Modification of (1R,2S)-1,2-Diphenyl-2-aminoethanol for the Highly Enantioselective, Asymmetric Alkylation of N-Diphenylphosphinoyl Arylimines with Dialkylzinc

Article abstract of DOI:10.1002/chem.200305418

Experimental studies on the modification of (1R,2S)-1,2-diphenyl-2-aminoethanol, which is used to promote the alkylation of N-diphenylphosphinoyl benzalimine with diethylzinc, revealed that N-monosubstituted amino alcohols exhibited higher enantioselectiv

Full text of DOI:10.1002/chem.200305418

FULL PAPER
Modification of (1R,2S)-1,2-Diphenyl-2-aminoethanol for the Highly
Enantioselective, Asymmetric Alkylation of N-Diphenylphosphinoyl
Arylimines with Dialkylzinc
Hai-Le Zhang,[a] Fan Jiang,[b] Xiao-Mei Zhang,[a] Xin Cui,[a] Liu-Zhu Gong,*[a]
Ai-Qiao Mi,[a] Yao-Zhong Jiang,[a] and Yun-Dong Wu*[b, c]
Abstract: Experimental studies on the
modification of (1R,2S)-1,2-diphenyl-2-
aminoethanol, which is used to pro-
mote the alkylation of N-diphenylphos-
phinoyl benzalimine with diethylzinc,
Application of the optimal chiral
ligand 3c to activate the reaction of N-
diphenylphosphinoyl arylimines with
diethylzinc and dibutylzinc resulted in
excellent enantiomeric selectivities of
up to 98% ee. The origin of the experi-
mentally observed enantioselectivities
was revealed by density functional cal-
culations (B3LYP/6-31G*) on the tran-
sition structures of several model reac-
tions.
revealed
that
N-monosubstituted
Keywords: amino
alcohols
¥
amino alcohols exhibited higher enan-
tioselectivities than their N,N-disubsti-
tuted counterparts and imino alcohols.
asymmetric additions
¥
density
functional calculations ¥ imines ¥ zinc
Introduction
zinc represents one of the most convenient routes to optical-
ly active amines. Since Soai and co-workers reported on the
MOPEP (an ephedrine derivative)-mediated addition of di-
ethylzinc to diphenylphosphinoylimine, enantioselective al-
kylations of N-diphenylphosphinoyl arylimines with dialkyl-
Chiral amines are widely used in the synthesis of natural
products and physiologically active substances, in chiral sep-
aration, and in asymmetric synthesis as chiral auxiliaries.[1,2]
There has been great interest in developing methods for
asymmetric preparation of chiral amines.[3,4] Enantioselec-
tive nucleophilic addition of organometallic reagents to
imines, which is very challenging, has been investigated in
recent years.[4] Asymmetric alkylation of imines with dialkyl-
f]
zinc that employ chiral amino alcohols,[5a chiral oxazoli-
h]
j]
nes,[5g polymeric chiral amino alcohols,[5i and chiral den-
drimers[5k] as ligands have been described. A recent study in
this area focused on the development of chiral complexes
for a catalytic version of the reaction.[6] Many chiral amino
alcohol ligands have been developed for the addition of di-
ethylzinc to diphenylphosphinoylimines, but most of them
are limited to the compounds containing a structurally rigid
backbone.[5e,f] There is a trend in previous reports that struc-
turally constrained chiral b-amino alcohols generally show
much higher enantioselectivities than their structurally flexi-
[a] H.-L. Zhang, X.-M. Zhang, X. Cui, Prof. L.-Z. Gong, Prof. A.-Q. Mi,
Y.-Z. Jiang
Key Laboratory for Asymmetric Synthesis and Chirotechnology
of Sichuan Province
Chengdu Institute of Organic Chemistry Chinese Academy
of Sciences
Chengdu, 610041 (China)
Fax : (+86)28-8522-3978
f]
ble counterparts.[5b However, the synthesis of structurally
rigid and restricted amino alcohols is inconvenient and often
involves a multistep-synthesis.[5e,7] This makes the addition
of diethylzinc to imines for the preparation of chiral amines
too expensive to compete with other families of chiral li-
gands, especially if stoichiometric amounts are needed.
Therefore, the development of easily accessible and eco-
nomical chiral reagents is still worthwhile.
In our laboratory, metal complexes of chiral 1,2-diphenyl-
2-aminoethanol and its derivatives have been developed
with the aim of promoting several reactions that have exhib-
ited high enantioselectivities in most cases.[8] Prompted by
these results and the fact that the size of the substituent
E-mail: gonglz@cioc.ac.cn
[b] F. Jiang, Prof. Y.-D. Wu
State Key Laboratory of Molecular Dynamics and Stable Species
College of Chemistry, Peking University
Beijing (China)
E-mail: chydwu@chem.pku.edu.cn
[c] Prof. Y.-D. Wu
Department of Chemistry, The Hong Kong University of Science and
Technology
Clear Water Bay, Kowloon, Hong Kong (China)
E-mail: chydwu@chem.pku.edu.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200305418
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

FULL PAPER
bonded to the nitrogen on chiral amino alcohols might play
an important role in influencing enantioselectivity, we envi-
sioned that highly enantioselective ligands for asymmetric
diethylzinc addition to N-diphenylphosphinoylimines might
be obtained by fine-tuning the substituents on the nitrogen
center of chiral 1,2-diphenyl-2-aminoethanol. A preliminary
report on this project has already been presented.[9] Herein
we report the comprehensive investigation of a library of
chiral b-amino alcohols (1 4), which exhibit subtle differen-
ces in their structures and which are derived from chiral 1,2-
diphenyl-2-aminoethanol, for the asymmetric alkylation of
imines with dialkylzinc. We also report a theoretical study
that sheds light on the origin of the observed enantioselec-
tivities (Scheme 1).
of 1,2-diphenyl-2-aminoethanol with substituted benzalde-
hydes in anhydrous ethanol followed by reduction with
NaBH4 in one pot furnished 3a k with good-to-high yields.
Compounds 3a d,g,h,j were treated with HCOOH and
HCHO under refluxing conditions to provide 2a g in high
yields.
Chiral imines 4a m were simply prepared by condensa-
tion of 1,2-diphenyl-2-aminoethanol with the corresponding
aldehyde in the presence of anhydrous sodium sulfate. All
these compounds were obtained as fine crystals, and were
identified by NMR and IR spectra.
Asymmetric addition of diethylzinc to N-diphenylphosphi-
noyl benzalimine mediated by N,N-disubstituted amino alco-
hols 1 and 2: We systematically
examined the effects of sub-
stituents on the enantioselectiv-
ity of the reaction of diethylzinc
with
N-diphenylphosphinoyl
benzalimine as a standard sub-
strate in the presence of stoi-
chiometric amounts of N,N-dis-
ubstituted amino alcohols 1 or
2. The size of the substituents
bonded to the nitrogen atom in
ligands 1 was important for ach-
ieving a high enantioselectivity
in the reactions (Table 1). The
ligand (1R,2S)-1a, which is ex-
cellent for enantioselective ad-
dition of diethylzinc to aldehy-
des,[8a] induced the reaction of
5a with Et2Zn in 89% ee
(Table 1, entry 1). A slight im-
provement in the enantioselec-
Scheme 1. Chiral ligands evaluated for this study.
Results and Discussion
Table 1. The addition of diethylzinc to N-diphenylphosphinoyl benzali-
Preparation of the chiral ligands: The preparation of N,N-
disubstituted amino alcohols 1a f from chiral 1,2-diphenyl-
2-aminoethanol has already been reported.[8] N,N-Disubsti-
tuted amino alcohols 2 bearing substituted phenyl and N-
monosubstituted amino alcohols 3 were prepared according
to a synthetic route shown in Scheme 2. The condensation
mine 5a in the presence of chiral N,N-disubstituted amino alcohols 1 or
2.[a]
Entry
Ligand
Yield[%][b]
ee[%][c]
Configuration[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
2g
9389
90
72
91
65
92
94
6392
9384
3
R
R
R
R
R
S
R
R
R
R91
R
R
R
94
89
85
80
40
95
5
87
94
80
95
93
93
[a] The reaction was carried out at room temperature in the presence of
stoichiometric amounts of amino alcohols for 48 h. [b] Yield of isolated
product based on imine 5a. [c] Determined by HPLC. [d] Determined by
comparison of the retention time with the literature.
Scheme 2. The preparation of compounds 2 and 3
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Enantioselective Alkylation of Arylimines with Dialkylzinc
1481 1492
tivity was realized when the reaction was catalyzed by 1b. A
further increase in the steric hindrance of the substituents at
the nitrogen atom in the chiral ligands led to a significant
decrease in the enantioselectivity (Table 1, entries 3 5).
Unlike the reported conformationally restricted amino alco-
hol 3a, in which a methyl group was removed from the ni-
trogen atom as compared with its N,N-disubstituted ana-
logue 2a, provided an excellent enantioselectivity of
95% ee. This result indicated that N-monosubstituted b-
amino alcohols could also serve as good ligands for the addi-
tion of diethylzinc to imine. Thus we surveyed other N-mon-
osubstituted b-amino alcohols 3b k for their ability to pro-
mote the above-mentioned reaction. As shown in Table 2,
f]
hols,[5d the use of the nitrogen-constrained ligand 1e as a
promoter resulted in a dramatic drop in both yield and
enantioselectivity (Table 1, entry 5). This is possibly attribut-
ed to the rigidity of the pyrrolidine ring in the ligands which
made it difficult for the ligand zinc alkoxide system to coor-
dinate to the substrate. Comparison of entries 2 and 6 in
Table 1, clearly shows that the configuration of the product
depends on the configuration of the carbon atom bonded to
the hydroxy group on the ligands. When the configuration
of this carbon atom was inverted while that of the carbon
atom bonded to the nitrogen atom was retained, as shown
from 1b to 1 f, the configuration of the product was inverted
from R to S. The ligand with the erythro form 1b showed
much better enantioselectivity than that with the threo form
1 f.
Most of the chiral N-methyl-N-aryl amino alcohols 2 gave
good enantioselectivities with up to 95% ee. The aryl sub-
stituents in the ligands had a pronounced effect on the enan-
tioselectivity. The ligands bearing a bulkier R group on the
benzene ring hindered the enantioselectivity. Ligand 2a, in
which the R group was a 4-methoxy group, promoted the re-
action to give the product 6a in 94% yield with 95% ee
(Table 1, entry 7), while 2b containing a bulkier benzyloxy
group resulted in a slightly reduced stereoselectivity of
92% ee (Table 1, entry 8). A further increase in the bulki-
ness of the R group by replacement of the 4-methoxybenzyl
group in 2a with a 2,4,6-trimethylbenzyl group to give 2c
led to a much lower ee of 84% (Table 1, entry 9). Most of
the ligands bearing a halogen on a benzyl group provided
excellent enantioselectivities. High enantioselectivities of
95% and 93% ee were obtained with 2e (R = 3-Cl) and 2 f
(R = 4-Cl), respectively (Table 1, entries 11 and 12). The
ligand 2d (R = 2-Br) also afforded a good enantioselectivi-
ty of 91% ee, but gave the product 6a only in 35% yield
(Table 1, entry 10).
Table 2. The addition of diethylzinc to N-diphenylphosphinoyl benzali-
mine (5a) in the presence of the chiral amino alcohols 3.[a]
Entry
Ligands
R
Yield[%][b]
ee[%][c]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3c
3d
3e
3 f
3g
3h
3i
4-MeO
4-BnO
2,4,6-trimethyl
2,4,6-trimethyl
2-Br
4-Br
2-Cl
3-Cl
4-Cl
99
68
92
81
99
91
90
78
99
91
85
95
95
95
97
93[d]
95
95
94
94
94
96
94
95
10
11
12
2,6-dichloro
3,4-(OCH2O)-
4-Me
3j
3k
[a] The reaction was carried out at room temperature in the presence of
stoichiometric amounts of amino alcohols for 48 h, unless specified other-
wise. [b] Yield of isolated product based on imine 5a. [c] Determined on
HPLC, and the absolute configuration is R. [d] The reaction was promot-
ed by 50 mol% of ligand 3c.
all of the amino alcohols 3 afforded higher or similar enan-
tioselectivities than the corresponding N,N-disubstituted
compounds 2. Ligands bearing a bulkier R group tended to
induce a higher enantioselectivity, in contrast to the situa-
tion of N,N-disubstituted amino alcohols 2. In particular,
ligand 3c, which contains a 2,4,6-trimethylbenzyl group, gen-
erated the highest enantioselectivity of 97% ee (Table 2,
entry 3). However, ligand 2c only resulted in 84% ee
(Table 1, entry 9). If the R group is a halogen, as in ligands
3d h, the results also supported the tendency of a larger R
group being beneficial to the enantioselectivity. For instance,
ligand 3d, which bears a Br on the benzyl group, gave an
enantioselectivity of 95% ee (Table 2, entry 5), higher than
those given by 3 f h in which the R groups were Cl. Howev-
er, the N,N-disubstituted amino alcohols 2d f, 2e, and 2 f
provided a higher stereochemical outcome than 2d. The
same substituent at a different position on the phenyl did
not change the enantioselectivity. For instance, 3d, which
bears a 2-bromophenyl group, gave an identical enantiose-
lectivity to 3e, which bears a 4-bromophenyl group (Table 2,
entries 5 and 6). Ligands 3 f h also provided the same enan-
tioselectivity of 94% ee for the reaction (Table 2, entries 7
9). Amino alcohol 3i, with two chlorides positioned at C2
and C6 on the phenyl group promoted the reaction with
96% ee (Table 2, entry 10), which is higher than the amino
alcohols (3a,b, 3d h, 3j, and 3k) that have a monosubstitut-
ed phenyl group. In the presence of 50 mol% of the best
ligand 3c, high yields of 81% and 93% ee were afforded
(Table 2, entry 4).
Asymmetric addition of diethylzinc to N-diphenylphosphi-
noyl benzalimine mediated by N-monosubstituted amino al-
cohols 3: N,N-Disubstituted b-amino alcohols have been
successfully employed for the addition of diethylzinc to car-
bonyl compounds with an extremely high enantioselectivity.
Generally, an N,N-disubstituent on the amino alcohol was
required to obtain high enantioselectivity.[10] Amongst the
approximate 260 individual chiral amino alcohols recently
reviewed by Pu and Yu for diethylzinc addition to alde-
hydes, only a few of the N-monosubstituted amino alcohols
have given more than 90% ee in the addition of diethylzinc
to aldehydes.[11] The use of N-monosubstituted b-amino al-
cohol to promote the addition of diethylzinc to diphenyl-
phosphinoylimines with high enantioselectivities is also
rare.[12] The dramatic dependence of enantioselectivity on
the size of the N-substituent of the ligand 2 prompted us to
screen the N-substituent with N-monosubstituted chiral
amino alcohols 3. It was encouraging that chiral amino alco-
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L.-Z. Gong, Y.-D. Wu et al.
FULL PAPER
N-monosubstituted b-amino alcohols 3l o, which bear
other substituents, such as furyl, 2-naphthyl, isopropanyl,
and a less sterically bulky methyl group, were also examined
(Scheme 3). All these ligands afforded high enantioselectivi-
cohol 4c and three equivalents of diethylzinc was stirred at
the room temperature for 48 h, compound 7 was not ob-
served (Scheme 4).
Addition of diethylzinc to aro-
matic imines mediated by opti-
mal ligands 2a, 3c, and 4c:
After we finished the systemat-
ic investigation of the relation-
ship between the ligand struc-
ture and the enantioselectivity,
optimal ligands, 2a, 3c, and 4c
were extended to activate the
Scheme 3. Results observed with N-monosubstituted b-amino alcohols 3l o.
ties (92 95% ee) and high yields (71 98%). The results fur-
ther indicate that the enantioselectivity is not very sensitive
to the substituent on the nitrogen of the amino alcohol.
Asymmetric addition of diethylzinc to N-diphenylphosphi-
noyl benzalimine mediated by imino alcohols 4: In our
recent work, we demonstrated that the chiral ligands incor-
porating sp2-hybridized nitrogen with a hydroxy group pro-
moted the addition of diethylzinc to imines with high enan-
tioselectivity.[5g,h] Therefore, we believed that the imino alco-
hols should also be good chiral ligands for the reaction.
Chiral imino alcohols 4 were thus surveyed to promote
the addition of diethylzinc to N-diphenylphosphinoyl benzal-
imine. As shown in Table 3, this family of chiral imino alco-
Scheme 4. The reaction of imino alcohol 4c with three equivalents of di-
ethylzinc.
addition of diethylzinc to other diphenylphosphinoylimines.
The corresponding results are recorded in Table 4. In the
presence of ligand 2a, enantioselectivities of 94 96% were
obtained for all of the imine substrates tested. Imino alcohol
Table 4. Asymmetric addition of diethylzinc to aromatic N-diphenylphos-
phinoyl imines 5a e promoted by 2a, 3c, and 4c.[a]
Table 3. The addition of diethylzinc to N-diphenylphosphinoyl benzal-
imine 5a in the presence of the chiral imino alcohols 4.[a]
Entry
Ligands
R
Yield[%][b]
ee[%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4i
H
92
85
70
78
74
60
65
65
76
56
68
60
67
91
92
95
93
92
90
92
93
91
90
89
91
87
4-MeO
2,4,6-trimethyl
3-Me
3-Cl
4-Cl
2-Br
3-Br
4-Br
Ar
Ph
Imine
Ligand
Yield[%][b]
ee[%][c]
5a
2a
3c
3c
4c
2a
3c
4c
2a
3c
4c
2a
3c
4c
2a
3c
4c
94
92
97
70
82
89
7394
90
92
70
89
95
81
98
86
62
95
97
98[d]
95
4-MeOC6H4
3,4-(OCH2O)-C6H3
4-MeC6H4
5b
5c
5d
5e
95
97
9
10
11
12
13
4j
4k
4l
4-BnO
4-Me2N
3,4-(OCH2O)-
95
97
95
96
98
96
94
96
94
4m
[a] The reaction was carried out at room temperature in the presence of
stoichiometric amounts of amino alcohols for 48 h. [b] yield of isolated
product based on imine. [c] Determined on HPLC, and the absolute con-
figuration is R.
3-MeC6H4
hols provided high enantioselectivities of up to 95% ee for
the model reaction. Variation in the size of the substituent
on the imino alcohols led to a slight change in the enantiose-
lectivity. The best enantioselectivity was observed with the
optimal ligand 4c (Table 3, entry 3, 95% ee) and the lowest
enantioselectivity was induced by ligand 4m (Table 3,
entry 13, 87% ee).
[a] The reaction was carried out at room temperature in the presence of
stoichiometric amounts of chiral ligands for 48 h. [b] Yield of isolated
product based on imines. [c] Determined on HPLC. [d] The reaction was
performed on the 1 mmol scale.
4c also promoted the reaction with high enantioselectivities
of 94 96% ee, but with lower yield (70 81%) in comparison
with its structural analogues 2a (94 98%) and 3c (86
97%). Basically, the substituents on the substrates had no
We found that the imino function of the ligands 4 was
stable to diethylzinc. When the mixture of optical imino al-
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Enantioselective Alkylation of Arylimines with Dialkylzinc
1481 1492
obvious effect on the enantioselectivity. Ligand 3c, on aver-
age, gave a slightly higher enantioselectivity than ligands 2a
and 4c. For all of the substrates examined, 3c afforded
enantioselectivities from 96% to 98% ee. Ligand 3c not
only gave the best results reported so far,[13] but it is also the
most easily accessible. It is noteworthy that although stoi-
chiometric amounts of amino alcohol had to be used, the
chiral ligand could be easily recovered by flash chromatog-
raphy.
Theoretical modeling of the stereoselectivity: Theoretical
calculations have been carried out to understand the origin
of the observed enantioselectivities. Our study started with a
simplified model. As shown in Scheme 5, the substrate was
Asymmetric addition of dibutylzinc to imines in the pres-
ence of ligand 3c: Asymmetric addition of butylmetallics to
imines in the presence of chiral ligands has attracted great
interest owing to chemical challenges and potential applica-
tions.[4b] Tomioka and co-workers were the first to report
that the addition of butyllithium to N-arylimines in the pres-
ence of stoichiometric or substoichiometric amounts of
amino ethers resulted in moderate-to-good enantioselectivi-
ties.[14] Itsuno and co-workers studied the addition of butyl-
lithium to benzaldehyde N-(trimethylsilyl)imine in the pres-
ence of chiral promoters, such as alcohols, diols, and amino
alcohols, to give the enantiomerically enriched primary
amine with high yields and moderate ee values.[15] The use of
both stoichiometric and catalytic amounts of (À)-sparteine
in the addition of butyllithium to N-arylimines resulted in
high yields and high enantioselectivities (<91% ee).[15b,16] In
1992, Soai et al. reported the use of a stoichiometric amount
of (1S,2R)-MOPEP in the addition of dibutylzinc to N-di-
phenylphosphinoyl benzalimine (5a) with a moderate yield
(56%) and a high enantioselectivity (87% ee).[5a] Since
chiral ligand 3c generally exhibited high enantioselectivity
for the addition of diethylzinc to imines, we investigated the
addition of dibutylzinc to N-diphenylphosphinoyl arylimines
in the presence of ligand 3c. As shown in Table 5, excellent
Scheme 5. Models for the theoretical study
reduced to 9 and dimethylzinc was modeled instead of di-
ethylzinc. Our model is similar to that used by Brandt et al.
for the addition of diethylzinc to N-diphenylphosphinoyl ar-
ylimines with cyclic hydroxylamine ligands,[5e] namely, the
hydroxy group of the chiral amino alcohol replaces one of
the alkyl groups of dialkylzinc and the alcoholic oxygen
atom coordinates with another equivalent of dialkylzinc to
form the real reagent.[5e,17] Three chiral reagents (10 12)
were modeled. All calculations were performed with the
Gaussian98 program.[18]
To search for all possible transition structures, a confor-
mational search with the PM3[19] and HF/3-21G methods
was first performed on four possible models (see the Sup-
porting Information) with complex 10. This resulted in
11 unique transition structures. All these transition struc-
tures are given in the Supporting Information. At the HF/3-
21G level, the three most favorable transition structures are
shown in Figure 1. Structure 13 is more stable than 14 and
15 by 2.9 and 4.1 kcalmolÀ1, respectively. While 13 gives the
R product, 14 and 15 lead to the formation of the S product.
Transition structures 13 15 were further calculated with
the nonlocal density functional method of B3LYP/6-31G*,[20]
which should give more reliable calculation results. Struc-
ture 13 is still the most stable. Structures 14 and 15 become
less stable by 1.8 and 2.2 kcalmolÀ1, respectively. Thus, the
simple model calculations give results in qualitative agree-
ment with the experimental observations, that is, the R
product is formed preferentially.
Table 5. The asymmetric addition of dibutylzinc to imines mediated by
chiral amino alcohol 3c.[a]
Ar
Imine
Yield[%][b]
ee[%][c]
Configuration[d]
All three transition structures have some similar features:
the Me2Zn attacks the C=N bond to form a four-membered-
ring. The other zinc atom coordinates to the oxygen of the
phosphinoyl group so that a six-membered-ring is fused with
the four-membered-ring on one side and with a five-mem-
bered-ring on the other side. In 13, the two methyl groups in
the chiral ligand point upward and away from the POMe2
group, and therefore there is little steric interaction. In 14,
the situation for the three fused rings is similar to that in 13.
Therefore, it does not have ring strain. However, the methyl
group at the C1 position of the chiral amino alcohol points
downward. It is close to one of the methyl groups of the
POMe2. The steric interaction between the two methyl
groups, as shown by arrows in Figure 1, causes a significant
destabilization. In 15, the two methyl groups of the amino
alcohol point away from the POMe2, and therefore, do not
Ph
5a
5b
5c
5d
5e
5 f
67
50
57
6396
55
97
95
97
R
R
R
R
R
R
4-MeOC6H4
3,4-(OCH2O)-C6H3
4-MeC6H4
3-MeC6H4
4-BrC6H4
97
96
59
[a] The reaction was carried out in the presence of stoichiometric
amounts of 3c. [b] Yield of isolated product. [c] The ee values were deter-
mined on HPLC. [d] Determined by comparison of the retention time
with the literatures.
enantioselectivities of 95 97% ee were observed. Compared
with the addition of diethylzinc to imines, this reaction gave
lower yields (50 67%). To the best of our knowledge, these
results represent the highest enantioselectivities for the ad-
dition of a butylmetallic species to imines.
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

L.-Z. Gong, Y.-D. Wu et al.
FULL PAPER
experimentally for a variety of
chiral amino alcohol ligands. It
should be pointed out that, al-
though we used POMe2 instead
of more sterically bulky OPPh2,
which is present in ligands 1 4,
the predicted stereoselectivity
should not be affected because
the two phenyl groups of the
chiral amino alcohol ligand are
far away from the group. Also
because of this, the model of di-
methylzinc for diethylzinc is
reasonable.
We have also studied the
transition structures with model
ligand 12 to understand the re-
versed stereoselectivity with
ligand 1 f observed experimen-
tally. Again, many transition
structures were explored. The
most stable transition structures
for the formation of the two
enantiomeric
products
are
given in Figure 2. The most
stable transition structure for
the formation of the R product
is 19. This structure is similar to
structures 15 and 18. Although
the steric interactions involving
the two phenyl groups of the
chiral amino alcohol are avoid-
ed, the structure is destabilized
by unfavorable ring fusion. The
Figure 1. Calculated transition structures for the methylation of 9 by chiral complexes 10 and 11. The calculat-
ed relative energies (B3LYP/6-31G*, kcalmolÀ1) are given in parentheses.
participate in a steric interaction. However, the fusion of the
(H3)C-Zn-N-C dihedral angle is about 408 and the Zn-N-P-
O dihedral angle is almost zero. The structure derived from
16 by changing the chirality of the C1 center is calculated to
be less stable by about 3kcalmol À1 as a result of severe
steric interaction between the phenyl group attached to C1
and the spectator methyl group of the ZnMe2. On the other
hand, the most stable transition structure for the formation
of the S product is 20. This structure is very similar to struc-
ture 17, except that the phenyl group attached to C1 has
now swapped places with the hydrogen atom. Structure 17 is
significantly destabilized by the steric interactions between
the phenyl group and the POMe2, but this steric interaction
is absent in structure 20. Thus, structure 20 is calculated to
be more stable than structure 19 by about 0.6 kcalmolÀ1.
This result is in good agreement with the experimental ob-
servation with ligand 1 f. That is, ligand 1 f gives rise to an
inversed configuration but low enantioselectivity compared
to its chiral counterpart ligand 1b.
À
three rings is not ideal. As can be seen, the N P bond has
À
rotated so that the P O bond is nearly eclipsed with the
À
Zn N bond, which is being formed. In addition, the four-
membered ring is not co-planar. The C-Zn-N-C dihedral
angle is ꢀ308. Thus, this transition structure is destabilized
by unfavorable ring strain.
Our next step was to change X from Me to Ph. The calcu-
lations only focused on the three favorable transition struc-
tures. As shown in Figure 1, the geometries of 16, 17, and 18
are quite similar to those of structures 13, 14, and 15, respec-
tively. The energy difference between 16 and 18 is about
1.9 kcalmolÀ1, similar to that between 13 and 15. However,
structure 17 becomes destabilized, and is calculated to be
about 3.7 kcalmolÀ1 less stable than 16. This is apparently
caused by the increased steric interaction between the
downward phenyl group of the amino alcohol and the
POMe2 (as indicated by the arrow in 17 (Figure 1)). In the
real substrate, the POMe2 is replaced by POPh2. This should
not affect the relative stabilities between 16 and 18. Howev-
er, 17 is expected to be destabilized even further. Therefore,
17 can be ruled out. We can conclude that the formation of
the R and S products is mainly determined by 16 and 18, re-
spectively. Since 18 is much less stable, it qualitatively ra-
tionalizes the generally high enantioselectivities observed
A more detailed modeling of the substituent effect on the
enantioselectivity using the real experimental chiral amino
alcohol ligands would require much more elaborate calcula-
tions. Our calculations of simplified imine substrate, dialkyl-
zinc, and chiral amino alcohol ligands do reveal the essential
factors for the generally high enantioselectivity for the reac-
tions studied experimentally. Our modeling of the chiral
1486
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1481 1492

Enantioselective Alkylation of Arylimines with Dialkylzinc
1481 1492
tions involving air- and moisture-sen-
sitive compounds were carried out
under a dry argon atmosphere with
standard Schlenk line techniques. Tol-
uene and THF were dried over
sodium/benzophenone. CH2Cl2 was
dried with CaH2. Petroleum ether
(PE) and ethyl acetate for column
chromatography were distilled before
use.
Materials: All starting materials were
purchased from Acros and used di-
rectly.
General experimental for the prepa-
ration of (1R,2S)-N-aryl-1,2-diphenyl-
2-aminoethanol (3a m) and (1R,2S)-
N-methyl-N-aryl-1,2-diphenyl-2-ami-
noethanol (2a 2g):
A solution of
(1R,2S)-1,2-diphenyl-2-aminoethanol
(5 mmol) and the appropriate aryl al-
dehyde (5 mmol) in anhydrous etha-
nol was stirred for 2 12 h at room
temperature, then sodium borohy-
dride (8 mmol) was added. The reac-
tion mixture was stirred for 2 h at
room temperature, quenched with 2m
Figure 2. Calculated most stable transition structures for the formation of the R product 19 and the S product
20 of the addition of ZnMe2 to imine 9 in the presence of a zinc complex of chiral amino alcohol model 12.
The calculated relative energies are given in parentheses.
HCl, and the ethanol was removed by evaporation. The residue was neu-
tralized with aqueous NaOH (0.5m, 20 mL). The mixture was extracted
with CH2Cl2 (3î20 mL), and the combined organic layers were washed
with water (3î). The organic layer was dried over anhydrous sodium sul-
fate and evaporated to dryness under reduced pressure. Purification of
the crude product by chromatography (silica) or by crystallization gave
3a m.
amino alcohol ligands 4 also indicates high enantioselectivity
(see the Supporting Information).
Conclusion
A mixture of 3 (3mmol) and methanoic acid (5 mL) was stirred for 0.5 h
at room temperature, and then aqueous formaldehyde (30%, 5 mL) was
added. The mixture was refluxed for 10 h, and the remaining excess
formaldehyde was removed with a rotary evaporator. The resulting resi-
due was dissolved in NaOH (0.5m, 10 mL), extracted with CH2Cl2(3î
15 mL), and the combined organic layers were washed with aqueous satu-
rated NaCl. The organic layer was dried over anhydrous sodium sulfate,
and evaporated to dryness under reduced pressure. Purification of the
crude product by chromatography (silica) or by crystallization gave 2a g.
By screening N,N-disubstituted, N-monosubstituted amino
alcohols and imino alcohols for the addition of diethylzinc
to imines, we found that N-monosubstituted amino alcohols
gave slightly higher enantioselectivities than their N,N-dis-
ubstituted counterparts. High enantioselectivities of up to
98% ee for addition of diethylzinc to imines were obtained
with the very easily accessible ligand 3c. So far, the highest
enantioselectivities, ranging from 95% to 97% ee for the ad-
dition of dibutylzinc to imines, were observed with ligand
3c. These results imply that the rigid and restricted structure
of the amino alcohol was not the absolute requirement for
the high enantioselective alkylation of diphenylphosphinoy-
limine with dialkylzinc. Studies on the transition states at
the B3LYP/6-31G* level of theory revealed that the chiral
amino alcohols promoted the reaction via the transition
structure 16. The accurate calculation to understand the re-
versed enantioselectivity with ligand 1 f resulted in a good
agreement with the experimentally observed result. The cal-
culation results indicated that higher enantioselectivity
might also be achieved by the use of simpler chiral ligands
and dimethylzinc.
(1R,2S)-N-Methyl-N-4’-methoxylbenzyl-1,2-diphenyl-2-aminoethanol
(2a): This compound was obtained as a white solid (0.991 g) in 95%
yield; m.p. 83 848C; [a]D25
=
À68.5 (c
=
1.01 in CHCl3); 1H NMR
(200 MHz, CDCl3): d = 2.28 (s, 3H), 2.83 3.02 (brs, 1H), 3.29 (d, J =
13.3 Hz, 1H), 3.59 3.64 (m, 2H), 3.79 (s, 3H), 5.37 (d, J = 5.6 Hz, 1H),
6.77 7.24 ppm (m, 14H); 13C NMR (75 MHz, CDCl3): d = 38.8, 55.2,
58.8, 72.6, 74.4, 113.5, 126.6, 127.1, 127.4, 127.7, 127.8, 129.6, 129.9, 130.8,
135.9, 141.8, 158.6 ppm; IR (Nujol): n˜ = 3491, 1611, 1514, 1459, 1251 (C-
O-C), 700 (CH2) cmÀ1; MS (CI): m/z (%): 28, 77 [C6H5]+, 91 [PhCH2]+,
121 [C8H9O]+, 240 [M+1ÀPhCH2ÀOH]+; elemental analysis calcd (%)
for C23H25NO2: C 79.51, H 7.25, N 4.03; found: C 79.50, H 7.11, N 4.10.
(1R,2S)-N-Methyl-N-4’-benzoxylbenzyl-1,2-diphenyl-2-aminoethanol
(2b): This compound was obtained as a white solid (1.143g) in 90%
yield; m.p. 93 948C; [a]D25
(300 MHz, CDCl3): d
=
À58.0 (c
2.30 (s, 3H), 2.90 (brs, 1H), 3.27 (d, J
=
1.00 in CHCl3); 1H NMR
=
=
13.8 Hz, 1H), 3.63 (m, 2H), 5.07 (s, 2H), 5.39 (d, J = 5.7 Hz, 1H), 6.88
7.46 ppm (m, 19H); 13C NMR (75 MHz, CDCl3): d = 38.9, 58.8, 70.0,
72.6, 74.5, 114.5, 126.5, 127.0, 127.4, 127.4, 127.7, 127.8, 127.9, 128.5,
129.5, 129.8, 131.2, 135.9, 137.1, 141.7, 157.8 ppm; IR (Nujol): n˜ = 3431
(OH), 1511, 1459 (N-CH3), 1237 (C-O-C), 1022 (C-O-C), 704
Experimental Section
(CH2) cmÀ1
;
MS (EI): m/z (%): 91, (100) [PhCH2]+,
3
16
[M+1ÀPhCH2ÀOH]+, 197; elemental analysis calcd (%) for C29H29NO2:
General: NMR spectra were recorded on a Brucker-200 or 300 MHz
spectrometer. Elemental analyses were performed on a Carlo Erba-1106
Analyzer. EI mass spectra were recorded on a VG-7010E, and IR spectra
on a NicroLab200SXV. Optical rotation was measured with a PE polar-
meter341. HPLC analysis was performed on Beckman110B chromatog-
raphy with Beckman168 variable wavelength detector. A ChiralpakAD
column was purchased from Daicel Chemical Industries, Ltd. All reac-
C 82.24, H 6.90, N 3.31; found: C 82.23, H 7.00, N 3.45.
(1R,2S)-N-Methyl-N-2’,4’,6’-trimethylbenzyl-1,2-diphenyl-2-aminoethanol
(2c): This compound was obtained as a white solid (1.002 g) in 93%
yield; m.p. 95 968C; [a]D25
(300 MHz, CDCl3): d = 2.17 (s, 9H), 2.29 (s, 3H), 2.83 2.89 (brs, 1H),
3.46 3.57 (m, 2H), 3.71 (d, J = 6.4 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H),
=
À66.7 (c
=
1.01 in CHCl3); 1H NMR
1487
Chem. Eur. J. 2004, 10, 1481 1492
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

L.-Z. Gong, Y.-D. Wu et al.
FULL PAPER
6.8 (s, 2H), 7.19 7.36 ppm (m, 10H); 13C NMR (50 MHz, CDCl3): d =
19.9, 20.6, 36.4, 53. 6, 72.5, 76.9, 126.2, 126.8, 127.2, 127.5, 127.9, 128.0,
128.7, 129.4, 131.5, 135.7, 136.0, 137.8, 141.6 ppm; IR (Nujol): n˜ = 3532
(OH), 1611, 1455 (N-CH3), 701 (CH2) cmÀ1; MS (EI): m/z (%): 77, 91,
133 (100), 252 (36); elemental analysis calcd (%) for C25H29NO: C 83.52,
H 8.13, N 3.90; found: C 83.34, H 7.08, N 3.81.
7.11 7.43ppm (m, 19H); 13C NMR (75 MHz, DMSO): d = 50.2, 67.8,
70.0, 78.4, 114.6, 115.3, 126.9, 127.2, 127.4, 127.6, 127.7, 127.8, 127.9,
128.2, 128.4, 128.6, 128.7, 128.8, 129.2, 137.3, 140.7, 142.9, 157.5 ppm; IR
(Nujol): n˜ = 3082, 3028, 1513, 1611, 1451, 1248 (C-O-C), 1010 (C-O-C),
699 (CH2) cmÀ1; MS (CI) m/z (%): 91 [PhCH2]+, 197 [CH2PhOBn]+, 3 02
[M+1ÀPhCH2ÀOH]+; elemental analysis calcd (%) for C28H27NO2: C
82.12, H 6.65, N 3.42; found: C 82.39, H 6.75, N 3.61.
(1R,2S)-N-Methyl-N-2’-bromobenzyl-1,2-diphenyl-2-aminoethanol (2d):
This compound was obtained as a viscid liquid (1.069 g) in 90% yield;
[a]2D5 = À33.7 (c = 0.986 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
2.31 (s, 3H), 2.90 (brs, 1H), 3.62 3.66 (m, 2H), 3.71 (d, J = 6.0 Hz, 1H),
5.42 (d, J = 6.0 Hz, 1H), 7.16 7.52 ppm (m, 14H); 13C NMR (75 MHz,
CDCl3): d = 39.1, 58.8, 69.9, 72.8, 75.2, 124.1, 126.6, 126.9, 127.2, 127.3,
127.5, 127.8, 127.9, 128.2, 129.0, 129.6, 130.5, 132.6, 135.9, 138.1,
(1R,2S)-N-2’,4’,6’-Trimethylbenzyl-1,2-diphenyl-2-aminoethanol
(3c):
This compound was obtained as a white solid (1.259 g) in 73% yield;
1
m.p. 124 1258C; [a]2D5 = +9.6 (c = 1.00 in CHCl3); H NMR (300 MHz,
CDCl3): d = 2.16 (s, 6H), 2.26 (s, 3H), 3.54 (d, J = 11.6 Hz, 1H), 3.62
(d, J = 11.6 Hz, 1H), 3.98 (d, J = 6.4 Hz, 1H), 4.79 (d, J = 6.4 Hz, 1H),
6.83(s, 2H), 7.19 7.37 ppm (m, 10H); 13C NMR (75 MHz, DMSO): d =
19.0, 20.8, 45.1, 70.0, 77.1, 127.1, 127.4, 127.9, 128.1, 128.7, 128.8, 133.9,
135.7, 136.7, 142.2, 143.8 ppm; IR (Nujol): n˜ = 3395 (OH), 3341, 3061,
3032, 1454, 702 (CH2) cmÀ1; MS (EI): m/z (%): 106 [PHCHO]+, 133 [CH2
(2,4,6-trimethyl benzene)], 238 [M+1ÀPhCH2ÀOH]+, 346 [M+1]; ele-
mental analysis calcd (%) for C24H27NO: C 83.44, H 7.88, N 4.05; found:
C 83.30, H 7.93, N 4.28.
141.7 ppm; IR (neat): n˜
= 3565, 3449 (OH), 1449 (N-CH3), 703
(CH2) cmÀ1; MS (EI): m/z (%): 77, 91, 118, 169 (77) [CH2Ph79Br], 171
(77) [CH2Ph81Br], 288 (100) [M+1ÀPhCH2ÀOH]+, 290 (98); elemental
analysis calcd (%) for C22H22BrNO: C 66.67, H 5.60, N, 3.53; found: C
66.56, H 5.66, N 3.64.
(1R,2S)-N-Methyl-N-3’-chlorobenzyl-1,2-diphenyl-2-aminoethanol (2e):
This compound was obtained as a viscous liquid (0.895 g) in 85% yield;
[a]2D5 = À135.9 (c = 0.504 in CHCl3); 1H NMR (300 MHz, CDCl3): d =
2.06 (s, 3H), 2.68 (brs, 1H), 3.05 (d, J = 13.8 Hz, 1H), 3.37 (d, J =
13.8 Hz, 1H), 3.46 (d, J = 6.7 Hz, 1H), 5.06 (d, J = 6.7 Hz, 1H), 6.73
7.18 ppm (m, 14H); 13C NMR (75 MHz, CDCl3): d = 34.8, 55.0, 68.8,
70.5, 122.6, 122.7, 123.1, 123.4, 123.6, 123.9, 124.0, 124.6, 125.4, 125.5,
130.1, 131.6, 137.3, 137.7 ppm; IR (neat): n˜ = 3563 (OH), 3446 (OH),
1596, 1450 (N-CH3), 705 (CH2) cmÀ1; MS (EI): m/z (%): 42, 77, 91, 105,
118, 125 (100) [CH2Ph35Cl], 127 (33) [CH2Ph37Cl], 244 (80)
[M+1ÀPhCH2ÀOH]+, 246 (26); elemental analysis calcd (%) for
C22H22ClNO: C 75.09, H 6.30, N, 3.98; found: C 75.06, H 7.48, N 4.13.
(1R,2S)-N-2’-Bromobenzyl-1,2-diphenyl-2-aminoethanol (3d): This com-
pound was obtained as a white solid (1.489 g) in 78% yield; m.p. 147
1
1488C; [a]2d5 = +27.9 (c = 0.82 in CHCl3); H NMR (300 MHz, CDCl3):
d = 3.64 (d, J = 13.6 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.89 (d, J =
6.0 Hz, 1H), 4.86 (d,
J
=
6.0 Hz, 1H), 7.11 7.50 ppm (m, 14H);
50.8, 67.9, 76.9, 123.5,
13C NMR (75 MHz, DMSO and CDCl3): d
=
127.0, 127.2, 127.3, 127.6, 127.8, 127.8, 128.8, 128.9, 130.3, 132.5, 139.3,
140.8, 143.0 ppm; IR (Nujol): n˜ = 3301, 3189, 3086, 3064, 3030, 1452, 702
(CH2) cmÀ1; MS (EI): m/z (%): 77, 91, 118, 169 [CH2Ph79BrÀ1], 171
[CH2Ph81BrÀ1], 274 [M+1ÀPhCH2ÀOH]+, 276; elemental analysis calcd
(%) for C21H20BrNO: C 65.98, H 5.27, N 3.66; found: C 66.08, H 5.27, N
4.01.
(1R,2S)-N-Methyl-N-4’-chlorobenzyl-1,2-diphenyl-2-aminoethanol (2 f):
This compound was obtained as a white solid (0.896 g) in 85% yield;
m.p. 102 1038C; [a]2D5 = À65.0 (c = 1.01 in CHCl3); 1H NMR (200 MHz,
CDCl3): d = 2.26 (s, 3H), 3.29 (d, J = 13.7 Hz, 1H), 3.58 3.66 (m, 2H),
5.35 (d, J = 6.30 Hz, 1H), 6.97 7.27 ppm (m, 14H); 13C NMR (75 MHz,
CDCl3): d = 38.7, 58.7, 72.6, 74.3, 126.6, 127.2, 127.6, 127.8, 127.9, 128.3,
129.5, 129.9, 132.5, 135.5, 137.4, 141.8 ppm; IR (Nujol): n˜ = 3488 (OH),
1401, 1455 (N-CH3), 703(CH 2) cmÀ1; MS (EI): m/z (%): 77, 91, 118, 125
(100) [CH2Ph35Cl], 127(33) [CH2Ph37Cl], 244 (80) [M+1ÀPhCH2ÀOH]+,
246 (26); elemental analysis calcd (%) for C22H22ClNO: C 75.09, H 6.30,
N, 3.98; found: C 75.08, H 6.29, N 4.04.
(1R,2S)-N-4’-Bromobenzyl-1,2-diphenyl-2-aminoethanol (3e): This com-
pound was obtained as a white solid (1.165 g) in 61% yield; m.p. 179
1
1808C; [a]2D9 = +23.5 (c = 0.51 in CHCl3); H NMR (300 MHz, CDCl3):
d = 2.06 2.75 (brs, 2H), 3.50 (d, J = 13.2 Hz, 1H), 3.70 (d, J = 13.2 Hz,
1H), 3.90 (d, J = 5.7 Hz, 1H), 4.86 (d, J = 5.4 Hz, 1H), 7.03 7.42 ppm
(m, 14H); 13C NMR (75 MHz, DMSO): d = 54.5, 66.4, 75.0, 117.2, 131.5,
131.9, 132.4, 132.6, 133.0, 133.5, 133.6, 147.5, 154.3 ppm; IR (Nujol): n˜ =
3314, 3029 cmÀ1
;
MS (EI) m/z (%): 169 [CH2Ph79BrÀ1], 171
[CH2Ph81BrÀ1], 274 [M+1ÀPhCH2ÀOH]+, 276, 277; 362 [MÀH2O]; ele-
mental analysis calcd (%) for C21H20BrNO: C 65.98, H 5.27, N 3.66;
found: C 65.83, H 5.24, N 3.66.
(1R,2S)-N-Methyl-N-piperonyl-1,2-diphenyl-2-aminoethanol (2g): This
compound was obtained as a white solid (0.886 g) in 80% yield; m.p.
105 1068C; [a]2D5 = À74.5 (c = 0.746 in CHCl3); 1H NMR (300 MHz,
CDCl3): d = 2.30 (s, 3H), 3.26 (d, J = 12.0 Hz, 1H), 3.57 3.67 (m, 2H),
5.40 (s, 1H), 5.95 (s, 2H), 6.70 6.73(m, 3H) 7.14 7.28 ppm (m, 10H);
(1R,2S)-N-2’-Chlorobenzyl-1,2-diphenyl-2-aminoethanol (3 f): This com-
pound was obtained as a white solid (1.249 g) in 75% yield; m.p. 142
1
1438C; [a]2D5 = +21.0 (c = 1.01 in CHCl3); H NMR (300 MHz, CDCl3):
d = 3.70 (d, J = 13.7 Hz, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.90 3.95 (m,
1H), 4.95 5.0 (m, 1H), 7.11 7.32 ppm (m, 14H); 13C NMR (75 MHz,
DMSO and CDCl3): d = 48.1, 67.9, 76.3, 110.3, 113.5, 117.3, 117.6, 118.1,
126.2, 126.8, 127.2, 127.7, 127.9, 128.5, 128.9, 129.1, 129.4, 130.4, 133.0,
143.2 ppm; IR (Nujol): n˜ = 3306, 3250, 3182 cmÀ1; MS (EI): m/z (%):
125 [CH2Ph35Cl], 127 [CH2Ph37Cl], 230 [M+1ÀPhCH2ÀOH]+, 232, 233,
319 [MÀH2O], 321; elemental analysis calcd (%) for C21H20ClNO: C
74.66, H 5.97, N 4.15; found: C 74.47, H 6.08, N 4.53.
13C NMR (75 MHz, CDCl3): d
= 38.7, 59.2, 72.7, 74.3, 100.8 (O-C-
O),107.7, 109.0, 121.7, 126.5, 127.2, 127.4, 127.7, 127.8, 129.5, 129.8, 132.8,
135.8, 141.7, 146.4, 147.5 ppm (Ar); IR (Nujol): n˜ = 3484 (OH), 1489,
1448, 1450,1459, 1245, 1038, 705 cmÀ1; MS (EI): m/z (%): 77, 91, 105, 135
(100) [BnOCH2O]+, 254 (39) [M+1ÀPhCH2ÀOH]+; elemental analysis
calcd (%) for C23H23NO3: C 76.43, H 6.41, N 3.88; found: C 76.18, H
6.37, N 4.00.
(1R,2S)-N-4’-Methoxylbenzyl-1,2-diphenyl-2-aminoethanol (3a): This
(1R,2S)-N-3’-Chlorobenzyl-1,2-diphenyl-2-aminoethanol (3g): This com-
compound was obtained as a white solid (1.249 g) in 75% yield; m.p.
pound was obtained as a white solid (1.146 g) in 68% yield; m.p. 152
156 1588C; [a]2D5
=
+18.9 (c = 1.02 in CHCl3); 1H NMR (300 MHz,
1538C; [a]2D5 0.814 in CHCl3); 1H NMR (300 MHz,
= +24.4 (c =
CDCl3): d = 3.26 (d, J = 13.1 Hz, 1H), 3.68 (d, J = 13.1 Hz, 1H), 3.81
(s, 3H), 3.94 (d, J = 5.7 Hz, 1H), 4.87 (d, J = 5.7 Hz, 1H), 6.84 (d, J =
8.7 Hz, 2H), 7.09 7.31 ppm (m, 12H); 13C NMR (75 MHz, DMSO): d =
50.0, 55.3, 67.5, 76.6, 113.8, 126.9, 127.2, 127.3, 127.8, 128.9, 129.2, 132.8,
141.3, 143.6, 158.3 ppm (Ar); IR (Nujol): n˜ = 3085, 3028, 1611, 1513,
1452 (O-CH3), 1247 (C-O-C), 699 (CH2) cmÀ1; MS (EI): m/z (%): 121
3 3 4M+[ 1]; elemental analysis
calcd (%) for C22H23NO2: C 79.25, H 6.95, N 4.20; found: C 78.95, H
6.88, N 4.46.
CDCl3): d = 3.51 (d, J = 13.7 Hz, 1H,), 3.71(d, J = 13.7 Hz, 1H), 3.90
(d, J = 6.0 Hz, 1H), 4.87 (d, J = 6.0 Hz, 1H), 7.04 7.34 ppm (m, 14H);
13C NMR (75 MHz, DMSO and CDCl3): d
= 54.9, 72.6, 81.5, 131.1,
131.4, 131.7, 131.9, 132.2, 132.6, 133.5, 134.5, 138.3, 145.3, 147.6,
147.9 ppm; IR (Nujol): n˜ = 3317 (OH), 3085, 3030, 1401, 1451, 1426, 703
(CH2) cmÀ1; MS (EI): m/z (%): 91, 125 [CH2Ph35Cl], 127 [CH2Ph37Cl],
230 [M35+1ÀPhCH2ÀOH]+, 23 2 [M37+1ÀPhCH2ÀOH]+, 3 3 8M[ +1]; ele-
mental analysis calcd (%) for C21H20ClNO: C 74.66, H 5.97, N 4.15;
found: C 74.54, H 6.02, N 4.43.
[C8H9O]+, 226 [M+1ÀPhCH2ÀOH]+,
(1R,2S)-N-4’-Benzoxylbenzyl-1,2-diphenyl-2-aminoethanol (3b): This
(1R,2S)-N-4’-Chlorobenzyl-1,2-diphenyl-2-aminoethanol (3h): This com-
compound was obtained as a white solid (1.452 g) in 71% yield; m.p.
pound was obtained as a white solid (1.095 g) in 65% yield; m.p. 174
1
182 1838C; [a]2D5
=
+18.3( c = 0.378 in CHCl3); 1H NMR (300 MHz,
1758C; [a]2D5 = +25.0 (c = 0.79 in CHCl3); H NMR (300 MHz, CDCl3):
CDCl3): d = 3.53 (d, J = 13.1 Hz, 1H), 3.73 (d, J = 13.1 Hz, 1H), 3.96
(d, J = 5.4 Hz, 1H), 4.97 (s, 1H), 5.03(s, 2H), 6.91(d, J = 8.7 Hz, 2H),
d = 3.53 (d, J = 13.5 Hz, 1H), 3.76 (d, J = 13.5 Hz, 1H), 3.91 (d, J =
5.7 Hz, 1H), 4.96 (d,
J = 3.6 Hz, 1H), 7.10 7.32 ppm (m, 14H);
1488
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1481 1492

Enantioselective Alkylation of Arylimines with Dialkylzinc
1481 1492
13C NMR (75 MHz, DMSO and CDCl3): d
131.9, 131.9, 132.4, 132.5, 132.9, 133.6, 134.4, 136.3, 144.4, 145.5,
=
54.6, 72.5, 81.3, 131.7,
(d, J = 6.0 Hz, 1H), 6.92 (d, J = 8.64 Hz, 2H), 7.23 7.40 (m, 10H), 7.68
(d, J = 8.7 Hz, 2H), 8.07 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d =
55.3, 78.2, 80.8, 113.8, 114.3, 127.1, 127.4, 127.5, 127.56, 127.7, 128.0,
128.1, 128.2, 128.4, 129.1, 129.8, 140.3, 140.7, 161.7 ppm; IR (Nujol): n˜ =
3389 (OH), 3032 (Ar-C-H), 1644 (Ar-C=N), 1606, 1513, 1455, 1257,
699 cmÀ1; HRMS calcd for C22H22NO2: 332.1645, found 332.1650.
147.9 ppm; IR (Nujol): n˜
= 3310 (OH), 3085, 3028, 1400, 701
(CH2) cmÀ1; MS (EI): m/z (%): 125 [CH2Ph35Cl], 127 [CH2Ph37Cl], 230
[M35+1ÀPhCH2ÀOH]+, 23 2 [M37+1ÀPhCH2ÀOH]+, 3 3 8M[ +1]; elemen-
tal analysis calcd (%) for C21H20ClNO: C 74.66, H 5.97, N 4.15; found: C
74.44, H 6.04, N 4.36.
(1R,2S)-N-2’,4’,6’-Trimethylbenzylidene-1,2-diphenyl-2-aminoethanol
(4c): This compound was obtained as white crystals (682 mg) in 84.6%
(1R,2S)-N-2’,6’-Dichlorobenzyl-1,2-diphenyl-2-aminoethanol (3i): This
compound was obtained as white crystals in 39% yield; m.p. 113 1148C;
yield; m.p. 1158C; [a]D25
=
À40.5 (c
=
0.50 in CHCl3); 1H NMR
[a]2d5
=
+13.0 (c = 1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d =
(300 MHz, CDCl3): d = 2.18 (s, 6H), 2.26 (s, 3H), 2.42 (brs, 1H), 4.48
(d, J = 6.9 Hz, 1H), 5.05 (d, J = 6.9 Hz, 1H), 6.82 (s, 2H), 7.27 7.48 (m,
2.15 (brs, 1H,), 3.13 (brs, 1H), 3.88 4.03 (m, 3H) 4.83 (d, J = 6.0 Hz,
1H), 7.08 7.29 ppm (m, 13H); 13C NMR (75 MHz, DMSO): d = 46.6,
68.3, 126.8, 127.6, 128.0, 128.2, 128.3, 128.9, 135.3, 135.9, 139.1,
140.2 ppm; IR (Nujol): n˜ = 3332, 3304 cmÀ1; MS (CI): m/z (%): 159
[CH2Ph35Cl35Cl], 161 [CH2Ph37Cl37Cl], 264 [M35+1ÀPhCH2ÀOH]+, 266
[M37+1ÀPhCH2ÀOH]+, 355, 371 [M35+1]; elemental analysis calcd (%)
for C21H19Cl2NO: C 67.75, H 5.14, N 3.76; found: C 67.75, H 5.31, N 4.05.
10H), 8.40 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d
= 20.5, 21.0,
78.3, 83.2, 127.3, 127.5, 127.6, 128.0, 128.3, 128.3, 129.3, 130.4, 137.7,
138.9, 140.6, 140.8, 162.1 ppm; IR (Nujol): n˜ = 3368 (OH), 3306, 3031
(Ar-C-H), 1646 (Ar-C=N) cmÀ1
; MS (EI): m/z (%): 236 (100)
+
[MÀPhCH2 ÀH2O], 237 [M+1ÀPhCH2ÀH2O]+, 343 [M]+; elemental
analysis calcd (%) for C24H25NO: C 83.93, H 7.34, N 4.08; found: C
83.92, H 7.26, N 4.10.
(1R,2S)-N-Piperonyl-1,2-diphenyl-2-aminoethanol (3j): This compound
was obtained as a white solid; m.p. 134 1358C; 1H NMR (300 MHz,
CDCl3): d = 3.47 (d, J = 13.2 Hz, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.94
(1R,2S)-N-3’-Methylbenzylidene-1,2-diphenyl-2-aminoethanol (4d): This
compound was obtained as white crystals in 78.5% yield; m.p. 748C;
[a]2D5
=
À22.4 (c
=
0.49 in CHCl3); 1H NMR (300 MHz, CDCl3):
(d, J
= 5.4 Hz, 1H), 4.89 (d, J = 5.7 Hz, 1H), 5.94 (s, 2H), 6.60
7.31 ppm (m, 13H); 13C NMR (75 MHz, DMSO): d = 50.7, 67.6, 100.8,
107.9,108.6, 121.2, 126.0, 126.7, 126.8, 126.6, 127.8, 127.9, 128.0, 128.2,
128.3, 133.4, 138.7, 140.3, 146.5, 146.5, 147.6 ppm; IR (Nujol): n˜ = 3313,
3088, 3027, 1254 (C-O-C), 1042 (C-O-C) cmÀ1; MS (EI): m/z (%): 135
(100) [BnOCH2O]+, 240 (100) [M+1ÀPhCH2ÀOH]+, 241, 348 [M+1];
elemental analysis calcd (%) for C22H21NO3: C 76.06, H 6.09, N 4.03;
found: C 76.06, H 6.39, N 3.90.
d = 2.39 (s, 3H), 2.60 (brs, 1H), 4.50 (d, J = 6.0 Hz, 1H), 5.09 (d,
J
= 6.0 Hz, 1H), 7.26 7.39 (m, 12H), 7.48 (d, 1H), 7.56 (s, 1H),
8.08 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d = 21.2, 78.1, 81.0,125.6,
127.1, 127.4, 127.7, 128.1, 128.3, 128.3, 128.6, 131.6, 136.0, 138.1, 140.1,
140.6, 162.0 ppm; IR (Nujol): n˜
=
3392 (OH), 3347, 3029 (Ar-C-H),
1647 (Ar-C=N) cmÀ1
; HRMS calcd for C22H22NO: 316.1696, found
316.1693.
(1R,2S)-N-4’-Methylbenzyl-1,2-diphenyl-2-aminoethanol (3k): This com-
(1R,2S)-N-3’-Chlorobenzylidene-1,2-diphenyl-2-aminoethanol (4e): This
pound was obtained as white crystals in 64% yield; m.p.167 1688C; [a]D25
compound was obtained as a white solid (684 mg) in 87.3% yield; m.p.
1
83 848C; [a]2D5
= +3.4 (c =
1.00 in CHCl3); 1H NMR (300 MHz,
= +14.7 (c = 1.03in CHCl ); H NMR (300 MHz, CDCl3): d = 2.33 (s,
3
3H), 3.54 (d, J = 13.5 Hz, 1H), 3.71 (d, J = 13.5, 1H), 3.96(d, J =
5.4 Hz, 1H) 4.83(d, J = 5.4 Hz, 1H), 7.07 7.29 ppm (m, 14H); 13C NMR
(75 MHz, DMSO and CDCl3): d = 21.0, 50.5, 67.8, 76.6, 111.2, 115.9,
119.2, 120.2, 120.5, 125.8, 126.9, 127.2, 127.8, 128.0, 128.9, 135.8, 137.7,
141.2, 143.4, 155.5 ppm; IR (Nujol): n˜ = 3315, 3059, 3024 cmÀ1; MS (EI):
m/z (%): 105, 210 [M+1ÀPhCH2ÀOH]+, 211 [M+1ÀPhCH2ÀOH]+, 3 18
[M+1]; elemental analysis calcd (%) for C22H23NO: C 82.24, H 7.30, N
4.41; found: C 83.21, H 7.52, N 4.59.
CDCl3): d = 2.18 (brs, 1H), 4.18 (d, J = 6.4 Hz, 1H), 4.76 (d, J =
6.4 Hz, 1H), 6.92 7.12 (m, 11H), 7.22 7.25 (m, 2H), 7.59 (s, 1H),
7.68 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d
= 78.1, 81.1, 126.5,
126.6, 127.1, 127.2, 127.4, 127.6, 127.6, 127.7, 127.8, 127.9, 128.3, 128.3,
129.7, 130.6, 134.6, 137.7, 140.4, 140.5, 160.2 ppm; IR (Nujol): n˜ = 3440
(OH), 3032 (Ar-C-H),1633 (Ar-C=N) cmÀ1
;
HRMS calcd for
C21H19NO35Cl: 336.1150, found 336.1149.
(1R,2S)-N-4’-Chlorobenzylidene-1,2-diphenyl-2-aminoethanol (4 f): This
(1R,2S)-N-Furyl-1,2-diphenyl-2-aminoethanol (3l): This compound was
compound was obtained as a white solid (672 mg) in 81.0% yield; m.p.
obtained as white crystals in 73.2% yield; m.p. 133 1348C; [a]D25
=
91 928C; [a]2D5
= +8.7 (c =
1.03in CHCl 3); 1H NMR (300 MHz,
+32.1 (c = 1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d = 3.56 (d,
J = 14.6 Hz, 1H), 3.75 (d, J = 14.6 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H),
4.90 (d, J = 6.0 Hz, 1H), 6.08 (d, J = 3.0 Hz, 1H), 6.29 (dd, J = 2.9,
1.9 Hz, 1H), 7.12 7.34 ppm (m, 11H); 13C NMR (75 MHz, DMSO): d =
43.4, 67.5, 76.5, 106.9, 110.4, 127.1, 127.2, 127.8, 128.9, 140.4, 141.9, 14.9,
154.0 ppm; IR (Nujol): n˜ = 3324, 3060, 3030 cmÀ1; elemental analysis
calcd (%) for C19H19NO2: C 77.79, H 6.53, N 4.77; found: C 77.61, H
6.54, N 4.67.
CDCl3): d = 2.49 (brs, 1H), 4.49 (d, J = 6.4 Hz, 1H), 5.07 (d, J =
6.4 Hz, 1H), 7.26 7.42 (m, 12H), 7.63(d, J = 8.3Hz, 2H), 8.02 ppm (s,
1H); 13C NMR (75 MHz, CDCl3): d = 78.1, 81.1, 126.5, 127.2, 127.4,
127.5, 127.6, 127.7, 127.8, 127.9, 128.3, 128.3, 128.5, 128.7, 129.4, 1340.5,
136.7, 140.1, 140.6, 160.4 ppm; IR (Nujol): n˜ = 3382 (OH), 3029 (Ar-C-
H), 1646 (Ar-C=N) cmÀ1 HRMS calcd for C21H19NO35Cl: 336.1150,
;
found 336.1154.
(1R,2S)-N-2’-Bromobenzylidene-1,2-diphenyl-2-aminoethanol (4g): This
compound was obtained as white crystals (589 mg) in 63.0% yield; m.p.
133 1348C; 4g [a]2D0 = + 9.4 (c = 1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3): d = 2.52 (brs, 1H), 4.59 (d, J = 6.3Hz, 1H), 5.08 (d, J =
6.3Hz, 1H), 7.24 7.53 (m, 13H), 8.05 8.08 (m, 1H), 8.44 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d = 78.2, 81.2, 125.1, 127.1, 127.4, 127.4,
127.5, 127.6, 127.6, 127.7, 127.7, 127.9, 128.3, 128.3, 128.9, 131.8, 132.9,
134.4, 140.4, 140.5, 160.8 ppm (C=N); IR (Nujol): n˜ = 3386 (OH), 3330,
3031 (Ar-C-H), 1638 (Ar-C=N) cmÀ1; MS (EI): m/z (%): 77, 89, 91, 165
(79), 169 [CH2Ph79Br], 171 [CH2Ph81Br], 193273(100)
[MÀPhCH2ÀH2O]+, 274 (55) [M+1ÀPhCH2ÀH2O]+ 380 [M]+; elemental
analysis calcd (%) for C21H18BrNO: C 66.33, H 4.77, N 3.68; found: C
66.38, H 4.83, N 3.68.
(1R,2S)-N-a-Naphthyl-1,2-diphenyl-2-aminoethanol (3m): This com-
pound was obtained as a white solid; m.p. 141 1428C; [a]2D5 = +14.3( c
=
1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d
=
3.99 (d, J
12.8 Hz, 1H), 4.05 (d, J = 5.9 Hz, 1H), 4.16(d, J = 13.0 Hz, 1H), 4.86
(d,
6.0 Hz, 1H), 7.10 7.88 ppm (m, 17H); 13C NMR (75 MHz,
=
J
=
DMSO and CDCl3): d = 49.0, 68.8, 76.6, 124.0, 125.7, 125.9, 126.1, 126.2,
127.1, 127.2, 127.3, 127.6, 127.8, 127.9, 128.7, 129.0, 131.7, 133.6,
136.4 ppm; IR (Nujol): n˜
= 3316 (OH), 3170, 3045, 1452, 1416, 710
(CH2) cmÀ1; MS (EI): m/z (%): 106, 141, 194, 246 [M+1ÀPhCH2ÀOH]+,
354 [M+1]; elemental analysis calcd (%) for C21H20ClNO: C 84.95, H
6.56, N 3.96; found: C 85.05, H 6.50, N 3.87.
General procedure for the preparation of (1R,2S)-N-aryl-1,2-diphenyl-
idene-2-aminoethanol (4a m): A solution of (1R,2S)-1,2-diphenyl-2-ami-
noethanol (2.35 mmol) and aryl aldehyde (2.50 mmol) in anhydrous etha-
nol (20 mL) was stirred for 2 12 h at room temperature. The solvent was
removed to give the crude product as a white solid that was purified by
crystallization in n-hexane to give 4a m.
(1R,2S)-N-3’-Bromobenzylidene-1,2-diphenyl-2-aminoethanol (4h): This
compound was obtained as white crystals (475 mg) in 53.2% yield; m.p.
1
888C; [a]2D5 = À2.1 (c = 0.99 in CHCl3); H NMR (300 MHz, CDCl3): d
= 2.18 (brs, 1H), 4.18 (d, J = 6.4 Hz, 1H), 4.76 (d, J = 6.4 Hz, 1H),
6.92 7.11 (m, 11H), 7.22 7.25 (m, 2H). 7.59 (s, 1H), 7.68 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d = 78.1, 81.2, 122.7, 127.1, 127.1, 127.6,
127.7, 127.8, 128.3, 130.0, 130.7, 133.6, 138.0, 140.0, 140.5, 160.1 ppm (C=
N); IR (Nujol): n˜ = 3468 (OH), 3032 (Ar-C-H), 1631 (Ar-C=N); HRMS
calcd for C21H19NO79Br: 380.0644, found 380.0651.
(1R,2S)-N-4’-Methoxylbenzylidene-1,2-diphenyl-2-aminoethanol
(4b):
This compound was obtained as white crystals (550 mg) in 68.5% yield;
m.p. 130 1318C; [a]2D5 = À27.4 (c = 1.01, CHCl3); 1H NMR (300 MHz,
CDCl3): d = 2.80 (brs, 1H), 3.85 (s, 3H), 4.50 (d, J = 6.0 Hz, 1H), 5.09
1489
Chem. Eur. J. 2004, 10, 1481 1492
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

L.-Z. Gong, Y.-D. Wu et al.
FULL PAPER
(1R,2S)-N-4’-Bromobenzylidene-1,2-diphenyl-2-aminoethanol (4i): This
been stirred for 48 h at room temperature, the reaction was quenched
with saturated aqueous ammonium chloride, and the aqueous layer was
extracted with CH2Cl2 (3î30 mL). The combined organic layers were
washed with brine, and dried over anhydrous Na2SO4. After evaporation
of the solvent, the residue was purified through column chromatography
on silica gel to give 6a as a white solid (324.8 mg). Yield: 97%; The
enantiomeric excess of 98% with the R isomer as the major product was
determined by HPLC (ChiracelAD column, hexane/propan-2-ol 80:20;
flow rate 1 mLminÀ1; R isomer, tR 7.05 min and S isomer, tR 9.28 min).
compound was obtained as white crystals (641 mg) in 68.5% yield; m.p.
104 1058C; [a]2D5
= +8.2 (c =
1.06 in CHCl3); 1H NMR (300 MHz,
CDCl3): d = 2.49 (brs, 1H), 4.48 (d, J = 6.3Hz, 1H), 5.06 (d, J =
6.3Hz, 1H), 7.25 7.58 (m, 14H), 8.00 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d = 78.1, 81.1, 125.1, 127.1, 127.5, 127.6, 127.8, 128.3, 129.6,
131.7, 134.9, 140.0, 140.5, 160.5 ppm; IR (Nujol): n˜
= 3389 (OH),
3031(Ar-C-H), 1647 (Ar-C=N) cmÀ1; HRMS calcd for C21H19NO79Br:
380.0644, found 380.0653.
N-[1-(4-Methoxyphenyl)propyl]-P,P-diphenylphosphinoylamide
(6b):
(1R,2S)-N-4’-Benzoxylbenzylidene-1,2-diphenyl-2-aminoethanol
(4j):
This compound was obtained as a white solid (32.5 mg) in 89% yield;
[a]1D5 = +50.0 (c = 0.122 in acetone); the enantiomeric excess of 97%
with the R isomer as the major product was determined by HPLC (Chir-
This compound was obtained as white crystals (700 mg) in 74.8% yield;
m.p. 109.98C; [a]2D5 = À19.6 (c = 0.50, CHCl3); 1H NMR (300 MHz,
CDCl3): d = 2.48 (brs, 1H), 4.48 (d, J = 6.0 Hz, 1H), 5.07 (d, J =
6.0 Hz, 1H), 5.11(s, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.25 7.44 (m, 10H),
7.68 (d, J = 8.4 Hz, 2H), 8.06 ppm (s, 1H); 13C NMR (75 MHz, CDCl3):
d = 69.9, 78.2, 80.8, 114.7, 126.9, 127.1, 127.4, 127.4, 127.5, 127.7, 128.1,
128.2, 128.4, 128.6, 129.3, 129.8, 136.5, 140.3, 140.7, 161.0 ppm; IR
(Nujol): n˜ = 3378 (OH), 3031(Ar-C-H), 1640 (Ar-C=N) cmÀ1; HRMS
calcd for C28H26NO2: 408.1958, found 408.1965.
acelAD column, hexane/propan-2-ol 80:20; flow rate 1 mLminÀ1
; R
isomer, tR 10.54 min and S isomer, tR 13.15 min).
N-{1-[3,4-(Methylenedioxy)phenyl]propyl}-P,P-diphenylphosphinamide
(6c): This compound was obtained as a white solid (34.7 mg) in 92%
yield; [a]1D5 = +58.49 (c = 0.106, acetone); the enantiomeric excess of
97% with the R isomer as the major product was determined by HPLC
(ChiracelAD column, hexane/propan-2-ol 80:20; flow rate 1 mLminÀ1; R
isomer, tR 8.32 min and S isomer, tR 13.82 min)
(1R,2S)-N-(4’-N,N-Dimethylbenzylidene)-1,2-diphenyl-2-aminoethanol
(4k): This compound was obtained as pale yellow crystals (670 mg) in
83.0% yield; m.p. 119 1208C; [a]D25
=
À79.2 (c
= 0.94 in CHCl3);
N-[1-(4-Methylphenyl)propyl]-P,P-diphenylphosphinoylamide (6d): This
1H NMR (300 MHz, CDCl3): d = 3.03 (s, 6H), 4.47 (d, J = 5.7 Hz, 1H),
5.07 (d, J = 5.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 2H), 7.19 7.29 (m, 10H),
7.62 (d, J = 8.7 Hz, 2H), 8.04 ppm (s, 1H); 13C NMR (75 MHz, CDCl3):
d = 40.1, 78.2, 80.5, 111.4, 124.3, 126.9, 127.1, 127.5, 127.6, 127.7, 127.9,
128.0, 128.2, 128.4, 129.7, 140.4, 140.8, 152.1, 161.5 ppm; IR (Nujol): n˜ =
3438 (OH), 3029(Ar-C-H), 1646 (Ar-C=N), 1606 cmÀ1; HRMS calcd for
C23H25N2O: 345.1961, found 345.1950.
compound was obtained as a white solid (33.3 mg) in 95% yield; [a]D15
=
+47.08 (c = 0.24 in acetone); the enantiomeric excess of 98% with the
R isomer as the major product was determined by HPLC (ChiracelAD
column, hexane/propan-2-ol 92:8; flow rate 1 mLminÀ1; R isomer, tR
7.79 min and S isomer, tR 9.44 min)
N-[1-(3-Methylphenyl)propyl]-P,P-diphenylphosphinamide (6e): This
compound was obtained as a white solid (30.1 mg) in 86% yield; [a]D15
=
(1R,2S)-N-Piperonylidene-1,2-diphenyl-2-aminoethanol (4l): This com-
+21.43( c = 0.154 in acetone); the enantiomeric excess of 96% with the
R isomer as the major product was determined by HPLC (ChiracelAD
column, hexane/propan-2-ol = 90:10; flow rate 1 mLminÀ1; R isomer, tR
5.82 min and S isomer, tR 9.59 min)
pound was obtained as white crystals (520 mg) in 65.5% yield; m.p. 105
1
1068C; [a]2D5 = À31.4 (c = 1.00 in CHCl3); H NMR (300 MHz, CDCl3):
d = 2.26 (brs, 1H), 4.46 (d, J = 6.3Hz, 1H), 5.05 (d, J = 6.3Hz, 1H),
6.00 (s, 2H), 6.79 (d, J = 7.8 Hz, 1H), 7.01(d, J = 7.8 Hz, 1H) 7.25 7.41
(m, 11H), 7.97 (s, 1H), 8.03ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d
= 78.2, 80.7, 101.3, 106.5, 107.9, 124.6, 126.9, 127.1, 127.5, 128.1, 128.3,
130.9, 140.3, 140.7, 148.1, 149.9, 160.8 ppm (C=N); IR (Nujol): n˜ = 3410
Enantioselective addition of dibutylzinc to N-diphenylphosphinoyl benzal-
imine (5a, 0.1 mmol) in the presence of 3c (0.1 mmol)
N-(1-Phenylpentyl)-P,P-diphenylphosphinoylamide (8a): This compound
was obtained as a white solid in 67% yield; m.p. 165 1668C; [a]D15
=
(OH), 3333, 3030(Ar-C-H), 1638 (Ar-C=N) cmÀ1
; HRMS calcd for
1
+24.74 (c = 0.19 in acetone); H NMR (300 MHz, CDCl3): d = 0.80 (t,
J = 6.8 Hz, 3H), 1.07 1.1.24 (m, 4H), 1.83 2.07 (m, 2H), 4.15 (m, 1H),
7.14 7.49 (m, 10H), 7.75 7.88 ppm (m, 5H); 13C NMR (75 MHz, CDCl3):
d = 13.8, 22.3, 28.1, 39.4, 55.8, 126.4, 126.9, 128.1, 128.3, 128.4, 130.9,
131.6, 131.7, 131.8, 132.2, 132.4, 132.5, 143.8 ppm; IR (Nujol): n˜ = 3221
(NH), 1183(P =O) cmÀ1; MS (EI): m/z (%): 363 [M]+, 305 [MÀBu], 216
[Ph2PONH]+, 201 [Ph2PO]+; elemental analysis calcd (%) for
C23H26NOP: C 76.01, H 7.21, N, 3.85; found: C 75.71, H 7.27, N 3.99. The
enantiomeric excess of 97% with the R isomer as the major product was
determined by HPLC (ChiracelOD column, hexane/propan-2-ol 80:20;
flow rate 1 mLminÀ1; R isomer, tR 3.583 min and S isomer, tR 5.169 min).
C22H20NO3: 346.1438, found 346.1427.
(1R,2S)-N-(a-Naphthylidene)-1,2-diphenyl-2-aminoethanol (4m): This
compound was obtained as a white solid (350 mg) in 42.1% yield; m.p.
1088C; [a]2D5 = À9.7 (c = 0.50 in CHCl3); 1H NMR (300 MHz, CDCl3):
d = 2.56 (brs, 1H), 4.62 (d, J = 6.6 Hz, 1H), 5.17 (d, J = 6.6 Hz, 1H),
7.27 7.90 (m, 16H), 8.69 (s, 1H), 8.71 ppm (d,
J = 7.3Hz, 2H);
13C NMR (75 MHz, CDCl3): d = 78.4, 82.6, 124.6, 125.2, 126.0, 127.1,
127.4, 127.5, 127.6, 127.9, 128.4, 128.5, 128.5, 129.4, 131.2, 131.2, 131.5,
133.7, 140.6, 140.9, 162.0 ppm; IR (Nujol): n˜ = 3528 (OH), 3458, 3030
(Ar-C-H), 1638 (Ar-C=N) cmÀ1; HRMS calcd for C25H22NO: 352.1696,
found 352.1691.
N-[1-(4-Methoxyphenyl)pentyl]-P,P-diphenylphosphinoylamide
This compound was obtained as a white solid in 50% yield; m.p. 135
1368C; [a]1D5 0.02 in acetone); 1H NMR (300 MHz,
+40.00 (c
(8b):
Enantioselective addition of diethylzinc to N-diphenylphosphinoyl benza-
limine: Typical experimental procedure for the enantioselective addition
of diethylzinc to N-diphenylphosphinoyl benzalimine (5a, 0.1 mmol) in
the presence of 3c (0.1 mmol): Imine 5a (30.5 mg, 0.1 mmol) and amino
alcohol 3c (34.5 mg, 0.1 mmol) were dissolved in toluene (2 mL) under
argon. To the mixture was added Et2Zn in hexane (1m, 0.5 mL,
0.5 mmol) at room temperature. After the reaction mixture had been stir-
red for 48 h, the reaction was quenched with saturated aqueous ammoni-
um chloride, and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were washed with brine, and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was purified by
column chromatography (silica gel) to give 6a as a white solid (30.8 mg).
=
=
CDCl3): d = 0.80 (t, J = 6.6 Hz, 3H), 1.07 1.21 (m, 4H), 1.78 2.0 (m,
2H), 3.32 (m, 1H), 3.80 (s, 3H), 4.06 4.11 (m, 1H), 6.81 7.47 (m, 10H),
7.73 7.87 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d = 13.8, 22.3, 28.2,
39.3, 55.1, 55.2, 113.7, 127.5, 128.1, 128.2, 128.4, 131.2, 131.5, 131.5, 131.6,
131.7, 131.8, 132.4, 132.5, 133.0, 134.1, 136.0, 158.4 ppm; IR (Nujol): n˜ =
3128(NH), 1189 (P=O) cmÀ1 MS (EI): m/z (%): 394 [M+1]+,
; 3 3 7
[M+1ÀBu], 336 [MÀBu], 319 [MÀBuÀ16 [Ph2PONH]+, 201 [Ph2PO]+,
192 [MÀO]+, 13 6 M[ +1ÀPh2POÀBu]+; elemental analysis calcd (%) for
C24H28NO2P: C 73.26, H 7.17, N 3.56; found: C 73.29, H 7.23, N 3.38 .
The enantiomeric excess of 95% with the R isomer as the major product
was determined by HPLC (ChiracelOD column, hexane/propan-2-ol
80:20; flow rate 1 mLminÀ1; R isomer, tR 4.294 min and S isomer, tR
5.534 min).
Yield: 92%; [a]1D5
= +34.55 (c = 1.01 in acetone); the enantiomeric
excess of 97% with the R isomer as the major product was determined
by HPLC (ChiracelAD column, hexane/propan-2-ol 80:20 ; flow rate
1 mLminÀ1; R isomer, tR 8.66 min and S isomer, tR 11.60 min).
N-{1-[3,4-(Methylenedioxy)phenyl]pentyl}-P,P-diphenylphosphinamide
(8c): This compound was obtained as a white solid in 57% yield; m.p.
Enantioselective addition of diethylzinc to N-diphenylphosphinoyl benzal-
imine (4a, 1 mmol) in the presence of 3c (1 mmol): Imine 5a (305.0 mg,
1 mmol) and amino alcohol 3c (345.1 mg, 1 mmol) were dissolved in tolu-
ene (20 mL) under argon. Et2Zn in hexane (1m, 5 mL, 5 mmol) was
added dropwise to the mixture at 0 58C. After the reaction mixture had
1598C; [a]1D5
= +42.50 (c =
0.12 in acetone); 1H NMR (300 MHz,
CDCl3): d = 0.80 (t, J = 6.0 Hz, 3H), 1.09 1.43 (m, 5H), 1.71 2.00 (m,
2H), 3.17 3.29 (brs, 2H,), 4.06 (m, 1H), 6.55 6.70 (m, 3H), 7.27
7.87 ppm (m, 10H); 13C NMR (75 MHz, CDCl3): d = 13.8, 22.2, 28.2,
1490
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 1481 1492

Enantioselective Alkylation of Arylimines with Dialkylzinc
1481 1492
39.4, 55.6, 100.8, 106.6, 107.9, 119.9, 127.6,128.4, 131.2, 131.6, 131.8, 132.4,
132.5, 132.9, 137.8, 146.3, 147.6 ppm; IR (Nujol): n˜ = 3157 (NH), 1249
(C-O-C), 1192 (P=O), 1042 (C-O-C) cmÀ1; MS (EI): m/z (%): 201 (70)
[Ph2PO]+, 206 (100) [M+1ÀPh2PO]+, 350 (65) [MÀC4H9], 408 [M+1]; el-
emental analysis calcd (%) for C24H26NO3P: C 70.75, H 6.43, N, 3.44;
found: C 70.51, H 6.50, N 3.78 . The enantiomeric excess of 97% with
the R isomer as the major product was determined by HPLC (Chirace-
lOD column, hexane/propan-2-ol 80:20; flow rate 1 mLminÀ1; R isomer,
tR 4.801 min and S isomer, tR 6.389 min).
6084; c) F. Y. Zhang, C. C. Pai, A. S. C. Chan, J. Am. Chem. Soc.
1998, 120, 5808; d) G. X. Zhu, X. M. Zhang, J. Org. Chem. 1998, 63,
9590; e) Y. Y. Yan, T. V. RajanBabu, Org. Lett. 2000, 2, 4137.
[4] a) S. E. Denmark, O. J.-C. Nicaise, Chem. Commun. 1996, 999;
b) S. E. Denmark, O. J.-C. Nicaise in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, pp. 923; c) S. Kobayashi, H. Ishitani, Chem. Rev. 1999,
99, 1069.
[5] a) K. Soai, T. Hatanaka, T. Miyazawa, J. Chem. Soc. Chem.
Commun. 1992, 1097; b) P. G. Andersson, D. Guijarro, D. Tanner,
Synlett 1996, 727; c) P. G. Andersson, D. Guijarro, D. Tanner, J. Org.
Chem. 1997, 62, 7364; d) D. Guijarro, P. Pinho, P. G. Andersson, J.
Org. Chem. 1998, 63, 2530; e) P. Brandt, C. Hedberg, K. Lawonn, P.
Pinho, P. G. Andersson, Chem. Eur. J. 1999, 5, 1692; f) C. Jimeno,
K. S. Reddy, L. Sola, A. Moyano, M. A. Pericas, A. Riera, Org. Lett.
2000, 2, 3157; g) X. M. Zhang, W. Q. Lin, L. Z. Gong, A. Q. Mi, X.
Cui, Y. Z. Jiang, M. C. K. Choi, A. S. C. Chan, Tetrahedron Lett.
2002, 43, 1535; h) X. M. Zhang, H. L. Zhang, W. Q. Lin, L. Z. Gong,
A. Q. Mi, X. Cui, Y. Z. Jiang, K. B. Yu, J. Org. Chem. 2003, 68,
4322; i) K. Soai, T. Suzuki, T. Shono, J. Chem. Soc. Chem. Commun.
1994, 317; j) T. Suzuki, T. Shibata, K. Soai, J. Chem. Soc. Perkin
Trans. 1, 1997, 2757; k) T. Suzuki, Y. Hirokawa, K. Ohtake, T. Shiba-
ta, K. Soai, Tetrahedron Asymmetry 1997, 8, 4033; l) I. Sato, R.
Kodaka, T. Shibata, Y. Hirokawa, N. Shirai, K. Ohtake, K. Soai, Tet-
rahedron Asymmetry 2000, 11, 2271; m) I. Sato, K. Hosoi, R.
Kodaka, K. Soai, Eur. J. Org. Chem. 2002, 3115.
N-[1-(4-Methylphenyl)pentyl]-P,P-diphenylphosphinoylamide (8d): This
compound was obtained as a white solid in 63% yield; m.p. 146.0
146.38C; [a]1D5
=
+31.82 (c = 0.132 in acetone); 1H NMR (300 MHz,
CDCl3): d = 0.80 (t, J = 6.5 Hz, 3H), 1.02 1.1.25 (m, 4H), 1.83 1.96 (m,
2H), 2.35 (s, 1H), 4.09 4.14 (1H, m), 7.03 7.49 (10H, m), 7.76 7.90 ppm
(4H, m); 13C NMR (75 MHz, CDCl3): d = 13.8, 21.0, 22.3, 28.2, 39.2,
39.3, 55.6, 126.3, 128.1, 128.2, 128.4, 129.1, 131.1,131.6, 131.8, 132.3, 132.4,
132.6, 132.8, 136.5, 140.8 ppm; IR (Nujol): n˜
= 3137(NH), 1191 (P=
O) cmÀ1; MS (EI): m/z (%): 377 [M]+, 376 [MÀ1], 321 [M+1ÀBu], 320
[MÀBu], 216 [Ph2PONH]+, 201 [Ph2PO]+, 176 [MÀPh2PO]+; elemental
analysis calcd (%) for C24H28NOP: C 76.37, H 7.48, N, 3.71; found: C
76.11, H 7.34, N 3.62. The enantiomeric excess of 95% with the R isomer
as the major product was determined by HPLC (ChiracelOD column,
hexane/propan-2-ol 80:20; flow rate 1 mLminÀ1; R isomer, tR 3.627 min
and S isomer, tR 4.665 min).
N-[1-(3-Methylphenyl)pentyl]-P,P-diphenylphosphinoylamide (8e): This
compound was obtained as a white solid in 55% yield; m.p. 1498C; [a]D15
[6] a) H. Fujihara, K. Nagai, K. Tomioka, J. Am. Chem. Soc. 2000, 122,
12055; b) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper,
J. Am. Chem. Soc. 2001, 123, 984; c) J. R. Porter, J. F. Traverse,
A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 10409;
d) A. A. Boezio, A. B. Charette, J. Am. Chem. Soc. 2003, 125, 1692;
e) C. Koradin, K. Polborn, P. Knochel, Angew. Chem. 2002, 114,
2651; Angew. Chem. Int. Ed. 2002, 41, 2535; f) S. Dahmen, S. Br‰se,
J. Am. Chem. Soc. 2002, 124, 5940.
1
= +21.43( c = 0.154 in acetone); H NMR (300 MHz, CDCl3): d = 0.80
(t, J = 6.6 Hz, 3H), 1.08 1.23 (m, 4H), 1.81 1.97 (m, 2H), 2.31 (s, 3H),
4.09 4.11 (m, 1H), 6.90 7.48 (m, 10H), 7.73 7.87 ppm (m, 4H);
13C NMR (75 MHz, CDCl3): d = 13.8, 21.4, 22.3, 28.2, 39.3, 55.8, 123.3,
127.7, 127.7,128.0, 128.2, 128.4, 131.5, 131.7, 131.8, 132.5, 137.9,
143.7 ppm; IR (Nujol): n˜ = 3157(NH), 1250, 1193 (P=O) cmÀ1; MS (EI):
m/z (%): 377 [M]+, 321 [M+1ÀBu], 320 [MÀBu], 319 [MÀBuÀ1], 216
[Ph2PONH]+, 201 [Ph2PO]+, 176 [MÀPh2PO]+; elemental analysis calcd
(%) for C24H28NOP: C 76.37, H 7.48, N, 3.71; found: C 76.24, H 7.50, N
3.68. The enantiomeric excess of 95% with the R isomer as the major
product was determined by HPLC (ChiracelOD column, hexane/propan-
2-ol 80:20; flow rate 1 mLminÀ1; R isomer, tR 3.531 min and S isomer, tR
4.604 min).
[7] K. S. Reddy, L. Sola, A. Moyano, M. A. Pericas, A. Riera, Synthesis
2000, 165.
[8] a) S. J. Li, Y. Z. Jiang, A. Q. Mi, Tetrahedron Asymmetry 1992, 3,
1467; b) A. Q. Mi, Z. Y. Wang, Y. Z. Jiang, Tetrahedron Asymmetry
1993, 4, 1957; c) A. Q. Mi, Z. Y. Wang, Z. W. Chen, Y. Z. Jiang,
A. S. C. Chan, T. K. Yang, Tetrahedron Asymmetry 1995, 6, 2641;
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Berlin, 1999, Vol. 2, Chapt. 26.1, pp. 911.
N-[1-(4-Bromophenyl)pentyl]-P,P-diphenylphosphinoylamide (8 f): This
compound was obtained as a white solid in 59% yield; [a]1D5 = +51.79
(c = 0.112 in acetone); 1H NMR (300 MHz, CDCl3): d = 0.81 (t, J =
6.6 Hz, 3H), 1.06 1.1.26 (m, 4H), 1.75 1.94 (m, 2H), 3.21 3.25 (m, 1H),
4.09 4.14 (m, 1H), 7.01 7.47 (m, 10H), 7.74 7.87 ppm (m, 4H);
13C NMR (75 MHz, CDCl3): d = 13.8, 22.3, 28.1, 30.8, 39.2, 55.1, 120.6,
128.1, 128.2, 128.3, 128.4, 130.9, 131.4, 131.6, 131.8, 131.9, 132.3, 132.4,
132.7, 133.7, 142.9 ppm; IR (Nujol): n˜ = 3194 (NH), 1183 (P=O) cmÀ1
;
HRMS calcd for C23H25BrNOP: 442.0930, found 442.0953. The enantio-
meric excess of 96% with the R isomer as the major product was deter-
mined by HPLC (ChiracelOD column, hexane/propan-2-ol 80:20; flow
rate 1 mLminÀ1; R isomer, tR 3.945 min and S isomer, tR 5.134 min).
[11] L. Pu, H. B. Yu, Chem. Rev. 2001, 101, 757.
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1996, 7, 2519.
[13] A structurally rigid chiral amino alcohol could give comparable re-
sults with our ligand 3c for the titled reaction in chlorobenzene.
See: P. Pinho, P. G. Andersson, Tetrahedron 2001, 57, 1615.
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Acknowledgment
We are grateful to the National Natural Science Foundation of China for
financial support (Projects 20102005, 203900505, 20325211, and
20225312).
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1491
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Received: August 1, 2003
Revised: October 27, 2003[F5418]
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1481 1492