Facile synthesis of thiochromeno[2,3-b]indol-11(6H)-ones and pyrido[3′,2′:5,6]thiopyrano[2,3-b]indol-5(10H)-ones

Article abstract of DOI:10.1016/j.tetlet.2013.07.012

Indole-2(3H)thiones were cyclized under the action of 2-fluorobenzoyl chlorides to give thiochromeno[2,3-b]indol-11(6H)-ones or under the action of 2-chloronicotinoyl chlorides to give pyrido[3′,2′:5,6]thiopyrano[2, 3-b]indol-5(10H)-ones. The reaction of

Full text of DOI:10.1016/j.tetlet.2013.07.012

Accepted Manuscript
Facile Synthesis of Thiochromeno[2,3-b]indol-11(6H)-ones and Pyrido[3’,2’:
5,6]thiopyrano[2,3-b]indol-5(10H)-ones
Mostafa Kiamehr, Firouz Matloubi Moghaddam, Volodymyr Semeniuchenko,
Alexander Villinger, Peter Langer, Viktor O. Iaroshenko
PII:
S0040-4039(13)01151-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.012
TETL 43210
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 April 2013
27 June 2013
2 July 2013
Please cite this article as: Kiamehr, M., Moghaddam, F.M., Semeniuchenko, V., Villinger, A., Langer, P.,
Iaroshenko, V.O., Facile Synthesis of Thiochromeno[2,3-b]indol-11(6H)-ones and Pyrido[3’,2’:5,6]thiopyrano[2,3-
b]indol-5(10H)-ones, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.012
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Graphical Abstract
Facile
Synthesis
of
Thiochromeno[2,3-b]indol-11(6H)-ones
and
Pyrido[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones
Mostafa Kiamehr, Firouz Matloubi Moghaddam,* Volodymyr Semeniuchenko, Alexander Villinger, Peter
Langer,* Viktor O. Iaroshenko.*
R2
O
R2
X
O
S
R3
R4
K2CO3,
DMF (abs)
R3
R4
Cl
S
+
N
R1
X
Y
N
R1
R2, R3, R4 = H, F
X= CH2, N; Y= Cl, F
R1 = H, Me, Et, Ph, 7-(CH2)3
________________________________________________________________________________________________________________________
Corresponding authors: Fax: 00 49 381 49864112; Tel: 0049 381 4986410; E-mail: viktor.iaroshenko@uni-
rostock.de; iva108@googlemail.com

2
Facile Synthesis of Thiochromeno[2,3-b]indol-11(6H)-ones and Pyri-
do[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones
Mostafa Kiamehr,a,b Firouz Matloubi Moghaddam,c* Volodymyr Semeniuchenko,d Alexander Villinger,a
Peter Langer,a,e* Viktor O. Iaroshenko.a,d*
a Institut für Chemie der Universität Rostock, Albert-Einstein-Straße 3a, D-18059 Rostock, Fax: (+49-381-498-6411). E-mail:
viktor.iaroshenko@uni-rostock.de, iva108@gmail.com
b Department of Chemistry, Faculty of Science, University of Qom, Qom, Iran.
c Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, P. O. Box
11155-9516 Tehran, Iran.
d National Taras Shevchenko University, Volodymyrska st 62., Kyiv-33, 01033, Ukraine.
e Leibniz Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, D-18059 Rostock.
Abstract: Indole-2(3H)thiones were cyclized under action of 2-fluorobenzoyl chlorides to give thi-
ochromeno[2,3-b]indol-11(6H)-ones or under action of 2-chloronicotinoyl chlorides to give pyri-
do[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones. The reaction of cyclization proceeds regioselec-
tively in DMF and does not require transition metals for completion. Obtained heterocycles are
isosteric analogues of various tetracyclic indole derived alkaloids.
Keywords: Heterocycles; Indole-2(3H)thione; Pyridines; Tetracycles.
Indole ring system is a privileged scaffold in medicinal chemistry.1 To introduce this system in a
complex molecule indole-2(3H)thiones are widely used since indole-2(3H)thione ring is an electron
rich heterocycle and a powerful 1,3-dinucleophile. Various compounds containing indole-
2(3H)thione moiety were explored in cyclization reactions under action of diverse bielectrophiles in
our2-6 and other scientific groups.7-10
In this article we report the reaction of indole-2(3H)thione with 2-fluorobenzoyl chlorides and 2-
chloronicotinoyl chlorides as bielectrophiles. Fluorine is known as an excellent leaving group in
aromatic nucleophilic substitution reaction11,12 and this is successfully explored in our research. The
target system of thiochromeno[2,3-b]indol-11(6H)-one (1) was reported to be formed by acid pro-
moted cyclization of 3-(2-mercaptobenzoyl)indolin-2-one,13,14 PPA promoted cyclization of methyl
1-methyl-2-(phenylthio)-1H-indole-3-carboxylate,14 PPA or polyphosphate ester promoted cycliza-
tion of 2-((1H-indol-3-yl)thio)benzoic acid,15 refluxing of (2-(ethylsulfinyl)phenyl)(1-methyl-1H-
indol-3-yl)methanone in p-xylene16 and TFA promoted cyclization of methyl 2-((1H-indol-2-
yl)thio)benzoate.15 On the other hand the target system of pyrido[3',2':5,6]thiopyrano[2,3-b]indol-
5(10H)-one (2) is reported only in one article15 to be formed by PPA or polyphosphate ester treat-
ment of 2-((1H-indol-3-yl)thio)nicotinic acid or its methyl ester, i.e. with sulfur migration to the 2nd
position of indole moiety.
2

3
O
S
O
S
N
N
N
H
H
2, pyrido[3',2':5,6]thiopyrano
[2,3-b]indol-5(10H)-one
1, thiochromeno[2,3-b]
indol-11(6H)-one
Figure 1. General structure of thiochromeno[2,3-b]indol-11(6H)-one and pyri-
do[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-one
Our target compounds belong to the class of indol-containing linear tetracyclic scaffolds, which at-
tract a constant interest because of their occurrence in nature as well their biological properties. De-
rivatives of ellipticine and cryptolepine (Figure 2) have a broad spectrum of biological activity,17-19
but mostly their anticancer activity is explored due to powerful DNA intercalating properties. Ca-
lothrixine B and its simpler analogue compound 3 were found to be anticancer in in vitro tests.20,21
Compound 4 and similar are inhibitors of anaplastic lymphoma kinase (ALK) hence have anticanc-
er properties in vitro.22 More complex analogue of cryptolepine, compound 5, was found to have
antiplasmodial activity against P. falciparum chloroquineresistant strain W2.23
Figure 2. Natural and synthetic indol-containing linear tetracyclic compounds with known
biologic activity.
3

4
In the first instance we have investigated the reaction of 1-methylindole-2(3H)thione with 2-
fluorobenzoylchloride (Scheme 1) to define the optimal conditions for this process. The effect of
base, solvent and temperature was studied (Table 1). It was found that K2CO3 is a best base for this
reaction, and the highest yields were observed in DMF. On the other hand temperature was proven
to have a great impact on the yield: running the reaction at 20 °C (Table 1, entry 3) gave no product
while that at 70 °C (Table 1, entry 4) or at 100 °C (Table 1, entry1) gave only moderate yield of de-
sired product. Heating the reaction to 85 °C (Table 1, entry 5) was the best choice, and reducing the
reaction time to 4 hours (Table 1, entry 6) with initial pre-stirring of reactants at 20 °C further im-
proved the yield of compound 6a, thus leading to the final experimental procedure.24
O
O
(i)
Cl
S
+
N
N
S
F
Me
Me
6a
Scheme 1. Synthesis of compound 6a. Reagents and conditions: (i) K2CO3, DMF, 20 then 85 °
C, 1 then 4 h.
Table 1. Optimization study
Entry
Base
Solvent
DMF
Temp. (°C)
100
Time (h) Yielda
b
1
2
K2CO3
5
55
20
0
b
NaHCO3
DMF
100
5
18
b
3
K2CO3
DMF
20
b
4
K2CO3
DMF
70
5
48
82
94
55
90
92
73
38
b
5
K2CO3
DMF
85
5
b
6
K2CO3
DMF
DMF
20 then 85
20 then 85
20 then 85
1 then 4
1 then 4
1 then 4
c
7
K2CO3
b
8
Cs2CO3
NaH b
DMF
9
DMF
-5 to 20 then 85 1 then 4
b
10
K2CO3
DMSO
CH3CN
20 then 85
20 then 85
1 then 4
1 then 4
b
11
K2CO3
a Yields of isolated products.
b Two equivalents of base were used.
c One equivalent of base was used.
To generalize this methodology, we investigated the scope and limitations of the reaction with a se-
ries of indole-2(3H)thiones 7 and 2-fluorobenzoyl chlorides 8 under the optimized reaction condi-
tions to yield thiochromeno[2,3-b]indol-11(6H)-ones 6 (Scheme 2). Table 2 presents the com-
4

5
pounds 6 together with their yields. The cyclization is regioselective, i.e. regioisomers of products 6
were not observed. On the other hand the reaction does not require any source of precious or toxic
transition metal, hence can be freely used for preparation of biologically active compounds. Worth
to mention that formation of tetracycles proceeds easily with various indole-2(3H)thiones but fails
in case of oxindoles.
R2
O
F
R2
O
K2CO3,
DMF (abs)
R3
R4
R3
R4
S
Cl
N
R1
+
85 C, 4 h
N
R1
S
7
8
6
Scheme 2. Synthesis of compounds 6.
Table 2. Compounds 6.
Structure
Yield
94 %
6a
6b
69 %
55 %
6c
87 %
6d
6e
52 %
47 %
6f
5

6
95 %
52 %
94 %
6g
6h
6i
6j
50 %
42 %
6k
1
13
The structures of all products 6 were characterized by IR, H, C NMR spectral data as well as
HRMS analysis. Finally the structure of the representative 6d was corroborated by X-ray single
crystal analysis (Figures 3).25
Figure 3. Ortep plot of structure 6d.
6

7
Inspired by these results we have performed the cyclization of indole-2(3H)thiones 7 by 2-
chloronicotinoyl chlorides 9 in the same conditions to yield pyrido[3',2':5,6]thiopyrano[2,3-b]indol-
5(10H)-ones 10 (scheme 3). Table 2 presents the compounds 10 together with their yields.
O
O
K2CO3,
S
DMF (abs)
Cl
N
R1
+
85 C, 4 h
N
Cl
N
R1
S
7
10
9
Scheme 3. Synthesis of compounds 10.
Table 3. Compounds 10
Structure
Yield
74 %
10a
10b
75 %
60 %
10c
10d
62 %
Plausible reaction mechanism is depicted in Scheme 4. We suppose the indole-2(3H)thione 7 is de-
protonated by potassium carbonate to form a stabilized anion 11. In DMF S-acylation of anion 11 is
favorable, although direct C-alkylation also cannot be excluded. In any way, either directly or via a
rearrangement of 12 we suppose the formation of intermediate 13 which is cyclized by elimination
of either HF (for 2-fluorobenzoylchrorides 8) or HCl (2-chloronicotinoyl chlorides 9), which is im-
mediately trapped by excessive amount of potassium carbonate. To obtained supports for the pro-
posed mechanism we have conducted simple mechanistic studies, namely: we have treated the 1-
methy-lindole-2(3H)thione with benzoyl chloride under our standard reaction conditions. Monitor-
ing the reaction mixture by TLC we have detected orange spot situated on the start. The latest
turned to dark green by the exposition to the air during 20-30 minutes or immediately by the heat-
7

8
ing. Hoverer, in GC-MS we could not observe any products of possible acylation reaction. Attempts
to isolate this spot resulted in an orange-read crude material not soluble in DMSO-d6, in CF3CO2D
it turned to dark green. The element analysis showed absence of the sulfur.
Scheme 4. Putative reaction mechanism for the formation of 6.
In conclusion, we have described a facile and efficient method for the preparation of thiochrome-
no[2,3-b]indol-11(6H)-ones and pyrido[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones from indole-
2(3H)thiones by an easy procedure. The cyclization does not require transition metals, proceeds re-
gioselectively, relies on nucleophilic substitution of fluorine (in benzene ring) or chloride (in pyri-
dine ring) and affords target products in good to excellent yields.
Supporting information associated with this article can be found in online version at
http://dx.doi.org/xxxxxx.xxxxxx
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9

10
24.
A mixture of 0.7 mmol of from indole-2(3H)thione 7, 0.7 mmol of appropriate 2-
fluorobenzoyl chloride 8 or 2-chloronicotinoyl chloride 9 and 1.4 mmol (194 mg, 2 equiv.)
of anhydrous K2CO3 in absolute DMF (5 mL) was stirred under an inert atmosphere at 20
°C for 1 h and then the mixture was stirred at 85 °C for 4 h. After evaporation of the solvent
under reduced pressure, the residue was subjected to column chromatography over silica gel
(EtOAc-Heptane) to afford the pure products 6 or 10.
25.
Crystallographic data (excluding structure factors) for the structure 6d, reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. 946459 and can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif.
10