Convenient synthesis of substituted 2-phenylbenzothiazoles using solid-supported triphenylphosphine

Article abstract of DOI:10.1080/00397911.2012.730648

We report an improved procedure using solid-supported triphenylphosphine for the concise synthesis of biologically relevant 2-phenylbenzothiazoles featuring a variety of substituents on both the benzothiazole and phenyl rings. Substituted 2-phenylbenzothi

Full text of DOI:10.1080/00397911.2012.730648

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Convenient Synthesis of Substituted
2-Phenylbenzothiazoles Using Solid-
Supported Triphenylphosphine
Ashley A. Weekes a , Jan Frydrych a b & Andrew D. Westwell a
a School of Pharmacy and Pharmaceutical Sciences , Cardiff
University , Cardiff , Wales , United Kingdom
b Department of Pharmaceutical Chemistry and Drug Control ,
Faculty of Pharmacy, Charles University in Prague , Hradec Králové ,
Czech Republic
Accepted author version posted online: 16 Apr 2013.Published
online: 26 Jun 2013.
To cite this article: Ashley A. Weekes , Jan Frydrych & Andrew D. Westwell (2013): Convenient
Synthesis of Substituted 2-Phenylbenzothiazoles Using Solid-Supported Triphenylphosphine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:19, 2656-2662
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Synthetic Communications1, 43: 2656–2662, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.730648
CONVENIENT SYNTHESIS OF SUBSTITUTED
2-PHENYLBENZOTHIAZOLES USING
SOLID-SUPPORTED TRIPHENYLPHOSPHINE
Ashley A. Weekes,1 Jan Frydrych,1,2 and Andrew D. Westwell1
1School of Pharmacy and Pharmaceutical Sciences, Cardiff University,
Cardiff, Wales, United Kingdom
2Department of Pharmaceutical Chemistry and Drug Control, Faculty of
´
Pharmacy, Charles University in Prague, Hradec Kralove, Czech Republic
´
GRAPHICAL ABSTRACT
Abstract We report an improved procedure using solid-supported triphenylphosphine for the
concise synthesis of biologically relevant 2-phenylbenzothiazoles featuring a variety of sub-
stituents on both the benzothiazole and phenyl rings. Substituted 2-phenylbenzothiazoles
were synthesized by heating equimolar quantities of 2-aminothiophenol disulfides with ben-
zaldehydes and p-toluenesulfonic acid in the presence of polymer-supported triphenylpho-
sphine in dimethylformamide/toluene. Appealing features of this new method include
simple isolation of product (removal of phosphine oxide by-product by filtration), avoid-
ance of column chromatography, and good yields of substituted 2-phenylbenzothiazole
products.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Antitumor agents; bicyclic compounds; heterocycles; 2-phenylbenzothiazoles;
solid-supported reagent
INTRODUCTION
Substituted 2-phenylbenzothiazoles can be regarded as a privileged pharmaco-
phore in medicinal chemistry.[1] A number of 2-phenylbenzothiazoles have been
reported to possess remarkable biological properties, leading to the clinical evalu-
ation of 2-phenylbenzothiazoles in some cases. For example, the potent and selective
2-(4-aminophenyl)benzothiazole series of antitumor agents have been developed
Received September 4, 2012.
Address correspondence to Andrew D. Westwell, School of Pharmacy and Pharmaceutical
Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, Wales CF10 3NB,
UK. E-mail: WestwellA@cf.ac.uk
2656

SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
2657
Figure 1. Representative biologically active 2-phenylbenzothiazoles.
over recent years.[2–6] This work has culminated in the identification of the lysyl
amide prodrug of 2-(4-aminophenyl)-5-fluorobenzothiazole (Phortress, Fig. 1) as a
clinical candidate with potent and selective cytotoxic activity concentrated in certain
tumor types characterized by inducible cytochrome P450 (CYP)1A1 activity.[7–9]
2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, Fig. 1) has also been
reported to possess a potent and selective antitumor activity profile reminiscent of
the corresponding 2-(4-aminophenyl)benzothiazole series.[10] In addition, radiola-
beled 2-(4-aminophenyl)benzothiazoles have been developed as amyloid imaging
agents using positron emission tomography (PET), for potential application in non-
invasive imaging of Alzheimer’s Disease and related neurodegenerative con-
ditions.[11] The 11C-labelled 6-hydroxy-4-(methylaminophenyl)benzothiazole known
as Pittsburgh compound B (Fig. 1) represents the most advanced candidate of this
class in clinical evaluation.[12] The structures of representative biologically active
2-phenylbenzothiazoles are shown in Fig. 1.
Synthetic access to 2-phenylbenzothiazoles unsubstituted on the benzothiazole
ring is frequently achieved via thermal- or microwave-promoted condensation of
2-aminothiophenol with benzaldehydes or benzoic acid derivatives.[1] Reaction of
2-aminothiophenol with benzaldehydes leads to the initial formation of a dihydro-
benzothiazole that is then oxidized to the more stable benzothiazole product either
in situ or more commonly by addition of an external oxidant. A number of oxidant
systems have been reported for conversion to the final benzothiazole product, includ-
ing from our previous work the inexpensive and nontoxic inorganic oxidant sodium
metabisulfite.[13,14] The synthesis of 2-phenylbenzothiazoles containing benzothia-
zole ring substituents is more challenging, because the required substituted 2-ami-
nothiophenols tend to be unstable (prone to oxidation) under ambient conditions
and are consequently not generally commercially available. Access to benzothiazole-
ring substituted 2-arylbenzothiazoles has been previously accomplished by our group
through regiospecific cyclization of 2-bromothioanilides.[15] We have also developed
concise and versatile methods to substituted 2-arylbenzothiazoles through reaction
of stable substituted 2-aminothiophenol disulfides with benzaldehydes promoted
by sodium metabisulfite,[14] or triphenylphosphine and p-toluenesulfonic acid.[4,10]
Synthetic routes to benzothiazole-ring substituted 2-arylbenzothiazoles are summar-
ized in Scheme 1.
The method outlined in Scheme 1 making use of triphenylphosphine=
p-toluenesulfonic acid gives rise to product 2-arylbenzothiazoles with a variety of

2658
A. A. WEEKES, J. FRYDRYCH, AND A. D. WESTWELL
Scheme 1. Synthetic routes to 2-arylbenzothiazoles substituted on the benzothiazole ring.
substitution patterns in moderate to good yields following product purification
by column chromatography (mainly to remove triphenylphosphine-derived by-
products). As part of our general strategy toward the concise and operationally
straightforward synthesis and purification of biologically relevant 2-arylbenzo-
thiazoles, we here report the use of polymer-supported triphenylphosphine in
mediating the reaction between 2-aminothiophenol disulfides and benzaldehydes.
The advantages of polymer-supported reagents (ease of reagent removal by
filtration, recovery, and reuse) have been previously exploited in benzothiazole library
synthesis. An example is provided by the use of the supported hypervalent iodine
reagent poly[4-diacetoxyiodo]styrene (PDAIS) for the synthesis of 2-substituted
benzimidazoles, benzoxazoles and benzothiazoles.[16] Our new method features the
use of commercially available polymer-supported triphenylphosphine to effect rapid
one-pot access to target 2-arylbenzothiazoles in good yields for a variety of substrate
substitution patterns. Target molecules can be accessed in good purity with simple
workup and purification protocols and without the need for column chromato-
graphy, making the method ideally suited for parallel (library) synthesis applications.
RESULTS AND DISCUSSION
Previously we reported the synthesis of 2-phenylbenzothiazoles by heating
2-aminothiophenol disulfides with benzaldehydes in the presence of triphenylpho-
sphine and p-toluenesulfonic acid (PTSA) in toluene.[10] Although this method was
successful in producing a variety of 2-phenylbenzothiazoles, column chromato-
graphy was required to remove phosphine oxide by-products. We now report an
improved method featuring polymer-supported triphenylphosphine that allows
removal of phosphine by-product by filtration, facilitating simple isolation and
purification of benzothiazole product. Initial reaction trials using dry acetonitrile
as solvent did not efficiently yield the desired product. However, the use of DMF
as cosolvent alongside toluene (according to literature precedent[17]) accelerated
the reaction to give full conversion to benzothiazole product after 2 h at reflux, in
good isolated yields (80–97%) following recrystallization from methanol.
In a typical optimized procedure, a mixture of (substituted) 2-aminothiophenol
disulfide (1a–c, 1.0 mol. equiv.), substituted benzaldehyde (2a–g, 0.98 mol. equiv.),
polymer-supported triphenylphosphine (0.98 mol. equiv.), and p-toluenesulfonic acid

SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
2659
Scheme 2. Synthetic route to substituted 2-phenylbenzothiazoles using polymer-supported
triphenylphosphine.
(0.2 mol. equiv.) in toluene=DMF (1:1) were heated under reflux for 2 h. Filtration,
washing (methanol, water), and recrystallization from methanol gave the pure
product (3a–o) in good yields. Isolated yields of benzothiazole products (3a–o) are
1
presented in Table 1. All products were characterized (mp, H and 13C NMR, mass
spectrometry and % C, H, N microanalysis) and compared to previous literature
values (see Supplementary Data). It should be noted that for the products unsubsti-
tuted on the benzothiazole ring (3a–f), commercially available 2-aminothiophenol
can be used in place of the corresponding disulfide to give benzothiazole products
in good yields. For this series of experiments, we used one particular grade of com-
mercially available polymer-bound triphenylphosphine (200–400 mesh, ꢀ3.0 mmol=
g loading, 2% cross-linked with divinylbenzene; Sigma-Aldrich UK product no.
366455); however, experimentation with other similar commercially available grades
did not significantly affect the reaction outcome.
Table 1. Isolated yields for 2-phenylbenzothiazoles 3a–o
Compound
R
R0
Yield (%)
3a
3b
3c
3d
3e
3f
H
H
4-OMe
3,4,5-triOMe
4-OH
97
92
97
83
94
86
88
87
93
92
89
87
94
87
80
H
H
4-NO2
3-NO2
4-Br
H
H
3g
3h
3i
6-F
6-F
6-F
6-F
6-F
6-OEt
6-OEt
6-OEt
6-OEt
4-OMe
4-OH
4-NO2
4-Br
4-CN
3j
3k
3l
4-OMe
4-OH
3m
3n
3o
4-NO2
4-Br

2660
A. A. WEEKES, J. FRYDRYCH, AND A. D. WESTWELL
In conclusion, we report a new, concise, and operationally straightforward
method for the synthesis of a range of biologically relevant substituted 2-phenylben-
zothiazoles in good (>80%) isolated yields, featuring simple product isolation and
purification.
EXPERIMENTAL
Instruments and Reagents
NMR spectra were recorded on a Bruker Avance 500-MHz instrument. All
commercially available starting materials and reagents were purchased
(Sigma-Aldrich, UK) and used without further purification. The required substituted
2-aminothiophenol disulfides (1b and c) were synthesized via hydrolytic ring opening
of the corresponding 2-aminobenzothiazoles as previously described,[10,14] except
unsubstituted disulfide (1a), which is commercially available. For illustrative pur-
poses, the preparative method and spectroscopic data for 2-(4-methoxyphenyl)
benzothiazole (3a) are presented.
Representative Synthesis of 2-(4-Methoxyphenyl)benzothiazole
A mixture of p-anisaldehyde (0.09 mL, 0.73 mmol), p-toluenesulfonic acid
(0.02 g, 0.14 mmol), polymer-supported triphenylphosphine (0.24 g, 0.74 mmol) and
bis(2-aminophenyl)disulfide (0.18 g, 0.74 mmol) was dissolved in toluene and DMF
(1:1, 10 mL). The mixture was heated under reflux for 2 h, allowed to cool, filtered
through celite, and washed with excess methanol (to remove polymer-bound by-
products). The filtrate was then concentrated in vacuo, followed by the addition
of excess water. The crude product precipitate that formed was collected by fil-
tration, washed with water, and recrystallized from methanol to give pure
2-(4-methoxyphenyl)benzothiazole (3a) as a white solid in 97% yield. Mp
122–124 ꢁC (lit. 123–125 ꢁC).[18] 1H NMR (CDCl3) d 7.96 (3H, m, H-4, H-20,
H-60), 7.79 (1H, d, J 7.5 Hz, H-7), 7.39 (1H, t, J 7.5 Hz, H-5), 7.27 (1H, t, J
7.5 Hz, H-6), 6.93 (2H, d, J 8.0 Hz, H-30, H-50), 3.81 (3H, s, OMe).
Supplementary Information
1
Mp and H NMR data for products 3b–o, corresponding to literature data
from previous benzothiazole syntheses, are available online.
ACKNOWLEDGMENTS
We thank the School of Pharmacy and Pharmaceutical Sciences, Cardiff
University, for PhD studentship funding (A. A. W.), and the EU Erasmus scheme
for visiting student support (J. F.). The EPSRC National Mass Spectrometry Centre
(Swansea, UK) is acknowledged for accurate mass determinations.

SUBSTITUTED 2-PHENYLBENZOTHIAZOLES
2661
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