Gold-catalyzed cascade friedel-crafts/ furan-alkyne cycloisomerizations for the highly efficient synthesis of arylated (Z)-enones or -enals

Article abstract of DOI:10.1021/ol901408u

An efficient domino approach for the synthesis of arylated (Z)-enones or -enals through gold(I)-catalyzed reactions of enynols with furans was developed. PPh₃AuNTf₂ was found to be an excellent catalyst to catalyze both of the Friede

Full text of DOI:10.1021/ol901408u

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3838-3841
Gold-Catalyzed Cascade Friedel-Crafts/
Furan-Alkyne Cycloisomerizations for
the Highly Efficient Synthesis of
Arylated (Z)-Enones or -Enals
Yifeng Chen,† Yuhua Lu,‡ Guijie Li,† and Yuanhong Liu*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China, and Department of Chemistry, Shanghai UniVersity,
Shangda RD. 99, Shanghai 200444, People’s Republic of China
yhliu@mail.sioc.ac.cn
Received June 22, 2009
ABSTRACT
An efficient domino approach for the synthesis of arylated (Z)-enones or -enals through gold(I)-catalyzed reactions of enynols with furans was
developed. PPh3AuNTf2 was found to be an excellent catalyst to catalyze both of the Friedel-Crafts and furan/alkyne cyclization reactions in
the same vessel. This method offers several advantages such as high stereoselectivities, mild reaction conditions, and easily accessible
starting materials.
The transition-metal-catalyzed cycloisomerization of alkynes
bearing proximate C, O, N nucleophiles has proven to be a
Scheme 1
powerful synthetic route to a wide variety of carbo- and/or
heterocycles.1 Especially in recent years, gold catalysts have
been found to be efficient alkynophilic Lewis acids to activate
the π- systems toward nucleophilic attack, rendering them
attractive reagents in organic synthesis.2 For example,
Hashmi et al. reported that an intramolecular alkyne/furan
† Shanghai Institute of Organic Chemistry.
‡ Shanghai University.
(1) For reviews, see: (a) Makamura, I.; Yamamoto, Y. Chem. ReV. 2004,
104, 2127. (b) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2258, and
references therein.
(2) For recent reviews on gold-catalyzed reactions, see: (a) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180. (b) Ma, S.; Yu, S.; Gu, Z. Angew.
cyclization could be catalyzed by gold to afford phenols 6
Chem., Int. Ed. 2006, 45, 200. (c) Li, Z.; Brouwer, C.; He, C. Chem. ReV.
(Scheme 1).3 Other transition metals with a d8 configuration
2008, 108, 3239. (d) Lipshutz, B. H.; Yamamoto, Y. Chem. ReV. 2008,
108, 2793. (e) Arcadi, A. Chem. ReV. 2008, 108, 3266. (f) Jimen´ez-Nu´ın˜ez,
E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326. (g) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351. (h) Patil, N. T.; Yamamoto,
Y. Chem. ReV. 2008, 108, 3395.
such as PtCl2, palladium(II), iridium(I), and rhodium(I) also
catalyze this transformation;3b,4 however, gold catalysts were
found to be most active. One of the drawbacks of these
10.1021/ol901408u CCC: $40.75
Published on Web 08/12/2009
 2009 American Chemical Society

reactions is that only terminal alkynes can be used in most
cases. A series of mechanistic investigations revealed that
the reactions proceed through the first formation of cyclo-
propyl carbenoid 2, which undergoes ring-opening to provide
the conjugated carbenoid 3, cyclization of 3 to the oxepine
4 and arene oxide 5, followed by ring-opening leading to
phenol 6.3o We envisioned that if a gold-carbenoid inter-
mediate with a 1,3-linked structure like 7 derived from an
endocyclization is formed (Figure 1), the transformation to
Table 1. Optimization Studies for the Formation of (Z)-Enones
catalyst
(5 mol %)
yield (%)
of 9aa
yield (%)
of 10aa
entry
time
1
2
3
4
AuCl3
AgOTf
Ph3PAuNTf2
Ph3PAuCl/AgOTf
30 min
1 h
1 h
86
87
87
57
2 h
16
a Isolated yields.
terminal alkynes. The iodide precursors were conveniently
synthesized from the corresponding propargylic alcohols by
their reaction with Red-Al followed by iodination of the
organoaluminum intermediate.6b,d,e,7 To probe the feasibility
of the proposed transformations, we initially investigated the
reactions of (Z)-1,3,5-triphenylpent-2-en-4-yn-1-ol 8a with
2-methylfuran (Table 1). It was found that the use of AuCl3
or AgOTf only afforded the arylated product 9a in good
yields. However, treatment of 8a and 2-methylfuran in DCE
Figure 1. Comparison of the key intermediates.
the arene oxide 5 could be avoided, which may provide
different products such as enones other than phenols.
However, such reactions have rarely been found in the
literature.5 Recently, we have developed gold-catalyzed
cycloisomerizations of (Z)-enynols6a,b and the straightforward
synthesis of allylic amines from allylic alcohols through
direct amination reactions, etc.6c Inspired by these methods,
we could further develop new domino processes for the
efficient construction of pyrroles6d and indole-fused
carbocycles6e directly from enynols. In this paper, we
describe our discovery and investigations of the gold-
catalyzed tendem reactions involving Friedel-Crafts reac-
tions of furans with enynols followed by the furan/alkyne
cyclizations in a one-pot procedure, which affords arylated
(Z)-enones or -enals in a highly stereoselective manner. The
furan cyclization step may involve an intermediate of type
7; furthermore, in our reactions, internal alkynes could also
be used (Scheme 2).
(3) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000,
122, 11553. (b) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001,
3, 3769. (c) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Catal. Today 2002,
72, 19. (d) Hashmi, A. S. K.; Ding, L.; Fischer, P.; Bats, J. W.; Frey, W.
Chem.sEur. J. 2003, 9, 4339. (e) Hashmi, A. S. K.; Grundl, L. Tetrahedron
2005, 61, 6231. (f) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.;
Kurpejovic´, E. Angew. Chem. 2004, 116, 6707. Hashmi, A. S. K.; Weyrauch,
J. P.; Rudolph, M.; Kurpejovic´, E. Angew. Chem., Int. Ed. 2004, 43, 6545.
(g) Hashmi, A. S. K.; Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.;
Bats, J. W. Angew. Chem. 2005, 117, 2858. Hashmi, A. S. K.; Rudolph,
M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.; Bats, J. W. Angew. Chem., Int.
Ed. 2005, 44, 2798. (h) Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.;
Frost, T. M.; Miehlich, B.; Frey, W.; Bats, J. W. Chem.sEur. J. 2006, 12,
5806. (i) Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey, W.; Bats,
J. W. AdV. Synth. Catal. 2006, 348, 709. (j) Hashmi, A. S. K.; Haufe, P.;
Schmid, C.; Nass, A. R.; Frey, W. Chem.sEur. J. 2006, 12, 5376. (k)
Hashmi, A. S. K.; Salathe´, R.; Frey, W. Chem.sEur. J. 2006, 12, 6991. (l)
Carretin, S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K. AdV. Synth. Catal.
2006, 348, 1283. (m) Hashmi, A. S. K.; Wo¨lfle, M.; Ata, F.; Hamzic, M.;
Salathe´, R.; Frey, W. AdV. Synth. Catal. 2006, 348, 2501. (n) Hashmi,
A. S. K.; Ata, F.; Kurpejovic, E.; Huck, J.; Rudolph, M. Top. Catal. 2007,
44, 245. (o) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.; Frey, W.;
Rominger, F.; Oeser, T. Chem.sEur. J. 2008, 14, 6672. (p) Hashmi,
A. S. K.; Rudolph, M.; Siehl, H.; Tanaka, M.; Bats, J. W.; Frey, W.
Scheme 2
Chem.sEur. J. 2008, 14, 3703
.
(4) (a) Mart´ın-Matute, B.; Ca´rdenas, D. J.; Echavarren, A. M. Angew.
Chem. 2001, 113, 4890. Mart´ın-Matute, B.; Ca´rdenas, D. J.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2001, 40, 4754. (b) Mart´ın-Matute, B.;
Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003,
125, 5757
.
(5) There is only one example of such type of reaction, in which a seven-
membered dihydrooxepine was observed in low yield (7%) in the formation
of isochromanes; see ref 3m.
(6) (a) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
5409. (b) Du, X.; Song, F.; Lu, Y.; Chen, H.; Liu, Y. Tetrahedron 2009,
65, 1839. (c) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964. (d) Lu, Y.; Fu,
X.; Chen, H.; Du, X.; Jia, X.; Liu, Y. AdV. Syn. Catal. 2009, 351, 129. (e)
Lu, Y.; Du, X.; Jia, X.; Liu, Y. AdV. Syn. Catal. 2009, 351, 1517
.
(7) Du, X.; Chen, H.; Liu, Y. Chem.sEur. J. 2008, 14, 9495. (b) Zhang,
Y.; Herndon, J. W. Org. Lett. 2003, 5, 2043. (c) Marshall, J. A.; Dehoff,
B. A. J. Org. Chem. 1986, 51, 863. (d) Kim, K. D.; Magriotis, P. A.
Tetrahedron Lett. 1990, 43, 6137. (e) Larrosa, I.; Da Silva, M. I.; Go´mez,
P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A.; Wilton,
D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042. (f) Shinada, T.;
The requisite enynols were easily prepared by the Sono-
gashira coupling reactions of iodinated allylic alcohols with
Sekiya, N.; Bojkova, N.; Yoshihara, K. Tetrahedron 1999, 55, 3675
.
Org. Lett., Vol. 11, No. 17, 2009
3839

Table 2. One-Pot Synthesis of (Z)-Enones or -Enals through the Reactions of Enynols with Furans
entry enynol
R1
R2
R3
R4
R5
time(h) product
yield(%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
8a
8b
8c
8d
8a
8a
8e
8f
8g
8h
8i
8j
8k
8l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
COOEt
CH2OCH3
n-C4H9
Ph
Ph
p-ClC6H4
p-MeOC6H4
n-C4H9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
TMS
Ph
Ph
1
1.5
2
1.5
1
1.2
1.5
1
1
1
1
1
10a
10b
10c
10d
10e
10f
10g
10h
10i
10b
10c
10j
10k
10l
87
82
66
80
87b
66c,d
67b
77b
66
Ph
p-ClC6H4
p-MeOC6H4
2-thienyl
n-C3H7
Ph
Me
Me
Me
Ph
Ph
Me
91
89
Ph
Ph
Ph
84
1.5
1
1.3
77b
80b
33
-(CH2)3-
-(CH2)4-
8m
Ph
10m
a Isolated yields. Unless noted, all of the reactions were carried out using 5 mol % of (PPh3)AuNTf2 and 2.0 equiv of furans at room temperature. b 1.2
equiv of furans was used. c First, 8a reacted with 10 equiv of 2-trimethylsilylfuran in the presence of 5 mol % of (PPh3)AuCl/AgOTf to afford the arylated
intermidiate 9f with the elimination of the TMS group, and then 9f was subjected to standard conditions. d Compound 10f is an enal in which R5 ) H in the
represented structure.
with 5 mol % of gold(I) complex PPh3AuNTf2 resulted in
the clean formation of enone 10a in 87% yield. It is
interesting to note that in this reaction, the C1-C5 in enynol
8a together with the C-5 carbon of furan are smoothly
transferred to the arene skeleton, while the remaining C2-C4
carbons of furan are converted into the enone moiety in
product 10. Remarkably, only (Z)-enone was observed
(coupling constant of two olefinic hydrogens is 12.4 Hz);
leading to 10d in 80% yield (entry 4). 2-Phenylfuran could
also be used in the reaction, and a 87% yield of 10e was
achieved (entry 5). When 2-trimethylsilylfuran was em-
ployed, the product could not be isolated as a pure form.
We then tried to carry out the reaction in a stepwise manner.
Thus, by stirring the reaction mixture in the presence of 5
mol % of (PPh3)AuCl/AgOTf and 10 equiv of 2-trimethy-
isilylfuran for 2 h, the intermediate of (Z)-2-(1,3,5-triph-
enylpent-2-en-4-ynyl)furan 9f with the elimination of a TMS
group was isolated in 70% yield. When 9f was subjected to
the gold-catalyzed reaction, the expected cyclization occurred
to generate enal 10f in 66% yield (entry 6). The substituent
effects on C-3 and C-1 of enynols have also been examined,
and a wide range of substituents, including alkyl-, aryl-, and
heteroaryl-substituted ones, are suitable in these domino
reactions (entries 7-13). Furthermore, the functionalities of
-CO2Et and -CH2OCH3 were well tolerated during the
reaction, affording 10g and 10h in 67% and 77% yields,
respectively (entries 7 and 8). It should be noted that the
substrates of 8b and 8h afforded the same product 10b, and
also 8c and 8i led to the same enone 10c. Enynols 8l and
8m fused with 5- or 6-membered rings generated the enones
10l and 10m in 80% and 33% yields, respectively (entries
14 and 15). The structure of 10e was unambiguously
confirmed by X-ray crystallographic analysis, which clearly
showed the (Z)-configuration of the enone (Figure 2). In the
solid structure, the CdC-CdO unit is oriented approxi-
mately perpendicular to the central benzene ring.
1
the (E)-isomer was not detected according to the H NMR
of the crude reaction mixture. The R,ꢀ-unsaturated aldehydes
or ketones (without arene formation) have been observed as
side products by Echavarren; these were formed by hydroly-
sis of a platium carbenoid intermediate; however, they
observed the (E)-isomer exclusively.4b A mixture of (Z)- and
(E)-isomers of R,ꢀ-unsaturated ketones have been isolated
also by Hashmi et al. as side products in gold-catalyzed
phenol synthesis.3m The formation of (Z)-isomer in their
report is in accordance with the cis-carbenoid 3 that is
suggested to be generated through rearrangement of cyclo-
propyl carbenoids 2 in the proposed reaction mechanism.
The present method could be applied successfully to
various enynols 8, whether acyclic or bearing a cyclic ring,
to provide the corresponding (Z)-enones or -enals in generally
good to high yields (Table 2). The substituent effects on the
alkyne terminus were first investigated. The aromatic ring
of R4 bearing an electron-withdrawing group (-Cl) or an
electron-donating group (-OMe) were all compatible, fur-
nishing the corresponding enones 10b and 10c in 82% and
66% yields, respectively (Table 2, entries 2 and 3). The alkyl-
substituted enynol 8d underwent cyclization smoothly,
To understand the reaction mechanism, the arylated
product 9e has been isolated in 82% yield by AuCl3-catalyzed
3840
Org. Lett., Vol. 11, No. 17, 2009

Scheme 5
Figure 2. X-ray crystal structure of enone 10e.
Au+-catalyzed Friedel-Crafts reaction with 2-substituted
furan through the electrophilic attack of the furan C5 to afford
the enyne 9. Coordination of gold complex to the triple bond
of 9 followed by the intramolecular nucleophilic attack of
the furan ring results in a 7-endo cyclization intermediate
12. Next, a cyclopropyl gold carbenoid 13 is formed, which
is analogous to the reaction intermediate 2 proposed in
Hashmi’s work. Rearrangement of 13 by cleavage of a C-C
and C-O bond affords carbonyl compound 14 with a cis-
configuration of the double bond. Elimination of a proton
followed by deauration leads to the enone 10.
substitution reaction. The intramolecular cyclization of 9e
catalyzed by (PPh3)AuNTf2 proceeded smoothly to provide
the same product of 10e as observed in the tandem process
(Scheme 3). The results strongly supported our assumption
Scheme 3
In summary, we have developed an efficient domino
approach for the synthesis of arylated (Z)-enones or -enals
through gold(I)-catalyzed reactions of enynols with furans.
PPh3AuNTf2 was found to be an excellent catalyst to catalyze
both the Friedel-Crafts and furan/alkyne cyclization reac-
tions in the same vessel. This method offers several
advantages such as high stereoselectivities, mild reaction
conditions, and easily accessible starting materials. Further
studies to extend the scope of synthetic utility for this Au-
catalyzed cascade reaction are in progress in our laboratory.
that the enone 10 was formed through Au(I)-catalyzed furan/
alkyne cyclization of intermediate 9 in the one-pot procedure.
Interestingly, when 3-phenylfuran was used, the expected
2-phenylacrylaldehyde was not obtained; instead, 3-phenyl-
acrylaldehyde 11 was isolated in 59% yield8 (Scheme 4).
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20872163, 20732008,
20821002), the Chinese Academy of Science, Science and
Technology Commission of Shanghai Municipality, and the
Major State Basic Research Development Program (Grant
No. 2006CB806105) for financial support.
Scheme 4
Supporting Information Available: Experimental details,
spectroscopic characterization of all new compounds, and
X-ray crystallography of compound 10e. This material is
available free of charge via the Internet at http://pubs.acs.org.
The results indicated that arylation took place selectively at
the C-2 position of furan, which might relate to an electronic
effect of the 3-phenyl substituent.
OL901408U
We propose the following reaction mechanism for this
tandem sequence (Scheme 5). The reaction is initiated by
(8) The geometry of the double bond in 11 is tentatively assigned to be
the (Z)-configuration.
Org. Lett., Vol. 11, No. 17, 2009
3841