Exceptional isolation of both imine and enamine desmotropes of 4,1-benzothiazepines

Article abstract of DOI:10.1016/j.tet.2010.02.084

The desmotropy of differently substituted (R*)-3-ethoxycarbonyl-2-aryl-3,5-dihydro-4,1-benzothiazepines and 3-ethoxycarbonyl-2-aryl-1,5-dihydro-4,1-benzothiazepines was investigated. The target 4,1-benzothiazepines were obtained via the ring transformation of (2R*,2aS*)-2-chloro-2a-aryl-2,2a-dihydro-2H,4H-azeto[1,2-a][ 3,1]benzothiazin-1-ones with sodium ethoxide in ethanol. The β-amino ester intermediate of the ring-enlargement reaction was isolated. Surprisingly, the desmotropes obtained could be separated by column chromatography and proved to be unexpectedly stable in solution. Further comparative studies revealed the existence of only the enamine forms of regioisomeric 2-ethoxycarbonyl-3-aryl-4,5-dihydro-7,8-dimethoxy-1,4-benzothiazepine derivatives; in this case, no desmotropy occurred. The structures were proved by means of NMR and IR spectroscopy.

Full text of DOI:10.1016/j.tet.2010.02.084

Tetrahedron 66 (2010) 3207–3213
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exceptional isolation of both imine and enamine desmotropes of
4,1-benzothiazepines
a
,
,
b
,
c
c,d,
*
Peter Csomos b, Lajos Fodor a , Antal Csampai , Pal Sohar
*
´
´
´
´
´
a Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of Sciences,
H-6720, Szeged, Eo¨tvo¨s u. 6., Hungary
b Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
c
´
Institute of Chemistry, Eo¨tvo¨s Lorand University, Hungary
d
´
Protein Modelling Research Group, Hungarian Academy of Sciences and Eo¨tvo¨s Lorand 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:
The desmotropy of differently substituted (R*)-3-ethoxycarbonyl-2-aryl-3,5-dihydro-4,1-benzothiaze-
pines and 3-ethoxycarbonyl-2-aryl-1,5-dihydro-4,1-benzothiazepines was investigated. The target
4,1-benzothiazepines were obtained via the ring transformation of (2R*,2aS*)-2-chloro-2a-aryl-2,2a-
Received 8 December 2009
Received in revised form 2 February 2010
Accepted 22 February 2010
Available online 25 February 2010
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-ones with sodium ethoxide in ethanol. The
b-amino
ester intermediate of the ring-enlargement reaction was isolated. Surprisingly, the desmotropes obtained
could be separated by column chromatography and proved to be unexpectedly stable in solution. Further
comparative studies revealed the existence of only the enamine forms of regioisomeric 2-ethoxy-
carbonyl-3-aryl-4,5-dihydro-7,8-dimethoxy-1,4-benzothiazepine derivatives; in this case, no desmotropy
occurred. The structures were proved by means of NMR and IR spectroscopy.
´
Dedicated to the memory of Professor Gabor
Berna´th PhD, DSc, University of Szeged, who
died on 1 October 2009
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Desmotropy
4,1-Benzothiazepine
1,4-Benzothiazepine
b
-Lactam
Ring transformation
1. Introduction
forms.4 Later, the present meaning of desmotropy was defined by
Hantzsch and Herrmann: if a substance can be isolated in two
Tautomerism frequently occurs among heterocyclic systems. It is
of great importance, e.g., for the correct interpretation of the detailed
mechanisms of reactions or the biological activities of potentially
tautomeric compounds.1 In particular cases, when the in-
terconversion of tautomers is slow, theycan be separated by means of
various instrumental chromatographic methods, but equilibration
usually proceeds relatively rapidly.2 There are examples of the iso-
lation of tautomers with complex-forming molecules.3 In rare cases,
when the energy barrier between the two tautomers is sufficiently
high, there is a possibility of the existence of both (all) of the in-
dividual tautomers as separate compounds. This latter phenomenon
is called desmotropy.
stable forms it should be called desmotropic, while if it cannot be
isolated it should be termed tautomeric.5 This was followed by the
modern definition of desmotropy as ‘tautomerism in which both
tautomers have been isolated.’6 They can be separated either by
crystallization from different solvents7 or in exceptional cases by
column chromatography.8 It is noteworthy that there have been
reports of the separation of tautomers where the authors did not
use the term desmotropy.9
In fact, only a few examples of desmotropy are known in the
literature.7,10–14 The pioneering IR-spectroscopic studies,10a,b later
confirmed by X-ray measurements, were performed on substituted
hydantoins, thiohydantoins, imidazolidinones and imidazolidin-
thiones.10c,d Desmotropic pairs were subsequently found amongst
pyrazole,7,11 tetrazole12 and pyridoxal13 derivatives. The known
examples have been investigated mainly with the aid of IR and
solid-state NMR spectroscopy and/or X-ray crystallography, be-
cause of the instability of the desmotropes in solution.
The term was introduced by Jacobson to describe certain sub-
stances, which may occur in either of two structurally different
* Corresponding authors. Tel.: þ36 66 463763; fax: þ36 66 526539 (L.F.);
tel.: þ36 1 3722911; fax: þ36 1 3722592 (P.S.); e-mail addresses: fodor@pandy.hu
We earlier investigated the ring-transformation reactions of dif-
ferent monochloro-b-lactam-fused benzothiazines in the presence of
´
(L. Fodor), sohar@chem.elte.hu (P. Sohar).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.084

3208
P. Csomo´s et al. / Tetrahedron 66 (2010) 3207–3213
base.8,15 These enlargement reactions led to benzene-fused 1,4- and
4,1-benzothiazepine derivatives, preparation of which otherwise
involves difficulties. During our studies of the ring transformation of
(2R*,2aS*)-2-chloro-2a-phenyl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]
benzothiazin-1-one (1) with sodium ethoxide in ethanol, a desmo-
tropic (imine and enamine) 4,1-benzothiazepine pair was obtained.8
In view of the fact that there are currently so few examples,
desmotropy seems to be a comparatively unexplored, but rather
exciting field of organic chemistry. Consequently, as a continuation
of our earlier work, we set out to study the possible desmotropy of
1,4- and 4,1-benzothiazepines.
separate desmotropes 5b–e and 6b–e as crystalline compounds in
relatively good yields. The pure desmotropes were stable for different
periods of time and it was possible to perform NMR spectroscopic
investigations in solution. However, it must be noted that under some
circumstances (either basic or acidic treatment) the isolated pure
products again formed equilibrium mixtures. As might be expected,
therefore, the compounds are able to equilibrate.
We earlier proposed a reaction mechanism for the ring trans-
formation of lactams, in which the first step is ethanolysis of the
b-lactam ring, furnishing the a-chloro-ester 7, which gives the
products, most probably through the episulfonium salt after
the elimination of HCl. Treatment of 4a with 0.9 equiv of sodium
ethoxide in ethanol led to the first isolation of a compound, structural
analysis of which indicated 7a, one of the possible intermediates.
Upon treatment of 7a with an excess of sodium ethoxide, 5a and 6a
were obtained (Scheme 2).
2. Results and discussion
The treatment of 2-aminobenzyl alcohol with thionyl chloride
resulted in 2-aminobenzyl chloride hydrochloride (1),16 fusion of
which with thiobenzamides 2a–e provided the key intermediate
4H-3,1-benzothiazine derivatives 3a–e in good yields (Scheme 1).16,17
In the next step, it appeared to be worthwhile to investigate
the ring transformations of the regioisomeric monochloro-b-lac-
R2
110-120 °C
R1
R3
5
8
4
neat, 30 min.
4a
8a
3
S
ClCH2COCl
6
7
Cl
S
67
S
−
82%
R2
R1
Et3N
N
2a
NH2 HCl
H2N
N
9
R2
R1
toluene, reflux
Cl
2
57−59%
1
1
O
R3
2a−e
R3
3a−e
4a−e
a: R1 = R2 = R3 = H; b: R1 = Cl, R2 = R3 = H;
c: R1 = Me, R2 = R3 = H;
d: R1 = OMe, R2 = R3 = H; e: R1 = H, R2 = R3 = OMe
Scheme 1.
For the preparation of our target monochloro-
b
-lactam
tam-condensed 1,3-thiazines 8a–d. The reactions of 8a–d with
sodium ethoxide gave only one product in each case, the en-
amine 1,4-benzothiazepines 9a–d being obtained in good yields.
Not even traces of the imines 10a–d were detected (Scheme 3).
Most probably in 10a–d continuous conjugation is not possible
and thus the enamine form is obviously preferred (see in
Structure part).
derivatives (4a–e), we made use of the Staudinger reaction. The
reactions of 3a–e with chloroacetyl chloride in refluxing toluene in
the presence of triethylamine gave azeto[2,1-a][3,1]benzothiazin-
1-one derivative 4a–e in relatively good yields (Scheme 1).
Toinvestigate the possible desmotropismfordifferentsubstituents
and to compare substituent effects, the monochloro-b-lactam de-
rivatives 4a–e were treated with sodium ethoxide in dry ethanol at
room temperature. The reactions proceeded rapidly: in 10 min the
starting materials had disappeared. In each case, two products, 5b–e
and 6b–e were obtained (Scheme 2). After column chromatography
and evaporation of the eluent, trituration with n-hexane furnished the
For further investigation of the desmotropes, X-ray and differ-
ential scanning calorimetry (DSC) investigations are in progress. To
obtain the energetics of the studied compounds theoretical calcu-
lations are also planned.
3. Structure
R2
The IR, 1H and 13C NMR data proving the presumed structures of
the new compounds are given in Tables 1 and 2. Only the following
additional remarks are necessary:
The presence of the aryl-iminothiohydrin moiety in 3d,e is un-
ambiguously demonstrated by the 13C NMR carbon signals at 160.8
and 161.1 ppm, respectively, of the N]C(Ar)–S group, and by the 1H
and 13C NMR signals of the arylsubstituent.
R2
0.9 equiv.
NaOEt
EtOH
rt, 5 min.
14%
R1
R3
R1
R3
S
S
N
H
N
Cl
Cl
4a−e
EtO2C
7a
O
1.4 equiv.
NaOEt
1.4 equiv.
NaOEt
The azetidinone structure of 4d,e follows straightforwardly
EtOH, rt, 15 min.
5b−e: 35−52%
6b−e: 19−23%
EtOH, rt, 15 min.
5a: 59%; 6a: 14%
from the
n
C]O IR band in the expected region18 (at 1769 and
1763 cmꢀ1), the carbonyl and NCquat.
S
13C NMR signals (at 160.0
and 70.8 ppm for 4d and at 159.6 and 70.9 ppm, respectively,
for 4e) and the 1H NMR singlet of the CHCl group (5.27 and
5.25 ppm).
As concerns the desmotropy of the pairs 5–6, in case of p-chloro (b)
and p-methoxy (d) derivatives, the tautomers proved to be stable in
DMSO-d6 solution: equilibration was not observed during the solvation
and measurements, and the samples investigated remained
homogeneous.
S
S
CO2Et
+
CO2Et
N
N
H
R2
R2
R1
5a−e
6a−e
R1
R3
R3
a: R1 = R2 = R3 = H; b: R1 = Cl, R2 = R3 = H;
c: R1 = Me, R2 = R3 = H;
d: R1 = OMe, R2 = R3 = H; e: R1 = H, R2 = R3 = OMe
The imine tautomeric forms 5b and 5d are unambiguously in-
Scheme 2.
dicated by the 1H and 13C NMR signals of the methine (SCH) group

P. Csomo´s et al. / Tetrahedron 66 (2010) 3207–3213
3209
R1
R2
R3
COOEt
R3
COOEt
NaOEt
S
Cl
O
MeO
MeO
S
MeO
MeO
MeO
MeO
S
EtOH
R1
H
R1
reflux
1h
89−95%
N
N
NH
R2
R3
R2
8a−d
9a−d
10a−d
a: R1 = R2 = R3 = H; b: R1 = Cl, R2 = R3 = H; c: R1 = R2 = OMe, R3 = H; d: R1 = R2 = H, R3 = Cl
Scheme 3.
(at 5.07 and 45.7 ppm for 5b and at 5.10 and 45.5 ppm for 5d, re-
spectively). In accordance, 6b and 6d reveal the characteristic IR,
1H and 13C NMR spectral data of the enamino (NH–C]C) moiety:
In the 1H NMR spectra of 6b–e and 9a–c, the methylene group
signal is likewise a singlet due to the fast inversion of the seven-
membered heteroring. Because of the steric hindrance between
the ester and the ortho-chloro-substituted phenyl groups, the
conformational motion in 9d is slow and hence the methylene Hs
become non-equivalent. They therefore display double doublets
(the neighbouring NH causes a further double split).
n
NH: 3312 cmꢀ1 (6d),
NC(sp2) and
100.4 ppm (6d).
d
NH: 8.59 (6b) and 8.56 ppm (6d), and
d
d
SC(sp2): 151.8 and 100.8 ppm (6b) and 153.1 and
The imine tautomeric forms of 5c (in CDCl3) and 5e (in DMSO-
d6) are similarly stable. These solutions did not change during the
solvation, during the measurement or subsequently. However,
when 5c was dissolved in DMSO-d6: a mixture of tautomers was
formed.
Compounds 6c and 6e, existing immediately after solvation
in DMSO-d6 as the pure enamines, slowly tautomerized to the
imine form. In the case of 6c, after 2 weeks the enamine:imine
ratio was w3:1. The 3,5-dimethoxyphenyl derivative 6e proved
to be a w6.5:1 mixture of the enamine and imine forms im-
mediately after solvation in DMSO-d6, the ratio changing to
w4:1 in 17 h.
4. Experimental
4.1. General
Melting points were determined on a Kofler micro melting ap-
paratus and are uncorrected. Elemental analyses were performed
with a Perkin–Elmer 2400 CHNS elemental analyser in the Institute of
Pharmaceutical Chemistry. Merck Kieselgel 60F254 plates were used
for TLC, and Merck Silica gel 60 (0.063–0.100) for column chroma-
tography. Benzothiazines 3a–c,16,17 azeto-1,3-thiazines 4a–c16,17 and
azeto-1,3-thiazines 8a–d21 were prepared by literature methods.
IR spectra were recorded in KBr pellets with a Bruker IFS 55
FT-spectrometer. 1H and 13C NMR spectra were recorded in DMSO-d6
solution in 5-mm tubes at room temperature, on a Bruker DRX 500
spectrometer at 500 (1H) or 125 (13C) MHz, with TMS (dTMS¼0 ppm)
as internal reference, and the deuterium signal of the solvent as the
lock. Assignments were supported by DEPT, HMQC and HMBC mea-
surements. DEPT spectra were run in a standard manner, using only
The thiazepines 9a–d are homogeneous enamine tautomers in
DMSO-d6 solution and equilibrization was not observed. This is
obvious from the appearance of the
n
NH IR band (3323ꢁ9 cmꢀ1
)
C
and the two C(sp2) lines (at 88.0ꢁ0.8 and 156.8ꢁ1.8 ppm) in the 13
NMR spectra.
In summary, desmotropy was observed in CDCl3 solution: the
pure tautomers remained unchanged for days. In DMSO-d6 solu-
tion, the originally preferred enamine form transformed slowly to
the imine tautomer. The equilibrium, however, remained in favour
of the enamine form.
the
Q
¼135ꢂ pulse to separate CH/CH3 and CH2 lines phased ‘up’ and
‘down’, respectively. 2D-HMQC and 2D-HMBC spectra were obtained
by using the standard Bruker pulse programs.
The mesomerism [–NH–C]C–COOEt4–NþH]C–C]C(OEt)Oꢀ]
of the b
-enaminoester19 moiety stabilizes the enamine form, but the
continuous conjugation via the C]N bond of the condensed aro-
matic ring and the Ar group can partly compensate the energetically
favoured structure in the imine form. The result is the existence of
a tautomeric equilibrium. In 9a–d, continuous conjugation is not
possible and thus the enamine form is obviously preferred.
The structure of 7a (of importance from the aspect of the pre-
sumed reaction mechanism) follows from the spectral data given
below:
4.2. General procedure for the preparation of 4H-3,1-
benzothiazine derivatives 3a–e from 2-aminobenzyl alcohol
To a stirred and cooled (10–15 ꢂC) mixture of thionyl chloride
(6.5 mL, 89 mmol) and chloroform (30 mL), 2-aminobenzyl alcohol
(5 g, 41 mmol) dissolved in chloroform (100 mL) was added drop-
wise during 1 h. After the addition, the reaction mixture was stirred
for a further 1 h at room temperature and then evaporated (50 ꢂC).
The crystalline residue was taken up in diethyl ether (40 mL),
filtered and washed with diethyl ether (2ꢃ40 mL). Compound 1
was used without further purification.
For the transformation of compounds 3, the method of
El-Desoky17 was used with slight modifications, as follows.
2-Aminobenzyl chloride hydrochloride (1) (2.7 g, 15 mmol) was
thoroughly mixed with the appropriate thioamide (2d,e) (15 mmol)
and the mixture was maintained at 110–120 ꢂC for 30 min. To the
cooled melt, chloroform (30 mL) was added and the solid formed
was suspended. To the suspension, water was added (10 mL) and
the aqueous phase was made just alkaline with 10% NaOH solution
under intensive shaking. The organic layer was separated, extracted
with water (30 mL), dried (Na2SO4), filtered and evaporated. The
residues thus obtained were purified by column chromatography
with n-hexane:ethyl acetate 9:1 as eluent to give 3a–e. 3a–c Are
A n
NH band appears at w3400 cmꢀ1 in the IR.
Two saturated C atoms, one tertiary and one quaternary, are
present in the molecule, as confirmed by the 13C NMR lines at 70.9
(Cquat.) and 62.2 ppm (CH).
The 1H NMR singlet of the CH group is also observed (at 4.93 ppm).
In consequence of the molecular symmetry, the methylene Hs of
3d,e are chemically equivalent (they give a singlet in the 1H NMR
spectra), while in the asymmetric azetidinones 4d,e the corre-
sponding Hs are non-equivalent (they give an AB-type spectrum:
two doublets). In the 1H NMR spectrum (recorded in CDCl3 solu-
tion) of 4e, however, the methylene group signal is a singlet be-
cause of accidental isochrony.20 This was confirmed by repeated
measurement in DMSO-d6 solution, when not a singlet, but two
doublets were observed (cf. Table 1, FN ‘k’).

Table 1
Characteristic IR frequenciesa and 1H NMR datab for 3d,e, 4d,e, 5b–e, 6b–e, 7a and 9a–dc
Compound
NNH
band
n
C]O
n
C–O band (ester)
g
CAr
H
CH3
XCH2
(2H)f
m
H-5wdd,g
H-6wtd,g
H-7wtd,g
H-8wdd,g
OCH2 qa
(2H)
ArH-20,60wd
(2H)
ArH-30,50w
d/t (2H)
ArH-40wt
(1H)
NH s
(1H)
band
bandd
(3H)e
3d
3e
4d
4e
5b
5c
5d
5e
6b
6c
6d
6e
7a
9a
9b
9c
9d
d
d
d
833
827
829
846
826
836
844
844
848
834
848
809
801
866
808
866
849
d
4.00
4.01
3.64, 3.72
3.70k
3.36, 3.60
3.45, 3.70
3.36, 3.63
3.38, 3.64
3.97
3.99
3.86
3.99
3.27, 3.57
4.78
7.18
7.18
7.16h
7.17h
7.25h
7.26
7.26h
7.28
7.02
7.07
7.28
7.06
6.89h
7.04
7.04
7.03
7.05h
7.39
7.39
7.16h
7.16h
7.05
7.12
7.05i
7.08
6.79
6.83
6.81
6.81
6.67
d
7.26
7.28
w7.38i
7.38
7.26h
7.32
7.28h
7.29
7.06
7.10
7.09
7.09
7.12
d
7.45
7.48
7.89
7.87
6.85
7.02
6.86
6.89
7.18
7.28
7.05
7.27
6.89h
6.95
6.96
6.96h
6.96
d
8.14
7.35
7.00
d
d
d
d
d
d
d
d
6.64
d
d
d
1769
1763
1725
1725
1742
1732m
1650
1667
1658
1667
1736
1638
1635
1670n
1636
d
d
d
w7.38i
w6.59l
8.00
6.89
d
d
d
d
d
d
6.44
d
d
d
1279, 1086
1214, 1023
1205, 1180, 1025
1195, 1152
1269, 1058
1212, 1057
1226, 1057, 1028
1220, 1129
1181, 1166
1275, 1260, 1054
1278, 1260, 1051
1231, 1055
1290, 1070,n 1027
0.88
1.01
0.93
0.94
0.74
0.76
0.77
0.80
0.85
0.62
0.72
0.70
0.72
3.64
3.85
3.67
3.69
3.66
3.69
3.70
3.71
3.88
3.58
3.64
3.62
3.63
7.56
7.29
7.06i
d
d
d
7.89
8.01
7.18
d
d
d
d
d
d
6.70
d
d
d
7.33
7.43
7.24h
6.96
d
7.25h
7.30
7.11
6.88o
7.06,h 7.30
8.59
8.56
8.56
8.56
d
7.00m
7.08m
6.95h
7.09h
3290
3312
3310
w3400
3321
3315
3332
3318
7.24h
7.27
d
d
6.51
7.55
7.10
7.34
6.56
7.25h
7.34
d
4.78
4.76
4.61, 4.94
d
d
d
d
6.66
d
d
d
7.37p
7.24
In KBr discs (cmꢀ1). Further IR bands,
gCArH and gCArCAr bands (mono- or para-disubstituted benzene ring): 765 (3d, 5d, 6e), 757 (3e, 5c,e, 6c,d, 9b–d), 742 (4d,e), 742, 698 (7a), 758, 701 (9a).
In DMSO-d6 or CDCl3 (3d,e, 4d,e, 5c, 7a) solution at 500 MHz. Chemical shifts in ppm (dTMS¼0 ppm), coupling constants in hertz. Further signals: ArCH3, s (3H): 2.43 (5c), 2.37 (6c); OCH3, s (3H): 3.89 (3d,e), 3.81 (4d), 3.77 (4e,
a
b
9a–d, for 9c two overlapping signals), 3.84 (5d), 3.79 (6d, 9d), 3.78 (9a,b), 3.70, 3.74 (9c); SCH, s (1H): 5.07 (5b), 4.54 (5c), 5.10 (5d,e); CHCl (7a), s (1H): 4.93.
c
Assignments were supported by DEPT (except for 5b and 6b), HMQC (except for 3d and 9d), HMBC (except for 3d).
Condensed benzene ring.
Ethyl group, J: 7.1 or 7.4 (6e, 9b).
d
e
f
X¼S, s (3d,e, 4e, 6b–e), 2ꢃd, J: 16.3 (4d), 12.6 (5b–e), 15.5 (9a), X¼NH, d, J: 5.0 (9a–c) or 2ꢃdd, J: 14.0 and 5.5 or 14.0 and 4.8 (11d).
g
The atom numbering of benzothiazines was also used for benzothiazepines.
h
Overlapping signals.
Overlapping signals.
i
k
In DMSO-d6: 3.44 and 4.04 2ꢃd, J: 16.5.
l
Broad.
t.
m
n
Split band-pair with the second maximum at 1714 (5e), 1650 (9c), 1054 (9d).
wd, H-6.
d, J: 8.8.
p
o

P. Csomo´s et al. / Tetrahedron 66 (2010) 3207–3213
3211
Table 2
13C NMR chemical shiftsa for 3d,e, 4d,e, 5b–e, 6b–e, 7a and 9a–db
c
Compound
CH3 Et
C]O
Cquat. (N)
SCH2
C-4a
C-5
C-6
C-7
C-8
C-8a
OCH2 Et
C-10
C-20,60
C-30,50
C-40
Benzothiazine or benzothiazepine
ringd
Aryl group
3d
3e
4d
4e
5b
5c
5d
5e
6b
6c
6d
6e
7a
9a
9b
9c
9d
d
d
160.8
161.1
70.8
29.1
29.1
29.8
29.8
29.9
30.8
30.0
29.9
41.3
41.9
42.1
41.6
29.3
87.7
88.1
87.2
88.8
120.2
120.1
121.3
121.2
126.9
126.7
127.1
127.0
133.3
132.8
132.5
127.2
127.3
128.98e
128.97e
129.2
129.3
129.7
129.8
129.5
129.6
129.7
129.6
118.3
115.9
116.0
115.9
116.0
128.8
128.9
125.1
125.1
126.2
125.9
125.7
126.0
122.0
121.6
121.6
121.7
128.5e
149.1
149.2
149.1e
149.1
127.6e
128.1
129.01e
129.03e
129.6
129.0
129.0
129.1
128.1
128.0
128.0
128.0
128.87e
149.6
149.6
149.5
149.5
127.3e
127.5
121.0
120.9
123.4
123.1
123.4
123.4
122.4
122.4
122.3
122.4
117.3
113.4
113.4
113.6
113.1
145.1
144.7
133.6
133.6
149.5
149.5
149.9
149.6
142.3
142.4
142.5
142.4
142.3
136.3
136.3
136.2
136.5
d
131.1
140.5
128.5
139.1
136.7
135.4
130.1e
140.0
140.0
138.3e
133.3
142.9
141.3
141.8
133.8
134.2
132.0
130.4
114.2
161.2
114.1
161.0
129.6
129.8
114.9
161.5
128.8
129.5g
114.2
160.9
128.1
128.6
1289.6
149.0e
130.3
162.9
104.5
160.4
100.8
136.8
141.6
162.6
103.9
134.2
139.1e
160.8
101.7
128.92e
129.2
140.5
150.3
127.5
d
d
d
106.5
129.3
106.5f
130.2
127.9
130.2e
106.5
131.4
129.3g
131.0
107.7
128.93
128.5
130.4
112.5
140.5
d
160.0
159.6
168.9
168.9
169.3
169.1
166.9
167.5
167.6
167.3
167.9
167.9
167.5
168.2
166.6
68.1
67.7
62.4
62.6
62.2
62.3
60.5
60.4
60.4
60.5
62.6
59.7
59.8
59.7
59.7
d
70.9
14.5
14.2
14.6
14.6
14.4
14.4
14.5
14.4
13.9
14.3
14.4
14.6
14.5
163.9
164.6
164.0
164.6
151.8
153.1
153.1
152.1
70.9
158.6
157.4
158.5
155.0
118.4
130.0
129.6
130.2
129.4
a
In ppm (dTMS¼0 ppm) at 125.7 MHz. Solvent: DMSO-d6, for 3d,e, 4d,e, 5c and 7a CDCl3. Further signals, ArCH3: 21.9 (5c), 21.7 (6c); NCH2 (thiazepine): 48.5 (9b,c), 48.4 (9a),
48.2 (9d); SCH or S(]C), thiazepine: 45.7 (5b), 46.9 (5c), 45.5 (5d), 46.0 (5e), 100.8 (6b), 100.5 (6c,e), 100.4 (6d); OCH3: 55.9 (3d), 56.0 (3e), 55.7 (4d), 55.8 (4e), 56.3 (5d), 56.4
(5e), 56.2 (6d,e), 56.63 (9a), 56.6 (9b), 56.4, 56.5, 56.6 (9c), 56.59, 56.63 (9d); CHCl: 62.2 (7a).
b
Assignments were supported by DEPT (except for 5b and 6b), HMQC (except for 3d and 9b) and HMBC (except for 3d) measurements.
NCH2 (9a–d).
The numbering of the carbons in the condensed ring of benzothiazine was also used for the benzothiazepine derivatives.
Reversed assignment is also possible.
Due to steric hindrance, a broadened signal.
Overlapping lines.
c
d
e
f
g
known compounds, the spectroscopical and analytical data were
identical to those reported.16,17
(0.40 mL, 3.0 mmol) was repeated twice under the same conditions
as above. The reaction mixture was then cooled and extracted with
brine (20 mL), and the organic layer was dried with Na2SO4. After
evaporation, the residue was taken up in benzene (5 mL) and
passed through a short column of silica, the solvent was evaporated
off, and the oily residue crystallized on trituration with ethanol.
4.2.1. 2-Phenyl-4H-3,1-benzothiazine (3a). Pale-yellow crystalline
powder, mp 54–56 ꢂC (from diisopropyl ether), lit.17 mp 55–58 ꢂC;
2.3 g, 67%; Rf (42%, n-hexane:ethyl acetate 9:1).
4.2.2. 2-(4-Chlorophenyl)-4H-3,1-benzothiazine (3b). Pale-yellow
crystalline powder, mp 121–123 ꢂC (from diisopropyl ether),
lit.17 mp 122–125 ꢂC; 2.7 g, 70%; Rf (40%, n-hexane:ethyl ace-
tate 9:1).
4.3.1. (2R*,2aS*)-2-Chloro-2a-(4-methoxyphenyl)-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (4d). A white crystalline
powder, mp 178–179 ꢂC (from methanol); 0.39 g, 59%; Rf (75%,
n-hexane:ethyl acetate 4:1). Anal. Calcd for C17H14ClNO2S (331.82):
C, 61.53; H, 4.25; N, 4.22; S, 9.66. Found: C, 61.82; H, 4.11; N, 4.34; S,
9.87.
4.2.3. 2-(4-Methylphenyl)-4H-3,1-benzothiazine (3c). Pale-yellow
crystalline powder, mp 104–106 ꢂC (from diisopropyl ether), lit.16
mp 104–106 ꢂC; 2.9 g, 81%; Rf (45%, n-hexane:ethyl acetate 9:1).
4.3.2. (2R*,2aS*)-2-Chloro-2a-(3,5-dimethoxyphenyl)-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (4e). A white crystalline
powder, mp 160–163 ꢂC (from methanol); 0.41 g, 57%; Rf
(70%, n-hexane:ethyl acetate 4:1). Anal. Calcd for C18H16ClNO3S
(361.84): C, 59.75; H, 4.46; N, 3.87; S, 8.86. Found: C, 59.57; H, 4.31;
N, 4.04; S, 9.10.
4.2.4. 2-(4-Methoxyphenyl)-4H-3,1-benzothiazine (3d). A pale-
yellow crystalline powder, mp 122–123 ꢂC (from diisopropyl
ether); 3.1 g, 82%; Rf (43%, n-hexane:ethyl acetate 9:1). Anal.
Calcd for C15H13NOS (255.34): C, 70.56; H, 5.13; N, 5.49; S,
12.56. Found: C, 70.82; H, 4.91; N, 5.73; S, 12.77.
4.2.5. 2-(3,5-Dimethoxyphenyl)-4H-3,1-benzothiazine (3e). A pale-
yellow crystalline powder, mp 57–58 ꢂC (from diisopropyl ether);
3.2 g 76%; Rf (40%, n-hexane:ethyl acetate 9:1). Anal. Calcd for
C16H15NO2S (285.36): C, 67.34; H, 5.30; N, 4.91; S, 11.24. Found: C,
67.62; H, 5.15; N, 5.02; S, 11.43.
4.4. General procedure for the preparation of (R*)-3-
ethoxycarbonyl-2-aryl-3,5-dihydro-4,1-benzothiazepines
(5b–e) and 3-ethoxycarbonyl-2-phenyl-1,5-dihydro-4,
1-benzothiazepines (6b–e)
Azeto-3,1-thiazine 4b–e (1 mmol) was dissolved in dichloro-
methane (1 mL). To this stirred solution, sodium ethoxide (100 mg,
1.41 mmol), dissolved in dry ethanol (10 mL) was added. The reaction
mixture was allowed to stand at room temperature for 15 min. After
evaporation, the residue was subjected to column chromatography
[Merck Silica gel 60 (0.063–0.100)], using n-hexane:ethyl acetate 9:1,
followed by n-hexane:ethyl acetate 4:1 as eluent (for the separation
of 5b and 6b, n-hexane:ethyl acetate:acetonitrile:dichloromethane
85:5:6:4 was used as eluent). After evaporation of the corresponding
4.3. General procedure for azetobenzothiazines (4d,e)
To a stirred solution of the corresponding 4H-3,1-benzothiazine
derivatives 3d,e (2.0 mmol) in anhydrous toluene, chloroacetyl
chloride (0.24 mL, 3.0 mmol) was added. The solution was treated
to reflux and triethylamine (0.40 mL, 3.0 mmol) in anhydrous tol-
uene or benzene (20 mL) was added dropwise during 4 h at reflux.
The addition of acid chloride (3.0 mmol) and triethylamine

3212
P. Csomo´s et al. / Tetrahedron 66 (2010) 3207–3213
fractions, the oily residues (5 or 6) crystallized on trituration with
n-hexane (3 mL).
Anal. Calcd for C18H18ClNO2S (347.86): C, 62.15; H, 5.22; N, 4.03; S,
9.22. Found: C, 62.31; H, 5.47; N, 4.22; S, 9.42.
4.4.1. (R*)-3-Ethoxycarbonyl-2-(4-chlorophenyl)-3,5-dihydro-4,1-
benzothiazepine (5b). A white crystalline powder, mp 167–170 ꢂC;
150 mg, 45%; Rf (58%, n-hexane:ethyl acetate:acetonitrile:
dichloromethane 85:5:6:4). Anal. Calcd for C18H16NO2ClS (345.84): C,
62.51; H, 4.66; N, 4.05; S, 9.27. Found: C, 62.80; H, 4.72; N, 4.17; S, 9.15.
4.6. General procedure for 1,4-benzothiazepines (9a–d)
Azeto-1,3-thiazine 8a–d (1.5 mmol) was dissolved in dry etha-
nol (20 mL). To this stirred solution, sodium ethoxide (200 mg,
3 mmol) was added. The reaction mixture was treated to reflux for
1 h, and then filtered. Upon cooling, the yellow crystals that sepa-
rated out were filtered off and recrystallized.
4.4.2. 3-Ethoxycarbonyl-2-(4-chlorophenyl)-1,5-dihydro-4,1-benzo-
thiazepine (6b). A white crystalline powder, mp 149–152 ꢂC; 76 mg,
22%; Rf (52%, n-hexane:ethyl acetate:acetonitrile:dichloromethane
85:5:6:4). Anal. Calcd for C18H16NO2ClS (345.84): C, 62.51; H, 4.66;
N, 4.05; S, 9.27. Found: C, 62.71; H, 4.50; N, 3.88; S, 9.41.
4.6.1. Ethyl 3-phenyl-4,5-dihydro-7,8-dimethoxy-1,4-benzothiaze-
pine-2-carboxylate (9a). A yellow crystalline powder, mp
166–167 ꢂC; 0.51 g, 91%; Rf (62%, toluene:methanol 9:1). Anal.
Calcd for C20H21NO4S (371.45): C, 64.67; H, 5.70; N, 3.77; S, 8.63.
Found: C, 64.86; H, 5.57; N, 3.90; S, 8.69.
4.4.3. (R*)-3-Ethoxycarbonyl-2-(4-methylphenyl)-3,5-dihydro-4,1-
benzothiazepine (5c). A white crystalline powder, mp 142–144 ꢂC;
127 mg, 39%; Rf (55%, n-hexane:ethyl acetate 4:1). Anal. Calcd for
C19H19NO2S (325.43): C, 70.12; H, 5.88; N, 4.30; S, 9.85. Found: C,
69.83; H, 5.81; N, 4.12; S, 9.60.
4.6.2. Ethyl 3-(4-chlorophenyl)-4,5-dihydro-7,8-dimethoxy-1,4-ben-
zothiazepine-2-carboxylate (9b). A yellow crystalline powder, mp
195–196 ꢂC; 0.54 g, 89%; Rf (65%, toluene:methanol 9:1). Anal. Calcd
for C20H20ClNO4S (405.90): C, 59.18; H, 4.97; N, 3.45; S, 7.90. Found:
C, 58.92; H, 5.21; N, 3.69; S 8.10.
4.4.4. 3-Ethoxycarbonyl-2-(4-methylphenyl)-1,5-dihydro-4,1-benzo-
thiazepine (6c). A white crystalline powder, mp 136–138 ꢂC; 68 mg,
21%; Rf (45%, n-hexane:ethyl acetate 4:1). Anal. Calcd for
C19H19NO2S (325.43): C, 70.12; H, 5.88; N, 4.30; S, 9.85. Found: C,
70.24; H, 6.11; N, 4.15; S, 9.68.
4.6.3. Ethyl 3-(3,4-dimethoxyphenyl)-4,5-dihydro-7,8-dimethoxy-
1,4-benzothiazepine-2-carboxylate (9c). A yellow crystalline pow-
der, mp 199–202 ꢂC; 0.62 g 95%; Rf (60%, toluene:methanol 9:1).
Anal. Calcd for C22H25NO6S (431.50): C, 61.24; H, 5.84; N, 3.25; S,
7.43. Found: C, 61.39; H, 5.94; N, 3.41; S, 7.63.
4.4.5. (R*)-3-Ethoxycarbonyl-2-(4-methoxyphenyl)-3,5-dihydro-4,1-
benzothiazepine (5d). A white crystalline powder, mp 108–110 ꢂC;
178 mg, 52%; Rf (55%, n-hexane:ethyl acetate 4:1). Anal. Calcd for
C19H19NO3S (341.43): C, 66.84; H, 5.61; N, 4.10; S, 9.39. Found: C,
66.74; H, 5.77; N, 3.92; S, 9.57.
4.6.4. Ethyl 3-(2-chlorophenyl)-4,5-dihydro-7,8-dimethoxy-1,4-ben-
zothiazepine-2-carboxylate (9d). A yellow crystalline powder, mp
196–198 ꢂC; 0.57 g, 94%; Rf (67%, toluene:methanol 9:1). Anal. Calcd
for C20H20ClNO4S (405.90): C, 59.18; H, 4.97; N, 3.45; S, 7.90. Found:
C, 59.01; H, 4.77; N, 3.39; S, 8.12.
4.4.6. 3-Ethoxycarbonyl-2-(4-methoxyphenyl)-1,5-dihydro-4,1-ben-
zothiazepine (6d). A white crystalline powder, mp 174–176 ꢂC;
79 mg, 23%; Rf (45%, n-hexane:ethyl acetate 4:1). Anal. Calcd for
C19H19NO3S (341.43): C, 66.84; H, 5.61; N, 4.10; S, 9.39. Found: C,
66.58; H, 5.79; N, 4.03; S, 9.55.
Acknowledgements
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA) for financial support. We are indebted
to Mrs. E. Juha´sz Dinya´ne´ for technical assistance.
4.4.7. (R*)-3-Ethoxycarbonyl-2-(3,5-dimethoxyphenyl)-3,5-dihydro-
4,1-benzothiazepine (5e). A white crystalline powder, mp
98–100 ꢂC; 189 mg, 51%; Rf (55%, n-hexane:ethyl acetate 4:1).
Anal. Calcd for C20H21NO4S (371.45): C, 64.67; H, 5.70; N, 3.77;
S, 8.63. Found: C, 64.83; H, 5.99; N, 3.81; S, 8.75.
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}
´
´
´
´
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