[4u202f+u202f1] Cyclization of benzohydrazide and ClCF2COONa towards 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5

Article abstract of DOI:10.1016/j.cclet.2021.08.089

A facile synthesis of 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d₅ via [4 + 1] cyclization of ClCF₂COONa with non-amine compounds containing amino groups is developed. Of note, this is the first time that halofluorinated compounds are used as C1 synthon to construct deuterated nitrogen-heterocyclic compounds. The current protocol features simple operation, readily accessible raw materials, wide substrate scope and valuable products

Full text of DOI:10.1016/j.cclet.2021.08.089

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
[4+1] cyclization of benzohydrazide and ClCF2COONa towards
1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5
Ya Wang a, Shiqiang Mua, Xin Lia, Qiuling Songa,b,c,∗
a Institute of Next Generation Matter Transformation, College of Materials Science & Engineering and College of Chemical Engineering at Huaqiao University,
Fujian 361021, China
b Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518055, China.
c State Key Laboratory of Organometallic Chemistry and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5 via [4 + 1] cyclization of ClCF2COONa with
non-amine compounds containing amino groups is developed. Of note, this is the first time that haloflu-
orinated compounds are used as C1 synthon to construct deuterated nitrogen-heterocyclic compounds.
The current protocol features simple operation, readily accessible raw materials, wide substrate scope
and valuable products
Received 14 June 2021
Revised 13 August 2021
Accepted 16 August 2021
Available online xxx
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Keywords:
Transition-metal-free catalyzed
[4+1] Cyclization
Halofluorinated compounds
1,3,4-oxadiazoles
Owing to the diverse beneficial effects brought by fluorine
atoms, fluorine chemistry has drawn much attention from chemists
over the past years [1–10]. Especially, halofluorinated compounds,
which are recognized as versatile building blocks, have been
emerging as one of the hottest research topic in fluorine chemistry
[10–30]. Various reaction modes of XCF2R have been established
by our group [10–24] and others [25–30]. For example, besides the
double cleavage of XCF2R, several intriguing utilities of XCF2R such
as playing the role of difluorocarbene precursors [25–27], serving
as C1 synthon via quadruple cleavage, and reacting with amines
to construct nitrogen-containing compounds have been demon-
strated [12–18]. Despite those achievements, the reaction between
the amino groups in hydrazine compounds and XCF2R has not yet
been explored. Previously, our group reported the first example
for synthesis of deuterated formamide from halofluorinated com-
pounds and amines (Scheme 1A) [13]. However, the utilization of
ClCF2COONa as C1 synthon and D2O as deuterium sources to con-
struct deuterated nitrogen-heterocyclic compounds has not been
documented so far.
biologically active molecules [31–36]. In view of the importance of
1,3,4-oxadiazoles and deuterated compounds in pharmaceuticals,
we reported an effective [4 + 1] cyclization of ClCF2COONa to syn-
thesize 1,3,4-oxadiazoles and more importantly, 1,3,4-oxadiazoles-
d5 in decent yields and with excellent deuteration ratios under
transition-metal-free conditions. To the best of our knowledge, the
direct construction of 1,3,4-oxadiazole-d5 has never been docu-
mented up to date. Thus our protocol provide a facile and straight-
forward route for divergent construction of 1,3,4-oxadiazoles and
1,3,4-oxadiazoles-d5 via a transition-metal-free [4 + 1] cyclization,
which represents the first example of efficient one-pot construc-
tion of 1,3,4-oxadiazoles-d5 (Scheme 1B).
To explore the feasibility of our hypothesis, we selected benzo-
hydrazide (1a) and ClCF2COONa (2a) as the model substrates for
our proof-of-concept study (Table 1). To our delight, when the re-
action was carried out in the presence of base Cs2CO3, the ex-
pected 2-phenyl-1,3,4-oxadiazole (3a) was obtained in 73% yield
(Table 1, entry 1). Inspired by this result and in light of our pre-
vious researches, a range of bases were screened, which turned
out that K3PO4 was the best choice to deliver the desired prod-
uct 3a (90% yield) (Table 1, entries 2–4). Next, we examined the
reaction temperature. Nevertheless, elevating or lowering the tem-
perature are both unfavorable for the reaction (Table 1, entries 5
and 6). In order to enhance the yield of 3a, we also inspected a
number of solvents (Table 1, entries 7–10). However, no superior
results gained and it was found that CH3CN was still the opti-
1,3,4-Oxadiazoles are a very important class of N-heterocyclic
compounds, which are extensively found in pharmaceuticals and
∗
Corresponding author at: Institute of Next Generation Matter Transformation,
College of Materials Science & Engineering and College of Chemical Engineering at
Huaqiao University, Fujian 361021, China.
E-mail address: qsong@hqu.edu.cn (Q. Song).
https://doi.org/10.1016/j.cclet.2021.08.089
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: Y. Wang, S. Mu, X. Li et al., [4+1] cyclization of benzohydrazide and ClCF2COONa towards 1,3,4-oxadiazoles
and 1,3,4-oxadiazoles-d5, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.08.089

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Table 1.
Screening of optimized reaction conditions.
Entry
Base
Solvent
Yield (%)a
1
Cs2CO3
Na2CO3
NaHCO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
73
2
78
3
67
4
90
5b
6c
7
50
70
30
8
1,4-dioxane
DCE
trace
trace
15
9
10
11d
12e
EA
CH3CN
CH3CN
91
93
Reaction condition: 1a (0.2 mmol), 2a (0.6 mmol) and base (0.6 mmol) in
slovent (2 mL) under N2 atmosphere at 100 °C for 1 h.
a
Isolated yield.
b
At 80 °C.
c
At 120 °C.
d
2a (0.3 mmol), base (0.5 mmol).
e
2a (0.3 mmol), base (0.3 mmol).
Scheme 2. Substrate scope for the synthesis of 1,3,4-oxadiazoles. Reaction condi-
tion: 1 (0.2 mmol), 2a (0.3 mmol), K3PO4 (0.3 mmol), CH3CN (2 mL), N2, 100 °C, 1
h.
Scheme 1. Transition-metal-free catalyzed synthesis of 1,3,4-oxadiazoles.
Scheme 3. Substrate scope of halodifluoromethyl compounds. Reaction condition:
1a (0.2 mmol), 2 (0.3 mmol), K3PO4 (0.3 mmol), CH3CN (2 mL), N2, 100 °C, 1 h.
mized solvent. Gratifyingly, when we reduced the amount of both
ClCF2COONa and the base to 1.5 equiv., the targeted 2-phenyl-1,3,4-
oxadiazole (3a) could be isolated in 93% yield (Table 1, entry 12).
With the optimized conditions in hand, we next investigated
the substrate generality of this [4 + 1] cyclization (Scheme 2).
To our delight, a wide range of easily accessible benzohydrazides
(1a–1u) could react smoothly with ClCF2COONa (2) to provide the
desired products 2-substituted-1,3,4-oxadiazoles (3a–3u) in good
yields by using CH3CN as solvent and K3PO4 as base. The struc-
ture of 3a was unambiguously confirmed by X-ray single crys-
tal analysis. As showcased in Scheme 2, a variety of benzohy-
drazides bearing both electron-donating and electron-withdrawing
groups were good candidates in this transformation, affording the
desired 2-substituted-1,3,4-oxadiazole products (3a–3m) in 53% to
98% yields. Moreover, halo-substituted benzohydrazides (1n–1r)
were also proven to be good candidates in this cyclization re-
action, enabling to formation of the desired 2-substituted-1,3,4-
oxadiazole products 3n–3r in 78% to 88% yields. In addition
to para-substituted benzohydrazides, ortho- and meta-substituted
benzohydrazides could also work well in this reaction, provid-
ing the corresponding 1,3,4-oxadiazoles 3q and 3r in good yields.
To our delight, heterocyclic benzohydrazides and alkyl hydrazide
demonstrated decent reactivity in this cyclization reaction as well,
finishing the targeted products 3s-3u in moderate to good yields.
Of note, the indole was well-tolerated under the standard condi-
tions without the difluoromethylation of the free N-H in indole.
As summarized in Scheme 3, we also investigated other halod-
ifluoromethyl compounds and it was found that all of them could
serve as carbon sources to forge 2-phenyl-1,3,4-oxadiazole un-
der the same conditions by using benzohydrazides 1a as the
model substrates. In addition to sodium chlorodifluoroacetate 2a,
ethyl chlorodifluoroacetate 2b, ethyl bromodifluoroacetate 2e and
ethyl iodifluoroacetate 2g were proved to be good C1 source
in this transformation, enabling to deliver 3a in 48% to 70%
yields, respectively. When difluorobromoacetic acid 2d was used
as C1 source, the yield of 3a could be isolated in 45% yield.
Diethyl(bromodifluoromethyl)phosphonate 2h provided the corre-
sponding 2-phenyl-1,3,4-oxadiazole 3a in a comparable 50% yields.
Compared to other halodifluoromethyl compounds, chlorodifluo-
romethane 2c and 2-bromo-2,2-difluoro-N-hexylacetamide 2f dis-
played lower reactivity, resulting in the target product 3a with 22%
and 10% yields, respectively.
Deuterium incorporation plays an important role in isotope la-
belling, which can be used in the investigation of reaction mech-
anism, as well as in nuclear magnetic resonance spectroscopy
2

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Scheme 4. Isotope-labelling experiments.
Scheme 6. Scale-ups and synthetic transformations.
Scheme 5. Deuteration with D2O as the deuterium source. Reaction condition: 1
(0.2 mmol), 2a (0.3 mmol), K3PO4 (0.3 mmol), D2O (20 equiv.), anhydrous CH3CN
(2 mL), N2, 100 °C, 1 h. All yields are the isolated yields, and the numbers in paren-
theses are the deuteration ratios of the corresponding deuterated products.
Scheme 7. Control experiments.
1,3,4-oxadiazole 7 via a Pd-catalyzed Suzuki-coupling (Scheme 6d)
[39].
We then turned our attention to shed light on the mecha-
nism of this [4 + 1] cyclization reaction. Radical trapping experi-
ments were investigated firstly (Scheme 7). When 2,6-di-tert-butyl-
4-methylphenol (BHT) and ethene-1,1-diyldibenzene were served
as radical scavengers under the standard conditions, this cycliza-
tion reaction has no significant influence (Schemes 7a and b, and
Scheme S7b in Supporting information), indicating that a radical-
type process might not be involved in this [4 + 1] cyclization.
Based on our previous quadruple cleavage of halogenated difluoro
compounds, difluorocarbenes (:CF2) was generated in-situ. To ver-
ify the production of difluorocarbene in this reaction, the difluoro-
carbene trapping experiment was conducted. When benzimidazole
was added as difluorocarbene trapper, the 1-(difluoromethyl)-1H-
benzo[d]imidazole (8) was obtained in 80% yield (Scheme 7c).
Based on the above experimental results and previous liter-
atures [40,41], a possible reaction mechanism for this cycliza-
tion reaction of benzohydrazides and ClCF2COONa is depicted in
Scheme 8. Firstly, difluorocarbene is formed via the dechlorina-
tion and decarboxylation of ClCF2COONa. The in-situ generated di-
fluorocarbene is immediately captured by the benzohydrazides 1
with the assistance of a base to afford the Intermediate A, which
rapidly undergoes the tautomerism to obtain Intermediate B. Si-
multaneously, the Intermediate B to give the intermediate C in
the presence of base. The intermediate C further goes through the
intramolecular cyclization and protonation or deuterate to affords
the target product 3.
(NMR) and mass spectrometry (MS) [37]. In addition, more and
more deuterated drugs are reported [38], which has created an
urgent need for synthetic methods to effectively generate deuter-
ated building blocks. Grounded in our current successful 1,3,4-
oxadiazoles formation via the base promoted [4 + 1] cyclization re-
action, we also invented a mild and generic method for the deuter-
ation of 1,3,4-oxadiazoles using D2O as an inexpensive deuterium
source (Scheme 4). Delightfully, when we replaced CH3CN with an-
hydrous CH3CN and add 20 equiv. of D2O for this cyclization re-
action, and the yields were barely affected along with excellent
deuteration ratios (Scheme 5). Both aryl and alkyl benzohydrazides
were inspected under the corresponding reaction conditions, the
corresponding target products (4a-4p) were procured in up to 88%
yields accompanied with excellent deuteration ratios.
We also studied the scalability of this [4 + 1] cyclization reac-
tion. When current protocol was scaled up ten times, the desired
1,3,4-oxadiazoles 3h and 3p could be readily obtained in 75% and
73% yields without the loss of efficiency, respectively (Schemes 6a
and b). Further transformations of the 1,3,4-oxadiazoles were ex-
ecuted. The ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-1H-imidazole-
4-carboxylate 5 could be obtained in moderate yield via a Cu-
catalyzed [3 + 1 + 1] type cyclization of ClCF2COONa for the
assembly of imidazoles via the in-situ generated isocyanides
(Scheme 6c) [12]. The synthetic utility of this approach was also
ꢀ
ꢀ
showcased by the assembly of 2-(4 -methoxy-[1,1 -biphenyl]-4-yl)-
3

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Scheme 8. Proposed reaction mechanism for the synthesis of 1,3,4-oxadiazole derivatives.
In conclusion, we have disclosed
a
novel transition-metal-
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The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
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Financial support from the National Natural Science Foundation
of China (Nos. 21772046, 2193103), and the Guangdong Provin-
cial Key Laboratory of Catalysis (No. 2020B121201002) is grate-
fully acknowledged. The authors also thank the Instrumental Anal-
ysis Center of Huaqiao University for analysis support. Y. Wang
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Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.cclet.2021.08.089.
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