AuCl3-catalyzed synthesis of highly substituted furans from 2-(1-alkynyl)-2-alken-1-ones

Article abstract of DOI:10.1021/ja0466964

Highly substituted furans have been synthesized by the reaction of 2-(1-alkynyl)-2-alken-1-ones and various nucleophiles under very mild reaction conditions in good to excellent yields. Gold and some other transition metals are efficient catalysts for thi

Full text of DOI:10.1021/ja0466964

Published on Web 08/20/2004
AuCl3-Catalyzed Synthesis of Highly Substituted Furans from
2-(1-Alkynyl)-2-alken-1-ones
Tuanli Yao, Xiaoxia Zhang, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received June 4, 2004; E-mail: larock@iastate.edu
Table 1. AuCl3-Catalyzed Synthesis of Substituted Furans by
Highly substituted furans play an important role in organic
Cyclization of 2-(1-Alkynyl)-2-alken-1-onesa
chemistry, not only as key structural units in many natural products
and important pharmaceuticals,1 but as useful building blocks in
synthetic chemistry.2 For this reason, the efficient synthesis of
multiply substituted furans continues to attract the interest of
synthetic chemists.3 Among the many different approaches to furans,
the transition metal-catalyzed cyclization of allenyl ketones and
3-alkyn-1-ones is particularly attractive,4 although its synthetic
utility is somewhat limited by a lack of general and practical routes
to the starting ketones.4b-d,5 We envisioned that 2-(1-alkynyl)-2-
alken-1-ones might also undergo a transition metal-catalyzed
cyclization to highly substituted furans (eq 1).
This unique cyclization is particularly attractive, because se-
quential nucleophilic domino attack onto a metal-complexed alkyne
should afford multiply substituted furans through simultaneous
formation of a C-O bond and a remote carbon-nucleophile bond.
Thus, the regioselective introduction of substituents about the furan
ring comes down to the appropriate choice of 2-(1-alkynyl)-2-alken-
1-one and nucleophile, which allows for considerable versatility,
since such ketones are readily available from simple alkenones and
alkynes (eq 2).
Herein, we report a highly efficient, gold-catalyzed, atom-
economical approach6 to multiply substituted furans. Overall, ready
access to a wide variety of polysubstituted furans is achieved upon
reaction of various 2-(1-alkynyl)-2-alken-1-ones with an unprec-
edented set of nucleophiles under very mild reaction conditions.
Alcohols and 1,3-diketones, as well as various electron-rich
aromatics, serve as efficient nucleophiles in this new process.
Preliminary studies have been carried out on 2-phenylethynyl-
2-cyclohexen-1-one (1) and methanol (1.5 equiv), using a series
of potential transition metal catalysts (1 mol %) in CH2Cl2. Initial
results indicated that AgO2CCF3 (10 h, 87%), Cu(O3SCF3)2 (9 h,
81%), AuCl3 (0.5 h, 88%), and Hg(O2CCF3)2 (8 h, 86%) all afford
good yields of furan 2. Among these salts, however, AuCl3 is the
most efficient catalyst based on reaction time. This is consistent
with previous work on the cyclization of 3-alkyn-1-ones to furans.4a
Pd(OAc)2 provided a low yield (6 h, 30%), mainly due to the facile
reduction of Pd(II) to Pd(0) in the presence of the alcohol.7 The
addition of 2 equivs of PPh3 to Pd(OAc)2 did stabilize the Pd(II)
salt, but slowed the reaction. Thus, AuCl3 was chosen as the catalyst
a All reactions were run under the following conditions, 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. b AuCl3 (2 mol %) was employed and added in
two equal portions. c The reaction took 48 h.
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
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10.1021/ja0466964 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
a proton and protonation of the resulting organogold intermediate
to afford furan 2 and simultaneously regenerate the catalyst AuCl3.
An alternative mechanism in which AuCl3 functions simply as a
transition metal is also possible (Scheme 3, cycle B).4a The
coordination of the triple bond of 1 to AuCl3 enhances the
electrophilicity of the triple bond, and subsequent nucleophilic attack
of the carbonyl oxygen on the electron-deficient triple bond
generates carbocation 2b. Intermolecular nucleophilic attack on the
carbocation and subsequent protonation of the carbon-gold bond
afford furan 2 and regenerate the catalyst AuCl3. The mechanism
illustrated in cycle B appears more likely since 1% AuCl3 fails to
catalyze the 1,4-addition of methanol to 2-cyclohexenone and
methyl vinyl ketone under our standard reaction conditions.
In summary, a new catalytic approach to highly substituted furans
has been developed through the cyclization of 2-(1-alkynyl)-2-alken-
1-ones with various nucleophiles under very mild reaction condi-
tions. The reaction is efficiently catalyzed by AuCl3 and several
other transition metal salts and likely proceeds by a novel
mechanism involving cyclization to produce a gold-containing
carbocationic intermediate.
Acknowledgment. We gratefully acknowledge the donors of
the Petroleum Research Fund, administered by the American
Chemical Society, and the National Science Foundation for partial
support of this research.
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
cyclization product 2 was obtained at all. These blank tests clearly
indicate that AuCl3 is required for the reaction to proceed.
The cyclization of 1 with various alcohols was first investigated
(Table 1). Not only simple alcohols, such as methanol (Table 1,
entry 1), but also labile alcohols, such as 3-phenyl-2-propyn-1-ol,
and a protected D-pyranose are effective nucleophiles (Table 1,
entries 2 and 3). The reaction of 1,3-cyclohexanedione proved quite
interesting as it afforded a high yield of a product in which the
new bond was formed only between the â-carbon of the R,â-
unsaturated ketone and the oxygen of the diketone (Table 1, entry
4). A distinctive feature of this novel approach to complex furans
is the facile introduction of electron-rich arenes, such as N,N-
dimethylaniline and indole, as carbon-based nucleophiles (Table
1, entries 5 and 6). N,N-Dialkylanilines can also be employed as
benzene surrogates, since the direct deamination of N,N-dialkyl-
anilines has recently been reported.8
A range of 2-(1-alkynyl)-2-alken-1-ones readily participate in
this gold-catalyzed cyclization. In addition to 2-(1-alkynyl)-
cyclohexenones 1, 8, and 18 (Table 1, entries 1-7 and 12),
chromone 10 (Table 1, entry 8) undergoes smooth cyclization. An
alkyne bearing a vinylic substituent (Table 1, entry 7) is readily
accommodated, but alkynes bearing H, alkyl, or TMS groups have
thus far failed. Acyclic 2-alken-1-ones also afford highly substituted
furans (Table 1, entries 9-11). Note that the latter acyclic substrates
readily accommodate additional carbon-carbon double or triple
bonds. Unfortunately, little stereoselectivity was observed in the
cyclization of ketone 18 (Table 1, entry 12).
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At least two conceivable mechanisms can be proposed for this
gold-catalyzed cyclization (Scheme 1). In one (cycle A), gold
functions as both a Lewis acid and a transition metal.9 AuCl3 first
acts as a Lewis acid, forming a complex with the carbonyl oxygen.
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double bond to produce 2a.10 Subsequent coordination of the alkynyl
moiety of the alkenynone 2a to AuCl3 induces a cyclization of the
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