Pd(OAc)2-catalyzed cyclization of 2,3-allenoic acids in the presence of terminal αβ-unsaturated alkynones: A one-pot highly stereoselective synthesis of 4-(3′-oxo-1′(E)-alkenyl)-2(5H)- furanones

Article abstract of DOI:10.1021/ol801610w

(Chemical Equation Presented) The Pd(OAc)₂-catalyzed cyclization reaction of 2,3-allenoic acids in the presence of terminal αβ- unsaturated alkynones afforded an EIZ mixture of 4-(3′-oxo-1′- alkenyl)-2(5H)-furanones. A subsequent complete isomerization of the Z-isomer to E-isomer was observed in DMSO at 90 °C, which led to a highly stereoselective synthesis of 4-(3′-oxo-1′(E)-alkenyl)-2(5H)- furanones. A possible mechanism is proposed.

Full text of DOI:10.1021/ol801610w

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4235-4238
Pd(OAc)2-Catalyzed Cyclization of
2,3-Allenoic Acids in the Presence of
Terminal r,ꢀ-Unsaturated Alkynones: A
One-Pot Highly Stereoselective
Synthesis of
4-(3′-Oxo-1′(E)-alkenyl)-2(5H)-furanones
Guofei Chen,† Rong Zeng,† Zhenhua Gu,‡ Chunling Fu,† and Shengming Ma*,§,†
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, P. R. China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
Received July 15, 2008
ABSTRACT
The Pd(OAc)2-catalyzed cyclization reaction of 2,3-allenoic acids in the presence of terminal r,ꢀ-unsaturated alkynones afforded an E/Z mixture
of 4-(3′-oxo-1′-alkenyl)-2(5H)-furanones. A subsequent complete isomerization of the Z-isomer to E-isomer was observed in DMSO at 90 °C,
which led to a highly stereoselective synthesis of 4-(3′-oxo-1′(E)-alkenyl)-2(5H)-furanones. A possible mechanism is proposed.
Transition-metal-catalyzed reactions of allenes have received
much attention from many synthetic organic chemists.1,2 We
and others have studied the cyclization of functionalized
allenes in the presence of organic halides,3 alkenes,4 allenes,5
and alkynes.6 In our previous studies with alkynes, we have
observed that the Pd(OAc)2-catalyzed cyclization of 2,3-
allenoic acids in the presence of methyl propiolate afforded
the 2(5H)-furanones with the incorporation of two molecules
of propynoate, which readily undergo double 1,7-hydrogen
shifts to afford 3-(1′(E)-alkenyl)-4-(2′,4′-bis(alkoxycarbonyl)-
1′(E)-alkenyl)-2(5H)-furanones as the final products.6b Herein,
we wish to report the cyclization reaction of 2,3-allenoic
§ Dedicated to Prof. Xiyan Lu on the occasion of his 80th birthday.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) For books, see: (a) The Chemistry of the Allenes; Landor, S. R.,
Ed.; Academic Press: London, 1982; Vol. 1. (b) Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vols.
1 and 2. (c) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M.,
Eds.; Wiley: New York, 1984. (d) The Chemistry of Ketenes, Allenes, and
Related Compounds; Patai, S., Ed.; Wiley: New York, 1980, Part 1.
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Pure Appl. Chem. 2002, 74, 175. (d) Ma, S. Acc. Chem. Res. 2003, 36,
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6149. (d) Ma, S.; Yu, Z. Angew. Chem., Int. Ed. 2003, 42, 1955. (e) Ma,
S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943. (f) Ma, S.; Jiao, N.;
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J.; Gao, W. Chem. Eur. J. 2007, 13, 247. (k) Alcaide, B.; Almendros, P.;
Martínez del Campo, T. Angew. Chem., Int. Ed. 2007, 46, 6684.
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10.1021/ol801610w CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society

acids in the presence of terminal R,ꢀ-unsaturated alkynones
(Scheme 1).
Table 1. Optimization of Reaction Conditions of the Reaction
of 2,3-Allenoic Acid 1a and Alkynone 2aa
Scheme 1
yield of 3ab
yield of 4ab c
,
entry
2a (equiv)
solvent
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.1
1.1
DMSO
DMF
THF
dioxane
Et2O
Cl3CMe
Cl3CMe
Cl3CMe
Cl3CMe
33
6
0
30
59
59
55
71
71
70d
67e
19
17
25
12
12
11
14
Initially, we used 2-methyl-4-phenyl-2,3-butadienoic acid
1a and 1-phenyl-2-propyn-1-one 2a to try the reaction. To
our surprise, different from the reaction of 1a and methyl
propiolate,6b no 1:2 product 5a was afforded. Instead, a 1:1
adduct, i.e., an E/Z mixture of 4-(3′-oxo-1′-alkenyl)-2(5H)-
furanone product 4a referring to the noncyclic CdC bond,
was formed together with the cycloisomerization product 3a
under the catalysis of 5 mol % Pd(OAc)2 in the presence of
BF3·OEt2, and Sc(OTf)3 was not necessary. After screening
different reaction conditions, no better E/Z ratio for 4a was
observed, and in most cases the E/Z isomeric ratio changed
constantly, which indicated an E/Z isomerization. Some
typical results are listed in Table 1, from which we concluded
that Cl3CMe is better than other solvents, such as DMSO,
DMF, THF, dioxane, Et2O, in terms of the yields of 4a
(compare entries 1-5 with entry 6, Table 1) and the influence
of concentration of the substrates was negligible (compare
entry 9 with entry 6, Table 1). Increasing the amount of
alkynone 2a or BF3·Et2O also failed to improve the yields
(compare entries 7 and 8 with entry 6, Table 1).
a The reaction was carried out using 0.25 mmol of 1a, 1.1 equiv of 2a,
5 mol % of Pd(OAc)2, and 1.0 equiv of BF3·Et2O in 0.5 mL of solvent
with stirring overnight at 35 °C, unless other noticed. b Yields were
determined by 1H NMR analysis with CH2Br2 or mesitylene as the internal
standard. c The E/Z isomeric ratio of 4a changed constantly. d 1.5 equiv of
BF3·Et2O was used. e The concentration of 1a was 0.125 M.
E-isomer was investigated. After some screening, we were
happy to observe that after evaporation the addition of
DMSO followed by heating at 90 °C for 7 h afforded E-4a
(E/Z ) 99/1) in 70% NMR yield (Scheme 2). The structure
Scheme 2
With the observation that the E/Z-isomer of 4a is
interconvertable, a protocol for complete conversion of
the Z-isomer to the thermodynamically more stable
(5) (a) Ma, S.; Yu, Z. Org. Lett. 2003, 5, 1507. (b) Ma, S.; Yu, Z. Chem.
Eur. J. 2004, 10, 2078. (c) Ma, S.; Yu, Z.; Gu, Z. Chem. Eur. J. 2005, 11,
2351. (d) Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291. (e) Ma, S.;
Gu, Z. J. Am. Chem. Soc. 2005, 127, 6182. (f) Gu, Z.; Wang, X.; Shu, W.;
Ma, S. J. Am. Chem. Soc. 2007, 129, 10948. (g) Deng, Y.; Yu, Y.; Ma, S.
J. Org. Chem. 2008, 73, 585. (h) Deng, Y.; Li, J.; Ma, S. Chem. Eur. J.
2008, 14, 4263. (i) Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl. 1995,
34, 1581. (j) Hashmi, A. S. K.; Ruppert, T. L.; Knofel, T.; Bats, J. W. J.
Org. Chem. 1997, 62, 7295. (k) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-
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Schwarz, L.; Bolte, M. Eur. J. Org. Chem. 2004, 1923. (m) Hashmi,
A. S. K.; Blanco, M. C.; Fischer, D.; Bats, J. W. Eur. J. Org. Chem. 2006,
1387. (n) Alcaide, B.; Almendros, P.; Martínez del Campo, T. Angew.
Chem., Int. Ed. 2006, 45, 4501. (o) Alcaide, B.; Almendros, P.; Martínez
del Campo, T. Eur. J. Org. Chem. 2007, 2844.
of E-4a was further confirmed by the X-ray diffraction
study (Figure 1).7
(8) Ma, S.; Wu, S. J. Org. Chem. 1999, 64, 9314.
(9) (a) Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Domling, A. Org.
Lett. 2001, 3, 2875. (b) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote,
F. J. Org. Chem. 2003, 68, 1780. (c) Hegedus, L. S.; Geisler, L. J. Org.
Chem. 2000, 65, 4200. (d) Guo, Y.-W.; Gavagnin, M.; Mollo, E.; Trivellone,
E.; Cimino, G. J. Nat. Prod. 1999, 62, 1194. (e) de March, P.; Figueredo,
M.; Font, J.; Raya, J. Org. Lett. 2000, 2, 163. (f) Bagal, S. K.; Adlington,
R. M.; Baldwin, J. E.; Marquez, R. J. Org. Chem. 2004, 69, 9100. (g)
Kapferer, T.; Bruckner, R.; Herzig, A.; Konig, W. A. Chem. Eur. J. 2005,
11, 2154. (h) Vaz, B.; Dominguez, M.; Alvarez, R.; de Lera, A. R. J. Org.
Chem. 2006, 71, 5914. (i) Aurrecoechea, J. M.; Suero, R.; de Torres, E. J.
Org. Chem. 2006, 71, 8767.
(6) (a) Ma, S.; Gu, Z.; Deng, Y. Chem. Commun. 2006, 94. (b) Gu, Z.;
Ma, S. Angew. Chem., Int. Ed. 2006, 45, 6002. (c) Alcaide, B.; Almendros,
P.; Aragoncillo, C. Chem. Eur. J. 2002, 8, 1719.
(7) Crystal data for compound E-4a:C20H16O3, Mw ) 304.33, mono-
clinic, space group P2(1)/n, Mo KR, final R indices [I > 2σ(I)], R1 )
0.0349, wR2 ) 0.0940, a ) 11.5238 (3) Å, b ) 8.6194 (2) Å, c ) 16.6138
(5) Å, R ) 90°, ꢀ ) 102.1820 (10)°, γ ) 90°, V ) 1613.06 (7) Å3, T )
296 (2) K, Z ) 4, number of reflections collected/unique: 18026/2841 (Rint
) 0.0205), number of observations: 2841 [I > 2σ(I)], parameters 209.
CCDC 691718 contains the supplementary crystallographic data.
(10) (a) Boeckman, R. K., Jr.; Delton, M. H.; Nagasaka, T.; Watanabe,
T. J. Org. Chem. 1977, 42, 2946. (b) Kido, F.; Tsutsumi, K.; Maruta, R.;
Yoshikoshi, A. J. Am. Chem. Soc. 1979, 101, 6420. (c) Wu, T.-S.; Jong,
T.-T.; Ju, W.-M.; McPhail, A. T.; McPhail, D. R.; Lee, K.-H. J. Chem.
Soc., Chem. Commun. 1988, 14, 956. (d) Azuma, M.; Yoshida, M.;
Horinouchi, S.; Beppu, T. Biosci. Biotech. Biochem. 1993, 57, 344.
4236
Org. Lett., Vol. 10, No. 19, 2008

unsaturated alkynone 2d was applied, only cycloisomeriza-
tion product 3c was afforded with 87% NMR yield, which
shows the steric effect of the alkynone on the reaction
(Scheme 3).
Scheme 3
A rationale for this reaction is depicted in Scheme 4. The
cyclic anti-oxypalladation of Pd(OAc)2 with 2,3-allenoic acid
Figure 1. ORTEP representation of E-4a.
Scheme 4
With the optimized reaction conditions in hand, the scope
of the reaction was explored with some typical structures as
summarized in Table 2. The substituent R1 and R3 can be
Table 2. Pd(OAc)2-Catalyzed Cyclization of 2,3-Allenoic Acids
and Terminal R,ꢀ-Unsaturated Alkynones and the Subsequent
One-Way Z to E Isomerizationa
entry
R1
R2
R3
yieldb of E-4
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-FC6H4
n-C4H9
n-C6H13
n-C6H13
n-C7H15
n-C7H15
Ph
Me
Me
Me
Et
Ph
70 (52) (4a)
54 (49) (4b)
64 (48) (4c)
57 (42) (4d)
61 (46) (4e)
56 (48) (4f)
66 (59) (4g)
62 (47) (4h)
49 (42) (4i)
51 (51) (4j)
53 (49) (4k)
51 (51) (4l)
57 (45) (4m)
42 (36) (4n)
p-ClC6H4
p-MeOC6H4
Ph
p-MeOC6H4
Ph
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
Ph
p-MeOC6H4
Ph
1 would form the furanonyl palladium intermediate M1.
Subsequent stereoselective insertion of M1 with the Ct C
triple bond of alkynone 2 woud form the intermediate M2.
Due to the presence of the ketonic carbonyl group, it may
be converted to the enolate intermediate M3, which may
explain the formation of E/Z isomeric mixture of 4 via
protonolysis. As compared to the ester group,6b the ketonic
carbonyl group may make the intermediates M2 and M3 to
be more prone to protonolysis due to its stronger electron-
withdrawing ability, and thus, no 5a-type 1:2 adduct was
formed.
In conclusion, we have developed a Pd(OAc)2-catalyzed
cyclization reaction of 2,3-allenoic acids and terminal R,ꢀ-
unsaturated alkynones in the presence of BF3·Et2O, which
leads to one-pot synthesis of E/Z mixtures of 4-(3′-oxo-
1′-alkenyl)-2(5H)-furanones. This E/Z-isomoric mixture
may be highly stereoselectively converted to the thermo-
dynamically more stable E-isomer exclusively after evapo-
ration, adding DMSO, and heating the resulting reaction
mixture at 90 °C for 7 h. As a result of the easy availability
of starting materials8 and the usefulness of the products,9,10
Et
n-Pr
n-Pr
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
13
14
p-MeOC6H4
n-C6H13
a The reaction was carried out using 0.25-0.5 mmol of 1, 1.1 equiv of
2, 5 mol % of Pd(OAc)2, and 1.0 equiv of BF3·Et2O in 0.5-1 mL of Cl3CMe
with stirring overnight at 35 °C. After evaporation, 2-4 mL of DMSO
was added, and the resulting mixture was heated at 90 °C with stirring for
7 h. b Yields were determined by 1H NMR analysis with CH2Br2 or
mesitylene as the internal standard; yields of the isolated products are given
in parentheses.
an aryl or alkyl group; the substituent R2 can be a normal
alkyl group. The isolated yield is generally good averaging
60-72% for each step. However, when nonterminal R,ꢀ-
Org. Lett., Vol. 10, No. 19, 2008
4237

the reaction may have potential in organic synthesis. Further
studies in this area are being pursued in our laboratory.
Supporting Information Available: Typical experimental
procedure and analytical data for all products not listed in
the text as well as the 1H/13C NMR spectra of all the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20732005) and
the Major State Basic Research Development Program
(2006CB806105) is greatly appreciated. S.M. is an adjunct
Qiushi Professor at Zhejiang University. We thank Mr. Jing
Li in our group for reproducing the results presented in
entries 2, 8, and 14 of Table 2.
OL801610W
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Org. Lett., Vol. 10, No. 19, 2008