Iron(III)/TEMPO-Catalyzed Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazoles by Oxidative Cyclization under Mild Conditions

Article abstract of DOI:10.1055/s-0036-1588747

A simple and efficient cationic Fe(III)/TEMPO-catalyzed oxidative cyclization of aroyl hydrazones has been developed for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives. The reaction offers a broad scope, good functional-group tolerance, and high yields under mild conditions in the presence of O ₂.

Full text of DOI:10.1055/s-0036-1588747

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
G. Zhang et al.
Letter
Synlett
Iron(III)/TEMPO-Catalyzed Synthesis of 2,5-Disubstituted 1,3,4-
Oxadiazoles by Oxidative Cyclization under Mild Conditions
Guofu Zhang
Yidong Yu◊
O
iron salt, TEMPO, MgSO4
DCE (or CH2Cl2), O2, 35 °C
N
R1
R2
O
R1
N
R2
H
Yiyong Zhao◊
Xiaoqiang Xie
Chengrong Ding*
N
N
R1 = aryl, thienyl, 2-naphthyl, phenethyl, t-Bu, i-Bu, n-Pr, n-pentyl
26 examples
R2 = H, Me, OMe, OH, CF3, I, Br, Cl, NO2
up to 97% yield
College of Chemical Engineering, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
dingcr@zjut.edu.cn
◊ These authors contributed equally to this work.
Received: 14.01.2017
Accepted after revision: 19.02.2017
Published online: 27.03.2017
H
N
NH
O
N
DOI: 10.1055/s-0036-1588747; Art ID: st-2017-w0039-l
Cl
HN
N
OH
Des 1 inhibitor
(inhibits dihydroceramide desaturase-1)
O
N
Abstract A simple and efficient cationic Fe(III)/TEMPO-catalyzed oxi-
dative cyclization of aroyl hydrazones has been developed for the syn-
thesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives. The reaction of-
fers a broad scope, good functional-group tolerance, and high yields
under mild conditions in the presence of O2.
OH
F
N
N
N
H
H
N
N
O
O
O
Raltegravir
(HIV integrase inhibitor)
Key words oxadiazoles, iron catalysis, cyclization, oxidation, aroyl hy-
drazones
O
N
N
The 1,3,4-oxadiazole motif is a prevalent heterocyclic
structure in many biologically active compounds and pho-
toelectric materials (Figure 1).1,2 Consequently, the develop-
ment of protocols for the synthesis of 2,5-disubstituted
1,3,4-oxadiazole derivatives has received significant atten-
tion. These compounds are usually prepared by oxidative
cyclization of benzoyl hydrazones in the presence of oxi-
dants.3,4
Butyl PBD
(liquid scintillator neutrino detector)
NH2
O
O
O2N
N
N
O
Furamizole
(antibiotic)
Figure 1 Pharmaceuticals and materials containing the 1,3,4-oxadi-
azole motif
Recently, a transition-metal-catalyzed oxidative cycliza-
tion strategy has been developed as an effective route to the
formation of 1,3,4-oxadiazoles (Scheme 1, a and b).5a,b In-
terestingly, Yadav and Yadav reported a novel route to 2,5-
disubstituted 1,3,4-oxadiazoles directly from aldehydes and
acyl hydrazides by using visible-light irradiation under air
in the presence of eosin Y as an organophotoredox catalyst
at room temperature (Scheme 1, c).5c
In 2009, Miura and co-workers described a copper-cata-
lyzed direct arylation of 1,3,4-oxadiazoles with aryl iodides
by using phosphorus ligands with the aid of carbonate bas-
es.6 Other progress in this field involves electrophilic substi-
tution of 2-substituted 1,3,4-oxadiazoles,7 cyclodehydra-
tion of 1,2-diacyl hydrazines,8 and reactions of carboxylic
acids or acyl chlorides with hydrazides.9 However, these
strategies require the use of expensive or toxic oxidants,
such as tetravalent lead reagents,3a,c Br2,3b chloramine T,3d
FeCl3,3e HgO/I2,3f KMnO4,3g ceric ammonium nitrate,3h or
H2O2/I2,3i or they require high reaction temperatures.5a,b We
previously described an efficient approach to the aerobic
oxidative deoximation of various ketoximes under mild
conditions by using commercially available FeCl3/TEMPO as
a catalyst with oxygen as the terminal oxidant.10 On the ba-
sis of this previous work, we surmised that a Fe3+/TEMPO-
catalyzed oxidative cyclization of aroyl hydrazones might
be established.
To test our hypothesis, we began an investigation by us-
ing N′-(2,2-dimethylpropylidene)benzohydrazide (1a) as a
model substrate. To our delight, the desired oxadiazole 2a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
G. Zhang et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa
Previous Work:
(a) Cu(OTf)2-catalyzed synthesis of 1,3,4-oxadiazoles
O
O
Aryl
Cu(OTf)2
O
O
[Fe], TEMPO
N
N
Aryl
O
Aryl
N
N
H
additive
N
CsCO3, O2, 110 °C
H
Aryl
Aryl
N
solvent, O2, 35 °C, 12 h
N
N
(b) Cu(OAc)2-catalyzed synthesis of 1,3,4-oxadiazoles
1a
2a
Aryl
O
Cu(OAc)2
N
Aryl
Aryl
N
Entry
Solvent
Temp (°C) [Fe]
Additive
Yieldb
N
DABCO, O2, 80 °C
H
N
DABCO: 1,4-diazabicyclo[2.2.2]octane
1
2
CH2Cl2
DCE
CHCl3
EtOAc
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
30
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(OTf)3
–
74%
87%
62%
59%
54%
92%
86%
51%
–
–
(c) Eosin Y-catalyzed synthesis of 1,3,4-oxadiazoles
Aryl
O
3
–
O
eosin Y, iPr2NEt, O2
N
Aryl
N
Aryl
N
Aryl
4
–
green LEDs, rt
N
H
5
–
This Work:
(d) Fe3+/TEMPO-catalyzed synthesis of 1,3,4-oxadiazoles
6
MgSO4
4 Å MSc
Na2SO4
NaOH
Na2CO3
NaHCO3
K2CO3
NaOAc
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
R
O
O
Fe(NO3)3⋅9H2O, TEMPO
7
N
R
Aryl
N
N
MgSO4, O2, 35 °C
Aryl
H
N
8
R = Aryl, Alkyl
9
Scheme 1 Catalyzed oxidative cyclization approaches to 1,3,4-oxadi-
azoles in the presence of O2
10
11
12
13
14
15
16
17
18
19
20
21
22d
23e
24f
25g
26h
27i
–
–
24%
<10%
<10%
–
was obtained in 74% isolated yield when 10 mol%
Fe(NO3)3·9H2O/TEMPO was used as a catalyst under O2 in
dichloromethane at 35 °C (Table 1, entry 1). Subsequently,
other reaction parameters, such as the solvent, additive, Fe
salt, reaction temperature, and reaction atmosphere, were
surveyed. Among the tested solvents (entries 1–5), dichlo-
roethane was found to be the most effective for this reac-
tion, providing the desired product 2a in 87% isolated yield
(entry 2). Surprisingly, we found that MgSO4 as an additive
increased the yield to 92% (entry 6; for further details see
Table S2 in the Supporting Information). With iron(III) tri-
flate as the Fe salt, the yield of the desired product 2a
dropped dramatically to less than 10% (entry 14), and none
of the desired product was obtained when FeBr3, FeF3,
FeSO4·7H2O, Fe(acac)2, Fe(OAc)2, or FeCl2·4H2O was using in
the transformation (entries 15–20). In addition, none of the
desired product 2a was obtained in the absence of an Fe
catalyst (entry 21), and the yield fell to 26% in the absence
of TEMPO (entry 22), demonstrating that the Fe salt and
TEMPO play essential roles in promoting the reaction. As
can be seen, the reaction is aerobic, as yields of product 2a
were also reduced under molecular nitrogen or air (entries
23 and 24). Fortunately, the progress of the reaction was
unaffected by shortening the reaction time (entries 25 and
26).
FeBr3
FeF3
–
FeSO4·7H2O
Fe(acac)2
–
–
Fe(OAc)2
–
FeCl2·4H2O
–
–
–
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
26%
36%
74%
92%
90%
88%
a Reaction conditions: 1a (0.5 mmol), [Fe] (10 mol%), TEMPO (10 mol%), ad-
ditive (2 equiv), solvent (5 mL), 12 h, in 100 mL sealed tube.
b Isolated yield.
c 0.5 g.
d Without TEMPO.
e Under N2.
g Under air.
h 6 h.
i 9 h.
To test the scope of our method, we surveyed a variety
of aryl aldehyde derived benzohydrazides 1 (Scheme 2).
Substrates bearing electron-withdrawing groups such as
chloro, bromo, trifluoromethyl, or iodo on the aromatic
rings were all easily converted into the corresponding prod-
ucts 2f–i in good to excellent yields (Scheme 2); other sub-
strates with electron-donating groups also gave high yields
of the corresponding products 2b, 2c, and 2j, showing that
electronic effects in the aromatic moiety had no significant
effect on the reaction. Curiously, when the aromatic group
was connected to one or more oxygen atoms, the yields of
2d, 2e, and 2l were reduced to 65–75%. Some results sug-
gested that steric hindrance in the aromatic substrate ap-
peared to have no effect (2g and 2h). Meanwhile, substrate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
G. Zhang et al.
Letter
Synlett
1k possessing both an electron-donating methyl group and
an electron-withdrawing nitro group gave product 2k in a
satisfactory yield (81%).
products 4f–h in moderate to good yields (55–85%). When
the aromatic ring had ortho-substituents, yields were re-
duced to 62–72% (4d and 4e), suggesting that steric hin-
drance is a major factor. Substrates 3 with 1-naphthyl, 2-
thienyl, or 2-phenylethyl substituents gave products 4l
(51%), 4j (40%), and 4k (90%), respectively. Intriguingly,
compounds with aliphatic substituents gave products 4l–n
in good yields (75–87%) when 15 mol% of TEMPO was used.
O
Fe(NO3)3 9H2O (10 mol%)
TEMPO (10 mol%)
O
N
N
N
MgSO4 (2 equiv)
R
H
N
R
DCE, O2, 35 °C, 6 h
1
2
O
R
Fe(NO3)3 9H2O (10 mol%)
TEMPO (10 mol%)
MgSO4 (2 equiv)
O
N
R
N
N
H
N
N
N
N
O
N
DCM, O2, 35 °C, 6 h
O
O
O
N
3
4
N
N
N
CF3
F
Br
MeO
2a: 92%
2b: 95%
2c: 97%
2d: 66%
N
O
O
N
N
O
O
N
N
N
N
N
O
N
O
N
O
O
N
N
N
N
N
N
4a: 82%
4b: 77%
4c: 90%
4d: 72%
OMe
I
OH
Cl
MeO
OMe
MeO
Br
2e: 75%
2f: 90%
2g: 97%
2h: 92%
Cl
O
F
N
N
N
O
N
O
O
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
N
MeO
4e: 62%
4f: 55%
4g: 73%
4h: 85%
MeO
F3C
2i: 93%
NO2
2k: 81%
OMe
2l: 65%
S
2j: 94%
N
N
N
N
N
N
O
N
O
Scheme 2 Scope of the reactions of N′-(2,2-dimethylpropylidene)ben-
zohydrazides 1. Reagents and conditions: 1 (0.5 mmol), Fe(NO3)3·9H2O
(10 mol%), TEMPO (10 mol%), MgSO4 (2 equiv), DCE (5 mL), 6 h, 100
mL sealed tube. The isolated yields are reported.
O
O
N
4l:a 87%
4i: 51%
4j: 40%
4k: 90%
Next, we investigated the scope of substrates by replac-
ing the tert-butyl group in the substrate (Scheme 3). Disap-
pointingly, we found that the reactions of N′-(arylmethy-
lene)benzohydrazides under our previously optimized con-
ditions did not reach our expectations. We therefore
reinvestigated the optimization of the reaction conditions
with N′-benzylidenebenzohydrazide as a substrate (for de-
tails, see Table S6 of the Supporting Information), and we
identified the following optimal conditions: Fe(NO3)3·9H2O
(10 mol%), TEMPO (10 mol%), MgSO4 (2 equiv), CH2Cl2 (5
mL), O2, 35 °C, 6 h.
With these optimal conditions in hand, we investigated
the scope of the oxidative cyclization of various N′-(al-
kylidene)benzohydrazides 3 (Scheme 3). Gratifyingly, we
found that substrates with electron-withdrawing substitu-
ents gave the corresponding products 4b–e in moderate to
excellent yields (62–90%) in six hours, whereas those with
electron-donating substituents gave the corresponding
O
O
N
N
N
N
4m:a 78%
4n:a 75%
Scheme 3 Scope with N′-(alkylidene)benzohydrazides. Reagents and
conditions: 3 (0.5 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%),
MgSO4 (2 equiv), CH2Cl2 (5 mL), 6 h, 100 mL sealed tube. Isolated yields
are reported. a TEMPO (15 mol%), DCE (5 mL).
To gain insight into the mechanism, we conducted some
preliminary control experiments (Scheme 4). When 0.2
equivalents of 2,6-di-tert-butyl-4-methylphenol (BHT), a
known radical-trapping reagent, were present in the reac-
tion of substrate 1a, the amount of product 2a that was
formed was markedly reduced to <10%, and when the
amount of BHT was increased to 0.5 equivalents, none of
the desired product 2a was obtained, implying that a sin-
gle-electron transfer pathway is involved in this reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
G. Zhang et al.
Letter
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hydrogen atom from the acyl hydrazone A to form TEMPO-
H, which regenerates TEMPO in the presence of O2. Mean-
while, acyl hydrazone A generates intermediate B. Subse-
quently, single-electron oxidation of B by Fe(NO3)3 affords
intermediate C, which gives the intermediate D through ad-
dition of an oxygen radical to the carbon atom of the C=N
moiety. Finally, compound D is converted into the desired
product E by TEMPO-assisted dehydrogenation.
Fe(NO3)3 9H2O (10 mol%)
TEMPO (10 mol%)
MgSO4 (2 equiv)
O
O
N
N
N
BHT (x equiv)
(a)
N
H
DCE, O2, 35 °C, 6 h
1a
2a
Isolated yield
<10%
–
x
0.2
0.5
In conclusion, we have developed an economical and
green Fe(III)/TEMPO-catalyzed oxidative cyclization of
aroylhydrazones to form 1,3,4-oxadiazoles12,13 under mild
conditions in the presence of inexpensive and convenient
O2 as an oxidant. In addition, both arylalkylidene and al-
kylidene benzohydrazides exhibited good compatibility
with the reaction conditions. From preliminary mechanistic
studies, a plausible pathway is proposed.
O
Fe(NO3)3 9H2O (10 mol%)
TEMPO (y equiv)
O
N
N
N
MgSO4 (2 equiv)
(b)
N
H
DCE, N2, 35 °C, 6 h
1a
2a
Isolated yield
12%
y
1.0
2.0
11%
Scheme 4 Control experiments. Reagents and conditions: 1a (0.5
mmol), Fe(NO3)3·9H2O (10 mol%), MgSO4 (2 equiv), DCE (5 mL), 6 h,
100 mL sealed tube. BHT = 2,6-di-tert-butyl-4-methylphenol.
Acknowledgment
We acknowledge financial support from the National Natural Science
Foundation of China (no. 20702051), the Natural Science Foundation
of Zhejiang Province (LY13B020017), and the Key Innovation Team of
Science and Technology in Zhejiang Province (no. 2010R50018).
(Scheme 4, a). Furthermore, when 1.0 or 2.0 equivalents of
TEMPO were added to the reaction system under N2, the
desired product 2a was obtained in only 12% and 11%, yield,
respectively (Scheme 4, b), revealing that the reaction in-
volves a radical pathway.
Supporting Information
Supporting information for this article is available online at
On the basis of these control experiments and related
reports in the literature,10,11 a plausible mechanism is pro-
posed, as outlined in Scheme 5. Initially, TEMPO captures a
http://dx.doi.org/10.1055/s-0036-1588747.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
O2
H2O
O2
–
–
–
(NO3 )n–1(NO2 )
(NO3
)
n
N
OH
N
O
Fe3+
H
N
Fe2+
R2
R2
N
R2
N
N
H
N
N
O
R1
H
A
O
O
R1
R1
H
B
SET
C
N
R2
N
R2
N
N
R1
R1
O
O
H
D
E
N
O
N
OH
O2
H2O
Scheme 5 Possible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
G. Zhang et al.
Letter
Synlett
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(12) 2-tert-Butyl-5-phenyl-1,3,4-oxadiazole (2a); Typical Proce-
dure
A mixture N′-(2,2-dimethylpropylidene)benzohydrazide (1a;
0.1021 g, 0.5 mmol), Fe(NO3)3·9H2O (0.0202 g, 0.05 mmol),
MgSO4 (0.1204 g, 1.0 mmol), TEMPO (0.0078 g, 0.05 mmol), and
DCE (5.0 mL) was added to a 100 mL sealed tube and vigorously
stirred under O2 at 35 °C for 6 h. H2O (20.0 mL) was then added
to the tube and the product was extracted with CH2Cl2 (3 × 15
mL). The organic phases were combined, dried (Na2SO4), and
concentrated under a vacuum. The residue was purified by
column chromatography to give a light yellow liquid; yield:
0.0931 g (92%). 1H NMR (500 MHz, DMSO-d6): δ = 7.99 (dd, J =
8.0, 1.6 Hz, 2 H), 7.63–7.54 (m, 3 H), 1.42 (s, 9 H). 13C NMR (125
MHz, DMSO-d6): δ = 172.67, 163.77, 131.71, 129.29, 126.37,
123.58, 32.02, 27.77. HRMS: m/z [M + 1]+ calcd for C12H15N2O:
203.1179; found: 203.1178.
(13) 2,5-Diphenyl-1,3,4-oxadiazole (4a): Typical Procedure
A mixture of N′-(benzylidene)benzohydrazide (0.1120 g, 0.5
mmol), Fe(NO3)3·9H2O (0.0202 g, 0.05 mmol), MgSO4 (0.1204 g,
1.0 mmol), TEMPO (0.0078 g, 0.05 mmol), and CH2Cl2 (5.0 mL)
was added to a 100 mL sealed tube and vigorously stirred under
O2 at 35 °C for 6 h. H2O (20.0 mL) was then added to the tube
and the product was extracted with CH2Cl2 (3 × 15 mL). The
organic phases were combined, dried (Na2SO4), and concen-
trated under a vacuum. The residue was purified by column
chromatography to give a light yellow solid; yield: 0.0911 g
(82%). 1H NMR (500 MHz, DMSO-d6): δ = 8.15–8.08 (m, 4 H),
7.66–7.60 (m, 6 H). 13C NMR (125 MHz, DMSO-d6): δ = 163.99,
131.99, 129.37, 126.65, 123.33. HRMS: m/z [M + 1]+ calcd for
C
14H11N2O: 223.0871; found: 223.0867.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E