Solid phase synthesis of benzothiazolyl compounds

Article abstract of DOI:10.1016/S0040-4039(01)00109-5

2-Aminobenzenethiol, bound through its thiol function to the 2-chlorotrityl (Clt)-, trityl (Trt)-, 4-methyltrityl (Mtt)- and 4-methoxytrityl (Mmt)-resins, was acylated at the amino-function by aliphatic and aromatic acids. The obtained 2-N-acyl-aminobenzenethiols were cleaved from the resin by treatment with trifluoroacetic acid solutions in dichloromethane. The 2-N-acyl-aminobenzenethiols released from the resin were cyclised to the corresponding 2-substituted benzothiazoles, by standing in a solution of dithiothreitol in DMF or methanol for 1-3 h at room temperature.

Full text of DOI:10.1016/S0040-4039(01)00109-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2201–2204
Solid phase synthesis of benzothiazolyl compounds
Spyros Mourtas, Dimitrios Gatos and Kleomenis Barlos*
Department of Chemistry, University of Patras, Patras, Greece
Received 25 April 2000; revised 4 January 2001; accepted 17 January 2001
Abstract—2-Aminobenzenethiol, bound through its thiol function to the 2-chlorotrityl (Clt)-, trityl (Trt)-, 4-methyltrityl (Mtt)-
and 4-methoxytrityl (Mmt)-resins, was acylated at the amino-function by aliphatic and aromatic acids. The obtained 2-N-acyl-
aminobenzenethiols were cleaved from the resin by treatment with trifluoroacetic acid solutions in dichloromethane. The
2-N-acyl-aminobenzenethiols released from the resin were cyclised to the corresponding 2-substituted benzothiazoles, by standing
in a solution of dithiothreitol in DMF or methanol for 1–3 h at room temperature. © 2001 Elsevier Science Ltd. All rights
reserved.
The benzothiazolyl-moiety is a structural element of
compounds with potent and selective antitumour activ-
ity,1–3 of wide spectrum Ca2+ channel antagonists4 and
of inhibitors of several enzymes such as monoamine
torial methods. We studied this possibility using
2-aminobenzenethiol 1 (Scheme 1) as the model starting
material.
oxidase
(MAO),5–8
lipoxygenase,9
acetylcholin-
For comparison to SPS, we reacted 1 with an equimo-
lar amount of benzoyl- and acetyl chloride and diiso-
propylethylamine (DIPEA) in dimethylformamide
(DMF). HPLC-analysis (Fig. 1a) of the reaction mix-
tures showed, besides the expected benzothiazole 2 and
minor byproducts, the formation of the azoxybenzene
derivative 3, as the main reaction product. Both were
identified by ES-MS (Fig. 1b: 2b, m/z=212.02 [M+H]+;
Fig. 1c: 3b, m/z=471.28 [M+H]+).
esterase,10 thrombin,11 of collagenase and neutral
proteases,12 of aldose reductase,13,14 of H+–K+
ATPase15 and of carbonic anhydrase.16
Benzothiazoles are synthesised in solution by the con-
densation of ortho-amino thiophenols with carboxylic
acid derivatives,17 the radical cyclisation of
thioacylbenzanilides18,19 or the base induced cyclisation
of the corresponding ortho-haloanilides.18–20 These
methods are performed under conditions not appropri-
ate for solid phase synthesis (SPS) and give in several
cases complex product mixtures. A SPS of benzothia-
zolyl compounds carried out under mild conditions
would therefore simplify the discovery of new pharma-
cologically interesting structures, by applying combina-
To suppress these side reactions, the thiol function of 1
should be protected. Groups of the trityl-type, which
are removed by mild acidolysis are suitable thiol pro-
tecting groups, as shown in the case of the protection of
cysteine during peptide synthesis.21 The corresponding,
commercially available, trityl-type resins 422–24 (Scheme
2) are, in addition, suitable solid supports for thiols.25
Scheme 1.
Keywords: benzothiazoles; benzothiazole equivalent; solid phase synthesis; trityl resin.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00109-5

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S. Mourtas et al. / Tetrahedron Letters 42 (2001) 2201–2204
Figure 1. (a) Analytical HPLC of the crude mixture obtained after the reaction of benzoyl chloride with 1 in DMF; Column:
Lichrospher RP-8, 5 mm; 4×250 mm; gradient: from 20 to 100% acetonitrile in water within 30 min; flow rate 1 ml/min; detection
at 265 nm; (b) ES-MS of the component A; (c) ES-MS of the component B.
Scheme 2.
To achieve the SPS of 2-benzothiazolyl compounds and
to suppress simultaneously the above side reactions
taking place in solution, we tested the resins 4 for the
attachment of 1 on solid phase. In fact, treatment of the
resin-chlorides with an equimolar amount of the thiol 1
and 0.7 equivalents of diisopropylethylamine (DIPEA)
in dichloromethane (DCM) for 0.5–4 h at rt, led to the
corresponding resins 5. Under these conditions, attach-
ment of 1 through its amine function onto the resin is
not possible. The remaining unreacted trityl chloride
was converted to the corresponding trityl-methyl ether,
by washing the resin with a mixture of DCM/methanol/
DIPEA (85:10:5). The loading of the resins obtained
was determined by sulfur analysis. We observed highest
attachment rates in the case of 4d. That affords the
resin 5d, within 30 min with a loading of 0.7–0.8 mmol
1/g. In contrast, 4a gave at the same time resins with a
loading of 0.3–0.4 mmol/g.
The acid stability of the thioether bond in 1 to the
various resins was tested by treating 5 with trifluo-
roacetic acid (TFA) solutions in DCM. The cleavage is
reversible and triethylsilane (TES) was added for scav-
enging the trityl-cations formed on the resin during
cleavage. As expected, the acid sensitivity increases
considerably from 5a to 5d. Thus, a 3×5 min treatment
of the resins with 65, 50, 15 and 1.1% TFA, respectively
in DCM/TES (95:5), led to 88, 90, 95 and 100% cleav-
age of 1 from the corresponding resin, while in the
absence of TES the cleavage yield dropped to 27, 48, 64
and 100%.
Resins 5 were then acylated with a threefold molar
excess of acyl- or aroyl chloride and DIPEA in DMF
for 3–4 h at rt. The acylation of 5 was also performed
using the acid anhydrides. Complete acylation (Scheme
2) in addition was achieved using several aliphatic and

S. Mourtas et al. / Tetrahedron Letters 42 (2001) 2201–2204
2203
Figure 2. (a) Analytical HPLC of the solution obtained during the cleavage of 7b from the 4-methoxy-trityl resin, by treatment
with 1.1% TFA (conditions as in Fig. 1); (b) ES-MS of component C; (c) HPLC-analysis of crude 7b after treatment with DTT.
Figure 3.
aromatic acids activated in situ with diisopropylcar-
bodiimide (DIC). 1-Hydroxybenzotriazole, frequently
used as an additive in peptide synthesis, led to slower
and in most cases incomplete acylations in this case.
The products 6 obtained were then treated with the
appropriate TFA solutions (see above) in order to
cleave the benzenethiols 7a–j from the various resins.
A sample of the mixtures obtained was concentrated
under a stream of nitrogen, and analysed by HPLC
(Fig. 2a shows the HPLC analysis of the mixture
obtained during the cleavage of 7b from the 4-methoxy-
Figure 4. (a) Analytical HPLC (conditions as in Fig. 1); (b)
ES-MS of crude 12.
trityl resin by treatment with 1.1% TFA). The individ-
ual components A–C were collected and subjected to
ES-MS analysis, after standing for 3 h at rt. Surpris-
ingly both components A and B showed identical
molecular masses, which corresponds to the benzothia-
zolyl compound 2b and C corresponds (Fig. 2b: 8b,
m/z=457.3 [M+H]+) to the oxidised dimer 8b. Azoxy-
benzene derivatives as 3b were not detected. We con-
so much favoured, that even the haloalkyl- and car-
boxy-derivatives 9–11 (Fig. 3), which can be considered
as precursors of various benzothiazolyl compounds,
gave the corresponding benzothiazoles in 90–95%
purity (Fig. 4a shows the HPLC-analysis of the reaction
mixture and Fig. 4b the ES-MS-analysis of the main
product obtained after the conversion of 11 to the
methylester of 2-benzothiazolylcarboxylic acid 12).
cluded that component
A
corresponds to the
acyl-derivative 7b. This cyclises spontaneously to the
corresponding benzothiazole by standing in the acetoni-
trile/water mixture used for their HPLC-elution. To
reduce the disulfide 8b, dithiothreitol (DTT) was added
to the solution. Indeed, we observed that 8b was con-
verted to 7b and 2b and the latter was the only product
(Fig. 2c: 2b) of the reaction after standing for 2–3 h at
rt. In all cases tested, the acylation of 5 with various
acids proceeded very similarly to that of the benzoyla-
tion reaction. These observations led to the develop-
ment of an improved protocol26 for the SPS, in 80–90%
yield, of several 2-alkyl- and aryl-benzothiazoles 2 in
90–97% purity. The ring closure reaction from 7 to 2 is
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