Rapid and convenient thermal or microwave-assisted synthesis of substituted 2-phenylbenzothiazoles

Article abstract of DOI:10.1080/00397910903353739

A simple one-step method for the synthesis of biologically relevant 2-phenylbenzothiazoles has been developed, using sodium metabisulfite as an oxidant following condensation between 2-aminothiophenol and substituted benzaldehydes. Attractive features of

Full text of DOI:10.1080/00397910903353739

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Rapid and Convenient Thermal or
Microwave-Assisted Synthesis of
Substituted 2-Phenylbenzothiazoles
Ashley A. Weekes a , Matthew C. Dix b , Mark C. Bagley b & Andrew
D. Westwell a
a Welsh School of Pharmacy, Cardiff University, Cardiff, Wales, UK
b School of Chemistry, Cardiff University, Cardiff, Wales, UK
Published online: 13 Sep 2010.
To cite this article: Ashley A. Weekes , Matthew C. Dix , Mark C. Bagley & Andrew D. Westwell
(2010) Rapid and Convenient Thermal or Microwave-Assisted Synthesis of Substituted 2-
Phenylbenzothiazoles, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:20, 3027-3032, DOI: 10.1080/00397910903353739
To link to this article: http://dx.doi.org/10.1080/00397910903353739
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Synthetic Communications1, 40: 3027–3032, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903353739
RAPID AND CONVENIENT THERMAL OR
MICROWAVE-ASSISTED SYNTHESIS OF
SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
Ashley A. Weekes,1 Matthew C. Dix,2 Mark C. Bagley,2 and
Andrew D. Westwell1
1Welsh School of Pharmacy, Cardiff University, Cardiff, Wales, UK
2School of Chemistry, Cardiff University, Cardiff, Wales, UK
A simple one-step method for the synthesis of biologically relevant 2-phenylbenzothiazoles
has been developed, using sodium metabisulfite as an oxidant following condensation
between 2-aminothiophenol and substituted benzaldehydes. Attractive features of this new
method include excellent yields under both microwave-assisted or thermal conditions (it is
tolerant of a variety of substituents on the phenyl ring) and simple product isolation without
the need for chromatographic purification.
Keywords: Antitumor
2-phenylbenzothiazoles
agents;
bicyclic
compounds;
heterocycles;
microwave
synthesis;
INTRODUCTION
Structurally simple 2-phenyl-1,3-benzothiazole derivatives have been shown to
possess remarkable biological properties, particularly in the area of cancer drug dis-
covery.[1,2] For example, 2-(4-amino-3-methylphenyl)benzothiazole (DF 203) was
found to possess potent and selective antitumor activity against panels of human
cancer cell lines, and a fluorinated DF 203 prodrug (Phortress) has now entered
clinical trials for cancer.[3–5] The structurally related 2-(3,4-dimethoxyphenyl)-
5-fluorobenzothiazole (PMX 610) has also shown potent and selective in vitro
antitumor properties[6] reminiscent of the (aminophenyl)benzothiazole series. In
addition, (aminophenyl)benzothiazole derivatives have attracted considerable
interest in potential diagnosis of Alzheimer’s disease using positron emission tom-
ography,[7,8] progressing to clinical evaluation in the case of Pittsburgh compound
B. The structures of these biologically relevant 2-phenylbenzothiazole derivatives
are presented in Fig. 1.
The synthesis of 2-phenylbenzothiazoles is most commonly accomplished by
the thermal or microwave-promoted condensation of 2-aminothiophenol with either
Received August 11, 2009.
Address correspondence to Andrew D. Westwell, Welsh School of Pharmacy, Redwood Building,
Cardiff University, King Edward VII Avenue, Cardiff, Wales, CF10 3NB, UK. E-mail: WestwellA@
cf.ac.uk
3027

3028
A. A. WEEKES ET AL.
Figure 1. Biologically relevant 2-phenylbenzothiazoles.
a substituted benzoic acid derivative (usually in a high-boiling solvent such as poly-
phosphoric acid) or a benzaldehyde. Synthetic methods and biological activity for
selected 2-phenylbenzothiazoles have recently been reviewed.[9] A wide range of sub-
stituted benzaldehydes is commercially available; nevertheless in the case of benzalde-
hydes, the initial product is a 2,3-dihydrobenzothiazole that must be further oxidized
to the fully aromatic benzothiazole. An example of where further oxidation is required
is the microwave-promoted synthesis[10] of 2-substituted benzothiazoles from benzal-
dehydes, where oxidation was achieved in the presence of cocatalysts=oxidants such
as iodine,[11,12] silica gel,[13] or zirconium(IV) oxide chloride=copper(II) sulfate.[14]
However, because these procedures required chromatographic purification following
microwave irradiation, there is still a need for the development of straightforward syn-
thetic routes to 2-phenylbenzothiazoles characterized by simple product isolation and
(nonchromatographic) purification. Sodium metabisulfite (Na2S2O5), an inexpensive
and nontoxic inorganic oxidant, has previously been used in the microwave-promoted
synthesis of 2-arylbenzimidazoles from benzaldehydes and o-phenylenediamine.[15]
In this work, we developed a simple method for rapid access to a range of sub-
stituted 2-phenylbenzothiazoles that could be applied to a parallel (library) synthesis
format, requiring no chromatographic purification. To meet our criteria of a rapid
one-pot method with simple workup and purification, we were particularly attracted
to the microwave method[10] using substituted benzaldehydes and 2-aminothiophenol
as condensation partners. We now report a simple and high-yielding synthesis of sub-
stituted 2-phenylbenzothiazoles under microwave-promoted or thermal conditions
from various benzaldehydes and 2-aminothiophenol in the presence of sodium
metabisulfite. The related oxidant, silica-supported sodium hydrogen sulfate, has pre-
viously been reported as a heterogenous catalyst for the synthesis of 2-arylbenzothia-
zoles in excellent yield.[16] Our new sodium metabisulfite–promoted method features
short reaction times with simple product isolation without the need for column
chromatography and is ideally suited for parallel (library) synthesis applications.
RESULTS AND DISCUSSION
We report herein a simple, one-pot method for the synthesis of biologically rel-
evant 2-phenylbenzothiazoles (3a–m) from 2-aminothiophenol (1) and substituted
benzaldehydes (2a–m) using sodium metabisulfite as a mild oxidant in dimethylsulf-
oxide (DMSO) at 120 ꢀC under both thermal and microwave conditions (Scheme 1).

SYNTHESIS OF SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
3029
Scheme 1. Reaction conditions for the synthesis of substituted 2-phenylbenzothiazoles.
Our investigations of solvent effects found that the most efficient conditions for
formation of benzothiazole product under thermal or microwave conditions were
obtained when DMSO was used as solvent. The efficiency of DMSO in promoting
reaction is likely a result of its optimal reagent dissolution and oxidizing agent
properties, and efficient dissolution is a particularly important consideration for
microwave-promoted reactions. Formation of benzothiazole products in excellent
yield could also be achieved using dimethylformamide (DMF) at 90 ꢀC as solvent,
although in these cases reaction times were longer (>2 h), in part because of the
lower solubility of reaction components in DMF. Although the use of sodium meta-
bisulfite or DMSO alone led to product formation, use of these reagents in combi-
nation led to a significant reduction in reaction time (to 25–120 min). Heating at
greater temperatures in the microwave led to shorter reaction times; however, the
formation of by-products necessitated chromatographic purification of product,
leading to more lengthy and complex purification procedures. In a typical optimized
procedure, 2-aminothiophenol (3.13 mmol) and benzaldehyde (3.16 mmol) in the
presence of sodium metabisulfite (3.16 mmol) and DMSO (2 mL) were heated under
thermal or microwave conditions at 120 ꢀC for the specified time (Table 1). On
addition of water, the corresponding substituted 2-phenylbenzothiazoles were
Table 1. Isolated product yields for the thermal and microwave-promoted synthesis of 2-arylbenzothiazolesa
Time (min)
MW
60
Yield (%)a
MW
Entry
Benzaldehyde
D
D
Mp (ꢀC)
Lit. mp (ꢀC)
Ref.
a
b
c
d
e
f
4-OH
3-OH
30
83
85
83
80
88
81
80
97
75
91
95
95
90
80
84
76
70
75
76
82
85
80
90
98
90
88
228–230
159–160
122–124
80–81
227
13
17
18
19
12
20
11
18
12
21
21
22
23
30
35
30
30
30
30
45
25
90
90
60
60
60
60
161–163
123–125
81–82
4-OMe
3-OMe
3,4-OMe
3,4,5-OMe
4-Br
25
30
129–131
142–145
127–129
230–232
186–188
156–159
169–172
97–99
132–133
141–144
132
35
30
g
h
i
4-NO2
3-NO2
4-CF3
4-CN
120
120
120
120
120
120
228–230
183–185
161–162
169–170
96.5
j
k
l
3-Cl
3-F
b
—
m
71–73
aAll yields refer to isolated products that were characterized by mp, 1H NMR, 13C NMR, mass spec-
trometry, and microanalysis (% C, H, N).
bCompound identity established by comparison of 1H NMR data.

3030
A. A. WEEKES ET AL.
obtained in good to excellent yields in high purity. All products were fully character-
1
ized (mp, H and 13C NMR, mass spectrometry and % C, H, N microanalysis) and
compared to previous literature values (Table 1).
To investigate the scope of the reaction, both electron-withdrawing and
electron-donating groups on the benzaldehyde were studied. Products containing
both electron-donating groups (e.g., OMe, 3c–d) or electron-withdrawing groups
(e.g., NO2, 3h–i) were efficiently transformed to the corresponding 2-phenylben-
zothiazole products in excellent yield following simple product workup and iso-
lation. Notably phenolic benzaldehydes (3a, b; R ¼ 4-OH or 3-OH) gave good
yields of product without the need for either protection of the phenolic group or
further purification. Alternatively, heating the reaction components in DMF at
90 ꢀC gave rise to products (3a–m) in >75% yield following the same simple workup
procedure, although with longer reaction times (4–10 h).
In conclusion, we have developed a simple one-step procedure for the synthesis
of biologically relevant 2-phenylbenzothiazoles under either thermal or microwave-
promoted conditions. Careful control over reaction conditions allowed the efficient
synthesis of a range of benzothiazoles in excellent yield with simple product isola-
tion and purification. Work is under way to extend this simple protocol to 2-
arylbenzothiazoles substituted on the benzothiazole ring and to investigate their
biological properties.
EXPERIMENTAL
Instruments and Reagents
The microwave-assisted reactions were performed using a CEM Discover
single-mode microwave synthesizer by moderating the initial power (100 W).
NMR spectra were recorded on a Bruker Avance 500-MHz instrument. All starting
materials and reagents were purchased (Sigma-Aldrich, UK) and used without
further purification. For illustrative purposes, the preparative method and
spectroscopic data for 4-benzothiazol-2-yl-phenol (3a, thermal conditions) and
4-bromophenylbenzothiazole (3g, microwave conditions) are presented.
Typical Synthesis for 4-Benzothiazol-2-yl-phenol (3a)
(Thermal Conditions)
A mixture of 2-aminothiophenol (0.33 mL, 3.13 mmol), 4-hydroxybenzalde-
hyde (0.39 g, 3.16 mmol), and sodium metabisulfite (0.60 g, 3.16 mmol) in DMSO
(2 mL) was heated at 120 ꢀC for 30 min. The reaction mixture was allowed to cool
to room temperature, excess water was added, and the solid precipitate was collected
by filtration. The precipitate was washed with excess water and dried to give
1
4-benzothiazol-2-yl-phenol (3a) in 83% yield. Mp 228–230 ꢀC (lit.[13] 227 ꢀC). H
NMR (500 MHz; DMSO-d6) 10.30 (1H, s, OH), 8.07 (1H, d, J 7.0 Hz, H-4), 7.98
(1H, d, J 8.0 Hz, H-7), 7.93 (2H, d, J 8.5 Hz, H-20, H-60), 7.50 (1H, t, J 7.5 Hz,
H-5), 7.4 (1H, t, J 7.5 Hz, H-6), 6.94 (2H, d, J 8.5 Hz, H-30, H-50). 13C NMR
(125 MHz, DMSO-d6) 167.43, 160.49, 153.7, 134.08, 129.01, 126.38, 124.86,

SYNTHESIS OF SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
3031
124.03, 122.26, 122.06, 116.06. Anal. calculated for C13H9NOS: C, 68.70; H, 3.99; N,
6.16. Found: C, 68.43; H, 4.05; N, 6.25.
Typical Synthesis of 4-Bromophenylbenzothiazole (3g)
(Microwave Conditions)
A homogenous mixture of 2-aminothiophenol (0.33 mL, 3.13 mmol), 4-bromo-
benzaldehyde (0.58 g, 3.16 mmol), and sodium metabisulfite (0.60 g, 3.16 mmol) in
DMSO (2 mL) was irradiated in a sealed tube at 120 ꢀC for 25 min by moderating
the initial power (100 W). The reaction mixture was allowed to cool to room
temperature, excess water was added, and the solid precipitate was collected by
filtration. The precipitate was washed with excess water and dried to give
1
4-bromobenzothiazole (3g) in 82% yield. Mp 127–129 ꢀC (lit.[11] 132 ꢀC). H NMR
(500 MHz; CDCl3) 8.10 (1H, d, J 8.0 Hz, H-4), 7.99 (2H, d, J 7.5 Hz, H-30, H-50),
7.93 (1H, d, J 8.0 Hz, H-7), 7.65 (2H, d, J 7.5 Hz, H-20, H-60), 7.53 (1H, t,
J 8.0 Hz, H-6), 7.43 (1H, t, J 8.0 Hz, H-5). 13C NMR (125 MHz, CDCl3) 166.69,
154.11, 135.07, 132.59, 132.25, 128.92, 126.51, 125.46, 125.42, 123.35, 121.67. Anal.
calcd. for C13H8BrNS: C, 53.81; H, 2.78; N, 4.82. Found: C, 53.91; H, 2.78; N, 4.70.
ACKNOWLEDGMENTS
We thank the Welsh School of Pharmacy, Cardiff University, for PhD student-
ship funding (ADW=AAW), and the BBSRC (BB=D524140) for research grant
funding (MCB=MCD).
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