Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles by visible-light-mediated decarboxylation–cyclization of hydrazides and diketones

Article abstract of DOI:10.1016/j.tetlet.2018.01.037

A visible-light-induced synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from simple diketones and hydrazides with the assistant of the photocatalyst eosin Y catalyzed decarboxylation and cyclization under mild conditions has been discovered. The reaction tolerates a wide range of functional groups and gives a variety of valuable 1,3,4-oxadiazoles in moderate to good yields. Finally, a plausible reaction mechanism was proposed.

Full text of DOI:10.1016/j.tetlet.2018.01.037

Accepted Manuscript
Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles by visible-light-mediated de-
carboxylation–cyclization of hydrazides and diketones
Pinhui Diao, Yanqin Ge, Wenpei zhang, Chen Xu, Nannan Zhang, Cheng Guo
PII:
S0040-4039(18)30061-3
https://doi.org/10.1016/j.tetlet.2018.01.037
TETL 49624
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 November 2017
9 January 2018
12 January 2018
Please cite this article as: Diao, P., Ge, Y., zhang, W., Xu, C., Zhang, N., Guo, C., Synthesis of 2,5-disubstituted
1,3,4-oxadiazoles by visible-light-mediated decarboxylation–cyclization of hydrazides and diketones, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.037
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Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles by
visible-light-mediated decarboxylation–cyclization of
hydrazides and diketones
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Pinhui Diao†, Yanqin Ge†, Wenpei zhang, Chen Xu, Nannan Zhang, Cheng Guo*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles by visible-light-mediated
decarboxylation–cyclization of hydrazides and diketones
Pinhui Diao†, Yanqin Ge†, Wenpei zhang, Chen Xu, Nannan Zhang, Cheng Guo∗
College of Chemistry and Molecular Engineering, Nanjing Tech University, 30 Puzhu South Road, Jiangsu, Nanjing 211816, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A visible-light-induced synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from simple diketones
and hydrazides with the assistant of the photocatalyst eosin Y catalyzed decarboxylation and
cyclization under mild conditions has been discovered. The reaction tolerates a wide range of
functional groups and gives a variety of valuable 1,3,4-oxadiazoles in moderate to good yields.
Finally, a plausible reaction mechanism was proposed.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Visible light;
Mild conditions;
Decarboxylation;
Cyclization;
1,3,4-oxadiazoles.
from hydrazides and diketones using eosin Y in the presence of
visible light are reported herein.
Introduction
In recent years, visible-light-induced photoredox catalysis was
proved to be a powerful method to initiate kinds of organic
reaction1 including cyclizations2, C−H functionalizations3, and
decarboxylative coupling reactions4 under mild reaction
conditions. Organic dye eosin Y, with strong absorption in the
visible part of the spectrum, which was less toxic and cheaper
compared to transition metal based catalysts, has been widely
used in photochemical organic transformations. König’s group
has demonstrated the use of eosin Y for (a) the formation of C−C
and C−P bonds5, (b) enantioselective transformations6, and (c) the
synthesis of substituted aromatic heterocycles7. We herewith
report the use of eosin Y as a photoredox catalyst, in the
reactions of hydrazides and diketones to give 2,5-disubstitued
1,3,4-oxadiazoles.
Previous work
a) synthesis by Wu et al (2015)
O
N
N
O
R1
CuI, K2CO3
O
O
NH2
+
R1
N
DMSO, 120°C, air
N
R2
R2
NH2
H
H
b) synthesis by Fan et al (2016)
This work
Functionalized 2,5-disubstituted 1,3,4-oxadiazoles have been
extensively utilized for its significant biological activities
including antimicrobial, antifungal, and anti-inflammatory.
Classic methods8 for the synthesis of 2,5-disubstitued 1,3,4-
oxadiazoles can be divided into two classes: (a) dehydrative
cyclization of 1,2-diacylhydrazines9; (b) oxidative cyclization of
acylhydrazones10. Wu and coworkers have reported the copper-
catalyzed intramolecular decarboxylative coupling between
isatins and hydrazides, giving 1,3,4-oxadiazoles at elevated
temperature (Scheme1, a)11. Recently, Fan and coworkers
reported a KI/TBHP-mediated oxidative cyclization of a-keto
acids with acylhydrazines for the synthesis of 2,5-disubstituted
1,3,4-oxadiazoles. (Scheme 1, b)12. Due to the high temperature
Scheme 1. Synthesis of 2,5-disubstitued-1,3,4-oxadiazoles
Results and discussion
At first, we started the investigation by using
benzoylhydrazine 1a and isatin 2a as model substrates in the
of the reaction and the use of Cu(Ⅰ) salt or I2 catalyst, we
combined the two reactions and proposed our methods, the
results for the synthesis of 2,5-disubstitued 1,3,4-oxadiazoles
∗ Corresponding author.
E-mail: guocheng@njtech.edu.cn (C. Guo).

b
rhodamine B, n.r. = no reaction. Isolated yield. No visible
c
presence of 5mol% of Eosin Y photocatalyst, 2 equiv of K2CO3
in 2mL DMSO at 45 ℃ . To our delight, the desired 2,5-
disubstituted 1,3,4-oxadiazoles 3aa was formed in 75% yield
under visible-light irradiation (Table 1, entry 1). In addition, a
series of control experiments were performed in the absence of
any one of visible light, Eosin Y, or K2CO3, which showed that
the visible light, photocatalyst and base are essential for the
formation of the desired product in a good yield (Table 1, entries
2−4). Next, we studied the effect of other parameters on the
reaction, including base, photocatalysts, and solvents. Several
inorganic and organic bases were also tested, but K2CO3 was
found to be optimal (Table 1, entries 1 and 5-8). Among various
photocatalysts, Eosin Y showed the highest activity (Table 1,
entries 1and 9-11). When use DMF, EtOH, MeCN, THF, and1,4-
Dixoane as solvent, the yield of 3aa was low (Table 1, entries 1
and 12-16), which indicates that the reaction is sensitive to
reaction media. DMSO was the best solvent in terms of the
reaction yield, hence it was used throughout the present work.
Finally, the effect of O2 was also investigated, which
demonstrated that O2 may be important in the reaction (Table 1,
entries 1, 17, and 18).
light. d N2 atmosphere. e O2 atmosphere.
Table 2. Substrate Scope for Oxadiazole Synthesisa,b
3aa(75%)
3ad(68%)
3ac(70%)
3ab(72%)
3ae(65%)
3ah(59%)
3af(61%)
3ai(63%)
Table 1. Optimization of Reaction Conditions a
3ag(58%)
3al: R=propyl (62%)
3am: R=tubyl (60%)
3aj(60%)
3ba(67%)
3ea(62%)
3ak(65%)
3ca(72%)
3fa(60%)
Yield b
(%)
Entry
PC
Base
Solvent
3da(69%)
3ga(42%)
1
2c
3
EY
EY
-
K2CO3
K2CO3
K2CO3
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
75
n.r.
trace
n.r.
65
a Reaction conditions: 1a (0.5mmol), 2a (0.5mmol), photocatalyst
(0.025mmol), K2CO3 (1mmol), DMSO(3mL), 45℃ , 24h, air
atmosphere. b Isolated yield.
4
EY
EY
EY
EY
EY
Na2-EY
MB
RB
EY
EY
EY
EY
EY
EY
EY
5
KHCO3
NaHCO3
Cs2CO3
Et3N
Under the optimized conditions, decarboxylation-cyclization
of various hydrazides with isatin has been examined. As
summarized in Table 2, this protocol allows the reaction of a
broad range of aromatic, heteroaromatic, and aliphatic hydrazides
and proved to be a general method to construct diverse 1,3,4-
oxadiazoles. We explored the substrate scope using various
benzoylhydrazine derivatives with isatin 2a (Table 2, 3ab−am).
The scope of the substrates was further successfully extended to
various electron-withdrawing halogenated substrates (Table 2,
3ab–3ad, 68-72%), which proceeded smoothly to afford the
corresponding 1,3,4-oxadiazoles in good yields. Reactions with
benzoylhydrazines bearing electron-neutral (H, 4-Me, 3-Me) and
electron-donating (4-OMe, 4-tBu) substituents resulted in
successful conversion to the corresponding products in moderate
to good yields (Table 2, 3aa, 3ae–3ah, 58-75%). Notably,
representative heteroaryl hydrazides compounds such as furan-2-
carbohydrazide and thiophene-2-carbohydrazide, were also
excellent substrates, providing desired products in good yields
(Table 2, 3ai, 3aj, 60%, 65% respectively). Additionally, alkyl
hydrazides, such as acetohydrazide, butyric acid hydrazide and
valeric acid hydrazide also exhibited good reactivity under
standard conditions (Table 2, 3ak-3am, 60%-65%). Next, isatins
containing both electron-donating and electron-withdrawing
substituents underwent decarboxylation–cyclization with
benzoylhydrazine 1a to afford the corresponding 2,5-disubstuted
6
36
7
<5
8
n.r.
55
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14
15
16
17d
18e
<5
16
<5
EtOH
n.r.
n.r.
n.r.
n.r.
n.r.
72
MeCN
THF
1,4-Dixoane
DMSO
DMSO
a
Reaction conditions: 1a (0.5mmol), 2a (0.5mmol), Base
(1mmol), Photocatalyst (0.025mmol), Solvent(3mL), 45℃, 24h,
air atmosphere, PC = photocatalyst. MB = methylene blue, RB =

3
1,3,4-oxadiazoles in moderate to good yields successfully (Table
2, 3ba−ga).
The method provides a decarboxylation-cyclization procedure
for the synthesis of 2,5-disubstitued 1,3,4-oxadiazoles under very
mild reaction conditions. When using phenylglyoxylic acid and
hydrazines as substrates, the reaction conditions differ from the
above and were screened on Table S (in Supporting Information),
while the products were accord with our expected results (Table
3). As summarized in Table 3, the reaction also showed good
compatibility and universality. We explored the substrate scope
using various benzoylhydrazine derivatives with phenylglyoxylic
acid (Table 3, 5a-5n). The scope of the substrates was extended
to electron-withdrawing and electron-donating groups
successfully. It is obviously that heteroaryl and aliphatic
hydrazides compounds, giving expected products, were good
substrates too.
Scheme2. Control experiments
On the basis of the above results and related literature
reports13, a plausible mechanism involving photoredox catalysis
for the decarboxylation and intramolecular cyclization for the
formation of 1,3,4-oxadiazoles was proposed in Scheme 3. Under
the reaction conditions, 2 underwent base-promoted hydrolysis14,
condensed with 1 to give the intermediate acylhydrazone A,
while eosin Y reaches its more stable excited state through
intersystem crossing upon excitation by visible light and
undergoes a single electron transfer (SET). A SET from A to
eosin Y* generates acyl radical B, which undergoes
decarboxylation and intramolecular cyclization, leading to the
formation of D15, following by the attack of O2 (air) to give the
product E.
Table 3. Scope of Hydrazides with Phenylglyoxylic acida,b
5b(72%)
5a(78%)
5c(73%)
5d(75%)
5e(74%)
5f(67%)
5h(68%)
5i(62%)
5g(66%)
5j(52%)
5
k
(
5l: R= Me(65%)
5
4
%
)
5m: R= propyl(67%)
5n: R= tubyl(63%)
Scheme3. Plausible Mechanism
a Reaction conditions: 1a (0.5mmol), 4 (0.5mmol), photocatalyst
(0.025mmol), DMF(3mL), 45℃, 12h, air atmosphere. b Isolated
yield.
Conclusion
In summary, we have developed a visible-light-mediated
decarboxylation–cyclization for the synthesis of 2,5-disubstitued
1,3,4-oxadiazoles directly from diketones and hydrazides in the
presence of eosin Y as a powerful photocatalyst under mild
conditions. A series of 2,5-disubstitued 1,3,4-oxadiazoles was
efficiently obtained in moderate to good yields. A wide range of
hydrazides and diketones were tolerated well in this process,
which is highly compatible with the goal of sustainable and green
chemistry. Further applications of eosin Y as a photoredox
catalyst are in progress.
To gain deeper insight into the possible mechanism for this
transformation, a series of control experiments were conducted
and the results are summarized in Scheme 2. When 4 equiv
radical
scavenger
TEMPO
(2,2,6,6-tetramethyl-1-
piperidinyloxyl) was employed in the reaction, no desired
product was detected(Scheme 2, a). This result suggested that the
reaction probably follow a radical reaction pathway. When
treatment of simplified precursor I were performed under the
standard conditions, the desired products 5a was detected, which
was not while 2 equiv TEMPO was added(Scheme 2, b),
suggesting that I may be the possible intermediate.
†These two authors contributed equally to this project.
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5
Highlights
1. The research was proceeded without using transition-metal
under visible-light.
2. The reaction was proceeded without using extra oxidant.
3. The protocol tolerates a wide range of functional groups.
4. A plausible mechanism was proposed.