Synthesis of N,N-dimethyl-2-amino-1,2-dicyclohexylethanol and its application in the enantioselective conjugate addition of diethylzinc to enones: A convenient upgrade of the chiral ligand via hydrogenation

Article abstract of DOI:10.1016/S0957-4166(01)00406-2

The effectiveness of N,N-dimethyl-2-amino-1,2-diphenylethanol as a chiral ligand was significantly improved via simple hydrogenation of the phenyl rings. Both the catalytic activity and the enantioselectivity of the resulting new ligand in the asymmetric

Full text of DOI:10.1016/S0957-4166(01)00406-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2301–2304
Synthesis of N,N-dimethyl-2-amino-1,2-dicyclohexylethanol and
its application in the enantioselective conjugate addition of
diethylzinc to enones: a convenient upgrade of the chiral ligand
via hydrogenation
Pui-Erh Tong, Pei Li and Albert S. C. Chan*
Open Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 18 July 2001; accepted 11 September 2001
Abstract—The effectiveness of N,N-dimethyl-2-amino-1,2-diphenylethanol as a chiral ligand was significantly improved via simple
hydrogenation of the phenyl rings. Both the catalytic activity and the enantioselectivity of the resulting new ligand in the
asymmetric conjugate addition of diethylzinc to enones were found to be superior to the original phenyl analog. © 2001 Published
by Elsevier Science Ltd.
1. Introduction
relatively easy, expanding the scope of these findings
may offer a convenient method for upgrading relevant
ligands containing phenyl rings on the chiral backbone.
Herein, we wish to report the synthesis of (1R,2S)-N,N-
dimethyl-2-amino-1,2-dicyclohexylethanol 4 from its
phenyl counterpart, (1R,2S)-N,N-dimethyl-2-amino-
1,2-diphenylethanol 2 via simple hydrogenation. The
significant improvement of rate and enantioselectivity
of the catalyst containing the new ligand as compared
to its phenyl analog is reported.
The asymmetric conjugate addition of organometallic
reagents to prochiral enones is a convenient method for
the preparation of optically active b-substituted ketones
which are synthetically useful.1 Traditionally, the asym-
metric conjugate addition required a stoichiometric
amount of chiral auxiliaries.2 The first breakthrough,
using sub-stoichiometric amounts of chiral auxiliary
was achieved by Soai et al.3 who studied the catalytic
asymmetric conjugate addition of diethylzinc to enones
with Ni(II)-(1S,2R)-N,N-dibutylnorephedrine (DBNE)
as a chiral ligand. The method was subsequently
modified and higher e.e.s were obtained with moderate
yield.4 Bolm et al.5 reported the use of homochiral
2,2-dipyridyl ligands for this reaction. Reaction
parameters such as the catalyst concentration and the
ratios of Ni(II)(acac)2/ligand/substrate were examined.
Recently, (+)-camphor-derived tridentate amino alcohol
ligands were synthesized by Feringa et al.6 and were
found to give high enantioselectivities in some
reactions.
2. Results and discussion
2.1. Synthesis of (1R,2S)-N,N-dimethyl-2-amino-1,2-
dicyclohexylethanol 4
Chiral 2-amino-1,2-diphenylethanol 1 was a useful lig-
and which effectively catalyzed asymmetric borane-
reduction8 and asymmetric transfer hydrogenation9
with excellent e.e.s. Its N,N-dimethylated derivative 2
was also found to catalyze the asymmetric addition of
diethylzinc to benzaldehyde with very high e.e.10 To the
best of our knowledge, the asymmetric conjugate addi-
tion of diethylzinc to enones using homochiral ligand 2
as well as its cyclohexyl analog 4 has not been reported.
Several reports pointed out that chiral ligands contain-
ing cyclohexyl groups are superior to their phenyl
analogs.7 Since the hydrogenation of phenyl rings is
(1R,2S)-N,N-Dimethyl-2-amino-1,2-diphenylethanol
2
was prepared from (1R,2S)-2-amino-1,2-diphenyl-
ethanol 1 in 74% yield by refluxing with formic
acid and formaldehyde for 24 h.11 The cyclohexyl
* Corresponding author. E-mail: bcachan@polyu.edu.hk
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00406-2

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P.-E. Tong et al. / Tetrahedron: Asymmetry 12 (2001) 2301–2304
2+Ni(II)(acac)2+2,2%-dipyridylM“eCNcatalyst A
Table 1. Solvent effects on the conjugate addition of
diethylzinc to chalcone 5 catalyzed by catalyst B
80°C
4+Ni(II)(acac)2+2,2%-dipyridylM“eCNcatalyst B
80°C
Solvent effects in the conjugate addition of diethylzinc
to chalcone 5 using catalyst B were examined and the
results are listed in Table 1.
It is clear from Table 1 that faster rate of reaction and
higher e.e. were achieved in MeCN than in other com-
mon solvents such as CH2Cl2 and toluene for the
alkylation of chalcone 5 to (S)-1,3-diphenylpentane-1-
one 6. When THF and diethyl ether were used as
solvents (entries 1 and 2), only trace amounts of 6 were
detected, probably due to the poor solubilities of the
substrate and the catalyst in these solvents.
Entry
Solvent
E.e. (%)
Conversion
(%)
Configuration
1
2
3
4
5
THF
/
/
Trace
Trace
30
21
89
/
/
S
S
S
Diethyl ether
CH2Cl2
Toluene
MeCN
41.8
45.8
82.0
A comparison of catalysts A and B in the asymmetric
conjugate addition of diethylzinc to chalcone 5 in both
toluene and acetonitrile was carried out and the results
are summarized in Table 2.
[5]=0.19 M; the molar ratio of substrate: Et2Zn:Ni(acac)2:ligand
4:2,2%-dipyridyl=1:1.2:0.07:0.17:0.07; reaction time=12 h; reaction
temperature=−30°C.
derivative 4 was synthesized by stirring 1 with platinum-
(II) oxide in the presence of acetic acid under 3
atmospheres of hydrogen pressure at room temperature
for 48 h (88% yield), followed by the reaction with
formic acid and formaldehyde under reflux for 24 h
(83% yield).
It was observed that the enantioselectivity of catalysts B
was substantially higher than that of catalyst A in both
solvent systems. The advantage of using a more steri-
cally-demanding 1,2-dicyclohexyl group in the chiral
backbone of catalyst B was clearly demonstrated in this
reaction. Since MeCN gave the best rate and enantiose-
lectivity, it was chosen as the solvent for the subsequent
study.
2.2. Application of 2 and 4 as chiral ligands in the
nickel-catalyzed conjugate addition of diethylzinc to
enones
The effect of the ligand-to-substrate ratio was also
studied and the results were summarized in Table 3.
Catalysts A and B were prepared via the reactions of
the chiral ligands 2 and 4 with 2,2%-dipyridyl and
Ni(II)(acac)2 in acetonitrile, respectively.
The enantioselectivities of the reactions with both cata-
lysts were found to be relatively insensitive to the
Table 2. Comparison of catalysts A and B on the asymmetric conjugate addition of diethylzinc to chalcone 5
Entry
Catalyst
Solvent
Conversion (%)
E.e. (%)
Configuration
1
2
3
4
A
B
A
B
Toluene
Toluene
MeCN
MeCN
43
21
53
89
1.6
45.8
33.2
82.0
S
S
S
S
[5]=0.19 M; the molar ratio of substrate: Et2Zn:Ni(acac)2:ligands:2,2%-dipyridyl=1:1.2:0.07:0.17:0.07; reaction time=12 h; reaction temperature=
−30°C.

P.-E. Tong et al. / Tetrahedron: Asymmetry 12 (2001) 2301–2304
2303
Table 3. The effect of ligand-to-substrate ratio on the asymmetric conjugate addition of diethylzinc to chalcone 5
Entry
Catalyst
L/S (%)
[5] (M)
E.e. (%)
Conversion (%)
Configuration
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
10
10
17
17
20
20
25
25
0.33
0.33
0.19
0.19
0.16
0.16
0.13
0.13
31.2
80.0
33.2
82.0
38.8
80.7
37.2
80.9
31
42
53
89
69
100
89
100
S
S
S
S
S
S
S
S
The molar ratio of Et2Zn:Ni(acac)2:ligands:2,2%-dipyridyl=7.1:0.41:1:0.41; different L/S ratio was performed by varying the amount of chalcone
5; reaction time=12 h; reaction temperature=−30°C; solvent=MeCN.
concentration of substrate used in this catalytic reaction
(entries 1, 3, 5, 7 and 2, 4, 6, 8). The superiority of
catalyst B over catalyst A was further established by
comparing their effectiveness in the asymmetric conju-
gate addition of diethylzinc to other similar enones as
shown in Table 4.
3. Experimental
Unless specified, commercial reagents were used as
received. All solvents used were dried according to
standard, published methods and were distilled under
N2 atmosphere prior to use.
The results in Table 4 again clearly show that catalyst B
is consistently better than catalyst A both in the rate of
conversion and enantioselectivity for a variety of conju-
gate enone substrates.
3.1. Preparation of (1R,2S)-2-amino-1,2-dicyclohexyl-
ethanol 3
A 50 mL autoclave with a magnetic stirring bar was
charged with (1R,2S)-2-amino-1,2-diphenylethanol 1
(0.2 g, 0.9 mmol), PtO2 (0.02 g, 0.09 mmol) and glacial
acetic acid (10 mL). The mixture was stirred for 48 h at
ambient temperature under 3 atmospheres of H2. After
releasing the hydrogen gas and removing the solid
catalyst by filtration, the mixture was neutralized with
aqueous NaHCO3 solution followed by extraction with
In conclusion, by simply hydrogenating the phenyl
rings of a diphenyl amino alcohol ligand, we are able to
develop an effective catalyst for the asymmetric conju-
gate addition of diethylzinc to enones. Further studies
using this catalyst in other reactions are currently in
progress.
Table 4. Application of catalysts A and B in the asymmetric conjugate addition of diethylzinc to enones

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P.-E. Tong et al. / Tetrahedron: Asymmetry 12 (2001) 2301–2304
ethyl acetate (3×20 mL). The combined extracts were
dried over sodium sulfate and the solvent was removed
by using a rotory evaporator to give 198 mg of crude
product which was purified by crystallization in ethanol
to give crystals of (1R,2S)-3 (185 mg, 88%). Analytical
data for (1R,2S)-3: mp: 144–146°C; +8.0° (c=1.0, etha-
nol); 1H NMR (400 MHz, CDCl3) l: 3.28 (dd, 1H,
J=6.2 and 4.4 Hz); 2.59 (dd, 1H, J=6.1 and 4.3 Hz);
1.79–1.10 (m, 22H). 13C NMR (101 MHz, CDCl3) l:
76.94, 57.87, 39.77, 30.85, 27.45, 27.42, 27.08, 26.97,
26.88, 26.71, 26.53 ppm; MS: 226 M+.
column. The conversion was calibrated against stan-
dard samples with known composition of substrate and
product.
Acknowledgements
We thank the Hong Kong Polytechnic University ASD
and The Hong Kong Research Grants Council for
financial support of this study (research grant number
PolyU 5152/98P).
3.2. Preparation of (1R,2S)-N,N-dimethyl-2-amino-1,2-
dicyclohexylethanol 4
A one neck round bottom flask was charged with
(1R,2S)-2-amino-1,2-dicyclohexylethanol 3 (0.2 g, 0.9
mmol), formic acid (2 mL) and formaldehyde (1 mL of
37% aqueous solution). The mixture was refluxed for 20
h. The solution was cooled to ambient temperature.
Sodium hydroxide (40 mL of 10% aqueous solution)
was added and white solids precipitated. The solids
were filtered and were re-dissolved in ethyl acetate (30
mL). The solution was washed by saturated sodium
chloride solution for three times. The organic phase was
dried with anhydrous magnesium sulfate. The solvent
was removed by rotory evaporation leaving a white
solid of pure (1R,2S)-4. (0.19 g, 83% theoretical yield).
MHz, CDCl3) l: 3.73 (dd, 1H, J=2.5); 2.79–2.54 (s,
7H); 1.95–0.79 (m, 22H) 13C NMR (101 MHz, CDCl3)
l: 73.62, 69.63, 69.46, 42.41, 41.00, 36.61, 32.60, 31.39,
31.03, 27.74, 27.00, 26.77, 26.68, 26.29 ppm; MS: 254
M+.
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