Phenylhydrazine1

PhNHNH2

[100-63-0]  · C6H8N2  · Phenylhydrazine  · (MW 108.16)

(forms hydrazones with carbonyl compounds;1,3 useful reagent for the formation of indoles4-19 and other heterocyclic ring systems20-27,31)

Physical Data: mp 18-20 °C; bp 238-241 °C, 52-53 °C/0.06 mmHg; d 1.098 g cm-3.

Solubility: misc EtOH, Et2O, CHCl3, benzene; sol dil acids; slightly sol H2O, petroleum ether.

Form Supplied in: yellow solid or yellow oil.

Preparative Method: from aniline via diazotization, followed by reduction of the resultant benzenediazonium chloride with Na2SO3.2

Handling, Storage, and Precautions: keep in tightly closed container; protect from light; toxic, possible carcinogen, irritant.

Introduction.

Although PhNHNH2 readily forms hydrazones with ketones and aldehydes, too many of the products thus formed tend to be oils and are difficult to detect visually.3 For this reason, 2,4-Dinitrophenylhydrazine is, instead, the preferred reagent of choice for making carbonyl derivatives. Phenylhydrazine, however, is very useful in the synthesis of various heterocyclic compounds.

Fischer Indole Synthesis.

Indolization of a phenylhydrazone, in the presence of a catalyst, was first observed by Fischer.4 Although Zinc Chloride is the classical reagent of choice for catalyzing these transformations, several other catalysts have since been successfully used.1b This method has emerged as a general and powerful method for making indoles (eq 1).5

The generally accepted mechanism for this reaction was originally proposed by Robinson and Robinson.6 There exists substantial evidence for this mechanism which involves a [3,3] sigmatropic rearrangement as a key step (eq 2).7-10 The phenylhydrazones are generally not isolated since many of these intermediates either cyclize under mild conditions or decompose upon attempted purification. The phenylhydrazone of cyclohexanone, for instance, is generated and converted into tetrahydrocarbazole in one step by adding phenylhydrazine to a refluxing mixture of the ketone and AcOH (eq 3).11 A mild, one-step protocol for preparing 2,3-disubstituted indoles in good yields (70-90%) involves treating a solution of a ketone and phenylhydrazine in benzene with Phosphorus(III) Chloride at room temperature for a few minutes.12-14 Elaborate polycyclic structures can be rapidly assembled by using this methodology. Indeed, when 4-oxo-1,2,3,4-tetrahydro-b-carboline (1) is heated with an excess of phenylhydrazine, the pyridinodiindole (2) is readily obtained (eq 4).15

Use of the bis-Fischer indole synthesis has culminated in the total synthesis of indolo[2,3-a]carbazole alkaloids.16,17 In a variation of the Rubottom oxidation of silyl enol ethers,18 the Diels-Alder adduct (3) is treated with m-Chloroperbenzoic Acid to presumably provide the dione (4), which is then exposed to 2 equiv of phenylhydrazine. Treatment of the osazone (5), thus obtained, with Trimethylsilyl Polyphosphate (PPSE), a mild catalyst, followed by aromatization of the central ring provides N-methylarcyriaflavin A (6) (eq 5).16

A variation of the Fischer protocol has been used for the preparation of the dihydropyrrole ring system. Reaction of phenylhydrazine with propionic anhydride (7) provides b-propionylphenylhydrazine (8) which, upon treatment with Calcium Hydride, loses NH3 and leads to the formation of 3-methyloxindole (9) (eq 6).19

Pyrazoles and Pyrazolines.

Phenylhydrazine has also been used in the synthesis of various five-membered heterocycles.20 Thermal treatment of 3-acetyl-1,4,5,6-tetrahydropyridine (10) with PhNHNH2, under acidic conditions, leads to a 1:1 mixture of isomeric pyrazoles (11) and (12) (eq 7).21 The oxidative cyclization of stannylhydrazones (13) provides the azocyclopropanes (14) in good yields. Whereas the formation of pyrazolines (15) is not observed via the direct ring-closure of (13), treatment of (14) with catalytic amounts of Tin(II) Chloride in benzene, at refluxing temperature, furnishes the five-membered heterocycles (15) in high yields (eq 8).22

Synthesis of b-Lactams.

Phenylhydrazones (16), when treated with phenoxyketene, give N-acylated products (17), which do not cycloadd to the ketene. However, N-alkylated phenylhydrazones (18)23 undergo [2 + 2] cycloaddition reactions with in situ generated phenoxyketene to provide b-lactams (19) (eq 9).24

Synthesis of Piperidines.

Reactions of Glutaraldehyde and hydrazines, in the presence of benzotriazole, lead to the formation of piperidines (eq 10).25

Reactivity with Heterocumulenes.

Reactions of phenylhydrazones with Phenyl Isocyanate, under thermal conditions, provide triazolidines (eq 11).26 A 1,3-dipolar reaction between ketone phenylhydrazones and Phenyl Isothiocyanate, in the presence of Sodium Hydride in DMF, leads to the formation of 4-phenyl-5-phenylimino-1,3,4-thiadiazolidines (eq 12).27 Reactions using Carbon Disulfide, instead of isothiocyanate, under similar conditions provide 4-phenyl-1,3,4-thiadiazolidine-5-thiones.27

Generation of Amines.

Phenylhydrazine has been used for the generation and regeneration of different kinds of amines. Reduction of phenylhydrazones has been utilized, for example, in the synthesis of aminophosphonates. The reaction of PhNHNH2 with oxophosphonates (20) provides hydrazones (21) in almost quantitative yields. Catalytic hydrogenation yields amines (22), and the diethylphosphonate moiety in (22) can be hydrolyzed to provide 1-aminoalkanephosphonic acids (24a) (eq 13).28 In a variation of the Ing-Manske procedure,29 where a phthalimide is heated with hydrazine to liberate a primary amine in an exchange reaction, the N-protective phthaloyl group of an amino acid or a peptide can be cleaved. Thus refluxing phthaloyl-L-leucine, in the presence of a tertiary amine in EtOH, can be used to access crystalline L-leucine (eq 14).30

Synthesis of Quinazolines.

Further utility of phenylhydrazine is apparent in the synthesis of quinazolines. Treatment of methyl anthranilate esters (24a) with orthoesters provides N-(2-methoxycarbonylphenyl) imidate esters (24b). The reaction of these imidate esters with PhNHNH2 leads to the formation of 3-amino-4(3H)-quinazolinones (26) in a stepwise mechanism, presumably via the intermediate amidrazones (25) (eq 15).31

Osazones.

Treatment of a-dicarbonyl compounds, a-hydroxy aldehydes and ketones,32,33 and a-halo ketones34-36 with PhNHNH2 leads to the formation of osazones (eq 16). Osazones are particularly important in carbohydrate chemistry and have been used in alkaloid synthesis (eq 5). In a reaction of phenacyl chloride (27) with PhNHNH2, the yellow crystalline pyridazine derivative (28) is rapidly formed and the gradual formation of the osazone (29) is also observed. Also produced from this reaction is another compound, a tetrahydropyridazine (30). It has been rationalized that the pathway to (28) involves the formation of the hydrazone followed by 1,4-elimination of HCl and a subsequent dimerization of the resultant ene-azo intermediate (31).37 It has also been proposed that a retro-Diels-Alder type reaction of (28) furnishes the intermediate (31), which then participates as the diene in a 1,4-cycloaddition reaction with the osazone (29) to provide cyclic (30) (eq 17).38

Triazolo Compounds.

Hydrazones of acylated heterocycles are widely used as precursors for the preparation of 1,2,4-triazolo compounds.39,40 Indeed, oxidative cyclizations of arylhydrazones of 2-acylpyridines, in the presence of Mercury(II) Acetate or Lead(IV) Acetate (LTA), are efficient means of accessing fused 1,2,4-triazoles and 1,2,3-triazolium systems. A coupling reaction of 2-benzoylpyridine (32) with PhNHNH2 provides the (E)-isomer of hydrazone (33), as established by X-ray structure analysis. An oxidative ring-closure of (33) with LTA leads to the formation of the corresponding 1,2,3-triazolium salt (34) in high yield (eq 18).41

Related Reagents.

N,N-Dimethylhydrazine; 2,4-Dinitrophenylhydrazine.


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Humayun S. Ateeq & Pir M. Shah

H. E. J. Research Institute of Chemistry, Karachi, Pakistan



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