Phosphine-Mediated Reductive Condensation of γ-Acyloxy Butynoates: A Diversity Oriented Strategy for the Construction of Substituted Furans

Article abstract of DOI:10.1021/ja049377l

Exposure of γ-acyloxy butynoates to stoichiometric quantities of triphenylphosphine results in reductive condensation to afford substituted furans, by way of allenic ester intermediates. As γ-acyloxy butynoates are readily obtained through condensation of ethyl propiolate with aldehydes followed by acylation, this method represents a powerful and mechanistically novel protocol for the convergent three-component construction of substituted furans. Copyright

Full text of DOI:10.1021/ja049377l

Published on Web 03/11/2004
Phosphine-Mediated Reductive Condensation of γ-Acyloxy Butynoates: A
Diversity Oriented Strategy for the Construction of Substituted Furans
Cheol-Kyu Jung, Jian-Cheng Wang, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received February 4, 2004; E-mail: mkrische@mail.utexas.edu
Derivatives of furan occur ubiquitously in nature,1,2 appear in
the structure of diverse therapeutic agents (e.g., ranitidine or zantac),
and serve as useful intermediates in organic synthesis. While
Scheme 1. Postulated Mechanism for Phosphine-Mediated
Reductive Condensation of γ-Acyloxy
3
numerous strategies for furan synthesis exist, convergent annulation
4
strategies are uncommon. Inspired by accounts of the thermally
promoted isomerization of allenic ketones to furans under the
5
conditions of flash vacuum thermolysis, as well as Marshall’s
seminal finding that such transformations may be catalyzed by Rh-
I) or Ag(I) salts,6 a convergent method for the in situ generation
,7
(
and isomerization of allenic carbonyl compounds to furans under
metal-free conditions was sought. Here, we report that exposure
of γ-acyloxy butynoates to stoichiometric quantities of triarylphos-
phine results in reductive condensation to afford substituted furans,
by way of allenic ester intermediates.8 As γ-acyloxy butynoates
are readily obtained through condensation of ethyl propiolate with
aldehydes followed by acylation, this method represents a powerful
diversity oriented protocol for the convergent construction of
substituted furans.
,9
Scheme 2. Isotopic Labeling Experiment Corroborating the
Proposed Mechanism
deficient γ-acyloxy moieties (Table 1, entries 1-3). In addition
to acetylenic esters, the acetylenic ketone 3a also participates in
the reductive condensation. As illustrated by the intramolecular
reductive condensation of substrates 5a-8a, haloaroyl- and het-
eroaroyl-substituted propargylic esters provide the corresponding
furans 5b-8b in good yield (Table 1, entries 4-7). Propargylic
esters 9a, 10a, and 11a, derived from oxalic acid, fumaric acid,
and crotonic acid, are also viable substrates (Table 1, entries 8-10).
Access to 2,4-disubstituted furans is achieved through the reductive
condensation of formic acid esters 12a and 13a (Table 1, entries
11 and 12). Finally, as demonstrated by the condensation of
14a-16a, trisubstituted furans may be obtained through this
method (Table 1, entries 13-15). In general, for highly electro-
philic γ-acyloxy partners as represented by substrates 6a, 11a, and
16a, reductive condensation proceeds most efficiently at ambient
temperature, and in the former two cases use of a sterically more
demanding triarylphosphine, tri-m-tolylphosphine, was required.
Direct exposure of simple mono-activated allenic esters to the
reaction conditions does not result in furan formation, presumably
because of internal coordination of the nascent enolate oxygen in
the form of the oxaphospholene.10
It was postulated that exposure of γ-acyloxy butynoates to
stoichiometric quantities of triphenylphosphine would result in
tandem conjugate addition-acyl substitution to afford betaine
intermediates, which upon extrusion of triphenylphosphine oxide
would produce allenic esters. The facile thermal and transition
metal-catalyzed isomerization of allenic carbonyl compounds to
furans suggests the feasibility of in situ transformation of the allenic
ester to the corresponding furan under the conditions of nucleophilic
catalysis (Scheme 1).
To assess the feasibility of the proposed transformation, the
intramolecular reductive condensation the propargylic p-nitroben-
zoate 2a was explored. Gratifyingly, through an assay of diverse
reactions conditions, it was eventually found that exposure of 2a
to triphenylphosphine (120 mol %) in ethyl acetate solvent at 110
°C in a sealed tube enables formation of the 2,3-disubstituted furan
2b in 81% isolated yield as a single isomer, as corroborated by
single-crystal X-ray diffraction analysis.
Under these optimized conditions, the phosphine-mediated
reductive condensation of γ-acyloxy butynoates was investi-
gated. As demonstrated by the intramolecular reductive condensa-
tion of propargylic esters 1a, 2a, and 4a, furan formation proceeds
most efficiently for substrates that embody increasingly electron-
To corroborate the proposed mechanism, in which the carbonyl
oxygen of the γ-acyloxy moiety is retained in the product, exposure
of O-enriched propargylic ester 2a to the aforementioned condi-
tions for reductive condensation provides the furan 2b, which retains
the isotopic label. Triphenylphosphine oxide isolated from the
18
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J. AM. CHEM. SOC. 2004, 126, 4118-4119
10.1021/ja049377l CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Phosphine-Mediated Reductive Condensation of γ-Acyloxy Butynoates To Form Furansa
a
Procedure: To a solution of the propargyl ester (100 mol %) in ethyl acetate (0.1 M) was added triphenylphosphine (120 mol %). The reaction vessel
was sealed, heated to 110 °C, and allowed to stir until complete consumption of starting material was observed. The reaction mixture was evaporated onto
b
silica gel and subjected to purification by flash chromatography (SiO2: EtOAc-hexane) to afford the furan. The reaction was conducted at ambient temperature.
c
The reaction was conducted at ambient temperature using (m-Tol)3P.
(
2) For isolation of selected furanosequiterpenes, see: (a) Pallescensin A:
Cimino, G.; De Stefano, S.; Guerriero, A.; Minale, L. Tetrahedron Lett.
1975, 1417, 1425. (b) Ricciocarpin A: Wurzel, G.; Becker, H. Phy-
tochemistry 1990, 29, 2565. (c) Gnididione: Kupchan, S. M.; Shizuri,
Y.; Baxter, R. L.; Haynes, H. R. J. Org. Chem. 1977, 42, 348. (d)
Pinguisanes: Zinsmeister, H. D.; Becker, H.; Eicher, T. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 130.
reaction mixture is not 18O-enriched. This result disqualifies
mechanisms involving loss of hydroxide followed by alkaline
cleavage of the intermediate phosphonium adduct to afford triph-
enylphosphine oxide (Scheme 2).11
In summation, a powerful and mechanistically novel protocol
for the convergent three-component assembly of substituted furans
has been developed. Future studies will focus on the development
of related transformations, and the application of this methodology
toward the synthesis of furan-containing natural products.
(
3) For selected reviews, see: (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
(b) Raczko, J.; Jurcak, J. Stud. Nat. Prod. Chem. 1995, 16, 639.
4) For a recent review on the regioselective synthesis of furans, see: Hou,
X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.;
Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(
(
5) For thermal isomerization of allenic carbonyl compounds to furans, see:
(
a) Jullien, J.; Pechine, J. M.; Perez, F.; Piade, J. J. Tetrahedron 1982,
3
8, 1413. (b) Huntsman, W. D.; Yin, T.-K. J. Org. Chem. 1983, 48, 3813.
(6) For Ag(I)- and Rh(I)-catalyzed isomerization of allenic ketones to furans,
Acknowledgment. We acknowledge the NIH (RO1GM65149-
see: (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450.
(b) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 960. (c) Marshall,
01), the Research Corporation Cottrell Scholar Award (CS0927),
J. A.; Wang, X.-J. J. Org. Chem. 1992, 57, 3387. (d) Marshall, J. A.;
Bartley, G. S. J. Org. Chem. 1994, 59, 7169. (e) Marshall, J. A.; Wallace,
E. M.; Coan, P. S. J. Org. Chem. 1995, 60, 796. (f) Marshall, J. A.; Sehon,
C. A. J. Org. Chem. 1995, 60, 5966. (g) Marshall, J. A.; Bartley, G. S.;
Wallace, E. M. J. Org. Chem. 1996, 61, 5729. (h) Marshall, J. A.; Van
Devender, E. A. J. Org. Chem. 2001, 66, 8037.
the Alfred P. Sloan Foundation, the Camille and Henry Dreyfus
Foundation, and Eli Lilly for partial support of this research. Joseph
E. Darty is acknowledged for skillful efforts toward the preparation
of furans 11b and 12b.
(
7) For Pd(II)- and Au(III)-catalyzed isomerization of allenic ketones to furans,
see: (a) Hashmi, A. S. K. Chem.-Eur. J. 1995, 1, 1581. (b) Hashmi, A.
S. K.; Ruppert, T. L.; Kn o¨ fel, T.; Bats, J. W. J. Org. Chem. 1997, 62,
Supporting Information Available: Spectral data for all new
7
295. (c) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (d) Ma, S.; Zhang, J. Chem. Commun.
000, 117.
1
13
compounds ( H NMR, C NMR, IR, HRMS). Single-crystal X-ray
crystallographic data for compound 2b (CIF). Mass spectroscopic data
corresponding to the isotopic labeling experiment (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
2
(
8) The triphenylphosphine-mediated conversion of γ-hydroxy ynones and
ynoates to dienones and dienoates is believed to proceed via intermediacy
of the allene: Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993,
394.
(
9) For the phosphine-mediated conversion of electron-deficient enynes to
furans, see: Kuroda, H.; Hanaki, E.; Kawakami, M. Tetrahedron Lett.
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