One-pot synthesis of a novel compound N-hydroxydecahydroacridine under microwave irradiation

Article abstract of DOI:10.1002/jhet.5570410519

A novel reaction to synthesis a series new N-hydroxyldecahydroacridine derivatives by a one-pot condensation of aldehyde, 1,3-dicarbonyl compound and NH₂OH in glycol under microwave irradiation is described. N-hydroxyldecahydroacridine was obtained in excellent yields (81-95%) within short reaction time (4-7 min).

Full text of DOI:10.1002/jhet.5570410519

Sep-Oct 2004
767
One-pot Synthesis of a Novel Compound N-Hydroxydeca-
hydroacridine under Microwave Irradiation
Shujiang Tu,* Fang Fang, Songlei Zhu, Tuanjie Li, Xiaojing Zhang, Qiya Zhuang
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant,
Xuzhou; Jiangsu, 221009, P. R. China
Received April 1, 2004
A novel reaction to synthesis a series new N-hydroxyldecahydroacridine derivatives by a one-pot conden-
sation of aldehyde, 1,3-dicarbonyl compound and NH OH in glycol under microwave irradiation is
2
described. N-hydroxyldecahydroacridine was obtained in excellent yields (81-95%) within short reaction
time (4-7 min)
J. Heterocyclic Chem., 41, 767 (2004).
1,4-Dihydropyridines (1,4-DHPs), an important class of
rates, higher yields of pure products, easier work-up, and
sometimes, to selective conversions.
compounds, have exhibited important pharmacological
properties, e.g. as calcium channel modulators [1], and in
the treatment of cardiovascular disorder [2]. The chemical
modifications of the DHP ring such as the introduction of
different substituents [3] or heteroatoms [4] have allowed
expansion of research on the structure-activity relationship
to afford new insight into molecular interactions at the
receptor level. In fact, it is well established that slight
structural modifications on the DHP ring may bring vari-
ous pharmacological effects [5]. In our previous paper, we
disclosed the modification of 1,4-DHPs fused with one [6]
or two [7] cyclohexanone rings and obtained the 1,4-
Dihydropyridines derivatives, such as decahydroacridine.
Suárez et al reported the synthesis of decahydroacridine
[8]. In order to look for some new compounds with inter-
esting biological properties, we would like to introduce a
hydroxyl on the nitrogen of decahydroacridine to modify
the decahydroacridine ring.
This reaction may occur via an condensation, addition,
cyclization, elimination mechanism (Scheme 2). The con-
densation between aldehyde and dimedone gave 2-arylli-
dene-5,5-dimethyl-1,3-cyclo-hexanedione 5. Michael
addition between 5 and 6 (obtained from dimedone and
NH2OH) then furnished the intermediate 7, which isomer-
ized to 8. Intramolecular cyclodehydration of 9 gave 4.
The results (Table 1) show a series of aldehydes that
u n d e rgo the cyclocondensation to give excellent yields
(81-95%) of the products. The procedure is simple to oper-
ate, and the work-up consists of simple filtration. All the
products were characterized by IR, 1H NMR analysis. And
the elemental analyses of these compounds are in agree-
ment with their structures. Furthermore, the structure of 4a
Scheme 2
In our previous paper, we have reported the method of
producing N-hydroxydecahydroacridine by the reaction of
aldoxime and dimedone. However the aldoxime must be
prepared from aldehyde and NH2OH [9]. In connection
with our previous studies, to modify 1,4-dihydropyridines,
we described here a facile one-pot condensation of alde-
hyde, cyclic 1,3-dicarbonyl compounds and NH2OH in
glycol under the irradiation of microwave to afford a new
type of heterocyclic compounds, the N-hydroxydecahy-
droacridine derivatives (Scheme 1).
The application of microwave irradiation as a non-con-
ventional energy source for activation of reactions, has
now gained extensive usage, as it leads to enhance reaction
Scheme 1

768
S. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, Q. Zhuang
Vol. 41
and 4i was established by an X-ray crystallographic analy-
sis [10] (Figures 1 and 2).
synthesis of N-hydroxydecahydroacridine derivatives
therefore is a simple, timesaving high-yielding, and envi-
ronmentally friendly process. Efforts are underway to
elaborate these to biologically active heterocycles and
these results will be reported in due course.
Figure 2. ORTEP diagram of 4i.
Figure 1. ORTEP diagram of 4a.
Table 1
Synthesis of 4 Under Microwave Irradiation
1
Entry
R
R
Time (min)
Yield (%)
Mp (°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4-FC H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
H
5 [a] (85 [b])
6 [a] (100 [b])
5 [a] (75 [b])
90 [a] (80 [b])
88 [a] (76 [b])
92 [a] (84 [b])
233-234
222-223
256-257
248-249
136-137
134-135
159-160
196-197
204-205
152-153
>300
6
2-ClC H
4
3
3
3
3
3
3
3
3
3
3
6
4-ClC H
4
6
3,4-OCH OC H
4
a
4
6
5
7
6
5
5
5
93
92
95
88
83
81
85
92
89
92
89
2
3-NO C H
6 3
a
2
4-NO C H
6
4
a
2
4-N(CH ) C H
6
4
a
3 2
6 3
a
2-Furan
CH CH
CH CH CH
a
3
2
a
3
2
2
a
4-ClC H
6
4-OCH C H
4
a
H
H
H
7
7
>300
>300
247-248
3
2,4-Cl C H
6 4
a
2
3,4-Cl C H
6
3
3
a
7
2
6
[a] Method A: in glycol, under microwave irradiation; [b] Method B: in glycol at 110 °C.
In conclusion, we have disclosed a novel microwave-
assisted reaction between aldehyde and 1,3-dicarbonyl
compounds, and realized the introduction of the hydroxyl
on the nitrogen of acridine derivatives. Moreover, the reac-
tion time assisted by microwave irradiation is dramatically
shorter than that of the conventional heating. This one-pot
EXPERIMENTAL
Microwave irradiation was carried out in a commercial
microwave oven (2450 MHz) under atmospheric pressure.
Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on a Shimadzu spectro-
1
meter. H NMR spectra were measured on a DPX 400 MHz spec-

Sep-Oct 2004
One-pot Synthesis of a Novel Compound N-Hydroxydecahydroacridine
769
trometer using TMS as internal standard, DMSO-d as solvent.
6
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3153, 2956, 2873, 1649, 1606, 1558, 1529,
1470, 1358, 1325, 1260, 1223, 1176, 1142, 1124, 999, 906, 810,
Elemental analyses were determined by using a Perkin-Elmer
240c elemental analysis instrument. X-ray crystallographic
analysis was performed with a Siemens SMART CCD and a
Semens P4 diffractometer.
1
733, 710, 687, 569. H NMR (ppm): δ 10.89 (s, 1H, OH), 7.52-
7.99 (m, 4H, ArH), 5.07 (s, 1H, CH), 2.04-2.71 (m, 8H, CH ),
2
1.05 (s, 6H, CH ), 0.88 (s, 6H, CH ).
3
Anal. Calcd. for C
3
H N O : C, 67.30; H, 6.38; N, 6.82.
General Procedure for Preparation of N-Hydroxydecahydro-
acridine 4.
23 26 2 5
Found: C, 67.18; H, 6.48; N, 6.93.
The mixture of substituted aldehyde (2 mmol), 1,3-dicarbonyl
compounds (4 mmol), and NH OH (2 mmol) in glycol (5 ml) was
3,3,6,6-Tetramethyl-N-hydroxy-9-(4-nitrophenyl)-1,8-dioxo-1,2,3,
4,5,6,7,8,9,10-decahydroacridine (4 f) .
2
irradiated for 4-7 min. The reaction mixture was cooled to room
temperature and poured into 50 mL of water, collection by filtra-
tion gave the crude product, which was further purified by recrys-
tallization from 95% ethanol. All products are characterized by
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3210, 2958, 2872, 1606, 1560, 1527, 1470,
1347, 1325, 1255, 1176, 1143, 1124, 1003, 899, 818, 735, 692,
1
1
569; H NMR (ppm): δ 10.79 (s, 1H, OH), 7.15 (d, 2H, J=8.7 Hz,
IR and H NMR spectral data.
ArH), 7.24 (d, 2H, J=8.7 Hz, ArH), 4.93 (s, 1H, CH), 2.02-2.68
(m, 8H, CH ), 1.04 (s, 6H, CH ), 0.87 (s, 6H, CH ).
3,3,6,6-tetramethyl- N-hydroxy-9-(4-fluorophenyl)-1, 8-dioxo-
1,2, 3,4,5,6,7,8,9,10-decahydroacridine (4a).
2
Anal. Calcd. for C
Found C, 67.23; H, 6.48; N, 6.98.
3
3
H N O : C, 67.30; H, 6.38; N, 6.82:
23 26 2 5
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3300, 2958, 2872, 2733, 2360, 1614, 1526,
1466, 1392, 1368, 1323, 1294, 1261, 1221, 1124, 1095, 1003,
3,3,6,6-Tetramethyl-N-hydroxy-9-(4-dimethylaminophenyl)-1,8-
dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine (4g).
1
851, 682, 661, 615, 569, 525, 428; H NMR (ppm): δ 10.79(s,
1H, OH), 7.00-7.05 (m, 4H, ArH), 4.94 (s, 1H, CH), 2.07-2.62
(m, 8H, CH ), 1.03 (s, 6H, CH ), 0.88(6H, s, CH ).
This compound was obtained according to the general
-1
method; IR (KBr, ν, cm ): 3257, 2958, 2863, 2788, 1606, 1520,
2
Anal. Calcd. for C
3
FNO : C, 72.04; H, 6.83; N, 3.65.
3
1
1368, 1225, 1141, 954, 832, 573. H NMR (ppm): δ 10.76 (s, 1H,
H
23 26
Found: C, 72.31; H, 6.54; N, 3.43.
3
OH), 6.94 (d, 2H, J=8.6 Hz, ArH), 6.52 (d, 2H, J=8.6 Hz, ArH),
4.84 (s, 1H, CH), 2.80 (s, 6H, CH ), 2.00-2.66 (m, 8H, CH ),
3
1.04 (s, 6H, CH ), 0.89 (s, 6H, CH ).
2
3,3,6,6-Tetramethyl-N-hydroxy-9-(2-chlorophenyl)-1,8-dioxo-
1,2,3,4,5,6,7,8,9,10-decahydroacridine (4b).
3
Anal. Calcd. for C
Found C, 73.28; H, 7.84; N, 6.93.
3
H N O : C, 73.50; H, 7.90; N, 6.86.
25 32 2 3
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3300, 2961, 2878, 2674, 1603, 1568, 1490,
1409, 1371, 1323, 1272, 1225, 1141, 1023, 902, 848, 565, 523;
1
3,3,6,6-Tetramethyl-N-hydroxy-9-(2-furanphenyl)-1,8-dioxo-
1,2,3,4,5,6,7,8,9,10-decahydroacridine (4h).
H NMR (ppm): δ 10.79(s, 1H, OH), 7.13-7.26 (m, 4H, ArH),
4.93 (s, 1H, CH), 2.02-2.68 (m, 8H, CH ), 1.04 (s, 6H, CH ),
0.87 (s, 6H, CH ).
2
3
This compound was obtained according to the general method;
3
A n a l. Calcd. for C
-1
IR (KBr, ν, cm ): 3308, 2958, 2930, 2867, 2728, 1605, 1562,
1501, 1469, 1359, 1324, 1262, 1220, 1142, 1072, 1007, 1072,
H ClNO : C, 69.08; H, 6.55; N, 3.50.
23 26 3
Found: C, 69.21; H, 6.48; N, 3.72.
1
979, 951, 921, 884, 781, 727, 683, 616, 600, 566; H NMR
3,3,6,6-Tetramethyl-N-hydroxy-9-(4-chlorophenyl)-1,8-dioxo-
1,2,3,4,5,6,7,8,9,10-decahydroacridine (4c).
(ppm): δ 10.85 (s, 1H, OH), 7.35 (d, 1H, J=0.81 Hz, CH), 6.25
(dd, 1H, J=3.0 Hz, CH), 5.84 (d, 1H, J=3.3 Hz, CH), 5.12 (s, 1H,
CH), 2.07-2.61 (m, 8H, CH ), 1.05 (s, 6H, CH ), 0.94 (s, 6H,
2
3
This compound was obtained according to the general method;
CH ).
-1
IR (KBr, ν, cm ): 3344, 3051, 2956, 2931, 2870, 2735, 1714,
1612, 1566, 1466, 1363, 1224, 1146, 1122, 1038, 947, 802, 746,
3
Anal. Calcd. for C
Found: C, 70.59; H, 7.31; N, 4.16.
H NO : C, 70.96; H, 7.09; N, 3.94.
21 25 4
1
656, 569. H NMR (ppm): δ 10.78 (s, 1H, OH), 7.25 (d, 2H,
J=8.4 Hz, ArH), 7.14 (d, 2H, J=8.4 Hz, ArH), 5.17 (s, 1H, CH),
1.92-2.66 (m, 8H, CH ), 1.03 (s, 6H, CH ), 0.85 (s, 6H, CH ).
3, 3, 6, 6-Tetramethyl-N-hydroxy-9-ethyl-1, 8-dioxo-1, 2, 3, 4, 5,
6,7,8,9,10-decahydroacridine(4i).
2
3
H ClNO : C, 69.08; H, 6.55; N, 3.50.
3
A n a l. Calcd for C
Found: C, 69.25; H, 6.42; N, 3.82.
23 26 3
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3298, 2962, 2958, 2966, 2657, 1627, 1552,
1464, 1389, 1298, 1233, 1172, 1144, 1074, 1002, 934, 905, 887,
3,3,6,6-Tetramethyl-N-hydroxy-9-(3,4-methylenedioxylphenyl)-
1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine(4d).
1
778, 740, 685, 612,3, 567; H NMR (ppm): δ 10.60 (s, 1H, OH),
3.85(t, 1H, J=5.25 Hz, CH), 2.06-2.63 (m, 8H, CH ), 1.16-1.20
2
(m, 2H, CH ), 1.05 (s, 6H, CH ), 1.02 (s, 6H, CH ), 0.66 (t, 3H,
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3091, 2960, 2873, 1647, 1550, 1497, 1434,
1
1372, 1318, 1216, 1174, 1140, 1036, 925, 760, 569; H NMR
2
J=7.50 Hz, CH ).
3
3
3
Anal. Calcd. for C
Found: C, 72.01; H, 8.45; N, 4.48.
H NO : C, 71.89; H, 8.57; N, 4.41.
19 27 3
(ppm): δ 10.75 (s, 1H, OH), 6.60-6.73 (m, 3H, ArH), 4.88 (s, 1H,
CH), 5.91 (s, 2H, CH ), 2.03-2.68 (m, 8H, CH ), 1.04 (s, 6H,
2
2CH ), 0.89 (s, 6H, CH ).
2
3,3,6,6-Tetramethyl-N-hydroxy-9-propalyl-1,8-dioxo-1,2,3,4,5,
6,7,8,9,10-decahydroacridine(4j).
3
Anal. Calcd. for C
3
H
NO : C, 70.40; H, 6.65; N, 3.42.
24 27
Found: C, 70.21; H, 6.78; N, 3.62.
5
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3269, 2962, 2932, 2871, 2682, 1616, 1560,
1464, 1424, 1386, 1350, 1293, 1237, 1220, 1168, 1139, 1053,
3, 3, 6, 6-Tetramethyl-N-hydroxy-9-(3-nitrophenyl)-1, 8-dioxo-
1,2,3,4,5,6,7,8,9,10-decahydroacridine (4e).

770
S. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, Q. Zhuang
Acknowledgments.
Vol. 41
1
1002, 885, 732, 686, 613, 605, 566; H NMR (ppm): δ 10.60 (1H,
s, OH), 3.87 (1H, t, J=5.25 Hz, CH), 2.06-2.63 (8H, m, CH ),
2
1.07-1.15 (4H, m, CH ), 1.05 (6H, s, CH ), 1.01 (6H, s, CH ),
We thank for the National Natural Science Foundation of
China (No. 20372057), the Nature Science Foundation of the
Jiangsu Province (No. BK2001142) and the Nature Science
Foundation of Jiangsu Education Department (No.
01KJB150008) and the Key Laboratory of Chemical Engineering
& Technology of the Jiangsu Province Open Foundation (No.
KJS02060) for financial support.
2
0.77 (3H, t, J=7.30 Hz, CH ,).
3
3
3
H NO : C, 72.47; H, 8.82; N, 4.23.
Anal. Calcd. for C
20 29 3
Found: C, 72.21; H, 8.95; N, 4.36.
N-Hydroxy-9-(4-chlorophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroacridine(4k).
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3313, 3221, 3078, 3043, 2950, 2883, 1664,
1
1639, 1470, 1357, 1168, 1127; H NMR (ppm): δ 9.48(s, 1H,
REFERENCE AND NOTES
[1a] F. Bossert, and W. Vater, Med. Res. Rev. 9, 291 (1989); [b]
R. A. Janis, and D. J. Triggle, Drug Dev. Res., 4, 257 (1984).
[2a] F. Bossert, and H. Meyer, E. Wehinger, Angew. Chem., 93,
755 (1981); [b] R. A. Janis, P. J. Silver, and D. J. Triggle, Adv. Drug
Res., 16, 309 (1987).
OH), 7.26(d, 2H, J=8.4 Hz, ArH), 7.17(d, 2H, J=8.4 Hz, ArH),
4.89 (s, 1H, CH), 1.83-2.35 (m, 12H, CH ).
A n a l. Calcd. for C
19 18 3
Found: C, 66.28; H, 5.48; N, 4.25.
2
H ClNO : C, 66.38; H, 5.28; N, 4.07.
[3a] U. Eisner, and J. Kuthan, Chem. Rev. 72(1), 1-42 (1972); [b]
D. M. Stout, and A. I. Meyers, Chem. Rev., 82, 223 (1982).
[4a] R. J. Chorvat, and K. J. Rorig, J. Org. Chem. 5 3, 5779
(1988); [b] C. O. Kappe, and W. M. F. Fabian, Tetrahedron 53, 2803
(1997); [c] C. O. Kappe, Tetrahedron 49, 6937 (1993).
[5a] M. Schramm, G. Thomas, R. Towart, and G. Franckowiak,
Nature 303, 535 (1983); [b] A. M. Brown, D. L. Kunze, and A. Yatani,
Nature 311, 570 (1984).
[6] S. J. Tu, X. Deng, D. Q. Shi, Y. Gao, and J. C. Feng, Chin. J.
Chem. 19, 714 (2001).
[7] S. J. Tu, Z. S. Lu, D. Q. Shi, C. S. Yao, Y. Gao and C. Guo,
Synth. Commun. 32, 2181 (2002).
N-Hydroxy-9-(4-methoxyphenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroacridine (4 l).
This compound was obtained according to the general method;
-1
IR (KBr, ν, cm ): 3277, 3185, 3052, 2945, 1644, 1603, 1490, 1362,
1
1229, 1173, 1127; H NMR (ppm): δ 9.37(s, 1H, OH), 6.74(d, 2H,
J=8.5 Hz, ArH), 7.07(d, 2H, J=8.5 Hz, ArH), 4.85 (s, 1H, CH),
1.76-2.53 (m, 12H, CH ).
2
Anal. Calcd. for C
H NO : C, 70.78; H, 6.24; N, 4.13.
20 21 4
Found: C, 70.58; H, 6.45; N, 4.29.
N-Hydroxy-9-(2,4-dichlorophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroacridine(4m) .
[8] M. Suárez, A. Loupy, E. Salfrán, L. Morán and E. Rolando,
Heterocycle, 51, 21 (1999).
[9] S. Tu, C. Miao, Y. Gao, F. Fang, Q. Zhuang, Y. Feng and D.
Shi, Synlett., 2, 255 (2004).
This compound was obtained according to the general method;
IR (KBr, ν, cm-1): 3272, 3196, 3062, 2939, 1649, 1603, 1490,
1
1367, 1234, 1178, 1137; H NMR (ppm): δ 9.51 (s, 1H, OH),
[10] The sing-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographicanalysis was performed with a
Siemens SMART CCD and a Semens P4 diffractometer (graphite
monochromator, MoKa radiation λ=0.71073 Å). The crystal crystal-
lizes with one water molecule. Crystal data for 4a: C23H28ClFNO4,
yellow, crystal dimension 0.58x0.58x0.40 mm, monoclinic, space
group P2(1)/c, a=12.638(2), b=14.039(3), c= 11.102(2)Å, 
=94. 60(1)°, V=2140. 2(6)Å 3, Mr=401.46, Z=4, Dc=1. 246g/cm 3,
λ=0.71073Å, µ(Mokα)=0.09mm-1, F(000)=856, S=0.906, R1=0.0398,
wR2=0.0932. Crystal data for 4i: C19H29NO4, yellow, crystal dimen-
sion 0.58x0.58x0.40 mm, monoclinic, space group P2(1)/c,
a=12.533(1), b=13.184(2), c=11.883(2) Å,  =90°,  =109.06(1)°,
 = 9 0 °, V=1856.0(5) Å3, M r =335.43, Z=4, D c =1.201 g/cm3,
λ=0.71073 Å, µ( M o k α)=0.083 mm- 1, F(000)=728, S= 1 . 0 8 6 ,
R1=0.0488, wR2=0.1456.
7.11-7.26 (m, 3H, ArH), 5.05 (s, 1H, CH), 1.88-2.48 (m, 12H,
CH ).
H Cl NO : C, 60.33; H, 4.53; N, 3.70.
2
Anal. Calcd for C
19 17 2 3
Found: C, 60.61; H, 4.18; N, 3.63.
N-Hydroxy-9-(3,4-dichlorophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroacridine (4 n).
This compound was obtained according to the general method;
IR (KBr, ν, cm-1): 3313, 3083, 3047, 2945, 1664, 1465, 1357,
1
1173, 1132; H NMR (ppm): δ 9.41 (s, 1H, OH), 7.21-7.38 (m,
3H, ArH), 4.95 (s, 1H, CH), 1.96-2.54 (m, 12H, CH ).
2
Anal. Calcd. for C19H Cl NO : C, 60.33; H, 4.53; N, 3.70.
17
Found: C, 60.65; H, 4.21; N, 3.53.
2
3