Regioselective bromination: Synthesis of brominated methoxyquinolines

Article abstract of DOI:10.1016/j.tet.2017.07.044

Simple synthetic methods are described for the synthesis of valuable polyfunctional brominated methoxyquinolines 10–13, 20–21, and 24–25. Three regioselective routes are described for convenient preparation of brominated methoxyquinolines at the C-2, C-3,

Full text of DOI:10.1016/j.tet.2017.07.044

Accepted Manuscript
Regioselective bromination: Synthesis of brominated methoxyquinolines
Osman Çakmak, Salih Ökten
PII:
S0040-4020(17)30786-X
10.1016/j.tet.2017.07.044
TET 28876
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 May 2017
Revised Date: 10 July 2017
Accepted Date: 24 July 2017
Please cite this article as: Çakmak O, Ökten S, Regioselective bromination: Synthesis of brominated
methoxyquinolines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.044.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Regioselective bromination: synthesis of
brominated methoxyquinolines
Osman Çakmak *, Salih Ökten
Leave this area blank for abstract info.
a,
b

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Regioselective bromination: synthesis of brominated methoxyquinolines
a,
b
Osman Çakmak *, Salih Ökten
a
Department of Nutrition and Dietetics, School of Health Sciences, İstanbul Gelişim University, 34315 Avcılar, İstanbul, Turkey
Department of Maths and Science Education, Faculty of Education, Kırıkkale University, 71450, Yahşihan, Kırıkkale, Turkey
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Simple synthetic methods are described for the synthesis of valuable polyfunctional brominated
methoxyquinolines 10-13, 20-21, and 24-25. Three regioselective routes are described for
convenient preparation of brominated methoxyquinolines at the C-2, C-3, and C-5 positions with
consecutive reaction steps under mild reaction conditions using molecular bromine. While
bromination of 6-bromo-8-methoxy-1,2,3,4-tetrahydroquinoline (8) selectively gave 3,6-dibromo-8-
methoxyquinoline (10) and 3,5,6-tribromo-8-methoxyquinoline (11), the reaction of 6,8-dimethoxy-
Available online
Keywords:
Quinoline
1
,2,3,4-tetrahydroquinoline (9) resulted in the formation of 3-bromo-6,8-dimethoxyqinoline (12) and
tribromide 13. On the other hand, direct bromination of 6-methoxy- 17 and 6,8-dimethoxyquinoline
19) gave 5-bromo derivatives 20 and 21. However, the reaction 3,6-dimethoxyquinoline (8) resulted
1
,2,3,4-tetrahydroquinoline
(
Bromo quinoline
Methoxy quinoline
Bromination of methoxy quinoline
Multifunctionalization of quinoline
Regioselective bromination
Molecular bromine
in dibromination to form 2,5-dibromoquinoline (24). This process selectively led to functionalization
of the quinoline ring at both the C-2 and C-5 positions.
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
Developments in the synthesis of new quinoline derivatives are progressing and expanding hugely due to their pharmaceutical
importance. Applications of quinoline derivatives have become widespread from anticancer drugs to almost every branch of medicinal
1-3
chemistry. A variety of heterocyclic ring systems for anticancer activity have been widely reported by a number of researchers to
3
develop new approaches to a variety of heterocyclic ring systems, especially including 3-substituted quinoline derivatives.
Several methods for the synthesis of haloquinolines have been reported, including direct halogenation, which always suffers from
4
5
poor regioselectivity and overhalogenation, but only a few methods for the regioselective synthesis of 3-haloquinolines are known.
The development of a new synthetic method for preparing halogen-containing quinolines would enable the synthesis of diverse
quinoline frameworks because the halogen atom could enhance biological activity in many cases6 and could also be used for further
7,8
functionalization in preparing other molecules.
There has been enormous interest in developing efficient methods for the synthesis of quinoline derivatives considering their
significant applications in the field of bioorganic, industrial, and synthetic organic chemistry. The Skraup, Friedländer, Doebner–von
8,9
Miller, and Combes syntheses of quinoline derivatives are important classical synthetic approaches. Almost all synthetic strategies are
9
based on metal catalyzed cyclizations or acid catalyzed cycloadditions. However, quinoline synthesis has important disadvantages,
10
such as harsh reaction conditions and highly acidic media, that make it tedious to isolate the product from the crude mixture. For
instance, the Skraup procedure includes reactions of meta- or 3,4-disubstituted anilines normally giving a mixture of regioisomers
1
1–13
11,13
13,14
difficult to isolate. Most of these methods are not fully satisfactory with respect to yield,
reaction conditions,
generality,
and
11,13
practical use.
these important heterocycles.
These synthetic problems have encouraged researchers to develop a practical efficient procedure for the synthesis of
15
It is interesting that despite the considerable synthetic and biological interest in quinoline derivatives, very few general synthetic
routes are available starting from quinoline or tetrahydroquinoline cores themselves. Recently, we have found that the bromination
reaction of substituted 1,2,3,4-tetrahydroquinolines is a good starting point for functionalizing both rings. In our previous publications,
9
,16
brominated tetrahydroquinolines were transformed to their respective derivatives.
Bromination of 6-bromo-8-cyano-1,2,3,4-
16
tetrahydroquinoline gave corresponding 3-brominated quinoline derivatives (Scheme 1). This methodology uses neither metal
catalyzed cyclizations nor acid catalyzed cycloadditions. The process constitutes a rapid and convenient method for obtaining selective
brominated aromatic compounds as the sole products in high yields.

2
Tetrahedron
ACCEPTED MANUSCRIPT
This work presented herein is a continuation of our ongoing research and focuses on the synthesis of polyfunctional quinolines,
starting from methoxy 1,2,3,4-tetrahydroquinoline, which provides an efficient synthesis of brominated derivatives at C-3 and C-5
(
Scheme 1). We are also interested in investigation of the biological activity and structure–activity relationship (SAR) results because
9,17-20
the synthesized quinoline derivatives exhibited promising anticancer activities and interesting SARs (Scheme 2).
Scheme 1. Preparation of 3-bromo quinolines from tetrahydroquinolines.
Scheme 2. Structure-Activity Relationship for compounds 2, 3 and 4.
2
. Results and Discussion
The starting compounds were synthesized according to our procedures reported previously starting from 1,2,3,4-
9,21-22
tetrahydroquinoline (1) (Scheme 3).
First we studied bromination of methoxy quinolines 8 and 9 with different equivalents of
bromine. The product ratios and conversions are compiled in Scheme 4. While bromination of 8 with three equivalents of bromine
afforded compound 10, bromination with four equivalents of bromine gave tribromide 11 (Scheme 4).
Scheme 3. Preparation of starting materials.

3
ACCEPTED MANUSCRIPT
Scheme 4. Bromination reaction of 6-bromo-8-methoxy THQ 8 and synthesis of dibromide 10 and tribromide 11.
Dimethoxide 9 was brominated with 3 equivalents of bromine, and the dibromide 12 was obtained as the sole product in high
yield (80%) in reaction conditions similar to those of compound 8. On the other hand, bromination of 9 with four equivalents of
bromine gave dibromide 13 in 78% yield. The dibromide 13 was also achieved by the bromination of compound 12 using one
equivalents of bromine in 85% yield (Scheme 5).
Scheme 5. Bromination of 6,8-dimethoxide 9
1
The H NMR spectra of compounds 10, 11, 12, and 13 exhibit simple aromatic signals, which are established easily by their
1
4
vicinal coupling patterns. The H NMR spectra of 10 consisted of four characteristic aryl signals with meta couplings ( J = 1.6 Hz),
1
indicating the positions of the bromine groups. The observation of meta couplings and a singlet signal (δ 4.1) in the H NMR spectrum
of 10 is consistent with the methoxy group at C-8 and two bromines bound to the C-3 and C-5 positions (Table 1). In the C NMR
1
3
spectrum of 10, methoxy (δ 55.6) and aryl signals also support the suggested structure.
C
1
Compound 11 was unambiguously assigned on the basis of its H NMR spectrum due to the three CH signals, which are one
singlet (7.31 ppm, H-7) and two doublets with meta coupling (J2,4 = 2.0 Hz) at δ 8.92 and 8.75, belonging to H-2 and H-4, respectively.
H
13
The presence of six quaternary and three CH carbon atoms in the C NMR spectrum confirms two bromine atoms at the C-3 and C-5
positions in the structure (Table 1).
1
The NMR spectroscopy clearly identified that the expected products 12 and 13 are formed. The H NMR spectrum of 3,6-
4
4
dibromide 12 exhibits four meta coupled aryl signals (δ 8.65 and 8.51, J = 1.8 Hz; δ 7.02 and 6.56, J = 2.0 Hz) appearing
H
5,7
H
2,4
9
1
downfield in comparison with starting material 9. However, the H NMR of 13 consists of two meta coupled doublets of H-4 (δ 8.68,
J2,4 = 2.0 Hz) and H-2 (δ 8.78), one singlet of H-7 (δ 6.89), and two methoxide signals (δ 4.08 and 4.14).
H
4
H
H
H
1
Table 1. H-NMR data of brominated methoxy quinoline 10-13.
Compounds
Protons
Coupling constants (Hz)
H2
H3
-
H4
H5
H6
-
H7
H8
-
1
0
8.91 d
8.21 d
7.51 d
7.16 d
J
J
2,4 = 1.6 Hz
5,7 = 1.6 Hz
4
.10 s, OCH
2,4 = 2 .0Hz
.10 s, OCH
3
1
1
1
2
8.92 d
8.65 d
-
-
8.75 d
8.51 d
-
-
-
7.31 s
6.56 d
-
J
4
3
7.02 d
J
J
4
2,4 = 2.0 Hz
5,7 = 1.8 Hz
.00, 3.94 s, OCH
2,4 = 2.0 Hz
.08, 4.14 s, OCH
3
1
3
8.78 d
-
8.68 d
-
-
6.89 s
J
4
3

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 6. Synthesis of starting compounds 17-19
The synthesis of 11 and 13 from 10 and 12, respectively, prompted us to study the bromination of methoxyquinolines 17, 18, and
1
9 (Schemes 7 and 8) to show whether the selectivity at the C-5 position can be generalized to other methoxy quinolones or not. For
21
this purpose, 6-methoxy 17 and 6,8-dimethoxide 19 were prepared from corresponding the bromoquinolines (3, 15) according to our
previously reported methods (Scheme 6). Additionally, we developed a new methodology for the formation of 3,6-dimethoxyquinoline
9
(18) from its corresponding bromo derivative 16 (Scheme 6). In this context, dibromo derivative 16 was treated with sodium methoxide
in DMF in the presence of copper iodide. Copper-assisted nucleophilic substitution afforded corresponding 3,6-dimethoxide 18 as the
23
sole product in a yield of 78%. Kobayashi et al. (2003) obtained 3,6-dimethoxide 18 using the Friedländer quinoline synthesis in a
five-step cyclization of 1-isocyano-2-(2-lithio-2-methoxyethenyl)benzene. Therefore, our method seems shorter and more practical than
the method in the literature.
Bromination of 6-methoxy 17 and 6,8-dimethoxyquinoline 19 produced selectively the compounds 20 and 21 as the sole products
(
yields 88%, 83%, respectively). Compounds 17 and 18 were also treated with excess bromine (two or more equivalents), but no
formation of dibrominated quinolines (22 and 23) was observed (Scheme 7).
5
-Bromo-6-methoxyquinoline 20 was generated from 6-methoxyquinoline 17 by bromination in acetic acid in low yield (52%) as
24 25
a patent procedure. Another patent described the same procedure, but was slightly modified and gave a lower yield (36%). Our
synthetic procedure involves simple reaction conditions; for example, using a common solvent (CHCl or CH Cl ), in high yield (88%),
3
2
2
at room temperature, with no extraction required.
Scheme 7. Bromination of methoxy quinolines (3, 13 and 14) and preparation of 5-bromo quinolines (22-24).
Bromination of dimethoxide 18 surprisingly resulted in dibromination, contrary to other methoxyquinolines (17, 19). Direct
bromination of dimethoxy 18 with 2 equivalents of bromine produced 2,5-dibromo-3,6-dimethoxy quinoline 24 in good yield (78%)
(Scheme 8). Monobrominated compound 25 was also obtained after bromination with one equivalent of bromine in 82% yield.
Actually, dibromination of 18 can lead to a multiplicity of isomers such as the formation of 4,5-, 2,5-, 5,7-, and 5,8-dibromoquinolines.
No formation of other isomers may be attributed to the orientation of the methyl group in methoxy substituents of 18 (Scheme 8). This
also explains the origin of selectivity in which bromination of 6-methoxy quinolines does not occur at the C-7 position. Furthermore,
the fact that dibromide 24 was obtained, instead of dibromide 27, can also be attributed to having enormous strain energy (46.83
kcal/mol) due to steric compression of the bromo groups in γ −gauche positions (Figure 1).

5
ACCEPTED MANUSCRIPT
2
7
24
18
15.58 kcal/mol (MM2)
Total energy:
46.83 kcal/mol (MM2)
23.46 kcal/mol (MM2)
Figure 1. 3D Structures of 18, 27, 24 and their total energies
Scheme 8. Bromination of dimethoxide 18 and preparation of dibromide 24
Thus, we have developled a new way to obtain 2-substituted quinolines with a bromo group at C-2. Our studies on the preparation
of C2-substituted quinoline derivatives are going on because quinolines substituted at C-2 on the quinoline scaffold have shown
26
interesting anticancer activity in a number of anticancer assays.
In the literature, studies on the bromination of methoxy quinolines using molecular bromine were reported. In one of the papers,
the Eisch bromination of 7,8-dimethoxyquinoline resulted in the formation of a product mixture of 3-bromo-, 5-bromo, and 3,5-dibromo
26
analogues in low yields. It is well known that quinoline itself and bromoquinolines are not brominated with molecular bromine but
8
,16
16,28
rather, form an N-bromine complex. The Eisch bromination
requires N-bromine complex formation in the first step. Trecourt et
27
al. reported that treatment of 7,8-dimethoxyquinoline with bromine involved complex formation. However, in our studies, we did not
observe any complex formation during the bromination of methoxy quinolines under our reaction conditions.
1
In the H NMR spectrum of 20, the characteristic doublet for H-2 of the quinoline scaffold was observed at δH 8.81 ppm.
1
Moreover, the protons of the benzene ring of 20 gave AB signal systems (J8,7 = 9.2 Hz), assigning bromine to C-5. In the H NMR
spectrum of 5-bromo-6,8-dimethoxide 21, four aromatic signals were observed. The doublets of H-2, H-3, and especially H-4 of 21 (δ
H
9
8
.78, 7.47 and 8.46, respectively) appeared more downfield compared with its starting material 19 (δ 8.57, 7.14, and 7.75,
H
respectively). Furthermore, the signal of H-5 disappeared and the signal of H-7 was observed as a singlet signal at δ 6.86.
H
1
In the H NMR spectrum of monobrominated 3,6-dimethoxy compound 25, protons of the benzene ring of 25 (J = 8.7 Hz) gave
8,7
1
AB signal systems, assigning bromine to C-5. Similarly, the H NMR spectrum of 24 consisted of two doublet and one singlet signals as
expected. It was seen that after bromination, the signal of H-2 disappeared, which is evidence for the existence of bromination of the C-
2
position. Furthermore, the signals for aromatic protons H-7 and H-8 (δ 7.35 and 8.06 ppm, respectively; J = 8.0 Hz) were shifted
H
8
,
7
downfield when compared with signals of the starting material 18 (H-7 and H-8; δ 7.22 and 7.95 ppm, respectively) in Table 2. The
H
signal of H-4 is a singlet at δ 7.73 ppm as expected. The characteristic methoxide signals (δ 55.1 and 55.7) and six quaternary carbons
H
C
13
in the C NMR spectra helped to confirm the structure of 24.
1
Table 2. The H-NMR values of methoxy quinoline derivatives 18-21 and 24-25
Compounds
Proton
Coupling constants (Hz)
H-2
8.54 d
H-3
-
H-4
7.32 d
H-5
7.03 d
H-6
-
H-7
7.22 d
H-8
7.95 d
1
1
2
8
9
0
J
J
J
2,4 = 2.4 Hz
8,7 = 9.2 Hz
7,5 = 2.8 Hz
3
.96, 3.94 s OMe
8.57 d
7.14 dd
7.46 dd
7.75 d
6.50 d
-
-
6.4 d
-
J
J
J
2,3 = 4.0 Hz
4,3 = 8.2 Hz
5,7 = 1.6 Hz
3
.68, 3.85 OMe
8.81 dd
8.52 dd
-
7.51 d
8.10 d
J
2,3 = 3.2 Hz,
J
J
4,3 = 8.8 Hz
8,7 = 9.2 Hz
4
.06 s OMe

6
Tetrahedron
ACCEPTED MANUSCRIPT
2
1
8.78 d
7.47 dd
8.46 d
-
-
6.86 s
-
J
J
4
2,3 = 4 Hz,
4,3 = 8.4 Hz
.06 s OMe
2
2
4
5
-
-
-
7.73 s
7.52 d
-
-
-
-
7.35 d
7.32 d
8.06 d
8.00 d
J
8,7 = 8.0 Hz
4
4
.02, 4.07 s OMe
J
J
8.60 d
2,4 = 2.2 Hz
8,7 = 8.7 Hz
.06, 3.96 s OMe
3
. Conclusion
Two regioselective routes are described for the convenient preparation of 3- and 5-brominated methoxy quinolines. Quinoline cores
are selectively functionalized at both the C-3 and C-5 positions under mild reaction conditions.
We found that methoxy 1,2,3,4-tetrahydroquinolines firstly were brominated at the C-3 and C-5 positions to give corresponding
bromoquinolines. Bromination of 6-bromo-8-methoxy-1,2,3,4-tetrahydroquinoline (9) under different equivalents of molecular bromine
selectively gave dibromo 10 and 11 using three and four equivalents of bromine, respectively. Similarly, bromination of 6,8-dimethoxy-
1
,2,3,4-tetrahydroquinoline (8) gave dibromo 12 (with three equivalents of Br ) and tribromo 13 (with four equivalents of Br )
2
2
methoxyquinolines. Selectivity at C-5 was also confirmed by separate bromination reactions of 17 and 19 to give 5-bromo 20 and 21 as
the sole products in high yields.
In the literature, functionalized 3-substituted quinolines were prepared by the condensation of substituted anilines in the presence of
28
some metals or Lewis acids used as catalyst. Due to general protocols to obtain 3-functionalized quinoline derivatives based on
cyclization or cycloaddition of substituted aniline or substituted benzene, the preparation of novel quinoline derivatives substituted at C-
3
or other positions was restricted. On the other hand, the bromine group is a good starting point for not only nucleophilic/electrophilic
substitution but also palladium catalyzed cross coupling reactions described in our ongoing research. We are currently working on the
nitration of bromo and methoxy derivatives of quinolines subsequently their nucleophilic substitution and palladium catalyzed cross
coupling reactions, especially Suzuki coupling with brominated tetrahydroquinolines and quinolines.
On the other hand, the reaction of 3,6-dimethoxyquinoline (8) with two equivalents of bromine resulted in dibromination (24) at C-5
and C-2. Thus, we not only opened up functionlization at C-3 and C-5 but also at the C-2 position of quinoline due to the bromine
group. Therefore, simple synthetic methods were described for the valuable polyfunctional methoxyquinolines 10, 11, 13, 18, 20, 21,
2
4, and 25, which can be converted to corresponding substituted quinolines, otherwise difficult to obtain (Scheme 9).
We found that both the methoxy derivatives of 1,2,3,4-tetrahydroquinolines and methoxy quinolines were highly reactive towards
bromination and investigations are ongoing regarding the generality and application of this approach to other substituted quinoline
derivatives. The reactivity difference of bromine atoms on the heterocyclic ring facilitates the consecutive substitution, leading to the
series of polysubstituted analogues. In summary, we have developed three selective routes for the synthesis of quinoline compounds
containing bromine substituents at the C-2, C-3, and C-5 positions that along with other bromo methoxides could be important starting
materials for the synthesis of polyfunctionalized quinoline derivatives (Scheme 9). The experimental methods are simple, require cheap
starting materials (1, 2, 14), promise large-scale synthesis with high yields, and involve easy isolation of the final products.

7
Br
ACCEPTED MANUSCRIPT
X
X
Br
X
Br
Br2
Br2
N
N
N
H
OCH3
OCH3
OCH3
1
0 X = Br
11 X = Br
13 X = OCH3
8
9
X = OCH3
X = Br
12 X = OCH3
NaOCH /CuI
3
Br
Br
Br2
Br2
N
N
H
N
H
H
Br
2
1
14
H CO
OCH3
3
H CO
3
N
N
1
7-19
18
Br2
Br2
Br
Br
H CO
3
OCH3
Br
H CO
3
N
0-21, 25
N
2
24
Scheme 9. General overwiev of bromination methods for methoxy quinolines/ tetrahydroquinolines
4
. Experimental section
General Methods. 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. Melting points were determined
on a Thomas-Hoover capillary melting point apparatus. Solvents were concentrated at reduced pressure. IR spectra were recorded on a
Jasco 430 FT/IR instrument. Elemental analyses were recorded on an Elementar Vario MICRO Cube. NMR spectra were recorded on a
1
13
Bruker spectrometer at 400 MHz for H NMR and at 100 MHz for C NMR.
4
.1. Synthesis of 3,6-dibromo-8-methoxyquinoline (10). To a solution of 6-bromo-8-methoxy-1,2,3,4-tetrahydroquinoline (8, 241 mg,
1
.0 mmol, 1 eq) in CHCl (20 mL), was added a solution of bromine (527 mg, 3.3 mmol, 3.3 eq) in CHCl (5 mL) over 10 min in the
3
3
dark at rt. After completion of the reaction (bromine completely consumed, 2 days), the resulting mixture was washed with a solution of
% aq NaHCO (3 × 20 mL) and dried over Na SO . After evaporation of the solvent, the crude material (253 mg) was passed through a
5
3
2
4
silica column eluting with AcOEt/hexane (1:3, 100 mL). The crude product was recrystalized in CHCl /hexane (1:3) to give 3,6-
3
l
dibromo-8-methoxyquinoline (10). White powder solid (242 mg, 77% yield): mp 134-136 °C; H NMR (400 MHz, CDCl ) δ 8.91 (d, J
3
24
1
3
=
1.6 Hz, 1H, H ), 8.21 (d, J = 2.0 Hz, 1H, H ), 7.51 (d, J = 1.6 Hz, 1H, H ), 7.16 (d, J = 1.2 Hz, 1H, H ), 4.10 (s, 3H, OCH ); C
2 42 4 57 5 75 7 3
-1
NMR (100 MHz, CDCl ) δ 156.1 (q), 150.4, 137.1 (q), 136.1, 130.9 (q), 121.9 (q), 120.7, 119.2 (q), 112.2, 56.5 (OCH ); IR (KBr, cm )
3
3
v 3047, 2925, 1727, 1592, 1558, 1482, 1371, 1346, 1255, 902, 858, 829, 788, 748; Anal. Calcd for C H Br NO: C, 37.89%; H, 2.23%;
10
7
2
N, 4.42%. Found: C, 36.90%; H, 2.32%; N, 4.48%.
4
.2. Synthesis of 3,5,6-tribromo-8-methoxyquinoline (11). The same procedure was applied in synthesis of 10 but 4.2 equivalents of
bromine (671 mg, 4.2 mmol) was used in CHCl (20 mL). The crude product was passed through a silica column eluting with
3
CHCl /hexane (1:3) to give 3,5,6-tribromo-8-methoxyquinoline (11) in 72% yield (282 mg) as yellow powder solid.
3
3
,5,6-Tribromo-8-methoxyquinoline (11) was synthesized by treating of 3,6-dibromo-8-methoxyquinoline (10) with 1 equivalent of
bromine for 1 day at rt. The reaction procedure is similar to the above process. This reaction afforded 3,5,6-tribromo-8-
l
methoxyquinoline (11). Yellow powder solid (282 mg, 76% yield): mp 164-166 °C; H NMR (400 MHz, CDCl ) δ 8.92 (d, J = 2.0 Hz,
3
24
13
1
1
1
3
H, H ), 8.75 (d, J = 2.0 Hz, 1H, H ), 7.31 (s, 1H, H ), 4.10 (s, 3H, OCH ); C NMR (100 MHz, CDCl ) δ 155.2 (q), 150.7, 138.0,
32.5 (q), 132.2 (q), 128.3 (q), 125.6 (q), 120.7 (q), 113.2, 56.6 (OCH ); IR (KBr, cm ) v 2960, 2925, 2852, 2360, 2337, 1731, 1641,
562, 1487, 1461, 1280, 1147, 1132, 1024, 943, 821, 765; Anal. Calcd for C H Br NO: C, 30.34%; H, 1.53%; N, 3.54%. Found: C,
2
42
4
7
3
3
-
1
3
10
6
3
0.40%; H, 1.49%; N, 3.77%.
4
.3. Synthesis of 3-bromo-6,8-dimethoxyquinoline (12). To a solution of 6,8-dimethoxy-1,2,3,4-tetrahydroquinoline (9, 193 mg, 1.0
mmol, 1 eq) in CHCl (15 mL), was added a solution of bromine (495 mg, 3.1 mmol, 3.1 eq) in CHCl (5 mL) over 5 min in the dark at
3
3

8
Tetrahedron
ACCEPTED MANUSCRIPT
rt. After completion of the reaction (bromine completely consumed, 3 days), the resulting mixture was washed with a solution of 5%
aq NaHCO (3 × 20 mL) and dried over Na SO . After evaporation of the solvent, the crude material (220 mg) was passed through a
3
2
4
silica column eluting with AcOEt/hexane (1:3, 100 mL). The crude product was recrystalized in CHCl /hexane (1:3) to give 3-bromo-
3
l
6
,8-dimethoxyquinoline (12). White powder solid (213 mg, 80% yield): mp 124-126 °C; H NMR (400 MHz, CDCl ) δ 8.65 (d, J = 2.0
3 24
Hz, 1H, H ), 8.51 (d, J = 2.0 Hz, 1H, H ), 7.02 (d, J = 1.8 Hz, 1H, H ), 6.56 (d, J = 1.8 Hz, 1H, H ), 4.00 (s, 3H OCH ), 3.94 (s, 3H,
2
42
4
57
5
75
7
3
13
OCH3); C NMR (100 MHz, CDCl ) δ 154.3 (q), 152.6 (q), 138.3, 134.2, 131.3 (q), 128.0 (q), 122.3, 100.6, 98.3 (q), 56.8, 54.4
OCH ); IR (KBr, cm ) v 3016, 2973, 2792, 1741, 1638, 1454, 1422, 1361, 1342 1361, 1297, 1238, 1110, 983, 912, 828, 689; Anal.
3
-
1
(
3
Calcd for C H BrNO : C, 49.28%; H, 3.76%; N, 5.22%. Found: C, 49.45%; H, 3.82%; N, 5.16%.
11
10
2
4
.4. Synthesis of 3,5-dibromo-6,8-dimethoxyquinoline (13). The same procedure was applied in synthesis of 12 but 4.2 equivalents of
bromine (671 mg, 4.2 mmol) in CHCl (20 mL) was used and the reaction was carried on a period of 5 days at rt. The crude product was
3
recrystalized in CHCl /hexane (1:3) to give 3,5-dibromo-6,8-dimethoxyquinoline (13) in 78% yield (269 mg) as white powder solid.
3
3
,5-Dibromo-6,8-dimethoxyquinoline (13) was synthesized by treating of 3-bromo-6,8-dimethoxyquinoline (12) with 1 equivalents
of bromine in CHCl (20 mL) for 2 day at rt. The reaction procedure is similar to the above precess. This reaction was afforded 3,5-
3
l
dibromo-6,8-dimethoxyquinoline (13) in 85% yield. White powder solid (269 mg, 85% yield): mp 133-135 °C; H NMR (400 MHz,
1
3
CDCl ) δ 8.78 (d, J = 2.0 Hz, 1H, H ), 8.68 (d, J = 2.0 Hz, 1H, H ), 6.89 (s, 1H, H ), 4.10 (s, 3H, OCH ), 4.14 (s, 3H, OCH ); C
3
24
2
42
4
7
3
3
NMR (100 MHz, CDCl ) δ 156.5 (q), 155.3 (q), 148.3, 135.8, 134.6 (q), 130.0 (q), 120.3 (q), 97.3, 97.1 (q), 57.1, 56.4 (OCH ); IR
3
3
-
1
(
KBr, cm ) v 2956, 2923, 2852, 1731, 1608, 1554, 1482, 1461, 1367, 1311, 1207, 1138, 1090, 993, 923, 808, 777; Anal. Calcd for
C H Br NO : C, 38.07%; H, 2.61%; N, 4.04%. Found: C, 37.40%; H, 2.42%; N, 4.09%.
11
9
2
2
15,27
4
.5. Synthesis of 3,6-dibromoquinoline (16). In the reported procedure,
3,6-dibromoquinoline was synthesized by Eisch bromination
of 6-bromoquinoline in yield of 82%.
4
.6. Synthesis of 3,6-dimethoxyquinoline (18). Freshly cut sodium (0.7 g, 30 mmol) was added to dry methanol (25 mL) under nitrogen
gas atmosphere. When dissolution was complete, the warm solution was diluted with dry dimethylformamid by addition of vacuum
dried cuprous iodide (1.0 g, 0.51 mmol). After dissolution, 3,6-dibromoquinoline (16) (450 mg, 1.05 mmol) into dry DMF (30 mL) was
added. The reaction mixture was stirred magnetically under a nitrogen gas atmosphere at reflux (ca 150 °C) for 6 h. The reaction’s
progress was monitored by TLC until the starting material was all consumed. After cooling to rt, H O (25 mL) and CHCl (50 mL) were
2
3
added to the reaction mixture. The organic layers were separated, washed with H O (2 × 20 mL), and dried over Na SO . The solvent
2
2
4
was removed and the crude product was passed through a short silica gel (3g) column eluting with AcOEt/hexane (1:3, 100 mL). After
filtration and purification, the resultant product was 3,6-dimethoxyquinoline (18). Pale yellow powder solid (156 mg, 78% yield): mp
1
8
7
4-86 °C: H NMR (400 MHz, CDCl ) δ 8.54 (d, J = 2.4 Hz, 1H, H ), 7.95 (d, J = 9.2 Hz, 1H, H ), 7.32 (d, J = 2.4 Hz, 1H, H ),
3
24
2
87
8
42
4
13
.22 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H, H ), 7.03 (d, J = 2.4 Hz, 1H, H ), 3.96 (s, 3H, OCH ), 3.94 (s, 3H, OCH ); C NMR (100
7
8
75
7
57
5
3
3
MHz, CDCl ) δ 158.4 (q), 153.7 (q), 141.7, 139.4 (q), 130.6, 130.1 (q), 119.0, 111.8, 104.8, 55.5 (OCH ), 55.4 (OCH ). All data were
3
3
3
22
identical to that reported in the literature.
4
.7. Synthesis of 5-bromo-6-methoxyquinoline (20). To a solution of 6-methoxyquinoline (17, 160 mg, 1.0 mmol, 1 eq) in CH Cl (15
2 2
mL) was added a solution of bromine (176 mg, 1.1 mmol, 1.1 eq) in CH Cl (15 mL) over 10 min in the dark at rt. After completion of
2
2
the reaction (bromine completely consumed, 2 days), the resulting mixture was washed with a solution of 5% aq NaHCO (3 × 20 mL)
3
and dried over Na SO . After evaporation of the solvent, the crude material (215 mg) was passed through a silica column eluting with
2
4
AcOEt/hexane (1:4, 150 mL). The crude product was recrystalized in CHCl /hexane (1:4) to give 5-bromo-6-methoxyquinoline (20).
3
1
Brown cubic crystal (208 mg, 88% yield): mp 79-81 °C; H NMR (400 MHz, CDCl ): δ 8.81 (d, J = 3.2 Hz, 1H, H ), 8.52 (d, J = 8.8
3
23
2
43
Hz, 1H, H ), 8.10 (d, J = 9.2 Hz, 1H, H ), 7.51 (d, J = 9.2 Hz, 1H, H ), 7.46 (dd, J = 4.0 Hz, J = 8.4 Hz, 1H, H ), 4.06 (s, 3H,
4
87
8
78
7
32
34
3
13
-1
OCH ); C NMR (100 MHz, CDCl ): δ 154.0, 148.8, 144.3, 134.5, 130.3, 128.6, 122.4, 116.5, 107.4, 57.1 (-OCH ); IR (KBr, cm ) v
3
3
3
2
5
925, 1612, 1587, 1552, 1496, 1321, 1261, 1064, 964, 897, 822, 806, 584; Anal. Calcd for C H BrNO: C, 50.45%; H, 3.39%; N,
10 8
.88%. Found: C, 50.40%; H, 3.32%; N, 5.98%.
.8. Synthesis of 5-bromo-6,8-dimethoxyquinoline (21). To a solution of 6,8-dimethoxyquinoline (19, 190 mg, 1.0 mmol, 1 eq) in CHCl3
4
(
15 mL) was added a solution of bromine (176 mg, 1.1 mmol, 1.1 eq) in CHCl (15 mL) over 10 min in the dark at rt. After completion
3
of the reaction (bromine completely consumed, 2 days), the resulting mixture was washed with a solution of 5% aq NaHCO (3 × 20
3
mL) and dried over Na SO . After evaporation of the solvent, the crude material (230 mg) was passed through a silica column eluting
2
4
with AcOEt/hexane (1:4, 150 mL). The crude product was recrystalized in CHCl /hexane (1:4) to give 5-bromo-6,8-
3
l
dimethoxyquinoline (21). Brown powder solid (221 mg, 83%yield): mp 58-59 °C; H NMR (400 MHz, CDCl ) δ 8.80 (d, J = 4.0 Hz,
3
23
1
H, H ), 8.49 (d, J = 8.4 Hz, 1H, H ), 7.48 (dd, J = 4.0 Hz, J = 8.4 Hz, 1H, H ), 6.86 (s, 1H, H ), 4.12 (s, 3H, OCH ), 4.05 (s, 3H,
2 43 4 32 34 3 7 3
13
OCH3); C NMR (100 MHz, CDCl ) δ 156.2 (q), 154.3 (q), 136.5 (q), 128.8 (q), 97.8 (q), 147.4, 134.4, 123.1, 97.0, 57.2 (OCH ), 56.2
3
3
-
1
(OCH ); IR (KBr, cm ) v 2931, 2848, 1722, 1610, 1587, 1500, 1471, 1365, 1247, 1213, 1124, 1084, 898, 809, 781; Anal. Calcd for
3
C H BrNO : C, 49.28%; H, 3.76%; N, 5.22%. Found: C, 49.25%; H, 3.74%, N, 5.15%.
11
10
2
4
.9. Synthesis of 2,5-dibromo-3,6-dimethoxyquinoline (24). To a solution of 3,6-dimethoxyquinoline (18) (190 mg, 1.0 mmol, 1 eq) in
CH Cl (15 mL), was added a solution of bromine (352 mg, 2.2 mmol, 2.2 eq) in CHCl (5 mL) over 10 min in the dark at rt. After
2
2
3
completion of the reaction (bromine completely consumed, 3 days), the resulting mixture was washed with a solution of 5% aq
NaHCO (3 × 25 mL) and dried over Na SO . After evaporation of the solvent, the crude material (280 mg) was passed through a silica
3
2
4
column eluting with AcOEt/hexane (1:3, 100 mL) The crude product was recrystalized in CHCl /hexane (1:4) to give 2,5-dibromo-3,6-
3
1
dimethoxyquinoline (24). White powder solid (269 mg, 78% yield): mp 138-140 °C; H NMR (400 MHz, CDCl ) δ 8.06 (d, J = 8.0
3
87
13
Hz, 1H, H ), 7.73 (s, 1H, H ), 7.35 (d, J = 8.0 Hz, 1H, H ), 4.07 (s, 3H, OCH ), 4.02 (s, 3H, OCH ); C NMR (100 MHz, CDCl ) δ
8
4
78
7
3
3
3
-
1
1
1
58.6 (q), 154.3 (q), 140.4 (q), 130.7, 130.2 (q), 129.0 (q), 125.6, 107.4, 99.8 (q), 55.7 (OCH ), 55.1 (OCH ); IR (KBr, cm ) v 2928,
3 3
618, 993; Anal. Calcd for C H Br NO : C, 38.07%; H, 2.61%; N, 4.04%. Found: C, 38.40%; H, 2.42%; N, 4.13%.
11
9
2
2

9
4
.10. Synthesis of 5-bromo-3,6-dimethoxyquinoline (25). The same procedure was applied in the synthesis of 24 but 1.1 equivalent of
ACCEPTED MANUSCRIPT
bromine (176 mg, 1.1 mmol) was used and the reaction was carried on a period of 2 days at rt. The crude product was recrystalized in
CHCl /hexane (1:4) to give 5-bromo-3,6-dimethoxyquinoline (25). White powder solid (219 mg, yield 82%): mp 117-119 °C; H NMR
1
3
(
1
400 MHz, CDCl ) δ 8.60 (d, J = 2.2 Hz, 1H, H ), 8.00 (d, J = 8.7 Hz, 1H, H ), 7.52 (d, J = 2.2 Hz, 1H, H ), 7.32 (dd, J = 8.7 Hz,
3
24
2
87
8
42
4
78
13
H, H ), 4.06 (s, 3H, OCH ), 3.96 (s, 3H, OCH ); C NMR (100 MHz, CDCl ) δ 158.2 (q), 153.9 (q), 140.6 (q), 139.4 (q), 130.6, 125.6
7 3 3 3
-1
(q), 122.4, 110.3, 104.8, 55.8 (OCH ), 55.2 (OCH ); IR (KBr, cm ) v 2965, 1603, 1023; Anal. Calcd for C H BrNO : C, 49.28%; H,
3
3
1
1
1
0
2
3
.76%; N, 5.22%. Found: C, 49.13%; H, 3.82%; N, 5.29%.
Acknowledgments
The study was supported by grants from the Scientific and Technological Research Council of Turkey (TUBITAK, Project number:
12T394).
1
References and notes
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