A Convenient FeCl3-Mediated Synthesis of 5-Trifluoromethyl-1,2,4-triazoles from Trifluoroacetimidoyl Chlorides and Hydrazides

Article abstract of DOI:10.1002/adsc.202001015

A low cost FeCl₃-mediated cascade annulation of trifluoroacetimidoyl chlorides and hydrazides for the efficient synthesis of 5-trifluoromethyl-1,2,4-triazoles has been developed. The transformation proceeds through a cascade base-promoted intermolecular C?N bond formation and FeCl₃-mediated intramolecular dehydration sequence under mild conditions. The protocol exhibits many notable features and can be readily scaled up to gram scale. (Figure presented.).

Full text of DOI:10.1002/adsc.202001015

Title: A Convenient FeCl3-Mediated Synthesis of 5-
Trifluoromethyl-1,2,4-triazoles from Trifluoroacetimidoyl Chlorides
and Hydrazides
Authors: Xiao-Feng Wu, Zhengkai Chen, Le-Cheng Wang, Shiying Du,
and Zuguang Yang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001015
Link to VoR: https://doi.org/10.1002/adsc.202001015

10.1002/adsc.202001015
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.2020
A Convenient FeCl3-Mediated Synthesis of 5-Trifluoromethyl-1,2,4-triazoles from
Trifluoroacetimidoyl Chlorides and Hydrazides
Shiying Du,a+ Le-Cheng Wang,a+ Zuguang Yang,a Zhengkai Chena,* and Xiao-Feng
Wua,b*
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China
b Leibniz-Institut fꢀr Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany
e-mail: zkchen@zstu.edu.cn, xiao-feng.wu@catalysis.de
+ These authors contributed equally to this work.
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.2020
Abstract. A low cost FeCl3-mediated cascade annulation of
trifluoroacetimidoyl chlorides and hydrazides for the
efficient synthesis of 5-trifluoromethyl-1,2,4-triazoles has
been developed. The transformation proceeds through a
cascade base-promoted intermolecular C-N bond formation
and FeCl3-mediated intramolecular dehydration sequence
under mild conditions. The protocol exhibits many notable
features and can be readily scaled up to gram scale.
Keywords: trifluoroacetimidoyl chlorides; hydrazides; 5-
trifluoromethyl-1,2,4-triazoles; cascade annulation reaction;
N-heterocyclic compounds
1,2,4-Triazoles are identified as important
heterocyclic scaffolds and have been widely applied
in the biological and pharmaceutical fields, ligand
chemistry as well as materials science.[1] Several
commercial drugs contain 1,2,4-triazole motifs, such
as maraviroc, trizaolam, sitagliptin, and deferasirox
(Figure 1).[2] Considering the unique properties of
fluorine atoms, the existence of trifluoromethyl or
perfluoroalkyl groups could evidently improve the
electronegaivity, bioavailability, metabolic stability
and lipophilicity of the parent molecules.[3]
Consequently, the exploration of efficient methods to
the synthesis of trifluoromethyl-substituted 1,2,4-
triazoles are of great significance and a series of
synthetic approaches regarding these frameworks
have been developed.
For instance, the reaction of 2,5-dichloro-
1,1,1,6,6,6-hexafluoro-3,4-diazahexa-2,4-dienes
3,5-bis(trifluoromethyl)-1,3,4-oxadiazoles
or
with
primary amines under diverse reaction conditions
could afford 3,5-bis(trifluoromethyl)-1,2,4-triazoles,
which were reported by Tipping and Reitz (Scheme
1a).[4] Funabiki described a synthetic method of
trifluoromethyl-substituted 1,2,4-triazoles, which
involved the in-situ generation of 2,2,2-
trifluoroacetohydrazide from the reaction of ethyl
2,2,2-trifluoroacetate with hydrazine hydrate and the
subsequent cyclization with amidines (Scheme 1b).[5]
The 5-trifluoromethylated 1,2,4-triazolium salts were
obtained by multistep reactions of ethyl-(1,1,1-
trifluoro-2-propylidene)carbazate
(Scheme 1c).[6] In addition, Vivona and Buscemi
disclosed hydrazinolysis reaction of 5-
trifluoromethyl-1,2,4-oxadiazoles to prepare
with
nitriles
a
fluorinated 1,2,4-triazoles (Scheme 1d).[7] Several
other synthetic pathways were also reported.[8]
Although much progress had been gained in this field,
most existing methods suffered from relatively harsh
reaction conditions, tedious synthetic procedures, and
narrow substrate scope. Pertinent to the present
research, the development of general and convenient
approach for the assembly of trifluoromethyl-
decorated 1,2,4-triazoles is still highly desirable.
Figure 1. Selected Examples of Drugs Containing 1,2,4-
Triazole Cores.
1
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10.1002/adsc.202001015
Advanced Synthesis & Catalysis
5
6
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
80
59
K2CO3
NaOAc
Na2CO3
64
23
83
67
44
47
79
80
7
80
8
NaHCO3 1,4-dioxane
80
9
K3PO4
NEt3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
10
11
12
13
14
80
NaHCO3
NaHCO3
NaHCO3
NaHCO3
40
100
120
80
trace-
64[c]
15
16
NaHCO3
NaHCO3
1,4-dioxane
1,4-dioxane
80
80
46[d]
68[e]
[a]
Reaction conditions: 1b (0.3 mmol), 2a (0.45 mmol), 4
Å MS (40 mg) and base (1.0 equiv) in solvent (2.0 mL)
o
under air at 40 C for 12 h, and then adding FeCl3 (0.3
mmol) at specified temperature for 8 h.
[b] Isolated yields.
[c] The FeCl3 was replaced with Fe(OTf)3 (53%), Cu(OTf)2
(64%), Sc(OTf)3 (trace) or I2 (15%), respectively.
[d] 0.5 equiv of FeCl3 was used.
Scheme 1. Synthesis of Trifluoromethyl-Substituted 1,2,4-
Triazole Derivatives.
[e] 1.5 equiv of FeCl3 was used. ND = No detection of the
product.
In recent years, the synthetic protocol employing
different trifluoromethyl synthons and suitable
reactive partners has been emerged as a mainstream
and attractive pathway to build trifluoromethyl-
containing heterocyclic compounds. In this context,
trifluoroacetimidoyl halides have been frequently
applied as versatile building blocks in synthetic
organofluorine chemistry.[9] Very recently, our group
reported an iodine-mediated annulation reaction of
trifluoroacetimidoyl chlorides and hydrazones to
prepare a variety of 5-trifluoromethyl-1,2,4-triazoles
in good yields (Scheme 1e).[10] Nevertheless, the
hydrazones derived from aliphatic aldehydes were
not applicable to the reaction, so 3-alkyl-fluorinated
1,2,4-triazoles could not be furnished. As a
continuation of our ongoing research on the synthesis
of trifluoromethyl-containing N-heterocycles,[10,11] we
herein present an FeCl3-mediated cascade annulation
of trifluoroacetimidoyl chlorides and hydrazides to
produce structurally diverse 5-trifluoromethyl-1,2,4-
triazoles under mild conditions (Scheme 1f).
Initially,
2,2,2-trifluoro-N-(p-tolyl)acetimidoyl
chloride 1b and acetohydrazide 2a were used as the
model substrates to optimize the reaction conditions.
Noteworthy was that the trifluoroacetimidoyl
chlorides could be easily obtained from the reaction
of the parent amine with trifluoroacetic acid, CCl4,
and PPh3.[12] The reaction proceeded smoothly with
1b and 2a in the presence of 1.0 equiv. of K2CO3 and
o
4 Å MS in CH3CN at 40 C for 12 h, and then 1.0
equiv FeCl3 was added to the reaction at elevated 80
oC for another 8 h. To our delight, the desired product
3b was delivered in 45% yield (Table 1, entry 1).
Then, a range of solvents were surveyed in the
transformation and 1,4-dioxane could afford the
highest yield (Table 1, entries 2-5). The choice of
additive was important for the transformation, and
different basic additives were added into the reaction,
including NaOAc, Na2CO3, NaHCO3, K3PO4, and
NEt3. The result showed NaHCO3 could render the
best reactivity (Table 1, entries 6-10). Further
Table 1. Optimization of reaction conditions.[a]
examination
towards
reaction
temperature
demonstrated that the low temperature was
detrimental to the reaction and the elevated
temperature had a marginal influence on the reaction
with the slight decrease of the reaction efficiency
(Table 1, entries 11-13). Other Lewis acids, such as
Fe(OTf)3, Cu(OTf)2, Sc(OTf)3, and molecular iodine,
were also tested in the transformation and their
reactivity was all inferior to that of FeCl3 (Table 1,
entry 14). Notably, reducing or increasing the amount
loading of FeCl3 in the second step could result in the
decline of the reaction yield (Table 1, entries 15-16).
Entry
Base
(equiv)
Solvent
(mL)
Temperatu Yield[b]
re (oC)
(%)
1
2
3
4
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
THF
80
80
80
80
45
34
DCE
trace
ND
DMF
2
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10.1002/adsc.202001015
Advanced Synthesis & Catalysis
With the optimized conditions in hand, we began
to investigate the scope and limitation of the
annulation reaction using wide range of
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), 4 Å
MS (40 mg) and NaHCO3 (1.0 equiv) in 1,4-dioxane (2.0
mL) under air at 40 oC for 12 h, and then adding FeCl3 (0.3
mmol) at 80 oC for another 8 h, isolated yields.
a
trifluoroacetimidoyl chlorides (Table 2). Diverse N-
aryltrifluoroacetimidoyl chlorides bearing electron-
donating or -withdrawing groups could react
smoothly with acetohydrazide 2a to give rise to the
[b] The reaction was performed on 2 mmol scale.
corresponding
5-trifluoromethyl-1,2,4-triazole
After examination of the scope of fluorinated
imidoyl chlorides, the generality of the protocol was
further evaluated by surveying diverse hydrazides
(Table 3). Different alkyl substituted hydrazides
reacted smoothly with trifluoroacetimidoyl chloride
1b to build the desired 1,2,4-triazole products in
moderate to good yields (4a-c). With respect to
arylhydrazides, the transformation proceeded well to
lead to the desired 2-aryl substituted 1,2,4-triazoles
4d-h in acceptable yields in the presence of 0.5 equiv
FeCl3. The inferior yields of arylhydrazides
presumably resulted from the reduced reactivity of
amino group and carbonyl group of the
arylhydrazides due to the conjugation effect of aryl
ring. When formohydrazide was used as substrate, 4-
(p-tolyl)-3-(trifluoromethyl)-4H-1,2,4-triazole 4i was
successfully furnished as desired product in 86%
yield. Noteworthy was that cinnamohydrazide was
also compatible with the optimized conditions,
providing the targeted 3-alkenyl-1,2,4-triazole 4j in
52% yield as a mixture of E/Z isomers.
products in good to excellent yields in most cases
(3a-o). Of note, the steric hindrance of
trifluoroacetimidoyl chlorides exerted an obvious
effect on the reaction, as demonstrated by the
gradually decrease of the reaction yields of products
3b-d. Meanwhile, the electron factors seemingly had
a marginal impact on the transformation (3a-o). The
protocol could be easily scaled up to 2 mmol scale for
product 3b without any difficulty. The compatibility
of the protocol was further proved by the good
tolerance of halogen atoms and strong electron-
withdrawing groups (3i-l). The trifluoroacetimidoyl
chlorides bearing naphthalene ring were also suitable
for the current reaction conditions to furnish the
desired 1,2,4-triazole products in 67-70% yields (3p-
q)
Unfortunately,
the
trifluoroacetimidoyl
chloride from aliphatic amine was not applicable to
the reaction system and only trace of product 3r was
observed, probably due to the instability of the N-
arylltrifluoroacetimidoyl chloride. The reaction was
amendable to several other fluorinated imidoyl
chlorides, as illustrated that diverse fluoroalkyl
groups, including CF2Cl, C2F5 and C3F7, could be
successfully incorporated into the 1,2,4-triazole core
in moderate to good yields (3s-u).
Table 3. Scope of Hydrazides.[a]
Table 2. Scope of Trifluoroacetimidoyl Chlorides.[a]
[a] Reaction conditions: 1b (0.3 mmol), 2 (0.45 mmol), 4 Å
MS (40 mg) and NaHCO3 (1.0 equiv) in 1,4-dioxane (2.0
mL) under air at 40 oC for 12 h, and then adding FeCl3 (0.3
o
mmol for 4a-c, 4i-j; 0.15 mmol for 4d-h) at 80 C for
another 8 h, isolated yields.
3
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10.1002/adsc.202001015
Advanced Synthesis & Catalysis
The reaction could be operated in a consecutive
one-pot manner as well (Scheme 2). At first, the
reaction of acetylchloride and hydrazine hydrate was
o
performed in 1,4-dioxane at 5 C for 30 minutes.
Then, trifluoroacetimidoyl chloride 1b was added to
the mixture in the presence of 1.0 equiv of NaHCO3.
The reaction was conducted at 40 oC for 12 hours and
then the coupling product 5b was formed and
unnecessary to be isolated. Finally, 1.0 equiv of FeCl3
was subjected into the mixture for another 8 hours at
Scheme 3. Mechanistic Investigations.
o
80 C and the desired 1,2,4-triazole product 3b could
be isolated in 70% overall yield.
Based on the results from the mechanistic
investigations and in previous literatures,[10,13]
a
plausible reaction mechanism was proposed as
depicted in Scheme 4. Initially, the base-mediated C-
N bond coupling of trifluoroacetimidoyl chloride 1
with hydrazide 2 generated amidine derivative 5.
Then, the coordination of Lewis acid FeCl3 to 5
formed the complex A with the activation of carbonyl
group. The intramolecular nucleophilic attack of
nitrogen to the activated carbonyl group led to
intermediate B, followed by the subsequent
dehydration process to deliver the 5-trifluoromethyl-
1,2,4-triazole product.
Scheme 2. One-pot Reaction.
Several control experiments were preformed to
gain some understanding of the reaction mechanism
(Scheme 3). We successfully synthesized the
coupling product 5b from trifluoroacetimidoyl
chloride 1b and acetohydrazide 2a and subjected it
into the reaction in the presence of 1.0 equiv of FeCl3.
Expectedly, the desired product 3b could be obtained
in 85% yield, which illustrated that compound 5b
possibly acted as the reaction intermediate (Scheme
3a). The radical trapping experiments were carried
out by the addition of 2.0 equiv. of radical scavengers.
The yield was reduced to 67% when TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) was added into
the reaction and trace of product was detected with
regard to BHT (2,4-di-tert-butyl-4-methylphenol).
Other radical scavengers, such as BQ (benzoquinone)
and 1,1-DPE (1,1-diphenylethylene), enabled the
formation of product 3b in 60 and 73% yield,
respectively (Scheme 3b). It was speculated that the
reaction did not proceed through a single electron
transfer (SET) process.
Scheme 4. Plausible Reaction Mechanism.
In conclusion, we have developed a facile
approach for the synthesis of 5-trifluoromethyl-1,2,4-
triazoles through FeCl3-mediated cascade annulation
of trifluoroacetimidoyl chlorides and hydrazides.
Notable features of the protocol include relatively
mild reaction conditions, low cost iron mediator,
simple operation, broad substrate scope and
scalability.
complementary route to the expeditious construction
of 5-trifluoromethyl-1,2,4-triazole derivatives.
The
transformation
offers
a
Further investigations toward the broader application
of trifluoroacetimidoyl halides are underway.
Experimental Section
Typical Procedure for the Synthesis of 5-
Trifluoromethyl-1,2,4-triazoles
NaHCO3 (25.2 mg, 0.3 mmol) and 4 Å MS (40
mg) were added to a solution of substrate 1 (0.3
mmol) and 2 (0.45 mmol) in 1,4-dioxane (2 mL). The
4
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10.1002/adsc.202001015
Advanced Synthesis & Catalysis
mixture was stirred at 40 °C under air for 12 h. Then,
FeCl3 (48.7 mg, 0.3 mmol) was added into the
reaction at 80 °C for another 8 h. After the
completion of the reaction (monitored by TLC), the
reaction mixture was cooled to ambient temperature,
quenched by water and extracted with ethyl acetate (3
x 15 mL). The extract was dried over anhydrous
Na2SO4 and the solvent was removed in vacuo to
provide a crude product, which was purified by
column chromatography on silica gel with petroleum
ether/EtOAc as eluent to afford the 5-trifluoromethyl-
1,2,4-triazole products 3 or 4.
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Acknowledgements
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4255-4262.
We acknowledge financial support from the National Natural
Science Foundation of China (21772177), the Natural Science
Foundation of Zhejiang Province (LY19B020016) and the
Fundamental Research Funds of Zhejiang Sci-Tech University
(2019Q065).
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5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001015
Advanced Synthesis & Catalysis
UPDATE
A Convenient FeCl3-Mediated Synthesis of 5-
Trifluoromethyl-1,2,4-triazoles
from
Trifluoroacetimidoyl Chlorides and Hydrazide
Adv. Synth. Catal. 2020, Volume, Page – Page
Shiying Du,a+ Le-Cheng Wang,a+ Zuguang Yang,a
Zhengkai Chena,*, Xiao-Feng Wua,b*
6
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