Asymmetric reduction of acetophenone using lithium aluminium hydride modified with some novel amino alcohol Schiff bases

Article abstract of DOI:10.1016/j.tetasy.2004.12.020

Some new chiral Schiff bases have been prepared in good yields from various carbonyl groups and two 2-amino alcohols. LiAlH₄ was treated with different equivalents of the Schiff bases. Enantioselective reduction of acetophenone is achieved in h

Full text of DOI:10.1016/j.tetasy.2004.12.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 865–868
Asymmetric reduction of acetophenone using lithium
aluminium hydride modified with some
novel amino alcohol Schiff bases
Recep Tumerdem,a,* Giray Topala and Yılmaz Turgutb
¨
aDicle University, Faculty of Education, Department of Chemistry, 21280 Diyarbakır, Turkey
bDicle University, Faculty of Science and Art, Department of Chemistry, 21280 Diyarbakır, Turkey
Received 2 November 2004; accepted 6 December 2004
Available online 29 January 2005
Abstract—Some new chiral Schiff bases have been prepared in good yields from various carbonyl groups and two 2-amino alcohols.
LiAlH4 was treated with different equivalents of the Schiff bases. Enantioselective reduction of acetophenone is achieved in high
chemical yield (up to 93%) with moderate enantiomeric excess (up to 22%) by use of the new reducing agents.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral modifiers are often easily obtained in only one
enantiomeric form, thus limiting control of the chiral
sense of the hydride transfer to the ketone.12
The synthesis of new types of chiral ligands is wide-
spread in asymmetric synthesis. Most of the common
ligands are bidentate; DIOP and BINAP as neutral or
TADDOL and BINNOL as dianionic structures.
Among higher coordinating ligands are the tetradentate
salen ligands, which are widely used in epoxidation,
epoxide ring opening and aziridination reactions.1,2
2. Results and discussion
In order to reach the pre-designed structure, initially
commercial and inexpensive L-amino acids were
selected. Only L-phenylalanine and L-valine have been
used. Firstly the amino acids were converted into the
corresponding amino alcohols by reduction with NaBH4
in THF under inert atmosphere. Generally, the reduc-
tion method gave a single enantiomer in high yield.11
Schiff bases can behave as multidentate ligands, depend-
ing on the number of donor atoms in their structure. If
there is any –OH or –SH, groups ortho to the azome-
thine bond, then six membered rings can form with met-
als, giving unreactive complexes.3
Next in order to achieve suitable symmetry and to create
a better steric barrier in general, different carbonyl com-
pounds were selected. These were benzaldehyde, salicyl-
aldehyde, benzil and 3-oxa-1,5-bis-(o-carboxaldehyde
phenoxy)pentane. The carbonyl compounds were treat-
ed with the two amino alcohols to synthesize various
Schiff bases.
In recent years, salen type chiral Schiff bases have been
extensively described. Symmetric and asymmetric transi-
tion metal complexes of these bases have been developed
and used as ligands/catalysts in many reactions such as
epoxidation,4 asymmetric synthesis,5 asymmetric sulfox-
idation,6 asymmetric silylcyanation7 and many other
applications.8–10
The synthesis of chiral Schiff bases according to a gen-
eral literature reaction12 is shown in Scheme 1 to gener-
ate ligands I–VI (Fig. 1).
The reported explanation for the reduction mechanism
was based on formation of a six membered ring.11,12
In this study we found that the enantioselectivity of
reducing agents was dependent on the mole ratios of
the modified hydride/acetophenone.
Asymmetric reduction experiments have been carried
out with new Schiff bases I–IV, which have various
donor atoms (Scheme 2).
*
Corresponding author. E-mail: rtumerdem@dicle.edu.tr
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.12.020

866
R. Tu¨merdem et al. / Tetrahedron: Asymmetry 16 (2005) 865–868
HO
A
H
'
O
R
CH N
CH N
'
+
OH
R
R
C
H
H
I
NH2
OH
R
H
H
C
'
R
:
N
OH
R : Phe, i-Pr
,
OH
OH
B
R
II
R'
R'
N
O
OH
OH
+
CH3
OH
R
H
CH3
O
NH2
R''
R''
N
N
C
H
R
OH
III
R' , R''
:
R : Phe, i-Pr
CH3
H
CH3
H
N
C
C
OH
OH
O
CH
O
O
IV
OH
R
+
NH2
H
N
C
CH
O
O
OH
OH
C
N
H
R
V
CH N
O
O
OH
OH
HO
OH
H
H
N
N
CH
CH
CH
O
N
O
O
O
R
R: Ph, i-Pr
Scheme 1. Synthesis of Schiff bases.
VI
Figure 1.
LiAlH4 complexes of the Schiff bases were prepared in
situ. Then acetophenone was added dropwise. The
reduction was complete in a short time at approximately
20 °C under inert atmosphere. As described in the liter-
ature, the structure of the complex formed is shown in
Figure 2.
The optimum ratio of LiAlH4/Schiff base was deter-
mined using ligands I–IV and acetophenone (Table 1).
The best results were obtained with a molar ratio of I/
LiAlH4 of 1:2 for the reduction of acetophenone. Pre-
sumably with molar ratios of 2:1 or 3:2, all the reducing
power of the aluminium hydride has been consumed by
the reaction with the excess ligand.
In complexes prepared according to this in situ reaction,
the highest literature eeÕs were achieved when only one
hydride remained on the Al.13
After chromatography, the enantiomeric excess values
were determined by optical rotation.

R. Tu¨merdem et al. / Tetrahedron: Asymmetry 16 (2005) 865–868
867
R1
3. Experimental
CH
Optical rotations were determined in a solution CH3OH
at 20 °C by using a Perkin–Elmer-341 digital polari-
meter. IR spectra were determined by a Mattson 1000
spectrometer. 1H NMR and 13C NMR spectra were
determined for solution in CDCl3 with tetramethylsilane
(TMS) as internal standard on a Bruker Avence dpx-400
spectrometer. CH analysis with an Carlo–Erba 1800
analyzer.
N
CH3
C
R2
LiAlH4
+
O
HO
-20oC, 1.5h reflux
3.1. Synthesis of amino alcohols
HO
CH3
L-Phenylalaninol and L-valinol were prepared according
to the literature.11
H
3.2. Synthesis of Schiff bases (general reaction)
O
Schiff base reactions were performed in ethanol at 65 °C.
Amino alcohols and aldehydes in appropriate mole
ratios, were put into a flask with 20 mL ethanol. This
mixture was stirred for 24 h at 60 °C. Then the alcohol
was evaporated. Schiff bases were recrystallized from
appropriate solvents.
:
R1
,
,
O
O
OH
R2 : Ph, i-Pr
3.2.1.
Benzaldehydene-(S)-2-amino-3-phenylpropanol
20
I. White solid, yield 78%, mp: 84–86 °C, ½aꢀ
¼
D
ꢁ246 (c 5, MeOH); IR (KBr) 3236, 3070, 3030, 2921,
Scheme 2.
2858, 1645, 1580, 1495, 1452, 1413, 1150, 1053, 746,
613 cmꢁ1 1H NMR (CDCl3) d ppm 2.67–2.95 (m,
;
2H), 3.48–3.66 (m, 1H), 3.67–3.95 (m, 2H), 7.22–7.67
(m, 10H), 7.90–7.97 (s, 1H); 13C NMR (CDCl3) d ppm
39.42, 66.29, 74.75, 126.60, 128.69, 130.12, 131.18,
136.09, 138.97, 162.99; Anal. Calcd for C16H17NO: C,
80.33; H, 7.11. Found: C, 80.26; H, 6.95.
-
H
H
H
+
Al
+
Li
C
N
-H2
H
H
OH
3.2.2. o-Hydroxy benzaldehydene-(S)-2-amino-3-phenyl-
propanol II. Yellow solid, yield 73%, mp: 62–64
°C, ½aꢀ ¼ ꢁ265 (c 5, MeOH); IR (KBr) 3394, 3066,
20
D
3032, 2924, 2875, 1642, 1581, 1497, 1465, 1430, 1155,
1045, 840, 750, 691 cmꢁ1 1H NMR (CDCl3) d ppm
;
H2
C
N
2.83–2.88 and 2.97–3.01 (2H), 3.49–3.55 (m, 1H), 3.71–
3.82 (2H), 6.82–7.32 (m, 10H), 8.14 (s, 1H); 13C NMR
(CDCl3) d ppm 39.43, 66.06, 73.44, 117.49, 119.05,
126.91, 128.91, 129.95, 132.04, 132.92, 138.34, 161.77,
166.32; Anal. Calcd for C16H17NO2: C, 75.29; H, 6.67.
Found: C, 74.97; H, 6.50.
+
-
Li
Al
O
H
H
Figure 2. Stable five membered ring.
3.2.3. Benzaldehydene-(S)-2-amino-3-methylbutanol III.
20
D
MeOH); IR (KBr) 3249, 3063, 2973, 2935, 1645, 1573,
White solid, yield 64%, mp: 71–72 °C, ½aꢀ ¼ ꢁ56:7 (c 5,
1
1503, 1471, 1452, 1053, 1022, 836, 758, 688 cmꢁ1; H
NMR (CDCl3) d ppm 0.77–0.96 (d, 6H), 1.80–2.08 (m,
1H), 2.87–3.02 (s, 1H), 3.17–3.65 (m, 1H), 3.68–3.80
(m, 2H), 7.24–7.67 (m, 5H), 8.07–8.16 (s, 1H); 13C
NMR (CDCl3) d ppm 19.78, 20.16, 30.38, 64.72, 79.74,
126.51, 128.82, 128.86, 130.98, 136.18, 162.44; Anal.
Calcd for C12H17NO: C, 75.39; H, 8.91. Found: C,
75.29; H, 8.81.
Table 1. Asymmetric reduction of acetophenone with Schiff base and
LiAlH4 complexes
Entry Schiff base Mole rate (Schiff/LiAlH4) % Yield % Ee
1
2
3
4
5
6
7
I
1/1
1/2
2/1
3/2
1/3
1/3
1/2
66
93
0
9
22
0
I
I
I
0
0
II
III
IV
0
0
3.2.4. o-Hydroxy benzaldehydene-(S)-2-amino-3-methyl-
butanol IV. Yellow solid, yield 55%, mp: 92–94 °C,
35
97
4
20
½aꢀ ¼ ꢁ19:1 (c 5, MeOH); IR (KBr) 3256, 2966, 2958,
8
D

868
R. Tu¨merdem et al. / Tetrahedron: Asymmetry 16 (2005) 865–868
2884, 1631, 1581, 1503, 1464, 1420, 1085, 1041, 836, 752,
portion. After mixing at room temperature for 30 min,
the mixture was cooled to ꢁ20 °C. Acetophenone–dry
ether mixture in dropping funnel was transferred drop-
wise over 30 min. The mixture was stirred at ꢁ20 °C
for 1.5 h and then 0.5 M NH4Cl was added. Water
and ether phases were separated. The ether phase was
dried with Na2SO4 and evaporated. The product was
purified in column (silica gel-60) (1:3 n-hexane–
ethylacetate).
1
655 cmꢁ1; H NMR (CDCl3) d ppm 0.83–1.05 (d, 6H),
1.80–2.03 (m, 1H), 2.93–3.13 (m, 1H), 3.62–3.89 (m,
2H), 6.76–7.38 (m, 4H), 8.33–8.40 (s, 1H); 13C NMR
(CDCl3) d ppm 18.87, 20.22, 30.37, 64.77, 117.52,
118.94, 131.93, 132.86, 162.00, 166.17; Anal. Calcd for
C12H17NO2: C, 69.56; H, 8.21. Found: C, 68.88; H, 8.30.
3.2.5. N,N0-Bis-(1,2-ethanedioniden)-(S)-2-amino-3-phen-
ylpropanol V. Brown solid, yield 40%, mp: 138–141 °C,
20
½aꢀ ¼ þ4 (c 5, MeOH); IR (KBr) 3351, 3176, 3033,
;
821, 738, 643 cmꢁ1 1H NMR (CDCl3) d ppm 2.75–
D
2909, 1676, 1621, 1578, 1493, 1454, 1433, 1079, 1025,
References
2.89 and 2.95–3.07 (m, 4H), 3.18–3.34 (m, 2H), 3.37–
3.51 and 3.52–3.65 (m, 4H), 4.01–4.8 (s, 2H), 7.11–8.41
(m, 20H); 13C NMR (CDCl3) d ppm 40.43, 60.10,
65.33, 132.10, 133.86, 134.41, 134.58, 137.89, 141.70,
199,87; Anal. Calcd for C32H32N2O2: C, 80.67; H,
6.72. Found: C, 79.81; H, 7.17.
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phenoxy)pentan]-(S)-2-amino-3-phenylpropanol
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N,N0-Bis-[3-oxa-1,5-bis-(o-carboxyaldehydene-
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20
D
IR (KBr) 3460, 3063, 3031, 2979, 2928, 2870, 1638,
1
1490, 1452, 1053, 760, 680 cmꢁ1; H NMR (CDCl3) d
ppm 2.25–2.93 (m, 4H), 3.20–3.62 (m, 2H), 3.62–4.35
(m, 12H), 6.62–7.96 (m, 18H), 8.3–8.6 (s, 2H); 13C
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Under a nitrogen atmosphere, a molar solution of
LiAlH4 in dry ether was prepared. The Schiff base in
dry ether (with different mole ratios) was added in one