Furan synthesis through AuCl3-catalysed cycloisomerisation of β-alkynyl β-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2011.03.086

AuCl₃ efficiently catalyses the cycloisomerisation of readily available β-alkynyl β-ketoesters to generate trisubstituted furans. The substrate scope is wide and the reaction is high yielding and operationally simple.

Full text of DOI:10.1016/j.tetlet.2011.03.086

Tetrahedron Letters 52 (2011) 2605–2607
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Furan synthesis through AuCl3-catalysed cycloisomerisation of b-alkynyl
b-ketoesters
⇑
Arantxa Rodríguez, Wesley J. Moran
Department of Chemical & Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
AuCl3 efficiently catalyses the cycloisomerisation of readily available b-alkynyl b-ketoesters to generate
Received 26 January 2011
Revised 8 March 2011
Accepted 18 March 2011
Available online 7 April 2011
trisubstituted furans. The substrate scope is wide and the reaction is high yielding and operationally
simple.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Furan
Cycloisomerisation
Gold catalysis
The furan ring is an important structural sub-unit present in
many natural products1 and drug molecules. Numerous synthetic
furan derivatives have been shown to exhibit a wide range of bio-
logical activities.2 Furans have also been incorporated into poly-
mers and macrocycles for materials applications.3 In addition, the
utility of furans as building blocks in synthesis has received consid-
erable attention.4 Accordingly, the development of new and effi-
cient syntheses of multi-substituted furan rings is an important
objective.
Belting and Krause have reported a similar 5-exo-dig cycloiso-
merisation reaction of b-alkynyl ketones employing Au(I) cataly-
sis.11 Interestingly, with their substrates, AuCl3 only produced
trace amounts of the furan product, and the use of alcohol solvents
with their Au(I) catalyst system led to the generation of tetrahy-
drofuranyl ethers instead of furans.
For our study, the substrates were readily prepared either by
alkylation of the requisite dicarbonyl compounds with the corre-
sponding substituted propargylic bromide or by alkylation with
Cycloisomerisation reactions are powerful methods for the
preparation of cyclic compounds because of their 100% atom econ-
omy. In particular, the recent explosion of interest in gold catalysis
has revealed many such systems that generate a variety of ring
structures.5
As part of our research programme, we became interested in
electrophilic cyclisation reactions onto alkynes. Au-catalysed 5-
endo-dig cycloisomerisations of alkynyl substrates to generate fur-
an rings have been reported for a number of systems, namely:
(Z)-alk-2-en-4-yn-1-ols,6 alka-2,3-dien-1-ones,7 alk-3-yn-1-ones8
and alkynyloxiranes.9 A variety of other metal-catalysed furan syn-
theses have also been reported.10
Herein we report our observation that b-alkynyl b-ketoesters
undergo 5-exo-dig cycloisomerisation with a catalytic amount of
gold(III) chloride in refluxing methanol to generate trisubstituted
furan rings in good yields. PtCl2 was also found to be an effective
catalyst for this reaction, but slightly diminished yields were
obtained.
O
O
R1
OR2
R1
O
O
OR2
R3
O
O
R1
O
R3
AuCl3
O
OR2
R1
OR2
R3
AuCl3
R1
O
R3
OR2
H
O
H
R3
AuCl3
⇑
Corresponding author. Tel.: +44 0 1484 473741; fax: +44 0 1484 472182.
E-mail address: w.j.moran@hud.ac.uk (W.J. Moran).
Scheme 1. Postulated cycloisomerisation mechanism.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.086

2606
A. Rodríguez, W. J. Moran / Tetrahedron Letters 52 (2011) 2605–2607
Table 1
AuCl3-catalysed cycloisomerisation to furans
O
O
O
R1
R3
5 mol% AuCl3
MeOH
R1
OR2
R3
O
OR2
65 o
C
Entry
1
Alkyne
Product
Yielda (%)
O
O
O
Ph
2a
OMe
73
O
1a
OMe
Ph
O
O
O
Ph
2b
OEt
2
71b
O
1b
OEt
O
Ph
O
O
Ph
O
R
Ph
OEt
OEt
O
R
3
4
5
6
1c R = H
1d R = Ph
1e R = p-C6H4Cl
1f R = p-C6H4OMe
2c
2d
2e
2f
77
78
68
54
O
O
Ph
O
S
Ph
OEt
7
32
2g
1g
OEt
O
S
O
O
Ph
O
Ph
OEt
O
8
9
51
2h
1h
OEt
O
O2N
O
OMe
99b
O2N
O
1i
2i
OMe
a
Yield of pure isolated product.
Reaction run in dry methanol.
b
propargyl bromide followed by Sonogashira coupling. The subse-
quent cycloisomerisation was found to be effective for all of the
substrates tested (Table 1).
1i, underwent quantitative cycloisomerisation, however, dry
methanol was required to minimise alkyne hydration in this case
as well (entry 9).
Alkyne 1a cycloisomerised to furnish the furan 2a in very
good yield in refluxing methanol. However, alkyne 1b underwent
competitive alkyne hydration under these conditions,12 therefore,
dry methanol was required in order to obtain 2b in high yield.
Alkyne 1c containing a terminal alkyne cyclised efficiently under
the reaction conditions. Cycloisomerisations of 1d–f demon-
strated a slight electronic effect with p-chlorophenyl and p-
methoxyphenyl alkyne substituents giving slightly diminished
yields of the furan compared to the phenyl (entries 4–6). The
reaction was also successful with a thiophene alkyne substituent
generating bis(heteroaryl)methane 2g, but in low yield (entry 7).
An alkyl substituted alkyne proved to be a good substrate for
this reaction (entry 8). Intriguingly, p-nitrophenylketone alkyne
The cycloisomerisation is proposed to proceed through alkyne
activation by Au(III) and subsequent intramolecular attack by the
ketone oxygen to form a zwitterionic intermediate. Protodemetala-
tion regenerates the gold catalyst and releases the heterocycle,
which isomerises to the furan product (Scheme 1).13
In conclusion, an operationally simple procedure for the prepa-
ration of functionalised furans from readily available b-alkynyl b-
ketoesters through gold catalysis is reported.
Acknowledgements
We thank the Leverhulme Trust for the award of a research
grant (F/01 582/D).

A. Rodríguez, W. J. Moran / Tetrahedron Letters 52 (2011) 2605–2607
2607
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