A novel practical synthesis of benzothiazoles via Pd-catalyzed thiol cross-coupling

Article abstract of DOI:10.1021/ol7015737

A convenient synthesis of substituted benzothiazoles from 2-bromoanilides has been accomplished. The various 2-bromoanilides were reacted with an alkyl thiolate in high yields using a palladium catalyst. The resulting sulfides were easily converted to the corresponding benzothiazoles via the simultaneous generation of thiols and condensation under basic or acidic conditions.

Full text of DOI:10.1021/ol7015737

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3687-3689
A Novel Practical Synthesis of
Benzothiazoles via Pd-Catalyzed Thiol
Cross-Coupling
Takahiro Itoh* and Toshiaki Mase
Process Research, PreClinical DeVelopment, Banyu Pharmaceutical Co., Ltd.,
3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
takahiro_itoh@merck.com
Received July 4, 2007
ABSTRACT
A convenient synthesis of substituted benzothiazoles from 2-bromoanilides has been accomplished. The various 2-bromoanilides were reacted
with an alkyl thiolate in high yields using a palladium catalyst. The resulting sulfides were easily converted to the corresponding benzothiazoles
via the simultaneous generation of thiols and condensation under basic or acidic conditions.
Substituted benzothiazole is an important class of hetero-
cyclic compounds that exhibits a wide range of biological
properties such as inhibitors of stearoyl-coenzyme A δ-9
desaturase,1 antitumor,2 antimicrobial,3 LTD4 receptor an-
tagonist,4 etc. For example, the investigations of benzo-
thiazole as a key pharmacore led to Merck investigational
new drugs such as the orexin receptor antagonist 15 and the
Gram-positive selective antibacterials 26 (Figure 1).
a direct conversion of 2-aminothiophenol with carboxylic
acids or aldehydes (approach A)8 and a condensation of
thioanilides via copper- or palladium-catalyzed Buchwald-
Hartwig-type carbon-heteroatom bond formation (approach
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Med. Chem. 1999, 42, 4172-4184. (c) Hutchinson, I.; Chua, M. S.; Browne,
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Figure 1. Structures of Merck investigational new drugs.
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Many reports have appeared in the literature describing
the formation of benzothiazoles.7 Scheme 1 describes the
major approaches for assembly of these compounds including
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Scheme 1. Major Approaches for the Synthesis of
Scheme 2. Synthesis of Benzothiazole via C-S Bond
Benzothiazoles
Formation
B).9,10 Approach A is the classical approach; however, it
suffers from difficulties in the preparation of readily oxidiz-
able 2-aminothiophenols. By comparison, the alternative
approach B suffers from functional group compatibility in
the preparation of the starting materials. Especially, func-
tional groups such as ketones, esters, and amides are often
incompatible with the method commonly used to prepare
the thioanilides.11 Therefore, a new alternative methodology
for the synthesis of benzothiazoles needs to be explored.
Recently, we have developed the Pd-catalyzed cross-coupling
reaction of aryl bromide/triflates and alkyl/aryl thiols.12 We
have also been interested in developing protocols that would
allow for the preparations of aryl thiols from aryl halides
via a thiol surrogate.13 In this regard, Ma et al. have recently
reported a Cu-catalyzed cascade process for the synthesis
of 1,2-disubstituted benzimidazoles.14 Herein, we wish to
report a new convenient method of benzothiazoles from
2-bromoanilides with a thiol surrogate coupling reaction.
In the initial study for the preparation of sulfide, we carried
out the reaction of 2′-bromoacetanilide (3) with a very
inexpensive and odorless 2-ethylhexyl 3-mercaptopropionate
as a thiol surrogate catalyzed by Pd2(dba)3/Xantphos to afford
the corresponding sulfide 4 (Scheme 2). The resulting sulfide
4 was treated with NaOEt at room temperature to afford the
corresponding sodium thiolate 5 followed by heating at reflux
to form 2-methylbenzothiazole (6) in 82% yield via intra-
molecular condensation. In the meantime, thiolate 5 can be
intercepted with an electrophile. For example, quenching
thiolate 5 with 4-chloronitrobenzene in situ gives sulfide 6
in 80% yield via a SNAr mechanism. Encouraged by these
results, the synthesis of benzothiazoles from 2-bromobenz-
anilides via Pd-catalyzed C-S bond formation with thiol
surrogates was further investigated.
As shown in Table 1, the various 2-bromobenzanilides
could be converted into the corresponding benzothiazoles
in good yields via Pd-catalyzed C-S bond formation
followed by deprotection and the condensation. The yields
of C-S bond formation did not depend on the substrates;
however, the yields and the conditions of the intramolecular
condensation depended on the substrates. The substrates
possessing an electron-deficient (entries 1 and 2) or neutral
(entry 3) carbonyl group of amides were rapidly cyclized
under basic conditions at reflux temperature. When the amide
was electron rich (entry 4), on the other hand, the yield of
the condensation under basic conditions was quite low. The
basic condensations of some anilides possessing electron-
withdrawing groups on the benzene ring were also sluggish
(entries 5 and 6). Unlike the basic conditions, the acidic
conditions were more effective (shorter reaction time and
higher yield). It was found that trifluoroacetic acid (TFA)
was the best reagent. An intermediate for the antitumor
agent,2 2-(3-methyl-4-nitrophenyl)benzothiazole, was ob-
tained in 77% yield under acidic condensation (entry 1). The
substrates possessing a ketone group gave the corresponding
benzothiazoles in high yield (entries 3, 6, and 8). In the case
of the pyridine substrate, higher reaction temperature and
longer reaction time were necessary for the condensation
even by using TFA (entry 7).
(9) (a) Couture, A.; Granclaudon, P. Heterocycles 1984, 22, 1383-1385.
(b) Bened´ı, C.; Bravo, F.; Uriz, P.; Ferna´ndez, E.; Claver, C.; Castillo´n, S.
Tetrahedron Lett. 2003, 44, 6073-6077. (c) Joyce, L. L.; Evindar, G.; Batey,
R. A. Chem. Commun. 2004, 446-447. (d) Evindar, G.; Batey, R. A. J.
Org. Chem. 2006, 71, 1802-1808.
This new methodology was successfully applied using an
unprotected secondary amine (entry 10) and an unprotected
phenol (entry 11). In the case of 2-bromophenylurea,
intramolecular cyclization did not proceed during the inter-
molecular C-S coupling reaction, and the following intra-
molecular cyclization took place to afford 2-hydroxybenzo-
thiazole instead of the formation of 2-aminobenzothiazole
(entry 12). Formamide was also converted into the benzo-
(10) For an alternative cyclization method under SNAr conditions:
Gilman, A.; Spero, D. M. Tetrahedron Lett. 1993, 34, 1751-1752.
(11) (a) Perregaad, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I.; Lawesson,
S. O. Bull. Soc. Chim. Belg. 1977, 86, 679-691. (b) Cava, M. P.; Levinson,
M. I. Tetrahedron 1985, 41, 5061-5087. (c) Foreman, M. S. J.; Woollins,
J. D. J. Chem. Soc., Dalton Trans. 2000, 1533-1543.
(12) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587-4590.
(13) Itoh, T.; Mase, T. J. Org. Chem. 2006, 71, 2203-2206.
(14) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598-
2601.
3688
Org. Lett., Vol. 9, No. 18, 2007

In the case of the reaction of a substrate which is labile
for basic conditions such as NaOEt, the alternative thiol
surrogate would be used. For example, the C-S bond
formation of 9 with 2-ethylhexyl 3-mercaptopropionate
proceeded smoothly to give the corresponding sulfide in good
yield. But, when the deprotection was conducted under basic
conditions using NaOEt, the complex mixture was obtained.
In that case, the thiol surrogate that could be deprotected
under acidic conditions should be used. The 2-bromobenz-
anilide 9 was reacted with a (4-methoxyphenyl)methanethiol
under typical conditions to obtain the corresponding sulfide
10. To this solution was directly added TFA to afford the
benzothiazole 11 in good yield (Scheme 3).
Table 1. Synthesis of Benzothiazoles
Scheme 3. Synthesis of Labile Thiazole Using an Alternative
Thiol Surrogate
In summary, we have demonstrated that the C-S bond
formation of 2-bromoanilides can be catalyzed by Pd2(dba)3/
Xantphos. On the basis of this observation, a novel practical
synthetic method for elaborating benzothiazoles has been
developed. To our knowledge, this is the first report of the
use of thiol surrogates in the synthetic approach for the
benzothiazole. Variation at the 2-position of the benzo-
thiazole is possible with variation in the amido groups of
the 2-bromoanilides. Therefore, this new methodology allows
for the assembly of a wide range of substituted benzo-
thiazoles.
Acknowledgment. We acknowledge Drs. M. Palucki and
N. Yasuda, Merck & Co., Inc., for helpful discussions.
Supporting Information Available: Detailed experi-
mental procedures and characterization data of each com-
pound. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL7015737
(15) For amines: (a) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 7838-7842. For halogen:
(b) Boga, C.; Vecchio, E. D.; Forlani, L.; Todesco, P. E. J. Organomet.
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M.; Matsumoto, Y.; Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.;
Kondo, Y. J. Am. Chem. Soc. 2007, 129, 1921-1930. For acyls: (e)
Chikashita, H.; Itoh, K. Heterocycles 1985, 23, 295-300. (f) Ohta, S.;
Hayakawa, S.; Moriwaki, H.; Tsuboi, S.; Okamoto, M. Heterocycles 1985,
23, 1759-1764. (g) Chikashita, H.; Ishibaba, M.; Ori, K.; Ito, K. Bull. Chem.
Soc. Jpn. 1988, 61, 3637-3648.
a
The condensation was conducted using NaOEt at reflux.
thiazole in high yield under the same conditions (entry 13).
The resulting 2-unsubstituted benzothiazole is a versatile
intermediate and can be converted to the various substituted
products such as 2-amino, 2-halogen, 2-acyl, and so forth
by general methodology.15
Org. Lett., Vol. 9, No. 18, 2007
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