Palladium-catalyzed direct cross-coupling reaction of glycals with activated alkenes

Article abstract of DOI:10.1021/ol201734w

An efficient method for a Pd(OAc)₂-catalyzed cross-coupling reaction of glycals with activated alkenes under mild conditions has been developed. This transformation provides an expedient synthetic method to C(2)-functionalized glycals, which ar

Full text of DOI:10.1021/ol201734w

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4394–4397
Palladium-Catalyzed Direct Cross-
Coupling Reaction of Glycals with
Activated Alkenes
Yaguang Bai, Jing Zeng, Shuting Cai, and Xue-Wei Liu*
School of Physical & Mathematical Sciences, Nanyang Technological University, 21
Nanyang Link, 637371 Singapore
xuewei@ntu.edu.sg
Received June 28, 2011
ABSTRACT
An efficient method for a Pd(OAc)2-catalyzed cross-coupling reaction of glycals with activated alkenes under mild conditions has been developed.
This transformation provides an expedient synthetic method to C(2)-functionalized glycals, which are common structural building blocks in
natural products and other biologically active compounds. The reaction scope includes different kinds of carbohydrates, protecting groups and
substituents on alkene. Moderate to excellent yields and pure E configuration selectivity were obtained.
The utility of saturated and unsaturated pyrans has
increased enormously over the years; pyrans are also an
important class of heterocycle which are widely found in
natural products with various biological activities (Figure 1).1
Consequently, a plethora of methods has been developed for
the synthesis of multifunctionalized pyran rings. Popular
methods include the Prins cyclization,2 Lewis acid and transi-
tion metal promoted intramolecular cyclizations,3 and hetero-
DielsÀAlder reactions.4 Most of the reported methods focus
on cyclization reactions to form the pyran rings from mole-
cules with existing functional groups.4
Figure 1. Pyran-containing natural products.
€
(1) (a) Adio, A. M.; Konig, W. A. Phytochemistry 2005, 66, 599. (b)
Sugar pyranoses are one of the most abundant pyrans
that are fully substituted with specific chiral centers.
Among the many sugar pyranose derivatives, glycals are
preeminent. While in past decades, only reactions on the
anomeric carbon of glycals have been intensively
investigated;5 to the best of our knowledge, there are only
several reports of the addition of functional groups to C2
Banskota, A. H.; Tezuka, Y.; Midorikawa, K.; Matsushige, K.; Kadota,
S. J. Nat. Prod. 2000, 63, 1227. (c) Supratman, U.; Fujita, T.; Akiyama,
K.; Hayashi, H. Phytochemistry 2001, 58, 311. (d) Valcic, S.; Zapp, J.;
Becker, H. Phytochemistry 1997, 44, 89.
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Lett. 2005, 7, 2683. (b) Barry, C. S.; Elsworth, J. D.; Seden, P. T.;
Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett. 2006, 8,
3319. (c) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499. (d) Kwon,
M. S.; Woo, S. K.; Na, S. W.; Lee, E. Angew. Chem., Int. Ed. 2008, 47,
1733. (e) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217. (f)
Hu, X.-H.; Liu, F.; Loh, T.-P. Org. Lett. 2009, 11, 1741.
(3) (a) Baeckvall, J. E.; Andersson, P. G. J. Am. Chem. Soc. 1992, 114,
6374. (b) Coppi, L.; Ricci, A.; Taddei, M. Tetrahedron Lett. 1987, 28,
973. (c) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53, 911. (d)
Huang, H.-L.; Liu, R.-S. J. Org. Chem. 2002, 68, 805.
(5) (a) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357. (b)
Dwek, R. A. Chem. Rev. 1996, 96, 683. (c) Toshima, K.; Tatsuta, K.
Chem. Rev. 1993, 93, 1503. (d) Varki, A. Glycobiology 1993, 3, 97. (e)
Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137.
(4) (a) Chemler, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001,
3, 2949. (b) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.;
Jørgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599.
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Lett. 1992, 33, 7681.
r
10.1021/ol201734w
Published on Web 07/27/2011
2011 American Chemical Society

carbon of glycals.6 C2-functionalized glycals could provide
access to a large number of natural products and sugar
derivatives. Among all the C2-functionalized glycals, for-
mation of a diene moiety by the addition of an alkene to a
glycal has attracted much attention because the diene
moiety can serve as a potential building blocks for natural
products such as Olivin,7 Forslolin,8 and Jamesoniellide9
by DielsÀAlder cyclization.
the reaction was carried out in mixed DMA and acetic acid
(v/v 1/1) with 10 mol % Pd(OAc)2, the desired product was
obtained in pure E form with an excellent isolated yield of
82%. Subsequently, when the catalyst loading was reduced
to 5 mol %, a lower yield (53%) was obtained (Table 1,
entry 10). On the other hand, further increase in the
catalyst loading to 20 mol % did not have significant effect
on increasing reaction yield (Table 1, entry 11). Screening
of a variety of catalysts revealed that Pd complexes such as
PdCl2 (Table 1, entry 2), Pd(TFA)2 (Table 1, entry 4),
Pd(PhCN)2Cl2 (Table 1, entry 5), and Pd(PPh3)2Cl2
(Table 1, entry 3) afforded much lower yields in contrast
to Pd(OAc)2. After elucidating the optimal catalyst, the
efficiency of different co-oxidants was examined. Intri-
guingly, the yield was much higher when the reaction
was conducted in the presence of 1 equiv of Cu(OTf)2
(Table 1, entry 8) as compared to 1 equiv of CuSO4
(Table 1, entry 6), Cu(OAc)2 (Table 1, entry 1) and
Ag2CO3 (Table 1, entry 7). Presumably the ligand ex-
change between Pd(OAc)2 and Cu(OTf)2 made Pd (II)
species more electrophilic and thus more prone to elec-
trophilic substitution at C(2). In addition, adjusting
reaction temperatures revealed that the reaction gave
the best yield (82%) at 70 °C in a reasonable reaction
time (24 h) (Table 1, entry 9).
Recently, palladium-catalyzed CÀH bond activation
reactions have attracted considerable attention.10 How-
ever, cross coupling reactions between alkenes to form
dienes have been rarely reported due to the difficulty in
activating the alkenyl carbonÀhydrogen bond in contrast
to the carbonÀhalogen bond. When the reactions are
applied to alkenes such as acrylates, in the presence of
common transition metals, dimerization often occurs to
generate dicarboxylates.11 In 2004, Ishii et al. reported an
elegant oxidative coupling methodology of acrylates with
vinyl carboxylates, catalyzed by Pd(OAc)2.12 Direct cross-
coupling reactions between simple olefins and acrylates
were also explored by Loh’s group.13 Recently, Yu et al.
reported another direct alkene alkene coupling by terminal
alkenes and functionalized 1,3-butadiene.14 In continua-
tion of our interest in functionalized sugar pyranose espe-
cially glycals,15 herein we describe a simple and general
method for functionalization of the C(2) position of glycals
through a cross-coupling reaction.
With the optimized reaction conditions in hand, we
proceeded to study the reaction with different alkene
coupling partners (Scheme 1). The reactivities of an array
of acrylates were first examined. To our delight, all the
acrylate reagents used in the reaction gave the
Initially, we examined the interaction of peracetylated
glucal with ethyl acrylate in the presence of Pd(II) catalysts
and 1 atm of oxygen (Table 1). It was observed that when
Scheme 1. Direct Coupling of Protected Glucals with Activated
Table 1. Direct Coupling Reaction of Peracetylated Glucal with
Ethyl Acrylatea
Alkenesa,b
temp
time
(h)
yieldb
(%)
entry
oxidant
catalyst (mol %)
(°C)
1
2
Cu(OAc)2 Pd(OAc)2 (10%)
Cu(OAc)2 PdCl2 (10%)
60
60
60
60
60
60
60
60
70
70
70
80
24
24
24
24
24
24
24
24
24
48
24
16
61
14
0
3
Cu(OAc)2 Pd(PPh3)2Cl2 (10%)
Cu(OAc)2 Pd(TFA)2 (10%)
Cu(OAc)2 Pd(PhCN)2Cl2 (10%)
4
56
0
5
6
CuSO4
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (5%)
Pd(OAc)2 (20%)
Pd(OAc)2 (10%)
36
23
71
82
53
85
59
7
Ag2CO3
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
9
10
11
12
a Reaction conditions unless otherwise specified: 1a (1 equiv), 2a (2
equiv), oxidant (1 equiv), O2 (1 atm) in the mixture of HOAc and DMA.
b Isolated yields. Key: HOAc, acetic acid; TFA, trifluoroacetate; DMA,
dimethylacetamide.
a Reaction conditions unless otherwise specified: 1 (1 equiv), 2
(2 equiv), Cu(OTf)2 (1 equiv), O2 (1 atm) at 70 °C in the mixture of
AcOH and DMA for 24 h. b All yields in Scheme 1 are isolated
yields. c Reactions were carried out at 45 °C for 72 h.
(7) Franck, R. W.; John, T. V. J. Org. Chem. 1983, 48, 3269.
Org. Lett., Vol. 13, No. 16, 2011
4395

corresponding (E) products (3aÀg) in good to excellent
yield (62À84%). Besides acrylates, alkenes such as methyl
vinyl ketone (3h) and acrynitrile (3i) provided pure E-
alkenes in moderate yield as well. Relatively electron-rich
alkenes such as styrene also afforded the desired product (3j)
in moderate yield. Subsequently, the effect of various pro-
tecting groups on the glucal substrate was examined. Glucal
substrates with acid tolerant protecting groups such as acetyl
(3a) and benzyl (3k) gave good yields. On the contrary,
unprotected glucal substrates and glucals with acid-sensitive
protecting groups of the (trimethylsilyl or isopropylidene)
failed to afford any desired product.
with a wider range of protecting groups. The results are
summarized in Scheme 3. Interestingly, substrates derived
from D-galactose (3mÀo), D-ribose (3pÀq), and L-6-deoxyl-
3,4-diacetyglucal (3rÀs) also afforded the desired products
in good to excellent yields. On top of that, other acid tolerant
protecting groups such as ethoxycarbonyloxyl (3m), piva-
loyl (2n), and benzoyl (3o) gave the desired products in good
yields too. In the case of 3q, X-ray crystallography (Figure 2)
further comfirmed the product structure.
Interestingly, we found that the reaction of glucal and
ethyl methacrylate afforded a mixture of compounds 3la
and 3 lb with a ratio of 1:2.5 in 74% total yield (Scheme 2).
Scheme 2. Direct Coupling of Peracetylated Glucal with Ethyl
Methacrylate
Figure 2. X-ray structure of compound 3q.
Scheme 4. Plausible Mechanism for the Coupling Reactions
Observed
Investigation ofthe reactivitiesof different carbohydrate
moieties was next carried out, and the reaction was tested
Scheme 3. Direct Coupling of Protected Glycals with Ac-
rylatesaÀc
a All reactions were carried out with 1 (1 equiv), 2 (2 equiv), Cu(OTf)2
(1 equiv), O2 (1 atm) for 24 h. b All yields in Scheme 3 are isolated
yields. c All of the products are in an E configuration.
(8) Tsang, R.; Fraser-Reid, B. J. Org. Chem. 1992, 57, 1065.
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D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S. J. Am. Chem.
Soc. 2006, 128, 12954. (c) Iwai, Y.; Gligorich, K. M.; Sigman, M. S.
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A plausible mechanism of this reaction is depicted in
Scheme 4. The Pd complex 5 is formed by electrophilic
substitution on the glycal at C(2) due to the latter being
4396
Org. Lett., Vol. 13, No. 16, 2011

electron rich. Carbopalladationof theacrylate then occurs
to give 6. The conformation 6 anti of complex 6 is
relatively more stable than conformation 6 syn as the
two bulky groups in 6 anti are situated at anti positions.
The formation of this intermediate justifies the observa-
tion that only E configuration products were afforded
from all of the substrates. Through β-hydride elimination,
final compounds are dissociated from the Pd complex.
Both products 3la and 3lb were formed due to the fact that
β-hydride elimination could take place on any of the two β
carbons of 6l. Pd(0) generated from reductive elimination
is then oxidized by Cu(II) to form the active Pd(II) catalyst
species once more.
In conclusion, we have developed an efficient Pd(OAc)2-
catalyzed coupling reaction of glycals with activated alkenes
under mild conditions. The reactions display high tolerance
to a vast scope of substrates, including glycals protected by
various protecting groups and a diversified range of acti-
vated alkenes. Pyran derivatives were obtained in moderate
to excellent yields with pure E selectivity. It is noteworthy
that the functionalized pyran products potentially provide
entries to many pyran-containing natural products, signify-
ing their immense potential in the synthetic field.
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Acknowledgment. We thank Prof. Koichi Narasaka for
his invaluable suggestion on reaction mechanism and Dr.
Yong-Xin Li for X-ray analyses. We gratefully acknowl-
edge Nanyang Technological University (RG50/08) and
the Ministry of Education, Singapore (MOE 2009-T2-1-
030) for financial support of this research.
Supporting Information Available. Experimental proce-
dures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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