NJC

PAPER

Formal [4+1] cyclization of (thio/imido)hydrazides

and ethyl 3,3,3-trifluoropropanoate: unified
Cite this: New J. Chem., 2022,
46, 20755 synthesis of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles
and 1,2,4-triazoles†
Lan Zhao, ab Jun Xu,c Jun Ma,ab Guangwei Yin,ab Fangyi Li, *ab
Tongchuan Suo *ab and Chunhua Wang *d

Received 19th August 2022, Here we report an efficient and practical one-step synthesis of a series of 1,3,4-oxadiazoles with ethyl ester
Accepted 3rd October 2022 decoration, which was accomplished by the formal [4+1] cyclization of hydrazides and commercially
DOI: 10.1039/d2nj04147b available ethyl 3,3,3-trifluoropropanoate. In contrast to previously reported synthetic processes, this method
features operational simplicity, easy scalability and good substrate tolerability. Furthermore, the present
rsc.li/njc synthetic method can be generalized to access 1,3,4-thiadiazoles and 1,2,4-triazoles.

Introduction In our recent medicinal chemistry program, we needed to

prepare a variety of 1,3,4-oxadiazoles with alkyl acetate decoration.
1,3,4-Oxadiazole is among the most prevalent structural units The conventional approach involves the dehydrative cyclization of
in pharmaceuticals, natural products and functional materi- diacylhydrazides, generated by the condensation of hydrazides
als;1 therefore, developing efficient methods for accessing with either acids or their activated derivatives (Fig. 1a). Effective as
compounds with this privileged structure is an important it is, this process typically requires multi-step operations and
endeavor in synthetic chemistry. During the past decades, (super)stoichiometric dehydrative reagents including phosphorus
numerous synthetic strategies have been developed for the pentoxide,6 thionyl chloride,7 phosphorus oxychloride,8 and the
construction of the 1,3,4-oxadiazole skeleton.2 Classically, Burgess reagent.9 The caustic nature of these reagents and the
dehydrative cyclization of diacylhydrazides and oxidative cycli- wastes generated have always been a major concern. Hence, it
zation of N-acylhydrazines dominate the synthesis of this would be highly desirable for us to realize a direct method that (1)
structural unit in medicinal chemistry studies. Recently, the avoids (super)stoichiometric dehydrative reagents and (2) operates
formal [4+1] annulation of hydrazides and a suitable C1 syn- in a fashion with fewer by-products in our laboratory.
thon has emerged as an appealing alternative approach to In the past decades, many reliable strategies have been developed
mono- or di-substituted 1,3,4-oxadiazoles due to its obvious for the functionalization of fluorine-containing molecules via C–F
straightforwardness.3 Additionally, a multicomponent Ugi-type bond cleavage.10 Among them, anion-driven breaking of the C–F
reaction of N-carbamoyl imines4 as well as photoinduced bond facilitates the CF3 group serving as the C1 donor for the
decarboxylative cyclization with hypervalent iodine reagents5 assembly of heteroatom-containing chemicals that are otherwise
also provides intriguing choices for the synthesis of 1,3,
4-oxadiazoles with special substituent patterns.

a
College of Pharmaceutical Engineering of Traditional Chinese Medicine,
State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin 301617, P. R. China.
E-mail: lifangyi@tjutcm.edu.cn, suotc@tjutcm.edu.cn
b
Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, P. R. China
c
School of Pharmaceutical Science & Technology, Tianjin University,
Tianjin 300072, P. R. China
d
School of Medicine, Foshan University, Foshan 528225, P. R. China.
E-mail: pharmwch@126.com
† Electronic supplementary information (ESI) available. CCDC 2170479, 2178538
and 2178536. For ESI and crystallographic data in CIF or other electronic format
see DOI: https://doi.org/10.1039/d2nj04147b Fig. 1 Synthesis of 1,3,4-oxadiazoles with alkyl acetate decoration.

This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2022 New J. Chem., 2022, 46, 20755–20759 | 20755
Paper NJC

difficult to access. This process, pioneered by Strekowski’s labo- successfully in the [4+1] cyclization process to form the desired
ratory,11 was initiated by elimination of hydrogen fluoride, leading products in good yields. Substituents at the ortho-, meta- and
to the gem-difluorovinyl intermediate, which is very reactive toward para-positions of the aryl ring were allowed. Substrates contain-
diverse nucleophiles. In the following years, several elegant works ing the disubstituted arene (2i) and naphthalene (2j) were also
along this path were reported.12 Inspired by these works, we competent in this reaction. In addition, the substrates with
envisioned that the cyclization of hydrazides and commercially hetero aryl rings (2k–2o), regardless of their electronic nature,
available ethyl 3,3,3-trifluoropropanoate under basic conditions were tolerated. Besides the (hetero)aryl substituents, alkyl sub-
may provide an efficient and general entry to the compounds that stituents (2p–2t) were also suitable. Interestingly, the oxygen-
we desire (Fig. 1b). We are glad to see that Li and co-workers thought substituted substrate (2u) also delivered the desired product in
alike and reported an analogous protocol very recently.13 Herein, we
report our synthetic method, which furthermore can be generalized
to the synthesis of 1,3,4-thiadiazoles and 1,2,4-triazoles. Table 2 Scope of hydrazidesa

Results and discussion

Table 1 summarizes our efforts to test the feasibility of our idea
and optimize the reaction parameters. Fortunately, in our first
attempt, an ethanol solution of benzoylhydrazine 1a and 3,3,
3-trifluoropropanoate was heated to 80 1C in the presence of
K2CO3, affording the desired product 2a in 79% yield (entry 1).
Then, we studied the efficiency of this process with regard to
the bases used (entries 2–5) Remarkably, the use of Na2CO3
gave rise to an improved yield of 2a (entry 3). Further evaluation
of the solvents indicated that protic solvents performed better
than aprotic solvents (entries 6–10), probably owing to the
increased solubility and nucleophilicity of benzoylhydrazine
in protic solvents. Decreasing the Na2CO3 loading from 2.0 to
1.5 equivalents resulted in a slight increase in the yield of 2a,
whereas no reaction was observed in the absence of a base
(entries 11 and 13, respectively).
With the optimized conditions in hand, we evaluated the
generality of the reaction with respect to the hydrazides.
Substrates bearing an electron-donating (2b, 2g) or electron-
withdrawing (2c–2f, 2h) group at the aryl ring can all participate

Table 1 Optimization of the reaction parametersa

Entry Base (equiv.) Solvent T (1C) Yieldb (%)

1 K2CO3 (2.0) EtOH 80 79
2 KHCO3 (2.0) EtOH 80 85
3 Na2CO3 (2.0) EtOH 80 92
4 NaHCO3 (2.0) EtOH 80 80
5 Et3N (2.0) EtOH 80 63
6 Na2CO3 (2.0) MeOH 70 90
7 Na2CO3 (2.0) H2O 100 87
8 Na2CO3 (2.0) CH3CN 80 35
9 Na2CO3 (2.0) THF 70 22
10 Na2CO3 (2.0) Toluene 120 o5
11 Na2CO3 (1.5) EtOH 80 95
12 Na2CO3 (1.0) EtOH 80 81
13 w/oc EtOH 80 N.R. a
Standard conditions: 1 (0.50 mmol), 3,3,3-trifluoropropanoate
a
Reaction conditions: 1a (0.50 mmol), 3,3,3-trifluoropropanoate (0.55 mmol), Na2CO3 (0.75 mmol), EtOH (5.0 mL). All yields are isolated
(0.55 mmol), base (0.75 mmol), solvent (5.0 mL). b Isolated yield. yields. b 90 1C. c 3,3,3-Trifluoropropanoate (0.75 mmol) was used and
c
Without a base. the reaction was run for 8 h.

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NJC Paper

good yield when higher temperature was employed. Encour-

aged by the above results, substrates derived from marketed
drugs, such as probenecid (2v), febuxostat (2w), felbinac (2x),
ibuprofen (2y) and clofibrate (2z), were surveyed. Unsurpris-
ingly, they proved to be compatible in this reaction and
provided the corresponding products in moderate to good
yields (Table 2).
We wondered whether thiohydrazides (3) and imidohydra-
zides (5) could be compatible in this reaction system, thus
allowing the direct formation of 1,3,4-thiadiazoles14 and 1,2,
4-triazoles15 with ethyl acetate decoration, because both are
also prevalent structural moieties in drug discovery. Pleasingly, Scheme 1 Synthetic utility reaction conditions: a KOH, EtOH, r.t., 6 h.
b
thiohydrazides worked well, furnishing the corresponding Benzylamine, toluene, reflux, 8 h. c NaBH4, tetrahydrofuran/water (5/1),
r.t., 3 h. d CH3CH2Br, K2CO3, CH3CN, 85 1C, 3 h. e 4-Ethoxycarbonyl-
1,3,4-thiadiazoles in good yields (Table 3). Similar to the case phenylboronic acid, Pd(PPh3)4 (5 mol%), K2CO3 (2.0 equiv.), N2, toluene,
of 2u, nitrogen-substituted substrates (4f, 4g) also worked to 90 1C, 5 h.
deliver the desired products, albeit with relatively low yields
despite the extended reaction time. Subsequently, our focus
shifted toward generating 1,2,4-triazoles using imidohydra- and subjected to identical conditions. However, these reactions
zides (Table 4). Several aryl imidohydrazides were prepared were not clean. The desired products (6a–6f) could be separated
from the reaction mixture carefully along with some unidenti-
fied byproducts. Suitable crystals of compound 6f for X-ray
Table 3 Scope of thiohydrazidesa
analysis were obtained by slow evaporation from the mixed
solvent of acetonitrile and ethyl acetate. The crystal structure
determination of 6f revealed an asymmetric unit containing
one crystallographically independent molecule of 6f. The term-
inal benzene ring in the crystal structure of 6f is disordered over
two orientations with refined occupancies of 0.52(2)/0.48(2).
To explore the synthetic utility of this process (Scheme 1),
gram-scale preparation of 2a and 2d was conducted under
standard conditions, which gave satisfied yields. The pendant
ethyl acetate in our products could potentially be used as a
handle for further transformation. For example, hydrolysis of
2a afforded the corresponding acid 7. Ester-amide exchange of
2a and benzylamine proceeded smoothly to give amide 8, which
a
Standard conditions: 3 (0.50 mmol), 3,3,3-trifluoropropanoate precipitates from the reaction mixture upon cooling. After
(0.55 mmol), Na2CO3 (0.75 mmol), EtOH (5.0 mL). All yields are isolated reduction by NaBH4, alcohol 9 could be obtained with high
yields. b 90 1C, 8 h.
efficiency. Ethylation at the a-position of ester in 2a with
bromoethane leads to the generation of 10. Finally, the arene
moiety of 2d could be modified by Suzuki cross-coupling
reaction and more structurally complex product 11 could be
Table 4 Scope of imidohydrazidesa
obtained.
Based on the literature precedent and our results, a plau-
sible mechanism for this reaction was proposed (Scheme 2),
where ethyl 3,3-difluoroacrylate A is formed upon base-assisted
b-F elimination. Subsequently, intermediate B is generated
upon nucleophilic addition by hydrazide 1. The addition
intermediate B then undergoes a-F elimination to generate
a-fluorinated acylhydrazone C, followed by intramolecular cycli-
zation via imidate O-attack to generate intermediate D. Finally,
the third HF is eliminated to afford desired product 2.

Conclusions
a In summary, we have developed a unified approach to 1,3,
Standard conditions: 5 (0.50 mmol), 3,3,3-trifluoropropanoate
(0.55 mmol), Na2CO3 (0.75 mmol), EtOH (5.0 mL). All yields are isolated 4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles with an
yields. ethyl acetate decoration by treating hydrazides, thiohydrazides

This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2022 New J. Chem., 2022, 46, 20755–20759 | 20757
Paper NJC

Activities of 1,3,4-Oxadiazole: A Review, Synth. Commun.,

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