pyrazolone derivatives (9c-f) in good yield (see Table 3). The c; Me Ph Me structures of the products (9c-f) were confirmed by their Reagents: i, MeNHz elemental and spectroscopic analyses. In particular, their mass spectrum showed an intense base peak corresponding to 4- (1) -L I (2) -furnish 5-methyl-4-(3-methyl-1-phenylureido)pyrazo1-3(2H)-one (9a)in 89 yield as the sole product.The structure of compound (9a) was supported by its elemental analysis and spectroscopic data. Since another possible structure, 5-methyl-3- methy lamino-4-phenyl-1,4-di hydro- 1,2,4-triazine-6-carboxylic X (9) Reagents: i, NHzNH,-HzO acid (13;R = Me, X = H),could be considered,* an alternative synthesis of compound (9a) for eventual comparison with the transformation product was attempted. Thus, methylation of 5-anilino-6-methyluracil (11)* with dimethyl sulphate afforded 5-anilino- 1,3,6-trimethyluracil (12), which was treated with hy- drazine hydrate to give 4-anilino-5-methylpyrazole-3(2H)-one (10) via a well known ring transformation (Scheme 3).Reaction of the pyrazolone (10) with methyl isocyanate under various conditions, however, failed to give the expected product (9a).It has been shown that NNW-trisubstituted ureas are reduced anilinopyrazolones (M -RNCO).On the other hand, analo- gous ring contraction of other 5-halogenouracil derivatives such as the 5-bromouracils (7a-c), 5-bromo- 1,3,6-trimethyl- uracil, 5-chloro-3-methyl- 1-phenyluracil, were carried out under various conditions, but the corresponding pyrazolones were not obtained; instead, the reactions gave a decomposition product, N-methyl-N'-phenylurea, or a complicated mixture of products. A reasonable mechanism for the transformation of the uracil (1) to the pyrazolone (9) is outlined in Scheme 2 (see above).A key intermediate (IV; X = NH,) could be similarly formed according to the sequence for the formation of the hydantoin (2). The intermediate (IV) subsequently undergoes an intramolecular nucleophilic attack of the terminal amino group on the 4-carbonyl group to give the pyrazolones (9).This double ring transformation differs from a well known uracil-to-pyrazolone transformation in terms of reaction mechanism. Furthermore, reaction of the 5-bromouracil (la) with methyl- hydrazine in refluxing propan-2-01 yielded a slight amount of 5-* Previously we had presented the incorrect structure (13) for the ring-transformation product (9) at the 8th Congress of Heterocyclic Chemistry (Japan) S. Senda, K. Hirota, K. Banno, T.Asao, J. Haruta, and Y. Yamada, Congress of Heterocyclic Chemistry (Kyoto), 8th, 1975, Abstracts of papers p. 149 (Chem. Abstr., 1976, 84, 164715); Heterocycles, 1975,3, 1128; see also: H. C. van der Plas and J. W. Streef, 'Aromatic and Heteroaromatic Chemistry,' eds C. W. Bird and G. W. H. Cheeseman, The Chemical Society, London, 1977, vol. 5, p. 2571. Scheme 2. 1140 J. CHEM. SOC. PERKIN TRANS. I 1985 Ph photometer. 'H N.m.r. spectra were determined with a Hitachi Perkin-Elmer R-20B (60 MHz) instrument for solutions in I __tHN$M!CONHMe (CD,)$O unless otherwise stated, using tetramethylsilane as internal standard. Chemical shifts are reported in p.p.m. (6) andHN signals are quoted as s(singlet), d (doublet), t (triplet),q (quartet), t iii H I Me Scheme 3.Reagents: i, NaBH,; ii, Me,S04; iii, NH,NH,-H,O H X (13) Table 3.4-(3-Alkyl-1-arylureido)-5-methylpyrazol-3-ones(9) Compound R X Recrystallization solvent (94 Me H EtOH-ether (94 Me OMe Pr'OH (94 Et H Pr'OH (94 CH,CH=CH, H Pr'OH (9f) Bu H Pr'OH m (multiplet), br (broad); J values are first order. Mass spectra were taken on a JEOL JMS-D300 machine operating at 70 eV. Reaction of N-substituted 5-Bromouracils (la-) with Amines. General Procedure (Table I).-A mixture of the 5-halogenouraci16." (la-), (6), or (7a--c) (10 mmol) and an aqueous solution of methylamine, ethylamine, or ammonia (50 mmol) in DMF (10 ml) was heated in a sealed tube at 100 "C for 18 h. The reaction mixture was treated as described below unless otherwise stated.The solvent was removed under reduced pressure and the residue was triturated with ether and water to give the hydantoin (2), the 5-aminouracil (S), or the 5-(methyl- amino)uracil (8). The ethereal filtrate was evaporated under reduced pressure and chromatographed on activated alumina with ether as eluant to give the 5-(methylumino)uracil(3b)and (3c). The products thus obtained were purified by recrystal- lization from an appropriate solvent as shown in Table 1. 3-Meth yl-1 -phen ylhydantoin (2a) and 3,6-Dimethyl-5-methyl- amino-1-phenyluracil(3a). The reaction mixture was kept over- night. The resulting precipitate was filtered off to give the hydantoin (2a). The mother liquor was evaporated under re- duced pressure and water was added to the residue.The mixture was extracted with chloroform and the extract was evaporated. The residue was distilled under reduced pressure (b.p. 165-17OoC/0.2 mmHg) to give the crude 5-(methyl- arnino)uracil(3a); 6, (CDCl,) 1.94 (3 H, s, 6-Me), 2.64 (3 H, s, Found (Requires) () C H N M.p. ("C) Yield () Formula , .A bsol; 254 256-257 89 57 c1 ZH 14N402 c1 JH 16N403 58.4 (58.556.4 5.75 5.75 5.8 22.7 22.75) 20.2 245-246 75 C13H 16N402 (56.5 59.8 5.85 6.2 20.3) 21.55 23 8-2 39 59 c14H 16N402 (60.0 61.45 6.2 5.95 21.55) 20.5 228-229 73 C15H20N402 (61.7562.5 5.9 7.05 20.6)19.45 amino-3,6-dimethyl-l-phenyluracil(5) together with recovery of most of the starting material (la).Heating compound (la) without any solvent at 100 "C improved the yield of the product (5). However, a mechanism for the formation of compound (5) is still uncertain. When compound (la) was treated with phenyl- hydrazine under the same conditions, practically no reaction took place and most of the starting material (la) was recovered unchanged. As a result of these investigations, we conclude that sub- stitution of phenyl groups at the l-position of uracils has a great influence on the occurrence of both ring contractions of the uracils (1) to the hydantoins (2) and to the pyrazolones (9). Experimental M.p.s were taken on a Yanagimoto melting-point apparatus and are uncorrected. 1.r. spectra were recorded with a Hitachi Model 21 5 spectrophotometer using KBr pellets.U.V.spectra were obtained from ethanol solutions on a Hitachi 323 spectro- (62.5 7.0 19.45) NHMe), 3.43 (3 H, s, 3-Me), and 7.15-7.68 (5 H, m, Ph); A,,,,,. 216 (E 10 200 dm3 mol-I cm-') and 282 nm (6 200); vmaX.1 690 (CO) and 3 360 cm-' (NH) (Found: C, 63.65; H, 6.1; N, 17.2. C,,H,,N302 requires C, 63.65; H, 6.15; N, 17.15). l-(p-ChlorophenyC)-3,6-dimethyl-5-(methylamino)uracil(3b). (Found: C, 55.8; H, 5.05; N, 15.05. C,,H,,ClN,O, requires C, 55.8; H, 5.05; N, 15.0). 1-(p-Methoxypheny~-3,6-dimet~yl-5-(methylamino)uracil (3c).6, 1.97 (3 H, s, 6-Me), 2.64 (3 H, s, NHMe), 3.17 (1 H, br, NH), 3.43 (3 H,s, 3-Me),3.88 (3 H,s,OMe),and 6.9amp;7.42(4 H, m, C,H,) (Found: C, 61.3; H, 6.35; N, 15.05.C,,H,,N303 requires C, 61.1; H, 6.2; N, 15.25). 3-Allyl- 1 -phenylhydantoin (2e). (a) The reaction mixture was evaporated under reduced pressure and the residue was sub- jected to column chromatography on silica gel with chloroform as eluant to give the hydantoin (2e). (b) A mixture of the 5-chlorouracil (6)(0.9 g, 3.2 mmol) and 30 aqueous methylamine (2.0 mi, 20 mmol) in DMF (10 ml)was treated as described in the General Procedure. The reaction J. CHEM. SOC. PERKIN TRANS. I 1985 mixture was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was filtered off and recrystallized from light petroleum (b.p. 75-120 "C) to give leaflets (0.59 g, 84), map. 124 "C; this product was identical with compound (2e)prepared above. 5-Amino-3,6-dimethyl-l-phenyluracil(5).6, 1.73 (3 H, s, 6-Me), 3.25 (3 H, s, 3-Me), 4.03 (2 H, br, NH,, deuterium exchangeable), and 7.22-7.61 (5 H, m, Ph); h,,,, 299 nm (Found: C, 62.55; H, 5.8; N, 18.2. C,,H,,N,O, requires C, 62.3; H, 5.65;N, 18.15). 6-Methyl-5-methylamino- l-phenyluracil (8a). 6, (CDCl,) 1.94 (3 H, s, 6-Me), 2.63 (3 H, s, NHMe), 3.01 (1 H, br, 5-NH, deuterium exchangeable), 7.167.59 (5 H, m, Ph), and 9.40 (1 H, br, 3-H, deuterium exchangeable) (Found: C, 62.4; H, 5.75; N, 17.85. Cl,Hl,N30, requires C, 62.3; H, 5.65; N, 18.15). 3-Methyl-5-Methylamino-1-phenyluracil(8b).6, (CDC1,) 2.72 (3H, s, NHMe), 3.45 (3 H, s, 3-Me),3.78 (1 H, br, NH, deuterium exchangeable),6.32 (1 H, s, 6-H),and 7.46 (5 H, s, Ph) (Found: C, 62.2; H, 5.6; N, 18.2).1,6-Dimethyl-5-rnethylamino-3-phenyluracil(amp;). 6, (CDCl,) 2.37 (3 H, s, 6-Me), 2.60 (3 H, s, NHMe), 3.21 (1 H, br, NH, deuterium exchangeable), 3.43 (3 H, s, l-Me), and 7.167.58 (5 H, m, Ph); h,,,. 293.5 nm (Found: C, 63.5; H, 6.4; N, 17.5. C13H,5N302 requires C, 63.65; H, 6.15; N, 17.15). 5-Amino-3,6-dimethyl-l-phenyluracil(5FA mixture of the uracil (la) (1.5 g, 5 mmol) and methylhydrazine (5 ml) was heated at 100 "C for 2.5 h. After the mixture had cooled, the resulting precipitate was collected by filtration to give the 5-aminouracil (5) (450 mg, 3973, which was identical with the product obtained from the reaction of compound (la) with ammonia.Alternative Synthesis of 3-Methyl-1-phenylhydantoin (2a).-1- Phenylhydantoin (4). A mixture of chloroacetyl chloride (5.5 g) and phenylurea (6.8 g) in DMF (40 ml) was kept overnight and then heated at 70 "C for 2 h. The solvent was removed under reduced pressure and the residue was triturated with water to give a crude product. Recrystallization from methanol gave N-chloroacetyl-N-phenylurea(5.0 g, 4773, m.p. 163-166 "C. The urea (5.0 g) was added to a solution of KOH (7 g) and water (7 ml) in ethanol (80 ml). The mixture was heated at 80 "C for 30 min. After being cooled, the reaction solution was acidified with HC1 and evaporated under reduced pressure. The resulting precipitate was collected by filtration, washed with water, and recrystallized from ethanol to give the hydantoin (4) (3.0 g, 72) as needles, m.p.203 "C (Found: C, 61.4; H, 4.85; N, 15.6. C,H8N,0, requires C, 61.35; H, 4.6; N, 15.9). 3-Methyl-l-phenylhydantoin(2a).The hydantoin (4) (1.7 g, 10 mmol) was dissolved in a solution of KOH (1.7 g) in water (30 ml) and then dimethyl sulphate (2.4 g) was added dropwise to the stirred mixture. The resulting precipitate was filtered off and recrystallized from methanol to give the hydantoin (2a) as needles (1.5 g, 79),m.p. 191 "C (lit.,' m.p. 185 "C). This product was identical with compound (2a) obtained by the ring- transformation reaction of the uracil (la). 4-(3-Alkyl-1-arylureido)-5-methylpyrazo1-3-ones (9a-e). General Procedure.--A solution of the bromouracil (la)or (lc-f) (5 mmol) and hydrazine hydrate (2.5 g, 50mmol) in propan-2- 01 (50 ml) was refluxed for 24 h.The solvent was removed under reduced pressure. Ethyl acetate (50 ml) was added to the residue and the mixture was heated to reflux. After the mixture had cooled, the precipitate was filtered off and recrystallized from an appropriate solvent (see Table 3). 5-Methyl-4-( 3-methyl- 1-phenylureido)pyrazol-3(2H)-one (9a). 6,2.00 (3 H, S, 5-Me),2.61 (3 H, d, J4.5 Hz, NHMe, collapsed to singlet by deuterium exchange), 5.98 (1 H, br, NH, deuterium exchangeable), and 7.00-7.40 (5 H, m, Ph); m/z 246 (M') and 1141 189 (A4-MeNCO, base peak); h,,,. 242 nm (E 10 700 dm3 molt' cm-'). 4-1-(p-Methoxypheny~-3-methylureido-5-methylpyrazol-3(2H)-one (9~).6, 1.98 (3 H, S, 5-Me), 2.55 (3 H, d, J 4.5 Hz, NMe, collapsed to singlet by deuterium exchange), 3.71 (3 H, s, OMe), 5.77 (1 H, br, NH, deuterium exchangeable), and 6.77 and 7.15 (each 2 H, each d, each J8 Hz, C,H,); m/z 276 (M') and 219 (M -p-MeOC,H,NCO, base peak); h,,,, 239 (E 12 700 dm3 mol-I cm-') and 282sh nm (1 700). 4-(3-Ethyl-1-phenylureido)-5-methylpyrazol-3(2H)-one(!M).SH 0.98 (3 H, t, J6.5 Hz, CH,Me), 1.96 (3 H, s, 5-Me), 3.04 2 H, m, CH,Me, collapsed to quartet (J 6.5 Hz) by deuterium ex- change, 5.93 (1 H, br, NH, deuterium exchangeable), and 7.1 8 (5 H, s, Ph); m/z 260 (M+)and 189 (M -EtNCO, base peak); A,,,. 243 nm (E 10 600 dm3 mol-' cm-'). 4-( 3 -A lly 1-1-phen y1ureido)- 5-me thylpyruzol- 3( 2H)-one ().6, 1.98 (3 H, s, 5-Me),3.63 (2 H, m, CH,CH=CH,), 4.88-6.17 (3 H, m, CH,CH=CH,), 6.95-7.24 (5 H, m, Ph), and 10.60 (1 H, br, NH, deuterium exchangeable); m/z 272 (M+)and 189 (M -CH,=CHCH,NCO, base peak); A,,,.242 nm (E 10700 dm3 mol-' cm-'). 4-( 3- Butyl- 1-phenylureido)-5-methylpyrazol-3(2H)-one(9f).6, 1.86 (3 H, t, J 5 Hz, CH,Me), 109-1.47 (4 H, m, NCH,- CH,CH,Me),2.00(3H,s,5-Me),3.04(2H,m,NCH2),5.92(1H, br, NH, deuterium exchangeable), and 7.24 (5 H, s, Ph); m/z 288 (M+)and 189 (M -BUNCO, base peak); A,,,. 243 (E 10 700 dm3 mol-' cm-I). 4-Anilino-5-methylpyrazol-3(2H)-one (lO).--(a) A mixture of the pyrazolone (9a) (0.49 g, 2 mmol) and sodium borohydride (0.09 g, 2.4 mmol) in dry pyridine (20 ml) was refluxed for 20 h.The solvent was removed under reduced pressure and dil. hydrochloric acid was added to the residue to give the crude product (0.26 g, 69). Recrystallization from methanol gave the 4-anilinopyrazolone (lo),m.p. 225-227 "C; 6, 1.98 (3 H, s, 5-Me), 6.38-7.14 (7 H, m, 2 x NH and Ph); the signal due to one NH-proton could not be observed; m/z 189 (M'); v,,,. 3 400 cm-' (NH); A,,,. (EtOH) 247 (E 16 600 dm3 mol-' cm-') and 291sh (2 500) (Found: C, 63.2; H, 5.8; N, 22.2. C,,H,,N,O requires C, 63.45; H, 5.85;N, 22.2). (b) A mixture of 5-anilino-1,3,6-trirnethyluracil(12) (see below) (1.0 g, 4 mmol) and hydrazine hydrate (50 ml) was refluxed for 20 h. The solution was evaporated under reduced pressure and the residue was treated with water to give the crude product (10) (0.67 g, 87).Recrystallization from ethanol gave the pyrazolone (lo), which was identical with the product obtained above. 5-Anilino-l,3,6-trimethyluracil(12~Toa stirred solution of 5-amino-6-methyluracil(ll) (14 g, 64.5 mmol) in 20 aqueous NaOH (31 ml) was added dropwise dimethyl sulphate (17.9 g, 142 mmol). The precipitate was collected by filtration and dissolved in 10 aqueous NaOH. Insoluble matter was filtered off and recrystallized from ethanol to give the uracil (12) (6.8 g, 4373, m.p. 205-206 "C;6, 2.18 (3 H, s, 6-Me), 3.22 and 3.40 (each 3 H, each s, each NMe), and 6.40-7.20 (5 H, m, Ph); the signal due to one NH-proton could not be observed; m/z 245 (M'); v,,,. 3 340 (NH) and 1 680 cm-' (CO) (Found: C, 63.8; H, 6.15; N, -17.15.Cl3HI5N3O2 requires C, 63.65; H, 6.15; N, 17.15). References 1 Part 52, K. Hirota, Y. Kitade, and S. Senda, J. Heterocycl. Chem., in the press. 2 Preliminary communications; S. Senda, K. Hirota, and K. Banno, Tetrahedron Lett., 1974,3087; K. Hirota, Y. Yamada, J. Haruta, and S. Senda, Heterocycles, 1982, 19, 2309. 3 For pertinent reviews, see: T. K. Bradshaw and D. W. Hutchinson, Chem. SOC.Rev., 1977,6,43; E.G. Sander, lsquo;Bioorganic Chemistry,rsquo; ed. E. E. van Tamelen, Academic Press, New York, 1978, vol. 2, pp. 273-297. 4 S. Senda, A. Suzui, and M. Honda, Chem. Pharm. Bull., 1958,6,487; P. Nantka-Namirski and J. Wojciechowski, Rocz. Chem., 1967, 41, 669 (Chem. Abstr., 1967, 67, 54099). 5 S. Senda and K. Hirota, J.Chem. SOC., Chem. Commun., 1974,483; K. Hirota, Y.Yamada, Y. Kitade, and S. Senda, J. Chem. Soc., Perkin Trans. I, 1981, 2943. 6 S. Senda, K. Hirota, and K. Banno, J. Med. Chem., 1972, 15,471. 7 H. Biltz and K. Slotta, J. Prakr. Chem., 1926,113,233 (Chem. Abstr., 1927, 21, 1794). J. CHEM. SOC. PERKIN TRANS. I 1985 8 F. R. Gerns, A. Perrotta, and G. H. Hitchings, J. Med. Chem., 1966,9, 108. 9 F. Lingens and H. Schneider-Bernlohr, Justus Liebigs Ann. Chem., 1965,686, 134 D. H. Hayes and F. Hayes-Baron, J. Chem. SOC.C, 1967, 1528. 10 Y. Kikugawa, S. Yamada, H. Nagashima, and K. Kaji, Tetrahedron Lett., 1969, 699. 11 S. Senda, K. Hirota, and T. Asao, Chem. Pharm. Bull., 1974,22,189. Received 17th September 1984; Paper 411583