Regiocontrolled Nitration of 4-Quinolones at Ambient Conditions

Article abstract of DOI:10.1080/00397911.2015.1085576

Regiocontrolled nitration of 4-quinolone, the highly privileged scaffold, has been developed at ambient conditions. The nitro group can selectively be introduced at diverse positions simply by tuning the reactivity of the moiety. Discrimination is being achieved through the selective functionalization of the free N-H group. The functional group has been screened theoretically with the help of Fukui function and local softness calculation. Theoretical predictions are synchronized well with the experimental findings. Finally, this nitration technique allows quick access to the structurally diverse 4-quinolones.

Full text of DOI:10.1080/00397911.2015.1085576

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Regio-Controlled Nitration of 4-Quinolones at
Ambient Conditions
Sonali Sarkar, Prasanjit Ghosh, Anirban Misra & Sajal Das
To cite this article: Sonali Sarkar, Prasanjit Ghosh, Anirban Misra & Sajal Das (2015): Regio-
Controlled Nitration of 4-Quinolones at Ambient Conditions, Synthetic Communications, DOI:
10.1080/00397911.2015.1085576
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Date: 24 September 2015, At: 11:37

Regio-Controlled Nitration of 4-Quinolones at Ambient Conditions
Sonali Sarkar1, Prasanjit Ghosh1, Anirban Misra1, Sajal Das1
1Department of Chemistry, University of North Bengal, Siliguri, Darjeeling 734013,
India
Author has equal contribution
Corresponding author: E-mail: sajal.das@hotmail.com
Abstract
Regio-controlled nitration of 4-quinolone, the highly privileged scaffold, has been
developed at ambient conditions. Nitro group can selectively be introduced at diverse
position simply by tuning the reactivity of the moiety. Discrimination is being achieved
through the selective functionalization of free N-H group. The functional group has
screened theoretically with the help of Fukui function and local softness calculation.
Theoretical predictions are synchronized well with the experimental findings. Finally,
this nitration technique allows the quick access of the structurally diverse 4-quinolones.
KEYWORDS: 4-quinolones, regio-controlled nitration, Fukui function, local softness,
ambient conditions
INTRODUCTION
1

Nitration is one of the extensively studied organic reactions since its discovery in 1834.[1]
Nitro compounds are significantly beneficial synthetic intermediates and have potential
application in various fields especially in chemical industry and in an array of
pharmaceuticals.[2] A variety of aromatic nitro compounds are used for the treatment of
insomnia, angina, Parkinson’s and trypanosomatid diseases.[2b] Various methodologies
have been employed to synthesize the aromatic nitro compounds. Nitration using mixed
acids is most widely used technique and results in the mixture of products. Afterwards
many regioselective nitration techniques viz. ipso-nitration/oxidation of amine[3] or
azide,[4] functional group directed nitration[5] etc., have been developed till now to
overcome those shortcomings. But these modern and sophisticated techniques could not
always be helpful for designing of target molecules.
In the arena of 4-quinolones, multi substituted 4-quinolones are prominent in bioactive
molecules and their selective functionalization remains a challenge. Our main effort was
directed towards the regio-selective functionalization of 4-quinolones.[6] Slight variation
in the substituent nature or position (Figure-I) brings inconsiderable to magnificent
potency of the quinolone based drugs.[7]
Nitro quinolone derivatives have been reported to possess antifilarial, antiviral,
antiallergic, antitumor and antibacterial capabilities.[8] Very limited, mostly 6-nitro
derivatives of 4-quinolones have been synthesized and their medicinal values are
evaluated so far.[8,9] This might be due to the problems associated with common
synthetic methodologies as these include the cyclization of nitro-substituted
2

anilines to form the desired nitro-quinolone.[8,9] It is difficult to opt the literature
method if one aiming to get 5 or 7-nitro 4-quinolone because the starting
unsymmetrical nitro anilines upon cyclization always resulting the formation of
mixture products (isomers), in turn leading to cumbersome separation process as
well as poor yield. No such direct technique for the selective nitration of 4-
quinolone is reported in the literature. Selectivity in the nitration reaction is governed
by various factors like steric effects, nature of solvent, interaction between substrate with
reagents and electronic effects.[10] Under the identical reaction conditions, regio-
selectivity is governed by the electronic effects of the substrate.
Herein for the first time, we report a complete regio-controlled nitration of 4-quinolones
at ambient conditions. Selectivity can easily be tuned by the selective functionalization of
free N-H group of 4-quinolone. The profound impacts of the free N-H and other
substituents in the nitration process of 4-quinolones have been screened with the help of
density functional theory (DFT) calculation. It was found a synchronized study based on
theoretical prediction and experimental observations.
RESULTS AND DISCUSSION
Our study began with the nitration of 4-quinolone 3-carboxylate using mixed acids at
ambient conditions. The unsubstituted 4-quinolone 3-carboxylate 1 has been selected as a
model compound for this study. There are five positions (C-2, C-5, C-6, C-7 and C-8)
available for nitration. But compound 1, on nitration with mixed acids at ambient
conditions results in 78% yield of the corresponding 5-nitro derivative upon isolation
3

(table-I). Carrying out the reaction in the presence of both dilute and concentrated nitric
acid did not provide any good result (table-I). During the modification of reaction
conditions, caring the presence of acid sensitive group in mind, we focused to develop the
nitration reaction in neutral conditions. Various set of well-known nitrating reagents were
used and corresponding results summarized in table 1. It is clear from the table that the
combination of nitronium tetrafluoroborate [NTFB] and acetonitrile (table 1, sl. no. 6) is
best suited in the present study which results in 90 % yield of the desired product within
5-minutes at ambient conditions. Nitration using NTFB generally proceeds via equation
1.[11]
ArH+NO2 BF
ArNO2 HF+BF
(1)
4
3
With the optimized conditions in our hand, the scope of selective nitration was
investigated (Scheme-I). Different substituted 4-quinolones 2 and 3 smoothly underwent
selective nitration to furnish the desired 5-nitro product in excellent yield. The results
clearly showed that the presence of electron donating group (-CH3) and electron
withdrawing group (-F) literally has no significant role in defining the position of
incoming electrophile (nitronium group).
But the problem begins while attempting the nitration of compound 4, where methoxy
group present at C-8 position. Compound 4 on nitration under the optimized conditions
always results in the corresponding 5, 7-dinitro derivatives (Scheme-II). This is probably
due to the +R effect of methoxy group which facilitated the second nitration in its ortho-
position.
4

This observation stipulates us to develop a regio-selective nitration technique. To bring a
control in nitration reaction we thought to tune the reactivity of compound 4.
Accordingly, an additional functional group has been introduced (functionalisation of
free N-H) into the moiety so that it could trim down the reactivity of the parent
compound 4 and thereby restrict the second nitration. Selection of the functional group
has been done with the help of B3LYP density functional theory (DFT) calculation using
the Gaussian 03W quantum chemical package.[12] Among the different density functional,
the hybrid functional B3LYP is by far the most popular in chemistry.[13] It is well
documented that B3LYP functional along with 6-31G(D) or 6-31G(D,P) basis function
can be used in studying various organic reactions.[14] Here we have chosen 6-31G(D,P)
basis function for our computation. Regio-selectivity as well as reactivity of any
molecule can be ascertained through evaluation of Fukui function[15] and local
i
softness.[16] The Fukui function (fk ), instigated in DFT by Parr and Yang,[15,16a] is the most
important local reactivity index. For electrophilic attack it is defined as,
−
fk = [ρk(N) – ρk(N−1)]
Where ρ(N) and ρ(N−1) are the electron densities of the N and (N−1) electron systems
respectively. Local softness (sk¯) is another parameter in analyzing the regio-selectivity,
i
i
which is related to Fukui function as sk = fk .S with i = + or −, where S is the global
softness given as S=1/2η where η is the global hardness.
¯
¯
The detail results of the nucleophilic Fukui function (fk ) and local softness (sk )
calculation are shown in table-II and S-I (see supporting information). It is clear from
theoretical analysis that either an alkylester or -CH2Ph group can be chosen for the
5

functionalization of free N-H to restrict the second nitration. Herein, we have selected the
alkylester group as the resulting moiety 5 can serve as an amino acid precursor. Nitration
of compound 5 under the optimized condition, selectively results in the corresponding 5-
nitroderivative in excellent yield upon isolation (Scheme-III).
Now the remaining major challenge is the introduction of nitro group selectively at 7-
position of the same moiety (compound 4). Screening of several protecting group with
the help of conceptual DFT, we found –SO2CF3 may be chosen in this case (Table-II). As
for –SO2CF3 N-protecting group C7 is susceptible for electrophilic attack having highest
¯
¯
reactivity indices (fk = 0.027, sk = 0.158) than the other probable sites C5 (0.020, 0.120)
and C6 (0.015, 0.091). Accordingly, the parent compound 4 on treatment with triflic
anhydride in the presence of tetrabutyl ammonium hydrogen sulfate (TBAHS) results in
desired N-protected 4-quinolone 6 in good yield. The protected quinolone (6) on nitration
under the optimized conditions results in the corresponding mono nitro-derivative after in
situ deprotection. The 7-nitro derivative of compound 6 has been isolated selectively in
moderate yield (Scheme-IV).
The above study showed that N-H group plays a pivotal role for defining the position of
nitro group in the nitration reaction of 4-quinolone moieties. Tuning of the reactivity in
the nitration reaction was further justified using another model compound 7 where methyl
group is present in C-6 position. The DFT calculation of compound 7 showed that the
most reactive position for the electrophilic attack is C-8. As it has the highest reactivity
¯
¯
index (fk = 0.042, sk = 0.240) than the other possible sites (C-5 and C-7, table -II).
6

Functionalization of free N-H either with alkylester or –SO2CF3 changes the reactivity
and C-5 becomes the most susceptible position for the attack of nitronium ion (Table-II
and S-I). Among alkylester and –SO2CF3, the former has highest reactivity indices and
accordingly, the free N-H of compound 7 was protected with alkylester (compound 8)
following the previous method (compound 5). Both the compounds 7 and 8 were
subjected to the nitration reaction in our optimized conditions and resulted in the
corresponding 8 and 5 nitro derivatives in 80 and 82 % yield respectively.
CONCLUSION
Finally, the newly developed technique allows introducing nitro group in the diverse
position of the 4-quinolone ring with maximum efficiency. This method would be very
useful for the target synthesis of new bioactive molecules based on 4-quinolone system.
The study showed that the N-H functional group plays pivotal role in defining the
position of incoming electrophile. Judicial functionalization of free N-H brings the
discrimination and allows selective nitration of 4-quinolones. Other part of the
development based on this moiety is currently underway.
EXPERIMENTAL SECTION
General Methods
Unless stated otherwise, all reagents such as o-anisidine, p-toluidine, aniline, o-F-aniline,
o-toluidine, EMME, potassium carbonate, tetrabutylammniumhydrogensulfate (TBAHS),
NTFB (nitronium tetrafluoroborate), (CF3SO2)O and solvents were used as received from
commercial suppliers. NMR spectra were recorded on 300 MHz spectrometer at 298 K
7

and calibrations were done on the basis of solvent residual peak. Mass spectra were
performed using ion trap mode. Products were purified using column chromatography on
silica gel (60-120 mesh) and a mixture of petroleum ether (60-80oC)/ethyl acetate was
used as an eluent. Progress of reaction was monitored by silica gel TLC.
Preparation Of Compound (1 - 4)[6]
A mixture of aniline (10 mmol), EMME (11 mmol) and toluene (30 mL) was refluxed in
a 250 ml round bottom flask for 5 hours. It was then cooled and washed with 3(N) 100
mL H2SO4. Toluene was distilled off afterwards. The mixture was scratched vigorously
to get solid anil product. This product (5g) was refluxed with biphenyloxide (50 mL) for
2 hours at 280ºC. It was then cooled and stirred for an hour after addition of small
amount (100 mL) of petroleum ether. Compound (1 - 4) was obtained by filtration on
Buchner funnel.
General Procedure Of Nitration Reaction (Compound 1a -8h)
A mixture 4-quinolone-3-carboxylate (1 mmol) in 5ml dry acetonitrile was taken in 25 ml
round bottom flask. Then, 2 mmol (0.266 g) of NTFB (nitronium tetrafluroborate) was
added into it at a time. The reaction mixture was stirred at room temperature for 5
minutes. The progress of reaction was monitored by TLC and upon completion; the
reaction mixture was poured into the ice water and a yellow solid appeared. The yellow
solid material was collected and dried completely. The crude material was further
purified by the silica gel column chromatography using ethyl acetate and petroleum ether
as an eluent.
8

Ethyl 1,4-Dihydro-8-Methoxy-5,7-Dinitro-4-Oxoquinoline-3-Carboxylate (4d)
Bright yellow solid, melting point: 1750C-1780C; 1H NMR (DMSO-d6, 300 MHz) δ 1.27
(t, J=7.2 Hz, 3H), 4.12 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 8.37 (s, 1H), 8.49 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz) δ 14.66, 60.75, 64.38, 113.25, 114.83, 121.48, 136.79,
142.12, 143.54, 146.13, 146.30, 164.18, 170.26; HRMS (ESI-TOF) m/z: [M+H]+, found
338.0522. C13H11N3O8 requires 338.0624.
ACKNOWLEDGEMENTS
We thank the DST, New Delhi for financial support (SR/FT/CS-017/2010). PG is grateful
to UGC for the award of fellowship.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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11

Table -I Optimisation of the reaction conditions
Sl. No Reagent(s)-Solvent
Time
1 h
Temperature
Yield(%)[a]
1
2
3
4
5
6
Mixed acids
HNO3 (dil.)
HNO3 (conc.)
0oC  rt
78
2 h
rt
rt
rt
rt
rt
30
2 h
52
Cu(NO3)2, p-TSA –DCM 12 h
No reaction
No reaction
90
Fe(NO3)3, Ac2O-DCM
NTFB
12 h
5 min.
[a] Isolated yield after column chromatography purification.
12

Table II: Fukui function (fk¯) and local softness (sk¯) calculation at B3LYP/6-31G(d,p)
Comp Fukui functions
ound
Local softness
Theore Experim
tically entally
Preferr Preferre
C-5
C-6
C-7
C- C-5
C-6
C-7
C-
8
8
ed
d
reactio reaction
n
centre
centre
1
2
3
4
0.043
0.038
0.042
0.037
0.030 0.015
0.027 0.020
0.027 0.020
0.025 0.027
-
-
-
-
0.248 0.173 0.085
0.220 0.156 0.113
0.238 0.150 0.111
0.217 0.145 0.156
-
-
-
-
C-5
C-5
C-5
C-5
C-5
C-5
C-5
C-5 &
C-7
5
6
7
0.033
0.020
0.041
0.027 0.019
0.015 0.027
-
-
0.193 0.160 0.113
0.120 0.091 0.158
-
-
C-5
C-7
C-5
C-7
C-8
-
0.018 0.0 0.238
42
-
0.105 0.2 C-8
40
8
0.038
-
0.015 0.0 0.220
37
-
0.088 0.2 C-5
18
C-5
13

Scheme-I: Substrate scope of selective nitration of 4-quinolones
14

Scheme-II: Dinitration of 8-methoxy-4-quinolone
15

Scheme-III: Controlled nitration of compound 5
16

Scheme-IV: Selective nitration of N-protected 8-methoxy 4-quinolone at C-7 position
17

Scheme-V: Selective nitration of 6-methyl 4-quinolone
18

Figure-I: Basic 4-quinolone scaffold
19