Regioselective C-7 Nitration of 8-Aminoquinoline Amides Using tert-Butyl Nitrite

Article abstract of DOI:10.1002/adsc.201701555

Regioselective C-7 nitration of 8-aminoquinoline amide has been achieved using tert-butyl nitrite under metal-free conditions at ambient temperature. The protocol is applicable to various aryl, heteroaryl as well as aliphatic carboxamides, and exhibits high functional group compatibility. The present method provides selective mononitrated quinoline derivatives. Experimental results suggest that the reaction likely proceeds through a radical pathway. (Figure presented.).

Full text of DOI:10.1002/adsc.201701555

Title: Regioselective C-7 Nitration of 8-Aminoquinoline Amides Using
tert-Butyl Nitrite
Authors: Alakananda Hajra, Susmita Mondal, and Sadhanendu
Samanta
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701555
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regioselective C-7 Nitration of 8-Aminoquinoline Amides Using
tert-Butyl Nitrite
Susmita Mondal,a Sadhanendu Samanta,a and Alakananda Hajraa,*
a Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
Email: alakananda.hajra@visva-bharati.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Regioselective C-7 nitration of 8- drawn tremendous attention. Based on chelation-
aminoquinoline amide has been achieved using tert-butyl
nitrite under metal-free conditions at ambient temperature.
The protocol is applicable to various aryl, heteroaryl as
well as aliphatic carboxamides, and exhibits high functional
group compatibility. The present method provides selective
mononitrated quinoline derivatives. Experimental results
suggest that the reaction likely proceeds through a radical
pathway.
assisted aromatic C-H functionalization, Stahl and co-
workers reported first halogenation at the C-5
position of 8-aminoquinoline amides.[9a] Afterwards,
various methodologies such as halogenation,[9]
sulfonylation,[10]
alkylation,[11a]
allylation,[11b]
amination,[11c] chalcogenation,[11d] fluoroalkylation,[12]
esterification,[13] etc. have been developed on
quinoline ring using Fe, Co, Pd, Ni, and Cu as
catalysts. Interestingly, most of these reported
methods provide functionalization at the C-5 position
of 8-aminoquinoline amides. The C-7 position of
quinoline is also very important.[14] Moreover, its
functionalization at C-7 position is still challenging
and rarely explored. Nitro-substituted quinoline
derivatives are used as anticancer agents, cathepsin β
inhibitors, endothelial cell proliferation inhibitors,
Keywords: regioselctivity; nitration; metal-free; radical;
ambient temperature
Aromatic nitro compounds are the important
building blocks in synthetic organic chemistry and
present in a variety of dyes, explosives, plastics,
natural products, and pharmaceuticals.[1] They are
also used as raw materials and synthetic precursors in
chemical industry.[2] Over 150 years, much attention
have been paid for the nitration of aromatic
compounds. Classical method for electrophilic
nitration of arenes involve a mixed acid system
(HNO3/H2SO4) as nitrating reagent.[3] This method
suffers from poor regioselectivity, over nitration of
compounds, limited functional group tolerance, and
harsh reaction conditions. Recently, several reliable
and efficient methods have also been developed for
regioselective nitration of arenes using metal nitrites
and nitrates.[4] In recent times, significant
advancement has been made in the transition metal-
catalyzed aromatic C_H nitration.[5] In addition, tert-
butyl nitrite (TBN) is also found as a mild, easy to
handle, commercially available nitrating reagent.[6]
8-Aminoquinoline is one of the important scaffolds
found in many bioactive molecules, natural products,
and pharmaceutical chemistry.[7] This moiety acts as a
bidentate directing group for metal catalyzed C-H
functionalization.[8] Recently, functionalization on
quinoline moiety of quinoline amide derivatives has
fluorescent probes, and also as
a
versatile
intermediates for organic synthesis.[15] Several groups
have made significant contributions for selective
nitration of aromatic carboxylic acid part[16] as well as
quinoline moiety[17] of N-(quinolin-8-yl)benzamide
derivatives. However, most of the methods are metal
catalyzed reaction with a mixture of mono- and
dinitrated quinoline derivatives at C-5[17] or both C-5
and C-7[17c] position. Considering the importance of
nitro substituted quinoline derivatives, we planned to
develop a monoselective nitration at C-7 position of
8-aminoquinoline amides. Herein, we report a new
method for selective nitration at C-7 position of
quinoline ring using tert-butyl nitrite under metal-free
conditions at ambient temperature (Scheme 1).
1
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
we checked the effect of different solvents like 1,2-
DCE, THF, DCM, 1,4-dioxane, and toluene (Table 1,
entries 2-6) but, these were not so effective as
CH3CN. The reaction did not proceed at all in ethanol
(Table 1, entry 7). In presence of high polar solvents
like DMF, DMSO, chlorobenzene, and 1,2-DCB,
only trace amount of product was observed (Table 1,
entries 8-11). The reaction yield was decreased to
54% with decreasing the loading of TBN from 3.0
equiv. to 2.0 equiv. but the yield remains unchanged
with further increment of TBN (4.0 equiv.) (Table 1,
entries 12 and 13). No significant improvement of the
yield was observed on increasing the temperature
even after 24 h (Table 1, entry 14). The yield of the
reaction was diminished significantly with decreasing
the reaction temperature and no improvement of the
selectivity was obtained at lower temperature (Table
1, entry 14). No further increment of the yield was
found in the presence of molecular oxygen (Table 1,
entry 15). Thus optimized reaction conditions was
achieved using 3.0 equiv. TBN in CH3CN at ambient
Scheme 1. Functionalization of 8-aminoquinoline amide.
We commenced our study by taking N-(quinolin-8-
yl)benzamide (1a) as a model substrate with tert-
butyl nitrite (TBN) as nitrating agent. The results are
summarized in Table 1. Initially we carried out the
reaction using 3.0 equiv. TBN in acetonitrile
(CH3CN) at room temperature (Table 1, entry 1).
Surprisingly, nitration took place selectively at C-7
position of quinoline ring of amide derivative in 76%
yield (2a) along with minor amount of C-5 nitrated
product (3a) after 8 h. Inspired by this initial result,
temperature for
8
h
(Table 1, entry 1).
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent (2 mL)
TBN (equiv.)
Conversion
Yield of
Yield of
3a [%][b]
16
trace
trace
12
trace
trace
-
[%]
92
<10
<15
76
23
<5
<5
<5
<8
<10
<5
62
95
2a [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3CN
1,2-DCE
THF
DCM
1,4-dioxane
toluene
ethanol
DMF
DMSO
chlorobenzene
1,2-DCB
CH3CN
CH3CN
CH3CN
CH3CN
3
3
3
3
3
3
3
3
3
3
3
2
4
3
3
76
5
11
64
21
trace
-
trace
trace
5
-
trace
trace
trace
8
trace
54
74
21
93[c], 41[d]
96[e]
75[c], 32[d]
77[e]
18[c], 9[d]
19[e]
[a] Reaction conditions: 0.2 mmol of 1a and 3.0 equiv. of TBN in 2 mL solvent at room temperature for 8 h.
[b] Isolated yields.
[c] Stirred at 60 °C for 24 h.
[d] Stirred at 0 °C for 8 h.
[e] In presence of molecular O2.
substituent at different positions of phenyl ring
afforded the selective C-7 nitrated products in good
yields (2b, 2c). Presence of electron-donating OCH3
group on phenyl ring also well tolerated (2d–2f).
Halogens (F, Cl, Br, and I) containing derivatives
With the optimized reaction conditions in hand, the
scope of substrates was explored and the results are
summarized in Table 2. Substrates containing CH3
2
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
afforded the corresponding products with moderate to
good yields (2g–2n). Strong electron-withdrawing
group such as CF3 and CN at phenyl ring also
produced the desired products in moderate yields (2o,
2p). 8-Aminoquinoline amide of (1,1'-biphenyl)-4-
carboxylic acid also worked well (2q). In addition,
furan-2-carboxamide was also suitable for this
transformation (2r). Both cyclohexyl and tert-butyl
amides reacted well (2s, 2t). We also checked the
reactivity of other protecting groups. Both phenyl
quinolin-8-ylcarbamate and benzyl quinolin-8-
ylcarbamate produced the C-7 nitrated product in
good yields (2u, 2v). Boc-protected quinoline amide
was also suitable for this reaction (2w).
Table 2. Substrate scopes of the present method.[a]
[a] Reaction conditions: 0.2 mmol of 1 and 3.0 equiv. of TBN in 2 mL CH3CN at room temperature for 8 h.
Next, the effect of substituents at different
positions of aminoquinoline part was studied (Table
3). The presence of different groups at C-5 position
of quinoline moiety produced the nitrated products in
good yields (5a–5c) while C-7 methyl substituted
quinoline derivative afforded C-5 nitro product in
very poor yield (5d). Moreover, only a trace amount
of dinitrated product 5c was formed when the
mononitrated derivative 2a was further nitrated under
the standard reaction conditions after 10 h. This
observation suggests that C-7 position is more facile
to produce the nitrated product under standard
conditions.
3
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
(Naphthalen-1-yl)benzamide (8) did not give any
nitrated product under the standard conditions. No
desired product was obtained when the substrate
changed to 8-acyloxyquinoline (9). In the case of 8-
aminoquinoline (10) and N-benzylquinolin-8-amine
(11), an inseparable mixture of products was obtained.
This result indicates that the presence of ancillary
benzoyl group and 8-aminoquinoline are necessary
for selective nitration. 4-Methyl-N-(quinolin-8-
yl)benzenesulfonamide (12) did not produce any
product under the optimized reaction conditions. The
nitration did not occur in the case of N-(pyridin-2-
yl)benzamide (13). 5-Aminoquinoline amide (14) and
5-aminoisoquinoline amide (15) were unable to
produce the nitrated product under standard
conditions. These results suggest that 8-
aminoquinoline amide moiety is important for
selective C-7 nitration.
Table 3. Nitration on substituted quinoline moiety.[a]
[a]
Reaction conditions: 0.2 mmol of 4 and 3.0 equiv. of
TBN in 2 mL CH3CN at room temperature for 5 h.
[b] Stirred for 15 h.
The synthetic utility of our method was
represented in Scheme 2. Gram-scale reaction of the
present methodology was carried out under the
normal laboratory setup by taking N-(quinolin-8-
yl)benzamide (1a) and TBN (Scheme 2, A). The
selective C-7 nitro product (2a) was observed without
significant decrease in yield which indicates the
practical applicability of our present protocol. The
nitrated product 2a was hydrolyzed with conc HCl in
ethanol under refluxing conditions and 7-
nitroquinolin-8-amine (6a) was isolated in 84% yield
(Scheme 2, B).
Scheme 3. Control experiments.
Based on the literature reports[6] and our previous
experiences on nitration,[18] here we proposed a
radical mechanism for this nitration reaction (Scheme
4). Initially, TBN undergoes thermal homolysis to
liberate an alkoxy radical and nitric oxide (NO).[6a]
Next, alkoxy radical abstract the carboxamide N-H
proton to give a nitrogen-based radical A that can be
delocalized into the quinoline ring. NO2, which is
formed by oxidation of NO by molecular oxygen,[6b]
reacts with quinoline radical (B and C) to produce
desired product (2a) selectively along with minor
amount of C-5 nitrated product (3a). The selectivity
arises may be due to the proximity effect.[19]
Scheme 2. Synthetic utility of the present protocol.
A few of control experiments were carried out to
understand the mechanistic pathway of the reaction
(Scheme 3). The reaction did not proceed in presence
of radical scavengers like 2,6-di-tert-butyl-4-methyl
phenol (BHT), p-benzoquinone (BQ), 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ), and 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO). These results
signify that the reaction probably proceeds through a
radical pathway. N-Methylated quinoline (7) did not
provide any desired product under the optimized
reaction conditions. This result suggests that the N-H
proton might be crucial for such C-H nitration. N-
4
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
SRF) and S.S. thanks UGC-New Delhi (UGC-SRF) for their
fellowships.
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In conclusion, we have developed a selective
nitration protocol for the preparation of C-7 nitrated
8-aminoquinolines using easily installable and
removable ancillary groups. Mild and metal-free
reaction conditions, ambient temperature, use of tert-
butyl nitrite as nitrating agent, wide functional group
tolerance are the notable advantages of our
methodology. Experimental results suggest that the
reaction likely proceeds through a radical pathway.
We believe the present operationally simple selective
nitration strategy will gain much importance in
organic synthesis, medicinal chemistry as well as in
material sciences.
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µL) was added to it and stirred at room temperature for 8 h.
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mesh) using petroleum ether:ethyl acetate = 4:1as an eluent
to afford the pure product (2a) (44 mg, 76%) as a white
solid.
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Acknowledgments
A.H. acknowledges the financial support from SERB-DST, (Grant
no. EMR/2016/001643). S.M. thanks CSIR-New Delhi (CSIR-
5
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201701555
Advanced Synthesis & Catalysis
UPDATE
Regioselective C-7 Nitration of 8-
Aminoquinoline Amides Using tert-
Butyl Nitrite
Adv. Synth. Catal. Year, Volume, Page
– Page
Susmita Mondal, Sadhanendu
Samanta, and Alakananda Hajra*
7
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