Solvent-free neat synthetic route to tetrahydroacridinones

Article abstract of DOI:10.1002/hc.20080

An environmentally benign approach for the synthesis of acridines using inorganic solid supports and "neat reaction" technology is described. These methodologies completely eliminate the use of solvent during the course of reaction. Moreover, microwave-assisted reactions reduce the reaction time from hours to minutes with improved yield.

Full text of DOI:10.1002/hc.20080

Heteroatom Chemistry
Volume 16, Number 2, 2005
Solvent-Free Neat Synthetic Route
to Tetrahydroacridinones
M. Kidwai and S. Rastogi
Department of Chemistry, University of Delhi, Delhi 110007, India
Received 7 June 2004; revised 15 October 2004
show marked positive inotropic effect [14]. An es-
ABSTRACT: An environmentally benign approach
for the synthesis of acridines using inorganic solid
supports and “neat reaction” technology is described.
These methodologies completely eliminate the use
of solvent during the course of reaction. More-
over, microwave-assisted reactions reduce the reac-
tion time from hours to minutes with improved
sential prerequisite for the therapeutic application
prompted us to undertake the title investigation.
We herein report a method that allows the
rapid, facile synthesis of acridines-related structures
and does not rely on the conventional procedure
[15]. Instead, our procedure involves a microwave-
promoted solvent-free variation of acridine syn-
thesis. The application of microwave irradiations
(MWI) in organic synthesis has been the focus of con-
siderable interest in recent years. Chemical technol-
ogy is increasingly facing eco-environmental pres-
sure and is thus obliged to re-examine, conventional
methodologies to seek ways of developing and ap-
plying more efficient eco-friendly strategies. One of
the areas wherein substantial progress has been seen
in our laboratory [16,17] is the microwave-assisted
solid support synthesis. These heterogeneous reac-
tions are facilitated by reagents immobilized on
porous solid supports (alumina, montmorillonite,
bentonite, etc.). These dry media reactions [18] have
advantages over conventional solution phase reac-
tions owing to dispersion of active reagent sites,
catalysis, associated selectivity, and recyclability. The
other one is the “neat reaction” technology. “Neat Re-
action” [7] is an alternative solvent-free approach in
which a mixture of reactants without any solvent is
irradiated under microwaves. This technique is fur-
ther beneficial as it obviates the requirement of the
solvent for the adsorption of reactants and elution
of product in pre- and post-reaction stages. Such
solvent-free synthesis is advantageous for environ-
mental reasons and offers the benefits of shorter
reaction time along with enhanced yield especially
when coupled with microwaves [19].
ꢀ
C
yield.
2005 Wiley Periodicals, Inc. Heteroatom Chem
16:138–141, 2005; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20080
INTRODUCTION
Acridines and its derivatives inhibit HIV-1 reverse
transcriptase by intercalating the template–primer
hybrid [1]. They are also well known as antimicro-
bials [2,3] and antitumor agents [4,5] and are used
for the treatment of urinary incontinence [6]. The
title compounds under investigation are also asso-
ciated with the structural aspects of dihydropyri-
dine (DHP) and quinoline moieties. The chemical
modifications carried out on the DHP ring [7] such
as the presence of different substituents [8] or het-
eroatoms [9] have allowed expansion of the structure
activity relationship and afforded some insights into
the molecular interactions at the receptor level. 1,4-
DHPs are well known because of their pharmacolog-
ical profiles [10,11]. Furthermore, hexahydroquino-
lines play an important role in medicinal chemistry
as anxiolytic [12] and memory enhancers [13] and
Correspondence to: M. Kidwai; e-mail: kidwai chemistry@
yahoo.co.uk.
c
ꢀ
2005 Wiley Periodicals, Inc.
138

Solvent-Free Neat Synthetic Route to Tetrahydroacridinones 139
Keeping in view the therapeutic importance
and physiological properties of the acridine, quino-
line, and dihydropyridine moieties coupled with mi-
crowave for environmentally benign synthesis, it was
thought worthwhile to develop a facile one-pot syn-
thetic route using neat reaction conditions under
microwave.
RESULTS AND DISCUSSION
Various reported methods of acridines synthesis in-
volve Bernthsen [20] synthesis in which dipheny-
lamine is condensed with aromatic carboxylic
acids, Ullman reaction to form diphenylamine-2-
carboxylic acids that can cyclize to the corre-
sponding acridone. Harsh reductive and oxidative
conditions are then required to form the acridines
derivatives [21]. Another one is the synthesis of
decahydroacridinones [22]. Also in close associa-
tion with acridines, the structure is the linearly
fused DHPs for which numerous synthetic modes
have been reported [23,24]. Quite well known is
the Hantzsch synthesis that involves the reaction
of an aldehyde, ꢀ-ketoester, and concentrated aque-
ous ammonia [25]. Cyclic 1,3-diketone when con-
densed with aldehyde and ꢀ-amino crotonate affords
a bicyclic 4-aryl-1,4-dihydropyridine with the ester
substitution at 3-position [26]. The present com-
munication reports the synthesis of novel acridine-
type-related structures related to 1,4-DHP as a
microwave-assisted extension leading to the linearly
fused tricylic 1,4-DHP. Close observation of the struc-
ture reveals that it is a tetrahydroacridinone moi-
ety that incorporates the 1,4-DHP ring. Classically
[27], the synthesis is carried out by refluxing equimo-
lar amounts of primary aromatic amines 2 in abso-
lute ethanol (20 mL) with 5,5-dimethylcyclohexan-
1,3-dione (dimedone) 1 and appropriate aromatic
or heteroaromatic aldehyde 3 for 5–10 h in 65–
75% yield (Scheme 1). This procedure although con-
ventional yet suffers from some setbacks as it re-
quires long reaction time, excessive solvent, gives
low yield and in the present case, instead of am-
monia, ammonium acetate, or alkyl ꢀ-crotonates,
aromatic amines are used. In another experiment,
same amounts of all reactants were adsorbed over
basic [28]/neutral [29] alumina which gave the same
product in 8–12 min in 70–80% yield. Results ob-
tained were better in basic alumina than neutral alu-
mina. But when an equimolar mixture of neat reac-
tants was irradiated under microwaves [30] without
any solvent, it proved to be a high-yielding protocol.
The reaction completed within 5 min with 82–87%
yield (Table 1). The structures were established on
the basis of spectroscopic data (Table 2). In IR, the
SCHEME 1
appearance of band around 3430 cm−1 due to sec-
ondary amine, and around 1630 cm−1 due to C C
stretching and in 1H NMR, the presence of signal at
5.3 δ due to methine proton and NH peak at 6.7–
8 δ confirmed the formation of products. Further,
the observation that product formed has the lin-
ear structure, i.e. an acridine derivative is evidenced
1
by H NMR spectra as the 4-H and 9-NH are not
coupled.
The reaction can be postulated as the Kno-
evenagel condensation of aldehyde and dimedone
followed by the Michael addition of the formed
arylidene dimedone intermediate with primary aro-
matic amine and subsequent ring closure to afford
the corresponding tetrahydroacridinone derivative
in which the DHP ring is enclosed.
In conclusion, we have developed a facile, one-
pot condensation solvent-free route to tetrahydro-
acridinone derivatives incorporating the DHP
system. This is developed as an extension of
Hantzsch synthesis as it has ability to withstand the
variations in the 1,3-diketone, carbonyl, and amine
part.
EXPERIMENTAL SECTION
Melting points were taken in Thomas Hoover melt-
ing point apparatus and were uncorrected. IR (KBr)
spectra (ν in cm−1) were obtained on a Perkin-
Elmer 1710 spectrophotometer. 1H NMR spectra
were recorded in CDCl3 on FT NMR Hitachi R-600
spectrometer operating at 60 MHz using TMS as
internal standard (chemical shifts in δ ppm). Ele-
mental analyses were performed on Heraeus CHN
Rapid Analyzer. A Kenstar (model no. OM 9925E)
household microwave oven (2450 MHz, 850 W) was
used for the experiment. The purity of compounds
was checked on silica gel coated aluminum plates
(Merck).

140 Kidwai and Rastogi
TABLE 1 Time/Yield of Compounds 4a–h
Microwave
Conventional
Solution
Solid Support Method B
Phase
Basic
Neutral
Neat
Melting
Point
Method A
Alumina
Alumina
Method C
Compd.
No.
R ꢁ
R
( ◦C)
t(h) Yield (%) t(min) Yield (%) t(min) Yield (%) t(min) Yield (%)
4a
Phenyl
3-Chloro-4-fluoro Phenyl
phenyl
Phenyl
192–194
278–280
7
6
73
72
10
10
78
75
10.5
10
78
76
2
2
85
84
4b
4c
4-Chloro-phenyl Benz[1,3]
180–182
5.5
75
9
80
10
78
1
85
dioxol-5-yl
Phenyl
3-Methyl-phenyl 3-Indolyl
4-Nitro-phenyl
4d
4e
4f
α-Naphthyl
260–26227
130–132
3-Quinolinyl 202–204
4
8
10
62
68
65
8.5
12
12
80
75
74
9
14
15
75
76
75
2
4
5
87
83
82
aldehyde 3 (0.01 mol) in ethanol, neutral/basic alu-
mina (15 g) was added with stirring and air dried. It
was then placed in an alumina bath used as heat sink
and subjected to microwave irradiation (MWI) inter-
mittently (approx. bulk temperature reached ∼80–
100◦C). The progress of reaction was monitored by
the TLC examination. Upon completion of the re-
action, the product was eluted from chloroform. Re-
covering the solvent under reduced pressure the solid
obtained was then recrystallized from ethanol.
General Procedure for the Synthesis
of 9-Aryl-1,2,3,4-tetrahydro-3,3-dimethyl-9H,
10H-acridin-1-one
Method A : Conventional Solution Phase. A mix-
ture of dimedone 1 (0.01 mol), primary aromatic
amine 2 (0.01 mol), and aromatic or heteroaromatic
aldehyde 3 (0.01 mol) in absolute ethanol (20 mL)
was refluxed for the appropriate time. The progress
of the reaction was monitored through the TLC
examination. Upon completion of reaction, the re-
action mixture was cooled and concentrated. The
solid obtained was filtered and recrystallized from
ethanol.
Method C: Microwave Neat Synthesis. A mix-
ture of dimedone 1 (0.01 mol), primary aromatic
amine 2 (0.01 mole), and aldehyde 3 (0.01 mole)
was taken in an Erlenmeyer flask. This was sub-
jected to MWI intermittently (approx. bulk temper-
ature reached ∼120–140◦C). Reaction progress was
Method B : Solid Support Microwave. To the so-
lution of dimedone 1 (0.01 mol), primary aromatic
amine 2 (0.01 mol) and aromatic or heteroaromatic
TABLE 2 Spectroscopic Data of Compounds 4a–f
IR (KBr, νmax cm−1
)
Compd. No.
NH
C C
1626
1643
1622
1H NMR (CDCl3, δ, ppm)
4a
4b
4c
3448
3450
3429
1.25 (s, 3H, CH3), 1.55 (s, 3H, CH3), 2.22 (s, 2H, CH2), 2.40 (s, 2H,
CH2), 5.28 (s, 1H, CH), 6.18 (s, 1H, NH), 6.75–7.35 (m, 9H, Ar-H)
0.98 (s, 3H, CH3), 1.56 (s, 3H, CH3), 2.03 (s, 2H, CH2), 2.17 (s, 2H,
CH2), 5.32 (s, 1H, CH), 7.11–7.37 (m, 8H, Ar-H and NH)
1.01 (s, 3H, CH3), 1.32 (s, 3H, CH3), 2.13 (s, 2H, CH2), 2.34 (s, 2H,
CH2), 5.35 (s, 1H, CH), 6.03 (s, 2H, OCH2O), 6.91–7.45 (m, 6H, Ar-H
and N-H)
4d
4e
3425
3440
1625
1630
1.07 (s, 3H, CH3), 1.25 (s, 3H, CH3), 2.13 (s, 2H, CH2), 2.61 (s, 2H,
CH2), 5.36 (s, 1H, CH), 7.04–8.08 (m, 11H, Ar-H), 8.32 (s, 1H, NH)
1.03 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.13 (s, 2H, CH2), 2.44 (s, 2H,
CH2), 2.52 (s, 3H, CH3), 5.44 (s, 1H, CH), 6.42–7.45 (m, 10H, Ar-H
and N-H)
4f
3435
1638
1.12 (s, 3H, CH3), 1.21 (s, 3H, CH3), 2.22 (s, 2H, CH2), 2.43 (s, 2H,
CH2), 5.42 (s, 1H, CH), 7.01–7.45 (m, 9H, Ar-H and N-H)

Solvent-Free Neat Synthetic Route to Tetrahydroacridinones 141
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