An efficient one-pot synthesis of N-carboxymethylacridine-1,8-dione derivatives under microwave irradiation

Article abstract of DOI:10.1002/jhet.5570430633

A series of N-carboxymethylacridine-1,8-dione derivatives were synthesized by one-pot reaction of aldehyde, dimedone and glycine in glycol under microwave irradiation without catalyst with excellent yields (78-92%) and short reaction time (4-8min). And th

Full text of DOI:10.1002/jhet.5570430633

Nov-Dec 2006
1647
An Efficient One-pot Synthesis of N-Carboxymethylacridine-1,8-
dione Derivatives under Microwave Irradiation
Shujiang Tu,* Qian Wang, Yan Zhang, Jianing Xu, Jinpeng Zhang, Xiaotong Zhu,
Feng Shi
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical
Plant, Xuzhou; Jiangsu, 221009, P. R. China
Received April 24, 2006
R
N
O
O
O
O
glycol
MWI
NH2
+
RCHO + 2
CO2H
CO2H
1
4
2
3
O
O
O
O
CHO
glycol
MWI
NH2
CO2H
R
+ 2
4
+
N
N
R
HO2C
CO2H
CHO
O
O
R=C6H4
5
A series of N-carboxymethylacridine-1,8-dione derivatives were synthesized by one-pot reaction of
aldehyde, dimedone and glycine in glycol under microwave irradiation without catalyst with excellent
yields (78-92%) and short reaction time (4-8min). And the reaction was not only suitable for aromatic
monoaldehyde, but also aromatic dialdehyde.
J. Heterocyclic Chem., 43, 1647 (2006).
Introduction.
organic chemists in the synthesis or structure
modifications of acridinedione derivatives remains high.
Shanmuguasundaramn et al. first synthesized two N-
Acridinediones have been identified as antimalaria [1]
and antitumor agents [2]. Decahydroacridine-1,8-dione
derivatives have been reported to have high fluorescence
efficiency and can be used as fluorescent molecular
probes for monitoring of polymerization process [3].
Furthermore, the acridinedione dyes have already been
reported as a class of laser dyes operating in the blue-
green region [4]. They are also receiving much attention
due to their likeness in properties with those of 1,4-
dihydropyridines [5]. As a consequence, the interest of
carboxymethylacridine-1,8-dione
derivatives
under
traditional heating condition [6]. However, the reaction
underwent two steps. The target compounds were
refluxed in acetic acid for 2 hours and chromatographed
over a column of silica and eluted with chloroform. This
method involved long reaction time, complicated
procedures, lower yields, and the use of a large quantity
of poisonous and volatile reagents. It goes without saying
Scheme 1
R
N
O
O
O
O
glycol
MWI
NH2
+
RCHO + 2
CO2H
CO2H
1
4
2
3
O O
R
O
O
CHO
R
glycol
MWI
NH2
+ 2
4
+
N
N
CO2H
HO2C
CO2H
CHO
O O
R=C6H4
5

1648
S. Tu, Q. Wang, Y. Zhang, J. Xu, J. Zhang, X. Zhu, F. Shi
Vol 43
that the most efficient and environmentally friendly
synthesis of functionalized organic compounds would be
one-pot reaction from commercially available and simple
starting materials.
Multi-component reactions (MCRs) by virtue of their
convergence, productivity, and ease of execution and
generally higher yields of products have attracted
considerable attention from the point of view of combi-
natorial chemistry [7]. The efficiency of microwave
irradiation (MWI) in promoting organic reaction and the
success of its application in heterocyclic synthesis [8]
triggered us to apply it to one-pot multi-component
reactions.
In our previous study [9], we have introduced hydroxyl
to the nitrogen of decahydroacridine-1,8-dione under
microwave irradiation. Through intensive research, we
have successfully introduced carboxymethyl to the nitro-
gen of decahydroacridine-1,8-dione. Herein, we reported
an efficient, high-yielding and simplified synthesis of N-
When aliphatic aldehyde was used as starting material
instead of aromatic aldehyde, we did not obtain the target
product 4 but rather intermediate product 8 (60%). In
addition, we discovered that the solvent played an
important role in the process. When 1c reacted with 2, 3
in glacial acetic acid, product 6 was obtained. While
ethanol was used as the solvent, the main product was 7
(Scheme 2).
The results (Table 1) showed that the protocol could be
applied to different aldehydes including aromatic
aldehyde and dialdehyde with excellent yields (78-92%).
The new procedure was simple to operate and the workup
was just simple filtration. All the target products were
characterized by IR, 1H NMR and elemental analysis.
Furthermore, the structure of 4c was established by an X-
ray crystallographic analysis [10] (Figure 1).
carboxymethylacridine-1,8-dione derivatives
4 under
MWI by employing one-pot condensation of aldehydes 1,
dimedone 2 and glycine 3 in glycol (Scheme 1).
Results and Discussion.
Initially, we explored the synthesis of 4c by 4-
cholorophenyl aldehyde 1c, 2 and 3 in glacial acetic acid
in 1:2:1.25 molar ratios at 98 °C with mechanical stirring.
Unfortunately, the main product was 6 (70%) even if the
reaction time was extended to 8 h. Therefore, we used
glycol as solvent in stead of acetic acid. The result
showed that the solvent was favourable, when 1c reacted
with 2, 3 for 6 hours at 98 °C in glycol, the goal product
4c was isolated in 70% yield. But the reaction time and
yield were still not perfect.
In order to shorten the reaction time and increase the
yield, the microwave technology was applied in the
reaction. Compared with the traditional heating
methodology, the reaction time was shortened to 4 min
from 6 hours and the yields were sharply increased to
86% from 70% for synthesizing 4c. It is obvious that the
microwave accelerates the reaction and improves the
reaction yield.
Figure 1. The structure of 4c.
This reaction may occur via a reaction sequence of
condensation, addition, cyclization and elimination
(Scheme 3). At first, the condensation between aldehyde
and dimedone gave 2-aryllidene-5,5-dimethyl-1,3-cyclo-
hexanedione 9 and simultaneously dimedone reacted with
glycine forming 8. Then, Michael addition between 9 and
8 furnished the intermediate 10, which isomerized to 11.
After that, intermolecular cyclization of 11 gave 12,
which upon dehydration gave 4. We have also synthesized
the goal products by the reaction of 8, aldehyde and
dimedone.
Scheme 2
Ar
N
O
O
R
O
O
O
R = aryl
glycol
glycol
acetic acid
NH2CH2CO2H
CO2H
O
6
R
+
O
2
O
4
RCHO
O
H
R=aliphatic
group
O
N
CO2H
ethanol
OH
OH
8
7
R= 4-ClC6H4

Nov-Dec 2006
An Efficient One-pot Synthesis of N-Carboxymethylacridine-1,8-dione Derivatives
1649
Table 1
Synthesis of 4 and 5 under microwave irradiation
Entry
R
Time (min)
Yield (%)
Mp (°C)
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
4-FC6H4
3-NO2C6H4
4-ClC6H4
6
6
4
6
6
6
4
6
7
8
91
85
86
79
78
85
88
80
92
89
241-242
227-228
300-302
214-216
288-289
225-226
186-188
163-165
273-239
254-256
3,4-Cl2C6H3
2,4-Cl2C6H3
3,4-(OCH3)2C6H3
3-OCH3-4-OHC6H3
C6H5
1,4-(CHO)2
1,3-(CHO)2
Scheme 3
of the Jiangsu Province (No. BK2006033) and the Key
Lab of Biotechnology for Medicinal Plants of Jiangsu
Province (01AXL 14) for financial support.
O
O
O
O
EXPERIMENTAL
ArCHO
NH2CH2COOH
Microwave irradiation was carried out with a modified
commercial microwave oven (2450 MHz, 650W) under
atmospheric pressure. Melting points were determined in open
capillaries and were uncorrected. IR spectra were recorded on a
TENSOR 27 spectrometer in KBr. 1H NMR spectra were
measured on a DPX 400 MHz spectrometer using TMS as
internal standard, DMSO-d6 as solvent. Elemental analyses were
determined by using a Perkin-Elmer 240c elemental analysis
instrument.
O
O
NHCH2COOH
..
CHAr
O
9
8
Ar
Ar
O
O
O
O
..
NH
O
N
O
General Procedure for the Synthesis of 4 and 5.
CO2H
CO2H
Method A: A solution of the appropriate aldehyde (2 mmol),
dimedone (4 mmol), glycine (2.5 mmol) and in glycol (0.25 mL)
was irradiated for 4-8 min with power 220 W. The reaction
mixture was cooled to room temperature, then poured into water
(50 mL), filtered to give the crude product, which was further
purified by recrystallization from EtOH (4a-4h).
Method B: The mixture of dimedone (2 mmol) and glycine
(2.5 mmol) in glycol (0.25 mL) was irradiated for 6 min with
power 220 W. Then aldehyde and dimedone were added into
this system, and reacted for 7-8 min with power 220 W. The
reaction mixture was cooled to room temperature, then poured
into water (50 mL), filtered to give the crude product, which was
further purified by recrystallization from EtOH(5a , 5b).
10
11
O
Ar
O
O
Ar
N
O
-H2O
N
OH
CO2H
CO2H
12
4
In conclusion, we disclosed an efficient one-pot and
microwave-assisted reaction by aldehyde, dimedone and
glycine, thus realizing the introduction of carboxymethyl
on the nitrogen of decahydroacridine-1,8-dione
derivatives. The two step synthesis was shortened to one
step efficiently. Particularly valuable features of this
method included excellent yields of the products, short
reaction time, environmental friendliness and ease of
workup. Great efforts are underway to clarify the
bioactivity of these new compounds and the results will
be reported in due course.
2-(9-(4-Fluorophenyl)-1,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetra-
methyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4a).
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3458, 1609, 1560 cm-1; H
nmr (DMSO-d6): ꢀ 13.35 (s, 1H, COOH), 7.25-6.93 (m, 4H,
ArH), 4.99 (s, 1H, CH), 4.61 (s, 2H, CH2), 2.67-2.05 (m, 8H,
4CH2), 0.99 (s, 6H, 2CH3), 0.88 (s, 6H, 2CH3).
Anal. Calcd for C25H28FNO4: C, 70.57; H, 6.63; N, 3.29;
Found C, 70.54; H, 6.51; N, 3.11.
2-(1,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetramethyl-9-(3-nitrophenyl)-
1,8-dioxoacridine-10(9H)-yl)acetic acid (4b).
Acknowledgments.
We thank for the National Natural Science Foundation
of China (No. 20372057), the Nature Science Foundation
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3450, 1616, 1569 cm-1; H

1650
S. Tu, Q. Wang, Y. Zhang, J. Xu, J. Zhang, X. Zhu, F. Shi
Vol 43
nmr (DMSO-d6): ꢀ 13.40 (s, 1H, COOH), 8.14 (s, 1H, ArH),
8.20 (dd, 1H, J1=9.6 Hz, J2=1.2 Hz, ArH), 7.85 (d, 1H, J=7.6
Hz, ArH), 7.46 (d, 1H, J=7.6 Hz, ArH), 8.14-7.45 (m, 4H, ArH),
5.10 (s, H, CH), 4.66 (s, 2H, CH2), 2.52-2.10 (m, 8H, 4CH2),
1.00 (s, 6H, 2CH3), 0.88 (s, 6H,2CH3).
2-(1,2,3,4,5,6,7,8-Octahydro-3,3,6,6-tetramethyl-1,8-dioxo-9-
phenylacridine-10(9H)-yl)acetic acid (4h).
This compound was obtained according to above general
procedure; ir (potassium bromide): 3446, 2960, 1734, 1634 cm-1;
1H nmr (DMSO-d6): ꢀ 13.29 (s, 1H, COOH), 7.20-7.01 (m, 5H,
ArH), 4.99 (s, H, CH), 4.60 (s, 2H, CH2), 2.67-2.03 (m, 8H,
4CH2), 1.01 (s, 6H, 2CH3), 0.94 (s, 6H, 2CH3).
Anal. Calcd for C25H28N2O6: C, 66.36; H, 6.24; N, 6.19;
Found C, 66.52; H, 6.08; N, 6.25.
Anal. Calcd for C25H29NO4: C, 73.68; H, 7.17; N, 3.44; Found
C, 73.82; H, 7.14; N, 3.22.
2-(9-(4-Chlorophenyl)-1,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetra-
methyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4c).
This compound was obtained according to above general
procedure; ir (potassium bromide): 3421, 1643, 1602 cm-1; 1H nmr
(DMSO-d6): ꢀ 13.36 (s, 1H, COOH), 7.36 (d, 2H, J=8.0 Hz, ArH),
7.06 (d, 2H, J=8.0 Hz, ArH), 4.98 (s, H, CH), 4.62 (s, 2H, CH2),
2.80-2.05 (m, 8H, 4CH2), 1.00 (s, 6H, 2CH3), 0.89 (s, 6H, 2CH3).
Anal. Calcd for C25H28ClNO4: C, 67.94; H, 6.39; N, 3.17;
Found C, 68.09; H, 6.43; N, 3.02.
1,4-Bis(3,3,6,6-tetramethyl-10-carboxymethyl-decahydroacridine-
1, 8-dione-yl) -benzene (5a).
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3446, 1633, 1571 cm-1. H
nmr (DMSO-d6): ꢀ 13.28 (s, 2H, 2COOH), 6.94-6.77 (m, 4H,
ArH), 4.90 (s, 2H, 2CH), 4.57 (s, 4H, 2CH2), 2.67-2.00 (m, 16H,
8CH2), 0.94(s, 12H, 4CH3), 0.84 (s, 12H, 4CH3).
Anal. Calcd for C44H52N2O8: C, 71.72; H, 7.11; N, 3.80;
Found C, 71.85; H, 7.02; N, 3.64.
2-(9-(3,4-Dichlorophenyl)-1,2,3,4,5,6,7,8-octahydro-3,3,6,6-
tetramethyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4d).
This compound was obtained according to above general
1
1,3-bis(3,3,6,6-Tetramethyl-10-carboxymethyl-decahydroacridine-
1, 8-dione-yl)- benzene (5b).
procedure; ir (potassium bromide): 3421, 1662, 1619 cm-1; H
nmr (DMSO-d6): ꢀ 13.35 (s, 1H, COOH), 7.31(d, 1H, J= 8.4 Hz,
ArH), 7.29 (s, 1H, ArH), 7.12(d, 1H, J= 8.0 Hz, ArH), 5.16 (s,
H, CH), 4.64 (s, 2H, CH2), 2.57-1.98 (m, 8H, 4CH2),1.01 (s, 6H,
2CH3), 0.86 (s, 6H, 2CH3).
Anal. Calcd for C25H27Cl2NO4: C, 63.03; H, 5.71; N, 2.94;
Found C, 63.15; H, 5.68; N, 3.11.
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3446, 1660, 1626 cm-1; H
nmr (DMSO-d6): ꢀ 13.30 (s, 2H, 2COOH), 7.08-6.94 (m, 4H,
ArH), 4.97 (s, 2H, 2CH), 4.48 (s, 4H, 2CH2), 2.59-2.00 (m, 16H,
8CH2), 1.04 (s, 12H, 4CH3), 0.89 (s, 12H, 4CH3).
Anal. Calcd for C44H52N2O8: C, 71.72; H, 7.11; N, 3.80;
Found C, 71.89; H, 7.23; N, 3.63.
2-(9-(2,4-Chlorophenyl)-1,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetra-
methyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4e).
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-
(1H)-xanthene-1,8(2H)-dione (6).
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3500, 1623, 1570 cm-1; H
This compound was obtained according to above general
procedure; ir (potassium bromide): 2980, 1680, 1660, 1620 cm-1;
1H nmr (CDCl3): ꢀ 7.26 (s, 4H, ArH), 4.64 (s, 1H, CH), 4.48 (s,
4H, 2CH2), 2.14-2.03 (m, 8H, 4CH2), 1.10 (s, 6H, 2CH3), 0.98
(s, 6H, 2CH3).
nmr (DMSO-d6): ꢀ 13.35 (s, 1H, COOH), 7.24(d, 1H, J= 8.4 Hz,
ArH), 7.20 (s, 1H, ArH), 7.10 (d, 1H, J= 8.0 Hz, ArH), 5.16 (s,
H, CH), 4.65 (s, 2H, CH2), 2.52-2.02 (m, 8H, 4CH2), 1.00 (s,
6H, 2CH3), 0.86 (s, 6H, 2CH3).
Anal. Calcd for C25H27Cl2NO4: C, 63.03; H, 5.71; N, 2.94;
Found C, 63.21; H, 5.56; N, 2.73.
Anal. Calcd for C23H25ClO3: C, 71.77; H, 6.54; Found C,
71.92; H, 6.32.
2-(1,2,3,4,5,6,7,8-Octahydro-9-(3,4-dimethoxyphenyl)-3,3,6,6-
tetramethyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4f).
2,2'-(4-Chlorophenyl)methylenebis(3-hydroxy-5,5-dimethyl-2-
cyclohexen-1-one(7).
This compound was obtained according to above general
1
procedure; ir (potassium bromide): 3303, 1655, 1620 cm-1; H
White acerose solid, m.p. 135-136°C (lit. [11] 134-135°C).
[(5,5-Dimethyl-3-oxocyclohex-1-en-1-yl)amino]acetic acid (8).
This compound was obtained according to above general
nmr (DMSO-d6): ꢀ 13.30 (s, 1H, COOH), 6.81(s, 1H, ArH), 6.76
(d, 1H, J= 8.4 Hz, ArH), 6.72 (d, 1H, J= 8.0 Hz, ArH), 4.95 (s,
H, CH), 4.61 (s, 2H, CH2), 3.66 (s, 3H,OCH3), 3.64 (s, 3H,
OCH3) 2.62-2.04 (m, 8H, 4CH2), 1.04 (s, 6H, 2CH3), 0.89 (s,
6H, 2CH3).
1
procedure; ir (potassium bromide): 3336, 2961,1716 cm-1; H
nmr (DMSO-d6): ꢀ 12.79 (s, 1H, COOH), 7.15 (s, 1H, NH), 4.68
(s, ꢀH, CH), 3.76 (d, 2H, J=6.0 Hz CH2), 2.23 (s, 2H, CH2),
1.97 (s, 2H, CH2), 0.98 (s, 6H, 2CH3).
Anal. Calcd for C27H33NO6: C, 69.36; H, 7.11; N, 3.00;
Found: C, 69.58; H, 7.02; N, 2.86.
Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10; Found
C, 61.02; H, 7.64; N, 7.08.
2-(1,2,3,4,5,6,7,8-Octahydro-9-(4-hdroxy-3-methoxyphenyl)-
3,3,6,6-tetramethyl-1,8-dioxoacridine-10(9H)-yl)acetic acid (4g).
This compound was obtained according to above general
procedure; ir (potassium bromide): 3480, 1632, 1593 cm-1; 1H nmr
(DMSO-d6): ꢀ 13.31 (s, 1H, COOH), 8.55 (s, 1H, OH), 6.76 (s, 1H,
ArH), 6.60 (d, 1H, J=8.0 Hz, ArH), 6.52 (d, 1H, J=8.0 Hz, ArH),
4.91 (s, H, CH), 4.43 (s, 2H, CH2), 3.66 (s, 3H, OCH3), 2.59-2.04
(m, 8H, 4CH2), 1.08 (s, 6H, 2CH3), 1.06 (s, 6H, 2CH3).
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Nov-Dec 2006
An Efficient One-pot Synthesis of N-Carboxymethylacridine-1,8-dione Derivatives
1651
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[10] The sing-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Semens P4 diffractometer (graphite
monochromator, MoKa radiation ꢀ=0.71073 Å). Crystal data for 4c:
Empirical formula C25H28ClNO4, light-yellow, crystal dimension
0.25ꢀ0.18ꢀ0.15 mm, monoclinic, space group P21/c, a =12.655(3), b
=16.582(3),
c
=11.500(3)Å,
=90°,
ꢁ
=107.708(6)°,
=90°, V
=2298.9(9)Å3, Mr =441.93, Z =4, Dc =1.277Mg/m3 , ꢀ =0.71073Å,
μ(Mokꢂ) =0.0197 mm-1, F(000) =936, S =1.124, R1 = 0.0770, wR2
=
0.1508.
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