I2 mediated synthesis of 5-substituted-3-methyl/benzyl-1,3,4-oxadiazol-2(3H)-ones via sequential condensation/oxidative cyclization and rearrangement

Article abstract of DOI:10.1039/c5ob02667a

A simple and efficient iodine-assisted protocol for the synthesis of 5-substituted-3-methyl/benzyl-1,3,4-oxadiazol-2(3H)-ones has been developed. The reaction involves a sequential condensation followed by tandem oxidative cyclization and rearrangement of

Full text of DOI:10.1039/c5ob02667a

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DOI: 10.1039/C5OB02667A
Journal Name
ARTICLE
I2 mediated synthesis of 5-substituted-3-methyl/benzyl-1,3,4-
oxadiazol-2(3H)-ones via sequential condensation/ oxidative
cyclization and rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
*a
DOI: 10.1039/x0xx00000x
Shyam Sunder Patel, Nisha Chandna, Shreemoyee Kumar, and Nidhi Jain
www.rsc.org/
A simple and efficient iodine-assisted protocol for synthesis of 5-substituted-3-methyl/benzyl-1,3,4-oxadiazol-2(3H)-ones
has been developed. The reaction involves a sequential condensation followed by tandem oxidative cyclization and
rearrangement of readily available methyl/benzyl carbazates and aldehydes as starting substrates. The presence of iodine
and base promotes an intramolecular C-O bond formation, followed by Chapman-like rearrangement of methyl/benzyl
group at 90 °C in the hydrazone intermediate formed during the condensation step. This transition-metal-free approach
has been adopted to generate a variety of oxadiazolones under mild conditions in good to excellent yields.
Generally, these methodologies can be divided into three
classes (Scheme 1): (a) substitution of 5-substituted-1,3,4-
INTRODUCTION
5
oxadiazol-2-(3H)-ones with alkyl halide (b) cyclization of N-
Nitrogen and oxygen containing heterocycles are an important
class of compounds, and constitute many biologically potent
9
substituted-acylhydrazines in the presence of phosgene or
11
1
selenium-activated carbon monoxide and N-acylhydrazine-
molecules. In this series, 1,3,4-oxadiazol-2(3H)-one is a
1
2
1
,2-dicarboxylates
on
heating
(c)
privileged five-membered heterocycle, and has a revitalized
interest due to its broad pharmaceutical scope encompassing
1
3, 14
transformations/conversions of heterocyclic rings.
2
3
activities such as antibacterial, antitubercular, anti-tumor
4
5
and anti HCV, inhibition of selective monoamine oxidase B
Cl
O
Cl
O
6
and hormone sensitive lipase (HSL). These rings are also
important structural components of agrochemicals such as
herbicides, and fungicides. The research on environmentally
benign protoporphyrinogen oxidase (PPO) inhibiting molecules
O
O
Cl
N
Cl
N
N
N
O
O
A
B
has led to the emergence of oxadiazon (A) and oxadiargyl (B)
bearing a 1,3,4-oxadiazol-2(3H)-one core as commercial
herbicides (Fig. 1). In addition, oxadiazolones which have
7
O
O
O
O
recently been reported as tetrazole and carboxylic acid
N
N
OH
N
8
N
N
bioisosteres, can be applied to novel drug design. 5-
N
Cl
substituted-3-methyl/benzyl-1,3,4-oxadiazol-2-ones are also
found to act as an essential part of the pharmacophore in
Cl
CF3
2+
openers of large-conductance Ca -activated potassium (Maxi-
C
D
9
10
K) channels (
C), fungicides (D) and function tools in chemical
Fig. 1 Structures of pharmacologically potent 1,3,4-oxadiazol-2(3H)-ones
science (Fig. 1).
Since these molecules are of considerable interest owing to
their wide commercial application, several strategies targeting
Although these procedures are useful for construction of 1,3,4-
oxadiazolone cores, they suffer from limitations of multistep
synthesis, use of expensive and toxic reagents and catalysts,
elevated temperatures, long reaction time, laborious reaction
procedures, and low product yields. Therefore development of
mild, efficient, and atom-economical methods for direct
installation of a methyl/benzyl moiety to the structurally
diverse 1,3,4-oxadiazolone scaffold remains highly desirable.
the
synthesis
of
5-substituted-3-methyl/benzyl-1,3,4-
oxadiazol-2-ones have been developed over the years.
a.
Department of Chemistry, Indian Institute of Technology, New Delhi-110016,
India
*Corresponding
Author
Phone:
011-2659-1562.
E-mail:
njain@chemistry.iitd.ac.in.
Electronic Supplementary Information (ESI) available: [Copies of H NMR,
1
13
†
C
NMR, and HR-MS for all the synthesized compounds, ORTEP and associated X-ray
crystallographic data for 4o, have been included.]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
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DOI: 10.1039/C5OB02667A
H
Previous Work
N
N
O
R2
O
on
ti
la
ky
O
N
O
R1
N
R1
al
O
O
O
N
NHNHR1 R2
R1
NH
R2
O
c clization
y
R2
O
O
tra
ns
for
O
m
a
tion
s
R1
R1
N
O
N
N
N
N
N R1
O
R2
R1
This Work
Aryl
N
N
O
Aryl
&
e eroar
H t
yl
O
1. Ethanol, r.t.
R1
O
&
CHO + H NHN
O
2
Heteroaryl
2. I , K CO DMSO
2
2
3,
1
R = Me or Bn
o
9
0 C, 1 h
Scheme 1 An overview of various methods for the construction of 5-substituted-3-alkyl-1,3,4-oxadiazol-2(3H)-ones
In recent years, nonmetallic molecular iodine has emerged purified by column chromatography, and confirmed as 3-
as a useful reagent in organic synthesis owing to its versatility, methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one 4a (Table 1).
affordability, ready availability and environmental Apparently, the reaction seemed to involve the migration of
(
)
sustainability. Wu and co-workers have developed new methyl group from 2-methoxy-5-phenyl-1,3,4-oxadiazole
synthetic routes for a variety of compounds using molecular generated in situ during the reaction, to N-3 resulting in 4a. A
1
5-19
iodine.
Several other groups have successfully employed similar 1,3-migratory rearrangement in oxadiazoles has
20
21
22, 23
31, 32
iodine for the synthesis of pyrazole, indole and oxazole
previously been reported by Chapman and others.
In order
derivatives. More recently, various oxadiazole derivatives like to confirm this observation, we carried out control experiment
symmetrical2 and unsymmetrical 2,5-disubstituted 1,3,4- at 40 °C. At this temperature, the reaction went up till
4,25
26
oxadiazoles,
2-amino-1,3,4-oxadiazoles , 3-amino-1,3,4- formation of oxadiazole, which was isolated and characterized
2
7
28
33
oxadiazoles and α-keto-1,3,4-oxadiazoles have also been by NMR. However, on increasing the temperature to 90 °C,
synthesized using molecular iodine. However, preparation of oxadiazole was found to rearrange to the isolated 1,3,4-
5
-substituted-3-alkyl-1,3,4-oxadiazol-2(3H)-ones
through oxadiazolone 4a. Michel Golfier et al. earlier reported that in
direct oxidative cyclization of the corresponding carbazates is case of 2-alkoxy-5-aryl-l,3,4-oxadiazole as substrate, this
not yet reported in literature. Appreciating these findings, and rearrangement occurred near 180 °C in neat molten conditions
anticipating the likelihood of an iminoether-amide (no reaction was found to occur in solution, at the same
31
rearrangement in 2-alkoxyoxadiazoles, we explored I - temperature). Further, they also documented that this
2
mediated tandem synthesis of 1,3,4-oxadiazol-2(3H)-one rearrangement was unusually fast in the solid crystalline state
framework starting from methyl/benzyl carbazates and for some derivatives of 2-methoxy-5-aryl-l,3,4-oxadiazoles due
aldehydes as the substrates.
to a double ionic mechanism, verified by theoretical and
3
4
experimental results. To the best of our knowledge, this is
the first report where a solvent mediated rearrangement of 2-
methoxy-5-substituted-1,3,4-oxadiazole derivatives at a much
lower temperature is being demsonstrated.
RESULT AND DISCUSSION
Transition metal-free approach that can construct the C−O
2
9, 30
In a quest to improve the yield of rearranged product 4a
,
bond through an intramolecular cyclisation
initially, to investigate the oxidative cyclization of the purified
-methoxy carbonylhydrazone (3a), prepared by condensation
of benzaldehyde (1a) and methylcarbazate ( ) in ethanol at
motivated us
different solvents were screened. It was found that switching
from DMF to DMSO (entry 2, Table 1) improved the yield of 4a
to 88%, while other solvents such as 1,4-Dioxane, Toluene,
DimethylAcetamide, N-Methyl-2-pyrrolidone etc. were less
effective for the reaction (entries 3-7). Encouraged by these
preliminary results, we initiated further optimization with
respect to catalyst, base, oxidant, and temperature. Use of
3
2
room temperature (Table 1). Compound 3a was treated with I2
in the presence of K CO in N,N-dimethylformamide (DMF) at
2
3
9
0 °C. On completion of reaction as seen on TLC, the workup
afforded a single product in moderate yield (72%) which was
2
| J. Name., 2012, 00, 1-3
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ARTICLE
other catalysts known to furnish iodine like TBAI, DIB, and KI the above optimized reaction conditions (I , K CO , DMSO, 90
2
2
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3
was found to be detrimental for the reaction, and gave 4a in °C) resulting in the formation of 4a in anDeOqIu: a10ll.y10g3o9/oCd5OyiBe0l2d6(6878A
trace amounts (entries 8-10).
%, Table 1). After determining the best conditions for a
sequential tandem reaction, we investigated its generality and
scope by reacting a range of aryl and heteroaryl aldehydes
with methylcarbazate (Table 2). Under the optimal reaction
conditions, mono-substituted benzaldehydes bearing both
electron-donating and electron-withdrawing groups (bromo,
chloro, fluoro) at ortho-, meta-, and para- positions were
converted to the corresponding 5-substituted phenyl-3-
methyl-1,3,4-oxadiazol-2(3H)-ones (4b−k) in good to excellent
yields. No acceleration or retardation in the reaction rate was
observed upon changing the position of the substituent on the
phenyl ring. With di- and tri-substituted benzaldehydes also,
the corresponding products were obtained in moderate to
high yields (4l and 4m). It is believed that steric hindrance
might be responsible for the reduced yield in case of tri-
substituted benzaldehyde (4m). However, reaction with
benzaldehydes bearing strong electron-withdrawing groups
Table 1: Optimization of reaction conditions for synthesis of 3-methyl-5-phenyl-1,3,4-
a, b
oxadiazol-2(3H)-one.
CH
3
CHO
N
N
H
O
N
OMe
O
O
Ethanol, r.t
N
Conditions
+
NH NHC OMe
2
O
1
a
2a
3a
4a
b
entry
reagent
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
.
.
.
.
.
.
.
.
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
TBAI
K
K
K
K
K
K
K
K
K
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
DMF
DMSO
72
88
2
3
3
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
1,4-Dioxane
Toluene
DMA
Trace
Trace
52
NMP
35
EtOAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Trace
Trace
Trace
18
72
29
such as NO gave low yield of 3-methyl-5-(3-nitrophenyl)-
2
1
,3,4-oxadiazol-2(3H)-one (4n) due to incomplete Chapman-
.
PhI(OAc)
KI
2
0.
1.
2.
3.
4.
5.
6.
7.
rearrangement, and the intermediate compound, 2-methoxy-
5-(3-nitrophenyl)-1,3,4-oxadiazole was also isolated along with
4n (see supporting data). With nitro- substitution at ortho-
and para- positions of benzaldehyde, the corresponding 1,3,4-
oxadiazol-2(3H)-ones were not obtained, and the reaction
mixture was found to decompose after 1 h of stirring at 90 °C.
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Iodine
Cs
K
KOH
DBU
NEt
2
CO
PO
3
3
4
11
Trace
Trace
Trace
3
t
LiO Bu
A
similar behavior was observed with benzaldehydes
c
d
e
f
K
2
CO
3
49 , 38 , 71 ,56
a
substituted with CN, and CF groups at para- position.
3
Reaction conditions: 1a (0.18 mmol, 1.0 equiv.), 2a (0.22 mmol, 1.0 equiv.), reagent
°
b
c
Surprisingly, however, reaction went smoothly with para-
COOMe substituted benzaldehyde probably due to a weaker
electron withdrawing infuence, and moderate yield of 4o was
(
1.2 equiv.), base (3.0 equiv.) in DMSO, stirred at 90 C in air for 1 hour. HPLC yield. I
2
d
e
°
f
°
used was 0.5 equiv.
2 3
K CO used was 1.5 equiv. 110 C. 70 C.
Further optimization with respect to various organic and obtained.
inorganic bases indicated potassium carbonate to be the base
of choice, as it yielded the highest yield of 4a (88% yield, entry Table 2: Synthesis of 3-methyl-5-substitued-1,3,4-oxadiazol-2(3H)-one derivatives
a, b
2
). With other bases like Cs CO , K PO , KOH, DBU, Et N, and
2 3 3 4 3
CH
N
N
3
t
LiO Bu (entries 11-17), the yields of product 4a lowered
significantly except for Cs CO where moderate yield (72%,
entry 11) was obtained. This suggested that organic bases
were inferior to the inorganic carbonate bases for this
reaction. Variation in amount of I and K CO was carried out
1
. Ethanol, r.t
R-CHO
+
NH NHCOOCH3
O
2
R
O
2. I , K CO
2
3
R
=
a yl/hete oa yl
r
r
r
2
2
3
o
4(a-t)
1
2a
DMSO,
90
C, 1 h
CH
3
CH
CH
3
CH3
N
CH3
N
N
3
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
2
2
3
MeO
Me
Br
Cl
next, and it was found that 1.2 equiv. of I and 3 equiv. of
K CO were ideal for the reaction (entry 17). The effect of
4a, 86%
4b
, 88%)
4c, 92%
4d, 75%
( )
(4e, 72%)
2
(
)
(
(
)
Br
CH
3
CH
CH
CH
N
3
CH
3
2
3
3
3
N
N
N
N
N
N
N
N
N
temperature on product yield was also monitored. Decreasing
and increasing the temperature from 90 °C resulted in lower
product yields (entry 17).
With the set of optimized conditions, we investigated if the
developed protocol could be executed in one pot. 1a and 2a
were taken in DMSO and heated at 90 °C. When formation of
O
O
O
O
O
O
O
O
O
O
Br
F
F
4g, 88%
)
(
4h, 85%
)
(4i, 88%)
CH3
(4j, 86%)
(
4f,
7
1%
)
(
Cl
CH
3
CH
3
CH3
N
N
N
N
N
N
CH3
N
N
O
N
N
O
O
O N
2
M
eO
O
O
O
O
O
O
O
Cl
MeO
MeO
OMe
MeOOC
O
Me
3
a
was seen (as evident by TLC), I and K CO were added in
4k, 83%
( )
4l, 84%
2
2
3
(
)
4m, 68%, 2 h
(4n, 30%, 2 h)
4o, 48%, 2 h
( )
CH
N
N
(
)
the same pot and reaction was run up to 4 hours at 90 °C. It
was found that the overall conversion was less, and only 58%
product was isolated. To improve the efficacy of the reaction,
a sequential approach was adopted. In this, after completion
of the first-step involving condensation of 1a and 2a in
ethanol, the solvent (ethanol) was evaporated under reduced
pressure and the resulting crude 3a was directly subjected to
CH3
N
CH3
N
3
CH3
N
N
CH
3
N
N
N
N
O
O
O
O
O
O
O
O
O
O
N
S
O
N
H
4%
)
4
q, %)
85
ORTEP of 4q
(
, %,
4r 83 2 h
)
(
4s, 79%, 1.5 h
)
( )
4t, 81%, 2 h
(
4p,
8
(
a
2 3
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), iodine (0.6 mmol), K CO (1.5
mmol) in DMSO (5 mL), stirred at 90 C under air for 1 hour. Isolated yield.
o
b
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The reaction with other aromatic/heteroaromatic
aldehydes such as α-naphthaldehyde, -picolinaldehyde, occurs to generate oxadiazole (
furfural, β-indolylaldehyde and 2-formylthiophene also gave hydroiodic acid (HI). (4) Finally,
(C). (3) A base assisted elimination and aromatization of C
View Article Online
DOI: 10.1039/C5OB02667A
β
D
) with the release of
a
3
1, 34
Chapman-like
the desired products (4p-4t) in satisfactory yields. The rearrangement at 90 C provides the desired oxadiazolone
structure of 3-methyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-2(3H)- product ( ).
one 4q (Table 2) was further confirmed by X-ray
o
E
(
)
DMSO
I2 +DMSO
crystallography (see Supporting Information).
I
I
Fortified by the successful synthesis of an array of 3-
methyl-5-substitued-1,3,4-oxadiazol-2(3H)-ones, we further
extended the scope of this consecutive approach by replacing
methylcarbazate with benzylcarbazate. Upon completion of
condensation of benzylcarbazate 2b and the corresponding
H
N
OMe
R1
N
A
O
R1
O
I
N
B
O
H NHN
OMe
aldehyde
1
in ethanol, the reaction mixture was concentrated,
2
N
O
H
OMe
redissolved in DMSO, and treated with molecular iodine and
potassium carbonate. Gratifyingly, stirring the resulting
mixture at 90 °C for 1−2 h (see the Experimental Section)
yielded the desired 3-benzyl-5-substitued-1,3,4-oxadiazol-
R1
H
Base
C
OMe
N
Me
O
N
N
R1
H
2
1
(3H)-ones (
5
) with a migrated benzyl group on the nitrogen of
D
N
I
O
R1
O
N
R1
O
,3,4-oxazolidinone ring. This sequential synthesis protocol
O
N
Me
E
also endured substituted aromatics with electron withdrawing
chloro, fluoro) and electron donating groups (methyl,
Chapman
rearrangement
(
HI
methoxy), as well as heteroaromatic aldehydes to provide a
series of 3-benzyl-5-substitued-1,3,4-oxadiazol-2(3H)-one
Fig. 2 Proposed mechanism for the formation of 5-substituted-3-alkyl-1,3,4-oxadiazol-
derivatives (5b-5i) in moderate yields (Table 3). With strong 2(3H)-ones
electron withdrawing groups such as NO at ortho-, meta-,
2
para- position or CN and CF at para- position of substituted
3
CONCLUSIONS
In summary, we have developed a method for the synthesis of
benzaldehydes, reaction with benzylcarbazate did not yield the
desired 1,3,4-oxadiazol-2(3H)-ones. Instead, a decomposed
reaction mixture was always observed. In contrast, para-
COOMe substituted benzaldehyde tolerated the reaction
conditions with benzyl carbazate as above with
methylcarbazate, and yielded the corresponding oxadiazol-2-
one 5i albeit in low yield.
5
-substituted-3-alkyl-1,3,4-oxadiazole-2-(3H)-ones
starting
from aldehydes and carbazates. The protocol involves a
sequential condensation, oxidative cyclization, and a facile
Chapman-like rearrangement in a tandem manner. The
strategy is highly economical, and uses stoichiometric amounts
of molecular iodine and potassium carbonate for effecting the
reaction. It boasts of a transition metal-free route, and is
highly versatile for synthesising a library of substituted-1,3,4-
oxadiazole-2-(3H)-one derivatives in good to excellent yields.
a, b
Table 3: Synthesis of 3-benzyl-5-substitued-1,3,4-oxadiazol-2(3H)-one derivatives
Ethanol, 10 min, r.t
N
N
R-CHO
+
NH NHCOOCH Ph
2
2
I
2
, K
2
CO
o
3
O
R= aryl/heteroaryl
R
O
5(a-i)
DMSO, 90 C, 1 h
1
2b
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
EXPERIMENTAL SECTION
General Information:
Cl
F
MeO
5
a, 88%
)
(5b, 86%)
(5c, 88%)
(5d, 87%)
(
N
N
N
All reactions were carried out under an air atmosphere in
oven-dried round bottom flasks. Melting points were
determined in open glass capillaries in an electrical melting
point apparatus, and were uncorrected. Reagents were
purchased at the highest commercial quality and used without
further purification, unless otherwise stated. Reactions were
monitored by thin layer chromatography (TLC) carried out on a
N
N
N
N
N
N
N
O
MeO
MeO
O
O
O
O
O
O
O
O
O
O
Me
Me
N
H
OOC
OMe
(
5
e, 85%
)
(
5f, 65%, 2 h
)
(
5g, 75%, 2 h
)
(
5h, 73%, 2 h
)
(
5i, 35%, 2 h
)
a
Reaction conditions: 1a (0.5 mmol), 2b (0.5 mmol), iodine (0.6 mmol), K
mmol) in DMSO (5 mL), stirred at 90 C under air for 1 hour. Isolated yield.
2 3
CO (1.5
o
b
2
4, 25
Based on literature reports
and control experiments, a
0
.25 mm silica gel plates (60F−254) and visualized under UV
plausible mechanism for the formation of 1,3,4-oxadiazolones
is outlined in Figure 2. The first step involves (1) condensation
of aldehyde and carbazate to afford the key hydrazone
illumination at 254 nm. Further visualization was achieved by
iodine vapour adsorbed on silica gel depending on the product
type. Organic extracts were dried over anhydrous sodium
sulphate. Solvents were removed in a rotary evaporator under
reduced pressure. Column chromatography was performed on
intermediate
iminium iodide
cyclization, the iminium carbon in
intramolecularly by the amidic oxygen to afford intermediate
A
. The imine nitrogen of
(2) Subsequently, during oxidative
is attacked
A attacks I to form an
2
B
.
B
silica gel 100−200 mesh using a mixture of hexane and ethyl
acetate as eluent, an isolated compounds were characterized
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 5 of 9
Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
1
13
+
by H NMR, C{1H} NMR, HRMS. NMR spectra for all the HRMS (ESI) m/z [M+Na] calc. for C H N NaO 213.0634,
1
0
10
2
View Article Online
2
DOI: 10.1039/C5OB02667A
samples were measured in deuterochloroform (CDCl ) and found 213.0637.
dimethylsufoxide-d (DMSO-d ). H and C-NMR spectra were
3
1
13
6
6
recorded at ambient temperature on 300 MHZ and 75 MHz
spectrometer using tetramethylsilane (TMS) as internal
reference. The chemical shifts are quoted in δ units, parts per
5
-(4-bromophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4d):
1
Yield 95 mg, 75%; white crystalline solid, m.p. 134-135 °C; H
NMR (300 MHz, CDCl ): 7.63 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J =
8
1
1
3
million (ppm) up field from the signal of internal TMS. H NMR
13
.4 Hz), 3.47 (s, 3H); C NMR (75 MHz, CDCl ): 153.41, 152.27,
3
data is represented as follows: Chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd =
double doublet), integration and coupling constant(s) J in Hertz
+
32.28, 126.91, 126.07, 122.71, 32.79; HRMS (ESI) m/z [M+H]
calc. for C H BrN O 254.9764, found 254.9765
9
8
2 2
(
Hz). High resolution mass spectra (HRMS) were recorded on a
Mass spectrometer using electrospray ionization-time of flight
ESI-TOF) reflectron experiments.
5
-(3-bromophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4e):
1
(
Yield 91 mg, 72%; white solid, m.p. 97-98 °C; H NMR (300
MHz, CDCl ): 7.97 (s, 1H), 7.74 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J
3
13
=
8.1 Hz), 7.36-7.31 (m, 1H), 3.50 (s, 3H); C NMR (75 MHz,
General procedure:
CDCl ): 153.40, 151.73, 134.46, 130.53, 128.45, 125.67, 124.06,
3
To a stirred solution of aldehyde (
1
, 0.5 mmol) in ethanol (1
+
1
2
23.07, 32.84; HRMS (ESI) m/z [M+H] calc. for C H BrN O
9 8 2 2
54.9764, found 254.9768.
mL), carbazate (
stirred at room temperature until condensation was complete
monitored by TLC). Thereafter, the solvent was evaporated
under reduced pressure, and the resulting residue was re-
2, 0.5 mmol) was added. The contents were
(
5
-(2-bromophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4f):
1
dissolved in dimethylsufoxide (DMSO) (5 mL), followed by Yield 90 mg, 71%; white solid, m.p. 70-71 °C; H NMR (300
addition of potassium carbonate (1.5 mmol) and iodine (0.6 MHz, CDCl ): 7.70 (d, 2H, J = 7.5 Hz), 7.41-7.33 (m, 2H), 3.53 (s,
3
1
3
mol) in sequence. The reaction mixture was stirred at 90 °C 3H); C NMR (75 MHz, CDCl ): 153.40, 151.77, 134.76, 132.22,
3
+
until complete conversion was observed (monitored by TLC, 130.40, 127.55, 124.67, 120.72, 32.88; HRMS (ESI) m/z [M+H]
1
5
3
−2 h). After cooling to room temperature, it was treated with calc. for C H BrN O 254.9764, found 254.9769.
9 8 2 2
% Na S O (20 mL) and extracted with ethyl acetate (10 mL ×
2
2 3
). The combined organic layer was dried over anhydrous 5-(4-fluorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4g):
sodium sulfate and concentrated. The residue was purified
through silica gel column chromatography using a mixture of
ethyl acetate and hexane (0.7:9.3 to 2:8) as eluent to afford
14
Yield 85 mg, 88%; white crystalline solid, m.p. 87-89 °C (lit.
1
mp 86-88 °C); H NMR (300 MHz, CDCl ): 7.71-7.67 (m, 2H),
.07-7.01 (m, 2H), 3.38 (s, 3H); C NMR (75 MHz, CDCl ):
3
64.50 (d, J = 251.2 Hz), 153.48, 152.21, 127.75 (d, J = 9
Hz), 120.11 (d, J = 3.7 Hz), 116.24 (d, J = 21.7 Hz), 32.63;
3
13
7
1
the
corresponding
5-substituted-3-methyl/benzyl-1,3,4-
and in 65-92% yield.
1
3
CF
CF
oxadiazol-2(3H)-ones
4
5
4
2
CF
CF
+
HRMS (ESI) m/z [M+H] calc. for C H FN O 195.0564, found
9
8
2 2
3
-methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (4a):
.5 mmol scale, yield 76 mg, 86%; white crystalline solid, m.p.
195.0565.
0
9
7
12
1
7-99 °C (lit. m.p. 98.2-99.8 °C); H NMR (300 MHz, CDCl ): 5-(2-fluorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4h):
3
13
.76 (s, 2H), 7.42 (d, 3H, J = 7.2 Hz), 3.44 (s, 3H); C NMR (75
1
Yield 82 mg, 85%; white crystalline solid, m.p. 62-64 °C; H
NMR (300 MHz, CDCl ): 7.64-7.59 (m, 1H), 7.37-7.24 (m, 1H),
MHz, CDCl ): 153.53, 152.88, 131.38, 128.87, 125.41, 123.75,
3
found 177.0658.
3
3
+
2.60; HRMS (ESI) m/z [M+H] calc. for C H N O 177.0659,
13
9
9 2 2
7
.14-7.07 (m, 2H), 3.38 (s, 3H); C NMR (75 MHz, CDCl3):
1
1
59.73 (d, J = 257.2 Hz), 153.09, 149.61, 149.57, 133.54 (d,
CF
3
4
2
JCF = 8.4 Hz), 128.25, 124.51 (d, J = 3.7 Hz), 116.82 (d, J
=
CF
CF
2
5
-(4-methoxyphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4b):
20.2 Hz), 112.13 (d, J = 11.1 Hz), 32.71; HRMS (ESI) m/z
CF
+
1
4
[M+H] calc. for C H FN O 195.0564, found 195.0564.
9
8
2 2
Yield 91 mg, 88%; white solid, m.p. 132-134 °C (lit. m.p. 133-
1
6
MHz, CDCl ): 162.20, 153.81, 153.21, 127.34, 116.31, 114.44, Yield 92 mg, 88%; white crystalline solid, m.p. 135-137 °C; H
5
2
1
35 °C); H NMR (300 MHz, CDCl ): 7.76 (d, 2H, J = 8.4 Hz),
3
13
5-(4-chlorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4i):
.96 (d, 2H, J = 8.7 Hz), 3.86 (s, 3H), 3.48 (s, 3H); C NMR (75
1
3
+
5.44, 32.64; HRMS (ESI) m/z [M+H] calc. for C H N O
NMR (300 MHz, CDCl ): 7.73 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J =
3
8.4 Hz), 3.49 (s, 3H); C NMR (75 MHz, CDCl ): 153.45, 152.21,
3
10
11
2
3
1
3
07.0764, found 207.0764.
+
1
37.68, 129.33, 126.78, 122.27, 32.77; HRMS (ESI) m/z [M+H]
calc. for C H ClN O 211.0269, found 211.0268.
9
8
2 2
3
-methyl-5-(p-tolyl)-1,3,4-oxadiazol-2(3H)-one (4c):
1
Yield 87 mg, 92%; white crystalline solid, m.p. 105-106 °C; H
5
-(3-chlorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4j):
NMR (300 MHz, CDCl ): 7.61 (d, 2H, J = 7.2 Hz), 7.19 (d, 2H, J =
3
1
13
Yield 90 mg, 86%; white solid, m.p. 98-99 °C; H NMR (300
MHz, CDCl ): 7.75 (s, 1H), 7.65 (d, 1H, J = 6.9 Hz), 7.43-7.38 (m,
6
1
.9 Hz), 3.42 (s, 3H), 2.35 (s, 3H); C NMR (75 MHz, CDCl3):
53.49, 153.01, 141.83, 129.49, 125.33, 120.95, 32.48, 21.43;
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 6 of 9
ARTICLE
Journal Name
1
3
+
2
1
(
H), 3.49 (s, 3H); C NMR (75 MHz, CDCl ): 153.33, 151.75, 124.76, 119.62, 32.74; HRMS (ESI) m/z [M+H] calc. for
3
View Article Online
DOI: 10.1039/C5OB02667A
35.07, 131.45, 130.30, 129.33, 125.42, 123.54, 32.78; HRMS C H N O 227.0815, found 227.0815.
13 11 2 2
+
ESI) m/z [M+H] calc. for C H ClN O 211.0269, found
9 8 2 2
2
11.0269.
3-methyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (4q):
Yield 75 mg, 85%; pale yellow crystalline solid, m.p. 124-127
1
5
-(2-chlorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4k):
Yield 87 mg, 83%; white crystalline solid, m.p. 83-85 °C;
NMR (300 MHz, CDCl ): 7.73 (d, 1H, J = 6.9 Hz), 7.47-7.31 (m,
°C; H NMR (300 MHz, CDCl ): 9.08 (t, 1H, J = 1.5 Hz ), 8.74 (dd,
3
1
1H, J = 4.8 Hz, J = 1.5 Hz ), 8.01 (dt, 1H, J = 8.1 Hz, J = 2.1
Hz), 7.43 (dd, 1H, J = 8.1 Hz, J = 4.8 Hz ), 3.5 (s, 3H); C NMR
(75 MHz, CDCl ):153.14, 152.03, 150.91, 146.67, 132.58,
3
23.59, 120.22, 32.77; HRMS (ESI) m/z [M+H] calc. for
1
2
1
2
H
13
1
2
3
13
3
1
H), 3.50 (s, 1H); C NMR (75 MHz, CDCl ): 153.10, 150.93,
3
+
1
32.21, 131.97, 131.34, 129.68, 126.94, 122.47, 32.72; HRMS
+
C H N O 178.0611, found 178.0611.
8
8 3 2
(ESI) m/z [M+H] calc. for C H ClN O 211.0269, found
9
8
2 2
2
11.0272.
5
-(furan-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4r):
1
4
5
-(3,4-dimethoxyphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4l):
Yield 69 mg, 83%; white solid, m.p. 92-95 (lit. m.p. 91-93 °C);
1
1
H NMR (300 MHz, CDCl ): 7.59 (dd, 1H, J = 1.8 Hz, J = 0.6 Hz),
.97 (dd, 1H, J = 3.6 Hz, J = 0.6 Hz ), 6.56 (dd, 1H, J = 3.6 Hz,
1 2 1
J2 = 1.8 Hz), 3.5 (s, 3H); C NMR (75 MHz, CDCl ): 152.79,
3
46.52, 145.55, 138.93, 113.44, 111.90, 32.81; HRMS (ESI) m/z
3
1
2
Yield 99 mg, 84%; white solid, m.p. 145-148 °C; H NMR (300
MHz, CDCl ): 7.42 (dd, 1H, J = 8.4 Hz, J = 2.1 Hz), 7.31 (d, 1H, J
=
NMR (75 MHz, CDCl ): 153.74, 153.11, 151.86, 149.29, 119.23,
1
6
3
1
1
13
1
3
1.8 Hz), 6.92 (d, 1H, J = 8.4 Hz), 3.93 (s, 6H), 3.48 (s, 3H); C
1
3
+
+
[M+H] calc. for C H N O 167.0451, found 167.0456.
7 7 2 3
16.27, 111.06, 107.88, 56.00, 32.63; HRMS (ESI) m/z [M+H]
calc. for C H N O 237.0870, found 237.0870.
11 13 2 4
5
-(1H-indol-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (4s):
3
-methyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2(3H)-one
1
Yield 84 mg, 79%; pale yellow solid, m.p. 128-131 °C; H NMR
300 MHz, CDCl and DMSO-d ): 10.90 (s, 1H), 7.96 (d, 1H, J =
(4m):
(
3
6
1
2
Yield 90 mg, 68%; white solid, m.p. 135-137 °C (lit. m.p. 6.9 Hz), 7.63 (s, 1H), 7.39 (d, 1H, J = 6.9 Hz), 7.20-7.11 (m, 2H,)
36.9-138.0 °C); H NMR (300 MHz, CDCl ): 7.06 (s, 2H), 3.90 3.40 (s, 3H); C NMR (75 MHz, CDCl and DMSO-d ): 148.76,
3 3 6
s, 9H), 3.5 (s, 3H); C NMR (75 MHz, CDCl ): 153.59 (here 146.91, 131.84, 121.92, 119.04, 118.28, 116.52, 115.79,
three quaternary carbon merged and gave one peak), 152.90, 107.34, 95.69, 27.73; HRMS (ESI) m/z [M+H] calc. for
40.90, 118.76, 102.71, 60.90, 56.22, 32.66; HRMS (ESI) m/z C H N O 216.0768, found 216.0767.
1
13
1
(
13
3
+
1
11 10 3 2
+
[
M+H] calc. for C H N O 267.0975, found 267.0974.
12 15 2 5
3
-methyl-5-(thiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one (4t):
1
3
-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (4n):
Yield 74 mg, 81%; white solid, m.p. 106-107 °C; H NMR (300
1
MHz, CDCl ): 7.59 (s, 1H), 6.97 (d, 1H, J = 3.6 Hz), 6.56-6.55 (m,
3
Yield 32 mg, 30%; white solid, m.p. 133-135 °C; H NMR (300
13
1
H), 3.49 (s, 3H); C NMR (75 MHz, CDCl ): 152.79, 146.51,
3
MHz, CDCl ): 8.70 (s, 1H), 8.36 (d, 1H, J = 6.3 Hz), 8.14 (d, J =
.3 Hz), 7.70 (s, 1H), 3.55 (s, 3H); C NMR (75 MHz, CDCl3):
53.20, 151.11, 148.65, 130.91, 130.66, 125.87, 125.54,
3
+
13
145.55, 138.92, 113.44, 111.90, 32.80; HRMS (ESI) m/z [M+H]
6
calc. for C H N O S 183.0223, found 183.0220.
7
7 2 2
1
1
+
20.62, 33.01; (ESI) m/z [M+H] calc. for C H N O 222.0509,
9
8 3 4
3
-benzyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (5a)
found 222.0528.
Yield 111 mg, 88%; white crystalline solid, m.p. 114-116 °C
1
2
1
Methyl 4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
(lit. mp 112-114 °C); H NMR (300 MHz, CDCl ): 7.84 (d, 2H, J
3 1
13
benzoate(4o):
= 6.6 Hz), 7.48-7.38 (m, 8H), 4.98 (s, 2H); C NMR (75 MHz,
Yield 56 mg, 48%; white solid, m.p. 153-155 °C; H NMR (300 CDCl ): 153.57, 153.35, 135.01, 131.54, 128.91, 128.87, 128.39,
MHz, CDCl ): 8.13 (d, 2H, J = 8.1 Hz), 7.90 (d, 2H, J = 8.1 Hz), 128.33, 125.71, 123.88, 49.79; HRMS (ESI) m/z [M+H] calc. for
1
3
+
3
13
3
1
.95 (s, 3H), 3.53 (s, 3H); C NMR (75 MHz, CDCl ): 166.03, C H N O 253.0972, found 253.0971.
3
15 13 2 2
53.47, 152.24, 132.63, 130.17, 127.58, 125.46, 52.45, 32.87;
+
HRMS (ESI) m/z [M+Na] calc. for C H N NaO 257.0533,
11
10
2
4
3
-benzyl-5-(4-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one (5b):
found 257.0538.
1
Yield 121 mg, 86%; white solid, m.p. 89-91 °C; H NMR (300
MHz, CDCl ): 7.62 (d, 2H, J = 8.4 Hz), 7.31-7.25 (m, 7H), 4.83 (s,
3
3
-methyl-5-(naphthalen-2-yl)-1,3,4-oxadiazol-2(3H)-one (4p):
1
3
2
1
H); C NMR (75 MHz, CDCl ): 153.33, 152.53, 137.76, 134.84,
3
1
2
Yield 95 mg, 84%; white crystalline solid, 110-113 °C (lit. m.p.
1
7
29.31, 128.90, 128.46, 128.36, 126.97, 122.33, 49.86; HRMS
1
12-115 °C ); H NMR (300 MHz, CDCl ): 8.69 (d, 1H, J = 8.1),
+
3
(ESI) m/z [M+Na] calc. for C H ClN NaO 309.0401, found
15
11
2
2
.72-7.64 (m, 3H), 7.43-7.34 (m, 2H), 7.22 (t, 1H, J = 7.6), 3.30
3
09.0406.
13
(s, 1H); C NMR (75 MHz, CDCl ): 153.13, 153.01, 133.65,
3
1
32.33, 129.18, 128.80, 127.92, 127.58, 126.51, 125.45,
3
-benzyl-5-(4-fluorophenyl)-1,3,4-oxadiazol-2(3H)-one (5c):
6
| J. Name., 2012, 00, 1-3
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Page 7 of 9
Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
1
1
Yield 119 mg, 88%; white solid, m.p. 93-95 °C; H NMR (300 Yield 54 mg, 35%; white solid, m.p. 120-122 °C; H NMR (300
View Article Online
DOI: 10.1039/C5OB02667A
MHz, CDCl ): 7.82-7.78 (m, 2H), 7.42-7.32 (m, 5H), 4.93 (s, 2H); MHz, CDCl3): 8.10 (d, 2H, J = 8.1 Hz), 7.88 (d, 2H, J = 8.1 Hz),
C NMR (75 MHz, CDCl ): 164.62 (d, J = 251.4 Hz), 153.44, 7.41-7.36 (m, 5H), 4.96 (s, 2H), 3.93 (s, 3H); 13C NMR (75 MHz,
52.60, 134.89, 128.88, 128.43, 128.34, 127.99 (d, J = 8.8 CDCl3):166.05, 153.29, 152.49, 134.71, 132.64, 130.11, 128.92,
CF
Hz), 120.19, 116.28 (d, J = 22.3 Hz), 49.80; HRMS (ESI) m/z 128.51, 128.39, 127.61, 126.97, 125.60, 65.35, 52.45, 49.95;
3
13
1
3
CF
1
1
1
CF
+
+
[
M+Na] calc. for C H FN NaO 293.0697, found 293.0701.
HRMS (ESI) m/z [M+Na] calc. for C H N NaO , 333.0846
17 14 2 4
1
5
11
2
2
found 333.0843.
3
-benzyl-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (5d):
1
Yield 123 mg, 87%; white solid, m.p. 116-118 °C; H NMR (300
ACKNOWLEDGEMENTS
MHz, CDCl ): 7.75 (d, 2H, J = 8.7 Hz), 7.42-7.34 (m, 5H), 6.95 (d,
H, J = 8.7 Hz) 4.94 (s, 2H), 3.84 (s, 3H); C NMR (75 MHz,
CDCl ): 162.22, 153.67, 153.43, 135.12, 128.84, 128.50, 128.29,
27.48, 116.31, 114.39, 55.43, 49.67; HRMS (ESI) m/z [M+Na]
3
13
The authors thank the Council of Scientific and Industrial
Research (CSIR), India (02(180)/14/EMR-II), for financially
supporting this work; and DST-FIST for funding the ESI-HRMS
facility at IIT Delhi. Author S. S. P. thanks CSIR, Delhi for
graduate fellowship. Dr. N. C. thanks CSIR for RA fellowship.
2
3
+
1
calc. for C H N NaO 305.0897, found 305.901.
16
14
2
3
3
-benzyl-5-(p-tolyl)-1,3,4-oxadiazol-2(3H)-one (5e):
1
REFERENCES
Yield 117 mg, 88%; white solid, m.p. 96-98 °C; H NMR (300
MHz, CDCl ): 7.68 (d, 2H, J = 7.5 Hz), 7.41-7.31 (m, 5H), 7.22 (d, 1. Z. Jin, Nat. Prod. Rep., 2003, 20, 584-605.
3
1
3
2
H, J = 7.8 Hz), 4.92 (s, 2H), 2.37 (s, 3H); C NMR (75 MHz, 2. J. C. Ruble, B. D. Wakefield, G. M. Kamilar, K. R. Marotti, E.
CDCl ): 153.63, 153.57, 142.09, 135.07, 129.61, 128.84, 128.33, Melchior, M. T. Sweeney, G. E. Zurenko and D. L. Romero,
3
+
1
28.31, 125.69, 121.12, 49.73, 21.59; HRMS (ESI) m/z [M+H] Bioorg. Med. Chem. Lett., 2007, 17, 4040-4043.
calc. for C H N O 267.1128, found 267.1128.
3. D. Zampieri, M. G. Mamolo, E. Laurini, M. Fermeglia, P.
Posocco, S. Pricl, E. Banfi, G. Scialino and L. Vio, Bioorg. Med.
Chem., 2009, 17, 4693-4707.
4. S. A. F. Rostom, M. A. Shalaby and M. A. El-Demellawy, Eur.
J. Med. Chem., 2003, 38, 959-974.
16 15 2 2
3
(
-benzyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2(3H)-one
5f):
Yield 111 mg, 65%; pale yellow solid, m.p. 106-109 °C (lit.
1
2
1
5
. F. Mazouz, S. Gueddari, C. Burstein, D. Mansuy and R.
Milcent, J. Med. Chem., 1993, 36, 1157-1167.
. Y. Ben Ali, R. Verger, F. Carriere, S. Petry, G. Muller and A.
Abousalhama, Biochimie, 2012, 94, 137-145.
. L. L. Jiang, T. Ying, X. L. Zhu, Z. F. Wang, Z. Yang, C. Qiong, X.
Zhen and G. F. Yang, J. Agric. Food Chem., 2010, 58, 2643-
m.p. 107-110 °C); H NMR (300 MHz, CDCl ): 7.40-7.35 (m, 5H),
3
13
7
1
1
.05 (s, 2H), 4.95 (s, 2H), 3.89 (s, 9H); C NMR (75 MHz, CDCl ):
3
6
53.61, 153.51, 153.18, 141.07, 135.00, 128.85, 128.44,
28.34, 128.17, 126.33, 118.84, 103.00, 60.92, 56.28, 49.74;
+
7
HRMS (ESI) m/z [M+H] calc. for C H N O 343.1288, found
18 19 2 5
3
43.1288.
2
8
651.
. G. Desforges, A. Bornbrun and A. Quattropani, J. Comb.
3
-benzyl-5-(furan-2-yl)-1,3,4-oxadiazol-2(3H)-one (5g):
Chem., 2008, 10, 671-680.
1
Yield 91 mg, 75%; light brown semi solid; H NMR (300 MHz, 9. J. L. Romine, S. W. Martin, N. A. Meanwell, V. K. Gribkoff, C.
CDCl ): 7.56 (dd, 1H, J = 1.8 Hz, J = 0.9 Hz ), 7.43-7.33 (m, 5H), G. Boissard, S. I. Dworetzky, J. Natale, S. Moon, A. Ortiz, S.
3
1
2
6
.96 (dd, 1H, J = 3.3 Hz, J = 0.6 Hz ), 6.53 (dd, 1H, J = 3.6 Hz, Yeleswaram, L. Pajor, Q. Gao and J. E. Starrett, J. Med. Chem.,
1
2
1
13
J2 = 1.8 Hz ), 4.94 (s, 2H); C NMR (75 MHz, CDCl ): 152.62, 2007, 50, 528-542.
3
1
1
46.72, 145.61, 138.95, 134.78, 128.87, 128.44, 128.39, 10. H. S. Chen, Z. M. Li and Y. F. Han, J. Agric. Food Chem.,
13.63, 111.95, 49.92; HRMS (ESI) m/z [M+Na] calc. for 2000, 48, 5312-5315.
+
C H N NaO 265.0584, found 265.0587.
11. T. Kihlberg, F. Karimi and B. Långström, J. Org. Chem., 2002,
13
10
2
3
6
7
, 3687-3692.
1
2. O. Sugimoto, T. Arakaki, H. Kamio and K.-i. Tanji, Chem.
3
-benzyl-5-(1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (5h):
Commun., 2014, 50, 7314-7317.
1
Yield 99 mg, 68%; pale yellow solid, m.p. 155-158; H NMR
300 MHz, DMSO-d ): 11.96 (s, 1H), 8.05 (s, 1H), 7.88 (d, 1H, J =
1
4
1
6
1
8
1
3. R. R. Kamble and B. S. Sudha, J. Heterocycl. Chem., 2006,
, 345-352.
(
7
6
3
.5 Hz), 7.52 (d, 1H, J = 7.5 Hz), 7.40-7.34 (m, 5H), 7.25-7.20
4. M. Bancerz and M. K. Georges, J. Org. Chem., 2011, 76
,
13
(m, 2H), 4.97 (s, 2H); C NMR (75 MHz, DMSO-d ): 153.18,
6
377-6382.
1
1
51.87, 136.92, 136.35, 129.17, 128.42, 128.33, 128.15,
5. G. Yin, B. Zhou, X. Meng, A. Wu and Y. Pan, Org. Lett., 2006,
, 2245-2248.
6. M. Gao, Y. Yang, Y.-D. Wu, C. Deng, L.-P. Cao, X.-G. Meng
23.90, 123.38, 121.60, 120.43, 112.93, 99.87, 49.22; HRMS
+
(ESI) m/z [M+Na] calc. for C H N NaO 314.0900, found
17
13
3
2
3
14.0902.
and A.-X. Wu, Org. Lett., 2010, 12, 1856-1859.
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1
Methyl 4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
yl)benzoate(5i):
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB02667A
Table of Contents
One-pottandemapproach
Transition Metal-free synthesis
High yield