One-step, synthesis of Hantzsch esters and polyhydroquinoline derivatives in fluoro alcohols

Article abstract of DOI:10.1016/j.jfluchem.2009.03.014

Hantzsch 1,4-dihydropyridine, polyhydroquinoline and 1,8-dioxodecahydroacridines derivatives were synthesized in excellent yields in trifluoroethanol (TFE). The solvent (TFE) can be readily separated from reaction products and recovered in excellent purity for direct reuse.

Full text of DOI:10.1016/j.jfluchem.2009.03.014

Journal of Fluorine Chemistry 130 (2009) 609–614
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
One-step, synthesis of Hantzsch esters and polyhydroquinoline derivatives
in fluoro alcohols
a
b
a
Akbar Heydari a, , Samad Khaksar , Mahmood Tajbakhsh , Hamid Reza Bijanzadeh
*
a Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran
b Chemistry Department, Mazandaran University, Babol Sar, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Hantzsch 1,4-dihydropyridine, polyhydroquinoline and 1,8-dioxodecahydroacridines derivatives were
synthesized in excellent yields in trifluoroethanol (TFE). The solvent (TFE) can be readily separated from
reaction products and recovered in excellent purity for direct reuse.
Received 19 February 2009
Received in revised form 25 March 2009
Accepted 30 March 2009
Available online 18 April 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Polyhydroquinoline
1,8-Dioxodecahydroacridines
TFE
Hydrogen bonding
1. Introduction
[16], in situ generated HCl [17], K7[PW11CoO40] [18], metal triflates
[19], I2 [20] silica-supported acids [21,22], ceric ammonium nitrate
Multicomponent reactions (MCRs) are one-pot processes that
combine three or more substrates simultaneously [1–4]. Such
processes are of great interest in diversity-oriented synthesis,
especially to generate compound libraries for screening purposes.
The Hantzsch [5] reaction and their products 1,4-dihydropyridines
(DHP) have attracted immense attention of synthetic chemists due
to their pharmacological properties [6,7]. In particular, dihydro-
pyridine drugs such as nifedipine, nicardipine and amlodipine are
effective cardiovascular agents for the treatment of hypertension
(Fig. 1).
[23], PTSA-SDS [24], tris(pentafluorophenyl)borane [25] and
boronic acids [26,27]. These methods, however, suffer from
drawbacks such as unsatisfactory yields, acidic or basic catalysts,
In addition, the dihydropyridine unit has been widely employed
as a hydride source for reductive amination [8]. Despite the
potential importance of 1,4-dihydropyridyl compounds from a
pharmaceutical, industrial, and synthetic point of view [9–11],
comparatively few methods for their preparation have been
reported. Classical method for the synthesis of 1,4-dihydropyr-
idines is one-pot condensation of aldehydes with ethyl acetoace-
tate, and ammonia in acetic acid or by refluxing in alcohol [5,12].
However, this method involves long reaction time, harsh reaction
conditions, the use of a large quantity of volatile organic solvents
and generally gives low yields. In recent years, several new
efficient methods have been developed including the use of
microwave [13], TMS iodide [14], ionic liquid [15], Bu4N+HSO4
À
* Corresponding author. Fax: +98 21 88006544.
E-mail address: akbar.heydari@gmx.de (A. Heydari).
Fig. 1. Typical dihydropyridine drugs.
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.03.014

610
A. Heydari et al. / Journal of Fluorine Chemistry 130 (2009) 609–614
Scheme 1.
Scheme 2.
extended reaction times, elevated temperatures, tedious work-up,
anhydrous organic solvents and the use of stoichiometric and/or
relatively expensive reagents. Moreover, the main disadvantage of
almost all existing methods is that the catalysts are destroyed in
the work-up procedure and cannot be recovered or reused.
Therefore, the search continues for a better catalyst for the
synthesis of 1,4-DHPs and polyhydroquinolines in terms of
operational simplicity, reusability, economic viability, and greater
selectivity. Fluoro alcohols are solvents with peculiar properties
[28] such as low nucleophilicity, high polarity, strong hydrogen
bond donating ability and ability to solvate water. The most
commonly used and cheapest fluorinated alcohols are 2,2,2-
trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP), which are available on a commercial scale and with a
relatively low toxicity [29–30]. These alcohols display interesting
properties, such as solvent, co-solvent, or additives in various
catalytic processes and consequently they are often used in studies
of peptide and protein structure [31], solvolysis [32–35], their
effect on various organic transformations [36–41] and notably the
activation of hydrogen peroxide for oxidation, epoxidation and the
Baeyer–Villiger rearrangement [42–48]. In continuation of our
effort towards the development of efficient synthetic procedures
for multicomponent reactions, we turned our attention towards
the synthesis of 1,4-dihydropyridines and polyhydroquinoline
Scheme 3.
2. Results and discussion
In an initial endeavor, the reaction was carried out by simply
mixing benzaldehyde, ethyl acetoacetate, and ammonium acetate
(Scheme 1, Table 1, entry 1) at 70 8C in trifluoroethanol. The
corresponding 1,4-dihydropyridine derivative 1a was obtained in
high yield (97%). The study was extended to
a,b-unsaturated
(entry 3), heteroaromatic (entry 5) and aliphatic (entries 4 and 10)
aldehydes furnishing the products by a smooth cyclocondensation
within 3 h. The yields in general are high regardless of the
structural variations in aldehyde. The results are summarized in
Scheme 1.
derivatives. We report herein
a practical synthesis of 1,4-
dihydropyridines and polyhydroquinoline derivatives in trifluor-
oethanol at 70 8C.
After successfully synthesizing a series of Hantzsch esters in
excellent yields, we turned our attention towards the synthesis of
Table 1
Synthesis of 1,4-dihydropyridine derivatives through Hantzsch reaction in TFEa.
Entry
1
Aldehyde
R1
Et
Yield (%)b
97
Product
1a
2
3
4
Et
96
95
96
1b
1c
1d
Me
Et

A. Heydari et al. / Journal of Fluorine Chemistry 130 (2009) 609–614
611
Table 1 (Continued )
Entry
Aldehyde
R1
Et
Yield (%)b
98
Product
5
6
1e
Et
Et
98
97
1f
7
8
9
1g
Et
Et
Et
95
96
97
1h
1i
10
1j
a
Reaction condition: aldehyde (1 mmol), acetoacetate ester (2 mmol), NH4OAc (1 mmol), TFE (2 mL), 3 h.
Isolated yield.
b
polyhydroquinoline derivatives via unsymmetrical Hantzsch
reactions with 2 equivalents of diketone with aromatic aldehydes
(Scheme 3). As expected, these substrates underwent smooth, one-
pot conversion to give the corresponding 1,8-dioxodecahydroa-
cridines 3a and b in excellent yields (Scheme 3).
After the reaction, TFE can be easily separated (by distillation)
and reused without decrease in its activity. For example, the
reaction of benzaldehyde, methyl acetoacetate and ammonium
acetate afforded the corresponding 1,4-dihydropyridine derivative
in 97%, 95%, and 94% isolated yield over three cycles. When we
carried out the reaction in TFE or HFIP at room temperature, the
reaction proceeded very slowly to give very poor yields. The result
using HFIP at reflux condition was similar to that in TFE at 70 8C.
reaction under similar conditions. We carried out the four-
component coupling reaction of cyclic 1,3-diketone, aldehyde,
acetoacetatic ester, and ammonium acetate in TFE (Scheme 2).
Aliphatic, aromatic, heterocyclic and conjugated aldehydes
afforded the desired products in high yields under the same
reaction conditions as shown in Table 2.
It is noteworthy to mention that the structural variation of the
aldehyde and substituents on the aromatic ring did not show any
obvious effect on this conversion, because the desired products
were obtained in high yields in relatively short reaction times. To
further expand the scope of the reaction, we next examined the
Table 2
Synthesis of octahydroquinoline derivatives through Hantzsch reaction in TFEa.
Entry
Aldehyde
R1
Yield (%)b
Product
1
2
Et
Et
98
95
2a
2b
3
4
Et
90
90
2c
Me
2d
5
6
Et
Et
78
98
2e
2f
7
Et
88
2g

612
A. Heydari et al. / Journal of Fluorine Chemistry 130 (2009) 609–614
Table 2 (Continued )
Entry
Aldehyde
R1
Et
Yield (%)b
90
Product
8
2h
9
Et
75
2i
10
Et
Et
95
90
2j
11
2k
a
Reaction condition: aldehyde (1 mmol), acetoacetate ester (1 mmol), dimedone (1 mmol), NH4OAc (1 mmol) (2 mL), 3 h.
Isolated yield.
b
3. Conclusions
4-Cyclohexyl-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic
acid diethyl ester (1d) [26]: Solid; Mp = 210–212 8C. 1H NMR (CDCl3,
In summary, we have described herein an efficient methodol-
ogy for Hantzsch reaction using various electronically and
structurally divergent aldehydes to give the product in good to
excellent isolated yields. In contrast to the existing methods using
potentially hazardous catalysts/additives, this new method offers
the following competitive advantages: (i) avoiding the use of any
base, metal or Lewis acid catalyst (ii) short reaction time, (iii) ease
of product isolation/purification by non-aqueous work-up, (iv)
high chemoselectivity, (v) no side reaction, and (vi) low costs and
simplicity in process and handling. The recovered TFE can be
reusable.
500 MHz):
H), 3.85 (d, J = 5.75 Hz, 1 H), 4.20 (q, J = 8.0 Hz, 4 H), 5.80 (br s, 1 H,
NH). 13C NMR (125 MHz, CDCl3):
= 15.1, 19.2, 26.2, 26.6, 32.7,
38.3, 45.6, 50.8, 101.5, 144.9, 169.1. IR (KBr): 2994, 1769, 1373,
1242 cmÀ1
d = 1.25 (t, J = 6.2 Hz, 6 H), 1.30–1.80 (m, 11 H), 2.25 (s, 6
d
.
4-Furan-2-yl-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic
acid diethyl ester (1e) [24]: Mp = 160–162 8C. 1H NMR (500 MHz,
CDCl3):
H), 5.20 (s, 1 H), 5.90 (br s, 1 H, NH), 6.11–6.22 (m, 2 H), 7.21–7.23
(m, 1 H). 13C NMR (125 MHz, CDCl3):
= 14.3, 19.4, 33.3, 59.9,
100.4, 104.4, 110.0, 140.8, 145.6, 158.7, 167.5. IR (KBr): 3342, 1697,
1648, 1480, 1361, 1211, 1132, 750 cmÀ1
d = 1.26 (t, J = 7.1 Hz, 6 H), 2.31 (s, 6 H), 4.17 (q, J = 7.1 Hz, 4
d
.
4. Experimental
2,6-Dimethyl-4-p-tolyl-1,4-dihydro-pyridine-3,5-dicarboxylic
acid diethyl ester (1f) [24]: Mp = 135–137 8C. 1H NMR (500 MHz,
General procedure: Aldehyde (1 mmol),
b
-keto ester or 1,3-
CDCl3):
J = 7.1 Hz, 4 H), 4.98 (s, 1 H), 6.09 (br s, 1 H, NH), 7.04 (d, J = 7.8 Hz, 2
H), 7.23 (d, J = 7.8 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
= 14.3,
19.4, 21.2, 39.1, 59.7, 103.9, 127.8, 128.9, 135.2, 144.3, 145.0, 168.0.
IR (KBr): 3343, 1690, 1651, 1491, 1213, 1122, 772 cmÀ1
d = 1.28 (t, J = 7.1 Hz, 6 H), 2.30 (s, 3 H), 2.32 (s, 6 H), 4.14 (q,
diketone (2 mmol) and NH4OAc (1 mmol) were dissolved in TFE
(2 mL) and stirred at 70 8C. After completion of the reaction as
indicated by TLC, the TFE was separated by distillation and the
crude product was purified by recrystallization from ethanol to
yield the highly pure Hantzsch 1,4-dihydropyridine, polyhydro-
quinoline and 1,8-dioxodecahydroacridine derivatives. The phy-
sical data (mp, IR, NMR) of known compounds were found to be
identical with those reported in the literature [19,20,24,26].
Spectroscopic data for selected examples are shown below.
2,6-Dimethyl-4-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic
acid diethyl ester (1a) [24,26]: Mp = 156–158 8C. 1H NMR (500 MHz,
d
.
4-(4-Bromo-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-
dicarboxylic acid diethyl ester (1g) [26]: Mp = 160–162 8C. 1H NMR
(500 MHz, CDCl3):
J = 7.1 Hz, 4 H), 5.32 (s, 1 H), 5.77 (br s, 1 H, NH), 7.18 (d, J = 8.4 Hz, 2
H), 7.34 (d, J = 8.4 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
= 14.1,
19.3, 39.4, 59.8, 103.9, 127.9, 130.9, 130.4, 142.3, 148.5, 167.8. IR
(KBr): 3340, 1690, 1643, 1492, 1211, 1120, 770 cmÀ1
d = 1.24 (t, J = 7.1 Hz, 6 H), 2.34 (s, 6 H), 4.12 (q,
d
.
CDCl3):
J = 7.1 Hz, 4 H), 5.01 (s, 1 H), 5.97 (br s, 1 H, NH), 7.11–7.32 (m, 5 H).
13C NMR (125 MHz, CDCl3):
= 14.1, 19.5, 39.4, 59.3, 104.1, 127.5,
128.8, 135.7, 144.1, 145.9, 167.8. IR (KBr): 3334, 1690, 1654, 1494,
1243, 1127, 721 cmÀ1
d
= 1.25 (t, J = 7.1 Hz, 6 H), 2.32 (s, 3 H), 2.33 (s, 3 H), 4.11 (q,
4-(4-Hydroxy-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-
dicarboxylic acid diethyl ester (1h) [26]: Mp = 230–232 8C. 1H NMR
d
(500 MHz, CDCl3):
J = 7.1 Hz, 4 H), 5.32 (s, 1 H), 5.77 (br s, 1 H, NH), 6.65 (d, J = 8.9 Hz,
2H), 7.16 (d, J = 8.4 Hz, 2H). 13C NMR (125 MHz, CDCl3):
= 14.1,
19.3, 39.4, 59.8, 103.9, 127.9, 130.9, 130.4, 142.3, 148.5, 167.8. IR
(KBr): 3331, 1689, 1656, 1490, 1244, 1126, 720 cmÀ1
d = 1.25 (t, J = 7.1 Hz, 6 H), 2.34 (s, 6 H), 4.12 (q,
.
d
4-(4-Chloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-
dicarboxylic acid diethyl ester (1b) [26]: Mp = 144–146 8C. 1H NMR
.
(500 MHz, CDCl3):
J = 7.2 Hz, 4 H), 4.97 (s, 1 H), 5.88 (br s, 1 H, NH), 7.23–7.19 (m, 4 H).
13C NMR (125 MHz, CDCl3):
= 14.3, 19.6, 39.2, 59.9, 103.8, 127.9,
129.4, 131.7, 144.1, 146.3, 167.5. IR (KBr): 3360, 1695, 1651, 1487,
1212, 1122, 789 cmÀ1
d
= 1.24 (t, J = 7.2 Hz, 6 H), 2.33 (s, 6 H), 4.11 (q,
2,6-Dimethyl-4-(4-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicar-
boxylic acid diethyl ester (1i) [26]: Mp = 130–132 8C. 1H NMR
d
(500 MHz, CDCl3):
J = 7.1 Hz, 4 H), 5.10 (s, 1 H), 6.16 (br s, 1 H, NH), 7.50 (d, J = 8.6 Hz, 2
H), 8.14 (d, J = 8.6 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
= 14.2,
19.5, 40.1, 60.3, 103.0, 123.6, 128.9, 145.0, 146.2, 155.2, 167.2. IR
(KBr): 3317, 1705, 1647, 1521, 1348, 1215, 1122, 707 cmÀ1
d = 1.23 (t, J = 7.1 Hz, 6 H), 2.35 (s, 6 H), 4.13 (q,
.
d
2, 6-Dimethyl-4-styryl-1,4-dihydro-pyridine-3,5-dicarboxylic acid
dimethyl ester (1c) [26]: Solid; Mp = 117–121 8C. 1H NMR (CDCl3,
.
500 MHz):
5.62 (br s, 1 H, NH), 6.17–6.19 (m, 2 H), 7.10–7.40 (m, 5 H). 13C NMR
(125 MHz, CDCl3): = 14.2, 19.3, 36.2, 51.1, 102.2, 126.3, 126.9,
128.0, 128.3, 131.8, 137.7, 145.4, 168.1. IR (KBr): 3335, 2949, 1700,
1650 cmÀ1
d
= 2.35 (s, 6 H), 3.72 (s, 6 H), 4.55 (d, J = 7.24 Hz, 1 H),
2,6-Dimethyl-4-pentyl-1,4-dihydro-pyridine-3,5-dicarboxylic
acid diethyl ester (1j) [24]: Syrup. 1H NMR (CDCl3, 500 MHz):
d
d
= 0.86 (t, J = 7.13 Hz, 3 H), 1.20 (t, J = 7.11 Hz, 6H), 1.30–1.70 (m, 8
H), 2.20 (s, 6 H), 3.85 (t, J = 5.23 Hz, 1 H), 4.18 (q, 4 H, J = 7.5 Hz),
5.60 (br s, 1 H, NH). 13C NMR (125 MHz, CDCl3):
= 14.1, 14.2,
.
d

A. Heydari et al. / Journal of Fluorine Chemistry 130 (2009) 609–614
613
16.20, 23.24, 29.4, 30.1, 30.5, 40.5, 60.3, 98.6, 143.3, 167.4. IR (KBr):
2993, 1769, 1684, 1241 cmÀ1
242 8C. 1H NMR (500 MHz, DMSO-d6):
1.08 (t, J = 7.3 Hz, 3H), 2.05–2.25 (m, 4H,), 2.37 (s, 3H), 4.00 (q,
J = 7.3 Hz, 2H), 5.05 (s, 1H), 6.01 (br s, 1 H, NH) 7.42 (d, J = 9.2 Hz,
2H), 8.05 (d, J = 9.2 Hz, 2H). 13C NMR (125 MHz, DMSO-d6):
d
= 0.89 (s, 3H), 1.09 (s, 3H),
.
2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,4a,5,6,7,8,8a-octahydro-qui-
noline-3-carboxylic acid ethyl ester (2a) [19]: Mp = 203–204 8C. 1H
NMR (500 MHz, DMSO-d6):
d
= 0.94 (s, 3H), 1.07 (s, 3H), 1.21 (t,
d = 12.9, 18.1, 25.7, 28.1, 31.4, 35.7, 39.5, 49.3, 58.7, 103.7, 109.7,
J = 7.1 Hz, 3H), 2.13–2.29 (m, 4H), 2.35 (s, 3H), 4.06 (q, J = 7.1 Hz,
119.9, 121.5, 127.3, 133.5, 143.4, 146.9, 148.1, 165.7, 194.3. IR
(KBr): 3506, 3285, 3193, 2447, 1912, 1678, 1518, 1484, 1306, 1284,
2H), 5.07 (s, 1H), 6.64 (br s, 1 H, NH), 7.08–7.33 (m, 5H). 13C NMR
(125 MHz, DMSO-d6):
d
= 12.9, 17.9, 25.8, 28.1, 31.3, 35.3, 39.6,
49.5, 58.5, 104.7, 110.7, 124.7, 126.5, 126.7, 142.4, 145.8, 147.4,
166.2, 194.4. IR (KBr): 3287, 3078, 2963, 1697, 1611 cmÀ1
1166, 870, 755 cmÀ1
.
2,7,7-Trimethyl-5-oxo-4-pyridin-3-yl-1,4,4a,5,6,7,8,8a-octahy-
dro-quinoline-3-carboxylic acid ethyl ester (2i) [19]: Mp = 66–67 8C.
.
4-(4-Chloro-phenyl)-2,7,7-trimethyl-5-oxo-1,4,4a,5,6,7,8,8a-
1H NMR (500 MHz, DMSO-d6):
d = 0.80 (s, 3H), 1.03 (s, 3H), 1.08 (t,
octahydro-quinoline-3-carboxylic acid ethyl ester (2b) [22]:
J = 7.3 Hz, 3H), 1.95–2.49 (m, 4H), 2.29 (s, 3H), 3.51 (q, J = 7.3 Hz,
2H), 4.84 (s, 1H), 7.20–7.48 (m, 2H), 8.26–8.35 (m, 2H), 9.16 (br s,
1H, NH). 13C NMR (125 MHz, DMSO-d6):
d = 18.2, 26.3, 28.9, 32.1,
33.8, 50.1, 50.6, 102.3, 109.2, 123.2, 134.5, 142.5, 146.1, 146.8,
148.6, 149.8, 166.9, 194.1. IR (KBr): 3344, 1696, 1652, 1487, 1367,
1211, 1132, 723 cmÀ1
.
4-(4-Bromo-phenyl)-2,7,7-trimethyl-5-oxo-1,4,4a,5,6,7,8,8a-
octahydro-quinoline-3-carboxylic acid ethyl ester (2j) [19]:
Mp = 253–255 8C. 1H NMR (500 MHz, DMSO-d6):
d = 0.93 (s, 3H),
1.08 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 2.19–2.40 (m, 7H), 4.05 (q,
J = 7.1 Hz, 2H), 5.01 (s, 1H), 5.71 (br s, 1H, NH), 7.19 (d, J = 8.2 Hz,
2H), 7.32 (d, J = 8.2 Hz, 2H). 13C NMR (125 MHz, DMSO-d6):
Mp = 245–246 8C. 1H NMR (500 MHz, DMSO-d6):
d
= 0.94 (s, 3H),
1.08 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H), 2.12–2.34 (m, 4H), 2.37 (s, 3H),
4.04 (q, J = 7.1 Hz, 2H), 5.04 (s, 1H), 6.46 (br s, 1 H, NH), 7.15–7.19
(d, J = 8.1 Hz, 2 H), 7.24–7.26 (d, J = 8.1 Hz, 2 H). 13C NMR (125 MHz,
DMSO-d6):
d
= 12.9, 18.0, 25.8, 28.1, 31.3, 34.9, 39.6, 49.4, 58.6,
104.4, 110.4, 126.4, 128.1, 130.3, 142.4, 144.3, 147.2, 165.9, 194.3.
IR (KBr): 3276, 3199, 3077, 2964, 1707, 1648, 1604 cmÀ1
.
2,7,7-Trimethyl-5-oxo-4-styryl-1,4,4a,5,6,7,8,8a-octahydro-qui-
noline-3-carboxylic acid ethyl ester (2c) [19]: Mp = 206–207 8C; 1H
NMR (500 MHz, DMSO-d6):
d = 1.09 (s, 3H), 1.12 (s, 3H), 1.28 (t,
J = 7.1 Hz, 3H), 2.19–2.33 (m, 4H), 2.37 (s, 3H), 4.18 (q, J = 7.1 Hz,
2H), 4.71 (d, J = 6.1 Hz, 1H), 6.16 (dd, J = 16.2, and 6.1 Hz, 1H), 6.58
(d, J = 16.2 Hz, 1H), 6.23 (d, J = 7 Hz, 2H), 7.21–7.32 (m, 5H), 9.03 (br
d
= 13.9, 16.4, 25.8, 28.1, 32.3, 34.9, 39.6, 49.4, 58.6, 97.5, 104.4,
110.4, 126.4, 128.1, 130.3, 142.4, 147.2, 165.9, 197.3. IR (KBr):
3272, 3200, 3070, 2962, 1707, 1648, 1600 cmÀ1
2,7,7-Trimethyl-5-oxo-4-propyl-1,4,4a,5,6,7,8,8a-octahydro-qui-
noline-3-carboxylic acid ethyl ester (2k) [19]: Mp = 147–148 8C; 1
NMR (500 MHz, DMSO-d6):
= 0.78 (t, J = 7.2 Hz, 3H), 1.08 (s, 6H),
s, 1 H, NH); 13C NMR (125 MHz, DMSO-d6):
d
= 13.1, 18.1, 25.8,
.
28.3, 31.3, 32.1, 39.7, 49.5, 54.1, 58.5, 102.7, 108.6, 109.5, 119.1,
121.8, 124.9, 125.4, 126.5, 130.8, 143.1, 147.2, 148.1, 166.3, 194.44.
H
IR (KBr): 3335, 3180, 2949, 1700, 1650 cmÀ1
.
d
2,7,7-Trimethyl-5-oxo-4-p-tolyl-1,4,4a,5,6,7,8,8a-octahydro-qui-
noline-3-carboxylic acid methyl ester (2d) [19]: Mp = 270 8C. 1H
1.10–1.37 (m, 6H), 2.13–2.32 (m, 7H), 4.01 (t, J = 6.1 Hz, 1H), 4.10–
4.23 (m, 2H), 5.59 (s, 1H). 5.58 (br s, 1H, NH). 13C NMR (125 MHz,
NMR (500 MHz, DMSO-d6):
d
= 0.96 (s, 3H), 1.09 (s, 3H), 2.15–2.38
DMSO-d6):
d
= 13.3, 14.1, 15.6, 22.1, 29.6, 35.3, 40.1, 44.3, 53.1,
60.1, 99.2, 108.2, 147.2, 149.2, 165.4, 196.4. IR (KBr): 2994, 1770,
1683, 1246 cmÀ1
(m, 10H), 3.62 (s, 3H), 5.04 (s, 1H), 5.96 (br s, 1 H, NH), 7.00 (d,
J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H). 13C NMR (125 MHz, DMSO-
.
d6):
d
= 17.4, 19.7, 25.6, 28.3, 31.3, 34.3, 49.4, 49.7, 102.6, 109.3,
126.3, 127.5, 133.7, 143.8, 144.2, 148.5, 166.5, 193.4. IR (KBr):
3283, 3192, 3071, 2956, 1687, 1602, 1491 cmÀ1
9-Phenyl-3,4,6,7,9,10-hexahydro-2H, 5H-acridine-1,8-dione (3a)
[25]: White solid; Mp = 279–281 8C. 1H NMR (500 MHz, DMSO-
.
d6):
d
= 1.75–2.48 (m, 12 H), 4.23 (s, 1 H), 7.09–7.31 (m, 2 H), 7.41–
7.63 (m, 3H), 9.41 (br s, 1H, NH). 13C NMR (125 MHz, DMSO-d6):
= 200.1, 156.6, 152.5, 132.9, 132.6, 117.6, 41.9, 37.3, 31.5, 25.9. IR
(neat): 3413, 1653, 1025, 1004 cmÀ1
4-Furan-2-yl-2,7,7-trimethyl-5-oxo-1,4,4a,5,6,7,8,8a-octahydro-
quinoline-3-carboxylic acid ethyl ester (2e) [19]: Mp = 248–249 8C;
d
1H NMR (500 MHz, DMSO-d6):
d
= 1.01 (s, 3H), 1.10 (s, 3H), 1.25 (t,
.
J = 7 Hz, 3H), 2.21–2.28 (m, 3H), 2.34–2.38 (m, 4H), 4.13 (q, J = 7 Hz,
9-(4-Chloro-phenyl)-3,4,6,7,9,10-hexahydro-2H, 5H-acridine-1,8-
dione (3b) [25]: White solid; Mp = 268–270 8C. 1H NMR (500 MHz,
2H), 5.20 (s, 1H), 5.81 (br s, 1 H, NH), 6.04–7.19 (m, 3H). 13C NMR
(125 MHz, DMSO-d6):
d
= 14.2, 19.3, 21.1, 27.5, 30.2, 36.9, 59.8,
DMSO-d6):
d
= 1.68–2.55 (m, 12 H), 4.88 (s, 1H), 7.18–7.19 (d,
J = 8 Hz, 2H), 7.21–7.22 (d, J = 8 Hz, 2H), 9.52 (br s, 1H, NH).13
NMR (125 MHz, DMSO-d6):
= 20.7, 26.2, 31.9, 36.6, 111.9, 127.5,
127.7, 129.3, 146.2, 151.4, 172.6, 194.6. IR (neat): 3423, 1643,
1045, 1014 cmÀ1
103.1, 104.7, 110.1, 140.8, 144.2, 150.5, 157.9, 167.2, 195.5. IR
C
(KBr): 3342, 3122, 1697, 1648, 1480, 1361, 1211, 1132, 750 cmÀ1
.
d
4-(4-Methoxy-phenyl)-2,7,7-trimethyl-5-oxo-1,4,4a,5,6,7,8,8a-
octahydro-quinoline-3-carboxylic acid ethyl ester (2f) [19]:
Mp = 257–259 8C. 1H NMR (500 MHz, DMSO-d6):
= 0.94 (s, 3H),
.
d
1.07 (s, 3H), 1.21 (t, J = 7.2 Hz,3H), 2.13–2.36 (m, 7H), 3.74 (s, 3H),
4.06 (q, J = 7.2 Hz, 2H), 5.00 (s, 1H), 6.01 (br s, 1 H, NH), 6.74 (d,
J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H). 13C NMR (125 MHz, DMSO-
Acknowledgment
Research supported by the National research Council of I.R. Iran
as a National Research project under the number 984.
d6):
d
= 14.2, 19.4, 27.1, 29.4, 32.6, 35.6, 41.1, 50.7, 55.1, 59.7, 106.3,
112.4, 113.2, 128.9, 139.5, 139.5, 143.1, 147.7, 157.7, 167.4, 195.5.
IR (KBr): 3292, 3224, 3087, 2958, 1699, 1605, 1491 cmÀ1
.
4-(4-Hydroxy-phenyl)-2,7,7-trimethyl-5-oxo-1,4,4a,5,6,7,8,8a-
References
octahydro-quinoline-3-carboxylic acid ethyl ester (2g) [19]:
Mp = 232–234 8C. 1H NMR (500 MHz, DMSO-d6):
d = 0.94 (s, 3H),
[1] (a) G. Guillena, D.J. Ramon, M. Yus, Tetrahedron: Asymmetry 18 (2007) 693–700;
(b) A. Do¨mling, Chem. Rev. 106 (2006) 17–89.
1.08 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H), 2.08–2.18 (m, 3H), 2.20–2.35
(m, 4H), 4.07 (q, J = 7.6 Hz, 2H), 4.98 (s, 1H), 5.62 (br s, 1 H, NH),
6.65 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H). 13C NMR (125 MHz,
[2] C. Simon, T. Constantieux, J. Rodriguez, Eur. J. Org. Chem. (2004) 4957–4980.
[3] A. Do¨mling, I. Ugi, Angew. Chem. Int. Ed. 39 (2000) 3168–3210.
[4] D.J. Ramo´n, M. Yus, Angew. Chem. Int. Ed. 44 (2000) 1602–1634.
[5] A. Hantzsch, Justus Liebigs, Ann. Chem. 1 (1882) 215.
[6] C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043–1052 (and references cited
therein).
[7] K.S. Atwal, B.N. Swanson, S.E. Unger, D.M. Floyd, S. Moreland, A. Hedberg, B.C.
O’Reilly, J. Med. Chem. 34 (1991) 806–811.
[8] T. Itoh, K. Nagata, M. Miyazaki, H. Ishikawa, A. Kurihara, A. Ohsawa, Tetrahedron
60 (2004) 6649–6655.
DMSO-d6):
d = 15.1, 19.1, 19.1, 27.4, 33.4, 36.7, 41.1, 51.7, 54.9,
60.2, 106.2, 112.6, 115.5, 130.1, 131.3, 140.4, 145.3, 149.7, 156.6,
168.4, 195.3. IR (KBr): 3331, 3122, 1686, 1656, 1495, 1234,
730 cmÀ1
.
2,7,7-Trimethyl-4-(4-nitro-phenyl)-5-oxo-1,4,4a,5,6,7,8,8a-octa-
hydro-quinoline-3-carboxylic acid ethyl ester (2h) [24]: Mp = 240–
[9] R. Ruppert, C. Jeandon, A. Sgambati, H. Callot, Chem. Commun. (1999) 2123–2124.

614
A. Heydari et al. / Journal of Fluorine Chemistry 130 (2009) 609–614
´
[10] S.J. Garden, C.R.W. Guimara˜es, M.B. Correa, C.A.F.D. Oleveira, A.D.C. Pinto, R.B.D.
(b) R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organic Fluorine Chemistry. Princi-
ples and Applications, Plenum, New York, 1994.
Alencastro, J. Org. Chem. 68 (2003) 8815–8822.
[11] S.G. Quellet, J.B. Tuttle, D.W.C. MacMillan, J. Am. Chem. Soc. 127 (2005) 32–33.
[12] B. Loev, K.M. Snader, J. Org. Chem. 30 (1965) 1914–1916.
[13] S.J. Tu, J.F. Zhou, X. Deng, P.J. Cai, H. Wang, J.C. Feng, Chin. J. Org. Chem. 21 (2001)
313–316.
[30] K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, Oxford, 2006
(Chapter 4).
[31] M. Fioroni, M.D. Diaz, S. Berger, J. Am. Chem. Soc. 124 (2002) 7737–7744 (and
references cited therein).
[14] G. Sabitha, G.S.K.K. Reddy, C.S. Reddy, J.S. Yadav, Tetrahedron Lett. 44 (2003)
4129–4131.
[32] D.N. Kevill, M.J. D’Souza, J. Phys. Org. Chem. 15 (2002) 881–888.
[33] J.P. Richard, M.M. Toteva, T.L. Amyes, Org. Lett. 3 (2001) 2225–2228.
[34] K.T. Liu, H.I. Chen, J. Chem. Soc. Perkin Trans. 2 (2000) 893–898.
[35] F.L. Schadt, T.V. Bentley, P.V.R. Schleyer, J. Am. Chem. Soc. 98 (1976) 7667–7674.
[36] A. Heydari, S. Khaksar, M. Tajbakhsh, Synthesis 19 (2008) 3126–3130.
[37] A. Heydari, S. Khaksar, M. Tajbakhsh, Tetrahedron Lett. 50 (2009) 77–80.
[38] R. Ben-Daniel, S.P. De Visser, S. Shaik, R. Neumann, J. Am. Chem. Soc. 125 (2003)
12116–12117.
[39] U. Habusha, E. Rozental, S. Hoz, J. Am. Chem. Soc. 124 (2002) 15006–15011.
[40] R. Takita, T. Ohshima, M. Shibasaki, Tetrahedron Lett. 43 (2002) 4661–4665.
[41] T.G. Levitskaia, B.A. Moyer, P.V. Bonnesen, A.P. Marchand, K. Krishnudu, Z. Chen, Z.
Huang, H.G. Kruger, A.S. McKim, J. Am. Chem. Soc. 123 (2001) 12099–12100.
[42] J.P. Be´gue´, D. Bonnet-Delpon, B. Crousse, Synlett (2004) 18–29.
[15] S.J. Ji, Z.Q. Jiang, J. Lu, T.P. Loh, Synlett (2004) 831–835.
[16] N. Tewari, N. Dwivedi, R.P. Tripathi, Tetrahedron Lett. 45 (2004) 9011–9014.
[17] G.V.M. Sharma, K.L. Reddy, P.S. Lakshmi, P.R. Krishna, Synthesis (2006) 55–58.
[18] M.M. Heravi, K. Bakhtiari, N.M. Javadi, F.F. Bamoharram, M. Saeedi, H.O. Oskooie, J.
Mol. Catal. A: Chem. 264 (2007) 50–52.
[19] L.M. Wang, J. Sheng, L. Zhang, J.W. Han, Z. Fan, H. Tian, C.T. Qian, Tetrahedron 61
(2005) 1539–1543.
[20] S. Ko, M.N.V. Sastry, C. Lin, C.F. Yao, Tetrahedron Lett. 46 (2005) 5771–5774.
[21] M. Maheswara, V. Siddaiah, Y.K. Rao, Y. Tzeng, C. Sridhar, C.J. Mol, Catal. A: Chem.
17 (2006) 179–180.
[22] R. Gupta, S. Paul, A. Loupy, Synthesis (2007) 2835–2838.
[23] S. Ko, C.F. Yao, Tetrahedron Lett. 62 (2006) 7293–7299.
[24] A. Kumar, R.A. Maurya, Synlett 6 (2008) 883–885.
[25] S. Chandrasekhar, Y.S. Rao, L. Sreelakshmi, B. Mahipal, C.R. Reddy, Synthesis
(2008) 1737–1741.
[26] R. Sridhar, P.T. Perumal, Tetrahedron 61 (2005) 2465–2470.
[27] A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Synlett (2008) 509–512.
[28] L. Eberson, M.P. Hartshorn, O. Persson, F. Radner, Chem. Commun. (1996) 2105–2112.
[29] (a) M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd ed., Ellis-
Horwood, New York, 1992;
´
´
[43] J. Iskra, D. Bonnet-Delpon, J.P. Begue, Tetrahedron Lett. 43 (2002) 1001–1003.
[44] J. Legros, B. Crousse, D. Bonnet-Delpon, J.P. Be´gue´, Eur. J. Org. Chem. (2002) 3290–
3293.
[45] K.S. Ravikumar, Y.M. Zhang, J.P. Be´gue´, D. Bonnet-Delpon, Eur. J. Org. Chem. (1998)
2937–2940.
[46] S. Kobayashi, H. Tanaka, H. Amii, K. Uneyama, Tetrahedron 59 (2003) 1547–1552.
[47] A. Berkessel, M.R.M. Andreae, H. Schmickler, J. Lex, Angew. Chem. Int. Ed. 4 (2002)
4481–4484.
[48] K. Neimann, R. Neumann, Org. Lett. 2 (2000) 2861–2863.