Phosphine-catalyzed synthesis of 6-substituted 2-pyrones: Manifestation of E/Z-isomerism in the zwitterionic intermediate

Article abstract of DOI:10.1021/ol050946j

(Chemical Equation Presented) We report a one-step phosphine-catalyzed annulation between aldehydes and ethyl allenoate to form 6-substituted 2-pyrones. The mechanistic rationale for this reaction requires explicit discussion of the E/Z-isomerism of the zwitterionic intermediate formed by the addition of a phosphine to the allenoate. Sterically demanding trialkylphosphines facilitate the shift of equilibrium toward the E-isomeric zwitterion and lead to the formation of 6-substituted 2-pyrones. Various aromatic as well as aliphatic aldehydes undergo the transformation in moderate to excellent yield.

Full text of DOI:10.1021/ol050946j

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
977-2980
Phosphine-Catalyzed Synthesis of
-Substituted 2-Pyrones: Manifestation
2
6
of E/Z-Isomerism in the Zwitterionic
Intermediate
Xue-Feng Zhu, Arnaud-Pierre Schaffner, Ronald C. Li, and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, 607
Charles E. Young DriVe East, Los Angeles, California 90095-1569
ohyun@chem.ucla.edu
Received April 27, 2005
ABSTRACT
We report a one-step phosphine-catalyzed annulation between aldehydes and ethyl allenoate to form 6-substituted 2-pyrones. The mechanistic
rationale for this reaction requires explicit discussion of the E/Z-isomerism of the zwitterionic intermediate formed by the addition of a phosphine
to the allenoate. Sterically demanding trialkylphosphines facilitate the shift of equilibrium toward the E-isomeric zwitterion and lead to the
formation of 6-substituted 2-pyrones. Various aromatic as well as aliphatic aldehydes undergo the transformation in moderate to excellent
yield.
1
2
-Pyrones are found in a large number of natural products
quently, much attention has been paid to the synthesis of
2
10
that display biological activities such as anti-HIV, telomerase
2-pyrones either by traditional approaches or by transition-
3
4
5
6
11
inhibition, antimicrobial, antifungal, cardiotonic, phero-
metal-catalyzed procedures. Despite the plethora of these
7
8
9
monal, androgen-like, and phytotoxic effects. Conse-
synthetic processes, there is a general lack of simple
procedures to synthesize 6-substituted 2-pyrones from com-
mercially available starting materials. Herein, we report a
one-step phosphine-catalyzed synthesis of 6-substituted 2-py-
rones from commercially available starting materials: alde-
(
1) For comprehensive reviews on 2-pyrones, see: (a) Brogden, P. J.;
Gabbutt, C. D.; Hepworth, J. D. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1984;
Vol. 3, Part 2B, Chapter 2.22, pp 573-646. (b) Ellis, G. P. In ref 1a, Chapter
1
2
2
.23, pp 647-736. (c) Hepworth, J. D. In ref 1a, Chapter 2.24, pp 737-
hydes and ethyl allenoate (eq 1).
8
84.
(2) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.; Ortwine, D. F.;
Dunbar, J. B.; Ferguson, D.; Tummino, P. J.; Hupe, D.; Tait, B. D.;
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1
16, 6989.
(3) Kanai, A.; Kamino, T.; Kuramochi, K.; Kobayashi, S. Org. Lett. 2003,
5
Nucleophilic phosphine catalysis of allenoates and bu-
tynoates represents a rapidly growing area of research interest
J. F.; Rojas, F. J.; Reyes, J. F. Tetrahedron 1993, 49, 141. (b) Abraham,
W. R.; Arfmann, H. Phytochemistry 1988, 27, 3310.
(
5) (a) Evidente, A.; Cabras, A.; Maddau, L.; Serra, S.; Andolfi, A.;
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W.; Ghisalberti, E. L.; Sivasithamparam, K. Soil Biol. Biochem. 1988, 20,
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2
Mycol. Soc. 1987, 88, 503. (d) Cutler, H. G.; Cox, R. H.; Crumley, F. G.;
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13013.
1
0.1021/ol050946j CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/03/2005

1
3
these days. In these reactions, the zwitterionic intermediate,
generated by addition of a phosphine to an allenoate, is
represented as 3 T 4 (Scheme 1). This zwitterionic inter-
ester group in 9 facilitates intramolecular lactonization and
results in the synthesis of 6-substituted 2-pyrone 11.
The Z-isomer 3 T 4 is favored due to the electrostatic
association between the dienolate oxygen anion and the
phosphonium cation. Consequently, we speculated that a
dominant steric bias would be needed to shift the equilibrium
toward E-isomer 5 T 6. In practice, sterically demanding
trialkylphosphines were used to shift the equilibrium toward
E-isomer 5 T 6 and led to the formation of 6-substituted
1
7
Scheme 1. Equilibrium of E- and Z-Isomers of the
Zwitterionic Intermediate Formed by the Addition of a
Phosphine to an Allenoate
2
-pyrones (Table 1, entries 1-3). Extremely bulky tri(tert-
butyl)phosphine produced no product (Table 1, entry 4), and
triphenylphosphine provided only 24% of product (Table 1,
entry 5). Tributylphosphine did not render any pyrone
formation (Table 1, entry 6). When the most efficient
tricyclopentylphosphine was used, ethyl allenoate, among
alkyl allenoates, provided the highest yield of pyrone (Table
1
(
, entries 7-11). Phenyl allenoate provided no product
Table 1, enytry 12). We speculate that this is due to the
diminished basicity of phenoxide, in comparison to alkoxides,
(11) (a) Rousset, S.; Abarbi, M.; Thibonnet, J.; Parrain, J.; Duch eˆ ne, A.
Tetrahedron Lett. 2003, 44, 7633. (b) Louie, J.; Gibby, J. E.; Farnworth,
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1
999, 64, 8770. (f) Reference 7. (g) Ogawa, Y.; Maruno, M.; Wakamatsu,
T. Heterocycles 1995, 41, 2587. (h) Liebeskind, L. S.; Wang, J. Tetrahedron
993, 49, 5461. (i) Tsuda, T.; Morikawa, S.; Saegusa, T. J. Chem. Soc.,
Chem. Commun. 1989, 9. (j) Cho, S. K.; Liebskind, L. S. J. Org. Chem.
1
1
987, 52, 2631. (k) Henry, W.; Hughes, R. P. J. Am. Chem. Soc. 1986,
108, 7862. (l) Inoue, Y.; Itoh, Y.; Kazama, H.; Hashimoto, H. Bull. Chem.
Soc. Jpn. 1980, 53, 3329.
12) Ethyl allenoate can also be easily prepared by a reaction between
(
1
4
mediate adds to imines exclusively at its R carbon, to
acid chloride and (carboetoxymethylene)triphenylphosphorane in the pres-
ence of triethylamine; see: Lang, R. W.; Hansen, H.-J. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VII, pp 232-235.
1
5
electron-deficient alkenes preferably at its R carbon, and
16
to aldehydes exclusively at its γ carbon. Nevertheless, the
alternative E-isomeric zwitterionic intermediate, 5 T 6, has
not been previously considered. The E- or Z-geometric
information is lost when the zwitterionic intermediate reacts
at the R carbon. However, when the addition occurs at the
γ carbon as with an aldehyde the geometric distinction in
the zwitterionic intermediate is conserved in the resulting
adduct (see 8 and 9). Thus, intermediate 8 incorporates
another equivalent of aldehyde and produces dioxanylidene
(
13) For a review, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2
001, 34, 535. For phosphine-catalyzed reactions, see: (b) Jung, C.-K.;
Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4118. (c) Wang,
J.-C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (d) Wang,
J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682. (e)
Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (f) Du,
Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (g) Kuroda, H.; Tomita, I.; Endo,
T. Org. Lett. 2003, 5, 129. (h) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002,
67, 8901. (i) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (j) Lu, B.; Davis, R.;
Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595. (k) Ung, A. T.;
Schafer, K.; Lindsay, K. B.; Pyne, S. T.; Amornraksa, K.; Wouters, R.;
Van der Linden, I.; Biesmans, I.; Lesage, A. S. J.; Skelton, B. W.; White,
A. H. J. Org. Chem. 2002, 67, 227. (l) Kumar, K.; Kapoor, R.; Kapur, A.;
Ishar, M. P. S. Org. Lett. 2000, 2, 2023 (m) Kumar, K.; Kapur, A.; Ishar,
M. P. S. Org. Lett. 2000, 2, 787. (n) Trost, B. M.; Dake, G. R. J. Am.
Chem. Soc. 1997, 119, 7595. (o) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.;
Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. For amine-catalyzed
reactions, see: (p) Zhao, G.; Huang, J.; Shi, M. Org. Lett. 2003, 5, 4737.
(q) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394.
(14) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.;
Lu, X. J. Org. Chem. 1998, 63, 5031. (c) Zhu, X.-F.; Henry, C. E.; Kwon,
O. Tetrahedron 2005, in press.
1
0. The close proximity of the alkoxide with respect to the
(
9) Sato, H.; Konoma, K.; Sakamura, S. Agric. Biol. Chem. 1981, 45,
675.
10) For the synthesis of 6-substituted 2-pyrones, see: (a) Komiyama,
T.; Takaguchi, Y.; Tsuboi, S. Tetrahedron Lett. 2004, 45, 6299. (b) Sheibani,
H.; Islami, M. R.; Khabazzadeh, H.; Saidi, K. Tetrahedron 2004, 60, 5931.
1
(
(
c) Ma, S.; Yu, S.; Yin, S. J. Org. Chem. 2003, 68, 8996. (d) Yao, T.;
Larock, R. C. J. Org. Chem. 2003, 68, 5936. (e) Biagetti, M.; Bellina, F.;
Carpita, A.; Rossi, R. Tetrahedron Lett. 2003, 44, 607. (f) Anastasia, L.;
Xu, C.; Negishi, E. Tetrahedron Lett. 2002, 43, 5673. (g) Kotretsou, S. I.;
Georgiadis, M. P. Org. Prep. Proc. Int. 2000, 32, 161. (h) Tidwell, T. T.;
Sammtleben, F.; Christl, M. J. Chem. Soc., Perkin Trans. 1 1998, 2031. (i)
Kepe, V.; Polanc, S.; Kocevar, M. Heterocycles 1998, 48, 671. (j) Dubuffet,
T.; Cimetiere, B.; Lavielle, G. Synth. Commun. 1997, 27, 1123. (k) Svete,
J.; Cadez, Z.; Stanovnik, B.; Tisler, M. Synthesis 1990, 70. (l) Dieter, R.
K.; Fishpaugh, J. R. J. Org. Chem. 1988, 53, 2031. (m) Takata, T.; Tajima,
R.; Ando, W. Chem. Lett. 1985, 665. (n) Ishibe, N.; Yutaka, S. J. Org.
Chem. 1978, 43, 2138. (o) B e´ langer, A.; Brassard, P. Can. J. Chem. 1975,
(15) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Xu, Z.;
Lu, X. Tetrahedron Lett. 1999, 40, 459.
(16) Zhu, X.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett.
2005, 7, 1387.
(17) For synthesis and characterization of cyclic pentavalent 1,2-λ5-
oxaphospholenes, see: (a) Ramirez, F.; Madan, O. P.; Heller, S. R. J. Am.
Chem. Soc. 1965, 87, 731. (b) Gorenstein, D.; Westheimer, F. H. J. Am.
Chem. Soc. 1970, 92, 634. (c) Buono, G.; Llinas, J. R. J. Am. Chem. Soc.
1981, 103, 4532. (d) McClure, C. K.; Jung, K.-Y. J. Org. Chem. 1991, 56,
867. (e) Vedejs, E.; Steck, P. L. Angew. Chem., Int. Ed. 1999, 38, 5855. (f)
Yavari, I.; Alizadeh, A. Synthesis 2004, 237. Our attempts to observe the
5
(
3, 195. (p) Izumi, T.; Kasahara, A. Bull. Chem. Soc. Jpn. 1975, 48, 1673.
q) Pittet, A. O.; Klaiber, E. M. J. Agric. Food Chem. 1975, 23, 1189. (r)
5
proposed Z-1,3-dipole (or its 2,2,2-trialkyl-1,2-λ -oxaphospholene form) or
Ho, T. L.; Hall, T. W.; Wong, C. M. Synth. Commun. 1973, 3, 79. (s) Hayasi,
Y.; Nozaki, H. Tetrahedron 1971, 27, 3085. (t) Jacobs, T. L.; Dankner, D.;
Dankner, A. R. J. Am. Chem. Soc. 1958, 80, 864.
E-1,3-dipole by NMR only lead to oligomerization of allenoates. We thank
a reviewer for pointing out the previous work of Westheimer and McClure
on oxaphospholenes.
2978
Org. Lett., Vol. 7, No. 14, 2005

Table 1. Optimization of Conditions for the Synthesis of
2
Table 2. Synthesis of 2-Pyrones 11 from Ethyl Allenoate and
Aldehydesa
-Pyrones 11a/11c from Alkyl Allenoates and Arylaldehydesa
yieldd
T (°C) time (%)
entry
R
PCyp3 (mol %) product yield (%)
b
R1
b
R
R2c
entry
1
2
3
4
5
6
7
8
9
Ph (7a)
10
20
10
10
20
10
20
20
30
30
30
30
11a
11b
11c
11d
11e
11f
11g
11h
11i
60
69
91
73
68
79
82
71
66
61
39
34
1
2
3
4
5
3-ClC6H4 (7c) i-Pr Et (2b)
60 24 h
60 24 h
60 24 h
60 24 h
60 24 h
60 24 h
60 48 h
60 48 h
60 48 h
60 48 h
60 48 h
60 48 h
rt 12 d
40 4 d
74
77
81
0
24
0
40
60
39
58
10
0
57
68
70
63
42
3-MeOC6H4 (7b)
3-ClC6H4 (7c)
2-ClC6H4 (7d)
4-FC6H4 (7e)
4-CNC6H4 (7f)
4-CF3C6H4 (7g)
2-CF3C6H4 (7h)
2-naphthyl (7i)
2-furyl (7j)
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
Ph (7a)
Ph
Cy
Cyp Et
t-Bu Et
Ph
Et
Et
e
6
n-Bu Et
7
8
9
Cyp Me (2a)
Cyp Et (2b)
Cyp i-Pr (2c)
Cyp TMSCH2 (2d)
Cyp t-Bu (2e)
Cyp Ph (2f)
Ph
Ph
Ph
Ph
10
11
12
11j
11k
11l
10
11
12
13
14
15
16
17
2-phenethyl (7k)
n-propyl (7l)
a
See the Supporting Information for experimental procedures. b Isolated
3-ClC6H4 (7c) i-Pr Et (2b)
yields.
f
f
f
f
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
i-Pr Et
i-Pr Et
i-Pr Et
i-Pr Et
60 49 h
84 35 h
120 14 h
ate exists in the 5 T 6 form rather than the 3 T 4 form to
minimize the steric interaction between the phosphonium
moiety and the ethoxycarbonyl group. The γ-addition of the
vinylphosphonium salt 5 T 6 to an aldehyde forms the
intermediate 9 in which the alkoxide moiety is in close
proximity to the ester functionality. An intramolecular
nucleophilic attack of the alkoxide to the ester furnishes
a
See the Supporting Information for experimental procedures. b 5 equiv
of 3-chlorobenzaldehyde and 15 equiv of benzaldehyde were used. c For
the synthesis of various aryl/alkyl allenoates, see the Supporting Information.
d
f
e
Isolated yields. 1,3-Dioxan-4-ylidene was formed: see ref 16 for details.
0 mol % of PR3 was used.
2
based on our proposed mechanism (vide infra). The reaction
was very sluggish at ambient temperature. Pyrone 11c was
obtained in 57% yield after 12 days at room temperature
Scheme 2. Proposed Mechanism for the Formation of 11
(Table 1, entry 13). The reaction proceeded faster at elevated
temperatures providing higher yield of products (Table 1,
entries 14-16). However, the product yield decreased at
much higher temperatures (Table 1, entry 17).
The optimized conditions were employed to establish the
scope of the aldehyde substrates (Table 2). Various aromatic
aldehydes bearing electron-withdrawing and electron-donat-
ing groups provided 6-aryl 2-pyrones in over 60% yield
(
Table 2, entries 1-8). 2-Naphthaldehyde and 2-furaldehyde
afforded pyrones in 66 and 61% yield, respectively (Table
, entries 9 and 10). Although reaction yields were moderate
2
for aliphatic aldehydes (Table 2, entries 11 and 12), the
reaction provides valuable products in only one step from
commercially available aldehydes. For instance, 6-n-propyl-
2
-pyrone (11l), which was obtained in 34% yield, possesses
18
creamy, sweet, coumarin-like, and herbal flavor, and is used
as an additive to alter the organoleptic properties of tobacco.
19
Our mechanistic proposal for the reaction is as follows
Scheme 2). When a sterically demanding trialkylphosphine
(
is added to an allenoate, the resulting zwitterionic intermedi-
(
18) Pittet, A. O.; Klaiber, E. M. J. Agric. Food Chem. 1975, 23, 1189.
(19) (a) Shuster, E. J.; Pittet, A. O. U.S. Patent 3 996 170, 1976. (b)
Vinals, J. F.; Quinn, A. D.; Pittet, A. O. U.S. Patent 3 890 981, 1975. (c)
Vinals, J. F.; Quinn, A. D.; Pittet, A. O. U.S. Patent 3 861 403, 1975.
Org. Lett., Vol. 7, No. 14, 2005
2979

lactone intermediate 12. The resulting ethoxide acts as a base
to generate zwitterionic intermediate 13 that is in resonance
with 14. Two consecutive proton-transfer processes produce
the intermediate 17, which dissociates to 2-pyrone 11 and
trialkylphosphine.
In conclusion, our effort to expand the scope of phosphine-
catalyzed annulations has led us to the rational design of a
new reaction to synthesize 6-substituted 2-pyrones from
various aldehydes and ethyl 2,3-butadienoate. The rationale
behind this reaction was highlighted by the discussion on
the E/Z-isomerism of the zwitterionic intermediate formed
by the addition of a phosphine to an allenoate. Sterically
demanding trialkylphosphines facilitated the shift of equi-
librium toward E-isomers and led to the formation of
6-substituted 2-pyrones. This process illustrates the potential
of nucleophilic catalysis of allenoates as a fertile ground for
the discovery of new reactions.
Acknowledgment. We gratefully acknowledge UCLA
(Seed Grant) and Amgen, Inc. (Young Investigator’s Award
to O.K.). A.-P.S. thanks the Swiss National Science Founda-
tion for a postdoctoral fellowship.
Supporting Information Available: Representative ex-
perimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL050946J
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Org. Lett., Vol. 7, No. 14, 2005