DMF as Methine Source: Copper-Catalyzed Direct Annulation of Hydrazides to 1,3,4-Oxadiazoles

Article abstract of DOI:10.1002/adsc.201900395

An unprecedented Cu-catalyzed direct annulation of hydrazides with N,N-dimethylformamide (DMF) was developed, providing an efficient synthesis of valuable 1,3,4-oxadiazoles. This process features the short reaction time and can be safely conducted on gram scale. The reaction also facilitated the convenient synthesis of 1,3,4-oxadiazole-2(3H)-ones. Moreover, the mechanistic studies suggest that the source of CH is from the N-methyl group of DMF. (Figure presented.).

Full text of DOI:10.1002/adsc.201900395

Title: DMF as Methine Source: Copper-Catalyzed Direct Annulation of
Hydrazides to 1,3,4-Oxadiazoles
Authors: Fanghua Ji, Guangbin Jiang, Shuhua Zhang, Xiangfei Kong,
Kai Wang, and Shoucai Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900395
Link to VoR: http://dx.doi.org/10.1002/adsc.201900395

10.1002/adsc.201900395
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
DMF as Methine Source: Copper-Catalyzed Direct Annulation
of Hydrazides to 1,3,4-Oxadiazoles
Shoucai Wanga, Kai Wanga, Xiangfei Konga, Shuhua Zhanga*, Guangbin Jianga,*,
Fanghua Jia,*
a
Guangxi Key Laboratory of Electrochemical and Magnetochemical Function Materials, College of Chemistry and
Bioengineering, Guilin University of Technology, Guilin 541004, China.
E-mail: jianggb@glut.edu.cn, fanghuaji@glut.edu.cn; Fax: 86-773-899-1304
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An unprecedented Cu-catalyzed direct
As one of the most inexpensive industrial raw
annulation of hydrazides with N,N-dimethylformamide
material and common polar solvents, N,N-
(DMF) was developed, providing an efficient synthesis of
dimethylformamide (DMF) is considered to be a
valuable 1,3,4-oxadiazoles. This process features the short
readily available multipurpose building block in
reaction time and can be safely conducted on gram scale.
organic transformations, such as the formylation,
The reaction also facilitated the convenient synthesis of
carbonylation, amination, cyanation, methylation and
1,3,4-oxadiazole-2(3H)-ones. Moreover, the mechanistic
other related reactions.[10] Similar to DMF, DMSO
studies suggest that the source of CH is from the N-methyl
has also been widely used in organic synthesis.[11] To
the best of our knowledge, employing the methyl
group of DMF.
group of DMF as the source of methine group (CH) in
a cyclization reaction was not reported until the
elegant works of Guan and Deng in 2014 (Scheme 1a
and 1b).[12] In 2017, the Liu group developed an
efficient method for the synthesis of symmetrical
tetrasubstituted pyridines using DMF as the carbon
source and (NH4)2S2O8 as the oxidant and nitrogen
source (Scheme 1c).[13] However, the application of
DMF as methine group source to construct 1,3,4-
oxadiazoles has not been demonstrated thus far.
Owing to our continuing interest in the construction
of heterocycles by employing simple and readily
available starting materials,[14] we disclosed an
efficient protocol for the synthesis of 1,3,4-
oxadiazoles using DMF as the source of methine
group (Scheme 1d).
Keywords: Cu-catalyzed, DMF, methine source, 1,3,4-
oxadiazoles, short reaction time, gram scale
1,3,4-oxadiazoles occupy an important position in
[1]
medicinal chemistry and material science.
Compounds bearing 1,3,4-oxadiazoles skeleton have
been broadly used as pharmaceutical molecules, such
[4]
as Raltegravir,[2] Furamizole,[3] Nesapidil
and
Tiodazosin (Figure 1).[5] Consequently, significant
efforts have been devoted to the preparation of the
1,3,4-oxadiazoles scaffold.[6] In 2013, Chang and co-
workers reported an I2-mediated oxidative C-O bond
formation for the synthesis of 1,3,4-oxadiazoles.[7]
Subsequently, Wu’s group described an oxidative
3
cleavage of Csp -H bonds of methyl ketones for the
synthesis of 1,3,4-oxadiazoles via direct annulation of
hydrazides.[8] Recently, an alternative strategy is
reported by Wu’s group via annulation of hydrazides
and benzene-1,3,5-triyl triformate under metal-free
conditions.[9]
Scheme 1. Different Procedures Employing DMF as the
Sources of Methine
Figure 1. Examples of Pharmaceuticals Containing 1,3,4-
Oxadiazoles
1
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10.1002/adsc.201900395
Advanced Synthesis & Catalysis
Our initial efforts focused on the optimization of
With the optimal conditions established, various
reaction conditions, we chose benzohydrazide as hydrazides were explored and the results were
substrate to evaluate different parameters (Table 1). summarized in Table 2. Aryl hydrazides bearing
After screening a series of copper catalysts, it was different electron-neutral (e.g., 4-H, 4-Me, 3-Me, 2-
found that CuI displayed the best ability in this Me, 4-tBu), electron-donating (e.g., 4-OMe, 3,4-
transformation (Table 1, entry 1-6). Then the reaction OCH2O), and electron-withdrawing (e.g., 4-NO2, 4-
was performed under an O2 atmosphere using K2S2O8 CF3, 4-Ph, 4-CN) groups were well tolerated under
as the co-oxidant, the desired product was observed the optimal reaction conditions (2a-2k) regardless of
with low yield (Table 1, entry 7). Furthermore, the their electronic and steric properties. Much to our
oxidants were found to be vital to the catalytic system, satisfaction, the substrates with functional groups
the optimization of oxidants showed that other such as fluoro, chloro, and bromo all gave the
oxidants, such as TBHP, Ag2CO3, AgNO3 and Ag2O, corresponding products in moderate yields (2l-2o),
were ineffective for the reaction (Table 1, entry 8-11). which allowed for easy further functionalization. It
Gratifyingly, when the reaction temperature was was worth noting that the substrates with naphthalene
o
changed to 120 C, the yield of 2a was increased to or heterocyclic ring were also tolerated in the reaction
68% (Table 1, entry 12-14). In addition, when the system, which significantly expanded the scope of the
catalyst lowding were reduced to 10 mol %, 2a could reaction (2p-2r). Disappointingly, pyridyl hydrazide
be obtained only in 57% (Table 1, entry 15). The and acetohydrazide did not give the desired products.
reason for the moderate yield is that the To our delight, the reaction can be successfully
corresponding products can be broken down rapidly conducted in gram scale.
in the reaction system according to our experimental
results.
Table 2. Synthesis of 1,3,4-oxadiazoles from Hydrazides
and DMF a,b
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
oxidant
T(oC)
yieldb (%)
1
2
CuI
CuCl
CuBr
Cu(OTf)2
Cu(OAc)2
Cu(TFA)2
CuI
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHPd
Ag2CO3
AgNO3
Ag2O
80
80
30
7
3
80
20
4
80
5
5
80
trace
15
6
7c
80
80
27
8
CuI
80
n.d.
n.d.
n.d
trace
25
9
CuI
80
10
11
12
13
14
15e
16f
17g
18g
CuI
80
CuI
80
CuI
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
60
CuI
100
120
120
120
120
140
50
CuI
68
CuI
57
CuI
35
I2
12
I2
27
a)
Reaction conditions: 1a (0.2 mmol), catalyst (25 mol %),
a)
oxidant (1 equiv), and DMF (2.0 mL) were stirred under air for 1
h.
b) Isolated yields; n.d. = not detected.
c) Under O2 atmosphere.
Reaction conditions: a mixture of 1 (0.2 mmol), K2S2O8 (1
equiv), CuI (25 mol %), and DMF (2.0 mL) were stirred at 120 °C
for 1 h.
b) Isolated yields.
d) TBHP (70% solution in water).
e) Catalyst loading is 10 mol%.
f) The reaction time is 2 hours.
g) I2 (1.5 equiv).
The further transformation of the resultant 1,3,4-
oxadiazoles was then demonstrated by the
construction of 1,3,4-oxadiazole-2(3H)-ones. 1,3,4-
2
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10.1002/adsc.201900395
Advanced Synthesis & Catalysis
oxadiazole-2(3H)-one core is a popular bioisostere for
To gain insight into the mechanism of the reaction,
improving the pharmaceutical activity.[15] This a variety of control experiments were conducted as
heterocycle is a privileged structure in medicinal shown in Scheme 3. In order to confirm the source of
chemistry.[16] The copper-catalyzed oxidation of CH is from N-methyl or formyl moiety of DMF, we
1,3,4-oxadiazoles at room temperature under air use formamide and N,N-diethylformamide instead of
provided a series of 1,3,4-oxadiazole-2(3H)-ones.[17] N,N-dimethylformamide, no reaction occurred under
As shown in Table 3, various substituents at the aryl, the optimal reaction conditions (Scheme 3a, 3b). As
such as methyl, fluoro, chloro, bromo and nitryl were expected,
N,N-dimethylacetamide
and
N,N-
all tolerated well. It is noteworthy that substrates with dimethylaniline gave the corresponding product with
naphthalene and heterocylic ring could also survive in relatively low yields (Scheme 3c, 3d). In order to
the reaction system.
have a deep insight into the mechanism, we traced the
reaction with carbon-13 labeled on carbonyl carbon of
Table 3. Synthesis of 1,3,4-oxadiazole-2(3H)-ones from DMF, and no corresponding product was obtained
1,3,4-oxadiazoles a,b
(Scheme 3e). These results demonstrated that the
methine source was from the N-methyl of DMF. In
addition, no products were obtained in the presence of
radical scavenger, such as BHT (2,6-di-tert-butyl-4-
methylphenol), BQ (p-benzoquinone) and TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl),
which
suggesting that the reaction probably proceeds
through a radical pathway (Scheme 3f).
Scheme 3. Control Experiments
a) Reaction conditions: a mixture of 2 (0.5 mmol), tBuOLi (0.6
mmol), CuCl2 (5 mol %), and DMF (2.0 mL) were added under
air at room tempereture.
b) Isolated yields.
c) Catalyst loading is 10 mol%.
To demonstrate the further transformation of the
reaction, the corresponding product 2a was used for
the construction of π-conjugated molecules containing
heterocycles via copper-mediated direct arylation
(Scheme 2a).[18] This kind of molecules constitute an
important class of compounds in material and
phamaceutical chemistry because of their good
electron-transporting and hole-blocking abilities.[19]
Moreover, the direct alkynylation of 1,3,4-
oxadiazoles with alkynyl bromides under copper
catalysis created the corresponding heteroaryl-alkynyl
linkage in good yields, which provided a convergent
access to oxadiazole core π-conjugated systems
(Scheme 2b).[20] Besides, 1,3,4-oxadiazoles as typical
electron-deficient arenes could be oxidized by
elemental sulfur via copper-catalyzed direct C–H
bond thiolation (Scheme 2c).[21]
Scheme 4. Proposed Mechanism
Scheme 2. Further transformation of 2a
3
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10.1002/adsc.201900395
Advanced Synthesis & Catalysis
Based on above observations and relevant literature [1] a) A. Zarghi, S. A. Tabatabai, M. Faizi, A. Ahadian, P.
reports,[22] a plausible mechanism of the reaction has
been proposed in Scheme 4. First, the intermediate A
and Cu(I) were formed via a single-electron transfer
from DMF to Cu(II). Then, electron-transfer of
persulfate can lead to the formation of iminium B.
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Subsequently,
nucleophilic
addition
of
benzohydrazide to species B produced intermediate C,
which was further oxidated into iminium intermediate
D. Then D transformed into intermediate E through
the cyclization process. Finally the desired product
was obtained via elimination of intermediate E.
In summary, we have developed a simple and
convenient approach for the synthesis of 1,3,4-
oxadiazoles by Cu-catalyzed oxidative cyclization
using DMF as economic reagent. The mechanism
investigation implied that the methine source is from
the methyl group of DMF. Moreover, the reaction was
confirmed to have good functional group tolerance
and a series of functionalized products., such as 1,3,4-
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Typical Experimental Procedure for Product 2
Aryl-hydrazide 1 (0.2 mmol), CuI (25 mol %), K2S2O8 (2
equiv) and DMF (2.0 mL) were sealed in a test tube under
air atmosphere. After this, the mixture was stirred at 120 oC
(oil bath temperature) for 1 h. After the reaction was
completed (monitored by TLC), the resulting mixture were
cooled to room temperature and extracted with ethyl
acetate. The combined organic layers were evaporated
under vacuum. The desired products 2 were obtained in the
corresponding yields after purification by column
Chromatography on silica gel with mixture of petroleum
ether and ethyl acetate.
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This work was supported by the Ph. D. Scientific Research
Foundation of Guilin University of Technology and Guangxi
Natural
Science
Fundation
(2017GXNSFBA198224,
2018GXNSFAA281203 and 2018GXNSFBA050024) and Key
Laboratory of Electrochemical and Magneto-chemical Function
Materials.
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5
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10.1002/adsc.201900395
Advanced Synthesis & Catalysis
COMMUNICATION
DMF as Methine Source: Copper-Catalyzed Direct
Annulation of Hydrazides to 1,3,4-Oxadiazoles
Adv. Synth. Catal. 2019, Volume, Page-Page
Shoucai Wanga, Kai Wanga, Xiangfei Konga,
Shuhua Zhanga, Guangbin Jianga,*, Fanghua Jia,*
6
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