Synthesis and applications in Henry reactions of novel chiral thiazoline tridentate ligands

Article abstract of DOI:10.1002/aoc.3347

Several novel chiral tridentate ligands containing thiazoline were efficiently synthesized from commercially available l=cysteine in high yield. These ligands were subsequently applied to the asymmetric Henry reaction of nitromethane and various aldehydes. It was found that the structures of the thiazoline ligands had a significant influence on the enantioselectivity. It was shown that the optimal catalyst for this reaction was a ligand complexed with CuCl, which was formed from chiral thiazoline with chiral aminoalcohol. At -20°C, with 10 mol% of this ligand, a product with (S)-configuration was isolated in 93% yield and 98% enantiomeric excess.

Full text of DOI:10.1002/aoc.3347

Full paper
Received: 13 February 2015
Revised: 23 May 2015
Accepted: 4 June 2015
Published online in Wiley Online Library: 14 July 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3347
Synthesis and applications in Henry reactions of
novel chiral thiazoline tridentate ligands
a
a
a
a
a
a
b
Ye Shi , Yang Li , Jingbo Sun , Qi Lai , Chiyu Wei , Zhiyong Gong , Qiang Gu
a
and Zhiguang Song *
Several novel chiral tridentate ligands containing thiazoline were efficiently synthesized from commercially available l=cysteine in
high yield. These ligands were subsequently applied to the asymmetric Henry reaction of nitromethane and various aldehydes. It
was found that the structures of the thiazoline ligands had a significant influence on the enantioselectivity. It was shown that the
optimal catalyst for this reaction was a ligand complexed with CuCl, which was formed from chiral thiazoline with chiral
aminoalcohol. At ꢀ20°C, with 10 mol% of this ligand, a product with (S)-configuration was isolated in 93% yield and 98% enan-
tiomeric excess. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: chiral thiazoline ligand; Henry reactions; asymmetric synthesis
secondary amine tridentate ligands 8 and 9, –NH– amide –OH
tridentate ligands 10–12 and –NH– amide imine tridentate ligand
Introduction
The asymmetric addition reaction of nitro compounds to aldehydes
Henry reaction) is an effective way of preparing chiral β-nitro-
13, are shown in Fig. 2. Furthermore, the catalytic potential of these
new ligands was tested in the asymmetric Henry reaction of nitro-
methane and various aldehydes.
(
[1,2]
secondary alcohols.
Chiral β-nitro-secondary alcohols are not
only widely present in many biologically active compounds, but
also are important building blocks, which can be reduced to
β-aminoalcohols, dehydrated to nitroalkenes or oxidized to
nitrocarbonyl compounds. Therefore, it is essential to develop cata-
lytic asymmetric Henry reactions of nitromethane and aldehydes
Results and discussion
(R)-Tetrahydrothiazo-2-thione-4-carboxylic acid (15) was prepared
[
3–6]
via the cyclization of L-cysteine and carbon disulfide under basic
with high enantioselectivity.
[
17]
conditions, according to a previous procedure. Then we synthe-
sized a series of novel chiral thiazoline tridentate ligands (6–14)
containing thiazoline (Scheme 1) via a two-step procedure from
compound 15. First, compound 15 was stirred with ethyl
chloroformate to form the anhydride 16, which was then reacted
with compound 17, 18, 19, 20, 21, 22, 23 or a solution of 8-
aminoquinoline (24) to facilitate a one-pot sequence to give ligands
In the field of catalytic asymmetric Henry reactions, a lot of typi-
cal, effective and widely used chiral catalysts have been reported.
Shibasaki and co-workers in 1995 first reported an asymmetric
Henry reaction catalyzed by a La(O-t-Bu) and chiral (S)-(ꢀ)-BINOL
3
[7–15]
complex.
Also, bisoxazoline ligands 1, bisimadozoline ligands
2, iminoalcohol ligands 3, chiral diamine ligands 4 and quinine li-
gands 5 (Fig. 1) can also promote Lewis acid-catalyzed asymmetric
6–13 in moderate yield. Ligand 14 was synthesized from com-
Henry reactions. However, asymmetric Henry reactions catalyzed
[
16]
pound 13 by reduction of LiAlH
4
.
by chiral thiazoline ligands have seldom been reported.
Before investigating the efficiency of the synthesized chiral li-
gands in the Henry reaction, we first optimized the reaction condi-
tions, which include solvent, amount of ligand and reaction
temperature. We examined these in the presence of 10 mmol%
CuCl and N,N-diisopropylethylamine (DIPEA) as base. The effect of
different solvents and the amount of ligand on yield and
enantioselectivity was investigated (Table 1). For example, the reac-
tion of p-nitrobenzaldehyde with nitromethane in the presence of
We first disclosed the design, synthesis and application of a series
of novel modular thiazoline-containing N,O ligands derived from
L-cysteine in asymmetric addition of diethylzinc to aromatic
[17]
aldehydes. In the reaction, the imino group of thiazoline is an ef-
fective amino unit, so iminoalcohol thiazoline could be deemed as a
member of the group of chiral β-aminoalcohol ligands. Recently we
reported novel thiazoline-containing amide catalysts which were
applied to asymmetric aldol reaction of aromatic aldehydes with
[
18]
high enantioselectivity. Encouraged by these successful efforts,
we explored the generality of these novel chiral scaffolds contain-
ing thiazoline. To obtain more metal-bonding sites, we decided to
add two more coordination sites by introducing some functional
groups such as cinchona alkaloid, benzimidazole, chiral
aminoalcohol and 8-aminoquinoline to form novel chiral thiazoline
tridentate ligands. These chiral thiazoline tridentate ligands, namely
*
Correspondence to: Zhiguang Song, College of Chemistry, Jilin University, No.
2519 Jiefang Road, Changchun 130021, China. E-mail: szg@jlu.edu.cn
a Department of Organic Chemistry, College of Chemistry, Jilin University,
Changchun 130021, China
b Department of Applied Chemistry, College of Chemistry, Jilin University,
–NH– amide tertiary amine tridentate ligands 6 and 7, –NH– amide
Changchun 130021, China
Appl. Organometal. Chem. 2015, 29, 661–667
Copyright © 2015 John Wiley & Sons, Ltd.

Y. Shi et al.
poorer ee values but higher yield. Different configurations of the
metal-bonding site lead to the same configuration of product, thus
indicating that the configuration of thiazoline not the configuration
of substituents on amide group controls the configuration of the
product (Table 2, entries 1 and 2). Among the ligands 6–14, ligands
13 and 14 prepared from chiral thiazoline and 8-aminoquinoline
provide the poorest enantioselectivity (Table 2, entries 8 and 9).
Ligand 14, whose amide is reduced to amine, does not give good
enantioselectivity. Possible reasons are that there is no chiral back-
bone in 8-aminoquinoline and the coordination activity of nitrogen
atoms in amide is better than that in amine.
The effects of different copper sources (Table 2, entries 7–9) were
also examined with the most efficient ligand 12. The results reveal that
CuCl gives better yield and enantioselectivity than Cu(OAc) ꢁH O. Thus
2
2
CuCl is chosen for further reactions.
With the optimized conditions in hand, the scope of the sub-
strate was extended. A variety of aldehydes were employed as sub-
strates to react with nitromethane, giving the corresponding
products with high yields and ee values (Table 3). The data clearly
show that electron-withdrawing substituents exhibit higher ee than
electron-donating substituents. The substrates with ortho-
substituent give lower enantioselectivities than others (Table 3, en-
tries 1 and 2 versus 3). An aliphatic aldehyde also reacts well with
nitromethane and gives the corresponding products with high
yield and ee value (Table 3, entry 9).
Figure 1. Chiral ligands applied to asymmetric Henry reaction.
[20–22]
According to the literature
and the stereochemistry of the
products, a plausible transition state is proposed, as shown in
Scheme 2. When copper coordinates with ligands, the configura-
tion of complex is tetrahedral. Two nitrogen and one oxygen anion
are bonded to copper(I). The last metal-bonding site is connected
with the oxygen of nitroalkane to activate the nitroalkane. The R
group of the aldehyde is located far away from benzene and isopro-
pyl. The methylene of the nitroalkane attacks the Si face of the alde-
hyde. Therefore, the configuration of the product is S which
corresponds to our result.
Figure 2. Novel chiral thiazoline tridentate ligands.
Experimental
General remarks
1
6
0 mol% ligand 12 and 10 mol% CuCl catalyst gives 70% yield with
2% enantiomeric excess (ee) in dichloromethane, while the reac-
1
13
H NMR and C NMR spectra were recorded with a Varian Mercury
tion in ethanol gives 90% yield with 98% ee. Thus, ethanol is
established as the best solvent for this reaction system. Also, the re-
action in the presence of 20 mol% ligand 12 gives 75% ee, while the
reaction in the presence of 10 mol% ligand 12 gives 98% ee. How-
ever, decreasing further the amount of ligand 12 gives a lower yield
and poorer enantioselectivity. When the reaction temperature is in-
creased from ꢀ20°C to room temperature, the reaction gives a
poorer enantioselectivity than before. Therefore, the optimized
conditions of the reaction are obtained: 10 mol% ligand 12, at
3
00 MHz NMR spectrometer or a Bruker AVANCE 400 MHz NMR spec-
trometer, using tetramethylsilane as an internal standard. Mass spectra
were obtained using an LC/MS 1100 (Agilent Technology Corp.). A
WZZ-1S digital automatic polarimeter (Shanghai Physical Optics Instru-
ment Factory) was used, with concentrations given as absolute values
expressed in grams per 100 ml. Melting points were determined with
an X-4 digital microscope. HPLC analyses were performed using a
Shimadzu LC-10A VP pump, SPD-10A VP UV detector and Shimadzu
CTO-10AC VP column oven with appropriate chiral columns.
ꢀ
20°C and ethanol as solvent.
The subsequent investigations of the steric and electronic effects
All commercial chemicals were of analytical grade, purchased
from Beijing Chemical Reagent Co. (China) and used without fur-
ther purification. Compound 24 was purchased from J&K Company.
Column chromatography was generally performed on silica gel
of the ligands 6–14 show that the reactivity and enantioselectivity
are closely related to the chiral backbone and the substituents of
the ligand moiety. Reactions were carried out using 10 mol% ligand
and CuCl in ethanol at ꢀ20°C (Table 2). The reaction in the presence
of ligand 12 gives 93% yield with 98% ee, while the reaction in the
presence of less sterically hindered ligands 10 and 11 provides a
poorer enantioselectivity. The reaction in the presence of benzimid-
azole ligands 8 and 9 gives good enantioselectivity, and sterically
hindered ligands lead to higher ee values (Table 2, entries 3 and
(300–400 mesh) and TLC on silica gel GF254 plates.
Syntheses
Synthesis of compound 15
[
17]
Compound 15 was produced as described previously.
M.p.
2
0
4). But in the presence of quinine ligands 6 and 7 the reaction gives
179–181°C; ½αꢂ = ꢀ86.3° (c 1.2, 0.5 N HCl).
D
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 661–667

Novel chiral thiazoline tridentate ligands
Table 1. Screening of solvents and catalyst loading for
a
diastereoselective Henry reaction
d
Entry
Solvent
12
Temp. Yield ee Configuration
b c
(
mol%) (°C) (%) (%)
1
2
3
4
5
6
Ethanol
10
10
10
20
5
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
25
90
70
86
95
55
96
98
62
78
75
73
82
S
S
S
S
S
S
Dichloromethane
Tetrahydrofuran
Ethanol
Ethanol
Ethanol
10
a
Reactions were carried out using p-nitrobenzaldehyde (1 mmol),
nitromethane (10mmol), CuCl (0.1 mmol), DIPEA (0.1 mmol) and ligand
1
2 (0.1 mmol) in solvent (2 ml) in nitrogen atmosphere for 48 h.
b
Isolated yield after column purification.
c
Enantiomeric excess values were determined by HPLC using Chiralcel
OD.
d
The absolute configuration of the products was assigned by
[19]
comparison with retention time from the literature.
Table 2. Screening of ligands 6–14 and copper sources for the
a
diastereoselective Henry reaction
Scheme 1. Synthesis of chiral thiazoline tridentate ligands.
Synthesis of aminoquinine (17, 18)
b
c
d
Entry
Ligand (10 mol%)
Yield (%)
ee (%)
Configuration
1
2
3
4
5
6
7
6 + CuCl
7 + CuCl
8 + CuCl
9 + CuCl
10 + CuCl
11 + CuCl
12 + CuCl
85
70
92
93
86
90
93
85
86
81
70
75
68
80
88
86
90
98
96
70
67
52
S
S
S
S
S
S
S
S
S
S
S
Quinine (2.5 mmol) and triphenylphosphane (0.8 g, 3 mmol) were
mixed in anhydrous tetrahydrofuran, and the whole mixture was
cooled to 0°C, and treated dropwise with diisopropyl
azodicarboxylate (0.6 ml, 3 mmol) and a solution of diphenyl-
phosphorylazide (0.65 ml, 3 mmol) in anhydrous tetrahydrofuran
(10 ml). After the addition, the mixture was heated to room temper-
e
8
e
12 + Cu(OAc)
2
ꢁH
2
O
ature for 24 h and then the mixture was warmed to 50°C for an-
other 3 h. Triphenylphosphane (0.85 g, 3.3 mmol) was then
added, and the mixture was stirred until no gas was released
9
2
12 + CuCl ꢁ2H
13 + CuCl
14 + CuCl
2
O
1
0
1
1
(about 3 h). After cooling the mixture to room temperature, 3
a
Reactions were carried out using p-nitrobenzaldehyde (1 mmol),
nitromethane (10 mmol), copper salt (0.1 mmol), DIPEA (0.1 mmol)
and ligand (0.1 mmol) in ethanol (2 ml) at ꢀ20°C in nitrogen
atmosphere for 48 h.
ml of water was added and the mixture was stirred at the
same temperature for 12 h. At 0°C, 1 M HCl was added slowly
to neutralize the mixture until pH = 2, after which it was
extracted with ethyl acetate three times. At 0°C, to the aque-
ous phase was added aqueous NaOH until pH = 10 and
subsequently extracted with ethyl acetate three times. The
b
Isolated yield after column purification.
c
Enantiomeric excess values were determined by HPLC using Chiralcel
OD.
d
combined organic layer was dried with Na
2
SO
4
and the sol-
The absolute configuration of the products was assigned by
[19]
vent was removed by evaporation under reduced pressure.
The crude product was purified using column chromatography
comparison with retention time from the literature.
e
The reaction was conducted in air.
(
ethyl acetate–methanol–triethylamine, 100:100:1 by volume)
to afford 17 and 18 as a yellow oil.
-Aminodeoxycinchonine (17). The crude product was purified
c
d
h
b
f
9
2
4
5
.18–2.26 (m, 2 H, C H, C H), 2.88–2.96 (m, 5 H, C H, C H
2
, C H
), 5.84–
2
), 7.60–7.68 (m, 2 H, C H, C H), 7.72–7.77
2
),
i
using column chromatography (ethyl acetate–methanol–
triethylamine, 100:100:1 by volume) to afford 17 as a yellow oil
.71 (d, J = 9.9 Hz, 1 H, C H), 5.04–5.13 (m, 2 H, –CH¼CH
2
o
k
.95 (m, 1 H, –CH¼CH
2
D
0
1
n
(
76% yield). ½αꢂ = +110° (c 1.0, CHCl
3
). H NMR (300 MHz, DMSO,
1 2 1 2
(td, J = 8.3, J = 1.3 Hz, 1 H, C H), 8.03 (dd, J = 8.3, J = 1.3 Hz, 1
g
g
e
p
m
j
δ, ppm): 0.94–1.05 (m, 1 H, C H), 1.43–1.48 (m, 3H, C H, C H ),
H, C H), 8.51 (brs, 1 H, C H), 8.86 (d, J = 4.2 Hz, 1 H, C H).
2
Appl. Organometal. Chem. 2015, 29, 661–667
Copyright © 2015 John Wiley & Sons, Ltd.
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Y. Shi et al.
Table 3. Diastereoselective Henry reaction of aldehydes with nitro-
methane catalyzed by ligand 12/CuCl
solution was cooled until crystals began to form. The crude product
was recrystallized from ethanol.
a
H-benzimidazole-2-methylamine dihydrochloride (19). Yield
1
6
0%; m.p. 264–266°C. H NMR (300 MHz, DMSO, δ, ppm): 4.56 (s, 2
2
7
8
2
H, C H ), 7.50 (q, J = 3.0 Hz, 2 H, C H, C H), 7.82 (q, J = 3.0 Hz, 2 H,
C H, C H), 9.21 (brs, 3 H, C H, –NH, –NH
6
9
1
2
).
b
c
d
1-H-benzimidazole-2-(S)-ethylamine dihydrochloride (20). Yield
Entry
R
Yield (%)
ee (%)
Configuration
1
5
0%; m.p. 130–132°C. H NMR (300 MHz, DMSO, δ, ppm): 1.82
2
1
2
3
4
5
6
7
8
9
4-NO
3-NO
2-NO
2
2
2
C
6
H
6
H
6
H
4
(a)
(b)
(c)
93
91
89
68
94
71
85
91
92
82
70
98
98
89
82
72
67
86
85
83
86
90
S
S
S
S
S
S
S
S
S
S
S
(dd, J = 1.5 Hz, J = 6.9 Hz, 3 H, CH ), 4.95–4.98 (m, 1 H, C H),
3
7
8
6
9
C
C
4
7.49–7.53 (m, 2 H, C H, C H), 7.80–7.84 (m, 2 H, C H, C H), 9.29
(brs, 3 H, –NH, –NH2).
4
2-OCH
3
C
6
H
4
(d)
Synthesis of L-amino tertiary alcohols (21–23)
4-ClC
3-ClC
6
H
H
4
(e)
(f)
ꢀ
1
6
4
To a solution of amino acid (50 mmol) in 2 mol l aqueous NaOH
ꢀ
1
4-FC
4-BrC
PhCH
(CH
Cyclohexyl (k)
6
H
4
(g)
(20 ml), benzyl chloroformate (CbzCl; 50 mmol) and 2 mol l aque-
ous NaOH were added at 0°C. The solution was kept at pH = 9–10
and stirred vigorously for 1 h. Then the solution was stirred at room
temperature for 1 h. The mixture was then extracted with diethyl
ether (2 × 15 ml). Then the aqueous phase was added to 20 ml of
6
H
4
(h)
2
(i)
1
0
1
)
3 2
CHCH
3
(j)
1
ꢀ
1
ethyl acetate and treated with 2 mol l aqueous HCl until pH = 1.
The combined organic phase was washed with saturated brine
a
Reactions were carried out using aldehydes (1 mmol), nitromethane
10mmol), CuCl (0.1 mmol), DIPEA (0.1 mmol) and ligand 12
0.1 mmol) in solvent (2 ml) in nitrogen atmosphere for 48 h.
(
(
2 4
twice, dried over anhydrous Na SO and concentrated under
reduced pressure. The crude product was used directly for subse-
quent steps without further purification.
b
Isolated yield after column purification.
c
Enantiomeric excess values were determined by HPLC using Chiralcel
OD, AD-H.
At ꢀ10°C, 3.8 ml of thionyl chloride was added dropwise to 35 ml
of anhydrous methanol and treated with a solution of 50 mmol of
amino acid protected by Cbz in anhydrous methanol (10 ml). The
solution was stirred at this temperature for 0.5 h. Then the mixture
was stirred at room temperature for 12 h. After that the solution
d
The absolute configuration of the products was assigned by
[
19]
comparison with retention time from the literature.
ꢀ
1
was poured into ice and then treated with 2 mol l aqueous NaOH
until pH = 9. The resulting solution was extracted with ethyl acetate
three times. The organic layers were combined, washed with brine,
2 4
dried over anhydrous Na SO and evaporated in vacuo to afford the
amino acid esters protected by Cbz, which were used directly for
subsequent steps without further purification.
Magnesium powder and 0.1 g of iodine were added to 10 ml of
anhydrous tetrahydrofuran and treated dropwise with a solution of
bromobenzene (12 mmol) in anhydrous tetrahydrofuran (10 ml),
keeping the mixture refluxed. After the addition, the mixture was
refluxed for 0.5 h. At 0°C, a solution of Cbz-amino acid esters
(
3 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise,
and then the mixture was stirred at room temperature for 12 h. The
Scheme 2. Plausible transition state for the Henry reaction.
reaction mixture was quenched with saturated aqueous NH Cl,
4
extracted with diethyl ether, washed with brine, dried over
9
-Aminodeoxyquinine (18). The crude product was purified
anhydrous Na SO and evaporated in vacuo. The crude product was
2
4
using column chromatography (ethyl acetate–methanol–
triethylamine, 100:100:1 by volume) to afford 18 as a yellow oil
purified using column chromatography (ethyl acetate–petroleum
ether, 1:3 v/v) to afford Cbz-protected amino tertiary alcohols.
Cbz-2-amino-1,1-diphenylethanol. White solid, 90% yield.
20
1
1
H
(
80% yield). ½αꢂ = +80° (c 1.0, CHCl
3
). H NMR (300 MHz, DMSO,
D
g
g
NMR (300 MHz, DMSO, δ, ppm): 3.85 (d, J = 5.4 Hz, 2 H, –NHCH –),
δ, ppm): 0.65–0.72 (m, 1 H, C H), 1.16–1.25 (m, 1 H, C H), 1.52
(
H, C H ), 2.91–2.99 (m, 1 H, C H), 3.141–3.22 (m, 1 H, C H), 3.93
(
2
e
d
b
4
.98 (s, 2 H, –CH Ph), 5.84 (s, 1 H, –OH), 6.83 (d, J = 5.4 Hz, 1 H,
m, 3 H, C H , C H), 2.24 (m, 2 H, C H ), 2.64–2.69 (m, 2
2
2
2
f
c
h
NH), 7.17–7.24 (m, 4 H, –Ph), 7.26–7.31 (m, 7 H, –Ph), 7.42–7.46 (m,
H, –Ph).
S)-Cbz-(R)-2-amino-1,1-diphenylpropan-1-ol. White solid, 87%
2
i
4
s, 3 H, –OCH ), 4.62 (d, J = 10.2 Hz, 1 H, C H), 4.91–5.02 (m, 2
3
(
H, –CH¼CH ), 5.77–5.88 (m, 1 H, –CH¼CH ), 7.40 (dd, J = 2.7
2
2
1
o
k
yield. H NMR (300 MHz, DMSO, δ, ppm): 0.92 (d, J = 6.3 Hz, 3 H, –
CH ), 4.72–4.82 (m, 1 H, –CH–), 4.90 (d, J = 12.9 Hz, 1 H, –CH Ph),
.10 (d, J = 12.9 Hz, 1 H, –CH Ph), 5.23 (s, 1 H, –OH), 6.86 (d, J =
Hz, J = 9.3 Hz, 1 H, C H), 7.59 (d, J = 4.5 Hz, 1 H, C H), 7,80
m
p
(
brs, 1 H, C H) 7.92 (d, J = 9.3 Hz, 1 H, C H), 8.70 (d, J = 4.5
3
2
j
5
6
7
2
Hz, 1 H, C H).
.3 Hz, 1 H, NH), 7.24–7.32 (m, 4 H, –Ph), 7.24–7.32 (m, 7 H, –Ph),
.46–7.52 (m, 4 H, –Ph).
Synthesis of alkylamino-1-H-benzimidazole (19, 20)
(
S)-Cbz-(R)-2-amino-3-methy-1,1-diphenylbutyl-1-ol. White solid,
1
o-Phenylenediamine and excess amino acid (1:1.2) were mixed and
93% yield. H NMR (300 MHz, CDCl
H, –CH ), 0.92 (d, J = 6.9 Hz, 3 H, –CH
3
, δ, ppm): 0.87 (d, J = 6.9 Hz, 3
), 1.78–1.88 (m, 1 H, –CH(CH ),
ꢀ
1
refluxed in 6 mol l aqueous HCl. The course of the reaction was
confirmed using TLC. After the reaction completed, the resulting
3
3
3 2
)
3.48 (s, 1 H, –OH), 4.67 (d, J = 10.2 Hz, 1 H, –CH–), 4.95 (d, J = 12.3 Hz,
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Copyright © 2015 John Wiley & Sons, Ltd. Appl. Organometal. Chem. 2015, 29, 661–667

Novel chiral thiazoline tridentate ligands
g
g
1
H, –CH
H, –NH), 7.17–7.23 (m, 5 H, –Ph), 7.28–7.34 (m, 6 H, –Ph), 7.43–7.49
m, 4 H, –Ph).
2
Ph), 5.06 (d, J = 12.3 Hz, 1 H, –CH
2
Ph), 5.27 (d, J = 10.2 Hz, 1
DMSO, δ, ppm): 0.71–0.72 (m, 1 H, C H), 1.54–1.59 (m, 4 H, C H,
d
e
b
c
f
C H, C H
2
), 2.25–2.37 (m, 3 H, C H
2
, C H), 2.67–2.72 (m, 2 H, C H),
5
h
(
3.18–3.37 (m, 2 H, C H
2
), 3.51–3.55 (m, 1 H, C H), 3.78–3.85 (m, 1
4
i
To Cbz-amino tertiary alcohol in 50 ml of anhydrous methanol
was added 2.0 g of Pd/C (5%), in hydrogen atmosphere, and stirred
at 50°C until the reaction completed. Pd/C was removed by filtra-
tion and the solvent was removed under reduced pressure. The
crude product was recrystallized from petroleum ether to obtain
H, C H), 3.95 (s, 3 H, –OCH
3
), 4.69–4.72 (m, 1 H, C H), 4.98–5.08
), 7.43 (d, J = 8.7
(m, 2 H, –CH¼CH ), 5.89–5.99 (m, 1 H, –CH¼CH
2
2
o
k
m
Hz, 1 H, C H), 7.51 (d, J = 3.6 Hz, 1 H, C H), 7.73 (s, 1 H, C H),
p
7
7.94–7.97 (d, J = 9.3 Hz, 1 H, C H), 7.84 (brs, 1 H, N H), 8.73–8.75
(d, J = 3.6 Hz, 1 H, C H). C NMR (75 MHz, DMSO, δ, ppm): 26.12
(C ), 27.03 (C ), 36.08 (C ), 40.78 (C ), 55.37 (C ), 55.66 (C ), 58.23 (–
j
13
e
d
g
c
5
f
the amino tertiary alcohol 13.
1
i
m
o
2
-Amino-1,1-diphenylethanol (21). White solid, 95% yield.
H
OCH ), 64.79 (C ), 102.45 (C ), 114.33 (–CH¼CH ), 120.03 (C ),
3
2
k p l r
2
NMR (300 MHz, CDCl , δ, ppm): 3.40 (s, 2 H, C H ), 7.21–7.27 (m, 2
H, C H, C H), 7.31–7.35 (m, 4 H, C H, C H, C H, C H), 7.36–7.47
121.34 (C ), 128.07 (C ), 131.23 (C ), 141.93 (–CH¼CH ), 144.09 (C ),
3
2
2
7
13
6
8
12
14
j n 6 2
147.54 (C ), 157.41 (C ), 168.17 (C ), 199.85 (C ). MS (ESI): m/z 469.1
5
9
11
15
+
(m, 4 H, C H, C H, C H, C H).
[M + H ].
(
S)-2-Amino-1,1-diphenylpropan-1-ol (22). White solid, 95% yield.
(R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-2-thioxothiazolidine-4-
carboxamide (8). The crude product was purified using column
chromatography (dichloromethane–methanol, 9:1 v/v) to afford a
1
H NMR (300 MHz, CDCl , δ, ppm): 0.94 (d, J = 6.3 Hz, 3 H, –CH ), 4.14
q, J = 6.3 Hz, 1 H, C H), 7.13–7.21 (m, 2 H, C H, C H), 7.24–7.34 (m, 4
H, C H, C H, C H, C H), 7.47 (d, J = 6.6 Hz, 2 H, C H, C H), 7.61 (d, J =
3
3
2
7
13
(
6
8
12
14
5
9
20
D
white solid, 83% yield, ½αꢂ = ꢀ10.2° (c 1.0, CH
3
OH), m.p. 224–
1
1
15
1
6
.6 Hz, 2 H, C H, C H).
S)-2-Amino-3-methy-1,1-diphenylbutyl-1-ol (23). White solid,
2
26°C. H NMR (300 MHz, DMSO, δ, ppm): 3.63 (q, J = 6.0 Hz, 1 H,
C H), 3.81 (dd, J = 9.0 Hz, J = 11.4 Hz, 1 H, C H), 4.48–4.63 (m, 2 H,
C H ), 4.85 (dd, J = 6.0 Hz, J = 9.0 Hz, 1 H, C H), 7.15 (m, 2 H, C H,
2
C H), 7.52 (m, 2 H, C H, C H), 8.87 (t, J = 5.7 Hz, 1 H, –N H),
5
5
(
1
8
4
13
9
5% yield. H NMR (300 MHz, CDCl , δ, ppm): 0.88 (d, J = 6.9 Hz, 3
H, –CH ), 0.92 (d, J = 6.9 Hz, 3 H, –CH ), 1.70–1.80 (m, 1 H, –CH(CH ) ),
.84 (d, J = 2.1 Hz, 1 H, C H), 7.13–7.20 (m, 2 H, C H, C H), 7.25–7.33
m, 4 H, C H, C H, C H, C H), 7.48–7.51 (m, 2 H, C H, C H), 7.60–7.63
3
14
12
15
7
3
3
3 2
2
7
13
10
13
3
(
(
1
0.26 (s, 1 H, –SH), 12.28 (s, 1 H, –N H). C NMR (75 MHz, DMSO,
6
8
12
14
5
9
8
5
4
12 15
δ, ppm): 35.82 (C ), 37.43 (C ), 65.07 (C ), 121.59 (C , C ), 151.34
11
15
13
14
6
2
+
m, 2 H, C H, C H).
(
C , C ), 168.62 (C ), 199.67 (C ). MS (ESI): m/z 293.1 [M + H ].
(R)-N-((S)-1-(1H-benzo[d]imidazol-2-yl)ethyl)-2-thioxothiazolidine-
Synthesis of chiral thiazoline tridentate ligands (6–13)
4-carboxamide (9). The crude product was purified using column
chromatography (dichloromethane–methanol, 9:1 v/v) to afford
Compound 15 (3.26 g, 20 mmol) and N-methylmorpholine (2.5 ml,
2
0
a white solid, 80% yield, ½αꢂ = ꢀ15° (c 1.0, CH OH), m.p. 150–
D
3
21 mmol) were dissolved in 20 ml of anhydrous tetrahydrofuran
1
1
–
52°C. H NMR (300 MHz, DMSO, δ, ppm): 1.54 (d, J = 6.9 Hz, 3 H,
CH ), 3.63 (q, J = 6.3 Hz, 1 H, C H), 3.81 (dd, J = 9.0 Hz, J = 11.4
3
Hz, 1 H, C H), 4.82 (dd, J = 6.9 Hz, J = 9.0 Hz, 1 H, C H), 5.13–5.23
dd, J = 6.3 Hz, J = 9.0 Hz, 1 H, C H), 7.14–7.18 (m, 2 H, C H,
C H), 7.45 (d, J = 7.2 Hz, 1 H, C H), 7.57 (d, J = 7.2 Hz, 1 H,
C H), 8.79 (d, J = 7.8 Hz, 1 H, –N H), 10.26 (s, 1 H, –SH), 12.28 (s,
and cooled to ꢀ10°C. Then the mixture was treated dropwise with
a solution of ethyl chloroformate (1.9 ml, 20 mmol) in tetrahydrofu-
ran (5 ml) and stirred for 0.5 h. Compound 17, 18, 19, 20, 21, 22, 23,
or a solution of 24 (20 mmol) in tetrahydrofuran (10 ml) was added
dropwise, and then the mixture was stirred for 12 h at room tem-
perature. The reaction mixture was quenched with saturated aque-
5
5
8
4
13
(
1
4
12
15
7
1
0
13
1
3
3
H, –N H). C NMR (75 MHz, DMSO, δ, ppm): 19.77 (–CH ),
5 8 4 12 15 13
ous NH Cl, extracted with ethyl acetate three times, washed with
4
5.68 (C ), 43.78 (C ), 65.16 (C ), 121.56 (C , C ), 155.17 (C ,
brine, dried over anhydrous Na SO and evaporated in vacuo. The
2
4
14
6
2
+
C ), 167.82 (C ), 199.71 (C ). MS (ESI): m/z 307.1 [M + H ].
R)-N-(2-hydroxy-2,2-diphenylethyl)-2-thioxothiazolidine-4-carbo-
crude product was purified using column chromatography to af-
ford compounds 6–13.
(
xamide(10). The crude product was purified using column chro-
matography (ethyl acetate–petroleum ether, 9:1 v/v) to afford a
(
4R)-N-((1R)-quinolin-4-yl(5-vinylquinuclidin-2-yl)methyl)-2-
thioxothiazolidine-4-carboxamide (6). The crude product was puri-
fied using column chromatography (dichloromethane–methanol,
2
D
0
white solid, 90% yield, ½αꢂ = ꢀ44° (c 1.0, CH
3
OH), m.p. 52–53°C.
1
5
2
D
0
H NMR (300 MHz, DMSO, δ, ppm): 2.85 (q, J = 5.7 Hz, 1 H, C H),
3.53 (dd, J = 9.3 Hz, J = 11.4 Hz, 1 H, C H), 3.71 (dd, J = 4.2 Hz, J =
13.8 Hz, 1 H, C H), 4.21 (dd, J = 6.9 Hz, J = 13.5 Hz, 1 H, C H), 4.71
9
:1 v/v) to afford a white solid, 80% yield, ½αꢂ = +48° (c 1.0, CHCl3),
5
1
m.p. 198–202°C. H NMR (300 MHz, DMSO, δ, ppm): 0.83–0.92 (m, 1
H, C H), 0.97–1.06 (m, 1 H, C H), 1.48–1.53 (m, 3 H, C H, C H ), 2.25
2
m, 1 H, C H), 2.82–2.98 (m, 4 H, C H , C H ), 3.14–3.19 (m, 3 H, C H,
2 2
8
8
g
g
d
e
4
13
19
c
b
f
h
(dd, J = 5.7 Hz, J = 9.3 Hz, 1 H, C H), 7.16–7.23 (m, 2 H, C H, C H),
(
12
14
18
20
11
5
4
7.26–7.33 (m, 4 H, C H, C H, C H, C H), 7.40–7.44 (m, 4 H, C H,
C H
CH¼CH
.57 (d, J = 4.4 Hz, 1 H, C H), 7.65–7.69 (td, J
2
), 3.75 (dd, J
1
= 9.3, J
2
= 11.4 Hz, 1 H, C H), 5.01–5.15 (m, 2 H, –
= 10.2, J ),
= 6.9 Hz, 1 H, –CH¼CH
= 1.5, J = 8.2 Hz, 1 H,
= 8.2 Hz, 1 H, C H), 8.04 (dd, J = 1.5, J
= 8.2 Hz, 1 H, C H), 8.62 (d, J
15
17
21
7
13
C H, C H, C H), 7.88–7.92 (m, 1 H, N H), 10.21 (s, 1 H, –SH).
C
2
), 5.92 (ddd, J
1
= 17.0, J
2
3
2
5
8
4
k
NMR (75 MHz, DMSO, δ, ppm): 35.88 (C ), 48.04 (C ), 64.71 (C ),
9 19 13 17 21 11
7
1
o
2
n
76.96 (C ), 125.91 (C ), 125.98 (C ), 126.56 (C , C ), 126.75 (C ,
C H), 7.75–7.80 (td, J
=
=
1
= 1.5, J
2
1
2
15
18 20
12 14
16
10
p
m
C ), 127.81 (C , C ), 127.99 (C , C ), 145.36 (C ), 145.92 (C ),
8.2 Hz, 1 H, C H), 8.36 (dd, J
1
= 1.5, J
5.9Hz, 1 H, N H), 8.89 (d, J = 4.4 Hz, 1 H, C H). C NMR (75 MHz,
2
6
2
+
7
j
13
168.54 (C ), 199.59 (C ). MS (ESI): m/z 357.2 [M ꢀ H ].
g
e
d
c
(R)-N-((S)-1-hydroxy-1,1-diphenylpropan-2-yl)-2-thioxothiazolidi-
ne-4-carboxamide (11). The crude product was purified using col-
DMSO, δ, ppm): 24.90 (C ), 25.80 (C ), 27.09 (C ), 35.91 (C ), 46.57
5
f
i
b
h
(
C ), 48.57 (C ), 55.94 (C ), 58.47 (C ), 64.70 (C ), 114.52 (–CH¼CH
2
),
m
k
o
p
n
umn chromatography (ethyl acetate–petroleum ether, 1:1 v/v) to
1
1
1
19.60 (C ), 123.46 (C ), 126.51 (C ), 126.71 (C ), 129.07 (C ),
l
q
r
j
20
29.74 (C), 140.70 (-CH¼CH
2
), 146.29 (C ), 147.82 (C ), 150.11 (C ),
67.93 (C ), 199.62 (C ). MS (ESI): m/z 438.8 [M + H ].
4R)-N-((1S)-(6-methoxyquinolin-4-yl)((5R)-5-vinylquinuclidin-2-
afford a white solid, 89% yield, ½αꢂD = ꢀ20° (c 1.0, CH
3
OH), m.p.
6
2
+
1
48–50°C. H NMR (300 MHz, DMSO, δ, ppm): 0.96 (d, J = 6.9 Hz, 3
H, –CH ), 3.04 (q, J = 6.3 Hz, 1 H, C H), 3.66 (dd, J = 9.0 Hz, J = 11.1
Hz, 1 H, C H), 4.57–4.64 (dd, J = 6.9 Hz, J = 9.0 Hz, 1 H, C H),
4.95–5.07 (dd, J = 6.3 Hz, J = 9.0 Hz, 1 H, C H), 7.15–7.30 (m, 6 H,
C H, C H, C H, C H, C H, C H), 7.43–7.51 (m, 4 H, C H, C H,
C H, C H), 7.64 (d, J = 9.0 Hz, 1 H, N H), 10.29 (s, 1 H, –SH).
5
(
3
5
8
yl)methyl)-2-thioxothiazolidine-4-carboxamide (7). The crude
product was purified using column chromatography (dichloro-
methane–methanol, 9:1 v/v) to afford a yellow solid, 85% yield,
4
13
19
12
14
18
20
11
15
2
D
0
1
17
21
7
13
½
αꢂ = ꢀ123.4° (c 1.0, CHCl
3
), m.p. 142–144°C. H NMR (300 MHz,
C
Appl. Organometal. Chem. 2015, 29, 661–667
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Y. Shi et al.
5
8
NMR (75 MHz, DMSO, δ, ppm): 15.57 (–CH ), 35.86 (C ), 50.21 (C ),
nitrogen atmosphere and stirred for 0.5 h. Then the solution was
cooled to ꢀ20°C, treated with aldehyde (1 mmol), nitromethane
(0.54 ml, 10 mmol) and DIPEA (0.018 ml, 0.1 mmol) and stirred at
this temperature for 48 h. The reaction mixture was quenched with
3
4
9
19
13
17 21
6
1
1
4.54 (C ), 79.14 (C ), 125.35 (C ), 125.46 (C ), 126.08 (C , C ),
26.25 (C , C ), 127.55 (C , C ), 127.87 (C , C ), 145.58 (C ),
1
1
15
18 20
12 14
16
1
0
6
2
+
45.98 (C ), 167.32 (C ), 199.49 (C ). MS (ESI): m/z 371.0 [M ꢀ H ].
(
R)-N-((S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl)-2-
saturated aqueous NH
with brine, dried over anhydrous Na
The crude product was purified using column chromatography
ethyl acetate–petroleum ether, 1:3 v/v) to afford chiral secondary
4
Cl, extracted with dichloromethane, washed
thioxothiazolidine-4-carboxamide (12). The crude product was
purified using column chromatography (ethyl acetate–petroleum
2
SO and evaporated in vacuo.
4
20
(
ether, 1:1 v/v) to afford a white solid, 86% yield, ½αꢂ = ꢀ56.5°
D
1
alcohol 25. Enantiomeric excess was determined using HPLC with
a Chiralcel column.
(
c 1.0, CH OH), m.p. 58–60°C. H NMR (300 MHz, DMSO, δ, ppm):
3
0
.77 (d, J = 6.9 Hz, 3 H, –CH ), 0.91 (d, J = 6.9 Hz, 3 H, –CH ),
3
3
(S)-2-Nitro-1-(4-nitrophenyl)ethanol (25a). Yield 93%, 98% ee, by
1
.75–1.82 (m, 1 H, –CH(CH ) ), 2.33 (dd, J = 5.1 Hz, J = 11.4 Hz, 1
H, C H), 3.34 (q, J = 9.3 Hz, 1 H, C H), 4.66 (dd, J = 5.1 Hz, J = 9.3
Hz, 1 H, C H), 4.85 (m, 1 H, C H), 7.08–7.34 (m, 6 H, C H, C H,
C H, C H, C H, C H), 7.51 (t, J = 7.5 Hz, 4 H, C H, C H, C H,
C H), 7.63 (d, J = 10.4 Hz, 1 H, N H). C NMR (75 MHz, DMSO, δ,
ppm): 17.04 (–CH ), 23.54 (–CH(CH ) ), 36.28 (C ), 60.45 (C ),
5.45 (C ), 81.34 (C ), 125.73 (C ), 126.20 (C ), 126.48 (C , C ),
26.57 (C , C ), 128.27 (C , C ), 128.46 (C , C ), 147.16 (C ),
3
2
5
5
HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol =
ꢀ
1
4
8
13
19
85:15, 0.5 ml min , 215 nm UV detector), t = 23.75 min (for minor)
R
1
12
14
18
20
11
15
17
and t = 34.35 min (for major). H NMR (300 MHz, CDCl , δ, ppm):
R
3
21
7
13
3.24 (s, 1 H, –OH), 4.57–4.61 (m, 2 H, –CH NO ), 5.60–5.64 (m, 1 H,
2 2
5
8
–CH–), 7.63 (d, J = 8.4 Hz, 2 H, –Ph), 8.26 (d, J = 8.4 Hz, 2 H, –Ph).
3
9
3 2
13
4
19
13
17 21
C NMR (75 MHz, CDCl , δ, ppm): 70.03 (–CHOH), 80.70 (–CH NO ),
6
1
1
3
2
2
1
1
15
18 20
12 14
16
124.13 (–Ph), 127.06 (–Ph), 145.42 (–Ph), 147.97 (–Ph).
1
0
6
2
(S)-2-Nitro-1-(3-nitrophenyl)ethanol (25b). Yield 91%, 98% ee, by
HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol =
48.89 (C ), 169.01 (C ), 200.10 (C ). MS (ESI): m/z 422.9 [M +
+
+
Na ], 382.8 [M + H ꢀ 18].
ꢀ
1
8
5:15, 0.8 ml min , 250 nm UV detector), t = 17.90 min (for minor)
(
R)-N-(quinolin-8-yl)-2-thioxothiazolidine-4-carboxamide (13). The
crude product was purified using column chromatography (ethyl
acetate–petroleum ether, 1:1 v/v) to afford a yellow solid, 88% yield,
R
1
and t = 20.28 min (for major). H NMR (400 MHz, CDCl , δ, ppm):
R
3
2 2
3.16 (brs, 1 H, –OH), 4.60–4.69 (m, 2 H, –CH NO ), 5.63 (d, J = 8.0
2
D
0
1
Hz, 1 H, –CH–), 7.64 (d, J = 8.0 Hz, 1 H, –Ph), 7.79 (d, J = 8.0 Hz, 1
H, –Ph), 8.25 (d, J = 8.0 Hz, 1 H, –Ph), 8.35 (s, 1 H, –Ph).
½
αꢂ = ꢀ62° (c 1.0, CHCl ), m.p. 98–100°C. H NMR (300 MHz, DMSO,
3
5
δ, ppm): 3.71 (dd, J = 4.8 Hz, J = 11.4 Hz, 1 H, C H), 4.00 (dd, J = 9.0 Hz,
5
4
(S)-2-Nitro-1-(2-nitrophenyl)ethanol (25c). Yield 89%, 89% ee, by
HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol =
J = 11.7 Hz, 1 H, C H), 5.32 (dd, J = 4.8 Hz, J = 9.0 Hz, 1 H, C H), 7.60–
.65 (m, 1 H, C H), 7.67 (m, 1 H, C H), 7.74 (dd, J = 1.2 Hz, J = 8.1 Hz,
1
1
15
7
1
=
ꢀ
1
1
4
12
90:10, 0.9 ml min , 215 nm UV detector), t
R
= 16.12 min (for minor)
= 18.27 min (for major). H NMR (400 MHz, CDCl , δ, ppm):
3.24 (brs, 1 H, –OH), 4.55-4.61 (m, 1 H, –CH–), 4.90 (d, J = 8.0 Hz, 1
H, –CH NO ), 6.08 (d, J = 8.8 Hz, 1 H, –CH NO ), 7.58 (t, J = 8.0 Hz,
H, C H), 8.44 (d, J = 1.5 Hz, J = 8.4 Hz, 1 H, C H), 8.66 (d, J = 1.2 Hz, J
1
1
6
10
3
7
13
and t
R
3
8.1 Hz, 1 H, C H), 8.96 (m, 1 H, C H), 10.59 (s, 2 H, N H, N H).
C
5
4
11
NMR (75 MHz, DMSO, δ, ppm): 32.23 (C ), 60.88 (C ), 111.93 (C ),
16.68 (C ), 117.63 (C ), 121.81 (C ), 122.53 (C ), 127.64 (C ),
31.14 (C ), 132.91 (C ), 143.41 (C ), 161.54 (C ), 198.54 (C ). MS
1
6
14
15
13
12
2
2
2
2
1
1
(
8
9
10
6
2
1 H, –Ph) 7.77 (t, J = 8.0 Hz, 1 H, –Ph), 7.98 (d, J = 8.0 Hz, 1 H, –Ph),
8.10 (d, J = 8.0 Hz, 1 H, –Ph).
+
ESI): m/z 290.2 [M + H ].
(S)-2-Nitro-1-(2-methoxyphenyl)ethanol (25d). Yield 68%, 82%
ee, by HPLC analysis (Daicel Chiralcel OD column, hexane–2-
Synthesis of chiral thiazoline tridentate ligand 14
ꢀ
1
propanol = 85:15, 0.8 ml min , 215 nm UV detector), t
R
= 17.90
= 20.28 min (for major). H NMR (400 MHz,
, δ, ppm): 3.16 (brs, 1 H, –OH), 3.91 (s, 3 H, –OCH ), 4.58–4.70
m, 2 H, –CH NO ), 5.66 (d, J = 8.0 Hz, 1 H, –CH–), 6.94 (d, J = 8.0
Hz, 1 H, –Ph), 7.04 (d, J = 8.0 Hz, 1 H, –Ph) 7.36 (d, J = 8.0 Hz, 1 H,
At 0°C, a solution of ligand 13 (0.6 g, 2 mmol) in anhydrous tetrahy-
drofuran (10 ml) was added slowly to a suspension of lithium
aluminium hydride (0.3 g, 6 mmol) in anhydrous tetrahydrofuran
1
min (for minor) and t
CDCl
R
3
3
(
2
2
(
2
10 ml), under nitrogen atmosphere, and refluxed with stirring for
4 h at this temperature. The reaction mixture was quenched with
saturated aqueous Na SO , extracted with diethyl ether, washed
–Ph), 7.47 (d, J = 8.0 Hz, 1 H, –Ph).
2
4
(S)-2-Nitro-1-(4-chlorophenyl)ethanol (25e). Yield 94%, 72% ee,
with brine, dried over anhydrous Na SO and evaporated in vacuo.
2
4
by HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol
The crude product was purified using column chromatography
ethyl acetate–petroleum ether, 1:2 v/v) to afford compound 14.
R)-4-((Quinolin-8-ylamino)methyl)thiazolidine-2-thione (14). Yel-
ꢀ1
=
85:15, 0.8 ml min , 215 nm UV detector), t = 12.82 min (for mi-
R
(
1
nor) and t = 15.90 min (for major). H NMR (400 MHz, CDCl , δ,
R
3
(
ppm): 2.90 (brs, 1 H, –OH), 4.50–4.63 (m, 2 H, –CH NO ), 5.47 (d, J
2
2
2
D
0
1
low solid, 78% yield, ½αꢂ = ꢀ11° (c 1.0, CHCl
3
), m.p. 144–146°C. H
= 9.2 Hz, 1 H, –CH–), 7.36–7.42 (m, 4 H, –Ph).
(S)-2-Nitro-1-(3-chlorophenyl)ethanol (25f). Yield 71%, 67% ee,
5
6
NMR (300 MHz, DMSO, δ, ppm): 3.45–3.57 (m, 3 H, C H , C H), 3.66–
2
6
4
3
.73 (m, 1 H, C H), 4.48–4.57 (m, 1 H, C H), 6.78 (d, J = 7.5 Hz, 1 H,
by HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol
3
11
15
ꢀ1
N H), 6.94 (m, 1 H, C H), 7.10 (d, J = 8.1 Hz, 1 H, C H), 7.38 (d, J =
= 85:15, 0.5 ml min , 215 nm UV detector), t = 20.88 min (for mi-
R
1
4
12
1
8
1
(
(
(
.1 Hz, 1 H, C H), 7.51 (q, J = 4.2 Hz, 1 H, C H), 8.22 (d, J = 8.1 Hz,
H, C H), 8.75–8.76 (m, 1 H, C H), 10.35 (s, 1 H, –SH). C NMR
nor) and t = 26.42 min (for major). H NMR (400 MHz, CDCl , δ,
R
3
1
6
10
13
ppm): 2.59 (brs, 1 H, –OH), 4.52–4.63 (m, 2 H, –CH NO ), 5.47 (d, J
2 2
5
6
4
75 MHz, DMSO, δ, ppm): 35.89 (C ), 44.50 (C ), 62.52 (C ), 104.25
= 8.0 Hz, 1 H, –CH–), 7.29–7.37 (m, 1 H, –Ph), 7.36 (m, 2 H, –Ph)
7.46 (s, 1 H, –Ph).
11
16
14
15
13
C ), 113.74 (C ), 121.77 (C ), 127.72 (C ), 128.35 (C ), 135.97
12
8
9
10
2
C ), 137.45 (C ), 144.13 (C ), 146.94 (C ), 198.54 (C ). MS (ESI):
(S)-2-Nitro-1-(4-fluorophenyl)ethanol (25g). Yield 85%, 86% ee, by
HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol =
+
m/z 276.1 [M + H ].
ꢀ
1
9
0:10, 0.5 ml min , 215 nm UV detector), t
R
= 22.58 min (for minor)
= 26.87 min (for major). H NMR (400 MHz, CDCl , δ, ppm):
.91 (brs, 1 H, –OH), 4.50–4.64 (m, 2 H, –CH NO ), 5.47 (d, J = 9.2
1
and t
2
R
3
General Procedure for Enantioselective Henry Reactions Cata-
lyzed by Novel Chiral Thiazoline Tridentate Ligands
2
2
Hz, 1 H, –CH–), 7.12 (t, J = 8.0 Hz, 2 H, –Ph), 7.40–7.43 (m, 2 H, –Ph).
(S)-2-Nitro-1-(4-bromophenyl)ethanol (25h). Yield 91%, 85% ee,
by HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol
At room temperature, CuCl (0.01 g, 0.1 mmol) was added to a solu-
tion of chiral ligand (0.1 mmol, 10 mol%) in ethanol (2 ml) in
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 661–667

Novel chiral thiazoline tridentate ligands
ꢀ
1
=
85:15, 0.9 ml min , 250 nm UV detector), t
R
= 11.47 min (for mi-
= 13.03 min (for major). H NMR (400 MHz, CDCl , δ,
ppm): 3.19 (brs, 1 H, –OH), 4.48–4.61 (m, 2 H, –CH NO ), 5.42 (d, J
8.8 Hz, 1 H, –CH–), 7.29 (d, J = 8.0 Hz, 2 H, –Ph), 7.54 (d, J = 8.0
Hz, 2 H, –Ph).
S)-1-Nitro-3-phenylpropan-2-ol (25i). Yield 92%, 83% ee, by
HPLC analysis (Daicel Chiralcel OD column, hexane–2-propanol
Acknowledgment
1
nor) and t
R
3
This work was supported by grants from the National Nature
Science Foundation of China (project 90813003).
2
2
=
(
References
ꢀ
1
=
90:10, 0.5 ml min , 215 nm UV detector), t = 38.25 min (for
R
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1
minor) and tR = 50.25 min (for major). H NMR (400 MHz,
CDCl , δ, ppm): 2.34 (brs, 1 H, –OH), 2.87–2.92 (m, 2 H, –CH Ph),
.39–4.48 (m, 2 H, –CH NO ), 4.59–4.60 (m, 1 H, –CH–), 7.24–7.38
m, 5 H, –Ph).
S)-4-Methyl-1-nitropentan-2-ol (25j). Yield 82%, 86% ee, by HPLC
analysis (Daicel Chiralcel AD-H column, hexane–2-propanol = 95:5,
.5 ml min , 210 nm UV detector), t = 27.42 min (for minor) and
t = 37.22 min (for major). H NMR (400 MHz, CDCl , δ, ppm):
.95–1.01 (m, 6 H, –CH(CH ) ), 1.21–1.30 (m, 1 H, –CH –), 1.50–1.56
m, 1 H, –CH –), 1.81–1.91 (m, 1 H, –CH–), 2.50 (brs, 1 H, –OH),
3
2
[
[
3] A. E. Aydin, E. Yuksekdanaci, Tetrahedron Asymmetry 2013, 24, 14.
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4
(
2 2
(
[
5] I. Panov, P. Drabina, Z. Padelkova, P. Simunek, M. Sedlak, J. Org. Chem.
2011, 76, 4787.
ꢀ
1
[
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R
1
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R
3
1
0
(
3 2 2
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2
4
.37–4.45 (m, 3 H, –CH NO , –CHOH–).
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2
2
J. Am. Chem. Soc. 2003, 125, 12692.
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(S)-1-Cyclohexyl-2-nitroethanol (25k). Yield 70%, 90% ee, by
[
[
HPLC analysis (Daicel Chiralcel AD-H column, hexane–2-propanol
=
ꢀ
1
95:5, 0.5 ml min , 210 nm UV detector), t = 27.45 min (for minor)
R
1
and t
R
= 31.94 min (for major). H NMR (400 MHz, CDCl
.11–1.85 (m, 11 H, cyclohexyl), 2.35 (brs, 1 H, –OH), 4.08–4.11 (m,
H, –CH–), 4.20–4.50 (m, 2 H, –CH NO ).
3
, δ, ppm):
[
[
1
1
2
2
[
[
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014, 70, 1827.
[
[
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We synthesized a series of chiral thiazoline-type tridentate ligands
with L-cysteine, and introduced various functional groups, such as
cinchona alkaloid, benzimidazole, chiral amino alcohol and 8-
aminoquinoline, to produce a series of novel chiral thiazoline
tridentate ligands. These ligands, together with CuCl, were able to
promote a highly enantioselective Henry reaction between nitro-
methane and various aldehydes. The study showed that the opti-
mal catalyst for this reaction was that with ligand 12, which was
formed from chiral thiazoline with chiral amino alcohol. At ꢀ20°C,
with 10 mol% of ligand 12 complexed with CuCl, in ethanol, the
product was obtained with S configuration and stereoselectity up
to 98% ee.
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Supporting information
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web-site.
Appl. Organometal. Chem. 2015, 29, 661–667
Copyright © 2015 John Wiley & Sons, Ltd.
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