FeF3 as a novel catalyst for the synthesis of polyhydroquinoline derivatives via unsymmetrical Hantzsch reaction

Article abstract of DOI:10.1016/j.jfluchem.2011.09.005

A facile and highly efficient one-pot synthesis of polyhydroquinoline derivatives is reported via four-component condensation reaction of aldehydes, β-keto compounds, active methylene compounds and ammonium acetate in the presence of FeF₃ as a catalyst in ethanol at 75-80 °C. The method offers several advantages including high yields, short reaction time, simple work-up procedure and catalyst reusability for several runs. The higher catalytic activity of FeF₃ ascribed due to its high acidity, thermal stability and water tolerance. The superiority of use of FeF₃ to the current process is compared with other Lewis acids, Fe-salts, fluoride sources and insights of the origin of the efficiency are discussed.

Full text of DOI:10.1016/j.jfluchem.2011.09.005

Journal of Fluorine Chemistry 135 (2012) 91–96
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
FeF3 as a novel catalyst for the synthesis of polyhydroquinoline derivatives
via unsymmetrical Hantzsch reaction
a
b
c
Rajendra Surasani a,c, Dipak Kalita a, , A.V. Dhanunjaya Rao , Kaviraj Yarbagi , K.B. Chandrasekhar
*
a Custom Pharmaceuticals Services, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
b Analytical Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
c Department of Chemistry, Institute of Science and Technology, JNT University of Anantapur, Anantapur 515002, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile and highly efficient one-pot synthesis of polyhydroquinoline derivatives is reported via four-
component condensation reaction of aldehydes, -keto compounds, active methylene compounds and
Received 29 March 2011
b
Received in revised form 5 August 2011
Accepted 13 September 2011
Available online 22 September 2011
ammonium acetate in the presence of FeF3 as a catalyst in ethanol at 75–80 8C. The method offers several
advantages including high yields, short reaction time, simple work-up procedure and catalyst reusability
for several runs. The higher catalytic activity of FeF3 ascribed due to its high acidity, thermal stability and
water tolerance. The superiority of use of FeF3 to the current process is compared with other Lewis acids,
Fe-salts, fluoride sources and insights of the origin of the efficiency are discussed.
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Polyhydroquinoline
FeF3
One-pot synthesis
Hantzsch condensation
1. Introduction
molecular iodine [13], PTSA [14], L-proline and derivatives [15],
nickel nano particle [16], polymers [17], Baker’s yeast [18], glycine
[19] and hafnium(IV) bis(perfluorooctanesulfonyl)imide complex
in fluorous media [20]. Most of these processes, however, suffer
from drawbacks such as unsatisfactory yields, high temperatures,
long reaction times and the use of stoichiometric and/or relatively
expensive reagents. Moreover, after completion of the reaction, the
excess Lewis acids/catalyst are destroyed in the aqueous quench,
liberating large amounts of harmful mixtures containing metal
ions and organic wastes that are detrimental to our delicate eco-
system [4–20]. Furthermore, the use of soluble metal catalysts in
these systems often necessitates a tedious catalyst separation step.
Consequently, there is a need for a greater catalytically efficient
method for these transformations which might work under mild
and more economical and environmental benign conditions. For
reasons of safety and health hazards especially in large-scale
preparation of polyhydroquinoline derivatives an alternative
method was sought and we found that use of FeF3 led to better
selectivity, highest yield, ease of catalyst recovery and reuse.
The use of iron as a catalyst has significant practical advantages
since it is inexpensive and non toxic. In particular, FeF3 is the most
widely known fluoride of iron. It is white in color and the crystals
have a rhombic structure. The most important industrial applica-
tion of the FeF3 is in the manufacture of Fe–Co–Nd magnets [21a],
hydro-cracking [21b], preparation of perfluoroacyl fluorides [21c],
hydrorefining of lubricating oils [21d], fluorinating agent [21e],
pin-hole prevention in cast iron [21f], for xenon-fluorine com-
In recent years, much attention has been devoted to the
synthesis of polyhydroquinoline compounds due to their diverse
therapeutic and pharmacological properties, such as vasodilator,
antitumor, bronchodilator, antiartherosclerotic, geroprotective
and hepatoprotective activity [1,2]. Particularly, 4-substituteted
1,4-dihydropyridines (1,4-DHPs) are well known as Ca2+ channel
blockers and have emerged as one of the most important class of
drugs for the treatment of cardiovascular diseases [3]. Despite their
importance from a pharmacological, industrial and synthetic point
of view, comparatively very few methods for their preparation
have been reported. Generally, 1,4-DHPs are synthesized by the
Hantszch condensation method, which involves cyclocondensa-
tion of aldehyde, b-ketoester and ammonia either in acetic acid at
room temperature or refluxing in alcohol for a long time [3].
However, this method involves long reaction times, harsh reaction
conditions and generally gives low yields of the products. Recently
much effort has been expended to develop more efficient methods
for the preparation of polyhydroquinoline derivatives such as
using solar thermal energy [4], ionic liquid [5], TMSCl–NaI [6],
metal triflates [7], grinding [8], Hy-Zeolite [9], montmorillonite K-
10 [10], cerium(IV) ammonium nitrate [11], HClO4–SiO2 [12],
* Corresponding author. Tel.: +91 4044658620; fax: +91 4044658699.
E-mail address: dipakk@drreddys.com (D. Kalita).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.09.005

92
R. Surasani et al. / Journal of Fluorine Chemistry 135 (2012) 91–96
Scheme 1. Synthesis of polyhydroquinoline derivative from benzaldehyde, dimedone, ethyl acetoacetate and ammonium acetate in the presence of FeF3 catalyst.
pounds [21g], and as a catalyst for aromatization, dealkylation,
polymerization and conversion of vinylidene chloride to the
fluoride [21h]. The chemistry of FeF3 in organic synthesis has
recently received increasing attention over its companion reagents
like FeCl3, FeBr3, and FeI3 owing to its stability in water and air
actively utilized as a catalyst for various types of organic syntheses
[22]. FeF3 has been utilized as an effective catalyst for bis-
indolylmethanes [22a], chemoselective addition of cyanotri-
methylsilane to aldehydes [21b], cross-coupling reactions [22c
and d] sulenylation and selenation reaction [22d and e], etc.
In addition the growing concern for the influence of the
chemical reagents on the environment as well as on human body,
recovery and reusability of the chemical reagents has attracted the
attention of synthetic organic chemists. More importantly
pharmaceutical industry has given more importance towards
recovery and reuse of chemical reagents to reduce the cost of a
product as well as the environmental burden. As part of continuing
effort in our laboratory towards the development of new methods
in organic synthesis, we became interested in the possibility of
developing a one-pot synthesis of polyhydroquinoline derivatives
catalyzed by FeF3. We present our results about a FeF3 catalyzed
four-component Hantzsch reaction in ethanol.
adduct was isolated. However, addition of a catalytic amount of
FeF3 to this mixture has rapidly induced four component
condensations in 1 h (Table 1). Hantzsch condensation of
dimedone, benzaldehyde, ethylacetoacetate and ammonium ace-
tate in the presence of catalytic amount of FeF3 (5 mol%) at 75–
80 8C in ethanol results in the formation of ethyl 2-methyl-5-oxo-
4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 1,
entry 8) in 92% yield. To the best of our knowledge this is the first
report for the polyhydroquinoline synthesis using FeF3 as a
homogeneous catalyst. We have not observed any fluorination
while FeF3 is used in the one-pot synthesis. In an attempt to
improve the catalytic activity of the reactions we have examined
other Lewis acids and iron salts such as FeBr3, FeCl3, FeI3,
Fe2(NO3).9H2O, Fe(SO4)3ÁnH2O for the synthesis of polyhydroqui-
nolines (Table 1, entries 4, 5, 11, 12). It was found that conventional
Lewis acids such as AlCl3 (Table 1, entry 2), ZnCl2 (Table 1, entry 3),
and FeCl3 (Table 1, entry 5) showed poor effect to the yield and
reaction time. This probably due to their poor water tolerance of
the reagents under the reaction condition we studied. Even large
amount of catalysts was used, the results were still unsatisfactory
and many side reactions were observed. When 5 mol% of FeBr3,
FeCl3, FeI3, Fe2(NO3)Á9H2O and Fe(SO4)3ÁnH2O (Table 1, entries 4, 5,
11, 12) was used for the synthesis of polyhydroquinolines, only 45,
60, 50 and 0% yield of the corresponding product were obtained.
FeF3 emerged as the best catalyst in terms of conversion and
reaction rates (Table 1, entries 6–10). While adding 100 mol% of
FeF3 into the system under similar reaction conditions, the speed of
the reaction was obviously accelerated, but the yield was not yet
satisfactory (Table 1, entry 6). Further studies showed that
decreasing the amount of FeF3 improve the reaction significantly.
Inspired by the results, we have changed the amount from
100 mol% to 10 mol% and 5 mol%, finding that 5 mol% of FeF3 was
good enough (Table 1, entry 8) to obtained very high yield of the
product in shorter reaction time.
2. Results and discussions
We report herein an efficient one-pot synthesis of polyhy-
droquinoline derivatives from four components coupling of
aromatic aldehydes, alkyl acetoacetate,
b-keto compounds and
ammonium acetate in the presence of a catalytic amount of FeF3 in
ethanol at 75–80 8C in excellent yield in short reaction time 1 h.
In an initial endeavor (Scheme 1), 1.0 equiv each of benzalde-
hyde 1, dimedone 2, ethyl acetoacetate 3 and ammonium acetate 4
were heated under reflux in ethanol without any catalyst. No
reaction was observed even after 12 h, only dimedone/aldehyde
FeF3 showed higher catalytic activity than other Fe-catalyst due
to the high acidity, high thermal stability and high water tolerance.
The acidity of 5 mol% FeF3 measured in water and found the pH
ꢀ2.7. The catalytic process of FeF3 using different solvents was also
investigated. The reaction of benzaldehyde 1, dimedone 2, ethyl
acetoacetate 3 and ammonium acetate 4 was chosen as a model
reaction for comparison of solvents, the results are shown in Table
Table 1
The reaction of benzaldehyde, ethylacetoacetate, dimedone and ammonium
acetate: effect of catalyst.a
Entry
Catalyst
Amount of
Time (h)
Yieldb (%)
catalyst (mol%)
1
2
None
AlCl3
ZnCl2
FeBr3
FeCl3
FeF3
–
5
12
24
24
24
24
1
Nonec
40
Table 2
The reaction of benzaldehyde, ethylacetoacetate, dimedone and ammonium
acetate: effect of solvents and temperature.a
3
5
36
4
5
45
5
5
60
Entry
Solvent
Temp. (8C)
Time (h)
Yield (%)b
6
100
10
5
80
c
7
FeF3
1
90
1
2
3
4
5
6
7
Ethanol
80
1
4
3
3
5
4
4
90
65
85
43
24
55
40
c
8
FeF3
1
92
Methanol
Acetonitrile
H2O
60
9
FeF3
2.5
5
2
75
80
10
11
12
FeI3
24
24
50
Reflux
Reflux
Reflux
Reflux
Fe2(NO3)Á9H2O
Fe(SO4)3ÁnH2O
5
None
None
Dichloromethane
Toluene
5
a
Cyclohexane
All reactions were carried out in ethanol at 75–80 8C.
Isolated yield.
b
c
a
All reactions were carried out using 5 mol% of FeF3.
Isolated yield.
b
Major product isolated was dimedone/aldehyde adduct.

R. Surasani et al. / Journal of Fluorine Chemistry 135 (2012) 91–96
93
Table 3
The reaction of benzaldehyde, ethylacetoacetate, dimedone and ammonium
acetate: screening of fluoride sources and temperature.a
Entry
Catalyst (Fluoride source)
Temp. (8C)
Time (h)
Yield (%)b
1
2
3
4
5
6
CaF2
CsF
80
12
12
1
20
30
92
35
15
30
80
FeF3
KF
80
80
12
12
12
NH4F
TBAF
80
Reflux
a
Conditions: benzaldehyde (1 mmol), ethylacetoacetate (1 mmol), dimedone
(1 mmol), and ammonium acetate (1 mmol), catalyst (5 mol%), ethanol (5 mL),
heating.
b
Isolated yield.
Fig. 2. Recycling and reuse of FeF3 for polyhydroquinoline synthesis.
2. In each case, the reactants were mixed together with 5 mol% of
FeF3 stirred with 5 mL solvent. The polar solvents such as ethanol
and acetonitrile were found to be better solvents than the non-
polar solvents like toluene, dichloromethane, cyclohexane, etc.
Obviously, the results could be attributed to the better solubility of
the catalyst and the reagents in the polar solvents. Among the two
solvents viz. ethanol and acetonitrile, ethanol stands out as the
solvent of choice, with its fast conversion, high yield and low
toxicity.
We have further compared the catalytic process of FeF3 by
screening other fluoride sources under the same reaction condi-
tions (Table 3), it was found that FeF3 is the most reactive than
other fluoride sources (Table 3, entry 3). The corresponding
product was obtained in low yield in the presence of CaF2, CsF, KF,
NH4F and TBAF (Table 3, entries 1, 2, 4–6), respectively.
The powder X-ray diffraction pattern of FeF3, recovered FeF3
(after 5th run) and FeCl3 (Fig. 1) were recorded on a Rigaku D/Max-
five successive runs. The yields obtained were from 90, 89, 89, 88
and 87% in the first, second, third, fourth and fifth run respectively.
In view of environment friendly methodologies, recovery and
reuse of the catalyst is highly preferable. More importantly
pharmaceutical industry has given more importance towards
recovery and reuse of chemical reagents to reduce the cost of a
product as well as the environmental burden.
Thus, we selected the optimized reaction condition to examine
the universality of this catalyst’s application with different
electron rich and deficient substrates. Various substituted
aromatic aldehydes,
b-keto esters and dimedone undergo the
Hantzsch reaction in the presence of catalytic amount of FeF3
(5 mol%) in ethanol at 75–80 8C (Scheme 2). The results of this
study are summarized in Table 4. It was indicated that both
electron deficient (Table 4, entries 1, 2, 8, 10–13, 15, 16) and
electron rich aromatic aldehydes (Table 4, entries 4–7, 9, 14)
worked well, giving high yields of the product in shorter reaction
time. Next we investigated the effect of substitution in 1,3-
cyclohexadione (dimedone) system. Aromatic aldehydes such as
3-nitro benzaldehyde (Table 4, entry 1), 4-chloro benzaldehyde
(Table 4, entry 2), 4-nitro benzaldehyde (Table 4, entry 3), 3,4-
dimethoxy benzaldehyde (Table 4, entry 5), 4-trifluoro benzalde-
hyde (Table 4, entry 6), 3,4-dihydroxy benzaldehyde (Table 4,
entry 7), etc., reacts with 5,5-dimethyl-1,3-cyclohexadione, ethyl
acetoacetate and ammonium acetate in the presence of FeF3 (5
mol%) in ethanol at 75–80 8C to afford the products in excellent
yields. Interestingly, 1,3-cyclohexadione (dimedone) reacts with
aromatic aldehyde (Table 4, entries 15 and 16), ethyl acetoacetate
2200 model diffractometer equipped with horizontal goniometer
˚
in u/2u geometry. The Copper Ka (l = 1.5418 A) radiation was used
and the sample was scanned between 3–45 degrees 2u. The sharp
peaks in the diffractogram indicate that the FeF3 and recovered
FeF3 (after 5th run) are crystalline in nature. FeCl3 showing absence
of any sharp peak in XRD pattern confirms the amorphous nature.
After completion of the reaction (TLC), the product was
extracted with ethyl acetate and the catalyst was recovered from
the aqueous layer. FeF3 is more soluble in water than that in
organic solvents. The catalyst was recovered almost quantitatively
from the aqueous layer, which was subsequently reused for several
runs. As indicated in Fig. 2, it showed almost no loss of activity after
Fig. 1. XRD profile of FeF3, recovered FeF3 (after 5th run) and FeCl3.

94
R. Surasani et al. / Journal of Fluorine Chemistry 135 (2012) 91–96
O
O
O
Ar
O
Ar
5 mol% FeF3
OR3
OR3
CH3
+
+
NH4OAc
+
R1
R2
CHO
EtOH, 75-80 0C
1 h
R1
R2
4
O
O
CH3
N
H
5a-5p
2a-2p
Ar = aryl
3
1
R3 = CH3, C2H5
R1 = H, R2 = H or
R1 = CH3, H = CH3
85-95% Yield
Scheme 2. Synthesis of polyhydroquinoline derivative from aldehydes, alkylacetoacetate,
b-keto compounds and ammonium acetate in the presence of a reusable FeF3
(5 mol%) catalyst.
Table 4
FeF3 catalyzed synthesis of polyhydroquinoline derivatives.a
Entry
R
R1
R2
R3
Time (h)
Product
Yieldb (%)
Mp (8C)
Observed
Reported
1
2
3-NO2C6H4
4-ClC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
5a
5b
5c
5d
5e
5f
92
92c
89
95
95
91
92
90
95
89
88
90
94
94
88
85
176–177
233–235
242–243
140–142
204–206
188–190
216–218
167–169
250–252
104–106
250–252
220–22
177–178 [12]
232–234 [13]
3
4-NO2C6H4
4-CNC6H4
242–244 [12]
4
–
5
3,4-OCH3C6H3
4-CF3C6H4
198–199 [12]
6
–
7
3,4-OHC6H3
5-OH2–NO2C6H3
4-OCH3C6H4
2-Cl4–CF3C6H3
4-NO2C6H4
4-ClC6H4
5g
5h
5i
–
8
–
9
256–257 [13]
10
11
12
13
14
15
16
5j
–
5k
5l
252–254 [20]
CH3
221–223 [13]
4-CNC6H4
CH3
5m
5n
5o
5p
220–222
209–211
204–206
92–94
–
3,4-OCH3C6H3
3-NO2C6H4
2-Cl4–CF3C6H3
CH3
–
198–200
–
C2H5
C2H5
H
H
a
All reactions were carried out in ethanol at 75–80 8C using 5 mol% FeF3.
Yields refer to isolated pure products.
b
c
Catalyst has been reused for 4 times.
and ammonium acetate in the presence of FeF3 (5 mol%) with little
lower yield. Aromatic aldehydes (Table 4, entries 11–14) reacts
with 5,5-dimethyl-1,3-cyclohexadione, methyl acetoacetate and
ammonium acetate in the presence of FeF3 (5 mol%) in shorter
reaction time with high yields. As seen from Table 4 the
methodology tolerates most of the substrates.
FeF3 in different organic syntheses are in progress in our
laboratory.
4. Experimental
4.1. General
3. Conclusions
All the reagents used are from commercial sources and used as
such. Unless stated otherwise, reactions were monitored by thin
layer chromatography (TLC) on silica gel plates (60 F254),
visualizing with ultraviolet light or iodine spray. Melting points
are recorded in Buchi Mp apparatus and are uncorrected. 1H and
13C NMR spectra were recorded in CDCl3 and DMSO-d6 solution
using 400 and 200 MHz spectrometers respectively. Proton
In conclusion, we have developed an easy and efficient method
to prepare a variety of polyhydroquinoline derivatives from the
reaction of different aryl aldehydes, b-keto compounds, including
1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione, al-
kyl acetoacetate and ammonium acetate in the presence of
catalytic amount of FeF3 at 75–80 8C. The higher catalytic activity
of FeF3 ascribed due to its high acidity, thermal stability and water
tolerance. Also the superiority of use of FeF3 towards the synthesis
of polyhydroquinoline is compared with other Lewis acids, Fe-
salts, fluoride sources and insights of the origin of the efficiency
are discussed. The mildness of the conversion, experimental
simplicity, compatibility with various functional groups, high
yields of the reaction product, shorter reaction times and the easy
workup procedure, etc., makes this procedure attractive to
synthesize a variety of these derivatives. Moreover, FeF3 can be
recovered and reused for several times, which makes it a useful
and attractive for synthesis of these classes of compounds for
economic viability and greater selectivity. Based on all the results
hitherto obtained it may be stated that FeF3 is an important
addition to the realm of Lewis acid to prepare verities of
polyhydroquinoline derivatives. Further studies of utilization of
chemical shifts (d) are relative to tetramethylsilane (TMS, d 0.0)
as internal standard and expressed in parts per million. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet), and m
(multiplet) as well as b (broad). Coupling constants (J) are given in
Hertz. Infrared spectra were recorded on a Perkin Elmer FTIR
spectrometer (Spectrum one). Mass spectra were recorded with PE
Sciex model API 3000 instrument. HRMS spectra were recorded
with Waters LCT Premier XE (Micro mass Qa-TOF) instrument. The
X-ray powder diffraction pattern recorded on a Rigaku D/Max-
2200 model diffractometer.
4.2. Typical procedure for the synthesis of polyhydroquinoline
derivatives 5
In a typical experimental procedure, a mixture of aldehyde 1
(1 mmol), dimedone 2 (1 mmol), alkyl acetoacetate 3 (1 mmol),

R. Surasani et al. / Journal of Fluorine Chemistry 135 (2012) 91–96
95
ammonium acetate (1 mmol), FeF3 (5 mol%) and ethanol (5 mL)
was placed in a 25 mL round bottomed flask equipped with a cold
water condenser and calcium chloride guard tube. The reaction
mixture was slowly heated to 75–80 8C. Typically the reaction
completed within one hour. After completion of the reaction (TLC),
the mixture was cooled and 15 mL of ethyl acetate and 5 mL of
water was added to the flask. The ethyl acetate layer was separated
and washed with cold water (20 mL). The organic layer was then
dried over anhydrous sodium sulfate, filtered and the solvent
distilled under vacuum to afford the crude product. The crude
product was finally recrystallized from ethanol to afford the pure
products 5a–5p. The aqueous layer containing the catalyst (FeF3)
was evaporated under reduced pressure to give a solid (slight pale
pink in color). The IR spectrum of the recovered catalyst was
identical to that of the commercially available catalyst (Aldrich),
which was further reused for the next reaction without loss in
activity. The catalyst has been recovered and reused five times
(reaction yields: 90, 89, 89, 88% and 87%).
730 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d
0.88 (s, 3H), 1.01 (s, 3H),
1.17 (t, J = 7.2 Hz, 3H), 2.00 (d, J = 16.4 Hz, 1H), 2.19 (d, J = 16.4 Hz,
1H), 2.30–2.26 (m, 4H), 2.44 (d, J = 17.2 Hz, 1H), 3.65 (s, 3H, OCH3),
3.66 (s, 3H, OCH3), 4.02 (q, J = 7.2 Hz, 2H), 4.79 (s, 1H), 6.63 (dd,
J = 2.0 & 8.4 Hz 1H), 6.77–6.74 (m, 2H), 9.02 (s, 1H, NH). 13C NMR
(50 MHz, DMSO-d6)
d 14.2, 18.2, 26.4, 29.2, 32.1, 35.1, 50.3, 55.3,
55.4, 59.0, 103.8, 110.0, 111.4, 111.7, 119.2, 140.4, 144.5, 146.9,
147.9, 149.3, 166.8, 194.2. MS (ES) m/z 400.50 (M+1). HRMS (ESI)
calculated for C23H30NO5 (M+H)+ 400.2124 found 400.2127.
Ethyl
2,7,7-trimethyl-5-oxo-4-(4-(trifluoromethyl)
phenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 5f). A yellow
solid; IR (KBr) 3281, 2938, 1710, 1603, 1496, 1382, 1324, 1216, 1136,
1065, 862, 598, 531 cmÀ1 1H NMR (400 MHz, DMSO-d6)
. d 0.83 (s,
3H), 1.00 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H), 2.00 (d, J = 16.0 Hz, 1H), 2.19
(d, J = 16.4 Hz, 1H), 2.32 (m, 4H), 2.45 (d, J = 16.4 Hz, 1H), 3.99 (q,
J = 7.2 Hz, 2H), 4.93 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6 Hz,
2H), 9.17 (s, 1H, NH). 13C NMR (50 MHz, DMSO-d6)
d 14.1, 18.3, 26.5,
29.0, 32.1, 36.3, 50.1, 59.1, 102.8, 109.3, 124.6, 124.7, 128.2, 145.7,
149.8, 151.8, 166.6, 194.1. MS (ES) m/z 408.50 (M+1). HRMS (ESI)
calculated for C22H25NO3F3 (M+H)+ 408.1787 found 408.1786.
Ethyl 4-(3,4-dihydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (compound 5g). A brown solid; IR
(KBr) 3504, 3276, 2960, 1681, 1603, 1487, 1380, 1286, 1217, 1074,
Ethyl 2,7,7-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-3-carboxylate (compound 5a). A pale yellow solid;
IR (KBr) 3289, 2959, 1702, 1607, 1528, 1487, 1349, 1217, 1073,
683 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d 0.83 (s, 3H), 1.01 (s, 3H),
1.13 (t, J = 7.2 Hz, 3H), 2.00 (d, J = 16.4 Hz, 1H), 2.21 (d, J = 16.0 Hz,
1H), 2.38 (m, 4H), 2.48 (d, J = 17.2 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H),
814, 659 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d 0.87 (s, 3H), 1.00 (s,
4.96 (s, 1H), 7.62–7.50 (m, 2H), 7.98 (m, 2H), 9.24 (s, 1H, NH). 13
C
3H), 1.16 (t, J = 7.2 Hz, 3H), 1.99 (d, J = 16.0 Hz, 1H), 2.16 (d,
J = 16.0 Hz, 1H), 2.27 (m, 4H), 2.40 (d, J = 17.2 Hz, 1H), 4.00 (q,
J = 7.2 Hz, 2H), 4.68 (s, 1H), 6.39 (dd, J = 2.0 and 8.4 Hz, 1H), 6.51 (d,
J = 8.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H, OH), 8.56 (s, 1H,
NMR (50 MHz, DMSO-d6)
d 14.0, 18.3, 26.3, 29.0, 32.2, 36.4, 50.0,
59.2, 102.6, 109.2, 120.8, 121.9, 129.3, 134.2, 146.0, 147.3, 149.6,
150.3, 166.3, 194.2. MS (ES) m/z 385.10 (M+1). HRMS (ESI)
calculated for C21H25N2O5 (M+H)+ 385.1763 found 385.1769.
Ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5, 6,7,8-hex-
ahydroquinoline-3-carboxylate (compound 5b). A off-white solid;
IR (KBr) 3275, 2958, 1706, 1604, 1488, 1381, 1214, 1214, 1071,
OH), 8.94 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
d 14.2, 18.0,
26.6, 29.2, 32.1, 34.9, 50.4, 59.0, 104.1, 110.3, 114.8, 115.2, 118.1,
138.6, 143.1, 144.1, 144.6, 149.0, 167.1, 194.3. MS (ES) m/z 372.60
(M+1). HRMS (ESI) calculated for C21H26NO5 (M+H)+ 372.1811
found 372.1817.
844, 534 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d0.83 (s, 3H), 1.00 (s,
3H), 1.13 (t, J = 7.2 Hz, 3H), 1.99 (d, J = 16.0 Hz, 1H), 2.19 (d,
J = 16.0 Hz, 1H), 2.25–2.28 (m, 4H), 2.43 (d, J = 17.2 Hz, 1H), 3.99
(q, J = 7.2 Hz, 2H), 4.83 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.25 (d,
Ethyl
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 5h).
yellow solid; IR (KBr) 3486, 3310, 2956, 1698, 1607, 1494, 1280,
1218, 1066, 856, 613 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
0.79 (s,
4-(5-hydroxy-2-nitrophenyl)-2,7,7-trimethyl-5-oxo-
A
J = 8.0 Hz, 2H), 9.12 (s, 1H, NH). 13C NMR (50 MHz, DMSO-d6)
d
4.1,
d
18.3, 26.4, 29.0, 32.1, 35.6, 50.1, 59.0, 103.0, 109.6, 127.6, 129.2,
130.2, 145.3, 146.5, 149.5, 166.5, 194.1. MS (ES) m/z 374.00 (M+1).
HRMS (ESI) calculated for C21H25NO3Cl (M+H)+ 374.1763 found
374.1756
Ethyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5, 6,7,8-hexa-
hydroquinoline-3-carboxylate (compound 5c). A yellow solid; IR
(KBr) 3295, 2959, 1699, 1605, 1517, 1482, 1345, 1218, 1073, 836,
694 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d 0.82 (s, 3H), 1.00 (s, 3H),
3H), 0.98 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 1.92 (d, J = 15.6 Hz, 1H),
2.13 (d, J = 15.6 Hz, 1H), 2.25 (d, J = 16.8 Hz, 1H), 2.29 (s, 3H), 2.42
(d, J = 16.8 Hz, 1H), 3.94 (q, J = 7.2 Hz, 2H), 5.77 (s, 1H), 6.62 (dd,
J = 2.4 & 8.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H),
9.06 (s, 1H, NH), 10.37 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6)
d
13.8, 18.2, 26.3, 28.8, 31.7, 32.0, 50.1, 59.0, 103.5, 100.3, 113.3,
166.5, 126.3, 140.1, 145.4, 145.8, 149.4, 161.5, 166.7, 193.9. MS
(ES) m/z 401.50 (M+1). HRMS (ESI) calculated for C21H25N2O6
(M+H)+ 401.1713 found 401.1721.
Ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4, 5,6,7,8-
hexahydroquinoline-3-carboxylate (compound 5i). A white solid;
IR (KBr) 3279, 2958, 1699, 1605, 1492, 1380, 1214, 1072, 1031,
849, 762, 536 cmÀ1 1H NMR (400 MHz, DMSO-d6)
. d 0.85 (s, 3H),
1.00 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.98 (d, J = 16.0 Hz, 1H), 2.17 (d,
J = 16.0 Hz, 1H), 2.29 (m, 4H), 2.43 (d, J = 16.8 Hz, 1H), 3.67 (s, 3H,
OCH3), 3.99 (q, J = 7.2 Hz, 2H), 4.78 (s, 1H), 6.74 (d, J = 8.4 Hz, 2H),
7.05 (d, J = 8.4 Hz, 2H), 9.00 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
1.12 (t, J = 7.2 Hz, 3H), 1.99 (d, J = 16.0 Hz, 1H), 2.20 (d, J = 16.0 Hz,
1H), 2.27–2.31 (m, 4H), 2.45 (d, J = 16.4 Hz, 1H), 3.98 (q, J = 7.2 Hz,
2H), 4.96 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 9.23
(s, 1H, NH). 13C NMR (50 MHz, DMSO-d6)
d 14.0, 18.3, 26.4, 29.0,
32.1, 36.6, 50.0, 59.2, 102.3, 109.0, 123.0, 128.7, 145.6, 146.0, 150.0,
154.9, 166.3, 194.1. MS (ES) m/z 385.10 (M+1). HRMS (ESI)
calculated for C21H25N2O5 (M + H)+ 385.1763 found 385.1756.
Ethyl 4-(4-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,5, 6,7,8-hexa-
hydroquinoline-3-carboxylate (compound 5d). A ash solid; IR (KBr)
3296, 2959, 2226, 1697, 1606, 1488, 1379, 1219, 1074, 845,
d6)
d 14.2, 18.2, 26.5, 29.1, 32.1, 34.9, 50.3, 54.8, 59.0, 103.9, 110.1,
555 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d
0.81 (s, 3H), 1.00 (s, 3H),
113.1, 128.4, 140.0, 144.6, 149.2, 157.3, 166.9, 194.2, MS (ES) m/z
370.50 (M+1). HRMS (ESI) calculated for C22H28NO4 (M+H)+
370.2018 found 370.2025.
Ethyl 4-(2-chloro-3-(trifluoromethyl)phenyl)-2,7,7-trimethyl-5-
oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 5j). A
white solid; IR (KBr) 3297, 2961, 1701, 1614, 1492, 1380, 1312,
1216, 1133, 803, 735, 597 cmÀ1 1H NMR (400 MHz, DMSO-d6)
. d
1.12 (t, J = 7.2 Hz, 3H), 1.99 (d, J = 16.4 Hz, 1H), 2.19 (d, J = 16.4 Hz,
1H), 2.30–2.26 (m, 4H), 2.44 (d, J = 17.2 Hz, 1H), 3.98 (q, J = 7.2 Hz,
2H), 4.90 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 9.19
(s, 1H, NH). 13C NMR (50 MHz, DMSO-d6)
d 14.1, 18.3, 26.4, 29.0,
32.1, 36.7, 50.1, 59.1, 102.4, 108.5, 109.1, 119.0, 128.5, 131.8, 146.0,
149.9, 152.8, 166.3, 194.1. MS (ES) m/z 365.10 (M+1). HRMS (ESI)
calculated for C22H25N2O3 (M+H)+ 365.1865 found 365.1852.
Ethyl 4-(3,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (compound 5e). A white solid; IR
(KBr) 3279, 2957, 1695, 1604, 1491, 1379, 1216, 1139, 1031, 788,
0.85 (s, 3H), 1.00 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.98 (d, J = 16.0 Hz,
1H), 2.17 (d, J = 16.0 Hz, 1H), 2.29 (m, 4H), 2.43 (d, J = 16.8 Hz, 1H),
3.99 (q, J = 7.2 Hz, 2H), 5.31 (s, 1H), 7.40 (m, 1H), 7.59 (m, 2H), 9.17
(s, 1H, NH). 13C NMR (50 MHz, DMSO-d6)
d 13.9, 18.3, 26.4, 29.0,

96
R. Surasani et al. / Journal of Fluorine Chemistry 135 (2012) 91–96
31.4, 35.0, 50.1, 59.0, 102.9, 109.4, 125.4, 126.0, 126.7, 129.5, 135.3,
145.7, 148.0, 150.0, 166.4, 193.9. MS (ES) m/z 442.40 (M+1). HRMS
(ESI) calculated for C22H24NO3F3Cl (M+H)+ 442.1397 found
442.1391.
Methyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4, 5,6,7,8-hex-
ahydroquinoline-3-carboxylate (compound 5k). A pale yellow solid;
IR (KBr) 3277, 2959, 1709, 1605, 1491, 1345, 1217, 1075, 866, 833,
533 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d 0.81 (s, 3H), 1.00 (s, 3H),
(s, 1H, NH), 7.24 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.63 (d,
J = 7.6 Hz, 1H). 13C NMR (50 MHz, CDCl3)
: 14.1, 19.2, 21.0, 27.3,
36.5, 37.0, 59.9, 104.7, 111.8, 125.5, 125.6, 125.8, 135.8, 144.3,
146.5, 151.2, 167.1, 195.7. MS (ES) m/z 414.40 (M+1). HRMS (ESI)
calculated for C20H20NO3ClF3 (M+H)+ 414.1084 found 414.1072.
d
Acknowledgments
2.00 (d, J = 16.4 Hz, 1H), 2.21 (d, J = 16.4 Hz, 1H), 2.32 (m, 4H), 2.46
(d, J = 17.2 Hz, 1H), 3.52 (s, 3H, OCH3), 4.98 (s, 1H), 7.42 (d,
J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 9.26 (s, 1H, NH). 13C NMR
The authors thank Dr. V. Dahanukar for his encouragement and
the analytical group for spectral data. Mr. Rajendra Surasani thanks
CPS – Dr. Reddy’s Laboratories Ltd., Hyderabad, India for allowing
him to pursue this work as a part of his Ph.D. program.
(50 MHz, DMSO-d6)
d 18.4, 26.4, 29.0, 32.1, 36.4, 50.0, 50.6, 102.0,
109.0, 123.2, 128.5, 145.6, 146.3, 150.0, 154.7, 166.8, 194.1. MS (ES)
m/z 371.50 (M+1). HRMS (ESI) calculated for C20H23N2O5 (M+H)+
371.1607 found 371.1616.
Appendix A. Supplementary data
Methyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4, 5,6,7,8-
hexahydroquinoline-3-carboxylate (compound 5l). A white solid;
IR (KBr) 3288, 2959, 1682, 1606, 1489, 1381, 1226, 1074, 1013,
. d 0.82 (s, 3H),
840, 776, 538 cmÀ1 1H NMR (400 MHz, DMSO-d6)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.09.005.
1.00 (s, 3H), 1.99 (d, J = 16.0 Hz, 1H), 2.19 (d, J = 16.0 Hz, 1H), 2.29
(m, 4H), 2.44 (d, J = 17.2 Hz, 1H), 3.52 (s, 3H, OCH3), 4.85 (s, 1H),
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C
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553 cmÀ1. 1H NMR (400 MHz, DMSO-d6)
d 0.80 (s, 3H), 1.00 (s, 3H),
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2.00 (d, J = 16.0 Hz, 1H), 2.20 (d, J = 16.0 Hz, 1H), 2.31 (m, 4H), 2.45
(d, J = 17.2 Hz, 1H), 3.51 (s, 3H, OCH3), 4.92 (s, 1H), 7.33 (d,
J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 9.22 (s, 1H, NH). 13C NMR
(50 MHz, DMSO-d6)
d 18.3, 26.4, 29.0, 32.1, 36.4, 50.0, 50.7, 102.1,
108.5, 109.1, 118.9, 128.3, 131.8, 146.2, 149.9, 152.6, 166.8, 194.1.
MS (ES) m/z 351.50 (M+1). HRMS (ESI) calculated for C21H23N2O3
(M+H)+ 351.1709 found 351.1705.
Methyl
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 5n).
white solid; IR (KBr) 3276, 2945, 1699, 1602, 1492, 1379, 1217,
1137, 1030, 858, 788, 768, 733, 657 cmÀ1 1H NMR (400 MHz,
DMSO-d6) 0.87 (s, 3H), 1.01 (s, 3H), 2.01 (d, J = 16.0 Hz, 1H), 2.20
4-(3,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-
A
.
d
(d, J = 16.0 Hz, 1H), 2.30 (m, 4H), 2.44 (d, J = 17.2 Hz, 1H), 3.55 (s,
3H, OCH3), 3.65 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 4.80 (s, 1H), 6.61
(d, J = 8.0 Hz, 1H), 6.77 (m, 2H), 9.04 (s, 1H, NH). 13C NMR (50 MHz,
DMSO-d6) d 18.2, 26.4, 29.2, 32.1, 34.9, 50.2, 50.6, 55.3, 55.4, 103.4,
110.0, 111.6, 118.9, 140.2, 144.8, 146.9, 148.01, 149.3, 167.3, 194.3.
MS (ES) m/z 386.50 (M+1). HRMS (ESI) calculated for C22H28NO5
(M+H)+ 386.1967 found 386.1971.
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2326.
Ethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydro-
quinoline-3-carboxylate (compound 5o). A yellow solid; IR (KBr)
3297, 2940, 1703, 1608, 1527, 1480, 1346, 1222, 1182, 1076, 718,
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680, 525 cmÀ1. 1H NMR (400 MHz, CDCl3)
d 1.19 (t, J = 7.2 Hz, 3H),
(b) H. Okazaki, M. Adachi, M. Ushio, U.S. Patent No. 4,895,822, January 23, 1990.;
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2.05–1.92 (m, 2H), 2.36–2.32 (m, 2H), 2.42 (s, 3H), 2.50–2.47 (m,
2H), 4.08 (q, J = 7.2 Hz, 2H), 5.18 (s, 1H), 6.06 (s, 1H, NH), 7.39 (m,
1H), 7.74 (d, J = 7.6 Hz, 1H), 7.99 (dd, J = 2.0 & 8.0 Hz, 1H), 8.09 (m,
1H). 13C NMR (50 MHz, CDCl3)
d 14.2, 19.2, 21.0, 27.2, 36.8, 60.0,
104.9, 112.22, 121.2, 122.8, 128.5, 134.7, 144.5, 148.2, 149.3, 150.8,
166.9, 195.8. MS (ES) m/z 357.50 (M+1). HRMS (ESI) calculated for
C
19H21N2O5 (M+H)+ 357.1450 found 357.1467.
(h) M. Elsheikh, U.S. Patent No. 4,827,055, March 7, 1988..
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Ethyl
4-(2-chloro-3-(trifluoromethyl)phenyl)-2-methyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3 carboxylate (compound 5p). A pale
yellow solid; IR (KBr) 3295, 2979, 1698, 1614, 1490, 1315, 1225,
1184, 1130, 977, 736, 697, 530 cmÀ1 1H NMR (400 MHz, CDCl3)
. d
1.16 (t, J = 7.2 Hz, 3H), 2.01–1.89 (m, 2H), 2.32–2.28 (m, 2H), 2.34
(s, 3H), 2.45–2.37 (m, 2H), 4.05 (q, J = 7.2 Hz, 2H), 5.51 (s, 1H), 6.00
(b) B.P. Bandgar, V.T. Kamble, Green Chem. 3 (2001) 265–266;
(c) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc. 129 (2007) 9844–9845;
(d) T. Hatakeyama, S. Hashimoto, K. Ishizuka, M. Nakamura, J. Am. Chem. Soc. 131
(2009) 11949–111963;
(e) X.L. Fang, R.Y. Tang, P. Zhong, J.H. Li, Synthesis (2009) 4183–4189;
(f) X.L. Fang, R.Y. Tang, P. Zhong, J.H. Li, Synthesis (2011) 1099–1105.