Chemoselective arylamination of β-bromovinylaldehydes followed by acid catalyzed cyclization: a general method for polycyclic quinolines

Article abstract of DOI:10.1016/j.tetlet.2007.05.111

A synthesis of polycyclic quinolines is described via palladium-catalyzed chemoselective arylamination of β-bromovinylaldehydes with aromatic amines followed by acid catalyzed cyclization.

Full text of DOI:10.1016/j.tetlet.2007.05.111

Tetrahedron Letters 48 (2007) 5013–5016
Chemoselective arylamination of b-bromovinylaldehydes
followed by acid catalyzed cyclization: a general method
for polycyclic quinolines
Surajit Some and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 11 April 2007; revised 11 May 2007; accepted 18 May 2007
Available online 24 May 2007
Abstract—A synthesis of polycyclic quinolines is described via palladium-catalyzed chemoselective arylamination of b-bro-
movinylaldehydes with aromatic amines followed by acid catalyzed cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Herein we report a simple, two-step procedure for the
facile synthesis of the polycyclic quinolines, which
involves selective Pd-catalyzed arylamination of b-bro-
movinylaldehydes by substituted aromatic amines
followed by acid catalyzed cyclization13 with trifluoro-
acetic acid (Scheme 1).
Polycyclic azaarenes (PAA)1,2 have attracted the atten-
tion of organic chemists due to the interesting properties
exhibited by these classes of compounds, in the form of
cavity shaped molecules,3 bay region diol epoxides,2,4
molecular tweezers,5 heterohelicenes,6 polycyclic aro-
matic alkaloids,7 quinoline-5,8-quinone,8 prototype
inhibitors of Hsp-90, geldamycin9 and substituted quino-
lines.10 Several methods have already been reported for
the synthesis of PAAs including the Combes method.11
Previously, we reported the synthesis of PAAs by ther-
mal cyclization of arylenaminoimine hydrochlorides.12
On the basis of our results and evidence in the litera-
ture,14 it was interesting and worthwhile to study the
amination of b-bromovinylaldehydes.
We found that b-bromovinylaldehyde 1a (1 mmol)
(Fig. 1) reacted with substituted aromatic amine 2a
R2 R1
R
H
R
Br
N
Pd2(dba)3, K2CO3
Br
H2N
+
R1
R
N
+
(R)-(+)-BINAP
R1
toluene
CHO
CHO
R2
H
R2
2
90 ºC, 3-4 h
4
3
1
TFA
10-12 h
R
N
R1
R2
5
Scheme 1.
Keywords: Polycyclic azaarenes; Acid cyclization; Selective amination.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222 282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.111

5014
S. Some, J. K. Ray / Tetrahedron Letters 48 (2007) 5013–5016
Br
Br
Br
CHO
CHO
1a
H
CHO
R
1b
1c = R = R' = H
1d = R = Me, R' = H
1e = R = H, R' = NO2
R'
Br
CHO
Br
1f = n = 1
1g = n = 2
1h = n = 3
1i = n = 4
n
1j
CHO
Figure 1. Structures of b-bromovinylaldehydes.
Table 1. Optimization of the reaction conditions for selective
Table 2. Reaction of 1a with various substituted anilines 2a–ha
arylaminationa
Entry
R
R1
R2
Yield (% of 3) Yield (% of 4)
Entry
Catalyst
Base
Yield
Yield
1
2
3
4
5
6
7
8
H
OMe H (2a)
80
50
70
45
18
30
18
24
0
5
8
2
(% of 3)
(% of 4)
Me
OMe
Me
OMe
OH
H
H
H
H
Me (2b)
H (2c)
H (2d)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
PdCl2(PPh3)4
PdCl2(PhCN)2
PdCl2(MeCN)2
Pd(dba)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
NaHCO3
NaH
75
0
20
60b
22
5
25
23
25
18
22b
20
18
5
55
10
66
64
68
60
40
75
80
20
0
H
OMe (2e) 95
H
OH
H
H (2f)
H (2g)
H (2h)
14
20
10
NO2
a b-Bromovinylaldehyde 1a (1 mmol), amine (1 mmol), Pd2(dba)3
(3 mol %), K2CO3 (1.4 mmol) and (R)-(+)-BINAP (4 mol %) at
90 °C for 3–4 h under an argon atmosphere.
3a–j were obtained in excellent yields (Table 3, Fig. 2).
The aminated products on treatment with trifluoroacetic
acid for 10–12 h at room temperature gave the corre-
sponding polycyclic quinolines 5a–j (Fig. 3) in moderate
to good yields. The experimental results are summarized
in Tables 3 and 4.
4
5
5
0
20
NaOAc
a b-Bromovinylaldehyde 1a (1 mmol), amine 2a (1 mmol), Pd catalyst
(3 mol %), base (1.4 mmol) and BINAP (4 mol %) at 90 °C for 3–4 h
under an argon atmosphere.
b (R)-(+)-BINAP not added.
In conclusion we have developed a two-step methodol-
ogy for the synthesis of various polycyclic quinolines.
We found that our method required short reaction times
and gave improved yields of products.
(1 mmol) at 90 °C in the presence of a Pd catalyst
(3 mol %), base (1.4 mmol) and BINAP (4 mol %) for
3–4 h under an argon atmosphere in toluene to afford
3a and 4a. We studied the reaction with various Pd
sources as well as the base (Table 1).
2. Typical experimental procedure for palladium-
catalyzed amination
Thus, the optimized conditions for reaction between 1a
and 2a required Pd2(dba)3 (3 mol %), K2CO3 (1.4 mmol),
(R)-(+)-BINAP (4 mol %) at 90 °C for 3–4 h under an
argon atmosphere. Next we used our optimized reaction
conditions to investigate the reaction between 1-bromo-
3,4-dihydronaphthalene-2-carbaldehyde 1a and various
substituted anilines to extend the scope of this method
for polycyclic quinoline synthesis (Table 2).
A round bottom flask was charged with bromovinyl-
aldehyde (1 mmol), 2,5-dimethoxyaniline (1 mmol),
Table 3. Selective Pd-catalyzed amination of bromovinylaldehydes 1a–
j with 2,5-dimethoxyaniline 2e
Entry b-Bromovinylaldehyde Producta Yield (%) Time (h)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
95
89
82
85
86
82
88
86
80
80
3
3
4
3.5
3.5
4
According to the above observations electron-donating
substituents present on aniline increase the reactivity.
Thus, 2,5-dimethoxyaniline was found to have greater
regioselectivity for 3e, which was obtained in high yield
(Table 2, entry 5).
1g
1h
1i
3g
3h
3i
3
3.5
3.5
4
Thus, when b-bromovinylaldehydes 1a–j were treated
with 2,5-dimethoxyaniline in toluene, in the presence
of K2CO3 and catalytic amounts of Pd2(dba)3 and (R)-
(+)-BINAP at 90 °C for 3–4 h, the aminated products
10
1j
3j
a See Figure 1 for the structures of the aminated products.

S. Some, J. K. Ray / Tetrahedron Letters 48 (2007) 5013–5016
5015
MeO
NH
OMe
MeO
NH
H
N
OMe
OMe
CHO
3b
CHO
CHO
3a
OMe
H
R
3c = R = R' = H
3d = R = Me, R' = H
3e = R = H, R' = NO2
MeO
OMe
R'
OMe
CHO
NH
CHO
HN
3f = n = 1
3g = n = 2
3h = n = 3
3i = n = 4
n
OMe
3j
Figure 2. Aminated products 3a–j, produced by selective Pd-catalyzed reactions between bromovinylaldehydes 1a–j and 2,5-dimethoxyaniline 2e.
MeO
OMe
OMe
OMe
N
N
N
OMe
5a
5b
OMe
N
5c = R = R' = H
R
5d = R= Me, R' = H
5e = R = H, R' = NO2
R'
OMe
OMe
N
5f = n = 1
5g = n = 2
5h = n = 3
5i = n = 4
n
OMe
OMe
5j
Figure 3. Polycyclic quinolines produced by acid cyclization of 3a–j.
the resultant solution was stirred for 10–12 h at room
temperature. The solvent was removed under reduced
pressure, the residue diluted with water and quenched
with solid NaHCO3 and extracted with dichlorometh-
ane. The organic layer was dried over Na2SO4 and the
crude product was purified by preparative thin layer
chromatography.
Table 4. Polycyclic quinolines prepared by acid catalyzed cyclization
of 3a–j with trifluoroacetic acid
Entry
Producta
Yield (%)
Time (h)
1
2
3
4
5
6
7
8
9
5a8
5b
88
85
80
82
80
45
85
65
60
45
10
10
12
10.5
12
12
10
11.5
11.5
12
5c9
5d
5e
5f15
5g7
5h
4. Selected spectroscopic data
4.1. Compound 3g
5i
10
5j
a See Figure 3 for the structures of the acid cyclized products.
1H NMR (CDCl3, 200 MHz): d 1.55–1.67 (m, 4H), 2.39–
2.47 (m, 4H), 3.75 (s, 3H), 3.80 (s, 3H), 6.62–6.71 (m,
2H), 6.79–6.84 (d, 1H, J = 8.7 Hz), 9.14 (s, 1H), 12.18
(br s, 1H). 13C NMR (CDCl3, 50 MHz): d 21.59,
22.67, 24.34, 27.29, 55.59, 56.19, 103.55, 109.82,
111.94, 112.25, 128.36, 147.16, 153.17, 159.63, 190.18.
HRMS: M++H, found, 262.1435; C15H20NO3 requires
M++H, 262.1443.
K2CO3 (1.4 mmol), Pd2(dba)3 (3 mol %) and (R)-(+)-BI-
NAP (4 mol %) in dry toluene (6 mL) under an argon
atmosphere. The reaction mixture was heated at 90 °C
for 3–4 h and then allowed to cool to room temperature.
The reaction mixture was diluted with diethyl ether,
washed thoroughly with water, dried over anhydrous
Na2SO4 and the solvent removed under reduced pres-
sure. The crude product was purified by preparative thin
layer chromatography.
4.2. Compound 5g
1H NMR (CDCl3, 200 MHz): d 1.85–2.02 (m, 4H), 2.94–
3.00 (t, 2H, J = 6.2 Hz), 3.16–3.22 (t, 2H, J = 6.2 Hz),
3.93 (s, 3H), 4.00 (s, 3H), 6.62–6.66 (d, 1H,
J = 8.4 Hz), 6.79–6.83 (d, 1H, J = 8.4 Hz), 8.19 (s,
1H). 13C NMR (CDCl3, 50 MHz): d 22.87, 23.15,
29.25, 33.68, 55.77, 55.88, 102.52, 105.53, 120.51,
130.05, 130.73, 138.66, 148.27, 148.82, 158.75. HRMS:
3. Typical experimental procedure for acid cyclization
with trifluoroacetic acid
The aminated product (1 mmol) was placed in a flask,
flushed with N2, then TFA (8–10 mL) was added and

5016
S. Some, J. K. Ray / Tetrahedron Letters 48 (2007) 5013–5016
M++H, found, 244.1347; C15H18NO2 requires M++H,
244.1338.
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Financial support from the CSIR (New Delhi) is greatly
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