Novel chiral thiazoline-containing NO ligands in the asymmetric addition of diethylzinc to aldehydes: Substituent effect on the enantioselectivity

Article abstract of DOI:10.1002/aoc.2820

Several novel chiral thiazoline primary and tertiary alcohols were easily synthesized from commercially available l-cysteine in three steps and with high yield. These ligands were subsequently applied to the asymmetric addition of diethylzinc (Et₂Zn) to various aldehydes. Products with S configuration were obtained when thiazoline-containing tertiary alcohol ligands were used as catalysts. The primary alcohol induced corresponding products with R configuration in 68% enantiomeric excess, which was a higher value relative to other NO ligands possessing a primary alcohol unit in the literature. Furthermore, a plausible transition state model was proposed to explain the observed enantioselectivities. Copyright

Full text of DOI:10.1002/aoc.2820

Full Paper
Received: 14 October 2011
Revised: 15 December 2011
Accepted: 17 December 2011
Published online in Wiley Online Library: 31 January 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2820
Novel chiral thiazoline-containing N-O ligands
in the asymmetric addition of diethylzinc to
aldehydes: substituent effect on the
enantioselectivity
Zhiyong Gong,a Qingwen Liu,a Pengchong Xue,a Kechang Li,a
Zhiguang Song,a* Zaiqun Liua and Yinghua Jinb
Several novel chiral thiazoline primary and tertiary alcohols were easily synthesized from commercially available L-cysteine in
three steps and with high yield. These ligands were subsequently applied to the asymmetric addition of diethylzinc (Et2Zn) to
various aldehydes. Products with S configuration were obtained when thiazoline-containing tertiary alcohol ligands were used
as catalysts. The primary alcohol induced corresponding products with R configuration in 68% enantiomeric excess, which was
a higher value relative to other N-O ligands possessing a primary alcohol unit in the literature. Furthermore, a plausible
transition state model was proposed to explain the observed enantioselectivities. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: thiazoline; chiral ligands; imino primary alcohol; asymmetric addition; diethylzinc
Introduction
Results and Discussion
Synthesis of Ligands
Asymmetric organic catalytic reactions are extremely important in
modern synthetic and pharmaceutical chemistry.[1–6] In this field,
the asymmetric addition of diethylzinc to aldehydes is an efficient
and feasible reaction for obtaining chiral secondary alcohols, which
are often applied in the synthesis of many biologically active
compounds.[7–10] Furthermore, It is also regarded as one of the
benchmark reactions for exploring the catalytic potential of new
ligands. Therefore, numerous efforts have been made to develop
new effective chiral ligands for asymmetric addition of diethylzinc
to benzaldehyde.[11–17]
Among various chiral ligands, the chiral b-amino alcohols have
been widely developed as a typical class of catalysts.[18–22] It was
found that b-amino tertiary alcohol ligands possessed high catalytic
activity to obtain high enantiomeric excess (ee) values in the
asymmetric addition of diethylzinc to aldehydes. However, under
the same condition, chiral primary alcohols always resulted in
corresponding products with lower ee values.[23–27] Therefore, the
development of efficient b-amino primary alcohol ligands for
asymmetric transformations is a challenge.
In our work, we report a simple three-step synthesis of a series of novel
chiral N-O ligands 5 containing a primary alcohol unit (Scheme 2). First,
(R)-tetrahydrothiazo-2-thione-4-carboxylic acid ((R)-TTCA)
2 was
obtained by cyclization between commercial L-cysteine and carbon
disulfide under basic conditions.[33] Alkyl bromide was then added
in situ to facilitate a tandem alkylation of 2 to 3 in moderate yield
(Table 1). Finally, thioether derivatives 3 were converted to chiral
b-imino primary alcohols (5a–5e) by NaBH4 treatment. Compound 6
could also be easily obtained from 4 by treatment with NaBH4. The
detail results are depicted in Table 1.
Conventionally, the reduction of ester to primary alcohol with
lithium aluminum hydride requires a relatively longer time, avoidance
from moisture, and low-temperature conditions.[34,35] Nevertheless, in
our study, the use of a sodium borohydride/MeOH system at room
temperature has provided a straightforward and higher-yield method
for obtaining chiral imino primary alcohols 5a–5e. This method also
successfully suppresses racemization and secures the optical purity
of the resulting alcohols. Furthermore, in Scheme 1, we have
Among the large variety of Lewis basic donor functionalities, the
imino moiety containing thiazoline[28–32] was found to an efficient
surrogate to the amino unit in the chiral b-amino alcohol catalyst.
However, to the best of our knowledge, there is no previous report
on the development of thiazoline-containing chiral b-imino primary
alcohol ligand-promoted enantioselective addition of diethylzinc to
aldehydes. In this study, we first disclose the design, synthesis, and
application of a series of novel modular, thiazoline-containing N-O
ligands derived from L-cysteine (Scheme 1) in asymmetric addition
of diethylzinc to aromatic aldehydes.
*
Correspondence to: Zhiguang Song, Department of Organic Chemistry, 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 Key Laboratory for Molecular Enzymology, Engineering of the Ministry of Edu-
cation, Jilin University, Jinlin 130012, China
Appl. Organometal. Chem. 2012, 26, 121–129
Copyright © 2012 John Wiley & Sons, Ltd.

Z. Gong et al.
Scheme 3. Preparation of thiazoline ligands 5f–5j.
Observation of Catalytic Activity
In order to detect the catalytic activity of thiazoline ligands, the
asymmetric addition of Et2Zn to benzaldehyde was chosen as a
model reaction to yield chiral 1-phenyl-1-propanol (7a). Our study
began with the solvent and ligand loading screening (Table 2).
We found that the solvent employed significantly affected the
conversion and enantioselectivity. For example, in the presence of
10 mol% 5b, the corresponding adduct 7a was obtained in 74%
yield and 41% ee in hexane with the R configuration. On the other
hand, when the reaction was carried out in toluene, a relatively
higher yield and ee (81% and 68%, respectively) were obtained.
Consequently, toluene was considered as an optimized solvent in
the following catalytic reactions. Moreover, we also found that 5b
loading had a significant influence on the activity of the catalyst
and a slight influence on yield. For example, 2 mol% 5b induced
7a in only 10% ee. Decreasing the 5b loading to 5 mol% led to
lower ee (33%) However, in the presence of up to 20 mol% 5b, only
48.4% ee was observed. Thus the optimized chiral ligand loading
was confirmed at 10 mol% relative to benzaldehyde.
Scheme 1. Molecular structures of thiazoline ligands.
We next explored the influence of the thioalkyl moiety of ligands
on conversion yield and enantioselectivity. Reaction conditions were
set as 10 mol% ligands in toluene at room temperature, as presented
in Table 3. Although all chiral primary alcohol ligands 5a–5e resulted
in moderate ee of the alcohol product with (R) configuration, to our
delight these initial results still represented a significant improve-
ment on the low ee obtained with other chiral b-amino primary
alcohol ligands documented in the literature.[23–27] Moreover,
thioethyl ligand 5b (R1 = Et, entry 2 in Table 3) led to the best enan-
tioselectivity (68% ee) in high yield (81%), whereas the least hindered
5a led to a diminished ee. Interestingly, the ligands 5c, 5d, 5e with
bulkier thio substituents (R1 =n-butyl, n-hexyl and Bn, respectively)
did not improve the enantioselectivity of the alcohol product as
expected. The ee decreased as the function of the bulk of the thio
substituents. Therefore, the 2-thio substituent group (R1) strongly
influenced the enantioselectivity of the ligand.
Scheme 2. The synthesis strategy for 5a–5e.
documented a new protocol for direct esterification of 2 to
obtain compound 4 at room temperature using catalytic TiCl4.
Compared to the conventional method with other Lewis acids,[36,37]
this new method significantly improved chemoselectivity and
overall efficiency, with complete retention of the original (R)
configuration of 2.
For comparison, we also synthesized thiazoline tertiary alcohol
ligands 5f–5j in moderate yield, which were easily formed via
nucleophilic addition reaction of the ester group of 3b by RMgBr,
as shown in Scheme 3. Therefore, our chiral ligands of imino
primary alcohols and imino tertiary alcohols could be easily
achieved in only three steps and with high yield from commercial
L-cysteine.
In comparison to primary alcohol ligand, the catalytic activity of
thiazoline tertiary alcohol ligands 5f–5j for asymmetric addition
Table 1. Preparation of thioether derivatives 3a–3e, 5a–5e and 6a
20
20
Entry
R
Product
Yield (%)b
½aꢀD
Product
Yield (%)b
½aꢀD
1
2
3
4
5
6
Methyl
Ethyl
n-Butyl
n-Hexyl
Bn
3a
3b
3c
3d
3e
4
80
88
72
76
56
99
+42
+39
+29
+23
+17
ꢁ43
5a
5b
5c
5d
5e
6
88
99
99
99
99
85
+62.6
+46.3
+28.4
+24.6
+21.6
+20
H
aSee Experimental section.
bCalculated in single step after column chromatography.
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 121–129

Chiral thiazoline
Table 2. Effect of amount chiral ligand 5b and solvent on asymmetric addition of Et2Zn to benzaldehydea
20
Entry
Solvent
Hexane
5b (mol%)
Yield (%)b
ee (%)c
½aꢀD
Configurationd
1
2
3
4
5
6
7
10
10
10
10
2
74
41
3
+18.3
+1.4
R
R
R
R
R
R
R
Tetrahydrofuran
Dichloromethane
Toluene
34
29
11
68
10
33
48
+4.8
81
+30.0
+4.5
Toluene
64.7
66.2
60
Toluene
5
+14.6
+21.4
Toluene
20
aThe reactions were run for 0.5 h at 0ꢂC and for 48 h at room temperature.
bYields after silica gel column chromatography.
cThe ee was determined by HPLC using a Daicel Chiral OD column.
dThe absolute configuration of the alcohol was assigned by comparison of the sign of the specific rotation to the literature value.[38–40]
Table 3. Asymmetric addition of Et2Zn to benzaldehyde catalyzed by ligands 5 and 6a
20
Entry
Ligand (10 mol%)
Yield (%)b
ee (%)c
½aꢀD
Configurationd
1
5a
5b
5c
5d
5e
6
66
81
68
71
70
40
70
60
62
70
80
44
68
47
42
34
10
19
16
14
20
6
+26.0
+30.0
+20.6
+18.0
+22.0
+6.0
R
R
R
R
R
R
R
S
S
S
S
2
3
4
5
6
7
5f
+6.0
8
5g
5h
5i
ꢁ7.0
ꢁ7.2
ꢁ11.9
ꢁ3.0
9
10
11
5j
aThe reactions were run for 0.5 h at 0ꢂC and for 48 h at room temperature.
bYields after silica gel column chromatography.
cThe ee was determined by HPLC using a Daicel Chiral OD column.
dThe absolute configuration of the alcohol was assigned by comparison of the sign of the specific rotation to the literature value.[38–40]
of Et2Zn to benzaldehyde was also determined. We found that all of
the tertiary alcohol ligands promoted the production of the
desired alcohol in good yield (60–80%, entries 7–11 in Table 3).
However, corresponding products possessed lower enantiomeric
excesses than those catalyzed by 5a–5e. For example, 5i led to
an alcohol product with 20.2% ee in 70% yield (entry 10 in Table 3).
Obviously, the thiazoline tertiary alcohol ligands are not a good
template for catalyst development for the asymmetric addition of
Et2Zn to benzaldehyde. More interestingly, the favored enantiomer
of the alcohol product obtained in the presence of 5g–5j was
revealed to possess an (S) configuration. Although there have been
reports on the dependence of absolute configuration of the
product on the structure of chiral ligands, especially on the steric
hindrance caused by substituents near to the postulated reaction
center,[41–45] our results indicate that catalytic processes in the
presence of primary and tertiary alcohols must have distinct
transition states.
Owing to the unproductive screening on the thiazoline tertiary
alcohol catalyst, we returned to the more promising thiazoline pri-
mary alcohol catalysts. To explore the influence of electronic and
steric effects of the substrate in the asymmetric addition of Et2Zn,
a series of aryl aldehydes were tested in the reactions in the pres-
ence of previously optimized primary alcohol ligand 5b (Table 4).
A general trend observed with respect to enantioselectivities of
the alcohol product as the function of the electron-donating or
electron-withdrawing substituents on the aryl aldehyde substrate
is also shown in Fig. 1. Substrates with electron-donating groups
of aryl aldehydes (entries 2–4) afforded slight lower enantioselectiv-
ities than that of benzaldehyde, but higher than those with elec-
tron-withdrawing groups (entries 5–7). On the other hand, para-
Appl. Organometal. Chem. 2012, 26, 121–129
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Z. Gong et al.
Table 4. Asymmetric addition of Et2Zn to various aldehydes catalyzed by ligand 5ba
20
Entry
R
Ligand (10 mol%)
Yield (%)b
ee (%)c
½aꢀD
Configurationd
1
2
3
4
5
6
7
H
5b
5b
5b
5b
5b
5b
5b
81
65
90
98
80
81
85
68
43
39
64
39
38
62
+30.0
+7.0
R
R
R
R
R
R
R
o-OCH3
m-OCH3
p-OCH3
o-Cl
+13.0
+27.3
+15.5
+10.3
+23
m-Cl
p-Cl
aThe reactions were run for 0.5 h at 0ꢂC and for 48 h at room temperature.
bYields after silica gel column chromatography.
cThe ee was determined by HPLC using a Daicel Chiral OD or AD column.
dThe absolute configuration of the alcohol was assigned by comparison of the sign of the specific rotation to the literature value.[38–40]
be in equatorial position because of weak steric hindrance between
the phenyl unit and small R2 (TS 11). Thus, a preferable re-face attack
of the ethyl group of ZnA to the carbonyl and lead to the formation of
the R enantiomer of the alcohol product. On the other hand, with the
increase in bulkiness of the 2-thio-substituent (R1) in the ligand, more
steric factors have to be taken into consideration. In the presence a
larger R1, it is more difficult to pose the phenyl group in an equatorial
position. Therefore, a gradual decrease of enantioselectivity in the
catalytic reactions was observed from 5b to 5e.
When R2 is a larger group, such as an ethyl, n-butyl, n-hexyl or phe-
nyl group, the phenyl group in the substrate is forced to dispose in the
axial position to avoid steric interaction with R2. Eventually, the ethyl
group of ZnA is transferred from the si-face of the benzaldehyde to
form the S enantiomer of the product (TS 12). Moreover, in the
presence of these tertiary alcohol ligands the energy difference
between TS 11 and TS 12 is small because the substrate phenyl group
Figure 1. Effect of the asymmetric addition of Et2Zn to various
is disposed equatorially in 11. Therefore, these thiazoline tertiary
aldehydes.
ligands only led to adduct products with poor ee values.
substituent aldehydes led to much higher enantioselectivities than
those of the ortho- or meta-aldehydes.
Experimental
Finally, based on experimental observations and related mechanistic
studies by other authors,[45–47] we proposed transition state models of
Materials and Instruments
the thiazoline alcohol ligand-promoted asymmetric diethylzinc addi-
tion to aromatic aldehydes (Fig. 2). First, Et2ZnA reacts rapidly with
the alcohol ligand by replacing the hydrogen in the hydroxyl group
to give the corresponding zinc monoalkoxide 8. The second equivalent
of Et2Zn then comes in and coordinates with complex 8 to form the
zinc monoalkoxide–diethylzinc complex 9, which finally isomerizes to
the complex 10 via thermodynamic equilibration.[48–50] The final
substrate aldehyde coordination with complex 10 set up the bis six-
membered ring transition states (TS), 11 and 12, respectively.[51,52]
Owing to electron density accumulation on the zinc atom with coordi-
nation of the oxygen and nitrogen atoms in the ligand, the
nucleophilicity-enhanced ethyl group of Et2ZnA would attack the
aldehyde carbonyl from either the re face or the si face.
Toluene, hexane and ethyl ether (Na, benzophenone) were dried by
distillation; other analytical-grade reagents were purchased from
Beijing Chemical Reagent Co. (China) and used without further
purification. The products were purified by neutral column chroma-
tography on silica gel (300–400 mesh). The structures of chiral
1
thiazoline ligands were identified by H NMR and 13C NMR (Varian
Mercury 300 NMR spectrometer), using tetramethylsilane as an
internal standard. Chemical shifts (d) are given in parts per million
and coupling constants are given as absolute values expressed in
hertz. Optical rotations were measured with a WZZ-1S digital
automatic polarimeter (Shanghai Physical Optics Instrument Factory).
Concentration is given as absolute values expressed in g 100 mlꢁ1
.
In the case that R2 in the ligand is a small group such as a hydrogen
atom or methyl group, the phenyl group in the substrate prefers to
High-performance liquid chromatographic analyses (HPLC) were per-
formed using Shimadzu LC-10A VP pump, SPD-10A VP UV detector,
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 121–129

Chiral thiazoline
Figure 2. A tentative mechanism for asymmetric addition of Et2Zn to aldehydes.
and Shimadzu CTO-10AC VP column oven with appropriate chiral
columns. Mass spectra were obtained using an LC/MS 1100 of Agilent
Technology Corp. and an Alltech ELSD 2000 instrument. Melting
points were determined using an X-4 digital microscopy apparatus.
C, H, and N elemental analyses were taken on a PerkinElmer 240C
elemental analyzer.x
analysis calculated for C6H9NO2S2: C, 37.68; H, 4.74; N, 7.32. Found:
C, 37.70, H, 4.70, N, 7.29.
(R)-2-Ethylthio-4-ethyloxycarbonyl-4,5-dihydro-1,3-thiazole (3b)
was obtained as a colorless oil, with 88% yield after purification
by column chromatography on silica gel (petroleum ether:EtOAc=
20
3:1), ½aꢀD = +38.8 (c 6.4, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm)
1.29–1.41 (m, 6 H, -CH3), 3.06–3.25 (m, 2H, -SCH2CH3), 3.56–3.71 (m,
2H, -SCH2CHN ), 4.25 (q, J = 6 Hz, 2H, -OCH2-), 5.06 (t, J = 7.2 Hz, 1 H,
N-CH-); 13C NMR (75 MHz, CDCl3) d (ppm) 14.08 (-SCH2CH3), 14.41
(-OCH2CH3), 27.34 (-SCH2CH3), 37.02 (-SCH2CHN ), 61.58 (-OCH2-),
77.23 ( N-CH-), 170.50 (-C = O). MS (ESI): m/z 220.3 [M+ H+]. Elemen-
tal analysis calculated for C8H13NO2S2: C, 43.81; H, 5.97; N, 6.39.
Found: C, 43.83, H, 5.96, N, 6.36.
Synthesis
(R)-Tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA] 2 was
20
synthesized by known methods;[33] m.p. 179–181ꢂC, ½aꢀD = ꢁ86.3
(c 1.2, 0.5 N HCl).
(R)-2-Butylthio-4-butyloxycarbonyl-4,5-dihydro-1,3-thiazole (3c)
was obtained as a colorless oil, with 72% yield after purification
by column chromatography on silica gel (petroleum ether:EtOAc=
5:1), ½aꢀD = +28.5 (c 6.7, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm)
General Procedure for Preparation of 3a–3e
To a solution of (R)-TTCA (2) (2.0 g, 12.3 mmol) in acetonitrile (40
ml), the corresponding halide (37.5 mmol) and anhydrous K2CO3
(3.4 g) were added at room temperature. The solution was then
stirred at 55ꢂC for 6 h. After cooling to room temperature, the
precipitate was removed by filtration, and acetonitrile was then
removed under reduced pressure. The residue was purified by
column chromatography on silica gel (petroleum ether:EtOAc).
(R)-2-Methylthio-4-methyloxycarbonyl-4,5-dihydro-1,3-thiazole (3a)
was obtained as a colorless oil, with 80% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 3:1),
20
0.92–0.95 (m, 6H, -CH3), 1.39–1.44 (m, 4 H, -CH2), 1.64–1.69 (m, 4H,
-CH2), 3.08–3.23 (m, 2H, -SCH2CH2-), 3.59–3.66 (m, 2H, -SCH2CHN ),
4.19 (t, J = 6.6 Hz, 2H, -OCH2-), 5.06 (t, J = 8.1 Hz, 1H, N-CH-);
13C NMR (75 MHz, CDCl3) d (ppm) 13.54 (-CH3), 13.63 (-CH3), 19.01
(-CH2), 21.79 (-CH2), 30.50 (-SCH2CH2-), 31.13 (-CH2), 32.75 (-CH2),
37.15 (SCH2CHN ), 65.47 (-OCH2-), 77.25 ( N-CH-), 170.65 (-C = O).
MS (ESI): m/z 276.3 [M+ H+]. Elemental analysis calculated
for C12H21NO2S2: C, 52.33; H, 7.68; N, 5.09. Found: C, 52.36, H, 7.69,
N, 5.06.
20
1
½aꢀD = +42 (c 3.1, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 2.59
(s, 3H, -SCH3), 3.62–3.71 (m, 2H, -SCH2-), 3.81 (s, 3H, -OCH3), 5.07
(t, J= 8.7 Hz, 1H, =N-CH-); 13C NMR (75 MHz, CDCl3) d (ppm) 15.56
(-SCH3), 37.27 (-SCH2-), 52.65 (-OCH3), 77.14 ( N-CH-), 170.93 (-C = O).
MS (electrospray ionization (ESI)): m/z 192.2 [M + H+]. Elemental
(R)-2-Hexylthio-4-hexyloxycarbonyl-4,5-dihydro-1,3-thiazole (3d)
was obtained as a colorless oil, with 76% yield after purification
by column chromatography on silica gel (petroleum ether:EtOAc=
20
5:1), ½aꢀD = +23.2 (c 3.5, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm)
Appl. Organometal. Chem. 2012, 26, 121–129
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Z. Gong et al.
0.86–0.89 (m, 6H, -CH3), 1.29–1.31 (m, 12H, -CH2), 1.65–1.71 (m, 4H,
-CH2), 3.08–3.20 (m, 2H, -SCH2CH2-), 3.56–3.70 (m, 2H, -SCH2CHN ),
4.16–4.21 (m, 2H, -OCH2-), 5.04–5.09 (m, 1H, NCH-); 13C NMR
(75 MHz, CDCl3) d (ppm) 13.95 (-CH3), 22.46 (-CH2), 22.48 (-CH2),
25.43 (-CH2), 28.36 (-CH2), 28.43 (-CH2), 29.02 (-CH2), 31.24 (-CH2),
31.34 (-CH2), 33.09 (-CH2), 37.15 (-SCH2CHN ), 65.78 (-OCH2-), 77.19
( NCH-), 170.69 (-C =O). MS (ESI): m/z 332.4 [M+ H+]. Elemental
analysis calculated for C16H29NO2S2: C, 57.96; H, 8.82; N, 4.22. Found:
C, 57.97, H, 8.80, N, 4.20.
(-SCH3), 36.26 (-SCH2CHN ), 64.09 (-CH2OH), 78.43 (-SCH2CHN ). MS
(ESI): m/z 165.0 [M + H+]. Elemental analysis calculated for C5H9NOS2:
C, 36.78; H, 5.56; N, 8.58. Found: C, 36.72, H, 5.58, N, 8.56.
(R)-2-Ethylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (5b) was
obtained as a colorless oil, with 99% yield after purification by column
20
chromatography on silica gel (petroleum ether:EtOAc = 1:2), ½aꢀD
=
+46.3 (c 2.8, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 1.36 (t, J=7.2
Hz, 3 H, -CH3), 2.06 (br, 1H, -OH), 3.07–3.14 (m, 2 H, -SCH2CH3), 3.27
(dd, J=8.7 Hz, J= 10.8 Hz, 1H, -SCH2CHN ), 3.42 (dd, J=8.1 Hz,
J=10.8 Hz, 1 H, -SCH2CHN ), 3.69 (dd, J=5.7 Hz, J=11.1 Hz, 1H,
-CH2OH), 3.88 (dd, J=4.8 Hz, J=11.1 Hz, 1 H, -CH2OH), 4.54–4.63
(m, 1 H, -SCH2CHN ); 13C NMR (75MHz, CDCl3) d (ppm) 14.39
(-CH3), 27.13 (-SCH2CH3), 35.84 (-SCH2CHN ), 63.76 (-CH2OH), 78.39
(-SCH2CHN ). MS (ESI): m/z 179.0 [M + H+]. Elemental analysis
calculated for C6H11NOS2: C, 40.65; H, 6.25; N, 7.90. Found: C, 40.67,
H, 6.23, N, 7.93.
(R)-2-Benzylthio-4-benzyloxycarbonyl-4,5-dihydro-1,3-thiazole (3e)
was obtained as a colorless oil, with 56% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 5:1),
20
1
½aꢀD =+17 (c 3.1, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 3.59–
3.62 (m, 2H, -SCH2CHN ), 4.34–4.45 (m, 2 H, -SCH2-Ph ), 5.12 (m, 1H,
NCH-), 5.25 (s, 2 H, -OCH2-Ph), 7.26–7.39 (m, 10 H, -Ph); 13C NMR
(75 MHz, CDCl3) d (ppm) 37.19 (-SCH2CHN ), 37.36 (-SCH2-Ph), 67.20
(-OCH2-) , 77.07 ( NCH-), 127.49 (-Ph), 128.15 (-Ph), 128.36 (-Ph),
128.55 (-Ph), 129.04 (-Ph), 135.34 (-Ph), 136.28 (-Ph), 170.21 (-C = O).
MS (ESI): m/z 344.2 [M + H+]. Elemental analysis calculated for
C18H17NO2S2: C, 62.94; H, 4.99; N, 4.08. Found: C, 62.97, H, 4.97, N, 4.07.
(R)-2-Butylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (5c) was
obtained as a colorless oil, with 99% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 1:2),
20
½aꢀD = +28.4 (c 3.9, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 0.93
(t, J= 7.5 Hz, 3H, -CH3), 1.37–1.49 (m, 2 H, -CH2-), 1.63–1.73 (m, 2 H,
-CH2-), 1.94 (br, 1 H, -OH), 3.12 (t, J= 7.5 Hz, 2 H, -SCH2-), 3.27 (dd,
J= 8.7 Hz, J=10.8 Hz, 1H, -SCH2CHN ), 3.42 (dd, J=8.4 Hz, J=10.8
Hz, 1H, -SCH2CHN ), 3.69 (dd, J=5.7 Hz, J=11.1 Hz, 1 H, -CH2OH),
3.89 (dd, J=4.8 Hz, J=11.1 Hz, 1H, -CH2OH), 4.54–4.63 (m, 1H,
-SCH2CHN ); 13C NMR (75 MHz, CDCl3) d (ppm) 13.47 (-CH3), 21.76
(-CH2-), 31.24 (-CH2-), 32.59 (-SCH2-), 35.90 (-SCH2CHN ), 64.04
(-CH2OH), 78.46 (-SCH2CHN ). MS (ESI): m/z 206.2 [M + H+]. Elemental
analysis calculated for C8H15NOS2: C, 46.79; H, 7.36; N, 6.82. Found:
C, 46.75, H, 7.38, N, 6.86.
Procedure for preparation of (R)-4-ethyloxycarbonyl-1,3-thiazoline-2-thione (4)
To a solution of (R)-TTCA (2) (0.65 g, 4.0 mmol) in ethanol (10 ml),
TiCl4 (0.1 ml, 1.0 mmol) was added at 0ꢂC. The solution was then
stirred at room temperature for 12 h. Then the solution was neutral-
ized with 5% sodium bicarbonate solution to pH 8 at 0ꢂC. The
mixture was then extracted twice with CH2Cl2. The combined
organic phase were washed with saturated brine twice, dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on sil-
ica gel (petroleum ether:EtOAc= 3:2) and was obtained as colorless
a oil, with 99% yield.
(R)-2-Hexylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (5d) was
obtained as a light-yellow oil, with 99% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 1:3),
(R)-4-Ethyloxycarbonyl-1, 3-thiazoline-2-thione (4) was obtained as
20
1
20
a colorless oil, with 99% yield. ½aꢀD = ꢁ42.9 (c 5.5, CHCl3), 1H NMR
½aꢀD = +24.6 (c 3.3, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 0.89
(t, J=6.9 Hz, 3 H, -CH3), 1.26–1.43 (m, 6H, -CH2-), 1.64–1.73 (m, 2H,
-CH2-), 1.94 (br, 1 H, -OH), 3.09 (t, J= 7.5 Hz, 2H, -SCH2-), 3.27 (dd,
J=8.7 Hz, J= 10.8 Hz, 1H, -SCH2CHN ), 3.42 (dd, J=8.4 Hz, J= 10.8 Hz,
1H, -SCH2CHN ), 3.64–3.73 (m, 1H, -CH2OH), 3.89 (dd, J=4.8 Hz,
J=11.1 Hz, 1H, -CH2OH), 4.54–4.63 (m, 1H, -SCH2CHN ); 13C NMR
(75 MHz, CDCl3) d (ppm) 13.93 (-CH3), 22.43 (-CH2-), 28.34 (-CH2-),
29.16 (-CH2-), 31.21 (-CH2-), 32.94 (-SCH2-), 35.92 (-SCH2CHN ), 64.11
(-CH2OH), 78.47 (-SCH2CHN ). MS (ESI): m/z 234.2 [M + H+]. Elemental
analysis calculated for C10H19NOS2: C, 51.46; H, 8.21; N, 6.00. Found:
C, 51.42, H, 8.22, N, 6.05.
(300 MHz, CDCl3) d (ppm) 1.34 (t, J= 7.2 Hz, 3 H, -CH3), 3.80 (d, J=3
Hz, 1H, -SCH2CHNH), 3.82 (d, J=3 Hz, 1H, -SCH2CHNH), 4.27–4.34
(m, 2H, -OCH2-), 4.83–4.88 (m, 1H, -SCH2CHNH), 8.21 (br, 1H, -NH);
13C NMR (75 MHz, CDCl3) d (ppm) 14.02 (-CH3), 35.41 (-SCH2CHNH),
62.78 (-OCH2-), 63.82 (-SCH2CHNH), 168.28 (-C = O). MS (ESI): m/z
192.1 [M + H+]. Elemental analysis calculated for C6H9NO2S2: C,
37.68; H, 4.74; N, 7.32. Found: C, 37.69, H, 4.76, N, 7.30.
General procedure for preparation of (R)-2-substituted thio-4-hydro-
xymethyl-4,5-dihydro-1,3-thiazoles (5a–5e) and (R)-4-hydroxymethyl-
1,3-thiazoline-2-thione (6)
(R)-2-Benzylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (5e) was
obtained as light-yellow oil, with 98% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 1:2),
To a solution of 3 or 4 (5.0 mmol) in methanol (15 ml), NaBH4 (0.57
g, 15.0 mmol) was added. The solution was then stirred at room
temperature for 0.5 h. When thin-layer chromatography revealed
that the reaction was completed, water was added to remove
excessive NaBH4. The mixture was then extracted twice with CH2Cl2.
The combined organic phase was washed with saturated brine
twice, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel to give the alcohol 5a–5e or 6.
(R)-2-Methylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (5a) was
20
1
½aꢀD = +21.6 (c 2.2, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 1.86
(s, 1 H, -OH), 3.29 (dd, J=8.4 Hz, J= 10.5 Hz, 1H, -SCH2CHN ), 3.44
(dd, J=8.1 Hz, J= 10.5 Hz, 1H, -SCH2CHN ), 3.65 (dd, J=5.7 Hz,
J=11.4 Hz, 1H, -CH2OH), 3.88 (dd, J=4.8 Hz, J=11.1 Hz, 1H, -CH2OH),
4.35 (m, 2H, -SCH2-Ph), 4.56–4.64 (m,1H, -SCH2CHN ), 7.28–7.38
(m, 5H, -Ph); 13C NMR (75 MHz, CDCl3) d (ppm) 36.26 (-SCH2CHN ),
37.06 (-SCH2-Ph), 64.09 (-CH2OH), 78.33 (-SCH2CHN ), 127.48 (-Ph),
128.52 (-Ph), 128.89 (-Ph), 136.43 (-Ph). MS (ESI): m/z 240.1 [M + H+].
Elemental analysis calculated for C11H13NOS2: C, 55.20; H, 5.47; N,
5.85. Found: C, 55.26, H, 5.44, N, 5.88.
obtained as a colorless oil, with 88% yield after purification by column
20
chromatography on silica gel (petroleum ether:EtOAc = 1:3), ½aꢀD
=
+62.6 (c 3.9, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 2.03 (s, 1 H, -
OH), 2.55 (s, 3H, -SCH3), 3.31 (dd, J=8.7 Hz, J=10.5 Hz, 1H, -SCH2CHN ),
3.45 (dd, J=8.4 Hz, J=10.5 Hz, 1H, -SCH2CHN ), 3.69 (dd, J=5.7 Hz,
J= 11.1 Hz, 1H, -CH2OH), 3.91 (dd, J=4.8 Hz, J=11.1 Hz, 1 H, -CH2OH),
4.57–4.62 (m, 1H, -SCH2CHN ); 13C NMR (75 MHz, CDCl3) d (ppm) 15.48
(R)-4-Hydroxymethyl-1,3-thiazoline-2-thione (6) was obtained as a
white solid, with 85% yield after purification by column chromatogra-
20
phy on silica gel (petroleum ether:EtOAc = 1:4), ½aꢀD = +20.0 (c 2.4,
MeOH), 1H NMR (300 MHz, DMSO) d (ppm) 3.36 (dd, J=6 Hz,
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 121–129

Chiral thiazoline
J= 11.1 Hz, 1H, -SCH2CHN ), 3.43–3.51 (m, 2H, -CH2OH), 3.56 (dd, J=5.4
Hz, J= 11.1 Hz, 1H, -SCH2CHN ), 4.16–4.25 (m, 1H, -SCH2CHN ), 7.02
(br, 1H, -NH); 13C NMR (75 MHz, DMSO) d (ppm) 34.47 (-SCH2CHN ),
61.08 (-CH2OH), 66.01 (-SCH2CHN ), 197.72 (-C = S). MS (ESI): m/z
150.0 [M + H+]. Elemental analysis calculated for C4H7NOS2: C, 32.19;
H, 4.73; N, 9.39. Found: C, 32.19, H, 4.77, N, 9.36.
(R)-7-(2-(Ethylthio)-4,5-dihydrothiazol-4-yl) tridecan-7-ol (5i) was
obtained as a yellow oil, with 60% yield after purification by column
20
chromatography on silica gel (petroleum ether:EtOAc = 6:1), ½aꢀD
1
=+6.7 (c 14.8, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 0.87–0.91
(m, 6 H, -CH3), 1.29–1.38 (m, 20 H, -CH2-), 1.67–1.76 (m, 3 H, -SCH2CH3),
3.02–3.13 (m, 2H, -SCH2-), 3.22–3.40 (m, 2H, -SCH2CHN ), 4.35 (dd,
J=8.1 Hz, J=11.4 Hz, 1H, -SCH2CHN ); 13C NMR (75 MHz, CDCl3) d
(ppm) 14.00 (-CH3), 14.66 (-SCH2CH3), 22.58 (-CH2), 23.24 (-CH2-),
23.48 (-CH2), 27.22 (-CH2), 29.91 (-CH2), 29.99 (-CH2), 31.75 (-CH2),
31.78 (-CH2), 34.96(-SCH2CH3), 35.16 (-SCH2CH3), 37.77 (-SCH2CHN ),
75.74 (-C(C6H13)2OH), 83.95 (-SCH2CHN ). MS (ESI): m/z 345.9 [M + H+],
327.9 [M + H+ ꢁ 18]. Elemental analysis calculated for C18H35NOS2: C,
62.55; H, 10.21; N, 4.05. Found: C, 62.54, H, 10.22, N, 4.07.
General procedure for preparation of 5f–5j
To magnesium (0.288 g) and a small piece of iodine in dry ethyl
ether (5 ml), a solution of RBr or ArBr (12 mmol) in dry ethyl ether
(10 ml) was added dropwise to keep the mixture at gentle reflux.
When the addition was completed, the reaction mixture was kept
refluxing for 1 h. The RMgBr or ArMgBr solution obtained was then
stored at 0ꢂC. To RMgBr or ArMgBr (12 mmol), a solution of 3a
(0.657 g, 3 mmol) in dry ethyl ether (10 ml) was added at 0ꢂC. The
reaction mixture was stirred at room temperature for 12 h. Then
the reaction was quenched by addition of saturated aqueous NH4Cl
and extracted with ethyl ether (20 mlꢃ 3). The combined organic
phase was washed with brine and dried over anhydrous Na2SO4.
The solvent was then removed under reduced pressure. The crude
product was purified by column chromatography on silica gel.
(R)-2-(2-(Ethylthio)-4,5-dihydrothiazol-4-yl) propan-2-ol (5f) was
obtained as a light-yellow oil, with 52% yield after purification by
column chromatography on silica gel (petroleum ether:EtOAc = 4:1),
(R)-(2-(Ethylthio)-4,5-dihydrothiazol-4-yl) diphenylmethanol (5j) was
obtained as a yellow oil, with 70% yield after purification by column
20
chromatography on silica gel (petroleum ether:EtOAc = 4:1), ½aꢀD
=
ꢁ31.9 (c 5.5, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 1.29
(t, J= 7.2 Hz, 3H, -CH3), 2.65 (s, 1H, (-C(Ph)2OH)), 2.87–2.94 (m, 1H,
-SCH2CH3), 2.99–3.06 (m, 1H, -SCH2CH3), 3.35 (t, J= 11.4 Hz,1H,
-SCH2CHN ), 3.47 (dd, J=7.2 Hz, J= 14.1 Hz, 1H, -SCH2CHN ), 5.45 (dd,
J=7.8 Hz, J=11.4 Hz, 1H, -SCH2CHN ), 7.19–7.25(m, 2H, -Ph), 7.29–
7.31 (m, 4 H, -Ph), 7.42–7.45 (m, 2H, -Ph), 7.57–7.59 (m, 2H, -Ph); 13
C
NMR (75 MHz, CDCl3) d (ppm) 14.46 (-CH3), 27.32 (-SCH2CH3), 36.16
(-SCH2CHN ), 78.68 (-C(Ph)2OH), 83.16 (-SCH2CHN ), 125.78 (-Ph),
126.82 (-Ph), 126.88 (-Ph), 127.06 (-Ph), 127.91 (-Ph), 128.09 (-Ph),
128.15 (-Ph), 130.45 (-Ph), 132.76 (-Ph), 144.24 (-Ph), 146.71 (-Ph). MS
(ESI): m/z 329.8 [M + H+], 312.8 [M + H+ ꢁ 18]. Elemental analysis
calculated for C18H19NOS2: C, 65.62; H, 5.81; N, 4.25. Found: C, 65.67,
H, 5.83, N, 4.23.
20
1
½aꢀD = +26.0 (c 11.8, CHCl3), H NMR (300 MHz, CDCl3) d (ppm) 1.21
(s, 3 H, -SCH2CH3), 1.37 (dd, J=7.5 Hz, J=10.2 Hz, 6 H, -C(CH3)2OH),
1.99 (br, 1 H, -OH), 3.08–3.16 (m, 2 H, -SCH2-), 3.25–3.39 (m, 2 H,
-SCH2CHN ), 4.32 (dd, J=8.4 Hz, J= 10.5 Hz, 1H, -SCH2CHN ); 13C NMR
(75 MHz, CDCl3) d (ppm) 14.64 (-CH3), 25.16 (-C(CH3)2OH), 27.17
(-SCH2-), 27.29 (-SCH2-), 35.29 (-SCH2CHN ), 72.37 (-C(CH3)2OH), 86.35
(-SCH2CHN ). MS (ESI): m/z 206.0 [M + H+], 188.1 [M + H+ ꢁ 18]. Elemen-
tal analysis calculated for C8H15NOS2: C, 46.79; H, 7.36; N, 6.82. Found: C,
46.72, H, 7.38, N, 6.88.
General procedure for the addition of Et2Zn to aldehydes
To a solution of chiral ligand 5a (1 mmol) in toluene (1.5 ml) at 0ꢂC,
a 1.0 M solution of diethylzinc in hexane (1.5 ml, 1.5 mmol) was
added. After stirring the mixture for 30 min, aldehyde (1 mmol)
was added to the reaction solution at 0ꢂC. The reaction mixture
was stirred for 48 h at room temperature. The reaction was
quenched by the addition of a saturated solution of ammonium
chloride (10 ml) and the mixture was extracted with diethyl ether
(20 ml ꢃ 2). The combined organic extracts were washed with brine
(30 ml ꢃ 2), dried (Na2SO4) and concentrated under vacuum. The
residue was purified by chromatography on silica gel using ethyl
acetate–hexanes (1:5) as the eluent to give the product alcohol.
(R)-3-(2-(Ethylthio)-4,5-dihydrothiazol-4-yl) pentan-3-ol (5g) was
obtained as a light-yellow oil, with 60% yield after purification by col-
umn chromatography on silica gel (petroleum ether:EtOAc = 6:1),
20
½aꢀD = +7.8 (c 12.8, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 0.94
(dd, J=7.5 Hz, J=15.9 Hz, 6 H, -CH3), 1.36 (t, J=7.2 Hz, 3 H, -SCH2CH3),
1.40–1.47 (m, 1 H, -CH2-), 1.53–1.61 (m, 1 H, -CH2-), 1.74–1.83 (m, 2 H, -
CH2-), 3.06–3.14 (m, 2 H, -SCH2-), 3.26 (dd, J=8.1 Hz, J=10.5 Hz, 1 H, -
SCH2CHN ), 3.37 (t, J= 11.1 Hz, 1H, -SCH2CHN ), 4.38 (dd, J=8.4 Hz,
J=11.1 Hz, 1H, -SCH2CHN ); 13C NMR (75 MHz, CDCl3) d (ppm) 7.63
(-CH3), 7.84 (-CH3), 14.66 (-SCH2CH3), 26.88 (-CH2-), 27.23 (-CH2-),
29.49 (-CH2-), 34.88 (-SCH2CHN ), 75.91 (-C(C2H5)2OH), 83.27 (-
SCH2CHN ). MS (ESI): m/z 233.8 [M + H+], 215.8 [M + H+ ꢁ 18]. Elemen-
tal analysis calculated for C10H19NOS2: C, 51.46; H, 8.21; N, 6.00.
Found: C, 51.44, H, 8.23, N, 6.09.
20
1-Phenyl-1-propanol (7a) 81% yield, ½aꢀD = +30 (c 4.8, CHCl3),
68% ee by HPLC (Daicel Chiralcel OD column, hexane:2-propanol =
97:3, 1 ml minꢁ1, 254 nm UV detector), tR = 10.42 min for (R) and
1
tS = 12.13 min for (S). H NMR (300 MHz, CDCl3) d (ppm) 0.91 (t,
(R)-5-(2-(Ethylthio)-4,5-dihydrothiazol-4-yl) nonan-5-ol (5h) was
obtained as a yellow oil, with 60% yield after purification by column
J = 7.5 Hz, 3 H, -CH3), 1.72–1.82 (m, 2 H, -CH2), 1.89 (s, 1 H, -OH),
4.58 (t, J= 6.6 Hz, 1 H, -CHOH), 7.25–7.37 (m, 5 H, -Ph). 13C NMR
(75 MHz, CDCl3) d (ppm) 10.00 (-CH3), 31.76 (-CH2), 75.88 (-CHOH),
125.90 (-Ph), 127.36 (-Ph), 128.28 (-Ph), 144.57 (-Ph).
20
chromatography on silica gel (petroleum ether:EtOAc= 10:1),½aꢀD
=
+6.1 (c 14.8, CHCl3), 1H NMR (300 MHz, CDCl3) d (ppm) 0.89–0.95 (m,
6 H, -CH3), 1.26–1.49 (m, 15 H, -CH2- and -SCH2CH3), 1.76 (s, 1 H, -C
(C4H9)2OH)), 3.05–3.13 (m, 2 H, -SCH2-), 3.25 (dd, J = 8.1 Hz, J = 10.5
Hz, 1H, -SCH2CHN ), 3.37 (t, J = 11.4 Hz, 1 H, -SCH2CHN ), 4.34 (dd,
J =8.1 Hz, J= 11.4 Hz, 1H, -SCH2CHN ); 13C NMR (75 MHz, CDCl3) d
(ppm) 14.03 (-CH3), 14.07 (-CH3), 14.68 (-SCH2CH3), 23.32 (-CH2-),
23.38 (-CH2-), 25.47 (-CH2), 25.73 (-CH2-), 27.23 (-CH2-), 34.73
(-SCH2-), 34.95 (-SCH2-), 37.47 (-SCH2CHN ), 75.66 (-C(C4H9)2OH),
83.88 (-SCH2CHN ). MS (ESI): m/z 289.9 [M + H+], 271.9 [M + H+ ꢁ 18].
Elemental analysis calculated for C14H27NOS2: C, 58.08; H, 9.40; N,
4.84. Found: C, 58.09, H, 9.45, N, 4.82.
1-(2-Methoxyphenyl)-1-propanol (7b) 65% yield, ½aꢀ2D0 = +7.0 (c 5.4,
CHCl3), 42.5% ee by HPLC (Daicel Chiralcel OD column, hexane:etha-
nol = 97:3, 0.5 ml minꢁ1, 254 nm UV detector), tR = 23.43 min for (R)
1
and tS =22.08 min for (S). H NMR (300 MHz, CDCl3) d (ppm) 0.95
(t, J= 7.5 Hz, 3H, -CH3), 1.77–1.87 (m, 2H, -CH2), 2.51 (br, 1 H, -OH),
3.85 (s, 3H, -OCH3), 4.79 (t, J= 6.6 Hz, 1H, -CHOH), 6.87–6.98 (m, 2H,
-Ph), 7.21–7.24 (m, 1H, -Ph), 7.26–7.31 (m, 1H, -Ph). 13C NMR (75
MHz, CDCl3) d (ppm) 10.40 (-CH3), 30.11 (-CH2), 55.20 (-CHOH),
72.40 (-OCH3), 110.50 (-Ph), 120.66 (-Ph), 127.02 (-Ph), 128.14 (-Ph),
132.35 (-Ph), 156.61 (-Ph).
Appl. Organometal. Chem. 2012, 26, 121–129
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Z. Gong et al.
20
explain the observed diverse stereoselectivities. This work could be
extended to other catalytic asymmetric reactions and provide a
promising route for designing novel chiral thiazoline ligands.
1-(3-Methoxyphenyl)-1-propanol (7c) 90% yield, ½aꢀD = +13.0
(c 28.0, CHCl3), 39.3% ee by HPLC (Daicel Chiralcel OD column,
hexane:ethanol = 97:3, 1 ml minꢁ1, 254 nm UV detector), tR = 18.19
min for (R) and tS = 21.13 min for (S) 1H NMR (300 MHz, CDCl3)
d (ppm) 0.92 (t, J= 7.5 Hz, 3H, -CH3), 1.72–1.82 (m, 2H, -CH2), 3.81
(s, 3H, -OCH3), 4.57 (t, J= 6.6 Hz, 1H, -CHOH), 6.79–6.83 (m, 1H, -Ph),
6.90–6.93 (m, 2H, -Ph), 7.23–7.28 (m, 1H, -Ph) 13C NMR (75 MHz, CDCl3)
d (ppm) 10.05 (-CH3), 31.79 (-CH2), 55.16 (-OCH3), 75.87 (-CHOH), 111.45
(-Ph), 112.89 (-Ph), 118.29 (-Ph), 129.33 (-Ph), 146.34 (-Ph), 159.72 (-Ph).
Acknowledgment
This work was supported by grants from the National Nature Science
Foundation of China (Project 90813003).
20
1-(4′-Methoxyphenyl)-1-propanol (7d) 98% yield, ½aꢀD = +27.3
(c 28.8, CHCl3), 64% ee by HPLC (Daicel Chiralcel OD column,
hexane:2-propanol = 97:3, 1 ml minꢁ1, 254 nm UV detector), tR =
13.68 min for (R) and tS =16.43 min for (S) 1H NMR (300 MHz, CDCl3)
d (ppm) 0.89 (t, J= 7.5 Hz, 3H, -CH3), 1.74–1.82 (m, 2 H, -CH2), 3.80 (s, 3
H, -OCH3), 4.54 (t, J= 6.6 Hz, 1H, -CHOH), 6.86–6.89 (m, 2H, -Ph), 7.25–
7.28 (m, 2H, -Ph). 13C NMR (75 MHz, CDCl3) d (ppm) 10.12 (-CH3),
31.74 (-CH2), 55.24 (-OCH3), 75.61 (-CHOH), 113.78 (-Ph), 127.15
(-Ph), 136.79 (-Ph), 159.02 (-Ph).
References
[1] B. List, Asymmetric Organocatalysis, Springer, Heidelberg, 2010.
[2] S. Bertelsen, K. A. Jogensen, Chem. Soc. Rev. 2009, 38, 2178.
[3] D. W. C. MacMillan, Nature 2008, 455, 304.
[4] A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 2008, 48, 4638.
[5] M. J. Gaunt, C. C. C. Johansson, A. McNally, N. T. Vo, Drug Discov. Today
2007, 12, 8.
[6] R.-X. Lin, C. Chen, J. Mol. Catal. A: Chem. 2006, 243, 89.
[7] Y. Li, W. P. Li, R. Wang, J. Org. Chem. 2010, 75, 6869.
[8] G. Qi, Z. M. A. Judeh, Tetrahedron: Asymmetry 2010, 21, 429.
[9] A. R. Abreu, M. Lourenc, D. Peral, M. T. S. Rosadoa, M. E. S. Eusebio, O.
Palacios, J. C. Bayon, M. M. Pereira, J. Mol. Catal. A: Chem. 2010, 325,
91.
[10] L. F. Tietze, T. Kinzel, C. C. Brazel, Acc. Chem. Res. 2009, 42, 367.
[11] R. Von Roenn, J. Christoffers, Tetrahedron 2011, 67, 334.
[12] S. Banerjee, A. J. Camodeca, G. G. Griffin, C. G. Hamaker, S. R. Hitchcock,
Tetrahedron: Asymmetry 2010, 21, 549.
20
1-(2′-Chlorophenyl)-1-propanol (7e) 80% yield, ½aꢀD = +15.5 (c 2.6,
CHCl3), 38.7% ee by HPLC (Daicel Chiralcel AD column, hexane:ethanol =
97:3, 1 ml minꢁ1, 254 nm UV detector), tR =9.35 min for (R) and tS =
10.63 min for (S) 1H NMR (300 MHz, CDCl3) d (ppm) 0.99 (t, J=7.5 Hz,
3H, -CH3), 1.76–1.82 (m, 2H, -CH2), 5.05–5.05 (m, 1H, -CHOH), 7.16–7.22
(m, 1H, -Ph), 7.26–7.34 (m, 2H, -Ph), 7.53–7.56 (m, 1H, -Ph). 13C NMR
(75 MHz, CDCl3) d (ppm) 10.00 (-CH3), 30.45 (-CH2), 71.97 (-CHOH),
126.98 (-Ph), 127.12 (-Ph), 128.31 (-Ph), 129.34 (-Ph), 131.98 (-Ph),
141.96 (-Ph).
[13] T. Bauer, S. Smolinski, Appl. Catal. A: Gen. 2010, 5, 247.
[14] V. Coeffard, H. Muller-Bunz, P. J. Guiry, Org. Biomol. Chem. 2009, 7, 1723.
[15] J.-W. Ruan, G. Lu, L.-J. Xu, Y.-M. Li, A. S. C. Chan, Adv. Synth. Catal.
2008, 350, 76.
[16] L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757.
[17] K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833.
20
1-(3′-Chlorophenyl)-1-propanol (7f) 81% yield, ½aꢀD = +10.3 (c 2.7,
CHCl3), 37.7% ee by HPLC (Daicel Chiralcel OD column, hexane:2-
propanol = 97:3, 0.5 ml minꢁ1, 254 nm UV detector), tR = 20.83 min
for (R) and tS = 20.19 min for (S) 1H NMR (300 MHz, CDCl3) d (ppm)
0.92 (t, J= 7.5 Hz, 3H, -CH3), 1.71–1.78 (m, 2H, -CH2), 1.80 (s, 1H,
-OH), 4.59 (t, J= 6.6 Hz, 1H, -CHOH), 7.19–7.23 (m, 1H, -Ph), 7.24–
7.30 (m, 2H, -Ph), 7.34–7.35 (m, 1H, -Ph). 13C NMR (75 MHz, CDCl3) d
(ppm) 9.91, 31.90, 75.29, 124.07 (-Ph), 126.12 (-Ph), 127.53 (-Ph),
129.62 (-Ph), 134.29 (-Ph), 146.63 (-Ph).
[18] S.-H. Gou, Z.-B. Ye, G.-J. Gou, M.-M. Feng, J. Chang, Appl. Organomet.
Chem. 2011, 25, 110.
[19] M. N. Patil, R. G. Gonnade, N. N. Joshi, Tetrahedron 2010, 66, 5036.
[20] N. Shibata, M. Okamoto, Y. Yamamoto, S. Sakaguchi, J. Org. Chem.
2010, 75, 5707.
[21] R. W. Parrott, S. R. Hitchcock, Tetrahedron: Asymmetry 2008, 19, 19.
[22] J. Huang, J. C. Ianni, J. E. Antoline, R. P. Hsung, M. C. Kozlowski, Org.
Lett. 2006, 8, 1565.
[23] R. Dave, N. A. Sasaki, Tetrahedron: Asymmetry 2006, 17, 388.
[24] Z. Szakonyi, A. Balazs, T. A. Martinek, F. Fulop, Tetrahedron: Asymmetry
2006, 17, 199.
[25] Y. Kawanami, T. Mitsuie, M. Miki, T. Sakamoto, K. Nishitani, Tetrahedron
2000, 56, 175.
20
1-(4′-Chlorophenyl)-1-propanol (7g) 85% yield, ½aꢀD = +23 (c 2.9,
CHCl3), 61.7% ee by HPLC (Daicel Chiralcel OD column, hexane:2-
propanol = 97:3, 0.5 ml minꢁ1, 254 nm UV detector), tR = 20.21 min
for (R) and tS = 19.49 min for (S) 1H NMR (300 MHz, CDCl3) d (ppm)
0.90 (t, J= 7.5 Hz, 3H, -CH3), 1.72–1.80 (m, 2H, -CH2), 4.59 (t, J=6.6
Hz, 1H, -CHOH), 7.26–7.34 (m, 4H, -Ph). 13C NMR (75 MHz, CDCl3) d
(ppm) 9.88, 31.90, 75.23, 127.30 (-Ph), 128.47 (-Ph), 133.07 (-Ph),
143.07 (-Ph).
[26] Y.-J. Wu, H.-Y. Yun, Y.-S. Wu, K.-L. Dong, Y. Zhou, Tetrahedron: Asymmetry
2000, 11, 3543.
[27] R. Noyori, S. Suga, K. Kawai, S. Okad, Y. Kitamura, J. Organomet.
Chem. 1990, 382, 19.
[28] A.-C. Gaumont, M. Gulea, J. Levillain, J. Chem. Rev. 2009, 109, 1371.
[29] S. C. McKeon, H. Mueller-Bunz, P. J. Guiry, Eur. J. Org. Chem. 2009,
28, 4833.
[30] A. Osorio-Lozada, H. F. Olivo, Org. Lett. 2008, 10, 617.
[31] I. Abrunhosa, M. Gulea, J. Levillain, S. Masson, Tetrahedron: Asymmetry
2001, 12, 2851.
[32] G. Helmchen, A. Krotz, K.-T. Ganz, D. Hansen, Synlett 1991, 257.
[33] Y.-Z. Li, X.-S. Hu, H.-M. Huang, Chin. Inv. Patent Bull. 1996.
[34] J. Kim, K. A. De Castro, M. Lim, H. Rhee, Tetrahedron 2010,
66, 3995.
[35] K. A. De Castro, H. Rhee, Synthesis 2008, 1841.
[36] Y.-M. Shang, J. Li, Z.-G. Song, Y.-Z. Li, H.-M. Huang, Chem. Res. Chin.
Univ. 2007, 23, 430.
[37] C.-T. Chen, Y. S. Munot, J. Org. Chem. 2005, 70, 8625.
[38] Y.-J. Chen, R.-X. Lin, C. Chen, Tetrahedron: Asymmetry 2004, 15, 3561.
[39] S.-W. Kang, D.-H. Ko, K. H. Kim, D.-C. Ha, Org. Lett. 2003, 5, 4517.
[40] S. Vyskocil, S. Jaracz, M. Smrcina, M. Sticha, V. Hanus, M. Polasek, P.
Kocovsky, J. Org. Chem. 1998, 63, 7727.
Conclusion
In summary, a series of modular, thiazoline-containing N-O ligands
were easily synthesized from L-cysteine in three steps and with high
yield. These compounds could be used as chiral ligands to catalyze
the asymmetric addition of diethylzinc (Et2Zn) to various aromatic
aldehydes. The configuration of the products could be tunable by
simple modification of the structures of thiazoline ligands. Products
with S configuration were obtained when the thiazoline tertiary
alcohol ligands were used as catalyst. Conversely, thiazoline primary
alcohol induced corresponding products with R configuration in 68%
ee. This represented a significant improvement on this type reaction
mediated by other primary amino alcohol catalysts in the literature.
Furthermore, plausible transition state models were proposed to
[41] E. Blocka, M. Jaworska, A. Kozakiewicz, M. Welniak, A. Wojtczak,
Tetrahedron: Asymmetry 2010, 21, 571.
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 121–129

Chiral thiazoline
[42] M. A. Dean, S. R. Hitchcock, Tetrahedron: Asymmetry 2009, 20, 2351.
[43] F. Lutz, L. Takashi, T. Kawasaki, K. Soai, J. Am. Chem. Soc. 2005, 127,
12206.
[44] F. Lutz, I. Sato, K. Soai, Org. Lett. 2004, 6, 1613.
[45] K. Soai, S. Yokoyama, T. Hayasaka, J. Org. Chem. 1991, 56, 4264.
[46] M. Kitamura, S. Okada, S. Suga, R. Noyori, J. Am. Chem. Soc. 1989,
111, 4028.
[48] M. Kitamura, M. Yamakawa, H. Oka, S. Suga, R. Noyori, Chem. Eur. J.
1996, 2, 1173.
[49] X. Yang, J. Shen, C. Da, R. Wang, M. C. K. Choi, L. Yang, K.-Y. Wong,
Tetrahedron: Asymmetry 1999, 10, 133.
[50] E. J. Corey, F. J. Hannon, Tetrahedron Lett. 1987, 28, 5237.
[51] M. Falorni, C. Collu, S. Conti, G. Giacomelli, Tetrahedron: Asymmetry
1996, 7, 293.
[47] E. J. Corey, F. J. Hannon, Tetrahedron Lett. 1987, 28, 5233.
[52] S. Conti, M. Falorni, G. Giacomelli, F. Soccolini, Tetrahedron 1992, 48, 8993.
Appl. Organometal. Chem. 2012, 26, 121–129
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc