Iodine-Mediated Domino Oxidative Cyclization: One-Pot Synthesis of 1,3,4-Oxadiazoles via Oxidative Cleavage of C(sp2)-H or C(sp)-H Bond

Article abstract of DOI:10.1021/acs.joc.6b01135

An I₂-promoted, metal-free domino protocol for one-pot synthesis of 1,3,4-oxadiazoles has been developed via oxidative cleavage of C(sp²)-H or C(sp)-H bonds, followed by cyclization and deacylation. In this reaction, the use of K₂CO₃ as a base is found to be an essential factor in the cyclization and the C-C bond cleavage. This procedure proceeded smoothly in moderate to high yields with good functional group compatibility.

Full text of DOI:10.1021/acs.joc.6b01135

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Note
Iodine-mediated Domino Oxidative Cyclization: One-pot Synthesis of
1,3,4-Oxadiazoles via Oxidative Cleavage of Csp2-H orCsp-H Bond
Yuxing Fan, Yongqin He, Xingxing Liu, Ting Hu, Haojie
Ma, Xiaodong Yang, Xinliang Luo, and Guosheng Huang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
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Iodine-mediated Domino Oxidative Cyclization: One-pot Synthesis of
1,3,4-Oxadiazoles via Oxidative Cleavage of C(sp2)-H or C(sp)-H
Bond
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Yuxing Fan, Yongqin He, Xingxing Liu, Ting Hu, Haojie Ma, Xiaodong Yang,
Xinliang Luo and Guosheng Huang*
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Stake Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou,
730000, P. R. China, and Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, Lanzhou, 730000, P. R. China.
Fax: 0931ꢀ8912596 Eꢀmail: hgs@lzu.edu.cn
Abstract: An I2 promoted, metalꢀfree domino protocol for oneꢀpot
synthesis of 1,3,4ꢀoxadiazoles has been developed via oxidative cleavage
of C(sp2)ꢀH or C(sp)ꢀH bond, followed by cyclization and deacylation. In
this reaction, the use of K2CO3 as a base is found to be an essential factor
in the cyclization and the CꢀC bond cleavage. This procedure proceeded
smoothly in moderate to high yields with good functionalꢀgroup
compatibility.
Domino strategy, due to its applicability to various types of reactions
like radical,1 pericyclic,2 photochemical,3 and transition metalꢀmediated4
reaction, has been extensively examined for the synthesis of organic
compounds in modern synthetic chemistry.5 In the past decade,
significant progress has been achieved in developing domino reactions.
For example, Jiang and coꢀworkers have developed a series of domino
protocols to construct heterocycle compounds.6 Wu’s group have
successfully led to various different compounds by the use of the
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multiplicative effect of a coupled domino strategy.7 In addition, the
efficiency and significance of domino strategy for one pot synthesis of
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2ꢀacylbenzothiazoles
from
multiform
substrates
were
also
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demonstrated.7b Inspired by these studies, we present a route through
domino cyclization for the formation of 1,3,4ꢀoxadiazoles using simple
and commercially available reagents via oxidative cleavage of C(sp2)ꢀH
or C(sp)ꢀH bond.
1,3,4ꢀoxadiazoles are nonꢀnaturally occurring fiveꢀmembered aromatic
heterocycles which have been widely used in many compounds with
biological and pharmaceutical activities,8 such as antifungal, antiviral,
and antibacterial properties.9 Consequently, a number of methods have
been reported for the synthesis of the 1,3,4ꢀoxadiazoles skeleton via
oxidative cyclization of Nꢀacylhydrazones10 or the dehydrative cyclization
of 1,2ꢀdiacylhydrazines.11 In 2013, Chang’s group described an
I2ꢀmediated oxidative CꢀO bond formation for the synthesis of
1,3,4ꢀoxadiazoles from aldehydes and hydrazides (Scheme 1, a).9
Subsequently, Wu’s group demonstrated a direct annulation of hydrazides
to 1,3,4ꢀoxadiazoles via oxidative C(CO)ꢀC(Methyl) bond cleavage of
methyl ketones (Scheme 1, b),12 where a wide range of ketones and
hydrazides were used as substrates, showing good functional group
tolerance and high selectivity. Furthermore, Cuꢀcatalyzed decarboxylative
coupling domino reaction for the formation of 2ꢀ(1,3,4ꢀoxadiazolꢀ2ꢀyl)
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anilines derivatives13 was disclosed. However, to our knowledge,
I2ꢀmediated oxidative cyclization for the synthesis of 1,3,4ꢀoxadiazoles
from hydrazides and styrene or phenyl acetylene has not yet been
reported. Herein, we choose hydrazides and styrene or phenyl acetylene
derivatives as the substrates to synthesize 1,3,4ꢀoxadiazoles in the
presence of O2 as the oxidant and K2CO3 as the base, achieving the
desired products in moderate to good yields.
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Scheme 1. Synthetic approaches to 1,3,4-oxadiazoles
Initial investigation was conducted by employing reaction of 2a (0.2
mmol) with 1a (0.6 mmol) in the presence of I2 (0.5 mmol), and K2CO3
o
(0.6 mmol) in DMSO (2.0 mL) under air at 120 C for 8 h, resulting in
6% yield of 3aa (Table 1, entry 1). To identify the appropriate conditions
for the reaction, firstly, various oxidants were examined, such as TBHP,
DDQ, IBX, PhI(OAc)2, and dioxygen (1 atm). These results illustrated
that dioxygen displayed the best ability in this transformation, and a 34%
yield of 3aa was obtained (Table 1, entries 2ꢀ6). Meanwhile, the yield of
side product 4aa was also increased to 50% when dioxygen (1 atm) was
used as the oxidant. In order to improve the yield of 3aa, different bases
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were tested, including K2CO3, NaOH, tꢀBuOK, K3PO4, Cs2CO3, and
NaHCO3. The results promoted us to use K2CO3 to conduct this reaction
(Table 1, entries 6ꢀ11). After screening the amount of K2CO3, we found
that the substrate showed the highest activity for this process when 6.0
equiv K2CO3 was added, affording 3aa in 85% yield (Table 1, entry 16).
Then different solvents were also evaluated for this conversion, and
DMSO effectively facilitated the reaction. Additionally, changing the
amount of iodine did not give better result (Table 1, entries 19ꢀ23).
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Table 1. Optimization of the Reaction Conditionsa
O
O
O
O
N
N
NH2
N
N
N
conditions
+
+
H
3aa
1a
2a
4aa
Entry
1c
Oxidant
ꢀ
I2 (equiv)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.5
1.0
1.5
2.0
Base (equiv)
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield3aab/4aa (%)
6/38
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
NaOH(3.0)
tꢀBuOK(3.0)
K3PO4(3.0)
Cs2CO3(3.0)
NaHCO3(3.0)
K2CO3(1.0)
K2CO3(2.0)
K2CO3(4.0)
K2CO3(5.0)
K2CO3(6.0)
K2CO3(6.0)
K2CO3(6.0)
K2CO3(6.0)
K2CO3(6.0)
K2CO3(6.0)
K2CO3(6.0)
2d
TBHP
DDQ
IBX
17/40
0/10
3d
4d
10/34
7/38
5d
PhI(OAc)2
O2
6
34/50
0/0
7
O2
8
O2
0/0
9
O2
21/65
27/40
0/7
10
11
12
13
14
15
16
17
18
19
20
21
22
O2
O2
O2
0/0
O2
5/50
O2
68/0
O2
75/0
O2
O2
85/0
0/0
O2
Toluene
DMSO
DMSO
DMSO
DMSO
0/0
O2
0/0
O2
0/0
O2
41/6
O2
51/8
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O2
3.0
K2CO3(6.0)
DMSO
68/6
aReaction conditions: 1a (0.6 mmol), 2a (0.2 mmol) in DMSO (2.0 mL) at 120 oC for 8 h. Dioxygen (1
atm) was used. bYields of isolated products. cOpen air. dOxidant (1.5 equiv). TBHP
=
6
7
terbutylhydroperoxide (5.0ꢀ6.0 M in decane), DDQ = 2,3ꢀdichloroꢀ5,6ꢀdicyanobenzoquinone, IBX =
2ꢀiodoxybenzoic acid, DMSO = demethyl sulfoxide, DMF = N,Nꢀdimethyl formamide.
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With the optimized conditions in hand, the reaction scope was tested
using styrene (1a) with different hydrazides (Table 2). A variety of
hydrazides proceeded smoothly to afford the corresponding products in
moderate to high yields (31ꢀ90%). Various functional groups on the aryl
ring of the hydrazides demonstrated that both electronꢀwithdrawing and
electronꢀdonating groups, including methyl, tertꢀbutyl, methoxy,
3,4ꢀmethylenedioxy, fluoro, chloro and bromo, were compatible well
with this reaction (3aa-3am). 2ꢀNaphthyl hydrazine also exhibited good
reactivity to give the desired product (3an) in 77% yield. Moreover,
heteroaryl hydrazides like furanyl and thienyl hydrazides could undergo
the tandem reaction smoothly to receive the expected products 3ao and
3ap in 48% and 72% yields. Unexpectedly, when we used pyridyl
hydrazide as the substrate, the desired product 3aq was not detected, but
the undeacylative byꢀproduct 4ab was obtained in 45% yield. In addition,
alkyl hydrazides, such as acetohydrazide and valeric acid hydrazide, were
also investigated. However, only the acetohydrazide could proceed to
afford the undeacylative product 4ac in 27% yield; the substrate of
valetric acid hydrazide was failed to accomplish this reaction (3as and
4ad).
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Subsequently, we explored the limitations of different hydrazides
reacting with phenyl acetylene (1b). As expected, we were pleased to find
that the reaction of 1b with a range of hydrazides transformed well under
the optimized conditions to give the corresponding 1,3,4ꢀoxadiazoles
products (Table 2, 3ba-3bp) in 40ꢀ83% yields. Disappointedly, pyridyl
hydrazide, acetohydrazide and valeric acid hydrazide did not give desired
products (3bq-3bs).
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Table 2. Synthesis of 1,3,4-oxadiazoles from styrene or phenyl acetylene and
hydrazidesa
O
I2 (2.5 equiv)
O
NH2
K2CO3 (6.0 equiv)
O2, DMSO, 120 oC, 8 h
or
N
+
R
N
H
N
R
1a
2a
1b
3a/3b
aReaction conditions: 2a (0.2 mmol), 1a or 1b (0.6 mmol), I2 (0.5 mmol) and K2CO3 (1.2 mmol) in DMSO (2.0
mL) at 120 oC under dioxygen (1 atm) for 8 h.
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To further expand the scope of the substrates, various styrene and
phenyl acetylene derivatives were carried out under the standard
conditions. As shown in Table 3, the results indicated that substituents at
different positions of the aryl ring did not affect the efficiency obviously.
Further studies proved that either electronꢀwithdrawing or
electron–donating groups of 1a and 1b all can be converted to the
corresponding products in moderate to good yields (35ꢀ86%).
Vinylnaphthalene was also tolerated in this transformation to produce the
desired 2ꢀphenylꢀ1,3,4ꢀoxadiazole in 82% yield.
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Table 3. Synthesis of 2-phenyl-1,3,4-oxadiazole from various styrene or phenyl
acetylene and benzoylhydrazidea
O
O
N
I2 (2.5 equiv)
NH2
N
N
K2CO3 (6.0 equiv)
O2, DMSO, 120 oC, 8 h
R1
or R2
+
H
1
1
2a
3aa/3ba
aReaction conditions: 2a (0.2 mmol), 1a or 1b (0.6 mmol), I2 (0.5 mmol) and K2CO3 (1.2 mmol) in DMSO (2.0 mL)
at 120 oC under dioxygen (1 atm) for 8 h.
On the basis of the above results and literature reports,5a,9,12,14 the
proposed mechanism for the synthesis of 1,3,4ꢀoxadiazoles is outlined in
Scheme 2. Using 1a or 1b and 2a as model substrates, initially, 1a or 1b
is converted into phenacyl iodide (A)5a,12,14 through consecutive
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iodination and oxidation under I2/O2, then A is further converted into
phenylglyoxal (B)5a,12,14 by a subsequent Kornblum oxidation in DMSO.7b
Benzoylhydrazide (2a) reacts with B to generate the Cꢀacyl
benzoylhydrazone (C).12 Subsequently, K2CO3ꢀpromoted oxidative
iodination of C gives an iodide intermediate D,9,12 which would be
converted to E via a SN2´ꢀtype9,12 cyclization, with a new CꢀO bond
formed. Consequently, 4aa/4ba is formed through subsequent
deprotonation by base.9 Finally, 4aa/4ba would go through deacylation to
generate the product 3aa/3ba with the aid of K2CO3.12
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Scheme 2. Possible mechanism
O
O
I
H
I2/O2
DMSO
HI +
or
O
S
1a
1b
A
B
O
NH2
Ph
N
H
2a
O
O
O
O
O
N
N
O
N
H
Ph
N
Ph I2, K2CO3
H
N
I
N
D
C
E
K2CO3
CO2
O
O
COOK
O
OK
O
O
N
O
N
N
N
K2CO3
3aa/3ba
4aa/4ba
In summary, we have developed an I2ꢀmediated direct oxidative
cyclization reaction for the synthesis of substituted 1,3,4ꢀoxadiazoles in a
oneꢀpot manner. This procedure employs dioxygen as oxidant and K2CO3
as base. In addition, K2CO3 plays an important role in the cyclization and
deacylation. This reaction system has broad substrates scope, providing a
facile pathway for the synthesis of 1,3,4ꢀoxadiazoles.
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Experimental Section
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General remarks. 1H NMR spectra were obtained at 400 MHz in CDCl3
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13
with tetramethylsilane (δ = 0.00 ppm) as an internal standard. C NMR
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spectra were recorded at 100 MHz and were calibrated with CDCl3 (δ =
77.00 ppm). The highꢀresolution mass spectra (HRMS) were recorded on
an FTꢀICR mass spectrometer using electrospray ionization (ESI). The
HRMS data and melting points for the same compounds that have been
prepared by two methods were obtained only by the samples of 3aa-3ap
and 4aa-4ac. Products were purified by flash chromatogrgraphy on
200ꢀ300 mesh silica gels. All melting points were determined without
correction. Unless otherwise noted, commercially reagents were used
without further purification.
General procedure for the synthesis of 3 (3aa/3ba as an example)
A test tube was charged with styrene or phenyl acetylene (0.6 mmol), I2
(0.5 mmol) in DMSO (2.0 mL). The mixture was stirred at 120 oC for 6 h
under 1 atm of dioxygen. After disappearance of the reactant, then added
benzoylhydrazide (0.2 mmol), K2CO3 (1.2 mmol), and the mixture was
o
heated at 120 C for 2 h under 1 atm of dioxygen. Upon completion, the
mixture was diluted with water and extracted with EtOAc (3×20 mL).
The extract was washed with 10% Na2S2O3 solution (w/w), dried over
anhydrous Na2SO4 and evaporation. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc = 5:1) to yield the
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desired product 3aa/3ba.
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2-phenyl-1,3,4-oxadiazole (3aa). Yellow solid. Yield 85% (24.8 mg). m.
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o
o
p. 33ꢀ34 C (lit.15 m. p. 34ꢀ36 C); 1H NMR (400 MHz, CDCl3): δ = 8.50
(s, 1H), 8.11 – 8.07 (m, 2H), 7.59 – 7.50 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ = 164.7, 152.6, 132.0, 129.1, 127.0, 123.4. HRMS (ESI) (m/z)
calcd for C8H6N2O [M+H]+ 147.0553; found 147.0556.
2-(4-(tert-butyl)phenyl)-1,3,4-oxadiazole (3ab). Light yellow solid.
Yield 72% (29.1 mg). m. p. 95ꢀ98 oC (lit.12 m. p. 94ꢀ97 oC); 1H NMR (400
MHz, CDCl3): δ = 8.46 (s, 1H), 8.04 – 8.00 (m, 2H), 7.56 – 7.53 (m, 2H),
1.36 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 164.8, 155.6, 152.4, 126.9,
126.1, 120.6, 35.0, 31.1. HRMS (ESI) (m/z) calcd for C12H14N2O [M+H]+
203.1179; found 203.1181.
2-(p-tolyl)-1,3,4-oxadiazole (3ac). Light yellow solid. Yield 63% (20.2
mg). m. p. 148ꢀ150 C (lit.12 m. p. 149ꢀ151 C); 1H NMR (400 MHz,
o
o
CDCl3): δ = 8.46 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 8.0, 0.5
13
Hz, 2H), 2.43 (s, 3H); C NMR (100 MHz, CDCl3): δ = 164.8, 152.3,
142.5, 129.7, 126.9, 120.6, 21.6. HRMS (ESI) (m/z) calcd for C9H8N2O
[M+H]+ 161.0746; found 161.0748.
2-(m-tolyl)-1,3,4-oxadiazole (3ad). Yellow oil. Yield 82% (26.2 mg). 1H
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NMR (400 MHz, CDCl3): δ = 8.48 (s, 1H), 7.92 (s, 1H), 7.88 (d, J = 7.4
Hz, 1H), 7.44 – 7.35 (m, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 164.9, 152.5, 139.0, 132.8, 129.0, 127.6, 124.2, 123.3, 21.3. HRMS
(ESI) (m/z) calcd for C9H8N2O [M+H]+ 161.0746; found 161.0747.
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2-(o-tolyl)-1,3,4-oxadiazole (3ae). Yellow oil. Yield 90% (28.8 mg). H
NMR (400 MHz, CDCl3): δ = 8.51 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.43
13
(t, J = 7.4 Hz, 1H), 7.34 (dd, J = 13.1, 7.0 Hz, 2H), 2.72 (s, 3H); C
NMR (100 MHz, CDCl3): δ = 164.8, 152.2, 138.5, 131.7, 131.4, 129.0,
126.1, 122.5, 22.0. HRMS (ESI) (m/z) calcd for C9H8N2O [M+H]+
161.0746; found 161.0749.
2-(4-methoxyphenyl)-1,3,4-oxadiazole (3af). Yellow solid. Yield 60%
o
o
(21.1 mg). m. p. 55ꢀ57 C (lit.16 m. p. 61ꢀ62 C); 1H NMR (400 MHz,
CDCl3): δ = 8.43 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz,
2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.6, 162.4, 152.1,
128.8, 115.9, 114.5, 55.4. HRMS (ESI) (m/z) calcd for C9H8N2O2 [M+H]+
177.0659; found 177.0661.
2-(3-methoxyphenyl)-1,3,4-oxadiazole (3ag). Light yellow solid. Yield
74% (26.0 mg). m. p. 105ꢀ107 oC (lit.12 m. p. 105ꢀ107 oC); 1H NMR (400
MHz, CDCl3): δ 8.48 (s, 1H), 7.66 – 7.60 (m, 2H), 7.42 (t, J = 8.0 Hz,
1H), 7.09 (dd, J = 8.3, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz,
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CDCl3): δ = 164.6, 159.9, 152.6, 130.2, 124.5, 119.4, 118.4, 111.7, 55.4.
HRMS (ESI) (m/z) calcd for C9H8N2O2 [M+H]+ 177.0659; found
177.0660.
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2-(2-methoxyphenyl)-1,3,4-oxadiazole (3ah). Light yellow solid. Yield
31% (11.0 mg). m. p. 50ꢀ52 oC (lit.12 m. p. 49ꢀ51 oC); 1H NMR (400 MHz,
CDCl3): δ 8.51 (s, 1H), 7.96 (dd, J = 7.8, 1.7 Hz, 1H), 7.56 – 7.51 (m,
1H), 7.10 (dd, J = 12.2, 4.6 Hz, 2H), 3.98 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 163.4, 157.8, 152.4, 133.3, 130.5, 120.7, 112.4, 111.9, 55.9.
HRMS (ESI) (m/z) calcd for C9H8N2O2 [M+H]+ 177.0659; found
177.0662.
2-(benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazole (3ai). Light yellow solid.
Yield 45% (17.0 mg). m. p. 146ꢀ148 oC (lit.12 m. p. 147ꢀ149 oC); 1H NMR
(400 MHz, CDCl3): δ = 8.43 (s, 1H), 7.63 (dd, J = 8.1, 1.7 Hz, 1H), 7.53
(d, J = 1.5 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H); 13C NMR (100
MHz, CDCl3): δ = 164.5, 152.2, 150.8, 148.3, 122.2, 117.2, 108.9, 107.1,
101.9. HRMS (ESI) (m/z) calcd for C9H6N2O3 [M+H]+ 191.0451; found
191.0453.
2-(4-fluorophenyl)-1,3,4-oxadiazole (3aj). Light yellow solid. Yield
o
o
61% (20.0 mg). m. p. 72ꢀ74 C (lit.17 m. p. 121.0ꢀ122.0 C); 1H NMR
(400 MHz, CDCl3): δ = 8.48 (s, 1H), 8.11 (dd, J = 8.9, 5.2 Hz, 2H), 7.23
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(t, J = 8.6 Hz, 2H); C NMR (100 MHz, CDCl3): δ = 165.1 (d, J = 223
Hz), 152.6, 129.4 (d, J = 8.9 Hz), 119.9 (d, J = 3.3 Hz), 116.6, 116.4.
HRMS (ESI) (m/z) calcd for C8H5FN2O [M+H]+ 165.0459; found
165.0460.
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2-(4-chlorophenyl)-1,3,4-oxadiazole (3ak). Light yellow solid. Yield
58% (20.9 mg). m. p. 134ꢀ136 C (lit.16 134ꢀ135 oC); 1H NMR (400 MHz,
o
CDCl3): δ = 8.51 (s, 1H), 8.03 (dd, J = 8.6, 2.0 Hz, 2H), 7.51 (dd, J = 8.6,
1.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 163.9, 152.7, 138.2, 129.4,
128.3, 121.8. HRMS (ESI) (m/z) calcd for C8H5ClN2O [M+H]+ 181.0163;
found 181.0166.
2-(3-chlorophenyl)-1,3,4-oxadiazole (3al). Light yellow solid. Yield
69% (24.8 mg). m. p. 79ꢀ82 C (lit.18 115.3 C); 1H NMR (400 MHz,
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CDCl3): δ = 8.51 (s, 1H), 8.09 (d, J = 1.4 Hz, 1H), 7.99 (dd, J = 7.7, 1.1
13
Hz, 1H), 7.54 (dd, J = 5.0, 3.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H); C
NMR (100 MHz, CDCl3): δ = 163.6, 152.8, 135.2, 132.1, 130.5, 127.1,
125.2, 125.0. HRMS (ESI) (m/z) calcd for C8H5ClN2O [M+H]+ 181.0163;
found 181.0167.
2-(4-bromophenyl)-1,3,4-oxadiazole (3am). Light yellow solid. Yield
71% (32.0 mg). m. p. 139ꢀ142 C (lit.12 m. p. 140ꢀ143 C);1H NMR (400
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MHz, CDCl3): δ = 8.51 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6
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Hz, 2H); C NMR (100 MHz, CDCl3): δ = 164.0, 152.7, 132.4, 128.4,
126.7, 122.2. HRMS (ESI) (m/z) calcd for C8H5BrN2O [M+H]+ 224.9658;
found 224.9662.
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2-(naphthalen-2-yl)-1,3,4-oxadiazole (3an). Light yellow solid. Yield
77% (30.2 mg). m. p. 58ꢀ60 oC (lit.19 m. p. 60ꢀ62 oC); 1H NMR (400 MHz,
CDCl3): δ = 8.57 (s, 1H), 8.52 (s, 1H), 8.16 – 8.12 (m, 1H), 7.95 (dd, J =
7.0, 4.5 Hz, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.62 – 7.54 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ = 164.9, 152.6, 134.7, 132.7, 129.0, 128.8, 128.0,
127.9, 127.6, 127.1, 123.1, 120.6. HRMS (ESI) (m/z) calcd for C12H8N2O
[M+H]+ 197.0710; found 197.0714.
2-(furan-2-yl)-1,3,4-oxadiazole (3ao). Yellow oil. Yield 48% (13.0 mg).
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1H), 7.68 (d, J = 1.0 Hz, 1H),
7.22 (d, J = 3.5 Hz, 1H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ = 157.5, 151.8, 146.0, 139.0, 114.6, 112.2. HRMS (ESI)
(m/z) calcd for C6H4N2O2 [M+H]+ 137.0346; found 137.0349.
2-(thiophen-2-yl)-1,3,4-oxadiazole (3ap). Yellow solid. Yield 72% (21.9
o
o
mg). m. p. 150ꢀ152 C (lit.12 m. p. 151ꢀ154 C); 1H NMR (400 MHz,
CDCl3): δ = 8.45 (s, 1H), 7.80 (dd, J = 2.9, 2.0 Hz, 1H), 7.59 (dd, J = 5.0,
13
1.2 Hz, 1H), 7.19 (ddd, J = 5.1, 3.7, 1.6 Hz, 1H); C NMR (100 MHz,
CDCl3): δ = 160.9, 151.9, 130.5, 130.1, 128.1, 124.5. HRMS (ESI) (m/z)
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calcd for C6H4N2OS [M+H]+ 153.0117; found 153.0119.
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Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (4aa). Light yellow
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solid. Yield 65% (33.0 mg). m. p. 95ꢀ97 C (lit.12 m. p. 95ꢀ97 C); H
NMR (400 MHz, CDCl3): δ = 8.62 – 8.55 (m, 2H), 8.28 – 8.20 (m, 2H),
7.72 (dd, J = 10.5, 4.3 Hz, 1H), 7.65 – 7.54 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ = 177.6, 166.0, 160.9, 134.9, 134.3, 132.9, 130.9, 129.2, 128.8,
127.8, 122.8. HRMS (ESI) (m/z) calcd for C15H10N2O2 [M+H]+ 251.0815;
found 251.0819.
Phenyl(5-(pyridine-4-yl)-1,3,4-oxadiazol-2-yl)methanone (4ab). Light
yellow solid. Yield 45% (23.0 mg). m. p. 148ꢀ150 oC (lit.12 m. p. 148ꢀ151
oC); H NMR (400 MHz, CDCl3): δ = 8.89 (d, J = 5.9 Hz, 2H), 8.60 –
1
8.54 (m, 2H), 8.07 (dd, J = 4.5, 1.5 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.59
(t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 177.2, 164.0, 161.2,
151.0, 135.2, 133.9, 130.9, 130.0, 128.9, 120.9. HRMS (ESI) (m/z) calcd
for C14H9N3O2 [M+H]+ 252.0732; found 252.0736.
(5-methyl-1,3,4-oxadiazol-2-yl)(phenyl)methanone (4ac). Brown solid.
Yield 27% (10.0 mg). m. p. 107ꢀ109 oC (lit.12 m. p. 106ꢀ109 oC); 1H NMR
(400 MHz, CDCl3): δ = 8.53 (d, J = 7.4 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H),
7.56 (t, J = 7.8 Hz, 2H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
177.6, 165.7, 161.4, 134.8, 134.0, 130.9, 128.7, 11.1. HRMS (ESI) (m/z)
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calcd for C10H8N2O2 [M+H]+ 189.0659; found 189.0660.
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2-phenyl-1,3,4-oxadiazole (3ba). Yellow solid. Yield 75% (21.9 mg). m.
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p. 33ꢀ34 C; 1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1H), 8.09 (dd, J =
8.1, 1.6 Hz, 2H), 7.58 – 7.51 (m, 3H). 13C NMR (100 MHz, CDCl3): δ =
164.8, 152.6, 132.0, 129.1, 127.1, 123.5. HRMS (ESI) (m/z) calcd for
C8H6N2O [M+H]+ 147.0553; found 147.0556.
2-(4-(tert-butyl)phenyl)-1,3,4-oxadiazole (3bb). Light yellow solid.
Yield 75% (30.3 mg). m. p. 95ꢀ98 C; 1H NMR (400 MHz, CDCl3): δ =
o
8.45 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 1.36 (s,
9H). 13C NMR (100 MHz, CDCl3): δ = 164.8, 155.6, 152.4, 126.9, 126.1,
120.7, 35.1, 31.1. HRMS (ESI) (m/z) calcd for C12H14N2O [M+H]+
203.1179; found 203.1181.
2-(p-tolyl)-1,3,4-oxadiazole (3bc). Light yellow solid. Yield 75% (24.0
mg). m. p. 148ꢀ150 C; 1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1H),
o
7.96 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 164.8, 152.3, 142.5, 129.7, 127.0, 120.7, 21.6.
HRMS (ESI) (m/z) calcd for C9H8N2O [M+H]+ 161.0746; found
161.0748.
2-(m-tolyl)-1,3,4-oxadiazole (3bd)
Yellow oil. Yield 75% (24.0 mg). 1H
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NMR (400 MHz, CDCl3): δ = 8.46 (s, 1H), 7.92 (s, 1H), 7.87 (d, J = 7.4
Hz, 1H), 7.43 – 7.34 (m, 2H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ = 164.9, 152.5, 139.0, 132.8, 129.0, 127.6, 124.2, 123.3, 21.3. HRMS
(ESI) (m/z) calcd for C9H8N2O [M+H]+ 161.0746; found 161.0747.
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2-(o-tolyl)-1,3,4-oxadiazole (3be)
Yellow oil. Yield 81% (25.9 mg).1H
.
NMR (400 MHz, CDCl3): δ = 8.50 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.43
(dd, J = 10.8, 4.2 Hz, 1H), 7.34 (dd, J = 13.6, 7.2 Hz, 2H), 2.72 (s, 3H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 152.2, 138.6, 131.7, 131.4,
129.1, 126.2, 122.6, 22.0. HRMS (ESI) (m/z) calcd for C9H8N2O [M+H]+
161.0746; found 161.0749.
2-(4-methoxyphenyl)-1,3,4-oxadiazole (3bf) Yellow solid. Yield 71%
.
(25.0 mg). m. p. 55ꢀ57 oC; 1H NMR (400 MHz, CDCl3): δ = 8.43 (s, 1H),
8.02 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 164.6, 162.4, 152.1, 128.8, 115.9, 114.5, 55.4.
HRMS (ESI) (m/z) calcd for C9H8N2O2 [M+H]+ 177.0659; found
177.0661.
2-(3-methoxyphenyl)-1,3,4-oxadiazole (3bg). Light yellow solid. Yield
o
60% (21.1 mg). m. p. 105ꢀ107 C; 1H NMR (400 MHz, CDCl3): δ = 8.48
(s, 1H), 7.66 – 7.60 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.11 – 7.07 (m, 1H),
3.88 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 164.6, 159.9, 152.6, 130.2,
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124.5, 119.4, 118.4, 111.7, 55.4. HRMS (ESI) (m/z) calcd for C9H8N2O2
[M+H]+ 177.0659; found 177.0660.
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2-(2-methoxyphenyl)-1,3,4-oxadiazole (3bh). Light yellow solid. Yield
40% (14.1 mg). m. p. 50ꢀ52 oC; 1H NMR (400 MHz, CDCl3): δ = 8.49 (s,
1H), 7.96 (d, J = 7.7 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.09 (t, J = 8.1 Hz,
2H), 3.97 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 163.4, 157.8, 152.4,
133.3, 130.5, 120.7, 112.4, 111.9, 55.9. HRMS (ESI) (m/z) calcd for
C9H8N2O2 [M+H]+ 177.0659; found 177.0662.
2-(benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazole (3bi). Light yellow solid.
Yield 68% (25.6 mg). m. p. 146ꢀ148 oC; 1H NMR (400 MHz, CDCl3): δ =
8.43 (s, 1H), 7.62 (dd, J = 8.2, 1.7 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 6.92
(d, J = 8.2 Hz, 1H), 6.07 (s, 2H). 13C NMR (100 MHz, CDCl3): δ = 164.4,
152.2, 150.8, 148.3, 122.2, 117.2, 108.8, 107.1, 101.8. HRMS (ESI) (m/z)
calcd for C9H6N2O3 [M+H]+ 191.0451; found 191.0453.
2-(4-fluorophenyl)-1,3,4-oxadiazole (3bj). Light yellow solid. Yield
55% (18.0 mg). m. p. 72ꢀ74 oC; 1H NMR (400 MHz, CDCl3): δ = 8.48 (s,
3H), 8.11 (dd, J = 8.9, 5.2 Hz, 6H), 7.24 (dd, J = 16.4, 7.9 Hz, 7H). 13C
NMR (100 MHz, CDCl3): δ = 165.1 (d, J=223 Hz), 152.6, 129.4 (d, J =
8.9 Hz), 119.9 (d, J = 3.3 Hz), 116.6, 116.4. HRMS (ESI) (m/z) calcd for
C8H5FN2O [M+H]+ 165.0459; found 165.0460.
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2-(4-chlorophenyl)-1,3,4-oxadiazole (3bk). Light yellow solid. Yield
o
83% (29.9 mg). m. p. 134ꢀ136 C; 1H NMR (400 MHz, CDCl3): δ = 8.49
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(s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ = 164.0, 152.7, 138.3, 129.5, 128.3, 121.9. HRMS (ESI)
(m/z) calcd for C8H5ClN2O [M+H]+ 181.0163; found 181.0166.
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2-(3-chlorophenyl)-1,3,4-oxadiazole (3bl). Light yellow solid. Yield
58% (20.9 mg). m. p. 79ꢀ82 oC; 1H NMR (400 MHz, CDCl3): δ = 8.50 (s,
1H), 8.08 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.47
(t, J = 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 163.6, 152.8, 135.3,
132.0, 130.5, 127.0, 125.2, 125.1. HRMS (ESI) (m/z) calcd for
C8H5ClN2O [M+H]+ 181.0163; found 181.0167.
2-(4-bromophenyl)-1,3,4-oxadiazole (3bm) Light yellow solid. Yield
o
62% (27.9 mg). m. p. 139ꢀ142 C; 1H NMR (400 MHz, CDCl3): δ = 8.50
(s, 1H), 7.95 (dd, J = 8.4, 1.2 Hz, 2H), 7.69 – 7.63 (m, 2H).13C NMR (100
MHz, CDCl3): δ = 164.0, 152.7, 132.4, 128.4, 126.7, 122.3. HRMS (ESI)
(m/z) calcd for C8H5BrN2O [M+H]+ 224.9658; found 224.9662.
2-(naphthalen-2-yl)-1,3,4-oxadiazole (3bn). Light yellow solid. Yield
63% (24.7 mg). m. p. 58ꢀ60 oC; 1H NMR (400 MHz, CDCl3): δ = 8.53 (s,
1H), 8.51 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 9.3 Hz, 2H), 7.86
(d, J = 7.5 Hz, 1H), 7.60 – 7.51 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
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= 164.8, 152.6, 134.6, 132.6, 129.0, 128.8, 128.0, 127.8, 127.5, 127.0,
123.0, 120.6. HRMS (ESI) (m/z) calcd for C12H8N2O [M+H]+ 197.0710;
found 197.0714.
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2-(furan-2-yl)-1,3,4-oxadiazole (3bo) Yellow oil. Yield 40% (10.8 mg).
.
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1H), 7.68 (d, J = 1.0 Hz, 1H),
7.22 (d, J = 3.5 Hz, 1H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ = 157.5, 151.8, 146.0, 139.0, 114.6, 112.2. HRMS (ESI)
(m/z) calcd for C6H4N2O2 [M+H]+ 137.0346; found 137.0349.
2-(thiophen-2-yl)-1,3,4-oxadiazole (3bp). Yellow solid. Yield 67% (20.4
o
o
1
mg). m. p. 150ꢀ152 C (lit.12 m. p. 151ꢀ154 C); H NMR (400 MHz,
CDCl3): δ = 8.42 (s, 1H), 7.80 (dd, J = 3.7, 1.0 Hz, 1H), 7.58 (dd, J = 5.0,
1.0 Hz, 1H), 7.19 (dd, J = 5.0, 3.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ = 160.9, 151.9, 130.5, 130.2, 128.2, 124.6. HRMS (ESI) (m/z) calcd for
C6H4N2OS [M+H]+ 153.0117; found 153.0119.
Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (4ba). Light yellow
solid. Yield 55% (27.9 mg). m. p. 95ꢀ97 oC; 1H NMR (400 MHz, CDCl3):
δ = 8.58 (d, J = 7.2 Hz, 2H), 8.24 (d, J = 6.9 Hz, 2H), 7.74 – 7.69 (m, 1H),
7.65 – 7.54 (m, 5H). 13C NMR (100 MHz, CDCl3): δ = 177.6, 166.0,
160.9, 134.9, 134.3, 132.8, 131.0, 129.3, 128.8, 127.8, 122.8. HRMS (ESI)
(m/z) calcd for C15H10N2O2 [M+H]+ 251.0815; found 251.0819.
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Phenyl(5-(pyridine-4-yl)-1,3,4-oxadiazol-2-yl)methanone (4bb). Light
yellow solid. Yield 48% (24.5 mg). m. p. 148ꢀ150 oC; 1H NMR (400 MHz,
CDCl3): δ = 8.90 (d, J = 6.0 Hz, 2H), 8.57 (d, J = 7.3 Hz, 2H), 8.09 (d, J
= 6.1 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ = 177.3, 164.1, 161.2, 151.0, 135.2, 134.0, 131.0,
130.1, 128.9, 121.0. HRMS (ESI) (m/z) calcd for C14H9N3O2 [M+H]+
252.0732; found 252.0736.
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(5-methyl-1,3,4-oxadiazol-2-yl)(phenyl)methanone (4bc). Brown solid.
Yield 32% (11.9 mg); m. p. 107ꢀ109 oC; 1H NMR (400 MHz, CDCl3): δ =
8.53 (dd, J = 8.4, 1.2 Hz, 2H), 7.72 – 7.68 (m, 1H), 7.56 (t, J = 7.8 Hz,
2H), 2.70 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 177.7, 165.8, 161.4,
134.9, 134.1, 130.9, 128.8, 11.2. HRMS (ESI) (m/z) calcd for C10H8N2O2
[M+H]+ 189.0659; found 189.0660.
Supporting Information
1
13
Copies of H and C NMR spectra for all reaction products. The
materials are available free of charge on the ACS Publications website.
Corresponding Author:
*Fax: +86 0931 8912596. Eꢀmail: hgs@lzu.edu.cn
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