The diaza-Nazarov cyclization involving a 2,3-diaza-pentadienyl cation for the synthesis of polysubstituted pyrazoles

Article abstract of DOI:10.1039/c7ob01949a

An unprecedented iodine-mediated diaza-Nazarov (DAN) type cyclization for the construction of substituted pyrazoles from easily available starting materials via an enamine-iminium ion intermediate is described. The oxidative cyclization worked under green conditions with remarkable regioselectivity. This one-pot, efficient and operationally simple three-component intramolecular regioselective DAN cyclization displayed a wide range of substrate scope. The dichotomy of reaction pathways has been explored with density functional theory in the gas phase and solution phase. Of the possible 1,5-, 1,6-, and 1,7-electrocyclizations, the DAN cyclization, i.e., the 1,5-pathway offers the lowest activation energy barrier supporting our experimental observations.

Full text of DOI:10.1039/c7ob01949a

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The diaza-Nazarov cyclization involving a
2,3-diaza-pentadienyl cation for the synthesis of
Cite this: DOI: 10.1039/c7ob01949a
polysubstituted pyrazoles†
Balakrishna Aegurla and Rama Krishna Peddinti
*
An unprecedented iodine-mediated diaza-Nazarov (DAN) type cyclization for the construction of substi-
tuted pyrazoles from easily available starting materials via an enamine–iminium ion intermediate is
described. The oxidative cyclization worked under green conditions with remarkable regioselectivity. This
one-pot, efficient and operationally simple three-component intramolecular regioselective DAN cycliza-
tion displayed a wide range of substrate scope. The dichotomy of reaction pathways has been explored
with density functional theory in the gas phase and solution phase. Of the possible 1,5-, 1,6-, and 1,7-
electrocyclizations, the DAN cyclization, i.e., the 1,5-pathway offers the lowest activation energy barrier
supporting our experimental observations.
Received 5th August 2017,
Accepted 31st October 2017
DOI: 10.1039/c7ob01949a
rsc.li/obc
diaza-Nazarov reaction for the synthesis of substituted pyra-
zoles from benzaldehyde hydrazone and acetophenone.
Introduction
The pyrazole moiety belongs to an important class of hetero-
In recent years, Lewis acid mediated Nazarov-type cycliza-
aromatic compounds owing to its frequent occurrence in tion has emerged as an important tool for the synthesis of
many natural products and biologically active compounds.1 five-membered carbocyclic compounds from dienones.13 In
Pyrazole ring containing compounds exhibit antidiabetic,2 general, the key step for the Nazarov reaction is the
anticancer,3 antiinflammatory,4 and analgesic5 activities. 4π-electrocyclization of a pentadienyl cation. A heteroatom
These are also important building blocks in the agrochemical involved Nazarov-type approach has attracted incredibly wide
industry.6 On account of their great biological importance, attention in the present research scenario owing to its remark-
diverse approaches were established for the synthesis of pyra- able ability to facilitate cationic 4π-electrocyclization of a
zoles. Traditionally, these pyrazoles can be synthesized by the pentadienyl system bearing an imino group instead of the clas-
reaction of 1,3-diketones/α,β-unsaturated carbonyls with hydra- sical ketone functionality. So far, only a few reports are
zine derivatives7 and the 1,3-dipolar cycloaddition of hydra- known describing the imino-Nazarov reaction. In 2007, the
zines with alkenes/alkynes.8 With the growing interest in the Klumpp research group developed the aza-Nazarov cyclization
synthesis of pyrazoles, many transition metal9 and metal-free10 reaction of N-acyliminium salts with CF3SO3H.14a Later in
approaches have been reported in the past few years. In 2014, 2010, Tius and co-workers revealed the enamine–iminium ion
Chang and co-workers established the iodine mediated syn- Nazarov cyclization of α-ketoenones via diamine salt catalyzed
thesis of pyrazoles from α,β-unsaturated aldehydes/ketones enamine–iminium ion formation.14b,c It is a big challenge to
and hydrazones.11 In 2015, Singh et al. reported the sulphur- develop the Nazarov-type reaction since the cyclization event of
promoted synthesis of pyrazoles through cross dehydrogena- a stable acyclic imino diene is not favourable in comparison to
tive cyclisation of acetophenone hydrazones with aldehydes.12 conventional Nazarov-type reactions. Subsequently Hsung,15a
Herein, for the first time we describe the iodine-mediated West,15b and Liu,15c explored the interrupted imino-Nazarov
electrocyclization. Recently, the Liao group reported the aza-
Nazarov reaction for the synthesis of N-hydroxy oxyindoles
where they described the involvement of an azaoxyallyl cation
as an intermediate.16 In 2009, the Würthwein group disclosed
Department of Chemistry, Indian Institute of Technology Roorkee, India.
E-mail: rkpedfcy@iitr.ac.in, ramakpeddinti@gmail.com
the synthesis of dihydrospiroindenepyrazoles and dihydroin-
denodiazepine derivatives by 1,5- and 1,7-cascade electrocycli-
zations under the superelectrophilic solvation conditions, with
the involvement of an iminium cation intermediate. To
support the mechanism, they calculated the relative energies
†Electronic supplementary information (ESI) available: Mass spectral analysis,
data from gas phase and solution phase electronic energy and single point
energy calculations, copies of 1H and 13C NMR spectra. CCDC 1510290. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7ob01949a
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MeOH using iodine (1.2 equiv.), the pyrazole derivative 3a was
obtained in 65% yield in 24 h (Table 1, entry 1). To evaluate
the effect of the solvent in the reaction, we screened various
solvents such as THF, CH3CN, 1,4-dioxane, H2O and EtOH.
The former solvents provided pyrazole 3a in 44, 56, 44, and
33% yield, respectively (entries 2–5). The reaction in EtOH
afforded the pyrazole 3a in a maximum yield of 70% (entry 6).
The reaction, when performed under solvent-free conditions,
afforded the desired product 3a in 42% yield in 24 h (entry 7).
By choosing EtOH as an optimum solvent, reagents such as
NCS, NBS, NIS, KI and PhI(OAc)2 were screened. No improve-
ment was observed in the yield of the product with NCS and
NBS-mediated reactions (entries 8 and 9). When the reaction
was performed with NIS, the starting material was recovered
along with traces of the product (entry 10). The reaction was
inefficient in the presence of KI and PhI(OAc)2 (entries 11 and
12). The yield was diminished by reducing the amount of
iodine to 0.5 equiv. (entry 13). We observed lower yield when
the amount of iodine was increased to 1.5 equiv. (entry 14). To
further improve the efficiency of the reaction, we evaluated the
effect of temperature. For that we performed the reaction at
50 °C, which afforded the product 3a in 69% yield (entry 15).
An increase in the yield of the product was observed when we
performed the model reaction at 70 °C (entry 16). The reaction
at 90 °C led to the formation of the product in a marginally
lower yield (entry 17). We further studied the effect of different
Table 1 Optimization of reaction conditionsa
Scheme 1 Nazarov-type cyclizations.
of Hückel- and Möbius-type transition states of both the
cyclizations.17
To the best of our knowledge, diaza-Nazarov-type
4π-electrocyclization is not reported for the synthesis of pyra-
zoles. Herein, we describe an iodine-mediated metal-free one-pot
approach for the synthesis of substituted pyrazoles via diaza-
Nazarov-type cyclization of the enamine–imino ion (Scheme 1)
under mild conditions by employing in situ generated aldehyde
hydrazones and acetophenone derivatives as starting materials.
Entry
Reagent
Solvent
Temp.
Time
Yieldb (%)
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
NCS
NBS
NIS
KI
DIB
I2
I2
I2
I2
I2
MeOH
THF
ACN
1,4-Dioxane
H2O
EtOH
Neat
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50 °C
70 °C
90 °C
70 °C
70 °C
70 °C
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
12 h
12 h
12 h
12 h
12 h
12 h
65
44
56
44
33
70
42
54
57
Traces
nr
Results and discussion
9
10
11
12
13c
14d
15
16
17
18
19
20
We envisaged that diaza-Nazarov type cyclization with a 1,3-
diene embedded with two nitrogen atoms would lead to the
generation of pyrazoles. As a prelude to our objective, we
started our investigation by choosing 4-chlorobenzaldehyde
(1a) and acetophenone (2a) as model substrates. At the begin-
ning, we performed a straightforward condensation of benz-
aldehyde and hydrazine hydrate under solvent-free conditions
for the in situ generation of the corresponding hydrazone
within a minute. The in situ generated hydrazone was then
treated with acetophenone in the presence of various promo-
ters. To our delight, when the reaction was carried out in
nr
52
60
69
76
72
nr
BF3·OEt2
ZrCl4
ZnCl2
nr
nr
a Reaction conditions: 1a (0.6 mmol), hydrazine hydrate 80%
(1 mmol), 2a (0.50 mmol), reagent (0.6 mmol). b Isolated yield. nr = no
reaction. c I2: 0.5 equiv., 24 h. d I2: 1.5 equiv.
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reagents such as BF3·OEt2, ZrCl4 and ZnCl2 on the reaction,
but no product was formed (entries 18–20). Thus these studies
identified EtOH as the optimum solvent at 70 °C and iodine as
the promoter for the reaction (entry 16).
With the optimized reaction conditions in hand, we
explored the scope of the present one-pot, three-component
diaza-Nazarov-type cyclization. Thus various substituted alde-
hydes 1a–e having electron-withdrawing as well as electron-
donating groups were selected and were reacted with acetophe-
none (2a) under optimized reaction conditions. In all cases,
the reactions proceeded cleanly to furnish the corresponding
pyrazole derivatives 3a–e in good to high yields of 67–82%
(Scheme 2). The reaction of thiophene aldehyde 1f with aceto-
phenone (2a) under a similar set of conditions furnished the
product 3f in moderate yield.
On the basis of the successful results obtained from the alde-
hydes 1a–f and acetophenone 2a, we further tested the scope of
the reaction with a series of acetophenones 2b–e. The reactions
are well tolerant of both electron-withdrawing and electron-
releasing groups. In all cases, the corresponding pyrazole
derivatives 4–7 were isolated in good to high yields (49–81%,
Scheme 3). We further extended the scope of the reaction by
using α-substituted acetophenone 2f with aldehydes 1b,c at
80 °C. To our delight, the cyclized products 8a and 8b were
obtained in 52 and 47% yield in 24 h, respectively (Scheme 4). It Scheme 3 Scope of different acetophenone and benzaldehyde deriva-
tives. Reaction conditions: 1a (0.6 mmol), hydrazine hydrate 80%
(1.0 mmol), 2 (0.5 mmol), iodine (0.6 mmol), EtOH (3 mL).
is noteworthy to mention here that about 10–15% of aryl alde-
hydes 1a–j were recovered in these reactions from the decompo-
sition of the corresponding hydrazones presumably due to the
presence of the HI by-product. The products were characterized
on the basis of spectroscopic data and the structure of the pyra-
zole 5a was further confirmed from its single crystal X-ray ana-
lysis (see ESI, Fig. S2†).18
To verify the radical pathway of the reaction, a radical trap-
ping agent TEMPO was used in varied amounts. However, the
reaction was not inhibited, albeit the product 3a was obtained
in a relatively lower yield. Based on the above results and the
previous reports,14–17 a plausible mechanism for the formation
of 3a is depicted in Scheme 8. The hydrazone, generated from
Scheme 4 DAN approach with propiophenone (2f).
aldehyde 1a and hydrazine hydrate, undergoes condensation
with acetophenone 2a to generate intermediate A. α-Iodination
of tautomer B with molecular iodine provides alkyl iodide C
with the concomitant removal of HI. The conformational
change of s-trans diimine C to s-cis diimine D followed by de-
iodination leads to 2,3-diaza-pentadienyl cation E, which is
stabilized by the delocalization of positive charge. This
enamine–iminium ion undergoes 4π-electrocyclization ring
closure to generate diaza-allyl cation F, which upon dehydro-
halogenation and aromatization furnishes exclusively five-
membered heterocycle 3. The other possible nitrogen-embedded
regioisomers from 6π-electron-6-atom and 6π-electron-7-atom
oxidative electro-cyclizations19 were not formed in this reaction
(Scheme 5, also see the ESI†). To gain insights into the mecha-
nism, we performed the reaction of tosyl substituted acetophe-
Scheme 2 Scope of benzaldehyde derivatives in DAN cyclization.
none 2g with 1b,c. In both cases, noncyclized 2,3-diaza-1,3-
dienes 9a and 9b were isolated in 50% yield in 24 h. The
Reaction conditions: 1a (0.6 mmol), hydrazine hydrate 80% (1.0 mmol),
2a (0.5 mmol), iodine (0.6 mmol), EtOH (3 mL).
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parent benzaldehyde hydrazone also reacted with 2g to afford
acyclic heterodiene 9c. This clearly indicates that the for-
mation of the 2,3-diaza-pentadienyl cation does not occur and
hence no diaza-Nazarov reaction product (Scheme 6). Our
efforts to cyclise 9 in the presence of reagents such as I2/TFA,
SnCl4 and FeCl3 did not result in success (see the ESI†). Since
the α-position of aza-diene was blocked with the tosyl group,
α-iodination did not take place. Thus it is indirectly proving
that α-iodination (as in intermediates C and D) is essential for
the success of the DAN cyclization (Scheme 8).
The obtained mass spectral evidence for the intermediate C
(Ar = Ph, 4-Cl-C6H4, 4-F-C6H4) also supports the proposed
mechanism
(see
the
ESI†).
The
reaction
of
α-iodoacetophenone (10) with aldehydes 1a and 1c and hydra-
zine provided pyrazoles 3a and 3c, which also confirms the
generation of intermediate C (Ar = 4-Cl-C6H4 and 4-F-C6H4)
(Schemes 7 and 8) (see the ESI†). The in situ generated 4-iso-
propylbenzaldehyde hydrazone did not undergo cyclization
with ketones such as cyclohexanone and cyclopentanone
under standard conditions. However, the isolated 4-iso-propyl-
benzaldehyde hydrazone reacted with cyclohexanone to
furnish the corresponding DAN product in 24% yield
(Scheme 9). Valeraldehyde failed to produce the product with
2a under the optimized conditions.
Scheme 5 Possible regioisomers during cyclization.
Scheme 6 Reaction of α-tosyl acetophenone (2g).
Scheme 7 DAN approach with α-iodoacetophenone (10).
Scheme 9 Substrate scope of DAN reaction.
Scheme 8 Plausible reaction mechanism.
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experimentally, we performed quantum chemical calculations
using hybrid B3LYP functional20,21 with a 6-311G** basis set22
in the gas phase. All DFT calculations were performed using a
G09, revision A.02, program package.23 All structures of 1,5-,
1,6- and 1,7-electrocyclization pathways were optimized.
Frequency calculations were also performed to confirm that
the structures are minima with all positive frequencies and
transition states (TSs) with one imaginary frequency. Intrinsic
reaction coordinate (IRC) calculations were also run to confirm
the nature of TSs.
The electrocyclic step begins with three different confor-
mations of the diaza-pentadienyl (DAP) cation for DFT calcu-
lations of 1,5-, 1,6- and 1,7-electrocyclization pathways. The
conformations were obtained from IRC calculations starting
from the transition structures and the lowest energy conformer
(1,5-) differ in energy by about −4.10 (1,6-) and 0.19 (1,7-)
kcal mol−1 (Scheme 10). From our results, two important things
were observed for DAN cyclization reaction using DFT calcu-
lations: (i) a comparative DFT study of 1,5-, 1,6- and 1,7-DAN
electrocyclization pathways, and (ii) a DFT calculation preferred
4π-1,5-electrocyclization pathway with the lowest activation
energy barrier (11.62 kcal mol−1) supporting our experimentally
observed 1,5-DAP. As shown in Fig. 1, the 1,6- (20.70
kcal mol−1) and 1,7- (26.67 kcal mol−1) electrocyclization path-
ways lead to higher activation energy barriers by 9.08 and 15.05
kcal mol−1, respectively, than that of the 4π-1,5-electrocyclization
pathway. DFT calculations show that the cyclization of the 1,5-
DAP cation can be considered as a process with a low activation
barrier and exothermicity (ΔH, −3.11 kcal mol−1), while the
unfavourable 1,6- and 1,7-cyclization products formed via
higher activation barriers and predicted to be highly endother-
mic with 19.89 and 11.05 kcal mol−1, respectively. Negative
Gibbs free energy (ΔG) results show that the 1,5-cyclization
pathway (−1.49 kcal mol−1) is the most favourable compared to
the six- (22.15 kcal mol−1) and seven- (14.36 kcal mol−1) cycliza-
tion pathways (see ESI, Table S4†). To evaluate the effect of the
solvent on activation barriers of electronic energy, we per-
formed B3LYP/6-311G** calculations using the CPCM model
with ethanol solvent. The activation energy barriers in the gas
Scheme 10 Calculated electronic energies (Erel) in kcal mol−1 relative
to 2,3-diaza-pentadienyl cation (E) for the 1,5-, 1,6- and 1,7-cyclization
pathways of electrocyclization step of the diaza-Nazarov reaction at the
B3LYP/6-311G** level of theory in the gas phase.
Computational study
In order to pay attention to a better understanding of the
plausible mechanism of the electrocyclization step (E to F) of
the diaza-Nazarov reaction and to validate the results found
phase and solution phase are very close (less than 1 kcal mol−1
)
and there is no significant change (see the ESI†).
We generated HOMO and LUMO plots using B3LYP/6-
311G** optimized geometries of TSs by using Gauss view visu-
Fig. 1 A comparative energy profile diagram for the 1,5-, 1,6- and 1,7-
cyclization pathways of electro-cyclization step of the diaza-Nazarov
reaction at the B3LYP/6-311G** level of theory in the gas phase.
Fig. 2 Optimised structures of TS with HOMO and HOMO−1 molecular diagrams of the 1,5-cyclization pathway of electrocyclization step of the
diaza-Nazarov reaction at the B3LYP/6-311G** level of theory in the gas phase (the bond forming distances between terminal atoms of TS are in Å).
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alization software.24 The binding interaction in TSEF is domi- derivative was added acetophenone derivative 2 (0.5 mmol) in
nated by HOMO−1 as shown in Fig. 2, while HOMO is loca- EtOH (3 mL) followed by iodine (0.154 g, 1.2 mmol). Then the
lized at the heterocyclic part.
reaction mixture was refluxed at 70 °C on a pre-heated oil bath
for 12 h. After completion of the reaction, as checked by TLC,
the reaction was quenched with a saturated sodium thiosulfate
solution and extracted twice with ethyl acetate (2 × 15 mL). The
organic layer was washed with water and dried over anhyd.
sodium sulfate. The solvent was evaporated under reduced
pressure, and the residue was subjected to silica gel column
chromatography using ethyl acetate in hexanes as the eluent to
afford a pure pyrazole derivative.
Conclusion
In conclusion, we have described the first examples of diaza-
Nazarov cyclization employing in situ generated hydrazones
and acetophenones. This iodine-mediated expedient
process furnished functionally-rich pyrazoles in ethanol under
aerobic conditions. The cascade reaction for the pyrazole
formation proceeds through enamine–imino diaza-Nazarov
4π-electrocyclization. The title five-membered heterocycles are
accessed in good to high yields from a one-pot three-
component protocol under mild conditions. The simplicity of
the experimental procedure and the ready accessibility of start-
ing materials thus make this an experimentally attractive
method for the preparation of the nitrogenous heterocycles.
Computational studies predicted that the cyclization of the
1,5-DAP cation is the most favourable pathway compared to
1,6- and 1,7-cyclizations supporting the experimentally
obtained DAN products.
Characterization data
3-(4-Chlorophenyl)-5-phenyl-1H-pyrazole (3a). Yield: 0.090 g
(71%) as a brown solid; mp: 218–219 °C; IR (KBr): νmax 3443,
1636, 1489, 1386, 1309, 1259, 1180, 1088, 1021, 968, 826 cm−1
;
1H NMR (400 MHz, DMSO-d6): δ 7.86 (d, J = 8.0 Hz, 2H), 7.82
(d, J = 7.2 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 7.6 Hz,
2H), 7.35 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 128.8, 126.8, 125.1, 99.9 ppm; HRMS:
m/z calculated for C15H12ClN2 (M + H)+: 255.0689, found:
255.0686.
3-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole
(3b).
Yield:
0.087 g (70%) as a brown solid; mp: 155–156 °C; 1H NMR
(400 MHz, CDCl3): δ 7.70 (d, J = 6.8 Hz, 2H), 7.62 (d, J = 8.8 Hz,
2H), 7.36 (t, J = 7.2 Hz, 2H), 7.32–7.30 (m, 2H), 6.87 (d, J =
8.8 Hz, 2H), 6.73 (s, 1H) 3.81 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 159.5, 131.4, 128.7, 128.0, 126.8, 125.5, 123.8, 114.1,
99.4, 55.2 ppm; HRMS: m/z calculated for C16H15N2O (M + H)+:
251.1179, found: 251.1178.
Experimental section
General information
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-
graphy was performed on 0.25 mm silica gel plates (60F-254)
using UV light as the visualizing agent. Silica gel
(100–200 mesh) was used for column chromatography. Melting
3-(4-Fluorophenyl)-5-phenyl-1H-pyrazole (3c). Yield: 0.084 g
(71%) as a brown solid; mp: 189–190 °C; IR (KBr): νmax 3443,
1620, 1510, 1467, 1444, 1304, 1253, 1181, 1029, 987, 865 cm−1
;
1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 8.4 Hz, 2H), 7.71
(d, J = 7.2 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.6 Hz,
2H), 7.25 (t, J = 7.6 Hz, 1H), 6.85 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3 + DMSO-d6): δ 146.7 (d, 1JC,F = 113 Hz), 135.3,
130.0, 128.5, 128.1, 127.4, 124.9, 124.8, 122.2, 99.3 ppm;
HRMS: m/z calculated for C15H12FN2 (M + H)+: 239.0979,
found: 239.0950.
points were determined on
a capillary point apparatus
equipped with a digital thermometer and are uncorrected.
Nuclear magnetic resonance spectra were recorded on 400 and
500 MHz spectrometers, and chemical shifts are reported in
δ units, parts per million (ppm), relative to residual chloroform
(7.26 ppm) or DMSO (2.5 ppm) in the deuterated solvent or
with tetramethylsilane (TMS, δ 0.00 ppm) as the internal stan-
dard. 13C NMR spectra were referenced to CDCl3 (δ 77.0 ppm,
the middle peak) and DMSO-d6 (δ 39.5 ppm, the middle peak).
Coupling constants are expressed in Hz. The following abbrevi-
ations are used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, m = multiplet, dd = doublet of doublets,
sp = septet, and brs = broad singlet. High resolution mass
spectra were recorded with a micro TOF-Q analyzer spectro-
meter by using the electrospray mode.
3-(3-Bromophenyl)-5-phenyl-1H-pyrazole (3d). Yield: 0.099 g
(67%) as a brown solid; mp: 165–166 °C; IR (KBr): νmax 3456,
1
2360, 1637, 1503, 1442, 1371, 1312, 1079, 976 cm−1; H NMR
(500 MHz, DMSO-d6): δ 13.47 (brs, 1H, NH), 8.06 (s, 1H), 7.83
(d, J = 17.5 Hz, 3H), 7.50–7.35 (m, 5H), 7.29 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 146.8, 146.2, 133.6,
130.0, 129.6, 129.5, 128.0, 127.4, 127.2, 124.6, 123.3, 121.8,
98.8 ppm; HRMS: m/z calculated for C15H12BrN2 (M + H)+:
299.0178, found: 299.0163.
3-(3-Nitrophenyl)-5-phenyl-1H-pyrazole (3e). Yield: 0.108 g
(82%) as a brown solid; mp: 207–209 °C; IR (KBr): νmax 3440,
General procedure for the synthesis of substituted pyrazoles
;
To a benzaldehyde derivative 1 (0.6 mmol) was added hydra- 1572, 1533, 1506, 1446 cm−1 1H NMR (500 MHz, DMSO-d6):
zine hydrate (80% in water, 1.0 mmol) under solvent-free con- δ 13.63 (brs, 1H, NH), 8.67 (s, 1H), 8.30 (d, J = 7.5 Hz, 1H), 8.17
ditions. After the addition of hydrazine hydrate, a yellow solid (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.0 Hz, 2H), 7.74 (t, J = 7.5 Hz,
was formed within a minute which indicated the formation of 1H), 7.48 (t, J = 7.0 Hz, 2H), 7.43 (s, 1H) 7.37 (t, J = 7.0 Hz, 1H)
the hydrazone derivative. To the thus formed hydrazone ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 147.0, 133.1,
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129.9, 128.9, 128.4, 127.4, 126.7, 124.0, 123.7, 120.5, 118.4,
5-(4-Fluorophenyl)-3-(3-methoxyphenyl)-1H-pyrazole
(4f).
98.6 ppm; HRMS: m/z calculated for C15H12N3O2 (M + H)+: Yield: 0.096 g (72%) as a brown solid; mp: 162–163 °C;
266.0924, found: 266.0921.
IR (KBr): νmax 3415, 1628, 1468, 1165, 1035, 985, 762 cm−1
;
5-Phenyl-3-(thiophen-2-yl)-1H-pyrazole (3f). Yield: 0.065 g 1H NMR (400 MHz, DMSO-d6): δ 7.92 (t, J = 5.6 Hz, 2H),
(58%) as a brown solid; mp: 185–184 °C; IR (KBr): νmax 3415, 7.46–7.43 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 7.6 Hz,
1577, 1487, 1404, 1174, 844, 755 cm−1
;
1H NMR (400 MHz, 2H), 7.18 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H) ppm; 13
C
1
DMSO-d6): δ 7.72 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 3H), NMR (100 MHz, DMSO-d6): δ 161.8 (d, JC,F = 243 Hz), 159.7,
7.26 (dd, J = 5.6 Hz, 7.6 Hz, 2H), 7.01 (t, J = 4.4 Hz, 1H), 6.74 129.9, 127.2, 127.1, 117.6, 115.7, 115.5, 113.4, 110.6, 99.8,
(t, J = 4.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO- 55.1 ppm; HRMS: m/z calculated for C16H14FN2O (M + H)+:
d6): δ 129.1, 127.4, 126.6, 126.2, 124.0, 123.1, 122.3, 122.1, 269.1085, found: 269.1088.
98.0 ppm; HRMS: m/z calculated for C13H11N2S (M + H)+:
3,5-Bis(4-chlorophenyl)-1H-pyrazole (5a). Yield: 0.084
g
227.0637, found: 227.0619.
(58%) as a brown solid; mp: 240–241 °C; IR (KBr): νmax 3448,
1
3-(4-Chlorophenyl)-5-(4-fluorophenyl)-1H-pyrazole (4a). Yield: 1638, 1506, 1025, 994, 829 cm−1; H NMR (400 MHz, DMSO-
0.096 g (70%) as a brown solid; mp: 209–210 °C; IR (KBr): d6): δ 7.75 (d, J = 8.4 Hz, 4H), 7.35 (d, J = 8.4 Hz, 4H), 6.93 (s,
νmax 3468, 1618, 1508, 1306, 1247, 1174, 1035, 912 cm−1
;
1H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 144.8,
1H NMR (500 MHz, DMSO-d6): δ 13.44 (brs, 1H, NH), 7.84 (s. 131.1, 128.5, 127.0, 125.0, 98.0 ppm; HRMS: m/z calculated for
4H), 7.50 (s, 2H), 7.28 (s, 2H), 7.17 (s, 1H) ppm; 13C NMR C15H11Cl2N2 (M + H)+: 289.0294, found: 289.0298.
(100 MHz, CDCl3 + DMSO-d6): δ 161.8 (d, 1JC,F = 245 Hz), 132.7,
5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole
(5b).
128.2, 126.7, 126.6, 126.2, 115.2, 114.9, 98.8 ppm; HRMS: m/z Yield: 0.086 g (61%) as a brown solid; mp: 157–159 °C; IR
calculated for C15H11ClFN2 (M
273.0589.
+ ;
H)+: 273.0589, found: (KBr): νmax 3425, 2911, 1615, 1508, 1450, 1254, 1074, 821 cm−1
1H NMR (500 MHz, DMSO-d6): δ 13.27 (brs, 1H, NH), 7.85 (d,
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole
(4b). J = 5.5 Hz, 2H), 7.74 (d, J = 6.5 Hz, 2H), 7.49 (s, 2H), 7.09 (s,
Yield: 0.088 g (66%) as a brown solid; mp: 205–206 °C; 1H), 7.02 (d, J = 6.5 Hz, 2H), 3.79 (s, 3H) ppm; 13C NMR
IR (KBr): νmax 3470, 1627, 1503, 1450, 1256, 1177, 965 cm−1
;
(100 MHz, DMSO-d6): δ 159.1, 128.9, 128.7, 126.7, 126.5, 114.3,
1H NMR (500 MHz, CDCl3): δ 7.57 (q, J = 5.5 Hz, 2H), 7.51 (d, 99.0, 55.1 ppm; HRMS: m/z calculated for C16H14ClN2O (M +
J = 8.5 Hz, 2H), 6.92 (t, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), H)+: 285.0789, found: 285.0789.
6.57 (s, 1H), 3.77 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
3-(3-Bromophenyl)-5-(4-chlorophenyl)-1H-pyrazole (5c). Yield:
δ 161.7 (d, JC,F = 245 Hz), 159.3, 148.0 (d, JC,F = 104), 127.9, 0.109 g (66%) as a brown solid; mp: 202–203 °C; IR (KBr):
127.1, 123.1, 115.5, 115.4, 114.0, 98.7, 55.0 ppm; HRMS: m/z νmax 3478, 3413, 1625, 1490, 1365, 629 cm−1 1H NMR
H)+: 269.1085, found: (500 MHz): δ 13.52 (brs, 1H, NH), 8.05 (s, 1H), 7.85 (s, 3H),
7.52–7.41 (m, 4H), 7.32 (d, J = 3.0 Hz, 1H) ppm; 13C NMR
1
2
;
calculated for C16H14FN2O (M
269.1087.
+
3,5-Bis(4-fluorophenyl)-1H-pyrazole (4c). Yield: 0.078
g
(100 MHz, DMSO-d6):
δ
131.0, 128.9, 127.5, 126.7,
1
(61%) as a brown solid; mp: 168–169 °C; H NMR (500 MHz, 124.0, 100.6 ppm; HRMS: m/z calculated for C15H1181BrClN2
DMSO-d6): δ 13.41 (brs, 1H, NH), 7.87 (s, 4H), 7.27 (s, 4H), 7.11 (M + H)+: 334.9769, found: 334.9770.
1
(s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 161.8 (d, JC,F
=
5-(4-Chlorophenyl)-3-(3-methoxyphenyl)-1H-pyrazole
(5d).
243 Hz), 127.1, 127.1, 115.8, 115.5, 99.5 ppm; HRMS: m/z cal- Yield: 0.102 g (72%) as a brown solid; mp: 165–166 °C; IR
culated for C15H11F2N2 (M + H)+: 257.0885, found: 257.0862.
(KBr): νmax 3418, 2925, 1621, 1491, 1453, 1300, 1232, 1159,
5-(4-Fluorophenyl)-3-(4-isopropylphenyl)-1H-pyrazole (4d). 1062, 994, 885, 758 cm−1 1H NMR (500 MHz, DMSO-d6):
Yield: 0.077 g (55%) as a brown solid; mp: 179–181 °C; IR δ 13.42 (brs, 1H, NH), 7.87 (s, 2H), 7.50–7.36 (m, 5H), 7.23 (s,
(KBr): νmax 3414, 1624, 1450, 1321, 1177, 1024, 832 cm−1 1H 1H), 6.92 (s, 1H), 3.82 (s, 3H) ppm; 13C NMR (100 MHz,
;
;
NMR (500 MHz, CDCl3): δ 12.13 (brs, 1H, NH), 7.57 (q, J = DMSO-d6): δ 159.6, 129.9, 128.8, 127.7, 125.1, 117.5, 113.4,
6.5 Hz, 2H), 7.53 (d, J = 10.5 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 110.4, 99.9, 54.9 (OCH3) ppm; HRMS: m/z calculated for
6.87 (t, J = 11.0 Hz, 2H), 6.61 (s, 1H), 2.88 (sp, J = 8.5 Hz, 1H), C16H14ClN2 (M + H)+: 285.0789, found: 285.0772.
1.26 (d, J = 9.0 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3):
5-(4-Chlorophenyl)-3-(furan-2-yl)-1H-pyrazole (5e). Yield:
δ 162.3 (d, 1JC,F = 246 Hz), 148.7, 148.1 (d, 2JC,F = 35 Hz), 128.1, 0.052 g (49%) as a brown solid; mp: 180–181 °C; IR (KBr): νmax
127.7, 127.1, 126.7, 125.4, 115.5, 115.3, 99.2, 33.7, 23.7 ppm; 3415, 1624, 1471, 1230, 1156, 1094, 611 cm−1 1H NMR
HRMS: m/z calculated for C18H18FN2 (M + H)+: 281.1449, (500 MHz, CDCl3): δ 7.63 (d, J = 8.5 Hz, 2H), 7.42 (s, 1H), 7.32
;
found: 281.1448.
(d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 6.60 (d, J = 3.5 Hz, 1H), 6.45 (d,
3-(3-Bromophenyl)-5-(4-fluorophenyl)-1H-pyrazole (4e). Yield: J = 1.5 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 145.6,
0.106 g (67%) as a brown solid; mp: 150–151 °C; IR (KBr): 142.5, 139.4, 134.2, 129.5, 129.0, 128.9, 126.9, 115.5, 107.0,
νmax 3415, 1621, 1495, 1233, 1165, 1091, 968, 826, 773 cm−1
;
99.3 ppm; HRMS: m/z calculated for C13H9ClN2NaO (M + Na)+:
1H NMR (500 MHz, DMSO-d6): δ 13.50 (brs, 1H, NH), 7.86 (s, 267.0296, found: 267.0271.
4H), 7.48–7.13 (m, 5H) ppm; 13C NMR (100 MHz, DMSO-d6):
3-(4-Fluorophenyl)-5-p-tolyl-1H-pyrazole (6a). Yield: 0.084 g
1
δ 161.8 (d, JC,F = 244 Hz), 15.6, 143.0, 132.3, 128.8, 127.2, (67%) as a brown solid; mp: 162–163 °C; IR (KBr): νmax 3417,
127.1, 126.4, 115.8, 115.6, 99.8 ppm; HRMS: m/z calculated for 2984, 1629, 1506, 1447, 1177, 959, 785 cm−1
;
1H NMR
C15H10BrFN2Na+ (M + Na)+: 338.9904, found: 338.9912.
(500 MHz, DMSO-d6): δ 13.31 (brs, 1H, NH), 7.88–7.70 (m, 4H),
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7.26 (s, 4H), 7.11 (s, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, (KBr): νmax 3429, 2852, 2357, 1638, 1403, 1023, 994 cm−1
;
1
DMSO-d6): δ 161.7 (d, JC,F = 243 Hz), 129.3, 127.0, 127.0, 1H NMR (400 MHz, CDCl3 + DMSO-d6): δ 7.56 (d, J = 8.0 Hz,
125.0, 115.5, 99.1, 20.7 ppm; HRMS: m/z calculated for 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.28 (d, J =
C16H14FN2 (M + H)+: 253.1136, found: 253.1110.
7.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.23 (s, 3H)
3-(4-Isopropylphenyl)-5-p-tolyl-1H-pyrazole (6b). Yield: 0.086 g ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 159.0, 128.7,
(65%) as a brown solid; mp: 182–183 °C; IR (KBr): νmax 3417, 128.3, 127.5, 127.3, 124.6, 113.8, 109.6, 55.1, 10.0 ppm; HRMS:
2985, 1629, 1506, 1447, 1177, 959, 785 cm−1
;
1H NMR m/z calculated for C17H17N2O (M + H)+: 265.1335, found:
(500 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 7.5 Hz, 265.1342.
2H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.5 Hz, 2H), 6.73 (s,
3-(4-Fluorophenyl)-4-methyl-5-phenyl-1H-pyrazole (8b). Yield:
1H), 2.91 (septet, J = 6.5 Hz, 1H), 2.35 (s, 3H), 1.27 (d, J = 0.059 g (47%) as a brown solid; mp: 199–200 °C; IR (KBr): νmax
1
7.0 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 148.8, 148.7, 3432, 2926, 1608, 1505, 1441, 1403, 1250, 835 cm−1; H NMR
148.5, 137.8, 129.4, 128.8, 128.5, 126.8, 125.6, 125.5, 99.4, 33.8, (400 MHz, CDCl3 + DMSO-d6): δ 7.56–7.52 (m, 4H), 7.38 (t, J =
23.8, 21.3 ppm; HRMS: m/z calculated for C19H21N2 (M + H)+: 8.8 Hz, 2H), 7.29 (t, J = 5.6 Hz, 1H), 7.06 (t, J = 7.2 Hz, 2H), 2.23
277.1699, found: 277.1670.
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 162.1
1
3-(3-Bromophenyl)-5-p-tolyl-1H-pyrazole (6c). Yield: 0.100 g (d, JC,F = 245 Hz), 129.2, 128.8, 128.4, 127.6, 127.5, 115.4,
(64%) as a brown solid; mp: 149–151 °C; IR (KBr): νmax 3479, 115.2, 110.0, 10.0 ppm; HRMS: m/z calculated for C16H14FN2
2947, 1629, 1315, 1180, 1024, 991 cm−1 1H NMR (500 MHz, (M + H)+: 253.1136, found: 253.1140.
;
DMSO-d6): δ 13.42 (brs, 1H, NH), 8.06 (s, 1H), 7.85 (d, J = 6.5 Hz,
1-(4-Methoxybenzylidene)-2-(1-phenyl-2-p-tosylethylidene)
1H), 7.72 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 6.0 Hz, 1H), 7.40 (t, J = hydrazine (9a). Yield: 0.099 g (49%) as a yellow solid; mp:
6.5 Hz, 1H), 7.26 (d, J = 6.0 Hz, 2H), 7.23 (s, 1H), 2.32 (s, 3H) 155–156 °C; IR (KBr): νmax 3463, 2910, 1545, 1485, 1042,
1
ppm; 13C NMR (100 MHz, DMSO-d6): δ 137.3, 130.9, 130.2, 839 cm−1; H NMR (400 MHz, CDCl3): δ 8.05 (m, 3H), 7.60 (d,
129.4, 127.5, 125.0, 124.0, 122.2, 99.8, 20.8 ppm; HRMS: m/z cal- J = 6.8 Hz, 2H), 7.51 (d, J = 7.2 Hz, 2H), 7.48 (m, 3H), 6.97 (d,
culated for C16H14BrN2 (M + H)+: 313.0335, found: 313.0335.
3-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole
J = 7.2 Hz, 2H), 6.93 (d, J = 7.2 Hz, 2H), 5.13 (s, 2H), 3.86 (s,
(7a). 3H), 2.10 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 162.1,
Yield: 0.067 g (50%) as a brown solid; mp: 128–129 °C; IR 159.1, 155.8, 144.5, 135.8, 135.5, 130.6, 130.4, 129.3, 128.4,
(KBr): νmax 3416, 2935, 1625, 1515, 1450, 1241, 1306, 1174, 128.3, 127.6, 126.6, 113.9, 55.3, 54.8, 21.3 ppm; HRMS: m/z cal-
1032 cm−1 1H NMR (500 MHz, DMSO-d6): δ 13.28 (brs, 1H, culated for C23H22N2NaO3S (M + Na)+: 429.1243, found:
;
NH), 7.89 (t, J = 6.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 429.1259.
8.0 Hz, 2H), 7.03 (d, J = 4.0 Hz, 2H), 7.01 (s, 1H), 3.78 (s, 3H) 1-(4-Fluorobenzylidene)-2-(1-phenyl-2-p-tosylethylidene)hydra-
zine (9b). Yield: 0.098 g (50%) as a brown solid; mp:
243 Hz), 159.1 127.1, 127.0, 126.5, 115.7, 115.6, 114.9, 114.3, 151–152 °C; IR (KBr): νmax 432, 2922, 1585, 1508, 1459, 1405,
114.2, 98.5, 55.1 ppm; HRMS: m/z calculated for C16H14FN2O 1301, 1253, 1075, 1033, 969, 830, 763 cm−1 1H NMR
(M + H)+: 269.1085, found: 269.1087.
(400 MHz, CDCl3): δ 7.77 (d, J = 7.2 Hz, 2H), 7.70 (t, J = 9.2 Hz,
1
ppm; 13C NMR (100 MHz, DMSO-d6): δ 161.7 (d, JC,F
=
;
5-(4-Methoxyphenyl)-3-(3-nitrophenyl)-1H-pyrazole (7b). Yield: 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.41 (d, J =
0.119 g (81%) as a brown solid; mp: 209–210 °C; IR (KBr): 8.0 Hz, 3H), 7.10 (d, J = 8.8 Hz, 1H), 7.06 (t, J = 4.8 Hz, 2H),
νmax 415, 2945, 1165, 1098, 1052, 964, 835 cm−1
(500 MHz, DMSO-d6): δ 13.46 (brs, 1H, NH), 8.65 (s, 1H), 8.27 (100 MHz, CDCl3): δ 163.8–161.4 (d, JC,F = 247 Hz), 155.6,
(d, J = 7.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 144.7, 136.7, 135.2, 131.1, 129.5, 128.9, 128.3, 128.0, 127.3,
;
1H NMR 6.79 (s, 1H), 4.87 (s, 2H), 2.28 (s, 3H) ppm; 13C NMR
1
1
2H), 7.71 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J = 8.0 Hz, 125.5, 115.8–115.6 (d, JC,F = 21 Hz), 99.9, 55.0, 21.5 ppm;
2H), 3.79 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 159.1, HRMS: m/z calculated for C22H20FN2O2S (M + H)+: 395.1224,
132.1, 128.7, 126.7, 126.5, 114.3, 99.0, 55.1 ppm; HRMS: m/z found: 395.1232.
calculated for C16H14N3O3 (M
296.1030.
+
H)+: 296.1031, found:
1-Benzylidene-2-(1-phenyl-2-tosylethylidene)hydrazine (9c).
Yield: 0.122 g (65%) as a yellow solid; 1H NMR (400 MHz,
(7c). CDCl3): δ 8.07–8.06 (m, 3H), 7.59 (t, J = 6.8 Hz, 2H), 7.48 (d, J =
3-(3-Fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole
Yield: 0.069 g (52%) as a brown solid; mp: 131–132 °C; IR 6.8 Hz, 2H), 7.57 (t, J = 8.0 Hz, 4H), 7.48–7.45 (m, 3H),
(KBr): νmax 463, 2920, 1620, 1510, 1467, 1444, 1304, 1253, 7.43–7.39 (m, J = 7.2 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.14 (s,
1181, 1029, 987, 865 cm−1 1H NMR (500 MHz, DMSO-d6): 2H), 2.09 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.0,
;
δ 13.39 (brs, 1H, NH), 7.77 (d, J = 8.5 Hz, 2H), 7.70 (t, J = 156.5, 144.6, 135.7, 135.4, 133.7, 131.3, 130.9, 129.4, 128.6,
6.5 Hz, 2H), 7.46 (q, J = 8.0 Hz, 1H), 7.14 (t, J = 7.0 Hz, 2H), 128.4, 128.4, 128.3, 128.2, 127.7, 55.0, 21.2 ppm; HRMS: m/z
7.02 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H) ppm; 13C NMR (100 MHz, calculated for C22H20N2NaO2S (M + H)+: 399.1138, found:
1
DMSO-d6): δ 162.6 (d, JC,F = 241 Hz), 159.1, 134.9, 130.7, 399.1125.
126.5, 123.5, 121.1, 114.2, 114.1, 111.7, 111.5, 99.3, 55.1 ppm;
3,5-Diphenyl-1H-pyrazole (11). Yield: 0.091 g (82%) as a
1
HRMS: m/z calculated for C16H14FN2O (M + H)+: 269.1085, brown solid; H NMR (400 MHz, CDCl3): δ 7.54–7.50 (m, 4H),
found: 269.1082.
3-(4-Methoxyphenyl)-4-methyl-5-phenyl-1H-pyrazole
7.46–7.07 (m, 4H), 7.04–7.01 (m, 2H), 6.58 (s, 1H) ppm.
(8a). 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 130.9, 127.9, 127.0,
Yield: 0.069 g (52%) as a brown solid; mp: 196–197 °C; IR 124.6, 98.5 ppm.
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3-(4-Isopropylphenyl)-4,5,6,7-tetrahydro-1H-indazole
(12).
2015, 17, 1521; (d) S. Mantenuto, F. Mantellini, G. Favi and
O. A. Attanasi, Org. Lett., 2015, 17, 2014.
Yield: 0.029 g (24%) as a brown solid; mp: 197–198 °C;
1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.6 Hz, 2H), 2.92 (sp, J = 7.4 Hz, 1H), 2.70 (t, J = 6.0 Hz, 2H),
2.59 (t, J = 6.0 Hz, 2H), 1.87–1.85 (m, 2H), 1.76–1.73 (m, 2H),
9 For metal-catalyzed pyrazole synthesis, see: (a) J. Cheng,
W. Li, Y. Duan, Y. Cheng, S. Yu and C. Zhu, Org. Lett., 2017,
19, 214; (b) J. González, J. Santamaría, Á. L. Suárez-Sobrino
and A. Ballesteros, Adv. Synth. Catal., 2016, 358, 1398;
(c) X. Tang, L. Huang, J. Yang, Y. Xu, W. Wu and H. Jiang,
Chem. Commun., 2014, 50, 14793; (d) M. Suri,
T. Jousseaume, J. J. Neumann and F. Glorius, Green Chem.,
2012, 14, 2193; (e) J. Hu, S. Chen, Y. Sun, J. Yang and
Y. Rao, Org. Lett., 2012, 14, 5030; (f) M. Zora and A. Kivrak,
J. Org. Chem., 2011, 76, 9379; (g) J. J. Neumann, M. Suri
and F. Glorius, Angew. Chem., Int. Ed., 2010, 49, 7790;
(h) V. Light, X. Fan, T. Lei, C. Zhou, Q. Meng, B. Chen,
C. Tung and L. Wu, J. Org. Chem., 2016, 81, 7172; (i) N. Liu,
J. Wu, L. Zhu and X. Qian, Synlett, 2008, 1341.
1.27 (s, 3H), 1.25 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3
+
DMSO-d6): δ 147.4, 139.5, 131.9, 126.5, 126.4, 113.4, 35.4, 33.8,
23.9, 23.2, 22.3, 21.6 ppm. HRMS: m/z calculated for C16H21N2
(M + H)+: 241.1699, found: 241.1682.
Conflicts of interest
There are no conflicts of interest to declare.
10 For metal-free pyrazole formation, see: (a) Y. Yu, W. Huang,
Y. Chen, B. Gao, W. Wu, H. Jiang, M.-O. Simon, C.-J. Li,
A. Chanda and V. V. Fokin, Green Chem., 2016, 18, 6445;
(b) J. Sun, J. K. Qiu, Y. L. Zhu, C. Guo, W. J. Hao, B. Jiang
and S. J. Tu, J. Org. Chem., 2015, 80, 8217; (c) W. M. Shu,
K. L. Zheng, J. R. Ma, H. Y. Sun, M. Wang and A. X. Wu,
Org. Lett., 2015, 17, 1914; (d) R. Harigae, K. Moriyama and
H. Togo, J. Org. Chem., 2014, 79, 2049.
Acknowledgements
We thank DST for providing the HRMS facility in the FIST
program, and BA thanks UGC, New Delhi, for a research
fellowship.
Notes and references
11 X. Zhang, J. Kang, P. Niu, J. Wu, W. Yu and J. Chang, J. Org.
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