Synthesis of highly substituted furans by the electrophile-induced coupling of 2-(1-alkynyl)-2-alken-1-ones and nucleophiles

Article abstract of DOI:10.1021/jo0510585

The coupling of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles, either catalyzed by AuCl₃ or induced by an electrophile, provides highly substituted furans in good to excellent yields under very mild reaction conditions. Various nucleophiles, i

Full text of DOI:10.1021/jo0510585

Synthesis of Highly Substituted Furans by the
Electrophile-Induced Coupling of 2-(1-Alkynyl)-2-alken-1-ones and
Nucleophiles
Tuanli Yao, Xiaoxia Zhang, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received May 26, 2005
The coupling of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles, either catalyzed by AuCl3 or induced
by an electrophile, provides highly substituted furans in good to excellent yields under very mild
reaction conditions. Various nucleophiles, including functionally substituted alcohols, H2O, carboxylic
acids, 1,3-diketones, and electron-rich arenes, and a range of cyclic and acyclic 2-(1-alkynyl)-2-
alken-1-ones readily participate in these cyclizations. Iodine, NIS, and PhSeCl have proven
successful as electrophiles in this process. The resulting iodine-containing furans can be readily
elaborated to more complex products using known organopalladium chemistry.
Introduction
used as commercial pharmaceutical agents, flavor and
fragrance compounds, insecticides, and antileukemic
agents.6 Polysubstituted furans can also be employed as
building blocks for the total synthesis of complicated
naturally occurring metabolites,7 and as versatile starting
materials for the preparation of a variety of heterocyclic
and acyclic compounds.8
Their important biological activity and great utility
have encouraged the search for ever newer, more efficient
methods for the synthesis of furans.9 The vast majority
of the previous routes to furans have involved the
chemical modification of acyclic precursors. A particularly
effective approach to the synthesis of functionalized
furans is through the transition metal-catalyzed cycliza-
tion of an alkynyl or allenyl ketone,10 alcohol,11 or
epoxide,12 or electrophilic cyclization of alk-3-yne-1,2-
Furans, one of the most important five-membered-ring
heterocycles,1 can be found in many naturally occurring
compounds arising from plants and marine organisms.2
For example, in a number of biologically significant
natural products, such as pinguisone,3 furodysinin,4 and
methyl vouacapenate,5 a 2,3-disubstituted furan ring
constitutes a distinctive structural feature. Furans are
(1) (a) Dean, F. A. Naturally Occurring Oxygen Ring Compounds;
Butterworth: London, UK, 1963. (b) Natural Products Chemistry;
Nakanishi, K., Goto, T., Ito, S., Natori, S., Nozoe, S., Eds.; Kodansha,
Ltd.: Tokyo, Japan, 1974; Vols. 1-3. (c) Dean, F. M. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New
York, 1982; Vol. 30, pp 167-238. (d) Dean, F. M. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New
York, 1983; Vol. 31, pp 237-344. (e) Sargent, M. V.; Dean, F. M. In
Comprehensive Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W.
H., Eds.; Pergamon Press: Oxford, UK, 1984; Vol. 3, pp 599-656. (f)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819.
(2) (a) Lee, J.; Li, J.-H.; Oya, S.; Snyder, J. K. J. Org. Chem. 1992,
57, 5301-5312. (b) Padwa, A.; Ishida, M.; Muller, C. L.; Murphree, S.
S. J. Org. Chem. 1992, 57, 1170-1178. (c) Jacobi, P. A.; Selnick, H. G.
J. Org. Chem. 1990, 55, 202-209.
(3) (a) Benesova, V.; Samek, Z.; Herout, V.; Sorm, F. Collect. Czech.
Chem. Commun. 1969, 34, 1807-1809. (b) Corbella, A.; Gariboldi, P.;
Jommi, G.; Orsini, F.; De Marco, A.; Immirzi, A. J. Chem. Soc., Perkin
Trans. 1 1974, 1875-1878.
(5) (a) King, F. E.; King, T. J.; Neill, K. G. J. Chem. Soc. 1953, 1055-
1059. (b) King, F. E.; King, T. J. J. Chem. Soc. 1953, 4158-4168. (c)
King, F. E.; Godson, D. H.; King, T. J. J. Chem. Soc. 1955, 1117-
1125.
(6) (a) Nakanishi, K. Natural Products Chemistry; Kodansha, Ltd.:
Tokyo, Japan, 1974. (b) The Chemistry of Heterocyclic Flavoring and
Aroma Compounds; Vernin, G., Ed.; Ellis Horwood: Chichester, UK,
1982. (c) Kubo, I.; Lee, Y. W.; Balogh-Nair, V.; Nakanishi, K.; Chapya,
A. J. Chem. Soc., Chem. Commun. 1976, 949-950. (d) Schulte, G.;
Scheuer, P. J.; McConnell, O. J. Helv. Chim. Acta 1980, 63, 2159-
2167.
(4) (a) Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Daly, J. J.;
Schoenholzer, P. Tetrahedron Lett. 1978, 19, 4951-4954. (b) Richou,
O.; Vaillancourt, V.; Faulkner, D. J.; Albizati, K. F. J. Org. Chem. 1989,
54, 4729-4730.
(7) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
J. Wiley: New York, 1989. (b) Nicolaou, K. C.; Sorensen, E. J. Classics
in Total Synthesis; VCH: Weinheim, Germany, 1996.
10.1021/jo0510585 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/20/2005
J. Org. Chem. 2005, 70, 7679-7685
7679

Yao et al.
diols,13 2,4-dialkenyl-1,3-dicarbonyl compounds,14 or 2-alky-
nyl carbonyl compounds.15 No attention has been paid
to 2-(1-alkynyl)-2-alken-1-ones as possible furan precur-
sors, although they are more readily accessible and more
easily manipulated than are alkynyl or allenyl ketones.16
The utilization of 2-(1-alkynyl)-2-alken-1-ones for transi-
tion metal-catalyzed or electrophilic cyclization should
significantly expand the range of suitable starting ma-
terials for the synthesis of functionally substituted
furans.
rasubstituted furans in good to excellent yields (eq 2).
These unique cyclizations are particularly attractive,
because sequential nucleophilic domino attack onto an
alkyne affords multiply substituted furans through si-
multaneous formation of a C-O bond and a remote
carbon-nucleophile bond. One of the advantages of this
approach to furans is that the regioselective introduction
of substituents about the furan ring comes down to the
appropriate choice of the 2-(1-alkynyl)-2-alken-1-one and
nucleophile, which allows for considerable versatility
(Scheme 1). Furthermore, the electrophile-induced cy-
clization provides a general and efficient approach to the
regioselective synthesis of tetrasubstituted furans, which
is still today a challenge in organic synthesis.
Recently, we have communicated a AuCl3-catalyzed
synthesis of substituted furans from 2-(1-alkynyl)-2-
alken-1-ones, which produces highly substituted furans
in good to excellent yields (eq 1).17 Now, we wish to report
a detailed study of the AuCl3-catalyzed synthesis of
substituted furans, together with a novel electrophile-
induced three-component reaction, which produces tet-
Results and Discussion
Our preliminary studies have been carried out on the
transition metal-catalyzed coupling of 2-phenylethynyl-
2-cyclohexen-1-one (1) and methanol to afford furan 2
(Table 1). As we previously communicated, silver, copper,
gold, and mercury salts afford good yields of furan 2
(Table 1, entries 1-4).17 Among these salts, AuCl3 is the
most efficient catalyst based on reaction time and yield.
This is consistent with previous work on the cyclization
(8) (a) Benassi, R. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, UK, 1996; Vol. 2, pp 259-295. (b) Heaney, H.; Ahn, J. S. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 2, pp
297-357. (c) Friedrichsen, W. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, UK, 1996; Vol. 2, pp 351-393. (d) Keay, B. A.; Dibble, P. W.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 2, pp
395-436. (e) Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, UK, 1991.
SCHEME 1
(9) Recent reviews: (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In
Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon Press: Oxford, UK, 2002; Vol. 14, pp 139-179. (b)
Cacchi, S. J. Organomet. Chem. 1999, 576, 42-64. (c) Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955-2020.
(10) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27,
4893-4894. (b) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J.
Org. Chem. 1991, 56, 5816-5819. (c) Kel’in, A. V.; Gevorgyan, V. J.
Org. Chem. 2002, 67, 95-98. (d) Ma, S.; Zhang, J. Chem. Commun.
2000, 117-118. (e) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1992,
57, 3387-3396. (f) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991,
56, 960-969. (g) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994,
59, 7169-7171. (h) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F.
Tetrahedron Lett. 1993, 34, 2813-2816. (i) Hashmi, A. S. K.; Schwarz,
L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285-
2288.
TABLE 1. Catalytic Cyclization and Coupling of
2-Phenylethynyl-2-cyclohexen-1-one (1) and Methanola
(11) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. Tetrahedron 1985, 41, 3655-3661. (b) Gabriele, B.; Salerno,
G.; Lauria, E. J. Org. Chem. 1999, 64, 7687-7692. (c) Seiller, B.;
Bruneau, C.; Dixneuf, P. H. J. Chem. Soc., Chem. Commun. 1994, 493-
494. (d) Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51,
13089-13102. (e) Ku¨cu¨kbay, H.; Cetinkaya, B.; Guesmi, S.; Dixneuf,
P. H. Organometallics 1996, 15, 2434-2439.
time
(h)
% yield
% recovery
entry
catalyst
AgO2CCF3
Cu(O3SCF3)2
AuCl3
Hg(O2CCF3)2
Pd(OAc)2
PtCl2
of 2b
of 1
1
2
10
9
0.5
8
6
24
24
24
24
24
1
87
81
90c
86
30d
10
27
0
0
0
0
0
65
81
68
95
71
90
0
3
(12) (a) Lo, C.-Y.; Guo, H.; Lian, J.-J.; Shen, F.-M.; Liu, R.-S. J. Org.
Chem. 2002, 67, 3930-3932. (b) Marshall, J. A.; DuBay, W. J. J. Am.
Chem. Soc. 1992, 114, 1450-1456. (c) Hashmi, A. S. K.; Sinha, P. Adv.
Synth. Catal. 2004, 346, 432-438.
4
5
6
7
Cu(NO3)2‚2.5H2O
RuCl3‚3H2O
PtCl2(PPh3)2
RhCl3
(13) Bew, S. P.; Knight, D. W. Chem. Commun. 1996, 1007-1008.
(14) Stefani, H. A.; Petragnani, N.; Valduga, C. J.; Brandt, C. A.
Tetrahedron Lett. 1997, 38, 4977-4980.
8
9
18
8
0
10
11
(15) (a) Rao, M. S.; Esho, N.; Sergeant, C.; Dembinski, R. J. Org.
Chem. 2003, 68, 6788-6790. (b) Sniady, A.; Wheeler, K. A.; Dembinski,
R. Org. Lett. 2005, 7, 1769-1772.
HBF4
a Reaction conditions: 1 (0.1 mmol), catalyst (0.001 mmol), and
MeOH (0.15 mmol) in CH2Cl2 (0.5 mL) at room temperature.
b Determined by 1H NMR spectroscopic analysis. c Compound 2
can be obtained cleanly within 40 min in an 88% yield when using
0.1 mol % AuCl3. Only a 30% yield of 2 was obtained after 24 h
when 0.01 mol % of AuCl3 was employed. d Pd black appeared.
(16) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582-
1583.
(17) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164-11165. (b) For a review of gold catalysis, see: Hashmi, A.
S. K. Gold Bull. 2004, 37, 51-65. (c) For the same reaction catalyzed
by copper(I), see: Patll, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem.
2005, 70, 4531-4534.
7680 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of Highly Substituted Furans
TABLE 2. Electrophile-Induced Cyclization and Coupling of 2-Phenylethynyl-2-cyclohexen-1-one (1) and Methanola
entry
electrophile
nucleophile
solvent
product
E ) I
% yieldb
1
2
3
4
5
6
7
I2
MeOH
MeOH
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
3
3
3
4
5
6
70
50c
80
I2
3.0 MeOH
8.0 MeOH
3.0 MeOH
3.0 MeOH
3.0 MeOH
3.0 MeOH
I2
NIS
60
NBS
E ) Br
0
PhSeCl
p-O2NC6H4SCl
E ) PhSe
45
E ) p-O2NC6H4S
∼20d
a Reaction conditions: a solution of 0.2 mmol of 1, 3 equiv of electrophile, the nucleophile indicated, and 3 equiv of NaHCO3 in 2 mL
of solvent was stirred at room temperature for 1 h. b Isolated yield. c Compound 7 was also isolated in a 17% yield. d An inseparable
mixture with p-O2NC6H4SOMe was obtained. The yield was determined by 1H NMR spectroscopic analysis.
of 3-alkyn-1-ones to furans.10i Pd(OAc)2 provided a low
yield, mainly due to the facile reduction of Pd(II) to Pd-
(0) in the presence of the alcohol (Table 1, entry 5).18 The
addition of 2 equiv of PPh3 to Pd(OAc)2 did stabilize the
Pd(II) salt, but slowed the reactions. PtCl2, Cu(NO3)2, and
RuCl3 (Table 1, entries 6-8) are not efficient catalysts,
in part due to their poor solubility in dichloromethane.
PtCl2(PPh3)2 does have good solubility, but shows poor
catalytic activity (Table 1, entry 9). RhCl3 is barely active
in this reaction (Table 1, entry 10). Thus, AuCl3 was
chosen as the catalyst for the cyclization of a number of
other substrates. When the reaction of 1 was performed
in the absence of AuCl3 or in the presence of a catalytic
amount of HBF4 instead of AuCl3, no cyclization product
2 was obtained at all (Table 1, entry 11). These blank
tests clearly indicate that AuCl3 is required for the
reaction to proceed.
To expand the scope of our Au-catalyzed process, we
have examined the use of other electrophiles. Our study
of the electrophile-induced cyclization has also been
carried out on 2-phenylethynyl-2-cyclohexen-1-one (1)
and methanol in the presence of NaHCO3. Initially, when
I2 was employed as the electrophile, and methanol was
utilized as both the solvent and the nucleophile, the
reaction afforded the desired 3-iodofuran 3 in a 70% yield
(Table 2, entry 1). To make the reaction more useful, 3
equiv of MeOH was used as the nucleophile together with
acetonitrile as the solvent (Table 2, entry 2). Unfortu-
nately, in addition to the desired 3-iodofuran 3 (50%),
compound 7 (see eq 3), which is obviously formed by
in CH3CN without any MeOH, compound 7 was isolated
in a 41% yield (eq 3). Thus, to totally trap the carbocation
intermediate, an excess of MeOH is required. We were
happy to see that when 8 equiv of MeOH was employed,
the desired 3-iodofuran 3 was obtained in an 80% yield,
without any of compound 7 being formed (Table 2, entry
3). NIS and PhSeCl can also be employed as electrophiles
in this process, albeit in lower yields (Table 2, entries 4
and 6). The electrophile p-O2NC6H4SCl afforded an
inseparable mixture of the desired furan product and
p-O2NC6H4SOMe in low yield (Table 2, entry 7). Unfor-
tunately, NBS did not afford any furan product (Table
2, entry 5).
With the optimized reaction conditions in hand, the
effect on the yield of the substituents on the alkyne was
examined next (Table 3, entries 1-11). Alkynes bearing
either electron-rich or electron-poor aryl groups are
readily accommodated in both the AuCl3-catalyzed and
I2-induced cyclizations (entries 3-7). The presence of a
vinylic group presents no difficulties in the AuCl3-
catalyzed cyclization (entry 8), but afforded only a modest
46% yield upon reaction with I2/MeOH (entry 9). Inter-
estingly, while the TMS-substituted alkyne did not afford
any furan product in the AuCl3-catalyzed cyclization
(entry 10), a good yield of 2,3-diiodofuran 21 was obtained
in the iodine-induced cyclization (entry 11). Obviously,
iododesilylation of the TMS group takes place either prior
to or soon after cyclization. Alkynes bearing H and alkyl
groups have thus far failed to provide any of the desired
products, using either AuCl3 or I2.
An unprecedented set of nucleophiles can be employed
in these cyclizations (Table 3, entries 12-30). Not only
simple alcohols, like methanol and 2-propanol (Table 3,
entries 12 and 13), but also labile alcohols, like allyl
alcohol, benzylic alcohols, 3-phenyl-2-propyn-1-ol, and a
protected D-pyranose, are effective nucleophiles in these
cyclizations (Table 3, entries 14-20). Even though H2O
and acetic acid did not afford furan products in the AuCl3-
catalyzed process, they work well in the I2-induced
cyclization (Table 3, entries 21-24). It should be noted
that the hydration of alkynes catalyzed by gold(I) and
gold(III) has been reported previously,19 which may
explain the failure of H2O in the AuCl3-catalyzed cycliza-
tion, even though we did not observe any hydration
products. Since iodide itself can serve as a nucleophile,
nucleophilic attack of iodide on the anticipated carboca-
tion intermediate (see the later discussion of the mech-
anism), was isolated in a 17% yield. This implied that I2
could serve as both an electrophile and a nucleophile in
the reaction. Indeed, when the reaction was carried out
(18) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125,
9578-9579 and references therein.
J. Org. Chem, Vol. 70, No. 19, 2005 7681

Yao et al.
TABLE 3. Cyclization and Coupling of 2-(1-Alkynyl)-2-alken-1-ones and Various Nucleophilesa
a For E ) H, the following procedure was employed unless otherwise specified: a solution of 0.2 mmol of 2-(1-alkynyl)-2-alken-1-one,
1 mol % of AuCl3, and 1.5 equiv of nucleophile in 1 mL of CH2Cl2 was stirred at room temperature for 1 h. For E ) I, the following
procedure was employed unless otherwise specified: a solution of 0.2 mmol of 2-(1-alkynyl)-2-alken-1-one, 3 equiv of I2, 8 equiv of nucleophile,
and 3 equiv of NaHCO3 in 2 mL of CH3CN was stirred at room temperature for 1 h. b The reaction took 4 h. c 1.5 equiv of nucleophile was
used and CH2Cl2 was employed as the solvent. d The reaction took 50 h. e 2 mol % of AuCl3 was used. f The reaction took 24 h.
7682 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of Highly Substituted Furans
SCHEME 2
affords a mixture of cis and trans products in both
cyclizations, with the latter predominating. Interestingly,
when pureisomer 69 or 70 was subjected to our standard
AuCl3-catalyzed cyclization conditions, they were both
readily isomerized to a 51:49 cis/trans mixture of 69 and
70 (eq 4).22 Thus, the ratio of stereoisomers 69 and 70
weak nucleophiles, like 1,3-cyclohexanedione and electron-
rich arenes, did not afford coupling products in the I2-
induced process (Table 3, entries 25, 27, and 29). On the
other hand, these weak nucleophiles work very well in
the AuCl3-catalyzed cyclization. Thus, the reaction of 1,3-
cyclohexanedione afforded a high yield of the ether 36
in which the new bond has been formed between the
â-carbon of the R,â-unsaturated ketone and the enol
oxygen of the diketone (Table 3, entry 26). Electron-rich
arenes, such as N,N-dimethylaniline and N-methylindole,
can also be easily introduced completely regioselectively
into furan products as carbon-based nucleophiles (Table
3, entries 28 and 30). N,N-Dialkylanilines can also be
employed as benzene surrogates, since the direct deami-
nation of N,N-dialkylanilines has recently been re-
ported.20 Overall, the AuCl3-catalyzed and I2-induced
cyclizations compliment each other.21 Together they
provide a general and efficient route to highly substituted
furans.
A range of 2-(1-alkynyl)-2-alken-1-ones readily partici-
pate in these cyclizations (Table 3, entries 31-47). In
addition to the successful cyclization of 2-(1-alkynyl)-
cyclohexenones 1 and 66 (see Scheme 3), 2-phenyleth-
ynyl-2-cyclopenten-1-one (41) afforded iodofuran 42 (74%)
after an unusually long reaction time, but this alkyne
was not reactive at all in the AuCl3-catalyzed cyclization
(Table 3, entries 31 and 32). A possible explanation is
that the reaction is slowed because the carbonyl group
is oriented away from the carbon-carbon triple bond.
2-Phenylethynyl-2-cyclohepten-1-one (44) (Table 3, en-
tries 33 and 34) and chromone 47 (Table 3, entries 35-
37) undergo smooth cyclizations. Interestingly, since the
carbocation intermediates in the chromones are reso-
nance stabilized by a neighboring oxygen (Scheme 2),
N,N-dimethylaniline now proves to be an effective carbon-
based nucleophile in the I2-induced cyclization (Table 3,
entry 37). Even sterically hindered chromone 51 afforded
3-iodofuran 52 in a good yield (Table 3, entry 38).
Furthermore, acyclic 2-alken-1-ones also afford highly
substituted furans in both the AuCl3-catalyzed and I2-
induced cyclizations (Table 3, entries 40-43). Note that
the acyclic substrates readily accommodate additional
carbon-carbon double or triple bonds in the AuCl3-
catalyzed cyclizations, but not in the I2-induced cycliza-
tions (Table 3, entries 44-47). Again, these two cycliza-
tions compliment each other.
reported in Scheme 3 appears to roughly reflect the
thermodynamic stability of the products. On the other
hand, no isomerization of 67 or 68 was observed when
they were subjected to our standard I2-induced cyclization
conditions.
This isomerization may occur through either Lewis
acid-promoted ionization of the methyl ether to the
corresponding cyclohexyl carbocation or electrophilic
aromatic substitution of 69 or 70 by AuCl3 to provide a
furyl-gold species,10i which reverts back to starting mate-
rial 66, followed by AuCl3-catalyzed recyclization of 66
to afford an equilibrium mixture of isomers (Scheme 4).
Further mechanistic studies have shown that neither
of the above proposed mechanisms are correct (Scheme
5). When a 51:49 cis/trans mixture of 69 and 70 was
subjected to our standard AuCl3-catalyzed cyclization
conditions using 5.0 equiv of CD3OD as the nucleophile,
no deuterium incorporation into the furan was observed,
although the OCH3 group was nearly completely replaced
by OCD3.
A reasonable pathway for this isomerization involves
reversible abstraction of methoxide from 69 or 70 by
oxophilic AuCl3, as shown in Scheme 6.
At least two mechanisms are plausible for the gold-
catalyzed cyclization (Scheme 7). In one (Cycle A), gold
functions as both a Lewis acid and a transition metal.23
AuCl3 first acts as a Lewis acid, forming a complex with
the carbonyl oxygen. This facilitates 1,4-addition of the
nucleophile to the carbon-carbon double bond to produce
72.24 Subsequent coordination of the alkynyl moiety of
the alkenynone 72 to AuCl3 induces a cyclization of the
carbonyl oxygen onto the triple bond, followed by elimi-
nation of a proton, and protonation of the resulting
organogold intermediate to afford furan 2 with simulta-
neous regeneration of the AuCl3 catalyst. An alternative
mechanism in which AuCl3 functions simply as a transi-
tion metal is also possible (Scheme 7, Cycle B).10i Coor-
dination of the triple bond of 1 to AuCl3 enhances the
electrophilicity of the triple bond. Subsequent nucleo-
philic attack of the carbonyl oxygen on the electron-
deficient triple bond generates carbocation 76. Intermo-
lecular nucleophilic attack on the carbocation and
subsequent protonation of the carbon-gold bond afford
We have also examined the stereochemistry of nucleo-
philic attack on the enone 66 (Scheme 3). This enone
(19) (a) Teles, J. H.; Brod, S.; Chabanas, M. Angew. Chem., Int. Ed.
1998, 37, 1415-1418. (b) Mizushima, E.; Sato, K.; Tanaka, M. Angew.
Chem., Int. Ed. 2002, 41, 4563-4565. (c) Casado, R.; Contel, M.;
Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003, 125, 11925-
11935. (d) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729-
3731. (e) Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537-
2538.
(20) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7894-7895.
(21) For the dehalogenation of halofurans, see: Gronowitz, S.; Holm,
B. J. Heterocycl. Chem. 1977, 14, 281-288.
(22) We gratefully acknowledge a reviewer, who recommended this
experiment.
(23) Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli,
F.; Rossi, E. E. J. Org. Chem. 2003, 68, 6959-6966.
(24) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4,
1319-1322.
J. Org. Chem, Vol. 70, No. 19, 2005 7683

Yao et al.
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 7
SCHEME 6
furan 2 and regenerate the catalyst AuCl3. The mecha-
nism illustrated in Cycle B appears more likely, since
1% AuCl3 fails to catalyze the 1,4-addition of methanol
to 2-cyclohexenone or methyl vinyl ketone under our
standard reaction conditions.
An experiment using fully deuterated methanol as the
nucleophile, although it cannot distinguish between Cycle
A and Cycle B in Scheme 7, produced furan 78 with 70%
deuterium incorporation into the furan (eq 5). The proton-
nol and/or the solvent. Using 3.0 equiv of fully deuterated
methanol improved the deuterium incorporation in the
furan to 85%.
containing furan product is apparently formed by inad-
vertent introduction of water into the deuterated metha-
7684 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of Highly Substituted Furans
SCHEME 8
thus providing a regioselective method for the prepara-
tion of 4-substituted benzofurans.
Conclusion
An efficient synthesis of highly substituted furans has
been developed through the cyclization of 2-(1-alkynyl)-
2-alken-1-ones in the presence of various nucleophiles.
If AuCl3 is used as a catalyst, a proton is introduced into
the 3 position of the furan. An iodide is readily introduced
into the 3 position by using I2 as the electrophile.
Selenium and sulfur electrophiles can also be utilized,
but the yields are low. An unprecedented range of
nucleophiles can be employed in these processes, which
are often complementary. This methodology accommo-
dates various functional groups and affords the antici-
pated furans in good to excellent yields under very mild
reaction conditions. The resulting iodine-containing prod-
ucts can be readily elaborated to more complex products
using known organopalladium chemistry.
Experimental Section
Representative Procedure for the AuCl3-Catalyzed
Cyclizations. A solution of AuCl3 (30.3 mg) in MeCN (970
mg) was prepared. To the appropriate 2-(1-alkynyl)-2-alken-
1-one (0.2 mmol) and nucleophile (1.5 equiv) in CH2Cl2 (1 mL)
was added the above AuCl3 solution (20 mg, 1 mol %). The
mixture was stirred at room temperature for 1 h unless
otherwise specified. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
on silica gel.
Representative Procedure for the I2-Induced Cycliza-
tions. To a mixture of the appropriate 2-(1-alkynyl)-2-alken-
1-one (0.2 mmol), I2 (3.0 equiv), and NaHCO3 (3.0 equiv) was
added a solution of the nucleophile (8.0 equiv) in MeCN (2 mL).
The resulting mixture was stirred at room temperature for 1
h unless otherwise specified. The mixture was diluted with
ether (25 mL), washed with saturated Na2S2O3 (25 mL), and
dried (MgSO4). The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
on silica gel.
The mechanism of the I2-induced cyclization is pre-
sumably similar to that shown in Cycle B (Scheme 7).
Coordination of the electrophile to the triple bond pro-
motes nucleophilic attack of the carbonyl oxygen on the
triple bond, generating a carbocation intermediate, which
then undergoes nucleophilic attack to afford the furan
product.
We have also investigated further transformations of
the furan products (Scheme 8). For example, palladium-
catalyzed intramolecular arylation,25 intramolecular hy-
droarylation,26 intramolecular Heck reaction,27 and car-
bonylation28 have afforded the anticipated products in
modest to good yields. Benzofuran 84 can also be pre-
pared through the DDQ-promoted dehydrogenation of 2,29
Acknowledgment. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, the National Science
Foundation, and the National Institute of General
Medical Sciences (GM070620) for partial support of this
research.
Supporting Information Available: Experimental de-
tails and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997,
62, 2-3. (b) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002,
41, 1569-1572.
(26) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52, 11479-11502.
(27) Knight, S. D.; Overman, L. E. Heterocycles 1994, 39, 497-501.
(28) (a) Konaklieva, M. I.; Shi, H.; Turos, E. Tetrahedron Lett. 1997,
38, 8647-8650. (b) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002,
67, 5616-5620.
JO0510585
(29) Zambias, R. A.; Caldwell, C. G.; Kopka, I. E.; Hammond, M. L.
J. Org. Chem. 1988, 53, 4135-4137.
J. Org. Chem, Vol. 70, No. 19, 2005 7685