A 1,5-benzothiazepine synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.01.098

The pharmaceutically active compound (±)-thiazesim was synthesized in four steps and 62% overall yield. This new approach to biologically relevant benzothiazepine ring systems features the use of water as a solvent, co-solvent or catalyst in three of the

Full text of DOI:10.1016/j.tetlet.2011.01.098

Tetrahedron Letters 52 (2011) 1490–1492
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A 1,5-benzothiazepine synthesis
⇑
Christopher B. W. Phippen, Christopher S. P. McErlean
School of Chemistry, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The pharmaceutically active compound ( )-thiazesim was synthesized in four steps and 62% overall yield.
This new approach to biologically relevant benzothiazepine ring systems features the use of water as a
solvent, co-solvent or catalyst in three of the four steps.
Received 11 October 2010
Revised 17 January 2011
Accepted 25 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzothiazepine
Heterocyclic chemistry
Aqueous chemistry
N-Acylpyrrole
Benzothiazepines constitute valuable structural units in the
field of pharmaceutical research.1,2 In particular, incorporation of
the 1,5-benzothiazepine unit has resulted in compounds with
attractive biological profiles.3 Some successfully marketed 1,5-
benzothiazepines are shown in Figure 1 and include the multi-bil-
lion dollar-a-year selling antipsychotic quetiapine (1) (tradename
SeroquelÒ),4–7 the angina relieving calcium channel blocker diltia-
zem (2)8–11 and the antihypertensive agent clentiazem (3).12–14
Such a wealth of biological activities has provided impetus for
chemists to invent a number of synthetic strategies to access the
1,5-benzothiazepine scaffold.1,2
A major challenge facing the pharmaceutical industry is the
development of sustainable manufacturing processes that deliver
target compounds in an energy efficient and ecologically benign
manner.15–17 In this regard, the use of water-tolerant chemistry
has become increasingly important.18–20 We have recently re-
ported the energy efficient and operationally simply ‘on-water’21
addition of anilines to N-acryloyl-2,5-dimethylpyrrole.22 During
that work, we noted that thiophenols were excellent substrates
for the reaction. In a competitive conjugate addition reaction, we
anticipated that the thiophenol would exert its greater nucleophi-
licity and participate in the exclusion of aniline (Scheme 1). As
such, we projected that the reaction of ortho-aminothiophenol
Figure 1. Examples of 1,5-benzothiazepines.
strategy required an extension of that methodology to include
substituted alkenes such as 6, necessary for access to important
pharmaceutical compounds. This Letter details the results of our
initial foray into the synthesis of 1,5-benzothiazepines.
As an initial target on which to focus our efforts, we were drawn
to the GABBAA blocker,23 thiazesim (4) (Fig. 1). This relatively sim-
ple 1,5-benzothiazepine-containing compound was one of the first
members of the class to be identified as an anti-depressant,24,25
and was marketed as the hydrochloride salt (tradename, Altinil).
As detailed retrosynthetically in Scheme 2, we envisaged that
(5) with a suitable a,b-unsaturated-N-acylpyrrole 6 would proceed
via initial conjugate addition of the thiol, leaving the amine avail-
able for a trans-amidation reaction with the N-acylpyrrole unit to
produce a benzothiazepinone ring 7. While our earlier work fo-
cused on terminal
a,b-unsaturated-N-acylpyrroles, the current
⇑
Corresponding author. Tel.: +61 2 9351 3970, fax: +61 2 9351 3329.
E-mail address: christopher.mcerlean@sydney.edu.au (C.S.P. McErlean).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.098

C. B. W. Phippen, C. S. P. McErlean / Tetrahedron Letters 52 (2011) 1490–1492
1491
Scheme 1. Competitive conjugate addition.
N-alkylation of the 1,5-benzothiazepinone core 8 would provide
thiazesim in a straightforward manner. Disconnection of the amide
C–N bond in 8 revealed 9, containing both an aniline and an
N-acyl-2,5-dimethylpyrrole activated acid equivalent. Disconnec-
tion of the C–S bond suggested an on-water conjugate addition
of ortho-aminothiophenol (5) to the N-cinnamoyl-2,5-dimethyl-
pyrrole 10. In keeping with our current research focus,22,26 com-
pound 10 was envisaged to arise via an aqueous Heck reaction
between alkene 11 and iodobenzene (12).
It is pertinent to note that we targeted the synthesis of ( )-thia-
zesim. In contrast to the recently reported application of a chiral
Brønsted acid in aqueous media27—where formation of a close-
ion pair allowed the chiral counterion to exert an influence over
the stereochemical course of a reaction—the acid-catalysis respon-
sible for on-water rate accelerations26 can only deliver the conju-
gate addition product 9 in a racemic fashion. However, we did
not view this as a major drawback. As long ago as 1927, it was
recognised that benzothiazepinones could be resolved with an
appropriate reagent.28 Since 1968, such resolution techniques have
been applied to the commercial synthesis of benzothiazepines.25,29
Given the resolvability of the enantiomers, we felt that the inher-
ent gains of such an operationally simple and relatively energy-fru-
gal synthetic route counter-balanced the need for a resolution step.
The racemic synthesis began with the efficient Heck coupling of
iodobenzene (12) and N-acryloyl-2,5-dimethylpyrrole (11) under
the aqueous conditions reported by Wang, Zhou and co-workers,30
(Scheme 3). The E-configured N-cinnamoyl-2,5-dimethylpyrrole
(10) was the sole product and was formed in high yield. Since iodo-
benzene (12) is more dense than water and the N-acryloyl-2,5-
dimethylpyrrole (11) is less dense than water, the conditions re-
ported employed a phase-transfer agent and the use of sonication
to ensure that the two reactants came into contact. We were intri-
gued by the possibility that emulsion formation would also serve
as a method to facilitate the reaction. We were encouraged by re-
ports of Heck couplings occurring at both room temperature and
Scheme 3. Synthesis of ( )-thiazesim 4.
elevated temperature in neat water.31,32 In the event, vigorously
stirring a mixture of 11 and 12 in water at ambient temperature
for 6 h delivered the desired product 10 in 14% yield. Increasing
the temperature to 50 °C with vigorous stirring gave the coupled
product 10 in 28% yield. Extending the reaction time to 24 h at
room temperature provided 10 in 50% yield. Whilst providing suc-
cessful access to 10 and being more energy efficient, this protocol
was not as satisfactory as the initial procedure in terms of yield.
Compound 10 was then reacted with ortho-aminothiophenol
(5) ‘on-water’,21 (Scheme 3). This delivered the coupled product
in high yield. We had hoped that the aniline unit would be nucle-
ophilic enough to undergo a spontaneous cascade lactamisation
with the acylpyrrole unit and provide 8 directly, but this proved
not to be the case. Attempts to encourage the lactamisation with
basic reagents such as DMAP or triethylamine led exclusively to
elimination of the b-thiophenol. This is not surprising given that
the carbonyl unit of N-acylpyrroles is more ketone-like than
amide-like, and the acidity of the
a-hydrogens is accordingly af-
fected.33 To circumvent this unwanted elimination reaction, an
acid-catalysed ring-closure was dictated. Since the lactamisation
reaction did not spontaneously occur under the ‘on-water’ condi-
tions used for effecting the conjugate addition, we concluded that
the interfacial water at the surface of the emulsion droplets was
not acidic enough to effect the desired transformation. Beattie
and co-workers have measured the isoelectric point of oil-in-water
emulsions to be between pH 3 and 4, suggesting a pKa of approxi-
mately 7 for the interfacial water molecules.34,35 We therefore
elected to employ a much stronger acid to effect the transforma-
tion. Reaction of compound 9 with HCl in acetone returned a com-
plex mixture that did not contain the desired product. Treating
compound 9 with para-toluenesulfonic acid in THF delivered the
desired benzothiazepinone 8 in moderate yield (22%) accompanied
by unreacted starting material. Increasing the reaction tempera-
Scheme 2. Retrosynthetic analysis.

1492
C. B. W. Phippen, C. S. P. McErlean / Tetrahedron Letters 52 (2011) 1490–1492
2. Levai, A.; Kiss-Szikszai, A. Arkivoc 2008, 65.
3. Bariwal, J. B.; Upadhyay, K. D.; Manvar, A. T.; Trivedi, J. C.; Singh, J. S.; Jain, K. S.;
Shah, A. K. Eur. J. Med. Chem. 2008, 43, 2279.
4. Snape, E. W. U.S. Pat. No. 6,372,734 B1, 1999; Chem. Abstr. 1999, 130, 173010.
5. Raggi, M. A.; Mandrioli, R.; Sabbioni, C.; Pucci, V. Curr. Med. Chem. 2004, 11, 279.
6. Capuano, B.; Crosby, I. T.; Lloyd, E. J. Curr. Med. Chem. 2002, 9, 521.
7. Goldstein, J. M. Drugs Today 1999, 35, 193.
8. Kugita, H.; Inoue, H.; Ikezaki, M.; Konda, M.; Takeo, S. Chem. Pharm. Bull. 1971,
19, 595.
9. Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr.
Med. Chem. 2007, 14, 279.
10. Buckley, M. M. T.; Grant, S. M.; Goa, K. L.; McTavish, D.; Sorkin, E. M. Drugs
1990, 39, 757.
ture by microwave irradiation of the THF solution, gave the desired
compound 8 in trace amounts only. We reasoned that the differ-
ence in product distribution between the two solvents (acetone
and THF) reflected their ability to stabilise the reactive conforma-
tion of the precursor 9. As the precursor 9 contains three aromatic
rings, we expected that employing an aromatic solvent may prove
useful. In the event, we were pleased to observe that treatment of 9
with para-toluenesulfonic acid in toluene delivered the desired
benzothiazepinone 8 in high yield (86%) in just 1 h. Although the
ring-closure required heating, the short reaction time represented
an improvement to the harsh conditions previously used to close
analogous seven-membered rings.1,2 To complete the synthesis,
compound 8 was N-alkylated with (2-chloroethyl)dimethylamine
in wet ethyl acetate to give ( )-thiazesim 4 in excellent yield.
In summary, we have completed a four step synthesis of the
pharmaceutically active compound ( )-thiazesim 4, in 62% overall
yield. This work illustrates a new synthetic approach to biologi-
cally relevant benzothiazepine ring systems. In keeping with the
need to develop water tolerant routes to pharmaceuticals, water
featured as a solvent, co-solvent or catalyst in three of the four
steps. We are currently exploring the scope of this new protocol
with the aim of rapidly accessing a library of benzothiazepine ana-
logues. The outcomes of that work will be reported in due course.
11. Chaffman, M.; Brogden, R. N. Drugs 1985, 29, 387.
12. Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Takahashi, K.; Gaino, M.; Date,
T.; Aoe, K.; Takeda, M.; Murata, S.; Narita, H.; Nagao, T. J. Med. Chem. 1991, 34,
675.
13. Suzuki, T.; Kurosawa, H.; Naito, K.; Otsuka, M.; Ohashi, M.; Takaiti, O. Eur. J.
Pharmacol. 1991, 194, 195.
14. Narita, H.; Zera, P. H.; Ginsburg, R. Cardiovasc. Drug Ther. 1990, 4, 1097.
15. Anastas, P. T. In Clean Solvents—Alternative Media for Chemical Reactions and
Processing, Abraham, M. A., Moens, L., Eds.; ACS Symposium Series; American
Chemical Society: Washington, DC, 2002, pp 1–9.
16. Anastas, P. T. Green Chem. 2003, 5, G29.
17. Lombardo, M.; Trombini, C. Curr. Opin. Drug Discov. Dev. 2010, 13, 717.
18. Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
19. Li, C. J. Chem. Rev. 2005, 105, 3095.
20. Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
21. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275.
22. Phippen, C. B. W.; Beattie, J. K.; McErlean, C. S. P. Chem. Commun. 2010, 8234.
23. Squires, R. F.; Saederup, E. Neurochem. Res. 1998, 23, 1283.
24. Krapcho, J.; Turk, C. F. J. Med. Chem. 1966, 9, 191.
Acknowledgement
25. Krapcho, J.; Turk, C. F.; Piala, J. J. J. Med. Chem. 1968, 11, 361.
26. Beattie, J. K.; McErlean, C. S. P.; Phippen, C. B. W. Chem. Eur. J. 2010, 16, 8972.
27. Rueping, M.; Theissmann, T. Chem. Sci. 2010, 1, 473.
28. Mills, W. H.; Whitworth, J. B. J. Chem. Soc. 1927, 2738.
29. Krapcho, J. U.S. Pat. No. 4,963,671, 1990; Chem. Abstr. 1991, 114, 143457.
30. Zhang, Z. H.; Zha, Z. G.; Gan, C. S.; Pan, C. F.; Zhou, Y. Q.; Wang, Z. Y.; Zhou, M.
M. J. Org. Chem. 2006, 71, 4339.
C.B.W.P. gratefully acknowledges receipt of an Australian Post-
graduate Award.
Supplementary data
31. Zhao, H.; Cai, M. Z.; Peng, C. Y. Synth. Commun. 2002, 32, 3419.
32. Zhao, H.; Cai, M. Z.; Peng, C. Y.; Song, C. S. J. Chem. Res. 2002, 28.
33. Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 7559.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.098.
34. Gray-Weale, A.; Beattie, J. K. Phys. Chem. Chem. Phys. 2009, 11, 10994.
35. Beattie, J. K.; Djerdjev, A. M. Angew. Chem., Int. Ed. 2004, 43, 3568.
References and notes
1. Levai, A. J. Heterocycl. Chem. 2000, 37, 199.