One-step ring-closure procedure for 4,5-dihydro-1,3-thiazino[5,4-b]indole derivatives with Lawesson's reagent. the fifth dihydro-1,3-thiazino[b]indole isomer

Article abstract of DOI:10.1002/jhet.607

We report a convenient approach for the synthesis of a new ring system: 4,5-dihydro-1,3-thiazino[5,4-b]indoles. The procedure involves the use of Lawesson's reagent in the presence of silica to achieve the one-step ring-closure reactions of 2-benzoylamino-3-hydroxymethylindole intermediates to furnish 4,5-dihydro-2-aryl-1,3-thiazino[5,4-b]indoles. 2-Phenylimino-1,3- thiazino[5,4-b]indoles were obtained via the corresponding 3-phenylthiourea-2- carboxylic acid ester derivatives by chemoselective reduction of the ester group, followed by ring closure under acidic conditions. The structures of the novel products were elucidated by IR, ¹H-NMR, and ¹³C-NMR spectroscopy, including 2D-HMQC, 2D-HMBC, and DEPT measurements.

Full text of DOI:10.1002/jhet.607

September 2011
One-Step Ring-Closure Procedure for 4,5-Dihydro-1,3-
thiazino[5,4-b]indole Derivatives with Lawesson’s Reagent. The
Fifth Dihydro-1,3-thiazino[b]indole Isomer
1079
Peter Csomos, Lajos Fodor,a,b* Gabor Bernath, †
a,b
a
´
´
´
´
c
Antal Csampai, and Pal Sohar
c,d
´
´
´
*
aInstitute of Pharmaceutical Chemistry, University of Szeged, and Research Group of
Stereochemistry of the Hungarian Academy of Sciences, Eo¨tvo¨s u. 6., Hungary
bCentral Laboratory, County Hospital, H-5701 Gyula, Hungary
c
´
¨
¨
Institute of Chemistry, Eotvos Lorand University, Hungary
Protein Modelling Research Group, Hungarian Academy of Sciences and Eotvos Lorand
University, H-1518 Budapest, Hungary
d
´
¨
¨
*E-mail: fodor@pandy.hu (or) sohar@chem.elte.hu
†Deceased
Received April 19, 2010
DOI 10.1002/jhet.607
Published online 19 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
We report a convenient approach for the synthesis of a new ring system: 4,5-dihydro-1,3-thiazino[5,4-
b]indoles. The procedure involves the use of Lawesson’s reagent in the presence of silica to achieve the
one-step ring-closure reactions of 2-benzoylamino-3-hydroxymethylindole intermediates to furnish 4,5-dihy-
dro-2-aryl-1,3-thiazino[5,4-b]indoles. 2-Phenylimino-1,3-thiazino[5,4-b]indoles were obtained via the corre-
sponding 3-phenylthiourea-2-carboxylic acid ester derivatives by chemoselective reduction of the ester
group, followed by ring closure under acidic conditions. The structures of the novel products were elucidated
1
by IR, H-NMR, and 13C-NMR spectroscopy, including 2D-HMQC, 2D-HMBC, and DEPT measurements.
J. Heterocyclic Chem., 48, 1079 (2011).
INTRODUCTION
(isocyclobrassinin) and its 2-benzylthio analogue, both of
which exerted good in vitro antiproliferative effects on
cervix adenocarcinoma (HeLa), breast adenocarcinoma
(MCF7), and squamous skin carcinoma (A431) cell lines
[7]. For structure-activity relationships, further analogues
were synthesized [8]. The highest cytotoxic effect was
displayed by 2-phenylimino-1,3-thiazino[5,6-b]indole,
which demonstrated inhibition activity comparable to that
of cisplatin on the above three cell lines. This sulfur ana-
logue of b-carboline proved to be a novel type of antitu-
mor compound [7].
In contrast with their valuable pharmacological activ-
ities, few derivatives are known of the six possible 1,3-
thiazinoindoles condensed at bond b of the indole skele-
ton (Fig. 1). Probably the best-known compounds of this
family are 1,3-thiazino[6,5-b]indole phytoalexins [1].
The phytoalexins, not present in healthy plant tissues,
are synthesized in plants in response to by attack patho-
gens or physical or chemical stress, probably as a result
of the de novo synthesis of enzymes [2]. Takasugi et al.
isolated the first thiazinoindole phytoalexin, cyclobrassi-
nin (2-methylthio-thiazino[6,5-b]indole), from Chinese
cabbage [3], and ꢀ30 phytoalexins are now known in
cruciferous plants, 6 of them possessing a thiazinoindole
skeleton [1]. Besides its antimicrobial activity, cyclo-
brassinin exerts an antiproliferative effect against human
cancer cell lines [4]. As concerns the remaining thia-
zino[6,5-b]indoles, only a few derivatives of cyclobrassi-
none [5] and 2-phenyl analogues of cyclobrassinin [6]
have been synthesized and investigated.
Procedures were also devised for a further two new
thiazinoindole ring systems: 4-thiaharmalan analogues
(2,5-dihydro-1,3-thiazino[5,6-b]indoles, 3 Fig. 1) [9] and
c-carboline analogue 2,9-dihydro-4-aryl-1,3-thiazino[6,5-
b]indoles (4, Fig. 1) were obtained [10].
Among the remaining positional isomers (types 5 and
6, Fig. 1), 1,5-dihydro-1,3-thiazino[5,4-b]indole-2,4-
dithione was prepared from 3-aminoindole with carbon
disulfide [11]. A series of 2-alkyl- or arylimino-1,3-thia-
zino[5,4-b]indol-4-one derivatives have been synthesized
by ring closure of the appropriate indolylthiourea deriva-
tives in polyphosphoric acid [12]. Members of this class
We recently prepared two regioisomeric 1,3-thiazinoin-
doles (2, Fig. 1); 2-methylthio-1,3-thiazino[5,6-b]indole
C
V
2011 HeteroCorporation

´ ´ ´ ´
P. Csomos, L. Fodor, G. Bernath, A. Csampai, and P. Sohar
1080
Vol 48
b]indoles (2, Fig. 1) [7] possessing in vitro antiproli-
ferative effects.
RESULTS AND DISCUSSION
For the preparation of different 1,3-thiazines, 1,3-
aminoalcohols are generally used by using two-compo-
nent reactions [16]. In our hands, the reduction of
ethyl 3-aminoindole-2-carboxylate (7) to obtain amino-
alcohol 8 under different reduction conditions failed.
One step procedures for 1,3-S,N heterocycles generally
utilize thioamides containing a hydroxy group [17] or
amides containing a hydroxy group [18]. In the latter
case 1,3-thiazines are formed in low yields, and side
products can also be isolated. To attempt one-compo-
nent ring-closure reactions, we prepared substituted
ethyl 3-benzoylaminoindole-2-carboxylate derivatives
10aꢁc from ethyl 3-aminoindole-2-carboxylate 7 and
the corresponding benzoyl chlorides 9aꢁc under Schot-
ten-Baumann conditions. The chemoselective reduction
of benzamido esters 10aꢁc with lithium aluminum
hydride in THF provided substituted N-benzoyl amino-
alcohols 11aꢁc under mild reaction conditions. The
one-step cyclization reaction of 11aꢁc with Lawes-
son’s reagent in toluene proceeded smoothly and vari-
ous side-products were observed on TLC. Interestingly,
when silica gel was added to the reaction mixture
(Lawesson’s reagent in toluene at 90ꢂC), the target
thiazines were achieved within a relatively short reac-
tion time and in good yield. Thus, 2-aryl-1,3-thia-
zino[5,4-b]indole derivatives 13aꢁc were obtained,
most probably via intermediates 12aꢁc.
Figure 1. R1 ¼ MeS, Ar; R2 ¼ MeS, BnS, Ar, PhN.
of compounds inhibit human leukocyte elastase and a-
chymotrysin. To the best of our knowledge, a procedure
for the synthesis of 4,5-dihydro-1,3-thiazino[5,4-
b]indoles (5, Fig. 1) has not yet been published
previously.
As a continuation of our work on S,N heterocycles
[13–15], including thiazinoindoles [6–10], we now
describe an efficient route for the synthesis of the
fifth 1,3-thiazinoindole isomer: 4,5-dihydro-1,3-thia-
zino[5,4-b]indoles (13aꢁc, Scheme 1) and 2-phenyli-
mino derivatives 17aꢁc (Scheme 2). These com-
pounds are bioisosteres of 4,5-dihydro-1,3-thiazino[5,6-
To prepare 2-phenylimino-substituted thiazinoindoles,
7 was reacted with phenyl isothiocyanates at 110ꢂC to
provide thioureas 15aꢁc. Chemoselective reduction of
Scheme 1. Reagents and conditions: (i) Toluene, chloroform, 6% NaOH, 20 min; (ii) LiAlH4,THF, 0ꢂC, 1 h; (iii) Lawesson’s reagent, silica gel,
toluene, 90ꢂC, 1 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 One-Step Ring-Closure Procedure for 4,5-Dihydro-1,3-thiazino[5,4-b]indole
Derivatives with Lawesson’s Reagent. The Fifth Dihydro-1,3-thiazino[b]indole Isomer
1081
Scheme 2. Reagents and conditions: (i) Neat, 110ꢂC, 30 min; (ii)
LiAlH4,THF, 0ꢂC, 1 h; (iii) 5% HCl/EtOH, reflux, 20 min.
In summary, we report a convenient approach for the
synthesis of a new ring system: 4,5-dihydro-1,3-thia-
zino[5,6-b]indoles. Indole 3-benzamido- and 3-phenyl-
thiourea-2-carboxylic acid esters (10aꢁc, 15aꢁc) were
chemoselectively reduced to the corresponding 2-
hydroxymethylindole derivatives (11aꢁc, 16aꢁc).
Treatment of intermediates 11aꢁc with Lawesson’s rea-
gent in the presence of silica gel provided thiazinoin-
doles 13aꢁc in good yields in a one-step protocol. The
target 2-phenyliminothiazinoindoles (17aꢁc) were
obtained from 16aꢁc by acidic treatment.
EXPERIMENTAL
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were per-
formed with a PerkinElmer 2400 CHNS elemental analyser.
Merck Kieselgel 60F254 plates were used for TLC, and Merck
Silica gel 60 (0.063–0.100) for column chromatography. Ethyl
3-aminoindole-2-carboxylate (7) was prepared by a literature
method [20].
the ester functionality with lithium aluminum hydride in
THF gave 2-hydroxymethylindole derivatives 16aꢁc. 2-
Phenylimino-1,3-thiazino[5,4-b]indoles 17aꢁc were
obtained from 16aꢁc in HCl/EtOH, followed by column
chromatographic purification.
1
The H- and 13C-NMR spectra were recorded in CDCl3 so-
lution in 5 mm tubes at room temperature, on a Bruker DRX
500 spectrometer at 500.13 (1H) and 125.76 (13C) MHz, with
the deuterium signal of the solvent as the lock and TMS as in-
ternal standard. The standard Bruker micro-program to gener-
ate NOE was used. DEPT spectra were run in a standard man-
ner, using only the y ¼ 135o pulse to separate CH/CH3 and
CH2 lines phased ‘‘up’’ and ‘‘down,’’ respectively. The 2D-
HSC spectra were obtained by using the standard Bruker pulse
program.
General procedure for substituted ethyl 3-benzoylami-
noindole-2-carboxylates (10aꢁc). Amino acid ester 7 (0.72 g,
3.5 mmol) was dissolved in a mixture of toluene (25 mL) and
chloroform (50 mL). To this solution, sodium hydroxide (0.62
g, 15.4 mmol) dissolved in water (10 mL) was added. After
the addition of benzoyl chloride (0.42 g, 3.9 mmol), the reac-
tion mixture was shaken intensively for 20 min. The crystals
that separated out were filtered off, washed in turn with water
and with toluene, and dried. The white crystalline benzamides
were recrystallized.
Ethyl 3-benzoylaminoindole-2-carboxylate (10a). White
crystalline needles, mp: 166–168ꢂC (from EtOH), Lit [21] mp:
171–171.5ꢂC yield 1.00 g (92%). Anal. Calcd. for C18H16N2O3
(308.33): C, 70.12; H, 5.23; N, 9.09. Found: C, 70.38; H,
5.39; N, 8.89.
Ethyl 3-(4-chlorobenzoyl)aminoindole-2-carboxylate (10b). White
crystalline powder, mp: 245–246ꢂC (from EtOH, CHCl3), yield
1.02 g (85%). Anal. Calcd. for C18H15ClN2O3 (342.78): C,
63.07; H, 4.41; N, 8.17. Found: C, 63.28; H, 4.55; N, 8.09.
1
The spectral data (IR, H- and 13C-NMR) on the new
compounds are reported in Tables 1 and 2. The pre-
sumed structures follow unambiguously from these data.
Only the following additional remarks are necessary:
The lower amide-I frequencies of 11a–c (1627 6 1
cm–1) are noteworthy relative to those of 10a–c (1655
6 6 cm–1). The values observed for the compounds of
type 11 do not lie in the expected interval characteristic
of secondary amides [19]. This can be explained by the
strong polarization of the amide group resulting in a
lower bond order and consequently lower amide-I fre-
quency in such derivatives. This effect is hindered in
10a–c by the electron-withdrawing influence of the 2-
carbethoxy group. This phenomenon confirms strong
conjugation between the ester and arylamide groups via
the 2,3-double bond of the indole skeleton of 10a–c. In
accord with this, the 13C-NMR chemical shifts of C-3
are higher for 10a–c (120–124 ppm) than for 11a–c
(~110 ppm), indicating lower electron density for the for-
mer carbons. A similar delocalization is not present in
thioureas 16a–c as the other NH substituent attached to
the thiocarbonyl group acts as an electron reservoir. The
high 1H-NMR chemical shift of the ortho aryl hydro-
gens (7.92 6 0.03 ppm) is a consequence of the tauto-
meric preference with a C¼¼N bond for 17a–c; this can
be explained by the substitution of the electron-attract-
ing C¼¼N bond (instead of NH) on CAr-1 and by the
upfield shift of the indole C-2 line in the 13C-NMR
spectra (113.4 6 0.1 ppm) as compared with those for
13a–c (116.2 6 0.2 ppm).
Ethyl
3-(4-methylbenzoyl)aminoindole-2-carboxylate
(10c). White crystalline needles, mp: 204–206ꢂC (from EtOH),
yield 0.94 g (83%). Anal. Calcd. for C19H18N2O3 (322.36): C,
70.79; H, 5.63; N, 8.69. Found: C, 70.65; H, 5.83; N, 8.84.
General procedure for chemoselective reduction of substi-
tuted ethyl 3-benzoylaminoindole-2-carboxylates (10aꢁc). To
intensively stirred and cooled (ice-water) THF (5 mL), lithium
aluminum hydride (0.24 g, 6.3 mmol) was added in small por-
tions. To this cooled suspension a solution of 10aꢁc (2.5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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P. Csomos, L. Fodor, G. Bernath, A. Csampai, and P. Sohar
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Vol 48
Table 1
Characteristic IR frequenciesa and 1H NMR datab for compounds 10a–c, 11a–c, 13a–c, 15a–c, 16a–c, and 17a–c.c
h
mNH þ
mOH
XCH2
s, d or
qa
H-20,60 H-30,50 H-40
mC¼O cCAr
H
CH3
H-4
ꢀdf
H-5 H-6
ꢀtf ꢀtf
H-7
ꢀdf
ꢀd
ꢀt
ꢀt
NH
amide
NH
indole
Compound
bandd
bande
bandf t(3H)g
(2H)i
(2H)j (1H)k
10a
10b
10c
11a
11b
11c
13a
13b
13c
15a
15b
15c
16a
16b
16c
17a
17b
17c
3322
3313
1681
1678
1676
1627
737
741
740
723
746
743
758
750
742
736
735
738
735
744
738
741
747
737
1.27
1.25
1.26
–
4.32
4.30
4.31
4.62
4.56
4.56
4.52
4.51
4.49
4.33
4.32
4.32
4.58
4.58
4.58
4.38
4.39
4.35
7.76 7.10 7.14
7.67 7.08 7.30
7.72 7.08 7.30
7.42 7.00 7.10
7.38 6.97 7.07
7.38 6.97 7.07
7.73 7.12 7.16
7.71 7.11 7.16
7.70 7.10 7.14
7.57 7.08 7.27
7.55l 7.08 7.28
7.57 7.08 7.27
7.36l 7.00 7.09
7.32
7.46
7.46
7.38
7.35
7.35
7.39
7.39
7.37
7.44
7.45
7.43
7.36l
8.09
8.07
7.96
8.08
8.07
7.96
8.04
8.03
7.92
7.52
7.55l
7.35
7.47m
7.57
7.64
7.36
7.55
7.61
7.34
7.60
–
10.14
10.2
10.03
9.90
9.94
9.78
–
11.80
11.8
3322
–
11.76
11.06
11.05
11.02
11.35
11.38
11.30
11.78
ꢀ3250
7.59
–
3355, 3265 1628
3352, 3266 1626
3250–2800 1582
–
–
–
–
7.51l 7.50l
3383
ꢀ3245
3311
1534
1532
1653
1651
1658
–
–
7.56
7.31
7.32
7.36
6.89
–
–
–
–
9.38
1.33
1.32
1.34
–
7.12
–
–
3311
3306
9.53, 9.72 11.81
9.22, 9.50 11.75
3350–2800 1661
3166 1524
7.29m 7.10
8.8, 9.3n
9.3n
8.88, 9.52 11.2
–
ꢀ7.35 7.00 7.09 ꢀ7.36 ꢀ7.35 ꢀ7.35
–
–
6.94
–
3299, 3180 1535
3200–2800 1605
–
–
7.37 7.01 7.09
7.36 ꢀ7.3l
6.87
ꢀ7.3,l ꢀ8.7 11.18
7.57 7.02 7.07 ꢀ7.3l
7.91 ꢀ7.3l
9.10
9.25
10.85
10.88
10.79
3390
3406
1600
1592
–
7.57 7.02 7.07
7.54 7.00 7.05
7.30
7.28
7.95
7.82
7.35
6.90
–
–
ꢀ8.93
a In KBr discs (cmꢁ1). Further bands, Amide-I: 1661 (10a), 1649 (10b), 1651 (10c); mCAO: 1253 (10a), 1248 (10b,c), 1023 (11a), 1007 (11b),
1015 (11c), 1271 (15a and 16a), 1263 (15b), 1243 (15c and 16b,c); cCArH and cCArCAr bands (mono- or para-disubst. benzene ring): 710 (10a),
843 (10b), 834 (10c), 688 (11a), 845 (11b), 836 (11c), 737, 686 (11a), 828 (13b, 15c, 16c and 17b), 819 (13c and 15b), 693 (16a), 832 (16b and
17c) 690 (17a).
b In DMSO-d6 solution at 500.1 MHz. Chemical shifts in ppm (dTMS ¼ 0 ppm), coupling constants in Hz. Further signals: ArCH3, s (3H): 2.40
(10c and 11c), 2.37 (13c); OCH3, s (3H): 3.74 (15c, 16c and 17c); OH, t, J: 5.3 (1H): 5.20 (11a), 5.16 (11b,c and 16c), 5.18 (16a,b).
c Assignments were supported by HMQC (except for 10c, 11c, 13c, 15c and 17a), HMBC (except for 10a,c, 11a,c, 13c, 15c and 17a)
d Broad or very broad overlapping bands of NH and OH groups, separated maximum at 3395 (17a).
e Ester (10a–c and 15a–c), amide I (11a–c), mC¼N (13a–c and 17a–c), thiourea (16a–c). Split, with the second maximum at 1511 (16a), 1583
(17a), 1579 (17c).
f Indole ring.
g Ethyl group, J: 7.1, 7.3 (15a,b).
h X¼O, qa (10a–c and 15a–c), X¼O, d (J: 5.2, (11a,c), 5.5 (11b and 15b) 4.9 (16a,c), X¼S, s (13a–c and 17a–c).
i,j,k A/B/C part of an AA0BB0C (for a-type compd.) or AA0BB0 spectrum (b and c-type compd.).
l,nOverlapping signals.
m Broad signal due to hindered rotation of the thiourea moiety.
mmol) in THF (10 mL) was added dropwise over a period of
30 min. The reaction mixture was stirred at the same tempera-
ture for 30 min. Ethyl acetate (40 mL) was then added drop-
wise during 5 min, followed by the dropwise addition of water
(30 mL) during 10 min. After stirring for 10 min, the phases
were separated, the organic phase was dried (sodium sulfate)
and evaporated (water bath <50ꢂC) and the residue was puri-
fied by column chromatography, with ethyl acetate:n-hexane
(2:1) as eluent to give 11a–c as a crystalline powder.
3-Benzoylamino-2-hydroxymethylindole (11a). Pale-brown
crystalline needles, mp: 222–224ꢂC, yield 0.47 g (71%). Anal.
Calcd. for C16H14N2O2 (266.29): C, 72.16; H, 5.30; N, 10.52.
Found: C, 72.28; H, 5.41; N, 10.39.
3-(4-Chlorobenzoyl)amino-2-hydroxymethylindole (11b). Pale-
brown crystalline powder, mp: 219–221ꢂC, yield 0.56 g
(74%). Anal. Calcd. for C16H13ClN2O2 (300.74): C, 63.90; H,
4.36; N, 9.31. Found: C, 64.15; H, 4.39; N, 9.09.
3-(4-Methylbenzoyl)amino-2-hydroxymethylindole (11c). Pale-
brown crystalline powder, mp: 208–212ꢂC, yield 0.46 g
(65%). Anal. Calcd. for C17H16N2O2 (280.32): C, 72.84; H,
5.75; N, 9.99. Found: C, 72.71; H, 5.57; N, 9.72.
General procedure for 4,5-dihydro-2-aryl-1,3-thia-
zino[5,4-b]indoles (13aꢁc) from 3-benzoylamino-2-hydroxy-
methylindole (11aꢁc). To a suspension of 3-benzoylamino-2-
hydroxymethylindoles (11aꢁc) (1.6 mmol) in toluene (20
mL), Lawesson’s reagent (0.7 g, 1.7 mmol) was added in one
portion, followed by the addition of silica gel powder (0.5 g).
The reaction mixture was stirred at 95ꢂC for 3 h. After evapo-
ration, the residue was purified by column chromatography,
with n-hexane:ethyl acetate 4:1 as eluent, to give 13aꢁc as a
crystalline powder.
4,5-Dihydro-2-phenyl-1,3-thiazino[5,4-b]indole (13a). Brownish-
green crystalline powder, mp: 180–186ꢂC, yield 0.26 g (61%).
Anal. Calcd. for C16H12N2S (264.35): C, 72.70; H, 4.58; N,
10.60; S, 12.13. Found: C, 72.92; H, 4.44; N, 10.51; S, 12.31.
4,5-Dihydro-2-(4-chlorophenyl)-1,3-thiazino[5,4-b]indole
(13b). Brownish-green crystalline powder, mp: 185–189ꢂC,
yield 0.25 g (53%). Anal. Calcd. for C16H11ClN2S (298.79):
C, 64.32; H, 3.71; N, 9.38; S, 10.73. Found: C, 64.54; H, 3.65;
N, 9.22; S, 10.97.
4,5-Dihydro-2-(4-methylphenyl)-1,3-thiazino[5,4-b]indole
(13c). Brownish-green crystalline powder, mp: 164–168ꢂC,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 One-Step Ring-Closure Procedure for 4,5-Dihydro-1,3-thiazino[5,4-b]indole
Derivatives with Lawesson’s Reagent. The Fifth Dihydro-1,3-thiazino[b]indole Isomer
1083
Table 2
13C NMR chemical shiftsa for compounds 10a–c, 11a–c, 13a–c, 15a–c, 16a–c, and 17a–c.b
C-4
C-5
OCH2
or
C-20,60
C-30,50
Com- CH3 C¼O C¼O
pound (Et) ester amidec
C-2
C-3
C-3a Indole Ring
C-6
C-7 C-7a SCH2
C-10
Aryl Group
C-40
d
10a
10b
10c
11a
11b
11c
13a
13b
13c
15a
15b
15c
16a
16b
16c
17a
17b
17c
15.1 162.3 165.9 119.7e 123.7 121.4e 122.9 120.5 126.1 113.5 136.2
15.1 162.1 165.0 120.2e 120.7e 123.9 122.5 120.6 126.1 113.5 136.1
15.1 162.3 165.7 119.5e 123.6 121.5e 123.0 120.4 126.1 113.4 136.2
61.3 135.3 128.4
61.3 134.0 130.4
61.3 132.4 129.9
55.8 135.5 128.6
55.7 134.2e 130.5
55.8 132.6 128.6
24.0 138.7 127.5
24.0 137.4 129.1
24.0 136.0 130.0
61.3 140.6 124.8
61.3 139.7 126.5
61.2 133.4 127.1
55.4 140.7 125.3f
129.4
129.5
128.5
129.2
129.3
129.7
129.5
129.5
127.5
129.1
128.9
114.4
129.0
128.8
114.2
129.4
129.3
114.6
132.5
137.3
142.5
132.2
137.0
142.1
131.1
135.7
141.0
125.3
129.1
157.4
125.3f
129.1
157.4
119.7h
125.5
154.8
–
–
–
–
–
–
–
–
–
–
–
–
166.7 134.2
110.4 125.3 119.1 119.4 121.9 112.2 134.8
165.6 134.16e 110.1 125.2 119.1 119.4 121.8 112.2 134.8
166.6 134.1
149.3 124.4
147.9 124.5
149.3 124.4
110.5 125.3 119.1 119.3 121.8 112.2 134.1
116.2 125.1 117.7 120.9 122.8 112.7 135.5
116.3 125.1 117.7 121.0 122.9 112.7 135.6
116.0 125.1 117.7 120.8 122.8 112.6 135.5
121.0 124.7 121.6 120.7 125.8 113.6 136.0
15.2 161.7 181.6 121.8
15.2 161.6 181.7 120.6e 122.0 124.7 121.4 120.8 125.9 113.6 136.0
15.2 161.7 181.8 121.69e 121.1e 124.7 121.75 120.7 125.8 113.5 136.0
–
–
–
–
–
–
–
–
–
–
–
–
181.9 135.6
181.9 135.6e
182.3 135.1
118.5 119.9 122.2 112.5 135.0
125.0 118.4 119.9 122.1 112.5 135.0f 55.4 139.8 127.5
127.4 125.2 118.5 119.9 122.1 112.5 135.7
144.2e 124.3g 113.4 124.5g 117.6 119.5h 122.0k 112.3 135.2
55.4 133.5 127.4
25.0 142.4e 122.13k
25.0 141.3 120.9
25.0 135.8 121.0
144.1 124.1
113.5 124.4 117.6 119.7 122.1 112.3 135.2
144.3 124.5e 113.3 124.6e 117.6 119.6 122.0 112.2 135.1
a In ppm (dTMS ¼ 0 ppm) at 125.7 MHz. Solvent: DMSO-d6. Further signals, ArCH3: 21.9 (10c and 11c), 21.8 (13c); OCH3: 56.1 (15c and 16c),
56.0 (17c). Due to slow motion (hindered rotation) of the thiourea moiety, it was not possible to identify the C-3 (16a,b) and C-3a lines(16a).
b Assignments were supported by DEPT (except for 16b and 15a), HMQC (except for 10c, 11c, 13c, 15c and 17a) and HMBC (except for 10a,c,
11a,c, 13c, 15c and 17a) measurements.
c C¼S (15a–c and 16a–c), C¼N (13a–c and 17a–c).
d For 13a–c and 17a–c.
Reversed assignments are also possible.
e g,h,k
f Overlapping lines.
yield 0.33 g (75%). Anal. Calcd. for C17H14N2S (278.37): C,
73.35; H, 5.07; N, 10.06; S, 11.52. Found: C, 73.18; H, 4.92;
N, 9.83; S, 11.77.
(0.24 g, 6.3 mmol) was added in small portions. To this cooled
suspension a solution of 15aꢁc (3.2 mmol) in THF (10 mL) was
added dropwise over a period of 30 min. The reaction mixture
was stirred at the same temperature for 30 min. Ethyl acetate (40
mL) was then added dropwise (5 min), followed by the dropwise
addition of water (1 mL). After stirring for 10 min. the reaction
mixture was filtered, and the filtrate dried (sodium sulphate)
evaporated (water bath <50ꢂC), and the residue was purified by
column chromatography, using ethylacetate:n-hexane (2:1) as
eluent to give 16a-c as a crystalline powder.
Phenyl thiourea alcohol derivative (16a). Pale-brown crys-
talline powder, mp: 195–197ꢂC, yield 0.51 g (54%). Anal.
Calcd. for C16H15N3OS (297.38): C, 64.62; H, 5.08; N, 14.13;
S, 10.78. Found: C, 64.82; H, 5.21; N, 13.91; S, 10.89.
4-Chlorophenyl thiourea alcohol derivative (16b). Pale-
brown crystalline powder, mp: 177–178ꢂC, yield 0.58 g
(55%). Anal. Calcd. for C16H14ClN3OS (331.82): C, 57.91; H,
4.25; N, 12.66; S, 9.66. Found: C, 58.21; H, 4.07; N, 12.42; S,
58.48.
General procedure for thiourea derivatives (15a-c) from
ethyl 3-aminoindole-2-carboxylate (7) and substituted phe-
nylisothiocyanates (14a-c). Amino acid ester 7 (1.2 g, 4.8
mmol) was mixed thoroughly with the corresponding substituted
phenyl isothiocyanate (14aꢁc) (5 mmol) in a round bottle, and
the mixture was heated at 110ꢂC for 30 min. To the crystalline
thiourea derivatives, ethyl acetate was then added. The crystals
were filtered off, washed with ethyl acetate, and recrystallized.
Phenyl thiourea ester derivative (15a). White crystalline
powder, mp: 194–196ꢂC (from EtOH, CHCl3), Lit [3] mp:
184–185ꢂC, yield 1.50
g
(92%). Anal. Calcd. for
C18H17N3O2S (339.41): C, 63.70; H, 5.05; N, 12.38; S, 9.45.
Found: C, 63.49; H, 5.12; N, 12.51; S, 9.67.
4-Chlorophenyl thiourea ester derivative (15b). White crys-
talline powder, mp: 187–188ꢂC (from EtOH, CHCl3), Lit [22]
mp: 179–180ꢂC, yield 1.68
g (94%). Anal. Calcd. for
C18H16ClN3O2S (373.86): C, 57.83; H, 4.31; N, 11.24; S, 8.58.
Found: C, 58.04; H, 4.53; N, 11.26; S, 8.42.
4-Methoxyphenyl thiourea alcohol derivative (16c). Pale-
brown crystalline powder, mp: 190–192ꢂC, yield 0.65 g (62 %).
Anal. Calcd. for C17H17N3O2S (327.40): C, 62.36; H, 5.23; N,
12.83; S, 9.79. Found: C, 62.55; H, 5.49; N, 12.61; S, 9.51.
General procedure for preparation of 2-arylimino-1,3-
thiazino[5,4-b]indoles 17a–c from thiourea alcohol deriva-
tives (16a–c). The appropriate thiourea alcohol derivative
16a–c (0.9 mmol) was suspended in absol. EtOH (10 mL).
20% HCl/EtOH (2.5 mL) was added to the mixture, and it was
refluxed for 20 min. After evaporation the residue was
4-Methoxyphenyl thiourea ester derivative (15c). White
crystalline flakes, mp: 181–182ꢂC (from EtOH), yield 1.15 g
(65%). Anal. Calcd. for C19H19N3O3S (369.43): C, 61.77; H,
5.18; N, 11.37; S, 8.68. Found: C, 61.52; H, 5.07; N, 11.49; S,
8.72.
General procedure for chemoselective reduction of thiou-
rea derivatives (15aꢁc). To an intensively stirred and cooled
(ice water) THF (5 mL) lithium aluminum hydride was added
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´ ´ ´ ´
P. Csomos, L. Fodor, G. Bernath, A. Csampai, and P. Sohar
1084
Vol 48
¨
hauser, C.; Pezutto, J. M.; Moon, R. C.; Moriarty, M. R. Chem Abstr
dissolved in an extraction funnel in CHCl3 (20 mL) and
MeOH (1 mL), water was added (10 mL) and the mixture was
neutralized with 10% NaHCO3 solution. The organic layer was
separated, extracted with water (10 mL), dried and evaporated.
The residue was purified by column chromatography, with
ethyl acetate:n-hexane (3:2) as eluent, to give 17a–c as a crys-
talline powder.
2-Phenylimino-1,3-thiazino[5,4-b]indole (17a). Pale-brown
crystalline powder, mp: 179–183ꢂC, yield 0.11 g (42%). Anal.
Calcd. for C16H13N3S (279.36): C, 68.79; H, 4.69; N, 15.04;
S, 11.48. Found: C, 68.71; H, 4.88; N, 14.87; S, 11.73.
2-(4-Chlorophenylimino)-1,3-thiazino[5,4-b]indole (17b). Pale-
brown crystalline powder, mp: 184–190ꢂC, yield 0.11 g (40%).
Anal. Calcd. for C16H12ClN3S (313.81): C, 61.24; H, 3.85; N,
13.39; S, 10.22. Found: C, 61.10; H, 4.02; N, 13.61; S, 10.51.
2-(4-Methoxyphenylimino)-1,3-thiazino[5,4-b]indole (17c). Pale-
brown crystalline powder, mp: 174–177ꢂC, yield 0.14 g (49 %).
Anal. Calcd. for C17H15N3OS (309.39): C, 66.00; H, 4.89; N,
13.58; S, 10.36. Found: C, 65.82; H, 6.17; N, 13.71; S, 10.56.
1995, 122, 230157.
´
´ˇ
[5] Kutschy, P.; Suchy, M.; Adreani, A.; Dzurilla, M.; Kovacik,
¨
V.; Alfoldi, J.; Rossi, M.; Gramatova, M. Tetrahedron 2002, 58, 9029.
´
´
´
´
[6] Csomos P.; Fodor L.; Sohar P.; Bernath G. Tetrahedron
2005, 61, 9257.
[7] (a) Csomos, P.; Zupko, I.; Rethy, B.; Fodor, L.; Falkay,
´
´
´
´ ´
G.; Bernath, G. Bioorg Med Chem Lett 2006, 16, 6273; (b) Csomos,
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P.; Zupko, I.; Rethy, B.; Fodor, L.; Falkay, G.; Bernath, G. Chem
Abstr 2006, 146, 114234.
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[8] Csomos, P.; Fodor, L.; Mandity, I.; Bernath, G. Tetrahedron
2007, 63, 4983.
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[9] Csomos, P.; Fodor, L.; Bernath, G.; Csampai, A.; Sohar, P.
Tetrahedron 2008, 64, 8646.
´ ´ ´ ´
[10] Csomos, P.; Fodor, L.; Bernath, G.; Csampai, A.; Sohar, P.
Tetrahedron 2009, 65, 1475.
[11] (a) Velezheva, V. S.; Yarosl, A. V.; Kozik, T. A.; Suvorov,
U. N. Khim Geterosikl Soedin 1978, 1497; (b) Velezheva, V. S.; Yar-
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Acknowledgments. The authors express their thanks to the Hun-
garian Scientific Research Foundation (OTKA) for financial sup-
´
port. They are indebted to Mrs. E. Juhasz Dinya for excellent
technical assistance.
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[13] Fodor, L.; Szabo. J.; Szu†cs, E.; Bernath, G.; Sohar, P.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet