Ruthenium-Catalyzed Formation of Quinolines via Reductive Cyclization of Nitroarenes with Tris(3-hydroxypropyl)amine in an Aqueous Medium

Article abstract of DOI:10.1002/jhet.5570400530

Nitroarenes react with tris(3-hydroxypropyl)amine in an aqueous medium (dioxane/H₂O) at 180° in the presence of a catalytic amount of a ruthenium catalyst and tin(II) chloride along with isopropanol as hydrogen donor to afford the corresponding quinolines in good yields. The presence of tin(II) chloride is essential for the formation of quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines, propanol group transfer from tris(3-hydroxypropyl)amine to anilines to form 3-anilino-l-propanols, N-alkylation of anilines by 3-anilino-1-propanol to form 1,3-dianilinopropane and intramolecular heteroannulation of 1, 3-dianilinopropane is proposed for this catalytic process.

Full text of DOI:10.1002/jhet.5570400530

Sep-Oct 2003
929
Ruthenium-Catalyzed Formation of Quinolines via Reductive Cyclization
of Nitroarenes with Tris(3-hydroxypropyl)amine in an Aqueous Medium
Chan Sik Cho*
Research Institute of Industrial Technology, Kyungpook National University, Taegu 702-701, Korea
Na Young Lee, Heung-Jin Choi, Tae-Jeong Kim and Sang Chul Shim*
Department of Industrial Chemistry, College of Engineering, Kyungpook National University,
Taegu 702-701, Korea
Received May 21, 2003
Nitroarenes react with tris(3-hydroxypropyl)amine in an aqueous medium (dioxane/H O) at 180° in the
2
presence of a catalytic amount of a ruthenium catalyst and tin(II) chloride along with isopropanol as hydro-
gen donor to afford the corresponding quinolines in good yields. The presence of tin(II) chloride is essential
for the formation of quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines,
propanol group transfer from tris(3-hydroxypropyl)amine to anilines to form 3-anilino-1-propanols, N-alky-
lation of anilines by 3-anilino-1-propanol to form 1,3-dianilinopropane and intramolecular heteroannulation
of 1,3-dianilinopropane is proposed for this catalytic process.
J. Heterocyclic Chem., 40, 929 (2003).
Introduction.
Compounds containing the quinoline framework have
frequently been used as antimalarial compounds. Thus,
along with conventional named routes such as Skraup,
Döbner-von Miller, Conrad-Limpach, Friedlaender and
Pfitzinger syntheses, homogeneous transition metal-cat-
alyzed synthetic methods have been attempted as alterna-
tive methods for quinolines [1]. In connection with this
report, during the course of our ongoing studies on homo-
geneous ruthenium-catalysis [1-9], we have directed our
attention to the synthesis of quinolines [2] and indoles [3]
via an alkyl group transfer from α-hydrogen containing
amines to anilines (amine exchange reaction [10])
(Scheme 1). Under these circumstances, we also reported
the direct use of nitroarenes instead of anilines for such
heterocycles since nitroarenes are precursors of anilines
from the viewpoint of industrial organic chemistry [11,12].
tris(3-hydroxypropyl)amine (2) under various conditions
are listed in Table 1 (Scheme 2). When 1a was treated with
2 at 180° in the presence of a catalytic amount of a ruthe-
nium catalyst (5 mol%) and SnCl along with isopropyl
2
alcohol as hydrogen donor, the reductive cyclization prod-
uct quinoline (3a) was produced with concomitant forma-
tion of aniline. As it has been observed in our recent report
on ruthenium-catalyzed reductive cyclization for quino-
lines and indoles [11a-c], the solvent system was critical
for the effective formation of 3a (runs 1-3). Performing the
reaction in an aqueous medium (H O/dioxane = 1 mL/9
2
mL) afforded 3a in best yield [14]. The presence of SnCl
2
was essential for the formation of 3a. The reaction in the
absence of SnCl did not proceed at all with low conver-
2
sion of 1a to aniline (run 4). Comparing the results shown
in runs 4 and 5 of Table 1, SnCl seems to play a decisive
2
role as both the reduction of 1a to aniline and cyclization
toward 3a. It is known that nitroarenes can be easily con-
verted into anilines in the presence of SnCl under aqueous
2
as well as non-aqueous media [15]. Among the activity of
various ruthenium precursors examined, RuCl •nH O/
3
2
Herein, as another example for the synthesis of N-hetero-
cycles using nitroarenes, we report a ruthenium-catalyzed
consecutive reduction and cyclization of nitroarenes with
tris(3-hydroxypropyl)amine [13] leading to quinolines via
an intrinsic amine exchange reaction.
3PPh and RuCl (PPh ) were revealed to be the catalysts
3
2
3 3
of choice (runs 5-10).
Given these results, with various nitroarenes 1 the reduc-
tive cyclized products were produced in the range of 42-
123% yields (Table 2). With para-substituted nitroarene
1b, the quinoline yield was higher than that when ortho-
and meta-substituted nitroarenes 1c and 1d were used. In
the reaction with 1c, the products quinolines were obtained
Results and Discussion.
Several attempted results of the ruthenium-catalyzed
reduction and cyclization between nitrobenzene (1a) and

930
C. S. Cho, N. Y. Lee, H.-J. Choi, T.-J. Kim and S. C. Shim
Vol. 40
Table 1
Optimization of Conditions for the Reaction of 1a with 2 Leading to 3a [a]
Run
Ruthenium catalysts
SnCl
(mmol)(mL/mL)
H O/dioxane
Time
(h)Conversion
1a
3a [obf]
Yield
2
2
1
2
3
4
5
6
7
8
9
RuCl •nH O/3PPh
1
1
1
-
1
1
1
1
0/10
1/9
5/5
1/9
1/9
1/9
1/9
1/9
1/9
5
5
41
78
100
20
100
100
100
95
16
52
0
3
2
3
3
3
3
3
RuCl •nH O/3PPh
3
2
RuCl •nH O/3PPh
20
20
20
20
20
20
20
3
2
RuCl •nH O/3PPh
0
3
2
RuCl •nH O/3PPh
91
92
84
67
61
3
2
RuCl (PPh )
2
3 3
RuCl (=CHPh)(PCy )
2
3 2
Ru (CO)
3
12
RuH (PPh )
1
79
2
3 4
10
Cp*RuCl (CO)1
1/9
20
62
40
2
[a] Reaction conditions: 1a (4 mmol), 2 (1 mmol), isopropanol (6 mmol), ruthenium catalyst (0.05 mmol), 180°, under Ar;
[b] GLC yield based on 2.
as a regioisomeric mixture, favoring 7-methyl isomer,
which was formed via less sterically hindered position on
1c. We found that nitroarenes substituted with either elec-
tron donating (1e) or electron withdrawing groups (1f-1i)
were readily cyclized with 2 to form the corresponding
quinolines in moderate to good yields. The reaction pro-
ceeds likewise with two-methyl substituted nitroarene 1j
to give 5,7-dimethylquinoline (3j) in high yield. The reac-
tion of 2-methyl-4-nitroanisole (1k) with 2 also proceeds
to give the corresponding quinoline 3k in 123% yield with
exclusive regioselectivity. The result of 123% yield indi-
cates that at least two propanol groups out of three in 2 are
available for the transfer. Similar regioselectivity was
reported in our recent article on ruthenium-catalyzed
cyclization of 1k with 3-amino-1-propanol [11a].
As to the reaction pathway, although the exact role of
SnCl is not yet fully understood and no intermediates have
2
yet been detected, this reaction seems to proceed via a
sequence involving initial reduction of 1a to aniline (4),
propanol group transfer from 2 to N-atom of 4 (amine
exchange reaction) to form 3-anilino-1-propanol (5) [10],
N-alkylation of 4 with 5 to form 1,3-dianilinopropane (6)
[16] and heteroannulation of 6 (Scheme 3). An alternative
route for 6 involves a sequence such as initial N-alkylation
of 4 with 2 to form 3-anilinoamine 7 and 3-aminopropyl
group transfer from 7 to 4. Watanabe and Tsuji reported that
5 reacted with 4 in the presence of a ruthenium catalyst to
give 3a and 6 was intramolecularly cyclized to give 3a [17].
In summary, we have demonstrated that nitroarenes are
reductively cyclized with tris(3-hydroxypropyl)amine in
an aqueous medium in the presence of a catalytic amount
of a ruthenium catalyst and SnCl along with isopropanol
2
to give quinolines in moderate to good yields. The present
reaction is an another example for the synthesis of N-hete-
rocycles using amine exchange reaction by the direct use
of nitroarenes.

Sep-Oct 2003
Ruthenium-Catalyzed Formation of Quinolines
931
vessel. After the system was flushed with argon, the reaction
mixture was stirred at 180° for 20 hours. The reaction mixture
was filtered through a short silica gel column (ethyl acetate-
chloroform mixture) to eliminate inorganic compounds and con-
centrated under reduced pressure. The residual mixture was sep-
arated by TLC to give the product quinoline. Except for 3i, spec-
troscopic data for 3b-3f [2c], 3g [11a], 3h [11a], 3j [2c] and 3k
[11a] are noted in our recent report.
6-Carbomethoxyquinoline (3i).
This compound was obtained as a pale yellow solid, mp 85-86°
-1
1
(hexane) (lit [19] mp 86-88°); ir (KBr): ν 1717 (C=O) cm ; H
NMR (CDCl ): δ 3.92 (s, 3H), 7.39 (dd, J = 4.0 and 8.3 Hz, 1H),
3
8.07 (d, J = 8.5 Hz, 1H), 8.17-8.24 (m, 2H), 8.51 (d, J = 1.5 Hz,
13
1H), 8.93 (dd, J = 1.5 and 4.0 Hz, 1H); C NMR (CDCl ): δ
3
51.4, 120.8, 126.4, 127.1, 127.9, 128.8, 130.0, 136.3, 149.1,
151.5, 165.6 (C=O).
Acknowledgment.
The present work was supported by the Korea Research
Foundation Grant (KRF-2002-005-C00009). C.S.C. gratefully
acknowledges a MOE-KRF Research Professor Program (KRF-
2001-050-D00015).
REFERENCES AND NOTES
[1] For transition metal-catalyzed quinoline synthesis: C. S. Cho,
B. H. Oh, J. S. Kim, T.-J. Kim and S. C. Shim, Chem. Commun., 1885
(2000) and references cited therein.
[2a] C. S. Cho, B. H. Oh and S. C. Shim, Tetrahedron Letters, 40,
1499 (1999); [b] C. S. Cho, B. H. Oh, S. C. Shim and D. H. Oh, J.
Heterocyclic Chem., 37, 1315 (2000); [c] C. S. Cho, B. H. Oh and S. C.
Shim, J. Heterocyclic Chem., 36, 1175 (1999); [d] C. S. Cho, J. S. Kim,
B. H. Oh, T.-J. Kim, S. C. Shim and N. S. Yoon, Tetrahedron, 56, 7747
(2000).
EXPERIMENTAL
H and C NMR (400 and 100 MHz) spectra were recorded
1
13
on a Bruker Avance Digital 400 spectrometer using Me Si as an
4
internal standard. Infrared spectrum was obtained on a Mattson
Galaxy 7020A spectrophotometer. GLC analyses were carried
out with Shimadzu GC-17A equipped with CBP10-S25-050 col-
umn (Shimadzu, a silica fused capillary column, 0.33 mm x 25 m,
[3] C. S. Cho, H. K. Lim, S. C. Shim, T. J. Kim and H.-J. Choi,
Chem. Commun., 995 (1998); C. S. Cho, J. H. Kim and S. C. Shim,
Tetrahedron Letters, 41, 1811 (2000); C. S. Cho, J. H. Kim, T.-J. Kim and
S. C. Shim, Tetrahedron, 57, 3321 (2001).
[4] C. S. Cho, M. J. Lee, B. T. Kim, T.-J. Kim and S. C. Shim,
Angew. Chem. Int. Ed. Engl., 40, 958 (2001).
[5] C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, J. Org.
Chem., 66, 9020 (2001); C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim,
Chem. Commun., 2576 (2001); C. S. Cho, B. T. Kim, T.-J. Kim and S. C.
Shim, Tetrahedron Letters, 43, 7987 (2002).
[6] C. S. Cho, J. H. Park, T.-J. Kim and S. C. Shim, Bull. Korean
Chem. Soc., 23, 23 (2002).
0.25 µm film thickness) using N as carrier gas. Commercially
available organic and inorganic compounds were used without
2
further purification. Cp*RuCl (CO) was prepared by the reported
2
method [18].
General Procedure for Ruthenium-Catalyzed Reactions between
Aniline (1a) and Tris(3-hydroxypropyl)amine (2) under Various
Conditions (For GLC Analysis).
A mixture of nitrobenzene (492 mg, 4 mmol), tris(3-hydrox-
ypropyl)amine (191 mg, 1 mmol), isopropanol (361 mg, 6
mmol), ruthenium catalyst (0.05 mmol), and SnCl (190 mg, 1
2
mmol) in solvent was charged in a 50 mL pressure vessel. After
the system was flushed with argon, the reaction mixture was
stirred at 180° for an appropriate time. The reaction mixture was
filtered through a short silica gel column (ethyl acetate-chloro-
form mixture) to eliminate inorganic compounds. To the extract
was added an appropriate amount of undecane as internal stan-
dard and analyzed by GLC.
[7] B. T. Kim, C. S. Cho, T.-J. Kim and S. C. Shim, J. Chem.
Research (S), in press.
[8] C. S. Cho, J. S. Kim, H. S. Kim, T.-J. Kim and S. C. Shim,
Synth. Commun., 31, 3791 (2001).
[9] C. S. Cho, J. H. Kim, H.-J. Choi, T.-J. Kim and S. C. Shim,
Tetrahedron Letters, 44, 2975 (2003).
[10] For transition metal-catalyzed amine exchange reaction, see:
S.-I. Murahashi, Angew. Chem. Int. Ed. Engl., 34, 2443 (1995).
[11a] As examples for the direct application of nitroarenes to amine
exchange reaction leading to indoles and quinolines: C. S. Cho, T. K.
Kim, T.-J. Kim, S. C. Shim and N. S. Yoon, J. Heterocyclic Chem., 39,
291 (2002); [b] C. S. Cho, T. K. Kim, B. T. Kim, T.-J. Kim and S. C.
Shim, J. Organomet. Chem., 650, 65 (2002); [c] C. S. Cho, T. K. Kim, S.
W. Yoon, T.-J. Kim and S. C. Shim, Bull. Korean Chem. Soc., 22, 545
(2001); [d] C. S. Cho, T. K. Kim, H.-J. Choi, T.-J. Kim and S. C. Shim,
Bull. Korean Chem. Soc., 23, 541 (2002).
General Procedure for Ruthenium-Catalyzed Synthesis of
Quinolines 3 from Nitroarenes 1 and Tris(3-hydroxypropyl)-
amine (2) (for Isolation).
A mixture of nitroarene (4 mmol), tris(3-hydroxypropyl)-
amine (191 mg, 1 mmol), isopropanol (361 mg, 6 mmol),
RuCl •nH O (13 mg, 0.05 mmol), and SnCl (190 mg, 1 mmol)
3
2
2
in dioxane/H O (9 mL/1 mL) was charged in a 50 mL pressure
2

932
C. S. Cho, N. Y. Lee, H.-J. Choi, T.-J. Kim and S. C. Shim
Vol. 40
[12] For transition metal-catalyzed reductive N-heterocyclization
and references cited therein.
of nitroarenes: M. Akazome, T. Kondo and Y. Watanabe, J. Chem. Soc.,
Chem. Commun., 1466 (1991); M. Akazome, T. Kondo and Y. Watanabe,
Chem. Lett., 1275 (1992); M. Akazome, T. Kondo and Y. Watanabe, J.
Org. Chem., 58, 310 (1993); M. Akazome, T. Kondo and Y. Watanabe, J.
Org. Chem., 59, 3375 (1994).
[13] F. Renaud, C. Decurnex, C. Piguet and G. Hopfgartner, J.
Chem. Soc., Dalton Trans., 1863 (2001).
[14] Aqueous-Phase Organometallic Catalysis, Ed. by B. Cornils
and W. A. Herrmann, eds, Wiley-VCH, Weinheim, 1998.
[15] F. D. Bellamy and K. Ou, Tetrahedron Letters, 25, 839 (1984)
[16] For transition metal-catalyzed N-alkylation of amines by alco-
hols: Y. Watanabe, Y. Morisaki, T. Kondo and T. Mitsudo, J. Org. Chem.,
61, 4214 (1996) and references cited therein.
[17] Y. Tsuji, H. Nishimura, K.-T. Huh and Y. Watanabe, J.
Organomet. Chem., 286, C44 (1985); Y. Tsuji, K.-T. Huh and Y.
Watanabe, J. Org. Chem., 52, 1673 (1987).
[18] D. H. Lee, S. I. Kim, J. H. Jun, Y. H. Oh and S. K. Kam, J.
Korean Chem. Soc., 41, 639 (1997).
[19] J. A. Hirsch and G. Schwartzkopf, J. Org. Chem., 39, 2044
(1974).