Polystyrene-supported p-toluenesulfonic acid: A new, highly efficient, and recyclable catalyst for the synthesis of hydropyridine derivatives under solvent-free conditions

Article abstract of DOI:10.1055/s-0032-1317670

A new environmentally benign method for the preparation of hydropyridine derivatives has been developed by a simple one-pot condensation reaction of dimidine, active methylene compounds with aldehydes, and ammonium acetate in the presence of polystyrene-supported p-toluenesulfonic acid as a highly active and reusable heterogeneous acid catalyst under solvent-free conditions at 60°C. This new protocol has the advantages of easy availability, stability, reusability, and eco-friendliness of the catalyst, high to excellent yields, simple and easy experimental workup procedure. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317670

LETTER
▌2985
letter
Polystyrene-Supported p-Toluenesulfonic Acid: A New, Highly Efficient, and
Recyclable Catalyst for the Synthesis of Hydropyridine Derivatives under Sol-
vent-Free Conditions
New Catalyst for the Synthesis of Hydropyridine Derivatives
Mudumala Veeranarayana Reddy, Yeon Tae Jeong*
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Korea
Fax +82(51)6296408; E-mail: ytjeong@pknu.ac.kr
Received: 28.09.2012; Accepted after revision: 29.10.2012
viewpoint of green chemistry. Green chemistry approach-
Abstract: A new environmentally benign method for the prepara-
es are significant due to the reduction of byproducts,
tion of hydropyridine derivatives has been developed by a simple
waste, and cost. The possibility of performing multicom-
ponent reactions under solvent-free conditions with a het-
one-pot condensation reaction of dimidine, active methylene com-
pounds with aldehydes, and ammonium acetate in the presence of
polystyrene-supported p-toluenesulfonic acid as a highly active and erogeneous catalyst could enhance their efficiency from
an economic as well as ecological point of view.21 Al-
though various catalysts have been developed to realize
reusable heterogeneous acid catalyst under solvent-free conditions
at 60 °C. This new protocol has the advantages of easy availability,
stability, reusability, and eco-friendliness of the catalyst, high to ex-
organic transformation under solvent-free conditions,22,23
cellent yields, simple and easy experimental workup procedure.
it is still difficult to achieve recovery and reuse of the cat-
alysts in many cases. On the other hand, organic reactions
Key words: polystyrene-supported p-toluenesulfonic acid, hydro-
pyridine derivatives, active methylene compounds, solvent-free
using polymer-supported catalysts have received much at-
conditions
tention because of their nature; the most important prop-
erties are enhanced stability, higher selectivity, easier
handling, simple workup procedures, nontoxicity, non-
Heterocycles are ubiquitous in natural products, pharma-
corrosiveness, mildness of the reaction conditions, ease of
ceuticals, organic materials, and numerous functional
recovery, and reuse of the catalyst.24,25 A wide variety of
molecules. Therefore, the interest for developing a new,
polymer-supported reagents have been used in organic
versatile, and efficient synthesis of heterocycles has al-
synthesis, like halogenations, condensation, oxidation,
ways been a thread in the synthetic community.1 Nitrogen
and reduction reactions.24 One of the most important and
heterocycles containing a hydroquinoline moiety are im-
highly applicable categories of polymer-supported re-
portant because they show biological and pharmacologi-
agents is the polymeric oxidizing agents, which have been
cal activities, such as calcium channel blockers,
used in numerous organic transformations.26,27 Polysty-
vasodilator, hepatoprotective, antiatherosclerotic, bron-
rene is one of the most widely studied heterogeneous and
chodilator, antitumor, geroprotective, and antidiabetic ac-
polymeric supports due to its environmental stability and
tivity.2,3 Furthermore, recent studies have revealed several
hydrophobic nature which protects water-sensitive Lewis
other medicinal applications that include neuroprotectant
acids from hydrolysis by atmospheric moisture until it is
and platelet antiaggregatory activity, cerebral anti-isch-
suspended in an appropriate solvent where it can be used
emic activity in the treatment of Alzheimer’s disease, and
in a chemical reaction.28 It is well known that p-toluene-
as a chemosensitizer in tumor therapy.4 Therefore, a num-
sulfonic acid is a strong organic acid and an important cat-
ber of methods have been reported in the literature for the
alyst in organic transformations. However, it hydrolyzes
synthesis of hydroquinoline derivatives.5–20 Unfortunate-
easily in organic solvent, so that its use, reuse, and sepa-
ly, many of these processes suffer from one or other limi-
ration from reaction mixtures are inconvenient and diffi-
tations such as harsh reaction conditions, low product
cult. Polystyrene-supported p-toluenesulfonic acid
yields, tedious workup procedures, relatively long reac-
(PS/PTSA), which is a tightly bound and stable complex
tion times, and difficulty in recovery and reusability of the
between PTSA and polystyrenedivinylbenzene copoly-
catalysts. Moreover, some of the reagents employed are
mer. The use of the PS/PTSA complex catalyst has several
very expensive. Therefore, the search continues for a bet-
advantages over a conventional acid catalyst, such as its
ter catalyst for the synthesis of heterocycles containing
ease of handling (as a bench-top catalyst), commercial
hydroquinolines ring fragment in terms of operational
availability, stability, cost-efficiency, recyclability, and
simplicity, reusability, economic viability, and greater se-
tunable Lewis acidity. Despite its great importance, only
lectivity.
a few papers are reported on its catalytic application in or-
ganic synthesis.29,30
Organic reactions under solvent-free conditions have at-
tracted much interest from chemists, particularly from the
As part of our continuing interest in heterogeneous catal-
ysis in organic synthesis,31,32 we report herein an efficient
and eco-friendly procedure for the synthesis of hydropyr-
idine derivatives from aldehydes with active methylene
compounds and ammonium acetate catalyzed by
SYNLETT 2012, 23, 2985–2991
Advanced online publication: 29.11.2012
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5
2
1
4
1
4
3
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2
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DOI: 10.1055/s-0032-1317670; Art ID: ST-2012-U0826-L
© Georg Thieme Verlag Stuttgart · New York

2986
M. V. Reddy, Y. T. Jeong
LETTER
R1
O
O
O
+
O
O
R2
PS/PTSA
O
R2
R1CHO
NH4OAc
+
+
O
solvent-free
60 °C
N
H
O
1
2a–o
3
4
PHQ 5a–o
Scheme 1 Synthesis of PHQ derivatives
PS/PTSA as a reusable heterogeneous acid catalyst under tate (3, 2.2 mmol), and ethyl acetoacetate (4, 1.5 mmol) at
solvent-free conditions at 60 °C (Scheme 1 and Scheme 60 °C without catalyst under solvent-free conditions were
2).33 Moreover, PS/PTSA has attracted much attention be- carried out in order to recognize the capability of the cat-
cause of its suitable acidity, eco-friendliness, easy avail- alyst. The reaction did not proceed even after prolonged
ability, and cost-efficiency, thereby acting as a promising reaction time, and no desired product was formed which
table-top reagent.
supported the catalytic activity of PS/PTSA. When the re-
action was performed in the presence PS/PTSA, it pro-
ceeded effectively to produce the desired product 5a in
high yields. Some other Lewis acid catalysts and support-
ed Lewis acid catalysts such as GaCl3, Li(OTf), TiO2–SiO2,
CAN–SiO2, ZnCl2–SiO2, and also simple PTSA exhibited
moderate to good catalytic properties. In most of these
cases comparative yields of the desired product were ob-
tained. From these experiments it was clearly demonstrat-
ed that the PS/PTSA was indeed an effective catalyst and
was convincingly superior to the reported procedures with
respect to reaction time, amount of catalyst, and yields un-
der solvent-free conditions. Even though using the PTSA
alone took higher reaction time and smaller yields (Table
2, entry 7). All the results are summarized in Table 2.
Moreover, we found that the yields were obviously affect-
ed by the amount of PS/PTSA loaded. When 10 mg, 20
mg, 30 mg, and 40 mg of PS/PTSA were used, the yields
were 75%, 85%, 92%, and 92%, respectively (Table 2, en-
tries 8–11).Therefore, 30 mg of PS/PTSA were sufficient,
The typical procedure for polyhydroquinoline (PHQ) in-
volves impregnating the mixture of ammonium acetate (3)
with dimedone (1), 2-fluoro-4-methoxybenzaldehyde
(2a), and ethyl acetoacetate (4a) and was used as a model
reaction to optimize the reaction conditions.
To investigate the effects of solvent, the condensation re-
action of dimedone (1, 1 mmol), 2-fluoro-4-methoxy-
benzaldehyde (2a, 1 mmol), ammonium acetate (3, 1.5
mmol), and ethyl acetoacetate (4, 1 mmol) in various or-
ganic solvents at 60 °C using PS/PTSA as the catalyst was
carried out. About 83% of the expected product 5a was
obtained when the solvent was ethanol. Obviously, polar
solvents such as ethanol and acetonitrile (Table 1, entries
1 and 3) were much better than nonpolar solvents. It was
observed that in the presence of solvent the reaction takes
longer time to give even lower yield of product under sim-
ilar reaction conditions. This may be due to the competi-
tive adsorption of the solvent with the substrate molecule
on the catalyst surface; hence reaction under solvent-free
conditions gives high yields in less time (Table 1, entry 6).
The better yield under solvent-free conditions could be
explained by a uniform distribution of the eutectic mixture
of reactants, being in closer proximity to react than in con-
ditions using ethanol as the solvent.
Table 2 Influence of the Catalyst on the Synthesis of Polyhydro-
quinoline Synthesisa
Entry
Catalyst (10 mol%)
Time
Yield (%)b
1
2
neat
6.0 h
2.0 h
25
To evaluate and optimize the catalytic system, four-com-
ponent condensations of dimedone (1, 1 mmol), 2-fluoro-
4-methoxybenzaldehyde (2a, 1 mmol), ammonium ace-
GaCl3
65
3
Li(OTf)
3.0 h
69
4
TiO2–SiO2
1.5 h
72
Table 1 Effect of Solvent on Polyhydroquinoline Synthesisa
5
CAN–SiO2
ZnCl2–SiO2
PTSA
1.5 h
88
Entry
Solvent (5 mL)
Time (h)
Yield (%)b
6
1.0 h
83
1
2
3
4
5
6
EtOH
1
83
40
75
55
40
92
7
1.0 h
86
CHCl3
4
8c
9
PS/PTSA (30 mg)
PS/PTSA (10 mg)
PS/PTSA (20 mg)
PS/PTSA (40 mg)
15 min
45 min
25 min
15 min
92, 91, 90, 88, 87
MeCN
2
75
85
92
toluene
CH2Cl2
solvent-free
3
10
11
4
0.25
a Reaction of 2-fluoro-4-methoxybenzaldehyde (1 mmol), dimedone
(1 mmol), ethyl acetoacetate (1 mmol), and NH4OAc (1.5 mmol) un-
der solvent-free conditions at 60 °C.
a Reaction of 2-fluoro-4-methoxybenzaldehyde (1 mmol), dimedone
(1 mmol), ethyl acetoacetate (1 mmol), and NH4OAc (1.5 mmol) us-
ing PS/PTSA (30 mg) at 60 °C.
b Isolated yield.
b Isolated yield.
c Catalyst was used five times.
Synlett 2012, 23, 2985–2991
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Catalyst for the Synthesis of Hydropyridine Derivatives
2987
O
R1
O
O
O
R2
R2
PS/PTSA
R2
O
O
R1CHO
+
2
NH4OAc
+
O
solvent-free
60 °C
2a–i
4
3
N
H
DHP 6a–i
O
R1
O
O
PS/PTSA
2
+
R1CHO
+
NH4OAc
solvent-free
60 °C
2a–f
3
N
H
O
1
PHA 7a–f
Scheme 2 Synthesis of DHP and PHA derivatives
and an excessive amount of catalyst did not increase the the PS/PTSA catalyst under solid-state reaction condi-
yields significantly (Table 2, entry 8).
tions is another remarkable feature of the procedure. From
these results, it is clear that a ring substituent like a me-
thoxy group was not affected, and the carbonyl derivative
was not oxidized further.
The cyclocondensation of active methylene compounds
with various aromatic aldehydes bearing electron-with-
drawing groups or electron-releasing groups and ammoni-
um acetate was carried out in the presence of PS/PTSA as In order to explore the applicability of this method, the
catalyst. The yields obtained were good to excellent with- same procedure has been extended, and the conditions
out the formation of any side products. We observed, irre- were applied for the synthesis of dihydropyridine (DHP)
spective of groups on the aromatic ring, that the reaction and polyhydroacridine (PHA) derivatives (Table 3) via a
time and yields are almost close to each other. The acid- similar one-pot, four-component condensation of two
sensitive heterocyclic/aliphatic aldehydes were also ob- equivalents of active methylene compounds [dimidine,
tained in good yields and the data coincide with reference ethyl acetoacetate, methyl acetoacetate (2 mmol)], alde-
compounds (Table 3, entries 8–10).
hydes (1 mmol), and ammonium acetate (1.5 mmol,
Scheme 2). We studied the synthesis of PHA 7a using
dimidine (2 equiv), ammonium acetate, and 2-fluoro-4-
methoxybenzaldehyde in the presence of a catalytic
amount of PS/PTSA at 60 °C under solvent-free condi-
tions (Scheme 2). Compound 7a was isolated in 95% yield
within ten minutes.
Other active methylene compounds such as ethyl acetoac-
etate and methyl acetoacetate also took part in this multi-
component reaction to provide the corresponding PHQ
derivatives in good yields under the optimized conditions.
The results obtained in the current method are illustrated
in Table 3.The simplicity, together with the use of inex-
pensive, nontoxic, and environmentally benign nature of
O
R2
O
O
R1
R1
H
+
O
O
OH
S
O
H2N
– H2O
step II
– H2O
step I
NH4OAC
O
6
O
OH
7
PS
O
S
step III
– H2O
OH
O
O
PS
O
O
O
O
R1
O
R1
O
OH
O
O
O
O
R2
R2
N
H
step V
NH4OAC
OH
O
5
S
OH
S
– H2O
O
O
O
– H2O
PS
R1
H
PS
O
step VI
O
– H2O
step IV
+
R
O
O
NH2
R2
8
9
Scheme 3 Proposed mechanism of the PS/PTSA-catalyzed synthesis of PHQ
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2985–2991

2988
M. V. Reddy, Y. T. Jeong
LETTER
A variety of substrates were submitted to the optimum re-
action conditions, and the desired products were obtained
in excellent yields. As can be seen from the results in Ta-
ble 3, aromatic aldehydes containing both electron-with-
drawing and electron-donating groups reacted smoothly
with 1,3-cyclohexanediones and β-keto esters (methyl and
ethyl acetoacatete) to produce high yields of products. All
the products obtained were fully characterized by spectro-
scopic methods such as 1H NMR and 13C NMR spectros-
copy and high-resolution mass spectrometry.
Table 3 PS/PTSA-Catalyzed Multicomponent Synthesis of Hydro-
pyridine Derivatives
Entry Compd Aldehyde R
R1
Yield Time Mp
(%)a (min) (°C)
PHQ
1
2
5a
5b
5c
2-F-4-MeOC6H3 Et
92
90
88
90
90
96
94
86
88
88
91
89
85
89
92
15
16
22
18
20
18
20
30
35
31
17
16
21
20
21
277–279
251–253
178–180
240–241
208–210
245–2477
242–24419
147–1497
144–1467
239–2418
261–263
252–254
192–194
255–257
261–263
3-F-4-MeC6H3
3-NO2-4-FC6H3
2,3-F2C6H3
3,5-F2C6H3
4-ClC6H4
4-O2NC6H4
n-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
To check the reusability of the catalyst, the condensation
of dimedone, 2-fluoro-4-methoxybenzaldehyde, ethyl
acetoacetate, and NH4OAc to provide the PHQ under the
conditions described with PS/PTSA as catalyst was run
for five consecutive cycles, furnishing the corresponding
PHQ in 92%, 91%, 90%, 88%, and 87% isolated yields,
which proved the efficiency of the catalyst for multiple
usage (Table 2, entry 8). Even though after five consecu-
tive cycles run for the reaction, the catalytic activity of
PS/PTSA did not decrease dramatically. We observed al-
most a close activity to that of the freshly used catalyst.
The gradual decrease in catalytic activity may be due to
blocking of some active sites on the catalyst surface by the
residues of the reaction.
4
5d
5e
5
6
5f
7
5g
5h
5i
8
9
Et
10
11
12
13
14
15
5j
2-thienyl
5k
5l
2-F-4-MeOC6H3 Me
3-F-4-MeC6H3
3-O2N-4-FC6H3
2,3-F2C6H3
Me
Me
Me
Me
5m
5n
5o
DHP
6a
6b
6c
Similar studies in the synthesis of DHP and PHA also led
to the conclusion that the catalyst is reusable without con-
siderable loss in activity.
3,5-F2C6H3
A possible mechanism to rationalize the product forma-
tion is shown in Scheme 3. PHQ 5 may be formed either
through steps I–III or through steps IV–VI. The role of
PS/PTSA comes in steps I and IV, where it catalyzes the
Knoevenagel-type coupling of aldehydes with active
methylene compounds and in steps III and VI, where it
catalyzes the Michael-type addition of intermediates 6
and 7 and 8 and 9 to give product 5.
16
17
18
19
20
21
22
23
24
3-F-4-MeC6H3
Me
93
89
90
90
91
90
90
93
90
14
15
20
19
17
20
20
14
16
159–161
170–172
154–156
150–152
160–162
165–167
133–135
113–115
140–142
2-F-4-MeOC6H3 Me
2-Br-4-FC6H3
2,3-F2C6H3
Me
Me
Me
Me
Et
6d
6e
In conclusion, PS/PTSA was found to be an efficient, en-
vironmentally benign, and stable heterogeneous polymer-
supported solid-acid catalyst for the preparation of hydro-
pyridine derivatives. The mild reaction conditions, high to
excellent yields, short reaction times, simple experimental
procedure, recyclability of the catalyst with no loss of its
activity, low cost, and easy handling of the polymeric cat-
alyst are important features of this new protocol to prepare
hydropyridine derivatives.
2,4-F2C6H3
6f
3-4-F2C6H3
6g
6h
6i
3-O2N-4-FC6H3
3-F-4-MeC6H3
3,4-F2C6H3
Et
Et
PHA
7a
7b
7c
25
26
27
28
29
30
2-F-4-MeOC6H3
3-O2N-4-FC6H3
2-Br-4-FC6H3
3-F-4-MeC6H3
2,3-F2C6H3
–
–
–
–
–
–
95
90
91
95
90
92
10
16
15
11
14
12
240–242
293–295
390–392
345–347
167–168
172–174
Acknowledgment
This research work was supported by the second stage of BK21 Pro-
gram.
7d
7e
References and Notes
(1) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Wiley-VCH: Weinheim, 2003.
(2) (a) Klusa, V. Drugs Future 1995, 20, 135. (b) Bretzel, R. G.;
Bollen, C. C.; Maeser, E.; Federlin, K. F. Am. J. Kidney Dis.
1993, 21, 54. (c) Boer, R.; Gekeler, V. Drugs Future 1995,
20, 499.
7f
3,5-F2C6H3
a Isolated yields.
Synlett 2012, 23, 2985–2991
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Catalyst for the Synthesis of Hydropyridine Derivatives
2989
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was recrystallized from EtOH to afford pure 5a in excellent
yield (92%). The spent polymeric catalyst from different
experiments was combined, washed with Et2O, and dried
overnight in a vacuum oven and reused. Yield 92%; white
solid; mp 277–279 °C. 1H NMR (400 MHz, CDCl3): δ =
7.27–7.20 (q, 1 H), 6.62 (s, 1 H), 6.55 (dd, J = 2.5, 11.0 Hz,
1 H), 6.46 (dd, J = 2.2, 14.2 Hz, 1 H), 5.14 (s, 1 H), 4.06–
4.01 (q, 2 H), 3.71 (s, 3 H), 2.29 (s, 3 H), 2.28 (d, J = 16.4
Hz, 2 H), 2.20 (d, J = 16.4 Hz, 2 H), 1.20 (t, J = 9.0 Hz, 3 H),
1.03 (s, 3 H), 0.93 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.5, 167.5, 159.1, 158.9, 148.8, 143.8, 131.6,
126.0, 125.9, 110.5, 109.2, 104.6, 101.2, 59.7, 55.3, 50.6,
40.8, 32.5, 31.7, 29.4, 26.8, 19.1, 14.0 ppm. ESI-HRMS: m/z
calcd for C22H26FNO4 [M + H+]: 387.1846; found: 387.1844.
Ethyl-4-(3-fluoro-4-methylphenyl)-1,4,5,6,7,8-
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carboxylate (5b)
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Yield 90%; white solid; mp 251–253 °C. 1H NMR (400
MHz, CDCl3): δ = 7.13 (s, 1 H), 6.98 (d, J = 5.1 Hz, 2 H),
6.92 (d, J = 11.3 Hz, 1 H), 5.01 (s, 1 H), 4.08–4.05 (q, 2 H),
2.30 (s, 3 H), 2.28 (s, 3 H), 2.21 (d, J = 16.1 Hz, 2 H), 2.17
(d, J = 16.1 Hz, 2 H), 1.21 (t, J = 6.9 Hz, 3 H), 1.05 (s, 3 H),
0.93 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.8,
167.3, 162.3, 159.8, 149.3, 146.9, 143.6, 130.6, 123.3,
122.1, 114.4, 111.4, 105.5, 59.8, 50.7, 40.7, 36.1, 32.5, 29.3,
27.0, 19.1, 14.5, 14.1 ppm. ESI-HRMS: m/z calcd for
C22H26FNO3 [M + H+]: 371.1897; found: 371.1897.
Ethyl-4-(4-fluoro-3-nitrophenyl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5c)
Yield 88%; yellow solid; mp 178–180 °C. 1H NMR (400
MHz, CDCl3): δ = 7.95 (dd, J = 2.2, 9.5 Hz, 1 H), 7.66–7.64
(m, 1 H), 7.15–7.10 (q, 1 H), 6.73 (s, 1 H), 5.10 (s, 1 H),
4.10–4.05 (q, 2 H), 2.39 (d, J = 16.2 Hz, 1 H), 2.38 (s, 3 H),
2.25 (d, J = 16.2 Hz, 2 H), 2.18 (d, J = 16.1 Hz, 1 H), 1.21 (t,
J = 6.9 Hz, 3 H), 1.09 (s, 3 H), 0.94 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 195.5, 166.7, 155.2, 152.6, 149.1,
144.6, 144.4, 135.5, 125.1, 117.4, 110.9, 104.7, 104.7, 60.0,
50.5, 40.7, 36.4, 32.7, 29.2, 27.0, 19.3, 14.1 ppm. ESI-
HRMS: m/z calcd for C21H23FN2O5 [M + H+]: 402.1591;
found: 402.1590.
(22) Reddy, M. V.; Lim, K. T.; Kim, J. T.; Jeong, Y. T. J. Chem.
Res. 2012, 36, 398.
(23) Reddy, M. V.; Jeong, Y. T. J. Fluorine Chem. 2012, 142, 45.
(24) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815.
(25) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1997, 1217.
(26) Frechet, J. M. J.; Darling, P.; Farrall, M. J. J. Org. Chem.
1981, 46, 1728.
(27) Tamami, B.; Parvanak Borujeni, K. Iran. Polym. J. 2009, 18,
191.
(28) Akela, A.; Moet, A. Functionalized Polymers and Their
Applications; Wiley: New York, 1990, 11.
Ethyl-4-(2,3-difluorophenyl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5d)
Yield 90%; white solid; mp 240–242 °C. 1H NMR (400
MHz, CDCl3): δ = 8.33 (s, 1 H), 7.01–6.98 (m, 1 H), 6.84–
6.79 (m, 2 H), 5.15 (s, 1 H), 3.97–3.91 (q, 2 H), 2.29 (s, 3 H),
2.11 (d, J = 16.4 Hz, 2 H), 1.99 (d, J = 16.4 Hz, 2 H), 1.10 (t,
J = 7.3 Hz, 3 H), 0.99 (s, 3 H), 0.85 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.5, 166.7, 149.4, 145.0, 136.5,
136.4, 125.1, 122.4, 113.8, 113.6, 109.1, 102.7, 58.9, 50.1,
39.5, 33.2, 31.2, 28.8, 26.3, 18.1, 13.4 ppm.
(29) Roberto, S.; Alberto, M.; Delia, M.; Julia, M. A. G.; Felix,
R. Adv. Synth. Catal. 2006, 348, 1841.
(30) Shinya, I.; Kei, M.; Shu, K. Org. Biomol. Chem. 2003, 1,
2416.
(31) Reddy, M. V.; Reddy, G. C. S.; Jeong, Y. T. Tetrahedron
2012, 68, 6820.
(32) Reddy, M. V.; Dindulkar, S. D.; Jeong, Y. T. Tetrahedron
Lett. 2011, 52, 4764.
(33) Synthesis of Ethyl-4-(2-fluoro-4-methoxyphenyl)-
1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carboxylate (5a)
Ethyl-4-(3,5-difluorophenyl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5e)
Yield 90%; white solid; mp 208–210 °C. 1H NMR (400
MHz, CDCl3): δ = 7.20 (s, 1 H), 6.86–6.81 (m, 2 H), 6.58–
6.52 (m, 1 H), 5.06 (s, 1 H), 4.10–4.06 (q, 2 H), 2.30 (s, 3 H),
2.27 (d, J = 16.1 Hz, 2 H), 2.19 (d, J = 16.4 Hz, 2 H), 1.21 (t,
J = 6.9 Hz, 3 H), 1.07 (s, 3 H), 0.94 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 195.8, 167.0, 163.9, 161.4, 150.9,
149.6, 144.6, 110.8, 104.8, 101.3, 59.9, 50.6, 40.6, 36.6,
32.5, 29.2, 27.0, 19.0, 14.1 ppm. ESI-HRMS: m/z calcd for
C21H23F2NO3 [M + H+]: 375.1646; found: 375.1643.
Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5f)
Yield 96%; white solid; mp 245–247 °C (244–246 °C).7 1H
NMR (400 MHz, CDCl3): δ = 7.23 (dd, J = 2.2, 12.0 Hz, 2
H), 7.15 (dd, J = 2.2, 10.2 Hz, 2 H), 6.91 (s, 1 H), 5.02 (s, 1
H), 4.07–4.03 (q, 2 H), 2.34 (s, 3 H), 2.23 (d, J = 16.2 Hz, 2
A mixture of dimedone (1, 1 mmol), 2-fluoro-4-
methoxybenzaldehyde (2a, 1 mmol), NH4OAc (3, 1.5
mmol), ethyl acetoacetate (4, 1 mmol), and PS/PTSA (30
mg) was stirred at 60 °C under solvent-free conditions for 15
min (Table 3, entry 1). The progress of the reaction was
monitored by TLC. After completion of the reaction, the
mixture was washed with EtOAc and filtered to recover the
catalyst. The filtrate was evaporated, and the crude product
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2985–2991

2990
M. V. Reddy, Y. T. Jeong
LETTER
H), 2.17 (d, J = 16.2 Hz, 2 H), 1.20 (t, J = 6.9 Hz, 3 H), 1.05
(s, 3 H), 0.91 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 194.56, 167.2, 144.9, 143.5, 131.7, 129.3, 127.9, 116.9,
108.8, 105.4, 53.7, 50.6, 41.0, 37.0, 32.5, 29.5, 27.6, 19.1,
14.5 ppm.
49.5, 39.5, 35.0, 31.6, 28.6, 26.2, 18.0, 13.3 ppm. ESI-
HRMS: m/z calcd for C21H24FNO3 [M + H+]: 357.1740;
found: 357.1745.
Methyl-4-(4-fluoro-3-nitrophenyl)-1,4,5,6,7,8-
hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carboxylate (5m)
Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5g)
Yield 85%; yellow solid; mp 192–194 °C. 1H NMR (400
MHz, CDCl3): δ = 7.92 (dd, J = 2.2, 9.1 Hz 1 H), 7.67–7.64
(m, 1 H), 7.15–7.10 (q, 1 H), 6.68 (s, 1 H), 5.11 (s, 1 H), 3.66
(s, 3 H), 2.35 (s, 3 H), 2.25 (d, J = 16.8 Hz, 2 H), 2.11 (d, J
= 16.2 Hz, 2 H), 1.09 (s, 3 H), 0.94 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 195.5, 167.2, 155.2, 153.2, 149.0,
144.8, 135.5, 124.9, 117.6, 110.9, 104.5, 51.1, 50.5, 40.8,
36.2, 32.7, 29.2, 27.0, 19.4 ppm.
Yield 94%; white solid; mp 242–244 °C (240–242 °C).19 1
H
NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.0 Hz, 2 H), 7.50
(d, J = 8.2 Hz, 2 H), 6.91 (s, 1 H), 5.16 (s, 1 H), 4.08–4.05
(q, 2 H), 2.38 (s, 3 H), 2.25 (d, J = 17.2 Hz, 2 H), 2.14 (d, J
= 16.2 Hz, 2 H), 1.19 (t, J = 6.2 Hz, 3 H), 1.07 (s, 3 H), 0.90
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.0, 164.9,
153.3, 149.0, 145.2, 143.0, 128.8, 123.2, 115.9, 106.8, 60.1,
50.5, 40.9, 37.2, 32.6, 29.4, 27.4, 19.4, 14.1 ppm.
Ethyl-2,7,7-trimethyl-5-oxo-4-propyl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (5h)
Methyl-4-(2,3-difluorophenyl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5n)
Yield 89%; white solid; mp 255–257 °C. 1H NMR (400
MHz, CDCl3): δ = 8.69 (s, 1 H), 7.06–703 (q, 1 H), 6.92–
6.88 (m, 2 H), 5.19 (s, 1 H), 3.56 (s, 3 H), 2.37 (d, J = 17.2
Hz, 2 H), 2.31 (s, 3 H), 2.17 (d, J = 16.1 Hz, 2 H), 1.06 (s, 3
H), 0.91 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
193.9, 166.7, 149.2, 136.2, 124.7, 123.3, 113.5, 113.3,
108.7, 102.1, 50.2, 49.8, 38.7, 31.5, 30.7, 28.6, 26.0, 17.8
ppm. ESI-HRMS: m/z calcd for C20H21F2NO3 [M + H+]:
361.1489; found: 361.1488.
Methyl-4-(3,5-difluorophenyl)-1,4,5,6,7,8-hexahydro-
2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5o)
Yield 92%; white solid; mp 261–263 °C. 1H NMR (400
MHz, CDCl3): δ = 8.54 (s, 1 H), 6.82–6.79 (m, 2 H), 6.54–
6.52 (m, 1 H), 5.02 (s, 1 H), 3.61 (s, 3 H), 2.37 (s, 3 H), 2.33
(d, J = 16.1 Hz, 2 H), 2.19 (d, J = 16.3 Hz, 2 H), 1.07 (s, 3
H), 0.92 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.6, 167.0, 163.8, 161.0, 151.2, 149.3, 145.4, 109.9,
102.8, 100.4, 50.2, 49.1, 39.6, 35.7, 31.8, 28.8, 26.6, 18.2
ppm.
Yield 86%; white solid; mp 147–149 °C (148–150 °C).7 1H
NMR (400 MHz, CDCl3): δ = 6.34 (s, 1 H), 4.22–4.11 (m, 2
H), 4.02 (t, J = 5.5 Hz, 1 H), 2.36 (d, J = 17.2 Hz, 2 H), 2.30
(s, 3 H), 2.23 (d, J = 17.2 Hz, 2 H), 1.40–1.32 (m, 2 H), 1.28
(t, J = 6.9 Hz, 3 H), 1.23–1.18 (m, 2 H), 1.09 (s, 6 H), 0.82
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.5, 166.4, 149.4, 145.2, 115.8, 108.1, 58.1, 40.6, 38.6,
36.6, 34.4, 32.5, 29.2, 27.0, 20.3, 19.0, 14.5, 14.1 ppm.
Ethyl-4-ethyl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (5i)
Yield 88%; white solid; mp 144–146 °C (144–146 °C).7 1H
NMR (400 MHz, CDCl3): δ = 6.44 (s, 1 H), 4.22–4.10 (m, 2
H), 4.01 (t, J = 5.2 Hz, 1 H), 2.35 (d, J = 16.2 Hz, 2 H), 2.31
(s, 3 H), 2.23 (d, J = 16.2 Hz, 2 H), 1.48–1.33 (m, 2 H), 1.27
(t, J = 7.2 Hz, 3 H), 1.09 (s, 6 H), 0.74 (t, J = 7.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 195.5, 168.6, 148.4,
146.2, 114.8, 105.1, 58.0, 39.6, 36.7, 35.6, 30.5, 29.2, 27.4,
22.3, 19.0, 14.5, 10.3 ppm.
Ethyl-2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5j)
Yield 88%; white solid; mp 239–241 °C (241–242 °C).8 1H
NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.00–6.98 (m, 1
H), 6.80–6.75 (m, 2 H), 5.30 (s, 1 H), 4.12–4.10 (q, 2 H),
2.37 (d, J = 16.2 Hz, 2 H), 2.33 (s, 3 H), 2.23 and 2.15 (AB
system, J = 19.2 Hz, 2 H), 1.25 (t, J = 6.9 Hz, 3 H), 1.08 (s,
3 H), 1.01 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
198.1, 167.4, 150.5, 147.9, 143.8, 125.2, 121.7, 118.2,
111.8, 105.5, 60.4, 50.6, 38.7, 31.3, 30.5, 28.5, 27.5, 19.5,
14.2 ppm.
Dimethyl-4-(3-fluoro-4-methylphenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6a)
Yield 93%; white solid; mp 159–161 °C. 1H NMR (400
MHz, CDCl3): δ = 7.00 (t, J = 8.0 Hz, 1 H), 6.94 (dd, J = 1.8,
9.5 Hz, 1 H), 6.88 (dd, J = 1.4, 12.8 Hz, 1 H), 5.90 (s, 1 H),
4.96 (s, 1 H), 3.65 (s, 6 H), 2.31 (s, 6 H), 2.18 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 167.9, 159.9, 147.2, 144.4,
130.8, 122.8, 114.0, 113.8, 103.4, 51.0, 38.7, 19.4, 14.1 ppm.
ESI-HRMS: m/z calcd for C18H20FNO4 [M + H+]: 333.1376;
found: 331.1378.
Dimethyl-4-(2-fluoro-4-methoxyphenyl)-1,4-dihydro-
2,6-dimethylpyridine-3,5-dicarboxylate (6b)
Methyl-4-(2-fluoro-4-methoxyphenyl)-1,4,5,6,7,8-
hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carboxylate (5k)
Yield 89%; yellow solid; mp 170–172 °C. 1H NMR (400
MHz, CDCl3): δ = 7.16 (t, J = 8.8 Hz, 1 H), 6.56 (dd, J = 2.5,
11.0 Hz, 1 H), 6.48 (dd, J = 2.5, 14.6 Hz, 1 H), 5.67 (s, 1 H),
5.14 (s, 1 H), 3.74 (s, 3 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.0, 144.0, 131.5, 127.1,
109.9, 103.3, 101.4, 57.4, 50.9, 35.3, 19.4 ppm. ESI-HRMS:
m/z calcd for C18H20FNO5 [M + H+]: 349.1326; found:
349.1325.
Yield 91%; white solid; mp 261–263 °C. 1H NMR (400
MHz, CDCl3): δ = 8.54 (s, 1 H), 7.16 (t, J = 8.4 Hz, 1 H),
6.53 (dd, J = 2.5, 10.9 Hz, 1 H), 6.43 (dd, J = 2.2, 14.2 Hz, 1
H), 5.07 (s, 1 H), 3.71 (s, 3 H), 3.56 (s, 3 H), 2.35 (d, J = 16.8
Hz, 2 H), 2.29 (s, 3 H), 2.03 (d, J = 16.2 Hz, 2 H), 1.06 (s, 3
H), 0.92 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.0, 167.1, 157.8, 148.8, 144.2, 130.5, 126.0, 109.1,
108.5, 102.7, 100.1, 99.9, 54.4, 49.9, 49.7, 38.2, 31.5, 30.2,
28.7, 26.0, 17.8 ppm.
Dimethyl-4-(2-bromo-4-fluorophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6c)
Yield 90%; yellow solid; mp 154–156 °C. 1H NMR (400
MHz, CDCl3): δ = 7.18–7.09 (m, 3 H), 5.70 (s, 1 H), 5.18 (s,
1 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.6, 144.5, 132.3, 127.3, 119.1, 118.8, 102.3,
50.9, 34.3, 19.4. ppm. ESI-HRMS: m/z calcd for
C17H17BrFNO4 [M + H+]: 397.0325; found: 397.0328.
Dimethyl-4-(2,3-difluorophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6d)
Methyl-4-(3-fluoro-4-methylphenyl)-1,4,5,6,7,8-
hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carboxylate (5l)
Yield 89%; white solid; mp 252–254 °C. 1H NMR (400
MHz, CDCl3): δ = 8.43 (s, 1 H), 7.00–6.94 (q, 2 H), 6.89 (d,
J = 11.3 Hz, 1 H), 5.10 (s, 1 H), 3.63 (s, 3 H), 2.37–2.30 (m,
5 H), 2.23–2.10 (m, 5 H), 1.06 (s, 3 H), 0.92 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 194.5, 167.1, 161.3, 158.9,
148.8, 146.6, 144.5, 129.8, 122.3, 120.9, 113.4, 110.1, 50.2,
Yield 90%; yellow solid; mp 150–152 °C. 1H NMR (400
MHz, CDCl3): δ = 7.24–7.20 (m, 1 H), 6.75–6.63 (m, 2 H),
Synlett 2012, 23, 2985–2991
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Catalyst for the Synthesis of Hydropyridine Derivatives
2991
5.69 (s, 1 H), 5.18 (s, 1 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm.
ppm. 13C NMR (100 MHz, CDCl3): δ = 194.1, 160.2, 154.9,
149.3, 131.8, 129.4, 118.2, 111.8, 110.5, 55.2, 50.2, 41.8,
32.0, 29.1, 28.0, 26.1 ppm. ESI-HRMS: m/z calcd for
C24H28FNO3 [M + H+]: 397.2053; found: 397.2053.
13C NMR (100 MHz, CDCl3): δ = 167.7, 149.2, 144.4, 141.2,
123.4, 116.4, 103.4, 51.0, 38.8, 19.5 ppm.
Dimethyl-4-(2,4-difluorophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6e)
9-(4-Fluoro-3-nitrophenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7b)
Yield 90%; yellow solid; mp 293–295 °C. 1H NMR (400
MHz, CDCl3): δ = 9.48 (s, 1 H), 7.82 (dd, J = 2.2, 9.5 Hz, 1
H), 7.60–7.57 (m, 1 H), 7.44–7.39 (m, 1 H), 4.88 (s, 1 H),
2.47 and 2.37 (AB system, J = 17.2 Hz, 4 H), 2.19 (d, J =
16.2 Hz, 2 H), 2.01 (d, J = 17.2 Hz, 2 H), 1.01 (s, 6 H), 0.87
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.4, 154.0,
151.4, 144.4, 136.0, 135.3, 124.2, 117.8, 110.3, 49.9, 39.6,
32.9, 32.1, 28.9, 26.4 ppm. ESI-HRMS: m/z calcd for
C23H25FN2O4 [M + H+]: 412.1798; found: 412.1795.
9-(2-Bromo-4-fluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7c)
Yield 91%; yellow solid; mp 390–392 °C. 1H NMR (400
MHz, CDCl3): δ = 9.36 (s, 1 H), 7.27–7.21 (m, 2 H), 7.14 (t,
J = 8.0 Hz, 1 H), 4.91 (s, 1 H), 2.27 and 2.16 (AB system, J
= 17.2 Hz, 4 H), 2.08 (s, 3 H), 1.93 (d, J = 17.2 Hz, 1 H), 1.00
(s, 6 H), 0.84 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 195.6, 161.5, 151.3, 135.5, 133.9, 128.0, 120.2, 119.6,
114.9, 51.9, 39.2, 33.5, 32.5, 30.5, 30.2, 27.7 ppm.
Yield 91%; yellow solid; mp 160–162 °C. 1H NMR (400
MHz, CDCl3): δ = 8.92 (s, 1 H), 7.23–7.17 (1, 3 H), 7.02–
6.91 (m, 2 H), 5.07 (s, 1 H), 3.49 (s, 6 H), 2.23 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 167.8, 163.2, 144.5, 131.5,
123.2, 110.9, 110.7, 102.5, 50.9, 34.0, 19.4 ppm. ESI-
HRMS: m/z calcd for C17H17F2NO4 [M + H+]: 337.1126;
found: 337.1124.
Dimethyl-4-(3,4-difluorophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6f)
Yield 90%; yellow solid; mp 165–167 °C. 1H NMR (400
MHz, CDCl3): δ = 7.02–6.96 (m, 3 H), 5.74 (s, 1 H), 4.97 (s,
1 H), 3.65 (s, 6 H), 2.32 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.7, 148.2, 144.4, 140.2, 123.4, 116.5, 116.3,
103.4, 51.0, 38.8, 19.5 ppm.
Diethyl-4-(4-fluoro-3-nitrophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6g)
Yield 90%; yellow solid; mp 133–135 °C. 1H NMR (400
MHz, CDCl3): δ = 7.94 (dd, J = 2.2, 9.1 Hz, 1 H), 7.58–7.56
(m, 1 H), 7.14–7.10 (m, 1 H), 5.99 (s, 1 H), 5.04 (s, 1 H),
4.14–4.08 (q, 4 H), 2.35 (s, 6 H), 1.23 (t, J = 6.9 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 155.3, 152.7,
145.0, 144.8, 135.3, 125.3, 117.4, 103.1, 60.0, 39.3, 19.5,
14.2 ppm. ESI-HRMS: m/z calcd for C19H21FN2O6 [M + H+]:
392.1384; found: 392.1382.
9-(3-Fluoro-4-methylphenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7d)
Yield 95%; yellow solid; mp 345–347 °C. 1H NMR (400
MHz, CDCl3): δ = 7.04 (t, J = 8.0 Hz, 1 H), 6.86–6.80 (q, 2
H), 4.77 (s, 1 H), 4.66 (s, 1 H), 2.44 and 2.34 (AB system, J
= 17.2 Hz, 4 H), 2.16 (d, J = 16.1 Hz, 2 H), 2.10 (s, 3 H), 1.98
Diethyl-4-(3-fluoro-4-methylphenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6h)
(d, J = 16.1 Hz, 2 H), 0.99 (s, 6 H), 0.86 (s, 6 H) ppm. 13
C
Yield 93%; white solid; mp 113–115 °C. 1H NMR (400
MHz, CDCl3): δ = 6.99–6.89 (m, 3 H), 5.86 (s, 1 H), 4.96 (s,
1 H), 4.13–4.08 (q, 4 H), 2.31 (s, 6 H), 2.18 (s, 3 H), 1.23 (t,
J = 7.3 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
167.5, 147.5, 130.6, 123.1, 122.2, 114.3, 103.7, 59.7, 39.1,
19.4, 14.2, 14.1 ppm. ESI-HRMS: m/z calcd for C20H24FNO4
[M + H+]: 361.1689; found: 361.1689.
NMR (100 MHz, CDCl3): δ = 194.3, 161.3, 159.0, 149.5,
147.2, 130.5, 123.1, 114.0, 111.0, 50.1, 38.8, 33.2, 32.1,
29.0, 26.4, 13.7 ppm. ESI-HRMS: m/z calcd for C24H28FNO2
[M + H+]: 381.2104; found: 381.2102.
9-(2,3-Difluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7e)
Yield 91%; white solid; mp 167–168 °C. 1H NMR (400
MHz, CDCl3): δ = 7.01–6.97 (m, 2 H), 6.89 (d, J = 8.8 Hz, 1
H), 5.65 (s, 1 H), 4.74 (s, 1 H), 2.40 and 2.34 (AB system, J
= 17.2 Hz, 4 H), 2.20 (d, J = 16.1 Hz, 2 H), 2.10 (d, J = 16.1
Hz, 2 H), 1.01 (s, 6 H), 0.88 (s, 6 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 189.2, 151.8, 150.2, 149.4, 128.6, 123.6,
123.0, 115.0, 114.8, 46.4, 39.2, 34.5, 31.1, 28.7, 28.0 ppm.
9-(3,5-Difluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7f)
Yield 92%; white solid; mp 172–174 °C. 1H NMR (400
MHz, CDCl3): δ = 6.64–6.58 (m, 3 H), 5.48 (s, 1 H), 4.88 (s,
1 H), 2.44–2.34 (m, 8 H), 1.22 (s, 6 H), 1.10 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 190.7, 164.1, 161.8, 142.8,
114.8, 110.0, 109.7, 101.6, 101.1, 46.9, 39.4, 32.8, 31.4,
29.4, 27.3 ppm. ESI-HRMS: m/z calcd for C23H25F2NO2 [M
+ H+]: 385.1853; found: 385.1857.
Diethyl-4-(3,4-difluorophenyl)-1,4-dihydro-2,6-
dimethylpyridine-3,5-dicarboxylate (6i)
Yield 90%; white solid; mp 140–142 °C. 1H NMR (400
MHz, CDCl3): δ = 7.12–7.08 (m, 2 H), 6.92 (d, J = 7.3 Hz 1
H), 5.89 (s, 1 H), 5.02 (s, 1 H), 4.10–4.06 (q, 4 H), 2.30 (s, 6
H), 1.22 (t, J = 6.9 Hz, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.7, 149.2, 144.2, 122.4, 116.9, 115.2, 102.9,
59.2, 39.8, 19.2, 142.2 ppm.
9-(2-Fluoro-4-methoxyphenyl)-3,4,6,7-tetrahydro-
3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione
(7a)
Yield 95%; yellow solid; mp 240–242 °C. 1H NMR (400
MHz, CDCl3): δ = 9.32 (s, 1 H), 7.07 (t, J = 8.4 Hz, 2 H),
6.74 (d, J = 7.6 Hz, 1 H), 4.87 (s, 1 H), 3.67 (s, 3 H), 2.39 and
2.27 (AB system, J = 17.2 Hz, 4 H), 2.20 (d, J = 16.2 Hz, 2
H), 2.04 (d, J = 17.2 Hz, 2 H), 1.02 (s, 6 H), 0.90 (s, 6 H)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2985–2991

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