One-pot synthesis of tetrahydroquinolines catalyzed by Dy(OTf)3 in aqueous solution

Article abstract of DOI:10.1081/SCC-120005937

Various 4-substituted-1-methyltetrahydroquinolines are easily accessible from the one-pot condensation reaction of N-methylaniline with commercial formaldehyde solution and electron-rich alkenes in the presence of Dy(OTf)₃ (1 mol %) under mild

Full text of DOI:10.1081/SCC-120005937

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ONE-POT SYNTHESIS OF TETRAHYDROQUINOLINES
CATALYZED BY Dy(OTf)3 IN AQUEOUS SOLUTION
Ruifang Chen a & Changtao Qian b
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
Version of record first published: 16 Aug 2006.
To cite this article: Ruifang Chen & Changtao Qian (2002): ONE-POT SYNTHESIS OF TETRAHYDROQUINOLINES CATALYZED BY
Dy(OTf)3 IN AQUEOUS SOLUTION, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:16, 2543-2548
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2543–2548, 2002
ONE-POT SYNTHESIS OF
TETRAHYDROQUINOLINES CATALYZED
BY Dy(OTf )3 IN AQUEOUS SOLUTION
*
Ruifang Chen and Changtao Qian
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai,
200032, China
ABSTRACT
Various 4-substituted-1-methyltetrahydroquinolines are easily
accessible from the one-pot condensation reaction of N-
methylaniline with commercial formaldehyde solution and
electron-rich alkenes in the presence of Dy(OTf)3 (1 mol %)
under mild conditions at ambient temperature and in the
absence of any organic solvents.
Key Words: Tetrahydroquinolines;
Aqueous solution reaction
Dy(OTf)3
catalyst;
Tetrahydroquinoline derivatives are an important class of natural
products, which exhibit both biological and pharmaceutical activities
in various fields.[1] In recent years many synthetic methods have been devel-
oped for 1,4-disubstituted-1,2,3,4-tetrahydroquinolines.[2] Katritzky and
*Corresponding author. E-mail: qianct@pub.sioc.ac.cn
2543
DOI: 10.1081/SCC-120005937
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2544
CHEN AND QIAN
Rachwal reported the reactions of N-alkyl-N-phenyl-1H-benzotriazole-1-
methanamines with alkenes, enol ethers and enamines giving the
corresponding 4-substituted 1-methyl-1,2,3,4-tetrahydroquinolines in the
presence of a catalytic amount of p-toluene sulfonic acid in three
steps.[3–5] Other methods for the synthesis of tetrahydroquinolines
involve ionization of triphenylhexahydro-1,3,5-triazine using TiCl4 as the
catalyst;[6,7] reactions of N-methyl-N-(phenylthiomethyl)aniline with
styrene, cyclopentane, trans-1-phenylpropene and cis-1-phenylpropene
[8,9]
catalyzed by TiCl4–PPh3.
Recent findings have shown that 7 mol % of
dysprosium triflate (Dy(OTf)3) can catalyze the one-pot reaction of benzal-
dehyde, aniline and endocyclic enamine to afford hexahydropyrrolo[3,2-
c]quinolines. However, the use of THF–water (4 : 1) as solvent the yield of
product decreased evidently from 91 to 47%.[10] Lanthanide triflate can
catalyze the reaction of dienes with in situ formed imines in the presence
of MgSO4.[11] None of these methods, however, are as simple and efficient as
our high yielding one-pot preparation of tetrahydroquinolines from N-
methylaniline and commercial formaldehyde solution in the presence of
dysprosium triflate (1 mol %) under mild conditions.
Commercial formaldehyde solution, which is an aqueous solution
containing 37% formaldehyde and 8–10% methanol, is cheap, easy to
handle, and stable even at room temperature.
The reaction of N-methylaniline 1 with commercial formaldehyde sol-
ution 2 and 2,3-dihydrofuran 3 catalyzed by 1 mol % of Dy(OTf)3 affords
tricyclic 4 in 85% yields in 30 min at room temperature in the absence of any
organic solvents (Scheme 1). The utility of aqueous reaction is now generally
recognized. Aqueous reactions of organic compounds avoid the use of
harmful organic solvents and are especially appealing, as they provide an
opportunity to develop green chemistry and a safe synthetic process.
Although Kobayashi et al have reported that Ln(OTf)3 catalyzed Aldol
reaction in aqueous media, in fact the reaction proceeded in co-solvent
(THF : water ¼ 4 : 1 to 6 : 1), and the yields were low. When water or
THF was used alone, only 18% yield of the product was isolated in 100%
water solution.[12]
There is a little effect of the choice of lanthanide triflate catalyst on the
outcome of the reaction, although Dy(OTf)3 gives marginally better yields.
Other Lewis acid, such as Zn(OTf)2 and Cu(OTf)2, as well as p-toluene sul-
fonic acid can also catalyze this three-component coupling reaction, but the
isolated yields of the adducts are obviously lower than the others (Entries 11–
13, Table 1).
Reactions of N-methylaniline and commercial formaldehyde solution
with a variety of electron-rich olefins rather than 2,3-dihydrofuran are
also examined in the presence of Dy(OTf)3 (1 mol%) at room temperature

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TETRAHYDROQUINOLINES CATALYZED BY Dy(OTf )3
2545
Table 1. One-Pot Synthesis of Furo[3,2-c]quinoline Catalyzed by
Lewis Acid Catalyst (1 mol %)
O
Dy(OTf) (1 mol %)
3
+
+
HCHO
r. t.
N
NH
Me
O
Me
3
1
2
4
Scheme 1.
Isolated
Yield (%)a
Entry
1
Catalyst
La(OTf)3
82
76
73
78
75
85
76
69
77
77
48
57
33
2Pr(OTf)
3
3
4
5
6
7
8
9
Nd(OTf)3
Sm(OTf)3
Gd(OTf)3
Dy(OTf)3
Ho(OTf)3
Yb(OTf)3
Y(OTf)3
10
11
Sc(OTf)3
Zn(OTf)2
12Cu(OTf)
13
2
p-TsOH
and the results are summarized in Table 2. To the most of the substrates,
especially the electron-donating alkenes, the reaction could proceed smoothly
in the absence of any organic solvents with very short reaction time to afford
the desired adduct in good yields. It is noteworthy that this condensation
reaction exhibited high atom selectivity, almost all atoms of the substrates
transferred to the product expected and no harmful by-product was formed.
However, the reactions of styrene and 1-octene with N-methylaniline and
commercial formaldehyde solution are somewhat difficult.
In summary, we have found a very simple and highly efficient
three-component condensation reaction of N-methylaniline, commercial
formaldehyde solution and electron-rich alkenes for the one-pot synthesis
of 1,4-disubstituted-1,2,3,4-quinolines using 1 mol % Dy(OTf)3 as catalyst
in the 100% water solution at ambient temperature. The aqueous solution
reaction can reduce hazardous pollution and achieve environmental benign
organic synthetic process.

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2546
CHEN AND QIAN
Table 2. Results of the Three-Component Condensation Reactions Catalyzed by
Dy(OTf)3 (1 mol%)
Entry
1
Alkene
Reaction Time (h)
0.5
Isolated Yield (%)
85
O
2
0.5
82
O
O
3
4
287
281
O
5
6
5
5
33
34
PhCH¼CH2
EXPERIMENTAL
General Procedure for the Synthesis of Tetrahydroquinolines
To a mixture of N-methylaniline (106 mg, 1 mmol) and commercial
formaldehyde solution (82mg, 1 mmol) was added Dy(OTf) 3 (6 mg,
0.01 mmol). After stirred for 5 min, 2,3-dihydrofuran (70 mg, 1 mmol) was
added. After stirring for 30 min at room temperature, the reaction was then
quenched with water and extracted with CH2Cl2 (3 Â 30 mL). The combined
organic extracts were washed with brine, dried, concentrated in vacuum.
The crude product was purified via flash chromatography to afford the
desired product furo[3, 2-c]quinoline in 85% yield.
Furo[3,2-c]quinoline: Colorless oil; 1H-NMR(300 MHz, CDCl3): ꢀ 1.72
(m, 1H), 2.19 (m, 1H); 2.49 (m, 1H); 2.75 (t, J ¼ 11.0 Hz, 1H); 2.85 (s, 3H);
2.96 (dd, J ¼ 5.1 and 11.2Hz); 3.76 (td, J ¼ 8.9 Hz and 6.2Hz); 3.90 (td,
J ¼ 8.4 and 5.8 Hz, 1H); 4.56 (d, J ¼ 5.5 Hz, 1 H); 6.70 (d, J ¼ 1.6 Hz, 1 H);
6.76 (t, J ¼ 7.7 Hz, 1 H); 7.17 (td, J ¼ 7.5 Hz and 1.6 Hz, 1H); 7.32(d,
J ¼ 7.5 Hz, 1H); IR (neat, cmÀ1): 3068, 3032, 2938, 2866, 2818, 1606,
1576, 1477, 1452, 1430, 1385, 1354, 1298, 1207, 1163, 1141, 1115, 1095,
1059, 1012, 960, 921, 859, 694, 643, 561, 533, 469, 426, 420; MS: 189
(Mþ, 94.85); 190(Mþþ1, 24.19); 158 (28.61); 146 (33.16); 145 (27.52); 144

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TETRAHYDROQUINOLINES CATALYZED BY Dy(OTf )3
2547
(100); 131 (13.49); 130 (11.97); Anal. calcd. for C12H15NO: C, 76.19; H, 7.94;
N, 7.40. Found C, 76.00; H, 7.63; N, 7.41.
Pyrano[3,2-c]quinoline: Colorless oil; 1H-NMR(300 MHz, CDCl3):
ꢀ 1.45 (m, 1H); 1.72–1.95 (m, 3H); 2.15 (m, 1H); 2.90 (s, 3H); 2.93 (dd,
J ¼ 4.0 and 1.2Hz), 3.51 (t, J ¼ 11.1 Hz, 1 Hz); 3.64 (td, J ¼ 10.4 and
2.4 Hz, 1H); 3.92 (m, 1H); 4.40 (d, J ¼ 3.0 Hz, 1H); 6.62(t, J ¼ 8.3 Hz,
1H); 6.65 (dd, J ¼ 1.0 Hz and 7.4 Hz, 1H); 6.65 (dd, J ¼ 1.0 and 7.4 Hz,
1H); 7.12–7.20 (m, 2H); IR (neat, cmÀ1): 3068, 3028, 2933, 2855, 1607,
1572, 1503, 1478, 1452, 1359, 1322, 1294, 1271, 1245, 1208, 1162, 1141,
1091, 1065, 1052, 1043, 1023, 1002, 977, 934, 911, 884, 865, 850, 746, 727,
703, 663, 642, 574, 541; MS: 203(Mþ, 48.46); 190 (24.19); 158 (28.61); 146
(33.16); 145 (27.52); 144 (100); 131 (13.49); 130 (11.97); Anal. calcd. for
C13H17NO: C, 76.84; H, 8.37; N, 6.90; Found C, 76.73; H, 7.93; N, 6.90.
1
1-Methyl-4-methoxy-1,2,3,4-tetrahydroquinoline: Colorless oil; H-NMR
(300 MHz, CCl4): ꢀ: 1.73–2.20 (m, 2H); 2.90 (s, 3H); 3.23 (s, 3H); 3.06–3.57
(m, 2H); 4.03 (t, 1H, J ¼ 3 Hz), 6.30–7.23 (m, 4H); IR (neat, cmÀ1): 3058,
3020, 1600, 1500, 1200, 1090, 742; Anal. calcd for C11H15NO: C, 74.54; H,
8.53; N, 7.90. Found: C, 74.21; H, 8.77; N, 7.74.
1-Methyl-4-ethoxy-1,2,3,4-tetrahydroquinoline: Colorless oil; 1H-NMR
(300 MHz, CCl4): ꢀ: 1.15 (t, 3H, J ¼ 7 Hz); 1.73–2.11 (m, 2H ); 2.88 (s, 1H);
2.96–3.63 (m, 2H); 3.60 (q, 2H, J ¼ 7.0 Hz); 4.15 (t, 1H, J ¼ 3.4 Hz),
6.30–7.21 (m, 4H); IR (neat, cmÀ1): 3058, 3020, 1600, 1500, 1325, 1220,
1080, 742; Anal. calcd. for C12H17NO: C, 75.37; H, 8.96; N, 7.32. Found:
C, 75.03; H, 9.06; N, 7.16.
1
1-Methyl-4-hexyl-1,2,3,4-tetrahydroquinoline: Colorless oil: H-NMR
(300 MHz, CCl4): ꢀ: 0.85 (t, 3H, J ¼ 4.0 Hz); 1.07–2.11 (m, 12H ); 2.43–
2.98 (m, 1H); 2.83 (s, 1H); 2.96–3.63 (m, 2H); 6.23–7.06 (m, 2H); IR
(neat, cmÀ1): 3058, 3020, 1600, 1501, 1320, 742; Anal. calcd. for C16H25N:
C, 83.06; H, 10.89; N, 6.05. Found: C, 83.01; H, 11.08; N, 5.95
1
1-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline: Colorless oil; H-NMR
(90MHz, CCl4): ꢀ: 1.94–2.41 (m, 2H); 2.79 (s, 3H); 3.01 (t, 2H, J ¼ 4.8 Hz);
3.85 (t, 1H, J ¼ 5.9 Hz); 6.15–7.50 (m, 9H); IR (neat, cmÀ1): 3058, 3019,
1600, 1500, 1320, 740, 700; Anal. calcd. for C16H17N: C, 86.06; H, 7.67;
N, 6.27. Found: C, 86.01; H, 7.75; N, 6.29.
ACKNOWLEDGMENTS
Financial support from the State Key Project of Basic Research
(Project 973, No. G 2000048007) and National Natural Sciences
Foundation of China are grateful acknowledged.

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2548
CHEN AND QIAN
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Received in the UK June 22, 2001