Copper-catalyzed rapid C-H nitration of 8-aminoquinolines by using sodium nitrite as the nitro source under mild conditions

Article abstract of DOI:10.1039/c6ra19583k

A mild, rapid and efficient method for copper-catalyzed nitration of quinolines at the C5 or C7 position was reported firstly by using sodium nitrite as the nitro source. A series of nitrated quinoline derivatives were achieved in moderate to good yields

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ARTICLE
Copper-catalyzed rapid C-H nitration of 8-aminoquinolines
by using sodium nitrite as the nitro source under mild
conditions
0Received 00th January 20xx,
Accepted 00th January 20xx
Xiaolei Zhu,a Li Qiao,a Pingping Ye,a Beibei Ying,a Jun Xu,a Chao Shenb and Pengfei Zhang*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild, rapid and efficient method for copper-catalyzed nitration
of quinolines at C5 or C7 position was reported firstly by using
sodium nitrite as the nitro source. A series of nitrated quinoline
derivatives were achieved in moderate to good yields via remote
C-H activation. The method overcomes some shortcomings
reported in previous nitration strategies, such as employing
expensive metal catalysts or using toxic and unstable nitrating
agents. Furthermore, some of products can be obtained through
filtration which displayed the operational simplicity of this
methodology. Importantly, this protocol may provide a practical
synthetic tool for the introduction of nitro group into drug
molecules.
Introduction
Scheme 1 A series of strategies leading to nitroarenes
Oganic nitro compounds are important raw materials in the
synthesis of dyes, plastics, explosives, perfumes and
pharmaceuticals.1 The traditional routes to aromatic nitro
compounds, such as the electrophilic aromatic nitration, usually
require harsh conditions(HNO3/H2SO4), and suffer from
regioselectivity issues as well as the unsatisfactory functional group
tolerance (Scheme 1 eq 1).2 To overcome these problems, recently
several strategies of regiospecific synthesis of nitroarenes, including
the ispo-nitration of aryl boronic acids,3 aryl halides,
pseudohalides,4 and aryl carboxylic acids5 have been developed
(Scheme 1 eq 2). Alternatively, ispo-oxidation of aryl amines or
azides also provided a nitration protocol to give the nitroarenes
indirectly.6 However, these promising approaches are low atom
economy. Furthermore, related wastes are produced.
In view of the encouraging achievements made in recent
transition-metal-catalyzed auxiliary-assisted C-H functionalization
which successfully construct C-C, C-O, C-S, C-N and C-halogen
bonds,7 a similar strategy would be appealing also for the direct C-H
nitration (Scheme 1 eq 3). Specially, liu et al. has shown a method
for palladium-catalyzed regiospecific synthesis of nitroarenes at 130
oC.8 Bi’s copper-catalyzed ortho nitration of (hetero)arenes also
required high temperature and used expensive AgNO2 as the nitro
source.9 The latest radical C-H nitration of arenes by Jiao and co-
o
workers performs at 80 C, but employed expensive Pd catalyst.10
Obviously, these protocols should abide a number of limitations,
mainly using expensive metal catalysis, choosing costly silver(I) salt
as the nitrating agent or requiring harsh reaction conditions.11
Therefore, mild and efficient strategies for selective nitration is still
a great need. In 2014, the carretero group have disclosed a mild
and efficient copper-catalyzed nitration of aromatic derivates but
using unstable nitric acid as the nitrating agent at 100 oC.12 Just
recently, the Ribas group reported a mild protocol for remote C-H
nitration of 8-aminoquinoline amides using inexpensive cobalt
nitrate hexahydrate as catalyst and tert-butyl nitrate(TBN) as nitro
source.13 However, the lack of selectivity for the unsymmetrical
a.College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310036 (China).E-mail: chxyzpf@hotmail.com
b.College of Biology and Environmental Engineering, Zhejiang Shuren University,
Hangzhou 310015 (China).
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and analytical data. CCDC 1444178 for 3a. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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quinoline rings(Ratio C5:C7: 3:1), the excess use of unstable and
toxic nitrating agent and long reaction times(18h) have limited the
synthesis value of this methodology. Herein, we report a copper-
catalyzed mild and efficient method for the remote C-H nitration of
8-aminoquinoline amides using cheap and stable sodium nitrite as
the nitro source (Scheme 1 eq 4). It is noteworthy that the reaction
was completed within one minute at room temperature.
Table 2 Substrate scope of Cu(II)-catalysed nitration of C5-H of 8-
aminoquinoline amidesa,b
Results and discussion
Our original goal was to achieve the copper-catalysed 8-
aminoquinoline directed ortho C-H nitration of benzoic acid
derivates. We started our study by choosing the reaction of
benzamide 1a with sodium nitrite as the model (Table 1). To our
surprise, the nitration product at the ortho position of benzoic acid
derivates was not observed. Instead, in the presence of Cu(NO3)2
o
(10 mol%), PivOH (20 mol%), and PhI(OAc)2 (2.0 equiv.) at 70 C in
CH3CN overnight, unexpected nitrated product 2a was obtained in
70% yield by filtration (Table 1, entry 15). Encouraged by this result,
we further investigated the reaction parameters from catalyst,
oxidant, and solvent. Gratifyingly, the reaction proceeded rapidly at
room temperature in higher yield when PhI(TFA)2 was used as an
oxidant, and the additive PivOH was indispensable (Table 1, entry
9). The transformation could not take place in the presence of other
oxidants, such as TBHP and K2S2O8 (Table 1, entries 16-17). The
a
Reaction conditions: 1 (0.20 mmol), sodium nitrite (0.22 mmol),
Cu(NO3)2 (10 mol %), PhI(TFA)2 (1.5 equiv.), PivOH (20 mol %), CH3CN
(2.0 mL); b Isolated yield.
Table 1 Screening of reaction conditions for nitration of 8-
aminoquinoline amidesa,b
yield of product 2a was declined slightly with reaction temperature
increasing (Table 1, entry 10). Instead of Cu(NO3)2, Cu(OAc)2
resulted in lower yield and longer reaction time (Table 1, entry 6).
Other metal salts such as CuI, PdCl2, AgNO3, Fe(NO3)2, Co(NO3)2
proved ineffective for this reaction (Table 1, entries 1-5). A
screening of different solvents showed that CH3CN was still the
optimum solvent and no reaction occurred in other solvents (Table
1, entries 18-21). When the reaction time was extended to 30 min,
however, the nitration product just be obtained in lower yield
(Table 1, entry 12). Impressively, control experiments revealed that
atmosphere has no effect on the reaction outcome, which
highlighted the operational simplicity of this method (Table 1,
entries 13 and 14). Furthermore, the reaction did not work in
Entry
1
2
Catalyst
CuI
PdCl2
Oxidant
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
none
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Yield(%)b
0
0
3
4
AgNO3
0
0
Fe(NO3)3
Co(NO3)2
Cu(OAc)2
Cu(NO3)2
none
5
0
76
6c
7
0
8
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(OAc)2
TBHP
0
9
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
86
Table 3 Substrate scope of Cu(II)-catalysed nitration of C7-H of 8-
aminoquinoline amidesa,b
10e
11d,e
12f
13g
14h
15
16
17
18
19
20
21
80
30
73
85
83
trace(70)e
0
K2S2O8
0
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
PhI(TFA)2
trace
trace
trace
trace
CH3NO2
dioxane
DCE
aReaction conditions: 1a (0.20 mmol), sodium nitrite (1.1 equiv),
catalyst (10 mol %), oxidant (1.5 equiv), PivOH (20 mol %),
b
c
solvent (2.0 mL); Isolated yield of 2a. The reaction was
completed in 5 min; d No PivOH was added; e The reaction was
carried out at 70 C; The reaction time was 30 min; Under N2;
a
o
f
g
Reaction conditions: 3 (0.20 mmol), sodium nitrite (0.22 mmol),
hUnder O2.
Cu(NO3)2 (10 mol %), PhI(TFA)2 (1.5 equiv), PivOH (20 mol %), CH3CN
(2.0 mL); b Isolated yield.
2 | J. Name., 2012, 00, 1-3
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absence of either Cu(NO3)2 or PhI(TFA)2 (entries 7-8).
With the optimized conditions in hand, the scope of this reaction
was investigated (Table 2). The results showed that a wide range of
8-aminoquinoline amides reacted smoothly with sodium nitrite to
generate the corresponding nitrated products (2a-2k). 8-
aminoquinolinebenzamide was successfully converted into the
desired product 2a in an excellent yield of 86% under the standard
conditions. The substrate bearing Me group on the phenyl ring
could afford the nitrated product 2b in 84% yield. Moreover,
aliphatic amides, including those with methyl, cyclopropyl,
cyclohexyl and tert-butyl could also be employed to afford the
target compounds 2c-2f in moderate to good yields. Aliphatic
amides with oxygen heteroatom 1g, 1i and 1j were also found apply
to this transformation. In addition, the furancarboxylic acid derived
substrate 1h was suitable for this reaction. Especially, the substrate
of Ph group on the quinoline ring was also been well tolerated,
giving the desired product 2k in 84% yield.
Encouraged by the wide functional group tolerance of this C5-H
nitration, we wondered whether this protocol could be applied to
the nitration of quinoline ring at C7 position. To our delight, the
reaction exclusively occurred at the C7 position of quinoline ring
under the typical reaction conditions if the C5 position was
brominated (table 3).14a Various C5-brominated aminoquinoline
amides reacted with sodium nitrite to obtain the desired product
4a-4f in moderate to good yields. The structure of the product 4a
was confirmed by X-ray crystallography (1444178, CCDC NO.), as
shown in the supporting information.
Given the easy available of the raw materials and the operational
simplicity of this method, we performed on a gram scale reaction
(Scheme 2), and the nitrated product 2a was obtained in 82% yield.
The obtained product could be further transformed into N-(5-
aminoquinolin-8-yl)benzamide
5
in 88% yield by Pd/C
hydrogenation.15 These two transformations demonstrated that the
nitration product is also provided with synthetic usefulness.
Importantly, quinolone derivate 1l was easily converted to C5
nitrated product 2l under standard conditions which might be
further used to synthesize some interesting compounds of
biological and pharmacological activities (Scheme 3).16
In order to obtain the mechanistic information about this
transformation, some control experiments were carried out.
Substrate 6 (1-aminonaphthalene derived benzoic acid) did not
give any nitrated product under standard conditions (Scheme 3, a).
No desired product was obtained in the reaction when the
substrate was changed into N-methyl aninoquinoline 7 or 8-
acyloxyquinoline 8 (Scheme 4, a). These reactions showed that the
formation of the bidentate structure was crucial to the remote C-H
nitration.17 To figure out whether the radical progress would be
involved in the reaction, a radical inhibition experiment of 1a with
the addition of radical scavenger TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) or hydroquinone was further performed under the
standard reactions (Scheme 4, b). Completely suppression of the
reaction suggested that a radical pathway might be responsible for
this transformation. In addition, capturing of radical test was
carried out to prove the feasibility of the radical progress and the
result revealed that the nitro radical(NO2•) was existent in the
reaction process (Scheme 4, c). The influence of the quantity of
PhI(TFA)2 and reaction atmosphere were further investigated
(Scheme 4, d; Table 1, entries 11 and 12). The results explained that
reducing the oxidant loading would apparently affect the reaction
efficiency. This phenomenon illustrated that the PhI(TFA)2 plays a
dual role in the reaction, generating nitro radical and oxidating the
intermediate in the reaction process.
Scheme 2 Gram scale reaction
NO2
O
O
standard
Cl
Cl
conditions
Ph
N
H
Ph
N
H
N
O
N
O
78%
2l
1l
O
O
Scheme 3 Application
Based on above experimental results and our previous studies,14
a plausible mechanism was depicted in Scheme 5. First, the
coordination of substrate 1a with Cu(II) produced chelated complex
Scheme 4 control experiments
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A. Afterwards, the deprotonation of the amide group leads to PivOH (4.0 mg, 0.04 mmol, 20 mol %), and CH3CN (2.0 mL) were
formation of the complex B. Then, nitro radical(NO2•) was released stirred at room temperature for 1 min. After completion (monitored
in the presence of PhI(TFA)2 and NaNO2. Subsequently, the single by TLC), the solvent was removed under reduced pressure and the
electron transfer (SET) occurred between the nitro radical(NO2•) residue was purified by silica gel column chromatography to give
and Cu(II) complex B to afford the Cu(I) intermediate C, followed by the corresponding product.
the formation of complex D through oxidation. Finally, the
Pd/C hydrogenation of 2a. Compound 2a (60.0 mg, 0.2 mmol), and
Pd/C (1.2 mg, 20%) were taken in a dried schlenk tube with a
magnetic stir bar under hydrogen, then MeOH (3.0 mL) was added
with a syringe and the resulting mixture was stirred for 6 h at room
temperature. After completion (monitored by TLC), the mixture was
filtered through a celite pad, and the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography to give the reduction product.
intermediate E generated through proton transfer process, and the
desired product 2a was obtained via ligand dissociation, along with
the regeneration of the Cu(II) species to complete the catalytic cycle.
Conclusions
In summary, we have developed a novel copper-catalyzed highly
regioselective direct C-H nitration of quinolines with cheap sodium
nitrite, which afforded good yields of C5-H or C7-H nitrated
quinoline derivates. This transformation featured a mild reaction
system, wide substrate scope as well as the short reaction times.
Importantly, this protocol may provide a green and practical
approach to construct nitrated quinoline derivatives, which were
the key intermediates in the drug synthesis.
Acknowledgements
Financial support from the National Natural Science Foundation of
China (No. 21376058, 21302171), Changjiang Scholars and
Innovative Research Team in Chinese University (IRT 1231), Zhejiang
Provincial Natural Science Foundation of China (No. LZ13B020001).
Experimental section
Notes and references
General information
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Press, Cambridge, 1980; (b) E. Mitscherlich, AnlnPhys.Chem.,
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Cambridge, 1980.
Unless indicated, all reagents were obtained commercially and used
without further purification. Flash chromatography was carried out
with silica gel (200-300 mesh). 1H and 13C NMR spectras were
recorded in CDCl3 or DMSO-d6 on
a Bruker Advance 500
spectrometer at ambient temperature with CDCl3 or DMSO-d6 as
1
solvent and tetramethylsilane (TMS) as the internal standard. H
NMR data were reported as follows: chemical shift (δ ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constant (J values, Hz). 13C NMR data were
reported in terms of chemical shift (δ ppm). Melting points were
determined on an X-5 Data microscopic melting point apparatus.
The small-angle X-ray diffraction(SAXRD) data was performed at
room temperature using German Bruker D4 X-ray diffractometer.
Analytical thin layer chromatography (TLC) was performed with
Merk precoated TLC (silica gel 60 F254) plates. High resolution mass
spectra (HRMS) were recorded using Agilent 6530 QTOF mass
spectrometer. 1a-1k were obtained according to literature
reported14, 3a-3f were formed according to literature reported.14a
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General procedure
General method for Copper(II)-catalyzed C5-H and C7-H nitration of
8-aminoquinoline amides. (2a, 2b, 2k, 4a and 4b): A mixture of
amide (0.2 mmol), NaNO2 (15.0 mg, 0.22 mmol, 1.1 equiv),
PhI(TFA)2 (129.0 mg, 0.3 mmol, 1.5 equiv), Cu(NO3)2 (3.8 mg, 0.02
mmol, 10 mol %), PivOH (4.0 mg, 0.04 mmol, 20 mol %), and CH3CN
(2.0 mL) were stirred at room temperature for 1 min. After
completion (monitored by TLC), the mixture was filtered through a
celite pad, then washed with CH3CN and dried to give the
corresponding product. (2c-2j, 4c-4f): A mixture of amide (0.2
mmol), NaNO2 (15.0 mg, 0.22 mmol, 1.1 equiv), PhI(TFA)2 (129.0 mg,
0.3 mmol, 1.5 equiv), Cu(NO3)2 (3.8 mg, 0.02 mmol, 10 mol %),
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DOI: 10.1039/C6RA19583K
Copper-catalyzed rapid C-H nitration of 8-aminoquinolines by using
sodium nitrite as the nitro source under mild conditions
Xiaolei Zhu,a Li Qiao,a Pingping Ye,a Beibei Ying,a Jun Xu,a Chao Shenb and Pengfei
Zhang*a
We report the first example of copper(II) catalyzed remote C-H nitration of
8-aminoquinoline amides by using sodium nitrite as nitration reagent under mild
conditions in 1 minute which undergoes single electron process.