Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones with DIFLUORPHOS and SYNPHOS analogues

Article abstract of DOI:10.1021/jo201187c

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,β-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF₃-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.

Full text of DOI:10.1021/jo201187c

ARTICLE
pubs.acs.org/joc
Rh-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to r,
β-Unsaturated Ketones with DIFLUORPHOS and SYNPHOS Analogues
Farouk Berhal, Zi Wu, Jean-Pierre Genet, Tahar Ayad,* and Virginie Ratovelomanana-Vidal*
Chimie ParisTech, Laboratoire Charles Friedel, (LCF), CNRS, UMR 7223, 11 rue P. et M. Curie, 75231 Paris cedex 05, France
S Supporting Information
b
ABSTRACT: Applications of electron-deficient DIFLUOR-
PHOS and SYNPHOS analogues in the rhodium-catalyzed
asymmetric conjugate addition of boronic acids to R,β-unsatu-
rated ketones afford the 1,4-addition adducts in yields up to 92%
and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-
addition of arylboronic acids to nonsubstituted maleimide
substrates using the (R)-3,5-diCF3-SYNPHOS ligand is also
reported. This protocol provides access to various enantioen-
riched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be
upgraded up to 99% ee, after a single crystallization.
’ INTRODUCTION
described the Pd-catalyzed asymmetric 1,4-addition of 3-methox-
yphenylboronic acid with N-phenyl and N-methyl substituted
maleimide derivatives using CHIRAPHOS as ligand, providing
the desired 1,4-addition products in 40% and 90% ee, respectively.
Interestingly, these authors have also demonstrated that the N-H
maleimide compound, which is known to be an inactive substrate
for this reaction, also reacted under the above conditions to give the
corresponding 1,4-adduct in high enantiomeric excess up to 90%.
Shintani and Hayashi et al.4g have reported 83% and 85% ee for the
reaction of 1-(2-tert-butylphenyl)maleimide substrate with phenyl-
boronic acid in the presence of 5 mol % of Rh catalysts bearing
(S)-BINAP6 and (S)-phosphoramidite,9 respectively. Recently, it
has been shown by several groups including ourselves10,11 that the
catalytic activity for Rh-promoted 1,4-addition of arylboronic acids
at room temperature could be significantly enhanced by using
electron-deficient ligands. In 2009, Sakai et al.10 reported a highly
active Rh/MeO-F12BIPHEP catalyst for the asymmetric 1,4-addition
of arylboronic acids to R,β-unsaturated ketone with excellent
enantioselectivities up to 99%. In this context, the introduction
of electron-withdrawing substituents on SYNPHOS12 ligand
enabled us to observe a significant electronic effect of (R)-3,5-
diCF3-SYNPHOS,11 which plays a crucial role in the rhodium-
mediated conjugate addition of arylboronic acids to a range of
cyclic and acyclic enones.11 In our ongoing program toward
the design and applications of atropisomeric ligands,11ꢀ15 we
report herein catalytic enantioselective conjugate addition of
arylboronic acids using electron-deficient diphosphines such
as DIFLUORPHOS L1,12a,15 (R)-4-CF3-SYNPHOS L2, (R)-
3,4,5-triF-SYNPHOS L3, and (R)-3,5-diCF3-SYNPHOS L4
at room temperature and a rhodium-catalyzed enantioselec-
tive conjugate addition of a range of arylboronic acids to
The transition-metal-catalyzed 1,4-addition of organometallic
reagents to activated alkenes is one of the most powerful processes
for CꢀC bond formation.1 In particular, the Rh-catalyzed asym-
metric conjugate addition of organoboron reagents has received a
lot of attention since the seminal breakthrough reported by Hayashi,
Miyaura et al.2 in 1998. Consequently, during the past two decades,
a plethora of highly efficient catalytic systems has been reported to
give chiral Michael 1,4-products with outstanding high level of
selectivity (>95% ee) for a wide- range of activated alkenes including
R,β-unsaturated ketones, esters, amides, phosphonates, and nitro-
alkenes.3 However, despite significant recent advances in this area,
there are still some challenging substrates for this reaction including
nonsubstituted maleimide derivatives. In this context, only few
efficient catalytic systems have been reported for asymmetric 1,4-
addition of boronic acid reagents to maleimides,4 despite the fact
that the corresponding 3-substituted succinimide units can be found
in several natural products and marketed drug molecules.5 Among
them, the rhodium complexes coordinated with chiral dienes and
phosphine-olefin ligands described by Hayashi et al.,4aꢀc,f Carnell
et al,.4h and Gr€utzmacher et al.4d represent, to date, the most active
catalyst systems for this particular reaction, resulting in high to
excellent selectivity ranging from 80% to 99% ee. In contrast to
the efficient enantioselective Rh-catalyzed synthesis of 1,4-adducts
bearing a quaternary stereocenter,4c Hayashi et al. have
clearly demonstrated that atropisomeric ligands4a such as BINAP,6
SEGPHOS,7 P-PHOS,8 and phosphoramidite9 turned out to be not
suitable for the rhodium-promoted conjugate addition of nonsub-
stituted challenging maleimide derivatives, since the corresponding
3-substituted succinimides were obtained in low to moderate ee in
the range of 21ꢀ58%. Surprisingly, to the best of our knowledge, no
improvement in terms of enantioselectivity based on the use of
atropisomeric ligands has been reported to date for this transforma-
tion. Two exceptions should be noted. In 2007, Miyaura et al.4e
Received: June 8, 2011
Published: June 29, 2011
r
2011 American Chemical Society
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|

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Table 1. Rh-Catalyzed Conjugate Addition of Phenylboronic
Acid to r,β-Unsaturated Ketones with Ligands L1ꢀL4
considered cyclic substrates (entries 2ꢀ4, 6ꢀ8, 10ꢀ12, 14ꢀ16,
41ꢀ95% yield) with excellent enantioselectivities up to 99% for
cyclohexenone 1a (entries 2ꢀ4), cyclopentenone 1b (entries
6ꢀ8, 88ꢀ97% ee), and cycloheptenone 1c (entries 10ꢀ12,
91ꢀ99% ee). A similar trend was observed for 5,6-dihydro-2H-
pyran-2-one 1d and 2(5H)-furanone 1e (entries 14ꢀ16, 18ꢀ20,
77ꢀ97% ee). Acyclic alkenones 1f and 1g afforded the corre-
sponding 1,4-adducts 3f and 3g with good yields (entries 21ꢀ28,
57ꢀ92% except for entry 27) and high enantioselectivities in the
range of 88ꢀ99% with all of the examined ligands L1ꢀL4.
In this context, (R)-3,5-diCF3-SYNPHOS L4 was selected for
the next experiments. Extending the rhodium(I)/(R)-3,5-diCF3-
SYNPHOS-catalyzed addition to a variety of boronic acids and
cyclohexenone 1a demonstrated excellent selectivities with either
with the electron-rich 4-MeC6H4, 3,5-diMeC6H3, 4-MeOC6H4,
and 3-MeOC6H4 boronic acids (Table 2, entries 1ꢀ4, up to
99% ee) or the electron-poor 4-BrC6H4 and 3-ClC6H4 boronic
acids (Table 2, entries 5, 6, up to 99% ee). A high selectivity up to
93% was also obtained with the hindered o-tolyl and naphthyl
boronic acids (entries 7, 8).
a After flash column chromatography on silica gel. b Determined by
chiral stationary phase HPLC analysis. c Reaction carried out at 30 °C.
nonsubstituted N-methyl maleimide substrate using (R)-3,
5-diCF3-SYNPHOS L4.
’ RESULTS AND DISCUSSION
We next turned our attention to the Rh-catalyzed asymmetric
1,4-addition of arylboronic acids to challenging R,β-unsaturated
monosubtituted maleimides using (R)-3,5-diCF3-SYNPHOS
L4. To establish the optimum reaction conditions, we prelimi-
narily studied the 1,4-addition of phenylboronic acid 2a to
various N-substituted maleimide substrates 4aꢀe, in the pre-
sence of 3 mol % of [Rh(C2H4)2Cl2]2/(R)-3,5-diCF3-SYNPHOS
catalyst. Several parameters such as metal precursor, solvent,
base, temperature, reaction time, and catalyst loading were
examined, and some representative results of these experiences
are summarized in Table 3. We found that the nature of the
substituent on the N-atom of the maleimide had a dramatic
impact on the stereochemical outcome of the reaction (Table 3,
entries 1ꢀ5). Whereas almost no reaction occurred with the
unprotected maleimide 4a, all other substrates 4bꢀe tested gave
full conversions but different selectivities ranging from 48% to
88% ee for the N-methyl derivative 4e. Other rhodium precursors
We first examined the catalytic properties of (R)-DIFLUOR-
PHOS L1, (R)-p-CF3-SYNPHOS L2, (R)-3,4,5-triF-SYNPHOS
L3, and (R)-3,5-diCF3-SYNPHOS L4 in the Rh-catalyzed asym-
metric 1,4-addition of phenylboronic acid to R,β-unsaturated
ketones at room temperature (Table 1). The reaction was per-
formed using 1.5 mol % of the corresponding rhodium com-
plexes in the presence of KOH in toluene/H2O (9:1) at 20 °C for
18 h. As shown in Table 1, high enantioselectivities ranging from
77% to 99% were obtained for the reaction between phenyl-
boronic acid 2a and R,β-unsaturated cyclic ketones 1aꢀ1e using
ligands L1ꢀL4. Although (R)-DIFLUORPHOS L1 led to excel-
lent enantiofacial discrimination up to 99%, moderate to good
yields in a range of 23ꢀ70% were reached at room temperature
(entries 5, 9, 13, 17, 21). Significant better yields were obtained
using, respectively, (R)-p-CF3-SYNPHOS L2, (R)-3,4,5-triF-
SYNPHOS L3, and (R)-3,5-diCF3-SYNPHOS L4 for all the
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Table 2. Rhodium(I)/(R)-3,5-diCF3-SYNPHOS-Catalyzed
Addition of Arylboronic Acids 2 to Cyclohexenone 1a
Table 3. Optimization of the Rh-Catalyzed Asymmetric 1,4-
Addition of Phenylboronic Acid 2a to Various Maleimides 4a
entry
Ar of boronic acid
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
4-MeC6H4
3,5-diMeC6H3
4-MeOC6H4
3-MeOC6H4
4-BrC6H4
90
90
84
50
81
82
86
81
99
99
99
96
99
99
93
90
3-ClC6H4
2-MeC6H4
1-naphthyl
a After flash column chromatography on silica gel. b Determined by
chiral stationary phase HPLC analysis.
with the potential for use as the catalyst in the reaction were also
screened. However, a significant decrease in the catalytic perfor-
mance was observed when the reaction was carried out with
[RhcodCl]2, [RhcodBr]2, and [Rh(C2H4)2acac] (see Table S1 in
Supporting Information). Further studies showed that this
reaction was strongly solvent-dependent. Nonpolar solvents gave
higher catalytic activity (Table 3, entries 6ꢀ9) than polar solvents
(Table 3, entries 10ꢀ11), the most efficient one being toluene/
H2O, which allowed the isolation of the 3-substituted succini-
mide 4e with an enantiomeric excess of 89% (Table 3, entry 6).
Additionally, we found that KOH was the most suitable base for
this reaction, giving rise to the desired product in 89% ee with
complete conversion. Inferior results in terms of both conversion
and selectivity were obtained when other organic or inorganic
bases were used (see Table S2 in Supporting Information).
Decreasing the temperature of the reaction from 50 to 30 °C
led to a substantial improvement in the selectivity with 93% ee,
whereas running the reaction at 15 °C did not further improve
the enantioselectivity (Table 3, compare entry 6 vs 12 and 13).
Interestingly, the reaction proceeded well even at a lower
catalyst loading, although a slight decrease of the selectivity
was observed (Table 3, entries 15, 16). Through these screen-
ings, the best reaction conditions were therefore set as the
following: 3 mol % of [Rh(C2H4)2Cl]2/L4 as catalyst, to-
luene/H2O (9:1) as solvent, in the presence of 0.5 equiv of
KOH as base, at 30 °C for 3 h.
a Reaction conditions (unless otherwise specified): 0.3 mmol of 4 with
2 equiv of 2a, 6 mol % of catalyst. b Determined by 1H NMR of crude
product. c Determined by chiral stationary phase-supercritical fluid
chromatography (CSP-SFC). Absolute configuration was determined
to be R by comparison of the specific rotation with reported data. d 4 mol %
of catalyst. e 2 mol % of catalyst.
Under the optimized reaction conditions, we then investigated
the scope of the Rh/(R)-3,5-diCF3-SYNPHOS catalyzed asym-
metric 1,4-addition of various arylboronic acids 2aꢀn to N-
methylmaleimide substrate 4e. As highlighted in Table 4, the
reaction proceeded well in all cases, giving the desired products in
high yields and good enantioselectivities (Table 4, entries 1ꢀ14,
75ꢀ90% yields, 80ꢀ93% ee). It appears from data of Table 4 that
the position and electronic nature of the substituents on the
aromatic ring of the arylboronic acid 2 significantly affect the
selectivity of the reaction. Reaction conducted with arylboronic
acids 2bꢀg bearing electron-withdrawing substituents resulted
in the formation of the desired products 5fꢀk in lower catalytic
efficiency to those obtained with phenylboronic acid 2a (Table 4,
compare entries 1 vs 2ꢀ7, 75ꢀ82% yields, 80ꢀ89% ee).
The only exception was the enantioselectivity of 92% obtained
with boronic acid 2h, bearing the trifluoromethyl group, which is
known to be a long-range electron-withdrawing substituent16
(Table 4, entry 8). In contrast, reaction performed with aryl-
boronic acids 2iꢀn having electron-donating groups provide the
corresponding R-substituted succinimides 5mꢀr with compar-
able or slightly lower results in terms of both yield and
selectivity compared with those obtained with phenylboronic
acid 2a (Table 4, compare entries 1 vs 9ꢀ14, 80ꢀ90% yields,
90ꢀ93% ee). Finally, we were pleased to find that the
enantiomeric excesses of all the 1,4-addition products 5eꢀr
could be easily upgraded up to 93ꢀ99%, after a single crystal-
lization, as outlined in Table 4.
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Table 4. Scope of the Asymmetric 1,4-Addition Reaction of Arylboronic Acids to Maleimide 4ea
a Reaction conditions (unless otherwise specified): 0.3 mmol of 4e with 2 equiv of 2, 3 mol % of catalyst. b After flash column chromatography on
silica gel. c Determined by chiral stationary phase-supercritical fluid chromatography (CSP-SFC). Absolute configuration was determined to be R by
comparison of the specific rotation with reported data. d Numbers in parentheses indicate the ee values after a single crystallization. e Reaction run in
dioxane/H2O (9:1).
’ CONCLUSION
catalyzed asymmetric 1,4-addition of arylboronic acids to chal-
lenging maleimide substrates. A salient feature of our catalytic
system relies on the fact that the reaction could be performed at
30 °C for 3 h, affording various synthetically and biologically
important chiral 3-substituted succinimide derivatives in high
yields and excellent enantiomeric excesses up to >99%, after
a single crystallization. Furthermore, it is worth noting that
In summary, this study demonstrates that electron-deficient
ligands DIFLUORPHOS and SYNPHOS derivatives can be used
in the rhodium-catalyzed conjugate addition of R,β-unsaturated
ketones at room temperature with high yields and ee’s up to 99%.
We have successfully developed a Rh/(R)-3,5-diCF3-SYNPHOS
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these results are the best ones reported so far in the literature
for this particular class of substrates with atropisomeric dipho-
sphine ligands.
163.0 (d), 139.2 (d), 130.8 (d), 123.0 (d), 115.0 (d), 114.7 (d), 45.5,
36.8, 25.3. [R]25D = ꢀ57.1 (c 0.98; CHCl3) ee = 89% (ee = 99%, 70%
yield after a single crystallization in absolute EtOH). CSP-SFC: Chir-
alcel AD-H column, P = 150 bar, scCO2/iPrOH 94:6, flow 4 mL/min,
λ = 215 nm, tR [(R)-enantiomer] = 3.52 mn (major), tR [(S)-enantiomer] =
4.10 mn (minor). Mp = 76 °C. HRMS (EI): m/z calcd for C11H10FNO2-
Na (M+) 230.0588, found 230.0591.
’ EXPERIMENTAL SECTION
General Information. All reactions were run under an atmosphere
of argon. Reaction vessels were flame-dried under vacuum and cooled
under a stream of argon. Toluene and dichloroethane (DCE) were
distilled on calcium hydride prior to use. THF, dioxane, and dimethox-
yether (DME) were distilled on sodium/benzophenone prior to use.
Isopropanol and methanol were distilled on sodium prior to use. All the
solvents including distilled water were degassed prior to use. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded using a
300 MHz apparatus. Chemical shifts are reported in delta (δ) units, parts
per million (ppm) downfield from tetramethylsilane (TMS) relative to
the singlet at 7.26 ppm for deuterochloroform. Coupling constants are
reported in hertz (Hz). The following abbreviations are used: s, singlet, d,
doublet, t, triplet, q, quartet, m, multiplet, br, broad. Carbon-13 nuclear
magnetic resonance (13C NMR) spectra were recorded using a 75 MHz
apparatus. Chemical shifts are reported in delta (δ) units, parts per
million (ppm) relative to the center line of the triplet at 77.0 ppm for
deuterochloroform. 13C NMR spectra were routinely run with broad-
band decoupling. Analytical thin layer chromatography (TLC) was
carried out using commercial silica gel plates, and spots were detected
with UV light and revealed with KMnO4 or KagiꢀMosher solutions.
Enantiomeric excesses were determined by chiral stationary phase-
supercritical fluid chromatography (CSP-SFC) using Chiralcel columns
(AD-H or AS-H) and eluting with a scCO2/isopropanol mixture as
indicated. Optical rotations were measured on a polarimeter at 589 nm
(sodium lamp). Melting points (mp) were determined on a slow fusion
melting point apparatus.
General Procedure for Asymmetric 1,4-Conjugate Addi-
tion of Arylboronic Acids to Nonsubstituted Maleimide
Substrates. In a 10 mL sealed tube under argon were introduced
successively 3 mol % of the rhodium complex and 21 mg of ligand (R)-
3,5-diCF3-SYNPHOS L4 (0.018 mmol, 6 mol %) in 0.75 mL of degassed
solvent (c = 0.4 M). The solution was stirred 5 min, and then 0.075 mL of
a 2 M aqueous solution of KOH (0.15 mmol, 0.5 equiv) was added. The
mixture was stirred at room temperature for 10 min, and then arylboro-
nic acid (0.6 mmol, 2 equiv) and desired maleimide compound (0.3
mmol, 1 equiv) were successively added. The reaction mixture was
stirred at the desired temperature under argon for the indicated time,
and then a saturated aqueous solution of ammonium chloride was added.
The aqueous phase was extracted three times with dichloromethane.
The organic layers were combined and dried over magnesium sulfate,
and the solvents were evaporated under reduced pressure. The crude
residue was then purified by flash chromatography on silica gel
(cyclohexane/AcOEt).
(R)-3-(3-Chloro-phenyl)-1-methyl-pyrrolidine-2,5-dione (5g).
Pale yellow solid: 0.050 g, 75% yield. H NMR (CDCl3, 300 MHz):
1
δ 7.35ꢀ7.28 (m, 2H), 7.22 (s, 1H), 7.15ꢀ7.08 (m, 1H), 4.0 (dd, J =
9.30 Hz, 4.80 Hz, 1H), 3.22 (dd, J = 18.30 Hz, 9.60 Hz, 1H), 3.07
(s, 3H), 2.81 (dd, J = 18.60 Hz, 5.10 Hz, 1H). 13C NMR (CDCl3, 75
MHz): δ 177.1, 175.7, 138.8, 135.0, 130.4, 128.2, 127.7, 125.6,
45.5, 36.8, 25.3. [R]25 = ꢀ54.1 (c 1.09; CHCl3) ee = 87% (ee =
D
99%, 62% yield after a single crystallization in absolute EtOH).
CSP-SFC: Chiralcel AD-H column, P = 150 bar, scCO2/iPrOH
90:10, flow 4 mL/min, λ = 215 nm, tR [(S)-enantiomer] = 2.46 mn
(minor), tR [(R)-enantiomer] = 2.64 mn (major). Mp = 77 °C.
HRMS (EI): m/z calcd for C11H10ClNO2Na (M+) 246.0292, found
246.0293.
(R)-3-(3-Bromo-phenyl)-1-methyl-pyrrolidine-2,5-dione (5h).
Pale yellow solid: 0.065 g, 81% yield. H NMR (CDCl3, 300 MHz):
1
δ 7.50ꢀ7.40 (m, 1H), 7.39 (s, 1H), 7.30ꢀ7.12 (m, 2H), 4.0 (dd, J =
9.30 Hz, 4.80 Hz, 1H), 3.21 (dd, J = 18.60 Hz, 9.60 Hz, 1H), 3.08 (s,
3H), 2.80 (dd, J = 18.60 Hz, 5.10 Hz, 1H). 13C NMR (CDCl3, 75 MHz):
δ 177.1, 175.7, 139.1, 131.2, 130.7, 130.6, 126.1, 123.2, 45.4, 36.8, 25.3.
[R]25D = ꢀ50.0 (c 1.1; CHCl3) ee = 80% (97%, 68% yield after a single
crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-H column,
P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(S)-
enantiomer] = 2.94 mn (minor), tR [(R)-enantiomer] = 3.32 mn
(major). Mp = 80 °C. HRMS (EI): m/z calcd for C11H10BrNO2Na
(M+) 291.9767, found 291.9767.
(R)-3-(4-Fluoro-phenyl)-1-methyl-pyrrolidine-2,5-dione (5i).
Pale yellow solid: 0.050 g, 81% yield. 1H NMR (CDCl3, 300 MHz): δ
7.23ꢀ7.17 (m, 2H), 7.10ꢀ7.0 (m, 2H), 4.0 (dd, J = 9.60 Hz, 4.80 Hz,
1H), 3.21 (dd, J = 18.30 Hz, 9.60 Hz, 1H), 3.07 (s, 3H), 2.79 (dd, J =
18.30 Hz, 4.80 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.6, 175.9,
162.3 (d), 132.7 (d), 129.1 (d), 116.1 (d), 45.1, 37.03, 25.2. [R]25
=
D
ꢀ57.8 (c 0.94; CHCl3) ee = 87% (ee = 97%, 71% yield after a single
crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-H column,
P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-
enantiomer] = 1.66 mn (major), tR [(S)-enantiomer] = 1.94 mn
(minor). Mp = 101 °C. HRMS (EI): m/z calcd for C11H10FNO2Na
(M+) 230.0588, found 230.0591.
(R)-3-(4-Chloro-phenyl)-1-methyl-pyrrolidine-2,5-dione (5j).
Pale yellow solid: 0.054 g, 80% yield. 1H NMR (CDCl3, 300 MHz): δ
7.35 (d, J = 8.60 Hz, 2H), 7.15 (d, J = 8.40 Hz, 2H), 4.0 (dd, J = 9.60 Hz,
4.94 Hz, 1H), 3.20 (dd, J = 18.50 Hz, 9.60 Hz, 1H), 3.06 (s, 3H), 2.80
(dd, J = 18.40 Hz, 4.90 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.3,
175.8, 135.3, 133.9, 129.3, 128.8, 45.2, 36.8, 25.2. [R]25 = ꢀ63.9
(R)-1-Methyl-3-phenyl-pyrrolidine-2,5-dione4a (5e). Pale
yellow solid: 0.050 g, 88% yield. 1H NMR (CDCl3, 300 MHz): δ
7.35ꢀ7.20 (m, 3H), 7.19ꢀ7.10 (m, 2H), 3.96 (dd, J = 9.60 Hz, 4.80 Hz,
1H), 3.15 (dd, J = 18.30 Hz, 9.60 Hz, 1H), 3.01 (s, 3H), 2.77 (dd, J =
18.60 Hz, 4.80 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.8, 176.2,
137.04, 129.2, 128.0, 127.4, 45.9, 37.1, 25.2. [R]25D = ꢀ61.4 (c 0.945;
CHCl3) ee = 93% (ee > 99%, 82% yield after a single crystallization in
absolute EtOH). CSP-SFC: Chiralcel AD-H column, P = 150 bar,
scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-enantiomer]
= 1.87 mn (major), tR [(S)-enantiomer] = 2.05 mn (minor).
(R)-3-(3-Fluoro-phenyl)-1-methyl-pyrrolidine-2,5-dione (5f).
Pale yellow solid: 0.050 g, 81% yield. 1H NMR (CDCl3, 300 MHz): δ
7.40ꢀ7.30 (m, 1H), 7.05ꢀ6.90 (m, 3H), 4.04 (dd, J = 9.57 Hz, 4.95 Hz,
1H), 3.23 (dd, J = 18.48 Hz, 9.67 Hz, 1H), 3.08 (s, 3H), 2.81 (dd, J =
18.42 Hz, 4.94 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.1, 175.8,
D
(c 1.04; CHCl3) ee = 87% (ee = 96%, 72% yield after a single
crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-H column,
P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-
enantiomer] = 2.55 mn (major), tR [(S)-enantiomer] = 3.29 mn
(minor). Mp = 95 °C. HRMS (EI): m/z calcd for C11H10ClNO2Na
(M+) 246.0292, found 246.0294.
(R)-3-(4-Bromo-phenyl)-1-methyl-pyrrolidine-2,5-dione (5k).
Pale yellow solid: 0.066 g, 82% yield. 1H NMR (CDCl3, 300 MHz): δ
7.49 (d, J = 8.40 Hz, 2H), 7.11 (d, J = 8.40 Hz, 2H), 3.99 (dd, J = 9.60 Hz,
5.10 Hz, 1H), 3.21 (dd, J = 18.60 Hz, 9.60 Hz, 1H), 3.06 (s, 3H), 2.78
(dd, J = 18.30 Hz, 4.80 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.2,
175.8, 135.9, 132.3, 129.1, 122.0, 45.3, 36.8, 25.3. [R]25 = ꢀ44.0
D
(c 0.92; CHCl3) ee = 85% (ee = 96%, 73% yield after a single
crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-H column,
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ARTICLE
P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-
enantiomer] = 3.24 mn (major), tR [(S)-enantiomer] = 4.30 mn
(minor). Mp = 96 °C. HRMS (EI): m/z calcd for C11H10BrNO2Na
(M+) 291.9767, found 291.9767.
(R)-1-Methyl-3-naphthalen-2-yl-pyrrolidine-2,5-dione (5q).
Pale yellow solid: 0.057 g, 80% yield. 1H NMR (CDCl3, 300 MHz): δ
7.89ꢀ7.75 (m, 3H), 7.70 (s, 1H), 7.52ꢀ7.45 (m, 2H), 7.30ꢀ7.25
(m, 1H), 4.19 (dd, J = 9.60 Hz, 4.80 Hz, 1H), 3.27 (dd, J = 18.60 Hz, 9.60
Hz, 1H), 3.11 (s, 3H), 2.92 (dd, J = 18.60 Hz, 4.80 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): δ 177.8, 176.2, 134.2, 133.3, 132.7, 129.2, 127.7,
(R)-1-Methyl-3-(4-trifluoromethoxy-phenyl)-pyrrolidine-
2,5-dione (5l). Pale yellow solid: 0.065 g, 80% yield. 1H NMR (CDCl3,
300 MHz): δ 7.30ꢀ7.20 (m, 4H), 4.06 (dd, J = 9.60 Hz, 5.10 Hz, 1H),
3.23 (dd, J = 18.30 Hz, 9.60 Hz, 1H), 3.07 (s, 3H), 2.81 (dd, J = 18.60
Hz, 5.10 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 177.3, 175.7, 148.8,
135.5, 128.9, 121.7, 45.2, 36.8, 25.3. [R]25D = ꢀ52.0 (c 1.02; CHCl3)
ee = 92% (ee = 99%, 72% yield after a single crystallization in absolute
EtOH). CSP-SFC: Chiralcel AD-H column, P = 150 bar, scCO2/
iPrOH 94/6, flow 4 mL/min, λ = 215 nm, tR [(R)-enantiomer] = 2.10
mn (major), tR [(S)-enantiomer] = 2.51 mn (minor). Mp = 54 °C.
HRMS (EI): m/z calcd for C12H10F3NO3Na (M+) 296.0505, found
296.0507.
127.6, 126.6, 126.3, 124.7, 46.0, 37.1, 25.2. [R]25 = ꢀ98.9 (c 0.99;
D
CHCl3) ee = 92% (ee = 98%, 73% yield after a single crystallization in
absolute EtOH). CSP-SFC: Chiralcel AD-H column, P = 150 bar,
scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-enantiomer] =
5.24 mn (major), tR [(S)-enantiomer] = 5.78 mn (minor). Mp = 142 °C.
HRMS (EI): m/z calcd for C15H13NO2Na (M+) 262.0838, found
262.0842.
(R)-3-(6-Methoxy-naphtalen-2-yl)-1-methyl-pyrrolidine-
2,5-dione (5r). Pale yellow solid: 0.072 g, 90% yield. 1H NMR
(CDCl3, 300 MHz): δ 7.72 (dd, J = 8.70 Hz, 14.40 Hz, 2H), 7.62
(s, 1H), 7.25ꢀ7.10 (m, 3H), 4.16 (dd, J = 9.60 Hz, 4.80 Hz, 1H), 3.92
(s, 3H), 3.27 (dd, J = 18.60 Hz, 9.60 Hz, 1H), 3.10 (s, 3H), 2.92 (dd, J =
18.30 Hz, 4.50 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 178.0, 176.3,
158.0, 134.0, 131.9, 129.2, 128.8, 128.0, 126.3, 125.3, 119.5, 105.6, 55.3,
45.9, 37.2, 25.2. [R]25D = ꢀ79.4 (c 1.02; CHCl3) ee = 90% (ee = 93%,
86% yield after a single crystallization in absolute EtOH). CSP-SFC:
Chiralcel AS-H column, P=150bar, scCO2/iPrOH 90:10, flow 4 mL/min,
λ = 215 nm, tR [(R)-enantiomer] = 5.41 mn (major), tR [(S)-
enantiomer] = 6.39 mn (minor). Mp = 155 °C. HRMS (EI): m/z
calcd for C16H15NO3Na (M+) 292.0944, found 292.0947.
(R)-1-Methyl-3-m-tolyl-pyrrolidine-2,5-dione (5m). Pale yellow
1
solid: 0.050 g, 83% yield. H NMR (CDCl3, 300 MHz): δ 7.30ꢀ7.22
(m, 1H), 7.14ꢀ7.10 (m, 1H), 7.0ꢀ6.98 (m, 2H), 3.99 (dd, J = 9.52 Hz,
4.73 Hz, 1H), 3.20 (dd, J = 18.47 Hz, 9.47 Hz, 1H), 3.08 (s, 3H), 2.82
(dd, J = 18.47 Hz, 4.71 Hz, 1H), 2.35 (s, 3H). 13C NMR (CDCl3, 75 MHz):
δ 177.9, 176.3, 138.9, 137.0, 129.0, 128.7, 128.0, 124.4, 45.9, 37.2, 25.2, 21.4.
[R]25D = ꢀ62.3 (c 1.06; CHCl3) ee = 91% (ee = 94%, 78% yield after a
single crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-H column,
P = 150 bar, scCO2/iPrOH 94/6, flow 4 mL/min, λ = 215 nm, tR [(R)-
enantiomer] = 3.44 mn (major), tR [(S)-enantiomer] = 4.31 mn (minor).
Mp = 82 °C. HRMS (EI): m/z calcd for C12H13NO2Na (M+) 226.0838,
found 226.0841.
’ ASSOCIATED CONTENT
(R)-3-(3-Methoxy-phenyl)-1-methyl-pyrrolidine-2,5-dione
(5n). Pale yellow solid: 0.056 g, 85% yield. 1H NMR (CDCl3, 300 MHz):
δ 7.35ꢀ7.25 (m, 1H), 6.90ꢀ6.75 (m, 3H), 4.0 (dd, J = 9.30 Hz, 4.80 Hz,
1H), 3.82 (s, 3H), 3.21 (dd, J = 18.30 Hz, 9.30 Hz, 1H), 3.08 (s, 3H),
2.84 (dd, J = 18.30 Hz, 4.80 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ
177.6, 176.2, 160.0, 138.5, 130.2, 119.4, 113.5, 113.0, 55.2, 45.9, 37.0,
25.2. [R]25D = ꢀ47.7 (c 0.65; CHCl3) ee = 90% (ee = 99%, 75% yield
after a single crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-
H column, P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ =
215 nm, tR [(S)-enantiomer] = 2.42 mn (minor) tR [(R)-enantiomer] =
2.68 mn (major). Mp = 74 °C. HRMS (EI): m/z calcd for C12H13NO3-
Na (M+) 242.0788, found 242.0785.
S
Supporting Information. Experimental details and copies
b
of 1H and 13C NMR and HPLC spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tahar-ayad@chimie-paristech.fr; virginie-vidal@
chimie-paristech.fr.
’ ACKNOWLEDGMENT
(R)-1-Methyl-3-p-tolyl-pyrrolidine-2,5-dione (5o). Paleyellow
solid: 0.049 g, 80% yield. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, J =
8.10 Hz, 2H), 7.10 (d, J = 8.10 Hz, 2H), 3.99 (dd, J = 9.60 Hz, 4.80 Hz,
1H), 3.19 (dd, J = 18.60Hz, 9.60Hz, 1H), 3.06 (s, 3H), 2.81 (dd, J = 18.60
Hz, 4.80 Hz, 1H), 2.34 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 178.0,
176.4, 137.7, 134.0, 129.8, 127.2, 45.6, 37.1, 25.2, 21.0. [R]25D = ꢀ69.6
(c 0.86; CHCl3) ee = 91% (ee = 97%, 73% yield after a single crystal-
lization in absolute EtOH). CSP-SFC: Chiralcel AD-H column, P =
150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ = 215 nm, tR [(R)-
enantiomer] = 2.08 mn (major), tR [(S)-enantiomer] = 2.28 mn (minor).
Mp = 84 °C. HRMS (EI): m/z calcd for C12H13NO2Na (M+) 226.0838,
found 226.0841.
(R)-3-(4-Methoxy-phenyl)-1-methyl-pyrrolidine-2,5-dione
(5p). Pale yellow solid: 0.053 g, 80% yield. 1H NMR (CDCl3, 300 MHz):
δ 7.13 (d, J = 8.70 Hz, 2H), 6.89 (d, J = 8.70 Hz, 2H), 3.97 (dd, J =
9.60 Hz, 4.80 Hz, 1H), 3.79 (s, 3H), 3.19 (dd, J = 18.30 Hz, 9.30 Hz, 1H),
3.06 (s, 3H), 2.79 (dd, J = 18.30 Hz, 4.80 Hz, 1H). 13C NMR (CDCl3,
75 MHz): δ 178.1, 176.3, 159.1, 128.9, 128.4, 114.5, 55.3, 45.1, 37.1,
25.1. [R]25D = ꢀ53.8 (c 0.39; CHCl3) ee = 93% (ee = 94%, 77% yield
after a single crystallization in absolute EtOH). CSP-SFC: Chiralcel AD-
H column, P = 150 bar, scCO2/iPrOH 90:10, flow 4 mL/min, λ =
215 nm, tR [(R)-enantiomer] = 2.71 mn (major), tR [(S)-enantiomer] =
3.07 mn (minor). Mp = 108 °C. HRMS (EI): m/z calcd for C12H13NO3-
Na (M+) 242.0788, found 242.0786.
Financial support from CNRS and the French Ministꢀere de
l0Education et de la Recherche are warmly acknowledged.
’ REFERENCES
(1) (a) Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13. (b) Christoffers,
J.; Koripelly, G.; Rosiak, A.; R€ossle, M. Synthesis 2007, 1279. (c) Alexakis,
A.; B€ackvall, J. E.; Krause, N.; Pꢀamies, O.; Diꢁeguez, M. Chem. Rev. 2008,
108, 2797. (d) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa,
B. L. Chem. Soc. Rev. 2009, 38, 1039.
(2) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
(3) For reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b) Hayashi,
T. Chem. Rev. 2003, 103, 2829. (c) Fagnou, K.; Lautens, M. Chem. Rev.
2003, 103, 169. (d) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313.
(e) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288. (f) Hayashi, T.
Pure Appl. Chem. 2004, 76, 465. (g) Miyaura, M. Bull. Chem. Soc. Jpn.
2008, 81, 1535. (h) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost,
C. G. Chem. Soc. Rev. 2010, 39, 2093 and references therein.
(4) (a) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett.
2004, 6, 3425. (b) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.;
Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 4611. (c) Shintani, R.; Duan,
W. L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628. (d) Piras, E.; L€ang,
F.; R€uegger, H.; Stein, D.; W€orle, M.; Gr€utzmacher, H. Chem.—Eur. J.
6325
dx.doi.org/10.1021/jo201187c |J. Org. Chem. 2011, 76, 6320–6326

The Journal of Organic Chemistry
ARTICLE
2006, 12, 5849. (e) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett.
2007, 36, 1442. (f) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T.
J. Am. Chem. Soc. 2007, 129, 2130. (g) Duan, W.-L.; Shintani, R.;
Hayashi, T. Tetrahedron 2007, 63, 8529. (h) Luo, Y.; Carnell, A. J. Angew.
Chem., Int. Ed. 2010, 49, 2750. (i) Thaler, T.; Guo, L.-N.; Steib, A. K.;
Raducan, M.; Karaghiosoff, K.; Mayer, P.; Knochel, P. Org. Lett. 2011,
13, 3182.
(5) (a) Ahmed, S. Drug Des. Discovery 1996, 14, 77. (b) Curtin,
M. L.; Garland, R. B.; Heyman, H. R.; Frey, R. R.; Michaelodes, M. R.; Li,
J.; Pease, L. J.; Glaser, K. B.; Marcotte, P. A.; Davidsen, S. K. Bioorg. Med.
Chem. Lett. 2002, 12, 2919.(c) Tonnaer, J.; Alphons, D. M. PCT Int.
Appl. WO2004110437, 2004. (d) Ballini, R.; Bosica, G.; Cioci, G.;
Fiorini, D.; Petrini, M. Tetrahedron 2003, 59, 3603.
(6) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
(7) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(8) Shi, Q.; Xu, L.; Li, X.; Jia, X.; Wang, R.; Au-Yeung, T. T.-L.; Chan,
A. S. C.; Hayashi, T.; Cao, R.; Hong, M. Tetrahedron Lett. 2003, 44, 6505.
(9) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003,
68, 9481.
(10) (a) Korenaga, T.; Osaki, K.; Maenishi, R.; Sakai, T. Org. Lett.
2009, 11, 2325. (b) Korenaga, T.; Maenishi, R.; Hayashi, K.; Sakai, T.
Adv. Synth. Catal. 2010, 352, 3247.
(11) Berhal, F.; Esseiva, O.; Martin, C.-H.; Tone, H.; Genet, J.-P.;
Ayad, T.; Ratovelomana-Vidal, V. Org. Lett. 2011, 13, 2806.
(12) (a) Duprat de Paule, S.; Champion, N.; Ratovelomanana-Vidal,
V.; Genet, J.-P.; Dellis, P. French Patent 2830254, 2001; WO Patent
03029259, 2003. (b) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-
Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Eur. J. Org. Chem.
2003, 1931. (c) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal,
V.; Genet, J.-P.; Champion, N.; Deschaux, G.; Dellis, P. Org. Process Res.
Dev. 2003, 7, 399.
(13) Guerreiro, P.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Dellis, P.
Tetrahedron Lett. 2001, 42, 3423.
(14) Lesseure, L.; Le Boucher d’Herouville, F.; P€untener, K.; Scalone,
M.; Genet, J.-P.; Michelet, V. Org. Lett. 2011, 13, 3250.
(15) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
Genet, J.-P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004,
43, 320.
(16) Castagnetti, C.; Schlosser, M. Chem.—Eur. J. 2002, 8, 799.
6326
dx.doi.org/10.1021/jo201187c |J. Org. Chem. 2011, 76, 6320–6326