Synthesis of novel P-ketimine bidentate ferrocenyl ligands with central and planar chirality and comparsion in the catalytic activity between P-ketimine and P-aldimine

Article abstract of DOI:10.1016/j.tetasy.2003.09.034

A series of novel ferrocenylphosphine-ketimine ligands 6 were prepared by reaction of (R,S_p)-PPFNH₂-R or (S,S_p)- PPFNH₂ with a variety of m-substituted acetophenones. A different catalytic activity was observed

Full text of DOI:10.1016/j.tetasy.2003.09.034

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3415–3421
Synthesis of novel P-ketimine bidentate ferrocenyl ligands with
central and planar chirality and comparsion in the catalytic
activity between P-ketimine and P-aldimine
Xiangping Hu, Huilin Chen, Huicong Dai and Zhuo Zheng*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, PR China
Received 26 August 2003; accepted 19 September 2003
Abstract—A series of novel ferrocenylphosphine-ketimine ligands 6 were prepared by reaction of (R,Sp)-PPFNH2-R or (S,Sp)-
PPFNH2 with a variety of m-substituted acetophenones. A different catalytic activity was observed between ferrocenylphosphine-
ketimine ligands and corresponding aldimine ligands. The efficiency and diastereomeric impact of these
ferrocenylphosphine-ketimine ligands in Pd-catalyzed asymmetric allylic alkylation were first investigated, and higher enantioselec-
tivity of over 98% e.e. with 95% yield was obtained by the use of ferrocenylphosphine-ketimine ligands. However, in Rh-catalyzed
asymmetric hydrosilylation of aryl ketones, only 42% e.e. was obtained by the use of ferrocenylphosphine-ketimine ligands
compared to 90% e.e. with the use of aldimine ligands.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
steric effect of the chiral ligand, which would lead to
the dramatic changes in the reactivity and enantioselec-
tivity of the catalytic reaction. Therefore, the investiga-
tion into the difference between aldimines and
ketimines in catalytic activity is very meaningful for the
design of efficient ligands for a variety of asymmetric
catalysis.
Chiral P,N-ligands have been found widespread appli-
cation in a variety of asymmetric catalysis in past
decade.1 As an important class of P,N-ligands, chiral
phosphine-imine compounds have been attracting con-
siderable attention recently since they are easily pre-
pared and readily modified in electronic and steric
properties. Recently, many fine-tuned chiral phosphine-
imine based ligands have been found to be very effec-
tive in a variety of asymmetric catalytic reactions.2
Recently, we have reported the application of some
ferrocenylphosphine-imine ligands from (R,Sp)-
PPFNH2 and a variety of benzaldehydes, and found
that ligands with m-electron-withdrawing substitutents
tended to give higher catalytic activities and enantiose-
lectivities in Pd-catalyzed asymmetric allylic alkylation.3
Compared to the extensive application of aldimine lig-
ands derived from aldehydes and primary amines, there
are few reports on the synthesis of ketimine ligands
from ketones and primary amines for asymmetric catal-
ysis partly due to the difficult synthesis and instability
of ketimine compounds.4 However, the introduction of
an alkyl or aryl group into the methylene moiety of
aldimines could significantly affect the electronic and
Recently, Reetz and Angermund have reported the
C2-symmetric diketimines
1
and C2-symmetric
dialdimines 2 exhibited different reactivity and enan-
tioselectivity in Pd–catalyzed asymmetric allylic alkyla-
tion.4b The Pd-complex derived from the diketimine 1
turned out to be a reasonably active catalyst, affording
the allylic alkylation product in 78% yield with an
e.e.-value of 92%, while the Pd-complex derived from
the dialdimine 2 surprisingly showed no activity what-
* Corresponding author. Tel.: +86-411-4663087; fax: +86-411-
4684746; e-mail: zhengz@dicp.ac.cn
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.034

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X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
soever. This interesting result stimulated us to develop a
series of novel ferrocenylphosphine-ketimine ligands
and investigate the different reactivity and enantioselec-
tivity between ferrocenylphosphine-ketimine and its
aldimine analogues in catalytic asymmetric reaction. To
the best of our knowledge, no reports have focused on
the difference between P-aldimines and P-ketimines in
the catalytic reaction before us.
cenylphosphine-ketimine products 6 were obtained by
the reaction of PPFNH2-R 4 with aryl alkyl ketones.
The target ketimine compounds can be prepared when
the reaction of PPFNH2-R 4 with a variety of m-substi-
tuted acetophenones was carried out in the presence of
active Al2O3, however, the yield was relatively low and
no target compounds were obtained over 50% yield
even after 2 days in refluxing toluene. It is fortunate
that this difficulty can be easily resolved when a com-
plex system of active Al2O3 and anhydrous MgSO4 was
used in synthetic reaction, and the reaction gave the
target ferrocenylphosphine-ketimine ligands 6 in rea-
sonable yields. However, an attempt to synthesize the
ketimines from other ketones failed. All of these phos-
phine-imine ligands have the (R,Sp)-configurations.
In order to investigate the impact of diastereomeric
ferrocenyl ligands in the catalytic asymmetric reactions,
the synthesis of (S,Sp)-PPFNH2 and its imine deriva-
tives was carried out, and their efficiency in the cata-
lytic reaction was also examined.
2. Results and discussion
To examine the effect of diastereomeric ligands on the
catalytic reactions, the corresponding ferrocenylphos-
phine-imine ligands (S,Sp)-6c was prepared in 57% yield
in the same manner by employing (S,Sp)-PPFA as
illustrated in Scheme 2.6,7
2.1. Synthesis of ferrocenylphosphine-aldimine 5 and P-
ketimine ligands 6
The novel ferrocenylphosphine-ketimine ligands 6 were
synthesized according to Scheme 1. As we have
reported previously, the ferrocenylphosphine-aldimine 5
could be easily prepared in high yields from ferro-
cenylphosphine-amines 4 [(R,Sp)-PPFNH2]5 with m-
substituted benzaldehydes in refluxing ethanol in the
presence of anhydrous MgSO4.3 However, compared to
the easy synthesis of aldimines, the preparation of
corresponding ferrocenylphosphine-ketimine 6 is more
difficult. Under the same reaction conditions, no ferro-
2.2. Catalytic activities of P-aldimine ligands 5 and
P-ketimine ligands 6 in Pd-catalyzed asymmetric allylic
alkylation
Palladium-catalyzed asymmetric allylic alkylation of
1,3-diphenylprop-2-en-1-yl pivalate 8 with dimethyl
malonate was first investigated using standard condi-
tion reported previously (Eq. (1)).8 The results were
summarized in Table 1.
Scheme 1. Synthesis of ferrocenylphosphine-imine ligands (R,Sp)-5 and (R,Sp)-6.

X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
3417
ligands 6 with a methyl group in benzylidene position
exhibited higher enantioselectivity (entries 1–4 versus
entries 5–8). When ketimine ligand 6e was used, the
best result was obtained in over 98% e.e. and 95% yield
(entry 9). This result was consistent with that reported
by Reetz based on C2-symmetric diimine 1 and 2. The
reason why a sterically encumbered catalyst show
higher activity than the seemingly less shielded homo-
logue are explained by Reetz et al. based on the AMS
model. This can be traced to a ‘locking-in’ effect of the
phenyl group in 6/Pd, in contrast, the phenyl group of
5/Pd rotates much more freely, resulting in considerably
enhanced steric shielding. The configuration of allylic
alkylation product 9a from these reactions was proved
to be S by comparing the specific rotation with the
literature values.9 When diethyl methylmalonate instead
of dimethyl malonate was used as the nucleophile,
P-ketimine ligand 6c also exhibited higher enantioselec-
tivity than the corresponding P-aldimine 5c (entry 11
versus entry 10), and up to 98% e.e.-value of allylic
product 9b was obtained (entry 11).
Scheme 2. Synthesis of ketimine (S,Sp)-6c.
As we have reported previously, all of these meta-sub-
stituted ferrocenylphosphine-aldimines exhibited good
catalytic activity and enantioselectivity (entries 1–4),
and up to 94% e.e. with 99% yield was obtained by the
use of m-NO2 substituted ligand 5c (entry 3). When a
methyl group was introduced into the benzylidene posi-
tion of the ferrocenylphosphine-aldimine skeleton, the
resulting ketimine ligands chelated with Pd to form a
more sterically encumbered catalyst, which was
expected to exhibit lower catalytic activity. However, as
shown in Table 1, all of the ferrocenylphosphine-
ketimine ligands 6 from (R,Sp)-PPFNH2-R and meta-
substituted acetophenones surprisingly gave the allylic
alkylation product 9a in good yield and e.e. (entries
5-9). Compared to their aldimine analogues 5, ketimine
We next investigated the impact of diastereomeric fer-
rocenyl ligands on the palladium-catalyzed asymmetric
allylic alkylation. Compared to (R,Sp)-6c, (S,Sp)-6c
showed lower enantioselectivity but gave the alkylation
product 9a with the same configuration (entry 7 versus
(1)
Table 1. Asymmetric allylic alkylation of 1,3-diphenylprop-2-en-1-yl pivalate 8 and cyclohexenyl acetate 11 using ligand 5
and 6a
Entry
Ligand
Substrate
Nucleophile
Yield (%)b
E.e. (%)c config.d
1
2
3
4
5
6
7
8
(R,Sp)-5a
(R,Sp)-5b
(R,Sp)-5c
(R,Sp)-5d
(R,Sp)-6a
(R,Sp)-6b
(R,Sp)-6c
(R,Sp)-6d
(R,Sp)-6e
(R,Sp)-5c
(R,Sp)-6c
(S,Sp)-6c
(R,Sp)-5c
(R,Sp)-6c
8
8
8
8
8
8
8
8
8
8
8
8
11
11
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
10b
10a
10a
10a
98
95
99
94
91
90
94
90
95
89
91
91
81
95
90 (S)
90 (S)
94 (S)
91 (S)
93 (S)
93 (S)
98 (S)
92 (S)
>98 (S)
96e
9
10
11
12
13
14
98e
88 (S)
83f
62f
a The reactions were carried out in toluene in the present of 2.0 mol% [Pd(h3-C3H5)Cl]2, 5.0 mol% of chiral ligand, 3.0 equiv. of dimethyl malonate
or diethyl methylmalonate, 3.0 equiv. of BSA and a catalytic amount of KOAc at rt
b Isolated yields.
c Determined by HPLC analysis using a chiralpak AD column (eluent:hexane: 2-propanol=90: 10, 1.0 mL/min).
d The S-configuration was confirmed by comparing the specific rotation with a literature value.9
e Determined by HPLC analysis using a chiralpak AD column (eluent:hexane: 2-propanol=97.5:2.5, 0.5 mL/min).
f Determined by GC analysis using a b-390 sationary capillary column.

3418
X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
Table 2. Asymmetric hydrosilylation of acetophenone 13
using ligand 5 and 6a
Hayashi et al. reported that ferrocenylphosphine-
aldimine ligands 5d–f were very effective ligands for
rhodium-catalyzed asymmetric hydrosilylation of
prochiral ketones.5a On the basis of the good results
obtained in Pd-catalyzed asymmetric allylic alkylation
by the use of ferrocenylphosphine-ketimine ligands, we
then presumed that these P-ketimine ligands are per-
phaps more effective ligands than corresponding
aldimine for Rh-catalyzed asymmetric hydrosilylation
of prochiral ketones. However, the results obtained by
the use of ferrocenylphosphine-ketimine ligands 6 are
very depressed, and the reaction gave the chiral alcohol
with unexpectedly low enantioselectivity compared to
the corresponding aldimine 5.
Entry
Ligand
Yield (%)b
E.e. (%)c config.d
1
2
3
4
5
6
7
8
(R,Sp)-5a
(R,Sp)-5b
(R,Sp)-5c
(R,Sp)-5d
(R,Sp)-6a
(R,Sp)-6b
(R,Sp)-6c
(R,Sp)-6d
(R,Sp)-6e
(S,Sp)-6c
92
90
89
90
76
71
59
74
54
51
90 (R)
80 (R)
81 (R)
90 (R)
42 (R)
38 (R)
29 (R)
40 (R)
31 (R)
26 (R)
9
10
a The reaction was carried out in 2.0 mL of THF in the presence of
[Rh(NBD)Cl]2 (0.01 mmol), ligand (0.03 mmol), acetophenone (2.0
mmol), Ph2SiH2 (2.5 mmol).
b Isolated yield.
c Determined by GC analysis with
a capillary chiral column
(cyclodex-b,2-,3-,6-methylated, 30 m×0.25 mm (i.d.)).
d The absolute configuration was determined by comparison of the
retention time of the enantiomers on the GC analysis with literature
values.
entry 12). This result indicated that (R)-central chirality
and (Sp)-planar chirality were matched in these ferro-
cenylphosphine-imine ligands for the palladium-cata-
lyzed asymmetric allylic alkylation.
(3)
(2)
As shown in Table 2, all of ferrocenylphosphine-
aldimine ligands 5 exhibited good catalytic activity
(entries 1–4), and up to 90% e.e. was obtained by the
use of ligands 5a and 5d (entries 1 and 4). Compared to
the results obtained in Pd-catalyzed asymmetric allylic
In order to show the validity of the developed ligands,
the applications to other substrates such as cyclohex-
enyl acetate were then investigated. Although the Pd-
catalyzed asymmetric allylic alkylation of acyclic
substrates is one of the most thoroughly investigated
C–C bond forming reactions, the corresponding substi-
tution of cycloalkenyl esters is still a major challenge.10
The reaction of cyclohexenyl acetate 11 with dimethyl
malonate was catalyzed by 5/Pd and 6/Pd complexes to
give the dimethyl (cyclohexen-2-yl)malonate 12 (Eq.
(2)). The results, summarized in Table 1 (entries 13 and
14), indicated that the more effective ligand in this
reaction was the ferrocenylphosphine-aldimine ligand
5c, and up to 83% e.e. of allylic product 12 was
achieved, which was in contrast to the results obtained
in the alkylation of 1,3-diphenylprop-2-en-1-yl pivalate
8.
alkylation, where ferrocenylphosphine-ketimines
6
exhibited higher enantioselectivity than their aldimine
analogues 5, extremely low enantioselectivity was
obtained in the Rh-catalyzed asymmetric hydrosilyla-
tion by the use of ketimine ligands 6 (entries 1–4 versus
entries 5–8). Only 42% e.e. was observed by the use of
ketimine ligand 6a, compared to an e.e.-value of 90%
with the corresponding aldimine 5a (entry 5 versus
entry 1). The reason why ketimine 6 and aldimine 5
showed dramatically different activity can be rational-
ized by mechanistic studies on the stereochemistry and
reaction course of Rh-catalyzed hydrosilylation by
Brunner et al.12 Using ketimine 6 as cocatalyst, the
methyl group in the benzylidene position blocked the
coordination site by a steric interaction. Therefore, the
complex of substrate with the central metal and subse-
quent addition of Ph2SiH2 to rhodium atom was lim-
ited, which resulted in the low enantioselectivity and
reactivity.
2.3. Catalytic activity of P-aldimine ligands 5 and P-
ketimine ligands 6 in Rh-catalyzed asymmetric hydrosi-
lylation of acetophenone
In addition, the impact of diastereomeric ferrocenyl
ligands on the rhodium-catalyzed asymmetric hydrosi-
lylation was also examined, and the experimental data
showed that the combination of (R)-central chirality
and (Sp)-planar chirality in these ferrocenylphosphine-
We next examined the difference in catalyst activity
between the chiral ferrocenylphosphine-aldimine lig-
ands 5 and ketimine ligands 6 in the Rh-catalyzed
asymmetric hydrosilylation of acetophenone.11 In 1995,

X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
3419
imine ligands were also advantageous to the catalytic
reaction. The configuration of alcohol product 14 from
these reactions was proved to be R.
diluted with toluene. MgSO4 and Al2O3 were removed
by filtration and the filtrate was concentrated under
reduced pressure. The residue was purified by column
chromatography.
3. Conclusion
4.2.1. (R)-N-[1-(3-Methoxyphenyl)ethylidene]-1-[(S)-2-
(diphenylphosphino)ferrocenyl]ethylamine 6a. Recrystal-
lized from n-hexane to afford orange needle solid;
54.8% yield; mp 130–131°C; [h]2D5=−351 (c 0.10,
In conclusion, we have developed a series of new ferro-
cenylphosphine-ketimine ligands 6 and investigated the
difference in the catalytic activity between P-ketimines
and P-aldimines in asymmetric catalysis. An extreme
difference in catalytic activity between aldimine ligands
5 and ketimine ligands 6 was observed. In Pd-catalyzed
asymmetric allylic alkylation of 1,3-diphenylprop-2-en-
1-yl pivalate 8, ferrocenylphosphine-ketimine ligands 6
exhibited higher enantioselectivity than the correspond-
ing aldimine ligands 5. When m-NO2 substituted
ketimine ligand 6e was used in the test reaction, over
98% e.e. with 95% yield of allylic alkylation product
was obtained. However, in Pd-catalyzed asymmetric
allylic alkylations of cyclohexenyl acetate, the more
effective ligand was the ferrocenylphosphine-aldimine
ligand 5c, and up to 83% e.e. was achieved. While in
Rh-catalyzed asymmetric hydrosilylation of prochiral
ketones, ferrocenylphosphine-ketimine ligands 6 gave
lower enantioselectivity, only 42% e.e. of alcohol was
obtained. This research also indicated that (R)-central
chirality and (Sp)-planar chirality in these ferro-
cenylphosphine-ketimine ligands were matched for the
test reactions. Further application and modification of
ligands are in progress.
1
CHCl3); H NMR (DMSO-d6) l 1.44 (d, J=6.4 Hz, 3
H), 2.07 (s, 3 H), 3.69 (s, 3 H), 3.69 (s, 1 H), 4.02 (s, 5
H), 4.38 (s, 1 H), 4.66 (s, 1 H), 4.99–5.00 (m, 1 H),
6.82–7.52 (m, 14 H); 31P NMR l −21.4. HRMS calcd
for C33H32NOPFe 545.1570, found 545.1569.
4.2.2.
(R)-N-[1-(3-Chlorophenyl)ethylidene]-1-[(S)-2-
(diphenylphosphino)ferrocenyl]ethylamine 6b. Orange
viscous liquid; 57.6% yield; [h]2D5=−366 (c 0.13, CHCl3);
1H NMR (CDCl3) l 1.57 (d, J=6.8 Hz,3 H), 2.16 (s, 3
H), 3.73 (s, 1 H), 4.06 (s, 5 H), 4.32 (s, 1 H), 4.67–4.68
(m, 1 H), 5.12–5.13 (m, 1 H), 6.85–7.48 (m, 14 H); 31P
NMR l −28.0. HRMS calcd for C32H29ClNPFe
549.1075, found 549.1072.
4.2.3.
(R)-N-[1-(3-Nitrophenyl)ethylidene]-1-[(S)-2-
(diphenylphosphino)ferrocenyl]ethylamine 6c. Recrystal-
lized from n-hexane to afford brown needle solid;
51.6% yield; mp 132–133oC; [h]2D5=−381 (c 0.13,
1
CHCl3); H NMR (DMSO-d6) l 1.47 (d, J=6.6, 3 H),
2.23 (s, 3 H), 3.67 (s, 1 H), 4.07 (s, 5 H), 4.39 (s, 1 H),
4.70 (s, 1 H), 5.08–5.12 (m, 1 H), 6.73–8.11 (m, 14 H);
31P NMR l −19.8. HRMS calcd for C32H29N2O2PFe
560.1311, found 560.1292.
4. Experimental
4.2.4.
(R)-N-[1-(3-Trifluoromethylphenylethylidene]-1-
4.1. General methods
[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine
6d.
Orange viscous liquid; 49.5% yield; [h]2D5=−348 (c 0.11,
1
Melting points were measured on a Yazawa micro
melting point apparatus (uncorrected). Optical rota-
tions were measured on a HORIBA SEPA-200 high
sensitive polarimeter. The 1H NMR spectra were
recorded on a BRUKER DRX 400 system with TMS
as an internal standard. The 31P NMR spectra were
recorded using a BRUKER DRX 400 system with 85%
phosphoric acid as the external standard. Enantiomeric
excesses (% e.e.) were determined by HPLC (Agilent
1100 series) analysis. All experiments were carried out
under an argon atmosphere. All solvents were dried
using standard procedures. 1,3-Diphenylprop-2-en-1-yl
pivalate 8 was derived from the reaction of 1,3-
diphenylprop-2-en-1-ol with pivaloyl chloride in pyri-
dine. 4 and 7 were synthesized following the literature
method.
CHCl3); H NMR (DMSO-d6) l 1.55 (d, J=4.0 Hz, 3
H), 2.59 (s, 3 H), 3.72 (s, 1 H), 4.06 (s, 5 H), 4.26 (s, 1
H), 4.68 (s, 1 H), 5.08–5.09 (m, 1 H), 6.94–7.91 (m, 14
H); 31P NMR l −28.0. HRMS calcd for C33H29F3NPFe
583.1339, found 583.1337.
4.2.5.
(R)-N-[1-(3-Nitrophenyl)ethylidene]-1-[(S)-2-
(diphenylphosphino)ferrocenyl]propylamine 6e. Orange
foam solid; 61.2% yield; [h]2D5=−369 (c 0.11, CHCl3);
1H NMR (DMSO-d6) l 0.83 (t, J=7.2 Hz, 3 H),
1.81–1.86 (m, 1 H), 2.20 (s, 3 H), 2.25–2.30 (m, 1 H),
3.63 (s, 1 H), 4.07 (s, 5 H), 4.39 (s, 1 H), 4.68 (s, 1 H),
4.84–4.86 (m, 1 H), 6.75–8.12 (m, 14 H); 31P NMR l
−22.1. HRMS calcd for C33H31N2O2PFe 574.1472,
found 574.1474.
4.3. Synthesis of (S,Sp)-ferrocenylphosphine-ketimine
4.2. General procedure for the synthesis of (R,Sp)-fer-
rocenylphosphine-ketimine 6
4.3.1. Synthesis of (S)-1-[(S)-2-(diphenylphosphino)-fer-
rocenyl]ethylamine 4a. The amine 7 (2.0 mmol) was
sealed in an air-free tube with acetic anhydride (1.5
mL). The tube was heated to 100°C for 2 h. After
cooled to rt, the reaction mixture was poured into 50
mL of 10% aqueous potassium carbonate with vigorous
stirring. Oil material was extracted with Et2O (20 mL×
2). The ether extract was successively washed with 2 M
To a solution of (R,Sp)-PPFNH2-R 4 (1.0 mmol) in
toluene (8.0 mL) were added the corresponding ace-
tophenones (1.0 mmol), active Al2O3 (500 mg) and
anhydrous MgSO4 (200 mg). The reaction mixture was
heated to reflux. After the reaction was complete
(detected by TLC after 24 h), the reaction mixture was

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X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
HCl, 5% K2CO3, and water, and dried over Na2SO4.
The solvent was removed under reduced pressure, the
residue was dissolved in a solution of 10 mL 25%
aqueous ammonia in 20 mL of CH3CN. The mixture
was then placed in a 100 mL autoclave and heated at
80°C for 8 h. The reaction mixture was diluted with 10
mL of CH2Cl2, and the solvent was evaporated. The
residue was extracted with CH2Cl2 (10 mL×2) and dried
over anhydrous Na2SO4. The solvent was removed
under reduced pressure, the residue was purified by
column chromatography (silica gel modified by 2%
Et3N, elution by hexanes:ethyl acetate:Et3N, 20:10:1 to
10:20:1) to give 443 mg (53.6% yield) of (S)-1-[(S)-2-
(diphenylphosphino)ferrocenyl]-ethylamine [(S,Sp)-4a]
as an orange crystals. mp 127–128°C; [h]2D5=−341 (c
Ph2SiH2 (230 mL, 230 mg, 1.25 mmol) sequentially, and
the mixture was stirred at rt for 1.5 h. The reaction
mixture was then quenched with 1.0 ml of methanol,
stirred at rt for 1 h, and subsequently hydrolysed by the
addition of 1 N HCl aq. This solution was extracted
with diethyl ether (50 mL×3) and the extract was dried
over anhydrous MgSO4. After the solvent was removed
under reduced pressure, the residue was purified by
column chromatography (hexane:ethyl acetate, 9:1) to
afford a pure product 14. The enantiomeric excess was
determined by GC analysis with a capillary chiral
column (cyclodex-b,2-,3-,6-methylated, 30 m×0.25 mm
(i.d.)).
1
0.11, CHCl3); H NMR (DMSO-d6) l 0.78 (d, J=6.4
Acknowledgements
Hz, 3 H), 3.34 (br, 2 H), 3.72 (s, 1 H), 4.02 (s, 1 H),
4.02 (s, 5 H), 4.31 (s, 1 H), 4.60 (s, 1 H), 7.10–7.13 (m,
2 H), 7.25–7.29 (m, 3 H), 7.43 (s, 3 H), 7.50–7.52 (m, 2
H); 31P NMR l −23.2.
The authors would like to thank the National Natural
Science Foundation of China for financial support of
this work (29933050).
4.3.2.
(S)-N-[1-(3-nitrophenyl)ethylidene]-1-[(S)-2-
(diphenylphosphino)ferrocenyl]ethylamine 6c. Yellow
solid; 57.1% yield; mp 147–149oC; [h]D25=−31.2 (c 0.076,
CHCl3); H NMR (DMSO-d6) l 0.96 (d, J=6.4 Hz, 3
References
1
H), 2.38 (s, 3 H), 3.70 (s, 1 H), 3.90 (s, 5 H), 4.41 (s, 1
H), 4.81 (s, 1 H), 4.88–4.91 (m, 1 H), 7.16–8.81 (m, 14
−22.5. HRMS calcd for
C32H29N2O2PFe 560.1311, found 560.1302.
1. (a) Ojima, I. Ed.; Catalytic Asymmetric Synthesis; VCH:
New York, 1999; (b) Fache, F.; Schulz, E.; Tommasino,
M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159–2231 and
references cited therein; (c) Sutcliffe, O. B.; Bryce, M. R.
Tetrahedron: Asymmetry 2003, 14, 2297–2325 and refer-
ences cited therein.
H); 31P NMR
l
4.4. General procedure for asymmetric allylic
alkylations
2. (a) Jang, H.-Y.; Seo, H.; Han, J. W.; Chung, Y. K.
Tetrahedron Lett. 2000, 41, 5083–5087; (b) Kohara, T.;
Hashimoto, Y.; Saigo, K. Synlett 2000, 517–519; (c)
Fukuda, T.; Takehara, A.; Iwao, M. Tetrahedron: Asym-
metry 2001, 12, 2793–2799; (d) Saitoh, A.; Achiwa, K.;
Tanaka, K.; Morimoto, T. J. Org. Chem. 2000, 65,
4227–4240; (e) Park, H.-J.; Han, J. W.; Seo, H.; Jang,
H.-Y.; Chung, Y. K.; Suh, J. J. Mol. Cat., A: Chem.
2001, 174, 151–157; (f) Lee, J. H.; Son, S. U.; Chung, Y.
K. Tetrahedron: Asymmetry 2003, 14, 2109–2113.
3. Hu, X.; Dai, H.; Hu, X.; Chen, H.; Wang, J.; Bai, C.;
Zheng, Z. Tetrahedron: Asymmetry 2002, 13, 1687–1693.
4. (a) Suzuki, Y.; Ogata, Y.; Hiroi, K. Tetrahedron: Asym-
metry 1999, 10, 1219–1222; (b) Reetz, M. T.; Haderlein,
G.; Angermund, K. J. Am. Chem. Soc. 2000, 122, 996–
997.
5. (a) Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron:
Asymmetry 1995, 6, 2503–2506; (b) Hu, X.; Chen, H.;
Hu, X.; Dai, H.; Bai, C.; Wang, J.; Zheng, Z. Tetra-
hedron Lett. 2002, 43, 9179–9182; (c) Kim, T.-J.; Lee,
H.-Y.; Ryu, E.-S.; Park, D.-K.; Cho, C. S.; Shim, S. C.;
Jeong, J. H. J. Organomet. Chem. 2002, 649, 258–267; (d)
Tu, T.; Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X.; Dong,
X.-C.; Yu, Y.-H.; Sun, J. Organometallics 2003, 22, 1255–
1265.
A solution of [Pd(h3-C3H5)Cl]2 (3.7 mg, 0.01 mmol)
and chiral ferrocenylphosphine-ketimine 6 or phos-
phine-aldimine 5 (0.025 mmol) in toluene (1.5 mL) was
stirred at room temperature for one hour under argon.
To this Pd-catalyst was added allylic pivalate 8 (0.50
mmol) or cyclohexenyl acetate 11 (0.50 mmol) in tolu-
ene (1.5 mL), followed by dimethyl malonate (170 mL,
1.5 mmol) or diethyl methylmalonate (260 mL, 1.5
mmol), N,O-bis(trimethylsilyl)acetamide (BSA, 0.37
mL, 1.5 mmol), and a catalytic amount of KOAc
sequentially. After stirring for 24 h, the reaction mix-
ture was quenched with saturated aqueous NH4Cl solu-
tion and diluted with CH2Cl2. The organic layer was
separated, dried over MgSO4, and concentrated under
reduced pressure. E.e. value for 9a determined by
HPLC (Chiralpak AD, hexanes: 2-propanol=90: 10,
1.0 mL/min); 9b by HPLC (Chiralpak AD, hexanes:
2-propanol=97.5: 2.5, 0.5 mL/min); 12 by GC (b-390
sationary capillary column). The absolute configuration
was determined by the specific rotation with a literature
value.9
4.5. General procedure for asymmetric hydrosilylation
of acetophenone
6. Hu, X.; Chen, H.; Dai, H.; Hu, X.; Zheng, Z. Tetra-
hedron: Asymmetry 2003, 14, 2073–2080.
7. Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.;
Nagashima, N.; Hamada, Y.; Matsumoto, A.;
Kawakami, S.; Konishi, M.; Yamamoto, K.; Kumada,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1138–1151.
A solution of [Rh(NBD)Cl]2 (2.3 mg, 0.005 mmol) and
chiral ferrocenylphosphine-imine ligand 5 and 6 (0.015
mmol) in THF (1.5 mL) was stirred at room tempera-
ture for 30 min under argon. To this Rh-catalyst was
added acetophenone (120 mg, 110 mL, 1.0 mmol) and

X. Hu et al. / Tetrahedron: Asymmetry 14 (2003) 3415–3421
3421
8. (a) Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977,
99, 1649–1651; (b) Trost, B. M.; Murphy, D. J.
Organometallics 1985, 4, 1143–1145; (c) Hayashi, T.;
Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi,
K. J. Am. Chem. Soc. 1989, 111, 6301–6311; (d) Trost, B.
M.; Vranken, D. L. V. Chem. Rev. 1996, 96, 395–422 and
references cited therein; (e) Fache, F.; Schulz, E.; Tom-
masino, M. L.; Lemaire, M. Chem. Rev. 2000, 100,
2159–2231 and references cited therein; (f) Hayashi, T.
Acc. Chem. Res. 2000, 33, 354–362; (g) Helmchen, G.;
Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345; (h) Kim, Y.
K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65,
7807–7813; (i) Mino, T.; Shiotsuki, M.; Yamamoto, N.;
Suenaga, T.; Sakamoto, M.; Fujita, T.; Yamashita, M. J.
Org. Chem. 2001, 66, 1795–1797; (j) Fukuda, T.; Take-
hara, A.; Iwao, M. Tetrahedron: Asymmetry 2001, 12,
2793–2799; (k) Stranne, R.; Vasse, J.-L.; Moberg, C. Org.
Lett. 2001, 3, 2525–2528; (l) Wang, Y.; Li, X.; Ding, K.
Tetrahedron Lett. 2002, 43, 159–161; (m) Dai, L.-X.; Tu,
T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res.
2003, 36, 659–667.
S.; Helmchen, G. Angew. Chem. Int. Ed. 1998, 37, 3047–
3050; (e) Dierkes, P.; Ramdeehul, S.; Barloy, L.; Cian, A.
D.; Fischer, J.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M.; Osborn, J. A. Angew. Chem. Int. Ed. 1998, 37,
3116-3118; (f) Gilbertson, S. R.; Xie, D. Angew. Chem.,
Int. Ed. 1999, 38, 2750–2752; (g) Evans, D. A.; Campos,
K. R.; Tedrow, J. S.; Michael, F. E.; Gagne, M. R. J.
Am. Chem. Soc. 2000, 122, 7905–7920; (h) Saitoh, A.;
Achiwa, K.; Tanaka, K.; Morimoto, T. J. Org. Chem.
2000, 65, 4227–4240; (i) Hou, D.-R.; Reibenspies, J. H.;
Burgess, K. J. Org. Chem. 2001, 66, 206–215; (j)
Hamada, Y.; Sakaguchi, K.; Hatano, K.; Hara, O. Tetra-
hedron Lett. 2001, 42, 1297–1299; (k) Xiao, L.; Weis-
sensteiner, W.; Mereiter, K.; Widhalm, M. J. Org. Chem.
2002, 67, 2206–2214; (l) Shibatomi, K.; Uozumi, Y. Tet-
rahedron: Asymmetry 2002, 13, 1769–1772.
11. For examples of Rh-catalyzed asymmetric hydrosilylation
of ketones, see: (a) Brunner, H.; Riepl, G.; Weitzer, H.
Angew. Chem. Int. Ed. 1983, 22, 331; (b) Nishiyama, H.;
Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.;
Itoh, K. Organometallics 1989, 8, 846–848; (c) Sawamura,
M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. 1994, 33,
111–113; (d) Sudo, A.; Yoshida, H.; Saigo, K. Tetra-
hedron: Asymmetry 1997, 8, 3205–3208; (e) Lee, S.-G.;
Lim, C. W.; Song, C. E.; Kim, I. O. Tetrahedron: Asym-
metry 1997, 8, 4027–4031.
9. von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1993, 32, 566–568.
10. For examples of Pd-catalyzed asymmetric allylic alkyla-
tion of cycloalkenyl substrates, see: (a) Trost, B. M.;
Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089–4090; (b)
Knuhl, G.; Sennhenn, P.; Helmchen, G. J. Chem. Soc.,
Chem. Commun. 1995, 1845–1846; (c) Nishimata, T.;
Mori, M. J. Org. Chem. 1998, 63, 7586–7587; (d) Kudis,
12. Brunner, H.; Brandl, P. Tetrahedron: Asymmetry 1991, 2,
919–930.