Ring transformations of β-lactam-condensed 1,3-benzothiazines to isoquinoline and thiazole derivatives by sulfur extrusion and addition sequences

Article abstract of DOI:10.1016/j.tet.2012.05.033

The ring transformations of dichloro-β-lactam-fused 2-aryl-1,3-benzothiazines with sodium methoxide were investigated. With 2 equiv of base, the dichloro-β-lactam derivatives underwent rearrangement and dihydro-1,4-benzothiazepines, 3,4-substituted isoquinolines and substituted thiazole disulfides were isolated. A possible reaction mechanism is proposed for the simultaneous formation of the novel products. The formation of isoquinoline and thiazole derivatives can be explained by sulfur extrusion and addition sequences.

Full text of DOI:10.1016/j.tet.2012.05.033

Tetrahedron 68 (2012) 6581e6586
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring transformations of
b-lactam-condensed 1,3-benzothiazines to isoquinoline
and thiazole derivatives by sulfur extrusion and addition sequences
,
b
,
c
,
a
,
b
,
c
d
d,
*
Lajos Fodor a
, Peter Csomos
, Antal Csampai , Pal Sohar
*
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
a
ꢀ
ꢀ
Institute of Health Care and Environmental Sanitation Studies, Szent Istvan University, Szent Istvan u. 17e19, H-5700 Gyula, Hungary
b Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
c
€
€
Institute of Pharmaceutical Chemistry, Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
Institute of Chemistry, Eotvos Lorand University, H-1518 Budapest, POB 32, Hungary
d
€
€
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring transformations of dichloro-
were investigated. With 2 equiv of base, the dichloro-
and dihydro-1,4-benzothiazepines, 3,4-substituted isoquinolines and substituted thiazole disulfides were
isolated. A possible reaction mechanism is proposed for the simultaneous formation of the novel
products. The formation of isoquinoline and thiazole derivatives can be explained by sulfur extrusion and
addition sequences.
b
-lactam-fused 2-aryl-1,3-benzothiazines with sodium methoxide
-lactam derivatives underwent rearrangement
Received 24 February 2012
Received in revised form 24 April 2012
Accepted 8 May 2012
b
Available online 15 May 2012
Keywords:
Ring transformation
Ó 2012 Elsevier Ltd. All rights reserved.
Dichloro-b-lactam
1,3-Benzothiazine
Isoquinoline
Benzothiazepine
Thiazole
1. Introduction
building blocks for natural products and different heterocycles.13
Such features serve as the driving force for the invention of many
Derivatives of four-membered nitrogen heterocyclic ring systems
are probably among the most widely studied families of heterocyclic
compounds.1 Within these ring systems, particular attention has
been paid to azetidin-2-one counterparts.2 The continuously in-
synthetic pathways for the preparation of b-lactams, and conse-
quently their reactions have been widely studied.1e13
Increasing attention has also been paid to halo-substituted b-
lactams.14e17 In view of their reactivity, besides the ring strain in
four-membered lactams, the introduction of a halo substituent
markedly extends the range of utilizability of these compounds,
allowing the development of novel reactions on the ring atoms,
leading to new functionalized derivatives14 or exceptionally in-
teresting rearragements or ring transformations.15e17 By means of
creasing research interest in b-lactam chemistry originated primarly
from the unquestionable usefulness of many such compounds in
everyday medical practice (e.g., penicillins, cephalosporins, carba-
penems, taxol derivatives, the cholesterol-lowering ezetimibe).3
Besides these drugs, a huge number of four-membered ring com-
pounds also exhibit valuable pharmacological effects4 (antidiabetic,5
anti-HIV,6 anti-inflammatory and analgesic,7 and inhibitors of hu-
man cytomegalovirus,8 human leukocyte elastase,9 tryptase10 and
thrombin11). From a chemical aspect, various modifications of these
these latter methods, chloro-
example, to aziridines,15 pyrrolidin-2-ones,16 bicyclic
or macrocyclic
-amino amides,18 which are valuable in-
b
-lactams have been transformed, for
g
-lactams17
b
termediates in the synthesis of homalium alkaloids.
ring systems have been achieved and, due to their strained nature,
lactams display relatively high reactivity. This makes them versatile
intermediates for a wide range of nitrogen-containing target com-
b
-
We recently reported a convenient and general synthetic
pathway for rare 2-aryl-3-alkoxycarbonyl-substituted 4,5-dihydro-
1,4-benzothiazepines, utilizing monochloro-b-lactam derivatives,
pounds, such as functionalized
b-amino acids,
b
-peptides, amino
trans-2-chloro-2a-aryl-2,2a-dihydro-5,6-dimethoxy-1H,8H-azeto
alcohols, and chiral catalysts.12 Moreover, they can be utilized as
[2,1-b][1,3]benzothiazin-1-ones, as starting materials.19 The ring
expansion of monochloro-b-lactams with sodium methoxide
afforded 1,4-benzothiazepines as single products in good yields. As
a further aim, in the present paper we set out to investigate the
transformations of the corresponding dichloro-b-lactams, 2,2-
* 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 (L.
ꢀ
Fodor), sohar@chem.elte.hu (P. Sohar).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.033

6582
L. Fodor et al. / Tetrahedron 68 (2012) 6581e6586
dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-arylazeto[2,1-b]
[1,3]benzothiazin-1-ones in response to basic treatment.
base-catalysed deprotonation, of which and subsequent sulfur ex-
trusion leads to isolable isoquinolines (6/10/11/12/13/4).
Besides sulfur elimination, the presumed benzo[f][1,4]thiazepine-
2-carboxylates 12 react with the elemental sulfur present in the
reaction mixture in a [4þ1] cycloaddition step to generate the
corresponding sulfur-bridged intermediate 14, which undergoes
ring opening associated with the formation of a thiazole ring. In the
final step, spontaneous oxidation of the resulting thiazolyl thio-
phenols gives disulfides 5 as isolable products.
2. Results and discussion
The Staudinger reaction was applied for the synthesis of the
starting dichloro-b-lactams 2aeg. The reactions of 1,3-
benzothiazines 1aeg with dichloroacetyl chloride in refluxing tol-
uene furnished azeto[2,1-b][1,3]benzothiazin-1-ones 2aeg in good
The structures of the compounds investigated follow un-
ambiguously from the data (Tables 2 and 3).
yields (Table 1). The treatment of dichloro-b-lactam 2a with excess
sodium methoxide led to the formation of three compounds, which
were separated by column chromatography. Surprisingly,
structure investigations demonstrated that the major product was
a known benzothiazepine, 7,8-dimethoxy-2-methoxycarbonyl-3-
(4-methylphenyl)-4,5-dihydro-1,4-benzothiazepine 6a. It was
identical with the compound obtained earlier in the rearrangement
The high
acteristic of
effect of the two vicinal chlorine atoms.
n
C]O frequencies of 2aeg (1794ꢀ4 cmꢁ1) are char-
b
-lactams.22 The frequencies are enhanced by the ꢁI
The downfield shifts of the H-5 and H-8 signals (by w0.47 and
0.66 ppm) in 4 as compared with 2 are striking. This can be explained
by the ꢁI effect of the condensed hetero ring and for H-8 by the an-
isotropic neighbouring effect of the ester carbonyl.23a The latter ob-
servation issupported by the higherdownfieldshift in4b and 4f(0.58
and 0.81 ppm) where the ortho-substituted Ar group (perpendicular
to the molecular skeleton in the preferred conformation because of
the steric hindrance between the Arand ester groups) forces the ester
carbonyl into a coplanar arrangement with the skeleton.
of monochloro-b
-lactam derivative 3a19 with sodium methoxide in
dry methanol under reflux (Table 1). Similar substituted 4,5-
dihydro-1,4-benzothiazepines have been prepared by the ring ex-
pansion of benzoisothiazoles on treatment with alkynes.20
6,7-Dimethoxy-4-methoxycarbonyl-3-(4-methylphenyl)iso-
quinoline 4a was identified as the second product. It is note-
worthy that the preparation of 3,4-disubstituted isoquinolines
with the tools of conventional synthetic organic chemistry is
relatively complicated, and novel reactions have therefore re-
cently been developed for the synthesis of these alkaloid-type
compounds.21 The remaining compound was identified as iso-
thiazole disulfide 5a. To extend the possibility of this novel ring
expansion, compounds 2beg were reacted under the same
conditions, which led to the analogous isoquinolines (3beg),
thiazole disulfides (4beg) and benzothiazepines (6beg).
This conformational preference is also revealed in the upfield
shift of the methyl singlet of the ester group in 4b and 4f relative to
the other molecules of type 4 (by 0.16 and 0.06 ppm), due to the
anisotropic effect of the perpendicularly oriented Ar ring23b in the
predominant conformation.
The downfield 1H NMR signal (9.14ꢀ0.04 ppm) and 13C NMR
line (151ꢀ3 ppm) of H-4 and C-4, respectively, in 4 are proof of the
isoquinoline moiety.23c Similarly, the high chemical shifts of C-2
(166.7ꢀ2 ppm) and C-4 (158.2ꢀ14 ppm) for thiazoles 5 confirm the
presence of this hetero ring.23d
A possible reaction pathway for the formation of these com-
pounds is depicted in Scheme 1. In the first step, methanol-induced
The downfield shiftof the H-5 signalis due to the anisotropy of the
near-lying lone pair on the N atom23e in the preferred rotamer. For
more extended electron delocalization including the three aromatic
and heteroaromatic rings, a coplanar arrangement predominates in
both halves of 5. To avoid steric interaction between H-5 and the ester
group, the S-cis arrangementof the two S atoms and consequently the
closeness of the H-5 and the nitrogen atoms are plausible.
dehalogenation is associated with the opening of the dichloro-b-
lactam ring, affording chloroketenes 7 and methyl hypochlorite. On
the addition of methanol followed by intramolecular S-alkylation
and subsequent tautomerization, the ketene intermediates are
transformed into dihydrobenzo[f][1,4]thiazepines (7/8/9/6).
These primary products in part undergo hypochlorite-mediated
S-chlorination, resulting in the corresponding sulfonium salt,
Table 1
Synthesis of isoquinolines, thiazole derivatives and 1,4-benzothiazines from 1,3-benzothiazines via the ring transformation of b-lactam-condensed 1,3-thiazine derivatives
Ar
R1
R2
b
-Lactam
Yield (%)
Isoquinoline
Yield (%)
Thiazole
Yield (%)
Thiazepine
Yield (%)
4-MeeC6H4
2-MeeC6H4
4-MeOeC6H4
3,4-diMeOeC6H3
4-CleC6H4
2-CleC6H4
Ph
MeO
MeO
MeO
MeO
MeO
MeO
EtO
MeO
MeO
MeO
MeO
MeO
MeO
EtO
2a
2b
2c
2d
2e
2f
92
90
94
95
89
90
88
4a
4b
4c
4d
4e
4f
16
17
5a
5b
5c
5d
5e
5f
24
21
21
19
6a
6b
6c
6d
6e
6f
26
25
32
28
22
24
28
a
-
-
a
a
15
16
9
-
21
a
2g
4g
5g
-
6g
a
Not isolated.

L. Fodor et al. / Tetrahedron 68 (2012) 6581e6586
6583
MeOOC
SH
Cl
Ar
Cl
R1
R2
SH
R1
R2
Ar
CH
R1
R2
S
Cl
MeOH
MeOH
Cl
Ar
N
N
N
C
O
O
8
2
7
-MeOH
-NaCl
NaOMe
Cl
S
COOMe
Ar
COOMe
Ar
R1
R2
COOMe
Ar
R1
R2
S
S
R1
R2
MeO-Cl
N
NH
NH
MeO
10
9
6
-MeOH
Cl
S
COOMe
Ar
COOMe
Ar
COOMe
Ar
S
R1
R2
S
R1
R2
R1
R2
NaOMe
-MeOH
-NaCl
N
N
N
N
H
H
11
13
-S
12
+S
[4+1] cycloaddition
COOMe
Ar
R1
SH
R1
R2
COOMe
Ar
S
S
R1
R2
S
COOMe
Ar
R2
N
N
H
14
15
4
oxidation
R1
R2
S
N
)
2
S
COOMe
Ar
5
Scheme 1.
In summary, we have investigated the ring transformation re-
actions of 2,2-dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-aryla-
zeto[2,1-b][1,3]benzothiazin-1-one derivatives in the presence of
sodium methoxide. The structures of the ring transformation products
formed simultaneously (7,8-dimethoxy-2-methoxycarbonyl-3-aryl-
2400 CHNS elemental analyser in the Institute of Pharmaceutical
Chemistry. Merck Kieselgel 60F254 plates were used for TLC, and
Merck Silica gel 60 (0.063e0.100) for column chromatography.
Dichloroacetyl chloride was purchased from Fluka. 1,3-
Benzothiazines 1aeg were prepared by literature methods.19,24
IR spectra were recorded in KBr pellets with a Bruker IFS 55
FT-spectrometer. 1H and 13C NMR spectra were recorded in
CDCl3 solution in 5 mm tubes at RT, on a Bruker DRX 500
4,5-dihydro-1,4-benzothiazepines,
6,7-dimethoxy-4-methoxycarb
onyl-3-arylisoquinolines and isothiazole disulfide derivatives) were
proved by means of IR and NMR spectroscopy. A possible mechanistic
pathway is proposed for the formation of novel compounds.
spectrometer at 500 (1H) or 125
(
13C) MHz, with TMS
(
dTMS¼0 ppm) as internal reference, and the deuterium signal of
3. Experimental
3.1. General
the solvent as the lock. Assignments were supported by DEPT,
HMQC and HMBC measurements. DEPT spectra were run in
a standard manner, using only the
CH3 and CH2 lines phased ‘up’ and ‘down’, respectively. 2D-
HMQC and 2D-HMBC spectra were obtained by using the stan-
dard Bruker pulse programs.
Q
¼135ꢂ pulse to separate CH/
Melting points were determined on a Kofler micro melting ap-
paratus. Elemental analyses were performed with a PerkineElmer

6584
L. Fodor et al. / Tetrahedron 68 (2012) 6581e6586
Table 2
Characteristic IR frequenciesa and 1H NMR datab of 2aeg, 4a, b, eeg and 5aed, fc
Compound
n
C]O
n
CeO ester
g
CAr
H
XCH3
(3H)e
s
OCH3
ester
OCH3
(Pos. 6,7)
NCH2 s,d
or ddf
H-5j s
(1H)
H-8j s H-20
H-60
H-30
Hꢁ50
H-40
band
bands
(1H)
Bandd
Bandd
Ar group attached to the heteroringg
2a
2b
2c
2d
2e
2f
2g
4a
4b
4e
4f
4g
5a
5b
5c
5d
5f
1794
1794
1795
1794
1797
1790
1792
1723
1717
1705
1722
1731
1711
1714
1721
1688
1718
d
809
740
801
809
810
744
748
820
749
823
780
705
822
755
832
759
760
843
831
853
868
845
832
827
846
841
835
839
853
875
869
870
877
875
2.38
2.60
3.81
3.89, 3.93
d
d
3.87, 3.84 4.20,4.89
3.89, 3.84 4.27,4.92
3.85, 3.83 4.22,4.88
3.86, 3.84 4.19,4.87
3.86, 3.83 4.20,4.88
3.86, 3.80 4.26,4.92
6.76
6.83
6.74
6.74
6.74
6.78
6.78
7.24
7.29
7.22
7.28
7.24
7.68
7.77
7.66
7.65
7.76
6.77
6.79
6.75
6.76
7.32
d
7.23
d
d
d
7.29
6.97
7.47
w7.25
6.86
d
d
7.36
6.91
7.37
d
6.92
d
d
d
d
d
d
d
d
d
d
d
6.76
6.79
7.31
7.37
7.29
7.57
7.31
7.09
7.06
7.12
7.12
7.05
w7.25i
w7.3i
w7.25i
7.39
d
d
1.42, 1.45
2.41
2.23
d
d
4.06h
4.20,4.87
7.42
7.57
d
1204,1151
1210,1154
1214,1161
1239,1155
1249,1164
1263,1019
1256,1017
1253,1021
1241,1029
1260,1019
3.73
3.55
3.71
3.61
3.69
3.82
3.77
3.84
3.84
3.78
4.03, 4.04 9.13
4.06, 4.05 9.16
7.26
7.20
7.48
7.28
7.34
4.02i
9.10
7.60
d
7.41
7.33
7.46
7.26
7.30
6.99
d
d
d
4.07, 4.05 9.17
7.40
7.39
d
1.55i
2.42
2.25
3.88
3.95i
d
4.25h
9.12
d
7.67
7.77
d
3.84, 3.79
3.88, 3.78
3.85, 3.80
3.86, 3.79
3.87, 3.80
d
7.37
7.26
7.35
d
d
7.89
7.61
d
d
7.58
7.54
6.96
7.33
d
d
7.49
7.38
a
In KBr discs (cmꢁ1). Further IR bands, CeCl: 1 or 2 bands between 662 and 698 cmꢁ1 (2aeg).
gCArCAr (ortho-disubstituted Ar group): 692 (2g), 679 4g; n
In CDCl3 solution at 500 MHz. Chemical shifts in ppm (dTMS¼0 ppm), coupling constants in Hz.
Assignments were supported by 2D-HMQC and 2D-HMBC measurements.
Ar/condensed (2, 4) or S-substituted (5) benzene ring.
2ꢃs (2ꢃ3H) for 2d, 5d, 2ꢃt (2ꢃ3H) for 2g, t (6H) for 4g, X: Ar (a, b), O (c, d), CH2 (g), J: 7.0 (2g), 7.0 (4g).
2ꢃd, J: 16.1 (2a), 15.6 (2b), 16.0 (2c), 15.8 (2d,e), 15.7 (2g), CH]N, s (1H) for 4.
AA0BB0-type spectrum, wd (2H), J: 8.1 (2a, 4a, 5a), 8.8 (2c, 4c, 5c), 8.3 (4e).
CH2(OEt), m (4H, 2g), qa (4H, 4g).
b
c
d
e
f
g
h
i
Two overlapping signals.
j
The IUPAC numbering of the benzothiazines (2) is used here and in the spectroscopic part of the text for the condensed (4) and S-substituted benzene ring (5).
3.2. General procedure for the preparation of dichloroazeto
[2,1-b][1,3]benzothiazines (2aeg)
chloride was washed with toluene. The organic layer was
extracted with brine (20 mL) and dried with Na2SO4. After
evaporation, the oily residue crystallized on trituration with
ethanol.
To a stirred solution of the 4H-1,3-benzothiazine (1aeg)
(2.0 mmol) in anhydrous toluene (10 mL), dichloroacetyl chloride
(3.0 mmol) was added. The solution was refluxed, and triethyl-
amine (0.4 mL, 3.0 mmol) in anhydrous toluene (20 mL) was
added dropwise over 1 h under reflux. The reaction mixture was
then cooled and filtered, and the remaining triethylammonium
3.2.1. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(4-
methylphenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2a). A white
crystalline powder; mp 118e120 ꢂC; 0.75 g, yield 92%; Rf (55%,
chloroform:methanol 99:1). Anal. Calcd for C19H17Cl2NO3S
Table 3
13C NMR chemical shiftsa of 2aeg, 4a, b, eeg and 5aed, fb
Compound C]O OCH3
Benzothiazine (2), isoquinoline
(4) or subst.-benzene and thiazole (5)d
NCc
C-4a
C-5
C-6
C-7
C-8
C-8a NeC quat.e Cq(sp3); C-10
Cq(sp2)f Ar attached to the skeleton (2,4) or thiazole (5)
C-20
C-60
C-30
C-50
C-40
2a
2b
2c
2d
2e
2f
2g
4a
4b
4e
4f
4g
5a
5b
5c
5d
5f
163.6 56.48, 56.52
163.6 56.5g
44.4 125.3 111.7 148.6 149.5 113.1 122.0
45.2 126.7 111.7 148.7 149.6 113.1 122.1
44.3 124.9 111.7 148.6 149.5 113.1 122.0
44.4 125.2 111.7 148.7 149.5 113.1 122.0
44.5 124.9 111.8 148.8 149.6 113.2 121.4
44.8 124.9 111.5 148.6 149.7 113.0 121.9
44.6 125.4 113.8 148.4 149.3 115.1 121.8
82.6
83.7
82.3
82.6
82.1
82.3
82.6
90.3
89.7
90.5
90.5
89.9
135.0
137.2
129.9
136.9
126.0
135.7 129.5 132.4
127.7 114.4
130.2 118.9 149.6
127.7
129.8
139.7
126.4h 125.4h
160.6
163.5 56.48, 56.51
163.6 56.3,h 56.6h
163.4 56.50, 56.53
163.3 56.5g
111.2
150.2
135.7h
127.3h
120.0
138.6
130.5
134.9
129.7h
128.6
139.6
129.2g
160.8
150.4h
130.4
136.6h 129.3
89.6
90.2
137.2
132.6 131.4 127.1h 130.7
163.6 62.22,i 62.26i
170.3 56.5, 56.6
129.1h
128.8
129.6h
129.5
151.3 123.5 105.9 150.9g 154.5 102.9 130.8 150.9g
121.7
123.1
122.0
121.9
122.7
122.6
124.8
121.8
121.9
126.1
138.2
136.8
139.5
140.4
141.1
131.7
135.0
126.9
127.0
134.7
169.2 56.57, 56.64 150.8 123.7 106.1 151.1 154.7 103.1 130.8 151.9
169.9 56.5, 56.6 151.3 123.7 105.9 151.1 154.7 102.9 130.8 149.4
168.7 56.56, 56.63 151.5 124.2 106.0 151.3 154.7 103.5 130.8 150.2
170.2 65.0,i 65.1i 151.2 123.6 107.0 150.5h 154.3 103.7 130.7 150.6h
140.3 129.3 125.7
130.3 129.0
133.4 129.8 126.9h 131.1
128.6
128.9
130.3
128.8
128.9
162.6 56.54, 56.45 166.6 129.1 112.7 150.3 150.9 117.8 126.5 159.8
162.2 56.5, 56.6
162.7 56.4, 56.5
166.7 129.2g 112.9 150.4 150.8 118.2 126.7 160.1
166.5 129.0 112.7 150.2 150.9 117.7 126.6 159.3
137.2 130.3 130.4
132.0 113.6
114.0 123.7 148.5
134.1 131.7 129.5
125.6
162.7 56.43,h 56.5h 166.5 128.7 112.7 150.2h 151.0 117.3 126.8 159.3
123.7
126.8
162.0 56.5, 56.6
166.9 129.5 112.9 150.6 150.8 118.6 126.4 156.6
a
In ppm (dTMS 0 ppm) at 125.7 MHz. Solvent: CDCl3. Further signals, CH3(Et): 15.1, 15.2 (2g), 14.8, 14.9 (4g); ArCH3: 21.6 (2a,b), 21.7 (4a), 20.2 (4b), 21.9 (5a), 20.4 (5b); OCH3
(Ar): 55.7 (2c), 56.50, 56.52 (2d)h 55.7 (5c), 56.32h 56.39h (5d); OCH3 (ester): 52.8 (4a,g), 52.5 (4b), 52.9 (4e), 52.6 (4f, 5aec), 52.7 (5d,f).
b
Assignments were supported by DEPT, HMQC and HMBC measurements.
c
NCH2 (2), N¼CH (4), NꢁC(sp2) eAr (5).
d
The IUPAC numbering of the benzothiazines (2) is used here and in the spectroscopic part of the text for the condensed (4) and S-substituted benzene ring (5).
SeCeN (2), C-3 (isoquinoline, 4), C-4 (thiazole, 5).
CCl2 (2), C-4 (isoquinoline, 4), C-5 (thiazole, 5).
Two overlapping lines.
Reversed assignments is also possible.
OCH2 (Et).
e
f
g
h
i

L. Fodor et al. / Tetrahedron 68 (2012) 6581e6586
6585
(410.31): C, 55.62; H, 4.18; N, 3.41; S, 7.82. Found: C, 55.93; H, 4.45;
N, 3.22; S, 8.05.
yield 17%; Rf (61%, chloroform:methanol 99:1). Anal. Calcd for
C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.11; H,
5.86; N, 4.01.
3.2.2. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(2-
methylphenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2b). A white
crystalline powder; mp 173e176 ꢂC; 0.74 g, yield 90%; Rf (56%,
chloroform:methanol 99:1). Anal. Calcd for C19H17Cl2NO3S
(410.31): C, 55.62; H, 4.18; N, 3.41; S, 7.82. Found: C, 55.88; H, 4.42;
N, 3.70; S, 7.61.
3.3.3. 6,7-Dimethoxy-4-methoxycarbonyl-3-(4-chlorophenyl)iso-
quinoline (4e). A white crystalline powder; mp 184e187 ꢂC; 0.27 g,
yield 15%; Rf (60%, chloroform:methanol 99:1). Anal. Calcd for
C19H16ClNO4 (357.79): C, 63.78; H, 4.51; N, 3.92. Found: C, 64.02; H,
4.80; N, 3.76.
3.2.3. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(4-
methoxyphenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2c). A white
crystalline powder; mp 143e146 ꢂC; 0.80 g, yield 94%; Rf (56%,
chloroform:methanol 99:1). Anal. Calcd for C19H17Cl2NO4S (426.31):
C, 53.53; H, 4.02; N, 3.29; S, 7.52. Found: C, 53.78; H, 4.28; N, 3.02; S,
7.32.
3.3.4. 6,7-Dimethoxy-4-methoxycarbonyl-3-(2-chlorophenyl)iso-
quinoline (4f). A white crystalline powder; mp 215e218 ꢂC; 0.29 g,
yield 16%; Rf (64%, chloroform:methanol 99:1). Anal. Calcd for
C19H16ClNO4 (357.79): C, 63.78; H, 4.51; N, 3.91. Found: C, 63.92; H,
4.66; N, 3.82.
3.3.5. 6,7-Diethoxy-4-methoxycarbonyl-3-phenylisoquinoline
(4g). A white crystalline powder; mp 153e155 ꢂC; 0.16 g, yield 9%;
Rf (60%, chloroform:methanol 99:1). Anal. Calcd for C21H21NO4
(351.40): C, 71.78; H, 6.02; N, 3.99. Found: C, 71.52; H, 6.20; N, 4.21.
3.2.4. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(3,4-
dimethoxyphenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2d). A white
crystalline powder; mp 202e204 ꢂC; 0.87 g, yield 95%; Rf (57%,
chloroform:methanol 99:1). Anal. Calcd for C20H19Cl2NO5S
(456.34): C, 52.64; H, 4.20; N, 3.07; S, 7.03. Found: C, 52.47; H, 4.48;
N, 3.31; S, 7.29.
3.3.6. 4,40,5,50-tetramethoxy-}2,20-di-[500-methoxycarbonyl-400-(4-
methylphenyl)-200-thiazolyl]}-diphenyl disulfide (5a). A yellow crys-
talline powder; mp 213e216 ꢂC; 0.96 g, yield 24%; Rf (82%, chlor-
oform:methanol 99:1). Anal. Calcd for C40H36N2O8S4 (800.99): C,
59.98; H, 4.53; N, 3.50; S, 16.01. Found: C, 60.23; H, 4.70; N, 3.65; S,
16.28.
3.2.5. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(4-
chlorophenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2e). A white
crystalline powder; mp 114e116 ꢂC; 0.77 g, yield 89%; Rf (58%,
chloroform:methanol 99:1). Anal. Calcd for C18H14Cl3NO3S
(430.73): C, 50.19; H, 3.28; N, 3.25; S, 7.44. Found: C, 49.98; H, 3.45;
N, 3.42; S, 7.71.
3.3.7. 4,40,5,50-tetramethoxy-}2,20-di-[500-methoxycarbonyl-400-(2-
methylphenyl)-200-thiazolyl]}ediphenyl disulfide (5b). A yellow
crystalline powder; mp 190e193 ꢂC; 0.84 g, yield 21%; Rf (83%,
chloroform:methanol 99:1). Anal. Calcd for C40H36N2O8S4 (800.99):
C, 59.98; H, 4.53; N, 3.50; S, 16.01. Found: C, 60.24; H, 4.70; N, 3.68;
S, 15.89.
3.2.6. 2,2-Dichloro-2,2a-dihydro-5,6-dimethoxy-1H,8H-2a-(2-
chlorophenyl)azeto[2,1-b][1,3]benzothiazin-1-one (2f). A white crys-
talline powder; mp 122e124 ꢂC; 0.78 g, yield 90%; Rf (56%, chlor-
oform:methanol 99:1). Anal. Calcd for C18H14Cl3NO3S (430.73): C,
50.19; H, 3.28; N, 3.25; S, 7.44. Found: C, 50.43; H, 3.45; N, 3.11; S, 7.52.
3.3.8. 4,40,5,50-tetramethoxy-}2,20-di-[500-methoxycarbonyl-400-(4-
methoxyphenyl)-200-thiazolyl]}ediphenyl disulfide (5c). A yellow
crystalline powder; mp 182e185 ꢂC; 0.87 g, yield 21%; Rf (82%,
chloroform:methanol 99:1). Anal. Calcd for C40H36N2O10S4
(832.99): C, 57.68; H, 4.36; N, 3.36; S,15.40. Found: C, 57.82; H, 4.58;
N, 3.11; S, 15.12.
3.2.7. 2,2-Dichloro-2,2a-dihydro-5,6-diethoxy-1H,8H-2a-phenyl-
azeto[2,1-b][1,3]benzothiazin-1-one (2g). A white crystalline pow-
der; mp 122e123 ꢂC; 0.75 g, yield 88%; Rf (52%, chloroform:methanol
99:1). Anal. Calcd for C20H19Cl2NO3S (424.34): C, 56.61; H, 4.51; N,
3.30; S, 7.56. Found: C, 56.85; H,; N, 4.73; S, 7.81.
3.3.9. 4,40,5,50-tetramethoxy-}2,20-di-[500-methoxycarbonyl-400-(3,4-
dimethoxyphenyl)-200-thiazolyl]}-diphenyl disulfide (5d). A yellow
crystalline powder; mp 192e195 ꢂC; 0.85 g, yield 19%; Rf (86%,
chloroform:methanol 99:1). Anal. Calcd for C42H40N2O12S4
(893.04): C, 56.49; H, 4.51; N, 3.14; S,14.36. Found: C, 56.65; H, 4.78;
N, 3.35; S, 14.59.
3.3. General procedure for the preparation 6,7-dimethoxy-4-
methoxycarbonyl-3-phenylisoquinoline (4), 4,40,5,50-
tetramethoxy-[2,20-di-(500-methoxycarbonyl-400-aryl-200-
thiazolyl)]-diphenyl disulfide (5) and 7,8-dimethoxy-2-
methoxycarbonyl-3-aryl-4,5-dihydro-1,4-benzotiazepines (6)
Compound 2 (5 mmol) was dissolved in methanol (20 mL), and
NaOMe (0.54 g, 10 mmol) was added, and the solution was stirred
under reflux. After 3 h, the reaction mixture was diluted with
chloroform (150 mL) and extracted with water. The organic layer
was dried (Na2SO4) and evaporated to dryness, the residue was
dissolved in the minimum amount of chloroform, and the solution
was chromatographed on a silica column. The column was de-
veloped with a 1% solution of methanol in chloroform.
3.3.10. 4,40,5,50-tetramethoxy-}2,20-di-[500-methoxycarbonyl-400-(2-
chlorophenyl)-200-thiazolyl]}-diphenyl disulfide (5f). A yellow crys-
talline powder; mp 153e155 ꢂC; 0.88 g, yield 21%; Rf (81%, chlor-
oform:methanol 99:1). Anal. Calcd for C38H30Cl2N2O8S4 (841.82): C,
54.22; H, 3.59; N, 3.33; S, 15.24. Found: C, 54.48; H, 3,76; N, 3.58; S,
15.10.
3.3.11. 7,8-Dimethoxy-2-methoxycarbonyl-3-aryl-4,5-dihydro-1,4-
benzotiazepines (6aeg). The physical and analytical data on 6aeg
were identical to those published earlier.19,24
3.3.1. 6,7-Dimethoxy-4-methoxycarbonyl-3-(4-methylphenyl)iso-
quinoline (4a). A white crystalline powder; mp 156e159 ꢂC; 0.27 g,
yield 16%; Rf (62%, chloroform:methanol 99:1). Anal. Calcd for
C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.42; H,
5.81; N, 3.98.
Acknowledgements
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA K-83874 and K-68887) for financial
support. The European Union and the European Social Fund also
3.3.2. 6,7-Dimethoxy-4-methoxycarbonyl-3-(2-methylphenyl)iso-
quinoline (4b). A white crystalline powder; mp 159e161 ꢂC; 0.29 g,

6586
L. Fodor et al. / Tetrahedron 68 (2012) 6581e6586
10. Sutton, J. C.; Bolton, S. A.; Hartl, K. S.; Huang, M.; Jacobs, G.; Meng, W.; Ogletree,
M. L.; Pi, Z.; Schumacher, W. A.; Seiler, S. M.; Slusarchyk, W. A.; Treuner, U.;
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provided financial support for the project under grant agreement
no. TAMOP 4.2.1./B-09/KMR-2010-0003.
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