Synthesis of 3′,4′-Diaryl-4′H-spiro[indoline-3,5′-[1′,2′,4′]oxadiazol]-2-ones via DMAP-catalyzed Domino Reactions and Their Antibacterial Activity

Article abstract of DOI:10.1002/cjoc.201600285

A convenient and metal-free DMAP-catalyzed domino reaction of isatins, arylamines and hydroximoyl chlorides has been developed to achieve 1,3-dipolar cycloaddition of imines into aryl nitrile oxides at ambient temperature. In this one-pot transformation,

Full text of DOI:10.1002/cjoc.201600285

FULL PAPER
DOI: 10.1002/cjoc.201600285
Synthesis of 3',4'-Diaryl-4'H-spiro[indoline-3,5'-[1',2',4']-
oxadiazol]-2-ones via DMAP-catalyzed Domino
Reactions and Their Antibacterial Activity
Guanghao Shi,a Xinwei He,a Yongjia Shang,*,a Liwei Xiang,a
Cheng Yang,a Guang Han,a and Bing Du*,b
a Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based
Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China
b Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
A convenient and metal-free DMAP-catalyzed domino reaction of isatins, arylamines and hydroximoyl chlo-
rides has been developed to achieve 1,3-dipolar cycloaddition of imines into aryl nitrile oxides at ambient tempera-
ture. In this one-pot transformation, a 1,2,4-oxadiazole skeleton was efficiently formed. This methodology needs no
extra additives and features wide substrate scope, good functional group tolerance and mild reaction conditions. A
plausible mechanism for this process was proposed. Moreover, the antibacterial activities of the products were
evaluated towards Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae
using the Broth microdilution method.
Keywords 4-dimethylaminopyridine, antimicrobial activity, isatins, domino reactions, oxadiazoles
Introduction
[4＋2] cycloaddition,[10] Diels-Alder reaction,[11] dom-
ino/cascade reaction,[12] multicomponent reantion[13] and
others were reported.[14] This study aimed to develop an
efficient organic synthesis with DMAP. Previously, we
presented an efficient synthesis approach for benzofu-
rans and naphthofurans via DMAP-catalyzed cascade
reactions.[15] As a part of our ongoing efforts to deter-
mine the organo-catalyzed multicomponent reactions,[16]
we reported the simplified synthesis of 3',4'-diaryl-4'H-
spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones using the
DMAP-catalyzed domino reaction of isatins, arylamines
and hydroximoyl chlorides in EtOH at an ambient tem-
perature (Scheme 1). In addition, assessment results
againsted S. epidermidis, E. coli, S. aureus and K.
pneumonia indicated that some compounds exhibited
significant antibacterial activity, specifically for the
multi-drug resistant strain, Staphylococcus aureus. This
work provided unusual leads for further optimization
during the drug discovery process.
Nitrogen-containing heterocycles were commonly
used as scaffolds on pharmacophores which could be
arranged to produce potent and selective drugs.[1] Within
the drug discovery and development industry, the
1,2,4-oxadiazole ring system has been proven to be a
privileged scaffold. The oxadiazole rings were an essen-
tial part of the pharmacophore for several drugs and
formed the lead molecules for drugs which were used to
treat a variety of diseases including diabetes, obesity,
inflammation, cancer and infection.[2] Many compounds
which contained the 1,2,4-oxadiazole motif exhibited
biological activities including anticancer activity,[3] an-
tiretroviral activity,[4] voltage-gated sodium activity,[5]
and the inhibition of acetyl-CoA carboxylase.[6] Because
of their medical application, significant efforts have
been focused on developing a general synthetic route to
access those compounds.[7] Therefore, more general and
ecofriendly procedures to synthesize 1,2,4-oxadiazoles
from readily available starting materials are desirable.
Organocatalysis has been widely applied in organic
synthesis for the new carbon-carbon/heteroatom bond
formation. Recently, 4-dimethylaminopyridine (DMAP)
and its analogs have been widely used as catalysts in
many organic synthesis reactions. Some example reac-
tions include acylation reactions,[8] aldol reactions,[9]
Results and Discussion
Initially, isatin (1a), p-toluidine (2b) and N-hydroxy-
benzimidoyl chloride (3a) were chosen as the starting
materials in the model reaction to optimize the reaction
conditions, and the results were presented in Table 1.
When the reaction was carried out with ethanol by using
*
E-mail: shyj@mail.ahnu.edu.cn, bdu@bio.ecnu.edu.cn; Tel.: 0086-0553-5910129; Fax: 0086-0553-5910126
Received May 11, 2016; accepted August 3, 2016; published online September 12, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600285 or from the author.
Chin. J. Chem. 2016, 34, 901—909
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Shi et al.
Table 1 Optimization of reaction conditionsa
FULL PAPER
Scheme
1
Synthesis of 3',4'-diaryl-4'H-spiro[indoline-3,5'-
[1',2',4']oxadiazol]-2-ones via the DMAP-catalyzed domino reac-
tion of isatins, arylamines, and hydroximoyl chlorides
DMAP as the catalyst, a higher yield of the desired
product was obtained (Table 1, Entry 9). In a control
experiment, only a small amount of the desired product
was detected by TLC in the absence of DMAP (Table 1,
Entry 22). Here, the yield was not improved by increas-
ing the amount of catalyst (Table 1, Entry 24). Although,
it also had good yield (85%) by decreasing the amount
of catalyst to 5 mol%, more by-products were produced
and the desired product was difficult to separate and
purify. Other solvents including CH2Cl2, tetrahydrofu-
ran (THF), Et2O, dimethylformamide (DMF), acetoni-
trile, toluene, methanol (MeOH) and H2O did not pro-
vide satisfactory results (Table 1, Entries 1－8). Differ-
ent catalysts were also tested (Table 1, Entries 10－16).
The use of other organic bases including pyridine,
1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), triethyla-
mine (TEA), and imidazole provided inferior results
(Table 1, Entries 10－13). Replacing the organic bases
with other inorganic bases including KHCO3, K2CO3,
and KOH decreased the reaction yields (Table 1, Entries
14－16). The effects of temperature and reaction time
were also investigated (Table 1, Entries 17－21). It was
found that increasing of the reaction temperature/time
did not improve the yield. Therefore, the optimum reac-
tion conditions, giving an 88% yield of the product,
were 10 mol % DMAP, 6 h reaction time, and ambient
temperature.
After the optimal conditions were determined, the
scope of this domino reaction was investigated (Table 2).
As summarized, a wide variety of isatin (1), arylamine
(2) and hydroximoyl chloride (3) analogs were tolerated,
and the resulting product yields were good to excellent.
For the isatins, substrates with electron-withdrawing
groups (F, Cl, Br, I) generally resulted in higher yields
(Table 2, Entries 3－6) than substrates with electron-
donating groups (CH3, CH2CH3) (Table 2, Entries 7, 8).
For the different arylamines (2), substrates with a strong
electron-donating group (OCH3) resulted in one of the
highest reported yields (Table 2, Entry 15). Among the
hydroximoyl chlorides (3) that were examined, sub-
strates bearing a strong electron-donating group (OCH3,
Entry
1
Base
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Pyridine
DBU
Solvent T/℃
Time/h
Yieldb/%
75
CH2Cl2
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
60
80
r.t.
r.t.
r.t.
r.t.
r.t.
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
12
6
6
6
2
78
3
Et2O
69
4
DMF
82
5
CH3CN
Toluene
MeOH
H2O
60
6
64
7
77
8
51
9
EtOH
EtOH
EtOH
EtOH
88
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
80
49
Et3N
78
Imidazole EtOH
52
KHCO3
K2CO3
KOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
57
60
51
DMAP
DMAP
DMAP
DMAP
DMAP
—
85
82
80
62
84
Trace
85
DMAP
DMAP
87
a
Reaction conditions: isatin (1a) (0.3 mmol), p-toluidine (2b)
(0.3 mmol), N-hydroxybenzimidoyl chloride (3a) (0.3 mmol),
base (0.03 mmol), and EtOH (5 mL). b Isolated yield. c 5 mol%
catalyst was used. d 20 mol% catalyst was used.
OCH2CH3, N(CH3)2) or a strong electron-withdrawing
group (NO2) lead to lower yields (Table 2, Entries 12,
13, 18, 19). The chemical structure of compound 4b was
unequivocally confirmed by single-crystal X-ray analy-
sis as shown in Figure 1.[17]
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Chin. J. Chem. 2016, 34, 901—909

Synthesis of 3',4'-Diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones
Table 2 Synthesis of 3',4'-diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones (4) via DMAP-catalyzed domino reactionsa
Entry
R1
H (1a)
R2
H (2a)
R3
Product
Yieldb/%
1
2
H (3a)
4a
4b
4c
4d
4e
4f
83
88
85
89
88
90
86
81
94
95
87
78
82
81
93
80
80
79
80
80
82
88
H (1a)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3 (2b)
CH3O (2c)
(CH3)2CH (2d)
F (2e)
H (3a)
3
F (1b)
H (3a)
4
Cl (1c)
H (3a)
5
Br (1d)
H (3a)
6
I (1e)
H (3a)
7
CH3 (1f)
CH3CH2 (1g)
H (1a)
H (3a)
4g
4h
4i
8
H (3a)
9
F (3b)
10
11
12
13
14
15
16
17
18
19
20
21
22
Cl (1c)
F (3b)
4j
Cl (1c)
Br (3c)
4k
4l
H (1a)
NO2 (3d)
(CH3)2N (3e)
BnO (3f)
H (3a)
F (1b)
4m
4n
4o
4p
4q
4r
4s
CH3 (1f)
CH3CH2 (1g)
Cl (1c)
BnO (3f)
Cl (3g)
Br (1d)
CH3O (1h)
(CH3)2CH (1i)
CH3O (1h)
Cl (1c)
Cl (2f)
CH3O (3h)
CH3CH2O (3i)
H (3a)
Br (2g)
I (2h)
4t
H (2a)
CN (3j)
4u
I (1e)
H (2a)
CH3 (3k)
4v
a Reaction conditions: isatin (1) (0.3 mmol), arylamine (2) (0.3 mmol) and hydroximoyl chlorides (3) (0.3 mmol), and DMAP (0.030
mmol) at room temperature in EtOH (5 mL) for 6 h. b Isolated yields.
Based on our experimental results,[18-20] a plausible
mechanism for the formation of 3',4'-diphenyl-4'H-
spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one was pro-
posed (Scheme 2). First, the condensation between isa-
tin 1a and arylamine 2a would form intermediate A.
Then, the 1,3-dipolar cycloaddition of intermediate A
with the 1,3-dipole B, which was generated in situ from
N-hydroxybenzimidoyl chloride 3a and treated with
DMAP, formed the desired product 4a, which is an al-
kaline compound. Subsequently, the compound 4a re-
acted with DMAP • HCl to regenerate the catalyst
DMAP.
Some control experiments were then carried out to
gain some insight into the mechanism of this reaction
(Scheme 3). Terminating the reaction of 1a with 2b af-
ter the first step of the reaction produced an intermedi-
Figure 1 X-ray crystal structure of 4b.
ate A in 97% yield (Scheme 3, Eq. (1)). Under the
Chin. J. Chem. 2016, 34, 901—909
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Shi et al.
FULL PAPER
Scheme 2 Proposed mechanism for the formation of 3',4'-diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones (4).
reaction conditions in Table 2, the intermediate A re-
acted with N-hydroxybenzimidoyl chloride 3a to give
the final product 4a in 80% yield [Scheme 2, Eq. (2)].
Subsequently, it was found that the reaction of interme-
diate A and 3a hardly took place when 4-(N,N-dimeth-
ylamino)pyridine hydrochloride (DMAP•HCl) was used
as a catalyst [Scheme 3, Eq. (3)]. In contrast, the reac-
tion was proceeded smoothly, and the desired 4a was
obtained in 82% yield when 4a (10 mol%) was used as
an additive in the reaction system [Scheme 3, Eq. (4)].
In the present study, the antibacterial activities of the
synthesized compounds were screened against two gram
negative and two gram positive bacterial strains (S. epi-
dermidis, E. coli, S. aureus and K. pneumonia) using the
Broth microdilution method. The results revealed that
some synthesized compounds exhibited antibacterial
activity against both S. epidermidis and S. aureus. The
results are summarized in Table 3 and Figure 2. Com-
pared to the standard bacteria against S. epidermidis, 4l
showed improved activity. In addition, 4k, 4j, 4f and 4v
exhibited significant antibacterial activity against the S.
aureus strain which was resistant to most known antibi-
otics (levofloxacin MIC=32 μg/mL).
Scheme 3 Control experiments
O
N
EtOH, r.t., 3 h
O
NH2
+
(1)
(2)
(3)
O
N
H
N
2a
H
1a
A (97% yield)
N
DMAP (10 mol%)
EtOH, r.t., 3 h
4a (80% yield)
+
N
O
OH
N
H
Cl
3a
A
N
DMAP HCl (10 mol%)
EtOH, r.t., 3 h
no reaction
+
N
O
OH
N
H
Cl
3a
A
N
DMAP HCl (10 mol%)
4a (10 mol%)
4a (82% yield)
+
N
O
(4)
EtOH, r.t., 3 h
OH
N
H
Cl
3a
A
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Synthesis of 3',4'-Diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones
Figure 2 Photos of antibacterial activities with the synthesized compounds.
Table 3 The MIC of all compounds against bacteria (µg/mL)
Compd. S. epidermidis E. coli S. aureus K. pneumoniae
against S. epidermidis. Similarly, compounds 4k, 4j, 4f
and 4v with halogen groups (Cl, I) on indole ring were
found to have significant antibacterial activity against S.
aureus. In fact its potency was comparable to standard
drug chloramphenicol and ciprofloxacin while far better
then ampicillin.[21]
4a
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
64
＞128 ＞128
＞128 ＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
64
4b
4c
＞128
＞128
＞128
＞128
＞128
128
128
128
64
4d
Conclusions
4e
4f
In conclusion, we developed an efficient DMAP-
catalyzed domino reaction for the synthesis of 3',4'-di-
phenyl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one
derivatives. This reaction possessed good to excellent
yields from readily available isatins, arylamines and
hydroximoyl chlorides. In comparison to the met-
al-catalyzed reactions, this route is a novel, highly ef-
fective, and environment-friendly process. The antibac-
terial activity of all compounds was also evaluated for
both gram negative and gram positive bacteria. Some of
the testing compounds inhibited the growth of the
Staphylococcus aureus, which could potentially solve
the problem of multidrug resistance.
4g
128
4h
＞128 ＞128
＞128 ＞128
4i
4j
＞128
＞128
＞128
＞128
64
64
4k
4l
128
128
4m
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
128
4n
＞128 ＞128
＞128 ＞128
4o
4p
＞128
128
4q
＞128 ＞128
4r
＞128
＞128
＞128
128
128
128
Experimental
4s
Chemistry
4t
Unless otherwise specified, all reagents and starting
materials were purchased from commercial sources and
used as received, and the solvents were purified and
dried by standard procedures. The chromatography sol-
vents were technical grade and distilled prior to use.
Flash chromatography was performed using 200－300
mesh silica gel with the indicated solvent system ac-
4u
4v
＞128 ＞128
＞128
＞128
64
32
levofloxacin
0.125
0.02
The spirooxindole system is the core structure of
many pharmacological agents and natural alkaloids. It
was the substitutions on indole ring and on the phenyl
ring of hydroximoyl chlorides functionality that had
distinctive effect on the potency of these compounds
against the tested bacterial strains. For instance com-
pound 41, with 4-NO2 substituent on the phenyl ring of
hydroximoyl chloride was found to be the most active
1
cording to standard techniques. The H and 13C NMR
data were recorded on 400 MHz NMR spectrometers,
unless otherwise specified. Chemical shifts (δ) in parts
per million are reported relative to the residual signals
1
of chloroform (δ 7.26 for H and 76.1 for 13C). Multi-
plicities are described as s (singlet), d (doublet), t (tri-
Chin. J. Chem. 2016, 34, 901—909
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Shi et al.
FULL PAPER
plet), q (quartet), or m (multiplet), and coupling con-
stants (J) are reported in hertz. HRMS analysis with a
quadrupole time-of-flight mass spectrometer yielded ion
mass/charge (m/z) ratios in atomic mass units. IR spec-
tra were measured as dry films (KBr), and peaks are
reported in terms of wave number (cm1).
2214, 1732, 1512, 1487, 1418, 1365, 1216, 818, 717,
524 cm1; HRMS (ESI) calcd for C22H17FN3O2 ([M＋
H]＋) 374.1305, found 374.1298.
5-Chloro-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4d) White solid; m.p.
1
229－231 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.79
(s, 1H), 7.75 (s, 1H), 7.48－7.37 (m, 6H), 7.01 (d, J＝
8.0 Hz, 2H), 6.87 (d, J＝8.4 Hz, 1H), 6.77 (d, J＝8.0 Hz,
2H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ:
172.5, 155.3, 142.0, 137.2, 133.8, 137.2, 132.5, 131.1,
130.2, 129.1, 128.5, 127.3, 127.2, 126.9, 126.5, 124.5,
112.9, 97.9, 20.8; IR (KBr) ν: 3248, 1752, 1619, 1597,
1511, 1475, 1445, 1389, 1252, 1196, 1149, 1119, 818,
751, 694, 616, 549 cm1; HRMS (ESI) calcd for
C22H17ClN3O2 ([M＋H]＋) 390.1009, found 390.1006.
5-Bromo-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4e) White solid. m.p.
General procedure for the synthesis of 3',4'-diphe-
nyl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one
derivatives 4
A solution of isatin 1 (1.0 mmol) and arylamine 2
(1.0 mmol) in EtOH (5 mL) was stirred for 3 h at room
temperature. When the TLC showed the reactants dis-
appeared, the chloro oxime 3 (1.0 mmol) and DMAP
(0.05 mmol) were added, and the reaction continued for
another 3 h. Upon completion of the reaction, the mix-
ture was evaporated in a vacuum, extracted by ethyl
acetate and a 5% NaOH solution three times, and then
washed with brine. Organic layers were combined, dried
over Na2SO4, filtered, and evaporated in a vacuum. The
residue was further purified by flash column chroma-
tography on silica gel (300－400 mesh) with ethyl ace-
tate and petroleum (3∶1, V/V) as the eluting solvent to
give the desired product.
1
205－207 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.73
(s, 1H), 7.87 (s, 1H), 7.54 (d, J＝5.6 Hz, 1H), 7.52－
7.39 (m, 5H), 7.02 (d, J＝7.6 Hz, 2H), 6.81－7.46 (m,
3H), 2.17 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ:
172.3, 155.3, 142.3, 137.2, 135.4, 133.7, 131.1, 130.2,
129.7, 129.1, 128.5, 127.2, 126.9, 124.5, 114.9, 113.4,
97.8, 20.8; IR (KBr) ν: 2360, 2341, 1749, 1616, 1595,
1575, 1540, 1472, 1418, 1394, 1197, 818, 770, 692, 668,
655 cm1; HRMS (ESI) calcd for C22H17BrN3O2 ([M＋
H]＋) 434.0504, found 434.0493.
3',4'-Diphenyl-4'H-spiro[indoline-3,5'-[1',2',4']-
oxadiazol]-2-one (4a) Gray solid. m.p. 221－222 ℃;
1H NMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H), 7.57
(d, J＝7.6 Hz, 1H), 7.49－7.33 (m, 6H), 7.19－7.04 (m,
4H), 6.86 － 6.79 (m, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 172.6, 155.25, 143.2, 136.8, 132.7, 131.2,
129.6, 129.2, 128.4, 127.4, 126.9, 126.8, 124.7, 124.4,
123.3, 111.3, 98.1; IR (KBr) ν: 3215, 3064, 1731, 1621,
1492, 1387, 1275, 1207, 1141, 843, 751, 690, 587 cm1;
5-Iodo-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-3,5'-
[1',2',4']oxadiazol]-2-one (4f)
White solid. m.p.
1
245－247 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.74
(s, 1H), 7.97 (s, 1H), 7.69 (d, J＝8.0 Hz, 1H), 7.53－
7.38 (m, 5H), 7.01 (d, J＝8.0 Hz, 2H), 6.75 (d, J＝8.0
Hz, 2H), 6.99 (d, J＝8.0 Hz, 1H), 2.17 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ: 172.0, 155.3, 142.8,
141.1, 137.2, 135.1, 133.8, 131.1, 130.2, 129.1, 128.5,
127.1, 127.1, 124.5, 113.7, 97.7, 86.1, 20.8; IR (KBr) ν:
2363, 1751, 1655, 1615, 1511, 1467, 1389, 1199, 817
cm1; HRMS (ESI) calcd for C22H17IN3O2 ([M＋H]＋)
482.0365, found 482.0356.
HRMS (ESI) calcd for C21H16N3O2 ([M ＋ H] ＋
342.1243, found 342.1238.
)
3'-Phenyl-4'-p-tolyl-4'H-spiro[indoline-3,5'-[1',2',
4']oxadiazol]-2-one (4b) Yellow solid. m.p. 187－
1
188 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.50 (s,
1H), 7.58 (d, J＝7.2 Hz, 1H), 7.47－7.33 (m, 6H), 7.08
(t, J＝7.6 Hz, 1H), 6.98 (d, J＝8.0 Hz, 2H), 6.84 (d, J＝
8.0 Hz, 1H), 6.71 (d, J＝8.0 Hz, 2H), 2.16 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ: 172.7, 155.3, 143.2,
137.0, 134.1, 132.6, 131.1, 130.1, 129.1, 128.4, 127.0,
126.9, 124.7, 124.5, 123.3, 111.3, 98.1, 20.8; IR (KBr) ν:
2970, 2363, 1736, 1560, 1508, 1473, 1458, 1365, 1229,
1216, 756, 696, 517 cm1; HRMS (ESI) calcd for
C22H18N3O2 ([M＋H]＋) 356.1399, found 356.1399.
5-Fluoro-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4c) White solid. m.p.
5-Methyl-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4g) White solid. m.p.
1
116－117 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.44
(s, 1H), 7.45－7.40 (m, 6H), 7.16 (d, J＝7.6 Hz, 1H),
6.99 (d, J＝8.0 Hz, 2H), 6.73 (t, J＝8.4 Hz, 3H), 2.28 (s,
3H), 2.16 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ:
172.6, 155.3, 140.6, 136.9, 134.0, 132.9, 132.5, 131.1,
130.1, 129.1, 128.3, 127.2, 127.0, 124.8, 124.7, 111.0,
98.3, 20.8, 20.8; IR (KBr) ν: 3031, 2970, 2360, 1743,
1648, 1560, 1512, 1493, 1458, 1388, 1289, 1216, 819,
752, 694 cm1; HRMS (ESI) calcd for C23H20N3O2
([M＋H]＋) 370.1556, found 370.1557.
1
113－115 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.61
(s, 1H), 7.60－7.58 (m, 1H), 7.47－7.39 (m, 5H), 7.19
(t, J＝8.4 Hz, 1H), 7.01 (d, J＝8.4 Hz, 2H), 6.85－6.81
(m, 1H), 6.77 (d, J＝8.0 Hz, 2H), 2.16 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ: 172.9, 157.6 (1JCF＝
238.4 Hz), 155.3, 139.3 (1JCF＝2.9 Hz), 137.2, 133.8,
131.1, 130.2, 129.1, 128.5, 127.3, 126.1 (3JCF＝7.4 Hz),
124.5, 119.3 (2JCF＝23.7 Hz), 114.7 (2JCF＝24.6 Hz),
112.4 (3JCF＝7.6 Hz), 98.1, 20.8; IR (KBr) ν: 2996,
5-Ethyl-3'-phenyl-4'-p-tolyl-4'H-spiro[indoline-3,
5'-[1',2',4']oxadiazol]-2-one (4h) Gray solid. m.p.
1
187－188 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.45
(s, 1H), 7.47－7.38 (m, 6H), 7.18 (d, J＝7.6 Hz, 1H),
6.98 (d, J＝8.4 Hz, 2H), 6.74－6.69 (m, 3H), 2.59－
13
2.54 (m, 2H), 2.15 (s, 3H), 1.15 (t, J＝8.4 Hz, 3H); C
NMR (100 MHz, DMSO-d6) δ: 172.7, 155.3, 140.9,
906
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Chin. J. Chem. 2016, 34, 901—909

Synthesis of 3',4'-Diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones
139.0, 137.0, 134.2,131.8, 131.1, 130.1, 129.1, 128.4,
127.1, 126.2, 124.8, 124.6, 111.0, 98.3, 28.0, 20.8, 16.3;
IR (KBr) ν: 3242, 2963, 1747, 1626, 1455, 1393, 1205,
819, 752, 694 cm1; HRMS (ESI) calcd for C24H22N3O2
([M＋H]＋) 384.1712, found 384.1704.
HRMS (ESI) calcd for C22H17N4O4 ([M ＋ H] ＋
)
401.1250, found 401.1246.
3'-(4-(Dimethylamino)phenyl)-5-fluoro-4'-p-tolyl-
4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4m)
1
Gray solid. m.p. 132－133 ℃; H NMR (400 MHz,
3'-(4-Fluorophenyl)-4'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4i) White solid. m.p.
211－213 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.56
DMSO-d6) δ: 10.55 (s, 1H), 7.47－7.45 (m, 1H), 7.19－
7.14 (m, 3H), 7.01 (d, J＝8.0 Hz, 2H), 6.83－6.80 (m,
1H), 6.75 (d, J＝7.6 Hz, 2H), 6.63 (d, J＝8.4 Hz, 2H),
2.91 (s, 6H), 2.17 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 173.2, 157.5 (1JCF＝238.3 Hz), 155.3,
151.7, 139.2 (1JCF＝1.4 Hz), 136.9, 134.5, 130.1, 129.4,
127.3, 126.5 (3JCF＝7.6 Hz), 119.1 (2JCF＝23.9 Hz),
114.4 (2JCF＝25.3 Hz), 112.2 (3JCF＝8.6 Hz), 111.7,
110.4, 97.7 (3JCF＝1.5 Hz), 20.8; IR (KBr) ν: 2359,
1748, 1610, 1526, 1488, 1387, 1272, 1201, 1180, 818
cm1; HRMS (ESI) calcd for C24H22FN4O2 ([M＋H]＋)
417.1727, found 417.1728.
1
(s, 1H), 7.59 (d, J＝7.2 Hz, 1H), 7.49－7.45 (m, 2H),
7.36 (t, J＝7.6 Hz, 1H), 7.28 (t, J＝8.8 Hz, 2H), 7.08 (t,
J＝7.6 Hz, 1H), 6.99 (d, J＝8.0 Hz, 2H), 6.84 (d, J＝
7.6 Hz, 1H), 6.72 (d, J＝8.4 Hz, 2H), 2.15 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ: 172.7, 164.8 (1JCF＝
247.4 Hz), 154.6, 143.1, 137.1, 133.8, 132.7, 130.9
(1JCF＝8.6 Hz), 130.2, 127.1 (2JCF＝18.3 Hz), 124.4,
123.3, 121.1 (3JCF＝3.4 Hz), 116.5 (2JCF＝22.0 Hz),
111.3, 98.1, 20.8; IR (KBr) ν: 3209, 1728, 1605, 1512,
1470, 1410, 1382, 1239, 1204, 1417, 821, 757,577 cm1;
HRMS (ESI) calcd for C22H17FN3O2 ([M ＋ H] ＋ )
374.1305, found 374.1294.
3'-(4-(Benzyloxy)phenyl)-5-methyl-4'-p-tolyl-4'H-
spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one
(4n)
1
White solid. m.p. 110－111 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.41 (s, 1H), 7.46－7.32 (m, 8H), 7.14 (d,
J＝8.0 Hz, 1H), 7.04－6.98 (m, 4H), 6.71 (t, J＝7.2 Hz,
3H), 5.11 (s, 2H), 2.27 (s, 3H), 2.17 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ: 177.4, 165.1, 159.6, 145.3,
141.7, 141.6, 139.0, 137.5, 137.2, 134.8, 134.7, 133.6,
133.1, 133.0, 131.9, 131.8, 129.7, 121.6, 120.1, 115.7,
102.9, 74.5, 25.6, 25.6; IR (KBr) ν: 3031, 1746, 1646,
1624, 1540, 1514, 1496, 1380, 1229, 818 cm1; HRMS
(ESI) calcd for C30H26N3O3 ([M＋H]＋) 476.1974, found
476.1971.
5-Chloro-3'-(4-fluorophenyl)-4'-p-tolyl-4'H-spiro-
[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4j) White
solid. m.p. 240 － 241 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 10.73 (s, 1H), 7.78 (s, 1H), 7.49－7.46
(m, 2H), 7.41－7.39 (m, 1H), 7.25 (t, J＝8.8 Hz, 2H),
7.01 (d, J＝7.6 Hz, 2H), 6.85 (d, J＝8.4 Hz, 1H), 6.77
(d, J＝8.0 Hz, 2H), 2.17 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 172.5, 164.8, 162.4, 154.5, 141.9, 137.4,
133.6, 132.6, 131.1, 131.0, 130.3, 127.3, 127.3, 126.4,
120.9, 116.4, 116.2, 112.9, 97.9, 20.8; IR (KBr) ν: 3180,
1749, 1606, 1515, 1477, 1445, 1418, 1393, 1252, 1225,
1194, 1150, 840, 816, 548 cm1; HRMS (ESI) calcd for
C22H16ClFN3O2 ([M＋H]＋) 408.0915, found 408.0916.
3'-(4-Bromophenyl)-5-chloro-4'-p-tolyl-4'H-spiro-
[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4k) White
solid. m.p. 226 － 227 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 10.73 (s, 1H), 7.77 (s, 1H), 7.62 (d, J＝
8.4 Hz, 2H), 7.40－7.34 (m, 3H), 7.02 (d, J＝8.0 Hz,
2H), 6.84 (d, J＝8.4 Hz, 1H), 6.75 (d, J＝8.0 Hz, 2H),
5-Ethyl-4'-(4-methoxyphenyl)-3'-phenyl-4'H-spiro-
[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4o) White
solid; m.p. 193 － 194 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 10.42 (s, 1H), 7.48－7.37 (m, 6H), 7.18 (d,
J＝7.6 Hz, 1H), 6.82 (d, J＝8.8 Hz, 2H), 6.73 (t, J＝8.4
Hz, 3H), 3.64 (s, 3H), 2.61－2.56 (m, 2H), 1.17 (t, J＝
7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 172.9,
158.4, 155.5, 140.9, 139.0, 131.7, 131.0, 129.3, 129.1,
129.0, 128.4, 126.3, 124.7, 124.7, 114.7, 111.0, 98.4,
55.5, 28.1, 16.3; IR (KBr) ν: 3180, 2965, 1726, 1626,
1606, 1455, 1511, 1491, 1455, 1393, 1284, 1248, 1211,
1189, 1022, 847, 834, 769, 700, 669 cm1; HRMS (ESI)
calcd for C24H22N3O3 ([M＋H]＋ ) 400.1661, found
400.1651.
13
2.16 (s, 3H); C NMR (100 MHz, DMSO-d6) δ: 172.4,
154.7, 141.9, 141.9, 137.5, 133.5, 132.6, 132.2, 130.5,
130.3, 127.4, 127.2, 127.1, 126.3, 124.7, 123.7, 112.9,
98.0, 20.8; IR (KBr) ν: 3213, 1750, 1621, 1512, 1476,
1402, 1385, 1251, 1196, 1069, 1011, 819, 714, 550 cm1;
HRMS (ESI) calcd for C22H16BrClN3O2 ([M＋H]＋)
468.0114, found 468.0108.
3'-(4-(Benzyloxy)phenyl)-5-chloro-4'-(4-isopropyl-
phenyl)-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-
1
3'-(4-Nitrophenyl)-4'-p-tolyl-4'H-spiro[indoline-3,
5'-[1',2',4']oxadiazol]-2-one (4l) Yellow solid. m.p.
one (4p) White solid. m.p. 201－202 ℃; H NMR
(400 MHz, DMSO-d6) δ: 10.73 (s, 1H), 7.66 (s, 1H),
7.44－7.33 (m, 8H), 7.07 (d, J＝8.0 Hz, 2H), 7.02 (d,
J＝8.8 Hz, 2H), 6.85 (d, J＝8.4 Hz, 1H), 6.77 (d, J＝
8.0 Hz, 2H), 5.09 (s, 2H), 2.79－2.72 (m, 1H), 1.08 (d,
J＝7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ:
172.6, 160.4, 155.1, 147.7, 141.8, 134.2, 136.8, 132.5,
130.1, 128.8, 128.4, 128.3, 127.5, 127.4, 127.1, 126.8,
126.6, 116.5, 115.3, 112.9, 97.7, 69.7, 33.1, 23.9, 23.8;
IR (KBr) ν: 2355, 1736, 1606, 1513, 1478, 1427, 1388,
1305, 1251, 1203, 1175, 829, 699 cm1; HRMS (ESI)
calcd for C31H27ClN3O3 ([M＋H]＋) 524.1741, found
1
113－114 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.62
(s, 1H), 8.27 (d, J＝8.8 Hz, 2H), 7.68 (d, J＝8.4 Hz,
2H), 7.64 (d, J＝7.2 Hz, 1H),7.38 (t, J＝7.6 Hz, 1H),
7.09 (t, J＝7.6 Hz, 1H), 7.02 (d, J＝8.0 Hz, 2H), 6.85 (d,
J＝8.0 Hz, 1H), 6.75 (d, J＝8.0 Hz, 2H), 2.16 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ: 172.4, 154.2, 148.9,
143.2, 137.4, 133.5, 132.9, 130.8, 130.4, 129.7, 127.1,
127.0, 124.4, 124.0, 123.4, 11.4, 98.6, 20.8; IR (KBr) ν:
3212, 2921, 2851, 2358, 1743, 1620, 1570, 1521, 1471,
1390, 1344, 1201, 1110, 849, 751, 692, 603 cm1;
Chin. J. Chem. 2016, 34, 901—909
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
907

Shi et al.
FULL PAPER
524.1736.
7.17 (m, 3H), 6.89－6.86 (m, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 172.1, 154.2, 142.0, 136.0, 133.1, 132.8,
129.9, 129.3, 129.0, 128.0, 127.4, 127.2, 127.0, 126.0,
118.4, 113.7, 113.0, 98.3; IR (KBr) ν: 2970, 2360, 2342,
1739, 1594, 1496, 1365, 1228, 1216, 1057, 838, 696,
668, 528 cm1; HRMS (ESI) calcd for C22H14ClN4O2
([M＋H]＋) 401.0805, found 401.0803.
5-Iodo-4'-phenyl-3'-p-tolyl-4'H-spiro[indoline-
3,5'-[1',2',4']oxadiazol]-2-one (4v) White solid. m.p.
129－131 ℃; 1H NMR (400 MHz, MeOD-d4) δ: 7.85 (s,
1H), 7.71 (d, J＝8.4 Hz, 1H), 7.37 (d, J＝8.0 Hz, 2H),
7.19－7.16 (m, 5H), 6.87－6.85 (m, 2H), 6.71 (d, J＝
8.4 Hz, 1H), 4.60 (s, 1H), 2.35 (s, 3H); 13C NMR (100
MHz, MeOD-d4) δ: 172.7, 156.0, 142.3, 141.4, 140.9,
136.2, 134.8, 129.0, 128.9, 128.0, 127.1, 126.8, 126.7,
120.9, 112.9, 97.8, 84.6, 20.0; IR (KBr) ν: 3213, 2357,
1751, 1614, 1594, 1494, 1469, 1384, 1197, 817, 694
cm1; HRMS (ESI) calcd for C22H17IN3O2 ([M＋H]＋)
482.0365, found 482.0360.
5-Bromo-3'-(4-chlorophenyl)-4'-(4-fluorophenyl)-
4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4q)
Yellow solid. m.p. 257－259 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.82 (s, 1H), 7.94 (s, 1H), 7.56－7.43 (m,
5H), 7.13 (t, J＝8.4 Hz, 2H), 6.96－6.93 (m, 2H), 6.83
1
13
(d, J＝8.4 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ:
172.1, 159.8 (1JCF＝244.4 Hz), 154.5, 142.4, 136.0,
135.6, 132.5, 152.4, 130.4, 129.9 (3JCF＝11.8 Hz), 129.7
(2JCF＝29.8 Hz), 126.3, 123.1, 116.9 (2JCF＝22.6 Hz),
115.0, 113.5, 98.0; IR (KBr) ν: 2969, 2231, 1740, 1618,
1594, 1508,1473, 1365, 1216, 1093, 832, 761, 527 cm1;
HRMS (ESI) calcd for C21H13BrClFN3O2 ([M＋ H]＋)
471.9864, found 471.9851.
4'-(4-Chlorophenyl)-5-methoxy-3'-(4-methoxyphe-
nyl)-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one
(4r) White solid. m.p. 115－117 ℃; H NMR (400
1
MHz, MeOD-d4) δ: 7.43 (d, J＝8.4 Hz, 2H), 7.16 (d,
J＝8.8 Hz, 3H), 6.96－6.92 (m, 3H), 6.84 (t, J＝8.0 Hz,
3H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,
MeOD-d4) δ: 173.4, 161.8, 156.6, 155.4, 135.5, 135.4,
132.5, 129.7, 128.8, 128.1, 125.3, 117.3, 115.6, 113.9,
112.2, 111.6, 98.4, 54.9, 54.5; IR (KBr) ν: 3254, 2836,
2358, 1742, 1608, 1492, 1383, 1256, 1177, 1028, 831,
575 cm1; HRMS (ESI) calcd for C23H19ClN3O4 ([M＋
H]＋) 436.1064, found 436.1058.
4'-(4-Bromophenyl)-3'-(4-ethoxyphenyl)-5-isopro-
pyl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-one
(4s) White solid. m.p. 91－93 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 10.55 (s, 1H), 7.37 (t, J＝6.8 Hz, 4H),
7.32 (s, 1H), 7.20 (d, J＝8.0 Hz, 1H), 6.97 (d, J＝8.8
Hz, 2H), 6.81－6.72 (m, 3H), 4.07－4.01 (m, 2H), 2.86
－2.79 (m, 1H), 1.37 (t, J＝6.8 Hz, 3H), 1.32－1.09 (m,
6H); 13C NMR (100 MHz, DMSO-d6) δ: 172.7, 160.7,
154.7, 143.7, 141.0, 137.0, 132.4, 130.5, 130.0, 128.8,
124.8, 123.9, 119.9, 116.2, 115.1, 111.0, 97.9, 63.7, 33.3,
24.4, 24.0, 14.9; IR (KBr) ν: 3423, 2969, 1739, 1609,
1515, 1489, 1379, 1253, 1216, 1105, 825 cm1; HRMS
(ESI) calcd for C26H25BrN3O3 ([M＋H]＋) 506.1079,
found 506.1070.
Biological assays
The bacterial strain of Staphylococcus aureus (Identi-
fication number: WXI-004) was obtained from WuXi
AppTec (Shanghai) Co., Ltd. Other bacterial strains,
such as Staphylococcus epidermidis (Identification
number: ATCC 35984), Escherichia coli (Identification
number: ATCC 25922), and Klebsiella pneumoniae
(Identification number: ATCC BAA-1898), were ob-
tained from American Type Culture Collection (ATCC).
Preparing compound testing plates
Testing compounds were balanced and transferred
into 1.5 mL sterile centrifuge tubes. Pure DMSO (Sigma
D5879-1L) was used to dissolve the compounds. This
stock solution was made and used on the day of testing.
On the day of testing, 980μCAMHB (Cation-adjusted
Muller Hinton Broth, BD-212322) was added into col-
umn 1 of a 96-deep well plate (Corning-3960).
Preparing bacterial inoculum
A day prior to the testing, 80 ℃ bacterial glycerol
stocks were streaked onto MHAII (Muller Hinton II
Agar, BD-211438) plates. The plates were incubated at
37 ℃ for 20 h. On the day of testing, single colonies
were picked from the plate and suspended in 5 mL of
sterile saline. A turbidity meter (Siemens MicroScan
Turbidity Meter) was used to adjust the turbidity to 0.5
McFarland standard, which is equivalent to a bacterial
density of ~1.0×108 CFU/mL. The bacteria/saline sus-
pension was diluted another 100× in a CAMHB to 1.0
×106 CFU/mL. This was used as the inoculum.
4'-(4-Iodophenyl)-5-methoxy-3'-phenyl-4'H-spiro-
[indoline-3,5'-[1',2',4']oxadiazol]-2-one (4t) White
solid. m.p. 131 － 133 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 10.47 (s, 1H), 7.55 (d, J＝8.0 Hz, 2H),
7.49－7.47 (m, 1H), 7.44 (s, 4H), 7.19 (s, 1H), 6.95 (d,
J＝6.8 Hz, 1H), 6.78 (d, J＝8.4 Hz, 1H), 6.61 (d, J＝
8.4 Hz, 2H), 3.73 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 172.4, 156.0, 154.9, 138.4, 136.7, 136.2,
131.3, 129.3, 128.8, 128.5, 125.2, 124.3, 118.2, 112.7,
112.2, 98.3, 93.1, 56.1; IR (KBr) ν: 3234, 2833, 1742,
1596, 1491, 1380, 1297, 1202, 1027, 820, 769, 749, 697
cm1; HRMS (ESI) calcd for C22H17IN3O3 ([M＋H]＋)
498.0315, found 498.0314.
Minimum inhibitory concentration (MIC) test
An aliquot of 100 µL bacterial inoculum was trans-
ferred into each well of the compound testing plates.
Each testing plate was inoculated with a single strain to
prevent cross contamination. The final testing concen-
trations were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125
4-(5-Chloro-2-oxo-4'-phenyl-4'H-spiro[indoline-3,
5'-[1',2',4']oxadiazole]-3'-yl)benzonitrile (4u) White
solid. m.p. 99－101 ℃; 1H NMR (400 MHz, DMSO-d6)
δ: 10.82 (s, 1H), 7.91 (d, J＝8.4 Hz, 2H), 7.81 (s, 1H),
7.62 (d, J＝8.4 Hz, 2H), 7.42－7.39 (m, 1H), 7.25－
908
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 901—909

Synthesis of 3',4'-Diaryl-4'H-spiro[indoline-3,5'-[1',2',4']oxadiazol]-2-ones
[9] Hagiwara, H.; Inoguchi, H.; Fukushima, M.; Hoshi, T.; Suzuki, T.
Tetrahedron Lett. 2006, 47, 5371.
and 0 µg/mL. The starting bacterial density was ~5×
105 CFU/mL. The testing plates were incubated at
37 ℃ for 20 h before the MICs were read.
[10] (a) Zhang, Q.; Meng, L.-G.; Zhang, J.; Wang, L. Org. Lett. 2015, 17,
3272; (b) Yang, H.-T.; Ren, W.-L.; Miao, C.-B.; Dong, C.-P.; Yang,
Y.; Xi, H.-T.; Meng, Q.; Jiang, Y.; Sun, X.-Q. J. Org. Chem. 2013,
78, 11630; (c) Chen, L.; Wu, Z.; Peng, L.; Wang, Q.; Xu, X.; Wang,
L. Chin. J. Chem. 2014, 32, 844.
Determining the MIC
After the 20 h incubation, the MICs were evaluated
by visual observation. Based on the CLSI-M7, the MIC
is defined as the minimum compound concentration that
completely or significantly inhibits the growth of bacte-
rium.
[11] Zhou, M.-Q.; Zhao, J.-Q.; You, Y.; Xu, X.-Y.; Zhang, X.-M.; Yuan,
W.-C. Tetrahedron 2015, 71, 3903.
[12] (a) Verma, G. K.; Shukla, G.; Nagaraju, A.; Srivastava, A.;
Raghuvanshi, K.; Singh, M. S. RSC Adv. 2014, 4, 11640; (b)
Castillo-Contreras, E. B.; Dake, G. R. Org. Lett. 2014, 16, 1642; (c)
Verma, G. K.; Shukla, G.; Nagaraju, A.; Srivastava, A.; Singh, M. S.
Tetrahedron 2014, 70, 6980; (d) Chang, M.; Wu, C.; Zheng, J.;
Huang, Y. Chem. Asian J. 2016, 11, 1512.
Acknowledgement
The work was partially supported by the National
Natural Science Foundation of China (Nos. 21172001,
21372008), the Natural Science Foundation of Educa-
tion Administration of Anhui Province (No.
KJ2016A267), the Special and Excellent Research Fund
of Anhui Normal University and the Doctoral Scientific
Research Foundation of Anhui Normal University (No.
2016XJJ110).
[13] (a) Meng, L.-G.; Li, C.-T.; Zhang, J.-F.; Xiao, G.-Y.; Wang, L. RSC
Adv. 2014, 4, 7109; (b) Derabli, C.; Boulcina, R.; Kirsch, G.; Car-
boni, B.; Debache, A. Tetrahedron Lett. 2014, 55, 200; (c) Han, C.;
Meng, W.; Liu, H.; Liu, Y.; Tao, J. Tetrahedron 2014, 70, 8768.
[14] (a) Gellis, A.; Kieffer, C.; Primas, N.; Lanzada, G.; Giorgi, M.; Ver-
haeghe, P.; Vanelle, P. Tetrahedron 2014, 70, 8257; (b) Sword, R.;
Baldwin, L. A.; Murphy, J. A. Org. Biomol. Chem. 2011, 9, 3560; (c)
Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N. Org. Biomol.
Chem. 2006, 4, 2525; (d) Chen, L.; Wu, Z.; Peng, L.; Wang, Q.; Xu,
X.; Wang, L. Chin. J. Chem. 2014, 32, 844; (e) Shang, Y.-J.; Ren,
L.-B.; Wang, D.-M. Chin. J. Chem. 2007, 25, 1202; (f) Mandai, H.;
Fujii, K.; Yasuhara, H.; Abe, K.; Mitsudo, K.; Korenaga, T.; Suga, S.
Nature Comm. 2016, 15, 11297; (g) Steglich, W.; Höfle, G. Angew.
Chem., Int. Ed. Engl. 1969, 8, 981; (h) Spivey, A. C.; Arseniyadis, S.
Angew. Chem., Int. Ed. 2004, 43, 5436.
[15] (a) Fan, C.-L.; He, X.-W.; Liao, K.-S.; Wang, C.-E.; Shang, Y.-J.
Chem. Res. Chin. Univ. 2016, 32, 62; (b) Shang, Y.-J.; Wang, C.-E.;
He, X.-W.; Ju, K.; Zhang, M.; Yu, S.-Y.; Wu, J.-P. Tetrahedron 2010,
66, 9629.
[16] Wu, J.-P.; Shang, Y.-J.; Wang, C.-E.; He, X.-W.; Yan, Z.-L.; Hu,
M.-M.; Zhou, F.-Y. RSC Adv. 2013, 3, 4643.
[17] Crystallographic data for 4b: space group P-1, a＝6.6117(8) Å, b＝
10.4562(13) Å, c＝13.3718(17) Å, α＝83.340(3)o, β＝79.712(3)o,
γ＝77.553(3)o, V＝885.30(19) Å3, T＝293 K, Z＝2. Crystallograph-
ic data for compound 4b (CCDC-1436324) reported in this paper
can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
References
[1] (a) Zheng, H. F.; Liu, X. H.; Feng, X. M. Angew. Chem., Int. Ed.
2015, 54, 10958; (b) Dmytro, H.; Borys, Z.; Roman, L. J. Med.
Chem. 2012, 55, 8630.
[2] (a) Neeraj, N. P.; Emily, A. M.; Webster, L. K. J. Med. Chem. 2015,
58, 1879; (b) Puneet, K. G.; Mohd, K. H.; Kanchan, H. New J. Chem.
2014, 38, 3062; (c) Carlos, E.; Puerto, G.; Vladimir, V. K. Org.
Biomol. Chem. 2013, 11, 7372.
[3] James, N. D.; Growcott, J. W. Drugs Future 2009, 34, 624.
[4] Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.;
Ferrara, M.; Fiore, F.; Gardelli, C.; Paz, O. G.; Hazuda, D. J.; Jones,
P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.;
Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.;
Witmer, M. V.; Rowley, M. J. Med. Chem. 2008, 51, 5843.
[5] Browne, L.; Lidster, K.; Al-Izki, S.; Clutterbuck, L.; Posada, C.;
Chan, A. W. E.; Riddall, D.; Garthwaite, J.; Baker, D.; Selwood, D.
L. J. Med. Chem. 2014, 57, 2942.
[18] (a) Rajasekaran, T.; Karthik, G.; Sridhar, B.; Reddy, B. V. S. Org.
Lett. 2013, 15, 1512; (b) Shi, G.-H.; He, X.-W.; Shang, Y.-J.; Xie,
M.-H. RSC Adv. 2016, 6, 10412; (c) Wang, C.-S.; Zhu, R.-Y.; Zheng,
J.; Shi, F.; Tu, S.-J. J. Org. Chem. 2015, 80, 512.
[6] Bourbeau, M. P.; Siegmund, A.; Allen, J. G.; Shu, H.; Fotsch, C.;
Bartberger, M. D.; Kim, K.-W.; Komorowski, R.; Graham, M.; Bus-
by, J.; Wang, M.; Meyer, J.; Xu, Y.; Salyers, K.; Fielden, M.; Véniant,
M. M.; Gu, W. J. Med. Chem. 2013, 56, 10132.
[19] (a) Vitale, P.; Nunno, L. D.; Scilimati, A. Snythesis 2010, 18, 3195;
(b) Strecker, B.; Werner, H. Z. Anorg. Allg. Chem. 1991, 605, 59.
[20] Liu, Z.; Ma, Q.; Liu, Y.; Wang, Q. Org. Lett. 2014, 16, 236.
[21] (a) Dandia, A.; Jain, A. K.; Laxkar, A. K. RSC Adv. 2013, 3, 8422;
(b) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal,
P. T. Eur. J. Med. Chem. 2012, 51, 79.
[7] (a) Ken-ichi, I.; Hiroshi, S.; Akira, H. C. Synthesis 2005, 1935; (b)
Bogdan, A. R.; Wang, Y. RSC Adv. 2015, 5, 79264; (c) Azizian, J.;
Jadidi, K.; Mehrdad, M.; Sarrafi, Y. Synth. Commun. 2000, 30,
2309.
[8] Wang, Y.-Z.; Kataeva, O.; Metz, P. Adv. Synth. Catal. 2009, 351,
2075.
(Pan, B.; Qin, X.)
Chin. J. Chem. 2016, 34, 901—909
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www.cjc.wiley-vch.de
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