Copper(II) complexes of 2-(pyridine-2-yl)imidazolidine-4-thione derivatives for asymmetric Henry reactions

Article abstract of DOI:10.1016/j.tetasy.2017.04.009

The preparation of a new series of 2-(pyridine-2-yl)imidazolidine-4-thione derivatives is described. Their corresponding copper(II) complexes were found to be highly enantioselective catalysts for asymmetric Henry reactions (up to 98% ee). Immobilization

Full text of DOI:10.1016/j.tetasy.2017.04.009

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Copper(II) complexes of 2-(pyridine-2-yl)imidazolidine-4-thione
derivatives for asymmetric Henry reactions
⇑
Gabriela Nováková, Pavel Drabina , Jan Svoboda, Miloš Sedlák
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of a new series of 2-(pyridine-2-yl)imidazolidine-4-thione derivatives is described. Their
corresponding copper(II) complexes were found to be highly enantioselective catalysts for asymmetric
Henry reactions (up to 98% ee). Immobilization of these complexes by anchoring onto MerrifieldTM resin
with respect to their use as recyclable catalysts was subsequently performed. The heterogeneous cata-
lysts prepared in this way were tested in the asymmetric Henry reactions and showed high catalytic
activity; they can be easily recycled, although their enantioselectivities were only moderate (ꢀ50% ee).
Ó 2017 Elsevier Ltd. All rights reserved.
Received 12 March 2017
Accepted 20 April 2017
Available online xxxx
1. Introduction
their homogeneous analogues. These heterogeneous catalysts can
be recovered and recycled more than ten times without any
The asymmetric Henry reaction represents one of the most
intensively studied asymmetric reactions, and is characterized by
the formation of a CAC bond and one or two stereogenic centers.1
The importance of this transformation is that it affords substituted
b-nitroalcohols, which are important synthetic building blocks for
the preparation of many poly-functionalized compounds, for
instance pharmaceutical substances.2 Therefore, the asymmetric
Henry reaction is one of the most popular reactions used for the
evaluation of the catalytic activity and enantioselectivity of newly
prepared catalytic systems.1–7 Many efficient catalysts suitable for
asymmetric Henry reactions are based on copper complexes con-
taining an enantiomerically pure nitrogen containing ligand. Chiral
oxazolines,3 diamines,4 Schiff bases5 and imidazolidine deriva-
tives6 are very successful ligands whose copper complexes have
been applied as enantioselective catalysts for Henry reactions.
Recently, we prepared and studied the catalytic activity and
enantioselectivity of a new class of ligands: 2-(pyridine-2-yl)
imidazolidine-4-thione derivatives.7 We found that their corre-
sponding complexes with copper(II) acetate exhibited high enan-
tioselectivity in Henry reactions of substituted aldehydes with
nitromethane as well as nitroethane. Moreover, the presence of
the thiolactam group in the ligand structure enabled their immobi-
lization into chloromethylated polystyrene resins (MerrifieldTM
resin, JandaJelTM resin etc.). Thus, these complexes were anchored
onto such polymeric carriers to provide heterogeneous forms of
catalysts, which were comparable enantioselective catalysts to
decrease of their enantioselectivity. The main disadvantage of
these catalysts is the lower stability in acidic media, in which
epimerization of the cis-form of the ligand into the trans-form
and vice versa was observed.7
Herein our aim was the preparation of 2-(pyridine-2-yl)imida-
zolidine-4-thione derivatives 1a–b derived from pyridine-2-car-
baldehyde (Chart 1). These ligands differ from previous ones7 p1
by the presence of a hydrogen substitution at the 2-position of
the imidazolidine ring instead of a methyl group. Therefore, their
structure is more similar to 2-(pyridine-2-yl)imidazolidine-4-one
derivatives p2, which have been studied in detail.6a We assumed
that this structural modification of the ligands’ design could
lead to an enhancement of their enantioselectivity. Hence,
another aim was the verification of the catalytic activity and
enantioselectivity of both copper(II) complexes of newly
prepared 2-(pyridine-2-yl)imidazolidine-4-thione derivatives 1–2
and their immobilized forms 3 in the asymmetric Henry reaction.
2. Results and discussion
The preparation of 2-(pyridine-2-yl)imidazolidine-4-thione
derivatives 1a–b was performed according to the literature6a from
enantiomerically pure (S)-2-amino-2,3-dimethylbutanethioamide
and pyridine-2-carbaldehyde under mild conditions in a total
yield of 81% (Scheme 1). The separation of epimers 1a and 1b was
carried out by column chromatography; the individual forms
were present in the ratio of ca. 1.4/1.0 (1a/1b). A certain amount
of the oxidized form of the product, imidazoline-4-thione
derivative 1c was isolated (16%). The formation of this undesired
⇑
Corresponding author. Tel.: +420 466 037 010; fax: +420 466 037 068.
E-mail address: pavel.drabina@upce.cz (P. Drabina).
http://dx.doi.org/10.1016/j.tetasy.2017.04.009
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009

2
G. Nováková et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
imidazoline system took place. On the other hand, it was observed
H
N
H
N
H
N
that in an acidic media, the epimerization of 2a into 2b as well as
1a into 1b and vice versa proceeded. For this reason, it was neces-
sary to carry out all manipulations with the ligands 1a–b and 2a–b
with exclusion of acidic media, unless the individual epimers 2a
and 2b can be separated by column chromatography.
S
O
S
N
N
N
HN
p1
HN
p2
HN
1
Chart 1.
The structures of ligands 2a–b are closest to the structures of
immobilized ligands 3a–b, therefore the copper(II) complexes of
2a–b can be considered as homogeneous variants of the heteroge-
neous catalysts 4a–b. Thus, the evaluation of the catalytic activity
and enantioselectivity of Cu(OAc)2/2a–b can serve as a basic level
for the comparison of these parameters obtained with immobilized
catalysts 4a–b in subsequent studies. Table 2 presents an overview
of the results of Henry reactions catalysed by Cu(OAc)2/2a–b. The
reaction conditions used were the same as those in the previous
study concerning the catalytic activity of Cu(OAc)2/1a–b for the
sake of comparison.
From the values of the chemical yields of the individual
2-nitroethanols attained using catalysts Cu(OAc)2/2a–b, it can be
seen that their catalytic activity are significantly higher than the
catalytic activities of catalysts Cu(OAc)2/1a–b. This fact was
confirmed by kinetic studies describing the dependence of the
conversion on the reaction time in the reaction of thiophene-2-car-
baldehyde with nitromethane catalysed by both Cu(OAc)2/1a and
Cu(OAc)2/2a (Fig. 1). The application of catalyst Cu(OAc)2/1a gave
a conversion of only ca. 13% after 96 h, while catalyst Cu(OAc)2/2a
gave a conversion more than 90% after 48 h. This phenomenon can
be explained by the possible participation of the sulfur atom of the
complex Cu(OAc)2/1a which behaves as a strong donor in the
formation of a coordination bond with copper(II) ion of other
molecule of the complex resulting in oligomeric/polymeric
adducts.10
by-product was suppressed by performing the condensation
reaction under an inert atmosphere. The absolute configuration
on the stereogenic centres at the 2-position of imidazolidine-4-
thione derivatives 1a–b was determined by means of 1H NMR 1D
NOESY spectroscopy, which confirmed the earlier findings;6–8 the
derivatives with a trans-arrangement in imidazolidine-4-one or
imidazolidine-4-thione ring have a higher Rf factor during chro-
matographic separation.
The in situ prepared copper(II) complexes of 2-(pyridine-2-yl)
imidazolidine-4-thiones 1a–b were studied as enantioselective
catalysts for asymmetric Henry reactions. The set of substrates
(aromatic and aliphatic aldehydes) and reaction conditions were
chosen with the respect to the possibility of comparison of their
catalytic activity and enantioselectivity with the previously stud-
ied 2-methyl derivatives.7 Table 1 summarizes the attained yields
and ee values for the individual aldehydes.
The application of the complex Cu(OAc)2/1a gave the corre-
sponding 2-nitroethanols with the prevailing (R)-configuration,
whereas catalysis of Cu(OAc)2/1b gave the products with the (S)-
configuration in excess. The ee values obtained when using catalyst
Cu(OAc)2/1a indicate that its enantioselectivity is very good
(89–97% ee) and slightly higher than those of the copper(II) com-
plex of the analogous trans-form of the ligand with the methyl
group at the 2-position.7 A significant difference between this pair
of catalysts (with and without a methyl group) was found in the
yield. Catalyst Cu(OAc)2/1a afforded only moderate yields of the
2-nitroethanols, with exception of two cases (entries 2 and 4),
while the yields observed with the catalyst with the methyl group
were generally high.7 In the case of Cu(OAc)2/1b, this catalyst
exhibited more variable and relatively lower enantioselectivities
(64–83% ee) with respect to the catalyst Cu(OAc)2/1a. The values
of these ee as well as the yields are comparable with the analogous
cis-form of the ligand with the methyl group.7 With imidazoline-4-
thione derivative 1c in hand, its catalytic activity and enantioselec-
tivity in the Henry reaction were also evaluated. However,
according to our expectations,9 the complex Cu(OAc)2/1c catalysed
the reaction of 2-methoxybenzaldehyde with nitromethane in low
yield of 17% and with very poor enantioselectivity (27% ee).
The corresponding S-benzyl derivatives of imidazolidin-4-
thiones 2a–b were prepared by treatment of benzyl bromide on
1a–b in methanol in the presence of DBU (Scheme 2). Only selec-
tive attack of benzyl bromide on the sulfur atom was confirmed
by 13C NMR spectroscopy; the value of the chemical shift of the
carbon atom at the 4-position of the imidazoline ring was
significantly changed (e.g. from 210.9 ppm for 1b to 180.7 for
2b). Moreover, the 1H, 13C NMR, 2D HMBC spectra indicated that
the hydrogen atom was fully localised at the 2-position of the imi-
dazoline ring of compounds 2a–b, and so no tautomerism in the
From the ee values found with catalyst Cu(OAc)2/2a, it can be
seen that its enantioselectivity is generally high, but lower (ca.
D
1–7% ee) than the enantioselectivity of the catalyst Cu(OAc)2/1a.
The parallel modification of catalyst Cu(OAc)2/1b into Cu(OAc)2/2b
led to remarkable enhancement of enantioselectivity (ca.
D 15–29%
ee). Thus, the ee values (89–98 %) obtained with catalyst Cu
(OAc)2/2b were comparable with the high enantioselectivities of
complex Cu(OAc)2/1a for the Henry reaction. In general, the com-
plex Cu(OAc)2/1a can be considered to be a suitable catalyst for
the synthesis of 2-nitroethanols with an (R)-configuration via
Henry reaction, whereas complex Cu(OAc)2/2b can be used for syn-
thesis of 2-nitroethanols with an (S)-configuration.
Lastly, the possibility of recycling the heterogeneous forms of
catalysts 4a–b for the Henry reaction was studied. The preparation
of catalysts 4a–b included anchoring of ligands 1a–b on a poly-
meric carrier bearing chloromethyl groups. MerrifieldTM resin was
chosen, because it contains non-coordinating divinylbenzene (1%)
as the cross-linking agent.7 The immobilization procedure for
ligands 1a–b on a polymeric carrier was performed at room tem-
perature in DMSO in the presence of DBU as a base. The ligands
1a–b were used in slight excess (1.5 equiv) to achieve complete
anchoring on all reactive sites. The completion of the immobiliza-
tion was confirmed by analysis of the content of residual chlorine
in compounds 3a–b, which was found under limit of determina-
tion. The polymers 3a–b were characterized by elemental analysis
H2N
S
H
N
H
N
AcOH
S
S
+
H2N
+
N
N
N
CHO
n-BuOH
reflux
HN
N
1c (S): 16 %
1a (2R,5S): 47 %
1b (2S,5S): 34 %
Scheme 1. Preparation of ligand 1a–b and oxidized form 1c.
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009

G. Nováková et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
Henry reaction of nitromethane with various aldehydes catalyzed by Cu(OAc)2/1a and Cu(OAc)2/1b
O
OH
1a
1b
or
NO2
+
CH3NO2
R
H
R
Cu(OAc)2
Entry
Aldehyde R
1a
1b
Yielda (%)
eeb (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph
44
79
39
55
34
23
15
25
43
92
92
92
89
92
97
94
90
93
62
81
53
96
44
28
29
50
25
À73
À64
À72
À67
À71
À83
À81
À73
À83
2-CH3OC6H4
4-ClC6H4
4-NO2C6H4
4-PhC6H4
t-Bu
Thien-2-yl
Naphth-2-yl
PhCH2CH2
a
Reaction conditions: aldehyde: 0.5 mmol; nitromethane: 0.5 mL; catalyst: 5 mol %; temperature: 6 °C; solvent: iPrOH (1 mL); reaction time: 6 days.
The enantiomeric excess determined by HPLC using Chiralcel OD-H or Chiralpak AD-H.
b
N
r.t.
S
BnBr
N
2a
(2R,5S): 84 %
HN
H
N
2b (2S,5S): 69 %
DBU; MeOH
S
N
HN
Merrifield
resin
DMSO
r.t.
N
N
S
Cu(OAc)2
MeOH
1a
S
(2R,5S)
N
N
1b (2S,5S)
N
H
HN
Cu
AcO
r.t.
OAc
3a (2R,5S): 96 %
3b (2S,5S): 95 %
4a (2R,5S): 91 %
4b
(2S,5S): 84 %
Scheme 2. Preparation of ligands 2a–b and immobilized catalysts 4a–b.
Table 2
Henry reaction of nitromethane with various aldehydes catalyzed by Cu(OAc)2/2a and Cu(OAc)2/2b
O
OH
2a or 2b
NO2
+
CH3NO2
R
H
R
Cu(OAc)2
Entry
Aldehyde R
2a
2b
Yielda (%)
eeb (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph
98
98
99
99
98
99
91
98
99
84
83
88
82
88
96
85
85
92
98
99
99
99
98
99
93
98
99
À90
À93
À91
À89
À89
À98
À89
À90
À91
2-CH3OC6H4
4-ClC6H4
4-NO2C6H4
4-PhC6H4
t-Bu
Thien-2-yl
Naphth-2-yl
PhCH2CH2
a
Reaction conditions: aldehyde: 0.5 mmol; nitromethane: 0.5 mL; catalyst: 5 mol %; temperature: 6 °C; solvent: iPrOH (1 mL); reaction time: 6 days.
The enantiomeric excess determined by HPLC using Chiralcel OD-H or Chiralpak AD-H.
b
and IR spectroscopy. The disappearance of the band at 675 cmÀ1
belonging to the stretching vibration of ACACl in IR spectra also
indicated successful modification of the starting resin into com-
pounds 3a–b. Catalysts 4a–b were finally prepared by subsequent
coordination of copper(II) acetate on the immobilized ligands
in polymers 3a–b. The copper content in compounds 4a–b
(0.81 mmol/g for 4a and 0.68 mmol/g for 4b respectively) was
determined by means of atomic absorption spectroscopy.
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009

4
G. Nováková et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3. Conclusions
In conclusion, the 2-(pyridine-2-yl)imidazolidine-4-thione
derivatives 1a–b were prepared by condensation of starting
(S)-2-amino-2,3-dimethylbutanethioamide with pyridine-2-
carbaldehyde. The corresponding copper(II) complex of (2R,5S)-5-
isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-thione 1a
exhibited high enantioselectivity in asymmetric Henry reactions
(89–97% ee), whereas the complex of the (2S,5S)-isomer 1b was
less enantioselective (64–83% ee). The modification of the ligands
1a–b by the introduction of benzyl groups on sulfur atom afforded
ligands 2a–b, whose copper(II) complexes gave significantly higher
catalytic activity in the Henry reaction. Moreover, in the case of the
copper(II) complex of the (2S,5S)-isomer 2b, an increase in the
enantioselectivity (89–98% ee) was observed compared with the
copper(II) complex of the (2S,5S)-isomer 1b. The catalytic activity
and enantioselectivity of the catalysts 4a–b prepared by anchoring
of the corresponding ligands into swellable chloromethylated
MerrifieldTM resin with subsequent coordination of copper(II)
acetate were also studied. These immobilized complexes (hetero-
geneous catalysts) 4a–b were tested in the asymmetric Henry
reaction and showed high catalytic activity. They could also be
easily recycled, although their enantioselectivity was only moder-
ate (ꢀ50% ee) probably due to their lower stability in the reaction
media. Therefore the compounds 4a–b cannot be considered as
suitable recyclable catalysts for the asymmetric Henry reaction.
On the other hand, the homogeneous catalysts, the copper(II)
complexes of 2-(pyridine-2-yl)imidazolidine-4-thione derivative
1a and the benzylated form 2b, possess a high potential for asym-
metric Henry reactions.
Figure 1. The time dependence (h) of conversion (determined by 1H NMR
spectroscopy) for reaction of nitromethane with thiophene-2-carbaldehyde catal-
ysed by 5 mol % of Cu(OAc)2/1a (d) and Cu(OAc)2/2a (j) at 6 °C.
Compounds 4a–b were tested as recyclable heterogeneous
catalysts for Henry reaction. After separation of the catalyst from
the reaction mixture by means of simple filtration and its
washing, it was reused in the next reaction cycle. The Sheldon’s
filtration tests11 were performed with the negative results, which
indicated that the reaction completely stopped after the filtration
of the catalyst. When catalysts 4a–b were tested in the Henry
reaction of 2-methoxybenzaldehyde with nitromethane, it was
found that under the same reaction conditions used in the study
of catalysts 1–2, it gave quantitative chemical yields. Unfortu-
nately, an almost racemic product was obtained, due to either
epimerization or oxidation of catalysts 4a–b, which probably
took place during their purification in a Soxhlet extractor with
hot methanol for 24 h. Therefore, a new series of catalysts 4a–b
was prepared, which were purified by only multiple washing at
room temperature. The results of the application and recycling
of the newly prepared catalysts 4a–b in Henry reactions of
2-methoxybenzaldehyde with nitromethane are summarized in
Table 3.
4. Experimental
4.1. General
If not otherwise stated, the starting chemicals and solvents
were obtained from Sigma–Aldrich or Acros Organics and
used without further purification. (S)-Amino-2,3-dimethylbu-
tanethioamide was prepared according to the literature.7 1H NMR
spectra were recorded on a Bruker Avance 400 instrument. Chem-
ical shifts d are referenced to the residual peak of the MeOD-d4 at
3.31 ppm. The 13C NMR spectra were calibrated with respect to the
middle signal in the quintet of solvent (d = 49.0 ppm). The IR spec-
tra were measured at room temperature using Thermo Scientific
Nicolet iS50 FT-IR Spectrometer with ATR technique, the resolution
was 4 cmÀ1, FT-IR data are presented in cmÀ1. The microanalyses
were performed on an apparatus of FISONS Instruments, EA 1108
CHNS. The determination of Cu was carried out with an Avanta P
double beam atomic absorption spectrometer (GBC Scientific
Equipment Pty. Ltd, Australia) in the flame atomization mode.
Microwave digestion of samples was carried out in the Speed-
waveTM MWS-3+ (Berghof, Germany) microwave system with the
maximum total output of the microwave generator 1450 W. The
quantification of the Cu concentrations was performed by estab-
lishing the calibration curve by linear regression. The optical
rotation was measured on a Perkin–Elmer 341 instrument; the
concentration c is given in g/100 mL. High-resolution mass spectra
were measured on the Thermo Fisher Scientific MALDI LTQ Orbi-
trap instrument. The used matrix was 0.2 M solution of 2,5-dihy-
droxybenzoic acid (DHB) in MeCN/H2O (95:5). HPLC analyses
were performed on Watrex HPLC instrument with UV–Vis DAD
(200–800 nm) SYKAM 3240 and with chiral Daicel columns:
Chiralcel OD-H and Chiralpak AD-H (250 mm  4.6 mm).
From the ee values obtained in the first reaction cycle (64% ee
resp. 59% ee) it can be seen that the catalysts 4a–b exhibited
significantly lower enantioselectivity than the homogeneous
variants of the catalysts, Cu(OAc)2/2a and Cu(OAc)2/2b. A further
decrease in enantioselectivity was observed in each subsequent
reaction cycle (ca.
D 2–3% ee). From this point of view, an unfa-
vourable process leading to modification of the ligand structure
took place during the Henry reaction: either epimerization of 4a
into 4b and vice versa, or their oxidation into the 4-sulfanylimida-
zole derivative. In order to protect the ligands attached to the
polymers 4a–b against oxidation, we used inert conditions for
the Henry reaction as well as for the preparation of the catalysts
4a–b. Nevertheless, these series of the catalysts 4a–b together with
the changed reaction conditions in this way also afforded
unsatisfactory results (Table 3).
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009

G. Nováková et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 3
Henry reaction of nitromethane with 2-methoxybenzaldehyde catalyzed by immobilized catalyst 4a and 4b
O
OH
NO2
CH3NO2; iPrOH
H
4a or 4b (5 mol %)
OCH3
OCH3
Cat. Cycle
4a
4b
Yielda (%)
eeb (%)
Yielda (%)
eeb (%)
1st
97
97
92
92
55
84
76
74
64
63
60
58
48
58
62
50
96
92
85
80
59
86
71
70
À59
À51
À48
À45
À42
À40
À37
À38
2nd
3rd
4th
5th
1stc
2ndc
3rdc
a
b
c
Reaction conditions: aldehyde: 0.5 mmol; nitromethane: 0.5 mL; catalyst: 5 mol %; temperature: 6 °C; solvent: iPrOH (1 mL); reaction time: 6 days.
The enantiomeric excess determined by HPLC using Chiralcel OD-H.
The reactions were performed under argon atmosphere with the catalysts prepared under inert conditions.
4.2. Synthesis
J = 3.2 Hz, Py), 8.26 (d, 1H, J = 8.0 Hz, Py), 8.00 (m, 1H, Py), 7.60
(m, 1H, Py), 2.20 (sp, 1H, J = 6.8 Hz, CH-iPr), 1.44 (s, 3H, Me), 1.17
(d, 3H, J = 6.8 Hz, CH3-iPr), 0.67 (d, 3H, J = 6.8 Hz, CH3-iPr); 13C
NMR (100 MHz, MeOD-d4): d 222.9, 161.7, 150.9, 147.6, 138.7,
127.7, 123.5, 90.2, 39.0, 25.7, 17.5, 16.9; Anal. Calcd for
4.2.1. 5-Isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-
thiones 1a and 1b
A solution of (S)-amino-2,3-dimethylbutanethioamide (439 mg;
3 mmol), pyridine-2-carbaldehyde (482 mg; 4.5 mmol) and three
drops of acetic acid in n-butanol was stirred at 100 °C for 5 h.
The solvent was evaporated under reduced pressure and the resi-
due was treated with CH2Cl2 (10 mL). The mixture was washed
with a saturated aqueous solution of NaKCO3 (10 mL) and the
organic layer was dried over Na2SO4. After evaporation of solvent,
a mixture of diastereomers 1a–b and an oxidized form 1c was
separated by column chromatography [SiO2/acetone/CH2Cl2 (1:3),
(v/v)].
C12H15N3S (233.33): C, 61.77; H, 6.48; N, 18.01; S, 13.74. Found:
C, 61.63; H, 6.71; N, 17.86; S, 13.47. HR-MALDI-MS (DHB): calcd
for C12H15N3S m/z 234.10147 ([M+H]+), found 234.10594.
4.2.2. 4-Benzylsulfanyl-5-isopropyl-5-methyl-2-(pyridine-2-yl)
imidazolines 2a and 2b
A
solution of imidazolidine-4-thione derivative 1a or 1b
(180 mg; 0.81 mmol), benzyl bromide (138 mg; 0.81 mmol) and
DBU (246 mg; 1.62 mmol) in methanol (3 mL) was stirred at room
temperature for 5 days under an argon atmosphere. After evapora-
tion of the solvent under reduced pressure, the crude product was
purified by column chromatography [SiO2/n-hexane/AcOEt (1:2),
(v/v)].
4.2.1.1. (2R,5S)-5-Isopropyl-5-methyl-2-(pyridine-2-yl)imidazo-
20
lidine-4-thione 1a.
Yield: 47%; yellow oil; Rf 0.51; [
a]
=
D
+10.5 (c 0.90, CH3OH); 1H NMR (400 MHz, MeOD-d4): d 8.59 (d,
1H, J = 4.8 Hz, Py), 7.88 (m, 1H, Py), 7.54 (d, 1H, J = 8.0 Hz, Py),
7.41 (m, 1H, Py), 5.65 (s, 1H, NCHN), 2.17 (sp, 1H, J = 6.8 Hz, CH-
iPr), 1.44 (s, 3H, Me), 1.05 (d, 3H, J = 6.8 Hz, CH3-iPr), 1.01 (d, 3H,
4.2.2.1. (2R,5S)-4-Benzylsulfanyl-5-isopropyl-5-methyl-2-(pyri-
dine-2-yl)imidazoline 2a.
Yield: 84%; yellow oil; Rf 0.47
J = 6.8 Hz, CH3-iPr); 13C NMR (100 MHz, MeOD-d4):
d
210.9,
[a
]
D
20 = À13.8 (c 0.80, CH3OH); 1H NMR (400 MHz, MeOD-d4): d
158.6, 150.5, 139.0, 125.5, 123.6, 79.6, 78.0, 38.0, 27.2, 18.1, 16.8;
Anal. Calcd for C12H17N3S (235.35): C, 61.24; H, 7.28; N, 17.85; S,
13.62. Found: C, 61.56; H, 7.54; N, 17.62; S, 13.28. HR-MALDI-MS
(DHB): calcd for
236.12177.
8.55 (d, 1H, J = 4.8 Hz, Py), 7.83 (m, 1H, Py), 7.47 (d, 1H,
J = 8.0 Hz, Py), 7.37 (m, 3H, Py+Ph), 7.24 (m, 3H, Ph), 5.83 (s, 1H,
NCHN), 4.28 (2Â d, 2H, J = 13.2 Hz, CH2Ph), 1.85 (sp, 1H,
J = 6.8 Hz, CH-iPr), 1.38 (s, 3H, Me), 1.01 (d, 3H, J = 6.8 Hz,
CH3-iPr), 0.92 (d, 3H, J = 6.8 Hz, CH3-iPr); 13C NMR (100 MHz,
MeOD-d4): d 180.1, 160.5, 149.8, 138.7, 138.6, 130.1, 129.5,
128.4, 124.7, 123.8, 91.5, 78.8, 37.3, 36.1, 25.6, 18.0, 17.0; Anal.
Calcd for C19H23N3S (325.47): C, 70.12; H, 7.12; N, 12.91; S, 9.85.
Found: C, 69.94; H, 7.32; N, 12.63; S, 9.55. HR-MALDI-MS (DHB):
calcd for C19H23N3S m/z 326.16854 ([M+H]+), found 326.16922.
C
12H17N3S m/z 236.12159 ([M+H]+), found
4.2.1.2. (2S,5S)-5-Isopropyl-5-methyl-2-(pyridine-2-yl)imidazo-
lidine-4-thione 1b.
Yield: 34%; yellow oil; Rf 0.40;
[
a]
D
20 = À58.0 (c 0.70, CH3OH); 1H NMR (400 MHz, MeOD-d4): d
8.59 (d, 1H, J = 4.8 Hz, Py), 7.89 (m, 1H, Py), 7.61 (d, 1H,
J = 8.0 Hz, Py), 7.42 (m, 1H, Py), 5.72 (s, 1H, NCHN), 2.33 (sp, 1H,
J = 6.8 Hz, CH-iPr), 1.40 (s, 3H, Me), 1.03 (d, 3H, J = 6.8 Hz,
CH3-iPr), 0.97 (d, 3H, J = 6.8 Hz, CH3-iPr); 13C NMR (100 MHz,
MeOD-d4): d 210.9, 158.0, 150.3, 138.9, 125.6, 123.8, 77.4, 77.0,
35.8, 24.8, 18.3, 17.0; Anal. Calcd for C12H17N3S (235.35): C,
61.24; H, 7.28; N, 17.85; S, 13.62. Found: C, 61.09; H, 7.34; N,
17.72; S, 13.61 HR-MALDI-MS (DHB): calcd for C12H17N3S m/z
236.12159 ([M+H]+), found 236.12164.
4.2.2.2. (2S,5S)-4-Benzylsulfanyl-5-isopropyl-5-methyl-2-(pyri-
dine-2-yl)imidazoline 2b.
Yield: 69%; yellow oil; Rf 0.28
[a
]
D
20 = À19.6 (c 0.63, CH3OH); 1H NMR (400 MHz, MeOD-d4): d
8.55 (d, 1H, J = 4.9 Hz, Py), 7.86 (m, 1H, Py), 7.57 (d, 1H,
J = 7.6 Hz, Py), 7.40–7.32 (m, 3H, Py+Ph), 7.29–7.21 (m, 3H, Ph),
5.86 (s, 1H, NCHN), 4.29 (2Â d, 2H, J = 13.2 Hz, CH2Ph), 1.96 (sp,
1H, J = 6.8 Hz, CH-iPr), 1.34 (s, 3H, Me), 1.02 (d, 3H, J = 6.8 Hz,
CH3-iPr), 0.89 (d, 3H, J = 6.8 Hz, CH3-iPr); 13C NMR (100 MHz,
MeOD-d4): d 180.7, 160.1, 149.9, 138.7, 138.7, 130.2, 129.6,
128.5, 124.9, 124.3, 88.7, 78.4, 36.2, 35.2, 24.0, 18.6, 17.5; Anal.
Calcd for C19H23N3S (325.47): C, 70.12; H, 7.12; N, 12.91; S, 9.85.
4.2.1.3. (S)-5-Isopropyl-5-methyl-2-(pyridine-2-yl)imidazoline-
4-thione 1c.
Yield: 16%; yellow oil; Rf 0.63; [
a]
20 = À53.3 (c
D
0.70, CH3OH); 1H NMR (400 MHz, MeOD-d4): d 8.74 (d, 1H,
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009

6
G. Nováková et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Williams, J. M. J. Catalysis in Asymmetric Synthesis; John Wiley & Sons: Oxford,
2009; (d) Drabina, P.; Harmand, L.; Sedlák, M. Curr. Org. Synth. 2014, 11, 879–
888; (e) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry
2006, 17, 3315–3326; (f) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2007, 2561–2574; (g) Luzzio, F. A. Tetrahedron 2001, 57, 915–945; (h) Alvarez-
Casao, Y.; Marques-Lopez, E.; Herrera, R. P. Symmetry 2011, 3, 220–245; (i)
Palomo, C.; Oirbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444;
(j) Blay, G.; Hernández-Olmos, V.; Pedro, J. R. Synlett 2011, 1195–1211; (k)
Milner, S. E.; Moody, T. S.; Maguire, A. R. Eur. J. Org. Chem. 2012, 3059–3067; (l)
Found: C, 70.13; H, 7.35; N, 12.81; S, 9.63. HR-MALDI-MS (DHB):
calcd for C19H23N3S m/z 326.16854 ([M+H]+), found 326.16931.
4.2.3. General procedure for the preparation of immobilized
ligands 3a and 3b
A
solution of imidazolidine-4-thione derivative 1a or 1b
(220 mg; 0.94 mmol), DBU (288 mg; 1.88 mmol) and NaI (7 mg;
0.05 mmol) in dry DMSO (4 mL) was mixed with MerrifieldTM resin
(0.63 mmol, calculated from Cl content) at room temperature
under argon atmosphere. The suspension was filtered after 7 days.
The resin was washed with methanol (10 Â 5 mL) and dried under
vacuum.
Ananthi, N.; Velmathi, S. Indian J. Chem., Sect.
B 2013, 52, 87–108; (m)
Murugavel, G.; Sadhu, P.; Punniyamurthy, T. Chem. Rec. 2016, 16, 1906–1917.
2. For example: (a) Selvakumar, S.; Sivasankaran, D.; Singh, V. K. Org. Biomol.
Chem. 2009, 7, 3156–3162; (b) Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org.
Chem. 2011, 76, 588–600; (c) Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem.
2011, 76, 588–600; (d) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett.
2002, 4, 2621–2623; (e) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Appl.
Organomet. Chem. 1995, 9, 421–426; (f) Sasai, H.; Yamada, Y. M. A.; Suzuki, T.;
Shibasaki, M. Tetrahedron 1994, 50, 12313–12318; (g) Guo, Z. L.; Deng, Y. Q.;
Zhong, S.; Lu, G. Tetrahedron: Asymmetry 2011, 22, 1395–1399; (h) Panov, I.;
Drabina, P.; Hanusek, J.; Sedlák, M. Synlett 2013, 1280–1282; (i) Uraguchi, D.;
Nakamura, S.; Ooi, T. Angew. Chem., Int. Ed. 2010, 49, 7562–7565; (j) Xu, K.; Lai,
G.; Zha, Z.; Pan, S.; Chen, H.; Wang, Z. Chem. Eur. J. 2012, 18, 12357–12362; (k)
Piccionello, A. P.; Pierro, P.; Accardo, A.; Buscemi, S.; Pace, A. RSC Adv. 2013, 3,
24946–24951; (l) Qin, D. D.; Yu, W.; Zhou, J. D.; Zhan, Y. C.; Ruan, Y. P.; Zhou, Z.
H.; Chen, H. B. Chem. Eur. J. 2013, 19, 16541–16544; (m) Rossi, S.; Benaglia, M.;
Porta, R.; Cotarca, L.; Maragni, P.; Verzini, M. Eur. J. Org. Chem. 2015, 2531–
2537.
4.2.3.1. Immobilized ligand 3a.
position: C, 76.93; H, 7.67; N, 6.62; S, 3.62; FT-IR: 3304, 2964,
2872, 1588, 1473, 1371, 1076, 1047 cmÀ1
Yield: 96%; elemental com-
.
4.2.3.2. Immobilized ligand 3b.
position: C, 76.66; H, 7.62; N, 6.30; S, 3.36; FT-IR: 3304, 2964,
2872, 1588, 1473, 1371, 1076, 1047 cmÀ1
Yield: 95%; elemental com-
.
3. Some selected papers: (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.;
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693; (b)
Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222–2223; (c)
Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4875–4881; (d) Risgaard, T.; Gothelf, K. V.; Jørgensen, K. A. Org. Biomol. Chem.
2003, 1, 153–156; (e) Rassapan, R.; Olbrich, T.; Reiser, O. Adv. Synth. Catal. 2009,
351, 1961–1967; (f) Lang, K.; Park, J.; Hong, S. J. Org. Chem. 2010, 75, 6424–
6435; (g) Reddy, B. V. S.; George, J. Tetrahedron: Asymmetry 2011, 22, 1169–
1175; (h) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561–
3651; (i) Cruz, H.; Aguirre, G.; Madrigal, D.; Chávez, D.; Somanathan, R.
Tetrahederon: Asymmetry 2016, 27, 1217–1221.
4.2.4. General procedure for preparation of heterogeneous
catalyst 4a and 4b
A solution of copper(II) acetate (120 mg; 0.66 mmol) in metha-
nol (12 mL) was mixed with polymer 3a or 3b (220 mg) at room
temperature under argon atmosphere. The suspension was filtered
after 24 h, the catalyst was washed with methanol (10 Â 5 mL) and
dried under vacuum.
4. Some selected papers: (a) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.;
Yanagisawa, A. Angew. Chem., Int. Ed. 2006, 45, 5978–5981; (b) Arai, T.;
Watanabe, M.; Yanagasiwa, A. Org. Lett. 2007, 9, 3595–3597; (c) Arai, T.;
Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008, 73,
4903–4906; (d) Arai, T.; Joko, A.; Sato, K. Synlett 2015, 209–214; (e) Bandini,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem. Commun.
2007, 616–618; (f) Chougnet, A.; Zhang, G.; Liu, K.; Haussinger, D.; Kagi, A.;
Allmendinger, T.; Woggon, W. D. Adv. Synth. Catal. 2011, 353, 1797–1806; (g)
Maheswaran, H.; Prasanth, K. L.; Krishna, G. C.; Ravikumar, K.; Sridhar, B.;
Kantam, M. L. Chem. Commun. 2006, 4066–4068; (h) Zhou, Y.; Gong, Y. Eur. J.
Org. Chem. 2011, 6092–6099; (i) Sanjeevakumar, N.; Periasamy, M. Tetrahedron:
Asymmetry 2009, 20, 1842–1847; (j) Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.;
Kanger, T. J. Org. Chem. 2010, 75, 1313–1316.
4.2.4.1. Catalyst 4a.
65.13; H, 6.46; N, 4.92; S, 2.87; Cu, 5.14; FT-IR: 3299, 2963,
2874, 1584, 1565, 1473, 1372, 1076, 1047 cmÀ1
Yield: 91%; elemental composition: C,
.
4.2.4.2. Catalyst 4b.
70.42; H, 7.01; N, 4.73; S, 2.42; Cu, 4.34; FT-IR: 3299, 2963,
2874, 1584, 1565, 1473, 1372, 1076, 1047 cmÀ1
Yield: 84%; elemental composition: C,
.
4.3. General procedure for the asymmetric Henry reaction
5. Some selected papers: (a) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M.-M.
Tetrahedron: Asymmetry 2006, 17, 725–728; (b) Gan, C. Can. J. Chem. 2008, 86,
261–263; (c) Lai, G.; Wang, S.; Wang, Z. Tetrahedron: Asymmetry 2008, 19,
1813–1819; (d) Ananthi, N.; Balakrishnan, U.; Velmathi, S. ARKIVOC 2010, xi,
370–379; (e) Boobalan, R.; Lee, G. H.; Chen, C. Adv. Synth. Catal. 2012, 354,
2511–2520; (f) Yao, L.; Wei, Y.; Wang, P.; He, W.; Zhang, S. Tetrahedron 2012,
68, 9119–9124; (g) Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Chen, J.-R.; Xiao, W.-J.
Chem. Commun. 2012, 5596–5598; (h) Qiang, G.-R.; Shen, T.-H.; Zhou, X.-C.; An,
X.-X.; Song, Q.-B. Chirality 2014, 26, 780–783; (i) Boobalan, R.; Chang, Y.-M.;
Chen, C.; Lee, G.-H. ChemSelect 2016, 1, 2028–2034.
A mixture of ligand 1a–c, 2a or 2b (27.5
lmol) and copper(II)
acetate (4.5 mg, 25 mol) or catalyst 4a–b (5 mol %) and nitro-
l
methane (0.5 mL; 10 mmol) in dry isopropyl alcohol (1 mL) was
stirred for 1 h at room temperature. The mixture was cooled to
6 °C, after which aldehyde (0.5 mmol) was added and the mixture
was stirred for 6 days. The catalyst was removed by flash
chromatography using AcOEt (for homogeneous catalysts) or by
filtration (for heterogeneous catalysts) and washed with AcOEt
(4 Â 5 mL). The solvents were evaporated under reduced pressure
and the residue was purified by column chromatography
[SiO2/n-hexane/AcOEt (1:3), (v/v)]. The enantiomeric excess was
determined by HPLC. The characterization data for all enantiomers
of 2-nitroethanols were in accordance with data published
previously.2–7
ˇ
6. (a) Panov, I.; Drabina, P.; Padelková, Z.; Šimu˚ nek, P.; Sedlák, M. J. Org. Chem.
2011, 76, 4787–4793; (b) Drabina, P.; Karel, S.; Panov, I. Tetrahedron:
ˇ
Asymmetry 2013, 24, 334–339; (c) Bhosale, D. S.; Drabina, P.; Palarcík, J.;
Hanusek, J. Tetrahedron: Asymmetry 2014, 25, 334–339; (d) Drabina, P.;
ˇ ˇ
Horáková, E.; Ru˚ zicková, Z. Tetrahedron: Asymmetry 2015, 26, 141–147; (e)
Harmand, L.; Drabina, P.; Pejchal, V.; Husáková, L.; Sedlák, M. Tetrahedron Lett.
ˇ
2015, 56, 6240–6243; (f) Bhosale, D. S.; Drabina, P.; Kincl, M.; Vlcek, M.
Tetrahedron: Asymmetry 2015, 26, 1300–1306.
7. Nováková, G.; Drabina, P.; Frumarová, B.; Sedlák, M. Adv. Synth. Catal. 2016, 358,
2541–2552.
8. Samulis, L.; Tomkinson, N. C. O. Tetrahedron 2011, 67, 4263–4267.
Acknowledgment
ˇ
˚ ˇ ˇ
9. (a) Sedlák, M.; Drabina, P.; Keder, R.; Hanusek, J.; Císarová, I.; Ruzicka, A. J.
Organomet. Chem. 2006, 691, 2623–2630; (b) Keder, R.; Drabina, P.; Hanusek, J.;
Sedlák, M. Chem. Pap. 2006, 60, 324–326; (c) Drabina, P.; Valenta, P.; Jansa, P.;
The authors acknowledge the financial support from the Project
ˇ
GACR 17-08499S.
ˇ ˇ
Ru˚ zicka, A.; Hanusek, J.; Sedlák, M. Polyhedron 2008, 27, 268–274.
10. (a) Maggi, R.; Lanari, D.; Oro, C.; Sartori, G.; Vaccaro, L. Eur. J. Org. Chem. 2011,
5551–5554; (b) Evans, D. A.; Woerpel, K. A.; Scott, M. J. Angew. Chem., Int. Ed.
References
ˇ ˇ
Engl. 1992, 31, 430–432; (c) Drabina, P.; Funk, P.; Ru˚ zicka, A.; Moncol, J.; Sedlák,
M. Polyhedron 2012, 34, 31–40.
11. Lempers, H. E. B.; Sheldon, R. A. J. Catal. 1998, 175, 62–69.
1. (a)Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH:
Weinheim, 2011; (b)New Frontiers in Asymmetric Catalysis; Mikami, K.,
Lautens, M., Eds.; John Wiley
& Sons: New Jersey, 2007; (c) Caprio, V.;
Please cite this article in press as: Nováková, G.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.009