Highly regioselective one-pot, three-component synthesis of 1-aryl-3,4-substituted/annulated-5-(cycloamino)/(alkylamino)pyrazoles from β-oxodithioesters

Article abstract of DOI:10.1002/ejoc.201101397

An efficient, highly regioselective protocol for the synthesis of the title compounds is reported. The reaction involves a one-pot, three-component cyclocondensation of β-oxodithioester, amine, and hydrazine in ethanol at reflux in the presence of a catal

Full text of DOI:10.1002/ejoc.201101397

FULL PAPER
DOI: 10.1002/ejoc.201101397
Highly Regioselective One-Pot, Three-Component Synthesis of 1-Aryl-3,4-
Substituted/Annulated-5-(Cycloamino)/(Alkylamino)pyrazoles from
β-Oxodithioesters
Ganesh C. Nandi,[a] Maya S. Singh,*[a] Hiriyakkanavar Ila,*[b] and
Hiriyakkanavar Junjappa[c]
Keywords: Multicomponent reactions / Nitrogen heterocycles / Regioselectivity / Synthetic methods
An efficient, highly regioselective protocol for the synthesis
of the title compounds is reported. The reaction involves a
alized pyrazoles were constructed through the cyclization of
a thioamide intermediate generated in situ from the β-oxodi-
one-pot, three-component cyclocondensation of β-oxodithio- thioester. This method allows a rapid and general synthesis
ester, amine, and hydrazine in ethanol at reflux in the pres-
ence of a catalytic amount of acetic acid. Densely function-
of previously inaccessible pyrazoles and synthetically de-
manding pyrazoles containing fused rings.
azole-containing bicyclic drugs including Zaleplon,[15] Via-
gra (Sildenafil),[3] and Allopurinol.[16] The chemistry of pri-
mary-amino-substituted pyrazoles have been widely investi-
gated and reviewed;[12] such compounds are usually synthe-
sized by cyclocondensation of β-oxonitriles (or their syn-
thetic equivalents) with hydrazine or phenylhydrazine. On
the other hand, alkyl/arylamino and N,N-disubstituted/(cy-
cloamino)pyrazoles are not well represented in the litera-
ture, and there are only limited studies on the synthesis of
these compounds,[13a,17] even though many of the 5-alkyl/
arylamino-1-arylpyrazoles have found applications as phar-
maceutical and agrochemical agents that exhibit a range of
biological activities.[13a] Reported methods for the synthesis
of 1-aryl-5-(alkyl/arylamino)pyrazoles require either harsh
conditions or are limited to a defined set of precur-
sors.[13a,17,18]
In a recent paper, Dodd and Martinez reported a
one-pot synthesis of 1-aryl-3-substituted-5-(disubsti-
tuted amino)pyrazoles by reaction of β-oxoamides with ar-
ylhydrazines and Lawesson’s reagent.[19] However, this pro-
tocol requires preformed β-oxoamides and, except for a few
examples, the yields of aminopyrazoles are moderate (with
formation of pyrazolones as side products), and substituent
diversity is limited to only 3-methyl/phenylpyrazoles.
Furthermore, the methodology has not been extended to
the synthesis of 5-(cycloamino)pyrazoles, which have found
applications in both pharmaceutical and agrochemical in-
dustries.[18b] Junjappa, Ila and co-workers[13a] recently re-
ported a highly regioselective synthesis of 1-aryl-3-(or 5)-
alkyl/aryl-5-(or 3)-(cycloamino)pyrazoles by cycloconden-
sation of arylhydrazines with common α-oxoketene (cy-
cloamino)-S,N-acetal precursors under defined conditions.
However, the methodology requires prior synthesis of N,S-
acetal precursors. During the course of our studies on the
Introduction
Substituted pyrazoles are important synthetic targets for
both the pharmaceutical industry and academic laborato-
ries, because they display a rich chemistry and have numer-
ous applications.[1] Both 1,3,5-tri- and 1,3,4,5-tetrasubsti-
tuted pyrazoles constitute the core structures of several
commercial drugs such as Celebrax,[2] Viagra,[3] and the in-
secticide Fipronil, as well as numerous developmental com-
pounds that exhibit a wide spectrum of biological activities
such as antihyperglycemic, analgesic, antiinflammatory,
sedative, and hypnotic properties.[4] Many of the substituted
pyrazoles are useful in crop protection.[5] Furthermore, sub-
stituted pyrazoles are also used as ligands in coordination
chemistry[6] as well as optical brighteners[7] and UV stabiliz-
ers,[8] as photoelectron-induced electron-transfer systems,[9]
and as supramolecular entity units.[10] Therefore, numerous
methods for the regiospecific synthesis of substituted pyr-
azoles have been established.[1,11]
Among the various functionalized pyrazoles, there has
been a considerable revival of interest in the synthesis of
aminopyrazoles,[12,13] because they serve as useful precur-
sors for condensed heterocycles[12a,14] such as aminopyr-
[a] Department of Chemistry, Faculty of Science, Banaras Hindu
University,
Varanasi 221005, India
Fax: +91-542-2368127
E-mail: mssinghbhu@yahoo.co.in
[b] New Chemistry Unit, Jawaharlal Nehru Centre for Advanced
Scientific Research,
Jakkur, Bangalore 560064, India
Fax: +91-80-22082766
E-mail: hila@jncasr.ac.in
[c] Reva Institute of Science and Management,
Kattigenahalli, Yelahanka, Bangalore 5600064, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101397.
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M. S. Singh, H. Ila et al.
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synthetic applications of β-oxodithioesters in heterocyclic phenylhydrazine in the presence of sodium hydride in DMF
synthesis,[11j,20] we have developed an efficient one-pot, (or with potassium tert-butoxide; Scheme 1).[13a] In another
three-component synthesis of 1-aryl-3,4-substituted-5-(cy- experiment, the β-oxothioamide 2a generated in situ from
cloamino)/(alkylamino)pyrazoles by the reaction of β-oxo- 1a and piperdine, was directly treated with phenylhydrazine
dithioesters with primary aliphatic or cyclic secondary in ethanol at reflux (3 h), in the presence of a trace amount
amines and arylhydrazines. β-Oxothioamide compounds of acetic acid in a one-pot, two-step procedure, yielding the
were shown to be the actual reactive species in these reac- pyrazole 3a in comparable yield (79%; Scheme 2, Table 1,
tions. The results of these studies are reported herein.
Entry 1).
Results and Discussion
The desired acyclic (1a–k) and cyclic (6a and 6b) β-oxo-
dithioesters were prepared in high yields by using a method
based on our previously reported procedure.[21a] The ap-
proach incorporated a modification developed by Asokan
and co-workers[21b] and involved reaction of the corre-
sponding acyclic and cyclic active methylene ketones with
S,S-dimethyl trithiocarbonate in the presence of sodium hy-
dride in a mixture of N,N-dimethylformamide (DMF) and
hexane at room temperature.[21b]
When β-oxodithioester 1a was treated with piperidine
(1 equiv.) in ethanol at reflux for 2 h (reaction monitored
by TLC), workup of the reaction mixture afforded the cor-
Scheme 1. Synthesis of 1,3-diphenyl-5-piperidinopyrazole.
This typical procedure was applied for the synthesis of
responding β-oxothioamide 2a in 88% yield. Further treat- other substituted 5-(cycloamino)pyrazoles as shown in
ment of pure thioamide 2a with phenylhydrazine in ethanol Scheme 2 and Table 1. Thus, the known 1,3-diaryl-5-(cy-
and a trace of acetic acid, under reflux (3 h), furnished 1,3- cloamino)pyrazoles 3b and 3c[13a] were isolated in high
diphenyl-5-piperidinopyrazole (3a) in 80% yield exclusively. yields as single regioisomers under identical conditions
This product was found to have physical and spectroscopic from the respective β-oxodithioesters 1a/1b and cyclic
data that were identical to our previously reported 5-piperi- amines (Table 1, Entries 2 and 3). The assigned regiochemi-
dinopyrazole, obtained by reaction of N,S-acetal 4 with stry of the product pyrazoles was further supported by X-
Scheme 2. Synthesis of 1,3-disubstituted-5-(cycloamino)pyrazoles.
Table 1. Synthesis of 1,3-disubstituted-5-(cycloamino)pyrazoles.
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Synthesis of Substituted/Annulated Alkylaminopyrazoles
ray crystallographic data of the newly synthesized 1-phenyl- 3-(cycloamino)pyrazoles could be isolated from the reaction
3-(4-methoxyphenyl)-5-(N-phenylpiperazino)pyrazole (3d; mixtures.
Table 1, Entry 4, and Figure 1).[22]
The scope and generality of this three-component, one-
pot procedure was further evidenced by the synthesis of 1-
aryl-3,4-annulated pyrazoles 5a, 5b, and 7a, as shown in
Scheme 3. Thus, treatment of β-oxodithioesters 6a and 6b,
derived from 1-tetralone and cyclohexanone, respectively,
with substituted arylhydrazines and N-substituted piper-
azine under the previously described conditions, yielded the
3,4-fused 1-aryl-5-(cycloamino)pyrazoles 5a, 5b, and 7a in
excellent yields (Scheme 3). The structures and regiochemis-
try of all newly synthesized pyrazoles 3a–n, 5a, 5b, and 7a
were established with the help of spectral and analytical
data.
We then extended our studies towards the synthesis of
secondary-amino-substituted pyrazoles such as 9, by using
primary amines as reaction partners in the reaction
(Schemes 4 and 5). Our studies revealed that the reaction
of β-oxodithioesters with primary aliphatic amines and ar-
ylhydrazines in ethanol at reflux with a trace of acetic acid
in a one-pot reaction also furnished the corresponding 1,3-
substituted-5-(alkylamino)pyrazoles exclusively in good
yields (Scheme 5 and Table 2). Thus, when β-oxothioester
1b was treated with cyclohexylamine in ethanol under re-
flux for 1 h, the isolated product was characterized as β-
oxo-N-cyclohexylthioamide (10a) on the basis of its spectral
and analytical data (Scheme 4). Treatment of thioamide 10a
(either generated in situ or pure) with phenylhydrazine un-
Figure 1. ORTEP diagram of 3d.
Further,
1-aryl-3-(4-chlorophenyl)-5-(cycloamino)pyr-
azole products 3e–f were also obtained in high yields by
cyclocondensation of (4-chlorophenyl)-substituted β-oxodi-
thioester 1c with either phenyl- or (3-fluorophenyl)hydraz-
ine and the appropriate cyclic secondary amines under sim-
ilar conditions (Table 1, Entries 5 and 6). To further intro-
duce substituent diversity into the product pyrazoles, β-oxo-
dithioesters 1d–g, derived from heterocyclic active methyl-
ene ketones, were also condensed with various arylhydraz-
ines and cyclic amines under these optimized reaction con-
ditions to afford the corresponding 1-aryl-3-(2-thienyl)-
(3g–h), -3-(2-furyl)- (3i), -3-[3-(N-methyl)pyrrolyl]- (3j),
and -3-(3-pyridyl)- (3k) -5-(cycloamino)pyrazoles in excel-
lent yields (Table 1, Entries 7–11). The new procedure was
found to be equally facile for the synthesis of tetrasubsti-
tuted 5-(cycloamino)pyrazoles 3l–m by treating α-methyl-β-
oxodithioester precursor 1h (derived from propiophenone)
with the appropriate amines and arylhydrazines under iden-
tical conditions (Table 1, Entries 12 and 13). Similarly, the
β-oxodithioester 1i, obtained from an aliphatic ketone, also
underwent smooth cyclization in the presence of (3-fluo-
rophenyl)hydrazine and N-phenylpiperazine to furnish 3-
isopropyl-1-(3-fluorophenyl)-5-(cycloamino)pyrazole (3n)
in 72% yield (Table 1, Entry 14). In all these examples, for-
mation of only one regioisomeric 5-(cycloamino)pyrazole
Scheme 4. Synthesis of 1,3-substituted 5-(cyclohexylamino)pyr-
was observed, and no trace of the corresponding 1,5-diaryl- azole.
Scheme 3. Synthesis of fused 5-(cycloamino)pyrazoles.
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M. S. Singh, H. Ila et al.
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Scheme 5. Synthesis of substituted/annulated 5-(alkylamino)pyrazoles.
Table 2. Synthesis of substituted/annulated 5-(alkylamino)pyrazoles 9a–l.
der the previously described reaction conditions, afforded pyrazoles was observed, and no trace of 3-(alkylamino)-
only 5-(cyclohexylamino)-3-(4-methoxyphenyl)-1-phenyl- pyrazoles could be isolated from the reaction mixtures.
pyrazole (9a) as a single regioisomer in 68% yield
Attempts at the synthesis of 1,3-diphenyl-5-anilinopyr-
(Schemes 4 and 5, and Table 2, Entry 1). Similarly, the cy- azole by treating β-oxodithioester 1a with aniline and phen-
clocondensation of acyclic β-oxodithioesters 1a, 1b, 1d, and ylhydrazine under conditions similar to those used to form
1f, with primary aliphatic amines such as cyclohexylamine, 5-(cycloamino)pyrazoles yielded only complex mixtures of
n-butylamine, 4-methylbenzylamine, and various aryl- 1,3-(or 5-)-diphenyl-3-(or 5-)anilinopyrazoles together with
hydrazines also proceeded smoothly under these conditions a number of side products. A preliminary study with se-
to furnish the corresponding 1,3-substituted 5-(alkylamino)- lected β-oxodithioesters and various substituted anilines
pyrazoles 9b–e in good to excellent yields (Table 2, En- under different reaction conditions revealed the formation
tries 2–5). The α-substituted β-oxodithioesters 1h and 1j of both β-oxothioanilides and anilino-S,N-acetals along
also followed a similar course to yield the tetrasubstituted with unreacted β-oxodithioesters in some cases, thus com-
5-(alkylamino)pyrazoles 9f and 9g in 80 and 76% yields, plicating further reaction with phenylhydrazine.
respectively (Table 2, Entries 6 and 7). The reaction was
found to be equally facile with aliphatic β-oxodithioesters
1i and 1k to provide 1-aryl-3-methyl/isopropyl-5-(alkyl-
amino)pyrazoles 9h and 9i, respectively, in good yields
Conclusions
(Table 2, Entries 8 and 9). The 3,4-annulated 5-(alkyl-
An efficient, highly regioselective, one-pot, three-compo-
amino)pyrazoles such as 9j–l could also be obtained in ex- nent synthesis of 1-aryl-3,4-substituted-5-(cycloamino)-
cellent yields from the cyclic β-oxodithioesters 6a or 6b un- and -5-(alkylamino)pyrazoles from easily accessible β-oxo-
der identical reaction conditions (Table 2, Entries 10–12). dithioesters under simple and mild reaction conditions has
In all these examples, the formation of only 5-(alkylamino)- been developed. These optimized reaction conditions were
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Eur. J. Org. Chem. 2012, 967–974

Synthesis of Substituted/Annulated Alkylaminopyrazoles
3-(4-Methoxyphenyl)-1-phenyl-5-(4-phenylpiperazino)-1H-pyrazole
either not applicable or not successful for a one-pot, re-
gioselective synthesis of 1,3-substituted 5-(arylamino)pyr-
azoles, and further work towards this goal is in progress
and will be published in due course.
(3d): White crystal; m.p. 175–176 °C. IR (KBr): ν = 3054, 2930,
˜
1
1599, 1561, 1495 cm–1. H NMR (300 MHz, CDCl3): δ = 7.89 (d,
J = 7.8 Hz, 2 H), 7.78 (d, J = 8.7 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 2
H), 7.29–7.25 (m, 3 H), 6.95–6.88 (m, 5 H), 6.18 (s, 1 H), 3.84 (s,
3 H), 3.23 (t, J = 3.9 Hz, 4 H), 3.09 (t, J = 3.9 Hz, 4 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.4, 152.4, 151.1, 150.8, 140.2,
129.1, 128.9, 126.7, 126.5, 126.1, 122.9, 120.2, 116.2, 113.9, 91.4,
55.2, 51.1, 49.0 ppm. ESI-MS: m/z = 410 [M+]. C26H26N4O
(410.52): calcd. C 76.07, H 6.38, N 13.65; found C 75.90, H 6.58,
N 13.88.
Experimental Section
General: All starting materials were commercially available and
used as received without further purification. Thin-layer
chromatography (TLC) was performed by using silica gel 60 F254
precoated plates. Infrared (IR) spectra were measured in KBr discs
with a Varian 3100 FT-IR spectrophotometer, and wavenumbers
3-(4-Chlorophenyl)-5-morpholino-1-phenyl-1H-pyrazole (3e): White
solid; m.p. 137–138 °C. IR (KBr): ν = 3053, 2935, 1596, 1551,
˜
1
1493 cm–1. H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 7.8 Hz,
(ν) are reported in cm–1. NMR spectra were recorded with JEOL
˜
2 H), 7.77 (d, J = 8.1 Hz, 2 H), 7.48–7.25 (m, 5 H), 6.18 (s, 1 H),
3.73 (t, J = 4.2 Hz, 4 H), 2.91 (t, J = 4.5 Hz, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.6, 149.9, 139.9, 133.5, 131.8, 129.0,
128.7, 126.9, 126.7, 123.0, 91.5, 66.4, 51.2 ppm. ESI-MS: m/z (%)
= 339 (100) [M+], 341 (33) [M+ + 2]. C19H18ClN3O (339.82): calcd.
C 67.15, H 5.34, N 12.37; found C 67.38, H 5.21, N 12.25.
AL 300 FT-NMR and 400 FT-NMR spectrometers operating at
300 and 400 MHz. Chemical shifts (δ) are given in parts per million
(ppm) by using the residual solvent peaks as reference relative to
TMS; J values are given in Hz. Mass spectra were recorded by
using electrospray ionization (ESI) mass spectrometry with a
Waters Acquity Ultra Performance LC spectrometer. Elemental
analyses were performed by the microanalytical laboratory.
3-(4-Chlorophenyl)-1-(3-fluorophenyl)-5-(4-phenylpiperazino)-1H-
pyrazole (3f): White solid; m.p. 154–155 °C. IR (KBr): ν = 3058,
˜
General Procedure for the Synthesis of 1,3-Diaryl-(or Alkyl-)-5-ami-
2985, 1592, 1557, 1503 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.80–7.72 (m, 4 H), 7.44–7.37 (m, 3 H), 7.31–7.26 (m, 2 H), 7.03–
6.89 (m, 4 H), 6.24 (s, 1 H), 3.27 (t, J = 3.3 Hz, 4 H), 3.12 (t, J =
3.6 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.0 (d, J
= 240 Hz), 153.0, 150.4, 141.5 (d, J = 7.5 Hz), 134.0, 131.7, 130.4,
130.3, 129.3, 128.9, 126.9, 120.6, 118.2, 116.6, 113.6 (d, J =
15.8 Hz), 110.2 (d, J = 19.1 Hz), 92.5, 51.4, 49.2 ppm. ESI-MS: m/z
(%) = 432 (100) [M+], 434 (34) [M+ + 2]. C25H22ClFN4 (432.93):
calcd. C 69.36, H 5.12, N 12.94; found C 69.10, H 5.31, N 12.71.
no(or cycloamino)pyrazole: To
a solution of β-oxodithioester
(1 mmol) in EtOH (5 mL), the corresponding amine (1.2 mmol)
was added, and the mixture was heated to reflux for 2–3 h (the
reaction was monitored by TLC analysis). After consumption of
the thioester, the reaction mixture was cooled to room temperature,
and phenylhydrazine (1.2 mmol) and a catalytic amount of AcOH
were added to the reaction mixture. The reaction mixture was
heated to reflux for a further 3–5 h until the reaction was complete.
The solvent was evaporated, and water (15 mL) was added to the
reaction mixture. The product was extracted with ethyl acetate
(3ϫ3 mL), and the organic layer was taken and dried with
Na2SO4, concentrated, and the residue was purified by column
chromatography (EtOAc/hexane, 5%).
1-Phenyl-5-(4-phenylpiperazino)-3-(2-thienyl)-1H-pyrazole (3g):
White solid; m.p. 130–131 °C. IR (KBr): ν = 3032, 2943, 1586,
˜
1561, 1501 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J =
7.8 Hz, 2 H), 7.46–7.24 (m, 7 H), 7.05 (t, J = 3.9 Hz, 1 H), 6.93–
6.88 (m, 3 H), 6.15 (s, 1 H), 3.22 (t, J = 4.2 Hz, 4 H), 3.08 (t, J =
4.2 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.4, 151.0,
146.5, 139.9, 136.8, 129.1, 128.9, 127.3, 126.7, 124.6, 123.7, 123.0,
120.2, 116.2, 91.9, 51.0, 48.9 ppm. ESI-MS: m/z = 386 [M+].
1,3-Diphenyl-5-piperidino-1H-pyrazole (3a): Pale-yellow solid; m.p.
80–81 °C. IR (KBr): ν = 3012, 2934, 1609, 1591, 1568, 1490 cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 7.88–7.83 (m, 4 H), 7.54–
7.34 (m, 6 H), 6.47 (s, 1 H), 2.84 (br., 4 H), 1.58 (br., 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 153.9, 150.8, 140.5, 133.5, 128.8,
128.4, 127.6, 126.3, 125.4, 122.6, 91.5, 52.4, 25.5, 23.9 ppm. ESI-
MS: m/z = 303 [M+]. C20H21N3 (303.41): calcd. C 79.17, H 6.98,
N 13.85; found C 79.44, H 6.75, N 13.70.
C
23H22N4S (386.51): calcd. C 71.47, H 5.74, N 14.50; found C
71.75, H 5.51, N 14.28.
1-(4-Chlorophenyl)-5-morpholino-3-(2-thienyl)-1H-pyrazole (3h):
White solid; m.p. 125–126 °C. IR (KBr): ν = 3062, 2923, 1591,
˜
1
1567, 1491 cm–1. H NMR (400 MHz, CDCl3): δ = 7.83–7.82 (m,
1,3-Diphenyl-5-morpholino-1H-pyrazole (3b): Pale-yellow solid;
m.p. 115–116 °C. IR (KBr): ν = 3056, 2932, 1591, 1553, 1491 cm–1.
2 H), 7.42–7.40 (m, 2 H), 7.35–7.34 (m, 1 H), 7.27–7.25 (m, 1 H),
7.06–7.04 (m, 1 H), 6.13 (s, 1 H), 3.76–3.74 (m, 4 H), 2.92–2.90 (m,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.6, 147.0, 138.5,
136.6, 132.4, 129.3, 127.5, 125.0, 124.2, 124.2, 92.4, 66.5, 51.5 ppm.
ESI-MS: m/z (%) = 345 (100) [M+ ], 347 (33) [M+ + 2].
C17H16ClN3OS (345.85): calcd. C 59.04, H 4.66, N 12.15; found C
58.78, H 4.86, N 12.42.
˜
1H NMR (300 MHz, CDCl3): δ = 7.89–7.83 (m, 4 H), 7.48–7.25
(m, 6 H), 6.22 (s, 1 H), 3.74 (t, J = 4.5 Hz, 4 H), 2.93 (t, J = 4.5 Hz,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.4, 151.0, 140.0,
133.2, 129.0, 128.5, 127.8, 126.8, 125.4, 123.0, 91.6, 66.4, 51.3 ppm.
ESI-MS: m/z = 305 [M+]. C19H19N3O (305.38): calcd. C 74.73, H
6.27, N 13.76; found C 74.98, H 6.01, N 13.99.
3-(4-Methoxyphenyl)-1-phenyl-5-piperidino-1H-pyrazole (3c): White
3-(2-Furyl)-1-phenyl-5-(4-phenylpiperazino)-1H-pyrazole (3i): White
solid; m.p. 116–117 °C. IR (KBr): ν = 2993, 2937, 1612, 1592, 1561,
solid; m.p. 136–137 °C. IR (KBr): ν = 3056, 2945, 1590, 1561,
˜
˜
1
1543, 1448 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J =
7.8 Hz, 2 H), 7.77 (d, J = 8.7 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 2 H),
7.25 (s, 1 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.10 (s, 1 H), 3.83 (s, 3 H),
1491 cm–1. H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.8 Hz,
2 H), 7.46–7.40 (m, 3 H), 7.32–7.25 (m, 3 H), 6.93–6.86 (m, 3 H),
6.71 (d, J = 3.3 Hz, 1 H), 6.46 (t, J = 1.8 Hz, 1 H), 6.18 (s, 1 H),
2.86 (t, J = 5.4 Hz, 4 H), 1.61–1.54 (m, 6 H) ppm. 13C NMR 3.22 (t, J = 4.8 Hz, 4 H), 3.07 (t, J = 4.8 Hz, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.3, 153.8, 150.6, 140.6, 128.7, 126.7, (75 MHz, CDCl3): δ = 152.2, 151.0, 148.7, 143.7, 141.9, 139.9,
126.4, 126.1, 122.5, 113.8, 91.1, 55.2, 52.4, 25.5, 23.9 ppm. ESI-
MS: m/z = 333 [M+]. C21H23N3O (333.43): calcd. C 75.65, H 6.95,
N 12.60; found C 75.42, H 7.20, N 12.77.
129.1, 128.9, 126.9, 123.1, 120.2, 116.3, 111.2, 105.9, 91.6, 51.0,
48.9 ppm. ESI-MS: m/z = 370 [M+]. C23H22N4O (370.45): calcd. C
74.57, H 5.99, N 15.12; found C 74.85, H 5.73, N 14.88.
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971

M. S. Singh, H. Ila et al.
FULL PAPER
Ethyl 4-[1-(2,4-Dichlorophenyl)-3-(N-methyl-1H-pyrrol-3-yl)-1H- 108.5, 63.1, 53.2, 50.7, 29.4, 19.9 ppm. ESI-MS: m/z (%) = 454
pyrazol-5-yl]piperazine-1-carboxylate (3j): Yellowish viscous liquid.
(100) [M+], 456 (34) [M+ + 2]. C28H27ClN4 (455.00): calcd. C 73.91,
H 5.98, N 12.31; found C 73.59, H 6.22, N 12.58.
1
IR (neat): ν = 2987, 1701, 1594, 1550 cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 7.52 (s, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.33 (d, J =
8.4 Hz, 1 H), 7.00 (s, 1 H), 6.58 (s, 1 H), 6.44 (s, 1 H), 5.96 (s, 1
H), 4.11 (q, J = 7.2 Hz, 2 H), 3.65 (s, 3 H), 3.39 (br., 4 H), 2.82
(br., 4 H), 1.23 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.3, 152.9, 148.9, 136.0, 134.7, 133.2, 130.4, 130.2,
127.7, 122.2, 119.2, 117.5, 106.5, 91.4, 61.4, 50.9, 43.3, 36.1,
14.5 ppm. ESI-MS: m/z (%) = 447 (100) [M+], 449 (66) [M+ + 2].
C21H23Cl2N5O2 (448.35): calcd. C 56.26, H 5.17, N 15.62; found C
56.09, H 5.45, N 15.91.
Ethyl 4-[2-(2,4-Dichlorophenyl)-4,5-dihydro-2H-benzo[g]indazol-3-
yl]piperazine-1-carboxylate (5b): Brown solid; m.p. 129–130 °C. IR
(KBr): ν = 3029, 2932, 1697 (CO), 1588, 1551, 1497 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.85 (d, J = 6.3 Hz, 1 H), 7.53 (s, 1 H),
7.43–7.34 (m, 2 H), 7.25–7.22 (m, 3 H), 4.12 (q, J = 7.2 Hz, 2 H),
3.34 (br., 4 H), 2.97–2.87 (m, 8 H), 1.24 (t, J = 6.9 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.3 (CO), 149.2, 146.5, 136.3,
136.2, 134.9, 133.4, 130.5, 129.9, 129.3, 128.1, 127.8, 127.6, 126.7,
122.1, 107.7, 61.4, 50.5, 44.0, 29.2, 19.3, 14.5 ppm. ESI-MS: m/z
(%) = 470 (100) [M+], 472 (67) [M+ + 2]. C24H24Cl2N4O2 (471.39):
calcd. C 61.15, H 5.13, N 11.89; found C 61.38, H 4.88, N 11.66.
1-(4-Chlorophenyl)-5-morpholino-3-(3-pyridyl)-1H-pyrazole (3k):
White solid; m.p. 145–146 °C. IR (KBr): ν = 3057, 2934, 1600,
˜
1555, 1487 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.0 (s, 1 H),
8.55 (d, J = 0.9 Hz, 1 H), 8.16–8.13 (m, 1 H), 7.86–7.83 (m, 2 H),
7.46–7.43 (m, 2 H), 7.34–7.31 (m, 1 H), 6.25 (s, 1 H), 3.78–3.75 (m,
4 H), 2.95–2.93 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
153.0, 149.1, 148.6, 147.1, 138.5, 132.9, 132.8, 129.4, 124.3, 123.7,
92.2, 66.5. 51.6 ppm. ESI-MS: m/z (%) = 340 (100) [M+], 342 (33)
[M+ + 2]. C18H17ClN4O (340.81): calcd. C 63.44, H 5.03, N 16.44;
found C 63.71, H 4.82, N 16.20.
2-(3-Fluorophenyl)-3-(4-phenylpiperazin-1-yl)-4,5,6,7-tetrahydro-
2H-indazole (7a): Red viscous liquid. IR (neat): ν = 3066, 2924,
˜
1
1589, 1488 cm–1. H NMR (400 MHz, CDCl3): δ = 7.62–7.57 (m,
2 H), 7.36–7.27 (m, 3 H), 6.95–6.87 (m, 4 H), 3.24–3.20 (m, 8 H),
2.74–2.67 (m, 4 H), 1.84–1.76 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 162.7 (d, J = 195.0 Hz), 150.5, 145.5, 141.6 (d, J =
7.7 Hz), 129.9, 129.8, 118.7, 118.6, 116.6, 113.0, 112.8, 110.5 (d, J
= 22.5 Hz), 109.5, 50.6, 49.9, 24.2, 23.6, 23.1, 21.8 ppm. ESI-MS:
m/z = 376 [M+]. C23H25FN4 (376.48): calcd. C 73.38, H 6.69, N
14.88; found C 73.63, H 6.41, N 15.11.
5-(4-Benzylpiperazino)-4-methyl-1,3-diphenyl-1H-pyrazole (3l):
White solid; m.p. 137–138 °C. IR (KBr): ν = 3045, 2933, 2818,
˜
1592, 1564, 1491 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71–7.65
(m, 4 H), 7.44–7.38 (m, 4 H), 7.32–7.25 (m, 7 H), 3.52 (s, 2 H),
3.16 (br., 4 H), 2.45 (br., 4 H), 2.27 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 150.7, 147.4, 139.8, 139.2, 134.0, 129.2,
128.5, 128.3, 128.2, 127.8, 127.4, 127.2, 126.6, 124.3, 107.6, 63.1,
53.4, 50.0, 9.8 ppm. ESI-MS: m/z = 408 [M+]. C27H28N4 (408.55):
calcd. C 79.38, H 6.91, N 13.71; found C 79.07, H 7.16, N 13.95.
5-(Cyclohexylamino)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole
(9a): Yellowish solid; m.p. 104–105 °C. IR (KBr): ν = 3442 (NH),
˜
3231, 3060, 2925, 1559, 1508, 1490 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.76 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 7.5 Hz, 2 H),
7.47 (t, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 6.91 (d, J =
8.7 Hz, 2 H), 5.78 (s, 1 H), 4.39 (s, 1 H), 3.83 (s, 3 H), 3.17 (br., 1
H, NH), 2.09–2.06 (m, 3 H), 1.76–1.72 (m, 2 H), 1.42–1.17 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.3, 151.4, 147.9,
138.8, 129.5, 127.1, 126.8, 126.4, 124.3, 113.7, 84.6, 55.2, 54.4, 33.3,
25.7, 24.8 ppm. ESI-MS: m/z = 347 [M+]. C22H25N3O (347.46):
calcd. C 76.05, H 7.25, N 12.09; found C 76.30, H 7.01, N 11.78.
Ethyl 4-[2-(3-Fluorophenyl)-4-methyl-5-phenyl-2H-pyrazol-3-yl]-
piperazine-1-carboxylate (3m): White solid; m.p. 112–113 °C. IR
(KBr): ν = 3023, 2930, 1697 (CO), 1590, 1570, 1493 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.64 (d, J = 7.2 Hz, 2 H), 7.56–7.49 (m, 2
H), 7.44–7.34 (m, 4 H), 7.00 (t, J = 7.8 Hz, 1 H), 4.15 (q, J =
6.9 Hz, 2 H), 3.52 (br., 4 H), 3.13 (br., 4 H), 2.25 (s, 3 H), 1.26 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.1 (d,
J = 243.0 Hz), 155.4 (CO), 151.3, 147.0, 141.0 (d, J = 10.2 Hz),
133.5, 129.8 (d, J = 8.6 Hz), 128.4, 127.8, 127.7, 119.4, 113.7 (d, J
= 21 Hz), 111.5 (d, J = 25.3 Hz), 108.5, 61.5, 50.1, 44.1, 14.6,
9.7 ppm. ESI-MS: m/z = 408 [M+]. C23H25FN4O2 (408.47): calcd.
C 67.63, H 6.17, N 13.72; found C 67.87, H 6.01, N 13.41.
5-(Cyclohexylamino)-1-(2,4-dichlorophenyl)-3-phenyl-1H-pyrazole
(9b): Yellowish solid; m.p. 101–102 °C. IR (KBr): ν = 3451 (NH),
˜
3224, 3061, 2930, 1565, 1517, 1485 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.82–7.79 (m, 2 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.49 (d,
J = 8.7 Hz, 1 H), 7.41 (t, J = 2.1 Hz, 1 H), 7.37–7.29 (m, 3 H),
5.83 (s, 1 H), 3.19 (br., 2 H, NH), 2.08 (m, 2 H), 1.76–1.71 (m, 2
H), 1.37–1.25 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
152.5, 149.1, 135.6, 134.6, 133.3, 133.2, 131.4, 130.3, 128.4, 128.3,
127.8, 125.6, 84.2, 54.5, 33.3, 25.6, 24.8 ppm. ESI-MS: m/z (%) =
385 (100) [M+], 387 (66) [M+ + 2]. C21H21Cl2N3 (386.32): calcd. C
65.29, H 5.48, N 10.88; found C 65.01, H 5.70, N 11.15.
1-(3-Fluorophenyl)-3-(1-methylethyl)-5-(4-phenylpiperazino)-1H-pyr-
azole (3n): White solid; m.p. 83–84 °C. IR (KBr): ν = 3034, 2926,
˜
1597, 1560, 1491 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.69–7.63
(m, 2 H), 7.38–7.25 (m, 3 H), 6.95–6.86 (m, 4 H), 5.77 (s, 1 H),
3.24 (t, J = 4.5 Hz, 4 H), 3.06 (t, J = 4.5 Hz, 4 H), 3.00–2.91 (m,
1 H), 1.28 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 162.8 (d, J = 244.2 Hz), 159.5, 151.8, 150.7, 141.5 (d, J =
9.8 Hz), 129.9 (d, J = 8.6 Hz), 129.0, 120.2, 117.6 (d, J = 3.0 Hz),
116.2, 112.6 (d, J = 21 Hz), 109.6 (d, J = 25.3 Hz), 91.8, 51.1, 48.9,
28.2, 22.5 ppm. ESI-MS: m/z = 364 [M+]. C22H25FN4 (364.46):
calcd. C 72.50, H 6.91, N 15.37; found C 72.82, H 6.62, N 15.21.
1-(3-Fluorophenyl)-3-(4-methoxyphenyl)-5-[(4-methylbenzyl)-
amino)]-1H-pyrazole (9c): White solid; m.p. 132–133 °C. IR (KBr):
ν = 3441 (NH), 3281, 2926, 1598, 1565, 1492 cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 7.73 (d, J = 8.4 Hz, 2 H), 7.43–7.39 (m, 3
H), 7.28–7.25 (m, 2 H), 7.16 (d, J = 7.8 Hz, 2 H), 7.00 (t, J =
6.9 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2 H), 5.83 (s, 1 H), 4.30 (d, J =
5.7 Hz, 2 H), 4.08 (br., 1 H, NH), 3.83 (s, 3 H), 2.35 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 163.0 (d, J = 247.0 Hz), 159.5,
151.7, 148.8, 140.3 (d, J = 9.9 Hz), 137.3, 135.0, 130.7 (d, J =
38.4 Hz), 129.4, 127.5, 126.8, 126.0, 118.8 (d, J = 3.0 Hz), 113.9,
113.6 (d, J = 14.2 Hz), 111.2 (d, J = 24.7 Hz), 85.7, 55.2, 49.9,
21.0 ppm. ESI-MS: m/z = 387 [M+]. C24H22FN3O (387.46): calcd.
C 74.40, H 5.72, N 10.85; found C 74.14, H 5.94, N 11.11.
3-(4-Benzylpiperazino)-2-(4-chlorophenyl)-4,5-dihydro-2H-benzo-
[g]indazole (5a): White solid; m.p. 156–157 °C. IR (KBr): ν = 3028,
˜
2933, 2818, 1592, 1564, 1491 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.88 (d, J = 6.9 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 2 H), 7.38 (d, J
= 8.7 Hz, 2 H), 7.32–7.31 (m, 3 H), 7.27–7.19 (m, 5 H), 3.52 (s, 2
H), 3.10 (br., 4 H), 2.93 (br., 4 H), 2.47 (br., 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.3, 145.7, 138.7, 137.7, 136.4, 131.7, 5-(Butylamino)-1-(2,4-dichlorophenyl)-3-(2-thienyl)-1H-pyrazole
129.5, 129.1, 128.7, 128.2, 128.0, 127.7, 127.2, 126.7, 124.6, 122.1, (9d): Pale-yellow solid; m.p. 129–130 °C. IR (KBr): ν = 3392 (NH),
˜
972
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 967–974

Synthesis of Substituted/Annulated Alkylaminopyrazoles
3031, 2931, 1591, 1556, 1492 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.54 (d, J = 2.1 Hz, 1 H), 7.46–7.36 (m, 3 H), 6.67 (d, J =
3.0 Hz, 1 H), 6.45 (s, 1 H), 5.77 (s, 1 H), 3.32 (br., 1 H, NH), 3.14
(q, J = 6.6 Hz, 2 H), 1.62–1.52 (m, 2 H), 1.40 (q, J = 7.8 Hz, 2 H),
0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
149.9, 148.7, 145.0, 141.7, 135.8, 134.3, 133.2, 131.4, 130.2, 128.3,
111.2, 106.0, 83.7, 45.5, 31.4, 20.0, 13.7 ppm. ESI-MS: m/z (%) =
365 (100) [M+], 367 (67) [M+ + 2]. C17H17Cl2N3S (366.31): calcd.
C 55.74, H 4.68, N 11.47; found C 55.44, H 4.91, N 11.72.
+ 2]. C17H16ClN3 (297.79): calcd. C 68.57, H 5.42, N 14.11; found
C 68.85, H 5.18, N 13.87.
3-(Benzylamino)-2-phenyl-4,5-dihydro-2H-benzo[g]indazole (9j):
Pale-yellow solid; m.p. 69–70 °C. IR (KBr): ν = 3445 (NH), 3294,
˜
2930, 1585, 1561, 1483 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.89 (d, J = 7.2 Hz, 1 H), 7.56 (d, J = 7.5 Hz, 2 H), 7.45 (t, J =
7.5 Hz, 2 H), 7.35–7.19 (m, 9 H), 4.29 (s, 2 H), 3.78 (br., 1 H, NH),
2.91 (t, J = 6.9 Hz, 2 H), 2.72 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.4, 142.5, 139.1, 139.1, 136.7, 129.9,
129.4, 128.6, 128.0, 127.5, 127.4, 127.3, 126.6, 124.7, 122.3, 101.7,
50.8, 29.7, 19.3 ppm. ESI-MS: m/z = 351 [M+]. C24H21N3 (351.45):
calcd. C 82.02, H 6.02, N 11.96; found C 81.72, H 6.28, N 12.20.
1-(3-Fluorophenyl)-5-[(4-methylbenzyl)amino]-3-(N-methylpyrrol-3-
yl)-1H-pyrazole (9e): White solid; m.p. 92–93 °C. IR (KBr): ν =
˜
3437 (NH), 3298, 2924, 1598, 1565, 1496 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.40–7.38 (m, 3 H), 7.27–7.25 (m, 2 H),
7.15 (d, J = 7.8 Hz, 2 H), 6.99–6.96 (m, 2 H), 6.58 (s, 1 H), 6.45
(s, 1 H), 5.66 (s, 1 H), 4.27 (d, J = 5.4 Hz, 2 H), 4.02 (br., 1 H,
NH), 3.66 (s, 3 H), 2.34 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.0 (d, J = 240.0 Hz), 148.8, 148.3, 140.5 (d, J = 10.5 Hz),
137.2, 135.1, 130.5 (d, J = 7.9 Hz), 129.3, 127.5, 122.1, 119.3, 118.8
(d, J = 12.3 Hz), 117.7, 113.3 (d, J = 21.0 Hz), 111.1 (d, J =
24.1 Hz), 106.7, 86.0, 49.9, 36.2, 21.0 ppm. ESI-MS: m/z = 360
[M+]. C22H21FN4 (360.43): calcd. C 73.31, H 5.87, N 15.54; found
C 73.55, H 5.73, N 15.39.
2-(3-Fluorophenyl)-3-[(4-methylbenzyl)amino]-4,5,6,7-tetrahydro-
2H-indazole (9k): Yellowish viscous liquid. IR (neat): ν = 3441
˜
(NH), 3293, 2853, 1586, 1567, 1480 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.34–7.30 (m, 3 H), 7.10–6.95 (m, 5 H), 4.17 (s, 2 H),
3.62 (br., 1 H, NH), 2.65 (t, J = 5.4 Hz, 2 H), 2.46 (t, J = 5.7 Hz,
2 H), 2.32 (s, 3 H), 1.75 (br., 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 162.8 (d, J = 244.7 Hz), 150.6, 142.8, 140.8 (d, J =
9.9 Hz), 137.2, 136.0, 130.2 (d, J = 8.6 Hz), 129.2, 127.4, 118.9 (d,
J = 3.1 Hz), 113.3 (d, J = 21.0 Hz), 111.0 (d, J = 24.0 Hz), 102.6,
50.4, 23.8, 23.4, 23.0, 21.0, 20.7 ppm. ESI-MS: m/z = 335 [M+].
C21H22FN3 (335.42): calcd. C 75.20, H 6.61, N 12.53; found C
75.41, H 6.43, N 12.39.
5-(Benzylamino)-1-(4-chlorophenyl)-4-methyl-3-phenyl-1H-pyrazole
(9f): Yellowish viscous liquid. IR (neat): ν = 3474 (NH), 3281, 2926,
˜
1584, 1563, 1492 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.70–7.65
(m, 4 H), 7.44–7.38 (m, 4 H), 7.35–7.24 (m, 4 H), 7.17 (d, J =
7.5 Hz, 2 H), 4.02 (d, J = 5.4 Hz, 2 H), 3.41 (br., 1 H), 2.07 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.7, 144.8, 138.6,
138.0, 133.8, 132.3, 129.1, 128.5, 128.3, 127.8, 127.5, 127.5, 124.9,
103.7, 52.3, 9.0 ppm. ESI-MS: m/z (%) = 373 (100) [M+], 375 (33)
[M+ + 2]. C23H20ClN3 (373.88): calcd. C 73.89, H 5.39, N 11.24;
found C 74.09, H 5.23, N 11.13.
3-(Butylamino)-2-(3-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole
(9l): Yellowish viscous liquid. IR (neat): ν = 3451 (NH), 3032, 2931,
˜
1588, 1558, 1492 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.39–7.32
(m, 3 H), 6.96 (q, J = 6.6 Hz, 1 H), 3.36 (br., 1 H, NH), 3.08 (t, J
= 6.9 Hz, 2 H), 2.65 (t, J = 5.4 Hz, 2 H), 2.54 (t, J = 6.0 Hz, 2 H),
1.79–1.77 (m, 4 H), 1.52–1.42 (m, 2 H), 1.35–1.25 (m, 2 H), 0.89
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.9
(d, J = 244.8 Hz), 150.7, 143.3, 140.9 (d, J = 10.5 Hz), 130.2 (d, J
= 9.2 Hz), 118.9 (d, J = 3.0 Hz), 113.2 (d, J = 21.0 Hz), 111.0 (d,
J = 24.1 Hz), 101.7, 46.1, 32.7, 23.8, 23.5, 23.1, 20.9, 19.8,
13.7 ppm. ESI-MS: m/z = 287 [M+]. C17H22FN3 (287.38): calcd. C
71.05, H 7.72, N 14.62; found C 70.21, H 7.54, N 14.86.
5-(Cyclohexylamino)-1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrazole
(9g): White solid; m.p. 113–114 °C. IR (KBr): ν = 3461 (NH), 3034,
˜
2918, 1598, 1550, 1492 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.69 (t, J = 7.8 Hz, 2 H), 7.49–7.22 (m, 11 H), 7.01 (t, J = 7.8 Hz,
1 H), 3.52 (br., 1 H, NH), 2.62 (s, 1 H), 1.72–1.38 (m, 5 H), 0.95–
0.84 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.8 (d, J
= 244.8 Hz), 149.4, 145.0, 141.3 (d, J = 14.0 Hz), 133.1 (d, J =
6.8 Hz), 130.2, 130.1, 128.7, 128.0, 127.7, 127.5, 126.9, 118.7 (d, J
= 12.3 Hz), 113.5 (d, J = 21.0 Hz), 110.9, 110.5, 110.1, 55.3, 33.6,
25.3, 24.6 ppm. ESI-MS: m/z = 411 [M+]. C27H26FN3 (411.52):
calcd. C 78.80, H 6.37, N 10.21; found C 79.14, H 6.01, N 10.02.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedure, analytical and spectroscopic data
of compounds 3, 5, and 9.
Acknowledgments
We gratefully acknowledge generous fiancial support from the
Council of Scientific and Industrial Research (CSIR) and the De-
partment of Science and Technology, New Delhi. G. C. N. is thank-
ful to the CSIR for financial support in the form of a Senior Re-
search Fellowship (SRF).
5-(Benzylamino)-1-(2,4-dichlorophenyl)-3-(1-methylethyl)pyrazole
(9h): White solid; m.p. 65–67 °C. IR (KBr): ν = 3451 (NH), 3280,
˜
2991, 1591, 1559, 1498 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.49 (d, J = 2.1 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.34–7.26 (m,
6 H), 5.40 (s, 1 H), 4.26 (d, J = 5.7 Hz, 2 H), 3.59 (br., 1 H, NH),
2.93–2.89 (m, 1 H), 1.26 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.6, 149.2, 138.2, 135.2, 134.7, 133.1,
131.1, 130.2, 128.8, 128.6, 128.1, 127.5, 84.4, 50.0, 28.3, 22.6 ppm.
ESI-MS: m/z (%) = 359 (100) [M+], 361 (67) [M+ + 2]. C19H19Cl2N3
(360.29): calcd. C 63.34, H 5.32, N 11.66; found C 63.69, H 5.08,
N 11.43.
[1] For recent reviews, see: a) J. Elguero in Comprehensive Hetero-
cyclic Chemistry II (Eds.: A. R. Katritzky, C. W. Rees, E. F. V.
Scriven), Pergamon Press, Oxford, 1996, vol. 3, pp. 1; b) M.
Sutharchanadevi, R. Murugan, in Comprehensive Heterocyclic
Chemistry II (Eds.: A. R. Katritzky, C. W. Rees, E. F. V.
Scriven), Pergamon Press, Oxford, 1996, vol. 6, pp. 221; c) C.
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5-(Benzylamino)-1-(4-chlorophenyl)-3-methyl-1H-pyrazole (9i):
White solid; m.p. 76–77 °C. IR (KBr): ν = 3482 (NH), 3290, 2926,
˜
1584, 1563, 1491 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.51–7.33
(m, 9 H), 5.38 (s, 1 H), 4.25 (d, J = 5.1 Hz, 2 H), 3.97 (br., 1 H,
NH), 2.22 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.8,
148.3, 138.1, 137.3, 132.3, 129.5, 128.7, 127.6, 127.4, 124.9, 88.7,
50.1, 13.9 ppm. ESI-MS: m/z (%) = 297 (100) [M+], 299 (34) [M+
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Received: September 24, 2011
Published Online: December 8, 2011
974
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 967–974