Synthesis of optically active β-amino alcohols by asymmetric transfer hydrogenation of α-amino ketones

Article abstract of DOI:10.1055/S-0029-1218619

A number of optically active amino alcohols were synthesized by direct asymmetric transfer hydrogenation of the corresponding amino ketones with good-to-high enantiomeric excesses (up to 95%) and excellent yields (up to 93%). When the range of substrates was broadened to include α-sulfonamido ketones or α-keto sulfones, the corresponding products were obtained with 100% enantiomeric excesses. The absolute configuration of (1R)-2-[(4- chlorophenyl) amino]-1-(4-methoxyphenyl) ethanol was confirmed by X-ray crystal structure analysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218619

PAPER
811
Synthesis of Optically Active b-Amino Alcohols by Asymmetric Transfer
Hydrogenation of a-Amino Ketones
O
a
ptically Activ
h
e
b
-Amino A
o
lcohols u Xu,*a Songlei Zhu,a Yongmin Liu,a Ling He,a Zhicong Geng,b Yawen Zhang*b
Department of Chemistry, Xuzhou Medical College, Xuzhou 221004, P. R. of China
Fax +86(512)65880340; E-mail: xuzhou8111@yahoo.com.cn
b
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Suzhou (Soochow) University, Suzhou 215123, P. R. of China
Received 24 September 2009; revised 13 November 2009
was chosen as a model substrate. As expected, the reac-
tion was complete within 24 hours, and the product was
obtained with 92% enantiomeric excess (ee). Encouraged
by these excellent results, we attempted to identify the op-
Abstract: A number of optically active amino alcohols were syn-
thesized by direct asymmetric transfer hydrogenation of the corre-
sponding amino ketones with good-to-high enantiomeric excesses
(up to 95%) and excellent yields (up to 93% ). When the range of
substrates was broadened to include a-sulfonamido ketones or a- timal conditions for the ATH reaction, such as the choice
keto sulfones, the corresponding products were obtained with 100%
of solvent and the amount of ligand (Table 1).
enantiomeric excesses. The absolute configuration of (1R)-2-[(4-
chlorophenyl)amino]-1-(4-methoxyphenyl)ethanol was confirmed
As can be seen from Table 1, acetonitrile was the best sol-
vent, and gave the product in up to 95% ee and 88% yield.
The reaction barely proceeded under solvent-free condi-
tions (Table 1, entry 3). When the reaction system was
rendered basic, the reaction hardly occurred at all, proba-
bly because of the poor solubility of the amino ketone in
isopropyl alcohol or methanol (Table 1, entries 2 and 5).
According to the results shown in Table 1, the optimal
conditions for the ATH reaction of a-amino ketones re-
quire the use of formic acid as the hydrogen donor and
acetonitrile as the solvent.
by X-ray crystal structure analysis.
Key words: amino alcohols, amino ketones, hydrogenations,
stereoselective synthesis, aziridines
The asymmetric transfer hydrogenation (ATH) reaction
of prochiral ketones and imines is a pivotal reaction for
the synthesis of chiral secondary alcohols or amines that
has recently attracted much attention.1 Many excellent
chiral ligands, such as N-[(1R,2R)-2-amino-1,2-diphenyl-
ethyl]-4-toluenesulfonamide [(1R,2R)-Ts-DPEN] and
(1R,2S)-1-aminoindan-2-ol, have been developed for use
in the ATH reaction.2–7 However, few papers have report-
ed on applications of those excellent chiral ligands in the
synthesis of new optically active compounds.8–20 Chiral
amino alcohols are important compounds, that are not
only useful as chiral ligands, but also as important build-
ing blocks for many natural products. To explore the util-
ity of the ATH reaction, we examined the direct
conversion of amino ketones into chiral amino alcohols.
Having optimized the reaction conditions, we decided to
screen a series of substrates to evaluate the scope of the re-
action. As shown by the results summarized in Table 2,
good enantioselectivities were achieved with most amino
ketones. The nature of the substituents on the substrates
plays an important role. When R1 is hydrogen, substitu-
ents R2 on the aromatic ring that contained electron-with-
drawing groups gave better results than substituents with
electron-donating groups (Table 2, entries 1–5 and 14).
When R1 was not hydrogen and R2 was an electron-with-
drawing group, decreased enantiomeric excesses of the
products were obtained, whereas when R2 was an elec-
tron-donating group, increased enantiomeric excesses of
the corresponding products were obtained (Table 2, en-
tries 6–10). When the range of substrates was broadened
to include a-methyl substituted amino ketones (Table 2,
entries 12–13), dynamic kinetic reactions of the substrates
were required. Disappointingly, although good diastereo-
The starting materials were synthesized in moderate-to-
good yields by the method shown in Scheme 1.21–25 These
amino ketones are stable at room temperature in air for a
month, and were used directly for the ATH reaction.
Initially, (1S,2S)-Ts-DPEN, a well-known ligand, was
chosen as a catalyst for the reaction in N,N-dimethylform-
amide.
2-[(4-Chlorophenyl]amino)-1-phenylethanone
O
b (R2 = H) or
O
O
H
c (R2 = Me)
N
R2
Br
a
R2
R2
R3
R1
R1
R1
Scheme 1 Synthesis of amino ketones. Reagents and conditions: (a) Br2, CCl4, 0 °C to r.t.; (b) NaHCO3, ArNH2, r.t.; (c) DME, reflux.
SYNTHESIS 2010, No. 5, pp 0811–0817
x
x
.
x
x
.2
0
1
0
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1218619; Art ID: F19109SS
© Georg Thieme Verlag Stuttgart · New York

812
Z. Xu et al.
PAPER
Table 1 Screening of Optimal Conditions for the ATH Reaction
O
OH
H
Ph
Ph
(1S,2S)-Ts-DPEN
N
H
N
[Ru(cymene)Cl2]2
H2N
NHTs
HCOOH, Et3N
Cl
MeCN
(1S,2S)-Ts-DPEN
Cl
Entry
1
Methoda,b
Solvent
DMF
Yield (%)c
ee (%)d
92
–
A
B
A
A
A
A
A
A
A
C
80
–
2
i-PrOH
–
3
<5
81
<5
78
79
76
88
79
89
72
–
4
CH2Cl2
MeOH
Et2O
89
–
5
6
94
92
90
95
89
90
88
7
DMSO
THF
8
9
MeCN
MeCN
MeCN
MeCN
10
11
12
A (S/C 160)
A (S/C 320)
a Reactions were performed at r.t. for 24 h by using amino ketone (0.5 mmol), solvent (2.0 mL), (1S, 2S)-Ts-DPEN (4.5 mg), [Ru(cymene)Cl2]2
(3.8 mg), and HCOOH/Et3N (0.2 mL).
b Method A: hydrogen donor HCOOH; HCOOH/Et3N = 5:2; Method B: hydrogen donor i-PrOH; Method C: as method A, HCOOH/Et3N = 1:1.
c Isolated yield.
d The enantiomeric excess was determined by chiral HPLC analysis of the products on a Chiralpak AD-H column.
meric ratios were obtained, the major isomer was obtained were obtained in up to 100% ee; however, substrates 3e–f
in only a small enantiomeric excess under the experiment failed to react. Although the reason for this is not clear, it
conditions. This may because the rate constant for the ra- is worth noting that specific interactions between sub-
cemization of the substrate is slower than the rate constant strates 3a–d and the catalyst may occur during the ATH
of the resolution step of the major isomer.
reaction. This presumed interaction between the sub-
strates and the catalyst may supply useful information re-
garding the mechanism of the reaction.
We then broaden the range of substrates to the a-hetero-
atom-substituted ketones 3a–f and examined their reac-
tions under similar reaction conditions, but using N,N- The absolute configuration of product 2i (Table 2, entry 9)
dimethylformamide as the solvent (Figure 1). To our sur- was confirmed to be R by X-ray analysis. As can be seen
prise, as shown in Figure 1, substrates 3a–d underwent from Scheme 2, the configuration of compound 2i is de-
the ATH reaction when formic acid was used as the hy- termined by the first step of the reaction. That is to say the
drogen source, and the corresponding products (4a–d) configurations of the amino alcohols are the same as those
O
F
O
H
O
H
N
N
S
OH
O
O
O
90% yield, 100% ee
88% yield, 25% ee
80% yield, 99% ee
3a26–28
3b29
3c30
O
O
O
O
O
OEt
S
P
O
O
OEt
93% yield, 100% ee
0% yield
3e
0% yield
3d31
3f
Figure 1 ATH reactions of a-heteroatom-substituted ketones
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York

PAPER
Optically Active b-Amino Alcohols
813
of the corresponding 2-bromo-1-phenylethanols. Thus, tive 2-bromo-1-phenylethanols (all R), as reported in the
the configurations of the other amino alcohols can be in- literature.32
ferred to be R from those of the corresponding optical ac-
Table 2 Scope of the ATH reaction
O
OH
H
H
(1S, 2S)-Ts-DPEN
[Ru(cymene)Cl2]2
N
N
R1
R3
1a–n
R3
2a–n
HCOOH, Et3N
MeCN
R2
R2
R1
Entry
1
Substratea
Product
Yieldb
81%
eec
O
OH
H
N
H
N
2a
86%
O
O
OH
OH
H
N
H
N
2
3
2b
2c
89%
71%
95%
77%
Cl
Cl
H
N
H
N
O
O
OH
OH
H
N
H
N
4
5
2d
2e
87%
93%
80%d
85%
H
N
H
N
OMe
OMe
O
OH
OH
H
H
N
N
6
2f
67%
57%
O2N
O2N
O
H
N
H
N
7
8
2g
2h
2i
92%
75%
67%
89%
80%
84%
93%
86%e
63%
85%
MeO
MeO
OH OH
OH
O
H
N
H
N
Cl
Cl
O
OH
H
N
H
N
9
Cl
MeO
MeO
Cl
Cl
O
Cl
OH
H
H
N
N
10
11
2j
Cl
Cl
Cl
Cl
O
OH
H
N
H
N
2k
MeO
Me
MeO
Me
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York

814
Z. Xu et al.
PAPER
Table 2 Scope of the ATH reaction (continued)
O
H
OH
H
(1S, 2S)-Ts-DPEN
[Ru(cymene)Cl2]2
N
N
R1
R3
1a–n
R3
2a–n
HCOOH, Et3N
MeCN
R2
R2
R1
Entry
12
Substratea
Product
Yieldb
91%
eec
O
OH
H
H
N
f
N
2l
–
OMe
OMe
O
OH
H
H
N
g
N
13
14
2m
2n
91%
81%
–
Cl
OMe
Cl
OMe
O
OH
H
N
H
N
59%
a The reactions were performed at r.t. for 24 h, using amino ketone (0.5 mmol), MeCN (2.0 mL), (1S, 2S)-Ts-DPEN (4.5 mg), [Ru(cymene)Cl2]2
(3.8 mg), and HCOOH/Et3N (5:2; 3.8 mg).25
b Isolated yields.
c The ee was determined by chiral HPLC analysis of the corresponding products on a Chiralpak AD-H column.
d The ee was determined by chiral HPLC analysis on a Chiralpak IA column.
e The configuration of product 2i was confirmed to be R by X-ray analysis.
f dr 90:10, determined by chiral HPLC. The ee values for the major and minor isomers were 14% and 90%, respectively.
g dr 98:2, determined by chiral HPLC; The ee values for the major and minor isomers were 3% and 50%, respectively.
In conclusion, we have developed a practical catalytic
synthesis of optically active amino alcohols by asymmet-
ric transfer hydrogenation of amino ketones with formic
acid as the source of hydrogen. The absolute configura-
tion of the product 2i was confirmed to be R by X-ray
crystal structure analysis.
All manipulations were carried out under an argon in degassed sol-
vents. The reactions were monitored by TLC. NMR spectra were
measured in CDCl3 on a Varian-Inova-400 NMR spectrometer with
TMS as an internal reference. Optical rotations were measured with
a HORIBA SEPA-200 high-sensitivity polarimeter. The enantio-
meric excess (ee) was determined by using a Chiralpak AD-H col-
umn, a Chiralpak IA column, or a Chiralcel OD-H column with
hexane–i-PrOH (90:10) as the solvent (unless otherwise stated) at a
flow rate of 1 mL/min (unless otherwise stated), and UV detection
at 254 nm. HRMS spectra were recorded under EI conditions. IR
spectra were recorded on a Varian FT-1000 IR spectrophotometer
using KBr disks in the 4000–400 cm–1 region.
Figure 2 Absolute configuration of product 2i confirmed by X-ray
crystal structure analysis
An example of the use of these chiral amino alcohols is
their conversion into chiral aziridines by the Mitsunobo
reaction, as shown in Scheme 3.33
OH
O
OH
H
N
Br
Br
4-ClC6H4NH2
step 2
(1S,2S)-TsDPEN
step 1
MeO
retains the same configuration
OH
Cl
MeO
MeO
O
H
H
N
N
(1S,2S)-TsDPEN
MeO
Cl
MeO
Cl
R-configuration determined by X-ray analysis
Scheme 2 Configurations determined by analogy
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York

PAPER
Optically Active b-Amino Alcohols
815
O
O
O
NH2
H
O
S
Br
O
N
NaHCO3
EtOH
S
O
+
O
(1S,2S)-Ts-DPEN
[Ru(cymene)Cl2]2
HCOOH, Et3N
O
OH
N
H
S
N
DEAD, Ph3P
0–20 °C
S
O
O
MeCN
Scheme 3 A literature synthesis of a chiral aziridine
Asymmetric Transfer Hydrogenation; General Procedure
13C NMR (100 MHz, CDCl3): d = 143.5, 142.5, 134.8, 129.1, 129.0,
128.5, 126.9, 126.3, 126.2, 125.3, 124.3, 120.4, 118.6, 105.6, 72.7,
52.1.
HRMS (EI): m/z calcd for [C18H17NO]+: 263.1310; found:
263.1306.
A suspension of [RuCl2(p-cymene)]2 (3.8 mg) and (1R,2R)-Ts-
DPEN ligand (4.5 mg) in MeCN (2.0 mL) was stirred at r.t. for 2 h.
HCOOH/Et3N (5:2; 0.2 mL) and substrate 1 (0.5 mmol) were add-
ed, and the mixture was stirred for 24 h. The product was then ex-
tracted with EtOAc (3 × 10 mL), and the combined extracts were
dried (Na2SO4) and concentrated under vacuum. The residue was
purified by flash column chromatography [silica gel H, EtOAc–
PE (1:5)] to give the pure product. For substrates 3a–f, the reaction
conditions were identical, except that the solvent was changed to
DMF.
2-(4-Tolylamino)-1-phenylethanol (2d)
[a]D25 +20.0 (c 1.03, abs. EtOH); yield: 87%; 80% ee [HPLC;
Chiralpak IA, i-PrOH–hexane (10:90); tR (minor) = 11.38 min, tR
(major) = 12.13 min].
IR (KBr): 3323, 3188, 3030, 2914, 2843, 1617, 1519 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.42–7.29 (m, 5 H), 7.00 (d,
J = 8.4 Hz, 2 H), 6.62 (d, J = 8.0 Hz, 2 H), 4.91 (dd, J = 8.8, 3.6 Hz,
1 H), 3.41 (dd, J = 12.8, 3.6 Hz, 1 H), 3.27 (dd, J = 12.8, 8.8 Hz, 1
H), 2.83 (s, 1 H), 2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.8, 142.5, 130.2, 129.0, 128.3,
127.9, 126.3, 114.2, 72.8, 52.7, 20.8.
1-Phenyl-2-(phenylamino)ethanol (2a)
[a]D25 +17.2 (c 0.98, acetone); yield: 81%; 86% ee [HPLC; Chiral-
pak AD-H, i-PrOH–hexane (10:90); tR (minor) = 12.20 min, tR
(major) = 14.53 min].
IR (KBr): 3401, 3027, 2926, 1602, 1507 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.30 (m, 6 H), 7.10 (d,
J = 8.8 Hz, 2 H), 6.56 (d, J = 8.4 Hz, 2 H), 4.89 (dd, J = 8.5, 3.8 Hz,
1 H), 4.05 (s, 1 H), 3.36 (dd, J = 13.1, 3.8 Hz, 1 H), 3.25 (dd,
J = 13.1, 8.5 Hz, 1 H).
HRMS (EI): m/z calcd for [C15H17NO]+: 227.1310; found:
227.1321.
13C NMR (100 MHz, CDCl3): d = 148.2, 142.4, 129.8, 129.0, 128.4,
2-[(4-Methoxyphenyl)amino]-1-phenylethanol (2e)
[a]D25 +13.3 (c 0.64, abs. EtOH); yield: 93%; 85% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (major) = 19.81 min,
tR (minor) = 21.08 min].
126.3, 118.6, 114.0, 72.8, 52.2.
HRMS (EI): m/z calcd for [C14H15NO]+: 213.1154; found:
213.1161.
IR (KBr): 3415, 2931, 2832, 1513 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.43–7.31 (m, 5 H), 6.81 (d,
J = 8.8 Hz, 2 H), 6.72 (d, J = 8.8 Hz, 2 H), 4.94 (dd, J = 8.8, 3.2 Hz,
1 H), 3.76 (s, 3 H), 3.39 (dd, J = 12.8, 3.6 Hz, 1 H), 3.27 (dd,
J = 12.8, 8.8 Hz, 1 H), 2.35 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 153.1, 142.0, 141.4, 129.0, 128.4,
126.3, 115.7, 115.3, 72.7, 56.2, 56.1.
2-(4-Chlorophenylamino)-1-phenylethanol (2b)
[a]D25 +33.1 (c 1.00, abs. EtOH); yield: 89%; 95% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (minor) = 15.96 min,
tR (major) = 17.64 min].
IR (KBr): 3306, 3202, 2917, 2848, 1599, 1499 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.31 (m, 5 H), 7.18 (t, J = 7.8
Hz, 2 H), 6.74 (t, J = 7.4 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 2 H), 4.89
(dd, J = 8.6, 3.9 Hz, 1 H), 3.40 (dd, J = 13.1, 3.9 Hz, 1 H), 3.27 (dd,
J = 13.1, 8.6 Hz, 1 H), 3.01 (s, 2 H).
HRMS (EI): m/z calcd for [C15H17NO2]+: 243.1259; found:
243.1259.
13C NMR (100 MHz, CDCl3): d = 146.7, 142.1, 129.4, 129.0, 128.4,
1-(4-Nitrophenyl)-2-(phenylamino)ethanol (2f)
[a]D25 +45.38 (c 1.04, abs. EtOH); yield: 67%; 57% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (minor) = 20.36 min,
tR (major) = 22.64 min].
126.1, 114.8, 114.7, 72.7, 52.0.
HRMS (EI): m/z calcd for [C14H14NOCl]+: 247.0764; found:
247.0775.
IR (KBr): 3318, 3274, 1602, 1515, 1344 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.16 (d, J = 8.4 Hz, 2 H), 7.53 (d,
J = 8.8 Hz, 2 H), 7.23–7.18 (m, 2 H), 6.76 (t, J = 7.2 Hz, 1 H), 6.66
(d, J = 7.6 Hz, 2 H), 4.97 (dd, J = 8.6, 3.4 Hz, 1 H), 3.51 (s, 1 H),
3.42 (dd, J = 13.6, 3.4 Hz, 1 H), 3.21 (dd, J = 13.6, 8.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 149.9, 147.8, 147.7, 129.9, 127.1,
124.1, 119.0, 114.0, 71.8, 52.1.
2-(1-Naphthylamino)-1-phenylethanol (2c)
[a]D25 +11.8 (c 0.29, abs. EtOH); yield: 71%; 77% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (major) = 12.40 min,
tR (minor) = 13.86 min].
IR (KBr): 3527, 3427, 3052, 2828, 1579, 1411 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.84–7.79 (m, 2 H), 7.48–7.40 (m,
6 H), 7.35 (t, J = 7.6 Hz, 2 H), 7.27 (t, J = 8.4 Hz, 1 H), 6.70 (d,
J = 7.2 Hz, 2 H), 5.11 (dd, J = 8.6, 3.7 Hz, 1 H), 3.60 (dd, J = 12.8,
3.8 Hz, 1 H), 3.47 (dd, J = 12.7, 8.6 Hz, 1 H), 2.45 (s, 1 H).
HRMS (EI): m/z calcd for [C14H14N2O3]+: 258.1004; found:
258.1014.
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York

816
Z. Xu et al.
PAPER
1-(4-Methoxyphenyl)-2-(phenylamino)ethanol (2g)
[a]D25 +22.8 (c 0.95, abs. EtOH); yield: 92%; 84% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (minor) = 17.61 min,
tR (major) = 18.87 min].
IR (KBr): 3410, 2925, 2853, 1599, 1499, 817 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 8.4 Hz, 1 H), 7.39 (s,
1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 2 H), 6.67 (d,
J = 8.8 Hz, 2 H), 5.28 (dd, J = 8.4, 2.4 Hz, 1 H), 3.52 (dd, J = 13.6,
2.8 Hz, 1 H), 3.08 (dd, J = 13.6, 8.4 Hz, 1 H), 2.59 (s, 2 H).
IR (KBr): 3329, 3250, 2961, 2898, 1602 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34 (d, J = 8.0 Hz, 2 H), 7.19 (t,
J = 8.8 Hz, 2 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.74 (t, J = 7.6 Hz, 1 H),
6.68 (d, J = 8.0 Hz, 2 H), 4.88 (dd, J = 8.4, 4.0 Hz, 1 H), 4.01 (s, 1
H), 3.82 (s, 3 H), 3.39 (dd, J = 13.2, 4.0 Hz, 1 H), 3.30 (dd, J = 13.2,
8.4 Hz, 1 H), 2.30 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 146.5, 138.2, 134.5, 132.6, 129.6,
128.6, 128.0, 123.4, 115.1, 69.0, 50.4.
HRMS (EI): m/z calcd for [C14H12NOCl3]+: 315.9974; found:
315.9974.
13C NMR (100 MHz, CDCl3): d = 159.8, 148.3, 134.5, 129.7, 127.6,
2-(4-Tolylamino)-1-(4-methoxyphenyl)ethanol (2k)
[a]D25 +17.0 (c 0.53, abs. EtOH); yield: 80%; 85% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (10:90); tR (major) = 18.65 min,
tR (minor) = 20.76 min].
118.4, 114.4, 113.8, 72.5, 55.7, 52.1.
HRMS (EI): m/z calcd for [C15H17NO2]+: 243.1259; found:
243.1253.
IR (KBr): 3421, 3004, 2920, 1612, 1514, 1248 cm–1.
2-{2-[(4-Chlorophenyl)amino]-1-hydroxyethyl}phenol (2h)
[a]D25 +7.8 (c 0.98, abs. EtOH); yield: 75%; 93% ee [HPLC; Chiral-
pak AD-H, i-PrOH–hexane (10:90); tR (minor) = 19.43 min, tR
(major) = 21.51 min].
1H NMR (400 MHz, CDCl3): d = 7.33 (d, J = 8.4 Hz, 2 H), 7.00 (d,
J = 8.0 Hz, 2 H), 6.92 (d, J = 8.4 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2 H),
4.87 (dd, J = 8.6, 3.6 Hz, 1 H), 4.62 (s, 1 H), 3.82 (s, 3 H), 3.37 (dd,
J = 12.8, 3.6 Hz, 1 H), 3.28 (dd, J = 12.8, 8.6 Hz, 1 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.8, 134.5, 130.3, 129.1, 128.3,
127.6, 114.5, 114.4, 72.3, 55.8, 53.0, 20.9.
IR (KBr): 3409, 3322, 1496 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22 (t, J = 8.0 Hz, 1 H), 7.16 (d,
J = 8.4 Hz, 2 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.88 (t, J = 7.6 Hz, 2 H),
6.63 (d, J = 8.8 Hz, 2 H), 5.03 (dd, J = 7.6, 1.6 Hz, 1 H), 3.46–3.44
(m, 2 H).
HRMS (EI): m/z calcd for [C16H19NO2]+: 257.1416; found:
257.1412.
13C NMR (100 MHz, CDCl3): d = 155.6, 146.2, 129.9, 129.7, 127.9,
125.3, 123.9, 120.7, 117.6, 115.5, 73.5, 50.6.
2-[(4-Methoxyphenyl)amino]-1-phenylpropan-1-ol (2l)
Yield: 91%.
HRMS (EI): m/z calcd for [C14H14NO2Cl]+: 263.0713; found:
IR (KBr): 3442, 3398, 2976, 2832, 1511, 1234 cm–1.
263.0715.
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 8.4 Hz, 3 H), 7.29–
7.28 (m, 2 H), 6.81 (d, J = 9.2 Hz, 2 H), 6.70 (d, J = 8.8 Hz, 2 H),
4.96 (d, J = 4.9 Hz, 1 H), 3.76 (s, 3 H), 3.71–3.66 (m, 1 H), 2.60 (s,
2 H), 0.99 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 153.1, 142.0, 141.4, 128.7, 127.7,
126.4, 116.4, 115.4, 74.5, 56.2, 56.1, 14.4.
2-[(4-Chlorophenyl)amino]-1-(4-methoxyphenyl)ethanol (2i)
[a]D25 +36.0 (c 0.51, abs. EtOH); yield: 67%; 86% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (5:95); flow rate: 0.5 mL/min; tR
(major) = 48.97 min, tR (minor) = 50.60 min].
IR (KBr): 3434, 3326, 2840, 1497 cm–1.
HRMS (EI): m/z calcd for [C16H19NO2]+: 257.1416; found:
257.1407.
1H NMR (400 MHz, CDCl3): d = 7.31 (d, J = 8.8 Hz, 2 H), 7.12 (d,
J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.58 (d, J = 8.8 Hz, 2 H),
4.86 (dd, J = 8.3, 4.3 Hz, 1 H), 3.82 (s, 3 H), 3.30 (dq, J = 12.9, 12.9,
12.9, 6.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.8, 146.8, 134.3, 129.5, 127.6,
122.9, 114.9, 114.4, 72.4, 55.7, 52.0.
1-(4-Chlorophenyl)-2-[(4-methoxyphenyl)amino]propan-1-ol
(2m)
Yield: 91%.
IR (KBr): 3447, 2976, 2832, 2905, 1511, 1233, 1090 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.28 (m, 4 H), 6.81–6.79 (m,
2 H), 6.69–6.67 (m, 2 H), 4.91 (d, J = 7.2 Hz, 1 H), 3.76 (s, 3 H),
3.64–3.62 (m, 1 H), 2.72 (s, 2 H), 0.96 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 153.2, 141.2, 140.6, 133.3, 128.8,
127.7, 116.5, 115.4, 73.7, 56.2, 56.1, 14.3.
HRMS (EI): m/z calcd for [C16H18NO2Cl]+: 291.1026; found:
291.1029.
HRMS (EI): m/z calcd for [C15H16NO2Cl]+: 277.0870; found:
277.0876.
X-ray Crystal Data for Product 2i
Careful evaporation of a soln of 2i in EtOAc–PE (1:5) gave a single
crystal suitable for crystallographic analysis. Selective crystal struc-
ture data: Empirical formula: C15H16NO2Cl; Formula weight:
277.08; Crystal system = monoclinic; space group P21; Unit cell
dimensions: a = 5.822(2) Å, b = 7.496(3) Å, c = 15.729(6) Å,
b = 96.681(9)°, V = 681.8(5) Å3, Z = 2, T = 293(2) K; Final R indi-
ces: R (reflections) = 0.0609, wR2 (reflections) = 0.1562, S = 1.061;
absolute structure parameter 0.00(13).
2-(2-Naphthylamino)-1-phenylethanol (2n)
[a]D25 +18.3 (c 0.78, CHCl3); yield: 81%; 59% ee [HPLC; Chiralcel
OD-H, i-PrOH–hexane (10:90); tR (major) = 24.38 min, tR
(minor) = 25.69 min].
The crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC
696223; copies can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033 or email: deposit@ccdc.cam.ac. uk].
IR (KBr): 3526, 3425, 3052, 2828, 1580 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.69–7.59 (m, 3 H), 7.45–7.33 (m,
6 H), 7.25–7.20 (m, 2 H), 6.94 (dd, J = 13.8, 2.8 Hz, 2 H), 5.02 (dd,
J = 8.60, 3.9 Hz, 1 H), 3.53 (dd, J = 13.0, 3.90 Hz, 1 H), 3.41 (dd,
J = 13.0, 8.62 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 145.6, 142.3, 135.3, 129.4, 128.9,
128.3, 128.1, 128.0, 126.7, 126.4, 126.2, 122.7, 118.6, 105.8, 72.6,
52.0.
2-[(4-Chlorophenyl)amino]-1-(2,4-dichlorophenyl)ethanol (2j)
[a]D25 –15.3 (c 1.02, abs. EtOH); yield: 89%; 63% ee [HPLC;
Chiralpak AD-H, i-PrOH–hexane (5:95); tR (major) = 26.10 min,
tR (minor) = 27.20 min].
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York

PAPER
Optically Active b-Amino Alcohols
817
HRMS (EI): m/z calcd for [C18H17NO]+: 263.1312; found:
263.1310.
(3) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562.
(4) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738.
(5) Püntener, K.; Schiwink, L.; Knochel, P. Tetrahedron Lett.
1996, 37, 8165.
(6) Palmer, M. J.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997,
62, 5226.
N-(2-Hydroxy-2-phenylethyl)-4-methylbenzenesulfonamide
(4a)
[a]D25 –45.6 (c 1.17, CHCl3); yield: 90%; 100% ee [HPLC; Chiral-
cel OD-H, i-PrOH–hexane (10:90); tR (minor) = 16.32 min, tR
(major) = 23.37 min].
(7) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J. Org. Biomol.
Chem. 2004, 2, 1818.
(8) Everaere, K.; Carpentier, J. F.; Mortreux, A.; Bulliard, M.
Tetrahedron: Asymmetry 1999, 10, 4083.
(9) Everaere, K.; Carpentier, J. F.; Mortreux, A.; Bulliard, M.
Tetrahedron: Asymmetry 1998, 9, 2971.
(10) Everaere, K.; Franceschini, N.; Mortreuxa, A.; Carpentier, J.
F. Tetrahedron Lett. 2002, 43, 2569.
(11) Šterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron Lett. 2004,
45, 535.
(12) Yamada, I.; Noyori, R. Org. Lett. 2000, 2, 3425.
(13) Koike, T.; Murata, K.; Ikariya, T. Org. Lett. 2000, 2, 3833.
(14) Cossy, J.; Eustache, F.; Dalko, P. I. Tetrahedron Lett. 2001,
42, 5005.
(15) Hannedouche, J.; Kenny, J. A.; Walsarove, T.; Wills, M.
Synlett 2002, 263.
1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 8.0 Hz, 1 H), 7.43–
7.28 (m, 8 H), 5.15 (dd, J = 10.0, 2.0 Hz, 1 H), 3.56 (s, 1 H), 3.31
(dd, J = 14.4, 10.4 Hz, 1 H), 3.18 (dd, J = 14.4, 3.0 Hz, 1 H), 2.39
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 144.1, 141.3, 134.9, 130.1, 128.8,
128.2, 127.7, 126.3, 72.5, 58.2, 21.8.
N-tert-butyl-2-(2-fluorophenyl)-2-hydroxyacetamide (4b)
[a]D25 +20.0 (c 0.05, abs. EtOH); yield: 88%; 25% ee [HPLC;
Chiralcel OD-H, i-PrOH–hexane (10:90); tR (minor) = 5.07 min, tR
(major) = 5.82 min].
1H NMR (400 MHz, CDCl3): d = 7.42 (dt, J = 7.6, 2.8 Hz, 1 H),
7.33–7.27 (m, 1 H), 7.16 (t, J = 7.6, 1 H), 7.07 (ddd, J = 10.6, 8.3,
0.8 Hz, 1 H), 5.88 (s, 1 H), 5.22 (d, J = 4.8 Hz, 1 H), 3.96 (d, J = 4.8,
1 H), 1.32 (s, 9 H).
(16) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000,
13C NMR (100 MHz, CDCl3): d = 170.8, 160.5 (d, JC,F = 240 Hz),
130.1 (d, JC,F = 7.5 Hz), 128.5, 127.6 (d, JC,F = 15.0 Hz), 124.9,
115.7 (d, JC,F = 22.5 Hz), 67.9, 51.9, 28.8.
41, 9277.
(17) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002,
67, 1712.
(18) Ursini, C. V.; Mazzeo, F.; Rodrigues, J. A. R. Tetrahedron:
Asymmetry 2006, 17, 3335.
(19) Kawamoto, A.; Wills, M. Tetrahedron: Asymmetry 2000,
11, 3257.
1-Phenyl-2-(phenylsulfonyl)ethanol (4d)
[a]D25 –35.9 (c 1.0, acetone); yield: 93%; 100% ee [HPLC; Chiral-
cel OD-H, i-PrOH–hexane (10:90); tR (major) = 28.1 min].
1H NMR (400 MHz, CDCl3): d = 7.97 (d, J = 7.2 Hz, 2 H), 7.71 (t,
J = 7.2 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 2 H), 7.35–7.27 (m, 5 H), 5.29
(d, J = 10.0 Hz, 1 H), 3.69 (s, 1 H), 3.51 (dd, J = 14.0, 10.0 Hz, 1
H), 3.35 (dd, J = 14.0, 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 140.8, 139.3, 134.4, 129.7, 129.0,
128.6, 128.2, 125.9, 68.7, 64.1.
(20) Kosmalski, T.; Wojtczak, A.; Zaidlewicz, M. Tetrahedron:
Asymmetry 2009, 20, 1138.
(21) Pal, M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987.
(22) Ganesh, T.; Kumar, C.; Krupadanam, G. L. D. Synth.
Commun. 1999, 29, 2069.
(23) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.;
Horaguchi, T. Chem. Commun. 2004, 470.
(24) Barata, L. E. S.; Santos, L. S.; Ferri, P. H.; Phillipson, J. D.;
Paine, A.; Croft, S. L. Phytochemistry 2000, 55, 589.
(25) Shindo, M.; Yoshimura, Y.; Hayashi, M.; Soejima, H.;
Yoshikawa, T.; Matsumoto, K.; Shishido, K. Org. Lett 2007,
9, 1963.
Acknowledgment
We are grateful to the Natural Science Foundation of Higher Edu-
cation Institutions of Jiangsu Province, China for a grant (No.
09KJB150012), and to the Special Presidential Foundation of
Xuzhou Medical College (09KJZ19) for financial support.
(26) Penso, M.; Lupi, V.; Albanese, D.; Foschi, F.; Landini, D.;
Tagliabue, A. Synlett 2008, 2451.
(27) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.
(28) Node, M.; Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, K.;
Kunishige, H. Tetrahedron 1997, 53, 12883.
(29) Radosevich, A.; Musich, C.; Toste, F. J. Am. Chem. Soc.
2005, 127, 1090.
(30) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;
Ikariya, T. Org. Lett 1999, 1, 1119.
(31) Bertus, P.; Phansavath, P.; Ratovelomanana-Vidal, V.;
Touati, A. R. Tetrahedron Lett. 1999, 40, 3175.
(32) Wang, F.; Liu, H.; Cun, L. F.; Zhu, J.; Deng, J. G.; Jiang, Y.
Z. J. Org. Chem. 2005, 70, 9424.
References
(1) For selective examples, see: (a) Blaer, H. U.; Malan, C.;
Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth.
Catal. 2003, 345, 101. (b) Noyori, R.; Hashiguchi, S. Acc.
Chem. Res. 1997, 30, 97. (c) Palmer, M. J.; Wills, M.
Tetrahedron: Asymmetry 1999, 10, 2045. (d) Fan, Q. H.; Li,
Y. M.; Chan, A. S. C. Chem. Rev. 2002, 102, 3385.
(e) Everaere, K.; Mortreux, A.; Carpentier, J. F. Adv. Synth.
Catal. 2003, 345, 67.
(2) Fujii, A.; Hashiguchi, S.; Uemastsu, N.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 2521.
(33) Mitsunobo, O. Synthesis 1981, 1.
Synthesis 2010, No. 5, 811–817 © Thieme Stuttgart · New York