Pd(II)-catalyzed cascade Wacker-Heck reaction: Chemoselective coupling of two electron-deficient reactants

Article abstract of DOI:10.1021/jo061292a

A novel palladium(II)-catalyzed oxy-carbopalladation process was developed allowing for the orchestrated union of hydroxyynones with ethyl acrylate, two electron-deficient reactants. With β-hydroxy ynones, this cascade Wacker-Heck process gave access to highly functionalized tri- or tetrasubstituted dihydropyranones featuring an unusual dienic system. For diastereomerically pure and for enantioenriched β-hydroxyynones, these reactions proceed without affecting the stereochemical integrity of the existing stereocenters. In addition, tetrasubstituted furanones can be prepared when α-hydroxyynones and ethyl acrylate are used as starting materials. The dihydropyranones and furanones obtained upon cyclization are novel compounds, but structurally related carbohydrate derivatives featuring a similar dienic system have been used as starting materials for the construction of polyannulated products, suggesting that these cascade Pd(II)-mediated oxidative heterocyclizations are of value for various synthetic applications.

Full text of DOI:10.1021/jo061292a

Pd(II)-Catalyzed Cascade Wacker-Heck Reaction: Chemoselective
Coupling of Two Electron-Deficient Reactants
Franck Silva,† Maud Reiter,† Rebecca Mills-Webb,† Marcin Sawicki,† Daniel Kla¨r,‡
Nicolas Bensel,‡ Alain Wagner,‡ and Ve´ronique Gouverneur*,†
Chemistry Research Laboratory, UniVersity of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK, and
NoValyst DiscoVery, 23 rue du Loess, 67037 Strasbourg, France
Veronique.gouVerneur@chemistry.oxford.ac.uk
ReceiVed June 22, 2006
A novel palladium(II)-catalyzed oxy-carbopalladation process was developed allowing for the orchestrated
union of hydroxy ynones with ethyl acrylate, two electron-deficient reactants. With â-hydroxy ynones,
this cascade Wacker-Heck process gave access to highly functionalized tri- or tetrasubstituted
dihydropyranones featuring an unusual dienic system. For diastereomerically pure and for enantioenriched
â-hydroxyynones, these reactions proceed without affecting the stereochemical integrity of the existing
stereocenters. In addition, tetrasubstituted furanones can be prepared when R-hydroxyynones and ethyl
acrylate are used as starting materials. The dihydropyranones and furanones obtained upon cyclization
are novel compounds, but structurally related carbohydrate derivatives featuring a similar dienic system
have been used as starting materials for the construction of polyannulated products, suggesting that these
cascade Pd(II)-mediated oxidative heterocyclizations are of value for various synthetic applications.
Introduction
important biologically active targets. Tietze et al. reported an
elegant enantioselective synthesis of vitamin E relying on a
domino Wacker-Heck sequence, starting with an oxidative
cyclization for the construction of the chroman framework,
followed by an intermolecular olefin insertion for the attachment
of part of the chain of vitamin E.3 An alternative Wacker-
Heck process was developed by Rawal et al. to construct a key
fragment necessary for the total synthesis of mycalamide A.4
In this study, the desired pyran ring featuring an exocyclic
double bond was the result of an intramolecular Heck reaction
of a σ-alkyl palladium species, arising from an intermolecular
Wacker reaction of an enol ether with methanol. The successful
outcome of these cascade reactions is likely the result of
combined inter- and intramolecular processes involving elec-
tronically complementary olefinic partners. Recently, we have
shown that the palladium(II)-mediated oxidative cyclization of
â-hydroxy enones led to the formation of di- or trisubstituted
dihydropyranones in high yields.5 This transformation did not
take place for hydroxyenones possessing a substituent on the
sp2 hybridized carbon R to the carbonyl group, a limitation
Palladium(0)-catalyzed cascade reactions are used extensively
in synthesis for the construction of highly functionalized carbo-
and heterocycles.1 Very often, these transformations involve a
reactive σ-alkyl Pd intermediate, which can undergo further
transformations prior to a terminal reductive process. Depending
on the reactants and the reaction conditions, it is possible to
trap these transient σ-alkyl Pd species by the insertion of carbon
monoxide or olefins, by nucleophilic attack, or through various
cross-coupling reactions.2 Pd(II)-catalyzed cascade reactions
were recently selected as key steps for the total synthesis of
* To whom correspondence should be addressed. Fax and Tel: + 44 (0)
1865 275644.
† University of Oxford.
‡ Novalyst Discovery.
(1) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131-163. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (c) Tietze, L.
F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453-3516. (d) Heumann,
A.; Re´glier, M. Tetrahedron 1996, 52, 9289-9346.
(2) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106,
1496-1498. (b) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M.
Tetrahedron Lett. 1989, 30, 4925-4928. (c) Semmelhack, M. F.; Zhang,
N. J. Org. Chem. 1989, 54, 4483-4485. (d) McCormick, M.; Monahan,
R., III; Soria, J.; Goldsmith, D.; Liotta, D. J. Org. Chem. 1989, 54, 4485-
4487. (e) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner,
M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035-2040.
(3) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Strecker, F. Angew.
Chem., Int. Ed. 2005, 44, 257-259.
(4) Sohn, J.-H.; Waizumi, N.; Zhong, M.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 7290-7291.
10.1021/jo061292a CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/28/2006
8390
J. Org. Chem. 2006, 71, 8390-8394

Pd(II)-Catalyzed Cascade Wacker-Heck Reaction
TABLE 1. Optimization Studies for the Ring Closure of 1a into 2a
SCHEME 1. Wacker-Heck Oxidative Heterocyclization of
Hydroxy Ynones
Pd source (mol %)
co-oxidant (mol %)
yield
(%)
entry
1
additives (mol %)
Na2HPO4 (10)
PdCl2 (10)
CuCl (10)
PdCl2 (10)
CuCl (10)
PdCl2 (10)
CuCl (100)
PdCl2 (10)
CuCl (10)
27
41
20
34
37
40
2
3
Na2HPO4 (10), PPh3 (10)
Na2HPO4 (10), PPh3 (20)
Na2HPO4 (100), PPh3 (20)
Na2HPO4 (10), PPh3 (10)
PPh3 (20)
preventing access to dihydropyranones substituted at this carbon.
To overcome this limitation, we devised a palladium(II)-
catalyzed Wacker-Heck reaction starting from â-hydroxy
ynones. Upon oxidative heterocyclization, these substrates
should lead to σ-alkenyl Pd intermediates, which cannot
â-eliminate, but could undergo olefin insertion to form trisub-
stituted dihydropyranones featuring an alkenyl substituent R to
the carbonyl. Herein, we report the feasibility of this Pd(II)-
catalyzed cascade process involving the union of structurally
diverse hydroxy ynones and ethyl acrylate, two electron-deficient
reactants. To the best of our knowledge, the cascade processes
reported to date, which feature a Pd(II)-catalyzed oxidative
heterocyclization, all involve at least one electron-rich olefinic
partner.3,4,6 The products resulting from the cascade reactions
reported herein are unusual functionalized dihydropyranones and
furanones, which are not accessible upon Pd(II)-catalyzed
oxidative heterocyclization of the corresponding adequately
substituted R- or â-hydroxy enones.
4
5
Pd(TFA)2
CuCl (10)
Pd(TFA)2
6a
7
benzoquinone (400)
(MeCN)4Pd(BF4)2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)4Pd(BF4)2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
(MeCN)2PdCl2 (10)
Cu(OAc)2‚H2O (10)
K2CO3 (10), PPh3 (20)
28
(38b)
43
8
K2CO3 (10)
PPh3 (10), LiBr (20)
K2CO3 (10)
PPh3 (10), LiBr (20)
PPh3 (20), LiBr (20)
(27b)
42
9
10
11
12c
13c
14
15
16
17
50
58
48
50
50
40
33
38
PPh3 (10), LiBr (20)
PPh3 (10), LiBr (20)
PPh3 (20), LiBr (20)
Et3N (10), LiBr (20)
sparteine (10), LiBr (20)
pyridine (10), LiBr (20)
DMSO (10), LiBr (20)
Results and Discussion
Optimization Studies. Our initial studies focused on the
development of an optimum set of reaction conditions for the
palladium-mediated coupling of ethyl acrylate with â-hydrox-
yynone 1a, a compound prepared in 78% yield by aldol
condensation of the commercially available 3-hexyn-2-one with
benzaldehyde (Scheme 1, Table 1). The results of our optimiza-
tion study are summarized in Table 1. The key to success lies
in the optimum combined choice for the catalyst, the solvent,
and the additives. Under the reaction conditions used for the
oxidative cyclization of hydroxyenones (PdCl2, CuCl, Na2HPO4,
O2, 65 °C),5 the reaction of the â-hydroxyynone 1a in the
presence of 20 equiv of ethyl acrylate led to the formation of
the desired adduct 2a in 27% yield (entry 1). The addition of
10 mol % of PPh3 led to an increased yield of 41%, possibly
due to the ability of this additive to stabilize the σ-alkenyl Pd
intermediate, therefore promoting the carbopalladation step
(entry 2).7 An increase in the loading of Na2HPO4 or CuCl was
not beneficial (entries 3 and 4). When Pd(TFA)2 was used as
the catalyst in the presence of benzoquinone as the co-oxidant,
compound 2a was isolated in 40% yield (entry 6). The use of
(MeCN)4Pd(BF4)2 and Cu(OAc)2‚H2O in combination with K2-
a Reaction carried out under argon atmosphere. b Yield of side product
3. c Reaction carried out for 48 h.
CO3 and PPh3 led to the formation of a new product identified
as the disubstituted dihydropyranone 3, in addition to the desired
trisubstituted dihydropyranone 2a, in 38% and 28% yield,
respectively (entry 7). The dihydropyranone 3 was the result
of a base-mediated 6-endo-dig process or a palladium-catalyzed
ring closure followed by protonolysis of the σ-alkenyl Pd
intermediate. Interestingly, the addition of LiBr6 minimized the
formation of 3 and increased the yield of 2a to 43% yield (entry
8). In the presence of (MeCN)2PdCl2, compound 3 could not
be detected in the crude reaction mixture (entry 9). After
extensive experimentation, it was found that the reaction of 1a
with ethyl acrylate was best performed at 65 °C in DME in the
presence of 20 mol % of LiBr and 10 mol % of (MeCN)2PdCl2,
Cu(OAc)2‚H2O and PPh3, under an atmospheric pressure of
oxygen leading to the dihydropyranone Heck trapping product
2a in a reasonable 58% isolated yield (entry 11). Ligands such
as triethylamine, sparteine, pyridine, or DMSO, commonly used
for other Pd(II)-mediated oxidative cyclizations, were tested in
an attempt to improve further the chemical yield, but none of
these reactions led to significant improvement (entries 14-17).8
Synthesis of Tri- and Tetrasubstituted Dihydropyranones.
The reaction was subsequently carried out with â-hydrox-
yynones 1b-f, which were all converted to the desired products
resulting from the cascade Wacker-Heck process with chemical
yields ranging from 44% to 56% (Table 2). All of the products
were formed as single geometrical E-isomers for the exocyclic
double bond. No starting material or side products resulting from
a 6-endo-dig ring closure, not followed by a Heck coupling,
were detected in the crude reaction mixtures.
(5) (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91-94.
(b) Reiter, M.; Turner, H.; Mills-Webb, R.; Gouverneur, V. J. Org. Chem.
2005, 70, 8478-8485.
(6) (a) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am.
Chem. Soc. 2006, 128, 3130-3131. (b) Scarborough, C. C.; Stahl, S. S.
Org. Lett. 2006, 8, 3251-3254. (c) Minami, K.; Kawamura, Y.; Koga, K.;
Hosokawa, T. Org. Lett. 2005, 7, 5689-5692. (d) Trudeau, S.; Morken, J.
P. Org. Lett. 2005, 7, 5465-5468. (e) Evans, M. A.; Morken, J. P. Org.
Lett. 2005, 7, 3371-3373. (f) Evans, M. A.; Morken, J. P. Org. Lett. 2005,
7, 3367-3370. (g) Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. Chem.
Eur. J. 2005, 11, 5708-5712. (h) Fugami, K.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1987, 28, 809-812. (i) Fugami, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. Jpn 1989, 62, 2050-2054.
(7) A 31P NMR of the crude reaction mixture after filtration of the Cu
salts revealed that no peaks corroborating with PPh3 or OPPh3 were detected;
the fate of PPh3 over the course of this reaction is still unknown. The 31P
NMR spectra are provided in the Supporting Information.
J. Org. Chem, Vol. 71, No. 22, 2006 8391

Silva et al.
TABLE 2. Wacker-Heck of â-Hydroxy Ynones 1b-f
SCHEME 3. Synthesis and Cascade Oxidative
Heterocyclization of (S)-1h and (S)-1i
entry
substrate
R1
R2
R3
product
yield (%)
1
2
3
4
5
1b
1c
1d
1e
1f
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
Ph(CH2)2-
-C4H4-
H
H
H
H
Et
Et
Me
Et
Me
2b
2c
2d
2e
2f
52
56
55
44
50
SCHEME 2. Pd(II)-Mediated Synthesis of Tetrasubstituted
syn-Dihydropyranone 2g
was readily available enantioenriched using a Baker’s yeast-
mediated catalytic asymmetric reduction.11 The reaction of
1-propynylmagnesium bromide or the lithium anion of phenyl-
acetylene with (S)-4 led to the formation of the desired
â-hydroxy ynones (S)-1h and (S)-1i in excellent yields. Both
products were obtained with an ee of 96%. Upon cyclization in
the presence of an excess of ethylacrylate, the desired dihydro-
pyranones (S)-2h and (S)-2i were formed in 45% and 47% yield,
respectively, and with enantiomeric excesses of 96%, leading
us to conclude that this cascade Wacker-Heck process occurred
with no detectable racemization (Scheme 3).
Synthesis of Tetrasubstituted Furan-3(2H)-ones. The domino
cyclization reaction was also applied to R-hydroxyynones 6a-
c, which were prepared in four steps from ethyl 2-hydroxy-2-
methylpropanoate. The cyclization of R-hydroxyynones with
alkyl or aryl substituents on the triple bond in the presence of
an excess of ethyl acrylate gave the corresponding tetrasubsti-
tuted furanones 7a-c in isolated yields ranging between 52%
and 65%. For susbtrate 6c with a phenyl substituent capping
the alkyne, the side product 8 resulting from a noncascade 5-
endo-dig cyclization was isolated in 26% yield in addition to
the desired product 7c, which was formed in 65% yield (Scheme
4).
We also cyclized the syn-â-hydroxyynone 1g readily prepared
in 59% yield and with excellent diastereoselectivity (>99% de)
from 4-hexyn-3-one 4 and benzaldehyde using a n-Bu2BOTf-
and i-Pr2EtN-mediated aldol reaction (Scheme 2, eq 1).9
Applying the optimized conditions for the Wacker-Heck
cyclization process, the desired tetrasubstituted syn-dihydropy-
ranone 2g was formed in 47% yield without affecting the relative
stereochemistry of the two existing stereocenters (>99% de)
(Scheme 2, eq 2).
With the successful outcome of the domino Wacker-Heck
coupling, we subsequently examined the stereochemical integrity
of enantiopure hydroxy ynones (S)-1h and (S)-1i upon hetero-
cyclization followed by C-C bond formation. Direct catalytic
asymmetric aldolizations leading to enantiopure â-hydrox-
yynones are rare, and the few reactions reported to date, although
elegant, are limited in scope.10 We therefore opted for an
operationally simple route to ynones (S)-1h and (S)-1i using as
starting material the known enantiopure Weinreb amide (S)-4
prepared from the corresponding â-hydroxy ester.5 This ester
Mechanism. A plausible mechanism for the palladium(II)-
catalyzed Wacker-Heck process presumably involves initial
coordination of the metal to the triple bond, resulting in
intramolecular nucleophilic attack by the proximal hydroxy
group (oxypalladation). This leads to the formation of a
σ-alkenyl palladium intermediate, which cannot undergo â-hy-
dride elimination. This intermediate can further react in a
subsequent carbopalladation process with ethyl acrylate present
in large excess. After â-hydride elimination, the tri- or tetra-
substituted dihydropyranone is formed with concomitant forma-
tion of a palladium hydride species which upon reductive
elimination would allow Pd(0) to re-enter the catalytic cycle
after oxidation by molecular oxygen. The side product 3
resulting from the cyclization of 1a can be formed upon a
6-endo-dig ring closure followed by rapid protonolysis of the
σ-alkenyl palladium intermediate, preventing subsequent Heck
(8) For selected Pd(II) heterocyclizations featuring the use of different
additives, see: (a) Tietze, L. T.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104,
3453-3516. (b) Sigman, M. S.; Schultz, M. J. Org. Biomol. Chem. 2004,
2, 2551-2554. (c) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-
3420. (d) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002,
41, 164-166. (e) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9,
625-655. (f) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (g) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907-2908. (h)
Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063-
5064. (i) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P.
J. Org. Chem. 1996, 61, 3584-3585. (j) Larock, R. C.; Hightower, T. R.
J. Org. Chem. 1993, 58, 5298-5300. (k) Zeni, G.; Larock, R. C. Chem.
ReV. 2004, 104, 2285-2310. (l) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am.
Chem. Soc. 1997, 119, 5063-5064. (m) Ferreira, E. M.; Stoltz, B. M. J.
Am. Chem. Soc. 2003, 125, 9578-9579.
(9) For related boron aldol reactions, see: (a) Paterson, I.; Osborne, S.
Tetrahedron Lett. 1990, 31, 2213-2216. (b) Paterson, I.; Wallace, D. J.;
Cowden, C. J. Synthesis 1998, 639-652.
(10) (a) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc.
2004, 126, 2660-2661. (b) Trost, B. M.; Frederiksen, M. U.; Papillon, J.
P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005,
127, 3666-3667.
(11) Athanasiou, N.; Smallridge, A. J.; Trewhella, M. A. J. Mol. Catal.
B: Enzymol. 2001, 11, 893-896.
8392 J. Org. Chem., Vol. 71, No. 22, 2006

Pd(II)-Catalyzed Cascade Wacker-Heck Reaction
SCHEME 4. Synthesis and Heterocyclization of r-Hydroxy Ynones 6a-c
synthesis.14 This chemistry belongs to a growing class of Pd-
SCHEME 5. Oxy-/Carbopalladation Reaction Mechanism
(II)-catalyzed oxidative heterocyclizations, an area of research
which has reappeared at the forefront of organometallic catalysis.
Further work is undergoing in our laboratories to study the
synthetic potential of these unusual products and to develop
alternative palladium-catalyzed cascade reactions involving
electron-deficient ynones.
Experimental Section
General Procedure A: Aldol Reaction. To a precooled (0 °C)
solution of diisopropylamine (1.5 equiv) in anhydrous THF was
added n-BuLi (1.6M in hexanes, 1.5 equiv). The solution was stirred
for 30 min at 0 °C and then cooled to -78 °C, and 3-hexyn-2-one
was added dropwise (1.3 equiv) in THF via cannula. The solution
was stirred for 20 min at -78 °C, and then the corresponding
aldehyde (1 equiv) was added in THF via cannula. The resulting
solution was stirred for 15 min. Then, it was quenched with a
saturated ammonium chloride solution and allowed to warm at room
temperature. The organic layer was separated and the aqueous layer
was partitioned with ethyl acetate. The combined organic extracts
were dried over MgSO4 and filtered under suction, and solvent was
removed in vacuo. The resulting residue was further purified by
silica gel chromatography.
General Procedure B: Preparation of â-Hydroxy Ynones by
Addition of a Grignard Reagent to a Weinreb Amide. To a flask
charged with the Weinreb amide (1 equiv) in THF was added at
-78 °C dropwise 1-propynylmagnesium bromide (0.5 M in THF,
2.4 equiv). The mixture was warmed to room temperature overnight
and then quenched with NH4Cl at 0 °C. The organic layer was
separated, and the aqueous layer was partitioned with ethyl acetate.
The organic layers were combined and dried over MgSO4. After
filtration, solvent was removed in vacuo. The resulting residue was
further purified by silica gel chromatography.
General Procedure C: Preparation of â-Hydroxy Ynones by
Addition of a Lithiated Alkyne. To a flask charged with the
correspondent alkyne (1.1 equiv) in THF was dropwise added
n-BuLi (2.5 M in THF, 1.1 equiv) at 0 °C for 30 min. Then, the
Weinreb amide in THF was added dropwise at -78 °C. The mixture
was warmed to room temperature overnight and quenched with
NH4Cl at 0 °C. The organic layer was separated, and the aqueous
layer was partitioned with ethyl acetate. The organic layers were
combined and dried over MgSO4. After filtration, solvent was
removed in vacuo. The resulting residue was further purified by
silica gel chromatography.
coupling. An alternative reaction pathway could be a base-
mediated ring-closure process.12 Notably, a control experiment
carried out without Pd(II) catalyst led only to recovered starting
material contaminated with a side product resulting from
dehydration of the hydroxy ynone (Scheme 5).13
Conclusion
In conclusion, we have developed a novel palladium(II)-
catalyzed Wacker-Heck process, which chemoselectively couples
two electron-poor substrates to afford novel trisubstituted
dihydropyranones or furanones. These compounds are unknown,
but structurally related carbohydrate derivatives featuring a
similar dienic system have been used in natural product
(12) For 6-endo-dig cyclization not catalyzed by palladium complexes,
see: (a) Hashimoto, S.; Ban, M.; Yanagiya, Y.; Sakata, S.; Ikegami, S.
Tetrahedron Lett. 1991, 32, 4027-4030. (b) Hashimoto, S.; Sonegawa, M.;
Sakata, S.; Ikegami, S. J. Chem. Soc., Chem. Commun. 1987, 1, 24-25.
(c) Dreessen, S.; Schabbert, S.; Schaumann, E. Eur. J. Org. Chem. 2001,
2, 245-251. (d) Pflieger, D.; Muckensturm, B. Tetrahedron Lett. 1990,
31, 2299-2300. (e) Pflieger, D.; Muckensturm, B. Tetrahedron 1989, 45,
2031-2040. (f) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. J. Am. Chem.
Soc. 1987, 109, 8115-8116. (g) Garc´ıa, H.; Iborra, S.; Primo, J. J. Org.
Chem. 1986, 51, 4432-4436. (h) Lavalle´e, J.-F.; Berthiaume, G.; Deslong-
champ, P.; Grein, F. Tetrahedron Lett. 1986, 27, 5455-5458.
(13) During our optimization study, we found that the cyclization of
6-hydroxy-8-phenyloct-2-yn-4-one (()-1h in the presence of PdCl2, CuCl,
Na2HPO4, Cu powder (10 mol %), ethyl acrylate (20 equiv), O2, DME, 65
°C led to the formation of the desired dihydropyranone (()-2h along with
a side product never observed otherwise, the acyclic (2E)-ethyl 8-hydroxy-
4-methyl-6-oxo-10-phenyldeca-2,4-dienoate (9% yield). However, this result
was not reproducible (reactions attempted several times, side product
observed once).
General Procedure D: Deprotection of the THP Group. To
a flask charged with the protected alcohol (1 equiv) was added at
(14) (a) Hayashi, M.; Tsukada, K.; Kawabata, H.; Lamberth, C.
Tetrahedron 1999, 55, 12287-12294. (b) Hayashi, M.; Tsukada, K.;
Kawabata, H.; Lamberth, C. J. Chem. Soc., Perkin Trans. 1 1999, 239-
240. (c) Rahman, M. A.; Fraser-Reid, B. J. Am. Chem. Soc. 1985, 107,
5576-5578. (d) Tsang, R.; Fraser-Ried, B. J. J. Org. Chem. 1992, 57,
1065-1067.
J. Org. Chem, Vol. 71, No. 22, 2006 8393

Silva et al.
room temperature a mixture of acetic acid/water/THF (4/2/1, 50
equiv) under Ar. The mixture was heated at 50 °C for 24 h, and
then solvent was evaporated in vacuo and the residue was further
purified by silica gel chromatography.
General Procedure E: Palladium-Catalyzed Domino Wacker-
Heck Reaction. To a flask charged with the ligand, base,
co-oxidant, additive, and catalyst was added the substrate in DME,
followed by ethyl acrylate in DME. The vessel was then degassed
and the atmosphere replaced by oxygen. The reaction was heated
at 65 °C under oxygen atmosphere for 24 h. The mixture was
filtered through a mixture of sand and Celite or silica. The filtrate
was evaporated in vacuo, and the residue was further purified by
silica gel chromatography.
1-Hydroxy-1-phenylhept-4-yn-3-one (1a). Compound 1a was
obtained from benzaldehyde (0.35 mL, 3.47 mmol) and 3-hexyn-
2-one (0.57 mL, 5.20 mmol) according to general procedure A.
Purification by silica gel chromatography (hexane/EtOAc, 9:1)
yielded the product (545 mg, 78% yield) as a pale yellow oil: Rf
(hexane/EtOAc, 1:1) ) 0.46; δ1H (400 MHz, CDCl3) 1.22 (3H, t,
J ) 7.6 Hz), 2.39 (2H, q, J ) 7.6 Hz), 2.94 (1H, dd, J ) 17.5, 3.4
Hz), 2.97 (1H, d, J ) 3.3 Hz), 3.04 (1H, dd, J ) 17.5, 9.1 Hz),
5.25 (1H, ddd, J ) 9.1, 3.4, 3.3 Hz), 7.27-7.40 (5H, m); δ13C (400
MHz, CDCl3) 12.6 (CH3), 12.7 (CH2), 54.0 (CH2), 69.8 (CH), 80.2
(C), 97.1 (C), 125.7 (2 × CH), 127.8 (CH), 128.6 (2 × CH), 142.4
(C), 186.9 (C); νmax (film/cm-1) 3031, 2982, 2941, 2213, 1668;
m/z (HRMS, FI) found 202.0989 ([M]+), C13H14O2 requires
202.0994.
1-Hydroxy-1-(4-methoxyphenyl)hex-4-yn-3-one (1d). Com-
pound 1d was obtained from 3-hydroxy-N-methoxy-3-(4-methox-
yphenyl)-N-methylpropanamide15 (300 mg, 1.22 mmol) and 1-pro-
pynylmagnesium bromide (0.5 M in THF, 6 mL) in THF according
to general procedure B. Purification by silica gel chromatography
(hexane/EtOAc, 3:1) yielded the product (203 mg, 77% yield) as a
pale yellow oil: Rf (hexane/EtOAc, 2:1) ) 0.30; δ1H (400 MHz,
CDCl3) 2.03 (3H, s), 2.88 (1H, dd, J ) 17.2, 3.4 Hz), 2.90 (1H, d,
J ) 3.3 Hz), 3.02 (1H, dd, J ) 17.3, 9.2 Hz), 3.80 (3H, s), 5.18
(1H, ddd, J ) 8.9, 3.3, 3.2 Hz), 6.88 (2H, d, J ) 8.8 Hz), 7.30
(2H, d, J ) 8.6 Hz); δ13C (400 MHz, CDCl3) 4.1 (CH3), 53.9 (CH2),
55.3 (CH3), 80.2 (C), 91.7 (C), 113.9 (2 × CH), 127.0 (2 × CH),
134.6 (C), 159.2 (C), 186.8 (C); νmax (film/cm-1) 3479, 2985, 2838,
2218, 1699, 1597, 1512; m/z (HRMS, FI) found 217.0875 ([M]+),
C13H13O3 requires 217.0865.
syn-1-Hydroxy-2-methyl-1-phenylhex-4-yn-3-one (1g). To a
stirred solution of diisopropylethylamine (1.3 equiv) and di-n-
butylboron triflate (1 M solution in DCM, 1.2 equiv) in anhydrous
DCM (10 mL) at -78 °C was added hex-4-yn-3-one 4 (1 equiv)
in dry DCM (2 mL). The reaction mixture was warmed to 0 °C
and stirred for 2 h, before it was cooled to -78 °C again and
benzaldehyde (2.5 equiv) was added. The reaction mixture was then
maintained at -78 °C for 2 h and at -26 °C for 16 h. The resulting
reaction mixture was quenched by addition of methanol (2 mL/
mmol), a pH 7 (PBS) buffer solution (2 mL/mmol), and a H2O2
peroxide solution (30% sol, 2 mL/mmol) at 0 °C. Stirring was
continued for 1 h. Then, the mixture was partitioned between H2O
(30 mL), and DCM (3 × 30 mL) and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue
was further purified by silica gel chromatography (hexane/diethyl
ether, 1:1) and yielded the product (160 mgs, 59% yield, >99%
de) as a colorless oil; Rf (hexane/diethyl ether, 1:1) ) 0.45; δ1H
(400 MHz, CDCl3) 1.15 (3H, d, J ) 7.2 Hz), 2.05 (3H, s), 2.70
(1H, d, J ) 3.3 Hz), 2.87 (1H, qd, J ) 7.2, 3.5 Hz), 5.30 (1H, dd,
J ) 3.4, 3.3 Hz), 7.24-7.38 (5H, m); δ13C (400 MHz, CDCl3) 4.2
(CH3), 9.5 (CH3), 55.0 (CH), 72.6 (CH), 79.6 (C), 92.3 (C), 125.9
(2 × CH), 127.4 (CH), 128.3 (2 × CH), 141.6 (C), 191.3 (C); νmax
(film/cm-1) 3457, 3031, 2982, 2938, 2217, 1667, 1494, 1453; m/z
(HRMS, ESI) found 225.0886 ([M + Na]+), C13H14NaO2 requires
225.0886.
(S)-5-Hydroxy-1,7-diphenylhept-1-yn-3-one (1i). Compound 1i
was obtained from (S)-4 (350 mg, 1.48 mmol) and phenylacetylene
(445 µL, 4.1 mmol) according to general procedure C. Purification
by silica gel chromatography (hexane/EtOAc, 4:1) yielded the
product (380 mg, 93% yield) as a pale yellow solid: mp ) 45-50
°C; Rf (hexane/EtOAc, 9:1) ) 0.28; The enantiomeric excess of
the product 1i was determined to be 96% ee by HPLC analysis
[column, DAICEL CHIRALCEL OD (0.46 cm Φ × 25 cm); eluent,
hexane/PriOH ) 9/1; flow rate, 1.0 mL/min; retention time: 28.5
min (minor), 69.9 min (major)]: [R]18D +17.7 (c 1.0, CHCl3); δ1H
(400 MHz, CDCl3) 1.79 (1H, dddd, J ) 16.6, 9.6, 7.0, 4.2 Hz),
1.90 (1H, dddd, J ) 17.2, 9.1, 8.4, 5.4 Hz), 2.71-2.86 (2H, m),
2.88-2.93 (2H, m), 4.24 (1H, m), 7.15-7.66 (10H, m); δ13C (400
MHz, CDCl3) 31.7 (CH2), 38.0 (CH2), 52.0 (CH2), 66.9 (CH), 87.8
(C), 91.9 (C), 125.9 (CH), 128.46 (2 × CH), 128.49 (2 × CH),
128.7 (2 × CH), 131.0 (CH), 133.2 (2 × CH), 141.7 (C), 187.6
(C); νmax (film/cm-1) 3449, 3026, 2928, 2203, 1666, 1490, 1299;
m/z (HRMS, ESI) found 301.1199 ([M + Na]+), C19H18NaO2
requires 301.1199.
(E)-Ethyl-3-(6-ethyl-4-oxo-2-phenyl-3,4-dihydro-2H-pyran-5-
yl)acrylate (2a). Compound 2a was obtained from 1a (62 mg, 0.25
mmol) according to general procedure E. Purification by silica gel
chromatography (hexane/EtOAc, 4:1) yielded the product as a pale
yellow oil: Rf (hexane/EtOAc, 4:1) ) 0.30; δ1H (400 MHz, CDCl3)
1.25 (3H, t, J ) 7.4 Hz), 1.32 (3H, t, J ) 7.1 Hz), 2.65 (1H, dq,
J ) 14.4, 7.5 Hz), 2.69 (1H, dq, J ) 14.4, 7.5 Hz), 2.74 (1H, dd,
J ) 16.7, 3.4 Hz), 2.95 (1H, dd, J ) 16.7, 14.0 Hz), 4.23 (2H, q,
J ) 7.1 Hz), 5.43 (1H, dd, J ) 14.2, 3.5 Hz), 6.97 (1H, d, J )
15.8 Hz), 7.34-7.45 (6H, m); δ13C (100 MHz, CDCl3) 11.7 (CH3),
14.4 (CH3), 26.2 (CH2), 43.4 (CH2), 60.2 (CH2), 80.3 (CH), 110.8
(C), 119.9 (CH), 126.0 (2 × CH), 128.9 (2 × CH), 129.0 (CH),
135.2 (CH), 137.5 (C), 168.3 (C), 180.4 (C), 190.4 (C); νmax (film/
cm-1) 1646; m/z (HRMS, ESI) found 301.1440 ([M + H]+),
C18H21O4 requires 301.1459.
6-Ethyl-2-phenyl-2H-pyran-4(3H)-one (3).16 Isolated side prod-
uct of the above reaction. Purification by silica gel chromatography
(hexane/EtOAc, 4:1) yielded the product as a pale yellow oil. The
NMR data of this compound are in agreement with the literature.16
2-Hydroxy-2-methylhex-4-yn-3-one (6a). Compound 6a was
obtained from 9a (580 mg, 2.75 mmol) according to general
procedure D. Purification by silica gel chromatography (hexane/
EtOAc, 3:2) yielded the product (267 mg, 77%) as a colorless oil:
Rf (hexane/EtOAc, 3:2) ) 0.40. δ1H (400 MHz, C6D6) 1.31 (3H,
s), 1.44 (6H, s), 3.70 (1H, br s); δ13C (C6D6) 3.2 (CH3), 26.5 (2 ×
CH3), 77.1 (C), 77.4 (C), 95.2 (C), 192.1 (C); νmax (film/cm-1) 3476,
2980, 2219, 1672, 1361, 1255, 1175; m/z (HRMS, FI) found
127.0749 ([M + H]+) C7H11O2 requires 127.0759.
Acknowledgment. The European Community is gratefully
acknowledged for generous financial support (MRTN-CT-2003-
505020 and COST Action D25). This work was also supported
by the EPSRC (GR/S68095/01) and the British Council (Chev-
ening Scholarship, M.R.).
Supporting Information Available: Experimental data for
1
substrates 1b,c,e-h, 2b-i, 5, 6b, 7a-c, 9a-c, and 10. H NMR
and 13C spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO061292A
(15) Silva, F. A.; Gouverneur, V. Tetrahedron Lett. 2005, 46, 8705-
8709.
(16) Danishefsky, S.; Harvey, D. F.; Quallich, G.; Uang, B. J. J. Org.
Chem. 1984, 49, 392-393.
8394 J. Org. Chem., Vol. 71, No. 22, 2006