Microwave induced new route to acridine and quinazoline derivatives using TLC plates

Article abstract of DOI:10.1002/jhet.5570420435

Microwave (MW) assisted synthesis of acridine and quinazoline derivatives was performed on thin layer chromatography (TLC) plates. This versatile, simple and economical green methodology is readily amenable to parallel synthesis of acridine and quinazoline compound libraries.

Full text of DOI:10.1002/jhet.5570420435

May-Jun 2005
703
Microwave Induced New Route to Acridine and Quinazoline
Derivatives Using TLC Plates
M. Kidwai*, S. Saxena and R. Mohan
Department of Chemistry, University of Delhi, Delhi-110007, INDIA
Telefax: 91 11 27666235; E-mail: kidwai_chemistry@yahoo.co.uk
Received September 14, 2004
Microwave (MW) assisted synthesis of acridine and quinazoline derivatives was performed on thin layer
chromatography (TLC) plates. This versatile, simple and economical green methodology is readily
amenable to parallel synthesis of acridine and quinazoline compound libraries.
J. Heterocyclic Chem., 42, 703 (2005).
In designing ecofriendly synthesis [1] of the target mol-
nium acetate (0.1 mol, 0.077 g) in 2 mL methanol for
Hantzsch reaction and a spot of solution of benzaldehyde
(0.1 mol, 0.101 mL), dimedone (0.1 mol, 0.140 g) and
thiourea (0.1 mol, 0.076 g) in 2 mL methanol for Biginelli
reaction was placed on a TLC plate and was subjected to
MWI at low power (560 Watts) at an interval of 40 seconds
intermittently. Then the TLC plate was run in an appropri-
ate system (Table 1). To our surprise, a prominent spot of
product was seen, the rf value of which was consistent with
that of the expected product (prepared by solid supported
MW method for comparison) although some amount of
unreacted reactants were also observed. In order to get an
appreciable yield of pure products the reaction was carried
out on a preparative TLC plate. An array of spots of 1:2:1
mole ratio of reactants for the synthesis of acridine and
1:1:1 mole ratio of reactants for the synthesis of quinazo-
lines in 1 ml methanol was put on a preparative TLC plate
along with a reference TLC with two spots one of the reac-
tants and other of the expected product (Figure 1a and
Figure 1b). Both the plates were subjected to MWI inter-
mittently at an interval of 40s at low power. The reference
TLC was viewed in an iodine chamber and accordingly that
portion of silica gel containing the product was scratched
from the preparative TLC plate and the product was
ecule the starting materials are made to react by modifying
the reaction conditions in such a way that it not only elim-
inates byproducts and wastes but also minimizes the use of
organic solvents [2]. Over the past decade Hantzsch [3]
and Biginelli [4] reactions have received considerable
attention as a consequence of the pharmacological profile
of 1,4-dihydropyridines (1,4-DHP) and 3,4-dihydropyrim-
idines as calcium channel blockers [5]. These classes of
compounds have been synthesized in our laboratory [6]
with modified procedures [7]. Thin layer chromatography
has been reported as a tool for reaction optimization in
microwave assisted synthesis [8]. This prompted us to
modify this procedure for an efficient synthesis of 9-sub-
stituted-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahy-
droacridine-1,8-dione (2a-d) and 4-substituted-7,7-
dimethyl-2-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline-2-
thione (3a-d) via cyclocondensation reaction of aldehyde
(1a-d), dimedone, ammonium acetate/thiourea by simply
spotting of the above reaction mixture on TLC plate and
then subjecting it to microwave irradiation.
In a typical experiment, a test reaction was carried out on
a 5 x 20 cm TLC plate. A spot of solution of benzaldehyde
(0.1 mol, 0.101 mL), dimedone (0.2 mol, 0.280 g), ammo-
extracted in CHCl . Evaporation of the solvent afforded
3
the desired product, which was recrystallized from ethanol.
Use of different heterocyclic aldehydes led to the synthesis
of some novel acridine and quinazoline derivatives. The
structure of the products was confirmed on the basis of
spectroscopic data. The appearance of singlet at δ 5.5 due
1
to H-9 and δ 4.6 due to H-4 in H NMR and signals at δ
13
32.5 due to C-9 and δ 51.2 due to C-4 in C NMR for com-
pounds 2a-d and 3a-d respectively confirmed the forma-
tion of product. In IR the appearance of broad band at 3440
-1
cm due to NH and band at 1660 due to C=C further con-
firmed the formation of products.
In conclusion, we have shown the viability and unique-
ness of this method that can serve as a useful tool for
rapid reaction optimization, which is necessary prior to
library synthesis. The advantages of this ecologically
safe protocol includes a simple reaction set up that does
not require specialized equipment, shorter reaction time,
elimination of solvent, cleaner products, optimum use of

M. Kidwai, S. Saxena and R. Mohan
704
Vol. 42
Table 1
TLC System and Reaction Time for Compounds 2a-d and 3a-d [a]
Compound No.
R
m.p. (°C)
TLC system Benzene:EthylAcetate
Time
Yield
(min.)
(%)
2a
2b
2c
2d
3a
3b
3c
3d
Phenyl
4-Chlorophenyl
Piperonyl
2-Chloro-3-quinolyl
Phenyl
4-Chlorophenyl
Piperonyl
2-Chloro-3-quinolyl
190-192 [10]
296-298 [11]
324-325 [11]
>300
160-162 [12]
218-220
80:20
80:20
90:10
60:40
80:20
90:10
80:20
60:40
4.3
3.2
4.0
3.2
2.0
3.2
2.3
3.2
82
84
83
80
85
83
86
81
208-210
298-300
[a] Microwave Heating (560 W, 2450 MHz, 95-105 °C, 40 seconds).
Kenstar Microwave Oven, Model No. OM 9925E (2450 MHz,
800 W). Temperature of the reaction was measured through AZ,
Mini Gun Type, Non-Contact IR Thermometer, Model No. 8868.
Reactions were carried and monitored by thin layer chromatogra-
phy plates (5 x 20 cm) with 0.2 mm silica Gel (G Spectrochem.
Cat. No. 011904) and the spots were viewed in UV or iodine
chamber. Dimedone, aldehydes (benzaldehyde, 4-chloroben-
zaldehyde, piperonal), thiourea and ammonium acetate were
obtained from commercial sources. 2-Chloro-3-quinoline alde-
hyde was prepared by literature method [9].
energy and usage of only few milligram of reactants in a
few drops of solvent.
EXPERIMENTAL
Melting points were determined on a Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were recorded on
1
a Perkin-Elmer FT IR-1710 spectrophotometer. H NMR and
13
C NMR were recorded on Bruker Avance Spectrospin 300 (300
MHz) instrument using TMS as internal standard and CDCl as
3
3,3,6,6-Tetramethyl-9-phenyl-1,2,3,4,5,6,7,8,9,10-decahydro-
acridine-1,8-dione (2a).
solvent. Elemental analysis was performed on a Heraeus CHN
Rapid Analyser. Microwave irradiation was carried out in

May-Jun 2005
Microwave Induced New Route to Acridine and Quinazoline Derivatives
705
This compound has the following spectral properties: ir: NH
CH ), 2.12-2.38 (m, 4H, CH ), 4.72 (s, 1H, H-4), 7.14-7.43 (m,
3 2
-1
1
3436, C=C 1660 cm ; H nmr: δ 1.09 (s, 6H, 2CH ), 1.23 (s, 6H,
4H, Ar-H), 7.82 (s, 1H, NH), 10.63 (s, 1H, NH).
3
13
2CH ), 2.28-2.38 (m, 8H, CH ), 5.55 (s, 1H, H-9), 7.08-7.22 (m,
C nmr: δ 196.1 (C5), 161.5 (C2), 143.8 (C9), 131.2, 129.4,
3
2
13
5H, Ar-H), 11.88 (s, 1H, NH). C nmr: δ 190.8 (C1, C8), 150.5
(C4a, C10a), 138.0, 128.2, 126.7, 125.8 (phenyl), 115.8 (C8a,
C9a), 47.0 (C2, C7), 46.8 (C4, C5), 33.1 (C9), 31.6 (C3, C6),
128.2, 126.2 (aryl), 115.7 (C10), 50.8 (C4), 41.4 (C6), 41.1 (C8),
32.3 (C7), 29.7, 27.7 (2CH ).
3
Anal. Calcd. for C
H ClN OS: C, 59.90; H, 5.30, N, 8.73.
16 17 2
Found: C, 60.02; H, 5.56; N, 8.86.
29.6, 27.5 (4CH ).
3
Anal. Calcd. for C
Found: C, 79.28; H, 7.68; N, 4.18.
H NO : C, 79.08; H, 7.73; N, 4.01.
23 27 2
4-Piperonyl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquina-
zoline-2-thione (3c).
3,3,6,6-Tetramethyl-9-(4-chlorophenyl)-1,2,3,4,5,6,7,8,9,10-deca-
hydroacridine-1,8-dione (2b).
This compound has the following spectral properties: ir: NH
-1
1
3430, C=C 1655 cm . H nmr: δ 0.97 (s, 3H, CH ), 1.07 (s, 3H,
3
CH ), 2.15-2.48 (m, 4H, CH ), 4.63 (s, 1H, H-4), 5.93 (s, 2H,
This compound has the following spectral properties: ir: NH
3
2
-1
1
OCH ), 6.66-6.78 (m, 3H, Ar-H), 8.01 (s, 1H, NH), 10.52 (s, 1H,
3340, C=C 1665 cm . H nmr: δ 0.96 (s, 6H, 2CH ), 1.08 (s, 6H,
2
3
13
NH). C nmr: δ 195.6 (C5), 161.2 (C2), 142.4 (C9), 147.4,
2CH ), 2.21-2.26 (m, 8H, CH ), 5.45 (s, 1H, H-9), 7.12-7.33 (m, 4H,
3
2
13
144.2, 128.5, 122.6, 114.2, 91.2 (piperonyl), 116.1 (C10), 51.0
Ar-H), 11.90 (s, 1H, NH). C nmr: δ 196.1 (C1, C8), 148.8 (C4a,
(C4), 41.9 (C6), 41.3 (C8), 32.3 (C7), 29.2, 27.2 (2CH ).
C10a), 139.2, 131.0, 129.7, 128.7 (aryl), 114.5 (C8a, C9a), 49.8 (C2,
3
Anal. Calcd. for C
Found: C, 61.70; H, 5.49; N, 8.52.
H N O S: C, 61.81; H, 5.45; N, 8.48.
C7), 41.5 (C4, C5), 32.9 (C9), 32.6 (C3, C6), 29.4, 27.9 (4CH ).
17 18 2 3
3
Anal. Calcd. for C
H ClNO : C, 71.96; H, 6.77; N, 3.65.
23 26 2
Found: C, 72.05; H, 6.85; N, 3.56.
4-(2-Chloro-3-quinolyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione (3d).
3,3,6,6-Tetramethyl-9-piperonyl-1,2,3,4,5,6,7,8,9,10-decahydro-
acridine-1,8-dione (2c).
This compound has the following spectral properties: ir: NH
-1
1
3431, C=C 1650 cm . H nmr: δ 1.00 (s, 3H, CH ), 1.17 (s, 3H,
This compound has the following spectral properties: ir: NH
3
-1 1
CH ), 2.18-2.42 (m, 4H, CH ), 5.05 (s, 1H, H-4), 7.14-7.63 (m,
3394, C=C 1635 cm . H nmr: δ 1.08 (s, 6H, 2CH ), 1.51 (s, 6H,
3
2
3
13
5H, quinolyl), 8.11 (s, 1H, NH), 11.31 (s, 1H, NH). C nmr: δ
194.3 (C5), 160.8 (C2), 141.8 (C9), 166.5, 149.10, 135.3, 132.4,
130.5, 129.2, 128.5, 128.1, 126.2 (quinolyl), 115.8 (C10), 51.2
2CH ), 2.14-2.39 (m, 8H, CH ), 5.12 (s, 1H, H-9), 5.83 (s, 2H,
3
2
13
OCH ), 6.61-6.92 (m, 3H, Ar-H), 11.72 (s, 1H, NH). C nmr: δ
2
191.5 (C1, C8), 150.2 (C4a, C10a), 147.4, 144.8, 137.3, 121.6,
114.9, 91.3 (piperonyl), 115.1 (C8a, C9a), 46.8 (C2, C7), 46.2
(C4, C5), 32.7 (C9), 31.1 (C3, C6), 29.5, 27.3 (4CH ).
(C4), 41.5 (C6), 41.1 (C8), 31.7 (C7), 29.3, 27.7 (2CH ).
3
Anal. Calcd. for C
H ClN OS: C, 61.37; H, 4.84; N, 11.30.
19 18 3
3
Found: C, 61.28; H, 4.96; N, 11.14.
Anal. Calcd. for C
H NO : C, 73.28; H, 6.87; N. 3.56.
24 27 4
Found: C, 73.19; H, 6.68; N, 3.46.
Acknowledgement.
3,3,6,6-Tetramethyl-9-(2-chloro-3-quinolyl)-1,2,3,4,5,
6,7,8,9,10-decahydroacridine-1,8-dione (2d).
The authors (M. Kidwai and S. Saxena) thank the University
Grants Commission, New Delhi for the financial assistance.
This compound has the following spectral properties: ir: NH
-1 1
3380, C=C 1640 cm . H nmr: δ 0.97 (s, 6H, 2CH ), 1.13 (s, 6H,
REFERENCES AND NOTES
3
2CH ), 2.21-2.35 (m, 8H, CH ), 5.61 (s, 1H, H-9), 7.21-7.90 (m,
3
2
13
5H, quinolyl), 11.87 (s, 1H, NH). C nmr: δ_ 193.7 (C1, C8),
151.1 (C4a, C10a), 166.8, 149.00, 136.8, 135.6, 130.8, 129.7,
128.7, 128.3, 126.8 (quinolyl), 115.7 (C8a, C9a), 48.9 (C2, C7),
[1] M. Kidwai, Pure Appl. Chem., 73, 1261 (2001).
[2a] M. Kidwai, S. Saxena, R. Mohan and R. Venkataramanan, J.
Chem. Soc.; Perkin Trans. 1, 16, 1845 (2002); [b] M. Kidwai, R.
Venkataramanan and B. Dave, J. Heterocyclic Chem., 39, 1045 (2002).
[3a] A. Hantzsch, Justus Liebigs Ann. Chem., 1, 215 (1882); [b] R.
Alajarin, J. J. Vaquero, J. L. G. Navio and J. Alvarez-Builla, Synlett., 297
(1992).
42.3 (C4, C5), 31.8 (C9), 31.2 (C3, C6), 29.5, 27.6 (4CH ).
3
Anal. Calcd. for C
H ClNO : C, 74.19; H, 6.42; N, 3.32.
26 27 2
Found: C, 74.25; H, 6.70; N, 3.04.
4-Phenyl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazo-
line-2-thione (3a).
[4a] P. Biginelli, Gazz. Chim. Ital., 23, 360 (1893); [b] C. O.
Kappe, Tetrahedron, 49, 6937 (1993); [c] D. S. Bose, L. Fatima and H. B.
Mereyala, J. Org. Chem., 68, 587 (2003).
[5a] J. P. McCarthy, R. Zhang and S. Moreland, J. Med. Chem., 38,
119 (1995); [b] R. Fossheim, K. Svarteng, A. Mostad, C. Romming, E.
Shefter and D. J. Triggle, J. Med. Chem., 25, 126 (1982).
[6] M. Kidwai and R. Mohan, Canadian J. Chem., 82, 427 (2004).
[7] M. Kidwai, R. Mohan and S. Saxena, Russ. Chem. Bull., 52,
2457 (2003).
[8] L. Williams, Chem. Commun., 435 (2000).
[9] O. Meth Cohn, B. Narine and B. Tarnowski, J. Chem. Soc.
Perkin Trans. 1, 1520 (1981).
[10] N. Martin, M. Quinteiro and C. Sewane, J. Heterocyclic
Chem., 32, 235 (1995).
[11] S. J. Tu, Z. Lu, D. Shi, C. Yao, Y. Gao and C. Guo, Synth.
Commun., 32(14), 2181 (2002).
This compound has the following spectral properties: ir: NH
-1
1
3443, C=C 1662 cm . H nmr: δ 0.97 (s, 3H, CH ), 1.08 (s, 3H,
3
CH ), 2.18-2.45 (m, 4H, CH ), 4.75 (s, 1H, H-4), 7.02-7.27 (m,
3
2
13
5H, Ar-H), 7.90 (s, 1H, NH), 10.81 (s, 1H, NH). C nmr: δ 196.8
(C5), 162.7 (C2), 144.6 (C9), 128.9, 128.5, 128.4, 126.8
(phenyl), 116.2 (C10), 51.3 (C4), 41.7 (C6), 41.3 (C8), 32.7 (C7),
29.9, 27.8 (2CH ).
3
Anal. Calcd. for C
H N OS: C, 67.13; H, 6.29; N, 9.79.
16 18 2
Found: C, 67.26; H, 6.38; N, 9.72.
4-(4-Chlorophenyl)-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahy-
droquinazoline-2-thione (3b).
This compound has the following spectral properties: ir: NH
[12] M. Yarim, S. Sarac, M. Ertan, F. S. Kihc and K. Erol,
Arzneimittel-Forschung, 52(1), 27 (2002).
-1
1
3440, C=C 1635 cm . H nmr: δ 0.98 (s, 3H, CH ), 1.10 (s, 3H,
3