A reusable TNF-tagged chiral bis(oxazoline)-copper catalyst for Diels- Alder transformations

Article abstract of DOI:10.1055/s-0031-1290918

A chiral bis(oxazoline) ligand, substituted on the methylene bridge by a covalent link to an electron-deficient moiety (2,4,7-trinitrofluoren-9-one, TNF), is a useful ligand associated to copper(II) salts to promote enantioselective Diels-Alder reactions between N-acyloxazolidinones and cyclopentadiene. Owing to different solubility properties, the corresponding catalyst was precipitated by pentane addition after reaction completion and was easily recovered by filtration. It was successfully reused in up to 20 successive catalytic cycles for the formation of the targeted products with no loss of either the activity or the enantioselectivity along with the recycling. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290918

LETTER
▌1309
lAetteRr eusable TNF-Tagged Chiral Bis(oxazoline)–Copper Catalyst for Diels–
Alder Transformations
Chiral Catalyst Recovery and Reuse
Dorian Didier,a Emmanuelle Schulz*a,b
a
Equipe de Catalyse Moléculaire, Univ Paris-Sud, ICMMO, UMR 8182, Orsay 91405, France
b
CNRS, Orsay 91405, France
Fax +33(1)69154680; E-mail: emmanuelle.schulz@u-psud.fr
Received: 09.01.2012; Accepted after revision: 06.03.2012
implied the solubilization of the polymeric species under
Abstract: A chiral bis(oxazoline) ligand, substituted on the methy-
the cyclopropanation reaction conditions for a transfor-
lene bridge by a covalent link to an electron-deficient moiety (2,4,7-
mation in homogeneous phase and its heterogeneization
by recombination after reaction completion for an easy re-
trinitrofluoren-9-one, TNF), is a useful ligand associated to cop-
per(II) salts to promote enantioselective Diels–Alder reactions be-
tween N-acyloxazolidinones and cyclopentadiene. Owing to covery by filtration and subsequent reuse.
different solubility properties, the corresponding catalyst was pre-
We have previously described another heterogeneization
cipitated by pentane addition after reaction completion and was eas-
ily recovered by filtration. It was successfully reused in up to 20
successive catalytic cycles for the formation of the targeted prod-
ucts with no loss of either the activity or the enantioselectivity along
with the recycling.
procedure that involves the recovery of bis(oxazoline)-
based copper catalysts by the formation of charge-transfer
complexes (CTC), as noncovalent interactions between a
donor (an electron-rich arene such as anthracene) and a re-
ceiver [an electron-deficient 2,4,7-trinitrofluoren-9-one
(TNF), for instance]. As CTC present different solubility
properties according to the solvent, the efficient precipita-
tion of the catalytic species could occur at the end of the
reaction by the addition of an apolar solvent, and the re-
covery of the active chiral copper complex was performed
through simple precipitation.
Key words: asymmetric catalysis, charge transfer complexes, cop-
per, Diels–Alder reaction, catalyst recovery
Bis(oxazoline) ligands have been widely used, associated
to various metallic precursors, as efficient and selective
promoters for asymmetric catalysis.1 They are specifically
popular for numerous copper-catalyzed reactions leading
to targeted compounds in both high yield and selectivity.2
Many attempts were thus made towards designing effi-
cient procedures for the easy recovery and reuse of these
complexes in asymmetric transformations, to minimize
environmental and economic losses. These efforts have
been recently exhaustively reviewed and concern the co-
valent linking via the ligand structure on organic or inor-
ganic supports, but also the use of bis(oxazoline)-based
catalysts in biphasic conditions allowing for simple sepa-
ration.3 Furthermore, the immobilization of chiral cata-
lysts on solid supports via noncovalent interactions has
been considered since such a process may involve few
synthetic steps to modify the ligand approximately.4 For
instance, Hutchings and coworkers5 have prepared a cop-
per-exchanged zeolite Y that, in the presence of bis(oxa-
zolines), promoted the enantioselective aziridination of
alkenes within the supercages of the microporous materi-
als. Noncovalent interactions on organic supports have
also been reported, showing that bis(oxazolines) were ef-
ficiently immobilized through electrostatic intercalation
with nafion-based supports for cyclopropanation reac-
tions.6 More recently, García et al. published another
strategy based on the formation of a self-supported cop-
per-coordination polymer from a ditopic chiral ligand
bearing two aza-bis(oxazoline) moieties.7 This approach
O
O
N
N
O
1
O
O
N
N
2
O2N
O2N
O
NO2
O
O
O
O
N
N
3
SYNLETT 2012, 23, 1309–1314
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-1290918; Art ID: ST-2012-D0017-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 1 Structure of bis(oxazoline) ligands: indabox (1) and its an-
thracene (2) and TNF (3) based derivatives

1310
D. Didier, E. Schulz
LETTER
Bis(oxazoline) ligand 2 (Figure 1) was thus prepared and of recovering this asymmetric catalyst by formation and
in association to copper triflate [Cu(OTf)2], it promoted precipitation of CTC with anthracene. Furthermore, this
Diels–Alder reactions,8 displaying activities and enanti- type of chiral ligand attached to an electron-deficient moi-
oselectivities comparable to reported results that involved ety could conceivably be immobilized through reversible
analogous ligands derived from the parent compound 1 CTC interactions on a commercially available electron-
(Figure 1).9
rich solid support, such as polystyrene, for a direct recov-
ery by filtration, for instance.
The recycling procedure was performed by adding TNF at
the end of the first run to form the CTC that was precipi- Ligand 3 was synthesized in a few synthetic steps with an
tated by subsequent addition of pentane, recovered by fil- overall 28% yield (Scheme 1) from 2,5,7-trinitro-9-oxo-
tration of the products containing solution and reused up 9H-fluorene-4-carboxylic acid (4) that was obtained ac-
to 12 times without loss of either activity or selectivity.10 cording to a previously described procedure, starting from
Such a recovery procedure was more recently also proven diphenic acid in two steps.14 Intermediate formation of the
to be efficient to catalyze Henry reactions11 but also car- acyl chloride with thionyl chloride and subsequent addi-
bonyl-ene reactions and cyclopropanations.12 By cova- tion of the preformed alcoholate of 1,4-butanediol led to
lently immobilizing the acceptor moiety on a solid support the hydroxy ester with 65% yield.15 It was then trans-
(polystyrene or silica), charge-transfer interactions al- formed into the mesylate derivative 5 in 73% yield. Sepa-
lowed the recovery of bis(oxazoline) copper catalysts un- rately, diethyl 2-methylmalonimidate (6)16 was refluxed
der heterogeneous conditions.13
in the presence of (1R,2S)-aminoindanol to yield bis(oxa-
zoline) 7 that was immediately engaged in the next step
without further purification. Deprotonation of 7 with
LDA, followed by the addition of mesylate 5, provided li-
gand 3 in 60% yield as a red solid.
Having successfully described the switchable binding of a
ligand covalently attached to an electron-rich anthracene
moiety, we report here the synthesis of bis(oxazoline) li-
gand 3 (Figure 1) linked to an electron-poor arene moiety
such as TNF and the study of its use in copper-catalyzed Diels–Alder reactions between N-acyloxazolidinones 8 or
transformations. We aimed at investigating the possibility 10 and cyclopentadiene (Scheme 2) were used as test
NO2
COOH
EtO
OEt
NH2 NH ⋅2HCl
O2N
NO2
O
4
6
NH2
1. SOCl2, DCE
2. 1,4-butanediol, Et3N
18 h, r.t., 65%
3. Et3N, DMAP, MsCl
CH2Cl2, 12 h, r.t., 73%
2
OH
CH2Cl2
18 h, reflux
O
O
NO2
OMs
O
O
N
N
O2N
NO2
O
5
7
O2N
TMEDA, n-BuLi
i-Pr2NH, THF
24 h, r.t., 60%
NO2
O
O
O
O2N
O
O
N
N
3
Scheme 1 Synthesis of TNF-modified bis(oxazoline) 3
Synlett 2012, 23, 1309–1314
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Catalyst Recovery and Reuse
1311
transformations to study the performance of the new cata-
lytic system Cu(OTf)2–3. Substrate 8 was thus engaged in
a first catalytic run in dichloromethane at room tempera-
ture in the presence of 10 mol% Cu(OTf)2 and 11 mol%
ligand 3 (Table 1, run 1). Expected products 9a and 9b
were isolated in high yield (92%) with 78% ee for 9a as
major isomer and 76% de, values comparable to those ob-
tained with ligand 1 under the same conditions.12 Delight-
fully, the presence of the TNF group on the bis(oxazoline)
ligand did not led to a drop of both the activity and the se-
lectivity of the corresponding catalyst. At the end of this
first catalytic run, an equimolar amount of anthracene (10
mol%) was added to the reaction mixture. Pentane was
then poured into the solution, leading to the precipitation
of a red species that was filtered off, washed, and re-
engaged in another transformation.
Table 1 Diels–Alder Reaction between Cyclopentadiene and 8 in
the Presence of Cu(OTf)2–3 and Anthracenea
Run
Time
(h)
Conv.
(%)b
Yield of 9a + 9b ee of 9a
(%)c
(%)d
1
2
3
4
5
6
6
>95
>95
>95
>95
>95
>95
92
90
90
91
89
90
78 (2R)
78 (2R)
81 (2R)
80 (2R)
79 (2R)
79 (2R)
3
1.5
2
2
2
a Reaction conditions: 8 (0.5 mmol), cyclopentadiene (3.5 mmol),
Cu(OTf)2 (0.05 mmol), 3 (0.055 mmol), r.t., CH2Cl2, after the first run
addition of anthracene (0.055 mmol).
b Determined by 1H NMR spectroscopy.
c Isolated yield.
R
O
d Determined by HPLC analysis (Whelk column), the product config-
uration was determined by comparison with literature data.9b
O
N
O
(major)
catalytic run. Other recycling procedures involving pre-
cipitation by solvent changes have already been described
in the literature for the efficient recovery of bis(oxazo-
line)-based catalysts covalently attached to poly(ethylene-
glycol), for example.18 Cu(OTf)2–3 was then used and
recovered by simple precipitation to promote 14 succes-
sive catalytic runs at room temperature involving sub-
strate 8, affording at each cycle the endo products 9a in up
to 79% ee and isolated in continued high yield (up to 92%,
Table 2, runs 1–14). Performing the transformation at –10 °C
(Table 2, run 12) afforded 9a with a lower yield (83%) but
an enhanced ee of 84%. This could be optimized to 87%
ee (Table 2, run 14) when the reaction was conducted at
–30 °C, but it was accompanied by an important decrease
of the catalyst activity, since the expected product was
isolated in only 40% yield even after a prolonged reaction
time (44 h). At the 15th run, the recovered catalyst batch
was then engaged with substrate 10 at –50 °C. Running
the reaction at low temperature is indeed essential to in-
hibit the competitive noncatalyzed racemic transforma-
tion between both substrates that otherwise occurs in a
non-negligible extent. The expected products 11a and 11b
were satisfyingly obtained in high yield (84%) and with a
good ee value for the major endo product 11a (87%, Table
2, run 15). Even after 14 successive catalytic cycles, these
values perfectly match the one that were obtained for the
transformation of 10 under homogeneous conditions with
Cu(OTf)2–1.9a Five more runs were then performed fol-
lowing the same precipitation procedure, and results
showed a stable efficiency in terms of yield and enantiose-
lectivity, with an ee up to 89%, and stable de values (91%,
Table 2, runs 15–20).
9a R = Me
11a R = H
O
ligand
(11 mol%)
O
+
R
N
O
Cu(OTf)2
(10 mol%)
CH2Cl2
O
O
8
R = Me
10 R = H
N
R
O
(minor)
9b R = Me
11b R = H
Scheme 2 Diels–Alder reaction between cyclopentadiene and 3-but-
2-enoyloxazolidin-2-one (8) or 3-acryloyloxazolidin-2-one (10)
The 1H NMR analysis of the concentrated crude filtrate re-
vealed, however, that the larger part of the previously add-
ed anthracene was recovered along with the products.
Nevertheless, the red precipitated species was successful-
ly used in a second catalytic run (Table 1, run 2), affording
the same targeted compounds with a high yield (90%) and
with similar ee for 9a as the one obtained in the previous
cycle. It thus appeared that, in this case, no CTC forma-
tion with anthracene was necessary to allow the efficient
recovery of the catalytically active complex Cu(OTf)2–3.
This species was furthermore easily recovered for four ad-
ditional catalytic runs by precipitation on addition of pen-
tane and led to the formation of the major adduct 9a
without loss of ee (up to 81%) or yield (Table 1, runs 3–
6). During the entire procedure, the de remained unaffect-
ed, with a value about 76%. By optimizing the reaction
procedure, a complete conversion could be achieved in
two hours.17
From this first experiment, it seems obvious that
Cu(OTf)2–3 could be easily recovered by precipitation,
owing to its different solubility properties, in CH2Cl2 or in
pentane. The procedure was thus renewed by using solely
Cu(OTf)2–3 without addition of anthracene after the first
After these transformations, twenty Diels–Alder reactions
were thus consecutively carried out with the same catalyst
batch involving two different substrates 8 and 10. No loss
of activity or enantioselectivity was observed leading to
the targeted compounds with high yields and enantiose-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1309–1314

1312
D. Didier, E. Schulz
LETTER
lectivities. Due to its efficient recyclability, the formal avoiding the precipitation step and thus the mixture of dif-
catalyst-to-substrate ratio used for this enantioselective ferent solvents and allowing the use of unmodified, cheap
carbon–carbon bond formation is consequently quite low. supports towards their application in continuous flow re-
It is important to note that typically the use of such low actor. A test was thus performed by mixing Cu(OTf)2–3
catalyst loadings for these reaction types does not lead to with polystyrene beads (200–400 mesh, 1:8 w/w) in di-
reliable results in terms of both yield and enantioselectiv- chloromethane for 12 hours. The supernatant was then fil-
ity values.
tered out and both the recovered polystyrene and the
resulting solution were submitted to a reaction at room
temperature between cyclopentadiene and N-acyloxa-
zolidinone 8. Unfortunately, however, no reaction oc-
curred in the presence of the polystyrenyl support,
indicating that the catalyst had not been immobilized at its
surface under these conditions. On the other hand, a com-
plete conversion in the Diels–Alder cycloadducts 9 (80%
ee for major endo-9a) was obtained with the supernatant
solution in six hours at room temperature proving the
presence of a high catalyst loading in the solution. CTC
interactions between the ligand and the polymeric insolu-
ble support were therefore probably not strong enough to
allow its immobilization at the near surface for an effi-
cient anchoring and subsequent recycling. As a perspec-
tive, anthracene-modified polystyrene should be prepared
and tested as a support with probably higher affinity than
the unmodified one to form CTC.
Table 2 Diels–Alder Reaction between Cyclopentadiene and 8 or 10
in the Presence of Cu(OTf)2–3a
Run
Substrate Time
(h)
Temp
(°C)
Conv.
(%)b
Yield ee
(%)c
(%)d
1
2
8
1.5
2.5
2
r.t.
77
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
88
72
89
90
87
91
89
87
90
90
91
89
83
92
40
84
88
86
87
92
90
73 (2R)
76 (2R)
79 (2R)
79 (2R)
77 (2R)
78 (2R)
77 (2R)
78 (2R)
79 (2R)
79 (2R)
79 (2R)
84 (2R)
79 (2R)
87 (2R)
87 (2R)
87 (2R)
89 (2R)
88 (2R)
88 (2R)
85 (2R)
8
r.t.
3
8
r.t.
4
8
2
r.t.
5
8
2
r.t.
6
8
r.t.
7
8
1.5
1.5
1.5
1.5
1.5
r.t.
8
8
r.t.
A new bis(oxazoline) ligand modified by an electron-de-
ficient moiety through a covalent link was thus prepared
and proved to promote efficiently the enantioselective
Diels–Alder reaction in the presence of copper(II) salts. A
charge-transfer complex was formed by addition of an-
thracene as electron-rich arene aiming at recovering the
chiral organometallic complex through its precipitation in
pentane. We have demonstrated that under these condi-
tions, the charge-transfer complex is dissociated, and an-
thracene is removed with the products solution due to its
high solubility in apolar solvents. Nevertheless, catalyst
Cu(OTf)2–3 could be entirely recovered by a simple pre-
cipitation procedure and reused in subsequent catalytic
runs showing its high stability for transforming two differ-
ent substrates and producing the corresponding com-
pounds in high yields and selectivities. Constant values
could indeed be recorded all along 20 runs increasing con-
siderably the TON of the catalyst. Such a methodology
combines efficiently the advantages of both homogeneous
catalysis, for undemanding mass transfer and short reac-
tion time, together with heterogeneous catalysis for a sim-
ple recovery of the active catalyst by filtration. To the best
of our knowledge, such a steady catalyst reuse has rarely
been described in the literature for enantioselective C–C
bond formation.
9
8
r.t.
10
11
12
13
14
15
16
17
18
19
20
8
r.t.
8
r.t.
8
18
1.5
44
–10
r.t.
8
>95
48
8
–30
–50
–50
–50
–50
–50
–50
10
10
10
10
10
10
3
93
1.5
1.5
1.5
1.5
1.5
>95
>95
>95
>95
>95
a Reaction conditions: 8 or 10 (0.5 mmol), cyclopentadiene (3.5
mmol), Cu(OTf)2 (0.05 mmol), 3 (0.055 mmol), CH2Cl2.
b Determined by 1H NMR spectroscopy.
c Isolated yield, eq. 1 9a + 9b, eq. 2 11a + 11b.
d For substrate 8 and 10 the ee of 9a and 11a, respectively, were de-
termined by HPLC analysis (Whelk or OD-H column), the product
configurations were determined by comparison with literature data.9
We next attempted an analogous procedure aiming at per-
forming direct heterogeneous catalysis on a polymeric
support modified by a chiral catalyst through CTC inter-
actions. Complex Cu(OTf)2–3 was a good candidate to
test this concept, possessing an electron-deficient moiety
that could led to a reversible immobilization on an elec-
tron-rich support such as commercially available cross-
linked polystyrene. This process could be of high interest,
All reactions were carried out under argon in oven-dried glassware
with magnetic stirring. Solvents were distilled before use from
CaH2. Cyclopentadiene was distilled by cracking dicyclopentadiene
1
over CaH2. H NMR spectra were recorded on a Bruker AM 250
(250 MHz), AM 300 (300 MHz), or AM 360 (360 MHz) as CDCl3
solutions, and data are reported in ppm relative to the solvent (7.27
ppm). 13C NMR spectra were recorded on a Bruker AM 250 (62.5
MHz) or AM 360 (90 MHz) as CDCl3 solutions, and data are report-
ed in ppm relative to the solvent (77.0 ppm). Optical rotations were
Synlett 2012, 23, 1309–1314
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Catalyst Recovery and Reuse
1313
measured as solutions in 10 cm cells using a Perkin-Elmer 241 po-
larimeter. Melting points were measured with a Reichert instru-
ment. Mass spectra were recorded on a Finnigan MAT 95 S
spectrometer. HPLC analyses were carried out on a Perkin-Elmer
chromatograph equipped with a diode array UV detector using an
OD-H or a Whelk column. IR spectra were recorded as KBr disks
using a Perkin-Elmer spectrometer. Elemental analyses were per-
formed by the C.N.R.S. Service of Microanalyses in Gif-sur-Yvette
(France). Substrates 8 and 10 were prepared as already described.10
Poly(styrene-co-divinylbenzene) (2% cross-linked, 200–400 mesh)
was purchased from Aldrich.
(3aR,3a′R,8aS,8a′S)-2,2′-{Ethane-1,1-diyl)bis(8,8a-dihydro-
3aH-indeno[1,2-d]oxazole} (7)
(1R,2S)-Aminoindanol (609 mg, 4.08 mmol) was added (as solid) to
a suspension of methylimidate 6 (500 mg, 2.04 mmol) in CH2Cl2
(40 mL). The mixture was heated to reflux for 18 h. The resulting
yellow solution was washed with H2O, and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried over MgSO4 and then concentrated to give 643 mg of the
crude product. For the next synthetic step, the crude mixture could
be directly used without further purification. For analysis, the prod-
uct was recrystallized in i-PrOH to give white needles (323 mg,
46% yield); mp 157 °C. 1H NMR (360 MHz, CDCl3): δ = 1.40 (d, 3
H, J = 7.1 Hz), 3.06 (dd, 2 H, J1 = 17.9 Hz, J2 = 9.1 Hz), 3.31–3.38
(m, 2 H), 3.46 (q, 1 H, J = 7.1 Hz), 5.29–5.31 (m, 2 H), 5.54 (d, 2
H, J = 7.7 Hz), 7.26–7.28 (m, 6 H), 7.48–7.50 (m, 2 H). 13C NMR
(90 MHz, CDCl3): δ = 14.7, 34.1, 39.6, 76.5, 83.3, 125.1, 125.5,
127.4, 128.4, 139.6, 141.7, 165.9. LRMS (ESI+): m/z = 344.2 [M+].
[α]D +245.5 (c 1, CHCl3).
General Procedure for the Catalytic Diels–Alder Reaction
Ligand 3 (42 mg, 0.055 mmol) dissolved in CH2Cl2 (1 mL) was add-
ed to Cu(OTf)2 (18 mg, 0.05 mmol), and the blue-green solution
was stirred for 1 h at r.t. Then, N-acyloxazolidinone (78 mg for 8 or
71 mg for 10, 0.5 mmol) was added to the previous solution, and the
homogeneous mixture was then stirred for 10 additional min at r.t.
for 8 or –50 °C for 10. Cyclopentadiene (260 μL, 3.5 mmol) was
then introduced dropwise, and the solution was further stirred at the
same temperature. [When the precipitation was done in the presence
of anthracene (9 mg, 0.05 mmol), it was added to the green mixture
and further stirred for additional 30 min]. The catalyst was precipi-
tated by addition of pentane (10 mL), recovered by filtration, and
dried. It was then reused in a renewed catalytic run after solubiliza-
tion in CH2Cl2 (1 mL). The product-containing solution was evapo-
rated under vacuum, the residue was purified by preparative TLC
(toluene–EtOAc = 4:1), and analyzed by HPLC for the determina-
tion of the ee.
5,5-Bis{(3aR,8aS)-8,8a-dihydro-3aH-Indeno[1,2-d]oxazol-2-
yl}hexyl 2,5,7-Trinitro-9-oxo-9H-fluorene-4-carboxylate (3)
In a dried Schlenk tube, TMEDA (174 μL, 1.17 mmol) and DIPA
(90 μL, 0.64 mmol) were mixed in THF (2 mL), and the solution
was cooled to –20 °C. The LDA solution was then obtained by a
slow addition of n-BuLi (804 μL, 1.6 M in hexane, 1.29 mmol) dur-
ing 30 min at –20 °C. The uncolored solution was then allowed to
stir at r.t. After 1 h, the solution of LDA was transferred in a second
Schlenk tube containing 7 (200 mg, 0.59 mmol) in THF (10 mL),
and the mixture was stirred at r.t. during 2 h. Compound 5 (420 mg,
0.83 mmol) in THF (4 mL) was then added to the previous solution,
and the mixture was stirred during 24 h. Then, H2O was added to the
solution, and the aqueous layer was extracted with EtOAc (10 × 15
mL). The combined organic layers were washed with a sat. solution
of NH4Cl, dried over MgSO4, and then concentrated. The crude
product was purified on silica gel (cyclohexane–EtOAc = 1:1) to af-
ford the pure product as a red-brown solid (267 mg, 60% yield).
4-(Methylsulfonyloxy)butyl 2,5,7-Trinitro-9-oxo-9H-fluorene-
4-carboxylate (5)
To a solution of 2,5,7-trinitro-9-oxo-9H-fluorene-4-carboxylic acid
(4, 2.68 g, 7.47 mmol) in DCE (15 mL) was added SOCl2 (8.13 mL,
112.00 mmol) with two drops of DMF, and the mixture was heated
to reflux during 16 h. Then solvent was removed under vacuum. In
a second Schlenk flask, 1,4-butanediol (3.32 mL, 37.33 mmol) was
mixed with Et3N (2.18 mL, 15.68 mmol) in DCE (33 mL), and the
solution was added dropwise to the first Schlenk flask at 0 °C. Then,
the dark solution was stirred at r.t. for 18 h. A solution of HCl (10
mL, 1.0 M) was added, and the aqueous layer was extracted with
CH2Cl2 (2 × 15 mL). Then, the combined organic layers were
washed with brine, dried over MgSO4, and concentrated to give
3.66 g of the crude hydroxy ester product. It was purified by chro-
matography on silica gel (CH2Cl2–EtOAc = 90:10) to yield the ex-
pected compound (2.09 g, 65%) as a yellow solid.15
1
Rf = 0.11 (cyclohexane–EtOAc = 1:1); mp 103–106 °C. H NMR
(250 MHz, CDCl3): δ = 1.29 (br, s, 3 H), 1.94–2.06 (m, 4 H), 3.28–
3.33 (m, 2 H), 3.38–3.51 (m, 4 H), 4.39 (t, 2 H, J = 5.6 Hz), 5.45 (td,
2 H, J1 = 7.8 Hz, J2 = 2.0 Hz), 5.57 (d, 2 H, J = 7.3 Hz), 7.30–7.41
(m, 6 H), 7.55–7.58 (m, 2 H), 8.02 (dd, 2 H, J1 = 7.5 Hz, J2 = 1.5
Hz), 8.60 (d, 1 H, J = 2.3 Hz), 8.73 (d, 1 H, J = 2.5 Hz). 13C NMR
(90 MHz, CDCl3): δ = 24.2, 24.7, 25.7, 39.4, 47.2, 66.0, 69.2, 76.6,
84.2, 121.1, 125.2, 125.4, 125.6, 127.6, 128.1, 128.7, 129.6, 130.0,
130.9, 137.1, 137.3, 139.2, 139.4, 141.0, 145.1, 146.2, 148.7, 164.9,
+
166.0, 187.0. HRMS (ESI+): m/z calcd (%) for C40H38ClN6O12
:
829.2236 [M + NH4Cl + H2O + H+]; found: 829.1782 (100); m/z
calcd for C40H32N5O11+: 758.2098 [M + H+]; found: 758.2195 (11).
[α]D33 +102 (c 0.5, CHCl3).
To a solution of this intermediate hydroxy ester (692 mg, 1.60
mmol) in CH2Cl2 (20 mL) were added successively Et3N (447 μL,
3.21 mmol) and DMAP (29 mg, 0.24 mmol) at 0 °C. After 10 min
stirring at this temperature, mesyl chloride (310 μL, 4.01 mmol)
was added at 0 °C, and the solution was allowed to stir at r.t. for 12
h. A 0.1 M solution of HCl in H2O (15 mL) was then added, and the
aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The com-
bined organic layers were successively washed with a sat. solution
of NaHCO3 and brine, dried over MgSO4, and concentrated to give
the crude product. Product 5 was purified on silica gel (CH2Cl2–
EtOAc = 95:5). The pure product was obtained as a yellow solid
(598 mg, 73% yield). Rf = 0.19 (CH2Cl2–EtOAc = 95:5); mp
198 °C. 1H NMR (360 MHz, CDCl3): δ = 2.01 (m, 4 H), 3.06 (s, 3
H), 4.35 (t, 2 H, J = 5.7 Hz), 4.47 (t, 2 H, J = 5.7 Hz), 8.78 (m, 1 H),
8.87 (m, 2 H), 8.97 (m, 1 H). 13C NMR (90 MHz, CDCl3): δ = 24.7,
25.8, 37.4, 66.6, 69.0, 121.8, 122.5, 125.3, 130.5, 132.3, 137.9,
138.9, 139.8, 143.6, 146.6, 149.4, 150.0, 164.5, 185.0. LRMS
(ESI+): m/z = 532.16 [M + Na+]. HRMS (ESI+): m/z cald for
C19H15N3O12NaS+: 532.0274; found: 532.0254. IR (KBr): 1717,
1542, 1341. Anal. Calcd (%) for C19H15N3O12S: C, 44.80; H, 2.97;
N, 8.25. Found: C, 44.57; H, 3.11; N, 7.86.
3-{(1R,2R,3S,4S)-3-methylbicyclo[2.2.1]hept-5-ene-2-carbon-
yl}oxazolidin-2-one (9a)
Thanks to a double elution (toluene–EtOAc = 4:1), exo (9a, Rf =
0.56) and endo (9b, Rf = 0.56) products were separated for 1H NMR
1
analysis. H NMR (360 MHz, CDCl3): δ (exo) = 0.88 (d, 3 H, J =
6.5 Hz), 1.23 (d, 1 H, J = 5.0 Hz), 1.40 (d, 1 H, J = 8.4 Hz), 1.68 (d,
1 H, J = 8.4 Hz), 2.68–2.75 (m, 1 H), 2.76 (br s, 1 H), 2.89–2.92 (m,
1 H), 4.02–4.08 (m, 2 H), 4.42 (t, 2 H, J = 8.1 Hz), 6.18 (dd, 1 H,
J = 5.8, 2.5 Hz), 6.34 (dd, 1 H, J = 5.8, 2.9 Hz); δ (endo) = 1.15 (d,
3 H, J = 6.8 Hz), 1.47–1.50 (m, 1 H), 1.72 (d, 1 H, J = 8.6 Hz), 2.10–
2.14 (m, 1 H), 2.55 (br s, 1 H), 3.30 (br s, 1 H), 3.55–3.57 (m, 1 H),
3.91–4.08 (m, 2 H), 4.42 (t, 2 H, J = 8.1 Hz), 5.81 (dd, 1 H, J = 5.8,
2.9 Hz), 6.39 (dd, 1 H, J = 5.8, 3.2 Hz). 13C NMR (62.5 MHz,
CDCl3): δ (exo) = 19.1, 37.7, 43.3, 46.9, 47.8, 50.9, 53.6, 62.0,
135.7, 137.1, 148.8, 175.8; δ (endo) = 20.6, 36.7, 43.3, 47.4, 47.7,
49.8, 51.6, 62.1, 131.2, 139.9, 153.6, 174.6. HRMS (ESI+): m/z
calcd for C12H15NO3Na+: 244.0944; found: 244.0941. HPLC:
Whelk (hexane–EtOH = 99:1, 0.8 mL min–1, 205 nm) tR (2S) =
35.88 min; tR (2R, major) = 38.50 min.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1309–1314

1314
D. Didier, E. Schulz
LETTER
3-{(1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbonyl}oxazolidin-
2-one (11a)
(5) Langham, C.; Piaggio, P.; Bethell, D.; Lee, D. F.; McMorn,
P.; Bulman Page, P. C.; Willock, D. J.; Sly, C.; Hancock, F.
E.; King, F.; Hutchings, G. J. Chem. Commun. 1998, 1601.
(6) Fraile, J. M.; García, J. I.; Mayoral, J. A.; Tarnai, T.; Harmer,
M. A. J. Catal. 1999, 186, 214.
Inseparable mixture of 11a and 11b, with a >95:5 proportion of 11a.
1H NMR (250 MHz, CDCl3): δ = 1.38–1.50 (m, 3 H), 1.89–1.99 (m,
1 H), 2.93 (br s, 1 H), 3.30 (br s, 1 H), 3.92–4.06 (m, 3 H), 4.39 (t,
2 H, J = 8.7 Hz), 5.86 (dd, 1 H, J = 5.5, 3.3 Hz), 6.24 (dd, 1 H, J =
5.5, 2.6 Hz). 13C NMR (62.5 MHz, CDCl3): δ = 29.5, 42.8, 42.9,
43.2, 46.4, 50.2, 61.9, 131.6, 138.0, 153.4, 174.7. HRMS (ESI+):
m/z calcd for C11H13NO3Na+: 230.0788; found: 230.0790. HPLC:
OD-H (hexane–i-PrOH = 98:2, 0.8 mL min–1, 205 nm): tR (2S) =
65.70 min; tR (2R, major) = 72.87 min.
(7) García, J. I.; Lopez-Sanchez, B.; Mayoral, J. A. Org. Lett.
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(8) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc.
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Acknowledgment
CNRS, MESR and the program ‘Chimie et Développement
Durables’ du CNRS are acknowledged for financial support.
(10) (a) Chollet, G.; Rodriguez, F.; Schulz, E. Org. Lett. 2006, 8,
539. (b) Chollet, G.; Guillerez, M.-G.; Schulz, E. Chem. Eur.
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(11) Didier, D.; Magnier-Bouvier, C.; Schulz, E. Adv. Synth.
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References and Notes
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(13) (a) Chollet, G.; Didier, D.; Schulz, E. Catal. Commun. 2010,
11, 351. (b) See also ref. 11.
(14) Sulzberg, T.; Cotter, R. J. J. Org. Chem. 1970, 35, 2762.
(15) Chuzel, O.; Magnier-Bouvier, C.; Schulz, E. Tetrahedron:
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(17) This simple precipitation procedure was already attempted
for a potential recycling of Cu(OTf)–2 (see ref. 10a).
Under analogous conditions, this catalyst could indeed be
recovered by pentane precipitation (in this case without the
need for TNF addition) but it maintained its activity and
selectivity for only three reuses, the 4th recycling leading to
a major loss of both the conversion and the enantio-
selectivity.
(18) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Pitillo, M. J. Org. Chem. 2001, 66, 3160. (b) Benaglia, M.;
Cinquini, M.; Cozzi, F.; Celentano, G. Org. Biomol. Chem.
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(b) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109,
2505.
(2) For some very recent examples, see: (a) Livieri, A.;
Boiocchi, M.; Desimoni, G.; Faita, G. Chem. Eur. J. 2011,
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(d) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem.
Soc. 2011, 133, 13778. (e) Harvey, J. S.; Simonovich, S. P.;
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(3) (a) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467.
(b) Fraile, J. M.; García, J. I.; Mayoral, J. A. Coord. Chem.
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(4) Fraile, J. M.; García, J. I.; Mayoral, J. A. Chem. Rev. 2009,
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Synlett 2012, 23, 1309–1314
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