AgNO2 as the NO Source for the Synthesis of Substituted Pyrazole N-Oxides from N-Propargylamines

Article abstract of DOI:10.1021/acs.orglett.6b03021

A straightforward method for synthesizing the pyrazole N-oxides from N-propargylamines and AgNO₂ through oxidation/cyclization reaction had been developed. AgNO₂ was used as the NO source for the first time to synthesize pyrazole N-o

Full text of DOI:10.1021/acs.orglett.6b03021

Letter
pubs.acs.org/OrgLett
AgNO2 as the NO Source for the Synthesis of Substituted Pyrazole
N‑Oxides from N‑Propargylamines
Bingxiang Yuan,† Fuming Zhang,† Zhuomei Li,‡ Shenghua Yang,† and Rulong Yan*,†
†State Key Laboratory of Applied Organic Chemistry, Key laboratory of Nonferrous Metal Chemistry and Resources Utiliztion of
Gansu Province, Department of Chemistry, Lanzhou University, Lanzhou, Gansu, China
‡The Middle School Attached to Lanzhou University, Lanzhou, Gansu, China
S
* Supporting Information
ABSTRACT: A straightforward method for synthesizing the pyrazole N-oxides from N-propargylamines and AgNO2 through
oxidation/cyclization reaction had been developed. AgNO2 was used as the NO source for the first time to synthesize pyrazole N-
oxides. Various substituted groups on N-propargylamines proceeded smoothly, and the desired products were obtained in good
yields.
Scheme 1. Typical Approaches and the Reactions for
Providing the NO Source
itrogen-containing compounds, such as pyrazoles, have
Ngreat importance in chemistry, biology, and materials
science.1 Heterocyclic N-oxides are important structural
scaffolds because of their significant biological activity in
numerous natural and pharmacological compounds and in
chiral ligands.2 The typical approaches to synthesize N-oxides
from corresponding N-heterocyclic compounds with various
organic oxidants are well-documented.3 However, these
systems suffer from a similar disadvantage, which is that the
substituted N-heterocycles need to be prepared in advance, and
then the N-oxides are prepared by overoxidization. Alter-
natively, transition-metal-catalyzed reactions to form N-oxides
through C−H bond functionalization have been well-studied
recently, while most methods also required the parent N-
heterocyclic compounds as the substrates.4 The direct synthesis
of N-oxides from simple substrates has rarely been exploited.
A variety of typical nitrogen sources, such as NaN3, TMSN3,
and tBuONO, have been heavily investigated to provide the
nitrogen atom to construct the scaffolds of heterocyclic
compounds.5 However, the sources for providing NO directly
are very limited. In particular, Jiao’s group reported that tert-
butyl nitrite was employed as the NO source to generate the
quinoxaline N-oxides under mild conditions (Scheme 1).6
Maiti’s group reported the efficient and stereoselective nitration
of mono- and disubstituted olefins with AgNO2 and 2,2,6,6,-
tetramethylpiperidinooxy (TEMPO), with AgNO2 serving as
the NO2 source.7 Recently, Saikia’s group developed an
efficient method for synthesis of 4-iodopyrazole N-oxides
from propargylamines through the NaNO2/AcOH/I2 reaction
system.8 Although AgNO2 has been widely utilized as an
oxidant and NO2 source for the incorporation of functional
groups into target molecules, there have been no reports about
AgNO2 as the NO source for the synthesis of heterocyclic
compounds.9 Herein, we report the first example of using
AgNO2 as the NO source for the direct synthesis of pyrazole N-
oxides with simple substrates in a one-pot manner.
Received: October 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03021
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a
We began by treating N-(3-phenylprop-2-yn-1-yl)aniline
(1a) and AgNO2 (2) in THF at 100 °C for 6 h. We found
that 1,3-diphenyl-1H-pyrazole N-oxide (3a) was obtained in
85% yield (Table 1, entry 1). The result was an interesting
Scheme 2. Synthesis of Substituted Pyrazole N-Oxides
a
Table 1. Optimization of Reaction Conditions
b
entry
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
AgNO2
AgNO3
NaNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
THF
85
80
−
56
53
25
31
79
83
THF
THF
EtOH
DMF
DMSO
PhMe
CH3CN
THF
c
9
a
Reaction conditions: 1a (0.5 mmol), NO sources (0.6 mmol), solvent
b
c
(2 mL), 100 °C. Yields of isolated products. Kept in the dark. Entry
in bold highlights the optimized reaction conditions, and the reaction
time was monitored by TLC.
discovery because the method for direct synthesis of pyrazole
N-oxides is very rare. The structure of 3a was confirmed by
spectroscopic analysis and further confirmed by single crystal
X-ray analysis. Thus, the substrate 1a was chosen as the model
substrate to optimize the reaction conditions. First, some
compounds, such as AgNO3 and NaNO2, were tested for this
process, and AgNO2 proved to be optimal (Table 1, entries 1−
3). Then, various solvents were evaluated for this reaction;
THF exhibited the highest efficiency and gave the correspond-
ing product in 85% yield (Table 1, entries 4−8). After
screening for temperature, light, and equivalent of substrates,
the optimized conditions were established as shown in Table 1,
entry 1.
a
Reaction conditions: 1a (0.5 mmol), AgNO2 (0.6 mmol), THF (2
mL), 100 °C.
Scheme 3. Reactions of 1-Substituted N-Propargylamines
and AgNO2
Using the optimized reaction conditions, the scope and
generality of this reaction were investigated, and the results are
illustrated in Scheme 2. A series of N-propargylamines with
electron-donating or -withdrawing groups reacted with AgNO2
efficiently, and the desired substituted pyrazole N-oxides were
obtained in good to excellent yields. As shown in Scheme 2, the
reaction was not significantly affected by the nature of the
groups in the aromatic ring of the N-propargylamines.
Additionally, the results indicated that the reaction was
insensitive to the steric effect of the ortho-position. The
substituent in the benzene ring of R1 and R2 gave the desired
products in satisfactory yields (Scheme 2, 3w−3aa). The N-(3-
(thiophen-2-yl)prop-2-yn-1-yl)aniline 1ab was also compatible
in this transformation, producing the desired furans 3ab in 95%
yield. The substrates of N-propargylamines based on alkyl
groups also performed well in this transformation, and the
desired products were isolated in high yields (Scheme 2, 3ac−
3af).
In order to gain further insight into this reaction, several
control experiments were investigated (Scheme 4). The radical
scavenger of TEMPO was used for this transformation, and the
yield of 3a sharply decreased (Scheme 4a). An important
intermediate 4a, which was synthesized with the substrate 1a
and tBuONO following the reported method,10 was subjected
to the standard conditions, and the desired product 3a was
obtained in 95% yield (Scheme 4b). The results showed that
the N-nitrosamine 4a should be the intermediate for this
transformation. Subsequently, the N-nitrosamine 4a was
The more challenging substrates, 1-substituted-N-propargyl-
amines, were employed for this procedure. When the
polysubstituted N-propargylamines, such as 1ag and 1ah,
were subjected to the optimized conditions, the target products
3ag and 3ah were isolated in 86% and 92% yields, respectively
(Scheme 3).
B
DOI: 10.1021/acs.orglett.6b03021
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Letter
coordinated complex, which underwent subsequent cyclization
to generate species B.11 B was protonated to generate
intermediate C, and finally, the desired product 3a was
produced through proton elimination.
Scheme 4. Control Experiments
In conclusion, we developed a direct method to synthesize
pyrazole N-oxides from N-propargylamines via a tandem
oxidation/cyclization reaction. AgNO2 was used for the first
time as the NO source for the synthesis of pyrazole N-oxides.
Various substituted groups on N-propargylamines proceeded
smoothly, and the desired pyrazole N-oxides were obtained in
good yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03021.
1
Experimental methods; H and 13C NMR spectra of all
compounds (PDF)
X-ray data for 3a (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yanrl@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
studied under the standard conditions with TEMPO, and the
yield of 3a had a slight decrease. Then, the N-nitrosamine 4a
was studied with 0.1 equiv of AgBF4 in THF at 100 °C, and the
desired 3a was isolated in 94% yield (Scheme 4c). These results
demonstrated that the transformation of the N-nitrosamine 4a
to 3a was not a radical process. 1,3-Diphenyl-1H-pyrazole 5a
was also employed for this process, and the target molecule 3a
was not detected (Scheme 4d).
Based on the control experiments, a possible mechanism is
proposed in Scheme 5. Under these conditions, a nitro radical
might be generated though the decomposition of AgNO2 first.
Then the substrate 1a reacted with the nitro radical to produce
HNO2 and the nitrogen radical A. The nitrogen radical A
coupled with the ·NO radical, which was produced from
HNO2, to give the important intermediate N-nitrosamine 4a.
The coordination of 4a with the silver catalyst gave the
This work was supported by National Natural Science
Foundation of China (21672086, 21202067), Gansu Province
Science Foundation for Youths (1606RJYA260), and the
Fundamental Research Funds for the Central Universities
(lzujbky-2016-39).
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