Microwave-assisted synthesis of benzothiazole derivatives using glycerol as green solvent

Article abstract of DOI:10.3184/174751912X13400085970187

A rapid method has been developed for the synthesis of benzothiazoles via the condensation of 2-aminothiophenol with aldehydes under CEM-focused microwave irradiation conditions. The reaction used glycerol as a green solvent without any catalyst, renderin

Full text of DOI:10.3184/174751912X13400085970187

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 489
AUGUST, 489–491
Microwave-assisted synthesis of benzothiazole derivatives using glycerol
as green solvent
Xia-Zhong Zhanga, Wen-Jun Zhou*a, Min Yanga, Jin-Xian Wangb, and Lin Baic
aKey Laboratory of Fruit WasteTreatment and Resource Recycling of the Sichuan Provincial College & College of Chemistry and Chemical
Engineering, Neijiang Normal University, Sichuan 641112, P. R. China
bInstitute of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning Road (E), Lanzhou 730070, P. R. China.
cInstitute of Green Chemistry Experiment andTeaching, Lanzhou City University, Lanzhou, P. R. China
A rapid method has been developed for the synthesis of benzothiazoles via the condensation of 2-aminothiophenol
with aldehydes under CEM-focused microwave irradiation conditions. The reaction used glycerol as a green solvent
without any catalyst, rendering this methodology valuable from both economic and environmental points of view.
Keywords: microwave irradiation, glycerol, benzothiazole, green chemistry
Five-membered heterocyclic rings, such as benzothiazole
derivatives, are present in natural products, in synthetic
agrochemical and pharmaceutical compounds and in organic
synthetic intermediates. They have been widely used in
therapeutic areas including anti-tumour agents, Gram-positive
selective antibacterials, HIV reverse transcriptase inhibitors,
and orexin-1 receptor antagonists.1–3 Classical methods for the
synthesis of benzothiazoles involve the condensation of o-
aminothiophenols with substituted nitriles, aldehydes, carb-
oxylic acids, acyl chlorides, or esters using strong oxidants as
catalysts, such as animal bone meal (ABM) and Lewis acids
doped ABMs,4 FeCl3·6H2O,5 mesoporous mixed metal oxide
nanocrystals,6 Lawesson’s reagent,7 H2O2/Fe(NO3)3,8 Na2S2O5,9
and other methods.10–13 Although successful, many of these
processes suffer from drawbacks such as drastic reaction con-
ditions, low yields, tedious work-up procedures or using toxic
metal salts as catalysts. The main disadvantages are the use of
toxic organic solvents and catalysts that are destroyed in the
work-up and cannot be recovered or reused. Hence, the search
for the better method is still being actively pursued.
Recently, due to environmental and safety considerations,
reduction of costs and the simplicity of the process, attention
has been drawn to reactions using green solvents.14–16 Glycerol
is usually produced as a major by-product of the biodiesel
industry. Indeed, glycerol is abundant, biodegradable, cheap,
non-toxic, non-flammable and has a very high boiling point.17
It is highly polar and immiscible with hydrocarbons and ethers.
It is suitable for biphasic catalysis and for product isolation by
liquid–liquid extraction. All of these properties indicated that
glycerol meets the requirements for consideration as a green
solvent.18,19
has not so far been reported. In our search for developing
efficient protocols for green synthesis,26,27 we describe here the
use of glycerol as a green solvent for the synthesis of benzo-
thiazole derivatives in good yields via the condensation of o-
aminothiophenols with substituted aldehydes under microwave
radiation conditions.
Results and discussion
As a starting point for the development of the microwave-
promoted synthesis of benzothiazole derivatives, we initially
studied the condensation of 2-aminothiophenol and benzalde-
hyde using glycerol as solvent in a CEM focused microwave.
We examined the effects of temperature and power on the
yields of the reaction.
It can be seen from Table 1 that a poor yield of the desired
product was obtained when the temperature was 100 °C at
low power (Table 1, entries 1 and 2). Fortunately, 180 W is
the appropriate power for the reaction and a 92% yield of the
corresponding 2-phenylbenzothiazole was obtained (Table 1,
entries 1–5). Furthermore, lowering or raising the reaction
temperature had no positive effect, and 100 °C was the best
temperature for the condensation (Table 1, entries 4–7).
Comparative reactions were also carried out with conventional
heating condition and an improved reflux microwave oven
which cannot control the temperature.28 The results were not
positive (Table 1, entries 8–10). In contrast to the improved
reflux microwave oven, CEM Focused Microwave can increase
Table
1
Optimised conditions via the condensation of
2-aminothiophenol and benzaldehydea
Microwave-assisted organic synthesis has had a profound
impact on the way that chemists approach organic synthesis.20–22
This enabling technology has now been generally accepted in
industrial research laboratories and is no longer an academic
curiosity. Several organic transformations have been success-
fully realised employing this technique. In contrast to conven-
tional heating, microwave-assisted organic synthesis has
proven to dramatically shorten reaction times, to deliver
cleaner reaction mixtures and hence increases overall yields.
In many instances, CEM focused microwave heating under
sealed vessel conditions has had a dramatic influence on reduc-
ing reaction times, increasing product yields, improving selec-
tivity, using less solvent, and enhancing product purities by
reducing unwanted side reactions compared to conventional
synthetic methods.23–25
Entry
Power/W
Temp/°C
Time/min
Yield/%b
1
2
80
100
120
180
200
180
180
180
600
–
100
100
100
100
100
110
90
–
–
100
8
8
26
42
3
4
67
4
4
92
5
4
89
6
4
90
7
4
82
8
4
Tracec
64c
56d
9
4
10
8 h
a Reaction conditions: 2-aminothiophenol (1.0 mmol), benzal-
dehyde (1.0 mmol), glycerol (2 mL), irradiating under CEM
Focused Microwave. b Isolated yield. c Reactions were performed
with an improved reflux microwave oven. d Conventional
heating was used and the reaction was stirred in an oil bath at
100 °C.
To the best of our knowledge, the synthesis of benzothiazole
derivatives in glycerol under microwave radiation conditions
* Correspondent. E-mail: zhouwj@njtc.edu.cn

490 JOURNAL OF CHEMICAL RESEARCH 2012
Table 2 Synthesis of benzothiazole via the condensation of 2-aminothiophenol and aldehydesa
Entry
Products
Time/min
Yield/%b
M.p./°C
Found
Lit.
1
2
3
4
5
6
7
8
9
R1 = R2 = R3 = R4 = H for 3a
4
4
4
4
4
5
5
8
8
4
4
92
96
94
92
96
94
91
86
90
94
95
113–114
123–124
95–96
110–11129
121–12230
97–9831
R1 = R3 = Cl, R2 = R4 = H for 3b
R1 = Cl, R2 = R3 = R4 = H for 3c
R2 = Cl, R1 = R3 = R4 = H for 3d
R3 = Cl, R1 = R2 = R4 = H for 3e
R3= Br, R1 = R2 = R4 = H for 3f
R3 =NO2, R1 = R2 = R4 = H for 3g
R1 = OH, R4 = Br, R2 = R3 = H for 3h
R3 = OH, R1 = R2 = R4 = H for 3i
R3 = CH3, R1 = R2 = R4 = H for 3j
R3 = OCH3, R1 = R2 = R4 = H for 3k
96–97
97–9831
188–189
147–148
246–247
167–168
226–227
85–86
187–18930
144–14529
244–24530
165–16632
228–22933
85–8629
10
11
121–122
120–12128
12
13
14
3l
3m
3n
8
8
8
82
80
78
135–136
100–101
131–132
137–13829
100–10134
125–12635
a Reaction conditions: 2-aminothiphenol (1.0 mmol), aldehyde (1.0 mmol) and glycerol (2 mL), P = 180 W at 100 °C for the appropri-
ate time. b Isolated yields.
Microwave reactions were conducted using a CEM Focused Micro-
wave Synthesis System (CEM Corp., Matthews, NC). The machine
consists of a continuous focused microwave power delivery system
with operator selectable power output from 0 to 300 W. The pressure
control system uses a load cell for an indirect measurement of the
reaction vessel contents. The load cell is connected to a 10-mL vessel
and senses changes in the external deflection of the septa on top of
the sealed pressure vessel. The temperature control system uses a
non-contact, IR sensor to measure temperature. It is located below the
microwave cavity floor and measures the temperature on the bottom
of the vessel. All experiments were performed using a stirring option
whereby the contents of the vessel are stirred by means of a rotating
magnetic plate located below the floor of the microwave cavity and a
Teflon-coated magnetic stir bar in the vessel.
the yield because it can efficiently stir the substrates and
accurately control the temperature and power.
In order to study the generality of this procedure, the applic-
ability of this green system was then examined for the reac-
tions of a series of aromatic aldehydes with 2-aminothiophenol
under the optimized reaction conditions. As shown in Table 2,
all of the substrates afforded the corresponding benzothiazoles
with good to excellent yields. The reaction of a variety of
aromatic aldehydes bearing electron-withdrawing substituents,
such as chloro, bromo and nitro groups, afforded high yields
of the products (Table 2, entries 2–7). In addition, a hydroxy
group can be tolerated under these condition, and good yields
of the desired products were obtained (Table 2, entries 8
and 9). Further study indicated that reaction of heterocyclic
aldehydes also provided the 2-heterocyclic-substituted benzo-
thiazoles in good yields (Table 2, entries 12–14).
Synthesis of benzothiazole derivatives; general procedure
A mixture of 2-aminothiophenol (1.0 mmol) and the aldehydes
(1.0 mmol) and a magnetic stirrer were placed in a 10 mL glass tube.
Then the vessel was sealed with a septum and placed into the micro-
wave cavity. With the irradiation of 180W, the temperature was ramped
from room temperature to 100 °C where the mixture was vigorously
stirred. After completion of the reaction, the mixture was cooled,
quenched with water (10 mL) and extracted with ethyl acetate (2×
10 mL). The organic layer was dried over anhydrous Mg2SO4 and
evaporated under reduced pressure to give the crude product. The pure
product was obtained by column chromatography on silica gel using
petroleum ether and acetone (10:1 v:v) as the eluent.
Conclusions
In summary, glycerol was found to be an effective and environ-
mentally benign medium for the synthesis of 2-substituted
benzothiazoles under CEM-focused microwave-irradiation
conditions. Excellent yields, short reaction times, mild
reaction conditions and easy work-up procedures make this
a green, facile and superior method for the synthesis of
benzothiazole derivatives.
2-Phenylbenzothiazole (3a): M.p. 113–114 °C, (lit.16 110–111 °C).
1
IR (υ/cm−1): 3240, 2965, 1655, 1526, 1260. H NMR (400 MHz,
Experimental
CDCl3): δ 8.11–8.07 (m, 3H), 7.90 (d, J = 7.6 Hz, 1H), 7.50–7.48 (m,
4H), 7.41–7.35 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 168.0, 154.1,
135.0, 133.6, 130.9, 129.0, 127.5, 126.3, 125.1, 123.2, 121.6. MS m/z
(%): 211 (M+, 100), 134 (81).
The melting points were determined on a WRS-1 A digital melting
point apparatus. IR spectra were measured for KBr discs using an
Alpha Centauri FT-IR spectrophotometer. 1H NMR spectra were
recorded on a Mercury plus 400 MHz spectrometer in CDCl3 with
TMS as an internal standard. 13C NMR spectra were obtained at
100 MHz in CDCl3 with TMS as an internal standard using a Mercury
plus 400 MHz spectrometer. EI-MS were measured on an HP5988A
mass spectrometer.
The work was supported by the project of Sichuan Province
Education Office (No. 12ZB074).

JOURNAL OF CHEMICAL RESEARCH 2012 491
15 P.J. Walsh, H. Li and C.A. De Parrodi, Chem. Rev., 2007, 107, 2503.
16 M.A.P. Martins, C.P. Frizzo, D.N. Moreira, L. Buriol and P. Machado,
Chem. Rev., 2009, 109, 4140.
Received 17 April 2012; accepted 23 May 2012
Paper 1201269 doi: 10.3184/174751912X13400085970187
Published online: 8 August 2012
17 M. Pagliaro, and M. Rossi, The future of glycerol: new usages for a versatile
raw material, RSC Publishing, Cambridge, 2008.
18 Y. Gu and F. Jérôme, Green Chem., 2010, 12, 1127.
19 A. Díaz-Álvarez, J. Feancos, B. Lastra-Barreira, P. Crochet andV. Cadierno,
Adv. Synth. Catal., 2011, 47, 6208.
References
1
E. Oksuzoglu, O. Temiz-Arpaci, B. Tekiner-Gulbas, H. Eroglu, G. Sen,
S. Alper, I. Yildiz, N. Diril, E. Aki-Sener and I. Yalcin, Med. Chem. Res.,
2008, 16, 1.
M. Hranjec, M. Kralj, I. Piantanida, M. Sedic, L. Suman, K. Pavelic and
G. Karminski-Zamola, J. Med. Chem., 2007, 50, 5696.
J.A. Grobler, G. Dornadula, M.R. Rice, A.L. Simcoe, D.J. Hazuda and
M.D. Miller, J. Biol. Chem., 2007, 282, 8005.
Y. Riadi, R. Mamouni, R.Azzalou, M. El Haddad, S. Routier, G. Guillaumet
and S. Lazar, Tetrahedron Lett., 2011, 52, 3492.
X. Fan, Y. He, Y. Wang, Z. Xue, X. Zhang and J. Wang, Tetrahedron Lett.,
2011, 52, 899.
20 P. Appukkuttan, V.P. Mehta and P. Van der Eycken, Chem. Soc. Rev., 2010,
39, 1467.
2
3
4
5
6
7
21 V. Polshettiwar and R.S. Varma, Green Chem., 2010, 12, 743.
22 C.O Kappe and E. Van der Eycken, Chem. Soc. Rev., 2010, 39, 1280.
23 L. Bai and J.-X. Wang, Adv. Synth. Catal., 2008, 350, 315.
24 C. Henry, A. Haupt and S.C. Turner, J. Org. Chem., 2009, 74, 1932.
25 S. Caddick and R. Fitzmaurice, Tetrahedron, 2009, 65, 3325.
26 W.-J. Zhou, K.-H. Wang and J.-X. Wang, J. Org. Chem., 2009, 74, 5599.
27 W. Shi and J.-X. Wang, J. Chem. Res., 2008, 270.
28 J.-X. Wang, Y. Xi, X. Wu, Y. Hu and Z. Du, Synth. Commun., 1998, 28,
4619.
29 G. Evindar and R.A. Batey, J. Org. Chem., 2006, 71, 1802.
30 E. Belgodere, R. Bossio, S. Chimichi, V. Parrini and R. Pepino, Dyes
Pigments, 1983, 1, 59.
P. Bandyopadhyay, M. Sathe, G.K. Prasad, P. Sharma and M.P. Kaushik,
J. Mol. Catal. A: Chem. 2011, 341, 77.
J.A. Seijas, M.P. Vázquez-Tato, M.R. Carballido-Reboredo, J. Crecente-
Campo and L. Romar-López, Synlett, 2007, 313.
8
9
K. Bahrami, M.M. Khodaei and F. Naali, Synlett, 2009, 569.
K.M. Khan, F. Rahim, S.A. Halim, M. Taha, M. Khan, S. Perveen,
M.A. Mesaik and M.I. Choudhary, Bioorg. Med. Chem., 2011, 19, 4286.
31 A. Brembilla, D. Roizard and P. Lochon,Synth. Commun.,1990, 21, 3379.
32 K. Anthony, R.G. Brown, J.D. Hepworth, K.W. Hodgson, B. May and
M.A. West, J. Chem. Soc. Perkin Trans., 1984, 2111.
10 V.I. Cohen and S. Pourabass, J. Heterocycl. Chem., 1977, 14, 1321.
11 D.E. Boger, J. Org. Chem., 1978, 43, 2296.
33 M.T. Bogert and H.B. Corbitt, J. Am. Chem. Soc., 1926, 48, 783.
34 B. Maleki, Collect. Czech. Chem. Commun., 2011, 76, 27.
35 E.B. Melnikova, M.M. Elchaninov, A.A. Milov and B.S. Lukyanov, Chem.
Heterocylic. Comp., 2008, 44, 1070.
13 A. Abbotto, S. Bradnmante, A. Facchetti and G.A. Pagani, J. Org. Chem.,
2002, 67, 5753.
14 N.R. Candeias, L.C. Branco, P.M.P. Gois, C.A.M. Afonso and A.F. Trindade,
Chem. Rev., 2009, 109, 2703.

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