Facile synthesis of C2-symmetric tridentate bis(thiazoline) and bis(oxazoline) ligands and their application in the enantioselective Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2004.09.011

A series of novel C₂-symmetric bis(thiazoline) ligands with a diphenylamine backbone as a linkage between two thiazoline rings were synthesized by the use of the simple reagent phosphorus pentasulfide. Their application in the catalytic asymmet

Full text of DOI:10.1016/j.tetasy.2004.09.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3433–3441
Facile synthesis of C2-symmetric tridentate bis(thiazoline)
and bis(oxazoline) ligands and their application
in the enantioselective Henry reaction
Shao-Feng Lu, Da-Ming Du,* Shi-Wei Zhang and Jiaxi Xu*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, PR China
Received 29 July 2004; accepted 6 September 2004
Abstract—A series of novel C2-symmetric bis(thiazoline) ligands with a diphenylamine backbone as a linkage between two thiazoline
rings were synthesized by the use of the simple reagent phosphorus pentasulfide. Their application in the catalytic asymmetric Henry
reaction of a-keto esters was investigated with comparison to the corresponding bis(oxazoline) ligands. Cu(II)–bis(oxazoline) com-
plexes furnished moderate enantioselectivities (up to 60% ee), while Cu(II)–bis(thiazoline) complexes gave higher enantioselectivities
(up to 70% ee) with neat nitromethane. The enantioselectivity was improved when a halogenated solvent, such as CH2Cl2 was used
(up to 82% ee), but the yield obtained lower than that in neat reactions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
used in asymmetric hydrosilylation2 and cyclopropan-
ation reactions.3 DBF-Box 2, DBT-Box 3 and carbaz-
ole-Box proved successful in some asymmetric
reactions.4 While these ligands allow only a meridional
(mer) coordination mode, ligands 45a and 55b may allow
both mer and facial (fac) coordination modes. However,
tridentate bis(thiazoline) ligands for asymmetric cata-
lytic reactions have seldom been reported.6 With the
replacement of oxygen with sulfur in the oxazoline rings,
the different electronic and steric effects may change the
chelating behaviour of the heterocycle of bis(thiazoline)
In recent years, the C2-symmetric chiral bis(oxazoline)
ligands have proven to be powerful in various catalytic
processes, while ligand design is becoming an increas-
ingly important area of synthetic organic chemistry.1
Among them, tridentate bis(oxazolinyl)-type ligands,
supposed to form a deeper chiral concave pocket around
the metal centre, have been reported and applied in sev-
eral asymmetric catalytic reactions. For example, Pybox
ligand 1 (Scheme 1) was designed by Nishiyama and
O
O
N
O
S
N
N
O
O
O
O
N
N
N
N
N
R
R
Ph
Ph
1
2
3
H
Ph
P
O
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
4
5
Scheme 1.
*
Corresponding authors. Fax: +86 10 62751708; e-mail addresses: dudm@pku.edu.cn; jxxu@pku.edu.cn
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.011

3434
S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
amides 9 and their mesylates successively as intermedi-
ates (Scheme 3). Thus, 2,20-dicarboxyl diphenylamine 8
was treated with SOCl2 to give the acid dichloride,
which was stirred with (S)-tert-leucinol and triethyl-
amine in dichloromethane (DCM) at room temperature
for 4h to give amide 9e in 92% yield. Then 9e was vigor-
ously stirred with phosphorus pentasulfide10c in pyridine
for 0.5h and then refluxed for 22h to give compound 6e
in 57% yield. The bis(thiazolines) 6a–d were synthesized
in the same way in 41–61% overall yields from 2,20-
dicarboxyl diphenylamine and the corresponding pure
chiral b-amino alcohols.
N
H
N
H
a, R = CH(CH3)2
b, R = CH2CH(CH3)2
c, R = Ph
O
O
S
S
N
N
N
N
d, R = CH2Ph
e, R = C(CH3)3
R
R
R
R
7
6
Scheme 2.
towards metals compared with the corresponding
bis(oxazoline).
The Henry or nitroaldol reaction is a powerful method-
ology of carbon–carbon bond formation in organic syn-
thesis and the resulting b-nitro alkanol can go through a
range of chemical transformation.7 Since 1992, asym-
metric catalytic Henry reactions have gained particular
attention.8,9 For example, Shibasaki and co-workers
have reported that rare-earth-lithium–BINOL com-
plexes can be applied as catalysts for the enantioselective
reaction of aldehydes with nitroalkanes.8a–e Jørgensen
and co-workers reported the catalytic asymmetric Henry
reaction of a-keto esters with nitromethane in the pres-
ence of chiral catalysts.8i,j Trost et al. have recently dis-
closed a catalytic enantioselective Henry reaction
employing a bimetallic zinc complex.8l,m Evans et al.
recently successfully developed the asymmetric Henry
reaction of aldehydes using a bis(oxazoline) complex.8p
In continuation with our groupꢀs research on the design,
synthesis and application of bis(oxazoline) and bis(thi-
azoline) ligands,10 we herein report the synthesis of a
series of new bis(thiazoline) ligands 6 and the compara-
tive study of bis(thiazoline) 6 and bis(oxazoline) 711
(Scheme 2) on Cu(II)-catalyzed asymmetric Henry
reaction.
Although bis(oxazolines) 7 have been synthesized previ-
ously, long reaction times (at least one week) and expen-
sive catalysts (Pd precursor and additional ligand) were
needed while the highest overall yield obtained 40%.11
With bis(hydroxyamides) 9 in hand, we preferred to
employ them to prepare bis(oxazolines) 7. Compound
9e was then treated with methanesulfonyl chloride in
the presence of triethylamine in dichloromethane at
room temperature to afford the crude dimesylate inter-
mediate, which was refluxed in aqueous-alcoholic
sodium hydroxide solution for 3h to afford compound
7e in 71% yield. In the same way, bis(oxazolines) 7a–d
were prepared in 41–83% overall yields.
2.2. Asymmetric Henry reaction using ligands 6 and 7
Chiral bis(oxazolines) have been proven to be one of the
most efficient chiral ligands for an asymmetric Henry
reaction.8i,j,p Before investigating the catalytic efficiency
of the newly synthesized bis(thiazolines), the corre-
sponding bis(oxazolines) were first examined. The effect
of chiral ligands, Lewis acids and bases have been
screened for the Henry reaction of ethyl pyruvate 10a
with nitromethane using 20% catalyst loading (Scheme
4).
2. Results and discussion
Initially, Lewis acids were screened12 with some repre-
sentative results summarized in Table 1. The combina-
tion of different Lewis acids with ligand 7a was first
investigated. Among them, Cu(OTf)2 gave a high yield
and good enantioselectivity (Table 1, entry 5). No better
results were found with other Lewis acids (Table 1,
2.1. Preparation of ligands 6 and 7
Compounds 6 and 7 were readily prepared from 2,20-
dicarboxyl diphenylamine 8 and enantiomerically pure
b-amino alcohols via the corresponding b-hydroxyl-
N
H
S
S
N
N
R
iii
N
H
R
i, ii
6
O
OH
O
HO
N
H
NH
R
HN
R
HOOC
COOH
iv,v
8
N
H
9
O
O
N
N
R
R
7
Scheme 3. Reagents and conditions: (i) SOCl2, reflux 8h; (ii) amino alcohol, DCM, Et3N; (iii) P2S5, pyridine, reflux 22h; (iv) MsCl, DCM, Et3N;
(v) NaOH, CH3OH–H2O, reflux 3h.

S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
3435
the amount of Et3N to 40mol% relative to the catalyst
(20mol%) gave a higher conversion and an almost race-
mic product, while a decrease in the amount of Et3N to
10mol% resulted in a significant reduction in both con-
version and enantioselectivity (Table 1, entries 10 and
11). Other bases such as pyridine, N-methylmorpholine
20% mol chiral ligand
20% mol Lewis acid
OH
*
O
+
CH3NO2
CO2Et
NO2
11
R
R
CO2Et
base
10
a, R = CH3; b, R = CF3
Scheme 4.
and Hunigꢀs base were also tested in the reaction
¨
although no better results than Et3N were obtained.
Table 1. Results for the screening of the reaction conditions for the
Henry reaction of ethyl pyruvate 10a (1equiv) with nitromethane
(64equiv) in the presence of Et3Na
Since ligand 7a gave a relatively high yield without a dis-
tinct decrease in enantioselectivity and is less cheaper
than 7e, various solvents were first evaluated using lig-
and 7a for further improving the enantioselectivity.
Reduction of the ratio of MeNO2 to ethyl pyruvate from
64:1 (no solvents) to 10:1 (using 1.5mL solvents) gave
inconsistent results (Table 2). The results indicate that
alkyl halides are the best solvent for enantioselectivity.
Using CHCl3 (Table 2, entry 4), ClCH2CH2Cl (Table
2, entry 5), and CH2Cl2 (Table 2, entries 6–8) as solvents
in the reaction gave higher enantioselectivity than that
without solvents, while other solvents gave the same
(Table 2, entry 10) or even worse (Table 2, entries 1–3
and 9) results. Decreasing the temperature did not in-
crease the enantioselectivity significantly (Table 2, entry
Entry Ligand Lewis
acid
Base Yield Ee
(%)b
Config.d
(%)
(%)c
1
7a
7a
7a
7a
7a
7b
7c
7d
7e
7e
7e
La(OTf)3
Zn(OTf)2
Cu(OAc)2
20
20
20
51
73
75
72
90
56
54
61
74
95
11
15
+16
0
S
2
R
3
4
Cu(ClO4)2 20
46
50
49
39
56
60
3
S
S
S
S
S
S
S
S
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
20
20
20
20
20
40
10
6
7
8
9
10
11
29
˚
a Reaction was performed with 20mol% complex at room
temperature.
b Isolated yield by column chromatography.
c Determined by HPLC on Daicel Chiracel OB column (hexane/2-
propanol 90:10, 1.0mL/min, tmajor = 12.2min, tminor = 14.3min).
d The absolute configurations were established by comparison the sign
of optical rotation with that of literature value.8j
7) while the addition of 4A molecular sieves (50mg)
caused a lower enantioselectivity (Table 2, entry 8).
However, the reaction in all solvents did not proceed
completely, with the yield being lower than that in neat
reaction. The main side reaction is the self-aldol addi-
tion of ethyl pyruvate. The yield of the Henry reaction
normally achieved was highest in 16–20h while longer
reaction time afforded more side product. When 7e
was used instead of 7a, the enantioselectivity did not im-
prove and an even lower enantioselectivity was ob-
tained, this phenomenon is difficult to explain at present.
entries 1–4). In contrast, the Zn(OTf)2 complex gave the
major enantiomer opposite to that obtained by the
Cu(II) complex. Next, different ligands were screened
and of the five chiral bis(oxazoline)–copper(II) catalysts
tested for the reaction, ligand 7e gave the most promis-
ing result (Table 1, entry 9). It was found that the con-
version and enantioselectivity were dependent upon the
amount of base relative to the catalyst. An increase of
According to the same procedure in Table 1 in the pres-
ence of 20mol% Et3N, bis(thiazoline) ligands 6 were
examined. Both ethyl pyruvate and ethyl trifluoropyru-
vate were investigated. For convenience, the obtained
results of ligands 6 and 7 are summarized and compared
Table 2. Screening solvents for the Henry reaction of ethyl pyruvate 10a with nitromethanea
Entry
Ligand
Solvent
Temp
Additive
Yield (%)b
Ee (%)c
Config.d
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7e
7e
EtOH
THF
Rt
Rt
No
No
No
No
No
No
No
˚
4A
No
˚
4A
19
20
11
22
32
43
29
30
27
21
23
32
27
42
39
53
76
80
82
69
41
50
32
19
S
S
S
S
S
S
S
S
S
S
S
S
2
3
THF
CHCl3
ꢀ20ꢁC
Rt
Rt
4
5
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Cyclohexane
CH2Cl2
ClCH2Cl2Cl
6
Rt
7
ꢀ20ꢁC
Rt
Rt
8
9
10
11
12
Rt
Rt
No
No
Rt
a Reaction was performed with ethyl pyruvate 10a (1equiv) and nitromethane (10equiv) in solvents (1.5mL) in the presence of Et3N (0.2equiv) and
Cu(OTf)2 complex (0.2equiv).
b Isolated yield by column chromatography.
c Determined by HPLC on Daicel Chiracel OB column (hexane/2-propane 90:10, 1.0mL/min, tmajor = 12.2min, tminor = 14.3min).
d The direction of specific rotation of major isomer is (ꢀ) with the absolute configurations established by comparison of the sign of the specific
rotation with that of the literature value.8j

3436
S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
Table 3. Enantioselective addition of nitromethane to a-keto esters
catalyzed by ligands 6 and 7 in the presence of Et3N as the basea
Entry a-Keto Ligands Yield (%)b Ee (%)
Config.e
esters
(11a/11b)
(11ac/11bd)
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10b
10b
10b
10b
7a/6a
7b/6b
7c/6c
7d/6d
7e/6e
7a/6a
7b/6b
7c/6c
7e/6e
90/76
56/40
54/30
61/75
74/55
52/88
23/12
84/38
66/14
50/47
49/8
39/63
56/9
60/70
11/10
6/0
S/S
S/S
S/S
S/S
S/S
S/S
S
23/13
0/0
S/S
a Reaction was performed with ethyl pyruvate 10 (1equiv) and nitro-
methane (64equiv) in the presence of Et3N (0.2equiv) and
Cu(OTf)2 complex (0.2equiv).
b Isolated yield by column chromatography.
a
Figure 1. Perspective view of compound 6c, showing 30% probability
ellipsoids.
c Determined by HPLC on Daicel Chiracel OB column (hexane/2-
propane 90:10, 1.0mL/min, tmajor = 12.2min, tminor = 14.3min).
d Determined by HPLC on Daicel Chiracel OJ column (hexane/2-
propane 90:10, 0.5mL/min, tmajor = 19.8min, tminor = 21.8min).
e The direction of the specific rotation of major isomer is (ꢀ) and the
absolute configurations were established by the comparison of the
sign of the specific rotation with that of the literature value.8j
hydrogen bond with the N–H of the diphenylamine
part, and thus the hydrogen bond interaction would
affect the coordination configuration. For example, in
compound 6c, there exists two hydrogen bonds, N(1)–
˚
HN1ꢁ ꢁ ꢁN(2) bond length is 2.16(2)A, bond angle is
˚
133.9(17)ꢁ; N(1)–HN1ꢁ ꢁ ꢁN(3) bond length is 2.27(2)A
in Table 3. Normally, the yield of 11b was lower than
11a, while the enantioselectivity was inconsistent. The
reason is still not clear and is currently under investiga-
tion. When ligand 6e was used instead of 7e, the enantio-
selectivity was higher (up to 70% ee) without obvious
loss of yield. The similar enantioselectivities and the
same absolute configurations of the adducts of 6 and 7
in the catalytic Henry reaction imply the two series of
C2-symmetric ligands may have similar coordinate fea-
tures in the transition states, although oxazoline and thi-
azoline ligands showed different enantioface selectivity
in the Pd-catalyzed allylic alkylation.10c The results
in Table 3 also suggest the usefulness of thiazoline
ligands, which enabled minor modification of
enantioselectivity.
and bond angle is 125.1(17)ꢁ.
Moreover, in order to confirm that in both cases the
complexation occurred via the nitrogen atoms, it would
be interesting to prepare the corresponding Cu(II) com-
plexes. However, our attempts to get a single crystal of
these complexes failed.
2.4. UV spectra
UV spectra were carried out in order to obtain further
information about the complexation feature of bis(oxaz-
oline) and bis(thiazoline). It is possible to use spectral
methods to investigate the coordination of the ligands
with Cu(OTf)2. The UV spectra of bis(oxazoline) 7c,
the 7c–Cu catalyst, bis(thiazoline) 6c, and the 6c–Cu cat-
alyst (the catalyst in molar ratios of 1:1) were deter-
mined in CH2Cl2 (Figs. 2 and 3). The results showed
that the UV spectra of bis(oxazoline) 7c and bis(thiazo-
line) 6c have similar absorption peaks, bis(oxazoline) 7c
with peaks at 232, 293 and 357nm; bis(thiazoline) 6c
with peaks at 235.5, 300.5 and 371.5nm. The 7c–Cu cat-
alyst had new complex peaks at 319.5, 435nm, whereas
the 6c–Cu catalyst had a similar new peak at 466.5nm.
This implies that bis(oxazoline) and bis(thiazoline) have
similar coordination sites with copper and result in a
similar tendency of UV peak change.
2.3. Crystal structure of bis(thiazoline) 6c
In order to further understand the structural effect of
the new bis(thiazoline) ligands on their catalytic activity,
the stereostructure of ligand 6c was determined by
X-ray crystal diffraction analysis.13 Compound 6c was
obtained as air-stable, pale yellow crystals upon slow
evaporation of a solution of 6c in petroleum ether/ethyl
acetate (10:1). A perspective view of compound 6c is
shown in Figure 1. The dihedral angle between C1–
C2–C3–C4–C5–C6 benzene ring and C16–C17–C18–
C19–C20–C21 benzene ring is 53.0ꢁ. The two thiazoline
rings have a dihedral angle of 27.5ꢁ. The two conjugated
benzene and thiazoline rings have dihedral angles of
43.4ꢁ and 43.1ꢁ, respectively. From the crystal structure
of 6c, we can see that the diphenylamine-linked bis(thi-
azoline) has good tridentate coordination conformation.
This conformation of two thiazolines may facilitate the
nitrogen atom to coordinate with copper, in contrast,
sulfur atom rather than nitrogen atom coordinate with
palladium as in our previous report.10c The two nitrogen
atoms of bis(oxazoline) or bis(thiazoline) may form a
The above structural and spectral data further support
that the same coordination mode of two types of ligands
has formed. If the coordination mode is different be-
tween bis(thiazoline) and bis(oxazoline) ligands, then
the absolute configurations of the Henry adducts should
be opposite on the basis of molecular modelling. As the
direction of substituents on thiazoline or oxazoline rings
in Cu complexes would determine the absolute configu-
ration of the products, the difference in coordination
modes should result in a switch of enantioface selection.

S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
3437
ands. This conclusion matches the UV spectra in Cu
complexes as both of them have the same tendency.
The UV spectra support the idea that both thiazoline
ligands and oxazoline ligands should have the same
coordination modes in case of current Cu complexes.
3. Conclusion
In conclusion, we have synthesized a series of new C2-
symmetric bis(thiazoline) ligands with a diphenylamine
backbone and improved the synthetic method for the
corresponding bis(oxazoline) ligands. By the use of
bis(hydroxyamides) as synthetic intermediates, these lig-
ands are prepared in good overall yields. The synthetic
procedures of tridentate ligands are quite efficient and
useful. Comparing results with the two types of C2-sym-
metric ligands in the catalytic asymmetric Henry reac-
tion, the bis(oxazoline)–copper(II) complex furnished
moderate enantioselectivities (up to 60% ee), while
bis(thiazoline) gave slightly better enantioselectivities
(up to 70% ee) without an obvious loss in yield. The
enantioselectivity was improved when halogenated sol-
vents, such as CH2Cl2, ClCH2CH2Cl, were used (up to
82% ee), although the yield is lower than that obtained
in neat reaction. The results herein showed that the cor-
responding bis(oxazoline) and bis(thiazoline) ligands
gave similar enantioselectivities for the asymmetric
nitroaldol reaction. Systematic studies comparing the
selectivity and reactivity of various tridentate chiral
bis(thiazoline) and bis(oxazoline) ligands gave impor-
tant information in the field of asymmetric catalysis.
Further studies are currently in progress in our labora-
tory in order to expand the application of these triden-
tate chiral ligands to other asymmetric reactions.
Figure 2. UV spectra of bis(oxazoline) 7c and 7c–Cu(OTf)2 complex in
CH2Cl2 (2.0 · 10ꢀ5 mol/L): (a) bis(oxazoline) 7c, (b) 7c–Cu(OTf)2 1:1
complex.
4. Experimental
4.1. General remarks
Melting points were measured on an XT-4 melting point
apparatus and are uncorrected. H NMR spectra were
Figure 3. UV spectra of bis(thiazoline) 6c and 6c–Cu(OTf)2 complex in
CH2Cl2 (2.0 · 10ꢀ5 mol/L): (a) bis(thiazoline) 6c, (b) 6c–Cu(OTf)2 1:1
complex.
1
recorded on a Mercury 200, Mercury 300 and Brucker
400MHz spectrometer with tetramethylsilane serving
as the internal standard. Elemental analyses were carried
out on an Elementar Vario EL instrument. Infrared
spectra were obtained on a Bruker Vector 22 spectro-
meter. Mass spectra were obtained on APEX II FT-
ICRMS (FAB), VG-ZAB-HS (EI) and Thermo Firrni-
gan LCQ Deca XP Plus (ESI) mass spectrometers. UV
spectra were measured on TU-1901 spectrophotometer.
Optical rotations were measured on a Perkin–Elmer 341
LC spectrometer. The enantiomeric excesses of 2-hyd-
roxy-2-methyl-3-nitropropanoic acid ethyl ester 11a
were determined by HPLC analysis using a chiral col-
umn (Daicel Chiralcel OB; eluent, hexane/isopropyl
alcohol 90:10; flow rate, 1.0mL/min; UV detector,
215nm). The enantiomeric excesses of 2-hydroxy-2-tri-
fluoromethyl-3-nitropropanoic acid ethyl ester 11b were
determined by HPLC analysis using Chiralcel OJ col-
umn. Solvents used were purified and dried by standard
procedures.
The results in Table 3 clearly suggest that both thiazo-
line and oxazoline ligands have a similar asymmetric
environment. Bis(thiazoline) ligands gave up to 70% ee
[(S)-adduct], while bis(oxazoline) ligands gave up to
60% ee in the same absolute configurations [(R)-adduct].
A difference between 60% ee and 70% ee is quite small
and the results imply that a similar chiral space was con-
structed. Interestingly, our group recently reported10c
the reversal in absolute configurations in Pd-catalyzed
asymmetric allylic alkylation reactions when comparing
bis(thiazoline) and bis(oxazoline) ligands. As a result,
we think that the coordination mode of thiazoline lig-
ands depends on the metal used. In the case of Pd, our
previously reported thiazoline ligands would coordinate
through sulfur, but with Cu, the thiazoline ligands syn-
thesized in this paper would coordinate through the
nitrogen atom in a similar manner as the oxazoline lig-

3438
S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
4.2. General procedure for the synthesis of bis(hydroxy-
amides) 9a–e
128.6, 127.5, 126.6, 123.7, 121.4, 119.4, 65.5, 55.6. IR
(KBr): m 3310, 3061, 2934, 2768, 1666, 1417, 1319,
1068, 776, 516cmꢀ1
.
HRMS(FAB): calcd for
A
solution of 2,20-dicarboxyl diphenylamine
8
C30H30N3O4 [M+H]+: 496.2231, found: 496.2224.
(7.0mmol) and thionyl chloride (10mL) was refluxed
for 4h. The excess SOCl2 was removed under reduced
pressure to afford the diacyl dichloride. The above diacyl
dichloride in CH2Cl2 (70mL) was added dropwise to a
solution of amino alcohol (14.0mmol) and Et3N
(4.9mL, 35.0mmol) in CH2Cl2 (20mL) at 0ꢁC and stir-
red at room temperature for 24h. The reaction mixture
was successively washed with saturated NH4Cl (aq),
HCl (1M), saturated NaHCO3 (aq) and brine. The
organic layer was dried over anhydrous Na2SO4,
concentrated and purified by silica gel column chroma-
tography using ethyl acetate as the eluting solvent to
afford the bis(hydroxyamide).
4.6. 2,20-Bis[N-(1S)-(1-benzyl-2-hydroxyethyl)carbamo-
yl]diphenylamine 9d
Yield: 74%, pale yellow solid. Mp: 70–72ꢁC.
20
D
1
½aꢂ ¼ ꢀ81:1 (c 0.40 in CHCl3). H NMR (CDCl3): d
9.27 (s, 1H), 7.39 (d, J = 7.6Hz, 2H), 7.24–7.10 (m,
14H), 6.97 (d, J = 6.7Hz, 2H), 6.81 (t, J = 7.4Hz, 2H),
4.30–4.26 (m, 2H), 3.70 (s, br, 2H), 3.60 (dd, J = 11.2,
2.5Hz, 2H), 3.51 (dd, J = 11.3, 4.5Hz, 2H), 2.84 (d,
J = 7.3Hz, 4H). 13C NMR (CDCl3): d 168.6, 141.7,
137.8, 131.7, 129.2, 128.8, 128.4, 126.4, 123.8,
121.0, 118.7, 63.1, 52.8, 36.9. IR (KBr): m 3323, 3060,
2934, 2768, 1667, 1417, 1323, 1039, 778, 516cmꢀ1
.
4.3. 2,20-Bis[N-(1S)-(1-isopropyl-2-hydroxyethyl)carbamo-
yl]diphenylamine 9a
ESIMS: calcd for C32H34N3O4 [M+H]+: 524.2, found:
524.2.
Yield: 88%, pale yellow solid. Mp: 134–136ꢁC.
4.7. 2,20-Bis[N-(1S)-(1-tert-butyl-2-hydroxyethyl)carbamo-
yl]diphenylamine 9e
20
1
½aꢂ ¼ ꢀ104:2 (c 0.81 in CHCl3). H NMR (CDCl3):
D
d 9.40 (s, 1H), 7.65 (dd, J = 7.8, 1.3Hz, 2H), 7.29–7.34
(m, 2H), 7.20 (d, J = 8.1Hz, 2H), 6.98 (t,
J = 7.3Hz, 2H), 6.86 (d, J = 8.8Hz, 2H), 3.88–3.92 (m,
2H), 3.68 (t, J = 4.4Hz, 4H), 3.06 (s, 2H), 1.88–
1.94 (m, 2H), 0.96 (d, J = 6.8Hz, 6H), 0.94 (d,
J = 6.8Hz, 6H). 13C NMR (CDCl3): d 168.9, 142.0,
131.9, 129.0, 124.1, 121.4, 119.2, 63.0, 57.0, 29.1, 19.5,
19.0. IR (KBr): m 3328, 3060, 2933, 2872, 2768, 1668,
1500, 1418, 1320, 1045, 778, 516cmꢀ1. HRMS (FAB)
calcd for C24H34N3O4 [M+H]+: 428.2544, found:
428.2552.
Yield: 92%, pale yellow solid. Mp: 94–96ꢁC.
20
D
1
½aꢂ ¼ ꢀ64:9 (c 0.64 in CHCl3). H NMR (CDCl3): d
9.35 (s, 1H), 7.66 (dd, J = 7.8, 1.2Hz, 2H), 7.35–7.30
(m, 2H), 7.18 (d, J = 8.2Hz, 2H), 7.02–6.98 (m, 2H),
6.85 (d, J = 9.4Hz, 2H), 4.03–3.98 (m, 2H), 3.82 (d,
J = 11.4Hz, 2H), 3.59 (dd, J = 11.5, 7.1Hz, 2H), 2.91
(s, br, 2H), 0.95 (s, 18H). 13C NMR (CDCl3): d 169.1,
142.0, 131.9, 129.0, 124.4, 121.4, 119.3, 62.1, 59.1,
34.0, 26.9. IR (KBr): m 3409, 3060, 2935, 2768, 1618,
1417, 1319, 1051, 779, 515cmꢀ1. HRMS [M+H]+ calcd
for C26H38N3O4: 456.2857, found: 456.2862.
4.4. 2,20-Bis[N-(1S)-(1-isobutyl-2-hydroxyethyl)carbamo-
yl]diphenylamine 9b
4.8. General procedure for the synthesis of bis(thiazoline)
ligands 6a–e
Yield: 87%, pale yellow solid. Mp: 79–81ꢁC.
20
1
½aꢂ ¼ ꢀ100:3 (c 0.64 in CHCl3). H NMR (CDCl3): d
To a solution of bis(hydroxyamide) 9 (2.75mmol) in dry
pyridine (25mL) was added P2S5 (11.0mmol) and the
mixture was refluxed for 22h. Then the reaction mixture
was cooled and 20% KOH solution (20mL) was added.
The aqueous phase was extracted with CH2Cl2
(10mL · 3). The organic phase was combined, washed
by 2N HCl, dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to give the crude product.
The crude product was purified by silica column chro-
matography using petroleum ether/ethyl acetate (20:1)
as the eluent.
D
9.38 (s, 1H), 7.62 (dd, J = 7.8, 1.4Hz, 2H), 7.29–7.33
(m, 2H), 7.19 (d, J = 8.1Hz, 2H), 6.94–6.98 (m, 2H),
6.75 (d, J = 8.4Hz, 2H), 4.18–4.23 (m, 2H), 6.68–3.71
(m, 2H), 3.50–3.56 (m, 2H), 3.17 (s, 2H), 1.58–1.64 (m,
2H), 1.33–1.49 (m, 4H), 0.92 (d, J = 3.5Hz, 6H), 0.91
(d, J = 3.5Hz, 6H). 13C NMR (CDCl3): d 168.7, 141.9,
131.9, 128.9, 123.9, 121.3, 119.1, 65.1, 49.9, 40.2, 24.9,
23.0, 22.2. IR (KBr): m 3307, 3063, 2954, 2869, 2768,
1651, 1501, 1321, 1163, 1046, 777, 515cmꢀ1. MS(EI):
m/z 455 (M+, 25), 437 (15), 321 (8), 221 (18), 196
(100). HRMS (FAB) calcd for C26H38N3O4 [M+H]+:
456.2857, found: 456.2864.
4.9. Bis[2-((4S)-4-isopropyl-4,5-dihydrothiazol-2-yl)phen-
yl]amine 6a
4.5. 2,20-Bis[N-(1S)-(1-phenyl-2-hydroxyethyl)carbamo-
yl]diphenylamine 9c
Yield: 54%, pale yellow solid. Mp: 64–66ꢁC.
20
D
1
½aꢂ ¼ þ22:9 (c 0.45 in CHCl3). H NMR (CDCl3): d
Yield: 88%, pale yellow solid. Mp: 96–98ꢁC.
10.83 (s, 1H), 7.64 (d, J = 7.9Hz, 2H), 7.30–7.23 (m,
4H), 6.95–6.90 (m, 2H), 4.45–4.39 (m, 2H), 3.27 (dd,
J = 10.8, 8.7Hz, 2H), 3.00 (dd, J = 10.6, 9.6Hz, 2H),
2.07–1.99 (m, 2H), 1.03 (d, J = 6.8Hz, 6H), 0.96
(d, J = 6.8Hz, 6H). 13C NMR (CDCl3): d 165.5, 142.4,
131.6, 130.9, 122.4, 120.3, 119.3, 84.1, 34.5, 33.2, 19.8,
19.0. IR (KBr): m 3430, 3062, 2956, 2768, 1669, 1448,
20
D
1
½aꢂ ¼ þ2:6 (c 0.55 in CHCl3). H NMR (CDCl3): d
9.46 (s, 1H), 7.64 (dd, J = 7.8, 1.2Hz, 2H), 7.50 (d,
J = 7.3Hz, 2H), 7.22–7.32 (m, 12H), 7.11 (d,
J = 8.2Hz, 2H), 6.95 (t, J = 7.5Hz, 2H), 5.12–5.16
(m, 2H), 3.73 (d, J = 4.9Hz, 4H), 3.84 (s, br, 2H). 13C
NMR (CDCl3): d 168.5, 142.2, 139.2, 132.1, 129.2,

S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
3439
1319, 1161, 981, 776, 515cmꢀ1. MS (70eV, EI): m/z (%)
423 (M+, 88), 380 (30), 278 (100), 219 (30). Anal. Calcd
for C24H29N3S2: C, 68.04; H, 6.90; N, 9.92. Found: C,
67.85; H, 6.71; N, 9.85.
10.73 (s, 1H), 7.68 (dd, J = 7.9, 1.2Hz, 2H), 7.29–7.22
(m, 4H), 6.96–6.91 (m, 2H), 4.32 (dd, J = 10.6, 8.8Hz,
2H), 3.18 (dd, J = 10.9, 8.8Hz, 2H), 3.05 (t,
J = 10.7Hz, 2H), 1.00 (s, 18H). 13C NMR (CDCl3): d
165.6, 142.6, 131.7, 131.0, 122.6, 120.5, 119.5, 87.4,
35.2, 33.0, 26.9. IR (KBr): m 3425, 3250, 3059, 2951,
2862, 2768,1637, 1517, 1449, 1321, 1210, 998, 776,
516cmꢀ1. MS (70eV, EI): m/z (%) 451 (M+, 48), 394
(75), 278 (100), 219 (8). Anal. Calcd for C26H33N3S2:
C, 69.14; H, 7.36; N, 9.30. Found: C, 69.09, H, 7.13;
N, 9.32.
4.10. Bis[2-((4S)-4-isobutyl-4,5-dihydrothiazol-2-yl)phen-
yl]amine 6b
20
D
Yield: 47%, yellow solid. Mp: 134–136ꢁC. ½aꢂ ¼ þ44:7
1
(c 0.82 in CHCl3). H NMR (CDCl3): d 10.83 (s, 1H),
7.63 (dd, J = 7.8, 1.3Hz, 2H), 7.29–7.19 (m, 4H), 6.93–
6.88 (m, 2H), 4.71–4.63 (m, 2H), 3.34 (dd, J = 10.7,
8.2Hz, 2H), 2.90 (dd, J = 10.6, 8.0Hz, 2H), 1.83–1.73
(m, 4H), 1.47–1.40 (m, 2H), 0.96 (d, J = 6.2Hz, 6H),
0.93 (d, J = 6.2Hz, 6H). 13C NMR (CDCl3): d 165.2,
142.2, 131.5, 130.8, 122.3, 120.2, 119.2, 76.0, 44.1,
37.5, 25.7, 23.0, 22.5. IR (KBr): m 3450, 3250, 3070,
2953, 2866, 2768, 1637, 1512, 1448, 1418, 1319, 1209,
776, 516cmꢀ1. MS (70eV, EI): m/z (%) 451 (M+, 40),
394 (8), 278 (18), 219 (25), 149 (12), 97 (34), 57 (100).
Anal. Calcd for C26H33N3S2: C, 69.14; H, 7.36; N,
9.30. Found: C, 68.91; H, 7.36; N, 9.14.
4.14. General procedure for the synthesis of bis(oxazoline)
ligands 7a–e
To an ice-cold solution of bis(hydroxyamide)
9
(3.71mmol) and Et3N (2.3mL) in CH2Cl2 (30mL) was
added methanesulfonyl chloride (8.2mmol) via syringe.
The reaction mixture was allowed to warm to room tem-
perature and stirred for 20h. Saturated NH4Cl solution
was then poured into the reaction mixture. The organic
layer was separated and the aqueous layer extracted
with CH2Cl2 (3 · 15mL). The combined extracts were
washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo to afford the crude bismesylate.
The crude bismesylate was dissolved in methanol
(7.5mL) and a solution of 0.3g NaOH in water
(7.5mL) added to it. The reaction mixture was refluxed
for 3h and cooled to room temperature. The methanol
was removed under reduced pressure and the residue ex-
tracted with CH2Cl2 (3 · 25mL). The combined organic
layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo to give the crude
product, which was purified by column chromatography
on silica gel using petroleum ether/ethyl acetate 10:1 as
the eluent.
4.11. Bis[2-((4S)-4-phenyl-4,5-dihydrothiazol-2-yl)phen-
yl]amine 6c
Yield: 47%, pale yellow crystal. Mp: 169–171ꢁC.
20
1
½aꢂ ¼ þ448:7 (c 0.78 in CHCl3). H NMR (CDCl3): d
D
11.35 (s, 1H), 7.67 (dd, J = 7.8, 1.4Hz, 2H), 7.49 (d,
J = 8.3Hz, 2H), 7.33–7.17 (m, 12H), 6.97–6.92 (m,
2H), 5.25 (t, J = 8.9Hz, 2H), 3.50 (dd, J = 10.8, 8.8Hz,
2H), 3.04 (dd, J = 10.8, 9.1Hz, 2H). 13C NMR (CDCl3):
d 167.6, 142.14, 142.09, 131.7, 131.0, 128.3, 127.2, 126.5,
121.8, 120.1, 118.7, 80.4, 40.3. IR (KBr): m 3250, 3060,
2934, 2768, 1636, 1506, 1449, 1418, 1320, 778,
515cmꢀ1. MS (70eV, EI): m/z (%) 491 (M+, 70), 354
(50), 219 (100), 135 (18), 91 (22). Anal. Calcd for
C30H25N3S2: C, 73.29; H, 5.12; N, 8.55. Found: C,
73.05; H, 5.14; N, 8.41.
4.15. Bis[2-((4S)-4-isopropyl-4,5-dihydrooxazol-2-yl)phen-
yl]amine 7a11
1
4.12. Bis[2-((4S)-4-benzyl-4,5-dihydrothiazol-2-yl)phen-
yl]amine 6d
Yield: 94%, pale yellow crystals. Mp: 114–116ꢁC. H
NMR (200MHz, CDCl3): d 10.72 (s, 1H), 7.81 (dd,
J = 7.8, 1.4Hz, 2H), 7.40 (d, J = 7.6Hz, 2H), 7.22–7.32
(m, 2H), 6.84–6.93 (m, 2H), 4.36–4.28 (m, 2H), 3.97–
4.15 (m, 4H), 1.71–1.84 (m, 2H), 1.01 (d, J = 6.6Hz,
6H), 0.91 (d, J = 6.8Hz, 6H).
Yield: 82%, pale yellow crystal. Mp: 129–131ꢁC.
20
D
1
½aꢂ ¼ þ97:6 (c 0.96 in CHCl3). H NMR (CDCl3): d
11.11 (s, 1H), 7.66 (dd, J = 7.8, 1.4Hz, 2H), 7.40 (d,
J = 8.2Hz, 2H), 7.32–7.27 (m, 2H), 7.22–7.18 (m,
10H), 6.98–6.93 (m, 2H), 4.93–4.88 (m, 2H), 3.28–3.20
(m, 4H), 3.03 (dd, J = 11.0, 6.7Hz, 2H), 2.84 (dd,
J = 13.6, 8.7Hz, 2H). 13C NMR (CDCl3): d 166.1,
142.2, 138.4, 131.7, 130.9, 129.3, 128.3, 126.3, 121.9,
120.1, 119.0, 79.0, 40.4, 36.3. IR (KBr): m 3254, 3056,
2931, 2856, 2768, 1651, 1505, 1447, 1317, 1214, 1031,
943, 775, 519cmꢀ1. MS (70eV, EI): m/z (%) 519 (M+,
70), 428 (65), 278 (100), 219 (10), 117 (12), 91 (25). Anal.
Calcd for C32H29N3S2: C, 73.95; H, 5.62; N, 8.09.
Found: C, 73.65; H, 5.85; N, 7.98.
4.16. Bis[2-((4S)-4-isobutyl-4,5-dihydrooxazol-2-yl)phen-
yl]amine 7b
20
D
Yield: 81%, yellow oil. ½aꢂ ¼ þ47:2 (c 1.17 in
1
CHCl3). H NMR (CDCl3): d 10.67 (s, 1H), 7.80 (d,
J = 7.9Hz, 2H), 7.40 (d, J = 8.3Hz, 2H), 7.27–7.23
(m, 2H), 6.87 (t, J = 7.2Hz, 2H), 4.42–4.30 (m, 4H),
3.88 (t, J = 7.2Hz, 2H), 1.83–1.69 (m, 4H), 1.40–1.33
(m, 2H), 0.96 (d, J = 6.5Hz, 6H), 0.94 (d,
J = 6.4Hz, 6H). 13C NMR (CDCl3): d 162.5, 143.0,
131.1, 130.3, 119.7, 118.3, 116.1, 71.9, 65.3, 45.4,
25.4, 22.9, 22.6. IR (KBr): m 3225, 3090, 3030,
2955, 2863, 1636, 1577, 1520, 1457, 1361, 1316,
1269, 1223, 1045, 974, 746, 687cmꢀ1. HRMS (70eV,
EI): m/z calcd for C26H33N3O2: 419.2573, found:
419.2580.
4.13. Bis[2-((4S)-4-tert-butyl-4,5-dihydrothiazol-2-yl)phen-
yl]amine 6e
Yield: 57%, pale yellow solid. Mp: 139–141ꢁC.
20
D
1
½aꢂ ¼ ꢀ43:4 (c 0.35 in CHCl3). H NMR (CDCl3): d

3440
S.-F. Lu et al. / Tetrahedron: Asymmetry 15 (2004) 3433–3441
4.17. Bis[2-((4S)-4-phenyl-4,5-dihydrooxazol-2-yl)phen-
yl]amine 7c11
was applied. The structure was solved by direct methods
and successive difference maps (SHELXS 98)14 and refined
by full-matrix least squares on F2 using all unique data
(SHELXL 98).15 The non-hydrogen atoms were refined
with anisotropic thermal parameters. All hydrogen
atoms were located theoretically and refined with riding
mode position parameters and fixed isotropic thermal
parameters. All computations were performed on a
FOUNDER FP+ 5-166 586 personal computer.
Yield: 68%, yellow solid. Mp: 55–56ꢁC. 1H NMR
(200MHz, CDCl3): d 11.07 (s, 1H), 7.88 (dd, J = 8.0,
1.4Hz, 2H), 7.53 (d, J = 8.2Hz, 2H), 7.12–7.37 (m,
12H), 6.87–6.96 (m, 2H), 5.17 (dd, J = 10.2, 8.2Hz,
2H), 4.46 (dd, J = 10.2, 8.2Hz, 2H), 3.98 (t, J = 8.2Hz,
2H).
4.18. Bis[2-((4S)-4-benzyl-4,5-dihydrooxazol-2-yl)phen-
yl]amine 7d11
Compound 6c C30H35N3S2, FW = 491.65, orthorhombic,
space group P2(1)2(1)2(1), a = 10.132(2), b = 11.519(2),
˚
c = 21.317(4)A; a = 90ꢁ, b = 90ꢁ, c = 90ꢁ, V =
Yield: 72%, yellow solid. Mp: 35–38ꢁC. 1H NMR
(200MHz, CDCl3): d 10.91 (s, 1H), 7.81 (dd, J = 7.8,
1.8Hz, 2H), 7.47 (d, J = 8.2Hz, 2H), 7.16–7.34 (m,
12H), 6.90 (ddd, J = 7.8, 7.2, 1.2Hz, 2H), 4.43–4.52
(m, 2H), 4.2 (dd, J = 9.4, 8.6Hz, 2H), 3.98 (dd,
J = 8.4, 7.4Hz, 2H), 3.17 (dd, J = 13.6, 5.4Hz, 2H),
2.72 (dd, J = 13.8, 8.6Hz, 2H).
2488.0(9)A , Z = 4, F(000) = 1032, Dc = 1.313Mg/m ,
l = 0.238mmꢀ1; index ranges ꢀ13 6 h 6 13, ꢀ14 6 k 6
14, ꢀ27 6 l 6 27; reflections collected/unique, 20,551/
3210 (Rint = 0.0476); data/restraints/parameters, 3210/0/
322; goodness-of-fit on F2 0.822; final R indices
[I > 2r(I)]: R1 = 0.0320, wR2 = 0.0619; R indices (all
data), R1 = 0.0523, wR2 = 0.0656; extinction coefficient
0.0148(7); absolute structure parameter 0.0(2); max.
and min. transmission 0.953 and 0.466; max. and mean
3
3
˚
4.19. Bis[2-((4S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)phen-
yl]amine 7e11
shift/sigma 0.001 andꢀ03.000; largest diff. peak and hole,
˚
0.177 and ꢀ0.187eA
.
Yield: 71%, white solid. Mp: 115–117ꢁC. 1H NMR
(300MHz, CDCl3):
d 10.81 (s, 1H), 7.83 (dd,
J = 7.8Hz, 2H), 7.40 (d, J = 8.1Hz, 2H), 7.27 (app t,
J = 7.2Hz, 2H), 6.89 (app t, J = 7.8Hz, 2H), 4.24 (dd,
J = 9.4, 7.8Hz, 2H), 4.02–4.13 (m, 4H), 0.91 (s, 18H).
13C NMR (CDCl3): 162.4, 143.4, 131.1, 130.4, 119.7,
118.6, 116.2, 76.4, 67.5, 33.9, 25.9.
Acknowledgements
We are grateful to the National Natural Science Foun-
dation of China (Grant nos. 20372001 and 20172001)
and Analytical Fund of Peking University for financial
support. We thank Professor Jianbo Wang for valuable
discussions.
4.20. General procedure for the catalytic asymmetric
Henry reaction
To a round bottom flask, Cu(OTf)2 (0.050mmol) and
the chiral ligand (0.050mmol) were added. The mixture
was stirred under vacuum for 2h and filled with N2. Dry
freshly distilled MeNO2 (1mL) was added and the solu-
tion stirred for 1h. Then a-keto ester (0.25mmol) was
added followed by the addition of Et3N (0.05mmol).
The mixture was stirred for 16h under N2 at room tem-
perature. The solvent was removed in vacuo and the res-
idue purified by silica chromatograph (25% AcOEt in
petroleum ether) to afford the pure product. Compound
11a was determined by HPLC on chiral column OB
(hexane/2-propanol 90:10, 1.0mL/min). Compound
11b was determined by HPLC on chiral column OJ (hex-
ane/2-propanol 90:10, 0.5mL/min).
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13. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC-239470. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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