The first 4,4′-imidazolium-tagged C2-symmetric bis(oxazolines): Application in the asymmetric Henry reaction

Article abstract of DOI:10.1039/c4ra14028a

Highly efficient and recyclable imidazolium-tagged bis(oxazolines), with an imidazolium tagged onto the 4,4′-position of the box, have been designed and prepared for the first time. They have been synthesized from dimethylmalonic acid and used as chiral l

Full text of DOI:10.1039/c4ra14028a

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The first 4,40-imidazolium-tagged C2-symmetric
bis(oxazolines): application in the asymmetric
Henry reaction†
Cite this: RSC Adv., 2015, 5, 4758
a
a
ab
Ying-Qiang Liu,a Li Daia
*
*
Li-Wei Tang, Xiao Dong, Zhi-Ming Zhou,
and Man Zhanga
Highly efficient and recyclable imidazolium-tagged bis(oxazolines), with an imidazolium tagged onto the
4,40-position of the box, have been designed and prepared for the first time. They have been synthesized
from dimethylmalonic acid and used as chiral ligands in the copper(II)-catalyzed classic asymmetric
Henry reaction between aldehydes and nitromethane. A systematic analysis of the anions showed that
the best ligand was one of a medium size; the catalyst achieved a high activity and enantioselectivity as
well as good recyclability, i.e., product (R)-11k was attained at 94% ee in MeOH. Moreover, the catalyst
was successfully recycled six times, without an obvious loss in activity or enantioselectivity. Finally, a
theoretical mechanistic study was conducted to explain the origin of the enantioselectivity and how the
size of anions affects the reaction.
Received 7th November 2014
Accepted 11th December 2014
DOI: 10.1039/c4ra14028a
www.rsc.org/advances
including unequal distribution, limited mobility, and accessi-
bility of the active sites.5
Introduction
Ionic liquids, especially task-specic ionic liquids (TSILs),
have recently received much more attention as recyclable
catalysts. Besides some common tunable properties6 of ionic
liquids, TSILs catalysts have several other remarkably
attractive advantages: (1) the high polarity and insoluble in
non-polar solvent, which make them easily separate from the
reagents and reaction products aer the reaction and recy-
cled for further use; (2) easier synthesized from inexpensive
starting compounds, more stable and lower loading capacity,
which let them be the more economic candidates; (3) their
properties can be altered easily by modifying the structure of
the cations or anions, in order to meet the requirements in
reactions, such as steric demand in asymmetric reactions.
Those advantages mentioned allow them to become the
attractive and ideal candidates for reusable homogeneous
catalysts in reactions. During our ongoing studies on the
development of recyclable box ligands, we have focused on
this novel ionic-liquid-supported (ILS) strategy, which
employs ionic liquids as recyclable supports for asymmetric
homogeneous catalysis in organic synthesis. Recently, a very
large number of catalysts designed by this methodology have
been successfully applied to a wide range of reaction
including cross-coupling,7 olen metathesis,8 Heck reac-
tion,9 oxidation,10 polymerization reaction,11 Biginelli reac-
tion12 and asymmetric organocatalysis.13
C2-Symmetric bis(oxazolines) (boxes) have been proven to be an
important class of chiral ligands and have been successfully
used in plenty of metal-catalyzed asymmetric reactions in the
past decade. These box ligands show excellent enantiose-
lectivity in a variety of organic reactions.1 Nowadays the recy-
cling of catalysts is a rapidly growing area of modern organic
chemistry. This not only reduces costs, but also reduces the
environmental pollution in line with the needs of green
chemistry. Speaking of this, the boxes present inherent disad-
vantages: hard to separate from the reaction mixture and to
recycle. These issues have been addressed by immobilizing box
ligands on supports.2,3
The immobilization of chiral catalysts based on box ligands
is conducive to the development of efficient chiral heteroge-
neous catalysts and homogeneous catalysts.3 The immobiliza-
tion strategy has been used and discussed extensively during
the past several decades. This strategy includes various
methods, e.g., immobilization by covalent or non-covalent
bonding on organic or on inorganic supports.4 Although
highly successful, heterogeneous catalysts, compared to
homogeneous catalysts, suffer from a series of drawbacks,
aR&D Center for Pharmaceuticals, School of Chemical Engineering and The
Environment, Beijing Institute of Technology, Beijing, PR China, 100081. E-mail:
zzm@bit.edu.cn; Fax: +86 010 68912664; Tel: +86 010 68912664
bState Key Laboratory of Explosion Science and Technology, Beijing Institute of
Technology, Beijing, PR China, 100081
Doherty and co-workers were interested in imidazolium ILS
bis-(oxazolines). For the rst time, they prepared and used the
unsymmetric imidazolium ILS boxes 1–3 (Fig. 1) as chiral
ligands in the copper(II)-catalyzed Diels–Alder reaction.14 They
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra14028a
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Results and discussion
Preparation of C2-symmetric imidazolium-tagged
bis(oxazoline)
Imidazolium-tagged bis(oxazolines) 9a, 9b, and 9c were identi-
ed as potential TSILs because they are relatively straightfor-
ward to prepare from inexpensive and readily available starting
materials. The synthesis of bis(oxazolines) 9a and 9b bearing a
pendent imidazolium tag is shown in Scheme 1. Starting from
the commercially available dimethylmalonic acid, compounds
4, 5, and 6 were prepared as previously reported.18 C2-Symme-
tricbox 7 was obtained when 6 was reacted with TsCl in DCM,
catalyzed by Et3N. The imidazolium tag was introduced in the
nal step by reacting 7 with 1,2-dimethylimidazole in toluene at
Fig. 1 C2-Unsymmetric imidazolium ILS boxes.
got excellent results that the reaction nished within 2 min in
[EMIM] [NTf2] with 100% conversion and 95% ee value.
Furthermore, the ILS catalyst was successfully recycled at least
ten times with no loss in activity or enantioselectivity.
Immediately aer, they utilized ILS ligand 3 for the copper(II)-
catalyzed asymmetric Mukaiyama aldol reaction under
homogeneous conditions.15 We have recently synthesized a
series of novel C2-symmetric imidazolium-tagged bis(oxazo-
line) ligands with excellent results.16 For instance, in the
copper-catalyzed asymmetric Diels–Alder reaction between
N-acryloyloxazolidin-ones and 1,3-cyclohexandiene in the
ionic liquid, the resulting product was isolated 98% yield
and 97% ee. In addition, the best catalyst was recycled
twenty times. These results conrmed that these C2-
symmetric ligands perform signicantly better than unsym-
metric ones.
ꢀ
90 C to afford the tosyl salt 9a; the anion exchange in water
with KPF6 afforded the desired hexauorophosphate imidazo-
lium salt 9b. 7 was reacted with NaI in acetone to give 8. Finally,
9c was obtained using the same method employed for 9a by the
reaction of 8 with 1,2-dimethyl-1H-imidazole in toluene at
ꢀ
90 C.
Asymmetric Henry reactions
Our initial studies focused on the catalytic activities of various
metal salts and catalyst loading for the asymmetric Henry
reaction, catalyzed by the catalyst based on 9a and 4-nitro-
ꢀ
benzaldehyde as a representative aldehyde in MeOH at 25 C
for 24
h (Table 1). The reaction was performed with
Zn(OAc)2$2H2O, Zn(OTf)2, Cu(OTf)2, CuCl2$2H2O, CuI, and
Co(OAc)2$4H2O, however, it turned out that the product
was obtained in moderate to good yield, but with low ee
values (Table 1, entries 2–8). As reported,19 the air-stable
Cu(OAc)2$H2O used as a Lewis acid (Table 1, entry 1),
providing the best result with 89% yield and 56% ee. We then
carried out the reaction under different amount of the catalyst
to investigate the effect of this factor (Table 1). A lower catalyst
loading resulted in lower activities and enantioselectivities
(Table 1, entries 11). However, an increase in the catalyst
loading did not bring us a signicant improvement in the
activity or enantioselectivity either (Table 1, entries 13 and 14).
As can be seen in Table 1, the optimal ratio of Cu(OAc)2$H2O to
ligand 9a proved to be 1 : 1 (Table 1, entry 1). Increasing or
decreasing this ratio led to lower activities or enantioselectiv-
ities (Table 1, entries 9 and 10).
Solvents always play an important role in asymmetric reac-
tions. The inuence of various solvents, including ionic liquids
and water, were tested in the asymmetric Henry reaction
between 4-nitro benzaldehyde with nitromethane in combina-
tion with Cu(OAc)2$H2O and 9a; results are summarized in
Table 2. Unfortunately, the ionic-tagged ligand showed almost
no reactivity in ionic liquids (Table 2, entries 5 and 6), which is
consistent with previous studies.16 Data in Table 2 showed that
solvents do affect the reaction activity and enantioselectivity. In
particular, protic solvents (alcohols) are superior to aprotic
solvents. In the case of alcohols, the activity and enantiose-
lectivity increased in certain order: iPrOH < EtOH < MeOH
(Table 2, entries 8–10); no reaction was observed in H2O
Though more and more C2-symmetric bis(oxazolines) have
been synthesized, one of their main differences is the
substituent at the 4,40-position, which intermediates in
important enantioselective catalytic processes. In the vast
majority of cases, the structure of 4-substituted groups of the
boxes, which are considered to be the best ligands in a large
number of reactions, is three-dimensional rather than
planar. In particular, tert-butyl-substituted bis(oxazolines)
are the most widely reported ligands in literature.1 Inspired
by this, we designed and prepared imidazolium ILS boxes,
with the imidazolium tagged onto the 4,40-position of the box.
Unlike previously reported systems, the imidazolium group,
in addition to facilitating catalyst recovery and reuse, is also
involved in the catalytic process. Most importantly, these
boxes have a further advantage: their chemical and physical
properties can be nely tuned for a range of applications by
varying the cations or anions; at the same time, the size of the
imidazolium fragment can be easily changed by ion exchange
to meet the steric demand needed in asymmetric reactions. In
this study, we describe the synthesis, characterization, and
application of the new imidazolium-tagged recyclable boxes
(Scheme 1). We then examine the applications of these boxes
in asymmetric catalysis, the asymmetric Henry reaction being
our initial focus. As one of the most important C–C bond-
forming reactions, the Henry reaction affords products that
are versatile building blocks and intermediates in organic
synthesis.17
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Scheme 1 Synthesis of imidazolium-tagged bis(oxazolines) 9a, 9b, 9c. (a) (COCl)2, DMF, DCM, rt, 85%; (b) L-threonine methyl ester hydro-
chloride, Et3N, DCM, 65%; (c) (NH4)2MoO4 (2 mol%), toluene, azeotropic reflux, 69%; (d) NaBH4, EtOH, rt, 75%; (e) TsCl, Et3N, DCM, 65%;
(f) 1,2-dimethyl-1H-imidazole, toluene, 90 ꢀC, 56%; (g) KPF6, H2O, rt, 85%; (h) NaI, acetone, reflux, 73%; (i) 1,2-dimethyl-1H-imidazole, toluene,
90 ꢀC, 51%.
(Table 2, entry 7). We then tried MeOH–H2O solvents, though hexauorophosphoric anion yielded higher enantioselectivities
we did not get the best results, it's much better than pure water and activities than with other anions (Table 3, entry 2–4). Thus,
(Table 2, entries 15–18). When other solvents were used, the our experimental results showed that the steric demand of these
reaction progressed with good yields, but the enantioselectivity reactions was met, and the best results were obtained by a
decreased (Table 2, entry 1–4). We also tested the base to nd if simple change in the size of the imidazolium fragment.
there has an enhancement effect on the enantioselectivity
The asymmetric Henry reaction was performed with
(Table 2, entries 11 and 12). The results showed that the addi- different aromatic aldehydes with electron-withdrawing and
tion of base signicantly decreased the enantioselectivity of the electron-donating substituents under the optimized conditions,
catalyst.
i.e., 10 mol% Cu(OAc)2$H2O in MeOH for ligands 9a and 9b. The
The reaction temperature has a signicant effect on the results summarized in Table 4 show that aromatic aldehydes
chemical yield and ee values of the nitroaldol product, so the react in very good yields with nitromethane, producing b-nitro
optimization of the temperature was examined (Table 2, entries alcohols in modest to good enantioselectivities. Benzaldehydes
13 and 14). Decreasing the reaction temperature from room with electron-withdrawing substituents gave better yields than
temperature to 0 ꢀC caused the ee value to increase considerably substrates with weakly electron-withdrawing or electron-
and increased the reaction time (Table 2, entry 13). However, at donating ones (Table 4, entries 1–14). In contrast,
ꢁ5 ꢀC, the selectivity was slightly decreased (Table 2, entry 14). benzaldehydes with electron-donating substituents gave better
We then screened the ligands to evaluate their catalytic enantiomeric excess.
performance on the asymmetric Henry reaction (Table 3). The
This observation is especially true for 3,4-dimethoxy-
imidazolium-tagged bis(oxazoline) 9b was found to be the benzaldehyde, which provides ee values of 94% with good
optimum ligand and yielded the highest ee of all studied yield (Table 4, entry 11). The most relevant difference between
ligands (Table 3, entry 3). The ligand 9b with our new ligands and the ligands that we reported previously is
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Table 1 Screening metal salts and catalyst loading in the asymmetric Table 2 Effects of the solvents and reaction temperature on the
Henry reactiona asymmetric Henry reactiona
Entry
Metal salt
Catalyst (mol%)
Yieldb (%)
eec (%) Entry
Solvent
Temp. (ꢀC)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O
Cu(OTf)2
CuSO4$5H2O
CuI
10
10
10
10
10
10
10
10
10
10
5
89
73
0
56
9
—
0
9
1
2
3
4
5
6
7
8
CH2Cl2
THF
Toluene
DMF
[Bmim]PF6
[Bmim]BF4
H2O
EtOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
48
78
53
72
Trace
Trace
Trace
86
84
89
95
98
78
65
83
73
54
71
35
37
33
48
—
—
—
46
42
56
23
1
65
57
43
20
14
49
71
63
84
75
65
65
67
70
89
72
67
Zn(OTf)2
Zn(OAc)2$2H2O
Co(OAc)2$4H2O
CuCl2$2H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
1
8
47
50
54
39
56
52
52
9d
10e
11
12
13
14
9
10
11d
12e
13f
14g
15
16
17
18
10
15
20
MeOH
ꢁ5
rt
rt
rt
0
MeOH/H2O, 8 : 1
MeOH/H2O, 2 : 1
MeOH/H2O, 1 : 2
MeOH/H2O, 8 : 1
a
All reactions were conducted on a 1 mmol scale with ligand 9a
(10 mol%), copper salt (10 mol%), and nitromethane (20 equiv.) in
MeOH (1 mL) at rt for 24 h. Values are isolated yields aer
chromatographic purication.
b
c
Enantiomeric excesses were
determined by HPLC using a Chiralcel OD-H column (hexane/i-PrOH:
a
All reactions were conducted on a 1 mmol scale with ligand 9a
(10 mol%), Cu(OAc)2$H2O (10 mol%), and nitromethane (20 equiv.) in
d
e
85 : 15, 0.8 mL minꢁ1). The rate of metal/ligand is 1/1.25. The rate
of metal/ligand is 1/0.8.
b
1 mL of solvent at rt for 24 h. Values are isolated yields aer
chromatographic purication.
c
Enantiomeric excesses were
determined by HPLC using a Chiralcel OD-H column (hexane/i-PrOH:
d
e
85 : 15, 0.8 mL minꢁ1). 10 mol% of Et3N used as a base. 10 mol%
K2CO3 used as a base. f Reaction time of 48 h. Reaction time of 62 h.
g
that, with [PF6]ꢁ, the ligand performs better in terms of
activity and enantioselectivity than with [OTs]ꢁ. The results
showed that ligand 9b is the best ligand for the Henry
reaction.
Table 3 Optimization of the reaction ligandsa
This asymmetric reaction was then applied to the synthesis
of the enantiomerically enriched compound 14; which is the key
intermediate of propanolol,20 the synthetic route being shown
in Scheme 2. Nitroalcohol 14 was obtained with 86% ee cata-
lyzed by our ligand 9b.
Entry
Ligand
Temp. (ꢀC)
Yieldb (%)
eec (%)
Recyclability of the catalysts
The recyclability of the catalyst based on the C2-symmetric
imidazolium-tagged box 9b was studied, results summarised in
Fig. 2. We performed the asymmetric Henry reaction between
3,4-dimethoxybenzaldehyde and CH3NO2. The reaction was
carried out in a homogeneous system, and then the catalyst was
separated through the formation of a heterogeneous system.
MeOH was removed under reduced pressure aer the comple-
1
2
3
4
7
0
0
0
0
73
79
84
82
57
65
75
25
9a
9b
9c
a
All reactions were conducted on a 1 mmol scale with 10 mol% ligand,
Cu(OAc)2$H2O (10 mol%), and nitromethane (20 equiv.) in 1 mL of
MeOH at
chromatographic purication.
b
0
ꢀC for 48 h.
Values are isolated yields aer
Enantiomeric excesses were
c
tion of the reaction, and owing to the insolubility of the catalyst determined by HPLC using a Chiralcel OD-H column (hexane/i-PrOH:
85 : 15, 0.8 mL minꢁ1).
in diethyl ether, the residue was extracted with diethyl ether
transferring the product and remaining material into diethyl
ether. The residual catalyst was subjected to vacuum to remove
traces of diethyl ether; it was then ushed with an inert gas and
charged with additional portions of MeOH, aldehyde, and
CH3NO2. The activity and the enantioselectivity were
maintained even aer the catalyst was reused six times. The
asymmetric Henry reaction with the catalyst based on 9b and
3,4-dimethoxybenzaldehyde as the substrate provided 61%
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Table 4 Substrate scope
Ligand 9a
Ligand 9b
Entry
R
Product
Yielda (%)
eeb (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Ph(a)
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
67
81
78
80
77
70
71
68
58
56
59
57
52
54
85
65
70
61
81
81
85
79
83
85
88
83
79
77
70
84
81
88
80
73
73
74
68
66
71
67
70
63
89
75
74
79
83
85
91
90
91
92
94
92
93
89
4-NO2C6H4(b)
2-NO2C6H4(c)
2,4-(Cl)2C6H3(d)
4-ClC6H4(e)
4-FC6H4(f)
2-MeC6H4(g)
4-MeC6H4(h)
2-OMeC6H4(i)
3-OMeC6H4(j)
3,4-(OMe)2C6H3(k)
3,5-(OMe)2C6H3(l)
3,4,5-(OMe)3C6H2(m)
1-Naphthyl(n)
9
10
11
12
13
14
a
b
Yields were calculated based on aldehyde. ee values were determined by HPLC analysis using Chiralcel OD-H, Chiralpak AD-H and Chiralcel
OJ-H columns.
Fig. 2 Variation in percentage conversion (red) and percentage ee
(blue) on recycling the Henry reactions between 11k and CH3NO2 in
MeOH using catalysts generated from 9b and Cu(OAc)2$H2O.
Scheme 2 Synthesis of (R)-14.
bearing moderately basic charged ligands may facilitate the
deprotonation of nitroalkanes as a rst step to the aldol addi-
tion. Based on this, the deprotonated nitromethane was
included into the new model. Calculations of the geometry
yield and 90% ee on the 6th cycle. It can be said that the ionic
tagged catalyst has a good recyclability.
of the complex Cu(OAc)2-ligands with the deprotonated
nitromethane were performed with the B3LYP/6-31G(d) level of
theory using the Gaussian03 soware package. For the sake of
comparison, models with large and small size anions, i.e.,
4-methylbenzenesulfonate and hexauorophosphate, were
employed. The optimal congurations as well as selected bond
lengths and angles of the two complex models are displayed in
Fig. 3. The optimized geometries of the two complexes resemble
the shape of an airplane, with the protonated methane sitting
Theoretical mechanistic study
A theoretical mechanistic study was conducted to explore the
origin of the enantioselectivity at a molecular level. A similar
work was carried out in our preliminary study; however, only a
complex consisting of a ligand and copper salt was considered,
without coordination of nitromethane. According to the model
proposed by Evans,19 a weakly Lewis acidic metal complex
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Fig. 3 B3LYP/6-31G(d) optimized geometries of CuOAc–9a–CH2NO2 and CuOAc–9b–CH2NO2 complex models (H omitted for clarity) and
possible transition structure for the asymmetric Henry reaction. Features are: 9b: Cu(20)–O(41) 1.96 A˚, Cu(20)/O(43) 2.05 A˚, C(44)/P(82)
4.24 A˚, N(42)–Cu(20)–C(32)–C(33) 167.8ꢀ; 9a: Cu(20)–O(41) 2.01 A˚, Cu(20)/O(43) 2.05 A˚, C(44)/C(36) 6.21 A˚, C(44)/C(35) 5.19,
N(42)–Cu(20)–C(16)–C(17) 67.1ꢀ.
on the belly of the airplane, and the anions being over
Conclusions
(for OTsꢁ) or beneath (for PF6ꢁ) the wings. For the complex
with sulfonate, the perpendicular position at the reactive C]N
double bond Re-face was blocked by the 5-methyl group on the
oxazoline ring; for the complex with phosphate, the anion and
the imidazole sterically hindered the Re-face of the reactive
C]N bond. A further comparison suggested that the difference
between the open dihedral angles of the Si-face of reactive
C]N bond may play a critical role in the activity and enan-
tioselectivity. A larger dihedral angle would obviously provide a
larger space for the Si-attack by the approaching aldehydes,
leading to highꢁer enantioselectivities. In fact, the complex
module for PF6 showed a larger dihedral angle, therefore
providing higher enantioselectivities than that of the complex
with sulfonate; this is demonstrated by our experimental
results shown in Table 4. Therefore, we concluded that,
although the ligand with Iꢁ has a signicantly larger dihedral
angle, it can exert only a small steric hindrance, which shields
the Si-face by the ion fragment. This explains the reasons why a
high yield and low ee value was obtained in the reaction cata-
lyzed by 9c.
Novel C2-symmetric 4,40-imidazolium-tagged bis(oxazoline)
ligands were successfully and conveniently prepared by two
relatively straightforward steps from readily available starting
materials; the anions of the ligands were simply altered by ion
exchange. The catalysts based on the new ligands and
Cu(OAc)2$H2O were applied to the asymmetric Henry reaction
between various aldehydes and CH3NO2. Our experiments
proved that the ion fragments play a key role in the steric
hindrance. A theoretical mechanistic study revealed that the
anions should possess a suitable size to asꢁsemble a favorable
conguration. This is the reason why PF6 ensured a better
selectivity than bulkier OTsꢁ or smaller Iꢁ. The catalyst derived
from 9b yielded the adduct (R)-11k with 94% ee in MeOH. In the
reaction of 3,4-dimethoxybenzaldehyde with CH3NO2, the
ligand 9b was recycled at least 6 times without an obvious loss
in activity or enantioselectivity. Furthermore, the synthetic
utility of the catalytic enantioselective Henry reaction was
demonstrated by the application of a short-step synthesis of
nitroalcohol 14, which, in two steps, led to the formation of
propranolol which as a b-adrenergic receptor blocking agent.
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While no studies about the use of 4,40-imidazolium tagged addition of brine (50 mL). The organic layer was washed with
box-based catalysts in asymmetric catalysis have been reported, water (3 ꢂ 40 mL) and dried over Na2SO4, the solvent was
this work has clearly shown the potential advantages of the removed under vacuum to afford the crude product, which was
strategy employed here, which include high enantioselectivities, puried by column chromatography (SiO2, EtOAc/PE, 1/10 to
efficient recovery and reuse of the catalyst, and great potential 2/1) to afford 7 as white crystal; yield: 1.5 g (65%). Mp: 104–
20
ꢀ
as an environmentally friendly process in the chemical industry. 106 C. [a]D ¼ 128.4 (c ¼ 0.50, CH2Cl2). Rf ¼ 0.15 (PE–EtOAc
Further research on C2-symmetric ionic-tagged box ligands and 1 : 2); IR (lm) 2981, 2931, 1642, 1353, 1177, 965, 811, 790 cmꢁ1
.
their performance in asymmetric reactions are underway in our 1H NMR (400 MHz, CDCl3) d ¼ 1H NMR (400 MHz, CDCl3) d
laboratory.
7.78–7.75 (m, 4H, Ar–H), 7.35–7.33 (m, 4H, Ar–H), 4.51–4.48 (m,
2H, oxazoline-CHN), 4.11 (dd, J ¼ 3.2 Hz, 2H, oxazoline-CHO),
3.887–3.78 (m, 4H, CH2-OTs), 2.44 (s, 6H, Ar-CH3), 1.38 (s, 6H,
CCH3), 1.25 (d, J ¼ 6 Hz, 6H, CHCH3). 13C NMR (400 MHz,
CDCl3) d ¼ 170.7, 145.2, 132.8, 130.0, 128.1, 79.3, 70.9, 70.3,
38.8, 23.9, 21.8, 20.8. MS (ESI): m/z ¼ 579.2 [M + 1]+.
Experimental section
General methods
All manipulations involving air-sensitive materials were per-
formed using standard Schlenk-line techniques under an
atmosphere of nitrogen or argon in oven-dried glassware. THF,
Et2O and toluene were distilled from Na. DCM was distilled
from calcium hydride. MeOH and EtOH were distilled from Mg.
All the chemicals used were purchased from commercial
suppliers and used as received without further purication. IR
Synthesis of 3,30-(((4R,40R,5R,50R)-2,20-(propane-2,2-diyl)
bis(5-methyl-4,5-dihydrooxazole-4,2-diyl))bis(methylene))
bis(1,2-dimethyl-1H-imidazol-3-ium) diOTs 9a
7 (0.252 g, 0.32 mmol) and 1,2-dimethyl-1H-imidazole (0.193 g,
2.0 mmol) were dissolved in 2 mL of toluene, and the solution
was heated to 90 ꢀC for 24 h under Ar atmosphere. Toluene was
removed under high vacuum. The residue was washed with
Et2O (3 ꢂ 10 mL) until it changed to a light-yellow solid; yield:
spectra were recorded on a Bruker Alpha-p. H and 13C NMR
1
spectra were recorded on a Varian mercury-plus 400 instru-
ment. High resolution mass spectra (HRMS) were recorded at
Analytical Instrumentation Center, Peking University. Enantio-
meric ratios were determined by chiral HPLC analysis using
Daicel Chiralpak AD-H and OD-H columns.
20
ꢀ
0.156 g (56%). Mp: 77–79 C. [a]D ¼ 96.2 (c ¼ 0.60, MeOH). IR
(lm) 2980, 2930, 1734, 1649, 1356, 1174, 1118, 1031, 1010, 816
cmꢁ1. 1H NMR (400 MHz, CDCl3) d ¼ 8.31 (s, 2H, imidazole-H),
7.99 (s, 2H, imidazole-H), 7.79–7.77 (d, 4H, Ar–H), 7.17–7.15 (d,
4H, Ar–H), 5.08 (s, 2H, CH2-OTs), 4.71 (d, J ¼ 16, 2H, oxazoline-
CHN), 4.24 (dd, J ¼ 4 Hz, 2H, oxazoline-CHO), 3.92 (s, 6H,
imidazole-NCH3), 2.55 (s, 6H, Ar-CH3), 2.34 (s, 6H, imidazole-
CCH3), 1.89 (s, 2H, CH2-OTs), 1.35 (d, J ¼ 4 Hz, 6H, CHCH3), 1.28
(s, 6H, CCH3). 13C NMR (400 MHz, CDCl3) d ¼ 170.9, 145.2,
132.8, 130.1, 128.2, 122.3, 121.6, 79.3, 71.0, 50.3, 38.8, 24.0, 21.8,
General procedure for the enantioselective Henry reaction
To an oven-dried 10 mL two necked round-bottomed ask, a
solution of ligand (0.013 mmol) and Cu(OAc)2$H2O (2.64 mg,
0.013 mmol) in MeOH (1 mL) was stirred for 1 h at 25 ꢀC. Then
the aldehyde (0.13 mmol) and nitromethane (2.6 mmol) were
added, and the resulting mixture was stirred at 0 ꢀC for the
appropriate time. Aer completion, as monitored by TLC, the
solvent was removed, and the resulting residue was puried by
column chromatography on silica gel (Merck, 60–120 mesh),
(ethyl acetate/hexane, 1 : 3) to afford the pure 2-nitroalcohol.
20.8, 9.7. MS (ESI): m/z (TsOꢁ) ¼ 171.0. HRMS (ESI): calc. for
2+
C
C
23H36N6O2
:
428.28888, found: 214.14451; calc. for
30H43N6O5S+ [M ꢁ OTs]+: 599.30102, found: 599.30069.
General procedure for recycling the catalyst
Synthesis of 3,30-(((4R,40R,5R,50R)-2,20-(propane-2,2-diyl)bis
(5-methyl-4,5-dihydrooxazole-4,2-diyl))bis(methylene))bis
(1,2-dimethyl-1H-imidazol-3-ium)dihexauorophosphate 9b
Aer the completion of the reaction, the MeOH was removed
under reduced pressure and the residue was extracted with
diethyl ether (until there was no product in diethyl ether could
be determined by TLC), and transferred to another ask. Owing
to the insoluble nature of the catalyst in diethyl ether, the
catalyst could be separated through the formation of a hetero-
geneous system. The residual catalyst was subjected to vacuum
for 1 h, ushed with an inert gas and charged with additional
portions of MeOH, aldehyde and CH3NO2.
9a (0.125 g, 0.16 mmol) was dissolved in 2 mL of H2O, KPF6
(0.048 g, 0.26 mmol) was added to the solution and stirred for
6 h at room temperature. The resultant white solid was ltered
and dried under vacuum to afford the product; yield: 0.100 g
(85%). Mp: 163–165 ꢀC. [a]D20 ¼ 93.7 (c ¼ 0.60, MeOH). IR (lm)
2983, 2940, 1731, 1650, 1375, 1241, 1175, 1041, 829 cmꢁ1. H
1
NMR (400 MHz, DMSO) d ¼ 7.64–7.62 (m, 4H, imidazole-H),
4.53–4.50 (m, 2H, oxazoline-CHN), 4.37 (dd, J ¼ 4 Hz, 2H, oxa-
zoline-CHO), 4.14–4.09 (m, 2H, CH2-OTs), 3.96–3.93 (m, 2H,
CH2-OTs), 3.77 (s, 6H, imidazole-NCH3), 2.59 (s, 6H, imidazole-
CCH3), 1.27 (s, 6H, CCH3), 1.22 (d, J ¼ 8 Hz, 6H, CHCH3). 13C
Synthesis of ((4R,40R,5R,50R)-2,20-(propane-2,2-diyl)bis
(5-methyl-4,5-dihydrooxazole-4,2-diyl))bis(methylene)bis
(4-methylbenzenesulfonate) 7
To a solution of 6 (1 g, 3.7 mmol) in dry DCM (30 mL), Et3N NMR (400 MHz, DMSO) d ¼ 168.8, 145.2, 122.3, 121.6, 78.4,
(1.5 g, 14.8 mmol) and TsCl (2.1 g, 11.1 mmol) were added at 71.2, 50.3, 34.8, 23.5, 20.3, 9.7. HRMS (ESI): calc. for
2+
0 ꢀC under Ar atmosphere, the mixture was stirred overnight at
r.t. The reaction mixture was subsequently quenched by the
C
C
23H36N6O2
:
428.28888; found: 214.14439, calc. for
23H36F6N6O2P+ [M ꢁ PF6]+: 573.25361, found: 573.25326.
4764 | RSC Adv., 2015, 5, 4758–4765
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RSC Advances
Synthesis of (4S,40S,5R,50R)-2,20-(propane-2,2-diyl)bis
(4-(iodomethyl)-5-methyl-4,5-dihydrooxazole) 8
and I. Escher, Angew. Chem., Int. Ed., 2006, 45, 4732–4762;
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A solution of 7 (440 mg, 0.76 mmol) in acetone (15 mL) was
treated with sodium iodide (1.14 g, 7.6 mmol) and the reaction
mixture was stirred under reux. Aer 12 h, the reaction
mixture was treated with saturated Na2S2O3 solution (15 mL).
The resulting solution was extracted with Et2O (3 ꢂ 20 mL) and
the combined organic extracts were washed with brine, dried
over Na2SO4, ltered and concentrated to give the product as
20
ꢀ
white solid; yield: 320 mg (73%). Mp: 114–116 C. [a]D ¼ 67.2
(c ¼ 0.25, CH2Cl2). Rf ¼ 0.2 (PE–EtOAc 1 : 2); IR (lm) 2969,
2924, 1638, 1376, 1259, 1143, 1032, 988, 871, 795 cmꢁ1. 1H NMR
(400 MHz, CDCl3) d ¼ 4.41–4.38 (m, 2H, oxazoline-CHN), 3.80–
3.76 (m, 2H, CH2-OTs), 3.35 (dd, J ¼ 3.6, 2H, oxazoline-CHO),
3.1–3.06 (m, 2H, CH2-OTs), 1.52 (s, 6H, CCH3), 1.3 (d, J ¼ 6.4 Hz,
6H, CHCH3). 13C NMR (400 MHz, CDCl3) d ¼ 170.0, 82.1, 72.9,
39.1, 24.3, 21.3, 10.6. MS (ESI): m/z ¼ 591.0 [M + 1]+.
Synthesis of 3,30-(((4R,40R,5R,50R)-2,20-(propane-2,2-diyl)bis
(5-methyl-4,5-dihydrooxazole-4,2-diyl))bis(methylene))bis
(1,2-dimethyl-1H-imidazol-3-ium) diI 9c
8 (0.252 g, 0.32 mmol) and 1,2-dimethyl-1H-imidazole (0.193 g,
2.0 mmol) were dissolved in 2 mL of toluene, and the solution
was heated to 90 ꢀC for 24 h under Ar atmosphere. Toluene was
removed under high vacuum. The residue was washed with
Et2O (3 ꢂ 10 mL) until it changed to a light-yellow solid; yield:
10 Y. X. Qiao, Z. Hou, H. Li, Y. Hu, B. Feng, X. Wang, L. Hua and
Q. Huang, Green Chem., 2009, 11, 1955–1960.
11 S. Kanaoka, N. Yagi, Y. Fukuyama, S. Aoshima,
H. Tsunoyama, T. Tsukuda and H. Sakurai, J. Am. Chem.
Soc., 2007, 129, 12060–12061.
20
ꢀ
0.156 g (51%). Mp: 77–79 C. [a]D ¼ 96.2 (c ¼ 0.60, MeOH). IR
(lm) 3091, 2978, 2928, 1728, 1648, 1518, 1454, 1281, 1240, 1121
ˆ
12 L. M. Ramos, B. C. Guido, C. C. Nobrega, J. R. Correa,
R. G. Silva, H. C. B. Oliveira, A. F. Gomes, F. C. Gozzo and
B. A. D. Neto, Chem.–Eur. J., 2013, 19, 4156–4168;
D. V. Jawale, U. R. Pratap, A. A. Mulay, J. R. Mali and
R. A. Mane, J. Chem. Sci., 2011, 123, 645–655.
1
cmꢁ1. H NMR (400 MHz, CDCl3) d ¼ 7.64–7.62 (m, 4H, imid-
azole-H), 4.53–4.50 (m, 2H, oxazoline-CHN), 4.37 (dd, J ¼ 4 Hz,
2H, oxazoline-CHO), 4.14–4.09 (m, 2H, CH2-OTs), 3.96–3.93 (m,
2H, CH2-OTs), 3.77 (s, 6H, imidazole-NCH3), 2.59 (s, 6H, imid-
azole-CCH3), 1.27 (s, 6H, CCH3), 1.22 (d, J ¼ 8 Hz, 6H, CHCH3).
13C NMR (400 MHz, DMSO) d ¼ 168.8, 145.2, 122.3, 121.6, 78.4,
71.2, 50.3, 34.8, 23.5, 20.3, 9.7. MS (ESI): m/z (Iꢁ) ¼ 126.9. HRMS
(ESI): calc. for C23H36N6O22+: 428.28888; found: 214.14439, calc.
for C23H36IN6O2+ [M ꢁ I]+: 555.19389, found: 555.19326.
13 S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu and J. Cheng, Angew.
Chem., Int. Ed., 2006, 45, 3093–3097.
14 S. Doherty, P. Goodrich, C. Hardacre, J. G. Knight,
ˆ
M. T. Nguyen, V. I. Parvulescu and C. Paun, Adv. Synth.
Catal., 2007, 349, 951–963.
ˆ
15 S. Doherty, P. Goodrich, C. Hardacre, V. I. Parvulescu and
C. Paun, Adv. Synth. Catal., 2008, 350, 295–302.
Acknowledgements
16 Z. Zhou, Z. Li, X. Hao, X. Dong, X. li, L. Dai, Y. Liu, J. Zhang,
H. Huang, X. Li and J. Wang, Green Chem., 2011, 13, 2963–
2971; Z. Zhou, Z. Li, X. Hao, J. Zhang, X. Dong, Y. Liu,
W. Sun, D. Cao and J. Wang, Org. Biomol. Chem., 2012, 10,
2113–2118; Z. Li, Z. Zhou, X. Hao, J. Zhang, X. Dong,
Y. Liu, W. Sun and D. Cao, Appl. Catal., A, 2012, 28, 425–426.
17 C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem., 2007,
2561–2574; F. A. Luzio, Tetrahedron, 2001, 57, 915–945.
18 A. Sakakura, R. Kondo, Y. Matsumura, M. Akakura and
K. Ishihara, J. Am. Chem. Soc., 2009, 131, 17762–17764.
19 D. A. Evans, D. Seidel, M. Rueping, H. W. Lam, J. T. Shaw and
C. W. Downey, J. Am. Chem. Soc., 2003, 125, 12692–12693;
D. A. Evans, K. A. Woerpel, M. M. Hinman and M. M. Faul,
J. Am. Chem. Soc., 1991, 113, 726–728.
The National Natural Science Fund Project (KZ200610011006) is
gratefully acknowledged for their nancial support.
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This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 4758–4765 | 4765