Enantioselective addition of dimethylzinc to aldehydes catalyzed by N-substituted mandelamide-Ti(IV) complexes

Article abstract of DOI:10.1016/j.tetasy.2005.04.011

Amides derived from (S)-(+)-mandelic acid in the presence of titanium isopropoxide catalyze the enantioselective addition of dimethylzinc to aromatic aldehydes with good yields and ee up to 90%.

Full text of DOI:10.1016/j.tetasy.2005.04.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1953–1958
Enantioselective addition of dimethylzinc to aldehydes catalyzed by
N-substituted mandelamide-Ti(IV) complexes
´
´
´
Gonzalo Blay, Isabel Fernandez, Vıctor Hernandez-Olmos,
*
´ ´
Alıcia Marco-Aleixandre and Jose R. Pedro
´ ` ´ `
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia, Dr. Moliner 50, E-46100 Burjassot, Spain
Received 25 February 2005; accepted 19 April 2005
Available online 23 May 2005
Abstract—Amides derived from (S)-(+)-mandelic acid in the presence of titanium isopropoxide catalyze the enantioselective
addition of dimethylzinc to aromatic aldehydes with good yields and ee up to 90%.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
N
Ph
OH
NMe2
OH
N Me
The formation of C–C bonds is one of the most chal-
lenging goals in organic synthesis. Among the existing
methods, the addition of dialkylzinc to aldehydes or
ketones to give alcohols is one of the most convenient
because these organometallic reagents can be easily
prepared, stored and are compatible with many func-
tional groups.1 This reaction can be carried out in an
enantioselective fashion to provide enantioenriched chi-
ral alcohols, and hence, a multitude of chiral ligands
have been used alone or in the presence of Lewis acids
for this purpose.2
OH
N
DAIB
O
Ph
Ph
N
OH
HO
Ph
Ph
N
Ph
OH
Ph
TolSO2 NH OH
O
Bn
NH2
Since the introduction of DAIB (Fig. 1) by Noyori,3 a
large variety of amino alcohols have been employed in
this reaction. 1,2-Amino alcohols4 have been mostly
used, but the class includes 1,3-,5 and 1,4-amino alco-
hols,6 and hydroxypyridines.7 Furthermore, the reac-
tion has been carried out in the presence of some of
their derivatives such as imino alcohols8 and hydroxy-
sulfonamides,9 these last usually in combination with
titanium isopropoxide. In the case of the hydroxy sul-
fonamides, the different acidity between the alcohol
(pKa ꢀ 16.5) and sulfonamide (pKa ꢀ 8) is considered
important for the activity and enantioselectivity of the
reaction.
But
OH
tBu
R'HN
Figure 1. Amino alcohols and related compounds used as ligands in
the enantioselective addition of dialkylzinc to aldehydes.
Recently, the use of nickel complexes from a-amino
amides as catalysts in the enantioselective Et2Zn addi-
tion to benzaldehyde has been reported.10 Again, the
presence of two atoms with different acidity and coordi-
nating capabilities was considered important for the
outcome of the reaction.
Finally, the use of hydroxy carboxylic acids, obtained by
diazotization of amino acids, as ligands for enantioselec-
tive addition of diethylzinc to aldehydes has recently
been reported.11
*
Corresponding author. Tel.: +34 96 3544329; fax: +34 96 3544328;
e-mail: jose.r.pedro@uv.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.011

1954
G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1953–1958
According to these antecedents, we considered a-hydroxy
amides as possible candidates to be used as ligands in
the enantioselective addition of dialkylzinc reagents to
aldehydes, and we have recently reported the use of C2
symmetric chiral bis(amino alcohol)oxalamides of type
I (Fig. 2) for this purpose.12 The presence of C2 symme-
try is generally considered an advantageous structural
feature,13 but recent examples show the potential of C1
symmetric ligands that, in some cases, can be more effi-
cient than related C2 systems.14 Herein, we report the
use of C1 symmetric hydroxy amides II derived from
(S)-mandelic acid (mandelamides) as chiral inducers in
the enantioselective dialkylzinc addition to aldehydes.
This kind of compounds has hardly been used as ligands
in asymmetric catalysis although they are readily pre-
pared from inexpensive and readily available sources,
stable and storable, and present some structural features
that make them very attractive in this respect. Thus, the
presence of two groups with different coordinating capa-
bilities, the hydroxyl and the N–H amide functionalities,
which can be both deprotonated, may favor the forma-
tion of strong metal complexes with a defined steric and
electronic environment, which can be optimized through
the appropriate selection of R.
DCC,
Ph
O
Ph
O
N-hydroxysuccinimide
+
RNH2
OH
RHN
OH
HO
THF
1
2
3
Scheme 1.
Table 1. Synthesis of ligands 3
Ligand 3
RNH2
Yield (%)a
80
NH2
a
NH2
NH2
b
c
94
80
NH2
N
d
e
74
94
Ph
Ph
Ph
NH
NH
Ph
NH2
O
O
OH
O
Ph
a Yields refer to isolated products.
RHN
OH
OH
Ph
Ph
II
I
2.2. Enantioselective addition of dimethylzinc to
aldehydes
Figure 2.
The addition of dimethylzinc to benzaldehyde was cho-
sen as the test reaction. The reaction was carried out
using 0.2 equiv of ligand 3 and 6 equiv of Me2Zn (2 M
in toluene) in dichloromethane solution at 0 ꢁC (Table
2). When ligand 3a was used alone in the absence of
other Lewis acids, no catalytic activity was observed
(entry 1). Therefore, we performed the reaction in the
presence of titanium isopropoxide since it is known that
this reaction tends to be more efficient and selective in
the presence of this particular Lewis acid.19 Under these
conditions, the reaction took place with good yield and
acceptable enantioselectivity (entry 2). The effect of the
amine substituent was studied with ligands 3b–e. Thus,
ligands 3b and 3c introduce an additional stereogenic
center on the amine, while in ligand 3d the benzene ring
was substituted by an electron deficient pyridine ring
with a potentially coordinating nitrogen atom. Finally,
ligand 3e was derived from a bulky aliphatic tert-butyl
amine. In all the cases (entries 3–6), both the yield and
ee of the reaction were lower than those obtained with
ligand 3a. The effect of other metal salts was also stud-
ied. However, the use of Cu(OAc)2 or Ni(OAc)2 in a
1:1 ratio (entries 7 and 8) gave disappointing results.
Copper acetate was completely inactive after 24 h while
nickel acetate gave an almost racemic mixture with low
yield after 48 h. These results contrast with the results
found for these metal salts using amino amides as
ligands.10
Herein, we have centered our attention to the addition
of dimethylzinc to aldehydes. Because of its lower reac-
tivity, asymmetric addition of Me2Zn has attracted less
attention than the corresponding Et2Zn additions. How-
ever, the chiral 1-hydroxyethyl moiety resulting from the
addition of a methyl group to an aldehyde is found
widespread in nature, and makes this reaction very
interesting from a synthetic point of view.15 N,N-Di-n-
butylnorephedrine has been used for the addition of
dimethylzinc to aliphatic aldehydes with good selectiv-
ity,16 and N,N-dialkyltriphenylaminoethanol derivatives
have provided good enantioselectivity in the addition of
this reagent to benzaldehyde and heptanal.17
2. Results and discussion
2.1. Synthesis of N-substituted mandelamides
Unlike a-amino amides, whose syntheses require protec-
tion of the amino group, a-hydroxy amides can be pre-
pared in just one step by treatment of commercially
available (S)-(+)-mandelic acid 1 with primary amines
RNH2 2 in the presence of dicyclohexylcarbodiimide
(DCC) and N-hydroxysuccinimide.18 The N-substituted
mandelamides 3 are generally obtained with excellent
yields (Scheme 1, Table 1).

G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1953–1958
1955
Table 2. Addition of Me2Zn to benzaldehyde in the presence of metal
complexes of 3
was a dramatic decrease in the ee in the case of p-nitro-
benzaldehyde (entry 3) with respect to other p-substi-
tuted benzaldehydes. In these cases, it appears that
electron-donating substituents increase the ee. On the
other hand, ortho-substituted benzaldehydes give higher
ee than meta-substituted, and those higher than para-
substituted ones, clearly indicating a dependence be-
tween the ee and the steric environment of the aldehyde
carbonyl group.
OH
O
3, Ti(OPri)4
H
+
Me2Zn
CH2Cl2
Entry
Ligand
Additive
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
—
—
85
47
57
65
69
—
59
70
—
78
49
57
19
35
—
4c
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Cu(OAc)2
Ni(OAc)2
Ti(OiPr)4
The enantiomeric excesses found when using aliphatic
aldehydes (entries 13–15) were lower than for aromatic
ones. Unlike these, aliphatic aldehydes give lower yields
and ees when increasing the steric hindrance in the prox-
imity of the carbonyl group.
3d
3e
3a
3a
3ad
51
a Yields refer to isolated products.
b (S)-(ꢁ)-1-Phenylethanol.
2.3. Mechanistic considerations
c (R)-(+)-1-Phenylethanol.
In all of the cases, the reaction led to an alcohol with an
(S)-configuration resulting from the attack of the alkyl
group to the Si face of the aldehyde carbonyl. The ste-
reochemical course of the reaction can be rationalized
in terms of a transition state related to that proposed
for the addition of dialkylzinc to carbonyl compounds
using hydroxy sulfonamides as ligands in the presence
of titanium isopropoxide (Fig. 3).9c In these cases, the
transition state is considered to be a bimetallic alkyltita-
nium species, bearing two titanium atoms, one being the
coordination center for the aldehyde and the other car-
rying a methyl group transferred from dimethylzinc.22,23
Coordination of the aldehyde to the titanium atom takes
place anti to the apical isopropoxy group,22,23 which is
directed toward the less hindered face of the five-mem-
bered ring described by the octahedral titanium and
the ligand, opposite to the mandelic acid phenyl group.
Alternatively, a pentacoordinated cationic titanium
atom may be considered, with the benzaldehyde being
coordinated in the same way.9c,24 The aldehyde is ar-
ranged in such a way that the Si face of the carbonyl
group is exposed to the methyl group, which is trans-
ferred from the second titanium atom. This arrangement
might be stabilized by a hydrogen bond between the
ligand oxygen and the aldehyde hydrogen in a similar
way as described by Corey and Lee for other enantiose-
lective reactions,25 and by a p-stacking effect between
the aldehyde aryl group and the benzyl substituent on
the amido group of 3a.9c
d Et2Zn was used. (S)-(ꢁ)-1-Phenylpropanol.
The influence of the dialkylzinc reagent was also tested.
Surprisingly, the reaction with diethylzinc (entry 9) gave
a lower ee than the corresponding dimethylzinc reagent.
It is noteworthy that this tendency is the opposite of that
found with aminoalcohols20 and hydroxy sulfonamide
ligands.9g,21
The catalytic system formed by 3a and Ti(OiPr)4 was ap-
plied to other aromatic aldehydes. The results are shown
in Table 3. Reasonable to good yields and enantioselec-
tivities are obtained with most of the aromatic aldehydes
(entries 1–12). In general, we observed little dependence
of the enantioselectivity with the electronic character of
the substituent in the ortho- (entries 9–12) and meta- (en-
tries 6–8) substituted benzaldehydes. However, there
Table 3. Addition of Me2Zn to aldehydes catalyzed by 3a and titanium
isopropoxide
3a, Ti(OPri)4
OH
O
+
Me2Zn
R
H
R
CH2Cl2
Entry
Aldehyde
Yield (%)a
ee (%)b
1
Benzaldehyde
85
94
92
83
91
97
96
90
82
75
45
95
75
70
33
78
74
49
82
80
82
85
78
85
89
90
85
63
61
55
2
p-Chlorobenzaldehyde
p-Nitrobenzaldehyde
p-Methylbenzaldehyde
3
4
5
p-Methoxybenzaldehyde
m-Nitrobenzaldehyde
m-Methylbenzaldehyde
m-Methoxybenzaldehyde
o-Nitrobenzaldehyde
o-Methylbenzaldehyde
o-Ethylbenzaldehyde
o-Methoxybenzaldehyde
Decanal
6
H
7
O
O
Ti
O
N
8
O
O
O
O
Ti
O
9
10
11
12
13
14
15
O
Si
H
Me
Re
Dihydrocinnamaldehyde
Cyclohexanecarboxyaldehyde
π-stacking
a Yields refer to isolated products.
b S configuration in all the cases.
Figure 3. Proposed TS for the addition of dimethylzinc to benzalde-
hyde catalyzed by ligand 3a and Ti(OPri)4.

1956
G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1953–1958
This last effect could explain the low ee obtained with
aliphatic aldehydes, as well as the low ee obtained with
benzaldehyde and ligand 3e.
succinimide (4.2 g, 36.1 mmol) in anhydrous tetrahydro-
furan (140 mL) at 0 ꢁC under an argon atmosphere. The
cooling bath was removed and reaction mixture stirred
overnight, filtered and the cake of dicyclohexylurea
washed with THF (2 · 10 mL). The solvent was
removed under reduced pressure, and the residue
dissolved with ethyl acetate. The solution was washed
successively with saturated sodium carbonate, water,
1 M HCl (except in the case of 3d), water and brine
and dried over MgSO4. The solvent was removed under
reduced pressure and the crude product purified by flash
chromatography on silica gel eluting with hexane–ethyl
acetate mixtures (Yields are reported in Table 1).
3. Conclusions
In conclusion, we have shown that a-hydroxy amides,
such as N-substituted mandelamides, which are easily
prepared from chiral mandelic acid and amines, can
be successfully used as ligands in the enantioselective
addition of dialkylzinc reagents to aldehydes in the
presence of titanium isopropoxide. The outcome of
the reaction is largely dependent on the amino substitu-
ent of the ligand, therefore the catalytic activity and
enantioselectivity can be tuned by a proper selection
of the amine. Of all the tested amides, N-benzylmandel-
amide was shown to be superior. Better results have
been obtained with dimethylzinc than with the corre-
sponding diethylzinc reagent, this behavior being unu-
sual for this type of reaction. The enantioselection is
higher for aromatic aldehydes (o > m > p) than for ali-
phatic ones. The stereochemical course of the reaction
may be explained in the terms of a bimetallic TS similar
to that proposed for analogous reactions catalyzed by
hydroxy sulfonamides. Further design and applications
of a-hydroxy amides as ligands for enantioselective
reactions are under investigation and will be reported
in due time.
4.2.1. N-Benzyl-(S)-mandelamide 3a. Mp 134–135 ꢁC
25
D
25
D
(CH3OH) ½aꢂ ¼ þ83.2 (c 0.54, CHCl3), ½aꢂ
¼
25
D
þ45.7 (c 0.52, CH3OH), {lit26 ½aꢂ ¼ þ82.2 (c 1.09,
CHCl3)}; spectral data identical to those reported in
the literature.26a
4.2.2. N-[(R)-1-Phenylethyl]-(S)-mandelamide 3b. Mp
25
D
57–58 ꢁC (CH3OH) ½aꢂ ¼ þ115.2 (c 0.52, CHCl3),
25
D
25
D
½aꢂ ¼ þ143.2 (c 0.52, CH3OH), {lit27 ½aꢂ ¼ þ111.4 (c
1.2, CHCl3)}; spectral data identical to those reported
in the literature.27
4.2.3. N-[(S)-1-Phenylethyl]-(S)-mandelamide 3c. Mp
25
D
108–110 ꢁC (CH3OH) ½aꢂ ¼ þ11.1 (c 0.50, CHCl3),
25
D
25
D
½aꢂ ¼ ꢁ49.1 (c 0.50, CH3OH), {lit27 ½aꢂ ¼ þ11.1 (c
25
D
0.64, CHCl3), lit28 ½aꢂ ¼ ꢁ52.4 (c 0.50, CH3OH)}; spec-
tral data identical to those reported in the literature.27
4. Experimental
4.1. General
4.2.4. N-(Pyridin-2-ylmethyl)-(S)-mandelamide 3d. Mp
25
D
132–133 ꢁC (CH3OH); ½aꢂ ¼ þ46.8 (c 0.52, CHCl3),
25
½aꢂ ¼ þ33.3 (c 0.52, CH3OH); IR m 3300, 3131,
D
Commercial reagents were used as purchased. Dichloro-
˚
methane was distilled from CaH2 and stored over 4 A
1656 cmꢁ1; MS(EI) 243 (M++1, 1), 136 (16), 135 (100),
93 (21), 92 (37); HRMS 243.1086 C14H15N2O2 required
1
molecular sieves. All asymmetric reactions were carried
out in dry glassware under an argon atmosphere. Reac-
tions were monitored by TLC analysis using Merck Silica
Gel 60 F-254 thin layer plates. Flash column chroma-
tography was performed on Merck silica gel 60, 0.040–
0.063 mm. Specific optical rotations were measured
using sodium light (D line 589 nm). IR were recorded
as liquid films in NaCl for oils and as KBr discs for sol-
243.1134; H NMR (CDCl3) d 8.13 (1H, d, J = 5.0 Hz),
7.81 (1H, unresolved t), 7.52 (1H, t, J = 7.8 Hz), 7.37
(2H, dd, J = 7.0, 1.5 Hz), 7.30–7.15 (3H, m), 7.10 (1H,
d, J = 7.8 Hz), 7.03 (1H, dd, J = 7.8, 5.0 Hz), 5.65 (1H,
br s), 5.07 (1H, s), 4.42 (2H, d, J = 5.4 Hz); 13C NMR
(CDCl3) d 172.6 (s), 156.4 (s), 148.7 (d), 139.9 (s),
137.1 (d), 128.6 (d), 128.2 (d), 126.8 (d), 122.5 (d),
122.4 (d), 74.3 (d), 44.0 (t).
1
1
ids. H NMR were run at 299.95 MHz for H and at
50.3 MHz for 13C NMR, and referenced to the solvent
as internal standard. The carbon type was determined
by DEPT experiments. MS(EI) were run at 70 eV. Chi-
ral GLC analyses were carried out in a Thermo Quest
Trace GC 2000 series instrument equipped with a flame
ionization detector using nitrogen (1 mL/min) as carrier
gas, Tinjector = 220 ꢁC, Tdetector = 220 ꢁC. Chiral HPLC
analyses were performed in an Agilent 1100 series
instrument equipped with a refraction index detector.
Retention times for GLC and HPLC are given in min.
4.2.5. (N)-(tert-Butyl)-(S)-mandelamide 3e. Mp 74–
76 ꢁC (CH3OH) ½aꢂ
25
D
¼
þ63.4 (c 0.53, CHCl3),
25
D
24
D
½aꢂ ¼ þ28.1 (c 0.54, CH3OH), {lit29 ½aꢂ ¼ þ28.8 (c
0.54, CH3OH)}; spectral data identical to those reported
in the literature.29
4.3. Enantioselective addition of dimethylzinc to
aldehydes
To a solution of ligand 3a (48 mg, 0.2 mmol) in dry
CH2Cl2 (5 mL) under Ar was added Ti(OPri)4
(0.42 mL, 1.4 mmol). After 1 h, the reaction mixture
was cooled to 0 ꢁC and a 2 M solution of dimethylzinc
in toluene (3 mL, 6 mmol) was added. After 30 min,
the aldehyde (1 mmol) was added and stirring continued
at this temperature for 24 h. Then, the reaction was
quenched with 1 M HCl (20 mL) (CAUTION! Exother-
4.2. General procedure for the synthesis of mandelamides
3a–e
N,N0-Dicyclohexylcarbodiimide (7.5 g, 36.1 mmol) was
added to a stirred solution of (S)-(+)-mandelic acid
(5 g, 32.9 mmol), amine (32.9 mmol) and N-hydroxy-

G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1953–1958
1957
mic reaction, gas evolution), filtered and extracted with
diethyl ether (3 · 15 mL). The organic layer was washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Flash chromato-
graphy on silica gel eluting with hexane–diethyl ether
mixtures gave the corresponding alcohol. Yields and
ee are included in Table 3.
part by Generalitat Valenciana (AVCYT, grupos 03/
168). A.M-A. thanks the MECCD for a grant (FPU
program).
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`
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co b-dex-225): tR = 87.2, tS = 88.3 (Tcolumn = 85 ꢁC).
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(Mega DETTBSIL b): tR = 43.6, tS = 41.2 (Tcolumn
95 ꢁC (30 min) to 200 ꢁC at 3 ꢁC/min).
(S)-(ꢁ)-1-(2-Methoxyphenyl)-1-ethanol. GC
=
4.3.13. (S)-(+)-2-Undecanol. HPLC (Chiralpack AD-
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´
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pack AD-H): tR = 27.0, tS = 24.6 (hexane/iPrOH 98:2,
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This work was financially supported by the Spanish
Government (MCYT, project BQU 2001-3017) and in

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