An expeditious synthesis for γ-carboline analogue 4-aryl-1,3-thiazino[6,5-b]indole derivatives via the trifluoromethanesulfonic acid-promoted isomerization of 3-amidomethylthioindole intermediates to 2-indolyl sulfides

Article abstract of DOI:10.1016/j.tet.2008.11.099

A highly efficient trifluoromethanesulfonic acid-mediated rearrangement of the benzoylaminomethylthio group of 3-benzoylaminomethylthioindoles (7a-e) to position 2 of the indole ring was developed. Thus, 2-benzoylaminomethylthioindoles (9a-e) were obtained in good yields and were involved as key intermediates in the synthesis of the new γ-carboline analogue ring system: 2,9-dihydro-4-aryl-1,3-thiazino[6,5-b]indole derivatives (11a-e). The target thiazinoindoles (11a-e) were prepared via 2-thiobenzoylaminomethylindoles (10a-e) in modified Bischler-Napieralski reactions.

Full text of DOI:10.1016/j.tet.2008.11.099

Tetrahedron 65 (2009) 1475–1480
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An expeditious synthesis for g-carboline analogue 4-aryl-1,3-thiazino[6,5-
b]indole derivatives via the trifluoromethanesulfonic acid-promoted
isomerization of 3-amidomethylthioindole intermediates to 2-indolyl sulfides
a
,
b
,
,
b,
c
, ,
y
b,
c
d
d,
e
, ,
z
Peter Csomos c, Lajos Fodor a
*
*
´
´
´ ´ ´ ´ ´
, Gabor Bernath , Antal Csampai , Pal Sohar
a Central Laboratory, County Hospital, H-5701 Gyula, PO Box 46, Hungary
b Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Szeged, Eo¨tvo¨s u. 6, Hungary
c Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720, Szeged, Eo¨tvo¨s u. 6, Hungary
d
´
Institute of Chemistry, Eo¨tvo¨s Lorand University, Hungary
e
´
Protein Modelling Research Group, Hungarian Academy of Sciences and Eo¨tvo¨s Lorand University, H-1518 Budapest, PO Box 32, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient trifluoromethanesulfonic acid-mediated rearrangement of the benzoylaminomethyl-
thio group of 3-benzoylaminomethylthioindoles (7a–e) to position 2 of the indole ring was developed.
Thus, 2-benzoylaminomethylthioindoles (9a–e) were obtained in good yields and were involved as key
Received 30 September 2008
Received in revised form 11 November 2008
Accepted 27 November 2008
Available online 6 December 2008
intermediates in the synthesis of the new
g-carboline analogue ring system: 2,9-dihydro-4-aryl-1,3-
thiazino[6,5-b]indole derivatives (11a–e). The target thiazinoindoles (11a–e) were prepared via 2-thio-
benzoylaminomethylindoles (10a–e) in modified Bischler–Napieralski reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thiazino[6,5-b]indole
Isomerization
Trifluoromethanesulfonic acid
Bischler–Napieralski reaction
IR
1H and 13C NMR
1. Introduction
produced by Amanita phalloides.8 Benzothienoindole derivatives
have been found to be selective estrogen receptor modulators.9
The indole substructure is a basic core unit for a huge number of
biologically active natural and synthetic molecules.1 This plays
a key role in the current interest in novel syntheses and trans-
formations of indole compounds.2 Special attention is focused on
the functionalization of the C-3 and C-2 positions of the indole ring
as reactive sites of the heterocyclic system. Sulfur-containing sub-
stituents at position C-3 or C-2 of indole moieties are common in
many pharmacologically important compounds. In particular, nu-
merous thioindoles demonstrate antiproliferative,3 cyclooxygenase
inhibitory,4 factor Xa inhibitory,5 HIV reverse transcriptase in-
hibitory,6 or antibacterial7 activities. A number of tricyclic or
polycyclic natural products or compounds having specific biological
activity also contain the indole-2- or 3-thiol fragment. Probably the
best known among them is the cyclic fungal toxin phalloidin,
Interesting tetracyclic counterparts were recently prepared by
intramolecular electrophilic sulfenylation from sulfinyl indoleani-
lides.10 A huge number of tricyclic derivatives can be found in S-
containing cruciferous phytoalexins.11 The phytoalexins are not
present in healthy plant tissue, but are synthesized in response to
pathogen attack or physical or chemical stress, probably as a result
of the de novo synthesis of enzymes.12 They also exhibit various
useful pharmacological effects (e.g., antimicrobial or anti-
proliferative activity). For example, 1,3-thiazino[6,5-b]indole or
isothiazolo[5,4-b]indole derivatives such as cyclobrassinin, brassi-
lexin, and sinalexin have been isolated from Chinese cabbage.11 In
the course of our studies on S- and N-containing condensed-skel-
eton heterocycles,13–16 we have developed novel methodologies for
the synthesis of different ring positional isomers of 1,3-thiazi-
noindole derivatives condensed at the b-bond of indole.3b,17–19
These synthesized derivatives include phytoalexins and analogous
substances (4,9-dihydro-1,3-thiazino[6,5-b]indoles, 1, Fig. 1),17
compounds with interesting in vitro antiproliferative effects (4,5-
dihydro-1,3-thiazino[5,6-b]indoles, 2, Fig. 1),3b,18 and 4-thiaharma-
lan analogues (2,5-dihydro-1,3-thiazino[5,6-b]indoles, 3, Fig. 1).19
* 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. Soha´r).
For synthesis contact Lajos Fodor.
y
z
´
´
For spectroscopy contact Pal Sohar.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.099

1476
P. Csomo´s et al. / Tetrahedron 65 (2009) 1475–1480
Ar
Unfortunately, the reaction of 9a under classical Bischler–
S
N
Napieralski conditions led to decomposition of the benzamido-
methyl moiety, and in some cases indole-2-thione was observed in
the reaction mixture. In order to perform a modified Bischler–
Napieralski reaction under non-acidic conditions, thioben-
zamidomethyl derivatives 10a–e were prepared by reaction of the
corresponding amides 9a–e and Lawesson’s reagent (Scheme 2).
The S-exchange reactions were carried out in refluxing THF after
the addition of a small amount of Et3N to the mixture; in this way,
thioamides 10a–e could be prepared in relatively good yields.
Treatment of thiobenzamidomethyl derivatives 10a–e with methyl
iodide in refluxing acetone provided the cyclized thiazinoindole
derivatives 11a–e after methyl mercaptan elimination (Scheme 2).
In summary, we report a convenient approach for the synthesis
N
Ar
N
H
S
N
H
1
2
Ar
S
N
N
N
N
S
H
H
Ar
4
3
Figure 1. Different aryl-substituted ring positional isomers of 1,3-thiazinoindole de-
rivatives condensed at the b-bond of indole.
of a new g-carboline analogue ring system: 4-aryl-1,3-thiazino[6,5-
We now describe an efficient route for the synthesis of the
fourth 1,3-thiazinoindole isomer: 2,9-dihydro-4-aryl-1,3-thia-
zino[6,5-b]indoles, 4 (Fig. 1). These compounds have a new ring
system and are thia analogues of pharmacologically important
b]indoles. For the intermediate 9a–e, a convenient TfOH-catalyzed
rearrangement was achieved with good yields: under mild condi-
tions, the 3-benzoylaminomethylthio group rearranged to position
2 of the indole ring. The target thiazinoindoles (11a–e) were pre-
pared via 10a–e under Bischler–Napieralski conditions.
g
-carbolines.20 The procedure utilizes the super acid-mediated
C-3/C-2 migration of the amidomethylthio group on the indole
ring of 3-benzoylaminomethylthioindole intermediates.
3. Structure
2. Results and discussion
The presumed structures of the new compounds were con-
firmed unambiguously via the IR and NMR spectra (Tables 1–3).
Only a few additional remarks are necessary.
The synthesis of the substituted 3-benzoylaminomethylth-
ioindole derivatives (7a–e) started from indole-3-thiol (5) by se-
lective benzamidomethylation under basic conditions with
substituted benzoylaminomethyltriethylammonium chlorides (6a–
e), prepared from chloromethylbenzamides. In refluxing CHCl3 in
the presence of Et3N, 7a–e were obtained in excellent yields. In
order to improve the 3C/2C migration of the 3-amidomethylthio
groups different reagents (trifluoroacetic acid and polyphosphoric
acid) and conditions were examined. To our surprise, in the initial
experiments, trifluoromethanesulfonic acid (TfOH) without any
solvent was found to be a powerful agent that promoted the above
migration. After optimization of the reaction conditions, isomeri-
zations were performed in TfOH at 45 ꢀC for 30 min 2-benzami-
domethyl thioether derivatives (9a–e) were obtained in relatively
good yields (69–84%). To the best of our knowledge, this is the first
example of the TfOH catalyzed isomerization of 3-indolyl sulfides
to 2-indolyl sulfides. It is noteworthy that successful extension of
this reaction would allow the convenient preparation of other
substituted indole derivatives with sulfur at position 2.
The ꢁI effect of the ortho-chloro substituent21 in 6d is revealed
in a n
C]O frequency higher by 39 cmꢁ1 in comparison with 6e.
A similar effect was not observed for the pairs 7d,e and 9d,e. A non-
planar conformation due to the bulky indole moiety may be
responsible for this fact. Such an arrangement in the latter com-
pounds is preferred, assuming a cyclic dimer association of the
amide group.
It is noteworthy that the Me hydrogens are more shielded in 11e
(by ca. 0.4 ppm) than in 7e, 9e, and 10e. This difference can be
explained in terms of the anisotropic shielding22a of the delocalized
electrons in the skeleton, due to the perpendicular arrangement of
the ortho-tolyl substituent to that in the preferred conformation
formed as a consequence of the steric hindrance between the
skeleton and the Me group. A similar, but more pronounced effect
(>0.5 ppm) can be observed for H-4 of the indole part in 11d and
11e (anisotropy of the ring current in the Ar group on H-4 lying
above the benzene ring).
Alternatively, 9a–e were prepared from indole-2-thione (8) and
different benzoylaminomethyltriethylammonium chlorides (6a–e)
under reflux in CHCl3 in the presence of Et3N (Scheme 1).
The signal C]S in the 13C NMR spectra of compounds of type
10 appears in the expected interval (197–201 ppm),22b in contrast
with the carbonyl signal (166–172 ppm) of compounds of types 6,
Ar
H
N
SH
O
S
CHCl3, Et3N
O
Cl(Et)3N
N
H
Ar
+
Δ, 2h
N
H
N
H
5
6a-e
7a-e
TfOH 45 °C, 30 min.
O
O
CHCl3, Et3N
Cl(Et)3N
N
Ar
+
H
Δ, 2h
N
S
N
H
S
N
H
Ar
H
8
6a-e
9a-e
Scheme 1. a: Ar¼Ph; b: Ar¼p-Cl-C6H4; c: Ar¼p-Me-C6H4; d: Ar¼o-Cl-C6H4; e: Ar¼o-Me-C6H4.

P. Csomo´s et al. / Tetrahedron 65 (2009) 1475–1480
1477
Ar
S
Lawesson's
MeI
acetone
Δ, 5 h
O
reagent
THF, Et3N
Δ, 5h
S
N
N
H
S
N
H
Ar
N
H
S
N
H
Ar
N
H
9a-e
10a-e
11a-e
Scheme 2. a: Ar¼Ph; b: Ar¼p-Cl-C6H4; c: Ar¼p-Me-C6H4; d: Ar¼o-Cl-C6H4; e: Ar¼o-Me-C6H4.
7, and 9. The attached thioamide group causes a downfield shift by
ca. 0.5 ppm on the NCH2S signal relative to that for amide com-
pounds. The more extensive conjugation in compounds of type 11
is manifested in a downfield shift of the indole-NH signal (ca.
12.2 ppm, as compared with 11.5 ppm for all the other
compounds).
We demonstrated earlier that a vicinal spin–spin coupling of H-
2 with the indole-NH leads to a splitting by 2.5 Hz in related
compounds.19 The analogue split is also observable for 7d,e, while
the similar allylic-type 4J interaction (between H-3 and the indole-
NH) causes only a smaller split (by 1.2–1.6 Hz) for 9b,d and 10a,d,e.
The NH signal (for 9c,e and 10b,c) and also the H-3 signal are sin-
glets in the routine spectra.
The condensed thiazine ring-containing compounds 11a–e give
singlet methylene 1H NMR signals, while the open-chain analogues
with a CH2NH group give doublet CH2 and triplet NH signals, split
by 6.5ꢂ0.5 Hz, due to the vicinal coupling of the hydrogens in this
moiety.
Of course, a few other changes also provide evidence of the
presumed condensed three-ring system. For example, instead
of the 13C NMR line of the thioamide carbon, 11a–e (see above)
have the C]N carbon signal at 140.5ꢂ1.0 ppm. The H-3 singlet
of 10a–e (6.65ꢂ0.05 ppm) is absent from the 1H NMR spectra of
11a–e.
Table 1
Characteristic IR frequenciesa of compounds 6d,e, 7d,e, 9b–e, 10a–e, and 11a–e
Compound
nNH band
Amide-I band
gCArH band
Ar
Indole
6d
6e
7d
7e
9b
9c
9d
9e
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
3500–3400
3500–3400
3313
3200
3275
3320
3297
3275, 3245
w3300
3354, 3165
3328
3350–2900
3350–2900
3500–1800
3500–1800
3500–1800
3500–1800
3500–1800
1709
1670
1646
1643
1631
1619
1629
1623
d
741
d
736
746b
739b
842
840
73b
d
746b
739b
748
742
737b
732b
744b
736
738
749c
747c
740
751
744
737b
747b
732b
744b
829
817
d
d
d
734c
730c
721
842
827
737b
747b
d
d
d
d
d
d
In KBr discs (cmꢁ1). Further bands,
gCACAr (Ar group): 690 (10a), 696 (11a), 827
a
(11c).
b
Coalesced bands.
Reversed assignments are also possible.
c
Table 2
1H NMR dataa on compounds 6d,e, 7d,e, 9b–e, 10a–e, and 11a–eb
Compound CH3 (3H) NCH2S dc or s H-2/3d de or s H-4d wd H-5d wt H-6d wt H-7d wd H-20,60 d (2H)f H-30,50 d/t (2H)g H-40 t (1H) NH amide NH indole
5j
6d
6e
7d
7e
9b
9c
9d
d
d
7.46
d
7.59
d
7.11
d
7.16
d
7.42
d
d
d
d
d
11.5
d
1.31
1.32
d
4.80
4.78
4.54
4.44
4.78
4.80
4.78
4.78
5.12
5.05
5.15
5.12
5.12
4.93
4.94
4.86
4.99
4.96
7.70
7.66
7.53
7.20h
7.91
7.81
7.53
7.35i
7.81
7.76
7.77
7.50
7.25
7.4–7.6
7.53h
7.37
7.50
7.15
7.51
7.58
7.47
7.48
7.27
d
9.98
9.75
9.11
8.80
9.43
9.28
9.30
9.11
11.0
11.0
10.9
11.2
11.0
d
d
d
d
d
d
7.34h
7.40
7.19h
7.60
7.32
7.44
7.26h
7.47
d
7.65
7.51
6.64
6.64
6.70
6.67
6.68
6.61
6.69
6.70
6.66
d
7.78
7.66
7.52
7.52
7.55
7.53
7.54
w7.45h
7.55
7.53
7.52
6.61
6.68
6.64
6.11
6.05
7.19
7.05
7.04
7.04
7.05
7.05
7.05
6.97
7.06
7.04
7.04
6.89
6.95
6.86
6.76
6.71
7.24
7.13
7.15
7.15
7.16
7.15
7.16
7.08
7.17
7.15
7.14
7.07
7.100
7.03
6.98
6.96
7.51
7.40
7.39
7.39
7.40
7.40
7.39
7.32
7.41
w7.4h
7.38
7.37
7.40
7.32
7.28
w7.27i
11.5
11.4
11.5
11.5
11.5
11.5
11.5
11.4
11.5
11.5
11.5
Br
2.25
d
2.40
d
d
7.49
7.37i
7.56
d
9e
2.35
d
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
d
w7.46h
7.28
w7.4h
7.21
2.39
d
d
w7.4h
7.30
w12.3
d
2.30
d
d
d
d
7.53h
7.23
7.48
w7.27i
d
w12.4
w12.2
w12.2
w12.1
2.35
d
d
d
d
d
7.42
7.36
d
1.96
d
d
a
In DMSO-d6 solution at 500 MHz. Chemical shifts in parts per million (dTMS¼0 ppm), coupling constants in hertz. Further signals: CH3 and CH2 (Et, 6d,e): 1.31, t, J: 7.3 and
3.30 qa, H-30 (d and e-type compds): 7.62 (6d), 7.34h (6e, 7d, 11d), 7.15h (7e), 7.43 (9d), 7.27 (9e,h 11ei), w7.4h (10d), 7.23 (10e).
b
Assignments were supported by HMQC (except for 9b) and HMBC (except for 9b), for compds 7e and 11d also by 2D-COSY measurements.
c
J: 6.2ꢂ0.2, 7.1 (NCH2N, 6d,e), s for 11a–e.
d
Indole skeleton.
e
J: 2.5 (7d,e), 1.6 (9b, 10a), 1.2 (9d, 10d,e), s (9c,e, 10b,c).
The A part of an AA0BB0C (a-type compd) or AA0BB0 spectrum (b and c-type compds), J: 8.4 (b-type compd), 7.9 (c-type compd), H-60 (d and e-type compds).
H-50 (d and e-type compds).
Overlapping signals.
Overlapping signals.
In CDCl3 solution, SH: 4.00.
f
g
h
i
j

1478
P. Csomo´s et al. / Tetrahedron 65 (2009) 1475–1480
Table 3
13C NMR chemical shiftsa of compounds 6d,e, 7d,e, 9b–e, 10a–e, and 11a–eb
e
e
Compound
CH3 (Ar)
C]O or
C]Xc
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
SCH2N or
NCH2Nd
C-10
C-20
C-30
C-40
Indole ring
Aryl group
5i
6d
6e
7d
7e
9b
9c
9d
d
d
129.8
d
96.4
d
130.3
d
122.6
d
120.2
d
119.4
d
112.7
d
137.1
d
d
d
d
d
d
d
169.2
171.8
166.8
169.5
166.1
167.0
167.1
169.8
198.7
197.1
198.3
197.2
201.2
141.3
141.3
140.5f
141.6
139.5
60.0
60.5
46.3
46.3
46.9
46.9
45.8
45.9
52.5
52.7
52.6
50.8
50.7
w51.2
51.4
135.9
135.4
130.9
137.4g
133.4
131.9
130.9
137.1
141.4
140.0
138.6
142.9
144.3
139.6
135.0
136.5g
132.3
136.0f
130.7
136.9
137.3f
136.4
130.2
128.3
137.0
136.4
128.2
130.0
128.3
129.2
133.5
129.0
131.4
129.6h
139.3
136.0f
130.6
131.6
129.8
126.2
129.3
129.7
127.9
128.0
128.8g
129.0
129.4
129.7
131.0
129.6
129.1
129.6h
130.9
131.0
132.6
131.3
131.7
130.3f
137.3
142.4
131.9
131.3
131.9
136.9
142.1
130.9
129.3
130.8
138.4
140.5f
128.3
129.7
d
d
d
d
d
d
d
d
d
d
132.2
131.9
129.0
129.0f
128.4
128.7
128.9f,g
128.7f
129.0f
128.4
128.6
165.2
164.0
w165
163.3
164.4
102.8
103.0
108.2
107.9
108.3
108.1
108.5
108.6
108.4
108.4
108.1
108.4
108.0
108.7
109.0
109.6
130.2
130.3f
128.7
129.0f
129.0
129.0
128.9f,g
128.7f
129.0f
128.9
128.9
125.4
125.2
126.0
125.7
126.2
119.5
119.4
120.4
120.4
120.4
120.4
120.5
120.6
120.5
120.5
120.4
119.4
119.3
119.4
117.9
118.1
120.5
120.4
120.1
120.0
120.1
120.0
120.1
120.2
120.1
120.1
120.1
121.5
121.7
121.5
121.8
121.7
122.6
122.6
122.5
122.4
122.5
122.5
122.7
122.7
122.6
122.6
122.6
122.6
122.7
122.7
122.7
122.8
112.9
112.9
111.9
111.8
111.8
111.8
111.9
111.9
111.9
111.9
111.8
112.4
112.4
w113
112.6
113.1
137.3f
137.3g
138.4
138.4
138.4
138.5
138.5
138.5
138.5
138.4
138.5
w137
136.8
135.9
137.5
136.0f
20.2
d
21.8
d
9e
20.2
d
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
d
21.8
d
19.7
d
d
21.9
d
w50.7
50.8
50.2
19.6
a
In parts per million (dTMS¼0 ppm) at 125.7 MHz. Solvent: DMSO-d6. Further signals, C-50 and C-60 (for d and e-type compounds): 128.1 and 130.2 (6d), 126.4 and 128.9 (6e),
127.8 and 130.5 (7d), 131.3 and 127.9 (7e), 129.8 and 130.6 (9d), 126.3 and 130.4 (9e), 127.8 and 130.3 (10d), 127.5 and 126.3 (10e), 131.3 and 130.4 (11d), 126.7 and 128.9 (11e);
CH3(Et): 8.2, 8.3 (6d,e); CH2(Et): 51.1 (6d,e).
b
Assignments were supported by DEPT (except for 11c–e), HMQC (except for 9b) and also by HMBC (except for 9b) measurements.
c
X¼S (10a–e), X¼N (11a–e).
d
For 6d,e.
e
C-2060 and C-30,50 lines for a–c-type compounds.
f
Overlapping lines.
Overlapping lines.
Reversed assignments are also possible.
Solvent: CDCl3.
g
h
i
4. Experimental
4.1. General
4.2. Preparation of 1H-indole-3-thiol (5)
For the preparation of compound 5, the method of Harris26 was
used, which is as follows.
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were per-
formed 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 chromatography. TfOH was purchased from AlfaAesar.
Indol-2-one was purchased from Fluka. Indole and thiourea were
purchased from Reanal. Substituted benzoylaminomethyl-
triethylammonium chlorides (6a–c),19,23 N-hydroxymethylbenz-
amides,24N-chloromethylbenzamides,25 and 3-benzoylaminome-
thylthio-1H-indoles (7a–c)19 were prepared by the literature
methods.
To a vigorously stirred solution of indole (7.0 g, 60 mmol) and
thiourea (4.7 g, 60 mmol) in 240 mL of methanol and water (2:l)
was added a potassium iodide iodine (10.0 g, 60 mmol; 15.2 g,
60 mmol) solution in 120 mL of methanol and water (2:l) dropwise.
The mixture was stirred (30 min) until the solution turned yellow.
The solution was then evaporated to remove methanol and
extracted with ethyl acetate. The remaining aqueous solution on
further concentration in vacuum (50 mL), after cooling with ice-
water yielded light brown crystals, which were filtered off and
recrystallized from water to give 16.2 g of S-(3-indolyl)isothiouro-
nium iodide. The isothiouronium salt (16.0 g, 50 mmol) was rapidly
added to a 10% sodium hydroxide solution (120 mL), purged with
nitrogen (0.5 h). With continued nitrogen purging, the mixture was
heated to reflux for another 15 min, cooled down and the solution
was filtered through a thin pad of Celite to a mixture of concen-
trated HCl (50 mL) and ice (60 g). The yellow precipitate formed
was filtered off, washed with H2O (3ꢃ20 mL) and dissolved in 10%
sodium hydroxide solution (100 mL) rapidly, and the solution was
filtered through a thin pad of Celite again to a mixture of concen-
trated HCl (40 mL) and ice (20 g). The precipitate formed was fil-
tered off, washed with H2O (4ꢃ20 mL), dried in vacuum exsiccator
to provide 5 (6.6 g). Compound 5 was used without further
purification.
ESI mass spectra were obtained with a Finnigan MAT 95S
double-focusing sector-field instrument. MeCN solutions of com-
pounds were infused into the ESI through a plastic capillary at
a constant flow of 100 mL/min (H2O/MeCN 50:50 containing 0.1%
AcOH). The ions were produced by using N2 as sheath gas at 2 psi,
with a spray voltage of 2.5 kV and a capillary temperature of
210 ꢀC. Poly(propylene glycol) solution was used for the calibra-
tion. 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 rt, on a Bruker DRX 500 spectro-
meter 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
measurements. DEPT spectra were run in a standard manner, us-
Small sample was purified further on a short column of silica
(CH2Cl2/n-hexane 3:2 purged with nitrogen) for analytical
investigations.
ing only the
Q
¼135ꢀ pulse to separate CH/CH3 and CH2 lines
Pale cream plates, mp: 101–103 ꢀC (lit.26 mp: 100–101 ꢀC).
[MþH]þ¼149. Anal. Calcd for C8H7NS (149.21): C, 64.39; H, 4.73; N,
9.39; S, 21.49. Found: C, 64.67; H, 4.51; N, 9.21; S, 21.72; Rf (CH2Cl2/
n-hexane 3:2) 0.63.
phased ‘up’ and ‘down’, respectively. 2D-HMQC and 2D-HMBC
spectra were obtained by using the standard Bruker pulse
programs.

P. Csomo´s et al. / Tetrahedron 65 (2009) 1475–1480
1479
4.3. General procedure for substituted benzoylamino-
methyltriethylammonium chlorides (6d,e)
evaporated to dryness, and the residue was purified by column
chromatography (n-hexane/EtOAc 4:1) to provide 9a–e.
The appropriate freshly synthesized substituted N-chloro-
methylbenzamide25(0.1 mol) dissolved in dry acetone (80 mL) was
added in one portion to a vigorously stirred solution of Et3N
(15.3 mL, 0.11 mol) in dry acetone (150 mL). After a white pre-
cipitate had formed, a further portion of acetone (100 mL) was
added and the mixture was stirred at room temperature for 1 h. The
white crystalline product was filtered off, and washed with acetone
(2ꢃ25 mL). Compounds 6d,e were used without further purifica-
tion. Small samples were recrystallized from CHCl3–acetone for
analytical investigations.
4.5.1. 2-Benzoylaminomethylthio-1H-indole (9a)
A white crystalline powder, mp: 147–148 ꢀC (mp:19 146–148 ꢀC),
yield 76%; Rf (n-hexane/EtOAc 4:1) 0.12. Analytical data are iden-
tical with the previously published results.19
4.5.2. 2-(4-Chlorobenzoylaminomethylthio)-1H-indole (9b)
A
white crystalline powder, mp: 116–117 ꢀC, yield 84%.
[MþH]þ¼317. Anal. Calcd for C16H13ClN2OS (316.81): C, 60.66; H,
4.14; N, 8.84; S, 10.12. Found: C, 60.82; H, 4.32; N, 8.92; S, 10.23; Rf
(n-hexane/EtOAc 4:1) 0.12.
4.3.1. 2-Chlorobenzoylaminomethyltriethylammonium
chloride (6d)
A white crystalline powder, mp: 122–125 ꢀC (decomp.), yield
82%. [MþH]þ¼269. Anal. Calcd for C14H22Cl2N2O (305.24): C, 55.09;
H, 7.26; N, 9.18. Found: C, 54.87; H, 7.37; N, 9.08.
4.5.3. 2-(4-Methylbenzoylaminomethylthio)-1H-indole (9c)
A
white crystalline powder, mp: 117–118 ꢀC, yield 79%.
[MþH]þ¼297. Anal. Calcd for C17H16N2OS (296.39): C, 68.89; H,
5.44; N, 9.45; S, 10.82. Found: C, 68.82; H, 5.61; N, 9.49; S, 10.68; Rf
(n-hexane/EtOAc 4:1) 0.12.
4.3.2. 2-Methylbenzoylaminomethyltriethylammonium
chloride (6e)
A white crystalline powder, mp: 102–105 ꢀC (decomp.), yield
58%. [MþH]þ¼249. Anal. Calcd for C15H25ClN2O (284.82): C, 63.25;
H, 8.85; N, 9.84. Found: C, 63.11; H, 9.02; N, 9.91.
4.5.4. 2-(2-Chlorobenzoylaminomethylthio)-1H-indole (9d)
A
white crystalline powder, mp: 59–62 ꢀC, yield 81%.
[MþH]þ¼317. Anal. Calcd for C16H13ClN2OS (316.81): C, 60.66; H,
4.14; N, 8.84; S, 10.12. Found: C, 60.83; H, 4.05; N, 8.69; S, 9.92; Rf
(n-hexane/EtOAc 4:1) 0.07.
4.4. General procedure for the preparation of substituted 3-
benzoylaminomethylthio-1H-indoles (7d,e) from 1H-indole-
3-thiol (5) and substituted benzoylaminomethyltri-
ethylammonium chlorides (6d,e)
4.5.5. 2-(2-Methylbenzoylaminomethylthio)-1H-indole (9e)
A
white crystalline powder, mp: 97–99 ꢀC, yield 69%.
[MþH]þ¼297. Anal. Calcd for C17H16N2OS (296.39): C, 68.89; H,
5.44; N, 9.45; S, 10.82. Found: C, 69.02; H, 5.59; N, 9.62; S, 10.77; Rf
(n-hexane/EtOAc 4:1) 0.12.
A mixture of 1H-indole-3-thiol 5 (3 g, 20.1 mmol), the corre-
sponding substituted benzoylaminomethyltriethylammonium
chloride (6d,e) (22.1 mmol) and Et3N (1.2 mL, 8.6 mmol) in CHCl3
(50 mL) was refluxed for 2 h. The organic phase was then extracted
with H2O (2ꢃ50 mL). The white precipitate formed in the second
extraction was filtered off, and washed with H2O (2ꢃ15 mL) and
CHCl3 (5 mL). The white crystalline powder was dissolved in CHCl3
(60 mL)þMeOH (2 mL). The organic layer was extracted with H2O
(30 mL), dried (Na2SO4), and evaporated to provide 7d,e.
4.6. Preparation of substituted 2-benzoylaminomethylthio-
1H-indoles (9b–e) from 1,3-dihydro-2H-indole-2-thione (8)
and substituted benzoylaminomethyltriethylammonium
chlorides (6b–e)
A mixture of 1,3-dihydro-2H-indole-2-thione 8 (1 g, 6.7 mmol),
the corresponding substituted benzoylaminomethyltriethyl-
ammonium chlorides (6b–e) (7.4 mmol) and Et3N (0.8 mL,
5.7 mmol) in CHCl3 (20 mL) was refluxed for 2 h. The organic phase
was then extracted with H2O (2ꢃ40 mL), dried (Na2SO4) and
evaporated, and the residue was purified by column chromato-
graphy (CHCl3/ethyl acetate 9:1) to provide 9b–e.
The analytical data on 9b–e were identical to those given above;
9b: yield 91%, Rf (CHCl3/ethyl acetate 9:1) 0.21; 9c: yield 78%, Rf
(CHCl3/ethyl acetate 9:1) 0.23; 9d: yield 64%, Rf (CHCl3/ethyl acetate
9:1) 0.25; 9e: yield 86%, Rf (CHCl3/ethyl acetate 9:1) 0.25.
4.4.1. 3-(2-Chlorobenzoylaminomethylthio)-1H-indole (7d)
A white crystalline powder, mp: 129–130 ꢀC (from chloroform),
yield 93%. [MþH]þ¼317. Anal. Calcd for C16H13ClN2OS (316.81): C,
60.66; H, 4.14; N, 8.84; S, 10.12. Found: C, 60.50; H, 4.17; N, 8.98; S,
9.96.
4.4.2. 3-(2-Methylbenzoylaminomethylthio)-1H-indole (7e)
A white crystalline powder, mp: 146–149 ꢀC (from chloroform),
yield 90%. [MþH]þ¼297. Anal. Calcd for C17H16N2OS (296.39): C,
68.89; H, 5.44; N, 9.45; S, 10.82. Found: C, 68.97; H, 5.50; N, 9.65; S,
10.99.
4.7. General procedure for the preparation of 2-thiobenzo-
ylaminomethylthio-1H-indoles (10a–e)
4.5. Preparation of substituted 2-benzoylaminomethylthio-
1H-indoles (9a–e) from substituted 3-benzoylamino-
methylthio-1H-indoles (7a–e)
To a solution of substituted 2-benzoylaminomethylthio-1H-in-
doles (9a–e) (4.0 mmol) in THF (60 mL), Lawesson’s reagent (0.96 g,
2.4 mmol) and Et3N (0.05 mL) were added in one portion. The re-
action mixture was then heated under reflux for 5 h. After the ad-
dition of Et3N (1 mL) and evaporation, the residue was purified by
column chromatography, using n-hexane/EtOAc 4:1 containing
0.25% Et3N as eluent, to give 10a–e.
To intensively stirred TfOH (1 mL), the well-powdered appro-
priate 3-benzoylaminomethylthio-(1H)-indole (7a–e) (0.5 g) was
added portionwise over a period of 10–15 min at room tempera-
ture. If dissolution was not complete, the undissolved compound
was dissolved by adjusting the mixture with a glass rod. The re-
action mixture was then heated and stirred at 45 ꢀC for 30 min,
followed by the addition of EtOAc (20 mL). The organic layer was
extracted with H2O (20 mL), 5% NaHCO3 solution (20 mL), and brine
(10 mL). The organic phase was dried (Na2SO4), filtered, and
4.7.1. 2-Thiobenzoylaminomethylthio-1H-indole (10a)
A yellow oil, yield 56%. [MþH]þ¼299. Anal. Calcd for C16H14N2S2
(298.43): C, 64.39; H, 4.73; N, 9.39; S, 21.49. Found: C, 64.61; H,
4.65; N, 9.41; S, 21.65; Rf (n-hexane/EtOAc 4:1) 0.27.

1480
P. Csomo´s et al. / Tetrahedron 65 (2009) 1475–1480
4.7.2. 2-(4-Chlorothiobenzoylaminomethylthio)-1H-indole (10b)
4.8.5. 2,9-Dihydro-4-(2-methylphenyl)-1,3-thiazino[6,5-b]-
indole (11e)
A yellow crystalline powder,þmp: 177–179 ꢀC (iodide salt mp:
263–266 ꢀC), yield 35%. [MþH] ¼279. Anal. Calcd for C17H14N2S
(278.37): C, 73.35; H, 5.07; N, 10.06; S, 11.52. Found: C, 73.48; H,
5.27; N, 10.14; S, 11.64.
A
yellow crystalline powder, mp: 101–103 ꢀC, yield 81%.
[MþH]þ¼333. Anal. Calcd for C16H13ClN2S2 (332.87): C, 57.73; H,
3.94; N, 8.42; S, 19.27. Found: C, 57.91; H, 3.84; N, 8.40; S, 19.45; Rf
(n-hexane/EtOAc 4:1) 0.29.
4.7.3. 2-(4-Methylthiobenzoylaminomethylthio)-1H-indole (10c)
A light-green crystalline powder, mp: 108–111 ꢀC, yield 68%.
[MþH]þ¼313. Anal. Calcd for C17H16N2S2 (312.45): C, 65.35; H, 5.16;
N, 8.97; S, 20.53. Found: C, 65.41; H, 5.23; N, 8.81; S, 20.74; Rf
(n-hexane/EtOAc 4:1) 0.23.
Acknowledgements
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA) for financial support. They are in-
´
debted to Dr. M. Juhasz for helpful discussions and the MS spectra
4.7.4. 2-(2-Chlorothiobenzoylaminomethylthio)-1H-indole (10d)
´
measurements, and to Mrs. E. Juhasz Dinya for excellent technical
A
yellow oil, yield 72%. [MþH]þ¼333. Anal. Calcd for
assistance.
C16H13ClN2S2 (332.87): C, 57.73; H, 3.94; N, 8.42; S, 19.27. Found: C,
57.62; H, 3.78; N, 8.40; S, 19.35; Rf (n-hexane/EtOAc 4:1) 0.15.
References and notes
4.7.5. 2-(2-Methylthiobenzoylaminomethylthio)-1H-indole (10e)
A light-green oil, yield 54%. [MþH]þ¼313. Anal. Calcd for
C17H16N2S2 (312.45): C, 65.35; H, 5.16; N, 8.97; S, 20.53. Found: C,
65.31; H, 4.92; N, 9.14; S, 20.70; Rf (n-hexane/EtOAc 4:1) 0.26.
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4.8. General procedure for the preparation of 2,9-dihydro-4-
aryl-1,3-thiazino[6,5-b]indole (11a–e)
A solution of 10a–e (0.5 g) and methyl iodide (0.5 mL) in acetone
(15 mL) and a catalytic amount of 4-dimethylaminopyridine was
heated to reflux for 5 h under an argon atmosphere with protection
from light (Al foil). The acetone solution was then concentrated
under reduced pressure. To the residue, EtOH (0.1 mL) and Et2O
(10 mL) were added to furnish the iodide salt of 11a–e as a yellow
crystalline powder. After filtration, the crystals were washed with
cold acetone (2ꢃ2 mL), and recrystallized from EtOH/Et2O. The
crystals were dissolved in H2O (20 mL) and a small amount of
MeOH (until complete dissolution), CHCl3 (15 mL) was added and
the mixture was neutralized by the portionwise addition of 10%
KOH solution. The organic layer was separated, washed with H2O
(10 mL), dried (Na2SO4) and evaporated. After trituration with
n-hexane, 11a–e were obtained as yellow crystalline powders.
4.8.1. 2,9-Dihydro-4-phenyl-1,3-thiazino[6,5-b]indole (11a)
A yellow crystalline powder,þmp: 209–211 ꢀC (iodide salt mp:
260–263 ꢀC), yield 58%. [MþH] ¼265. Anal. Calcd for C16H12N2S
(264.35): C, 72.70; H, 4.58; N, 10.60; S, 12.13. Found: C, 72.91; H,
4.63; N, 10.74; S, 12.01.
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}
´
´
´
´
13. Fodor, L.; Szabo, J.; Szucs, E.; Bernath, G.; Sohar, P.; Tamas, J. Tetrahedron 1984,
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4.8.2. 2,9-Dihydro-4-(4-chlorophenyl)-1,3-thiazino[6,5-b]-
indole (11b)
A yellow crystalline powder, mp: 245–247 ꢀC (iodide salt mp:
256–258 ꢀC), yield 62%. [MþH]þ¼299. Anal. Calcd for C16H11ClN2S
(298.79): C, 64.32; H, 3.71; N, 9.38; S,10.73. Found: C, 64.11; H, 3.75;
N, 9.47; S, 10.86.
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´
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indole (11c)
A yellow crystalline powder,þmp: 227–229 ꢀC (iodide salt mp:
254–257 ꢀC), yield 65%. [MþH] ¼279. Anal. Calcd for C17H14N2S
(278.37): C, 73.35; H, 5.07; N, 10.06; S, 11.52. Found: C, 73.18; H,
5.26; N, 9.92; S, 11.65.
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´
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A yellow crystalline powder, mp: 146–148 ꢀC (iodide salt mp:
257–259 ꢀC), yield 57%. [MþH]þ¼299. Anal. Calcd for C16H11ClN2S
(298.79): C, 64.32; H, 3.71; N, 9.38; S, 10.73. Found: C, 64.27; H,
3.87; N, 9.46; S, 10.81.
´
´
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