Regioselective rapid analog synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/ heteroaryl-5-(or 3-)(methylthio)pyrazoles via Suzuki cross-coupling

Article abstract of DOI:10.1016/j.tet.2011.02.043

Regioselective routes for the synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/ heteroaryl-5-(or 3-)(methylthio)pyrazoles via Suzuki cross-coupling of 4-bromo (or 4-iodo)-1,3-(or 1,5-)diphenyl-5-(or 3-)(methylthio)pyrazoles have been reported.

Full text of DOI:10.1016/j.tet.2011.02.043

Tetrahedron 67 (2011) 2961e2968
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective rapid analog synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/heteroaryl-
5-(or 3-)(methylthio)pyrazoles via Suzuki cross-coupling
,
Taukeer A. Khan a, Sarvesh Kumar a, Chelvam Venkatesh a, Hiriyakkanavar Ila b
*
a Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
b New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 January 2011
Received in revised form 15 February 2011
Accepted 15 February 2011
Available online 22 February 2011
Regioselective routes for the synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/heteroaryl-5-(or 3-)(methylthio)-
pyrazoles via Suzuki cross-coupling of 4-bromo (or 4-iodo)-1,3-(or 1,5-)diphenyl-5-(or 3-)(methylthio)-
pyrazoles have been reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Halogenation
Regioselective
Pyrazole
Suzuki coupling
1. Introduction
these de novo approaches, each method has its scope and efficiency
limitations.14b,15 Since subtle variation and combination of aryla-
Substituted pyrazoles, though rarely found in nature, serve as
important targets in medicinal chemistry and pharmaceutical in-
dustry because the pyrazole motif constitutes the core structure of
numerous biologically active compounds1 including block buster
drugs, such as celebrex,2 viagra,3 and acomplia. Numerous 1,3,5- and
1,3,4,5-substitued pyrazoles are being developed in a wide range of
therapeutical areas including anti-inflammatory,4 anticancer,5 anti-
bacterial,6 analgesic,7 CNS-,8 endothelin-antagonists9 as well as in
agrochemistry to obtain herbicides10 and pesticides.11 As a result,
there is continuing interest in the development of versatile methods
to access highly substituted pyrazoles.12
While there are many novel methods available for the assembly
of substituted pyrazoles, perhaps the most commonly used and
convenient method remains the condensation of 1,3-dicarbonyl
compounds or their equivalents with a hydrazine derivative (Knorr
reaction).1 However, this route often suffers major drawback of
poor regioselectivity during ring annulation yielding inseparable
mixture of isomeric pyrazoles.13 Another important method in-
volving 1,3-dipolar cycloaddition of diazoalkanes or nitrileimines
with olefins and alkynes has found only limited application because
1,3-dipoles are often difficult to prepare and potentially explosive.14
Although recent efforts have greatly expanded the generality of
tion pattern on the pyrazole motif has profound effect on the bi-
ological activity,2,5b,16 efficient and simple protocols by which the
pyrazole ring could be elaborated in a regiocontrolled fashion to
polysubstituted pyrazoles at a later stage of the reaction sequence
are highly desirable.
We have recently reported an efficient general regiocontrolled
synthesis of 1-aryl-3,4- or 4,5-substitued 5-(or 3-)(methylthio)pyr-
azoles by cyclocondensation of aryl hydrazines with either
a-oxoke-
tene dithioacetals or
b
-oxodithioesters, respectively (Scheme 1).17
R1
R1
N
H
ArNHNH2/KOt-Bu/t-BuOH
O
SMe
N
Ar
MeS SMe
80-90 °C/12 h
1
2
, 51-96%
MeS
SMe
S
ArNHNH2
R1
N
N
EtOH/Δ/ 5h
O
R1
Ar
3
4
, 45-88%
1-4, R1 = substituted aryl, alkyl, 3-pyridyl, CH(OMe)2
2, 4, Ar = C6H5, 4-FC6H4
* Corresponding author. Tel.: þ91 80 2208 2714; fax: þ91 80 2208 2766; e-mail
Scheme 1.
address: hila@jncasr.ac.in (H. Ila).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.043

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T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
The 5-(or 3)(methylthio) functionality in these isomeric pyrazoles
could befurtherelaborated for regioselective introduction of5-(or 3-)
aryl/alkyl groups by nickel-catalyzed cross-coupling with the ap-
propriate Grignard reagents. The methodology was also applied for
the regioselective synthesis of 4-ethyl-1,3,5-triarylpyrazoles as es-
trogen receptor ligands.17 With a number of isomeric 1,3-(or 1,5-)
diaryl-5-(or 3-)(methylthio)pyrazoles in hand from readily accessible
precursors, we further envisaged of introducing more diversity in
these trisubstituted pyrazoles by installinga 4-aryl/heteroaryl moiety
thus leading to the regiospecific synthesis of isomeric tetrasub-
stituted pyrazoles. We choose to investigate transition metal catalysis
for introduction of a 4-aryl/heteroaryl group into these fully assem-
bled trisubstituted pyrazoles. Of particular interest was Suzuki cross-
coupling reaction,18 as it is well established dependable process,
widely used in pharmaceutical industry19 utilizing commercially
available boronic acids as the organometallic coupling partners. This
reaction is also unaffected by the presence of water and is compatible
with broad range offunctional groups onbothpartners. Ourliterature
survey revealed that there have been few reports of Suzuki cross-
couplingreactionsperformedon N-aryl/alkylmonoanddisubstituted
halopyrazoles.20,21 Also, there have been few reports of Suzuki cross-
coupling accomplished with pyrazole triflates,22 nonaflates23 as well
as pyrazole boronic acid derivatves.24,25
involved using PdCl2(PPh3)2 as Pd(0) catalyst in the presence of
Na2CO3 as base in DME/H2O solvent, which gave 7a (from 5a) in
modest yield (52%). However, efficient cross-coupling (with 5a)
could be accomplished by switching over to Pd(PPh3)4 (10 mol %) as
palladium source, Na2CO3 (5 equiv) as base, and toluene/ethanol/
water solvent under reflux, which afforded 7a in 80% yield (Table 1,
Table 1
Synthesis of 4-aryl/heteroaryl-5-(methylthio)-1,3-diphenylpyrazoles 7
Ph
Ph
R
X
Pd(PPh3)4 (10 mol%)
N
N
SMe
SMe
N
Ph
N
Ph
RB(OH)2/aq. Na2CO3
PhMe/EtOH/90-120 °C/10-12 h
5a-b
7a-j
Entry
5
Boronic acid
7
Yield 7 (%)
X
Ph
X
B(OH)2
N
SMe
N
Ph
1
2
3
5a
5b
5b
11a, X¼H
11b, X¼OMe
11c, X¼MeCO
7a, X¼H
80 (83)a
75
51
In the present paper, we wish to highlight the results of our in-
vestigation on synthetic elaboration of regioisomeric 1,3-diphenyl-
5-(methylthio) and 1,5-diphenyl-3-(methylthio)pyrazoles to novel
unsymmetrically tetrasubstituted 5- or 3-(methylthio)pyrazoles via
Suzuki cross-coupling in highly regiocontrolled fashion. Reductive
dethiomethylation of few of these newly synthesized (methylthio)
pyrazoles to the corresponding 1,3,4- or 1,4,5-triaryl/heteroaryl
pyrazoles with Raney nickel is also described.
7b, X¼OMe
7c, X¼MeCO
Ph
X
B(OH)2
X
N
SMe
N
Ph
4
5
5a
5a
11d, X¼S
11e, X¼O
7d, X¼S
7e, X¼O
50
30 (70)b
2. Results and discussion
N
Ph
B(OH)2
N
The isomeric 1,3-diphenyl-5-(methylthio) and 1,5-diphenyl-3-
(methylthio)pyrazoles 2a and 4a were selected as the corre-
sponding partners for their further elaboration at 4-position by
Suzuki coupling with various boronic acids (Scheme 2). The pyr-
azoles 2a (R1¼Ph) and 4a (R1¼Ph) were prepared by our earlier
N
SMe
N
Ph
6
7
8
9
5b
5a
5a
5b
5b
11f
7f
0 (0)b
N Me
reported17 procedure from the corresponding
a
-oxoketene
(HO)2B
dithioacetal 1 (R1¼Ph) or
b
-oxodithioester 3 (R1¼Ph) by treatment
Ph
N
with phenyl hydrazine under different reaction conditions as out-
lined in the Scheme 1. The desired 4-halopyrazole cross-coupling
templates (5 and 6) were generated from 2a and 4a by treatment
with either NBS or iodine mono chloride furnishing the isomeric 4-
bromo (or 4-iodo) 1,3- (or 1,5-)diphenyl-5-(or 3-)(methylthio)pyr-
azoles 5a,b and 6a,b in excellent yields (Scheme 2).
N
Me
SMe
N
Ph
11g
B(OH)2
7g
60
SO2Ph
N
Ph
N
Pyrazoles 5a,b were chosen to define optimal reaction condi-
tions for their 4-arylation with phenyl boronic acid 11a under
standard Suzuki cross-coupling reaction conditions. Initial studies
N
SMe
SO2Ph
N
Ph
11h
7h
52
Ph
Ph
X
a or b
Ph
O
B(OH)2
B(OH)2
N
N
SMe
SMe
N
N
O
N
N
SMe
Ph
Ph
N
Ph
5a
, X = Br, 98%
, X = I, 98%
2a
5b
11i
7i
68
MeS
MeS
X
a or b
N
Ph
N
N
Ph
Ph
N
N
Ph
Ph
N
SMe
N
4a
6a, X =Br, 92%
Ph
6b
, X =I, 90%
10
11j
7j
70
a
Yield of 7a with 5b.
a: NBS/CCl4/rt/1 h; b: ICl/NaOAc/AcOH/rt/1 h
b
Reaction condition: Pd(OAc)2 (4 mol %)/S-Phos (10 mol %)/K3PO4 (2 equiv)/tol-
uene/reflux/36 h.
Scheme 2.

T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
2963
entry 1).26 These optimized reaction conditions were applied
throughout our studies (with one exception) to further probe the
scope of this cross-coupling reaction with various aryl/heteroaryl
boronic acids and the results are demonstrated in Table 1. Thus
these reactions were found to be compatible with electron rich
(4-methoxyphenyl)boronic acid 11b to give 4-(4-methoxyphenyl)
pyrazole 7b in 75% yield (entry 2). However, the coupling of the
boronic acid 11c bearing an electron withdrawing 4-acetyl func-
tionality gave only modest yield (51%) of the 4-(4-acetylphenyl)
pyrazole 7c under identical conditions (Table 1, entry 3) and no
attempts were made to further optimize the reaction conditions for
improved yield of 7c. Entries 4e10 demonstrate the scope of this
coupling protocol with various heteroaryl boronic acids (Table 1).
Thus, the reaction of the thiophene-2-boronic acid with 5a under
the above described conditions provided 4-(2-thienyl)pyrazole 7d
in 50% yield (entry 4, see Fig. 1 for X-ray diagram of 7d27). However,
these reaction conditions were not compatible for cross-coupling of
2-furyl and 3-pyridyl boronic acids 11e,f with either 5a or 5b
resulting in low yield (30%) of the pyrazole 7e (entry 5), while no
trace of the 4-(3-pyridyl)pyrazole 7f could be isolated from the
reaction mixture under these conditions furnishing only unreacted
starting materials 11f and 5b (entry 6). Nevertheless, switching
over to electron rich bulky ligand S-Phos (2-dicyclohex-
ylphosphino-20,60-dimethoxybiphenyl), Pd(OAc)2 (4 mol %) as pal-
ladium source and K3PO4 (2 equiv) as base dramatically improved
the yield of 7e (70%) (entry 5), whereas the 4-(3-pyridyl)pyrazole 7f
could not also be obtained under these modified conditions even in
low yield (entry 6).
reaction with various aryl/heteroaryl boronic acids 11aej. These
results are highlighted in Table 2. Thus, reasonably good yields of
4-aryl-1,5-diphenyl-3-(methylthio)pyrazoles 8aec were obtained
when 6a or 6b were subjected to cross-coupling with aryl boronic
acids 11aec under our earlier optimized conditions (Table 2, entries
1e3). Interestingly, the coupling reaction of 6b also proceeded
smoothly with 2-thienyl and 3-pyridyl boronic acids 11d and 11f
Table 2
Synthesis of 3-methylthio-4-aryl/heteroaryl-1,5-diphenylpyrazoles 8
MeS
MeS
X
R
Pd(PPh3)4 (10 mol%)
N
N
Ph
Ph
N
Ph
N
Ph
RB(OH)2/aq. Na2CO3
PhMe/EtOH/90-120 °C/10-12 h
6a-b
8a-j
Entry
6
Boronic acid
8
Yield 8 (%)
X
MeS
X
B(OH)2
N
Ph
N
Ph
1
2
3
6a
6b
6b
11a, X¼H
11b, X¼OMe
11c, X¼MeCO
8a, X¼H
78 (83)a
84
68
8b, X¼OMe
8c, X¼MeCO
MeS
X
B(OH)2
X
N
Ph
N
Ph
4
5
6b
6a
11d, X¼S
11e, X¼O
8d, X¼S
8e, X¼O
62
63b
N
MeS
B(OH)2
N
N
Ph
N
Ph
6
7
8
9
6b
6b
6a
11f
8f
62
72
55
N Me
(HO)2B
MeS
N
N
Me
Ph
Ph
8g
N
11g
B(OH)2
SO2Ph
N
MeS
N
Fig. 1. ORTEP diagram of 7d.
N
Ph
SO2Ph
N
Ph
11h
8h
Additional structural diversity at the 4-position of the pyrazole
5a,b could be introduced by their cross-coupling with boronic acids
11gej derived from benzoheterocycles (entries 7e10). Thus, both 5-
and 3-indolyl boronic acids 11g,h were well tolerated as coupling
partners with 5a under our optimized reaction conditions yielding
4-[5-(N-methyl)indolyl]- and 4-[3-(N-phenyl sulfonyl)indolyl]-
pyrazoles 7g,h in 60% and 52% yields, respectively (entries 7,8).
Similarly, effective cross-coupling could also be accomplished with
2-(benzofuryl)- and 3-(quinolinyl)-boronic acids 11i,j providing the
corresponding 4-(2-benzofuryl) and 4-(3-quinolinyl)pyrazoles in
good yields under similar reaction conditions (Table 1, entries 9,10).
We next extended our Suzuki cross-coupling protocol for the
synthesis of regioisomeric 1,5-diphenyl-3-(methylthio)-4-aryl/
heteroarylpyrazoles 8aej by utilizing 1,5-diphenyl-3-(methylthio)-
4-bromo/iodopyrazoles 6a,b as cross-coupling templates in their
MeS
O
B(OH)2
B(OH)2
O
N
Ph
N
Ph
8i
6a
6b
11i
75
80
N
MeS
N
N
Ph
N
Ph
8j
10
11j
a
Yield of 8a with 6b.
b
Reaction condition: Pd(OAc)2 (4 mol %)/S-Phos (10 mol %)/K3PO4 (2 equiv)/tol-
uene/reflux/20 h.

2964
T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
under these optimized conditions (unlike with 5a,b) affording the
corresponding 3-(methylthio)-4-(2-thienyl) and 4-(3-pyridyl)pyr-
azoles 8d and 8f both in 62% yield (entries 4 and 6; see Fig. 2 for
X-ray diagram of 8d27). On the other hand, the reaction of 6a with
2-furyl boronic acid 11e under identical reaction conditions yielded
only inseparable mixture of 4-(2-furyl)-3-(methylthio)pyrazole 8e
and 6a, however, pure 8e could be obtained in 63% yield under
modified reaction conditions (Pd(OAc)2/S-Phos/K3PO4) (Table 2,
entry 5) earlier applied for the synthesis of isomeric 7e. Similarly,
benzo-fused heteroaryl boronic acids 11gej also participated
readily in Suzuki cross-coupling reaction with pyrazoles 6a or 6b
under above described conditions affording 1,5-diphenyl-3-
(methylthio)-4-(2/3/5-heteroaryl) pyrazoles 8gej in satisfactory
yields (Table 2, entries 7e10).27
Ph
Ph
MeS
or
Ph
Ph
5b 6b
or
N
N
Ph
N
Ph
SMe
N
PdCl2(PPh3)2 (3 mol%)/CuI
(3 mol%)/K2CO3
Ph
12, 64%
13, 66%
(3 equiv)/DMF/100 °C/10 h
Scheme 4.
3. Conclusion
In summary, we have developed a general regioselective flexible
route for hitherto unreported novel tetrasubstitued 3- and 5-(meth-
ylthio)-1,4,5-triaryl/heteroaryl and 1,3,4-triaryl/heteroarylpyrazoles.
The synthesis relies on installing an aryl/heteroaryl group at the C-4
position of the 1,3,5-trisubstituted pyrazoles through halogenation
followed by the Suzuki cross-coupling with a series of aryl/heteroaryl
boronic acids. The coupling conditions were found to be tolerant for
a broad range of aryl/heteroaryl boronic acid components. Also, this
approach avoids necessity to ‘custom make’ difficultly accessible un-
symmetrical desoxybenzoin precursors required for our previous ap-
proaches (conventional approaches),17 involving cyclocondenastion of
a-oxoketene dithioacetals with aryl hydrazines. Subsequent reductive
dethiomethylation of these tetrasubstituted pyrazoles provides
regioselective route for the synthesis25 of unsymmetrical 1,3,4- and
1,4,5-triaryl pyrazoles. It should be noted that 1,3,4-trisubstituted
pyrazoles, though pharmaceutically important,4a,5b,28 yet are less
represented in the literature, probably due to synthetic difficulties,
since the Knorr condensation of the substituted hydrazines with
b
-keto aldehydes usually favors 1,4,5-trisubstituted pyrazoles.28 The
(methylthio) functionality in these isomeric 5- and 3-(methylthio)
tetrasubstituted pyrazoles can be further elaborated29 for introducing
functionalgroup diversityat 5-or 3-position by nickel-catalyzedcross-
coupling with alkyl or aryl Grignard reagents as demonstrated in our
earlier studies.17 Our efforts in this direction are under progress.
Fig. 2. ORTEP diagram of 8d.
4. Experimental section
4.1. General
In order to complete our synthetic exploration, a few of these
newly synthesized tetrasubstituted isomeric 5-(or 3-)(methylthio)
pyrazoles 7 and 8 were subjected to reductive dethiomethylation in
the presence of Raney-Ni since this would provide a regioselective
route for the synthesis of unsymmetrical 1,3,4- and 1,4,5-tri-
substituted pyrazoles (Scheme 3). Thus, the desulfurization of the
pyrazoles 7a,b,e, 8a,b and e proceeded smoothly in the presence of
Raney-Ni in refluxing ethanol yielding the isomeric 1,3-diphenyl-4-
aryl/heteroaryl- (9a,b,e) and 1,5-diphenyl-4-aryl/heteroaryl (10a,b,e)
pyrazoles in excellent yields (Scheme 3).
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on Jeol JNM Lambda Spectrometer with CDCl3 as the sol-
vent and TMS as an internal standard. Meltingpoints weremeasured
using Mel-Temp apparatus and are uncorrected. IR spectra were
recorded on a Perkin Elmer 1320 spectrometer. Mass spectra were
recorded on Jeol SX 102/DA-6000 Mass Spectrometer/Data System.
Elemental analyses were carried out on a Elementar Vario EL III
analyzer at Central Drug Research Institute, Lucknow (India).
All boronic acids were obtained from commercial sources.
Ph
Ar
H
Ar
Ph
7a-b, 7e
Raney Ni
4.2. Procedure for the preparation of 4-bromo-5-(methylthio)-1,
3-diphenyl- and 4-bromo-3-(methylthio)-1,5-diphenyl-1H-pyra-
zoles (5a, 6a)
or
8 a-b, 8e
or
N
N
EtOH/Δ/2-7h
H
N
N
Ph
9a, Ar = Ph, 82%
9b, Ar = 4-MeOC6H4, 10b, Ar = 4-MeOC6H4,
Ph
10a, Ar = Ph, 85%
Pyrazole 2a or 4a (0.50 g, 1.88 mmol) was dissolved in CCl4
(20 mL) and NBS (0.30 g, 2.0 mmol) was added to the solution at
room temperature. Reaction mixture was further stirred at room
temperature for 1 h (monitored by TLC). It was then filtered on
Buchner funnel and residue was washed with CCl4 (3ꢀ5 mL). Fil-
trate was concentrated under reduced pressure to give bromopyr-
azoles, which were purified by column chromatography over silica
gel using hexane/EtOAc (9:1) as eluent.
86%
96%
9e
10e
, Ar = 2-furyl, 76%
, Ar = 2-furyl, 81%
Scheme 3.
The regioisomeric 4-iodopyrazoles 5b and 6b also participated
readily in Sonogashira coupling reaction with phenylacetylene
under standard conditions to afford tetrasubstituted 1,3-(or 1,5-)
diphenyl-5-(or 3-)(methylthio)-4-(phenylethynyl)pyrazoles 12 and
13 in good yields in highly regiocontrolled fashion (Scheme 4).
4.2.1. 4-Bromo-5-(methylthio)-1,3-diphenyl-1H-pyrazole (5a). Yield
98% (0.63 g); light yellow solid; mp 80 ꢁC; Rf 0.38 (9.2:0.8 hexanes/
EtOAc); IR (KBr): 3034, 2919, 1591, 1490, 1447, 1303, 963, 766,

T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
2965
691 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.17 (s, 3H, SCH3), 7.29 (t,
combined organic extracts were washed with water (2ꢀ50 mL),
brine (1ꢀ30 mL), and dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure to give products, which
were purified by column chromatography over silica gel using
hexane/EtOAc as eluent (7.5:2.5).
J¼7.0 Hz, 1H, ArH), 7.35 (t, J¼7.8 Hz, 2H, ArH), 7.40 (t, J¼8.0 Hz, 3H,
ArH), 7.53 (dd, J¼8.1, 1.4 Hz, 2H, ArH), 7.88 (dd, J¼8.3, 1.4 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3):
d 18.3, 102.4, 125.4, 127.6, 128.3,
128.4, 128.5, 128.8, 131.6, 136.1, 139.5, 149.5; MS (m/z, %): 347 (Mþ,
100), 345 (Mþ, 95). Anal. Calcd for C16H13BrN2S (345.26): C, 55.66;
H, 3.80; N, 8.11%. Found C, 55.73; H, 3.77; N, 7.95%.
4.4.1. 5-(Methylthio)-1,3,4-triphenyl-1H-pyrazole (7a)17. Yield 80%
(0.34 g); colorless solid; mp 97e98 ꢁC; Rf 0.47 (9.2:0.8 hexanes/
EtOAc); IR (KBr): 3058, 2921, 1678, 1594, 1494, 1436, 1373 cmꢂ1; 1H
4.2.2. 4-Bromo-3-(methylthio)-1,5-diphenyl-1H-pyrazole (6a). Yield
83% (0.54 g); light yellow solid; mp 78e79 ꢁC; Rf 0.38 (9.2:0.8 hex-
anes/EtOAc); IR (KBr): 3063, 2923, 1591, 1494, 1346, 1022, 963, 771,
NMR (400 MHz, CDCl3): d 1.85 (s, 3H, SCH3), 7.17e7.19 (m, 3H, ArH),
7.31e7.32 (m, 5H, ArH), 7.36 (t, J¼7.3 Hz,1H, ArH), 7.42e7.46 (m, 4H,
694 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
2.60 (s, 3H, SCH3), 7.17e7.18
ArH), 7.66 (d, J¼7.6 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d 18.7,
(m, 1H, ArH), 7.19 (d, J¼1.9 Hz, 1H, ArH), 7.21e7.28 (m, 5H, ArH), 7.33
125.7, 125.8, 127.3, 127.7, 128.06, 128.08, 128.2, 128.3, 128.8, 130.4,
132.8, 132.9, 134.4, 139.7, 150.0.
(dd, J¼5.0, 1.9 Hz, 3H, ArH); 13C NMR (100 MHz, CDCl3):
d 15.0, 96.9,
124.5, 127.4, 128.4, 128.5, 128.8, 129.0, 129.8, 139.6, 141.7, 147.7; MS
(m/z, %): 347 (Mþ, 98), 345 (Mþ, 100). Anal. Calcd for C16H13BrN2S
(345.26): C, 55.66; H, 3.80; N, 8.11%. Found C, 55.54; H, 3.81; N, 8.10%.
4.4.2. 4-(4-Methoxyphenyl)-5-(methylthio)-1,3-diphenyl-1H-pyrazole
(7b). Yield 75% (0.35 g); colorless solid; mp 115e116 ꢁC; Rf 0.31
(9.0:1.0 hexanes/EtOAc); IR (KBr): 3005, 2932, 2833, 1594, 1537,
4.3. Procedure for the preparation of 1,3-diphenyl-4-iodo-5-
(methylthio) and 1,5-diphenyl-4-iodo-3-(methylthio)
pyrazoles (5b, 6b)
1490, 1438, 1245, 1031, 965 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 1.85
(s, 3H, SCH3), 3.75 (s, 3H, OCH3), 6.85 (d, J¼8.5 Hz, 2H, ArH), 7.18 (dd,
J¼5.1, 1.9 Hz, 3H, ArH), 7.21 (d, J¼8.5 Hz, 2H, ArH), 7.33 (t, J¼7.3 Hz,
1H, ArH), 7.40e7.44 (m, 4H, ArH), 7.64 (d, J¼7.8 Hz, 2H, ArH); 13C
To a mixture of pyrazole 2a or 4a (0.50 g, 1.88 mmol), CH3COONa
(0.17 g, 2.0 mmol), and acetic acid (3.0 mL), iodine mono chloride
(0.10 mL, 2.0 mmol) was added at room temperature. Reaction
mixture was further stirred at room temperature for 1 h (monitored
by TLC). It was then poured into 30 mL of cold water and extracted
with CH2Cl2 (3ꢀ30 mL). The combined organic extracts were
washed with water (2ꢀ50 mL), brine (1ꢀ30 mL), and dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure to give products, which were purified by column chro-
matography over silica gel using hexane/EtOAc (9:1) as eluent.
NMR (100 MHz, CDCl3): d 18.6, 55.1, 124.9, 125.3, 125.6, 127.6, 128.0,
128.04, 128.1, 128.8, 131.4, 132.7, 134.2, 139.6, 149.9, 158.7; MS (m/z,
%): 373 (Mþþ1, 100), 372 (Mþ, 92). Anal. Calcd for C23H20N2OS
(372.48): C, 74.16; H, 5.41; N, 7.52%. Found C, 73.96; H, 5.24; N, 7.33%.
4.4.3. 4-(4-Acetylphenyl)-5-(methylthio)-1,3-diphenyl-1H-pyrazole
(7c). Yield 51% (0.25 g); white solid; mp 145e146 ꢁC; Rf 0.32
(9.0:1.0 hexanes/EtOAc); IR (KBr): 3056, 2920, 1679, 1601, 1496,
1261, 964, 771 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 1.89 (s, 3H,
SCH3), 2.58 (s, 3H, COCH3), 7.22e7.24 (m, 3H, ArH), 7.40 (d,
J¼7.08 Hz, 3H, ArH), 7.46 (t, J¼8.2 Hz, 4H, ArH), 7.68 (d, J¼7.8 Hz, 2H,
ArH), 7.93 (d, J¼8.32 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
4.3.1. 4-Iodo-5-(methylthio)-1,3-diphenyl-1H-pyrazole (5b). Yield 98%
(0.72 g); light yellow solid; mp 131e132 ꢁC; Rf 0.38 (9.2:0.8 hexanes/
EtOAc); IR (KBr): 3049, 2921,1592,1494,1444, 960, 761, 692 cmꢂ1; 1H
d
18.7, 26.6, 124.5, 125.7, 128.0, 128.2, 128.31, 128.35, 128.9, 130.5,
132.3, 134.6, 135.7, 137.9, 139.4, 150.2, 197.8; MS (m/z, %): 385
(Mþþ1, 100), 384 (Mþ, 37). Anal. Calcd for C24H20N2OS (384.49): C,
74.97; H, 5.24; N, 7.29%. Found C, 74.85; H, 5.17; N, 7.50%.
NMR (400 MHz, CDCl3):
d
2.16 (s, 3H, SCH3), 7.31 (t, J¼7.3 Hz, 1H,
ArH), 7.37 (t, J¼7.3 Hz, 2H, ArH), 7.42 (t, J¼7.8 Hz, 3H, ArH), 7.53 (dd,
J¼8.5, 1.4 Hz, 2H, ArH), 7.82 (dd, J¼8.2, 1.4 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3):
d
18.96, 72.75, 125.55, 128.20, 128.24, 128.51,
4.4.4. 5-(Methylthio)-1,3-diphenyl-4-(thiophen-2-yl)-1H-pyrazole
(7d). Yield 50% (0.22 g); white solid; mp 107e108 ꢁC; Rf 0.4 (9:1
hexanes/EtOAc); IR (KBr): 3061, 2922, 1592, 1493, 1443, 1376, 1077,
128.53, 128.82, 132.46, 139.78, 153.02; MS (m/z, %): 393 (Mþþ1, 100),
392 (Mþ, 30). Anal. Calcd for C16H13IN2S (392.26): C, 48.99; H, 3.34; N,
7.14%. Found C, 48.81; H, 3.46; N, 7.19%.
758, 690 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 2.06 (s, 3H, SCH3), 7.02
(d, J¼2.6 Hz, 1H, ArH), 7.06 (t, J¼4.8 Hz, 1H, ArH), 7.31 (dd, J¼4.8,
1.7 Hz, 3H, ArH), 7.37 (d, J¼4.8 Hz,1H, ArH), 7.43 (t, J¼7.3 Hz, 1H, ArH),
7.51 (t, J¼7.8 Hz, 2H, ArH), 7.56e7.58 (m, 2H, ArH), 7.69 (d, J¼7.8 Hz,
4.3.2. 4-Iodo-3-(methylthio)-1,5-diphenyl-1H-pyrazole
(6b). Yield
88% (0.65 g); light yellow solid; mp 106e107 ꢁC; Rf 0.38 (9.2:0.8
hexanes/EtOAc); IR (KBr): 3047, 2921, 1592, 1493, 1445, 961, 770,
2H, ArH); 13C NMR (100 MHz, CDCl3):
d 18.9, 118.9, 125.7, 126.1, 127.1,
696 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
2.54 (s, 3H, SCH3), 7.09e7.10
127.9, 128.0, 128.23, 128.26,128.8, 132.5, 133.5,135.3,139.5,150.7; MS
(m/z, %): 349 (Mþþ1, 100), 348 (Mþ, 72). Anal. Calcd for C20H16N2S2
(348.49): C, 68.93; H, 4.63; N, 8.04%. Found C, 68.84; H, 4.72; N, 8.10%.
(m, 1H, ArH), 7.11 (d, J¼7.3 Hz, 1H, ArH), 7.13e7.20 (m, 5H, ArH), 7.27
(dd, J¼5.0, 1.9 Hz, 3H, ArH); 13C NMR (100 MHz, CDCl3):
d 15.4, 65.7,
124.4, 127.3, 128.4, 128.7, 128.9, 129.5, 130.0, 139.6, 144.9, 151.2; MS
(m/z, %): 393 (Mþþ1, 100), 392 (Mþ, 25). Anal. Calcd for C16H13IN2S
(392.26): C, 48.99; H, 3.34; N, 7.14%. Found C, 49.26; H, 3.17; N, 7.26%.
4.4.5. 4-(Furan-2-yl)-5-(methylthio)-1,3-diphenyl-1H-pyrazole
(7e). Yield 30% (0.13 g); yellow solid; mp 85e86 ꢁC; Rf 0.41 (9:1
hexanes/EtOAc); IR (KBr): 3053, 2925, 1592, 1493, 1075, 764,
4.4. General procedure for Suzuki cross-coupling of aryl/
heteroaryl boronic acids with 1,3-(or 1,5)-diphenyl-4-halo-5-
(or 3-)(methylthio)pyrazoles 5a,b and 6a,b: synthesis of 1,3-(or
1,5-)diphenyl-4-aryl/heteroaryl-5-(or 3-)(methylthio)
pyrazoles 7aej and 8aej
690 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 2.02 (s, 3H, SCH3),
6.41e6.44 (m, 2H, Ar), 7.25 (d, J¼7.3 Hz, 3H, ArH), 7.35 (t, J¼7.3 Hz,
1H, ArH), 7.40e7.44 (m, 3H, ArH), 7.49 (dd, J¼7.8, 1.9 Hz, 2H, ArH),
7.59 (dd, J¼7.9, 1.2 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d 18.8,
109.8, 111.1, 115.7, 125.7, 127.8, 128.0, 128.2, 128.3, 128.8, 132.6, 135.8,
139.4, 142.2, 146.2, 150.7; MS (m/z, %): 333 (Mþþ1, 100), 332 (Mþ,
78). Anal. Calcd for C20H16N2OS (332.42): C, 72.26; H, 4.85; N, 8.43%.
Found C, 72.47; H, 4.75; N, 8.32%.
In a typical experiment, a mixture of 4-halopyrazole 5a,b or 6a,b
(1.27 mmol), aryl/heteroaryl boronic acids 11aej (1.90 mmol), Pd
(PPh3)4 (146 mg, 0.127 mmol), EtOH (3.0 mL), and 2 M solution of
aq Na2CO3 (3.0 mL) in toluene (8.0 mL) was heated at 90e120 ꢁC for
10e12 h (monitored by TLC). The reaction mixture was then poured
into 30 mL of cold water and extracted with CHCl3 (3ꢀ30 mL). The
4.4.6. 4-(1-Methyl-lH-indol-5-yl)-5-(methylthio)-1,3-diphenyl-1H-
pyrazole (7g). Yield 60% (0.30 g); white solid; mp 168e170 ꢁC; Rf
0.44 (7.5:2.5 hexane/EtOAc); IR (KBr): 3060, 2923, 1593, 1496, 1443,

2966
T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
1370, 1328, 1078, 759, 693 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
1.93
%): 373 (Mþþ1, 100), 372 (Mþ, 76). Anal. Calcd for C23H20N2OS
(372.48): C, 74.16; H, 5.41; N, 7.52%. Found C, 73.99; H, 5.21; N,
7.47%.
(s, 3H, SCH3), 3.82 (s, 3H, NCH3), 6.51 (d, J¼2.9 Hz, 1H, ArH), 7.08 (d,
J¼2.9 Hz, 1H, ArH), 7.20e7.25 (m, 4H, ArH), 7.35 (d, J¼7.8 Hz, 1H,
ArH), 7.44 (d, J¼7.3 Hz, 1H, ArH), 7.51e7.57 (m, 4H, ArH), 7.68 (dd,
J¼5.2, 1.4 Hz, 1H, ArH), 7.78 (d, J¼7.3 Hz, 2H, ArH); 13C NMR
4.4.12. 4-(4-Acetylphenyl)-3-(methylthio)-1,5-diphenyl-1H-pyrazole
(8c). Yield 68% (0.33 g); white solid; mp 196e197 ꢁC; Rf 0.32
(9.0:1.0 hexanes/EtOAc); IR (KBr): 3053, 2925, 1671, 1600, 1493,
(100 MHz, CDCl3): d 18.7, 32.8, 101.1, 109.1, 122.7, 123.7, 124.2, 124.6,
125.6, 127.5, 127.9, 128.0, 128.2, 128.4, 128.7, 129.1, 132.9, 136.0,
139.7, 149.9; MS (m/z, %): 396 (Mþþ1, 100), 395 (Mþ, 95). Anal.
Calcd for C25H21N3S (395.52): C, 75.92; H, 5.35; N, 10.62%. Found C,
76.06; H, 5.35; N, 10.73%.
1265, 761, 696 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 2.49 (s, 3H,
SCH3), 2.53 (s, 3H, COCH3), 6.97 (d, J¼7.1 Hz, 2H, ArH), 7.13e7.24 (m,
10H, ArH), 7.77 (d, J¼7.6 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d
15.0, 26.5, 120.1, 124.9, 127.2, 128.2, 128.6, 128.69, 128.74, 129.4,
4.4.7. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-5-(methylthio)-1,3-di-
phenyl-1H-pyrazole (7h). Yield 52% (0.34 g); white solid; mp
82e83 ꢁC; Rf 0.32 (7.5:2.5 hexanes/EtOAc); IR (KBr): 3058, 2923,
129.5, 130.1, 135.1, 137.2, 139.4, 141.5, 146.8, 197.7; MS (m/z, %): 385
(Mþþ1, 100), 384 (Mþ, 44). Anal. Calcd for C24H20N2OS (384.49): C,
74.97; H, 5.24; N, 7.29%. Found C, 74.82; H, 5.25; N, 7.31%.
1596, 1497, 1444, 1373, 1178, 750, 689 cmꢂ1 1H NMR (400 MHz,
;
CDCl3):
d
1.74 (s, 3H, SCH3), 7.02 (t, J¼7.3 Hz, 3H, ArH), 7.10 (t,
4.4.13. 3-(Methylthio)-1,5-diphenyl-4-(thiophen-2-yl)-1H-pyrazole
(8d). Yield 62% (0.27 g); white solid; mp 188e190 ꢁC; Rf 0.43
(9.2:0.8 hexanes/EtOAc); IR (KBr): 3063, 2930, 1586, 1493, 1365,
J¼7.0 Hz, 2H, ArH), 7.23 (t, J¼7.3 Hz, 1H, ArH), 7.33e7.38 (m, 5H,
ArH), 7.45 (t, J¼8.4 Hz, 3H, ArH), 7.57 (s, 1H, ArH), 7.66 (d, J¼7.5 Hz,
2H, ArH), 7.80 (dd, J¼8.2, 1.2 Hz, 2H, ArH), 7.98 (d, J¼8.2 Hz, 1H,
763, 693 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 2.61 (s, 3H, SCH3), 6.95
ArH); 13C NMR (100 MHz, CDCl3):
d
18.7, 113.8, 115.5, 115.9, 121.0,
(t, J¼4.3 Hz, 1H, ArH), 6.97 (d, J¼3.4 Hz, 1H, ArH), 7.17 (d, J¼5.6 Hz,
123.4, 124.9, 125.5, 125.7, 126.7, 127.3, 127.8, 128.20, 128.23, 128.8,
129.2, 130.4, 132.5, 133.7, 135.2, 136.0, 138.1, 139.5, 158.8; MS (m/z,
%): 521 (Mþ, 47). Anal. Calcd for C30H23N3O2S2 (521.65): C, 69.07; H,
4.44; N, 8.06%. Found C, 68.84; H, 4.31; N, 8.01%.
3H, ArH), 7.24e7.32 (m, 8H, ArH); 13C NMR (100 MHz, CDCl3):
d
15.2, 115.2, 124.7, 124.9, 126.5, 126.8, 127.1, 128.5, 128.7, 128.8,
129.6, 130.5, 133.0, 139.6, 141.3, 146.9; MS (m/z, %): 349 (Mþþ1, 72),
348 (Mþ, 62). Anal. Calcd for C20H16N2S2 (348.48): C, 68.93; H, 4.63;
N, 8.04%. Found C, 68.99; H, 4.66; N, 8.00%.
4.4.8. 4-(Benzofuran-2-yl)-5-(methylthio)-1,3-diphenyl-1H-pyrazole
(7i). Yield 68% (0.33 g); white solid; mp 152e154 ꢁC; Rf 0.40 (9:1
hexanes/EtOAc); IR (KBr): 3057, 2921, 1592, 1496, 1449, 1250, 972,
4.4.14. 4-(Furan-2-yl)-3-(methylthio)-1,5-diphenyl-1H-pyrazole
(8e). Yield 63% (0.26 g); white solid; mp 147e148 ꢁC; Rf 0.40 (9:1
hexanes/EtOAc); IR (KBr): 3061, 2924, 1595, 1497, 1358, 1026,
776, 693 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 2.99 (s, 3H, SCH3), 7.80
(s, 1H, ArH), 8.14e8.22 (m, 5H, ArH), 8.36 (d, J¼7.0 Hz, 2H, ArH),
741 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.57 (s, 3H, SCH3), 6.13 (d,
J¼4.4 Hz, 1H, Ar), 6.26 (dd, J¼4.3, 2.4 Hz, 1H, Ar), 7.13e7.20 (m, 7H,
ArH), 7.21e7.27 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3):
15.2,
8.42 (t, J¼7.0 Hz, 2H, ArH), 8.49e8.52 (m, 3H, ArH), 8.60 (d,
J¼7.3 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d
18.9, 106.3, 111.2,
d
115.3, 120.8, 122.7, 124.0, 125.8, 128.0, 128.2, 128.4, 128.8, 128.9,
132.4, 136.5,139.3,148.3,151.0,154.7; MS (m/z, %): 383 (Mþþ1,100),
382 (Mþ, 90). Anal. Calcd for C24H18N2OS (382.48): C, 75.37; H, 4.74;
N, 7.32%. Found C, 75.43; H, 4.90; N, 7.30%.
107.8, 111.2, 112.8, 125.2, 127.5, 128.8, 129.1, 129.2, 130.4, 130.7, 139.9,
141.4, 141.8, 146.8, 147.0; MS (m/z, %): 333 (Mþþ1, 100), 332 (Mþ,
63). Anal. Calcd for C20H16N2OS (332.42): C, 72.26; H, 4.85; N, 8.43%.
Found C, 72.15; H, 4.76; N, 8.52%.
4.4.9. 4-(Quinolin-3-yl)-5-(methylthio)-1,3-diphenyl-1H-pyrazole
(7j). Yield 70% (0.35 g); white solid; mp 156e157 ꢁC; Rf 0.31 (7.5:2.5
hexanes/EtOAc); IR (KBr): 3056, 2919, 1595, 1493, 1448, 1340, 762,
4.4.15. 4-(Pyridin-3-yl)-3-(methylthio)-1,5-diphenyl-1H-pyrazole
(8f). Yield 62% (0.27 g); yellow solid; mp 163e166 ꢁC; Rf 0.28
(7.5:2.5 hexanes/EtOAc); IR (KBr): 3051, 2922, 1592, 1498, 1380,
696 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
1.86 (s, 3H, SCH3), 7.17e7.20
1356, 762, 696 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.58 (s, 3H,
SCH3), 7.03 (d, J¼7.6 Hz, 2H, ArH), 7.19e7.29 (m, 10H, ArH), 8.44 (br
s, 2H, ArH); 13C NMR (100 MHz, CDCl3):
15.1, 117.8, 123.1, 124.8,
(m, 3H, ArH), 7.36e7.42 (m, 3H, ArH), 7.46 (t, J¼8.0 Hz, 2H, ArH),
7.51 (d, J¼7.5 Hz, 1H, ArH), 7.69 (d, J¼8.0 Hz, 3H, ArH), 7.74 (br s, 1H,
ArH), 8.11 (d, J¼7.0 Hz, 1H, ArH), 8.16 (s, 1H, ArH), 8.83 (br s, 1H,
d
127.2, 128.6, 128.7, 129.1, 130.0, 136.8, 139.4, 141.6, 146.8, 147.6,
150.3; MS (m/z, %): 344 (Mþþ1, 90), 343 (Mþ, 44). Anal. Calcd for
C21H17N3S (343.44): C, 73.44; H, 4.99; N, 12.23%. Found C, 73.51; H,
4.86; N, 12.40%.
ArH); 13C NMR (100 MHz, CDCl3):
d 18.8, 121.9, 125.6, 127.0, 127.9,
128.0,128.1,128.4,128.5,128.8,128.9,129.7,132.1,135.3,137.1,139.4,
146.3, 150.5, 151.6; MS (m/z, %): 394 (Mþþ1, 100), 393 (Mþ, 40).
Anal. Calcd for C25H19N3S (393.50): C, 76.31; H, 4.87; N, 10.68%.
Found C, 76.47; H, 4.72; N, 10.53%.
4.4.16. 4-(1-Methyl-lH-indol-5-yl)-3-(methylthio)-1,5-diphenyl-1H-
pyrazole (8g). Yield 72% (0.36 g); white solid; mp 177e178 ꢁC; Rf
0.44 (7.5:2.5 hexanes/EtOAc); IR (KBr): 3057, 2923, 1592, 1500,
4.4.10. 3-(Methylthio)-1,4,5-triphenyl-1H-pyrazole (8a)17. Yield 83%
(0.36 g); white solid; mp 204e205 ꢁC; Rf 0.43 (9:1 hexanes/EtOAc);
1425, 1384, 1355, 766, 732, 697 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
IR (KBr): 3055, 2923, 1595, 1499, 1445, 1385, 698 cmꢂ1
;
1H NMR
d
2.53 (s, 3H, SCH3), 3.70 (s, 3H, NCH3), 6.38 (d, J¼3.1 Hz, 1H, ArH),
(400 MHz, CDCl3):
d
2.56 (s, 3H, SCH3), 7.03 (d, J¼6.8 Hz, 2H, ArH),
6.97e7.20 (m, 2H, ArH), 7.04 (dd, J¼8.3, 1.7 Hz, 2H, ArH), 7.11e7.20
(m, 5H, ArH), 7.24 (d, J¼4.1 Hz, 4H, ArH), 7.50 (d, J¼1.2 Hz, 1H, ArH);
7.16e7.27 (m, 13H, ArH); 13C NMR (100 MHz, CDCl3):
d
15.1, 121.4,
124.9, 126.7, 126.9, 128.1, 128.3, 128.4, 128.7, 129.7, 129.8,130.3, 131.9,
139.8, 140.9, 146.8.
13C NMR (100 MHz, CDCl3):
d 15.1, 32.3, 101.1, 108.9, 122.2, 122.5,
122.7, 123.8, 124.9, 126.80, 128.0, 128.2, 128.6, 128.9, 130.1, 130.3,
135.6, 139.9, 140.6, 147.1; MS (m/z, %): 396 (Mþþ1, 100), 395 (Mþ,
82). Anal. Calcd for C25H21N3S (395.52): C, 75.92; H, 5.35; N, 10.62%.
Found C, 76.10; H, 5.45; N, 10.73%.
4.4.11. 4-(4-Methoxyphenyl)-3-(methylthio)-1,5-diphenyl-1H-pyr-
azole (8b). Yield 84% (0.39 g); white solid; mp 152e154 ꢁC; Rf 0.34
(9:1 hexane/EtOAc); IR (KBr): 3049, 2921, 1506, 1248, 1175,
692 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.56 (s, 3H, SCH3), 3.76 (s,
4.4.17. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-3-(methylthio)-1,5-di-
phenyl-1H-pyrazole (8h). Yield 55% (0.36 g); white solid; mp
168e171 ꢁC; Rf 0.32 (7.5:2.5 hexanes/EtOAc); IR (KBr): 3057, 2925,
3H, OCH3), 6.80 (d, J¼8.2 Hz, 2H, ArH), 7.04 (d, J¼7.6 Hz, 2H, ArH),
7.13 (d, J¼8.5 Hz, 2H, ArH), 7.18e7.28 (m, 8H, ArH); 13C NMR
(100 MHz, CDCl3):
d
15.1, 55.0, 113.6, 121.0, 124.2, 124.8, 126.9, 128.2,
1594, 1496, 1444, 1363, 1177, 754, 692 cmꢂ1 1H NMR (400 MHz,
;
128.3, 128.6, 129.9, 130.2, 130.8, 139.8, 140.6, 146.7, 158.3; MS (m/z,
CDCl3):
d
2.45 (s, 3H, SCH3), 6.92 (d, J¼7.6 Hz, 2H, ArH), 6.97 (t,

T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
2967
J¼7.5 Hz, 1H, ArH), 7.03 (t, J¼7.8 Hz, 3H, ArH), 7.12e7.22 (m, 7H,
ArH), 7.33 (t, J¼7.8 Hz, 2H, ArH), 7.42 (s, 1H, ArH), 7.45 (t, J¼7.3 Hz,
1H, ArH), 7.70 (d, J¼7.8 Hz, 2H, ArH), 7.88 (d, J¼8.3 Hz, 1H, ArH); 13C
113.7, 118.9, 125.6, 126.5, 128.3, 128.4, 128.5, 129.4, 133.0, 139.6, 141.1,
147.1, 150.1; MS (m/z, %): 287 (Mþþ1, 100). Anal. Calcd For C19H14N2O
(286.33): C, 79.70; H, 4.93; N, 9.78%. Found C, 79.81; H, 4.87; N, 9.86%.
NMR (100 MHz, CDCl3): d 15.0, 112.4, 113.4, 114.3, 121.0, 123.1, 124.7,
124.9, 125.6, 126.7, 127.2, 128.3, 128.4, 128.8, 129.1, 129.5, 129.7,
130.1, 133.6, 134.9, 137.9, 139.6, 142.2, 148.0; MS (m/z, %): 521 (Mþ,
100). Anal. Calcd for C30H23N3O2S2 (521.65): C, 69.07; H, 4.44; N,
8.06%. Found C, 68.83; H, 4.46; N, 7.91%.
4.5.4. 1,4,5-Triphenyl-1H-prazole (10a). Ref. 17.
4.5.5. 4-(4-Methoxyphenyl)-1,5-diphenyl-1H-prazole (10b). Yield
96% (0.12 g); white solid; mp 150e151 ꢁC (lit. 151 ꢁC);30 Rf 0.30 (9:1
hexanes/EtOAc); IR (KBr): 3054, 2923, 1512, 1377, 1246, 767 cmꢂ1
;
4.4.18. 4-(Benzofuran-2-yl)-3-(methylthio)-1,5-diphenyl-1H-pyr-
azole (8i). Yield 75% (0.36 g); white solid; mp 182e184 ꢁC; Rf 0.41
(9:1 hexanes/EtOAc); IR (KBr): 3057, 2921, 1591, 1495, 1398, 1005,
1H NMR (400 MHz, CDCl3):
2H, ArH), 7.05e7.08 (m, 4H, ArH), 7.15e7.24 (m, 8H, ArH), 7.79 (s,
1H, ArH); 13C NMR (100 MHz, CDCl3):
55.1,113.9,122.1,125.1,127.1,
d
3.70 (s, 3H, OCH3), 6.72 (d, J¼8.5 Hz,
d
755, 693 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
2.61 (s, 3H, SCH3), 6.49
128.3, 128.5, 128.7, 129.1, 130.2, 130.4, 138.7, 139.6, 139.9, 158.2; MS
(m/z, %): 327 (Mþþ1, 100), 326 (Mþ, 34). Anal. Calcd for C22H18N2O
(326.39): C, 80.96; H, 5.56; N, 8.58%. Found C, 80.91; H, 5.41;
N, 8.67%.
(s, 1H, ArH), 7.08 (t, J¼6.1 Hz, 2H, ArH), 7.14e7.21 (m, 7H, ArH),
7.22e7.29 (m, 4H, ArH), 7.38 (dd, J¼6.1, 1.7 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3):
d 14.6, 103.4, 110.9, 111.7, 120.4, 122.6, 123.5,
124.8, 127.2, 128.3, 128.7,128.9, 129.7,130.3, 139.3,142.0,147.1,149.1,
154.1; MS (m/z, %): 383 (Mþþ1, 97), 382 (Mþ, 100). Anal. Calcd for
C24H18N2OS (382.48): C, 75.37; H, 4.74; N, 7.32%. Found C, 75.53; H,
4.66; N, 7.50%.
4.5.6. 4-(2-Furyl)-1,5-diphenyl-1H-pyrazole(10e). Yield 81% (0.09 g);
white solid, mp 156e157 ꢁC; Rf 0.31 (9:1 hexane/EtOAc); IR (KBr):
3062, 2956, 1627, 1496, 1445, 1380, 960, 762, 694 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): 5.95 (dd, J¼2.6, 0.7 Hz, 1H, ArH), 6.29 (dd, J¼2.6,
1.6 Hz,1H, ArH), 7.21e7.29 (m, 7H, ArH), 7.35e7.38 (m, 4H, ArH), 8.02
(s, 1H, ArH); 13C NMR (100 MHz, CDCl3): 104.7, 110.9, 114.3, 124.8,
127.2, 128.5, 128.6, 128.83, 128.84, 130.0, 130.3, 138.2, 139.6, 140.9,
147.6; MS (m/z %): 287 (Mþþ1, 100). Anal. Calcd for C19H14N2O
(286.33): C, 79.70; H, 4.93; N, 9.78%. Found C, 79.63; H, 5.04; N,
9.83%.
4.4.19. 4-(Quinolin-3-yl)-3-(methylthio)-1,5-diphenyl-1H-pyrazole
(8j). Yield 80% (0.40 g); white solid; mp 178e180 ꢁC; Rf 0.31
(7.5:2.5 hexanes/EtOAc); IR (KBr): 3045, 2924,1594, 1495, 1357, 757,
694 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 2.57 (s, 3H, SCH3), 7.04 (d,
J¼8.3 Hz, 2H, ArH), 7.06e7.28 (m, 8H, ArH), 7.48 (t, J¼7.1 Hz, 1H,
ArH), 7.64 (t, J¼8.0 Hz, 1H, ArH), 8.04 (d, J¼8.3 Hz, 1H, ArH), 7.72 (d,
J¼8.0 Hz, 1H, ArH), 8.58 (s, 1H, ArH), 8.11 (s, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 15.1,117.6,124.9,125.5,126.8, 127.3,127.7,128.7,
128.8, 128.9, 129.1, 129.4, 130.1, 136.1, 139.4, 141.7, 145.9, 147.2, 151.1;
MS (m/z, %): 394 (Mþþ1, 100), 393 (Mþ, 55). Anal. Calcd for
C25H19N3S (393.50): C, 76.31; H, 4.87; N, 10.68%. Found C, 76.20; H,
5.01; N, 10.73%.
4.6. General procedure for Sonogashira cross-coupling of
4-iodopyrazoles 5b and 6b with phenylacetylene
A mixture of 4-iodopyrazole 5b or 6b (1.27 mmol), phenyl-
acetylene (1.68 mmol), PdCl2(PPh3)2 (26.6 mg, 0.038 mmol), CuI
(7.2 mg, 0.038 mmol), and K2CO3 (0.60 g, 3.8 mmol) in degassed
DMF (8.0 mL) was heated at 100 ꢁC for 10 h (monitored by TLC). The
reaction mixture was allowed to cool to room temperature and was
filtered on Buchner funnel to remove K2CO3. Residue was washed
with chloroform (2ꢀ10 mL). The filtrate was diluted with 75 mL of
water and was extracted with CH2Cl2 (3ꢀ30 mL). The combined
organic extracts were washed with water (2ꢀ50 mL), brine
(1ꢀ30 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give products, which were
purified by column chromatography over silica gel using hexane/
EtOAc (9:1) as eluent.
4.5. General procedure for Raney nickel dethiomethylation of
pyrazoles 7a,b,e and 8a,b,e
To a solution of appropriate pyrazole (0.4 mmol) in ethanol
(10 mL), Raney nickel (W4, four times by weight) was added and the
suspension was refluxed with stirring for 2e7 h (monitored by
TLC). The reaction mixture was filtered through sintered funnel and
the residue was washed with ethanol. The filtrate was concentrated
in vacuum and passed through small silica gel column using hex-
ane/EtOAc (7.5:2.5) as eluent.
4.5.1. 1,3,4-Triphenyl-1H-prazole (9a). Ref. 17.
4.6.1. 5-(Methylthio)-1,3-diphenyl-4-phenylethynyl-1H-prazole
(12). Yield 64% (0.30 g); colorless solid; mp 101 ꢁC; Rf 0.42 (9:1
hexanes/EtOAc); IR (KBr): 3065, 2926, 1592, 1491, 1446, 1372, 975,
4.5.2. 4-(4-Methoxyphenyl)-1,3-diphenyl-1H-prazole
88% (0.11 g); light yellow semisolid; Rf 0.34 (9.0:1.0 hexanes/
(9b). Yield
EtOAc); IR (CH2Cl2): 3055, 2928, 1603, 1556, 1499, 1250, 1031,
757, 690 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 2.40 (s, 3H, SCH3),
698 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
3.69 (s, 3H, OCH3), 6.76 (d,
7.24e7.32 (m, 4H, ArH), 7.34e7.37 (m, 2H, ArH), 7.41 (t, J¼8.2 Hz,
3H, ArH), 7.46 (dd, J¼7.5, 1.4 Hz, 2H, ArH), 7.54 (d, J¼8.01 Hz, 2H,
ArH), 96.07, 8.13 (dd, J¼7.8, 1.4 Hz, 2H, ArH); 13C NMR (100 MHz,
J¼8.8 Hz, 2H, ArH), 7.15 (d, J¼8.8 Hz, 3H, ArH), 7.22 (d, J¼7.8 Hz,
3H, ArH), 7.34 (t, J¼8.2 Hz, 2H, ArH), 7.51 (dd, J¼7.42, 2.4 Hz, 2H,
ArH), 7.67 (dd, J¼8.5, 1.2 Hz, 2H, ArH), 7.83 (s, 1H, ArH); 13C NMR
CDCl3):
d 18.2, 81.5, 96.1, 107.1, 123.4, 125.5, 126.9, 128.2, 128.4,
(100 MHz, CDCl3):
d
55.2, 113.9, 118.8, 122.5, 125.1, 126.2, 127.7,
128.5, 128.8, 131.2, 132.2, 139.0, 139.9, 152.1; MS (m/z, %): 367
(Mþþ1, 100), 366 (Mþ, 67). Anal. Calcd for C24H18N2S (366.48): C,
78.66; H, 4.95; N, 7.64%. Found C, 78.81; H, 4.78; N, 7.48%.
128.2, 128.3, 129.3, 129.8, 133.2, 139.9, 150.2, 158.6; MS (m/z, %):
394 (Mþþ1, 100), 393 (Mþ, 55). Anal. Calcd for C22H18N2O
(326.39): C, 80.96; H, 5.56; N, 8.58%. Found C, 80.70; H, 5.51;
N, 8.72%.
4.6.2. 3-(Methylthio)-1,5-diphenyl-4-phenylethynyl-1H-prazole
(13). Yield 66% (0.31 g); colorless solid; mp 156e157 ꢁC; Rf 0.4 (9:1
hexanes/EtOAc); IR (KBr): 3055, 2930, 2210, 1592, 1494, 1399, 752,
4.5.3. 4-(Furan-2-yl)-1,3-diphenyl-1H-prazole(9e). Yield 76% (0.09 g);
viscous semisolid; Rf 0.32 (9:1 hexanes/EtOAc); IR (CH2Cl2): 3062,
694 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
2.63 (s, 3H, SCH3),
7.22e7.26 (m, 8H, ArH), 7.28e7.29 (m, 3H, ArH), 7.34e7.36 (m, 2H,
ArH), 7.38e7.40 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3):
14.7,
1599, 1535, 1504, 1452, 1394, 756, 694 cmꢂ1 1H NMR (400 MHz,
;
CDCl3): 6.23 (d, J¼3.4 Hz, 1H, ArH), 6.37 (dd, J¼3.4, 2.0 Hz, 1H, ArH),
d
7.27e7.49 (m, 7H, ArH), 7.70 (d, J¼8.8 Hz, 2H, ArH), 7.78 (d, J¼8.8 Hz,
80.2, 94.6, 104.3, 123.3, 124.9, 127.5, 127.9, 128.1, 128.3, 128.6, 128.8,
2H, ArH), 8.19 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d
106.3, 111.0,
129.3, 131.1, 139.4, 145.1, 150.6; MS (m/z, %): 367 (Mþþ1, 100), 366

2968
T.A. Khan et al. / Tetrahedron 67 (2011) 2961e2968
(Mþ, 63). Anal. Calcd for C24H18N2S (366.48): C, 78.66; H, 4.95; N,
7.64%. Found C, 78.80; H, 4.87; N, 7.71%.
Angew. Chem., Int. Ed. 2010, 49, 7790; (p) Majumder, S.; Gipson, K. R.; Staples, R.
J.; Odom, A. L. Adv. Synth. Catal. 2009, 351, 2013.
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Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2004, 4348; (b) Heller, S. T.;
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H.; Rudge, A. J. J. Org. Chem. 2000, 65, 5253; (d) Kashima, C.; Harada, H.; Kita, I.;
Fukuchi, I.; Hosomi, A. Synthesis 1994, 61.
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1984; Vol. 1; (b) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003,
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Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley:
New York, NY, 2002.
Acknowledgements
T.A.K. and S.K. thank DST and CSIR, New Delhi, respectively, for
research fellowships. Financial assistance under DST project is also
acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.043.
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5a with boronic acid 11a resulted in lower yield of 7a (52%) under similar
reaction conditions.
27. The structures of regioisomeric pyrazoles were further confirmed by X-ray
crystallographic data of isomeric 1,3-diphenyl-4-(2-thienyl)-5-methylthio and
1,5-diphenyl-4-(2-thienyl)-3-methylthio-pyrazoles 7d and 8d. The CCDC de-
position number of 7d is 806142; molecular formula C20H16N2S2, chemical
formula weight 348.49, monoclinic, unit cell parameters: a¼6.086 (3), b¼7.444
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(5), c¼18.675 (4),
a
¼90,
b
¼94.440 (5), ¼90, space group P21. The CCDC de-
g
position number of 8d is 806143; molecular formula C20H16N2S2, chemical
formula weight 348.49, monoclinic, unit cell parameters: a¼5.722 (2), b¼8.231
12. (a) Singh, S. K.; Reddy, M. S.; Shivaramakrishna, S.; Kavitha, D.; Vasudev, R.;
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(3), c¼17.850 (7),
a
¼90,
b
¼99.192 (7), ¼90, space group P1c1. Crystallographic
g
data (excluding structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.Uk).
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