Denitrative imino-diaza-Nazarov cyclization: Synthesis of pyrazoles

Article abstract of DOI:10.1039/d0ob01200a

An iodine-catalyzed denitrative imino-diaza-Nazarov cyclization (DIDAN) methodology has been developed for the synthesis of pyrazoles with high to excellent yields by using α-nitroacetophenone derivatives and in situ generated hydrazones. The key transformation of this oxidative 4π-electrocyclization proceeds through an enamine-iminium ion intermediate. This rapid one-pot DIDAN protocol results in the selective generation of C-C and C-N bonds and cleavage of a C-N bond. This journal is

Full text of DOI:10.1039/d0ob01200a

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Denitrative imino-diaza-Nazarov cyclization:
synthesis of pyrazoles†
Cite this: DOI: 10.1039/d0ob01200a
Balakrishna Aegurla, Nisha Jarwal and Rama Krishna Peddinti
*
An iodine-catalyzed denitrative imino-diaza-Nazarov cyclization (DIDAN) methodology has been devel-
oped for the synthesis of pyrazoles with high to excellent yields by using α-nitroacetophenone derivatives
and in situ generated hydrazones. The key transformation of this oxidative 4π-electrocyclization proceeds
through an enamine–iminium ion intermediate. This rapid one-pot DIDAN protocol results in the selec-
tive generation of C–C and C–N bonds and cleavage of a C–N bond.
Received 10th June 2020,
Accepted 14th July 2020
DOI: 10.1039/d0ob01200a
rsc.li/obc
1
5,16
Five-membered nitrogen containing heterocyclic rings are struction of 5-membered heterocyclic compounds.
In the
excellent auxiliary structures that broadly exist in natural pro- beginning of the twentieth century, the concept of imino/aza-
ducts, biologically active compounds, and functional Nazarov cyclization has been introduced. The Nazarov reaction
1
materials. Of particular note is the pyrazole unit that forms that proceeds through an imino/enamine–imino intermediate,
the core scaffold of bioactive molecules displaying antibacter- instead of the classical ketone functionality, is called the
2
3
4
ial, antiinflammatory, antimicrobial and analgesic activities. imino-Nazarov reaction (Scheme 1).
5
a,16b,d
17
18
19
20
They also form the core structural architectures of valuable
therapeutic agents that have been successfully commercia- Liao,
The Frontier,
Tius, Klumpp, Hsung, West,
5
21a
21b
22
Liu
and Würthwein research groups explored the
lized, such as the bestseller drugs Viagra, Celebrex, and advancement of the Nazrov cyclization reactions. We success-
6
Acomplia. Apart from these applications, pyrazoles can also fully established a new approach for the synthesis of polysub-
be used as ligands in various transition metal-catalyzed cross-
7
coupling reactions. As a result, numerous synthetic routes
have been investigated for the preparation of pyrazoles via the
8
cyclization process. Routinely, these pyrazoles can be syn-
thesized by the 1,3-dipolar cycloaddition of hydrazines with
9
alkenes/alkynes and by the condensation of 1,3-diketones/
1
0
11
α,β-unsaturated carbonyls and β-nitrostyrenes with hydra-
zine derivatives. With the developing enthusiasm for the con-
1
2
struction of pyrazoles, several transition metal-mediated and
1
3
metal-free approaches have been explored over the past few
decades.
8
–14
Despite the sizeable work presented in the literature,
new and sustainable synthetic techniques for the synthesis of
pyrazoles with high selectivity under mild and economic con-
ditions are still in high demand. Among them the Nazarov-
type cyclization reaction is one of the most versatile and
efficient methods for C–C and C–N bond formation in the con-
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247667,
Uttarakhand, India. E-mail: rkpeddinti@cy.iitr.ac.in; Fax: +91-133-227-3560;
Tel: +91-133-228-5438
†
Electronic supplementary information (ESI) available. CCDC 1855981. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob01200a
Scheme 1 Nazarov-type cyclizations.
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stituted pyrazoles via the diaza-Nazarov (DAN) cyclization 7). To investigate the effect of the solvent on the reaction, we
involving a 2,3-diazapentadienyl cation using a stoichiometric performed the reaction in solvents such as MeOH, CH CN,
3
2
3
amount of iodine. It occurred to us that the in situ generated THF, and DCE. These reactions afforded pyrazole 3a in 76, 77,
aldehyde hydrazones would undergo molecular Lewis acid- 57, and 64% yields, respectively, along with uncyclized product
catalyzed imino-diaza-Nazarov (IDAN) cyclization and/or B in about 20% yield (entries 8–11). EtOH was considered to
DIDAN cyclization with α-nitroacetophenones to provide the be the best solvent for this transformation (entry 4).
3 2
corresponding pyrazoles (Scheme 1). Thus, in continuation of Furthermore, catalysts such as PTSA, BF ·OEt and TFA were
2
4
our endeavours to develop green conventions, we carried out screened. No improvement in the yield of product 3a was
the reaction of in situ generated aldehyde hydrazones with observed with these promoters (entries 12–14). On the basis of
α-nitroacetophenones in the presence of a catalytic amount of the above findings, we recognised that iodine (20 mol%) in
iodine leading to diversely substituted pyrazoles and herein, EtOH with model substrates at 80 °C was optimum in terms of
we present our results.
the reaction efficiency and yield (entry 4). The uncyclized B,
To probe the conceived objective, in a pilot experiment, we under optimization conditions, could be transformed into pyr-
inspected the reaction between benzaldehyde (1a), hydrazine azole 3a in 61% yield.
hydrate and α-nitroacetophenone (2a) under solvent-free con-
With the optimized reaction conditions in hand, we scruti-
ditions. The reaction afforded the pyrazole product 3a only in nized the generality of this one-pot, iodine-catalysed denitra-
a trace amount (entry 1, Table 1). The in situ generated hydra- tive-imino-diaza-Nazarov-type (DIDAN) cyclization. In this
zone underwent the reaction with α-nitroacetophenone (2a) in direction, we have chosen different benzaldehydes 1a–c and
the presence of equimolar molecular iodine in EtOH at 80 °C. performed the reaction with α-nitroacetophenones 2a–f under
The reaction was accomplished in 6 h to afford a complex the above mentioned conditions. In these cases, substrates 1
mixture of products from which the major denitrative pyrazole and 2 bearing electron-donating as well as electron-withdraw-
derivative 3a was isolated in 67% yield along with uncyclized ing substituents provided the corresponding pyrazole deriva-
compound B in 20% yield (entry 2). When 50 mol% of mole- tives 3–8 in high to excellent yields of 68–94% (Scheme 2). The
cular iodine was used in the reaction, product 3a was obtained structures of the cyclized products were assigned on the basis
1
13
in an improved yield of 78% (entry 3). A perfect isolation of 3a of their H (400 MHz) and C (100 MHz) NMR data and DEPT
in 94% yield was achieved in 2 h when the reaction was carried spectroscopic and ESI-MS spectrometric analysis. The struc-
out in the presence of 20 mol% iodine (entry 4). No improve- ture of pyrazole 7c was further confirmed by its single-crystal
ment in the yield of 3a was observed on lowering the amount
of iodine (entry 5). Screening of the reaction temperature was
also carried out, and 80 °C was found to be the optimal temp-
erature to obtain the products in better yields (entries 4, 6 and
a
Table 1 Optimization of reaction conditions
b
Reagent
Entry (mol%)
Temp.
Solvent (°C)
Time
(h)
% yield 3a/
B
1
2
3
4
5
6
7
8
9
1
1
1
1
1
I
I
I
I
I
I
I
I
I
I
I
2
2
2
2
2
2
2
2
2
2
2
(0)
Neat
80
80
80
80
80
90
70
6
6
6
2
4
2
2
24
24
24
24
24
24
24
Traces
67/20
78/12
94/traces
91/traces
90/traces
86/traces
76/19
77/20
57/16
64/23
86/traces
71/15
(100)
(50)
(20)
(10)
(20)
(20)
(20)
(20)
(20)
(20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH 80
ACN
THF
DCE
80
80
80
80
80
80
0
1
2
3
4
PTSA (20)
BF ·OEt (20)
TFA (20)
EtOH
EtOH
EtOH
3
2
78/traces
a
Reaction conditions: 1a (0.6 b mmol), hydrazine hydrate 80% Scheme 2 Substrate scope for the DIDAN cyclization reaction of
α-nitroacetophenones 2.
(1 mmol), 2a (0.4 mmol), reagent. Isolated yield.
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X-ray diffraction analysis (see the ESI, Fig. S1†). The NMR
spectra of products 3b & 4a are identical. Similarly, each
product of the other two sets 3c & 5a and 4c & 5b has identical
spectral data. This indicates that, most likely, the proton in the
pyrazole ring is delocalized between the two nitrogen atoms of
the heterocycle. Although the position of the proton in the pyr-
azole ring is shown in the structures on one nitrogen atom, in
principle, it can be on either of the two nitrogen atoms due to
2
5
prototropic tautomerism.
The reaction presumably proceeds through regioselective
denitrative imino-diaza-Nazarov (DIDAN) cyclization. The oxi-
dative
cyclization
reaction
occurs
between
easily
accessible in situ generated aldehyde hydrazones with
α-nitroacetophenone derivatives through the enamine–
iminium ion intermediate to furnish various substituted pyra-
Scheme 4 Scope of the DIDAN cyclization reaction for aliphatic
zoles in excellent yields (vide supra). To the best of our knowl- α-nitroketone 2g.
edge, α-nitroacetophenones were not accounted for the con-
struction of pyrazoles.
Further to investigate the extent of this metal-free DIDAN
protocol, we tested heteroaromatic aldehydes such as 2-for-
mylthiophene (1d) and furfural (1e). Notably, the reaction of
2
a,b with 1d afforded products 9a and 9b in 2 h in 75 and
6
7% yields, respectively. In the case of 2c, the reaction
afforded the pyrazole product 9c only in trace amounts.
Similarly, when we performed the reaction between 1e and 2a,
the pyrazole derivative 10a was obtained in trace amounts Scheme 5 Gram-scale preparation.
(Scheme 3).
The functionalization of the aliphatic compounds is a
more challenging task than functionalizing aromatic com-
pounds due to the less reactivity of the former compounds. optimal conditions, and the product 4a was isolated in 74%
Our previous DAN approach failed to provide the yield (Scheme 5).
2
3
cyclized product in the case of aliphatic ketones.
Remarkably, this current one-pot, three-component DIDAN Lewis acid catalysts such as PTSA, BF
The DDIAN cyclization reaction is successful in the case of
3
·OEt and TFA. Only a
2
strategy was successful with easily accessible aliphatic 1-nitro- catalytic amount of molecular iodine was used to activate the
nonan-2-one 2g with aldehydes 1a–c. To our delight, the reaction. The reaction would require a stoichiometric amount
cyclized products 11a–c were obtained in 2 h in high yields of of I
3–81% (Scheme 4).
indicates that there is no C–I bond formation in the reaction
To scrutinize the scalability of the established protocols, and I simply acted as a Lewis acid promoter for the synthesis
2
to proceed through an α-iodinated intermediate. This
7
2
the synthesis of 2b on a gram-scale was carried out under the of pyrazoles via activating the diamine–iminium ion inter-
1
mediate C (Scheme 6). H NMR evidence for intermediate B/C
supports this assumption (see the ESI†). These observations
suggest that the cyclization takes place without α-iodination,
unlike in the diaza-Nazarov cyclization of acetophenones,
23
where iodine was used in a stoichiometric amount.
Based on the above findings and previous literature
1
4,22,23,26
studies,
a plausible mechanism for the DIDAN cycliza-
tion is proposed in Scheme 6. Initially the hydrazone, gener-
ated from aldehyde 1 and hydrazine hydrate, undergoes con-
densation with α-nitroacetophenone 2a to produce intermedi-
ate A which tautomerizes to enamine–imine B. Next the mole-
cular iodine activates the nitro group of B to deliver diimine–
iminium ion intermediate C. The conformational variation of
s-trans diimine C to s-cis diimine subsequently leads to 2,3-
diaza-pentadienyl cation D, which is stabilized by the delocali-
zation of the positive charge. The cation D then undergoes
4π-electrocyclization ring closure to produce diaza-allyl cation
Scheme 3 Scope of the DIDAN cyclization reaction of heteroaromatic
aldehydes 1.
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Scheme 6 Possible reaction mechanism.
E, which upon denitrative aromatization provides exclusively 5%) was added as a co-D-solvent to CDCl3 to solubilise the
five-membered heterocycle 3.
compound.
Conclusions
General procedure for the synthesis of
27
α-nitroketones 2
In summary, we have delineated an unprecedented iodine-
catalyzed denitrative-imino-diaza-Nazarov cyclization for the
synthesis of pyrazoles using in situ generated hydrazones and
α-nitroacetophenones. This one-pot, three-component protocol
provided pyrazoles in good to excellent yields under eco-
friendly conditions. The transformation proceeds through the
enamine–imino diaza-Nazarov 4π-electrocyclization. The sim-
plicity of the experimental procedure and the ready accessibil-
ity of the precursors thus make this an experimentally attrac-
tive technique for the construction of nitrogenous
heterocycles.
t
To a DMSO (25 mL) solution of KO Bu (3.1 g, 27.5 mmol)
was added nitromethane (1.48 mL, 27.5 mmol) at RT and
stirred for 1 h and then phenyl benzoate (2.0 g, 10.1 mmol)
was added. The reaction contents were further stirred at RT
for 2 h. The reaction mixture was poured in ice water and
1
2
mol L− aq. HCl solution was added to neutralise the
mixture. The resulting solid substance was filtered and dried
to obtain α-nitroketone product 2 as a white solid in quanti-
tative yield. This was used for the next step without
purification.
General information
General procedure for the synthesis of
substituted pyrazoles 3–10
Unless otherwise noted, chemicals were purchased from com-
mercial suppliers at the highest purity grade available and
were used without further purification. Thin layer chromato- To a benzaldehyde derivative 1 (0.4 mmol) was added hydra-
graphy was performed on 0.25 mm silica gel plates (60F-254) zine hydrate (80% in water, 0.033 g, 1.0 mmol) under solvent-
using UV light as the visualizing agent. Silica gel free conditions. After the addition of hydrazine hydrate, a
(100–200 mesh) was used for column chromatography. Melting yellow solid was formed within a minute which indicated the
points were determined on capillary point apparatus equipped formation of the hydrazone derivative. To the thus formed
with a digital thermometer and were uncorrected. Nuclear hydrazone derivative was added the above synthesized
magnetic resonance spectra were recorded on 400 and α-nitroketone 2 (0.3 mmol) in EtOH (4 mL) followed by iodine
5
00 MHz spectrometers, and chemical shifts are reported in δ (0.016 g, 0.06 mmol, 20 mol%). Then the reaction mixture was
units, parts per million (ppm), relative to residual chloroform refluxed at 80 °C on a pre-heated oil bath for 2 h. After com-
7.26 ppm) or DMSO (2.5 ppm) in the deuterated solvent or pletion of the reaction, as judged by TLC, the reaction mixture
with tetramethylsilane (TMS, δ 0.00 ppm) as the internal stan- was quenched with a saturated sodium thiosulfate solution
(
1
3
dard. C NMR spectra were referenced to CDCl
3
(δ 77.0 ppm, and extracted twice with ethyl acetate (2 × 15 mL). The organic
the middle peak) and DMSO-d (δ 39.5 ppm, the middle peak). layer was washed with water and dried over anhyd. sodium
6
Coupling constants were expressed in Hz. The following sulfate. The solvent was evaporated under reduced pressure,
abbreviations were used to explain the multiplicities: s = and the residue was subjected to silica gel column chromato-
singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of graphy using ethyl acetate in hexanes as the eluent to afford a
doublet, brs = broad singlet. In some cases, DMSO-d (about pure pyrazole derivative.
6
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7
2
.60 (d, J = 9.2 Hz, 2H), 7.32–7.23 (m, 3H), 6.81 (t, J = 9.2 Hz,
Characterization data
1
3
H), 6.69 (s, 1H), 3.77 (s, 3H); C NMR (100 MHz, CDCl +
3
3
,5-Diphenyl-1H-pyrazole (3a)
6
DMSO-d ): δ 159.4, 148.9, 147.9, 131.6, 128.6, 127.8, 126.8,
1
Yield: 0.062 g (94%) as a brown solid; H NMR (400 MHz, 125.5, 123.8, 114.0, 99.1, 55.1.
CDCl ): δ 7.69 (d, J = 5.6 Hz, 4H), 7.33–7.29 (m, 6H), 6.80 (s,
3
1
3
3
-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole (5b)
Yield: 0.066 g (82%) as a brown solid; mp: 128–129 °C;
NMR (500 MHz, CDCl + DMSO-d ): δ 7.66 (q, J = 14.4 Hz, 2H),
1
1
H); C NMR (100 MHz, CDCl
25.6, 100.0; HRMS (ESI) m/z: [M + H] calculated for
3
): δ 148.7, 131.2, 128.8, 128.1,
+
1
H
C H N , 221.1073; found, 221.1041.
1
5
12 2
3
6
7
.58 (d, J = 9.2 Hz, 2H), 6.97 (t, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8
3
-(4-Fluorophenyl)-5-phenyl-1H-pyrazole (3b)
Yield: 0.061 g (86%) as a brown solid; mp: 189–190 °C;
NMR (200 MHz, CDCl + DMSO-d ): δ 7.76–7.72 (m, 4H),
.36–7.33 (m, 2H), 7.27–7.23 (m, 1H), 7.05–7.01 (m, 2H), 6.75
1
3
3
Hz, 2H), 6.61 (s, 1H), 3.75 (s, 3H); C NMR (100 MHz, CDCl +
DMSO-d
1
m/z: [M + H] calculated for C16
269.1082.
1
1
H
6
): δ 162.2 (d, JC,F = 244 Hz), 159.3, 148.2, 147.1,
3
6
28.2, 127.1, 127.0, 115.4, 115.2, 113.9, 98.6, 55.0; HRMS (ESI)
+
7
H14FN
2
O, 269.1085; found,
1
3
(
s, 1H); C NMR (100 MHz, CDCl + DMSO-d ): δ 161.6 (d,
J
3
6
1
2
C,F = 245 Hz), 146.9 (d,
JC,F = 39 Hz), 130.7, 128.1, 127.2,
1
26.6, 126.5, 124.8, 114.9, 114.7, 98.6; HRMS (ESI) m/z: [M + 3,5-Bis(4-methoxyphenyl)-1H-pyrazole (5c)
+
H] calculated for C H FN , 239.0979; found, 239.0986.
1
1
5
12
2
Yield: 0.057 g (68%) as a brown solid; mp: 171–173 °C;
NMR (500 MHz, CDCl + DMSO-d
.83 (d, J = 9.2 Hz, 4H), 6.60 (s, 1H), 3.75 (s, 6H (2-OCH3);
NMR (100 MHz, CDCl + DMSO-d ): δ 159.2, 148.0, 126.7,
24.3, 113.9, 98.2, 55.0; HRMS (ESI) m/z: [M + H] calculated
for C H N O , 281.1285; found, 281.1297.
H
3
6
): δ 7.61 (d, J = 9.2 Hz, 4H),
3
-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole (3c)
Yield: 0.061 g (81%) as a brown solid; mp: 155–156 °C;
NMR (400 MHz, CDCl ): δ 7.70 (d, J = 7.6 Hz, 2H), 7.62 (d, J =
.0 Hz, 2H), 7.37–7.30 (m, 3H), 6.87 (d, J = 8.0 Hz, 2H), 6.72 (s,
1
3
6
C
1
H
3
6
3
+
1
8
1
1
1
7
17 2 2
1
3
H), 3.81 (s, 3H); C NMR (100 MHz, CDCl ): δ 159.6, 149.0,
3
48.2, 131.5, 128.8, 128.0, 126.9, 126.8, 125.7, 114.2, 99.4, 55.3;
5
-(3-Chlorophenyl)-3-phenyl-1H-pyrazole (6a)
Yield: 0.061 g (80%) as a brown solid; mp: 208–207 °C;
NMR (500 MHz, CDCl3 + DMSO-d ): δ 7.73–7.58 (m, 4H),
+
HRMS (ESI) m/z: [M + H] calculated for C16
found, 251.1178.
H
15
N
2
O, 251.1179;
1
H
6
1
3
7
3
.32–7.14 (m, 5H), 6.73 (s, 1H); C NMR (100 MHz, CDCl +
5
-(4-Fluorophenyl)-3-phenyl-1H-pyrazole (4a)
Yield: 0.062 g (87%) as a brown solid; mp: 188–190 °C;
NMR (500 MHz, CDCl + DMSO-d
t, J = 9.0 Hz, 2H), 7.26–7.23 (m, 1H), 7.05–7.01 (m, 2H), 6.74
DMSO-d ): δ 134.2, 129.7, 128.5, 127.7, 127.3, 125.2, 125.4,
1
6
H
+
9
2
9.4; HRMS (ESI) m/z: [M + H] calculated for C H ClN ,
15
11
2
3
6
): δ 7.74–7.71 (m, 4H), 7.34
55.0684; found, 255.0683.
-(3-Chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazole (6b)
(
1
3
(s, 1H); C NMR (125 MHz, CDCl + DMSO-d + CD OD): δ
3 6 3
5
1
1
61.7 (d, JC,F = 245 Hz), 147.1, 130.6, 128.1, 127.3, 126.6,
1
Yield: 0.065 g (79%) as a brown solid; mp: 202–201 °C;
NMR (500 MHz, CDCl + DMSO-d
7.31–7.22 (m, 4H), 7.16 (d, J = 4.0 Hz, 1H), 6.97 (s, 1H), 6.65 (s,
H
1
26.6, 124.8, 115.0, 114.8, 99.7.
3
6
): δ 7.66 (d, J = 6.8 Hz, 2H),
3
,5-Bis(4-fluorophenyl)-1H-pyrazole (4b)
1
3
1
1
1H); C NMR (100 MHz, CDCl + DMSO-d ): δ 162.4 (d, J
=
3
6
C,F
Yield: 0.062 g (80%) as a brown solid; mp: 168–169 °C;
NMR (500 MHz, CDCl + DMSO-d ): δ 7.67 (t, J = 6.0 Hz, 4H),
H
247 Hz), 134.5, 133.6, 129.9, 127.6, 127.4, 127.2, 127.1, 125.4,
3
6
+
1
3
123.5, 115.7, 115.5, 99.6; HRMS (ESI) m/z: [M + H] calculated
7
+
1
.10 (t, J = 8.6 Hz, 4H), 6.64 (s, 1H); C NMR (100 MHz, CDCl
3
1
for C H ClFN , 273.0589; found, 273.0600.
1
5
10
2
DMSO-d
15.5, 115.3, 99.0; HRMS (ESI) m/z: [M + H] calculated for
, 257.0885; found, 257.0862.
6
): δ 162.2 (d, JC,F = 244 Hz), 127.7, 127.1, 127.0,
+
(
3-Chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole (6c)
Yield: 0.061 g (71%) as a brown solid; mp: 128–129 °C;
NMR (500 MHz, CDCl + DMSO-d ): δ 7.74 (s, 1H), 7.59 (d, J =
.4 Hz, 3H), 7.26–7.16 (m, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.56 (s,
H), 3.73 (s, 3H); C NMR (100 MHz, CDCl + DMSO-d ): δ
59.2, 148.1, 146.5, 134.2, 129.7, 127.3, 126.6, 125.3, 123.4,
15 11 2 2
C H F N
1
H
5
-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole (4c)
Yield: 0.062 g (77%) as a brown solid; mp: 205–206 °C;
NMR (500 MHz, CDCl ): δ 7.57 (q, J = 5.5 Hz, 2H), 7.51 (d, J =
.5 Hz, 2H), 6.92 (t, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H),
): δ 162.4
C,F = 247 Hz), 159.5, 148.7, 147.5, 128.0, 127.2, 127.1,
26.7, 123.2, 115.6, 115.4, 114.1, 98.9, 55.1; HRMS (ESI) m/z:
3
6
1
8
1
1
1
H
1
3
3
6
3
8
6
+
1
3
23.3, 113.9, 99.8, 55.0; HRMS (ESI) m/z: [M + H] calculated
.56 (s, 1H), 3.76 (s, 3H); C NMR (100 MHz, CDCl
3
1
for C H ClN O, 285.0789; found, 285.0785.
(d,
J
16 13
2
1
+
3-Phenyl-5-(m-tolyl)-1H-pyrazole (7a)
[M
+
H] calculated for
16 2
C H14FN O, 269.1085; found,
1
2
69.1088.
Yield: 0.053 g (76%) as a brown solid; mp: 180–182 °C; H
NMR (500 MHz, CDCl ): δ 7.71–7.69 (m, 2H), 7.49–7.47 (m,
3
5
-(4-Methoxyphenyl)-3-phenyl-1H-pyrazole (5a)
2
H), 7.29–7.26 (m, 3H), 7.18 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.4
1
13
Yield: 0.060 g (79%) as a brown solid; mp: 153–154 °C;
H
3
Hz, 1H), 6.76 (s, 1H), 2.25 (s, 3H); C NMR (100 MHz, CDCl ):
NMR (500 MHz, CDCl + DMSO-d ): δ 7.69 (d, J = 8.4 Hz, 2H), δ 148.6, 138.2, 131.3, 130.1, 128.6, 128.5, 127.8, 126.2, 125.5,
3
6
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+
1
22.7, 99.7, 21.3; HRMS (ESI) m/z: [M + H] calculated for 127.7, 125.7, 101.0, 31.8, 29.2, 29.0, 26.4, 22.6, 14.1; HRMS
+
C H N , 235.1230; found, 235.1222.
(ESI) m/z: [M + H] calculated for C H N , 243.1856; found,
16 22 2
1
6
14
2
2
43.1860.
3
-(4-Fluorophenyl)-5-(m-tolyl)-1H-pyrazole (7b)
Yield: 0.060 g (79%) as a brown solid; mp: 158–159 °C;
NMR (500 MHz, CDCl ): δ 7.69–7.66 (m, 2H), 7.45 (d, J = 8.0
Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.02
1
3-(4-Fluorophenyl)-5-heptyl-1H-pyrazole (11b)
H
1
3
Yield: 0.059 g (76%) as a brown solid; mp: 214–215 °C;
NMR (400 MHz, CDCl ): δ 7.70 (t, J = 6.8 Hz, 2H), 7.07 (t, J =
.0 Hz, 2H), 6.31 (s, 1H), 2.63 (t, J = 7.6 Hz, 2H), 1.69–1.61 (m,
H
3
13
(t, J = 8.8 Hz, 2H), 6.74 (s, 1H), 2.32 (s, 3H); C NMR
8
2
1
1
3
(100 MHz, CDCl
3
): δ 162.5 (d,
JC,F = 246 Hz), 148.6, 148.0,
H), 1.32–1.27 (m, 8H), 0.88 (m, 3H); C NMR (100 MHz,
1
1
9
2
38.4, 130.5, 128.9, 128.7, 127.8, 127.2, 126.2, 122.6, 115.7,
3
CDCl ): δ 162.5 (d, JC,F = 245 Hz) 149.9, 147.3, 129.1, 127.3,
127.3 115.7, 115.4, 100.8, 31.7, 29.2, 29.0, 26.2, 22.6, 14.1;
HRMS (ESI) m/z: [M + H] calculated for C H FN , 261.1762;
+
9.7, 21.3; HRMS (ESI) m/z: [M + H] calculated for C H FN ,
1
6
13
2
+
53.1136; found, 253.1134.
1
6
22
2
found, 261.1735.
3
-(4-Methoxyphenyl)-5-(m-tolyl)-1H-pyrazole (7c)
1
Yield: 0.060 g (75%) as a brown solid; mp: 127–128 °C;
NMR (500 MHz, CDCl
H
5-Heptyl-3-(4-methoxyphenyl)-1H-pyrazole (11c)
Yield: 0.060 g (73%) as a brown solid; mp: 207–208 °C;
NMR (400 MHz, CDCl ): δ 7.64 (d, J = 8.0 Hz, 2H), 6.88 (d, J =
.0 Hz, 2H), 6.27 (s, 1H), 3.81 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H),
.66–1.60 (m, 2H), 1.28–1.26 (m, 8H), 0.88 (t, J = 6.0 Hz, 3H);
3
): δ 7.59 (d, J = 8.8 Hz, 2H), 7.47 (d, J =
.8 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H),
.79 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 3.77 (s, 3H), 2.26 (s, 3H);
C NMR (100 MHz, CDCl ): δ 159.2, 148.9, 148.0, 138.1, 131.4,
3
28.5, 126.8, 126.2, 123.9, 122.7, 113.9, 99.0, 55.0, 21.2; HRMS 13
1
H
6
6
3
8
1
1
3
1
(
C NMR (100 MHz, CDCl
3
): δ 159.3, 149.5, 148.1, 126.9, 125.4,
+
16 2
ESI) m/z: [M + H] calculated for C17H N O, 265.1335; found,
1
14.0, 100.3, 55.2, 31.7, 29.3, 29.0, 26.5, 22.6, 14.1; HRMS (ESI)
2
65.1344.
+
m/z: [M + H] calculated for C H N O, 273.1961; found,
1
7
24 2
273.1947.
5
-(2-Chlorophenyl)-3-phenyl-1H-pyrazole (8a)
1
Yield: 0.058 g (76%) as a brown solid; mp: 218–219 °C;
H
NMR (500 MHz, CDCl ): δ 7.74 (d, J = 8.4 Hz, 2H), 7.63 (d, J =
3
Conflicts of interest
8
7
1
1
2
.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39–7.30 (m, 3H),
1
3
.27–7.11 (m, 2H), 6.99 (s, 1H); C NMR (100 MHz, CDCl
3
): δ
There are no conflicts to declare.
31.8, 131.3, 130.4, 130.2, 129.8, 129.2, 128.7, 128.0, 127.0,
+
25.7, 103.6; HRMS: m/z calculated for C15
H11ClN
2
(M + H) :
55.0684; found, 255.0690.
Acknowledgements
5
-Phenyl-3-(thiophen-2-yl)-1H-pyrazole (9a)
We gratefully acknowledge the SERB [Research grant no. EMR/
017/000174] for financial support and the DST for providing
1
Yield: 0.051 g (75%) as a brown solid; mp: 184–185 °C;
H
2
NMR (400 MHz, CDCl + DMSO-d ): δ 7.76 (s, 1H), 7.69 (q, J =
3
6
the HRMS facility in the FIST program. BA thanks UGC, New
Delhi, and NJ thanks MHRD for research fellowships.
8
.0 Hz, 2H), 7.62 (t, J = 7.6 Hz, 3H), 7.31–7.27 (m, 1H), 7.24 (t,
1
3
J = 8.8 Hz, 2H), 7.05 (t, J = 8.4 Hz, 1H), 6.73 (s, 1H); C NMR
100 MHz, CDCl3 + DMSO-d ): δ 146.3, 144.4, 135.3, 130.4,
(
6
1
28.5, 127.8, 127.3, 125.3, 124.2, 123.5, 99.4; HRMS (ESI) m/z:
Notes and references
+
[M + H] calculated for C13
H
11
N
2
S, 227.0637; found, 227.0679.
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-(4-Fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole (9b)
1
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3
6
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NMR (100 MHz, DMSO-d ): δ 161.8 (d, J
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10 2
[M + H] calculated for C13H N S, 245.0543; found, 245.0579.
5
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2
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