Low melting oxalic acid/proline mixture as dual solvent/catalyst for efficient synthesis of 13-aryl-13H-benzo[g]benzothiazolo[2,3-b]buinazoline-5,4-diones under microwave irradiation

Article abstract of DOI:10.1016/j.molliq.2017.07.060

Oxalic acid and proline based deep eutectic solvent (DES) has been identified as an effective catalyst and environmentally benign reaction medium for one-pot synthesis of 13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones via three-component

Full text of DOI:10.1016/j.molliq.2017.07.060

Accepted Manuscript
Low melting oxalic acid/proline mixture as dual solvent/catalyst
for
efficient
synthesis
of
13-aryl-13H-
under
benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones
microwave irradiation
Cui-Ting Ma, Peng Liu, Wei Wu, Zhan-Hui Zhang
PII:
DOI:
Reference:
S0167-7322(17)32620-X
doi: 10.1016/j.molliq.2017.07.060
MOLLIQ 7638
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
16 June 2017
9 July 2017
15 July 2017
Please cite this article as: Cui-Ting Ma, Peng Liu, Wei Wu, Zhan-Hui Zhang , Low melting
oxalic acid/proline mixture as dual solvent/catalyst for efficient synthesis of 13-aryl-13H-
benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones under microwave irradiation,
Journal of Molecular Liquids (2017), doi: 10.1016/j.molliq.2017.07.060
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ACCEPTED MANUSCRIPT
Low melting oxalic acid/proline mixture as dual solvent/catalyst for efficient
synthesis of 13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-
5,14-diones under microwave irradiation
Cui-Ting Ma, Peng Liu, Wei Wu, Zhan-Hui Zhang*
College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, P. R. China
ABSTRACT
Oxalic acid and proline based deep eutectic solvent (DES) has been identified as an effective catalyst and
environmentally
benign
reaction
medium
for
one-pot
synthesis
of
13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones via three-component reaction of aromatic
aldehydes, 2-aminobenzothiazole and 2-hydroxy-1,4-naphthoquinone under microwave irradiation. The reported
approach shows significant advantages such as easy work-up, environment-friendly process, short reaction times,
excellent yields, one-pot multicomponent reaction, chromatography-free purification, the recycling and the re-use
of the DES.
Keywords:
Deep eutectic solvents, Oxalic acid/proline, Multicomponent reaction, 2-Hydroxy-1,4-naphthoquinone, Aldehydes,
2-aminobenzothiazole, 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones
____________________________________________________________________________
*Corresponding
author.
Fax:
+86
31180787431.
E-mail
address:
zhanhui@hebtu.edu.cn,
zhanhui@mail.nankai.edu.cn (Z.-H. Zhang)
1

ACCEPTED MANUSCRIPT
1. Introduction
Nitrogen and sulfur containing heterocycles played a significant role in medicinal chemistry and in the
development of pharmaceutically interesting drugs. Among them, pyrimidines and thiazoles have been well
documented in medicinal chemistry with respect to their significant biological activities such as antimicrobial [1],
antiproliferative [2], antidiabetic [3], anti-cancer [4], antimalarial [5], antiviral [6], antidiabetic [7], and
antiproliferative activities [8]. Pyrimidine derivatives can also be used as acidizing corrosion inhibitors [9]. In
addition, the 1,4-naphthoquinone ring is an important structural motif found in a large number of natural or
synthesized bioactive compounds. These naphthoquinone-based molecules have been shown to possess various
biological activities, such as antimicrobial [10], antiradical [11], antioxidant [12], antileukemic [13] and
anticancer properties [14]. When two or more different heterocyclic moieties are present in a single molecule, a
more pronounced effect is usually observed because it may have all the properties of the moiety and enhance the
pharmacological activity. Despite the significant advancements have been made to develop atom- and
step-economic strategies toward polyheterocylic compounds by combining various structurally diverse motifs [15],
the development of an environmentally friendly methodology for the synthesis of a single structural framework by
combining pyrimidines, thiazoles and 1,4-naphthoquinone motifs is still needed.
From the viewpoint of green chemistry, the development of a high efficiency, environmentally benign, atom-
and step-economical synthesis strategy is a research priority in the field of organic chemistry. One of the most
promising green synthetic strategies is the use of microwave in combination with a green solvent to develop a
one-pot multicomponent reaction (MCR). In recent years, a new family of solvents, so-called low melting
mixtures (LMMs) [16], low-transition-temperature mixtures [17] or deep eutectic solvents (DESs) [18-19] has
introduced as a new nascent sustainable solvent. DESs have similar physical and chemical properties as ionic
liquids (ILs) [20-21] such as non-flammability, low volatility and recyclability but are less toxic, better
biodegradable, attractive low prices, and easier synthesis process. DESs can be simply obtained by mixing and
gently warming a suitable hydrogen bond acceptor (HBA) such as choline chloride (ChCl) with hydrogen-bond
donors (HBD) such as acids, alcohols, amines or carbohydrates. The melting point of DESs is much lower than
that of the individual components and most DESs stay as liquids at room temperature. These inherent beneficial
properties allow DESs to replace volatile organic solvents and ILs in many physical and chemical processes,
especially in extraction and separation processes [22], polymerization and material sciences [23-24], biomass
processing [25] as well as organic synthesis [26-43]. In addition, one-pot MCRs have become an important tool
2

ACCEPTED MANUSCRIPT
for the development of medicinal, organic, and combinatorial chemistry and have become one of the most
powerful synthetic methods for the construction of novel and structurally complex molecules in a single step
without isolation of intermediates from three or more reactants [44]. MCRs offer high synthetic efficiency over
conventional multistep synthesis.
Microwave assisted organic synthesis (MAOS) has recently gained popularity as a widely accepted method
due to a key advantage of modern scientific microwave apparatus. In comparison with traditional heating methods,
the procedure is more convenient, fast, simple and easy to manipulate. A large number of organic reactions can be
carried out under microwave irradiation in higher yields, shorter reaction times, better product purity, lower costs
and easier workup. The successes in MAOS may be attributed to specific microwave effects, low inertia of
heating, the absence of contact between the heated body and the heater, and the possibility of selective heating of
reaction mixture components. The temperature increase is likely to remain uniform throughout the sample which
minimizes the formation of by-products and decomposition products [45]. Thus, the combination of MCR and
DES under microwave irradiation should ensure that the reaction process is convenient, environmentally friendly
and efficient to utilize all reactants in the product framework.
As part of our continuing interest in the development of efficient and environmentally benign synthetic
methodologies [46-49], herein we report
a
novel and effective method for synthesis of
13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones via one-pot three-component reactions of
aromatic aldehydes, 2-aminobenzothiazole and 2-hydroxy-1,4-naphthoquinone under the combination of DES and
microwave irradiation (Scheme 1).
Scheme 1. Synthesis of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones in oxalic acid/proline
2. Experimental section
2.1 General
All reagents were commercially available and used without further purification. Melting points were
determined on an X-5 digital melting point apparatus and are uncorrected. IR spectra were determined on a Bruker
Tensor 27 Fourier transform infrared spectrometer using KBr disks. NMR spectra were recorded on a Bruker
3

ACCEPTED MANUSCRIPT
DRX-500 spectrometer (500 MHz for 1H NMR, 125 MHz for 13C NMR) using CDCl3 as the solvent with TMS as
internal standard. High-resolution mass spectroscopy (HRMS) was recorded on Thermo Scientific LTQ FT Ultra
FT-MS.
2.2. Preparation of oxalic acid and proline based deep eutectic solvent
Oxalic acid and proline based deep eutectic solvent was prepared according to reported method in literatures
[40-41]. Briefly, a mixture of oxalic acid dihydrate (12.6 g, 100 mmol) and proline (11.5 g, 100 mmol) was heated
at 80 oC until a yellowish viscous liquid appeared. It can be directly used without any further purification.
2.3. Typical procedure for preparation of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones
A
mixture of aromatic aldehydes (1 mmol), 2-hydroxy-1,4-naphthoquinone (1 mmol) and
2-aminobenzothiazole (1 mmol) in DES (1.0 ml) was stirred under microwave irradiation at 80 °C for an
appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, the
mixture was cooled to room temperature and cold water was added to the reaction mixture. The insoluble crude
product was isolated by filtration, washed with water and purified by recrystallization from ethanol.
2.4. Selected spectra data for some new compounds
13-(2-Methoxyphenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4b).
Yellow solid; IR (KBr): v 3069, 1639, 1645, 1558, 1515, 1448, 1401, 1322, 1235, 1174, 1078, 948, 750 cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.07-8.11 (m, 4H), 7.74 (t, J = 7.5 Hz, 2H), 7.68 (t, J = 7.5 Hz, 2H), 7.24 (d, J =
7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.87 (t, J = 8.0 Hz, 2H), 6.33 (s, 1H), 3.76 (s, 3H) ppm; 13C NMR (CDCl3,
125 MHz) δ: 184.2, 181.5, 157.4, 154.1, 135.0, 133.0, 129.5, 128.7, 128.1, 127.2, 126.6, 126.2, 122.8, 121.6,
120.3, 113.2, 110.3, 55.7 ppm; HRMS (ESI, m/z): calcd for C25H17N2O3S (M+H)+: 425.0960; found 425.0959.
13-(3-Methoxyphenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4c).
1
Brown solid; IR (KBr): v 3055, 1673, 1625, 1478, 1462, 1361, 1327, 1265, 1128, 1040, 958, 761 cm-1; H
NMR (CDCl3, 500 MHz) δ: 8.12-8.10 (m, 4H), 7.72 (t, J = 9.0, 2H), 7.68 (t, J = 9.0, 2H), 7.20 (d, J = 9.0, 1H),
6.87 (d, J = 9.0, 1H), 6.83 (s, 1H), 6.78-6.76 (m, 1H), 6.23 (s, 1H), 3.72 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz)
δ: 185.3, 181.6, 160.2, 154.1, 139.0, 136.8, 135.0, 134.8, 133.2, 129.7, 126.3, 122.4, 115.1, 113.8, 57.6 ppm;
HRMS (ESI, m/z): calcd for C25H17N2O3S (M+H)+: 425.0960; found 425.0962.
13-(4-Methoxyphenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4d).
1
Yellow solid; IR (KBr): v 3065, 1672, 1525, 1488, 1466, 1363, 1317, 1262, 1148, 1043, 968, 781 cm-1; H
NMR (CDCl3, 500 MHz) δ: 8.09 (d, J = 7.5, 4H), 7.74 (t, J = 7.5, 2H), 7.69 (t, J = 7.5, 2H), 7.19 (d, J = 8.5, 2H),
4

ACCEPTED MANUSCRIPT
6.81 (d, J = 8.5, 2H), 6.17 (s, 1H), 3.77 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 184.8, 181.3, 158.4, 154.7,
135.0, 133.2, 132.7, 129.7, 129.6, 129.2, 127.2, 126.3, 122.9, 113.8, 55.2 ppm; HRMS (ESI, m/z): calcd for
C25H17N2O3S (M+H)+: 425.0960; found 425.0961.
13-(3,4-Dimethoxyphenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4e).
1
Brown solid IR (KBr): v 3066, 1674, 1612, 1513, 1462, 1416, 1361, 1265, 1139, 1024, 971, 724 cm-1; H
NMR (CDCl3, 500 MHz) δ: 8.10 (t, J = 7.5, 4H), 7.76 (d, J = 7.0, 2H), 7.69 (d, J = 7.0, 2H), 6.84-6.80 (m, 2H),
6.76 (d, J = 8.5, 1H), 6.20 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 184.6, 181.7,
148.9, 147.9, 135.0, 133.1, 132.8, 129.7, 127.2, 127.1, 126.3, 122.9, 120.2, 116.2, 112.0, 110.8, 110.4, 56.0, 55.8
ppm; HRMS (ESI, m/z): calcd for C26H19N2O4S (M+H)+: 455.1066; found 455.1065.
13-(4-(tert-Butyl)phenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4h).
1
Brown solid; IR (KBr): v 2961, 1696, 1674, 1571, 1541, 1467, 1362, 1277, 1217, 1107, 829, 728 cm-1; H
NMR (CDCl3, 500 MHz) δ: 8.11 (t, J = 9.0 Hz, 4H), 7.83 (d, J = 9.0 Hz, 2H), 7.75 (t, J = 7.0 Hz, 2H), 7.70 (d, J =
7.0 Hz, 2H), 7.19 (d, J = 7.5 Hz, 2H), 6.32 (s, 1H), 1.37 (s, 9H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 184.8, 158.5,
134.8, 133.0, 129.8, 127.4, 127.2, 126.6, 126.2, 126.0, 125.3, 123.0, 122.4, 113.3, 55.8, 31.1 ppm; HRMS (ESI,
m/z): calcd for C28H23N2O2S(M+H)+: 451.1480; found 451.1483.
13-(2-Chlorophenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4j).
Orange solid; IR (KBr): v 3065, 1646, 1602, 1542, 1431, 1408, 1338, 1305, 1223, 1204, 1012, 922, 723cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.10 (t, J = 9.0 Hz, 4H), 7.76 (t, J = 7.5 Hz, 2H), 7.69 (t, J = 7.5 Hz, 2H),
7.57-7.53 (m, 2H), 7.22-7.17 (m, 2H), 6.36 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 183.7, 181.6, 136.7,
135.2, 134.1, 133.0, 132.9, 129.9, 129.4, 129.3, 128.1, 127.3, 126.4, 126.3, 121.6, 58.3 ppm; HRMS (ESI, m/z):
calcd for C24H14ClN2O2S (M+H)+: 429.0465; found 429.0464.
13-(3-Chlorophenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4k).
Brown solid; IR (KBr): v 3066, 1656, 1662, 1523, 1473, 1448, 1368, 1355, 1233, 1224, 1052, 926, 736 cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.12 (d, J = 7.5 Hz, 2H), 8.06 (d, J = 7.5 Hz, 2H), 7.73 (t, J = 7.5 Hz, 2H), 7.66 (t,
J = 7.5 Hz, 2H), 7.48-7.44 (m, 2H), 7.17 (s, 1H), 6.38 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 184.2, 141.0,
135.0, 133.0, 132.8, 131.1, 129.7, 129.4, 128.2, 127.8, 127.2, 126.3, 125.4, 122.6, 122.1, 113.0, 55.8 ppm; HRMS
(ESI, m/z): calcd for C24H14ClN2O2S (M+H)+: 429.0465; found 429.0466.
13-(4-Bromophenyl)-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4m).
Brown solid; IR (KBr): v 3161, 1662, 1644, 1588, 1715, 1484, 1467, 1362, 1279, 1253, 1071, 931, 739 cm-1;
5

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1H NMR (CDCl3, 500 MHz) δ: 8.10 (t, J = 7.5 Hz,4H), 7.75 (t, J = 7.5 Hz, 2H), 7.69 (t, J = 7.5 Hz, 2H), 7.38 (d, J
13
= 8.0 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.21 (s, 1H) ppm; C NMR (CDCl3, 125 MHz) δ: 184.3, 140.8, 135.5,
134.5, 133.0, 132.9, 130.0, 129.5, 129.3, 128.3, 128.0, 127.3, 127.2, 126.4, 126.3, 115.5, 63.3 ppm; HRMS (ESI,
m/z): calcd for C24H14BrN2O2S (M+H)+: 472.9959; found 472.9959.
4-(7,12-dioxo-12,13-dihydro-7H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazolin-13-yl)benzonitrile (4o).
Brown solid; IR (KBr): v 3068, 1671, 1605, 1574, 1543, 1469, 1366, 1278, 1218, 1159, 1019, 965, 740 cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.12 (d, J = 7.5 Hz, 2H), 8.06 (d, J = 7.5 Hz, 2H), 7.74 (t, J = 7.5 Hz, 2H), 7.68 (t,
J = 7.5 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 6.47 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz)
δ: 184.0, 163.5, 163.0, 135.0, 133.0, 132.9, 129.9, 129.8, 128.8, 127.2, 126.2, 121.8, 119.1, 109.9, 62.2 ppm;
HRMS (ESI, m/z): calcd for C25H14N3O2S (M+H)+: 420.0807; found 420.0809.
1-Methyl-13-phenyl-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4r).
Orange solid; IR (KBr): v 3063, 1667, 1643, 1596, 1525, 1479, 1411, 1366, 1277, 1140, 1039, 963, 726 cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.08-8.14 (m, 4H), 7.75 (t, J = 7.5 Hz, 2H), 7.69 (t, J = 7.5 Hz, 2H), 7.38 (d, J =
7.5 Hz, 1H), 7.21-7.23 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.37 (s, 1H), 2.56 (s, 3H) ppm;
13C NMR (CDCl3, 125 MHz) δ: 184.5, 182.8, 138.9, 134.7, 134.5, 133.0, 132.7, 130.1, 129.8, 129.0, 128.5, 128.2,
127.8, 127.1, 126.2, 126.0, 125.5, 124.0, 123.1, 119.0, 61.8, 17.8 ppm; HRMS (ESI, m/z): calcd for C25H17N2O2S
(M+H)+: 409.1011; found 409.1010.
3-Nitro-13-phenyl-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione (4s).
Brown solid; IR (KBr): v 3065, 1668, 1651, 1574, 1506, 1460, 1335, 1295, 1278, 1128, 1045, 892, 725 cm-1;
1H NMR (CDCl3, 500 MHz) δ: 8.11 (t, J = 8.5 Hz, 4H), 7.76 (t, J = 7.5 Hz, 3H), 7.70 (t, J = 7.5 Hz, 3H), 7.55 (t, J
13
= 7.5 Hz, 1H), 7.22-7.27 (m, 1H), 6.31 (s, 1H) ppm; C NMR (CDCl3, 125 MHz) δ: 184.7, 181.7, 155.7, 138.2,
135.0, 133.1, 132.8, 129.7, 129.0, 128.3, 128.0, 127.2, 126.6, 126.3, 122.7, 117.5, 63.2 ppm; HRMS (ESI, m/z):
calcd for C24H14N3O4S (M+H)+: 440.0705; found 440.0704.
3. Results and Discussion
The preparation of oxalic acid and proline based DES was performed by mixing oxalic acid and proline
under heating at 80 ºC until a homogenous yellowish viscous liquid was formed (Scheme 2). Then, the mixture
was cool to room temperature and the resulting eutectic solvent can be used directly without any further
purification. This method gives DES with a 100% atomic economy because there is no by-product formation
during the preparation of DES.
6

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Scheme 2. Preparation of oxalic acid and proline based DES
Then, the three-component reaction of benzaldehyde, 2-hydroxynaphthalene-1,4-dione and
2-aminobenzothiazole was chosen as the model reaction for optimisation of the experimental parameters. Initially,
the efficiency of different DESs was evaluated. As seen in Table 1, some DESs such as choline chloride
(ChCl)/FeCl3, ChCl/ZnCl2, ChCl/urea, ChCl/itaconic acid, ChCl/tartaric acid, ChCl/p-TsOH acid, ChCl/citric acid,
ChCl/oxalic acid could catalyze the reaction under microwave irradiation to furnish the expected product 4a in
42-84% yield (Table 1, entries 2-9). To our great delight, the yield could be increased to 95% when oxalic
acid/proline was used (entry 18). Based on these results, the reaction temperature was further evaluated. It was
o
found that lower yields were obtained when the reactions were performed at lower temperature (< 80 C,
o
entries11-13). Therefore, 80 C was chosen for subsequent studies. We further optimized the amount of oxalic
acid/proline and found that the best amount of DES was 1.0 ml. A control experiment showed that only trace of
product could be observed in the absence of DES. In addition, we also investigated the influence of not having
microwave irradiation for this reaction (entry 18). It was found that the reaction under simple heating condition
required longer reaction time and the expected product was obtained in relatively lower yield than under
microwave irradiation. The effect of microwave power on the reaction was also examined. The results showed
that 500 W was the appropriate power for this reaction. These results indicated that microwave irradiation
effectively accelerated this three-component reaction.
In order to display the practical applicability, this methodology was assessed on a larger scale. Gratifyingly,
the model reaction was found to proceed smoothly on a 100-mmol scale to afford the desired product in 94% yield
(entry 22). On the same scale, the recovery and recyclability of deep eutectic solvent was also investigated for the
selected model reaction. At the end of the reaction, the mixture was cooled to room temperature and cold water
was added to the reaction mixture. The insoluble product was isolated by simple filtration and subsequent washing
o
with water. The filtrate including DES was evaporated under reduced pressure, dried in a vacuum at 100 C. The
recycled DES was reused in the next run. The results showed that even five cycles the DES could also drive the
reaction and provide the product in a fairly good yield (entry 23).
7

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Table 1
Optimization of the reaction conditionsa
Entry DES
Temperature (oC)
80
MW (W) Time (min)
Yield (%)b
trace
1
No
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
0
60
30
30
30
30
30
30
30
30
20
20
20
20
20
20
20
20
120
40
30
20
30
20
2
ChCl/FeCl3 (1:2)
80
80
80
80
80
80
80
80
80
50
60
70
90
80
80
80
80
80
80
80
80
80
42
3
ChCl/ZnCl2 (1:2)
45
4
ChCl/urea (1:2)
54
5
ChCl/itaconic acid (1:1)
ChCl/tartaric acid (2:1)
ChCl/p-TsOH acid (1:1)
ChCl/citric acid (1:2)
ChCl/oxalic acid (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
Oxalic acid/proline (1:1)
72
6
76
7
78
8
81
9
84
10
11
12
13
14
15c
16d
17e
18
19
20
21
22f
23g
95
53
52
85
95
65
82
95
90
300
400
600
500
500
88
89
95
94
92, 90, 89, 86, 85
a Reaction conditions: benzaldehyde (1 mmol), 2-hydroxynaphthalene-1,4-dione (1 mmol), 2-aminobenzothiazole
o
(1 mmol) in solvent (1.0 ml) at 80 C under microwave irradiation (500 W) unless otherwise specified in the
table.
b Isolated yield.
c The reaction was performed in 0.50 ml oxalic acid/proline.
d The reaction was performed in 0.75 ml oxalic acid/proline.
e The reaction was performed in 1.25 ml oxalic acid/proline.
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f The reaction was carried out in 100 mmol scale.
g DES was reused for 5 times.
Under the optimizing the reaction conditions, the scope and generality of this protocol were explored. As
t
summarized in Table 2, various aromatic aldehydes bearing electron-rich (OMe, Me and Bu) or electron-poor
groups (F, Cl, Br, NO2 and CN) reacted with 2-hydroxynaphthalene-1,4-dione and 2-aminobenzothiazole to afford
the desired products in high yields. The product yields were only slightly affected by the location of the
substituents (on ortho-, meta-, or para-positions of the benzene ring). Notably, halo-substituted aldehydes were
successfully converted into target products, which allowed for easy further synthetic modifications. Furthermore,
the acid-sensitive heterocyclic aldehydes such as furan-2-carbaldehyde and 2-thiophene-carbaldehyde were found
to be suitable substrates for this reaction and generated the corresponding products in 85% and 89% yields,
respectively (entries 16 and 17). Unfortunately, reactions with aliphatic aldehydes such as 3-methylbutyraldehyde
and cyclohexanecarbaldehyde were unsuccessful. Notably, the current reaction with electronically-differentiated
2-aminobenzothiazoles also worked well to afford the corresponding products 4r and 4s in high yield (entries 18
and 19).
Table 2
Synthesis of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones in oxalic acid/proline.
m.p./oC
Entry Ar
R1
Product
Time/min
Yield/%a
Found
Reported
1
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10
15
12
10
20
20
10
10
25
25
20
20
20
20
20
95
92
90
93
91
91
92
91
88
92
94
95
92
93
93
262-263
261-262 [50]
4a
4b
4c
4d
4e
4f
2
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
4-MeC6H4
4-(CH3)3CC6H4
4-FC6H4
213-214
247-248
224-225
236-237
278-279
227-228
228-229
290-292
210-211
239-240
271-272
216-217
310-311
260-261
3
4
5
6
278-279 [50]
228-229 [50]
7
4g
4h
4i
8
9
289-290 [50]
10
11
12
13
14
15
2-ClC6H4
4j
3-ClC6H4
4k
4l
4-ClC6H4
272-273 [50]
310-311 [50]
4-BrC6H4
4m
4n
4o
4-NO2C6H4
4-CNC6H4
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16
17
18
19
2-Furanyl
H
20
20
25
25
85
89
85
86
310-311
309-310
234-235
239-240
309-310 [50]
308-309 [50]
4p
4q
4r
4s
2-Thiophenyl
H
Ph
Ph
4-Me
6-NO2
a Isolated yield.
On the basis of the experimental results described above and previous literature report [50], a plausible
mechanism for the synthesis of 13-phenyl-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]quinazoline-7,12(13H)-dione
(4a) is proposed (Scheme 3). It is assumed that DES may play dual role as solvent and catalyst in promoting
Knoevenagel condensation between benzaldehyde and 2-hydroxy-1,4-naphthoquinone by activation of carbonyl
carbon of benzaldehyde through hydrogen bonding to give intermediate I. This is followed by Michael addition
of 2-aminobenzothiazole to the C=C bond of intermediate I and on tautomerization to generate intermediate II.
Then, an intramolecular cyclic condensation between the amino and the carbonyl groups of the Michael adduct
II occurred to yield intermediate III, which finally underwent dehydration and aromatization to afford the
desired product 4a. We think that the hydrogen bonding nature of DES enhances the electrophilicity of the
carbonyl groups in three steps: Knoevenagel condensation, Michael addition, and intramolecular cyclization.
Scheme 3. A plausible mechanism for the synthesis of 13-phenyl-12H-benzo[g]benzo[4,5]thiazolo[2,3-b]
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quinazoline-7,12(13H)-dione
4. Conclusion
In summary, we have successfully developed a novel process for synthesis of 13-aryl-13H-benzo[g]benzothiazolo
[2,3-b]quinazoline-5,14-diones
via one-pot three-component reactions of aromatic aldehydes,
2-aminobenzothiazole and 2-hydroxy-1,4-naphthoquinone using oxalic acid and proline based deep eutectic
solvent as an effective catalyst and environmentally benign reaction medium under microwave irradiation. The
current method can be readily scaled up to a preparative scale with some advantages such as cleaner reaction
profile, short reaction time, high yields, simple workup procedure and avoidance of the use of toxic organic
solvents and chromatographic separation.
Acknowledgments
Financial support for this work from the Nature Science Foundation of Hebei Province (No. B2015205182) and
the National Natural Science Foundation of China (No. 21272053) is gratefully acknowledged.
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Graphical abstract
Low melting oxalic acid/proline mixture as dual solvent/catalyst for efficient synthesis of
13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones under microwave irradiation
Cui-Ting Ma, Peng Liu, Wei Wu, Zhan-Hui Zhang*
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Highlights
 The preparation of oxalic acid and proline based deep eutectic solvent is very easy.
 The DES plays dual role as solvent and catalyst for one-pot three-component reaction.
 The separation and purfication procedure are very simple.
 The DES can be easily recovered and reused.
16