A convenient synthesis of 1,4-benzothiazepines from 1,3-benzothiazines via the ring transformation of -lactam-condensed 1,3-benzothiazine derivatives

Article abstract of DOI:10.1055/s-0030-1258155

A convenient synthesis was devised for rare 2,3-disubstituted 4,5-dihydro-1,4-benzothiazepines from 2-aryl-4H-1,3-benzothiazines. The Staudinger reaction of 1,3-benzothiazines obtained with chloroacetyl chloride selectively furnished trans-monochloro β- lactam-condensed thiazines. The ring expansion of azeto[2,1-b][1,3]benzothiazin-1-one derivatives with sodium methoxide afforded 1,4-benzothiazepines as the sole product in good yields. The structures of the new molecules were proved by means NMR and IR spectroscopy.

Full text of DOI:10.1055/s-0030-1258155

PAPER
2943
A Convenient Synthesis of 1,4-Benzothiazepines from 1,3-Benzothiazines
via the Ring Transformation of b-Lactam-Condensed 1,3-Benzothiazine
Derivatives
S
ynthesis of 1,4
a
-Benzothia
j
z
epines
o
from 1,3-Be
s
nzothiazines Fodor,*a,b Péter Csomós,a,b Antal Csámpai,c Pál Sohár*c,d
a
Central Laboratory, County Hospital, POB 46, 5701 Gyula, Hungary
Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of
Sciences, Eötvös u. 6., 6720 Szeged, Hungary
b
Fax +36(66)526539; E-mail: fodor@pandy.hu
Institute of Chemistry, Eötvös Loránd University, POB 32, 1518 Budapest, Hungary
Fax +36(1)3722592; E-mail: sohar@chem.elte.hu
c
d
Protein Modelling Research Group, Hungarian Academy of Sciences and Eötvös Loránd University, POB 32, 1518 Budapest, Hungary
Received 30 March 2010; revised 28 April 2010
each other.17 Surprisingly, these 4,1-benzothiazepines
could be separated by column chromatography and they
manifested the rare phenomenon of desmotropy. As a
continuation, our present aim was to devise a convenient
Abstract: A convenient synthesis was devised for rare 2,3-disubsti-
tuted 4,5-dihydro-1,4-benzothiazepines from 2-aryl-4H-1,3-ben-
zothiazines. The Staudinger reaction of 1,3-benzothiazines obtained
with chloroacetyl chloride selectively furnished trans-monochloro-
b-lactam-condensed thiazines. The ring expansion of azeto[2,1- and general procedure for differently substituted 4,5-dihy-
b][1,3]benzothiazin-1-one derivatives with sodium methoxide af-
dro-1,4-benzothiazepines and to investigate their struc-
forded 1,4-benzothiazepines as the sole product in good yields. The
tures in order to reveal possible desmotropy.
structures of the new molecules were proved by means NMR and IR
In the synthesis of the starting thiazines, {[(benzoylami-
no)methyl]sulfanyl}benzene derivatives 1a–f were treated
with phosphorus oxychloride (Scheme 1). Interestingly,
instead of the expected Bischler–Napieralski products, the
4-aryl-2H-1,3-benzothiazines 2, which could be isolated
in trace amounts only, the isomeric 2-aryl-2H-1,3-benzo-
thiazine derivatives 3a–f were formed in moderate yields.
The mechanism can be explained via an intermediate
formed by proton-catalyzed intermolecular rearrange-
ment of acid amide-thioether-type compounds to the N-
aroyl-2-sulfanylbenzylamine, followed by ring closure to
the benzothiazine.18
spectroscopy.
Key words: 1,4-benzothiazepine, 1,3-benzothiazine, b-lactams,
ring expansion, S,N-heterocycles
During recent years, increased attention has been focused
on the synthesis of condensed S,N-heterocycles.1 Several
representatives of this group are bioisosteres of various al-
kaloids or drugs, e.g. 1,3-benzothiazine derivatives are
analogues of isoquinoline alkaloids and 1,4-benzothiaz-
epines related to the well-known 1,4-benzodiazepine fam-
ily of drugs, and a broad range of pharmacological effects
have been observed for these heterocycles. Besides 1,3-
benzothiazines, which exhibit a wide variety of pharma-
cological effects,2–5 1,4-benzothiazepines exert bile acid
absorption inhibitory activity,6 antidepressant activity,7
anti-arrhythmic activity,8 and reversal of P-glycoprotein-
mediated multidrug resistance.9
R1
R2
S
R1
R2
S
Ar
R1
POCl3
S
NH
Ar
N
100 °C
R2
N
O
2
1a–f
3a–f
Ar
a–c R1 = R2 = MeO
d–f R1 = H, R2 = Me
a Ar = 4-BrC6H4
b Ar = 3-BrC6H4
c Ar = 3,4,5-(MeO)3C6H2
d Ar = 4-ClC6H4
2,3,4,5-Tetrahydro-1,4-benzothiazepine derivatives can
be prepared relatively easily from the corresponding bi-
functional thioamide or aminothiol derivatives.10 On the
other hand, there are only rare examples of the synthesis
of 4,5-dihydro-1,4-benzothiazepines.11–13
e Ar = 4-FC6H4
f Ar = 4-MeC6H4
Scheme 1
In the course of our recent studies on S- and N-containing
condensed-skeleton heterocycles,14–16 we prepared and
isolated 2,3-disubstituted 4,1-benzothiazepines: ethyl
2-phenyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate
and ethyl 2-phenyl-1,5-dihydro-4,1-benzothiazepine-3-
carboxylate, which are in a tautomeric relationship with
The reaction most widely used for the construction of aze-
tidinone rings is [2+2] ketene–imine cycloaddition, the
Staudinger reaction.19 For our target b-lactams 4a–f, we
set out to use this process. The reaction of 3a with chloro-
acetyl chloride in refluxing toluene furnished azeto[2,1-
b][1,3]benzothiazin-1-one derivative 4a in good yield
(Table 1). Compounds 4b–f were obtained under similar
conditions.
SYNTHESIS 2010, No. 17, pp 2943–2948
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258155; Art ID: T07910SS
© Georg Thieme Verlag Stuttgart · New York

2944
L. Fodor et al.
PAPER
Table 1 Synthesis of 1,4-Benzothiazines from 1,3-Benzothiazines via the Ring Transformation of b-Lactam-Condensed 1,3-Thiazine Deriv-
atives
Cl
Ar
Ar
Cl
O
R1
R2
S
Ar
NaOMe
MeOH
ClCH2COCl
toluene
R1
R2
S
R1
R2
S
H
COOMe
N
N
Et3N
reflux
NH
reflux
3a–f
4a–f
5a–f
COOMe
Cl–
COOMe
COOMe
Ar
R1
R2
S
R1
R2
S
R1
R2
S+
Ar
Ar
NH
NH
N
7a–f
8
6a–f
Entry
Ar
R1
R2
Thiazine
Yield (%)
41
b-Lactam Yield (%)
Thiazepine Yield (%)
1
2
3
4
5
6
4-BrC6H4
3-BrC6H4
OMe
OMe
OMe
H
OMe
OMe
OMe
Me
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
92
7a
7b
7c
7d
7e
7f
83
85
82
85
89
79
37
90
3,4,5-(MeO)3C6H2
4-ClC6H4
ref. 23
ref. 14
16
95
ref. 14
90
4-FC6H4
H
Me
4-MeC6H4
H
Me
12
87
The reactions of monochloro-b-lactam derivatives 4a–f Concerning the cis- or trans-position of the substituents
with sodium methoxide in dry methanol at reflux temper- on the azetidinone ring (2-Cl and 2a-Ar), the identical 13C
ature in each case afforded only one product 7a–f NMR chemical shifts of the three carbons in the four-
(Table 1). NMR investigations demonstrated only the membered ring of 4a to those for the Ar = Ph analogue22
presence of the enamine tautomer of 4,5-dihydro-1,4-ben- confirm the trans-position of the substituents (cis-orienta-
zothiazepines. In contrast with the 4,1-benzothiazepine tion of the 2-Cl and 2a-Ar groups). In accord with our ear-
derivatives, desmotropy was not observed for 1,4-ben- lier results,22 the proof of this arrangement of the
zothiazepines.17b
substituents was provided by comparison of the 1H NMR
chemical shifts of the protons of the aryl group in the 2-
chloro and 2-phenyl analogues. The mutual anisotropic
shielding of the two benzene rings in the 2,2a-diphenyl
compounds revealed in dramatic upfield shifts (0.55 and
0.70 ppm) of the protons in both rings.
Since the 13C NMR shifts of the azetidinone carbons did
not change more than expected as a consequence of the
difference in the substitution, the analogous stereo-
structure was obvious. The same holds for compounds
4a–c,e,f.
In this reaction, the first step is most probably alcoholysis
of the b-lactam ring of 4a–f, resulting in a-chloro esters
5a–f, which lead to the products 7a–f through episulfo-
nium salt 6a–f after elimination of HCl (Table 1).
1
The IR and H and 13C NMR spectral data given in
Tables 2 and 3 offer unambiguous proof of the presumed
structures.
The presence of the azetidinone ring in 4a–c,e,f is obvious
from the C=O IR frequency in the expected region20 be-
tween 1774 and 1791 cm–1 and from the presence of the
carbonyl line in the 13C NMR spectra (d = 164.6–165.2) in
the region of chemical shifts characteristic of b-lac-
tams.21a The molecular asymmetry caused by the con-
densed ring leads to chemical non-equivalence (2 d) of
CH2 protons in the 4-type compounds, in contrast with the
It should be noted that, as H2 lies on the opposite side of
the four-membered ring from the aryl group, NOE could
not be expected between them. Thus, NOE measurements
could only provide negative results on the structural prob-
lem in question.
symmetric starting compounds of type 3, where the CH2 The analogous stereostructure of the 4-type molecules fol-
1
signal is a singlet (at d = 4.75 0.02). One of the methyl- lows straightforwardly from the very similar H and 13C
ene protons in 4a–c,e,f is more shielded (d = 4.22–4.30) NMR chemical shifts of the CHCl group (d = 5.12 0.03
than the other (d = 4.94 0.02), and also than those in and 68.8 0.5, respectively).
3a,b,e,f, due to anisotropy of the aromatic ring21b at C2a.
As concerns the tautomerism/desmotropy of 7a–f, they
are all in the enamine tautomeric form, as confirmed by
Synthesis 2010, No. 17, 2943–2948 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzothiazepines from 1,3-Benzothiazines
2945
Table 2 Characteristic IR and 1H NMR Data of Compounds 3a,b,e,f, 4a–c,e,f, and 7a–f
3, 4, 7 IRa (KBr, cm–1) 1H NMRb–d
N–H C=O CAr–He CAr–Hf CH2
d
6,7-OMe CHCl H5
(s or 2 d, 2 H)g(2 s, 6 H)h (s, 1 H)(1 H)
H8
H7
(1 H)
H2¢, H6¢ H3¢, H5¢ H4¢
NH
(1 H)
(d, 2 H)i (d/t, 2 H) (dd, 1 H)(t, 1 H)
3a
3b
3e
3f
–
–
–
–
–
–
–
–
–
–
–
–
–
855
856
837
759
810j 4.73
3.90, 3.91
3.91, 3.92
2.38
–
–
–
–
6.86 (s) 6.88 (s) –
6.86 (s) 6.88 (s) –
7.87
8.17
7.57
–
–
–
–
–
–
–
–
–
–
765
814
815
810
806
815
829
819
831
756
863
4.75
7.31k 7.60
4.75
7.17 (~s) 7.27l
7.17 (~s) 7.28l
7.13m
8.01
7.11m
7.24
7.51
–
–
–
4.76
2.41
7.12 (~d) 7.90
4a
4b
4c
4e
4f
1791 849
1782 857
1774 848
1776 846
1782 757
4.28, 4.94
4.30, 4.95
4.22, 4.92
4.30, 4.96
4.30, 4.96
4.78
3.83, 3.85 5.11
3.86, 3.85 5.11
3.84, 3.85 5.09
6.68 (s) 6.67 (s) –
6.69 (9 s) 6.69(6 s)–
6.69 (s) 6.76 (s) –
7.33
7.61
6.66
7.27k 7.49
3.87n 3.85n
2.30
5.12
7.02 (~s) 7.12l
7.01m 7.12l
7.01 (~d) 7.45
7.08o
7.21
7.48
–
–
–
2.30
5.14
–
7.00m
7.35
7.04
7.32
6.40
7a
7b
7c
7d
7e
7f
3253 1656 877
3277 1685 860
3278 1653 863
3292 1645 759
3290 1659 758
3381 1660 752
3.77, 3.78
3.86, 3.88
3.86, 3.88
2.30
6.96 (s) 7.05 (s) –
6.78 (s) 7.16 (s) –
6.74 (s) 7.14 (s) –
7.13
4.52
4.63
4.88
–
7.15k 7.42
3.76n 3.80n
4.90
–
815 4.80
837 4.80
–
~7.12m
~7.12m
~7.35p
7.35l
~7.15m ~7.34p
~7.11m
–
–
–
~7.11m
7.12m
7.02
2.30
–
~7.12m
7.09–7.15 –m
817
4.78
2.30
–
7.11 (~s) 7.34l
7.13 (~d) 6.98
7.10
a Further bands, C=N: 1 or 2 two strong–medium bands between 1499–1602; C–O: 2–4 strong bands between 1282–1046.
b The numbering of 3a–f was used such that protons have retained the same number in 4a–f and 7a–f.
c In CDCl3 or DMSO-d6 (7a,d–f) soln at 500 MHz. Further signals: Ar-CH3 (s, 3 H): 2.38 (3f), 2.36 (4f), 2.29 (7f); OCH3 (ester group) (s, 3 H):
3.25 (7a,d), 3.40 (7c), 3.22 (7e), 3.20 (7f).
d Assignments were supported by HMQC and HMBC (except for 3b) measurements.
e Benzothiazine or benzothiazepine ring.
f Ar substituent.
g 2 × 1 H for 4-type compounds, 2 × d and d for 4- and 7-type compounds, respectively, J = 16.2 Hz (4a,b), 16.5 Hz (4c,e,f), 5.2 0.1 Hz
(7a,d–f), 5.6 Hz (7c).
h 6-CH3 for d,e,f-type compounds.
i A part of an AA¢BB¢ spectrum (for a,d–e-type compounds), H2¢ signal for b-type compounds (t, J = 1.8 Hz) (3b, 4b, 7b), (dd, 3JH,H and 4JF,H
=
8.8 and 5.4 Hz) (3e), (dd, 3JH,H and 4JF,H = 8.5 and 5.2 Hz) (4e), (s, 2 H) (4c and 7c); H6¢: (~d, J = 8.0 Hz) (~d, J = 7.92 Hz) (3b), (~d, J = 7.39
Hz) (4b), (~d, J = 7.10 Hz (7b).
j Split band with the second maximum at 826 (3a), 1633 (7e).
k H5¢ (t, 1 H).
l (d, J = 7.8 0.1).
m Overlapping signals.
n OCH3: 3¢-OCH3, 5¢-OCH3 (s, 6 H), 4¢-OCH3 (s, 3 H).
o For 4e t, 3JH,H and 3JF,H couplings of similar values.
p Overlapping signals.
1
the presence of (a) NH signals in the IR and H NMR In summary, we report a convenient and general synthesis
spectra, (b) the doublet and triplet split of the CH2 and NH for a rare ring system, 2,3-disubstituted 4,5-dihydro-1,4-
1H NMR signals, respectively, (c) the 13C NMR shifts of benzothiazepines, from 2-aryl-4H-1,3-benzothiazines.
the olefinic carbons (S–C= and NH–C=) in the azepine The Staudinger reactions of 1,3-benzothiazines with chlo-
ring in the expected regions (d = 86.5–91.5 and 155.8– roacetyl chloride provided condensed thiazines selective-
159.2, respectively), and (d) the absence of a methine 13C ly, in which the 2a-aryl is cis to the 2-chloro substituent.
NMR line (SCH group), as proved by DEPT measure- The ring expansion reactions of azeto[2,1-b][1,3]ben-
ment. It is worthy of note that the methylene protons in the zothiazin-1-one derivatives with sodium methoxide yield-
azepine ring of 7a–f are chemically equivalent, demon- ed 1,4-benzothiazepines, in each case as a single product
strating a fast inversion of the seven-membered ring in with an enamine structure in good yield.
these compounds.
Synthesis 2010, No. 17, 2943–2948 © Thieme Stuttgart · New York

2946
L. Fodor et al.
PAPER
Table 3 13C NMR Chemical Shiftsa,b (d) of Compounds 3a,b,e,f, 4a–c,e,f, and 7a–fc
3,4,7 6-Me 6,7-OMed 4-CH2 CH C=Of Benzothiazine/benzothiazepinea
C=Ng C4a
C5 C6
Aryl groupj
e
h
i
or Cq
C7
C8
C8a
C1¢
Co
Cm
Cp
3a
3b
–
–
56.6k
57.0
57.0
–
–
–
161.4 123.6 110.6 149.5 149.2 110.0 121.7 136.3 129.6 132.1 126.1
161.0 123.5 110.6 149.5 149.2 110.0 121.7 139.3 131.1 123.1 134.3
56.60,
56.61
–
3e
3f
21.5
–
57.1
57.1
43.4
–
–
161.2 131.6 128.0 138.0 128.8 126.8 127.7 133.7 130.2 115.9 165.1
162.2 131.8 127.9 137.8 128.7k 126.8 128.7k 134.9 128.1 129.6 141.8
71.2 121.9 111.6 148.7 149.2 112.9 120.1 136.2 121.1 132.0 123.7
21.8 21.5
–
–
4a
–
56.46,
68.3
164.6
56.48
56.5k
56.5
–
4b
4c
4e
4f
–
43.5
43.5
43.6
43.6
48.4
68.5
69.1
68.9
69.2
87.2
164.6
165.2
164.8
165.0
71.0 122.1 111.6 148.7 149.3 112.9 120.1 139.4 130.42 123.1 132.6
72.0 122.7 111.6 148.6 149.3 112.8 120.7 132.3 104.8 153.6 139.0
71.3 129.9 129.6 137.5 129.3l 130.0 126.3 132.9 129.2 l 115.9 163.3
71.8 130.1 129.2 137.2 129.5 129.9 126.7 134.1 127.2 129.6 139.3
–
21.3
21.3 21.6
7a
–
–
–
51.5,m
167.7 158.0 136.3 113.3 149.6 149.2 116.0 129.5 140.7 130.6 131.6 122.4
167.9 155.8 135.5 111.8 149.5 149.3 116.1 129.4 143.3 130.7 122.4 132.1
168.5 157.1 135.6 111.9 149.4 149.2 116.0 129.7 137.0 105.1 153.3 138.8
56.6k
7b
7c
51.9,m
56.6k
49.3
49.3
91.5
90.6
51.9,m
56.6k
7d 21.6 51.5m
48.8
48.8
48.8
87.1
87.0
86.5
167.6 158.0 143.3 129.9 139.3 130.1 132.2 135.4 133.8 128.7 130.4 140.2
167.8 158.1 143.3 129.9 139.2 130.1 132.2 135.5 137.7 130.7 115.5 163.0
168.0 159.2 143.3 130.0l 139.1n 129.9l 132.1 135.8 138.6n 128.4 129.2 138.4n
7e
7f
21.6 51.5m
21.63 l 21.67,l
51.4m
a The numbering of 3a–f was used such that carbons have retained the same number in 4a–f and 7a–f.
b 125.7 MHz. Solvent: CDCl3/TMS or DMSO-d6/TMS (7a,d–f).
c Assignments were supported by DEPT (except for 3e), HMQC and HMBC (except for 3b) measurements.
d ArCH3 for f-type compounds OCH3 (Ar): 56.8 (4c) and 56.54 (7c)k (3¢-OCH3, 5¢-OCH3), 61.2 (4c, 7c, 4¢-OCH3).
e SC= for 4-type compound.
f Azetidinone or ester group for 4- and 7-type compounds, respectively.
g SCqN (4a–c,e,f), NHC= (7a–f).
h C2¢, C6¢: 126.7 (3b), 126.1, (4b), 126.7 (7b).
i C3¢, C5¢: 130.4 (3b), 130.37, (4b), 130.1 (7b).
j Doublets for 3e, 4e, and 7e due to C,F-couplings, 1J = 251.1 Hz (3e), 248.4 Hz (4e), 244.9 Hz (7e), 2J = 22.0 Hz (3e, 4e), 21.8 Hz (7e), 3J =
9.2 Hz (3e), 8.3 Hz (7e), 4J = <1 Hz (3e), 2.8 Hz (4e, 7e).
k Two overlapping lines.
l Reversed assignments are also possible.
m Ester group.
n Reversed assignments are also possible.
lock) on a Bruker DRX 500 spectrometer at 500 (1H) or 125 (13C)
Melting points were determined on a Kofler micromelting appara-
MHz. Assignments are supported by DEPT, HMQC and HMBC
measurements. DEPT spectra were run in a standard manner, using
only the Q = 135° 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.
tus and are uncorrected. Elemental analyses were performed with a
Perkin-Elmer 2400 CHNS elemental analyzer 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
chromatography. Chloroacetyl chloride was purchased from Fluka.
Substituted (hydroxymethyl)benzamides, {[(benzoylamino)meth-
yl]sulfanyl}benzene derivatives 1a–f, 1,3-benzothiazines 3c,d, and
azetobenzothiazin-1-one 4d were prepared by literature meth-
ods.14,23
4H-1,3-Benzothiazine Derivatives 3a,b,e,f; General Procedure
Substituted
N-{[(3,4-dimethoxyphenyl)sulfanyl]methyl}benz-
amides (33 mmol) were heated with POCl3 (10 mL) on a boiling wa-
ter bath for 1 h. The mixture was cooled and then the reaction was
treated with ice, neutralized with Na2CO3, and extracted with tolu-
ene. The combined toluene extracts were dried (Na2SO4) and the
IR spectra were recorded in KBr pellets with a Bruker IFS 55 FT-
spectrophotometer. 1H and 13C NMR spectra were recorded
(DMSO-d6 soln, 5-mm tubes, r.t., TMS internal reference, CDCl3
Synthesis 2010, No. 17, 2943–2948 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzothiazepines from 1,3-Benzothiazines
1,4-Benzothiazepines 7a–f; General Procedure
2947
solvent was evaporated off. The residue was dissolved in hot EtOH
(6 mL) and crystallized.
Azeto-1,3-thiazine 7a–f (0.70 mmol) was dissolved in dry MeOH
(40 mL). To this stirred soln, NaOMe (76 mg, 1.40 mmol) was add-
ed. The mixture was stirred at reflux for 2 h. The solvent was evap-
orated and then the residue was dissolved in CH2Cl2 (20 mL). The
organic phase was extracted with H2O (10 mL), dried (Na2SO4), and
evaporated.
2-(4-Bromophenyl)-6,7-dimethoxy-4H-1,3-benzothiazine (3a)
White crystalline powder; mp 119–120 °C.
Anal. Calcd for C16H14BrNO2S (364.26): C, 52.76; H, 3.87; N, 3.85;
S, 8.80. Found: C, 52.58; H, 3.79; N, 3.94; S, 8.90.
Methyl 3-(4-Bromophenyl)-4,5-dihydro-7,8-dimethoxy-1,4-
benzothiazepine-2-carboxylate (7a)
Pale yellow crystalline powder; mp 185–186 °C.
2-(3-Bromophenyl)-6,7-dimethoxy-4H-1,3-benzothiazine (3b)
White crystalline powder; mp 101–102 °C.
Anal. Calcd for C16H14BrNO2S (364.26): C, 52.76; H, 3.87; N, 3.85;
S, 8.81. Found: C, 52.82; H, 3.98; N, 3.92; S, 8.93.
Anal. Calcd for C19H18BrNO4S (436.32): C 52.30; H 4.16; N 3.21;
S 7.35. Found: C, 52.15; H, 4.23; N, 3.02; S, 7.51.
2-(4-Fluorophenyl)-6-methyl-4H-1,3-benzothiazine (3e)
White crystalline powder; mp 107–108 °C.
Methyl 3-(3-Bromophenyl)-4,5-dihydro-7,8-dimethoxy-1,4-
benzothiazepine-2-carboxylate (7b)
Pale yellow crystalline powder; mp 135–137 °C.
Anal. Calcd for C15H12FNS (257.33): C, 70.01; H, 4.70; N, 5.44; S,
12.46. Found: C, 69.82; H, 4.56; N, 5.68; S, 12.70.
Anal. Calcd for C19H18BrNO4S (436.32): C, 52.30; H, 4.16; N, 3.21;
S, 7.35. Found: C, 52.47; H, 4.30; N, 3.31; S, 7.42.
2-(4-Methylphenyl)-6-methyl-4H-1,3-benzothiazine (3f)
White crystalline powder; mp 101–102 °C.
Methyl 4,5-Dihydro-7,8-dimethoxy-3-(3,4,5-trimethoxyphe-
nyl)-1,4-benzothiazepine-2-carboxylate (7c)
Pale yellow crystalline powder; mp 235–236 °C.
Anal. Calcd for C16H15NS (253.36): C, 75.85; H, 5.97; N, 5.53; S,
12.66. Found: C, 75.72; H, 6.11; N, 5.67; S, 12.80.
Anal. Calcd for C22H25NO7S (447.50): C, 59.85; H, 5.90; N, 3.03;
S, 6.95. Found: C, 60.02; H, 5.77; N, 3.21; S, 7.06.
Azetobenzothiazines 4a–c,e,f; General Procedure
To a stirred soln of the 4H-1,3-benzothiazine derivative 3a–c,e,f
(2.0 mmol) in anhyd toluene (10 mL) was added ClCH2COCl (3.0
mmol). The soln was refluxed and Et3N (0.4 mL, 3.0 mmol) in an-
hyd toluene (20 mL) was added dropwise over 1 h under reflux. The
mixture was then cooled and filtered, and the remaining Et3NHCl
was washed with toluene. The organic layer was extracted with
brine (20 mL) and dried (Na2SO4). After evaporation, the oily resi-
due crystallized on trituration with EtOH.
Methyl 3-(4-Chlorophenyl)-4,5-dihydro-7-methyl-1,4-benzo-
thiazepine-2-carboxylate (7d)
Pale yellow crystalline powder; mp 189–190 °C.
Anal. Calcd for C18H16ClNO2S (345.84): C, 59.05; H, 5.63; N, 3.13;
S, 7.17. Found: C, 59.32; H, 5.76; N, 3.21; S, 7.35.
Methyl 3-(4-Fluorophenyl)-4,5-dihydro-7-methyl-1,4-benzo-
thiazepine-2-carboxylate (7e)
Pale yellow crystalline powder; mp 211–212 °C.
trans-2a-(4-Bromophenyl)-2-chloro-2,2a-dihydro-5,6-
dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (4a)
White crystalline powder; mp 189–190 °C.
Anal. Calcd for C18H16FNO2S (329.39): C, 65.63; H, 4.90; N, 4.25;
S, 9.74. Found: C, 65.78; H, 5.04; N, 4.43; S, 9.88.
Anal. Calcd for C18H15BrClNO3S (440.74): C, 49.05; H, 3.43; N,
3.18; S, 7.28. Found: C, 49.20; H, 3.52; N, 3.09; S, 7.35.
Methyl 4,5-Dihydro-7-methyl-3-(4-methylphenyl)-1,4-benzo-
thiazepine-2-carboxylate (7f)
Pale yellow crystalline powder; mp 165–167 °C.
trans-2a-(3-Bromophenyl)-2-chloro-2,2a-dihydro-5,6-
dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (4b)
White crystalline powder; mp 147–149 °C.
Anal. Calcd for C19H19NO2S (325.43): C, 70.12; H, 5.88; N, 4.30;
S, 9.85. Found: C, 70.36; H, 6.10; N, 4.17; S, 9.68.
Anal. Calcd for C18H15BrClNO3S (440.74): C 49.05; H 3.43; N
3.18; S, 7.28. Found: C, 49.22; H, 3.62; N, 3.34; S, 7.46.
Acknowledgment
trans-2-Chloro-5,6-dimethoxy-2,2a-dihydro-2a-(3,4,5-tri-
methoxyphenyl)-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one
(4c)
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA) for financial support.
White crystalline powder; mp 199–201 °C.
Anal. Calcd for C21H22ClNO6S (451.92): C, 55.81; H, 4.91; N, 3.10;
S, 7.10. Found: C, 55.69; H, 3.25; N, 3.31; S, 7.21.
References
(1) Bergman, J.; Janosik, T. In Comprehensive Heterocyclic
Chemistry III, Vol. 8; Katritzky, A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier: Oxford,
2008, 269.
trans-2-Chloro-2a-(4-fluorophenyl)-2,2a-dihydro-6-methyl-
1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (4e)
White crystalline powder; mp 133–134 °C.
Anal. Calcd for C17H13ClFNOS (333.81): C, 61.17; H, 3.93;N, 4.20;
S, 9.61. Found: C, 61.05; H, 4.11; N, 4.07; S, 9.78.
(2) Vinkler, E.; Szabó, J.; Varga, I. Acta Pharm. Hung. 1966,
36, 155.
(3) Garofalo, A.; Campiani, I.; Fiorini, I.; Nacci, V. Farmaco
1993, 48, 275.
(4) Matysiak, J. Bioorg. Med. Chem. 2006, 14, 2613.
(5) Solomon, V. R.; Haq, W.; Srivastava, K.; Puri, S. K.; Katti,
S. B. J. Med. Chem. 2007, 50, 394.
trans-2-Chloro-2,2a-dihydro-6-methyl-2a-(4-methylphenyl)-
1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (4f)
White crystalline powder; mp 153–154 °C.
Anal. Calcd for C18H16ClNOS (329.84): C, 65.54; H, 4.89; N, 4.25;
S, 9.72. Found: C, 65.39; H, 5.02; N, 4.34; S, 9.65.
(6) Hallén, S.; Björquist, A.; Ostlund-Lindqvist, A. M.; Sachs,
G. Biochemistry 2002, 41, 14916.
Synthesis 2010, No. 17, 2943–2948 © Thieme Stuttgart · New York

2948
L. Fodor et al.
PAPER
(7) Liégeois, J.-L.; Seutin, V.; Scuveée-Moreau, J.; Dresse, A.;
Bruhwyler, J.; Géczy, J.; Delarge, J.; Damas, J. Eur. J.
Pharm. 1999, 386, 211.
(8) Wehrens, X. H. T.; Lehnart, S. E.; Reiken, S. R.; Deng, S.-
X.; Vest, J. A.; Cervantes, D.; Coromilas, J.; Landry, D. W.;
Marks, A. R. Science 2004, 304, 292.
(9) Chea, X.-F.; Nakajimaa, Y.; Sumizawaa, T.; Ikedaa, R.;
Rena, X.-Q.; Zhenga, C.-L.; Mukaia, M.; Furukawaa, T.;
Haraguchia, M.; Gaoa, H.; Sugimotob, Y.; Akiyama, S.
Cancer Lett. 2002, 187, 111.
(10) Dehaen, W.; Ngo, T. H. In Comprehensive Heterocyclic
Chemistry III, Vol. 13; Katritzky, A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier: Oxford,
2008, 255.
(16) Csomós, P.; Fodor, L.; Bernáth, G.; Csámpai, A.; Sohár, P.
Tetrahedron 2009, 65, 1475.
(17) (a) Csomós, P.; Fodor, L.; Sinkonen, J.; Pihlaja, K.; Bernáth,
G. Tetrahedron Lett. 2006, 47, 5665. (b)Csomós, P.; Fodor,
L.; Csámpai, A.; Sohár, P. Tetrahedron 2010, 66, 3207.
(18) Szabó, J.; Bani-Akoto, E.; Dombi, G. y.; Günther, G.;
Bernáth, G.; Fodor, L. J. Heterocycl. Chem. 1992, 29, 1321.
(19) (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008,
108, 3988. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Rev. 2007, 107, 4437. (c) Alcaide, B.; Almendros, P.
Prog. Heterocycl. Chem. 2007, 19, 92. (d) Fu, N.; Tidwell,
T. T. Tetrahedron 2008, 64, 10465.
(20) Holly, S.; Sohár, P. In Theoretical and Technical
Introduction to the Series Absorption Spectra in the Infrared
Region; Láng, L.; Prichard, W. H., Eds.; Akadémiai Kiadó:
Budapest, 1975, 97.
(11) Fodor, L.; Szabó, J.; Bernáth, G.; Párkányi, L.; Sohár, P.
Tetrahedron Lett. 1981, 22, 5077.
(12) Fodor, L.; Szabó, J.; Szűcs, E.; Bernáth, G.; Sohár, P.;
Tamás, J. Tetrahedron 1984, 40, 4089.
(13) Dölling, W.; Biedermann, M.; Hartung, H. Eur. J. Org.
Chem. 1998, 1237.
(21) (a) Sohár, P. In Nuclear Magnetic Resonance Spectroscopy,
Vol. 2; CRC Press: Boca Raton FL, 1983, 180. (b)Sohár,P.
In Nuclear Magnetic Resonance Spectroscopy, Vol. 1; CRC
Press: Boca Raton FL, 1983, 35.
(14) Fodor, L.; Bernáth, G.; Sinkkonen, J.; Pihlaja, K.
(22) Fodor, L.; Szabó, J.; Sohár, P. Tetrahedron 1981, 37, 963.
(23) Szabó, J.; Katócs, A.; Bernáth, G.; Sohár, P. Monatsh. Chem.
1989, 120, 463.
J. Heterocycl. Chem. 2002, 39, 927.
(15) Csomós, P.; Fodor, L.; Bernáth, G.; Sinkkonen, J.;
Salminen, J.; Wiinamäki, K.; Pihlaja, K. Tetrahedron 2008,
64, 1002.
Synthesis 2010, No. 17, 2943–2948 © Thieme Stuttgart · New York