Ruthenium-catalyzed enantioselective synthesis of β-amino alcohols from 1,2-diols by "borrowing hydrogen"

Article abstract of DOI:10.1002/ejoc.201300692

Enantioselective synthesis of β-amino alcohols from 1,2-diols by the use of [RuCl₂(p-cymene)]₂/(S,R)-JOSIPHOS catalysis was developed. Several 1,2-diols were treated with secondary amines to afford the corresponding optically active

Full text of DOI:10.1002/ejoc.201300692

FULL PAPER
DOI: 10.1002/ejoc.201300692
Ruthenium-Catalyzed Enantioselective Synthesis of β-Amino Alcohols from
1,2-Diols by “Borrowing Hydrogen”
Anggi Eka Putra,[a] Yohei Oe,*[a] and Tetsuo Ohta[a]
Keywords: Enantioselectivity / Amino alcohols / Diols / Ruthenium / Asymmetric catalysis
Enantioselective synthesis of β-amino alcohols from 1,2-diols
by the use of [RuCl2(p-cymene)]2/(S,R)-JOSIPHOS catalysis
was developed. Several 1,2-diols were treated with second-
ary amines to afford the corresponding optically active β-
amino alcohols in up to 99% yield with 77%ee.
1,2-diols are used as substrates are limited.[15] One success-
ful application of the “borrowing hydrogen” methodology
for β-amino alcohol preparation from 1,2-diols was re-
ported by Beller and co-workers, who used an [Ru3-
(CO)12] catalyst.[15a] To the best of our knowledge, however,
no application of this methodology for the preparation of
optically active amino alcohols has been reported in spite
of the importance of asymmetric synthesis of β-amino
alcohols. Here we report the first enantioselective reaction
of 1,2-diols with amines that provides an optically active β-
amino alcohol (Scheme 1).
Introduction
Since the last century, when asymmetric synthetic chem-
istry began being used, optically active β-amino alcohols
have played important roles in organic chemistry and re-
lated research fields.[1] This class of organic compounds has
been widely used as chiral ligands or chiral auxiliaries,[2]
organocatalysts,[3] and versatile intermediates in the synthe-
sis of various medicines[4] and unnatural amino acids.[5] In
addition, various biologically active natural compounds
contain β-amino alcohols.[6] Consequently, numerous meth-
ods for the preparation of optically active β-amino alcohols
have been reported,[7] such as asymmetric reduction of
amino ketones,[8] ring-opening of enantioenriched epox-
ides,[9] and Sharpless asymmetric aminohydroxylation of
alkenes.[10]
An environmentally friendly method, the so-called “bor-
rowing hydrogen” methodology, has recently received much
attention as a highly atom-efficient synthetic strategy in or-
ganic synthesis.[11] Alcohols are usually converted into reac-
tive haloalkanes and related compounds by treatment with
halogenated reagents before the reaction with nucleo-
philes.[12] Under “borrowing hydrogen” methodology con-
ditions, on the other hand, alcohols are transformed in situ
into aldehydes or ketones, which are more reactive in nucle-
ophilic addition reactions than alcohols. This in situ trans-
formation provides a wide range of ways to deal with
alcohols as alkylation reagents. The only byproduct ex-
pected is water, so the reaction proceeds with high atom
efficiency. Although there are many reports on the use of
ruthenium, iridium, and palladium catalysts in the alkyl-
ation of amines[13] and oxo nitriles,[14] examples in which
Scheme 1. Synthesis of optically active β-amino alcohols described
in this work.
Results and Discussion
The reaction of 2 mol-equiv. of 1-phenyl-1,2-ethanediol
(1a) and morpholine (2a) was initially carried out in the
presence of [RuCl2(p-cymene)]2 and chiral ligand (S)-
BINAP at 120 °C for 24 h. The reaction proceeded success-
fully to give the desired β-amino alcohol 3a in 88% yield
and 12%ee (Table 1, Entry 1). Although the enantio-
selectivity was low, this result encouraged us to investigate
the novel asymmetric reaction further. To enhance the
enantioselectivity, we investigated such reaction conditions
as the catalyst, the balance of starting materials, and the
temperature (Table 1). Increasing the amount of (S)-BINAP
to 1.2 equiv. of ruthenium increased the yield to 95% with
17%ee; further increasing the amount to 1.5 equiv. Ru,
however, resulted in the formation of an almost racemic
product. Addition of an excess amount of 1a slightly in-
creased the ee (Entries 4 and 5). Reducing of temperature
[a] Department of Biological Information, Faculty of Life and
Medical Sciences, Doshsiha University,
Kyotanabe, Kyoto 610-0394, Japan
E-mail: yoe@mail.doshisha.ac.jp
Homepage: http://www.doshisha.ac.jp/english/faculties/
undergraduate/life/information.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300692.
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Enantioselective Synthesis of β-Amino Alcohols
from 120 to 110 °C doubled the ee (32%), but decreased took place when (S)-BINAP was used at 100 °C (Entry 10).
the yield by a factor of four, from 92 to only 23% yield of The Ru/JOSIPHOS catalyst did not work well at 90 °C (En-
3a (Entry 6).
try 12).
Table 1. Optimization of reaction conditions.[a]
Table 2. Ligand and temperature effects.[a]
Entry
Ligand
Temp. [°C] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
(S)-Tol-BINAP
(S)-SEGPHOS
(S)-DM-SEGPHOS
(S)-DTBM-SEGPHOS
(R,S)-IndaBox(Me2)
(S)-MONOPHOS
(S,R)-JOSIPHOS
(–)-DIOP
110
110
110
110
110
110
110
110
110
100
100
90
86
98
99
92
45
23
99
99
0
0
4
1
5
10
25
18
–
–
48
29
Entry Ru/Ligand 1a/2a Temp. [°C] Yield [%][b] ee [%][c]
1
2
3
4
5
6
1:1
2:1
2:1
2:1
3:1
5:1
3:1
120
120
120
120
120
110
88
95
95
92
92
23
12
17
4
21
16
32
1:1.2
1:1.5
1:1.2
1:1.2
1:1.2
none
(S)-BINAP
(S,R)-JOSIPHOS
(S,R)-JOSIPHOS
NR
NR
99
10
11
12
50
[a] Reaction conditions: 1-phenyl-1,2-ethanediol, morpholine
(1 mmol), [RuCl2(p-cymene)]2 (2.5 mol-%), (S)-BINAP, under Ar,
toluene (1 mL), heated for 24 h. [b] Determined by 1H NMR spec-
troscopic analysis. [c] Determined by HPLC analysis.
[a] Reaction conditions: 1-Phenyl-1,2-ethanediol (3 mmol), morph-
oline (1 mmol), [RuCl2(p-cymene)]2 (2.5 mol-%), ligand (6 mol-%),
under Ar, toluene (1 mL), heated for 24 h. [b] Determined by 1H
NMR spectroscopic analysis. [c] Determined by HPLC analysis.
We next focused on the effect of the chiral ligand
(Table 2, Figure 1). When (S)-Tol-BINAP was used, the ra-
With the conditions required to obtain good selectivity
cemic amino alcohol was obtained, although the reaction with Ru/JOSIPHOS catalysis established, we investigated
proceeded with up to 86% yield (Entry 1). Use of the the scope and limitations of the optimized enantioselective
SEGPHOS family of ligands in the reaction delivered high preparation of β-amino alcohols. We started by testing sev-
reactivity (up to 99% yield) but yielded almost racemic eral secondary amines (Table 3). Five- and six-membered
products (Entries 2–4). Employing chiral bis(oxazoline) li- cyclic amines showed good reactivity under the optimized
gand (R,S)-IndaBox(Me2) afforded the desired amino reaction conditions (Entries 1–4), and both piperidine (2b)
alcohol in a yield of 45%, however, with little enantio- and pyrrolidine (2c) reacted with 1-phenyl-1,2-ethandiol
selectivity (Entry 5). Both the catalytic activity and enantio- (1a) to afford the corresponding β-amino alcohols in almost
selectivitywerereducedwhenthephosphoramiditeligand(S)- quantitative yield with good enantioselectivity (62 and
MONOPHOS was used (Entry 6). We then tested other di- 55%ee, respectively). Tetrahydroisoquinoline (2d) afforded
phosphane ligands. (–)-DIOP provided 99% yield of the de- the desired product in 87% isolated yield with 64%ee (En-
sired β-amino alcohol with 18%ee (Entry 8), and (S,R)- try 4). The present reaction was also used to prepare β-
JOSIPHOS provided 99% yield of the desired amino amino alcohol 3e with an acetal protecting group with
alcohol with 25%ee (Entry 7). We investigated temperature 48%ee, although the yield was only 62% (Entry 5). In con-
effects on reactions with (S)-BINAP and (S,R)-JOSIPHOS. trast, acyclic amine, di-n-propylamine (2f), showed low re-
When (S,R)-JOSIPHOS was used, the highest ee value activity and gave the product 3f in only 25% yield as a
(48%) was obtained at 100 °C, and this was obtained with- racemic compound (Entry 6). Aromatic amine 2g did not
out reduction in the chemical yield (Entry 11); no reaction react under the optimized conditions (Entry 7).
Figure 1. Chiral ligands screened for the asymmetric amination of 1,2-diol.
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A. Eka Putra, Y. Oe, T. Ohta
Table 4. Amination of 1,2-diols with morpholine.[a]
FULL PAPER
Table 3. Amination of 1-phenyl-1,2-ethanediol by secondary
amines.[a]
[a] Reaction conditions: 1,2-diol (3 mmol), morpholine (1 mmol),
[RuCl2(p-cymene)]2 (2.5 mol-%), (S,R)-JOSIPHOS (6 mol-%), un-
1
der Ar, toluene (1 mL), 100 °C, 24 h. [b] Determined by H NMR
spectroscopic analysis. [c] Determined by HPLC analysis. [d] Iso-
lated yield.
[a] Reaction conditions: 1-phenyl-1,2-diol (3 mmol), amine
(1 mmol), [RuCl2(p-cymene)]2 (2.5 mol-%), (S,R)-JOSIPHOS
(6 mol-%), toluene (1 mL), 100 °C, 24 h. [b] Determined by 1H
NMR spectroscopic analysis. [c] Determined by HPLC analsysis.
[d] Isolated yield in parentheses.
Several 1,2-diols were also tested under the optimized
reaction conditions (Table 4). First, 1-aryl-1,2-ethanediols
(1b–g) were examined. Use of diol 1c, with a methyl group
at the para position, gave 78% yield of the desired β-amino
alcohol 4c with 59%ee (Entry 2). Substrates with other sub-
stituents, such as a methoxy group, a chlorine atom, or a
trifluoromethyl group, suppressed the reaction (Entries 1, 3,
and 4). Use of 1-(1-naphthyl)-1,2-ethanediol (1f) gave only
55% isolated yield with 22%ee (Entry 5). On the other
hand, we were pleased to find that 1-(2-naphthyl)-1,2-
ethanediol (1g) afforded the highest ee (77%ee, 76% yield;
Entry 6). We also examined aliphatic 1,2-diols and found
that the reaction of acyclic aliphatic diol 1,2-hexanediol
(1h) and morpholine (2a) gave β-amino alcohol 4h in 80%
yield with 38%ee (Entry 7).
Scheme 2. Reaction of deuterium-labeled 1-phenyl-1,2-ethanediol
(1a-D) with morpholine (2a).
We examined several possible reaction mechanisms.
Checking the enantiopurity of recovered diol 1a by chiral
HPLC revealed that 1a was recovered as a racemic product. alcohol 3a.
Scheme 3. Asymmetric reduction of amino ketone 5a to β-amino
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Enantioselective Synthesis of β-Amino Alcohols
Scheme 4. Possible pathways from diols 1 to amino ketones 5.
Given this, we hypothesized that the reaction did not pro-
To verify the feasibility of Path A, we first investigated
ceed through kinetic resolution of the racemic diol by the the change of the ee value for amino alcohol 3a under the
chiral ruthenium complex and that the secondary alcohols optimized reaction conditions. When racemic 3a, prepared
in diols participate in a “borrowing hydrogen” reaction. To independently, was exposed to the reaction conditions, the
test this hypothesis, we used deuterium-labeled diol 1a-D ee value of recovered 3a was less than 11% (Scheme 5).
(Scheme 2). Diol 1a-D was treated with morpholine 2a in
the presence of Ru/(S,R)-JOSIPHOS catalyst at 100 °C to
afford the desired amino alcohol 3a-D in 99% yield. Deu-
terium atoms were found at the C-1 and C-2 positions and
even at the α-position of the morpholine ring. This scram-
bling of deuterium atoms revealed that the hydrogen trans-
fer reaction from 1a to the ruthenium complex occurred to
form hydroxy ketone 6a, oxo aldehyde 7a, and/or amino
Scheme 5. Treatment of rac-3a with 1a and chiral ruthenium cataly-
sis.
ketone 5a (see Scheme 4 below). To determine which inter-
In addition, almost optically pure amino alcohol 3a
mediates were mainly formed under the present reaction (Ͼ95%ee), which was prepared by an authentic pro-
conditions, a GC–MS analysis of the crude reaction was cedure,[8] was slightly racemized under the optimized reac-
performed at an early stage (5 h). Oxo aldehyde 7a and tion conditions to afford 3a with an ee of 74% (Scheme 6).
hydroxy ketone 6a, accompanied by amino ketone 5a and These results suggested that an enantioselective redox reac-
amino alcohol 3a, were detected, whereas hydroxy aldehyde tion took place at the benzylic position under the optimized
8a (a possible oxidized product) was not observed. This re- reaction conditions, although the reaction rate is considered
sult suggested that the double oxidation of diols to oxo al- to be relatively slow. We therefore thought that the oxi-
dehydes occurred under our catalytic conditions and that dation of amino alcohol 3 (Path A) is not the main route for
the amino ketone is an important intermediate in the pro- the formation of amino ketone 5. Although the secondary
cess leading to enantioenriched amino alcohols. We there- alcohol in aliphatic diols is expected to be oxidized slower
fore next examined the reaction of amino ketone 5a by than the primary alcohol, this trend is also inconsistent
using starting diol 1a and the present chiral ruthenium ca- with the feasibility of Path A. In addition, several selective
talysis (Scheme 3). Thus, amino ketone 5a was treated with oxidations of secondary alcohols in 1,2-diol[16] and isomer-
2 equiv. of 1-phenyl-1,2-ethanediol (1a) under the opti- ization of hydroxy aldehyde to hydroxy ketone[17] have been
mized reaction conditions to obtain the corresponding reported, supporting the possibility that double oxidation
amino alcohol 3a in 29% yield with 73%ee. The reaction could have taken place on the aliphatic diols under the pres-
using 5 equiv. 1a also afforded 3a in 69% yield with 73%ee. ent reaction conditions.
The formation of amino alcohol 3a with reasonable optical
Given the results of these mechanistic studies, we pro-
purity from 1a is consistent with amino ketone 5a being a pose the following main reaction pathway (Scheme 7). The
key intermediate in the enantiodetermining step. Two pos- starting diol is converted into oxo aldehyde I by ruthenium-
sible routes to form amino ketone intermediate 5a are de- catalyzed double dehydrogenation. Oxo aldehyde I reacts
picted in (Scheme 4): (1) oxidation of product amino with the amine to afford iminium ion intermediate II, which
alcohol 3a (Path A); (2) reaction of morpholine after the is converted into amino ketone III. Amino ketone III is
double oxidation of the starting diol (Path B), which is sup- finally converted into the desired amino alcohol IV by a
ported by GC–MS analysis of the reaction mixture at an second transfer hydrogenation reaction. Enantioselection
early stage of the reaction.
occurs in the final step.
Scheme 6. Racemization of enantioenriched β-amino alcohol 3a.
Eur. J. Org. Chem. 2013, 6146–6151
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A. Eka Putra, Y. Oe, T. Ohta
FULL PAPER
1-Phenyl-2-(piperidin-1-yl)ethanol (3b): White solid; m.p. 65–66 °C;
62%ee by HPLC [Daicel Chiralcel OJ-H; λ = 225 nm; EtOH/hex-
ane = 3:97; flow = 0.15 mL/min; tR = 43.20 (minor), 46.40 (major)
1
min]. H NMR: δ = 1.47–1.49 (m, 2 H), 1.61–1.64 (m, 4 H), 2.34–
2.51 (m, 4 H), 2.69–2.71 (m, 2 H), 4.73 (dd, J = 10.5, 3.6 Hz, 1 H),
7.24–7.37 (m, 5 H) ppm. 13C NMR: δ = 24.2, 26.1, 54.4, 66.9,
68.60, 125.8, 127.4, 128.2, 142.4 ppm. FAB-MS: m/z = 206 [M +
H+].
1-Phenyl-2-(pyrrolidin-1-yl)ethanol (3c): White solid; m.p. 44–48 °C;
53%ee by HPLC [Daicel Chiralcel OJ-H; λ = 225 nm; iPrOH/hex-
ane = 10:90; flow = 0.5 mL/min; tR = 15.82 (minor), 16.99 (major)
Scheme 7. Proposed reaction mechanism of enantioselective amin-
ation of 1,2-diols.
1
min]. H NMR: δ = 1.78–1.82 (m, 4 H), 2.45–2.57 (m, 3 H), 2.72–
2.82 (m, 3 H), 3.81 (br., 1 H), 4.70 (dd, J = 10.6, 3.3 Hz, 1 H),
7.24–7.41 (m, 5 H) ppm. 13C NMR: δ = 23.6, 53.8, 64.1, 70.7,
125.8, 127.3, 128.2, 142.5 ppm.
Conclusions
We have achieved the first enantioselective preparation
of β-amino alcohols from 1,2-diols by application of the
ruthenium-catalyzed “borrowing hydrogen” methodology.
1-Phenyl-2-(tetrahydroisoquinolin-2-yl)ethanol (3d): Light-yellow
oil; 28%ee by HPLC [Daicel Chiralcel OD-H; λ = 225 nm; iPrOH/
hexane = 20:80; flow = 0.5 mL/min; tR = 14.07 (minor), 15.19
1
Our mechanistic studies suggest that the reaction proceeds (major) min]. H NMR: δ = 2.65–2.78 (m, 3 H), 2.94–3.04 (m, 3
H), 3.68 (d, J = 15 Hz, 1 H), 3.94 (d, J = 14.7 Hz, 1 H), 4.86 (dd,
J = 9.8, 4.2 Hz, 1 H), 7.04–7.43 (m, 9 H) ppm. 13C NMR: δ =
29.2, 50.9, 55.8, 66.0, 69.0, 125.7, 125.8, 126.2, 126.4, 127.4, 128.3,
128.6 ppm. FAB-MS: m/z = 254 [M + H+].
mainly through amino ketone intermediates that are con-
verted into the corresponding optically active β-amino
alcohols. Investigations aimed at improving the enantio-
selectivity and applying the present method for the synthe-
sis of bioactive compounds are in progress in our labora-
tory.
2-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-1-phenylethanol (3e): White
solid; m.p. 104–107 °C; 48%ee by HPLC [Daicel Chiralcel OJ-H;
λ = 225 nm; EtOH/hexane = 96:4; flow = 0.7 mL/min; tR = 22.38
(minor), 23.43 (major) min]. 1H NMR: δ = 1.75–1.80 (m, 4 H),
2.42–2.53 (m, 4 H), 2.82–2.84 (m, 2 H), 3.95 (s, 4 H), 4.70 (dd, J
= 10.3, 3.9 Hz, 1 H), 7.24–7.37 (m, 5 H) ppm. 13C NMR: δ = 34.9,
51.3, 64.3, 65.7, 68.9, 107.0, 125.8, 127.5, 128.3, 142.1 ppm. FAB-
MS: m/z = 264 [M + H+].
Experimental Section
General Information: NMR spectra were recorded with Varian
Mercury Plus 300-4N spectrometers by using TMS (δ = 0 ppm) as
an internal standard for 1H NMR and CDCl3 (δ = 77 ppm) for 13
C
2-(Dipropylamino)-1-phenylethanol (3f): Yellow oil; racemic by
HPLC (Daicell Chiralcell OJ-H; λ = 225 nm; EtOH/hexane = 2:98;
NMR spectroscopy. Enantiomeric excess (ee) values were measured
with a Hitachi L-7100 HPLC with a chiral column (Daicel Chi-
ralcel OD-H or OJ-H) under the conditions described below. All
reactions were carried out under argon in a sealed tube. Reagents
obtained from commercial sources were used without further puri-
fication. Toluene was dried by a standard method and distilled un-
der argon. Molecular sieves (4 Å) were activated by heating at
350 °C for 2 h before use.
1
flow = 0.4 mL/min; tR = 12.26, 12.71 min). H NMR: δ = 0.92 (t,
J = 7.5 Hz, 6 H), 1.46–1.56 (m, 4 H), 2.40–2.53 (m, 4 H), 2.56–
2.63 (m, 2 H), 4.64 (dd, J = 10.5, 3.6 Hz, 1 H), 7.26–7.39 (m, 4 H)
ppm. 13C NMR: δ = 11.9, 20.4, 56.0, 63.2, 69.3, 125.7, 127.2, 128.2,
142.4 ppm. FAB-MS: m/z = 222 [M + H+].
1-(4-Methoxyphenyl)-2-(morpholin-4-yl)ethanol (4b): White solid;
m.p. 76–77 °C; 28%ee by HPLC [Daicel Chiralcel OJ-H; λ =
225 nm; EtOH/hexane = 20:80; flow = 0.5 mL/min; tR = 28.03
(minor), 31.74 (major) min]. 1H NMR: δ = 2.41–2.51 (m, 4 H),
2.70–2.77 (m, 2 H), 3.69–3.77 (m, 4 H), 3.79 (s, 3 H), 4.70 (dd, J
= 8.85, 4.8 Hz, 1 H), 6.85–6.90 (m, 2 H), 7.27–7.21 (m, 2 H) ppm.
13C NMR: δ = 53.5, 55.3, 66.7, 67.0, 68.2, 113.8, 127.1, 133.8,
159.1 ppm. FAB-MS (m/z): 238 [M + H+].
General Procedure for the Synthesis of β-Amino Alcohols from 1,2-
Diols: To an argon-purged reaction tube containing 4 Å molecular
sieves (0.62 g) was added the respective 1,2-diol (3 mmol), amine
(1 mmol), [RuCl2(p-cymene)Cl2]2 (0.0154 g, 0.025 mmol), (S,R)-
JOSIPHOS (0.0356 g, 0.060 mmol), and anhydrous toluene (1 mL).
The mixture was degassed by using three freeze-pump-thaw cycles
and then purged with argon. The reaction mixture was stirred at
100 °C for 24 h, then filtered, and the filtrate was concentrated un-
der reduced pressure. The inorganic wastes and excess amount of
the starting diol were removed by Kugelrohr distillation. The crude
product was purified by column chromatography or extracted by
using an acidic aqueous solution to give the corresponding β-amino
alcohol.
1-(4-Methylphenyl)-2-(morpholin-4-yl)ethanol (4c): White solid;
m.p. 75–76 °C; 59%ee by HPLC [Daicel Chiralcel OJ-H; λ =
225 nm; iPrOH/hexane = 10:90; flow = 0.5 mL/min; tR = 45.68
(minor), 49.66 (major) min]. 1H NMR: δ = 2.33 (s, 3 H), 2.41–2.50
(m, 4 H), 2.71–2.73 (m, 2 H), 3.72–3.76 (m, 4 H), 4.72 (dd, J =
9.45, 4.2 Hz, 1 H), 7.15 (d, J = 7.8 Hz, 2 H), 7.26 (d, J = 5.1 Hz,
2 H) ppm. 13C NMR: δ = 21.1, 53.4, 66.7, 67.0, 68.3, 125.8, 129.0,
137.2, 138.8 ppm. FAB-MS: m/z = 222 [M + H+].
2-Morpholino-1-phenylethanol (3a): White solid; m.p. 78–79 °C;
48%ee by HPLC [Daicel Chiralcel OD-H; λ = 225 nm; iPrOH/
1-(4-Chlorophenyl)-2-(morpholin-4-yl)ethanol (4d): White solid; m.p.
hexane = 20:80; flow = 0.5 mL/min; tR = 15.86 (minor), 17.22 69–70 °C; 29%ee by HPLC [Daicel Chiralcel OJ-H; λ = 225 nm;
1
(major) min]. H NMR: δ = 2.42–2.57 (m, 4 H), 2.73–2.76 (m, 2
H), 3.73–3.81 (m, 4 H), 4.75 (dd, J = 10.2, 3.9 Hz, 1 H), 7.24–7.35
(m, 5 H) ppm. 13C NMR: δ = 53.4, 66.6, 67.0, 68.5, 125.8, 127.5,
128.3, 141.8 ppm. GC-MS: m/z = 207. FAB-MS: m/z = 208 [M +
H+].
iPrOH/hexane = 20:80; flow = 0.5 mL/min; tR = 22.82 (minor),
26.80 (major) min]. 1H NMR: δ = 2.41–2.50 (m, 4 H), 2.70–2.77
(m, 2 H), 3.72–3.77 (m, 5 H), 4.70 (dd, J = 10.5, 3.6 Hz, 2 H), 7.31
(m, 4 H) ppm. 13C NMR: δ = 53.4, 66.5, 67.0, 67.9, 127.2, 128.5,
133.2, 140.3 ppm. FAB-MS: m/z = 242 [M + H+].
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Enantioselective Synthesis of β-Amino Alcohols
[6] For examples, see: a) S. C. Bergmeie, D. M. Stanchina, J. Org.
Chem. 1999, 64, 2852–2859; b) A.-M. C. Carroll, D. J. Kavan-
agh, F. P. McGovern, J. W. Reilly, J. J. Walsh, J. Chem. Educ.
2012, 89, 1578–1581; c) S. Maehara, P. Simanjuntak, C. Kita-
mura, K. Ohashi, H. Shibuya, Chem. Pharm. Bull. 2012, 60,
1301–1304.
2-Morpholino-1-(1-naphthyl)ethanol (4f): White viscous oil; 22%ee
by HPLC [Daicel Chiralcel OJ-H; λ: 225 nm; EtOH/hexane =
10:90; flow = 0.5 mL/min; tR = 28.51 (minor), 30.22 (major) min].
1H NMR: δ = 2.50–2.63 (m, 3 H), 2.81–2.86 (m, 3 H), 3.75–3.83
(m, 4 H), 5.60 (dd, J = 10.5, 3.0 Hz, 1 H), 7.47–7.53 (m, 3 H), 7.78
(d, J = 7.8 Hz, 2 H), 7.87 (d, J = 18.3 Hz, 1 H), 8.0 (d, J = 10.2 Hz,
1 H) ppm. 13C NMR: δ = 53.6, 65.6, 65.7, 67.1, 122.5, 123.1, 123.4,
125.7, 126.0, 127.9, 129.0, 130.4, 133.7, 137.2 ppm. FAB-MS: m/z
= 258 [M + H+].
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2-Morpholino-1-(2-naphthyl)ethanol (4g): White solid; m.p. 92–
100 °C; 77%ee by HPLC [Daicel Chiralcel OJ-H; λ = 225 nm;
iPrOH/hexane = 20:80; flow = 0.5 mL/min; tR = 38.70 (minor),
44.63 (major) min]. 1H NMR: δ = 2.47–2.65 (m, 4 H), 2.75–2.79
(m, 2 H), 3.09–3.82 (m, 5 H), 4.92 (dd, J = 10.05, 3.6 Hz, 1 H),
7.45 (dd, J = 9.3, 6.6 Hz, 3 H), 7.80–7.84 (m, 4 H) ppm. 13C NMR:
δ = 53.51, 66.56, 67.03, 68.65, 123.76, 124.52, 125.64, 125.97,
127.56, 127.76, 128.01, 132.88, 133.20, 139.16 ppm. FAB-MS: m/z
= 258 [M + H+].
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1-Morpholino-2-hexanol (4h): Colorless oil; 38%ee by HPLC
[Daicel Chiralcel OD-H; λ = 225 nm; iPrOH/hexane = 10:90; flow
1
= 1 mL/min; tR = 10.11 (minor), 10.63 (major) min]. H NMR: δ
= 0.84 (t, J = 6.6 Hz, 3 H), 1.22–1.40 (m, 6 H), 2.15–2.35 (m, 4
H), 2.55–2.57 (m, 2 H), 2.60 (br., 1 H), 3.62–3.69 (m, 5 H) ppm.
13C NMR: δ = 14.0, 22.7, 27.7, 34.4, 53.5, 64.7, 65.8, 66.9 ppm.
FAB-MS: m/z = 188 [M + H+].
Supporting Information (see footnote on the first page of this arti-
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1
cle): Copies of H and 13C NMR spectra of the amino alcohols.
Acknowledgments
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A. E. P. gratefully thanks the Yoshida Scholarship Foundation for
awarding a doctoral scholarship. We also thank Takasago Chemical
for SEGPHOS ligands support.
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Received: May 11, 2013
Published Online: July 31, 2013
Eur. J. Org. Chem. 2013, 6146–6151
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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