Gallium(III)-catalyzed tandem cycloisomerization/Friedel-Crafts alkylation: A facile synthesis of 2,5-disubstituted furans

Article abstract of DOI:10.1016/j.tetlet.2012.02.074

A tandem cycloisomerization/Friedel-Crafts alkylation of indoles has been achieved in a one-pot process to produce 2,5-disubstituted furans using gallium-catalyzed sequential nucleophilic addition onto metal-activated 1-alkynyl-2,3-epoxy acetates. The rea

Full text of DOI:10.1016/j.tetlet.2012.02.074

Tetrahedron Letters 53 (2012) 2500–2503
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gallium(III)-catalyzed tandem cycloisomerization/Friedel–Crafts alkylation:
a facile synthesis of 2,5-disubstituted furans
⇑
B.V. Subba Reddy , B. Bramha Reddy, K.V. Raghavendra Rao, J.S. Yadav
Natural Product Chemistry, Indian Institute of Chemical Technology, CSIR, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem cycloisomerization/Friedel–Crafts alkylation of indoles has been achieved in a one-pot process
to produce 2,5-disubstituted furans using gallium-catalyzed sequential nucleophilic addition onto metal-
activated 1-alkynyl-2,3-epoxy acetates. The reaction proceeds efficiently under mild conditions with
complete regioselectivity to afford the substituted furan derivatives in good yields with high diversity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 6 January 2012
Revised 13 February 2012
Accepted 16 February 2012
Available online 22 February 2012
Keywords:
Gallium(III) chloride
1-Alkynyl-2,3-epoxy acetates
2,5-Disubstituted furans
Friedel–Crafts alkylation
The furan subunits are often found in many natural products and
biologically active molecules.1 They are extensively used as syn-
thetic intermediates for carbocycles and heterocycles in organic
synthesis.2 Therefore, several efforts have been devoted for the syn-
thesis of furan scaffolds.3,4 Recently, metal-mediated cyclizations of
an allene or an alkyne with an oxygen functionality have appeared
in the literature.5 Among various approaches to substituted fur-
ans,3,4 the cycloisomerization of alkynyl oxiranes catalyzed by tran-
sition metals is particularly versatile and attractive.6–8 In general,
furan synthesis from alkynyl oxiranes mostly involves the use of
transition metal catalysts such as Hg(II), Mo, Ru, SmI2/Pd, Ag(I)/
TsOH, Au(III), and Pt(II).6–8 However, many of these methods in-
volve the use of expensive catalysts and hazardous reagents in stoi-
chiometric amounts. In case of Mo and Ru, the formation of furan is
limited to terminal alkynes.
Recently there has been a growing interest in gallium mediated
transformations due to its ability to activate alkynes under mild
conditions.9 In particular, gallium(III) chloride is considered to be
an effective Lewis acid to activate alkynes/alkenes under extremely
mild conditions.10 However, there have been no reports on the use
of gallium(III) chloride for the synthesis of 2,5-disubstituted furan
derivatives.
1-alkynyl-2,3-epoxy acetates. Accordingly, we first attempted the
Friedel–Crafts alkylation of indole with 1-alkynyl-2,3-epoxy acetate
using a catalytic amount of InCl3. Though the reaction proceeds in
1,4-dioxane at 80 °C, the desired 2,5-substituted furan derivative
3a was obtained in 60% yield. In order to improve the conversion,
we attempted the above reaction with various Lewis acids such as
BiCl3, FeCl3, and GaCl3. Interestingly, the yield of 3a was
dramatically increased to 85% when GaCl3 was used as a catalyst
(Scheme 1).
Inspired by a high catalytic performance of GaCl3,11 we carried
out further reactions with GaCl3. Interestingly, a wide range of in-
doles participated well under the influence of gallium(III) chloride
(Table 1, entries b–l). We next attempted the ability of other nucle-
ophiles such as allyltrimethylsilane and acetyl acetone to initiate
the cycloisomerization. Like an indole, allyltrimethylsilane also
promoted the cycloisomerization of alkynyl-2,3-epoxy acetate to
afford the allyl substituted furan derivative 4 in good yield
(Scheme 2).
In this Letter, we report a novel protocol for the one-pot
synthesis of 3,5-disubstituted furan derivatives by means of a nucle-
ophile induced cycloisomerization and Friedel–Crafts alkylation of
Ph
OAc
Ph
Ph
GaCl3 (10 mol%)
Dioxane, 80 °C
O
+
N
O
H
Ph
N
H
3a
⇑
Corresponding author. Fax: +91 40 7160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
2
1
The author acknowledges the partial support by King Saud University for Global
Research Network for Organic Synthesis (GRNOS).
Scheme 1. Indole-induced formation of furan 3a.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.074

B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 2500–2503
2501
Table 1
Cascade alkylation of indole and furan formation
Entry
Epoxy propargyl acetate (1)
Indole (2)
Product (3)a
Time (h)
4.5
Yieldb (%)
OAc
N
H
NH
a
85
82
O
Ph
Ph
O
Ph
Ph
Ph
OAc
Me
N
H
NH
Me
b
c
5.0
6.0
O
Ph
Ph
O
Ph
OAc
Cl
Br
Cl
N
O
H
80
NH
NH
Ph
Ph
Ph
O
Ph
OAc
Br
N
H
O
d
e
f
6.0
6.0
6.0
80
85
78
Ph
Ph
Ph
O
Ph
Ph
OAc
N
N
H
N
NH
NH
O
Ph
Ph
O
Ph
OAc
O2N
O2N
N
O
H
Ph
Ph
Ph
O
Ph
OAc
OMe
N
H
OMe
NH
g
4.0
5.0
86
78
O
Ph
O
Ph
OAc
Me
OMe
N
H
OMe
OMe
OMe
OMe
NH
Me
h
O
Ph
O
O
O
Ph
Ph
Ph
Ph
OAc
Cl
Cl
OMe
N
O
H
i
5.5
5.5
6.0
80
80
NH
NH
NH
Ph
OAc
Br
Br
OMe
N
H
O
j
Ph
OAc
O2N
O2N
OMe
N
O
H
k
80
Ph
O
(continued on next page)

2502
B. V. S. Reddy et al. / Tetrahedron Letters 53 (2012) 2500–2503
Table 1 (continued)
Entry
Epoxy propargyl acetate (1)
Indole (2)
Product (3)a
Time (h)
6.2
Yieldb (%)
OAc
N
OMe
N
H
N
OMe
NH
l
72
O
Ph
O
Ph
a
All products were characterized by NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
OAc
OAc
Ph
Ph
GaCl3 (10 mol%)
Dioxane, 80 °C
AcO
Ga
R
Ga(III)
R
+
O
Si
O
O
..
R
R
O
4
Ph
Ph
R
4a: R = C6H5, 4h, 86%
4b: R = 2-MeOC6H4, 3.5h, 90%
Nu
Ph
O
Scheme 2. Allyltrimethylsilane-induced formation of furan 4.
Nu
Scheme 5. Alternative reaction pathway.
O
OAc
Ph
GaCl3 (10 mol%)
Dioxane, 80 °C
Ph
Ph
O
+
the reaction was successful in acetonitrile and 1,2-dichloroethane
under reflux conditions, the desired product was obtained in low
yields. Of these solvents, dioxane gave the best results. The scope
of this method is illustrated with respect to various nucleophiles
and alkynyl-2,3-epoxy acetates and the results are presented in
Table 1.12
O
O
O
R
O
5
5a: R = C6H5, 5h, 82%
5b: R = 2-MeOC6H4, 4h, 85%
In absence of the catalyst, no reaction was observed even after
long reaction time (12 h) under reflux conditions. Mechanistically,
the reaction proceeds via the activation of both alkyne and epoxide
by gallium(III). This is followed by the addition of nucleophile on
epoxide and then isomerization of propargylic acetate results in
the formation of 2,5-disubstituted furan as shown in Scheme 4.
Alternatively, gallium(III) activates the alkyne to initiate the for-
mation of cyclic oxonium ion which is likely attacked by a nucleo-
phile as shown in Scheme 5. Mechanistic studies showed that a
cascade pathway rather than a direct intramolecular nucleophilic
addition of the oxirane oxygen atom to the intermediate acety-
Scheme 3. Acetyl acetone-induced formation of furan 5.
OAc
Nu OAc
+
Nu
Ga(III)
R
Ph
O
R
OH
..
Ga
(III)
Ph
Ph
O
O
Ga
Protodemetallation
-AcOH
Ph
Nu
R
R
O
O
lene–metal p-complex occurs. Further studies addressing these is-
sues are currently underway in our laboratory.
H
Nu
Scheme 4. A plausible reaction pathway.
In summary, we have developed a novel strategy for the synthe-
sis of 2,5-disubstituted furan derivatives by means of gallium-cat-
alyzed addition of nucleophile onto metal activated alkynyl-2,3-
epoxy acetate. This method involves the cycloisomerization of
alkynyl-2,3-epoxy acetates followed by the Friedel–Crafts alkyl-
ation of indoles.
Similarly, acetyl acetone also induced the cycloisomerization of
alkynyl-2,3-epoxy acetate to furnish the corresponding 2,5-
disubstituted furan derivative 5 in good yield (Scheme 3).
Other 1-alkynyl-2,3-epoxy acetates also underwent a smooth
cycloisomerization with indoles to give the corresponding 3-
indolyl furan derivatives in good yields (Table 1, entries b–l).
The products are fully characterized by NMR, IR, and mass
spectroscopy. Both electron-rich and electron-deficient indoles
are found to be equally effective for this conversion (Table 1).
The catalytic efficiency of various metal halides such as InCl3,
ZnCl2, CeCl3Á7H2O, and metal triflates like In(OTf)3, Bi(OTf)3,
Sc(OTf)3, Yb(OTf)3 was screened for this conversion. Surprisingly,
none of these catalysts gave the desired product in satisfactory
yields. Furthermore, Brønsted acids such as montmorillonite K10,
heteropoly acid, and ion-exchange resins failed to produce the de-
sired product. In the absence of an external nucleophile, mixtures
of hydroxyl- and chloro-substituted products were obtained. The
effect of various solvents was examined for this reaction. Though,
Acknowledgment
B.B.R. and K.V.R.R. thank the CSIR, New Delhi for the award of
fellowships.
References and notes
1. (a) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; p 657. Vol. 4; (b)
Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H.
N. C. Tetrahedron 1955, 1998, 54.
2. Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.; Weinheim VCH,
1995; p 231.
3. (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford, 2002; p 139. Vol. 14; (b)
Cacchi, S. J. Organomet. Chem. 1999, 576, 42; (c) Brown, R. C. D. Angew. Chem.,
Int. Ed. 2005, 44, 850.

B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 2500–2503
2503
4. (a) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277;
(b) Ma, S.; Zhang, J.; Lu, L. Chem. Eur. J. 2003, 9, 2447; (c) Ma, S.; Zhang, J. Chem.
Commun. 2000, 117; (d) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285; (e) Marshall, J. A.; Bartley, G. S. J. Org.
Chem. 1994, 59, 7169; (f) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 960;
(g) Hashmi, A. S. K.; Ruppert, T. L.; Knofel, T.; Bats, J. W. J. Org. Chem. 1997, 62,
7295.
5. (a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56,
5816; (b) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett. 1993,
34, 2813; (c) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687; (d)
Seiller, B.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1994, 493; (e) Pan, Y. M.;
Zhao, S. Y.; Ji, W.-H.; Zhan, Z.-P. J. Comb. Chem. 2009, 11, 103; (f) Liu, Y.; Zhou, S.
Org. Lett. 2005, 7, 4609; (g) Sniady, A.; Durham, A.; Morreale, M. S.; Wheeler, K.
A.; Dembinski, R. Org. Lett. 2007, 9, 1175; (h) Yao, T.; Zhang, X.; Larock, R. C. J.
Am. Chem. Soc. 2004, 126, 11164.
6. (a) Hashmi, A. S. K.; Sinha, P. Adv. Synth. Catal. 2004, 346, 432; (b) Yoshida, M.;
Al-Amin, M.; Matsuda, K.; Shishido, K. Tetrahedron Lett. 2008, 49, 5021.
7. (a) Marson, C. M.; Harper, S. J. Org. Chem. 1998, 63, 9223; (b) Blanc, A.; Tenbrink,
K.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 4360; (c) Blanc, A.; Tenbrink, K.;
Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 5342; (d) Kang, J. Y.; Connell, B. T. J.
Org. Chem. 2011, 76, 2379; (e) Lo, C. Y.; Guo, H.; Lian, J. J.; Shen, F. M.; Liu, R. S. J.
Org. Chem. 2002, 67, 3930; (f) Aurrecoechea, J. M.; Perez, E. Tetrahedron Lett.
2001, 42, 3839.
8. (a) Ji, K.-G.; Shu, X.-Z.; Chen, J.; Zhao, S.-C.; Zheng, Z.-J.; Liu, X.-Y.; Liang, Y.-M.
Org. Biomol. Chem. 2009, 7, 2501; (b) Blanc, A.; Alix, A.; Weibel, J.-M.; Pale, P.
Eur. J. Org. Chem. 2010, 1644; (c) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.; Guo,
L.-N.; Qi, C.-Z.; Liang, Y. M. Adv. Synth. Catal. 2007, 349, 2493.
11. (a) Yadav, J. S.; Reddy, B. V. S.; Padmavani, B.; Gupta, M. K. Tetrahedron Lett 2004,
45, 7577; (b) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.; Gupta, M. K.; Biswas, S.
K. Tetrahedron Lett. 2005, 46, 1161; (c) Yadav, J. S.; Reddy, B. V. S.; Bhasker, E. V.;
Raghavendra, S.; Narsaiah, A. V. Tetrahedron Lett. 2007, 48, 677; (d) Yadav, J. S.;
Reddy, B. V. S.; Biswas, S. K.; Sengupta, S. Tetrahedron Lett. 2009, 50, 5798; (e)
Yadav, J. S.; Reddy, B. V.; Sengupta, S.; Biswas, S. K. Synthesis 2009, 1301.
12. General procedure: A mixture of 1-alkynyl-2,3-epoxy acetate (1.0 mmol), indole
(1.5 mmol), and GaCl3 (10 mol %) in dioxane (5 mL) was heated at 80 °C for the
appropriate time. After completion of the reaction as indicated by TLC, the
solvent was removed and the resulting residue was diluted with water and
extracted with dichloromethane (2 Â 15 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated in vacuo and purified by
column chromatography on silica gel (Merck, 100–200 mesh, ethyl acetate–
hexane, 1:9) to afford pure 2,5-disubstituted furan. The spectral data of the
products was identical with the data reported in the literature.6–8 Spectral data
for selected products: 3j: 5-Bromo-3-((5-(2-methoxyphenyl)furan-2-
yl)(phenyl)methy)-1H-indole: Pale yellow colour liquid, IR (neat): mmax
3425, 2922, 2853, 1599, 1457, 1245, 756 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
7.95 (s, 1H), 7.59–7.49 (m, 3H), 7.31–7.06 (m, 7H), 6.89–6.73 (m, 3H), 6.48 (d,
1H, J = 3.0 Hz), 6.05 (br s, 1H), 5.90 (d, 1H, J = 3.0 Hz), 3.76 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 156.6, 151.3, 149.8, 139.5, 133.4, 131.0, 129.6, 129.1, 128.5,
127.8, 126.8, 124.9, 124.8, 124.3, 123.4, 122.1, 120.4, 117.1, 114.1, 112.6, 112.4,
110.6, 109.3, 105.5, 55.5, 34.8; EIMS: m/z: 427 [M+], 429 [M2+]. 4a: 2-Phenyl-5-
(1-phenylbut-3-enyl)furan: Brown liquid, IR (neat): mmax 3027, 2923, 2853,
1490, 1444, 1262, 1151, 967, 755 cmÀ1 1H NMR (500 MHz, CDCl3): d 7.60–7.52
;
(m, 2H), 7.34–7.12 (m, 8H), 6.50 (d, 1H, J = 2.9 Hz), 6.06 (d, 1H, J = 2.9 Hz), 5.77–
5.67 (m, 1H), 5.07–4.94 (m, 2H), 4.07–4.01 (m, 1H), 2.94–2.86 (m, 1H), 2.73–
2.65 (m, 1H); 13C NMR (75 MHz, CDCl3): d 156.9, 152.6, 142.0, 136.0, 131.0,
130.8, 128.7, 128.5, 128.4, 127.9, 126.8, 126.6, 123.4, 116.6, 107.9, 105.5, 45.5,
9. (a) Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002, 124,
10294; (b) Yamaguchi, M.; Tsukagoshi, T.; Arisawa, M. J. Am. Chem. Soc. 1999,
121, 4074; (c) Asao, N.; Asano, T.; Ohishi, T.; Yamamoto, Y. J. Am. Chem. Soc.
2000, 122, 4817; (d) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67,
1414.
10. (a) Matsuo, J.-I.; Kobayashi, S. CHEMTRACTS 2000, 13, 431; (b) Kobayashi, K.;
Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2002, 124, 8528; (c) Viswanathan,
G. S.; Wang, M.; Li, C.-J. Angew. Chem., Int. Ed. 2002, 41, 2138; (d) Viswanathan,
G. S.; Li, C.-J. Synlett 2002, 1553; (e) Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett.
2002, 43, 1613.
39.2;
yl)methyl)pentane-2,4-dione: Colorless liquid, IR (neat): mmax 3028, 2921,
2851, 1739, 1598, 1490, 1439, 1354, 1280, 1249, 1149, 755 cmÀ1 1H NMR
(300 MHz, CDCl3): 7.55–7.50 (m, 2H), 7.35–7.18 (m, 8H), 6.47 (d, 1H,
EIMS
(M+H):
m/z:
275.
5a:
3-(Phenyl(5-phenylfuran-2-
;
d
J = 3.2 Hz), 6.03 (d, 1H, J = 3.2 Hz), 4.89 (d, 1H, J = 11.8 Hz), 4.56 (d, 1H,
J = 11.8 Hz), 2.19 (s, 3H), 1.93 (s, 3H); 13C NMR (75 MHz, CDCl3): d 202.2, 201.9,
153.7, 153.3, 138.5, 130.8, 130.4, 128.8, 128.6, 128.2, 127.5, 127.3, 123.4, 109.0,
105.7, 73.3, 45.1, 30.1, 29.1; EIMS (M+Na): m/z: 355.