Ceric Ammonium Nitrate (CAN) catalyzes the one-pot synthesis of polyhydroquinoline via the Hantzsch reaction

Article abstract of DOI:10.1016/j.tet.2006.05.037

A facile and efficient one-pot synthesis of high yields of polyhydroquinoline derivatives at ambient temperature using Ceric Ammonium Nitrate (CAN) as catalyst via the Hantzsch reaction was reported. The process is simple and environmentally benign and th

Full text of DOI:10.1016/j.tet.2006.05.037

Tetrahedron 62 (2006) 7293–7299
Ceric Ammonium Nitrate (CAN) catalyzes the one-pot synthesis
of polyhydroquinoline via the Hantzsch reaction
*
Shengkai Ko and Ching-Fa Yao
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 116, Taiwan, ROC
Received 21 March 2006; revised 15 May 2006; accepted 17 May 2006
Available online 12 June 2006
Abstract—A facile and efficient one-pot synthesis of high yields of polyhydroquinoline derivatives at ambient temperature using Ceric
Ammonium Nitrate (CAN) as catalyst via the Hantzsch reaction was reported. The process is simple and environmentally benign and the
catalyst is commercially available and inexpensive.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
temperature,9 TMSCl–NaI,10 metal triflates,11 and I2.12
However, the use of high temperatures, expensive metal pre-
cursors, catalyst that are harmful to the environment, and
long reaction times limits the use of these methods. Thus,
the development of a simple and efficient method for the
preparation of polyhydroquinoline derivatives is an active
area of research and there is scope for further improvement
involving milder reaction conditions and higher product
yields.
In recent years, much attention has been focused on the syn-
thesis of 1,4-dihydropyridyl compounds, due to their signif-
icant biological activity.1 Cardiovascular agents such as
nifedipine, nicardipine, amlodipine, and other related deriv-
atives are dihydropyridyl compounds, which are effective
for the treatment of hypertension.2 4-Aryl-1,4-dihydropyri-
dines are analogues of NADH coenzymes, which have
been explored for their calcium channel activity and the het-
erocyclic rings are found in a variety of bioactive compounds
such as bronchodilator, antiatherosclerotic, antitumour, va-
sodilator, antidiabetic, geroprotective, and heptaprotective
agents.3 Extensive studies indicate that these compounds ex-
hibit different medical functions, acting as neuroprotectants,
platelet antiaggregators, cerebral antiischemic agents, and
chemosensitizers.4 For these reasons, polyhydroquinoline
compounds not only have attracted the attention of chemists
to synthesize but also represent an interesting research chal-
lenge. Numerous methods have been reported for the syn-
thesis of polyhydroquinoline derivatives, because of the
biological importance associated with these compounds.
The classical method involves the three-component coupling
of an aldehyde with ethyl acetoacetate, and ammonia in ace-
tic acid or in refluxing alcohol.5,6 However, these methods
suffer from several drawbacks such as a long reaction
time, an excess of organic solvent, lower product yields,
and harsh refluxing conditions. Thus, chemists have devel-
oped several alternate and more efficient methods for the
synthesis of polyhydroquinoline derivatives, which include
the use of microwaves,7 ionic liquids,8 refluxing at high
The use of Ceric Ammonium Nitrate (CAN) has recently re-
ceived considerable attention as an inexpensive, nontoxic,
commercially available catalyst for various organic transfor-
mations to afford the corresponding products in excellent
yields. Due to the numerous advantages associated with
this eco-friendly compound, CAN has been explored as
a powerful catalyst for different reactions, such as oxidation,
nitration, 1,3-dipolar cycloaddition, thiocyanation, protec-
tion, esterification, 1,4-addition, and the Biginelli reaction.13
Because polyhydroquinoline derivatives are important bio-
logically active compounds, which have potential medical
applications, improvement and the development of a prepa-
ration of this type of compound using CAN are worthy of
study.
2. Results and discussion
We had the opportunity to further explore the catalytic activ-
ity of CAN in the synthesis of 1,4-dihydropyridines. Herein,
we wish to report on a novel synthesis of 1,4-DHP promoted
by a catalytic amount of CAN under ambient conditions to
give excellent yields. In an initial endeavor, 1 equiv each
of benzaldehyde 1a, 1,3-cyclohexanedione 2, ethyl aceto-
acetate 3a, and ammonium acetate 4 were stirred at ambient
temperature in ethanol. After 4 h, only 56% of the expected
Keywords: CAN; Catalyst; One-pot synthesis; Polyhydroquinoline;
Hantzsch.
* Corresponding author. Tel.: +886 2 29309092; fax: +886 2 29324249;
e-mail: cheyaocf@scc.ntnu.edu.tw
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.05.037

7294
S. Ko, C.-F. Yao / Tetrahedron 62 (2006) 7293–7299
product 5aa was obtained when after workup and recrystal-
lization of the crude product from ethanol (Eq. 1 and entry 1
of Table 1). To improve the yield and optimize the reaction
conditions, the same reaction was carried out in the presence
of a catalytic amount of 2 mol % of CAN under similar con-
ditions. Surprisingly, a significant improvement was ob-
served and the yield of 5aa was dramatically increased to
93% after stirring; the mixture was stirred for only 2 h (entry
2). With this optimistic result in hand, we further investi-
gated the best reaction conditions by using different amounts
of CAN. An increase in the quantity of CAN from 2 mol %
to 5 mol % not only decreased the reaction time from 2 h to
1.5 h, but also increased the product yield slightly from 93%
to 98% (entry 3). Although the use of 10 mol % of CAN per-
mitted the reaction time to be decreased to 1 h, the yield
unexpectedly decreased to 65% (entry 4). A possible expla-
nation for the low product yield is that the starting material
or the product may have been destroyed during the reaction
when excess amount (10 mol %) of CAN was used in the
exothermic reaction and that 5 mol % CAN was sufficient
to catalyze the reaction effectively.
conditions. As expected, satisfactory results were observed
and the results are summarized as Eq. 2 and Table 2. Both
aromatic (entries 1–9) and heteroaromatic aldehydes (entries
10 and 11) gave the corresponding products in good yields
(88–98%). Concerning aromatic aldehyde, it appears that
the presence of different or the same substituted groups
does not have a significant effect on the final products.
We next tried to observe the effect of substituents in 1,3-cy-
clohexanedione 2 using 5,5-dimethyl-1,3-cyclohexanedione
6. Both aromatic and heteroaromatic aldehydes 1 reacted
well with 6, 3a, and 4 in the presence of 5 mol % of CAN
to afford 7 in good to high yields under similar conditions
(Table 3). Compared to the results shown in Table 2, the de-
crease in reaction time can be explained by the assumption
that 6 is slightly more reactive than 2 in most cases due to
the presence of the methyl groups in the ring.
Finally, we also examined whether other b-keto compounds
such as 2,4-pentanedione 3b, methyl acetoacetate 3c, and 2-
methoxyethyl acetoacetate 3d also react with these reagents
to produce similar results. Aromatic and heteroaromatic
aldehydes 1 such as benzaldehyde 1a and 2-thiophenecar-
boxaldehyde 1k were reacted with 2, 3b–3d, and 4 in the
presence of 5 mol % of CAN to afford the expected product
Based on above observations, we conducted the same reac-
tions using aromatic and heteroaromatic aldehydes 1b–1k,
2, 3a, and 4 in the presence of 5 mol % of CAN under similar
Table 1. Optimizing the reaction conditionsa (1)
O
O
CHO
O
O
CAN
r.t.
O
NH4OAc
(1)
O
O
O
N
H
1a
2
3a
4
5aa
Entry
CAN (equiv)
Time (h)
Yield (%)b
1
2
3
4
0
4
2
1.5
1
56
93
98
65
0.02
0.05
0.1
a
Benzaldehyde/1,3-cyclohexanedione/ethyl acetoacetate/ammonium acetate ¼ 1:1:1:1.
b
Isolated yields.
Table 2. CAN catalyzed the synthesis of polyhydroquinoline derivatives through Hantzsch reaction (2)
O
Ar
O
O
O
CAN
r.t.
O
NH4OAc
(2)
ArCOH
O
N
H
O
O
1
2
3a
4
5
Entry
1
Ar
Ph
Time
Product
Yield (%)a
Mp (ꢀC)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1.5 h
1.5 h
2.5 h
2 h
4 h
2.5 h
50 min
50 min
25 min
35 min
25 min
5aa
5ba
5ca
5da
5ea
5fa
5ga
5ha
5ia
98
98
88
98
90
93
93
98
98
90
90
240–241
241–242
193–195
243–244
234–235
220–222
190–191
198–200
204–205
210–212
233–234
p-MeC6H4
p-OMeC6H4
p-FC6H4
p-ClC6H4
p-HOC6H4
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
2-Furyl
9
10
11
1j
1k
5ja
5ka
2-Thienyl
a
Isolated yields.

S. Ko, C.-F. Yao / Tetrahedron 62 (2006) 7293–7299
7295
Table 3. CAN catalyzed the synthesis of polyhydroquinoline derivatives through Hantzsch reaction with 5,5-dimethyl-1,3-cyclohexanedione (3)
O
Ar
O
O
O
CAN
r.t.
O
NH4OAc
(3)
ArCOH
O
N
H
O
O
1
6
3a
4
7
Entry
1
Ar
Ph
Time
Product
Yield (%)a
Mp (ꢀC)
1
2
3
4
5
1a
1c
1e
1f
1 h
7aa
7ca
7ea
7fa
7ka
92
98
88
93
85
209–210
243–245
230–232
237–238
224–226
p-MeOC6H4
p-ClC6H4
p-HOC6H4
2-Thienyl
1.75 h
35 min
2 h
1k
1 h
a
Isolated yields.
8 in medium to high yields (Table 4). It was surprising to find
that the use of 3b only led to medium yields (60–65%) of
products (entries 1 and 4) compared to substrates 3c and
3d (entries 2, 3, 5, and 6). A possible explanation of the dif-
ferences is that 3b (approximate pKa value of 9) is much
more reactive than 3c and 3d (approximate pKa value of
11) so that the other side reactions might have occurred or
side reaction products also could have been formed when
3b was used.
can be used as Lewis acids to catalyze the reaction. To
prove this assumption, different Lewis acids such as
CeF4, NH4Cl, and CeCl3$7H2O were used in the same re-
actions (Table 5). Surprisingly, CeF4 and NH4Cl catalyzed
the reaction more efficiently than CeCl3$7H2O. The reac-
tion completed more rapidly and the yields were also higher
when CeF4 and NH4Cl were used (entries 1 and 2). These
results indicate that both cerium (IV) ions and ammonium
ions, which are present in CAN actually can also catalyze
the reaction. Although CeCl3$7H2O can also induce the
reaction, the results were not as good as the two other
reagents.
It is important to understand the role of CAN in the reac-
tion. One possibility is that both Ce(IV) and NH+4 in CAN
Table 4. CAN catalyzed the synthesis of polyhydroquinoline derivatives through Hantzsch reaction with different b-keto compounds (4)
O
Ar
O
O
O
CAN
r.t.
R1
NH4OAc
(4)
ArCOH
R1
N
H
O
O
1
2
3b-d
4
8
Entry
1
3
R1
CH3
Time (h)
Product
Yield (%)a
Mp (ꢀC)
1
2
3
4
5
6
1a
1a
1a
1k
1k
1k
3b
3c
3d
3b
3c
3d
1
1
1
5
2
7
8ab
8ac
8ad
8kb
8kc
8kd
65
85
87
60
90
64
229–230
222–224
150–152
218–219
216–217
207–209
OMe
OCH2CH2OMe
CH3
OMe
OCH2CH2OMe
a
Isolated yields.
Table 5. To address the role of CAN in this reactiona (5)
O
O
CHO
O
O
catalyst
r.t.
O
NH4OAc
(5)
O
O
O
N
H
1a
2
3a
4
5aa
Entry
Catalyst (equiv)
Time (h)
Yield (%)b
1
2
3
CeF4 (0.05)
NH4Cl (0.1)
CeCl3$7H2O (0.05)
1.75
2
4
90
85
60
a
Benzaldehyde/1,3-cyclohexanedione/ethyl acetoacetate/ammonium acetate ¼ 1:1:1:1.
b
Isolated yields.

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S. Ko, C.-F. Yao / Tetrahedron 62 (2006) 7293–7299
3. Conclusion
4.1.1.2. 2-Methyl-5-oxo-4-(4-methylphenyl)-1,4,5,6,
7,8-hexahydroquinoline-3-carboxylic acid ethyl ester
(5ba). 1H NMR (CDCl3, 400 MHz) d 1.21 (t, 3H, J¼
7.2 Hz), 1.80–2.10 (m, 2H), 2.20–2.51 (m, 10H), 4.07 (q,
2H, J¼7.2 Hz), 5.05 (s, 1H), 7.00 (d, 2H, J¼7.6 Hz), 7.18
(d, 2H, J¼7.6 Hz), 7.36 (s, 1H). 13C NMR (CDCl3,
100 MHz) d 14.15, 18.92, 20.93, 26.93, 35.88, 37.03,
59.66, 105.71, 112.68, 127.69, 128.51, 129.56, 135.28,
143.87, 144.42, 151.42, 167.63, 196.29. MS m/z (relative in-
tensity) 325 (M+, 33), 296 (10), 235 (15), 234 (100), 206
(22). HRMS calcd for C20H23NO3 (M+) 325.1678; found
325.1685.
In conclusion, we successfully developed a facile and effi-
cient method for preparing a variety of 4-substituted-1,4-di-
hydropyridines from the reactions of different aromatic or
heteroaromatic aldehydes, b-keto compounds, including
1,3-cyclohexanedione, 5,5-dimethyl-1,3-cyclohexanedione,
or 2,4-pentadione, and alkyl acetoacetate, and ammonium
acetate in the presence of a catalytic amount of CAN at
room temperature. The catalytic activity of CAN is remark-
able and the use of the environmentally benign, com-
mercially available CAN as catalyst in the synthesis of
4-substituted-1,4-dihydropyridines in good yields is also
significant. The advantages such as shorter reaction times,
milder conditions, simplicity of the reaction, good product
yields, and the easy procedures involved in the reaction
make the inexpensive and commercially available CAN
a powerful catalyst for the synthesis of different organic
compound.
4.1.1.3. 2-Methyl-5-oxo-4-(4-methoxyphenyl)-1,4,5,6,
7,8-hexahydroquinoline-3-carboxylic acid ethyl ester
(5ca). 1H NMR (CDCl3, 400 MHz) d 1.20 (t, 3H, J¼
6.8 Hz), 1.80–2.10 (m, 2H), 2.30–2.60 (m, 7H), 3.74 (s, 3H),
4.06 (q, 2H, J¼6.8 Hz), 5.04 (s, 1H), 5.95 (s, 1H), 7.10 (d,
2H, J¼8.4 Hz), 7.20 (d, 2H, J¼8.4 Hz). 13C NMR (CDCl3,
100 MHz) d 14.20, 19.36, 21.05, 27.49, 35.52, 37.02,
55.12, 59.77, 106.33, 113.29, 113.72, 128.94, 139.67,
142.92, 149.20, 157.80, 167.47, 195.71. MS m/z (relative in-
tensity) 341 (M+, 52), 312 (20), 268 (16), 235 (15), 234
(100), 206 (33). HRMS calcd for C20H23NO4 (M+)
341.1627; found 341.1623.
4. Experimental
4.1. Material and general
All reactions were performed at room temperature. All
chemicals were purchased from Aldrich Chemical Co. and
the solvent were used directly without further purification.
Analytical thin-layer chromatography was performed with
E. Merck silica gel 60F glass plates. MS or HRMS were
measured by JEOL JMS-D300 or JEOL JMS-HX110 spec-
trometer. 1H and 13C NMR spectra were recorded with
Bruker Aavance EX 400.
4.1.1.4. 2-Methyl-5-oxo-4-(4-fluorophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5da).
1H NMR (DMSO-d6, 400 MHz) d 1.17 (t, 3H, J¼7.2 Hz),
1.80–2.10 (m, 2H), 2.20–2.70 (m, 7H), 4.06 (q, 2H,
J¼7.2 Hz), 5.07 (s, 1H), 6.03 (s, 1H), 6.85–6.89 (m, 2H),
7.23–7.27 (m, 2H). 13C NMR (DMSO-d6, 100 MHz)
d 14.60, 18.72, 21.26, 26.58, 35.55, 37.15, 59.54, 103.89,
111.52, 114.78, 114.99, 129.54, 129.62, 144.49, 145.57,
151.90, 167.27, 195.16. MS m/z (relative intensity) 329
(M+, 36), 235 (15), 234 (100), 206 (28). HRMS calcd for
C19H20NFO3 (M+) 329.1427; found 329.1425.
4.1.1. Typical experimental procedure for the synthesis
of Hantzsch polyhydroquinoline derivatives 5, 7, and 8.
A typical experimental procedure for the preparation of 5
is described as follows: a 10 mL round-bottomed flask
charged with aldehyde 1 (1.0 mmol), 1,3-cyclohexanedione
2 or 5,5-dimethyl-1,3-cyclohexanedione 6 (1.0 mmol), 2,4-
pentadione or acetoacetate derivatives 3 (1.0 mmol), ammo-
nium acetate 4 (1.0 mmol), and Ceric Ammonium Nitrate
(CAN) (0.05 mmol) followed by 0.5 mL of ethanol. The
mixture was then stirred at room temperature until the reac-
tion was completed (monitored by TLC). The reaction mix-
ture was treated with brine solution, extracted with ethyl
acetate (2ꢁ20 mL). After evaporation of the solvent, the
crude yellow product was recrystallized from ethanol to
give a yellow or brown solid.
4.1.1.5. 2-Methyl-5-oxo-4-(4-chlorophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5ea).
1H NMR (CDCl3, 400 MHz) d 1.18 (t, 3H, J¼7.2 Hz),
1.80–2.10 (m, 2H), 2.30–2.50 (m, 7H), 4.05 (q, 2H,
J¼7.2 Hz), 5.05 (s, 1H), 6.34 (s, 1H), 7.18 (d, 2H,
J¼8.8 Hz), 7.24 (d, 2H, J¼8.8 Hz). 13C NMR (CDCl3,
100 MHz) d 14.17, 19.33, 20.96, 27.37, 36.07, 36.87,
59.93, 105.77, 112.96, 128.01, 129.40, 131.61, 143.53,
145.63, 150.29, 167.22, 195.92. MS m/z (relative intensity)
345 (M+, 24), 316 (12), 235 (16), 234 (100), 206 (36).
HRMS calcd for C19H20ClNO3 (M+) 345.1132; found
345.1130.
4.1.1.1. 2-Methyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahy-
droquinoline-3-carboxylic acid ethyl ester (5aa). 1H
NMR (CDCl3, 400 MHz) d 1.18 (t, 3H, J¼6.8 Hz), 1.80–
2.10 (m, 2H), 2.30–2.44 (m, 7H), 4.05 (q, 2H, J¼6.8 Hz),
5.09 (s, 1H), 6.07 (s, 1H), 7.10 (t, 1H, J¼7.6 Hz), 7.20 (t,
2H, J¼7.6 Hz), 7.30 (d, 2H, J¼7.6 Hz). 13C NMR (CDCl3,
100 MHz) d 14.16, 19.34, 21.01, 27.46, 36.38, 37.00,
59.78, 106.06, 113.46, 125.99, 127.90, 127.98, 143.30,
147.12, 149.58, 167.41, 195.52. MS m/z (relative intensity)
311 (M+, 27), 282 (8), 235 (15), 234 (100), 206 (27).
HRMS calcd for C19H21NO3 (M+) 311.1521; found
311.1526.
4.1.1.6. 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,
7,8-hexahydroquinoline-3-carboxylic acid ethyl ester
1
(5fa). H NMR (Acetone-d6, 400 MHz) d 1.17 (t, 3H, J¼
7.2 Hz), 1.70–2.00 (m, 2H), 2.19–2.23 (m, 1H), 2.34 (s,
3H), 2.50–2.54 (m, 2H), 4.02 (q, 2H, J¼7.2 Hz), 5.05 (s,
1H), 6.63 (d, 2H, J¼8.4 Hz), 7.08 (d, 2H, J¼8.4 Hz). 13C
NMR (Acetone-d6, 100 MHz) d 15.07, 19.12, 22.41,
27.75, 36.57, 38.23, 60.24, 106.30, 113.84, 115.66, 130.14,
140.66, 145.27, 151.47, 156.63, 168.50, 195.72. MS m/z
(relative intensity) 327 (M+, 37), 298 (15), 254 (12), 235
(15), 234 (100), 206 (35). HRMS calcd for C19H21NO4
(M+) 327.1471; found 327.1465.

S. Ko, C.-F. Yao / Tetrahedron 62 (2006) 7293–7299
7297
4.1.1.7. 2-Methyl-5-oxo-4-(2-nitrophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5ga).
1H NMR (CDCl3, 400 MHz) d 1.10 (t, 3H, J¼7.2 Hz),
1.70–2.00 (m, 2H), 2.20–2.50 (m, 7H), 4.02–4.09 (m, 2H),
5.87 (s, 1H), 7.22–7.24 (m, 1H), 7.39 (s, 1H), 7.40–7.60
(m, 2H), 7.69 (m, 1H). 13C NMR (CDCl3, 100 MHz)
d 13.82, 18.66, 20.70, 26.68, 32.23, 36.63, 59.67, 104.55,
111.86, 123.49, 126.41, 131.01, 132.49, 141.75, 145.20,
148.12, 152.27, 167.22, 196.11. MS m/z (relative intensity)
356 (M+, 26), 327 (12), 235 (16), 234 (100), 206 (36).
HRMS calcd for C19H20N2O5 (M+) 356.1372; found
356.1380.
4.1.1.12. 2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (7aa).
1H NMR (CDCl3, 400 MHz) d 0.94 (s, 3H), 1.07(s, 3H),
1.20 (t, 3H, J¼7.2 Hz), 2.10–2.40 (m, 7H), 4.06 (q,
2H, J¼7.2 Hz), 5.06 (s, 1H), 6.22 (s, 1H), 7.10 (t, 1H,
J¼7.6 Hz), 7.20 (t, 2H, J¼7.6 Hz), 7.31 (d, 2H, J¼
7.6 Hz). 13C NMR (CDCl3, 100 MHz) d 14.18, 19.22, 27.19,
29.33, 32.50, 36.25, 41.27, 50.66, 59.87, 106.16, 112.56,
125.97, 127.88, 127.99, 143.35, 146.52, 148.58, 167.61,
195.97. MS m/z (relative intensity) 339 (M+, 12), 263 (16),
262 (100), 234 (28). HRMS calcd for C21H25NO3 (M+)
339.1834; found 339.1840.
4.1.1.8. 2-Methyl-5-oxo-4-(3-nitrophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5ha).
1H NMR (CDCl3, 400 MHz) d 1.19 (t, 3H, J¼7.2 Hz),
1.80–2.10 (m, 2H), 2.30–2.50 (m, 7H), 4.07 (q, 2H,
J¼7.2 Hz), 5.18 (s, 1H), 6.88 (s, 1H), 7.35–7.40 (m,
1H), 7.72 (d, 2H, J¼8.0 Hz), 7.98 (d, 2H, J¼8.0 Hz),
8.33 (s, 1H). 13C NMR (CDCl3, 100 MHz) d 14.19,
19.30, 21.02, 27.24, 33.01, 36.88, 60.07, 105.77, 112.29,
121.26, 122.89, 128.65, 134.83, 144.63, 148.29, 149.42,
151.03, 167.02, 196.03. MS m/z (relative intensity) 356
(M+, 12), 339 (15), 235 (15), 234 (100), 206 (31).
HRMS calcd for C19H20N2O5 (M+) 356.1372; found
356.1378.
4.1.1.13. 2,7,7-Trimethyl-5-oxo-4-(4-methoxyphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
ester (7ca). H NMR (CDCl3, 400 MHz) d 0.94 (s, 3H),
1
1.07 (s, 3H), 1.21 (t, 3H, J¼7.2 Hz), 2.13–2.36 (m, 7H),
3.74 (s, 3H), 4.06 (q, 2H, J¼7.2 Hz), 5.00 (s, 1H), 6.01 (s,
1H), 6.74 (d, 2H, J¼8.4 Hz), 7.22 (d, 2H, J¼8.4 Hz). 13C
NMR (CDCl3, 100 MHz) d 14.21, 19.40, 27.17, 29.40,
32.69, 35.67, 41.12, 50.72, 55.10, 59.77, 106.36, 112.42,
113.23, 128.95, 139.56, 139.56, 143.02, 147.72, 157.75,
167.49, 195.52. MS m/z (relative intensity) 369 (M+, 33),
340 (13), 263 (15), 262 (100), 234 (23). HRMS calcd for
C22H27NO4 (M+) 369.1940; found 369.1931.
4.1.1.14. 2,7,7-Trimethyl-5-oxo-4-(4-chlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
ester (7ea). H NMR (CDCl3, 400 MHz) d 0.92 (s, 3H),
4.1.1.9. 2-Methyl-5-oxo-4-(4-nitrophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5ia).
1H NMR (CDCl3, 400 MHz) d 1.18 (t, 3H, J¼6.8 Hz),
1.80–2.10 (m, 2H), 2.30–2.60 (m, 7H), 4.03–4.09 (m, 2H),
5.18 (s, 1H), 7.30 (s, 1H), 7.48 (d, 2H, J¼7.6 Hz), 8.10 (d,
2H, J¼7.6 Hz). 13C NMR (CDCl3, 100 MHz) d 14.08,
19.19, 20.94, 27.12, 36.88, 37.13, 60.10, 104.63, 111.89,
123.32, 128.99, 134.83, 144.91, 146.41, 151.62, 154.78,
167.07, 196.23. MS m/z (relative intensity) 356 (M+, 12),
339 (40), 235 (17), 234 (100), 206 (50). HRMS calcd for
C19H20N2O5 (M+) 356.1372; found 356.1365.
1
1.06 (s, 3H), 1.17 (t, 3H, J¼7.2 Hz), 2.10–2.50 (m, 7H),
4.02–4.10 (m, 2H), 5.04 (s, 1H), 6.13 (s, 1H), 7.15–7.20
(m, 2H), 7.25–7.30 (m, 2H). 13C NMR (CDCl3,
100 MHz) d 14.17, 19.30, 27.04, 29.39, 32.64, 36.20,
40.93, 50.65, 59.87, 105.65, 111.71, 127.95, 129.39,
131.56, 143.71, 145.58, 167.21, 195.56. MS m/z (relative
intensity) 373 (M+, 14), 263 (16), 262 (100), 234 (26).
HRMS calcd for C21H24ClNO3 (M+) 373.1445; found
373.1442.
4.1.1.10.
2-Methyl-5-oxo-4-(furan-2-yl)-1,4,5,6,7,8-
4.1.1.15. 2,7,7-Trimethyl-5-oxo-4-(4-hydroxyphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
ester (7fa). H NMR (Acetone-d6, 400 MHz) d 0.91 (s,
hexahydroquinoline-3-carboxylic acid ethyl ester (5ja).
1H NMR (CDCl3, 400 MHz) d 1.25 (t, 3H, J¼7.2 Hz),
1.90–2.10 (m, 2H), 2.30–2.60 (m, 7H), 4.12–4.19 (m, 2H),
5.27 (s, 1H), 5.95–5.99 (m, 1H), 6.02–6.10 (m, 1H), 6.20–
6.26 (m, 1H), 7.21 (s, 1H). 13C NMR (CDCl3, 100 MHz)
d 14.27, 19.37, 21.08, 27.56, 30.21, 36.95, 59.88, 103.02,
104.74, 110.10, 140.81, 144.20, 150.56, 157.94, 167.23,
195.56. MS m/z (relative intensity) 301 (M+, 50), 272 (22),
256 (19), 245 (29), 228 (100), 200 (19). HRMS calcd for
C17H19NO4 (M+) 301.1314; found 301.1313.
1
3H), 1.04 (s, 3H), 1.21 (t, 3H, J¼7.2 Hz), 2.13–2.36 (m,
7H), 3.74 (s, 3H), 4.06 (q, 2H, J¼7.2 Hz), 5.00 (s, 1H),
6.01 (s, 1H), 6.74 (d, 2H, J¼8.4 Hz), 7.22 (d, 2H,
J¼8.4 Hz). 13C NMR (Acetone-d6, 100 MHz) d 15.01,
19.09, 19.16, 27.49, 33.40, 36.70, 41.14, 51.77, 54.98,
60.20, 106.29, 112.65, 115.57, 130.13, 131.38, 140.43,
145.31, 149.71, 156.62, 168.41, 195.36. MS m/z (relative
intensity) 356 (M+, 28), 326 (12), 282 (11), 263 (14), 262
(100), 234 (24). HRMS calcd for C21H25NO4 (M+)
355.1784; found 355.1776.
4.1.1.11. 2-Methyl-5-oxo-4-(thiophene-2-yl)-1,4,5,6,
7,8-hexahydroquinoline-3-carboxylic acid ethyl ester
(5ka). 1H NMR (CDCl3, 400 MHz) d 1.19 (t, 3H, J¼
7.2 Hz), 1.80–2.10 (m, 2H), 2.30–2.50 (m, 7H), 4.07 (q,
2H, J¼7.2 Hz), 5.45 (s, 1H), 6.18 (s, 1H), 6.80–6.90 (m,
2H), 7.13–7.20 (d, 1H, J¼7.6 Hz). 13C NMR (CDCl3,
100 MHz) d 14.27, 19.35, 21.08, 27.42, 31.11, 36.98, 59.96,
105.59, 112.81, 123.15, 123.33, 126.46, 143.73, 149.85,
151.18, 167.15, 195.57. MS m/z (relative intensity) 317
(M+, 100), 288 (67), 244 (68), 234 (55), 206 (45), 161
(24). HRMS calcd for C17H19SNO3 (M+) 317.1086; found
317.1084.
4.1.1.16. 2,7,7-Trimethyl-5-oxo-4-(thiophene-2-yl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
ester (7ka). H NMR (CDCl3, 400 MHz) d 1.05 (s, 3H),
1
1.13 (s, 3H), 1.28(t, 3H, J¼7.2 Hz), 2.20–2.55 (m, 7H),
4.17 (q, 2H, J¼7.2 Hz), 5.42 (s, 1H), 6.20 (s, 1H), 6.81–
6.90 (m, 2H), 7.00–7.05 (m, 2H). 13C NMR (CDCl3,
100 MHz) d 14.28, 19.40, 27.25, 29.50, 31.22, 32.69,
41.04, 50.67, 59.96, 105.55, 111.68, 123.05, 123.42,
126.40, 143.87, 148.31, 150.98, 167.17, 195.36. MS m/z
(relative intensity) 345 (M+, 100), 316 (65), 272 (68), 262

7298
S. Ko, C.-F. Yao / Tetrahedron 62 (2006) 7293–7299
(69), 234 (34). HRMS calcd for C19H23NSO3 (M+)
345.1399; found 345.1397.
(M+, 100), 288 (65), 264 (48), 244 (70). HRMS calcd for
C18H21NSO4 (M+) 347.1191; found 347.1191.
4.1.1.17.
2-Methyl-3-acetyl-5-oxo-4-phenyl-1,4,5,6,
Acknowledgements
7,8-hexahydroquinoline (8ab).14 1H NMR (CDCl3,
400 MHz) d 1.80–2.00 (m, 2H), 2.14 (s, 3H), 2.32–2.43
(m, 7H), 5.13 (s, 1H), 6.22 (s, 1H), 7.14 (t, 1H, J¼7.6 Hz),
7.22–7.32 (m, 4H). 13C NMR (CDCl3, 100 MHz) d 20.14,
20.81, 27.42, 29.50, 36.98, 37.01, 113.10, 113.98, 126.37,
127.89, 128.38, 143.04, 145.91, 149.21, 195.78, 199.60.
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowl-
edged.
References and notes
4.1.1.18. 2-Methyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahy-
droquinoline-3-carboxylic acid methyl ester (8ac). 1H
NMR (DMSO-d6, 400 MHz) d 1.60–1.75 (m, 1H), 1.85–
2.00 (m, 1H), 2.20–2.60 (m, 7H), 3.56 (s, 3H), 4.95 (s,
1H), 7.00–7.30 (m, 5H), 9.19 (s, 1H). 13C NMR (DMSO-
d6, 100 MHz) d 18.25, 20.78, 26.12, 35.38, 36.71, 50.66,
103.16, 111.12, 125.68, 127.21, 127.91, 145.24, 147.63,
151.41, 167.39, 194.69. MS m/z (relative intensity) 297
(M+, 16), 221 (15), 220 (100). HRMS calcd for
C18H19NO3 (M+) 297.1365; found 297.1366.
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4.1.1.19. 2-Methyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahy-
droquinoline-3-carboxylic acid (2-methoxyethyl) ester
(8ad). H NMR (CDCl3, 400 MHz) d 1.80–2.00 (m, 2H),
1
2.20–2.50 (m, 7H), 3.31 (s, 3H), 3.52 (t, 2H, J¼4.8 Hz),
4.14–4.18 (m, 2H), 5.11 (s, 1H), 6.66 (s, 1H), 7.08–7.32
(m, 5H). 13C NMR (CDCl3, 100 MHz) d 19.24, 20.99,
27.22, 36.39, 37.01, 58.77, 62.75, 70.44, 105.53, 113.16,
125.97, 127.88, 127.95, 144.03, 147.12, 150.20, 167.35,
195.89. MS m/z (relative intensity) 341 (M+, 12), 265 (12),
264 (100). HRMS calcd for C20H23NO4 (M+) 341.1627;
found 341.1620.
4.1.1.20. 2-Methyl-3-acetyl-5-oxo-4-(thiophene-2-yl)-
1,4,5,6,7,8-hexahydroquinoline (8kb).14 1H NMR
(CDCl3, 400 MHz) d 1.92–2.01 (m, 2H), 2.22 (s, 3H),
2.34–2.48 (m, 7H), 5.39 (s, 1H), 6.80–6.88 (m, 2H), 7.01–
7.03 (m, 1H), 7.23 (s, 1H). 13C NMR (CDCl3, 100 MHz)
d 20.00, 20.92, 27.05, 29.27, 32.06, 36.87, 112.61, 113.31,
123.68, 123.87, 126.67, 144.18, 150.13, 150.62, 195.85,
199.10.
4.1.1.21. 2-Methyl-5-oxo-4-(thiophene-2-yl)-1,4,5,6,
7,8-hexahydroquinoline-3-carboxylic acid methyl ester
(8kc). H NMR (CDCl3, 400 MHz) d 1.94–2.01 (m, 2H),
2.30–2.55 (m, 7H), 3.72 (s, 3H), 5.42 (s, 1H), 6.79–6.86 (m,
2H), 6.94 (br, 1H), 7.02–7.06 (m, 1H). 13C NMR (CDCl3,
100 MHz) d 19.14, 21.05, 27.16, 36.97, 51.11, 104.97,
112.42, 123.12, 123.19, 126.53, 144.58, 151.15, 167.68,
196.00. MS m/z (relative intensity) 303 (M+, 90), 288 (25),
244 (57), 220 (100). HRMS calcd for C16H17NSO3 (M+)
303.0929; found 303.0927.
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4.1.1.22. 2-Methyl-5-oxo-4-(thiophene-2-yl)-1,4,5,6,
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ethyl) ester (8kd). H NMR (CDCl3, 400 MHz) d 1.93–
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J¼4.8 Hz), 4.22–4.27 (m, 2H), 5.51 (s, 1H), 6.80–6.83 (m,
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104.91, 112.40, 123.09, 123.33, 126.50, 144.69, 150.79,
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