Indium-catalyzed synthesis of furans and pyrroles via cyclization of α-propargyl-β-keto esters

Article abstract of DOI:10.1055/s-0030-1259930

In(OTf)₃ or In(NTf₂)₃ effectively catalyze the cyclo-isomerization reaction of -propargyl - keto esters and their imine analogues to afford trisubstituted furans and pyrroles, respectively. Both terminal and internal alkyn

Full text of DOI:10.1055/s-0030-1259930

LETTER
1015
Indium-Catalyzed Synthesis of Furans and Pyrroles via Cyclization of
a-Propargyl-b-keto Esters
Indium-Catalyzed
aFuranand
P
yrrole Synth
a
e
sis to Tsuji,* Ken-ichi Yamagata, Yasuyuki Ueda, Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58006889; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Received 2 December 2010
Dedicated to Professor Xiyan Lu and Professor Lixin Dai
gave the products in 99%, 92%, and 95% yield, respec-
tively (Table 1, entries 4–6). Bromobenzoyl acetate 1g
tolerated the reaction conditions and gave 2-(p-bromo-
phenyl)furan in 95% yield (Table 1, entry 7).
Abstract: In(OTf)3 or In(NTf2)3 effectively catalyze the cyclo-
isomerization reaction of a-propargyl-b-keto esters and their imine
analogues to afford trisubstituted furans and pyrroles, respectively.
Both terminal and internal alkynes take part in the reaction with
good functional-group compatibility in the presence of only a small
amount of the catalyst.
Internal alkynes were found to require the more reactive
9
In(NTf2)3 catalyst (Table 1, entries 8–14). Thus, in the
Key words: indium catalyst, keto ester, cyclization, furan, pyrrole
presence of 5 mol% of In(NTf2)3 at 60 °C, aliphatic
alkyne 1h and TBDMS-protected alkyne 1i afforded the
corresponding furan derivatives in 89% and 88% isolated
yield, respectively (Table 1, entries 8 and 9), while the re-
action of 1i using 5 mol% of InCl3 afforded the furan
product in 53% NMR yield. Aryl groups on the triple
bond (R2) had a significant effect on the reactivity. A sub-
strate having a phenylethynyl group 1j gave 5-benzylfu-
ran in 74% yield (Table 1, entry 10). The reaction of
electron-rich p-tolylethynyl compound 1k afforded the
furan compound in moderate yield (56%, Table 1, entry
11), together with a mixture of unknown compounds. In
contrast, electron-deficient (p-trifluoromethylphenyl)-
ethynyl compound 1l required higher reaction tempera-
ture and furnished the furan in 86% yield (Table 1, entry
12). A substrate having the sterically hindered o-trifluo-
romethylphenyl group 1m required a longer reaction time
than the p-substituted counterpart and gave the furan com-
pound in good yield (74%, Table 1, entry 13). A halogen
atom on the aromatic group was tolerated. A substrate
with a p-bromophenyl group 1n afforded 5-(p-bromophe-
nyl)methylfuran in 84% yield (Table 1, entry 14).
The utility of indium reagents and catalysts has been
widely proven by organic reactions involving carbonyl
groups,1 such as the Barbier reaction,2 aldol reaction,3 and
Hosomi–Sakurai reaction.4 Indium can also activate C–C
triple bonds to form new C–C bonds, because of its soft-
ness, as reported by us5 and others.6 Formation of carbon–
heteroatom bonds via activation of triple bonds has also
been reported. For instance, Tan et al.7a described that 10
mol% of InCl3 promotes one-pot synthesis of furan deriv-
atives via tandem reaction that involves intermolecular
condensation of a propargylic alcohol and a 1,3-dicarbon-
yl compound, mainly 1,3-diketones, in refluxing chlo-
robenzene. Herein we report that In(OTf)3 and In(NTf2)3
are very effective for cycloisomerization of a-propargyl-
b-keto esters and their imine analogues to afford trisubsti-
tuted furans and pyrroles under low-catalyst loading and
rather mild reaction conditions (Scheme 1).8
Ethyl a-propargylacetoacetate 1a afforded 2,5-dimethyl-
furan 2a in 86% yield in the presence of 1 mol% of
In(OTf)3 at room temperature in 0.5 M toluene (Table 1,
entry 1). This substrate provided only a trace amount of
the furan product 2a when 1 mol% of InCl3 was used in
refluxing toluene. We then investigated the efficiency of
In(OTf)3 for this O-centered nucleophilic 5-exo-dig cy-
clization using various a-propargyl-b-keto esters as a sub-
strate. Sterically hindered pivaloyl compound 1b and a
substrate with a linear alkyl substituent having a benzyl
ether 1c gave the corresponding furan derivatives in 84%
and 89% yield, respectively (Table 1, entries 2 and 3). Ar-
omatic keto esters showed no effect on the reactivity and
afforded 2-arylfurans in high yield. Benzoylacetate 1d, an
electron-rich methoxy-substituted compound 1e, and an
electron-deficient trifluoromethylbenzoyl substrate 1f
R1
cat. In(OTf)3 or In(NTf2)3
CO2Et
O
toluene (0.5 M)
r.t. to reflux
R1
R2
2a–n
CO2Et
O
R2
R1
1a–n
R3NH2 (1.2 or 0.5 equiv)
cat. In(OTf)3 or In(NTf2)3
CO2Et
R3
N
toluene (0.5 M)
60 °C to reflux
R2
3–8
SYNLETT 2011, No. 7, pp 1015–1017
Advanced online publication: 29.03.2011
x
x.
x
x.
2
0
1
1
Scheme 1
DOI: 10.1055/s-0030-1259930; Art ID: W32810ST
© Georg Thieme Verlag Stuttgart · New York

1016
H. Tsuji et al.
LETTER
Table 1 Synthesis of Trisubstituted Furans by Indium-Catalyzed
Cycloisomerization
In(OTf)3 and In(NTf2)3 can be employed with equally
high efficiency for this indium-catalyzed intramolecular
cyclization of the b-keto esters to furnish pyrrole in the
presence of a primary amine (Scheme 3), similarly to the
previously reported intermolecular version.7b,c Thus, reac-
tion of a-propargylacetoacetate 1a and 1.2 equivalents of
benzylamine in the presence of 1 mol% of In(OTf)3 at
60 °C gave the corresponding enamine, formation of
which was detected by 1H NMR, and upon increasing the
reaction temperature the trisubstituted pyrrole derivative
3 was obtained in 95% isolated yield (Table 2, entry 1).
Furan 2a did not form under these reaction conditions.
Similarly, use of butylamine and aniline afforded N-butyl-
and N-phenylpyrrole derivatives 4 and 5 in 93% and 86%
yield, respectively (Table 2, entries 2 and 3). The cycliza-
tion step using an aliphatic amine required reflux condi-
tions, while that using aniline proceeded at 60 °C,
suggesting that formation of an extended p-conjugated
system is the significant driving force of this N-phe-
nylpyrrole synthesis. When tetramethylenediamine was
used, tetramethylene-tethered dipyrrole compound 6 was
obtained in 82% yield (Table 2, entry 4). Sterically de-
manding benzoyl acetoacetate 1d required a higher tem-
perature for enamine formation, and gave pyrrole 7 in
90% yield (Table 2, entry 5). Similar to the furan synthe-
ses, In(NTf2)3 was effective for the pyrrole synthesis; us-
ing internal alkyne 1j with aniline gave pyrrole 8 in 86%
yield.
Entry R1
R2
Substrate Conditionsa Yield
(%)
1
2
Me
H
1a
1b
1c
1d
1e
1f
A
A
A
A
A
A
A
B
86
84
89
99
92
95
95
89
88
74
56
86
74
84
t-Bu
H
3
BnO(CH2)7
H
4
Ph
H
5
4-MeOC6H4
H
6
4-F3CC6H4
H
7
4-BrC6H4
H
1g
1h
1i
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
9
TBDMS
Ph
B
10
11
12
13
14
1j
B
4-MeC6H4
4-F3CC6H4
2-F3CC6H4
4-BrC6H4
1k
1l
B
Bb
Bc
B
1m
1n
a Conditions A: In(OTf)3 (1 mol%), r.t., 4 h. Conditions B: In(NTf2)3
(5 mol%), 60 °C, 24 h.
b Reflux, 12 h.
c Reflux, 24 h.
R1
R1
CO2Et
R3NH2 (1.2 equiv)
In(OTf)3 or In(NTf2)3
H
CO2Et
O
R3
R2
N
The reactivity dependence on the electronic nature of the
R2 group suggests that the reaction involves electrophilic
activation of the C–C triple bond, as is the case with our
previously developed indium-catalyzed addition of active
methylene to alkynes.5 There are a priori two possible
paths to the furan product – one involving cyclization of a
keto tautomer of the substrate (path 1) and another involv-
ing an enolate tautomer (path 2), as shown in Scheme 2.
Considering that there is no explicit base in the reaction
system, we prefer to consider that path 1 is more plausible.
toluene (0.5 M)
conditions
R2
1a R1 = Me, R2 = H
1d R1 = Ph, R2 = H
1j R1 = Ph, R2 = Ph
R1
3 R1 = Me, R2 = H, R3 = Bn
4 R1 = Me, R2 = H, R3 = Bu
5 R1 = Me, R2 = H, R3 = Ph
7 R1 = Ph, R2 = H, R3 = Ph
8 R1 = Ph, R2 = Ph, R3 = Ph
CO2Et
R3
N
R2
CO2Et
H
R1
NH2
R1
H2N
path 1
– H+
CO2Et
N
H
In(OTf)3 (1 mol%)
CO2Et
1a
O
O+
toluene (0.5 M)
conditions
R1
R2
R2
InXn
CO2Et
InXn
N
O
EtO2C
– H+
path 2
R1
R2
Scheme 3
R1
2a–n
CO2Et
CO2Et
– M
O
In conclusion, we found that In(OTf)3 and In(NTf2)3 are
effective catalysts for the cycloisomerization of a-propar-
gyl-b-keto esters and their aza analogues for the synthesis
of trisubstituted furans and pyrroles. This reaction fea-
tures functional-group tolerance, high catalytic efficiency,
MO
R2
InXn
R2
InXn
A (E-isomer)
B
Scheme 2
Synlett 2011, No. 7, 1015–1017 © Thieme Stuttgart · New York

LETTER
Indium-Catalyzed Furan and Pyrrole Synthesis
1017
B. C. Eur. J. Org. Chem. 2000, 2347. (d) Podlech, J.;
Table 2 Synthesis of Trisubstituted Pyrroles by Indium-Catalyzed
Maier, T. C. Synthesis 2003, 633. (e) Nair, V.; Ros, S.;
Jayan, C. N.; Pillai, B. S. Tetrahedron 2004, 60, 1959.
(f) Augé, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007,
1739. (g) Yadav, J. S.; Antony, A.; George, J.; Reddy, B. V.
Eur. J. Org. Chem. 2010, 591.
Cycloisomerization of Enamines
Entry R1 R2
Substrate R3
Product Conditionsa Yield
(%)
1
Me
Me
Me
Me
Ph
H
H
H
H
H
1a
1a
1a
1a
1d
1j
Bn
3
4
5
6
7
8
A
A
B
A
C
D
95
93
86
82
90
86
(2) For example, see: Haddad, T. D.; Hirayama, L. C.;
Singaram, B. J. Org. Chem. 2010, 75, 642.
(3) For example, see: Muñoz-Muñiz, O.; Quintanar-Audelo, M.;
2
Bu
Juaristi, E. J. Org. Chem. 2003, 68, 1622.
3
Ph
(4) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941.
(5) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem.
Soc. 2003, 125, 13002. (b) Nakamura, M.; Endo, K.;
Nakamura, E. Org. Lett. 2005, 7, 3279. (c) Nakamura, M.;
Endo, K.; Nakamura, E. Adv. Synth. Catal. 2005, 347, 1681.
(d) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E.
J. Am. Chem. Soc. 2007, 129, 5264. (e) Tsuji, H.;
Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem. Int. Ed. 2007, 46, 8060.
(f) Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura, M.;
Nakamura, E. Org. Lett. 2008, 10, 1219. (g) Fujimoto, T.;
Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 4492. (h) Itoh, Y.; Tsuji, H.;
Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161.
(i) Tsuji, H.; Tanaka, I.; Endo, K.; Yamagata, K.-i.;
Nakamura, M.; Nakamura, E. Org. Lett. 2009, 11, 1845.
(6) (a) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.;
Kawakami, Y. Chem. Commun. 2003, 2454. (b) Mamane,
V.; Hannen, P.; Fürstner, A. Chem. Eur. J. 2004, 10, 4556.
(c) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki,
M. Org. Lett. 2005, 7, 1363. (d) Miura, K.; Fujisawa, N.;
Toyohara, S.; Hosomi, A. Synlett 2006, 1883.
4b
5
(CH2)4NH2
Ph
Ph
6
Ph Ph
a Conditions A: In(OTf)3 (1 mol%), 60 °C, 6 h, then reflux, 12 h. Con-
ditions B: In(OTf)3 (1 mol%), 60 °C, 6 h. Conditions C: In(OTf)3 (1
mol%), reflux, 6 h. D: In(NTf2)3 (5 mol%), reflux, 24 h.
b Reaction conditions: 0.5 equiv of amine were used.
and no need for diluted conditions. In view of the im-
mense importance of furans and pyrroles in the chemistry
of bioactive compounds10 and organic semiconducting
materials,11 the present study provides an attractive access
to complex heterole structures.12
Typical Procedure for the Furan Synthesis (Table 1, Entry 4)
In(OTf)3 (36 mg, 64 mmol) was added to a solution of ethyl 2-ben-
zoylpent-4-ynoate (1d, 1.45 g, 6.3 mmol) in toluene (12.5 mL). Af-
ter stirring for 4 h at r.t., the resulting reaction mixture was passed
through a pad of silica gel (eluent: Et2O). After concentration in
vacuo, purification by silica gel column chromatography (3%
EtOAc in hexane as the eluent) afforded ethyl 5-methyl-2-phenyl-
furan-3-carboxylate (2d, 1.43 g, 99%). Analytical data were in good
accordance with those reported in the literature.13
(e) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem. Int. Ed. 2008, 47, 6244.
(f) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A.
Angew. Chem. Int. Ed. 2009, 48, 4577.
(7) (a) Feng, X.; Tan, Z.; Chen, D.; Shen, Y.; Guo, C.-C.; Xiang,
J.; Zhu, C. Tetrahedron Lett. 2008, 49, 4110. (b) Liu, X.-T.;
Huang, L.; Zheng, F.-j.; Zhan, Z.-P. Adv. Synth. Catal. 2008,
350, 2778. (c) Lin, M.; Hao, L.; Ma, R.-D.; Zhan, Z.-P.
Synlett 2010, 2345.
(8) FeCl3-catalyzed reaction has been also reported: Zhan, Z.-P.;
Cai, X.-B.; Wang, S.-P.; Yu, J.-L.; Liu, H.-J.; Cui, Y.-Y.
J. Org. Chem. 2007, 72, 9838.
Typical Procedure for the Pyrrole Synthesis (Table 2, Entry 1)
Ethyl 3-oxo-2-(prop-2-yn-1-yl)butanoate (1a, 1.04 g, 6.2 mmol)
was added to a solution of In(OTf)3 (35 mg, 62 mmol) and benzyl-
amine (0.77 g, 7.2 mmol) in toluene (12.0 mL). After stirring for 6
h at 60 °C, the reaction mixture was warmed to reflux temperature
and then stirred for an additional 12 h. After being cooled to r.t., the
reaction mixture was filtered through a pad of silica gel (eluent:
Et2O). After concentration in vacuo, purification by silica gel col-
umn chromatography (5% EtOAc in hexane) afforded ethyl 1-
benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate (3, 1.51 g, 95%).
Analytical data were in good accordance with those reported in the
literature.14
(9) Frost, C. G.; Hartley, J. P.; Griffin, D. Tetrahedron Lett.
2002, 43, 4789.
(10) For recent reviews of the synthesis and utilization of furan
and pyrrole derivatives, see: (a) Brown, R. C. D. Angew.
Chem. Int. Ed. 2005, 44, 850. (b) Kirsch, S. F. Org. Biomol.
Chem. 2006, 4, 2076. (c) D’Souza, D. M.; Müller, T. J. J.
Chem. Soc. Rev. 2007, 36, 1095. (d) Álvarez-Corral, M.;
Muñoz-Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008,
108, 3174.
(11) (a) Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E.
J. Am. Chem. Soc. 2007, 129, 11902. (b) Tsuji, H.; Mitsui,
C.; Sato, Y.; Nakamura, E. Adv. Mater. 2009, 21, 3776.
(c) Tsuji, H.; Yokoi, Y.; Mitsui, C.; Ilies, L.; Sato, Y.;
Nakamura, H. Chem. Asian J. 2009, 4, 655.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(12) Ma, S. Handbook of Cyclization Reactions; Wiley-VCH:
Weinheim, 2010.
We thank MEXT (KAKENHI for E.N., No. 22000008, H.T., No.
20685005) and the Global COE Program for Chemistry Innovation.
(13) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004,
6, 3679.
(14) Pancote, C. G.; de Carvalho, B. S.; Luchez, C. V.;
Fernandes, J. P. S.; Politi, M. J.; Brandt, C. A. Synthesis
2009, 3963.
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Synlett 2011, No. 7, 1015–1017 © Thieme Stuttgart · New York