Microwave-assisted Vilsmeier-Haack synthesis of Pyrazole-4-carbaldehydes

Article abstract of DOI:10.1002/jhet.3824

The synthesis of 4-formylpyrazoles using Vilsmeier-Haack reagent is a common protocol in pyrazole chemistry. An efficient microwave-assisted synthesis of 4-formylpyrazoles by employing Vilsmeier-Haack reagent (OPC-VH) derived from phthaloyl dichloride/dimethylformamide has been described. This method offers the advantages of operational simplicity, avoiding the use of POCl₃ as toxic reagents and reuse of the by-product in the preparation of phthaloyl dichloride.

Full text of DOI:10.1002/jhet.3824

Received: 8 August 2019
DOI: 10.1002/jhet.3824
Revised: 24 August 2019
Accepted: 22 October 2019
A R T I C L E
Microwave‐assisted Vilsmeier‐Haack synthesis of Pyrazole‐
4‐carbaldehydes
Poonam Kumari | Sumit Sood | Anil Kumar | Karan Singh
Department of Chemistry, Akal College of
Abstract
Basic Sciences, Eternal University, Baru
The synthesis of 4‐formylpyrazoles using Vilsmeier‐Haack reagent is a common
Sahib, District Sirmaur, Himachal
Pradesh, India
protocol in pyrazole chemistry. An efficient microwave‐assisted synthesis of 4‐
formylpyrazoles by employing Vilsmeier‐Haack reagent (OPC‐VH) derived from
Correspondence
Karan Singh, Department of Chemistry,
Akal College of Basic Sciences, Eternal
University, Baru Sahib, Sirmaur 173101,
Himachal Pradesh India.
phthaloyl dichloride/dimethylformamide has been described. This method
offers the advantages of operational simplicity, avoiding the use of POCl3 as toxic
reagents and reuse of the by‐product in the preparation of phthaloyl dichloride.
Email: karansinghji@rediffmail.com;
karan.sagwal@yahoo.com
1 | INTRODUCTION
and regioselective formylation of pyrrole‐2‐carboxylate
using the OPC‐VH reagent is well documented in the
Pyrazoles, a vital member of the heterocyclic family, have
attracted wide attention in medicinal and pesticidal
chemistry due to their significant biological activities.[1–
literature.[15,17]
Although OPC‐VH reagent mediated cyclization
potential of hydrazones using thermal condition has been
already explored, the cyclization potential of hydrazones
of keto compounds using OPC‐VH under microwave con-
ditions is still have the scope for further investigation. In
continuation of our work in the synthesis of heterocyclic
compounds[11–14,18–23] and owing the importance of OPC‐
VH reagent, we reported here the synthesis of various 4‐
formylpyrazoles using microwave‐assisted Vilsmeier‐
Haack (OPC‐VH) reaction.
7]
Among functional pyrazoles, 4‐formylpyrazoles occu-
pied a prominent place as they are valuable precursors
for several synthetically useful building blocks including
carboxylic acids, amides, esters, hydrazides, alcohols,
nitriles, amines, Schiff bases, and various organic as well
as heterocyclic compounds.[7–10]
To see the potential applications of 4‐formylpyrazoles as
precursors in the synthesis of other organic and heterocy-
clic compounds, there is still a lot of interest to search
new methods for the preparation of 4‐formylpyrazoles.
The 4‐formylpyrazole synthesis through Vilsmeier‐Haack
reaction is a common method in the pyrazole chemis-
try.[11–14] This protocol is an alternative approach relies on
[4 + 1] disconnection involving the reaction of C‐1 electro-
phile with CCNN binucleophile scaffold. A literature search
revealed that the particular Vilsmeier‐Haack reagent (OPC‐
VH) can be prepared from phthaloyl dichloride (OPC) and
dimethylformamide (DMF) and isolated almost in pure
form, obviating the use of toxic reagents (Scheme 1). The
by‐product, phthalic anhydride, can be easily recovered
and reused in the preparation of phthaloyl dichloride.[13–16]
The synthesis of acid chlorides from carboxylic acid,
alkyl chloride from alcohol, alkyl formates from alcohols
2 | RESULTS AND DISCUSSION
Although the use of POCl3/DMF adduct,[9,11,12]
TCT/DMF adduct[24,25] are well documented for the cycli-
zation of hydrazones of keto compounds, the search for
the new methods for conversion of hydrazones into 4‐
formylpyrazoles is still in progress.
Recently, we reported the conversion of hydrazones,
resulted from acetophenones to their corresponding 4‐
formylpyrazoles using OPC‐VH reagent.[13] To check the
prospect of OPC‐VH reagent during cyclization of
hydrazones, an optimization study was carried out by
performing a series of experiments using various solvents
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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KUMARI ET AL.
SCHEME 1 Synthesis of OPC‐VH reagent
SCHEME 2 Synthesis of 4‐formylpyrazoles 3 using microwave‐assisted OPC‐VH reaction
TABLE 1 Optimization of the OPC‐VH cyclization
OPC‐VH
(equiv.)
Temp
(°C)
Yielda
(%)
Entry
Solvent
Time
1
3.0
2.0
2.5
3.0
3.0
4.0
3.0
3.0
3.0
3.0
3.0
3.0
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Toluene
DMF
60
60
60
60
60
60
60
60
60
80
80
90
4 hours
55b
45
60
70
62
57
62b
70
85
72
70
65
2
10 minutes
10 minutes
10 minutes
10 minutes
10 minutes
2 hours
3
4
5
6
7
8
DMF
5 minutes
10 minutes
5 minutes
10 minutes
5 minutes
9
DMF
10
11
12
DMF
DMF
DMF
Note: Reaction conditions: Hydrazone 2a (1 equiv.), OPC‐VH, Solvent (10 mL), μW, power, temperature.
aYields of isolated products.
bThe reaction was performed at 60°C without any μW activation.
in conventional heating and had established the opti-
mized condition. We thus, already, reported a series of
compounds having a number of substituents using the
optimized reaction condition. The reported yields were
found uniformly good and were not particularly
substituent‐dependent.[13]
These results encouraged us to probe the synthesis of
4‐formylpyrazoles using microwave‐assisted Vilsmeier‐
Haack reaction (Scheme 2).
The hydrazones required for the present study were
synthesized by the condensation of phenylhydrazine with
various acetophenones 1 in methanol containing a cata-
lytic amount of glacial acetic acid and according to the lit-
erature procedure[13] as outlined in Scheme 2.
Having these hydrazones in hand, the study of OPC‐VH
reaction was undertaken using 2a as a model substrate.
According to the previous report,[13] cyclization of
hydrazones with OPC‐VH reagent in 1,4‐dioxane at 60°C
within 4 hours gave the corresponding 4‐formylpyrazoles
in 65‐85% yield. With the same objective, we were wonder-
ing whether this OPC‐VH mediated cyclization could be
further optimized owing to microwave activation. It is well
reported in the literature that microwaves can generally
speed up reactions, lowering any possible degradation,
and improve the overall yield.[26] As a blank experiment,
the hydrazone 2a was reacted under standard thermal con-
ditions[13] at 60°C with OPC‐VH (3 equiv.) in 1,4‐dioxane,
affording after 4 hours the desired cyclized product 3a in

KUMARI ET AL.
3
TABLE 2 Scope of the microwave‐assisted OPC‐VH cyclization
Entry
R1
R2
R3
Producta
Yieldb (%)
1
2
3
4
5
6
7
H
H
H
H
H
H
Cl
H
H
H
Br
H
H
H
H
3a
3b
3c
3d
3e
3f
85
88
87
91
79
78
87
Cl
CH3
F
OCH3
Br
H
3g
aReaction Conditions: Hydrazone 2 (1 equiv.), OPC‐VH (3 equiv.), DMF, MW, 850 W, 60°C.
bYields of isolated products.
SCHEME 3 Synthesis of pyrazolylthiazoles 7 using microwave‐assisted OPC‐VH reaction
55% yield. Microwave irradiation was next studied, varying
the solvent, temperature and the amount of OPC‐VH
(entries 2‐6 and 8‐12, Table 1).
The use of microwave proved to be efficient, allowing
the formation of desired product 3a in 70% yield within
10 minutes, leading to a 15% increase of the yield at the
same temperature (entry 4 vs 1 Table 1).
procedure and synthesized a series of pyrazolylthiazole
derivatives 7a‐g (Scheme 3).
The phenacyl bromides 5 required for the present
investigation were prepared by the bromination of the
corresponding propiophenone in acetic acid[11]
(Scheme 4).
The 4‐substituted acetophenones were treated under
reflux for 2 hours with thiosemicarbazide in methanol
Raising the reaction time from 5 minutes to 10 minutes
for DMF as solvent afforded the cyclized product 3a in
85% yield (entries 8‐9, Table 1). In DMF, repeating the
experiment at 80°C and 90°C resulted in a significant
decrease of the yield (70% and 65% respectively, entries
11 and 12, Table 1). Whereas the conventional thermal
heating of hydrazone 2a at 60°C with OPC‐VH (3 equiv.)
in DMF for 2 hours afforded the desired cyclized product
3a in 62% yield. The best condition appeared thus to be
the use of 3.0 equivalent of OPV‐VH in DMF (entry 9,
Table 1) and consequently, we thus used the reaction
conditions of entry 9 of Table 1 for further exploration
of the preparing compound 3, having a number of substit-
uents. The results are summarized in Table 2. Under the
optimal reaction conditions, yields were uniformly good
and were not particularly substituents dependent.
The investigation is not restricted to pyrazoles 3.
Indeed, we extended the scope and generality of the
to afford thiosemicarbazones
4
of corresponding
acetophenones. Condensation of thiosemicarbazones 4
with phenacyl bromides 5 according to well‐known
Hantzsch‐thiazole synthesis[11] yielded the hydrazones 6
in good yields ranging between 65% and 85%. The
hydrazones 6 were subjected to the optimized condition
for 3a to give pyrazolylthiazoles 7 in good to excellent
yields and the results are summarized in Table 3.
In order to compare the effect of microwave on the
reaction yield, the earlier reported hydrazone[13] was
SCHEME 4 Synthesis of phenacyl bromides 5

4
KUMARI ET AL.
TABLE 3 Scope of the microwave‐assisted OPC‐VH cyclization of hydrazones 6a‐g
Entry
R
R′
Producta
Yieldb (%)
1
2
3
4
5
6
7
H
H
H
H
H
Cl
Cl
Cl
7a
7b
7c
7d
7e
7f
83
85
91
89
77
82
87
Br
CH3
OCH3
H
Br
CH3
7g
aReaction Conditions: Hydrazone 6 (1 equiv.), OPC‐VH (3 equiv.), DMF (10 mL), MW, 850 W, 60°C.
bYields of isolated products.
further studied. Condensation of acetophenone with 2‐
hydrazinobenzothiazole in ethanol containing a catalytic
amount of glacial acetic acid afforded acetophenone
benzothiazol‐2‐yl‐hydrazone 8. The hydrazone 8 was sub-
jected to the optimized microwave condition afforded
1‐(benzo[d]thiazol‐2‐yl)‐3‐phenyl‐1H‐pyrazole‐4‐
work‐up, high yielding and reuse of the by‐product in
the preparation of phthaloyl dichloride can make the
method useful for organic as well as medicinal chemists.
Notably, many of the resulting formylpyrazoles are previ-
ously unknown and can function as versatile building
blocks for diversified synthesis of various useful heterocy-
clic compounds that may be of great interest in develop-
ing the novel pyrazole‐based drugs. It is our hope that
this route will lead to further exploration of these novel
compounds.
carbaldehyde 9 in 83% yield as compared to 65% yield
obtained in thermal heating method (Scheme 5).
The structures of product 7a‐g were determined by
1
spectroscopic (IR, H NMR, 13C NMR, and ESI‐MS) and
elemental analysis data.
The IR of 7a showed C═O stretching at 1680 cm−1
along with C─H stretching at 2776 and 2861 cm−1 which
suggested the presence of aldehyde group in compound
7a. The presence of formyl group was further confirmed
4 | MATERIALS AND METHODS
by H NMR and 13C NMR. H NMR showed a singlet at
δ 10.02 which is due to –CHO functional group. The pres-
ence of a singlet at δ 9.30 belongs to pyrazole─H, con-
firmed the formation of pyrazole ring. In 13C NMR, the
presence of a peak at δ 184.61 further confirmed the for-
mation of 4‐formyl pyrazolylthiazoles.
Melting points were determined in open glass capillaries
on a Fisher‐Johns melting point apparatus and are uncor-
rected. 1H NMR (400 MHz) was recorded at room temper-
ature in CDCl3 as solvent and tetramethylsilane (TMS) as
an internal standard (δ = 0 ppm), and the values were
reported in the following order: chemical shift
(δ = 0 ppm), multiplicity (s = singlet, d = doublet, t = trip-
let, q = quartet, m = multiplet), coupling constant (J in
Hz), and integration. 13C NMR (100 MHz) spectra were
recorded in CDCl3 solutions with TMS as internal stan-
dard. IR spectra were taken as KBr pellets on a Perkin
Elmer RXI FT‐IR spectrometer. The mass spectra were
recorded on a JOEL JMS 600 mass spectrometer at an
ionizing potential of 70 eV (EI) electron impact ionization
mode using the direct inlet system. All the reactions were
monitored by thin‐layer chromatography (TLC) on pre‐
coated silica gel 60 F254 (mesh); spots were visualized
1
1
1
The IR, H NMR and 13C NMR of all the unknown
final compounds 3 and 7 were recorded and confirmed
the structures accordingly.
3 | CONCLUSIONS
In summary, a convenient microwave‐assisted Vilsmeier‐
Haack synthesis of pyrazole‐4‐carbaldehydes has been
reported. The advantages such as avoiding the use of
POCl3 as toxic reagents, operational simplicity, easy
SCHEME 5 Synthesis of 1‐(benzo[d]
thiazol‐2‐yl)‐3‐phenyl‐1H‐pyrazole‐4‐
carbaldehyde 9: Comparison between
conventional heating and microwave‐
assisted methods

KUMARI ET AL.
5
under UV light at 254 nm. Elemental analyses were
obtained using a Carlo Erba EA1108 microanalyzer.
Acetophenone
4‐phenyl‐5‐methylthiazol‐2‐
ylhydrazone 6a. White solid; 73% yield; m.p. 224–
226°C. IR (υ cm−1, KBr): 1608 (C═N str), 3420 (NH str).
1H NMR (400 MHz, DMSO‐d6): 7.89–7.91 (m, 2H, ArH),
7.50–7.55 (m, 5H, ArH), 7.42–7.44 (m, 3H, ArH), 2.50 (s,
3H, thiazole‐CH3), 2.38 (s, 3H, CH3─C═N─). ESI‐MS
(m/z): 308.21 [M + H]+. Anal. Calcd for C18H17N3S: C,
70.33; H, 5.57%. Found: C, 70.23; H, 5.51%.
4.1 | General procedure for the synthesis
of substituted acetophenone phenyl
hydrazones (2a–g)
A
mixture of phenylhydrazine (9.16 mmol) and
4′‐Bromoacetophenone 4‐phenyl‐5‐methylthiazol‐2‐
ylhydrazone 6b. Light yellow solid; 82% yield; m.p.
230–231°C. IR (υ cm−1, KBr): 1617 (C═N str), 3395 (NH
substituted acetophenones 1a‐g (8.33 mmol) in methanol
(60 mL) containing glacial acetic acid (4 mL) was heated
at reflux for 1 hour. The precipitate formed after cooling
was filtered and washed with methanol. After drying in
vacuum over P2O5, the hydrazones 2a‐g were obtained
in 80–91% yields.
1
str). H NMR (400 MHz, CDCl3): 12.68 (bs, 1H, NH),
7.65 (d, J = 8.7 Hz, 2H, ArH), 7.45–7.66 (m, 7H, ArH),
2.55 (s, 3H, thiazole‐CH3), 2.46 (s, 3H, CH3─C═N─).
ESI‐MS (m/z): 388.03 [M + H, 81Br]+, 386.04 [M + H,
79Br]+. Anal. Calcd for C18H16BrN3S: C, 55.96; H, 4.17%.
Found: C, 55.87; H, 4.11%.
4′‐Methylacetophenone 4‐phenyl‐5‐methylthiazol‐2‐
ylhydrazone 6c. Yellow solid; 77% yield; m.p. 208–
210°C. IR (υ cm−1, KBr): 1622 (C═N str), 3417 (NH str).
1H NMR (400 MHz, CDCl3): 12.80 (bs, 1H, NH), 7.68 (d,
J = 8.2 Hz, 2H, ArH), 7.53–7.58 (m, 2H, ArH), 7.49–7.51
(m, 2H, ArH), 7.45–7.47 (m, 1H, ArH), 7.22 (d,
J = 8.2 Hz, 2H, ArH), 2.54 (s, 3H, thiazole‐CH3), 2.45 (s,
3H, CH3─C═N─), 2.39 (s, 3H, CH3). ESI‐MS (m/z):
322.23 [M + H]+. Anal. Calcd for C19H19N3S: C, 70.99;
H, 5.96%. Found: C, 70.91; H, 5.92%.
4′‐Methoxyacetophenone 4‐phenyl‐5‐methylthiazol‐
2‐ylhydrazone 6d. White solid; 88% yield; m.p. 228–
229°C. IR (υ cm−1, KBr): 1624 (C═N str), 3407 (NH str).
1H NMR (400 MHz, CDCl3): 7.75 (d, J = 8.9 Hz, 2H,
ArH), 7.45–7.58 (m, 5H, ArH), 6.93 (d, J = 8.9 Hz, 2H,
ArH), 3.86 (s, 3H, OCH3), 2.53 (s, 3H, thiazole‐CH3),
2.45 (s, 3H, CH3─C═N─). ESI‐MS (m/z): 338.45
[M + H]+. Anal. Calcd for C19H19N3OS: C, 67.63; H,
5.68%. Found: 67.54; H, 5.63%.
4.2 | General procedure for the synthesis
of 4‐substituted acetophenone
thiosemicarbazones (4a‐d)
A mixture of substituted acetophenones 1 (0.01 mol) and
thiosemicarbazide (0.01 mol) in ethanol (50 ml) contain-
ing glacial acetic acid (4 mL) was heated at reflux for
1 hour. The solid formed after cooling was filtered,
washed with water, dried and purified by crystallization
with benzene to give 4a‐d as colorless solid in 75–85%
yields (Table 4).
4.3 | General procedure for the synthesis
of 4′‐substituted acetophenone
4‐aryl‐5‐methylthiazol‐2‐ylhydrazones (6a‐
g).
A mixture of acetophenone thiosemicarbazone 4a (1 g,
5.18 mmol) and 2‐bromo‐1‐phenylpropan‐1‐one (1.09 g,
5.18 mmol) in absolute ethanol (25 mL) was refluxed for
1 hour. On completion of reaction, reaction mixture was
cooled to room temperature. The separated solid was fil-
tered, washed with ethanol, dried and recrystallized from
Acetophenone 4‐(3‐chlorophenyl)‐5‐methylthiazol‐
2‐ylhydrazone 6e. Light yellow solid; 84% yield; m.p.
231–232°C. IR (υ cm−1, KBr): 1622 (C═N str), 3417 (NH
1
str). H NMR (400 MHz, DMSO‐d6): 7.79 (d, J = 7.8 Hz,
2H, ArH), 7.65 (t, J = 1.7 Hz, 1H, ArH), 7.55 (d,
J = 7.8 Hz, 1H, ArH), 7.35–7.46 (m, 5H, ArH), 2.44 (s,
3H, thiazole‐CH3), 2.33 (s, 3H, CH3─C═N─). ESI‐MS
ethanol
to
afford
acetophenone
4‐phenyl‐5‐
methylthiazol‐2‐ylhydrazone 6a in 73% yield.
TABLE 4 Physical data of 4‐substituted acetophenone thiosemicarbazones (4a‐d)
m.p.
(lit
Mol.
Mol.
Entry
Compound
R
Formula
Wt
Yield
m.p.)
1
2
3
4
4a
4b
4c
4d
H
C9H11N3S
193.27
272.16
207.30
223.29
79
75
81
85
169–171 (170[27]
181–183 (185[27]
152–154 (155[28]
)
)
)
4‐Br
C9H10BrN3S
C10H13N3S
C10H13N3OS
4‐CH3
4‐OCH3
159–161 (160–165[29]
)

6
KUMARI ET AL.
(m/z): 344.93 [M + H, 37Cl], 342.06 [M + H, 35Cl], Anal.
Calcd for C18H16ClN3S: C, 63.24; H, 4.72%. Found: C,
63.16; H, 4.68%.
cooling‐jet cooled the reaction vessel to ambient
temperature.
A mixture of hydrazones 2 or 6 (1.92 mmol) in DMF
(10 mL) in a microwave vial was added OPC‐VH reagent
(0.73 g, 5.76 mmol) at 0°C and stirred for 1 minutes. The
vial was sealed with the Teflon septum and aluminum
crimp, using an appropriate crimping tool. The vial was
then subjected to microwave irradiation and the temper-
ature was being ramped from room temperature to 60°C
with the holding time of 10 minutes. The reaction was
brought to room temperature, and quenched with ice,
neutralized with saturated NaHCO3 solution, and then
extracted with ethyl acetate (2 × 50 mL). The organic
layer was washed with brine solution (2 × 15 mL). The
organic layer was dried over anhydrous Na2SO4, filtered
and the filtrate was concentrated under reduced pressure
to afford crude compound 3 and 7 which were recrystal-
lized with refluxing CHCl3‐EtOH.
4′‐Bromoacetophenone
4‐(3‐chlorophenyl)‐5‐
methylthiazol‐2‐ylhydrazone 6f. Yellow solid; 90%
yield; m.p. 241–243°C. IR (υ cm−1, KBr): 1616 (C═N
1
str), 3425 (NH str). H NMR (400 MHz, CDCl3): 12.96
(bs, 1H, NH), 7.65 (d, J = 8.6 Hz, 2H, ArH), 7.56 (d,
J = 8.6 Hz, 2H, ArH), 7.46–7.52 (m, 4H, ArH), 2.55 (s,
3H, thiazole‐CH3), 2.47 (s, 3H, CH3─C═N─). ESI‐MS
(m/z): 423.97 [M + H, 81Br37Cl], 421.92 [M + H,
81Br35Cl and 79Br37Cl], 419.97 [M + H, 79Br35Cl]. Anal.
Calcd for C18H15BrClN3S: C, 51.38; H, 3.59%. Found: C,
51.30; H, 3.55%.
4′‐Methylacetophenone
4‐(3‐chlorophenyl)‐5‐
methylthiazol‐2‐ylhydrazone 6g. Yellow solid; 87%
yield; m.p. 247–249°C. IR (υ cm−1, KBr): 1614 (C═N
1
str), 3416 (NH str). H NMR (400 MHz, CDCl3): 7.67 (d,
J = 8.2 Hz, 2H, ArH), 7.44–7.51 (m, 4H, ArH), 7.22 (d,
J = 8.2 Hz, 2H, ArH), 2.54 (s, 3H, thiazole‐CH3), 2.45 (s,
3H, CH3─C═N─), 2.40 (s, 3H, CH3). ESI‐MS (m/z):
358.06 [M + H, 37Cl]+, 356.08 [M + H, 35Cl]+. Anal. Calcd
for C19H18ClN3S: Found: C, 64.12; H, 5.10%. Found: C,
64.02; H, 5.06%.
1,3‐Diphenyl‐1H‐pyrazole‐4‐carbaldehyde 3a. Yel-
low Solid; 85% yield; m.p. 142–145°C (Lit.[30] 145–
147°C). IR (υ cm−1, KBr): 1671 (C═O str), 2780, 2881
1
(CH str). H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H,
CHO), 8.55 (s, 1H, Pyrazole─H), 7.78–7.83 (m, 4H,
ArH), 7.47–7.53 (m, 5H, ArH), 7.41 (t, J = 2.4 Hz, 1H,
ArH). ESI‐MS (m/z): 249.20 [M + H]+. Anal. Calcd for
C16H12N2O: C, 77.40; H, 4.87%. Found: C, 77.33; H, 4.82%.
3‐(4‐Chlorophenyl)‐1‐phenyl‐1H‐pyrazole‐4‐
4.4 | Method for preparing the OPC‐VH
reagent
carbaldehyde 3b. Yellow Solid; 88% yield; m.p. 109–
111°C (Lit.[31] 106–108°C). IR (υ cm−1, KBr): 1670 (C═O
A mixture of DMF (32.0 g, 0.44 mol) and OPC (45.0 g,
0.22 mol) in 2‐chlorotoluene (105 mL, 0.88 mol) was
stirred for 3 hours at 50°C to afford the OPC‐VH reagent
as white crystals (23 g, 82% yield), which were subse-
quently filtered under nitrogen and dried under reduced
pressure. The dried OPC‐VH reagent was characterized
by its melting point {m.p. 128–130°C (decomp.; lit.[15]
132°C)}.
1
str), 2778, 2831 (CH str). H NMR (400 MHz, CDCl3): δ
10.04 (s, 1H, CHO), 8.54 (s, 1H, Pyrazole─H), 7.83 (d,
J = 8.4 Hz, 2H, ArH), 7.78 (d, J = 7.6 Hz, 2H, ArH),
7.52 (t, J = 7.2 Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H,
ArH), 7.41 (t, J = 7.2 Hz, 1H, ArH). ESI‐MS (m/z):
285.20 [M + H, 37Cl]+, 283.22 [M + H, 35Cl]+. Anal. Calcd
for C16H11ClN2O: C, 67.97; H, 3.92%. Found: C, 67.90; H,
3.87%.
1‐Phenyl‐3‐(p‐tolyl)‐1H‐pyrazole‐4‐carbaldehyde 3c.
Yellow Solid; 87% yield; m.p. 99–101°C (Lit.[32] 97°C). IR
4.5 | General procedure of
4‐formylpyrazoles (3a‐g, 7a‐g)
1
(υ cm−1, KBr): 1670 (C═O str), 2779, 2856 (CH str). H
NMR (400 MHz, CDCl3): δ 10.05 (s, 1H, CHO), 8.53 (s,
1H, Pyrazole─H), 7.79 (d, J = 8.4 Hz, 2H, ArH), 7.71 (d,
J = 8.4 Hz, 2H, ArH), 7.51(t, J = 8.4 Hz, 2H, ArH), 7.38
(t, J = 7.2 Hz, 1H, ArH), 7.32 (d, J = 8.4 Hz, 2H, ArH),
2.43 (s, 3H, CH3). ESI‐MS (m/z): 263.21 [M + H]+. Anal.
Calcd for C17H14N2O: C, 77.84; H, 5.38%. Found: C, 77.80;
H, 5.33%.
All compounds 3 and 7 were synthesized using Anton
Paar Monowave‐300 reactor (Gaas, Austria), operating
at a frequency of 2.455 GHz with continuous irradiation
power of 0 to 850 W. The reactions were carried out in
a G‐4 borosilicate glass vial sealed with Teflon septum
and placed in a microwave cavity. Initially, microwave
of required power was used, and temperature was being
ramped from room temperature to the desired tempera-
ture. Once this temperature was attained, the process vial
was held at this temperature for a required time. The
reactions were continuously stirred. Temperature was
measured by an IR sensor. After the experiments, a
3‐(3‐Bromo‐4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazole‐
4‐carbaldehyde 3d. Yellow Solid; 91% yield; m.p. 128–
130°C. IR (υ cm−1, KBr): 1688 (C═O str), 2768, 2822
1
(CH str). H NMR (400 MHz, CDCl3): δ 10.03 (s, 1H,
CHO), 8.53 (s, 1H, Pyrazole─H), 8.16 (dd, J = 6.4,
2.0 Hz, 1H, ArH), 7.87 (ddd, J = 8.6, 4.6, 2.0 Hz, 1H,

KUMARI ET AL.
7
ArH), 7.79 (d, J = 7.6 Hz, 2H, ArH), 7.54 (t, J = 5.6 Hz,
2H, ArH), 7.43 (t, J = 7.6 Hz, 1H, ArH), 7.24 (t,
J = 8.6 Hz, 1H, ArH). ESI‐MS (m/z): 347.13 [M + H,
Pyrazole─H), 7.92 (dd, J = 6.7, 1.9 Hz, 2H, ArH), 7.74
(dd, J = 8.5, 1.4 Hz, 2H, ArH), 7.69 (dd, J = 6.7, 1.9 Hz,
2H, ArH), 7.49 (t, J = 7.5 Hz, 2H, ArH), 7.41 (t,
J = 7.5 Hz, 1H, ArH), 2.62 (s, 3H, thiazole‐CH3). 13C
NMR (100 MHz, CDCl3): δ 183.89 (C═O), 153.50,
148.63, 134.09, 132.70, 131.88, 130.51, 129.57, 128.58,
128.43, 128.12, 126.90, 124.19, 122.65, 12.83 (CH3). ESI‐
MS (m/z): 426.0023 [M + H, 81Br]+, 424.0043 [M + H,
79Br]+. Anal. Calcd for C20H14BrN3OS: C, 56.61; H,
3.33%. Found: C, 56.51; H, 3.29%.
81Br]+, 345.11 [M
+
H, 79Br]+. Anal. Calcd for
C16H10BrFN2O: C, 55.68; H, 2.92%. Found: C, 55.61; H,
2.87%.
3‐(4‐Methoxyphenyl)‐1‐phenyl‐1H‐pyrazole‐4‐
carbaldehyde 3e. Yellow Solid; 79% yield; m.p. 134–
136°C (Lit.[33] 136–138°C). IR (υ cm−1, KBr): 1671 (C═O
1
str), 2780, 2836 (CH str). H NMR (400 MHz, CDCl3): δ
10.04 (s, 1H, CHO), 8.52 (s, 1H, Pyrazole─H), 7.78–7.80
(m, 4H, ArH), 7.50 (t, J = 8.0 Hz, 2H, ArH), 7.38 (t,
J = 8.0 Hz, 1H, ArH), 7.03 (d, J = 8.8 Hz, 2H, ArH),
3.88 (s, 3H, OCH3). ESI‐MS (m/z): 279.26 [M + H]+. Anal.
Calcd for C17H14N2O2: C, 73.37; H, 5.07%. Found: C,
73.31; H, 4.99%.
1‐(5‐Methyl‐4‐phenylthiazol‐2‐yl)‐3‐(p‐tolyl)‐1H‐
pyrazole‐4‐carbaldehyde 7c. Light yellow solid; 68%
yield; m.p. 162–164°C. IR (υ cm−1, KBr): 1679 (C═O
str), 2770, 2828 (CH str). 1H NMR (400 MHz,
DMSO‐d6):
δ 10.02 (s, 1H, CHO), 9.24 (s, 1H,
Pyrazole─H), 7.32–7.82 (m, 9H, ArH), 2.60 (s, 3H,
thiazole‐CH3), 2.40 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 184.72 (C═O), 155.45, 155.17,
148.52, 139.82, 134.20, 131.40, 129.47, 128.89, 128.55,
128.43, 128.04, 127.76, 126.71, 122.64, 21.43 (CH3),
12.82 (CH3). ESI‐MS (m/z): 360.1096 [M + H]+. Anal.
Calcd for C21H17N3OS: C, 70.17; H, 4.77%. Found: C,
70.08; H, 4.69%.
3‐(4‐Methoxyphenyl)‐1‐(5‐methyl‐4‐phenylthiazol‐
2‐yl)‐1H‐pyrazole‐4‐carbaldehyde 7d. Light yellow
solid; 84% yield; m.p. 175–177°C. IR (υ cm−1, KBr): 1689
(C═O str), 2772, 2831 (CH str). 1H NMR (400 MHz,
CDCl3): δ 10.04 (s, 1H, CHO), 8.95 (s, 1H, Pyrazole─H),
7.84 (d, J = 8.8 Hz, 2H, ArH), 7.68 (d, J = 8.5 Hz, 2H,
ArH), 7.48 (t, J = 7.8 Hz, 2H, ArH), 7.40 (t, 1H,
J = 7.8 Hz, ArH), 7.02 (d, J = 8.8 Hz, 2H, ArH), 2.60 (s,
3H, thiazole CH3), 3.88 (s, 3H, OCH3). 13C NMR
(100 MHz, CDCl3): δ 184.56 (C═O), 160.84, 155.46,
154.71, 148.51, 134.20, 131.89, 130.38, 128.55, 128.43,
128.04, 126.65, 123.12, 122.54, 114.17, 55.41 (OCH3),
12.82 (CH3). ESI‐MS (m/z): 376.0992 [M + H]+. Anal.
Calcd for C21H17N3O2S: C, 67.18; H, 4.56%. Found: C,
67.08; H, 4.59%.
1‐(4‐(3‐Chlorophenyl)‐5‐methylthiazol‐2‐yl)‐3‐phe-
nyl‐1H‐pyrazole‐4‐carbaldehyde 7e. Light yellow solid;
67% yield; m.p. 159–160°C. IR (υ cm−1, KBr): 1679
(C═O str), 2741, 2859 (CH str). 1H NMR (400 MHz,
CDCl3): δ 10.07 (s, 1H, CHO), 8.98 (s, 1H, Pyrazole─H),
7.85 (dd, J = 7.8, 1.7 Hz, 2H, ArH), 7.70 (t, J = 1.7 Hz,
1H, ArH), 7.50–7.61 (m, 4H, ArH), 7.40 (t, J = 7.5 Hz,
1H, ArH), 7.35 (m, 1H, ArH), 2.61 (s, 3H, thiazole‐CH3).
13C NMR (100 MHz, CDCl3): δ 184.55 (C=O), 155.60,
155.17, 147.01, 135.87, 134.54, 131.53, 130.54, 129.79,
129.75, 129.00, 128.79, 128.50, 128.11, 127.72, 126.42,
122.79, 12.86 (CH3). ESI‐MS (m/z): 382.0550 [M + H,
37Cl]+, 380.0582 [M + H, 35Cl]+. Anal. Calcd for
C20H14ClN3OS: C, 63.24; H, 3.71%. Found: Found: C,
63.14; H, 3.65%.
3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazole‐4‐
carbaldehyde 3f. Yellow Solid; 78% yield; m.p. 155–
157°C (Lit.[32] 159°C). IR (υ cm−1, KBr): 1677 (C═O str),
2780, 2865 (CH str). 1H NMR (400 MHz, CDCl3): δ
10.03 (s, 1H, CHO), 8.53 (s, 1H, Pyrazole─H), 7.75–7.79
(m, 4H, ArH), 7.63 (d, J = 8.8 Hz, 2H, ArH), 7.50 (t,
J = 8.0 Hz, 2H, ArH), 7.41 (t, J = 8.8 Hz, 1H, ArH).
ESI‐MS (m/z): 328.91 [M + H, 81Br]+, 326.96 [M + H
79Br]+. Anal. Calcd for C16H11BrN2O: C, 58.74; H,
3.39%. Found: C, 58.68; H, 3.35%.
3‐(2‐Chlorophenyl)‐1‐phenyl‐1H‐pyrazole‐4‐
carbaldehyde 3g. Yellow Solid; 87% yield; m.p. 147–
149°C (Lit.[34] 150–151°C). IR (υ cm−1, KBr): 1675 (C═O
1
str), 2780, 2881 (CH str). H NMR (400 MHz, CDCl3): δ
9.80 (s, 1H, CHO), 8.54 (s, 1H, Pyrazole─H), 7.78 (d,
J = 7.6 Hz, 2H, ArH), 7.49–7.59 (m, 4H, ArH), 7.37–7.45
(m, 3H, ArH). ESI‐MS (m/z): 285.03 [M + H, 37Cl]+,
283.02 [M + H 35Cl]+. Anal. Calcd for C16H11ClN2O: C,
67.97; H, 3.92%. Found: C, 67.88; H, 3.89%.
1‐(5‐Methyl‐4‐phenylthiazol‐2‐yl)‐3‐phenyl‐1H‐
pyrazole‐4‐carbaldehyde 7a. Yellow Solid; 83% yield; m.
p. 169–171°C. IR (υ cm−1, KBr): 1680 (C═O str), 2776,
1
2861 (CH str). H NMR (400 MHz, DMSO‐d6): δ 10.02
(s, 1H, CHO), 9.30 (s, 1H, Pyrazole─H), 7.91–7.93 (m,
2H, ArH), 7.75 (d, J = 7.8 Hz, 2H, ArH), 7.49–7.54 (m,
5H, ArH), 7.42 (t, J = 7.3 Hz, 1H, ArH), 2.59 (s, 3H,
thiazole‐CH3). 13C NMR (100 MHz, CDCl3): δ 184.61
(C═O), 155.39, 155.09, 148.55, 134.17, 131.49, 130.62,
129.70, 129.01, 128.78, 128.56, 128.43, 128.07, 126.79,
122.68, 12.84 (CH3). ESI‐MS (m/z): 346.0992 [M + H]+.
Anal. Calcd for C20H15N3OS: C, 69.54; H, 4.38%. Found:
C, 69.46; H, 4.33%.
3‐(4‐Bromophenyl)‐1‐(5‐methyl‐4‐phenylthiazol‐2‐
yl)‐1H‐pyrazole‐4‐carbaldehyde 7b. Light yellow solid;
75% yield; m.p. 202–204°C. IR (υ cm−1, KBr): 1679
(C═O str), 2780, 2871 (CH str). 1H NMR (400 MHz,
DMSO‐d6):
δ 10.04 (s, 1H, CHO), 9.34 (s, 1H,

8
KUMARI ET AL.
[3] I. V. Magedov, M. Manpadi, S. van Slambrouck, W. F. Steelant,
E. Rozhkova, N. M. Przheval'skii, S. Rogelj, A. Kornienko,
J. Med. Chem. 2007, 50, 5183.
3‐(4‐Bromophenyl)‐1‐(4‐(3‐chlorophenyl)‐5‐
methylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carbaldehyde
7f.
Light yellow solid; 80% yield; m.p. 182–184°C. IR (υ
cm−1, KBr): 1691 (C═O str), 2723, 2812 (CH str). 1H
NMR (400 MHz, CDCl3): δ 10.05 (s, 1H, CHO), 8.97 (s,
1H, Pyrazole─H), 7.80 (d, J = 8.5 Hz, 2H, ArH), 7.70 (t,
J = 1.6 Hz, 1H, ArH), 7.64 (d, J = 8.5 Hz, 2H, ArH),
7.56 (td, J = 7.4, 1.6 Hz, 1H, ArH), 7.41 (t, J = 7.4 Hz,
1H, ArH), 7.37 (td, J = 7.4, 1.6 Hz, 1H, ArH), 2.61 (s,
3H, thiazole‐CH3). 13C NMR (100 MHz, CDCl3): δ
183.83 (C═O), 153.58, 147.08, 135.80, 134.56, 132.75,
131.90, 130.50, 129.81, 129.49, 128.52, 128.17, 127.83,
126.41, 124.25, 122.77, 12.86 (CH3). ESI‐MS (m/z):
461.9701 [M + H, 81Br37Cl], 459.9726 [M + H, 81Br35Cl
and 79Br37Cl], 457.9794 [M + H, 79Br35Cl]. Anal. Calcd
for C20H13BrClN3OS: C, 52.36; H, 2.86%. Found: C,
52.25; H, 2.79%.
[4] A. K. Tewari, P. Srivastava, V. P. Singh, A. Singh, R. K. Goel, C.
G. Mohan, Chem. Pharm. Bull. 2010, 58, 634.
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Akçamur, J. Heterocyc. Chem. 2002, 39, 869.
[7] O. Prakash, R. Pundeer, P. Ranjan, K. Pannu, Y. Dhingra, K.
Aneja, Indian J. Chem. 2009, 48B, 563.
[8] R. Sridhar, P. T. Perumal, S. Etti, G. Shanmugam, M. N.
Ponnuswamy, V. R. Prabavathy, N. Mathivanan, Bioorg. Med.
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[9] P. K. Sharma, N. Chandak, P. Kumar, C. Sharma, K. R. Aneja,
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1‐(4‐(3‐Chlorophenyl)‐5‐methylthiazol‐2‐yl)‐3‐(p‐
tolyl)‐1H‐pyrazole‐4‐carbaldehyde 7g. Yellow solid;
83% yield; m.p. 155–157°C. IR (υ cm−1, KBr): 1677
(C═O str), 2759, 2863 (CH str). 1H NMR (400 MHz,
CDCl3): δ 10.05 (s, 1H, CHO), 8.95 (s, 1H, Pyrazole─H),
7.55–7.81 (m, 4H, ArH), 7.30–7.40 (m, 4H, ArH), 2.60 (s,
3H, thiazole‐CH3), 2.43 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 184.68 (C═O), 146.97, 139.89,
135.90, 134.52, 131.89, 131.45, 130.50, 129.78, 129.49,
128.88, 128.50, 128.09, 127.64, 126.42, 122.75, 21.43
(CH3), 12.85 (CH3). ESI‐MS (m/z): 396.0627 [M + H,
37Cl]+, 394.0683 [M + H, 35Cl]+. Anal. Calcd for
C21H16ClN3OS: C, 64.03; H, 4.09%. Found: C, 63.92; H,
4.01%.
[11] P. K. Sharma, K. Singh, S. Dhawan, S. Singh, Indian J. Chem.
2002, 41A, 2071.
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J. Heterocyclic Chem. 2018, 55, 2507.
[14] R. Bala, P. Kumari, S. Sood, H. Phougat, A. Kumar, K. Singh,
J. Heterocyclic Chem. 2019, 56, 1787.
[15] Y. Kimura, D. Matsuura, Int. J. Org. Chem. 2013, 3, 1.
[16] Y. Kimura, D. Matsuura, T. Hanawa, Y. Kobayashi, Tetrahe-
dron Lett. 2012, 53, 1116.
[17] T. Warashina, D. Matsuura, T. Sengoku, M. Takahashi, H.
Yoda, Y. Kimura, Org. Process Res. Dev. 2019, 23, 614.
[18] P. K. Sharma, K. Singh, S. Kumar, P. Kumar, S. Dhawan,
S. Lal, H. Ulbrich, G. Dannhardt, Med. Chem. Res. 2011,
20, 239.
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ACKNOWLEDGMENTS
Singh, Curr. Bioact. Compd. 2018, 14, 428.
The authors are grateful to Prof. H.S. Dhaliwal, Vice‐
Chancellor, Eternal University, Baru Sahib for providing
facilities and financial assistance. The authors would like
to acknowledge GVK Biosciences Pvt. Ltd. Hyderabad
and Regional Sophisticated Instrumentation Centre, Pun-
jab University, Chandigarh, for recording the analytical
data during the study.
[20] K. Singh, P. Sharma, Int. J. Pharm. Pharm. Sci. 2014, 6, 429.
[21] S. Sood, R. Bala, V. Kumar, N. Singh, K. Singh, Curr. Bioact.
Compd. 2018, 14, 273.
[22] Y. Pulipati, V. Gurram, S. V. Laxmi, Y. Satyanarayana, K.
Singh, V. Kumar, S. Sharma, N. Pottabathini, V. B. R. Iska,
Syn. Commun. 2017, 47, 1142.
[23] R. Arora, R. Bala, P. Kumari, S. Sood, A. N. Yadav, N. Singh, K.
Singh, Lett. Org. Chem. 2018, 15, 606.
[24] L. De Luca, G. Giacomelli, S. Masala, A. Porcheddu, Synlett
2004, 2004, 2299.
ORCID
Karan Singh https://orcid.org/0000-0001-8956-5558
[25] B. F. Abdel‐Wahab, R. E. Khidre, A. A. Farahat, ARKIVOC
2011, 1, 196.
[26] L. Le Corre, L. Tak‐Tak, A. Guillard, G. Prestat, C. Gravier‐
Pelletier, Org. Biomol. Chem. 2015, 13, 409.
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How to cite this article: Kumari P, Sood S,
Kumar A, Singh K. Microwave‐assisted Vilsmeier‐
Haack synthesis of Pyrazole‐4‐carbaldehydes. J
Heterocyclic Chem. 2019;1–9. https://doi.org/
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