Synthesis of novel chiral 1,3-aminophenols and application for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2007.05.027

Novel chiral 1,3-aminophenols were efficiently synthesized by applying a Friedel-Crafts reaction and optical resolution. The catalytic activity of the aminophenols was studied for the addition of diethylzinc to benzaldehyde. The results showed that (S)-5a with bulky tert-butyl groups on the stereogenic carbon atom and 4,6-positions of phenol favored higher enantioselectivity (94% ee). The same ligand was also used with other aldehydes, to give optically active alcohols in good chemical yields and ee values (up to 99%).

Full text of DOI:10.1016/j.tetasy.2007.05.027

Tetrahedron: Asymmetry 18 (2007) 1257–1263
Synthesis of novel chiral 1,3-aminophenols and application
for the enantioselective addition of diethylzinc to aldehydes
Xiao-Feng Yang,a,b Zhao-Hui Wang,a Tomoaki Koshizawa,a Mikio Yasutake,a
Guang-You Zhangb and Takuji Hirosea,*
aDepartment of Applied Chemistry, Faculty of Engineering, Saitama University, 255 Shimo-ohkubo, Sakura, Saitama 338-8570, Japan
bDepartment of Chemical Engineering, University of Jinan, 106 Jiwei Road, Jinan, Shandong Province 250022, China
Received 1 May 2007; accepted 22 May 2007
Abstract—Novel chiral 1,3-aminophenols were efficiently synthesized by applying a Friedel–Crafts reaction and optical resolution. The
catalytic activity of the aminophenols was studied for the addition of diethylzinc to benzaldehyde. The results showed that (S)-5a with
bulky tert-butyl groups on the stereogenic carbon atom and 4,6-positions of phenol favored higher enantioselectivity (94% ee). The same
ligand was also used with other aldehydes, to give optically active alcohols in good chemical yields and ee values (up to 99%).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In recent years, there has been a great deal of interest in the
synthesis of chiral ligands which work for catalytic asym-
metric carbon–carbon bond formation with high enantio-
selectivity.1 The chiral ligands for this purpose mainly
include aminoalcohols, with a few examples of amino-
thiols, amines, diols, disulfides, and diselenides.2 Amino-
alcohols have mostly been used as chiral ligands in the
alkylation of aldehydes with dialkylzinc. Although
aminophenols are analogous to amino alcohols, they were
not used as chiral ligands in asymmetric catalysis until
Cardellicchio’s work in 1998, in which they gave high
enantioselectivities.3 Since then, interest in their application
for the asymmetric catalysis of aminophenols and their
derivatives has increased significantly.4 Herein, we report
the synthesis of novel chiral 1,3-aminophenol ligands
4a–b, 5a–b and 6a–b as well as their uses as chiral ligands
for the enantioselective addition of diethylzinc to
aldehydes.
2.1. Synthesis of optically active 1,3-aminophenols 4a–b,
5a–b and 6a–b
Chiral aminophenols 1a and 1b can be prepared from 2-
methoxybenzaldehyde and 2-methoxybenzoic acid in five
steps, according the literature,5 in overall yields of 64%
and 40%, respectively, with enantiomeric excess exceeding
99%.
The synthesis of aminophenol 3a starts from commercially
available
1-(2-methoxy-5-methylphenyl)-2-phenylethyl-
amine 2a. The resolution of 2a was realized by the recrys-
tallization of the D-(ꢀ)-tartaric acid salt to obtain (R)-2a
in >99% ee. The deprotection step was performed by treat-
ing (R)-2a with anhydrous AlBr3 in dry toluene at 0 ꢁC for
50 h. After chromatography, (R)-3a was obtained in 75%
yield (Scheme 1).
The synthesis of aminophenol 3b is very similar to that of
3a with a modification in the resolution process. As shown
in Scheme 2, commercially available amine 2b was depro-
tected to afford aminophenol rac-3b in 78% yield. Subse-
quently, the optical resolution of rac-3b was realized by
recrystallization of the dehydroabietic acid (DAA)6 salt
to obtain (ꢀ)-3b in 36% yield in >99% ee.
*
Corresponding author. Tel./fax: +81 48 858 3522; e-mail: hirose@apc.
saitama-u.ac.jp
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.027

1258
X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
OMe NH2 OH NH2
Bn Bn
OMe NH2
Bn
AlBr3, toluene
D-(-)-tartaric acid
ethanol
25%
0 oC, 50 h
75%
(R)-3a
> 99% ee
(R)-2a
2a
OH NH2
rac-3b
> 99% ee
Scheme 1.
OMe NH2
OH NH2
AlBr3, toluene
DAA
*
0 oC, 50 h
78%
80% ethanol
36%
(-)-3b
> 99% ee
2b
Scheme 2.
Novel chiral 1,3-aminophenols 4a–b, 5a–b and 6a–b were
synthesized by Friedel–Crafts alkylation of 1 and 3 with
urea and t-BuOH in 75% H2SO4 at room temperature for
72 h in 13–79% yields in 99% ee after chromatography
(Scheme 3).7
The structures of (S)-5a and (S)-5b were determined by sin-
gle crystal X-ray diffraction analysis (Figs. 1 and 2).8,9
2.2. Catalytic asymmetric addition of diethylzinc to
aldehydes
It is well known that the reaction of aldehydes with dieth-
ylzinc to give the corresponding sec-alcohols takes place in
the presence of a catalytic amount of amino alcohols.2
Excellent chiral inductions including asymmetric amplifica-
tions by use of chiral aminoalcohols in this reaction have
been reported.2 This interesting reaction has been widely
utilized for the evaluation of chiral ligands. In order to
clarify the chiral induction abilities of the present novel
1,3-aminophenols, we first examined the enantioselective
addition reaction of diethylzinc to benzaldehyde in the
presence of catalytic amounts (10 mol %) of these 1,3-
aminophenols (Scheme 4, Table 1).
Figure 1. X-ray structure of compound (S)-5a.
tert-butyl groups on the stereogenic carbon atom and 4,6-
positions of phenol (Table 1, entry 4). This result suggests
that high stereoselectivity can be achieved by introduction
of sterically bulky substituents into the chiral ligand. To
our surprise, when using chiral ligand (S)-1a or (S)-4a with-
out a tert-butyl group at the ortho-position of phenol, the
opposite enantiomer was obtained (Table 1, entries 1 and
2). These results mean that from the single stereogenic cen-
As shown in Table 1, a high yield and high ee could be
achieved by using the chiral aminophenol (S)-5a with bulky
OH NH2
OH NH2
4a: R1 = t-Bu (71%)
tBu
OH NH2
urea
t-BuOH
R1
R1
R1
4b: R1 = i-Pr (79%)
*
*
*
75% H2SO4
+
r.t., 72 h
5a: R1 = t-Bu (15%)
5b: R1 = i-Pr (18%)
tBu
tBu
1
4
5
OH NH2
R2
OH NH2
urea
t-BuOH
75% H2SO4
tBu
6a: R2 = Bn (20%)
*
R2
*
6b: R2 = Me (13%)
r.t., 72 h
6
3
Scheme 3.

X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
1259
2, entries 1–3). Toluene or toluene/hexane (1:1, v/v) gave
the best results with 62%, 71% yields and 86%, 85% ee,
respectively (Table 2, entries 1 and 3). The presence of hex-
ane lowered the ee value of the resulting alcohol (Table 2,
entry 2). Therefore, toluene/hexane (1:1, v/v) was selected
as the reaction solvent in the following reactions.
The reaction was also studied with several different alde-
hydes using 10 mol % of (S)-5a in toluene/hexane (1:1, v/
v) at ꢀ17 ꢁC (Table 3). Using (S)-5a, the catalytic diethyl-
zinc addition proceeded in high enantioselectivity toward
the aldehyde possessing an electron-withdrawing or elec-
tron-donating group at the para-position of the aromatic
ring (all up to 99% ee, entries 2–6). These results suggested
there is no effect of a substituent at the para-position on the
enantioselectivity. However, an ortho-substituent lowered
the enantiomeric purity of the product while the effect of
a meta-substituent was small (entries 7–10). On the other
hand, the chemical yield decreases in the order of para-,
meta-, ortho-substitution, probably due to the steric hin-
drance except for p-MeO–, and NO2–benzaldehyde. These
two aldehydes remained unreacted after the reaction time,
which is contrary to the literature;1a,f the reaction is appar-
ently retarded by these functional group but the effect is
not clear at present. The reaction was also tested with ali-
phatic aldehydes (Table 3, entries 11 and 12) and provided
the corresponding alcohols with lower yields than the aro-
matic ones due to lower reactivity. The electronic or steric
effect causing large differences in enantiomeric excess (95%
ee for decanal and 28% ee for phenylpropanal) should be
the subject of further studies. In all cases some amounts
of imines derived from condensation of aldehydes and
chiral ligands were also formed.
Figure 2. X-ray structure of compound (S)-5b.
O
OH
*
chiral ligand
+
Et2Zn
R3
H
R3
Scheme 4.
Table 1. Enantioselective addition reaction of diethylzinc to benzaldehyde
(R3 = C6H5) in the presence of 10 mol % chiral 1,3-aminophenol ligands
4a–b, 5a–b and 6a–b
The currently accepted mechanism for the addition of di-
alkylzinc to aldehydes12 has been reviewed and applied to
the present system. In analogy to that established by Noy-
ori and Yamakawa12d for the b-amino alcohols, a six-mem-
bered Zn-chelate species is initially formed by the reaction
of 1,3-aminophenol (S)-1a with diethylzinc. This complex
coordinates to a new molecule of diethylzinc and aldehydes
by the O and Zn atoms, respectively (Fig. 3). Such coordi-
nation activates the molecules to cause the enantioselective
addition reaction through tricyclic 6/4/4-membered Noy-
ori’s anti type transition states (Fig. 3). The energy differ-
ences between the transition states, which lead to the
opposite enantiomers by means of semi-empirical PM5 cal-
culations13 show that the structure anti-(S) is more stable,
with a small difference of 1.42 kcal/mol. This value sup-
ports the experimental result, which shows the (S)-1-phe-
nylpropanol with a low enantioselectivity (32% ee) as the
major product (Table 1, entry 1). Taking the results into
account, we can attempt to provide a rationale for the ste-
reochemical outcome of the reaction with (S)-5a, as well as
of the influence of the substituent present at the ortho-posi-
tion of phenol. From two transition states anti-(S) and
anti-(R) in (S)-5a (Fig. 4) we can see that in anti-(R) the
Entry
Ligand
Yieldc (%)
eed (%)
Configuratione
1a
2a
3a
4b
5b
6b
7b
(S)-1a
(S)-4a
(S)-4b
(S)-5a
(S)-5b
(R)-6a
(ꢀ)-6b
18
18
19
65
46
36
40
32
14
6
93
66
56
55
(S)
(S)
(R)
(R)
(R)
(S)
(S)
a Reaction conditions: toluene, 22 h, rt.
b Reaction conditions: toluene/hexane (1:1, v/v), 22 h, ꢀ17 ꢁC.
c Isolated yields.
d Based on HPLC analysis using Chiralcel OB-H.
e Determined by comparison of the sign of optical rotation values with
those in Ref. 10.
ter of 1a both enantiomers were obtained in low to high ee
values in the case of R3 = Ph. Under these conditions, we
also observed the formation of some amounts of imines
derived from the condensation of aldehydes and chiral
ligands in all cases.
t
equatorial tert-butyl Bu# and the ethyl group on zinc
t
(Et#) are on opposite sides, while in anti-(S) the Bu# and
Chiral ligand 5a was further investigated by varying reac-
tion solvent and temperature (Table 2). The solvent had
an important role in the enantioselective process (Table
Et# moieties are on the same sides. Therefore, greater
destabilization of the anti-(S) with respect to the anti-(R)
transition state results, giving rise to a greater energy differ-

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X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
Table 2. Optimization of the enantioselective addition of diethylzinc to benzaldehyde (R3 = C6H5) by chiral ligand 5aa
Entry
Ligand
Reaction conditions
Yieldc (%)
eed (%)
Configuratione
1
2
3
4
5
6
7b
(R)-5a
(R)-5a
(R)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
Toluene, rt
Hexane, rt
62
54
71
71
79
65
59
86
71
85
85
86
93
92
(S)
(S)
(S)
(R)
(R)
(R)
(R)
Toluene/hexane (1:1, v/v), rt
Toluene/hexane (1:1, v/v), rt
Toluene/hexane (1:1, v/v), 0 ꢁC
Toluene/hexane (1:1, v/v), ꢀ17 ꢁC
Toluene/hexane (1:1, v/v), ꢀ17 ꢁC
a In the presence of 10 mol % chiral 1,3-aminophenol ligand 5a for 22 h.
b In the presence of 15 mol % chiral 1,3-aminophenol ligand (S)-5a for 22 h.
c Isolated yields.
d Based on HPLC analysis using Chiralcel OB-H.
e Determined by comparison of the sign of specific rotation values with those in Ref. 10.
Table 3. Enantioselective addition reaction of diethylzinc to aldehydes in the presence of 10 mol % chiral ligand (S)-5aa
Entry
R3
Yieldb (%)
ee (%)
Configurationg
1
2
3
4
5
6
7
8
9
C6H5
p-ClC6H4
65
89
71
66
29
41
64
48
41
38
18
22
93c
99c
99c
99c
99c
99c
88c
99d
74c
72c
95e
28f
(R)
(R)
(R)
(R)
(R)
(R)
(R)
n.d.
(R)
(R)
(R)
(R)
p-BrC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
m-ClC6H4
m-NO2C6H4
o-ClC6H4
o-MeC6H4
CH3(CH2)8
C6H5CH2CH2
10
11
12
a Reaction conditions: toluene/hexane (1:1, v/v), 22 h, ꢀ17 ꢁC.
b Isolated yields.
c Determined by HPLC analysis using Chiralcel OB-H.
d Determined by HPLC analysis using Chiralcel OD-H.
e Determined by HPLC analysis of corresponding benzonate using Chiralcel OJ.
f Determined by HPLC analysis using Chiralcel OJ.
g Determined by comparison of the sign of the specific rotation values with those in Refs. 10 and 11.
ence14 between the two transition states, and leading to the
higher enantioselectivity experimentally observed for (S)-
5a.
tBu
H
tBu
H
Et
Et
O
O
Zn
Zn
Zn
Et
O
N
N
Zn
CH3
H
H
Et
CH3
H
H
O
H
3. Conclusions
Ph
H
Ph
In conclusion, novel chiral 1,3-aminophenols have been
synthesized and proven to be good promoters of the addi-
tion of diethylzinc to aldehydes. The results obtained
clearly show that the enantioselectivity was strongly influ-
enced by the presence of bulky tert-butyl groups on the ste-
reogenic carbon atom and 4,6-positions of phenol. Ligand
(S)-5a gave good asymmetric induction not only with aro-
matic aldehydes (best ee up to 99%) but also with aliphatic
aldehydes (best ee 95%). Work is now in progress on the
use of these compounds for other enantioselective
transformations.
anti (R)
anti (S)
Figure 3.
tBu
tBu
tBu#
tBu#
Zn
tBu
H
tBu
H
Et
O
Et#
O
Zn
Et#
Zn
Zn
Et
N
O
N
CH3
H
H
H
CH3
H
O
H
Ph
H
4. Experimental
Ph
anti (S)
anti (R)
1H NMR spectra were recorded on a Bruker AC300 or
DPX400 MHz in Molecular Analysis and Life Science Cen-
Figure 4.

X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
1261
ter (Saitama University). The chemical shifts were reported
in ppm downfield from Me4Si in CDCl3 solution. Coupling
constants are given in Hz. IR spectra were recorded on an
FT/IR 400. Enantiomeric excess determination was carried
out using a set of JASCO LC 900 series with chiral col-
umns. Optical rotations were measured with a JASCO
DIP-370 polarimeter. Melting points were determined with
a Mitamura Riken Kogyo MEL-TEMP instrument and re-
ported uncorrected. All reagents that were commercially
available were purchased at the highest quality and purified
by distillation when necessary. Hexane and toluene were
distilled and stored on a sodium wire before use.
J = 6.6 Hz, CH), 2.24 (s, 3H, ArCH3), 1.46 (d, 3H,
J = 6.6 Hz, CH3CO). IR (KBr) 2981, 2899, 2492, 2190,
1652, 1612, 1528, 1481, 1267, 821, 792, 626 cmꢀ1. Anal.
as HCl salt. Calcd for C9H14ClNO: C, 57.60; H, 7.52; N,
7.46. Found: C, 57.46; H, 7.56; N, 7.36.
4.4. Optical resolution of 3b
Racemic 3b (1.91 g, 0.013 mol) and DAA (dehydroabietic
acid) (3.80 g, 0.013 mol) were dissolved in ethanol. After
the ethanol was removed, the diastereomeric salt was
recrystallized from 75% ethanol 3 times to yield the less-
soluble diastereomerically pure salt of (ꢀ)-3bÆDAA
20
4.1. Optical resolution of 2a
(1.29 g, 23%). ½aꢁD ¼ þ31:4 (c 0.5, MeOH). The less-solu-
ble salt (ꢀ)-3bÆDAA (1.13 g, 2.5 mmol) was dissolved in
6 M aqueous HCl solution. Precipitated DAA was sepa-
rated and 6 M aqueous NaOH solution added to the fil-
trate till pH 8–9. Precipitated aminophenol was extracted
with chloroform and the organic layer dried with anhy-
drous Na2SO4, filtered, and the solvent removed under
Racemic 2 (23.6 g, 97.8 mmol) and D-(ꢀ)-tartaric acid
(14.60 g, 97.3 mmol) were dissolved in ethanol to prepare
the diastereomeric salt. After the ethanol was removed,
the diastereomeric salt was recrystallized from 80% ethanol
3 times to give the diastereomerically pure less-soluble salt
of (R)-(ꢀ)-2ÆD-(ꢀ)-tartaric acid (6.69 g, 19.0 mmol, 39%).
reduced pressure to give enantiomerically pure (ꢀ)-3b
16
20
½aꢁD ¼ ꢀ71:9 (c 0.5, H2O). The less-soluble salt was liber-
(0.35 g, total yield, 36%). ½aꢁD ¼ ꢀ16:2 (c 0.5, 0.1 M HCl
ated by 6 M aqueous NaOH solution and the aqueous
(aq)). Enantiomeric excess >99% ee was determined by
HPLC analysis (CHIRALCEL OD-H, hexane–i-PrOH
85:15, 0.5 ml/min) of the corresponding acetamide deriva-
tive at retention time: t = 12.5 min.
layer extracted with diethyl ether to give enantiomerically
16
pure (R)-(ꢀ)-2 (3.97 g, total yield, 25%). ½aꢁD ¼ ꢀ21:2 (c
0.5, MeOH). Enantiomeric excess >99% was determined
by HPLC analysis (CHIRALCEL OD-H, hexane–i-PrOH
80:20, 0.5 ml/min) of the corresponding acetamide deriva-
tive at retention time: t = 12.7 min.
4.5. General procedure for the synthesis of chiral 1,3-
aminophenols 4a–b, 5a–b, 6a–b
4.2. 2-((R)-1-Amino-2-phenylethyl)-4-methylphenol (R)-(ꢀ)-
After dissolving urea (2.51 g, 42.0 mmol) in 75% H2SO4
(20 ml), the solution was cooled to below 10 ꢁC. tert-BuOH
(7.92 ml, 84 mmol) was then added in one portion, and the
mixture stirred at the same temperature for a further 1 h.
Enantiomerically pure (R)-1a (3.45 g, 21.0 mmol) was
added and the mixture stirred at rt for 72 h. At 0 ꢁC, a sat-
urated aqueous solution of Na2CO3 was added to make the
solution pH 8–9 and the mixture was extracted with ethyl
acetate (10 ml · 3). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude mixture was purified by column chro-
matography of silica gel (eluent: CHCl3) to give a white
solid (R)-4a (3.67 g, 16.6 mmol, 71%) and a white solid
(R)-5a (1.04 g, 3.75 mmol, 15%). In the same way, (R)-4a
was reacted further with urea and tert-BuOH in 75%
H2SO4 to obtain (R)-5a and recovered (R)-4a. Using enan-
tiomerically pure (S)-1a, (S)-4a and (S)-5a were synthe-
sized, respectively.
3a
A solution of (R)-(ꢀ)-2a (2.40 g, 10 mmol) in dry toluene
(50 ml) was added dropwise to AlBr3 (10.40 g, 38.6 mmol)
and the yellow solution stirred at 0 ꢁC for 50 h. The reac-
tion was quenched with a saturated aqueous solution of
NaHCO3 (100 ml) at 0 ꢁC and the mixture was extracted
with ethyl acetate (15 ml · 4). The organic layer was dried
with anhydrous Na2SO4 and the solvent removed under re-
duced pressure. The crude product was purified by column
chromatography of silica gel (eluent: ethyl acetate) to give a
white solid (R)-(ꢀ)-3a (6.59 g, 29.0 mmol, 75%). Mp: 90–
20
92 ꢁC. ½aꢁD ¼ ꢀ48:0 (c 0.5, MeOH). Enantiomeric excess
>99% was determined by HPLC analysis (CHIRALCEL
OD-H, hexane–i-PrOH 80:20, 0.5 ml/min) at retention time
1
t = 11.9 min. H NMR (400 MHz, CDCl3, d ppm): 7.30
(m, 5H, ArH), 6.97 (d, J = 8.0 Hz, 1H, ArH), 6.78 (d,
J = 8.0 Hz, 2H, ArH), 4.26 (dd, J = 4.3 Hz, J = 5.9 Hz,
1H, CHNH2), 3.07 (dd, J = 4.3 Hz, J = 9.1 Hz, 1H,
ArCH2), 2.94 (dd, J = 3.2 Hz, J = 10.2 Hz, 1H, ArCH2),
2.24 (s, 3H, ArCH3). IR (KBr) 3075, 3030, 1807, 1779,
1638, 1605, 1543, 1445, 1388, 1300, 1261, 1179, 904, 849,
757 cmꢀ1. Anal. as HCl salt. Calcd for C15H18ClNO: C,
68.30; H, 6.88; N, 5.31. Found: C, 68.44; H, 7.00; N, 5.21.
4.5.1. 2-(1-Amino-2,2-dimethylpropyl)-4-tert-butylphenol 4a.
20
A white solid. Mp: 99–101 ꢁC. (S)-4a; ½aꢁD ¼ ꢀ6:8 (c 0.326,
20
diethyl ether), (R)-4a, ½aꢁD ¼ þ8:4 (c 0.330, diethyl ether).
Enantiomeric excess >99% was determined by HPLC anal-
ysis (CHIRALCEL OD-H, hexane–i-PrOH 90:10, 0.5 ml/
min) at retention time: tS = 12.7 min; tR = 13.8 min. 1H
NMR (400 MHz, CDCl3, d ppm): 7.15 (dd, J = 8.6 Hz,
J = 1.4 Hz, 1H, ArCH), 6.88 (d, J = 1.3 Hz, 1H, ArH),
6.74 (d, J = 8.6 Hz, 1H, ArH), 3.85 (s, 1H, (CH3)3CHAr),
1.27 (s, 9H, (CH3)3Ar), 0.978 (s, 9H, (CH3)3CHAr). IR
(KBr) 3067, 2983, 1598, 1485, 1448, 1386, 1298, 1137,
913, 868 cmꢀ1. Anal. Calcd for C15H25NO: C, 76.55; H,
10.71; N, 5.95. Found: C, 76.67; H, 10.85; N, 6.01.
4.3. 2-(1-Aminoethyl)-4-methylphenol 3b
This compound was synthesized via the same procedure as
3a. A pale yellow solid. Yield 78%. Mp: 96–98 ꢁC. 1H
NMR (300 MHz, CDCl3,
d
ppm): 6.94 (d, 1H,
J = 8.1 Hz, ArH), 6.75 (m, 2H, ArH), 4.27 (q, 1H,

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X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
4.5.2. 2-(1-Amino-2-methylpropyl)-4-tert-butylphenol 4b.
A colorless oil, 79% yield. (S)-4b; ½aꢁD ¼ ꢀ13:9 (c 0.36,
HPLC analysis (CHIRALCEL OD-H, hexane–i-PrOH
90:10, 0.5 ml/min) at retention time: t = 9.6 min. 1H
NMR (300 MHz, CDCl3, d ppm): 6.97 (s, 1H, ArCH),
6.66 (s, 1H, ArH), 4.26 (q, J = 6.6 Hz, 1H, CHNH2),
2.24 (s, 3H, ArCH3), 1.47 (d, J = 6.6 Hz, 3H, CH CH3),
1.41 (s, 9H, (CH3)3). IR (KBr) 3004, 1631, 1596, 1467,
1384, 1308, 1260, 1173, 1115, 917, 907, 783 cmꢀ1. Anal.
Calcd for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found:
C, 75.13; H, 10.32; N, 6.66.
20
CHCl3). Enantiomeric excess >99% was determined by
HPLC analysis (CHIRALCEL OD-H, hexane–i-PrOH
90:10, 0.5 ml/min) at retention time: t = 12.8 min. 1H
NMR (400 MHz, CDCl3, d ppm): 7.15 (dd, J = 8.5 Hz,
J = 2.6 Hz, 1H, ArCH), 6.89 (d, J = 2.8 Hz, 1H, ArH),
6.75 (d, J = 8.5 Hz, 1H, ArH), 3.83 (d, J = 7.0 Hz, 1H,
CHNH2), 2.08 (m, 1H, (CH3)2CH), 1.33 (s, 9H, (CH3)3)
1.02 (d, J = 6.6 Hz, 3H, CH3), 0.838 (d, J = 6.6 Hz, 3H,
CH3). IR (neat) 3379, 3302, 2961, 1588, 1496, 1470, 1387,
1366, 1256, 1175, 825, 754 cmꢀ1. Anal. as HCl salt. Calcd
for C14H24ClNO: C, 65.23; H, 9.38; N, 5.43. Found: C,
65.34; H, 9.35; N, 5.49.
4.6. General procedure for the enantioselective addition of
diethylzinc to aldehydes
Diethylzinc (1.0 M solution in hexane, 1.20 mmol) was
added to a solution of chiral ligand (0.1 mmol) in anhy-
drous mixed solvents toluene/hexane (1.5 ml, v/v, 1:1).
After 30 min, a solution of aldehyde (1 mmol) in mixed sol-
vents toluene/hexane (2.0 ml, v/v, 1:1) was added dropwise
and the resulting mixture stirred for 22 h. The reaction was
quenched by 1 M aqueous HCl solution (4 ml) and the
product extracted three times with ethyl acetate. The com-
bined organic phase was washed by saturated aqueous
solution of NaCl and dried over anhydrous Na2SO4. After
filtration and evaporation of the solvent, the crude alcohol
was purified by TLC of silica gel to give the enantiomer en-
riched alcohol. The ee values of the alcohols were deter-
mined by chiral HPLC analysis.
4.5.3.
2-(1-Amino-2,2-dimethylpropyl)-4,6-di-tert-butyl-
phenol 5a. A white solid. Mp: 108–110 ꢁC. (S)-5a;
20
20
½aꢁD ¼ þ22:0 (c 0.5, CH3COOCH2CH3), (R)-5a; ½aꢁD
¼
ꢀ12:7 (c 1.0, MeOH). Enantiomeric excess >99% was
determined by HPLC analysis (CHIRALCEL OJ, hex-
ane–i-PrOH 85:15, 0.5 ml/min) at retention time:
1
tS = 8.63 min, tR = 13.2 min. H NMR (400 MHz, CDCl3,
d ppm): 7.18 (d, J = 2.7 Hz, 1H, ArCH), 6.74 (d,
J = 2.7 Hz, 1H, ArH), 3.86 (s, 1H, (CH3)3CHAr), 1.41 (s,
9H, (CH3)3ArOH), 1.28 (s, 9H, (CH3)3Ar), 0.965 (s, 9H,
(CH3)3CHAr). IR (KBr) 3485, 2977, 2957, 1693, 1627,
1604, 1454, 1376, 1353, 1331, 1268, 1244, 1151, 969, 958,
794 cmꢀ1. Anal. Calcd for C19H33NO: C, 78.29; H, 11.41;
N, 4.81. Found: C, 78.41; H, 11.31; N, 4.90.
Acknowledgement
4.5.4. 2-(1-Amino-2-methylpropyl)-4,6-di-tert-butylphenol
20
The authors, X.-F.Y. and G.-Y.Z., greatly thank from the
Scientific Fund of University of Jinan (B0001) for the
financial support.
5b. A white solid. Mp: 98–100 ꢁC. (S)-5b; ½aꢁD ¼ þ5:8
(c 0.584, diethyl ether). Enantiomeric excess >99% was
determined by HPLC analysis (CHIRALCEL OJ, hex-
ane–i-PrOH 97:3, 0.5 ml/min) at retention time:
1
t = 11.1 min. H NMR (400 MHz, CDCl3, d ppm): 7.18
References
(d, J = 2.1 Hz, 1H, ArCH), 6.76 (d, J = 2.1 Hz, 1H,
ArH), 3.76 (d, J = 7.5 Hz, 1H, CHNH2), 2.07 (m, 1H,
(CH3)2CH), 1.41 (s, 9H, (CH3)3), 1.28 (s, 9H, (CH3)3),
1.01 (d, J = 7.0 Hz, 3H, CH3), 0.817 (d, J = 7.0 Hz, 3H,
CH3). IR (KBr) 3366, 3295, 2959, 1579, 1477, 1439, 1387,
1362, 1251, 1234, 1159, 981, 882, 823 cmꢀ1. Anal. Calcd
for C18H31NO: C, 77.92; H, 11.26; N, 5.05. Found: C,
78.09; H, 11.55; N, 5.14.
1. (a) Scarpi, D.; Lo Galbo, F.; Guarna, A. Tetrahedron:
´
Asymmetry 2006, 17, 1409–1414; (b) Blay, G.; Fernandez, I.;
Aleixandre, A. M.; Pedro, J. R. Tetrahedron: Asymmetry
2005, 16, 1207–1213; (c) Jeon, S. J.; Chen, Y. K.; Walsh, P. J.
Org. Lett. 2005, 7, 1729–1732; (d) Li, H. M.; Walsh, P. J. J.
Am. Chem. Soc. 2005, 127, 8355–8361; (e) Lurain, A. E.;
Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70, 1262–1268;
(f) Scarpi, D.; Lo Galbo, F.; Occhiato, E. G.; Guarna, A.
Tetrahedron: Asymmetry 2004, 15, 1319–1324; (g) Wang,
M.-C.; Liu, L.-T.; Zhang, J.-S.; Shi, Y.-Y.; Wang, D.-K.
Tetrahedron: Asymmetry 2004, 15, 3853–3859; (h) Barroso,
4.5.5. 2-((R)-1-Amino-2-phenylethyl)-6-tert-butyl-4-methyl-
20
phenol (R)-(ꢀ)-6a. A colorless oil. (R)-6a; ½aꢁD ¼ ꢀ26:1
(c 1.8, CHCl3). Enantiomeric excess >99% was determined
by HPLC analysis (CHIRALCEL OJ, hexane–i-PrOH
90:10, 0.5 ml/min) at retention time: t = 16.1 min. 1H
NMR (400 MHz, CDCl3, d ppm): 7.30 (m, 5H, ArH),
7.00 (d, J = 2.1 Hz, 1H, ArCH), 6.71 (d, J = 2.1 Hz, 1H,
ArH), 4.26 (dd, J = 4.3 Hz, J = 5.9 Hz, 1H, CHNH2),
3.02 (m, 2H, ArCH2), 2.24 (s, 3H, ArCH3), 1.43 (s, 9H,
(CH3)3). IR (neat) 3080, 3067, 3003, 1805, 1793, 1633,
1600, 1552, 1420, 1395, 1375, 1306, 1223, 1174, 786, 772,
700 cmꢀ1. Anal. as HCl salt. Calcd for C19H26ClNO: C,
71.34; H, 8.19; N, 4.38. Found: C, 71.45; H, 8.10; N, 4.26.
´
S.; Blay, G.; Fernandez, I.; Pedro, J. R. Tetrahedron Lett.
´
2004, 45, 8583–8586; (i) Blay, G.; Fernandez, I.; Monje, B.;
Pedro, J. R. Tetrahedron Lett. 2004, 45, 8039–8042; (j) Xu,
M.-H.; Pu, L. Org. Lett. 2002, 4, 4555–4557; (k) Steiner, D.;
Sethofer, S. G.; Goralski, C. T.; Singaram, B. Tetrahedron:
Asymmetry 2002, 13, 1477–1483; (l) Xu, Q.; Wu, X.; Pan, X.;
Chan, A. C. S.; Yang, T.-K. Chirality 2002, 14, 28–31.
2. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
3. (a) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.
Tetrahedron: Asymmetry 1998, 9, 3667–3675; (b) Cardellic-
chio, C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortrella, P.
Tetrahedron 1999, 55, 14685–14692.
4. (a) Yang, X.-F.; Wang, D.-Q.; Zhang, G.-Y.; Hirose, T. Acta
Crystallogr., Sect. E 2006, 62, o2622–o2624; (b) Yang, X.-F.;
Zhang, G.-Y.; Zhang, Y.; Zhao, J.-Y.; Wang, X.-B. Acta
Crystallogr., Sect. C 2005, 61, o262–o264; (c) Wang, X.-Y.;
4.5.6. (ꢀ)-2-(1-Aminoethyl)-6-tert-butyl-4-methylphenol 6b.
20
A pale green solid. Mp: 40–42 ꢁC. (ꢀ)-6a; ½aꢁD ¼ ꢀ21:2 (c
0.6, CHCl3). Enantiomeric excess >99% was determined by

X.-F. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 1257–1263
1263
Dong, Y.-M.; Sun, J.-W.; Xu, X.-N.; Li, R.; Hu, Y.-F. J.
Org. Chem. 2005, 70, 1897–1900; (d) Xu, X.-N.; Lu, J.; Dong,
Y.-M.; Li, R.; Ge, Z.-M.; Hu, Y.-F. Tetrahedron: Asymmetry
2004, 15, 475–479; (e) Xu, X.-N.; Lu, J.; Li, R.; Ge, Z.-M.;
Dong, Y.-M.; Hu, Y.-F. Synlett 2004, 122–124; (f) Velmathi,
S.; Swamalakshmi, S.; Narasimhan, S. Tetrahedron: Asym-
metry 2003, 14, 113–117; (g) Ji, J. X.; Qiu, L. Q.; Yip, C. W.;
Chan, A. S. C. J. Org. Chem. 2003, 68, 1589–1590; (h)
Bringmann, G.; Pfeifer, R.-M.; Rummey, C.; Hartner, K.;
R1 = 0.0578, xR2 = 0.1503. Data collection for the crystal
structure determination was carried out on a diffractometer
˚
using Mo Ka radiation (k = 0.71069 A) at a temperature of
123(2) K. Of the 25,665 reflections measured in the
1.03 6 h 6 27.50ꢁ range, 8380 reflections were unique and
7471 reflections with I > 2r(I) were used in structure solution
2
and refinement, Rint = 0.1222, w ¼ 1=½r2ðF o2Þ þ ð0:1000PÞ þ
0:0000Pꢁ, where P ¼ ðF o2 þ 2F 2cÞ=3. The structure was solved
by direct method using SHELXL-97. All of the non-hydrogen
atoms were refined by Full-matrix least-squares on F2 using
anisotropic displacement parameters.
Breuning, M. J. Org. Chem. 2003, 68, 6859–6863; (i) Munoz-
˜
Muniz, O.; Juaristi, E. J. Org. Chem. 2003, 68, 3781–3875; (j)
˜
Brunner, H.; Henning, F.; Weber, M. Tetrahedron: Asymme-
9. Crystallographic data for the structure of compound 5b have
been deposited with the Cambridge Crystallographic Data
Center as Supplementary Publication No. CCDC 644402.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB21EZ,
UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.ca-
m.ac.uk]. Crystal data of 5b: C18H31N1O1, M = 277.44,
´
try 2002, 13, 37–42; (k) Gama, A.; Flores-Lopez, L. Z.;
Aguirre, G.; Parra-Hake, M.; Somanathan, R.; Walsh, P. J.
Tetrahedron: Asymmetry 2002, 13, 149–154; (l) Shi, M.;
Wang, C. J. Tetrahedron: Asymmetry 2002, 13, 2161–2166;
(m) Dahmen, S.; Bra¨se, S. J. Chem. Soc., Chem. Commun
2002, 26–27; (n) Lu, J.; Xu, X. N.; Wang, S. Z.; Wang, C.;
Hu, Y. F.; Hu, H. W. J. Chem. Soc., Perkin Trans. 1 2002,
2900–2903; (o) Cimarelli, C.; Palmieri, G.; Volpini, E.
Tetrahedron: Asymmetry 2002, 13, 2417–2426; (p) Trost, B.
M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861–863;
(q) Ongeri, S.; Piarulli, U.; Richard, F.; Jackson, W. Eur. J.
Org. Chem. 2001, 803–807; (r) Cimarelli, C.; Palmieri, G.;
Volpini, E. Tetrahedron 2001, 57, 6089–6096; (s) Cimarelli,
C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org. Chem.
2001, 66, 4759–4765; (t) Liu, D. X.; Zhang, L. C.; Wang, Q.;
Da, C. S.; Xiu, Z. Q.; Wang, R.; Michael, C. K. C.; Chan, A.
S. C. Org. Lett. 2001, 3, 2733–2735; (u) Palmieri, G.
Tetrahedron: Asymmetry 2000, 11, 3361–3373; (v) Chataig-
ner, Z.; Gennari, U. P.; Ceccarelli, S. Angew. Chem., Int. Ed.
2000, 39, 916–918.
˚
monoclinic, space group C2, a = 27.828(6) A, b =
3
˚
˚
˚
5.9272(12) A,
c = 10.734(2) A,
V = 1730(6) A ,
D =
1.065 Mg/m3, l = 0.064 mmꢀ1, F(000) = 616, Z = 4, R1 =
0.0522, xR2 = 0.1114. Data collection for the crystal struc-
ture determination was carried out on a diffractometer using
˚
Mo Ka radiation (k = 0.71069 A) at a temperature of
123(2) K. Of the 4801 reflections measured in the
1.50 6 h 6 27.50ꢁ range, 3190 reflections were unique and
2634 reflections with I > 2r(I) were used in structure solution
2
and refinement, Rint = 0.0164, w ¼ 1=½r2ðF o2Þ þ ð0:0285PÞ þ
5:0566Pꢁ, where P ¼ ðF o2 þ 2F 2cÞ=3. The structure was solved
by direct method using SHELXL-97. All of the non-hydrogen
atoms were refined by Full-matrix least-squares on F2 using
anisotropic displacement parameters.
5. Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.;
Ripa, A.; Schupfer, P.; Treptow, B.; Kundig, E. P. Chirality
2000, 12, 529–539.
6. Zhang, G.; Liao, Y.; Wang, Z.; Nohira, H.; Hirose, T.
Tetrahedron: Asymmetry 2003, 14, 3297–3300.
10. Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988,
110, 7877–7878.
11. Kang, J.; Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem.
Commun. 1994, 2009–2010.
12. (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (b)
Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028–4036; (c) Kitamura, M.; Suga, S.; Oka,
H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800–9809; (d)
Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6327–6335.
13. Semi-empirical PM5 calculations were performed with the
MOPAC 2002 Version 2.5.3 of CAChe Version 7.5.0.85.
14. The transition state anti-Re, which is more stable than anti-Si
of 2.75 kcal/mol by means of semi-empirical PM5 calcula-
tions, leads to the alkyl addition of the benzaldehyde to the
Re face to afford (R)-1-phenylpropanol, which is in agreement
with the experimental results.
7. Nevrekar, Nitin B.; Sawardekar, Sagar R.; Pandit, Tushar S.;
Kudav, Narayan A. Chem. Ind. 1983, 206–207.
8. Crystallographric data for the structure of compound 5a have
been deposited with the Cambridge Crystallographic Data
Center as Supplementary Publication No. CCDC 644401.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB21EZ,
UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk]. Crystal data of 5a: C19H33N1O1, M = 291.46,
˚
orthorhombic, space group C2221, a = 13.4310(14) A, b =
3
˚
˚
˚
13.7194(14) A, c = 39.470(4) A, V = 7272.9(13) A , D =
1.065 Mg/m3, l = 0.064 mmꢀ1
,
F(000) = 2592, Z = 16,