Novel indole syntheses by ring transformation of β-lactam-condensed 1,3-benzothiazines into indolo[2,3-b][1,4]benzothiazepines and indolo[3,2-c]isoquinolines

Article abstract of DOI:10.1016/j.tet.2011.11.036

ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1- ones with sodium methoxi

Full text of DOI:10.1016/j.tet.2011.11.036

Tetrahedron 68 (2012) 851e856
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel indole syntheses by ring transformation of -lactam-condensed
b
1,3-benzothiazines into indolo[2,3-b][1,4]benzothiazepines
and indolo[3,2-c]isoquinolines
,
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, H-5700 Gyula, Szent Istvan st. 17e19, Hungary
b Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
c
€
€
Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of Sciences, 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:
ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole
syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto
[2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4-
benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b]
[1,4]benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were ob-
tained. The structures of the new ring systems were determined by means of NMR spectroscopy.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 September 2011
Received in revised form 24 October 2011
Accepted 14 November 2011
Available online 19 November 2011
Keywords:
Indole synthesis
b
-Lactam
1,3-Benzothiazine
Ring transformation
Indolo-1,4-benzothiazepine
Indolo[3,2-c]isoquinoline
IR, 1H and 13C NMR
1. Introduction
any reducing agent. Reactions of this type were investigated by
Wrobel et al.,9 and some earlier examples can also be found in the
Because of their privileged role in nature and medicine, indole
compounds are of continuously increasing research interest.1 Al-
though basic synthetic pathways for the preparation of indoles
have long been known,2 several modifications of named indole
syntheses have been published to provide a variety of substitution
pattern and more efficient reactions, which occur under mild
conditions.1 On the other hand, new indole synthetic strategies,
such as the CeH amination of azides,3 Pd-catalysed CeH func-
tionalization,4 Nb-promoted CeF functionalization5 and rear-
rangement reactions,6 have also been developed.
Among the most widely used practical methods of indole syn-
thesis, such as those of Bartoli7 and Cadogan-Sundberg,8 reductive
N-heterocyclization utilizes the ortho-nitro group of a phenyl
moiety for the construction of an indole nitrogen. In contrast, there
are only rare examples (not even mentioned in main indole re-
views) in which an ortho-nitroaryl compound under basic condi-
tions furnishes an N-hydroxy-indole ring without the addition of
literature.10 By means of these methods, N-hydroxyindoles have
been obtained.9,10
During our recent investigations of the ring-enlargement re-
actions of 2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1-
ones to 1,4-benzothiazepines,11 we observed that the reaction of
ortho-nitro-2-phenyl-substituted b-lactam with sodium methoxide
in methanol gave an indole compound.12 Somewhat surprisingly,
treatment with a large excess of sodium methoxide led to the for-
mation of indolo-1,4-benzothiazepines via a novel rearrange-
ment.12 As a continuation of that work, we set out to extend this
novel indole synthesis to different derivatives and to investigate the
substituent-reactivity pattern. On the other hand, these com-
pounds in our view promise the possibility of rearrangement to
indenoisoquinolines, which have been described as pharmacolog-
ically interesting compounds.13
2. Results and discussion
The starting 4H-1,3-benzothiazines were obtained from aroy-
lamide thioethers 1aee through an acid-catalysed intermolecular
rearrangement with phosphorus oxychloride (Scheme 1).14
* 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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.036

852
L. Fodor et al. / Tetrahedron 68 (2012) 851e856
concerns the exploration of the role of the nitro group in the
rearrangement reaction, meta- and para-substituted monochloro-
-lactams 9a,b were also synthesized from the corresponding
b
benzothiazines 8a,b (Scheme 2). The treatment of 9a,b with sodium
methoxide (2e5 equiv) gave only benzothiazepines 10a,b. In the
reactions of 9a,b, no other rearrangement was observed in which
the nitro group could have been involved.
Sulfur extrusion reactions are attractive synthetic processes. If
these reactions could be achieved by extrusion of either a sulfur
atom or a sulfur monoxide moiety, various heterocycles,15 including
alkaloids,16 could be obtained by ring contraction. In our case
indolothiazepines 5 seemed to be suitable starting materials for the
preparation of
(Scheme 1).
d
-carboline17 analogue indolo[3,2-c]isoquinolines 7
There are only a few examples for the preparation of this indole
ring system;13 such compounds were recently developed as
poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors.13d The treat-
ment of 5a,b,d in refluxing dimethylformamide afforded 7a,b,d in
good yields. The reaction most probably takes places through 6. It is
generally considered, that episulfides, such as 6 are intermediates in
the extrusion pathway of thiepines, benzothiepines and
benzothiazepines.15aec Elimination of sulfur from 5 with the for-
mation of indoloisoquinoline is energetically a very favourable pro-
cess. The free enthalpy changes calculated by the B3LYP/6-31 G(d)
method for the conversion of 5a,c to 7a,c are presented in Scheme 3.
A possible mechanistic pathway of the novel indole formation
reaction is depicted in Scheme 4.
The key intermediates are 1,4-benzothiazepines, as proved
earlier in the preparation of a derivative of 5.12 The next step most
probably involves the formation of N-hydroxyindole derivatives
11 through reaction with sodium methoxide (Scheme 4).9 Addi-
tion of methanol to 11 provides 12. The formation of 5 can be
further explained through 13, followed by a 1,5-proton shift
(Scheme 4).
Scheme 1.
Scheme 2.
The key intermediate azetobenzothiazine derivatives 3aee were
obtained in excellent yields through the reaction of 1,3-
benzothiazines 2aee14 and chloroacetyl chloride in the presence
of base in refluxing toluene (Scheme 1).
These reactions resulted only in the formation of that di-
astereomer of 3aee in which the orientation of the chloro atom and
the aryl group is cis.11 The reactions of monochloro-
b-lactam de-
rivatives 3aee with 2 equiv of sodium methoxide in dry methanol
at reflux afforded the enamine forms of 4,5-dihydro-1,4-
benzothiazepines 4aec (Scheme 1).12 In these latter reactions, the
first step is most probably alcoholysis of the
in -chloro esters, which lead to the products through episulfonium
salts after the elimination of HCl. On the other hand, by the treat-
ment of monochloro- -lactams 3aee with 5 equiv of sodium alk-
b-lactam ring, resulting
a
Scheme 3.
b
oxide, we could extend the preparation of variously substituted
indolo-1,4-benzothiazepines 5aef via the novel rearrangement
(Scheme 1). The reactions proceeded well either in methanol
(5aed) or ethanol (5f) with the appropriate sodium alkoxides. As
In summary, we have developed a general procedure for the
synthesis of the indolo[2,3-b][1,4]benzothiazepine ring system
5aef from ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]ben-
zothiazin-1-ones 3aee, using 5 equiv of sodium methoxide in

L. Fodor et al. / Tetrahedron 68 (2012) 851e856
853
The benzothiazine skeleton in the compounds of types 2 and 8 is
confirmed by the chemical equivalence of the methylene H’s with
a singlet signal of 2H intensity. The downfield-lying carbon line of
the SeC(Ar)]N group (158.7e161 ppm) provides further evidence
of this structure.
The difference in the chemical shifts of the methylene H’s
in 2d,e (w4.6 ppm) and in 8a,b (w4.8 ppm) can be explained
by the different conformations in these molecules. The
electron-attracting nitrophenyl substituent is coplanar with
the molecular skeleton in 2d,e, whereas in 8a,b it must lie
perpendicular to that plane because of the steric hindrance
between the nitro group and the skeleton. Consequently, the
ꢀI effect resulting in a downfield shift of the CH2 signal can act
only in 8a,b.
The presence of the condensed azetidinone ring in the
compounds of types 3 and 9 follows straightforwardly from
the very high
n
C]O IR frequency (1781e1794 cmꢀ1), in
accordance with the literature data.18a The asymmetric struc-
ture of these molecules follows from the chemical non-
equivalence of the methylene H’s, with two doublets split by
16.0e16.9 Hz. The 13C NMR chemical shifts of the carbon atoms
Scheme 4.
in the four-membered ring (Cquat.
:
70.4ꢁ0.2 ppm, CH:
68.8ꢁ0.8 ppm and C]O: 164.6ꢁ0.2 ppm) suggest the trans
position of the H in this ring with the aryl substituent.
These values are very similar to those for compounds with
analogous structures measured earlier11,19 (71.5ꢁ0.5, 68.8ꢁ0.5
and 164.9ꢁ0.3 ppm11).
methanol under reflux. In the further transformations of indolo-
benzothiazepines by sulfur extrusion, alkaloid-type indolo[3,2-c]
isoquinolines 7a,b,d were obtained in good yields. The structures of
the novel ring expansion products were proved by means of NMR
spectroscopy.
It is noteworthy that the unusual high shift differences
(w0.6 ppm) of the methylene H’s in 3d,e and 9a,b arise from the
anisotropic effect20a of the aryl substituents lying near to the quasi-
axial H’s.
3. Structure
Similarly, the 1H NMR chemical shifts of the CH groups in the
azetidinone ring are practically identical: here 5.12e5.36 ppm,
while the corresponding chemical shifts for the compounds in
Ref. 11 were 5.09e5.14 ppm.
The postulated structures of the molecules investigated are
unambiguously confirmed by the spectral data (Tables 1 and 2).
Only the following remarks are necessary.
Table 1
Characteristic IR frequenciesa and 1H NMR datab on compounds 2d,e, 3d,e, 5d,e,f, 7a,b,d, 8a,b, 9a,b and 10a,bc
Compound
nNH band
n
C]O
g
CAr
H
CH3
(3H)
OCH3
NCH2 s,
d or ddf
CH s
(1H)
H-5 s
(1H)
H-8 s
(1H)
H-20
H-60
H-30
H-50
H-40
NH
broad
band
bandd
(Pos. 6, 7)e
Ar group attached to the heteroringg
2d
2e
3d
3e
5d
5e
5f
7a
7b
7d
8a
8b
9a
9b
10a
10b
d
d
854
840
813
831
872
872
863
825
834
856
850
846
851
853
858
843
2.31
d
3.81, 3.80
3.83, 3.80
3.74, 3.69
3.79, 3.70
3.73, 3.78
3.76, 3.80
3.76, 3.79
3.85, 3.93
3.91, 3.99
3.92, 4.03
3.92, 3.91
3.91, 3.90
3.85, 3.81
3.84, 3.82
3.88, 3.90
3.76, 3.77
4.60
4.63
4.34, 4.90
4.44, 4.98
d
d
6.72
6.76
6.55
6.62
7.14
7.16
7.15
7.52
7.56
7.59
6.87
6.85
6.70
6.68
6.75
6.97
6.74
6.72
6.48
6.43
6.91
6.95
6.94
7.82
7.80
8.06
6.89
6.88
6.66
6.67
7.15
7.05
d
7.59
7.52
7.16
7.20
d
d
7.35
d
7.30
7.45
7.22
7.39
6.89
7.09
7.09
7.27
d
d
d
d
d
7.85
d
d
d
1788
1781
d
2.34
d
5.13
5.36
d
d
7.28
d
d
d
d
8.10
6.86
7.27
7.25
7.50
7.08
d
8.29k
d
8.23k
d
d
3390
3320
3350
3250e2800
w 3160
w 3190
d
2.38
d
1.45h
d
d
7.30
d
11.1
11.5
11.2
11.7
11.5
11.4
d
d
d
d
d
7.49
7.47
7.94
7.44
7.86
d
4.47i
d
d
d
6.99
720
d
d
d
d
d
d
d
d
d
d
2.65
d
d
d
d
7.09
7.15
d
d
4.81
4.76
4.35, 4.95
4.34, 4.94
4.94
d
8.17k
8.61
7.61k
8.08
7.35k
7.63
d
d
2.65
d
d
8.13
7.36
7.33
7.41
7.58
7.40
d
d
d
1794
1784
1682
1671
5.15
5.12
d
d
d
d
2.60
d
d
d
4.51l
3380
3392
8.14k
d
d
2.49
4.80
d
d
7.27l
In KBr discs (cmꢀ1). Further bands, nasNO2 and nsNO2 (2, 3, 8e10): 1531e1501 and 1336e1366;
n
CeO: 1257e1265 and 1044e1056 (2, 3, 8), 1255ꢁ4 (5), 1175ꢁ2 (5) and
a
1045ꢁ(5d,e) and 1023 (5f), respectively, 1212ꢁ3 and 1007ꢁ3 (7a,d), 1258, 1209, 1190, 1038 and 1004 (7b), 1211 and 1049ꢁ4 (9), 1228ꢁ3 and 1062ꢁ6 (10);
gCArH (p-di-
substituted Ar group): 811 (8a, 10a), 821 (9a).
b
In CDCl3 (2, 3, 8, 9 and 10a) or DMSO-d6 (5, 7 and 10b) solution at 500 MHz. Chemical shifts in ppm (dTMS¼0 ppm), coupling constants in Hz. Further signals: OCH3 on the
thiazepine at 3.98 (5d) and 4.01 (5e) or on the pyridine ring at 4.08(7a) and 4.15 (7b,d) or in the ester group at 3.45 (10a) and 3.27 (10b).
c
Assignments were supported by 2D-HMQC and 2D-HMBC measurements.
Condensed benzene ring.
For 9b reversed assignment is also possible.
d
e
f
s (2, 8), 2ꢂd, J: 16.8(3d,e), 16.0 (9a), 16.5 (9b), d, J: 6.0 (10a), 5.1 (10b).
g
Benzene ring condensed to the pyrrole.
h
OEt group, t (3H), J: 7.1.
OEt group, qa (2H), J: 7.1.
AA0BB0-type spectrum, wd (2H), J: 8.8 (8a, 9a, 10a).
i
k
l
t.

854
L. Fodor et al. / Tetrahedron 68 (2012) 851e856
Table 2
13C NMR chemical shiftsa of compounds 2d,e, 3d,e, 5d,e,f, 7a,b,d, 8a,b, 9a,b and 10a,bb
Compound CH3 C]O or OCH3
C]Nc
NCH2
C-4a
C-5
C-6
C-7
C-8
C-8a
C-10
C-20
C-60
C-30
C-50
C-40
Benzothiazine (2, 3, 8, 9), benzothiazepine (5, 10) or isoquinoline (7) part
Aryl group (2, 3, 8e10) or benzene ring of indole (5, 7)
2d
2e
3d
3e
5d
5e
5f
7a
7b
7d
8a
8b
9a
9b
10a
10b
18.2 159.2
158.7
19.6 164.8
164.5
17.4 159.8
160.2
15.1 159.4
56.6d
56.8
57.2
43.0
43.4
d
122.2
122.4
119.2
119.0
128.4
128.2
128.5
113.2
112.1
113.1
123.0
123.0
121.9
121.5
135.4
136.3
110.7
110.8
111.2
111.0
113.8
113.9
113.9
105.3
105.3
105.2
110.6
110.6
111.7
111.6
111.7
113.4
149.7
149.7
148.8
148.9
149.5
149.6
149.5
149.4
148.8
149.3
149.7f
149.7
149.0
148.9
149.7
149.7
149.3
149.4
149.2
149.4
152.4
152.5
152.4
153.2
153.2
153.2
149.4
149.3
149.4
149.3
149.5
149.2e
109.7
109.6
112.7
112.4
114.6
114.8
114.6
102.4
101.9
102.7
110.0
110.0
113.0
113.0
116.2
116.1
121.1
121.3
119.9
119.9
129.0
128.4
129.0
122.8
122.9
123.0e,g
121.1
121.0
119.5
119.6
129.0d
129.2
130.9
139.8
132.0
136.9
136.2
135.0
136.6
128.9
133.6
138.2
142.9
136.3
144.4
136.9
147.9f
140.3
w150
146.9
148.6
145.0
121.7
114.8
112.3
112.4
96.1
128.3
131.2
126.8
128.9
124.1
125.5
124.4
138.8
115.6
121.5
131.6
126.4
130.5
135.7
130.9
140.9
115.7
117.2
118.1
119.5
101.8
117.1
133.9
130.9
133.7
130.3
120.2
125.2
120.0
119.8
145.2
119.9
149.7f
136.9
148.5
135.0
148.1f
133.5f
d
56.6, 56.6g
56.5, 56.4g
56. 6, 56.4
56.6, 56.7
56.6, 56.7
56.6, 56.7
56.4, 56.7
56.6, 56.7g
56.4, 56.8
56.6, 56.6g
56.6d
d
128.4
123.5
123.5
123.0
112.4
149.4
125.6
124.1
149.7f
124.0
149.4
123.9
149.3e
d
d
d
d
155.3
155.0
d
d
d
17.9 155.3
160.5
20.9 w161
164.4
20.8 164.3
167.4
20.1 167.5
d
123.0e,g
128.9
124.4
128.5
123.9
129.0d
124.2
d
57.3
56.6d
43.8
43.5
49.4
48.3
132.0
133.5
133.5f
133.5
131.9
133.1
d
56.5d
56.5d
d
56.6, 56.6g
56.5d
a
In ppm (dTMS 0 ppm) at 125.7 MHz. Solvent: CDCl3 (2, 3, 8, 9 and 10a) or DMSO-d6 (5, 7 and 10b). Further signals, OCH3 (ester group): 52.1 (10a), 51.7 (10b); OCH3 [on the
thiazepine (5) or pyridine (7) ring]: 54.4 (5d), 54.6 (5e), 54.1 (7a), 54.0 (7b,d); OCH3 (on the indole ring in 7b): 56.4 (Pos. 3), 56.9 (Pos. 4); OCH2 (5e): 62.5; CH (azetidinone
ring): 69.7 (3d), 69.5 (3e), 68. 0 (9a,b); Cquat. (azetidinone ring): 70.2 (3d), 70.3 (3e), 70.6 (9a,b); SeC(sp2), heteroring: 92.3 (10a), 87.8 (10b); NHeC(sp2), heteroring: 115.9 (5d),
118.2 (5e), 116.0 (5f), 125.3 (7a), 124.4 (7b), 125.2 (7d), 155.1 (10a), 156.7 (10b); N(sp2)eC, pyrrole ring: 126.4 (5d), 124.8 (5e), 126.0 (5f), 138.8 (7a), 129.4 (7b,d).
b
Assignments were supported by DEPT (except for 2d and 8b), 2D-HMQC and 2D-HMBC measurements.
c
X¼N (2, 5,7,8).
d
Two (three in 8b) overlapping lines.
e
Reversed assignment is also possible.
Two (three in 8b) overlapping lines.
Two lines with a distance<0.1 ppm.
f
g
The structures of molecules of type 5 were earlier proved
by using single-crystal diffraction and IR, 1H and 13C NMR spec-
troscopy.12 The measured data on compounds 5def characteristic
of the presumed four-membered ring-condensed skeleton are
very similar to those observed for the above-mentioned analogues,
and thus the structures of the new molecules in question can be
considered proven. As examples, C(OMe)]N: 160.312 and
159.8ꢁ0.4 ppm (5def), N(sp2)eC(pyrrole): 127.38ꢁ0.212 and
125.6ꢁ0.8 ppm (5def), OMe (1H and 13C NMR shifts): 4.12ꢁ0.0112
and 3.98 ppm (5d) and 4.01 (5e), respectively, and 54.312 and
54.5 (5d,e).
Desulfuration led to structures 7a,b,d. This follows straightfor-
wardly from the presence of the practically unchanged signals of
the NH and 4-OMe groups and the two condensed benzene rings,
respectively, and the upfield shifts of the C-4a and C-8a signals as
compared with those of molecules of type 5: C-4a: 128.4ꢁ0.2 ppm
(5def) versus 112.6ꢁ0.5 ppm (7a,b,d), and C-8a: 128.7ꢁ0.3 ppm
(5def) versus 122.9 ppm (7a,b,d).
carbon shifts mentioned above is significantly smaller in 10a
(62.8 ppm) than in 10b (68.9 ppm).
4. Experimental
4.1. General
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were per-
formed with a PerkineElmer 2400 CHNS elemental analyser.
Merck Kieselgel 60F254 plates were used for TLC, and Merck Silica
gel 60 (0.063e0.100) for column chromatography. The 1H and 13
C
NMR spectra were recorded in CDCl3 solution in 5 mm tubes at
room temperature, on a Bruker DRX 500 spectrometer at 500
(1H) and 126 (13C) MHz, with the deuterium signal of the solvent
as the lock and TMS as internal standard. The standard Bruker
micro program NOEMULT.AU to generate NOE was used with
a selective preirradiation time. DEPT spectra were run in a stan-
In the IR spectrum of 10a,b, instead of the high frequency of
b
-
dard manner, using only the
Q
¼135ꢃ pulse to separate CH/CH3
lactams, the ester bands appear: C]O (
n
b
-enamino esters21): 1682
and CH2 lines phased ‘up’ and ‘down’, respectively. The 2D-HSC
and 2D-HMBC spectra were obtained by using the standard
Bruker pulse programs. 1,3-Benzothiazines14 (2aec) and com-
pounds 3aec, 4aec and 5aec were prepared by earlier
methods.12
and 1671 cmꢀ1 nasCeO: 1225 and 1230 cmꢀ1 and nsCeO: 1055 and
,
1068 cmꢀ1, as expected.18b
The ring expansion is proved by the presence of the
CH2eNHeC]C(COOMe) moiety. Due to the vicinal coupling, the
methylene and NH signals in the 1H NMR spectra are split to
a doublet and a triplet, respectively. The chemical equivalence of
the methylene H’s indicates fast inversion of the azepine ring in
10a,b.
4.2. General procedure for the preparation of 4H-1,3-
benzothiazine derivatives 2d,e and 8a,b
The carbon signals of the enone group (
b
and
a
to the carbonyl)
The appropriately substituted N-(3,4-dimethoxyphenylthiome-
thyl)-aroylamides (33.0 mmol) were heated with phosphorus oxy-
chloride (10 mL) on a boiling water bath for 1 h. After cooling, the re-
action mixturewas decomposedwith ice, neutralizedwith Na2CO3 and
extracted with toluene. The toluene solution was dried over Na2SO4
and the solvent was removed under reduced pressure. The residue was
dissolved in hot ethanol (6 mL) and crystallized.
display very different chemical shifts: C(NH): 155.1 and 156.7 ppm,
C(S): 92.3 and 87.8 ppm, in accordance with the literature.20b The
polarization of the enone moiety is restrained by the electron-
withdrawing effect of the para-nitrophenyl substituent in 10a,
due to the coplanar arrangement of this group and the enone
moiety. Because of the steric interaction arising from the ortho-
nitro group in 10b, the aryl group is forced into an orientation
perpendicular to the enone moiety and its ꢀI effect cannot act in
4.2.1. 2-(3-Methyl-2-nitrophenyl)-6,7-dimethoxy-4H-1,3-benzothia-
zine (2d). A pale-yellow crystalline powder, mp: 141e143 ꢃC, yield
this arrangement. Consequently, the difference in the
b
- and
a
-

L. Fodor et al. / Tetrahedron 68 (2012) 851e856
855
47%; Rf (n-hexane/EtOAc 4:1) 0.24. Anal. Calcd for C17H16N2O4S
(344.39): C, 59.29; H, 4.68; N, 8.13; S, 9.31. Found: C, 59.03; H, 4.92;
N, 7.91; S, 9.60.
appropriate sodium alkoxide (3.30 mmol) was added. The reaction
mixture was stirred under reflux for 3 h. After evaporation, the
residue was dissolved in dichloromethane (20 mL). The organic
phase was extracted with water (10 mL), dried (Na2SO4) and
evaporated.
4.2.2. 2-(5-Chloro-2-nitrophenyl)-6,7-dimethoxy-4H-1,3-benzothia-
zine (2e). A pale-yellow crystalline powder, mp: 167e169 ꢃC, yield
44%; Rf (n-hexane/EtOAc 4:1) 0.22. Anal. Calcd for C16H13ClN2O4S
(364.80): C, 52.68; H, 3.59; N, 7.68; S, 8.79. Found: C, 52.44; H, 3.81;
N, 7.70; S, 8.88.
4.4.1. 6H-2,3,12-Trimethoxy-7-methylindolo[2,3-b][1,4]benzothiaze-
pine (5d). A pale-yellow powder, mp: 127e130 ꢃC, yield 62%; Rf (n-
hexane/EtOAc 4:1) 0.78. Anal. Calcd for C19H18N2O3S (354.42): C,
64.39; H, 5.12; N, 7.90; S, 9.05. Found: C, 64.28; H, 5.30; N, 7.82; S,
9.23.
4.2.3. 2-(4-Nitrophenyl)-6,7-dimethoxy-4H-1,3-benzothiazine (8a).
A pale-yellow crystalline powder, mp: 187e189 ꢃC, yield 49%; Rf (n-
hexane/EtOAc 4:1) 0.26. Anal. Calcd for C16H14N2O4S (330.36): C,
58.17; H, 4.27; N, 8.48; S, 9.71. Found: C, 58.44; H, 3.98; N, 8.75; S,
9.95.
4.4.2. 6H-2,3,12-Trimethoxy-9-chloroindolo[2,3-b][1,4]benzothiaze-
pine (5e). A pale-yellow powder, mp: 164e166 ꢃC, yield 64%; Rf (n-
hexane/EtOAc 4:1) 0.80. Anal. Calcd for C18H15ClN2O3S (374.84): C,
57.68; H, 4.03; N, 7.47; S, 8.55. Found: C, 57.49; H, 4.33; N, 7.69; S,
8.82.
4.2.4. 2-(4-Methyl-3-nitrophenyl)-6,7-dimethoxy-4H-1,3-benzothia-
zine (8b). A pale-yellow crystalline powder, mp: 143e144 ꢃC, yield
46%; Rf (n-hexane/EtOAc 4:1) 0.25. Anal. Calcd for C17H16N2O4S
(344.39): C, 59.29; H, 4.68; N, 8.13; S, 9.31. Found: C, 59.l2; H, 4.82;
N, 7.82; S, 9.52.
4.4.3. 6H-2,3-Dimethoxy-12-ethoxyindolo[2,3-b][1,4]benzothiaze-
pine (5f). A pale-yellow powder, mp: >350 ꢃC, yield 57%; Rf (n-
hexane/EtOAc 4:1) 0.78. Anal. Calcd for C19H18N2O3S (354.42): C,
64.39; H, 5.12; N, 7.90; S, 9.05. Found: C, 64.69; H, 5.34; N, 7.61; S,
8.80.
4.3. General procedure for azetobenzothiazines 3d,e and 9a,b
To a stirred solution of the appropriately substituted 4H-1,3-
benzothiazine derivative (2 or 8) (2.00 mmol) in anhydrous tolu-
ene (10 mL), monochloroacetyl chloride (3.00 mmol) was added.
The solution was heated to reflux, and triethylamine (0.40 mL,
3.00 mmol) in anhydrous toluene (20 mL) was added dropwise
during 4 h under reflux. The reaction mixture was then cooled and
filtered, and the remaining triethylammonium 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.
4.5. General procedure for indolo[3,2-c]isoquinolines 7a,b,d
Indolo[2,3-b][1,4]benzothiazepine 5a,b,d (0.30 mmol) was dis-
solved in dimethylformamide and the solution was heated at reflux
for 3 h. After evaporation, the oily residue crystallized on trituration
with ethanol.
4.5.1. 11H-2,3,5-Trimethoxyindolo[3,2-c]isoquinoline (7a). A pale-
yellow powder, mp: 260e263 ꢃC, yield 86%; Rf (n-hexane/EtOAc
4:1) 0.45. Anal. Calcd for C18H16N2O3 (308.33): C, 70.11; H, 5.23; N,
9.09. Found: C, 70.32; H, 4.99; N, 9.21.
4.3.1. trans-2-Chloro-2a-(3-methyl-2-nitrophenyl)-2,2a-dihydro-
5,6-dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one
(3d). A
4.5.2. 11H-2,3,5,8,9-Pentamethoxyindolo[3,2-c]isoquinoline (7b). A
pale-yellow powder, mp: 271e273 ꢃC, yield 81%; Rf (n-hexane/
EtOAc 4:1) 0.48. Anal. Calcd for C20H20N2O5 (368.38): C, 65.21; H,
5.47; N, 7.60. Found: C, 64.95; H, 5.67; N, 7.48.
pale-yellow crystalline powder, mp: 222e224 ꢃC, yield 87%; Rf (n-
hexane/EtOAc 4:1) 0.58. Anal. Calcd for C19H17ClN2O5S (420.87): C,
54.22; H, 4.07; N, 6.66; S, 7.62. Found: C, 54.51; H, 3.89; N, 6.82; S,
7.90.
4.5.3. 11H-10-Methyl-2,3,5-trimethoxyindolo[3,2-c]isoquinoline
(7d). A pale-yellow powder, mp: 280e283 ꢃC, yield 79%; Rf (n-
hexane/EtOAc 4:1) 0.50. Anal. Calcd for C19H18N2O3 (322.36): C,
70.79; H, 5.63; N, 8.69. Found: C, 70.68; H, 5.90; N, 8.81.
4.3.2. trans-2-Chloro-2a-(5-chloro-2-nitrophenyl)-2,2a-dihydro-5,6-
dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (3e). A pale-
yellow crystalline powder, mp: 230e234 ꢃC, yield 92%; Rf (n-hex-
ane/EtOAc 4:1) 0.60. Anal. Calcd for C18H14Cl2N2O5S (441.29): C,
48.99; H, 3.20; N, 6.35; S, 7.27. Found: C, 50.21; H, 3.35; N, 6.08; S,
7.48.
4.6. General procedure for 4,5-dihydro-1,4-benzothiazepines
10a,b
4.3.3. trans-2-Chloro-2a-(4-nitrophenyl)-2,2a-dihydro-5,6-
dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one (9a). A pale-
yellow crystalline powder, mp: 157e159 ꢃC, yield 90%; Rf (n-hex-
ane/EtOAc 4:1) 0.60. Anal. Calcd for C18H15ClN2O5S (406.84): C, 53.14;
H, 3.72; N, 6.89; S, 7.88. Found: C, 53.08; H, 4.01; N, 6.95; S, 8.12.
Azeto-1,3-thiazine 9a,b (0.66 mmol) was dissolved in dry
methanol (40 mL). To the stirred solution, sodium methoxide
(70 mg, 1.32 mmol) was added, and stirring was continued under
reflux for 1 h. After evaporation, the residue was dissolved in
dichloromethane (20 mL). The organic phase was extracted with
water (10 mL), dried (Na2SO4) and evaporated.
4.3.4. trans-2-Chloro-2a-(4-methyl-3-nitrophenyl)-2,2a-dihydro-
5,6-dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one
(9b). A
pale-yellow crystalline powder, mp: 159e160 ꢃC, yield 94%; Rf (n-
hexane/EtOAc 4:1) 0.56. Anal. Calcd for C19H17ClN2O5S (420.87): C,
54.22; H, 4.07;N, 6.66;S, 7.62. Found:C, 54.48; H, 4.24;N, 6.38; S, 7.79.
4.6.1. Methyl 3-(4-nitrophenyl)-4,5-dihydro-7,8-dimethoxy-1,4-
benzothiazepine-2-carboxylate (10a). An orange-yellow crystalline
powder, mp: 200e202 ꢃC, yield 87%; Rf (n-hexane/EtOAc 4:1) 0.41.
Anal. Calcd for C19H18N2O6S (402.42): C, 56.71; H, 4.51; N, 6.96; S
7.97. Found: C, 56.49; H, 4.66; N, 7.20; S, 8.01.
4.4. General procedure for indolo[2,3-b][1,4]
benzothiazepines 5def from azetobenzothiazines 3d,e,a
4.6.2. Methyl 3-(4-methyl-3-nitrophenyl)-4,5-dihydro-7,8-
dimethoxy-1,4-benzothiazepine-2-carboxylate (10b). An orange-
yellow crystalline powder, mp: 179e185 ꢃC, yield 91%; Rf (n-
Azeto-1,3-thiazine 3d,e,a (0.66 mmol) was dissolved in dry
methanol or in ethanol (40 mL). To the stirred solution, the

856
L. Fodor et al. / Tetrahedron 68 (2012) 851e856
ꢀ
9. (a) Wrobel, Z.; Makosza, M. Tetrahedron 1993, 49, 5315; (b) Makosza, M. Pure
hexane/EtOAc 4:1) 0.43. Anal. Calcd for C20H20N2O6S (416.45): C,
57.68; H, 4.84; N, 6.73; S, 7.70. Found: C, 57.82; H, 5.19; N, 6.98; S,
7.82.
ꢀ
Appl. Chem. 1997, 69, 59; (c) Bobin, M.; Kwast, A.; Wrobel, Z. Tetrahedron 2007,
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Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier Ltd.: Oxford,
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ꢀ
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11. Fodor, L.; Csomos, P.; Csampai, A.; Sohar, P. Synthesis 2010, 2943.
12. Fodor, L.; Csomos, P.; Holczbauer, T.; Kalman, A.; Csampai, A.; Sohar, P. Tetra-
Acknowledgements
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ꢀ
ꢀ
ꢀ
hedron Lett. 2011, 52, 224.
ꢀ
ꢀ
ꢀ
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA 101548 and K-68887) for financial
support. The European Union and the European Social Fund also
provided financial support for the project under grant agreement
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