Synthesis of tetrasubstituted furans via In-catalyzed propargylation of 1,3-dicarbonyl compounds-cyclization tandem process

Article abstract of DOI:10.1016/j.tetlet.2008.04.142

An efficient method to synthesize tetrasubstituted furans using simple starting materials such as propargylic alcohols and 1,3-dicarbonyl compounds has been developed. It was discovered that InCl₃ could catalyze this transformation efficiently

Full text of DOI:10.1016/j.tetlet.2008.04.142

Tetrahedron Letters 49 (2008) 4110–4112
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Tetrahedron Letters
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Synthesis of tetrasubstituted furans via In-catalyzed propargylation
of 1,3-dicarbonyl compounds-cyclization tandem process
*
*
*
Xunbo Feng, Ze Tan , De Chen, Youming Shen, Can-Cheng Guo , Jiannan Xiang , Chengliang Zhu
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method to synthesize tetrasubstituted furans using simple starting materials such as propar-
gylic alcohols and 1,3-dicarbonyl compounds has been developed. It was discovered that InCl3 could
catalyze this transformation efficiently while other simple iron, copper and silver salts were proven to
be ineffective.
Received 16 December 2007
Revised 24 April 2008
Accepted 25 April 2008
Available online 29 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The synthesis of furans has always been an area of intensive re-
search by synthetic chemists due to their wide presence in a vari-
ety of natural products and pharmaceuticals.1 They can also serve
as important intermediates for many organic transformations.
Classical methods for their syntheses2 involve the uses of Diels–
Alder reactions, condensations, cross-couplings, etc. However,
methods for the synthesis of highly substituted furans are still lim-
ited. During the last decade progress on this front3 has been made
via various isomerization and cyclization processes catalyzed by
Pd,3a,f Cu,3d Ag,3i Au,3e,g,h Ru,3b etc. But most of them require the
preparation of rather advanced starting materials such as alkynon-
es and allenones. Synthesis of furans starting from simple
compounds is still rare. Recently, Sanz et al. reported efficient
propargylation4a and benzylation4b of 1,3-dicarbonyl compounds
catalyzed by p-toluenesulfonic acid (PTSA hereafter). In several
cases,4a they demonstrated that the substitution products could
be transformed to tetrasubstituted furans by adding stoichiometric
amount of K2CO3 to the reaction mixture (Scheme 1). Though the
two-step one-pot synthesis of furan from simple starting material
is attractive, the need to stop the reaction in the middle and add
stoichiometric amount of K2CO3 to induce the desired cyclization
makes the procedure much less desirable. Therefore, there is much
room to be improved. Inspired by the recent huge influx of reports
on In-,5,6 Fe-catalysis,7 and their extensive uses as Lewis acids, we
envision that the same transformation can be catalyzed by Lewis
acids such as Indium or Iron salts, eliminating the need for
K2CO3, thus making the reaction truly catalytic. We report herein
a highly efficient procedure for the synthesis of tetrasubstituted
furans using propargylic alcohol, 1,3-diketones or 1,3-ketoesters,
and catalytic amount of InCl3.8
In- and Fe-catalysis has received much attention lately because
of the relatively cheap prices of Indium and Iron salts compared to
some of the noble metals and their environmental friendliness due
to their low toxicity. They have been used frequently as Lewis acids
and a plethora of transformations have been developed. In this
context, recent reports of In- and Fe-catalyzed benzylation9,10 of
aromatics and 1,3-dicarbonyl compounds are particularly relevant.
In order to make our procedure operationally simple, several com-
mon, commercially available indium and iron salts were screened
as catalysts (Table 1). The reaction of 1-phenyl-2-nonyn-1-ol with
acetylacetone was chosen as the model reaction as this type of
starting material has worked very well for Sanz et al. It was found
that the choices of catalyst and solvent were very important for
effecting the furan formation. For example, the use of FeCl3 in
refluxing dichloroethane only led to the substitution product B.
With stronger Lewis acid such as InCl3, the major product is still
the substitution product B accompanied by a small amount of
desired furan A when the reaction was performed in refluxing
dichloroethane. Finally, running the reaction in chlorobenzene at
110 °C afforded the desired furan A in excellent yield. Surprisingly,
when the much more Lewis acidic In(OTf)3 was used as catalyst,
the reaction gave a complex mixture. We surmised that other
byproducts such as indene derivatives arising from Friedel–Crafts
type reaction of the phenyl ring with the carbonyl group could also
be formed.11 This clearly suggested that the success of the reaction
critically hinged on the use of Lewis acid with appropriate acidity.
Lewis acids that are either too strong or too weak are not effective
O
O
K2CO3
cat.
p-TSA
O
CH3CN
R1
one-pot two-step process
OH
O
O
O
+
R1
R1
cat. Lewis acid?
Scheme 1. Synthesis of tetrasubstituted furans from propargylic alcohol and 1,3-
dicarbonyl compounds.
* Corresponding authors. Tel.: +86 0731 882 2400; fax: 86 0731 8822484 (Z.T.).
E-mail address: ztanze@gmail.com (Z. Tan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.142

X. Feng et al. / Tetrahedron Letters 49 (2008) 4110–4112
4111
Table 1
Table 2
Optimization of reaction conditions
Synthesis of furans via In-catalyzed propargylation of 1,3-diketones-cyclization
tandem process
O
O
O
OH
O
O
O
cat. Lewis acid
OH
+
O
Ph
+
O
O
solvent
Temperature
cat.InCl
nC6H13
Ph
Ph
3
1
O
3 eq.
R
+
nC6H13
nC6H13
chlorobenzene
1
2
R
R
o
3 eq.
110
C
A
B
2
R
Catalyst
Solvent
Temperature (°C)
Time (h)
Product (yield %)
Entry R1
R2
Time
(h)
Yielda
(%)
R2
FeCl3
InCl3
InCl3
ClCH2CH2Cl
ClCH2CH2Cl
Chlorobenzene
Reflux
Reflux
110
12
24
20
B (P95)
A (<10) B (83)
A (68)a
1
2
3
Phenyl
p-Chlorophenyl
p-
n-C6H13
n-C6H13
n-C6H13
20
20
20
89
87
Messy
n-C6H13
n-C6H13
InCl3
Chlorobenzen e
110
20
A (89)
In(OTf)3
CuBr2
CuBr
CuCl
CuI
AgCl
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
110
110
110
110
110
110
110
110
24
24
20
20
20
20
20
20
Messy
B Only
B Only
B Only
No reaction
No reaction
No reaction
Messy
Methoxyphenyl
p-Methylphenyl
Phenyl
4
5
n-C6H13
TMS
TMS
TMS
H
n-C4H9
n-C4H9
Phenyl
Phenyl
Phenyl
p-
24
22
20
16
32
24
24
24
24
24
24
81
83
80
76
53
81
91
70
80
65
76
n-C6H13
b
b
b
6
7
8
p-Chlorophenyl
p-Methylphenyl
Phenyl
H
AgI
AgOTf
9
p-Methylphenyl
Phenyl
Phenyl
p-Chlorophenyl
p-Methylphenyl
Phenyl
n-C4H9
n-C4H9
Phenyl
Phenyl
Phenyl
p-
10
11
12
13
14
a
Only 2 equiv of acetylacetone was used.
for the transformation to take place efficiently. For comparison,
several copper and silver salts were tested too. Only product B
was obtained with catalysts CuBr2, CuCl, and CuBr, while the use
of CuI, AgCl, or AgI resulted in no reaction. The use of AgOTf gave
a complex mixture. We also found that the use of three equivalent
of acetylacetone was necessary to achieve high yield. Otherwise
the yield of furan is lower. Based on the above results, we decided
to set reacting the propargyl alcohol with three equivalent of
acetylacetone and 10 mol % of InCl3 in chlorobenzene at 110 °C as
the standard condition.12
Chlorophenyl
p-
Chlorophenyl
Chlorophenyl
p-
Chlorophenyl
15
p-Chlorophenyl
24
89
a
All yields are isolated yields.
TMS group was replaced with a hydrogen atom.
b
Table 3
Synthesis of furans via In–catalyzed propargylation of ethyl acetoacetate-cyclization
tandem process
O
After optimizing the reaction conditions, we set out to investi-
gate the scope of the reaction. When the phenyl ring in 1-phe-
nyl-2-nonyn-1-ol was replaced with a simple alkyl group such as
the isopropyl group, its reaction with acetylacetone only produced
the Meyer–Schuster rearrangement product.13 This result is consis-
tent with what was reported by Sanz et al.4a It also highlights the
need to have a benzylic cation which is sufficiently long-lived to
react with 1,3-dicarbonyl compounds. Next, the scope of the sub-
strate was further explored as summarized in Table 2. The reac-
tions of substrates bearing chloro and methyl substituents on the
phenyl ring with acetylacetone proceeded smoothly, giving the de-
sired furans in 87% and 81% yield, respectively (Table 2, entries 2
and 4). On the other hand, substrate bearing p-methoxyl group
gave a complex mixture (Table 2, entry 3). It is thought that the
electron rich aromatic ring can also participate in the second cycli-
zation step. As for the substituent on the alkyne moiety, all sub-
strates bearing alkyl, aryl, trimethylsilyl groups all gave
satisfactory results. It is interesting to note that 1-phenyl-2-pro-
pyn-1-ol, a terminal alkyne containing propargyl alcohol could also
participate in the reaction, even though the yield is lower and the
reaction rate is somewhat slower (Table 2, entry 8). With the tri-
methylsilyl-substituted alkyne containing propargylic alcohols,
we were surprised to find that the final products obtained did
not contain the TMS group (Table 2, entries 5–7). Instead, the
TMS group was replaced with a hydrogen atom. Since the reaction
of trimethylsilyl-substituted alkyne containing propargyl alcohol
with acetylacetone was faster than the one without the TMS group,
we reasoned that the trimethylsilyl group was probably lost after
the furan formation. It should be noted that our yields of furans
are significantly higher than those of the PTSA-catalyzed version
though we do not know whether this is due to the use of excess
amount of nucleophile or not.
OH
O
O
EtO
cat. InCl
3
1
O
R
+
OEt
chlorobenzene
1
2
R
R
o
3 eq.
110 C, 20 h
2
R
Entry
R1
R2
Yielda (%)
R2
1
2
3
4
5
6
7
Phenyl
n-C6H13
TMS
TMS
p-Chlorophenyl
TMS
n-C4H9
n-C4H9
56
65
61
46
63
53
44
n-C6H13
b
p-Chlorophenyl
p-Methylphenyl
Phenyl
Phenyl
Phenyl
b
p-Chlorophenyl
b
n-C4H9
n-C4H9
p-Methylphenyl
a
All yields are isolated.
TMS group was replaced with a hydrogen atom.
b
acetone with ethyl acetoacetate. The yields of furans are lower
than those of acetylacetone. This may be due to the fact that 1,3-
diketones are better nucleophiles than 1,3-ketoesters. It is also
worthwhile to note that the reaction of propargylic alcohols with
simple ketones such as acetone did not succeed either.
A tentative mechanism for the reaction is outlined in Scheme 2.
First, the InCl3 catalyst coordinates with the oxygen atom of the
propargyl alcohol to generate a carbocation, which is subsequently
trapped by the dicarbonyl compounds to form the substitution
product C. Next, the InCl3 catalyst coordinates with the triple bond
in C and the triple bond was attacked by the lone-pair electrons of
the carbonyl group to generate D. The carbon–indium bond was
protonized6f,i and the desired furan product was obtained through
a series of proton addition/elimination, double bond isomerization
processes (Scheme 2).
In order to confirm that the cyclization step was truly catalyzed
by InCl3, we first isolated the substitution product B, and then trea-
ted it with catalytic amount of InCl3 in chlorobenzene. After 12 h at
As shown in Table 3, a variety of tetrasubstituted furans bearing
a carboxylate group can be readily synthesized by replacing acetyl-

4112
X. Feng et al. / Tetrahedron Letters 49 (2008) 4110–4112
O
O
H
References and notes
InCl3
O
O
OH
O
InCl3
InCl3
R1
R1
1. Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry II; Katritzky,
R1
R2
R2
A. R., Rees, C. W., Eds.; Elsevier: Oxford, 1997; vol. 2, pp 395–436.
2. (a) Hou, X. L.; Cheung, T. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955 and references cited therein; (b) Kirsch, S. F.
Org. Biomol. Chem. 2006, 4, 2076.
3. (a) Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995, 117, 7255; (b)
Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S.
Angew. Chem., Int. Ed. 2003, 42, 2681; (c) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc.
2004, 126, 9645; (d) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2004, 43, 2280; (e) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7,
3925; (f) Brown, R. D. Angew. Chem., Int. Ed. 2005, 44, 850; (g) Liu, Y.; Song, F.;
Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409; (h) Zhou, C.; Chan, P. W. H.;
Che, C. Org. Lett. 2006, 8, 325; (i) Ma, C.; Ding, H.; Zhang, Y.; Bian, M. Angew.
Chem., Int. Ed. 2006, 45, 7793.
R2
C
O
O
O
OH
- H+
H
+ H+
O
O
R1
InCl3
R1
R1
Cl2In
R2
R2
R2
Cl2In
D
O
O
O
- H+
+ H+
O
O
O
R1
R1
R1
H
H
R2
R2
R2
H
H
4. (a) Sanz, R.; Migue, D.; Martínez, A.; Álvarez-Gutiérrez, J. M.; Rodríguez, F. Org.
Lett. 2007, 9, 727; (b) Sanz, R.; Migue, D.; Martínez, A.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Org. Lett. 2007, 9, 2027.
Scheme 2. Possible mechanism for the furan formation.
5. (a) Lee, P. H.; Lee, K.; Kim, S. Org. Lett. 2001, 3, 3205; (b) Sakai, N.; Hirasawa, M.;
Konakahara, J. Tetrahedron Lett. 2003, 44, 4171; (c) Takami, K.; Mikami, S.;
Yorimitsu, H.; Shinorubo, H.; Oshima, K. J. Org. Chem. 2003, 68, 6627; (d) Ranu,
B.; Samanta, S. J. Org. Chem. 2003, 68, 7130; (e) Hayashi, N.; Shibata, I.; Baba, A.
Org. Lett. 2004, 6, 4981; (f) Takita, R.; Fukuto, Y.; Tsuji, R.; Ohshima, T.;
Shibasaki, M. Org. Lett. 2005, 7, 1363; (g) Hayashi, N.; Shibata, I.; Baba, A. Org.
Lett. 2005, 7, 3093; (h) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. . J. Am.
Chem. Soc. 2005, 127, 13760.
O
O
O
cat. InCl3
O
95%
chlorobenzene
Ph
110 o
C
Ph
nC6H13
nC6H13
6. For the use of Indium salts as Lewis acids, see: (a) Tsuchimoto, T.; Maeda, T.;
Shirakawa, E.; Kawakami, Y. Chem. Commun. 2000, 1573; (b) Loh, T.; Hu, Q.;
Tan, K.; Cheng, H. Org. Lett. 2001, 3, 2660; (c) Loh, T.; Chen, S. Org. Lett. 2002, 4,
3647; (d) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002, 124,
13690; (e) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami, Y. Chem.
Commun. 2003, 2454; (f) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 13002; (g) Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am. Chem.
Soc. 2004, 126, 7186; (h) Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6,
1527; (i) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett. 2005, 7, 3279; (j)
Chan, K.; Loh, T. Org. Lett. 2005, 7, 4491; (k) Miyanohana, Y.; Chatani, N. Org.
Lett. 2006, 8, 2155; (l) Zhang, Z.; Yin, L.; Wang, Y. Adv. Synth. Catal. 2006, 348,
184; (m) Cook, G. R.; Hayashi, R. Org. Lett. 2006, 8, 1045; (n) Sakai, N.; Annaka,
K.; Konakahara, T. Tetrahedron Lett. 2006, 47, 631.
7. (a) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856; (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217; (c)
Pavan, C.; Legros, J.; Bolm, C. Adv. Synth. Catal. 2005, 347, 703.
8. During the submission of the manuscript, one referee alerted us to a recent
paper describing similar transformation catalyzed by a Ru-complex and TFA:
Cadierno, V.; Gimeno, J.; Nebra, N. Adv. Synth. Catal. 2007, 349, 382.
9. Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793.
10. (a) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2005, 44, 3913; (b) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M. Adv.
Synth. Catal. 2007, 349, 865.
B
A
Scheme 3.
110 °C, the desired product A was isolated in 95% yield (Scheme 3).
This result firmly established the fact that furans were indeed pro-
duced through intermediate C and InCl3 did catalyze the cycliza-
tion process.
In summary, we have developed an efficient protocol for the
synthesis of tetrasubstituted furans from propargylic alcohols
and 1,3-dicarbonyl compounds. The success of the method de-
pended on the use of InCl3 as catalyst. Our reaction is relatively
favorable compared with the reported method in terms of both
the product yields and operational simplicity. Our method uses
only a catalytic amount of InCl3, requiring no stop in the middle
of the reaction and it also does not require the addition of stoichi-
ometric amount of base to effect the cyclization step. The proce-
dure that we developed not only extended the scope of
In-catalysis but also could be complementary to the existing
methods for the synthesis of furans. It could be easily adapted
for combinatory library synthesis. Detailed mechanistic investiga-
tion on this particular transformation is still ongoing.
11. Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825.
12. General procedure for the synthesis of furans via In-catalyzed propargylation of
1,3-dicarbonyl compounds-cyclization tandem process: Synthesis of 3-acetyl-5-n-
heptyl-2-methyl-4-phenylfuran (A). In
a 25-mL round-bottomed flask
equipped with reflux condenser were placed acetylacetone (300 mg,
a
3 mmol), 1-phenyl-2-nonyn-1-ol (216 mg, 1 mmol), 10 mol % InCl3 (22 mg,
0.1 mmol) and 5 mL of chlorobenzene. The mixture was heated to 110 °C for
20 h under N2 before it was cooled to room temperature. The mixture was
diluted with ether and quenched with saturated NH4Cl. The organic phase was
separated and the aqueous phase was extracted twice with ether. The organic
phases were combined, dried over MgSO4, and concentrated via vacua. The
crude product was purified through column chromatography (silica gel,
petroleum ether/ethyl acetate, 30/1) to afford 266 mg of the desired furan A
in 89% yield. 1H NMR (CDCl3, 400 MHz) d 0.85 (t, J = 6.8 Hz, 3H), 1.2–1.3 (m,
8H), 1.5–1.6 (m, 2H), 1.90 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 2.54 (s, 3H), 7.24 (d,
J = 7.6 Hz, 2H), 7.3–7.45 (m, 3H); 13C NMR (CDCl3, 100 MHz) d 13.99, 14.25,
22.53, 25.69, 28.41, 28.80, 28.89, 30.65, 31.63, 120.57, 122.85, 127.28, 128.31
(2C), 129.93 (2C), 133.78, 151.04, 156.20, 196.06; IR: 1562, 1674, 2856,
2927 cmÀ1; LRMS (CI) for C20H26O2 [M+H]+ calcd 299, found 299.
Acknowledgments
We thank the financial support from 985 project. We also thank
Professor Qing-hong Li for technique assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.04.142.
13. Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819.