Microwave irradiation: Novel and facile methods for the synthesis of new pyrimidinones

Article abstract of DOI:10.1016/j.cclet.2014.03.048

We describe here a rapid process for the preparation of new 9-chloromethyl-12-aryl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones 5a-d and 10-chloromethyl-7-aryl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones 6a-d by two different methods utilizing microwave irradiation. This methodology provides better yields (72%-80%) and high purity of the title compounds.

Full text of DOI:10.1016/j.cclet.2014.03.048

Accepted Manuscript
Title: Microwave irradiation: Novel and facile methods for the
synthesis of new pyrimidinones
Author: Aida Chaker Fathi Zribi Franc¸oise Nepveu Fakher
Chabchoub
PII:
S1001-8417(14)00150-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2014.03.048
CCLET 2934
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
7-10-2013
6-3-2014
10-3-2014
Please cite this article as: A. Chaker, F. Zribi, F. Nepveu, F. Chabchoub, Microwave
irradiation: Novel and facile methods for the synthesis of new pyrimidinones, Chinese
Chemical Letters (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.048
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Graphical Abstract
Microwave irradiation: Novel and facile methods for the synthesis of new
pyrimidinones
Aida Chaker a, b, Fathi Zribi a, Françoise Nepveu b,c, Fakher Chabchoub a, ∗
a Department of Chemistry, University of Sfax, road Soukra km 4-3000 Sfax, Tunisia
b UPS, UMR 152 PHARMA-DEV, University of Toulouse III, 118 road of Narbonne, F-31062 cedex 9, Toulouse, France
c IRD, UMR 152, F-31062 cedex 9 Toulouse, France
Ar
Ar
O
CN
CN
Cl
O
Cl
Cl
MW, DMF, 150 W
40 °C, 15-20 min
O
N
H
O
NH2
3 or 4
1 or 2
M
W
W
h
a
,
)
0
D
1
:
0
3
,
5
.
4
M
1
(
1
0
,
Cl
F
e
°
W
C
,
C
,
°
3
O 3
n
M
o
t
0
0
3
C
e
7
0
c
h
W
K 2
,
Cl
O
/
r
e
P
O
N
Ar
t
H
a
U
w
NH
Cl
O
5 or 6
A synthesis of new pyrimidinones by two different methods utilizing microwave (MW) irradiation is described.
Original article
Microwave irradiation: Novel and facile methods for the synthesis of new
pyrimidinones
Aida Chaker a, b, Fathi Zribi a, Françoise Nepveu b,c, Fakher Chabchoub a, ∗
a Department of Chemistry, University of Sfax, road Soukra km 4-3000 Sfax, Tunisia
b UPS, UMR 152 PHARMA-DEV, University of Toulouse III, 118 road of Narbonne, F-31062 cedex 9, Toulouse, France
c IRD, UMR 152, F-31062 cedex 9 Toulouse, France
ARTICLE INFO
ABSTRACT
We describe here a rapid process for the preparation of new 9-chloromethyl-12-aryl-10,12-
dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones 5a-d and 10-chloromethyl-7-aryl-7,9-
dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones 6a-d by two different methods utilizing
microwave irradiation. This methodology provides better yields (72%-80%) and high purity of
the title compounds.
Article history:
Received 7 October 2013
Received in revised form 6 March 2014
Accepted 10 March 2014
Available online
Keywords:
Microwave-irradiation
Aminonitriles naphtopyraniques
Chloroacetylchloride
Pyrimidinones
———
∗ Corresponding author.
E-mail address: fakher.chabchoub@yahoo.fr
∗ Corresponding author.
Page 1 of 7

———
E-mail address: fakher.chabchoub@yahoo.fr
Page 2 of 7

1. Introduction
Heterocycles are a very important class of compounds and an interesting field for research with great opportunities for the synthesis
of novel drugs. Pyrimidinone derivatives are widely distributed in nature and exhibit various biological activities such as antimalarials
[1-3], antibacterial [4], antifungal [5], anti-HIV [6], antiviral [7], anticancer [8], and anti-inflammatory agents [9, 10]. In previous
reports we demonstrated that aminonitrile naphtopyranique derivatives 1 or 2 are basic substrates for the synthesis of a new series of
pyrimidinones [11-12], and new molecules with a broad range of biological activities, such as triazolopyrimidins [13] and quinoline
derivatives [14-16]. We used microwave assisted synthesis to control pollution, convert hours into minutes in chemical preparation,
enhance yields and stop excessive use of solvents [17].
The present work describes the synthesis of a new series of chloromethylnaphtopyranopyrimidinones 5a-d and 6a-d under mild
conditions using microwave irradiation.
2. Experimental
Commercially available, reagent grade chemicals were used as received without additional purification. All reactions were followed
by TLC (E. Merck Kieselgel 60 F-254), with detection by UV light at 254 nm. IR spectra were recorded on a Perkin Elmer FT-IR
spectrophotometer (4000-400 cm-1) using KBr pellets. The 1H NMR and 13C NMR spectra were recorded on an AC Bruker
spectrometer at 300 MHz (1H NMR) and 75 MHz (13C NMR) in deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts (δ) are
reported in parts per million (ppm) relative to tetramethylsilane (0 ppm) as internal reference and the following multiplicity
abbreviations used: s, singlet; d, doublet; t, triplet; m, multiplet. Mass spectra (MS) were recorded on a spectrometer (Finnigan LCQ
Deca XP Max). The ionization method used is electrospray (ESI). All solvents were dried by standard methods. The microwave
assisted reactions were carried out in a synthetic microwave apparatus: Monowave 300 with a maximum power of 300 W.
General procedure of method 1: To a solution of 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles 1a-d or 2-amino-4-aryl-4H-
benzo[h]chromene-3-carbonitriles 2a-d (0.5g, 1.6 mmol) in DMF (4 mL), chloroacetylchloride (0.36 g, 3.2 mmol) was added dropwise
at 0 °C. The reaction mixture was irradiated in a microwave at 40 °C, for 15-20 min at a power of 150 W. After cooling, 100 mL of
water were added. A precipitate formed and was filtered, washed with water (3 × 20 mL) and dried in a vacuum drying oven
(dessicator cabinet) to give 3a-d or 4a-d. To a mixture of 3a-d or 4a-d (0.1 g, 0.26 mmol) and acetone/H2O (1:1, v/v, 4 mL) was added
K2CO3 (0.053 mmol) and urea hydrogen peroxide (UHP) (0.53 mmol). The reaction mixture was irradiated in a microwave at 70 °C,
for 1.5-2 h at a power of 300 W. After cooling, 100 mL of water were added. A precipitate formed and was filtered, washed with water
(3 × 20 mL) and dried in a vacuum drying oven (dessicator cabinet) to give compounds 5a-d and 6a-d.
General procedure of method 2: A mixture of 1a-d or 2a-d (1 g, 2.4 mmol) and chloroacetylchloride (6 equiv.) in DMF (4 mL), was
irradiated in a microwave at 40 °C, for 2 h. at a power of 300 W. After cooling, the solid product that formed was filtered, washed with
ether, and dried, to give compounds 5a-d or 6a-d in good yields.
Characterization data of the synthesized compounds are listed below.
2-Chloro-N-(2-cyano-1-phenyl-1H-benzo[f]chromen-3-yl)-acetamide (3a): Yellow solid, mp 236-238 °C; IR (KBr, cm-1): 1670
(C=O), 2222(CN), 3340(NH); 1H NMR (300 MHz, DMSO-d6): δ 4.35 (s, 2H), 5.69 (s, 1H), 7.31–8.01 (m, 11H, arom.), 11.06 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): δ 39.7, 43.0, 85.9, 114.8, 116.9, 117.3, 124.1, 125.9, 127.8, 127.8 (2C), 128.0 (2C), 129.4 (2C),
130.3, 130.5, 131.8, 143.7, 147.3, 150.5, 165.6; MS (ESI): m/z 373 (M−).
2-Chloro-N-(2-cyano-1-p-methylphenyl-1H-benzo[f]chromen-3-yl)-acetamide (3b): Yellow solid, mp 228-230 °C; IR (KBr, cm-1):
1
1723 (C=O), 2210 (CN), 3324 (NH); H NMR (300 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.35 (s, 2H), 5.63 (s, 1H), 7.10–8.00 (m, 10H,
arom.), 11.02 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 21.0, 39.9, 43.0, 86.1, 114.9, 117.0, 117.2, 124.2, 125.8, 127.6, 127.9,
128.8 (2C), 129.7 (2C), 130.3, 130.4, 131.8, 137.1, 140.8, 147.2, 150.3, 165.6; MS (ESI): m/z 387 (M−).
2-Chloro-N-(2-cyano-1-p-methoxyphenyl-1H-benzo[f]chromen-3-yl)-acetamide (3c): Yellow solid, mp 230-232 °C, IR (KBr, cm-1):
1
1720 (C=O), 2210 (CN), 3216 (NH); H NMR (300 MHz, DMSO-d6): δ 3.66 (s, 3H), 4.45 (s, 2H), 5.68 (s, 1H), 7.01–8.01 (m, 10H,
arom.), 11.08 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 42,3, 43.1, 55.6, 85.7, 112.4, 114.6, 114.6, 116.9, 117.1, 120.2, 124.3,
125.8, 127.8, 129.1 (2C), 130.4, 130.5, 131.8, 145.2, 147.4, 150.88, 159.8, 165.7; MS (ESI): m/z 403 (M−).
2-Chloro-N-(2-cyano-1-m-methoxyphenyl-1H-benzo[f]chromen-3-yl)-acetamide (3d): Yellow solid, mp 226-228 °C; IR (KBr, cm-
1): 1715 (C=O), 2220 (CN), 3214 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.70 (s, 3H), 4.35 (s, 2H), 5.66 (s, 1H), 6.79–8.01 (m, 10H,
arom.), 11.04 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 39.9, 43.0, 55.4, 85.8, 112.5, 114.4, 114.7, 116.9, 117.2, 120.2, 124.2,
125.9, 127.8, 129.0 (2C), 130.4, 130.5, 131.7, 145.1, 147.3, 150.66, 159.9, 165.6; MS (ESI): m/z 403(M−).
2-Chloro-N-(3-cyano-4-phenyl-4H-benzo[h]chromen-2-yl)-acetamide (4a): Yellow solid, mp 220-222 °C; IR (KBr, cm-1): 1660
(C=O), 2200 (CN), 3300 (NH); 1H NMR (300 MHz, DMSO-d6): δ 4.45 (s, 2H), 5.25 (s, 1H), 7.18–8.16 (m, 11H, arom.), 11.19 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): δ 42.4, 43.2, 83.7, 114.6, 117.0, 117.5, 121.0, 123.1, 125.6, 126.3, 127.6 (2C), 128.1, 128.2,
128.4 (2C), 129.4 (2C), 133.3, 143.2, 143.7, 151.5, 165.7; MS (ESI): m/z 373 (M−).
2-Chloro-N-(3-cyano-4-p-methylphenyl-4H-benzo[h]chromen-2-yl)-acetamide (4b): Yellow solid, mp 214-216 °C; IR (KBr, cm-1):
1
1668 (C=O), 2210 (CN), 3350 (NH); H NMR (300 MHz, DMSO-d6): δ 2.27 (s, 3H) 4.44 (s, 2H), 5.19 (s, 1H), 7.15–8.15 (m, 10H,
arom.), 11.17 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 21.0, 42.0, 43.2, 117.0, 117.6, 121.0, 123.1, 125.5, 126.3, 127.5, 128.2,
128.3 (2C), 129.9 (2C), 133.2, 137.3, 140.9, 143.1, 151.3, 165.7; MS (ESI): m/z 387(M−).
2-Chloro-N-(3-cyano-4-p-methoxyphenyl-4H-benzo[h]chromen-2-yl)-acetamide (4c): Yellow solid, mp 210-212 °C; IR (KBr, cm-1):
1
1664 (C=O), 2213 (CN), 3250 (NH); H NMR (300 MHz, DMSO-d6): δ 3.73 (s, 3H), 4.60 (s, 2H), 5.69 (s, 1H), 7.03–8.03 (m, 10H,
Page 3 of 7

arom.), 11.10 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 42.1, 43.4, 55.6, 86.7, 112.8, 114.5, 114.7, 116.8, 117.3, 120.2, 124.2,
125.9, 127.8, 129.0 (2C), 130.4, 130.5, 131.8, 145.2, 147.3, 150.6, 159.9, 165.7; MS (ESI): m/z 403 (M−).
2-Chloro-N-(3-cyano-4-m-methoxyphenyl-4H-benzo[h]chromen-2-yl)-acetamide (4d): Yellow solid, mp 212-214 °C; IR (KBr, cm-
1): 1670 (C=O), 2200 (CN), 3320 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.74 (s, 3H) 4.45 (s, 2H), 5.22 (s, 1H), 6.85–8.15 (m, 10H,
arom.), 11.17 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 42.3, 43.2, 55.5, 83.7, 113.1, 114.3, 114.5, 117.0, 117.4, 120.5, 121.0,
123.1, 125.6, 127.6, 128.0, 129.2 (2C), 130.6, 133.3, 145.2, 151.6, 160.0, 165.8; MS (ESI): m/z 403 (M−).
9-Chloromethyl-12-phenyl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones (5a): White solid, mp 266-268 °C; IR (KBr,
cm-1): 1663 (C=O), 3396 (NH); 1H NMR (300 MHz, DMSO-d6): δ 4.46 (s, 2H), 5.21(s, 1H), 7.05–8.11 (m, 11H, arom.), 12.97 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): δ 38.3, 42.2, 101.5, 112.5, 119.5, 121.5, 122.8, 124.5, 127.4, 128.0 (2C), 128.4 (2C),129.0 (2C),
129.7, 133.9, 137.8, 143.5, 158.6, 161.2, 166.1; MS (ESI): m/z 373 (M−).
9-Chloromethyl-12-p-methylphenyl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones (5b): White solid, mp 268-270 °C;
IR (KBr, cm-1): 1683 (C=O), 3440 (NH); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (s, 3H) 4.38 (s, 2H), 5.18 (s, 1H), 7.26–8.28 (m, 10H,
arom.), 12.78 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 21.3, 41.1, 43.2, 85.2, 105.1, 114.5, 120.2, 121.2, 123.6, 124.9, 127.1,
128.3 (2C), 128.9 (2C), 129.5 (2C), 133.2, 137.8, 143.8, 158.3, 161.7, 165.8; MS (ESI): m/z 387 (M−).
9-Chloromethyl-12-p-methoxyphenyl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones (5c): White solid, mp 266-268
°C; IR (KBr, cm-1): 1655 (C=O), 3390 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.65 (s, 3H) 4.49 (s, 2H), 5.28 (s, 1H), 7.19–8.19 (m,
10H, arom.), 12.92 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 38.3, 42.6, 55.5, 85.4, 102.8, 114.3, 119.6, 121.1, 123.5, 124.9,
127.1, 127.8 (2C), 128.2 (2C), 129.4 (2C), 133.2, 137.7, 143.9, 158.4, 161.4, 166.4; MS (ESI): m/z 403 (M−).
9-Chloromethyl-12-m-methoxyphenyl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones (5d): White solid, mp 270-272
°C; IR (KBr, cm-1): 1656 (C=O), 3374 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.66 (s, 3H) 4.45 (s, 2H), 5.24 (s, 1H), 7.15–8.15 (m,
10H, arom.), 12.96 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 36.8, 44.0, 55.3, 95.7, 111.5, 114.7, 117.3, 118.0, 120.2, 123.8,
125.5, 127.5, 129.0, 129.6, 130.1, 130.7, 131.5, 146.6, 147.2, 148.9, 159.5, 165.0, 169.2; MS (ESI): m/z 403 (M−).
10-Chloromethyl-7-phenyl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones (6a): White solid, mp 256-258 °C; IR (KBr,
cm-1): 1665 (C=O), 3401 (NH); 1H NMR (300 MHz, DMSO-d6): δ 4.45 (s, 2H), 5.20 (s, 1H), 6.91–8.20 (m, 11H, arom.), 13.01 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): δ 37.7, 43.4, 99.5, 113.4, 118.3, 119.5, 123.4, 123.9, 127.3, 127.8 (2C), 128.1(2C), 129.5 (2C),
134.4, 137.7, 143.8, 147.3, 158.4, 163.1, 168.1; MS (ESI): m/z 373 (M−).
10-Chloromethyl-7-p-methylphenyl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones (6b): White solid, mp 252-254 °C; IR
1
(KBr, cm-1): 1685 (C=O), 3442 (NH); H NMR (300 MHz, DMSO-d6): δ 2.45 (s, 3H) 4.35 (s, 2H), 5.15 (s, 1H), 7.25–8.29 (m, 10H,
arom.), 12.91 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 21.4, 40.3, 42.8, 102.1, 113.9, 119.8, 121.3, 123.4, 124.7, 127.2, 127.8
(2C), 128.4 (2C), 129.5 (2C), 133.5, 137.9, 143.8, 147.3, 158.5, 165.1, 167.4; MS (ESI): m/z 387 (M−).
10-Chloromethyl-7-p-methoxyphenyl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones (6c): White solid, mp 250-252 °C;
IR (KBr, cm-1): 1682 (C=O), 3387 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.66 (s, 3H) 4.45 (s, 2H), 5.24 (s, 1H), 7.15–8.15 (m, 10H,
arom.), 12.96 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 38.2, 42.6, 55.4, 102.8, 114.2, 119.6, 121.1, 123.5, 124.9, 127.1, 128.1
(2C), 128.9 (2C), 129.4 (2C), 133.1, 137.7, 143.9, 147.6, 158.4, 161.4, 167.2; MS (ESI): m/z 403 (M−).
10-Chloromethyl-7-m-methoxyphenyl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones (6d): White solid, mp 250-252 °C;
IR (KBr, cm-1): 1683 (C=O), 3350 (NH); 1H NMR (300 MHz, DMSO-d6): δ 3.62 (s, 3H) 4.44 (s, 2H), 5.27 (s, 1H), 7.11–8.11 (m, 10H,
arom.), 12.80 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ 38.5, 42.7, 55.5, 101.9, 113.3, 119.6, 121.3, 123.6, 124.8, 127.1, 128.1
(2C), 128.8 (2C), 129.5 (2C), 133.2, 137.6, 143.8, 147.6, 158.4, 161.5, 167.6; MS (ESI): m/z 403 (M−).
3. Results and discussion
The compounds, 9-chloromethyl-12-aryl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones 5a-d and 10-chloromethyl-7-
aryl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones 6a-d, were synthesized by two different methods.
In the first method, the synthesis of compounds 5 and 6 involves two steps. Starting materials 3-amino-1-aryl-1H-benzo[f]chromene-
2-carbonitriles 1a-d or 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles 2a-d reacted with excess of chloroacetylchloride (2
equiv.) to afford 2-chloro-N-(2-cyano-1-aryl-1H-benzo[f]chromen-3-yl)-acetamide 3a-d or 2-chloro-N-(3-cyano-4-aryl-4H-
benzo[h]chromen-2-yl)-acetamide 4a-d, followed by Radziszewski’s reaction using urea hydrogen peroxide (UHP) as a mild, safe and
non-hazardous oxidizing agent, leading to compounds 5 and 6. We proceeded initially by conducting the first step in both classical and
microwave-assisted conditions, to compare these two methods (Scheme 1). Under classical conditions, compounds 3 and 4 are
obtained in 39%-51% yields after 48 h reaction time, while with microwave irradiation the same products are isolated in 87%-98%
yields after only 15-20 min reaction time (Table1). We then compared classical conditions versus microwave-assisted procedures for
the second step of the first method. In classical conditions (72 h at 84 °C), the derivatives 5a-d and 6a-d are obtained in 39%-50%
yields, and under microwave irradiation (2 h, reaction time at 70 °C), the same products are prepared in 69%-80% yields (Table 2). The
mechanism of transformation of substrates 3 and 4 to products 5 and 6 proceed via oxidation of the nitrile function to amide followed
by cyclization (Scheme 2).
In the second method, a one step reaction allows the synthesis of pyrimidinones derivatives 5a-d and 6a-d (Scheme 3).
Condensation of compounds 1a-d or 2a-d with a large excess (6 equiv.) of chloroacetylchloride provides the final product 5 or 6. In
this study, we investigate the reaction under classical conditions by varying the temperature and reaction time. After several assays, the
optimum result is obtained when the reaction is carried out in DMF for seven days, at room temperature, but unfortunately, the yields
(32%-35%) obtained were much lower than those previously observed. Under microwave irradiation, the best results are obtained in
Page 4 of 7

DMF at 40 °C during 120 min of reaction (44%-56%) (Table 3). However, it was very difficult to determine conditions providing 5 or
6 without traces of intermediates 3 and 4, even by increasing reaction time and temperature.
4. Conclusion
In the present study, we have investigated the preparation of new naphtopyranopyrimidinones 5a-d and 6a-d using microwave
irradiation. This method is easily and rapidly performed and affords these compounds in very good yield. A second method allows us
to readily synthesize, in one step, the same compounds from aminonitrile naphtopyranque and chloroacetylchloride. In conclusion, the
microwave assisted methods offer significant advantages for the rapid synthesis in high yield and purity of all compounds presented in
this study. The required reaction times and volumes of solvents are much lower.
Acknowledgments
The authors acknowledge the Ministry of Higher Education, Scientific Research and Technology of Tunisia and the University of
Toulouse for financial support.
References
[1] C. Santelli-Rouvier, B. Pradines, M. Berthelot, et al., Arylsulfonyl acridinyl derivatives acting on plasmodium falciparum, Eur. J. Med.
Chem. 39 (2004) 735–744.
[2] A.K. Bhattacharjee, M.G. Hartell, D.A. Nichols, et al., Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6,12-diones
(tryptanthrins). Three dimensional pharmacophore modeling and identification of new antimalarial candidates, Eur. J. Med. Chem. 39 (2004) 59-67.
[3] P. Verhaeghe, N. Azas, S. Hutter, et al., Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines, Bioorg. Med. Chem. 17 (2008)
396-401.
[4] A.S. Hossan, H.M. Abu-Melha, M.A. Al-Omar, et al., Synthesis and antimicrobial activity of some new pyrimidinone and oxazinone derivatives fused with
thiophene rings using 2-chloro-6-ethoxy-4-acetylpyridine as starting material, Moleculs 17 (2012) 13642-13655.
[5] M. Ashok, B.S. Holla, N.S. Kumari, Convenient one pot synthesis of some novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-
methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities, Eur. J. Med. Chem. 42 (2007) 380-385.
[6] F. Hamy, V. Brondani, A. Flörsheimer, W. Stark, et al., A new class of HIV-1 Tat antagonist acting through Tat−TAR Inhibition, Biochemistry 37 (1998)
5086–5095.
[7] A.S. Galabov, E. Velichkova, A. Karparov, et al., Antiviral activity of tetrahydro-2(1H)-pyrimidinones and related compounds, Arzneimittelforschung 34
(1984) 9-14.
[8] S. Karkola, A. Lilienkampf, K. Wähälä, A 3D QSAR model of 17β-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core applying molecular
dynamics simulations and ligand–protein docking, Chem. Med. Chem. 3 (2008) 461–472.
[9] E.S. Lee, J.G. Park, Y. Jahng, A facile synthesis of simple alkaloids-synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids Tetrahedron
Lett. 44 (2003) 1883–1886.
[10] G. Romeo, F. Russo, A. Caruso, et al., Synthesis of new thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones with analgesic and anti-inflammatory activities,
Arzneimittelforschung 48 (1998) 167-172.
[11] M. Messaâd, F. Chabchoub, M. Salem, Action of primary amines and hydroxylamine on ethoxymethyleneaminonaphtopyranes: synthesis of new
naphtopyrano [2,3-d] pyrimidines derivatives, Heterocycl. Commun. 9 (2005) 401–404.
[12] K. Mkaouar, F. Chabchoub, A. Samadi, et al., Convenient synthesis of 11-aryl-1,12-dihydro11H-naphthopyrano[2,3-d]pyrimidin-12-ones, Synth. Commun.
40 (2010) 3405–3414.
[13] F. Chabchoub, M. Messaâd, Ben Mansour, L.C. Ghdira, et al., Synthesis and antigenotoxic activity of some naphtho[2,1-b]pyrano[3,2-e][1,2,4]triazolo[1,5-
c]pyrimidine derivatives, Eur. J. Med. Chem., 42 (2007) 715-718.
[14] E. Maalej, F. Chabchoub, A. Samadi, Cristóbal, et al., Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-
benzo[5,6]chromeno[2,3-b]quinolin13-amines, Bioorg. Medicinal Chem. Lett. 21 (2011) 2384-2388.
[15] E. Maalej, F. Chabchoub, M.J. Oset-Gasque, et al., Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-
benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer’s disease, Eur. J. Med. Chem. 54 (2012) 750-763.
[16] M. Esquivias-Pérez, E. Maalej, A. Romero, F. Chabchoub, et al., Nontoxic and neuroprotective β-naphthotacrines for Alzheimer’s disease, Chem. Res.
Toxicol. 26 (2013) 986-992.
[17] A. Diaz-Ortiz, A. De La Hoz, A. Moreno, Selectivity in organic synthesis under microwave irradiation. Curr. Org. Chem. 8 (2004) 903-918.
Page 5 of 7

Ar
CN
Ar
O
O
CN
Cl
O
N
H
Classical conditions:
DMF, r.t., 48 h
3a-d
NH2
MW conditions:
DMF, 150 W, 40 °C,
15-20 min
1a-d 2a-d
or
Ar
CN
O
O
Cl
O
N
H
Cl
Cl
4a-d
a: Ar = C6H5, b: Ar = p-Me-C6H4, c: Ar = p-MeO-C6H4, d: Ar = m-MeO-C6H4
Scheme 1. General synthetic route of the compounds 3a-d and 4a-d.
Ar
Ar
O
N
O
N
CHNH
O
NH
NH
Cl
Cl
O
Ar
O
O
N
O
H
C
UHP, K2CO3
water/acetone (1:1)
3a-d
5a-d
NH2
O
NH
Classical conditions: 90 °C, 72 h
MW conditions: 70 °C, 1.5-2 h
Ar
Ar
Cl
CN
O
Cl
Cl
O
O
N
H
4a-d
6a-d
a: Ar = C6H5, b: Ar = p-Me-C6H4, c: Ar = p-MeO-C6H4, d: Ar = m-MeO-C6H4
Scheme 2. General synthetic route of the target compounds 5a-d and 6a-d.
Ar
Ar
O
N
CN
O
NH
Ar
Cl
Cl
O
N
H
O
CN
5a-d
3a-d
O
NH2
Ar
O
O
Ar
Cl
CN
NH
O
Cl
Cl
Cl
O
N
O
N
H
4a-d
6a-d
a: Ar = C6H5, b: Ar = p-Me-C6H4, c: Ar = p-MeO-C6H4, d: Ar = m-MeO-C6H4
Scheme 3. General synthetic route of the target compounds 5a-d and 6a-d in one step.
Table 1
Microwave-assisted synthesis of compounds 3a-d and 4a-d.
Products
Ar
CCa
MWb
Yield (%)
Time (h)
48
48
48
48
48
48
48
48
Yieldc (%)
Time (min)
C6H5
51
44
50
42
45
45
39
40
98
89
90
87
96
90
93
88
15
16
17
17
15
20
20
20
3a
3b
3c
3d
4a
4b
4c
4d
p-MeC6H4
p-MeOC6H4
m-MeOC6H4
C6H5
p-MeC6H4
p-MeOC6H4
m-MeOC6H4
a CC: classical conditions.
b MW: microwave conditions.
c Isolated yield.
Page 6 of 7

Table 2
Microwave-assisted synthesis of compounds 5a-d and 6a-d with method 1.
Products
CCa
MWb
Yield (%)
Time (h)
72
72
72
72
72
72
72
72
Yieldc (%)
Time (h)
1.5
2
1.5
1.5
2
2
1.5
1.5
48
39
42
42
50
44
45
42
78
69
72
75
80
74
78
69
5a
5b
5c
5d
6a
6b
6c
6d
a CC: classical conditions.
b MW: microwave conditions.
c Isolated yield.
Table3
Microwave-assisted synthesis of compounds 5a-d and 6a-d with method 2.
Products
CCa
MWb
Yield (%)
Time (days)
Yieldc (%)
Time (h)
35
35
32
32
35
33
35
32
6
7
6
7
7
7
6
7
50
55
56
53
48
44
52
49
2
2.5
2
3
2
3
2.5
3
5a
5b
5c
5d
6a
6b
6c
6d
a CC: classical conditions.
b MW: microwave conditions.
c Isolated yield.
Page 7 of 7