9
180
X. Hu et al. / Tetrahedron Letters 43 (2002) 9179–9182
genic carbon center. Through introduction of a desired
functional group on the side chain according to the
reaction type, modified ferrocenyl ligands can bring
about high enantioselectivity in a variety of catalytic
asymmetric reactions including hydrogenation, cross-
coupling, cyclopropanation, allylic alkylation, aldol
reactions, the addition of dialkylzinc to aldehydes and
mixture of N,O-bis(trimethylsilyl)acetamide (BSA) and
a catalytic amount of metal acetate.
Optimization of the reaction conditions was first exam-
ined using ligand 6a. The results are listed in Table 1.
The reaction was initially carried out in toluene by
using 1,3-diphenylprop-2-en-1-yl acetate 8a as the sub-
strate and KOAc as the base to afford the product in
3
so on. Herein we report the synthesis of a new type of
8
7% e.e. (entry 1). Replacing 8a with 8b as the sub-
ferrocenyl P,N ligand where an amidino group was
introduced on the ferrocenylmethyl position and that
high enantioselectivity can be obtained in palladium-
catalyzed asymmetric allylic alkylation by using these
ligands.
strate, the enantioselectivity was significantly increased
to 92% e.e. in 96% yield (entry 2). The effects of bases
were also evaluated. Using sodium acetate or lithium
acetate instead of potassium acetate, the product was
obtained in 90 and 99% yields with 88 and 84% e.e’s,
respectively (entries 3 and 4). The use of cesium acetate
gave comparable enantioselectivity (92% e.e.) (entry 5).
The synthesis of the ferrocenylphosphine-amidine lig-
ands is shown in Scheme 1. The initial step in the
synthesis involved the catalytic asymmetric reduction of
ferrocenyl ketones 1 to the corresponding alcohols 2
with the R-configuration using Corey’s chiral B-methyl-
ated oxazaborolidine complex, which has been reported
to be a highly effective reagent for the reduction of
3
The reduction of the amount of [Pd(h -C H )Cl] from
3
5
2
0
.02 to 0.01 mol. equiv. caused a decrease in the
reaction rate, and only a slight drop in enantioselectiv-
ity (entry 6). The effect of solvents on this reaction was
also investigated and a remarkable variation in the
catalytic activity due to the nature of the solvent was
observed. CH Cl , which is usually a good solvent for
4
several ferrocenyl ketones. All the alcohols 2 were
2
2
obtained with high yields (>90%) and very high enan-
tioselectivity (>98% e.e.). Following sequential treat-
Pd-catalyzed allylic alkylation, proved to be not so
good for our catalytic system, and only a 65% e.e. with
a 31% yield was obtained (entry 7). The reaction pro-
ceeded at a low reaction rate with only moderate
enantioselectivity in THF (entry 8). When the reaction
ment with Ac O/pyridine and HNMe /CH CN, chiral
2
2
3
alcohols 2 were transformed into the optically active
tertiary amines 3 with complete configurational reten-
5
tion and in nearly quantitative yields. The highly
was carried out in benzene or Et O, somewhat lower
2
diastereoselective ortho-lithiation of amines 3 followed
enantioselectivities with a slightly increased yield were
obtained (entries 9 and 10). Increasing the reaction
temperature resulted in decreased enantioselectivity
(entry 11) while lowering the reaction temperature
decreased both the enantioselectivity and reactivity
(entry 12). The configuration of the product 9 from
these reactions was proved to be S by comparing the
by treatment with ClPPh gave phosphine–amine com-
2
6
pounds (PPFA-R) 4, which have the (R,S)-configura-
tions. After the reaction of the ferrocenyl-
phosphine–amines 4 with Ac O at 100°C followed by
2
treatment with a large excess of ammonia in methanol
or acetonitrile in an autoclave at 80°C, the Me N group
2
10
specific rotation with literature values.
of 4 was substituted by an NH group to form the
2
7
key intermediate, (R)-(S)-PPFNH -R 5. Nucleophilic
substitution on the ferrocenylmethyl position was
2
From the reaction condition screening experiments, we
selected 8b as substrate, toluene as solvent, and potas-
sium acetate as base for the completion of the palla-
dium-catalyzed asymmetric allylic alkylation with a
family of ligands. The results are summarized in Table
demonstrated to proceed with retention of configura-
1c,6b
tion at the stereogenic carbon center.
Treatment of
5
with N,N-dimethylformamide dimethyl acetal at
room temperature gave nearly quantitative yields of
2
.
amidines 6.
Of the ligands 6a–c possessing a different substituent,
R, on the stereogenic carbon center, the ligand 6b
The replacement of the dimethylamino group of the
amidines 6 by other secondary amines was also exam-
(
(
R=Et) exhibited the best enantioselectivity (94% e.e.)
entry 2), while the ligand 6c (R=Ph) gave the product
8
ined. The exchange reaction was carried out by simply
mixing compound 6a and a large excess of piperidine or
morpholine in the presence of a catalytic amount of
with an unexpectedly low yield and enantioselectivity
(
entry 3). For ligands 7a–b with piperidine or morpho-
1
0-camphorsulfonic acid at the corresponding reflux
line in place of the dimethylamino group, both yield
temperature to give the modified amidine ligands 7a
and 7b in 56 and 88% yields, respectively. However,
attempts to prepare the pyrrolidine modified amidine
ligand failed and no amidine product was detected even
after 24 h at reflux.
and enantioselectivity were decreased significantly
(
entries 4 and 5). It was noted that using PPFA–Et (4b)
as the ligand for the asymmetric allylic alkylation
resulted in a product with much lower enantioselectivity
(
entry 6).
The chiral ferrocenylphosphine-amidine ligands were
then applied to the palladium-catalyzed asymmetric
allylic alkylation of 1,3-diphenylprop-2-en-1-yl acetate
In conclusion, we have prepared a family of novel
ferrocenylphosphine–amidine ligands and applied them
to palladium-catalyzed asymmetric allylic alkylation.
When ligand 6b was used, up to 94% e.e. was achieved.
Further applications and modification of these ligands
are in progress.
9
or pivalate (8a, 8b) with dimethyl malonate. This
reaction was carried out in the presence of 2.0 mol% of
3
[
Pd(h -C H )Cl] , 5.0 mol% of the chiral ligand, a
3
5
2
Hu, Xiangping
