Activation of 6-bromoquinoline by nitration: synthesis of morpholinyl and piperazinyl quinolines

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 (S N Ar) reaction.


Introduction
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.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. 5heme 1. Functionalization of substituted quinolines via bromination.
][8][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. 10Therefore, 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 S N Ar method due to the activation of bromine group on the quinoline core by the nitro group, due to its 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. 11Halogenation at C-2 and nitration at C-4 or C-5 12 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 nitroderivatives 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 aminosubstituted 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.17][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 HNO 3 /H 2 SO 4 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 -NO 2 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. 106-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 microwaveassisted reaction conditions (Scheme 3).Activation of the benzene ring by introduction of the -NO 2 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.
The formations of ( 17) and (18) were confirmed by 1 H and 13 C NMR spectral data.The appearance of aliphatic triplets in the 1 H NMR spectra of compound (17) (3.85 and 3.20 ppm, 3 J 4.5 Hz) and (18) (3.21 and 3.05 ppm, 3 J 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 ( 3 J 4.0 Hz), and doublets for H-7 and H-8 at 7.62 and 8.19 ppm ( 3 J 9.0 Hz), respectively.The aromatic-region doublet of doublets at δ H 7.51 ppm (J 3,2 8.5 Hz, J 3,4 4.0 Hz) belongs to H-3.The appearance of two aliphatic (52.3 and 46.1 ppm) and nine aromatic carbons in 13 C 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/H 2 O 2 or m-CPBA (Scheme 5).Both AcOH/H 2 O 2 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).
ARKAT USA, Inc Scheme 4. N-oxidation reactions of bromoquinolines ( 13) and ( 19).The 1 H and 13 C NMR spectra of the 6-bromoquinoline-1-oxide (20) are quite similar to those of 6bromoquinoline (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 δ H 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).(20) and its starting material (13).
Bromination of 6-bromoquinoline-1-oxide (20) has recently been reported. 11Therefore, we focused on the nitration of 6-bromoquinoline-1-oxide (20).The slow addition of a mixture of HNO 3 /H 2 SO 4 to an ice-chilled solution of (20) provided a mixture of 5-nitro-6-bromoquinoline-1-oxide ( 25) and 4-nitro-6-bromoquinoline-1oxide (26).The products were isolated by column chromatography in yields of 57% and 29%, respectively (Scheme 6).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.1] 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). 21Some 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.
The structures of 25 and 26 were characterized by FT/IR, 1 H NMR, 13 C NMR, and elemental analysis.X-ray crystallography was also performed for 25.In the 1 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, respectively.In the 1 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 NO 2 group in 25 (Figure 2).
The 1 H NMR spectrum of amino-substituent product 27 consists of the same signals with a shift upfield due to the electron-donating feature of the NH 2 group.The successful reduction was inferred from the 1 H NMR spectrum showing a broad singlet of the two -NH 2 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 ( 1 H, 13 C NMR and IR) of 5amino-6-bromoquinoline (28) corresponded with those in the literature. 19heme 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 (S N Ar) 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. 235-Nitro-6-bromoquinoline was found to be highly reactive towards S N Ar 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 F 254 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 1 H and at 125 MHz for 13 C 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 H 2 SO 4 (1.5 mL) and HNO 3 (1.5 mL) acid 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 H 2 SO 4 / HNO 3 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 CH 2 Cl 2 (5 × 5 mL).The organic phase was neutralized with a NaHCO 3 (10%) solution and dried over Na 2 SO 4 .The solvent was removed in-vacuo.Yellow-colored needle crystals were obtained as the sole product in quantitative yield (0.

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).