A new simple route to the thieno[2,3-b]indole ring system

Article abstract of DOI:10.1055/s-2008-1072720

A simple and effective method has been elaborated for the synthesis of thieno[2,3-b]indole ring system. It is based on the electrophilic recyclization of 2-alkyl-5-(2-isothiocyanoaryl)furans in the presence of anhydrous AlCl ₃. Georg Thieme Ver

Full text of DOI:10.1055/s-2008-1072720

LETTER
1145
A New Simple Route to the Thieno[2,3-b]indole Ring System
S
ynthesis of thieno
l
[2,3-
b
]
e
indoles xander V. Butin,*a Fatima A. Tsiunchik,a Vladimir T. Abaev,b Valery E. Zavodnikc
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology,
Moskovskaya st. 2, Krasnodar 350072, Russian Federation
Fax +7(861)2596592; E-mail: alexander_butin@mail.ru; E-mail: av_butin@yahoo.com
North-Ossetian State University, Vatutina st. 46, Vladikavkaz 362025, Russian Federation
Karpov Institute of Physical Chemistry, Vorontsovo pole st. 10, Moscow 103064, Russian Federation
b
c
Received 22 October 2007
and heteroaromatic substrates. Later we showed the gen-
erality of this reaction, as it was bound to be applicable to
various o-isothiocyanotriarylmethanes.15 The key step of
the furan migration is the A-to-B rearrangement. The for-
mation of the relatively stable carbocation is a prerequisite
of this reaction. Otherwise, the furan fails to migrate.
Abstract: A simple and effective method has been elaborated for
the synthesis of thieno[2,3-b]indole ring system. It is based on the
electrophilic recyclization of 2-alkyl-5-(2-isothiocyanoaryl)furans
in the presence of anhydrous AlCl3.
Key words: furan, ring opening, ring closure, fused-ring system,
thieno[2,3-b]indole
The thieno[2,3-b]indole ring system has been little studied
to date and few methods of its synthesis have been report-
ed.1–7 Nevertheless, thieno[2,3-b]indoles are promising as
physiologically active compounds. In particular, thienod-
olin {6-chlorothieno[2,3-b]indole-2-carboxamide} isolat-
ed from the culture broth of Streptomyces albogriseolus8
and characterized by Japanese researches was proved to
have plant-growth-regulation activity. The parent
thieno[2,3-b]indole also demonstrates antifungal activi-
ty.9
O
O
O
+
R
R
O
R
R
N
N
SH
C
H+
S
A
1
In continuation of our studies in furan chemistry10 we
studied intramolecular interactions of the furan ring and
isothiocyano group. It is well known that isothiocyanates
react with aromatic and heterocyclic compounds under
Friedel–Crafts reaction conditions yielding thioamides.11
In this reaction the carbon atom of isothiocyano group
acts as an electrophile with regard to the aromatic ring.
When this reaction is performed in intramolecular mode,
the cyclic thioamides are usually formed.12 However, di-
rect thiocarbamoylation of furans with isothiocyanates
under the Friedel–Crafts conditions has not been reported,
a fact that can be attributed to the known sensitivity of fu-
ran compounds to acids. The known furan thioamides are
usually synthesized by use of lithiated furan derivatives.13
O
O
R
+
R
R
S
S
O
O
R
N
N
H
2
B
R = H, OMe
Scheme 1 Synthesis of 2,4-difuryl-4H-3,1-benzothiazines via a
furan ring migration
It was of interest to study the intramolecular interaction of
furan and isothiocyano groups in substrates wherein the
furan ring migration is impossible due to structural fea-
tures of the molecule. For this investigation we chose aryl-
furans wherein the aryl group and furan ring are linked
directly.
In 1997 we have described the first example of the acid-
catalyzed intramolecular reaction of an isothiocyano
group with the furan moiety. We found that treatment of
2-[bis(2-furyl)methyl]aryl isothiocyanates with perchlo-
ric acid in 1,4-dioxane led to the formation of 2,4-difuryl-
4H-3,1-benzothiazines derivatives (Scheme 1).14 In this
case the intramolecular ipso substitution followed by fu-
ran ring migration occurred instead of cyclic thioamide
formation which is the usual process for most aromatic
As starting compounds for the synthesis of the desired
isothiocyanates we used carbonyl derivatives of 2-(o-ni-
troaryl)furans 3 obtained by the arylation of furfural and
2-acetylfuran.16 Reduction of compounds 3 with NaBH4
in the presence of equimolar amounts of AlCl3 in anhy-
drous THF led to 2-alkyl-5-(2-nitroaryl)furans 417 and
subsequent reduction of the nitro group with Raney Ni
and hydrazine furnished amines 5.18 Isothiocyanates 6
were obtained by the treatment of compounds 5 with thio-
SYNLETT 2008, No. 8, pp 1145–1148
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072720; Art ID: D33807ST
© Georg Thieme Verlag Stuttgart · New York

1146
A. V. Butin et al.
LETTER
O
decomposition largely occurred under these reaction con-
ditions.
R2
R2
O
O
We tested different Brønsted and Lewis acids and finally
found that transformation of compounds 6 was the most
efficient when treated with anhydrous AlCl3 in 1,2-dichlo-
roethane. To our surprise, the spectroscopic data showed
that we obtained thieno[2,3-b]indoles 8 instead of the tar-
get furoquinolines 7 (Scheme 4, Table 2).20 Structures of
these products were unambiguously confirmed by single-
crystal X-ray data for 8a (Figure 1).21
a
b
R1
NO2
R1
NO2
4a–e
3a–e
R2
R2
O
O
c
A possible mechanism for the formation of thieno[2,3-
b]indoles 8 is shown in Scheme 4. The first step of this re-
R1
NH2
R1
NCS
5a–e
6a–e
R2
R2
Scheme 2 Synthesis of starting materials. Reagents and conditions:
a) NaBH4, AlCl3, THF; b) Ra-Ni, NH2NH2, EtOH; c) CSCl2,
NaHCO3, CH2Cl2, H2O.
O
O
R1
AlCl3
(CHCl2)2
N
Table 1 Yields of Compounds 4–6
C
R1
NCS
S
Compd R1
4–6
R2
Yield of 4 Yield of 5 Yield of 6
6a–e
AlCl3
(%)
67
83
63
60
81
(%)
76
89
78
80
78
(%)
94
77
79
52
76
R2
O
a
b
c
H
H
O
+
R2
H
Me
H
H
S
R1
Cl
R1
N
S
N
_
AlCl3
d
e
Me
OMe
H
H
O
phosgene in the presence of aqueous NaHCO3 and CH2Cl2
(Scheme 2, Table 1).19
R2
S
R1
N
H
We expected that treatment of isothiocyanates 6 with per-
chloric acid by procedure similar to that used for 2-[bis(2-
furyl)methyl]aryl isothiocyanates14 should lead to in-
tramolecular Friedel–Crafts cyclization onto the b-posi-
tion of the furan ring (Scheme 3). However,
8a–e
Scheme 4 Synthesis of thieno[2,3-b]indoles 8
Table 2 Yields of Compounds 8
Entry
Compd
8a
R1
R2
H
Yield of 8 (%)
R2
R2
O
1
2
3
4
5
H
67
83
63
60
81
O
HClO4
R1
8b
H
Me
H
N
8c
Cl
or AlCl3
R1
NCS
C
8d
Me
OMe
H
AlCl3
S
6
8e
H
R2
R2
O
+
O
H
S
R1
N
R1
N
S
_
H
AlCl3
7
Figure 1 ORTEP Diagram of 8a.
Scheme 3
Synlett 2008, No. 8, 1145–1148 © Thieme Stuttgart · New York

LETTER
Synthesis of Thieno[2,3-b]indoles
1147
(11) (a) Friedmann, A.; Gattermann, L. Ber. Dtsch. Chem. Ges.
1892, 25, 3525. (b) Tust, K.; Gattermann, L. Ber. Dtsch.
Chem. Ges. 1892, 25, 3528. (c) Jagodzinski, T. Synthesis
1988, 717. (d) Jagodzinski, T.; Jagodzinska, E.; Jabzonsky,
Z. Tetrahedron 1986, 42, 3683. (e) Papadopoulos, E. P.
J. Org. Chem. 1976, 41, 962. (f) Looney-Dean, V.;
Lindamood, B. S.; Papadopoulos, E. P. Synthesis 1984, 68.
(g) Deck, L. M.; Turner, S. D.; Deck, J. A.; Papadopoulos,
E. P. J. Heterocycl. Chem. 2001, 38, 343. (h) Naik, P. U.;
Nara, S. J.; Harjani, J. R.; Salunkhe, M. M. Can. J. Chem.
2003, 81, 1057.
(12) (a) Gittos, M. W.; Robinson, M. R.; Verge, J. P.; Davies, R.
V.; Iddon, B.; Suschitzky, H. J. Chem. Soc., Perkin Trans. 1
1976, 33. (b) Davies, R. V.; Iddon, B.; Paterson, T. McC.;
Pickering, M. W.; Suschitzky, H.; Gittos, M. J. Chem. Soc.,
Perkin Trans. 1 1976, 138. (c) Davies, R. V.; Iddon, B.;
Suschitzky, H.; Pickering, M. W.; Gallagher, P. T.; Gittos,
M. W.; Robinson, M. D. J. Chem. Soc., Perkin Trans. 1
1977, 2357. (d) Molina, P.; Alcantara, J.; Lopez-Leonardo,
C. Tetrahedron 1996, 52, 5833. (e) Duceppe, J. S.;
Gauthier, J. J. Heterocycl. Chem. 1984, 21, 1685.
(13) Jagodzinski, T. S.; Dziembowska, T. M.; Szczodrowska, B.
Bull. Soc. Chim. Belg. 1989, 98, 327.
action is electrophilic attack by the carbon of the isothio-
cyano group activated with anhydrous AlCl3 onto the a-
position of the furan ring. Furan ring opening followed by
cyclization due to intramolecular attack of the sulfur atom
on the carbocation intermediate furnishes the final prod-
ucts 8.
In summary, we have studied the transformation of 2-
alkyl-5-(2-isothiocyanoaryl)furans under the Friedel–
Crafts conditions. It has been demonstrated that this reac-
tion proceeds via electrophilic recyclization of the furan
ring rather than direct intramolecular cyclization. The
transformation is a simple and elegant method for the syn-
thesis of rare thieno[2,3-b]indole derivatives.
Acknowledgment
Financial support was provided by Bayer HealthCare AG (Germa-
ny) and the Russian Foundation of Basic Research (grant 07-03-
00352-a).
(14) (a) Butin, A. V.; Abaev, V. T.; Stroganova, T. A.; Gutnov,
A. V. Molecules 1997, 2, 62. (b) Abaev, V. T.; Tsiunchik, F.
A.; Gutnov, A. V.; Butin, A. V. J. Heterocycl. Chem. 2008,
45, 475.
(15) Abaev, V. T.; Tsiunchik, F. A.; Gutnov, A. V.; Butin, A. V.
Tetrahedron Lett. 2006, 47, 4029.
References and Notes
(1) Kobayashi, G.; Furukawa, S.; Matsuda, Y.; Natsuki, R.
Yakugaku Zasshi 1969, 89, 58; Chem. Abstr. 1969, 70,
96665.
(2) Levy, J.; Royer, D.; Guilhem, J.; Cesario, M.; Pascard, C.
Bull. Soc. Chim. Fr. 1987, 193.
(16) (a) Compounds 3 were prepared using the Meerwein
method. For a typical procedure, see ref. 16b.
(3) Olesen, P. H.; Hansen, J. B.; Engelstoft, M. J. Heterocycl.
General Procedure for the Arylation Reaction
A mixture of substituted 2-nitroaniline (0.3 mol), H2O (400
mL) and 36% HCl (200 mL) was stirred for 30 min at 80 °C.
The solution was then cooled to 0 °C to –10 °C. The resulting
suspension of aniline hydrochloride was treated with NaNO2
(25 g, 0.36 mol) in H2O (120 mL). The resulting solution of
the diazonium salt was stirred for 40 min at 0 °C to –5 °C and
filtered. A solution of furfural or 2-acetylfuran (0.3 mol) in
acetone (150 mL) was added, followed by CuCl2 (8 g, 0.06
mol) in H2O (100 mL). The reaction mixture was stirred for
12 h at r.t. When the reaction was complete, the resulting
precipitate was filtered off and crystallized from EtOH–
acetone; yields of 5-arylfurfurals 3a,c–e: 45–53%; yield of
2-acetyl-5-phenylfuran (3b): 41%. (b)Janda, L.;Voticky, Z.
Chem. Zvesti 1984, 38, 507.
Chem. 1995, 32, 1641.
(4) Smitrovich, J. H.; Davies, I. V. Org. Lett. 2004, 4, 533.
(5) Engqvist, R.; Javaid, A.; Bergman, J. Eur. J. Org. Chem.
2004, 2589.
(6) Appukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett
2005, 127.
(7) Majumdar, K. C.; Alam, S. J. Chem. Res., Synop. 2006, 289.
(8) (a) Kanbe, K.; Okamura, M.; Hattori, S.; Naganawa, H.;
Hamada, M.; Okami, Y.; Takeuchi, T. Biosci. Biotech.
Biochem. 1993, 57, 632. (b) Kanbe, K.; Naganawa, H.;
Nakamura, K. T.; Okami, Y.; Takeuchi, T. Biosci. Biotech.
Biochem. 1993, 57, 636.
(9) Pedras, M. S. C.; Suchy, M. Bioorg. Med. Chem. 2006, 14,
714.
(10) (a) Abaev, V. T.; Gutnov, A. V.; Butin, A. V.; Zavodnik, V.
E. Tetrahedron 2000, 56, 8933. (b) Butin, A. V.; Abaev, V.
T.; Mel’chin, V. V.; Dmitriev, A. S. Tetrahedron Lett. 2005,
46, 8439. (c) Butin, A. V.; Smirnov, S. K. Tetrahedron Lett.
2005, 46, 8443. (d) Mel’chin, V. V.; Butin, A. V.
Tetrahedron Lett. 2006, 47, 4117. (e) Butin, A. V.;
Smirnov, S. K.; Stroganova, T. A. J. Heterocycl. Chem.
2006, 43, 623. (f) Abaev, V. T.; Dmitriev, A. S.; Gutnov, A.
V.; Podelyakin, S. A.; Butin, A. V. J. Heterocycl. Chem.
2006, 43, 1195. (g) Butin, A. V.; Mel’chin, V. V.; Abaev, V.
T.; Bender, W.; Pilipenko, A. S.; Krapivin, G. D.
Tetrahedron 2006, 62, 8045. (h) Butin, A. V.; Smirnov, S.
K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D.
Tetrahedron 2007, 63, 474. (i) Stroganova, T. A.; Butin, A.
V.; Vasilin, V. K.; Nevolina, T. A.; Krapivin, G. D. Synlett
2007, 1106. (j) Butin, A. V.; Dmitriev, A. S.; Kostyukova,
O. N.; Abaev, V. T.; Trushkov, I. V. Synthesis 2007, 2208.
(k) Dmitriev, A. S.; Abaev, V. T.; Bender, W.; Butin, A. V.
Tetrahedron 2007, 63, 9437.
(17) (a) Compounds 4 were synthesized according to the reported
procedure, see ref. 17b.
General Procedure for the Preparation of Compounds
4a–e
To a cooled (0–5 °C) solution of compound 3 (17 mmol) in
THF (120 mL), anhyd AlCl3 (4.5 g, 34 mmol) and NaBH4
(1.3 g, 34 mmol) were added portionwise under stirring. The
resulting suspension was stirred at 0–5 °C for 20 min and
then brought to reflux. After 1–2 h when the starting
compound 3 vanished (TLC monitoring), the reaction
mixture was cooled and poured into H2O (400 mL). The
organic layer was separated and the water layer was
extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried over anhyd Na2SO4, treated with activated
charcoal, and the solvent evaporated under the reduced
pressure. The residue 4 was used in the next step without
further purification. (b) Ono, A.; Suzuki, N.; Kamimura, J.
Synthesis 1987, 736.
(18) General Procedure for the Preparation of Compounds
5a–e
To an ethanolic solution (50 mL) of compound 4 (6 mmol),
Synlett 2008, No. 8, 1145–1148 © Thieme Stuttgart · New York

1148
A. V. Butin et al.
LETTER
Raney Ni (1.5 g) and hydrazine hydrate (2.5 mL) were added
and the reaction mixture was refluxed for 1–2 h. After
completion of the reaction (TLC monitoring), the catalyst
was filtered off and the filtrate was evaporated under
reduced pressure. The residue was dissolved in benzene–PE
(1:1), filtered through a pad of silica gel, and the solvent
evaporated under reduced pressure. The residue 5 was used
in the next step without further purification.
Aluminum chloride (1.6 g, 12 mmol) was added to a solution
of compound 6 (6 mmol) in 1,2-dichloroethane (30 mL). The
reaction mixture was stirred for 30 min at 50 °C (TLC
monitoring), then poured into H2O (200 mL) and extracted
with CH2Cl2 (2 × 40 mL). The combined extracts were dried
over Na2SO4 and the solvent was removed under reduced
pressure. The residue was crystallized from the appropriate
solvent: benzene–PE for 8a; benzene for 8b; EtOH for 8c;
EtOAc–PE for 8d; EtOH for 8e.
WARNING: Care should be taken when handling benzene
as a solvent due to its carcinogenic properties.
WARNING: Care should be taken when handling benzene
as a solvent because of its carcinogenic properties.
Selected Analytical Data of 8e
(19) General Procedure for the Preparation of Compounds
6a–e
A solution of thiophosgene (0.5 mL, 6.5 mmol) in CH2Cl2
(10 mL) and NaHCO3 (1.3 g, 15.5 mmol) in H2O (50 mL)
were simultaneously added at r.t. to a stirred solution of
compound 5 (5 mmol) in CH2Cl2 (15 mL). When the
reaction had finished (TLC monitoring), the mixture was
poured into H2O (200 mL) and stirred for 6 h. The organic
layer was separated and water layer was extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were
dried over anhyd Na2SO4, the dried extract was reduced to
the half of its volume, and PE was added until the solution
became cloudy. The solution was filtered through a pad of
silica gel, evaporated to one third of its volume, and left to
allow crystallization of the compounds 6.
Mp 225–226 °C. IR: nmax = 1628, 1608, 1584, 1508, 1480,
1472, 1400, 1280, 1236, 1196, 1156, 1092, 1024, 936, 824,
808 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.53 (s, 3 H,
CH3), 3.81 (s, 3 H, OCH3), 6.81 (dd, J = 2.3, 8.6 Hz, 1 H,
HAr), 7.04 (d, J = 2.3 Hz, 1 H, HAr), 7.73 (d, J = 8.6 Hz, 1 H,
HAr), 8.29 (s, 1 H, HTh), 11.86 (s, 1 H, NH). 13C NMR (75
MHz, CDCl3): d = 25.7, 55.3, 96.1, 109.2, 115.9, 120.1,
124.7, 126.2, 135.8, 143.5, 146.6, 156.8, 190.5. MS: m/z
(%) = 245 (85) [M+], 231 (22), 230 (100), 203 (11), 202 (57),
188 (13), 187 (18), 160 (17), 159 (16), 158 (17), 115 (11), 69
(18), 57 (12). Anal. Calcd for C13H11NO2S: C, 63.65; H,
4.52; N, 5.71. Found: C, 63.69; H, 4.41; N, 5.77.
(21) Crystal Data of Compound 8a
Selected Analytical Data of 6e
C12H9NOS, orthorhombic, space group Pbca; a = 11.982(2)
Å, b = 10.837(2) Å, c = 15.752(3) Å, V = 2045.4(6) Å3,
Z = 8, Dcalcd = 1.398 Mg/m3, F(000) = 896; 1797 reflections
collected, 1797 unique (Rint = 0.0000); final R indices (935
observed collections I > 2sI): R1 = 0.0309, wR2 = 0.0924;
final R indices (all data): R1 = 0.0859, wR2 = 0.1005.
Crystallographic data (excluding structure factors) for the
structure in this article have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 657300. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or e-mail: deposit@ccdc.cam.ac.uc]. Each
request should be accompanied by the complete citation of
this paper.
Mp 85–86 °C. IR: nmax = 2136, 1616, 1600, 1568, 1548,
1496, 1296, 1200, 1176, 1032, 976, 880, 804, 788 cm–1. 1H
NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H, CH3), 3.80 (s, 3
H, OCH3), 6.10 (d, J = 3.3 Hz, 1 H, HFur), 6.67 (d, J = 3.3 Hz,
1 H, HFur), 6.78 (d, J = 2.6 Hz, 1 H, HAr), 6.84 (dd, J = 2.6,
8.8 Hz, 1 H, HAr), 7.62 (d, J = 8.8 Hz, 1 H, HAr). 13C NMR
(75 MHz, CDCl3): d = 13.8, 55.6, 108.0, 109.0, 112.4, 114.6,
120.5, 126.2, 127.3, 134.7, 148.0, 152.0, 158.7. MS: m/z
(%) = 245 (85) [M+], 230 (37), 212 (23), 202 (29), 188 (32),
171 (20), 160 (17), 159 (19), 127 (13), 116 (13), 115 (26), 76
(14), 59 (23), 43 (38). Anal. Calcd for C13H11NO2S: C,
63.65; H, 4.52; N, 5.71. Found: C, 63.86; H, 4.38; N, 5.79.
(20) General Procedure for the Preparation of Compounds
8a–e
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