Iodine-promoted one-pot synthesis of 1,3,4-oxadiazole scaffolds: Via sp3 C-H functionalization of azaarenes

Article abstract of DOI:10.1039/c9nj03573g

An efficient iodine-mediated one-pot synthetic protocol for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole scaffolds has been developed via sp³ C-H functionalization. Gratifyingly, this method involves oxidative amination with concomitant base-mediated cyclization of methylhetarenes and acylhydrazines by employing iodine and Cs₂CO₃. The key features of the present method include good functional group tolerance, a clean protocol, metal-free conditions and high yields, making this protocol an attractive strategy towards the synthesis of bioactive molecules and their key building blocks.

Full text of DOI:10.1039/c9nj03573g

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Iodine-promoted one-pot synthesis of 1,3,4-
oxadiazole scaffolds via sp3 C–H functionalization
of azaarenes†
Cite this: New J. Chem., 2019,
43, 15999
Geeta Sai Mani,a Kavitha Donthiboina,a Nagula Shankaraiah *a and
abc
Ahmed Kamal
*
An efficient iodine-mediated one-pot synthetic protocol for the synthesis of 2,5-disubstituted 1,3,4-
oxadiazole scaffolds has been developed via sp3 C–H functionalization. Gratifyingly, this method involves
oxidative amination with concomitant base-mediated cyclization of methylhetarenes and acylhydrazines
by employing iodine and Cs2CO3. The key features of the present method include good functional
group tolerance, a clean protocol, metal-free conditions and high yields, making this protocol an
attractive strategy towards the synthesis of bioactive molecules and their key building blocks.
Received 10th July 2019,
Accepted 6th September 2019
DOI: 10.1039/c9nj03573g
rsc.li/njc
to their wide range of biological and pharmaceutical activities.
Currently available marketed drugs based on this oxadiazole
Introduction
In recent years, oxidative sp3 C–H bond functionalization has nucleus are raltegravir (i, antiretroviral), tidazosin (ii, anti-
attained significant attention in both industry and academia. hypertensive), furamizole (iii, antibiotic), and nesapidil (iv, anti-
Indeed, it is a powerful tool for the construction of C–C and hypertensive), shown in Fig. 1.8 Moreover, they are also reported
C–heteroatom bonds in synthetic chemistry. Moreover, C–H to possess anticancer,9 mycobacterial,10 anti-inflammatory,11
functionalization offers a novel method of disconnecting the analgesic,12 anti-diabetic,13 anthelmenthic14 and anticonvulsant
molecule using retrosynthetic analysis, thus providing a more properties.15 The oxadiazole nucleus also acts as a good bioisostere
efficient synthetic route from simple starting materials.1 In this for ester and amide functional groups, and moreover, it contributes
context, considerable attention has been paid to the oxidative to the pharmacological activity of drug molecules by participating in
functionalization of sp3 C–H bonds to construct different hydrogen-bonding interactions with several receptors. In a few
heterocyclic motifs, and various methods have been developed. instances, it acts as a flat aromatic linker to offer an appropriate
Among them, combinations of a metal catalyst with peroxide or orientation to the molecule.16
molecular oxygen, such as copper/peroxide,2 iron/O2 and
Numerous methods have been developed for the synthesis of
3
cobalt/O2,4 are the best catalytic systems for oxidative C–H 1,3,4-oxadiazoles, such as Cu(II)-catalyzed oxidation,17 oxidative
bond functionalization. Other efficient approaches include cyclization of acyl hydrazones using Fe(NO3)3,18a FeCl3,18b Br2,18c
using S8 and iodine reagents with oxidants such as S8/oxidant,5 chloramine T,18d HgO/I2,18e cerium ammonium nitrate,18f tetra-
hypervalent iodine/azide,6 and iodine reagents/peroxide.7 However, valent lead reagents,18g hypervalent iodine reagents,18h–j and
these catalytic systems are usually limited exclusively to symmetrical dehydrative cyclization of acyl hydrazines using SOCl2, H2SO4
alkanes and aryl methyl ketones. Thus, developing an efficient and PPA, etc.19 Nevertheless, many of these synthetic methods
strategy for sp3 C–H oxidative functionalization is challenging and
a highly desirable target for synthetic chemists.
1,3,4-Oxadiazoles are important five-membered heterocyclic
scaffolds in the realm of natural and synthetic chemistry, due
a Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad 500037, India.
E-mail: shankar@niperhyd.ac.in
b Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India. E-mail: ahmedkamal@iict.res.in
c School of Pharmaceutical Education and Research (SPER), Jamia Hamdard,
Fig. 1 Representative biologically active molecules containing 1,3,4-
New Delhi, 110062, India
oxadiazole.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj03573g
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Table 1 Optimization of reaction conditionsa
suffer from certain limitations, such as limited substrate scope,
harsh reaction conditions, low yield, long reaction times, com-
plicated work-up procedures leading to the production of toxic
metal waste and problems with scalability. Therefore, the develop-
ment of a facile, environmentally benign, metal-free method for the
synthesis of these valuable heterocycles is highly desirable. In this
Additive
Base
Temp. Time Yieldb
context, iodine has attained significant attention from researchers Entry (equiv.)
(equiv.)
Solvent (1C)
(h)
(%)
due to its potential catalytic nature, as a greener alternative to
1
2
3
4
5
6
7
8
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
NIS (1.0)
K2CO3 (3)
Cs2CO3 (3) DMSO
DBU (3)
Et3N (3)
Cs2CO3 (3) CH3CN
Cs2CO3 (3) Toluene 100
Cs2CO3 (3) DMF
Cs2CO3 (3) DMSO
DMSO
100
100
100
100
80
12
12
12
12
12
12
12
12
12
12
6
5
5
5
5
5
5
12
5
5
56
41
19
NF
NF
18
21
NF
NF
70
82
80
74
71
84
78
45
89
transition metals. In 2013, Yu et al. developed a highly efficient
I2-mediated synthesis of 1,3,4-oxadiazoles via the oxidative
cyclization of acylhydrazones.20 However, this method exhibits
certain disadvantages, such as the use of chemically unstable
aldehydes as starting materials, involving the synthesis and isolation
of an acyl hydrazone intermediate. Therefore, the development of
an inexpensive, metal-free strategy for the synthesis of these hetero-
cycles in a one-pot manner is urgently needed. Although numerous
synthetic methods have been reported for the synthesis of 1,3,4-
oxadiazoles, the concept of oxidative addition through sp3 C–H
bond amination with concomitant base-mediated cyclization
has not yet been exploited. As part of our research program for
the development of novel synthetic methodologies21 towards
medicinally important compounds in an environmentally
friendly manner, and to overcome the limitations of previous
approaches, herein, we communicate an oxidative benzylic C–H
bond amination of heteroaromatic methanes to afford medicinally
important 1,3,4-oxadiazoles in a one-pot manner.
DMSO
DMSO
100
100
100
100
100
100
100
100
100
120
150
80
9
PhI(OAc)2 (1.0) Cs2CO3 (3) DMSO
10
11
12
13
14
15
16
17
18
19c
TBAI (1.0)
I2 (1.4)
I2 (1.8)
I2 (2.0)
I2 (1.8)
I2 (1.8)
I2 (1.8)
I2 (1.8)
I2 (1.8)
I2 (1.8)
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (5) DMSO
Cs2CO3 (2) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
Cs2CO3 (3) DMSO
120
a
All the reactions were performed using 1a (1 mmol), 2a (1 mmol).
Isolated yields. Iodine (1.8 equiv.) was added to a solution of 2a
b
c
(1 mmol) in DMSO and was stirred for 1 h, followed by addition of 1a along
with base (Cs2CO3, 3 equiv.). DMSO: dimethyl sulfoxide; DMF: dimethyl
formamide; NIS: N-iodosuccinimide; TBAI: tetrabutylammonium iodide.
the product yield of 3a (entry 13, Table 1). Additionally, altering the
quantity of base did not improve the yield of 3a (entries 14–15,
Results and discussion
Initially, our investigation began with the reaction of benzo- Table 1). This reaction was also tested at different temperatures to
hydrazide (1a) and 2-methyl quinoline (2a) in the presence of improve the reaction yield and 120 1C was found to be the
iodine (1 equiv.) and K2CO3 (3 equiv.) using DMSO as a solvent optimum temperature (entries 16–18, Table 1). Gratifyingly, the
at 100 1C for 12 h, resulting in the formation of 3a in 5% yield reaction efficiency was further increased, providing the formation
(entry 1, Table 1). To find optimum conditions for this reaction, of 3a in 89% yield when iodine was added to a solution of 2a in
various bases were initially screened, such as Cs2CO3, DBU and DMSO and stirred for 1 h with subsequent addition of 1a and base
Et3N (entries 2–4, Table 1). The results illustrated that Cs2CO3 (entry 19, Table 1), followed by stirring at 120 1C for 5 h. Therefore,
exhibited the best conversion, and the desired product 3a was systematic screening of the reaction conditions revealed that
obtained (entry 2, Table 1) in 56% yield. In order to improve the the synthesis of 1,3,4-oxadiazoles was most efficient when I2
yield of 3a, different solvents were also screened, including (1.8 equiv.) and Cs2CO3 (3 equiv.) were employed in DMSO at
acetonitrile, toluene and dimethylformamide (entries 5–7, 120 1C (entry 19, Table 1).
Table 1). These results encouraged us to use DMSO as a suitable
With the optimized conditions in hand, we then focused on
solvent and may well imply that DMSO is involved in the investigating the substrate scope of the protocol towards the
oxidation of the C(sp3)–H bond. Thereafter, different iodine synthesis of different disubstituted 1,3,4-oxadiazoles. In this
sources, including N-iodosuccinimide (NIS), PhI(OAc)2 and context, a wide range of acyl hydrazines and methylhetarenes
tetrabutylammonium iodide (TBAI), were used instead of I2 in bearing electron-withdrawing and electron-donating groups
DMSO (entries 8–10, Table 1). However, these reagents were not were successfully employed to study the substrate scope of
effective and only NIS furnished the desired product 3a (entry 8, the protocol. As depicted in Table 2, all the reactions proceeded
Table 1) in 21% yield. Once we established an appropriate base smoothly to furnish the corresponding products in excellent
and solvent, we then directed our attention towards fixing the yields ranging from 73 to 94%. The electronic nature of the
quantity of iodine required for the reaction. Initially, we substituents on acyl hydrazine and methylhetarenes had an
employed 1 equivalent of iodine and noticed 56% formation influence on the reaction yields and reaction efficiency. For
of the desired product 3a. Interestingly, the product 3a for- instance, acylhydrazines bearing electron-withdrawing groups such
mation was increased to a greater extent by employing iodine at as methoxy (3d, 91%), dimethoxy (3e, 94%) and methyl (3f, 91%)
1.8 equivalents (entries 11–12, Table 1). However, further reacted efficiently at a faster rate to afford the corresponding 1,3,4-
increasing the amount of iodine led to a detrimental effect on oxadiazoles in excellent yields. However, acylhydrazines bearing an
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Table 2 Iodine-catalyzed one-pot synthesis of various 1,3,4-oxadiazoles
(3a–j) from acylhydrazines (1a–f) and 2-methylquinolines (2a–d)a,b
Table 3 Iodine-mediated one-pot synthesis of various 1,3,4-oxadiazoles
(5a–n) from acylhydrazines (1a–l) and 2-methylpyridines (4a and b)a,b
a
All the reactions were performed with 1a–f (1 mmol), 2a–d (1 mmol),
iodine (1.8 mmol), and Cs2CO3 (3 equiv.) in DMSO at 120 1C for 4–6 h.
b
Isolated yields.
a
All the reactions were performed with 1a–l (1 mmol), 4a and b
(1 mmol), iodine (1.8 mmol) and Cs2CO3 (3 equiv.) in DMSO at
120 1C for 4–6 h. Isolated yields.
b
electron-withdrawing group such as chloro furnished 3b and 3c in
moderate yields of 75% and 73%, respectively. Interestingly, chloro
group substitution at the 4th position obtained the corresponding
product with a slightly higher yield (3b, 75%) when compared to
substitution at the 3rd position (3c, 73%). Subsequently, we focused
our attention on the substrate scope diversity of other components,
i.e. 2-methylquinolines. Substituted 2-methylquinolines (chloro,
bromo and methoxy) were employed, as they were expected to
furnish the corresponding products with excellent yields (3g–j,
Table 2). Interestingly, a reaction performed with methoxy-
Scheme 1 Gram-scale reaction for the synthesis of 3a and 5a.
In order to extend the synthetic applicability of the present
substituted acylhydrazine and chloro-substituted 2-methylquinoline protocol, a gram scale synthesis was performed by reacting the
also proceeded well to afford the corresponding product 3j in substrates 2a (5.2 g, 36.7 mmol) and 4a (4.9 g, 36.7 mmol) with
86% yield.
1a (5 g, 36.7 mmol) under standard conditions. The quantitative
Later, we were also interested to explore this protocol by yield of the products 3a and 5a (Scheme 1) in 85% and 79% yield
employing 2-methyl pyridine as a substrate to deliver the different in a gram scale revealed that this protocol has the potential for
1,3,4-oxadiazole scaffolds. To our delight, 2-methyl pyridine was utility in industrial scale-up operations.
amenable to this reaction and reacted well with various substituted
To elucidate the reaction pathway for the formation of the
acylhydrazines to afford the products 5a–n in moderate to good various disubstituted 1,3,4-oxadiazoles, a few control experiments
yields (Table 3). The electronic nature of acylhydrazine had an were performed (Scheme 2). Initially, we performed a reaction with
effect on the reaction rate and reaction yields. Substrates bearing 2-methyl quinoline (2a) in the presence of iodine (1.0 equiv.) in
an electron-withdrawing group, such as chloro, bromo, trifluoro- DMSO at 120 1C for 30 min without using acyl hydrazine (1a) and
methyl, and nitro functionalities, delivered the 1,3,4-oxadiazoles obtained a quinoline-2-carbaldehyde (7) in 39% yield. The starting
5b–f in moderate yields after prolonged reaction times, whereas material 2a (48%) was recovered, whereas 7 was not detected in the
electron-donating groups, such as methoxy, dimethoxy and methyl absence of iodine and 2a was completely recovered (Scheme 2a).
groups, furnished the products 5g–i in good yields in a shorter
Considering that previous literature reports22 revealed that
reaction time (Table 3). Investigations with heteroaryl acylhydrazines, the nucleophilic reactivity of 2-methyl quinoline (2a) is mediated
such as pyridyl, thiophene and furan, were also found to be fruitful by iodine, 2-methyl quinoline might undergo a nucleophilic
and delivered the products 5j–l in 81%, 73% and 78% yields, halogenation in the presence of iodine to furnish a 2-iodomethyl
respectively (Table 3). In order to explore the synthetic applicability quinoline (6). However, the iodo intermediate 6 is unstable and
and efficiency of the presented method, we executed the reaction cannot be isolated, and it undergoes a Kornblum oxidation leading
with 4-methylpyridine and acylhydrazine. However, the reaction to the formation of quinoline-2-carbaldehyde (7), in agreement
proceeded in a very sluggish manner and furnished the corres- with a report from Wu et al.23 To avoid the Kornblum oxidation
ponding products 5m and 5n in lower yields.
step for the formation of quinoline 2-carbaldehyde (7), 6 could
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nucleophilic halogenation with iodine to form a 2-iodomethyl
azaarene II. Next, in path-A, intermediate II is further oxidized to
provide aldehyde III via Kornblum oxidation with DMSO,24
followed by condensation with acylhydrazine (1a) to afford an
acyl hydrazone V. Alternatively, in path-B, intermediate II under-
goes subsequent nucleophilic amination with acyl hydrazine to
form an intermediate IV, which is oxidized further with iodine to
furnish intermediate V. Finally, V undergoes a base-promoted
oxidative iodination to furnish the iodinated intermediate VI,
which subsequently undergoes SN2 type cyclization to form a
C–O bond, followed by deprotonation with base to furnish the
desired product 3a. The base neutralizes the HI which is
generated in the reaction medium.
Conclusion
Scheme 2 Control experiments.
In conclusion, an efficient I2-mediated oxidative amination with
concomitant base-mediated cyclization for the synthesis of various
disubstituted 1,3,4-oxadiazoles has been developed in a one-pot
manner. This method employs Cs2CO3 as an efficient base, which
plays an important role in the cyclization process. The key features
of this methodology are operational simplicity, high yields,
good functional group tolerance and low environmental impact.
Additionally, this method utilizes a wide range of substrates and
progresses under metal-free conditions using DMSO as an efficient
oxidant. Moreover, a gram-scale synthesis was also achieved and
this protocol may find significant applications in the design of new
chemical entities (NCEs) in the drug discovery process for various
therapeutic purposes.
instead undergo nucleophilic amination directly with acyl hydrazine
(1a) to produce an intermediate 9. Hence, we conducted a control
experiment with acylhydrazine (1a) and 2-chloromethylquinoline (8)
under standard conditions, which affords the desired product 3a in
92% yield (Scheme 2b). This reaction may be advanced through
the in situ halide exchange of the chloro group in 2-chloromethyl-
quinoline (8) with an iodo group in the presence of iodine to form
a 2-iodomethyl quinoline (6). Subsequently, we performed a
reaction with 1a and quinoline-2-carbaldehyde (7) using two
cases in the presence and absence of iodine, which furnished
the product 3a only in the presence of iodine, whereas product 3a
was not detected in the latter case, i.e. in the absence of iodine
(Scheme 2c). Therefore, control experimental data revealed that
2-iodomethyl quinoline (6) and quinoline 2-carbaldehyde (7)
might be the potential intermediates in this reaction process.
Based on the literature reports and control experimental results, a
plausible mechanistic pathway for the synthesis of 1,3,4-oxadiazole is
depicted in Scheme 3. At the onset, 2-methylazaarene exists in
equilibrium with the more nucleophilic enamine via imine–enamine
tautomerization via [1,3]H-shift, which subsequently undergoes a
Experimental section
General information
All the reagents and chemicals were obtained from commercial
sources and used without further purification. Analytical thin layer
chromatography (TLC) was performed with silica gel (MERCK silica
gel 60-F254; 0.5 mm) precoated glass plates. TLC plates were
visualized by exposure to ultraviolet light. Column chromatography
was performed using 100–200 mesh silica gel, and the eluent was as
1
a mixture of ethyl acetate and n-hexane. H and 13C NMR spectra
were recorded on a Bruker 500 MHz NMR instrument in CDCl3 or
DMSO-d6 with tetramethylsilane (TMS) as an internal standard.
Chemical shifts (d) and coupling constants (J) are reported in parts
per million (ppm) and Hertz (Hz), respectively. The peak patterns
are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, doublet of doublet; dt, doublet of triplet; td, triplet of
doublet; ddd, doublet of doublet of doublet. Melting points were
determined using an electrothermal apparatus (Model IA9200)
and are uncorrected. High-resolution mass spectra (HRMS) were
recorded on LC-QTOF mass spectrometer.
General procedure for the synthesis of 1,3,4-oxadiazole
(3a–j, 5a–n)
In a 25 ml round bottomed flask, methyl quinoline (1 mmol)
Scheme 3 Plausible reaction mechanism.
and iodine (1.8 mmol) in DMSO were refluxed at 120 1C
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followed by the addition of acylhydrazine (1 mmol) after 1 h, 143.42, 137.40, 130.54, 130.15, 128.72, 128.29, 127.78, 125.15,
and continued refluxing at 120 1C for 3–5 h. After completion of 119.89, 105.23, 104.96, 55.74; HRMS (ESI): m/z calcd for
the reaction (monitored with TLC), the reaction mixture was
quenched with a saturated solution of sodium thiosulphate and
C
19H16N3O3 [M + H]+ 334.1186, found 334.1202.
2-(Quinolin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole (3f). 261 mg (91%)
extracted with ethyl acetate. The combined organic layers were of 3f was obtained as a white solid; Rf = 0.233 (ethyl acetate/
washed with water and brine, dried over anhydrous Na2SO4, n-hexane, 2 : 3); Mp. 176–178 1C; 1H NMR (500 MHz, CDCl3):
filtered and concentrated under reduced pressure. The residue d 8.39 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.29 (d, J =
obtained was purified by silica-gel column chromatography 8.5 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.1 Hz, 1H), 7.86–
using ethyl acetate–hexane as the eluent in increasing polarity 7.80 (m, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 2.46
to afford the desired 1,3,4-oxadiazoles 3a–j and 5a–n.
(s, 3H); 13C NMR (125 MHz, CDCl3): d 166.13, 164.07, 148.10,
2-Phenyl-5-(quinolin-2-yl)-1,3,4-oxadiazole (3a). 242 mg (89%) 143.67, 142.72, 137.37, 130.51, 130.23, 129.81, 128.76, 128.24,
of 3a was obtained as a yellow solid; Rf = 0.766 (ethyl acetate/ 127.81, 127.51, 121.01, 119.94, 21.71; HRMS (ESI): m/z calcd for
n-hexane, 1 : 1); Mp. 164–166 1C; 1H NMR (500 MHz, CDCl3): C18H14N3O [M + H]+ 288.1131, found 288.1134.
d 8.40 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.31–8.27
2-(7-Chloroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3g). 257 mg
(m, 3H), 7.91 (d, J = 8.1 Hz, 1H), 7.85–7.80 (m, 1H), 7.69–7.64 (84%) of 3g was obtained as a pale yellow solid; Rf = 0.800 (ethyl
(m, 1H), 7.62–7.54 (m, 3H); 13C NMR (125 MHz, CDCl3): d 165.96, acetate/n-hexane, 1 : 1); 1H NMR (500 MHz, CDCl3): d 8.38
164.08, 147.80, 143.28, 137.64, 132.12, 130.68, 130.00, 129.08, (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 4.2,
128.74, 128.36, 127.81, 127.52, 123.63, 119.88; HRMS (ESI): m/z 1.7 Hz, 2H), 8.27–8.25 (m, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.62–7.59
calcd for C17H11N3NaO [M + Na]+ 296.0794, found 296.0810.
(m, 1H), 7.59–7.57 (m, 2H), 7.57–7.54 (m, 1H); 13C NMR
2-(4-Chlorophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3b). 230 mg (125 MHz, CDCl3): d 166.06, 163.96, 148.34, 144.41, 137.27,
(75%) of 3b was obtained as a white solid; Rf = 0.866 (ethyl acetate/ 136.60, 132.20, 129.33, 129.12, 129.07, 128.96, 127.51, 127.05,
n-hexane, 1 : 1); Mp. 184–186 1C; 1H NMR (500 MHz, CDCl3): d 8.39 123.58, 120.09; HRMS (ESI): m/z calcd for C17H11ClN3O [M + H]+
(d, J = 8.5 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 308.0585, found 308.0598.
8.25–8.21 (m, 2H), 7.92 (d, J = 8.2 Hz, 1H), 7.86–7.81 (m, 1H), 7.70–
2-(7-Bromoquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3h). 301 mg
7.65 (m, 1H), 7.57–7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): (86%) of 3h was obtained as a white solid; Rf = 0.699 (ethyl acetate/
d 165.08, 164.32, 147.94, 143.18, 138.43, 137.51, 130.64, 130.08, n-hexane, 2 : 3); Mp. 194–196 1C; 1H NMR (500 MHz, CDCl3): d 8.41
129.48, 128.75, 128.73, 128.38, 127.82, 122.12, 119.87; HRMS (ESI): (d, J = 8.6 Hz, 1H), 8.30–8.24 (m, 3H), 8.16 (d, J = 9.0 Hz, 1H), 8.08
m/z calcd for C17H11ClN3O [M + H]+ 308.0585, found 308.0597.
(d, J = 2.1 Hz, 1H), 7.89 (dd, J = 9.0, 2.2 Hz, 1H), 7.62–7.54 (m, 3H);
2-(3-Chlorophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3c). 224 mg 13C NMR (125 MHz, CDCl3): d 166.06, 163.79, 146.33, 143.56,
(73%) of 3c was obtained as a yellow solid; Rf = 0.666 (ethyl 136.61, 134.27, 132.23, 131.56, 129.90, 129.69, 129.12, 127.52,
acetate/n-hexane, 2 : 3); Mp. 146–148 1C; 1H NMR (500 MHz, 123.49, 122.64, 120.75; HRMS (ESI): m/z calcd for C17H10BrN3NaO
CDCl3): d 8.38 (q, J = 8.5 Hz, 2H), 8.29 (d, J = 8.5 Hz, 1H), 8.15 [M + Na]+ 373.9899, found 373.9908.
(d, J = 6.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H),
2-(8-Methoxyquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3i). 278 mg
7.66 (t, J = 7.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.1 Hz, (92%) of 3i was obtained as a white solid; Rf = 0.350 (ethyl
1H), 7.46 (t, J = 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): acetate/n-hexane, 2 : 3); Mp. 149–151 1C; 1H NMR (500 MHz,
d
164.32, 164.22, 147.76, 143.04, 137.82, 133.67, 132.69, CDCl3): d 8.45 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H),
131.68, 131.26, 130.79, 130.06, 128.84, 128.50, 127.80, 127.12, 8.32–8.29 (m, 2H), 7.62–7.53 (m, 4H), 7.50–7.46 (m, 1H),
123.07, 119.93; HRMS (ESI): m/z calcd for C17H10ClN3NaO 7.18–7.13 (m, 1H), 4.16 (s, 3H); 13C NMR (125 MHz, CDCl3): d
[M + Na]+ 330.0405, found 330.0416.
165.93, 164.25, 155.72, 142.31, 139.92, 137.39, 131.99, 129.94,
2-(4-Methoxyphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3d). 128.95, 128.79, 127.58, 123.67, 120.58, 119.50, 108.70, 56.16;
275 mg (91%) of 3d was obtained as a white solid; Rf = 0.530 HRMS (ESI): m/z calcd for C18H13N3NaO2 [M + Na]+ 326.0900,
(ethyl acetate/n-hexane, 2 : 3); Mp. 167–168 1C; 1H NMR (500 MHz, found 326.0906.
CDCl3): d 8.39 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.29
2-(7-Chloroquinolin-2-yl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole
(d, J = 8.5 Hz, 1H), 8.25–8.19 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), (3j). 257 mg (84%) of 3j was obtained as a white solid; Rf = 0.800
7.85–7.79 (m, 1H), 7.68–7.63 (m, 1H), 7.08–7.04 (m, 2H), 3.91 (ethyl acetate/n-hexane, 2 : 3); Mp. 206–207 1C; 1H NMR (500 MHz,
(s, 3H); 13C NMR (125 MHz, CDCl3): d 165.88, 163.76, 162.69, CDCl3): d 8.41 (d, J = 8.5 Hz, 1H), 8.36 (t, J = 6.7 Hz, 2H), 8.26–8.22
147.93, 143.55, 137.38, 130.50, 130.07, 129.30, 128.66, 128.17, (m, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.7, 2.0 Hz, 1H), 7.10–
127.77, 119.83, 116.14, 114.52, 55.48; HRMS (ESI): m/z calcd for 7.05 (m, 2H), 3.92 (s, 3H); 13C NMR (125 MHz, CDCl3): d 166.05,
C
18H13N3NaO2 [M + Na]+ 326.0900, found 326.0911.
163.42, 162.78, 148.16, 144.40, 137.32, 136.60, 129.35, 129.24,
2-(3,4-Dimethoxyphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3e). 128.96, 128.90, 126.97, 120.02, 115.96, 114.57, 55.52; HRMS
275 mg (91%) of 3e was obtained as a white solid; Rf = 0.322 (ESI): m/z calcd for C18H12ClN3NaO2 [M + Na]+ 360.0510, found
(ethyl acetate/n-hexane, 2 : 3); Mp. 184–186 1C; 1H NMR (500 MHz, 360.0517.
CDCl3): d 8.40 (t, J = 6.3 Hz, 2H), 8.36 (d, J = 8.8 Hz, 1H), 7.92
(dd, J = 8.2, 1.0 Hz, 1H), 7.86–7.82 (m, 1H), 7.69–7.65 (m, 1H), of 5a was obtained as a white solid; Rf = 0.233 (ethyl acetate/
7.44 (d, J = 2.3 Hz, 2H), 6.67 (t, J = 2.3 Hz, 1H), 3.91 (s, 6H); 13 n-hexane, 2 : 3); Mp. 121–124 1C; 1H NMR (500 MHz, CDCl3):
2-Phenyl-5-(pyridin-2-yl)-1,3,4-oxadiazole (5a). 187 mg (84%)
C
NMR (125 MHz, CDCl3): d 165.87, 164.21, 161.24, 148.02, d 8.83 (dd, J = 4.7, 0.5 Hz, 1H), 8.35–8.32 (m, 1H), 8.25–8.21
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(m, 2H), 7.95–7.89 (m, 1H), 7.60–7.51 (m, 3H), 7.51–7.46 162.74, 149.60, 143.04, 137.87, 129.37, 125.76, 123.48, 115.90,
(m, 1H); 13C NMR (125 MHz, CDCl3): d 165.72, 163.50, 149.91, 114.62, 55.75; HRMS (ESI): m/z calcd for C14H11N3NaO2
143.19, 137.74, 132.09, 129.08, 127.38, 125.95, 123.53, 123.38; [M + Na]+ 276.0743, found 276.0747.
HRMS (ESI): m/z calcd for C13H9N3NaO [M + Na]+ 246.0638,
2-(3,4-Dimethoxyphenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5h).
found 246.0645.
251 mg (89%) of 5g was obtained as a white solid; Rf = 0.128
2-(4-Fluorophenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5b). 163 mg (ethyl acetate/n-hexane, 2 : 3); Mp. 179–181 1C; 1H NMR
(68%) of 5b was obtained as a white solid; Rf = 0.173 (ethyl acetate/ (500 MHz, CDCl3): d 8.83 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.94
n-hexane, 2 : 3); Mp. 156–158 1C; 1H NMR (500 MHz, CDCl3): (t, J = 7.7 Hz, 1H), 7.55–7.48 (m, 1H), 7.37 (d, J = 1.5 Hz, 2H), 6.64
d 8.85–8.79 (m, 1H), 8.36–8.30 (m, 1H), 8.27–8.19 (m, 2H), (d, J = 1.5 Hz, 1H), 3.88 (s, 6H); 13C NMR (125 MHz, CDCl3):
7.96–7.89 (m, 1H), 7.52–7.47 (m, 1H), 7.26–7.20 (m, 2H); 13C NMR d 165.75, 163.52, 161.25, 149.91, 143.22, 137.72, 125.95, 125.03,
(125 MHz, CDCl3): d 165.04 (d, J = 253.76 Hz), 164.88, 163.62, 123.43, 105.08, 55.78; HRMS (ESI): m/z calcd for C15H14N3O3
150.03, 143.21, 137.64, 129.71 (d, J = 9.0 Hz), 125.98, 123.37, [M + H]+ 284.1030, found 284.0949.
119.89 (d, J = 3.28 Hz), 116.46 (d, J = 22.3 Hz); HRMS (ESI):
2-(Pyridin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole (5i). 201 mg (85%)
m/z calcd for C13H8FN3NaO [M + Na]+ 264.0544, found 264.0552. of 5h was obtained as a white solid; Rf = 0.173 (ethyl acetate/
2-(4-Chlorophenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5c). 179 mg n-hexane, 2 : 3); Mp. 152–154 1C; 1H NMR (500 MHz, CDCl3):
(70%) of 5c was obtained as a white solid; Rf = 0.260 (ethyl acetate/ d 8.83 (d, J = 4.3 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.12
n-hexane, 2 : 3); Mp. 170–172 1C; 1H NMR (500 MHz, CDCl3): d 8.83 (d, J = 8.2 Hz, 2H), 7.95–7.90 (m, 1H), 7.49 (dd, J = 7.0,
(d, J = 3.7 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.6 Hz, 2H), 4.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H); 13C NMR
7.93 (t, J = 7.6 Hz, 1H), 7.56–7.48 (m, 3H); 13C NMR (125 MHz, (125 MHz, CDCl3): d 165.83, 163.45, 150.11, 143.53, 142.69,
CDCl3): d 164.85, 163.84, 150.23, 143.34, 138.42, 137.49, 129.50, 137.47, 129.78, 127.33, 125.80, 123.27, 120.80, 21.68; HRMS
128.62, 126.01, 123.41, 122.07; HRMS (ESI): m/z calcd for (ESI): m/z calcd for C14H11N3NaO3 [M + Na]+. 260.0794, found
C13H8ClN3NaO [M + Na]+ 280.0248, found 280.0259.
260.0803.
2-(Pyridin-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (5j). 181 mg
2-(3-Chlorophenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5d). 174 mg
(68%) of 5d was obtained as a white solid; Mp. 164–166 1C; (81%) of 5i was obtained as a yellow solid; Rf = 0.130 (ethyl
1H NMR (500 MHz, CDCl3): d 8.83 (d, J = 4.7 Hz, 1H), 8.32 acetate/n-hexane, 4 : 1); Mp. 148–150 1C; 1H NMR (500 MHz,
(d, J = 7.9 Hz, 1H), 8.11 (dd, J = 7.8, 1.6 Hz, 1H), 7.96–7.89 CDCl3): d 9.45 (s, 1H), 8.82 (d, J = 4.4 Hz, 2H), 8.56 (dt, J = 8.0,
(m, 1H), 7.61–7.56 (m, 1H), 7.54–7.47 (m, 2H), 7.46–7.41 (m, 1H); 1.7 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.93 (td, J = 7.8, 1.7 Hz, 1H),
13C NMR (125 MHz, CDCl3): d 164.10, 163.86, 150.36, 143.41, 7.59–7.53 (m, 1H), 7.53–7.48 (m, 1H); 13C NMR (125 MHz,
137.39, 133.52, 132.62, 131.50, 131.25, 127.08, 125.98, 123.39, CDCl3): d 164.35, 163.46, 152.44, 150.42, 148.04, 143.31,
123.01; HRMS (ESI): m/z calcd for C13H8ClN3NaO [M + Na]+ 137.34, 134.67, 126.12, 123.89, 123.48, 120.33; HRMS (ESI):
280.0248, found 280.0255.
m/z calcd for C12H9N4O3 [M + H]+ 225.0771, found 225.0774.
2-(Pyridin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (5k). 167 mg
2-(Pyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole
(5e). 191 mg (65%) of 5e was obtained as a white solid; Rf = 0.533 (73%) of 5j was obtained as a white solid; Rf = 0.100 (ethyl acetate/
(ethyl acetate/n-hexane, 2 : 3); Mp. 137–139 1C; 1H NMR n-hexane, 2 : 3); Mp. 120–122 1C; 1H NMR (500 MHz, CDCl3):
(500 MHz, CDCl3): d 8.87–8.82 (m, 1H), 8.39–8.34 (m, 3H), d 8.80 (d, J = 3.3 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.94–7.87
7.99–7.91 (m, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.55–7.50 (m, 1H); (m, 2H), 7.58 (dd, J = 5.0, 1.2 Hz, 1H), 7.47 (dd, J = 6.9, 5.0 Hz, 1H),
13C NMR (125 MHz, CDCl3): d 164.52, 164.02, 150.03, 142.93, 7.18 (dd, J = 5.0, 3.8 Hz, 1H); 13C NMR (125 MHz, CDCl3):
137.79, 133.67 (q, J = 32.94), 127.70, 126.78, 123.59, 123.55 d 163.26, 161.88, 150.02, 143.28, 137.46, 130.75, 130.61, 128.27,
(q, J = 271.89 Hz), 126.23, 126.14 (q, J = 3.74 Hz); HRMS (ESI): 125.90, 124.80, 123.33; HRMS (ESI): m/z calcd for C11H7N3NaOS
m/z calcd for C14H8F3N3NaO [M + Na]+. 314.0512, found [M + Na]+ 252.0202, found 252.0208.
314.0522.
2-(Furan-2-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5l). 166 mg
2-(4-Nitrophenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5f). 174 mg (78%) of 5k was obtained as a white solid; Rf = 0.133 (ethyl
(65%) of 5f was obtained as a yellow solid; Rf = 0.225 (ethyl acetate/n-hexane, 2 : 3); Mp. 118–120 1C; 1H NMR (500 MHz,
acetate/n-hexane, 2 : 3); Mp. 180–182 1C; 1H NMR (500 MHz, CDCl3): d 8.79 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.93–7.84 (m, 1H),
DMSO): d 8.85 (d, J = 3.7 Hz, 1H), 8.47 (dd, J = 7.2, 3.8 Hz, 2H), 7.69–7.62 (m, 1H), 7.52–7.42 (m, 1H), 7.34–7.29 (m, 1H), 6.61
8.39 (dd, J = 6.1, 2.7 Hz, 2H), 8.32 (dd, J = 7.3, 4.2 Hz, 1H), 8.16– (dd, J = 3.5, 1.8 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 163.11,
8.09 (m, 1H), 7.76–7.64 (m, 1H); 13C NMR (125 MHz, DMSO): d 158.31, 150.35, 146.10, 143.22, 139.17, 137.29, 125.96, 123.34,
164.75, 163.82, 150.90, 149.80, 142.98, 138.44, 129.28, 128.67, 114.92, 112.32; HRMS (ESI): m/z calcd for C11H7N3NaO2
127.19, 125.14, 123.87; HRMS (ESI): m/z calcd for C13H8N4NaO3 [M + Na]+ 236.0430, found 236.0438.
[M + Na]+. 291.0489, found 291.0492.
2-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazole (5m). 44 mg (20%)
2-(4-Methoxyphenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (5g). 317 mg of 5l was obtained as a white solid; Rf = 0.166 (ethyl acetate/
(86%) of 5g was obtained as a white solid; Rf = 0.140 (ethyl n-hexane, 2 : 3); Mp. 138–140 1C; 1H NMR (500 MHz, CDCl3):
acetate/n-hexane, 2 : 3); Mp. 158–160 1C; 1H NMR (500 MHz, d 8.84 (d, J = 5.8 Hz, 2H), 8.18–8.11 (m, 2H), 8.03–7.97 (m, 2H),
CDCl3): d 8.84 (s, 1H), 8.35 (d, J = 7.78 Hz, 1H), 8.19 (d, J = 8.9 Hz, 7.62–7.52 (m, 3H); 13C NMR (125 MHz, CDCl3): d 165.52, 162.75,
2H), 7.97 (t, J = 7.5 Hz, 1H), 7.60–7.48 (m, 1H), 7.04 (d, J = 8.8 Hz, 150.78, 132.31, 131.17, 129.24, 127.17, 123.37, 120.37; HRMS (ESI):
2H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3): d 165.82, 162.85, m/z calcd for C13H10N3O [M + H]+ 224.0818, found 224.0905.
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2-(4-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole (5n). 46 mg
(18%) of 5m was obtained as a white solid; Rf = 0.200 (ethyl acetate/
n-hexane, 2 : 3); Mp. 144–146 1C; 1H NMR (500 MHz, CDCl3): d 8.86
(d, J = 5.8 Hz, 2H), 8.13–8.08 (m, 2H), 8.04 –8.00 (m, 2H), 7.57–7.53
(m, 2H); 13C NMR (125 MHz, CDCl3): d 164.76, 162.84, 150.66,
138.75, 131.13, 129.68, 128.43, 121.81, 120.43; HRMS (ESI): m/z
calcd for C13H9ClN3O [M + H]+ 258.0429, found 258.0480.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
G. S. M. and K. D. are thankful to the Department of Pharma-
ceuticals (DoP), the Ministry of Chemicals and Fertilizers Govt.
of India, New Delhi for the award of Research Fellowships.
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