The regiospecific synthesis of 5- and 7-monosubstituted and 5,6- disubstituted 2-arylbenzothiazoles

Article abstract of DOI:10.1016/S0040-4039(99)02076-6

The regiospecific synthesis of a range of antitumour 2- arylbenzothiazoles substituted in the benzothiazole ring is described. In this procedure a bromine atom situated ortho to the anilido nitrogen is used to direct a regiospecific cyclisation where, in the absence of bromine, a mixture of regioisomers is produced. The chemistry described is applicable to the synthesis of 2-arylbenzothiazoles bearing both electron-withdrawing (- NO₂) and electron-donating (-NH₂) substituents on the aryl ring.

Full text of DOI:10.1016/S0040-4039(99)02076-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 425–428
The regiospecific synthesis of 5- and 7-monosubstituted and
5,6-disubstituted 2-arylbenzothiazoles†
Ian Hutchinson, Malcolm F. G. Stevens and Andrew D. Westwell ∗
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, UK
Received 6 October 1999; accepted 2 November 1999
Abstract
The regiospecific synthesis of a range of antitumour 2-arylbenzothiazoles substituted in the benzothiazole ring
is described. In this procedure a bromine atom situated ortho to the anilido nitrogen is used to direct a regiospecific
cyclisation where, in the absence of bromine, a mixture of regioisomers is produced. The chemistry described
is applicable to the synthesis of 2-arylbenzothiazoles bearing both electron-withdrawing (-NO2) and electron-
donating (-NH2) substituents on the aryl ring. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: benzothiazoles; regiospecificity; antitumour compounds; cyclisation.
2-(4-Aminophenyl)benzothiazoles 1, represent a novel class of potent and selective antitumour agents
which exhibit nanomolar inhibitory activity against a range of human breast, ovarian, colon and renal
cell lines in vitro.1 These compounds are the subject of intense current interest in our laboratories due to
their extremely interesting antitumour profile of activity and unique mechanism of action.
Recent studies directed to better understand the biological mechanism of action of the lead compound
1 (X=Me, R=H) have focused on the crucial role of oxidative metabolism mediated by the cytochrome
P450 isoform CYP1A1, resulting in the formation of the 6-hydroxy metabolite (X=Me, R=6-OH).2 In
order to circumvent this undesirable hydroxylation, we required the synthesis of a range of mono- and di-
fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles 1 (X=Me, R=F) which might divert metabolism
elsewhere in the molecule and lead to a new generation of more potent and efficacious antitumour agents.3
∗
†
Corresponding author.
Part 9 of the series ‘Antitumour benzothiazoles’.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02076-6
tetl 16004

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2-Arylbenzothiazoles are most commonly synthesised via one of two major routes. The most common
direct method involves the condensation of an ortho-amino thiophenol with a substituted aromatic
aldehyde, carboxylic acid, acyl chloride or nitrile.4 This method, however, is often not appropriate
for many substituted 2-arylbenzothiazoles due to the difficulties encountered in the synthesis of the
readily oxidisable 2-amino thiophenols bearing substituent groups. Another method which we have
used extensively in our laboratories is that based on the potassium ferricyanide (Jacobsen) radical
cyclisation of thiobenzanilides.5 In the case where cyclisation onto either carbon atom ortho to the
anilido nitrogen produces only one product, the Jacobsen cyclisation is a highly effective strategy for
benzothiazole synthesis (e.g. for the synthesis of 6-substituted benzothiazoles). In the case of the radical
cyclisation of the 3-fluoro- or 3,4-difluoro-substituted thiobenzanilides 2a or 2b, however, a mixture
of the regioisomeric fluorinated benzothiazole products 3a/3b or 4a/4b was produced, which proved
difficult to separate by column chromatography (Scheme 1).
Scheme 1.
A similar mixture of regioisomeric products from the Jacobsen cyclisation has also been observed
previously by Roe and Tucker for the synthesis of 5- and 7-fluoro-2-phenylbenzothiazoles.6 A re-
giospecific synthesis of 2-arylbenzothiazoles unsubstituted in the phenyl ring was developed by the
same authors through the use of a bromo substituent ortho to the anilido nitrogen and formation of
a benzyne intermediate followed by intramolecular cyclisation. A similar strategy has been developed
for the synthesis of a range of 7-substituted benzothiazoles via directed ortho metallation followed by
benzyne formation and subsequent cyclisation.7 These strategies, however, were found to be incompatible
with the nitro functionality on the aryl ring and do not represent a general route to functionalised 2-
arylbenzothiazoles.
In this paper we report the independent synthesis of 5-fluoro- and 7-fluoro-2-(4-amino-3-
methyl)benzothiazole via a base-induced cyclisation/bromide displacement strategy. The methodology
has been extended to the synthesis of the corresponding 5,6-difluoro and 5-bromo benzothiazoles, in all
cases from readily available precursors.
The precursor ortho-bromothiobenzanildes 5a–d are available from 2-bromo-5-fluoro aniline,6 2-
bromo-3-fluoroaniline,8 2-bromo-4,5-difluoroaniline9 and 2,5-dibromoaniline, respectively, via a well-
established route involving amide-formation and thionation.5 The key benzothiazole formation step
is based on methodology reported by Spitulnik10 for the synthesis of 2-methylbenzothiazoles and
involves cyclisation of the thiobenzanilides using sodium hydride in NMP at 140°C in excellent yields,
as shown below. A related base-induced cyclisation/chloride displacement has been reported for 2-
arylbenzothiazoles bearing nitro functionality on the benzothiazole ring.11,12 Reduction of the nitrophen-

427
ylbenzothiazoles 6a–d using tin(II) chloride in ethanol5 gives the desired antitumour 2-(4-amino-3-
methylphenyl)benzothiazoles 7a–d13 as single regioisomers in good yield (Scheme 2).
Scheme 2.
The methodology reported herein represents an attractive alternative to radical cyclisations as a strategy
for benzothiazole formation. The Bu3SnH/AIBN promoted cyclisation of aryl radicals onto thioamides
to form simple 2-arylbenzothiazoles has previously been reported;14 however under these conditions the
(nitrophenyl)thioamides 5 underwent decomposition rather than benzothiazole formation.
An alternative strategy for regiospecific formation of 7 was designed which demonstrates that the
regiospecific ring-forming methodology described herein can be extended to examples where the aryl
substituent is an electron-donating (-NH2) rather than an electron-withdrawing (-NO2) group. Reduction
of the (nitrophenyl)thioamide 5c to the corresponding (aminophenyl)thioamide 8 was accomplished
in 65% yield using the mild indium-mediated reduction conditions recently reported by Moody and
Pitts.15 Although yields for the reduction of other (nitrophenyl)thioamides 5 were at best moderate, this
procedure represents an unusual example of the reduction of an aromatic nitro group in the presence of a
thioamide. The facile cyclisation of 8 was then effected using milder basic conditions than for cyclisation
of 6 (K2CO3 in refluxing acetone) to give benzothiazole product 7c via an alternative route (Scheme 3).
Scheme 3.
In conclusion, the regiospecific synthesis of 5- and 7-monosubstituted and 5,6-disubstituted 2-
arylbenzothiazoles has been accomplished. The methodology described herein is expected to be quite
general for the synthesis of a wide range of substituted 2-arylbenzothiazoles, and work is currently
underway to expand the scope of the key reaction.

428
Acknowledgements
The authors would like to acknowledge the Cancer Research Campaign, UK, for funding. We also
thank Prof. W. R. Bowman (University of Loughborough) for constructive comments and Mr. Bo Wang
and Miss Stephanie Lockwood for preliminary experiments.
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13. General cyclisation procedure: Sodium hydride (1.1 equiv.) was added slowly to a solution of thiobenzanilide in NMP
(10 equiv.) with stirring at room temperature. The mixture was heated at 140°C for 2 h then allowed to cool and poured
into excess water. The resulting white precipitate was collected by filtration and purified by flash column chromatography
(chloroform) to give the required nitrophenylbenzothiazole. Reduction using tin(II) chloride (see Ref. 5) gave the desired
substituted 2-(4-aminophenyl)benzothiazole. 1H NMR data for product 2-(4-aminophenyl)benzothiazoles 7a–d: 7a (DMSO-
d6) 8.07 (1H, dd, J 5.5, 8.8 Hz, H-7), 7.75 (1H, dd, J 2.5, 10.0 Hz, H-4), 7.69 (1H, d, J 1.5 Hz, H-20), 7.65 (1H, dd, J 1.5,
8.3 Hz, H-60), 7.26 (1H, dt, J 2.5, 8.8 Hz, H-6), 6.70 (1H, d, J 8.3 Hz, H-50), 5.77 (2H, brs, NH2), 2.10 (3H, s, CH3); 7b
(DMSO-d6) 7.74 (3H, m, ArH), 7.51 (1H, td, J 5.8, 8.2 Hz, H-5), 7.26 (1H, m, ArH), 6.76 (1H, d, J 5.3 Hz, H-50), 2.16 (3H,
s, CH3); 7c (DMSO-d6) 8.22 (1H, dd, J 8.0, 10.3 Hz, H-7), 7.98 (1H, dd, J 7.4, 11.4 Hz, H-4), 7.63 (2H, m, H-20, H-60),
6.71 (1H, d, J 8.3 Hz, H-50), 2.15 (3H, s, CH3); 7d (CDCl3) 8.13 (1H, d, J 2.0 Hz, H-4), 7.81 (1H, d, J 2.2 Hz, H-20), 7.73
(1H, dd, J 2.2, 8.3 Hz, H-60), 7.69 (1H, d, J 8.5 Hz, H-7), 7.42 (1H, dd, J 1.8, 8.5 Hz, H-6), 6.72 (1H, d, J 8.3 Hz, H-50),
2.25 (3H, s, CH3).
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