A facile and expeditious one-pot synthesis of α-Keto-1,3,4- oxadiazoles

Article abstract of DOI:10.1055/s-0033-1340981

An efficient and high-yielding protocol for the preparation of α-keto-1,3,4-oxadiazoles has been developed. Formation of α-keto-1,3,4-oxadiazoles involves the 2-iodoxybenzoic acid/ tetraethylammonium bromide mediated oxidative cyclization of hydrazide-hyd

Full text of DOI:10.1055/s-0033-1340981

LETTER
▌1137
lAetteFr acile and Expeditious One-Pot Synthesis of α-Keto-1,3,4-oxadiazoles
One-Pot Synthesis of α-Keto-1,3,4-oxadiazoles
Dalip Kumar,* Meenakshi Pilania, V. Arun, Bhupendra Mishra
Department of Chemistry, Birla Institute of Technology and Science, Pilani – 333 031, Rajasthan, India
Fax +44(113)3436565; E-mail: dalipk@pilani.bits-pilani.ac.in
Received: 24.12.2013; Accepted after revision: 19.02.2014
of hydrazide-hydrazones using IBX in an approach to
biologically important α-keto-1,3,4-oxadiazoles.
Abstract: An efficient and high-yielding protocol for the prepara-
tion of α-keto-1,3,4-oxadiazoles has been developed. Formation of
α-keto-1,3,4-oxadiazoles involves the 2-iodoxybenzoic acid/tetra-
ethylammonium bromide mediated oxidative cyclization of hydra-
zide-hydrazones generated in situ from the reaction of aryl glyoxal
and hydrazides. This one-pot protocol is reasonably general for the
preparation of α-keto-1,3,4-oxadiazoles under mild conditions in
short reaction times.
Recently, α-keto-1,3,4-oxadiazoles have been identified
as inhibitors of cathepsin K, a cysteine protease expressed
in osteoclasts and responsible for bone resorption.11 α-
Keto-1,3,4-oxadiazoles also display inhibitory activity
against human neutrophil elastase (HNE)12 and fatty acid
amide hydrolase (FAAH).13 Rydzewski et al. described a
series of oxadiazoles as remarkably potent inhibitors of
the 20S proteasome.14 Other analogues of α-keto-1,3,4-
oxadiazoles such as 2-aryl-4-benzoylthiazoles and 4-aryl-
2-benzoylimidazoles have been reported to show excel-
lent inhibition activity against various cancer cells.15
Papaveralidine, an isoquinoline alkaloid with an α-keto
functionality, exhibits antispasmodic activity (Figure 1).16
Key words: nitrogen heterocycles, hypervalent iodine reagents,
oxidation, cyclization
1,3,4-Oxadiazoles and their derivatives display a wide
range of biological properties such as antimicrobial, anti-
inflammatory, antifungal, anticancer and insecticidal ac-
tivity.1 These five-membered heterocyclic compounds are
frequently employed as bioisosteres of ester and amide
functionalities.2 Apart from their potential use in pharma-
ceutical chemistry, they also find numerous applications
in the field of materials science as liquid crystals and
organic light emitting diodes (OLEDs).3
N
N
MeOOC
O
O
FAAH inhibitor
F
Hypervalent iodine reagents have been widely used in or-
ganic transformations because of their mild oxidizing na-
ture.4 Furthermore, these reagents are environmentally
benign compared with heavy-transition-metal-derived re-
agents such as Pb(IV), Hg(II), Cr(VI), and Tl(III).5 Due to
their strong electrophilic character, hypervalent iodine(V)
reagents have frequently been used in various oxidative
transformations.6 In 2012, Donohoe et al. explored the use
of o-iodoxybenzoic acid (IBX) in the construction of var-
ious heterocycles including thiazoles, thiazolines, imidaz-
oles, and imidazo-pyridines.7 Moorthy et al. prepared
various benzimidazoles from primary alcohols and aryl-
methyl bromides by using the oxidative properties of
IBX.8 Recently, Bhanage and co-workers developed a
metal-free protocol for the synthesis of 2-aminobenzoxa-
zoles through oxidative C–H bond amination of benzoxa-
zoles with amines in the presence of IBX.9 By employing
this reagent, Prabhu et al. developed a mild protocol to
synthesize 2-amino-1,3,4-oxadiazoles.10
N
N
O
H2N
N
N
O
N
O
H
O
HNE inhibitor
N
O
O
OMe
OMe
OMe
N
NH
S
OMe
OMe
OMe
2-aryl-4-benzoyl thiazole
(IC50 = 1nM, PC3)
4-aryl-2-benzoylimidazole
(IC50 = 6–24 nM)
MeO
MeO
N
OMe
OMe
O
As a part of our ongoing research to develop efficient
methods for the construction of bioactive azaheterocycles
using relatively benign hypervalent iodine reagents, we
became interested in exploring the oxidative cyclization
papaveralidine
Figure 1 Representative bioactive α-keto-1,3,4-oxadiazoles and
their analogues
SYNLETT 2014, 25, 1137–1141
Advanced online publication: 24.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340981; Art ID: ST-2013-D1164-L
© Georg Thieme Verlag Stuttgart · New York

1138
D. Kumar et al.
LETTER
dihydrazides with triethyl orthoesters but, unexpectedly,
the α-keto-1,3,4-oxadiazole was also formed as a minor
by-product.17 This dearth of synthetic approaches prompt-
ed us to develop an alternative protocol for the preparation
of α-keto-1,3,4-oxadiazoles from readily available aryl-
gyloxals 1 and hydrazides 2 (Scheme 2).
N
N
N
R2
K2Cr2O7
R1
O
O
route a17
H2SO4
OH
N
N
N
R2COCl
Et2O, r.t.
R2
R1
O
Synthesis of the α-keto-1,3,4-oxadiazoles was carried out
as depicted in Scheme 2. The key intermediate hydrazide-
hydrazone 3a was synthesized by the reaction of phenyl-
glyoxal (1a) with phenylhydrazide (2a) in acetonitrile at
room temperature. On treatment of 3a with IBX in aceto-
nitrile at room temperature, it was found that both the
starting materials remained unchanged even after stirring
the reaction mixture for 24 hours. Different hypervalent
iodine reagents such as (diacetoxy)iodobenzene (DIB)
and Dess–Martin periodinane (DMP) were also screened
but no product formation was observed (Table 1, entries
1–3). It was reported20 that IBX can be activated by tetra-
ethylammonium bromide (TEAB) and so we explored the
oxidative cyclization of hydrazide-hydrazone 3a by using
IBX together with a catalytic amount of TEAB (Table 1,
entry 4). However, the desired α-keto-1,3,4-oxadiazole 4a
was isolated in only moderate yield (40%).
R1
SiMe3
route b18
O
(i) CN-N=PPh3
CH2CI2, r.t.
route c19
R2COCl
(ii) R1COOH, Et3N
Scheme 1 Previous work
To the best of our knowledge, there are only four reports
on the synthesis of α-keto-1,3,4-oxadiazoles. An earlier
strategy involved the oxidation of 2-(1-hydroxy-1-
phenylmethyl)-1,3,4-oxadiazoles by using a mixture of
K2Cr2O7 and H2SO4 (Scheme 1, route a).17 Another meth-
od involves acylation of 2-aryl-5-trimethylsilyl-1,3,4-
oxadiazoles with an appropriate acid chloride over 2–96
hours to produce α-keto-1,3,4-oxadiazoles in 54–81%
yield (Scheme 1, route b).18 Recently, Cui et al. reported
the synthesis of α-keto-1,3,4-oxadiazoles in moderate
yields (36–69%) by employing acyl chlorides and (N-iso-
cyanimine) triphenylphosphorane via an α-keto imidoyl
chloride intermediate, which was trapped by carboxylic
acids (Scheme 1, route c).19 Finally, Kudelko et al. report-
ed an efficient approach to symmetrically substituted
bis(1,3,4-oxadiazol-2-yl-phenylmethyl)sulfides by acetic
acid catalyzed reactions of 1,1′-diphenylthiodiacetic acid
After screening higher temperatures and substoichiomet-
ric ratios of reagents, we optimized the conditions to using
IBX (1 equiv) and TEAB (1.2 equiv) for the oxidative cy-
clization of hydrazide-hydrazone 3a to achieve α-keto-
1,3,4-oxadiazole 4a in 90% yield (Table 1, entry 5).
Therefore, IBX/TEAB was found to be optimal in terms
of isolated product yield and reaction time, as shown in
Table 1. Thus far, we had approached this conversion in
R2CONHNH2
O
O
O
N
N
IBX, TEAB
r.t., 3 h
2
H
R1
N
R1
N
H
R2
R1
O
R2
MeCN, r.t., 3 h
O
O
1
3
4a–m
Scheme 2 Synthesis of α-keto-1,3,4-oxadiazoles
Table 1 Optimization of the Reaction Conditions for 4a
N
N
PhCONHNH2
O
O
O
IBX, TEAB
MeCN, r.t.
2a
Ph
H
N
O
Ph
Ph
Ph
N
Ph
MeCN, r.t.
H
O
O
3a
4a
1a
Entry
Reagent
Additive
Time (h)
Yield (%)a
1
2
3
4
5
6
IBX
DIB
DMP
IBX
IBX
DMP
–
–
–
24
24
24
12
3
no reaction
no reaction
no reaction
40
TEAB (0.2 equiv)
TEAB (1.2 equiv)
TEAB (1.2 equiv)
90
6
65
a Isolated yield.
Synlett 2014, 25, 1137–1141
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of α-Keto-1,3,4-oxadiazoles
Table 2 Synthesis of α-Keto-1,3,4-oxadiazoles 4a–m
1139
two steps; the first step being preparation of intermediate
hydrazide-hydrazone 3a, while in the second step, isolat-
ed 3a was treated with IBX/TEAB to produce α-keto-
1,3,4-oxadiazole 4a. Our next efforts focused on combin-
ing these steps to develop a one-pot protocol.
Entrya Product
Yield (%)b Mp (°C)
N
N
O
The reaction of phenylglyoxal (1a) and benzohydrazide
(2a) in acetonitrile at room temperature generated hydra-
zide-hydrazone 3a in situ, which was then treated with
IBX/TEAB to produce 4a in 90% yield. To explore the
generality of this protocol under the optimized conditions,
the reaction was extended to a variety of aryl and hetero-
aryl glyoxaldehydes and alkyl, aryl and heteroaryl hydra-
zides, and a series of diverse α-keto-1,3,4-oxadiazoles
4a–m was prepared (Table 2).21
8
88
167–168
N
O
4h
OMe
OMe
OMe
N
N
9
86
85
144
165
O
O
4i
Table 2 Synthesis of α-Keto-1,3,4-oxadiazoles 4a–m
N
N
N
N
Entrya Product
Yield (%)b Mp (°C)
O
O
10
O
O
N
N
4j
O
1
90
91
91
143–144
142–143
169–170
O
S
4a
11
93
95
90
167
N
N
4k
O
N
N
2
O
Me
S
O
12
185
4b
O
Me
N
N
4l
O
N
N
3
O
O
S
MeO
O
13
210–211
O
4c
Cl
N
N
4m
MeO
a Reaction conditions: arylglyoxal 1 (1.0 equiv), arylhydrazide 2 (1.0
equiv), IBX (1.0 equiv), TEAB (1.2 equiv).
b Isolated yield.
O
4
94
132
MeO
OMe
4d
Formation of α-keto-1,3,4-oxadiazole 4a was confirmed
on the basis of its H NMR spectrum, which was devoid
1
N
N
of the characteristic singlet of the imine proton (–CH=N–)
O
observed for hydrazide-hydrazone 3a. The IR spectrum of
5
86
82
87
183–184
O
Cl
4a showed a band at 1666 cm–1 (C=O stretch). In the 13
C
NMR spectrum, the quaternary C=O carbon of 4a dis-
played a characteristic signal at δ = 182.13 ppm. The mass
spectrum of 4a displayed a molecular ion peak at m/z
251.1, in agreement with the calculated value.
4e
N
N
Me
O
6
7
110
O
We also synthesized α-keto-1,2,4-triazolo[4,3-a]pyri-
dines 7a–e from arylglyoxals 1 and 2-hydrazinopyridine
(5; Scheme 3). In this reaction, intermediate 6 was formed
within five minutes and was further treated with the
IBX/TEAB combination to afford the desired products
7a–e rapidly (15–20 min) in excellent yields (Table 3).22
The reaction conditions were suitable for use with sub-
strates bearing either electron-releasing or electron-with-
4f
N
N
O
105
O
N
4g
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1137–1141

1140
D. Kumar et al.
LETTER
N
N
O
O
N
NHNH2
R
IBX, TEAB
MeCN, r.t.
H
N
5
N
R
R
N
N
H
O
MeCN, r.t.
O
1
6
7a–e
Scheme 3 Synthesis of α-keto-1,2,4-triazolo[4,3-a]pyridines
drawing groups, and the corresponding α-keto-1,2,4-
triazolo[4,3-a]pyridines were produced in 85–92% yields.
O
Br
N(Et)4
N(Et)4
O
OH
I
O
O
O
H
N
I
Br
Table 3 Synthesis of α-Keto-1,2,4-triazolo[4,3-a]pyridines 7a–e
R2
OH
N
Entrya
Product
Yield (%)b Mp (°C)
O
IBX
R2
O
O
O
R1
II
N
N
N
O
I
O
O
1
90
92
85
167
R2
N
NH
N
O
O
N
O
O
I
O
HO
Br
H
O
I
7a
R1
III
R1
– H2O
O
N(Et)4
OMe
O
3
OMe
OMe
N
N
N
O
N
R1
+
R2
2
3
152–153
165–166
IBA
N
O
O
4
7b
Scheme 4 A plausible mechanism for the formation of 4
Cl
N
N
N
To demonstrate the practical use of the protocol, we also
performed a gram-scale synthesis by reacting phenylgly-
oxal (1 g) with phenylhydrazide and then treating the hy-
drazide-hydrazone 3a formed in situ with IBX to afford
4a in 83% yield. Upon completion of the reaction, the
o-iodosylbenzoic acid was recovered in 80% yield and re-
used for the preparation of IBX.
N
O
O
7c
7d
7e
N
S
N
4
5
85
85
192
182
In conclusion, we have developed a facile one-pot proce-
dure for the synthesis of α-keto-1,3,4-oxadiazoles and
α-keto-1,2,4-triazolo[4,3-a]pyridines starting from readi-
ly available arylglyoxals and hydrazides through the use
of IBX–TEAB mediated oxidative cyclization of the
intermediate hydrazide-hydrazones generated in situ.
Our approach provides an efficient and scalable route to
α-keto-1,3,4-oxadiazoles and α-keto-1,2,4-triazolo[4,3-a]-
pyridines in excellent yields. A biological evaluation of
the synthesized α-keto azoles is under way in our labora-
tory.
N
N
N
O
a Reaction conditions: arylglyoxal 1 (1.0 equiv), 2-hydrazinopyridine
5 (1.0 equiv), IBX (1.0 equiv), TEAB (1.2 equiv).
b Isolated yield.
A plausible mechanism for this IBX-promoted oxidative
cyclization is depicted in Scheme 4. It is proposed that
TEAB initially facilitates the polarization of the I=O bond
of IBX to generate reactive adduct I. Subsequent nucleo-
philic displacement of bromine in I by the imine nitrogen
of hydrazide-hydrazone 3 is proposed to form adduct II,
which, upon oxidative cyclization and loss of water, gen-
erates α-keto-1,3,4-oxadiazoles 4.
Acknowledgment
The authors sincerely thank the CSIR, New Delhi for financial sup-
port. M.P. is thankful to CSIR, New Delhi for a Junior Research Fel-
lowship. We also thank SAIF, Chandigarh and JNU for analytical
support.
References and Notes
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Synlett 2014, 25, 1137–1141
© Georg Thieme Verlag Stuttgart · New York

LETTER
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One-Pot Synthesis of α-Keto-1,3,4-oxadiazoles
1141
was stirred in acetonitrile at r.t. for 3 h. After consumption of
the starting materials, IBX (1 mmol) was added to the
reaction mixture followed by addition of TEAB (1.2 mmol)
and stirring was continued at r.t. for another 3 h. Upon
completion of the reaction, solvent was removed in vacuo
and the crude material thus obtained was diluted with H2O
and extracted with EtOAc (3 × 25 mL). The combined
organic layers were washed with saturated NaHCO3 (20
mL), brine (20 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated under reduced pressure
and the residue was recrystallized from ethanol to afford
analytically pure α-keto-1,3,4-oxadiazoles 4a–m in
excellent yields.
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Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (4a):
Yield: 90%; white solid; mp 143–144 °C (Lit.19 143–
145 °C). IR (KBr): 1666, 1535, 1411, 1380, 1280, 1180 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.45 (dd, J = 8.3,
1.1 Hz, 2 H), 8.15 (dd, J = 8.2, 1.3 Hz, 2 H), 7.74 (t, J =
7.4 Hz, 1 H), 7.64–7.56 (m, 5 H). 13C NMR (101 MHz,
DMSO-d6): δ = 182.13, 170.13, 165.71, 139.76, 139.31,
137.90, 135.60, 134.48, 133.78, 132.43, 127.70. MS (ESI):
m/z [M + H]+ calcd for C15H10N2O2: 251.08; found: 251.1.
Phenyl(5-p-tolyl-1,3,4-oxadiazol-2-yl)methanone (4b):
Yield: 91%; white solid; mp 142–143 °C (Lit.19 139–
141 °C). IR (KBr): 1659, 1489, 1450, 1381, 1265, 1173 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.47 (dd, J = 8.4,
1.2 Hz, 2 H), 8.06–8.04 (m, 2 H), 7.79–7.75 (m, 1 H), 7.65–
7.61 (m, 2 H), 7.45 (d, J = 8 Hz, 2 H), 2.46 (s, 3 H). 13
C
NMR (101 MHz, DMSO-d6): δ = 176.85, 165.49, 160.26,
143.13, 134.36, 133.64, 130.27, 129.66, 128.39, 127.13,
119.47, 21.17. MS (ESI): m/z [M + H]+ calcd for
C16H12N2O2: 265.1; found: 265.2.
[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]phenyl-
methanone (4c): Yield: 91%; white crystalline solid; mp
169.6–170 °C. IR (KBr): 1612, 1574, 1551, 1489, 1380,
1285 cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 8.41 (d,
J = 7.7 Hz, 2 H), 8.10 (d, J = 8.5 Hz, 2 H), 7.81 (t, J =
7.2 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz,
2 H), 3.89 (s, 3 H). MS (ESI): m/z [M + H]+ calcd for
C16H12N2O3: 281.09; found: 281.2.
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mixture of arylglyoxal (1 mmol) and 2-hydrazinopyridine
(1 mmol) was stirred in acetonitrile at r.t. for 5 min.
Subsequently, IBX (1 mmol) was added to the reaction
mixture, followed by the addition of TEAB (1.2 mmol) in
portions. The resulting mixture was stirred at r.t. for 15 min.
Upon completion of the reaction, solvent was removed in
vacuo, the contents were diluted with H2O, and the mixture
was extracted with EtOAc (3 × 25 mL). The combined
organic layers were washed with saturated NaHCO3 (20
mL), brine (20 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was removed under reduced pressure
and the residue thus obtained was recrystallized from
ethanol to afford α-keto-1,2,4-triazolo[4,3-a]pyridines 7a–e
in excellent yields.
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10431.
(19) Cui, L.; Liu, Q.; Yu, J.; Ni, C.; Yu, H. Tetrahedron Lett.
2011, 52, 5530.
(20) Bellale, E. V.; Bhalerao, D. S.; Akamanchi, K. G. J. Org.
Chem. 2008, 73, 9473.
(21) One-Pot Synthesis of 4a–m; General Procedure: A
mixture of arylglyoxal (1 mmol) and arylhydrazide (1 mmol)
(1,2,4-Triazolo[4,3-a]pyridine-3-yl)phenylmethanone
(7a): Yield: 90%; light-yellow solid; mp 167 °C. IR (KBr):
1658, 1573, 1496, 1450, 1411, 1380 cm–1. 1H NMR (400
MHz, DMSO-d6): δ = 9.51 (dd, J = 7.0, 1.0 Hz, 1 H), 8.51
(dd, J = 5.2, 3.3 Hz, 2 H), 8.05 (dd, J = 8.1, 1.0 Hz, 1 H),
7.73–7.67 (m, 2 H), 7.62–7.57 (m, 2 H), 7.32 (t, J = 7.4 Hz,
1 H). MS (ESI): m/z [M + H]+ calcd for C13H10N3O: 224.08;
found: 224.2.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1137–1141

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