Sulfonic acid–functionalized Wang resin (Wang-OSO3H) as polymeric acidic catalyst for the ecofriendly multicomponent synthesis of polyhydroquinolines via Hantzsch condensation

Article abstract of DOI:10.1080/00397911.2016.1213850

An efficient and green approach has been developed for the synthesis of polyhydroquinoline derivatives via Hantzsch condensation reaction directly from corresponding substituted aromatic and aliphatic aldehydes, β-keto compounds, active methylene compound

Full text of DOI:10.1080/00397911.2016.1213850

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Sulphonic Acid Functionalized Wang Resin (Wang-
OSO H) as Polymeric Acidic Catalyst for the
3
Eco-Friendly Multi-Component Synthesis of
Polyhydroquinolines via Hantzsch Condensation
A. V. Dhanunjaya Rao, Surasani, B. P. Vykunteswararao, T. Bhaskarkumar,
B. Srikanth, Nivrutti R. Jogdand, Dipak Kalita, Jaydeep kumar D. Lilakar,
Vidavalur Siddaiah, Paul Douglas Sanasi & Akula Raghunadh
To cite this article: A. V. Dhanunjaya Rao, Surasani, B. P. Vykunteswararao, T. Bhaskarkumar,
B. Srikanth, Nivrutti R. Jogdand, Dipak Kalita, Jaydeep kumar D. Lilakar, Vidavalur Siddaiah,
Paul Douglas Sanasi & Akula Raghunadh (2016): Sulphonic Acid Functionalized Wang Resin
(
Wang-OSO H) as Polymeric Acidic Catalyst for the Eco-Friendly Multi-Component Synthesis
3
of Polyhydroquinolines via Hantzsch Condensation, Synthetic Communications, DOI:
0.1080/00397911.2016.1213850
1
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1213850
Accepted author version posted online: 22
Jul 2016.
Published online: 22 Jul 2016.
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Date: 02 August 2016, At: 12:46

3
Sulphonic acid functionalized Wang resin (Wang-OSO H) as polymeric acidic
catalyst for the eco-friendly multi-component synthesis of polyhydroquinolines via
Hantzsch condensation
1
,2
1
1
1
A. V. Dhanunjaya Rao , Surasani , B. P. Vykunteswararao , T. Bhaskarkumar , B.
1
1
1
3
Srikanth , Nivrutti R. Jogdand , Dipak Kalita , Jaydeep kumar D. Lilakar , Vidavalur
2
4
1
Siddaiah , Paul Douglas Sanasi , Akula Raghunadh
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s
1
2
Laboratories Ltd, Hyderabad, India, Department of Organic Chemistry, Foods, Drugs
3
and Water, Andhra University, Visakhapatnam, India, Research & Development,
Bachupally, Dr. Reddy’s Laboratories Ltd, Hyderabad, India, Department Of
4
Engineering Chemistry, College Of Engineering, Andhra University, Visakhapatnam,
India
Corresponding author: E-mail: dhanunjayaraoav@drreddys.com
Abstract
An efficient and green approach has been developed for the synthesis of
polyhydroquinoline derivatives via Hantzsch condensation reaction directly from
corresponding substituted aromatic and aliphatic aldehyde, β-keto compounds, active
methylene compounds and ammonium chloride using recyclable polymer supported
sulphonic acid catalyst under aqueous conditions. Environmental acceptability,
operational simplicity, low cost, excellent functional group compatibility and high yields
are the important features of this protocol.
GRAPHICAL ABSTRACT
1

KEYWORDS: Reusable catalyst, Wang-SO
3
H, polyhydroquinoline derivatives,
Hantzsch condensation, water, green chemistry
INTRODUCTION
,4-dihydropyridyl (DHP) skeletons constitute a class of synthetic compounds
1
that have pharmaceutical activities, clinical applications and their significant biological
1
activities. Some representative examples of drug molecules having 1,4-dihydropyridyl
(DHP) skeleton are given in Figure 1 which are effective for the treatment of
2
hypertension. Particularly, 4-substituteted 1,4-dihydropyridines (1,4-DHPs) are well
2
+
known as Ca channel blockers and have emerged as one of the most important class of
3
drugs for the treatment of cardiovascular diseases and the heterocyclic rings are found in
a variety of bioactive compounds such as bronchodilator, antiatherosclerotic, antitumour,
4
vasodilator, antidiabetic, geroprotective, and heptaprotective activity. More studies
indicate that these compounds exhibit different medical functions, acting as
neuroprotectants, platelet antiaggregators, cerebral antiischemic agents, and
5
chemosensitizers. Despite their importance from a pharmacological, industrial and
synthetic point of view chemists have attracted the attention to synthesize
polyhydroquinoline compounds.
In the past decade, a variety of synthetic methods have been employed for the
preparation of functionalized 1,4-DHPs ( 1,4-Dihydropyridines) and the level of interest
in the current domain is clearly shown by the number of publications. Recently, a number
of classical methods for the synthesis of 1,4-DHPs ( 1,4-Dihydropyridines) have been
2

reported in the literature involving the cyclo condensation with aldehydes, β-ketoesters,
and ammonia either acetic acid or refluxing in alcohol for a longer time. However, the
yields of 1,4-Dihydropyridines obtained by the Hantzsch method are generally poor. In
recent years, several new methods have been reported for the synthesis of 1,4-
6
Dihydropyridines. In the presence of various catalysts like including the use of grinding ,
7
8,9
+
10
11
thermal energy , ionic liquids Bu
4
N HSO
4
, in situ generated HCl,
1
2
13
14,15
16
K
7
[PW11CoO40], I
2
, silica-supported acids,
4 2
silica perchloric acid (HClO –SiO ),
1
7
18
19
20
21
3
TMSCl-NaI, Sc(OTf) , HY-Zeolite, montmorillonite K-10, p-TSA , microwave,
2
2,23
24
25
26
ultra sound
, 3-nitrophenylboronic acid , L-Proline , morpholine , SBA-Pr-
27
28
SO
3
H, silica-supported super Para magnetic Fe
3
O
4
nanoparticle, Fe
3
O
4
/SiO
2
–
2
9
30
31
OSO
3
3 4 3 3
H, Fe O /cellulose-OSO H, and FeF . However, the above mentioned methods
have been associated with different drawbacks such as the use of hazardous organic
solvents, low yields, strongly acidic conditions, expensive moisture sensitive catalysts, or
tedious work-up conditions. Therefore, it is necessary to develop an efficient and
versatile method for the preparation of 1, 4-Dihydropyridines.
In spite of the efficiency of homogeneous acidic catalysts, their use is associated
with generation of unwanted waste and with the corrosion of process equipment. In
contrast, the use of heterogeneous acid catalysis often benefits from a substantial process
improvement including greater catalyst stability, recovery & regeneration and enhanced
process selectivity.
3

The researchers continue for finding a better catalyst for the synthesis of
polyhydroquinoline compounds in terms of operational simplicity, economic viability,
and greater selectivity.
The objective of the present study was the development of a novel heterogeneous
catalyst for efficient preparation of polyhydroquinoline compounds. A new Sulfonic acid
3
functionalized resin (Wang-SO H) catalyst is an efficient, green, inexpensive, reusable,
32
and polymeric heterogeneous solid acid catalyst which can easily be handled and
removed from the reaction mixture by simple filtration.
3
2
Wang resin is most often used for the attachment of organic and inorganic acids.
In particular, treatment of Wang resin with chlorosulfonic acid in the presence of N,N-
33
diisopropylethylamine (DIPEA) results in the formation of a monosulfate ester. (Wang-
OSO H, Scheme 1).
3
In this work, we report an efficient procedure for the preparation of synthesis of
polyhydroquinoline derivatives from four components through a reaction between
variously substituted aromatic and aliphatic aldehydes, β-keto compound, alkyl
acetoacetate, ammonium chloride under thermal condition in the presence of Wang-
3
4, 35
OSO
3
H as an efficient, green, inexpensive, reusable, and polymeric catalyst
. It is
pertinent to mention that this is the first report on the synthesis of polyhydroquinoline
derivatives installing Wang-OSO
3
H catalyzed protocol in aqueous media (Scheme 2).
4

This process not only increases the yield of the product but also reduce the number of
laboratory operations along with the quantities of solvents and chemicals used.
We found that β-keto compound, alkyl acetoacetate; ammonium chloride readily reacts
with a variety of aldehydes 2a-2q under the catalysis with Wang-OSO
polyhydroquinoline derivatives 5a-5q.
3
H resin to form
RESULTS & DISCUSSION
The reaction conditions were optimized with respect to the quantity of catalyst (Table
) , the solvent (Table 2), study of reusability (Table 3), comparison activity of different
1
catalysts (Table 4) and reaction with different amines (Table 5) by studying the
condensation of Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0 mmol),
Dimedone (1.0 mmol) and ammonium chloride (1.0 mmol) and resin bound Wang-
3
SO H (10 %w/w) with respect to aldehyde in water at reflux conditions. The highest
isolated yields of compound 5a were obtained by carrying out the process in water at
reflux temperature for 1.0-1.6 hr.
To explore the effect of solvent on the model reaction, various solvents such as DMSO,
DMF, 1,4-dioxane, ethanol, DCM, acetonitrile, methanol, toluene and water were tested
3
at their respective reflux temperatures using 10 % w/w of Wang-OSO H with respect to
aldehyde (Table 2, entries 1–9). Among the solvents tested, none of them could match
the efficiency of the water as a solvent which was found superior over the other solvents
in terms of both product yield and reaction time (Table 2, entry 9). Water is obviously
5

the first choice of an alternative solvent. Water is clean, non-toxic, inexpensive, and the
most environmentally.
3
The recovery and reuse of Wang-OSO H were examined in the reaction of 3-
Nitrobenzaldehyde (1.0 mmol), Dimedone (1.0 mmol), ammonium chloride (1.0 mmol)
in water at 100 °C. When the reaction was completed, methanol was added to the reaction
mixture and the catalyst was recovered by filtration.
The recovered catalyst was washed with methanol, water and then acetone, dried under
vacuum and reused for several times without significant loss of activity. It was found that
the catalytic activities and pH of the subsequent reaction mass of the recovered catalyst
were almost the same as that of fresh catalyst over four runs (Table 3, entries 1–5).
The experimental details captured in the table (Table 4, entries 1-12) clearly indicates
that the yields obtained in the optimized reaction conditions using Dowex 50 and
3
Amberlyst 15 are low compared to resin bound Wang-SO H. Of course, the product
formation is minimal without catalyst. Previously, various catalysts reported for similar
type of reactions, wherein the reaction time was more or the process involved organic
solvents or lower yields. The present catalyst is capable of catalyzing the four component
reaction carried under aqueous conditions. Obviously, water would be the first choice of
an alternative for any solvent since it is clean, non-toxic, inexpensive, and eco-friendly.
6

From Table 5, one can see that the reaction yields of ammonium compounds (Table 5,
entry 1 entry 2 and entry 3) are higher than for aromatic amines (Table 5, entry 4 and 5).
This is probably due to the lower solubility of the aromatic amines in water and lower
reactivity than that of the ammonium compounds. The increasing of the dosage of
ammonium compound is because of the easy resolvability. (Scheme 3)
The scope and the utility of the suggested synthetic protocol was demonstrated by
reacting compound 2 (2a-2q, Table 6) with a wide variety of aliphatic, aromatic and
heteroaromatic aldehydes to result in the target polyhydroquinoline derivatives 5 (5a-5q,
Table 6) in invariably high yields (85-96%).
3
We propose a mechanism for the Wang-SO H catalyzed synthesis of
4
0
polyhydroquinolines (Scheme 4). Polyhydroquinoline derivatives 5 may be formed
acid-catalyzed cyclocondensation of intermediates I and II, generated respectively by
Knoevenagel condensation of one equivalent of dimedone with aldehyde and reaction
with one equivalent of ethyl acetoacetate with ammonia generated from ammonium
chloride (Scheme 4).
EXPERIMENTAL
General methods: Unless stated otherwise, reactions were performed under nitrogen
atmosphere using oven dried glassware. Reactions were monitored by thin layer
chromatography (TLC) on silica gel plates (60 F254), visualizing with ultraviolet light or
iodine spray. Flash chromatography was performed on silica gel (100-200 mesh) using
7

1
13
distilled hexane, ethyl acetate, dichloromethane. H NMR and C NMR spectra were
determined in CDCl or DMSO-d solution by using 400 or 100 MHz spectrometers,
3
6
respectively. Proton chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.00)
as internal standard and expressed in ppm. 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. Melting points were determined using melting point B-540 apparatus and
are uncorrected. HRMS was determined using waters LCT premier XETOF ARE-047
apparatus.
Typical Experimental Procedure For The Synthesis Of Hantzsch
Polyhydroquinoline Derivatives (5) Under Aqueous Medium
In a typical experimental procedure, dimedone 1 (1 mmol), aldehyde 2 (1 mmol),
acetoacetate ester 3 (1 mmol), ammonium chloride 4 (1 mmol) was dissolved in 10 ml of
3
water and Wang-OSO H (10% w/w) with respect to aldehyde was added and the reaction
slowly heated to reflux under stirring. Stirring was continued in for the stipulated period
of time (5a-5q, Table 6). The progress of the reaction was monitored with TLC. After
completion of the reaction, the reaction mixture was cooled diluted with 10volumes
methanol to dissolve the precipitated product and the catalyst was removed simply by
filtration. The residual catalyst was repeatedly washed with methanol (3 * 5 volumes).
The combined filtrate and washings, on evaporation, gave the crude product. The pure
product was obtained through crystallization from ethanol.
Analytical Data For Selected Compounds:
8

Ethyl 2, 7, 7-Trimethyl-5-Oxo-4-Phenyl-1, 4, 5, 6, 7, 8-Hexahydroquinoline-3-
Carboxylate, 5a
3
1
1
Off white solid; mp: 203-206 ºC (lit. 203-204 ºC); H NMR (400 MHz, DMSO-d
6
) δ :
), 1.99-1.95 (m,
H, CH), 2.14-2.11 (m, 1H, CH), 2.30-2.26 (m, 1H, CH), 2.28 (s, 3H, =C-CH ), 2.49-
.43 (m, 1H, CH), 3.99-3.94 (q, J = 8.00 Hz, 2H, CH ), 4.85 (s, 1H, CH), 7.04 (d, J = 7.2
0
1
2
3 3 3
.84 (s, 3H, CH ), 0.96 (s, 3H, CH ), 1.14-1.10 (t, J = 8.00 Hz, 3H, CH
3
2
13
Hz, 1H, H-Ar), 7.19-7.05 (m, 4H, H-Ar), 9.04 (br s, 1H, NH). C NMR (100 MHz,
DMSO-d );δ14.14, 18.30, 26.43, 29.15, 32.15 (2C), 35.84, 50.23, 59.03, 103.59, 109.96,
25.69, 127.47 (2C), 127.73 (2C), 145.01, 147.66, 149.52, 166.84, 194.27, HRMS (ESI):
6
1
+
3
Anal.calcd for C21H26NO (M+H) 340.1913, Found 340.1912.
Ethyl 2, 7, 7-Trimethyl-4-(Naphthalen-2-Yl)-5-Oxo-1, 4, 5, 6, 7, 8-
Hexahydroquinoline-3-Carboxylate, 5b
1
Light yellow solid; mp: 233-236 ºC; H NMR (400 MHz, DMSO-d
6
) δ: 0.83 (s, 3H,
), 1.98-1.93 (m, 1H, CH),
), 2.34-2.32 (m, 1H, CH),2.47-2.43 (m, 1H,
), 5.03 (s, 1H,CH), 7.44-7.37 (m, 3H, H-Ar), 7.58
CH
.20-2.16 (m, 1H, CH), 2.30 (s, 3H, =C-CH
CH), 3.99-3.94 (q, J = 6.8 Hz, 2H, CH
3 3 3
), 1.01 (s, 3H, CH ), 1.13-1.10 (t, J = 6.8 Hz, 3H, CH
2
3
2
13
(
s, 1H, H-Ar), 7.79-7.72 (m, 3H, H-Ar ), 9.10 (br s, 1H, NH). C NMR (100 MHz,
DMSO-d
6
) δ: 194.3, 166.85, 149.7, 145.2, 145.0, 132.7, 131.6, 127.6, 127.3, 127.2,
1
1
26.7, 125.7, 125.3, 125.1, 109.7, 130.4, 59.0, 50.2, 36.2, 32.1(2C), 29.1, 26.3, 18.3,
+
3
4.1; HRMS (ESI): Anal.calcd for C25H28NO (M+H) 390.2069, Found 390.2069.
9

Ethyl 4-Isobutyl-2, 7, 7-Trimethyl-5-Oxo-1, 4, 5, 6, 7, 8-Hexahydroquinoline-3-
Carboxylate, 5c
1
Off white solid; mp: 172-174 ºC ; H NMR (400 MHz, DMSO-d
6
): δ 0.79-0.77 (d, J =
), 1.01-1.00 (m, 6H,
), 1.39-1.33 (m, 1H, CH), 2.13-2.07 (m, 1H,
), 2.33-2.24 (m, 1H, CH), 3.82-3.79
8
2
.0 Hz, 3H, CH
3 3 3
), 0.84-0.83 (d, 3H, CH ), 0.98-0.96 (s, 3H, CH
CH ), 1.22-1.18 (t, J = 8.0 Hz, 3H, CH
3
3
CH), 2.20-2.16 (m, 1H, CH), 2.21 (s, 3H, =C-CH
3
13
(t, J = 8.0 Hz, 1H, CH), 4.09-4.02 (q, J = 8.0 Hz, 2H, CH
2
), 8.93 (br s, 1H, NH). C
NMR (100 MHz, DMSO-d
6
): δ 194.6, 167.1, 150.2, 145.3, 110.1, 103.9, 58.9, 50.4, 46.9,
4
0.1, 31.9, 29.4, 26.8, 26.0, 23.5, 23.3, 22.8, 18.1, 14.2; HRMS (ESI): Anal.calcd for
+
C
19 3
H30NO (M+H) 320.2226, Found 320.2235
CONCLUSION
In conclusion, we have reported a highly efficient and ecofriendly method for the
synthesis of novel polyhydroquinoline derivatives products with good yield using resin
bound Wang sulfonic acid as an inexpensive, biodegradable and recyclable catalyst. In
this reaction Wang sulfonic acid act as a very efficient “green” promoter and prominent
advantages of this method are broad scope, operational simplicity, practicability,
economic viability, good yield of the products in shorter reaction time, easy work-up, and
reusability of the catalyst.
ACKNOWLEDGMENTS:
The authors would like to thank Dr. Vilas Dahanukar, Dr. Upadhya Timmana, Dr. H.
Rama Mohan, and the analytical group of CPS-DRL for spectral data. Mr A.V.D. Rao
thanks the CPS-DRL, Hyderabad, India for his encouragement.
1
0

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7
62-765
1
3

3
3. Preparation of Wang-OSO
3 3
H: Wang-OSO H was prepared by adding freshly
distilled ClSO H (2.0 mmol) to wang resin (1.0 mmol), DIPEA (5.0 mmol) in DCM (10
3
volumes) and the resulting solution was stirred at 25-35 °C for 2 hr. The reaction mass
was filtered and washed with DMF (5 x 10 volumes), DCM (5 x 10 volumes) and
0
Isopropanol (5 x 10 volumes) and the wang catalyst was dried at 130 C for 3 hr.
3
4. (a) Widdecke, H. Hogde, S. P. (Eds.), Synthesis and Separations Using Functional
Polymers, Wiley, New York, 1998, p. 149; (b) Harland, C. E. Ion Exchange, 2nd ed.,
Royal Society of Chemistry, London, 1994; (c) Corma, A. Chem. Rev. 1995, 95, 559; (d)
Clark, J. H.; Macqquarrie, D. J. Chem. Soc. Rev. 1996, 25, 310; (e) Harmer, M. A.; Sun,
Q. Appl. Catal. A . 2001, 221, 45; (f) Chakraborthy, A.; Sharma, M. M. React. Funct.
Polym. 1993, 20, 1. (g) Gogoi, P. Synlett 2005, 14, 2263. (h) Meziani, M. J.; Zajac, J.;
Jones, D. J.; Partyka, S.; Roziere, J.; Auroux, A. Langmuir 2000, 16, 2262; (i) Brunel,
D.; Blanc, A. C.; Galarneau, A.; Fajula, F. Catal. Today, 2002, 73, 139.
3
5. (a) Olah, G. A. Iyer, P. S.; Suryaprakash, G. K. Synthesis, 1986, 513; (b) Sandmacher,
K.; Kunne, H.; Kunz, H. Chem. Eng. Technol. 1998, 21, 6; (c) Harmer, M. A. Sun, Q.;
Farneth, W. E. J. Am. Chem. Soc. 1996, 118, 7708; (d) Harmer, M. A. Sun, Q.; Farneth,
W. E. Adv. Mater. 1998, 10, 1255; (e) Harmer, M. A.; Sun, Q.; Vega, A. J.; Farneth, W.
E.; Heidekum, A.; Hoeldrich, W. F. Green Chem. 2000, 2, 7.
3
3
6. Safari. J, Banitaba. S. H.; Khalili S. D, J. Mol. Catal. A: Chem., 2011, 335, 46–50.
7. Debache. A.; Ghalem. W.; Boulcina. R.; Belfaitah A.; Rhouati S.; Carboni. B,
Tetrahedron Lett., 2009, 50, 5248–5250.
3
3
8. Antonyraj C. A.; Kannan. S.; Appl. Catal., A, 2008, 338, 121–129.
9. Adharvana Chari. M.; Syamasundar. K.; Catal. Commun., 2005, 6, 624–626.
1
4

4
2
0. Raman Gupta.; Rajive Gupta.; Satya Paul.; Andre Loupy. Synthesis, 2007, 18, 2835–
838.
1
5

a
Table 1. Optimization of catalyst loading
b
Entry
1
Catalyst (% w/w)
No Resin
Time (hr)
4.0
Yield (%)
20
2
3
4
5
1.3
1.2
1.0
1.0
88
92
91
91
10
15
20
5
a
Reaction and conditions: Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0
mmol), Dimedone (1.0 mmol), Ammonium chloride (1.0 mmol) and resin bound Wang-
b
SO
3
H (10 %w/w) in water at 100 °C. Yield refers to pure products after crystallization.
1
6

a
Table 2. Screening of solvents .
b
Entry
Solvent (Temp. °C)
Time (hr)
1.5
Yield (%)
1
2
3
4
5
6
7
8
DMSO (100)
DMF (100)
65
60
68
85
75
82
70
60
92
1.5
1,4-Dioxane (100)
Ethanol (78)
DCM (38)
2.0
1.0
1.0
Acetonitrile (80)
Methanol (64)
Toluene (110)
Water (100)
3.0
2.5
3.0
9
1.2
a
Reaction and conditions: Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0
mmol), Dimedone (1.0 mmol), ammonium chloride (1.0 mmol) and resin bound Wang-
b
SO
3
H (10 %w/w) wrt aldehyde in solvent at respective temperature. Yield refers to pure
products after crystallization.
1
7

a
Table 3. Recyclability of the catalyst
b
Entry
Cycle
Time (hr)
Yield (%)
pH of the reaction
mass
2.3
1
2
3
4
Fresh
1.2
1.3
1.3
1.5
1.6
92
92
91
90
89
1
2
3
4
2.3
2.4
2.5
5
2.5
a
Reaction and conditions: Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0
mmol), Dimedone (1.0 mmol), ammonium chloride (1.0 mmol) and resin bound Wang-
b
SO
3
H (10 %w/w) in water at 100 °C. Yield refers to pure products after crystallization.
1
8

a
Table 4. synthesis of polyhydroquinoline derivatives in the presence of various catalysts
b
Entry catalyst
solvent
Temp.
Time
(hr)
5.0
1.2
4.0
5.5
2-5
5.0
6.5
5-8
4.0
3.0
0.5
6.0
Yield
Lit. Ref.
0
(
C)
(%)
1
2
3
4
5
6
7
8
9
1
1
No catalyst
Wang-SO
Dowex 50
H
H
H
H
H
2
2
2
2
2
O
O
O
O
O
Reflux
Reflux
Traces
85-96
78
Present work
3
H
Present work
Reflux
Present work
Amberlyst 15
Reflux
72
Present work
Cellulose sulfuric acid
Reflux
78-92
72
36
37
38
39
28
28
28
31
PPh
MgAl
NaHSO
3
C
2
H
5
OH Reflux
CN 25-35
CN 25-35
2
/hydrotalcites
CH
CH
3
3
32-75
75-90
60
4
/SiO
2
Fe
Fe
Fe
3
O
O
O
4
/SiO
4
/SiO
4
/SiO
2
2
2
C
2
2
2
H
H
H
5
5
5
OH 25-35
OH 25-35
OH 25-35
Reflux
0
1
2
3
/PPh
3
3
C
70
3
/PPh
/[CrO
3
Br] C
87-96
28
1
PTSA
2
H O
a
Reaction and conditions: Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0
mmol), Dimedone (1.0 mmol), ammonium chloride (1.0 mmol) and resin bound Wang-
b
SO3H (10 %w/w) in water at 100 °C. Yield refers to pure products after crystallization
1
9

a
Table 5. Reaction time and yield for the reaction of different amines/ammonium salts
b
Entry Amine
6a-e)
Time Product Product (R) Yield (%)
(
(hr)
1.5
1.2
1.3
2.0
2.5
(7a-e)
H
1
2
3
4
NH
NH
NH
4
4
4
OAc
7a
7b
7c
7d
7e
90
92
91
78
69
Cl
H
HCO
3
H
C
6
H
5
NH
2
6 5
C H
5
2-CH -C
3
6
H
5
-NH
2
3 6 5
2-CH -C H
a
Reaction and conditions: Ethyl acetoacetate (1.0 mmol), 3-Nitrobenzaldehyde (1.0
mmol), Dimedone (1.0 mmol), Amine (1.0 mmol) and resin bound Wang-SO3H (10
b
%
w/w) in water at 100 °C. Yields refers to pure products after crystallization.
2
0

a
Table 6. Wang-OSO
3
H catalyzed synthesis of polyhydroquinoline derivatives
1
2
3
Entr Aldehyde (R) (2a-
R
R
R
Prod Tim Yiel M.P. (°C)
b
y
q)
uct
e
d
Observe Reported
d
(5a-
(hr) (%)
1.2 96
1.3 94
q)
3
1
1
2
3
4
5
6
7
Benzaldehyde, 2a CH CH C
2
2
2
2
H 5a
203-206 203-204
3
3
5
2-Napthaldehyde, CH CH C
H 5b
H 5c
H 5d
233-236
…
2
b
3
3
5
Isovaleraldehyde, CH CH C
1.3 85* 172-174 ….
2
c
3
3
5
Furfural, 2d
CH CH C
1.2 90* 245-247
…
3
3
5
3
1
3
1
3
1
4-Nitro
CH CH CH
3
3
5e
5f
1.1 90
1.3 90
1.2 89
251-253 252-254
223-225 220-222
166-168 167-169
benzaldehyde, 2e
4-Cyano
3
3
CH CH CH
benzaldehyde, 2f
5-Hydroxy-2–
Nitro
3
3
2
CH CH C H 5g
3
3
5
benzaldehyde, 2g
4-Chloro
1
1
3
6
8
9
CH CH CH
3
5h
1.3 91
1.2 92
221-224 221-223
175-178 177-178
bezaldehyde, 2h
3-
3
3
2
CH CH C H 5i
2
1

Nitrobezaldehyde,
3
3
5
2
i
1
1
3
6
3
1
1
1
1
0
1
2
3,4-Dimethoxy
benzaldehyde, 2j
4-Methoxy
CH CH C
2
2
2
H 5j
H 5k
H 5l
1.3 90
1.3 93
1.4 93
197-201 198-199
254-256 256-257
203-205 204-206
3
3
5
CH CH C
benzaldehyde, 2k
3-
3
3
5
H
H
C
Nitrobezaldehyde,
5
2
l
3
3
1
1
1
1
3
4
3,4-Dimethoxy
benzaldehyde, 2m
4-
CH CH CH
3
5m
1.3 94
1.3 90
208-210 209-211
188-191 188-190
3
3
2
CH CH C H 5n
(Trifluoromethyl)
3
3
5
benzaldehyde, 2n
4-Cyano
3
1
1
3
1
1
5
6
CH CH C
2
H 5o
H 5p
1.3 93
1.5 94
141-143 140-142
231-233 232-234
Benzaldehyde, 2o
4-
3
3
5
CH CH C
2
Chlorobenzaldehy
de, 2p
3
3
5
1
6
1
7
4-
2
CH CH C H 5q
1.6 95
243-245 242-244
Nitrobezaldehyde,
3
3
5
2
q
2
2

a
0
3
All reactions were carried out in water at 100 C using catalyst Wang-SO H(10 %w/w)
wrt aldehyde.
b
Yields refer to pure products after crystallization.
*
Yields refer to pure products after column purification.
2
3

3
Scheme 1. Preparation of Wang-OSO H.
2
4

3
Scheme 2. Wang-SO H mediated synthesis of polyhydroquinoline derivatives.
2
5

3
Scheme 3. Wang-SO H mediated synthesis of polyhydroquinoline.
2
6

Scheme 4. Proposed mechanism for polyhydroquinoline derivatives catalyzed by Wang
sulfonic acid.
2
7

Figure 1. Structures of some biologically active natural products containing a 1,4-
dihydropyridyl (DHP).
2
8