Investigation of catalytic activity and catalytic mechanism of chiral amino diol tridentate ligands in the asymmetric addition of aldehydes in the present of methyllithium reagent

Article abstract of DOI:10.1016/j.jorganchem.2014.06.012

Several highly modular chiral amino diol tridentate ligands were found to be effective for the asymmetric alkylation reaction of aromatic aldehydes in the presence of methyllithium reagent, providing up to 96% ee values and up to 94% yields under relatively mild conditions. The investigation of the catalytic activity of these ligands shows a correlation of enantioselectivities of ligands with steric properties of substituent N-alkyl and nucleophilic Li-alkyl. With the addition of Ti(O-i-Pr)₄ to the ligand 3c, the ¹H NMR spectrum reveals a hexa-coordinate Ti transition state complex with only one Ti metal center generated in solution.

Full text of DOI:10.1016/j.jorganchem.2014.06.012

Journal of Organometallic Chemistry 768 (2014) 50e55
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Investigation of catalytic activity and catalytic mechanism of chiral
amino diol tridentate ligands in the asymmetric addition of aldehydes
in the present of methyllithium reagent
An-Lin Zhang, Li-Wen Yang*, Nian-Fa Yang*, Da-Cai Liu
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University,
Hunan 411105, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Several highly modular chiral amino diol tridentate ligands were found to be effective for the asymmetric
alkylation reaction of aromatic aldehydes in the presence of methyllithium reagent, providing up to 96%
ee values and up to 94% yields under relatively mild conditions. The investigation of the catalytic activity
of these ligands shows a correlation of enantioselectivities of ligands with steric properties of substituent
N-alkyl and nucleophilic Li-alkyl. With the addition of Ti(O-i-Pr)4 to the ligand 3c, the 1H NMR spectrum
reveals a hexa-coordinate Ti transition state complex with only one Ti metal center generated in solution.
© 2014 Elsevier B.V. All rights reserved.
Received 7 February 2014
Received in revised form
18 May 2014
Accepted 16 June 2014
Available online 28 June 2014
Keywords:
Organolithium
Asymmetry
Alkylation
Enantioselectivity
Introduction
underutilized in organic synthesis. It is also well known that
enantioselectivities of chiral ligand-catalyzed reactions are always
b
-amino alcohols are the most often used chiral auxiliaries. In
related to the steric effects of ligands besides their electronic effects
[12,13]. Thus, it should be of interest to explore the catalytic ability
of bulky amino diol ligands derived from (R)-ECH.
recent years, aromatic and aliphatic amino diols bearing a 1, 2- or a
1, 3-amino alcohol moiety have proven to be useful building blocks
[1e3]. They have been applied as chiral catalysts or starting ma-
terials in the stereoselective synthesis of compounds of pharma-
cological interest. In addition to their synthetic importance, amino
diols can also be applied as chiral ligands and auxiliaries in enan-
tioselective transformations [4e6]. In this regard, the asymmetric
addition of organometallic reagents to aldehydes has become a
highly investigated model reaction, with the application of chiral
promoters such as 1,2- or 1,3-difunctionalized ligands [7e9].
Although numerous enantiopure chelating ligands have been pre-
pared, there is still a need for new types obtainable by concise
syntheses from inexpensive starting materials. Enantiopure
epichlorohydrin (ECH) is a key chiral synthon and building block for
preparing chiral pharmaceuticals and agrochemicals such as
Over the past decades, an overwhelming majority of chiral
catalysts have been developed and applied for the reaction of
organolithium reagents with aromatic aldehydes, while most of the
ligands could not simultaneously show good yields and enantio-
selectivities in the organolithium additions to a broad range of ar-
omatic substrates [14e19], and successful methods often require
non-ideal conditions (temperatures < ꢀ100 ꢁC and equimolar
quantities of chiral ligand) [20]. In addition, The catalytic enantio-
selective addition of terminal alkynes to aldehydes has recently
generated a tremendous amount of interest [21,22]. The resulting
propargylic alcohols are versatile building blocks for fine chemicals,
pharmaceuticals, and natural products [23,24]. However, on the
one hand, in the wonderful studies [25,26], synthetic chiral ligands
served for metals, while on the other hand, there is only few reports
of high enantioselectivity for the alkynylation of carbonyl com-
pound in the presence of organolithium rather than organozinc
[27e29], Herein, we report a highly efficient catalytic system
(Scheme 1) for the asymmetric additions of several organometallic
reagents to aldehydes using chiral amino diol tridentate ligands
3aed with bulky substituent and Ti(O-i-Pr)4 as cocatalysts.
pheromones,
L-carnitine and b-blockers [10,11]. (R)-ECH are
commercially available enantiopure epoxides that has been
* Corresponding authors.
E-mail addresses: yangliwen_0519@163.com (L.-W. Yang), nfyang@xtu.edu.cn,
xtu1986xtu@gmail.com (N.-F. Yang).
http://dx.doi.org/10.1016/j.jorganchem.2014.06.012
0022-328X/© 2014 Elsevier B.V. All rights reserved.

A.-L. Zhang et al. / Journal of Organometallic Chemistry 768 (2014) 50e55
51
best asymmetric activity with 80% ee and 90% yield (Table 1, entry
3). The ligand 3c was then used for the addition of methyllithium to
several aromatic aldehydes under the optimal reaction conditions
(Table 1, entries 5e11). The reactions were performed using
10% mol of the catalyst in toluene. With regard to the additions of
LiCH3 to various aromatic aldehydes with electron-donating group
or electron-withdrawing group, good enantioselectivities and good
chemoselectivities were observed (Table 1, entries 5e9). As can be
seen from the summarized results (Table 1), this method was highly
efficient for all of aromatic aldehydes studied; the sec-alcohols
were obtained with 80e86% ee value and up to 80e92% yield. It was
Scheme 1. Synthetic strategy for the synthesis of chiral amino diol tridentate ligands.
Results and discussion
worth mentioning that, in previous reports, when chiral b-amino
alcohols were used as catalysts for the asymmetric addition of
organolithium to aldehydes, the reaction had to be performed in
the presence of chiral ligand at a lower temperature in order to
obtain good yields and good enantioselectivities because of the
increased reactivity of organolithium with raising the reaction
temperature [15,31].
The synthesis of new amino diol ligands 3aed is straightforward
(Scheme 1). Considering the strongly rigidity nature of triphe-
nylmethyl, we speculated that the introduction of bulky and rigid
triphenylmethyl group on the side chains can make the structure of
amino diols become more rigid. One possible reason is that the
strong repulsive interaction between the bulky and rigid triphe-
nylmethyl group and the alkyl on the nitrogen atom of the amino
diol chain leads to this tetrahedral structure that is a stable
conformation. Another reason is due to formation of an intra-
molecular hydrogen bond [30], which further prevents nitrogen
inversion. The stable rigid structures could be beneficial to the
investigation of catalytic activity and catalytic mechanism of amino
diol ligands.
Given these, the new amino diol ligands were initially applied in
the enantioselective addition of methyllithium to benzaldehyde in
toluene. As shown, 3aed derived from (R)-ECH gave good yields
and good enantioselectivities under the optimal reaction condi-
tions (Table 1, entries 1e4). The enantioselectivity depended on the
rigidity of R1 on the nitrogen atom of the amino diol, namely, the
order was A < B < C < D, which indicated that increase in the
bulkiness of the achiral auxiliary increased the enantioselectivity of
the reaction. The ee value of product increased with increasing
bulkiness of the N-alkyl group (R1) in the following order: 3a(n-
Bu) < 3b(cyclohexyl) < 3c(Ph2CH2) < 3d(tert-Bu), i.e., there was a
trend among ligands 3a, 3b, 3c, 3d that the catalytic enantiose-
lectivity was higher with more sterically hindered substituting
group at the amide nitrogen (Table 1, entries 1e4). According to the
obtained ee values and isolated yields, 3c was considered as the
most effective ligand among these amino diol ligands, affording the
The contrasting induction abilities of ligands 3aed call for an
explanation. These ligands differ from each other only by the sub-
stitution at the amide nitrogen center, so this center has to be
responsible for the changes in enantioselectivity. However, we still
believe that the type of substitution is less important than the
configuration of chiral carbon. Although the exact mechanism of
the titanium-promoted addition of methyllithium to aldehydes is
so far unknown, recent structural and mechanistic investigations
have shown that the active catalytic intermediate could be
a methyltitanium species derived from the transfer of an methyl
group from lithium to titanium [14]. The variation of the addition
order of titanium and lithium reagents, leading to virtually identical
asymmetric induction indicates a monometallic transition state,
which has been postulated several times in the literature for other
ligands and other organometallic such as diethyizinc and dime-
thylzinc [34e36]. Thus, a plausible explanation of the stereo-
chemical outcome of the reaction can be based on model transition
states Ia, IIa, Ib, IIb depicted at Scheme 2.
For picture simplicity, addition of methyllithium to benzalde-
hyde in the presence of amino diol 3c is analyzed (Scheme 2). In the
model Ia and IIa re attack leads to products with the observed
configuration R, opposite to that observed in experiments. In
models Ib and IIb the si attack leads to the absolute configuration S,
but the apical position of the bulky isopropoxy group in the model
IIa and Ib are not very likely, due to a steric hindrance from tri-
phenylmethyl. In all four we postulate the presence of hydrogen
Table 1
The chiral induction ability of 3aed toward the reaction of methyllithium reagents
with aromatic aldehydes.a
Entry
Ligand
RCHO
Yield/%b
E.e.(%)c
Config.d
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3c
3c
3c
3c
3c
3c
3c
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
p-Methoxybenzaldehyde
p-Methylbenzaldehyde
m-Methoxybenzaldehyde
p-Chlorobenzaldehyde
p-Nitrobenzaldehyde
1-Naphthaldehyde
Cinnamaldehyde
85
90
90
80
80
90
80
82
82
91
92
70
75
80
82
85
86
84
82
80
85
81
R
R
R
R
R
R
R
R
R
R
R
9
10
11
a
RCHO: 1 mmol; reaction time: 24 h; reaction temperature: ꢀ20 ꢁC; n(R1CHO)/
n(3c)/n(Ti(O-i-Pr)4)/n(LiCH3) ¼ 1/0.1/1.5/2.
b
The isolated yield.
The e.e. of the product was determined by chiral HPLC.
the absolute configurations of the products were determined by comparing
c
d
their rotation sign with that reported by literatures [32,33].
Scheme 2. Stereochemical models for a methylation of aldehydes.

52
A.-L. Zhang et al. / Journal of Organometallic Chemistry 768 (2014) 50e55
bonding between ligand's hydroxy and formyl hydrogen of the
coordinated aldehyde. Such bonding was already postulated by
Corey [37], and was proved to be a very important factor influ-
encing asymmetric induction in enantioselective reactions. Its
presence substantially rigidifies transition states leading to good
enantiomeric excess, but the hydrogen bonding in Ib and IIb are
unstable due to the high steric energy resulting from the unfavored
interaction between benzaldehyde and the front Ph3CCH2 group.
Given these, the model transition state Ia in our opinion is the best
explanation of the observed asymmetric induction. It is obvious
that N-alkyl in Ia promote the methyl group to attacks the Re face of
the carbonyl group to create R product. We also speculate the
substitution of the methyl group in Ia by bulky alkyl such as alkynyl
could result in Re-attack increase. To support our hypothesis
further, 3c was used as ligand in the enantioselective addition of
phenylacetylene to aromatic aldehydes in the presence of methyl-
lithium. This catalytic reaction was a two-step procedure. Firstly,
deprotonation of phenylacetylene with methyllithium yielded the
corresponding alkynyl lithium reagent. Secondly, the alkynyl
lithium reagent reacted with aldehyde in the presence of sub-
stoichiometric amounts of chiral ligand 3c and Ti(O-i-Pr)4.
In a similar vein, we found that the amino diol 3c, was more
effective than the others. Various aldehydes were examined using
the titanium complex of ligand 3c under the optimized reaction
conditions and the results are listed in Table 2. The chiral propargyl
alcohols could be obtained in good isolated yields of 80%e94% and
excellent enantioselectivities of 90e96% ee for aromatic aldehydes
(Table 2, entries 1e7). For substituted benzaldehydes, the one with
strong electron-donating group gave a little higher enatioselecti-
vities(Table 2, entries 3e5), while the aldehydes with moderate
electron-withdrawing group gave a slightly lower enantioselecti-
Scheme 3. Stereochemical models for an alkynylation of aldehydes.
ligands [41,42], which were almost completely based on simple
speculation. In the present work, we have, in all cases, proposed
that Ti(O-i-Pr)4 coordinated with 3c in the form of mono-metallic
and hexa-coordinated cyclic titanates complex, which was shown
in Schemes 2 and 3.
For demonstrating the presence of the mono-metallic hexa-
coordinated titanium complex, 1H NMR study of 3c without and
with the addition of Ti(O-i-Pr)4 was conducted and the selected 1H
NMR spectra in the
The eCHeO methyne resonance of 3c is at
d
2.0 ppme
d
5.0 ppm region are shown in Fig. 1.
3.60 ppm (Fig. 1a).
d
(3c)2Ti is readily prepared by azeotropic removal of isopropanol
from a 1: 2 mixture of Ti(O-i-Pr)4 and the amino diol 3c in toluene,
and it is a crystalline solid which is stable enough to moisture to be
handled in air without precautions. The 1H NMR spectrum of
(3c)2Ti show that the eCHeO methyne resonance of (3c)2Ti com-
plex remains almost unchanged (
the N atom participates the coordination). i-PrOH methyne reso-
nance is at 4.04 ppm (Fig. 1c) and the eCHeO methyne resonance
d 3.60 ppm, Fig. 1b) (maybe due to
d
of Ti(O-i-Pr)4 is at 4.43 ppm (Fig. 1d). Mixing the spirotitanate
(3c)2Ti with Ti(O-i-Pr)4 in a 1: 1 ratio gives the titanate 3c-Ti
quantitatively and instantaneously (Fig. 1e), Fig. 1f shows the
eCHeO methyne resonance of the mixture derived from the
titration of 3c by titanium tetraisopropoxide for the ratio 1/2.
In Fig. 1f, A and B belongs respectively to the eCHeO methyne
resonance of Ti(Oi-Pr)4 and i-PrOH and C and D are the eCHeO
methyne resonance of complexes formed by coordination of Ti with
other coordinating group such as eNCHOe, eNCHOHe, i-PrOe or i-
PrOHe. Fig. 1g and h shows respectively the eCHeO methyne
resonance of the mixture derived from the titration of 3c by tita-
nium tetraisopropoxide for the ratio 1/3 and 1/5. From the numbers
of A, C and D, we can calculate the number (m) of Ti coordinated by
other group.
vity(Table 2, entries 6e7). a, b-unsaturated cinnamaldehyde affor-
ded 91% enantioselectivity (Table 2, entry 8). These results
suggested that the substitution of the methyl group in Scheme 1-Ia
by bulky alkynyl could result in Re-attack increase. It allows for at
least two possible transition states IceIIc depicted in Scheme 3 and
seems to be the main cause of the excellent asymmetric induction
observed in Table 2 and the proposed stereochemical models in
Scheme 2.
It is well known that both transition states involving mono-
metallic titanium complex and bimetallic titanium complex have
been suggested for the addition reactions of organometallic re-
agents to aldehydes in previous research [39,40]. The hexa-
coordinated transition structure and the penta-coordinated tran-
sition were often proposed in the coordination of titanium with
The 1H NMR spectrum of a CDCl3 solution of 3c and titanium
tetraisopropoxide (1 equiv) showed a set of resonances derived
from 3c-Ti complex, but without any signals of Ti(O-i-Pr)4 (Fig. 1e).
The 1H NMR signals of Ti(O-i-Pr)4 were present with up to 1 equiv
excess of titanium tetraisopropoxide (Fig. 1f), and NMR analysis
indicates that excess titanium tetraisopropoxide does not lead to
new species such as doubly titanated 3c (Fig. 1g and h). All these
show the stabilization of the monomeric-Ti aggregation form.
Table 3 listed the numbers of the coordination group in the
initiate feeds and titration mixtures, the number of Ti and the
number of the calculated coordination group in titration mixtures.
Table 3 shows us that the coordination number (m) of the Ti
complex in solution in the presence of 3c is 6, i.e., Ti(O-i-Pr)4 co-
ordinated with 3c in the form of mono-metallic titanium complex
which can be ultimately converted to hexa-coordinated cyclic
titanates.
Table 2
Enantioselective alkynylation of various aldehydes using 3c as the ligand.a
Entry
ReCHO
Yield/%b
E.e.(%)c
Config.d
1
2
3
4
5
6
7
8
Benzaldehyde
1-Naphthaldehyde
86
94
85
92
90
82
80
92
94
92
96
96
94
90
92
91
R
R
R
R
R
R
R
R
p-Methoxybenzaldehyde
p-Methylbenzaldehyde
m-Methoxybenzaldehyde
p-Chlorobenzaldehyde
p-Nitrobenzaldehyde
Cinnamaldehyde
a
RCHO: 1 mmol; reaction time: 24 h; reaction temperature: ꢀ20 ꢁC; n(ReCHO)/
In summary, on the one hand, the catalytic activity and stereo-
selectivity in the enantioselective addition of two organolithium
reagents to aromatic aldehydes using simple chiral amino diols as
ligands was found highly dependent upon the steric requirements
of the substituents in the amide nitrogen. 3c can be used in the
n(3c)/n(Ti(O-i-Pr)4)/n(LiCH3)/n(phenylacetylene) ¼ 1/0.10/0.5/2/2.
b
The isolated yield.
The e.e. of the product was determined by chiral HPLC.
The absolute configurations of the products were determined by comparison to
c
d
the literature data [38].

A.-L. Zhang et al. / Journal of Organometallic Chemistry 768 (2014) 50e55
53
Fig. 1. 1H NMR spectra of 3c, (3c)2Ti complex, i-PrOH and titration of 3c by titanium tetraisopropoxide. a: 3c; b: (3c)2Ti complex obtained from evaporating the mixture of 2 mmol of
3c and 1 mmol of titanium tetraisopropoxide. c: i-PrOH; d: Ti(O-i-Pr)4. eeh: Titration of 3c by titanium tetraisopropoxide for the ratio 1:1 (e), 1:2 (f), 1:3 (g) and 1:5 (h).
methylation of methyllithium to aromatic aldehydes with good
enantioselectivities under relatively mild condition. The cross-
effects reach the best compromize in amino diol 3c bearing a
diphenylmethyl group in the amide nitrogen and a triphenylmethyl
in the side chain with which 80%e94% yields and 90%e96% ee
values have been obtained in the enantioselective addition of
phenylacetylene to aromatic aldehydes in the presence of methyl-
lithium. The 1H NMR spectrum of complex 3ceTi show mono-
metallic transition state with only one six-coordinate titanium
center present in solution.
ether were distilled from sodium-benzophenone under argon
before use. Optically active epichlorohydrin (ECH) was purchased
from Yueyang Branch Company, Shenzhen Yawang Technology Ltd.
Other reagents were commercially available reagent without spe-
cial treatment.
Synthesis of (R)-4,4,4-triphenyl-1-butene oxide (2)
n-BuLi solution in hexane (18 mL, 2.5 M) was gradually dropped
into a solution of triphenylmethane (10 g, 40 mmol) in THF(80 mL)
under nitrogen atmosphere with stirring. The reaction mixture was
stirred at 0 ꢁC for 2 h to give a dark red triphenylmethyllithium
solution, then a solution of chiral epichlorohydrin (5 mL) in dry THF
(6 mL) was slowly added in at ꢀ60 ꢁC. The mixture was stirred for
20 min after the addition finished. The mixture was then warmed to
room temperature and stirred at this temperature for 3 h before
distilled water (20 mL) was carefully added. The mixture was
exacted with diethyl ether (2 ꢂ 30 mL). The extracts were
successively washed with diluted H2SO4 (10%) and water, and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum and the residue was recrsytallized from ethanol to give
pure product (colorless crystal, 8.5 g, yield 68.4%). M.p. 127.8 ꢁC. ee
Experimental
Instruments and materials
1H NMR and 13C NMR spectra were recorded on a Brucker
Avance 400 at 400 MHz and 100 MHz respectively using CDCl3 as
solvent. Optical rotations were measured using a PerkineElmer 341
LC polarime-ter. The chiral HPLC was measured on Dionex P680
using Chiracel®OD-H column (25 cm ꢂ 0.46 cm) detecting at
254 nm and using a mixture of n-hexane and isopropanol as an
eluent. methyllithium (1.3 M in n-hexane) and titanium (IV) iso-
propoxide were from Aladdin Company, Shanghai. THF and diethyl
value: 98%. Specific optical rotation of (R)-TPBO:
D ¼ þ26.4(c ¼ 5 mg/ml, THF). Anal. Calcd for C22H20O: C, 87.94; H,
6.73. Found C, 87.90; H, 6.78.1H NMR (CDCl3)
(ppm): 7.21e7.45 (m,
[a]20
d
Table 3
H, AreH), 3.30 (dd, 1H, J ¼ 3.5 Hz, J ¼ 14.5 Hz, CH2), 2.90e2.93 (m,
1H NMR titration of 3c in CDCl3 by titanium tetraisopropoxide.a
1H, CH), 2.49e2.51 (m, 1H, CH2), 2.42 (dd,1H, J ¼ 6.8 Hz, J ¼ 14.4 Hz,
Run Ratiob The number of the group
participating coordination
eCHOe in the 3ceTi
mixture
md
CH2), 2.14 (m, 1H, CH2); 13C NMR (CDCl3)
127.9, 126.2, 55.8, 50.2, 48.9, 43.7.
d (ppm): 146.8, 129.0,
eNCH2CHOe
N
Me2CHOeTi Ti
A
C
D
Ec
1
2
3
1/2
1/3
1/5
2
2
2
1
1
1
8
12
20
2
3
5
1.70 5.71 2.18 1.58 6.01
6.14 6.46 0.87 1.47 6.00
15.22 3.09 3.00 1.20 6.07
General procedure of the preparation of chiral amino diol tridentate
ligands
a
b
c
Determined by 1H NMR in CDCl3 using TMS as an internal standard.
The initial mole ratio of 3c to Ti(O-i-Pr)4.
The number of Ti coordinated by other coordinating group, calculated from the
A small autoclave with stirrer was charged with 1 mmol of
amine, 2 mmol of substituted propylene epoxide and 10 mL of
ethanol. The autoclave was sealed and heated with an oil bath at
120 ꢁC for 10 h. Ethanol was evaporated under reduced pressure.
The residue was purified by chromatography on silica gel using a
formula: （Me2CHOeTi e A) ÷ 4.
d
Coordination number calculated from the formula: (C þ D) ÷ E þ 1 (the number
of nitrogen atom).

54
A.-L. Zhang et al. / Journal of Organometallic Chemistry 768 (2014) 50e55
mixture of petroleum ether and ethyl acetate as eluate to obtain
amino diol.
product. The enantiomeric excesses were determined by HPLC
analysis using a chiral column (Chiralcel OD-H; eluent: hexane-
isopropylalcohol(98/2); flow rate: 0.6 mL/min; UV detector:
254 nm)
n-Butyl bis[3-triphenylmethyl-2(R)-hydroxypropyl] amine (3a)
Colorless oily liquid; Yield: 72.12%;
[
a
]20
D
¼
þ70.12ꢁ
(c ¼ 10 mg/ml, THF); Elem. Anal. calcd for C48H51NO2: C, 85.55; H,
1-Phenylethanol: Retention time: t(R)
¼
8.853 min,
7.63; N, 2.08. Found: C, 85.32; H, 7.81; N, 2.02. 1H NMR (CDCl3)
t(S) ¼ 10.653 min.
d
(ppm): 7.36 (d, J ¼ 7.2 Hz, 10H, AreH), 7.28 (d, J ¼ 11.3 Hz, 18H,
1-(4-Methoxyphenyl)ethanol:
Retention time:
AreH), 7.20 (d, J ¼ 7.0 Hz, 2H, AreH), 3.58 (s, 2H, CH), 3.04 (d,
J ¼ 14.7 Hz, 1H, CH2), 2.57 (d, J ¼ 14.5 Hz, 1H, CH2), 2.20e2.41 (m,
4H, CH2), 1.93 (d, J ¼ 11.9 Hz, 4H, CH2), 1.32 (d, J ¼ 19.5 Hz, 4H,
t(R) ¼ 12.346 min, t(S) ¼ 15.604 min.
1-(4-Methylphenyl)ethanol: Retention time: (R) ¼ 18.365 min,
t(S) ¼ 16.612 min.
CH2), 0.87 (d, J ¼ 6.9 Hz, 3H, CH3); 13C NMR (CDCl3)
d
(ppm):
1-(3-Methoxyphenyl)ethanol:
Retention
time:
147.24, 129.27, 128.00, 126.08, 67.31, 55.85, 48.86, 46.17, 32.04,
20.27, 13.91.
t(R) ¼ 11.346 min, t(S) ¼ 14.604 min.
1-(4-Chlolophenyl)ethanol: Retention time: t(R) ¼ 10.365 min,
t(S) ¼ 9.612 min.
Cyclohexyl bis[3-triphenylmethyl-2(R)-hydroxypropyl] amine (3b)
1-(4-Nitrophenyl)ethanol: Retention time: t(R) ¼ 16.545 min,
t(S) ¼ 18.180 min.
Yellowish Oily liquid; Yield: 68.50%;
[
a
]20
D
¼
þ72.60ꢁ
(c ¼ 10 mg/ml, THF); Elem. Anal. calcd for C50H53NO2: C, 85.80; H,
4-Phenylbut-3-en-2-ol: Retention time: t(R) ¼ 16.590 min,
t(S) ¼ 24.132 min.
7.63; N, 2.00. Found C, 85.55; H, 7.62; N, 1.95. 1H NMR (CDCl3)
d
(ppm) : 7.04e7.44 (m, 15H, AreH), 3.52 (s, 2H, CH), 3.06 (d,
1-(1-Naphthyl)ethanol: Retention time: t(R) ¼ 20.043 min,
t(S) ¼ 16.363 min.
J ¼ 14.6 Hz, 1H, CH2), 2.53 (d, J ¼ 14.5 Hz, 1H, CH2), 1.93e2.26 (m,
8H, CH2), 1.61 (d, J ¼ 11.5 Hz, 2H, CH2),1.12 (s, 4H, CH2), 0.99 (d,
J ¼ 6.4 Hz, 2H, CH2), 0.88 (d, J ¼ 10.6 Hz, 2H, CH2); 13C NMR (CDCl3)
d
(ppm): 147.27, 129.29, 127.99, 126.06, 67.76, 56.02, 51.76, 46.90,
General procedure for the asymmetric addition of phenylacetylene
to aromatic aldehyde
33.95, 33.41, 26.06, 24.99.
Diphenylmethyl bis[3-triphenylmethyl-2(R)-hydroxypropyl] amine
Under nitrogen, phenylacetylene (2.2 mmol, 242 mL) and lithium
(3c)
methide (2.0 mmol, 1.54 mL, 1.3 M in hexane) were added to a flask
(25 mL) containing toluene (15.0 mL). This solution was stirred for
0.5 h at room temperature. To the above reaction mixture was
added the synthetic amino diol ligand (0.10 mmol) and toluene
(10 mL). After the mixture was stirred at room temperature for
Colorless oily liquid; Yield: 69.12%;
[a
]20
D
¼
þ69.40ꢁ
(c ¼ 10 mg/ml, THF); Elem. Anal. calcd for C57H53NO2: C, 87.43; H,
6.69; N, 1.79. Found: C, 88.12; H, 6.07; N, 1.72. 1H NMR (CDCl3)
d
(ppm): 1H NMR (400 MHz, CDCl3)
d 6.99 e7.34 (m, 40H, AreH),
4.55 (s, 1H, CH), 3.60 (s, 2H, CH), 2.79 (dd, J ¼ 14.9, 4.9 Hz, 2H, CH2),
30 min, Ti(O-i-Pr)4 (0.5 mmol, 148 mL) was added and the mixture
2.54e2.66 (m, 2H, CH2), 2.20e2.34 (m, 2H, CH2), 2.02e2.14 (m, 2H,
was stirred at 0 ꢁC for 30 min, 1.0 mmol of aldehyde was added
at ꢀ20 ꢁC and the mixture was stirred at ꢀ20 ꢁC for 24 h. The re-
action was quenched with aqueous ammonium chloride. The
organic layer was separated. The aqueous layer was extracted with
ethyl acetate (20 mL ꢂ 3). The combined organic layer was washed
with brine and dried over anhydrous Na2SO4. After removal of the
solvent, the crude product was purified by chromatography on
silical gel (ethyl acetate: petroleum ¼ 1:8) to give the optically
active propargylic alcohols.
CH2); 13C NMR (400 MHz, CDCl3)
d(ppm):147.17, 129.19, 128.46,
127.99, 127.14, 126.10, 68.22, 66.94, 54.45, 46.26.
Tert-butyl bis[3-triphenylmethyl-2(R)-hydroxypropyl] amine (3d)
Colorless oily liquid; Yield: 86.26%; [
a
]20 D ¼ þ82.5ꢁ (c ¼ 10 mg/
ml, THF); Elem. Anal. calcd for C48H51NO2: C, 85.55; H, 7.63; N, 2.08.
Found: C, 85.62, H, 7.77; N, 2.10. 1H NMR (CDCl3)
d (ppm): 7.35e7.37
(m, 9H, AreH), 7.25e7.29 (m, 14H, AreH), 7.16e7.20 (t, J ¼ 16.0 Hz,
7H, AreH), 3.48e3.49 (d, J ¼ 4.0 Hz, 2H, CH), 3.05e3.09 (dd, J ¼ 4.0,
3.6 Hz, 1H, CH2), 2.53e2.57 (dd, J ¼ 4.0, 3.6 Hz, 1H, CH2), 2.10e2.15
(t, J ¼ 20.0 Hz, 4H, CH2), 1.87e1.91 (dd, J ¼ 2.8, 2.2 Hz, 2H, CH2), 0.93
1,3-Diphenyl-2-propyn-1-ol: ee determined by HPLC analysis
(Chiralcel OD-H column, IPA:hexane ¼ 2:98, 0.8 mL/min,
254 nm UV detector). Retention time: tmajor ¼ 6.12 min and
tminor ¼ 12.54 min.
(s, 9H, CH3); 13C NMR (CDCl3)
d (ppm): 147.29, 129.29, 127.95,
126.03, 68.34, 56.25, 50.31, 48.93, 46.50, 28.96.
1-(4-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol: ee determined
by HPLC analysis (Chiralcel OD-H column, IPA:hexane ¼ 5:95,
0.8 mL/min, 254 nm); Retention time: tmajor ¼ 6.20 min and
tminor ¼ 14.82 min;
The typical asymmetric addition reaction of methyllithium with
aldehydes induced by chiral amino diol tridentate ligands
A flask flushed with argon was charged with 15 mL of toluene
and 0.05 mmol of chiral amino diol tridentate ligand. Into the flask,
was added 2.0 mmol of Ti(O-i-Pr)4 under argon stream. The mixture
was stirred at 0 ꢁC for 1 h. 1.25 mL of methyllithium solution in
toluene (1.6 mol/L) was added dropwise and the mixture was
stirred at 0 ꢁC for 30 min.1.0 mmol of aldehyde was added at ꢀ20 ꢁC
and the mixture was stirred at ꢀ20 ꢁC for 24 h. The reaction was
quenched with 15 mL of saturated NH4Cl solution, the organic layer
was separated and the water layer was extracted with 10 mL of
ethyl acetate. The organic layer and extraction were combined. The
combined solution was dried over anhydrous MgSO4 and concen-
trated under reduced pressure to obtain a colorless liquid. The
colorless liquid was concentrated under reduced pressure and the
residue was chromatographed on silica gel to obtain the addition
1-(4-Methylphenyl)-3-phenyl-prop-2-yn-1-ol: ee determined
by HPLC analysis (Chiralcel OD column, IPA:hexane ¼ 10:90,
rate: 1 mL/min, 254 nm). Retention time: tminor ¼ 8.54 min and
tmajor ¼ 14.71 min.
1-(3-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol: ee determined
by HPLC analysis (Chiralcel OD-H column, IPA:hexane ¼ 10:90,
flow rate
tmajor ¼ 10.8 min and tminor ¼ 21.3 min.
¼
1.0 mL/min, 254 nm). Retention time:
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol: ee determined by
HPLC analysis (Chiralcel OD-H column, IPA:hexane ¼ 2:98, flow
rate ¼ 0.8 mL/min, 254 nm). Retention time: tmajor ¼ 5.68 min
and tminor ¼ 12.28 min.
1-(4-Nitrophenyl)-3-phenyl-prop-2-yn-1-ol. ee determined by
HPLC analysis(Chiralcel OD-H column, IPA:hexane ¼ 5:95,

A.-L. Zhang et al. / Journal of Organometallic Chemistry 768 (2014) 50e55
55
ꢀ
[14] B. Lecachey, C. Fressigne, H. Oulyadi, A. Harrison-Marchand, J. Maddaluno,
Chem. Commun. 47 (2011) 9915e9917.
0.8 mL/min, 254 nm). Retention time: tmajor ¼ 6.26 and
tminor ¼ 24.84 min.
[15] J. Granander, R. Sott, G. Hilmersson, Tetrahedron Asymmetry 14 (2003)
439e447.
[16] A. Corruble, D. Davoust, S. Desjardins, C. Fressigne, C. Giessner-Prettre,
A. Harrison- Marchand, H. Houte, M.C. Lasne, J. Maddaluno, H. Oulyadi,
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1-(1-Naphthyl)-3-phenylprop-2-yn-1-ol: ee determined by
HPLC analysis (Chiralcel OD-H column, IPA:hexane ¼ 5:95; flow
rate ¼ 0.8 mL/min, 254 nm). Retention time: tmajor ¼ 7.68 min
and tminor ¼ 15.36 min.
ꢀ
1,5-Diphenyl-pent-1-en-4-yn-3-ol: ee determined by HPLC
[18] P. Ro1nnholm, M. So1dergren, G. Hilmersson, Org. Lett. 9 (2007) 3781e3783.
analysis (Chiralcel OD column IPA:hexane
¼
2:98, flow
ꢀ
ꢀ
[19] E. Fernandez-Mateos, B. Macia, M. Yus, Eur. J. Org. Chem. (2012) 3732e3736.
[20] R.L. Matthew, F.B. William, R.L. Mark, D.F. Justin, J.D. Robert, B.S. Michael,
Tetrahedron Asymmetry 20 (2009) 981e998.
[21] F. Yang, P. Xi, L. Yang, J. Lan, R. Xie, J. You, J. Org. Chem. 72 (2007) 5457e5460.
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2668e2673.
rate ¼ 1.0 mL/min, 254 nm). Retention time: tmajor ¼ 12.1 min
and tminor ¼ 20.3 min.
Acknowledgment
[23] F. Diederich, P.J. Stang, R.R. Tykwinski (Eds.), Acetylene Chemistry: Chemistry,
Biology and Material Science, Wiley-VCH, Weinheim, Germany, 2005, pp.
101e138.
[24] P.J. Stang, F. Diederich (Eds.), Modern Acetylene Chemistry, VCH, Weinheim,
Germany, 1995.
We are grateful to the National Natural Science Foundation of
China (No. 21172186) for generous financial support for our
programs.
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