Ruthenium-catalyzed synthesis of quinolines via reductive heteroannulation of nitroarenes with 3-amino-1-propanols

Article abstract of DOI:10.1002/jhet.5570390207

Nitroarenes are reductively cyclized with 3-amino-1-propanols in dioxane/H₂O in the presence of a ruthenium catalyst and tin(II) chloride dihydrate together with isopropanol to afford the corresponding quinolines. A reaction pathway involving i

Full text of DOI:10.1002/jhet.5570390207

Mar-Apr 2002
Ruthenium-Catalyzed Synthesis of Quinolines via Reductive
Heteroannulation of Nitroarenes with 3-Amino-1-propanols
Chan Sik Cho*, Tae Kyung Kim, Tae-Jeong Kim and Sang Chul Shim*
291
Department of Industrial Chemistry, College of Engineering,
Kyungpook National University, Taegu 702-701, Korea
Nam Sik Yoon
Department of Dyeing and Finishing, College of Engineering,
Kyungpook National University, Taegu 702-701, Korea
Received March 8, 2001
Nitroarenes are reductively cyclized with 3-amino-1-propanols in dioxane/H O in the presence of a
2
ruthenium catalyst and tin(II) chloride dihydrate together with isopropanol to afford the corresponding
quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines, propanol group transfer
from 3-amino-1-propanols to anilines, N-alkylation of anilines by 3-anilino-1-propanols and hetero-
annulation of 1,3-dianilinopropanes is proposed.
J. Heterocyclic Chem., 39, 291 (2002).
Introduction.
4 and 5). The presence of SnCl •2H O was essential for
2 2
the effective formation of 4a. The reaction in the absence
of SnCl •2H O did not proceed at all. The yield of 4a
The Skraup, Döbner-von Miller, Conrad-Limpach,
Friedlaender and Pfitzinger syntheses have been used for
the formation of quinolines. Recently, many homogeneous
transition metal-catalyzed reactions have been attempted
as alternative synthetic methods for quinolines [1-4].
During our studies on homogeneous transition metal-
catalyzed organic transformations, we have recently
focused on a carbon-nitrogen bond activation of
alkylamines by ruthenium catalyst. Thus, we have
developed and reported an alkyl group transfer from alkyl-
amines to anilines [5-11] as well as α-carbon atom of
ketones [12]. The former leads to indoles [5-7] and quino-
lines [8-11] and is well known as an amine exchange reac-
tion [13]. The synthesis of N-heterocycles using the amine
exchange reaction methodology has previously been
limited to palladium-catalyzed synthesis of pyrimidines
and imidazoles [14]. Herein, we report a ruthenium-
catalyzed reductive heteroannulation of nitroarenes with
2
2
increased with increasing amounts of SnCl •2H O up to
2
2
1
mmol (runs 6-8). Considering the conversion of the
starting 1a into aniline, SnCl •2H O might be participated
2
2
as reducing agent in present reaction. It is well known that
nitroarenes can be easily converted into anilines in the
presence of tin(II) chloride under both aqueous and non-
aqueous media [15]. Next, the activity of various
ruthenium precursors was examined. Interestingly, all
ruthenium catalysts ranging from zero to trivalent
exhibited the similar catalytic activity as RuCl •nH O/-
3
2
3
PPh (runs 10-14).
3
3
-amino-1-propanols which leads to the formation of
quinolines.
Results and Discussion.
The results of ruthenium-catalyzed heteroannulation
between nitrobenzene (1a) and 3-amino-1-propanol (2a)
under various conditions are listed in Table 1 (Scheme 1).
In order to reduce nitrobenzene (1a) to aniline, we
employed isopropanol (3) as hydrogen donor and tin(II)
Given these results, several reactions of various
nitroarenes 1 with 2a as well as 3-dimethylamino-1-
propanol (2b) were screened using RuCl •nH O/3PPh
catalytic system. Representative results are summarized in
Table 2. As is the case for the reaction with 2a, the use of 2b
3
2
3
chloride dihydrate (SnCl •2H O)/aqueous medium
2
2
as C -fragment also worked well for the formation of quino-
(
H O/dioxane). Generally, 1a was treated with 2a and 3 in
3
2
solvent in the presence of a ruthenium catalyst at 180° for
0 hours to afford quinoline (4a). As has been observed
previously [5-11], the yield of 4a was affected by the
molar ratio of 1a to alkyl group transfer agent 2a (runs
lines (runs 2, 3, 8, 11, 14, and 16). As shown in Table 2, the
quinoline yield was considerably affected by the position of
the substituent on nitroarene. With ortho-substitued
nitroarene, the quinoline yield was lower than that when
meta- and para-substitued nitroarenes were used (run 6).
Expectedly, in the reaction with 4-methyl-2-nitroanisole
2
1
-3). The use of either dioxane or reverse amount of
H O/dioxane stopped the reaction almost completely (runs
2

2
92
C. S. Cho, T. K. Kim, T.-J. Kim, S. C. Shim and N. S. Yoon
Vol. 39
Table 1
Ruthenium-Catalyzed Synthesis of 4a from 1a and 2 under Various Reaction Conditions [a]
Run
Ruthenium catalysts
mmol)
Molar ratio
1a:2a:3
SnCl •2H O
(mmol)
H O/Dioxane
(mL/mL)
Conversion of
Yield of
4a [b]
2
2
2
(
1a
1
2
3
4
5
6
7
8
9
RuCl •nH O/3PPh (0.1)
4:1:6
2:1:6
6:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
4:1:6
1
1
1
1
1
-
0.2
2
1
1
1/9
1/9
1/9
0/10
9/1
1/9
1/9
1/9
1/9
1/9
1/9
1/9
1/9
1/9
100
100
90
24
100
37
47
31
44
1
0
0
3
2
3
RuCl •nH O/3PPh (0.1)
3
2
3
RuCl •nH O/3PPh (0.1)
3
2
3
RuCl •nH O/3PPh (0.1)
3
2
3
RuCl •nH O/3PPh (0.1)
3
2
3
RuCl •nH O/3PPh (0.1)
3
2
3
RuCl •nH O/3PPh (0.1)
54
9
3
2
3
RuCl •nH O/3PPh (0.1)
100
100
94
88
100
82
46
38
40
41
41
5
3
2
3
RuCl •nH O/3PPh (0.05)
3
2
3
10
RuCl (PPh ) (0.05)
2
3 3
1
1
RuH (PPh ) (0.05)
1
1
1
1
2
3 4
12
13
14
RuCl (=CHPh)(PCy ) (0.05)
2
3 2
Cp*RuCl (CO) (0.05) [c]
2
Ru (CO) (0.05)
89
44
3
12
5
[
a] Reaction conditions: 180°, 20 hours. [b] Determined by GLC based on 2a. [c] Cp* = η -C Me .
5 5
(
1k) which has a bulkier substituent near the nitro group,
As concerns the reaction pathway, although the exact
role of SnCl •2H O is not yet fully understood [16] and no
although 1k was considerably reduced to 2-methoxy-5-
methylaniline, the corresponding quinoline (4k) was not
formed at all (run 17). In the case of 3-nitrotoluene (1c), the
corresponding quinolines (4c) were obtained as a regioiso-
meric mixture, favoring the 7-methyl isomer which was
formed via less sterically hindered position on 1c (run 5).
Isomeric molar ratio between 5-methylquinoline and
2
2
intermediates were detected, it seems to proceeded via a
sequence involving initial reduction of nitroarenes to
anilines, propanol group transfer from 2 to anilines to form
3-anilino-1-propanol, N-alkylation of anilines by
3-anilino-1-propanol to form 1,3-dianilinopropanes and
heteroannulation of 1,3-dianilinopropanes to produce
quinolines. Watanabe and Tsuji reported that 3-anilino-1-
propanol and 1,3-dianilinopropane are key intermediates
7
-methylquinoline was determined from the signal areas of
1
the methyl protons in H NMR spectrum.
Table 2
Ruthenium-Catalyzed Synthesis of 4 from 1 and 2 [a]
Run
Nitroarene 1
3-Amino-1-propanol 2
Quinoline 4
Yield [b]
1
2
3
4
5
6
7
8
9
R = H (1a)
1a
R = 4-Me (1b)
1b
R = 3-Me (1c)
R = 2-Me (1d)
R = 4-OMe (1e)
1e
R = 4-Cl (1f)
R = 4-Acetyl (1g)
1g
R = 4-Benzoyl (1h)
R = 3,5-Me (1i)
1i
R = 3-Me, 4-OMe (1j)
1j
2a
2b
2a
2b
2a
2a
2a
2b
2a
2a
2b
2a
2a
2b
2a
2b
2a
R = H (4a)
4a
R = 6-Me (4b)
4b
40
46 [c]
48
42
46 [d]
14
40
38
28
40
40
21
51
45
43
43
0
R = 5- and 7-Me (4c)
R = 8-Me (4d)
R = 6-OMe (4e)
4e
R = 6-Cl (4f)
R = 6-Acetyl (4g)
4g
R = 6-Benzoyl (4h)
R = 5,7-Me (4i)
4i
R = 6-OMe, 7-Me (4j)
4j
10
1
1
12
13
14
15
16
17
R = 2-OMe, 5-Me (1k)
R = 5-Me, 8-OMe (4k)
[
a] Reaction conditions: 1 (4 mmol), 2 (1 mmol), isopropanol (3) (6 mmol), RuCl •nH O (n = 3, 10 mol% based on 2), PPh (30 mol% based on 2),
3
2
3
SnCl •2H O (1 mmol), H O/dioxane (= 1 mL/9 mL), at 180 °, for 20 hours. [b] Isolated yield based on 2. [c] GLC yield. [d] Regioisomeric ratio was
2
2
2
1
determined by H NMR (400 MHz): 7-methylquinoline/5-methylquinoline=3.6/1.

Mar-Apr 2002
Ruthenium-Catalyzed Synthesis of Quinolines via Reductive Heteroannulation
293
in the ruthenium-catalyzed synthesis of quinolines from
anilines and 1,3-diols [3f]. They confirmed that 3-anilino-
steel autoclave. 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) to eliminate inorganic compounds and
concentrated under reduced pressure. The organic layer was
poured into saturated brine and extracted with chloroform. To the
extract was added appropriate amount of an internal standard and
analyzed by GLC.
1-propanol reacted with aniline in the presence of a ruthe-
nium catalyst to give quinoline and 1,3-dianilinopropane
was intramolecularly cyclized to give quinoline. In a sepa-
rate experiment, we also observed that 1,3-diamino-
propane (5) can be used as C -fragment under the similar
3
conditions, resulting in 13% quinoline yield from the reac-
tion between 1a and 5 (Scheme 2). This result indicates
that the reaction proceeds via a double amine exchange
reaction between aniline and both amino moieties of 5.
General Procedure for Ruthenium-Catalyzed Synthesis of
Quinolines 4 from Nitroarenes 1 and 3-Amino-1-propanols 2
(For Isolation).
A mixture of nitrobenzene (4 mmol), 3-amino-1-propanol
1 mmol), isopropanol (361 mg, 6 mmol), ruthenium(III) chloride
(
hydrate (26 mg, 0.1 mmol), triphenylphosphine (79 mg,
.3 mmol), and tin(II) chloride dihydrate (226 mg, 1 mmol) in
0
dioxane/H O (9 mL/1 mL) was placed in a 50 mL stainless steel
2
pressure vessel. After the system was flushed with argon, the
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
concentrated under reduced pressure. The organic layer was
poured into saturated brine, extracted with chloroform, dried over
anhydrous sodium sulfate, and evaporated under reduced
pressure. The residual oily material was separated by column
chromatography (ethyl acetate-hexane) to give the product
quinoline. The products obtained by the above procedure were
characterized spectroscopically. Spectroscopic data of the
products 4a-4f and 4i are noted in our recent report [9].
In summary, we have demonstrated that nitroarenes
were reductively cyclized with 3-amino-1-propanols in the
presence of a ruthenium catalyst and SnCl •2H O together
2
2
with isopropanol as hydrogen donor in an aqueous
medium to give quinolines.
6
-Acetylquinoline (4g).
EXPERIMENTAL
This compound was obtained as pale yellow solid, mp 72-73°
1
(
(
ethanol) (lit [21] mp 75-76°); H NMR (CDCl ): δ 2.74
s, 3H, -COCH ), 7.48 (dd, J = 4.5 and 8.3 Hz, 1H), 8.16 (d, J =
The 1H (400 MHz) and 13C (100 MHz) NMR spectra were
3
3
recorded on a Bruker Avance Digital 400 spectrometer using
TMS as an internal standard. Infrared spectra were recorded on a
Mattson Galaxy 6030E FT-IR spectrophotometer. Electron
impact mass spectra were obtained on a Shimadzu QP-1000
spectrometer. GLC analyses were carried out with Shimadzu
GC-17A equipped with CBP10-S25-050 column (Shimadzu,
fused silica capillary column, 0.33 mm x 25 m, 0.25 µm film
thickness) using nitrogen as the carrier gas. GLC yields were
determined using undecane as an internal standard. Melting
points were determined on a Thomas Scientific Capillary Melting
Points Apparatus and are uncorrected. The isolation of pure
products was carried out via column chromatography (silica gel
9
.0 Hz, 1H), 8.25-8.29 (m, 2H), 8.44 (d, J = 1.5 Hz, 1H), 9.01 (dd,
13
J = 1.5 and 4.5 Hz, 1H); C NMR (CDCl ): δ 26.8, 122.0, 127.5,
3
127.7, 129.9, 130.1, 134.9, 137.6, 150.1, 152.6, 197.4 (C=O).
6-Benzoylquinoline (4h).
This compound was obtained as white solid, mp 59-61°
-1
(
petroleum ether) (lit [22] mp 63°); ir (KBr): ν 1657 (C=O) cm ;
H NMR (CDCl ): δ 7.39-7.46 (m, 3H), 7.55 (t, J = 7.3 Hz, 1H),
1
3
7
1
1
.77 (d, J = 8.0 Hz, 2H), 8.06-8.17 (m, 4H), 8.94 (d, J = 3.5 Hz,
13
H); C NMR (CDCl ): δ 121.0, 126.2, 127.4, 128.5, 128.8,
3
29.1, 130.3, 131.7, 134.4, 136.3, 136.4, 148.8, 151.5, 195.0
+
(C=O); ms: m/z (%) 233 (M , 99), 156 (100), 128 (69), 105 (86),
60 HF254, 70-230 mesh, Merck) and thin layer chromatography.
77 (90).
Commercially available organic and inorganic compounds were
used without further purification. Ruthenium catalysts such as
RuCl (PPh ) [17], RuH (PPh ) [18], Cp*RuCl (CO) [19] and
6
-Methoxy-7-methylquinoline (4j).
This compound was obtained as pale yellow oil; H NMR
(CDCl ): δ 2.77 (s, 3H, -CH ), 3.89 (s, 3H, -OCH ), 6.90 (d, J =
1
2
3 3
2
3 4
2
Ru (CO) [20] were prepared by literature methods.
3
12
3
3
3
1
.5 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 4.0 and 8.0
Hz, 1H), 8.00 (dd, J = 1.5 and 8.0 Hz, 1H), 8.78 (dd, J = 1.5 and
General Procedure for Ruthenium-Catalyzed Synthesis of
Quinoline (4a) from Nitrobenzene (1a) and 3-Amino-1-propanol
1
3
4
1
.0 Hz, 1H); C NMR (CDCl ): δ 18.1, 55.3, 103.1, 121.2,
3
(2a) (For GLC Analysis).
22.2, 129.4, 135.0, 138.4, 143.8, 146.8, 157.3.
A mixture of nitrobenzene (2-6 mmol), 3-amino-1-propanol
75 mg, 1 mmol), isopropanol (361 mg, 6 mmol), ruthenium
catalyst (0.05-0.1 mmol), triphenylphosphine [in the case of the
use of ruthenium(III) chloride hydrate, 3-fold molar amount to
ruthenium(III) chloride hydrate], and tin(II) chloride dihydrate
Ruthenium-Catalyzed Synthesis of Quinoline (4a) from
Nitrobenzene (1a) and 1,3-Diaminopropane (5).
(
A mixture of nitrobenzene (492 mg, 4 mmol), 1,3-diamino-
propane (74 mg, 1 mmol), isopropanol (361 mg, 6 mmol),
ruthenium(III) chloride hydrate (26 mg, 0.1 mmol),
(
226 mg, 1 mmol) in solvent was charged in a 50 mL stainless

294
C. S. Cho, T. K. Kim, T.-J. Kim, S. C. Shim and N. S. Yoon
Vol. 39
triphenylphosphine (79 mg, 0.3 mmol), and tin(II) chloride dihy-
[5]
S. C. Shim, Y. Z. Youn, D. Y. Lee, T. J. Kim, C. S. Cho,
drate (226 mg, 1 mmol) in dioxane/H O (9 mL/1 mL) was placed
S. Uemura and Y. Watanabe, Synth. Commun., 26, 1349 (1996);
D. Y. Lee, C. S. Cho, J. H. Kim, Y. Z. Youn, S. C. Shim and H. Song, Bull.
Korean Chem. Soc., 17, 1132 (1996).
2
in a 50 mL stainless steel pressure vessel. After the system was
flushed with argon, the mixture was stirred at 180° for 20 hours.
The reaction mixture was filtered through a short silica gel
column (ethyl acetate-chloroform mixture), poured into saturated
brine, extracted with chloroform and dried over anhydrous
sodium sulfate. GLC analysis revealed the presence of quinoline
[
6] C. S. Cho, H. K. Lim, S. C. Shim, T. J. Kim and H.-J. Choi,
Chem. Commun., 995 (1998).
7] C. S. Cho, J. H. Kim and S. C. Shim, Tetrahedron Letters, 41,
811 (2000); C. S. Cho, J. H. Kim, T.-J. Kim and S. C. Shim,
Tetrahedron, 57, 3321 (2001).
8] C. S. Cho, B. H. Oh and S. C. Shim, Tetrahedron Letters, 40,
[
1
(13%).
[
Acknowledgment.
1499 (1999); C. S. Cho, B. H. Oh, S. C. Shim and D. H. Oh,
J. Heterocyclic Chem. 37, 1315 (2000).
This work was supported by the Korea Research Foundation
Grant (KRF-2000-015-DP0248) and grant of Post-Doc. (C.S.C.)
Program from Kyungpook National University (2000).
[
9] C. S. Cho, B. H. Oh and S. C. Shim, J. Heterocyclic Chem.
6, 1175 (1999).
10] C. S. Cho, B. H. Oh, J. S. Kim, T.-J. Kim and S. C. Shim,
Chem. Commun. 1885 (2000).
11] C. S. Cho, J. S. Kim, B. H. Oh, T.-J. Kim, S. C. Shim and
N. S. Yoon, Tetrahedron, 56, 7747 (2000).
12] C. S. Cho, B. T. Kim, M. J. Lee, T.-J. Kim and S. C. Shim,
Angew. Chem. Int. Ed. Engl., 40, 958 (2001).
13] For transition metal-catalyzed amine exchange reaction:
3
[
[
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3