Palladium-Catalyzed cascade carbonylative synthesis of 1,2,4-triazol-3-ones from hydrazonoyl chlorides and NaN3

Article abstract of DOI:10.1021/acs.orglett.0c04167

A palladium-catalyzed three-component carbonylative reaction for the synthesis of 3H-1,2,4-triazol-3-ones from hydrazonoyl chlorides and NaN₃ has been achieved. The reaction presumably proceeds through a cascade carbonylation, acyl azide format

Full text of DOI:10.1021/acs.orglett.0c04167

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Letter
Palladium-Catalyzed Cascade Carbonylative Synthesis of 1,2,4-
Triazol-3-ones from Hydrazonoyl Chlorides and NaN3
Shiying Du, Wei-Feng Wang, Yufei Song, Zhengkai Chen,* and Xiao-Feng Wu*
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ABSTRACT: A palladium-catalyzed three-component carbonylative reaction for the synthesis of 3H-1,2,4-triazol-3-ones from
hydrazonoyl chlorides and NaN3 has been achieved. The reaction presumably proceeds through a cascade carbonylation, acyl azide
formation, Curtius rearrangement, and intramolecular nucleophilic addition sequence. A wide variety of structurally diverse 3H-
1,2,4-triazol-3-ones were constructed in moderate to excellent yields. Benzene-1,3,5-triyl triformate (TFBen) was applied as a solid
and convenient CO surrogate.
1,2,4-Triazol-3-ones, as potent and privileged heterocyclic
scaffolds, have been found to possess a great variety of
biological activities, including antifungal, anti-inflammatory,
antitumor, antiviral, and anticonvulsant activities (Figure 1).1
Scheme 1. Representative Methods for the Synthesis of
1,2,4-Triazol-3-ones
Figure 1. Selected examples of bioactive 1,2,4-triazol-3-one
molecules.
They are successfully applied as effective tyrosinase inhib-
itors,2a CB receptors,2b angiotensin II AT1 receptor antago-
nists,2c and NK1 antagonists.2d Consequently, numerous
synthetic methods have been developed for the construction
of structurally diverse 1,2,4-triazol-3-ones.
Traditionally, 2,4-dihydro-5-phenyl-3H-1,2,4-triazol-3-one
could be synthesized in a rather low yield from the
condensation of benzoic acid hydrazide and urea with the
promotion of KOH (Scheme 1a).3 The synthetic route to 2,4-
dihydro-2-methyl-5-phenyl-3H-1,2,4-triazol-3-one involved the
Received: December 16, 2020
Published: January 12, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04167
© 2021 American Chemical Society
Org. Lett. 2021, 23, 974−978
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a
S-methylation of triazole-3-thione, oxidation with m-CPBA,
and an alkaline hydrolysis sequence (Scheme 1b).4 Kubota and
Uda reported athe reaction of hydrazides with isocyanates, and
the subsequent cyclization afford 2-unsubstituted 1,2,4-triazol-
3-ones (Scheme 1c).5 Additionally, the treatment of N-
ethoxycarbonylthioamide with hydrazines was developed to
form 2,4-dihydro-3H-1,2,4-triazol-3-ones (Scheme 1d).6 Kam-
ble and co-workers developed the dealkyllation of 3-aryl-5-
alkyl-2-oxo-Δ4-1,3,4-oxadiazoles with formamide under high
temperatures, which led to 2-aryl-2H-1,2,4-triazol-3(4H)-ones
as the major product (Scheme 1e).7 A cascade reaction of acyl
isocyanates and mono-protected hydrazines, the removal of the
hydrazine protecting group, and then intramolecular cycliza-
tion to deliver 2,5-substituted 1,2,4-triazol-3-ones was
disclosed by Deng and co-workers (Scheme 1f).8 The reaction
of ethyl chloroformate and N1-tosylamidrazones could also
produce tosylated 1,2,4-triazole-3-ones.9 Recently, Cheng and
co-workers presented a base-mediated annulation of 2-
hydrazinylpyridine and CO2 for the producing of a series of
triazolone frameworks.10 Although a great deal of impressive
advances regarding the synthesis of 1,2,4-triazol-3-one have
been made, most of the existing methods suffer from harsh
reaction conditions, multistep procedures, poor efficiencies, or
starting materials that are not readily available. Therefore, the
development of a more efficient and practical approach for the
synthesis of 1,2,4-triazol-3-ones is still highly desirable.
Table 1. Optimization of Reaction Conditions
b
entry [Pd] (mol %) ligand (mol %) solvent (mL)
yield (%)
1
2
3
4
5
6
7
8
PdCl2
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
PPh3
PCy3
Sphos
DPEphos
dppf
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
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
1,4-dioxane
THF
CH3CN
DMF
DMSO
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
42
30
54
39
35
39
30
35
41
52
26
20
trace
trace
32
43
69
77
Pd(OAc)2
Pd2(dba)3
Pd(acac)2
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
9
10
11
12
13
14
15
16
17
18
19
c
d
e
ef
,
efg
, ,
89 (84)
a
Reaction conditions are as follows: 1a (0.2 mmol), NaN3 (1.5
Hydrazonoyl chlorides are a type of important building
blocks that are frequently employed to build a range of
valuable heterocycles.11 Additionally, the palladium-catalyzed
cascade carbonylative reaction has emerged as a powerful tool
for the construction of diverse carbonyl-containing chem-
icals.12 Recently, our group described a palladium-catalyzed
carbonylative synthesis of unsymmetrical ureas from aryl
iodides, amines, and sodium azide.13 In the transformation, a
Curtius rearrangement of the in situ-formed aroyl azide
constituted the key step. Prompted by the above reaction
mode and the merger of carbonylative transformations with
versatile hydrazonoyl chlorides, we envisioned that the cascade
carbonylative reaction of hydrazonoyl chlorides with sodium
azide could proceed to deliver 1,2,4-triazol-3-ones by involving
carbonylation, a Curtius rearrangement, and the subsequent
intramolecular nucleophilic addition sequence. The challenges
of the reaction lie in the propensity for the decomposition or
dimerization of hydrazonoyl chlorides as well as some
undesired intermolecular side-reactions. In this context, the
choice of the appropriate catalytic system of palladium
catalysts and ligands is vital to the success of the reaction.
Encouraged by our continuous pursuit of the construction of
diverse nitrogen-containing heterocycles,14 we herein commu-
nicate our recent research findings on the palladium-catalyzed
cascade carbonylative reaction of readily accessible hydrazo-
noyl chlorides and NaN3 for the synthesis of 3H-1,2,4-triazol-
3-ones with TFBen as a safe CO surrogate (Scheme 1g).
Notable advantages of the cascade protocol include the
avoidance of toxic and flammable CO gas, a broad substrate
scope, a high efficiency, and the good regioselectivity.
equiv), [Pd] (2.5 mol %), ligand (10 mol % for monodentate ligands,
5 mol % for bidentate ligands), and [CO] (TFBen + NEt3, 1 mmol)
b
in solvent (1.0 mL) at 100 °C for 16 h. Yields were determined by
GC analysis using dodecane as an internal standard. The isolated yield
c
d
is given in parentheses. The reaction was run at 80 °C. The reaction
e
f
was run at 120 °C. NaN3 (2.5 equiv) was used. [CO] (TFBen +
Na2CO3, 1 mmol) in solvent (2.0 mL). The reaction was run for 24
g
h.
entry 1). Then, various palladium catalysts were surveyed in
the reaction; Pd2(dba)3 was the most effective catalyst,
delivering the product 2a in a 54% yield (Table 1, entries
2−5). The ligand effect was investigated by screening a series
of phosphorus ligands, including PPh3, PCy3, Sphos, DPEphos,
and DPPF. The results showed that an obvious increase in the
reaction efficiency was not observed (Table 1, entries 6−10).
Further optimization toward the solvents indicated that the
efficacy of the reaction in other solvents was inferior to that of
1,4-dioxane (Table 1, entries 11−14). Both lowering an
elevating the reaction temperature exerted a harmful influence
on the transformation (Table 1, entries 15 and 16,
respectively). Notably, the reaction yield increased to 69%
when 2.5 equiv of NaN3 was adopted (Table 1, entry 17). By
switching the NEt3 to Na2CO3 to promote TFBen to release
CO and simultaneously reducing the concentration of the
reaction, the target product 2a could be delivered in a higher
yield (Table 1, entry 18). Further tuning the reaction
conditions by prolonging the reaction time to 24 h was
beneficial for this cascade carbonylative reaction, demonstrated
by the fact that the highest isolated yield (84%) of 2a was
achieved (Table 1, entry 19). It should be noted that the
hydrazonoyl chlorides were very stable under the reaction
conditions, and no decomposition was observed.
We initially selected N′-phenylbenzohydrazonoyl chloride
1a as a model substrate to optimize the reaction conditions.
Using the PdCl2 and Xantphos combination as the catalytic
system and TFBen15 as a CO supplier, the reaction was
performed in the presence of 1.5 equiv of NaN3 in 1,4-dioxane
at 100 °C for 16 h. To our delight, the desired 3H-1,2,4-triazol-
3-one product 2a was obtained in a moderate yield (Table 1,
With the optimal reaction conditions in hand, we
investigated the generality and limitation of this transformation
by employing a variety of hydrazonyl chlorides obtained from
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different acyl chlorides (Scheme 2). The reaction proceeded
well with respect to the hydrazonyl chlorides from aromatic
Scheme 3. Scope of Hydrazonyl Chlorides from Diverse
Hydrazines
a
Scheme 2. Scope of Hydrazonyl Chlorides from Diverse
a
Acyl Chlorides
a
Reaction conditions are as follows: 1 (0.2 mmol), NaN3 (2.5 equiv),
Pd2(dba)3 (2.5 mol %), Xantphos (5 mol %), and [CO] (TFBen +
Na2CO3, 1 mmol) in 1,4-dioxane (2.0 mL) at 100 °C for 24 h; values
are isolated yields.
marginal effect on the reaction because the comparable yields
of these substrates were observed. Aside from the good
tolerance of halogen atoms located on the aryl ring, this
developed protocol was also amendable to hydrazonyl
chlorides with a disubstituted aryl group and a naphthalene
ring (3h and 3i, respectively). Gratifyingly, good to excellent
yields (62−96%) could be obtained (3j−l) when hydrazonyl
chlorides from alkylhydrazines were employed as the
substrates, presumably due to the increased nucleophilicity of
the nitrogen atom connected with the alkyl groups. The exact
structure of the 3H-1,2,4-triazol-3-one product 3j was further
determined by single X-ray diffraction analysis (CCDC
2044120).16
Several control experiments were conducted to elucidate the
reaction mechanism (Scheme 4). Initially, the reaction
proceeded smoothly with the addition of 2.0 equiv of radical
scavengers, where trace, 76%, or 74% yields of product 2a were
observed with regard to TEMPO (2,2,6,6-tetramethylpiper-
idine 1-oxyl), BHT (2,4-di-tert-butyl-4-methylphenol), or 1,1-
DPE (1,1-diphenylethylene), respectively (Scheme 4a). The
a
Reaction conditions are as follows: 1 (0.2 mmol), NaN3 (2.5 equiv),
Pd2(dba)3 (2.5 mol %), Xantphos (5 mol %), and [CO] (TFBen +
Na2CO3, 1 mmol) in 1,4-dioxane (2.0 mL) at 100 °C for 24 h; values
are isolated yields. The reaction was performed on a 1 mmol scale.
b
acyl chlorid, resulting in the formation of 3H-1,2,4-triazol-3-
one products 2a−I in moderate to good yields. Steric
hindrance exerted a slight influence on the outcome of the
reaction (2b−d), whereas obvious an electronic effect was
observed due to the relatively lower yields of hydrazonyl
chlorides bearing electron-withdrawing groups (2g and 2h).
The reaction can be scaled up to a 1 mmol scale in an
acceptable 65% yield for product 2a. The obviously decreased
yield of the large-scale reaction possibly originates from the
generation of some undesirable intermolecular coupling
products. A naphthalene ring can be readily incorporated
into the desired product 2j in a 72% yield. Notably,
heterocyclic moieties, such as furan and thiophene, were also
compatible with the current reaction system to build the
corresponding products 2k and 2l with a high efficiency.
Furthermore, hydrazonyl chloride from pivaloyl chloride
served as a viable substrate, leading to the tert-butyl-substituted
1,2,4-triazol-3-ones 2m in up to a 91% yield.
Scheme 4. Mechanistic Investigations
The scope of this palladium-catalyzed cascade carbonylative
reaction was further examined using hydrazonyl chlorides from
diverse hydrazines, which is summarized in Scheme 3.
Hydrazonyl chlorides from a variety of arylhydrazines can
smoothly participate in the transformation to deliver the
corresponding 3H-1,2,4-triazol-3-one products 3a−i in mod-
erate to good yields. The electronic effect (3a−h) and steric
hindrance (3a−c, 3f−h) of the aryl ring seemingly had a
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obtained results indicated that a single-electron-transfer (SET)
process might not be involved in the reaction. Furthermore,
the reaction of 1-isocyanato-4-methylbenzene 4 with aniline 5
in the presence or absence of the Pd2(dba)3 and Xantphos
catalytic system could furnish the urea product 6 in an
excellent yield in both cases (Scheme 4b). The above
observation data demonstrated that hydrazonoyl isocyanate
presumably served as the key intermediate, and the
nucleophilic addition of the amine to the isocyanate moiety
readily occurred with or without the palladium catalyst.
On the basis of the preliminary mechanistic investigation
and precedent literature,13,17−19 a plausible mechanism was
proposed, which is outlined in Scheme 5. First, the oxidative
was evitable. The newly developed protocol offers an
alternative and straightforward pathway to biologically active
3H-1,2,4-triazol-3-one derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04167.
General comments, general procedure, optimization
details, analytic data, and NMR spectra (PDF)
Accession Codes
CCDC 2044120 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Plausible Reaction Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
Zhengkai Chen − Department of Chemistry, Zhejiang Sci-
Tech University, Hangzhou 310018, P. R. 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, 116023 Dalian, Liaoning, China;
Leibniz-Institut für Katalyse e. V. an der Universität Rostock,
18059 Rostock, Germany; orcid.org/0000-0001-6622-
3328; Email: xiao-feng.wu@catalysis.de
Authors
Shiying Du − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, P. R. China
Wei-Feng Wang − Department of Chemistry, Zhejiang Sci-
Tech University, Hangzhou 310018, P. R. China
Yufei Song − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, P. R. China
addition of Pd(0) to the C−Cl bond of hydrazonoyl chloride
1a gives the hydrazonoyl−palladium complex A, which
possibly underwent the following two reaction pathways to
lead to palladium species D: (1) the coordination and insertion
of carbon monoxide to deliver the acyl−palladium inter-
mediate B,17 followed by Cl−/N3 ligand exchange, and (2)
−
the anionic ligand exchange of complex A with NaN3 to
generate the palladium intermediate C with subsequent
carbonylation.18 Then, the reductive elimination of D could
afford the acyl azide compound E with the regeneration of the
Pd(0) species. Next, a Curtius rearrangement of E occurred
with palladium catalysis, enabling the formation of the
isocyanate intermediate F with the release of a nitrogen
molecule.13 Finally, an intramolecular nucleophilic addition of
F and the following hydrogen transfer process gave rise to the
desired 3H-1,2,4-triazol-3-one product 2a.19 Of note, we
cannot rule out the possibility of a direct transformation from
complex C to the isocyanate intermediate F through a
palladium nitrene species.20
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04167
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Natural Science
Foundation of Zhejiang Province (LY19B020016). The
authors wish to acknowledge Prof. Leifang Liu at Dezhou
University for the single-crystal X-ray diffraction analysis of
compound 3j.
In conclusion, we have developed a palladium-catalyzed
cascade carbonylative reaction of hydrazonoyl chlorides and
NaN3 for the direct assembly of structurally diverse 1,2,4-
triazol-3-ones. This one-pot reaction includes a cascade
carbonylation, acyl azide formation, a Curtius rearrangement,
intramolecular nucleophilic addition, and a hydrogen-transfer
sequence. Several notable features of this protocol lie in the
readily available reagents, a broad substrate scope, and the high
efficiency. Benzene-1,3,5-triyl triformate (TFBen) was used as
a solid CO surrogate, and the manipulation of toxic CO gas
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