A new and facile synthesis of thieno[2,3-b]indole derivatives via condensation of isocyanide and indolin-2-thiones

Article abstract of DOI:10.1055/s-0028-1088107

A new one-pot synthesis of thieno[2,3-b]indole ring systems is described. Condensation of cyclohexyl isocyanide with indolin-2-thiones yielded 3-cyclohexyaminomethylene-indolin-2-thiones, which upon reaction with α-halocarbonyl compounds produced the titl

Full text of DOI:10.1055/s-0028-1088107

LETTER
1047
A New and Facile Synthesis of Thieno[2,3-b]indole Derivatives via
Condensation of Isocyanide and Indolin-2-thiones
Synthesis of
T
i
hieno[2
r
,3-
b
]ind
o
ole
D
erivativ
u
e
s
z Matloubi Moghaddam,* Hamdollah Saeidian, Zohreh Mirjafary, Salman Taheri, Somayyeh Kheirjou
Laboratory of Organic Synthesis and Natural Product, Department of Chemistry, Sharif University of Technology,
P. O. Box 11155-9516, Tehran, Iran
Fax +98(21)66012983; E-mail: matloubi@sharif.edu
Received 25 November 2008
ethyl phosphate as solvent is the main method to
synthesize framework 2 (Scheme 1).6 This nitrene-medi-
ated reductive cyclization procedure suffers from poor
substituent tolerance, drastic reaction conditions, and long
reaction times, although an improved Cadogan reductive
cyclization has also been developed.7
Abstract: A new one-pot synthesis of thieno[2,3-b]indole ring sys-
tems is described. Condensation of cyclohexyl isocyanide with in-
dolin-2-thiones yielded 3-cyclohexyaminomethylene-indolin-2-
thiones, which upon reaction with a-halocarbonyl compounds pro-
duced the title compounds.
Key words: thieno[2,3-b]indole derivatives, isocyanide, thioamide
S
Thiophene derivatives are important chemical building
blocks. A variety of molecules containing the thiophene
ring display a wide range of biological activity and find
applications as pharmaceuticals.1 Heterocyclic-fused sys-
tems such as thieno-indoles have attracted a great deal of
interest, due to their presence in natural products,2 as
novel conducting polymers3 and antifungal agents.4
Thieno[2,3-b]indole derivatives are useful for the treat-
ment of epilepsy, neurological diseases such as senile de-
mentia, Parkinson’s disease, pain, and deficiencies of
mental and motoric performance seen after conditions of
brain ischemia (Figure 1).5
(EtO)3P
S
N
NO2
H
1
2
Scheme 1
In 2004, Bergman et al. reported an efficient total synthet-
ic pathway to the alkaloid thienodolin starting from 2-
chloroindole-3-carbaldehyde.8 Thienodolin was isolated
from the culture broth of Streptomyces albogriseolus and
was shown to have both growth promoting and inhibiting
activities in rice seedlings.2 Recently the Friedel–Crafts
(FC) reaction has also been used for the preparation of
thieno[2,3-b]indole derivatives;9 wherein the authors re-
ported their results on the electrophilic recyclization of
isothiocyanates in the presence of anhydrous AlCl3.
Thieno[2,3-b]indoles can also be synthesized by tandem
cyclization involving sequential sigmatropic rearrange-
ments.10
CONH2
S
S
N
NH
H
Cl
antifungal agent
natural product
R4
R3
R5
R6
It is evident that a novel and flexible protocol with wide
substituent tolerance and mild reaction conditions is desir-
able in the preparation of thieno[2,3-b]indoles. Thioam-
ides have been used as useful synthones in the substrates
of heterocycles.11 Previously we have reported an effi-
cient synthesis of 5-acyl thiophenes 5 as anti-inflammato-
ry agents using thioamides (Scheme 2).12
S
R2
S
N
R
N
R1
R7
monomers of conducting polymers
R = H, Me
neurological diseases curative agent
R
R
1 = H, alkyl
2–7 = alkyl, alkenyl, alkynyl
Figure 1
O
However, limited attention has been given to the synthesis
of thieno[2,3-b]indole ring systems. To the best of our
knowledge, there are few methods for synthesis of the
thieno[2,3-b]indole skeleton in the literature. The deoxy-
genative cyclization of o-nitro arenes 1 in refluxing tri-
N
Ar1
Ar2
HN
Ar1
N
H
KF⋅Al2O3
N
Ar2
Cl
+
MW, 7 min
N
S
O
O
S
O
O
3
4
5
Scheme 2
SYNLETT 2009, No. 7, pp 1047–1050
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088107; Art ID: D39408ST
© Georg Thieme Verlag Stuttgart · New York

1048
F. M. Moghaddam et al.
LETTER
The starting thioamides 3 were obtained by the reaction of Mechanistically, it is conceivable that the reaction in-
the corresponding thioacetomorpholides with morpholine volves the initial deprononation of an indolin-2-thione 6
and triethyl orthoformate. However, extention of this by cyclohexyl isocyanide 7. Then, the positively charged
strategy to indoline-2-thiones failed. On the other hand, ion might be attacked by the anion of the indolin-2-thione
isocyanides are compounds with an extraordinary reactiv- 6 leading to 9. Such an addition product may isomerize
ity that have been investigated for over one and half cen- under the reaction conditions employed to produce 8
turies.13 In the context of our general interest in the (Scheme 4).
synthesis of thiophene derivatives using thioamides,14 we
were intrigued by the possibility of the reaction of cyclo-
hexyl isocyanide with indoline-2-thiones to obtain cyclo-
hexyaminomethylene-indolin-2-thiones, which, upon
reaction with a-halocarbonyl compounds, could produce
the desired thieno[2,3-b]indole framework.
Reaction of 8 with a-halocarbonyl compounds 10 under
basic conditions led to desired thieno[2,3-b]indole ring
system 11 with high yield. To our knowledge, the
thieno[2,3-b]indole ring system 11 is unprecedented. The
reaction proceeded in aqueous acetonitrile (2:1) and was
complete within 3 hours at room temperature. The struc-
Thus, when indolin-2-thiones 6 were treated with cyclo- tures of the products 11 were confirmed by analytical da-
1
hexyl isocyanide 7 in water and stirred for 5 hours at ta, H NMR and 13C NMR spectra,15 and by comparison
50 °C, cyclohexyaminomethylene-indolin-2-thiones 8 with known data in the literature for 11e.9
were obtained in good yields (Scheme 3).
To generalize this method, we used a series of a-halocar-
bonyl compounds and indolin-2-thione derivatives to ob-
tain their corresponding thieno[2,3-b]indoles (Table 1).
NC
HN
H2O
A plausible mechanism for the formation of the
S
+
50 °C, 5 h
thieno[2,3-b]indoles is shown in Scheme 5. Component 8
undergoes S-alkylation with a-haloketone 10 affording
the iminium ion 12. Subsequently 12 can hydrolyze to
corresponding aldehyde 13 or be transformed to 14. Sub-
sequent treatment with K2CO3 leads to formation of
thieno[2,3-b]indole 11 with elimination of water and
cyclohexylamine.
N
N
R1
R1
H
S
6
7
8
Scheme 3
The 1H NMR and 13C NMR spectra of the product clearly
indicated the formation of 8. The 1H NMR spectrum of 8
(R1 = Me) consisted of a broad line at d = 12.08 ppm (ex-
changeable with D2O) correlating with the NH, a doublet
for the vinyl proton at d = 8.05 ppm (J = 13.71 Hz), four
lines for the aromatic protons at d = 7.44-7.13 ppm, a
sharp singlet for NCH3 at d = 3.77 ppm, a multiplet for the
NCH cyclohexyl proton at d = 3.50–3.49 ppm, and a mul-
tiplet for the cyclohexyl ring between d = 1.37–2.11 ppm.
The 1H-decoupled 13C NMR spectrum of 8 showed 14 dis-
tinct resonances in agreement with the proposed structure.
To confirm the proposed mechanism, the reaction of
chloroacetonitrile 15 with 8 in H2O was studied in order
to trap 16 (Scheme 6). Indeed, in this case the iminium ion
was hydrolyzed to 17, which was isolated and its structure
was confirmed.
In conclusion, we have reported a new and efficient one-
pot synthesis of thieno[2,3-b]indoles from various indo-
line-2- thiones and a-halocarbonyl compounds. The
present procedure has the advantages, not only of good
functional-group tolerance and high yields, but also the
reaction can be performed under mild conditions.
The effect of the reaction temperature was studied by car-
rying out the model reaction at room temperature and
50 °C. It was observed that the yield was increased by
raising the temperature. Low yields with long reaction
time were observed in the organic solvents such as CH2Cl2
and MeCN.
H
H
+
H
C
S
N
–
H2O
–C
N
SH
+
50 °C, 5 h
N
N
Me
Me
6
7
N
isomerization
HN
H
N
H
H
Me
N
S
Me
9
S
8
Scheme 4
Synlett 2009, No. 7, 1047–1050 © Thieme Stuttgart · New York

LETTER
Synthesis of Thieno[2,3-b]indole Derivatives
1049
Table 1 Synthesis of Thieno[2,3-b]indoles
O
1. cyclohexyl isocyanide
H2O, 50 °C, 5 h
+
S
H
N
R2
H
N
H
H
N
R1
2. K2Me, MeCN,
O
S
R2
O
N
R1
X
+
S
X
R2
S
R2
O
N
N
Me
Me
Entry
1
R1
H
R2
X
Product Yield (%)
8
10
O
12
HN
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
Me
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Cl
Br
Br
Cl
11a
11b
11c
11d
11e
11f
87
81
74
85
73
83
85
83
79
84
68
80
77
71
75
78
71
75
70
75
R2
O
2
H
H
S
R2
N
3
H
14
S
Me
O
N
4
H
13
Me
5
H
O
6
Me
Me
Me
Me
Me
Me
Et
Ph
R2
S
7
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
Me
11g
11h
11i
N
Me
8
11
9
Scheme 5
10
11
12
13
14
15
16
17
18
19
20
11j
11k
11l
H
Ph
+
N
H
N
H
Et
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
Me
11m
11n
11o
11p
11q
11r
11s
11t
H
X
NC
+
Et
S
N
S
N
CN
Me
8
15
16
Et
Me
O
Et
H
– C6H13
N
Et
CN
S
N
Ph
Ph
Ph
4-ClC6H4
4-PhC6H4
Me
Me
17
Scheme 6
References and Notes
General Procedure for the One-Pot Synthesis of
(1) Gronowitz, S. The Chemistry of Heterocyclic Compounds:
Thiophene and Its Derivatives, Vol. 44; Wiley: New York,
1991.
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US 5536721, 1996. (b) Jakobsen, P.; Kanstrup, A.; Faarup,
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(6) (a) Cadogan, J. I. G. Synthesis 1969, 11. (b) Sundberg, R. J.
J. Org. Chem. 1965, 30, 3604.
Thieno[2,3-b]indoles 11a–t
Indoline-2-thiones 6 and a-halocarbonyl compounds 10
were prepared according to previously reported proce-
dures.16 Cyclohexyl isocyanide 7 (1 mmol) was added to
a stirred suspension of indoline-2-thione 6 (1 mmol) in
H2O (4 mL). The reaction mixture was stirred at 50 °C for
5 h. After completion of the reaction, a-halocarbonyl
compound 10 (1 mmol) in MeCN (2 mL) and K2CO3 (1
mmol) were added to mixture. The reaction mixture was
stirred at r.t. for 3 h, and the progress of the reaction was
monitored by TLC. After completion of reaction, the mix-
ture was extracted with CH2Cl2 (3 × 5 mL). The combined
organic extracts were dried with MgSO4, filtered, and then
evaporated. The residue was subjected to column chroma-
tography (EtOAc–hexane, 1:5) on SiO2 to obtain pure
products.
(7) (a) Scott, T. L.; Soderberg, B. C. Tetrahedron Lett. 2002, 43,
1621. (b) Soderberg, B. C.; Shriver, J. A. J. Org. Chem.
Synlett 2009, No. 7, 1047–1050 © Thieme Stuttgart · New York

1050
F. M. Moghaddam et al.
LETTER
1997, 62, 5838. (c) Smitrovich, J. H.; Davies, I. W. Org.
Lett. 2004, 6, 533. (d) Appukkuttan, P.; Eycken, E. V.;
Dehaen, W. Synlett 2005, 127.
(CH), 106.58 (C), 58.76 (CH), 34.15 (CH2), 29.75 (CH3),
25.60 (CH2), 24.62 (CH2) ppm.
Compound 11a: mp 285–287 °C. 1H NMR (500 MHz,
CDCl3/DMSO): d = 11.33 (s, 1 H), 7.48 (s, 1 H), 7.35–7.30
(m, 3 H), 7.26 (d, J = 8.30 Hz, 2 H), 7.03 (d, J = 8.17 Hz, 1
H), 6.83 (t, J = 7.67 Hz, 1 H), 6.73 (t, J = 7.51 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3/DMSO): d = 187.19, 149.22,
143.10, 137.71, 135.26, 131.71, 130.50, 128.38, 126.04,
125.79, 123.71, 122.35, 120.55, 119.71, 112.16 ppm.
Compound 11b: mp 280–282 °C. 1H NMR (500 MHz,
CDCl3/DMSO): d = 11.33 (s, 1 H), 7.49 (s, 1 H), 7.40 (d,
J = 8.36 Hz, 2 H), 7.35 (d, J = 7.73 Hz, 1 H), 7.10 (d, J = 8.36
Hz, 2 H), 7.04 (d, J = 8.12 Hz, 1 H), 6.85 (t, J = 7.38 Hz, 1
H), 6.76 (t, J = 7.40 Hz, 1 H)ppm. 13C NMR (125 MHz,
CDCl3/DMSO): d = 187.11, 149.21, 143.11, 137.50, 137.29,
135.33, 130.35, 128.77, 128.33, 125.80, 123.72, 122.37,
120.55, 119.71, 112.17 ppm.
(8) Engqvist, R.; Javaid, A.; Bergman, J. Eur. J. Org. Chem.
2004, 2589.
(9) Butin, A. V.; Tsiunchik, F. A.; Abaev, V. T.; Zavodnik,
V. E. Synlett 2008, 1145.
(10) Majumdar, K. C.; Alam, S. J. Chem. Res. 2006, 5, 289.
(11) Jagodzinski, S. T. Chem. Rev. 2003, 103, 197.
(12) Saeidian, H.; Sadeghi, A.; Mirjafary, Z.; Moghaddam, F. M.
Synth. Commun. 2008, 38, 2043.
(13) Dömling, A. Chem. Rev. 2006, 106, 17.
(14) (a) Moghaddam, F. M.; Mirjafary, Z.; Saeidian, H.; Javan,
M. J. Synlett 2008, 892. (b) Moghaddam, F. M.; Saeidian,
H.; Mirjafary, Z.; Sadeghi, A. Lett. Org. Chem. 2007, 4,
576. (c) Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.;
Taheri, S. J. Sulfur Chem. 2006, 27, 545. (d) Moghaddam,
F. M.; Zali Boinee, H. Synlett 2005, 1612. (e) Moghaddam,
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(f) Moghaddam, F. M.; Zali Boinee, H. Tetrahedron Lett.
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Compound 17: mp 145–147 °C. 1H NMR (500 MHz,
CDCl3): d = 10.43 (s, 1 H), 8.38 (d, J = 7.95 Hz, 1 H), 7.48–
7.47 (m, 2 H), 7.42–7.40 (m, 1 H), 4.07 (s, 3 H), 3.67 (s, 2
H) ppm. 13C NMR (125 MHz, CDCl3): d = 186.02, 138.82,
136.22, 125.96, 125.84, 124.18, 122.13, 121.48, 115.69,
110.87, 31.17, 23.33 ppm.
(15) Representative Analytical Data
Compound 8b: 1H NMR (500 MHz, CDCl3): d = 12.08 (m,
1 H), 8.06 (d, J = 13.71 Hz, 1 H), 7.43 (d, J = 7.55 Hz, 1 H),
7.21 (t, J = 7.51 Hz, 1 H), 7.13–7.16 (m, 2 H), 3.77 (s, 3 H),
3.50–3.49 (m, 1 H), 2.11–2.07 (m, 2 H), 1.93–1.89 (m, 2 H),
1.69–1.59 (m, 3 H), 1.51–1.37 (m, 3 H) ppm. 13C NMR (125
MHz, CDCl3): d = 175.69 (C=S), 148.33 (CH), 139.86 (C),
127.68 (C), 123.16 (CH), 122.01 (CH), 114.61 (CH), 109.21
(16) (a) Scheeren, J. W.; Ooms, P. H. J.; Nivard, R. J. F. Synthesis
1973, 149. (b) Vogel, A. I.; Tatchell, A. R.; Furnis, B. S.;
Hannaford, A. J.; Smith, P. W. G. Vogel’s Textbook of
Practical Organic Chemistry, 4th ed; Longman: New York,
1978, 815.
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