Palladium(II)-catalyzed asymmetric coupling of allylic alcohols and vinyl ethers: Insight into the palladium and copper bimetallic catalyst

Article abstract of DOI:10.1021/jo802807w

The use of PdX₂, CuX₂ (X = OAc, OCOCF₃, or Cl), and catechol together with (S,S)-4,4'-bisbenzyl- 2,2'-bioxazoline under O₂ induces the asymmetric coupling of cinnamyl alcohols and vinyl ethers to give (R)-(+)-2-alkoxy-4-benzylidenetetrahydrofurans in 40-53% ee (79% yield). The present study provides implications for the so-called Wacker catalyst of PdX₂ and CuX₂, in terms of that the anionic ligands (X) of Pd and Cu interchange between two metals.

Full text of DOI:10.1021/jo802807w

Palladium(II)-Catalyzed Asymmetric Coupling of Allylic Alcohols
and Vinyl Ethers: Insight into the Palladium and Copper Bimetallic
Catalyst
Yasufumi Kawamura, Yasuhiro Kawano, Tomohiro Matsuda, Yuˆta Ishitobi, and
Takahiro Hosokawa*
Department of EnVironmental Systems Engineering, Kochi UniVersity of Technology,
185 Miyanokuchi, Tosayamada, Kami-City, Kochi 782-8502, Japan
hosokawa.takahiro@kochi-tech.ac.jp
ReceiVed December 25, 2008
The use of PdX2, CuX2 (X ) OAc, OCOCF3, or Cl), and catechol together with (S,S)-4,4′-bisbenzyl-
2,2′-bioxazoline under O2 induces the asymmetric coupling of cinnamyl alcohols and vinyl ethers to
give (R)-(+)-2-alkoxy-4-benzylidenetetrahydrofurans in 40-53% ee (79% yield). The present study
provides implications for the so-called Wacker catalyst of PdX2 and CuX2, in terms of that the anionic
ligands (X) of Pd and Cu interchange between two metals.
Introduction
type of reaction, such as O2 with or without CuX2, or
p-benzoquinone. Although recent intensive studies have dis-
closed the behavior of XPdH and O2,2 little concern has been
paid into the role of CuX2, which is a standard cocatalyst in
Wacker-type oxidations.3,4 Asymmetric versions of the Wacker-
type reaction have also attracted interests in terms of developing
selective oxidative reactions. Since we reported the first asym-
metric, intramolecular Wacker-type oxidation in 1978 (Scheme
2),5 several groups have made advances in its utility for
synthesizing optically active O-atom-containing heterocycles in
high ee.6 For the asymmetric reactions, p-benzoquinones are
frequently employed as the stoichiometric oxidant,7 but it is
rare to use O2 as the oxidant with the CuX2 cocatalyst.6b,8
The palladium(II)-catalyzed reaction of alkenes with O-atom
nucleophiles, the so-called Wacker-type reaction, is undoubtedly
a powerful tool for synthesizing a wide range of O-atom-
containing functionalized compounds. A number of review
articles1 highlights fascinating developments based on this
reaction. As illustrated in Scheme 1, the reaction proceeds via
nucleophilic attack of ROH toward alkenes coordinated to PdX2,
the process of which is referred to as oxypalladation. The
resulting σ-alkyl palladium(II) intermediate undergoes XPdH
elimination to afford products oxidatively. The fate of XPdH
species formed is crucial for the catalysis associated with the
function of stoichiometric oxidants, which are required for this
(2) For recent representative references, see: (a) Konnick, M. M.; Stahl, S. S.
J. Am. Chem. Soc. 2008, 130, 5753–5762. (b) Popp, B. V.; Stahl, S. S. J. Am.
Chem. Soc. 2007, 129, 4410–4422. (c) Keith, J. M.; Goddard, W. A., III; Oxgaard,
J. J. Am. Chem. Soc. 2007, 129, 10361–10369. (d) Muzart, J. Chem. Asian J.
2006, 1, 508–515. (e) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420.
(3) For our studies on this subject, see: (a) Hosokawa, T.; Nomura, T.;
Murahashi, S.-I. J. Organomet. Chem. 1998, 551, 387–389. (b) Hosokawa, T.;
Takano, M.; Murahashi, S.-I. J. Am. Chem. Soc. 1996, 118, 3990–3991. (c)
Hosokawa, T. Petrotech 2002, 25, 801–805.
SCHEME 1
(4) For recent reviews on the Wacker reaction, see: (a) Cornell, C. N.; Sigman,
M. S. Inorg. Chem. 2007, 46, 1903–1909. (b) Punniyamurthy, T.; Velusamy,
S.; Iqbal, J. Chem. ReV. 2005, 105, 2329–2363. (c) Takacs, J. M.; Jiang, X.-T.
Curr. Org. Chem. 2003, 7, 369–396. (d) A recent representative paper: Keith,
J. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III. J. Am. Chem. Soc. 2007,
129, 12342–12343.
(5) (a) Hosokawa, T.; Miyagi, S.; Murahashi, S.-I.; Sonoda, A. J. Chem.
Soc., Chem. Commun. 1978, 687–688. (b) Hosokawa, T.; Uno, T.; Inui, S.;
Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318–2323. (c) Hosokawa, T.;
Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49–54.
(1) For recent reviews, see: (a) Beccalli, E. M.; Broggini, G.; Martinelli,
M.; Sottocrnola, S. Chem. ReV. 2007, 107, 5318–5365. (b) Muzart, J. Tetrahedron
2005, 61, 5955–6008. (c) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285–
2309. (d) Hosokawa, T.; Murahashi, S.-I. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: New
York, 2002; Vol. II, pp 2141-2192. (e) For a recent paper on intramolecular
Wacker-type cyclization, see: Mun˜iz, K. AdV. Synth. Catal. 2004, 346, 1425–
1428.
3048 J. Org. Chem. 2009, 74, 3048–3053
10.1021/jo802807w CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

Palladium and Copper Bimetallic Catalyst
SCHEME 2
shown in Scheme 3. In this study, the value of the percentage of
ee obtained, albeit not higher, was used as a clue to understanding
the behavior of the palladium(II) catalyst. Results of the present
study provide intriguing implications on the role of the CuX2
cocatalyst which remains uncertain in this type of reactions.
Results and Discussion
In addition, fundamental information is lacking on the
intermolecular Wacker-type reaction where the enantioface of
prochiral alkenes is intermolecularly differentiated by Pd(II).9
This is because the usual reaction shown in Scheme 1 results
in no asymmetry in products. However, depending on substrate
structures, the pathway could be modified to induce chirality
in the products. Scheme 3 is one such reaction. Thus, when
Shown in Scheme 4 is the asymmetric reaction of (E)-
cinnamyl alcohol (1a) and ethyl vinyl ether (2a) with a catalyst
system of Pd(OAc)2, Cu(OAc)2, catechol (4), and (S,S)-
bisoxazolines (5) under O2 (balloon). Representative results are
given in Table 1. As reported previously, the catalytic efficiency
of Pd(OAc)2 and Cu(OAc)2 in a nonasymmetric reaction was
enhanced by using catechol (4) as an additive (Table 1, entries
SCHEME 3a
SCHEME 4
a A catalyst system in the present study is composed of Pd(II), Cu(II),
catechol, L*, and O2.
cinnamyl alcohols 1 are used as nucleophiles toward vinyl ethers
2, the resulting intermolecular oxypalladation adducts undergo
cyclization to give 2-alkoxy-4-benzylidenetetrahydrofurans 3
bearing chirality at the 2-position. Reported herein is the first
asymmetric coupling of cinnamyl alcohols 1 and vinyl ethers 2
as an intermolecular Wacker-type oxidation. Our previous
studies on the original reaction10 developed by Oshima and
Uchimoto,11 revealed that the catalysis by Pd(OAc)2 and
Cu(OAc)2 under O2 is remarkably enhanced by utilizing catechol
as an additive. On the basis of this fact, we have aimed to shed
further light on the function of PdX2 and CuX2 as well as to
elucidate fundamental characteristics of the asymmetric reaction
1 and 2).10b This was also the case for the present asymmetric
reaction. Thus, in the presence of catechol (4) (Pd/Cu/4/5a )
1/1/2/2), the reaction gave (R)-(+)-3a in 40% ee and 71% yield
(24 h) (entry 3),12 but the absence of catechol (4) decreased
the product yield only to 26% (entry 4). In addition, the
enantioselectivity was also greatly lowered to 29% ee. This
TABLE 1. Study for the Catalyst Composition in Enantioselective
Coupling of Cinnamyl Alcohol (1a) and Ethyl Vinyl Ether (2a)a
3a
Pd(OAc)2 Cu(OAc)2
(S,S)-5a
yield
ee
entry (mol %) (mol %) 4 (mol %) (mol %) solvent (%)b (%)c
1
2
3
4
5
6
7
5
5
5
5
5
5
5
5
5
5
5
5
10
10
MeCNd 82 (42)e
MeCNd 38 (15)e
toluene 71
(6) (a) Wang, F.; Zhang, Y. J.; Yang, G.; Znang, W. Tetrahedron Lett. 2007,
48, 4179–4182. (b) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 17778–17788. (c) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.;
Stecker, F. Angew. Chem., Int. Ed. 2005, 44, 257–259. (d) Uozumi, Y.; Kato,
K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064. (e) Uozumi, Y.; Kyota,
H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620–1625.
(f) Hocke, H.; Uozumi, Y. Synlett 2002, 12, 2049–2053. (g) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907–2908. (h) Koranne,
P. S.; Tsujihara, T.; Arai, M. A.; Bajracharya, G. B.; Suzuki, T.; Onitsuka, K.;
Sasai, H. Tetrahedron: Asymmetry 2007, 18, 919–923.
(7) (a) Popp, B. V.; Stahl, S. S. In Organometallic Oxidation Catalysis;
Springer-Verlag: Berlin, Heidelberg, 2007; pp 149-189. (b) Popp, B. V.;
Thorman, J. L.; Stahl, S. S. J. Mol. Catal. A: Chem. 2006, 251, 2–7.
(8) (a) For recent representative references for the use of only O2 as a
stoichiometric oxidant in Pd(II)-catalyzed oxidation, see: Cornell, C. N.; Sigman,
M. S. Org. Lett. 2006, 8, 4117–4120. (b) Mitsudome, T.; Umetani, T.; Nosaka,
N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed.
2006, 45, 481–485. (c) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006,
128, 4348–4355, and references cited therein.
(9) (a) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076–3077,
and references cited therein. (b) El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M.
J. Organomet. Chem. 2002, 656, 168-176; Tetrahedron Lett. 2002, 43, 4229-
4231. (c) Itami, K.; Palmgren, A.; Thorarensen, A.; Ba¨ckvall, J.-E. J. Org. Chem.
1998, 63, 6466–6471. (d) For a review on enantioselective palladium-catalyzed
transformations, see: (e) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004,
104, 3453–3516.
(10) (a) Kawamura, Y.; Imai, T.; Hosokawa, T. Synlett 2006, 18, 3110–
3114. (b) Minami, K.; Kawamura, Y.; Koga, K.; Hosokawa, T. Org. Lett. 2005,
7, 5689–5692. (c) For related reactions, see: Evans, M. A.; Morken, J. P. Org.
Lett. 2005, 7, 3367–3370. (d) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006,
8, 3251–3254.
10
10
20
10
10
40
29
38
39
39
toluene 26
toluene 18
10
toluene 17f
toluene 13f
a 1a (1 mmol), 2a (4 mmol), toluene (2.5 mL), O2 (1 atm), rt, 24 h.
b Isolated yield. c Measured by chiral HPLC. d MeCN (1.0 mL), 3 h.
e Toluene as the solvent, 24 h. f NMR yield.
decrease in percentage of ee could be interpreted as follows:
When catechol is absent, the ligand 5a is able to coordinate to
Cu(OAc)2 as well as Pd(OAc)2;13 that is, coordination of 5a to
Pd(OAc)2 is interfered by Cu(OAc)2, lowering the percentage
of ee.14 In other words, catechol greatly prefers to combine with
Cu(OAc)2. Therefore, when catechol is present, coordination
(12) The percentage of ee was determined by HPLC using an analytical
column packed with cellulose tribenzoate coated on silica gel (250 mm × 4.6
mm, i-PrOH/n-hexane ) 1/19, 0.5 mL/min, 258 nm). The optical rotation of 3a
obtained was [R]D25 ) +64.2° (c 0.335, CHCl3), and thus the maximum rotation
of 3a is calculated to be 160.5 (CHCl3).
(13) Chiral bis(oxazoline) ligands can coordinate to Cu, Pd, and other metals;
see ref 15.
(14) When the amount of 5a was increased to 4 equiv per Pd, the percentage
of ee was not decreased (entry 5, Table 1). This must be due to the coordination
of 5a to Pd(OAc)2 sufficiently taking place even in the absence of catechol,
thereby not lowering the percentage of ee.
(11) (a) Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1987, 28,
809–812. (b) Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1989,
62, 2050–2054.
J. Org. Chem. Vol. 74, No. 8, 2009 3049

Kawamura et al.
TABLE 2. Change of Enantioselectivity with Changing
of 5a takes place prevailingly on the side of Pd(OAc)2. This
interpretation is likely supported by preferential isolation (>75%
yield) of PdCl2-(S,S)-5a complex (Scheme 5) from a solution
of Pd(OAc)2, Cu(OAc)2, catechol (4), and 5a (1/1/1/1) in toluene
which was stirred for 1 h under O2 (balloon) and then treated
with a saturated NaCl solution. In the absence of catechol, this
complex was only isolated in 31% yield, probably because
coordination of 5a to Cu(OAc)2 concurrently takes place.
Substituent (R) of Vinyl Ether 2a
SCHEME 5
a 1a (1 mmol), 2 (4 mmol), Pd(OAc)2 (5 mol %), Cu(OAc)2 (5 mol
%), catechol (4) (10 mol %), (S,S)-5a (10 mol %), toluene (2.5 mL), O2
(1 atm). b NMR yield. c Measured by chiral HPLC. d Isolated yield.
propyl, butyl, hexyl, and octyl.16 Of those, butyl vinyl ether afforded
3c (R ) n-Bu) in 53% ee, which was the highest value in the
present study. The value itself is not necessarily high in current
outstanding advances in this field, but it is ranked higher among
the asymmetric Wacker-type oxidations using copper salts as the
cocatalyst.9a The effect of bulky side chains of OR, such as a tert-
and sec-butyl group, on enantioselectivity was not examined,
because of inaccessibility for preparing such vinyl ethers. This
subject remains to be studied in the future.
The results in Table 1 provide further implications on the
role of catechol in the catalyst system: (1) Without Cu(OAc)2
but in the presence of catechol (4), the enantioselectivity was
not lowered (39% ee) from 40% (entries 6 and 3), but the yield
of 3a was remarkably decreased (17%). This means that
Cu(OAc)2 does not affect the enantioselectivity, and that the
reactivity of catalyst is enhanced by a combination of catechol
and Cu(OAc)2. (2) In the absence of both Cu(OAc)2 and
catechol, the enantioselectivity was again not lowered (39% ee)
(entry 7), but the yield of 3a was only 13%. Thus, it can be
said that the enantioselectivity is exerted by a combination of
Pd(OAc)2 and 5a, and that the reactivity is dependent on the
assembly of Cu(OAc)2 and catechol.
The (+)-enantiomer of 3a (R ) Et) obtained as the major
product (Scheme 4) was assigned as the (R) configuration by
the following experiments (Scheme 6). Thus, 4-nitrocinnamyl
SCHEME 6a
After surveying the amounts of 4 and 5a used per Pd and
Cu, we have decided a combination of Pd/Cu/4/5a ) 1/1/2/2
to be suitable for the catalysis, and it has been used as a standard
in the present study. The detail of our survey was given in the
Supporting Information. In the present asymmetric reaction,
toluene proved to be superior (Table 1, entry 3). Results using
other solvents such as benzene, THF, methylene chloride, and
1,2-dichloroethane are also given as Supporting Information.
The use of acetonitrile, which was a good solvent for the
nonasymmetric version, results in only 9% ee of 3a in 59%
yield under the standard condition. The chiral coordination
environment of the catalyst is probably compromised by
preferential coordination of acetonitrile to Pd(II), significantly
reducing the percentage of ee.
The use of simple chiral bisoxazolines 515 bearing other
substituents R at the 4,4′-position (Scheme 4), instead of R )
CH2Ph (5a), afforded no good results for percentage of ee. For
example, under the standard conditions, the product 3a was
formed in 85% yield and 32% ee with (S,S)-5b (R ) i-Pr), 85%
yield and 32% ee with (S,S)-5c (R ) i-Bu), 29% yield and 1%
ee with (S,S)-5d (R ) t-Bu), and 52% yield and 1% ee with
(R,R)-5e (R ) Ph), respectively.
a (i) 1b (2 mmol), 2a (8 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 (10
mol %), catechol (4) (20 mol %), (S,S)-5a (20 mol %), toluene (5.0 mL),
rt, 28 h. (ii) (+)-3g (0.5 mmol), NH2NH2 ·H2O (4 equiv), FeCl3 (0.5 equiv),
active-carbon (7 equiv per FeCl3), 2.5 mL each of THF and EtOH, 70 °C,
2 h. (iii) (+)-6 (0.23 mmol), (R)-7 (0.23 mmol), THF (0.9 mL), rt, 21 h.
(iv) Crystallization from MeO(CH2)2OMe-iPr2O for X-ray analysis.
alcohol (1b) was first reacted with ethyl vinyl ether (2a) using
(S,S)-5a. The resulting (Z)-(+)-4-(4-nitrobenzylidene)-2-ethox-
ytetrahydrofuran (3g) (74% yield, 34% ee)17 was converted into
the corresponding 4-aminobenzylidene derivative 6 (FeCl3,
NH2NH2 ·H2O). Treatment of 6 with commercially available (R)-
As shown in Table 2, the percentage of ee was also not improved
by changing the alkyl side chain of OR in vinyl ethers 2 with ethyl,
(15) (a) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. ReV. 2006, 106,
3561–3651. (b) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151–
4202. (c) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1–45.
(16) (a) For preparation of vinyl ethers, see: Okimoto, Y.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2002, 124, 1590–1591. (b) Bosch, M.; Schlaf, M. J.
Org. Chem. 2003, 68, 5225–5227.
(17) The optical rotation of each enantiomer 3g being collected repeatedly
25
by semi-preparative HPLC was [R]D ) +142° (c 1.01, CHCl3) and -142°
(c 1.01, CHCl3) for (+)-3g and (-)-3g, respectively.
3050 J. Org. Chem. Vol. 74, No. 8, 2009

Palladium and Copper Bimetallic Catalyst
TABLE 4. Effect of the Base on the Reaction of Cinnamyl Alcohol
(1a) and Ethyl Vinyl Ether (2a) Using Pd(TFA)2-Cu(OAc)2 as a
Catalysta
(s)-(1-isocyanatoethyl)naphthalene (7) gave urea 8 as a 65:35
mixture of two diastereomers, from which a single crystal
suitable for X-ray analysis was obtained upon crystallization
from 1,2-dimethoxyethane and diisopropyl ether. The ORTEP
drawing, which is given as Supporting Information, indicates that
its structure has a (R,2S) configuration. The crystal used for X-ray
analysis was, unexpectedly, found to be the minor diastereomer
of 8 by HPLC and NMR (also see the Supporting Information).
Therefore, the absolute configuration of (+)-3a obtained as the
major enantiomer in Scheme 4 was assigned as (R).
3a
10 yield yield
entry
base
(%)b
(%)b ee (%)c
pKa
1
2
3
4
5
6
7
8
9
10
5
5
0
0
0
0
0
0
0
57
46
52
79
80
78
80
63
60
44
41
7
pyridine
2,4,6-tritert-butylpyridine
NEt3
(i-Pr)2NEt
proton sponge
DBU
Ca(OH)2
Na2CO3
Cs2CO3
5.33
7.02
10.87
11.26
12.50
13.47
31
43
41
40
41
43
39
47
Following the survey of fundamental characteristics, we next
examined the effect of anionic ligands (X) of Pd(II) or Cu(II)
on the reaction of 1a and 2a. As shown in entry 1 of Table 3,
10.33
10.33
10
TABLE 3. Effect of Anionic Ligands of Pd(II) and Cu(II) on the
Reaction of Cinnamyl Alcohol (1a) and Ethyl Vinyl Ether (2a)a
a 1a (1 mmol), 2a (4 mmol), Pd(TFA)2 (5 mol %), Cu(OAc)2 (5 mol
%), catechol (10 mol %), (S,S)-5a (10 mol %), base (10 mol %), toluene
(2.5 mL), rt, 24 h. b NMR yield. c Measured by chiral HPLC.
10 (31%) with 3a (31% yield, 8% ee) (Table 3, entry 12). Thus,
a stronger acid such as CF3COOH may cleave the Pd-C bond
of intermediate 9 (Scheme 7) to afford 10. Alternatively, 10
may be formed by simple addition of 1a to 2a catalyzed by a
stronger acid.19 The formation of 11 is explained by either
Pd(II)- or acid-catalyzed Pd-OEt elimination from 9, because
such a process has been precedent.20
3a
10 yield 11 yield yield ee
entry Pd(II)
Cu(II)
L*
base (%)b
(%)b (%)b (%)c
1
2
3
4
5
6
7
8
9
Pd(OAc)2 Cu(TFA)2 (S,S)-5a
Pd(TFA)2 Cu(OAc)2 (S,S)-5a
Pd(OAc)2 Cu(TFA)2
Pd(TFA)2 Cu(OAc)2
Pd(OAc)2 CuCl2
PdCl2 Cu(OAc)2 (S,S)-5a
Pd(OAc)2 Cu(TFA)2 (S,S)-5a NEt3
Pd(TFA)2 Cu(OAc)2 (S,S)-5a NEt3
11
10
18
7
11
3
65
57
9
6
9
35
41
11
14
12
5
SCHEME 7
(S,S)-5a
26
28
37
43
3
64
79
51
67
10
31
Pd(OAc)2 Cu(TFA)2
NEt3
NEt3
10 Pd(TFA)2 Cu(OAc)2
11 PdCl2
12 Pd(TFA)2 Cu(TFA)2 (S,S)-5a
Cu(OAc)2 (S,S)-5a NEt3
29
8
31
a 1a (1 mmol), 2a (4 mmol), Pd(II) (5 mol %), Cu(II) (5 mol %),
catechol (4) (10 mol %), L* ) (S,S)-5a (10 mol %), NEt3 (10 mol %),
toluene (2.5 mL), rt, 24 h. b NMR yield. c Measured by chiral HPLC.
The similarity in the product distribution observed in Table 3
suggests that an anionic ligand of Pd is exchangeable with that of
Cu and vice versa. If in the Pd(OAc)2-Cu(TFA)2 system, the OAc
ligand of Pd is not exchanged with the TFA ligand of Cu, the
oxypalladation occurs only with Pd(OAc)2 to produce only
CH3COOH. Therefore, no formation of 10 is expected, but this is
not the case (Table 3, entry 1). Accordingly, it can be said that the
OAc ligand of Pd is replaced by TFA on Cu to produce CF3COOH
in the stage of oxypalladation. In the Pd(TFA)2-Cu(OAc)2 system,
the anionic ligands of Pd and Cu are also exchangeable with each
other, thereby resulting in the product distribution similar to that
in Pd(OAc)2-Cu(TFA)2 (Table 3, entries 1 and 2).
In the present catalyst system, the chiral ligand 5a must
preferentially coordinate to Pd(II), because a higher yield of Pd(II)
complex bearing 5a was able to be isolated from a solution of
Pd(OAc)2, Cu(OAc)2, 4, and 5a (1/1/1/1) in toluene (Scheme 5).
Although the reactivity of the catalyst is effected by a combination
of catechol and Cu(OAc)2, catechol may be acting as o-quinone,
because it is readily oxidized into o-quinone upon treatment with
O2 in the presence of the Pd(OAc)2-Cu(OAc)2 catalyst, as reported
previously.10b On the basis of these considerations, we propose a
simplified model of the catalyst assembly such as 12 in which
the use of Pd(OAc)2 and Cu(TFA)2 with 4 and (S,S)-5a gave
3a in 65% yield (35% ee) along with byproduct 10 (11%), an
addition product of 1a to 2a. When the anionic ligands were
reversed, the use of Pd(TFA)2 and Cu(OAc)2 also gave 3a and
10 in similar yields as above (entry 2). When (S,S)-5a was not
used, an additional byproduct 11, besides 10, was formed in
both systems (entries 3 and 4). The byproduct 11 corresponds
to ether exchange in the alkoxy moiety of vinyl ether 2a with
1a. Here again, the product distributions are closely similar
between these two systems. The similarity in the product
distribution was also observed between the Pd(OAc)2-CuCl2
and PdCl2-Cu(OAc)2 system (entries 5 and 6).18 In all cases,
the presence of NEt3 completely inhibits the formation of 10
and 11 without substantially changing the product yields and
percentage of ee (entries 7 and 8). Not only NEt3 but also a
variety of bases including inorganic bases can suppress the
formation of 10 and/or 11 as shown in Table 4. The effectiveness
of base appears to be dependent on their pKa values.
The original reaction using Pd(OAc)2-Cu(OAc)2 gave no
byproduct 10 (Table 1, entry 3). This reaction undoubtedly
produces CH3COOH in the stage of oxypalladation leading to
9 (Scheme 7). In contrast, a combination of Pd(TFA)2 and
Cu(TFA)2, which produces CF3COOH, gave a higher yield of
(19) In fact, when a solution of 1a (1 mmol) in toluene (1.5 mL) was treated
with 2a (4 mmol) in the presence of CF3COOH (0.05 mmol) in 1,2-dichloroethane
(1.0 mL) for 24 h at room temperature, it gave 10 in 56% yield (NMR).
(20) For ꢀ-heteroatom elimination, see: Zhao, H.; Ariafard, A.; Lin, Z.
Organometallics 2006, 25, 812–819.
(18) Detailed results using PdCl2 as the catalyst are given in the Supporting
Information.
J. Org. Chem. Vol. 74, No. 8, 2009 3051

Kawamura et al.
present oxypalladation (syn or anti addition) and the enantioface-
differentiation process.
Conclusions
In conclusion, we presented fundamental data for the first
asymmetric coupling of cinnamyl alcohols and vinyl ethers using
(S,S)-4,4′-benzylbisoxazoline with the so-called Wacker catalyst
of PdX2 and CuX2 under O2, in which the catalytic activity is
enhanced by addition of catechol to the catalyst system. The present
study provided the following insights into the PdX2-CuX2 catalyst.
(1) The catalysis must be of Pd-Cu bimetallic form with anionic
bridging ligands, in which the anionic ligands are interchangeable
between two metals. (2) The enantioselectivity is exerted by
Pd(OAc)2 and a chiral ligand such as 5a, whereas the reactivity is
dependent on the assembly of Cu(OAc)2 and catechol.
FIGURE 1. Simplified representation for the anion exchange in the
Pd(OAc)2-Cu(TFA)2 catalyst.
Experimental Section
General methods and the X-ray crystallographic study are
described in the Supporting Information.
Representative Procedures for Asymmetric Coupling. (a)
(Z)-4-Benzylidene-2-ethoxytetrahydrofuran (3a). Pd(OAc)2 (11.2
mg, 0.05 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), catechol (4) (11.0
mg, 0.1 mmol), and (S,S)-4,4′-bisbenzyl-2,2′-bioxazoline (5a)
(32.0 mg, 0.1 mmol) were dissolved in toluene (1.5 mL) in a 25 mL
side-armed round-bottomed flask under O2 (balloon), and the reaction
mixture was stirred for 30 min at room temperature. Ethyl vinyl ether
(2a) (288 mg, 4.0 mmol) was added to the flask, and a solution of
(E)-3-phenyl-2-propen-1-ol (1a) (134 mg, 1.0 mmol) in toluene (1.0
mL) was then added. After the reaction mixture was stirred for 24 h
at room temperature, the mixture was filtered through a Florisil column
(10 mm × 80 mm, 3 g, EtOAc/n-hexane ) 1/20, Rf ) 0.62), and the
solvent was evaporated under reduced pressure to give 3a in nearly
pure form. Purification by thin-layer chromatography on silica gel gave
3a in 71% isolated yield (145 mg, 0.71 mmol) as a colorless oil. The
enantiomer excess (40% ee) was determined by HPLC analysis (i-
PrOH/n-hexane ) 1/19, 0.5 mL/min, 258 nm). Bp (bulb-to-bulb):
105-108 °C (15 mmHg). FTIR (neat, cm-1): 3053, 3025, 1739, 1598,
1184, 1095, 1032, 997. GCMS: m/e 204 (M+). 1H NMR (400 MHz,
CDCl3): δ 1.21 (t, J ) 7.2 Hz, 3H), 2.72 (dm, J ) 16.4 Hz, 1H), 2.94
(ddddd, J ) 16.4, 5.2, 2.4, 2.4, 2.4 Hz, 1H), 3.51 (dq, J ) 9.6, 7.2
Hz, 1H), 3.77 (dq, J ) 9.6, 7.2 Hz, 1H), 4.70 (ddd, J ) 2.4, 2.4, 1.6
Hz, 1H), 5.23 (d, J ) 4.4 Hz, 1H), 6.43 (br s, 1H), 7.13 (d, J ) 7.6
Hz, 2H), 7.21 (t, J ) 7.6 Hz, 1H), 7.34 (t, J ) 7.6 Hz, 2H). 13C NMR
(101 MHz, CDCl3): δ 15.2, 41.2, 62.6, 67.9, 102.0, 121.6, 126.4, 127.8,
128.4, 137.4, 139.1. Anal. Calcd for C13H16O2: C, 76.42; H, 7.89.
Found: C, 76.32; H, 7.49.
FIGURE 2. Examples of Pd-Cu bimetallic complexes.
o-quinone is incorporated to Cu(II) as the ligand (Figure 1).21 The
representation of Pd-Cu bimetallic complex-bearing anionic bridge
is based on our previous studies3 for isolation of bimetallic
complexes such as 13 and 14, where Cl acts as the bridge ligand
between Pd and Cu (Figure 2). These complexes 13 and 14 are
readily formed in the reaction of PdCl2 and CuCl2 with DMF3a or
with HMPA and O2.3b Since Pd(OAc)2 itself exists as a trimeric
complex bearing OAc bridges,22 it is not unreasonable to postulate
such OAc bridging. In bimetallic complexes 12, the anionic ligands
(X, Y) of OAc and TFA can be exchangeable with each other,
resulting in the similarity of product distribution.
So far, several studies have outlined that the catalysis in this
type of reaction is initiated by XPdH species which reacts with O2
to give XPdOOH species. Alternatively, the XPdH species is
converted into Pd(0) and HX, and the resulting Pd(0) reacts with
O2 to give η2-peroxoPd(II) species from which XPdOOH species
is formed by the action of HX. In either case, the XPdOOH species
acts as the catalyst.2,23-25 The catalysis of the present reaction must
be also exerted by the XPdOOH species derived from XPdH
formed during the reaction.26 The species is likely bimetallic with
copper. Further study is obviously necessary to address the catalysis
and mechanistic questions including the stereochemistry for the
(b) (Z)-4-Benzylidene-2-n-butoxytetrahydrofuran (3c). Pd(OAc)2
(11.2 mg, 0.05 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), catechol (4)
(11.0 mg, 0.1 mmol), and (S,S)-4,4′-bisbenzyl-2,2′-bioxazoline (5a)
(32.0 mg, 0.1 mmol) were dissolved in toluene (1.5 mL) in a 25 mL
side-armed round-bottomed flask under O2 (balloon), and the mixture
was stirred for 30 min at room temperature. n-Butyl vinyl ether (2c)
(401 mg, 4.0 mmol) was added to the flask, and a solution of (E)-3-
phenyl-2-propen-1-ol (1a) (134 mg, 1.0 mmol) in toluene (1.0 mL)
was then added. After the reaction mixture was stirred for 24 h at
room temperature, the mixture was filtered through a Florisil column
(10 mm × 80 mm, 3 g, EtOAc/n-hexane ) 1/20, Rf ) 0.67), and the
solvent was evaporated under reduced pressure to give 3c in pure form
as a colorless oil. The yield was determined to be 86% (161 mg, 0.86
mmol) by NMR (terephthalaldehyde as an internal standard). The
enantiomer excess (53% ee) was determined by HPLC analysis (i-
PrOH/n-hexane ) 1/19, 0.5 mL/min, 258 nm). Bp (bulb-to-bulb):
115-117 °C (15 mmHg). FTIR (neat, cm-1): 3026, 2930, 2870, 1599,
1492, 1449, 1423, 1345, 1180, 1097, 1038, 925, 840, 749, 695. GCMS:
(21) For an example of copper-quinone complexes, see: Rall, J.; Kalm, W.
J. Chem. Soc., Faraday Trans. 1994, 90, 2905–2908.
(22) Skapski, A. C.; Smart, M. L. Chem. Commun. 1970, 658–659.
(23) For representative references on the behavior of XPdH and O2, see ref
2 and also: (a) Gligorich, K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2006,
45, 6612–6615. (b) Keith, J. M.; Muller, R. P.; Kemp, R. A.; Goldberg, K. I.;
Goddard, W. A., III; Oxgaard, J. Inorg. Chem. 2006, 45, 9631–9633. (c) Keith,
J. M.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III. J. Am. Chem. Soc. 2005,
127, 13172–13179. (d) Privalov, T.; Linde, C.; Zetterberg, K.; Moberg, C.
Organometallics 2005, 24, 885–893.
(24) For isolation of PdOOH species, see: (a) Konnick, M. M.; Gandhi, B. A.;
Guzei, I. A.; Stahl, S. S. Angew. Chem., Int. Ed. 2006, 45, 2904–2907. (b)
Konnick, M. M.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 10212–
10213. (c) Denney, M. C.; Smythe, N. A.; Cetto, K. L.; Kemp, R. A.; Goldberg,
K. I. J. Am. Chem. Soc. 2006, 128, 2508–2509.
(25) Muzart, J. Tetrahedron 2003, 59, 5789–5816.
(26) In the present reaction, the presence of base entirely suppressed the
formation of byproducts 10 and 11 possibly formed by the action of acid HX
(X ) OCOCF3 or Cl) (Tables 3 and 4). If this means that the acid (HX) generated
during the reaction is completely captured by base, the XPdOOH species could
not be formed by η2-peroxoPd(II) species and HX (for such an argument, see
ref 25).
1
m/e 232 (M+). H NMR (400 MHz, CDCl3): δ 0.92 (t, J ) 7.6 Hz,
3H), 1.32-1.41 (m, 2H), 1.54-1.60 (m, 2H), 2.72 (dm, J ) 16.4 Hz,
3052 J. Org. Chem. Vol. 74, No. 8, 2009

Palladium and Copper Bimetallic Catalyst
1H), 2.93 (ddddd, J ) 16.4, 5.2, 2.8, 2.8, 2.8 Hz, 1H), 3.45 (dt, J )
9.6, 6.8 Hz, 1H), 3.72 (dt, J ) 9.6, 6.8 Hz, 1H), 4.70 (ddd, J ) 2.0,
2.0, 2.0 Hz, 2H), 5.22 (d, J ) 5.2 Hz, 1H), 6.43 (br s, 1H), 7.14 (d,
J ) 7.2 Hz, 2H), 7.21 (t, J ) 7.2 Hz, 1H), 7.34 (t, J ) 7.2 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ 13.8, 19.3, 31.7, 41.1, 67.0, 67.9,
102.2, 121.5, 126.4, 127.8, 128.4, 137.4, 139.1. Anal. Calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.53; H, 8.62.
(R,2R)- and (R,2S)-8 in 72% NMR yield (0.72 mmol, terephthalalde-
hyde as an internal standard). Further purification was made by column
chromatography on silica gel (EtOAc/n-hexane ) 1/1) to give a
mixture of (R,2R)- and (R,2S)-8 in 66% yield (56.3 mg, 0.66 mmol)
as a powder. The diastereomer excess was determined by HPLC
analysis (i-PrOH/n-hexane ) 1/9, 3.0 mL/min, 300 nm) to be 30% de
(65/35). FTIR (KBr, cm-1): 3735, 3324, 3048, 2974, 2926, 2369, 1637,
1588, 1545, 1454, 1415, 1373, 1341, 1316, 1231, 1184, 1097, 1051,
1031, 998, 926, 780, 655, 614, 527, 444. 1H NMR (400 MHz, CDCl3):
δ 1.19 (t, J ) 7.2 Hz, 3.9H), 1.20 (t, J ) 7.2 Hz, 2.1H), 1.71 (d, J )
6.8 Hz, 6H), 2.66 (dm, J ) 16.4 Hz, 0.7 H), 2.68 (dm, J ) 16.4 Hz,
1.3H), 2.91 (dm, J ) 16.4 Hz, 2H), 3.45 (dq, J ) 9.6, 7.2 Hz, 2H),
3.76 (dq, J ) 9.6, 7.2 Hz, 2H), 4.60-4.68 (m, 4H), 4.87 (d, J ) 7.2
Hz, 2H), 5.21 (d, J ) 5.2 Hz, 0.7H), 5.22 (d, J ) 5.2 Hz, 1.3H),
5.76-5.86 (m, 2H), 6.08 (s, 2H), 6.35 (br s, 2H), 7.02 (dm, J ) 8.8
Hz, 2H), 7.19 (dm, J ) 8.4 Hz, 2H), 7.44-7.61 (m, 4H), 7.82 (d, J )
(c) (Z)-4-(4-Nitrobenzylidene)-2-ethoxytetrahydrofuran (3g).
Pd(OAc)2 (22.5 mg, 0.1 mmol), Cu(OAc)2 (18.2 mg, 0.1 mmol),
catechol (4) (22.0 mg, 0.2 mmol), and (S,S)-4,4′-bisbenzyl-2,2′-
bioxazoline (5a) (64.0 mg, 0.2 mmol) were dissolved in toluene (4.0
mL) in a 25 mL side-armed round-bottomed flask under O2 (balloon),
and the mixture was stirred for 30 min at room temperature. Ethyl
vinyl ether (2a) (577 mg, 8.0 mmol) was added to the flask, and a
solution of (E)-3-(4-nitrophenyl)-2-propen-1-ol (1b) (358 mg, 2.0
mmol) in toluene (1.0 mL) was then added. After the reaction mixture
was stirred for 24 h at room temperature, the mixture was filtered
through a Florisil column (15 mm × 60 mm, 5 g, EtOAc). Evaporation
of the solvent under reduced pressure gave 3g in a solid state. The
pure product 3g was obtained by column chromatography (100-200
mesh silica gel, EtOAc/n-hexane ) 1/4) in 74% yield (367 mg, 0.74
mmol) as a brown solid. The enantiomer excess (34% ee) was
determined by HPLC analysis (i-PrOH/n-hexane ) 1/9, 2.0 mL/min,
258 nm). Mp: 75-76 °C. FTIR (Nujol, cm-1): 2927, 1652, 1592, 1513,
1099, 1049, 996. GCMS: m/e 249 (M+). 1H NMR (400 MHz, CDCl3):
δ 1.21 (t, J ) 7.2 Hz, 3H), 2.77 (d, J ) 16.8 Hz, 1H), 2.98 (ddddd,
J ) 16.9, 5.2, 2.4, 2.4, 2.4 Hz, 1H), 3.52 (dq, J ) 9.7, 7.2 Hz, 1H),
3.78 (dq, J ) 9.7, 7.2 Hz, 1H), 4.71 (ddd, J ) 2.4, 2.4, 1.6 Hz, 2H),
5.26 (d, J ) 5.2 Hz, 1H), 6.51 (br s, 1H), 7.20 (d, J ) 8.9 Hz, 2H),
8.19 (d, J ) 8.9 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 15.1, 41.6,
62.8, 67.8, 101.9, 120.0, 123.9, 128.2, 143.4, 143.7, 145.0. Anal. Calcd
for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.38; H, 6.05;
N, 5.50.
8.4 Hz, 1H), 7.89 (dm, J ) 7.6 Hz, 1H), 8.19 (d, J ) 8 Hz, 1H). 13
C
NMR (101 MHz, CDCl3): δ 15.2, 21.7, 35.8, 41.0, 41.1, 46.0, 62.6,
67.9, 102.0, 106.1, 120.4, 120.5, 120.9, 122.5, 123.2, 125.3, 125.9,
126.6, 128.3, 128.6, 128.8, 130.9, 133.0, 134.0, 136.7, 137.9, 138.6,
154.5. HRMS (EI): calcd for C26H28N2O3, 416.2100 (M+); found,
416.2107. When the resulting powder was treated with ethyl acetate,
yellow-orange material was dissolved into the ethyl acetate solution.
The remaining powder was white. A portion of the white powder (10.3
mg) was dissolved into 1,2-dimethoxyethane in a sample tube. The
tube was placed in a bottle containing diisopropyl ether overnight in
the refrigerator, and then the mixture stood at room temperature. As
the result, colorless single crystals (mp: 189-192 °C) were obtained,
1
which was found to be (R,2S)-8 by X-ray analysis. H NMR (400
MHz, CDCl3): δ 1.19 (t, J ) 7.2 Hz, 3H), 1.70 (d, J ) 7.2 Hz, 3H),
2.68 (dm, J ) 16.8 Hz, 1H), 2.90 (dm, J ) 16.8 Hz, 1H), 3.49 (dq,
J ) 9.6, 7.2 Hz, 1H), 3.76 (dq, J ) 10.0, 7.2 Hz, 1H), 4.62-4.65 (m,
2H), 4.86 (d, J ) 7.6 Hz, 1H), 5.21 (d, J ) 4.8 Hz, 1H), 5.76-5.84
(m, 1H), 6.07 (s, 1H), 6.34 (br s, 1H), 7.01 (dm, J ) 8.4 Hz, 2H),
7.18 (dm, J ) 8.8 Hz, 2H), 7.44-7.59 (m, 4H), 7.81 (d, J ) 8.0 Hz,
1H), 7.88 (d, J ) 8.4 Hz, 1H), 8.19 (d, J ) 8.8 Hz, 1H).
Synthesis of (Z)-4-(4-Aminobenzylidene)-2-ethoxytetrahydro-
furan (6). 3g (125 mg, 0.5 mmol), FeCl3 (40.6 mg, 0.25 mmol), and
active-C (284 mg, 7 equiv per FeCl3) were dissolved in THF (2.5 mL)
and EtOH (2.5 mL) in a 25 mL side-armed round-bottomed flask.
Hydrazine monohydrate (0.1 mL, 2 mmol) was added to the mixture
at 70 °C with stirring. After stirring for 2 h at 70 °C, the reaction
mixture was filtered through filter paper, and the solvent was
evaporated under reduced pressure. The resulting mixture was diluted
by adding ethyl acetate (30 mL), washed with water (2 × 20 mL) and
brine (30 mL), and dried (MgSO4). Removal of the solvent gave pure
6 in 62% NMR yield (68.2 mg, 0.62 mmol, terephthalaldehyde as an
internal standard) as a brown solid. Mp: 44-45 °C. FTIR (KBr, cm-1):
3449, 3356, 3218, 2979, 2933, 1627, 1606, 1516, 1459, 1422, 1374,
1348, 1291, 1182, 1114, 1091, 1052, 1035, 995, 912, 865, 851, 570,
Isolation of PdCl2-(S,S)-5a Complex from a Catalyst Solu-
tion. Pd(OAc)2 (67.4 mg, 0.3 mmol), Cu(OAc)2 (54.5 mg, 0.3 mmol),
catechol (4) (33.0 mg, 0.3 mmol), and (S,S)-4,4′-bisbenzyl-2,2′-
bioxazoline (5a) (96.1 mg, 0.3 mmol) were dissolved in toluene (9.0
mL) in a 25 mL side-armed round-bottomed flask under O2 (balloon),
and the reaction mixture was stirred for 1 h at room temperature. The
solution was diluted with CH2Cl2 and washed with a saturated NaCl
solution (50 mL). The organic layer was collected, dried over MS3Å
powder, filtered, and concentrated under reduced pressure. The resulting
black powder was dissolved into the least amount of CH2Cl2. The
solution was passed through a Florisil column (10 mm × 40 mm,
1.5 g, CH2Cl2), and evaporation of the solvent gave a PdCl2-(S,S)-5a
complex as a nearly pure form in 74% NMR yield (terephthalaldehyde
as an internal standard) (109.8 mg, 0.22 mmol) as a brown solid. Mp:
257-258 °C. 1H NMR (400 MHz, CDCl3): δ 3.01 (dm, J ) 13.6 Hz,
2H), 3.63 (dm, J ) 13.6 Hz, 2H), 4.69-4.82 (m, 6H), 7.24-7.40 (m,
10H). 13C NMR (101 MHz, CDCl3): δ 29.7, 39.4, 64.1, 127.5, 129.0,
129.7, 134.5, 159.8. Anal. Calcd for C20H20N2O2PdCl2: C, 48.26; H,
4.05; N, 5.62. Found: C, 48.58; H, 4.08; N, 5.66. In the absence of
catechol, the same complex was obtained only in 31% NMR yield.
1
528, 419. H NMR (400 MHz, CDCl3): δ 1.20 (t, J ) 7.2 Hz, 3H),
2.67 (dm, J ) 16.4 Hz, 1H), 2.90 (ddddd, J ) 16.0, 5.2, 2.4, 2.4, 2.4
Hz, 1H), 3.50 (dq, J ) 9.6, 7.2 Hz, 1H), 3.76 (dq, J ) 9.6, 7.2 Hz,
1H), 4.64-4.66 (m, 2H), 5.21 (d, J ) 4.4 Hz, 1H), 6.31 (br s, 1H),
6.65 (dm, J ) 8.4 Hz, 2H), 6.94 (dm, J ) 8.4 Hz, 2H). 13C NMR
(101 MHz, CDCl3): δ 15.2, 41.0, 62.6, 68.0, 102.0, 115.0, 121.3, 128.3,
129.0, 135.0, 144.9. HRMS (EI): calcd for M+ - C2H5O (C13H17NO2),
174.0913; found, 174.0900.
Synthesis of (Z)-4-(4-N-(R)-(1-Naphthylethyl)ureylene)ben-
zylidene-2-ethoxytetrahydrofuran (8). The amine 6 (50 mg, 0.23
mmol) was dissolved in THF (0.9 mL) in a 25 mL side-armed round-
bottomed flask, and the reaction mixture was stirred at room temper-
ature. Isocyanic acid (R)-(-)-(1-isocyanatoethyl)naphthalene (7) (0.04
mL, 0.23 mmol) was added to the flask, and the reaction mixture was
stirred for 21 h at room temperature. N,N-Dimethyl-1,3-propanediamine
(0.01 mL, 0.08 mmol) was then added to the flask, and the mixture
was stirred for 30 min. After the reaction mixture was evaporated under
reduced pressure, the resulting mixture was diluted by adding 30 mL
of chloroform, washed with 3% citric acid (2 × 20 mL) and brine (30
mL), and dried (MgSO4). Removal of the solvent gave a mixture of
Supporting Information Available: Detailed experimental
procedures and characterization data for all reported new com-
pounds and X-ray crystallographic data for single diastereomer
(R,2S)-8. 1H and 13C NMR spectra for all reported new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802807W
J. Org. Chem. Vol. 74, No. 8, 2009 3053