PHENYLHYDRAZINE 1
using this methodology. Indeed, when 4-oxo-1,2,3,4-tetrahydro-
Phenylhydrazine1
²-carboline (1) is heated with an excess of phenylhydrazine, the
pyridinodiindole (2) is readily obtained (eq 4).15
PhNHNH2
H
H+ [3,3]
[100-63-0] C6H8N2 (MW 108.16)
N CH2R2 N
N N R2
InChI = 1/C6H8N2/c7-8-6-4-2-1-3-5-6/h1-5,8H,7H2
H H
R1 R1
InChIKey = HKOOXMFOFWEVGF-UHFFFAOYAN
R2
R2 R2
(forms hydrazones with carbonyl compounds;1,3 useful reagent
(2)
R1
NH2  [NH3]
for the formation of indoles4 19 and other heterocyclic ring
R1
+
+
NH2 R1
systems20 31)
N N
NH2
H H
H
ć% ć% ć%
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;
PhNHNH2
slightly sol H2O, petroleum ether.
(3)
AcOH
Form Supplied in: yellow solid or yellow oil.
O
N
85%
Preparative Method: from aniline via diazotization, followed
H
by reduction of the resultant benzenediazonium chloride with
Na2SO3.2
Handling, Storage, and Precautions: keep in tightly closed con-
tainer; protect from light; toxic, possible carcinogen, irritant.
O
N
PhNHNH2 HN
NH (4)
N
NH
Introduction. Although PhNHNH2 readily forms hydrazones H
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,
(1) (2)
2,4-Dinitrophenylhydrazine is, instead, the preferred reagent of
choice for making carbonyl derivatives. Phenylhydrazine, how-
Use of the bis-Fischer indole synthesis has culminated in
ever, is very useful in the synthesis of various heterocyclic com-
the total synthesis of indolo[2,3-a]carbazole alkaloids.16,17 In a
pounds.
variation of the Rubottom oxidation of silyl enol ethers,18 the
Diels adduct (3) is treated with m-Chloroperbenzoic Acid to
Fischer Indole Synthesis. Indolization of a phenylhydrazone,
in the presence of a catalyst, was first observed by Fischer.4 presumably provide the dione (4), which is then exposed to 2
equiv of phenylhydrazine. Treatment of the osazone (5), thus
Although Zinc Chloride is the classical reagent of choice for cat-
obtained, with Trimethylsilyl Polyphosphate (PPSE), a mild
alyzing these transformations, several other catalysts have since
catalyst, followed by aromatization of the central ring provides
been successfully used.1b This method has emerged as a general
N-methylarcyriaflavin A (6) (eq 5).16
and powerful method for making indoles (eq 1).5
R2
O O
H
OTMS O
ZnCl2 PhNHNH2
m-CPBA
(1)
N CH2R2 R1 Me N Me N
N
EtOH
N
OTMS O
R1
H H
O O
(3) (4)
The generally accepted mechanism for this reaction was origi-
nally proposed by Robinson and Robinson.6 There exists substan-
O O
H
tial evidence for this mechanism which involves a [3,3] sigmat- NH
PhNHN
1. PPSE
ropic rearrangement as a key step (eq 2).7 10 The phenylhydra-
(5)
N Me Me N
2. Pd/C
zones are generally not isolated since many of these intermediates
PhNHN
NH
H
O O
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
(5) (6)
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 A variation of the Fischer protocol has been used for the prepa-
solution of a ketone and phenylhydrazine in benzene with Phos- ration of the dihydropyrrole ring system. Reaction of phenylhy-
phorus(III) Chloride at room temperature for a few minutes.12 14 drazine with propionic anhydride (7) provides ²-propionylphenyl-
Elaborate polycyclic structures can be rapidly assembled by hydrazine (8) which, upon treatment with Calcium Hydride,
Avoid Skin Contact with All Reagents
2 PHENYLHYDRAZINE
loses NH3 and leads to the formation of 3-methyloxindole (9) R1 R2 R1 R2
O
PhOCH2COCl
(eq 6).19
N N OPh
Et3N, CH2Cl2
NH N
Ph Ph
O
(16) (17)
H
O O
PhNHNH2 CaH2
N
MeI
N
(9)
O
NaH
H
R1 R2
R1
(7) (8)
PhO
PhOCH2COCl
R2
N Me
N Et3N, CH2Cl2
N
(6)
O Me
O N
Ph
N
Ph
H
(18) (19)
(9)
R1 = H, Me, Ph; R2 = Ar
Pyrazoles and Pyrazolines. Phenylhydrazine has also been
N
1. PhNHNH2
used in the synthesis of various five-membered heterocycles.20 + N (10)
N
CHO CHO 2. NaBH4
N
Thermal treatment of 3-acetyl-1,4,5,6-tetrahydropyridine (10)
H NHPh
with PhNHNH2, 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)
Reactivity with Heterocumulenes. Reactions of phenylhy-
is not observed via the direct ring-closure of (13), treatment of
drazones with Phenyl Isocyanate, under thermal conditions, pro-
(14) with catalytic amounts of Tin(II) Chloride in benzene, at
vide triazolidines (eq 11).26 A 1,3-dipolar reaction between ke-
refluxing temperature, furnishes the five-membered heterocycles
tone phenylhydrazones and Phenyl Isothiocyanate, in the pres-
(15) in high yields (eq 8).22
ence of Sodium Hydride in DMF, leads to the formation of
4-phenyl-5-phenylimino-1,3,4-thiadiazolidines (eq 12).27 Reac-
Ph
tions using Carbon Disulfide, instead of isothiocyanate, un-
N N
der similar conditions provide 4-phenyl-1,3,4-thiadiazolidine-5-
O Ph
N N
thiones.27
PhNHNH2
+ (7)
N
H
H
N
Ph
NH2 NH2 PhN=C=O
N
Et
(11)
NNHPh
(10) (11) (12)
N
Et
O Ph
NHPh
NPh
NBS, CH2Cl2
N
H
N
N
R SnBu3 64 87% Ph
R NaH
N
Et
(12)
NNHPh
(13) (14)
PhN=C=S
S
Et
SnCl2
NPh
Ph
(8)
N 87 96%
N
R
Generation of Amines. Phenylhydrazine has been used for
(15)
the generation and regeneration of different kinds of amines. Re-
R = Me, t-Bu, Ph
duction of phenylhydrazones has been utilized, for example, in the
synthesis of aminophosphonates. The reaction of PhNHNH2 with
oxophosphonates (20) provides hydrazones (21) in almost quanti-
Synthesis of ²-Lactams. Phenylhydrazones (16), when tative yields. Catalytic hydrogenation yields amines (22), and the
treated with phenoxyketene, give N-acylated products (17), which diethylphosphonate moiety in (22) can be hydrolyzed to provide
do not cycloadd to the ketene. However, N-alkylated phenylhydra- 1-aminoalkanephosphonic acids (24a) (eq 13).28 In a variation of
zones (18)23 undergo [2 + 2] cycloaddition reactions with in situ the Ing Manske procedure,29 where a phthalimide is heated with
generated phenoxyketene to provide ²-lactams (19) (eq 9).24 hydrazine to liberate a primary amine in an exchange reaction, the
N-protective phthaloyl group of an amino acid or a peptide can be
Synthesis of Piperidines. Reactions of Glutaraldehyde and cleaved. Thus refluxing phthaloyl-L-leucine, in the presence of a
hydrazines, in the presence of benzotriazole, lead to the formation tertiary amine in EtOH, can be used to access crystalline L-leucine
of piperidines (eq 10).25 (eq 14).30
A list of General Abbreviations appears on the front Endpapers
PHENYLHYDRAZINE 3
O
NHPh
2 equiv PhNHNH2
N NH2 AcOH
O NNHPh
PhNHNH2 H2, Pd/C
O
(16)
R P
O O
X NNHPh
R P R P HCl
EtO OEt
EtO OEt EtO OEt
X = OH, OAc, Cl, Br an osazone
(20) (21) (22)
R = alkyl, aryl
NH2
O
O
(13)
+ PhNHNH2
Cl
R P
Ph
HO OH
(27)
(23)
Ph
Ph
Ph Ph N Ph
HN
O
N
N Ph
N
CO2H
PhNHNH2 + +
N N N (17)
H
N N N NH
Ph
Bu3N N
Ph Ph HN
Ph N Ph
Ph
O
(28) (29) (30)
O
CO2H
Ph
H2N N Ph
(29)
+ (14)
NH
N
N
O
Ph
(31)
Synthesis of Quinazolines. Further utility of phenylhydrazine
is apparent in the synthesis of quinazolines. Treatment of methyl
Triazolo Compounds. Hydrazones of acylated heterocycles
anthranilate esters (24a) with orthoesters provides N-(2-methoxy-
are widely used as precursors for the preparation of 1,2,4-triazolo
carbonylphenyl) imidate esters (24b). The reaction of these
compounds.39,40 Indeed, oxidative cyclizations of arylhydrazones
imidate esters with PhNHNH2 leads to the formation of 3-amino-
of 2-acylpyridines, in the presence of Mercury(II) Acetate or
4(3H)-quinazolinones (26) in a stepwise mechanism, presumably
Lead(IV) Acetate (LTA), are efficient means of accessing fused
via the intermediate amidrazones (25) (eq 15).31
1,2,4-triazoles and 1,2,3-triazolium systems. A coupling reac-
tion of 2-benzoylpyridine (32) with PhNHNH2 provides the (E)-
CO2Me
X CO2Me X
isomer of hydrazone (33), as established by X-ray structure
RC(OEt)3 PhNHNH2
R
analysis. An oxidative ring-closure of (33) with LTA leads to the
NH2 N OEt
formation of the corresponding 1,2,3-triazolium salt (34) in high
(24a) (24b)
yield (eq 18).41
Ph
O
PhNHNH2
LTA
(18)
Ph Ph N
CO2Me
X X NHPh
N N N
N N
NHNHPh +
(15)
O N
Cl Ph
NHPh
N R N R
(32) (33) (34)
(25) (26)
X = H, Cl, Br; R = Me, Et
Related Reagents. N,N-Dimethylhydrazine; 2,4-Dinitro-
phenylhydrazine.
Osazones. Treatment of Ä…-dicarbonyl compounds, Ä…-hydroxy
aldehydes and ketones,.32,33 and Ä…-halo ketones34 36 with
PhNHNH2 leads to the formation of osazones (eq 16). Osazones
1. (a) Butler, R. N.; Scott, F. L.; O Mahony, T. A. F., Chem. Rev. 1973, 73,
are particularly important in carbohydrate chemistry and have
93. (b) Robinson, B., Chem. Rev. 1969, 69, 227. (c) Buckingham, J., Q.
been used in alkaloid synthesis (eq 5). In a reaction of phenacyl
Rev., Chem. Soc. 1969, 23, 37. (d) Robinson, B Chem. Rev. 1963, 63, 373.
chloride (27) with PhNHNH2, the yellow crystalline pyridazine
(e) Fusco, R.; Sannicolo, F., Tetrahedron 1980, 36, 161. (f) Robinson,
derivative (28) is rapidly formed and the gradual formation of
B. The Fischer Indole Synthesis; Wiley: New York, 1982.
the osazone (29) is also observed. Also produced from this reac-
2. Coleman, G. H Org. Synth., Coll. Vol. 1941, 1, 442.
tion is another compound, a tetrahydropyridazine (30) It has been
3. Shriner, R. L.; Curtin, D. Y.; Fuson, R. C.; Morrill, T. C. The Systematic
rationalized that the pathway to (28) involves the formation of
Identification of Organic Compounds; Wiley: New York, 1980; p 165.
the hydrazone followed by 1,4-elimination of HCl and a subse-
4. (a) Fischer, E.; Jourdan, F., Chem. Ber. 1883, 16, 2241. (b) Fischer, E.;
quent dimerization of the resultant ene azo intermediate (31).37
Hess, O., Chem. Ber. 1884, 17, 559.
It has also been proposed that a retro-Diels Alder type reaction
5. (a) Laronze, J.-Y.; El Boukili, R.; Royer, D.; Levy, J., Tetrahedron 1991,
of (28) furnishes the intermediate (31), which then participates as
47, 4915. (b) Shriner, R. L.; Ashley, W. C.; Welch, E., Org. Synth., Coll.
the diene in a 1,4-cycloaddition reaction with the osazone (29) to Vol. 1955, 3, 725.
provide cyclic (30) (eq 17).38 6. Robinson, G. M.; Robinson, R., J. Chem. Soc. 1918, 113, 639.
Avoid Skin Contact with All Reagents
4 PHENYLHYDRAZINE
7. Forrest, T. P.; Chen, F. M. F., J. Chem. Soc., Chem. Commun. 1972, 1067. 23. Lerch, U.; Konig, J., Synthesis 1983, 157.
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9. Bajwa, G. S.; Brown, R. K., Can. J. Chem. 1970, 48, 2293. 25. Katritzky, A. R.; Fan, W. Q., J. Org. Chem. 1990, 55, 3205.
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1976, 2243.
11. Rogers, C. U.; Corson, B. B., Org. Synth., Coll. Vol. 1967, 4, 884.
27. Motoyoshiya, J.; Nishijima, M.; Yamamoto, I.; Gotoh, H.; Katsube, Y.;
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A list of General Abbreviations appears on the front Endpapers