Efficient synthesis of tetrahydroquinolinones by acetic acid-mediated formal [3+3] cycloaddition

Article abstract of DOI:10.1007/s00706-012-0762-0

A simple and efficient method to synthesize a variety of tetrahydroquinolinones was successfully achieved by reacting various β-enaminones with several α,β-unsaturated aldehydes. This strategy can be viewed as a Bronsted acid-mediated formal [3+3] cycloaddition. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0762-0

Monatsh Chem (2012) 143:1421–1426
DOI 10.1007/s00706-012-0762-0
ORIGINAL PAPER
Efficient synthesis of tetrahydroquinolinones by acetic
acid-mediated formal [3+3] cycloaddition
•
Quang Huy To Yong Rok Lee Sung Hong Kim
•
Received: 28 September 2011 / Accepted: 20 March 2012 / Published online: 18 April 2012
Ó Springer-Verlag 2012
Abstract A simple and efficient method to synthesize a
variety of tetrahydroquinolinones was successfully achieved
by reacting various b-enaminones with several a,b-unsatu-
rated aldehydes. This strategy can be viewed as a Brønsted
acid-mediated formal [3?3] cycloaddition.
synthesis of tetrahydroquinolinones despite the existence of
the two aforementioned current methods.
We previously developed new methodologies to prepare
pyran derivatives from 1,3-dicarbonyls and a,b-unsaturated
aldehydes using formal [3?3] cycloadditions catalyzed by
indium(III) chloride or ethylenediamine diacetate (EDDA)
as a key strategy (Scheme 1) [10–12]. Later, novel
approaches were also designed by other groups using
BF3ÁEt2O, TiCl4, and In(OTf)3 Lewis acids as catalysts
[13], phosphoric acids as Brønsted acid catalysts [14], and
EDDA/ZnCl2 as co-catalysts [15].
Keywords Tetrahydroquinolinones Á b-Enaminones Á
Formal [3?3] cycloaddition Á Acetic acid
Introduction
In order to extend the utility of this methodology, further
reactions between a series of b-enaminones and a,b-
unsaturated aldehydes were examined using several Lewis
acids or Brønsted acids. We report herein a simple and
efficient synthesis of a variety of tetrahydroquinolinones by
a formal [3?3] cycloaddition of b-enaminones with a,b-
unsaturated aldehydes in the presence of acetic acid as
shown in Scheme 2.
Tetrahydroquinolinones and their derivatives have various
biological activities of interest to the pharmaceutical indus-
try; for instance, they are potential agents for the treatment of
Alzheimer’s disease [1, 2] and modulators of metabotropic
glutamate receptors [3–5]. Several synthetic approaches to
tetrahydroquinolinones have been described [6, 7]. In related
work, Hsung et al. [8] reported a strategy to construct tetra-
hydroquinolinones by reacting vinylogous amides with a,
b-unsaturated iminium salts. Recently, Renaud et al. [9]
reported a method to prepare tetrahydroquinolinones by
reacting vinylogous amides with a,b-unsaturated aldehydes
in the presence of an organophosphoric acid which has a
complicated structure and also high cost. Therefore, it would
be desirable to have simple and facile methods for the
Results and discussion
b-Enaminones have been widely used as versatile synthetic
intermediates [16–19]. The required b-enaminones 1a–1g
were prepared in 72–91 % yield by heating corresponding
cyclic 1,3-dicarbonyls and amines (Scheme 3) according to
a known reaction [20].
Recently, Brønsted acids were demonstrated to serve as
active catalysts in a variety of synthetically useful reactions
[21–24]. For this reason, Brønsted acids were employed in
our new methodology for the preparation of various ben-
zopyrans [25–34]. As a part of our ongoing evaluation of
the synthetic efficacy of Brønsted acids, we first investi-
gated the reaction of b-enaminone 1a with 3-methyl-2-
Q. H. To Á Y. R. Lee (&)
School of Chemical Engineering, Yeungnam University,
Gyeongsan 712-749, Korea
e-mail: yrlee@yu.ac.kr
S. H. Kim
Analysis Research Division, Daegu Center, Korea Basic Science
Institute, Daegu 702-701, Korea
123

1422
Q. H. To et al.
O
O
O
O
Table 1 Reaction of 1a and 3-methyl-2-butenal in the presence of
various acids
InCl3
or
EDDA
H
+
R1
R2
R1
R2
R3
R4
O
O
R3 R4
OH
O
O
various acids
H
+
Scheme 1
NH
N
1a
2a
O
O
H
AcOH
n
n
R1
R2
+
R1
R2
R4
R5
Acid
I2 (20 mol %)
Conditions
Yield/%
NH
R3
R4 R5
N
R3
CH3CN, reflux, 12 h
CH2Cl2, reflux, 12 h
CH3CN, reflux, 12 h
Toluene, reflux, 12 h
Toluene, reflux, 18 h
Toluene, reflux, 18 h
Toluene, reflux, 18 h
Toluene, reflux, 18 h
THF, reflux, 18 h
0
n= 0,1
BF3ÁOEt2 (20 mol %)
InCl3 (20 mol %)
FeCl3 (20 mol %)
p-TsOH (20 mol %)
EDDA (20 mol %)
EDTA (20 mol %)
EDTA (1 equiv)
0
Scheme 2
0
26
42
20
71
62
0
butenal using several Brønsted acids, but also Lewis acids
and other reagents (Table 1). With 20 mol % of iodine as a
catalyst in refluxing acetonitrile for 12 h, no products
were obtained. Both BF3ÁOEt2 (20 mol %) and InCl3
(20 mol %) as Lewis acids in refluxing methylene chloride
or acetonitrile for 12 h gave no adducts. With 20 mol % of
FeCl3 in refluxing toluene for 12 h, the desired product
2a was produced in 26 % yield. Applying p-TsOH
(20 mol %) and EDDA (20 mol %) in refluxing toluene for
18 h afforded the product 2a in 42 and 20 % yield,
respectively. On comparison, the use of ethylenediamine-
tetraacetic acid (EDTA) as a catalytic (20 mol %) and
stoichiometric reagent (1 equivalent) in refluxing toluene
for 18 h gave product 2a in 71 and 62 % yield, respec-
tively. However, with tetrahydrofuran (THF), no adducts
were produced. Interestingly, the best yield (82 %) was
obtained in the presence of two equivalents of acetic acid.
Support for the structural assignment of 2a comes from
spectroscopic analysis. The carbonyl group of an enone is
EDTA (20 mol %)
AcOH (20 mol %)
AcOH (2 equiv)
Toluene, reflux, 18 h
Toluene, reflux, 18 h
53
82
To explore the scope of this methodology, reactions of
several b-enaminones 1a–1g with a,b-unsaturated alde-
hydes were performed in the presence of two equivalents of
acetic acid. The results are summarized in Table 2. The
method worked well for N-substituted b-enaminones 1a–1c
and several a,b-unsaturated aldehydes. For example, the
treatment of 1a with crotonaldehyde, trans-2-hexen-1-al,
trans-cinnamaldehyde, and citral provided products 2b–2e
in 75, 72, 68, and 65 % yield, respectively (entries 1–4).
Reaction of 1b with 3-methyl-2-butenal gave 2f in 72 %
yield, whereas that of 1c with 3-methyl-2-butenal provided
2g in high yield (90 %) (entries 5, 6). Reactions of 1d and
1e, bearing a methyl or phenyl on the 6-membered ring,
identified by the IR absorption at 1,603 cm-1. In the H
1
NMR spectrum, the expected chemical shifts of two vinylic
protons are shown at d = 6.59 (d, J = 9.9 Hz) and 4.97
(d, J = 9.9 Hz) ppm.
Scheme 3
O
O
n
R1
R2
100 °C
n
R1
R2
R3NH2
+
NH
R3
O
n= 0,1
O
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
NH
MeO
1a
1b
1c
91%
1d
1e
1f
1g
84%
85%
80%
88%
80%
72%
123

Efficient synthesis of tetrahydroquinolinones
1423
Table 2 Synthesis of a variety of tetrahydroquinolinones 2 (see Scheme 2)
Entry
1
R1
R2
R3
R4
R5
n
2
Time/h
Yield/%
1
1a
1a
1a
1a
1b
1c
1d
1e
1f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
H
CH3
CH3
CH3
CH3
CH3
CH3
H
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4-CH3O-C6H5CH2
C6H5
CH3
H
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
2b
2c
2d
2e
2f
18
18
20
24
18
10
18
24
15
18
18
18
24
10
12
75
72
68
65
72
90
76
66
87
72
75
78
61
62
60
2
n-C3H7
C6H5
C6Ha11
CH3
H
3
H
4
CH3
CH3
CH3
CH3
CH3
CH3
H
5
6
CH3
2g
2h
2i
7
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3
8
H
CH3
9
H
CH3
2j
10
11
12
13
14
15
a
1f
H
H
CH3
2k
2l
1f
H
H
n-C3H7
C6H5
C6Ha11
CH3
H
1f
H
H
H
2m
2n
2o
2p
1f
H
H
CH3
CH3
CH3
1g
1g
H
H
H
H
C6Ha11
4-Methyl-3-pentenyl
with 3-methyl-2-butenal provided products 2h and 2i in 76
and 66 % yield, respectively (entries 7, 8). Similarly,
b-enaminone 1f, without any substituent on the 6-mem-
bered ring, gave products 2j–2n in 87, 72, 75, 78, and 61 %
yield, respectively (entries 9–13). Interestingly, reactions
between b-enaminone 1g, which contains a 5-membered
ring, and 3-methyl-2-butenal or citral gave 1,2-dihydro-
pyridin-5-ones 2o and 2p in 62 and 60 % yield, respectively
(entries 14, 15). Overall these reactions provide a rapid route
to synthesize a variety of tetrahydroquinolinones and
dihydropyridinones. To investigate the limitations of this
cycloaddition, further reactions with a,b-unsaturated ketones
such as trans-4-phenyl-3-buten-2-one and trans-3-penten-2-
one were carried out; however, treatment of 1a with these
ketones in the presence of two equivalents of AcOH in
refluxing toluene for 18 h did not afford the desired products.
According to the mechanism reported by Hsung [8] and
Renaud [9], the formation of 2a may be explained by a
domino reaction as shown in Scheme 4. The b-enaminone
1a first attacks the protonated aldehyde to yield interme-
diate 3, which is then dehydrated upon heating to give 4.
Deprotonation of the intermediate 4 is followed by
6p-electrocyclization to give cycloadduct 2a.
OH
O
O
OH
O
H
H
H
N
N
NH
- H2O
1a
3
4
O
O
-H
N
N
5
2a
Scheme 4
method lies in much cheaper and easily available reagent,
good yields, and ease of handling.
Experimental
1,3-Diketones and aldehydes were obtained from Aldrich
Chemicals. Merck precoated silica gel plates (Art. 5554)
with fluorescence indicator were used for analytical TLC.
Flash column chromatography was performed using silica
In summary, we have developed a new and efficient
method to synthesize a variety of tetrahydroquinolinones
starting from b-enaminones and a,b-unsaturated aldehydes
in refluxing toluene in the presence of acetic acid. This
method has also been successfully applied to biologically
interesting dihydropyridinone derivatives. The value of this
gel 9385 (Merck). H and 13C NMR spectra were recorded
1
using a Bruker Model ARX spectrometer (300 and 75 MHz,
respectively) in CDCl3. The IR spectra were measured on a
123

1424
Q. H. To et al.
111 mg (72 %) 2c as an oil. Rf = 0.38 (hexane/ethyl
1
acetate 1:1); H NMR (300 MHz, CDCl3): d = 7.37–7.17
Jasco FTIR 5300 spectrophotometer. The HRMS spectra
were carried out at the Korea Basic Science Institute.
(m, 5H), 6.70 (d, J = 9.6 Hz, 1H), 5.16 (dd, J = 9.6,
5.1 Hz, 1H), 4.78 (d, J = 16.8 Hz, 1H), 4.33 (d,
J = 16.8 Hz, 1H), 3.98–3.93 (m, 1H), 2.32–2.10 (m, 4H),
1.73–1.61 (m, 1H), 1.46–1.26 (m, 3H), 1.00 (s, 3H), 0.89
(s, 3H), 0.87 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 191.9, 159.7, 137.5, 129.6, 128.3, 126.6,
121.2, 114.0, 108.0, 60.8, 53.5, 49.9, 40.9, 38.1, 32.7, 29.4,
28.9, 17.6, 14.7 ppm; IR (KBr):m = 2,959, 1,659, 1,603,
1,543, 1,422, 1,320, 735 cm-1; HRMS: m/z (M?) calcd for
C21H27NO 309.2093, found 309.2093.
General procedure for the synthesis
of tetrahydroquinolinones 2a–2n
and dihydropyridinones 2o, 2p
To a solution of vinylogous amide (0.5 mmol) and a,b-
unsaturated aldehyde (0.6 mmol) in 3 cm3 toluene was
added 60 mg acetic acid (1 mmol) at room temperature.
The reaction mixture was refluxed for 10–24 h and then
cooled to room temperature. The solution was concentrated
under vacuum and 50 cm3 water was added. The mixture
was extracted with ethyl acetate (3 9 20 cm3) and washed
with saturated sodium bicarbonate (2 9 30 cm3) and
30 cm3 brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give
the crude residue. Purification of the residue by column
chromatography on silica gel gave the products.
1-Benzyl-2,6,7,8-tetrahydro-7,7-dimethyl-2-
phenylquinolin-5(1H)-one (2d, C24H25NO)
Reaction of 115 mg 1a (0.5 mmol) with 79 mg trans-
cinnamaldehyde (0.6 mmol) in refluxing toluene for 20 h
afforded 117 mg (68 %) 2d as an oil. Rf = 0.36 (hexane/
ethyl acetate 1:1); 1H NMR (300 MHz, CDCl3):
d = 7.36–7.15 (m, 10H), 6.69 (d, J = 9.9 Hz, 1H), 5.16
(dd, J = 9.9, 4.8 Hz, 1H), 5.00 (d, J = 4.8 Hz, 1H), 4.64 (d,
J = 17.1 Hz, 1H), 4.08 (d, J = 17.1 Hz, 1H), 2.36–2.12 (m,
4H), 1.00 (s, 3H), 0.94 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 191.1, 158.7, 142.6, 135.9, 129.0, 128.9, 128.2,
127.7, 126.8, 126.0, 118.6, 114.9, 105.2, 64.2, 51.5, 49.1,
40.1, 32.0, 29.1, 28.1 ppm; IR (KBr):m = 2,946, 1,608,
1,542, 1,441, 1,337, 1,251, 699 cm-1; HRMS: m/z (M?)
calcd for C24H25NO 343.1936, found 343.1938.
1-Benzyl-2,6,7,8-tetrahydro-2,2,7,7-tetramethylquinolin-
5(1H)-one (2a, C20H25NO)
Reaction of 115 mg 1a (0.5 mmol) with 50 mg 3-methyl-2-
butenal (0.6 mmol) in refluxing toluene for 18 h afforded
121 mg (82 %) 2a as a solid. Rf = 0.38 (hexane/ethyl acetate
1:1); m.p.: 139–141 °C; 1H NMR (300 MHz, CDCl3):
d = 7.37–7.16 (m, 5H), 6.64 (d, J = 9.9 Hz, 1H), 5.02 (d,
J = 9.9 Hz, 1H), 4.64 (s, 2H), 2.24 (s, 2H), 2.23 (s, 2H), 1.29 (s,
6H), 0.92 (s, 6H)ppm; 13C NMR (75 MHz, CDCl3): d = 191.4,
160.4, 138.5, 129.1, 127.5, 125.5, 121.2, 118.3, 106.4, 60.0,
48.8, 48.1, 41.0, 32.5, 29.0, 28.5 ppm; IR (KBr):m = 2,959,
1,603, 1,534, 1,428, 1,334, 730 cm-1; HRMS: m/z (M?) calcd
for C20H25NO 295.1936, found 295.1935.
1-Benzyl-2,6,7,8-tetrahydro-2,7,7-trimethyl-2-
(4-methylpent-3-enyl)quinolin-5(1H)-one (2e, C25H33NO)
Reaction of 115 mg 1a (0.5 mmol) with 91 mg citral
(0.6 mmol) in refluxing toluene for 24 h afforded 118 mg
(65 %) 2e as an oil. Rf = 0.52 (hexane/ethyl acetate 1:1);
1H NMR (300 MHz, CDCl3): d = 7.31–7.13 (m, 5H), 6.67
(d, J = 10.2 Hz, 1H), 5.02–4.97 (m, 1H), 4.83 (d,
J = 10.2 Hz, 1H), 4.57 (d, J = 18.3 Hz, 1H), 4.47 (d,
J = 18.3 Hz, 1H), 2.26–1.71 (m, 8H), 1.60 (s, 3H), 1.49 (s,
3H), 1.20 (s, 3H), 0.89 (s, 3H), 0.81 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d = 191.4, 160.9, 138.7, 132.2, 129.1,
127.5, 125.7, 124.0, 119.6, 119.4, 106.2, 63.2, 49.4, 47.9,
42.3, 40.8, 32.4, 29.9, 29.6, 27.6, 26.0, 22.9, 18.0 ppm; IR
(KBr):m = 2,934, 1,720, 1,609, 1,536, 1,427, 1,342, 1,155,
1-Benzyl-2,6,7,8-tetrahydro-2,7,7-trimethylquinolin-5(1H)-
one (2b, C19H23NO)
Reaction of 115 mg 1a (0.5 mmol) with 42 mg crotonalde-
hyde (0.6 mmol) in refluxing toluene for 18 h afforded
105 mg (75 %) 2b as a solid. Rf = 0.32 (hexane/ethyl
acetate 1:1); m.p.: 104–106 °C; 1H NMR (300 MHz,
CDCl3): d = 7.37–7.19 (m, 5H), 6.66 (d, J = 9.6 Hz, 1H),
5.14 (dd, J = 9.6, 5.1 Hz, 1H), 4.73 (d, J = 17.1 Hz, 1H),
4.39 (d, J = 17.1 Hz, 1H), 4.08–4.00 (m, 1H), 2.33–2.10 (m,
4H), 1.17 (d, J = 6.3 Hz, 3H), 1.02 (s, 3H), 0.91 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): d = 191.5, 158.5, 137.1,
129.2, 127.9, 126.2, 120.0, 115.2, 106.9, 56.4, 52.6, 49.5,
40.5, 32.3, 29.2, 28.4, 21.3 ppm; IR (KBr):m = 2,962, 2,926,
1,730, 1,608, 1,534, 1,415, 1,300, 742 cm-1; HRMS:
m/z (M?) calcd for C19H23NO 281.1780, found 281.1781.
732 cm-1
;
HRMS: m/z (M?) calcd for C25H33NO
363.2562, found 363.2564.
2,6,7,8-Tetrahydro-1-(4-methoxybenzyl)-2,2,7,7-
tetramethylquinolin-5(1H)-one (2f, C21H27NO2)
Reaction of 130 mg 1b (0.5 mmol) with 50 mg 3-methyl-
2-butenal (0.6 mmol) in refluxing toluene for 18 h afforded
117 mg (72 %) 2f as a solid. Rf = 0.28 (hexane/ethyl
acetate 1:1); m.p.: 138–140 °C; 1H NMR (300 MHz,
CDCl3): d = 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d,
J = 8.4 Hz, 2H), 6.64 (d, J = 9.6 Hz, 1H), 4.98 (d,
1-Benzyl-2,6,7,8-tetrahydro-7,7-dimethyl-2-
propylquinolin-5(1H)-one (2c, C21H27NO)
Reaction of 115 mg 1a (0.5 mmol) with 59 mg trans-2-
hexenal (0.6 mmol) in refluxing toluene for 18 h afforded
123

Efficient synthesis of tetrahydroquinolinones
1425
J = 9.6 Hz, 1H), 4.57 (s, 2H), 3.79 (s, 3H), 2.26 (s, 2H),
2.17 (s, 2H), 1.27 (s, 6H), 0.94 (s, 6H) ppm; 13C NMR
(75 MHz, CDCl3): d = 191.5, 159.4, 158.9, 130.5, 126.6,
120.9, 118.5, 114.4, 106.5, 59.6, 55.4, 49.4, 47.3, 40.9,
32.4, 28.9, 28.6 ppm; IR (KBr):m = 2,948, 1,600, 1,529,
1,434, 1,340, 1,246, 1,170, 816 cm-1; HRMS: m/z (M?)
calcd for C21H27NO2 325.2042, found 325.2041.
1-Benzyl-2,6,7,8-tetrahydro-2,2-dimethylquinolin-5(1H)-
one (2j) [8]
Reaction of 100 mg 1f (0.5 mmol) with 50 mg 3-methyl-2-
butenal (0.6 mmol) in refluxing toluene for 15 h afforded
116 mg (87 %) 2j as a solid. Rf = 0.22 (hexane/ethyl
acetate 1:1); m.p.: 128–130 °C. NMR spectra agreed with
those reported in the literature [8].
2,6,7,8-Tetrahydro-2,2,7,7-tetramethyl-1-phenylquinolin-
5(1H)-one (2g, C19H23NO2)
1-Benzyl-2,6,7,8-tetrahydro-2-methylquinolin-5(1H)-one
(2k) [35]
Reaction of 108 mg 1c (0.5 mmol) with 50 mg 3-methyl-
2-butenal (0.6 mmol) in refluxing toluene for 10 h afforded
126 mg (90 %) 2g as a solid. Rf = 0.44 (hexane/ethyl
acetate 1:1); m.p.: 155–157 °C; 1H NMR (300 MHz,
CDCl3): d = 7.40–7.10 (m, 5H), 6.62 (d, J = 9.9 Hz,
1H), 5.05 (d, J = 9.9 Hz, 1H), 2.13 (s, 2H), 1.79 (s, 2H),
1.16 (s, 6H), 0.87 (s, 6H) ppm; 13C NMR (75 MHz,
CDCl3): d = 192.0, 158.3, 140.0, 130.6, 129.3, 128.5,
121.4, 118.5, 106.6, 59.5, 49.7, 42.7, 32.6, 29.6, 28.5 ppm;
IR (KBr):m = 2,958, 1,616, 1,536, 1,419, 1,324, 1,221,
1,149, 714 cm-1; HRMS: m/z (M?) calcd for C19H23NO2
281.1780, found 281.1776.
Reaction of 100 mg 1f (0.5 mmol) with 42 mg crotonal-
dehyde (0.6 mmol) in refluxing toluene for 18 h afforded
91 mg (72 %) 2k as a solid. Rf = 0.22 (hexane/ethyl
acetate 1:1); m.p.: 118–121 °C; 1H NMR (300 MHz,
CDCl3): d = 7.38–7.19 (m, 5H), 6.67 (d, J = 9.9 Hz,
1H), 5.15 (dd, J = 9.9, 5.1 Hz, 1H), 4.72 (d, J = 17.1 Hz,
1H), 4.39 (d, J = 17.1 Hz, 1H), 4.09–4.01 (m, 1H),
2.45–2.39 (m, 2H), 2.33–2.28 (m, 2H), 1.96–1.76 (m,
2H), 1.18 (d, J = 6.3 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 191.8, 159.9, 136.8, 129.1, 127.8, 126.1,
120.0, 115.4, 107.8, 56.2, 52.5, 35.6, 26.8, 21.4, 21.1 ppm;
IR (KBr):m = 2,939, 1,607, 1,536, 1,430, 1,296, 1,176,
738 cm-1
.
1-Benzyl-2,6,7,8-tetrahydro-2,2,7-trimethylquinolin-5(1H)-
one (2h, C19H23NO)
1-Benzyl-2,6,7,8-tetrahydro-2-propylquinolin-5(1H)-one
(2l) [8]
Reaction of 108 mg 1d (0.5 mmol) with 50 mg 3-methyl-
2-butenal (0.6 mmol) in refluxing toluene for 18 h afforded
107 mg (76 %) 2h as a solid. Rf = 0.27 (hexane/ethyl
acetate 1:1); m.p.: 138–140 °C; 1H NMR (300 MHz,
CDCl3): d = 7.32–7.11 (m, 5H), 6.58 (d, J = 9.9 Hz,
1H), 4.94 (d, J = 9.9 Hz, 1H), 4.58 (s, 2H), 2.43–2.29 (m,
2H), 1.98–1.89 (m, 3H), 1.23 (s, 3H), 1.20 (s, 3H), 0.87 (d,
J = 5.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 192.0, 160.4, 138.7, 129.1, 127.4, 125.5, 121.2,
118.6, 107.3, 59.7, 48.0, 44.0, 35.5, 29.4, 29.1, 28.7,
21.4 ppm; IR (KBr):m = 2,948, 1,610, 1,531, 1,429, 1,348,
1,148, 728 cm-1; HRMS: m/z (M?) calcd for C19H23NO
281.1780, found 281.1780.
Reaction of 100 mg 1f (0.5 mmol) with 59 mg trans-2-
hexenal (0.6 mmol) in refluxing toluene for 18 h afforded
105 mg (75 %) 2l as an oil. Rf = 0.20 (hexane/ethyl
acetate 1:1). NMR spectra agreed with those reported in the
literature [8].
1-Benzyl-2,6,7,8-tetrahydro-2-phenylquinolin-5(1H)-one
(2m) [9]
Reaction of 100 mg 1f (0.5 mmol) with 79 mg trans-
cinnamaldehyde (0.6 mmol) in refluxing toluene for 18 h
afforded 123 mg (78 %) 2m as an oil. Rf = 0.20 (hexane/
ethyl acetate 1:1). NMR spectra agreed with those reported
in [9].
1-Benzyl-2,6,7,8-tetrahydro-2,2-dimethyl-7-
phenylquinolin-5(1H)-one (2i, C24H25NO)
1-Benzyl-2,6,7,8-tetrahydro-2-methyl-2-(4-methylpent-3-
enyl)quinolin-5(1H)-one (2n) [9]
Reaction of 139 mg 1e (0.5 mmol) with 50 mg 3-methyl-
2-butenal (0.6 mmol) in refluxing toluene for 24 h afforded
113 mg (66 %) 2i as a solid. Rf = 0.35 (hexane/ethyl
acetate 1:1); m.p.: 170–172 °C; 1H NMR (300 MHz,
CDCl3): d = 7.30–7.01 (m, 10H), 6.63 (d, J = 9.9 Hz,
1H), 4.98 (d, J = 9.9 Hz, 1H), 4.56 (s, 2H), 3.16–3.07 (m,
Reaction of 100 mg 1f (0.5 mmol) with 91 mg citral
(0.6 mmol) in refluxing toluene for 24 h afforded 102 mg
(61 %) 2n as an oil. Rf = 0.40 (hexane/ethyl acetate 1:1).
NMR spectra agreed with those reported in [9].
1-Benzyl-1,2,6,7-tetrahydro-2,2-dimethyl-5H-
cyclopenta[b]pyridin-5-one (2o, C17H19NO)
1H), 2.68–2.40 (m, 4H), 1.25 (s, 3H), 1.23 (s, 3H) ppm; 13
C
NMR (75 MHz, CDCl3): d = 191.6, 160.4, 143.9, 138.9,
129.6, 129.3, 127.9, 127.5, 127.3, 125.8, 122.0, 118.9,
107.9, 60.4, 48.5, 42.9, 40.3, 35.7, 29.9, 29.1 ppm;
IR (KBr):m = 2,970, 1,606, 1,528, 1,430, 1,336, 1,149,
Reaction of 94 mg 1g (0.5 mmol) with 50 mg 3-methyl-2-
butenal (0.6 mmol) in refluxing toluene for 10 h afforded
78 mg (62 %) 2o as an oil. Rf = 0.16 (hexane/ethyl acetate
1:2); 1H NMR (300 MHz, CDCl3): d = 7.30–7.12 (m, 5H),
6.22 (d, J = 9.9 Hz, 1H), 4.92 (d, J = 9.9 Hz, 1H), 4.54 (s,
2H), 2.42–2.38 (m, 2H), 2.31–2.28 (m, 2H), 1.26 (s, 6H)
735 cm-1
;
HRMS: m/z (M?) calcd for C24H25NO
343.1936, found 343.1934.
123

1426
Q. H. To et al.
ppm; 13C NMR (75 MHz, CDCl3): d = 197.0, 174.1,
138.1, 129.1, 127.6, 125.6, 123.7, 116.1, 110.2, 61.7, 48.2,
34.2, 29.1, 25.9 ppm; IR (KBr):m = 2,968, 1,634, 1,557,
1,486, 1,444, 1,321, 738 cm-1; HRMS: m/z (M?) calcd for
C17H19NO 253.1467, found 253.1466.
6. Sklenicka HM, Hsung RP, Wei LL, McLaughlin MJ, Gerasyuto
AI, Degen SJ (2000) Org Lett 2:1161
7. Sydorenko N, Hsung RP, Darwish OS, Hahn JM, Liu J (2004) J
Org Chem 69:6732
8. Hsung RP, Wei LL, Sklenicka HM, Douglas CJ, McLaughlin MJ,
Mulder JA, Yao LJ (1999) Org Lett 1:509
9. Moreau J, Hubert C, Batany J, Toupet L, Roisnel T, Hurvois JP,
Renaud JL (2009) J Org Chem 74:8963
10. Lee YR, Kim DH, Shim JJ, Kim SK, Park JH, Cha JS, Lee CS
(2002) Bull Korean Chem Soc 23:998
11. Lee YR, Choi JH, Trinh DTL, Kim NW (2005) Synthesis 3026
12. Lee YR, Kim DH (2006) Synthesis 603
13. Kurdyumov AV, Lin N, Hsung RP, Gullickson GC, Cole KP,
Sydorenko N, Swidorski JJ (2006) Org Lett 8:191
14. Hubert C, Moreau J, Batany J, Duboc A, Hurvois JP, Renaud JL
(2008) Adv Synth Catal 350:40
15. Garcia A, Borchardt D, Chang CEA, Marsella MJ (2009) J Am
Chem Soc 131:16640
16. Elassar AZA, El-Khair AA (2003) Tetrahedron 59:8463
17. Valla A, Valla B, Cartier D, Le Guillou R, Labia R, Potier P
(2005) Tetrahedron Lett 46:6671
18. Wang XH, Hao WJ, Tu SJ, Zhang XH, Cao XD, Yan S, Wu SS,
Han ZG, Shi F (2009) J Heterocycl Chem 46:742
19. Stanovnik B, Svete J (2004) Chem Rev 104:2433
20. Wang GW, Miao CB (2006) Green Chem 8:1080
21. Bolm C, Rantanen T, Schiffers I, Zani L (2005) Angew Chem Int
Ed 44:1758
1-Benzyl-1,2,6,7-tetrahydro-2-methyl-2-(4-methylpent-3-
enyl)-5H-cyclopenta[b]pyridin-5-one (2p, C22H27NO)
Reaction of 94 mg 1g (0.5 mmol) with 91 mg citral
(0.6 mmol) in refluxing toluene for 12 h afforded 96 mg
(60 %) 2p as an oil. Rf = 0.35 (hexane/ethyl acetate 1:2);
1H NMR (300 MHz, CDCl3): d = 7.32–7.17 (m, 5H), 6.35
(d, J = 9.9 Hz, 1H), 5.05–4.99 (m, 1H), 4.87 (d,
J = 9.9 Hz, 1H), 4.56 (d, J = 17.7 Hz, 1H), 4.49 (d,
J = 17.7 Hz, 1H), 2.55–1.78 (m, 8H), 1.63 (s, 3H), 1.54 (s,
3H), 1.25 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 196.6, 175.2, 137.9, 132.3, 129.1, 127.6, 125.7, 123.6,
122.1, 117.4, 110.1, 65.1, 48.0, 41.8, 34.2, 29.4, 25.8, 25.7,
23.0, 17.8 ppm; IR (KBr): m = 2,923, 1,636, 1,558, 1,486,
1,443, 736 cm-1; HRMS: m/z (M?) calcd for C22H27NO
321.2093, found 321.2095.
Acknowledgments This study was supported by grant No. RTI04-
01-04 from the Regional Technology Innovation Program of the
Ministry of Knowledge Economy (MKE).
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26. Lee YR, Lee WK, Noh SK, Lyoo WS (2006) Synthesis 853
27. Lee YR, Kim JH (2007) Synlett 2232
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