Synthesis of 3 H-1,2,4-Triazol-3-ones via NiCl2-Promoted Cascade Annulation of Hydrazonoyl Chlorides and Sodium Cyanate

Article abstract of DOI:10.1021/acs.orglett.1c00568

A nickel-promoted cascade annulation reaction for the facile synthesis of 3H-1,2,4-triazol-3-ones from readily available hydrazonoyl chlorides and sodium cyanate has been developed. The transformation occurs through a cascade nickel-promoted intermolecular nucleophilic addition-elimination process, intramolecular nucleophilic addition, and a hydrogen-transfer sequence. The method has been successfully applied for the construction of the core skeleton of the angiotensin II antagonist.

Full text of DOI:10.1021/acs.orglett.1c00568

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Letter
Synthesis of 3H‑1,2,4-Triazol-3-ones via NiCl2‑Promoted Cascade
Annulation of Hydrazonoyl Chlorides and Sodium Cyanate
Shiying Du, Zuguang Yang, Jianhua Tang, Zhengkai Chen,* and Xiao-Feng Wu*
Cite This: Org. Lett. 2021, 23, 2359−2363
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ABSTRACT: A nickel-promoted cascade annulation reaction for the facile
synthesis of 3H-1,2,4-triazol-3-ones from readily available hydrazonoyl
chlorides and sodium cyanate has been developed. The transformation
occurs through a cascade nickel-promoted intermolecular nucleophilic
addition−elimination process, intramolecular nucleophilic addition, and a
hydrogen-transfer sequence. The method has been successfully applied for
the construction of the core skeleton of the angiotensin II antagonist.
1,2,4-Triazol-3-ones are identified as a kind of important five-
membered heterocyclic molecules, which display various
potent biological activities.1 The privileged N-heterocycles
have been successfully applied in various fields with prominent
potency (Figure 1). For instance, 2,4,5-trisubstituted-3H-1,2,4-
able byproducts. Considering the urgent demand for environ-
mental friendliness and sustainability, green synthesis has
emerged as a mainstream alternative to conventional synthetic
pathways. An elegant example was presented by Cheng and
coworkers, which realized the facile synthesis of 1,2,4-triazol-3-
ones through the metal-free mediated annulation of 2-
hydrazinylpyridine or benzamidrazone and atmospheric
pressure of CO2.5 In 2021, we disclosed an efficient approach
for the construction of 1,2,4-triazol-3-ones via a palladium-
catalyzed cascade carbonylative reaction of hydrazonoyl
chlorides and NaN3 with TFBen (benzene-1,3,5-triyltrifor-
mate) as a convenient CO surrogate.6 In this transformation,
the toxic and flammable CO gas was avoidable, but the
employment of hazardous NaN3 slightly weakened the
significance and application of the protocol. Consequently,
we wish to seek another greener and more economic route to
assemble structurally diverse 1,2,4-triazol-3-ones.
Sodium or potassium cyanate (NaOCN or KOCN) is a kind
of cheap and less toxic salt that has usually been applied to
transition-metal-catalyzed cross-coupling reactions with aryl
halides or arylboronic acids for the construction of a range of
carbamates or ureas. In 2011, Kianmehr and coworkers
developed a copper-catalyzed coupling of aromatic boronic
acids with potassium cyanate and alcohol for the preparation of
arylcarbamates under mild conditions (Scheme 1a).7 Later,
Buchwald and coworkers reported a palladium-catalyzed cross-
coupling of aryl chlorides or triflates with sodium cyanate for
building unsymmetrical ureas via aryl isocyanates or their
phenyl carbamate intermediates (Scheme 1b).8 The protocol
Figure 1. Selected examples of bioactive 1,2,4-triazol-3-one
molecules.
triazol-3-ones with an acidic biphenylsulfonamide moiety are
utilized as dual AT1/AT2 receptor antagonists with enhanced
affinity.2 A series of 2,4-dihydro-3H-1,2,4-triazol-3-ones have
been identified as PPARα agonists for clinical studies.3
Therefore, tremendous attention has been directed toward
the synthetic routes to 1,2,4-triazol-3-ones over the past few
decades.
Although numerous synthetic methods for producing 1,2,4-
triazol-3-ones have been reported,4 most of the traditionally
developed strategies have suffered from several drawbacks,
such as preactivation of substrates, multistep procedures, harsh
reaction conditions, low efficiency, or generation of undesir-
Received: February 17, 2021
Published: March 10, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00568
© 2021 American Chemical Society
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a
Scheme 1. Coupling Reactions of Sodium/Potassium
Cyanate
Table 1. Optimization of Reaction Conditions
b
entry
[M]
base
NEt3
solvent
yield (%)
c
1
2
3
4
5
6
7
8
Pd2(dba)3
Cu(OTf)2
FeCl3
NiCl2
ZnCl2
Sc(OTf)3
BF3OEt2
NiCl2 6H2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
77
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
DIPEA
DBU
NaHCO3
71
84
95
90
67
34
84
31
82
72
43
61
58
21
56
37
9
10
11
12
13
14
15
16
17
18
19
20
21
22
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
THF
CH3CN
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
had been adopted to synthesize aryl carbamates by employing
diverse alcohols as the nucleophiles.9 The acyl carbamates
could be assembled by the Pd-catalyzed four-component
carbonylation of aryl and heteroaryl bromides, potassium
cyanate, and alcohols, which was described by Skrydstrup and
coworkers (Scheme 1c).10 Notably, Ma’s group achieved a
series of similar coupling reactions of aryl halides with
potassium cyanate under copper catalysis and a bidentate
ligand (Scheme 1d).11 Sodium/potassium cyanate was also
utilized as a reactive partner in the Rh(I)-catalyzed asymmetric
ring-opening of oxabicyclic alkenes to construct chiral
oxazolidinone scaffolds12 or a copper-catalyzed coupling
reaction through C−H bond functionalization for the
formation of acetanilide derivatives.13 Although various
impressive coupling reactions involving cyanate salts have
been exploited, the application of salts cyanate to the
production of heterocyclic compounds is still limited and
highly desirable.
Encouraged by the excellent viability of the cyanate anion in
transition-metal-catalyzed cross-coupling reactions and our
continuous interest in the efficient synthesis of structurally
diverse N-heterocycles,14 we herein report a general and atom-
economical approach for the preparation of biologically
valuable 1,2,4-triazol-3-ones from the nickel-mediated cascade
annulation of hydrazonoyl chlorides and sodium cyanate
(Scheme 1e). Hydrazonoyl chlorides have frequently been
applied as a versatile building block to build diverse
heterocycles.15 The first nickel-catalyzed coupling reaction
with metal cyanates was developed by Tkatchenko in 1986, but
the reaction efficiency was generally lower.16 In our trans-
formation, notable features include the use of an inexpensive
earth-abundant nickel promoter, readily available starting
materials, a broad substrate scope, high efficiency, and
scalability.
d
NEt3
NEt3
NEt3
NEt3
NEt3
74−86
86
94
80
48 ,
e
f
g
fh
a
Reaction conditions: 1a (0.3 mmol), NaOCN (2.0 equiv), [M] (5
mol %), and NEt3 (1.0 equiv) in solvent (2.0 mL) at 100 °C under a
N2 atmosphere for 24 h. Isolated yield. t-BuXPhos (5 mol %) as a
b
c
d
ligand. Reaction was conducted at 80 (74%) or 120 °C (86%).
e
f
g
h
Under air. NiCl2 (2.5 mol %). NiCl2 (0.5 mol %). KOCN instead
of NaOCN.
Considering palladium as a precious metal catalyst, several low-
cost metal salts were examined, including Cu(OTf)2, FeCl3,
and NiCl2, and the highest 95% yield was observed with regard
to NiCl2 (Table 1, entries 2−4). Then, other nickel catalysts
were surveyed but inferior results were obtained. (See the
details in the Supporting Information.) Owing to the
availability of Cu(OTf)2 and FeCl3, we envisaged that the
reaction was driven by a Lewis acid and did not undergo a
catalytic process, as verified by the validity of ZnCl2 and
Sc(OTf)3 (Table 1, entries 5 and 6). Another frequently used
Lewis acid, BF3OEt2, showed inferior reactivity, and only a
37% yield was observed (Table 1, entry 7). NiCl2·6H2O also
promoted the transformation with high efficiency (Table 1,
entry 8). The transformation could occur in the absence of any
metal to afford the product 2a in 31% yield, further confirming
the above hypothesis (Table 1, entry 9). The solvent effect was
tested by using diverse organic solvents, and 1,4-dioxane was
the optimal choice (Table 1, entries 10−13). Other organic or
inorganic bases were screened in the reaction, whereas a lower
efficiency was observed than that of NEt3 (Table 1, entries 14−
16). The reaction proceeded in the absence of a base to give
the product 2a in 37% yield, revealing the key role of the base
(Table 1, entry 17). Lowering or elevating the reaction
temperature resulted in a decrease in the reaction yields (Table
1, entry 18). When the reaction was performed under an air
atmosphere, product 2a could be obtained in 86% yield (Table
1, entry 19). Notably, reducing the loading amount of NiCl2 to
First, N′-phenylbenzohydrazonoyl chloride 1a and NaOCN
were chosen as model substrates to initiate the investigation.
The reaction proceeded smoothly under a Pd2(dba)3/t-
BuXPhos catalytic system with NEt3 as a base in 1,4-dioxane
at 100 °C for 24 h. Gratifyingly, the 3H-1,2,4-triazol-3-one
product 2a was isolated in 77% yield (Table 1, entry 1).
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2.5 mol % gave a comparable yield, and 0.5 mol % NiCl2 could
enable the formation of 2a in 80% yield (Table 1, entries 20
and 21). The observation data indicated the high economy and
efficiency of this transformation. Switching NaOCN to KOCN
led to a sharp decline of the reaction yield (Table 1, entry 22).
With the establishment of the optimized reaction conditions,
the scope and limitation of the reaction were examined by the
use of various hydrazonyl chlorides derived from different acyl
chlorides (Scheme 2). Good compatibility of the protocol was
diverse hydrazines (Scheme 3). The reaction was amenable to
a variety of hydrazonyl chlorides from arylhydrazines for the
Scheme 3. Scope of the Hydrazonyl Chlorides from Diverse
a b
,
Hydrazines
Scheme 2. Scope of the Hydrazonyl Chlorides from Diverse
a b
,
Acyl Chlorides
a
Reaction conditions: 1 (0.3 mmol), NaOCN (2.0 equiv), NiCl2 (2.5
mol %), and NEt3 (1.0 equiv) in 1,4-dioxane (2.0 mL) at 100 °C
b
under a N2 atmosphere for 24 h. Isolated yields.
a
Reaction conditions: 1 (0.3 mmol), NaOCN (2.0 equiv), NiCl2 (2.5
mol %), and NEt3 (1.0 equiv) in 1,4-dioxane (2.0 mL) at 100 °C
b
c
under a N2 atmosphere for 24 h. Isolated yields. 1 mmol scale.
production of 3H-1,2,4-triazol-3-one products 3a−3i in
moderate to good yields. The electronic effect (3a−3h) and
steric hindrance (3a−3c, 3f, and 3g) of the aryl ring both
exerted a negligible effect on the reaction. The halogen atoms
attached on the aryl ring were well tolerated in the reaction
(3e−3h), albeit with a relatively lower yield of product 3h,
providing a synthetic handle for the further transformation.
The hydrazonyl chloride from 2-hydrazineylpyridine could not
be prepared by common synthetic methods. With regard to the
hydrazonyl chlorides from alkylhydrazines, the reaction also
proceeded smoothly for the assembly of N-alkyl-substituted
3H-1,2,4-triazol-3-ones (3j and 3k) in 70−87% yields.
Unfortunately, the dialkyl-substituted hydrazonyl chlorides
were unstable under the current reaction conditions.
To gain more insights into the reaction mechanism, several
control experiments were performed (Scheme 4). Initially, the
radical trapping experiments were carried out by the addition
2.0 equiv of radical scavengers. The results revealed that no
sharp decrease in the reaction yield was observed with regard
to TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl), BHT (2,4-
observed, as it was demonstrated that moderate to excellent
yields of the desired 3H-1,2,4-triazol-3-one products 2a−2h
were obtained when hydrazonyl chlorides from aromatic acyl
chlorides were used as substrates. The steric factor had a
moderate impact on the reaction (2b and 2c), and the
reactivity of hydrazonyl chlorides with electron-donating
groups (2b−2e, 2g) is generally higher than that of hydrazonyl
chlorides bearing electron-withdrawing groups (2f and 2h).
The reaction could be performed on a 1 mmol scale in 79%
yield for product 2a. The heterocyclic frameworks, including
furan and thiophene, were smoothly incorporated into the 3H-
1,2,4-triazol-3-one products in good yields (2i and 2j). It
should be noted that hydrazonyl chlorides from aliphatic acyl
chlorides also successfully participated in the transformation to
afford the corresponding 3H-1,2,4-triazol-3-ones 2k and 2l
with alkyl substituents with excellent efficiency.
The generality of this cascade annulation reaction was
further investigated by utilizing hydrazonyl chlorides from
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4-ylmethyl side chain is defined as an orally active angiotensin
II antagonist.2 The core skeleton of angiotensin II antagonist 6
could be smoothly constructed in 72% yield by employing our
developed protocol (Scheme 6), which underscores the
promising application prospect of this methodology.
Scheme 4. Mechanistic Investigations
Scheme 6. Synthetic Applications
di-tert-butyl-4-methylphenol), or 1,1-DPE (1,1-diphenylethy-
lene) (Scheme 4a), indicating that the transformation did not
involve a single-electron transfer (SET) process. Considering
the difficulty of the isolation of isocyanate species from
hydrazonoyl chloride, we synthesized the structurally similar
trifluoroacetimidoyl chloride 4 and subjected it to the standard
conditions. The coupling product isocyanate 5 between
trifluoroacetimidoyl chloride 4 and NaOCN was successfully
detected by GC-MS in the presence or absence of a nickel
catalyst (Scheme 4b). The positive result suggested that
hydrazonoyl isocyanate might act as the key intermediate of
the reaction, which was consistent with the assumption of our
previous report.6
Considering the following observations, (1) the reaction was
viable without any metal catalyst, (2) divalent nickel was used
in the reaction in the absence of ligand, and (3) several Lewis
acids, including FeCl3, Cu(OTf)2, ZnCl2, and Sc(OTf)3, all
could promote the reaction, it is speculated that NiCl2 serves
as a Lewis acid to promote the reaction by activating the CN
and CO double bonds. On the basis of the results of
preliminary mechanistic investigations and the precedent
literature,6,8,17 a tentative mechanism is proposed as depicted
in Scheme 5. Initially, the coordination of hydrazonoyl chloride
In summary, we have developed an atom-economical and
sustainable strategy for the efficient preparation of 3H-1,2,4-
triazol-3-ones via the nickel-promoted cascade annulation
reaction of hydrazonoyl chlorides and sodium cyanate. Notable
advantages include readily accessible starting materials, the use
of an inexpensive nickel promoter, high efficiency, scalability,
and NaCl as the sole harmless byproduct, which enable the
great application prospect of this transformation. Further
investigations toward the broader application scenarios of this
protocol are ongoing.
ASSOCIATED CONTENT
* Supporting Information
Scheme 5. Plausible Reaction Mechanism
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00568.
General comments, general procedure, analytic data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhengkai Chen − Department of Chemistry, Zhejiang Sci-
Tech University, Hangzhou 310018, China; orcid.org/
0000-0002-5556-6461; Email: zkchen@zstu.edu.cn
Xiao-Feng Wu − Dalian National Laboratory for Clean
Energy, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, Liaoning, China;
̈
Leibniz-Institut fur Katalyse e. V. an der Universität Rostock,
18059 Rostock, Germany; orcid.org/0000-0001-6622-
3328; Email: xiao-feng.wu@catalysis.de
1 with NiCl2 formed nickel complex A to activate the CN
bond. Then, the intermolecular nucleophilic addition of
cyanate anion into A led to the isocyanate intermediate B
with the elimination of a NaCl byproduct. Finally, the NiCl2-
and NEt3-promoted intramolecular nucleophilic addition of B
and the subsequent hydrogen-transfer process afforded the 3H-
1,2,4-triazol-3-one product 2 or 3.6,8 Of note, because of the
key role of a base in the reaction and the easy generation of the
nitrilimine intermediate from hydrazonoyl chloride in the
presence of a base, we cannot totally exclude the possibility of
a direct [3 + 2] cycloaddition reaction of in-situ-formed
nitrilimine with sodium cyanate.17
Authors
Shiying Du − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, China
Zuguang Yang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, China
The 2,4,5-trisubstituted-3H-1,2,4-triazol-3-one with an
acidic sulfonamide moiety at the 2′-position of the biphenyl-
Jianhua Tang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, China
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Letter
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00568
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Natural
Science Foundation of Zhejiang Province (grant no.
LY19B020016).
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