An enantiopure galactose oxidase model: synthesis of chiral amino alcohols through oxidative kinetic resolution catalyzed by a chiral copper complex

Article abstract of DOI:10.1016/j.tetasy.2009.02.013

An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available (R)-BINAM and Cu(OTf)₂, and the enantiopure GO model has been effectively used in situ as an efficient chiral catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through oxidative kinetic resolution.

Full text of DOI:10.1016/j.tetasy.2009.02.013

Tetrahedron: Asymmetry 20 (2009) 497–502
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An enantiopure galactose oxidase model: synthesis of chiral amino
alcohols through oxidative kinetic resolution catalyzed by a chiral copper
complex
*
Sreedevi Mannam, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available (R)-
BINAM and Cu(OTf)2, and the enantiopure GO model has been effectively used in situ as an efficient chiral
catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where
molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and
para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through
oxidative kinetic resolution.
Received 27 January 2009
Accepted 10 February 2009
Available online 18 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
zylic alcohols,6 NKR of racemic amino alcohols that will produce
the corresponding enantiopure amino alcohols is a less explored
The synthesis of chiral amino alcohols is very important in or-
ganic synthesis, since intermediates of this type are major building
blocks in the synthesis of many pharmaceutically important mole-
cules including antihistaminic, anesthetic, diuretic, antidepressive,
antiarrhythmic, antitumoral, and anticholinergic compounds
(Fig. 1).1 Gererally, these chiral amino alcohols can be synthesized
method in the literature. The pioneering works done by Sharpless
using stoichiometric quantities of a chiral titanium tartrate com-
plex through N-oxide formation in the early eighties7 followed
by Nishiyama where he used stoichiometric quantities of a chi-
ral-halogenating agent [(R)-BINAM-NCS] for the NKR of an amino
alcohol8 are the only few reports in the literature. Herein, for the
first time we report the catalytic NKR of racemic amino alcohols
using a chiral copper complex as a bio-mimetic model of galactose
oxidase enzyme.
Galactose oxidase (GO) is a copper-containing fungal enzyme,
which oxidizes alcohols to the corresponding aldehydes with con-
comitant reduction of molecular oxygen.9 Its crystal structure re-
veals a unique mononuclear copper site with two nitrogens
(from histidine imidazole groups) and two oxygens (from tyrosine
groups) as donor atoms, plus an exogenous water or acetate mole-
cule in a distorted square-pyramidal co-ordination.10 GO enzyme
contains chiral copper in its active site, wherein chirality is due
to the histidine and tyrosine residues. This enzyme has so far in-
spired several research groups to design a variety of achiral or race-
mic synthetic analogues.9,11
by reduction of optically active a
-amino acids2 or enantioselective
reduction of the corresponding prochiral amino ketones.3 Kinetic
resolution of amino alcohols through enzyme-catalyzed acylation
or deacylation is also one of the most efficient methods for the syn-
thesis of chiral amino alcohols.4 Non-enzymatic kinetic resolution
(NKR) is an alternative for the enzymatic process, which is consid-
ered to be a challenging issue in organic synthesis.5
COOMe
O
O
*
NH OH
*
N
O
N
OMe
N
*
OMe
N
*
O
Cl
Cl
N -isonicotinoyl derivarive
of 2-aminoalcohol
(rice plant growth regulator)
batracylin
(antitumoural agent)
4,1-benzoxazepine derivative
(squalene synthase inhibitor)
2. Results and discussion
Figure 1. Some of the pharmaceutically important molecules, where chiral amino
alcohols are used as important building blocks.
As a continuation to our copper-catalyzed oxidation chemis-
try,12 very recently, for the first time we have synthesized an enan-
tiopure model of galactose oxidase enzyme from readily available
(R)-BINAM and Cu(OTf)2 in our laboratory, and this enantiopure
GO model has been successfully used as an efficient chiral catalyst
for the first chiral copper-catalyzed oxidative kinetic resolution of
racemic benzoins.13 Further, we wish to extend our investigations
Although various efficient transition metal-based catalysts are
reported in the literature for the NKR of racemic secondary ben-
* Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.013

498
S. Mannam, G. Sekar / Tetrahedron: Asymmetry 20 (2009) 497–502
Table 1
Screening of different chiral ligands and copper salts for the OKR of amino alcohol ( )-1a
Cu salts (5 mol%)
Ligand (10 mol%)
TEMPO (5 mol%)
NH2 OH
NH2
O
NH2 OH
*
toluene, 60 oC,
O2
1
1a
(
)-
1b
Cl
Cl
Cl
Entry
Ligand
Cu salts
Time (h)
Yieldb
% ee of Amino alcoholc
Ketone
Amino alcohol
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl
CuCl2
CuBr
CuI
Cu(OAc)2
24
35
29
33
31
36
29
27
48
29
57
59
58
60
57
65
59
60
61
57
29
29
31
33
32
29
27
31
32
27
71
12
07
05
02
06
05
00
00
06
10
a
Reaction conditions: 10 mol % ligand, 5 mol % Cu salt, 5 mol % TEMPO, 1 mmol amino alcohol, O2 at 60 °C.
Isolated yields.
% Ee was determined by HPLC using Diacel chiral AS-H column.
b
c
Table 2
by employing the enantiopure GO model that is a (R)-BINAM–
Cu(OTf)2 complex as an efficient catalyst for the oxidative kinetic
resolution of racemic amino alcohols to synthesize biologically
important, optically active amino alcohols. It is important to men-
tion that this is the first chiral copper-catalyzed OKR of racemic
amino alcohols, where molecular oxygen is used as sole oxidant.
During our initial optimization studies, we had taken racemic
(2-amino-5-chlorophenyl)(phenyl)methanol 1 as the model sub-
strate for the chiral copper-catalyzed OKR, and the results are sum-
marized in Table 1. Treatment of 1 with the (R)-BINAM–Cu(OTf)2
complex at 60 °C in the presence of TEMPO and molecular oxygen
provided 29% of the recovered alcohol 1b in 24 h with 71% ee,
which encouraged us to continue our optimization with the same
racemic amino alcohol 1. Later, we screened reactions with differ-
ent nitrogen-containing ligands (Fig. 2)14 to improve the enantio-
meric excess of the recovered amino alcohol. Unfortunately, none
of these ligands were successful and provided very poor enantio-
meric excess for the recovered amino alcohol 1b (Table 1).
Effect of different ratios of (R)-BINAM and Cu(OTf)2 on the OKR of ( )-1a
Cu(OTf)2
(R)-BINAM
TEMPO (5 mol%)
NH2 OH
NH2
O
NH2 OH
*
toluene, 60 oC, O2
1a
(
)-1
1b
Cl
Cl
Cl
Entry Cu(OTf)2
(mol %)
(R)-BINAM
(mol %)
Time
(h)
% Yieldb
% ee of Amino
alcoholc
Amino
alcohol
Ketone
1
2
3
5
5
5
5
10
20
48
24
10
29
29
25
55
57
59
33
71
63
a
Reaction conditions: different ratios of Cu salts and ligands, 5 mol % TEMPO,
1 mmol alcohol, O2 (balloon) at 60 °C.
b
Isolated yields.
c
% Ee was determined by HPLC using Diacel chiral AS-H column.
Then we screened different copper salts, which revealed that
Cu(OTf)2 is the best source of copper salt along with (R)-BINAM
(Table 1, entry 1). Later, we employed different ratios of Cu(OTf)2
and (R)-BINAM, where 5 mol % Cu(OTf)2 and 10 mol % of (R)-BI-
NAM (1:2 complex) provided the best result (Table 2, entry 2) over
1:1 and 1:4 Cu-BINAM complex (entry 2 vs entries 1 and 3). This
result clearly shows that an optimized 2:1 ratio of (R)-BINAM
and Cu(OTf)2 is the appropriate combination for effective catalytic
activity, and this ratio corresponds unequivocally exactly to the ra-
tio obtained from our crystal structure of GO model.15 Examination
of various organic solvents showed that toluene was the best
choice of the solvent (Table 3). There was no significant reaction
observed without using either Cu(OTf)2 or (R)-BINAM or both. Sim-
ilarly, there was no reaction without TEMPO. Based on the above
results, we have a strong insight that TEMPO might act as a hydro-
gen acceptor during the catalytic cycle.16
Table 3
Screening of different solvents for the OKR of amino alcohol ( )-1a
Cu salts (5 mol%)
Ligand (10 mol%)
TEMPO (5 mol%)
solvent, 60 oC, O2
NH2 OH
NH2
O
NH2 OH
*
(
)-1
1a
1b
Cl
Cl
% Yieldb
Amino alcohol Ketone
Cl
Entry Solvent
Time (h)
% ee of Amino alcoholc
1
2
3
4
5
6
7
8
Toluene
Xylene
DCM
Benzene 31
THF
DMF
DMSO
CH3NO2
24
28
23
29
27
32
34
29
30
28
32
57
59
60
61
63
62
64
65
71
52
12
23
15
19
12
05
21
14
9
L1: R1 = R2 = H
NR1R2
NR1R2
L2: R1 = H; R2 = Me
L3: R1 = R2 = Me
21
N
N
a
: R1 = H; R2 = Bn
Reaction conditions: 5 mol % Cu(OTf)2, 10 mol % (R)-BINAM, 5 mol % TEMPO,
L4
L5
1 mmol alcohol, O2 (balloon) at 60 °C.
b
Isolated yields.
c
% Ee was determined by HPLC using Diacel chiral AS-H column.
Figure 2. Different chiral ligands screened for the OKR of ( )-1.

S. Mannam, G. Sekar / Tetrahedron: Asymmetry 20 (2009) 497–502
499
Table 4
monitor the effect of temperature in this chiral copper-catalyzed
OKR, and the results are summarized in Table 4. We were surprised
to observe a totally different behavior in the OKR of amino alcohol
( )-1. When the amino alcohol 1 was subjected to OKR at 60 °C, the
recovered amino alcohol 1b was obtained with 71% ee, and the cor-
responding ketone 1a was obtained 59% in 24 h (Table 4, entry 1).
When the temperature was increased to 70 °C, the ee was in-
creased to 75% with 29% and 61% isolated yields of recovered alco-
hol 1b and ketone 1a, respectively (entry 2). Similarly, when the
temperature was raised to 80 °C, the ee was drastically increased
to 92% with 27 and 57% isolated yields of recovered alcohol 1b
and ketone 1a, respectively (entry 3). However, a further increase
in temperature from 80 °C to 90 °C meant that the % ee of 1b
dropped drastically to 37% (entry 4). Similarly, when the reaction
was carried out at room temperature, no oxidation was observed
even after two days (entry 5). The best catalytic conditions for
the oxidative kinetic resolution of 1 after optimization studies
turned out to be 5 mol % Cu(OTf)2/10 mol % (R)-BINAM/5 mol %
TEMPO/O2 at 80 °C.
Effect of temperature on OKR of ( )-1a
Cu(OTf)2 (5 mol%)
NH2 OH
NH2
Cl
O
NH2 OH
*
L1 (10 mol%)
TEMPO (5 mol%)
toluene, O2
1
(
)-
1a
1b
Cl
Cl
Entry Cu(OTf)2
(mol %)
(R)-
Temp Time
Yieldb
% ee of
BINAM
(mol %)
(°C)
Amino
Ketone Amino
alcohol
alcoholc
1
2
3
4
5
5
5
5
5
5
10
10
10
10
10
60
70
80
90
rt
24 h
19 h
11h
6 h
2
days
59
61
57
58
29
29
27
71
75
92
37
00d
25
No reaction
a
Reaction conditions: 10 mol % (R)-BINAM, 5 mol % Cu(OTf)2 5 mol % TEMPO,
1 mmol alcohol, O2 (balloon) at different temperatures.
b
Isolated yields.
c
% Ee was determined by HPLC using Diacel chiral AS-H column.
Reaction was not proceeded beyond 10–15% even after longer hours.
d
Having the optimized condition in hand, we next investigated
the substrate scope of this enantioselective oxidation with several
amino alcohols18, and the results are summarized in Table 5.
Different ortho amino alcohols such as (2-amino-5-chloro-
phenyl)(phenyl)methanol 1, (2-amino-5-chlorophenyl)(2-fluoro-
In general, increasing the temperature of an enantioselective or-
ganic transformation reduces the selectivity.17 So, we proceeded to
Table 5
Oxidative kinetic resolution of different amino alcoholsa
Cu(OTf)2 (5 mol %)
(R)-BINAM (10 mol %)
TEMPO (5 mol %)
OH
*
OH
O
toluene, 80 oC, O2
+
(
)
H2N
H2N
H2N
Entry
1
( )-Amino alcohol
Time (h)
Ketone
Yieldb
57
Amino alcohol
Yieldb
29
% eec
92
Configd
—
NH2 OH
NH2
NH2 OH
O
*
11
18
1b
1a
(
)-1
Cl
Cl
Cl
NH2 OH
F
NH2
F
NH2 OH
F
O
*
2
59
23
91
—
2b
2a
Cl
-2
)
Cl
Cl
(
NH2 OH
NH2
O
NH2 OH
*
3
4
5
24
22
21
57
51
53
25
20
21
87
93
71
(S)
(S)
(S)
(
)-3
3b
3a
NH2 OH
NH2
O
NH2 OH
CH3
CH3
CH3
*
4b
4
(
)-
4a
O
OH
OH
*
H2N
H2N
H2N
5
( )-
5b
5a
OH
OH
O
6
10 days
55
35
00
—
NH2
NH2
NH2
(
)-6
6a
6b
a
Reaction conditions: 10 mol % (R)-BINAM, 5 mol % Cu(OTf)2 5 mol % TEMPO, 1 mmol alcohol, O2 (balloon) at 80 °C.
Isolated yields.
% Ee was determined by HPLC using Diacel columns.
b
c
d
Absolute configuration was determined by comparing the literature values.

500
S. Mannam, G. Sekar / Tetrahedron: Asymmetry 20 (2009) 497–502
phenyl)methanol 2, (2-aminophenyl)(phenyl)methanol 3, and 1-(2-
aminophenyl)ethanol 4 were resolved with enantiomeric excess
varying from 87% to 93% in 11–24 h (Table 5, entries 1–4). para
Amino alcohol such as (4-aminophenyl)(phenyl)methanol 5 was
also resolved with 71% enantiomeric excess, and the isolated
yields of recovered alcohol and ketone were 21% and 53%, respec-
tively (entry 6). In the case of meta amino alcohol (3-aminophe-
4.2. General procedure for the oxidative kinetic resolution of
racemic amino alcohols
To a 10 mL reaction tube equipped with a magnetic stir bar that
was charged with Cu(OTf)2 (9.0 mg, 0.025 mmol) and (R)-BINAM
(14.20 mg, 0.05) was added toluene (5.0 mL). The reaction mixture
was allowed to stir for 5 min at room temperature. Then TEMPO
(3.92 mg, 0.025 mmol) was added to the reaction mixture. To the
resulting reaction mixture amino alcohol ( )-1 (116.9 mg,
0.5 mmol) was added, and the reaction mixture was allowed to stir
at 80 °C until 50–60% completion of the reaction (monitored by
TLC). After that, the reaction mixture was allowed to cool to room
temperature, and the solvent was evaporated by rotary evaporator.
The residue left after evaporation was purified by a silica gel col-
umn chromatography to give corresponding ketone (65.83 mg,
57%) and recovered alcohol 1b (33.79 mg, 29%) whose enantiopu-
rity was measured by HPLC using chiral column. Spectral data of
Product 1a:19 Brownish solid, mp 95–99 °C (lit. 95–98 °C);
Rf = 0.60 (30% ethyl acetate in hexane); IR (neat): 3414, 3308,
nyl)(phenyl)methanol
6 the resolution rate was very slow
(10 days), and the recovered alcohol was racemic with an isolated
yield 35% (entry 6). It can be seen clearly from Table 5 that in case
of ortho amino alcohols the enantiomeric excess of the recovered
amino alcohols is high (entries 1–4), and the enantiomeric excess
decreases when the amino substitution is at the para position (en-
try 5). When the amino group is substituted at the meta position,
the enantiomeric excess is further reduced, and only racemic
alcohols were recovered, and the reaction took very long time to
progress (entry 6). Enantiomeric excess (% ee) of recovered amino
alcohols was determined by HPLC on a chiral stationary phase
(see Section 4 for full details). This copper-catalyzed OKR is very
versatile in that the sole by-product accompanying our oxidation
process is water, making our system more eco-friendly and green
as well.
1609 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.55 (d, J = 7.2 Hz, 2H),
,
7.50–7.32 (m, 4H), 7.19–7.13 (m, 1H), 6.61 (d, J = 8.8 Hz, 1H),
6.00 (br s, 2H); 13C NMR (100 MHz, CDCl3): d 198.1, 149.5, 139.5,
134.3, 133.4, 131.7, 129.3, 128.5, 120.1, 119.0, 118.6; HRMS
(ESI): m/z calcd. for C13H11NOCl [M+H+]: 232.0529; found:
232.0527.
3. Conclusion
Spectral data of recovered amino alcohol 1b:20 Brownish solid,
In conclusion, we have developed an efficient (R)-BINAM–
Cu(OTf)2 complex-catalyzed oxidative kinetic resolution method
for the synthesis of highly important enantiomerically enriched
amino alcohols. To the best of our knowledge, this is the first chiral
copper-catalyzed oxidative kinetic resolution of racemic amino
alcohols, where molecular oxygen is used as the sole oxidant. Un-
der the proposed catalytic conditions, ortho amino alcohols were
resolved with high enatioselectivities when compared to the para
amino alcohols, where the enantioselectivities were moderate.
mp 129–132 °C (lit.20 131–132 °C); Rf = 0.36 (30% ethyl acetate in
hexane);
½
a 2D0
;
ꢂ
¼ ꢀ36:0 (c 1, CHCl3); IR (neat): 3385, 3308,
3206 cmꢀ1
1H NMR (400 MHz, CDCl3): d 7.31–7.22 (m, 5H),
7.02–6.94 (m, 2H) 6.58 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 3.20 (br s,
3H); 13C NMR (100 MHz, CDCl3): d 142.6, 141.2, 129.6, 128.9,
128.8, 128.4, 128.2, 126.8, 123.9, 118.9, 74.4. The enantiomeric ex-
cess (ee) was determined to be 92% by HPLC using Diacel, Chir-
alPAK AS-H column (10% i-PrOH/hexanes, 1 mL/min, 220 nm):
Retention time (minor, 14.142 min), Retention time (major,
11.825 min).
4. Experimental
4.3. Spectroscopic data for the products amino ketones
4.1. General methods
4.3.1. (2-Amino-5-chlorophenyl)(2-fluorophenyl)methanone,
2a21
All oxidation reactions were performed under an oxygen atmo-
sphere using an oxygen balloon. All the solvents used in the exper-
iments were obtained from Merck, and dried by Vogel’s procedure.
Reactions were monitored by TLC plates (Silica Gel 60 F254, ob-
tained from Merck) using an appropriate mixture of ethyl acetate
and hexane. Product purification was done by silica gel (100–200
mesh) column chromatography using hexane and ethyl acetate
mixture as eluent. Cu(OTf)2, CuI, (ꢀ)- sparteine, and TEMPO were
obtained from the Sigma–Aldrich company. CuCl, CuBr, Cu(OAc)2,
and CuCl2ꢁ2H2O were obtained from SRL chemicals, India. (R)-
1,10-Binaphthyl-2,20-diamine (BINAM) ligand was purchased from
GERCHEM chemicals, Hyderabad, India, and some of the ligands
were synthesized using literature procedures. Racemic amino alco-
hols used in Table 5 were prepared from the corresponding amino
ketones by reduction with NaBH4. All the products were character-
ized by 1H and 13C NMR (Bruker 400 MHz), FT-IR (Thermo Nicolet
6700), mass spectra (Q-Tof micro hybrid quadruple time of flight
mass spectrometer), and melting points (Toshniwal melting point
apparatus). 1H NMR spectra were reported relative to Me4Si (d
0.0 ppm) or residual CHCl3 peak (d 7.26 ppm). 13C NMR were re-
ported relative to CDCl3 (d 77.16 ppm). All yields reported in this
publication refer to isolated yields of compounds. Optical rotations
were determined at 589 nm (sodium D line) by using Rudolph,
AUTOPOL IV digital polarimeter. Enantioselectivities were deter-
mined by HPLC using JASCO PU-2080 with Diacel chiral columns
(Chiralpak/Chiralcel AS-H, OD-H, AD-H and OJ columns).
Brownish solid, mp 96–99 °C (lit.26 95–98 °C); Rf = 0.70 (30%
ethyl acetate in hexane); IR (neat): 3439, 3331, 1612 cmꢀ1 1H
;
NMR (400 MHz, CDCl3): d 7.46–7.07 (m. 6H), 6.66 (d, J = 8.8 Hz,
1H), 4.50 (br s, 2H); 13C NMR (100 MHz, CDCl3): d 196.5, 149.8,
139.2, 135.3, 133.3, 130.9, 130.2, 128.6, 126.9, 120.4, 118.8,
118.3; HRMS (ESI): m/z calcd for C13H10NOClF [M+H+]: 250.0435;
found: 250.0431.
4.3.2. (2-Aminophenyl)(phenyl)methanone, 3a22
Brownish solid, mp 104–108 °C (lit. 103–107 °C); Rf = 0.73 (30%
ethyl acetate in hexane); IR (neat): 3431, 3313, 1619 cmꢀ1 1H
;
NMR (400 MHz, CDCl3): d 7.70–7.64 (m, 2H) 7.58–7.45 (m, 4H),
7.35–7.29 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.68–6.60 (m, 1H),
5.97 (br s, 2H); 13C NMR (100 MHz, CDCl3): d 199.2, 150.9, 140.3,
134.7, 134.3, 131.1, 129.2, 128.2, 118.5, 117.2, 115.8; HRMS
(ESI): m/z calcd for C13H12NO [M+H+]: 198.0919; found: 198.0919.
4.3.3. (2-Aminophenyl)ethanone, 4a23
Light yellowish liquid; Rf = 0.53 (30% ethyl acetate in hexane);
IR (neat): 3431, 3313, 1619; 1H NMR (400 MHz, CDCl3): d 7.75–
7.71 (m, 1H), 7.31–7.25 (m, 1H), 6.70–6.64 (m, 2H), 6.20 (br s,
2H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3): d 200.9, 150.3,
134.5, 132.1, 118.4, 117.3, 115.9, 27.9; HRMS (ESI): m/z calcd for
C8H10NO [M+H+]: 136.0762; found: 136.0766.

S. Mannam, G. Sekar / Tetrahedron: Asymmetry 20 (2009) 497–502
501
4.3.4. (4-Aminophenyl)(phenyl)methanone, 5a24
m/z calcd. for C13H14NO [M+H+]: 200.1075; found: 200.1074. The
enantiomeric excess (ee) was determined to be 71% by HPLC using
Diacel, ChiralPAK, OD-H column (5% i-PrOH/ hexanes, 1 mL/min,
220 nm): Retention time (minor, 15.817 min), Retention time (ma-
jor, 11.258 min).
Brownish solid, mp 118–122 °C (lit. 121–124) °C; Rf = 0.79 (30%
ethyl acetate in hexane); IR (neat): 3405, 3325, 1615 cmꢀ1 1H
;
NMR (400 MHz, CDCl3): d 7.77–7.70 (m, 4H) 7.58–7.44 (m, 3H),
6.69 (d, J = 8.0 Hz, 2H), 4.11 (br s, 2H); 13C NMR (100 MHz, CDCl3):
d 195.5, 151.0, 138.9, 133.0, 131.5, 129.6, 128.2, 127.6, 113.9;
HRMS (ESI): m/z calcd for C13H12NO [M+H+]: 198.0919; found:
198.0920.
4.4.5. (3-Aminophenyl)(phenyl)methanol, 6b
Brownish semi solid; Rf = 0.23 (40% ethyl acetate in hexane); IR
(neat): 3424, 3350, 3227 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 7.29–
7.13 (m, 5H), 7.01 (t, J = 7.6 Hz, 1H), 6.67–6.62 (m, 2H), 6.48 (d,
J = 7.6 Hz, 1H), 5.62 (s, 1H), 3.17 (br s, 3H); 13C NMR (100 MHz,
CDCl3): d 146.2, 145.4, 143.9, 129.6, 128.6, 127.6, 126.7, 117.5,
114.8, 113.6, 76.3; HRMS (ESI): m/z calcd for C13H14NO [M+H+]:
200.1075; found: 200.1073. The enantiomeric excess (ee) was
determined to be 00% by HPLC using Diacel, ChiralPAK, AS-H col-
umn (10% i-PrOH/ hexanes, 1 mL/min, 220 nm).
4.3.5. (3-Aminophenyl)(phenyl)methanone, 6a25
Brownish solid, mp 80–85 °C (lit. 81–84 °C); Rf = 0.42 (40% ethyl
acetate in hexane) IR (neat): 3383, 3309, 3201, 1646; 1H NMR
(400 MHz, CDCl3): d 7.82 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.6 Hz,
1H), 7.48 (t, J = 7.6 Hz, 2H), 7.29–7.13 (m, 3H), 6.93–6.89 (m, 1H),
3.61 (br s, 2H); 13C NMR (100 MHz, CDCl3): d 197.0, 146.6, 138.9,
138.0, 132.4, 130.1, 129.2, 128.3, 120.8, 119.1, 116.1; HRMS
(ESI): m/z calcd for C13H12NO [M+H+]: 198.0919; found: 198.0915.
Acknowledgments
4.4. Spectroscopic data for the recovered amino alcohols
We thank DST (Project No.: SR/S1/OC-06/2008), New Delhi, for
the financial support. S.M thanks CSIR, India, for fellowship. We
thank DST, New Delhi, for the funding toward the 400 MHz NMR
machine to the Department of Chemistry, IIT-Madras under the IR-
PHA scheme and ESI-MS facility under the FIST program.
4.4.1. (2-Amino-5-chlorophenyl)(2-fluorophenyl)methanol,
2b18
Brownish semi solid; Rf = 0.40 (20% ethyl acetate in hexane);
½
a 2D5
ꢂ
¼ þ37:5 (c 1.0, MeOH); IR (neat): 3382, 3307, 3113 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 7.40–7.17 (m, 4H), 6.97 (dd, J = 2.4,
6.0 Hz, 1H), 6.78 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 3.55
(br s, 3H); 13C NMR (100 MHz, CDCl3): d 141.3, 136.8, 131.3,
128.1, 127.7, 127.0, 126.9, 126.0, 125.9, 125.6, 121.9, 116.3, 68.6;
HRMS (ESI): m/z calcd. for C13H12NOClF [M+H+]: 252.0591; found:
252.0585. The enantiomeric excess (ee) was determined to be 91%
by HPLC using Diacel, ChiralPAK, AS-H column (15% i-PrOH/hex-
anes, 1 mL/min, 220 nm): Retention time (minor, 46.233 min),
Retention time (major, 40.900 min).
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Brownish semi solid; Rf = 0.31 (30% ethyl acetate in hexane);
½
a 2D0
ꢂ
¼ þ43:7 (c 1.0, MeOH), [lit.12
½
a 2D5
ꢂ
¼ þ44:5 (c 1.0, MeOH)];
IR (neat): 3443, 3367, 3204; 1H NMR (400 MHz, CDCl3): d 7.43–
7.30 (m, 5H) 7.18–7.13 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.81–6.76
(m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.85 (s, 1H), 3.59 (br s, 3H); 13C
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127.7, 126.7, 118.7, 117.3, 75.0; HRMS (ESI): m/z calcd for
C13H14NO [M+H+]: 200.1075; found: 200.1079. The enantiomeric
excess (ee) was determined to be 87% by HPLC using Diacel, Chir-
alPAK, AS-H column (3% i-PrOH/ hexanes, 1 mL/min, 220 nm):
Retention time (minor, 25.892 min), Retention time (major,
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a stoichiometric chiral complex
4.4.3. (2-Aminophenyl)ethanol, 4b3f
(1.2 equiv of titanium tartrate complex was used) and tert butylhydroperoxide,
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4350.
Brownish semi solid; Rf = 0.29 (30% ethyl acetate in hexane);
½
a 2D0
ꢂ
¼ þ52:5 (c 1.0, CHCl3); IR (neat): 3416, 3329, 3218 cmꢀ1
;
1H
8. Non-enzymatic kinetic resolution of b-tertiary amino alcohols by
NMR (400 MHz, CDCl3): d 7.05 (t, J = 7.6 Hz, 2H), 6.70–6.49 (m,
2H), 4.71 (q, J = 6.4 Hz, 1H), 2.89 (br s, 3H); 1.38 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 147.4, 146.7, 129.6, 115.8,
114.4, 112.2, 70.6, 25.1; HRMS (ESI): m/z calcd for C8H12NO
[M+H+]: 138.0919; found: 138.0913. The enantiomeric excess
(ee) was determined to be 93% by HPLC using Diacel, ChiralPAK,
OD-H column (15% i-PrOH/hexanes, 0.5 mL/min, 220 nm): Reten-
tion time (minor, 22.500 min), Retention time (major, 16.058 min).
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a stoichiometric chiral-halogenating
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½
a 2D0
ꢂ
¼ ꢀ27:5 (c 1.0 MeOH); IR (neat): 3382, 3307, 3113 cmꢀ1
;
1H
NMR (400 MHz, CDCl3): d 7.31–6.95 (m, 6H), 6.57–6.33 (m, 3H),
5.64 (s, 1H), 2.83 (br s, 3H); 13C NMR (100 MHz, CDCl3): d 128.7,
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502
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