Palladium-catalyzed Sonogashira coupling reaction followed by isomerization and cyclization

Article abstract of DOI:10.1016/j.jorganchem.2005.06.002

2-Iodoaniline reacts with terminal acetylenic carbinols in THF at 80 °C in the presence of a catalytic amount of PdCl₂(PPh₃) ₂ and CuI along with aqueous tetrabutylammonium hydroxide to afford the corresponding 2-arylquinolines in good yields. The catalytic pathway seems to be proceeded via a sequence involving initial Sonogashira coupling between 2-iodoaniline and terminal acetylenic carbinols to form coupled acetylenic carbinols, isomerization of coupled acetylenic carbinols to α,β- unsaturated ketones, and cyclodehydration.

Full text of DOI:10.1016/j.jorganchem.2005.06.002

Journal of Organometallic Chemistry 690 (2005) 4094–4097
www.elsevier.com/locate/jorganchem
Note
Palladium-catalyzed Sonogashira coupling reaction followed
by isomerization and cyclization
*
Chan Sik Cho
Research Institute of Industrial Technology, Kyungpook National University, Bukku, Daegu 702-701, Republic of Korea
Received 21 February 2005; accepted 1 June 2005
Available online 12 July 2005
Abstract
2-Iodoaniline reacts with terminal acetylenic carbinols in THF at 80 ꢀC in the presence of a catalytic amount of PdCl2(PPh3)2 and
CuI along with aqueous tetrabutylammonium hydroxide to afford the corresponding 2-arylquinolines in good yields. The catalytic
pathway seems to be proceeded via a sequence involving initial Sonogashira coupling between 2-iodoaniline and terminal acetylenic
carbinols to form coupled acetylenic carbinols, isomerization of coupled acetylenic carbinols to a,b-unsaturated ketones, and
cyclodehydration.
ꢁ 2005 Published by Elsevier B.V.
Keywords: Cyclization; Isomerization; Palladium catalyst; Quinolines; Sonogashira coupling; Tetrabutylammonium hydroxide
1. Introduction
tion with this report, Kundu et al. have also reported
on the step-by-step synthesis of quinolines by an initial
Sonogashira coupling reaction of o-iodoanilide or
o-iodoaniline with terminal acetylenic carbinols and
subsequent treatment of the coupled acetylenic carbinols
with a base or Pd(OAc)2-LiCl [5]. Under these circum-
stances, herein this report describes a one-pot conve-
nient palladium-catalyzed synthesis of 2-arylquinolines
from 2-iodoaniline and terminal acetylenic carbinols
[6–8].
Pd/Cu-catalyzed sp-carbon-sp2-carbon bond forming
reaction by the cross-coupling of terminal alkynes with
aryl and vinyl halides (or triflates) is known as Sono-
gashira coupling reaction [1]. This protocol has been
widely used as a powerful synthetic tool for the forma-
tion of conjugated acetylenic compounds, which fre-
quently plays an important role as an intermediate for
the design of pharmaceuticals and organic materials
[1]. Thus, many elegant systems which facilitate Sono-
gashira coupling under a milder conditions have been
developed by the tuning of phosphine ligand combined
with palladium [2] or the addition of promoter [3]. As
an exceptional case, it was reported by several groups
that limited aromatic halides are coupled with terminal
acetylenic carbinols to give coupled enones via isomeri-
zation of initially coupled acetylenic carbinols under
usual Sonogashira coupling conditions [4]. In connec-
2. Results and discussion
The results of several attempted reactions of
2-iodoaniline (1) with 1-phenylprop-2-yn-1-ol (2a) are
listed in Table 1. Typically, 1 was subjected to react with
2a in the presence of PdCl2(PPh3)2 (2 mol%) and CuI (4
mol%) along with an additive to afford 2-phenylquino-
line (3a). Among the activity of several additives exam-
ined, tetrabutylammonium hydroxide (TBAOH, 1 M
aqueous solution) is the choice of preference for the
*
Corresponding author. Tel.: +82 53 950 7318; fax: +82 53 950 6594.
E-mail address: cscho@knu.ac.kr.
0022-328X/$ - see front matter ꢁ 2005 Published by Elsevier B.V.
doi:10.1016/j.jorganchem.2005.06.002

C.S. Cho / Journal of Organometallic Chemistry 690 (2005) 4094–4097
4095
Table 1
Palladium-catalyzed reaction of 1 with 2a under several conditionsa
I
OH
PdCl2(PPh3)2, CuI
THF, 80 o
+
C
Ph
NH2
N
Ph
1
2a
3a
Time (h)
Run
Additives
Isolated yield (%)
1
2
3
4
5
a
Bu4NOH (1 M aqueous)
Pr4NOH (1 M aqueous)
Bu4NF (1 M THF)
Bu4NCl
20
20
40
40
20
84
67–74b
11c
0
KOH
3
Reaction conditions: 1 (1 mmol), 2a (1.2 mmol), PdCl2(PPh3)2 (2 mol%), CuI (4 mol%), additive (2 mmol), THF (5 ml), 80 ꢀC.
Several runs.
3-(2-Aminophenyl)-1-phenylprop-2-yn-1-ol was formed in 65% yield.
b
c
effective formation of 3a (run 1). The activity toward the
stabilization as compared with that produced from 1
and 2a–2l. Similar treatment of 1 with bispropargyl
alcohol 2n under the employed conditions afforded bis-
quinoline 3n [9] in 64% yield.
formation of 3a using tetrapropylammonium hydroxide
(TPAOH, 1 M aqueous solution) was revealed to be as
similarly effective as that using TBAOH (run 2). It is
known that TBAOH and tetrabutylammonium fluoride
(TBAF) are used as an activator in Pd/Cu-catalyzed
coupling reaction of terminal alkynes with aryl halides
(Sonogashira coupling) [3c]. However, in contrast to
TBAOH, TBAF was not effective for the formation of
3a (11% yield), whereas conventional Sonogashira cou-
pling product was rather produced as a major identifi-
able product (65%) (run 3). On the other hand, neither
coupling nor cyclization took place at all with the intro-
duction of tetrabutylammonium chloride (run 4). Per-
forming the reaction under the addition of KOH
produced 3a in only 3% yield without the production
of coupled acetylenic carbinols and both startings were
recoverd almost completely (run 5).
As to the reaction pathway, this seems to proceed
via initial coupling between 1 and 2 to produce cou-
pled acetylenic carbinol 4, which in turn triggers isom-
erization to form a,b-unsaturated carbonyl compound
6 via an allenol 5 and subsequent cyclodehydration to
give quinoline 3 (Scheme 1). It is known that several
bases [10] and transition metals [5b,11] catalyze the
isomerization of propargyl alcohols to enones or en-
als. Thus, it appears that TBAOH in the present reac-
tion works as a promoter for both coupling [3c] and
isomerization.
3. Conclusion
Having controlled reaction conditions, various termi-
nal acetylenic carbinols 2 were subjected to react with 1
in order to investigate the reaction scope and several
representative results are summarized in Table 2. With
terminal acetylenic carbinols (2a–2j) the coupling and
cyclized products (3a–3j) were formed in the range of
59–92% yields without any identifiable side product.
The product yield was not significantly affected by the
electronic nature of the substituent on the aromatic ring
of 2a–2j, whereas the position of that had some rele-
vance to the product yield. The reaction proceeds like-
wise with 1-(2-thienyl)prop-2-yn-1-ol (2k) to give the
corresponding quinoline 3k in similar yield. 1-(2-Naph-
thyl)prop-2-yn-1-ol (2l) was also readily coupled and
cyclized with 1 to afford 2-(2-naphthyl)quinoline (3l) in
68% yield. In the case of dec-1-yn-3-ol (2m), the reaction
did not proceed at all toward cyclization, coupling prod-
uct, 1-(2-aminophenyl)dec-1-yn-3-ol being produced in
68% yield as an only identifiable product. The uneasy
isomerization of a coupled acetylenic carbinol produced
from 1 and 2m seems to be due to deficient resonance
In summary, it has been shown that 2-iodoaniline
undergoes tandem coupling, isomerization and cyclode-
hydration with an array of terminal acetylenic carbinols
in the presence of a catalytic amount of PdCl2(PPh3)2
and CuI along with aqueous tetrabutylammonium
hydroxide to give 2-arylquinolines in high yields. The
present reaction is a convenient one-pot synthetic route
for 2-arylquinolines from 2-iodoaniline and terminal
acetylenic carbinols. Further study on the synthetic
applications for heterocycles using present catalytic sys-
tem is currently under investigation.
4. 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
(m.p.) were determined on a Thomas–Hoover capillary
melting point apparatus and were uncorrected. The

4096
C.S. Cho / Journal of Organometallic Chemistry 690 (2005) 4094–4097
I
Table 2
Palladium-catalyzed synthesis of 3 from 1 and 2a
OH
[Pd], CuI
TBAOH
+
Ar
NH2
N
Ar
O
2
3
Yield (%)
OH
1
2
3
N
R
R
OH
Ar
Ar
2a R = H
3a R = H
84
59
92
90
74
84
68
71
74
70
2b R = 2-Me
2c R = 3-Me
2d R = 4-Me
2e R = 2-OMe
2f R = 3-OMe
2g R = 4-OMe
2h R = 4-Cl
2i R = 4-F
3b R = 2-Me
3c R = 3-Me
3d R = 4-Me
3e R = 2-OMe
3f R = 3-OMe
3g R = 4-OMe
3h R = 4-Cl
3i R = 4-F
NH2
NH2
4
6
OH
Ar
2j R = 2,3-(OMe)2
3j R = 2,3-(OMe)2
OH
NH2
S
80
S
N
5
2k
3k
Scheme 1.
OH
68
N
4.1. Typical experimental procedure
2l
3l
A mixture of 1 (0.219 g, 1 mmol), 2a (0.159 g,
1.2 mmol), PdCl2(PPh3)2 (0.014 g, 0.02 mmol), CuI
(0.008 g, 0.04 mmol) and tetrabutylammonium hydrox-
ide (2 ml of 1 M aqueous solution) in THF (5 ml) was
placed in a 20 ml flask and allowed to react at 80 ꢀC
(oil bath temperature). The reaction mixture was filtered
through a short silica gel column (ethyl acetate) to elim-
inate inorganic salts. Removal of the solvent left a crude
mixture, which was separated by column chromatogra-
phy (silica gel, EtOAc-hexane = 1/5) to give 3a
(0.172 g, 84%).
OH
0b
N
6
6
2m
3m
OH
OH
N
N
64c
2n
a
3n
All reactions were carried out with 1 (1 mmol), 2 (1.2 mmol),
PdCl2(PPh3)2 (0.02 mmol), CuI (0.04 mmol), and TBAOH (2 mmol) in
Except for 3n, all quinolines prepared by the above
procedure were characterized by GLC and spectroscopic
comparison with authentic samples synthesized by our
recent reports [7g,10c].
THF (5 ml) at 80 ꢀC for 24 h unless otherwise stated.
1-(2-Aminophenyl)dec-1-yn-3-ol was isolated in 58% yield.
b
c
Reaction conditions: 1 (2 mmol), 2n (1.2 mmol), PdCl2(PPh3)2
(0.04 mmol), CuI (0.08 mmol), and TBAOH (4 mmol) in THF (5 ml)
4.1.1. 1,3-Di-(20-quinolinyl)benzene (3n)
at 80 ꢀC for 24 h.
Yellow orange solid, m.p. 138–139 ꢀC (from ether–
CH2Cl2) (lit. [9] 139–140 ꢀC); 1H NMR (CDCl3): d
7.51 (td, J = 7.5 and 1.0 Hz, 2H), 7.66 (t, J = 7.8 Hz,
1H), 7.70–7.74 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.97
(d, J = 9.0 Hz, 2H), 8.19–8.28 (m, 6H), 8.95 (s, 1H);
13C NMR (CDCl3): d 119.09, 126.33, 126.75, 127.26,
127.48, 128.49, 129.37, 129.67, 136.81, 140.18, 148.25,
157.04.
GLC analyses were carried out with Shimadzu GC-17A
(FID) equipped with CBP10-S25-050 column (Shima-
dzu, a silica fused capillary column, 0.33 mm · 25 m,
0.25 lm film thickness) using N2 as carrier gas. The iso-
lation of pure products was carried via column chroma-
tography (silica gel 60, 70–230 mesh, Merck).
Commercially available organic and inorganic com-
pounds were used without further purification. Terminal
acetylenic carbinols (2a–2n) were prepared from alde-
hydes and ethynylmagnesium bromide by the reported
method [12].
Acknowledgement
The present work was supported by a Research Pro-
fessor Grant of Kyungpook National University (2004).

C.S. Cho / Journal of Organometallic Chemistry 690 (2005) 4094–4097
4097
[7] (a) For our recent report on ruthenium-catalyzed synthesis of
quinolines: C.S. Cho, B.H. Oh, S.C. Shim, Tetrahedron Lett. 40
(1999) 1499;
References
[1] (a) K. Sonogashira, Y. Tohda, N. Hagiwaha, Tetrahedron Lett.
(1975) 4467;
(b) C.S. Cho, B.H. Oh, S.C. Shim, J. Heterocycl. Chem. 36 (1999)
1175;
(b) K. Sonogashira, J. Organomet. Chem. 653 (2002) 46;
(c) K. Sonogashira, in: B.M. Trost, I. Fleming (Eds.), Compre-
hensive organic synthesis, vol. 3, Pergamon, Oxford, 1991, p. 521;
(d) K. Sonogashira, in: P.J. Stang, F. Diederich (Eds.), Metal-
catalyzed cross-coupling reactions, Wiley-VCH, Weinheim, 1998,
pp. 203–229.
(c) C.S. Cho, J.S. Kim, B.H. Oh, T.-J. Kim, S.C. Shim,
Tetrahedron 56 (2000) 7747;
(d) C.S. Cho, B.H. Oh, J.S. Kim, T.-J. Kim, S.C. Shim, Chem.
Commun. (2000) 1885;
(e) C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, Chem. Commun.
(2001) 2576;
[2] (a) W.A. Herrmann, C.-P. Reisinger, M. Spiegler, J. Organomet.
Chem. 557 (1998) 93;
(f) C.S. Cho, T.K. Kim, B.T. Kim, T.-J. Kim, S.C. Shim, J.
Organomet. Chem. 650 (2002) 65;
(b) W.A. Herrmann, V.P.W. Bo¨hm, C.-P. Reisinger, J. Organo-
met. Chem. 576 (1999) 23;
(g) C.S. Cho, B.T. Kim, H.-J. Choi, T.-J. Kim, S.C. Shim,
Tetrahedron 59 (2003) 7997.
(c) T. Hundertmark, A.F. Littke, S.L. Buchwald, G.C. Fu, Org.
Lett. 2 (2000) 1729;
[8] (a) For our recent report on palladium-catalyzed synthesis of
cyclic compounds: C.S. Cho, D.K. Lim, N.H. Heo, T.-J. Kim,
S.C. Shim, Chem. Commun. (2004) 104;
(d) V.P.W. Bo¨hm, W.A. Herrmann, Eur. J. Org. Chem. (2000)
3679.
(b) C.S. Cho, D.K. Lim, J.Q. Zhang, T.-J. Kim, S.C. Shim,
Tetrahedron Lett. 45 (2004) 5653.
[3] (a) A. Mori, J. Kawashima, T. Shimada, M. Suguro, K.
Hirabayashi, Y. Nishihara, Org. Lett. 2 (2000) 2935;
(b) A. Mori, T. Kondo, T. Kato, Y. Nishihara, Chem. Lett.
(2001) 286;
[9] C. Bonnefous, A. Chouai, R.P. Thummel, Inorg. Chem. 40 (2001)
5851.
[10] (a) A. Arcadi, S. Cacchi, F. Marinelli, D. Misti, Tetrahedron
Lett. 29 (1988) 1457;
(c) A. Mori, T. Shimada, T. Kondo, A. Sekiguchi, Synlett (2001)
649.
[4] (a) K. Minn, Synlett (1991) 115;
(b) T. Ishikawa, T. Mizuta, K. Hagiwara, T. Aikawa, T. Kudo,
S. Saito, J. Org. Chem. 68 (2003) 3702;
(b) N.G. Kundu, P. Das, J. Chem. Soc., Chem. Commun. (1995)
99;
(c) T.J.J. Muller, M. Ansorge, D. Aktah, Angew. Chem. Int. Ed.
¨
(c) C.S. Cho, N.Y. Lee, T.-J. Kim, S.C. Shim, J. Heterocycl.
Chem. 41 (2004) 409.
[11] (a) X. Lu, J. Ji, C. Guo, W. Shen, J. Organomet. Chem. 428
(1992) 259;
39 (2000) 1253.
[5] (a) N.G. Kundu, J.S. Mahanty, P. Das, B. Das, Tetrahedron
Lett. 34 (1993) 1625;
(b) Y. Shvo, Y. Blum, D. Reshef, J. Organomet. Chem. 238
(1982) C79;
(b) J.S. Mahanty, M. De, P. Das, N.G. Kundu, Tetrahedron 53
(1997) 13397.
(c) Y. Tsuji, Y. Yokoyama, K.-T. Huh, Y. Watanabe, Bull.
Chem. Soc. Jpn. 60 (1987) 3456;
[6] (a) It is known that several cyclic compounds are directly formed
during Sonogashira coupling: N.G. Kundu, M. Pal, J.S. Mahanty,
S.K. Dasgupta, J. Chem. Soc., Chem. Commun. (1992) 41;
(b) N.G. Kundu, M. Pal, J. Chem. Soc., Chem. Commun. (1993)
86;
(d) D. Ma, X. Lu, J. Chem. Soc., Chem. Commun. (1989) 890;
(e) B.M. Trost, R.C. Livingston, J. Am. Chem. Soc. 117 (1995)
9586;
(f) M.K.E. Saiah, R. Pellicciari, Tetrahedron Lett. 36 (1995)
4497;
(c) J.W. Herndon, Y. Zhang, K. Wang, J. Organomet. Chem. 634
(2001) 1;
(g) D. Ma, X. Lu, Tetrahedron Lett. 30 (1989) 2109.
[12] M.C. Bagley, K.E. Bashford, C.L. Hesketh, C.J. Moody, J. Am.
Chem. Soc. 122 (2000) 3301.
(d) M.M. Heravi, A. Keivanloo, M. Rahimizadeh, M. Bakavoli,
M. Ghassemzadeh, Tetrahedron Lett. 45 (2004) 5747.