1,3-Thiazino[6,5-b]indol-4-one derivatives. The first synthesis of indole phytoalexin cyclobrassinon

Article abstract of DOI:10.1016/S0040-4039(01)01422-8

The first synthesis of indole phytoalexin cyclobrassinon in six steps, in 12% overall yield and some of its analogues, possessing a 1,3-thiazino[6,5-b]indol-4-one tricyclic ring system was performed, starting from 2-chloroindole-3-carboxaldehyde and employing the intramolecular Et₃N-mediated nucleophilic substitution of a chlorine atom in the 2-position of an indole ring with sulfur as a key step.

Full text of DOI:10.1016/S0040-4039(01)01422-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6961–6963
1,3-Thiazino[6,5-b]indol-4-one derivatives. The first synthesis of
indole phytoalexin cyclobrassinon
Mojm´ır Suchy´,a,* Peter Kutschy,a Milan Dzurilla,a Vladim´ır Kova´cˇik,b Aldo Andreanic and
Juraj Alfo¨ldib
a
&
Department of Organic Chemistry, P. J. Safa´rik University, Moyzesova 11, 041 67 Kosˇice, Slovak Republic
bInstitute of Chemistry, Slovak Academy of Sciences, Du´bravska´ cesta 9, 842 38 Bratislava, Slovak Republic
cDepartment of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
Received 22 June 2001; revised 24 July 2001; accepted 2 August 2001
Abstract—The first synthesis of indole phytoalexin cyclobrassinon in six steps, in 12% overall yield and some of its analogues,
possessing a 1,3-thiazino[6,5-b]indol-4-one tricyclic ring system was performed, starting from 2-chloroindole-3-carboxaldehyde
and employing the intramolecular Et3N-mediated nucleophilic substitution of a chlorine atom in the 2-position of an indole ring
with sulfur as a key step. © 2001 Elsevier Science Ltd. All rights reserved.
Phytoalexins are low molecular weight secondary
metabolites, produced by plants after their exposure to
physical, biological or chemical stress.1 A specific group
of these natural products represent indole phytoalexins
produced by economically important plants of the fam-
ily Cruciferae and cultivated worldwide.2,3 With respect
to the well known anticarcinogenic properties of bras-
sica vegetables4 it is quite important to study the bio-
logical activity of indole phytoalexins. Isolation from
plants is difficult and time consuming and therefore the
amounts required for screening should be provided by
synthesis. Approximately 30 hitherto known indole
phytoalexins have been synthesized3 and biological
screening disclosed antifungal,5 cancerprotective6,7 and
antitumor8,9 activity of several compounds. The synthe-
sis and biological properties of cyclobrassinon (6a),
isolated in 1994 from kohlrabi,10 have not been
described to date.
toalexin brassinin [N-(indol-3-ylmethyl)dithiocarba-
mate] with pyridinium bromide perbromide,13,15 or N-
bromosuccinimide.7 The other example is an unstable-
2-imino-2H-1,3-thiazino[6,5-b]indole
hydrochloride,
obtained by heating of 2-chloroindole-3-carboxalde-
hyde with thiourea.16
To achieve the synthesis of 6a, it was decided to use
2-chloroindole-3-carboxaldehyde (1)16 as a starting
material. Its transformation to monothiocarbamate of
the type 4 via the corresponding acid, acid halide and
isothiocyanate, and subsequent cyclization should
afford the desired cyclobrassinon (6a). The preparation
of the required 2-chloroindole-3-carboxylic acid was
accomplished by oxidation of aldehyde 1 with KMnO4
in aqueous acetone in the presence of a phosphate
buffer17 or NaClO2 in aqueous dioxane in the presence
of 2-methyl-but-2-ene.18 However, oxidation of 1 in our
hands did not afford 2-chloroindole-3-carboxylic acid
in a reasonable yield. The same situation occurred with
protected aldehyde 2. Therefore, we turned our atten-
tion to the radical bromination of aldehydes (NBS,
AIBN, CCl4, reflux) to form substituted benzoyl bro-
mides and aliphatic acid bromides.19 However, under
these conditions, aldehyde 1 completely decomposed.
The problem was solved by introduction of the t-
butoxycarbonyl (Boc) protecting group. Reaction of
1-Boc-2-chloroindole-3-carboxaldehyde (2) under the
conditions of radical bromination gave the correspond-
ing unstable acid bromide, which after treatment with
KSCN afforded surprisingly stable-1-Boc-2-chloroin-
dole-3-ylcarbonylisothiocyanate (3, Scheme 1).
In continuation of our interest in the synthesis of indole
phytoalexins,11,12 we have decided to study the synthesis
of cyclobrassinon, possessing the structurally unique
1,3-thiazino[6,5-b]indol-4-one ring system. To the best
of our knowledge, there are only several examples of
analogous compounds. One of them is another indole
phytoalexin cyclobrassinin (2-methylsulfanyl-4H-1,3-
thiazino[6,5-b]indole),13 and two related compounds.3,14
Cyclobrassinin was prepared by cyclization of phy-
* Corresponding author. Tel.: +421-55-62-22610, ext. 195; fax: +421-
55-62-22124; e-mail: suchymo@kosice.upjs.sk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01422-8

6962
M. Suchy´ et al. / Tetrahedron Letters 42 (2001) 6961–6963
CHO
CONCS
CHO
Cl
i
ii, iii
iv
Cl
Cl
N
N
N
H
Boc
Boc
2
3
1
S
O
Z
O
O
NH
Cl
N
N
vi
v
Z
Z
S
S
N
H
N
N
Boc
Boc
5a-5d
6a-6d
4a-4d
Scheme 1. For 4–6 Z=OCH3 (a), OC2H5 (b), NHCH3 (c), N(CH2)5 (d). Reagents and conditions: (i) Boc2O, DMAP, THF, 5°C,
1 h, 68%; (ii) NBS, AIBN, tetrachloromethane, reflux, 10 min; (iii) KSCN, acetone, rt, 15 min, 41% (based on aldehyde 2); (iv)
a: CH3OH, acetone, rt, 2 h, b: C2H5OH, acetone, rt, 2.5 h, c: CH3NH2, acetone, 0°C, 10 min, 44%, d: piperidine, acetone, 0°C,
5 min; (v) a: Et3N, rt, 1 h, 61%, b: Et3N, rt, 1.5 h, 64%, c: Et3N, acetone, reflux, 3 h, 70%, d: Et3N, acetone, rt, 2 h, 67% (for
5a, 5b and 5d yields are based on isothiocyanate 3); (vi) a: 165–170°C, 40 min, 70%, b: 165–170°C, 30 min, 80%, c: 180–185°C,
20 min, 72%, d: 155–160°C, 25 min, 77%.
hexane gave 0.167 g (61%) of Boc-cyclobrassinon (5a)
as colourless crystals, mp 212–214°C. Boc-cyclobrassi-
non (5a, 0.15 g, 0.45 mmol) was heated without solvent
at 165–170°C for 40 min. Crystallization from methanol
afforded 0.074 g (70%) of cyclobrassinon (6a) as
colourless crystals, mp 221–223°C.
Nucleophilic addition of methanol to isothiocyanate 3
afforded the corresponding monothiocarbamate 4a.
Cyclization of 4a to 9-Boc-cyclobrassinon 5a proceeded
smoothly by triethylamine-mediated nucleophilic sub-
stitution of chloride, significantly facilitated by the acti-
vating effect of the Boc group. The Boc group can be
removed thermally20 or under acidic21 or basic22 condi-
tions. We have found that deprotection of 5a to 6a can
be effectively achieved by heating without solvent to
165–170°C, whereas treatment with acidic and basic
reagents afforded decomposition products. The elabo-
rated six-step procedure for the synthesis of cyclobrassi-
non (6a) can be successfully applied to the synthesis of
its ethoxy-, methylamino- and 1-piperidinyl-analogues
(6b–6d, Scheme 1). Employment of this synthetic
sequence to the preparation of other 1,3-thiazino[6,5-
b]indoles and the biological activity of synthesized com-
pounds will be described elsewhere.
Spectral data for cyclobrassinon:23 IR (KBr, cm−1):
1
1567, 1627 (CꢀN–CꢀO). H NMR (300 MHz, DMSO-
d6; l, ppm): 4.18 (s, 3H, OCH3); 7.39 (m, 2H, H-6,
H-7); 7.66 (d, 1H, J=7.5 Hz, H-8); 8.27 (d, 1H, J=7.5
Hz, H-5); 12.69 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6; l, ppm): 57.60 (CH3); 102.24 (C); 111.92
(CH); 120.42 (CH); 122.01 (CH); 124.03 (CH); 124.29
(C); 136.88 (C); 137.52 (C); 165.50 and 165.66 (CꢀN–
CꢀO). EIMS, [70 eV, m/z (%)]: 232 (M+, 45), 175 (100),
146 (23), 120 (33).
Experimental procedure for the preparation of cyclo-
brassinon: To a solution of 2 (0.55 g, 2 mmol) in dry
tetrachloromethane (3 ml) was added a catalytic
amount of AIBN and NBS (0.464 g, 2.6 mmol). The
mixture was stirred at reflux for 10 min, cooled to 3°C,
separated precipitate filtered off and the filtrate treated
with a solution of KSCN (0.196 g, 2 mmol) in dry
acetone (10 ml). After stirring for 15 min at room
temperature and filtration with charcoal, the filtrate
was evaporated and the residue was flash chro-
matographed on SiO2 (10 g, benzene), to afford isothio-
cyanate 3 (0.277 g, 41%) as colourless crystals, mp
131–132°C (dichloromethane/hexane). A mixture of
isothiocyanate 3 (0.277 g, 0.82 mmol) in methanol (11
ml) and acetone (11 ml) was stirred for 2 h at room
temperature. Triethylamine (0.166 g, 0.23 ml, 1.64
mmol) was then added and stirring was continued for 1
h at room temperature. Then, 35 ml of water was added
and the mixture was set aside for 1 h at 3°C. The
separated precipitate was filtered off, washed with
water and dried. Crystallization from dichloromethane/
Acknowledgements
We thank the Grant Agency for Science, Slovak
Republic (grant No. 1/6080/99) for financial support of
this work.
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