Thiocarbonyl induced heterocumulenic Pauson-Khand type reaction: Expedient synthetic method for thieno[2,3-b]indol-2-ones

Article abstract of DOI:10.1039/b712739a

The first examples of C=S induced Pauson-Khand type reactions are described; 2-alkynylphenyl isothiocyanates were converted to 3-substituted-2H-thieno[2,3-b]indol-2-ones in the presence of a stoichiometric amount of Mo(CO)₆ or Co₂(CO

Full text of DOI:10.1039/b712739a

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Thiocarbonyl induced heterocumulenic Pauson–Khand type reaction:
expedient synthetic method for thieno[2,3-b]indol-2-ones{
Takao Saito,* Hiroshi Nihei, Takashi Otani, Toshiyuki Suyama, Naoki Furukawa and Masatoshi Saito
Received (in Cambridge, UK) 17th August 2007, Accepted 28th September 2007
First published as an Advance Article on the web 16th October 2007
DOI: 10.1039/b712739a
a streptomycete strain identified as Streptomyces albogriseolus
The first examples of CLS induced Pauson–Khand type
MJ286-76F6, has both growth promoting and inhibiting activities
in rice seedlings.10
reactions are described; 2-alkynylphenyl isothiocyanates were
converted to 3-substituted-2H-thieno[2,3-b]indol-2-ones in the
presence of a stoichiometric amount of Mo(CO)6 or Co2(CO)8,
or a catalytic amount of Rh catalyst under an atmospheric
pressure of carbon monoxide.
The Pauson–Khand (PK) reaction (including the Pauson–Khand
type reaction) is a metal-promoted three-component reaction,
formulated as a formal [2 + 2 + 1] cocycloaddition of an alkyne, an
alkene and carbon monoxide leading to a cyclopentenone.1,2
Allenes instead of alkenes have also been utilized successfully in the
PK reaction to give 4- and/or 5-alkylidenecyclopentenones.3 The
hetero PK reaction using a heteroalkene counterpart such as an
aldehyde, ketone or imine, leading to, e.g., d-butyrolactones or
lactams, has been reported.4 Extensive efforts have been made to
develop transition metal-catalyzed transformations in carbo- and
heterocyclic synthesis.5 Nevertheless, the known PK (type)
reagents (metal carbonyl complexes, promoters) which are
applicable to the hetero PK (type) reaction seem to be still very
limited compared to those for the carbo PK reaction.
To explore the feasibility of an isothiocyanate-PK reaction and
to develop a new synthetic method for the target thienoindole
derivatives, we took advantage of an intramolecular variant by
choosing alkynyl-isothiocyanate 4, in which an isothiocyanate
function and an alkynyl group are present as ortho substituents on
a benzene ring. Scheme 1 illustrates our preparative method for
o-alkynylphenyl isothiocyanates11 4 from commercially available
o-iodoaniline via (a) Sonogashira coupling, (b) conversion to the
iminophosphorane and (c) aza-Wittig reaction with CS2. The
substrates 4a–4h were obtained in high yields (Table 1).
We first carried out the PK reaction of 4a using Co2(CO)8
(Scheme 2).1 TheresultsareshowninTable2. When4a wastreated
with Co2(CO)8 (1.1 equiv.) in the absence of a promoter in CH2Cl2
at room temperature for 40 h, the expected PK product 5a, the
2H-thieno[2,3-b]indol-2-one, was obtained in 21% yield (entry 1).
Heating in toluene or THF–dimethyl sulfoxide (DMSO)12 was
much less effective (0–8% yield of 5a, entries 2 and 3). Remarkably,
N-methylmorpholine-N-oxide (NMO, 6 equiv.)13 promotes the
reaction very well to give 2,3-dihydrothieno[2,3-b]indol-2-one 6a
in 46% yield together with a small amount of 5a (2% yield, entry 4).
The formation of 6a can be regarded as a result of a reductive PK
reaction.2b,14 In fact, 6a was formed in good yield from 5a when
isolated 5a was treated with Co2(CO)8 (1.0 equiv.) in the presence
of NMO (6 equiv.) in CH2Cl2.
Very recently, we succeeded in performing the stoichiometric
and catalytic heterocumulenic PK cyclocarbonylation that incor-
porates a carbodiimide function together with an internal alkyne
and carbon monoxide to give 1H-pyrrolo[2,3-b]indol-2-ones and
4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones.6 Mukai et al.
reported a Co2(CO)8-catalyzed version of the method for
construction of the pyrrolo[2,3-b]indol-2-one ring system and
applied the method to the synthesis of the indole alkaloid, (¡)-
physostigmine.7 To develop the heterocumulenic PK method,8 we
next focused on a thiacumulenic PK reaction using an isothiocya-
nate system.8a Despite the expectation that a thiocarbonyl bond-
involved PK reaction would be a convenient method for the
synthesis of thiolactones, no successful thia-PK reactions have
been reported so far.
15
Next, we used Mo(CO)6 in the PK reaction of 4a since this
catalyst proved to be effective in the stoichiometric carbodiimide-
PK reaction.6a Treatment of 4a with Mo(CO)6 in the absence of a
We report here an isothiocyanate PK reaction, which represents
the first example of a hetero PK reaction involving a thiocarbonyl
functionality. Furthermore, the present PK reaction also offers a
novel and efficient synthetic method for 2H-thieno[2,3-b]indol-2-
ones. Thieno[2,3-b]indole derivatives are also target compounds
because they have potentially biological activities.9 For example,
thienodolin (I), which was isolated from the fermentation broth of
Department of Chemistry, Faculty of Science, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.
E-mail: tsaito@rs.kagu.tus.ac.jp
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and characterization data for all new compounds. See
DOI: 10.1039/b712739a
Scheme 1 Preparation of o-alkynyl isothiocyanates. Reagents and
conditions: (a) Pd(PPh3)2Cl2 (2 mol%), CuI (1 mol%), Et3N, rt, 2 h; (b)
PPh3 (1.2 equiv.), C2Cl6 (1.2 equiv.), Et3N (2.4 equiv.), benzene, rt, 4 h; (c)
CS2, rt, 12 h.
172 | Chem. Commun., 2008, 172–174
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Table 1 Yields of isolated products 2–4
Table 3 Pauson–Khand reaction of 4 bearing a variety of substitu-
ents
Yield (%)
Yielda (%)
Entry
R
1–4
2
3
4
Entry
4
R
R9
R0
5
7 (E : Z)b
1
2
3
4
5
6
7
8
t-Bu
i-Pr
n-Bu
n-Pen
n-Hex
Bn
a
b
c
d
e
f
99
98
99
99
99
99
99
99
85
81
77
78
82
78
75
81
96
88
99
99
99
90
99
86
1
2
3
4
4a
4b
4c
4d
4e
4f
t-Bu
i-Pr
—
—
Me
H
H
H
H
—
—
75
32
0
0
0
0
14
64
—
22
Me
n-Pr
n-Bu
n-Pen
Ph
n-Bu
n-Pen
n-Hex
Bn
50 (70 : 30)
54 (69 : 31)
59 (71 : 29)
58 (.95 : 5)
—
5
TMS
TBS
g
h
6
7c
8c
a
4g
4h
TMSd
TBSe
—
—
—
b
c
Isolated yield. Ratio in equilibrium. Substrate 4g,4h was slowly
2
d
added during the reaction; time
t-Butyldimethylsilyl.
h.
Trimethylsilyl.
e
yields without the initial products 5c–5f (entries 3–6). Isomers E-7
and Z-7 were separated by column chromatography on silica gel
and their geometries were determined from NMR spectroscopy
(NOE). It was found that they isomerized readily to reach
equilibrium in CDCl3. The E : Z ratios of isomers 7c–7f depended
upon the substituent R9. While the reaction of unsubstituted
ethynylphenyl isothiocyanate 4 (R = H) failed to afford any
cycloadduct 5 or 6, the silyl substituted isothiocyanates 4g (R =
TMS) and 4h (R = TBS) gave the corresponding PK products 5g
and 5h in 14 and 64% yields, respectively (entries 7 and 8). Product
5h is stable enough to allow its isolation in better yield, whereas 5g
gradually decomposes during the reaction and work-up. The TBS-
substituted thienoindolone 5h was readily converted to an
analogue, 8, of a thienodolin (I) precursor via the dihydro
derivative 6h (Scheme 4).
Scheme 2 Pauson–Khand reaction of 4a with Co2(CO)8 or Mo(CO)6.
promoter in refluxing toluene resulted in a complex mixture
containing only a trace amount of the expected 3-tert-butyl-
2H-thieno[2,3-b]indol-2-one (5a) (entry 5). After screening promo-
ters and reaction conditions, DMSO was found to give the best
yield of 5a (75%, entry 9).
Under the optimized reaction conditions (entry 9, Table 2), the
Mo(CO)6-mediated PK reactions of isothiocyanates 4b–4f bearing
a variety of substituents (R) on the acetylene carbon were
performed (Scheme 3, Table 3). Surprisingly, the reaction of 4b
(R = i-Pr) afforded the H-migrated PK product 7b in 22% yield
and 5b in 32% yield (entry 2). Compound 7b must be formed by
1,5-H migration from 5b rather than by the direct PK reaction of
the allenylphenyl isothiocyanate generated from 4b under the
conditions, because separated 5b was transformed into 7b
quantitatively under the same reaction conditions. The reactions
of 4c–4f, bearing a primary alkyl group or benzyl group at R,
afforded 7c–7f as E,Z-isomer mixtures (ca. 7 : 3) in relatively good
Since the early report of the catalytic PK reaction by Pauson
and co-workers,1b catalytic PK reactions, including asymmetric
variants, have also been extensively studied.2 In these catalytic PK
reactions, Co,2,16 Ti,17 Ru,18 Rh,19 and Ir20 complexes were often
used as transition metal catalysts. We recently succeeded with
catalytic carbodiimide-PK reactions using in situ prepared
[RhCl(CO)dppp]2 under an atmospheric pressure of carbon
monoxide, and therefore, we applied the catalytic system to the
isothiocyanate-PK reaction (Scheme 5). Treatment of 4a in the
presence of [RhCl(CO)dppp]2 (5 mol%), prepared from
[RhCl(cod)]2 (5 mol%) and dppp (11 mol%) under a carbon
monoxide atmosphere in refluxing toluene, resulted in the
formation of 5a in only 5% yield (Table 4, entry 1). Gratifyingly,
however, the isothiocyanates 4b–4f, bearing various substituents
Table 2 Pauson–Khand reaction of 4a with Co2(CO)8 or Mo(CO)6
Yielda (%)
Mx(CO)y Promoter
Entry 1.1 equiv. Solvent (equiv.)
Conditions 5a
6a
1
2
3
4
5
6
7
8
9b
a
Co2(CO)8 DCM None
Co2(CO)8 MePh None
40 h, rt
1 h, 115 uC
21
0
8
0
0
0
46
0
0
0
0
0
Co2(CO)8 THF
Co2(CO)8 DCM
DMSO (5.0) 1 h, 50 uC
NMO (6.0) 0.1 h, rt
2
Mo(CO)6 MePh None
Mo(CO)6 MePh DMF (5.0)
Mo(CO)6 MePh DMF (5.0)
3 h, 115 uC Trc
3 h, 115 uC
0
1 h, 115 uC Trc
Mo(CO)6 MePh DMSO (5.0) 2 h, 115 uC 60
Mo(CO)6 MePh DMSO (10) 3 h, 115 uC 75
b
c
Isolated yield. 2.0 equiv. of Mo(CO)6 was used. Trace amount
of 5a was detected in a crude mixture.
Scheme 4 Conversion of 5h to dihydrothieno[2,3-b]indolone 8.
Scheme 3 Pauson–Khand reaction of 4 with Mo(CO)6.
Scheme 5 Rhodium catalyzed Pauson–Khand reaction of 4.
Chem. Commun., 2008, 172–174 | 173
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Table 4 Rhodium-catalyzed Pauson–Khand reaction of 4
Yielda (%)
7 C. Mukai, T. Yoshida, M. Sorimachi and A. Odani, Org. Lett., 2006, 8,
83.
8 (a) This research was presented at: 85th Annual Meeting of the
Chemical Society of Japan, Yokohama, March, 2005, Abstract 1B2-25;
(b) Very recently, the Ru-catalyzed intermolecular PK type cocyclization
of isocyanates has been reported. T. Kondo, M. Nomura, Y. Ura,
K. Wada and T. Mitsudo, J. Am. Chem. Soc., 2006, 128, 14816; see also:
(c) Y. Ohshiro, K. Kinugasa, T. Minami and T. Agawa, J. Org. Chem.,
1970, 35, 2136; (d) H. Hoberg and B. W. Oster, J. Organomet. Chem.,
1982, 234, C35.
9 (a) M. Soledade, C. Pedras and M. Suchy, Bioorg. Med. Chem., 2006,
14, 714. Despite the relative simplicity of the structure, there is only one
report on the total synthesis of thienodolin (I): (b) R. Engqvist, A. Javaid
and J. Bergman, Eur. J. Org. Chem., 2004, 2589. For synthesis of
thieno[2,3-b]indoles, see: (c) K. C. Majumdar and S. Alam, J. Chem.
Res., 2006, 289; (d) J. Levy, D. Royer, J. Guilhem, M. Cesario and
C. Pascard, Bull. Soc. Chim. Fr., 1987, 193; (e) P. Olesen, J. Hansen and
M. Engelstoft, J. Heterocycl. Chem., 1995, 32, 1641.
10 (a) K. Kanbe, M. Okamura, S. Hattori, H. Nakagawa, K. M. Hamada,
Y. Okami and T. Takeuchi, Biosci., Biotechnol., Biochem., 1993, 57, 632;
(b) K. Kanbe, H. Nakagawa, K. T. Nakamura, Y. Okami and
T. Takeuchi, Biosci., Biotechnol., Biochem., 1993, 57, 636.
11 There is a report of the preparation of isothiocyanate 4 (R = Ph) from
the reaction of 2 (R = Ph) with thiophosgene: (a) L. Benati, G. Calestani,
R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo, S. Strazzari and
G. Zanardi, J. Org. Chem., 2003, 68, 3454; (b) M. Minozzi, D. Nanni,
G. Zanardi and G. Calestani, ARKIVOC, 2006(6), 6.
Entry
4
R
R9
R0
5
7
1
2
3
4
5
6
a
4a
4b
4c
4d
4e
4f
t-Bu
i-Pr
n-Bu
n-Pen
n-Hex
Bn
—
Me
n-Pr
n-Bu
n-Pen
Ph
—
Me
H
H
H
5
Trace
0
0
0
0
—
52
46
45
50
50
H
Isolated
yield.
E
+
Z
mixture
for
7.
dppp:
diphenylphosphinopropane.
such as a secondary alkyl (i-Pr), primary alkyl (n-Bu, n-Pen, n-Hex)
or arylalkyl (Bn) group on the acetylene carbon, reacted efficiently
to afford the PK products 7b–7f in fairly good yields.
In conclusion, we have developed stoichiometric and catalytic
isothiocyanate PK reactions that are the first CLS bond-involved
PK (type) cyclocarbonylations. Continued studies to extend this
thia- and heterocumulenic PK method to provide thienodolin (I)
and a variety of heterocycles are under way.
This work was partly supported by a Grant-in-Aid for Young
Scientist (B) from JSPS (to T. O.).
12 Y. K. Chung, B. Y. Lee, N. Jeong, M. Hudecek and P. L. Pauson,
Organometallics, 1993, 12, 220.
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1990, 31, 5289; (b) N. Jeong, Y. K. Chung, B. Y. Lee, S. H. Lee and
S.-E. Yoo, Synlett, 1991, 204.
14 (a) A.-M. Montan˜a, A. Moyano, M. A. Pericas and F. Serratosa,
Tetrahedron, 1985, 41, 5995; (b) C.-S. Li and E. Lacassew, Tetrahedron
Lett., 2002, 43, 3565.
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1993, 34, 4027; (b) J. L. Kent, H. Wan and K. M. Brummond,
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174 | Chem. Commun., 2008, 172–174
This journal is ß The Royal Society of Chemistry 2008