A new versatile route to the synthesis of a novel series of highly substituted 1,1′-carbonylbispyrazole derivatives

Article abstract of DOI:10.1055/s-0033-1340737

The reaction of 1H-pyrazole-1-carbohydrazide with various α,β-unsaturated nitriles under suitable conditions leads to a cyclocondensation reaction, thereby providing a novel route for the synthesis of a series of highly substituted 1,1′-carbonylbispyrazole derivatives.

Full text of DOI:10.1055/s-0033-1340737

LETTER
▌889
lAetteNr ew Versatile Route to the Synthesis of a Novel Series of Highly Substituted
1,1′-Carbonylbispyrazole Derivatives
Novel Highly Substituted 1,1′-Carbonylbispyrazoles
Sattar Saberi,a Hossein Eshghi,*a Mohamad Rahimizadeh,a Khalil Abnousb
a
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
E-mail: heshghi@um.ac.ir; E-mail: satar.saberi@gmail.com; Fax +98(511)8795457
b
Pharmaceutical Research Center, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences,
Mashhad, Iran
Received: 05.12.2013; Accepted after revision: 15.01.2014
free radicals in vivo.15 Some bispyrazoles have found ap-
Abstract: The reaction of 1H-pyrazole-1-carbohydrazide with var-
plication as antitumor agents (C and D, Figure 1).16
ious α,β-unsaturated nitriles under suitable conditions leads to a cy-
clocondensation reaction, thereby providing a novel route for the
synthesis of a series of highly substituted 1,1′-carbonylbispyrazole
derivatives.
1,1′-Carbonylbispyrazoles have been most commonly
synthesized by a substitution reaction involving phosgene
and other derivatives with pyrazoles.17–24 However, this
synthetic procedure is efficient only when the starting ma-
terials are symmetrically substituted or unsubstituted pyr-
azoles, because unsymmetrical 3- or 5-substituted
pyrazoles may exist in two tautomeric structures in solu-
tion and their N-1-substitution reactions could lead to
three possible carbonyl-bispyrazoles isomers. More re-
cently, Bonacorso reported the synthesis of carbonyl-
bispyrazoles prepared by the reaction of 4-methoxy-4-
aryl(heteroaryl)-1,1,1-trihalobut-3-en-2-ones with 1,3-di-
aminoguanidine monohydrochloride in ethanol and water
as solvents.25
Key words: 1H-pyrazole-1-carbohydrazide, pyrazoles, α,β-unsatu-
rated nitriles, carbonylbispyrazoles, cyclizations, heterocycles
Pyrazoles have attracted significant interest among the
azole family due to their diverse therapeutic potential for
anticancer,1 antifungal,2 antimicrobial,3 and osteogenesis
treatment.4 The pyrazole moiety is the main pharmaco-
phore in the established anti-inflammatory drugs,
celecoxib5 and SC-5586 (A and B, Figure 1). The recent
success of functionalized pyrazole derivatives as cannabi-
noid-1 (CB1) receptor antagonists,7 kinase inhibitors, and
σ1 receptor antagonists8 has further highlighted the impor-
tance of this heterocycle in medicinal chemistry.9
We now wish to report an approach to the synthesis of
highly substituted 1,1′-carbonylbispyrazole derivatives
5a–f (Scheme 2) based on the retrosynthetic analysis out-
lined in Scheme 1. To the best of our knowledge, this mul-
tistep reaction for 1,1′-carbonylbispyrazoles is unprec-
edented.
A survey of the literature revealed that few reports deal
with the synthesis of the pyrazole ring linked to another
pyrazole. Synthetic routes to obtain these compounds and
studies on their potential as pharmaceuticals and agro-
chemicals have been relatively little explored.10–12 The
synthesis of bispyrazoles and their application as het-
eroscorpionate precursor ligands in organometallic and
bioinorganic chemistry has been investigated in recent
years.13,14 In addition, some authors15 have reported
bispyrazole derivatives capable of capturing oxygen and
The target compounds were synthesized according to the
steps outlined in Scheme 2. The key intermediates 2a and
2b were synthesized by condensation of the commercially
available hydrazine carboxylic acid ethyl ester 1 with the
synthesized α,β-unsaturated nitriles 4a,b.26 Treatment of
the pyrazole derivatives 2a,b with four equivalents of hy-
drazine hydrate led to pyrazole derivatives 3a,b contain-
NH2
O
NH2
O
O
N
O
S
S
HO
H3C
Br
N
N
N
N
N
OH
OH
R2
O
N
N
O
N
R2
N
N
N
CF3
CF3
R1
R1
A
B
D
C
Figure 1 Scaffolds A–D
SYNLETT 2014, 25, 0889–0893
Advanced online publication: 14.02.2014
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3
6
-
5
2
1
4
1
4
3
7
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2
0
9
6
DOI: 10.1055/s-0033-1340737; Art ID: ST-2013-D1113-L
© Georg Thieme Verlag Stuttgart · New York

890
S. Saberi et al.
LETTER
(Me)H
N
N
N
N
(Me)H
CN
NH2
X
N
N
N
N
N
X
NH2
(Me)H
NH2
NH2
(Me)H
N
N
O
O
O
N
NH
NH2
H
N
N
X
R3
H2N
NH2NH2
R2
O
X
R2
R3
Scheme 1 Retrosynthetic analysis of highly substituted series of 1,1′-carbonylbispyrazole derivatives
ing a carbohydrazide moiety in 90% and 80% yield, 5b showed the presence of two signals at δ = 2.52 and 8.67
respectively.27 The structures of 3a,b were supported by ppm corresponding to the methyl group and the pyrazolyl
1
FTIR and 1H NMR spectroscopy and elemental analysis. proton, respectively. Whereas the H NMR spectrum of
For example, the IR spectrum of 3a showed absorption the precursor 3a showed the signals corresponding to NH2
bands at 3416–3178, 2238, and 1646 cm–1 indicating the and NH at δ = 6.82 and 12.09 ppm, respectively, which
presence of NH2 and NH, cyano and C=O groups, respec- disappeared upon addition of D2O, the 1H NMR spectrum
tively. The 1H NMR spectrum of 3a showed a signal at δ of the cyclized product 5b did not show these resonances.
= 7.72 ppm corresponding to azomethine proton (N=CH). Instead, an exchangeable broad singlet at δ = 9.23 ppm in
Furthermore, the disappearance of the characteristic pat- DMSO-d6 confirmed that heterocyclization had occurred.
tern of the ethoxy group in addition to the presence of two The 13C NMR spectrum of 5b revealed the appearance of
singlets corresponding to two NH2 and NH protons at δ = two signals at δ = 113.9 and 115.5 ppm, attributed to the
6.82 and 12.09 ppm confirmed the structure of the prod- two cyano groups confirming that heterocyclization with
uct.
the α,β-unsaturated nitrile 2b had occurred. The carbonyl
carbon interfacing the two pyrazole rings of 5b appeared
as a resonance at δ = 164.6 ppm.
Condensation of the 1H-pyrazole-1-carbohydrazide de-
rivatives 3a,b with different α,β-unsaturated nitrile deriv-
atives 4a–e28–33 in the appropriate refluxing solvent The reaction of 3a,b with α,β-unsaturated nitrile deriva-
furnished the novel series of 1,1′-carbonylbispyrazole de- tives was studied under different conditions and optimal
rivatives 5a–f in good to excellent yields (78–93%).34,35
conditions for the preparation of 5a,b were achieved by
refluxing the reaction mixture in ethanol. Other com-
pounds 5 were prepared in high yield by refluxing the re-
actants in pyridine.
The structural assignment of compounds 5a–f was based
on spectroscopic and microanalytical data. For example,
the IR spectrum of 5b revealed the presence of an addi-
tional cyano band at 2220 cm–1. The 1H NMR spectrum of
N
N
N
NH2
EtO
H
NH2
abs. EtOH
NH2NH2, EtOH
EtO
N
H
N
+
NH2
OEt
NH2
R1
N
N
R1
O
R1
N
N
N
O
1
4a,b
R1 = H, Me
O
R1 Product Yield (%)
R1 Product Yield (%)
H
3a
3b
90
80
H
2a
2b
84
81
Me
Me
N
R4
2 R6
NC
NH
R3
R2
R5
R4
NH2
abs. EtOH or pyridine, reflux
78–93%
+
R1
H
R2
N
N
R1
N
N
N
N
NH2
N
4a–e
O
O
4a: R2 = H, R3 = OEt, R4 = CN, R5 = CN
4b: R2 = Me, R3 = OEt, R4 = CN, R5 = CN
4c: R2 = SMe, R3 = SMe, R4 = CN, R5 = CN
4d: R2 = SEt, R 3= SEt, R4 = CN, R 5= CN
4e: R2 = SMe, R3 = SMe, R4 = COOEt, R5 = COMe
5a–f
3a,b
3a: R1 = H
3b: R1 = Me
5a: R1 = H, R2 = H, R4 = CN, R6 = NH2
5b: R1 = H, R2 = Me, R4 = CN, R6 = NH2
5c: R1 = H, R2 = SMe, R4 = CN, R6 = NH2
5d: R1 = H, R2 = SEt, R4 = CN, R6 = NH2
5e: R1 = H, R2 = SMe, R4 = COOEt, R6 = Me..
5f: R1 = Me, R2 = Me, R4 = CN, R6 = NH2
Scheme 2 Procedure to construct fully substitute 1,1′-carbonylbispyrazole derivatives 5a–f
Synlett 2014, 25, 889–893
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Highly Substituted 1,1′-Carbonylbispyrazoles
891
1H and 13C chemical shifts of compounds 5a–c,f are them by alternative methods.17–25 This procedure affords
shown in Figure 2.
the products in good to excellent yields, requiring short re-
action times and a simple workup. A wide range of α,β-
unsaturated compounds has been tested, suggesting that
this method can be used to synthesize a large variety of
highly substituted 1,1′-carbonylbispyrazoles. The route
described herein may open the door to various substitu-
tions and transformations to access to libraries of biologi-
cally active heterocyclic compounds.
N
N
9.37
9.37
NH2
NH2
N
N
H
8.74
8.54
H
N
N
150.1
8.67
150.4
8.67
O
N
N
5a
115.0
80.7
NH2
164.1
O
NH2
113.4
76.9
23.8
2.52
8.67
N
N
H
Acknowledgment
Me
N
N147.4
147.4
We are grateful to the Department of Chemistry, Ferdowsi Univer-
sity of Mashhad, Iran for financial Support (Grant No. 3/15421).
5b
150.5
9.03
150.1
9.03
N
N
113.9
74.6
114.3
NH2 NH2
2.64
13.1
80.9
References and Notes
166.5
N
N
H
8.38
S
N
N 147.7
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147.7
N
N
O
5c
9.13
9.13
NH2 NH2
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N
Me
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Me 2.47
N
N
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A suggested mechanism for the formation of 5 is depicted
in Scheme 3. Assembly of the pyrazole ring is envisaged
to occur by intramolecular heterocyclization of intermedi-
ate I, which arises from precursor 3 by conjugate addition
to 4 followed by aromatization to form the pyrazole ring.
N
N
N
R4
R3
NH2
NH2
N
R3
X
H
N
H
R1
N
R1
N
N
N
NH2
N
N
R4
H
O
O
4
3
I
R4
NC
NH
N
NC
R4
2H2N
NH
2HN
R1
R1
R2
R2
N
N
N
N
N
N
N
O
H
O
II
5
Scheme 3 Postulated mechanism for formation of 1,1′-carbonyl-
bispyrazole derivatives
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Raymond, C. F.; Seager Laura, E.; Elsegood Mark, R. J.
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In conclusion, a general and scalable procedure has been
successfully developed to synthesize 5-amino-4-cyano-
1H-pyrazole-1-carbohydrazides and 5-amino-4-cyano-3-
methyl-1H-pyrazole-1-carbohydrazides as novel precur-
sors using inexpensive starting materials, via the reaction
with α,β-unsaturated nitriles to obtain a large variety of
highly substituted 1,1′-carbonyl-bispyrazole derivatives.
All 1,1′-carbonylbispyrazoles described herein are new
chemical entities and it would be difficult to synthesize
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 889–893

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S. Saberi et al.
LETTER
ice water. After cooling in the refrigerator overnight, the
solid residue was filtered and washed with cold water and
dried to give 3 as a white solid.
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Merzabani, M. M.; Darwish, M. A. A. J. Heterocycl. Chem.
2009, 46, 548.
5-Amino-4-cyano-1H-pyrazole-1-carbohydrazide (3a)
Yield 8.2 g (90%); mp 175 °C. IR: νmax = 3416, 3341, 3284,
3240, 3178, 2956, 2238, 1646, 1570, 1034 cm–1. 1H NMR
(100 MHz, DMSO-d6): δ = 6.82 (s, 4 H, 2 NH2), 7.72 (s, 1 H,
CH), 12.09 (s, 1 H, NH). Anal. Calcd for C5H6N6O: C,
36.15; H, 3.64; N, 50.58. Found: C, 36.08; H, 3.58; N, 50.49.
5-Amino-4-cyano-3-methyl-1H-pyrazole-1-
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J.; Sanchez-Barba, L. F. Eur. J. Inorg. Chem. 2008, 5309.
(15) Heitaro, O.; Takashi, I.; Kazuhisa, S.; Tetsuo, O. US
612130519, 2000.
carbohydrazide (3b)
Yield 7.9g (80%); mp 125–127 °C. IR: νmax = 3403, 3341,
3284, 3242, 2994, 2217, 1660, 1298 cm–1. 1H NMR (100
MHz, CD3COCD3): δ = 2.20 (s, 3 H, CH3), 5.35 (s, 4 H, 2
NH2), 11.19 (s, 1 H, NH). Anal. Calcd for C6H8N6O: C,
40.00; H, 4.48; N, 46.65. Found: C, 39.01; H, 4.41; N, 46.60.
(28) Dooley, M. J.; Quinn, R. J.; Scammells, P. J. Aust. J. Chem.
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(34) Synthesis of 1,1′-Carbonylbis(5-amino-1H-pyrazole-4-
carbonitrile) (5a)
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Compound 4a (0.62 g, 5 mmol) was added to a stirring
solution of 3a (0.82 g, 5 mmol) in EtOH (10 mL). The
contents were stirred at r.t. for a further 30 min and then
refluxed for 3 h. After the completion of the reaction
[monitoring by TLC using CHCl3–MeOH (4:1, v:v) as
eluent], the white solid was filtered under suction and
washed with cold EtOH (1.1g, 93%); mp >300 °C (dec.). IR:
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Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.;
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νmax = 3321, 3277, 3126, 2235, 1688, 1610, 1570, 1487,
1338, 1329, 1262 cm–1. 1H NMR (100 MHz, DMSO-d6): δ =
8.54 (s, 1 H, arom.), 8.72 (s, 1 H, arom.), 9.37 (br, 4 H, NH2,
D2O exchangeable). Anal. Calcd for C9H6N8O: C, 44.63; H,
2.50; N, 46.27. Found: C, 44.54; H, 2.55; N, 46.12.
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(26) General Procedure for the Synthesis of Pyrazoles 2
A mixture of 4 (82 mmol) and hydrazinecarboxylic acid
ethyl ester (1, 8.52 g, 81 mmol) was stirred under reflux in
abs. EtOH (120 mL) for 4 h. After cooling in the refrigerator
overnight, the precipitate was filtered and washed with cold
Et2O to afford 2 as colorless needles.
Synthesis of 5-Amino-1-(5-amino-4-cyano-1H-pyrazole-
1-carbonyl)-3-methyl-1H-pyrazole-4-carbonitrile (5b)
Compounds 4b (0.54 g, 4 mmol) and 3a (0.66 g, 4 mmol)
were added to a solution of Na of NaOEt prepared by adding
(0.21 g, 9 mmol) to abs. EtOH (10 mL). The mixture was
stirred at r.t. for 30 min and then heated to reflux for 3 h.
After the completion of the reaction [monitoring by TLC
using CHCl3–MeOH (3:1, v/v) as eluent], the mixture was
cooled to r.t. H2O (5 mL) was added, and the mixture was
neutralized by HCl. The collected solid was recrystallized
Ethyl 5-Amino-4-cyano-1H-pyrazole-1-carboxylate (2a)
Yield 12.4 g (84%); mp 165–167 °C. IR: νmax = 3493, 3280,
3214, 3128–3156, 2219, 1771, 1628 cm–1. 1H NMR (100
MHz, CDCl3): δ = 1.48 (t, 3 H, CH3), 4.54 (q, 2 H, CH2), 6.32
(s, 2 H, NH2), 7.57 (s, 1 H, CH).
from MeOH (0.81 g, 81%); mp >300 °C (dec.). IR: νmax
=
3340, 3310, 3248, 3180, 3116, 2232, 2221, 1650, 1594 cm–1.
Ethyl 5-Amino-4-cyano-3-methyl-1H-pyrazole-1-
carboxylate (2b)
1H NMR (100 MHz, DMSO-d6): δ = 2.52 (s, 3 H, CH3), 8.67
(s, 1 H, arom.), 9.25 (br, 4 H, NH2, D2O exchangeable). 13
C
Yield 12.7 g (81%); mp 180–181 °C. IR: νmax = 3406, 3320,
3247, 2990, 2213, 1736, 1646, 1563, 1471, 1332, 1256, 1021
cm–1. 1H NMR (100 MHz, CDCl3): δ = 1.43 (t, 3 H, CH3),
2.25 (s, 3 H, CH3), 4.48 (q, 2 H, CH2), 6.48 (s, 2 H, NH2).
Anal. Calcd for C8H10N4O2: C, 49.48; H, 5.19; N, 28.85.
Found: C, 49.38; H, 5.11; N, 28.78.
NMR (100 MHz, DMSO-d6): δ = 24.3, 77.4, 81.1, 113.9,
115.5, 147.9,150.6, 150.9, 164.6. Anal. Calcd for C10H8N8O:
C, 46.88; H, 3.15; N, 43.73. Found: C, 46.78; H, 3.04; N,
43.60.
(35) General Procedure for the Synthesis of 1,1′-
Carbonylbispyrazole Derivatives 5c–f
(27) General Procedure for the Synthesis of 1H-Pyrazole-1-
carbohydrazides 3
A mixture of of 4c–e (4 mmol) and 3 (4 mmol) in pyridin (5
mL) was heated to reflux for 4 h, then poured onto ice water
and the mixture neutralized with concd HCl. The
precipitated solid was filtered, washed with H2O, and
crystallized from an appropriate solvent.
Hydrazine monohydrate (10 mL, 206 mmol) was added to a
solution of 2 (55 mmol) in abs. EtOH (60 mL), and the
mixture was refluxed for 3 h. The excess of solvent was
distilled off, and the crude product obtained was poured into
Synlett 2014, 25, 889–893
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-Amino-1-(5-amino-4-cyano-1H-pyrazole-1-carbonyl)-
Novel Highly Substituted 1,1′-Carbonylbispyrazoles
893
Ethyl 1-(5-Amino-4-cyano-1H-pyrazole-1-carbonyl)-5-
methyl-3-(methylthio)-1H-pyrazole-4-carboxylate (5e)
3-(methylthio)-1H-pyrazole-4-carbonitrile (5c)
Yield 0.89 g (78%, DMF); mp >300 °C. IR: νmax = 3353,
3304, 3027, 3186, 2240, 2218, 1659, 1607, 1567, 1384,
1342, 1291 cm–1. 1H NMR (100 MHz, DMSO-d6): δ = 2.64
(s, 3 H, SCH3), 8.37 (s, 1 H, arom.), 9.03 (br, 4 H, NH2, D2O
exchangeable). 13C NMR (100 MHz, DMSO-d6): δ = 13.2,
74.6, 80.9, 113.9, 114.3, 147.7, 150.1, 150.4, 166.5. Anal.
Calcd for C10H8N8OS: C, 41.66; H, 2.80; N, 38.87; S, 11.12.
Found: C, 41.56; H, 2.46; N, 38.57; S, 11.04.
Yield 1.09g (82%, n-hexane); mp 128–129 °C. IR: νmax =
3351, 3313, 3250, 3219, 3184, 2239, 2217, 1658, 1607,
1566, 1534, 1462, 1384, 1342, 1278 cm–1. 1H NMR (100
MHz, CDCl3): δ = 1.38–1.52 (t, 3 H, OCH2CH3), 2.65 (s, 3
H, CH3), 2.88 (s, 3 H, SCH3), 4.33–4.56 (q, 2 H, OCH2CH3),
8.29 (s, 1 H, arom.). 13C NMR (100 MHz, DMSO-d6): δ =
14.1, 14.2, 15.3, 62.8, 81.9, 112.9, 115.4, 146.6, 147.4,
149.0, 164.1, 164.6. Anal. Calcd for C13H14N6O3S: C, 46.70;
H, 4.22; N, 25.14; S, 9.59. Found: C, 46.62; H, 4.15; N,
25.09; S, 9.59.
5-Amino-1-[4-amino-5-cyano-3-(ethylthio)-1H-pyrazole-
1-carbonyl]-1H-pyrazole-4-carbonitrile (5d)
Yield 1.05g (87%, EtOH); mp >300 °C (dec.). IR: νmax
=
5-Amino-1-(4-amino-5-cyano-3-methyl-1H-pyrazole-
1-carbonyl)-1H-pyrazole-4-carbonitrile (5f)
3350, 3320, 3252, 3187, 3101, 2994, 2941, 2217, 1657,
1597, 1563, 1534, 1465, 1380, 1339, 1286, 1248 cm–1. 1H
NMR (100 MHz, DMSO-d6): δ = 1.26–1.41 (t, 3 H,
SCH2CH3), 3.11–3.30 (q, 2 H, SCH2CH3), 8.62 (s, 1 H,
arom.), 9.19 (br, 4 H, NH2, D2O exchangeable). 13C NMR
(100 MHz, DMSO-d6): δ = 15.7, 25.8, 75.8, 81.9, 115.3,
148.8, 151.4, 151.6, 167.2. Anal. Calcd for C11H10N8OS: C,
43.70; H, 3.33; N, 37.07; S, 10.61. Found: C, 51.64; H, 3.29;
N, 37.42; S, 10.55.
Yield 0.87g (81%, MeOH). IR: νmax = 3327, 3277, 3120,
2234, 1680, 1609, 1565, 1485, 1335 cm–1. 1H NMR (100
MHz, DMSO-d6): δ = 2.47 (s, 3 H, CH3), 2.52 (s, 3 H, CH3),
9.13 (br, 4 H, 2 NH2, D2O exchangeable). 1H NMR (100
MHz, CD3COCD3): δ = 2.49 (s, 3 H, CH3), 2.59 (s, 3 H,
CH3), 8.40 (br, 4 H, 2 NH2, D2O exchangeable). Anal. Calcd
for C11H10N8O: C, 48.89; H, 3.73; N, 41.46. Found: C,
48.81; H, 3.69; N, 41.40.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 889–893

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