A recyclable palladium-catalyzed modified Friedl?nder quinoline synthesis

Article abstract of DOI:10.1016/j.jorganchem.2007.06.022

2-Aminobenzyl alcohol reacts with an array of ketones in toluene/poly(ethylene glycol) (PEG-2000) at 100 °C in the presence of a palladium catalyst along with KOH under an atmosphere of air to give the corresponding quinolines in good yields. The catalytic system could be recovered and reused five times without any loss of catalytic activity.

Full text of DOI:10.1016/j.jorganchem.2007.06.022

Journal of Organometallic Chemistry 692 (2007) 4182–4186
www.elsevier.com/locate/jorganchem
Note
A recyclable palladium-catalyzed modified Friedlander
¨
quinoline synthesis
a,
b
Chan Sik Cho *, Wen Xiu Ren
a
Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, Republic of Korea
Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea
b
Received 20 April 2007; received in revised form 12 June 2007; accepted 12 June 2007
Available online 23 June 2007
Abstract
2-Aminobenzyl alcohol reacts with an array of ketones in toluene/poly(ethylene glycol) (PEG-2000) at 100 ꢀC in the presence of a
palladium catalyst along with KOH under an atmosphere of air to give the corresponding quinolines in good yields. The catalytic system
could be recovered and reused five times without any loss of catalytic activity.
ꢁ 2007 Elsevier B.V. All rights reserved.
Keywords: 2-Aminobenzyl alcohol; Ketones; Recyclable palladium catalyst; Poly(ethylene glycol); Quinolines
1. Introduction
and secondary alcohols [8] (modified Friedla¨nder quinoline
synthesis) (Scheme 1) [9,10]. It was also disclosed that
2-aminobenzyl alcohol was found to be oxidatively coupled
and cyclized with ketones and aldehydes in the presence of
an inexpensive copper catalyst [11,12]. However, these
protocols have some drawbacks requiring an expensive
consumable transition metal catalyst. Under these circum-
stances, we have directed our attention to the discovery of
a reusable catalyst for the synthesis of quinolines from 2-
aminobenzyl alcohol and ketones. Herein, this report
describes a recyclable palladium-catalyzed protocol for
the modified Friedla¨nder quinoline synthesis.
Besides conventional named quinoline routes such as
Skraup, Do¨bner-von Miller, Conrad-Limpach, Friedla¨nder
and Pfitzinger syntheses [1], homogeneous transition metal-
catalyzed reactions have also been developed as alternative
methods for the construction of quinoline framework
because of the facility and efficiency of reaction and the
wide availability of substrate [2]. We also reported on sev-
eral transition metal catalyzed routes for quinolines via
ruthenium-catalyzed alkyl or alkanol group transfer from
alkylamines or alkanolamines to N-atom of anilines (amine
exchange reaction [3]) [2b,4] and palladium-catalyzed cou-
pling, isomerization and cyclization between 2-iodoaniline
and propargylic alcohols [5]. Furthermore, in connection
with this report, during the course of our continuous stud-
ies on ruthenium-catalyzed carbon–carbon bond forming
reactions between ketones (or secondary alcohols) and pri-
mary alcohols (or aldehydes) [6], we have also reported on
ruthenium-catalyzed synthesis of quinolines via an oxida-
tive cyclization of 2-aminobenzyl alcohol with ketones [7]
2. Results and discussion
Based on our recent report on ruthenium- and copper-
catalyzed oxidative coupling and cyclization of 2-aminob-
enzyl alcohol (1) with ketones (2) and aldehydes [7,8,11],
Table 1 shows several attempted results of reactions
between 1 and acetophenone (2a) under various palladium
catalytic systems. Treatment of 1 with 2 equiv of 2a in tol-
uene in the presence of a catalytic amount of Pd(OAc)2
(2 mol%) along with KOH at 100 ꢀC for 20 h afforded
2-phenylquinoline (3a) in 83% yield with concomitant
*
Corresponding author. Tel.: +82 53 950 7318; fax: +82 53 950 6594.
E-mail address: cscho@knu.ac.kr (C.S. Cho).
0022-328X/$ - see front matter ꢁ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.06.022

C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 692 (2007) 4182–4186
4183
2000 (condition B), and several representative results are
summarized in Table 2. Various aryl(methyl) ketones
(2a–h) having electron donating and withdrawing
substituents on the aromatic ring were readily coupled
and cyclized with 1 to give the corresponding quinolines
(3a–h) along with minimal formation of aryl(methyl) car-
binols as identifiable direct transfer hydrogenation prod-
ucts. Generally, the catalytic system using Pd(OAc)2
combined with PEG-2000 (condition B) was superior to
that using nano-palladium (condition A) toward the
formation of 3. Under condition A, the product yield
was not significantly affected by the position of the substi-
tuent on the aromatic ring of 2a–h, whereas the electronic
nature of that had some relevance to the product yield.
However, under condition B, quinolines were produced
nearly invariable yields irrespective of the position and
electronic nature of that. 20-Acetonaphthone (2i) were also
readily coupled and cyclized with 1 to afford 2-(2-naph-
thyl)quinoline (3i) in similar yields under both reaction
conditions. With heteroaryl(methyl) ketone 2j, the product
yield was lower than that when aryl(methyl) ketones were
used. Higher reaction rate and yield were observed with
alkyl(aryl) ketones (2k and 2l), which has only methylene
reaction site. In the reaction of alkyl- (methyl) ketones
(2m and 2n) the corresponding quinolines were obtained
CHO
NH2
base
conventional
R
O
OH
R
R
R
R
R
N
[M], base
modified
OH
NH2
Scheme 1. Friedlander quinoline synthesis.
Table 1
Palladium-catalyzed reaction of 1 with 2a under several conditionsa
OH
NH2
O
Pd, KOH
+
toluene, 100 oC, 20 h
Ph
N
Ph
1
2a
3a
Entry
Palladium catalysts
Isolated yield (%)
1
2
3
4
5
6
1
2
3
4
5
a
Pd(OAc)2
Nano-Pd
Pd(OAc)2/PEG-2000b
PdCl2/PEG-2000b
Pd/C/PEG-2000b
83
75
76
71
50
75
80
60
71
69
77
67
66
68
58
71
74
75
78
67
53
74
88
58
72
Reaction conditions: 1 (1 mmol), 2a (2 mmol), palladium catalyst
(0.02 mmol), KOH (3 mmol), toluene (3 ml), 100 ꢀC, 20 h.
as
a
regioisomeric mixture in similar yields and
b
PEG-2000 (0.3 g).
distributions under both reaction conditions, favoring
cyclization at less-hindered position over a-methylene.
With dialkyl ketone 2p 3-butyl-2-pentylquinoline (3p)
was also formed in 31% and 41% yields, respectively,
under condition A and condition B and the product yield
was lower than that when previously described ketones
were used. Cyclic ketones such as 4-phenylcyclohexanone
(2q) and 1-tetralone (2r) were also reacted with 1 to give
3-phenyl-1,2,3,4-tetrahydroacridine (3q) and 5,6-dihydro-
benzo[c]acridine (3r) in 89% (94%) and 72% (79%) yields,
respectively, under condition A (condition B).
Similar treatment of 1 with octyl aldehyde (4) under
nano-Pd catalytic system afforded 3-hexylquinoline (3s) in
44% yield along with a considerable amount of oxazine 5
(9% yield) (Scheme 2). When the catalyst was reused, the
yield of 3s decreased from 44%, 34% (first reuse), to 24%
(second reuse), while that of 5 increased from 9%, 22%
(first reuse), to 30% (second reuse).
formation of 1-phenylethanol by transfer hydrogenation
of 2a by 1 (58% yield based on 1 by GLC analysis of
the crude mixture) (entry 1) [13]. Prompted by this result,
we have directed our attention to the recyclable palladium
catalytic system for the present cyclization. It is recently
known that palladium nanoparticles (nano-Pd) can be pre-
pared by treatment of poly(ethyleneglycol) (PEG) with
Pd(OAc)2 and are found to be a highly stable and reusable
catalyst for Heck reaction [14]. Applying of this nano-Pd
prepared from Pd(OAc)2 and PEG-2000 to the present
reaction resulted in 75% yield of 3a and the recycling
potential of the catalytic system could be reused five times
without any loss of catalytic activity (entry 2). It is also
reported by several groups that poly(ethylene glycol)
(PEG) is used as a recyclable medium along with a transi-
tion metal catalyst [15]. The addition of PEG-2000 to the
catalytic system of entry 1 resulted in 76% yield of 3a and
a palladium catalyst could be easily solidified along with
PEG-2000 by cooling and separated by filtration (entry
3). The recovered palladium/PEG-2000 could also be
reused five times without any loss of catalytic activity.
The catalytic systems using palladium precursors such as
PdCl2 and Pd/C combined with PEG-2000 exhibited sim-
ilar catalytic activity as Pd(OAc)2/PEG-2000 system
(entries 4 and 5).
3. Conclusion
In summary, we have shown that 2-aminobenzyl alcohol
undergoes oxidative cyclization with an array of ketones in
the presence of a palladium catalyst combined with PEG-
2000 along with KOH to give quinolines in good yields.
The palladium/PEG-2000 catalytic system could be easily
recovered from reaction mixture and reused five times
without any loss of catalytic activity. To the best of our
knowledge, this protocol is the first recyclable transition
metal-catalyzed strategy for modified Friedla¨nder quino-
line synthesis.
Given these results, the reactions of 1 with various
ketones 2 were screened using two sets of reaction condi-
tions, nano-palladium (condition A) and Pd(OAc)2/PEG-

4184
C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 692 (2007) 4182–4186
Table 2
Recyclable palladium-catalyzed synthesis of quinolines 3 from 1 and 2a
Ketones 2
Quinolines 3
Yield (%)
Condition Ab
Condition Bc
O
R
N
R
2a R = Ph
3a R = Ph
75
58
78
68
60
75
73
47
61
38
76
80
85
70
76
85
87
78
78
35
2b R = 4-MeC6H4
2c R = 3-MeC6H4
2d R = 2-MeC6H4
2e R = 4-MeOC6H4
2f R = 3-MeOC6H4
2g R = 2-MeOC6H4
2h R = 3-CF3C6H4
2i R = 2-naphthyl
2j R = 2-thienyl
3b R = 4-MeC6H4
3c R = 3-MeC6H4
3d R = 2-MeC6H4
3e R = 4-MeOC6H4
3f R = 3-MeOC6H4
3g R = 2-MeOC6H4
3h R = 3-CF3C6H4
3i R = 2-naphthyl
3j R = 2-thienyl
85
88
O
Ph
N
N
N
Ph
Ph
2k
3k
3l
69
79
O
Ph
Ph
2l
Ph
47d
47e
58
49f
49g
65
O
Ph
2m
Ph
3m
3n
O
N
N
2n
O
Ph
Ph
2o
3o
3p
31
89
41
94
O
3
4
4
N
3
2p
Ph
O
N
3q
Ph
2q

C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 692 (2007) 4182–4186
4185
Table 2 (continued)
Ketones 2
Quinolines 3
Yield (%)
Condition Ab
72
Condition Bc
79
O
N
2r
3r
a
Reaction conditions: 1 (1 mmol), 2 (2 mmol), palladium (0.02 mmol), KOH (3 mmol), toluene (3 ml), 100 ꢀC, for 20 h.
Nano-Pd (0.02 mmol).
Pd(OAc)2 (0.02 mmol), PEG-2000 (0.3 g).
3-Benzyl-2-methylquinoline was also formed in 18% yield.
3-Butyl-2-methylquinoline was also formed in 23% yield.
3-Benzyl-2-methylquinoline was also formed in 28% yield.
3-Butyl-2-methylquinoline was also formed in 15% yield.
b
c
d
e
f
g
erator, the solidified Pd/PEG-2000 was filtered, washed
with dry ether, dried under vacuo and subjected to a sec-
ond run by charging with 1, 2a, KOH and toluene [18].
Removal of the solvent of the filtrate left an oil, which
was purified by thin-layer chromatography (silica gel, ethyl
acetate/hexane = 1/5) to give 2-phenylquinoline (3a)
(0.155 g, 75%).
Except for 3l, 3o, 3s and 5, all quinolines prepared by
the above procedure were characterized by GLC and
spectroscopic comparison with authentic samples synthe-
sized by our recent reports [7,8,16,17].
OH
nano-Pd, KOH
CHO
+
toluene, 100 oC, 20 h
NH2
1
4
O
+
N
N
H
3s
5
Scheme 2.
4. Experimental
4.1.1. 3-Benzyl-2-phenylquinoline (3l)
Solid, m.p. 91–92 ꢀC (from hexane–CHCl3) (lit. [19]
84–88 ꢀC); 1H NMR (CDCl3): d 4.12 (s, 2H), 6.99 (d,
J = 6.5 Hz, 2H), 7.16–7.25 (m, 3H), 7.40–7.52 (m, 6H),
7.65–7.69 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H),
8.14 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3): d 39.49,
126.65, 126.87, 127.50, 127.91, 128.57, 128.67, 128.87,
129.24, 129.39, 129.53, 129.70, 132.89, 137.39, 140.34,
141.03, 147.03, 161.13.
1H and 13C NMR (400 and 100 MHz) spectra were
recorded on a Bruker Avance Digital 400 spectrometer
using TMS as an internal standard. Melting points were
determined on a Thomas-Hoover capillary melting point
apparatus and were uncorrected. GLC analyses were car-
ried out with a Shimadzu GC-17A instrument equipped
with a CBP10-S25-050 column (Shimadzu, fused silica cap-
illary column, 0.33 mm · 25 m, 0.25 lm film thickness)
using nitrogen as carrier gas. The isolation of pure prod-
ucts was carried out via column chromatography (silica
gel 60, 70–230 mesh, Merck) and thin layer chromatogra-
phy (silica gel 60 GF254, Merck). Nano-Pd catalyst was
prepared from Pd(OAc)2 and PEG-2000 [poly(ethylene gly-
col-2000)] by the reported method [14]. Commercially
available organic and inorganic compounds were used
without further purification except for toluene, which was
distilled by known method before use.
4.1.2. 2-Isopropyl-3-phenylquinoline (3o)
Solid, m.p. 87–88 ꢀC (from hexane–CHCl3) (lit. [20]
194–195 ꢀC (picrate)) 1H NMR (CDCl3): d 1.29 (d,
J = 7.0 Hz, 6H), 3.21–3.24 (sp, 1H), 7.37–7.49 (m, 6H),
7.65–7.69 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H),
8.10 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3): d 22.87,
32.56, 126.27, 126.84, 127.76, 127.78, 128.67, 129.36,
129.77, 135.50, 136.65, 140.68, 147.92, 165.82.
4.1.3. 3-Hexylquinoline (3s) [12a]
4.1. Typical experimental procedure
Oil; 1H NMR (CDCl3): d 0.89 (t, J = 6.6 Hz, 3H), 1.29–
1.40 (m, 6H), 1.68–1.75 (m, 2H), 2.79 (t, J = 7.8 Hz, 2H),
7.49–7.53 (m, 1H), 7.63–7.67 (m, 1H), 7.76 (d,
J = 8.0 Hz, 1H), 7.90 (d, J = 1.0 Hz, 1H), 8.08 (d,
J = 8.5 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H); 13C NMR
(CDCl3): d 14.04, 22.54, 28.83, 31.07, 31.61, 33.17,
126.46, 127.25, 128.16, 128.44, 129.10, 134.05, 135.35,
146.71, 152.10.
A mixture of 2-aminobenzyl alcohol (1) (0.123 g,
1 mmol), acetophenone (2a) (0.240 g, 2 mmol), KOH
(0.168 g, 3 mmol), Pd(OAc)2 (0.0045 g, 0.02 mmol) and
PEG-2000 (0.300 g) in toluene (3 ml) was placed in a
5 ml screw-capped vial and allowed to react at 100 ꢀC for
20 h. After the brown black solution was cooled in refrig-

4186
C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 692 (2007) 4182–4186
[9] (a) P. Friedla¨nder, Chem. Ber. 15 (1882) 2572;
4.1.4. 2-Heptyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (5)
Oil; 1H NMR (CDCl3): d 0.89 (t, J = 6.8 Hz, 3H), 1.29–
1.34 (m, 8H), 1.43–1.57 (m, 2H), 1.63–1.79 (m, 2H), 4.54 (t,
J = 5.5 Hz, 1H), 4.80 (d, J = 14.6 Hz, 1H), 4.94 (d,
J = 14.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.79 (t,
J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 7.06 (t,
J = 7.5 Hz, 1H); 13C NMR (CDCl3): d 14.48, 23.04,
24.91, 29.58, 29.87, 32.16, 35.60, 68.06, 84.79, 117.60,
120.02, 123.00, 125.38, 127.71, 141.98. Anal. Calcd for
C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.37;
H, 9.85; N, 5.91%.
(b) J.M. Muchowski, M.L. Maddox, Can. J. Chem. 82 (2004) 461.
[10] For a review, see: C.-C. Cheng, S.-J. Yan, Org. React. 28 (1982) 37.
[11] C.S. Cho, W.X. Ren, S.C. Shim, Tetrahedron Lett. 47 (2006) 6781.
[12] (a) For similar ruthenium- and iridium-catalyzed oxidative cyclization
of 2-aminobenzyl alcohol with ketones leading to quinolines: K.
Motokura, T. Mizugaki, K. Ebitani, K. Kaneda, Tetrahedron Lett.
45 (2004) 6029;
´
´
(b) R. Martınez, G.J. Brand, D.J. Ramon, M. Yus, Tetrahedron
Lett. 46 (2005) 3683;
(c) K. Taguchi, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 46 (2005)
4539.
[13] (a) For recent reviews on transition metal-catalyzed transfer hydro-
genation, see: G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev.
92 (1992) 1051;
Acknowledgement
(b) J.-E. Ba¨ckvall, R.L. Chowdhury, U. Karlsson, G. Wang, in: A.F.
Williams, C. Floriani, A.E. Merbach (Eds.), Perspectives in Coordi-
nation Chemistry, VCH, New York, 1992, pp. 463–486;
(c) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 30 (1997) 97;
(d) T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 98 (1998)
2599;
C.S.C. gratefully acknowledges a Research Professor
Grant of Kyungpook National University (2006).
(e) M. Palmer, M. Wills, Tetrahedron: Asymmetry 10 (1999)
2045.
References
[14] C. Luo, Y. Zhang, Y. Wang, J. Mol. Cat. A: Chem. 229 (2005) 7.
[15] (a) For poly(ethylene glycol) (PEG) as a recyclable medium along
with a transition metal catalyst, see: S. Chandrasekhar, Ch. Nars-
ihmulu, S.S. Sultana, N.R. Reddy, Org. Lett. 4 (2002) 4399;
(b) D.J. Heldebrant, P.G. Jessop, J. Am. Chem. Soc. 125 (2003)
5600;
[1] G. Jones, in: A.R. Katritzky, C.W. Rees (Eds.), Comprehensive
Heterocyclic Chemistry, vol. 2, Pergamon, New York, 1984, p. 395.
[2] (a) H. Amii, Y. Kishikawa, K. Uneyama, Org. Lett. 3 (2001) 1109,
and references cited therein;
(b) C.S. Cho, B.H. Oh, J.S. Kim, T.-J. Kim, S.C. Shim, Chem.
Commun. (2000) 1885, and references cited therein.
[3] For a review: S.-I. Murahashi, Angew. Chem., Int. Ed. Engl. 34
(1995) 2443.
(c) J.-H. Li, Q.M. Zhu, Y. Liang, D. Yang, J. Org. Chem. 70
(2005) 5347;
(d) J.-H. Li, W.-J. Liu, Y.-X. Xie, J. Org. Chem. 70 (2005) 5409;
(e) W. Mai, L. Gao, Synlett (2006) 2553;
(f) L. Wang, Y. Zhang, L. Liu, Y. Wang, J. Org. Chem. 71 (2006)
1284;
(g) S. Chandrasekhar, S.S. Sultana, S.R. Yaragorla, N.R. Reddy,
Synthesis (2006) 839.
[4] (a) C.S. Cho, B.H. Oh, S.C. Shim, Tetrahedron Lett. 40 (1999) 1499;
(b) C.S. Cho, B.H. Oh, S.C. Shim, J. Heterocycl. Chem. 36 (1999)
1175;
(c) C.S. Cho, J.S. Kim, B.H. Oh, T.-J. Kim, S.C. Shim, Tetrahedron
56 (2000) 7747;
(d) C.S. Cho, T.K. Kim, B.T. Kim, T.-J. Kim, S.C. Shim, J.
Organomet. Chem. 650 (2002) 65.
[16] C.S. Cho, N.Y. Lee, T.-J. Kim, S.C. Shim, J. Heterocycl. Chem. 41
(2004) 409.
[17] C.S. Cho, W.X. Ren, S.C. Shim, Bull. Korean Chem. Soc. 26 (2005)
1286.
[5] C.S. Cho, J. Organomet. Chem. 690 (2005) 4094.
[6] (a) C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, Tetrahedron Lett. 43
(2002) 7987;
[18] The weight of solidified catalytic mixture gradually increased from
0.480 g (first), 0.638 g (second), to 0.735 g (third) due to further
addition of KOH. Further addition of KOH was necessary for the
effective formation of 3a. Performing the reaction using first recovered
solidified catalytic mixture under no further addition of KOH
afforded 3a in only 14% isolated yield.
(b) C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, J. Org. Chem. 66
(2001) 9020;
(c) C.S. Cho, B.T. Kim, H.-S. Kim, T.-J. Kim, S.C. Shim, Organo-
metallics 22 (2003) 3608.
[7] C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, Chem. Commun. (2001)
2576.
[8] C.S. Cho, B.T. Kim, H.-J. Choi, T.-J. Kim, S.C. Shim, Tetrahedron
59 (2003) 7997.
[19] S. Tanaka, M. Yasuda, A. Baba, J. Org. Chem. 71 (2006) 800.
[20] E.H. Sund, H.R. Henze, J. Chem. Eng. Data 15 (1970) 578.