Expected and unexpected reactions of 1,3-benzothiazine derivatives, II. Formation of isomeric 5,6-dihydro-1,5-benzothiazocines

Article abstract of DOI:10.1016/j.tetlet.2010.11.136

A method for the synthesis of medium-sized 1,5-benzothiazocines by ring enlargement of 1,3-benzothiazines has been developed. When N-alkyl-1,3- benzothiazines were reacted with dimethyl acetylenedicarboxylate in acetonitrile at room temperature, regioisom

Full text of DOI:10.1016/j.tetlet.2010.11.136

Tetrahedron Letters 52 (2011) 592–594
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Tetrahedron Letters
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Expected and unexpected reactions of 1,3-benzothiazine derivatives, II.
Formation of isomeric 5,6-dihydro-1,5-benzothiazocines
Lajos Fodor a,b,c, , Péter Csomós a,b,c, Antal Csámpai d, Pál Sohár d,e, , Tamás Holczbauer f, Alajos Kálmán f
⇑
⇑
a Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
b Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary
c Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720 Szeged, Eötvös u. 6., Hungary
d Institute of Chemistry, Eötvös Loránd University, H-1518 Budapest, POB 32, Hungary
e Protein Modelling Research Group, Hungarian Academy of Sciences and Eötvös Loránd University, H-1518 Budapest, POB 32, Hungary
f Institute of Structural Chemistry, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the synthesis of medium-sized 1,5-benzothiazocines by ring enlargement of 1,3-benzothi-
azines has been developed. When N-alkyl-1,3-benzothiazines were reacted with dimethyl acetylenedi-
carboxylate in acetonitrile at room temperature, regioisomeric 5,6-dihydro-2H-1,5-benzothiazocines
and 5,6-dihydro-4H-1,5-benzothiazocines were obtained as novel ring systems. Dimethyl acetylenedicar-
boxylate could attack either the nitrogen or the sulfur atom of the thiazines. NMR spectroscopic and
X-ray crystallographic investigations confirmed the structures of the products.
Received 14 September 2010
Revised 12 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Ring expansion
Medium-sized ring
1,5-Benzothiazocines
DMAD
NMR
X-ray crystallography
Medium-sized heterocycles (8- to 10-membered rings) are of
significance as biologically active natural products and drug candi-
dates.1 On the other hand, the synthesis of these heterocycles is a
challenge, as standard cyclization methods are ineffective, in par-
ticular cases, due to enthalpic and entropic reasons.1h,2 Conse-
quently, the development of general and effective protocols, to
construct medium-sized heterocyclic systems is an interesting
goal.
Among medium-sized rings, N-containing condensed eight-
membered heterocycles are important, because many alkaloids
and biologically active compounds (e.g., apparacine, magallanesin,
buflavine, balasubramide, manzamines, moschamide, neodihydro-
thebaine, securamine A, and rhazinilam) contain a benzazocine
moiety.3 For their preparation, and as an alternative to cyclization
methods, novel and efficient ring-expansion reactions were devel-
oped and investigated by Voskressensky et al.1a,4 These were based
on enlargement of condensed tetrahydropyridine derivatives in the
presence of activated alkynes.
teric thiazocines. Regarding eight-membered rings containing
one N and one S atom at the 1,5-positions (e.g., 1,5-thiazocine,
5,1-benzothiazocine and dibenzo-1,5-thiazocine), only a few deriv-
atives have been prepared (we found no examples of 1,5-ben-
zothiazocines), mainly through unimolecular cyclizations.6 Most
of the prepared compounds exhibited valuable pharmacological
effects.7–12
In the course of our investigations on S,N-containing condensed
heterocycles,13 we earlier studied the cycloadditions of dimethyl
acetylenedicarboxylate (DMAD) to 1,3-benzothiazines and 1,4-
benzothiazepines,14 and the ring transformations of b-lactam-
condensed 1,3-benzothiazines to 4,1- or 1,4-benzothiazepine
isomers.15 In continuation of this work, we report the ring enlarge-
ment of 1,3-benzothiazines with DMAD.
The synthesis of the key N-alkylthiazines 3a,b was achieved
starting from 2-phenyl-4H-1,3-benzothiazine 1 (Scheme 1). After
quaternization of 1 with methyl iodide or ethyl bromide, salts
2a,b were obtained and then reduced with Zn/HCl in ethanol to
furnish N-alkylthiazines 3a,b in good yields.
When compounds 3a,b were reacted with DMAD in acetonitrile
at room temperature, the regioisomeric novel ring systems, 1,5-
thiazocines 5a,b and 7a,b were obtained in ca. 1:1 ratios. DMAD
can attack either the N or S atom of 3a,b. The key intermediates
in the formation of 5,6-dihydro-2H-1,5-benzothiazocines 5a,b are
In contrast with the importance of N-containing 8-membered
heterocycles,5 much less attention has been paid to their bioisos-
⇑
Corresponding authors. Tel.: +36 66 463763; fax: +36 66 526539 (L.F.); tel.: +36
1 3722911; fax: +36 1 3722592 (P.S.).
E-mail addresses: fodor@pandy.hu (L. Fodor), sohar@chem.elte.hu (P. Sohár).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.136

L. Fodor et al. / Tetrahedron Letters 52 (2011) 592–594
593
MeI
or
MeO
MeO
S
MeO
MeO
S
MeO
MeO
S
Zn/HCl
EtOH
X
N
N
N
EtBr
reflux
R
R
1
2a,b
3a: 84%
3b: 75%
a: R = Me, X = I;
b: R = Et, X = Br
Scheme 1.
MeO
MeO
S
N
R
3a,b
rt, 8-10 d
DMAD/ MeCN
MeOOC
COOMe
Ph
S
MeO
MeO
MeO
MeO
S
COOMe
COOMe
C
N
N
C
R
R
4a,b
6a,b
COOMe
COOMe
S
MeO
MeO
S
MeO
MeO
COOMe
COOMe
N
N
R
R
7a: R = Me, 36%
7b: R = Et, 35%
5a: R = Me, 32%
5b: R = Et, 30%
Scheme 2.
Figure 1. ORTEP diagrams of 5a (left) and 7a (right) indicating the atomic numbering of the non-hydrogen atoms. Hydrogen positions are shown but not labelled.

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L. Fodor et al. / Tetrahedron Letters 52 (2011) 592–594
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5,6-dihydro-4H-1,5-benzothiazocines 7a,b could be explained via
intermediates 6a,b. Alternatively, during the formation of 7a,b,
DMAD could also attack an open-chain intermediate of 3a,b
(Scheme 2). Structural and conformational analyses of the products
were achieved by NMR spectroscopic (Supplementary data) and
X-ray crystallographic investigations.
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The X-ray structures of compounds 5a and 7a are shown in
Figure 1.16
In summary, we have demonstrated the synthesis of medium
ring-sized 1,5-benzothiazocine isomers via ring enlargement of
N-alkyl-3,1-benzothiazines with DMAD. As expected, 5,6-dihy-
dro-2H-1,5-benzothiazocines were formed most probably via a
zwitterionic intermediate. Unexpectedly, 5,6-dihydro-4H-1,5-ben-
zothiazocines were also formed, as a consequence of attack of
DMAD on the S atom of the starting 1,3-benzothiazine. Further
experiments to extend the scope of these novel ring-enlargement
reactions and investigations of the reaction mechanisms are in
progress.
Acknowledgment
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The authors express their thanks to the Hungarian Scientific Re-
search Foundation (OTKA) for financial support. The European Un-
ion and the European Social Fund have provided financial support
to the project under the grant agreement no. TÁMOP 4.2.1./B-09/
KMR-2010-0003.
Supplementary data
13. (a) Fodor, L.; MacLean, D. B. Can. J. Chem. 1987, 65, 18; (b) Fodor, L.; Szabó, J.;
Bernáth, G.; Sohár, P. Tetrahedron Lett. 1995, 36, 753; (c) Csomós, P.; Fodor, L.;
Sinkonen, J.; Pihlaja, K.; Bernáth, G. Tetrahedron Lett. 2006, 47, 5665; (d) Fodor,
L.; Csomós, P.; Csámpai, A.; Sohár, P. Tetrahedron Lett. 2010, 51, 3205.
14. (a) Fodor, L.; Szabó, J.; Bernáth, G.; Sohár, P. Heterocycles 1982, 19, 488; (b)
Fodor, L.; Bernáth, G.; Sohár, P.; Gröschl, D.; Meier, H. Monatsh. Chem. 2006,
137, 231; (c) Fodor, L.; Csomós, P.; Sohár, P.; Holczbauer, T.; Kálmán, A.
Monatsh. Chem. 2010, 141, 431.
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Fodor, L.; Csomós, P.; Csámpai, A.; Sohár, P. Synthesis 2010, 2943; (c) Fodor, L.;
Csomós, P.; Holzbauer, T.; Kálmán, A.; Csámpai, A.; Sohár, P. Tetrahedron Lett.
2011, 52, 224.
Supplementary data (general information, procedures and spec-
tral data) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.11.136.
References and notes
1. For selected recent reviews on medium heterocyclic rings, see: (a)
Voskressensky, L. G.; Kulikova, L. N.; Borisova, T. N.; Varlamov, A. V. Adv.
Heterocycl. Chem. 2008, 96, 81; (b) Shiina, I. Chem. Rev. 2007, 107, 239; (c)
Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073; (d) Mehta, G.; Singh, V. Chem.
Rev. 1999, 99, 881; (e) Molander, G. A. Acc. Chem. Res. 1998, 31, 603; (f)
Rousseau, G. Tetrahedron 1995, 51, 2777; (g) Evans, P. A.; Holmes, A. B.
Tetrahedron 1991, 44, 9131.
2. (a) Tripathi, D.; Pandey, S. K.; Kumar, P. Tetrahedron 2009, 65, 2226; (b)
Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
3. (a) Oniciu, D. C. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Taylor, R. J. K., Eds.; Elsevier Ltd: Oxford, 2008; Vol. 14, p 2; (b)
Carotti, A.; de Candia, M.; Catto, M.; Borisova, T. M.; Varlamov, A. V.; Mendez-
16. Crystal data: Rigaku R-axis rapid diffractometer, Mo
k = 0.71073 Å 5a 23H25NO6S, M = 443.50, chunk, white monoclinic, space
group P21/c, a = 13.1878(5), b = 14.7708(6), c = 12.7873(4) Å, b = 115.343(1)°,
V = 2251.17(14) Å3, Z = 4, Dcalcd = 1.309 Mg mÀ3 = 0.182 mmÀ1
T = 294 K,
R = 0.0377, Rw = 0.1027, Rtot = 0.0514, N = 4260, CCDC 783264. Compound 7a
23H25NO6S, M = 443.50, chunk, white monoclinic, space group P21/c,
a = 12.7820(18), b = 8.5249(13), c = 22.027(3) Å, b = 113.979(7)°, V =
2193.0(5) Å3, Z = 4, Dcalcd = 1.343 Mg mÀ3 = 0.187 mmÀ1
T = 294 K, R =
0.0351, Rw = 0.0999, Rtot = 0.0419, N = 5021, CCDC 783263.
Ka radiation,
C
,
l
,
C
,
l
,