Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of methyl-azaheteroarenes and hydrazides

Article abstract of DOI:10.1016/j.tet.2019.130887

An oxidative sp³ C–H bond of methyl-azaheteroarenes protocol was reported for the synthesis of 1,3,4-oxadiazoles via [4 + 1] annulation with hydrazides. This protocol enables 1,3,4-oxadiazole and quinoline linked diheterocycles via selective oxidation of sp³ C–H bond of methyl-azaheteroarenes in the presence of I₂-DMSO. The reaction has a broad substrate scope and good functional group tolerance for methyl-azaheteroarenes and hydrazides.

Full text of DOI:10.1016/j.tet.2019.130887

Journal Pre-proof
Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of
methyl-azaheteroarenes and hydrazides
Zhi-Hao Shang, Ji-Na Sun, Jiang-Shan Guo, Yuan-Yuan Sun, Wei-Zhao Weng, Zhen-
Xiao Zhang, Zeng-Jing Li, Yan-Ping Zhu
PII:
S0040-4020(19)31299-2
https://doi.org/10.1016/j.tet.2019.130887
TET 130887
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 October 2019
Revised Date: 28 November 2019
Accepted Date: 17 December 2019
Please cite this article as: Shang Z-H, Sun J-N, Guo J-S, Sun Y-Y, Weng W-Z, Zhang Z-X, Li Z-J,
Zhu Y-P, Facile synthesis of 1,3,4-oxadiazoles via iodine promoted oxidative annulation of methyl-
azaheteroarenes and hydrazides, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2019.130887.
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Facile Synthesis of 1,3,4-Oxadiazoles via Iodine
Promoted Oxidative Annulation of
Leave this area blank for abstract info.
Methyl-azaheteroarenes and Hydrazides
Zhi-Hao Shang,‡ Ji-Na Sun,‡ Jiang-Shan Guo,‡ Yuan-Yuan Sun,‡ Wei-Zhao Weng, Zhen-Xiao Zhang, Zeng-
Jing Li, Yan-Ping Zhu,*
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education,
Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of
Shandong,Yantai University, Shandong, Yantai, 264005, P. R. China.
X
X
R1
O
R1
R
N
Y
Y
N
CH3
CH3
N
N
N
O
I2-DMSO
K2CO3
or
R
NHNH2
N
O
R
R1
R1
36 examples
Up to 82% yield
N
N
Oxidative Sp3 C-H bond
Metal-free
orth, para-methyl oxidation
Broad scope Simple conditions

1
Tetrahedron
journal homepage: www.elsevier.com
Facile Synthesis of 1,3,4-Oxadiazoles via Iodine Promoted Oxidative Annulation of
Methyl-azaheteroarenes and Hydrazides
Zhi-Hao Shang,‡ Ji-Na Sun,‡ Jiang-Shan Guo,‡ Yuan-Yuan Sun,‡ Wei-Zhao Weng, Zhen-Xiao Zhang,
Zeng-Jing Li, Yan-Ping Zhu*
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced
Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Shandong, Yantai, 264005, P. R. China.
ARTICLE INFO
ABSTRACT
An oxidative sp3 C-H bond of methyl-azaheteroarenes protocol was reported for the
synthesis of 1,3,4-oxadiazoles via [4+1] annulation with hydrazides. This protocol
enables 1,3,4-oxadiazole and quinoline linked diheterocycles via selective oxidation
of sp3 C-H bond of methyl-azaheteroarenes in the presence of I2-DMSO. The reaction
has a broad substrate scope and good functional group tolerance for methyl-
azaheteroarenes and hydrazides.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
1,3,4-Oxadiazoles
Methyl-azaheteroarenes
Hydrazides
Oxidative annulation
Iodine
Heterocycles
2019 Elsevier Ltd. All rights reserved
.
1. Introduction
Recently, I2 as an efficient oxidant or promoter attracted much
attention. It could promote simple substrates to form C-C bond,
C-X bond and heterocycles.[5] Within this field, some new and
efficient protocols were developed for 1,3,4-oxadiazole synthesis
from simple and easily available starting materials with mild
reaction conditions. For example, the group of Chang in 2013
reported an I2-promoted oxidative annulation of in-situ generated
N-acylhydrazone from aldehydes and hydrazides for the
synthesis of 1,3,4-oxadiazoles in one-pot (Figure 2a).[6] In 2015,
Wu and co-workors developed an elegant approach for synthesis
of 1,3,4-oxadiazoles through annulation of simple methyl ketones
with hydrazides (Figure 2b). With the condition of I2 and K2CO3
in DMSO-H2O, (het)aryl methyl ketones could couple with
hydrazides to access 1,3,4-oxadiazoles via C(CO)−C(methyl)
bond cleavage of (het)aryl methyl ketones. Through simple
switched base and solvent, the reaction could selectively deliver
2-acyl-1,3,4-oxadiazoles.[7] Subsequently, the group of Huang
also demonstrated a graceful domino protocol for one-pot
synthesis of 1,3,4-oxadiazoles from diversity substrates styrene,
phenyl acetylene and hydrazides (Figure 2c).[8] Interestingly, this
protocol could generate 1,3,4-oxadiazoles via oxidative cleavage
of C(sp2)−H or C(sp)−H bonds in the presence of I2 and K2CO3
with O2.
Oxadiazole is an important heterocyclic scaffold which is
widely presented in natural products, synthetic drugs (e.g.
Furamizole, Tiodazosin, Nesapidil), “ drug like” small
molecules, dyestuff industry and materials (Figure 1).[1] In
particular, many 1,3,4-oxadiazole contained compounds show
significant biological activities and pharmaceutical activities,
such as, antimicrobial, antifungal, and anti-inflammatory.[2]
Figure 1. Examples of 1,3,4-oxadiazole containing medicines.
In view of the biological and pharmaceutical activities of
oxadiazoles, great attention and efforts have been paid on their
synthesis. Up to now, many different synthetic protocols have
been reported.[3] The general methods for synthesis of 1,3,4-
oxadiazole are oxidative cyclization of N-acylhydrazones and the
dehydrative cyclization of 1,2-diacylhydrazines, while N-
acylhydrazones and 1,2-diacylhydrazines are usually by
generating through the condensation of aldehydes or carboxylic
Inspired by these pioneered works, we envisioned that I2
might oxidize sp3 C-H bond of methyl-azaheteroarenes,[9]
followed by annulation with hydrazides to deliver 1,3,4-
oxadiazoles and azaheteroarenes linked diheterocycles. Herein,
we report a novel I2-DMSO promoted oxidative [4+1] annulation
of methyl-azaheteroarenes with hydrazides to access 1,3,4-
acids with hydrazides.[4]
———
* Corresponding author. e-mail: chemzyp@foxmail.com (Y.-P. Zhu). ‡ These authors contributed equally to this work.

2
Tetrahedron
oxadiazoles (Figure 2d). This protocol could selectively oxidate
presented either low efficiency or no reactivity (Entry 6-10).
Moreover, the amount of K2CO3 was investigated. When
decreasing the amount of K2CO3 to 5.0 equivalent, the yield was
slightly decreased (69%). Whereas the yield was significantly
decreased, when 4.0 and 3.0 equivalent of K2CO3 was employed.
sp3 C-H bond of methyl-azaheteroarenes in the presence of I2-
DMSO.
With the optimal reaction conditions in hand, we firstly
explored the scope of hydrazides (Table 2). Various hydrazides,
such as aryl hydrazides, heteroaryl hydrazides, cinnamohydrazide,
alkenyl hydrazide and alkyl hydrazide were tested. We firstly
studied the aryl hydrazides in which on the phenyl ring had
electron-rich substituents (e.g. 2-Me, 3-Me, 4-Me, 4-OMe, 2,4-
Me2, 3,4-OCH2O), and the annulation reactions proceeded
smoothly to deliver products 3ab-3ag in 60-76% yields. While
the phenyl ring of hydrazides bearing halogen atoms (e.g. 4-Cl,
2-Br), the reactions could also afford the desired products (3ah
and 3ai) in moderate yields. However, the reaction efficiency
was low, when 4-nitrobenzohydrazide was employed (3aj).
Moreover, the sterically hindered 2-naphthohydrazide 2k, 1-
naphthohydrazide 2l and 2-phenylbenzohydrazide 2m also
reacted smoothly with benzohydrazide (2a) to furnish the target
products 3ak-3am in good yields (54-62%). Notably, heteroaryl
hydrazides, such as furan-2-carbohydrazide 2n and thiophene-2-
carbohydrazide 2o, were also tolerant under the standard
conditions to generate the expected products 3an and 3ao in good
yields. In addition, cinnamohydrazide 2p also reacted smoothly
with 2-methyl quinoline to generate the desired product 3ap, in
which the double bond of cinnamohydrazide did not affect the
reaction. Encouraged by this result, alkenyl hydrazide 2q was
also employed, but the reaction efficiency was low and only 35%
of 3aq was isolated. Alkyl substrate acethydrazide 2r is also
suitable for this reaction. However, only low yield product 3ar
was obtained.
Figure 2. The protocols for 1,3,4-oxadiazoles synthesis.
2. Results and discussion
Table 1. Optimization of the reaction conditions a
Base
(equiv)
Entry
I2 (equiv)
Yield (%)b
Table 2. Scope of Substituted Hydrazides. a, b
1
2
3
4
5
6
7
8
9
10
11
12
13
1.0
1.5
2.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
K2CO3 (6.0)
K2CO3 (6.0)
K2CO3 (6.0)
K2CO3 (6.0)
Na2CO3 (6.0)
Cs2CO3 (6.0)
NaHCO3 (6.0)
KH2PO4 (6.0)
K3PO4 (6.0)
NaOH (6.0)
K2CO3 (5.0)
K2CO3 (4.0)
K2CO3 (3.0)
40
56
65
I2 (2.5 equiv.)
O
K2CO3 (6 equiv.)
O
NH2
N
DMSO, 110 o
C
R
N
R
N
H
72 (74)c (71)d
N
N
3
1a
2
67
n.r.
42
n.r.
20
n.r.
69
40
Me
Me
O
O
O
N
N
N
N
N
N
N
N
N
N
3aa: 72%
3ab: 67%
3ac: 60%
O
O
O
Me
OMe
Me
N
N
N
N
N
N
N
N
3ad: 65%
3ae: 71%
3af: 69%
Me
Br
15
a
Reaction conditions: 2-methyl quinoline 1a (0.5 mmol), benzohydrazide 2a
(0.6 mmol), I2 and base were heated in DMSO (3 mL). b Isolated yields. c 3.0
equivalent of iodine were added. d 4.0 equivalent of iodine were added.
O
O
O
Cl
N
N
N
O
N
N
N
N
N
N
O
3ag: 76%
3ah: 68%
3ai: 62%
At the outset, commercially available 2-methyl quinoline (1a)
and benzohydrazide (2a) were chosen as model substrates for
evaluating the reaction conditions (Table 1). Given the success in
using I2-DMSO as reaction conditions for the synthesis of 1,3,4-
oxadiazoles from methyl ketones, styrene and phenyl acetylene,
we initially performed the reaction of 2-methyl quinoline 1a (0.5
mmol) with benzohydrazide 2a (0.6 mmol) in the presence of I2
(1.25 mmol), K2CO3 (3.0 mmol) and DMSO at 110 oC.
Delightfully, 1,3,4-oxadiazole 3aa was obtained in 40% yield
(Table 1, entry 1). When increasing the amount of I2 to 1.5, 2.0
and 2.5 equivalent, the reaction yield was significantly increased
to 56%, 65% and 72%, respectively (Entry 2-4). Further
increasing the amount of iodine to 3.0 and 4.0 equivalent, the
yield did not increase. Subsequently, a series of bases, such as
Na2CO3, Cs2CO3, NaHCO3, KH2PO4, K3PO4 and NaOH, were
screened. Among them, Na2CO3 was effective for this
transformation, 3aa was afforded in 67% yield. Other bases
O
O
O
N
N
NO2
N
N
N
N
N
N
N
N
3aj: 45%
3ak: 62%
3al: 59%
Ph
S
O
O
O
O
N
N
N
N
N
N
N
N
3an: 61%
3am: 54%
3ao: 63%
O
O
O
N
N
N
Ph
N
N
N
N
N
N
3aq: 35%
3ap: 40%
3ar: 32%
a Reaction conditions: 1a (0.5 mmol), I2 (1.25 mmol) in DMSO (3 mL) at 110
oC for 4-6 h, then added 2 (0.6 mmol), K2CO3 (3.0 mmol) and stirred at 110
oC until the disappearance of 2 (4-6 h, monitored by TLC). b Isolated yields
provided.
We next examined the scope of this reaction for methyl-
azaheteroarenes 1 (Table 3). For example, 2-methyl quinolines

3
attached with electron-donating groups (6-Me, 6-OMe) and
halogen atoms (6-Cl, 7-Cl, 6-Br, 6-F) were tolerant for this
reaction to afford the corresponding products (3ba-3ga). The
results showed that 2-methyl quinolines bearing electron-
donating groups could give high yields than those bearing
halogen atoms substrates. It should be noted that 4-methyl
quinoline 1i was also tolerant for this reaction to generate the
desired product 3ia (63% yield). Moreover, two heteroatoms
containing substrates 2-methylquinoxaline 1j and 2-methyl-1,8-
naphthyridine 1k were also tolerant to react with benzohydrazide,
generating the desired products 3ja and 3ka in 64% and 61%
yields, respectively. As we know, multiheterocyclic compounds
are important scaffolds, which usually have enhanced biological
and pharmaceutical activities. We subsequently examied the
reaction of furan-2-carbohydrazide 2n and thiophene-2-
carbohydrazide 2o with 4-methyl quinoline 1m, 2-
methylquinoxaline 1j and 2-methyl-1,8-naphthyridine 1k. To our
satisfaction, multiheterocyclic scaffolds 3in, 3io, 3jn, 3jo, 3kn
and 3ko were obtained in moderate yields under the standard
conditions (50-59%). Moreover, the reaction is compatible with
monocyclic heteroarenes, such as 2-methyl pyridine and 4-
methyl pyridine. When 2-methyl pyridine and 4-methyl pyridine
were chosen as substrates, the reactions could perform to
generate the desired products 3la and 3ma in 10% and 19%
yields, respectively.
starting material 1a (0.716 g), giving the desired product 3aa in
72% yield. Even the amount of 1a was increased to 10 mmol
scale (1.432 g), the reaction could also proceed smoothly to
generate the desired product 3aa in 62% yield.
To understand the mechanism of the reaction, some control
experiments were conducted (Scheme 2). 2-Methylquinoline
could absolutely transfer to quinoline-2-carbaldehyde in 88%
o
yield in the presence of I2 in DMSO at 110 C for 4 hours,
whereas this reaction could not proceed without I2. While the
reaction of 2-methylquinoline with iodine performed at 110 oC in
DMSO for 30 minutes, 2-(iodomethyl)quinoline and quinolin-2-
carboxaldehyde could be detected in 42% and 30% yields,
respectively (Scheme 2a). There results disclosed I2 is very
essential for this transformation. Subsequently, the reaction of 2-
(iodomethyl)quinoline with benzohydrazide (2a) under standard
conditions performed well to generate the desired product 3aa in
75% yield. However, the reaction could not give the desired
product without I2. (Scheme 2b). Next, we examined the reaction
of quinoline-2-carbaldehyde with benzohydrazide (2a) under
standard conditions, the product 3aa could be obtained in good
yield (Scheme 2c). The reaction of quinoline-2-carbaldehyde
with benzohydrazide (2a) in EtOH at reflux could afford N'-
(quinolin-2-ylmethylene)benzohydrazide (1ac), which could
further transfer to the product 3aa under standard conditions
(Scheme
2e).
Moreover,
N'-(quinolin-2-
Table 3. Scope of Substituted Methyl-azaheteroarenes and
ylmethylene)benzohydrazide (1ac) generated in-situ from
quinoline-2-carbaldehyde and benzohydrazide (2a) in EtOH
without isolation could also perform the product 3aa under
standard conditions (Scheme 2f). These results uncovered that 2-
(iodomethyl)quinoline, quinoline-2-carbaldehyde and N'-
(quinolin-2-ylmethylene)benzohydrazide are the potential
intermediates in this reaction.
Hydrazinylpyridine. a, b
Conditions
(a)
DMSO, 110 o
C
I
N
N
N
CHO
1ab
1aa
1a
standard conditions, without I2: 1aa: not detected
standard conditions:
30 mins, 1aa: 30% yield, 1ab: 42%
4 h, 1ab: 88% yield, 1aa: not detected
O
Conditions
DMSO, 110 o
C
(b)
O
N
I
Ph
Ph
NHNH2
Ph
N
N
N
2a
1aa
Standard conditions: 3aa: 75% yield
without I2: 3aa: not observed
O
Standard conditions
O
N
(c)
(d)
NHNH2
Ph
N
CHO
N
N
3aa: 89% yield
2a
1ab
O
EtOH, reflux
O
a Reaction conditions: 1 (0.5 mmol), I2 (1.25 mmol) in DMSO (3 mL) at 110
oC for 4-6 h, then added 2 (0.6 mmol), K2CO3 (3.0 mmol) and stirred at 110
oC until the disappearance of 2 (4-6 h, monitored by TLC). b Isolated yields
provided.
N
Ph
O
NHNH2
N
N
H
Ph
N
CHO
N
1ac
2a
1ab
Standard conditions
O
N
N
N
N
Ph
Ph
(e)
(f)
H
N
1ac
3aa: 91% yield
Standard
conditions
EtOH
reflux
2a
O
N
Ph
N
CHO
N
N
3aa: 82% yield
1ab
Scheme 1. Scaled-up Reactions for the Synthesis of 1,3,4-Oxadiazoles
3aa.
In order to show the application of this methodology, the
scaled-up reaction was performed under the standard conditions.
To our satisfied, the reaction could perform with 5 mmol of
Scheme 2. Control Experiments.
On the basis of these mechanistic findings and previous
reports,[10] a plausible reaction mechanism was proposed in
scheme 3. Firstly, 2-methylpyridine 1a undergoes an iodination

4
Tetrahedron
reaction with I2 to afford the intermediate 2-
(iodomethyl)quinolone (1aa). Subsequently, 2-
TLC), then added benzohydrazide (2a) (81.6 mg, 0.6 mmol, 1.2
o
equiv.) , K2CO3 (414.0 mg, 3.0 mmol, 6.0 equiv.) at 110 C for
(iodomethyl)quinolone (1aa) is oxidized by DMSO to generate
quinoline-2-carbaldehyde 1ab via Kornblum oxidation. Next,
quinoline-2-carbaldehyde 1ab undergoes condensation with
benzohydrazide to afford intermediate N'-(quinolin-2-
ylmethylene)benzohydrazide 1ad, which performs annulation
and deprotonation process to finish the product 3aa.
another 4-6 h. After the reaction completed, and added 50 mL
water to the mixture, then extracted with EtOAc 3 times (3 × 50
mL). The extract was washed with 10% Na2S2O3 solution (w/w),
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column
chromatography on silica gel to yield the corresponding product
3aa as a yellow solid (72% yield).
4.3. Characterization data
2-Phenyl-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aa)
Yellow solid, m.p.: 123-126 °C, 1H-NMR (400 MHz, CDCl3):
δ (ppm) 8.40 (t, J = 8.4 Hz, 2H), 8.33 (s, 1H), 8.27-8.31 (m, 2H),
7.91 (dd, J = 1.2, 8.4 Hz, 1H), 7.83 (dt, J = 1.2, 8.4 Hz, 1H), 7.67
(dt, J = 1.2, 8.4 Hz, 1H), 7.58-7.60 (m, 2H), 7.55-7.56 (m, 1H),
13C-NMR (100 MHz, CDCl3): δ (ppm) 147.9, 143.4, 137.5, 132.1,
130.6, 130.1, 129.1, 129.0, 128.7, 128.3, 127.8, 127.5, 123.6,
119.9, HRMS (ESI): m/z [M+H]+ calcd for C17H12N3O: 274.0975;
found: 274.0985.
Scheme 3. A plausible mechanism for the preparation of 1,3,4-
oxadiazoles.
3. Conclusion
In summary, we developed an oxidative functionalization
protocol for the synthesis of 1,3,4-oxadiazoles via [4+1]
annulation of methyl-azaheteroarenes with hydrazides. This
protocol enables to 1,3,4-oxadiazole and quinoline linked
diheterocycles via selective oxidation of sp3 C-H bond of methyl-
azaheteroarenes in the presence of I2-DMSO. It has a broad
substrate scope and good functional group tolerance for methyl-
azaheteroarenes and hydrazides. Moreover, this protocol could
efficiently afford furan, quinoline and oxadiazole containing
multiheterocyclic scaffolds, which might have enhanced
biological and pharmaceutical activities.
2-(Quinolin-2-yl)-5-(o-tolyl)-1,3,4-oxadiazole (3ab)
Yellow solid, m.p.: 115-118 °C, 1H-NMR (400 MHz, CDCl3):
δ (ppm) 8.31 (t, J = 8.8 Hz, 2H), 8.25 (t, J = 8.4 Hz, 1H), 8.14 (d,
J = 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 (dt, J = 1.2, 8.4 Hz,
1H), 7.58 (dt, J = 1.2, 8.0 Hz, 1H), 7.41 (dt, J = 1.2, 8.4 Hz, 1H),
7.32-7.35 (m, 2H), 2.78 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ
(ppm) 165.9, 163.5, 147.8, 143.3, 138.7, 137.2, 131.6, 131.3,
130.3, 130.0, 129.3, 128.5, 128.1, 127.6, 126.0, 122.6, 119.6,
22.1. HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O: 288.1131;
found: 288.1139.
4. Experimental
4.1. General
Unless stated otherwise, all solvents and commercially
available reagents were obtained from commercial suppliers and
used without further purification. In addition petroleumether (b.p.
2-(Quinolin-2-yl)-5-(m-tolyl)-1,3,4-oxadiazole (3ac)
White solid, m.p.: 120-124 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.30 (q, J = 8.4 Hz, 2H), 8.26 (s, 1H), 8.05 (s, 1H), 8.02 (s,
1H), 7.84 (d, J = 8.4 Hz,1H), 7.77 (t, J = 8.4 Hz, 1H), 7.59 (t, J =
7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H),
2.43 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.8, 163.9,
147.7, 143.2, 138.7, 137.2, 132.7, 130.3, 129.9, 128.8, 128.5,
128.1, 127.7, 127.6, 124.4, 123.2, 119.6, 21.1. HRMS (ESI): m/z
[M+H]+ calcd for C18H14N3O: 288.1131; found: 288.1142.
o
60-90 C), which was used for Column chromatography, was
distilled prior to use. Non-commercial starting materials were
prepared as described below or according to literature
procedures. TLC analysis was performed using pre-coated glass
plates. Column chromatography was performed using silica gel
(200-300 mesh).
Nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker Advance 400 MHz spectrometer at ambient temperature
using the non or partly deuterated solvent as internal standard
(1H: δ 7.26 ppm and 13C{1H}: δ 77.0 ppm for CDCl3). Chemical
shifts (δ) are reported in ppm, relative to the internal standard of
tetramethylsilane (TMS). The coupling constants (J) are quoted
in hertz (Hz). Resonances are described as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), br (broad) or
combinations thereof. High resolution mass-spectrometric
(HRMS) were obtained on an Apex-Ultra MS equipped with an
electrospray source. Melting points were determined using SGW
X-4 apparatus and not corrected.
2-(Quinolin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole (3ad)
White solid, m.p.: 165-170 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.35 (q, J = 8.4 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.16 (d,
J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.81 (dt, J = 1.6, 7.6,
1H), 7.64 (dt, J = 1.2 , 7.6, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s,
3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 147.9,
143.5, 142.7, 137.4, 130.5, 130.1, 129.7, 128.6, 128.2, 127.7,
127.4, 120.8, 119.8, 21.7. HRMS (ESI): m/z [M+H]+ calcd for
C18H14N3O: 288.1131; found: 288.1137.
4.2 General procedure for synthesis of 5-(quinolin-2-yl)-1,3,4-
oxadiazoles 3 (3aa as an example)
2-(4-Methoxyphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ae)
White solid, m.p.: 196-198 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.28 (t, J = 8.8 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d,
J = 8.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.7.4 (t, J = 7.6 Hz,
1H), 7.56 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 3.83 (s,
3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.7, 163.6, 162.5,
A 25 mL pressure vial was charged with 2-methylquinoline
(1a) (71.5 mg, 0.50 mmol, 1.0 equiv.), I2 (317.3 mg, 1.25 mmol,
2.5 equiv.) and DMSO (3.0 mL). The vial was sealed and the
resulting mixture was stirred at 110 °C for 4-6 h under an air
atmosphere, after disappearance of the reactant (monitored by

5
147.8, 143.4, 137.2, 130.4, 130.0, 129.2, 128.5, 128.1, 127.7,
119.7, 116.0, 114.4, 55.4. HRMS (ESI): m/z [M+H]+ calcd for
C18H14N3O2: 304.1081; found: 304.1090.
2-(Naphthalen-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ak)
White solid, m.p.: 208-211 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.74 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz,
2H), 8.27 (s, 1H), 7.97 (t, J = 8.4 Hz, 2H), 7.87 (d, J = 8.0 Hz,
2H), 7.80 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.55-7.58
(m, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 164.2,
147.9, 143.4, 137.4, 134.8, 132.7, 130.5, 130.1, 128.93, 128.90,
128.6, 128.1, 128.0, 127.9, 127.7, 127.1, 123.4, 120.7, 119.8.
HRMS (ESI): m/z [M+H]+ calcd for C21H14N3O: 324.1131; found:
324.1149.
2-(2,4-Dimethylphenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3af)
White solid, m.p.: 169-172 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.34 (t, J = 8.4 Hz, 2H), 8.28 (t, J = 8.4 Hz, 1H), 8.06 (d, J
= 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H),
7.61 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 2.78 (s, 3H),
2.39 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.1, 163.4,
147.9, 143.4, 141.8, 138.6, 137.2, 132.4, 130.3, 130.0, 129.4,
128.5, 128.0, 127.7, 127.6, 126.8, 119.8, 119.7, 22.1, 21.3.
HRMS (ESI): m/z [M+H]+ calcd for C19H16N3O: 302.1288; found:
302.1294.
2-(Naphthalen-1-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3al)
White solid, m.p.: 201-204 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.38 (d, J = 8.4 Hz, 1H), 8.49 (dd, J = 1.2, 7.2 Hz, 1H),
8.45 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H),
8.09 (d, J = 8.4 Hz, 1H), 7.92-7.98 (dq, J = 1.2, 8.4 Hz, 2H),
7.82-7.86 (dt, J = 1.2, 8.4 Hz, 1H), 7.72-7.76 (dt, J = 1.2, 8.4 Hz,
1H), 7.65-7.69 (dt, J = 1.2, 8.4 Hz, 2H), 7.61-7.65 (dt, J = 1.2, 8.4
Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 163.8,
148.1, 143.4, 137.5, 133.9, 133.0, 130.6, 130.2, 129.2, 128.8,
128.7, 128.3, 127.8, 126.8, 126.3, 124.9, 120.2. 120.0, HRMS
(ESI): m/z [M+H]+ calcd for C21H14N3O: 324.1131; found:
324.1143.
2-(Benzo[d][1,3]dioxol-5-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole
(3ag)
White solid, m.p.: 180-183 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.36 (t, J = 8.8 Hz, 2H), 8.27 (d, J = 9.6 Hz, 1H), 7.90 (d,
J = 8.4 Hz, 1H), 7.79-7.85 (dq, J = 1.6, 8.4 Hz, 2H), 7.71 (d, J =
2.0 Hz, 1H), 7,62-7.66 (dt, J = 1.2, 7.2 Hz, 1H), 6.96 (d, J = 8.0
Hz, 1H), 6.08 (s, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm)
165.7, 163.9, 151.0, 148.3, 148.0, 143.5, 137.4, 130.5, 130.1,
128.7, 128.2, 127.8, 122.8, 119.8, 117.4, 108.9, 107.5, 101.9.
HRMS (ESI): m/z [M+H]+ calcd for C18H12N3O3: 318.0873;
found: 318.0888.
2-([1,1'-Biphenyl]-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3am)
White solid, m.p.: 142-144 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.21 (t, J = 8.8 Hz, 2H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz,
2H), 7.77 (dt, J = 1.2, 8.4 Hz, 1H), 7.58-7.65 (m, 2H), 7.51-7.56
(m, 2H), 7.36-7.41 (m, 5H), 13C-NMR (100 MHz, CDCl3): δ
(ppm) 165.9, 163.9, 147.8, 142.9, 142.4, 140.3, 137.1, 131.4,
130.9, 130.3, 130.0, 128.7, 128.4, 128.1, 128.0, 127.6, 127.5,
122.4, 119.2, HRMS (ESI): m/z [M+H]+ calcd for C23H16N3O:
350.1288; found: 350.1297.
2-(4-Chlorophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ah)
Yellow solid, m.p.: 185-188 °C, 1H-NMR (400 MHz, CDCl3):
δ (ppm) 8.33 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.24
(d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.0 Hz,
1H), 7.79 (t, J = 8.4 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.49 (d, J =
8.4 Hz, 2H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.0, 164.2,
147.9, 143.2, 138.3, 137.4, 130.5, 130.0, 129.4, 128.7, 128.6,
128.3, 127.7, 122.0, 119.8. HRMS (ESI): m/z [M+H]+ calcd for
C17H11ClN3O: 308.0585; found: 308.0590.
2-(Furan-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3an)
White solid, m.p.: 130-134 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.36 (q, J = 8.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 1H), 7.89 (dd,
J = 1.2, 8.4 Hz, 1H), 7.78-7.83 (dt, J = 1.2, 7.2 Hz, 1H), 7.70 (q,
J = 0.8 Hz, 1H), 7.62-7.66 (dt, J = 1.2, 6.8 Hz, 1H), 7.38 (dd, J =
0.8, 3.2 Hz, 1H), 6.64 (q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz,
CDCl3): δ (ppm) 163.5, 158.6, 148.0, 146.2, 143.1, 139.2, 137.5,
130.6, 130.2, 128.7, 128.4, 127.8, 119.9, 115.2, 112.3, HRMS
(ESI): m/z [M+H]+ calcd for C15H10N3O2: 264.0768; found:
264.0774.
2-(2-Bromophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ai)
1
Brown solid, m.p.: 175-180 °C, H-NMR (400 MHz, CDCl3):
δ (ppm) 8.38 (q, J = 8.8 Hz, 2H), 8.29-8.31 (m, 1H), 8.28-8.29
(m, 1H), 7.91 (dd, J = 1.2, 8.0 Hz, 1H), 7.81-7.85 (dt, J = 1.6, 8.4
Hz, 1H), 7.66-7.69 (dt, J = 1.2, 8.0 Hz, 1H), 7.55-7.60 (m, 3H),
13C-NMR (100 MHz, CDCl3): δ (ppm) 165.9, 164.2, 148.0, 143.5,
137.4, 132.1, 130.6, 130.2, 129.1, 129.0, 128.7, 128.3, 127.8,
127.5, 123.7, 119.9, HRMS (ESI): m/z [M+H]+ calcd for
C17H11BrN3O: 352.0080; found: 352.0089.
2-(Quinolin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3ao)
White solid, m.p.: 187-190 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.34 (q, J = 8.4 H, 2H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (dd,
J = 1.2, 3.6 Hz, 1H), 7.88 (dd, J = 1.2, 8.4 Hz, 1H), 7.78-7.82 (dt,
J = 1.6, 7.2 Hz, 1H), 7.61-7.65 (dt, J = 1.2, 8.0 Hz, 1H), 7.60 (dd,
J = 1.2, 4.8 Hz, 1H), 7.21-7.23 (q, J = 4.8 Hz, 1H), 13C-NMR
(100 MHz, CDCl3): δ (ppm) 163.6, 162.1, 147.9, 143.2, 137.4,
130.8, 130.5, 130.1, 128.7, 128.3, 128.2, 127.8, 124.8, 119.8,
HRMS (ESI): m/z [M+H]+ calcd for C15H10N3OS: 280.0539;
found: 280.0545.
2-(4-Nitrophenyl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aj)
1
Brown solid, m.p.: 238-241 °C, H-NMR (400 MHz, DMSO-
d6): δ (ppm) 8.60 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H),
8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8..0 Hz, 1H), 7.87-7.91 (dt,
J = 1.2, 8.4 Hz, 1H), 7.84 (dt, J = 2.4, 8.8 Hz, 2H), 7.71-7.75 (dt,
J = 1.2, 8.0 Hz, 1H), 6.76 (t, J = 1.2 Hz, 1H), 6.74 (t, J = 1.2 Hz,
1H), 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 165.9, 162.5,
152.7, 147.2, 143.2, 137.8, 130.8, 129.3, 128.5, 128.19, 128.18,
128.15, 119.5, 113.7, 109.2, HRMS (ESI): m/z [M+H]+ calcd for
C17H11N4O3: 319.0826; found: 319.0836.
(E)-2-(Quinolin-2-yl)-5-styryl-1,3,4-oxadiazole (3ap)

6
Tetrahedron
White solid, m.p.: 112-115 °C, 1H-NMR (400 MHz, CDCl3):
White solid, m.p.: 190-195 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.38 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.28-
8.29 (m, 1H), 8.27-8.28 (m, 1H), 8.25-8.26 (m, 1H), 7.83 (d, J =
8.8 Hz, 1H), 7.61 (d, J = 2,0 Hz, 1H), 7.58-7.59 (m, 1H), 7.56-
7.57 (m, 1H), 7.55-7.56 (m, 1H), 13C-NMR (100 MHz, CDCl3): δ
(ppm) 166.0, 163.9, 148.3, 144.3, 137.3, 136.6, 132.2, 129.3,
129.1, 129.0, 128.9, 127.5, 127.0, 123.5, 120.0. HRMS (ESI):
m/z [M+H]+ calcd for C17H11ClN3O: 308.0585; found: 308.0590.
δ (ppm) 8.08 (d, J = 8.8 Hz, 2H), 8.03 (dt, J = 1.2, 7.2 Hz, 1H),
7.94-7.97 (m, 7H), 7.77 (dt, J = 1.6, 8.4 Hz, 1H), 7.66-7.70 (dt, J
= 1.6, 8.8 Hz, 1H), 7.47-7.51 (dt, J = 1.2, 8.4 Hz, 1H), 13C-NMR
(100 MHz, CDCl3): δ (ppm) 154.6, 147.8, 142.9, 136.5, 136.1,
130.2, 129.8, 129.6, 129.0, 128.9, 127.9, 127.6, 127.5, 126.7,
126.5, 121.5, 117.7, HRMS (ESI): m/z [M+H]+ calcd for
C19H14N3O: 300.1131; found: 300.1139.
2-(Prop-1-en-2-yl)-5-(quinolin-2-yl)-1,3,4-oxadiazole (3aq)
2-(6-Bromoquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3fa)
1
White solid, m.p.: 87-91 °C, H-NMR (400 MHz, CDCl3): δ
White solid, m.p.: 206-209 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.39 (s, 1H), 8.37 (s，1H), 8.25 (s, 1H), 8.23-8.24 (m, 1H),
8.22 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H),
7.86 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 2.4 Hz, 1H), 7.54 (s, 1H),
13C-NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 146.5, 143.7,
136.4, 134.1, 132.2, 131.7, 129.9, 129.7, 129.1, 127.5, 123.5,
122.5, 120.7. HRMS (ESI): m/z [M+H]+ calcd for C17H11BrN3O:
352.0080; found: 352.0089.
(ppm) 9.44 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz,
2H), 8.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.71-7.75 (dt, J = 1.2,
8.0 Hz, 1H), 7.54-7.58 (dt, J = 1.2, 8.0 Hz, 1H), 2.44 (s, 3H), 13C-
NMR (100 MHz, CDCl3): δ (ppm) 173.4, 153.2, 148.0, 144.1,
136.6, 130.1, 129.4, 128.4, 127.8, 127.5, 117.6, 32.0, HRMS
(ESI): m/z [M+H]+ calcd for C14H12N3O: 238.0975; found:
238.0986.
2-Methyl-5-(quinolin-2-yl)-1,3,4-oxadiazole (3ar)
2-(6-Fluoroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ga)
1
White solid, m.p.: 200-205 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.40 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.29 (d, J = 8.0 Hz,
1H), 8.27 (t, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.57-7.59
(m, 1H), 7.57 (t, J = 2.4 Hz, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.51
(dd, J = 3.2, .8 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm)
165.9, 164.0, 162.7, 160.2, 145.1, 142.9, 136.8, 136.7, 132.8,
13.7, 132.1, 129.1, 127.5, 123.6, 121.1, 120.1, 120.6, 111.1,
110.8, HRMS (ESI): m/z [M+H]+ calcd for C17H11FN3O:
292.0881; found: 292.0889.
White solid, m.p.: 93-95 °C, H-NMR (400 MHz, CDCl3): δ
(ppm) 8.34 (s, 2H), 8.26 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz,
1H), 7.81 (dt, J = 1.2, 7.6 Hz, 1H), 7.65 (dt, J = 1.2, 8.0 Hz, 1H),
2.72 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.2, 164.4,
147.8, 143.4, 137.6, 130.6, 130.0, 128.7, 128.3, 127.8, 29.7.
HRMS (ESI): m/z [M+H]+ calcd for C12H10N3O: 212.0818; found:
212.0825.
2-(6-Methylquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ba)
White solid, m.p.: 175-180 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.31 (d, J = 8.4 Hz, 1H), 8.24-8.27 (m, 2H), 8.21 (d, J =
8.4 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H),
7.54-7.57 (m, 2H), 7.53-7.54 (m, 1H), 2.55 (s, 3H), 13C-NMR
(100 MHz, CDCl3): δ (ppm) 165.7, 164.3, 146.6, 142.5, 138.6,
136.6, 132.9, 132.0, 129.7, 129.0, 128.8, 127.4, 126.6, 123.7,
119.9, 21.7, HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O:
288.1131; found: 288.1140.
2-(Benzo[f]quinolin-3-yl)-5-phenyl-1,3,4-oxadiazole (3ha)
White solid, m.p.: 215-219 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.12 (d, J = 8.8 Hz, 1H), 8.67 (d, J = 9.2 Hz, 1H), 8.52 (d,
J = 8.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 2.8 Hz,
1H), 8.14 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.97 (dd,
J = 2.0, 8.0 Hz, 1H), 7.73 (dt, J = 1.6, 9.2 Hz, 1H), 7.53-7.59 (m,
4H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 165.8, 164.2, 148.2,
142.8, 132.2, 132.1, 132.03, 131.96, 129.2, 129.1, 128.9, 128.1,
127.6, 127.4, 126.6, 123.7, 123.1, 120.3, HRMS (ESI): m/z
[M+H]+ calcd for C21H14N3O: 324.1131; found: 324.1142.
2-(6-Methoxyquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ca)
1
White solid, m.p.: 191-193°C, H-NMR (400 MHz, CDCl3): δ
(ppm) 8.30 (d, J = 8.8 Hz, 1H), 8.24-8.26 (m, 2H), 8.17 (q, J =
8.4 Hz, 2H), 7.54-7.56 (m, 2H), 7.52-7.54 (m, 1H), 7.43 (dd, J =
2.8, 9.2 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 3.95 (s, 3H), 13C-NMR
(100 MHz, CDCl3): δ (ppm) 165.6, 164.3, 159.2, 144.1, 140.9,
135.8, 131.9, 131.6, 130.1, 129.0, 127.4, 123.7, 123.5, 120.2,
105.0, 55.7, HRMS (ESI): m/z [M+H]+ calcd for C18H14N3O2:
304.1081; found: 304.1090.
2-Phenyl-5-(quinolin-4-yl)-1,3,4-oxadiazole (3ia)
White solid, m.p.: 133-135 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.20 (d, J = 8.4 Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), 8.10-
8.15 (m, 3H), 7.96 (d, J = 4.4 Hz, 1H), 7.75 (dt, J = 1.2, 7.6 Hz,
1H), 7.66 (dt, J = 1.2, 7.6 Hz, 1H), 7.48-7.53 (m, 3H), 13C-NMR
(100 MHz, CDCl3): δ (ppm) 164.6, 162.7, 149.5, 148.8, 132.1,
130.0, 129.0, 128.4, 127.6, 127.0, 126.0, 123.6, 123.1, 120.2.
HRMS (ESI): m/z [M+H]+ calcd for C17H12N3O: 274.0975; found:
274.0979.
2-(6-Chloroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3da)
White solid, m.p.: 180-184 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.77 (s, 1H), 8.26-8.29 (m, 4H), 7.90 (s, 1H), 7.87 (s, 1H),
7.57-7.59 (m, 3H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 166.2,
162.7, 143.7, 143.0, 141.8, 138.6, 132.4, 131.8, 131.2, 130.0,
129.6, 129.2, 127.6, 123.3, HRMS (ESI): m/z [M+H]+ calcd for
C17H11ClN3O: 308.0585; found: 308.0592.
2-(Furan-2-yl)-5-(quinolin-4-yl)-1,3,4-oxadiazole (3in)
1
White solid, m.p.: 73-77 °C, H-NMR (400 MHz, CDCl3): δ
(ppm) 9.26 (d, J = 8.8 Hz, 1H), 9.07 (d, J = 8.8 Hz, 1H), 8.20 (d,
J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.82 (dt, J = 1.2, 8.4 Hz,
1H), 7.74 (dt, J = 1.2, 8.8 Hz, 1H), 7.71-7.72 (m, 1H), 7.33 (d, J
= 4.0 Hz, 1H), 6.65 (q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz,
CDCl3): δ (ppm) 162.2, 157.7, 149.7, 149.1, 146.3, 139.0, 130.3,
2-(7-Chloroquinolin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ea)

7
130.2, 128.7, 127.6, 126.2, 123.8, 120.5, 115.2, 112.5, HRMS
(ESI): m/z [M+H]+ calcd for C15H10N3O2: 264.0768; found:
264.0776.
(q, J = 2.0 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm)
163.1, 159.0, 155.6, 154.9, 146.4, 146.1, 139.2, 138.8, 137.0,
123.7, 123.5, 121.1, 115.6, 112.4, HRMS (ESI): m/z [M+H]+
calcd for C14H9N4O2: 265.0270; found: 265.0285.
2-(Quinolin-4-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3io)
2-(1,8-Naphthyridin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole
(3ko)
White solid, m.p.: 144-148 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.26 (dd, J = 1.2, 8.4 Hz, 1H), 9.08 (d, J = 4.4 Hz, 1H),
8.21 (dd, J = 2.0, 8.4 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.92 (dd,
J = 1.2, 3.6 Hz, 1H), 7.81 (dt, J = 1.2, 8.4 Hz, 1H), 7.74 (dt, J =
1.2, 8.8 Hz, 1H), 7.63 (dd, J = 1.2, 5.2 Hz, 1H), 7.23 (dd, J = 4.0,
4.8 Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 162.3, 161.2,
149.7, 149.1, 131.1, 130.6, 130.3, 130.2, 128.7, 128.4, 127.7,
126.2, 123.8, 120.4, HRMS (ESI): m/z [M+H]+ calcd for
C15H10N3OS: 280.0539; found: 280.0545.
1
White solid, m.p.: 75-80 °C, H-NMR (400 MHz, CDCl3): δ
(ppm) 9.23 (q, J = 2.0 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.40 (d,
J = 8.4 Hz, 1H), 8.29 (dd, J = 2.0, 8.4 Hz, 1H), 8.01 (dd, J = 1.2,
3.6 Hz, 1H), 7.59-7.62 (m, 2H), 7.22 (dd, J = 3.6, 8.8 Hz, 1H),
13C-NMR (100 MHz, CDCl3): δ (ppm) 163.3, 162.7, 155.7, 154.9,
146.3, 138.7, 137.0, 131.1, 128.4, 124.8, 123.6, 123.5, 121.1,
HRMS (ESI): m/z [M+H]+ calcd for C14H9N4OS: 281.0492;
found: 281.0499.
2-Phenyl-5-(quinoxalin-2-yl)-1,3,4-oxadiazole (3ja)
2-Phenyl-5-(pyridin-2-yl)-1,3,4-oxadiazole (3la)
White solid, m.p.: 210-214 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.41 (d, J = 8.4 Hz, 1H), 8.27-8.28 (br, 2H), 8.25-8.26 (m,
1H), 8.22 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.73-7.76
(dd, J = 2.4, 9.2 Hz, 1H), 7.57-7.58 (m, 2H), 7.55 (s, 1H), 13C-
NMR (100 MHz, CDCl3): δ (ppm) 166.0, 163.9, 146.4, 143.7,
136.5, 134.3, 132.2, 131.7, 131.6, 129.2, 129.1, 127.5, 126.5,
123.5, 120.8, HRMS (ESI): m/z [M+H]+ calcd for C16H11N4O:
275.0927; found: 275.0934.
1
White solid, m.p.: 121-124 °C, H-NMR (400 MHz, CDCl3): δ
(ppm) 8.81 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.31 (dt, J = 8.0, 1.2
Hz, 1H), 8.24-8.18 (m, 2H), 7.90 (td, J = 7.6, 1.6 Hz, 1H), 7.59-
7.50 (m, 3H), 7.47 (ddd, J = 6.0, 3.6, 1.2 Hz, 1H).13C-NMR (100
MHz, CDCl3): δ (ppm) 165.5, 163.8, 150.3, 143.6, 137.2, 132.0,
129.0, 127.3, 125.8, 123.5, 123.2, 123.2. HRMS (ESI): m/z
[M+H]+ calcd for C13H10N3O: 224.1808; found: 224.1817.
2-(Furan-2-yl)-5-(quinoxalin-2-yl)-1,3,4-oxadiazole (3jn)
2-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazole (3ma)
1
White solid, m.p.: 200-204 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.74 (s, 2H), 8.17-8.27 (m, 1H), 7.85-7.88 (m, 2H), 7.72 (q,
J = 1.2 Hz, 1H), 7.40 (dd, J = 0.8, 3.6 Hz, 1H), 6.65 (q, J = 2.0
Hz, 1H), 13C-NMR (100 MHz, CDCl3): δ (ppm) 161.9, 158.8,
146.5, 143.7, 143.0, 141.8, 138.9, 138.3, 131.9, 131.3, 130.0,
129.6, 115.7, 112.5, HRMS (ESI): m/z [M+H]+ calcd for
C14H9N4O2: 265.0720; found: 265.0733.
White solid, m.p.: 145-147 °C, H-NMR (400 MHz, CDCl3): δ
(ppm) 8.86-8.78 (m, 2H), 8.18-8.10 (m, 2H), 8.03-7.92 (m, 2H),
7.62-7.55 (m, 2H), 7.55-7.51 (m, 1H). 13C-NMR (100 MHz,
CDCl3): δ (ppm) 165.4, 162.72, 150.9, 132.2, 131.0, 129.2, 127.1,
123.31, 120.3. HRMS (ESI): m/z [M+H]+ calcd for C13H10N3O:
224.1808; found: 224.1819.
Acknowledgments
2-(Quinoxalin-2-yl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3jo)
This work was supported by the National Natural Science
Foundation of China (21702091) and Key Research & Development
Project of Shandong Province (2018GGX109014). This work was
also supported by Yantai “Double Hundred Plan” and Talent
Induction Program for Youth Innovation Teams in Colleges and
Universities of Shandong Province. The College Students Innovation
and Entrepreneurship Training Program of Shandong Province
(201911066033) are gratefully acknowledged (for J.-N. Sun). The
laboratory open project of Yantai University are gratefully
acknowledged (for Z.-J. Li and Z.-X. Zhang).
White solid, m.p.: 267-269 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.75 (s, 1H), 8.26-8.29 (m, 1H), 8.19-8.22 (m, 1H), 8.01
(dd, J = 0.8, 3.6 Hz, 1H), 7.87-7.90 (m, 2H), 7.64 (dd, J = 1.2,
5.2 Hz, 1H), 7.23 (d, J = 4.2 Hz, 1H), 13C-NMR (100 MHz,
CDCl3): δ (ppm) 162.5, 162.1, 143.7, 143.0, 141.8, 138.4, 131.8,
131.3, 131.2, 130.0, 129.6, 128.4, 124.5, HRMS (ESI): m/z
[M+H]+ calcd for C14H9N4OS: 281.0492; found: 281.0499.
2-(1,8-Naphthyridin-2-yl)-5-phenyl-1,3,4-oxadiazole (3ka)
Supplementary data
White solid, m.p.: 217-220 °C, 1H-NMR (400 MHz, CDCl3): δ
(ppm) 9.23 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz,
1H), 8.30 (d, J = 7.2 Hz, 3H), 7.55-7.62 (m, 4H), 13C-NMR (100
MHz, CDCl3): δ (ppm) 166.3, 163.8, 155.6, 154.8, 146.4, 138.7,
137.0, 132.2, 129.1, 129.0, 127.5, 123.4, 121.0. HRMS (ESI):
m/z [M+H]+ calcd for C16H11N4O: 275.0927; found: 275.0938.
Supplementary data related to this article can be found online at
doi:
References and notes
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·Metal-free approach for oxidation of sp3 C-H bond of
methyl-azaheteroarenes.
·This protocol enables furan, quinoline and oxadiazole containing
multiheterocyclic scaffolds in the presence of I2-DMSO.
·The reaction has a broad substrate scope and good functional group
tolerance for methyl-azaheteroarenes and hydrazides.
·This protocol presents a gram scaled-up synthesis.

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships
√
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: