Phenylhydrazone of ethyl

The phenylhydrazone of ethyl pyruvate on heating with sulfuric acid in acetic acid forms indole-2-carboxyIic acid (58%). When the phenylhydrazone has nuclear substituents like alkyl, halo, or nitro groups, the corresponding 4-, 5-, 6-, or 7-substituted indoles are obtained. When pbenylhydrazine is added to a boiling mixture of cyclohexanone and... 

New examples of base- or acid-induced ring contraction of pyridazines include the formation of azoles. An investigation of the known cyclization of the phenylhydrazone of ethyl levulinate to pyridazinone revealed that in the presence of BF3-etherate the corresponding indole derivative (262) is obtained. The latter is formed also from the pyridazinone and ethanolic hydrogen chloride. 5-Phenylpyridazinone-4-oxime, when treated with zinc in acetic acid, is rearranged to the pyrrole 263. ... 

In 1887, in an attempt to prepare the azo ester 4 by coupling benzenediazonium chloride 2 with ethyl 2-methylacetoacetate 1, Japp and Klingemann obtained a product which was recognized as the phenylhydrazone of ethyl pyruvate 3.1"4... 

Japp and Klingemann found that benzenediazonium salt 2 coupled with ethyl methylacetoacetate 1 in alkaline solution to give the phenylhydrazone of ethyl pyruvate 3 with elimination of acetic acid. However, if the ketonic ester was first hydrolyzed with alkali and then coupled, the product was monophenylhydrazone 10, with carbon dioxide being eliminated rather than acetic acid.6... 

In this reaction, the phenylhydrazone of ethyl acetoacetate was isolated as an intermediate and converted into the product. Further intermediates were detected by means of C-NMR spectroscopy [137]. Acetylenecarboxylic esters also react with hydrazines to give pyrazolones. 

Some weak electrophilic reagents, which are usually inert toward azoles, also react with quaternized azoles. Diazonium salts yield phenylhydrazones (Scheme 48) in a reaction analogous to the Japp-Klingemann transformation of /S-keto esters into phenylhydrazones in the dithiolylium series illustrated the product has bicyclic character. Cyanine dye preparations fall under this heading (see also Section 4.02.1.6.5). Monomethine cyanines are formed by reaction with an iodo quaternary salt, e.g. Scheme 49. Tri- and penta-methinecar-bocyanines (384 n = 1 and 2, respectively) are obtained by the reaction of two molecules of a quaternary salt with one molecule of ethyl orthoformate (384 n = 1) or/S-ethoxyacrolein acetal (384 n =2), respectively. 

The methyl group position was fixed both by cleavage of the isoxazole ring with sodium ethylate and by isolation of the cyanacetone sodium salt 125. The reaction of this salt with phenylhydrazine resulted in the phenylhydrazone of cyanacetone (126) (69ZOR1179). 

Dichloroethylphosphine has been shown to react with methyl vinyl ketone to form 2-ethyl-5-methyl-A -l,2-oxaphospholen-2-oxide (25), which has been converted to (26) by chlorination in the presence of base. The same phosphine adds to methyl acrylate in the presence of acetic acid to give the phosphine oxide (27). Further examples have appeared of the reactions of the phenylhydrazones of methyl ketones with phosphorus trichloride to produce the heterocycles (28). 

The reaction of aroylhydrazines with DMAD gives rise to the hydrazones of oxaloacetic ester, which undergo thermal transformation to the corresponding diaroylhydrazines. b. Hydrazones. Ethyl l,3,5-triphenylpyrazole-4-carboxylate has been reported to be formed in the reaction of benzaldehyde phenylhydrazone with ethyl phenylpropiolate. In a detailed investigation, George and co-workers have shown that aldehyde phenylhydrazones react with DMAD, yielding a mixture of pyrazoles and pyrazolines. Thus, in the reaction of benzaldehyde phenylhydrazone with DMAD, products such as dimethyl l,3-diphenylpyrazoline-4,5-dicarboxylate (129), dimethyl... 

This general procedure is effective for the preparation of many types of phenylhydrazones. For example, a substituted diazo compound can be employed.2 Alkylated acetoacetic esters 8 and ethyl benzoylacetate 4 may be used. For the higher homologs, the a-formyl derivatives of ketones may be used in place of ethyl acetoacetate.6 6 Ethyl pyridylacetates may also be substituted for ethyl acetoacetate.7 The products in these cases are the phenylhydrazones of 2-acylpyridines. 

The pyrazolo[4,3-e][l,2,5]oxadiazin-3-ones (163) are formed by the action of phosgene or ethyl chloroformate on the aminonitrosopyrazoles (162) (Equation (22)). They have been used as intermediates in peptide synthesis <761ES70). A pyrazolo[4,3-e][l,3,4]oxadiazine (165) is formed together with a pyrazolotriazine (166) (Equation (23)) by the reaction of the phenylhydrazone of a pyrazolone (164) with cyanogen bromide <85JCS(P1)1499>. 

As reported by Mannich (29AP(267)699>, reaction of ethyl cyclopentanone-2-carboxylate with phenylhydrazine and subsequent cyclization of the phenylhydrazone at elevated temperature under strongly basic conditions gives tetrahydro-2-phenylcyclopentapyrazol-3-one (equation 19) (a = b = CH2). The method has been used to prepare thieno[3,4-c]pyrazol-3-ones, thieno[3,2-c]pyrazol-3-ones and pyrrolo[3,4-c]pyrazolones (71JMC454,71JMC1129). 

Yamamoto and Maruoka found that organoaluminum amides are highly effective in the Fischer indole synthesis. In particular, DATMP is the reagent of choice for regioselective Fischer indole synthesis [120]. For instance, treatment of the E)-N-methyl-A-phenylhydrazone of 5-methyl-3-heptanone (123) with DATMP affords 3- ec-butyl-2-ethyl-l-methylindole (125) as the sole isolable product its (Z) isomer gives l,3-dimethyl-2-(2-methylbutyl)indole (124) with high regioselectivity under similar reaction conditions, as illustrated in Sch. 84. 

Hejerence. The above procedure is the author s modiheatiou of the procedure described by Shepard, J. Am. Chem. Soc., 54, 2952 (1932), for the preparation of 2-methyl-5-ethylthiophenc in 40% yield. The method has been used for the preparation of 2,5-dimethylthiophene by the author an 80% yield of distilled product was obtained. Steinkopf, Frommel, and Leo, /Inn., 546, 199 (1941) used another modification of this method involving the phenylhydrazone of 2-ethyl-5-acetylthiophene to prepare 2,5-diethylthiophene in 50% yield. 

Ishii, H., Sugiura, T., Akiyama, Y., Ichikawa, Y., Watanabe, T., Murakami, Y. Fischer indolization and its related compounds. XXIII. Fischer indolization of ethyl pyruvate 2-(2,6-dimethoxyphenyl)phenylhydrazone. Chem. Pharm. Bull. 1990, 38, 2118-2126. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

An acidic ion-exchange resin, Amberlite IR-120, was also employed by Yamada et al. to effect the cyclization of the phenylhydrazones of ketones including ethyl-methyl ketone, propiophenone, and cyclohexanone in water under reflux [15]. Yields of 60-90% were obtained but acetone phenylhydrazone proved unreactive under these conditions. 

A soln. of acrolein in benzene dropped at a moderate rate into a suspension of ethyl acetamidomalonate in benzene containing a catalytic amount of Na-methoxide, stirred 2 hrs. longer, and isolated as the phenylhydrazone —y-acetamido-y,y-dicarbethoxy-butyraldehyde phenvlhydrazone. Y 87%. (F. e. s. O. A. Moe and D. T. Warner, Am. Soc. 70, 2763 (1948) 71, 2586 (1949).)... 

Phenylhydrazones exhibit another mode of reaction (Scheme 65). The reaction of butadiene with the phenylhydrazone of acetaldehyde 204 (1 mol % (Ph3P)4Pd, THF, 110 °C, 24 h) affords a 2 1 mixture of 205 and 206 (86%). A small amount of the protic (H—Y) trapping prodnct was also observed. The formation of 205 can be rationalized by addition of the phenylhydrazone in the fashion of a R (R )C=Y-type electrophile to a palladacycle in an Sgs fashion to 208 followed by hydride transfer to 209. Rednctive elimination conld acconnt for the formation of 205. Thns, 206 could be formed via a similar pathway, by addition of the phenylhydrazone in an rather than fashion. The proposed hydride transfer invoked to rationalize the formation of the observed products offers interesting possibilities and appears worthy of further investigation. Phenylhydrazones derived from propanal, acetone, and methyl ethyl ketone behave similarly (60-95% yield), although the ratio of 205/206 and the proportion of the protic (H—Y-type) trapping product vary. 

DL-Isoleucine is synthesized in about 56% over-all yield by the method of Hamlin and Hartung (366). o-Oximino- -methyl-w-valeric acid (A) is prepared in 70% yield from ethyl sec.-bulyl acetoacetate, butyl nitrite and sulfuric acid. DL-Isoleucine is prepared in 80% yield by the reduction of (A) with hydrogen, palladium chloride and ethanol. This method is essentially the same as that originated by Bouveault and Locquin (117, 118, 525). By the comparable procedure of Feofilaktov (264, 265) the phenylhydrazone of methyl ethyl pyruvic acid, prepared from sec.-butyl acetoacetate and phenyldiazonium chloride (aniline and NaN02) in 68% yield, is reduced by means of rinc and alcoholic HCl to nearly the theoretical yield of a mixture of DL-isoleucine and DL-allo-isoleucine. Ehrlich (235) synthesized a mixture of isoleucine and allo-isoleucine from 2-methyl-n-butyraldehyde by the Strecker reaction. 

Syntheses of leucine from isovaleraldehyde by the Strecker reaction (704), ethyl isobutylacetoaeetate by reduction of the intermediates > codminoisocaproic acid (116) and the phenylhydrazone of isopropylpy-ruvic acid (264-267), isobutylhydantoin by alkaline hydrolyras (6 ), isobutyraldehyde by the azlactone method (259), and ethyl cyanoacetate... 

---