Efficient asymmetric addition of diethylzinc to aldehydes using C 2-novel chiral pyridine β-amino alcohols as chiral ligands

Article abstract of DOI:10.1002/aoc.3161

A series of novel C₂-symmetric chiral pyridine β-amino alcohol ligands have been synthesized from 2,6-pyridine dicarboxaldehyde, m-phthalaldehyde and chiral β-amino alcohols through a two-step reaction. All their structures were characterized by ¹H NMR, ¹³C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2R)-2,2-((pyridine-2,6-diylbis(methylene)) bisazanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was used in toluene at room temperature. The ligand 3g (2S,2R)-2,2-((1,3-phenylenebis(methylene)) bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright

Full text of DOI:10.1002/aoc.3161

Full Paper
Received: 2 March 2014
Revised: 25 March 2014
Accepted: 9 April 2014
Published online in Wiley Online Library: 21 May 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3161
Efficient asymmetric addition of diethylzinc to
aldehydes using C2-novel chiral pyridine
β-amino alcohols as chiral ligands
Weijie Zhang, Ruiren Tang*, Huirong Yu and Shu Gao
A series of novel C2-symmetric chiral pyridine β-amino alcohol ligands have been synthesized from 2,6-pyridine
dicarboxaldehyde, m-phthalaldehyde and chiral β-amino alcohols through a two-step reaction. All their structures were
characterized by 1H NMR, 13C NMR and IR. Their enantioselective induction behaviors were examined under different
conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results
show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric
excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2′R)-2,2′-((pyridine-2,6-diylbis(methylene))
bisazanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was used in toluene at room temperature. The ligand 3g (2S,2′R)-2,2′-
((1,3-phenylenebis(methylene))bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was prepared in which the pyridine ring
was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring
in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the
asymmetric induction reaction. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: amino alcohol; C2-symmetric; diethylzinc; aldehydes; enantioselective addition; (S)-secondary alcohol
designed and synthesized; also their chiral inductive effects in
asymmetric addition of diethylzinc to aldehydes were investi-
Introduction
Synthesis of a chiral secondary alcohol by asymmetric addition of
dialkylzincs to an aldehyde is one of the most successful areas in
asymmetric synthesis of optically and biologically active
compounds. In order to develop more efficient ligands for the
reaction, much effort has been devoted towards the design and
preparation of various novel chiral ligands such as β-amino
alcohols,[1] amino thiols,[2] pyridyl alcohols,[3] amines,[4]
aminonaphthol,[5] o-hydroxylbenzylamines,[6] BINOL,[7] Ti
complexes,[8] polymers tethered to chiral ligands[9] and their
derivatives. Since the pioneering work of Oguni et al. in
1984,[10] the enantioselective addition of organozinc reagents
to aldehydes using chiral amino alcohols has received wide
attention as a model system for exploring asymmetric carbon–
carbon bond formation. Recently, this method has been used to
synthesize active natural product prostaglandin ω-side chain in
high enantioselectivity.[11] β-Amino alcohols, as one kind of
important ligand, may accelerate and direct the stereochemical
outcome of the asymmetric alkylation of aldehydes by zinc
dialkyls, sometimes achieving high stereoselectivity,[12] which
can be easily prepared and modified from natural, cheap chiral
amino acids, and are tolerant to moisture, oxygen and many
types of reagents. On the other hand, chiral C2-symmetric ligands
are one of the most widely employed catalysts for asymmetric
catalysis and have been shown to exhibit excellent
enantioselectivity in the alkylzinc addition to aldehydes, because
chiral C2-symmetric ligands have the advantage of reducing the
number of possible competing, diastereomeric transition
states.[13] Taking into account the above advantage of C2-
symmetric ligands and β-amino alcohols, a series of ligands
combining C2-symmetric ligands and β-amino alcohols were
gated. The pyridyl moiety, whose N atom has strong coordination
ability, was introduced into the ligands in order to investigate the
influence of the pyridine unit of chiral β-amino alcohols on
catalytic enantioselective additions of diethylzinc to aldehydes.
To the best of our knowledge, there has been only one report
so far, disclosed by Williams and co-workers applying 2,6-
disubstituted pyridiylmethyl amino alcohols as chiral ligands for
the enantioselective diethylzinc addition to aldehydes.[14] Instead
of setting (1R,2S)-ephedrine as the asymmetric center as Williams
did, we initially use a serial of chiral amino acid analogues which
comparatively make the study more systematic.
Williams carried out an extensive study on pyridine-based
dimeric amino alcohol ligand L2 in diethylzinc addition and com-
pared it with L1 containing no pyridine ring (Fig. 1). According to
the catalytic results of C2-symmetric ligands based upon incorpo-
ration of the two units (À)-(1R,2S)-ephedrine,[15] the two ligands
were found to lead to products with opposite chirality under
similar reaction conditions; in most cases, the enantioselectivity
of L2 was higher than that of L1. It was also found that L2 was
the most enantioselective ligand, giving 90% ee for the addition
reaction. Thus we hoped that C2-symmetric novel chiral pyridine
β-amino alcohol ligands could also catalyze the asymmetric
addition of diethylzinc to aldehydes. Herein we report a new type
*
Correspondence to: Ruiren Tang, School of Chemistry and Chemical
Engineering, Central South University, Hunan 410083, People’s Republic of
China. E-mail: trr@csu.edu.cn
School of Chemistry and Chemical Engineering, Central South University,
Hunan 410083, People’s Republic of China
Appl. Organometal. Chem. 2014, 28, 545–551
Copyright © 2014 John Wiley & Sons, Ltd.

W. Zhang et al.
the methyl ester hydrochloride in order to introduce a gem-diphenyl
group to the methyl ester hydrochloride provided the corresponding
amino alcohols 1a–f with 46–63% yield.
The route to the novel chiral C2-symmetric ligands 3a–g is shown
in Scheme 2. 2,6-Pyridinedicarboxaldehyde or m-phthalaldehyde
was mixed with β-amino alcohols 1a–f in dry ethanol and cyclohex-
ane and refluxed for 2 h; a Dean–Stark trap for removing water was
used for a further 2 h. Upon the removal of solvent, the Schiff bases
2 were obtained in viscous oil which could be directly used in the
next step without purification. The reduction of the Schiff bases 2
is the key step for preparation of the ligands. Sodium borohydride
was first employed in ethanol at room temperature for about 24 h;
thin-layer chromatography (TLC) showed that the reductions
proceeded rather sluggishly and too much solvent was needed in
the reaction. Sodium triacetoxyborohydride was then used in dry
l,2-dichloroethane (DCE) to reduce the Schiff bases following the
procedure of Christopher[15] and 3a–g were obtained in moderate
yields (46-66%); the work-up step was simple.
Figure 1. C2-symmetric ligands based upon incorporation of the two
units (À)-(1R,2S)-ephedrine.
of efficient C2-symmetric β-amino alcohol ligand, obtained from
naturally occurring L-α-amino acid based on active pyridine sys-
tems. Their enantioselective induction in enantioselective addi-
tions of diethylzinc to aldehydes are described and discussed in
detail.
Another route is designed to prepare the title compound
as shown in Scheme 3. Pyridine-2,6-dicarbonyl dichloride and
β-amino alcohol (take 1a as an example) were mixed together
in the presence of triethylamine in DCM and the 2a′ obtained
with 74% yield, then lithium aluminum hydride was used to try
to reduce amide 2a′ to afford the target product 3a. Unfortu-
nately, too many byproducts were found by TLC and the desired
product 3a could not be liberated through the reaction. This
synthetic route is not suitable for the title compound.
Results and Discussion
Synthesis of 1a–f, 2,6-Disubstituted Pyridylmethyl Amino
Alcohols 3a–f and 1,3-Disubstituted Benzyl Amino Alcohol 3g.
The synthesis of compounds 1a–f is shown in Scheme 1. The
corresponding β-amino alcohols 1a–f could be prepared from
the commercially available natural amino acids. We envisioned
an alternative synthesis of 1a–f in one-pot synthesis to give an
economical preparative method in which the reaction product
of the initial step was used directly without purification for the next
step. The key steps are shown as follows. 1a′–f′ were converted into
the methyl esters hydrochloride 1a″–f″ with excess SOCl2 in MeOH,
with 97% yield. Addition of excess phenylmagnesium bromide to
Enantioselective Addition of Diethylzinc to Aldehydes
2,6-Disubstituted pyridylmethyl amino alcohols 3a–f with differ-
ent substituent groups R were used as optically active ligands
to induct the asymmetric addition of diethylzinc
to benzaldehyde. The results are summarized in
Table 1.
The results showed that the enantioselectivity
(% ee) of the product catalyzed by ligands 3b
(5% ee), 3d (6% ee) and 3e (9% ee) was low.
However, when the ligand possessing a CH2
group at the α-carbon was used to catalyze the
addition reaction, the enantioselectivity improved
greatly. Comparing 3c with 3b, the former has a
CH2 group at the α-carbon, while the latter does
not; enantioselectivity was significantly improved
from 5% to 86% in the asymmetric induction. The
same result can also be found in ligands 3e and
3f, in which enantioselectivity increased from 9%
ee to 78% ee for the latter after inserting a CH2
side chain into the α-carbon of the ligand. It was also found
that ligand 3c, with an s-butyl group at the α-carbon,
provided higher enantioselectivity than that of ligand
3a or 3f, which possessed a relatively smaller methyl or
benzyl group. Bulkiness of the R group in 3a, 3c and 3f
increased in the order CH3 < CH2Ph < CH2CH(CH3)2, while
enantioselectivity improved from 55% ee (3a), to 78% ee
(3g) and 86% ee (3c). These results suggest that the
substituent at α-carbon plays a critical role in the
enantioselection of the addition reaction.
Scheme 1. Synthesis of 1a–f.
The influence and contribution exerted by the pyridine
of the ligands in the asymmetric diethylzinc addition to
benzaldehyde were also investigated. Three β-amino
alcohol derivatives – 3c, 3g and 1c – were investigated.
Scheme 2. Synthesis of 3a–g.
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Appl. Organometal. Chem. 2014, 28, 545–551

Efficient asymmetric addition of diethylzinc to aldehydes
Subsequently, reaction factors such as type of solvent,
catalytic amount and temperature for the asymmetric
induction reaction were optimized, and the results are
shown in Table 2. First, three types of solvent (THF,
DCM, toluene) were examined and the results revealed
that the less polar aromatic solvent toluene gave the
product with the highest enantioselectivity and accept-
able yield (Table 2, entries 2, 8 and 9). The effect of
amount of ligand on enantioselectivity was also
investigated. When the quantity of 3c was decreased from 20 to
3 mol%, the enantioselectivity in the ethylation of benzaldehyde
remained at 89% ee, but an even lower amount of ligand 3c
(1mol%) led to a sharp decrease in the enantioselectivity (69%
ee) in this reaction (Table 2, entry 1). Therefore, when the ratio of
ligand 3c to benzaldehyde was 3 mol%, high enantioselectivity
can be achieved. Concerning reaction temperature, it is noteworthy
that decreasing temperature affected neither the yield nor the
enantioselectivity to a great extent (Table 2, entries 5 and 6;
Table 1, entry 3).
Scheme 3. Synthesis of 3a.
From Table 1, ligand 3c, possessing the pyridine ring, gave a
product with enantioselectivity 86% ee, while 3g and 1c, which
did not possess a pyridine ring, gave a lower enantioselectivity
(75% ee and 68% ee). This result shows that the coordination of the
pyridine ring in 3c is required for high asymmetric induction.
Concerning the configuration (R or S) of product, only ligand
3e induces the addition reaction to give (R)-configuration of
alcohol, whereas a series of reverse (S)-configurations in the
stereochemistry of the product are achieved by other ligands in
the addition reaction.
Next, a series of aldehydes with different substituents were
examined under the optimal reaction conditions and the results
are summarized in Table 3. In all cases the reactions were
carried out smoothly in toluene at room temperature and as
with the addition to benzaldehyde, the corresponding alcohol
of (S)-configuration was obtained as the major enantiomer.
Obviously, the catalytic diethylzinc addition to aldehyde
possessing an electron-withdrawing group in the para position
of the aromatic ring proceeded with higher enantioselectivity
than the addition to an aldehyde with an electron-donating
group (Table 3, entries 1–4) probably due to an electronic
effect,13 and the same result (Table 3, entries 5 and 7) could be
obtained from the ortho-substituent aromatic aldehydes. The best
Table 1. Screening of ligands 3a–g, 1c for the enantioselective
addition of diethylzinc to benzaldehydea
Ligand
R
Yieldb (%)
eec (%)
Config.d
3a
3b
3c
3d
3e
3f
―CH3
70
79
83
72
82
78
80
79
55
5
S
S
S
S
R
S
S
S
―CH(CH3)2
―CH2CH(CH3)2
―CHCH3(CH2CH3)
―Ph
86
6
9
―CH2Ph
78
75
68
3g
1c
―CH2CH(CH3)2
―CH2CH(CH3)2
aThe reaction was carried out in toluene with 3 mol% ligand, 3.0–3.5
equiv. of diethylzinc (1.0 M solution in hexane) to benzaldehyde for
5 h at room temperature.
bIsolated yields by chromatographic purification.
Table 3. Enantioselective addition of diethylzinc to various aldehydes
in the presence of ligand 3ca
cDetermined by HPLC using a chiral OD-H column.
dDetermined by comparison of optical rotations with the literature.
Table 2. Optimization of the asymmetric addition of diethylzinc to
benzaldehyde catalyzed by 3ca
Entry
Aldehyde
Yieldb ( %)
eec (%)
Config.d
1
2
4-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
79
78
75
80
76
74
83
78
80
78
82
79
83
86
77
89
84
76
85
32
S
S
S
S
S
S
S
S
S
S
Entry Mol%,
T
(°C)
Solvent Time Yieldb
eec
(%)
Config.d
2c
(h)
(%)
3
1
2
3
4
5
6
7
8
9
1.0
3.0
5
r.t.
r.t.
r.t.
r.t.
0
T/H
T/H
T/H
T/H
T/H
5
5
75
84
86
78
82
74
74
78
81
69
89
84
83
86
88
84
78
72
S
S
S
S
S
S
S
S
S
4
4-BrC6H4CHO
5
2-MeC6H4CHO
3-MeC6H4CHO
2-ClC6H4CHO
5
6
20
5
7
10
10
5
28
28
28
5
8
(E)-Cinnamaldehyde
2-Naphthaldehyde
2-Furaldehyde
À20 T/H
9
0
T/H
10
10
10
r.t.
r.t.
DCM/H
THF/H
aThe reaction was carried out in toluene with 3 mol% ligand, 3.0–3.5
equiv. of diethylzinc (1.0M solution in hexane) to benzaldehyde for 5 h
at room temperature.
bIsolated yields by chromatographic purification.
cDetermined by HPLC using a chiral OD-H or AD-H column.
dDetermined by comparison of optical rotations with the literature.
5
aT/H, Toluene/hexane, 4/1 (v/v); DCM/H, THF/H, 4/1 (v/v).
bIsolated yields by chromatographic purification.
cDetermined by HPLC using a chiral OD-H column.
dDetermined by comparison of optical rotations with the literature.
Appl. Organometal. Chem. 2014, 28, 545–551
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W. Zhang et al.
asymmetric induction was found using m-methyl benzaldehyde as
the substrate, which gave up to 89% ee compared with other
substituted benzaldehydes (Table 3, entries 1–7). However,
2-furaldehyde was the poorest substrate of the addition reaction,
giving 32% ee. This result can be explained by the heteroatoms
on the ring participating in the competition coordination, which
interfere with enantiomeric recognition (Table 3, entry 10). In testing
some representative aromatic aldehydes, when the enantio-
selective addition of diethylzinc to α,β-unsaturated aldehyde
(E)-cinnamaldehyde was performed under the same reaction
conditions, unfortunately the enantioselectivity was at a lower level
compared with that obtained from aromatic aldehydes (Table 3,
entries 4, 6, 8 and 9). The reactions on aliphatic aldehydes cannot
be carried out due to lack of baseline separation of products on
chiral columns and the limited analysis conditions available in
our laboratory.
alkoxide from 8 afforded the product 9 with the elimination
of 5. Aqueous workup led to (S)-1-phenylpropan-1-ol, in
accord with the experimental results.
Conclusion
In summary, a novel range of C2-symmetric chiral amino alcohols
3a–g has been conveniently synthesized from 2,6-pyridine-
dicarboxaldehyde, m-phthalaldehyde and chiral β-amino
alcohols. They were applied to the asymmetric addition to
various aldehydes with diethylzinc. Among them, 3c was found
to give highly efficient asymmetric induction (up to 89% ee),
which can be attributed to the presence of the pyridine ring
and a CH2 group at the α-carbon as a side chain. It is also noted
that with 3 mol% ligand 3c, at room temperature, the less polar
aromatic solvent toluene was the most effective for asymmetric
induction. Further applications of this type of chiral ligand for
asymmetric reduction of prochiral ketone with borane are under
investigation and will be reported in due course.
Possible Reaction Mechanism
By comparing the experimental results catalyzed by ligand 3c
(up to 86% ee) with 3g (up to 75% ee) (Table 1), we can
conclude that the coordination of the N atom on the pyridine
ring with diethylzinc plays an important role in the reaction.
Perhaps it is because the modes of the initial coordination of
the aldehyde in the ligand 3c and 3g system were different.
Based on the above experimental results, theoretical analysis
and the related mechanism suggested by Wu[16] and Corey[17]
a possible reaction mechanism was proposed, as shown in
Fig. 2. 3 reacts with diethylzinc to generate the corresponding
zinc complex 4 and then converts to a tricyclic transition state
5. The alkoxy oxygen atom in complex 5 coordinates with 1
equiv. of diethylzinc to give the transition state 6. In the
second step the benzaldehyde coordinates the zinc atom to
afford 7, then the ethyl group attacks the carbonyl group to
form a six-membered cyclic structure 8. Removal of zinc
Experimental
General Methods
Melting points were recorded on an X-4 apparatus and are
uncorrected. 13C NMR and H NMR spectra were recorded on a
1
Bruker DPX 500 or 400 spectrometer using CDCl3 or deuterated
DMSO-d6 as the solvent and TMS as an internal standard. Optical
rotations were recorded with a Jasco-P-2000 digital polarimeter.
IR spectra were recorded on KBr pellets on a Nicolet Impact 400D
spectrophotometer. Enantioselectivity values were measured by
HPLC, which was carried out on a Waters 600E type instrument
using a chiral column (Chiralcel OD-H, AD-H Daicel Chemical
Industries) and UV detector at 254 nm for determining the
optical purity of the products by elution of
isopropanol and hexane. Preparative TLC was
performed on dry silica gel (60 F254) plates. Merck
silica gel 60 (particle size 0.04–0.063 mm) was
employed for flash chromatography.
General Procedure for the Synthesis of Amino Alcohols
1a–f
All reactions were carried out under nitrogen
atmosphere. 1,2-Dichloroethane, THF and toluene were
dried over 4 Å molecular sieves. L-α-Amino acids and
diethylzinc as a 1.0M solution in hexane were purchased
from Aldrich Chemical Company.
(S)-2-Amino-1,1-diphenyl-propan-1-ol (1a)
1a was easily prepared by the portion-wise addition of
L-alanine methyl ester hydrochloride (3.1 g, 22.4 mmol)
to phenylmagnesium bromide (24.4 g, 134.4 mmol) in
THF at 0°C; the above solution was heated to room
temperature and stirred for 20 h. After quenching with
crushed ice and NH4Cl salt, the organic layer was
separated and the aqueous layer was extracted with
AcOEt (25 ml × 3). Combined organic extracts were
dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel
column chromatography (ethyl acetate and petroleum
Figure 2. The proposed catalytic mechanism.
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Appl. Organometal. Chem. 2014, 28, 545–551

Efficient asymmetric addition of diethylzinc to aldehydes
ether, 4:1, v/v ) to give the title compound 1a. White solid; yield
and followed by the addition of 1,2-dichloroethane (20 ml) and
sodium triacetoxyborohydride (6.3 g, 114.8 mmol). The mixture
was stirred at room temperature for 4 h. After removal of the solvent,
saturated aqueous Na2CO3 (35 ml) solution was added to the resi-
due and stirred for 0.5 h. The aqueous solution was extracted with
ethyl acetate (25 ml × 3). The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The resi-
due was loaded on a silica gel column chromatograph and purified
by methanol and water or ethanol to afford the pure product.
63%; m.p. 93–94°C; [α]2D5 = À55.0 (c = 0.5, CH2Cl2); IR (KBr) vmax
=
3432, 3390, 3324, 3082, 3057, 2986, 2902, 1588, 1488, 1446,
1
1362, 1175, 968, 746, 702 cmÀ1; H NMR (400 MHz, DMSO-d6) δ:
0.80 (d, 3H, J = 4.0 Hz, CH3), 3.99 (m, 1H, CHNH2), 5.20 (s, 1H,
OH), 7.11–7.62 (m, 10H, PhH).
(S)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol (1b)
This compound was synthesized by the same procedures as 1a and
purified by silica gel column chromatography (ethyl acetate and petro-
leum ether, ranging from 2:1 to 4:1, v/v) to give the title compound 1b.
White solid; yield 57%; m.p. 92–93°C; [α]2D5 =À128.0 (c=0.5, CHCl3); IR
(KBr) vmax = 3344, 3277, 2960, 2873, 1592, 1491, 1446, 1380, 1173,
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(1,1-diphenyl-
propan-1-ol) (3a)
1048, 749, 699 cmÀ1 1H NMR (400 MHz, CDCl3) δ: 0.86 (d, 3H,
;
J=5.2Hz, CH3), 0.88 (d, 3H, J=5.2Hz, CH3), 1.70 (m, 1H, CH(CH3)2),
2.20 (s, 1H, OH), 3.85 (d, 1H, J = 2.0 Hz, CHNH2), 5.38 (s, 2H, NH2),
7.18–7.62 (m, 10H, PhH).
(S)-2-Amino-4-methyl-1,1-diphenylpentan-1-ol (1c)
The crude product was purified by silica gel column chromatogra-
phy (methylene chloride and ethyl acetate, 1:2, v/v), then
recrystallized by methanol and water. 3a was obtained as a white
solid in 66% yield; m.p. 88–89°C; [α]2D5 =À28.0 (c=0.5, CH2Cl2); IR
(KBr) vmax = 3326, 3261, 3086, 3057, 2968, 2926, 1574, 1491, 1449,
This compound was synthesized by the same procedures as 1a and
purified by silica gel column chromatography (methylene chloride
and petroleum ether, ranging from 1:2 to 1:0, v/v). White solid; yield
46%; m.p. 137–139°C; [α]2D5 = À106.0 (c = 0.5, CHCl3); IR (KBr) vmax
=
;
1
748, 705 cmÀ1; H NMR (400 MHz, CDCl3) δ: 0.93 (d, 6H, J=8.0Hz,
3337, 3267, 2954, 2886, 1595, 1492, 1448, 1056, 746, 700 cmÀ1
1H NMR (400 MHz, CDCl3) δ: 0.86 (d, 3H, J = 6.8 Hz, CH3), 0.89
(d, 3H, J = 6.4 Hz, CH3), 1.15 (m, 1H, CH(CH3)2), 2.20 (s, 1H, OH), 1.62
(m, 2H, CH2CH(CH3)2), 3.97 (t, 1H, CHNH2), 7.26–7.62 (m, 10H, PhH).
CH3), 1.15–1.19 (s, 2H, OH), 3.75–3.79 (m, 2H, CHNH), 3.61–3.39
(m, 4H, PyCH2), 5.44 (s, 2H, CHNH), 6.93–6.95 (d, 2H, J=8.0Hz, PhH),
7.08–7.49 (m, 21H, PyH, PhH). 13C NMR (500 MHz, CDCl3) δ: 15.7 (C4),
54.8 (C5), 67.9 (C6), 78.8 (C7), 120.0 (C11), 125.8, 126.0, 126.3, 126.5
(C9), 127.3, 127.9 (C10), 136.9 (C8), 146.2 (C2), 149.7 (C1), 158.2 (C3).
(S)-2-Amino-3-methyl-1,1-diphenylpentan-1-ol (1d)
This compound was synthesized by the same procedures as 1a and
purified by recrystallization from ethanol. White solid; yield 52%;
m.p. 174–176°C; [α]D25 =À95.0 (c=0.9, CHCl3); IR (KBr) vmax = 3320,
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(3-methyl-1,
1-diphenylbutan-1-ol) (3b)
1
3200, 3100, 3016, 2920, 1483, 1446, 1170, 1000, 745, 699 cmÀ1; H
NMR (400 MHz, DMSO-d6) δ: 0.86 (d, 3H, J=5.2Hz, CH3), 0.88 (d, 3H,
J=5.2Hz, CH3), 1.70 (m, 1H, CH(CH3)2), 2.20 (s, 1H, OH), 3.85 (d, 1H,
J=12Hz, CHNH2), 5.38 (s, 2H, NH2), 7.18–7.62 (m, 10H, PhH).
(S)-2-Amino-1,1,2-triphenylethanol (1e)
The crude product was purified by silica gel column chromatog-
raphy (methylene chloride and ethyl acetate ranging from 1:0 to
0:1, v/v ), then recrystallized by ethanol. 3b was obtained as a white
solid in 46% yield; m.p. 174–175°C; [α]2D5 = À76.0 (c = 0.5, CH2Cl2); IR
(KBr) vmax = 3325, 3062, 3022, 2952, 2871, 1580, 1489, 1446, 1059,
This compound was synthesized by the same procedures as
1a and purified by recrystallization from ethanol. White solid;
yield 50%; m.p. 146–148°C; [α]2D5 = À76.0 (c = 0.5, CHCl3); IR (KBr)
v
max = 3385, 3312, 3060, 3027, 1578, 1491, 1448, 749, 730,
698 cmÀ1 1H NMR (400 MHz, CDCl3) δ: 1.65 (s, 2H, NH2), 5.04
;
(s, 1H, PhCHN), 4.71 (s, 1H, OH), 7.46–7.79 (m, 2H, PhH), 7.15–7.33
1
754, 705 cmÀ1; H NMR (400 MHz, CDCl3) δ: 0.71 (d, 6H, J = 4.2Hz,
CH(CH3)2 ), 0.87 (d, 6H, J = 4.0 Hz, CH(CH3)2 ) 1.95–1.98 (m, 2H, CH
(CH3)2), 3.24 (s, 2H, PyCH2), 3.38 (s, 2H, PyCH2), 3.52 (s, 2H, CHNH),
5.23 (s, 2H, CHNH), 6.65–7.65 (m, 23H, PhH, PyH). 13C NMR
(500 MHz, CDCl3) δ: 16.0(C12), 22.7 (C13), 29.0 (C4), 55.3 (C5), 68.7
(C6),78.6 (C7), 120.7(C11), 125.8, 126.1, 126.4 (C9), 127.9, 136.6
(C10), 145.4(C2), 149.2(C1), 158.5(C3).
(m, 4H, PhH), 7.03–7.09 (6H, m, PhH).
(S)-2-Amino-1,1,3-triphenylpropan-1-ol (1f)
This compound was synthesized by the same procedures as 1a and
purified by recrystallization from ethanol. White solid; yield 55%;
m.p. 152–153°C; [α]D25 = À67.0 (c= 0.5, CHCl3); IR (KBr) vmax = 3366,
3058, 3023, 2962, 2861, 1597, 1491, 1449, 1055, 748, 700 cmÀ1; H
1
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(4-methyl-1,
1-diphenylpentan-1-ol) (3c)
NMR (400 MHz, CDCl3) δ: 1.20 (s, 2H, NH2 ), 2.34 (t,1H, J=12Hz,
H2Ph), 2.56 (d, 1H, J= 12.0 Hz, CH2Ph), 2.20 (s, 1H, OH), 3.85 (d, 1H,
J= 12.0 Hz, CHNH2), 7.10–7.58 (m, 15H, PhH).
General Procedure for the Synthesis of Ligands 3a–3g
A solution of compound 1a–f (7.4 mmol), 2,6-disubstituted pyridine-
carboxaldehyde (0.25 g, 3.7 mmol) or m-phthalaldehyde (0.25 g,
3.72 mmol) in ethanol/cyclohexane was heated to reflux for 2 h,
followed by use of a Dean–Stark trap for removing water for a
further 2 h. The solvent was evaporated under reduced pressure,
The crude product was purified by silica gel column chroma-
tography (methylene chloride and ethyl acetate ranging from
Appl. Organometal. Chem. 2014, 28, 545–551
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

W. Zhang et al.
1:0 to 0:1, v/v), then recrystallized by ethanol. 3c was obtained as
white solid in 51% yield; m.p. 137–138°C; [α]2D5 = À60.0 (c = 0.5,
CH2Cl2); IR (KBr) vmax = 3349, 3060, 3027, 2951, 1591, 1491, 1449,
The crude product was purified by silica gel column chroma-
tography (methylene chloride and ethyl acetate ranging from
1:0 to 0:1), then recrystallized by methanol and water. 3f was
obtained as a white solid in 56% yield; m.p. 72–73°C; [α]2D5 = À32.0
(c = 0.5, CH2Cl2); IR (KBr) vmax = 3326, 3058, 3062, 1594, 1492, 1449,
1052, 746, 699 cmÀ1; 1H NMR (400 MHz, CDCl3) δ: 2.96–3.00 (d, 2H,
J = 16.0Hz, PhCH2), 3.13–3.24 (m, 6H, PhCH2 , PyCH2), 3.99–4.01
(d, 2H, J = 8.0 Hz, CHNH), 5.32 (s, 2H, CHNH), 6.47–6.49 (d, 2H,
J = 8.0 Hz, PhH), 7.05–7.70 (m, 31H, PhH, PyH). 13C NMR (500 MHz,
CDCl3) δ: 37.8 (C4), 53.9 (C5), 68.5(C6), 78.6(C7) , 119.9 (C11, C15),
125.8(C9), 126.1, 126.2(C10), 126.5(C13), 126.7(C14), 128.2(C12),
136.29(C8), 139.6 (C2), 145.2 (C1), 147.6 (C3).
1031, 749, 705 cmÀ1 1H NMR (400 MHz, CDCl3) δ: 0.66 (d, 6H,
;
J = 6.4 Hz, CH(CH3)2), 0.76 (d, 6H, J = 6.4 Hz, CH(CH3)2), 1.34–1.65
(m, 6H, CHCH2(CH3)2), 3.10–3.39 (s, 2H, PyCH2), 3.40–3.60 (s, 2H,
PyCH2), 3.60–3.70 (s, 2H, CHNH), 4.70–5.40 (s, 2H, CHNH), 6.70–
6.80 (d, 2H, J = 8.2 Hz, PhH), 7.10–7.58 (m, 21H, PyH, PhH). 13C
NMR (500 MHz, CDCl3) δ: 21.6 (C4), 24.0 (C13), 40.6(C12), 54.3(C6),
62.8(C5), 78.6(C7), 120.7(C11), 125.9, 126.1, 126.3, 126.5(C9), 128.0
(C10), 136.6(C8), 145.2(C2), 148.1(C1), 158.9(C3).
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(3-methyl-
1, 1-diphenylpentan-1-ol) (3d)
(2S,2′R)-2,2′-((1,3-Phenylenebis(methylene))bis(azanediyl))bis(4-methyl-1,
1-diphenylpentan-1-ol (3g)
The crude product was purified by silica gel column chromatog-
raphy (methylene chloride and ethyl acetate ranging from 1:0 to
0:1, v/v), then recrystallized by ethanol. 3d was obtained as a white
solid in 49% yield; m.p. 177–179°C; [α]2D5 = -84.0 (c= 0.5, CH2Cl2); IR
(KBr) vmax = 3349, 3060, 3027, 2951, 1591, 1575, 1491, 1449, 1050,
The crude product was purified by silica gel column chroma-
tography (ethyl acetate and petroleum ether, 1:9, v/v) and 3g
was obtained as white solid in 46% yield; m.p. 56–58°; [α]D25
=
À68.0 (c = 0.5, CH2Cl2); IR (KBr) vmax = 3432, 3057, 3026, 2954,
1597, 1491, 1448, 1464, 1383,1364, 1031, 748, 703 cmÀ1 1H
;
1
749, 704 cmÀ1; H NMR (400 MHz, CDCl3) δ: 0.52 (s, 8H, CH2CH3),
NMR (400 MHz, DMSO-d6) δ: 0.76–0.80 (dd,12H, J = 16.0 Hz, CH
(CH3)2), 1.07–1.13 (m, 2H, CH(CH3)2), 1.13–1.49 (m, 4H, CH2CH),
1.59–1.63 (s, 2H, OH), 3.06–3.09 (d, 2H, J= 12.0 Hz, PyCH2), 3.26–3.29
(d, 2H, J=12.0Hz, PyCH2), 3.59–3.61 (m, 2H, CHCH2(CH3)2),
6.89–7.29 (m, 16H, PhH), 7.52–7.69 (m, 8H, PhH). 13C NMR (500 MHz,
CDCl3) δ: 20.1 (C4), 24.9 (C13), 39.8 (C12), 53.2 (C6), 61.4 (C5), 78.5
(C7), 119.0 (C11), 123.2 (C2), 124.7, 125.1, 124.9 (C9), 125.6 (C1),
127.3 (C10), 130.2 (C15), 131.4 (C3), 136.8 (C8).
0.78 (m, 10H, CH2CH3, CH2CH), 3.33 (s, 2H, PyCH2), 3.46–3.49 (s,
2H, J = 12.0Hz, PyCH2), 5.75 (s, 2H, CHNH), 6.66–6.68 (d, 2H,
J = 8.0Hz, PhH), 7.06–7.64 (m, 21H, PhH, PyH). 13C NMR (500MHz,
CDCl3) δ: 12.3 (C14), 18.7 (C13) 22.4 (C12), 36.2 (C16), 55.3 (C5),
69.7 (C6), 78.5 (C7), 120.7(C11), 125.9, 126.1, 126.2, 126.5 (C9),
127.8(C10), 136.8 (C8), 145.4 (C2), 149.2 (C1), 158.5 (C3).
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(1,1,2-triphen-
ylethanol) (3e)
General Procedure for the Enantioselective Diethylzinc Ad-
dition to Aldehydes
To a stirring mixture of ligand 3c (0.01 mmol) in toluene, diethylzinc
(1.0M in n-hexane, 3.0–3.5 mmol) was added by syringe at room
temperature and the mixture was stirred for 2 h, followed by
addition of the corresponding aldehyde (0.1 mmol). The mixture
was stirred for 5–28 h at room temperature, and then quenched
with 10–15 ml of a 10% solution of hydrochloric acid. The organic
layer was separated and the aqueous phase was extracted with
AcOEt (15 ml × 3). The organic layers were combined and dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate and petroleum ether, 1:9, v/v) to afford the corresponding
The crude product was purified by silica gel column chromatog-
raphy (ethyl acetate and petroleum ether, 1:8, v/v), then
recrystallized by methanol and water. 3e was obtained as a white
solid in 56% yield; m.p. 185–187°C; [α]2D5 = À42.0 (c = 0.5, CH2Cl2);
IR (KBr) vmax = 3419, 3059, 3026, 1592, 1492, 1449, 1032, 748,
697 cmÀ1; 1H NMR (400 MHz, DMSO-d6) δ: 3.51–3.52 (d, 4H, PyCH2),
4.69 (s, 2H, PyCH), 5.65 (s, 2H, NH), 6.94–7.24 (m, 31H, PhH, PyH),
7.57–7.62 (m, 2H, PyH). 13C NMR (500 MHz, CDCl3) δ: 52.8 (C5),
70.2 (C6), 78.4 (C7) 112.0 (C11), 124.9 (C9, C12), 125.7 (C14), 127.7
(C10, C13), 128.4 (C4), 135.6 (C8), 139.2 (C2), 144.7 (C1), 148.2 (C3).
chiral alcohol as
a
colorless oil or light-yellow solid.
Enantioselectivity was determined by HPLC analysis using a
Chiralcel OD-H or AD-H column. Conditions of HPLC analysis:
Chiralcel OD-H and Chiralcel AD-H 4.0mm× 250 mml; detection,
254 nm light. OD-H: for (R)-1-phenyl-propan-1-ol: eluent: hexane/
(2S,2′R)-2,2′-((Pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(1,1,3-triphen-
ylpropan-1-ol) (3f)
i-PrOH, 98:2; flow rate: 1.0 mlminÀ1
.
For (R)-1-(2-naphthyl)-
propan-1-ol: eluent: hexane/i-PrOH, 95:5; flow rate: 1.0 mlminÀ1
For (R)-1-(4-Bromo-phenyl)-propan-1-ol: eluent: hexane/i-PrOH,
96:4; flow rate: 0.5 mlminÀ1
For (R)-1-(4-methoxy-phenyl)-
propan-1-ol: eluent: hexane/i-PrOH, 97:3; flow rate: 0.5 mlminÀ1
.
.
.
For (R)-1-m-tolyl-propan-1-ol: eluent: hexane/i-PrOH 98:2; flow
rate: 0.5mlminÀ1. For (R)-1-(4-chloro-phenyl)-propan-1-ol: eluent:
hexane/i-PrOH, 97:3; flow rate: 0.5 mlminÀ1. For 1-phenyl-pent-1-
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 545–551

Efficient asymmetric addition of diethylzinc to aldehydes
en-3-ol: eluent: hexane/i-PrOH, 97:3; flow rate: 1.0 mlminÀ1. For
(R)-1-(2-furyl)-1-propanol: eluent: hexane/i-PrOH, 99:1; flow rate:
[5] a) C. Cardellicchio, G. Ciccarella, F. Naso, F. Perna, P. Tortorella,
Tetrahedron 1999, 55, 14685–14692. b) D. X. Liu, C. Z. Li, Q. Wang,
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1.0 ml minÀ1
. AD-H: for (R)-1-o-tolyl-propan-1-ol, (R)-1-p-tolyl-
propan-1-ol, (R)-1-(2-chloro-phenyl)-propan-1-ol: eluent: hexane/
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Acknowledgments
This work was financially supported by the National Natural Sciences
Foundation of the People’s Republic of China (No. 21071152).
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Appl. Organometal. Chem. 2014, 28, 545–551
Copyright © 2014 John Wiley & Sons, Ltd.
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