Synthesis of 4-thiaharmalan analogue 4-aryl-1,3-thiazino[5,6-b]indole derivatives by prevention of rearrangements to position two of the indole moiety

Article abstract of DOI:10.1016/j.tet.2008.07.014

An efficient and selective non-acidic protocol has been developed for the synthesis of derivatives of a new ring system: 4-aryl-1,3-thiazino[5,6-b]indole, a 4-thiaharmalan analogue. The convenient amidomethylation of indole-3-thiol (5) afforded 3-benzoylaminomethylthio-1H-indole (7a), with ortho-amidomethylated 2-benzoylamino-methyl-3-benzoylaminomethylthio-1H-indole (8) as side product. Following the Bischler-Napieralski reaction of 7a the rearranged 2-benzoylaminomethylthio-1H-indole 11 could be isolated. In order to prevent such rearrangements the target thiazinoindoles were prepared via 3-thiobenzoylaminomethylthioindole (13) via a modified Bischler-Napieralski reaction.

Full text of DOI:10.1016/j.tet.2008.07.014

Tetrahedron 64 (2008) 8646–8651
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4-thiaharmalan analogue 4-aryl-1,3-thiazino[5,6-b]indole derivatives
by prevention of rearrangements to position two of the indole moiety
a
,
,
b
,
a
c
c
Peter Csomos b, Lajos Fodor a , Gabor Bernath , Antal Csampai , Pal Sohar
*
´
´
´
´
´
´
´
a Institute of Pharmaceutical Chemistry, University of Szeged, and Organic Catalysis and Stereochemistry Research Group of the Hungarian
Academy of Sciences, H-6701, PO Box 427, Hungary
b Central Laboratory, County Hospital, H-5701 Gyula, PO Box 46, Hungary
c
´
´
Institute of Chemistry, Eo¨tvo¨s Lorand University, and Protein Modelling Research Group, Hungarian Academy of Sciences and Eo¨tvo¨s Lorand
University, PO Box 32, H-1518 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and selective non-acidic protocol has been developed for the synthesis of derivatives of
a new ring system: 4-aryl-1,3-thiazino[5,6-b]indole, a 4-thiaharmalan analogue. The convenient ami-
domethylation of indole-3-thiol (5) afforded 3-benzoylaminomethylthio-1H-indole (7a), with ortho-
amidomethylated 2-benzoylamino-methyl-3-benzoylaminomethylthio-1H-indole (8) as side product.
Following the Bischler–Napieralski reaction of 7a the rearranged 2-benzoylaminomethylthio-1H-indole
11 could be isolated. In order to prevent such rearrangements the target thiazinoindoles were prepared
via 3-thiobenzoylaminomethylthioindole (13) via a modified Bischler–Napieralski reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 April 2008
Received in revised form 18 June 2008
Accepted 3 July 2008
Available online 8 July 2008
Keywords:
Amidomethylation
4-Thiaharmalan
Thiazino[5,6-b]indole
Bischler–Napieralski reaction
1. Introduction
lines.6 A series of 2-alkyl- or arylimino-1,3-thiazino[5,4-b]indol-4-
one derivatives (2, Fig. 1) are also pharmacologically interesting;
Synthetic interest in compounds containing an indole core has
been fuelled by the wide range of indole derivatives, which occur in
nature and by the biological activity of many natural and synthetic
indole derivatives. The family of indole compounds includes a huge
number of pharmaceuticals, alkaloids and potentially therapeutic
agents. Accordingly, there is a continuous demand for novel syn-
thetic procedures for indole alkaloid analogues and indoles con-
densed with different heterocycles.1 Although there are natural
phytoalexins with 1,3-thiazinoindoles condensed at bond b of the
indole skeleton, few synthetic indole compounds of this type are
known.2 Phytoalexins are antimicrobial substances formed in
plants in response to pathogen attack or physical or chemical stress,
probably as a result of the de novo synthesis of enzymes.3 Since
Takasugi et al. isolated the first cruciferous phytoalexins, among
them cyclobrassinin (1) (2-methylthio-thiazino[6,5-b]indole, Fig. 1)
from Chinese cabbage,4 increasing attention has been paid to 1,3-
thiazino[6,5-b]indole derivatives. Approximately 30 phytoalexins
are known so far in cruciferous plants, of which six of them are
thiazinoindoles.5 Cyclobrassinin, the most valuable of these com-
pounds, exerts an antiproliferative effect against human cancer cell
they inhibit human leukocyte elastase and a
-chymotrypsin.7
We recently prepared 2-methylthio-1,3-thiazino[5,6-b]indole
(isocyclobrassinin) and its 2-benzylthio analogue (3, Fig. 1), which
exerted good in vitro antiproliferative effects on cervical adeno-
carcinoma (HeLa), breast adenocarcinoma (MCF7) and squamous
skin carcinoma (A431) cell lines. For the investigation of structure–
activity relationships, further 2-aryl-1,3-thiazino[5,6-b]indole
analogues were synthesized. The highest cytotoxic effect was dis-
played by 2-phenylimino-1,3-thiazino[5,6-b]indole, which dem-
onstrated inhibitory activity on the above three cell lines
comparable to that of cisplatin.8
Subsequent to our recent investigations on 1,3-thiazinoindole
derivatives2,8,9 and the chemistry of sulfur- and nitrogen-contain-
ing condensed-skeleton heterocycles,10–13 we set out to devise an
efficient route for the synthesis of new 4-aryl-1,3-thiazino[5,6-
b]indoles. The formation of positional isomers of possible 1,3-
thiazinoindoles is a great challenge,2 because counterparts of this
isomer are analogues of the b-carboline indole alkaloid harmalan
(4, Fig. 1).
2. Results and discussion
The planned route for the synthesis of the target molecule, 4-
aryl-1,3-thiazino[5,6-b]indole, was via the Bischler–Napieralski
* Corresponding author. Tel.: þ36 66 463763; fax: þ36 66 526539.
E-mail address: fodor@pandy.hu (L. Fodor).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.014

P. Csomo´s et al. / Tetrahedron 64 (2008) 8646–8651
8647
H
N
of decomposed non-separable products.23 In polyphosphoric acid
(PPA) at 100 ꢀC, an interesting product, 2-benzamidomethylthio-
indole (11), was isolated in low yield from the reaction mixture.
After optimization of the reaction conditions, treatment with poly-
phosphoric acid at 60 ꢀC for 20 min led to 11 in good yield
(Scheme 2). This type of reaction was examined in a few cases
previously for 3-substituted indole thioethers by Ottenheijm
et al.24,25 An extensive series of elegant experiments were per-
formed by Hamel et al. for the sulfenylation of indole derivatives,
including reactions relating to the mechanism of isomerization of
3-indolyl sulfides to 2-indolyl sulfides.26,27 They found evidence for
a complex intermolecular process in polyphosphoric acid. Although
7a is not a simple thioether, the mechanism is most probably the
same in our case. For verification of the structure of 2-benzami-
domethylthioether (11), this compound was also prepared from
indole-2-thione (9) and benzamidomethyltriethylammonium
chloride19 (10a) (Scheme 2). To the best of our knowledge, this is
the first example of the selective amidomethylation of the sulfur of
a thioamide functional group.
N
R1
N
S
N
H
SMe
R2
N
H
S
S
O
2
1
R1 = alkyl or aryl
N
N
N
H
N
H
3
4
R
2 = alkylthio or arylimino
Figure 1. 1,3-Thiazinoindole derivatives.
reaction of 3-benzamidomethylthioindole 7a (Scheme 1). However,
different methodologies are available to introduce a sulfur moiety
at position 3 of the indole ring.14–16 In our case, indole-3-thiol (5)
proved to be the ideal starting material.17 For the construction of
the benzamidomethylthioether core, different agents have been
utilized in the literature. N-Benzotriazol-1-ylmethylamides react
readily with a variety of thiols.18 In some cases, the amidoalkylation
of thiols is possible with triethylaminomethylacylamides.19 The
most widely used and readily available amidomethylating de-
rivatives are hydroxymethylacylamides, which have been applied
successfully for the formation of thioethers.20 In the present case,
the reaction of indole-3-thiol with N-hydroxymethylbenzamide
under mild acidic conditions gave two products, which could be
separated by fractionated crystallization. As the major product, 3-
benzoylaminomethylthioindole 7a was obtained from chloroform
in good yield. On dilution of the evaporation residue with ethanol,
the 2-benzoylaminomethyl derivative 8 was isolated as minor
product. The latter compound was most probably formed by
a Tscherniak–Einhorn reaction; under the mildly acidic conditions,
the ortho-amidomethylation of the indole moiety took place. For
the reaction of 7a under classical Bischler–Napieralski conditions,
several solvents were examined. In the presence of phosphorus
oxychloride, the reaction mixture gave different non-separable
products: decomposition occurred. Several modified Bischler–
Napieralski reactions were also tried. Hell et al. recently developed
an environmentally friendly, mild and efficient Ersorb 4, small-
pore-size zeolite-catalysed variation of the Bischler–Napieralski
reaction to obtain dihydroisoquinoline derivatives.21 Unfortunately,
in our case under similar conditions, no reaction occurred.
H
N
S
PPA
O
O
60 °C
20 min.
N
H
S
N
H
N
H
11
7a
CHCl3, Et3N
Δ, 2 h
O
ClEt3N
N
H
+
N
H
S
10a
9
Scheme 2.
Finally, the selective benzamidomethylation of indole-3-thiol (5)
was performed under basic conditions with substituted benzoyla-
minomethyltriethylammonium chlorides (10a–c) obtained from
chloromethylbenzamides. In chloroform at reflux in the presence of
triethylamine, 7a–c were obtained in excellent yields.
For the preparation of 1-methyl-3,4-dihydro-b-carboline de-
rivatives, mild, non-acidic conditions were applied by Ishida et al.28
This modified Bischler–Napieralski reaction involves the treatment
of a thioamide moiety with an alkyl halide. In order to avoid
acidic conditions in the Bischler–Napieralski reaction, thio-
benzamidomethyl derivatives 13a–c were prepared by the reaction
of the corresponding amides 7a–c and Lawesson’s reagent. During
this reaction under reflux conditions in tetrahydrofuran, the partial
decomposition of 7a–c takes place, especially in the case of p-
chloro-substituted 7b, N-mercaptomethyl-p-chlorothiobenzamide
disulfide 12b could be isolated from the reaction mixture as de-
composition product, which exist in dimethylsulfoxide solution as
a 1:2 mixture of two possible rotamers. After the addition of tri-
ethylamine to the sulfur-exchange reaction mixture, at lower
temperature the decomposition was not observed, and thioamides
13a–c could be prepared in relatively good yields. Treatment
of thiobenzamidomethyl derivatives 13a–c with methyl iodide in
acetone at reflux gave thiazinoindole derivatives 14a–c via a thio-
iminium salt intermediate (Scheme 3).
Similarly, no reaction was observed with the triphenylphos-
phine–carbon tetrachloride system.22 Harsher conditions, such as
phosphorus pentachloride in dichloromethane also gave a mixture
O
SH
HO
N
H
+
N
H
6
5
HCl/EtOH
Δ , 2 min. - r.t., 5 h
H
N
H
N
S
S
O
O
+
H
N
H
N
N
H
Insummary, anovelmethodhasbeen developedforthesynthesis
of derivatives of a new ring system, 4-aryl-1,3-thiazino[5,6-b]indole,
a 4-thiaharmalan analogue with potential pharmacological activity.
O
7a
8
Scheme 1.

8648
P. Csomo´s et al. / Tetrahedron 64 (2008) 8646–8651
O
detected, whereas for 7a–c only one. The mobile NH (or OH) hy-
SH
drogen of the polarized amide or iminohydrin group is capable of
forming strong H-bonds, which leads to an extremely diffuse, un-
Cl(Et)3N
N
H
+
N
H
X
identifiable nNH (nOH) band. The amide-I band has a strikingly low
frequency for 7a–c (w1610 cmꢁ1), while for 10b,c the values are in
the expected region (1672 and 1664 cmꢁ1). This supports the
strong polarization of the amide group in 7a–c.
5
10a-c
CHCl3, Et3N
To clear this problem we carried out 15N,1H-HMQC and 2D-COSY
measurements with 7a and 13a, respectively. The analogous N,H-
correlations for 7a proved that an NH/OH change (tautomeriza-
tion) did not happen and the COSY spectrum of 13a confirmed the
NH(1), H-2 interaction. The absence of the split of NH signal in 13-
type compounds is due to exchange processes of the H’s in this
group resulting in broadening of the NH signal and thus the
merging of the two split lines.
Δ, 2 h
X
S
H
N
Lawesson's
reagent
S
N
H
S
O
THF, Δ
Cl
N
H
2
12b
7a-c
The condensed thiazine ring-containing compounds 14a–c give
singlet methylene signals in the 1H NMR spectra, while the open-
chain analogues with CH2NH group give doublet CH2 (and singlet
NH) signals, split by 6.5ꢂ0.5 Hz, due to the vicinal coupling of the
hydrogens in this moiety. Naturally, numerous other changes also
provide evidence of the presumed condensed three-ring system.
For example, instead of the 13C NMR line of the thioamide carbon
(at 197.3ꢂ0.8 ppm for 13-type compounds), 14a–c have the C]N
carbon signal at 159.6ꢂ0.5 ppm. The H-2 singlet of 13a–c
(7.56ꢂ0.02 ppm) is absent in the 1H NMR spectra of 14a–c.
THF, Et3N
50 °C, 5 h
Lawesson's
reagent
X
H
N
MeI
S
X
S
acetone
S
N
cat. DMAP
Δ, 10 h
N
H
N
H
13a-c
14a-c
4. Experimental
4.1. General
a: X = H; b: X = Cl; c: X = Me
Scheme 3.
Melting points were determined on a Kofler micromelting ap-
paratus and are uncorrected. Elemental analyses were performed
with a Perkin–Elmer 2400 CHNS elemental analyser. Merck Kie-
selgel 60F254 plates were used for TLC and Merck silica gel 60
(0.063–0.200) for column chromatography. Indol-2-one was
purchased from Fluka. Indole-3-thiol,17 benzoylaminomethyl-
triethylammonium chloride,19 hydroxymethylbenzamides29 and N-
chloromethylbenzamides30 were prepared by literature methods.
ESI mass spectra were obtained with a Finnigan MAT 95S double
focussing sector-field instrument. Acetonitrile solutions of com-
The reaction of indole-3-thiol and N-hydroxymethylbenzamide
furnished 3-benzamidomethylthioindole (7a) and ortho-amidome-
thylated 2-benzoylaminomethyl-3-benzoylaminomethylthioindole
(8). The Bischler–Napieralski reaction of 7a was performed under
different conditions. Interestingly, under acidic conditions, the 3-
benzoylaminomethylthio group rearranged to position 2, affording
2-benzoylaminomethylthioindole (11) in good yield. Further
investigations on the possible mechanism of this reaction are cur-
rently in progress. The target thiazinoindole compounds 14a–c were
prepared via 3-thiobenzoylaminomethylthioindole (13a–c) in
a modified, non-acidic Bischler–Napieralski reaction.
pounds were infused into the ESI at a constant flow of 100 mL/min
(water–acetonitrile 50:50 containing 0.1% acetic acid) through
a plastic capillary. The ions were produced by using N2 as sheath
gas at 2 psi, with a spray voltage of 2.5 kV and a capillary temper-
ature of 210 ꢀC. Poly(propylene glycol) solution was used for the
calibration. 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
spectrometer at 500 (1H) or 125 (13C) MHz, with TMS (dTMS¼0 ppm)
as internal reference, and the deuterium signal of the solvent as the
lock. Assignments were supported by DEPT (except for 7c and 14a),
HMQC (7a, 8, 11 and 14a), HMBC (8, 11 and 14a), for 7a also by 2D-
COSY measurements. DEPT spectra were run in a standard manner,
3. Structure
The structures of the new compounds in this paper follow
straightforwardly from the IR and NMR spectral data (Tables 1 and
2 in Supplementary data). Only a few remarks are necessary.
An interesting difference was observed in the 1H NMR spectra of
7a–c and 13a–c. The H-2 signal of the thioamides 13a–c is a singlet,
while it is a doublet for 7a–c, the amide analogues.
In view of the same solvent (DMSO-d6) and the identical
structure of the indole moiety in 7 and 13, it is conceivable that this
splitting isn’t the consequence of spin–spin coupling with the NH in
position 1. Furthermore, the NH signal is a singlet for 7a–c and the
splitting of the H-2 signal (2.5 Hz) is smaller than would be
expected for a vicinal coupling.
using only the
Q
¼135ꢀ pulse to separate CH/CH3 and CH2 lines
phased ‘up’ and ‘down’, respectively. 2D-HMQC and 2D-HMBC
spectra were obtained by using the standard Bruker pulse
programs.
The strong polarization of the amide group or the shift of the
amide–iminohydrin tautomeric equilibrium towards the latter
form may lead to the existence of two geometric isomers of the
iminohydrin and consequently to two different environments for
H-2. On the other hand, a similar duplication for e.g., the methylene
signal was not observable.
4.2. Preparation of 3-benzoylaminomethylthio-1H-indole
(7a) and 2-benzoylamino-methyl-3-benzoylaminomethyl-
thio-1H-indole (8) from 1H-indole-3-thiol (5) and N-
hydroxymethylbenzamide (6)
Indole-3-thiol
(1.49 g,
10 mmol)
and
N-hydroxy-
This presumption seems to be supported by the IR spectra. For
methylbenzamide (1.51 g, 10 mmol) were dissolved in ethanol
(5 mL) and to the solution was added a saturated solution of
13a–c, two broadened, but well identifiable
nNH bands are

P. Csomo´s et al. / Tetrahedron 64 (2008) 8646–8651
8649
hydrogen chloride in ethanol (2 mL). The mixture was heated to its
4.3.2. 4-Methylbenzoylaminomethyltriethylammonium
chloride (10c)
A white crystalline powder, mp 180–183 ꢀC (dec), yield 64%. nmax
boiling point, allowed to cool and left to stand for 5 h at ambient
temperature. The reaction mixture was then poured onto ice
(100 g), extracted exhaustively with ethyl acetate (4ꢃ80 mL), and
the extract was dried and evaporated. The residue was taken up in
chloroform (5 mL), from which compound 7a separated as a white
crystalline powder (0.78 g). The mother liquor from the separation
of 7a was evaporated to dryness and the residue was taken up in
ethanol (2 mL). The ethanol solution slowly deposited 8 as a white
crystalline powder (0.11 g).
(KBr disc) 3499 and 3486 (nNH), 1664 (nC]O), 836 (g
CArH). 1H NMR
(DMSO-d6)
d
: 9.85 (1H, br, NH), 7.98 (2H, J¼8.0 Hz, H-20,60)
*
, 7.31
(2H, m, H-30,50)
*
, 4.73 (2H, s, NCH2N), 3.24 (6H, q, J¼7.1 Hz, CH2CH3),
*
2.37 (3H, s, CH3), 1.27 (9H, t, J¼7.1 Hz, CH2CH3); part of an AA0BB0
spectrum; 13C NMR (DMSO-d6) : 169.3 (C]O), 138.2 (C-40), 130.5
d
(C-10), 129.8** (C-30,50), 129.3** (C-20,60), 61.0 (NCH2N), 51.2
(CH2CH3), 21.9 (CH3), 8.4 (CH2CH3); **reversed assignments are also
possible. [MþH]þ¼249. Anal. Calcd for C15H25ClN2O (284.82): C,
63.25; H, 8.85; N, 9.84. Found: C, 63.44; H, 8.69; N, 9.88.
4.2.1. 3-Benzoylaminomethylthio-1H-indole (7a)
A white crystalline powder, mp 121–123 ꢀC (from chloroform),
yield 28%. nmax (KBr disc) 3276 and 3200–2500 (
740 ( CArH, indole and monosubstituted benzene ring), 690 (
CAr, monosubstituted benzene ring). 1H NMR (DMSO-d6)
: 11.40
(1H, br, indole-NH), 9.04 (1H, br, CONH), 7.79 (2H, d, H-20,60)
, 7.63
(1H, d, H-4), 7.52 (1H, t, H-40)
, 7.49 (1H, d, J¼2.5 Hz, H-2), 7.44 (2H,
n
NH), 1620 (
n
C]O),
4.4. Preparation of 2-benzoylaminomethylthio-1H-
indole (11)
g
gCAr
d
*
4.4.1. Preparation of 2-benzoylaminomethylthio-1H-indole (11)
from 3-benzoylaminomethylthio-1H-indole (7a)
*
m, H-30,50)
*
, 7.41 (1H, d, H-7), 7.14 (1H, t, H-6), 7.05 (1H, t, H-5), 4.45
3-Benzoylaminomethylthio-1H-indole (7a) (0.5 g, 1.77 mmol)
was thoroughly mixed with polyphosphoric acid and heated at
60 ꢀC for 20 min. Water (10 mL) was added to the reaction mixture
and then was neutralized by the addition of a solution of 10% so-
dium carbonate. The aqueous phase was extracted with chloroform
(2ꢃ10 mL), and the organic phase was dried (sodium sulfate), fil-
tered and evaporated to dryness. The residue was triturated with
diethyl ether–n-hexane to give a light-grey crystalline powder,
which was recrystallized from diisopropyl ether.
*
(2H, d, J¼6.2 Hz, SCH2N); part of an AA0BB0C spectrum; 13C NMR
(DMSO-d6) d
: 166.7 (C]O), 137.3 (C-7a), 135.0 (C-10), 132.2 (C-40),
131.8 (C-2), 130.2 (C-3a), 129.1 (C-30,50), 128.1 (C-20,60), 122.6 (C-6),
120.4 (C-5),119.4 (C-4),112.8 (C-7),103.1 (C-3), 46.9 (CH2). MS (ESI):
[MþH]þ¼283. Anal. Calcd for C16H14N2OS (282.36): C, 68.06; H,
5.00; N, 9.92; S, 11.36. Found: C, 67.83; H, 5.21; N, 9.81; S, 11.47.
4.2.2. 2-Benzoylaminomethyl-3-benzoylaminomethylthio-
1H-indole (8)
A light-grey crystalline powder, mp 146–148 ꢀC, yield 68%. nmax
A white crystalline powder, mp 235–238 ꢀC (from ethanol, N,N-
(KBr disc) 3297 (
n
NH), 1629 (
n
C]O), 751 (
g
CArH, indole ring), 704
CArCAr, mono-
substituted benzene ring). 1H NMR (DMSO-d6)
d: 11.40 (1H, br, in-
dimethylformamide), yield 3%. nmax (KBr disc) 3286 (
1610 ( C]O), 732 ( CArH, indole and monosubstituted benzene
ring), 694 (
CArCAr, monosubstituted benzene ring). 1H NMR
(DMSO-d6)
n
NH),1641 and
(gCArH, monosubstituted benzene ring), 668 (g
n
g
g
dole-NH), 9.33 (1H, br, CONH), 7.87 (2H, d, J¼7.5 Hz, H-20,60)
*
, 7.54
d
: 11.30 (1H, br, indole-NH), 9.09 (1H, br s, CONH), 7.89–
(1H, t, H-40)
*
, 7.48 (1H, d, H-4), 7.47 (2H, m, H-30,50)
, 7.36 (1H, d, H-
*
7.39 (12H, overlapping m’s, H-4, H-7, H-20-60, H-200-600), 7.11 (1H, t,
7), 7.11 (1H, t, H-6), 7.00 (1H, t, H-5), 6.62 (1H, s, H-3), 4.78 (2H, d,
*
H-6), 7.04 (1H, t, H-5), 4.75 (2H, d, J¼5.3 Hz, CCH2N), 4.48 (2H, d,
J¼6.0 Hz, SCH2N); part of an AA0BB0C spectrum; 13C NMR (DMSO-
J¼6.2 Hz, SCH2N); 13C NMR (DMSO-d6)
d
: 167.2 (C]O, in Pos. 2),
d6) d
: 167.2 (C]O), 138.4 (C-7a), 134.7 (C-10), 132.4 (C-40), 129.2
166.9 (C]O), 142.4 (C-2), 136.6 (C-7a), 134.9 (C-100), 134.8 (C-10),
(C-30,50), 129.0 (C-2), 128.9 (C-3a), 128.3 (C-20,60), 122.5 (C-6), 120.4
(C-4), 120.1 (C-5), 111.9 (C-7), 108.1 (C-3), 46.8 (CH2). MS (ESI):
[MþH]þ¼283. Anal. Calcd for C16H14N2OS (282.36): C, 68.06; H,
5.00; N, 9.92; S, 11.36. Found: C, 68.18; H, 5.11; N, 9.94; S, 11.52.
132.2
*
(C-40 and C-400), 129.1 (C-30,50 and C-300,500), 128.3 (C-200,600),
*
128.1 (C-20,60), 122.6 (C-6), 120.5 (C-5), 119.2 (C-4), 112.6 (C-7), 101.2
(C-3), 46.9 (SCH2N), 36.0 (CH2 in Pos. 2); *overlapping lines.
[MþH]þ¼416. Anal. Calcd for C24H21N3O2S (415.51): C, 69.37; H,
5.09; N, 10.11; S, 7.72. Found: C, 69.19; H, 5.22; N, 9.97; S, 7.85.
4.4.2. Preparation of 2-benzoylaminomethylthio-1H-indole (11)
from 1,3-dihydro-2H-indole-2-thione (9) and benzoylaminomethyl-
triethylammonium chloride (7a)
4.3. General procedure for substituted benzoylamino-
methyltriethylammonium chlorides (10b,c)
A
mixture of 1,3-dihydro-2H-indole-2-thione
9
(1,0 g,
6.7 mmol), benzoylaminomethyltriethylammonium chloride (10a)
(2.0 g, 7.4 mmol) and triethylamine (0.8 mL, 5.7 mmol) in chloro-
form (20 mL) was heated at reflux for 2 h. The organic phase was
then extracted with water (2ꢃ40 mL), dried (sodium sulfate) and
evaporated, and the residue was purified by column chromato-
graphy (n-hexane–ethyl acetate 3:2) to provide 11. Yield: 91%
(analytical data identical to those given above).
To a vigorously stirred solution of triethylamine (15.3 mL,
110 mmol) in dry acetone (150 mL), freshly synthesized substituted
N-chloromethylbenzamide30 (100 mmol) dissolved in dry acetone
(80 mL) was added in one portion. A white precipitate formed
immediately. After the addition of a further portion of acetone
(100 mL), the mixture was stirred at rt for 1 h. The white precipitate
was filtered off, washed with acetone (2ꢃ25 mL) and recrystallized
from chloroform–acetone.
4.5. General procedure for the preparation of substituted 3-
benzoylaminomethylthio-1H-indoles (7a–c) from 1H-indole-
3-thiol (5) and substituted benzoylaminomethyl-
triethylammonium chlorides (10a–c)
4.3.1. 4-Chlorobenzoylaminomethyltriethylammonium
chloride (10b)
A white crystalline powder, mp 151–154 ꢀC (dec), yield 73%. nmax
(KBr disc) 3490 and 3407 (
n
NH), 1672 (
n
C]O), 787 (
g
CArH). 1H NMR
A mixture of 1H-indole-3-thiol 5 (2.0 g, 13.4 mmol), the corre-
sponding substituted benzoylaminomethyltriethylammonium
chloride (10a–c) (14.7 mmol) and triethylamine (0.8 mL, 5.7 mmol)
in chloroform (30 mL) was heated at reflux for 2 h. The organic
phase was then extracted with water (2ꢃ40 mL). The white pre-
cipitate formed in the second extraction was filtered off, and
washed with water (2ꢃ10 mL) and chloroform (5 mL). The white
crystalline powder was dissolved in chloroform (50 mL)þmethanol
(DMSO-d6)
d
: 10.10 (1H, br, NH), 8.14 (2H, d, J¼8.5 Hz, H-20,60)
*
, 7.58
(2H, m, H-30,50)
*
, 4.74 (2H, s, NCH2N), 3.24 (6H, q, J¼7.1 Hz, CH2CH3),
1.27 (9H, t, J¼7.1 Hz, CH2CH3); *part of an AA0BB0 spectrum; 13C NMR
(DMSO-d6) d
: 168.5 (C]O), 138.2 (C-40), 132.1 (C-10), 131.3 (C-20,60),
129.3 (C-30,50), 60.9 (NCH2N), 51.2 (CH2CH3), 8.4 (CH2CH3).
[MþH]þ¼269. Anal. Calcd for C14H22Cl2N2O (305.24): C, 55.09; H,
7.26; N, 9.18. Found: C, 55.38; H, 6.99; N, 9.42.

8650
P. Csomo´s et al. / Tetrahedron 64 (2008) 8646–8651
(1 mL). The organic layer was extracted with water (20 mL), dried
(sodium sulfate) and evaporated to provide 7a–c.
4.6.2. 3-(4-Chlorothiobenzoylaminomethylthio)-1H-indole (13b)
A yellow crystalline powder, mp 95–97 ꢀC, yield 79%. nmax (KBr
disc) 3363 and 3328 (
nNH), 831 (gCArH, para-disubstituted benzene
4.5.1. 3-Benzoylaminomethylthio-1H-indole (7a)
ring), 756 (g d: 11.50 (1H, br,
CArH, indole ring). 1H NMR (DMSO-d6)
Yield: 89% (analytical data identical to those given above).
indole-NH), 10.80 (1H, br, CONH), 7.73 (2H, d, J¼8.3 Hz, H-20,60)
*
,
7.64 (1H, d, H-4), 7.58 (1H, s, H-2), 7.47 (3H, m, H-7, H-30,50)
, 7.18
*
4.5.2. 3-(4-Chlorobenzoylaminomethylthio)-1H-indole (7b)
(1H, t, H-6), 7.10 (1H, t, H-5), 4.88 (2H, d, J¼5.5 Hz, SCH2N); *part of
A white crystalline powder, mp 120–123 ꢀC (from chloroform),
an AA0BB0 spectrum; 13C NMR (DMSO-d6)
d: 196.5 (C]S), 140.2 (C-
yield 94%. nmax (KBr disc) 3269 (
para-disubstituted benzene ring), 741 (
NMR (DMSO-d6)
n
NH), 1610 (
CArH, indole ring). 1H
d: 11.40 (1H, br, indole-NH), 9.16 (1H, br, CONH),
n
C]O), 852 (
g
CArH,
10), 137.3 (C-7a), 136.6 (C-40), 132.3 (C-2), 130.3 (C-3a), 129.9 (C-
20,60),128.8 (C-30,50), 122.7 (C-6),120.6 (C-5),119.4 (C-4),113.0 (C-7),
102.9 (C-3), 52.9 (CH2). [MþH]þ¼333. Anal. Calcd for C16H13N2S2Cl
(332.87): C, 57.73; H, 3.94; N, 8.42; S, 19.27. Found: C, 57.56; H, 4.11;
N, 8.34; S, 19.52.
g
7.81 (2H, d, J¼8.5 Hz, H-20,60)
*
, 7.63 (1H, d, H-4), 7.51 (1H, d,
J¼2.5 Hz, H-2), 7.51 (2H, m, H-30,50)
*
, 7.42 (1H, d, H-7), 7.14 (1H, t,
*
H-6), 7.06 (1H, t, H-5), 4.46 (2H, d, J¼6.0 Hz, SCH2N); part of an
AA0BB0 spectrum; 13C NMR (DMSO-d6)
d
: 165.7 (C]O), 137.3 (C-
4.6.3. 3-(4-Methylthiobenzoylaminomethylthio)-1H-indole (13c)
A yellow crystalline powder, mp 133–135 ꢀC, yield 77%. nmax (KBr
40)**, 137.1 (C-7a)**, 133.7 (C-10), 132.0 (C-2), 130.2 (C-3a), 130.1
(C-20,60), 129.2 (C-30,50), 122.6 (C-6), 120.5 (C-5), 119.4 (C-4), 112.9
(C-7), 102.9 (C-3), 46.9 (CH2); **reversed assignments are also
possible. [MþH]þ¼317. Anal. Calcd for C16H13N2OSCl (316.81): C,
60.66; H, 4.14; N, 8.84; S, 10.12. Found: C, 60.78; H, 4.04; N, 8.62;
S, 10.24.
disc) 3382 and 3349 (nNH), 755 (g
CArH, indole ring). 1H NMR
(DMSO-d6) d: 11.40 (1H, br, indole-NH), 10.60 (1H, br, CONH), 7.64
(2H, d, J¼8.0 Hz, H-20,60)
*
, 7.63 (1H, d, H-4), 7.55 (1H, s, H-2), 7.44
(1H, d, H-7), 7.20 (2H, m, H-30,50)
, 7.17 (1H, t, H-6), 7.09 (1H, t, H-5),
*
*
4.86 (2H, d, J¼4.9 Hz, SCH2N), 2.33 (3H, s, CH3); part of an AA0BB0
spectrum; 13C NMR (DMSO-d6) : 197.7 (C]S), 141.8 (C-40), 138.8
d
4.5.3. 3-(4-Methylbenzoylaminomethylthio)-1H-indole (7c)
(C-10), 137.3 (C-7a), 132.2 (C-2), 130.2 (C-3a), 129.3 (C-30,50), 128.2
(C-20,60), 122.7 (C-6), 120.6 (C-5), 119.4 (C-4), 112.9 (C-7),103.1 (C-3),
52.9 (CH2), 21.7 (CH3). [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, 5.23;
N, 8.87; S, 20.71.
A white crystalline powder, mp 154–156 ꢀC (from chloroform),
yield 92%. nmax (KBr disc) 3260 (
para-disubstituted benzene ring), 737 (
n
NH), 1610 (
nC]O), 842 (gCArH,
g
CArH, indole ring). 1H NMR
(DMSO-d6) d: 11.40 (1H, br, indole-NH), 8.99 (1H, br, CONH), 7.71
(2H, d, J¼8.0 Hz, H-20,60)
, 7.63 (1H, d, H-4), 7.48 (1H, d, J¼2.5 Hz, H-
*
*
2), 7.42 (1H, d, H-7), 7.24 (2H, m, H-30,50)
, 7.14 (1H, t, H-6), 7.06 (1H,
4.7. General procedure for the preparation of 2,5-dihydro-4-
aryl-1,3-thiazino[5,6-b]indole (14a–c)
t, H-5), 4.46 (2H, d, J¼6.2 Hz, SCH2N), 2.35 (3H, s, CH3); *part of an
AA0BB0 spectrum; 13C NMR (DMSO-d6) : 166.6 (C]O), 142.1 (C-40),
d
137.3 (C-7a), 132.2 (C-10), 131.8 (C-2), 130.2 (C-3a), 129.7 (C-30,50),
128.2 (C-20,60), 122.6 (C-6),120.4 (C-5),119.4 (C-4), 112.8 (C-7),103.2
(C-3), 46.9 (CH2), 21.8 (CH3). [MþH]þ¼297. Anal. Calcd for
A solution of 13a–c (3.4 mmol), methyl iodide (1.0 mL,
16.1 mmol) and a catalytic amount of 4-dimethylaminopyridine
(DMAP) in acetone (15 mL) was heated at reflux for 10 h under an
argon atmosphere with protection from light. The acetone solution
was then concentrated under reduced pressure. To the residue,
ethanol and diethyl ether were added to furnish the iodide salt of
14a–c as a red crystalline powder. After filtration, the crystals were
washed with cold acetone (2ꢃ2 mL) and recrystallized from etha-
nol–diethyl ether. The crystals were dissolved in water (10 mL) and
a small amount of methanol (until complete dissolution), chloro-
form was added and the mixture was neutralized by the portion-
wise addition of 10% potassium hydroxide solution. The organic
layer was separated, washed with water, dried (sodium sulfate) and
evaporated. After trituration with n-hexane, 14a–c were obtained
as yellow crystalline powders.
C
17H16N2OS (296.39): C, 68.89; H, 5.44; N, 9.45; S, 10.82. Found: C,
68.95; H, 5.31; N, 9.27; S, 10.97.
4.6. General procedure for preparation of 3-
thiobenzoylaminomethylthio-1H-indoles (13a–c)
To a solution of substituted 3-benzoylaminomethylthio-1H-
indole (7a–c) (4.0 mmol) in tetrahydrofuran (40 mL), triethyl-
amine (0.36 mmol, 0.05 mL) and Lawesson’s reagent (0.96 g,
2.4 mmol) were added in one portion. The reaction mixture was
heated under reflux for 5 h. After the addition of more triethyl-
amine (1.0 mL) and evaporation, the residue was purified by
column chromatography, using n-hexane–ethyl acetate 4:1 con-
taining 0.25% triethylamine as eluent, to give 13a–c as a crystalline
powder after trituration with n-hexane and a few drops of diiso-
propyl ether.
4.7.1. 2,5-Dihydro-4-phenyl-1,3-thiazino[5,6-b]indole (14a)
A yellow crystalline powder, mp 181–183 ꢀC (dec), yield 54%.
nmax (KBr disc) 3200–2500 (
benzene ring), 718 ( CArH, indole ring), 697 (
substituted benzene ring). 1H NMR (DMSO-d6)
: 11.50 (1H, br, in-
dole-NH), 7.70 (2H, d, H-20,60) , 7.55 (3H, m, H-4, H-30,50)
, 7.53 (1H,
t, H-40)
, 7.46 (1H, d, H-7), 7.30 (1H, t, H-6), 7.14 (1H, t, H-5), 4.87
(2H, s, CH2); part of an AA0BB0C spectrum; 13C NMR (DMSO-d6)
n
NH), 748 (gCArH, monosubstituted
g
g
CArCAr, mono-
d
4.6.1. 3-Thiobenzoylaminomethylthio-1H-indole (13a)
*
*
A yellow crystalline powder, mp 114–116 ꢀC, yield 67%. nmax (KBr
*
*
disc) 3556 and 3406 (
n
NH), 770 (
g
CArH, monosubstituted benzene
CArCAr, monosubstituted
: 11.50 (1H, br, indole-NH),
d:
ring), 755 ( CArH, indole ring), 686 (
g
g
160.1 (C]N), 138.0 (C-10), 137.7 (C-7a), 131.1 (C-40), 129.6 (C-20,60),
129.4 (C-30,50), 127.6 (C-3), 126.1 (C-6), 124.9 (C-3a), 121.0 (C-5),
120.8 (C-4), 114.4 (C-2), 114.0 (C-7), 50.3 (CH2). [MþH]þ¼265. Anal.
Calcd for C16H12N2S (264.35): C, 72.70; H, 4.58; N, 10.60; S, 12.13.
Found: C, 72.75; H, 4.51; N, 10.54; S, 12.15.
benzene ring). 1H NMR (DMSO-d6)
d
10.70 (1H, br s, CSNH), 7.70 (2H, d, J¼7.5 Hz, H-20,60)
*
, 7.64 (1H, d, H-
4), 7.57 (1H, s, H-2), 7.48 (1H, t, H-40)
, 7.44 (1H, d, H-7), 7.40 (2H, m,
*
H-30,50)
SCH2N); *part of an AA0BB0C spectrum; 13C NMR (DMSO-d6)
*
, 7.17 (1H, t, H-6), 7.09 (1H, t, H-5), 4.85 (2H, d, J¼6.0 Hz,
: 198.1
d
(C]S), 141.7 (C-10), 137.3 (C-7a), 132.2 (C-40), 131.7 (C-2), 130.2 (C-
3a), 128.8 (C-30,50), 128.1 (C-20,60), 122.7 (C-6), 120.6 (C-5), 119.4 (C-
4), 112.9 (C-7), 103.0 (C-3), 52.8 (CH2). [MþH]þ¼299. Anal. Calcd for
4.7.2. 2,5-Dihydro-4-(4-chlorophenyl)-1,3-thiazino[5,6-b]-
indole (14b)
A yellow crystalline powder, mp 199–202 ꢀC (dec), yield 48%.
C
16H14N2S2 (298.42): C, 64.39; H, 4.73; N, 9.39; S, 19.27. Found: C,
nmax (KBr disc) 3200–2500 (
n
NH), 832 (
g
CArH, para-disubstituted
64.65; H, 4.63; N, 9.45; S, 19.39.
benzene ring), 734 ( d
g
CArH, indole ring). 1H NMR (DMSO-d6)
: 11.50

P. Csomo´s et al. / Tetrahedron 64 (2008) 8646–8651
8651
(1H, br, indole-NH), 7.71 (2H, J¼8.5 Hz, H-20,60)
*
, 7.59 (2H, m, H-
References and notes
30,50)
, 7.56 (1H, d, H-4), 7.45 (1H, d, H-7), 7.31 (1H, t, H-6), 7.13 (1H,
*
*
t, H-5), 4.87 (2H, s, CH2); part of an AA0BB0 spectrum; 13C NMR
1. Sundberg, R. J. Indoles; Academic: London, 1996.
´
´
´
2. Csomos, P.; Fodor, L.; Mandity, I.; Bernath, G. Tetrahedron 2007, 63, 4983–4989.
3. Dixon, R. A.; Lamb, C. J. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1990, 41,
339–367.
(DMSO-d6)
d
: 159.1 (C]N), 137.7 (C-7a), 136.7 (C-10)**, 135.9 (C-
40)**, 131.5 (C-20,60), 129.4 (C-30,50), 127.3 (C-3), 126.3 (C-6), 124.9 (C-
3a), 121.1 (C-5), 120.8 (C-4), 114.7 (C-2), 114.0 (C-7), 50.3 (CH2);
**reversed assignments are also possible. [MþH]þ¼299. Anal. Calcd
for C16H11ClN2S (298.79): C, 64.32; H, 3.71; N, 9.38; S, 10.73. Found:
C, 64.38; H, 3.87; N, 9.32; S, 10.85.
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indole (14c)
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A yellow crystalline powder, mp 188–191 ꢀC (dec), yield 57%.
nmax (KBr disc) 3200–2500 (
n
NH), 827 (
g
CArH, para-disubstituted
: 11.50
, 7.56 (1H, d, H-4),
9. Csomo´s, P.; Fodor, L.; Soha´r, P.; Berna´th, G. Tetrahedron 2005, 61, 9257–9262.
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benzene ring), 737 (g d
CArH, indole ring). 1H NMR (DMSO-d6)
(1H, br, indole-NH), 7.60 (2H, d, J¼8.0 Hz, H-20,60)
*
7.46 (1H, d, H-7), 7.30 (1H, t, H-6), 7.24 (2H, m, H-30,50)
*
, 7.13 (1H, t,
*
H-5), 4.87 (2H, s, CH2), 2.40 (3H, s, CH3); part of an AA0BB0 spec-
trum; 13C NMR (DMSO-d6) : 159.9 (C]N), 140.8 (C-40), 137.6 (C-
d
7a), 135.2 (C-10), 129.9 (C-30,50)**, 129.6 (C-20,60)**, 127.6 (C-3), 126.0
(C-6), 124.9 (C-3a), 121.0 (C-5), 120.7 (C-4), 114.2 (C-2), 114.0 (C-7),
50.3 (CH2), 21.8 (CH3); **reversed assignments are also possible.
[MþH]þ¼279. Anal. Calcd for C17H14N2S (278.37): C, 73.35; H, 5.07;
N, 10.06; S, 11.52. Found: C, 73.42; H, 5.14; N, 10.12; S, 11.67.
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The authors express their thanks to the Hungarian Scientific
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(E4a) zeolite samples, to Dr. M. Juhasz for the helpful discussions
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Supplementary data
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.014.