New aziridine sulfide ligands for palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1055/s-2004-825588

Aziridine sulfides, a new type of chiral S,N-ligand, have been easily synthesized in a straightforward synthetic route, from an inexpensive and easily available chiral pool. They were used in the Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethymalonate anion, furnishing the alkylated product in excellent yields and stereo selectivity up to 99%.

Full text of DOI:10.1055/s-2004-825588

LETTER
1297
New Aziridine Sulfide Ligands for Palladium-Catalyzed Asymmetric Allylic
Alkylation
N
ew
A
ziridine Sul
n
fide
L
igands
t
for Pa
o
lladium-Cata
n
lyzed
A
symm
i
etric
A
o
llylic
A
lkylation L. Braga,* Marcio W. Paixão, Priscila Milani, Claudio C. Silveira, Oscar E. D. Rodrigues,
Elenilson F. Alves
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Fax +55(55)2208031; E-mail: albraga@quimica.ufsm.br
Received 31 October 2003
with DEAD and triphenylphosphine in THF afforded the
Abstract: Aziridine sulfides, a new type of chiral S,N-ligand, have
been easily synthesized in a straightforward synthetic route, from an
inexpensive and easily available chiral pool. They were used in the
Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-pro-
penyl acetate with dimethymalonate anion, furnishing the alkylated
product in excellent yields and stereoselectivity up to 99%.
desired aziridine sulfides 5a and 6a–c8 in 69% and 61%
yield, respectively (Scheme 1).
R
c
a,b
(R)-cysteine
S
OH
S
OH
3 R = Et
2
HN
HN
4 R = Bn
Key words: asymmetric allylic alkylation, asymmetric catalyst,
palladium, chiral pool, aziridine, S,N-ligands
2
Ar
Ar
d
R
The palladium-catalyzed allylic alkylation reaction is
without a doubt one of the most important protocols in or-
ganic chemistry for the formation of carbon-carbon
bonds, and the topic has been the subject of several recent
high profile reports.1 The enantioselectivity of this pro-
cess may be influenced by the base, the counter-cation and
the concentration of the nucleophile, but is mainly in-
fluenced by the chiral ligand coordinated to the palladium
atom.2
Ar =
S
N
5 R = Et
6 R = Bn
Cl
c
a
b
Ar
Scheme 1 Reagents and conditions: a) EtOH, ArCHO; b) THF,
NaBH4/I2 then O2; c) EtOH, NaOH, NaBH4, RX; d) THF, PPh3,
DEAD.
The optical purity of these ligands has been verified by
HPLC analyses.
Several efficient enantioselective catalysts such as C2-
and C1-symmetric bidentate chiral ligands1b and non-C2-
symmetric ligands such as phosphineoxazolines3 have
been explored for these reactions. Heterobidentate sulfur-
nitrogen ligands have found less attention in the search for
an effective catalyst.4 Although asymmetric bidentate
ligands with an oxazoline unit as chiral modifier have
been investigated extensively,4a–e applications in asym-
metric palladium-catalyzed allylic alkylation of heterobi-
dentate ligands with an aziridine moiety are scarcely
described.5
With this sterically and electronically varied set of enan-
tiopure S,N-ligands in hand, we examined the efficacy of
these compounds as chiral catalysts in the palladium-cat-
alyzed asymmetric allylic alkylation reaction. First, asym-
metric allylic substitution of rac-1,3-diphenyl-2-propenyl
acetate was examined using chiral aziridine 6a. These
results are summarized in Table 1.
The reaction with dimethyl malonate under standard con-
ditions: 2.5 mol% of [Pd(h3-C3H5)Cl]2, 2.5 mol% of chiral
aziridine 6a, and a mixture of N,O-bis-(trimethysilyl)ace-
tamide (BSA) and a catalytic amount of KOAc in
CH2Cl2,9 proceeded smoothly to give a quantitative yield
but unsatisfactory ee (entry 1). We decided to find other
reaction conditions to conduct the alkylation reaction. By
changing the base, an important improvement of the level
of enantioselectivity was observed. Preparing the nucleo-
phile from the previous reaction of dimethyl malonate
with NaH and using THF as solvent (entry 2), the alkylat-
ed product was obtained with a satisfactory level of enan-
tiomeric excess in quantitative yield.
As part of a broader program to explore the preparation
and use of chiral organochalcogen compounds in asym-
metric catalysis,6 we wish to describe herein the applica-
tion of aziridine sulfides as efficient ligands for the
palladium-catalyzed asymmetric allylic alkylation.
The chiral aziridine sulfides are readily prepared from
(R)-cysteine in a straightforward three steps synthetic
route. Initially, (R)-cysteine was converted into disulfide
amino alcohols 2 by treatment with different aldehydes
followed by NaBH4/I2 reduction and air oxidation.7 Disul-
fides 2 were reduced with NaBH4 and alkylated, to give
thioethers 3 and 4 in good yields.6d Treatment of 3 or 4
Variations of ligand-to-metal ratio had a small influence
in this work (entries 2–4). Using 2.5 mol% loading of 6a,
which corresponds to a 1:1 ratio of bidentade ligand to
palladium, proved to be the best condition (entry 2). An
increased ratio in our system apparently had only a small
SYNLETT 2004, No. 7, pp 1297–1299
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-825588; Art ID: S09903ST
© Georg Thieme Verlag Stuttgart · New York

1298
A. L. Braga et al.
LETTER
Table 1 Asymmetric Palladium-Catalyzed Allylic Alkylation of 7 with Dimethyl Malonate 8a,b
O
O
2.5 mol% [Pd(η3-C3H5)Cl]2
N,S-Ligand, base, solvent, r.t.
OAc
Ph
O
O
MeO
Ph
OMe
Ph
MeO
OMe
Ph
7
8
9
Entry
Ligand
Base
Solvent
CH2Cl2
THF
Temp (°C)
Time (h)
24
Yield (%)c
100
100
100
100
100
87
Ee (%)d
1
2
6a (2.5 mol%)
6a (2.5 mol%)
6a (5 mol%)
BSA/KOAc
NaH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
64 (S)
75 (S)
74 (S)
70 (S)
72 (S)
56 (S)
80 (S)
85 (S)
81 (S)
99 (S)
24
3
NaH
THF
24
4
6a (10 mol%)
5a (2.5 mol%)
6a (2.5 mol%)
6a (2.5 mol%)
6a (2.5 mol%)
6b (2.5 mol%)
6c (2.5 mol%)
NaH
THF
24
5
NaH
THF
24
6
NaH
CH2Cl2
Toluene
Toluene
Toluene
Toluene
24
7
NaH
24
93
8
NaH
48
89
9
NaH
0
48
90
10
NaH
0
48
87
a Entries 1–7: NaH (1.5 equiv), dimethyl malonate (2 equiv), and acetate (1 equiv).
b Entries 8–12: N,O-bis(trimethylsilyl)acetamide (BSA, 3 equiv), dimethyl malonate (3 equiv), KOAc (cat. quantity), and acetate (1 equiv).
c Determined by GC.
d Determined by HPLC with a chiralcel OD-H column. The absolute configuration of the product was assigned by comparison of the sign of
specific rotations with literature data.
influence, resulting in an enantiomeric excess of 74% in vate the aromatic nucleus.13 The chloro substituent in this
the case of a 2:1 ratio (entry 3).
ligand system has a complex mixture of steric and elec-
tronic properties and further studies are underway to un-
derstand them.
A decrease in the enantioselectivity when a 4:1 ratio (en-
try 4) was used might be caused by a change in the coor-
dination of the ligand to palladium. The coordination of These results suggest that the influence of the benzyl
two monodentate ligands to the Pd center, instead of one group attached to nitrogen is important in obtaining high
bidentate ligand, can be considered as a possible explana- asymmetric induction (the dominant stereocontrol ele-
tion to the lower level of enantioselectivity observed.10,11
ment) and the substituent at the sulfur atom has a small
effect in the conversion of the alkylation reaction (entries
2 vs. 5).
The effect of solvent on the reaction was also examined.
When the reaction was carried out in toluene, the enanti-
oselectivity obtained was higher than with THF or CH2Cl2 In the present runs, the absolute configuration of the major
(entry 7 vs. entries 2 and 6).
enantiomer was determined to be S in all cases by the op-
tical rotation and the comparision of peaks in chiral HPLC
analysis.
Performing the allylation at 0 °C led to a further improve-
ment of the enantioselectivity providing diester 9 with
85% ee and 89% yield (entry 8).
In summary, we described in this paper, the use of new
aziridine containing sulfides as chiral ligands in palladium
catalyzed asymmetric allylic alkylation, furnishing the
product in high yields as well as excellent levels of stere-
oselectivity. Besides, it should be mentioned that the prep-
aration of our catalysts begins from inexpensive and
easily available (R)-cysteine. Although this first genera-
tion of new sulfur/aziridines based catalyst is not yet de-
veloped as the more traditional phosphine1b we are
confident that they will prove to be a useful alternative to
existing methods as has already shown in other allylic
substitutions.1d,g,3d Further studies dealing with their im-
provement and application in asymmetric synthesis are in
progress.
Thus, the best results were obtained by performing the re-
action with 2.5 mol% of the chiral ligand, 2.5 mol% of the
palladium catalyst and toluene as solvent at 0 °C.12
With all the conditions optimized, we decided to extend
this reaction to other chiral aziridine-sulfide ligands syn-
thesized. The electronic and steric properties of the N-ar-
omatic group have been briefly investigated. It would
appear that an electron-donating substituent has little ef-
fect (entries 8 vs. 9), whereas an electron-withdrawing
substituent gives higher enantiomeric excess (entries 8 vs.
10). The lone pairs of halogens are known to overlap with
aromatic p-systems, but at the same time halogens deacti-
Synlett 2004, No. 7, 1297–1299 © Thieme Stuttgart · New York

LETTER
New Aziridine Sulfide Ligands for Palladium-Catalyzed Asymmetric Allylic Alkylation
1299
H. R.; Silveira, C. C.; Bottega, D. P. Synthesis 2002, 2338.
(d) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira, C.
C.; Wessjohann, L. A. Tetrahedron: Asymmetry 1999, 10,
1733. (e) Braga, A. L.; Appelt, H. R.; Schneider, P. H.;
Rodrigues, O. E. D.; Silveira, C. C.; Wessjohann, L. A.
Tetrahedron 2001, 57, 3291. (f) Braga, A. L.; Vargas, F.;
Andrade, L. H.; Silveira, C. C. Tetrahedron Lett. 2002, 43,
2335. (g) Braga, A. L.; Paixão, M. W.; Lüdtke, D. S.;
Silveira, C. C.; Rodrigues, O. E. D. Org. Lett. 2003, 5, 2635.
(7) (a) Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar,
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(8) General Procedure for the Synthesis of Compound 6a.
To a suspension of PPh3 (1.048 g, 4 mmol) in THF (10 mL),
DEAD (0.696 g, 4 mmol) was added at –78 °C under argon
atmosphere. After 2 h, sulfide aminoalcohol 4a (1.148 g, 4
mmol) was added and the mixture was stirred for 12 h at r.t.
Then, the solvent was evaporated and the residue was
partitioned between H2O and CH2Cl2. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were dried over
MgSO4 and the solvent was evaporated under reduced
pressure. The crude product was purified by flash
Acknowledgment
We are grateful to the CAPES, CNPq and FAPERGS for financial
support. E. F. A. thanks CAPES for a Ph. D. fellowship. The authors
are also grateful to Professor Robert. A. Burrow (UFSM) for the
revision of this manuscript.
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Malonate: A toluene (1 mL) solution of [Pd(h3-C3H5)Cl]2
(9.1 mg, 25 mmol, 2.5 mol%) and the ligand (2.5 mol%) was
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(3 × 15 mL). The combined organic layers were dried over
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Synlett 2004, No. 7, 1297–1299 © Thieme Stuttgart · New York