TfOH-promoted transformation from 2-alkynylphenyl isothiocyanates to quinoline-2-thiones or indoles

Article abstract of DOI:10.1016/j.tetlet.2009.04.045

A variety of 4-arylquinoline-2-thiones and 3-arylthieno[2,3-b]indoles were synthesized in high yields via TfOH-promoted tandem Friedel-Crafts alkenylation-cyclization reactions of 2-alkynylphenyl isothiocyanates.

Full text of DOI:10.1016/j.tetlet.2009.04.045

Tetrahedron Letters 50 (2009) 3853–3856
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Tetrahedron Letters
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TfOH-promoted transformation from 2-alkynylphenyl isothiocyanates
to quinoline-2-thiones or indoles
*
*
Takashi Otani , Shinichi Kunimatsu, Taku Takahashi, Hiroshi Nihei, Takao Saito
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 February 2009
Revised 7 April 2009
Accepted 9 April 2009
Available online 14 April 2009
A variety of 4-arylquinoline-2-thiones and 3-arylthieno[2,3-b]indoles were synthesized in high yields via
TfOH-promoted tandem Friedel–Crafts alkenylation–cyclization reactions of 2-alkynylphenyl isothio-
cyanates.
Ó 2009 Elsevier Ltd. All rights reserved.
Azacumulenes, such as isocyanates, isothiocyanates, and carbo-
diimides, are versatile building blocks for the synthesis of nitrogen-
containing heterocycles because azacumulenes can participate in
roacetic acid was very low (entry 1). Similarly, Tf2NH, MeSO3H, and
C8F17SO3H did not work sufficiently well for the formation of the
required 3a (entries 2–4). On the other hand, sulfuric acid was
found to be a better catalyst (entry 5), and TfOH showed the high-
est catalytic activity (entry 6 vs entries 1–5). Gratifyingly, isothio-
cyanate 1A was completely converted to 3a in the presence of
3.0 equiv of TfOH in 10 min. (entry 8). Similarly, 2-(2-(trimethyl-
silyl)ethynyl)phenyl isothiocyanate (1B) and 2-(1-ethynyl)phenyl
isothiocyanate (1C) afforded 3a. However, the yields (88% and
87%, respectively, of 3a) are slightly lower than that of the reaction
of 1A. We assumed that an excess of TfOH is required to maintain
the high acidity of the reaction mixture because the products are
basic compounds and would reduce the acidity of the reaction
mixture.
various cyclizations, serving as an electrophile or a 2p component
with high reactivity. For example, multi-functionalized azacumu-
lenes such as N-(2-alkynylphenyl)azacumulenes have attracted
attention, and their transformation into poly-substituted and/or
ring-fused indoles has been investigated intensively.1 However,
their transformation into quinoline derivatives has hardly been
reported.1i,2 Because of our ongoing interest in the reactions of
functionalized carbodiimides,3 we envisioned that
a tandem
Friedel–Crafts alkenylation4–cyclization strategy applied to N-(2-
alkynylphenyl) isothiocyanates (1) could be an alternative for the
quinoline and indole syntheses (Scheme 1).
Our initial study showed that In(III) promoted the reaction of 2-
(3,3-dimethylbutynyl)phenyl isothiocyanate (1A) with arenes to
afford 4-arylquinoline-2-thiones with elimination of isobutene
from the t-Bu group (R = t-Bu ? H) via path a in Scheme 1; how-
ever, the reaction required high temperature (>120 °C), and one
or more electron-donating groups on the arene.5 In recent years,
stronger Brønsted acids6 have been used successfully in Friedel–
Crafts alkenylation reactions at lower temperatures.7 Therefore,
to widen the scope of our tandem strategy, we examined reactions
using Brønsted acids as effective and inexpensive promoters in-
stead of In(III). We report here a trifluoromethanesulfonic acid
(TfOH)-induced facile and regioselective transformation from
N-(2-alkynyl)phenyl isothiocyanates into not only poly-substi-
tuted quinoline-2(1H)-thiones (Scheme 1, path a) but also indo-
line-2-thiones (path b).
Based on the above results, we examined the reactions of 1A with
a variety of arenes in the presence of 3.0 equiv of TfOH at 0 °C or
20 °C (Table 2). Arenes bearing one or more electron-donating
groups reacted smoothly to provide the corresponding quinoline-
2-thiones 3b–h in nearly quantitative yields (entries 1–7). It is note-
worthy that even halobenzenes 2i–k of electron-poor nucleophiles
could react with 1A to provide the corresponding quinolines 3i–k
Ar
Ar
R
S
path a
R
Ar–
a
H
b
H
N
N
S
•
H
R
2'
1'
First, we evaluated the catalytic activity of various Brønsted
acids in the reaction of 2-(3,3-dimethylbutynyl)-phenyl isothiocy-
anate (1A) with benzene (Table 1). The catalytic activity of trifluo-
Ar
N
S
R
•
1
S
path b
N
H
* Corresponding authors. Tel.: +81 3 5228 4272; fax: +81 3 5261 4631 (T.O.).
E-mail addresses: totani@rs.kagu.tus.ac.jp (T. Otani), tsaito@rs.kagu.tus.ac.jp (T.
Saito).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.045

3854
T. Otani et al. / Tetrahedron Letters 50 (2009) 3853–3856
Table 1
Table 2
Optimization of Brønsted acidsa
Scope of arenesa
Ph
Ar
TfOH
t-Bu
t-Bu
Brønsted
Acid
0 °C
(3.0 equiv)
+ PhH (neat)
2a
+ Ar–H
0 °C
10 min
N
H
S
N
H
S
2b–k
N
S
•
N
S
•
1A
3a
NMR yield (%)
3Aa 1A (S.M.)
1A
3b–k
Yieldb (%)
98
Entry
Brønsted acid
Equiv
Time (h)
Entry
2: Ar–H
Product
p:oc
1
2
3
4
5
6
7
8
CF3COOH
Tf2NH
MeSO3H
C8F17SO3H
H2SO4
TfOH
TfOH
TfOH
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
10 min
2
7
2
1
16
28
57
100
98
93
98
99
84
72
43
0
MeO
H
1
3b
55:45
2b
OMe
2d
3c
84
97
—
H
a
2c
MeO
Me
All reactions were carried out using 0.50 mmol of 1A in 2 mL of 2a.
OMe
albeit in moderate yields (entries 8–10), because In(III) did not pro-
mote the reaction with 2 k despite heating at 200 °C for 10 h.
Next, with the expectation of obtaining 3,4-disubstituted quin-
olines 4Db, 2-(1-hexynyl)phenyl isothiocyanate (1D) was sub-
jected to the TfOH-promoted reaction with anisole (2b) (Table 3).
To our surprise, 1D reacted with anisole on the C-20 atom to pro-
vide (E)-1,3-dihydro-3-(1-(p-methoxy-phenyl)pentylidene)-2H-in-
dol-2-thione (5Db) exclusively in 83% yield, when the reaction was
carried out in the presence of TfOH at ꢀ40 °C (entry 1). Although
5Db is stable in the solid state for months, partial oxidative cycli-
zation occurred in solution to give 8H-thieno[2,3-b]indole 6Db.
When the separated 5Db was left in DMF below 20 °C under aero-
bic conditions for 5 h, 6Db was obtained in 98% yield. For this rea-
son, 6Db was indeed obtained instead of 5Db at 60 °C and 120 °C
(entries 3 and 4). Thieno[2,3-b]-indoles are expected to have
important physiological activities such as growth-promoting and
growth-inhibiting activities in rice seedlings,8 and only a few
methods for accessing the ring system have been reported.9 The
present method provides a facile way to create 3-arylthienoindoles
6. On the other hand, 3-butyl-4-(methoxyphenyl)-2(1H)-quinolin-
ethione (4Db) was also formed, and the yields increased in accord
with rising temperature from 20 °C to 60 °C (entries 2 and 3). At
120 °C, the reaction became messy and the yield of 4Db decreased
slightly (39%, entry 4). When the reaction was carried out in the
presence of In(OTf)3 at 120 °C, the highest yield of 4Db was ob-
tained (53%, entry 5).
Having optimized the conditions (Table 3, entry 1), we wanted
to confirm the generality of the protocol for the synthesis of indo-
lines 5 and thienoindoles 6 having a variety of substituents. Thus,
isothiocyanates 1D–F were allowed to react with arenes 2b, 2c, 2g
in the presence of TfOH (3.0 equiv) at ꢀ40 °C (Table 4). In all
entries, aqueous work-up of the mixture gave the corresponding
indoline-2-thiones 5 in an almost pure state, with no quinoline-
2-thiones 4 detected. The indolinethiones 5Dg, 5Eb, 5Eg, 5Fg were
isolated while 5Dc, 5Ec, 5Fb, 5Fc were not, because conversion of
the latter compounds to thienoindoles 6 occurred rapidly. Thus,
thienoindoles 6 were obtained in good to excellent yields.
3
3d
76:24e
H
2d
OMe
4e
3e
3f
93
99
95
>95:5e
78:22
—
H
2e
Br
5
Me
H
2f
Me
6
3g
H
2g
Me
Me
Me
7
3h
92
—
H
2h
Me
8f
9f
3i
61
59
55
>95:5
>95:5
>95:5
Br
Cl
I
H
2i
H
2j
3j
10f
3k
H
2k
a
All reactions were carried out using 0.50 mmol of 1A in 2 mL of 2.
Isolated yield of a mixture of o- and p-isomers.
Ratio determined by 1H NMR.
Dichloromethane (2 mL) was added as a solvent.
Ratio of o:m with respect to MeO group.
At 20 °C.
b
c
d
e
f
It is noteworthy that the arenes added to the C-20 atom of the
alkyne moiety in 1D–F leading to 5/6 (Table 4). As far as we know,
the reported intermolecular Friedel–Crafts alkenylations of aryl al-
kynes all took place on the C-10 atom.4,6 Indeed, when 3-phenyl-1-
propyne (7), instead of 1E, was treated with p-xylene (2g) in the
presence of TfOH at ꢀ40 °C, the reaction occurred at the C-1 atom
of 7 to afford (Z)-1-(2,5-dimethylphenyl)-1-phenyl-1-propene (8)
in 74% yield (Scheme 2). Addition of the arene to the C-20 atom
of the alkyne moiety (Table 4) could be reasonably explained in
terms of participation of the neighboring isothiocyanate group at
an early stage of the reaction of 1D–F. Thus, the protonated isothi-
ocyanate group might undergo intramolecular reaction with the al-
kyne moiety of 1D–F, and vinyl cation 9 could be generated. This
cation might react with arene to give 5 as the final product
(Scheme 3).
Meanwhile, a possible pathway for the TfOH-promoted forma-
tion of quinoline-2-thiones 4 is illustrated in Scheme 4. At a higher
temperature, further protonation of the resulting monocation 9

T. Otani et al. / Tetrahedron Letters 50 (2009) 3853–3856
3855
Table 3
Reactions of 1D with 2b under various conditionsa
Me
Me
Me
Me
TfOH
TfOH (3.0 equiv)
(40 mol %)
+
Me
Me
1'
or
n-Bu
–40 °C
74%
In(OTf)3 (1.0 equiv)
+
OMe
7
2g
8
N
1D
S
•
2b
Scheme 2.
DMF, 20°C
OMe
MeO
98%
OMe
n-Bu
S
Y
Y
R
2'
n-Bu
R
2
n-Pr
+
+
S
S
TfOH
N
H
S
N
•
S
N
H
5Db
N
H
6Db
at a lower
temperature
N
H
1
5
4Db
Y
Entry
Acid
Conditions
Isolated yield (%)
TfOH
4Dbb (o:p)c
—
27 (37:63)
40 (38:62)
39 (35:65)
53 (33:67)
5Db
83
62
—
6Db
—
—
49
27
—
1
2
3
4
5
TfOH
TfOH
TfOH
TfOH
ꢀ40 °C, 3 h
R
R
20 °C, 10 min
60 °C, 10 min
120 °C, 10 min
120 °C, 4 h
—
—
S
In(OTf)3
N
•
S
N
a
H
H
All reactions were carried out using 0.50 mmol of 1D in 2 mL of 2b.
Isolated yield of a mixture of o- and p-isomers.
Ratio determined by 1H NMR.
b
c
9
Scheme 3.
could occur, yielding dication 11. This dication could react with
arene 2 to give 12, which could cyclize to 4 as the final product.
In summary, we have found that TfOH is a superior promoter for
the tandem Friedel–Crafts alkenylation–cyclization reaction of 2-
alkynylphenyl isothiocyanates. Thus, the reaction between 1A–C
and arenes furnished 4-aryl-3-unsubstituted quinoline-2-thiones
3 at 0 °C. On the other hand, the reaction of 1D–F produced indo-
line-2-thiones 5, which were readily converted to the correspond-
R
R
TfOH
TfOH
1
N
• S
N
•
S
at a higher
temperature
H
H
9
11
Y
Y
Y
Table 4
Generality of the formation of indoline-2-thiones 5 and thienoindoles 6a
2
R
R
R
TfOH (3.0 equiv)
+
Ar–H
N
H
S
N
• S
−40 °C
H
2b,c,g
3 h
N
S
12
4
•
1D
2b
(R = n-Pr)
1E (R = H)
1F (R = Ph)
: MeOC6H5
2c: p-MeOC6H4OMe
2g: p-MeC6H4Me
Scheme 4.
R
Ar
Ar
R
ing thienoindoles
6
via the dehydrogenative cyclization.
Applications of this method for the synthesis of a variety of the
nitrogen-containing heterocycles are currently under way in our
laboratory.
S
DMF
20 °C
time
S
N
H
N
H
5
6
Supplementary data
Entry
1
2
5 Yield (%)
Time (h)
6 Yield (%)
1b
2
1D
1D
1E
1E
1E
1F
1F
1F
2c
2g
2b
2c
2g
2b
2c
2g
—
4
6Dc (81)c
6Dg (96)
6Eb (92)d
6Ec (80)c
6Eg (74)
6Fb (57)c
6Fc (58)c
6Fg (97)
Supplementary data (general information, procedure, com-
pound data and NMR spectral data for all new compounds) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.04.045.
5Dg (82)
5Eb (85)
—
5Eg (74)
—
25
16
5
30
4
3
4b
5
6
7b
8
—
3
10
References and notes
5Fg (52)
a
All reactions were carried out using 0.50 mmol of 1 in 2 mL of 2.
Dichloromethane (2 mL) was added as a solvent.
Two-step yield from 1.
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p:o = > 95:5.

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T. Otani et al. / Tetrahedron Letters 50 (2009) 3853–3856
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