Synthesis of thiazino[6,5-b]indole derivatives, analogues of the phytoalexin cyclobrassinin. A new method for preparation of 3-aminomethylindole

Article abstract of DOI:10.1016/j.tet.2005.07.068

An efficient non-reductive synthesis of 3-aminomethylindole (6) was developed from gramine (1) via 3-phthalimidomethylindole (2). The reactions of amine 6 with substituted methyl dithiobenzoates gave 3- (arylthiocarbonylaminomethyl)indoles. The Hugerschoff ring-closure reactions of the thiobenzamide intermediates (11a-f) with phenyltrimethylammonium tribromide and subsequent basic treatment furnished 2-arylthiazino[6,5-b]indole derivatives (14a-f). By use of the latter bromine source, the phytoalexin cyclobrassinin (8) was prepared in a considerably higher yield than described previously. The structures of the novel products were elucidated by IR, ¹H and ¹³C NMR spectroscopy, including 2D-HMQC, 2D-HMBC and DEPT measurements.

Full text of DOI:10.1016/j.tet.2005.07.068

Tetrahedron 61 (2005) 9257–9262
Synthesis of thiazino[6,5-b]indole derivatives,
analogues of the phytoalexin cyclobrassinin.
A new method for preparation of 3-aminomethylindole
a,e
b,c
d,e
Peter Csomos, Lajos Fodor,a,e, Pal Sohar and Gabor Bernath
*
´
´
´
´
´
´
aCentral Laboratory, County Hospital, H-5701 Gyula, PO Box 46, Hungary
¨ ¨
´
Department of General and Inorganic Chemistry, Eotvos Lorand University, H-1518 Budapest, PO Box 32, Hungary
b
c
¨ ¨
´
Research Group for Structural Chemistry and Spectroscopy, Hungarian Academy of Sciences and Eotvos Lorand University,
H-1518 Budapest, PO Box 32, Hungary
dInstitute of Pharmaceutical Chemistry, H-6701, PO Box 121, Hungary
eResearch Group for Heterocyclic Chemistry, Hungarian Academy of Sciences and University of Szeged, H-6701, POB 121, Hungary
Received 3 May 2005; revised 5 July 2005; accepted 21 July 2005
Available online 10 August 2005
Abstract—An efficient non-reductive synthesis of 3-aminomethylindole (6) was developed from gramine (1) via 3-phthalimidomethylindole
(2). The reactions of amine 6 with substituted methyl dithiobenzoates gave 3-(arylthiocarbonylaminomethyl)indoles. The Hugerschoff ring-
closure reactions of the thiobenzamide intermediates (11a–f) with phenyltrimethylammonium tribromide and subsequent basic treatment
furnished 2-arylthiazino[6,5-b]indole derivatives (14a–f). By use of the latter bromine source, the phytoalexin cyclobrassinin (8) was
prepared in a considerably higher yield than described previously. The structures of the novel products were elucidated by IR, 1H and 13
NMR spectroscopy, including 2D-HMQC, 2D-HMBC and DEPT measurements.
q 2005 Elsevier Ltd. All rights reserved.
C
1. Introduction
Among these compounds, brassinin (7) and cyclobrassinin
(8) exhibit antitumour activity,5 and brassinin also exerts an
antiproliferative effect in human acute T-lymphoblastic
leukaemia cells.6 These compounds can serve as lead
compounds for the generation of more efficient analogues.7
As a continuation of our earlier work on the chemistry of
sulfur- and nitrogen-containing condensed-skeleton hetero-
cycles,8–10 our present aim was the preparation and
structural characterization of thiazino[6,5-b]indole deriva-
tives, analogues of cyclobrassinin (8).
The phytoalexins are a group of structurally diverse, low
molecular weight, generally lipophilic antimicrobial sub-
stances formed in plants.1 They are not present in healthy
plant tissue and are synthesized in response to pathogen
attack or physical or chemical stress, probably as a result of
the de novo synthesis of enzymes. The accumulation of
phytoalexins is one of an array of induced defence responses
associated with plant disease resistance.2
Numerous phytoalexins are known in cruciferous plants that
are important from economic and dietary aspects.3 Brassinin
has been identified as a constituent of cabbage. Some of the
cruciferae species that have been examined accumulate a
novel series of specific indole-sulfur compounds. The basic
structures are characterized by an indole ring variably
substituted at positions 2 and/or 3 with nitrogen- and sulfur-
containing substituents.4
2. Results and discussion
For the synthesis of the above phytoalexins, the key
intermediate is usually 3-aminomethylindole (6).11 In the
present work too this amine was the first choice as
intermediate for the preparation of 7 and 8 and their aryl
analogues.
Compound 6 was earlier obtained by the reduction of oxime
3 (Scheme 1),5,12–15 although some of the reduction
procedures (metallic sodium in ethanol,12 lithium
aluminium hydride,13 and Devarda’s alloy14) have been
reported to be difficult to reproduce and gave low yields.14–16
Keywords: Phytoalexins; 3-Aminomethylindole; Thiazino[6,5-b]indole;
Hugerschoff reaction.
*
Corresponding author. Address: Central Laboratory, County Hospital,
H-5701 Gyula, PO Box 46, Hungary. Tel.: C36 66 463763; fax: C36 66
526539; e-mail: fodor@pandy.hu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.068

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9258
Scheme 1. (i) Phthalimide, neat, 2 h, vacuum; (ii) hydrazine hydrate, EtOH, D.
Good yields were obtained by nickel bromide-catalysed
reduction with sodium borohydride and subsequent purifi-
cation by column chromatography15 and by catalytic
hydrogenation with Raney nickel,5 though amine 6 was
not isolated in the latter case.
several reaction conditions were investigated. Finally, this
step was performed with hydrazine hydrate under very strict
reaction conditions (reflux, 10 min), resulting in 6 in good
yield (Scheme 1).
Starting from amine 6, brassinin (7) was prepared in 71%
yield by a slight modification of a literature procedure,19
using chloroform as solvent and triethylamine and catalytic
4-dimethylaminopyridine as base (Scheme 2).
Another possible route to 6 is the catalytic reduction of the
3-cyano compound 4.17 A milligram-scale non-reductive
procedure has been reported, starting with the quaterniza-
tion of gramine (1) and subsequent treatment with
concentrated ammonia solution. In this case, bis(indolyl-
methylamine) was formed as a by-product in 13% yield.16
3-Aminomethylindole was found to be rather unstable as the
free base, and air and light accelerated its decomposition.
As solid compounds, quaternary ammonium perhalogenides
constitute convenient halogen sources. For the ring-closure
reaction of brassinin, pyridinium tribromide (yield 35%),19
N-bromosuccinimide (yield 34%)5 and dioxane dibromide
(yield 47%)20 have been applied earlier. We used
phenyltrimethylammonium tribromide. This has been stated
to be a selective brominating reagent for arylalkyl ketones,
ketones and ketals, which contain double bonds or activated
aromatic nuclei, which would be attacked by bromine.21 We
found that a selective Hugerschoff ring-closure reaction
with phenyltrimethylammonium tribromide gives cyclo-
brassinin (8) in higher yield (59%) than reported previously
(Scheme 2).
After unsuccessful attemps to reproduce the literature
procedures,13,14 we set out to develop a new method for
the gram-scale preparation of 6. Our attention turned to the
phthalimido derivative 218 and an effective, non-reductive
method has been developed starting from gramine (1). To
the best of our knowledge, the preparation of 6 from 2 has
not been described previously.
The phthalimide derivative 2 was obtained by a literature
procedure.18 For the splitting-off of the phthalimido group,
The reactions of amine 6 in dichloromethane at rt with
Scheme 2. (i) CHCl3, Et3N, DMAP, CS2, MeI; (ii) CH2Cl2, PhMe3NBr3; (iii) Et3N; (iv) toluene, 5% NaOH, PhCOCl; (v) Lawesson’s reagent, THF, rt;
(vi) CH2Cl2, Et3N, DMAP.

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9259
substituted methyl dithiobenzoates (9a–f) furnished
4. Experimental
3-(arylthiocarbonylaminomethyl)indoles (11a–f). Alterna-
tively, 11a was prepared by sulfurization from the
corresponding benzamide 10a, using Lawesson’s reagent
in tetrahydrofuran.
4.1. General
Melting points were determined on a Kofler apparatus and
are uncorrected. Elemental analyses were performed with a
Perkin-Elmer 2400 CHNS elemental analyser. Merck
Kieselgel 60F254 plates were used for TLC; the eluent was
dichloromethane–n-hexane 9/1. Gramine was prepared
from indole, 35% formaldehyde solution and a 40% aqueous
solution of dimethylamine.24 Compounds 9a–f were
prepared from substituted benzyl halides and sulfur in the
presence of triethylamine by the method of Thiel and
Mayer.25
The Hugerschoff reactions of thiobenzamides 11a–f were
also performed with phenyl-trimethylammonium tri-
bromide, affording moderate to good yields. The bromine-
mediated cyclization process most probably involves
electrophilic addition to the thiocarbonyl moiety, to furnish
12 as a transient intermediate, which is then attacked by the
p-electron system of the aromatic ring to give 13, followed
by the rapid formation of 14a–f in the presence of base
(Scheme 2).22
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, using TMS (dTMSZ0 ppm) as internal reference, with
the deuterium signal of the solvent as the lock. Assignments
were supported by DEPT, HMQC (except for 14d,e) and
HMBC (except for 14d–f) mesaurements. DEPT spectra
were run in a standard manner, using only the QZ1358
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
INV4GS and INV4GSLPLRND, respectively.
3. Structure
The structures of the new compounds follow straight-
1
forwardly from the IR, H and 13C NMR data. Only a few
additional remarks are necessary.
The ring closure of 11-type thioamides to thiazines was
proved by the characteristic changes in the spectra:
(1) Instead of the characteristic23a downfield line of the
thiocarbonyls (194.3–197.5 ppm for compounds 7 and
11a–f), the C]N bond of the thiazines gives a 13C NMR
line in the interval 150.0–152.0 ppm in the spectra of 8
and 14a–f.
4.2. 3-Aminomethylindole (6)
To a suspension of 3-phthalimidomethylindole18,26 (2)
(6.4 g, 23 mmol) in 27 mL of dry ethanol, 85% hydrazine
hydrate (10.0 g, 170 mmol) was added and the mixture was
intensively stirred on a preheated oil bath at 120 8C for
10 min (after w1.5 min, 8 has dissolved and after 4 min, a
white precipitate has formed). The reaction mixture was
then poured into a mixture of ice-water (120 g) and diethyl
ether (100 mL). The mixture was shaken in an ice-bath,
while 20% NaOH solution (40 mL) was added. The white
precipitate partially dissolved and the aqueous phase was
extracted with diethyl ether carefully in a separation funel.
The extraction was repeated with diethyl ether (2!
100 mL). The combined organic phase was extracted in
turn with 10% NaOH (50 mL) and with water (100 mL) and
dried (Na2SO4), and the organic solvent was evaporated off
(water bath !50 8C). The residue was coevaporated with
toluene (2!20 mL; water bath !60 8C) and it was taken up
in n-hexane and filtered. The crystalline residue was purified
by recrystallization from diisopropyl ether and ethyl acetate.
After standing at K18 8C, a white crystalline powder was
obtained (2.2 g; yield 65%; mp 101–102 8C), lit.14 mp 103–
105 8C. Anal. Calcd for C9H10N2 (146.19): C, 73.94; H,
6.89; N, 19.16. Found: C, 73.67; H, 7.02; N, 19.24.
(2) In consequence of the KI effect of the neighbouring
thioimino moiety in the thiazines, the line of the
methylene carbon is shifted downfield (48.8–49.3 ppm)
as compared with that for the thioamides, where the
electron-donating NH group is attached to the methylene
carbon (42.0–43.1 ppm). The analogous change was also
be observed in the 1H NMR shifts, which are about 5.10
and 5.33 ppm for compounds in the series of types 11 and
14.
(3) The b effect23b of the S substitution on C-9a leads to a
significant upfield shift of the C-4a line in the 13C NMR
specra of thiazines (from w110.7 to w99.5 ppm).
The H and 13C NMR chemical shifts of the condensed
1
benzene ring are not sensitive to ring closure because of the
isolating function of the 9-NH group, which has an electron
reservoir nature. Similarly, the aryl substituent does not
have a significant influence on the spectral data of the other
moieties of these molecules as a consequence of the
equalizing role of the thioamide or thioimine groups. The
spectroscopic characteristics, IR frequencies, H and 13C
1
NMR chemical shifts, intensities, multiplicities and coup-
ling constants are all in accord with those expected for the
various aryl groups.
4.2.1. 3-(S-Methyldithiocarbamoylaminomethyl)indole
(7, brassinin). To a stirred solution of 3-aminomethylindole
(5) (1.0 g, 6.9 mmol) in chloroform (20 mL), triethylamine
(0.96 mL, 6.9 mmol) and 4-dimethylaminopyridine (0.06 g,
0.5 mmol) were added. Carbon disulfide (0.46 mL,
7.59 mmol) was next added dropwise under ice cooling
and the mixture was stirred at the same temperature for 2 h.
Methyl iodide (0.44 mL, 6.9 mmol) in chloroform (5 mL)
It is worthy of mention that the acidity of 9-NH is slightly
stronger in the thiazines, due to the electron-withdrawing
effect of the condensed hetero ring: the NH signal is
downfield-shifted by w0.5 ppm relative to that for the
thioamides, from w11.0 to w11.5 ppm.

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9260
was then added dropwise to the solution and it was stirred
for 5 h at rt. The organic phase was extracted in turn with
3% hydrochloric acid (10 mL) and with water (10 mL),
dried (Na2SO4) and evaporated. Diisopropyl ether was
added to the residue to give 1 as a crystalline powder. White
crystals, mp 133–135 8C (lit.19 mp 132–133 8C), yield 71%
(from dichloromethane, n-hexane). Anal. Calcd for
C11H12N2S2 (236.36): C, 55.90; H, 5.12; N, 11.85; S,
27.37. Found: C, 55.65; H, 5.24; N, 11.62; S, 27.40; nmax
(KBr disc) 3392, 3302, 1480, 1073, 745 cmK1; dH
(500 MHz, DMSO-d6) 10.99 (1H, s, NHCH), 10.21 (1H,
s, NHCH2), 7.62 (1H, dd, H-4), 7.38 (1H, dd, H-7), 7.34
(1H, s, H-2), 7.10 (1H, dt, H-6), 7.01 (1H, dt, H-5), 4.98
(2H, d, JZ5 Hz, CH2), 2.53 (3H, s, CH3); dC (126 MHz,
DMSO-d6) 197.3 (NCSS), 137.0 (C-7a), 127.4 (C-3a), 125.8
(C-2), 122.1 (C-6), 119.6 (C-4 and C-5, overlapping lines),
112.4 (C-7), 111.0 (C-3), 43.1 (CH2), 18.2 (CH3).
4.2.4. 3-(Thiobenzoylaminomethyl)indole (11a) from
benzamide 10a. To a solution of 3-(benzoylaminomethyl)-
indole (10a) (0.2 g, 0.8 mmol) in tetrahydrofuran (15 mL),
Lawesson’s reagent (0.32 g, 0.8 mmol) was added in one
portion. The reaction mixture was stirred at rt for 24 h. After
evaporation the residue was purified by column chroma-
tography using dichloromethane–n-hexane as eluent to give
11a as a pale-yellow crystalline powder (analytical data
identical to those given above).
4.3. General procedure for 3-(arylthiocarbonylamino-
methyl)indoles (11a–f) from 6 and methyl dithiobenzo-
ates (9a–f)
Amine 6 (0.52 g, 2.53 mmol) was dissolved in dichloro-
methane (20 mL). To this solution, triethylamine (0.50 g,
11.12 mmol) and 4-dimethylaminopyridine (0.06 g,
0.5 mmol) were added. After the addition of the appropriate
methyl dithiobenzoate (9a–f) (2.78 mmol), the reaction
mixture was left at rt in a good hood for 2-3 days. After
evaporation, the residue was dissolved in dichloromethane
(30 mL). The organic phase was extracted in turn with 3%
hydrochloric acid (10 mL), 3% sodium hydroxide (10 mL)
and water (10 mL), dried (Na2SO4) and evaporated.
Trituration of the residue with diisopropyl ether gave
11a–f as crystalline powders.
4.2.2. 4,9-Dihydro-2-methylthio-1,3-thiazino[6,5-b]
indole (8, cyclobrassinin). To an intensively stirred
solution of brassinin 7 (0.20 g, 0.85 mmol) in dichloro-
methane (10 mL) at rt, phenyltrimethylammonium tri-
bromide (0.32 g, 0.85 mmol) was added in one portion.
After stirring for 45 s, triethylamine (0.24 mL, 1.7 mmol)
was added in one portion. The mixture was evaporated
(water bath !50 8C) and the residue was purified by column
chromatography, using dichloromethane–n-hexane (1/1,
followed by 2/1) as eluent, to give 8 after evaporation as a
crystalline powder (0.12 g). White crystals, mp 135–136 8C
(lit.19 mp 136–137 8C), yield 59%. Anal. Calcd for
C11H10N2S2 (234.34): C, 56.38; H, 4.30; N, 11.95; S,
27.37. Found: C, 56.21; H, 4.42; N, 12.02; S, 27.42; nmax
(KBr disc) 3370, 1602, 765 cmK1; dH (500 MHz, DMSO-
d6) 11.43 (1H, s, NH), 7.48 (1H, dd, H-5), 7.34 (1H, dd,
H-8), 7.09 (1H, dt, H-7), 7.03 (1H, dt, H-6), 5.06 (2H, s,
CH2), w2.50 (3H, s, CH3 overlapped by the light isotope
signal of the solvent); dC (126 MHz, DMSO-d6) 151.7
(C-2), 137.4 (C-8a), 125.4 (C-4b), 122.3* (C-9a), 122.2*
(C-7), 120.2 (C-6), 117.8 (C-5), 111.9 (C-8), 102.5 (C-4a),
48.9 (C-4), 15.5 (CH3), *interchangeable assignments.
4.3.1. 3-(Thiobenzoylaminomethyl)indole (11a). Pale-
yellow crystals, mp 145–146 8C (from dichloromethane,
n-hexane), yield 74%. Anal. Calcd for C16H14N2S (266.36):
C, 72.15; H, 5.30; N, 10.52; S, 12.04. Found: C, 72.35; H,
5.51; N, 10.32; S, 12.30; nmax (KBr disc) 3359, 3268, 1480,
1233, 775, s750, 690 cmK1; dH (500 MHz, DMSO-d6)
11.02 (1H, s, NHCH), 10.59 (1H, s, NHCH2), 7.72–7.73
(3H, m, H-4 and H20,60,0 overlapping signals), 7.38–7.45
(5H, m, H-2, H-7, H-30,5 and H-40, overlapping signals),
7.12 (1H, dt, H-6), 7.03 (1H, dt, H-5), 5.14 (2H, d, JZ
4.2 Hz, CH2); dC (126 MHz, DMSO-d6) 197.5 (CS), 142.3
(C-100), 0137.1 (C-7a), 131.3 (C-40), 128.7 (C-30,50), 128.2
(C-2 ,6 ), 127.6 (C-3a), 125.8 (C-2), 122.1 (C-6), 119.6 (C-4
and C-5, two overlapping lines), 112.4 (C-7), 111.1 (C-3),
43.1 (CH2).
4.2.3. 3-(Benzoylaminomethyl)indole (10a). Amine 6
(0.72 g, 3.50 mmol) was dissolved in toluene (25 mL). To
this solution, sodium hydroxide (0.62 g, 15.40 mmol)
dissolved in water (10 mL) was added. After the addition
of benzoyl chloride (0.42 g, 3.85 mmol), the reaction
mixture was shaken intensively for 20 min. The crystals
that separated out were filtered off and washed in turn with
water and with toluene and dried. The white crystalline
benzamide was recrystallized from diisopropyl ether. White
powder, mp 157–159 8C, 0.82 g, yield 85%. Anal. Calcd for
C16H14N2O (250.30): C, 76.78; H, 5.64; N, 11.19. Found: C,
76.92; H, 5.81; N, 11.29; nmax (KBr disc) 3416, 3302, 1628,
738, 695 cmK1; dH (500 MHz, DMSO-d6) 10.90 (1H, s,
NHCH), 8.80 (1H, s, NHCH2), 7.87 (2H, H20,60), 7.66 (1H,
dd, H-4), 7.45 (1H, H-40), 7.43 (2H, H-30,50), 7.36 (1H, dd,
H-7), 7.29 (1H, d, H-2), 7.07 (1H, dt, H-6), 6.98 (1H, dt,
H-5), 4.64 (2H, d, JZ5.6 Hz, CH2); dC (126 MHz, DMSO-
d6) 166.9 (CO), 137.2 (C-7a), 134.5 (C-10), 131.9 (C-40),
129.1 (C-30,50), 128.1 (C-20,60), 127.4 (C-3a), 124.8 (C-2),
122.0 (C-6), 119.7 (C-4), 119.4 (C-5), 113.5 (C-3), 112.3
(C-7), 35.5 (CH2).
4.3.2. 3-(2-Chlorothiobenzoylaminomethyl)indole (11b).
White crystals, mp 113–115 8C (from dichloromethane,
n-hexane), yield 62%. Anal. Calcd for C16H13ClN2S
(300.81): C, 63.89; H, 4.36; N, 9.31; S, 10.66. Found: C,
63.59; H, 4.32; N, 9.50; S, 10.82; nmax (KBr disc) 3411,
3309, 1456, 1240, 756, 741 cmK1; dH (500 MHz, DMSO-
d6) 11.02 (1H, s, NHCH), 10.80 (1H, s, NHCH2), w7.4 (3H,
m, H-2, H-7, H-60, overlapping signals), w7.32 (3H, m,
H-30,50 and H-40, overlapping signals), 7.69 (1H, dd, H-4),
7.12 (1H, dt, H-6), 7.04 (1H, dt, H-5), 5.05 (2H, d, JZ
5.0 Hz, CH2); dC (126 MHz, DMSO-d6) 195.5 (CS), 143.5
(C-100), 137.1 (C-7a), 130.4* (C-400), 130.1 (C-60), 129.5*
(C-3 ), 129.1 (C-20), 127.7* (C-5 ), 127.5 (C-3a), 125.8
(C-2), 122.2 (C-6), 119.7 (C-4), 119.6 (C-5), 112.4 (C-7),
110.4 (C-3), 42.0 (CH2). *interchangeable assignments.
4.3.3. 3-(4-Chlorothiobenzoylaminomethyl)indole (11c).
Yellow crystals, mp 148–150 8C (from dichloromethane,
n-hexane), yield 65%. Anal. Calcd for C16H13ClN2S
(300.81): C, 63.89; H, 4.36; N, 9.31; S, 10.66. Found: C,

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9261
63.78; H, 4.50; N, 9.22; S, 10.82; nmax (KBr disc) 3359,
3262, 1447, 1233, 839, 813, 751 cmK1; dH (500 MHz,
DMSO-d6) 11.03 (1H, s, NHCH), 10.66 (1H, s, NHCH2), 7.74
(2H, H-20,60), 7.68 (1H, dd, H-4), 7.45 (2H, m, H-30,50), 7.42
(1H, s, H-2), 7.40 (1H, dd, H-7), 7.11 (1H, dt, H-6), 7.02 (1H,
dt, H-5), 5.11 (2H, s, CH2); dC (126 MHz, DMSO-d6) 195.9
(CS), 140.8 (C-10), 137.1 (C-7a), 136.1 (C-40), 130.0 (C-20,60),
128.7 (C-30,50), 127.6 (C-3a), 125.8 (C-2), 122.1 (C-6), 119.7
(C-5), 119.6 (C-4), 112.4 (C-7), 110.8 (C-3), 42.8 (CH2).
(0.85 mmol) in dichloromethane (10 mL) at rt phenyl-
trimethylammonium tribromide (0.32 g, 0.85 mmol) was
added in small portions during 1 min. After stirring for
5 min, triethylamine (0.24 mL, 1.7 mmol) was added in one
portion. The mixture was evaporated (water bath !50 8C)
and the residue was purified by column chromatography,
using first dichloromethane–n-hexane (1/1, followed by 2/1)
as eluent to give 14a–f as a crystalline powder.
4.4.1. 4,9-Dihydro-2-phenyl-1,3-thiazino[6,5-b]indole
(14a). Orange crystals, mp 132–135 8C (ethanol), yield
51%. Anal. Calcd for C16H12N2S (264.35): C, 72.70; H,
4.58; N, 10.60; S, 12.13. Found: C, 72.62; H, 4.74; N, 10.81;
4.3.4. 3-(4-Fluorothiobenzoylaminomethyl)indole (11d).
Yellow crystals, mp 125–127 8C (from dichloromethane,
n-hexane), yield 57%. Anal. Calcd for C16H13FN2S
(284.35): C, 67.58; H, 4.61; N, 9.85; S, 11.28. Found: C,
67.36; H, 4.82; N, 10.02; S, 11.10; nmax (KBr disc) 3390,
3252, 1456, 840, 742 cmK1; dH (500 MHz, DMSO-d6)
11.02 (1H, s, NHCH), 10.60 (1H, s, NHCH2), 7.72 (2H,
H-20,60), 7.68 (1H, dd, H-4), 7.41 (1H, s, H-2), 7.39 (1H, dd,
H-7), 7.22 (2H, H-30,50), 7.10 (1H, dt, H-6), 7.01 (1H, dt,
H-5), 5.10 (2H, d, JZ5.3 Hz, CH2); dC* (126 MHz, DMSO-
d6) 196.0 (CS), 164.3 (C-40), 138.6 (C-10), 137.1 (C-7a),
130.7 (C-20,60), 127.5 (C-3a), 125.8 (C-2), 122.1 (C-6),
119.63 (C-4), 119.58 (C-5), 115.5 (C-30,50), 112.4 (C-7),
110.9 (C-3), 42.8 (CH2), *due to F,C-couplings, the signals
S, 12.02; nmax (KBr disc) 3390, 1620, 761, 737, 698 cmK1
;
dH (500 MHz, DMSO-d6) 11.53 (1H, s, NH), 7.89 (2H,
H-20,60), 7.55 (1H, H-40), w7.50 (3H, m, H-5 and H-30,50,
overlapping signals), 7.37 (1H, dd, H-8), 7.11 (1H, dt, H-7),
7.05 (1H, dt, H-6), 5.32 (2H, s, CH2); dC (126 MHz, DMSO-
d6) 152.0 (C-2), 138.2 (C-10), 137.5 (C-8a), 132.1 (C-40),
129.7 (C-30,50), 127.5 (C-20,60), 125.3 (C-4b), 123.0 (C-9a),
122.1 (C-7), 120.3 (C-6), 118.0 (C-5), 111.8 (C-8), 99.7
(C-4a), 49.0 (C-4).
4.4.2. 4,9-Dihydro-2-(2-chlorophenyl)-1,3-thiazino[6,5-
b]indole (14b). Brown crystals, mp 143–145 8C (ethanol),
yield 64%. Anal. Calcd for C16H11ClN2S (298.79): C,
64.32; H, 3.71; N, 9.38; S, 10.73. Found: C, 64.15; H, 3.92;
N, 9.45; S, 10.75; nmax (KBr disc) 3500–2000, 1630, 759,
745 cmK1; dH (500 MHz, DMSO-d6) 11.49 (1H, s, NH),
7.58 (1H, H-60), w7.50 (3H, m, H-5 and H-30,50,
overlapping signals), 7.45 (1H, H-40), 7.36 (1H, dd, H-8),
7.11 (1H, dt, H-7), 7.07 (1H, dt, H-6), 5.34 (2H, s, CH2); dC
(126 MHz, DMSO-d6) 150.7 (C-2), 138.6 (C-20), 137.4
(C-8a), 132.2 (C-50), 131.4 (C-10), 130.8 (C-60), 130.4
(C-30), 128.5 (C-40), 125.3 (C-4b), 122.9 (C-9a), 122.2
(C-7), 120.3 (C-6), 118.0 (C-5), 111.8 (C-8), 99.2 (C-4a),
49.3 (C-4).
1
2
of the aryl group are doublets, J(F,C): 248.4 Hz, J(F,C):
22.8 Hz, J(F,C): 9.2 Hz, J(F,C): 2.7 Hz.
3
4
4.3.5. 3-(4-Methylthiobenzoylaminomethyl)indole (11e).
Yellow crystals, mp 133–135 8C (from dichloromethane,
n-hexane), yield 55%. Anal. Calcd for C17H16N2S (280.39):
C, 72.82; H, 5.75; N, 9.99; S, 11.44. Found: C, 72.96; H,
5.92; N, 10.18; S, 11.25; nmax (KBr disc) 3302, 3250, 1456,
1278, 844, 737 cmK1; dH (500 MHz, DMSO-d6) 11.00 (1H,
s, NHCH), 10.47 (1H, s, NHCH2), 7.70 (1H, dd, H-4), 7.66
(2H, H-20,600), 7.40 (1H, s, H-2), 7.39 (1H, dd, H-7), 7.19
(2H, m, H-3 ,50), 7.11 (1H, dt, H-6), 7.01 (1H, dt, H-5), 5.12
(2H, d, JZ5.3 Hz, CH2), 2.31 (3H, s, CH3); dC (126 MHz,
DMSO-d6) 197.1 (CS), 141.3 (C-40), 139.4 (C-10), 137.1
(C-7a), 129.2 (C-30,50), 128.3 (C-20,60), 127.6 (C-3a), 125.7
(C-2), 122.1 (C-6), 119.66 (C-4), 119.59 (C-5), 112.4 (C-7),
111.2 (C-3), 42.6 (CH2), 21.7 (CH3).
4.4.3. 4,9-Dihydro-2-(4-chlorophenyl)-1,3-thiazino[6,5-
b]indole (14c). Light-brown crystals, mp 147–149 8C
(ethanol), yield 61%. Anal. Calcd for C16H11ClN2S
(298.79): C, 64.32; H, 3.71; N, 9.38; S, 10.73. Found: C,
64.11; H, 3.80; N, 9.56; S, 10.85; nmax (KBr disc) 3500–
2000, 1624, 834, 748 cmK1; dH (500 MHz, DMSO-d6)
11.54 (1H, s, NH), 7.89 (2H, H-20,60), 7.56 (2H, H-30,50),
7.50 (1H, dd, H-5), 7.36 (1H, dd, H-8), 7.11 (1H, dt, H-7),
7.05 (1H, dt, H-6), 5.34 (2H, s, CH2); dC (126 MHz, DMSO-
d6) 151.0 (C-2), 137.5 (C-8a), 136.9 (C-10), 136.8 (C-40),
129.8 (C-30,50), 129.2 (C-20,60), 125.2 (C-4b), 122.5 (C-9a),
122.2 (C-7), 120.3 (C-6), 118.0 (C-5), 111.8 (C-8), 99.7
(C-4a), 49.0 (C-4).
4.3.6. 3-(2,4-Dichlorothiobenzoylaminomethyl)indole
(11f). White crystals, mp 148–150 8C (from dichloro-
methane, n-hexane), yield 71%. Anal. Calcd for
C16H12Cl2N2S (335.25): C, 57.32; H, 3.61; N, 8.36; S,
9.56. Found: C, 57.18; H, 3.78; N, 8.28; S, 10.15; nmax (KBr
disc) 3302, 3248, 1456, 1281, 819, 801*, 758 cmK1; dH
(500 MHz, DMSO-d6) 11.04 (1H, s, NHCH), 10.84 (1H, s,
NHCH2), 7.69 (1H, dd, H-4), 7.59 (1H, s, H-30), 7.30–7.40
(4H, m, H-2, H-7, H-50, H-20,60, overlapping signals), 7.12
(1H, dt, H-6), 7.04 (1H, dt, H-5), 5.05 (2H, d, JZ4.5 Hz,
CH2); dC (126 MHz, DMSO-d6) 194.3 (CS), 142.3 (C-10),
137.1 (C-7a), 134.01 (C-40), 130.8 (C-60), 130.3 (C-20), 129.5
(C-30), 128.0 (C-5 ), 127.5 (C-3a), 125.9 (C-2), 122.2 (C-6),
119.6 (C-4 and C-5, two overlapping lines), 112.4 (C-7),
110.2 (C-3), 42.1 (CH2).
4.4.4. 4,9-Dihydro-2-(4-fluorophenyl)-1,3-thiazino[6,5-b]
indole (14d). Brown crystals, mp 144–149 8C (ethanol),
yield 54%. Anal. Calcd for C16H11FN2S (282.33): C, 68.06;
H, 3.93; N, 9.92; S, 11.36. Found: C, 67.70; H, 4.11; N,
10.1; S, 11.46; nmax (KBr disc) 3397, 1633, 1247, 842,
740 cmK1; dH (500 MHz, DMSO-d6) 11.53 (1H, s, NH),
7.94 (2H, H-200,600), 7.50 (1H, dd, H-5), 7.36 (1H, dd, H-8),
7.34 (2H, H-3 ,5 ), 7.11 (1H, dt, H-7), 7.05 (1H, dt, H-6),
5.33 (2H, s, CH2); dC* (126 MHz, DMSO-d6) 164.7 (C-40),
150.9 (C-2), 137.5 (C-8a), 134.7 (C-10), 129.9 (C-20,60),
125.3 (C-4b), 122.7 (C-9a), 122.2 (C-7), 120.3 (C-6), 118.8
4.4. General procedure for 4,9-dihydro-2-aryl-1,3-thia-
zino[6,5-b]indole (14a–f) from 3-(arylthiocarbonyl-
aminomethyl)indoles (11a–f)
To an intensively stirred solution of thiocarboxamide 11a–f

´
P. Csomos et al. / Tetrahedron 61 (2005) 9257–9262
9262
(C-5), 116.7 (C-30,50), 111.8 (C-8), 99.7 (C-4a), 48.9 (C-4),
*due to F,C-couplings, the signals of the aryl group are
doublets, 1J(F,C): 249.3 Hz, 2J(F,C): 22.0 Hz, 3J(F,C):
50 Years.; Daniel, M., Purkayasta, R. P., Eds.; Marcel Dekker:
New York, 1995; pp 1–39.
2. Dixon, R. A.; Lamb, C. J. Ann. Rev. Plant Physiol. Plant Mol.
Biol. 1990, 41, 339–367.
4
9.2 Hz, J(F,C): 2.7 Hz.
3. Pedras, M. S. C.; Okanga, F. I.; Zaharia, I. L.; Khan, A. Q.
Phytochemistry 2000, 66, 391–411.
4.4.5. 4,9-Dihydro-2-(4-methylphenyl)-1,3-thiazino[6,5-
b]indole (14e). Light-brown crystals, mp 148–150 8C
(from dichloromethane, n-hexane), yield 71%. Anal.
Calcd for C17H14N2S (278.37): C, 73.35; H, 5.07; N,
10.06; S, 11.52. Found: C, 73.52; H, 5.12; N, 10.27; S,
11.61; nmax (KBr disc) 3400, 1633, 842, 736 cmK1; dH
(500 MHz, DMSO-d6) 11.51 (1H, s, NH), 7.78 (2H,
H-200,600), 7.49 (1H, dd, H-5), 7.36 (1H, dd, H-8), 7.29 (2H,
H-3 ,5 ), 7.10 (1H, dt, H-7), 7.05 (1H, dt, H-6), 5.31 (2H, s,
CH2), 2.35 (3H, s, CH3); dC (126 MHz, DMSO-d6) 151.8
(C-2), 142.0 (C-40), 137.4 (C-8a), 135.5 (C-10), 130.2
(C-30,50), 127.4 (C-20,60), 125.3 (C-4b), 123.1 (C-9a), 122.1
(C-7), 120.2 (C-6), 117.9 (C-5), 111.7 (C-8), 99.8 (C-4a),
48.8 (C-4), 21.8 (CH3).
4. Harborne, J. B. Biochem. Syst. Ecol. 1999, 27, 335–367.
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6. Pilatova, M.; Sarissky, M.; Kutschy, P.; Mirossay, A.;
´
´
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´
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Mezencev, R.; Curillova, Z.; Suchy, M.; Monde, K.; Mirossay,
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´
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L.; Mojzis, J. Leuk. Res. 2005, 29, 415–421.
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˝
´ ´ ´ ´
8. Fodor, L.; Szabo, J.; Szucs, E.; Bernath, G.; Sohar, P.; Tamas,
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´ ´
9. Szabo, J.; Fodor, L.; Bani-Akoto, E.; Talpas, G. S.; Bernath,
´
G.; Sohar, P. Tetrahedron 1992, 48, 4957–4962.
´
10. Fodor, L.; Bernath, G.; Sinkkonen, J.; Pihlaja, K.
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Chem. 2003, 7, 1635–1647.
4.4.6. 4,9-Dihydro-2-(2,4-chlorophenyl)-1,3-thiazino[6,5-
b]indole (14f). Brown crystals, mp 157–160 8C (ethanol),
yield 42%. Anal. Calcd for C16H10Cl2N2S (333.24): C,
57.67; H, 3.02; N, 8.41; S, 9.56. Found: C, 57.82; H, 3.15;
N, 8.53; S, 9.44; nmax (KBr disc) 3366, 824, 753 cmK1; dH
(500 MHz, DMSO-d6) 11.50 (1H, s, NH), 7.75 (1H, H-30),
7.57 (1H, H-60), 7.53 (1H, H-50), 7.50 (1H, dd, H-5), 7.36
(1H, dd, H-8), 7.11 (1H, dt, H-7), 7.06 (1H, dt, H-6), 5.34
(2H, s, CH2); dC (126 MHz, DMSO-d6) 150.0 (C-2),
137.40* (C-40), 137.38* (C-8a), 136.0 (C-200), 132.7
(C-10), 131.8 (C-60), 130.5 (C-30), 128.7 (C-5 ), 125.3
(C-4b), 122.5 (C-9a), 122.3 (C-7), 120.3 (C-6), 118.0 (C-5),
111.8 (C-8), 99.2 (C-4a), 49.3 (C-4), *interchangeable
assignments.
12. Putochin, N. Ber. Dtsch. Chem. Ges. 1926, 59, 1987–2003.
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Acknowledgements
´
ˇ
20. Kutschy, P.; Suchy, M.; Monde, K.; Harada, N.; Maruskova,
ˇ
R.; Curillova, Z.; Dzurilla, M.; Miklosova, M.; Mezencev, R.;
ˇ
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA) for financial support (OTKA
grants T-034422, T-043634 and TS-040732). We are
´
indebted to Dr. A. Csampai, Ms. V. Kudar and Dr. Gy.
Turos for measuring the NMR and IR spectra and to Ms. E.
ˇ ˇ
Mojzis, J. Tetrahedron Lett. 2002, 43, 9489–9492.
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Juhasz Dinya for technical assistance.
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Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
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References and notes
1. Purkayastha, R. P. Handbook of Phytoalexin Metabolism and
Action. In Progress in Phytoalexin Research During the Past