C-C bond cleavage studies in bipyrazoles: A convenient synthesis of pyrazolo-5-ols

Article abstract of DOI:10.1081/SCC-200049811

The treatment of 4-acetoacetyl derivative (3) of the pyrazoles with hydrazines in ethanol/HCl furnished a variety of bipyrazoles (4). However, when the reaction was performed in sodium acetate/acetic acid/ethanol, different hydrazines gave different products. Under these conditions an unexpected C-C bond cleavage was observed thus affording a convenient route for the formation of pyrazolo-5-ols (5 and 6).

Full text of DOI:10.1081/SCC-200049811

Synthetic Communicationsw, 35: 611–619, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200049811
C-C Bond Cleavage Studies in Bipyrazoles:
A Convenient Synthesis of Pyrazolo-5-ols
Shiv P. Singh
Department of Chemistry, Kurukshetra University, Kurukshetra, India
Rajesh Naithani
Department of Chemistry, University of Illinois at Chicago,
Chicago, USA
Ranjana Aggarwal and Om Prakash
Department of Chemistry, Kurukshetra University, Kurukshetra, India
Abstract: The treatment of 4-acetoacetyl derivative (3) of the pyrazoles with hydra-
zines in ethanol/HCl furnished a variety of bipyrazoles (4). However, when the
reaction was performed in sodium acetate/acetic acid/ethanol, different hydrazines
gave different products. Under these conditions an unexpected C-C bond cleavage
was observed thus affording a convenient route for the formation of pyrazolo-5-ols
(5 and 6).
Keywords: C-C bond cleavage, bipyrazoles, hydrazines, dehydroacetic acid
The reaction between hydrazines and dehydroacetic acid (DHAA) has been
under investigation in our laboratory for the last few years.[1] The formation
of the hydrazone of DHAA which underwent smooth skeletal rearrangement
to yield the corresponding acetoacetyl derivative (3) of the pyrazole has
already been reported.[2] Treatment of this derivative with hydrazines in
ethanol/HCl furnished a variety of bipyrazoles (4) in excellent yield
(Scheme 1). However, when the reaction is performed in sodium acetate/
Received in the USA 11 November 2004
Address correspondence to Rajesh Naithani, Department of Chemistry, University
of Illinois at Chicago, Chicago, IL 60607, USA. E-mail: naithani@uic.edu

612
S. P. Singh et al.
For 2 and 3 R55
(a)55C6H5
(b) 552,4-DNP (d) 554-methyl-2-quinolyl
(c)55C6H4Cl (p)
(e) 556-methyl-2-benzothiazolyl
Scheme 1.
acetic acid/ethanol different products were obtained depending upon the nature
of the hydrazines employed. In some cases, bipyrazoles were the sole products
(Scheme 2), whereas when other hydrazines were employed an unexpected
carbon-carbon bond fission was observed (Scheme 4).
In order to shed some light on the mechanistic aspects of this rather
unusual C-C bond cleavage and to know the factors responsible for such a
fission, the present study was undertaken.[2]
In the present study the experiments were designed to focus our attention
on the following studies:
1. Nature of the hydrazines employed in the reaction
2. Stereochemical factors which may affect the course of the reaction
In order to get a generalized picture of these transformations a variety of
hydrazines were treated with 3 under the following conditions:
(i) HCl/Ethanol (ii) sodium acetate/acetic acid/ethanol
More specifically 3 was treated with phenylhydrazine, arylhydrazines
(having strong electron withdrawing groups) such as para-nitrophenyl-
hydrazine, 2,4-dinitrophenylhydrazine, and heterocyclylhydrazine such as

C-C Bond Cleavage Studies in Bipyrazoles
613
For 4 (a-g)
Compd. No.
R
R1
a
b
c
d
e
f
Phenyl
Phenyl
Phenyl
Phenyl
p-nitrophenyl
2,4-dinitrophenyl
1-naphthyl
para-chlorophenyl
phenyl
phenyl
2-pyridyl
4-methyl-2-quinolyl
6-methyl-benzothiazolyl
g
4-methyl-2-quinolyl
Scheme 2.
2-benzothiazolylhydrazine, 2-quinolylhydrazine, and 2-pyridylhydrazine
under both the above conditions. Reactions of 3 with all the hydrazines led
to the exclusive formation of bipyrazoles (4) in HCl/ethanol. However,
when the reaction was carried out in sodium acetate/acetic acid/ethanol,
different products were formed depending upon the hydrazine involved.
Phenylhydrazine, pyridylhydrazine, and para-nitrophenylhydrazine led to
the exclusive formation of the bipyrazole (4) but in case of 2,4-dinitrophenyl-
hydrazine, 2-benzothiazolylhydrazines, 2-quinolylhydrazines a C-C cleavage
occurred to give 5 and 6 under the identical conditions (Scheme 2). It may
be suggested that electron withdrawing nature of hydrazines play a role in
the bond fission. Pyrazol-5-ols can be obtained when C-C bond cleavage
takes place in the intermediate 7 (Scheme 3). The divergent behavior of the
pyridyl and quinolyl hydrazines brings into focus that it may be the bulky
nature of the hydrazines which plays a more important role in the C-C
cleavage as compared to the electron-withdrawing nature of the hydrazine.
In order to further substantiate this observation, 1-naphthylhydrazine was
treated with 3 under identical conditions as used for phenylhydrazine. Indeed
it is quite interesting to see that whereas bipyrazolyl was the sole product
in the case of phenylhydrazine, products of the C-C bond fission were

614
S. P. Singh et al.
Scheme 3.
obtained in case of the naphthylhydrazine (Scheme 4), thus confirming bulk of
hydrazine facilitates cleavage. The structure of the all pyrazol-5-ols were
1
confirmed by elemental analysis and their H NMR characteristics. A signal
around d 2.34 (s, 3H, CH3) indicated the presence of CH3 at position-3 of
the pyrazole ring. As expected the characteristics signal due to the methyl
group at 30 of the bipyrazole was absent thereby confirming the bond
cleavage. Interestingly this route can be employed for synthesis of the various
pyrazolyl-5-ols which may be otherwise difficult to synthesize, thus this route
provides a convenient and a high-yield procedure for the pyrazolyl-5-ol.
In one of our earlier study, the C-C bond cleavage in bipyrazole was
sought to be correlated to the shielding of the methyl group at position-3
of the bipyrazoles.[3,5] It was suggested that the protons of the two methyl
group resonate close to each other in those bipyrazoles whose precursor
have a tendancy to undergo bond fission. On the other hand the
4,50-bipyrazolyles whose precursors do not have a tendency to undergo C-C

C-C Bond Cleavage Studies in Bipyrazoles
615
For 5 and 6 (a-d)
Compd. No.
R
R1
a
b
c
Phenyl
1-naphtyl
4-methyl-2-quinolyl
2-benzothiazolyl
2,4-dinitrophenyl
4-methyl-2-quinolyl
2-benzothiazolyl
2,4-dinitrophenyl
d
Scheme 4.
bond cleavage displays one of the methyl group relatively deshielded. This
may be explained by a consideration of chemical shifts of methyl groups in
the two pyrazolyls (4a and 4d).
Whereas the signals appeared at d 1.78 and d 2.38 in compound 4a repre-
senting the protons of C3 and C30 of the two methyl groups, the corresponding
signals were observed at d 2.22 and d 2.43 for compound 4d. In other words
the difference in the shifts of two methyl groups in 4a is greater (Dd 0.5), the
cleavage does not take place. Whereas if the difference is less (Dd 0.2)
the cleavage does take place (Table 1).
On basis of our studies it appears that there might be some correlation
between the chemical shifts of the two methyl groups of the 4,50-bipyrazolyls
and ability of their precursor to undergo C-C cleavage. However additional
experimental data needs to be generated in order to present a comprehensive
profile of the mechanistic pathway.
The following two conclusion may be suggested from the present study:
1. The steric factor appears to be playing an important role in the bond
cleavage.
2. Nature of the hydrazine employed in the second step of the reaction might
have some role in the fission which needs to be investigated in detail.

616
S. P. Singh et al.
Table 1.
Compd.
no.
Shift value
(d) of C3
Shift value
(d) of C30
R
R1
4a
4b
4c
4d
4e
4f
Phenyl
Phenyl
Phenyl
Phenyl
1.78
1.97
2.08
2.24
2.25
2.20
2.18
2.30
2.35
2.34
2.40
2.39
2.41
2.41
p-nitrophenyl
2,4-dinitrophenyl
1-naphthyl
p-chlorophenyl
Phenyl
Phenyl
2-pyridyl
4-methyl-2-quinolyl
6-methyl-2-
benzothiazolyl
4g
4-methyl-2-
quinolyl
EXPERIMENTAL
All the melting points were determined in open capillaries and are uncor-
rected. The 1H NMR spectra were recorded on Bruker 300 MHz spectrometer.
The elemental analysis was carried out in a Perkin Elmer-2400 instrument and
mass spectra were recorded on Kratos MS-50 mass spectrometer.
Phenyl Hydrazone of DHAA (2a)
Dehydroacetic acid (DHAA) (3.36 g, 0.02 mol) was dissolved in ethanol
(50 mL) by warming and phenylhydrazine (2 mL, 0.02 mol) was added to
the shaken solution. The contents were stirred for 10 min and allowed
to stand at the room temperature for 2 h. The yellow solid obtained was
filtered and recrystallized from acetonitrile.Yield 81% (4.2 g), m.p. 211–
2128C, lit.[4] m.p. 212–2138C.
Other hydrazones (2a–e) were also prepared similarly by treating DHAA
with the corresponding hydrazines.
1
(2b) Yield 80% (2.78 g), m.p.1928C; H NMR (CDCl3): d 2.29 (s, 3H,
CH3), 2.75 (s, 3H, CH3), 6.01(s, 1H, pyrone-5H), 7.43–7.49 (m, 3H, Ar-H).
Elemental Analysis: Calculated for C14H12N4O7 (348.26): C, 48.27; H,
3.44; N, 16.09. Found: C, 48.07; H, 3.14; N, 15.89. The physical data of the
other hydrazones are given in Table 2.
5-Hydroxy-3-methyl-1-phenylpyrazol-4-yl-1,3-butanedione (3a)
Phenylhydrazone of DHAA (2.46 g, 0.01 mol) was dissolved in glacial acetic
acid and the solution refluxed for 1.5 h. The solvent was distilled off under
reduced pressure and residue was crystallized from acetonitrile. Yield 66%

C-C Bond Cleavage Studies in Bipyrazoles
617
Table 2.
Compound no.
m.p. (8C)
Lit. m.p. (8C)
Reference
2c
2d
2e
251
188
210
252
190
212
[4]
[5]
[5]
(1.7 g), m.p. 1018C, lit.[5] m.p. 1018C. All the other compounds (3b–e) were
synthesized following the above procedure.
1
(3b)Yield 60% (2.08 g), m.p. 2168C; H NMR(CDCl3): d 2.16 (s, 3H,
CH3), 2.50 (s, 3H, CH3), 3.91 (s, 2H, COCH2CO), 5.90 (s, 1H, vinylic),
8.2–9.2 (m, 3H, Ar-H). Elemental Analysis: Calculated for C14H12N4O7
(348.26): C, 48.27; H, 3.44; N, 16.09. Found: C, 47.59; H, 3.21; N, 16.21.
The physical data of 3c–e is given in Table 3.
1,10-Diphenyl-3,30-dimethyl-(4,50-bipyrazol)-5-ol (4a)
To an ethanolic solution (30 mL) of 3a (0.005 mol) was added phenylhydra-
zine (0.5 mL, 0.005 mol) and the contents were refluxed for 2.5 h. containing
a few drops of conc. HCl. The crude solid obtained after concentrating and
cooling the reaction mixture was filtered and crystallized from ethanol and
N,N-dimethylformadide.
(4a) Yield 70% (1.15 g), m.p.2588C, lit.[4] m.p. 2608C. All other 1,10-
disubstituted-3,30-dimethyl-(4,5-bipyrazol)-5-ols were prepared similarly
by treating 3 with various arylhydrazines.
1
(4b) Yield 58% (2.17 g), m.p. 1688C; H NMR (CDCl3): d 1.97 (s, 3H, CH3),
2.35 (s, 3H, CH3), 6.31 (C40 -H), 7.20–8.22 (m, 10H, Ar-H). Elemental
Analysis: Calculated for C20H17N5O3: C, 64.10; H, 4.53; N, 18.20.
Found: C, 63.86; H, 4.60; N, 18.56.
(4c) Yield 54% (2.20 g), m.p. 2128C, 1H NMR (CDCl3): d 2.08 (s, 3H, C3-CH3),
2.34 (s, 3H, C30 -CH3), 6.28 (s, 1H, C40 -H), 7.33–8.62 (m, 9H, Ar-H). Elemental
Table 3.
Compound no.
m.p. (8C)
Lit. m.p. (8C)
Reference
3c
3d
3e
150
212
198
151
214
199
[5]
[4]
[5]

618
S. P. Singh et al.
Analysis: Calculated for C20H16N6O5:C, 56.14; H, 3.80; N, 20. Found: C,
57.04; H, 3.40; N, 19.80.
(4d) Yield 58% (2.40 g), m.p. 2188C; 1H NMR (CDCl3): d 2.24 (s, 3H, CH3),
2.40 (s, 3H, C30 -CH3) 6.40 (s, 1H, C40 -H), 7.43–8.04 (m, 12H, Ar-H).
Elemental Analysis: Calculated for C24H19ClN4O: C, 69.58; H, 4.58; N,
13.52. Found: C, 68.86; H, 4.53; N, 13.41.
1
(4e) Yield 60% (2.18 g), m.p. 2208C, lit.[6] m.p. 2398C; H NMR (CDCl3)
d 2.25 (s, 3H, CH3), 2.39 (s, 3H, C30 -CH3), 6.23 (s, 1H, C40 H), 7.24–8.31
(m, 9H, Ar-H).
1
(4f) Yield 69% (2.28 g), m.p. 2388C, lit.6 m.p. 2398C; H NMR (CDCl3):
d 2.20 (s, 3H, C3-CH3), 2.41 (s, 3H, C30 -CH3), 2.76 (s, 3H, C4-CH3 of the
quinolyl), 6.38 (s, 1H, C40 -H), 7.25–8.08 (m, 10H, Ar-H).
(4g) Yield 56% (2.60 g), m.p. 2288C; 1H NMR (CDCl3) d 2.18 (s, 3H, C3-CH3),
2.41 (s, 3H, C6-CH3 of the benzothiazolyl), 2.78 (s, 3H, C4-CH3 of the
quinolyl), 6.35 (s, 1H, C40 -H), 7.13–8.01 (m, 9H, Ar-H). Elemental
Analysis: Calculated for C26H22N6OS: C, 66.95, H, 4.72. N, 18.02. Found:
C, 66.67; H, 4.32; N, 17.99.
Reaction in the Presence of Sodium Acetate/Acetic Acid/Ethanol
General Procedure
Equimolar amounts (0.005 moles) of the 3 and the appropriate hydrazine were
refluxed for 2 h in ethanol containing acetic acid 0.1 mL/sodium acetate
0.1 gm. After cooling the reaction mixture a solid was obtained which
was filtered washed with ethanol and dried. The data of the pyrazol-5-ols
(5 and 6) have been given below:
(5a) Yield 25% (0.43 g), m.p. 1258C, Lit.[6] m.p. 1278C.
(6a) Yield 28% (0.62g), m.p. 1178C; 1H NMR (CDCl3): d 2.14 (s, 3H, CH3),
5.81 (s, 1H, C4-H), 6.55–7.80 (m, 7H, Ar-H). Elemental Analysis: Calcu-
lated for C14H12N2O: C, 75.00; H, 5.31; N, 12.50. Found: C, 75.00; H,
5.21; N, 12.68.
1
(5b/6b) Yield 56% (1.33 g), m.p. 1708C; H NMR (CDCl3) d 2.29 (s, 3H,
CH3), 2.75 (s, 3H, C4-CH3 of the quinolyl), 5.47 (s, 1H, C4-H), 7.34–
7.98 (m, 5H, Ar-H). Elemental Analysis: Calculated for C14H13N3O: C,
70.29; H, 5.40; N, 17.57. Found: C, 70.21; H, 5.38; N, 17.50.
1
(5c/6c) Yield 56% (1.29 g), m.p. 1688C; H NMR (CDCl3): d 2.29 (s, 3H,
CH3), 5.45 (s, 1H, C4-H), 7.31–7.83 (m, 4H, Ar-H). Elemental Analysis:

C-C Bond Cleavage Studies in Bipyrazoles
619
Calculated for C11H9N3SO: C, 57.14; H, 3.89; N, 18. 18. Found: C, 57.32;
H, 3.79; N, 18.32.
1
(5d/6d) Yield 60% (1.58 g), m.p. 1708C; H NMR (CDCl3): d 2.18 (s, 3H,
CH3), 7.19–9.41(m, 4H, Ar-H). Elemental Analysis: Calculated for
C10H8N4O5: C, 45.44; H, 30.33; N, 21.21. Found:C, 45.18; H, 30.01;
N, 21.20.
ACKNOWLEDGMENTS
The authors are thankful to RSIC, Panjab University, Chandigarh (India)
for NMR, IR and elemental analysis data. Financial help from CSIR, New
Delhi (India) and Ranbaxy Research Laboratories, New Delhi (India) is
gratefully acknowledged.
REFERENCES
1. Singh, S. P.; Prakash, O.; Vaid, R. K. Indian J. Chem. 1986, 23B, 191 and references
cited therein.
2. Vaid, R. K. University of Kurukshetra: India, 1984; Ph.D Thesis.
3. Grover, M. University of Kurukshetra: India, 1987; M.Phil. Dissertation.
4. Kumar, D.; Singh, S. P.; Martinez, A.; Fruchier, A.; Elguero, J.; Martinez, M. R.;
Carrio, J.; Virgils, A. Tetrahedron 1995, 51, 4891.
5. Naithani, R. University of Kurukshetra: India, 2000; Ph.D Thesis.
6. Kumar, D. University of Kurukshetra: India, 1987; Ph.D Thesis.