An improved synthesis of quinolines from β-bromovinyl aldehydes and primary arylamines in the presence of a palladium catalyst

Article abstract of DOI:10.1002/aoc.1709

β-Bromovinyl aldehydes are effectively cyclized with primary arylamines in DMF at 110 °C in the presence of a catalytic amount of a palladium catalyst to give the corresponding quinolines in high yields. Copyright

Full text of DOI:10.1002/aoc.1709

Full Paper
Received: 11 May 2010
Revised: 30 June 2010
Accepted: 5 July 2010
Published online in Wiley Online Library: 28 September 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1709
An improved synthesis of quinolines
from β-bromovinyl aldehydes and primary
arylamines in the presence of a palladium
catalyst
a∗
a
a
b
Chan Sik Cho , Hyo Bo Kim , Wen Xiu Ren and Nam Sik Yoon
◦
β-Bromovinyl aldehydes are effectively cyclized with primary arylamines in DMF at 110 C in the presence of a catalytic amount
of a palladium catalyst to give the corresponding quinolines in high yields. Copyright ꢀc 2010 John Wiley & Sons, Ltd.
Keywords: arylamines; β-bromovinyl aldehydes; cyclization; palladium catalyst; quinolines
Introduction
are listed in Table 1. Treatment of equimolar amount of 1a and 2a
in DMF in the presence of a catalytic amount of PdCl2 at 110 C
◦
β-Bromovinyl aldehydes are readily prepared from α-methylene
ketones via the bromo analog of the Vilsmeier reaction and
for 10 h afforded 1,2,3,4-tetrahydroacridine (3a) in 77% yield as a
sole cyclization product (entry 1). The yield of 3a increased with
prolonging the reaction time up to 20 h (entry 2). From the activity
of several palladium precursors examined under the employed
conditions, all exhibited nearly the same catalytic activity as PdCl2
used as a building block for the construction of versatile cyclic
compounds.[
1–16]
In connection with this report, we recently
found that 2-bromobenzaldehyde is carbonylatively cyclized with
primary amines in the presence of a palladium catalyst along
with a base under carbon monoxide pressure to give isoindol-1-
ones.[ This was discovered during the course of the extension
of this carbonylative cyclization protocol to the reaction with
β-bromovinyl aldehydes. Namely, when β-bromovinyl aldehydes
were treated with primary arylamines under similar conditions, in
addition to the expected carbonylatively cyclized hydroisoindol-
(
entries 3–6). However, performing the reaction in the absence of
a palladium catalyst resulted in lower yield of 3a (entry 7). This
result indicates that palladium plays an ancillary role in cyclization.
Lower reaction temperature also resulted in lower yield of 3a
17]
(entry 8). When the reaction was carried out with further addition
of K2CO3, unidentifiable complex mixture was formed without the
formation of 3a (entry 9). Among the solvents examined, DMF was
crucial for the formation of 3a. Performing the reaction in toluene
or dioxane scarcely afforded 3a with incomplete conversion of 1a
[
18]
1-ones, quinolines were produced as minor product. Regarding
the formation of quinolines, it is known that β-chlorovinyl
aldehydes react with anilines in acetic acid to afford quinolines,
D, via N-arylenaminoimine hydrochloride intermediate, A, in
low to moderate yields (Scheme 1, route a) and thermolysis of
(entries 10 and 11).
After the reaction conditions had been established, various β-
bromovinyl aldehydes, 1, were subjected to reaction with anilines,
, in order to investigate the reaction scope and several repre-
[
19–21]
intermediate A always shows such a cyclization mode.
On
2
the other hand, Kirsch et al. have reported that β-chlorovinyl
aldehydes can undergo a selective amination on their chloro
position with anilines without imine formation in the presence of
sentative results are summarized in Table 2. Cyclic β-bromovinyl
aldehyde, 1a, was readily cyclized with an array of anilines having
electron-donating and -withdrawing substituents to give the cor-
responding quinolines (3a–j) in the range of 59–76% yields. The
product yield was not significantly affected by the position and
electronic nature of the substituent on the aromatic ring of 2a–j.
[
22]
a palladium catalyst along with a base.
Based on this result,
severalgroupsdevelopedatwo-stepprocedureforthesynthesisof
quinolines by such a selective palladium-catalyzed arylamination
of β-halovinyl aldehydes by arylamines followed by CF3COOH-
2
-Bromo-5-methylcyclohex-1-enecarbaldehyde (1b) reacts simi-
and p-toluenesulfonic acid-catalyzed cyclization (Scheme 1, route
larly with 2a to afford 2-methyl-1,2,3,4-tetrahydroacridine (3k).
To test the effect of the position of formyl group and bromide
b).[
21,23]
Imines, C, formed from β-halovinyl aldehydes and anilines
by tuning the reaction conditions were found to be cyclized to D as
well as E (Scheme 1, route c).
[
21,22,24,25]
Herein this report describes
an improved palladium-catalyzed synthesis of quinolines from
β-bromovinyl aldehydes and arylamines.
∗
Correspondence to: Chan Sik Cho, Department of Applied Chemistry, Kyung-
pookNationalUniversity,Daegu702-701,SouthKorea.E-mail: cscho@knu.ac.kr
a Department of Applied Chemistry, Kyungpook National University, Daegu
Results and Discussion
702-701, South Korea
The results of several attempted cyclizations of 2-bromocyclohex-
b Department of Textile System Engineering, Kyungpook National University,
1-enecarbaldehyde (1a) with aniline (2a) under various conditions
Daegu 702-701, South Korea
Appl. Organometal. Chem. 2010, 24, 817–820
Copyright ꢀc 2010 John Wiley & Sons, Ltd.

C. S. Cho et al.
Scheme 1. Synthetic routes for quinolines from β-bromovinyl aldehydes and anilines.
Conclusion
Table 1. Optimization of conditions for the reaction of 1a with 2aa
Insummary,ithasbeenshownthatthecyclizationofβ-bromovinyl
aldehydes with a variety of primary arylamines was accelerated
by the addition of a catalytic amount of a palladium catalyst.
Although the role of a palladium catalyst is still obscure, it seems
to work as a Lewis acid.
CHO
+
H2N Ph
Br
N
1a
2a
3a
Temperature
◦
b
Entry Palladium catalyst Solvent
( C)
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9d
PdCl2
PdCl2
DMF
DMF
110
110
110
110
110
110
110
80
10
20
20
20
20
20
20
20
20
20
20
77
86
Experimental
1H and 13C NMR (400 and 100 MHz) spectra were recorded on
a Bruker Avance Digital 400 spectrometer using Me4Si as an
internal standard. Melting points were determined on a Standford
Research Inc. MPA100 automated melting point apparatus. GLC
analyses were carried out with Shimadzu GC-17A equipped with a
CBP10-S25-050 column (Shimadzu, a silica fused capillary column,
0.33 mm × 25 m, 0.25 µm film thickness) using N2 as carrier gas.
The isolation of pure products was carried out via thin-layer (silica
gel 60 GF254, Merck) chromatography. Commercially available
organic and inorganic compounds were used without further
purification. β-Bromovinyl aldehydes 1 were synthesized from the
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(OAc)2
PdCl2/2PPh3
–
DMF
81
DMF
81
DMF
74
DMF
79
63–66c
DMF
PdCl2(PhCN)2
PdCl2
DMF
47
DMF
110
110
110
0
1
1
0
1
PdCl2
Toluene
Dioxane
0
PdCl2
5
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), palladium catalyst
(
0.02 mmol), solvent (10 ml), under argon.
GLC yield.
Several runs.
In the presence of K2CO3 (1 mmol).
[
1]
b
c
3 3
corresponding ketones by treatment of PBr –DMF–CHCl .
d
Typical Experimental Procedure for the Formation of Quino-
lines 3 from β-Bromovinyl Aldehydes 1 and Anilines 2 in the
Presence of a Palladium Catalyst
To an organic reactor were added 2-bromocyclohex-1-
enecarbaldehyde (1a) (0.095 g, 0.5 mmol), aniline (2a) (0.047 g,
0.5 mmol) and PdCl2 (0.0035 g, 0.02 mmol) in DMF (10 ml). After
thesystemwasflushedwithargon,thereactionmixturewasstirred
on cyclic β-bromovinyl aldehydes, 1d and 1e were employed.
Even though the cyclization took place irrespective of the po-
sition, higher product yield was observed with 1d. From the
reactions with several cyclic β-bromovinyl aldehydes (1f–h), the
corresponding quinolines were also produced and the product
yield was not significantly affected by the ring size of 1f–h. Lower
reaction rate and yield were observed with acyclic β-bromovinyl
aldehyde 1i, the product being obtained in only 34% yield. On
the other hand, similar treatment of 2-bromobenzaldehyde with
◦
at110 Cfor20 h. Thereactionmixturewasfilteredthroughashort
silica gel column (ethyl acetate–chloroform mixture) to eliminate
black precipitate. To the extract was added an appropriate amount
of undecane as internal standard and it was analyzed by GLC. Re-
moval of the solvent left a crude mixture, which was separated
by thin-layer chromatography (silica gel, ethyl acetate–hexane
mixture) to give 1,2,3,4-tetrahydroacridine (3a; 0.070 g, 76%). Ex-
cept for new compounds (3e, 3g, 3r), which were characterized
2
a under the employed conditions did not produce acridine
at all.
wileyonlinelibrary.com/journal/aoc
Copyright ꢀc 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 817–820

An improved synthesis of quinolines
Table 2. Palladium-catalyzed synthesis of quinolines 3 from 1 and 2a
β-Bromovinyl aldehyde 1
Aniline 2
Quinoline 3
Isolated yield (%)
CHO
H N
2
R
R
N
Br
1
a
2a R = H
3a
3b
3c
3d
3e
3f
76
69
62
68
72
66
68
59
64
72
2
2
2
2
2
2
2
2
2
b R = 2-Me
c R = 3-Me
d R = 4-Me
e R = 2, 3-(Me)2
f R = 2, 5-(Me)2
g R = 3, 5-(Me)2
h R = 4-OMe
i R = 2, 5-(OMe)2
j R = 4-Cl
3g
3h
3i
3j
CHO
Br
N
N
1
1
b
d
2a
2a
3k
3l
70
86
Br
CHO
CHO
Br
N
1
1
e
f
2a
2a
3m
64
CHO
Br
N
R
3n
3o
74
75
2
d
CHO
Br
N
R
1
1
g
h
2a
3p
76
CHO
Br
N
R
2a
3q
3r
69
70
2
f
Ph
Br
CHO
Ph
N
1
i
2a
3s
34
a
◦
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), PdCl2 (0.02 mmol), DMF (10 ml), 110 C, for 20 h under Ar.
spectroscopically as shown below, all quinolines were identified
by spectroscopic comparision with those in the literature.[
C), 125.65 (aromatic C), 128.51 (aromatic C), 129.52 (aromatic
C), 133.51 (aromatic C), 135.10 (aromatic C), 135.94 (aromatic C),
26–33]
1
45.94 (aromatic C), 158.15 (aromatic C). Anal. Calcd for C15H17N:
C, 85.26; H, 8.11; N, 6.63. Found: C, 85.21; H, 8.06; N, 6.49.
5
,6-Dimethyl-1,2,3,4-tetrahydroacridine(3e)
◦
1
Solid; m.p. 117–118 C. H NMR (400 MHz, CDCl3) δ 1.84–1.91 (m,
H, CH2), 1.94–2.00 (m, 2H, CH2), 2.46 (s, 3H, CH3), 2.73 (s, 3H,
CH3), 2.92 (t, JHH = 6.3 Hz, 2H, CH2), 3.11 (t, JHH = 6.4 Hz, 2H, CH2),
.22 (d, JHH = 8.3 Hz, 1H, CH), 7.42 (d, JHH = 8.3 Hz, 1H, CH), 7.68
s, 1H, CH). C NMR (100 MHz, CDCl3) δ 13.36 (CH3), 20.81 (CH3),
3.32 (CH2), 23.64 (CH2), 29.22 (CH2), 34.15 (CH2), 124.02 (aromatic
6
,8-Dimethyl-1,2,3,4-tetrahydroacridine(3g)
2
◦
1
Solid; m.p. 85–86 C. H NMR (400 MHz, CDCl3) δ 1.85–1.92 (m, 2H,
CH2), 1.94–2.01 (m, 2H, CH2), 2.47 (s, 3H, CH3), 2.58 (s, 3H, CH3), 2.96
(t, JHH = 6.2 Hz, 2H, CH2), 3.09 (t, JHH = 6.6 Hz, 2H, CH2), 7.09 (s, 1H,
7
(
2
1
3
1
3
CH), 7.60 (s, 1H, CH), 7.88 (s, 1H, CH). C NMR (100 MHz, CDCl3) δ
Appl. Organometal. Chem. 2010, 24, 817–820
Copyright ꢀc 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

C. S. Cho et al.
1
(
8.67(CH3), 21.95(CH3), 23.24(CH2), 23.51(CH2), 29.62(CH2), 33.59
CH2), 124.71 (aromatic C), 125.77 (aromatic C), 128.50 (aromatic
C), 129.63 (aromatic C), 131.59 (aromatic C), 133.38 (aromatic C),
38.25 (aromatic C), 147.35 (aromatic C), 158.70 (aromatic C). Anal.
[3] Y. Zhang, J. W. Herndon, Org. Lett. 2003, 5, 2043.
[
[
[
[
4] S. K. Mal, D. Ray, J. K. Ray, Tetrahedron Lett. 2004, 45, 277.
5] D. Ray, S. K. Mal, J. K. Ray, Synlett 2005, 2135.
6] D. Ray, J. K. Ray, Tetrahedron Lett. 2007, 48, 673.
7] S. Some, B. Dutta, J. K. Ray, Tetrahedron Lett. 2006, 47, 1221.
1
calcd for C15H17N: C, 85.26; H, 8.11; N, 6.63. Found: C, 85.38; H, 8.03;
N, 6.44.
[8] R. Jana, S. Paul, A. Biswas, J. K. Ray, Tetrahedron Lett. 2010, 51, 273.
[9] C. S. Cho, D. B. Patel, S. C. Shim, Tetrahedron 2005, 61, 9490.
10] S. Some, J. K. Ray, M. G. Banwell, M. T. Jones, Tetrahedron Lett. 2007,
[
48, 3609.
6
,7,8,9,10,11,12,13,14,15-Decahydro-1,4-
[11] C. S. Cho, H. S. Shim, Tetrahedron Lett. 2006, 47, 3835.
[12] C. S. Cho, D. B. Patel, Tetrahedron 2006, 62, 6388.
dimethylcyclododeca[b]quinoline (3r)
[13] C. S. Cho, J. U. Kim, H.-J. Choi, J. Organomet. Chem. 2008, 693, 3677.
◦
1
Solid; m.p. 130.9–132.2 C. H NMR (400 MHz, CDCl3) δ 1.36–1.58
m, 12H, -(CH2)6-], 1.76–1.83 (m, 2H, CH2), 1.97–2.03 (m, 2H, CH2),
[14] M. K. Halder, G. K. Kar, J. K. Ray, J. Chem. Research (S) 1993, 46.
[
[
[
[
15] J. K. Ray, G. K. Kar, M. K. Halder, Synth. Commun. 1996, 26, 3959.
16] S. Brahma, J. K. Ray, Tetrahedron Lett. 2008, 64, 2883.
17] C. S. Cho, W. X. Ren, Tetrahedron Lett. 2009, 50, 2097.
18] C. S. Cho, H. B. Kim, S. Y. Lee, J. Organomet. Chem. 2010, 695, 1744.
[
2
3
.59 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.85 (t, JHH = 7.7 Hz, 2H, CH2),
.00 (t, JHH = 7.7 Hz, 2H, CH2), 7.12 (d, JHH = 7.1 Hz, 1H, CH), 7.31
1
3
(
d, JHH = 7.1 Hz, 1H, CH), 8.00(s, 1H, CH). CNMR(100 MHz, CDCl3)
[19] J. M. F. Gagan, D. Lloyd, Chem. Commun. 1967, 1043.
[20] G. K. Kar, A. C. Karmakar, A. Makur, J. K. Ray, Heterocycles 1995, 41,
δ 18.06 (CH3), 18.68 (CH3), 23.43 (CH2), 23.56 (CH2), 25.62 (CH2),
911.
2
3
5.78 (CH2), 26.31 (CH2), 26.76 (CH2), 28.36 (CH2), 30.00 (CH2),
0.50 (CH2), 32.53 (CH2), 125.76 (aromatic C), 126.43 (aromatic
[
21] P. Karthikeyan, A. Meena Rani, R. Saiganesh, K. K. Balasubramanian,
S. Kabilan, Tetrahedron 2009, 65, 811.
C), 128.06 (aromatic C), 131.37 (aromatic C), 132.51 (aromatic
C), 134.02 (aromatic C), 134.60 (aromatic C), 146.04 (aromatic C),
[
22] S. Hesse, G. Kirsch, Tetrahedron 2005, 61, 6534.
[23] S. Some, J. K. Ray, Tetrahedron Lett. 2007, 48, 5013.
1
4
60.84 (aromatic C). Anal. Calcd for C21H29N: C, 85.37; H, 9.89; N,
.74. Found: C, 85.39; H, 9.92; N, 4.65.
[24] K. Rajendra Prasad, M. Darbarwar, Org. Prep. Proc. Int. 1995, 27, 547.
[
25] K. S. Swaminathan,
R. S. Ganesh,
C. S. Venkatachalam,
K. K. Balasubramanian, Tetrahedron Lett. 1983, 24, 3653.
26] A. R. Katritzky, M. Arend. J. Org. Chem. 1998, 63, 9989.
27] V. A. Petrow, J. Chem. Soc. 1942, 693.
28] M. M. Blanco, C. Avenda n˜ o, J. C. Men e´ ndez, Tetrahedron 1999, 55,
12637.
[
[
[
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea funded by the
Ministry of Education, Science and Technology (2009-0072207).
[
[
29] H. Vander Mierde, N. Ledoux, B. Allaert, P. V. D. Voort, R. Drozdzak,
D. De Vos, F. Verpoort, New. J. Chem. 2007, 31, 1572.
30] N. P. Buu-Hoi, R. Royer, N. D. Xuong, P. Jacquignon, J. Org. Chem.
1
953, 18, 1209.
[31] R. J. Olsen, Tetrahedron Lett. 1991, 32, 5235.
[32] B. R. McNaughton, B. L. Miller, Org. Lett. 2003, 5, 4257.
[33] M. A. Ciufolini, J. W. Mitchell, F. Roschangar, Tetrahedron Lett. 1996,
37, 8281.
References
[
[
1] R. M. Coates, P. D. Senter, W. R. Baker, J. Org. Chem. 1982, 47, 3597.
2] J. K. Ray, M. K. Haldar, S. Gupta, G. K. Kar, Tetrahedron 2000, 56, 909.
wileyonlinelibrary.com/journal/aoc
Copyright ꢀc 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 817–820