Proline-catalyzed simple and efficient synthesis of 1,8-dioxo- decahydroacridines in aqueous ethanol medium

Article abstract of DOI:10.1080/00397910802044306

Proline-catalyzed synthesis of 1,8-dioxo-decahydroacridines is achieved via one-pot, three-component condensation of aromatic aldehydes, cyclic diketone, and aryl amines in aqueous ethanol medium. This method offers the advantages of proceeding in neutral

Full text of DOI:10.1080/00397910802044306

This article was downloaded by: [University of Sussex Library]
On: 26 March 2013, At: 21:32
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Proline-Catalyzed Simple and
Efficient Synthesis of 1,8-
Dioxo-decahydroacridines in
Aqueous Ethanol Medium
K. Venkatesan a , Suresh S. Pujari a & Kumar V.
Srinivasan a
a Division of Organic Chemistry: Technology, National
Chemical Laboratory, Pune, India
Version of record first published: 22 Dec 2008.
To cite this article: K. Venkatesan , Suresh S. Pujari & Kumar V. Srinivasan (2008):
Proline-Catalyzed Simple and Efficient Synthesis of 1,8-Dioxo-decahydroacridines in
Aqueous Ethanol Medium, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:2, 228-241
To link to this article: http://dx.doi.org/10.1080/00397910802044306
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.

The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 39: 228–241, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802044306
Proline-Catalyzed Simple and Efficient Synthesis of
1,8-Dioxo-decahydroacridines in Aqueous
Ethanol Medium
K. Venkatesan, Suresh S. Pujari, and Kumar V. Srinivasan
Division of Organic Chemistry: Technology, National Chemical Laboratory,
Pune, India
Abstract: Proline-catalyzed synthesis of 1,8-dioxo-decahydroacridines is achi-
eved via one-pot, three-component condensation of aromatic aldehydes, cyclic
diketone, and aryl amines in aqueous ethanol medium. This method offers the
advantages of proceeding in neutral and mild conditions, giving high to excellent
yields of acridines with easy workup procedure.
Keywords: Aqueous media, 1,8-dioxodecahydroacridines, one-pot MCR, proline
INTRODUCTION
1,8-Dioxo-9-aryl-10-aryl-decahydroacridines and their derivatives are
polyfunctionalized 1,4-dihydropyridine derivatives. In recent years, 1,4-
dihydropyridines and their derivatives have attracted strong interest for
the treatment of cardiovascular diseases, such as angina pectoris[1] and
hypertension.[2] Acridine derivatives have been used to synthesize labeled
conjugates with medicinals, peptides, proteins, and nucleic acids[3–5] that
exhibit antitumor and DNA-binding properties. Multicomponent reac-
tions (MCRs) constitute an especially attractive synthetic strategy for
rapid and efficient library generation because the products are formed
in a single step and diversity can be achieved simply by varying the react-
ing components.[6] Thus, new routes utilizing a MCR protocol for the
Received January 16, 2008.
Address correspondence to Kumar V. Srinivasan, Division of Organic Chem-
istry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune, 411008, India. E-mail: kumarv.srinivasan@gmail.com
228

1,8-Dioxo-decahydroacridines
229
synthesis of these molecules can attract considerable attention in the
search for rapid-entry methods to these heterocycles.
The chemical industry is a major contributor to environmental pol-
lution. With increasing regulatory pressure focusing on organic solvents,
the development of nonhazardous alternatives is of great importance.[7]
Recently, organic reactions conducted in aqueous media have received
much attention[8] because water is nontoxic, cheap, abundantly available
and benign to the environment. Water not only increased the rate and the
yield of reaction but also enhanced enantioselectivity in chiral synthesis.[9]
The major drawbacks of using water as a solvent are its poor ability to
solubilize organic reactants and unsuitability for use with moisture-sensi-
tive organic compounds and catalysts. One of the more efficient and ver-
satile methods of increasing solubility, and one that does not require
modification of the solute, is use of an organic cosolvent. Some of
the most commonly used cosolvents are the lower alcohols, dimethyl
formamide (DMF), acetone, and acetonitrile. Proline is an abundant
bifunctional chiral molecule that is inexpensive and available in both
enantiomeric forms. The two functional groups (viz secondary NH and
COOH groups) act as acid or base and can also facilitate chemical trans-
formations in concert, similar to enzymatic catalysis.[10]
Reportedly, the conventional synthesis of acridines and their deriva-
tives has been performed in an organic solvent such as HOAc.[11]
Recently, few methodologies are reported in the literature for the syn-
thesis of decahydroacridines.[12] Each of these methods have limitations
such as poor yields, cumbersome workup procedure, and generation of
polluting effluents. Consequently, there is scope for further innovation
of methods with milder reaction conditions, short reaction times,
increase in variation of the substituents in the components, and better
yields in the synthesis of 1,8-dioxodecahydroacridines, which can poss-
ibly be achieved by choosing D,L-proline as a catalyst for this MCR.
As a part of our ongoing research efforts to develop more efficient
and simple methods in heterocycle synthesis, our investigations include
synthesis of quinolines,[13] dihydropyrimidones,[14] and trisubstituted
triazines.[15] Herein we report for the first time a facile synthesis of
1,8-dioxodecahydroacridines catalyzed by proline in an aqueous ethano-
lic medium as a step toward a clean and efficient synthesis of acridines
(Scheme 1).
To determine the scope of the designed novel protocol, a number of
commercially available aldehydes have condensed with cyclic ketones and
aryl amines under optimized reaction conditions, and the results are
summarized in Table 1. We investigated further the electronic effect of
different substituents present on the aldehyde component. We observed
that a wide range of aldehydes having both electron-donating and

230
K. Venkatesan, S. S. Pujari, and K. V. Srinivasan
Scheme 1. Synthesis of decahydroacridine derivatives in aqueous ethanolic
medium.
electron-withdrawing groups are equally facile for the reaction, resulting
in the formation of decahydroacridine derivatives in very good yields.
We also observed that various amines such as aniline, p-toludine,
benzyl amine, and p-isopropylaniline reacted smoothly under our con-
ditions. All the known and new compounds were well characterized by
1
melting point, IR, H NMR, 13C NMR, and elemental analyses. For
the known compounds, the values were in agreement with those reported
in literature. A plausible mechanistic pathway of this MCR is shown in
Scheme 2.
In conclusion, commercially available, inexpensive DL-proline has
proved to be a useful and novel catalyst for the synthesis of 1,8-dioxode-
cahydroacridines by the three-component coupling of aldehydes, amines,
and cyclic diketone under neutral aqueous alcoholic conditions. The
experimental procedure is simple and convenient, and the reaction con-
ditions are amenable to scale-up. This method provides easy access to
substituted decahydroacridines with diverse chemical structures. The cur-
rent methodology has the advantages of operational simplicity, neutral
reaction conditions, excellent yields of products, and the absence of toxic
effluents.
EXPERIMENTAL
All reactions requiring anhydrous conditions were performed under posi-
tive pressure of argon using oven-dried glassware (110 ꢀC), which was
cooled under argon. Melting points were recorded in open capillaries
using a Buchi melting-point B-540 apparatus. Thin-layer chromato-
¨
graphy (TLC) was carried out using aluminum sheets precoated with
silica gel 60F254 (Merck). All chemicals used were reagent grade, pro-
cured commercially and used without further purification. 1H NMR

231

232

233

234

1,8-Dioxo-decahydroacridines
235
Scheme 2. Plausible mechanistic pathway of the reaction.
and 13C NMR spectra were recorded on a Bruker Avance DPX 200
spectrometer using TMS as internal standard. Elemental analysis was
performed on a Flash EA 1112 Thermo Finnigan instrument.
General Procedure for the Synthesis of 1,8-Dioxo-decahydroacridines (4)
A mixture of aromatic aldehyde 1 (1 mmol), diketone 2 (2 mmol),
aromatic amine 3 (1 mmol), and proline (10 mol%) in 15 mL of ethanol
containing 3 mL of water was heated at 65 ꢀC for the appropriate time.
After completion of the reaction (as indicated by TLC), the volume of
the solution was reduced to half, and H2O (10 mL) was added and stir-
red for 30 min. The reaction mixture was extracted with ethyl acetate
(3 ꢁ 10 mL) and the organic solvent was separated, dried over Na2SO4,
and concentrated in vacuo to get the product as a residue. The resulting
crude product was recystallized from hot ethanol to afford acridines
(products) in very good isolated yields. The decahydroacridines thus
isolated were homogeneous on TLC and were pure enough for all prac-
tical purposes.

236
K. Venkatesan, S. S. Pujari, and K. V. Srinivasan
Characterization Data
3,4,6,7-Tetrahydro-9-phenyl-10-p-tolylacridine-1,8-(2H,5H,9H,
10H)dione (4a)
Recrystallized from EtOH. Off-white solid. IR (CHCl3, t): 3012, 2960,
2930, 2874, 1636, 1571, 1510, 1454, 1379, 1363, 1285, 1233, 1182, 1108,
816, 756, 700, 667 cmꢂ1. 1H NMR (200 MHz, CDCl3): d 1.64–1.83
(m, 4H), 1.99–2.28 (m, 8H), 2.37 (s, 3H), 5.31 (s, 3H), 7.01–7.36
(m, 9H). 13C NMR (200 MHz, CDCl3): d 20.9, 21.1, 28.2, 31.9, 36.7,
115.3, 125.8, 127.6, 128.1, 136.2, 139.4, 146.5, 151.8, 196.1. Anal. calcd.
for C26H25NO2: C, 81.43; H, 6.57; N, 3.65%. Found: C, 81.49; H,
6.51; N, 3.58%.
3,4,6,7-Tetrahydro-9-(2,5-dimethoxyphenyl)-10-p-tolylacridine-1,8-
(2H,5H,9H,10H)-dione (4b)
Recrystallized from EtOH. Pale yellow-colored solid. IR (CHCl3, t):
3017, 2952, 2930, 2833, 1635, 1572, 1510, 1454, 1377, 1363, 1236,
1216, 1183, 1108, 1019, 956, 756, 667 cmꢂ1. 1H NMR (200 MHz,
CDCl3): d 1.64–1.77 (m, 4H), 1.97–2.02 (m, 4H), 2.12–2.22 (m, 2H),
2.38 (s, 3H), 3.72 (s, 3H), 3.78 (s, 3H), 5.35 (s, 1H), 6.55–6.61
(m, 1H), 6.70–6.75 (m, 1H), 7.00–7.22 (m, 5H). 13C NMR
(200 MHz, CDCl3): d 21.2, 28.5, 30.7, 36.7, 55.5, 57.5, 112.1, 113.9,
114.7, 117.1, 135.9, 136.8, 139.2, 151.8, 153.4, 196.0 Anal. calcd. for
C28H29NO4: C, 75.82; H, 6.59; N, 3.16%. Found: C, 75.88; H, 6.52;
N, 3.25%.
3,4,6,7-Tetrahydro-9-(4-methoxyphenyl)-10-p-tolyl-acridine-1,8-
(2H,5H,9H,10H)-dione (4c)
Recrystallized from EtOH. Off-white solid. IR (CHCl3, t): 3015, 2956,
2936, 2873, 1635, 1571, 1509, 1455, 1362, 1287, 1216, 1182, 1108, 1034,
1
955, 858, 756, 667 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.69–1.81 (m,
4H), 1.98–2.11 (m, 4H), 2.18–2.28 (m, 4H), 2.38 (s, 3H), 3.68 (s, 3H),
5.24 (s, 1H), 6.71 (d, J ¼ 8.7 Hz, 2H), 7.04 (d, J ¼ 8.4 Hz, 2H), 7.20–
7.28 (m, 4H). 13C NMR (200 MHz, CDCl3): d 21.1, 28.2, 31.2, 36.7,
55.1, 113.5, 115.6, 128.7, 136.4, 139.1, 139.4, 151.5, 157.7, 196.2. Anal.
calcd. for C27H27NO3: C, 78.42; H, 6.58; N, 3.39%. Found: C, 78.49;
H, 6.64; N, 3.47%.

1,8-Dioxo-decahydroacridines
237
9-(2-Chlorophenyl)-3,4,6,7-tetrahydro-10-p-tolyl-acridine-
1,8(2H,5H,9H,10H)dione (4d)
Recrystallized from EtOH. Off-white solid. IR (CHCl3, t): 3017, 2960,
2930, 2875, 1636, 1567, 1511, 1470, 1361, 1288, 1216, 1183, 1135, 1080,
1034, 1002, 958, 858, 754, 667 cmꢂ1. 1H NMR (200 MHz, CDCl3): d
1.66–1.75 (m, 4H), 1.93–2.02 (m, 4H), 2.14–2.21 (m, 4H), 2.38 (s, 3H),
5.43 (s, 1H), 6.93–7.27 (m, 8H). 13C NMR (200 MHz, CDCl3): d 21.3,
28.5, 35.0, 36.7, 113.4, 126.1, 127.4, 134.0, 136.6, 139.5, 142.3, 152.7,
196.2. Anal. calcd. for C26H24ClNO2: C, 74.72; H, 5.79; Cl, 8.48; N,
3.35%. Found: C, 74.66; H, 5.73; Cl, 8.40; N, 3.41%.
4-(1,2,3,4,5,6,7,8,9,10-Decahydro-1,8-dioxo-10-p-tolylacridin-9-yl)-
benzonitrile (4e)
Recrystallized from EtOH. White solid. IR (CHCl3, t): 3014, 2950, 2930,
2227, 1637, 1571, 1509, 1452, 1364, 1283, 1216, 1182, 1135, 1073, 1016,
958, 856, 754, 667 cmꢂ1. 1H NMR (200 MHz, CDCl3): d 1.69–1.81
(m, 4H), 1.99–2.10 (m, 4H), 2.19–2.27 (m, 4H), 2.38 (s, 3H), 5.30 (s, 1H),
7.03 (d, J ¼ 8.3Hz, 2H), 7.24 (d, J ¼ 8.4 Hz, 2H), 7.45 (m, 4H). 13C NMR
(200 MHz, CDCl3): d 20.9, 28.2, 32.9, 36.6, 109.4, 114.3, 128.6, 132.0, 135.9,
139.8, 151.8, 152.4, 195.9. Anal. calcd. for C27H24N2O2: C, 79.39; H, 5.92; N,
6.86%. Found: C, 79.33; H, 5.97; N, 6.80%.
9-(3-Bromophenyl)-3,4,6,7-tetrahydro-10-p-tolyl-acridine-
1,8(2H,5H,9H,10H)dione (4f)
Recrystallized from EtOH. Off-white solid. IR (CHCl3, t): 3015, 2953,
2871, 1636, 1570, 1510, 1455, 1378, 1362, 1287, 1215, 1182, 1135, 1071,
1
1018, 956, 858, 759, 667 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.70–1.85
(m, 4H), 2.00–2.10 (m, 4H), 2.25–2.30 (m, 4H), 2.38 (s, 3H), 5.27 (s, 1H),
7.03–7.08 (m, 3H), 7.15–7.36 (m, 4H), 7.39–7.41 (m, 1H). 13C NMR
(200 MHz, CDCl3): d 21.0, 28.2, 32.0, 36.6, 114.9, 122.3, 126.8, 136.1,
139.6, 148.8, 152.1, 196.0. Anal. calcd. for C26H24BrNO2: C, 67.54; H,
5.23; Br, 17.28; N, 3.03%. Found: C, 67.49; H, 5.31; Br, 17.17; N, 3.11%.
9-(Furan-2-yl)-3,4,6,7-tetrahydro-10-p-tolylacridine-1,8-
(2H,5H,9H,10H)dione (4g)
Recrystallized from EtOH. Pale yellow-colored solid. IR (CHCl3, t):
3008, 2949, 2871, 1637, 1572, 1510, 1454, 1359, 1287, 1228, 1181, 1134,

238
K. Venkatesan, S. S. Pujari, and K. V. Srinivasan
1
1008, 955, 858, 754, 665 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.69–1.86
(m, 4H), 1.99–2.31 (m, 8H), 2.37 (s, 3H), 5.45 (s, 1H), 6.01 (d, J ¼ 3.2 Hz,
1H), 6.15–6.17 (m, 1H), 7.05–7.26 (m, 5H). 13C NMR (200 MHz, CDCl3):
d 20.9, 25.8, 28.0, 36.6, 104.5, 110.1, 112.1, 136.1, 139.4, 140.7, 152.9,
157.4, 195.9. Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75%.
Found: C, 77.25; H, 6.28; N, 3.69%.
3,4,6,7-Tetrahydro-9,10-di-p-tolylacridine-1,8-
(2H,5H,9H,10H)dione (4h)
Recrystallized from EtOH. Pale yellow-colored solid. IR (CHCl3, t):
3018, 2953, 2871, 1636, 1572, 1511, 1454, 1428, 1378, 1362, 1286, 1215,
1
1182, 1135, 1039, 955, 857, 755, 668 cmꢂ1. H NMR (200 MHz, CDCl3):
d 1.65–1.89 (m, 4H), 1.98–2.10 (m, 4H), 2.16–2.18 (m, 2H), 2.20 (s, 3H),
2.25–2.30 (m, 2H), 2.37 (s, 3H), 5.26 (s, 1H), 6.96–7.07 (m, 4H), 7.19–7.26
(m, 4H). 13C NMR (200 MHz, CDCl3): d 21.0, 28.2, 31.5, 36.7, 115.5,
127.6, 128.9, 135.0, 136.4, 139.4, 143.7, 151.6, 196.1. Anal. calcd. for
C27H27NO2: C, 81.58; H, 6.85; N, 3.52%. Found: C, 81.65; H, 6.79; N,
3.58%.
3,4,6,7-Tetrahydro-9-(pyridin-3-yl)-10-p-tolyl-acridine-1,8-
(2H,5H,9H,10H)dione (4i)
Recrystallized from EtOH. Pale yellow-colored solid. IR (CHCl3, t):
3017, 2959, 2874, 1637, 1574, 1510, 1427, 1379, 1362, 1286, 1182, 1134,
1
956, 756, 667 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.64–1.87 (m, 4H),
2.00–2.31 (m, 8H), 2.38 (s, 3H), 5.25 (s, 1H), 7.06–7.14 (m, 3H), 7.22–
7.28 (m, 2H), 7.77 (d, J ¼ 7.8 Hz, 1H), 8.26–8.29 (m, 1H), 8.47 (d,
J ¼ 1.9 Hz, 1H). 13C NMR (200 MHz, CDCl3): d 20.9, 28.1, 30.6, 36.5,
114.4, 123.0, 135.9, 136.3, 139.6, 142.0, 146.8, 148.7, 149.3, 152.3,
195.9. Anal. calcd. for C25H24N2O2: C, 78.10; H, 6.29; N, 7.29%. Found:
C, 78.03; H, 6.20; N, 7.37%.
3,4,6,7-Tetrahydro-9,10-diphenylacridine-1,8-
(2H,5H,9H,10H)dione (4l)
Recrystallized from EtOH. Off-white solid. IR (CHCl3, t): 3019, 2948,
2890, 1637, 1593, 1569, 1492, 1429, 1363, 1286, 1216, 1135, 1074, 955,
1
858, 756, 667 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.71–2.28 (m, 12H),
5.32 (s, 1H), 7.03–7.50 (m, 10H). 13C NMR (200 MHz, CDCl3): d 21.0,
28.2, 31.9, 36.7, 115.4, 125.9, 127.6, 128.1, 129.3, 138.9, 146.4, 151.6,

1,8-Dioxo-decahydroacridines
239
196.2. Anal. calcd. for C25H23NO2: C, 81.27; H, 6.27; N, 3.79%. Found:
C, 81.35; H, 6.20; N, 3.84%.
3,4,6,7-Tetrahydro-10-(4-isopropylphenyl)-9-phenyl-acridine-
1,8(2H,5H,9H,10H)-dione (4m)
Recrystallized from EtOH. Pale yellow-solid. IR (CHCl3, t): 3010, 2962,
2891, 1635, 1604, 1571, 1508, 1454, 1379, 1364, 1286, 1182, 1135, 1073,
1
1016, 956, 859, 755, 666 cmꢂ1. H NMR (200 MHz, CDCl3): d 1.22 (s,
3H), 1.26 (s, 3H), 1.71–1.82 (m, 4H), 1.99–2.28 (m, 8H), 2.87–3.00 (m,
1H), 5.31 (s, 1H), 7.04–7.37 (m, 9H). 13C NMR (200 MHz, CDCl3): d
21.0, 23.8, 28.2, 31.8, 33.7, 36.7, 115.3, 125.9, 127.6, 128.1, 136.5,
146.5, 150.2, 151.9, 196.1. Anal. calcd. for C28H29NO2: C, 81.72; H,
7.10; N, 3.40%. Found: C, 81.66; H, 7.18; N, 3.49%.
10-Benzyl-3,4,6,7-tetrahydro-9-phenylacridine-1,8-(2H,5H,9H,10H)
dione (4n)
Recrystallized from EtOH. Pale yellow-colored solid. IR (CHCl3, t):
3017, 2954, 2891, 1630, 1568, 1510, 1454, 1381, 1361, 1281, 1216, 1176,
1052, 956, 859, 756, 667 cmꢂ1. 1H NMR (200 MHz, CDCl3): d 1.87–
2.02 (m, 4H), 2.29–2.35 (m, 4H), 2.52–2.79 (m, 4H), 4.99 (s, 2H), 5.26
(s, 1H), 6.95–6.99 (m, 2H), 7.08–7.16 (m, 4H), 7.30–7.41 (m, 4H). 13C
NMR (200 MHz, CDCl3): d 20.3, 25.6, 29.7, 35.5, 47.7, 114.8, 124.4,
126.5, 127.6, 128.1, 134.0, 135.9, 142.2, 151.9, 194.8. Anal. calcd. for
C26H25NO2: C, 81.43; H, 6.57; N, 3.65%. Found: C, 81.34; H, 6.50; N,
3.73%.
ACKNOWLEDGMENT
K.V. thanks University Grants Commission, New Delhi, for providing a
research fellowship.
REFERENCES
1. Antman, E.; Muller, J.; Goldberg, S.; Macalpin, R.; Rubenfire, M.; Tabatz-
nik, B.; Liang, C.; Heupler, F.; Achuff, S.; Reichek, N.; Geltman, E.; Kerin,
N. Z.; Neff, R. K.; Raunwald, E. Nifedipine therapy for coronary-artery
spasm—Experience in 127 patients. N. Engl. J. Med. 1980, 302, 1269–1273.
2. (a) Guazzi, M.; Olivari, M.; Polese, A.; Fiorentini, C.; Margrini, F.; Moruzzi,
P. Nifedipine, a new antihypertensive with rapid action. Clin. Pharmacol.
Ther. 1977, 22, 528–532; (b) Hornung, R. S.; Gould, B. A.; Jones, R. I.;

240
K. Venkatesan, S. S. Pujari, and K. V. Srinivasan
Sonecha, T. N.; Raferty, E. B. Nifedipine tablets for systemic hypertension: A
study using continuous ambulatory intraarterial recording. Am. J. Cardiol.
1983, 51, 1323–1325.
3. Delfourne, E.; Roubin, C.; Bastide, J. The first synthesis of the pentacyclic
pyridoacridine marine alkaloids: Arnoamines A and B. J. Org. Chem.
2000, 65, 5476–5479.
4. Antonini, J.; Polucci, P.; Magnano, A.; Martelli, S. Synthesis, antitumor
cytotoxicity, and DNA binding of novel N-5,2-di(x-aminoalkyl)-2,6-
dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides. J. Med. Chem. 2001, 44,
3329–3333.
5. Ferlin, M. G.; Marzano, C.; Chiarelotto, G.; Baccichetti, F.; Bordin, F.
Synthesis and antiproliferative activity of some variously substituted acridine
and azacridine derivatives. Eur. J. Med. Chem. 2000, 827–837.
6. For MCR reviews, see (a) Weber, L. The application of multi-component
reactions in drug discovery. Curr. Med. Chem. 2002, 9, 2085–2093;
(b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T.A. Multiple-component condensation strategies for combinatorial library
synthesis. Acc. Chem. Res. 1996, 29, 123–131.
}
7. Lindstrom, U. M. Stereoselective organic reactions in water. Chem. Rev.
2002, 102, 2751–2772.
8. (a) Li, C. -J.; Chan, T. -H. Organic Reactions in Aqueous Media; Wiley: New
York, 1997; (b) Grieco, P. A. Organic Synthesis in Water; Blackie Academic
and Professional: London, 1998; (c) Li, C. -J. Organic reactions in aqueous
media—with a focus on carbon–carbon bond formations: A decade update.
Chem. Rev. 2005, 105, 3095–3165; (d) Kobayashi, S.; Manabe, K. Develop-
ment of novel lewis acid catalysts for selective organic reactions in aqueous
media. Acc. Chem. Res. 2002, 35, 209–217.
9. Ribe, S.; Wipf, P. Water-accelerated organic transformations. Chem. Commun.
2001, 299–307.
10. (a) List, B. Proline-catalyzed asymmetric reactions. Tetrahedron 2002, 58,
5573–5590, and references cited therein; (b) Enders, D.; Gasperi, T. Proline
organocatalysis as a new tool for the asymmetric synthesis of ulosonic acid
precursors. Chem. Commun. 2007, 88–90; (c) Notz, W.; Tanaka, F.; Barbas,
C. F. Enamine-based organocatalysis with proline and diamines: The
development of direct catalytic asymmetric aldol, Mannich, Michael, and
Diels–Alder reactions. Acc. Chem. Res. 2004, 37, 580–591.
11. (a) Martin, N.; Quinteiro, M.; Seoane, C.; Soto, L.; Mora, A.; Suarez, M.;
Ockoa, E.; Morals, A. Synthesis of conformational study of acridine deriva-
tives related to 1,4-dihydropyridines. J. Heterocyl. Chem. 1995, 32, 235–238;
(b) Suarez, M.; Loupy, A.; Salfran, E.; Moran, L.; Rolando, E. Synthesis of
decahydroacridines under microwaves using ammonium acetate supported
on alumina. Heterocycles 1999, 51, 21–27.
12. (a) Dabiri, M.; Baghbanzadeh, M.; Arzroomchilar, E. 1-Methylimidazolium
trifluoroacetate ([Hmim]TFA): An efficient reusable acidic ionic liquid for
the synthesis of 1,8-dioxo-octahydroxanthenes and 1,8-dioxodecahydroacri-
dines. Catal. Commun. 2008, 9, 939–942; (b) Das, B.; Thirupathi, P.;

1,8-Dioxo-decahydroacridines
241
Mahender, I.; Reddy, V. S.; Rao, Y. K. Amberlyst-15: An efficient reusable
heterogeneous catalyst for the synthesis of 1,8-dioxo-octahydroxanthenes
and 1,8-dioxo-decahydroacridines. J. Mol. Catal. A: Chem. 2006, 247,
233–239; (c) Jin, T. S.; Zhang, J. S.; Guo, T. T.; Wang, A. Q.; Li, T. S. One-
pot clean synthesis of 1,8-dioxo-decahydroacridines catalyzed by p-dodecyl-
benezenesulfonic acid in aqueous media. Synthesis 2004, 2001–2005; (d)
Wang, X. S.; Shi, D. Q.; Wang, S. H.; Tu, S. J. Synthesis of 9-aryl-10-
(4-methylphenyl)polyhydroacridine under microwave irradiation. Chin. J.
Org. Chem. 2003, 23, 1291–1293; (e) Schekotikhin, Y. M.; Getmanenko,
Y. A.; Nickolaeva, T. G.; Kriven’ko, A. P. Synthesis of 9-R1-10-R-1,8-
dioxodecahydroacridines and dioximes on their basis. Khim. Geterotsikl.
Soedin. 2001, 10, 1344–1349.
13. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Ionic liquid-promoted regiospecific friedlander annulation: Novel synthesis
of quinolines and fused polycyclic quinolines. J. Org. Chem. 2003, 68,
9371–9378.
14. Gholap, A. R.; Venkatesan, K.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Ionic liquid–promoted novel and efficient one pot synthesis of 3,4-dihydro-
pyrimidin-2-(1H)-ones at ambient temperature under ultrasound irradiation.
Green Chem. 2004, 3, 147–150.
15. Potewar, T. M.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Efficient synthesis
of 3,5,6-trisubstituted-1,2,4-triazines in the Brønsted acidic ionic liquid,
1-n-butylimidazolium tetrafluoroborate ([Hbim]BF4). Synth. Commun.
2007, 37, 261–269.