Yb(OTf)3-catalyzed cyclization of an N-silylenamine with 2-methylene-1,3-cyclohexanedione to afford a 7,8-dihydroquinolin-5(6H)-one derivative and its application to the one-pot conversion to a 2,3,5-trisubstituted quinoline derivative

Article abstract of DOI:10.1016/j.tetlet.2005.12.080

A catalytic amount of ytterbium triflate (Yb(OTf)₃) promotes the cyclization of an N-silylenamine with in situ generated 2-methylene-1,3- cyclohexanedione and 2-methylenecyclohexanone to produce the corresponding 2,3-disubstituted 7,8-dihydroqu

Full text of DOI:10.1016/j.tetlet.2005.12.080

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1261–1265
Yb(OTf)3-catalyzed cyclization of an N-silylenamine with
2-methylene-1,3-cyclohexanedione to afford a 7,8-dihydroquinolin-
5(6H)-one derivative and its application to the one-pot conversion
to a 2,3,5-trisubstituted quinoline derivative
Norio Sakai, Daisuke Aoki, Toshihiro Hamajima and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
Received 16 November 2005; revised 9 December 2005; accepted 15 December 2005
Abstract—A catalytic amount of ytterbium triflate (Yb(OTf)3) promotes the cyclization of an N-silylenamine with in situ generated
2-methylene-1,3-cyclohexanedione and 2-methylenecyclohexanone to produce the corresponding 2,3-disubstituted 7,8-dihydroquin-
olin-5-one and 5,6,7,8-tetrahydroquinolin-5-one in moderate to good yields. A one-pot conversion of 7,8-dihydroquinolin-5-one to
the quinoline derivative also proceeded in good yield.
Ó 2005 Elsevier Ltd. All rights reserved.
A practical synthesis of polysubstituted quinolines and
their dihydro/tetrahydro quinolines has attracted con-
siderable interest in the fields of organic and pharmaceu-
tical chemistry, since this basic skeleton is widespread in
natural products and biologically active substances.1
Hence, a number of methods, including the Conrad–
Limpach–Knorr synthesis,2 the Skraup synthesis,3 and
the Friedla¨nder synthesis,4 have been developed for
the preparation of this skeleton. However, most of these
classical methods generally require high temperatures
and strong basic/acidic conditions, which may induce
a decrease in product yield and the production of by-
products via the polymerization of carbonyl compo-
nents. Using a catalyst such as a Lewis acid, several
groups have recently developed methods for the facile
preparation of quinoline skeletons, which can be used
under relatively mild conditions.5 On the other hand,
we previously reported on the cyclization of an N-silyl-
1-azaallyl anion,6 which can easily be generated from a
functionalized silane and an aromatic nitrile in the
presence of a base,7 with 1,2-diketones, a,b-unsaturated
ketones, and tropolones, leading to the preparation of
heterocycles, such as pyrroles, pyridines, and azaazu-
lenes.8 During our continuing studies of the synthesis
of heterocycles, we found that a combination of an
N-silylenamine, formed by quenching the 1-azaallyl
anion with water,9 and an appropriate cyclic a,b-unsatu-
rated compound leads to the production of quinoline
skeletons (Scheme 1). We report herein on the Yb(OTf)3-
catalyzed cyclization of an N-silylenamine with 2-meth-
ylene-1,3-cyclohexanedione leading to a 2,3-disubsti-
tuted 7,8-dihydroquinolin-5(6H)-one derivative.10 We
also describe the efficient one-pot conversion to a
2,3,5-trisubstituted quinoline starting from the 2,3-
disubstituted quinolin-5-one derivative.
We initially investigated the cyclization of N-silylen-
amine 1a, prepared from a functionalized silane and
benzonitrile in the presence of n-BuLi, with [(2,6-
dioxocyclohexyl)methyl]dimethylammonium chloride11
(2a), a 2-methylene-1,3-diketone precursor as a model
reaction.12 Table 1 shows the results of a search for opti-
mized conditions. When conducted in THF, benzene,
and acetonitrile, the reaction proceeded to produce the
desired quinoline derivative 3aa, but the yields were
moderate (runs 1–3). Although DMSO showed a similar
solvent effect for the cyclization, the use of DMF
resulted in the production of a complex mixture (runs
4 and 5). Interestingly, when the reaction was run in
Keywords: N-Silylenamine; 7,8-Dihydroquinolin-5-one; Quinoline;
Ytterbium triflate.
*
Corresponding author. Tel.: +81 4 7122 9502; fax: +81 4 7123
9326; e-mail: konaka@rs.noda.tus.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.080

1262
N. Sakai et al. / Tetrahedron Letters 47 (2006) 1261–1265
R1
SiMe3
NHMe2Cl
O
NHMe2Cl
O
R1
R2
1) n-BuLi
2) H2O
- HNMe2•HCl
+
O
O
O
HO
SiMe3
R2CN
∆
N
H
X
O
R1
R2
R1
R2
N
N
Scheme 1. Schematic method for quinoline synthesis by the cyclization of an N-silylenamine with 2-methylene-1,3-cyclohexanedione.
Table 1. Optimization of the cyclization of N-silylenamine 1a with 2-methylene-1,3-cyclohexanedione precursor 2a
+
-
O
NHMe2Cl
2-Py
Ph
2-Py
Ph
Lewis acid
solvent
O
+
O
SiMe3
N
H
N
3aa
2a (1.2 equiv)
1a
Run
Additive (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
—
—
—
—
—
—
THF
PhH
MeCN
DMSO
Reflux
Reflux
Reflux
100
100
rt
rt
Reflux
rt
rt
70
rt
rt
12
12
12
12
12
12
40
40
40
40
40
40
40
32
16
21
38
ND
69
37
73
75
78
68
84
85
DMF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
AlCl3 (0.2)
AlCl3 (0.2)
Hf(OTf)4 (0.2)
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.05)
Yb(OTf)3 (0.02)
9
10
11
12
13
a NMR yields.
1,4-dioxane, the desired product 3aa was formed at
room temperature in 69% yield (run 6). Thus, to activate
the carbonyl group of 2-methylene-1,3-cyclohexane-
dione generated in situ, we investigated the use of a Lewis
acid as an additive. Among the compounds tested,13 in
case of AlCl3, the reaction proceeded at room tempera-
ture, and the yield of 3aa was increased to 73% under
reflux (runs 7 and 8). It is noteworthy that, when the
reaction was carried out in the presence of a catalytic
amount of Hf(OTf)4 or Yb(OTf)3,14 the cyclization also
proceeded at room temperature to afford the corre-
sponding quinolinone derivative 3aa in good yield (runs
9 and 10). Surprisingly, even when the amount of the
ytterbium catalyst was decreased to 0.05 or 0.02 equiv
for the N-silylenamine, the catalyst showed a high cata-
lytic activity and the product 3aa was produced in excel-
lent yield (runs 12 and 13). The structure of quinolinone
the results are summarized in Table 2. The reaction of
N-silylenamine 1b containing an electron-donating
group on the benzene ring with endione precursor 2a
produced the corresponding quinoline 3ba in good yield
(run 2). In contrast, the reaction of enamine 1c, contain-
ing an electron-withdrawing group, resulted in a moder-
ate yield, due to the reduced nucleophilicity of the
enamine (run 3). When the reaction of 2a with N-silylen-
amine 1d containing an alkyl group as R2 was conducted
at room temperature, the product yield was low. How-
ever, at 60 °C, a satisfactory yield was obtained (run
4). Similarly, when the reaction of enamine 1e with
another heterocycle, such as a 3-methyl-5-isoxazolyl
group with endione precursor 2b having dimethyl groups
was carried out at room temperature, the yield of product
3eb was rather low. However, the yield was also
improved to 60% when the reaction was run at 60 °C
(run 8). Moreover, the reaction with an enamine having
an ester or an amide group also gave the corresponding
products in moderate to good yields (runs 9 and 10). For
example, when the reaction of enamine 1f, containing an
N,N-dimethylamide group with an endione precursor
was carried out under optimal conditions, the desired
product 3fa was obtained in 62% yield (run 9).
1
3aa was confirmed by H and 13C NMR spectroscopy,
mass spectrometry, and elemental analysis.
To examine the general applicability of this cyclization,
reactions of various N-silylenamines with two types of 2-
methylene-1,3-cyclohexanedione (endione) precursors
were carried out under the optimized conditions and

N. Sakai et al. / Tetrahedron Letters 47 (2006) 1261–1265
1263
Table 2. Yb(OTf)3-catalyzed cyclization of N-silylenamine 1 with the 2-methylene-1,3-cyclohexanedione precursor 2 leading to quinolinone
derivative 3a
R1
R2
O
NHMe2Cl
O
R1
R2
Yb(OTf)3 (0.02 equiv)
1,4-dioxane, rt, 40 h
O
+
SiMe3
N
H
R3
N
R3
R3 R3
1
3
2
Run
N-Silylenamine 1
1,3-Diketone 2
R3
Yield of 3 (%)
R1
R2
1
2
3
4
5
6
7
8
9
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-pyridyl
2-Pyridyl
2-Pyridyl
3-Methyl-5-isoxazolyl
3-Methyl-5-isoxazolyl
CONMe2
Ph
1a
1b
1c
1d
1a
1b
1e
1e
1f
H
H
H
H
Me
Me
H
Me
H
2a
2a
2a
2a
2b
2b
2a
2b
2a
2a
3aa
3ba
3ca
3da
3ab
3bb
3ea
3eb
3fa
3ga
84
77
48
34 (60)b
4-MeO–C6H4
4-Cl–C6H4
n-Bu
Ph
77
51
64
4-MeO–C6H4
Ph
Ph
Ph
2-Pyridyl
trace (60)b
62
36
10
CO2t-Bu
1g
H
a N-Silylenamine 1 (0.5 mmol), 2-methylene-1,3-diketone precursor 2 (1.2 equiv), and Yb(OTf)3 (0.02 equiv) were used in 1,4-dioxane solution
(1 mL).
b Reaction was carried out at 60 °C.
O
O
We then examined the cyclization of enamines with
2-methylene-1-cyclohexanone (enone) as a Michael
acceptor; these reactions produced tetrahydroquinoline
derivatives (Scheme 2). For example, when the reaction
of N-silylenamine 1a with enone precursor 4 was carried
out at 60 °C for 30 h, the desired tetrahydroquinoline 5a
was produced in 57% yield. While the use of an N-silyl-
NBS
AIBN
2-Py
Ph
2-Py
Ph
CCl4, reflux, 1 h
N
N
Br
3aa
6aa
PTS (1 equiv)
MeOH, reflux, 24 h
enamine containing
a 3-methyl-5-isoxazolyl group
decreased the yield of 5e.15
OMe
2-Py
Ph
Finally, we examined the one-pot conversion16 of the
7,8-dihydroquinolinone derivative 3aa to quinoline
derivative 7aa. Quinolinone 3aa was treated with
N-bromosuccinimide (NBS) in the presence of 2,20-
azobis(isobutyronitrile) (AIBN) producing 8-bromi-
nated quinolinone 6aa, followed by the treatment with
p-toluenesulfonic acid in methanol without further puri-
fication, leading to the production of the corresponding
2,3,5-trisubstituted quinoline 7aa in 83% yield (Scheme
3).17
N
7aa: 83%
Scheme 3. One-pot conversion to the quinoline derivative starting
from the quinolinone derivative.
vated by the ytterbium salt, initially occurs to produce
intermediate 8, followed by an in situ keto-enol isomer-
ization to form the corresponding diketone intermediate
9. An intramolecular attack of nitrogen atom in inter-
mediate 9 on the activated carbonyl group then occurs
to give the cyclization product 10, followed by the elim-
ination of silanol from 10 and subsequent oxidation,
forming the desired quinolinone product 3. The reaction
A plausible mechanism for the cyclization of the enam-
ine with 2-methylene-1,3-cyclohexanedione in the pres-
ence of Yb(OTf)3 is shown in Scheme 4. Nucleophilic
attack of the b-carbon of the enamine on the b-position
of the a,b-unsaturated carbonyl group, which is acti-
R1
O
NMe2HCl
R1
Yb(OTf)3
+
SiMe3
dioxane
Ph
N
H
R2
N
4
1a: R1= 2-pyridyl
1e: R1= 3-methyl-5-isoxazolyl
5a: 57%
5e: 25%
60˚C, 30 h
rt, 40 h
Scheme 2. Cyclization of N-silylenamine 1 with 2-methylene-1-cyclohexanone precursor 4.

1264
N. Sakai et al. / Tetrahedron Letters 47 (2006) 1261–1265
2004, 963; (b) Breitmaier, E.; Gassenmann, S.; Bayer, E.
O
R1
O
R1
R2
Tetrahedron 1970, 26, 5907; (c) Breitmaier, E.; Bayer, E.
Tetrahedron Lett. 1970, 11, 3291; (d) Breitmaier, E.; Bayer,
E. Angew. Chem., Int. Ed. Engl. 1969, 8, 765; (e) Fehnel, E.
A. J. Org. Chem. 1966, 31, 2899.
R2
Me3Si
SiMe3
N
N
O
H
H
O
5. (a) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46,
1647; (b) Theoclitou, M.-E.; Robinson, L. A. Tetrahedron
Lett. 2002, 43, 3907; (c) Jiang, B.; Si, Y.-G. J. Org. Chem.
2002, 67, 9449.
1
Yb(OTf)3
8
2
O
R1
O
O
H
R1
R2
R1
R2
6. Mangelinckx, S.; Giubellina, N.; Kimpe, N. D. Chem.
Rev. 2004, 104, 2353.
7. Konakahara, T.; Murayama, T.; Sano, K.; Kubota, S. J.
Chem. Res. (S) 1996, 136.
-Me3SiOH
[O]
R2
Me3Si
N
O
N
N
OSiMe3
10
Yb(OTf)3
3
8. (a) Sakai, N.; Hattori, N.; Tomizawa, N.; Abe, N.;
Konakahara, T. Heterocycles 2005, 65, 2799; (b) Konaka-
hara, T.; Sugama, N.; Yamada, A.; Kakehi, A.; Sakai, N.
Heterocycles 2001, 55, 313; (c) Konakahara, T.; Ogawa,
R.; Tamura, S.; Kakehi, A.; Sakai, N. Heterocycles 2001,
55, 1737; (d) Hojahmat, M.; Konakahara, T.; Tamura, S.
Heterocycles 2000, 53, 629; (e) Konakahara, T.; Watan-
abe, A.; Maehara, K.; Nagata, M.; Hojahmat, M.
Heterocycles 1993, 35, 1171.
9
Scheme 4. Plausible mechanism for the cyclization of the N-silyl-
enamine with 2-methylene-1,3-cyclohexanedione.
mechanism is analogous to that for the synthesis of pyr-
idine from the N-silylenamine with a,b-unsaturated
ketones.8b,18
9. Konakahara, T.; Sato, K. Bull. Chem. Soc. Jpn. 1983, 56,
1241.
In summary, we demonstrate that the Yb(OTf)3-
catalyzed cyclization of an N-silylenamine with in situ
generated 2-methylene-1,3-cyclohexanedione and 2-
methylenecyclohexanone leads to a 7,8-dihydroquino-
lin-5-one derivative. The ytterbium salt functions as a
good catalyst, permitting the reaction to proceed under
mild conditions. We also succeeded in the one-pot con-
version of the quinolin-5-one derivative to the 2,3,5-tri-
substituted quinoline derivative in good yield.
10. For selected reviews and paper of a reaction using
Yb(OTf)3, see: (a) Kobayashi, S.; Sugiura, M.; Kitagawa,
H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227; (b)
Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37,
7357; (c) Kobayashi, S. Synlett 1994, 689.
11. Sielemann, D.; Keuper, R.; Risch, N. Eur. J. Org. Chem.
2000, 543.
12. General procedure for the preparation of 7,8-dihydro-
quinolin-5-one 3: To a 1,4-dioxane solution (1 mL) of
[(2,6-dioxocyclohexyl)methyl]dimethylammonium chlo-
ride (2a, 125 mg, 0.60 mmol) and N-silylenamine
1
Acknowledgements
(0.50 mmol) was added Yb(OTf)3 (6.2 mg, 0.010 mmol)
at room temperature. The reaction mixture was stirred at
the same temperature for 40 h and its progress was
monitored by TLC. To quench the reaction, H2O (2 mL)
was added to the mixture. After the usual work-up, the
crude product was purified by silica gel column chroma-
tography (hexane/EtOAc = 1:1) to give 7,8-dihydroquin-
olin-5-one 3. Spectral data for selected novel compounds:
7,8-dihydro-7,7-dimethyl-2-phenyl-3-(2-pyridinyl)-quino-
lin-5(6H)-one (3ab); white solid; mp 160–162 °C; 1H NMR
(CDCl3, 500 MHz) d 8.58 (m, 1H), 8.50 (s, 1H), 7.43–6.95
(m, 8H), 3.08 (s, 2H), 2.53 (s, 2H), 1.10 (s, 6H); 13C NMR
(CDCl3, 125 MHz) d 197.6, 161.7, 161.1, 157.2, 149.8,
139.3, 137.2, 135.8, 134.1, 129.7, 128.7, 128.1, 125.6, 124.8,
122.1, 52.1, 46.4, 33.0, 28.3; MS (FAB) m/z 329 (M+H,
100%); Anal. Calcd for C22H20N2O2: C, 80.46; H, 6.14; N,
8.53. Found: C, 80.17; H, 6.13; N, 8.55; 7,8-dihydro-3-(3-
This work was partially supported by Grants-in-Aid for
Scientific Research from MEXT (16550148), 2004–2005,
a grant from the Japan Private School Promotion Foun-
dation, and a fund for ‘High-Tech Research Center’
Project for Private Universities: a matching fund subsidy
from MEXT, 2000–2004, and 2005–2007.
References and notes
1. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science Ltd: Oxford, 2000; pp 121–150; (b)
Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 5, pp 245–300; (c) Erian, A. W. Chem. Rev. 1993, 93,
1991.
2. For selected papers for the reactions from arylamines and
1,3-dicarbonyl compounds, see: (a) Tanyeli, C.; Akhme-
dov, I. M.; Isik, M. Tetrahedron Lett. 2004, 45, 5799; (b)
Curran, A. C. W. J. Chem. Soc., Perkin Trans. 1 1976, 975.
3. For selected papers for the reactions from arylamines and
a,b-unsaturated carbonyl compounds (a) Kobayashi, K.;
Takanohashi, A.; Watanabe, S.; Morikawa, O.; Konishi,
H. Tetrahedron Lett. 2000, 41, 7657; (b) Robinson, J. M.;
Brent, L. W.; Chau, C.; Floyd, K. A.; Gillham, S. L.;
McMahan, T. L.; Magda, D. J.; Motycka, T. J.; Pack, M.
J.; Roberts, A. L.; Seally, L. A.; Simpson, S. L.; Smith, R.
R.; Zalesny, K. N. J. Org. Chem. 1992, 57, 7352.
methyl-5-isoxazolyl)-2-phenylquinolin-5(6H)-one
(3ea);
white solid; mp 133–134 °C; 1H NMR (CDCl3,
500 MHz) d 8.67 (s, 1H), 7.41 (m, 5H), 5.55 (s, 1H), 3.22
(t, 2H, J = 6.5 Hz), 2.74 (t, 2H, J = 6.5 Hz), 2.24 (q, 2H,
J = 6.5 Hz), 2.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) d
196.9, 166.7, 163.9, 160.8, 159.9, 139.0, 135.7, 129.4, 128.6,
128.5, 126.5, 121.6, 104.4, 38.5, 32.6, 21.6, 11.4; MS (FAB)
m/z 305 (M+H, 100%); Anal. Calcd for C19H16N2O2: C,
74.98; H, 5.48; N, 9.20. Found: C, 74.96; H, 5.48; N, 9.20;
5,6,7,8-tetrahydro-2-phenyl-3-(2-pyridinyl)quinoline (5aa);
1
white solid; mp 126–127 °C; H NMR (CDCl3, 500 MHz)
d 8.67 (m, 1H), 7.71 (s, 1H), 7.38–6.88 (m, 8H), 3.04 (t, 2H,
J = 7.0 Hz), 2.87 (t, 2H, J = 7.0 Hz), 1.95 (q, 2H,
J = 7.0 Hz), 1.86 (q, 2H, J = 7.0 Hz); 13C NMR
(125 MHz, CDCl3) d 157.8, 157.0, 154.1, 149.4, 140.1,
138.7, 135.1, 132.1, 130.7, 129.5, 127.8, 127.4, 125.0, 121.3,
32.3, 28.1, 22.9, 22.5; MS (FAB) m/z 287 (M+H, 100%);
4. For selected papers for the reactions from o-acylaryl-
amines and a-methylene carbonyl compounds, see: (a)
Yadav, J. S.; Reddy, B. V. S.; Premalatha, K. Synlett

N. Sakai et al. / Tetrahedron Letters 47 (2006) 1261–1265
1265
HRMS (FAB): Calcd for C20H19N2: 287.1548. Found
287.1540 (M+H).
13. Typical Lewis acids, such as MgBr2, ZnCl2, EtAlCl2, and
InCl3 were ineffective for the reaction.
14. A reaction with 2 mol % of Hf(OTf)4 resulted in 75% of
the product yield.
15. Although the reaction of enamine 1e with the enone
precursor 4 ran at 60 °C for 24 h, the product yield of 5e
was not improved (25%).
16. Procedure for the one-pot preparation of quinoline 7aa:
To a carbon tetrachloride solution (1 mL) of NBS (59 mg,
0.33 mmol), and AIBN (1 mg, 0.006 mmol) was added
dihydroquinolinone 3aa (100 mg, 0.330 mmol) and the
mixture was refluxed. After 45 min, the reaction mixture
was cooled to room temperature, and methanol (4 mL)
and p-toluenesulfonic acid monohydrate (63 mg,
0.33 mmol) were added and the solution was refluxed for
a further 24 h. The solvent was removed under reduced
pressure and the residue purified by silica gel column
chromatography (hexane/AcOEt = 1:1) to give 5-meth-
oxy-2-phenyl-3-(2-pyridinyl)quinoline (7aa) as a white
solid (86 mg, 83%); mp 147–149 °C; 1H NMR (CDCl3,
500 MHz) d 8.83 (s, 1H), 8.62 (m, 1H), 7.73–6.81 (m,
11H), 3.96 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 158.3,
158.2, 155.6, 149.7, 148.5, 140.5, 135.5, 133.5, 132.6, 130.1,
129.9, 128.1, 128.1, 125.3, 121.7, 119.6, 104.4, 55.7; MS
(FAB) m/z 313 (M+H, 100%); HRMS (FAB): Calcd for
C21H17N2O: 313.1341. Found 313.1334 (M+H).
17. Akbarzadeh, T.; Shafiee, A. Synth. Commun. 2004, 34,
1455.
18. (a) Konakahara, T.; Hojahmat, M.; Tamura, S. J. Chem.
Soc., Perkin Trans. 1 1999, 2803; (b) Konakahara, T.;
Mojahmat, M.; Sujimoto, K. Heterocycles 1997, 45,
271.