Enantioselective addition of diethylzinc to aldehydes catalyzed by (S)-1-alkyl-2-(arylamino)methylpyrrolidine

Article abstract of DOI:10.1246/bcsj.20120105

Several chiral diamines, (S)-1-alkyl-2-(arylamino)methylpyrrolidine, were used as chiral catalysts for the enantioselective addition of diethylzinc to aldehydes. The best results were obtained by employing 0.15 equiv of (S)-2-anilinomethyl-1-benzylpyrrolidine, and chiral secondary alcohols were obtained with high enantiomeric excesses (up to 94% ee).

Full text of DOI:10.1246/bcsj.20120105

1014 Bull. Chem. Soc. Jpn. Vol. 85, No. 9, 1014-1022 (2012)
© 2012 The Chemical Society of Japan
Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed
by (S)-1-Alkyl-2-(arylamino)methylpyrrolidine
Naoya Hosoda, Hiroki Ito, Tatsuya Takimoto, and Masatoshi Asami*
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501
Received April 4, 2012; E-mail: m-asami@ynu.ac.jp
Several chiral diamines, (S)-1-alkyl-2-(arylamino)methylpyrrolidine, were used as chiral catalysts for the
enantioselective addition of diethylzinc to aldehydes. The best results were obtained by employing 0.15 equiv of (S)-
2-anilinomethyl-1-benzylpyrrolidine, and chiral secondary alcohols were obtained with high enantiomeric excesses (up to
94% ee).
Asymmetric synthesis of chiral secondary alcohols has been
widely studied, because of their significance as intermediates
in the syntheses of natural products and pharmaceuticals. The
catalytic enantioselective alkylation of aldehydes is one impor-
tant method for preparing chiral secondary alcohols.1 Since
Oguni and Omi reported2 the reaction of diethylzinc and
benzaldehyde in the presence of a catalytic amount of chiral
alcohol, amine, or amino alcohol, a number of chiral catalysts
have been reported.3-9 Most of the successful results have
been obtained by using sterically constrained amino alcohols.4
Several diols,5 sulfonamides,6 and amino thiols/disulfide
compounds7 were also recently reported to show high selec-
tivity. Although chiral amines have also been used as cata-
lysts,8,9 the selectivity has not been high, except for a few
cases.8c,8d,9
On the other hand, we have been working on asymmetric
synthesis using chiral 1,2-diamines prepared from (S)-pro-
line8g,10-15 or (S)-indoline-2-carboxylic acid.9a,14-16 Previously,
we reported the enantioselective addition of dialkylzinc to
aldehydes catalyzed by chiral di- or triamines derived from (S)-
proline8g or (S)-indoline-2-carboxylic acid,9a and it was found
that the high acidity of the aromatic amine moiety of the
indoline ring is important to achieve high enantioselectivity.
We expected that (S)-1-alkyl-2-(arylamino)methylpyrrolidine
1, which has an acidic aromatic amine moiety, would also
act as an efficient catalyst for the enantioselective addition of
dialkylzinc to aldehydes (Scheme 1). As 1 is easily prepared
from a natural amino acid, (S)-proline, it would be advanta-
geous if high enantioselectivity could be achieved using 1.
Thus we examined the enantioselective addition of diethylzinc
to aldehydes using various diamines 1a-1q as catalysts. Di-
amine 1i (Ar = phenyl, R1 = benzyl) showed high selectivity
in the case of aromatic aldehydes, and corresponding secondary
alcohols were obtained in good yields with 81-94% ee.
Results and Discussion
In the first place, the reaction of diethylzinc and benzalde-
hyde was examined in the presence of chiral diamines, (S)-2-
(arylamino)methyl-1-methylpyrrolidine (1a: Ar = phenyl,17,18
1b: Ar = 2-tolyl,19 1c: Ar = 2,6-xylyl,18 1d: Ar = 1-naph-
thyl17,18), as the catalysts to investigate the steric effect of
the aryl group attached to the nitrogen atom of the side chain
on the enantioselectivity. To a mixture of benzaldehyde (1.0
equiv) and 1 (0.05 equiv) in cyclohexane, a hexane solution of
diethylzinc (1.8 equiv) was added at 0 °C, and stirring was
continued for 18 h at room temperature. The results are shown
in Table 1. The reaction using 1a afforded (R)-1-phenyl-1-
propanol in 91% yield with 67% ee (Entry 1). On the other
hand, the yield and selectivity decreased when 1b or 1d was
used as the catalyst (Entries 2 and 4). Furthermore, 1c hardly
Table 1. Enantioselective Addition of Diethylzinc to Benz-
aldehyde Catalyzed by 1a-1d
H
O
Ar
N
N
Ph
H
H
(1.0 equiv)
Me
HO
Ph
Et
H
1a-d (0.05 equiv)
+
H
Cyclohexane-Hexane
rt, 18 h
Et Zn
2
Ar
N
(1.8 equiv)
cat.
N
H
Entry
Catalyst (Ar)
Yield/%a)
ee/%b)
1
R
O
1
2
3
4
1a (phenyl)
1b (2-tolyl)
1c (2,6-xylyl)
1d (1-naphthyl)
91
78
57
85
67
50
5
HO
Et
H
1
+
Et Zn
2
2
2
H
R
R
56
Scheme 1. Enantioselective addition of diethylzinc to alde-
hydes catalyzed by 1.
a) Isolated yield. b) ee was determined by HPLC analysis.
Published on the web August 21, 2012; doi:10.1246/bcsj.20120105

N. Hosoda et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012) 1015
Ph CHBr (1.1 equiv),
3
2
R COCl
H
H
O
O
or
Et N (1.1 equiv)
3
3
Ph
Ph
(1.1 equiv),
(R CO) O
2
N
N
H
H
O
O
N
N
CH Cl
H
H
2
2
H
Et N (1.1 equiv)
3
CHPh
Ph
2
Ph
N
2
N
N
N
H
CH Cl
H
2
2
3j
H
O
2
3
64%
R
3
H
H
BH (4.0 equiv)
3
BH (4.0 equiv)
Ph
3
N
Ph
N
N
H
N
THF
H
THF
CHPh
3
2
R
1
1j
Yield / %
73%
3
R
3
1
Scheme 3. Preparation of 1j.
a)
e
quant.
99
75
84
CH
3
1
a)
R X (2.0 equiv),
g
CH(CH )
H
H
3 2
K CO (2.0 equiv)
2
3
a)
b)
b)
b)
b)
b)
b)
99
98
67
80
82
87
74
73
62
h
i
C(CH )
Ph
Ph
3 3
N
N
N
N
acetone-H O
H
2
H
H
Ph
CH Ph
1
R
4
1
98
l
2
m
n
p
q
1
98
CH OPh
2
X
Yield / %
R
quant.
quant.
96
2-CH C H
6 4
3
1f
CH(CH )
59
30
87
I
3 2
2-CH OC H
3
6
4
1k
1o
CPh
3
Cl
Br
4-CH OC H
6 4
3
CH (4-NO C H )
2
2 6 4
a) Acid anhydride was used.
b) Acyl chloride was used.
Scheme 4. Preparation of 1f, 1k, and 1o.
Scheme 2. Preparation of 1e, 1g-1i, 1l-1n, 1p, and 1q.
which indicates that no racemization of anilide 2 occurs during
the N-acylation or N-alkylation of 2 under the basic condition.
Next, the enantioselective addition of diethylzinc to benz-
aldehyde using 1e-1m was examined under the same reaction
conditions as Table 1. The results are summarized in Table 2.
At first, 1e-1h having linear or branched aliphatic alkyl chains
were employed as the catalysts. When 1e or 1f was used,
almost the same enantioselectivity was observed as 1a (Entries
1-3). On the other hand, the enantioselectivity was improved to
81% ee when the reaction was carried out using 1g having an
isobutyl group (Entry 4). The use of 1h having a neopentyl
group resulted in the decrease in the selectivity (47% ee,
Entry 5). Next, 1i-1k having phenyl-substituted methyl groups
were used. The selectivity was further improved to 84% ee
when 1i having a benzyl group was employed (Entry 6).
The introduction of two or three phenyl groups to the methyl
group resulted in the production of the corresponding alcohol
with low ee (34 and 1% ee, Entries 7 and 8, respectively).
The decrease in the selectivity by using 1h, 1j, and 1k is
rationalized as follows. Namely, the sterically hindered sub-
stituent prevents the nitrogen atom of the pyrrolidine ring from
coordinating to the zinc atom, which inhibits the formation of
rigid diamine-zinc complex to afford the alcohol with low
enantiomeric excesses. On the other hand, the results using 1g
and 1i indicate that the introduction of an optimized primary
alkyl substituent is effective for the improvement of the
served as a chiral catalyst (57% yield, 5% ee, Entry 3). These
results imply that the introduction of the sterically hindered aryl
group reduces the enantioselectivity.
Next, various (S)-1-alkyl-2-(anilinomethyl)pyrrolidines 1e-
1q were prepared from (S)-prolinanilide (2) or (S)-2-(anilino-
methyl)pyrrolidine (4) as a starting material to examine the
effect of the alkyl group (R1) attached to the nitrogen atom
of the pyrrolidine ring on the enantioselectivity. The synthetic
routes of these chiral diamines and yields are shown in
Schemes 2-4. Chiral diamines having ethyl (1e),20 isobutyl
(1g), neopentyl (1h), benzyl (1i), benzhydryl (1j), 2-phenyl-
ethyl (1l), 2-phenoxyethyl (1m), 2-methylbenzyl (1n), 2-
methoxybenzyl (1p), and 4-methoxybenzyl (1q) groups were
prepared from 2 by the N-acylation or N-alkylation followed
by the reduction of corresponding anilides 3 in good to excel-
lent yields, respectively (Schemes 2 and 3). Diamines 1f (R1 =
isopropyl), 1k (R1 = trityl), and 1o (R1 = 4-nitrobenzyl) were
synthesized from 4 by the selective alkylation of the nitrogen
atom of the pyrrolidine ring (Scheme 4). The diamines in
Schemes 2 and 3 were also prepared from 4 by N-acylation
followed by the reduction of corresponding amides or by N-
alkylation although the yields were lower than those prepared
from 2 (data not shown). The specific rotations of 1 prepared
from 2 were identical with those prepared from 4 respectively,

1016 Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Asymmetric Alkylation with Diamine Catalysts
Table 2. Enantioselective Addition of Diethylzinc to Benz-
aldehyde Catalyzed by 1e-1m
Table 4. Effect of Amounts of 1i on Yield and Enantio-
selectivity
H
H
O
O
Ph
N
Ph
N
N
N
Ph
H
H
H
Ph
1
H
(1.0 equiv)
R
(1.0 equiv)
Ph
HO
Ph
Et
H
1e-m (0.05 equiv)
+
HO
Ph
Et
H
1i
+
Cyclohexane-Hexane
rt, 18 h
Et Zn
2
Cyclohexane-Hexane
rt, 18 h
Et Zn
2
(1.8 equiv)
(1.8 equiv)
Entry
1
Catalyst (R1)
Yield/%a)
ee/%b)
Entry
1i/equiv
Yield/%a)
ee/%b)
1a (CH3)
91
67
1
2
3
0.05
0.10
0.15
0.15
0.20
0.20
0.25
0.25
86
89
89
86
91
87
92
87
84
86
87
88
88
87
88
87
2
3
4
5
6
7
8
9
10
1e (CH2CH3)
91
88
89
83
86
54
42
90
88
69
68
81
47
84
34
1
1f (CH(CH3)2)
1g (CH2CH(CH3)2)
1h (CH2C(CH3)3)
1i (CH2Ph)
4c)
5
6c)
7
1j (CHPh2)
1k (CPh3)
8c)
1l (CH2CH2Ph)
1m (CH2CH2OPh)
71
58
a) Isolated yield. b) ee was determined by HPLC analysis.
c) The reaction was carried out at 0 °C.
a) Isolated yield. b) ee was determined by HPLC analysis.
Table 3. Enantioselective Addition of Diethylzinc to Benz-
aldehyde Catalyzed by 1n-1q
group at the 2-position also decreased the selectivity to 58% ee
(Entry 4), while the reaction using 1q having a methoxy group
at the 4-position afforded the chiral alcohol with the same
selectivity as 1i (84% ee, Entry 5). These results imply that
the steric or electronic effect of the benzyl group does not
contribute to the improvement of the selectivity and the
unsubstituted benzyl group is the most efficient substituent
on the nitrogen atom of the pyrrolidine ring.
Next, the effect of the amounts of 1i was examined. Diamine
1i was added in the range of 0.05 to 0.25 equiv based on
benzaldehyde. As shown in Table 4, the enantioselectivity was
improved by increasing the amounts of 1i (Entries 1-3, 5, and
7), and the alcohol was obtained in 88% ee by using 0.15 equiv
of 1i at 0 °C (Entry 4). The selectivity was not further improved
even when 0.20 or 0.25 equiv of 1i was used (Entries 6 and 8).
The effect of solvents was also examined. The reaction was
carried out in various solvents in the presence of 0.15 equiv
of 1i at 0 °C. The results are summarized in Table 5. The
enantioselectivity was improved to 90-92% ee by using
various other solvents (Entries 2-9). The best result (94%
yield, 92% ee) was obtained when the reaction was carried
out in toluene-hexane (Entry 9).
H
Ph
N
N
H
O
Ph
(1.0 equiv)
H
4
R
HO
Ph
Et
H
1n-q (0.05 equiv)
Cyclohexane-Hexane
rt, 18 h
+
Et Zn
2
(1.8 equiv)
Entry
1
Catalyst (R4)
Yield/%a)
ee/%b)
1i (H)
86
84
2
3
4
5
1n (2-CH3)
1o (4-NO2)
1p (2-CH3O)
1q (4-CH3O)
86
76
73
94
82
62
58
84
a) Isolated yield. b) ee was determined by HPLC analysis.
selectivity. The reaction using 1l (R1 = 2-phenylethyl) or
1m (R1 = 2-phenoxyethyl) was also examined. However, the
improvement of the selectivity was not observed (71 and 58%
ee, Entries 9 and 10, respectively).
Next, steric or electronic effect of the benzyl group was
examined using 1n-1q. The results of the enantioselective
addition are shown in Table 3. At first, the steric effect was
examined using 1n, which has a methyl group at the 2-position
of the benzyl substituent. The enantioselectivity only slightly
changed (82% ee, Entry 2). Next, 1o-1q were employed
to evaluate the electronic effect. The introduction of an elec-
tron-withdrawing nitro group resulted in the decrease in the
selectivity to 62% ee (Entry 3). An electron-donating methoxy
Finally, the reaction was applied to various aldehydes using
the optimized reaction condition in order to examine the
usefulness of 1i as the catalyst. As shown in Table 6, high
enantioselectivities were achieved for aromatic aldehydes
(81-94% ee, Entries 1-5). In particular, the reaction of 1-
naphthaldehyde and diethylzinc showed the best selectivity
(94% ee, Entry 3). In the case of aliphatic aldehydes, high
selectivities were not attained (14-27% ee, Entries 6-8).
The assumed stereochemical model to explain the enantio-
selective addition of diethylzinc to aldehydes with 1i is shown
in Scheme 5. Initially, cis-fused five-membered bicyclic com-
plex 5 is generated by the reaction of 1i and diethylzinc. The
formation of 5 is important to achieve high selectivity as

N. Hosoda et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012) 1017
Table 5. Effect of Solvents on Yield and Enantioselectivity
in the Reaction Using 1i as a Catalyst
Et Zn
2
N
N Ph
H
N Ph
N
Zn
H
Ph
Ph
Et
Ph
O
N
1i
N
5
H
Et Zn
2
Ph
H
Ph
(1.0 equiv)
O
HO
Ph
Et
H
1i (0.15 equiv)
2
+
R
H
Solvent
0 °C, 18 h
Et Zn
2
(1.8 equiv)
Et
Zn
Entry
Solvent
Cyclohexane-Hexane
Yield/%a)
ee/%b)
N
1
86
88
Ph
H
H
N
2
3
4
5
6
7
8
9
Ether-Hexane
76
79
88
90
88
85
68
94
91
91
90
91
90
90
91
92
OZnEt
Et
O
Dichloromethane-Hexane
o-Xylene-Hexane
m-Xylene-Hexane
p-Xylene-Hexane
Benzene-Hexane
Anisole-Hexane
Toluene-Hexane
2
2
Zn
Et
R
R
Me
(major)
6 (favored)
Et
N
a) Isolated yield. b) ee was determined by HPLC analysis.
Zn
Ph
2
2
R
R
N
OZnEt
Et
Table 6. Enantioselective Addition of Diethylzinc to Alde-
hydes Catalyzed by 1i
O
Zn
H
H
H
Me
Et
(minor)
Ph
7 (disfavored)
O
N
N
H
2
H
R
Scheme 5. Stereochemical model for enantioselective addi-
tion of diethylzinc to aldehydes catalyzed by 1i.
Ph
(1.0 equiv)
HO
Et
H
1i (0.15 equiv)
Toluene-Hexane
0 °C, 18 h
+
2
R
the effect of the alkyl group (R1) attached to the nitrogen atom
of the pyrrolidine ring on the enantioselectivity as follows. The
nonbonded repulsion between R2 in the aldehyde and the
complex becomes effective when an appropriate size group
such as an isopropyl group (1g) and a phenyl group (1i) is
connected to the nitrogen atom by one methylene (CH2) group.
Thus (R)-alcohol was obtained with high enantiomeric excesses
by using 1g or 1i. Diamines 1a, 1e, 1f, 1l, and 1m were
not effective because the substituent is small (1a and 1e),
an isopropyl group is attached to the nitrogen atom directly
(1f), or a phenyl group is connected to the nitrogen atom by a
longer ethylene (CH2CH2) (1l) or oxyethylene (OCH2CH2)
(1m) group. High selectivities are attained in the reaction of
aromatic aldehydes, as the aromatic ring and the carbonyl
group are located on the same plane by the conjugation effect
and the nonbonded interaction between R2 and the complex
in less preferred transition state 7 (Scheme 5) becomes more
evident.
Et Zn
2
(1.8 equiv)
ee/%
Entry
1
R2
Yield/%a)
(Config.)b)
92 (R)
Ph
94
2
3
4
5
6
7
8
2-BrC6H4
86
79
88
95
65
57
65
81 (R)
94 (R)
92 (R)
90 (R)
27 (R)
18 (R)
14 (R)c)
1-Naphthyl
2-CH3OC6H4
4-CH3OC6H4
(E)-PhCH=CH
PhCH2CH2
c-C6H11
a) Isolated yield. b) ee was determined by HPLC analysis,
and the absolute configuration was determined by specific
rotation.9a,21,22 c) Determined by HPLC analysis of the
corresponding 4-methoxybenzoate.
mentioned above. Next, another diethylzinc is chelated with a
nitrogen atom of aniline moiety to form the dinuclear zinc
complex. The enantioselective addition occurs via transi-
tion state 6, in which the carbonyl oxygen of the aldehyde
approaches the more Lewis acidic diamine-chelated zinc atom
from the less hindered side of the complex in such a manner as
to prevent a nonbonded repulsion between R2 in the aldehyde
and the complex to yield (R)-alcohol preferentially. We assume
Conclusion
The enantioselective addition of diethylzinc to aldehydes
catalyzed by (S)-1-alkyl-2-(arylamino)methylpyrrolidine 1 was
studied. It was found that (S)-2-anilinomethyl-1-benzylpyrroli-
dine (1i) served as the most efficient catalyst for the reac-
tion. Chiral secondary alcohols having (R)-configuration were
obtained with high enantiomeric excesses from aromatic

1018 Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Asymmetric Alkylation with Diamine Catalysts
27
aldehydes under the optimized reaction conditions using 1i. As
the corresponding hydroxy compound having no substituent
on the side chain ((S)-N-methylprolinol) afforded racemic 1-
phenyl-1-propanol in the same reaction,23 our result shows that
the aniline moiety of the diamines plays an important role to
achieve high enantioselectivity. Furthermore, we previously
reported that the reaction using (S)-2-(1-pyrrolidinylmethyl)-
pyrrolidine, which was also prepared from (S)-proline, afforded
the chiral secondary alcohols with (S)-configuration from aro-
matic aldehydes with relatively high enantiomeric excesses.8g
Therefore, both enantiomers of the secondary alcohols can be
obtained using the diamine catalysts derived from naturally
occurring (S)-proline.
White solid; mp 183.8-184.3 °C; ½¡ꢀD ¹120.7 (c 1.00,
EtOH); IR (KBr, cm¹1): 3270, 1698, 1614, 1554, 1437;
1H NMR (500 MHz, CDCl3): ¤ 1.86-1.92 (m, 1H), 2.01-2.17
(m, 2H), 2.63-2.68 (m, 1H), 3.51 (dt, J = 6.8, 10.6 Hz, 1H),
3.58 (dt, J = 6.8, 10.6 Hz, 1H), 5.00 (dd, J = 4.9, 7.7 Hz, 1H),
7.06 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 2H), 7.41-7.48
(m, 3H), 7.53 (dd, J = 1.6, 7.1 Hz, 2H), 7.56 (d, J = 7.7 Hz,
2H), 9.57 (br, 1H); 13C NMR (126 MHz, CDCl3): ¤ 25.5, 26.4,
50.6, 60.7, 119.8, 124.0, 127.1, 128.5, 128.9, 130.5, 135.9,
138.3, 168.7, 171.9; Anal. Calcd for C18H18N2O2: C, 73.45; H,
6.16; N, 9.52%. Found: C, 73.35; H, 6.14; N, 9.45%.
N-Substituted (S)-prolinanilide 3e, 3g, 3h, 3j, 3l-3n, 3p, and
3q were prepared from 2 (2.0 mmol) in a similar manner.
(S)-N-Acetylprolinanilide (3e). (S)-Prolinanilide (2) was
reacted with acetic anhydride. The crude product was recrystal-
lized from ethyl acetate to give 3e. The residue of the
recrystallization was also purified by column chromatography
(silica gel, ethyl acetate) to give 3e (464.1 mg, 2.00 mmol,
quant.).
Experimental
General.
Most manipulations were carried out under
an atmosphere of argon. Solvents were dried and purified
in the usual manner. (S)-2-Anilinomethyl-1-methylpyrrolidine
(1a), (S)-1-methyl-2-(2-toluidinomethyl)pyrrolidine (1b), (S)-
1-methyl-2-(2,6-xylidinomethyl)pyrrolidine (1c), and (S)-1-
methyl-2-(1-naphthylamino)methylpyrrolidine (1d) were pre-
pared from (S)-N-(t-butoxycarbonyl)proline via coupling with
the corresponding aromatic amines using N,N¤-dicyclohexyl-
carbodiimide and the subsequent reduction with LiAlH4
according to the literature.17 (S)-Prolinanilide (2) and (S)-2-
(anilinomethyl)pyrrolidine (4) were prepared in a manner
reported previously.24
Melting points were determined on a Stuart melting point
apparatus SMP3 and are uncorrected. Specific rotations were
measured on a JASCO P-1010 polarimeter. Infrared spec-
tra were recorded on a HORIBA FT-730 spectrometer. 1H
and 13C NMR spectra were obtained on a Bruker biospin
DRX500 spectrometer using CDCl3 as a solvent. 1H and
13C NMR chemical shift values are given in ppm relative to
Me4Si. Elemental analyses were carried out on a Vario EL III
Elemental analyzer. High-performance liquid chromatography
(HPLC) analyses were carried out with JASCO instruments
(pump, PU-2080 Plus; detector, UV-2075 Plus). Thin layer
chromatography (TLC) analyses were carried out on silica gel
60 F254-coated plates (E. Merck). Column chromatography was
carried out with Wakogel C-200 with indicated eluent unless
otherwise described. Preparative TLC was performed on silica
gel-coated plates (Wakogel B-5F, 20 cm © 20 cm).
19
White solid; mp 174.0-175.1 °C; ½¡ꢀD ¹183.8 (c 1.11,
26
CH2Cl2) [lit.20 ½¡ꢀD ¹176 (c 1.1, CH2Cl2)]; IR and NMR spec-
tral data were identical with those reported in the literature.20
(S)-N-Isobutyrylprolinanilide (3g). (S)-Prolinanilide (2)
was reacted with isobutyric anhydride. The crude product was
recrystallized from a mixture of ethyl acetate/hexane (1/5)
to give 3g. The residue of the recrystallization was also
purified by column chromatography (silica gel, ethyl acetate/
hexane = 1/1) to give 3g (516.2 mg, 1.98 mmol, 99%).
28
White solid; mp 133.9-134.6 °C; ½¡ꢀD ¹100.0 (c 1.00,
EtOH); IR (KBr, cm¹1): 3274, 2973, 1697, 1625, 1555, 1442,
1
760; H NMR (500 MHz, CDCl3): ¤ 1.17 (d, J = 6.6 Hz, 3H),
1.18 (d, J = 6.6 Hz, 3H), 1.82 (tt, J = 7.5, 12.1 Hz, 1H), 2.01-
2.06 (m, 1H), 2.13-2.23 (m, 1H), 2.58-2.62 (m, 1H), 2.73 (sep,
J = 6.6 Hz, 1H), 3.52 (dt, J = 6.9, 9.8 Hz, 1H), 3.59-3.63 (m,
1H), 4.81 (d, J = 7.3 Hz, 1H), 7.05 (tt, J = 0.9, 7.7 Hz, 1H),
7.27 (t, J = 7.7 Hz, 2H), 7.50 (dd, J = 0.9, 7.7 Hz, 2H), 9.72
(br, 1H); 13C NMR (126 MHz, CDCl3): ¤ 18.6, 19.5, 25.1, 26.2,
32.5, 47.4, 60.5, 119.7, 123.8, 128.8, 138.5, 169.1, 178.4;
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%.
Found: C, 69.01; H, 7.74; N, 10.67%.
(S)-N-Pivaloylprolinanilide (3h).
(S)-Prolinanilide (2)
was reacted with pivalic anhydride. The crude product was
recrystallized from a mixture of ethyl acetate/hexane (11/16)
to give 3h. The residue of the recrystallization was also purified
by column chromatography (silica gel, ethyl acetate/hexane =
1/2) to give 3h (542.7 mg, 1.98 mmol, 99%).
Preparation of (S)-N-Benzoylprolinanilide (3i).
To a
dichloromethane (5.0 mL) solution of (S)-prolinanilide (2)
(380.9 mg, 2.00 mmol) was added a dichloromethane (2.0 mL)
solution of triethylamine (224.6 mg, 2.22 mmol) and a di-
chloromethane (2.0 mL) solution of benzoyl chloride (321.1
mg, 2.28 mmol) at room temperature and stirring was continued
overnight at room temperature. After water was added to the
reaction mixture, the aqueous layer was separated and extracted
with dichloromethane, and the combined organic layer was
washed with brine. The organic layer was dried over anhydrous
sodium sulfate, and the solvent was removed under reduced
pressure. The crude product was recrystallized from a mixture
of ethyl acetate/hexane (8/5) to give 3i. The residue of the
recrystallization was also purified by column chromatography
(silica gel, ethyl acetate/hexane = 1/1) to give 3i (575.5 mg,
1.96 mmol, 98%).
27
White solid; mp 171.9-172.5 °C; ½¡ꢀD ¹69.3 (c 1.01,
EtOH); IR (KBr, cm¹1): 3276, 2980, 1698, 1599, 1553, 1443,
1
1415, 756; H NMR (500 MHz, CDCl3): ¤ 1.30 (s, 9H), 1.81-
1.88 (m, 1H), 1.95-2.02 (m, 1H), 2.15-2.24 (m, 1H), 2.43-2.49
(m, 1H), 3.68 (ddd, J = 4.4, 7.9, 10.1 Hz, 1H), 3.76 (dt,
J = 7.6, 10.1 Hz, 1H), 4.85 (dd, J = 2.7, 8.0 Hz, 1H), 7.06
(t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 2H), 7.50 (d, J =
7.7 Hz, 2H), 9.25 (br, 1H); 13C NMR (126 MHz, CDCl3): ¤
26.0, 27.6 (©2), 39.4, 48.4, 62.4, 119.8, 123.8, 128.8, 138.4,
169.9, 178.6; Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08;
N, 10.21%. Found: C, 69.95; H, 8.12; N, 10.16%.
(S)-N-Benzhydrylprolinanilide (3j). (S)-Prolinanilide (2)
was reacted with benzhydryl bromide. The crude product was

N. Hosoda et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012) 1019
purified by column chromatography (silica gel, ether/hexane =
1/2) to give 3j (456.3 mg, 1.28 mmol, 64%).
7.4 Hz, 1H), 7.20-7.25 (m, 3H), 7.29-7.33 (m, 3H), 7.57 (dd,
J = 0.9, 8.5 Hz, 2H), 9.75 (br, 1H); 13C NMR (126 MHz,
CDCl3): ¤ 18.9, 25.0, 26.4, 49.4, 60.2, 119.8, 124.0, 125.3,
126.1, 129.0, 129.4, 130.7, 133.8, 136.3, 138.3, 168.6, 172.3;
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08%.
Found: C, 73.89; H, 6.55; N, 8.99%.
25
White solid; mp 148.1-148.7 °C; ½¡ꢀD ¹75.2 (c 1.00,
EtOH); IR (KBr, cm¹1): 3331, 3303, 2799, 1667, 1527, 1440,
1
762, 710, 695; H NMR (500 MHz, CDCl3): ¤ 1.78-1.83 (m,
2H), 2.06-2.11 (m, 1H), 2.15-2.23 (m, 1H), 2.53 (dt, J = 8.0,
9.9 Hz, 1H), 3.21-3.25 (m, 1H), 3.56 (dd, J = 3.5, 9.8 Hz, 1H),
4.82 (s, 1H), 7.09 (tt, J = 1.1, 7.6 Hz, 1H), 7.14 (tt, J = 1.6,
7.3 Hz, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.26 (tt, J = 1.6, 7.3 Hz,
1H), 7.30-7.37 (m, 6H), 7.43 (dd, J = 1.6, 7.3 Hz, 2H), 7.49
(dd, J = 1.1, 7.6 Hz, 2H), 9.49 (br, 1H); 13C NMR (126 MHz,
CDCl3): ¤ 24.6, 30.5, 53.1, 65.8, 73.5, 119.3, 124.0, 127.4,
127.6, 128.17, 128.18, 128.5, 128.6, 129.0, 137.7, 141.6,
141.9, 172.9; Anal. Calcd for C24H24N2O: C, 80.87; H, 6.79; N,
7.86%. Found: C, 80.42; H, 6.81; N, 7.73%.
(S)-N-(2-Methoxybenzoyl)prolinanilide (3p). (S)-Prolin-
anilide (2) was reacted with 2-methoxybenzoyl chloride. The
crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane = 1/1) to give 3p (648.7 mg, 2.00
mmol, quant.).
27
White solid; mp 158.6-159.2 °C; ½¡ꢀD ¹128.2 (c 1.00,
EtOH); IR (KBr, cm¹1): 3291, 1696, 1598, 1543, 1447, 1247,
1
1019, 754; H NMR (500 MHz, CDCl3): ¤ 1.85-1.93 (m, 1H),
1.97-2.11 (m, 2H), 2.59-2.63 (m, 1H), 3.27-3.32 (m, 1H),
3.36-3.40 (m, 1H), 3.85 (s, 3H), 4.99 (dd, J = 3.2, 7.9 Hz, 1H),
6.96 (d, J = 8.5 Hz, 1H), 7.02 (dt, J = 0.7, 7.4 Hz, 1H), 7.09 (tt,
J = 1.1, 7.4 Hz, 1H), 7.28-7.33 (m, 3H), 7.38-7.41 (m, 1H),
7.56 (dd, J = 1.1, 8.5 Hz, 2H), 9.44 (br, 1H); 13C NMR
(126 MHz, CDCl3): ¤ 24.7, 27.4, 48.6, 55.8, 60.4, 111.2,
120.1, 121.2, 124.1, 126.0, 127.5, 128.9, 129.0, 131.1, 138.3,
155.2, 169.0; Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21;
N, 8.64%. Found: C, 69.70; H, 6.38; N, 8.53%.
(S)-N-(Phenylacetyl)prolinanilide (3l). (S)-Prolinanilide
(2) was reacted with phenylacetyl chloride. The crude prod-
uct was purified by column chromatography (silica gel, ethyl
acetate/hexane = 1/2) to give 3l (605.9 mg, 1.96 mmol, 98%).
28
White solid; mp 99.4-99.7 °C; ½¡ꢀD ¹124.0 (c 1.01, EtOH);
IR (KBr, cm¹1): 3276, 1701, 1635, 1604, 1554, 1443, 759, 733,
1
695; H NMR (500 MHz, CDCl3): ¤ 1.82 (tt, J = 7.4, 12.1 Hz,
1H), 1.98-2.04 (m, 1H), 2.10-2.20 (m, 1H), 2.57 (dd, J = 6.5,
12.1 Hz, 1H), 3.50 (dt, J = 7.0, 9.9 Hz, 1H), 3.57-3.61 (m, 1H),
3.72 (d, J = 15.1 Hz, 1H), 3.75 (d, J = 15.1 Hz, 1H), 4.82
(d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 7.25-7.34 (m,
7H), 7.48 (dd, J = 0.9, 8.0 Hz, 2H), 9.56 (br, 1H); 13C NMR
(126 MHz, CDCl3): ¤ 25.1, 26.5, 41.9, 47.9, 60.8, 119.8, 123.9,
127.1, 128.8 (©2), 128.9, 134.0, 138.2, 168.8, 172.2; Anal.
Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08%. Found: C,
73.90; H, 6.53; N, 8.96%.
(S)-N-(4-Methoxybenzoyl)prolinanilide (3q). (S)-Prolin-
anilide (2) was reacted with 4-methoxybenzoyl chloride. The
crude product was purified by column chromatography (silica
gel, ether) to give 3q (623.0 mg, 1.92 mmol, 96%).
27
White solid; mp 171.7-172.5 °C; ½¡ꢀD ¹86.7 (c 1.01,
EtOH); IR (KBr, cm¹1): 3285, 1668, 1627, 1539, 1424, 1251,
1
1188, 850, 756; H NMR (500 MHz, CDCl3): ¤ 1.85-1.91 (m,
1H), 2.00-2.14 (m, 2H), 2.64-2.67 (m, 1H), 3.60-3.61 (m, 2H),
3.84 (s, 3H), 4.99 (t, J = 6.9 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H),
7.06 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 2H), 7.53 (d,
J = 8.7 Hz, 2H), 7.55 (d, J = 7.7 Hz, 2H), 9.55 (br, 1H);
13C NMR (126 MHz, CDCl3): ¤ 25.6, 26.3, 50.9, 55.4, 60.8,
113.7, 119.8, 124.0, 127.9, 128.9, 129.4, 138.3, 161.4, 168.9,
171.6; Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N,
8.64%. Found: C, 70.16; H, 6.22; N, 8.53%.
(S)-N-(Phenoxyacetyl)prolinanilide (3m).
(S)-Prolin-
anilide (2) was reacted with phenoxyacetyl chloride. The crude
product was purified by column chromatography (silica gel,
ethyl acetate/hexane = 1/1) to give 3m (636.0 mg, 1.96 mmol,
98%).
26
White solid; mp 157.8-158.3 °C; ½¡ꢀD ¹106.1 (c 1.01,
EtOH); IR (KBr, cm¹1): 3269, 1647, 1600, 1550, 1496, 1443,
1
1244, 1225, 754, 691; H NMR (500 MHz, CDCl3): ¤ 1.83-
Preparation of (S)-2-Anilinomethyl-1-benzylpyrrolidine
(1i). To a THF (7.5 mL) solution of (S)-N-benzoylprolin-
anilide (3i) (441.5 mg, 1.50 mmol) was added borane-THF
1.91 (m, 1H), 2.02-2.09 (m, 1H), 2.16-2.26 (m, 1H), 2.53-2.58
(m, 1H), 3.57 (dt, J = 7.3, 9.6 Hz, 1H), 3.65-3.69 (m, 1H), 4.69
(d, J = 14.2 Hz, 1H), 4.74 (d, J = 14.2 Hz, 1H), 4.84 (dd,
J = 1.6, 7.9 Hz, 1H), 6.94 (dd, J = 0.9, 8.4 Hz, 2H), 6.99 (tt,
J = 0.9, 7.4 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 7.23-7.29 (m,
4H), 7.43 (d, J = 7.9 Hz, 2H), 9.28 (br, 1H); 13C NMR
(126 MHz, CDCl3): ¤ 25.2, 26.4, 46.8, 61.1, 67.3, 114.6,
119.9, 121.9, 124.1, 128.8, 129.7, 138.0, 157.8, 168.4, 169.0;
Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64%.
Found: C, 69.81; H, 6.27; N, 8.43%.
¹3
complex (1.08 mol dm THF solution, 5.6 mL, 6.0 mmol) at
0 °C, and the mixture was refluxed for 3 h with stirring. After
¹3
the mixture was cooled to 0 °C, 6 mol dm aqueous HCl
(4 mL) was added and the reaction mixture was stirred at
room temperature for 30 min. The acidic aqueous mixture was
washed with ether and 1 mol dm¹3 aqueous NaOH (26 mL) was
added to basify the solution. The mixture was extracted with
ether and the combined organic layer was washed with brine.
The organic layer was dried over anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane = 1/4) to give 1i (318.9 mg, 1.20
mmol, 80%).
(S)-N-(2-Methylbenzoyl)prolinanilide (3n).
(S)-Prolin-
anilide (2) was reacted with 2-methylbenzoyl chloride. The
crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane = 1/1) to give 3n (616.7 mg, 2.00
mmol, quant.).
26
26
White solid; mp 132.2-132.5 °C; ½¡ꢀD ¹131.2 (c 1.00,
Light yellow oil; ½¡ꢀD ¹36.6 (c 1.10, EtOH); IR (neat,
EtOH); IR (KBr, cm¹1): 3274, 1701, 1654, 1617, 761; 1H NMR
(500 MHz, CDCl3): ¤ 1.87-1.94 (m, 1H), 1.95-2.02 (m, 1H),
2.05-2.14 (m, 1H), 2.30 (s, 3H), 2.69-2.74 (m, 1H), 3.19-3.28
(m, 2H), 5.01 (dd, J = 2.7, 8.0 Hz, 1H), 7.09 (tt, J = 0.9,
cm¹1): 3393, 2964, 2799, 1604, 1505, 748, 692; 1H NMR
(500 MHz, CDCl3): ¤ 1.67-1.77 (m, 2H), 1.79-1.86 (m, 1H),
1.91-1.98 (m, 1H), 2.23 (dt, J = 8.1, 9.3 Hz, 1H), 2.79-2.83
(m, 1H), 2.99 (ddd, J = 3.1, 6.4, 9.3 Hz, 1H), 3.14 (dd, J = 4.7,

1020 Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Asymmetric Alkylation with Diamine Catalysts
11.5 Hz, 1H), 3.20 (d, J = 11.5 Hz, 1H), 3.27 (d, J = 12.9 Hz,
1H), 3.97 (d, J = 12.9 Hz, 1H), 4.32 (br, 1H), 6.61 (dd, J = 0.9,
8.6 Hz, 2H), 6.68 (tt, J = 0.9, 7.3 Hz, 1H), 7.17 (dd, J = 7.3,
8.6 Hz, 2H), 7.22-7.26 (m, 1H), 7.28-7.32 (m, 4H); 13C NMR
(126 MHz, CDCl3): ¤ 22.8, 28.6, 45.0, 54.4, 58.5, 62.5, 112.8,
116.9, 126.9, 128.3, 128.8, 129.2, 139.5, 149.0; Anal. Calcd
for C18H22N2: C, 81.16; H, 8.32; N, 10.52%. Found: C, 81.14;
H, 8.48; N, 10.60%.
12.3 Hz, 1H), 2.99 (dd, J = 3.6, 12.3 Hz, 1H), 3.01 (dt, J = 3.5,
6.8 Hz, 1H), 3.08-3.13 (m, 1H), 4.11 (br, 1H), 4.75 (s, 1H),
6.33 (dd, J = 0.9, 8.5 Hz, 2H), 6.62 (tt, J = 0.9, 7.4 Hz, 1H),
7.07 (dd, J = 7.4, 8.5 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.21-
7.25 (m, 3H), 7.30 (t, J = 7.4 Hz, 2H), 7.39 (d, J = 7.4 Hz,
2H), 7.41 (d, J = 7.4 Hz, 2H); 13C NMR (126 MHz, CDCl3): ¤
23.4, 29.0, 46.5, 52.2, 59.8, 72.1, 112.7, 116.7, 126.9, 127.0,
128.25 (©2), 128.31, 128.5, 129.1, 142.4, 143.5, 148.6; Anal.
Calcd for C24H26N2: C, 84.17; H, 7.65; N, 8.18%. Found: C,
84.22; H, 7.82; N, 8.13%.
(S)-1-Alkyl-2-(anilinomethyl)pyrrolidine 1e, 1g, 1h, 1j, 1l-
1n, 1p, and 1q were prepared from corresponding anilides
3 (1.5 mmol) in a similar manner.
(S)-2-Anilinomethyl-1-(2-phenylethyl)pyrrolidine (1l).
The crude product was purified by column chromatography
(silica gel, ethyl acetate/hexane = 1/1) to give 1l (344.2 mg,
1.23 mmol, 82%).
(S)-2-Anilinomethyl-1-ethylpyrrolidine (1e). The crude
product was purified by column chromatography (silica gel,
ethyl acetate) to give 1e (229.7 mg, 1.12 mmol, 75%).
21
25
26
Light yellow oil; ½¡ꢀD ¹56.1 (c 1.12, CH2Cl2) [lit.20 ½¡ꢀD
¹53 (c 1.0, CH2Cl2)]; IR and NMR spectral data were identical
with those reported in the literature.20
Light yellow oil; ½¡ꢀD ¹79.0 (c 1.09, EtOH); IR (neat,
cm¹1): 3358, 2947, 2798, 1603, 1505, 747, 692; 1H NMR
(500 MHz, CDCl3): ¤ 1.70-1.80 (m, 3H), 1.84-1.93 (m, 1H),
2.28 (q, J = 8.4 Hz, 1H), 2.46 (ddd, J = 4.8, 8.4, 11.9 Hz, 1H),
2.66-2.71 (m, 1H), 2.77 (dt, J = 8.4, 13.4 Hz, 1H), 2.82 (ddd,
J = 4.8, 8.4, 13.4 Hz, 1H), 2.99 (dt, J = 8.4, 11.9 Hz, 1H), 3.05
(dd, J = 4.9, 11.6 Hz, 1H), 3.11 (d, J = 11.6 Hz, 1H), 3.28-
3.32 (m, 1H), 4.03 (br, 1H), 6.49 (dd, J = 0.6, 8.3 Hz, 2H), 6.65
(t, J = 7.3 Hz, 1H), 7.14 (dd, J = 7.3, 8.3 Hz, 2H), 7.18 (dd,
J = 0.9, 7.3 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.27 (t, J =
7.3 Hz, 2H); 13C NMR (126 MHz, CDCl3): ¤ 22.9, 28.5, 35.3,
44.8, 54.0, 55.7, 62.9, 112.8, 116.8, 126.0, 128.4, 128.7, 129.1,
140.5, 148.9; Anal. Calcd for C19H24N2: C, 81.38; H, 8.63; N,
9.99%. Found: C, 81.34; H, 8.69; N, 10.07%.
(S)-2-Anilinomethyl-1-isobutylpyrrolidine (1g).
The
crude product was purified by column chromatography (silica
gel, ethyl acetate) to give 1g (294.2 mg, 1.27 mmol, 84%).
26
Light yellow oil; ½¡ꢀD ¹105.1 (c 1.07, EtOH); IR (neat,
cm¹1): 3362, 2953, 2794, 1604, 1506, 747, 691; 1H NMR
(500 MHz, CDCl3): ¤ 0.85 (d, J = 6.6 Hz, 3H), 0.92 (d, J =
6.6 Hz, 3H), 1.67-1.82 (m, 4H), 1.84-1.91 (m, 1H), 2.05 (dd,
J = 4.4, 11.3 Hz, 1H), 2.11 (q, J = 8.5 Hz, 1H), 2.28 (t, J =
11.3 Hz, 1H), 2.59-2.63 (m, 1H), 3.06 (dd, J = 4.7, 11.3 Hz,
1H), 3.13 (dd, J = 1.9, 11.3 Hz, 1H), 3.15-3.19 (m, 1H), 4.41
(br, 1H), 6.60 (dd, J = 0.9, 8.2 Hz, 2H), 6.67 (t, J = 7.3 Hz,
1H), 7.16 (dd, J = 7.3, 8.2 Hz, 2H); 13C NMR (126 MHz,
CDCl3): ¤ 20.4, 21.3, 22.9, 27.5, 28.4, 44.5, 54.1, 62.6, 63.1,
112.9, 116.8, 129.2, 149.2; Anal. Calcd for C15H24N2: C,
77.53; H, 10.41; N, 12.06%. Found: C, 77.19; H, 10.47; N,
12.23%.
(S)-2-Anilinomethyl-1-(2-phenoxyethyl)pyrrolidine (1m).
The crude product was purified by column chromatography
(silica gel, ethyl acetate) to give 1m (388.9 mg, 1.31 mmol,
87%).
27
Light yellow oil; ½¡ꢀD ¹4.5 (c 1.08, EtOH); IR (neat, cm¹1):
(S)-2-Anilinomethyl-1-neopentylpyrrolidine (1h).
The
3366, 2948, 2821, 1603, 1505, 1245, 751, 691; 1H NMR
(500 MHz, CDCl3): ¤ 1.73-1.85 (m, 3H), 1.87-1.97 (m, 1H),
2.38 (dt, J = 7.6, 9.0 Hz, 1H), 2.68 (dt, J = 5.3, 13.0 Hz, 1H),
2.80-2.84 (m, 1H), 3.13 (dd, J = 4.9, 11.8 Hz, 1H), 3.17 (ddd,
J = 5.3, 6.9, 13.0 Hz, 1H), 3.17 (d, J = 11.8 Hz, 1H), 3.28-
3.32 (m, 1H), 4.04 (dt, J = 5.3, 9.5 Hz, 1H), 4.08 (ddd, J = 5.3,
6.9, 9.5 Hz, 1H), 4.34 (br, 1H), 6.61 (dd, J = 1.1, 8.6 Hz, 2H),
6.67 (tt, J = 1.1, 7.4 Hz, 1H), 6.88 (dd, J = 1.1, 8.8 Hz, 2H),
6.93 (tt, J = 1.1, 7.3 Hz, 1H), 7.16 (dd, J = 7.4, 8.6 Hz, 2H),
7.26 (dd, J = 7.3, 8.8 Hz, 2H); 13C NMR (126 MHz, CDCl3): ¤
23.2, 28.4, 45.5, 53.3, 55.0, 63.0, 67.0, 112.9, 114.5, 116.9,
120.7, 129.2, 129.4, 148.9, 158.8; Anal. Calcd for C19H24N2O:
C, 76.99; H, 8.16; N, 9.45%. Found: C, 76.73; H, 8.29; N,
9.36%.
crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane = 1/4) to give 1h (248.0 mg, 1.01
mmol, 67%).
26
Light yellow oil; ½¡ꢀD ¹83.8 (c 1.15, EtOH); IR (neat,
cm¹1): 3368, 2952, 2869, 1604, 1505, 747, 690; 1H NMR
(500 MHz, CDCl3): ¤ 0.89 (s, 9H), 1.70-1.79 (m, 3H), 1.80-
1.87 (m, 1H), 2.12 (d, J = 13.2 Hz, 1H), 2.30 (dt, J = 7.8,
9.4 Hz, 1H), 2.43 (d, J = 13.2 Hz, 1H), 2.71-2.76 (m, 1H), 2.99
(dd, J = 4.9, 11.6 Hz, 1H), 3.14 (dd, J = 1.9, 11.6 Hz, 1H),
3.28-3.32 (m, 1H), 4.32 (br, 1H), 6.60 (dd, J = 0.9, 8.6 Hz,
2H), 6.67 (tt, J = 0.9, 7.3 Hz, 1H), 7.16 (dd, J = 7.3, 8.6 Hz,
2H); 13C NMR (126 MHz, CDCl3): ¤ 23.9, 28.0, 28.8, 32.6,
45.5, 57.7, 65.1, 68.3, 112.9, 116.8, 129.2, 149.1; Anal. Calcd
for C16H26N2: C, 77.99; H, 10.64; N, 11.37%. Found: C, 78.04;
H, 10.71; N, 11.38%.
(S)-2-Anilinomethyl-1-(2-methylbenzyl)pyrrolidine (1n).
The crude product was purified by column chromatography
(silica gel, ethyl acetate/hexane = 1/4) to give 1n (309.3 mg,
1.10 mmol, 74%).
(S)-2-Anilinomethyl-1-benzhydrylpyrrolidine (1j). The
reaction was carried out using (S)-N-benzhydrylprolinanilide
(3j) (358.1 mg, 1.00 mmol) and borane-THF complex (1.08
mol dm¹3 THF solution, 3.7 mL, 4.0 mmol). The crude product
was purified by column chromatography (silica gel, ether/
hexane = 1/4) to give 1j (251.3 mg, 0.73 mmol, 73%).
28
Light yellow oil; ½¡ꢀD ¹37.2 (c 1.03, EtOH); IR (neat,
cm¹1): 3375, 2964, 2797, 1603, 1505, 745, 691; 1H NMR
(500 MHz, CDCl3): ¤ 1.68-1.76 (m, 2H), 1.80-1.86 (m, 1H),
1.93-2.01 (m, 1H), 2.23 (q, J = 8.8 Hz, 1H), 2.34 (s, 3H),
2.79-2.84 (m, 1H), 2.94 (ddd, J = 4.2, 5.0, 8.8 Hz, 1H), 3.12
(dd, J = 4.7, 11.6 Hz, 1H), 3.19 (dd, J = 2.4, 11.6 Hz, 1H),
3.27 (d, J = 12.9 Hz, 1H), 3.96 (d, J = 12.9 Hz, 1H), 4.23 (br,
1H), 6.57 (dd, J = 0.6, 8.2 Hz, 2H), 6.67 (t, J = 7.3 Hz, 1H),
28
Light yellow oil; ½¡ꢀD ¹20.1 (c 1.06, CHCl3); IR (neat,
cm¹1): 3419, 2958, 1603, 1505, 1452, 1320, 1261, 747, 706;
1H NMR (500 MHz, CDCl3): ¤ 1.66-1.82 (m, 3H), 1.86-1.95
(m, 1H), 2.39 (ddd, J = 6.8, 8.4, 9.9 Hz, 1H), 2.69 (dd, J = 6.5,

N. Hosoda et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012) 1021
7.12-7.17 (m, 5H), 7.26-7.29 (m, 1H); 13C NMR (126 MHz,
CDCl3): ¤ 19.2, 23.0, 28.6, 45.1, 54.7, 56.9, 63.1, 112.7, 116.9,
125.7, 127.0, 129.2, 129.5, 130.2, 136.8, 137.6, 148.9; Anal.
Calcd for C19H24N2: C, 81.38; H, 8.63; N, 9.99%. Found: C,
81.12; H, 8.68; N, 10.05%.
1H NMR (500 MHz, CDCl3): ¤ 0.98 (d, J = 6.5 Hz, 3H), 1.11
(d, J = 6.5 Hz, 3H), 1.67-1.79 (m, 3H), 1.80-1.89 (m, 1H),
2.53 (dt, J = 7.3, 8.0 Hz, 1H), 2.89-3.03 (m, 4H), 3.10 (d,
J = 9.5 Hz, 1H), 4.17 (br, 1H), 6.61 (d, J = 8.1 Hz, 2H), 6.67
(t, J = 7.3 Hz, 1H), 7.16 (dd, J = 7.3, 8.1 Hz, 2H); 13C NMR
(126 MHz, CDCl3): ¤ 16.0, 22.4, 23.5, 29.4, 46.5, 47.2, 49.4,
58.4, 112.8, 116.9, 129.2, 149.0; Anal. Calcd for C14H22N2: C,
77.01; H, 10.16; N, 12.83%. Found: C, 76.63; H, 10.23; N,
12.79%.
(S)-2-Anilinomethyl-1-(2-methoxybenzyl)pyrrolidine
(1p). The crude product was purified by column chromatog-
raphy (silica gel, ethyl acetate) to give 1p (325.7 mg, 1.10
mmol, 73%).
28
Light yellow oil; ½¡ꢀD ¹36.2 (c 1.05, EtOH); IR (neat,
(S)-1-Alkyl-2-(anilinomethyl)pyrrolidine 1k and 1o were
prepared from 4 (1.0 mmol) in a similar manner.
cm¹1): 3358, 2956, 2834, 1603, 1505, 1246, 751, 692;
1H NMR (500 MHz, CDCl3): ¤ 1.66-1.75 (m, 2H), 1.76-1.84
(m, 1H), 1.88-1.96 (m, 1H), 2.26 (dt, J = 7.9, 9.2 Hz, 1H),
2.79-2.84 (m, 1H), 3.02 (ddd, J = 2.8, 6.5, 9.2 Hz, 1H), 3.19
(dd, J = 3.2, 11.7 Hz, 1H), 3.22 (dd, J = 4.4, 11.7 Hz, 1H),
3.25 (d, J = 12.9 Hz, 1H), 3.75 (s, 3H), 4.04 (d, J = 12.9 Hz,
1H), 4.53 (br, 1H), 6.63 (dd, J = 0.9, 8.5 Hz, 2H), 6.66 (tt,
J = 0.9, 7.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.91 (dt, J =
0.9, 7.8 Hz, 1H), 7.16 (dd, J = 7.4, 8.5 Hz, 2H), 7.23 (dt, J =
1.6, 7.8 Hz, 1H), 7.27 (dd, J = 1.6, 7.8 Hz, 1H); 13C NMR
(126 MHz, CDCl3): ¤ 22.8, 28.5, 44.8, 52.6, 54.5, 55.5, 62.5,
110.4, 112.9, 116.7, 120.2, 127.5, 128.2, 129.1, 130.6, 149.3,
157.7; Anal. Calcd for C19H24N2O: C, 76.99; H, 8.16; N,
9.45%. Found: C, 76.84; H, 8.35; N, 9.40%.
(S)-2-Anilinomethyl-1-tritylpyrrolidine (1k).
(S)-2-
(Anilinomethyl)pyrrolidine (4) was reacted with trityl chloride.
The crude product was purified by column chromatography
(silica gel, ether/hexane = 1/19) and subsequent recrystalliza-
tion from hexane to give 1k (124.9 mg, 0.30 mmol, 30%).
19
Light yellow solid; mp 171.4-171.9 °C; ½¡ꢀD ¹113.0 (c
1.03, CHCl3); IR (KBr, cm¹1): 3390, 2862, 1600, 1505, 1310,
1
1249, 1182, 738, 708; H NMR (500 MHz, CDCl3): ¤ 0.65-
0.71 (m, 1H), 0.77-0.85 (m, 1H), 1.35-1.45 (m, 2H), 2.96-3.04
(m, 2H), 3.24-3.29 (m, 1H), 3.46 (d, J = 12.0 Hz, 1H), 3.54
(m, 1H), 3.81 (br, 1H), 6.44 (d, J = 7.6 Hz, 2H), 6.63 (t,
J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.3 Hz,
3H), 7.25 (t, J = 7.3 Hz, 6H), 7.60 (d, J = 7.3 Hz, 6H);
13C NMR (126 MHz, CDCl3): ¤ 24.0, 28.9, 48.5, 50.2, 59.4,
77.7, 112.5, 116.8, 126.1, 127.6, 129.2, 129.6, 145.2, 148.3;
Anal. Calcd for C30H30N2: C, 86.08; H, 7.22; N, 6.69%. Found:
C, 85.80; H, 7.31; N, 6.51%.
(S)-2-Anilinomethyl-1-(4-methoxybenzyl)pyrrolidine
(1q). The crude product was purified by column chromatog-
raphy (silica gel, ethyl acetate) to give 1q (277.1 mg, 0.93
mmol, 62%).
26
Light yellow oil; ½¡ꢀD ¹20.9 (c 1.01, EtOH); IR (neat,
(S)-2-Anilinomethyl-1-(4-nitrobenzyl)pyrrolidine (1o).
(S)-2-(Anilinomethyl)pyrrolidine (4) was reacted with 4-nitro-
benzyl bromide. The crude product was purified by column
chromatography (silica gel, ethyl acetate/hexane = 1/1) to
give 1o (269.9 mg, 0.87 mmol, 87%).
cm¹1): 3393, 2955, 2833, 1604, 1512, 1247, 749, 692;
1H NMR (500 MHz, CDCl3): ¤ 1.66-1.75 (m, 2H), 1.76-1.84
(m, 1H), 1.90-1.97 (m, 1H), 2.22 (dt, J = 8.0, 9.2 Hz, 1H),
2.76-2.81 (m, 1H), 2.97 (ddd, J = 3.0, 6.5, 9.2 Hz, 1H), 3.12
(dd, J = 5.0, 11.7 Hz, 1H), 3.19 (dd, J = 2.0, 11.7 Hz, 1H),
3.22 (d, J = 12.9 Hz, 1H), 3.78 (s, 3H), 3.89 (d, J = 12.9 Hz,
1H), 4.31 (br, 1H), 6.61 (dd, J = 1.1, 8.5 Hz, 2H), 6.68 (tt,
J = 1.1, 7.3 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.17 (dd, J =
7.3, 8.5 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H); 13C NMR (126 MHz,
CDCl3): ¤ 22.7, 28.6, 45.0, 54.3, 55.3, 57.8, 62.3, 112.8, 113.6,
116.9, 129.2, 129.9, 131.5, 149.0, 158.6; Anal. Calcd for
C19H24N2O: C, 76.99; H, 8.16; N, 9.45%. Found: C, 76.84; H,
8.32; N, 9.41%.
26
Yellow oil; ½¡ꢀD +17.8 (c 1.00, EtOH); IR (neat, cm¹1):
1
3401, 2965, 2810, 1603, 1520, 1346, 749, 693; H NMR (500
MHz, CDCl3): ¤ 1.72-1.90 (m, 3H), 1.94-2.03 (m, 1H), 2.22
(q, J = 8.6 Hz, 1H), 2.84-2.90 (m, 1H), 2.95-3.00 (m, 1H),
3.15 (dd, J = 4.9, 12.0 Hz, 1H), 3.23 (dd, J = 2.9, 12.0 Hz,
1H), 3.39 (d, J = 13.9 Hz, 1H), 4.06 (d, J = 13.9 Hz, 1H), 4.21
(br, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.70 (t, J = 7.3 Hz, 1H),
7.18 (dd, J = 7.3, 8.5 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 8.16
(d, J = 8.7 Hz, 2H); 13C NMR (126 MHz, CDCl3): ¤ 22.8, 28.4,
45.1, 54.5, 57.9, 62.8, 112.7, 117.2, 123.6, 129.1, 129.3, 147.0,
147.5, 148.6; Anal. Calcd for C18H21N3O2: C, 69.43; H, 6.80;
N, 13.49%. Found: C, 69.25; H, 6.84; N, 13.24%.
Preparation of (S)-2-Anilinomethyl-1-isopropylpyrroli-
dine (1f). To an acetone (1.5 mL) solution of (S)-2-(anilino-
methyl)pyrrolidine (4) (180.5 mg, 1.02 mmol) was added an
aqueous (3.0 mL) solution of potassium carbonate (277.0 mg,
2.00 mmol) and an acetone (1.5 mL) solution of isopropyl
iodide (340.0 mg, 2.00 mmol) at room temperature, and the
mixture was refluxed for 12 h with stirring. After the mixture
was cooled to room temperature, the mixture was extracted
with dichloromethane and the combined organic layer was
washed with brine. The organic layer was dried over anhydrous
sodium sulfate, and the solvent was removed under reduced
pressure. The crude product was purified by column chroma-
tography (ethyl acetate/hexane = 1/19) using Chromatorex
NH-DM1020 (Fuji Silysia Chemical Ltd.) to give 1f (131.4 mg,
0.60 mmol, 59%).
The Enantioselective Addition of Diethylzinc to Benzal-
dehyde Catalyzed by (S)-2-Anilinomethyl-1-benzylpyrroli-
dine (1i): Typical Procedure (Table 5, Entry 9).
To a
toluene (7.5 mL) solution of benzaldehyde (159.2 mg, 1.50
mmol) and 1i (60.1 mg, 0.23 mmol) was added diethylzinc
¹3
(1.1 mol dm hexane solution, 2.45 mL, 2.70 mmol) over 10
min at 0 °C, and the reaction mixture was stirred at 0 °C
for 18 h. Saturated aqueous ammonium chloride (3 mL) and
¹3
2 mol dm aqueous HCl (3 mL) were added to the reaction
mixture, and the mixture was extracted with ether. The com-
bined organic layer was washed with brine, and dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the resulting oily substance was purified
by preparative TLC (silica gel, ether/hexane = 1/9) to give
27
Light yellow oil; ½¡ꢀD ¹49.4 (c 1.01, EtOH); IR (neat,
cm¹1): 3415, 2964, 2871, 1604, 1505, 1319, 747, 691;

1022 Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Asymmetric Alkylation with Diamine Catalysts
6
Recent examples: a) T. Hirose, K. Sugawara, K. Kodama,
(R)-1-phenyl-1-propanol (192.1 mg, 1.41 mmol, 94%). The ee
was determined to be 92% by HPLC analysis using a chiral
column (Daicel Chiralcel OD-H (25 © 0.46 cm i.d.)); eluent,
3% 2-propanol in hexane; flow rate, 0.5 mL min¹1; tR, 18.4 min
for major peak, 22.1 min for minor peak. The enantioselective
addition of diethylzinc to the other aldehydes was performed
in a similar manner. The ees were determined by HPLC
using Daicel Chiralcel OD-H, OB, or AS-H (25 © 0.46 cm
i.d.) column. 1-(2-Bromophenyl)-1-propanol: OD-H; eluent,
1% 2-propanol in hexane; flow rate, 0.5 mL min¹1; tR, 33.4 min
for major peak, 36.4 min for minor peak. 1-(1-Naphthyl)-1-
propanol: OD-H; eluent, 10% 2-propanol in hexane; flow rate,
0.5 mL min¹1; tR, 14.4 min for minor peak, 24.9 min for major
peak. 1-(2-Methoxyphenyl)-1-propanol: OB; eluent, 10% 2-
propanol in hexane; flow rate, 0.5 mL min¹1; tR, 10.6 min for
minor peak, 13.6 min for major peak. 1-(4-Methoxyphenyl)-1-
propanol: OB; eluent, 10% 2-propanol in hexane; flow rate,
0.5 mL min¹1; tR, 17.1 min for minor peak, 20.5 min for major
peak. (E)-1-Phenyl-1-penten-3-ol: OD-H; eluent, 5% 2-propa-
nol in hexane; flow rate, 0.5 mL min¹1; tR, 22.2 min for major
J. Org. Chem. 2011, 76, 5413. b) D. Murtinho, M. E. S. Serra,
A. M. d’A. R. Gonsalves, Tetrahedron: Asymmetry 2010, 21, 62.
c) J. E. D. Martins, M. Wills, Tetrahedron: Asymmetry 2008, 19,
1250.
7
Recent examples: a) A. L. Braga, F. Z. Galetto, O. E. D.
Rodrigues, C. C. Silveira, M. W. Paixão, Chirality 2008, 20, 839.
b) M. Mellah, A. Voituriez, E. Schulz, Chem. Rev. 2007, 107,
5133. c) A. L. Braga, E. F. Alves, C. C. Silveira, G. Zeni, H. R.
Appelt, L. A. Wessjohann, Synthesis 2005, 588. d) A. L. Braga,
D. S. Lüdtke, L. A. Wessjohann, M. W. Paixão, P. H. Schneider,
J. Mol. Catal. A: Chem. 2005, 229, 47. e) S.-L. Tseng, T.-K. Yang,
Tetrahedron: Asymmetry 2004, 15, 3375. f) A. L. Braga, F. Vargas,
C. C. Silveira, L. H. de Andrade, Tetrahedron Lett. 2002, 43, 2335.
8
Recent examples: a) G. Qi, Z. M. A. Judeh, Tetrahedron:
Asymmetry 2010, 21, 429. b) Z. Zhang, X. Bai, R. Liu, G. Zi,
Inorg. Chim. Acta 2009, 362, 1687. c) M. I. Burguete, J.
Escorihuela, S. V. Luis, A. Lledós, G. Ujaque, Tetrahedron
2008, 64, 9717. d) R. Melgar-Fernández, R. González-Olvera,
J. L. Olivares-Romero, V. González-López, L. Romero-Ponce,
M. del R. Ramírez-Zárate, P. Demare, I. Regla, E. Juaristi, Eur. J.
Org. Chem. 2008, 655. e) V. M. Mastranzo, E. Santacruz, G.
Huelgas, E. Paz, M. V. Sosa-Rivadeneyra, S. Bernès, E. Juaristi, L.
Quintero, C. A. de Parrodi, Tetrahedron: Asymmetry 2006, 17,
1663. f) M. L. Richmond, C. T. Seto, J. Org. Chem. 2003, 68,
7505. g) M. Asami, S. Inoue, Bull. Chem. Soc. Jpn. 1997, 70,
1687.
peak, 37.3 min for minor peak. 1-Phenyl-3-pentanol: OB;
¹1
eluent, 0.5% 2-propanol in hexane; flow rate, 0.3 mL min
;
tR, 64.3 min for major peak, 73.9 min for minor peak. 1-Cyclo-
hexyl-1-propanol (as the corresponding 4-methoxybenzoate):
AS-H; eluent, 0.1% 2-propanol in hexane; flow rate,
0.5 mL min¹1; tR, 11.9 min for major peak, 13.4 min for minor
peak.
9
a) M. Asami, H. Watanabe, K. Honda, S. Inoue, Tetra-
hedron: Asymmetry 1998, 9, 4165. b) J. Eilers, J. Wilken, J.
Martens, Tetrahedron: Asymmetry 1996, 7, 2343. c) S. Niwa, K.
Soai, J. Chem. Soc., Perkin Trans. 1 1991, 2717. d) G. Chelucci, S.
Conti, M. Falorni, G. Giacomelli, Tetrahedron 1991, 47, 8251.
10 M. Asami, J. Synth. Org. Chem., Jpn. 1996, 54, 188, and
references cited therein.
The authors are grateful to Mr. Shinji Ishihara (Instrumental
Analysis Center, Yokohama National University) for his tech-
nical assistance in the elemental analysis.
References
11 M. Asami, S. Sato, K. Honda, S. Inoue, Heterocycles 2000,
52, 1029.
1
R. Noyori, Asymmetric Catalysis in Organic Synthesis,
John Wiley & Sons, New York, 1994, Chap. 5.
12 A. Seki, M. Asami, Tetrahedron 2002, 58, 4655.
13 N. Hosoda, Y. Iogawa, Y. Shimada, M. Asami, Bull. Chem.
Soc. Jpn. 2008, 81, 274.
2
3
N. Oguni, T. Omi, Tetrahedron Lett. 1984, 25, 2823.
For reviews: a) R. Noyori, M. Kitamura, Angew. Chem., Int.
Ed. Engl. 1991, 30, 49. b) K. Soai, S. Niwa, Chem. Rev. 1992, 92,
833. c) L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757.
14 M. Asami, S. Sato, H. Watanabe, Chem. Lett. 2000, 990.
15 S. Sato, H. Watanabe, M. Asami, Tetrahedron: Asymmetry
2000, 11, 4329.
4
Recent examples: a) C. Andrés, R. Infante, J. Nieto,
Tetrahedron: Asymmetry 2010, 21, 2230. b) A. K. Yadav, M.
Kumar, T. Yadav, R. Jain, Synlett 2010, 712. c) S. Leśniak, M.
Rachwalski, E. Sznajder, P. Kiełbasiński, Tetrahedron: Asymmetry
2009, 20, 2311. d) N. Ananthi, U. Balakrishnan, A. Vinu, K.
Ariga, S. Velmathi, Tetrahedron: Asymmetry 2009, 20, 1731.
e) Z.-L. Wu, H.-L. Wu, P.-Y. Wu, B.-J. Uang, Tetrahedron:
Asymmetry 2009, 20, 1556. f) S. Rodríguez-Escrich, K. S. Reddy,
C. Jimeno, G. Colet, C. Rodríguez-Escrich, L. Solà, A.
Vidal-Ferran, M. A. Pericàs, J. Org. Chem. 2008, 73, 5340.
g) Y. Hari, T. Aoyama, Synthesis 2005, 583. h) S. N. Joshi, S. V.
Malhotra, Tetrahedron: Asymmetry 2003, 14, 1763. i) C.-s. Da,
Z.-j. Han, M. Ni, F. Yang, D.-x. Liu, Y.-f. Zhou, R. Wang,
Tetrahedron: Asymmetry 2003, 14, 659. j) J. Lu, X. Xu, C. Wang,
J. He, Y. Hu, H. Hu, Tetrahedron Lett. 2002, 43, 8367.
16 M. Asami, M. Wada, S. Furuya, Chem. Lett. 2001, 1110.
17 S. Kobayashi, H. Uchiro, Y. Fujishita, I. Shiina, T.
Mukaiyama, J. Am. Chem. Soc. 1991, 113, 4247.
18 R. W. Stevens, T. Mukaiyama, Chem. Lett. 1983, 1799.
19 H. Kato, E. Koshinaka, Y. Arata, M. Hanaoka, Yakugaku
Zasshi 1974, 94, 1566.
20 The synthesis of 1e from 2 was previously reported: K.
Suzuki, A. Ikegawa, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1982,
55, 3277.
21 M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am. Chem.
Soc. 1986, 108, 6071.
22 W.-M. Dai, H.-J. Zhu, X.-J. Hao, Tetrahedron: Asymmetry
2000, 11, 2315.
23 K. Soai, A. Ookawa, T. Kaba, K. Ogawa, J. Am. Chem. Soc.
1987, 109, 7111.
5
Recent examples: a) R. Roudeau, D. G. Pardo, J. Cossy,
Tetrahedron 2006, 62, 2388. b) I. Sarvary, Y. Wan, T. Frejd,
J. Chem. Soc., Perkin Trans. 1 2002, 645.
24 M. Asami, H. Ohno, S. Kobayashi, T. Mukaiyama, Bull.
Chem. Soc. Jpn. 1978, 51, 1869.