Oxone-DMSO Triggered Methylene Insertion and C(sp2)-C(sp3)-H-C(sp2) Bond Formation to Access Functional Bis-Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b03477

Metal-free insertion of a methylene group was achieved for the construction of a new C(sp²)-C(sp³)-H-C(sp²) bond in order to prepare novel bis-heterocyclic scaffolds. The complete mechanistic investigations included experimental study and DFT calculations, and various symmetric and unsymmetric bis-pyrazoles as well as other pyrazole-based bis-heterocyclic molecules were prepared in moderate to high yields. Further modification of the bridged methylene group in the unsymmetric pyrazoles generated a chiral center to extend the scope of this method.

Full text of DOI:10.1021/acs.joc.9b03477

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Article
Oxone-DMSO Triggered Methylene Insertion and C(sp2)—C(sp3)-
H—C(sp2) Bond Formation to Access Functional Bis-Heterocycles
Jaspreet Kour, Vunnam Venkateswarlu, Praveen Kumar Verma, Yaseen Hussain,
GURUDUTT DUBEY, Prasad V. Bharatam, Subash C. Sahoo, and Sanghapal D. Sawant
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03477 • Publication Date (Web): 04 Mar 2020
Downloaded from pubs.acs.org on March 5, 2020
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Page 1 of 13
The Journal of Organic Chemistry
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Oxone-DMSO Triggered Methylene Insertion and C(sp2)—C(sp3)-H—
C(sp2) Bond Formation to Access Functional Bis-Heterocycles
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Jaspreet Kour,†,‡,▲ Vunnam Venkateswarlu,†,‡,▲ Praveen K. Verma,† Yaseen Hussain,†,‡ Gurudutt
Dubey,§ Prasad V. Bharatam,§ Subash C. Sahoo,¶ and Sanghapal D. Sawant*,†,‡
†Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
§Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar
160062 Punjab, India.
¶Department of Chemistry and Center of Advanced Studies in Chemistry, Panjab University Chandigarh, Chandigarh-
160014, India.
▲Equal contribution as first authors
Supporting Information Placeholder
DMSO
Heterocycle
2
Heterocycle
1
Heterocycle
1
+
Heterocycle
2
Bis-heterocycles
chiral centre
active methylene
C(sp3)-H bond
activation
OH
*
C(sp2)-H bond
activation
two steps
R2
N
N
N
N
N
N
N
O
S
N
N
N
R2
R1
R2
R1
N
N
R1
Oxone
S
150 oC, 2 h
intermediate capture
via ESIMS and
confirmed by DFT
study
KOAc
N
N
- C(sp2)- C(sp3)-H- C(sp2)-Bond Formation
- DMSO as dual function (-CH2- source; solvent)
R1
- first report on pyrazole - functional group tolerance
- DFT calculations and experimental mechanistic study
- metal-free - symmetric and unsymmetric bis-pyrazoles
ABSTRACT: Metal-free insertion of methylene group was achieved for construction of new C(sp2)—C(sp3)-H—C(sp2) bond to
get the novel bis-heterocyclic scaffolds. The complete mechanistic investigations included experimental study and DFT calculations
and various symmetric as well as unsymmetric bis-pyrazoles and other pyrazole based bis-heterocyclic molecules were prepared in
moderate to high yields. Further modification of bridged methylene group in unsymmetric pyrazoles generated a chiral centre to
extend the scope of this method.
H2O2.4b The insertion of methylene is highly attractive
synthetic strategy for assembling the functional molecules.
INTRODUCTION
Dimethyl sulfoxide (DMSO) has been recognized for its
function as a high boiling reaction medium in organic
synthesis due to easy accessibility, low reactivity, high
polarity and high stability.1 Being one of the least reactive
solvent, its activation as a reagent attracts many synthetic
chemists. Since from its decomposition studies observed by
Traynelis and Hergenrother2a numerous methods have
developed for its usage as synthone2-4 for the installation of
key functionalities in organic synthesis such as -CH2SMe, –
Me, -CH2, =CH, –CHO, –CN, –SMe, -SO2Me, etc. Li and
Mhaske have synthesized bis-type of molecules from various
amides using DMSO as a source of methylene promoted by
cyanogen chloride3a and ammonium persulfate,3b respectively
(Scheme 1c and 1d). Recently, DMSO has also been explored
as a source of methylene for the construction of bis-
Herein, we have disclosed a new method for insertion of
methylene in C—C bond formation to access divergent bis-
heterocyclic molecules.
The methyl group of DMSO was activated by oxone and
inserted in between the two C(sp2)-H bonds of two same or
different pyrazole moieties or pyrazole and other heterocyclic
moiety. DMSO acts as a solvent as well as the source of
methylene in the present oxone mediated transformation to
supply various symmetric and unsymmetric bis-pyrazoles.
Apart from bis-pyrazoles, further thriving extension to other
heterocyclic scaffolds, presented the generality of this method.
The use of DMSO is advantageous as compared to other
carbon donor solvents because it is produced from the
renewable process in the paper production industry. It is
synthesized from dimethylsulfide which is the byproduct of
4a
heterocyclic scaffolds (Scheme 1e and 1f) using H3PO4 and
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the kraft process. DMSO is very low toxic to human and substrate and DMSO as
Page 2 of 13
source of methylene and
a
1
2
3
4
5
6
7
8
environment.
systematically tested the reaction temperature, additive x, and
solvents (Table 1). The optimization experiments revealed that
the model reaction did not start at room temperature and even
Scheme 1. DMSO in methylene insertion for construction
of various scaffolds
o
upto 100 C (entries 1 and 2). Increasing the temperature upto
o
Previous reports - DMSO as source of methylene
a) Traynelis and Hergenrother (1964)2a: first decomposition study of DMSO
O
120 C initiated the reaction and conferred the desired bis-
pyrazole product to moderate yield (entry 3). Further
increasing the temperature to 150 oC, afforded the desired
product in good yield, however, refluxing conditions slightly
improve the yield of product (entries 4 and 5). Apart from
oxone, other additives which are known for their oxidizing
properties such as TBHP, HTIB, H2O2, m-CPBA, and DDQ
were also tested on the model substrate with DMSO, however,
none of these was found to be more efficient in terms of the
yield of the desired product (entries 6-10). I2 completely
suppress the reaction product (entry 11). Hence, oxone was
found to be most suitable additive (oxidant) for the activation
O
O
OH
O
S
HO
190 oC, 72 h
O
NH2
190 oC, 34 h
O
N
H
N
H
b) Kayser (2007)2c: oxazolidines from 1,2-amino-alcohols
9
O
O
O
S
10
11
12
13
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22
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60
N
R
OEt
OH
NH
R
OEt
P2O5, rt
O
DMSO as source of methylene in bis-type constructions
O
c) Li (2008)3a
cyanogen
chloride
d) Mhaske (2015)3b
2 (NH2)S2O8
O
O
O
O
R
NH
o
of DMSO at 150 C, however, other solvents bearing methyl
or methylene moiety such as DMF, PEG-200, ethylene glycol,
MeOH, MeCN,
+
O
R
N
N
R
R
N
N
H
R
toluene
H
H
1,4-dioxane
H
100 o
C
S
R = aryl
R = aryl/heteroaryl
DMSO as source of methylene in bis-heterocyclic constructions
e) Sun (2016)4a
H3PO4, DMSO
Table 1. Optimization studiesa
toluene 115 o
C
N
N
N
R
N
N
f) Yadav (2016)4b
H2O2, DMSO
N
N
N
Additive (1 equiv)
N
N
N
R
R
N
125 o
C
Solvent (4 ml)
Temp (oC), 2 h
1
2
This work (first report on methylene insertion from DMSO in pyrazoles)
solvent
entry
additive x
temp. (oC) yieldb (%)
R
R
DMSO
1
2
3
4
5
6
7
8
rt
100
120
150
reflux
150
150
150
150
0
0
Oxone
Oxone
Oxone
Oxone
Oxone
TBHP
HTIB
H2O2
mCPBA
DDQ
I2
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
N
N
+
Heterocycle
2
Heterocycle
N
N
2
40
Ar/
R'
R'
Ar/
Het-Ar
71
Het-Ar
Heterocycle 1
72 (73)c
Bis-heterocycles
31
62
26
20
active methylene
C(sp3)-H bond activation
O
N
S
N
N
R1
N
9
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21d
150
150
40
Oxone (1 equiv.)
150 oC, 2 h
bis-pyrazoles
-Homo and
hetero dimers
R1
0
) -
2
N
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
traces
b o n d
a c t i v a t i o
n
R2
R2
C ( s p
H
0
0
0
0
0
0
0
PEG-200
Ethylene glycol
O
S
MeOH
MeCN
DCM
Xylene
H2O
R1
N
N
N
R1
Oxone (1 equiv.)
KOAc (4 equiv.)
150 oC, 2 h
S
N
methylthiomethylation
45
PMSO
DESO
- C(sp2)- C(sp3)-H- C(sp2)- Bond Formation
- DMSO as dual function (-CH2- source; solvent)
35 (9)e
aReaction conditions: 1 (1 mmol), additive (1 equiv) in solvent (4 ml)
were stirred at 150 oC for 2 h. bIsolated yields. cReaction time 12 h.
dLCMS based concentration. eethylene insertion product.
PMSO = phenylmethylsulfoxide; DESO = diethylsulfoxide
- metal-free
- symmetric and assymetric bis-pyrazoles
- first report on pyrazole
- functional group tolerance
- computaional (DFT) and experimental mechanistic study
Pyrazoles5 are privileged scaffold in various drugs and
DCM and xylene were not activated under these conditions to
offer methylene source for the construction of bis-pyrazole
(entries 12-18). Only traces of desired product was observed,
when DMF was used as solvent (entry 12), and obviously,
reaction did not proceed in absence of non methylated solvents
such as H2O without DMSO (entry 19). Increasing the reaction
time did not improve the yield of the desired product (entry 5).
Reaction was also applicable to other sulfoxides such as
phenylmethyl sulfoxide (entry 20) and diethylsulfoxide (entry
21). However, in case of diethylsulfoxide, in addition to
methyl insertion, ethylene insertion was also observed (entry
21).
pharmacologically active molecules and introduction of bis-
type of heterocyclic scaffolds particularly pyrazoles6 in a
molecules has been recognized advantageous for potential
relevance against Alzhimer’s disease,6a for neuroprotective
properties,6d and employed as the ligands7 for the synthesis of
molecular organic frameworks (MOFs).
RESULTS AND DISCUSSION
Our continued interest in development of metal-free methods8
and further to extend our recent work on synthesis of 1,3,5-
trisubstituted pyrazoles and dihydropyrazoles,9 we start our
studies on optimization towards activation of DMSO for the
construction of bis-pyrazole scaffold. We commenced our
studies with 3,5-dimethyl-1-phenyl-1H-pyrazole as a model
Having established the optimization of reaction conditions,
we examined the scope of developed method to explore the
generality of the reaction. In order to synthesize symmetric
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bis-pyrazoles, various pyrazole derivatives bearing diverse heteroaromatic (-2-pyridinyl) moiety also furnished the
1
2
3
4
5
6
7
8
substitutions on phenyl ring were reacted with DMSO under
optimal reaction conditions (Table 2). Mono- and di-halogen
atoms, irrespective to their positions (o-, m-, p-), were well
tolerated on the phenyl ring and afforded corresponding
symmetric bis-pyrazoles in reasonable yields along with the
simple phenyl ring derivative (2a-2l).
targeted product in reasonable yield (2v). Introduction of
deuterium in a molecule with high yields is also demanding
due to its prevalent applications in pharmaceutical fields11 and
DMSO-d6 has been frequently used for this application.11g
Herein, we envisioned that the reaction using DMSO-d6 could
have similar applications and it afforded the corresponding
bis-pyrazole with two deuterium atoms in methylene moiety in
good yield (2w). To expand the scope of the method, instead
of dimethyl substituted pyrazoles, we have tried to explore
other substitutions. Unfortunately, the reaction of 1,3,5-
triphenyl-1H-pyrazole did not give desired product (trace of
expected product appeared on TLC and LCMS) under present
conditions even on increasing the reaction time, however,
methylthiomethyl substituted intermediate was observed in
moderate yield (2x) in this substrate. We assume that steric
factor might be playing a role in this case. On decreasing the
steric hindrance, i.e. in case of 5-methyl-1,3-diphenyl-1H-
pyrazole (2y), desired product was observed in low yield along
with its methylthiomethylated intermediate. Gram scale (4.0 g)
reaction of the model substrate (1) afforded the corresponding
bis-pyrazole in good yield (2a, 54%, 4.47 g),.
Table 2. Substrate scope for synthesis of symmetric bis-
pyrazolesa,b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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N
N
N
N
Oxone (1 equiv)
N
N
DMSO (4 ml)
150 oC, 2 h
R
R
R
2a-2w
e
2a
2b
2c
2d
2e
, R = H; 71% (54%)
, R = o-F; 64%
, R = m-F; 66%
, R = p-F; 69%
, R = o-Cl; 65%
, R = m-Cl; 65%
N
N
N
N
R
R
2a-2u
2f
Furthermore, we have also investigated the scope of the
present method for the synthesis of unsymmetric bis-pyrazoles
executing the reactions with equivalent amounts of two
different types of pyrazoles under optimal conditions (Table
3). The reactions of model substrate 1 (phenyl substituted
pyrazole) with different halogens (-F, -Cl, -Br), methoxy and
trifluoromethyl phenyl substituted pyrazoles, afforded the
corresponding unsymmetric bis-pyrazoles as the major product
in good to moderate yields (3a-3d and 3i) along with two
homo-dimers as symmetric bis-pyrazoles as minor products
(see supporting information, Scheme S4). The methylene
insertion reaction was also well supported in two pyrazoles
with different substituents on phenyl rings providing
unsymmetric bis-pyrazoles in good yields (3e-3h). On
replacing phenyl ring of one pyrazole with heteroaromatic (-2-
pyridinyl) ring also supported the formation of desired product
(3j). The structure of 3j was also confirmed using x-ray single
crystal analysis (Table 3, 3j). While carrying out control
experiments, 4-methyl(thiomethyl) substituted pyrazole
intermediate was isolated. In some earlier reports,12,2p DMSO
has been decisively used for such transformations at various
positions. The prologue of these types of thioethers is highly
applicable as isosteres to alkenes, amides and ethers.13 Herein,
after cautious optimizations (provided in supporting
information), we have revealed that another additive(y),
KOAc, to the standard methylene insertion conditions,
afforded the 4-methyl(thiomethyl) substituted pyrazoles in
high yield (Scheme 2). Hence, we have explored the reactions
for different pyrazoles providing corresponding 4-
methyl(thiomethyl)pyrazoles in high yields (Scheme 2, 4a-4e).
2g
2h
, R = p-Cl; 78%
, R = o-Br; 63%
, R = m-Br; 68%
, R = p-Br; 80%
2i
2j
N
N
N
N
2k
, R = o-F, p-F; 61%
N
N
2l
, R = o-Cl, p-Cl; 63%
2v
; 71%
2m
, R = o-CH3; 72%
, R = m-CH3; 73%
, R = p-CH3; 74%
2n
2o
2p
2q
D
D
, R = m-CH3, p-CH3; 76%
, R = m-CF3; 71%
N
N
N
N
2r
, R = p-CF3; 71%
2s
, R = p-OCF3; 68%
2w
; 70%
2t
2u
, R = p-OCH3; 70%
d
, R = m-NO2; 20% (38%)
Ph
Ph
Ph
Ph
N
N
N
N
N
Ph
N
N
N
Ph
Ph
Ph
2x
Ph
Ph
c
c
; traces (56%)
2y
; 22% (26%)
aReaction conditions: 1 (1 mmol), oxone (1 equiv) were stirred in
DMSO (4 ml) at 150 oC for 2 h. bIsolated yields. cReaction time 12 h.
Yield of intermediate (methylthiomethylation) in parenthesis. dReaction
time 24 h. oxone (3 equiv). eGram scale (4 g of reactant) reaction.
Notably, the yields of desired products were slightly higher in
case of mono-p-halogen (-F, -Cl, -Br) substituted pyrazoles
(2d, 2g and 2j). The reaction of methyl and dimethyl
substituted pyrazoles provide the targeted product in high
yields (2m-2p). The reaction of pyrazole having
In literature,6a structurally similar to bis-pyrazoles, bis-
imidazopyridine, having central carbonyl group, are known for
their medicinal importance. Therefore, the synthesized
symmetric as well as unsymmetric bis-pyrazole scaffolds were
further exploited to the oxidized carbonyl compounds bearing
bis-pyrazole scaffolds using TBHP as solvent and oxidant
(Scheme 3, 5a and 5b). These carbonyl compounds were
investigated for the reduction14c-d via simple sodium
borohydride (Scheme 3, 5aa and 5bb) in high yields.
Furthermore, these carbonyl compounds opens new area to
trifluoromethyl
and
trifluoromethoxy
groups,
pharmaceutically important functional groups,10 also
undergone methylene insertion and gave product in good
yields (2q-2s). Reaction of p-methoxy substituted pyrazole
also provide the desired product in good yield (2t) and, m-
nitro substituted compound gives the reaction intermediate
under present conditions, however, on increasing the reaction
time (24h) and quantity of oxidizing agent (3 equiv), both
reaction intermediate (38%) and desired bis product (20%)
were observed (2u). The reaction of pyrazole enclosing
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exploit for other organic transformations such as amination14
Page 4 of 13
O
1
2
3
etc. and two chiral centers can be easily generated in the
complex molecule with very simple transformations (Scheme
3).
oxidation
TBHP (2 ml)
70 oC, 7 h
N
N
N
N
N
N
N
N
4
5
6
7
8
9
R1
R1
R2
R2
, R = R = H; 85%
1
2
5a
5b
R3
Table 3. Substrate scope for synthesis of unsymmetric bis-
pyrazolesa,b
on
i
HN
R4
t
1
2
, R = H, R = p-OCH3; 82%
NaBH4 (1 equiv)
MeOH, rt, 4h
amina
reduction
OH
R3
R4
N
*
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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46
47
48
49
50
51
52
53
54
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57
58
59
60
R1
N
N
N
N
Oxone (1 equiv)
N
N
N
*
3
4
N
N
N
N
N
DMSO (4 ml)
150 oC, 2 h
N
R1
R2
3a-3i
N
R1
R2
R2
N
R1
R2
1
2
bis-heterocyclic (symmetrical
or assymetrical) functional
molecules with chiral centre(s)
5aa
5bb
, R = R = H; 79%
1
2
, R = H, R = p-OCH3; 73%
1
2
3a
3b
3c
3d
3e
, R = H, R = o-Cl; 65%
1
2
, R = H, R = p-Cl; 68%
1
2
, R = H, R = p-Br; 70%
Scheme 4. Reaction of pyrazole with benzofuran [LC-MS
(52%) characterization and isolated (48%) yields, homo-
coupled bis-pyrazole also formed during the reaction but
was not isolated; bis-benzofuran was not formed]
N
N
1
2
N
N
, R = H, R = o-CF3; 40%
1
2
, R = m-Cl, R = p-Cl; 75%
1
2
3f
, R = m-Cl, R = m-CF3; 62%
R1
R2
1
2
3g
3h
, R = m-Br, R = p-OCH3; 62%
3a-3h
1
2
N
, R = p-Br, R = p-OCH3; 63%
Oxone (1 equiv)
O
N
Ph
+
Ph
N
1
2
DMSO (4 ml)
N
3i
O
, R = H, R = p-OCH3; 67%
150 oC, 2 h
5c
48% isolated yield
(calcd. m/z = 303.3 (M+H)+)
N
N
N
N
mAU
254nm,4nm
225
200
175
150
125
100
75
N
observed m/z = 303.3 (M+H)+
3jc
3j
; 69%
Br
crystal structure of
aReaction conditions: 3 (1 mmol), 4 (1 mmol), oxone (1 equiv) were
stirred in DMSO (4 ml) at 150 oC for 2 h. bIsolated yields. cX-ray
crystallography analysis of compound 3j.
50
25
0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
27.5
30.0
32.5
35.0
37.5
min
Scheme 2. Methyl thiomethylation of pyrazoles (Isolated
yields)
To explore the generality of the developed method,
reactions for merging of two different type of heterocycles
were examined. Reaction of 3,5-dimethyl-1-phenyl-1H-
pyrazole with benzofuran afforded the desired product (5c) in
fair yield (Scheme 4). Furthermore, reactions of different
heterocycles afforded the hetero coupled heterocycles as the
major product, although required longer reaction time even for
Oxone (1 equiv)
KOAc (4 equiv)
N
N
N
S
DMSO (4 ml)
150 oC, 2 h
N
R
R
4a-4d
4c
4a
4d
4b
; R = H; 79%
; R = m-CH3; 82%
; R = o-CF3; 70%
4e
; R = m-F; 73%
moderate
yields
(Table
4).
Reaction
of
2-
; R = m-Cl, p-Cl; 69%
phenylimidazopyridine afforded the reaction intermediate, 3-
((methylthio)methyl)-2-phenylimidazo[1,2-a]pyridine in 6 h in
good yield and on increasing the reaction time to 24 h,
symmetric bis-heterocyclic scaffold was obtained in moderate
yield (6a). Reaction of 2-phenylimidazopyridine with other
heterocyclic systems such as 3,5-dimethyl-1-phenyl-1H-
pyrazole (6b), 3,5-dimethyl-1-(3-chlorophenyl)-1H-pyrazole
(6c) and benzofuran (6d) afforded the desired hetero coupled
heterocyclic scaffolds in moderate yields. 6-methyl-2-
phenylimidazopyridine also coupled with 3,5-dimethyl-1-
phenyl-1H-pyrazole in moderate yield (6e). Reaction of 3,5-
dimethyl-1-phenyl-1H-pyrazole with 2-methylfuran and 2-
methylthiophene gave the hetero coupled heterocyclic
scaffolds in low yields (6f and 6g). The reaction of 3,5-
dimethyl-1-phenyl-1H-pyrazole with 3-methylthiophene gave
the mixture (at o and o’ positions) of desired hetero coupled
products (6h). Similarly, in case of reaction of 3,5-dimethyl-1-
Scheme 3. Various important organic transformations
with synthesized bis-pyrazoles
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phenyl-1H-pyrazole with benzothiophene, hetero coupled Reactions in the presence of free radical scavenger (TEMPO)
1
2
3
4
5
6
7
8
mixture of products (at 2 and 3 positions) were obtained (6j).
Reaction of 1-methylbenzimidazole with 3,5-dimethyl-1-
phenyl-1H-pyrazole provide the desired bis heterocyclic
scaffold in low yield (6i).
afforded the desired product in good yield, ruling out the
possibility of free radical pathway4b for the present method.
The intramolecular kinetic isotope effect (KIE, KH/KD) of the
methyl in DMSO was calculated and found to be 1.3. It
indicated that the cleavage of C–H bond of DMSO is not the
rate-determining step in the present reaction (Scheme 5).
Further confirmation of the proposed plausible pathway
(Scheme 6) was carried out using DFT studies (Scheme S10).
The quantum chemical study revealed that the overall reaction
is exothermic by 59.1 kcal/mol, thus indicating the
thermodynamic feasibility of the reaction. Long-lived triplet
state cation,15 thionium ion intermediate I (or 9),2r,16 is
generated from DMSO and oxone by 136.9 kcal/mol of
energy. Intermediate I reacts with 1 to form III via de-
protonation of II and this process is exothermic by 169.4
kcal/mol. The reaction of III with I leading to the formation of
IV16b is exothermic by 26.0 kcal/mol and further results into
dithiopentane (12)16b as the side product. The C‒C bond
formation via TS along this pathway requires activation
energy of 7.8 kcal/mol. Spontaneous de-protonation of VI in
To shed some light on the mechanism of the reaction, some
control experiments (Scheme 5), mass analysis and DFT
calculations were performed on the model reaction. Firstly, the
deuterium labeling experiment confirmed the incorporation of
methylene from the DMSO. One of the proposed intermediate
(10) was isolated and, successfully, its reactions were carried
out under standard conditions with two different pyrazole
scaffolds for the synthesis of symmetric as well as
unsymmetric bis-pyrazoles, confirming the possibility of
formation of this intermediate in the proposed route. The
LCMS study was also carried out by collecting the aliquots at
different time intervals (45 min, 60 min, 90 min and 120 min)
for mass comparisons (Figure S1). As perceived from the mass
spectrum, intermediate 10D is appearing at 45, 60 and 90 min.
The reactant 1 is decreased as time progresses and formation
of product 2 increases. This clearly supports the predicted
route for formation of desired product (2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
presence of KOH and HSO5 results into the final product 2 by
releasing 138.3 kcal/mol energy.
Table 4. Substrate scope for synthesis of bis-
heterocyclesa,b,f
Scheme 5. Control (a-d) and KIE (e) experiments
Deuterium labeling experiment
D
D
Oxone (1 equiv)
O
a)
D
D
D
Het.
Het. 1
Het. 2
1
N
N
Ph
D
S
D
DMSO (4 ml)
150 oC
Oxone
150 oC, 2 h
N
Het.
2
N
Ph
+
N
N
D
Ph
70% yield
Isolation of intermediate
b)
N
N
Oxone (1 equiv)
N
N
N
N
N
N
S
N
N
N
DMSO (4 ml)
150 oC, 1 h
N
N
N
N
N
Cl
10
intermediate ( , 56 % yield)
Reaction of isolated intermediate
c
d
c
c
6a
6b
6c
, 45% (70%)
, 59%
, 55%
O
N
Ph
c)
N
N
Ph
N
N
Ph
N
N
Standard
conditions
N
symmetric
(20% yield)
N
Ph
O
N
N
N
N
N
N
N
N
Ph(4-Br)
N
N
S
N
N
N
e
c
d
6d
6e
, 56%
, 50%
S
intermediate (10)
6f
, 38%
Ph
unsymmetric
(55% yield)
Ph(4-Br)
Reaction with free radical scavanger (TEMPO)
d)
N
N
TEMPO
Oxone
DMSO (4 ml)
150 oC, 2 h
S
N
N
N
N
S
N
N
Ph
+
N
N
Ph
N
N
69% yield Ph
d
d
6g
, 35%
Intramolecular kinetic isotope effect (KIE = KH/KD)
e)
6h
, 40%
S
D(H)
(H)D
Standard conditions
N
N
Ph
N
N
Ph
N
Ph
N
N
N
N
N
DMSO+DMSO-d6 (1:1, 4 ml)
S
N
N
N
+
KH/KD = 1.3
N
d
d
6i
, 30%
6j
, 38%
Scheme 6. Plausible reaction pathway
aReaction conditions: Het. 1 (0.515 mmol), Het. 2 (0.515 mmol),
oxone (0.515 mmol) were stirred in DMSO (4 ml) at 150 oC for 2 h.
bIsolated yields, Yield of intermediate (methylthiomethylation) in
parenthesis. cReaction time 24 h. dReaction time 6 h. eReaction time
f
26 h. homo-coupled bis-pyrazoles and bis-phenylimidazopyridines
also formed in minor amount (based on TLC pattern) where pyrazole
and phenylimidazopyridine scaffolds were used during the reaction
but not isolated; other homo-coupled bis-heterocycles were not
formed.
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Page 6 of 13
refined with the ShelXL22 refinement package using Least
Squares minimization.
General Procedure for Synthesis of Pyrazole Starting
Materials. Pyrazole starting materials were prepared
according to our earlier report 9 (Scheme S1A).
Synthesis of 1,3,5-Triphenyl-1H-pyrazole. 1,3,5-
triphenyl-1H-pyrazole was prepared according to earlier
reports23 (Scheme S1B).
D
S
D
D
D
O
S
O
S
D
O
D
D
O
O
D
D
O
D
D
S+
D
1
2
3
4
5
6
7
8
+K O-
O
K+ -
O
S
O
D
D
D
D
OH
D
D
9
8
6
KDSO5
7
N
Ph
N
1
D
D
D
(a)
D
S
Observed at 45 min,
60 min, 90 min in LC-
MS
N
Ph
10D
N
General Procedure for Synthesis of Symmetric Bis-
pyrazoles. A dry round bottom flask (25 ml) was charged with
pyrazole (100 mg, 0.581 mmol), oxone® (356 mg,
m/z :238.1456 (M+H+)
D
S+
D
9
D
D
D
D
N
N
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
D
N
N
D
0.581mmol)) in DMSO (4 ml) at 150 C in oil-bath for 2 h.
N
9
D
N
D
+
S
1
After completion (monitored by TLC), the reaction mixture
was dried under vacuum, dissolved in ethyl acetate and
washed with H2O (3 times). The organic phases were
combined and concentrated on rotary evaporator. The crude
residue was purified using silica gel (ethyl acetate: n-hexane)
to give the desired symmetric bis-product (Scheme S2).
D
D
N
2
D
D
D
D
D
D
D
D
D
S
S
D
N
D
S
11
D
12
D
Bis(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methane (2a)
Light yellow liquid, yield = 71% (146 mg). Rf 0.4 (EtOAc:n-
CONCLUSION
1
Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.31-7.36 (m,
In conclusion, we have reported a novel method for the
activation of DMSO towards methylene insertion in pyrazoles
for the synthesis of bis-pyrazole scaffold via formation of new
C—C bonds. We describe the dual role of DMSO as
'methylene source' and 'solvent' for the present reaction. We
also extended the current method for synthesis of
methylthiomethylated pyrazoles, oxidized bis-pyrazoles and
incorporation of chiral centers in the bis-pyrazole scaffolds.
Present protocol tolerated the variety of functional groups and
afforded the symmetric as well as unsymmetric bis-pyrazoles
in reasonably good yields. The mechanism of the current
method was well established with the help of experimental,
analytical (LC-MS) and computational (DFT) analysis.
8H), 7.24–7.28 (m, 2H), 3.50 (s, 2H), 2.12 (s, 12H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 148.5, 141.1, 136.2,
130.2, 130.1, 127.8, 123.1, 122.5, 116.1, 18.4, 12.3, 11.1 ppm.
HRMS (ESI) Calcd for C23H25N4 [M+H]+ 357.2074; found
357.2055.
Bis(1-(2-fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2b). Light yellow solid, m.p. 122-124 oC, yield =
64% (132 mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). 1H NMR (400
MHz, CDCl3) δ 7.43-7.32 (m, 4H), 7.25-7.15 (m, 4H), 3.56 (s,
2H), 2.16 (s, 6H), 2.03 (d, J = 1.0 Hz, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 156.9 (d, J = 251.1 Hz), 148.8,
138.2, 129.8 (d, J = 7.8 Hz), 127.9 (d, J = 12.1 Hz), 124.6 (d, J
= 3.9 Hz), 116.4 (d, J = 20.2 Hz), 114.8, 18.5, 12.2, 9.8 (d, J =
4.0 Hz).19F NMR (400 MHz, CDCl3) δ -121.2 – -122.3 (m)
ppm. HRMS (ESI) Calcd for C23H23F2N4 [M+H]+ 393.1885;
found 393.1863.
EXPERIMENTAL SECTION
General Experimental. All solvents were purified and
dried as per standard protocols. All reagents were obtained
Bis(1-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-
1
from commercial sources and used without purification. H
o
yl)methane (2c). Light yellow solid, m.p. 76-78 C, yield =
and 13C NMR spectra were recorded on Brucker-Avance DPX
1
66% (136mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). H NMR (400
FT-NMR 400 and 500 MHz instruments. H and 13C positive
1
MHz, CDCl3) δ 7.42-7.37( m, 2H), 7.22-7.16 (m, 4H), 7.05-
7.01 (m, 2H), 3.56 (s, 2H), 2.23 (s, 6H), 2.18 (s, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (d, J = 247.2 Hz),
148.5, 141.4 (d, J = 9.9 Hz), 136.2, 130.2 (d, J = 9.2 Hz),
120.16 (d, J = 3.2 Hz), 116.17 (s), 114.04 (d, J = 21.1 Hz),
112.2 (d, J = 24.2 Hz), 18.5, 12.3, 11.2. 19F NMR (400 MHz,
CDCl3) δ -111.40 – -111.47 (m) ppm. HRMS (ESI) Calcd for
C23H23F2N4 [M+H]+ 393.1885; found 393.1883.
chemical shifts (δ) are downfield from tetramethylsilane and
are given in parts per million (ppm). Multiplicity (s = singlet,
d = doublet, t = triplet, m = multiplet, br = broad singlet,
coupling constant(s) in Hz, integration). The HRMS spectra
were recorded on Agilent 6540 Ultra-High-Definition (UHD)
Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) liquid
chromatography/mass spectrometry (LC/MS) system.
Computational Studies. All DFT studies17 were
performed using Gaussian09 suite software package.18 The
geometry optimization of all structures and transition state was
carried out without any symmetry constraints using B3LYP
method and 6-311+G(d,p) basis set.19 Frequencies were
calculated at the same level to confirm the nature of the
stationary points of all geometries and transition state.
Transition state was characterized by single imaginary
frequency.
X-ray Crystal Structure Determination Studies of 3j.
Single crystals of C22H22BrN5 [sub-kas-csir, 3j] were prepared
by slow evaporation. A suitable crystal was selected on a
SuperNova, single source at offset/far, HyPix3000
diffractometer. The crystal was kept at 293(2) K during data
collection. Using Olex2,20 the structure was solved with the
SIR200421 structure solution program using direct methods and
Bis(1-(4-fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2d). Light yellow solid, m.p. 132-134 oC, yield =
1
69% (142mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). H NMR (400
MHz, CDCl3) δ 7.36–7.30 (m, 4H), 7.10 (t, J =16 Hz, 4H),
3.53 (s, 2H), 2.15 (s, 6H), 2.13 (s, 6H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 161.7 (d, J = 247.1 Hz), 148.0, 136.3,
136.2 (d, J = 2.6 Hz), 126.8 (d, J = 8.6 Hz), 116.0, 115.7 (d, J
= 18.8 Hz), 18.5, 12.3, 10.9.19F NMR (400 MHz, CDCl3) δ -
114.43 – -114.43 (m) ppm. HRMS (ESI) Calcd for C23H23F2N4
[M+H]+ 393.1885; found 393.1856.
Bis(1-(2-chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2e). Pale yellow liquid, yield = 65% (134mg). Rf
1
0.4 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ
7.51-7.47 (m, 2H), 7.39-7.34 (m, 6H), 3.57 (s, 2H), 2.17 (s,
6H), 1.98 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
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NMR (101 MHz, CDCl3) δ 148.8, 138.2, 136.4, 135.5, 133.5,
148.4, 138.1, 137.7, 132.7, 130.2 ,130.1, 127.6, 114.5, 18.5,
12.4, 10.0 ppm. HRMS (ESI) Calcd for C23H23Cl2N4 [M+H]+
425.1294; found 425.1284.
130.9, 130.1, 128.0, 114.8, 18.5, 12.3, 10.0 ppm. HRMS (ESI)
Calcd for C23H21Cl4N4 [M+H]+ 493.0515; found 493.0491.
Bis(3,5-dimethyl-1-(o-tolyl)-1H-pyrazol-4-yl)methane
1
2
3
4
5
6
7
8
Bis(1-(3-chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2f). Pale yellow semi-solid, yield = 65% (134
mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz,
CDCl3) δ 7.44 (t, J = 1.9 Hz, 2H), 7.35 (dd, J = 8.6, 7.1 Hz,
2H), 7.31-7.26 (m, 4H), 3.54 (s, 2H), 2.20 (s, 6H), 2.16 (s, 6H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 148.5, 141.0, 136.3,
134.7, 130.0, 127.2, 125.0, 122.7, 116.1, 18.5, 12.3, 11.2 ppm.
HRMS (ESI) Calcd for C23H23Cl2N4 [M+H]+ 425.1294; found:
425.1270.
o
(2m). White solid, m.p. 75-76 C, yield = 72% (148 mg). Rf
1
1
0.3 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ
7.31-7.20 (m, 6H), 7.17 (d, J = 7.6 Hz, 2H), 3.57 (s, 2H), 2.15
(s, 6H), 2.00 (s, 6H), 1.92 (s, 6H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 147.4, 138.9, 137.1, 136.3, 130.8, 128.9,
128.1, 126.5, 114.2, 18.5, 17.2, 12.3, 10.0 ppm. HRMS (ESI)
Calcd for C25H29N4 [M+H]+ 385.2387; found 385.2360.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(3,5-dimethyl-1-(m-tolyl)-1H-pyrazol-4-yl)methane
(2n). Yellow liquid, yield = 73% (150 mg). Rf 0.4 (EtOAc:n-
Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.21 (t, J = 7.7
Bis(1-(4-chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2g). Brown solid, m.p. 142-144 oC, yield = 78%
1
1
(160 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H NMR (400
Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 8.4 Hz , 4H),
3.47 (s, 2H), 2.30 (s, 6H), 2.10 (s, 6H), 2.09 (s, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 147.8, 140.0, 139.1,
136.2, 128.7, 128.0, 125.7, 121.9, 115.6, 21.3, 18.6, 12.3, 11.1
ppm. HRMS (ESI) Calcd for C25H29N4 [M+H]+ 385.2387;
found 385.2359.
MHz, CDCl3) δ 7.41-7.38 (m, 4H), 7.35-7.31 (m, 4H), 3.54 (s,
2H), 2.17 (s, 6H), 2.16 (s, 6H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 148.4, 138.5, 136.3, 132.9, 129.2, 126.0, 116.0, 18.5,
12.3, 11.1 ppm. HRMS (ESI) Calcd for C23H23Cl2N4 [M+H]+
425.1294; found 425.1290.
Bis(1-(2-bromophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2h). Yellow liquid, yield = 63% (129 mg). Rf 0.6
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.66
Bis(3,5-dimethyl-1-(p-tolyl)-1H-pyrazol-4-yl)methane
(2o). Light yellow solid, m.p. 158-160 oC, yield = 74% (152
1
1
mg). Rf 0.3 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz,
(dd, J = 8.0, 1.2 Hz, 2H), 7.41-7.33 (m, 4H), 7.30-7.25 (m,
2H), 3.57 (s, 2H), 2.18 (s, 6H), 1.98 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 148.2, 139.4, 137.9, 133.3, 130.4,
130.2, 128.2, 122.8, 114.6, 18.5, 12.4, 10.2 ppm. HRMS (ESI)
Calcd for C23H23Br2N4 [M+H]+ 513.0284; found 513.0254.
Bis(1-(3-bromophenyl)-3,5-dimethyl-1H-pyrazol-4-
CDCl3) δ 7.23-7.20 (m, 4H), 7.18 (m, 4H), 3.51 (s, 2H), 2.34
(s, 6H), 2.13 (s, 6H), 2.11 (s, 6H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 147.7, 137.7, 137.2, 136.3, 129.6, 125.0,
115.5, 21.1, 18.6, 12.3, 11.0 ppm. HRMS (ESI) Calcd for
C25H29N4 [M+H]+ 385.2387; found 385.2365.
Bis(1-(3,4-dimethylphenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2p). Yellow liquid, yield = 76% (156 mg). Rf 0.3
o
yl)methane (2i). White solid, m.p. 168-170 C, yield = 68%
1
1
(139 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H NMR (400
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.17
MHz, CDCl3) δ 7.59 (t, J = 1.9 Hz, 2H), 7.45-7.43 (m, 2H),
7.34-7.28 (m, 4H), 3.53 (s, 2H), 2.19 (s, 6H), 2.15 (s, 6H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 148.5, 141.1,
136.3,130.2, 130.1,127.8, 123.1, 122.5, 116.1, 18.4, 12.3, 11.2
ppm. HRMS (ESI) Calcd for C23H23Br2N4 [M+H]+ 513.0284;
found 513.0281.
(dd, J = 9.5, 5.0 Hz, 4H), 7.07 (dd, J = 8.0, 2.2 Hz, 2H), 3.55
(s, 2H), 2.28 (s, 12H), 2.18 (s, 6H), 2.14 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 147.5, 137.9, 137.5, 136.2, 135.7,
129.9, 126.3, 122.3, 115.3, 19.8, 19.4, 18.6, 12.3, 11.0 ppm.
HRMS (ESI) Calcd for C27H33N4 [M+H]+ 413.2700; found
413.2687.
Bis(1-(4-bromophenyl)-3,5-dimethyl-1H-pyrazol-4-
Bis(3,5-dimethyl-1-(3-(trifluoromethyl)phenyl)-1H-
pyrazol-4-yl)methane (2q). Pale yellow liquid, yield = 71%
(145 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H NMR (400
o
yl)methane (2j). White solid, m.p. 170-172 C, yield = 80%
1
1
(164 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H NMR (400
MHz, CDCl3) δ 7.54 (d, J = 8.6 Hz, 4H), 7.27 (d, J = 8.6 Hz,
4H), 3.53 (s, 2H), 2.17 (s, 6H), 2.15 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 148.3, 139.0, 136.1, 132.1, 126.2,
120.7, 116.0, 18.5, 12.3, 11.1 ppm. HRMS (ESI) Calcd for
C23H23Br2N4 [M+H]+ 513.0284; found 513.0273.
MHz, CDCl3) δ 7.69 (s, 2H), 7.60-7.54 (m, 6H), 3.56 (s, 2H),
2.22 (s, 6H), 2.17 (s, 6H) ppm. 13C NMR{1H}(101 MHz,
CDCl3) 13C{1H} NMR (101 MHz, CDCl3) δ 152.6, 144.2,
140.0, 135.4 (q, J = 32.8 Hz), 133.4, 131.4, 128.8, 127.5 (q, J
= 3.8 Hz), 126.1, 125.3 (q, J = 3.9 Hz), 120.1, 22.2, 16.1, 14.9
ppm. 19F NMR (400 MHz, CDCl3) δ -62.6 (s) ppm. HRMS
(ESI) Calcd for C25H23F6N4 [M+H]+ 493.1821; found
493.1824.
Bis(1-(2,4-difluorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2k). Light yellow solid, m.p. 136-138 oC, yield =
1
61% (125mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H NMR (400
MHz, CDCl3) δ 7.40-7.34 (m, 2H), 6.96-6.88 (m, 4H), 3.53 (s,
2H), 2.12 (s, 6H), 1.98 (d, J = 4 Hz, 6H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 162.3 (dd, J = 251.0,11.1 Hz),159.8 (dd,
J = 265.6,11.1 Hz), 157.2 ( dd = 255.5, 17.1 Hz), 149.1, 138.4,
130.2 (dd, J = 10.1, 1.0 Hz), 124.3 (dd, J = 12.1, 4.0 Hz),
115.1, 111.8 (dd, J = 23.2, 4.0 Hz), 105.1, 104.7 (d, J = 3.0
Hz),104.6, 18.6, 12.35, 9.9 (d, J = 3.0 Hz) ppm. 19F NMR (400
MHz, CDCl3) δ -108.39 – -108.42 (m),-117.02 – -117.09 (m)
ppm. HRMS (ESI) Calcd for C23H21F4N4 [M+H]+ 429.1697;
found 429.1688.
Bis(3,5-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-
pyrazol-4-yl)methane (2r). White solid, m.p. 127-129 C,
yield = 71% (145 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 2.0 Hz, 4H), 7.56 (d, J
= 2.0 Hz, 4H), 3.58 (s, 2H), 2.26 (s, 6H), 2.18 (s, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 142.9, 136.3, 128.9
(d, J = 32.7 Hz), 126.3 (q, J = 3.7 Hz), 125.5 (d, J = 27.2 Hz),
124.4, 122.5, 116.6, 18.6, 12.4, 11.4ppm. 19F NMR (400 MHz,
CDCl3) δ -62.3 (s) ppm. HRMS (ESI) Calcd for C25H23F6N4
[M+H]+ 493.1821; found 493.1827.
o
1
Bis(1-(2,4-dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-
Bis(3,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-
pyrazol-4-yl)methane (2s). Pale yellow solid, m.p. 108-110
oC, yield = 68% (139 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). 1H
NMR (400 MHz, CDCl3) δ 7.50-7.37 (m, 4H), 7.27 (d, J = 8.0
Hz, 4H), 3.54 (s, 2H), 2.18 (s, 6H), 2.15 (s, 6H) ppm. 13C{1H}
o
yl)methane (2l). Light yellow solid, m.p. 132-134 C, yield =
1
63% (129mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H NMR{1H}
(400 MHz, CDCl3) δ 7.51 (d, J = 1.9 Hz, 2H), 7.33-7.29 (m,
4H), 3.56 (s, 2H), 2.15 (s, 6H), 1.97 (s, 6H) ppm. 13C{1H}
ACS Paragon Plus Environment

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NMR (101 MHz, CDCl3) δ 148.5, 147.9 (d, J = 1.7 Hz), 138.6,
Page 8 of 13
128.1, 126.4, 124.5, 117.1, 18.6, 12.4 ppm. HRMS (ESI)
Calcd for C33H29N4 [M+H]+ 481.2387; found 481.2361.
3-methyl-4-((methylthio)methyl)-1,5-diphenyl-1H-
pyrazol e (Intermediate).Colourless liquid, yield = 26%(125
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4
5
6
7
8
136.3, 126.1, 121.7 (d, J = 8.6 Hz), 119.2, 116.0, 18.5, 12.3,
11.1ppm. 19F NMR (400 MHz, CDCl3) δ -58.0 (s) ppm.
HRMS (ESI) Calcd for C25H23F6N4O2 [M+H]+ 525.1720;
found 525.1724.
1
mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz,
Bis(1-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methane (2t). Light brown solid, m.p. 158-160 oC, yield =
70% (144 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). 1H NMR (400
MHz, CDCl3) δ 6.65-6.61 (m, 4H), 6.29 (d, J = 8.9 Hz, 4H),
3.17 (s, 6H), 2.89 (s, 2H), 1.52 (s, 6H), 1.46 (s, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 158.8, 147.4, 136.4,
133.2, 126.6, 115.2, 114.2, 55.6, 18.6, 12.3, 10.8 ppm. HRMS
(ESI) Calcd for C25H29N4O2 [M+H]+ 417.2285; found
417.2279.
CDCl3) δ 7.35 (m, 3H), 7.27 (m, 3H), 7.24 (s, 1H), 7.20 (m,
3H), 3.58 (s, 2H), 2.44 (s, 3H), 2.01 (s, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 149.0, 141.4, 139.9, 130.3, 129.9,
128.7, 128.5, 128.3, 126.7, 124.6, 115.6, 27.3, 15.7, 12.1 ppm.
HRMS (ESI) Calcd for C18H19N2S [M+H]+ 295.1263; found
295.1260.
General Procedure for Synthesis of Unsymmetric Bis-
pyrazoles. A dry round bottom flask (25 ml) was charged with
pyrazole 1 (100 mg, 0.581 mmol), pyrazole 2 (119 mg, 0.581
mmol)), oxone (357 mg, 0.581 mmol) in DMSO (4 ml) at 150
oC in oil-bath for 2 h (3a). After completion (monitored by
TLC), the reaction mixture was dried under vacuum, dissolved
in ethyl acetate and washed with H2O (3 times). The organic
phases were combined and concentrated on rotary evaporator.
The crude residue was purified using silica gel (ethyl acetate:
n-hexane) to give the desired unsymmetric bis-product
(Scheme S3).
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Bis(3,5-dimethyl-1-(3-nitrophenyl)-1H-pyrazol-4-
yl)methane (2u). Bis-pyrazole. Colourless liquid, yield = 20%
(41 mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz,
CDCl3) δ 8.32 (m, 2H), 8.20 (dd, J = 8.2, 1.1 Hz, 2H), 7.84 (d,
J = 8.0 Hz, 2H), 7.65 (t, J = 8.1 Hz, 2H), 3.61 (s, 2H), 2.31 (s,
6H), 2.21 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
149.3, 148.6, 140.9, 136.3, 129.9 (d, J = 2.7 Hz), 121.5, 119.0,
116.7, 18.4, 12.3, 11.3. HRMS (ESI) Calcd for C23H23N6O4
[M+H]+ 447.1775; found 447.1779.
1-(2-chlorophenyl)-4-((3,5-dimethyl-1-phenyl-1H-
pyrazol-4-yl)methyl)-3,5-dimethyl-1H-pyrazole (3a). Light
yellow solid, m.p. 94-95 C, yield = 65% (147 mg). Rf 0.6
3,5-dimethyl-4-((methylthio)methyl)-1-(3-nitrophenyl)-
1H-pyrazole (Intermediate). Colourless liquid, yield = 38%
(48 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz,
CDCl3) δ δ 8.32 (m, 1H), 8.18 (dd, J = 8.2, 1.2 Hz, 1H), 7.83
(dd, J = 8.0, 1.0 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 3.57 (s, 2H),
2.37 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 149.7, 148.5, 140.8, 137.4, 130.0, 129.8,
121.5, 119.0, 115.7, 27.0, 15.3, 11.9, 11.3 ppm. HRMS (ESI)
Calcd for C13H16N3O2S [M+H]+ 278.0958; found 278.0960
Bis(3,5-dimethyl-1-(pyridin-2-yl)-1H-pyrazol-4-
o
(EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.53-
7.47 (m, 1H), 7.46-7.30 (m, 8H), 3.59 (s, 2H), 2.20 (s, 3H),
2.19 (d, J = 2.9 Hz, 6H), 2.00 (s, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 148.2, 147.9, 140.0, 137.9, 137.6, 136.2,
132.5, 130.1, 130.0, 128.9, 127.5, 127.1, 124.8, 115.5, 114.5,
18.4, 12.3, 12.2, 10.9, 9.9 ppm. HRMS (ESI) Calcd for
C23H24ClN4 [M+H]+ 391.1684; found 391.1666.
1-(4-chlorophenyl)-4-((3,5-dimethyl-1-phenyl-1H-
yl)methane (2v). White solid, m.p. 115-118 oC, yield = 71%
pyrazol-4-yl)methyl)-3,5-dimethyl-1H-pyrazole
(3b).
1
(146 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H NMR (400
Yellow semi-solid, yield = 68% (154 mg). Rf 0.4 (EtOAc:n-
1
MHz, CDCl3) δ 8.44-8.40 (m, 1H), 7.81-7.76 (m, 2H), 7.15-
7.12 (m, 2H), 3.58 (s, 2H), 2.59 (s, 6H), 2.18 (s, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 153.7, 149.2, 147.5,
138.2, 137.9, 120.7, 117.2, 116.2, 18.0, 12.6 ppm. HRMS
(ESI) Calcd for C21H23N6 [M+H]+ 359.1979; found 359.1982.
Bis(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methane-d2
Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.46-7.37 (m,
6H), 7.36-7.30 (m, 3H), 3.56 (s, 2H), 2.18 (d, J = 2.7 Hz, 12H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 148.4, 147.9, 140.1,
138.7, 136.3, 132.9, 129.2, 129.1, 127.3, 126.0, 125.0, 116.2,
115.5, 18.6, 12.4, 12.3, 11.1 ppm. HRMS (ESI) Calcd for
C23H24ClN4 [M+H]+ 391.1684; found 391.1671.
o
(2w). Pale yellow solid, m.p. 120-122 C, yield = 70% (145
1-(4-bromophenyl)-4-((3,5-dimethyl-1-phenyl-1H-
1
mg). Rf 0.5 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz,
pyrazol-4-yl)methyl)-3,5-dimethyl-1H-pyrazole (3c). White
viscous, yield = 70% (177 mg). Rf 0.3 (EtOAc:n-Hexane =
CDCl3) δ 7.46-7.36 (m, 8H), 7.33-7.29 (m, 2H), 2.18 (d, J =
1.5 Hz,12H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 147.9,
140.0 ,136.2, 128.9, 127.1, 124.9, 115.5, 12.2, 11.0 ppm.
HRMS (ESI) Calcd for C23H23D2N4 [M+H]+ 359.2199; found
359.2201.
1
3:7). H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.46-
7.39 (m, 4H), 7.32 (m, 3H), 3.56 (s, 2H), 2.19 (d, J = 4.0 Hz,
12H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 148.4, 147.9,
140.0, 139.1, 136.2,132.1, 129.0, 127.3, 126.2, 124.9, 120.7,
116.2, 115.5, 18.5, 12.3, 11.1 (d, J = 4.0 Hz) ppm. HRMS
(ESI) Calcd for C23H24BrN4 [M+H]+ 435.1179; found
435.1187.
4-((methylthio)methyl)-1,3,5-triphenyl-1H-pyrazole
(intermediate) (2x). Orange liquid, yield = 56%(67mg). Rf
1
0.6 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ
8.03-8.01 (m, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.45-7.41 (m, 6H),
7.36-7.25 (m, 5H), 3.73 (s, 2H), 2.05 (s, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 151.5, 142.4, 139.9, 133.3, 130.1,
128.7, 128.6, 128.5, 128.2, 128.0, 127.0, 124.8, 115.3, 28.4,
16.3 ppm. HRMS (ESI) Calcd for C23H21N2S [M+H]+
357.1420; found 357.1408.
Bis(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)methane
(2y). Brown viscous, yield = 22%(45 mg). Rf 0.6 (EtOAc:n-
Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.2
Hz, 6H), 7.14 (d, J = 7.6 Hz, 4H), 7.08 (m, 6H), 6.95 (m, 4H),
3.62 (s, 2H), 1.99 (s, 6H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 148.5, 140.6, 140.1, 130.8, 130.1, 128.6, 128.3,
4-((3,5-dimethyl-1-(2-(trifluoromethyl)phenyl)-1H-
pyrazol-4-yl)methyl)-3,5-dimethyl-1-phenyl-1H-pyrazole
(3d). Light brown semi-solid, yield = 40% (106 mg). Rf 0.4
1
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.79
(d, J = 7.0 Hz, 1H), 7.64 (t, J = 7.1 Hz, 1H), 7.57 (t, J = 7.6
Hz, 1H), 7.45-7.38 (m, 4H), 7.35-7.30 (m, 2H), 3.57 (s, 2H),
2.19 (s, 3H), 2.15 (d, J = 4.5 Hz, 6H), 1.91 (s, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 148.1, 140.2, 138.3,
138.0, 136.4, 132.7, 130.9, 129.5, 129.1, 127.3 (d, J = 5.0 Hz),
127.3, 125.1, 115.6, 114.6, 18.6, 12.3, 12.2, 10.9, 10.1 ppm.
19F NMR (400 MHz, CDCl3) δ -60.34 (s) ppm. HRMS (ESI)
Calcd for C24H24F3N4 [M+H]+ 425.1948; found 425.1948.
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Page 9 of 13
The Journal of Organic Chemistry
1-(3-chlorophenyl)-4-((1-(4-chlorophenyl)-3,5-
CDCl3) δ 153.6, 149.1, 148.4, 147.4, 139.0, 138.1, 137.8,
136.2, 132.1, 126.2 , 120.7, 117.1, 116.1, 116.0, 18.2, 12.6,
12.5, 12.2, 11.0 ppm. HRMS (ESI) Calcd for C22H23BrN5
[M+H]+ 436.1131; found 436.1136.
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8
dimethyl-1H-pyrazol-4-yl)methyl)-3,5-dimethyl-1H-
pyrazole (3e). Dark brown semi-solid, yield = 75% (165 mg).
Rf 0.6 (EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ
7.42 (s, 1H), 7.37-7.34 (m, 2H), 7.32 (s, 2H), 7.27-7.24 (m,
3H), 3.52 (s, 2H), 2.18 (s, 3H), 2.14 (m, 9H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 148.4, 148.2, 140.9, 138.4, 136.17,
134.6, 132.7, 129.9, 129.0, 127.1, 125.8, 124.8, 122.5, 116.0,
116.0, 115.8, 115.8, 18.3, 12.2, 11.1, 11.0 ppm. HRMS (ESI)
Calcd for C23H23Cl2N4 [M+H]+ 425.1294; found 425.1294.
1-(3-chlorophenyl)-4-((3,5-dimethyl-1-(3-
General Procedure for Methyl Thiomethylation of
Pyrazoles. A dry round bottom flask (25 ml) was charged
with pyrazole (100 mg, 0.581 mmol), oxone (357 mg,0.581
mmol), KOAc (57 mg, 0.581 mmol) in DMSO (4 ml) at 150
oC in oil- bath for 2 h. After completion (monitored by TLC),
the reaction mixture was dried under vacuum, dissolved in
ethyl acetate and washed with H2O (3 times). The organic
phases were combined and concentrated on rotary evaporator.
The crude residue was purified using silica gel (ethyl acetate:
n-hexane) to give the desired product (Scheme S5).
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(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methyl)-3,5-
dimethyl-1H-pyrazole (3f). Yellow oil, yield = 62% (138
1
mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz,
CDCl3) δ 7.71 (s, 1H), 7.62-7.56( m, 3H), 7.45 (s, 1H), 7.38-
7.29 (m, 3H), 3.56 (t, J = 3.0 Hz, 2H), 2.22 (q, J = 1.0 Hz,
6H), 2.18 (q, J = 1.0 Hz, 6H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 148.9, 148.6, 141.1, 140.5, 136.3, 134.8, 132.0,
131.6, 130.0, 129.7, 127.7, 127.3, 125.1, 123.8, 122.8, 121.6
(q, J = 4.0 Hz), 116.4 (d, J = 7.0 Hz), 116.1 (d, J =7.0 Hz),
18.6, 12.4, 11.2 ppm. 19F NMR (400 MHz, CDCl3) δ -62.68 (s)
ppm. HRMS (ESI) Calcd for C24H22ClF3N4 [M+H]+ 459.1558;
found 459.1561.
3,5-dimethyl-4-((methylthio)methyl)-1-phenyl-1H-
pyrazole (4a). Colourless liquid, yield = 79% (106 mg). Rf 0.6
(EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.48-
7.42 (m, 4H), 7.38-7.34 (m,1H), 3.60 (s, 2H), 2.34 (s, 3H),
2.30 (s, 3H), 2.10 (s, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 148.2, 139.8, 137.3, 129.0, 127.3, 124.8, 114.1, 27.1,
15.2, 11.9, 11.0 ppm. HRMS (ESI) Calcd for C13H17N2S
[M+H]+ 233.1107; found 233.1101.
3,5-dimethyl-4-((methylthio)methyl)-1-(2-
1-(3-bromophenyl)-4-((1-(4-methoxyphenyl)-3,5-
(trifluoromethyl)phenyl)-1H-pyrazole (4b). Colourless
liquid, yield = 70% (86 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7).
1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.63
(t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6
Hz, 1H), 3.55 (s, 2H), 2.28 (s, 3H), 2.03-1.99 (m, 6H) ppm.
13C NMR{1H}(101 MHz, CDCl3) δ 148.3, 139.3, 137.5, 132.6,
130.6, 129.5, 128.5 (d, J = 31.4 Hz), 127.2 (q, J = 4.9 Hz),
123.9, 121.7, 112.8, 26.7, 14.5, 11.8, 9.9 ppm. 19F NMR (400
MHz, CDCl3) δ -60.50 (s) ppm. HRMS (ESI) Calcd for
C14H16F3N2S [M+H]+ 301.0981; found 301.0981.
dimethyl-1H-pyrazol-4-yl)methyl)-3,5-dimethyl-1H-
o
pyrazole (3g). Light brown solid, m.p. 142-144 C, yield =
62% (115 mg). Rf 0.3 (EtOAc:n-Hexane = 3:7). 1H NMR (400
MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 2H), 7.34-7.30 (m, 2H),
7.28-7.23 (m, 2H), 6.92 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 3.53
(s, 2H), 2.17-2.14 (m, 9H), 2.10 (s, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 158.8, 148.4, 147.3, 138.6, 136.4, 136.2,
133.2, 132.8, 129.1, 126.5, 125.9, 116.2, 114.9, 114.2, 55.5,
18.5, 12.2, 11.1, 10.8 ppm. HRMS (ESI) Calcd for
C24H26BrN4O [M+H]+ 465.1285; found 465.1290.
1-(3-fluorophenyl)-3,5-dimethyl-4-
1-(4-bromophenyl)-4-((1-(4-methoxyphenyl)-3,5-
((methylthio)methyl)-1H-pyrazole (4c). Colourless liquid,
1
dimethyl-1H-pyrazol-4-yl)methyl)-3,5-dimethyl-1H-
yield = 73% (96 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H
o
pyrazole (3h). Light yellow solid, m.p. 168-170 C, yield =
NMR (400 MHz, CDCl3) δ 7.45-7.40 (m, 1H), 7.25-7.22 (m,
2H), 7.09-7.04 (m, 1H), 3.58 (s, 2H), 2.33 (d, J = 3.5 Hz, 6H),
2.10 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 162.7
(d, J = 247.2 Hz), 148.8, 141.1 (d, J = 10.1 Hz), 137.3, 130.2
(d, J = 9.1 Hz), 120.0 (d, J = 3.1 Hz), 114.7, 114.1 (d, J = 21.1
Hz), 112.0 (d, J = 24.4 Hz), 27.0, 15.2, 11.9, 11.19 ppm. 19F
NMR (400 MHz, CDCl3) δ -111.34 - (-111.41) ppm. HRMS
(ESI) Calcd for C13H16FN2S [M+H]+ 251.1013; found
251.1006.
63% (117 mg). Rf 0.3 (EtOAc:n-Hexane = 3:7). 1H NMR (400
MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.31-7.29 (m, 4H), 6.97-
6.94 (m, 2H), 3.84 (s, 3H), 3.56 (s, 2H), 2.20-2.18 (m, 9H),
2.13 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 158.8,
148.5, 147.4, 139.15, 136.41, 136.1, 133.2, 132.1, 126.5,
126.2, 120.6, 116.3, 114.9, 114.2, 55.5, 18.5, 12.2, 11.1, 10.8
ppm. HRMS (ESI) Calcd for C24H26BrN4O [M+H]+ 465.1285;
found 465.1268.
4-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1-
(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole (3i). Light
yellow viscus, yield = 67% (150 mg). Rf 0.3 (EtOAc:n-Hexane
= 3:7). 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz, 1H),
7.40 (d, J = 7.0 Hz, 2H), 7.35 (d, J = 7.0 Hz, 1H), 7.30 (s, 1H),
7.28 (s, 1H), 7.26 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.84 (s,
3H), 3.57 (s, 2H), 2.19 (s, 9H), 2.13 (s, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 158.8, 147.9, 147.3, 136.4, 136.2,
129.0, 127.2, 126.5, 124.9, 115.7, 115.0, 114.1, 55.5, 18.5,
12.2, 11.0, 10.8 ppm. HRMS (ESI) Calcd for C24H27N4O
[M+H]+ 387.2179; found 387.2169.
3,5-dimethyl-4-((methylthio)methyl)-1-(m-tolyl)-1H-
pyrazole (4d). Colourless liquid, yield = 82% (108 mg). Rf 0.6
1
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.32
(t, J = 7.7 Hz, 1H), 7.27-7.24 (m, 1H), 7.16 (t, J = 7.0 Hz, 2H),
3.57 (s, 2H), 2.40 (s, 3H), 2.31 (d, J = 0.6 Hz, 3H), 2.28 (s,
3H), 2.08 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
148.1, 139.7, 139.2, 137.3, 128.7, 128.1, 125.6, 121.7, 113.9,
27.1, 21.3, 15.2, 11.9, 11.0 ppm. HRMS (ESI) Calcd for
C14H19N2S [M+H]+ 247.1263; found 247.1252.
1-(3,4-dichlorophenyl)-3,5-dimethyl-4-
((methylthio)methyl)-1H-pyrazole (4e). Colourless liquid,
1
2-(4-((1-(4-bromophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methyl)-3,5-dimethyl-1H-pyrazol-1-yl)pyridine
yield = 69% (86 mg). Rf 0.6 (EtOAc:n-Hexane = 3:7). H
(3j).
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 2.4 Hz, 1H), 7.53 (d, J
= 8.6 Hz, 1H), 7.32-7.29 (m, 1H), 3.57 (s, 2H), 2.33 (d, J = 3.5
Hz, 6H), 2.10 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3)
δ 149.2, 139.1, 137.3, 133.0, 131.1, 130.6, 126.3, 123.4, 115.1,
27.0, 15.3, 11.8, 11.1 ppm. HRMS (ESI) Calcd for
C13H15Cl2N2S [M+H]+ 301.0328; found 301.0309.
White solid, m.p. 140-142 oC, yield = 69% (173 mg). Rf 0.4
(EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 8.46-
8.40 (m, 1H), 7.79 (m, 2H), 7.60-7.54 (m, 2H), 7.34-7.27 (m,
2H), 7.17-7.14 (m, 1H), 3.58 (s, 2H), 2.59 (s, 3H), 2.20 (s,
3H), 2.18 (d, J = 2.3 Hz, 6H) ppm. 13C{1H} NMR (101 MHz,
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General Procedure for Oxidation of Bis-pyrazoles combined and concentrated on rotary evaporator. The crude
1
2
3
4
5
6
7
8
(Synthesis of 5a and 5b). A dry round bottom flask (25 ml)
was charged with bis-pyrazole (100 mg, 0.280 mmol) in
TBHP (2 ml) at 70 oC for 7 h. After completion (monitored by
TLC), the reaction mixture was dried under vacuum, dissolved
in ethyl acetate and washed with H2O (3 times). The organic
phases were combined and concentrated on rotary evaporator.
The crude residue was purified using silica gel (ethyl acetate:
n-hexane) to give the desired product (Scheme S6).
residue was purified using silica gel (ethyl acetate: n-hexane)
to give the desired product (Scheme S8).
4-(benzofuran-2-ylmethyl)-3,5-dimethyl-1-phenyl-1H-
pyrazole (5c). Colourless liquid, yield = 48% (84 mg). Rf 0.3
(EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.47-
7.41 (m, 6H), 7.37-7.33 (m, 1H), 7.26-7.16 (m,2H), 6.30
(s,1H), 3.91 (s, 2H), 2.30 (d, J = 4.3 Hz, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 157.5, 154.9, 148.2, 139.9, 137.2,
129.0, 128..8, 127.3, 124.8, 123.3, 122.5, 120.3, 113.1, 110.8,
102.4, 23.3, 11.9, 11.0 ppm. MS (ESI) Calcd for C20H19N2O
[M+H]+ 303.1492; found 303.1491.
bis(2-phenylimidazo[1,2-a]pyridin-3-yl)methane (6a).
Light brown liquid, yield = 45% (92mg). Rf 0.4 (EtOAc:n-
Hexane = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.3
Hz, 4H), 7.56–7.49 (m, 6H), 7.43 (t, J = 7.3 Hz,2H), 7.35 (d, J
= 6.9 Hz, 2H), 7.09–7.02 (m, 2H), 6.48 (t, J = 6.8 Hz, 2H),
5.00 (s, 2H)ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 145.0,
144.1, 134.2, 128.9, 128.8, 128.2, 124.3, 123.7, 117.4, 114.3,
112.3, 19.7. HRMS (ESI) Calcd for C27H21N4 [M+H]+
401.1761; found 401.1780.
3-((methylthio)methyl)-2-phenylimidazo[1,2-a]pyridine
(6a). Yellow liquid, yield = 65 % (85 mg). Rf 0.5 (EtOAc:n-
Hexane = 2:8). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 6.7
Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H),
7.49 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.31–7.21
(m, 1H), 6.92 (t, J = 6.8 Hz, 1H), 4.24 (s, 2H), 2.02 (s, 3H)
ppm. 13C{1H} NMR (101 MHz, CDCl3)δ 145.1, 144.8, 134.2,
128.6, 128.5, 127.8, 124.5, 124.1, 117.6, 115.2, 112.1, 27.3,
15.0 ppm. HRMS (ESI) Calcd for C15H15N2S [M+H]+
255.0950; found 255.0964.
Bis(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methanone
(5a). Light yellow liquid, yield = 85% (88 mg). Rf 0.5
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.49
(m, 4H), 7.43 (m, 6H), 2.36 (s, 6H), 2.31 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 187.7, 149.4, 141.9, 138.8, 129.2,
128.4, 125.4, 122.2, 13.1, 11.9 ppm. HRMS (ESI) Calcd for
C23H23N4O [M+H]+ 371.1866; found 371.1854.
(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)(1-(4-
methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)methanone
(5b). Colourless liquid, yield = 82% (85 mg). Rf 0.6
1
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.49
(d, J = 5.9 Hz, 2H), 7.44 (s, 3H), 7.33 (d, J = 6.4 Hz, 2H), 6.99
(d, J = 6.3 Hz, 2H), 3.86 (d, J = 2.7 Hz, 3H), 2.37 (d, J = 2.7
Hz, 3H), 2.32 (m, 9H) ppm. 13C{1H} NMR (101 MHz, CDCl3)
δ 187.7, 159.6, 149.3, 149.1, 142.1, 141.8, 138.8, 131.7, 129.2,
128.4, 126.9, 125.4, 122.2, 121.8, 114.4, 55.6, 13.1, 11.9,
11.8. HRMS (ESI) Calcd for C24H25N4O2 [M+H]+ 401.1972;
found 401.1947.
General Procedure for Reduction of 5a and 5b
(Synthesis of 5aa and 5bb). A dry round bottom flask (25 ml)
was charged with 5a or 5b (100 mg, 0.270 mmol.), NaBH4 (10
mg, 0.270 mmol.) in methanol (4 ml) at rt for 4 h. After
completion (monitored by TLC), the reaction mixture was
dried under vacuum, dissolved in ethyl acetate and washed
with H2O (3 times). The organic phases were combined and
concentrated on rotary evaporator. The crude residue was
purified using silica gel (ethyl acetate: n-hexane) to give the
desired product (Scheme S7).
Bis(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methanol
(5aa). Colourless liquid, yield = 79% (79 mg). Rf 0.3
(EtOAc:n-Hexane = 3:7). 1H NMR (400 MHz, MeOD) δ 6.65-
6.61 (m, 4H), 6.57-6.49 (m, 6H), 5.08 (s, 1H), 1.35 (s, 6H),
1.28 (s, 6H) ppm. 13C{1H} NMR (101 MHz, MeOD) δ 147.1,
139.2, 137.6, 128.9, 127.9, 125.5, 118.8, 62.0, 11.2, 9.9 ppm.
HRMS (ESI) Calcd for C23H25N4O [M+H]+ 373.2023; found
373.2017.
3-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl)-2-
phenylimidazo[1,2-a]pyridine (6b). Light brown liquid, yield
1
= 59% (115 mg). Rf 0.4 (EtOAc:n-Hexane = 3:7). H NMR
(400 MHz, H NMR (400 MHz, CDCl3) δ 7.77 (s, 3H), 7.69 (d,
J = 8.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.42 – 7.36 (m, 3H),
7.32 (s, 3H), 7.20 (s, 1H), 6.78 (s, 1H), 4.31 (s, 2H), 2.08 (s,
3H), 1.85 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
147.6, 144.5, 139.6, 136.6, 134.6, 128.9, 128.6,128.5, 127.7,
127.4, 125.0, 124.0, 123.3, 117.6, 117.3, 112.3, 111.5, 19.7,
12.0, 10.4ppm. HRMS (ESI) Calcd for C25H23N4 [M+H]+
379.1917; found 379.1933.
3-((1-(3-chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-
yl)methyl)-2-phenylimidazo[1,2-a]pyridine
(6c).
Light
(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)(1-(4-
yellow liquid, yield = 55% (116 mg). Rf 0.3 (EtOAc:n-Hexane
= 3:7). 1H NMR (400 MHz, CDCl3) δ 7.75 (t, J = 6.3 Hz, 3H),
7.70 (d, J = 9.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.37 (dd, J =
7.7, 5.9 Hz,2H), 7.31 (dd, J = 12.1, 7.8 Hz, 2H), 7.21 (dd, J =
10.9, 3.6 Hz, 2H), 6.80 (t, J = 6.7 Hz,1H), 4.30 (s, 2H), 2.07
(s, 3H), 1.88 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
148.3, 144.4, 143.4, 140.5, 136.7, 134.7, 134.1, 130.0, 128.6,
128.0, 127.5, 125.2, 124.4, 123.3, 122.8, 117.5, 117.2, 112.6,
112.2, 19.6, 12.0, 10.5 ppm. HRMS (ESI) Calcd for
C25H22N4Cl [M+H]+ 413.1528; found 413.1536.
methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)methanol
(5bb). Colourless liquid, yield = 73% (73 mg). Rf 0.6
(EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ 7.45
(d, J = 7.4 Hz,2H), 7.42 – 7.37 (m, 3H), 7.29 (d, J = 8.9
Hz,2H), 6.96 (d, J = 8.9 Hz, 2H), 5.99 (s, 1H), 3.85 (s, 3H),
2.28 (s, 3H), 2.22 (d, J = 2.9 Hz, 9H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 159.1, 147.2, 146.7, 139.6, 137.1, 136.8,
132.6, 129.0, 127.6, 126.9, 125.4, 118.6, 118.1, 114.2, 63.5,
55.5, 12.8, 12.8, 11.4, 11.2 ppm. HRMS (ESI) Calcd for
C24H27N4O2 [M+H]+ 403.2129; found 403.2119.
1
General Procedure for Synthesis of 5c. A dry round
bottom flask (25 ml) was charged with pyrazole 1 (100 mg,
0.581 mmol), benzofuran (68 mg, 0.581 mmol), oxone (356
3-(benzofuran-2-ylmethyl)-2-phenylimidazo[1,2-
a]pyridine (6d). Dark yellow liquid, yield = 56 % (93 mg). Rf
1
0.5 (EtOAc:n-Hexane = 3:7). H NMR (400 MHz, CDCl3) δ
o
mg, 0.581 mmol) in DMSO (4 ml) at 150 C in oil-bath for 2
7.97 (d, J = 6.9 Hz, 1H), 7.89–7.81 (m, 2H), 7.70 (d, J = 9.1
Hz, 1H), 7.46 (t, J = 7.3 Hz, 4H), 7.37 (t, J = 7.4 Hz, 1H),
7.29–7.16 (m, 3H), 6.81 (t, J = 6.7 Hz, 1H), 6.35 (s, 1H), 4.56
(s, 2H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 156.5,
h. After completion (monitored by TLC), the reaction mixture
was dried under vacuum, dissolved in ethyl acetate and
washed with H2O (3 times). The organic phases were
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155.2, 146.4, 145.7, 135.5, 130.1, 129.8, 129.3, 125.9, 125.4, = 7.8 Hz, 1H), 7.74 (d, J = 7.9 Hz, 0.16 H), 7.65 (d, J = 7.9
1
2
3
4
5
6
7
8
124.8, 124.3, 122.1, 119.1, 116.1, 113.8, 112.4, 105.1, 25.7
ppm. HRMS (ESI) Calcd for C22H17N2O [M+H]+ 325.1335;
found 325.1349.
Hz, 0.20 H), 7.46 (d, J = 4.1 Hz, 0.5 H), 7.40 (d, J = 4.5 Hz,
0.81 H), 7.36 (dd, J = 10.4, 5.9 Hz, 1.69 H), 7.29 (d, J = 8.0
Hz, 0.23 H), 7.26 (s, 1.58 H), 6.96 (s, 0.16 H), 6.84 (s, 0.95
H), 4.03 (s, 0.34 H), 3.95 (s, 2H), 2.28 (d, J = 4.0 Hz, 1.09 H),
2.23 (d, J = 7.4 Hz, 6H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 148.3, 148.0, 145.6, 140.9, 140.1, 138.7, 136.9,
135.0, 129.0, 127.2, 127.2, 124.9, 124.8, 124.3, 124.1, 124.0,
123.6, 123.0, 122.9, 122.1, 121.5, 120.5, 114.8, 30.9, 25.1,
23.1, 12.0, 11.1 ppm. HRMS (ESI) Calcd for C20H19N2S
[M+H]+ 319.1263; found 319.1276.
General Procedure for Gram Scale Synthesis of
Symmetric Bis-pyrazoles (Table 2, entry 2a). A dry round
bottom flask (50 ml) was charged with 3,5-dimethyl-1-phenyl-
1H-pyrazole (4.0 g, 23.26 mmol), oxone® (14.28 g, 23.26
mmol)) in DMSO (10 ml) at 150 oC in oil-bath for 2.5 h. After
completion (monitored by TLC), the reaction mixture was
dried under vacuum, dissolved in ethyl acetate and washed
with H2O (3 times). The organic phases were combined and
concentrated on rotary evaporator. The crude residue was
purified using silica gel (ethyl acetate: n-hexane) to give the
desired symmetric bis-pyrazole product (2a, 4.47 g, 54%).
3-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl)-6-
methyl-2-phenylimidazo[1,2-a]pyridine (6e). Light yellow
liquid, yield = 50 % (94 mg). Rf 0.5 (EtOAc:n-Hexane = 3:7).
1H NMR (400 MHz, CDCl3) δ 7.79 – 7.77 (m, 2H), 7.61 –
7.56 (m, 2H), 7.49 – 7.41 (m, 4H), 7.39 – 7.32 (m, 4H), 7.08-
7.05 (dd, J = 9.2, 1.4 Hz, 1H), 4.29 (s, 2H), 2.32 (s, 3H), 2.12
(s, 3H), 1.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
149.1, 145.1, 144.8, 141.0, 138.0, 136.3, 130.3, 129.9,129.9
128.9, 128.8, 128.4, 126.4, 123.2, 122.3, 118.4, 118.3, 113.2,
21.1, 19.9, 13.4, 11.8 ppm. HRMS (ESI) Calcd for C26H25N4
[M+H]+ 393.2074; found 393.2085.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3,5-dimethyl-4-((3-methylfuran-2-yl)methyl)-1-phenyl-
1H-pyrazole (6f). Yellow liquid, yield = 38 % (58 mg). Rf 0.5
1
1
(EtOAc:n-Hexane = 0.5:9.5). H NMR (400 MHz, CDCl3) H
NMR (400 MHz, CDCl3) δ 7.46–7.41 (m, 4H), 7.34-7.31 (m,
1H), 5.83 (s, 1H), 5.77 (s, 1H), 3.70 (s, 2H), 2.25 (d, J = 4.4
Hz, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.5, 150.5,
147.8, 140.1, 137.1, 128.8, 127.1, 124.8, 114.5, 105.8, 22.8,
13.5, 11.9, 10.9 ppm. HRMS (ESI) Calcd for C17H19N2O
[M+H]+ 267.1492; found 267.1501.
The KIE Experiment. A dry round bottom flask (25 ml)
was charged with pyrazole (100 mg, 0.581 mmol), oxone (356
mg, 0.581 mmol)) in DMSO (2 ml), DMSO-d6 (2 ml) at 150
oC for 2 h. After completion (monitored by TLC), the reaction
mixture was dried under vacuum, dissolved in ethyl acetate
and washed with H2O (3 times). The organic phases were
combined and concentrated on rotary evaporator. The crude
3,5-dimethyl-4-((5-methylthiophen-2-yl)methyl)-1-
phenyl-1H-pyrazole (6g). Colourless liquid, yield = 35 % (57
mg). Rf 0.5 (EtOAc:n-Hexane = 0.5:9.5). 1H NMR (400 MHz,
CDCl3) δ 7.46–7.39 (m, 1H), 7.34-7.30 (m, 1H), 6.53 (s, 2H),
3.86 (s, 1H), 2.40 (s, 3H), 2.25 (d, J = 6.1 Hz, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 147.9, 142.1, 140.1,
137.8, 136.6, 129.0, 127.1, 124.8, 124.6, 123.7, 116.6, 24.3,
15.3, 11.9, 11.0 ppm. HRMS (ESI) Calcd for C17H19N2S
[M+H]+ 283.1263; found 283.1272.
1
residue was analyzed by H NMR for determination of KH/KD
value (Scheme S9).
ASSOCIATED CONTENT
Supporting Information
DFT study, X-ray crystal structure data of 3j, characterization data
of all compounds; 1H and 13C NMR and HRMS spectra. (PDF)
3,5-dimethyl-4-((3-methylthiophen-2-yl)methyl)-1-
phenyl-1H-pyrazole
and
3,5-dimethyl-4-((4-
methylthiophen-2-yl)methyl)-1-phenyl-1H-pyrazole (6h).
Colourless liquid, yield = 40 % (65 mg). Rf 0.5 (EtOAc:n-
Hexane = 0.5:9.5). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 0.28
H), 7.44 (d, J = 6.1 Hz, 4H), 7.42 (s, 0.35 H), 7.34 (dd, J = 7.4,
4.9 Hz, 1H), 7.01 (d, J = 5.1 Hz, 1H), 6.80 (d, J = 5.1 Hz, 1H),
6.68 (s, 0.21H), 6.56 (s, 0.23 H), 3.89 (s, 0.54 H), 3.83 (s, 2H),
2.26 (s, 0.73 H), 2.25 (s, 3 H), 2.23 (d, J = 3.5 Hz, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 147.9, 144.3, 140.1, 138.2,
137.4, 136.7, 132.2, 130.0, 129.0, 127.2, 126.5, 124.9, 121.6,
118.5, 116.6, 24.3, 22.4, 15.8, 13.8, 12.0, 11.0 ppm. HRMS
(ESI) Calcd for C17H19N2S [M+H]+ 283.1263; found 283.1274.
2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1-
methyl-1H-benzo[d]imidazole (6i). Colourless liquid, yield =
AUTHOR INFORMATION
Corresponding Author
* Email: sdsawant@iim.res.in; sdsawant@iiim.ac.in
Author Contributions
▲These authors contributed equally.
ACKNOWLEDGMENT
The funding support from CSIR-India funded project HCP0008 is
gratefully acknowledged. PKV is thankful to DST-SERB for the
Fast-track Young Scientist Grant. IIIM communication No.
IIIM/2019.
1
30 % (55 mg). Rf 0.5 (MeOH: DCM = 2:8). H NMR (400
MHz, CDCl3) δ 8.74 (s, 1H), 7.84–7.59 (m, 3H), 7.56–7.36 (m,
4H), 5.65 (s, 1H), 4.27 (s, 2H), 2.36 (d, J = 37.9 Hz, 6H), 2.17
(s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 147.8, 139.8,
139.1, 132.5, 131.1, 129.2, 128.1, 127.0, 125.2, 113.1, 112.7,
109.4, 42.4, 31.1, 12.4, 11.2 ppm. HRMS (ESI) Calcd for
C20H21N4 [M+H]+ 317.1761; found 317.1777.
REFERENCES
(1)
(a) Martin, D.; Weise, A.; Niclas, H. J. The Solvent
Dimethyl Sulfoxide. Angew. Chem., Int. Ed. 1967, 6, 318-334. (b)
Wang, Z.; Richter, S. M.; Gates, B. D.; Grieme, T. A. Safety
Concerns in a Pharmaceutical Manufacturing Process Using Dimethyl
Sulfoxide (DMSO) as a Solvent. Org. Process Res. Dev. 2012, 16,
1994-2000. (c) Ashcroft, C. P.; Dunn, P. J.; Hayler, J. D.; Wells, A. S.
Survey of Solvent Usage in Papers Published in Organic Process
Research & Development 1997–2012. Org. Process Res. Dev. 2015,
19, 740-747.
4-(benzo[b]thiophen-2-ylmethyl)-3,5-dimethyl-1-
phenyl-1H-pyrazole and 4-(benzo[b]thiophen-3-ylmethyl)-
3,5-dimethyl-1-phenyl-1H-pyrazole (6j). Yellow liquid,
yield = 38 % (70 mg). Rf 0.5 (EtOAc:n-Hexane = 9.5:0.5). 1H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.83 (d, J
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