Microwave assisted synthesis of N-arylheterocyclic substituted-4- aminoquinazoline derivatives

Article abstract of DOI:10.3390/11040272

A simple, efficient, and general method has been developed for the synthesis of various N-aryl heterocylic substituted-4-aminoquinazoline compounds from 4-chloro-quinazoline and aryl heterocyclic amines under microwave irradiation using 2-propanol as solvent. The advantages of the use of microwave irradiation in relation to the classical method were demonstrated.

Full text of DOI:10.3390/11040272

Molecules 2006, 11, 272-278
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Microwave Assisted Synthesis of N-Arylheterocyclic
Substituted-4-aminoquinazoline Derivatives
*
Gang Liu, Song Yang, Baoan Song , Wei Xue, Deyu Hu, Linhong Jin and Ping Lu
Center for Research and Development of Fine Chemicals, Guizhou University, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang, 550025, P. R.
China
E-mails: fcc.gliu@gzu.edu.cn, yangsdqj@126.com, shouldww@163.com, fcc.dyhu@gzu.edu.cn,
fcc.lhjin@gzu.edu.cn, luping217@sohu.com
*
Author to whom correspondence should be addressed; e-mail:songbaoan22@yahoo.com
Tel.:(+86)851 3620521, Fax: (+86)851 3622211
Received: 16 January 2006; in revised form: 25 March 2006 / Accepted: 7 April 2006 /
Published: 10 April 2006
Abstract: A simple, efficient, and general method has been developed for the synthesis of
various N-aryl heterocylic substituted-4-aminoquinazoline compounds from 4-chloro-
quinazoline and aryl heterocyclic amines under microwave irradiation using 2-propanol as
solvent. The advantages of the use of microwave irradiation in relation to the classical
method were demonstrated.
Keywords: 4-Aminoquinazoline, Heterocyclic moiety, Microwave irradiation.
Introduction
As part our ongoing research program on heterocyclic compounds which may serve as leads for
designing novel antitumor agents, we were particularly interested in 4-substituted quinazolines [1-2].
We considered the well known activity of the quinazoline nucleus in chemotherapy, where many of its
substituted derivatives are effective antitumor agents [3-6]. Furthermore, more recent data has reported
that a broad class of quinazolines also act as potent and highly selective inhibitors of epidermal growth
factor receptor (EGFR) or epidermal growth factor receptor tyrosine kinase (EGFR-TK) [7-9];

Molecules 2006, 11
273
members of this class are expected to have great therapeutic potential in the treatment of malignant and
nonmalignant epithelial diseases [10-11]. In view of these facts, and in order to study the influence of
4
-position substituted on antitumor activity, we have now prepared a series of new 4-aryl heterocyclic
aminoquinazolines containing diverse heterocyclic moieties in the hope of discovering more active
ATP site inhibitors. In the classical synthesis of these compounds [12-13], a mixture of
4
-chloroquinazoline and aniline are refluxed at 80°C for 12 h. in 2-propanol. This method, however,
involves long reaction times and complex handling and gives low yields of products. We have recently
developed a new synthesis method for the target compounds using microwave irradiation in 2-propanol
(
Scheme 1). The new method requires short reaction times, is very easy and mild and environmentally
friendly. To the best of our knowledge, this is the first report on the synthesis of new quinazoline
compounds containing heterocycle moieties using microwave irradiation.
Scheme 1. Synthesis of N-arylheterocyclic substituted-4-aminoquinazoline derivatives.
O
OH
X
COOH
O
X
X
NH
N
+
NH2
H
NH
2
4-5h
Cl
N
N
X
X
X
1
2
3
R
HN
N
X
X
PCl /POCl3
N
RNH ,MW
2
5
N
24h
i-PrOH,reflux
N
X
X
4
5
X=H, Cl; R= aryl heterocycle
Results and Discussion
The reaction results with or without microwave irradiation are shown in Table 1. It can be seen that
the presence of microwave irradiation both accelerated the reactions and gave higher yields. The
reaction time for synthesis of compounds 5a~5g was shortened from 12 h. to only 20 min. with the
one-step microwave-assisted procedure.
In order to optimize the reaction parameters, we selected compound 5b for further study under
different conditions. These results are shown in Table 2. Without microwave irradiation (Table 1)
compound 5b could be obtained in 37.3% after 12 h. When the reaction was carried out under
microwave irradiation at 80°C for 10 min. the yield of 5b was increased to 91.0%, and increased
further to 96.5% when the reaction time was extended to 20 min. (Table 2, entries 1 and 2). However,
no further improvement of the yield was noted when the reaction time was prolonged to 30 min. (Table
2
, entry 3) and the yield even decreased a little, a fact we attribute to the formation of byproducts.
Consequently, we chose 20 min. as the optimum reaction time (Table 2, entry 2). As for the effect of
the microwave power, it could be seen that when it was increased from 40 to 60, 80 and 100W, the
yields of 5b were 75.9%, 96.5%, 98.8%, and 97.0%, respectively (Table 2, entries 2 and 4-6). Hence,
it’s better for the reaction to be carried out at 60W or higher power settings than at 40W. No
improvement was observed under irradiation when the microwave power varied from 80 to 100W

Molecules 2006, 11
274
(
Table 2, entries 5 and 6). When the reaction temperature was increased from 30°C to 50°C, 70°C or
8
0°C, 5b was obtained in 79.9 %, 84.0 %, 90.0 % and 96.5 % yields respectively (Table 2, entry 2 and
entries 7-9).
a
Table 1 Yields and reaction conditions used for the microwave assisted synthesis of 5a-5g.
b
c
Microwave method
Classical method
Product
Reaction time
20 min.
Yield(%)
84.0
96.5
80.1
79.1
83.1
89.0
92.5
Reaction time
Yield(%)
29.5
5
a
12h
12h
12h
12h
12h
12h
12h
5b
20 min.
20 min.
20 min.
20 min.
20 min.
20 min.
37.3
43.2
38.7
51.3
45.9
24.4
5
c
5d
5
e
5
f
5
g
a
b
c
Yields of isolated products.
Reaction conditions: i-PrOH, reflux under MW (60W power).
Reaction conditions: i-PrOH, reflux temperature.
Table 2. Different conditions used for the microwave assisted synthesis of 5b.
Reaction
a
Entry Reaction time
Power / Watt
Yield / %
temperature / °C
1
2
3
4
5
6
7
8
9
10 min.
20 min.
30 min.
20 min.
20 min.
20 min.
20 min.
20 min.
20 min.
60
60
60
40
80
100
60
60
60
80
80
80
80
80
80
30
50
70
91.0
96.5
92.5
75.9
98.8
97.0
79.9
84.0
90.0
a
Yields of isolated products. Each reaction was repeated three times and the result was averaged.
Conclusions
In summary, the present new method of the formation of N-arylheterocyclic
substituted-4-aminoquinazoline derivatives 5a~5g under microwave irradiation offers several
advantages: faster reaction rates and high yields, while the classical method of formation of
N-arylheterocyclic substituted-4-aminoquinazoline derivatives involves long reaction times (12 h). All
compounds 5a~5g were fully characterized by spectroscopic methods.
Acknowledgements
This work was financially supported by the National Nature Science Foundation of China (Grant
No. 20562002) and the Foundation for New Century Talent in Universities of China and the

Molecules 2006, 11
275
Foundation for Science and Technology Excellent Talent in Guizhou Province, China.
Experimental
General
Unless otherwise indicated, all common reagents and solvents were used as obtained from
commercial supplies without further purification. All melting points of the products were determined
on a XT-4 binocular microscope (Beijing Tech Instrument Co., China) and are not corrected. The
1
infrared spectra were recorded on a Bruker VECTOR22 spectrometer in KBr disks. H-NMR (solvent
1
3
DMSO-d
6
) and C-NMR spectra (solvent DMSO-d
6
) were recorded on a Varian-Inova 400 MHz
O exchange was used to confirm
spectrometer at room temperature using TMS as internal standard. D
2
the assignment of the signals of NH protons. The mass spectra were taken on an HP5988A
spectrometer. Elemental analysis was performed by an Elementar Vario-III CHN analyzer. Microwave
TM
reactions were performed on a variable power Focused Microwave Synthesis, Discover LabMate
equipped with a high sensitivity IR sensor for temperature control and measurement. The following
compounds were prepared as described in the literature: 3,5-dichloro-2-aminobenzoic acid (1b): white
needles, yield 86.4%; m.p. 231~233°C (lit. [14], m.p. 231°C); quinazolin-4-one (3a); white solid, yield
9
5.4%; m.p. 214~215°C (lit. [15], m.p. 215.5~216.5°C); 6,8-dichloroquinazoline-4-one (3b): grey
solid, yield 77.8%; m.p. >300°C (lit. [16], m.p. >300°C); 4-chloroquinazoline (4a): white solid, yield
4.5%; m.p.92~93°C (lit. [15], m.p. 96.5~97.5°C) and 4,6,8-trichloroquinazoline (4b): pale solid,
5
yield 15.3%; m.p.145.5~147.5°C (lit. [17], m.p. 139~140°C).
Synthesis of N-arylheterocyclic substituted-4-aminoquinazolines 5a-g (microwave method): A mixture
of 4-chloroquinazoline (3.0 mmol) and aryl heterocyclic amine (3.0 mmol) in 2-propanol (30 mL) was
stirred for three min., then the mixture was irradiated in the microwave oven at 60W for 20 min. Upon
completion of the reaction, as monitored by TLC, the solvent was removed under reduced pressure and
the residue was washed with water, filtered off and purified by silica gel column chromatography
(
petroleum ether-ethyl acetate, 5:1 v:v) to give the title compounds.
Synthesis of N-arylheterocyclic substituted-4-aminoquinazolines 5a-g (classical method): A solution of
-chloroquinazoline (3.0 mmol) and aryl heterocyclic amine (3.0 mmol), in 2-propanol (30 mL) was
4
stirred under reflux for 12 h. The work-up was carried out as described for the microwave method.
N-(5-methylisoxazol-3-yl)-4-aminoquinazoline (5a). Pale yellow needles, m.p. 188∼190°C; IR: 3275.1,
-1
1
3
149.8, 2988.2, 2850, 1631.7, 1475.5, 1575.8 cm ; H-NMR: δ 10.86 (s, 1H, NH), 8.69 (s, 1H,
quinazoline H-2), 8.62 (d, 1H, J=7.6Hz, quinazoline H-8), 7.60-7.90 (m, 3H, quinazoline H-5,6,7),
1
3
6
3
.99 (s, 1H, isoxazole H-4), 2.37 (s, 3H, CH ); C-NMR: δ 169.1 (quinazoline C-4), 159.1
(
(
(
quinazoline C-2), 157.2 (isoxazole C-5), 154.2 (quinazoline C-9), 149.9 (isoxazole C-3), 133.6
quinazoline C-7), 127.9 (quinazoline C-8), 126.8 (quinazoline C-6), 123.3 (quinazoline C-5), 114.9
+
quinazoline C-10), 98.5 (isoxazole C-4), 12.2 (CH
3
); EIMS: m/z 226 (M , 18.1); Anal. Calc. for
12 10 4
C H N (226.2): C, 63.87; H, 4.34; N, 24.31. Found: C, 63.71; H, 4.46; N, 24.77.

Molecules 2006, 11
276
N-(2-methoxydibenzofuran-3-yl)-4-aminoquinazoline (5b). Pale yellow needles, m.p. 263~264°C; IR:
-
1
1
3
8
4
421.7, 1618.3, 1469.8, 1572.0 cm ; H-NMR: δ 9.23 (s, 1H, NH), 8.84 (s, 1H, quinazoline H-2),
.51(s, 1H, dibenzofuran H-9), 7.24-7.87 (m, 9H, quinazoline H-5,6,7,8 + dibenzofuran H-4,5,6,7,8),
1
3
.05 (s, 3H, OCH3); C-NMR: δ 156.6 (quinazoline C-4), 156.4 (quinazoline C-2), 154.7
(
dibenzofuran C-13), 150.7 (quinazoline C-9), 149.6 (dibenzofuran C-10), 145.2 (quinazoline C-7),
32.7 (dibenzofuran C-2), 128.9 (quinazoline C-8), 128.0 (dibenzofuran C-3), 126.7 (dibenzofuran
C-12), 126.0 (quinazoline C-6), 124.6 (dibenzofuran C-8), 122.4 (dibenzofuran C-7), 120.1
dibenzofuran C-6), 119.7 (quinazoline C-5), 117.7 (quinazoline C-10), 115.7 (dibenzofuran C-5),
11.5 (dibenzofuran C-9), 103.9 (dibenzofuran C-4), 100.7 (dibenzofuran C-11), 56.6 (OCH ); EIMS:
1
(
1
3
+
m/z 341 (M , 14.8); Anal. Calc. for C H N O (341.4): C, 73.93; H, 4.17; N, 12.21. Found: C, 73.89;
2
1
15
3
2
H, 4.43; N, 12.31.
N-(6-methoxybenzothiazol-2-yl)-4-aminoquinazoline (5c). yellow solid, m.p. 231~233°C; IR: 3200,
-1
1
2
982, 2200, 1625.1, 1608.6, 1554.1, 1464.1, 1283.3, 1267.2, 1055.1 cm ; H-NMR: δ 9.14 (s, 1H,
NH), 8.62 (d, 1H, J=8.0Hz, quinazoline H-8), 7.17-8.08 (m, 6H, quinazoline H-2,5,6,7 + Ar-H), 3.85
+
(
s, 3H, OCH ); EIMS: m/z 308 (M , 14.8); Anal. Calc. for C H N OS (308.4): C, 55.73; H, 3.80; N,
3
16 12
4
1
6.25. Found: C, 55.51; H, 3.93; N, 16.32.
N-(6-methoxybenzothiazol-2-yl)-4-aminoquinazoline hydrochloride (5d) Yellow solid, m.p. 300°C
-
1 1
(
(
decomposed); IR: 3100, 2981, 2300, 1645.3, 1580.3, 1453.1 cm ; H-NMR: δ 9.20 (s, 1H, NH), 8.65
d, 1H, J=8.0Hz, quinazoline H-8), 7.19-8.13 (m, 6H, quinazoline H-2,5,6,7 + Ar-H), 3.98 (s, 3H,
+
OCH
3
); EIMS: m/z 345 (M , 11.1); Anal. Calc. for C16
H13ClN
4
OS (344.8): C, 55.73; H, 3.80; N, 16.25.
Found: C, 55.64; H, 3.97; N, 16.03.
N-(6-methylbenzothiazol-2-yl)-4-aminoquinazoline hydrochloride (5e) Orange needles, m.p. 90~92°C;
-1
1
IR: 3093.5, 1612.5, 1556.6, 1483.3, 1323.2 cm ; H-NMR: δ 14.46 (s, 1H, N-H), 8.91 (s, 1H,
quinazoline H-2), 8.19 (d, 1H, J=8.0Hz, quinazoline H-8), 7.65-7.98 (m, 3H, quinazoline H-5,6,7),
+
7
.14-7.48 (m, 3H, Ar-H), 2.28 (s, 3H, CH ); EIMS: m/z 328 (M , 13.0); Anal. Calc. for C H ClN S
3
16 13
4
(
328.8): C, 58.44; H, 3.98; N, 17.04. Found: C, 58.37; H, 3.90; N, 17.11.
6
,8-dichloro-N-(5-methylisoxazol-3-yl)-4-aminoquinazoline (5f). Pale yellow crystals, m.p. 226~228°C;
-1 1
IR: 3259.7, 3223.1, 3030, 1627.9, 11573.9, 1450.5 cm ; H-NMR: δ 11.07 (s, 1H, NH), 8.82 (s, 1H,
quinazoline H-2), 8.79 (s, 1H, quinazoline H-7), 8.21 (s, 1H, quinazoline H-5), 6.98 (s, 1H, isoxazole
+
H-4), 2.46 (s, 3H, CH ); EIMS: m/z 295 (M , 13.0); Anal. Calc. for C H Cl N O (295.1): C, 48.84; H,
3
12
8
2
4
2
.73; N, 18.98. Found: C, 48.64; H, 2.50; N, 19.19.
6
,8-dichloro-N-(2-methoxydibenzofuran-3-yl)-4-aminoquinazoline (5g). Yellow crystals, m.p.
-1
1
2
92~294°C; IR: 3417.9, 1614.4, 1556.6, 1469.8 cm ; H-NMR: δ 9.88 (s, 1H, N-H), 8.69 (d, 1H,
J=2.0Hz, dibenzofuran H-4), 8.58 (s, 1H, quinazoline H-2), 8.19(d, 1H, J=2.0Hz, dibenzofuran H-5),
8
.16 (d, 1H, J=8.0Hz, H-9 dibenzofuran), 7.99 (s, 1H, quinazoline H-7), 7.92 (s, 1H, quinazoline H-5),
.68 (d, 1H, J=8.0Hz, dibenzofuran H-6), 7.52-7.39 (m, 2H, dibenzofuran H-7,8), 3.27 (s, 3H, OCH );
7
3
1
3
C-NMR: δ 158.3 (quinazoline C-4), 156.2 (quinazoline C-2), 155.8 (dibenzofuran C-13), 150.4
(
quinazoline C-9), 149.2 (dibenzofuran C-10), 145.2 (quinazoline C-7), 133.0 (dibenzofuran C-2),

Molecules 2006, 11
277
1
29.8 (quinazoline C-8), 127.2 (dibenzofuran C-3), 126.5 (dibenzofuran C-12), 124.0 (quinazoline
C-6), 123.0 (dibenzofuran C-8), 121.8 (dibenzofuran C-7), 121.5 (dibenzofuran C-6), 121.0
(
quinazoline C-5,10), 116.7 (quinazoline C-10), 111.7 (dibenzofuran C-5,9), 110.5 (dibenzofuran C-4),
+
1
03.3 (dibenzofuran C-11), 56.4 (OCH ); EIMS: m/z 410 (M ,14.1); Anal. Calc. for C H Cl N O
3
21 13
2
3
2
(
410.3): C, 61.48; H, 3.19; N, 10.24. Found: C, 61.20; H, 2.99; N, 10.36.
References
1
2
3
4
5
6
.
.
.
Szczepankiewicz, W.; Suwinski J.; Bujok, R. Synthesis of 4-arylaminoquinazolines and
-aryl-4-arylaminoquinazolines from 2-aminobenzonitrile, anilines and formic Acid or
2
benzaldehydes. Tetrahedron. 2000, 56, 9343-9349.
Tobe, M.; Isobe, Y.; Tomizawa, H.; Nagasaki, T.; Obara, F.; Hayashi, H. Structure-activity
relationships of 6-fluoroquinazolines: dual-acting compounds with inhibitory activities toward
both TNF-alpha production and T cell proliferation. Bioorg. Med. Chem. 2003, 11, 609-616.
Rosowsky, A.; Papoulis, A. T.; Forsch, R. A.; Queener, S. F. Synthesis and antiparasitic and
antitumor activity of 2, 4-diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of
piritrexim. J. Med. Chem. 1999, 42, 1007-1017.
. Jackman, A.L.; Kimbell, R.; Brown, M.; Brunton, L.; Harrap, K. R.; Wardleworth J. M. ; Boyle, F.
T. The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase
inhibitor. Adv Exp Med Biol. 1994, 370, 185-188.
.
Gangjee, A. ; Zaveri, N ; Kothare, M.; Queener, S. F. Nonclassical 2,4-diamino-6-(aminomethyl)
5,6,7,8-tetrahydroquinazoline antifolates: synthesis and biological activities. J. Med. Chem., 1995,
8, 3660-3668.
-
3
.
Griffin, R. J.; Srinivasan, S.; Bowman, K.; Calvert, A. H.; Curtin, N. J.; Newell, D. R.;
Pemberton, L. C.; Golding, B. T. Resistance-modifying agents. 5. Synthesis and biological
properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase
(PARP). J. Med. Chem. 1998, 41, 5247-5256.
7
8
9
.
Smaill, J. B.; Rewcastle, G. W.; Loo, J. A.; Greis, K. D.; Chan, O. H.; Reyner, E. L.; Lipka, E.;
Showalter, H. D. H.; Vincent, P. W.; Elliott, W. L.; Denny, W. A. Tyrosine kinase inhibitors. 17.
Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and
4
-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions.
J. Med. Chem. 2000, 43, 1380-1397.
. Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B. Jr.; Greenberger, L. M.;. Gruber, B. C.;
Johnson, B.D.; Mamuya, N.; Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou, H. R.; Upeslacis, E.;
Wang, Y. F.; Wu, B.; Ye, F.; Zhang, N. 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors
of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-
dialkoxyquinazoline inhibitors. J. Med. Chem. 2000, 43, 3244-3256.
.
Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D. H.;
Fry, D. W.; Kraker, A. J.; Denny, W.A. Tyrosine kinase inhibitors .8. An unusually steep
structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD
1
2
53035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem. 1996, 39,
67-276.

Molecules 2006, 11
278
1
0. Discafani, C. M.; Carroll, M. L.; Floyd, M. B. Jr.; Hollander, I. J.; Husain, Z.; Johnson, B. D.;
Kitchen, D.; May, M. K.; Malo, M. S.; Minnick, A. A. Jr.; Nilakantan, R.; Shen, R.; Wang, Y.-F.;
Wissner, A.; Greenberger, L. M. Irreversible inhibition of epidermal growth factor receptor
tyrosine kinase with in vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-
2
-butynamide (CL-387,785). Biochem. Pharmacol. 1999, 57, 917-925.
1
1. Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Showalter, H. D. H.; Sun, L.; Nelson, J.;
McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny, W. A. Tyrosine kinase inhibitors. 9. Synthesis
and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine
kinase activity of the epidermal growth factor receptor. J. Med. Chem. 1996, 39, 918-928.
2. Lee, J. Y.; Park, Y. K.; Seo, S. H.; So, I. S.; Chung, H. K.; Yang, B. S.; Lee, S. J.; Park, H.; Lee,
Y. S. 1,4-dioxane-fused 4-anilinoquinazoline as inhibitors of epidermal growth factor receptor
kinase. Archiv der Pharmazie., 2001, 334, 357-360.
1
1
3. Lee, Y. S.; Park, H. K.; Lee, J. Y.; Yang, B. S.; Suh, S. H. Preparation of 4-phenylamino-[1,4]
dioxano[2,3-g]quinazolines as tyrosine kinase inhibitors. JP Patent 2003026682 (2003); Chem.
Abstr. 2003, 138, 122652c.
1
1
4. Jersak, U.; Scheuermann, H. Halogenated benzoic acid compounds. DE Patent 2721133 (1978);
Chem. Abstr. 1978, 91, 056647n.
5. Endicott, M. M.; Wick, E.; Mercury, M. L.; Sherrill, M. L. Quinazoline derivatives. I. The
synthesis of 4-(4’-diethylamino-1’-methylbutylamino)quinazoline (SN 11,534) and the
corresponding 2-phenylquinazoline (SN 11,535). J. Am. Chem. Soc., 1946, 68, 1299-1301.
6. Sen, A. B.; Singh, P. R. Search for new antimalarials. III. Synthesis of some substituted
quinazolines. J. Indian Chem. Soc. 1959, 36, 787-791.
1
1
7. Armarego, W. L. F. Quinazolines. IV. Covalent hydration in the cations of sustituted quinazolines.
J. Chem. Soc. 1962, 561-572.
Sample Availability: Samples of the compounds are available from authors.
2006 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.
©