HetPHOX: A new class of easily prepared modular chiral ligands

Article abstract of DOI:10.1016/j.tetasy.2004.06.014

The synthesis of a new class of modular chiral phosphino-oxazoline ligands containing the diphenylphosphino group at different positions of the heterocyclic backbone is described. HetPHOX ligands were tested in enantioselective allylations and in transfer

Full text of DOI:10.1016/j.tetasy.2004.06.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2235–2239
HetPHOX: a new class of easily prepared modular chiral ligands
Nicole End,b Catherine Stoessel,b Ulrich Berens,b Pierino di Pietroa and
Pier Giorgio Cozzia,*
aDipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, Bologna 40126, Italy
bCiba Specialty Chemicals, Group Research, K-420.2.18, 4002 Basel, Switzerland
Received 23 March 2004; revised 18 May 2004; accepted 9 June 2004
Available online 10 July 2004
Abstract—The synthesis of a new class of modular chiral phosphino-oxazoline ligands containing the diphenylphosphino group at
different positions of the heterocyclic backbone is described. HetPHOX ligands were tested in enantioselective allylations and in
transfer hydrogenation reactions. The synthesis of the ligands is facile with high enantioselectivity (99% ee) obtained in the
Pd-catalyzed addition of malonate to diphenylallyl acetate using ligand 10.
ꢀ 2004Elsevier Ltd. All rights reserved.
1. Introduction
PHOX and, in certain instances, the new ligands turned
out to be superior. Herein, we report the use of these
new ligands in two standard PHOX catalyzed reactions;
(i) the asymmetric transfer hydrogenation of acetophe-
none and (ii) the asymmetric allylation of 1,3-diphen-
ylallyl acetate with malonate.
Chiral phosphino-oxazoline ligands 1 (PHOX; Fig. 1)
represent a class of well established ligands, which have
been used in a variety of asymmetric catalytic transfor-
mations.1 Diversity was exploited by the synthesis of
different scaffolds coupled with several phosphorus
groups.2 In order to further expand the library of
modular PN ligands,3 we became interested in hetero-
cyclic rings.4 The advantage of having a choice between
electron-rich or electron-deficient ring systems in con-
junction with the facile and regioselective metallation5
make heterocyclic scaffolds valuable.6 We have prepared
2. Results and discussion
For these studies, we have selected HetPHOX ligands
obtained from thiophene and benzo[b]thiophene as
backbone templates. In addition, we were interested in
changing the relative position of the phosphine and
oxazoline group on the heterocyclic ring.
a
series of heterocyclic phosphino-oxazolines
(HetPHOX) and applied them in the enantioselective Ir-
promoted hydrogenation of unfunctionalized alkenes7
as well as a Pd-catalyzed Heck reaction.8 For both of the
cited examples HetPHOX ligands performed as well as
In the case of ligands with a thiophene backbone, we
started from 2-cyano-thiophene, which was converted
into oxazolines 2 and 3 as previously reported.9 Selective
metallation of 2 and 3 at the 3-position with Et2O as
solvent10 and introduction of the Ph2P group took place
without any difficulties giving the desired ligands 4 and 5
(Scheme 1).
O
R
iPr
N
O
PPh2
PPh2
N
R
S
HetPHOX
For the syntheses of the benzo[b]thiophene derivatives a
different methodology was applied. Benzo[b]thiophene
was brominated at the 3-position and converted to the
corresponding benzothiophene carboxylic acid by trap-
ping the Grignard reagent with CO2. The latter was
transformed into the 3-oxazolines 6, 10 and 11 using
standard reaction conditions (Scheme 2).11
PHOX
iPr
Figure 1.
* Corresponding author. Tel.: +39-051-2099511; fax: +39-051-20994-
56; e-mail: piergiorgio.cozzi@unibo.it
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.014

2236
N. End et al. / Tetrahedron: Asymmetry 15 (2004) 2235–2239
In order to compare HetPHOX with PHOX, we chose
ZnCl2
O
acetophenone as the substrate for the reduction fol-
lowing Helmchen’s protocol. All reactions were stopped
after 30 min (Scheme 3). It can be seen from the data
reported in Table 1 that HetPHOX ligands derived from
benzo[b]thiophene displayed diminished activity in this
reaction when compared to PHOX ligands.
Chlorobenzene, reflux
H2N
OH
CN
S
S
N
R
R
R = iPr, 2
R = tBu, 3
PPh2
O
O
1) BuLi
S
OH
O
S
N
0.001 mol% Ru(PPh3)3Cl2
0.0013mol% HEtPHOX
Et2O, -78°C 30min,
0°C 30min
2) ClPPh2, -7 8°C to rt
N
R
R
R = iPr, 2
R = tBu, 3
R = iPr, 4
R = tBu, 5
0.025mol% NaOH, iPrOH
30 minutes, 82°C
Scheme 1.
Scheme 3.
COCl
Table 1. Enantioselective reduction of acetophenone via transfer
hydrogenation catalyzed by RuHetPHOX
CONH
R
OH
R
Et3N
CH2Cl2
Yielda
Eeb
S
Ligand
H2N
OH
S
1
81
85c
c
R
1
8479
82
5
66
99d
O
N
5
22
CONH
OH
1) SOCl2, reflux
9
4
27
7
89
10
11
81
R
R = iPr, 6
R = tBu, 7
R = Ph, 8
S
S
S
2470
a Isolated yields after chromatographic purification. All the reactions
were stopped after 30 min.
2) NaOH/ MeOH, reflux
R
b The enantiomeric excess was determined by chiral HPLC analysis
(Chiralcel OD).
O
N
O
R
c The reaction time was 60 min.
d The reaction was run at room temperature.
N
1) BuLi -78°C, 1 hour
S
2) ClPPh2, -78°C to rt
PPh2
R = iPr, 9
Although the alcohol could be isolated with an excellent
enantiomeric excess, the Ru-complex derived from
ligand 5 showed a low catalytic activity at room tem-
perature. However, when the reaction was performed at
reflux, the activity of the thiophene based oxazoline was
similar to PHOX, but the enatiomeric excess of the
product was slightly inferior.
R = tBu, 10
R = Ph, 11
Scheme 2.
Metallation in the 2-position with n-BuLi proved easy
and treatment of the lithiated species with Ph2PCl
afforded the desired phosphino-oxazoline ligands 9, 10
and 11 in good yields.
Another comparison between the performances of our
HetPHOX ligands and the PHOX ligands was studied by
considering the well established palladium-catalyzed
allylic alkylations of diphenylallyl acetate with dimethyl
malonate (Scheme 4). As a matter of fact, PHOX ligands
such as 1 have been reported to give high enantiomeric
excesses in this reaction.14 The required palladium
complexes were prepared in situ by mixing [Pd(C3H3)Cl]2
with the phosphino-oxazolines 4, 5, 9, 10 and 11,
respectively, in CH2Cl2 at room temperature, and then
allylation performed following Trost’s protocol.15
It is worthy of note that the relatively high acidity of
thiophene and benzo[b]thiophene allows the preparation
of phosphino-oxazolines by direct metallation, whereas
for the preparation of PHOX ligands usually required
an exchange reaction between a bromo derivative. This
can be a considerable advantage in the synthetic design
of substituted thiophene or benzo[b]thiophene phos-
phino-oxazoline ligands.
Thiophene ligand 5 and benzo[b]thiophene derivatives 9,
10 and 11 were evaluated in a catalytic enantioselective
transfer hydrogenation reaction.12 The use of PHOX
ligand 1 in transfer hydrogenation reactions has previ-
ously been reported by Langer and Helmchen in 1996.13
The catalyst was prepared in situ by mixing PHOX and
RuCl2(PPh3)3 with the complex able to reduce aceto-
phenone within 30 min. The corresponding alcohol was
isolated with an enantiomeric excess of 85%.
MeOOC
Ph
COOMe
Ph
OAc
1.5 mol% [Pd(allyl)Cl]2
3 mol% HEtPHOX
Ph
Ph
BSA, KOac cat. , CH2Cl2
MeOOC COOMe
Scheme 4.

N. End et al. / Tetrahedron: Asymmetry 15 (2004) 2235–2239
2237
From the data reported in Table 2, the HetPHOX
ligands derived from thiophene or benzo[b]thiophene
are both capable of inducing high enantiomeric excesses
in this reaction.
Varian 75 MHz spectrometer with proton decoupling.
Chemical shifts are reported in parts per million from
tetramethylsilane with the solvent as internal standard
(deuterochloroform: d 77.0 ppm). Mass spectra were
performed at an ionizing voltage of 70 eV. Chromato-
graphic purification was done with 240–400 mesh silica
gel (Merck). Analytical gas chromatography (GC) was
performed on a Hewlett–Packard HP 6890 gas chro-
matograph with a flame ionization detector and split
mode capillary injection system, using a Cross-linked
5% PHME Siloxane (30 m) column or a Megadex5
chiral (25 m) column. Analytical high performance
liquid chromatography (HPLC) was performed on a HP
1090 liquid chromatograph equipped with a variable
wavelength UV detector (deuterium lamp 190–600 nm),
using a Daicel ChiralcelTM OD column (0.46 cm
I.D. · 25 cm). HPLC grade isopropanol and hexane were
used as the eluting solvents. Elemental analyses were
carried out using a EACE 1110 CHNOS analyzer. All
reactions were carried out under a nitrogen atmosphere
in flame-dried glassware using standard inert techniques
for introducing reagents and solvents. Acetophenone
was distilled prior to use. All other commercially
obtained reagents were used as received. Anhydrous
CH2Cl2, THF and Et2O, were purchased from Fluka.
BuLi 1.6 M in hexane and BuLi 2.5 M in hexane were
purchased from Aldrich. Thiophene-2-yl-4-iso-propyl-
4,5-dihydro-oxazoline 2 and thiophene-2-yl-4-tert-butyl-
4,5-dihydro-oxazoline 3 were prepared as described in
literature.7 4-iso-Propyl-2-(3-diphenyl-phosphino-thio-
phene-2-yl)-4,5-dihydrooxazole and 4-tert-butyl-2-(3-
diphenylphosphino-thiophene-2-yl)-4,5-dihydrooxazole
were prepared as described.8;17
Table 2. Catalytic enantioselective allylation promoted by HetPHOX
ligands
Entry
Ligand
Yielda
Eeb
Time (h)
1
2
3
5
6
7
4
5
90
30
50
82
72
62
95
80
80
943
99
97
0.5
3
5
16
9
10
11
16
16
a Yields after chromatographic purification.
b The enantiomeric excess was determined by chiral HPLC analysis
chiralcel OD with hexane/isopropanol 99.5:0.5 as the eluent. The
absolute configuration of the product was established by comparison
with reported analytical data.
Differences in the reactivity of ligands 4 and 9 can be
attributed to the different electronic properties of the
thiophene and benzo[b]thiophene moiety.16 It is well
known that it is possible to modulate the electron-donor
properties of the phosphorus atom by changing the
supporting heterocyclic system.16 This tuning is also
influenced by the relative positions of the phosphine and
oxazoline group on the thiophene and benzo[b]thio-
phene backbone, respectively, and may be responsible
for the differences in reactivity exhibited by the palla-
dium complexes.
3. Conclusions
4.1.1. 2-Benzo[b]thiophene-3-yl-4-iso-propyl-4,5-dihydro-
oxazole 6. A solution of (S)-valinol (4.41 g, 42.7 mmol)
and triethylamine (6.63 mL, 47.0 mmol) in CH2Cl2
(120 mL) was cooled to 0 ꢁC, and then a solution
of benzo[b]thiophene-3-carboxylchloride (8.40 g, 42.7
mmol) in CH2Cl2 (120 mL) added dropwise within
30 min. The mixture was stirred at room temperature
overnight. The formed precipitate was dissolved com-
pletely by adding 700 mL of CH2Cl2, and then washed
with a solution of 1 M HCl (500 mL). The organic phase
was dried over Na2SO4 and evaporated under reduced
pressure. The crude solid was re-crystallized from
CH2Cl2/hexane to give a colourless product (9.30 g,
83%). The amide (9.30 g, 35.5 mmol) was dissolved in
CH2Cl2 (145 mL) and SOCl2 (6.33 mL, 86.1 mmol) then
added. The solution was stirred for 2 h at 70 ꢁC and then
allowed to cool to room temperature. A saturated
solution of NaHCO3 (150 mL) was added and the
organic layer separated. The aqueous layer was
extracted with CH2Cl2 (2 · 80 mL) and the organic
phases combined, dried over Na2SO4 and evaporated
under reduced pressure to give a colourless solid (9.68 g,
97%). The benzo[b]thiophene 3-(1-chloromethyl-2-
methyl-propyl)carboxyamide (9.68 g, 34.4 mmol) was
dissolved in MeOH (200 mL) and then a solution of
NaOH (1.44 g, 36.1 mmol) in MeOH (50 mL) added.
The resulting mixture was stirred for 2 h at 70 ꢁC. The
MeOH was then evaporated under reduced pressure and
In conclusion, we have described a facile synthesis of a
new type of phosphino-oxazoline ligands. Clearly, this
new class of PN ligands needs to be further evaluated in
different reactions, where the electron-rich or electron-
poor nature of the heterocyclic scaffold can play a
decisive role in controlling the reaction rate and
enantioselectivity.17 The large variety of heterocyclic
scaffolds, which can be used to prepare tailored Het-
PHOX ligands adds further value to this new ligand
family. Further studies on different C–C bond forming
reactions are currently under investigation and will be
disclosed in due time.
4. Experimental
4.1. General procedures
1H NMR spectra were recorded on Varian 200 MHz,
Varian 300 MHz or Brucker 300 MHz spectrometer.
Chemical shifts are reported in parts per million from
tetramethylsilane with the solvent resonance as the
internal standard (deuterochloroform: d 7.27 ppm).
Data are reported as follows: chemical shifts, multi-
plicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
br ¼ broad, m ¼ multiplet), coupling constants (Hz). 13C
NMR spectra were recorded on a Varian 50 MHz or

2238
N. End et al. / Tetrahedron: Asymmetry 15 (2004) 2235–2239
the residue treated with CH2Cl2 (300 mL). The resulting
solution was extracted with a saturated solution of
NaHCO3 (150 mL). The organic phase was dried over
Na2SO4 and evaporated under reduced pressure to give
an oil, which was purified by chromatography (hexane/
AcOEt 7:3). Yield 7.4g, 84%. C 14H15NOS Fw ¼ 245.34.
1H, J ¼ 6.8 Hz); 3.88 (dd, 1H, J ¼ 7.6, 7.8 Hz);. 3.95–
4.04 (m, 1H); 4.16 (dd, 1H, J ¼ 7.6, 8.9 Hz); 7.28–7.49
(m, 12H); 7.65–7.69 (m, 1H); 8.57 (d, 1H, J ¼ 8.2 Hz).
13C NMR (75 MHz, CDCl3): d 18.7; 19.0; 32.9; 69.5;
72.5; 121.8; 124.6; 124.7 (d, J ¼ 1.4Hz); 124.9; 128.0 (d,
J ¼ 16.3 Hz); 128.3 (d, J ¼ 7.5 Hz); 128.4(d, J ¼ 7.5 Hz);
129.1; 129.2; 133.5 (d, J ¼ 21.2 Hz); 134.0 (d,
J ¼ 21.2 Hz); 136.9 (d, J ¼ 39.4Hz); 137.0 (d, J ¼
40.1 Hz); 139.5; 141.8; 147.6 (d, J ¼ 42.1 Hz); 159.54.
31P (124MHz, CDCl 3): d )12.4. GC–MS 429 (Mþ, 4 );
358 (100); 338 (48); 239 (40); 41 (50). Element. Anal.
Calcd for C26H24NOPS: C, 72.71; H, 5.63; N, 3.26.
Found: C, 72.68; H, 5.60; N, 3.28.
½aŠ ¼ )45.0 (c 1.09, CHCl3). 1H NMR (CDCl3,
D
300 MHz): d 0.99 (d, 3H, J ¼ 6.7 Hz); 1.11 (d, 3H,
J ¼ 6.7 Hz); 1.90 (sept, 1H, J ¼ 6.7 Hz); 4.11 (dd, 1H,
J ¼ 7.6, 15.2 Hz); 4.16–4.23 (m, 1H); 4.38 (dd, 1H,
J ¼ 7.4, 9.1 Hz); 7.37–7.52 (m, 2H); 7.82–7.90 (m, 1H);
8.07 (s, 1H); 8.78–8.83 (m, 1H). 13C NMR (CDCl3,
75 MHz): d 18.7; 19.2; 33.3; 69.4; 73.3; 122.6; 125.1;
125.3; 125.5; 131.9; 137.1; 140.3; 159.3. GC–MS: 245
(Mþ, 15); 202 (100); 174(28); 147 (32). Element. Anal.
Calcd for C14H15NOS: C, 68.54; H, 6.16; N, 5.71.
Found: C, 68.51; H, 6.13; N, 5.68.
4.1.5. 2-(2-Diphenylphosphino)-benzo[b]thiophene-3-yl-4-
tert-butyl-4,5-dihydrooxazole 10. Compound 10 was
prepared following the procedure described for com-
pound 9. Yield 0.638 g, 52%. C27H26NOPS Fw ¼ 443.54.
4.1.2. 2-Benzo[b]thiophene-3-yl-4-tert-butyl-4,5-dihydro-
oxazole 7. Compound 7 was prepared following the
procedure described for compound 6. Yield 0.8 g, 70%.
½aŠ ¼ )52.9 (c 1.04, CHCl3). 1H NMR (CDCl3,
D
300 MHz): d 0.81 (s, 9H); 3.90–5.15 (m, 3H); 7.27–7.46
(m, 12H); 7.64–7.69 (m, 1H); 8.56–8.62 (m, 1H). 13C
NMR (CDCl3, 75 MHz): d 26.0; 34.0; 68.2; 76.3; 121.8;
124.9; 125.0; 125.1; 125.2; 128.6 (d, J ¼ 7.7 Hz); 129.4
(d, J ¼ 15.5 Hz); 133.7 (d, J ¼ 20.7 Hz); 134.2 (d,
J ¼ 20.7 Hz); 137.1 (d, J ¼ 29.4Hz); 137.5 (d,
J ¼ 30.4Hz); 139.8; 142.1; 147.9; (d, J ¼ 42.5 Hz); 159.8.
31P (124MHz, CDCl 3): d )12.4. GC–MS 443 (Mþ, 6);
386 (61); 358 (100); 239 (30). Element. Anal. Calcd for
C27H26NOPS: C, 73.11; H, 5.91; N, 3.16. Found: C,
73.13; H, 5.92; N, 3.15.
C15H17NOS Fw ¼ 259.37. ½aŠ ¼ )56.1 (c 0.9, CHCl3).
D
1H NMR (CDCl3, 300 MHz): d 1.02 (s, 9H); 4.11–4.23
(m, 2H); 7.37–7.52 (m, 2H); 7.87 (d, 2H, J ¼ 8.2 Hz);
8.08 (s, 1H); 8.79 (d, 1H, J ¼ 7.9 Hz). 13C NMR (CDCl3,
75 MHz) d: 26.2; 34.3; 67.8; 122.6; 124.7; 125.1; 125.3;
125.5; 131.8; 137.2; 140.3; 159.1. GC–MS 260 ([M+1]þ,
100); 386 (61); 358 (100); 239 (30). Element. Anal. Calcd
for C15H17NOS: C, 69.46; H, 6.61; N, 5.40. Found: C,
69.43; H, 6.58; N, 5.38.
4.1.3. 2-Benzo[b]thiophene-3-yl-4-phenyl-4,5-dihydroox-
azole 8. Compound 8 was prepared following the pro-
cedure described for compound 6. Yield 1.35 g, 84%.
4.1.6. 2-(2-Diphenylphosphino)-benzo[b]thiophene-3-yl-4-
phenyl-4,5-dihydrooxazole 11. Compound 11 was pre-
pared following the procedure described for compound
9. Yield 0.89 g, 52%. C29H22NOPS Fw ¼ 463.54.
C17H13NOS Fw ¼ 279.36. ½aŠ ¼ )55 (c 0.67, CHCl3). 1H
D
NMR (CDCl3, 300 MHz): d 4.24 (dd, 1H, J ¼ 8.1,
8.1Hz); 4.77 (dd, 1H, J ¼ 8.2, 10.1 Hz); 5.51 (dd, 1H,
J ¼ 8.2, 10.0 Hz); 7.30–7.35 (m, 7H); 7.82–7.92 (m, 1H);
8.22 (s, 1H); 8.87–8.92 (m, 1H). 13C NMR (CDCl3,
75 MHz): d 70.7; 74.0; 126.2; 124.3; 125.3; 125.4; 125.6;
127.0; 127.8; 129.0; 132.8; 137.0; 140.3; 142.8; 160.8.
GC–MS 280 ([M+1]þ. Element. Anal. Calcd for:
C17H13NOS: C, 73.09; H, 6.08; N, 5.01. Found: C, 73.05;
H, 6.10; N, 5.66.
½aŠ ¼ )5.4(
c
0.92, CHCl3). 1H NMR (CDCl3,
D
300 MHz): d 3.96 (dd, 1H, J ¼ 8.3, 8.3 Hz); 4.56 (dd, 1H,
J ¼ 8.3, 10.3 Hz); 5.34(dd, 1H, J ¼ 8.8, 10.3 Hz); 7.04–
7.09 (m, 2H); 7.22–7.52 (m, 15H); 7.58–7.72 (m, 1H);
8.60–8.66 (m, 1H). 13C NMR (75 MHz, CDCl3): d 70.1;
74.1; 121.7; 125.0; 125.1; 125.3; 126.9; 127.5; 127.8;
128.7; 128.8 (d, J ¼ 7.7 Hz); 129.6 (d, J ¼ 10.9 Hz); 133,9
(d, J ¼ 21.3 Hz); 134.3 (d, J ¼ 1.3 Hz); 137.0
(J ¼ 20.6 Hz); 137.2 (d, J ¼ 16.6 Hz); 139.8; 142.0; 142.6;
148.9 (d, J ¼ 42.8 Hz); 161.3. 31P (124MHz, CDCl 3): d
)12.4. GC–MS 463 (Mþ, 4); 358 (100); 296 (12); 239
(18). Element. Anal. Calcd for C27H22NOPS: C, 75.14;
H, 4.78; N, 3.02. Found: C, 75.15; H, 4.80; N, 3.06.
4.1.4. 2-(2-Diphenylphosphino)-benzo[b]thiophene-3-yl-4-
a solution of
iso-propyl-4,5-dihydrooxazole 9. To
benzo[b]thiophene oxazoline 6 (0.92 g, 3.83 mmol.) in
Et2O (10 mL) at )78 ꢁC, a solution of 1.6 M BuLi in
hexane (2.63 mL, 4.20 mmol) was added and the result-
ing suspension agitated at )78 ꢁC for 1.5 h. Diphenyl-
chlorophosphine (0.69 mL, 3.83 mmol) was added at
)78 ꢁC, and the reaction mixture warmed to room
temperature and stirred for 30 min. The reaction was
quenched by adding water (30 mL) and pentane (40 mL).
The organic layer was separated, dried over Na2SO4 and
purified by chromatography (hexane/ether 9:1). Yield
4.1.7. Catalytic enantioselective reduction of acetophe-
none with Ru(HetPHOX). Ru(PPh)3Cl2 (9 mg,
0.01 mmol) and the HetPHOX ligand (0.013 mmol) were
dissolved under an inert atmosphere in a flask contain-
ing dried and degassed iPrOH (5 mL). The flask was
heated at reflux for 30 min, and then a solution of ace-
tophenone (10 mmol) in iPrOH (3 mL) added. The
mixture was stirred for 15 min and then a solution of
NaOH (10 mg, 0.25 mmol) in 2 mL of iPrOH added and
the mixture stirred for 30 min. The solvent was evapo-
0.754g, 79%. C 26H24NOPS Fw ¼ 429.51. ½aŠ ¼ )74.0. (c
D
1
0.96, CHCl3). H NMR (CDCl3, 300 MHz): d 0.8 (d,
3H, J ¼ 6.8 Hz); 0.90 (d, 3H, J ¼ 6.8, 7.6 Hz); 1.69 (sept,

N. End et al. / Tetrahedron: Asymmetry 15 (2004) 2235–2239
2239
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4.1.8. Catalytic enantioselective allylation reaction.
[Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol) and the HetPHOX
ligand (0.025 mmol) were added to a reaction flask,
which contained degassed CH2Cl2. The mixture was
stirred at room temperature for 30 min. 1,3-Diphenyl-
allyl acetate (1 mmol), BSA (3 mmol) and dimethyl
malonate (3 mmol) were added to the reaction flask,
followed by a catalytic amount of CH3COOK (1 mg).
The mixture was degassed through a freezing-pump
cycle and then the reaction mixture stirred at room
temperature for 3–16 h. The solvent was evaporated and
the reaction mixture purified directly by chromatogra-
phy (cyclohexane/ethylacetate 9:1) to give a clear oil.
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Acknowledgements
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References and notes
1. Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
2. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–
345.
3. Modular chiral ligands are effectively used in combinato-
rial catalysis, see: Gennari, C.; Piarulli, U. Chem. Rev.
2003, 103, 3071–3100.
4. Chiral ligands based on heterocyclic frameworks: (a)
Berens, U.; Brown, J. M.; Long, J.; Selke, R. Tetrahedron: