pubs.acs.

org/joc Article

HFIP-Mediated Multicomponent Reactions: Synthesis of Pyrazole-

Linked Thiazole Derivatives
Riddhiman Banerjee,† Danish Ali,† Nurabul Mondal, and Lokman H. Choudhury*
Cite This: J. Org. Chem. 2024, 89, 4423−4437 Read Online

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ABSTRACT: The development of one-pot, atom, and step-economic new methods avoiding metal, harsh reaction conditions, and
toxic reagents for the synthesis of medicinally important hybrid molecules bearing more than one bioactive moieties is currently one
of the hot topics in organic synthesis. Herein, we report a green and efficient room temperature multicomponent reaction for the
synthesis of novel pyrazole-linked thiazoles involving a one-pot C−C, C−N, and C−S bond-forming process from the reaction of
aryl glyoxal, aryl thioamide, and pyrazolones in 1,1,1,3,3,3-hexafluoroisopropanol, a hydrogen bond donating reaction medium. A set
of diverse hybrid molecules bearing thiazole and pyrazole moieties were prepared in good to excellent yields by using this method.
This methodology can also be extended to prepare thiazole-linked barbiturates as well as imidazole-linked pyrazoles. All the products
were fully characterized by spectroscopic techniques. The notable features of this protocol are room temperature, metal as well as
additive-free reaction conditions, use of recyclable solvent, water as the byproduct, wide substrate scope, operational simplicity, easy
purification, applicability for gram-scale synthesis, high atom economy, and the presence of two bioactive pyrazole and thiazole
moieties in the products.

■ INTRODUCTION
The design and development of new eco-friendly methods for
Thiazoles are five-membered sulfur- and nitrogen-containing
heterocycles, often found in various natural products, and
polymers as well as in several synthetic drugs.10 Thiazoles
the synthesis of novel molecules bearing important bioactive
possess diverse medicinal activities like cytotoxicity, antibacte-
moieties is an ever-enduring challenge for both organic and
rial, antimalarial, anticancer, antiprotozoal, anti-inflammatory,
medicinal chemists.1 In this pursuit, chemists are now turning to
antihypertension, antiretroviral activities, etc.11 The thiazole
greener approaches while creating new synthetic methods for
moiety is also found in vitamin B1 and many other important
important molecules. These approaches include developing
natural products like bleomycins, urukthapelstatin A, bistrata-
energy-efficient methodologies, utilizing environment-friendly
mide D,12 as well as in many commercially available dyes and
solvents, employing reusable catalysts, maintaining a high atom
fungicides.13 Recently, some thiazole derivatives have been
economy, minimizing the number of steps, and reducing
reported as photographic sensitizers and organic semiconduc-
byproduct formation.2 To move away from traditional heating
tors.14 Thiazole derivatives also exhibit chemosensing properties
conditions, alternative energy input systems such as microwave
for the detection of various ions such as CN−, Hg2+, Cu2+, etc.15
irradiation3 mechanochemical grinding,4 photocatalysis,5 elec-
tro organic synthesis,6 and the utilization of solvents with
exceptional properties7 are being explored. Multicomponent Received: November 8, 2023
reactions (MCRs) stand out as simple one-pot processes with Revised: January 21, 2024
excellent atom economy and high bond-forming indices (BFIs), Accepted: January 26, 2024
making them highly valuable from the perspective of green Published: March 14, 2024
chemistry.8 MCRs are often seen as favorable alternatives to
sequential multistep syntheses.9

© 2024 American Chemical Society https://doi.org/10.1021/acs.joc.3c02567

4423 J. Org. Chem. 2024, 89, 4423−4437
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Figure 1. Structures of some bioactive thiazoles and pyrazolones and our products.
Structures of a few important substituted thiazoles and our
designed products are shown in Figure 1.
Similar to thiazoles, pyrazolone derivatives are also considered
very important heterocycles for drug development. Antipyrine is
one of the oldest synthetic drugs, which was extensively used as
an analgesic and antipyretic drug.16 Apart from this, many
marketed drugs have a pyrazolone core. A few representative
examples are depicted in Figure 1. Edaravone is an FDA-
approved drug used for the treatment of stroke and amyotrophic
lateral sclerosis, commonly known as Lou Gehrig’s disease.17
Meloxicam (D), dipyrone (E), and propyphenazone (F) are
analgesic and antipyretic drugs.18 Similarly, eltombopag (G) is
pyrazolone-containing drug used for the treatment of
thrombocytopenia.19 Considering the wide applications and
enormous importance of the substituted thiazoles and
pyrazolone derivatives, it is expected that our hybrid molecules
(H) bearing these two bioactive moieties will show promising
medicinal properties.
HFIP, also known as 1,1,1,3,3,3-hexafluoroisopropanol, has
transformed from an uncommon and exotic solvent to a crucial
player in organic synthesis.20 It possesses strong polarity and
serves as a significant hydrogen bond-donating solvent.21 The
ability of HFIP to stabilize ionic species, facilitate proton
transfer, and engage in various intermolecular interactions has
sparked significant interest in recent times.22 Moreover, HFIP
stands out due to its easy recovery and recyclability. Addition-
ally, the majority of reactions involving HFIP do not necessitate
high temperatures, extensive workup procedures, or meticulous
purification. These attributes make HFIP an environmentally
safer solvent choice.23 Very recently, Hazra et al. have utilized
HFIP in combination with PTSA for the synthesis of
unsymmetrical diaryl- and triarylmethanes.24
Conventionally thiazoles are prepared by Hantzsch thiazole
synthesis involving α-halo ketone and thioamides.25 Consider-
ing the importance of green chemistry and the requirement for
better alternative methods for the synthesis of substituted
thiazoles, over the years, many methods have been developed
using the combinations of different starting materials as well as
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catalysts and reaction conditions.26 Comparison of a few recent
methods with our present method for the synthesis of
substituted thiazoles is shown in Scheme 1. In 2015, Chen et
al.27 reported a method for the synthesis of disubstituted 2-
amino thiazoles using palladium catalysis via the reaction of vinyl
azide and potassium thiocyanate under heating conditions with
12 h reaction time (Scheme 1, eq a).
Synthesis of 4,5-disubstituted-2-aminothiazoles was reported
by Tang et al. from the coupling of oxime acetates with
isothiocyanates in the presence of a Cu(I) catalyst and Cs2CO3
as a base under heating at 105 °C for 8 h (Scheme 1, eq b).28
Another interesting methodology for synthesizing substituted
thiazoles was reported by Jiang et al. from the reaction of aryl
aldehyde, aryl methyl ketone, ammonium iodide, and sulfur in a
pyridine/water solvent system under heating at 150 °C (Scheme
1, eq c).29 This method also needs heating for a long period of
time. A novel method for the synthesis of trisubstituted thiazoles
from the reaction of enaminoesters, Bromodifluoroacetamides/
esters, and elemental sulfur was reported in 2020 (Scheme 1, eq
d).30 Excess amounts of S8 and Cs2CO3 were used in that
method, and the reaction was performed under heating
conditions at 90 °C for a very long time (48 h). An
electrochemical method to synthesize 2-amino-5-substituted
thiazole derivatives by the reaction of enaminones and thioureas
was reported by Guo et al. as shown in Scheme 1, eq e.31 In this
electro-organic synthesis, strong acid HCl is required. Very
recently, Li et al. reported synthesis of disubstituted thiazole
derivatives from a three-component reaction of enaminones
with potassium thiocyanate and alcohols using electro-organic
synthesis (Scheme 1, eq f).32 In this method also, excess amount
of LiClO4 is required. Although all these methods are very useful
for the synthesis of substituted thiazoles, they suffer from one or
another limitation such as the use of harsh reaction conditions,
the use of a base or strong acid or additive, long reaction time, as
well as use of excess amount of reagents, which are considered as
detrimental in terms of green chemistry.
To the best of our knowledge, there is no report so far in the
literature for the room-temperature synthesis of pyrazole-linked
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Scheme 1. Comparison of Our Methodology with Some Recent Methods for the Synthesis of Substituted Thiazoles
thiazoles without involving any metal or hazardous reagents.
Herein, we report for the first time a greener approach for the
synthesis of trisubstituted thiazoles at room temperature
reaction conditions in HFIP solvent without involving any
additives (Scheme 1, eq g). We have also extended this strategy
for the synthesis of thiazole-linked barbiturates, pyrazole-linked
imidazoles, and even synthesized a molecule having three
pharmacophores, i.e., pyrazole, thiazole, and triazole.
■ RESULTS AND DISCUSSION
In the initial attempt for the synthesis of the pyrazole-linked
trisubstituted thiazole 4a, the three-component reaction of
phenylglyoxal monohydrate 1a, thiobenzamide 2a, and 3-
methyl-1-phenyl-1H-pyrazol-5(4H)-one 3a was chosen as a
model reaction. In the first attempt, the three-component
reaction using 1a, 2a, and 3a in a 1:1:1 ratio was performed in an
ethanol medium at room temperature. Even though the desired
product 4a was formed, we observed only 15% yield even after
12 h of reaction time (Table 1, entry 1). Interestingly, when the
reaction was performed under heating conditions keeping the
reaction temperature at 80 °C, for 6 h, the observed yield
increased slightly to 23% (Table 1, entry 2). The desired product
4a was then fully characterized using 1H, 13C{1H} NMR, and
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HRMS. Motivated by this result, next, we replaced the solvent
system and tried the reaction in DMSO, DCE, isopropanol,
toluene, acetic acid, DMF, and acetonitrile at both room
temperature as well as at elevated temperatures (entry 3−16,
Table 1). Among all these screenings, only the reaction in acetic
acid keeping the reaction temperature at 130 °C provided a good
yield of 4a (entry 12, Table 1). As our objective was to develop a
multicomponent reaction at ambient temperature, we again
tried this model reaction at room temperature using some acidic
catalysts such as PTSA and citric acid. The room temperature
reaction in ethanol medium in the presence of the catalytic
amounts of p-toluenesulfonic acid (PTSA) and citric acid
provided 52 and 45% yields, respectively (Table 1, entries 17
and 18). Next, we performed reactions in 2,2,2-trifluoroethanol
(TFE) (Table 1, entry 19) and HFIP (Table 1, entry 20). To our
delight, we found that HFIP provides an excellent yield of our
desired product at room temperature stirring within 6 h. With
this optimized reaction condition in hand, we explored the
generality and scope of this newly developed methodology by
varying all the components of the reaction, i.e., arylglyoxals (1),
thiobenzamides (2), and pyrazolones (3). First, various
pyrazolone derivatives with different substitutions at 1 or 3
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Table 1. Optimization of the Reaction Conditionsa,b

entry catalyst (mol %) solvent temperature (°C) time (hour) isolated yieldb of 4a (%)
1 none EtOH rt 12 15
2 none EtOH 80 6 23
3 none DMSO rt 6 nil
4 none DMSO 80 6 20
5 none DCE rt 6 nil
6 none DCE 80 6 nil
7 none iPrOH rt 6 15
8 none iPrOH 80 6 28
9 none toluene rt 6 nil
10 none toluene 80 6 nil
11 none AcOH rt 6 nil
12 none AcOH 130 6 77
13 none DMF rt 6 nil
14 none DMF 80 6 nil
15 none ACN rt 6 nil
16 none ACN 80 6 15
17 PTSA (20) EtOH rt 6 52
18 citric acid (20) EtOH rt 6 45
19 none TFE rt 6 65
20 none HFIP rt 6 85
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), and 3a (0.5 mmol) in the presence of 1.0 mL of solvent. bIsolated yield.

positions of the ring were taken to check for electronic as well as
steric effects on the outcome of the reaction.
Thus, initially, the substrate scope of pyrazolone was checked
by keeping 1a and 2a fixed and taking different pyrazolones, to
prepare 4b−4i (Table 2). In all these cases, the reaction worked
smoothly and the corresponding thiazoles were obtained in
good to excellent yields.
Next, the effect of substituents on the thiobenzamide moiety
was tested by performing three component reactions of 1a, 3a,
and various thioamides under the standard reaction conditions.
Thiobenzamide bearing 4-methyl, 4-OMe, 4-CF3, 4-Br, 4-F,
and 4-Cl provided the corresponding trisubstituted thiazole-
linked pyrazoles 4j−4o in good to very good yields as shown in
Table 3. Interestingly, 4-pyridinethioamide and 2-methyl
thiobenzamide provided relatively lesser yields, which may be
due to the basic character of the pyridine ring in 4p and due to
steric reason in ortho-substituted thiobenzamide. Aliphatic
thioamide such as thioacetamide was not suitable for this
multicomponent reaction.
After this, we checked the substrate scope of arylglyoxals. For
this study, we kept 2a and 3a fixed and varied different
arylglyoxals having either electron-withdrawing or electron-
donating groups. Arylglyoxals having 4-methyl, 4-methoxy, 4-
chloro, 4-bromo, 4-ethyl, 4-nitro, 3-trifluoromethyl, 4-phenyl,
3,4-dichloro, and 3,4-methylenedioxy substituents underwent
three component reactions under the standard reaction
conditions to provide the corresponding thiazole-linked
pyrazole derivatives in good to very good yields as shown in
Table 4. Similar to these, we also prepared 4z and 4aa in very
good yields using naphthyl glyoxal and biphenyl glyoxal
derivatives. We found that the substituents present in arylglyoxal
4426
do not have much influence on the observed yield in these three-
component reactions. Further, we have checked the feasibility of
the reaction in case of aliphatic glyoxal. For that, we have
replaced arylglyoxal by methylglyoxal and the corresponding
thiazole-linked pyrazole derivative 4ad was obtained in 75%
yield.
From Tables 2−4, it is evident that this methodology can be
used for the preparation of diverse trisubstituted thiazole
derivatives linked with the pyrazole moiety.
Considering the high price of HFIP, the use of this highly
efficient solvent cum reaction promoter in large-scale reactions
is one of the major concerns.33 Therefore, we investigated the
possibility of recovering and reusing this solvent by performing
one of the reactions in gram scale synthesis (Scheme 2). For this
purpose, we tried the reaction of 1a, 2a, and 3a on a 12.0 mmol
scale using 24.0 mL of HFIP as the solvent. The corresponding
three-component product 4a was obtained in 83% (4.078 g)
yield. After completion of the reaction, we recovered 21.0 mL of
the HFIP solvent just by distillation from the reaction pot. The
recovered solvent was further used for the next cycle. In the
second cycle, we performed the same reaction in a 6.0 mmol
scale using 12.0 mL of recovered HFIP for the preparation of 4a
in 2.064 g (84%). From this cycle, we recovered 10.0 mL of
HFIP after the reaction. Next, we again used recycled HFIP (6.0
mL) for the 3.0 mmol scale reaction and in this case also, the
reaction went smoothly and provided 1.044 g of the desired
product (85% yield) and we could recover 3.5 mL of HFIP as
shown in Scheme 2. Thus, in the process, total of 17.5 mL of
HFIP was recovered initially starting with 24.0 mL of the solvent
and 7.192 g of 4a was produced overall. Considering this, we
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Table 2. Substrate Scope of Pyrazolonesa
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), and 3 (0.5 mmol) in the presence of 1.0 mL of HFIP, stirring at room temperature (25 °C)
for 6−8 h. Isolated yield.
believe this method may find application for cost-effective large-
scale synthesis.
After preparing the set of diverse thiazole-linked pyrazoles, we
turned our attention to further functionalizing our synthesized
molecules 4 (Scheme 3). For this purpose, first, we prepared N-
alkylated product 5a from the reaction of 4a with 4-bromobut-1-
yne in the presence of Cs2CO3 as a base. Interestingly, in this
reaction, we did not observe O-alkylation. The compound 5a
was fully characterized by recording 1H, 13C{1H} NMR, and
HRMS.
Similarly, a series of N-alkylated derivatives (5b, 5c, 5d) were
synthesized using the same protocol on reaction with propargyl
bromide, benzyl bromide, and epichlorohydrine, respectively.
Additionally, we synthesized the molecule 5b′ by performing a
simple copper-catalyzed click reaction of benzyl azide and the N-
propargylated derivative (5b). The resulting molecule 5b′
contains three important pharmacophores, i.e., pyrazolone,
thiazole, and triazole.
All these products were fully characterized by 1H and 13C{1H}
NMR as well as HRMS. Additionally, single-crystal XRD of
compound 5b was recorded for the determination of the exact
structure of the molecule (Figure 2).
To study the mechanism involved in this methodology,
initially, we performed a two-component reaction of phenyl
glyoxal (1a) and thiobenzamide (2a) in HFIP medium at room
temperature for 1 h [Scheme 4, eq (i)]. By HRMS, we detected
the formation of an intermediate, which can exist in tautomeric
form A, A′, and A″. The exact mass of this intermediated was
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determined by HRMS. Subsequently, pyrazolone derivative
(3a) was added to this intermediate, and stirred at room
temperature, and the desired compound 4a was obtained
[Scheme 4, eq (ii)].
Based on the results of the control experiments and a literature
report,33 we have proposed a plausible reaction pathway as
depicted in Scheme 5.
We believe that first, HFIP activates phenyl glyoxal (1a) by H-
bonding, and then nucleophilic attack of thiobenzamide (2a)
generates intermediates A. This intermediate then gets attacked
by nucleophile pyrazolone (3a) and forms intermediate B. HFIP
also facilitates the formation of trisubstituted methane
intermediate B, which finally undergoes intramolecular
cyclization followed by water elimination to give our desired
product 4a.
Next, we turned out attention to synthesize some imidazole-
linked pyrazole molecules in a similar fashion and for that, we
initially tried the reaction with 4-methoxy phenylglyoxal
monohydrate 1c, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
3a, and Benzamidine 6a (instead of thiobenzamide) with an
expectation of obtaining the trisubstituted imidazole 7a.
Interestingly, we found that this reaction also proceeded
smoothly to provide the corresponding imidazole-linked
pyrazole derivatives within 8 h. However, in this reaction,
relatively lesser yield was observed as compared to the
corresponding benzothioamide. The compound 7a was fully
characterized by recording 1H, 13C{1H} NMR, and HRMS.
With this positive result, next we turned our attention to prepare
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Table 3. Substrate Scope of Thiobenzamidesa
a
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), and 3a (0.5 mmol) in the presence of 1.0 mL of HFIP, stirring at room temperature (25 °C)
for 6−8 h. Isolated yield.
a set of imidazole-linked pyrazoles using this protocol. The
hybrid molecules having both bioactive imidazole and pyrazole
moieties, i.e., 7b to 7f, were prepared by varying aryl glyoxal and
pyrazolone derivatives, and the observed results are summarized
in Table 5.
Finally, we extended this methodology for the preparation of
pyrimidine-linked thiazoles by replacing pyrazolone with 1,3-
dimethyl barbituric acid (9) and performed the reaction under
the same conditions (HFIP solvent at room temperature). First,
we prepared 10a, from the reaction of phenylglyoxal
monohydrate, thiobezamide, and 1,3-dimethyl barbituric acid
following the same procedure in HFIP medium at room
temperature reaction for 6 h. In this reaction, we observed 83%
yield of the desired three-component product (Table 6).
Similarly, we prepared products 10b and 10c by varying phenyl
glyoxal derivatives.
■ CONCLUSIONS
In summary, we have developed a new method for the
preparation of trisubstituted thiazole-linked pyrazole derivatives
from readily available starting materials at room temperature by
a multicomponent reaction in HFIP as a reusable solvent. This
methodology can be extended for the preparation of thiazole-
linked pyrimidines as well as imidazole-linked pyrazoles. This
method is significant from a green chemistry point of view
considering the room temperature reaction, high atom
economy, one-pot reaction, water as a byproduct, and high
yields, as well as recovery and reusability of the solvent. In
addition to the above factors, this method requires no column
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chromatography for purification, and thus we believe that this
operationally simple method will find many applications in
synthetic organic chemistry and medicinal chemistry.
■ EXPERIMENTAL SECTION
General Information. All the reagents including starting materials
1, 2, and 3 were procured from commercial sources (Sigma-Aldrich,
Merck and Alfa Aesar and others), and no additional purification was
done to any of the chemicals before use; organic extracts were dried
over anhydrous sodium sulfate. Solvents were removed by using a
rotary evaporator under reduced pressure. Heating reactions were
performed using a silicone oil bath using a heating cum magnetic stirrer.
The progress of reactions was monitored by TLC. Melting points were
recorded using SRS EZ-Melt automated melting point apparatus by
capillary methods and uncorrected. NMR spectra were recorded in
Bruker 400 MHz and Jeol 500 MHz spectrometer in CDCl3 or DMSO-
d6. Due to poor solubility of some of the products, we used mixed
solvent DMSO6 + 40% NaOD in D2O for recording their NMR spectra.
Chemical shift values are reported in δ values. HRMS were recorded
using Bruker (HD UHR-TOF, ESI with positive mode) and XEVO G2-
XS QTOF mass spectrometer. Column chromatographic separations
were performed using Merck silica gel (60−120 mesh). Single-crystal
XRD was recorded in a Bruker D8 VENTURE SC-XRD.
Experimental Procedure. General Experimental Procedure for
the Synthesis of 4a. Phenylglyoxal monohydrate (76 mg, 0.5 mmol),
thiobenzamide (69 mg, 0.5 mmol), and 3-methyl-1-phenyl-5-
pyrazolone (87 mg, 0.5 mmol), were mixed with 1.0 mL of HFIP and
transferred to a 5.0 mL round-bottom flask, and the mixture was stirred
at room temperature. The progress of the reaction was monitored using
TLC. After completion of the reaction, the solvent HFIP was removed
using rotavapor. The crude product was purified by crystallization in
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Table 4. Substrate Scope of Arylglyoxalsa
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), and 3a (0.5 mmol) in the presence of 1.0 mL of HFIP, stirring at room temperature (25 °C)
for 6 h. Isolated yield.
ethyl acetate. The other derivatives 4b−4ad were prepared using
similar methods.
4-(2,4-Diphenylthiazol-5-yl)-3-methyl-1-phenyl-1H-pyrazol-5-ol
(4a). The product was purified by crystallization in ethyl acetate. Yield
174 mg (85%); white solid; mp 304−306 °C; 1H NMR (500 MHz,
DMSO-d6): δ 11.65 (br s, 1H), 8.01 (d, J = 5.0 Hz, 2H), 7.75 (t, J = 10.0
Hz, 4H), 7.56−7.46 (m, 5H), 7.41 (t, J = 5.0 Hz, 2H), 7.34 (t, J = 5.0
Hz, 1H), 7.27 (t, J = 10 Hz, 1H), 1.80 (s, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.6, 146.9, 145.9,
141.9, 137.6, 134.5, 131.9, 129.5, 128.5, 128.1, 126.9, 125.9, 121.8,
117.9, 89.6, 14.9. HRMS: m/z [M + H]+ calculated for C25H20N3OS+,
410.1322; found, 410.1319.
4-(2,4-Diphenylthiazol-5-yl)-3-ethyl-1-phenyl-1H-pyrazol-5-ol
(4b). The product was purified by crystallization in ethyl acetate. Yield
178 mg (84%); white solid; mp 254−256 °C; 1H NMR (400 MHz,
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DMSO-d6): δ 11.67 (br s, 1H), 8.02 (d, J = 4.0 Hz, 2H), 7.76 (d, J = 8.0
Hz, 4H), 7.55−7.46 (m, 5H), 7.40 (t, J = 8.0 Hz, 2H), 7.34−7.26 (m,
2H), 2.22 (q, J = 8.0 Hz, 2H), 0.92 (t, J = 8.0 Hz, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.8, 162.0, 151.4,
147.8, 142.1, 137.3, 134.4, 131.9, 129.7, 129.5, 128.5, 128.4, 128.1,
127.1, 125.9, 121.8, 118.0, 88.1, 22.1, 13.1. HRMS: m/z [M + H]+
calculated for C26H22N3OS+, 424.1478; found, 424.1485.
3-(tert-Butyl)-4-(2,4-diphenylthiazol-5-yl)-1-phenyl-1H-pyrazol-
5-ol (4c). The product was purified by crystallization in ethyl acetate.
Yield 196 mg (87%); white solid; mp 287−289 °C; 1H NMR (400
MHz, DMSO-d6): δ 11.56 (s, 1H), 8.05 (d, J = 4.0 Hz, 2H), 7.78 (d, J =
8.0 Hz, 4H), 7.54 (q, J = 8.0 Hz, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.37 (t, J
= 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 1.09 (s, 9H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 164.6, 163.9, 156.8,
151.7, 142.5, 136.6, 134.1, 133.5, 130.1, 129.6, 128.43, 128.38, 128.2,
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Scheme 2. Use of HFIP in the Gram Scale Synthesis of 4a and Recyclability and Reusability Test

Scheme 3. Late-Stage Functionalization

4-(2,4-Diphenylthiazol-5-yl)-1-phenyl-3-(trifluoromethyl)-1H-
127.3, 126.1, 121.6, 118.1, 84.3, 33.8, 30.2. HRMS: m/z [M + H]+ pyrazol-5-ol (4d). The product was purified by crystallization in ethyl
calculated for C28H26N3OS+, 452.1791; found, 452.1806. acetate. Yield 183 mg (79%); gray solid; mp 258−260 °C; 1H NMR

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Figure 2. Single-crystal XRD of 5b with 50% ellipsoidal probability (CCDC 2246446).
Scheme 4. Control Experiments
(500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.05 (d, J = 5.0 Hz,
2H), 7.74 (d, J = 10.0 Hz, 2H), 7.70 (d, J = 5.0 Hz, 2H), 7.55 (t, J = 10.0
Hz, 5H), 7.44−7.38 (m, 3H), 7.33 (t, J = 10.0 Hz, 1H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 164.3, 163.3, 151.8,
141.3, 138.5 (d, J(C−F) = 34.0 Hz), 138.1, 136.0, 133.9, 130.3, 129.7,
128.9, 128.4, 128.2, 127.6, 127.3, 126.2, 123.9, 122.6 (d, J(C−F) = 268.0
Hz), 119.2, 85.4. HRMS: m/z [M + H]+ calculated for C25H17F3N3OS+,
464.1039; found, 464.1044.
4-(2,4-Diphenylthiazol-5-yl)-3-methyl-1H-pyrazol-5-ol (4e). The
product was purified by crystallization in ethyl acetate. Yield 135 mg
(81%); pale yellow solid; mp 298−300 °C; 1H NMR (400 MHz,
DMSO-d6): δ 11.70 (br s, 1H), 10.12 (br s, 1H), 7.98 (d, J = 8.0 Hz,
2H), 7.67 (d, J = 4.0 Hz, 2H), 7.52 (q, J = 8.0 Hz, 3H), 7.37 (t, J = 8.0
Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 1.74 (s, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 164.9, 161.0, 146.3, 144.2,
137.7, 134.5, 132.7, 129.4, 129.3, 128.3, 128.1, 126.7, 125.7, 88.3, 14.9.
HRMS: m/z [M + H]+ calculated for C19H16N3OS+, 334.1009; found,
334.0993.
1-(4-Chlorophenyl)-4-(2,4-diphenylthiazol-5-yl)-3-methyl-1H-
pyrazol-5-ol (4f). The product was purified by crystallization in ethyl
acetate. Yield 173 mg (78%); white solid; mp 309−311 °C; 1H NMR
(400 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.16 (d, J = 8.0 Hz,
2H), 7.91 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0
Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.28 (d, J =
8.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 1H), 1.45 (s, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.5, 161.8, 147.2, 146.5,
140.5, 137.3, 134.2, 131.2, 129.4, 129.3, 128.3, 128.2, 127.9, 126.9,
125.7, 125.2, 119.1, 89.4, 14.6. HRMS: m/z [M + H]+ calculated for
C25H19ClN3OS+, 444.0932; found, 444.0905.
4-(2,4-Diphenylthiazol-5-yl)-3-methyl-1-(4-nitrophenyl)-1H-pyr-
azol-5-ol (4g). The product was purified by crystallization in ethyl
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acetate. Yield 182 mg (80%); brown solid; mp 331−333 °C; 1H NMR
(500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.39 (d, J = 10 Hz, 2H),
8.16 (d, J = 10.0 Hz, 2H), 7.91 (d, J = 5.0 Hz, 2H), 7.77 (d, J = 5.0 Hz,
2H), 7.49 (t, J = 10.0 Hz, 2H), 7.42 (t, J = 5.0 Hz, 1H), 7.35 (t, J = 10.0
Hz, 2H), 7.25 (t, J = 10.0 Hz, 1H), 1.50 (s, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 164.5, 161.9, 149.6, 147.5,
146.8, 140.4, 136.9, 133.9, 130.4, 129.5, 129.3, 128.3, 127.9, 126.9,
125.7, 124.9, 116.2, 88.9, 14.6. HRMS: m/z [M + H]+ calculated for
C25H19N4O3S+, 455.1173; found, 455.1154.
4-(2,4-Diphenylthiazol-5-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5-
ol (4h). The product was purified by crystallization in ethyl acetate.
Yield 182 mg (86%); white solid; mp 307−309 °C; 1H NMR (500
MHz, DMSO-d6 + 40% NaOD in D2O): δ 7.98 (d, J = 10.0 Hz, 2H),
7.90 (d, J = 5.0 Hz, 2H), 7.79 (d, J = 10.0 Hz, 2H), 7.47 (t, J = 10.0 Hz,
2H), 7.40 (t, J = 10.0 Hz, 1H), 7.33 (t, J = 10.0 Hz, 2H), 7.23 (t, J = 10.0
Hz, 1H), 7.06 (d, J = 10.0 Hz, 2H), 2.25 (s, 3H), 1.45 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.2, 161.0,
146.4, 144.9, 139.4, 137.4, 134.2, 131.9, 129.9, 129.1, 128.6, 128.1,
127.8, 126.5, 125.5, 117.6, 89.3, 20.5, 14.7. HRMS: m/z [M + H]+
calculated for C26H22N3OS+, 424.1478; found, 424.1504.
4-(2,4-Diphenylthiazol-5-yl)-1,3-diphenyl-1H-pyrazol-5-ol (4i).
The product was purified by crystallization in ethyl acetate. Yield 27
mg (92%); light brown solid; mp 315−317 °C; 1H NMR (500 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 8.10 (d, J = 10.0 Hz, 2H), 7.93 (d, J
= 10.0 Hz, 2H), 7.85 (d, J = 5.0 Hz, 2H), 7.50−7.45 (m, 3H), 7.42 (d, J
= 5.0 Hz, 2H), 7.33 (t, J = 10.0 Hz, 2H), 7.22 (t, J = 10.0 Hz, 2H), 7.15
(t, J = 5.0 Hz, 3H), 7.12−7.05 (m, 2H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.7, 150.6, 147.8, 140.9, 135.9,
135.0, 133.7, 129.9, 129.3, 128.5, 128.0, 127.9, 127.7, 127.1, 126.4,
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 5. Proposed Reaction Mechanism for the Synthesis of Compound 4a

Table 5. Synthesis of Pyrazole-Linked Imidazole Systems by Replacing Thiobenzamide with Benzamidinea

a
Reaction conditions: 1 (0.5 mmol), 6a (0.5 mmol), and 3 (0.5 mmol) in the presence of 1.0 mL of HFIP, stirring at 50 °C temperature for 6−8 h.
Isolated yield.

125.9, 123.2, 119.1. HRMS: m/z [M + H] + calculated for
C30H22N3OS+, 472.1478; found, 472.1457.
3-Methyl-1-phenyl-4-(4-phenyl-2-(p-tolyl)thiazol-5-yl)-1H-pyra-
zol-5-ol (4j). The product was purified by crystallization in ethyl
acetate. Yield 178 mg (84%); off white solid; mp 307−309 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.12 (d, J = 10.0
Hz, 2H), 7.80 (d, J = 10.0 Hz, 4H), 7.33 (t, J = 10.0 Hz, 2H), 7.29−7.21
(m, 5H), 6.93 (t, J = 10.0 Hz, 1H), 2.34 (s, 3H), 1.48 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.6,
146.6, 145.8, 142.0, 139.1, 137.6, 131.8, 131.5, 129.9, 128.4, 128.3,

4432 https://doi.org/10.1021/acs.joc.3c02567
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The Journal of Organic Chemistry
Table 6. HFIP Mediated Multicomponent Synthesis of Pyrimidine-Linked Thiazolesa
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), and 9 (0.5 mmol) in the presence of 1.0 mL of HFIP, stirring at room temperature (25 °C) for
6 h. Isolated yield.
128.0, 126.8, 125.7, 121.5, 117.7, 89.4, 21.2, 14.9. HRMS: m/z [M +
H]+ calculated for C26H22N3OS+, 424.1478; found, 424.1506.
4-(2-(4-Methoxyphenyl)-4-phenylthiazol-5-yl)-3-methyl-1-phe-
nyl-1H-pyrazol-5-ol (4k). The product was purified by crystallization in
ethyl acetate. Yield 191 mg (87%); white solid; mp 296−298 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 7.95 (d, J = 10.0
Hz, 2H), 7.77−7.73 (m, 4H), 7.48 (t, J = 10.0 Hz, 2H), 7.40 (t, J = 10.0
Hz, 2H), 7.32 (t, J = 10.0 Hz, 1H), 7.27 (t, J = 10.0 Hz, 1H), 7.09 (d, J =
10.0 Hz, 2H), 3.84 (s, 3H), 1.80 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.6, 160.4, 146.5, 145.8,
142.0, 137.6, 130.9, 128.4, 128.3, 128.0, 127.3, 126.7, 121.5, 117.7,
114.7, 89.3, 55.6, 14.8. HRMS: m/z [M + H]+ calculated for
C26H22N3O2S+, 440.1427; found, 440.1399.
3-Methyl-1-phenyl-4-(4-phenyl-2-(4-(trifluoromethyl)phenyl)-
thiazol-5-yl)-1H-pyrazol-5-ol (4l). The product was purified by
crystallization in ethyl acetate. Yield 189 mg (79%); dark green solid;
mp 258−260 °C; 1H NMR (400 MHz, DMSO-d6): δ 11.87 (br s, 1H),
8.23 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 8.0 Hz,
4H), 7.47 (t, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz,
1H), 7.27 (t, J = 8.0 Hz, 1H), 1.78 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6): δ 162.9, 151.8, 146.6, 137.6, 136.4, 134.6, 129.6 (d, J(C−F) =
31.0 Hz), 128.6, 128.1, 127.5, 127.3, 126.3, 125.9 (q, J(C−F) = 3.75 Hz),
125.1, 124.6, 123.7 (q, J(C−F) = 270.0 Hz), 119.9, 12.1. HRMS: m/z [M
+ H]+ calculated for C26H19F3N3OS+, 478.1196; found, 478.1188.
4-(2-(4-Bromophenyl)-4-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4m). The product was purified by crystallization in
ethyl acetate. Yield 195 mg (80%); white solid; mp 315−317 °C; 1H
NMR (500 MHz, DMSO-d6): δ 11.68 (br s, 1H), 7.96 (d, J = 10.0 Hz,
2H), 7.75 (t, J = 10.0 Hz, 6H), 7.48 (t, J = 10.0 Hz, 2H), 7.41 (t, J = 10.0
Hz, 2H), 7.34 (t, J = 10.0 Hz, 1H), 7.27 (t, J = 10.0 Hz, 1H), 1.79 (s,
3H). 13C{1H} NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ
163.7, 160.2, 147.1, 145.9, 141.9, 137.5, 133.7, 132.6, 132.4, 128.6,
128.5, 128.2, 127.8, 127.1, 122.5, 121.9, 117.9, 89.8, 14.9. HRMS: m/z
[M + H]+ calculated for C25H19BrN3OS+, 488.0427; found, 488.0413.
4-(2-(4-Fluorophenyl)-4-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4n). The product was purified by crystallization in
ethyl acetate. Yield 162 mg (76%); white solid; mp 279−281 °C; 1H
NMR (500 MHz, DMSO-d6): δ 11.66 (br s, 1H), 8.06 (q, J = 5.0 Hz,
2H), 7.75 (t, J = 10.0 Hz, 4H), 7.48 (t, J = 10.0 Hz, 2H), 7.42−7.32 (m,
5H), 7.27 (t, J = 10.0 Hz, 1H), 1.80 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.7, 162.9 (q, J(C−F) = 245.0 Hz),
160.5, 146.9, 145.9, 141.9, 137.6, 132.1, 131.1, 128.51, 128.46, 128.0 (d,
J(C−F) = 8.75 Hz), 127.9, 126.9, 121.8, 117.9, 116.5 (d, J(C−F) = 21.0
Hz), 89.6, 14.9. HRMS: m/z [M + H]+ calculated for C25H19FN3OS+,
428.1228; found, 428.1233.
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4-(4-(4-Chlorophenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4o). The product was purified by crystallization in
ethyl acetate. Yield 175 mg (79%); white solid; mp 328−330 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.10 (d, J = 5.0
Hz, 2H), 7.92 (d, J = 10.0 Hz, 2H), 7.77 (d, J = 5.0 Hz, 2H), 7.52 (d, J =
10.0 Hz, 2H), 7.34 (t, J = 10.0 Hz, 2H), 7.25 (t, J = 10.0 Hz, 3H), 6.93
(t, J = 10.0 Hz, 1H), 1.45 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6
+ 40% NaOD in D2O): δ 163.4, 159.6, 146.6, 145.4, 141.7, 137.3, 133.5,
133.0, 132.4, 129.2, 128.2, 127.9, 127.2, 126.7, 121.4, 117.5, 89.4, 14.7.
HRMS: m/z [M + H]+ calculated for C25H19ClN3OS+, 444.0932;
found, 444.0906.
3-Methyl-1-phenyl-4-(4-phenyl-2-(pyridin-4-yl)thiazol-5-yl)-1H-
pyrazol-5-ol (4p). The product was purified by crystallization in ethyl
acetate. Yield 142 mg (69%); green solid; mp 274−276 °C; 1H NMR
(500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.62 (d, J = 5.0 Hz,
2H), 8.12 (d, J = 10.0 Hz, 2H), 7.83 (d, J = 5.0 Hz, 2H), 7.76 (d, J = 10.0
Hz, 2H), 7.37 (t, J = 10.0 Hz, 2H), 7.26 (t, J = 10.0 Hz, 3H), 6.94 (t, J =
10.0 Hz, 1H), 1.43 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6 +
40% NaOD in D2O): δ 163.8, 157.4, 150.6, 146.9, 145.4, 141.8, 141.1,
137.5, 134.7, 128.5, 128.4, 128.2, 127.1, 121.7, 119.6, 117.7, 90.1, 15.1.
HRMS: m/z [M + H]+ calculated for C24H19N4OS+, 411.1274; found,
411.1282.
3-Methyl-1-phenyl-4-(4-phenyl-2-(o-tolyl)thiazol-5-yl)-1H-pyra-
zol-5-ol (4q). The product was purified by crystallization in ethyl
acetate. Yield 125 mg (59%); light brown solid; mp 260−262 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 7.97 (d, J = 10.0
Hz, 2H), 7.79−7.76 (m, 3H), 7.36−7.29 (m, 7H), 7.25 (t, J = 10.0 Hz,
1H), 7.04 (t, J = 10.0 Hz, 1H), 2.65 (s, 3H), 1.63 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 162.9, 148.2,
146.2, 140.3, 136.7, 135.7, 132.9, 131.8, 129.3, 129.1, 128.6, 128.4,
127.8, 127.1, 126.5, 123.0, 118.6, 91.4, 21.7, 13.9. HRMS: m/z [M +
H]+ calculated for C26H22N3OS+, 424.1478; found, 424.1499.
3-Methyl-1-phenyl-4-(2-phenyl-4-(p-tolyl)thiazol-5-yl)-1H-pyra-
zol-5-ol (4r). The product was purified by crystallization in ethyl
acetate. Yield 178 mg (84%); light brown solid; mp 312−314 °C; 1H
NMR (500 MHz, DMSO-d6): δ 11.64 (br s, 1H), 8.00 (d, J = 5.0 Hz,
2H), 7.77 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.55−7.46 (m,
5H), 7.27 (t, J = 10.0 Hz, 1H), 7.21 (d, J = 10.0 Hz, 2H), 2.31 (s, 3H),
1.81 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6 + 40% NaOD in
D2O): δ 163.7, 161.5, 147.1, 145.9, 142.0, 136.1, 134.8, 134.5, 131.3,
129.5, 129.1, 128.5, 128.0, 125.9, 121.7, 117.8, 89.6, 21.2, 15.0. HRMS:
m/z [M + H]+ calculated for C26H22N3OS+, 424.1478; found,
424.1501.
4-(4-(4-Methoxyphenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phe-
nyl-1H-pyrazol-5-ol (4s). The product was purified by crystallization in
ethyl acetate. Yield 178 mg (81%); white solid; mp 302−304 °C; 1H
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The Journal of Organic Chemistry
NMR (500 MHz, DMSO-d6): δ 11.66 (br s, 1H), 8.00 (d, J = 5.0 Hz,
2H), 7.77 (d, J = 5.0 Hz, 2H), 7.70 (d, J = 10.0 Hz, 2H), 7.55−7.46 (m,
5H), 7.27 (t, J = 10.0 Hz, 1H), 6.96 (d, J = 10.0 Hz, 2H), 3.77 (s, 3H),
1.83 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6 + 40% NaOD in
D2O): δ 163.4, 161.8, 158.2, 147.3, 146.1, 141.7, 134.3, 130.0, 129.9,
129.5, 129.4, 129.3, 128.5, 125.8, 121.9, 117.9, 113.7, 89.5, 55.3, 14.6.
HRMS: m/z [M + H]+ calculated for C26H22N3O2S+, 440.1427; found,
440.1426.
4-(4-(4-Chlorophenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4t). The product was purified by crystallization in
ethyl acetate. Yield 177 mg (80%); white solid; mp 328−330 °C; 1H
NMR (500 MHz, DMSO-d6): δ 11.70 (br s, 1H), 8.01 (d, J = 10.0 Hz,
2H), 7.78−7.76 (m, 4H), 7.54 (q, J = 10.0 Hz, 3H), 7.49−7.46 (m,
4H), 7.27 (t, J = 10.0 Hz, 1H), 1.87 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.5, 161.8, 145.7, 145.6, 141.9,
136.4, 134.3, 132.5, 131.3, 129.8, 129.6, 129.5, 128.5, 128.4, 125.9,
121.8, 117.9, 89.4, 14.9. HRMS: m/z [M + H]+ calculated for
C25H19ClN3OS+, 444.0932; found, 444.0903.
4-(4-(4-Fluorophenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4u). The product was purified by crystallization in
ethyl acetate. Yield 167 mg (78%); dark gray solid; mp 313−315 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.11 (s, 2H),
7.91 (s, 2H), 7.84 (s, 2H), 7.48 (s, 2H), 7.42 (s, 1H), 7.26 (s, 2H), 7.16
(s, 2H), 6.93 (s, 1H), 1.53 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-
d6 + 40% NaOD in D2O): δ 163.6, 161.7, 161.2(d, J(C−F) = 242.5 Hz),
146.0, 145.8, 141.9, 134.3, 134.0, 131.8, 130.1 (d, J(C−F) = 7.5 Hz),
129.5, 129.4, 128.5, 125.8, 121.7, 117.8, 115.2 (d, J(C−F) = 21.0 Hz),
89.2, 14.9. HRMS: m/z [M + H]+ calculated for C25H19FN3OS+,
428.1228; found, 428.1220.
4-(4-(4-Bromophenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4v). The product was purified by crystallization in
ethyl acetate. Yield 188 mg (84%); off white solid; mp 322−324 °C; 1H
NMR (400 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.09 (d, J = 8.0
Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.53−7.42
(m, 5H), 7.26 (t, J = 8.0 Hz, 2H), 6.94 (t, J = 8.0 Hz, 1H), 1.56 (s, 3H).
13
C{1H} NMR (100 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.3,
161.8, 145.64, 145.59, 141.8, 136.7, 134.2, 132.4, 131.3, 130.1, 129.7,
129.5, 128.5, 125.9, 121.9, 119.8, 117.9, 89.6, 14.9. HRMS: m/z [M +
H]+ calculated for C25H19BrN3OS+, 488.0427; found, 488.0422.
4-(4-(4-Ethylphenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phenyl-
1H-pyrazol-5-ol (4w). The product was purified by crystallization in
ethyl acetate. Yield 179 mg (82%); light gray solid; mp 273−275 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.11 (d, J = 5.0
Hz, 2H), 7.91 (d, J = 10.0 Hz, 2H), 7.71 (d, J = 10.0 Hz, 2H), 7.47 (t, J =
10.0 Hz, 2H), 7.40 (t, J = 10.0 Hz, 1H), 7.26 (t, J = 10.0 Hz, 2H), 7.17
(d, J = 5.0 Hz, 2H), 6.93 (t, J = 10.0 Hz, 1H), 2.59 (q, J = 5.0 Hz, 2H),
1.48 (s, 3H), 1.17 (t, J = 10.0 Hz, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.5, 147.2, 145.9, 142.4,
142.0, 135.0, 134.5, 131.3, 129.4, 128.5, 128.1, 127.8, 125.8, 121.7,
117.8, 89.6, 28.3, 15.9, 14.9. HRMS: m/z [M + H]+ calculated for
C27H24N3OS+, 438.1635; found, 438.1648.
3-Methyl-4-(4-(4-nitrophenyl)-2-phenylthiazol-5-yl)-1-phenyl-
1H-pyrazol-5-ol (4x). The product was purified by crystallization in
ethyl acetate. Yield 182 mg (80%); brown solid; mp 295−297 °C; 1H
NMR (500 MHz, DMSO-d6): δ 11.87 (br s, 1H), 8.28 (d, J = 10.0 Hz,
2H), 8.03 (t, J = 5.0 Hz, 4H), 7.76 (d, J = 10.0 Hz, 2H), 7.56−7.46 (m,
5H), 7.28 (t, J = 10.0 Hz, 1H), 1.91 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 163.3, 161.9, 145.6, 145.4, 144.4,
143.8, 141.8, 135.9, 134.0, 129.9, 129.5, 128.5, 126.0, 123.8, 121.9,
117.9, 90.2, 15.2. HRMS: m/z [M + H]+ calculated for C25H19N4O3S+,
455.1173; found, 455.1170.
3-Methyl-1-phenyl-4-(2-phenyl-4-(3-(trifluoromethyl)phenyl)-
thiazol-5-yl)-1H-pyrazol-5-ol (4y). The product was purified by
crystallization in ethyl acetate. Yield 170 mg (76%); cream solid; mp
279−281 °C; 1H NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ
8.18−8.11 (m, 4H), 7.93 (d, J = 10.0 Hz, 2H), 7.57−7.43 (m, 5H), 7.26
(t, J = 10.0 Hz, 2H), 6.94 (t, J = 10.0 Hz, 1H), 1.60 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.4, 161.7,
145.4, 144.7, 141.9, 138.4, 134.1, 133.5, 130.6 (d, J(C−F) = 244.0 Hz),
129.43, 129.37, 128.9 (d, J(C−F) = 31.0 Hz), 128.4, 125.9, 124.2, 123.6,
4434
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123.1, 121.7, 117.8, 89.1, 14.9. HRMS: m/z [M + H]+ calculated for
C26H19F3N3OS+, 478.1196; found, 478.1204.
3-Methyl-4-(4-(naphthalen-2-yl)-2-phenylthiazol-5-yl)-1-phenyl-
1H-pyrazol-5-ol (4z). The product was purified by crystallization in
ethyl acetate. Yield 182 mg (79%); off white solid; mp 248−250 °C; 1H
NMR (500 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.12 (d, J = 10.0 Hz, 2H),
7.96−7.92 (m, 3H), 7.87−7.82 (m, 3H), 7.51−7.41 (m, 5H), 7.27 (t, J
= 5.0 Hz, 2H), 6.95 (t, J = 10.0 Hz, 1H), 1.44 (s, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.8, 146.6,
145.9, 141.9, 135.4, 134.5, 133.5, 132.5, 132.2, 129.6, 129.5, 128.6,
128.3, 127.9, 127.6, 126.6, 126.5, 126.1, 125.9, 121.9, 117.9, 89.9, 15.0.
HRMS: m/z [M + H]+ calculated for C29H22N3OS+, 460.1478; found,
460.1485.
4-(4-([1,1′-Biphenyl]-4-yl)-2-phenylthiazol-5-yl)-3-methyl-1-phe-
nyl-1H-pyrazol-5-ol (4aa). The product was purified by crystallization
in ethyl acetate. Yield 201 mg (83%); orange solid; mp 280−282 °C; 1H
NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.03 (d, J = 5.0
Hz, 2H), 7.86 (d, J = 10.0 Hz, 2H), 7.78 (d, J = 5.0 Hz, 2H), 7.73 (t, J =
10.0 Hz, 4H), 7.57−7.52 (m, 3H), 7.50−7.45 (m, 4H), 7.37 (t, J = 10.0
Hz, 1H), 7.28 (t, J = 10.0 Hz, 1H), 1.89 (s, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.7, 161.4, 146.3, 145.8,
142.0, 140.1, 138.1, 136.8, 134.4, 132.3, 129.42, 129.38, 129.3, 128.5,
128.4, 127.6, 126.7, 126.4, 125.8, 121.5, 117.6, 89.5, 15.0. HRMS: m/z
[M + H]+ calculated for C31H24N3OS+, 486.1635; found, 486.1671.
4-(4-(3,4-Dichlorophenyl)-2-phenylthiazol-5-yl)-3-methyl-1-phe-
nyl-1H-pyrazol-5-ol (4ab). The product was purified by crystallization
in ethyl acetate. Yield 187 mg (78%); light brown solid; mp 266−268
°C; 1H NMR (500 MHz, DMSO-d6 + 40% NaOD in D2O): δ 8.13 (d, J
= 10.0 Hz, 2H), 8.07 (s, 1H), 7.92 (d, J = 10.0 Hz, 2H), 7.84−7.82 (m,
1H), 7.56 (d, J = 10.0 Hz, 1H), 7.49 (t, J = 10.0 Hz, 2H), 7.42 (t, J = 10.0
Hz, 1H), 7.26 (t, J = 10.0 Hz, 2H), 6.93 (t, J = 10.0 Hz, 1H), 1.69 (s,
3H). 13C{1H} NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ
163.3, 161.3, 145.3, 143.3, 141.9, 137.9, 133.9, 133.8, 130.9, 130.3,
129.5, 129.3, 128.5, 128.3, 127.8, 125.8, 121.4, 117.5, 88.8, 15.1.
HRMS: m/z [M + H]+ calculated for C25H18Cl2N3OS+, 478.0542;
found, 478.0572.
4-(4-(Benzo[d][1,3]dioxol-5-yl)-2-phenylthiazol-5-yl)-3-methyl-1-
phenyl-1H-pyrazol-5-ol (4ac). The product was purified by crystal-
lization in ethyl acetate. Yield 179 mg (79%); cream solid; mp 288−290
°C; 1H NMR (500 MHz, DMSO-d6): δ 11.66 (br s, 1H), 8.00 (d, J = 5.0
Hz, 2H), 7.76 (d, J = 5.0 Hz, 2H), 7.55−7.46 (m, 5H), 7.29−7.25 (m,
3H), 6.96 (d, J = 5.0 Hz, 1H), 6.04 (s, 2H), 1.87 (s, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.6, 161.4, 147.3,
146.8, 146.1, 145.9, 142.0, 134.4, 131.6, 130.8, 129.5, 128.5, 125.8,
121.9, 121.7, 117.8, 108.5, 108.4, 101.2, 89.2, 14.9. HRMS: m/z [M +
H]+ calculated for C26H20N3O3S+, 454.1220; found, 454.1226.
3-Methyl-4-(4-methyl-2-phenylthiazol-5-yl)-1-phenyl-1H-pyra-
zol-5-ol (4ad). The product was purified by column chromatography.
Eluent: hexane/ethyl acetate (8.5:1.5). Yield 130 mg (75%); light pink
solid; mp 242 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (d, J = 8 Hz,
2H), 7.76 (d, J = 8 Hz, 2H), 7.52−7.44 (m, 5H), 7.27 (t, J = 8 Hz, 1H),
2.33 (s, 3H), 2.17 (s, 3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ
164.6, 150.9, 147.5, 133.3, 129.9, 129.2, 128.9, 125.7, 125.68, 125.4,
121.9, 16.1, 16.05. C20H18N3OS+: 348.1165, found 348.1169.
General Experimental Procedure for Synthesis of 5b. 4-(2,4-
Diphenylthiazol-5-yl)-3-methyl-1-phenyl-1H-pyrazol-5-ol (4a, 204 mg,
0.5 mmol), Cs2CO3 (326 mg, 2 equiv), and propargyl bromide (57 μL,
1.5 equiv) were taken in a mixture of DMF and DMSO (3:1; 2 mL)
solvent and heated to 50 °C with constant stirring for 5 h. After
completion of the reaction, 3.0 mL of water was added to the reaction
mixture and extracted using 2 × 10 mL of ethyl acetate. The combined
organic layer was dried over anhydrous Na2SO4 and finally, the crude
product was obtained by evaporating the solvent using a rotavapor. The
compound 5b was purified by column chromatography using a mixture
of ethyl acetate/hexane as the eluent. A similar procedure was followed
for the preparation of derivatives 5a, 5c, and 5d just by changing the
alkylating reagents.
1-(But-3-yn-1-yl)-5-methyl-2-phenyl-4-(2-phenyl-4-(p-tolyl)-
thiazol-5-yl)-1H-pyrazol-3(2H)-one (5a). The product was purified by
column chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield
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The Journal of Organic Chemistry
136 mg (57%); yellow semisolid; 1H NMR (500 MHz, chloroform-d):
δ 8.07 (d, J = 5.0 Hz, 2H), 7.78 (d, J = 5.0 Hz, 2H), 7.74 (d, J = 10.0 Hz,
2H), 7.48−7.44 (m, 5H), 7.31 (t, J = 10.0 Hz, 1H), 7.19 (d, J = 5.0 Hz,
2H), 4.04 (t, J = 10.0 Hz, 2H), 2.41−2.37 (m, 5H), 2.09 (s, 3H), 1.89 (t,
J = 5.0 Hz, 1H). 13C{1H} NMR (125 MHz, chloroform-d): δ 166.9,
152.9, 150.6, 148.7, 138.3, 137.9, 133.6, 132.2, 130.2, 129.3, 129.02,
128.99, 127.8, 126.7, 126.5, 122.4, 120.9, 96.7, 79.6, 71.1, 70.3, 21.4,
19.9, 13.4. HRMS: m/z [M + H]+ calculated for C30H26N3OS+,
476.1791; found, 476.1803.
4-(2,4-Diphenylthiazol-5-yl)-5-methyl-2-phenyl-1-(prop-2-yn-1-
yl)-1H-pyrazol-3(2H)-one (5b). The product was purified by
recrystallization in ethyl acetate. Yield 146 mg (65%); yellow crystalline
solid; mp 189−191 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.01 (d, J =
10.0 Hz, 2H), 7.81 (d, J = 5.0 Hz, 2H), 7.56−7.52 (m, 5H), 7.47−7.41
(m, 4H), 7.39−7.37 (m, 2H), 4.40 (d, J = 5.0 Hz, 2H), 3.54 (t, J = 5.0
Hz, 1H), 1.89 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 166.2,
163.7, 155.3, 152.5, 134.7, 134.4, 132.9, 130.5, 129.3, 128.7, 128.0,
127.8, 126.9, 126.1, 123.7, 121.2, 105.1, 76.8, 75.9, 38.2, 12.0. HRMS:
m/z [M + H]+ calculated for C28H22N3OS+, 448.1478; found,
448.1486.
Procedure for the Preparation of 5b′. In a 5 mL round-bottom
flask, 4-(2,4-diphenylthiazol-5-yl)-5-methyl-2-phenyl-1-(prop-2-yn-1-
yl)-1H-pyrazol-3(2H)-one (5b) (112 mg, 0.25 mmol) and benzyl
azide (32 μL, 0.25 mmol) were taken. To this mixture, DMF (2.0 mL)
and Cu(OAc) (2 mg, 5 mol %) were added. The mixture was kept
under constant stirring, keeping the reaction temperature at 80 °C for 2
h. After the completion of the reaction, 5 mL of H2O and 2 × 10 mL of
ethyl acetate were used for extraction. The combined organic layer was
collected and passed over anhydrous Na2SO4. The filtrate was collected,
and the solvent was removed by using a rotavapor. Finally, the
compound 5b′ was purified by using silica gel column chromatography
using a hexane/ethyl acetate mixture (9:1) as the eluent.
1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-4-(2,4-diphenylthia-
zol-5-yl)-5-methyl-2-phenyl-1H-pyrazol-3(2H)-one (5b′). The prod-
uct was purified by column chromatography. Eluent: hexane/ethyl
acetate (9.0:1.0). Yield 134 mg (92%); white solid; mp 222−224 °C;
1
H NMR (500 MHz, chloroform-d): δ 7.99 (d, J = 10.0 Hz, 2H), 7.57
(d, J = 10.0 Hz, 2H), 7.48−7.41 (m, 7H), 7.37−7.30 (m, 7H), 7.21 (d, J
= 5.0 Hz, 2H), 7.07 (s, 1H), 5.51 (s, 2H), 4.79 (s, 2H), 1.96 (s, 3H).
13
C{1H} NMR (125 MHz, chloroform-d): δ 167.4, 165.3, 154.4, 153.3,
140.2, 135.5, 134.8, 134.4, 133.9, 130.0, 129.6, 129.4, 129.1, 128.9,
128.8, 128.4, 128.0, 127.9, 126.9, 126.6, 123.7, 122.6, 121.3, 105.9, 54.4,
43.5, 13.1. HRMS: m/z [M + H]+ calculated for C35H29N6OS+,
581.2118; found, 581.2088.
1-Benzyl-4-(2,4-diphenylthiazol-5-yl)-5-methyl-2-phenyl-1H-pyr-
azol-3(2H)-one (5c). The product was purified by column chromatog-
raphy. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 155 mg (62%);
yellow crystalline solid; mp 211−213 °C; 1H NMR (500 MHz, DMSO-
d6): δ 7.97 (d, J = 5.0 Hz, 2H), 7.61 (d, J = 10.0 Hz, 2H), 7.56−7.50 (m,
5H), 7.42−7.31 (m, 9H), 6.96−6.94 (m, 2H), 4.87 (s, 2H), 1.94 (s,
3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 165.7, 163.6, 152.6,
152.2, 134.9, 134.7, 134.5, 132.9, 130.4, 129.3, 128.7, 128.5, 128.1,
127.8, 127.7, 127.3, 127.2, 126.0, 124.9, 122.2, 100.6, 49.9, 12.1.
HRMS: m/z [M + H]+ calculated for C32H26N3OS+, 500.1791; found,
1809.
4-(2,4-Diphenylthiazol-5-yl)-5-methyl-1-(oxiran-2-ylmethyl)-2-
phenyl-1H-pyrazol-3(2H)-one (5d). The product was purified by
column chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield
124 mg (53%); yellowish semisolid; 1H NMR (500 MHz, chloroform-
d): δ 8.05 (d, J = 5.0 Hz, 2H), 7.81 (d, J = 5.0 Hz, 2H), 7.72 (d, J = 10.0
Hz, 2H), 7.49−7.44 (m, 5H), 7.38 (t, J = 10.0 Hz, 2H), 7.33−7.30 (m,
2H), 4.17 (dd, J = 10.0, 5.0 Hz, 1H), 3.79 (dd, J = 10.0, 5.0 Hz, 1H),
3.00 (m, 1H), 2.64 (t, J = 5.0 Hz, 1H), 2.38 (m, 1H), 2.07 (s, 3H).
13
C{1H} NMR (125 MHz, chloroform-d): δ 167.2, 152.8, 150.7, 148.8,
138.2, 134.9, 133.5, 130.4, 129.2, 129.1, 128.7, 128.2, 127.9, 126.9,
126.6, 122.5, 121.6, 96.5, 73.9, 49.7, 44.3, 13.4. HRMS: m/z [M + H]+
calculated for C28H24N3O2S+, 466.1584; found, 466.1589.
Experimental Procedure for the Synthesis of 7a. 4-Methoxyphe-
nylglyoxal monohydrate (91 mg, 0.5 mmol), benzamidine hydro-
chloride (78 mg, 0.5 mmol), and 3-methyl-1-phenyl-5-pyrazolone (87
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mg, 0.5 mmol) were transferred to a 5 mL round-bottom flask. To this
mixture, 1.0 mL of HFIP was added, and the reaction mixture was
stirred at room temperature. The progress of the reaction was
monitored using TLC. After completion of the reaction, solvent
HFIP was removed by using a rotavapor, and 2 mL of water was added
to the crude. Next ,the desired product was extracted used 2 × 5 mL of
ethyl acetate, and the combined organic layer was dried over anhydrous
sodium sulfate and filtered. Finally, the solvent was removed by using a
rotavapor, and the crude product was purified by using column
chromatography using a mixture of ethyl acetate and hexane. The other
derivatives 7b−7f were prepared following the same protocol.
4-(4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole-5-yl)-3-methyl-
1-phenyl-1H-pyrazol-5-ol (7a). The product was purified by column
chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 137 mg
(65%); white solid; mp 276−278 °C; 1H NMR (500 MHz, DMSO-d6):
δ 8.04 (d, J = 10 Hz, 2H), 7.79 (d, J = 10 Hz, 2H), 7.64 (d, J = 10 Hz,
2H), 7.49−7.45 (m, J, 4H), 7.36 (t, J = 10 Hz, 1H), 7.26 (t, J = 5 Hz,
1H), 6.91 (d, J = 5 Hz, 2H), 3.74 (s, 3H), 1.92 (s, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.2, 155.2, 151.5,
147.7, 142.4, 138.5, 136.7, 133.2, 128.1, 127.9, 127.8, 126.5, 124.2,
123.5, 120.9, 117.9, 112.9, 96.3, 54.9, 14.4. HRMS: m/z [M + H]+
calculated for C26H23N4O2+, 423.1816; found, 423.1792.
3-Ethyl-4-(4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-yl)-1-
phenyl-1H-pyrazol-5-ol (7b). The product was purified by column
chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 155 mg
(71%); white solid; mp 280−282 °C; 1H NMR (500 MHz, DMSO-d6 +
40% NaOD in D2O): δ 8.19 (d, J = 5.0 Hz, 2H), 8.01 (d, J = 10.0 Hz,
2H), 7.76 (d, J = 10.0 Hz, 2H), 7.40 (t, J = 10.0 Hz, 2H), 7.28−7.23 (m,
3H), 6.90 (t, J = 10.0 Hz, 1H), 6.82 (d, J = 5.0 Hz, 2H), 3.72 (s, 3H),
2.09 (q, J = 5.0 Hz, 2H), 0.85 (t, J = 10.0 Hz, 3H). 13C{1H} NMR (125
MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.8, 157.1, 152.1, 142.9,
142.5, 135.9, 131.4, 129.9, 128.7, 128.1, 127.2, 127.1, 124.6, 124.4,
120.9, 117.7, 113.3, 87.1, 55.1, 21.9, 13.1. HRMS: m/z [M + H]+
calculated for C27H25N4O2+, 437.1972; found, 437.1963.
3-Methyl-1-phenyl-4-(2-phenyl-4-(p-tolyl)-1H-imidazole-5-yl)-
1H-pyrazol-5-ol (7c). The product was purified by column
chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 148
mg (73%); reddish white solid; mp 301−303 °C; 1H NMR (500 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 8.18 (d, J = 10.0 Hz, 2H), 8.01 (d, J
= 5.0 Hz, 2H), 7.71 (d, J = 5.0 Hz, 2H), 7.41 (t, J = 10.0 Hz, 2H), 7.27−
7.24 (m, 3H), 7.07 (d, J = 10.0 Hz, 2H), 6.91 (t, J = 10.0 Hz, 1H), 2.27
(s, 3H), 1.67 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6 + 40%
NaOD in D2O): δ 163.5, 146.7, 143.1, 142.3, 133.8, 131.3, 128.7, 128.5,
128.2, 127.3, 125.9, 124.6, 121.1, 117.7, 88.5, 20.9, 14.7. HRMS: m/z
[M + H]+ calculated for C26H23N4O+, 407.1867; found, 407.1885.
4-(4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole-5-yl)-3-methyl-
1-(p-tolyl)-1H-pyrazol-5-ol (7d). The product was purified by column
chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 162 mg
(74%); off white solid; mp 282−284 °C; 1H NMR (500 MHz, DMSO-
d6 + 40% NaOD in D2O): δ 8.04 (d, J = 5.0 Hz, 2H), 8.00 (d, J = 10.0
Hz, 2H), 7.74 (d, J = 10.0 Hz, 2H), 7.40 (t, J = 10.0 Hz, 2H), 7.27 (t, J =
10.0 Hz, 1H), 7.05 (d, J = 5.0 Hz, 2H), 6.83 (d, J = 10.0 Hz, 2H), 3.73
(s, 3H), 2.25 (s, 3H), 1.66 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-
d6 + 40% NaOD in D2O): δ 163.3, 157.2, 146.2, 142.9, 149.9, 135.5,
131.4, 129.95, 129.87, 128.8, 128.7, 127.4, 124.6, 124.5, 117.9, 113.4,
88.5, 55.2, 20.7, 14.6. HRMS: m/z [M + H]+ calculated for
C27H25N4O2+, 437.1972; found, 437.1996.
1-(4-Chlorophenyl)-3-methyl-4-(2-phenyl-4-(p-tolyl)-1H-imida-
zole-5-yl)-1H-pyrazol-5-ol (7e). The product was purified by column
chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield 139 mg
(63%); cream solid; mp 317−319 °C; 1H NMR (500 MHz, DMSO-d6
+ 40% NaOD in D2O): δ 8.22 (d, J = 5.0 Hz, 2H), 8.00 (d, J = 5.0 Hz,
2H), 7.70 (d, J = 10.0 Hz, 2H), 7.40 (t, J = 10.0 Hz, 2H), 7.28 (d, J =
10.0 Hz, 3H), 7.06 (d, J = 10.0 Hz, 2H), 2.26 (s, 3H), 1.66 (s, 3H).
13
C{1H} NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.6,
147.7, 141.1, 135.9, 134.7, 133.7, 128.8, 128.6, 128.2, 127.0, 126.0,
124.9, 124.7, 119.5119.2, 21.1, 14.6. HRMS: m/z [M + H]+ calculated
for C26H22ClN4O+, 441.1477; found, 441.1510.
4-(4-(Benzo[d][1,3]dioxol-5-yl)-2-phenyl-1H-imidazole-5-yl)-3-
methyl-1-phenyl-1H-pyrazol-5-ol (7f). The product was purified by
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J. Org. Chem. 2024, 89, 4423−4437
The Journal of Organic Chemistry
column chromatography. Eluent: hexane/ethyl acetate (9.5:0.5). Yield
127 mg (58%); red solid; mp 278−280 °C; 1H NMR (500 MHz,
DMSO-d6 + 40% NaOD in D2O): δ 8.17 (d, J = 10.0 Hz, 2H), 7.99 (d, J
= 5.0 Hz, 2H), 7.42−7.35 (m, 4H), 7.29−7.23 (m, 3H), 6.91 (t, J = 10.0
Hz, 1H), 6.81 (d, J = 5.0 Hz, 1H), 5.93 (s, 2H), 1.72 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6 + 40% NaOD in D2O): δ 163.6, 146.9,
146.8, 144.7, 142.9, 142.3, 135.7, 131.5, 131.3, 128.8, 128.2, 127.4,
124.6, 121.1, 119.4, 117.7, 107.9, 106.8, 100.5, 88.1, 14.6. HRMS: m/z
[M + H]+ calculated for C26H21N4O3+, 437.1608; found, 437.1595.
General Experimental Procedure for Synthesis of 10a. Phenyl-
glyoxal monohydrate (76 mg, 0.5 mmol), 1,3-dimethyl barbituric acid
(60 mg, 0.5 mmol), and thiobenzamide (69 mg, 0.5 mmol) were
transferred to a 5 mL round-bottom flask. To this mixture, 1.0 mL of
HFIP was added, and the reaction was kept under constant stirring at
room temperature. The progress of the reaction was monitored using
TLC. The reaction was complete within 6 h. On completion of the
reaction, HFIP was removed from the reaction mixture by a rotavapor,
and the crude product was purified by crystallization from ethyl acetate.
The other derivatives of this series 10b and 10c were prepared using the
similar procedure.
5-(2,4-Diphenylthiazol-5-yl)-1,3-dimethylpyrimidine-2,4,6-
(1H,3H,5H)-trione (10a).34 The product was purified by crystallization
in ethyl acetate. Yield 163 mg (83%); white solid; 1H NMR (500 MHz,
DMSO-d6): δ 7.90 (d, J = 5.0 Hz, 2H), 7.80 (d, J = 5.0 Hz, 2H), 7.49 (t,
J = 10.0 Hz, 2H), 7.43 (t, J = 10.0 Hz, 1H), 7.29 (t, J = 10.0 Hz, 2H),
7.19 (t, J = 10.0 Hz, 1H), 3.08 (s, 6H). 13C{1H} NMR (125 MHz,
DMSO-d6): δ 162.6, 161.4, 153.0, 150.5, 136.9, 134.2, 132.6, 129.5,
129.3, 127.8, 127.5, 126.7, 125.8, 79.1, 27.4.
5-(4-(4-Methoxyphenyl)-2-(p-tolyl)thiazol-5-yl)-1,3-dimethylpyri-
midine-2,4,6(1H,3H,5H)-trione (10b). The product was purified by
crystallization in ethyl acetate. Yield 198 mg (91%); bright yellow solid;
mp 256−258 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.85 (d, J = 5.0
Hz, 2H), 7.68 (d, J = 5.0 Hz, 2H), 7.33 (d, J = 5.0 Hz, 2H), 6.93 (d, J =
10.0 Hz, 2H), 3.76 (s, 3H), 3.17 (s, 6H), 2.37 (s, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6): δ 164.9, 160.5, 158.7, 151.3, 140.1, 130.4,
129.9, 128.8, 127.7, 125.9, 113.6, 81.5, 55.1, 28.2, 21.1. HRMS: m/z [M
+ H]+ calculated for C23H22N3O4S+, 436.1326; found, 436.1335.
5-(4-([1,1′-Biphenyl]-4-yl)-2-phenylthiazol-5-yl)-1,3-dimethylpyr-
imidine-2,4,6(1H,3H,5H)-trione (10c). The product was purified by
crystallization in ethyl acetate. Yield 199 mg (85%); orange solid; mp
254−256 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.99 (dd, J = 10.0, 5.0
Hz, 2H), 7.87 (d, J = 5.0 Hz, 2H), 7.70 (t, J = 10.0 Hz, 4H), 7.55−7.50
(m, 3H), 7.47 (t, J = 10.0 Hz, 2H), 7.36 (t, J = 10.0 Hz, 1H), 3.18 (s,
6H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 164.7, 160.4, 151.3,
139.7, 138.8, 134.5, 133.2, 130.1, 129.3, 128.9, 127.9, 127.4, 126.7,
126.5, 126.3, 125.9, 81.4, 28.1. HRMS: m/z [M + H]+ calculated for
C27H22N3O3S+, 468.1376; found, 468.1400.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information.
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.3c02567.
1
H and 13C{1H} NMR spectra of all compounds;
crystallographic description of compound 5b; recycling
and reusability of HFIP; and characterization data (1H
NMR and 13C{1H} NMR) for the synthesis of all
products and XRD data (PDF)
Accession Codes
CCDC 2246446 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
4436
pubs.acs.org/joc Article
■ AUTHOR INFORMATION
Corresponding Author
Lokman H. Choudhury − Department of Chemistry, Indian
Institute of Technology Patna, Patna 801106, India;
orcid.org/0000-0003-1735-1985; Email: lokman@
iitp.ac.in, lokman.iitp@gmail.com
Authors
Riddhiman Banerjee − Department of Chemistry, Indian
Institute of Technology Patna, Patna 801106, India
Danish Ali − Department of Chemistry, Indian Institute of
Technology Patna, Patna 801106, India; orcid.org/0000-
0003-4431-3757
Nurabul Mondal − Department of Chemistry, Indian Institute
of Technology Patna, Patna 801106, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.3c02567
Author Contributions
†
R.B. and D.A. contributed equally.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors are thankful to SERB, DST, Govt. of India, for the
financial assistance with project no. CRG/2021/003716 for this
work. We are also grateful to IIT Patna for providing the
platform and the general research facilities to carry out this work.
D.A. and N.M. are grateful to IIT Patna and SERB, DST for their
fellowships. The authors are thankful to SAIF IIT Patna, for
providing NMR and HRMS data.
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