Synthesis of quinoline-2-thiones via tandem indium(III)-promoted friedel-crafts alkenylation-cyclization of 2-alkynylphenyl isothiocyanates

Article abstract of DOI:10.1021/ol7024668

A new approach to the synthesis of 4-aryl- or 4-arylthioquinoline-2-thiones via indium(III) reagent-mediated tandem Friedel-Crafts alkenylation-cyclization of 2-alkynylphenyl isothiocyanates is described.

Full text of DOI:10.1021/ol7024668

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5513-5516
Synthesis of Quinoline-2-thiones via
Tandem Indium(III)-Promoted
Friedel−Crafts Alkenylation−Cyclization
of 2-Alkynylphenyl Isothiocyanates
Takashi Otani,* Shinichi Kunimatsu, Hiroshi Nihei, Yuko Abe, and Takao Saito*
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
totani@rs.kagu.tus.ac.jp; tsaito@rs.kagu.tus.ac.jp
Received October 10, 2007
ABSTRACT
A new approach to the synthesis of 4-aryl- or 4-arylthioquinoline-2-thiones via indium(III) reagent-mediated tandem Friedel
−Crafts alkenylation−
cyclization of 2-alkynylphenyl isothiocyanates is described.
The quinoline ring system is commonly found in a broad
range of both natural and synthetic biologically active
compounds. Although the structural core of quinolines can
be prepared using various conventional methods such as
Skraup, Friedla¨nder, Do¨bner-Miller, Pfitzinger, and Con-
rad-Limpach syntheses, the development of new synthetic
methods for these species is always of fundamental impor-
tance in organic chemistry. For example, quinoline-2-thiones
have been investigated from a variety of viewpoints, such
as synthetic intermediates,1 biologically active compounds,2
sulfur-nitrogen mixed donor ligands,3 and protective groups
of thiols.4 The synthesis of quinoline-2-thiones is usually
achieved by thiation of corresponding quinoline-2-ones2,5 or
2-haloquinolines.1a,6 However, direct synthetic methods that
involve construction of a quinoline skeleton with simulta-
neous introduction of a thiocarbonyl have hardly been
(3) For examples, see: (a) Xavier, J. Fresenius’ J. Anal. Chem. 1958,
163, 182. (b) Nakano, S.; Yoshida, T.; Taniguchi, H.; Suzuki, N. Chem.
Pharm. Bull. 1977, 25, 1658. (c) Leeaphon, M.; Ondracek, A. L.;
Thomas, R. J.; Fanwick, P. E.; Walton, R. A. J. Am. Chem. Soc. 1995,
117, 9715.
(4) For examples, see: (a) Zhang, J.; Matteucci, M. D. Tetrahedron Lett.
1999, 40, 1467. (b) Nakamura, S.; Furutani, A.; Toru, T. Eur. J. Org. Chem.
2002, 1690.
(5) For examples, see: (a) Albert, A.; Barlin, G. B. J. Chem. Soc.
1959, 2384. (b) Wilhelm, M.; Schmidt, P. HelV. Chim. Acta 1970, 53,
1697.
(6) For examples, see: (a) Tanasescu, I.; Denes, I.; Rusu, G. Chem. Ber.
1957, 90, 1295. (b) Ismail, M. M.; Abass, M.; Hassan, M. M. Molecules
[online computer file] 2000, 5, 1224. (c) Nithyadevi, V.; Sampathkumar,
N.; Rajendran, S. P. Asian J. Chem. 2004, 16, 1594.
(1) For examples, see: (a) Alhaider, A. A.; Abdelkader, M. A.; Lien, E.
J. J. Med. Chem. 1985, 28, 1394. (b) Segawa, J.; Kitano, M.; Kazuno, K.;
Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.
J. Med. Chem. 1992, 35, 4727. (c) Jinbo, Y.; Taguchi, M.; Inoue, Y.; Kondo,
H.; Miyasaka, T.; Tsujishita, H.; Sakamoto, F.; Tsukamoto, G. J. Med.
Chem. 1993, 36, 3148.
(2) For example, see: Joseph, B.; Darro, F.; Behard, A.; Lesur, B.;
Collignon, F.; Decaestecker, C.; Frydman, A.; Guillaumet, G.; Kiss, R. J.
Med. Chem. 2002, 45, 2543.
10.1021/ol7024668 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/21/2007

reported so far.7 From our ongoing interests in the synthesis
of nitrogen-containing heterocycles using functionalized
azacumulenes as key intermediates,8 we envisioned that a
tandem nucleophilic reaction-cyclization of N-(2-alkynyl-
phenyl)isothiocyanate9 would be a convenient synthetic
method for quinoline-2-thiones if the nucleophile first attacks
the alkyne and a subsequent cyclization involving the cumu-
lene function occurs (Scheme 1). To achieve this strategy,
the yield was unsatisfactory (37%, entry 1). Interestingly,
the same compound 3a was obtained by use of the masked
1a, 2-(trimethylsilylethynyl)phenyl isothiocyanate (1b), and
2-(3,3-dimethylbutynyl)phenyl isothiocyanate (1c), giving
3a in 86 and 94% yields, respectively (entries 2 and 3).
The formation of 3-tert-butyl or 3-trimethylsilylquinoline-
2-thione was not observed in the crude mixture. Among
the alkynes 1a-c examined, 1c was found to provide the
best yield of 3a, and hereafter we used 1c.12 Indium(III)
halides13 were also effective catalysts for these reactions.
InCl3 required 2.0 equiv amounts and longer reaction time
to give 3a in quantitative yield (entry 4). InBr3 shortened
the reaction time while maintaining a 95% yield of 3a
(entry 5). When the amount of InBr3 was reduced to 0.40
equiv, the yield decreased to 38% (entry 6). These results
suggest that the reaction requires a stoichiometric amount
of the indium(III) reagent. To prove the superiority of
In(III) reagents, some other Lewis acids were examined in
the reaction of 1c with anisole at 150 °C. Sc(OTf)3, which
was successfully used in the Friedel-Crafts alkenylation of
1-phenyl-1-propyne,11a gave only a trace amount of 3a
with recovery of the majority of 1c. Among other Lewis
acids tested, only BF3‚Et2O promoted the reaction to give
the expected 3a in 21% yield. Using AlCl3, Cu(OTf)2,
and PdCl2(PPh3)2 resulted in the formation of complex
mixtures.
Scheme 1
important points are the choice of the nucleophile (NuH)
and activation of the alkyne moiety because a nucleophile
usually first attacks an isothiocyanate group of higher
reactivity than an alkyne moiety.10 In this context, metal-
promoted Friedel-Crafts (FC) alkenylation11 of arenes with
alkynes would be the choice of triggered reaction for this
tandem reaction. We now wish to report our preliminary
results for the synthesis of 4-arylquinoline-2-thiones via
indium(III)-promoted tandem FC alkenylation-cyclization
of 2-alkynylphenyl isothiocyanates.
On the basis of these results, we examined the reaction
of 1c with a variety of arenes in the presence of InBr3 or
With the expectation of obtaining 3-unsubstituted quino-
lines, we first selected 2-ethynylphenyl isothiocyanate (1a)
as a substrate, electron-rich anisole as an arene, and In(OTf)3
which is known as an effective catalyst for the Friedel-
Crafts alkenylation11a (Table 1). The reaction in the presence
(7) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1989, 30,
2847.
(8) (a) Saito, T.; Nakane, M.; Endo, M.; Yamashita, H.; Oyamada, Y.;
Motoki, S. Chem. Lett. 1986, 1350. (b) Saito, T.; Nakane, M.; Miyazaki,
T.; Motoki, S. J. Chem. Soc., Perkin Trans. 1 1989, 2140. (c) Saito, T.;
Ohmori, H.; Furuno, E.; Motoki, S. J. Chem. Soc., Chem. Commun. 1992,
22. (d) Saito, T.; Ohkubo, T.; Maruyama, K.; Kuboki, H.; Motoki, S. Chem.
Lett. 1993, 1127. (e) Saito, T.; Ohmori, H.; Ohkubo, T.; Motoki, S. J. Chem.
Soc., Chem. Commun. 1993, 1802. (f) Saito, T.; Tsuda, K.; Saito, Y.
Tetrahedron Lett. 1996, 37, 209. (g) Saito, T.; Tsuda, K. Tetrahedron Lett.
1996, 37, 9071. (h) Saito, T.; Ohkubo, T.; Kuboki, H.; Maeda, M.; Tsuda,
K.; Karakasa, T.; Satsumabayashi, S. J. Chem. Soc., Perkin Trans. 1 1998,
3065. (i) Saito, T.; Shiotani, M.; Otani, T.; Hasaba, S. Heterocycles 2003,
60, 1045. (j) Saito, T.; Sugizaki, K.; Otani, T.; Suyama, T. Org. Lett. 2007,
9, 1239. (k) Saito, T.; Nihei, H.; Otani, T.; Suyama, T.; Furukawa, N.;
Saito M. Chem. Commun. In press.
Table 1. Optimization of Alkyne Moiety and Reagenta
(9) For synthesis and radical cyclization of N-(2-alkynylphenyl)iso-
thiocyanate, see: (a) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.;
Nanni, D.; Spagnolo, P.; Strazzari, S.; Zanardi, G. J. Org. Chem. 2003, 68,
3454.
(10) There are examples in which a nucleophile (amine, alcohol, thiol)
first attacked the heterocumulene followed by subsequent cyclization onto
an alkyne or alkene; see refs 8f, 8g, and 9.
InX3
(11) (a) Tsuchimoto, T.; Maeda, T.; Shirakawa, E.; Kawakami, T. Chem.
Commun. 2000, 1573. (b) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002,
67, 6264. (c) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami, Y.
Chem. Commun. 2003, 2454. (d) Song, C. E.; Jung, D.; Choung, S. Y.;
Roh, E. J.; Lee, S. Angew. Chem., Int. Ed. 2004, 43, 6183. (e) Tsuchimoto,
T.; Matsubayashi, H.; Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew.
Chem., Int. Ed. 2005, 44, 1336. (f) Tsuchimoto, T. J. Synth. Org. Chem.,
Jpn. 2006, 64, 752. (g) Soriano, E.; Marco-Contelles, J. Organometallics
2006, 25, 4542. (h) Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219.
(i) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem.
2007, 72, 4462.
entry
1
R
X
equiv conditions yieldb
o:p c
1
2
3
4
5
6
1a
H
OTf
1.0
1.0
1.0
2.0
1.5
0.4
150 °C, 3 h
150 °C, 1 h
120 °C, 1 h
150 °C, 9 h
150 °C, 2 h
150 °C, 7 h
37
86
94
99
95
38
29:71
47:53
47:53
37:63
40:60
43:57
1b TMS OTf
1c t-Bu
1c t-Bu
1c t-Bu
1c t-Bu
OTf
Cl
Br
Br
a All reactions were carried out using 0.50 mmol of 1 in 2 mL of 2a.
b Isolated yield of a mixture of o- and p-isomers. c Ratio determined by 1H
NMR.
(12) The reaction of 1 bearing another substituent in R, e.g., n-Bu, with
1,4-dimethoxybenzene in the presence of 1.0 equiv of In(OTf)3 at 120 °C
for 4 h gave 3-butyl-4-(2,5-dimethoxyphenyl)-2(1H)-quinolinethione in 53%
yield.
(13) (a) Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969. (b) Agnusdei,
M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A. J. Org. Chem. 2003, 68,
7126. (c) Angeli, M.; Bandini, M.; Garelli, A.; Piccinelli, F.; Tommasi, S.;
Umani-Ronchi, A. Org. Biomol. Chem. 2006, 4, 3291.
of 1.0 equiv of In(OTf)3 proceeded at 150 °C to give the
expected quinoline 3a as a mixture of o- and p-isomers, but
5514
Org. Lett., Vol. 9, No. 26, 2007

Table 2. Scope of Arenesa
Table 3. Reaction of 1c with Aryl Sulfide and Thiola
InX3
product
yieldb (%)
entry
2
R
R′
X
equiv
conditions
1
2
3
4
5
6
7
8
9
2j
2j
2j
Me
Me
Me
H
OTf
Br
Cl
Br
Br
1.5
1.5
2.0
1.5
1.5
2.0
0
1.0
1.0
1.0
1.2
130 °C, 7 h
130 °C, 5 h
130 °C, 2 h
150 °C, 5 h
150 °C, 2 h
150 °C, 6 h
150 °C, 25 h
150 °C, 25 h
150 °C, 25 h
150 °C, 25 h
150 °C, 12 h
4 (31)
4 (67)
4 (60)
4 (55)
3 (61)
5 (53)
4 (9)
4 (66)
4 (72)
4 (64)
5 (75)
H
H
H
H
2k Et
2l Ph
2m Me Me Br
2n
2n
2n
2n
2o
H
H
H
H
H
H
H
H
H
-
OTf
Br
Cl
10
11
Me Br
a All reactions were carried out using 0.50 mmol of 1c in 2 mL of
chlorobenzene for entries 1-3 and bromobenzene for entries 4-11.
b Isolated yield.
1c with thioanisole (10 equiv) in the presence of In(OTf)3
gave 4-phenylthioquinolinethione 4 in 31% yield instead of
the expected FC-type adduct 3j (entry 1). As far as we know,
this is the first example of the intermolecular C-S bond-
forming reaction of alkynes with thioanisole.14 The yield was
improved by use of InBr3 (67%) or InCl3 (60%) (entries 2
and 3). With ethyl phenyl sulfide 2k, the reaction (InBr3)
also afforded 4 in 55% yield (entry 4), whereas the reaction
with diphenyl sulfide 2l gave the FC-type adduct 3l in 61%
yield (entry 5). Similarly, 4-p-tolylquinolinethione 5 was
obtained in 53% yield (entry 6). For a more straightforward
synthesis of 4 or 5, hydrothiolation15 of 1c was examined
by exposing 1c to thiophenol (1.0 equiv) (entries 7-11).
Without an In(III) reagent, the reaction with thiophenol 2n
was sluggish and resulted in a lower yield (9%) of 4 (entry
7). In the presence of 1.0 equiv of In(OTf)3, InBr3, and InCl3,
the reactions proceeded smoothly to afford 4 in 66, 72, and
64% yield, respectively (entries 8-10). In the same way,
p-toluenethiol afforded 5 in a satisfactory yield (75%) (entry
11).
a All reactions were carried out with 0.50 mmol of 1c in 2 mL of 2.
1
b Isolated yield. c Determined by H NMR. d Ratio of o:m with respect to
MeO group. e At 120 °C. f In(OTf)3 (2 equiv) was used. g At 80 °C. h In a
i
sealed tube. At 200 °C.
In(OTf)3 (Table 2). Electron-rich arenes bearing an alkoxy
or aryloxy group reacted smoothly to afford the correspond-
ing quinolinethiones in up to 99% yield (entries 1-4).
Weakly nucleophilic mesitylene and toluene also reacted
under similar conditions to afford 3f and 3g in good yields
(entries 5 and 6). Benzene was less reactive as the yield of
3h was 52% (entry 7), even when the reaction was carried
out using 2.0 equiv of In(OTf)3 at refluxing temperature (80
°C) for 60 h. By heating at 120 °C in a sealed tube for 8 h,
the yield was improved to 71% (entry 8). In the reactions
with electron-poor arenes, bromobenzene 3i was obtained
in a 12% yield after heating at 200 °C for 10 h in a sealed
tube (entry 9). The reaction with weak nucleophiles, such
as chlorobenzene and ethyl benzoate, at 150 °C for 10 h
failed to give the expected products with recovery of 1c (ca.
80%).
(14) Intramolecular C-S bond-forming reaction: (a) Larock, R. C.; Yue,
D. Tetrahedron Lett. 2001, 42, 6011. (b) Yue, D.; Larock, R. C. J. Org.
Chem. 2002, 67, 1905.
(15) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc.
1999, 121, 5108.
Aryl sulfides and arenethiols were also subjected to the
indium(III)-mediated tandem reaction of 1c in chlorobenzene
or bromobenzene as the solvent (Table 3). The reaction of
Org. Lett., Vol. 9, No. 26, 2007
5515

plex A, and following regioselective addition of an aromatic
nucleophile to the benzylic alkynyl carbon atom in a Friedel-
Crafts manner gives an alkenylisocyanate B. The regiose-
lectivity in these cases agrees with reported reactions of aryl-
substituted alkynes.11 Meanwhile, alkyl aryl sulfides 2j, 2k,
and 2m and aryl thiols 2n and 2o react preferentially on the
more nucleophilic sulfur atom to give a sulfonium salt F,
from which elimination of RX proceeds to form an aryl-
thioalkenyl indium intermediate G. In the case of diphenyl
sulfide (R ) Ph), such an elimination does not occur because
of the poor leaving ability of the phenyl group in F. Under
such acidic conditions, alkenyl intermediates B and G
eliminate the t-Bu group, which was trapped by aromatic
nucleophiles.16 6π-Electrocyclization and successive aroma-
tization of C and H led to quinolines E and J via D and I.17
Their tautomerization and/or aqueous workup furnished
quinoline-2-thiones 3-5.
Scheme 2. A Possible Pathway
In summary, we have developed an indium(III)-mediated
tandem FC alkenylation-cyclization method for straight-
forward and facile synthesis of 4-aryl- or 4-arylthioquinoline-
2-thiones from 2-alkynylphenyl isothiocyanates. The appli-
cation of this method to the synthesis of variously substituted
quinoline-2-thiones and extending the method are currently
underway in our laboratory.
Supporting Information Available: Spectroscopic data
and experimental procedure. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL7024668
(16) 2-tert-Butyl-1,4-dimethoxybenzene was actually isolated in 20%
yield (Table 2, entry 2).
(17) NMR monitoring of the reaction of (3,3-dimethylbut-1-ynyl)benzene
with 2c in 10 mol % of In(OTf)3 revealed an initial formation of
2,5-dimethoxy-1-[(1Z)-3,3-dimethyl-1-phenyl-1-butenyl]benzene and its
subsequent decomposition leading to 2-tert-butyl-1,4-dimethoxybenzene and
1-(2,5-dimethoxyphenyl)-1-phenylethene, albeit in low yield. These results
support the pathways 1c to C via A and B in Scheme 2.
An assumed pathway for the formation of 3-5 is illu-
strated in Scheme 2. First, the In(III) reagent (InX3) coor-
dinates to an acetylene bond to form an alkyne-InX3 com-
5516
Org. Lett., Vol. 9, No. 26, 2007