Expected and unexpected reactions of 1,3-benzothiazine derivatives, I. Ring transformation of β-lactam-condensed 1,3-benzothiazines into 4,5-dihydro-1,4-benzothiazepines and indolo-1,4-benzothiazepines

Article abstract of DOI:10.1016/j.tetlet.2010.10.160

The ring-enlargement reactions of monochloro-β-lactam-fused 2-aryl-1,3-benzothiazines revealed that the reactions of ortho-nitro aryl-substituted derivatives with sodium methoxide in methanol provided two products, depending on the amount of the base. Wit

Full text of DOI:10.1016/j.tetlet.2010.10.160

Tetrahedron Letters 52 (2011) 224–227
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expected and unexpected reactions of 1,3-benzothiazine derivatives, I. Ring
transformation of b-lactam-condensed 1,3-benzothiazines into
4,5-dihydro-1,4-benzothiazepines and indolo-1,4-benzothiazepines
Lajos Fodor a,b, , Péter Csomós a,b, Tamás Holczbauer c, Alajos Kálmán c, Antal Csámpai d, Pál Sohár d,e,
⇑
⇑
a Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
b Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720 Szeged, Eötvös u. 6., Hungary
c Institute of Structural Chemistry, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary
d Institute of Chemistry, Eötvös Loránd University Hungarian Academy of Sciences and 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2010
Revised 18 October 2010
Accepted 29 October 2010
Available online 4 November 2010
The ring-enlargement reactions of monochloro-b-lactam-fused 2-aryl-1,3-benzothiazines revealed that
the reactions of ortho-nitro aryl-substituted derivatives with sodium methoxide in methanol provided
two products, depending on the amount of the base. With 2 equiv of reagent, the expected 1,4-
benzothiazepines were obtained. Somewhat surprisingly, treatment with a large excess of sodium
methoxide led to the formation of indolo-1,4-benzothiazepines via a novel rearrangement. The structures
of the new ring systems were determined by means of X-ray crystallography and NMR spectroscopy.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ring enlargement
b-Lactam
1,3-Benzothiazine
Indolo-1,4-benzothiazepine
Condensed S,N-heterocycles constitute an important group of
biologically active compounds targeted towards various therapeu-
tic end-points. Besides b-lactam antibiotics (penicillins, cephalo-
sporins)1 and versatile pharmacophoric 1,5-benzothiazepines,2
several members of this group are bioisosteres of various drugs,
for example, 1,4-benzothiazepine derivatives are analogues of the
well-known 1,4-benzodiazepine family, and a broad range of
pharmacological effects has been observed for these heterocycles.
1,4-Benzothiazepines exert antidepressant activity,3 antiarrhyth-
mic activity,4 reversal of P-glycoprotein-mediated multidrug resis-
tance5 and bile acid absorption inhibitory activity.6
The preparation of 1,4-benzothiazepines is usually achieved by
ring closure of bifunctional compounds (e.g., aminothiol deriva-
tives),7 but for rare 4,5-dihydro-1,4-benzothiazepines whose prep-
aration otherwise involves difficulties,8–12 ring transformation
reactions of b-lactam-condensed thiazines are also used.9–12
In the course of recent studies on S- and N-containing
heterocycles, we prepared and isolated the 2,3-disubstituted
(imine–enamine) with each other.11,13 Surprisingly, these 4,1-ben-
zothiazepines could be separated by column chromatography and
manifested the rare phenomenon of desmotropy. We recently
devised
a convenient synthesis for rare 2,3-disubstituted 4,
5-dihydro-1,4-benzothiazepines from 2-aryl-4H-1,3-benzothia-
zines.12 The Staudinger reactions of 1,3-benzothiazines with mono-
chloroacetyl chloride furnished selectively trans monochloro-b-
lactam-condensed thiazines. The ring expansion of azeto[2,1-b]
[1,3]benzothiazin-1-one derivatives with sodium methoxide affor-
ded 1,4-benzothiazepines as single products in good yields.12 On
continuation of our work, we found that the ring-enlargement reac-
tion of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzo-
thiazin-1-one (2a) with an excess of sodium methoxide in
methanol provided an unexpected product, 3. Our present aim
was to shift the reaction path of the previously examined ring-
enlargement reactions towards such new compounds and to carry
out structural investigations.
The reaction of 1a14 with chloroacetyl chloride in refluxing tol-
uene furnished azeto[2,1-b][1,3]benzothiazin-1-one (2a) in good
yield (Scheme 1). Compounds 2b,c were obtained under similar
conditions from 1b,c.14
4,1-benzothiazepines:
3-ethoxycarbonyl-2-phenyl-3,5-dihydro-
4,1-benzothiazepine and 3-ethoxycarbonyl-2-phenyl-1,5-dihydro-
4,1-benzothiazepine, which are in
a tautomeric relationship
Surprisingly, treatment of monochloro-b-lactam 2a with excess
sodium methoxide led to the formation of the previously unknown
indolo-1,4-benzothiazepine ring system 3a via a novel rearrange-
ment (Scheme 1). To investigate the possibility of the extension
⇑
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.2010.10.160

L. Fodor et al. / Tetrahedron Letters 52 (2011) 224–227
225
R
R
R1
R1
O2N
ClCH2COCl
Cl
H
MeO
MeO
S
MeO
MeO
S
Et3N
(92−95%)
N
N
NO2
O
2a−c
1a−c
5.0 equiv.
NaOMe
2.0 equiv.
NaOMe
reflux
MeOH
MeOH, reflux
(78−83%)
(55−64%)
R1
H
COOMe
N
3.0 equiv.
NaOMe
S
MeO
MeO
MeO
MeO
R
S
R
MeOH
reflux
(52%)
R1
NH
O2N
N
MeO
3a−c
a: R, R1 = O-CH2-O;
(for 4b
3b)
4b−c
c: R = R1 = OMe
b: R = R1 = H;
Scheme 1.
of this novel ring expansion, compounds 2b,c were also reacted un-
der the same conditions and indolo[2,3-b][1,4]benzothiazepines
3b,c were obtained in good yields. The reactions of monochloro-
b-lactam derivatives 2b,c with 2 equiv of sodium methoxide in
dry methanol at reflux temperature afforded the expected products
4b,c (Scheme 1). NMR investigations demonstrated the presence of
the enamine tautomers of 4,5-dihydro-1,4-benzothiazepines only.
In contrast to the 4,1-benzothiazepine derivatives, desmotropy
was not observed for the 1,4-benzothiazepines.11,12 In this latter
reaction, the first step is most probably alcoholysis of the b-lactam
Cyclizations of o-nitroaryl-alkene type compounds to the 1-
hydroxyindole skeleton under basic conditions are known in the
literaure.15 The second step of the present ring transformation of
2 via 4 most probably involves the formation of N-hydroxyindole
derivatives 8 under treatment with sodium methoxide (Scheme
2). Addition of methanol to 8 provides intermediate 9. The forma-
tion of 3 can be further explained through intermediate 10, fol-
lowed by 1,5-proton shift. Further studies relating to the possible
reaction mechanism are in progress.
The unexpected structures of the novel ring expansion products
could be inferred from the NMR spectra only after the crystal struc-
ture of 3a had been determined (Fig. 1).16
The structures of the compounds were also supported by IR and
1H and 13C NMR, and for 3a–c, also by 15N NMR spectroscopy
(Supplementary data). Additionally, techniques such as HMQC,
HMBC and DEPT were employed. The spectral data are given in
Tables 1 and 2 (Supplementary data).
ring in 2b,c, resulting in a
-chloro esters,11 which leads to the prod-
ucts 4b,c through episulfonium salts after elimination of HCl.
Investigations have been performed on the reaction mechanism
of the formation of 3a–c from 2a–c. Treatment of 4b with 3 equiv
of sodium methoxide provided 3b (Scheme 1), which indicated 1,4-
benzothiazepines 4 as one of the possible intermediates in the for-
mation of indolo-1,4-benzothiazepines 3 (Scheme 2).
Figure 1. An ORTEP diagram of 3a, showing the atomic numbering of the non-hydrogen atoms. Hydrogen positions are shown, but not labelled.

226
L. Fodor et al. / Tetrahedron Letters 52 (2011) 224–227
O
N
MeO2C
MeO2C
S
O2N
H
OH
MeO
MeO
S
MeO
MeO
NaOMe
MeOH
R
R
N
N
R1
R1
5a−
c
4a−c
MeOH
-CO(OMe)2
O
N
O
OH
N
S
MeO
MeO
S
MeO
MeO
-H2O
R
R
N
H
N
R1
R1
H
H
7a−c
6a−c
OH
OH
N
N
S
S
MeO
MeO
MeO
MeO
MeOH
R
R
N
N
R1
R1
H
MeO
H
8a−c
9a
−c
-H2O
H
N
N
S
MeO
MeO
S
MeO
MeO
1,5-proton
shift
R
R
N
N
R1
R1
MeO
3a
MeO
H
−
c
10a c
−
a: R,R1 = O-CH2-O;
b: R = R1 = H;
c: R = R1 = OMe
Scheme 2.
In summary, we have developed a convenient and general syn-
References and notes
thesis of the new ring system, indolo[2,3-b][1,4]benzothiazepines
(3a–c), from ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]-
benzothiazin-1-ones 2a–c using 5 equiv of sodium methoxide in
methanol under reflux. The structures of the novel ring expansion
products were proved by means of NMR spectroscopy and X-ray
crystallography. In order to study the structure–reactivity relation-
ships, the preparation of further derivatives is in progress.
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V = 3562.4(3) Å3, Z = 4, Dc = 1.433 mg mÀ3 = 0.216 mmÀ1
T = 294 K, R =
0.0625, Rw = 0.1897, Rtot = 0.0825, N = 2038, CCDC reference number: 783262.
a
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,
l
,