Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl isocyanide insertion

Article abstract of DOI:10.1039/c5ob01328c

An efficient one-pot palladium-catalyzed reaction for the synthesis of diazoles from readily available hydrazides and aryl halide via isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs diazoles in good to excellent yields with the advantages of wide functional group tolerance and operational simplicity.

Full text of DOI:10.1039/c5ob01328c

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Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl
isocyanide insertion
Received 00th January 20xx,
Accepted 00th January 20xx
Xiang-Yuan Fan, Xiao Jiang, Ying Zhang, Zhen-Bang Chen, Yong-Ming Zhu*
An efficient one-pot palladium-catalyzed reaction for the synthesis of diazoles from readily available
hydrazides and aryl halide via isocyanide insertion/cyclization sequence has been developed. This
methodology efficiently constructs diazoles in good to excellent yields with the advantages of wide
functional group tolerance and operational simplicity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
with acylhydrazines (Scheme 2). 12
Introduction
Oxadiazoles are a valuable class of heterocycles and they display
a wide range of biological activities, including antibacterial, anti-
inflammatory, anticonvulsant, anticancer, antidiabetic, analgesic,
antiviral, and antifungal activities.1 Among the four different
isomers (two 1,2,4-isomers, a 1,3,4-isomer, and a 1,2,5-isomer), the
1,3,4-oxadiazoles have received the most considerable attention.2
There is an increased interest in 1,3,4-oxadiazoles in drug discovery
Nevertheless, the drawbacks of this method are obvious, such as
long reaction time, fussy operation, etc. Still, the novel synthetic
methods for 1,3,4-oxadiazoles are desired.
research.
A
small molecule drug, Zibotentan3 (Scheme 1,a),
containing a 1,3,4-oxadiazole motif, has good antitumor activity.
Raltegravir 4 (Scheme 1,b) has been launched onto the marketplace
for the treatment of HIV infection. To this end, 1,3,4-oxadiazole
motifs are identified as promising compounds in new drug
discovery.
Scheme 1. Structures of Zibotentan and Raltegravir.
A large amount of approaches have been reported for the
synthesis of 1,3,4- oxadiazoles: (a) Direct reaction of acyl chlorides
or methyl ketones with hydrazides.5 (b) Cyclodehydration of 1,2-
diacylhydrazines with reagents such as thionyl chloride, PPA,
phosphorus oxychloride, or sulfuric acid.6 (c) Oxidative cyclization of
N-acylhydrazones with various oxidizing agents.7 (d) C-H
activation/Cu mediated arylation of preformed 2-substituted 1,3,4-
oxadiazole.8 (e) Cu(II) catalyzed imine C-H functionalization leading
to synthesis of 2,5-substituted 1,3,4-oxadiazoles.9 (f) I2 - Mediated
oxidative C−O bond formation for the synthesis of 1,3,4-oxadiazoles
from aldehydes and hydrazides.10 (g) Copper-catalyzed
Intramolecular decarboxylative to synthsize 1,3,4-oxadiazoles.11 (h)
Recently, the groups of Skrydstrup have reported the construction
of diacylhydrazines through a Pd-catalyzed carbonylative coupling
R1
O
H
R2-I
N
H
N
O
H
N
O
N
R1
R2
R1
R2
NH
NH
Cu
ligand
path-d
O
R1
H
R2
O
1) EtOH,reflux
cyclodehydration
path-b
N
R1
N
R1CHO
NH2NHCOR2
R2
H
N
2)K2CO3,DMSO
O
N
path-f
O
LnPd(0)
CO
O
path-h
NH2
N
O
H
O
O
O
N
H
R1-Br
R1
X=Cl,C
X
H2NHN
R2
R2
NHNH2
Scheme 2. Strategies for the formation of 1,3,4-oxadiazole
framework.
College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
E-mail: zhuyongming@suda.edu.cn
During the last few years, our group has been involved in the
development of transition metal-catalyzed carbonylative reactions
employing isocyanide insertion. As our continuing efforts to
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structure heterocycles through a tandem strategy,13 herein, we
report an efficient Pd-catalyzed isocyanide insertion reaction, via
sequential isocyanide insertion reaction to synthesis 1,3,4-
oxadiazoles in one pot (Scheme 3). To our surprise, replacing
6
7
Dioxane
THF
NaOAc
NaOAc
NaOAC
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
PdCl2/DPPP
trace
trace
0
PdCl2/DPPP
PdCl2/DPPP
8
Toluene
DMF
benzohydrazide with benzothiohydrazide
,
1,3,4-thiadiazoles,
possessing diverse biological properties,14 could be obtained
through this isocyanide insertion-cyclization reaction, and few of
approaches to synthesize thiadiazoles have been reported.15, 16
9
PdCl2/ DPPP
76
10
11
12
13
DMF
PdCl2/(R)-BINAP
PdCl2/DPEphos
PdCl2/Xantphos
Pd(OAc)2/ DPPP
19
DMF
trace
0
DMF
DMF
38
Scheme 3. This work
14
DMF
NaOAc
Pd2(dba)3/DPPP
trace
a Reaction conditions: all reactions were performed under N2 with 1a
(0.5 mmol), tert-butyl isocyanide (0.75 mmol), catalyst (0.0125 mmol),
ligand (0.025 mmol), and base (1.0 mmol) in 2.0 mL of solvent at 130
°C for 3 h. b Isolated yield by silica gel chromatography.
Results and discussion
In a pilot experiment, iodobenzene and benzohydrazide were
reacted with tert-butyl isocyanide in the presence of PdCl2, DPPP
o
With optimal conditions in hand, we next investigated the scope
of this reaction, as illustrated in Table 2. Iodobenzenes bearing
electron-donating substituents all gave the desired products in
good to excellent yields (Table 2, entries 1-4). It is worth noting that
iodobenzenes containing functional groups such as p-Cl and p-F and
p-CF3 were all tolerated (Table 2, entries 7−8). Besides,
disubstituted aryl iodobenzenes were also efficiently transformed
into the desired products (Table 2, entries 9 and 10).
and NaOAc . When the reaction was performed in DMSO at 130 C
for 3 h, the desired product 2,5-diphenyl-1,3,4-oxadiazole was
formed in 32% yield (Table 1, entry 1). By switching the base from
NaOAC to Cs2CO3 or t-BuONa, no product generated (entries 2-3);
other bases gave diminished yields (entries 4-5). Solvent screening
revealed that DMF appeared to be the best solvent and the yield
was significantly increased to 76% (Table 1,entries 6-9). Other
ligands were also tested. However, none of them were found to
superior to DPPP (Table 1, entries 10−12). In comparison with PdCl2,
other palladium sources such as Pd(OAc)2 and Pd2(dba)3 resulted in
lower yields (Table 1,entries 13 and 14). Therefore, the optimal
reaction conditions were PdCl2 (5 mol %) and DPPP (10 mol %) as
the catalyst system, with NaOAc (2 equiv) as base and DMF as
solvent.
Table 2. Synthesis of 1,3,4-oxadiazoles from various aryl halides via
palladium-catalyzed one-pot cyclization.a,b
Table 1. Condition optimizations a,b
Yield(%)b
76/47c
Entry
Substrate
Product
1
1a
1aa
1ab
2
68
81
Entry
Solvent
Base
Catalyst/ Ligand
Yield(%)
1b
1
2
3
4
5
DMSO
DMSO
DMSO
DMSO
DMSO
NaOAc
Cs2CO3
t-BuONa
CsOAc
PdCl2/DPPP
PdCl2/DPPP
PdCl2/DPPP
PdCl2/DPPP
PdCl2/DPPP
32
O
3
4
1c
1ac
1ad
I
0
84
80
1d
19
15
Na2CO3
5
2
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1e
1ae
3
70
2c
2ac
6
57
4
88
1f
1af
2d
2e
2ad
2ae
2af
7
5
59
47
74
1g
50
1ag
8
6
76
2f
1h
1ah
1ai
7
9
2g
91
1i
2ag
8
76
10
50
1j
2ah
2ai
1aj
2h
2i
a All reactions were performed under N2 with 1a (0.5 mmol), tert-butyl
isocyanide (0.75 mmol), PdCl2 (0.0125 mmol), DPPP (0.025 mmol), and
NaOAc (1.0 mmol) in 2.0 mL of DMF at 130 °C for 3h. b Isolated yield by
silica gel chromatography. c Choosing bromobenzene as substrate.
9
93
66
2j
10
11
2aj
62c
To extend the application of this reaction,
a variety of
2ak
2k
2l
benzhydrazides were investigated, and the results are summarized
in Table 3. 2-methylbenzohydrazide led to 50% isolated yield (Table
3, entry 1). This is probably due to the steric hindrance in the ortho-
position. Benzhydrazides containing electron-rich substituents
(Table 3, entries 2-4 ) afforded higher yields than electron-poor
ones (Table 3, entries 5-6). Moreover, biphenyl-4-carbohydrazide,
3,4,5-trimethoxybenzohydrazide, 1-naphthohydrazide (Table 3,
entries 7-9 ) and several heteroaromatic substrates (Table 3, entries
11-13) were successfully converted into the corresponding products
in good yields. To our delight, hydrazides with aliphatic subsituents
gave the targeted products (Table 3, entries 14-15), which would
successfully expand the scope of this reaction.
12
13
59 c
2al
74 c
42
2am
2m
14
15
2n
2an
2ao
31
2o
a Reaction conditions: all reactions were performed under N2 with 1a (0.5
mmol), tert-butyl isocyanide (0.75 mmol), PdCl2 (0.0125 mmol), DPPP
(0.025 mmol), and NaOAc (1.0 mmol) in 2.0 mL of DMF at 130 °C for 3 h.b
Isolated yield by silica gel chromatography. c Using CsOAc as base.
Table 3. Synthesis of 1,3,4-oxadiazoles from various aryl halides via
palladium-catalyzed one-pot cyclization.a,b
Next, we conducted the reaction of benzothiohydrazide with a
number of aryl iodides under the modified conditions by switching
NaOAc to Na2CO3. As shown in Table 4, varieties of electron-
donating groups were compatible under the reaction conditions.
Entry
Substrate
Product
Yield(%) b
50
1
2aa
2a
2b
Table 4. Synthesis of 1,3,4-thiadiazoles from various aryl halides
via palladium-catalyzed one-pot cyclization.a,b
2
74
2ab
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In summary, we have described a novel method for the synthesis
of 1,3,4-oxadiazoles by an efficient palladium-catalyzed three-
component reaction, which proceeded in reasonable to excellent
yields. It works with a range of aryl halide and hydrazides (both aryl
and alkyl substituted), showing good functional group tolerance. In
this one-pot process, 1,3,4-oxadiazoles are generated through the
insertion of tert-butyl isocyanide, sequently coupling of hydrazids
and finally elimination of tert-butylamine. Interestingly, by changing
Entry
Substrate
Product
Yield (%)b
1
3aa
3ab
3a
3b
46
54
50
base, we furnished
thiadiazoles.
a convenient access to synthesize 1,3,4-
2
3
Experimental section
3ac
3c
General procedure for 1,3,4-oxadiazoles.
Synthesis of 2,5-diphenyl-1,3,4-oxadiazole. The reaction were
performed under N2 with 1a (0.5 mmol), tert-butyl isocyanide (0.75
mmol), PdCl2 (0.0125 mmol), DPPP (0.025 mmol), and NaOAc (1.0
mmol) in 2.0 mL of DMF at 130 °C for 3 h. After completion of the
reaction (confirmed by mass and TLC analysis), poured in to water
(50 mL) and extracted by ethyl acetate (2×50 mL), dried (Na2SO4)
and evaporated. The residue was purified on a silica gel column
using petroleum ether/EtOAc as the eluent to give the pure target
product.
3d
4
62
3ad
3ae
S
NHNH2
3e
5
37
a Reaction conditions: all reactions were performed under N2 with 4a (0.5
mmol), tert-butyl isocyanide (0.75 mmol), PdCl2 (0.0125 mmol), DPPP (0.025
mmol), and Na2CO3 (1.0 mmol) in 2.0 mL of DMF at 130 °C for 3 h. b Isolated
yield by silica gel chromatography.
2,5-Diphenyl-1,3,4-oxadiazole (1aa)17
.
White solid, mp 136-138
oC, 84 mg, yield 76%, 1H NMR (400 MHz, CDCl3): δ 8.50 – 7.72 (m,
4H), 7.53 (m, J = 5.8 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 164.7,
131.8, 129.2, 127.0, 124.0. LRMS (ESI): m/z calcd for C14H10N2O [M +
H]+, 223.1; found, 223.0.
A plausible mechanism for this reaction is depicted in Scheme 4.
Oxidative addition of aryl halides to the Pd(0) catalyst facilitates the
formation of palladium complex 2, followed by insertion to get
palladium(II) species 3. Then, under the assistance of NaOAc, the
addition of benzhydrazide gives the generation of 4. Finally, the
reductive elimination of 4 gives compounds 5, which leads to the
1aa after cyclization with losing tertbutylamine.
2-Phenyl-5-p-tolyl-1,3,4-oxadiazole (1ab)19. White solid, mp 122-
1
123 oC, 80 mg, yield 68%, H NMR (400 MHz, CDCl3): δ 8.14 – 8.01
(m, 2H), 7.98 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 5.1, 1.9 Hz, 3H), 7.28
(d, J = .0 Hz, 2H), 2.36 (d, J = 18.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 164.6, 164.2, 142.2, 131.6, 129.7, 129.0, 126.8, 123.9, 121.0 ,
21.6. LRMS (ESI): m/z calcd for C15H12N2O [M + H]+, 237.1; found,
237.0.
2-Phenyl-5-m-tolyl-1,3,4-oxadiazole (1ac)20. White solid, mp 108-
1
110 oC, 96 mg, yield 81%, H NMR (400 MHz, CDCl3): δ 8.15 (dd, J =
7.4, 2.1 Hz, 2H), 8.00 – 7.89 (m, 2H), 7.57 – 7.49 (m, 3H), 7.42 (t, J =
7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 164.7, 164.5, 139.0, 132.5, 131.7, 129.1, 129.0, 127.4,
126.9, 124.1, 124.0, 123.8, 21.4. LRMS (ESI): m/z calcd for
C15H12N2O [M + H]+, 237.1; found, 237.0
2-(4-tert-Butylphenyl)-5-phenyl-1,3,4-oxadiazole (1ad)9. White
solid, mp 101-102 oC, 117 mg, yield 84%, 1H NMR (400 MHz, CDCl3):
δ 8.17 – 8.10 (m, 2H), 8.07 (s, 1H), 8.05 (s, 1H), 7.55 (d, J = 4.5 Hz,
1H), 7.54 – 7.49 (m, 4H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
164.7, 164.4, 155.4, 131.7, 129.1, 126.9, 126.8, 126.1, 124.1, 121.2,
35.2, 31.2. LRMS (ESI): m/z calcd for C18H18N2O [M + H]+, 279.1;
found, 279.0.
Scheme 4. Plausible Mechanism
4
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2-(3-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (1ae)21
. White δ 164.7, 164.2, 162.5, 131.7, 129.1, 128.8, 126.9, 124.2, 114.6, 55.6.
1
solid, mp 86-87 oC, 101 mg, yield 80%, H NMR (400 MHz, CDCl3): δ LRMS (ESI): m/z calcd for C15H12N2O2 [M + H]+, 253.1; found, 253.0.
8.15 – 8.06 (m, 2H), 7.65 (dd, J = 15.9, 4.5 Hz, 2H), 7.55 – 7.46 (m,
N,N-Dimethyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline
(2ad)23
.
3H), 7.40 (t, J = 8.0 Hz, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 3.86 (s, Yellow solid, mp 84-85 oC, 117 mg, yield 88%, 1H NMR (400 MHz,
3H). 13C NMR (101 MHz, CDCl3): δ 164.6, 164.5, 160.0, 131.8, 130.3, CDCl3): δ 8.16 – 8.10 (m, 2H), 7.99 (d, J = 8.9 Hz, 2H), 7.55 – 7.49 (m,
129.1, 127.0, 125.0, 123.9, 119.3, 118.2, 111.6, 55.6. LRMS (ESI): 3H), 6.78 (d, J = 8.8 Hz, 2H), 3.07 (s, 6H). 13C NMR (101 MHz, CDCl3):
m/z calcd for C15H12N2O2 [M + H]+, 253.1; found, 253.0.
δ 165.4, 163.6, 152.4, 131.3, 129.1, 128.4, 126.8, 124.5, 111.8,
111.2, 40.3. LRMS (ESI): m/z calcd for C16H15N3O [M + H]+, 266.1;
2-(4-Fluorophenyl)-5-phenyl-1,3,4-oxadiazole (1af)7e. White solid, found, 266.0.
1
mp 132-133 oC, 68 mg, yield 57%, H NMR (400 MHz, CDCl3): δ 8.19
– 8.07 (m, 4H), 7.53 (d, J = 6.1 Hz, 3H), 7.22 (t, J = 8.0 Hz, 2H). 13C
2-(Biphenyl-4-yl)-5-phenyl-1,3,4-oxadiazole (2ag)7e. White solid,
NMR (151 MHz, CDCl3): δ 165.7, 164.7, 164.1, 163.9, 131.9, 129.3, mp 167-168 oC, 110 mg, yield 74%, 1H NMR (400 MHz, CDCl3): δ 8.13
129.4, 129.2, 127.0, 123.9, 116.5, 116.6. LRMS (ESI): m/z calcd for – 8.01 (m, 4H), 7.64 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.48 –
C14H9FN2O [M + H]+, 241.1; found, 241.0.
7.41 (m, 3H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 7.1 Hz, 1H). 13C NMR
(101 MHz, CDCl3): δ 164.7, 164.8, 144.5, 139.8, 131.9, 129.2, 129.1,
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (1ag)7e. White 128.3, 127.8, 127.5, 127.3, 127.0, 124.0, 122.7. LRMS (ESI): m/z
1
solid, mp 160-161 oC, 64mg, yield 50%, H NMR (400 MHz, CDCl3): δ calcd for C20H14N2O [M + H]+, 299.1; found, 299.0.
8.11 (dd, J = 7.5, 1.7 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.56 – 7.47 (m,
5H). 13C NMR (101 MHz, CDCl3): δ 164.8, 163.8, 138.1, 132.0, 129.5,
2-Phenyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole
(2ah)17
.
129.2, 128.2, 127.0, 123.8, 122.4. LRMS (ESI): m/z calcd for White solid, mp 117-118 oC, 119 mg, yield 76%, H NMR (400 MHz,
C14H9ClN2O [M + H]+, 257.0; found, 256.9.
1
CDCl3): δ 8.09 – 8.01 (m, 2H), 7.46 (d, J = 6.0 Hz, 3H), 7.27 (d, J = 1.3
Hz, 2H), 3.89 (dd, J = 12.3, 1.2 Hz, 9H). 13C NMR (101 MHz, CDCl3): δ
164.3, 153.5, 141.0, 131.6, 128.9, 126.8, 123.7, 118.8, 104.0, 60.9,
2-Phenyl-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (1ah)21
.
1
White solid, mp 149-150 oC, 110 mg, yield 76%, H NMR (400 MHz, 56.3, 29.6. LRMS (ESI): m/z calcd for C17H16N2O4 [M + H]+, 313.1;
CDCl3): δ 8.25 (d, J = 8.2 Hz, 2H), 8.13 (dd, J = 7.8, 1.4 Hz, 2H), 7.79 found, 313.1.
(d, J = 8.3 Hz, 2H), 7.58 – 7.47 (m, 3H). 13C NMR (151 MHz, CDCl3): δ
165.2, 163.5, 133.5, 133.3, 132.2, 129.3, 127.3, 127.1, 126.2, 126.2,
124.6, 123.7. LRMS (ESI): m/z calcd for C15H9F3N2O [M + H]+, 291.1; solid, mp 132-133 oC, 126mg, yield 93%, H NMR (400 MHz, CDCl3):
2-(Naphthalen-1-yl)-5-phenyl-1,3,4-oxadiazole (2ai)18
.
White
1
found, 290.9.
δ 9.30 (d, J = 8.6 Hz, 1H), 8.26 – 8.12 (m, 3H), 7.99 (d, J = 8.2 Hz, 1H),
7.89 (d, J = 8.2 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.61 – 7.47 (m, 5H).
2-(3,5-Dimethylphenyl)-5-phenyl-1,3,4-oxadiazole (1ai)24. White 13C NMR (101 MHz, CDCl3): δ 164.6, 164.1, 133.8, 132.6, 131.8,
solid, mp 164-165 oC, 114 mg, yield 91%, H NMR (400 MHz, CDCl3): 130.1, 129.1, 128.7, 128.4, 128.2, 127.0, 126.7, 126.2, 124.9, 123.9,
1
δ 8.17 – 8.10 (m, 2H), 7.74 (s, 2H), 7.57 – 7.48 (m, 3H), 7.15 (s, 1H), 120.4. LRMS (ESI): m/z calcd for C18H12N2O [M + H]+, 273.1; found,
2.40 (s, 6H). 13C NMR (101 MHz, CDCl3) :δ 164.9, 164.5, 138.9, 373.0.
133.5, 131.7, 129.1, 127.0, 124.7, 124.1, 123.7, 21.3. LRMS (ESI):
m/z calcd for C16H14N2O [M + H]+, 251.1; found, 251.0.
2-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-1,3,4-oxadiazole
White solid, mp 105-106 oC, 88 mg, yield 66%. 1H NMR (400 MHz,
(2aj)22
.
2-(3,5-Difluorophenyl)-5-phenyl-1,3,4-oxadiazole (1aj). White CDCl3): δ 8.12 (dd, J = 7.4, 2.0 Hz, 2H), 7.69 (dd, J = 8.1, 1.6 Hz, 1H),
solid, mp 134-135 oC, 65 mg, yield 50%, 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 1.3 Hz, 1H), 7.58 – 7.49 (m, 3H), 6.95 (d, J = 8.1 Hz, 1H),
8.13 (d, J = 6.8 Hz, 2H), 7.67 (d, J = 5.7 Hz, 2H), 7.55 (d, J = 7.6 Hz, 6.08 (s, 2H). 13C NMR (101 MHz, CDCl3): δ 164.5, 164.4, 150.8,
3H), 7.00 (t, J = 8.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 165.2, 148.5, 131.8, 129.2, 127.0, 124.1, 122.2, 117.9, 109.0, 107.2, 102.0.
164.7, 164.6, 162.9, 162.2, 162.1, 132.3, 129.3, 127.2, 110.3, 110.3, LRMS (ESI): m/z calcd for C15H10N2O3 [M + H]+, 267.1; found, 267.1.
110.1, 110.1, 107.8, 107.6, 107.3, 107.2, 107.1. HRMS (ESI): m/z
calcd for C14H8F2N2O [M + H]+, 259.0692; found, 259.0683.
2-(Furan-3-yl)-5-phenyl-1,3,4-oxadiazole (2ak)17. White solid, mp
84-85 oC, 66 mg, yield 62%. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H),
2-Phenyl-5-o-tolyl-1,3,4-oxadiazole (2aa)17. White solid, mp 102- 8.12 (dd, J = 7.7, 1.5 Hz, 2H), 7.56 (dt, J = 12.9, 3.7 Hz, 4H), 7.01 (s,
1
103 oC, 58 mg, yield 49%, H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 1H). 13C NMR (101 MHz, CDCl3): δ 164.3, 159.7, 144.4, 143.8, 131.6,
6.2 Hz, 2H), 8.03 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 5.6 Hz, 3H), 7.41 (d, J 129.2, 127.0, 123.3, 111.7, 108.6. LRMS (ESI): m/z calcd for
= 6.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 2.76 (s, 3H). 13C NMR (101 C12H8N2O2 [M + H]+, 213.1; found, 212.9.
MHz, CDCl3): δ 164.9, 164.2, 138.5, 131.9, 131.8, 131.3, 129.2,
129.0, 127.0, 126.3, 124.0, 123.0, 76.8, 22.2. LRMS (ESI): m/z calcd
for C15H12N2O [M + H]+, 237.1; found, 237.0.
2-Phenyl-5-(thiophen-3-yl)-1,3,4-oxadiazole (2al)18. White solid,
1
mp 117-118 oC, 67 mg, yield 59%. H NMR (400 MHz, CDCl3): δ 8.12
(s, 3H), 7.74 (d, J = 4.8 Hz, 1H), 7.51 (dd, J = 19.7, 4.3 Hz, 4H). 13C
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (2ac)19
. White NMR (75 MHz, CDCl3): δ 164.1, 161.5, 131.8, 129.2, 127.6, 127.6,
solid, mp 149-150 oC, 88 mg, yield 70%, 1H NMR (400 MHz, CDCl3): δ 127.0, 126.2, 125.4, 123.9. LRMS (ESI): m/z calcd for C12H8N2OS [M +
8.12 (d, J = 4.3 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 5.1 Hz, H]+, 229.0; found, 228.9.
3H), 7.03 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3):
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ARTICLE
2-(1-Methyl-1H-indol-3-yl)-5-phenyl-1,3,4-oxadiazole
Journal Name
(2am)26
.
121.1, 117.9, 112.7, 55.9. LRMS (ESI): m/z calcd for C12H8N2OS [M +
1
Yellow solid, mp 198-199 oC, 102 mg, yield 74%. H NMR (400 MHz, H]+, 267.1; found, 267.0.
CDCl3): δ 8.36 – 8.29 (m, 1H), 8.16 (dd, J = 6.2, 3.1 Hz, 2H), 7.92 (s,
1H), 7.59 – 7.49 (m, 3H), 7.44 – 7.33 (m, 3H), 3.91 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 162.2, 161.7, 136.7, 130.8, 130.4, 128.5, 126.2,
Acknowledgements
124.7, 123.8, 122.9, 121.4, 120.9, 109.5, 99.4, 33.1. LRMS (ESI): m/z
calcd for C17H13N3O [M + H]+, 275.1; found, 275.0.
We gratefully acknowledge financial support by the PAPD (A Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions) and NSFC (National Nature Science
Foundation of China, No. 21172162).
2-Methyl-5-phenyl-1,3,4-oxadiazole (2an)19. White solid, mp 64-
65 oC, 34 mg, yield 41%. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 6.5
Hz, 2H), 7.50 (t, J = 6.8 Hz, 3H), 2.61 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 165.3, 164.1, 132.0, 129.5, 127.2, 124.4, 11.6. LRMS (ESI):
m/z calcd for C17H13N3O [M + H]+, 160.1; found, 160.0.
References and notes
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2-Cyclohexyl-5-phenyl-1,3,4-oxadiazole (2ao)17. White solid, mp
o
103-104 C, 35 mg, yield 31%. 1H NMR (400 MHz, CDCl3): δ 8.06 –
7.99 (m, 2H), 7.49 (d, J = 6.7 Hz, 3H), 2.99 (t, J = 11.3 Hz, 1H), 2.14
(d, J = 11.5 Hz, 2H), 1.91 – 1.80 (m, 2H), 1.79 – 1.61 (m, 3H), 1.46 –
1.28 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 169.5, 163.9, 130.9,
128.5, 126.3, 123.7, 34.8, 29.7, 25.1, 24.9. LRMS (ESI): m/z calcd for
C17H13N3O [M + H]+, 228.1; found, 228.0.
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2,5-Diphenyl-1,3,4-thiadiazole (3aa)15. White solid, mp 198-199
oC, 46 mg, yield 39%, 1H NMR (400 MHz, CDCl3): δ 8.02 (dd, J = 6.5,
2.8 Hz, 4H), 7.56 – 7.43 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 167.7,
130.6, 129.7, 128.7, 127.5, 76.9, 76.6, 76.3. LRMS (ESI): m/z calcd
for C12H8N2OS [M + H]+, 239.0; found, 239.0.
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2-Phenyl-5-p-tolyl-1,3,4-thiadiazole (3ab)15. White solid, mp 137-
138 oC, 57 mg, yield 45%, 1H NMR (400 MHz, CDCl3): δ 8.05 – 7.95
(m, 2H), 7.91 (d, J = 8.1 Hz, 2H), 7.54 – 7.44 (m, 3H), 7.38 – 7.21 (m,
2H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 167.8, 167.2, 141.1,
130.5, 129.8, 129.4, 128.7, 127.4, 127.4, 127.0, 21.1. LRMS (ESI):
m/z calcd for C15H12N2S [M + H]+, 252.1; found, 252.0.
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solid, mp 137-138 oC, 67 mg, yield 50%, 1H NMR (400 MHz, CDCl3): δ 2, 186. (c) F.W.J. Short, Hetercyl. Chem., 1969, 6, 707. (d) E.
8.06 – 7.94 (m, 2H), 7.64 (s, 1H), 7.51 (dd, J = 9.1, 6.9 Hz, 4H), 7.39 Klingsbreg, J. Am. Chem. Soc., 1958, 80, 5768. (e) C. K. Reddy, C. V.
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7 H. M. Flidallah, E. M. Sharshira, S. A. Basaif, A. E. K. A-Ba-Oum,
129.6, 128.4, 121.1, 118.0, 112.7, 55. LRMS (ESI): m/z calcd for
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8.83 (d, J = 8.4 Hz, 1H), 8.11 – 8.04 (m, 2H), 8.02 (d, J = 8.3 Hz, 1H),
7.95 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.64 – 7.50 (m, 6H).
13C NMR (101 MHz, CDCl3): δ 168.3, 166.8, 133.5, 131.0, 130.7,
130.1, 129.6, 129.3, 128.8, 128.0, 127.6, 127.3, 126.4, 126.2, 125.3,
124.6. LRMS (ESI): m/z calcd for C18H12N2S [M + H]+, 288.1; found,
288.0.
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.
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