Activation of 6-bromoquinoline by nitration: Synthesis of morpholinyl and piperazinyl quinolones

Article abstract of DOI:10.24820/ark.5550190.p010.374

Quinoline forms the key skeletal component of a number of important natural products and pharmacologically-Active compounds. Despite a tremendous amount of research pertaining to the derivatization of quinoline, very few general synthetic routes are described in the literature starting from quinoline or tetrahydroquinoline. A simple and convenient method for the polyfunctionalization of quinolines via nitration of bromoquinolines has been developed. This method represents a new synthetic approach to convert brominated nitroquinoline derivatives into useful cyclic amines via nucleophilic-substitution (SNAr) reaction. Formula parented.

Full text of DOI:10.24820/ark.5550190.p010.374

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Arkivoc 2018, part v, 0-0
Activation of 6-bromoquinoline by nitration: synthesis of morpholinyl and
piperazinyl quinolines
Osman Çakmak*a, Salih Öktenb, Dilek Alımlıc, Aisha Saddiqad, and Cem Cüneyt Ersanlıe
aDepartment of Chemisty, Faculty of Science, Yıldız Technical University, 34220 İstanbul, Turkey
bDepartment of Mathematic and Science Education, Division of Science Education, Faculty of Education,
Kırıkkale University, 71450, Yahşihan, Kırıkkale, Turkey
cDepartment of Chemistry, Faculty of Science, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey
dDepartment of Chemistry, Faculty of Natural Science, Government College Women University, Sialkot,
Pakistan
eDepartment of Physics, Faculty of Arts and Science, Sinop University, 570109, Sinop, Turkey
Email: cakmak.osman@gmail.com
Received 10-25-2017
Accepted 02-17-2018
Published on line 05-29-2018
Abstract
Quinoline forms the key skeletal component of a number of important natural products and pharmacologically-
active compounds. Despite a tremendous amount of research pertaining to the derivatization of quinoline, very
few general synthetic routes are described in the literature starting from quinoline or tetrahydroquinoline. A
simple and convenient method for the polyfunctionalization of quinolines via nitration of bromoquinolines has
been developed. This method represents a new synthetic approach to convert brominated nitroquinoline
derivatives into useful cyclic amines via nucleophilic-substitution (SNAr) reaction.
Keywords: Nitration, N-oxidation, 6-bromoquinoline, aminoquinoline, quinoline N-oxides, morpholinyl and
piperazinyl quinolines.
DOI: https://doi.org/10.24820/ark.5550190.p010.374
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Introduction
We have recently explored a new synthetic strategy for the synthesis of 6,8-dibromo-1,2,3,4-
tetrahydroquinoline (2), 6-bromo-1,2,3,4-tetrahydroquinoline (3) and 3,6,8-tribromoquinoline (4) based on the
bromination reaction of substituted or unsubstituted 1,2,3,4-tetrahydroquinolines (1), good starting materials
with functionality on both rings of quinoline. 1-2 The direct halogenation of quinoline and tetrahydroquinoline
seems the most attractive, however, it is still a challenging strategy as haloquinolines are also the best
precursors of many other derivatives. In our previous publications, brominated tetrahydroquinolines were
transformed into their respective derivatives (Scheme 1).3-4 Bromination of cyano- and methoxy- 1,2,3,4-
tetrahydroquinoline (5, 7, and 8) gave their corresponding 3-brominated quinoline derivatives (6, and 9-12,
respectively) (Scheme 1).4-5 We found that methoxy 1,2,3,4-tetrahydroquinolines (7, 8) were brominated not
only at the C-3, but also at the C-5 positions, to give the corresponding bromoquinolines.5
Scheme 1. Functionalization of substituted quinolines via bromination.
The quinoline moiety forms the key skeleton of several natural-product and pharmacologically-active
compounds, displaying a broad spectrum of biological activities.6–9
We have investigated a new strategy for the polyfunctionalization of quinolines via nitration of
bromoquinolines due to the fact that the nitro group has commonly activated adjacent bromo groups for
nucleophilic substitution. Nitro groups are also good starting groups for amine formation.
6-Bromo-5-nitroquinoline (14) (DIE-17) exhibits high anti-proliferative, cytotoxic and apoptotic effects on
several cancer-cell lines.10 Therefore, we planned to construct derivatives of (14) by simple substitution of the
bromine with hetrocyclic rings. This substitution procedure would enable the introduction of heteroatoms via
an SNAr method due to the activation of bromine group on the quinoline core by the nitro group, due to its
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strong electon-withdrawing effect, which could lead to other potentially bioactive molecules. e.g., (17) and (18)
(Scheme 3).
It is evident from the literature that quinoline N-oxide assists bromination and nitration reactions at the C-
2 and C-4 positions.11 Halogenation at C-2 and nitration at C-4 or C-512 via the corresponding N-oxides provides
an important alternative route because 2-, 4-, and 5-substituted quinolines with N-functionality are common
themes in pharmacologically-active molecules. This led us to focus on the synthesis of bromo- and nitro-
derivatives of quinolines at the C-2, C-4 and C-5 positions.
Although the piperazine- and morpholine-substituted quinolines have a wide range of biological
importance,13-14 the available literature lacks syntheses of these piperazine- and morpholine-based derivatives
on the benzene ring of quinolines by substitution methods.
Herein we report our prelimenary results for the synthesis of morpholine-, piperazine- and amino-
substituted quinolines starting from 6-bromo-5-nitroquinoline (14) and N-oxide derivatives. The work presented
is a continuation of our ongoing research and focuses on the synthesis of polyfunctional quinolines, starting
from bromoquinolines. We are also interested in the biological activity and structure-activity relationship (SAR)
of the synthesized compounds as many quinoline derivatives have exhibited promising pharmacological
activities.7, 15-18
Results and Discussion
6-Bromoquinoline (13) was synthesized according to our previously reported procedures, starting from 1,2,3,4-
tetrahydroquinoline (1) (Scheme 1).1 Following nitration using a mixture of HNO3/H2SO4 at 0°C for one hour with
stirring, (13) yielded 6-bromo-5-nitroquinoline (14) as the sole product in quantitative yield (Scheme 2). Actually,
nitration of quinoline can lead to a multiplicity of products as also shown in Scheme 2. The reaction proceeded
smoothly, however, to selectively give (14). The nitro-group substituent results in activation of the bromine
group in substitution reactions due to the electron-accepting nature of the nitro group. The -R effect of the -
NO2 group favours the substitution reactions with bromine. Previously, our group has reported the synthesis of
6-bromo-5-nitroquinoline (14) and its biological activity as an abstract at the Third International Molecular
Biology and Biotechnology Congress.10 6-Bromo-5-nitroquinoline (14) (DIE-17) exhibits high antiproliferative,
cytotoxic and appoptotic effects on several cancer cell lines. Synthesis of the compound was also later reported
by Chuang et al.20
After selective synthesis of 6-bromo-5-nitroquinoline (14) and its successful isolation and characterization,
(14) was subjected to nucleophilic-substitution reactions with morpholine and piperazine in microwave-assisted
reaction conditions (Scheme 3). Activation of the benzene ring by introduction of the –NO2 group facilitated the
subsequent substitution of the adjacent bromine atom by morpholine and piperazine due to its resulting
electron- deficiency effect on the quinoline ring.
6-Bromo-5-nitroquinoline was treated with morpholine or piperazine in triethylamine under microwave
conditions (150 W at 90-120 ᵒC) which furnished morpholinyl (17) and piperazinyl (18) quinolines in high yields
(98% and 87%, respectively).
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Scheme 2. Synthesis of (14) and possible other products of the nitration of (13).
Scheme 3. Synthesis of morpholinyl- (17) and piperazinyl- (18) quinoline derivatives.
The formations of (17) and (18) were confirmed by 1H and 13C NMR spectral data. The appearance of aliphatic
triplets in the 1H NMR spectra of compound (17) (3.85 and 3.20 ppm, 3J 4.5 Hz) and (18) (3.21 and 3.05 ppm, 3J
4.5 Hz) confirmed that morpholine and piperazine had replaced the bromine atom at C-6. The additional singlet
of N-H appears at 2.51 ppm in compound (18). The rest of the NMR spectrum is quite similar to that of the
reactant (14) with a doublet for H-2 at 8.87 ppm (3J 4.0 Hz), and doublets for H-7 and H-8 at 7.62 and 8.19 ppm
(3J 9.0 Hz), respectively. The aromatic-region doublet of doublets at δH 7.51 ppm (J3,2 8.5 Hz, J3,4 4.0 Hz) belongs
to H-3. The appearance of two aliphatic (52.3 and 46.1 ppm) and nine aromatic carbons in 13C NMR further
confirmed the proposed structure of (18).
To afford the 2- and 4-nitro-substituted-bromoquinoline derivatives (22) and (23), it was first attempted to
convert bromoquinolines (13) and (19) into the quinoline N-oxides (20) and (21), respectively (Scheme 4). which
facilitated the nitration at the pyridine ring of the quinoline moiety due to +R effect of the N-oxide form. The N-
oxidations of 6-bromo (13) and 6,8-dibromoquinoline (19) were carried out in the presence of AcOH/H2O2 or m-
CPBA (Scheme 5). Both AcOH/H2O2 and m-CPBA reacted smoothly with (13) and afforded the N-oxide derivative
(20) in good yield (60% and 87%, respectively). Several attempts to effect the same results for the N-oxidation
of (19) to yield (21) failed, however, under the same or similar conditions. These attempts resulted in polymeric
materials instead of the expected product. It is thought that the unsuccessful formation of the N-oxide (21) may
have been the result of steric-hindrance effects of the bulky bromine group at C-8 (Scheme5).
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Scheme 4. N-oxidation reactions of bromoquinolines (13) and (19).
Scheme 5. Molecular models showing the possible steric-hindrance effect of the C-8 Br group in the attempted
formation of 6,8-dibromoquinoline-1-oxide (21).
1
The H and 13C NMR spectra of the 6-bromoquinoline-1-oxide (20) are quite similar to those of 6-
bromoquinoline (13) with a little upfield shift of the aromatic protons of the pyridine ring and H-8. The signal of
H-5 is a doublet at δH 8.06 (2.5 Hz, meta coupling). The upfield shift of H-2 of (20) compared with starting
material (13), as expected, appears at 8.56 ppm as a doublet (6.0 Hz). Due to the ɣ-gauche effect of the N-O
group, the signal of H-8 shifts downfield (8.63 ppm, 9.2 Hz) (Figure 1).
Figure 1. 1H NMR values of compound (20) and its starting material (13).
Bromination of 6-bromoquinoline-1-oxide (20) has recently been reported.11 Therefore, we focused on the
nitration of 6-bromoquinoline-1-oxide (20). The slow addition of a mixture of HNO3/H2SO4 to an ice-chilled
solution of (20) provided a mixture of 5-nitro-6-bromoquinoline-1-oxide (25) and 4-nitro-6-bromoquinoline-1-
oxide (26). The products were isolated by column chromatography in yields of 57% and 29%, respectively
(Scheme 6).
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Scheme 6. Results of nitration of 6-bromoquinoline-1-oxide (20)
The proposed mechanism for the synthesis of (25) and (26) is represented in Scheme 6. In highly acidic
conditions, strong nitrating agents prefer selectively the C-5 position on quinoline N-oxide. The reasons for the
regioselectivity may be explained in two ways. First, the protonated nitronium ion contributes to regioselectivity
at C-5 or the deprotonated quinoline-1-oxide (20) (Scheme 6).20-21 Alternatively, regioselectivity at C-5 may
occur due to electrostatic repulsion between the electrophile and the positive charge of the oxonium ion of the
6-bromoquinoline N-oxide (24) (Scheme 6).21 Some of the N-oxide molecules are probably not protonated at
low temperatures. For that reason, non-protonated N-oxides were nitrated at C-4 in a small ratio.
1
13
The structures of 25 and 26 were characterized by FT/IR, H NMR, C NMR, and elemental analysis. X-ray
1
crystallography was also performed for 25. In the H NMR spectra of 25 and 26, the disappearance of the
doublets of H-5 and H-4 from starting compound 20 was good evidence for the formations of 25 and 26,
1
respectively. In the H NMR spectra of 25, signals of H-8 and H-2 were observed downfield, having similar
chemical-shift values as the starting molecule 20, while the signal of H-7 (δ 7.96) was observed more downfield
due to the NO2 group in 25 (Figure 2).
1
In the H NMR spectrum of 4-nitro-6-bromoquinoline-1-oxide (26), H-5 (J57 2.0 Hz) shifted more downfield
(δH 9.11) due to the gamma gauche effect of the NO2 group bonded at C-4 (Figure 2). While H-7 gave a doublet
of doublets signal (3J 9.3 and 4J 2.0 Hz) at 7.96 ppm, the doublet signal of H-3 (3J 6.9 Hz) at 8.26 ppm was shifted
more downfield compared to the signal of H-3 (δ 7.35, 3J 8.4 and 6.0 Hz) of starting material 20. This evidence
indicated that a NO2 group was bonded to 6-bromoquinoline-1-oxide (20) at the C-4 position.
1
Figure 2. H NMR values and coupling constants of 5-nitro-6-bromoquinoline-1-oxide (25) and 4-nitro-6-
bromoquinoline-1-oxide (26).
The structure of compound 25 was confirmed by X-ray diffraction studies (Table 1 and Figure 3). The dihedral
angle between pyridine rings (C1-C4/C9/N1 and C19-C22/C27/N5) and phenyl rings (C4-C9 and C22-C27) for (I)
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and (III) is 0°. The dihedral angle between pyridine rings [(C10-C13/C18/N3) with a maximum deviation of
0.0062(1) Å for C18] and phenyl rings [(C13-C18) with a maximum deviation of 0.0068(1) Å for C16] is 0.80° for
(II). The C-N, C-Br, and N-O bond distances [1.315(13), 1.488(11), 1.861(9), 1.277(10), and 1.197(6) Å for (I);
1.330(10), 1.480(8), 1.889(7), 1.310(8), and 1.213(8) Å for (II); and 1.325(12), 1.482(11), 1.898(8), 1.299(10), and
1.167(7) Å for (III), respectively, are the most sensitive indicators of the formation of 25. The carbon-carbon,
carbon-nitrogen, and nitrogen-oxygen bond lengths in compound 25 are comparable with those reported for a
similar structure.22 Interesting intermolecular C-H…Br and C-H…O interactions are observed in the crystal
structure of 25 (Figure 3). All bond lengths are provided in the supporting material.
Table 1. Selected crystal data and structure-refinement parameters for 25
Crystal data and structure- refinement parameters
Identification code
Crystal system
Space group
a (Å)
25
Orthorhombic
Pmc21
Identification code
μ (mm-1)
25
4.422
θ range (º)
Measured refls.
Independent refls
Rint
2.886-28.337
78841
13.6694(13)
9.6036(10)
14.1177(16)
1853.3(3)
8
b (Å)
4108
c (Å)
V (Å3)
0.0464
S
1.221
Z
R1/wR2
max/min (eÅ-3)
0.0448/0.0751
0.624/-0.737
Dc (g cm-3)
1.929
a
b
c
Figure 3. ORTEP diagram of 25 (a and b); Crystal packing diagram of 25 (c).
Nitroquinolines are good precursors for amino-group derivatives. For this reason, the metal-based reduction
of 25 was carried out in the presence of acetic acid. The reduction was performed by adding powdered metal
(Fe) to the solution of 25 in aq. AcOH. After the addition of the metal, the mixture was stirred at 60 °C until the
reactant disappeared on TLC. The extraction and normal work-up afforded 27 in 60% yield (Scheme 7).
We have also explored the deoxygenation of aromatic N-oxides using zinc dust (Scheme 7). The mixture of
zinc and ammonium chloride in THF provides the mild conditions which furnished 5-amino-6-bromoquinoline
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(28) in high yield (81%). The synthesis of 5-amino-6-bromoquinoline by reduction of 5-nitro-6-bromoquinoline
(14) is already available in the literature, but in lower yield (68%) as compared to our results.
The 1H NMR spectrum of amino-substituent product 27 consists of the same signals with a shift upfield due
1
to the electron-donating feature of the NH2 group. The successful reduction was inferred from the H NMR
spectrum showing a broad singlet of the two -NH2 protons. Moreover, the disappearance of an absorption signal
of N=O and appearance of a new signal of N-H stretching vibrations at 3420 cm-1 in the IR spectrum also provide
clear evidence of formation of the reduced product 28. The spectral values (1H, 13C NMR and IR) of 5-amino-6-
bromoquinoline (28) corresponded with those in the literature.19
Scheme 7. Reduction reactions of 25 using Fe and of 27 using Zn.
Conclusions
A simple and convenient method for the polyfunctionalization of quinolines via nitration of bromoquinolines
has been developed. This represents a new synthetic approach to convert brominated nitroquinoline derivatives
into useful cyclic amines by nucleophilic-substitution (SNAr) reactions. We have developed a selective route for
the synthesis of both 6-substituted morpholine and piperazine quinolines containing nitro substituents at the
C-5 positions that could be converted to amino groups. The compounds exhibit high biological activities.23 5-
Nitro-6-bromoquinoline was found to be highly reactive towards SNAr nucleophilic substitution and
investigations are ongoing regarding the generality and application of this approach to other bromoquinoline
derivatives. On the other hand, the activation of the quinoline ring at different positions to obtain novel
quinoline derivatives was enabled by N-oxidation of 6-bromoquinoline using m-CPBA.
Experimental Section
General. Thin-layer chromatography was carried out on Merck silica F254 0.255-mm plates, and spots were
visualized by UV at 254 nm. Flash column chromatography was performed using Merck 60 (70-230 Mesh) silica
gel. The microwave reactions were run in a CEM Discover Labmate instrument. Melting points were determined
on a Thomas Hoover Capillary Melting Point Apparatus. Solvents were removed under reduced pressure. IR
spectra were recorded on a Jasco 430 FT/IR instrument. High-resolution Mass spectra (HRMS) were recorded
on a mass spectrometer under electron-impact (EI) and chemical-ionization conditions. Elemental analysis was
recorded on an Elementar Vario MICRO Cube instrument. NMR spectra were recorded on a Bruker 500 MHz for
1H and at 125 MHz for 13C NMR.
Synthesis of 6-Bromo-5-nitroquinoline (14). 6-Bromoquinoline (13) (0.190 g, 0.932 mmol) was dissolved in 4
mL of sulphuric acid, and cooled at -5 ᵒC with a salt-ice bath. A mixture of H2SO4 (1.5 mL) and HNO3 (1.5 mL) acid
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was prepared and the acid mixture was cooled at -5 ᵒC. The solution obtained was cooled at 0 ᵒC on a salt-ice
bath. While the 6-bromoquinoline (13) solution was stirred with a magnetic stirrer, the H2SO4 / HNO3 mixture
was added dropwise with the aid of a Pasteur Pipette within one hour so the solution temperature did not
exceed 0 ᵒC. The dark brown color of the reaction solution turned into a dark yellow color. After one hour the
reaction was compete. The reaction mixture was poured over crushed ice (20 g) in a beaker. After the ice melted,
the mixture was extracted with CH2Cl2 (5 × 5 mL). The organic phase was neutralized with a NaHCO3 (10%)
solution and dried over Na2SO4. The solvent was removed in-vacuo. Yellow-colored needle crystals were
obtained as the sole product in quantitative yield (0.23 g). mp 128-130 ᵒC. IR (solid KBr, vmax, cm-1): 3050, 3019,
1
2953, 2918, 2850, 1563, 1486, 1414, 1387, 1351, 1318, 1145, 1045, 831, 807, 755. H NMR (500 MHz, ppm,
CDCl3): δH 9.05 (1H, dd, J2,3 4.2 Hz,J2,4 1.6 Hz, H-2), 8.15 (1H, d, J7,8 9.0 Hz, H-7), 8.05 (1H, d, J4,3 8.6 Hz, H-4), 7.92
(1H,d, J8,7 9.0 Hz, H-8), 7.61 (1H, dd, J3,4 8.6 Hz; J3,2 4.2 Hz, H-3). 13C NMR (125 MHz, CDCl3): δC 152.1, 146.6, 133.3,
132.9, 129.8, 123.8, 123.4, 121.4, 112.2 Anal. calcd for C9H5BrN2O2 (251.95): C, 42.72; H, 1.99; N, 11.07. Found:
C, 42.54; H, 2.03; N, 11.12.
Synthesis of 5-nitro-6-(morpholin-1-yl)quinoline (17). A mixture of 6-bromo-5-nitroquinoline (14) (0.1 g, 0.395
mmol), morpholine (0.103 g, 1.185 mmol) and triethylamine (0.040 g, 0.395 mmol) was heated slowly to 80 ᵒC
over 30 min while stirring. The open reaction vessel was placed into the microwave cavity. Microwave irradiation
of 150 W was used and the temperature was ramped from room temperature to the desired temperature of
90-119 ᵒC. The reaction mixture was stirred continuously under microwave irridation at an average of 105 ᵒC for
45 min. The reaction mixture was cooled to room temperature and taken up in CH2Cl2 (15 mL). The organic layer
was washed with 5% aq NaHCO3 (40 mL) and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure. The crude product was filtered by a short silica gel column eluted with a mixture of n-
hexane/EtOAc (1:1) to afford the desired yellow solid product (116 mg, 98% yield). mp 95-97 ᵒC. IR (solid KBr,
1
vmax, cm-1): 2967, 2916, 2895, 2854, 1738, 1620, 1589, 1341, 1262, 1211, 1068, 869, 815, 780, 731. H NMR
(500 MHz, CDCl3): δH 8.90 (1H, dd, 4J 1.5 Hz; 4.5 Hz, H-2), 8.21 (1H, d, 3J 9.0 Hz, H-4), 8.06 (1H, d, 3J 9.0 Hz, H-8),
3
7.63 (1H, d, 3J 9.0 Hz, H-7), 7.53 (1H, dd, J 9.0 Hz; 4.5 Hz, H-3), 3.85 (4H, t, 3J 4.5 Hz), 3.20 (4H, t, 3J 4.5 Hz).13C
NMR (125 MHz, CDCl3): δC150.0, 144.1, 142.2, 139.9, 133.5, 129.5, 123.8, 123.4, 121.5, 66.7, 51.8. HRMS for
(C13H13N3O3 [M+H] +) (ESI,m/z). Calcd: 260.0994. Found: 260.1035
Synthesis of 5-nitro-6-(piperazin-1-yl)quinoline (18). A mixture of 6-bromo-5-nitroquinoline (14) (0.118 g, 0.446
mmol), piperazine (0.115 g, 1.39 mmol), and triethylamine (0.045 g, 0.446 mmol) was heated slowly to 80 ᵒC
over 30 min while stirring. The open reaction vessel was placed into the microwave cavity. Microwave irradiation
of 150 W was used and the temperature ramped up from room temperature to the desired temperature of 68-
78 ᵒC. The reaction mixture was stirred continuously under microwave irradiation at average 74 ᵒC for 45 min.
The reaction mixture was cooled to room temperature and taken up in CH2Cl2 (25 mL). The organic layer was
washed with 5% aq NaHCO3 (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure. The crude product was filtered by a short silica gel column eluting with MeOH to afford the brown oil
product (87%; 0.100 g). Rf 0.19 (MeOH). IR (solid KBr, vmax, cm-1): 3320, 2836, 1620, 1513, 1495, 1343, 1248,
1138, 1014, 978, 831, 795, 770, 541. 1H NMR (500 MHz, CDCl3): δH 8.87 (1H, d, 3J 4.0 Hz, H-2), 8.19 (1H, d, 3J 9.0
Hz, H-8), 8.06 (1H, d, 3J 8.5 Hz, H-4), 7.62 (1H, d, 3J 9.0 Hz, H-7), 7.51 (1H, dd, 3J 8.5 Hz,3J 4.0 Hz, H-3), 3.21 (4H,
3
3
t, J 4.5 Hz), 3.05 (4H, t, J 4.5 Hz), 2.51 (1H, s, NH). 13C NMR (125 MHz, CDCl3): δC 149.7, 143.8, 142.8, 139.1,
133.4, 129.4, 124.2, 123.4, 121.6, 52.3, 46.1. HRMS for (C13H14N4O2[M+H]+) (ESI, m/z). Calcd: 259.1195. Found:
259.1157.
Synthesis of 6-bromoquinoline-1-oxide (20). Method A: To a solution of 6-bromoquinoline (13) (0.32 g, 1.54
mmol) in acetic acid (20 mL), hydrogen peroxide (2 mL) was added and stirred in an oil bath at reflux
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temperature for 2 h. The reaction was monitored by thin layer chromatography (TLC) until consuming starting
material. The solution was cooled at room temperature and diluted with distilled water (30 mL). The pale yellow
mixture was cooled to -5 ᵒC with mixture of salt and ice. The mixture was neutralized by adding a solution of
Na2CO3 (10%) and extracted with CH2Cl2 (2 × 25 mL). The organic layer was dried over Na2SO4 and filtered. The
solvent was evaporated to dryness under reduced pressure. A yellow solid was obtained (0.20 g, 60%). Rf: 0.07
(3:1; EtOAc/ hexane).
Method B: To a solution of 6-bromoquinoline (13) (0.73 g, 3.26 mmol) in cooled CH2Cl2 (43 mL), m-
chloroperbenzoic acid (1.21 g, 7 mmol) was added and stirred at room temperature overnight. The reaction was
monitored by TLC. The reaction mixture was diluted with CH2Cl2 (20 mL) and extracted with KOH (6 N, 3 × 15
mL). The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated to dryness under reduced
pressure. A yellow solid, 0.69 g, (87%) was obtained. Rf 0.15 in EtOAc. mp 131-133 ᵒC. IR (solid KBr, vmax, cm-
1): 3289, 3092, 3067, 2920, 2850, 1560, 1590, 1142, 1064, 776, 732. 1H NMR (500 MHz, CDCl3, ppm): δH 8.63 (1H,
d, 3J 9.2 Hz, H-8), 8.56 (1H, d, 3J 6.0 Hz, H-2), 8.06 (1H, d, 4J 1.9 Hz, H-5), 7.84 (1H, dd, 3J 9.2, 4J 1.9 Hz, H-7), 7.68
3
3
3
(1H, d, J 8.4 Hz, H-4), 7.35 (1H, dd, J 8.4, J 6.0 Hz, H-3). 13C NMR (125 MHz, CDCl3): δC 140.0, 135.9, 133.9,
131.6, 130.1, 125.0, 123.3, 122.2, 121.8. Anal. calcd for C9H6BrNO (222.96): C, 48.25; H, 2.70; N, 6.25. Found: C,
48.12; H 2.83; N, 6.32.
Nitration of 6-bromoquinoline-1-oxide (20). To the solution of 6-bromoquinoline-1-oxide (20) (1 eq, 0.6 g, 2.67
mmol) in H2SO4 (5 mL) at 0 ᵒC, HNO3 (3 eq, 0.8 mL) was added drop-wise and stirred for 4 h. The reaction mixture
was poured onto ice and filtered. The solid mass was washed with H2O (3 × 10 mL) and the crude product purified
by column chromatography. The elution with 5% EtOAc in n-hexane (250 mL) afforded 4-nitro-6-bromoquinoline
1-oxide (26) (0.21 g, 29%) as a yellow powder, and, with crystallization with 8% EtOAc in n-hexane (500 mL),
furnished 5-nitro-6-bromoquinoline 1-oxide (25) (0.41 g, 57%).
6-Bromo-5-nitroquinoline 1-oxide (25) Yellow needles, 0.41 g (57%), Rf 0.30 (EtOAc/hexane 3:7). mp 204-206
1
ᵒC. IR (solid KBr, vmax, cm-1): 3050 (aromatic C-H), 1480 (N-O), 700 (C-Br). H NMR (500 MHz, CDCl3): δH 7.46
(1H, dd, 3J 6.0 Hz, 3J 3.1 Hz, H3), 7.54 (1H, d, 3J 3.1 Hz, H4), 7.96 (1H, d, 3J 9.4 Hz, H7), 8.58 (1H, d, 3J 6.0 Hz, H2),
8.79 (1H, d, 3J 9.4 Hz, H8); 13C NMR (125 MHz, CDCl3): δC 147.9, 140.6, 136.6, 133.7, 124.3, 124.2, 123.5, 118.6,
115.2. Anal. calcd for C9H5BrN2O3 (267.95): C, 40.18; H, 1.87; N, 10.41. Found: C, 40.28; H 1.83; N, 10.52.
6-Bromo-4-nitroquinoline 1-oxide (26). Yellow powder (0.21 g, 29%). mp 214-215 ᵒC. Rf 0.68 (EtOAc /hexane
3:7). IR (solid KBr, vmax, cm-1): 2995 (aromatic C–H), 1537 (N-O), 730 (C-Br). 1H NMR (500 MHz, CDCl3,): δH 7.96
(1H, dd, 3J 9.3, 4J 2.0 Hz, H-7), 8.26 (1H, d, 3J 6.9 Hz, H-3), 8.50 (1H, d, 3J 6.9 Hz, H-2), 8.64 (1H, d, 3J 9.3 Hz, H-8),
9.11 (1H, d, 4J 2.0 Hz, H-5). 13C NMR (125 MHz, CDCl3): δC 141.7, 138.4, 135.0, 134.3, 127.6, 127.1, 123.5, 122.0,
120.4. Anal. calcd for C9H5BrN2O3 (267.95): C, 40.18; H, 1.87; N, 10.41. Found: C, 40.28; H 1.83; N, 10.52.
Synthesis of 5-amino-6-bromoquinoline-1-oxide (27). To the stirring solution of 5-nitro-6-bromoquinoline 1-
oxide (25) (1 eq, 122 mg, 0.045 mmol) in H2O (10 mL), and one drop of CH3COOH (0.1 mL) the powdered Fe (6
eq, 15.1 mg, 0.27 mmol) was added and refluxed for 3 h. The flask was removed and cooled to room
temperature. The mixture was diluted with water (30 mL), extracted with EtOAC (3×10 mL), dried over
anhydrous Na2SO4 (5 g), filtered, and the solvent was removed to afford the crude product (100 mg) which, upon
further crystalization in CH2Cl2 (5 mL), furnished the titled compound (27) as needle-like crystals. White needles
(65 mg, 60%), Rf 0.35 (EtOAc/hexane 3:7). mp 162-164 ᵒC. IR (solid KBr, vmax, cm-1): 3550 (N-H), 3000 (aromatic
C-H) 1480 (N-O). 1H NMR (500 MHz, CDCl3): δH 7.31 (1H, dd, 3J 4.0 Hz, 3J 8.5 Hz, H-4), 7.38 (1H, d, 3J 9.5 Hz, H-7),
7.64 (1H, d, 3J 9.0 Hz, H-8), 8.10 (1H, d, 3J 8.5 Hz, H-3), 8.83 (1H, d, 3J 4.0 Hz, H-8), 4.65 (s, 2H, NH2). 13C NMR (125
MHz, CDCl3): δC 149.0, 140.9, 135.4, 132.4, 130.2, 120.8,109.7, 104.3, 102.6. Anal. calcd for C9H7BrN2O (237.97):
C, 45.22; H, 2.95; N, 11.72. Found: C, 45.28; H 2.98; N, 11.58.
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Synthesis of 5-amino-6-bromoquinoline (28). Method A: 6-Bromo-5-nitroquinoline (250 mg, 1.0 mmol, 1.0 eq)
was dissolved in CH3COOH (5 mL). Fe powder (335 mg, 6.0 mmol, 6.0 eq) was added and the reaction heated to
approx. 75 °C for 150 min. Upon cooling, the mixture was filtered through filter paper and celite, and extracted
with CH2CI2 (3x20 mL) and a solution of 10% aq Na2CO3 (3x15 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by chromatography
on silica gel (40% EtOAc/60% hexanes eluant) to provide 5-amino-6-bromoquinoline as a light yellow,
amorphous solid (193 mg, 87% yield).
Method B: To a magnetically stirred suspension of the 5-amino-6-bromoquinoline 1-oxide (20) (1 eq, 1 mmol,
269 mg) and freshly activated Zinc dust (4 mmol) in THF (2 mL) was added a saturated solution of ammonium
chloride (10 mL). The resulting reaction mixture was stirred for 30 min at room temperature. The catalyst was
removed by filtration and washed with 5% solution of Na2CO3 (10 mL). The organic layer was dried over
anhydrous Na2SO4. The residue obtained following evaporation of the solvent was purified by column
chromatography on silica gel (EtOAc/hexane ; 3:7) to give the amorphous solid (28) (190 mg, 1 mmol, 81% yield).
1
IR (solid KBr, vmax, cm-1): 3423, 3297, 3162, 1635, 1581, 1569, 1457, 1398, 1357, 1323. H NMR (500 MHz,
3
3
3
CDCl3) : δH 8.90 (1H, dd, 3J 4.5 Hz, 4J 1.5 Hz, H2), 8.18 (1H, d, J 8.5, H-4), 7.71 (d, J 9.0 Hz, 1H, H-8), 7.44 (d, J
9.0 Hz, 1H, H-7), 7.39 (dd, 3J 8.5 Hz, 3J 4.5 Hz, 1H, H-3), 4.70 (s, 2H, NH2). 13C NMR (125 MHz, CDCl3, in ppm): δC
150.3, 148.1, 139.6, 133.3, 129.4, 120.7, 120.2, 118.7, 104.3 (Lit19). Anal. calcd for C9H7BrN2 (221.98): C, 48.46;
H, 3.16; N, 12.56. Found: C, 48.78; H 3.21; N, 12.37.
Crystal structure determination for 6-bromo-5-nitroquinoline-1-oxide (25). A suitable sample of size 0.15 x
0.11 x 0.09 mm was selected for the crystallographic study. All diffraction measurements were performed at
room temperature (296°K) using graphite monochromatic MoKα radiation and a Bruker APEX-II CCD
diffractometer. A total of 4795 reflections with [2.886o < θ < 28.337o] were collected in the rotation mode and
cell parameters were determined by using SAINT software.24 The structure was solved by direct methods using
SHELXS-97.25The refinement was carried out by full-matrix least-squares method on the positional and
anisotropic temperature parameters of the non-hydrogen atoms,26 or equivalently corresponding to 311
crystallographic parameters. All non-hydrogen atom parameters were refined anisotropically and all H atom
parameters were fixed to 0.93 Å for C-H. The Uiso values of H atoms were also fixed to 1.2 times the Ueq value of
parent atom for C-H. Other data-collection conditions and parameters of refinement process arepresented in
Table 1.
Acknowledgements
This study was financially supported by grants from the Scientific and Technological Research Council of Turkey
(TÜBİTAK, Project number: 112T394). The authors thank the Scientific and Technological Research Application
and Research Center, Sinop University, Turkey, for the use of the Bruker D8-QUEST diffractometer.
Supplementary Materials
Copies of 1H NMR spectra of compounds 14, 17, 18, 20, 25, 26, 27 and 28 and 13C NMR spectra of compounds
14, 17, 18, 20, 25 and 26 are represented in a Supplementary Materials Addendum.
An X-ray crystallographic file in CIF format, for the structure of compound 25 CCDC: 1525693 has been
deposited with the Cambridge Crystallographic Data Center. The data can be obtained free of charge from The
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Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif by e-mailing data
requests @ccdc cam.ac.uk. or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0) 1223-33603.
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