Phenylhydrazine addition

Equip a 500 ml. three-necked flask with a dropping funnel, a mechanical stirrer and a reflux condenser. Place a solution of 72 g. (65 ml.) of redistilled phenylhydrazine (Section IV,89) CAUTION poisonous) in 300 ml. of ether in the flask, stir vigorously, and add 33 g. (26 ml.) of A.R. carbon disulphide slowly during about 30 minutes. A precipitate is formed immediately upon the addition of the carbon disulphide, the mixture becomes warm and the temperature soon approaches the boiling point maintain the temperature just below the b.p. by cooling with ice water if necessary. When the addition is complete, stir for a further 30 minutes, then filter the precipitate at the pump, wash it with about 25 ml. of ether, and spread it upon filter paper for 20 minutes to permit of the evaporation of the ether. The yield of the salt (I) is 92 g. 

Phenyl-3-oxopropanoic acid (25 mmol) and EtjN (87.5 mmol) were dissolved in THF (150 ml) and cooled to —40°C. Ethyl chloroformate (27.5 mmol) was added dropwise to this solution and then the reaction mixture was stirred for 30 min at —20°C. Di-n-hexylamine (27.5 mmol) was added to the suspension and it was stirred at room temperature for an additional hour. The reaction mixture was diluted with water (100 ml) and extracted with ether (400 ml). The extract was washed with aq. 5% HCl (100 ml) and brine (2 X 100 ml) and dried over NajSO. The crude amide was obtained by removal of the solvent in vacuo and phenylhydrazine (25 mmol) was added. The mixture was heated to 100°C for 30 min. The residue was held in vacuo to remove the water formed and then powdered ZnCl2 (125 mmol) was added. The mixture was heated at 170"C with manual stirring for 5 min. The cooled residue was dissolved in acetone (100 ml) and diluted with ether (500 ml). Water (100 ml) was added. The organic layer was separated and washed successively with 5% aq. HCl (100 ml) and brine (2 x 100 ml) and dried over NajSO. The solvent was removed in vacuo, and the residue was recrystallized from EtOAc-hexane. The yield was 79%. 

Normally, phenylhydrazine reacts with the enol form of 1,1,1-trifluorometh-ylpentane-2,4-dione to give 5-methyl-l-phenyl-3-tnfluoromethylpyrazole as the major product. However, the use of pyrrolidine as a transient carbonyl-blocking group can completely reverse the regiochemistry of the addition and leads to 3-methyl-l-phenyl-5-trifluoromethylpyrazole [102] (equation 88)... 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (80JHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3-ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates—66a-f, 68a-f, 69a-f, and 70a-f— were proposed for this reaction. 

Phenylhydrazine Methods.—In addition to the general reaction between almost all aldehydes and ketones and hydroxylamine, there is another... 

The addition of hydrazine (and phenylhydrazine) to these polymers proceeds with the opening of the C=N bonds. If the main chain consists of appropriate fragments, this reaction is followed by the degradation of this chain. 

The mature red blood cell cannot synthesize protein. Reticulocytes are active in protein synthesis. Once reticulocytes enter the circulation, they lose their intracellular organelles (ribosomes, mitochondria, etc) within about 24 hours, becoming young red blood cells and concomitandy losing their ability to synthesize protein. Extracts of rabbit reticulocytes (obtained by injecting rabbits with a chemical—phenylhydrazine—that causes a severe hemolytic anemia, so that the red cells are almost completely replaced by reticulocytes) are widely used as an in vitro system for synthesizing proteins. Endogenous mRNAs present in these reticulocytes are destroyed by use of a nuclease, whose activity can be inhibited by addition of Ca +. The system is then pro-... 

Gelman et al. (1978) found that the interaction between lead and phenylhydrazine produced an additive effect in the acute hemolytic phase of anemia and a probable synergistic effect during the compensatory phase of anemia in rabbits. The mechanism postulated for anemic interaction appears to be primarily related to depressed bone marrow production of erythrocytes rather than to increased hemolysis. 

In the first example of water as the reaction medium for Fischer indole synthesis, 2,3-dimethylindole was obtained in 67% yield from phenylhydrazine and butan-2-one, at 220 °C for 30 min (Scheme 2.15). Neither a preformed hydrazone nor addition of acid was required [33]. 

The reaction of these aldehydes, derived from periodate oxidation, with carbonyl reagents has also been investigated. Studies 147 148 were made on oxidized laminarin, a (1 —> 3)-linked polysaccharide, in which only the terminal residues had been oxidized. The addition of phenylhydrazine acetate detached the remainder of the terminal residue as glyoxal phenyl-osazone. When the aldehydic compounds derived from the periodate oxidation of raffinose and trehalose818a were reacted with p-nitrophenylhydrazine, the authors were surprised to find that one molecule of oxidized raffinose, containing six aldehydic functions, reacts with only three molecules of the reagent, and that the four aldehydic functions of the oxidized trehalose molecule react with only two. The reactions of periodate-oxidized carbo-... 

A. fi-Propionylphenylhydrazine. To 130 g. (1.0 mole) of propionic anhydride (Note 1), contained in a 500-ml. wide-mouthed Erlenmeyer flask which is cooled in an ice bath, there is added slowly with swirling 108 g. (1.0 mole) of phenylhydrazine (Note 1) at such a rate that the maximum temperature does not exceed 60°. After addition is complete, the flask is corked (not so tightly as to give a vacuum which may collapse the flask) and allowed to stand 72 hours at room temperature. At the end of this period, the resultant solid cake is broken up and slurried with 100 ml. of toluene. The suspension is cooled to 5° in an ice bath then the product is collected by suction filtration and washed with 200 ml. of a mixture of equal parts of cyclohexane and toluene, precooled to 5°. The yield of vacuum-dried, almost white crystals, m.p. 158-159°, is 140-145 g. (85-88%). 

The Sn2 reaction of quinazolinone 147 with phenylhydrazine was followed by rearrangement of the tautomerized intermediate 148 <00T7987>. The loss of both ammonia and aniline was followed by the addition of a second equivalent of phenylhydrazine to the resulting imine to produce quinazolinone hydrazone 149. Subsequent Fischer indolization of 149 followed by condensations with aldehydes led to 7-azarutacarpines. 

Sugar lactones react readily with hydrazine to give crystalline derivatives useful for isolation and identification (127). Thus, addition of hydrazine to a reaction mixture containing an aldonolactone facilitates isolation of the product. The lactone may be regenerated from the hydrazide by treatment with nitrous acid (128). The phenylhydrazides obtained on treatment of aldonolactones with phenylhydrazine are also useful for characterization (129,130). 

With phenylhydrazine, a mixture of pyrazoles 587 and 3H-indoles 591 were formed via conjugate addition, C=C bond migration and cyclic animation of the nitrile group or [3,3]-sigmatropic rearrangement of 3-amino-3-alkenenitriles 585, respectively [268a],... 

The sulphurous acid liberated in the second phase of the process by the addition of hydrochloric acid hydrogenates the azo-double bond, probably via an addition product A, of which one S03H-group is easily removed by hydrolysis with the formation of the sodium salt of phenylhydrazine sulphonic acid. 

Furfural even in dilute aqueous solution gives, almost at once, a precipitate of the phenylhydrazone with phenylhydrazine acetate. Collect the precipitate at the pump and dry. Purify by dissolution in a little ether and careful addition of petrol ether until crystallisation begins. Melting point 97°-98°. Method for quantitative determination of furfural. 

Data of Alves el al. (1978), in 20% ethanol. The intermolecular reference reaction is the general acid catalysed addition of phenylhydrazine to the methyl ether, calculated from feH,o using a = 0.35 and determined for the reaction with o-methoxybenzaldehyde (Bastos and do Amaral, 1979). The EM, which is in some doubt because of possible mechanistic complications, is determined by comparison of the rate constant given (dm3 mol-1 s 1) with the third order rate constant for the reference reaction... 

Chakrabarty et al. reported the syntheses of 9-carbethoxy-3-methylcarbazole (5) and 9-formyl-3-methylcarbazole (6) to confirm the assigned structures (17). The syntheses use 3-methylcarbazole (2) as a common intermediate, which was obtained under Fischer-Borsche conditions starting from phenylhydrazine (524) and 4-methylcyclohexanone (1006). Reaction of 3-methylcarbazole (2) with sodium hydride (NaH), followed by addition of ethyl chloroformate, afforded 9-carbethoxy-3-methylcarbazole (5). 9-Formyl-3-methylcarbazole (6) was obtained by reaction of 3-methylcarbazole (2) with formic acid (17) (Scheme 5.145). 

Treatment of a 2-acetyl-3-methoxy-3,4-dihydro-l, 2,3-diazaphosphole with phenylhydrazine gives the 2-phenyl derivative in addition to the deacylated 1,2,3-diazaphosphole <77ZOB576>. 

A mixture of 98 g. (1 mole) (Note 1) of cyclohexanone and 360 g. (6 moles) of acetic acid contained in a 1-1. three-necked round-bottomed flask equipped with a reflux condenser, a slip-sealed stirrer, and a dropping funnel is heated under reflux and stirred while 108 g. (1 mole) of phenylhydrazine is added during 1 hour. The mixture is heated under reflux for an additional hour and poured into a 1.5-1. beaker and stirred by hand (Note 2) while it solidifies. It is then cooled to about 5° and filtered with suction,... 

To an ice-cooled (0°C to-—10°C) stirred flask containing 300 ml of water and 55.5 ml of concentrated hydrochloric acid is added dropwise over a 10 min period 33.5 gm (0.31 mole) of freshly distilled phenylhydrazine. Phenyl-hydrazine hydrochloride crystals precipitate as they are formed. Addition of... 

A solution of l-(a-chlorobenzylidene)-2-phenylhydrazine (0.2 g, 0.87 mmol) and Et3N (0.6 mL, 4.3 mmol) in cyclooctatetraene (5 mL, 43 mmol) was kept in the dark at 25 X for 48 h. The precipitated hydrochloride was filtered off and the excess cyclooctatetraene and Et, N were evaporated under normal pressure in the dark to give a residue which was dissolved in EtOAc, then precipitated by addition of MeOH at — 10 X yield 0.16 g (62%) mp 128 131 X yellow needles. 

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