Gold-catalyzed tandem cycloisomerization-hydroalkoxylation of homopropargylic alcohols

Article abstract of DOI:10.1021/ol061751u

The tandem cycloisomerization-hydroalkoxylation of various homopropargylic alcohols in the presence of an alcohol and a dual catalyst system, consisting of a gold precatalyst and a Bronsted acid, provides an efficient route to tetrahydrofuranyl ethers und

Full text of DOI:10.1021/ol061751u

ORGANIC
LETTERS
2
006
Vol. 8, No. 20
489-4492
Gold-Catalyzed Tandem
Cycloisomerization Hydroalkoxylation of
4
−
Homopropargylic Alcohols
Volker Belting and Norbert Krause*
Organic Chemistry II, Dortmund UniVersity, D-44221 Dortmund, Germany
norbert.krause@uni-dortmund.de
Received July 17, 2006
ABSTRACT
The tandem cycloisomerization−hydroalkoxylation of various homopropargylic alcohols in the presence of an alcohol and a dual catalyst
system, consisting of a gold precatalyst and a Brønsted acid, provides an efficient route to tetrahydrofuranyl ethers under mild reaction
conditions. The reaction can be carried out in various solvents, including alcohol, with both terminal and internal alkynes as the substrate.
Tetrahydrofuranyl ethers are important building blocks in
organic synthesis. In addition to their function as protecting
groups, these cyclic acetal skeletons occur in a variety of
nosoma cruzi. Furthermore, oxidation of the cyclic acetal4
offers a convenient access to substituted γ-lactones, which
are also important structural units of many natural products.5
Thus, it is not surprising that numerous pathways for the
synthesis of cyclic acetals have been developed. Besides the
1
natural products that possess diverse biological activities
(Figure 1).
6
radical cyclization of haloacetals, transition metal catalysis
has been utilized frequently for this purpose, for example,
in the Pd-catalyzed coupling of allylic alcohols and vinyl
7
ethers, as well as the Ir-catalyzed cycloisomerization-
hydroalkoxylation of bis-homopropargylic alcohols.8
Because of their unique ability to activate carbon-carbon
multiple bonds, the use of gold catalysts plays an important
9
role in modern transition metal catalysis. Of particular value
are cycloisomerization reactions, which are perfect examples
1
0
for atom efficiency. Recent instances of these include the
Figure 1. Naturally occurring tetrahydrofuranyl ethers.
gold-catalyzed cycloisomerization of R-hydroxyallenes,11
(
4) (a) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
4
19. (b) Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1989,
These include cytotoxic compounds such as vernolide-A
1) and the methoxylated protolimonoid (2), which shows
6
2, 2050. (c) Ueno, Y.; Moriya, O.; Chino, K.; Watanabe, M.; Okawara,
2
3
(
M. J. Chem. Soc., Perkin Trans. 1 1986, 1351.
inhibitory activity against trypomastigote forms of Trypa-
(5) Review: Koch, S. S. C.; Chamberlin, A. R. Stud. Nat. Prod. Chem.
995, 16, 687.
1
(
6) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J.
(
1) (a) Kruse, C. G.; Broekhof, N. L. J. M.; Van der Gen, A. Tetrahedron
Lett. 1976, 1725. (b) Ochiai, M.; Sueda, T. Tetrahedron Lett. 2004, 45,
557.
2) Kuo, Y.-H.; Kuo, Y.-J.; Yu, A.-S.; Wu, M.-D.; Ong, C.-W.; Yang
Kuo, L.-M.; Huang, J.-T.; Chen, C.-F.; Li, S.-Y. Chem. Pharm. Bull 2003,
1, 425.
3) Biavatti, M. W.; Vieira, P. C.; Da Silva, M. F. G. F.; Fernandes, J.
B.; Albuquerque, S. J. Nat. Prod. 2002, 65, 562.
Am. Chem. Soc. 1982, 104, 5564. (b) Stork, G.; Mook, R.; Biller, S. A.;
Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741. (c) Hayashi, Y.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 63. (d) Villar, F.;
Equey, O; Renaud, P. Org. Lett. 2000, 2, 1061.
(7) (a) Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1987,
28, 809. (b) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3367.
(8) Genin, E.; Antoniotti, S.; Michelet, V.; Genet, J.-P. Angew. Chem.
2005, 117, 5029; Angew. Chem. Int. Ed. 2005, 44, 4949.
3
(
5
(
1
0.1021/ol061751u CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/09/2006

R-aminoallenes,12 and R-thioallenes,13 which provide an
efficient and stereoselective access to chiral five-membered
heterocycles. More recently, these transformations have been
extended to the gold-catalyzed cyclization of â-hydroxy- and
â-aminoallenes to the corresponding dihydropyrans and
3
yields. Whereas Ph PAuCl alone was unreactive (entry 1),
formation of a cationic gold species by addition of silver
salts led to a clean and rapid formation of the desired product
4a in good yield (entry 2). Decreasing the catalyst loading
from 5 to 2 or 0.1 mol % only marginally affected the
reaction time and chemical yield (entries 3-5). Compared
to the cationic system, other gold precatalysts were less
reactive and afforded lower yields of the acetal 4a (entries
6-11). With gold(I) chloride, an increase of the yield from
53% to 67% was observed in the presence of pyridine; this
might indicate an activation of the hydroxy group by the
base. Not surprisingly, HAuCl acts both as gold source and
4
Brønsted acid, so that the presence of p-TsOH is not required
with this precatalyst (entry 11). In contrast to this, sodium
tetrachloroaurate is inactive (entry 12), as are AgBF or
4
p-TsOH alone (or a combination of both; entries 13-15),
ruling out the possibilty of a simple silver- or acid-catalyzed
process.
14
tetrahydropyridins, respectively. In contrast to this, the gold-
catalyzed cycloisomerization of hetero-substituted alkynes
15
usually leads to aromatic heterocycles, even though Genet
and co-workers16 have recently reported the gold-catalyzed
cycloisomerization of bis-homopropargylic diols to strained
bicyclic ketals. Herein we report an unprecedented tandem
cycloisomerization-hydroalkoxylation of homopropargylic
alcohols to tetrahydrofuranyl ethers using a dual catalyst
17
system consisting of a gold precatalyst and a Brønsted acid.
The starting materials of our study are readily available
18
by Sonogashira coupling of but-3-yn-1-ol with various aryl
1
9
halides, as well as by Yamaguchi-Hirao alkynylation of
oxiranes. Initial experiments were performed using alcohol
3
as model substrate, which was treated with catalytic
To shed light on the reaction mechanism, we treated
amounts of a gold salt and p-TsOH in ethanol as solvent at
3 4
homopropargylic alcohol 3 with Ph PAuCl/AgBF for 8 h
room temperature (Table 1).
in the absence of a Brønsted acid and obtained a 1:3 mixture
of the cyclic acetal 4a and the dihydrofuran 5, albeit in low
yield (Scheme 1). Treatment of the reaction mixture (after 8
Table 1. Gold-Catalyzed Tandem
Cycloisomerization-Hydroalkoxylation of Homopropargylic
Alcohol 3 to Tetrahydrofuranyl Ether 4
Scheme 1
entry
mol %
Au salt
additive
time
yield (%)
1
2
3
4
5
6
7
8
9
2
5
2
0.1
2
2
2
2
2
2
2
2
-
-
-
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
AuCl
-
5 d
1 h
1 h
2 h
2 h
3 h
4 h
12 h
4 h
6 h
8 h
5 h
4 d
4 d
5 d
-
77
76
64
74
53
67
30
76
54
67
-
AgBF4
AgBF4
AgBF4
AgSbF6
-
pyridine
-
-
-
-
-
AgBF4
AgBF4
-
h reaction time) with catalytic amounts of p-TsOH for 45
min gave mainly tetrahydrofuranyl ether 4a and only traces
AuCl
Au(OH)3
Au(OAc)3
AuCl3
(11) (a) Hoffmann-R o¨ der, A; Krause, N. Org. Lett. 2001, 3, 2537. (b)
10
11
12
13
14
15
Krause, N.; Hoffmann-R o¨ der, A.; Canisius, J. Synthesis 2002, 1758.
(12) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
a
HAuCl4
(
13) Morita, N.; Krause, N. Angew. Chem. 2006, 118, 1930; Angew.
NaAuCl4
Chem. Int. Ed. 2006, 45, 1897.
a
a
-
-
-
-
(
14) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
-
-
(15) (a) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432.
(b) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2
004, 6, 4391. (c) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004,
610. (d) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
1164. (e) Liu, Y.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
16) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am. Chem.
a
Without addition of p-TsOH.
1
(
Soc. 2005, 127, 9976. See also: Barluenga, J.; Dieguez, A.; Fernandez,
A.; Rodriguez, F.; Fananas, F. J. Angew. Chem. 2006, 118, 2145; Angew.
Chem. Int. Ed. 2006, 45, 2091.
Both gold(I) and gold(III) precatalysts were found to be
active and afforded the cyclic acetal 4a in moderate to good
(17) Examples for the gold-catalyzed intermolecular addition of nucleo-
philes to alkenes and alkynes: (a) Teles, J. H.; Brode, S.; Chabanas, M.
Angew. Chem. 1998, 110, 1475; Angew. Chem., Int. Ed. 1998, 37, 1415.
(b) Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett. 2005, 7,
673. (c) Liu, Y.; Liu, M.; Guo, S.; Tu, H.; Zhou, Y.; Gao, H. Org. Lett.
2006, 8, 3445. (d) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D.
J. Am. Chem. Soc. 2006, 128, 8132.
(18) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Tykwinsky, R. R. Angew. Chem. 2003, 115, 1604; Angew. Chem.
Int. Ed. 2003, 42, 1566.
(
9) Recent reviews on homogeneous gold catalysis in organic synthesis:
a) Hoffmann-R o¨ der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (b)
Hashmi, A. S. K. Angew. Chem. 2005, 117, 7150; Angew. Chem. Int. Ed.
2
7
(
005, 44, 6990. (c) Arcadi, A.; Giuseppe, S. D. Curr. Org. Chem. 2004, 8,
95.
(
10) (a) Trost, B. M. Angew. Chem. 1995, 107, 285; Angew. Chem. Int.
Ed. Engl. 1995, 34, 259. (b) Sheldon, R. A. Pure Appl. Chem. 2000, 72,
233.
1
4490
Org. Lett., Vol. 8, No. 20, 2006

Scheme 2
of dihydrofuran 5. Thus, the acetal 4a is probably formed
by gold-catalyzed cycloisomerization of 3 to the correspond-
The gold- and acid-catalyzed tandem cycloisomerization-
hydroalkoxylation can also be carried out in non- or weakly
coordinating solvents. Treatment of substrate 3 with 2 equiv
of ethanol afforded the cyclic acetal 4a with yields ranging
from 46% to 71% in toluene, dichloromethane, THF, or
diethyl ether as the solvent (Table 2, entries 5-8). These
conditions may be advantageous for valuable or solid
alcohols. Only the strongly coordinating acetonitrile failed
to give any cyclization product (entry 9), probably because
of deactivation of the gold catalyst.
ing 2,3-dihydrofuran, followed by the known acid-catalyzed
2
0
hydroalkoxylation of the latter.
We next extended the scope of the tandem cycloisomer-
ization-hydroalkoxylation to different alcohols and solvents
(
Table 2). The cyclic acetals 4b-d were obtained in
Table 2. Synthesis of Tetrahydrofuranyl Ethers 4 Using
To further examine the scope of the tandem cycloisomer-
ization-hydroalkoxylation, we treated various homoprop-
argylic alcohols 6 with the dual catalyst system and different
alcohols as the solvent (Table 3). Electronically diverse aryl
Different Alcohols and Solvents
Table 3. Gold- and Acid-catalyzed Synthesis of
Tetrahydrofuranyl Ethers 7
entry
ROH
solvent
MeOH
iPrOH
time
4 (yield, %)
1
2
3
4
5
6
7
8
9
1 h
3 h
3 h
5 d
45 min
1 h
2 h
2 h
3 h
4b (68)
4c (58)
4d (78)
-
4a (69)
4a (46)
4a (66)
4a (71)
-
MeO(CH2)2OH
tBuOH
a
EtOH
toluene
CH2Cl2
THF
Et2O
MeCN
a
a
a
a
EtOH
EtOH
EtOH
EtOH
entry
R1
R2
R3
R4
7 (yield/%)
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeOC6H4
4-MeO2CC6H4
4-MeO2CC6H4
4-MeO2CC6H4
Ph
Ph
Ph
nBu
tBu
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
Me
Me
Et
Et
Et
Me
iPr
Et
Et
Et
Et
Et
Et
7a (50)
7b (36)
7c (67)
7d (71)
7e (63)
7f (63)
a
Two equivalents.
5
8-78% yield by using the Ph
catalyst in methanol, 2-propanol, or 2-methoxyethanol
entries 1-3). Only in the presence of the bulky tert-butyl
alcohol, the starting material remained unchanged even after
days at room temperature.
3 4
PAuCl/AgBF /p-TsOH
a
7g (69 )
a
7h (72 )
(
a
7i (44 )
1
1
0
1
-
-
5
Me3Si
a
dr ) 60:40.
(19) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(
20) (a) Brown, C. D. S.; Simpkins, N. S. Tetrahedron Lett. 1993, 34,
1
31. (b) Barton, D. H. R.; Launay, F. Tetrahedron 1997, 43, 14565. (c)
Toyooka, N.; Nagaoka, M.; Sasaki, E.; Qin, H.; Kakuda, H.; Nemoto, H.
Tetrahedron 2002, 58, 6097. (d) El-Seedi, H. R.; Yamamura, S.; Nishiyama,
S. Tetrahedron 2002, 58, 7485.
groups at the alkyne terminus are tolerated (entries 1-8) with
electron-rich systems giving the lowest yield (entry 2). Again,
Org. Lett., Vol. 8, No. 20, 2006
4491

different alcohols can be used without compromising the
yield of the tetrahydrofuranyl ether 7 (entries 3-5). Substi-
tutents at C-1 and C-2 did not cause any problems (entries
alcohols 3/6. Finally, we were delighted to observe a clean
cycloisomerization the 2-alkynylphenol 12 to the benzofuran
13 in the presence of AuCl, AuCl , or HAuCl ; the latter
3 4
7
7
-9). Secondary alcohols afforded the corresponding acetals
h/i as 60:40 mixture of diastereomers (entries 8 and 9),
gave the highest yield of 86%. Because of its mildness and
efficiency, our method competes well with known protocols
for this transformation.
2
1
indicating that there is almost no stereocontrol in the
hydroalkoxylation of the chiral 2,3-dihydrofuran formed in
the cyclization step. The latter example shows that the
method can also be applied to substrates with an alkyl
substituent at the triple bond. However, the cyclization is
sensitive to steric hindrance at this position since the tert-
butyl- or trimethylsilyl-substituted substrates did not react
under the standard conditons. (entries 10 and 11).
Based on the assumption that the tandem cycloisomeriza-
tion-hydroalkoxylation of homopropargylic alcohols to
tetrahydrofuranyl ethers takes place via 2,3-dihydrofurans
(see Scheme 1), we propose the mechanism shown in Scheme
2. Coordination of the gold catalyst to the triple bond of the
substrate A gives rise to the formation of the π-complex B,
which upon nucleophilic attack of the oxygen is transformed
into the σ-gold complex C. Protodemetalation of the latter
affords the 2,3-dihydrofuran D and releases the gold catalyst
into the first catalytic cycle. The dihydrofuran enters the
second catalytic cycle and is transformed into the intermedi-
ates E and F by protonation and nucleophilic attack of the
Further extensions of gold-catalyzed cyclization are shown
in Scheme 3. The transformation of homopropargylic 8
Scheme 3
2
alcohol R OH, respectively. Finally, deprotonation closes the
second catalytic cycle and releases the cyclic acetal G.
In summary, we have developed a mild and efficient
tandem cycloisomerization-hydroalkoxylation of homopro-
pargylic alcohols to tetrahydrofuranyl ethers in the presence
of an alcohol and a dual catalyst system, consisting of a gold
precatalyst and a Brønsted acid. The method was applied to
the cyclization of the bis-homopropargylic alcohols 10, as
well as to the 2-alkynylphenol 12. The reaction can be carried
out in various solvents, including alcohol, with both terminal
and internal alkynes as the substrate. Further work will be
devoted to the extension of the method to other functionalized
alkynes, as well as to the application of the method in target-
oriented synthesis.
Acknowledgment. Financial support of our work by the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie is gratefully acknowledged.
alcohol into the cyclic acetal 9 shows that the tandem
cycloisomerization-hydroalkoxylation is not restricted to
internal alkynes but can be applied to terminal acetylenes
as well. Compared to substrates bearing a bulky substituent
at the triple bond (Table 3, entries 10 and 11), this reaction
also demonstrates that steric hindrance in alkyl chain does
not prevent the tandem cycloisomerization-hydroalkoxyla-
tion. Increasing the distance between the triple bond and
hydroxy group is also possible: the bis-homopropargylic
alcohols 10 afforded the tetrahydrofuranyl ethers 11 with
good yield under the same conditions as the homopropargylic
Supporting Information Available: Experimental pro-
cedure and NMR data of cyclization products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061751U
(21) (a) Monteiro, N.; Balme, G. Synlett 1998, 746. (b) Yoshida, M.;
Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron 2005, 61, 4381. (c) Li,
X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437.
4492
Org. Lett., Vol. 8, No. 20, 2006