Enantioselective addition of diethylzinc to aryl aldehydes catalyzed by novel chiral imino alcohol ligands

Article abstract of DOI:10.1007/BF03245865

The enantioselective alkylation of aryl aldehydes by diethylzinc in the presence of catalytic amounts of several novel chiral imino alcohol ligands, synthesized from the reaction of (R)-2-amino-1-butanol with aromatic aldehydes, was studied. The influence of temperature and ligand structure was investigated and enantioselectivity up to 81% was obtained.

Full text of DOI:10.1007/BF03245865

J. Iran. Chem. Soc., Vol. 7, No. 1, March 2010, pp. 100-106.
JOURNAL OF THE
Iranian
Chemical Society
Enantioselective Addition of Diethylzinc to Aryl Aldehydes Catalyzed by Novel Chiral
Imino Alcohol Ligands
P. Salehia,*, M. Dabirib,* and G. Kozehgaryb
aDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C.,
Evin, Tehran 1983963113, Iran
bDepartment of Chemistry, Faculty of Science, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
(Received 5 September 2008, Accepted 30 January 2009)
The enantioselective alkylation of aryl aldehydes by diethylzinc in the presence of catalytic amounts of several novel chiral
imino alcohol ligands, synthesized from the reaction of (R)-2-amino-1-butanol with aromatic aldehydes, was studied. The
influence of temperature and ligand structure was investigated and enantioselectivity up to 81% was obtained.
Keywords: Imino-alcohols, Alkylation, Diethylzinc, Aryl aldehydes, Enantioselective
INTRODUCTION
addition of dialkylzinc to aldehydes (Fig. 1), most of which
are rather expensive [10].
The formation of C-C bonds is one of the most challenging
goals in organic synthesis. Among the existing methods, the
addition of dialkylzinc to aldehydes or ketones is one of the
most convenient [1]. The high ligand dependence of this
reaction is illustrated by the fact that aliphatic and aromatic
aldehydes do not significantly react with dialkylzinc reagents
in the absence of an appropriate ligand.
Herein we report the synthesis and utility of novel chiral
imino alcohol ligands in diethylzinc addition to aromatic
aldehydes and the effect of their structure and temperature on
the enantioselectivity of the reactions. A substantial advantage
of these ligands is that they are cheap, stable in air and can be
prepared in large quantities without any special precaution.
Since the introduction of (-)-3-exo-dimethylamino-
isoborneol (DAIB) by Noyori et al. [2], a large variety of
amino alcohol derivatives such as acyclic amine-based amino
alcohols [3], cyclic amine-based amino alcohols [4], pyridyl
alcohols [5], carbohydrate-based amino alcohols [6],
ferrocene-based amino alcohols [7], and sulfonamide alcohols
[8] have been employed in this reaction.
In contrast to the great number of chiral imino alcohol
derivatives used as ligands for asymmetric catalyses [9], only
few cases have so far been reported for stereoselective
EXPERIMENTAL
General
Melting points were obtained in open capillary tubes
measured on an electrothermal 9200 apparatus and were not
corrected. Mass spectra were recorded on a FINNIGAN-
MAT8430 mass spectrometer operating at an ionization-
potential of 70 eV. Elemental analysis was performed using a
Gmbh varioEL instrument. IR spectra were recorded on KBr
pellets on
a Nicolet Impact 400D spectrophotometer.
Conversions were determined with a Hewlett-Packard HP-
5890 GC instrument equipped with a flame ionization detector
*Corresponding author. E-mail: p-salehi@sbu.ac.ir

Salehi et al.
H3C
H3C
H
H
N
N
t-Bu
t-Bu
Ph
N
OH
HO
OH
Ph
t-Bu
t-Bu
N
1
2
R2
H3C
N
R1
N
3
R2
OH
OH
OH
N
CH3
HO
4
R1
Fig. 1. Imino alcohols used as ligands in the enantioselective addition of dialkylzinc to aldehydes.
and a 30 m HP-1 capillary column, using nitrogen (2 ml min-1)
appropriate temperature for the time reported in Table 1.
Saturated aqueous NH4Cl was added (10 ml) and the mixture
was extracted with ethyl acetate (3 × 20 ml). The collected
organic phases were washed with water, dried over Na2SO4
and analyzed by GC, after suitable dilution.
as carrier gas. The enantiomeric ratios were determined with
the aforemationed apparatus using a 30 m WCOT fused silica
1
capillary column (HP-chiral). H and 13C NMR spectra were
determined on a Bruker 300 DRX Avance instrument at
300.13 and 75.47 MHz, respectively.
(R)-2-(4-Dimethylamino)benzylidene amino)butan-1-ol
(5a). 83% Yield as colorless crystals; m.p.: 77.5-79.5 °C; [ꢀ
Preparation of Ligands
]
25 = +27.5 (c = 1.02, DMSO); IR (KBr) 3203, 2961, 1607,
D
Preparation
of
2-((E-(R)-1-hydroxybutan-2-ylimino)
1529, 1369, 1185, 1059, 816 cm-1; Ms (EI) 220 (M+, 85), 189
(100), 160 (82), 134 (70), 77 (18), 31 (33); 1H NMR (DMSO-
d6) ꢀ 0.77 (3H, t, J = 7.36 Hz), 1.37-1.44 (1H, m), 1.57-1.64
(1H, m), 2.94 (6H, s), 2.98-3.02 (1H, m), 3.38-3.42 (1H, m),
3.46-3.51 (1H, m), 4.51 (1H, t, J = 5.35 Hz), 6.71 (2H, d, J =
8.70 Hz), 7.55 (2H, d, J = 8.70 Hz), 8.09 (1H, s); 13C NMR
(DMSO-d6) ꢀ 160.1, 152.1 (2C), 129.6, 124.6 (2C), 111.8
(2C), 74.7, 65.5, 25.5, 11.1 (Found: C, 70.90; H, 9.35; N,
12.54; C13H21N2O requires: C, 70.87; H, 9.15; N, 12.72).
(R)-2-(3-Nitrobenzylideneamino)butan-1-ol (5b). 80%
Yield as colorless crystals; m.p.: 114.5-116 °C; [ꢀ]D25 = +21.0
(c = 1.00, DMSO); IR (KBr) 3218, 2980, 1646, 1524, 1340,
1059, 826, 734, 676 cm-1; Ms (EI) 223 (M++1, 47), 191 (100),
136 (30), 117 (45), 89 (34), 63 (22), 31 (33); 1H NMR
(DMSO-d6) ꢀ 0.79 (3H, t, J = 7.35 Hz), 1.45-1.52 (1H, m),
1.60-1.64 (1H, m), 3.14-3.19 (1H, m), 3.38-3.58 (2H, m), 4.64
(1H, t, J = 5.55 Hz), 7.73 (1H, t, J = 7.89 Hz), 8.22 (1H, dd,
J = 32.4, 7.59 Hz), 8.43 (1H, s), 8.56 (1H, S); 13C NMR
methyl) phenol (5e): to a solution of (R)-2-amino-1-butanol
(0.979 g, 11 mmol) in dry methanol (15 ml) was added 1.22 g
(10 mmol) of salicylaldehyde. After stirring for 15 h at room
temperature (TLC monitoring), the solvent was distilled off
under vacuum and the residue was purified by column
chromatography on silica gel (eluting with n-hexane-ethyl
acetate mixtures) to give 1.64 g (85% yield) of the ligand 5e as
a yellow solid.
General Procedure for the Enantioselective Addition
of Diethylzinc to Benzaldehyde
The ligand (0.11 mmol) was placed in a test tube and
dissolved in dry toluene (2 ml). The solution was stirred for 5
min. A 1.0 M solution of diethylzinc in n-hexane (2.2 mmol,
2.2 ml) was then added, and after the mixture was stirred for 5
min, a solution of benzaldehyde (1.11 mmol) in dry toluene (1
ml) was added by a syringe. The mixture was stirred at the
101

Enantioselective Addition of Diethylzinc to Aryl Aldehydes
(DMSO-d6) ꢀ 158.8, 148.5, 138.2, 134.7, 130.7, 125.2, 122.1,
74.5, 64.9, 25.1, 11.0 (Found: C, 59.34; H, 7.00; N, 12.32
C11H14N2O3 requires: C, 59.18; H, 6.77; N, 12.55).
(CDCl3) ꢀ 0.98 (3H, t, J = 7.38 Hz), 1.64-1.73 (2H, m), 1.86
(1H, m), 3.30-3.38 (1H, m), 3.78-3.84 (2H, m), 7.17-7.38 (3H,
m), 8.47 (1H, s); 13C NMR (CDCl3) ꢀ 157.9, 134.3, 133.4,
130.3, 128.5, 75.5, 65.9, 24.5, 10.7 (Found: C, 53.59; H, 5.57;
N, 5.67 C13H11Cl2NO requires: C, 53.68; H, 5.32; N, 5.69).
(2R,2'R)-2,2'-{Benzene-1,4-diylbis[methylylidenenitrilo]}
dibutan-1-ol (5g). 89% Yield as colorless crystals; m.p.: 139-
140.5 °C; [ꢁ]D25 = -3.77 (c = 1.06, DMSO); IR (KBr) 3223,
2961, 1636, 1302, 1054 cm-1; Ms (EI) 277 (M++1, 25), 245
(100), 173 (25), 146 (51), 117 (20), 91 (23), 55 (25), 31 (75);
1H NMR (DMSO-d6) ꢀ 0.78 (3H, t, J = 7.05 Hz), 1.40-1.49
(1H, m), 1.61 (1H, m), 3.10 (1H, m), 3.35-3.56 (2H, m), 4.59
(1H, t, J = 4.75 Hz), 7.8 (4H, s), 8.31 (1H, s); 13C NMR
(DMSO-d6) ꢀ 160.2 (2C), 138.3 (2C), 128.5 (4C), 74.7 (2C),
65.1 (2C), 25.2 (2C), 11.0 (2C) Found: C, 69.25; H, 9.05; N,
9.83 C16H24N2O2 requires: C, 69.53; H, 8.75; N, 10.14).
4-((E)-(R)-1-Hydroxybutan-2-ylimino) methyl)phenol
(5c). 74% yield as colorless crystals; m.p.: 163.5-165 °C;
25
[ꢀ]D = +28.84 (c = 1.04, DMSO); IR (KBr) 3155, 2961,
1636, 1607, 1515, 1287, 1054 cm-1; Ms (EI) 194 (M+1, 65),
1
162 (100), 107 (55), 41 (9); H NMR (DMSO-d6) ꢀ 0.76 (3H,
t, J = 7.35 Hz), 1.34-1.44 (1H, m), 1.56-1.64 (1H, m), 3,00
(1H, m), 3.33-3.52 (2H, m), 4.52 (1H, t, J = 5.35 Hz), 6.80
(2H, d, J = 8.28), 7.57 (2H, d, J = 8.28), 8.13 (1H, s), 9.86
(1H, s); 13C NMR (DMSO-d6) ꢀ 160.0, 159, 130.0, 128.0 (2C),
115.7 (2C), 74.6, 65.3, 25.3, 11.1 (Found: C, 68.11; H, 8.10;
N, 7.09 C11H15NO2 requires: C, 68.37; H, 7.82; N, 7.25).
(R)-2-((Anthracen-10-yl)methyleneamino)butan-1-ol
25
(5d). 90% Yield as green crystals; m.p.: 156-158.5 °C; [ꢀ]D
= -7.84 (c = 1.02, DMSO); IR (KBr) 3194, 2932, 1646, 1073,
889, 739 cm-1; Ms (EI) 277 (M+, 75), 246 (100) ,230 (24) , 204
(83), 109 (15), 31 (60); H NMR (DMSO-d6) ꢀ 0.99 (3H, t,
RESULTS AND DISCUSSION
1
J = 7.39 Hz), 1.61-1.75 (2H, m), 3.45 (1H, m), 3.55-3.63 (1H,
m), 3.70-3.75 (1H, m), 4.84 (1H, t, J = 5.28 Hz), 7.51-7.59
(4H, m), 8.10-8.13 (2H, m), 8.58-8.66 (3H, m), 9.35 (1H, s);
13C NMR (DMSO-d6) ꢀ 159.9, 131.2, 129.6, 129.3, 129.1,
129.0, 127.0, 125.8, 125.5, 76.3, 65.1, 25.2, 11.4 (Found: C,
82.09; H, 7.20; N, 5.02 C19H19NO requires: C, 82.28; H, 6.9;
N, 5.05).
A series of novel chiral ligands (Fig. 2) were synthesized
by the reaction of R-(2)-amino-1-butanol with the appropriate
aromatic aldehyde.
Imines are unreactive to dialkylzinc even at elevated
temperature and it is not surprising that the same reaction fails
to provide amines because of low reactivity of imines towards
nucleophilic attack [11].
2-((R)-1-Hydroxybutan-2-ylimino)methyl)phenol (5e).
85% Yield as yellow crystals; m.p.: 52.5-55.5 °C; [ꢀ]D25 = +7
(c = 1.00, DMSO); IR (KBr) 3262, 2961, 1631, 1277, 1059,
758 cm-1; Ms (EI) 193 (M+, 86), 162 (77), 145 (85), 107 (69),
First, we examined the reaction of diethylzinc and
benzaldehyde in the presence of catalytic amounts of chiral 2-
imino-1-alcohols 5a-g (Scheme 1). The results are
summarized in Table 1. The reactions were performed
using 10 mol% of the catalyst in toluene at different
temperatures, and good enantioselectivity was obtained for
meta and para substituted ligands. In all cases the major
enantiomer of the produced 1-phenyl-propanol possessed the S
configuration. The highest enantioselectivities were obtained
with chiral ligand 5c (Table 1, entries 8-12). By increasing the
ratio of ligand 5c to benzaldehyde, an increase in the
enantioselectivity of (S)-1-phenyl-1-propanol was observed,
and the best enantioselectivity (78% ee) was obtained, when
20 mol% of 5c was used (Table 1, entry 12). Racemic product
was obtained from the C2-symmetry para-substituted ligand
5g (Table 1, entries 23-25). Addition of titanium isopropoxide
has been reported to increase the ee in many cases [12].
1
77 (30), 51 (22), 31 (52); H NMR (DMSO-d6) ꢀ 0.83 (3H, t,
J = 7.39 Hz), 1.43-1.52 (1H, m), 1.61-1.67 (1H, m), 3.13-3.20
(1H, m), 3.37-3.45 (1H, m), 3.55-3.58 (1H, m), 4.80 (1H, m),
6.85-6.91 (2H, m), 7.29-7.34 (1H, m), 7.45 (1H, d, J = 7.44
Hz), 8.49 (1H, s); 13C NMR (DMSO-d6) ꢀ 165.7, 161.3, 132.5,
132.0, 119.0, 118.7, 116.9, 72.6, 64.8, 25.1, 10.8 (Found: C,
68.19; H, 8.10; N, 7.1 C11H15NO2 requires: C, 68.37; H, 7.82;
N, 7.25).
(R)-2-(2,6-Dichlorobenzylideneamino)butan-1-ol (5f).
25
98% Yield as colorless crystals; m.p.: 68.5-69.5 °C; [ꢀ]D
=
+28.4 (c = 1.02, DMSO); IR (KBr) 3291, 2961, 1650, 1427,
1054, 783 cm-1; Ms (EI) 246 (M+, 16), 214 (100), 159 (70),
1
123 (32), 100 (17), 75 (19), 41 (81), 31 (63); H NMR
102

Salehi et al.
Table 1. Enantioselective Addition of Et
2Zn to C6H5CHO Catalyzed by Chiral Catalysts at Different
Temperatures
Entry
Ligand
T (ºC)
Time (h)
Yield (%)a
Ee (%)b,c
1
2
3
4
5
6
7d
8
5a
5a
5a
5b
5b
5b
5b
5c
+30
+10
-10
+30
+10
-10
40
40
22
40
40
22
40
40
81
64
16
67
48
12
25
71
27
39
56
52
56
58
67
62
-30
+30
9
5c
5c
5c
5c
5c
5d
5d
5d
5e
5e
5e
5f
5f
5f
5g
5g
5g
-
+10
-10
40
40
40
40
40
40
40
20
40
40
22
40
40
20
40
40
20
40
40
22
39
20
9
67
68
67
78
6.5
10
14
5
10
11
12d
13e
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
-23
-30
51
66
73
60
20
40
17
6
+10
+30
+10
-10
+30
+10
-10
3
5
3
+30
+10
-10
68
56
21
68
50
21
26
22
5
0
21
0
+30
+10
-10
0
3
0
+30
+10
-10
0
-
0
-
0
aGC yield on the mixture of the two enantiomers. bEe was determined by GC using a chiral capillary
column (HP-Chiral). cAbsolute configuration of the major enantiomer was determined by
d
comparison with authentic sample. In all cases the major product had the S configuration. This
reaction was carried out with 20 mol% of ligand. eWith 120 mol% of Ti(OiPr)4.
103

Enantioselective Addition of Diethylzinc to Aryl Aldehydes
H3C
CH3
OH
N
O2N
N
HO
N
HO
HO
N
HO
N
5d
HO
5b
5a
5c
OH
N
HO
Cl
N
Cl
HO
N
HO
N
5e
5f
5g
Fig. 2. Chiral ligands synthesized by the reaction of R-(2)-amino-1-butanol.
Chiral Catalyst (10 mol%)
OH
Et
C6H5
Et2Zn
+ C6H5CHO
Toluene, n-Hexane
-30 to +30oC
H
Scheme 1
However, in our experiments, treatment of 5c with 120 mol%
of titanium isopropoxide led to a significant decrease of the
enantioselectivity (Table 1, entry 13).
We observed that, in the majority of cases, lower
temperatures favored the enantioselectivity of the reaction,
thus when the reactions were carried out at 30 ºC with 10
mol% of the catalyst, lower ee values were obtained compared
to 10 ºC or -10 ºC. The correlation of enantioselectivities with
temperature for the three best ligands is depicted in Fig. 3. In
addition to spectroscopic data, the spatial arrangement of
groups in 5c was established by X-ray analysis. The ORTEP
of 5c is shown in Fig. 4. As can be seen, the C=N had the E
geometry in the ligand. After optimizing the best conditions
for the reaction of diethylzinc with benzaldehyde, we applied
the same condition to other aromatic aldehydes. According to
the obtained results by 5c (Table 1, entries 8-12) and similarity
of the ees in +10 °C and -10 °C the optimized reactions were
carried out at +10 °C and -30 °C. The results for the addition
of diethylzinc in the presence of 5c are summarized in Table 2.
For substituted aromatic aldehydes, as shown in Table 2, fair
to good selectivities were obtained. Generally, electron-
Fig. 3. Correlation of enantioselectivity with temperature for
three ligands: (ꢂ) 5a, (ꢃ) 5b, (,) 5c.
Fig. 4. The ORTEP view of 5c.
withdrawing substituents in para position gave better ee
values, while introduction of substituents in ortho position or
presence of an electron-donating group on para, led to a slight
104

Salehi et al.
Table 2. Enantioselective Addition of Diethylzinc to Aromatic Aldehydes Catalyzed
by Chiral Imino Alcohol 5ca
Entry
Aldehyde
Yield (%)b
Ee (%)c,d
1
2
3
4
5
6
7
8
p-FC6H4CHO
p-ClC6H4CHO
78 (70)e
80 (61)
79 (68)
67 (60)
46 (35)
87 (80)
95 (90)
90 (85)
71 (81)e
70 (77)
68 (70)
65 (60)
56 (44)
32 (51)
48 (45)
51 (50)
p-BrC6H4CHO
p-MeC6H4CHO
p-MeOC6H4CHO
o,p-(MeO)2C6H3CHO
o-MeOC6H4CHO
o-ClC6H4CHO
aCondition: 10 °C, 40 h and 10 mol% of 5c. Measured as conversion% by GC.
cDetermined by capillary chiral GC analysis using the chiral column (HP-chiral).
dAbsolute configuration was determined by comparing the sign of specific rotation
b
e
[13-16]. The major enantiomer in all cases had the S configuration. Values in
parentheses are for condition: -30 °C, 40 h and 20 mol% of 5c.
Table 3. Enantioselective Addition of Et2Zn to C6H5CHO Catalyzed by Different Chiral
Imines [10]
Entry
Ligand
T (ºC)
Time (h)
Yield (%)
Ee (%)
1
2
3
4
5
1
2
3
4
0
24
25
18
48
40
99
75
82
57
51
71
70
25
15
78
-40 to 25
rt
rt
-30
5c
decrease in the enantioselectivity. The best enantioselectivity
up to 81% ee was obtained with p-fluorobenzaldehyde (Table
2, entry 1). A comparison between some previously reported
methods with the present procedure has been summarized in
Table 3.
comparison with previous imino alcohols (Fig. 1) that have
been used for this purpose.
ACKNOWLEDGEMENTS
We are grateful to Shahid Beheshti University Research
Council and Catalysis Center of Excellence (CCE) for the
financial support of this work.
CONCULSIONS
In conclusion, we have shown that imino alcohol 5c, which
is easily prepared from (R)-2-amino-1-butanol and p-hydroxy
benzaldehyde can be successfully used as a ligand in the
enantioselective addition of diethylzinc to aryl aldehydes. The
method offers the use of a cheap and stable ligand in
REFERENCES
[1] a) K. Soai, S. Niwa, Chem. Rev. 92 (1992) 833; b) L. Pu,
H. Bin Yu, Chem. Rev. 101 (2001) 757.
105

Enantioselective Addition of Diethylzinc to Aryl Aldehydes
[2]
a) M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am.
Shirae, M. Sakamoto, T. Fujita, J. Organomet. Chem.
691 (2006) 4297; b) S. Brase, S. Hofener, F.
Lauterwasser, Adv. Synth. Catal. 346 (2004) 755; c) F.
Keller, A. Rippert, J. Helv. Chem. Acta 82 (1999) 125;
d) P.G. Cozzi, A. Papa, A. Umani-Ronchi, Tetrahedron
Lett. 37 (1996) 4613; e) R. Fleischer, M. Braun, Synlett
12 (1998) 1441.
Chem. Soc. 108 (1986) 6071; b) R. Noyori, M.
Kitamura, Angew. Chem. Int. Ed. Engl. 30 (1991) 49.
K. Soai, S. Yokoyama, T. Hayasaka, J. Org. Chem. 56
(1991) 4264.
a) K. Soai, T. Konishi, T. Shibata, Heterocycles 51
(1999) 1421; b) M. Dabiri, P. Salehi, G. Kozehgary, S.
Heydari, A. Heydari, M. Esfandyari, Tetrahedron:
Asymmetry 19 (2008) 1970.
[3]
[4]
[11] X.L. Hou, L.X. Dai, X.L. Zheng, Tetrahedron Lett. 39
(1998) 6949.
[5]
[6]
[7]
[8]
[9]
C. Bolm, M. Eald, M. Relder, G. Schlingloff, Chem.
Ber. 125 (1992) 1169.
B.T. Cho, N. Kim, J. Chem. Soc., Perkin Trans. 1
(1996) 2901.
G. Nicolosi, A. Patti, R. Morrene, M. Piattelli,
Tetrahedron: Asymmetry 5 (1994) 1639.
K. Ito, Y. Kimura, H. Okamura, T. Katsuki, Synlett
(1992) 573.
a) T. Mino, K. Oishi, M. Yamashita, Synlett (1998)
965; b) R. Fleischer, M. Braun, Synlett (1998) 1441.
[12] M. Yus, D.J. Ramon, Tetrahedron: Asymmetry 8
(1997) 2479.
[13] J. Kang, J.W. Lee, J.I. Kim, J. Chem. Soc., Chem.
Commun. (1994) 2009.
[14] H.R.K. Prasad, N.N. Joshi, J. Org. Chem. 62 (1997)
3770.
[15] M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am.
Chem. Soc. 108 (1986) 6071.
[16] M.R. Paleo, I. Cabeza, J.F. Saradina, J. Org. Chem. 65
(2000) 2108.
[10] a) T. Mino, A. Suzuki, M. Yamashita, S. Narita, Y.
106