Copper(II)-Catalyzed C-H Nitrogenation/Annulation Cascade of Ketene N, S-Acetals with Aryldiazonium Salts: A Direct Access to N2-Substituted Triazole and Triazine Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b04335

Direct synthesis of N²-substituted triazole and triazine derivatives has been a challenge in N-heterocyclic chemistry. Under copper(II) catalysis ketene N,S-acetals, that is, alkylthio-substituted enaminones, efficiently reacted with aryldiazon

Full text of DOI:10.1021/acs.orglett.9b04335

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(II)-Catalyzed C−H Nitrogenation/Annulation Cascade of
Ketene N,S‑Acetals with Aryldiazonium Salts: A Direct Access to
N2‑Substituted Triazole and Triazine Derivatives
Ping Wu,†,‡ Yuan He,†,‡ Hongmei Wang,*,§ Yong-Gui Zhou,*,† and Zhengkun Yu*,†,∥
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, P.R. China
‡University of Chinese Academy of Sciences, Beijing 100049, P.R. China
§State Key Laboratory of NBC Protection for Civilian, Beijing 102205, P.R. China
∥State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: Direct synthesis of N2-substituted triazole and
triazine derivatives has been a challenge in N-heterocyclic
chemistry. Under copper(II) catalysis ketene N,S-acetals, that
is, alkylthio-substituted enaminones, efficiently reacted with
aryldiazonium salts to allow the regioselective generation of
functionally diverse N2-substituted 1,2,3-triazoles and 2,3-
dihydro-1,2,4-triazines. The oxidant and base-dependent
reaction yielded the five- and six-membered N-heterocyclic
products, respectively. The synthetic protocol features broad
substrate scopes and good functional group tolerance under mild conditions. The mechanistic studies have revealed that the
reaction proceeds via alkenyl azo/imino hydrazone intermediates.
-Heterocyclic compounds have been demonstrated to
have versatile applications in pharmaceuticals, agro-
be readily accessed, and their direct synthesis has remained a
great challenge due to the uncontrollable regioselectivity of the
conventional synthetic reactions. Thus, N−H functionalization
of NH-1,2,3-triazoles has usually been used to make N2-
substituted 1,2,3-triazole derivatives, including N2-arylation,7
alkylation,8 allylation,9 and vinylation10 (Scheme 2a).
Oxidative cyclization of arylhydrazones11 and azobenzenes,12
copper(I)-catalyzed carboamination cascade between vinyl
azides and aryldiazonium salts,13 and coupling of oxime
acetates with diazonium tetrafluoroborates14 have also been
applied for the same purpose. It should be noted that use of
explosive azides is potentially dangerous,13 while in the azide-
free method only p-methoxybenzenediazonium tetrafluorobo-
rate worked well as the coupling partner at a relatively high
temperature.14 Despite the significant advances, direct
methods for the regioselective synthesis of N2-substituted
1,2,3-triazoles, starting from azide-free substrates under mild
conditions, is still highly desirable.
N
chemicals, functional materials, and coordination chemistry,1
among which 1,2,3-triazole and 1,2,4-triazine derivatives have
shown diverse anticancer, antibacterial, antiepileptic, and
antiviral activities (Scheme 1).2 Due to their potential
Scheme 1. Representative Biologically Active 1,2,3-Triazole
and 1,2,4-Triazine Derivatives
The condensation reaction of 1,2-diketones and equivalents
with hydrazines has been utilized to prepare 3,5-disubstituted
or 3,5,6-trisubstituted 1,2,4-triazines (Scheme 2b).15 The
metal-free methods such as BF3·OEt2-promoted ring-open-
ing/cyclization/oxidation cascade of aziridines with N-tosyl-
hydrazones16 and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-
mediated [3 + 3] cyclization of imines with α-diazocarbonyls17
applications, general methods for their regioselective synthesis
have been strongly desired. In this regard, many efforts have
been devoted to the synthesis of N1-substituted 1,2,3-triazoles
by means of Huisgen cycloaddition,3 transition-metal-catalyzed
azide−alkyne cycloaddition,4 and other metal-free5 or azide-
free6 strategies. However, N2-substituted 1,2,3-triazoles can not
Received: December 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04335
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Letter
oxidation, 3.0 equiv of K3PO4 as base, MeCN as the solvent, 25
°C, 5 h in O2 (see the Supporting Information for details).
Compound 3a was considered to be formed from the
intermolecular oxidative olefinic C−H nitrogenation/debenzy-
lation cascade of 1a and 2a, and compound 4a was generated
from the intermolecular oxidative double C−H nitrogenation/
annulation process.
Scheme 2. Strategies for the Construction of 1,2,3-Triazole
and 1,2,4-Triazine Derivatives
Next, the protocol generality for the synthesis of N2-
substituted 1,2,3-triazoles 3 was explored under the optimal
conditions (Scheme 3). Thus, the benzylamine-derived ketene
Scheme 3. Synthesis of N2-Aryl-Substituted 1,2,3-Triazoles
a
3
were also applied for the synthesis of 3,5,6-trisubstituted-1,2,4-
triazines. However, these methods usually afford C-3-, C-5-,
and/or C-6-substituted 1,2,4-triazines. Although copper-
catalyzed tandem nucleophilic ring-opening/intramolecular
oxidative amidation of N-tosylaziridines with hydrazones was
successfully applied for the synthesis of N1-substituted 1,2,4-
triazines,18 and polycyclic 1,2,4-triazine scaffolds were
synthesized by [3 + 3] annulation,19 the synthetic methods
for N2-substituted 1,2,4-triazines from readily accessible
starting materials and with excellent functional group tolerance
have been seldom reported.
Transition-metal-catalyzed tandem C−H functionalization/
annulation strategy has been well explored for the construction
of N-heterocycles through C−C/C−N bond formation.20
However, such a strategy has not yet been successfully applied
for the direct synthesis of triazole and triazine derivatives.
Enaminones have been known for the synthesis of N-
heterocyclic compounds.21,22 Recently, we found that α-oxo
ketene N,S-acetals, that is, alkylthio-substituted enaminones,
could act as diverse building blocks for functionalized N-
heterocycles.22 Thus, we envisioned that C−H diazotization of
these enaminones with aryldiazonium salts might be employed
to synthesize five- and six-membered N-heterocyclic 1,2,3-
triazole and 1,2,4-triazine derivatives. Herein, we disclose a
Cu(II)-catalyzed annulation protocol of alkylthio-enaminones
with aryldiazonium salts for the tunable direct synthesis of N2-
aryl-substituted 1,2,3-triazole and 2,3-dihydro-1,2,4-triazine
derivatives under mild conditions (Scheme 2c).
Initially, the reaction of (Z)-3-(benzylamino)-3-(methyl-
thio)-1-phenylprop-2-en-1-one (1a) and p-methylbenzene-
diazonium tetrafluoroborate (2a) was conducted to optimize
the reaction conditions for the formation of N2-aryl-substituted
1,2,3-triazole (3a) and 2,3-dihydro-1,2,4-triazine (4a). The
reaction conditions for synthesis of 3a were optimized to molar
ratio of 1a:2a = 1:2, 30 mol % CuCl2 as the catalyst, 1.0 equiv
of K2S2O8 as the oxidation, 0.5 equiv of K3PO4 as base, MeCN
as the solvent, 25 °C, 5 h in O2. The reaction conditions for
synthesis of 4a were optimized to molar ratio of 1a:2a = 1:2,
30 mol % CuCl2 as the catalyst, 0.5 equiv of K2S2O8 as the
a
Conditions: 1 (0.30 mmol), 2 (0.60 mmol), CuCl2 (0.09 mmol),
K2S2O8 (0.30 mmol), K3PO4 (0.15 mmol), MeCN (3 mL), 0.1 MPa
O2, 25 °C, 5 h. Scale-up synthesis: 1a (1 mmol), 2a (2 mmol),
CuCl2 (0.3 mmol), K2S2O8 (1.0 equiv), K3PO4 (0.5 equiv), MeCN
(10 mL).
b
N,S-acetals were used to react with various aryldiazonium
tetrafluoroborates to give N2-aryl-1,2,3-triazole derivatives. In
most of the cases using p-tolyldiazonium tetrafluoroborate
(2a), the target products were obtained in good to excellent
yields (70−90%) with a tolerance for methyl, methoxy, bromo,
fluoro, and trifluoromethyl on the aryl group of the aroyl
moieties in the α-aroyl ketene N,S-acetal substrates, and 3a
could also be obtained in 80% yield on a 1 mmol scale of 1a. o-
OMe and o-CF3 groups exhibited a negative steric impact on
the reaction efficiency, leading to 3e (58%) and 3l (70%),
respectively, whereas o-F facilitated the reaction to form
product 3i (90%). Usually, the m-substituted α-aroyl ketene
N,S-acetals produced the target products less efficiently than
the corresponding para-substituted analogues. α-Heteroaroyl
ketene N,S-acetals, that is, the furoyl- and thienoyl-based
ketene N,S-acetals, were also suitable substrates for the
reaction, affording 3m and 3n in 71−77% yields. The ketene
N,S-acetals functionalized at the α-position by 2-naphthoyl,
acetyl, and cyclopropylcarbonyl reacted well with 2a to give the
corresponding products 3o (85%), 3p (80%), and 3q (75%),
respectively. The ethylthio- and benzylthio-based N,S-acetals
B
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1r and 1s exhibited a reactivity lower than that of their
methylthio analogue 1a, and their reactions with 2a gave 3r
(72%) and 3s (65%), respectively, while the reaction of 1a
with 2a gave 3a in 80% yield. When the aryl groups in
ArN2BF4 salts were changed to phenyl, 4-methoxy, and 4-
ethoxyphenyl, the target products 3t−3v were yielded in 73−
80% yields, whereas the relatively sterically hindered m-methyl,
and electron-withdrawing 3-Br, 4-Br, 4-OCF3, 4-CF3, 4-
CO2Me, or 4-CN on the aryl moiety of the aryldiazonium
salts diminished the yields from 55% to 26% for 3w-3zc.
Product 3zd could not be detected when 4-NO2-benzenedia-
zonium tetrafluoroborate was used as the substrate. It should
be noted that the aryldiazonium salts except for 4-OMe- and 4-
OMe-2-Me-benzenediazonium tetrafluoroborates did not react
under Jiang’s conditions14 (Scheme 2a). The molecular
structure of compound 3v was further confirmed by the X-
ray single-crystal crystallographic determination (Scheme 3,
see the Supporting Information for details).
for the synthesis of N2-aryl-1,2,3-triazoles 3i−3k (72−90%)
(Scheme 3). The α-furoyl- and thienoyl-based ketene N,S-
acetals also efficiently reacted with 2a to afford 4j and 4k (67−
74%). 2-Naphthoyl-, acetyl-, and cyclopropylcarbonyl-func-
tionalized ketene N,S-acetals reacted with 2a less efficiently
than those reactions employed for the synthesis of compounds
3o−3q (75−85%) (Scheme 3), giving the corresponding
products 4l (64%), 4m (61%), and 4n (58%). The EtS- and
BnS-based ketene N,S-acetals also reacted less efficiently with
2a than the corresponding methylthio-N,S-acetals, forming 4o
(61%) and 4p (63%). When the aryl groups in aryldiazonium
salts were changed to 3-methyl- and 4-methoxyphenyls, the
target products 4q and 4r were obtained in moderate yields
(43−48%). Halogen (4-Br) and electron-withdrawing (4-
OCF3 and 4-COMe) substituents on the aryl moiety of the
aryldiazonium salts also diminished the yields of 4s (49%), 4t
(30%), and 4u (52%), respectively, while 4-NO2-benzenedia-
zonium tetrafluoroborate did not react with 1a under the same
conditions. Other benzylamines such as m-MeO-benzylamine
and ethyl 2-amino-2-phenylacetate were also utilized to
prepare the ketene N,S-acetal substrates for the double C−H
nitrogenation/annulation cascade. It was found that the m-
MeO-benzylamine-derived ketene N,S-acetal exhibited a
reactivity inferior to that of ketene N,S-acetal 1a generated
from the NH-unprotected benzylamine, and its reaction with
2a formed 4w in 59% yield, whereas the ketene N,S-acetal
derived from the ethoxycarbonyl group-functionalized benzyl-
amine showed a higher reactivity than 1a, and its reaction with
2a gave the corresponding product 4x in 77% yield. In a similar
fashion, such a relatively reactive ketene N,S-acetal was used to
react with various aryldiazonium salts, affording compounds
4y-4zf (32−69%). Diverse functional groups were tolerant,
including methyl, methoxy, chloro, bromo, fluoro, trifluor-
omethyl, and methoxycarbonyl. The molecular structure of
compound 4m was unambiguously confirmed by the X-ray
single-crystal crystallographic determination (Scheme 4, see
the Supporting Information for details).
Then, the synthetic methodology was investigated for the
synthesis of N2-aryl-2,3-dihydro-1,2,4-triazine derivatives (4)
(Scheme 4). Under the optimal conditions, benzylamine-
Scheme 4. Synthesis of N2-Aryl-Substituted 2,3-Dihydro-
a
1,2,4-triazines 4
To gain insights into the reaction mechanism, the reaction of
ketene N,S-acetal 1a with aryldiazonium salt 2a was conducted
in the presence of 3.0 equiv of a radical scavenger such as
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT) or a single electron transfer
(SET) inhibitor nitrobenzene under the optimal reaction
conditions for the synthesis of compounds 3, and the target
product 3a was formed in 24−73% yields (eq 1). These results
a
Conditions: 1 (0.30 mmol), 2 (0.60 mmol), CuCl2 (0.09 mmol),
K2S2O8 (0.15 mmol), K3PO4 (0.90 mmol), MeCN (3 mL), 0.1 MPa
O2, 25 °C, 5 h.
derived ketene N,S-acetals efficiently reacted with p-tolyldia-
zonium tetrafluoroborate (2a) to give the target products 4a−
4p in 50−75% yields. During the reaction, compounds of type
3 were always accompanied as the side products, which led to
less efficient isolation of products 4 than compounds 3 from
the reaction mixtures. The substituent effect varied from the
substituent groups on the aroyl moieties of the ketene N,S-
acetal substrates. For example, the 4-CF3-bearing ketene N,S-
acetal reacted with 2a to form the target product 4h in 75%
yield, while the 2-F- and 3-CF3-substituted α-aroyl ketene N,S-
acetals gave the products 4g and 4i in 50% and 41% yields,
respectively, which is contrary to the phenomenon observed
exclude a radical reaction pathway. In our previous work,23
alkenyl azobenzenes could be obtained from the interaction of
α-oxo ketene dithioacetals and aryldiazonium salts, thus we
reasonably envisioned that similar alkenyl azobenzenes might
also be generated as the reaction intermediates in the current
transformation.The control experiments were then conducted
by carrying out the reaction of ketene N,S-acetal 1c with o-
fluorobenzene-diazonium tetrafluoroborate (2m) in the
absence of oxidant K2S2O8 under an argon atmosphere or
performing it under the optimal conditions for synthesizing 3
C
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(Scheme 5). In both cases, the corresponding target products
of types 3 and 4 were not isolated in a detectable amount from
402.1640) corresponding to species 5b/5b′. This result further
demonstrates that the alkenyl azo or imino hydrazone
compounds may be the reaction intermediates.
Moreover, enaminone 1v with replacement of the
methylthio functionality by a methyl, reacted with 2a in the
presence of NaOAc to unambiguously form azo-hydrazone
tautomer 5c/5c′ in 87% yield [eq 3]. The 5c/5c′ tautomer was
Scheme 5. Control Experiments
the reaction mixture. However, the azo-hydrazone tautomer
5a/5a′ was isolated in 40% yield (Scheme 5). Recrystallization
of the tautomer gave single crystals of compound 5a′ suitable
for structural characterization by the X-ray single-crystal
crystallographic determination (Scheme 5, see the Supporting
Information for details). It is noteworthy that the NMR spectra
of compound 5a′ only revealed a mixture of 5a/5a′ in CDCl3
due to the quick tautomerization between 5a′ and 5a in
solution.24 The 15N NMR spectrum of 5a/5a′ revealed six
resonance signals at δ = −35.27, −35.66, −51.98, −65.21,
−237.49, and −241.84 ppm by using nitromethane (δ = 0.0) as
the external standard. This result suggests that 5a and 5a′ exist
as the discrete isomers in solution. To further identify the
possibility of 5a/5a′ as the reaction intermediates, the 5a/5a′
tautomer was treated under the standard conditions for
synthesizing compounds 4. To our delight, 1,2,3-triazole 3ze
(25%) and 2,3-dihydro-1,2,4-triazine 4zg (41%) were isolated
from the reaction [eq 2], which suggests that 5a/5a′ may be
then treated under the standard conditions for synthesizing
compounds 3 or 4, respectively. 1,2,3-Triazole 3zf was not
detected, but 2,3-dihydro-1,2,4-triazine 4zh was obtained in
48% yield from the reaction (eq 4), further suggesting that the
azo/hydrazone compounds may be the reaction intermediates.
A plausible reaction mechanism is proposed in Scheme 7.
Initially, ketene N,S-acetal 1 undergoes alkenyl C−H
Scheme 7. Control Experiments
the reaction intermediates toward the N2-arylated 1,2,3-triazole
and 2,3-dihydro-1,2,4-triazine derivatives. A one-pot, two-step
procedure was also investigated by initial treatment of 1a with
2a in the presence of 0.5 equiv K3PO4 under an argon
atmosphere, followed by reacting with 1.0 equiv K2S2O8 in the
presence of the CuCl2 catalyst under an oxygen atmosphere,
1
giving 3a (54%) and 4a (20%) as the final products by H
diazotization with aryldiazonium tetrafluoroborate 2 to
generate alkenyl azo/imino hydrazone intermediate 5/5′
under the basic conditions.23,24 Interaction of the copper(II)
catalyst with 5 forms complex A from which debenzylation
proceeds25 to give the imino-Cu(II) hydrazone complex B.
Analysis of the reaction mixture by HRMS revealed a
molecular ion peak of benzoic acid (HRMS [M − H]: m/z
= 121.0295; calcd for PhCOO−, 121.0289). Reductive
elimination from intermediate B affords the product of type
3 and copper(0) species. In the presence of the oxidant and
base, the copper(II) catalyst is regenerated from Cu(0) (path
a). The imino hydrazone intermediate 5′ interacts with the
copper(II) catalyst to form imino-Cu(II) hydrazide complex
C. A Cu(II)-promoted intramolecular benzylic C−H bond
activation proceeds to yield the benzyl-Cu(II) hydrazone
complex D. Reductive elimination from intermediate D gives
NMR analysis (Scheme 6). Analysis of the reaction mixture
from the first step action by HRMS method revealed a strong
molecular ion peak (m/z = 402.1636; calcd for 5b and 5b′,
Scheme 6. One-Pot, Two-Step Procedure
D
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the product of type 4 and regenerates the copper(II) catalyst
under the oxidative conditions (path b). The formation of
PhCOOH may be attributed to the in situ generated benzyl
chloride (or dichloride) which is hydrolyzed to benzyl alcohol
(or benzaldehyde) during the reaction. Both benzyl alcohol
and benzaldehyde can be oxidized to PhCOOH under the
oxidation conditions. It should be noted that benzyl chloride
was not detected in the reaction mixture.
In conclusion, copper(II)-catalyzed regioselective synthesis
of N2-aryl-substituted 1,2,3-triazole and 2,3-dihydro-1,2,4-
triazine derivatives was achieved by means of tunable C−H
nitrogenation/annulation cascades of ketene N,S-acetals and
aryldiazonium salts under mild conditions. The protocol
features simple operation, readily available starting materials,
broad substrate scope, and good functional group tolerance.
The target products were obtained in good to excellent yields,
avoiding use of explosive azides. The mechanism studies have
implicated that the reaction proceeds through alkenyl azo/
imino hydrazone intermediates. The present method provides
a direct protocol to access N2-aryl-substituted 1,2,3-triazole
and 2,3-dihydro-1,2,4-triazine derivatives.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04335.
Experimental materials and procedures, NMR of
compounds, and X-ray crystallographic analysis for
compounds 3v, 4m, and 5a′ (PDF)
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CCDC 1830695, 1830698, and 1863889 contain 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.
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AUTHOR INFORMATION
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Corresponding Authors
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*E-mail: zkyu@dicp.ac.cn.
*E-mail: wanghongmei@dicp.ac.cn.
*E-mail: ygzhou@dicp.ac.cn.
ORCID
Ping Wu: 0000-0003-2650-9043
Yuan He: 0000-0001-6600-8433
Hongmei Wang: 0000-0003-1057-334X
Yong-Gui Zhou: 0000-0002-3321-5521
Zhengkun Yu: 0000-0002-9908-0017
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21672209 and 21871253) and the National Basic
Research Program of China (2015CB856600) for support of
our research.
E
DOI: 10.1021/acs.orglett.9b04335
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