Pyrazolin-5-ones, methylation

Methyl-l -phenyl-2-pyrazolin-5 -one CDCI3 -186.4 -54.5 C- N and H- coupling constants 77JCS P2)1024 ... 

Scheme 19 contains all the reactions observed in different examples, none being so complex (B-76MI40402). Most studies deal with the methylation of 3-methyl-1-phenyl-pyrazolone, since in this case one of the products obtained is antipyrine (2,3-dimethyl-l-phenyl-3-pyrazolin-5-one), one of the classical antipyretic agents (Section 4.04.4.1.1). 

Sulfonation of 2- and 3-pyrazolin-5-ones occurs at position 4. Thus 3-methyl-1-phenyl-pyrazolin-5-one with 20% oleum at 10-15 °C yields the corresponding 4-sulfonic acid (304) (64HC(20)l). Higher temperatures cause sulfonation not only of the heterocycle but also of the phenyl group. Antipyrine treated with sulfuric acid and acetic anhydride yields (305). 

Finally, benzpiperylon or l-(l-methyl-4-piperidyl)-3-phenyl-4-benzyl-2- (or 3-) pyrazolin-5-one has been utilized by Sandoz as an investigational agent in connective tissue disorders (B-76MI40404). 

Methyl-l-phenyl-3-pyrazolin-5-one gives a green-black dye (736) with 4-nitroso- or 4-amino-dimethylaniline and silver chlorides in the presence of light, a process of great importance in colour photography (B-76MI40403). 

Pyrazolin-5-one, 3-methyl- H NMR, 5, 187 (B-73NMR165) 2-Pyrazolin-5-one, 3-methyl-1 -phenyl- H NMR, 5, 187 (B-73NMR165)... 

A total of 222 g of 3)5-acetoxy-5a-pregn-9(l l)-en-20-one-[17a,16a-c]-A -pyrazoline is added portionwise and with stirring during a period of 25 min to 880 ml of diethylene glycol held at 165°. When nitrogen evolution ceases the mixture is cooled to 100° and 3 liters of water is added. The crude product is crystallized from ethanol to yield 146 g (71%) of 3 -acetoxy-16-methyl-5a-pregna-9(ll),16-dien-20-one mp 139-142° [aj 53° (CHCI3) 249 mf.1 (e 8,600). 

Substituted pyrazolin-5-ones have only three and -substituted pyrazolin-3-ones only two tautomers, since now the corresponding 19c and 19d structures are isomers. The calculations involved l-methylpyrazolin-5-one (PM3/6-3H-G, anions and cations), l-phenyl-3-methyl-2-pyrazolin-5-one (DFT, radical reactions) [97JPC(A)3769], and l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one [B3LYP/6-31G and the crystal structure (Section V,D,2)] (98NJC1421). 

A mixture of 16.3 g of 4-methyl-6-methoxy-2-pyrimidinyl-hydrazine, 13.7 g of ethyl acetoacetate and 16.3 ml of methanol was refluxed 2 hours on a water bath. After a mixture of 4.7 g of sodium hydroxide, 4.7 ml of water and 27 ml of methanol was added dropwise thereto at about 50°C, the reaction mixture was refluxed for 2 hours more, then methanol was distilled off and the residue was dissolved in 130 ml of water. The solution was adjusted to pH 6 with acetic acid. The precipitate was filtered, washed with water and dried to give 24 g (yield 95.3%) of crystals, MP 97° to 98°C. Recrystallization from ligroin gave 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-3-pyrazoline-5-one, MP 102° to 103°C. 

To a solution of 4.76 g of 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-3-pyrazoline-5-one in 200 ml of ether was added an ether solution containing 6 molar equivalents of diazomethane and the reaction mixture was allowed to stand at room temperature for 20 hours. After distilling off the solvent, the residue was dissolved in 160 ml of water, made alkaline (pH 10) with sodium hydroxide solution and extracted three times with 140 ml of benzene. The extract was washed with a small amount of water, dried over sodium sulfate and evaporated to give a crystalline mass. Recrystallization from isopropylether gave 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-5-methoxypyrazole (3.96 g, 84%) as colorless prisms, MP 90° to 92°C. 

The present method9 affords the methyl ester directly in high yields from 2-pyrazolin-5-ones, which are readily prepared in nearly quantitative yields from readily accessible, /3-keto-esters. In addition, the reaction is simple to carry out, conditions are mild, and the product is easily isolated in a high state of purity. A limitation of the reaction is that only the methyl ester can be made, as other alcohols have been found to give poor yields and undesirable mixtures of products. Table I illustrates other examples of the reaction.10... 

Pyran, tetrahydro-, 3 chloro 2 methyl [2H Pyran, tetrahydro, 3 chloro-2-mcthyl ], cis, trans mixture, 55, 64 2-PYRAZOLIN-5-ONES, 3-alkyl-, 55, 73 2-Pyrazolin 5-one, 3-(l-propyl)-, 55, 73 Pyridine, 2-amino-, p-bromination of, 55, 23... 

The linking methine chain includes an even number of methine groups (0,2,4). They are commonly named as derivatives of the ketomethylene ring, for example, 3-ethyl-5-(3-ethyl-4,5-diphenylthiazolin-2-ylidene)-rhodanine (5) and 4-[4-(3-methyl-4,5-diphenylthiazolin-2-ylidene)-2-butenylidene]-3-methyl-l-p-sulfophenyl-2-pyrazolin-5-one (6) (Scheme 4). 

As it is known from experience that the metal carbenes operating in most catalyzed reactions of diazo compounds are electrophilic species, it comes as no surprise that only a few examples of efficient catalyzed cyclopropanation of electron-poor alkeiies exist. One of those examples is the copper-catalyzed cyclopropanation of methyl vinyl ketone with ethyl diazoacetate 140), contrasting with the 2-pyrazoline formation in the purely thermal reaction (for failures to obtain cyclopropanes by copper-catalyzed decomposition of diazoesters, see Table VIII in Ref. 6). 

Cycloadditions are in general an effective way of constructing cyclobutane rings. A wide variety of heterocyclic systems dimerize in this way. 1,3-Diacetylindole, for example, affords the head-to-tail dimer 242 on irradiation in ethanol.185 Ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxy-late is similarly converted in diethyl ether into the trans head-to-head dimer.186 Notable among many analogous photodimerizations are those reported in 1,4-dihydropyridines,187 in furo[3,2-b]pyridin-2(4//)-ones,188 in 8-methyl-s-triazolo[4,3-a]pyridine,189 and in 2H-2-benzazepine-1,3-diones.190 The [ 2 + 2] dimerization of amidopyrine is the first reported example of a photocycloaddition in a 4-pyrazolin-3-one.191... 

Diazoacetaldehyde dimethylacetal (12) has been used as a substitute for diazoacetaldehyde in 1,3-dipolar cycloadditions with l-benzopyran-2(//)-ones (40), styrene, methyl methacrylate, 1-cyanocyclopentene, and methyl cyclohexene-1-carboxylate (41). The resulting A -pyrazolines were readily transformed in two steps into cyclopropanecarbaldehydes [e.g., 13 —> 14 (Scheme 8.4)]. In a similar manner, 3-phenylcyclopropane-l,2-dicarbaldehyde was obtained from the reaction of 12 with dimethyleneketal of cinnamic aldehyde. 

Other novel diazo compounds that have been subjected to 1,3-dipolar cycloaddition with activated alkenes, and that give unusually functionalized pyrazolines (Scheme 8.7), include l-diazo-3-trimethylsilylpropan-2-one (20) (49), 2-diazo-methyl-4(57/)-furanones (21) (50), methyl 2-diazo-5-methylanilino-5-oxopentano-ate (22) (51), 2-(acylamino)-2-diazoacetates (23) (51), ethyl 2-diazo-4,4,4-trichloro-3-(ethoxycarbonylamino)butyrate (24) (52), and diazopropyne (53). 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

The reaction of 3-amino-2-pyrazolin-5-one with diketene afforded 2-hy-droxy-7-methyl-1,2-dihydropyrazolo[ 1,5-a]pyrimidine-5-one (49US2481466) (Scheme 1). 

---