Synthesis of novel cyano quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.07.092

6,8-Dibromo-1,2,3,4-tetrahydroquinoline (2) and 3,6,8-tribromoquinoline (3) were converted into the corresponding cyano derivatives via copper assisted nucleophilic substitution reactions. While bromination of 6-bromo-8-cyanotetrahydroquinoline (11) gave 3,6-dibromo-8-cyanoquinoline (8), the reaction of dicyano-1,2,3,4-tetrahydroquinoline (12) resulted in the formation of an unexpected dimer (15).

Full text of DOI:10.1016/j.tetlet.2015.07.092

Tetrahedron Letters 56 (2015) 5337–5340
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel cyano quinoline derivatives
Salih Ökten a, Osman Çakmak b,
⇑
a Department of Primary Education, Division of Science Education, Faculty of Education, Kırıkkale University, 71450 Yahßsihan, Kırıkkale, Turkey
b
_
Department of Chemistry, Faculty of Art and Science, Yıldız Technical University, 34210 Davutpaßsa, Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
6,8-Dibromo-1,2,3,4-tetrahydroquinoline (2) and 3,6,8-tribromoquinoline (3) were converted into the
corresponding cyano derivatives via copper assisted nucleophilic substitution reactions. While bromina-
tion of 6-bromo-8-cyanotetrahydroquinoline (11) gave 3,6-dibromo-8-cyanoquinoline (8), the reaction of
dicyano-1,2,3,4-tetrahydroquinoline (12) resulted in the formation of an unexpected dimer (15).
Ó 2015 Elsevier Ltd. All rights reserved.
Received 22 January 2015
Revised 15 July 2015
Accepted 30 July 2015
Available online 5 August 2015
Keywords:
Quinoline
Bromo quinoline
Cyano quinoline
Bromination
Introduction
Results and discussions
The quinoline moiety forms the key skeleton of several natural
and pharmacologically active compounds which display a broad
spectrum of biological activities.1–4 Notably, cyano quinoline com-
pounds substituted at the C-3 position can act to deactivate the
action of growth factor receptor protein tyrosine kinases.5–8
Agents with cyano groups also act as small molecule inhibitors,
binding with biological systems.9 A significant body of work has
been reported on the synthesis and derivatization of the quinoline
substructure. The most common strategies are cyclization reac-
tions of N-functionalized benzene or cyclohexane.10–13 The asym-
metric syntheses of 2-cyano substituted dihydro and
tetrahydroquinolines have been accomplished using the Reissert
reaction14 while 8-cyano substituted quinoline compounds have
been synthesized by the treatment of cyano aniline with ketone
functionalized alkynes in polar solvents.15 However, cyclizations
using cyano substituted N-functionalized aromatics, allow only
the synthesis of mono cyano substituted quinolines.16 Due to this,
the synthesis of poly cyano substituted quinolines has been
restricted.
Previously, we have reported the one pot synthesis of 3,6,8-
tribromoquinoline by bromination of 6,8-dibromo-1,2,3,4-
3
tetrahydroquinoline 2 which proceeded in high yield (90%).19 As
a continuation of this, we initially studied in detail both this reac-
tion and alternative approaches towards the synthesis of 3.
Interestingly, 1,2,3,4-tetrahydroquinoline 1 was found to react
with 5 equiv of bromine at ambient temperature to afford the
3,6,8-tribromoquinoline 3 in good yield (82%) (Scheme 2). As an
alternate method for the synthesis of 3, 6,8-dibromoquinoline
4
17,20 was brominated using Eisch’s procedure.21 It is proposed that
6,8-dibromoquinoline 4 initially reacts to produce bromine salt 7
which upon heating at reflux in the presence of pyridine undergoes
conversion to 3,6,8-tribromoquinoline 3 via substitution at the C-3
position (Scheme 2).
In our previous publication,18 the copper induced cyanation of
6,8-dibromoquinoline 4 was investigated and we initially applied
the same strategy to 3,6,8-tribromoquinoline 3 (Scheme 3) and
6,8-dibromo-1,2,3,4-tetrahydroquinoline 2 (Scheme 4). Tribromo
compound 3 was reacted with CuCN in refluxing DMF to afford a
mixture of cyanoquinolines 8, 9 and 10 (Scheme 3). The effect of
reaction duration on the product ratio was investigated and it
was observed that a reaction time of 6 h gave monocyanide 8 in
good yield (76%, entry 1), whereas prolonged reaction times
(14 h) yielded a mixture of cyanoquinolines 9 and 10 (entry 2).
Gratifyingly after 24 h, tricyanide 10 was obtained as the sole
product albeit in low yield (36%, entry 3).
The work presented is
a continuation of our ongoing
research17,18 and focuses on the synthesis of polysubstituted
quinolines, starting from substituted 1,2,3,4-tetrahydroquinoline
5, which provides an efficient synthesis of C-3 bromoderivatives
6 (Scheme 1). Herein, we present preliminary results focused on
the generality and application of this strategy.
The low yield of 10 could be explained by the longer reaction
time which caused polymerization/decomposition of tricyanide
⇑
Corresponding author. Tel.: +90 212 383 4224; fax: +90 212 383 4234.
E-mail address: ocakmak@yildiz.edu.tr (O. Çakmak).
http://dx.doi.org/10.1016/j.tetlet.2015.07.092
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5338
S. Ökten, O. Çakmak / Tetrahedron Letters 56 (2015) 5337–5340
tribromide 3, except they were shifted to a higher field. In the 1H
NMR spectra of 3,6,8-tricyanoquinoline 10, a downfield shift for
H-2 (dH 9.36, d, J2,4 = 1.6 Hz) was observed which was characteris-
tic for a quinoline ring; the doublet of H-4 was observed at dH 8.74
(J4,2 = 1.6 Hz). Two signals with meta coupling at dH 8.56 and 8.45
(J5,7 = 2.0 Hz), belonging to H-5 and H-7, respectively, were also in
good agreement with the proposed structure. The 13C NMR spectra
of 10, consisted of twelve sp2 resonances, eight of which were qua-
ternary carbons. 1H NMR of all compounds are listed in Table 1.
The structure of cyanides 8 and 9 were determined by 1H and
13C NMR, 2D NMR (HMBC, HETCOR), and elemental analysis. The
1H NMR spectrum of dibromide 8 consisted of four signals
(Table 1). The resonance for H-2 appeared at d 9.05 with a coupling
constant value (J2,4 = J5,7 = 1.6 Hz), which is characteristic for a
quinoline ring. Meta coupling doublets for H-5 and H-7 (dH 8.19,
8.34, respectively, J5,7 = 1.6 Hz) as well as H-2 and H-4 (dH 9.04,
8.16, respectively, J2,4 = 1.6 Hz) were evidence for the position of
the two bromine substituents. 2D NMR was used to establish the
position of the cyano groups in both 8 and 9. For example, in the
HBMC spectra of 8, the cyano carbon atom (dH 115.2) correlated
with H-7 (dH 8.34 ppm) but did not correlate with H-5 (dH
8.19 ppm) confirming that the cyano group was substituted at C-
8. Highly downfield shifts were evidence that the compound con-
tained a cyano group. The 13C NMR studies of compound 8 dis-
played ten resonances of which six signals were quaternary
which was in accordance with the aromatic skeleton being tri
substituted.
Br
Br
Br
a
a,c
90%
82%
N
H
N
H
N
N
Br
Br
1
2
3
c
b
90%
Br
Y
Y
Br
a,c
3
N
N
H
X
5
X
6
Br
4
Scheme 1. Approaches to the synthesis and functionalization of quinoline and
hydroquinoline derivatives. (a) bromination; (b) substitution; (c) aromatization.
Br
Br
Br
b
82%
N
H
N
Br
3
85%
e
1
a
90%
Br
Br
c
d
90%
94%
N
N
Br
N
H
Br
Br
4
Br
7
Br
2
Scheme 2. Reagents and conditions (a) Br2 (2 equiv), CHCl3, dark, 2 h, rt; (b) Br2
(5 equiv), CHCl3, dark, 3 d, rt; (c) DDQ (2.5 equiv), benzene, 3 h, reflux; (d) Br2
(1 equiv), CCl4, 3 h, rt; (e) pyridine (1 equiv), reflux, 15 h.
When 6,8-dibromo-1,2,3,4-tetrahydroquinoline 2 was treated
with CuCN in refluxing DMF, the 1H NMR spectrum indicated for-
mation of a mixture of cyano tetrahydroquinolines (11, 12) and
quinolines (13, 14) which varied in composition by reaction time.
It was observed that after 4 h, two cyano tetrahydroquinoline
derivatives 11 and 12 had formed in a 20:40 ratio (conversion
60%, entry 1), as assigned by 1H NMR spectroscopy. The starting
material was consumed in 6 h (entry 2) giving 11 and 12 in a
Br
Br
Entry Time Product Ratio
Yield (%)
8
9
-
71
-
10
-
8
9
10
N
1
2
3
6 h 100
76
-
-
Br
3
14 h
24 h
-
-
29
100
-
-
36
a
Table 1
5
4
Summary of the 1H NMR data of compounds 8–14
NC
CN
Br
6
3
Br NC
+
Br
+
Compound
dH
J = (Hz)/other
7
2
N
N
N
8
signals
1
H-2
H-3
—
H-4
H-5
H-7
CN
8
CN
9
CN
10
8
9.05
(d)
8.16
(d)
8.19.
(d)
8.34
(d)
8.33
(d)
8.45
(d)
7.28
(d)
J2,4 = 1.6,
J7,5 = 1.6
J2,4 = 2.0,
J5,7 = 2.0
J2,4 = 1.6,
J5,7 = 2.0
J2,3 = 4.4,
J4,3 = 6.4
J7,5 = 2.0; 4.87
(s) NH
Scheme 3. Reagents and conditions (a) CuCN (6 equiv), DMF, reflux.
9
9.23
(d)
9.36
(d)
—
—
8.57
(d)
8.74
(d)
8.37
(d)
8.56
(d)
10
11
Br
3.42
(t)
1.93
(m)
2.74
(t)
7.16
(d)
a
Entry Time Product Ratio
Yield (%)
11 12 13 14 11 12
2
90%
N
H
N
H
1
2
3
4 h
6 h
18 h
40 20 40
0 28 72
0 14 81
0
0
4
0
0
1
Br
2
28 72
1
12
3.50
(t)
1.97
(m)
2.78
(t)
7.50
(s)
7.29
(s)
J2,3 = 6.4,
J4,3 = 6.0
5.48 (s) NH
J2,3 = 4.0,
J3,4 = 8.0
J2,3 = 4.0,
J3,4 = 8.0
J2,4 = 1.6,
J7,5 = 1.6
b
13
14
9.08
(d)
9.27
(dd)
7.58
(dd)
7.74
(dd)
8.17–8.22 (m)
Br
NC
Br
NC
+
+
+
8.36
(dd)
8.50
(d)
8.30
(d)
N
N
H
N
N
H
CN
11
CN
12
CN
13
CN
14
c
75%
Scheme 4. Reagents and conditions (a) Br2 (2 equiv), CH2Cl2, dark, 2 h, rt; (b); CuCN
(4 equiv), DMF, reflux; (c) DDQ, benzene, 44 h, reflux.
Br
Br
Br
a
85%
N
N
H
CN
8
CN
10. Interestingly, the first substitution occurred at the C-8 position
instead of C-3 as expected, which was potentially assisted by Cu-N
complexation. The 1H NMR of 10 displayed similar signals to
11
Scheme 5. Reagents and conditions (a) Br2 (3 equiv), CHCl3, dark, rt, 2 d.

S. Ökten, O. Çakmak / Tetrahedron Letters 56 (2015) 5337–5340
5339
Br
4'
5'
6' CN
3'
2'
5
4
NC
NC
NC
NC
7'
N
b
75%
a
+
6
7
8'
3
1'
CN
2
N
N
H
N
N
8
1
CN
CN
CN
CN
14, 28%
14
12
15, 25%
Scheme 6. Reagents and conditions (a) Br2 (3 equiv), CHCl3, dark, rt, 2 d; (b) DDQ, benzene, 3 h, 80 °C.
28:72 ratio which could be separated by flash column chromatog-
raphy to give yields of 28% and 72%, respectively. Interestingly,
longer reaction times also gave the aromatized side products 13
and 14 (entry 3). Aromatization of compound 12 with DDQ in
refluxing benzene provided 6,8-dicyanoquinoline 14 in good yield
(75%) (Scheme 4). All spectral data of 14 corresponded to those
reported in the literature.18
8.55, 8.31) respectively. Another set of HMBC correlations were
4
observed between C-2 and H-4 (dH 8.52, J = 2.0 Hz), H-30 (dH
8.55, s) providing evidence for the connecting position of the two
rings in the dimer. In a selective TOCSY experiment, correlations
between H-2 (dH 9.24) and H-4 (dH 8.52) as well as H-5 (dH 8.31)
and H-7 (dH 8.38) were observed. Additionally the structure 15
was consistent with HETCOR and APT assignments.
The structures of cyanide containing compounds 11 and 12
were confirmed by 1H and 13C NMR, 2D NMR (HMBC, HETCOR)
and elemental analysis while the structures of 13 and 14 were
assigned by comparison to their literature values.18 HMBC correla-
tions of 11 were used to confirm this structure; especially the
Conclusion
We have developed two selective routes towards the synthesis
of compound 8, containing bromine substituents at the C-3 and C-6
positions which along with other bromo cyanides could be impor-
tant starting materials for the synthesis of polyfunctionalized
quinoline derivatives.
Additionally, the cyano derivatives of 1,2,3,4-tetrahydroquinoli-
nes were found to be highly reactive towards bromination and
investigations are ongoing regarding the generality and application
of this approach to other substituted quinoline derivatives.
In conclusion, we have reported for the first time the synthesis
of 3-bromine substituted quinolines starting from 5/6/7/8-substi-
tuted quinolines or tetrahydroquinolines. This represents a new
synthetic approach to convert 1,2,3,4-tetrahydroquinoline deriva-
tives into synthetically useful intermediate bromoquinolines via
bromination of the heterocyclic ring of a quinoline.
strong correlation (2JCH
) between the cyano carbon atom
(116.9 ppm) and the aromatic proton at H-7 (dH 7.28 ppm). No cor-
relation was observed with H-5 (dH 7.18 ppm), verifying the
attachment of the cyano group at C-8. Furthermore, the correlation
of C-6 (dC, 106.1) with H-5 and H-7 supported the formation of 11.
In the 1H NMR spectrum of 12, signals for the aromatic protons H-5
and H-7 (dH 7.29 and 7.50, respectively) were shifted downfield
when compared to signals of the starting material 220 (H-5 and
H-7; dH 7.29, 6.96, respectively). Finally the 13C NMR of 12 con-
sisted of six sp2 resonances and two cyano resonances, six of which
were quaternary carbons, as well as three sp3 resonances.
Characteristic cyano signals (dC, 116.2 and 118.7) in the 13C NMR
spectra helped to confirm the structure of 12.
Our previous studies had indicated that tetrahydroquinolines
were very reactive towards bromine giving 3-brominated aromatic
derivatives.17,18,20 Therefore, 6-bromo-8-cyano-1,2,3,4-tetrahydro-
quinoline 11 was proposed as a good precursor for the synthesis of
3-brominated derivatives. Mono cyano tetrahydroquinoline 11
was treated with 3 equiv of bromine at room temperature to form
3,6-dibromo-8-cyanoquinoline 8 in good yield (85%) (Scheme 5).
Thus, we have opened up two effective and selective methods for
the synthesis of cyanide 8, which is a potential precursor for other
quinoline derivatives due to the bromine substituents.
On the other hand, unexpected behaviour was observed when
compound 12 was subjected to bromination giving a mixture of
compounds 14 and 15 instead of the expected product
cyanoquinoline 9 (Scheme 6). Elemental analysis, mass spec-
troscopy, and 2D NMR analysis (NOESY, HETCOR, HMBC, APT,
selective TOCSY) supported the assignment of 15 as a dimeric
structure. When Eisch’s procedure21 was applied to compound
14, formation of the dicyano N-bromine complex was not
observed, probably due to the electron deficient nature of 14.
The 13C NMR of 15 supported the attachment of four cyano
groups. It displayed 22 resonances of which were 15 quaternary
signals, which was in accordance with the molecule skeleton hav-
ing five substituents. In the 1H NMR spectrum a characteristic dou-
blet at dH 9.24 (d, 4J = 2.0 Hz) corresponding to H-2, was shifted
more downfield. The HMBC, TOCSY and HETCOR experiments pro-
vided additional evidence for structural verification. A singlet at dH
8.55 belonging to C-30 showed no correlation to any proton in the
selective TOCSY experiment. The quaternary carbons at C-3 (dC
139.5) and C-40 (dC 136.7) showed correlations with the protons
at H-2, H-4, H-5 (dH 9.24, 8.52, 8.41) and H-2, H-30, H-50 (dH 9.24,
Acknowledgement
The study was supported by grants from the Scientific and
Technological Research Council of Turkey (TUBITAK, Project num-
ber: 112T394).
Supplementary data
Supplementary data (experimental details, 1H and 13C NMR
spectra for all compounds and 2D NMR spectra of selected com-
pounds) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2015.07.092.
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