Gold catalysed synthesis of 3-alkoxyfurans at room temperature

Article abstract of DOI:10.1039/c3cc48290a

Synthetically important 3-alkoxyfurans can be prepared efficiently via treatment of acetal-containing propargylic alcohols (obtained from the addition of 3,3-diethoxypropyne to aldehydes) with 2 mol% gold catalyst in an alcohol solvent at room temperature. The resulting furans show useful reactivity in a variety of subsequent transformations. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc48290a

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Gold catalysed synthesis of 3-alkoxyfurans at
room temperature†
Cite this: Chem. Commun., 2014,
50, 1302
Matthew N. Pennell,a Robert W. Foster,a Peter G. Turner,b Helen C. Hailes,a
Christopher J. Tameb and Tom D. Sheppard*a
Received 29th October 2013,
Accepted 11th December 2013
DOI: 10.1039/c3cc48290a
www.rsc.org/chemcomm
Synthetically important 3-alkoxyfurans can be prepared efficiently
We have recently reported that the gold-catalysed rearrange-
via treatment of acetal-containing propargylic alcohols (obtained ment of propargylic alcohols to enones (the Meyer–Schuster
from the addition of 3,3-diethoxypropyne to aldehydes) with 2 mol% rearrangement) proceeds at room temperature in toluene, in
gold catalyst in an alcohol solvent at room temperature. The resulting the presence of a small amount of alcohol additive (MeOH or
furans show useful reactivity in a variety of subsequent transformations. EtOH).16 During the course of our study into the scope of this
reaction, we observed that attempted rearrangement of acetal-
Furans are important structural motifs which appear in a wide containing propargylic alcohol 1a (Scheme 1, R1 = 4-CF3C6H4)
array of natural products, biologically active compounds and
pharmaceuticals.1 They also have potential uses in the construction
of conjugated polymers for applications such as organic electronics.2
As a consequence, the synthesis of polysubstituted furans has
attracted considerable interest. Recent synthetic approaches
have included a number of transition-metal catalysed cyclisation
reactions3 mediated by a variety of catalysts4–8 including systems
based on palladium,4 rhodium,5 ruthenium6 and silver.7 Over
the past few years, the use of homogeneous gold catalysts for
facilitating the addition of nucleophiles to carbon–carbon multiple
bonds has emerged as a very powerful synthetic method9 and a
number of gold-catalysed approaches to the synthesis of hetero-
cyclic aromatic rings,10 including simple furans,11 have been
reported. Simple 3-alkoxyfurans such as 3-methoxyfuran are
highly electron rich systems which show useful reactivity,12
and have found application in natural product synthesis13 as
well as in the construction of polysubstituted tetrahydrofurans.14
However, the chemistry of more complex 3-alkoxyfurans has not
been widely explored, largely as a consequence of their synthetic
inaccessibility.15 Herein, we describe a gold-catalysed method for the
synthesis of a wide variety of 3-alkoxyfurans from readily available
propargylic alcohols, via a process that allows straightforward varia-
tion of substituents both on the furan ring and the alkoxy group.
a Department of Chemistry, University College London, 20 Gordon St, London,
WC1H 0AJ, UK. E-mail: tom.sheppard@ucl.ac.uk; Fax: +44 (0)7679 7463;
Tel: +44 (0)7679 2467
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Herts, SG1 2NY, UK
Scheme 1 Gold-catalysed synthesis of 3-ethoxyfurans and 3-methoxyfurans.
600 mg scale reaction. Clean conversion of the aldehyde in propargylic
alcohol 1o into the dimethylacetal occurred under the reaction conditions.
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data for all compounds and 1H and 13C NMR spectra for
novel compounds. See DOI: 10.1039/c3cc48290a
a
b
1302 | Chem. Commun., 2014, 50, 1302--1304
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gave a mixture of the expected enone 2a and 3-ethoxyfuran 3a,
where the alcohol additive had become incorporated.17 Given
the importance of polysubstituted furans in a wide variety of
applications, we sought to optimise this transformation.18
Pleasingly in ethanol furan 3a was formed in 89% yield with
complete selectivity. With these optimised conditions in hand, the
synthesis of a wide range of 3-ethoxyfurans and 3-methoxyfurans
was then explored. High yields (68–98%) of the corresponding
furans 3 and 4 were obtained with a selection of propargylic alcohols
1a–1o. A wide range of aromatic groups can be incorporated at the
2-position of the furan ring, including electron deficient (1a, 1h,
1m), electron rich (1c, 1n) and sterically encumbered (1f ) benzene
rings, as well as thiophene (1i) and furan (1j) rings. Propargylic
alcohols containing aliphatic groups were also smoothly converted
into the corresponding 2-alkyl furans (1b, 1d, 1g, 1k). When
methanol was used as the reaction solvent, direct solvolysis to
generate the 3-methoxyfurans 4 occurred selectively over formation
of 3-ethoxyfurans 3, which could potentially occur via incorporation
of an ethoxy group derived from the acetal group. Many functional
groups including an alkene (1g), a nitrile (1h), a halide (1l), an ester
(1m), and even a free phenol (1n) were compatible with the reaction.
In the case of the aldehyde containing substrate 1o, concomitant
formation of the corresponding dimethylacetal 4o was observed.
The synthesis of furan 3b was performed on a 600 mg scale without
difficulty to give the alkyl furan in 85% yield.
Scheme 3 Synthesis of polycyclic furans.
Scheme 4 Possible mechanism for the gold-catalysed conversion of
propargylic alcohols 1 to furans 3.
The synthesis of more complex 3-alkoxyfurans was then formation, and that the reaction was unlikely to be catalysed by
explored, by incorporation of other alcohols in the furan Brønsted acid (Tf2NH)20 or silver salts (AgNTf2).16b,21 The furan
formation reaction (Scheme 2). Primary (5b, 6b, 7b), secondary formation reaction potentially proceeds via regioselective gold-
(8b) and tertiary (9b) alcohols were incorporated efficiently, catalysed addition of the alcohol to the alkyne to generate vinyl
including functionalised examples such as allyl alcohol (6b) gold intermediate 11 (Scheme 4). Loss of ethanol can then lead
and ethylene glycol (7b).
to allenyl ether 12 which can undergo further activation by gold
It was also possible to construct a conjugated bis-(3-alkoxy-2- to give oxonium ion 13. Oxonium ion 13 can then be attacked
furyl)benzene 4p in excellent yield by gold-catalysed reaction of by the nearby alcohol to generate dihydrofuran intermediate 14
bis-propargylic alcohol 1p with MeOH (Scheme 3). The conjugated which will evolve to the furan 3 after protodeauration and loss of
triaryl unit in 4p is reminiscent of the oligofuran systems currently ethanol. An alternative pathway which proceeds via Lewis-acid
being investigated for a variety of applications in organic electronics.2 activation of the acetal to generate oxonium ion 15, followed by
Interestingly, propargylic alcohol 1q containing a nearby alkene unit conjugate addition of the alcohol to give 12, can also be
underwent tandem alcohol addition/ene-yne cyclisation to give fused envisaged. However, this seems less likely given the fact that
cyclohexylfurans 10 in excellent yield, with incorporation of the the furan formation does not readily occur in the presence of a
alcohol on the cyclohexane ring. This provides a rapid assembly of simple Brønsted acid catalyst.18
the fused furan–cyclohexane motif present in the terpene natural
product furadysin.19
The electron-rich 3-alkoxyfurans are highly reactive, and
care should be taken during the isolation of these compounds
Appropriate control experiments18 were performed to in order to prevent decomposition of the products via atmo-
demonstrate that the gold catalyst was required for the furan spheric oxidation.18 The reactivity of these furan systems can
nevertheless be readily harnessed in a variety of other useful
transformations (Scheme 5). Furan 4b readily underwent a
Diels–Alder reaction with N-methylmaleimide at room temperature
to generate the cycloadduct 16 as a 2 : 1 mixture of separable
stereoisomers in excellent overall yield (94%). Treatment of the
major diastereoisomer with TFA led to stereoselective cyclisation
to give the polycyclic ether 17 in 69% yield. Cyclohexyl fused
furan 10b gave tertiary amine 18 in 92% yield upon reaction with
Eschenmoser’s salt.12a We were also able to promote Claisen
rearrangement22 of the allyloxyfuran 6b by heating at reflux in
toluene to generate 2,2-disubstituted 3-furanone 19 in 80% yield.
Electrophilic bromination23 of furan 3e proceeded in 75% yield
Scheme 2 Incorporation of different alcohols in the 3-alkoxyfuran for-
mation reaction with 1b.
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Scheme 5 Selected reactions of the furan products.
to give bromide 20, providing a useful building block for cross-
coupling reactions.
In summary, we have developed a mild gold-catalysed
method for the formation of synthetically useful 3-alkoxyfurans
which enables these versatile molecules to be prepared in two steps
from readily available aldehydes, alcohols and 3,3-diethoxypropyne.
The reaction gives access to a wide range of 3-alkoxyfurans in good
to excellent yield, and the products can be used in subsequent
transformations to access more complex structures.
We would like to acknowledge the Engineering and Physical
Sciences Research Council (EP/E052789/1 and EP/G040680/1)
and GlaxoSmithKline (CASE award, PhD studentship support
and supply of selected aldehydes) for supporting this work.
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