Efficient and selective synthesis of quinoline derivatives

Article abstract of DOI:10.1016/j.tet.2008.08.018

The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination

Full text of DOI:10.1016/j.tet.2008.08.018

Tetrahedron 64 (2008) 10068–10074
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient and selective synthesis of quinoline derivatives
,
a
a
b
Ayse Sahin a, Osman Cakmak a , Ibrahim Demirtas , Salih Okten , Ahmet Tutar
*
a Gaziosmanpasa University, Faculty of Art and Science, Department of Chemistry, TR-60240 Tokat, Turkey
b Sakarya University, Faculty of Art and Science, Department of Chemistry, TR-54187 Adapazarı, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2008
Received in revised form 18 July 2008
Accepted 7 August 2008
Available online 9 August 2008
The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular
bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-
dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination of 1,2,3,4-tetrahydroquinoline (7) in efficient
yields (75 and 90%, respectively). 6-Bromo- (4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (6) were
converted to 6-bromo- (1) and 6,8-dibromo quinolines (2), respectively, by aromatization with DDQ in 83
and 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared
via lithium–halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi
followed by quenching with electrophiles [Si(CH3)3Cl, S2(CH3)2, I2] regioselectively proceeded at C-4 and
C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation of tri-
bromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield.
Copper-induced nucleophilic substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxy-
quinoline (17) in 60% yield.
Keywords:
Bromination
Lithiation
1,2,3,4-Tetrahydroquinoline
4,6,8-Tribromoquinoline
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
previously may have been due to inadequate separation and
identification methods.
The presence of the quinoline skeleton in the frameworks of
pharmacologically active compounds and natural products has
spurred on the development of different strategies for their
synthesis. Quinoline derivatives have long been known for their
wide range of biological activities1 and chemotherapeutic
activities.2 In addition, they are used as dyestuffs and photographic
sensitizers.3 They are valuable reagents for the synthesis of nano-
and mesostructures with enhanced electronic and photonic
properties.4
Bromoquinolines have been of interest for chemists as
precursors for heterocyclic compounds with multifunctionality,
giving accessibility to a wide variety of compounds through, e.g.,
couplings and Grignard reactions. These building blocks have
especially been used within medicinal chemistry as starting ma-
terials for numerous compounds with pharmacological activity.
Ring substitution of quinoline by halogens is rather complex,
with products depending on the conditions used. Earlier works
indicate that direct bromination of quinoline is difficult because
quinoline is electron-deficient in nature and because of the easy
formation of N-bromo complexes.5 The conflicting results obtained
3-Bromoquinoline is conveniently prepared in 82% yield by
heating the quinoline–bromine adduct in an inert solvent with
pyridine as the hydrogen bromide scavenger.5 The treatment of
quinoline in concentrated sulfuric acid containing silver sulfate with
one mole of bromine results in a mixture of 5- and 8-bromoquino-
line in about equal quantities and some 5,8-dibromoquinoline.6
5-Bromoquinoline is formed in 78% yield if the quinoline–aluminum
chloride complex is heated with bromine.7 Further bromination
in sulfuric acid or in the presence of aluminum chloride yields 5,8-
dibromo-, 5,6,8-tribromo-, and 5,7,8-tribromoquinolines.7
Several different strategies for the preparation of substituted
quinolines are known. Most synthetic routes leading to these cy-
clic structures consist of cyclization reactions starting from ben-
zene (or cyclohexane) derivatives substituted with nitrogen
functions.8 Such reactions include the Skraup, Friedlander, Doeb-
ner-von Millet, and Combes syntheses.9 Although different
methods are described in the literature for the synthesis of the
quinoline ring, these methods allow restricted synthesis of quin-
oline derivatives, especially in the case of di- and trisubstituted
derivatives.
Recently we developed simple and selective bromination
methods on naphthalene, hydronaphthalenes, and anthracene.10 As
an extension of these works we are interested in the bromination of
azanaphthalenes, i.e., quinoline and isoquinoline. In this report,
one-pot synthesis of 4,6,8-tribromoquinoline (3) by direct
* Corresponding author. Tel.: þ90 (0) 356 2521616x3010; fax: þ90 (0) 356
2521585.
E-mail addresses: ocakmak@gop.edu.tr, cakmak.osman@gmail.com (O. Cakmak).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.018

A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
10069
Table 1
bromination of 1,2,3,4-tetrahydroquinoline (THQ, 7) is presented
1H NMR data of compounds 4–6
and the values of brominated products 3 as precursors to the
corresponding substituted quinoline derivatives are illustrated.
We describe selective and convenient synthesis methods for
6-bromo- (6-BrQ, 1), 6,8-dibromoquinoline (6,8-diBrQ, 2), 6-
bromo-(6-BrTHQ, 4), and 4,6-dibromo-1,2,3,4-tetrahydroquinoline
(6,8-diBrTHQ, 6) (Scheme 1).
Compounds Proton
Coupling
constants
(Hz)
1
2
3
4
5
6
7
8
4
5
3.80 s 3.40 t 1.91 p 2.71 t 7.10 s
d
6.32 d 7.05 d J78¼8.3
J32¼5.8
3.60 s 3.40 t 1.92 p 2.75 d 7.17 d 6.40 t 6.96 d
d
J56¼7.8
J67¼7.8
J32¼5.8
J43¼6.3
J57¼1.6
J32¼5.8
J43¼6.3
Br
Br
Br
Br
Br
6
4.43 s 3.34 t 1.92 p 2.73 t 7.31 d
d
6.96 d
d
N
N
N
Br
Br
Br
Br
1
2
3
Br
evidence for the 6-bromo structure. H7 and H8 resonate as an AB
system (
d
6.32 and 7.05, J78¼8.3 Hz). Nine 13C NMR resonance sig-
N
N
N
nals of the compound are accord with the suggested structure. 1H
NMR spectra of 6,8-diBrTHQ clearly show a 6,8-dibromo structure
due to two aryl signals with a meta coupling constant (Table 1).
H
6
H
H
4
5
Scheme 1.
Three aliphatic and NH shifts [d 3.34 (t), 2.73 (t), 1.92 (p), 4.43 (br s,
NH)] are in accord with the expected product. In the 13C NMR
spectra, the four quaternary carbon resonances in the sp2 region are
also in agreement with the suggested structure.
Obviously, 6,8-diBrTHQ 6 and 6-BrTHQ 4 are precursors for 6,8-
diBrQ 2 and 6-BrQ 1, respectively. Therefore, they were submitted
to aromatization with DDQ. After reactions, 6,8-diBrQ and 6-BrQ
were obtained in high yields (83 and 77%, respectively). In the 1H
NMR spectra of 6,8-diBrQ, shifting downfield resonance of H2
(9.04 ppm, dd) is characteristic for quinoline rings. The doublet of
2. Results and discussion
The reaction of THQ 7 with 1 equiv of NBS was examined in CCl4
under reflux. After the reaction, 1H NMR spectra of the mixture
products indicated 6-BrTHQ 4, 8-BrTHQ 5, 6,8-diBrTHQ 6, 4,6,8-
TriBrQ 3, and the starting material (THQ, 7) in
a ratio of
31:8:36:5:20. After silica gel chromatography combined with pre-
parative TLC, the compounds were isolated in yields of 22% for 4, 8%
for 5, 16% for 6, and 2% for 3.
doublets (J23¼4.2 Hz, J34¼8.3 Hz) of H3 and H4 appears at
d 7.49 and
We studied the same reaction under photolytic conditions. For
irradiation, a projector lamp (250 W, visible light) in an immersion
photochemical apparatus was used. A new product 6,8-diBrQ 2
appeared and the product ratio was changed. Photobromination of
THQ 7 with 2 and 3 equiv of NBS also resulted in the formation of a
complex mixture. With molecular bromine, the bromination of
THQ 7 is more selective and effective. Bromination of THQ with
1 equiv of bromine afforded a mixture of 6-BrTHQ 4 and 6,8-
diBrTHQ 6 (product ratio: 25:50 for 4 and 6, conv. 75%) at room
temperature. However, the product ratio changed at lower tem-
perature and the conversion increased. When the bromination was
repeated at ꢀ23 ꢁC using 1.5 equiv of Br2, 6-BrQ 4 and 6,8-diBTHQ 6
were obtained in 50:50 ratio as assigned by NMR spectra. The
product mixture was efficiently and easily separated by short silica
gel column chromatography eluting with hexane–ethylacetate
(Scheme 2). On the other hand, 6,8-diBrTHQ 6 was obtained as the
sole product in efficient yield (90%) upon treatment of THQ with
2 equiv of bromine (Scheme 2).
8.09. Two signals with meta coupling are also in good agreement
with the structure (
d
8.16 and 7.96, J57¼2.4 Hz). The 13C NMR
spectra of dibromide consist of nine sp2 resonances, four of which
are quaternary carbons. In the NMR spectra of 6-BrQ 1, two AB
systems (H3 and H4) and (H7 and H8) are consistent with the sug-
gested structure. A singlet of H5 appears at
d 8.00 and a doublet of
H2 at
d
8.90 (J23¼2.6 Hz) (Table 2). The 13C NMR spectra are con-
sistent with a monobromoquinoline structure. 6-BrQ 1 is prepared
Table 2
1H NMR data of compounds 1–3 and 13–17
Compounds Proton
2
Coupling constants
(Hz)/other signals
3
4
5
7
8
1
8.90 d 7.44 dd 8.10 d 7.90 s 7.80 dd 8.00 d J34¼8.3
J23¼2.6
J78¼9.2
J57¼2.2
1H NMR spectra of 6-BrTHQ 4 consist of aryl Hs, alkyl Hs, and NH
signals (Table 1). Resonance of H5 is a singlet at
2
9.04 dd 7.49 dd 8.09 dd 7.96 d 8.16 d
d
J23¼4.2
J24¼1.6
d
7.10, which is clear
J57¼2.4
J34¼8.3
J57¼2.2
J23¼2.2
J23¼1.5, J57¼2.1
Silyl
3
8.99 d 8.20 d
8.99 d 8.14 d
d
d
8.14 d 7.86 d
7.96 d 7.86 d
d
d
Br
Br
+
Br2 (1.5 equiv)
CHCl3, -20 °C
13
N
H
N
H
N
H
Br
d 0.39 s, 0.45 s
7
6, 35%
4, 45%
14
8.76 d 8.20 d
9.05 d 8.40 d
d
d
7.60 d 7.79 d
8.35 d 7.80 d
d
J23¼3.0, J57¼2.0
Br2 (2 equiv)
SCH3
DDQ
d
3.07, 3.05
CHCl3, -20 °C
Benzene, rt
15
16
d
d
J57¼2.7
J23¼2.0
J57¼2.6
J23¼4.2
J34¼8.3
J24¼1.6
Br
Br
9.00 dd 7.42 dd 8.00 dd 7.95d 8.40 d
Br
DDQ
Benzene, rt
N
H
N
N
Br
Br
17
8.40 d 7.18 d
d
6.40 d 6.50 d
d
J23¼2.7, J57¼2.4
1, 77%
2, 83%
Scheme 2.
6, 90%
OMe
d
3.87 s, 3.89 s, 3.97 s

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A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
by the Skraup synthesis starting from the p-bromoaniline.5,11 In-
corporation of 6-BrQ 1 into novel chelating ligands is important for
the construction of useful molecular devices in field of nanoscale
chemistry.12
The two silyl signals in compound 13 and two dimethylthio
signals in compound 14 in the NMR spectra are clear evidence of
the formation of the compounds. Treatment of dilithio (6) with
iodine gave two iodo derivatives (15 and 16) after chromatography.
The similarity of the signal systems of compounds 3 and 15 (the
same is true for compounds 2 and 16) is quite helpful for identifi-
cation of the structures of iodines 15 and 16.
Lastly, tribromide 3 was treated with MeONa in the presence of
CuI in DMF at ca. 100 ꢁC according to the literature method (Scheme
4).14 Copper-induced substitution of tribromide 3 resulted in the
formation of 4,6,8-trimethoxyquinoline (17) as the sole product (ca.
60%). Trimethoxide 17 exhibits a similar 1H NMR spectrum to that
of the tribromide 3, with the lower shifting due to donor methoxy
protons (Table 1).
Finally, photobromination of THQ 7 with 5 equiv of NBS in CCl4
at reflux temperature of the solvent was carried out. For irradia-
tion, a projector lamp (70 W, visible light) in an immersion pho-
tochemical apparatus was used. Interestingly, the reaction
produced 4,6,8-tribromoquinoline (3) in the absence of other
products. After the reaction, tribromide 3 was obtained as a sole
product in a yield of 50%. When the NBS bromination was carried
out at room temperature in CHCl3, surprisingly, the yield increased
to 75% and the reaction period was shorter.
The structure of 3 was determined by 1H and 13C NMR spec-
troscopy, including 2D NMR experiments (COSY, HETCOR) and high
resolution mass spectrometry. The formula of compound
3
3. Conclusion
(C9H4NBr3) was determined by HR-ESIMS (362.790454, calculated
by mass spectrometry 362.789382). The 1H NMR spectrum of tri-
We demonstrated that 1,2,3,4-tetrahydroquinoline (7) is quite
reactive toward bromination. Therefore, the difficulty in the bro-
mination of quinoline due to the formation of N-bromo complexes
or its electron-deficient nature is not a problem in case of THQ 7.
We opened up a new route to quinoline derivatives using com-
mercially available and cheap starting material THQ 7, which is
obtained by the simple reduction of quinoline. Convenient and
selective reaction procedures are described for 6-BrQ 1, 6,8-diBrQ 2,
4,6,8-triBrQ 3, 6-BrTHQ 4, and 6,8-diBrTHQ 6, which can be con-
verted to corresponding substituted quinolines and tetrahy-
droquinolines, which are otherwise difficult to obtain. In summary,
the lithium–halogen exchange reaction of 4,6,8-triBrQ 3 provides
a method for synthesizing 4,8-disubstituted-6-bromoquinolines.
The lithium–halogen exchange reaction of 4,6,8-triBrQ 3, 6,8-diBrQ
2, 6-BrTHQ 4, and 6,8-diBrTHQ 6 may serve for the synthesis of
natural bioactive quinolines derivatives because there are many
biological active quinolines functionalized 4,6, or 8- positions such
as quinine, pentaquine, and plasmoquine.
bromide 3 consists of four signals (Table 1). H2 appears at
d 8.99
with a lower coupling constant value (J23¼2.2 Hz), which is char-
acteristic for a quinoline ring. Meta coupling doublet of H7 and H5 is
clear evidence for the position of bromines. The 13C NMR studies of
compound 3 displayed nine resonances; five signals of these are
quaternary in accord with the molecule skeleton being bonded to
three bromine atoms.
We assume that the one-pot reaction giving tribromide 3 ac-
tually consists of five sequential reaction steps. Aniline-like reso-
nances of tetrahydroquinoline led to substitution at the C-6 and C-8
sites of the aryl ring. We also assume that the reaction probably
proceeds through the pentabromide 8 and subsequent aromatiza-
tion results in the formation of tribromide 3.
We revealed that double bromination occurs at benzylic sites of
tetraline (9) (Scheme 3).10f Therefore, we assume that THQ 7 reacts
at C-4 and C-3 positions of higher reactivity (Scheme 3).
4. Experimental
4.1. General
Br
Br
Br
Br
Br
NBS/hv
CHCl3
N
H
N
H
Br
N
Br
Thin layer chromatography was carried out on Merck silica F254
0.255 mm plates and spots were visualized by UV fluorescence at
254 nm. Classic column chromatography was performed using
Merck 60 (70–230 mesh) silica gel. Melting points were determined
on a Thomas-Hoover capillary melting points apparatus. Solvents
were concentrated at reduced pressure. IR spectra were recorded
on a Perkin–Elmer 980 instrument. Mass spectra were recorded on
a VG Zab Spec GC–MS spectrometer under electron-impact (EI) and
chemical ionization conditions. NMR spectra were recorded on
Bruker 400 MHz for 1H and at 100 MHz for 13C NMR.
Br
7
8
3, 75%
Br
Br
Br
t-BuOK/THF
Br2/hv
Br
Br
10, 92%
Br
11, 95%
9
Scheme 3.
The lithium–halogen exchange reaction is the method of choice
for the preparation of new heteroaromatic compounds.13 Therefore,
to demonstrate its value as a precursor for other useful compounds,
tribromoquinoline 3 was investigated by metal–halogen exchange
using BuLi, followed by the addition of electrophiles for the prep-
aration of new derivatives.
Treatment of tribromide with 2 equiv of BuLi and subsequent
addition of water resulted in 6-bromoquinoline (1) as the sole
product in a yield of 65%. To determine if this reaction was general
for other electrophiles, a study was carried out and the results are
shown in Scheme 4. After lithiation, treatment of dilithioquinoline
(12) with trimethylsilyl chloride gave 6-bromo-4,8-trimethylsi-
lylquinoline (13), while treatment with 1,2-dimethyldisulfane
afforded 6-bromo-4,8-bis(methylthio) quinoline (14) in high yields
(90%) and as sole product.
4.2. Bromination of 1,2,3,4-tetrahydroquinoline (7) with
1 equiv of NBS
To a solution of 1,2,3,4-tetrahydroquinoline (1.0 g, 7.5 mmol) in
CCl4 (20 mL) were added AIBN (18 mg, 0.10 mmol) as catalyst and
NBS (1.33 g, 7.5 mmol). Drying tube containing pellet KOH for
absorbing the evolved hydrogen bromide was attached to the
condenser. The magnetically stirred mixture was irradiated for 5 h
under reflux (77 ꢁC). Reaction progress was monitored with TLC.
After the reaction was complete, the precipitated succinimide
particles were removed by filtration and washed with CCl4 at 0 ꢁC.
The solvent was removed by vacuum and the residue was redis-
solved in CHCl3 (30 mL). After removing the solvent, the residue
(1.18 g) was subjected to silica gel (85 g) column chromatography
combined with preparative thin layer chromatography eluting with

A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
10071
OCH3
N
Br
H3CO
Br
NaOCH3
Br
CuI, DMF
N
N
OCH3
Br
3
1, 65%
17, 60%
H2O
n-BuLi/THF (2 eq)
Si(CH3)3
SCH3
Li
Br
Br
Br
SiMe3Cl
(CH3)2S2
N
N
SCH3
N
Si(CH3)3
Li
12
14, 85%
13, 85%
I2
I
Br
Br
+
N
N
I
I
16, 50%
15, 10%
Scheme 4.
EtOAc/hexane (1:20). 8-BrTHQ 5 (110 mg, 7%), 6-BrTHQ 4 (240 mg,
15%), 6,8-diBrTHQ 6 (240 mg, 11%), and 4,6,8-triBrTHQ 3 (50 mg,
2%) were isolated. Rf values (EtAcO–hexane, 1:9) for compounds 4,
5, 7, 6, and 3 are 0.33, 0.34, 0.40, 0.60, and 0.70, respectively. Be-
cause pure 8-BrTHQ 5 could not be obtained due to the very similar
Rf values of the compounds, the 13C NMR and IR spectrometer
values of 5 are not available.
apparatus (cylindrical immersion-well reaction apparatus, 80 mL)
were added AIBN (18 mg, 0.10 mmol) and NBS (1.34 g, 7.5 mmol).
Drying tube containing pellet KOH for absorbing the evolved hy-
drogen bromide was attached to the side arms of the apparatus.
Stirring was performed with simultaneous irradiation with a pro-
jector lamp (70 W projector lamp) under reflux. Upon completion
of the reaction (1 h), the resulting succinimide was collected on
a filter and the filtrate concentrated under vacuum. The crude
product was dissolved in chloroform (30 mL), washed with water
(7ꢂ20 mL), and dried over sodium sulfate. The solvent was re-
moved in vacuo. The mixture consisted of 6,8-diBrTHQ 6, 6-BrTHQ
4, 4,6,8-TriBrQ 3, and 6,8-diBrQ 2 in a ratio of 55:30:10:5 as
assigned by 1H NMR.
4.2.1. 6-BrTHQ 4
Pale yellow oil; 1H NMR (300 MHz, CDCl3)
d 7.10 (s, 1H, H5), 7.05
(d, J87¼8.6 Hz, 1H, H8), 6.32 (d, J78¼8.3 Hz, 1H, H7), 3.40 (t,
J23¼5.8 Hz, 2H, H2), 2.71 (t, J43¼6.3 Hz, 2H, H4), 1.91 (p, J32¼5.8 Hz,
2H, H3), 3.8 (s, 1H, NH); 13C NMR (75 MHz, CDCl3)
d
144.0, 132.1,
nmax 3450,
129.8, 123.6, 115.8, 108.4, 42.2, 27.1, 21.9; IR (neat, cmꢀ1
)
3047, 1589, 1540, 1457, 1305, 1083, 968, 904, 871, 856, 815, 781, 680,
595. Anal. Calcd for C9H10NBr (212.09): C, 50.97; H, 4.75. Found: C,
51.07; H, 4.80.
4.4. Synthesis of 4,6,8-tribromoquinoline (3)
Method A. A solution of 1,2,3,4-tetrahydroquinoline (1.0 g,
7.5 mmol) in CCl4 (20 mL) in an internal type photochemical re-
action apparatus (cylindrical immersion-well reaction apparatus,
80 mL) were added NBS (1.1 equiv, 1.52 g, 8.5 mmol) and AIBN
(18 mg, 0.10 mmol) as catalyst. The drying tube containing pellet
KOH for absorbing the evolved hydrogen bromide was attached to
the side arms of the apparatus. The magnetically stirred mixture
was irradiated with a sun lamp (70 W projector lamp, cooled by air
pump). First, 1 equiv of NBS (1.52 g, 8.5 mmol, 1.1 equiv) was added
to the solution. In total 5.5 equiv of NBS (7.6 g, 42.5 mmol) was
added over 6 h, adding 1 equiv per hour. The reaction mixture was
irradiated for 6 h under reflux. Turbidity was observed due to the
precipitated material (i.e., succinimide). Upon completion of the
reaction (TLC monitoring), the resulting reaction mixture was
cooled (0 ꢁC) and the succinimide formed was collected on a filter
and the solvent (CCl4) was removed from the filtrate under vacuum.
The precipitated residue was dissolved in chloroform (30 mL) and
washed with water (7ꢂ20 mL). The organic layer was dried over
Na2SO4. After removing the solvent and recrystallizing from
CH2Cl2–hexane (2:1, 15 mL) in a refrigerator, 4,6,8-tribromoquino-
line (3) was obtained (1.34 g, 50%) as white solid cubic crystals, mp
4.2.2. 8-BrTHQ 5
Pale yellow oil; 1H NMR (300 MHz, CDCl3)
d
7.17 (d, J56¼7.8 Hz,
1H, H5), 6.96 (d, J76¼7.8 Hz, 1H, H7), 6.40 (t, J65¼J67¼7.8 Hz, 1H, H6),
3.40 (t, J23¼5.8 Hz, 2H, H2), 2.75 (t, J43¼6.3 Hz, 2H, H4), 1.92 (p,
J32¼5.8 Hz, 2H, H3), 3.60 (s, 1H, NH).
4.2.3. 6,8-DiBrTHQ 6
Pale yellow oil; 1H NMR (400 MHz, CDCl3)
d
7.31 (d, J57¼1.6 Hz,
1H, H5), 6.96 (d, J75¼1.6 Hz, 1H, H7), 3.34 (t, J23¼5.8 Hz, 2H, H2), 2.73
(t, J43¼6.3 Hz, 2H, H4), 1.92 (p, J32¼5.8 Hz, 2H, H3), 4.43 (s, 1H, NH);
13C NMR (CDCl3, 100 MHz)
d 141.0, 132.0, 131.1, 124.4, 108.8, 107.2,
42.1, 27.5, 21.5; IR (neat, cmꢀ1
) nmax 3416, 2927, 2837, 1592, 1497,
1466, 1291, 1164, 856, 616. Anal. Calcd for C9H9NBr2 (290.98): C,
37.15; H, 3.12. Found: C, 37.20; H, 3.16.
4.3. Photobromination of 1,2,3,4-tetrahydroquinoline with
1 equiv of NBS
To a solution of 1,2,3,4-tetrahydroquinoline (7) (1.0 g, 7.5 mmol)
in CCl4 (20 mL) in an internal type photochemical reaction
168–170 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.99 (d, J23¼2.2 Hz,1H, H2),

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A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
8.14 (d, J57¼2.2 Hz, H5), 7.86 (d, J75¼2.2 Hz, 1H, H7), 8.20 (d,
4.7. Synthesis of 6,8-dibromoquinoline (2)
J32¼2.2 Hz, 1H, H3); 13C NMR (75 MHz, CDCl3)
d 152.7, 142.7, 136.7,
136.6, 131.0, 128.9, 126.0, 121.6, 119.7; MS (EI) m/z 365, 363, 286,
DDQ (2 g, 6.35 mmol) was dissolved in freshly distilled and
dried benzene (30 mL) under an argon atmosphere. To a solution of
6,8-diBrTHQ 6 (0.88 g, 3.02 mmol) in benzene (30 mL) was added
the solution of DDQ. The mixture was refluxed at 80 ꢁC for 44 h.
Upon cooling, the dark green solidified mixture was filtered and the
solvent was removed in vacuo. The residue was filtered from a short
silica column (1:9, EtOAc–hexane, Rf¼0.65). Recrystallization of the
product from hexane–chloroform gave 6,8-diBrQ 2 in a yield of 83%
(725 mg), white needle crystals, mp 99–100 ꢁC. 1H NMR (CDCl3,
205, 126; HRMS (EI) calcd for C9H4NBr3 (Mþ): 362.7893, found:
362.7904; IR (KBr, cmꢀ1
) nmax 3160, 2545, 2329, 1693, 1373, 1294,
1193, 1002, 935, 819, 640, 555, 424.
Method B. To a solution of 1,2,3,4-tetrahydroquinoline (7) (1.0 g,
7.5 mmol) in CHCl3 (80 mL) in an internal type photochemical re-
action apparatus (cylindrical immersion-well reaction apparatus)
were added NBS (6.8 g, 8.5 mmol) and AIBN (120 mg, 0.10 mmol) as
catalyst. The magnetically stirred mixture was irradiated with a sun
lamp (70 W projector lamp). No turbidity was observed and pre-
cipitated material (i.e., succinime particles) was collected in the
bottom of the flask. Upon completion of the reaction (TLC moni-
toring), the resulting reaction mixture was cooled (0 ꢁC) and
the succinimide particles formed were collected on a filter and the
filtrate was washed with water (30 mLꢂ7). After removing the
solvent the residue was filtered through silica gel (10 g, eluted with
hexane–EtOAc) and recrystallized from CH2Cl2–hexane (5:1, 30 mL)
and 4,6,8-tribromoquinoline (3) was obtained in 75% yield (2.7 g).
400 MHz)
d
9.04 (dd, J23¼4.2 Hz, J24¼1.6 Hz, 1H, H2), 8.16 (d,
J57¼2.4 Hz, 1H, H7), 8.09 (dd, J43¼8.3 Hz, J24¼1.6 Hz, 1H, H4), 7.96 (d,
J57¼2.4 Hz, 1H, H5), 7.49 (dd, J32¼4.2 Hz, J34¼8.3 Hz, 1H, H3); 13C
NMR (100 MHz, CDCl3) d 151.5, 144.1135.9, 135.7, 130.1, 129.7, 125.9,
122.7, 119.9; IR (KBr, cmꢀ1
) nmax 3414, 3069, 3028, 2924, 1955, 1923,
1638, 1617, 1588, 1547, 1481, 1469, 1348, 1308, 1290, 1084, 964, 861,
780, 676, 594. Anal. Calcd for C9H5NBr2 (286.95): C, 37.67; H, 1.76.
Found: C, 37.78; H, 1.82.
4.8. Synthesis of 6-bromoquinoline (1)
4.5. Bromination of THQ 7 with molecular bromine
DDQ (504 mg, 1.68 mmol) was dissolved in dry benzene (20 mL)
under argon atmosphere. To a solution of 6,8-diBrTHQ 6 (180 mg,
0.84 mmol) in dry benzene (20 mL) was added the solution of DDQ.
The mixture was refluxed at 80 ꢁC for two days. The dark green
solidified mixture was filtered and the solvent was removed in
vacuo. The residue was filtered from a short silica column (1:9,
EtOAc–hexane). Recrystallization of the product from hexane–
chloroform gave 6-diBrQ 1 in a yield of 77% (145 mg), brownish oil.
To
a
solution of 1,2,3,4-tetrahydroquinoline (7) (0.5 g,
3.75 mmol) in CHCl3 (15 mL) was added a solution of bromine
(0.66 g, 4.13 mmol) in CHCl3 (5 mL) over 5 min. The mixture was
stirred at room temperature for 2 h in the dark. After completion of
the reaction (bromine consumed completely), the resulting yellow
solid was dissolved in CHCl3 (15 mL). The organic layer was washed
with 5% NaHCO3 solution (3ꢂ15 mL) and dried over Na2SO4. After
evaporation of the solvent, NMR analysis of the residue (0.96 g)
showed the formation of 6,8-diBrTHQ 6 and 6-BrTHQ 4. The re-
action conversion was 75%. When the reaction was repeated at
ꢀ78 ꢁC under the same reaction conditions, the conversion was 90%
and the product ratio was 20:70 for 6,8-diBrTHQ 6 and 6-BrTHQ 4,
respectively, as assigned by 1H NMR.
Bromination of THQ 7 was repeated with 1.5 equiv of bromine at
ꢀ20 ꢁC in the dark. The starting material (THQ, 0.27 g, 2.02 mmol)
in CHCl3 (20 mL) was combined with solution of bromine (0.486 g,
3.04 mmol) in CHCl3 (5 mL). After completion of the reaction
(25 min), the resulting yellow solid was dissolved in CHCl3 (20 mL).
The organic layer was washed with NaHCO3 solution (5%, 3ꢂ20 mL)
and dried over Na2SO4. Mixture of 6,8-diBrTHQ 6 and 6-BrTHQ 4
was formed in ratio of 1:1 as assigned by 1H NMR. The product
mixture (450 mg) was applied to a short silica gel (20 g) chroma-
tography column eluting with hexane–EtOAc (600 mL, 4:2) (Rf¼0.5
for 6 and 0.25 for 4). 6,8-DiBrTHQ 6 was collected as first eluant
(350 mL). Solvent polarity was increased to 9:4 (hexane–EA) ratio.
6,8-DiTHQ 6 (206 mg, 35%) and 6-BrTHQ 4 (193 mg, 45%) were
isolated in pure forms.
1H NMR (400 MHz)
d
8.90 (d, J23¼2.6 Hz, 1H, H2), 8.10 (d,
J34¼8.3 Hz, 1H, H4), 8.00 (d, J87¼9.2 Hz, 1H, H8), 7.90 (d, J57¼2.2 Hz,
1H, H5), 7.80 (dd, J78¼9.2 Hz, J75¼2.2 Hz, 1H, H7); 13C NMR
(100 MHz)
d 150.7, 146.8, 135.1, 133.0, 131.2, 129.8, 129.5, 121.9,
120.5; IR (KBr, cmꢀ1
)
nmax 3450, 1635, 1589, 1540, 1457, 1305, 1083,
968, 904, 871, 856, 815, 781, 680, 595, 526 cmꢀ1. CAS Number:
005332-25-2.
4.8.1. 6-Bromoquinoline (1)
n-Butyllithium (4 mL, 1.6 M, 6.03 mmol, 2.2 equiv) was added to
a vacuum-dried flask containing tribromide 3 (1 g, 2.74 mmol) in
THF (20 mL) at ꢀ78 ꢁC. After the mixture was stirred for 90 min,
distilled water (3.0 mL) was added at ꢀ78 ꢁC. The mixture was
stirred at ꢀ78 ꢁC for 30 min and then at room temperature for 1 h.
After quenching the mixture with water (30 mL), the aqueous layer
was extracted with diethyl ether (3ꢂ20 mL), and the combined
organic layers were sequentially washed with water (2ꢂ20 mL) and
dried over sodium sulfate. After removing the solvent with evap-
oration the crude product was purified by short column chroma-
tography (9:1, hexane-EtOAc, Rf¼0.92), and after recrystallization
from EtOAc–hexane (2:1) 6-bromoquinoline (1) was obtained in
a yield of 65% (370 mg).
4.6. Synthesis of 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6)
Note. When the lithiation of tribromide 3 and subsequent water
addition reaction was carried out using 1 equiv of n-BuLi instead of
2 equiv of n-BuLi, a complex reaction mixture was obtained. 1H
NMR analysis of the mixture revealed 4,6-dibromoquinoline as the
main product along with 6-BrQ 1, 6,8-diBrQ 2, and small amounts of
some other unidentified products. The attempts to separate the
mixture did not lead to any pure compounds.
To a solution of 1,2,3,4-tetrahydroquinoline (1 g, 7.5 mmol) in
CHCl3 (20 mL) was dropped bromine (2.56 g, 16 mmol) in CHCl3
(10 mL) over 5 min in the dark and at ꢀ20 ꢁC. After completion of
the reaction (bromine consumed completely, 2 h), the solid was
dissolved in CHCl3 (25 mL) and the organic layer was washed with
5% NaHCO3 solution (3ꢂ20 mL) and dried over Na2SO4. After
evaporation of the solvent, the crude material (2.12 g) was passed
through a short alumina column eluting with EtOAc–hexane (1:19,
250 mL) (hexane–EA, 9:1, Rf¼0.6). The pale yellow oil residue at
room temperature was solidified in a freezer (ꢀ20 ꢁC). The mixture
was recrystallized from the solvent (CH2Cl2–petroleum ether) in
4.9. 6-Bromo-4,8-bismethlysilylquinoline (13)
n-Butyllithium (4 mL, 1.6 M, 6.03 mmol, 2.2 equiv) was added to
a vacuum-dried flask containing tribromide 3 (1 g, 2.74 mmol) in
THF (20 mL) at ꢀ78 ꢁC. After the mixture was stirred for 90 min,
chlorotrimethylsilane (4.0 mL, 3.42 mmol) was added at ꢀ78 ꢁC.
a
freezer (ꢀ20 ꢁC) to give pure 6,8-dibromo-1,2,3,4-tetrahy-
droquinoline (6) in 90% yield (1.97 g).

A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
10073
The mixture was stirred at ꢀ78 ꢁC for 30 min and then at room
4.11.2. Compound 16
temperature for 1 h. After quenching the mixture with water
(30 mL), the aqueous layer was extracted with diethyl ether
(3ꢂ25 mL), and the combined organic layers were washed se-
quentially with water (2ꢂ25 mL) and dried over sodium sulfate.
The solvent was removed by rotary evaporation and the crude
product was purified by short silica gel column chromatography
(CH2Cl2–hexane, 1:4, Rf¼0.90) to give 13 (860 mg, 90%) as a yellow
Yellow needle; 1H NMR (400 MHz, CDCl3)
d
9.00 (dd, J23¼4.2 Hz,
J42¼1.6 Hz, 1H, H2), 8.40 (d, J57¼2.6 Hz,1H, H7), 8.00 (dd, J43¼8.3 Hz,
J42¼1.6 Hz, 1H, H4), 7.95 (d, J32¼2.6 Hz, 1H, H5), 7.42 (dd, J34¼8.3 Hz,
J23¼4.2 Hz, 1H, H3); 13C NMR (100 MHz, CDCl3)
d
151.5, 144.1, 135.9,
nmax 3037, 2921,
135.7, 130.1,129.7, 125.9, 122.7, 119.9; IR (KBr, cmꢀ1
)
2852, 1716, 1569, 1533, 1454, 1301, 1234, 1174, 1074, 959, 937, 906,
584. Anal. Calcd for C9H5BrIN (333.95): C, 32.37; H, 1.51. Found: C,
32.40; H, 1.38.
oil. 1H NMR (400 MHz, CDCl3)
d
8.99 (d, J23¼1.5 Hz, 1H, H1,), 8.14 (d,
J32¼1.5 Hz, 1H, H3), 7.96 (d, J57¼2.1 Hz, 1H, H5,), 7.86 (d, J75¼2.1 Hz,
1H, H7), 0.45 (s, 3H), 0.39 (s, 3H); 13C NMR (400 MHz, CDCl3)
4.12. Synthesis of 4,6,8-trimethoxyquinoline (17)
d
154.0, 152.2, 146.0, 142.4, 140.0, 134.4, 132.0, 129.6, 121.7, 0.9, 0.0;
IR (neat, cmꢀ1
)
nmax 2935, 1571, 1461, 1405, 1361, 1249, 1218, 1101,
Freshly cut sodium (0.28 g, 12.3 mmol) was added under nitro-
gen gas to dry methanol (12 mL). When dissolution was completed,
the warm solution was diluted with dry dimethylformamide then
vacuum-dried cuprous iodide (0.39 g, 1.37 mmol) was added. After
dissolution, 4,6,8-tribromoquinoline (3) (0.5 g, 1.37 mmol) in dry
DMF (12 mL) was added. The reaction mixture was stirred mag-
netically under a nitrogen gas atmosphere and heated at reflux (ca.
100 ꢁC) for 48 h. The reaction’s progress was monitored by TLC and
the starting material was consumed. After cooling to room tem-
perature, H2O (50 mL) and chloroform (70 mL) were added to the
reaction mixture. The organic layers were separated, washed with
H2O (2ꢂ20 mL), and dried over sodium sulfate. The solvent was
removed and the crude product was passed through a short column
packed with silica gel (5 g). Recrystallization from a mixture of
CH2Cl2 and hexane (1:1) at room temperature yielded 4,6,8-tri-
methoxyquinoline (17) (0.18 g, 60%), colorless solid, mp 115–116 ꢁC.
993, 925, 840, 809, 754, 694, 644. Anal. Calcd for C15H22BrNSi2
(352.42): C, 51.12; H, 6.29. Found: C, 51.17; H, 6.33.
4.10. 6-Bromo-4,8-bis(methylthio)quinoline (14)
n-Butyllithium (4 mL, 1.6 M, 6.03 mmol, 2.2 equiv) was added to
a vacuum-dried flask containing tribromide 3 (1 g, 2.74 mmol) in
THF (20 mL) at ꢀ78 ꢁC. After stirring for 90 min, 1,2-dimethyldi-
sulfane [(CH3S)2, 1.6 mL, 6.85 mmol] was added to the mixture at
ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for 30 min and then at
room temperature for 1 h. After quenching with water (30 mL), the
aqueous layer was extracted with diethyl ether (3ꢂ25 mL), and the
combined organic layers were washed sequentially with water
(2ꢂ25 mL) and dried over sodium sulfate. The solvent was removed
by vacuum and the crude product was purified by short silica gel
column chromatography (2:1, hexane–EtOAc, Rf¼0.80). Re-
crystallization from CH2Cl2–Et2O (1:3, 8 mL) gave 14 (742 mg, 90%),
pale yellow needle, mp 134–135 ꢁC. 1H NMR (300 MHz, CDCl3)
1H NMR (300 MHz, CDCl3)
d
8.40 (d, J23¼2.7 Hz, 1H, H2), 7.18 (d,
J23¼2.7 Hz, 1H, H3), 6.50 (d, J57¼2.4 Hz, 1H, H7), 6.40 (d, J57¼2.4 Hz,
1H, H5), 3.97 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d
159.4,156.8,154.6,140.4, 132.0,131.4, 112.4, 99.1, 96.9, 56.4,
nmax 3002, 2960, 2937, 2841, 1617, 1581,
d
8.76 (d, J23¼3.0 Hz, 1H, H2), 8.20 (d, J32¼3.0 Hz, 1H, H3), 7.60 (d,
J57¼2.0 Hz, 1H, H5), 7.79 (d, J75¼2.0 Hz, 1H, H7), 3.07 (s, 3H, SCH3),
3.05 (s, 3H, SCH3); 13C NMR (75 MHz, CDCl3)
148.2, 142.6, 141.6,
135.0, 129.6, 128.9, 124.6, 124.1, 121.0, 15.5, 14.3; IR (KBr, cmꢀ1
nmax
55.8, 55.8; IR (KBr, cmꢀ1
)
1502, 1453, 1385, 1214, 1160, 1133, 1050, 1029, 869, 827, 782. MS (EI,
70 eV) 219, 218, 190, 188, 175, 160. HRMS (EI) calcd for C12H13NO3
(Mþ): 219.0882, found: 219.0884.
d
)
3500, 1650, 1587, 1549, 1459, 1430, 1390, 1371, 1311, 1238, 1087, 989,
964, 921, 881, 860, 825, 781, 698, 605. Anal. Calcd for C11H10BrNS2
(300.24): C, 44.00; H, 3.36. Found: C, 44.03; H, 3.33.
Acknowledgements
The authors are indebted to the Gaziosmanpasa University Re-
search Fund of the Department of Chemistry (BAP, Project no.:
2003/36), State Planning Organization (DPT, Project no.:
2003K120510), and the Scientific and Technological Research
Council of Turkey (TUBITAK, Grant no.: TBAG-2027) for financial
and technical supports.
4.11. 6-Bromo-4,8-diiodoquinoline (15) and 6-bromo-8-
iodoquinoline (16)
n-Butyllithium (4 mL, 1.6 M, 6.03 mmol, 2.2 equiv) was added to
a vacuum-dried flask containing tribromide 3 (1 g, 2.74 mmol) in
THF (25 mL) at ꢀ78 ꢁC. After the mixture was stirred for 90 min,
vacuum-dried iodine (1.78 g, 7 mmol) and THF (7 mL) were added.
The mixture was stirred at ꢀ78 ꢁC for 30 min and then at room
temperature for 1 h. After quenching with saturated sodium thio-
sulfate (50 mL), the aqueous layer was extracted with diethyl ether
(3ꢂ20 mL), and the combined organic layers were washed se-
quentially with water (30 mL) and dried over sodium sulfate. After
evaporation of the solvent, formed products were purified by silica
gel columnchromatography (EtOAc–hexane,1:20). Recrystallization
from CH2Cl2–Hexane gave compounds 16 (220 mg, 46%) and 15
(80 mg, 0.87 mmol, 6%). Rf16¼0.66, Rf15¼0.32 (1:4, CH2Cl2–hexane),
mp16 194–196 ꢁC, mp15 185 ꢁC (dec).
Supplementary data
1H and 13C NMR spectra for selected compounds (15 pages) are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.08.018.
References and notes
1. (a) Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem. 2001, 8, 1535–1542; (b)
Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, NY, 1996; Vol. 5, p 245;
(c) Yates, F. S. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., McKillop,
A., Eds.; Pergamon: Oxford, 1984; Vol. 2, Part 2A, pp 511–524; (d) Chen, Y.-L.;
Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001, 44, 2374–2377;
(e) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem.
2000, 35, 1021–1026; (f) Morizawa, Y.; Okazoe, T.; Wang, S.-Z.; Sasaki, J.; Ebisu,
H.; Nishikawa, M.; Shinyama, H. J. Fluorine Chem. 2001, 109, 83–86; (g) Ferrarini,
P. L.; Mori, C.; Badawneh, M.; Calderone, V.; Greco, R.; Manera, C.; Martinelli, A.;
Nieri, P.; Saccomanni, G. Eur. J. Med. Chem. 2000, 35, 815–819.
4.11.1. Compound 15
Pale yellow needle; 1H NMR (400 MHz, CDCl3)
d 9.05 (d,
J23¼2.0 Hz, 1H, H2), 8.40 (d, J32¼2.0 Hz, 1H, H2), 8.35 (d, J57¼2.7 Hz,
1H, H5), 7.80 (d, J75¼2.7 Hz, 1H, H7); 13C NMR
d (100 MHz, CDCl3)
157.2, 144.6, 143.4, 143.2, 130.6, 129.8, 121.6, 104.6, 92.3; IR (KBr,
d
cmꢀ1
)
nmax 3019, 2401, 1639, 1423, 1214, 1047, 929, 877, 755, 669.
2. Antibiotics II, Biosynthesis; Gottlieb, D., Shaw, P. D., Eds.; Springer: New York, NY,
1967; Vol. 2, p 105.
3. Noverty, J.; Collins, C. H.; Starts, F. W. J. Pharm. Sci. 1974, 63, 1264–1267.
Anal. Calcd for C9H4BrI2N (459.85): C, 23.51; H, 0.88. Found: C,
23.64; H, 0.94.

10074
A. Sahin et al. / Tetrahedron 64 (2008) 10068–10074
4. (a) Aggarwal, A. K.; Jenekhe, S. A. Macromolecules 1991, 24, 6806–6808; (b)
Zhang, X.; Shetty, A. S.; Jenekhe, S. A. Macromolecules 1999, 32, 7422–7429; (c)
Jenekhe, S. A.; Lu, L.; Alam, M. M. Macromolecules 2001, 34, 7315–7324.
5. Eisch, J. J. J. Org. Chem. 1962, 27, 1318–1323 and literature available therein.
6. De La Mare, P. B. D.; Kiamud-din, M.; Ridd, J. H. J. Chem. Soc. 1960, 561–565.
7. Gordon, M.; Pearson, D. E. J. Org. Chem. 1964, 29, 329–332.
8. Jones, G. Chem. Heterocycl. Compd. 1977, 32, 93–318.
9. Chemistry of Heterocyclic Compounds: Quinolines; Gurnos, J., Ed.; Interscience
Publishers: London, 1977; Vol. 32, Part I.
Erenler, R.; Cakmak, O. J. Chem. Res. 2004, 545–549; (d) Cakmak, O.;
Demirtas, I.; Balaydin, H. T. Tetrahedron 2002, 58, 5603–5609; (e) Demirtas, I.;
Erenler, R.; Cakmak, O. J. Chem. Res., Synop. 2002, 2–4; (f) Cakmak, O.;
Kahveci, I.; Demirtas, I.; Smith, K. Collect. Czech. Chem. Commun. 2000, 65,
1791–1804.
11. Yale, H. L.; Bernstein, J. J. Am. Chem. Soc. 1948, 70, 254.
12. Hu, Y.-Z.; Zhang, G.; Thummel, R. P. Org. Lett. 2003, 5, 2251–2253.
13. (a) Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon:
New York, NY, 1974; (b) Comins, D. L.; Nolan, J. S.; Bori, I. D. Tetrahedron Lett.
2005, 6697–6699.
10. (a) Cakmak, O.; Erenler, R.; Tutar, A.; Celik, N. J. Org. Chem. 2006, 71, 1795–
1801; (b) Tutar, A.; Cakmak, O.; Balci, M. J. Chem. Res. 2006, 507–511; (c)
14. Lindley, J. Tetrahedron 1984, 40, 1433–1456.