PHENYLHYDRAZINE

1

Phenylhydrazine

1

PhNHNH

2

[100-63-0]

C

6

H

8

N

2

(MW 108.16)

InChI = 1/C6H8N2/c7-8-6-4-2-1-3-5-6/h1-5,8H,7H2
InChIKey = HKOOXMFOFWEVGF-UHFFFAOYAN

(forms hydrazones with carbonyl compounds;

1,3

useful reagent

for the formation of indoles

4

–

19

and other heterocyclic ring

systems

20

–

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, Et

2

O, CHCl

3

, benzene; sol dil acids;

slightly sol H

2

O, 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
Na

2

SO

3

.

2

Handling, Storage, and Precautions:

keep in tightly closed con-

tainer; protect from light; toxic, possible carcinogen, irritant.

Introduction. Although PhNHNH

2

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, how-
ever, is very useful in the synthesis of various heterocyclic com-
pounds.

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 cat-
alyzing 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

N

N

CH

2

R

2

R

1

N
H

R

2

R

1

(1)

ZnCl

2

The generally accepted mechanism for this reaction was origi-

nally proposed by Robinson and Robinson.

6

There exists substan-

tial evidence for this mechanism which involves a [3,3] sigmat-
ropic rearrangement as a key step (eq 2).

7

–

10

The phenylhydra-

zones 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 Phos-
phorus(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-
β

-carboline (1) is heated with an excess of phenylhydrazine, the

pyridinodiindole (2) is readily obtained (eq 4).

15

N
H

N

CH

2

R

2

R

1

N
H

R

2

R

1

N
H

H
N

R

1

R

2

NH

2

R

2

R

1

NH

2

N

R

2

R

1

NH

2

H H

(2)

[3,3]

+

+

–[NH

3

]

H

+

O

(3)

N
H

PhNHNH

2

AcOH

85%

N
H

NH

O

HN

N

NH

(4)

(1)

(2)

PhNHNH

2

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– 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

N

O

O

OTMS

OTMS

Me

N

O

O

O

O

Me

H

H

N

O

O

PhNHN

PhNHN

Me

H

H

N

O

O

Me

m

-CPBA

(5)

NH

NH

1. PPSE

(3)

(4)

(6)

(5)

PhNHNH

2

2. Pd/C

EtOH

A variation of the Fischer protocol has been used for the prepa-

ration of the dihydropyrrole ring system. Reaction of phenylhy-
drazine with propionic anhydride (7) provides β-propionylphenyl-
hydrazine (8) which, upon treatment with Calcium Hydride,

Avoid Skin Contact with All Reagents

2

PHENYLHYDRAZINE

loses NH

3

and leads to the formation of 3-methyloxindole (9)

(eq 6).

19

O

O

O

H
N

N
H

O

N
H

O

(6)

(8)

(7)

(9)

CaH

2

PhNHNH

2

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 PhNHNH

2

, under acidic conditions, leads to a 1:1 mixture of

isomeric pyrazoles (11) and (12) (eq 7).

21

The oxidative cycliza-

tion 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

(12)

N
H

O

N

N

Ph

NH

2

N

N

NH

2

(7)

(10)

+

(11)

Ph

PhNHNH

2

R

SnBu

3

N

NHPh

N

N

Ph

R

SnCl

2

N

R

NPh

NBS, CH

2

Cl

2

(13)

(14)

(15)

87–96%

R = Me, t-Bu, Ph

(8)

64–87%

Synthesis of β-Lactams.

Phenylhydrazones (16), when

treated with phenoxyketene, give N-acylated products (17), which
do not cycloadd to the ketene. However, N-alkylated phenylhydra-
zones (18)

23

undergo [2 + 2] cycloaddition reactions with in situ

generated phenoxyketene to provide β-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

N

R

1

R

2

NH

Ph

N

R

1

R

2

N

Ph

O

OPh

N

R

1

R

2

N

Ph

Me

N

O

N Me

Ph

R

2

R

1

PhO

PhOCH

2

COCl

(16)

(17)

(18)

PhOCH

2

COCl

(19)

(9)

R

1

= H, Me, Ph; R

2

= Ar

MeI
NaH

Et

3

N, CH

2

Cl

2

Et

3

N, CH

2

Cl

2

CHO CHO

N

N

N
H

N

NHPh

+

1. PhNHNH

2

(10)

2. NaBH

4

Reactivity with Heterocumulenes. Reactions of phenylhy-

drazones with Phenyl Isocyanate, under thermal conditions, pro-
vide triazolidines (eq 11).

26

A 1,3-dipolar reaction between ke-

tone phenylhydrazones and Phenyl Isothiocyanate, in the pres-
ence of Sodium Hydride in DMF, leads to the formation of
4-phenyl-5-phenylimino-1,3,4-thiadiazolidines (eq 12).

27

Reac-

tions using Carbon Disulfide, instead of isothiocyanate, un-
der similar conditions provide 4-phenyl-1,3,4-thiadiazolidine-5-
thiones.

27

NNHPh

Et

N

H
N

N

O

Ph

Ph

Et

(11)

PhN=C=O

NNHPh

Et

S

H
N

N

NPh

Ph

Et

(12)

NaH

PhN=C=S

Generation of Amines. Phenylhydrazine has been used for

the generation and regeneration of different kinds of amines. Re-
duction of phenylhydrazones has been utilized, for example, in the
synthesis of aminophosphonates. The reaction of PhNHNH

2

with

oxophosphonates (20) provides hydrazones (21) in almost quanti-
tative 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

A list of General Abbreviations appears on the front Endpapers

PHENYLHYDRAZINE

3

O

R

P

O

EtO OEt

N

R

P

O

EtO OEt

NHPh

NH

2

R

P

O

EtO OEt

NH

2

R

P

O

HO OH

H

2

, Pd/C

(13)

(20)

(21)

(22)

(23)

R = alkyl, aryl

PhNHNH

2

AcOH

HCl

(14)

N

O

O

CO

2

H

H

2

N

CO

2

H

NH

N

O

O

Ph

+

PhNHNH

2

Bu

3

N

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-methoxy-
carbonylphenyl) imidate esters (24b). The reaction of these
imidate esters with PhNHNH

2

leads to the formation of 3-amino-

4(3H)-quinazolinones (26) in a stepwise mechanism, presumably
via the intermediate amidrazones (25) (eq 15).

31

X

CO

2

Me

NH

2

X

CO

2

Me

N

OEt

R

X

CO

2

Me

N

R

NHNHPh

N

N

X

R

NHPh

O

(15)

(24a)

(24b)

(25)

(26)

X = H, Cl, Br; R = Me, Et

RC(OEt)

3

PhNHNH

2

Osazones. Treatment of α-dicarbonyl compounds, α-hydroxy

aldehydes and ketones,.

32,33

and α-halo ketones

34

–

36

with

PhNHNH

2

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 PhNHNH

2

, the yellow crystalline pyridazine

derivative (28) is rapidly formed and the gradual formation of
the osazone (29) is also observed. Also produced from this reac-
tion 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 subse-
quent 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

2 equiv PhNHNH

2

(16)

X

O

NNHPh

NNHPh

an osazone

X = OH, OAc, Cl, Br

O

Ph

Cl

N

N

Ph

Ph

N

N

Ph

Ph

Ph

N

N Ph

NH

N

N

Ph

HN

Ph

N

H
N

N

Ph

Ph

HN

Ph

+

PhNHNH

2

(27)

N

Ph

N

Ph

+

+

(30)

(29)

(28)

(29)

(31)

Ph

(17)

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 reac-
tion of 2-benzoylpyridine (32) with PhNHNH

2

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

N

Ph

O

N

Ph

N

NHPh

N N

N

Ph

Ph

(18)

(32)

(33)

LTA

Cl

–

+

(34)

PhNHNH

2

Related

Reagents. N,N-Dimethylhydrazine;

2,4-Dinitro-

phenylhydrazine.

1.

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93. (b) Robinson, B., Chem. Rev. 1969, 69, 227. (c) Buckingham, J., Q.
Rev., Chem. Soc. 1969

, 23, 37. (d) Robinson, B Chem. Rev. 1963, 63, 373.

(e) Fusco, R.; Sannicolo, F., Tetrahedron 1980, 36, 161. (f) Robinson,
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2.

Coleman, G. H Org. Synth., Coll. Vol. 1941, 1, 442.

3.

Shriner, R. L.; Curtin, D. Y.; Fuson, R. C.; Morrill, T. C. The Systematic
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; Wiley: New York, 1980; p 165.

4.

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5.

(a) Laronze, J.-Y.; El Boukili, R.; Royer, D.; Levy, J., Tetrahedron 1991,
47

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, 3, 725.

6.

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Avoid Skin Contact with All Reagents

4

PHENYLHYDRAZINE

7.

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8.

Douglas, A. W., J. Am. Chem. Soc. 1978, 100, 6463; 1979, 101, 5676.

9.

Bajwa, G. S.; Brown, R. K., Can. J. Chem. 1970, 48, 2293.

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11.

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12.

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13.

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14.

(a) Baccolini, G.; Bartoli, G.; Marotta, E.; Todesco, P. E., J. Chem. Soc.,
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, 535.

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Gribble, G. W.; Berthel, S. J., Tetrahedron 1992, 48, 8869.

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Humayun S. Ateeq & Pir M. Shah

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

A list of General Abbreviations appears on the front Endpapers