Ruthenium-catalyzed synthesis of quinolines from anilines and allylammonium chlorides in an aqueous medium via amine exchange reaction

Article abstract of DOI:10.1016/S0040-4020(00)00694-3

Anilines react with allylammonium chlorides in an aqueous medium (H₂O-dioxane) in the presence of a catalytic amount of RuCl₂(PPh₃)₃ together with SnCl₂·2H₂O to give the corresponding quinolines in moderate to good yields. The existence of SnCl₂·2H₂O is necessary for the effective formation of quinolines, and a reaction pathway involving amine exchange reaction between anilines and allylammonium chlorides to form an imine is proposed for this catalytic process. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00694-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7747±7750
Ruthenium-Catalyzed Synthesis of Quinolines from Anilines and
Allylammonium Chlorides in an Aqueous Medium via Amine
Exchange Reaction
Chan Sik Cho,a Joon Seok Kim,a Byoung Ho Oh,a Tae-Jeong Kim,a Sang Chul Shima,
*
and Nam Sik Yoonb
aDepartment of Industrial Chemistry, College of Engineering, Kyungpook National University, Taegu 702-701, South Korea
bDepartment of Dyeing and Finishing, College of Engineering, Kyungpook National University, Taegu 702-701, South Korea
Received 10 July 2000; accepted 7 August 2000
AbstractÐAnilines react with allylammonium chlorides in an aqueous medium (H2O±dioxane) in the presence of a catalytic amount of
RuCl2(PPh3)3 together with SnCl2´2H2O to give the corresponding quinolines in moderate to good yields. The existence of SnCl2´2H2O is
necessary for the effective formation of quinolines, and a reaction pathway involving amine exchange reaction between anilines and
allylammonium chlorides to form an imine is proposed for this catalytic process. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
The several results of the ruthenium-catalyzed heteroannu-
lation between aniline (1a) and N,N-diallyl-N,N-dipropy-
lammonium chloride (2a) under various reaction
conditions are listed in Table 1 (Scheme 1). The reaction
was performed under analogous reaction conditions such as
the molar ratio of 1a to 2a and the amount of SnCl2´2H2O
as has been optimized in our recent ruthenium-catalyzed
synthesis of indoles and quinolines.6±10 In all cases, N-
propylaniline (4) was formed as a side product by an
alkyl group transfer between 1a and 2a and hydrogenation
under the ruthenium catalyst. As shown in Table 1, the
yield of 2-ethyl-3-methylquinoline (3a) was considerably
affected by solvent system, the aqueous medium of H2O/
dioxane (1/9) being shown to be best for obtaining 3a (runs
1±4). Dioxane could be alternatively used as solvent,
whereas the yield of 4 was higher than that when an
aqueous medium was used (run 5). The existence of
SnCl2´2H2O was necessary for the effective formation of
3a as has been observed in our ruthenium-catalyzed synth-
esis of indoles and quinolines, the yield of 3a being 47% in
the absence of SnCl2´2H2O for a longer reaction time (run
6). A variety of phosphorus chelating and phosphite
ligands combined with RuCl3´nH2O can also be used in
place of PPh3, but the yield of 3a was generally lower
than when PPh3 was used (runs 7±11). Among catalyst
precursors examined, RuCl2(PPh3)3 exhibited nearly the
same catalytic activity as RuCl3´nH2O/3PPh3 under the
employed reaction conditions (runs 12±14) and the forma-
tion of N-propylaniline was suppressed in comparison to
the catalytic activity of RuCl3´nH2O/3PPh3.
It is well known that quinoline nucleus plays an important
role as an intermediate for the design of many antimalarial
compounds. Various named reactions such as the Skraup,
È
Dobner-von Miller, Conrad-Limpach, Friedlaender and P®t-
zinger syntheses are commonly used routes for the forma-
tion of quinolines. In contrast to the conventional syntheses
which frequently require harsh and cumbersome acidic
reaction conditions, the formation of quinoline skeletons
also has been attempted by a remarkable catalytic action
of transition metal catalysts such as palladium,1 rhodium,2
ruthenium,3 and iron.4 As part of our continuing studies on
transition metal-catalyzed synthesis of N-heterocyclic
compounds, we recently developed and reported a novel
ruthenium-catalyzed synthetic approach for the formation
of indoles5±8 and quinolines9,10 via a mechanistic amine
exchange reaction between anilines and funtionalized
aliphatic amines.11 However, a clear-cut example for the
synthesis of N-heterocyclic compounds using amine
exchange reaction seems to be limited to palladium-cata-
lyzed synthesis of pyrimidines and imidazoles11d and afore-
mentioned our indoles and quinolines. We here report
another ruthenium-catalyzed approach for the synthesis of
quinolines from an array of anilines and allylammonium
chlorides in an aqueous medium via amine exchange reac-
tion.
Keywords: ruthenium; catalyst; cyclization; quinolines; aqueous medium.
* Corresponding author. Tel.: 182-53-950-5586; fax: 182-53-950-6594;
e-mail: scshim@kyungpook.ac.kr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00694-3

7748
C. S. Cho et al. / Tetrahedron 56 (2000) 7747±7750
Table 1. Ruthenium-catalyzed synthesis of 3a from 1a and 2a under various conditions (except as noted, all reaction were carried out with 1a (6 mmol), 2a
(1 mmol), ruthenium catalyst (5 mol% based on 2a), and SnCl2´2H2O (1 mmol) at 1808C)
Run
Ruthenium catalysts
H2O/Dioxane (mL/mL)
t(h)
Products and yield (%)a
3a
4
1
2
3
4
RuCl3´nH2O/3PPh3
RuCl3´nH2O/3PPh3
RuCl3´nH2O/3PPh3
RuCl3´nH2O/3PPh3
RuCl3´nH2O/3PPh3
RuCl3´nH2O/3PPh3
RuCl3´nH2O/1.5dppm
RuCl3´nH2O/1.5dppe
RuCl3´nH2O/1.5dppp
RuCl3´nH2O/1.5dppf
RuCl3´nH2O/3P(OEt)3
RuH2(PPh3)4
1/9
5/5
9/1
10/0
0/10
1/9
1/9
1/9
1/9
1/9
1/9
1/9
1/9
1/9
20
24
24
24
24
30
20
20
20
20
20
20
20
20
69
45
4
51
2
5
5
6
5
69
47
57
57
48
44
40
48
74
4
81
17
28
33
18
12
24
31
11
55
6b
7
8
9
10
11
12
13
14
RuCl2(PPh3)3
Ru3(CO)12
a Determined by GLC based on 2a.
b In the absence of SnCl2´2H2O.
From the reaction of an array of anilines (1b±1m) with
allylammonium chlorides (2a±2d) the corresponding
quinolines (3b±3m) were also formed in good yields, and
several representative results are summarized in Table 2. All
reactions were also accompanied by the formation of N-
propylanilines as a side product. The quinoline yield was
not decisively affected by the substituent effect in the aniline
derivatives. However, the product yield was generally lower
in the use of ortho-substituted anilines than in the employ-
ment of meta- and para-substituted anilines.12 In the cases
of meta-substituted anilines such as m-toluidine (1c) and m-
anisidine (1f), the corresponding quinolines (3c and 3f) were
obtained as a regioisomeric mixture, favoring 7-substituted
isomers which were formed via less sterically hindered posi-
tion on meta-substituted anilines. As shown in Table 2, the
reaction of an array of anilines with tetraallylammonium
chloride (2d) under the identical reaction conditions
afforded the corresponding quinolines 3 in higher yields as
compared with that in the reaction with allylammonium
chlorides 2a±2c.
Scheme 2. Quaternary ammonium salt 2 seems to be
converted into tertiary amine by cleavage of the
carbon±nitrogen bond in an aqueous medium.14 The
initial coordination of tertiary amine to ruthenium
followed by oxidative insertion of ruthenium in the
adjacent C±H bond forms an alkylruthenium complex
5, which rapidly equilibrates with an iminium ion
complex 6. Nucleophilic attack of 1a to the complex
6 gives a,b-unsaturated imine 7 along with [Ru]H2.
This is followed by selective reduction of 7 by
[Ru]H2 to afford imine 8. Subsequent steps seem to
proceed via the known Schiff-base dimerization and
Table 2. Ruthenium-catalyzed synthesis of 3 from 1 and 2 (all reactions
were carried out with 1 (6 mmol), 2 (1 mmol), RuCl2(PPh3)3 (5 mol% based
on 2), and SnCl2´2H2O (1 mmol) in H2O±dioxane (ˆ1 mL/9 mL) at 1808C
for 20 h)
1 (Rˆ)
2
3 (Rˆ)
H (3a)
Yield (%)a
H (1a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
2d
2d
57
64
48b
45
58
50c
34
62
23
62
66
62
63
37
33
93
82
74
86
48
91
4-Me (1b)
3-Me (1c)
2-Me (1d)
4-OMe (1e)
3-OMe (1f)
4-Cl (1g)
4-Et (1h)
2-Et (1i)
4-Bu (1j)
4-sec-Bu (1k)
3,5-Me (1l)
4-Acetyl (1m)
1a
1a
1a
1b
1d
1e
1g
1k
6-Me (3b)
5- and 7-Me (3c)
8-Me (3d)
6-OMe (3e)
7-OMe (3f)
6-Cl (3g)
6-Et (3h)
8-Et (3i)
6-Bu (3j)
6-sec-Bu (3k)
5,7-Me (3l)
6-Acetyl (3m)
3a
3a
3a
3b
3d
3e
3g
3k
Although the details of the present reaction pathway
including the role of SnCl2´2H2O are not yet fully
understood, a plausible pathway is presented is Scheme
2.13 The reaction seems to proceed via an initial forma-
tion of imines by ruthenium-catalyzed amine exchange
reactions between anilines and allylammonium chlor-
ides. It is well-known that the intermolecular alkyl
group transfer between alkylamines proceeds through
iminium ion complex under transition metals such as
palladium and ruthenium.11 Thus, the transfer of allylic
moiety from 2 to 1a can be rationalized by Cycle A in
a Isolated yield based on 2. In almost all cases N-propylanilines (,15%)
were formed.
1
b Regioisomeric ratio was determined by H NMR (300 MHz): 2-ethyl-
3,7-dimethylquinoline/2-ethyl-3,5-dimethylquinolineˆ9/1.
c Even if 2-ethyl-5-methoxy-3-methylquinoline is present, its amount is a
trace.
Scheme 1.

C. S. Cho et al. / Tetrahedron 56 (2000) 7747±7750
7749
Scheme 2.
ruthenium-mediated heteroannulation shown in Cycle B
in Scheme 2. It is known that anilines react with alipha-
tic aldehyde to give Schiff-base dimer on simple mixing
at room temperature.15 Watanabe et al. reported that the
Schiff-base dimer 9 was cyclized to give quinolines
under ruthenium catalyst through oxidative addition of
the ortho C±H bond of 9 to low valent ruthenium via
orthometallation, insertion of CvN double bond into
Ru±C bond of 10, reductive elimination of 11, and
deamination and dehydrogenation of 12.3c A similar
catalytic cycle has already been proposed in ruthe-
nium-catalyzed synthesis of indoles and quinolines by
us.
tion will be successfully applied for the synthesis of other N-
heterocyclic compounds.
Experimental
1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Varian Unity Plus 300 spectrometer using
TMS as an internal standard. Chemical shift are reported
in d units down®eld from TMS. GLC analyses were carried
out with Shimadzu GC-17A equipped with CBP10-S25-050
column (Shimadzu, a silica fused capillary column,
0.33 mm£25 m, 0.25 mm ®lm thickness) using N2 as carrier
gas. The isolation of pure products was carried out with
column chromatography (silica gel 60, 70±230 mesh,
On the other hand, when N,N-dibutyl-N,N-dicrotylammo-
nium chloride was used as cyclization counterpart in the
reaction with 1a under the same reaction conditions, the
reaction did not proceed satisfactory toward quinoline
formation (the yield of 3-ethyl-2-propylquinolineˆ9%),
instead, much more N-monoalkylated aniline was
produced (the yield of N-butylanilineˆ91%). Similar
treatment of 1a with tetrabutylammonium bromide
under identical reaction conditions afforded 3-ethyl-2-
propylquinoline in 11% yield together with N-butyl-
aniline (33%). This result indicates that the propyl
moiety of 2a also participates in the formation of quino-
lines.
Merck). RuH2(PPh3)4,16 RuCl2(PPh3)3,17 and Ru3(CO)12
18
were prepared by the reported method.
Typical procedure for ruthenium-catalyzed synthesis of
quinolines from anilines and allylammonium chlorides
A mixture of aniline (0.559 g, 6 mmol), N,N-diallyl-N,N-
dipropylammonium
chloride
(0.218 g,
1 mmol),
RuCl2(PPh3)3 (0.048 g, 0.05 mmol) and SnCl2´2H2O
(0.226 g, 1 mmol) in H2O±dioxane (1 mL/9 mL) was
placed in a pressure vessel. After the system was ¯ushed
with argon, the mixture was stirred at 1808C for 20 h. The
reaction mixture was passed through a short silica gel
column, poured into brine, extracted with CHCl3 and
dried over Na2SO4. Removal of the solvent left an oil
which was separated by column chromatography (ethyl ace-
tate±hexane mixture) to give 2-ethyl-3-methylquinoline
(0.098 g, 57%). All compounds are known except for 3i
and 3m.2d,8b
In summary, we have demonstrated that quinolines can be
synthesized by reaction of an array of anilines with allylam-
monium chlorides in the presence of a ruthenium catalyst in
an aqueous medium. The present aquatic heteroannulation is
a novel synthetic approach leading to quinolines via an
amine exchange reaction. We believe that this aquatic
process combined with a mechanistic amine exchange reac-

7750
C. S. Cho et al. / Tetrahedron 56 (2000) 7747±7750
1
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1067±1068. (b) Watanabe, Y.; Tsuji, Y.; Ohsugi, Y. Tetrahedron
Lett. 1981, 22, 2667±2670. (c) Watanabe, Y.; Tsuji, Y.; Ohsugi,
Y.; Shida, J. Bull. Chem. Soc. Jpn 1983, 56, 2452±2457. (d) Wata-
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438. (e) Tsuji, Y.; Nishimura, H.; Huh, K.-T.; Watanabe, Y.
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K.-T.; Watanabe, Y. J. Org. Chem. 1987, 52, 1673±1680.
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gami, Y. Bull. Chem. Soc. Jpn 1978, 51, 3397±3398.
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2,8-Diethyl-3-methylquinoline (3i). Pale yellow oil; H
NMR (CDCl3) d 1.38 (t, Jˆ7.5 Hz, 3H), 1.41 (t,
Jˆ7.5 Hz, 3H), 2.41 (s, 3H), 2.95 (q, Jˆ7.5 Hz, 2H), 3.30
(q, Jˆ7.5 Hz, 2H), 7.33 (t, Jˆ7.8 Hz, 1H), 7.43 (br d,
Jˆ6.3 Hz, 1H), 7.51 (dd, Jˆ7.8, 1.2 Hz, 1H), 7.73 (s,
1H); 13C NMR (CDCl3) d 11.9, 15.0, 18.9, 24.7, 29.1,
124.5, 125.3, 126.5, 127.1, 129.0, 135.4, 142.5, 144.9,
161.1. Anal. Calcd for C14H17N: C, 84.37, H, 8.60; N,
7.03. Found: C, 84.01; H, 8.48; N, 6.87.
6-Acetyl-2-ethyl-3-methylquinoline (3m). White solid
(hexane); mp 86±888C; 1H NMR (CDCl3) d 1.27 (t,
Jˆ7.5 Hz, 3H), 2.36 (s, 3H), 2.57 (s, 3H), 2.87 (q,
Jˆ7.5 Hz, 2H), 7.75 (s, 1H), 7.91 (d, Jˆ8.7 Hz, 1H), 8.02
(dd, Jˆ8.7, 1.8 Hz, 1H), 8.17 (d, Jˆ1.8 Hz, 1H); 13C NMR
(CDCl3) d 12.3, 18.9, 26.5, 29.4, 126.2, 126.4, 128.7, 128.8,
130.4, 133.9, 136.6, 148.4, 165.7, 197.4; MS m/z (relative
intensity) 213 (M1, 93), 212 (100). Anal. Calcd for
C14H15NO: C, 78.84, H, 7.09; N, 6.57. Found: C, 78.69;
H, 7.00; N, 6.39.
7. Cho, C. S.; Lim, H. K.; Shim, S. C.; Kim, T. J.; Choi, H.-J.
Chem. Commun. 1998, 995±996.
8. Cho, C. S.; Kim, J. H.; Shim, S. C. Tetrahedron Lett. 2000, 41,
1811±1814.
9. (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett. 1999,
40, 1499±1500. (b) Cho, C. S.; Oh, B. H.; Shim, S. C.; Oh, D. H.
J. Heterocycl. Chem. 2000, in press.
10. Cho, C. S.; Oh, B. H.; Shim, S. C. J. Heterocycl. Chem. 1999,
36, 1175±1178.
Acknowledgements
11. For transition metal-catalyzed amine exchange reactions, see:
(a) Yoshimura, N.; Moritani, I.; Shimamura, T.; Murahashi, S.-I.
J. Am. Chem. Soc. 1973, 95, 3038±3039. (b) Murahashi, S.-I.;
Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978, 100, 348±350. (c)
Murahashi, S.-I.; Kondo, K.; Hakata, T. Tetrahedron Lett. 1982,
23, 229±232. (d) Murahashi, S.-I.; Yoshimura, N.; Tsumiyama, T.;
Kojima, T. J. Am. Chem. Soc. 1983, 105, 5002±5011. (e) Muraha-
shi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443±2465.
12. In contrast to the present aquatic process, similar ruthenium-
catalyzed reaction between o-toluidine and triallylamine in an
organic medium failed to form quinoline, whereas N-allyl-o-tolui-
dine was only detectable product.9
This work was supported by Korea Research Foundation
Grant (KRF-99-015-DI0064) and grant of Post-Doc.
(C. S. C.) Program from Kyungpook National University
(1999).
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