Novel nitrogen ligands based on imidazole derivatives and their application in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2006.03.005

Recently prepared chiral amines have been used in the preparation of novel tridentate ligands based on an imidazole ring with an additional (hetero)ring. The synthesis was carried out by the reaction of chiral amines with suitable aldehydes (2-phenylimida

Full text of DOI:10.1016/j.tetasy.2006.03.005

Tetrahedron: Asymmetry 17 (2006) 900–907
Novel nitrogen ligands based on imidazole derivatives and
their application in asymmetric catalysis
a,
a
a
a
*
Filip Bure sˇ , Tom a´ sˇ Szotkowski, Ji rˇ ´ı Kulh a´ nek, Old rˇ ich Pytela,
a
b
Miroslav Ludwig and Michal Hol cˇ apek
a
ˇ
Department of Organic Chemistry, University of Pardubice, n a´ m. Cs. Legi ı´ 565, Pardubice 53210, Czech Republic
b
ˇ
Department of Analytical Chemistry, University of Pardubice, n a´ m. Cs. Legi ı´ 565, Pardubice 53210, Czech Republic
Received 16 December 2005; accepted 6 March 2006
Available online 4 April 2006
Abstract—Recently prepared chiral amines have been used in the preparation of novel tridentate ligands based on an imidazole ring with
an additional (hetero)ring. The synthesis was carried out by the reaction of chiral amines with suitable aldehydes (2-phenylimidazole-4-
carbaldehyde, 2-hydroxybenzaldehyde or pyridine-2-carbaldehyde) under reductive conditions (H /Pd or NaBH ). All ligands prepared
2
4
6
showed strong hydrogen bonds in d -DMSO solution, which resulted in hindered imidazole tautomerism. The observed hindered tau-
1
tomerism was studied by H NMR spectroscopy. The structures of the prepared ligands were also confirmed by APCI mass spectro-
scopy. Both chiral amines and tridentate compounds have been applied as ligands in copper (II)-catalyzed nitroaldol reactions
(
Henry reaction). Various reaction conditions for the Henry reaction have been studied (influence of temperature, molar ratio, solvent
or copper (II) precursors). The compounds prepared with the two imidazole rings showed fast reaction times and a reversal in enantio-
selectivity compared to other chiral amines.
ꢀ
2006 Elsevier Ltd. All rights reserved.
2
1. Introduction
The nitroaldol reaction (Henry reaction ) is one of the oldest
carbon–carbon bond forming reactions in organic synthesis.
1
3,4
Recently we have published the synthesis of chiral deriva-
tives of 2-fenylimidazole (Scheme 1) by the condensation of
a-bromoketones with benzamidine in the solvent/base sys-
tem THF/water/K CO . The application of the resulting
It has been shown that five-membered heterocycles, gua-
5
,6
nidine-based compounds or amino alcohols promoted
7
–9
by diethylzinc, can be used as ligands in the copper-cata-
lyzed modification of this reaction. The reaction provides 2-
nitroalcohols as products, which are versatile building
blocks and intermediates in organic synthesis.
2
3
amines as heterocyclic chiral intermediates in further
organic syntheses or in asymmetric catalyzed reactions is
currently of interest.
Novel tridentate ligands with two heterocyclic rings have
been proposed and synthesized as suitable ligands (Scheme
2
). The synthesis starts from the previously prepared chiral
R
NH2
amines that were condensed with aromatic aldehydes. Iso-
lation of the formed imine intermediates was unsuccessful
and therefore the imines were reduced directly. The reduc-
tion was carried out by hydrogen in the presence of a pal-
1
1
1
a – CH3- (S)
b – CH3- (R)
c – (CH3)2CH- (S)
N
HN
1d – (CH ) CHCH - (S)
3
2
2
1
e – CH3CH2CH(CH3)- (S)
10
11
ladium catalyst or by using sodium borohydride.
Ph
1
f – PhCH2- (S)
1
Scheme 1. Chiral amines.
2. Results and discussion
*
Corresponding author. Tel.: +420 4660 37018; fax: +420 4660 37068;
e-mail: filip.bures@upce.cz
The tridentate ligand synthesis is a simple reductive amina-
tion. The commercially available products have been used
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.005

F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
901
OHC
N
NH
R
R
Ph
N
H
HN
Ph
NH
Ph
H2/Pd/MeOH
N
N
2
3
N
N
CHO
N
R
NH2
N
H
HN
Ph
N
HN
Na SO /MeOH/NaBH
2
4
4
Ph
CHO
1
HO
R
N
H
HN
Ph
4
N
H2/Pd/MeOH
HO
Scheme 2. Tridentate ligand synthesis.
1
as suitable aldehydes (2-hydroxybenzaldehyde or pyridine-
-carbaldehyde). 2-Phenylimidazole-4-carbaldehyde was
prepared from dihydroxyacetone following the literature
procedure. The first and the last aldehydes named above
were condensed with chiral amines in the presence of
hydrogen (Method A). Reductive amination under hydro-
genation conditions was unsuccessful in the case of pyri-
dine-2-carbaldehyde. Hence, the reaction was carried out
in methanol in the presence of a drying agent (sodium sul-
fate) and completed by reduction with sodium borohydride
tions. Figure 1 depicts the dependence of the H NMR
2
spectra on temperature (ligand 2b). At 300 K, nearly four
broad signals of imidazole hydrogens (H-6,7) are visible
in the aromatic area (6.8–7.1 ppm). At 350 K, the
NMR spectrum was recorded with estimated spin–spin
interactions due to a restored fast proton exchange. There
are only two broader signals of the imidazole hydrogens
(H-6,7) visible. The hindered imidazole tautomerism was
not observed if the sample was measured in deuterated
1
2
1
H
1
13
methanol (see Fig. 2, ligand 2b). Hence, the H and
C
(
Method B). Method A provided better yields than method
NMR spectra listed in Experimental were measured in
B. Some of the properties of the compounds prepared are
summarized in Table 1.
CD OD.
3
The nitroaldol Henry reaction (Scheme 3) was chosen as a
model reaction for an enantioselectivity test of the pre-
pared compounds, and chiral amines as well as tridentate
ligands were tested. The catalysts were prepared in situ
by stirring a copper (II) precursor with the chiral ligands
and then nitromethane after which the aldehyde was
added. The reaction was followed by TLC. The yields,
reaction times and the enantiomeric excesses obtained are
reported in Tables 2 and 3. All reactions were carried
out in a Teflon coated flask using copper (II) complex
catalysis to minimize the formation of styrene derivatives
Table 1. Properties of tridentate ligands (see Scheme 2)
2
D
0
Ligand Structure (R)
Yield mp
%) (ꢁC)
Configuration=½aꢀ
3
(
(c 0.5, CH OH)
2
2
2
2
3
3
3
4
a
b
c
CH
(CH
(CH
PhCH
(CH
(CH
3
–
87
89
88
78
62
65
69
60
110–112 (S)/ꢁ43.0
119–120 (S)/ꢁ66.2
120–121 (S)/ꢁ30.8
118–119 (S)/ꢁ10.0
3
)
2
CH–
3
)
2
CHCH
2
–
d
a
b
c
2
–
3
)
)
2
CH–
CHCH
67–69
67–68
60–61
(S)/ꢁ49.8
(S)/ꢁ29.4
(S)/+34.0
3
2
2
–
–
PhCH
(CH
2
–
(Table 2, compare with entry 2.1). There have been some
3
)
2
CHCH
2
160–162 (S)/ꢁ28.0
changes of the reaction conditions and we made several
observations. Decreasing the temperature resulted in a
longer reaction time with a small effect on ee (Table 2, en-
try 2.9). Replacement of the ethanol by THF resulted in a
lower yield and ee (Table 2, entry 2.12). Preparation of the
catalyst in a 2:1 ratio (ligand:precursor) and a change of
the nitromethane concentration did not cause any signifi-
cant changes (Table 2, entries 2.11 and 2.13). Application
of copper (II) chloride as metal precursor and an external
base (triethylamine) under standard reaction conditions
were carried out as well (Table 2, entry 2.18). Application
of copper (II) benzoate provided sufficient yield (moderate
reaction time) but higher enantiomeric excess (Table 2,
The NMR structural analyses of the tridentate ligands
showed the presence of strong hydrogen bonds in
d -DMSO solution, which resulted in hindered imidazole
6
1
13
tautomerism. H and C spectra showing broad signals
without estimated spin–spin interactions were obtained.
The strong hydrogen bonds and hindered imidazole
tautomerism were observed for each prepared compound,
independent of the sample concentration, pH value or
addition of water into the sample. The hindered imidazole
tautomerism disappeared under high temperature condi-

902
F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
1
Figure 1. Dependence of H NMR spectrum on temperature—ligand 2b (d
6
-DMSO).
entry 2.15). A very quick reaction time was achieved by
using copper (II) 4-methoxybenzoate as a metal precursor
and weaker fixed anions showed longer reaction times,
and hence the probability of a nitroaldol condensation in
the solution instead of on the active chiral catalyst is high-
er. The attained enantiomeric excesses obtained are then
lower.
(
(
Table 2, entry 2.17). On the other hand, the use of copper
II) 4-nitrobenzoate resulted in a longer reaction time,
poor yield and ee (Table 2, entry 2.16). In general, the
Henry reaction can be catalyzed or promoted by many dif-
ferent sets of conditions or catalysts, but the most fre-
Tridentate ligands with two imidazole rings 2a, 2b, 2c and
2d showed fast reaction times and moderate enantiomeric
excesses using copper (II) acetate as a metal precursor
(Table 3, entries 3.1–3.4). The application of copper (II)
4-methoxybenzoate (Table 3, entry 3.5) caused a decrease
in reaction time, similar to that observed in the case of
ligands 1. The nitrogen ligands based on the imidazole ring
are stronger bases than the frequently published bisoxaline
1
3
quently used are organic bases. The electron rich 4-
methoxybenzoate (pK of 4-methoxybenzoic acid in etha-
a
1
4
nol is 10.61) is a stronger base than 4-nitrobenzoate
pK of 4-nitrobenzoic acid in ethanol is 8.91) and, there-
1
4
(
a
fore, the deprotonation of nitromethane proceeds more
easily. The analogous observation may be seen from the
comparison of acetate and electron poor trifluoroacetate
anions (Table 2, see entries 2.7 and 2.14). The application
of trifluoroacetate anion showed a long reaction time with
low conversion and ee. The formation of 1-(4-nitrophenyl)-
3
,4
derivatives and this fact furthermore facilitates deproto-
nation of nitromethane. For these reasons, the application
of the electron rich copper (II) 4-methoxybenzoate and
tridentate ligand 2d, with a bulky benzyl group as the
2
-nitroethene has also been observed. The electron poor

F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
903
1
Figure 2. H NMR spectrum—ligand 2b (CD
3
OD).
NO2
moiety, where the reversed enantioselectivity has not been
observed. Unfortunately, the preparation of a suitable sin-
gle crystal of ligands or copper (II) complex proved difficult
and therefore X-ray analysis failed.
CH3NO2
CHO
EtOH/Cu2+ catalyst
R1
R1
OH
Scheme 3. Henry reaction.
3. Conclusion
substituent R, seems to be the most powerful combination
fast reaction time and the highest ee attained). These
Recently prepared chiral amines have been applied as a
starting material for tridentate ligands synthesis. The
reductive amination was carried out using catalytic hydro-
genation or reduction with sodium borohydride. All novel
(
findings are in agreement with the reaction mechanism pro-
3
posed by Evans et al.
1
13
compounds prepared have been characterized by H,
C
Although the absolute configuration of all chiral ligand
prepared is (S) (except for 1b), the tridentate ligands 2
and 3 showed a reversed enantioselectivity in the Henry
reaction compared to the chiral amines 1. According to
NMR and APCI mass spectroscopy. Tridentate ligands
showed strong hydrogen bonds, which resulted in hindered
tautomerism if measured in dimethylsulfoxide. The mea-
surements in deuterated methanol provided spectra with
estimated spin–spin interactions.
3
the reaction mechanism proposed by Evans et al., the
coordination and deprotonation of nitromethane occurs
before the coordination of the aldehyde. In the case of tri-
dentate ligands 2 and 3, the second (hetero)ring may dis-
criminate the addition of the aldehyde from the same side
as in the case of ligands 1 and, therefore enantioselective
reversal was observed. Other feasible explanation of the
reversal of enantioselectivity could be due to another kind
of complexation—coordination of copper to the second
All compounds prepared have been tested as ligands in the
copper (II) catalyzed Henry reaction. The best results were
achieved by using chiral amines (Table 2, entry 2.21) or tri-
dentate ligands (Table 3, entry 3.5) with the bulky benzyl
group as the R substituent and copper (II) 4-methoxy-
benzoate as a metal precursor. Increasing bulkiness of the
substituent R and the anion used resulted in increasing
ee. Electron rich copper (II) 4-methoxybenzoate has been
shown as the anion of choice (fast reaction times and
higher ee). Conversely by using electron poor copper (II)
4-nitrobenzoate or trifluoracetate resulted in a longer reac-
tion time and poor ee. The most frequently used copper (II)
acetate showed moderate yields and enantiomeric excesses.
(
hetero)ring and another complex formation. This supposi-
tion supports the application of a chiral amine with an
additional pyrrolidine ring [Table 2, entry 2.22, prepared
1
from (S)-proline ], where the reversed enantioselectivity
has been observed as well. This is also supported by triden-
tate ligand 4 (Table 3, entry 3.9) with a hydroxyphenyl

904
F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
Table 2. Henry reaction (chiral amines as ligands 1—see Schemes 1 and 3)
2
D
5
a
Entry
Aldehydes (R
1
)
Ligand
Time (h)
Yield (%)
½aꢀ (c 1, CH
—
2
Cl
2
)
Configuration/ee (%)
b
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
.1
.2
.3
.4
.5
.6
.7
.8
.9
4-NO
4-NO
4-NO
4-NO
4-NO
H
2
2
2
2
2
—
—
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1e
1f
72
144
12
12
12
24
13
24
48
48
22
24
24
120
48
240
2.5
24
14
14
3
98
52
92
93
96
68
97
0
94
91
91
75
84
32
88
48
97
94
94
91
95
—
c
0.0
(R,S)/0.0
(R)/9.8
(S)/10.6
(R)/12.8
(R)/6.3
(R)/12.1
—
(R)/13.9
(R)/9.4
(R)/10.4
(R)/5.4
(R)/10.4
(R)/2.7
(R)/16.1
(R)/3.5
(R)/13.6
(R)/12.5
(R)/13.3
(R)/22.5
(R)/27.9
ꢁ4.0
+4.1
ꢁ5.2
ꢁ2.8
ꢁ4.9
—
ꢁ5.6
ꢁ3.8
ꢁ4.2
ꢁ2.4
ꢁ4.2
ꢁ1.1
ꢁ6.5
ꢁ1.4
ꢁ5.5
ꢁ5.1
ꢁ5.4
ꢁ9.1
ꢁ11.3
4-NO
2
Acetophenone
d
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
2
2
2
2
2
2
2
2
2
2
2
2
2
e
f
.10
.11
.12
.13
.14
.15
.16
.17
.18
.19
.20
.21
g
h
i
j
k
l
m
l
1f
NH
2.22
4-NO
2
22
92
+3.1
(S)/7.7
HN
N
Ph
a
b
c
d
e
f
Determined by chiral HPLC analysis.
Reaction of aldehyde with nitromethane without the presence of a catalyst in a glass flask (product is 1-(4-nitrophenyl)-2-nitroethene).
Reaction of aldehyde with nitromethane in ethanol in the presence of Cu(OAc) .
2
Temperature 5 ꢁC.
Half concentration of catalyst (formation of 1-(4-nitrophenyl)-2-nitroethene observed).
Molar ratio of ligand:precursor 2:1.
THF as solvent.
Half concentration of nitromethane (0.25 ml; 0.5 mmol).
g
h
i
Copper (II) trifluoroacetate as metal precursor (formation of 1-(4-nitrophenyl)-2-nitroethene observed).
Copper (II) benzoate as metal precursor.
j
k
Copper (II) 4-nitrobenzoate as metal precursor.
Copper (II) 4-methoxybenzoate as metal precursor.
l
m
3
Copper (II) chloride as metal precursor (with addition of Et N (1:1)).
Table 3. Henry reaction (tridentate ligands—see Schemes 2 and 3)
2
D
5
a
Entry
Aldehyde (R
1
)
Tridentate ligand
Time (h)
Yield (%)
½aꢀ (c 1, CH
2
Cl
2
)
Configuration/ee (%)
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
2
2
2
2
2
2
2
2
2
2a
2b
2c
2d
2d
3a
3b
3c
4
6
6
6
6
4
72
72
48
120
94
95
96
96
95
94
95
89
54
+5.2
+5.4
+5.8
+7.9
+12.9
+3.9
+4.1
+5.7
ꢁ3.4
(S)/12.7
(S)/13.3
(S)/14.5
(S)/19.4
(S)/31.8
(S)/9.9
(S)/10.1
(S)/14.1
(R)/8.4
b
a
Determined by chiral HPLC analysis.
Copper (II) 4-methoxybenzoate as metal precursor.
b
The tridentate ligands showed a reversed enantioselectivity
compared to other chiral amines.
4. Experimental
1
13
H and C NMR spectra were recorded in CD OD or
3
Overall, the prepared ligands were applied in the Henry
reaction and showed good yields/reaction times but the
enantiomeric excesses were moderate (31.8% ee max).
CDCl at 500 MHz with Bruker AVANCE 500 instru-
ments. NMR techniques, such as COSY, HMBC and
HMQC were used for regular assignment of particular
3

F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
905
signals. Chemical shifts are reported in parts per million
and calibrated to the signal of hexamethyldisiloxane
product was purified by silica gel chromatography
(methanol).
(
0.05 ppm). J values are given in hertz.
5.2.1. (1S)-1-(2-Phenyl-1H-imidazol-4-yl)-N-(2-phenyl-1H-
The positive-ion and negative-ion atmospheric pressure
chemical ionization (APCI) mass spectra were measured
on an Esquire 3000 ion trap analyzer (Bruker Daltonics,
Bremen, Germany) within the mass range m/z = 50–600.
Samples were dissolved in acetonitrile and analyzed by
direct infusion at a flow rate of 40 lL/min. The ion source
temperature was 300 ꢁC, the APCI probe temperature was
imidazol-4-ylmethyl) ethanamine 2a. Prepared from chiral
amine 1a and 2-phenylimidazole-4-carbaldehyde by the
method A to give title compound 2a as a white solid, yield
20
87%, mp 110–112 ꢁC, ½aꢀ ¼ ꢁ43:0 (c 0.5, CH OH),
D
3
ee >95%. Found: C 73.9; H 6.1; N 20.2. C H N requires
2
1
21
5
1
C 73.4; H 6.2; N 20.4, molecular weight (MW) = 343. H
NMR (d/ppm, 500 MHz, CD OD) 1.49 (3H, d, J = 6.7,
3
3
3
50 ꢁC; the flow rate and the pressure of nitrogen were
CH ), 3.77 (2H, s, J = 6.7, NHCH ), 4.01 (1H, m,
3
2
l/min and 25 psi, respectively. The tuning of the mass
NH CH), 7.03 (1H, s, H ), 7.08 (1H, s, H ), 7.34 (2H,
2 im im
1
3
spectrometer was optimized for the target mass m/z 400.
For MS/MS measurements, the isolation width of precur-
sor ions was 4 m/z, and the collision amplitude was 1 V
in all cases.
m, ArH), 7.40 (4H, m, ArH), 7.84 (4H, m, ArH).
C
NMR (d/ppm, 125 MHz, CD OD) 21.7, 46.9, 51.6, 114.5,
3
120.2, 126.5, 126.6, 126.8, 127.1, 129.9, 130.0, 130.1,
130.2, 131.6, 131.7, 148.1, 148.2. Positive-ion APCI-MS
(
see Scheme 4 for the explanation of fragment ions A
+
+
Optical rotation values were measured on a Perkin Elmer
and B): m/z 344 [M+H] , 174 [ion B+NH ] , 171 [ion
A] (100%), 157 [ion B] . Positive-ion APCI-MS/MS of
3
+
+
3
41 instrument, concentration c is given in g/100 ml. The
+
+
enantiomeric excesses of all the ligands prepared were
m/z 344: m/z 186 [Mꢁion B] , 174 [ion B+NH ]
3
1
+
determined by the H NMR spectra measured with Mosher
(100%), 157 [ion B] . Negative-ion APCI-MS: m/z 342
ꢁ
ꢁ
ꢁ
acid (comparison of enantiomerically pure products and
racemates spectra, ee > 95% in all cases). The enantiomeric
excesses of the Henry reaction products were determined
by HPLC on a Daicel Chiracel OB column and simulta-
[MꢁH] (100%), 186 [Mꢁion B] , 172 [ion B+NH] , 169
ꢁ ꢁÅ
[ion Aꢁ2H] , 156 [ion BꢁH] . Negative-ion APCI-MS/
ꢁ
MS of m/z 342: m/z 325 [MꢁHꢁNH ] , 186 [Mꢁion
3
ꢁ
ꢁ
ꢁ
B] , 172 [ion B+NH] (100%), 169 [ion Aꢁ2H] .
3
neously deduced from [a] values. Hydrogenations were
1
carried out in ROTH pressure vessel. The chiral amines
and 2-phenylimidazole-4-carbaldehyde
1
2
were prepared
following literature procedures. Copper (II) benzoates were
prepared by heating freshly prepared copper (II) hydroxide
with the appropriate benzoic acid in aqueous solution.
Copper (II) salts were isolated through filtration of the
boiling reaction mixture and were purified by multiple
washing with ether. The other compounds and solvents
have been used as commercially available.
Scheme 4. Mass fragmentation.
5.2.2. (1S)-2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(2-
5
. Tridentate ligands
phenyl-1H-imidazol-4-ylmethyl) propanamine 2b. Pre-
pared from chiral amine 1c and 2-phenylimidazole-4-carb-
aldehyde by the method A to give title compound 2b as a
5
.1. Method A
20
white solid, yield 89%, mp 119–120 ꢁC, ½aꢀ ¼ ꢁ66:2 (c
D
Into a solution of chiral amine 1 (0.87 mmol) and 2-phenyl-
imidazole-4-carbaldehyde (0.87 mmol; 0.15 g) or 2-hydroxy-
benzaldehyde (0.87 mmol; 0.11 g) in dry methanol (10 ml),
0.5, CH OH), ee >95%. Found: C 74.1; H 6.8; N 18.9.
3
1
C H N requires C 74.4; H 6.8; N 18.9. MW = 371. H
2
3
25
5
NMR (d/ppm, 500 MHz, CD OD) 0.87 (3H, d, J = 6.8,
3
ꢂ
catalyst Pd/active carbon (0.5 g; 10%; Aldrich ) was
(CH ) CH), 1.00 (3H, d, J = 6.8, (CH ) CH), 2.04 (1H,
3
2
3 2
added. The solution was degassed and saturated with
hydrogen in an autoclave under 1 MPa pressure and
m, (CH ) CH), 3.61 (1H, d, NHCHCH(CH ) ), 3.70 (2H,
3 2 3 2
2 · d, J = 14.0, NHCH ), 7.00 (1H, s, H ), 7.03 (1H, s,
2
im
5
5 ꢁC until TLC (methanol) showed reaction completion.
H ), 7.35 (2H, m, ArH), 7.42 (4H, m, ArH), 7.80 (2H,
im
1
3
The catalyst was then filtered off, the solvent evaporated
and crude product 2 or 4 was purified by silica gel chroma-
tography (methanol).
d, ArH), 7.84 (2H, d, ArH).
C NMR (d/ppm,
125 MHz, CD OD) 19.5, 20.3, 34.4, 47.1, 62.5, 114.4,
3
120.1, 126.5, 126.6, 126.7, 126.8, 129.8, 129.9, 130.1,
1
30.2, 131.6, 131.8, 147.8, 148.1. Positive-ion APCI-MS:
+
+Å
+
5
.2. Method B
m/z 372 [M+H] , 215 [M+Hꢁion B] , 199 [ion A]
+
+
(100%), 174 [ion B+NH ] , 157 [ion B] . Positive-ion
3
+
Å
Into a solution of chiral amine 1 (0.87 mmol) and pyridine-
-carbaldehyde (0.87 mmol; 0.09 g) in dry methanol
10 ml), sodium sulfate (1 g) was added and the reaction
mixture was stirred overnight. Sodium borohydride
0.9 mmol; 0.035 g) was added after cooling and filtration
and the reaction mixture was stirred for further 5 h. Water
1 ml) was then added, methanol evaporated and crude
APCI-MS/MS of m/z 372: m/z 215 [M+Hꢁion B] , 199
+
+
+
2
(
[ion A] , 174 [ion B+NH ] (100%), 157 [ion B] . Nega-
3
ꢁ
tive-ion APCI-MS: m/z 370 [MꢁH]
(100%), 353
ꢁ
ꢁ
ꢁ
[MꢁHꢁNH ] , 214 [Mꢁion B] , 197 [ion Aꢁ2H] , 172
3
ꢁ
ꢁÅ
(
[Mꢁion A] , 156 [ion BꢁH] . Negative-ion APCI-MS/
ꢁ
ꢁ
MS of m/z 370: m/z 353 [MꢁHꢁNH ] , 214 [Mꢁion B]
3
ꢁ
ꢁ
(
(100%), 197 [ion Aꢁ2H] , 172 [Mꢁion A] .

906
F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
5
.2.3. (1S)-3-Methyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(2-
ppm, 125 MHz, CD OD) 19.3, 20.1, 33.4, 51.9, 63.2,
3
phenyl-1H-imidazol-4-ylmethyl) butanamine 2c. Prepared
from chiral amine 1d and 2-phenylimidazole-4-carbalde-
hyde by the method A to give title compound 2c as a white
114.8, 124.4, 124.5, 126.6, 126.7, 130.0, 130.1, 131.3,
138.9, 148.5, 149.4, 150.1. Positive-ion APCI-MS: m/z
+
+Å
+
307 [M+H] , 215 [M+Hꢁion B] , 199 [ion A] (100%),
20
+
solid, yield 88%, mp 120–121 ꢁC, ½aꢀ ¼ ꢁ30:8 (c 0.5,
109 [ion B+NH ] . Positive-ion APCI-MS/MS of m/z
307: m/z 199 [ion A] , 109 [ion B+NH ] (100%). Nega-
D
3
+
+
CH OH), ee >95%. Found: C 74.3; H 7.2; N 18.1.
3
3
1
ꢁ
C H N requires C 74.8; H 7.1; N 18.2. MW = 385. H
tive-ion APCI-MS: m/z 305 [MꢁH]
(100%), 213
2
3
25
5
ꢁ
Å
ꢁ
ꢁ
NMR (d/ppm, 500 MHz, CD OD) 0.87 (3H, d, J = 6.6,
[MꢁHꢁion B] , 197 [ion Aꢁ2H] , 183 [ion AꢁHꢁCH ] .
3
3
(
CH ) CH), 0.92 (3H, d, J = 6.6, (CH ) CH), 1.54 (1H,
Negative-ion APCI-MS/MS of m/z 305: m/z 197 [ion
3
2
3 2
ꢁ
ꢁ
m, (CH ) CH), 1.67+1.78 (2 · 1H, 2 · m, CH CH(CH ) ),
Aꢁ2H] , 183 [ion AꢁHꢁCH ] (100%).
3
2
2
3 2
3
3
7
.70 (2H, 2 · d, J = 14.0, NHCH ), 3.90 (1H, m, NHCH),
2
.00 (1H, s, H ), 7.01 (1H, s, H ), 7.29–7.36 (2H, m,
5.2.6. (1S)-3-Methyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(pyr-
idine-2-ylmethyl) butanamine 3b. Prepared from chiral
amine 1d and pyridine-2-carbaldehyde by the method B
to give title compound 3b as a white solid, yield 65%, mp
im
im
ArH), 7.36–7.44 (4H, m, ArH), 7.80 (2H, d, ArH), 7.85
1
3
(
2H, d, ArH). C NMR (d/ppm, 125 MHz, CD OD)
3
2
1
1
3.1, 24.0, 26.7, 46.5, 48.4, 63.5, 114.5, 120.7, 125.0,
26.8, 127.0, 127.2, 129.1, 130.1, 130.2, 130.5, 131.9,
32.1, 148.5, 148.6. Positive-ion APCI-MS: m/z 386
20
67–68 ꢁC, ½aꢀ ¼ ꢁ29:4 (c 0.5, CH OH), ee >95%. Found:
D
3
C 74.7; H 7.6; N 17.4. C H N requires C 75.0; H 7.6; N
2
0
24
4
+
+
+
1
[
M+H] , 213 [ion A] (100%), 174 [ion B+NH ] , 157
17.5. MW = 320. H NMR (d/ppm, 500 MHz, CD OD)
3
3
+
[
ion B] . Positive-ion APCI-MS/MS of m/z 386: m/z 228
0.91 (3H, d, J = 6.7, (CH ) CH), 0.93 (3H, d, J = 6.6,
3
2
+
+
+
[
1
Mꢁion B] , 213 [ion A] , 174 [ion B+NH ] (100%),
(CH ) CH), 1.53 (1H, m, (CH ) CH), 1.78+2.04 (2 · H,
3
3 2
3 2
+
ꢁ
ꢁ
57 [ion B] . Negative-ion APCI-MS: m/z 384 [MꢁH] ,
2 · m, CHCH CH(CH ) ), 4.07 (2H, 2 · d, J = 14.7,
2
3 2
ꢁ
ꢁ
3
67 [MꢁHꢁNH ] , 228 [Mꢁion B] , 211 [ion Aꢁ2H]
NHCH ), 4.21 (1H, dd, J = 5.1, NHCH), 7.22 (1H, s,
3
2
ꢁ
ꢁÅ
(
100%), 172 [Mꢁion A] , 156 [ion BꢁH] . Negative-ion
H ), 7.31 (1H, t, ArH), 7.38 (2H, m, ArH), 7.44 (2H, t,
im
ꢁ
APCI-MS/MS of m/z 384: m/z 367 [MꢁHꢁNH ] , 228
ArH), 7.75 (1H, t, ArH), 7.86 (2H, d, ArH), 8.54 (1H, d,
3
ꢁ
ꢁ
ꢁ
13
[
Mꢁion B] , 211 [ion Aꢁ2H] , 172 [Mꢁion A] (100%).
ArH). C NMR (d/ppm, 125 MHz, CD OD) 22.1, 23.7,
3
26.3, 43.7, 51.2, 55.9, 119.1, 122.3, 124.3, 124.5, 126.7,
5
.2.4. (1S)-2-Phenyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(2-phen-
130.1, 130.2, 131.4, 137.1, 138.8, 149.0, 150.3. Positive-
+
+Å
yl-1H-imidazol-4-ylmethyl) ethanamine 2d. Prepared from
chiral amine 1f and 2-phenylimidazole-4-carbaldehyde by
the method A to give title compound 2d as a white solid,
ion APCI-MS: m/z 321 [M+H] , 229 [M+Hꢁion B] ,
+
+
213 [ion A] (100%), 109 [ion B+NH ] . Positive-ion
3
+
APCI-MS/MS of m/z 321: m/z 213 [ion A] , 157 [ion
20
+
+
yield 88%, mp 120–121 ꢁC, ½aꢀ ¼ ꢁ10:0 (c 0.5, CH OH),
Aꢁbutene] , 109 [ion B+NH ] (100%). Negative-ion
D
3
3
ꢁ ꢁÅ
ee >95%. Found: C 77.3; H 6.1; N 16.5. C H N requires
APCI-MS: m/z 319 [MꢁH] , 227 [MꢁHꢁion B] , 211
ꢁ ꢁ
3 2
2
7
25
5
1
C 77.3; H 6.0; N 16.7. MW = 419. H NMR (d/ppm,
[ion Aꢁ2H] (100%), 169 [ion Aꢁ2HꢁCH CHCH ] .
5
2
6
00 MHz, CD OD) 3.16 (2H, m, CH Ph), 3.90 (2H,
Negative-ion APCI-MS/MS of m/z 319: m/z 211 [ion
3
2
ꢁ
ꢁ
· d, J = 14.6, NHCH ), 4.12 (1H, t, J = 7.2, NH CH),
Aꢁ2H] , 169 [ion Aꢁ2HꢁCH CHCH ] (100%).
2
2
3
2
.94 (1H, s, H ), 7.04–7.44 (10H, m, ArH), 7.69 (1H, t,
im
1
3
ArH), 7.80 (2H, d, ArH), 8.42 (1H, m, ArH). C NMR
5.2.7. (1S)-2-Phenyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(pyr-
idine-2-ylmethyl) ethanamine 3c. Prepared from chiral
amine 1f and pyridine-2-carbaldehyde by the method B
(
d/ppm, 125 MHz, CD OD) 43.0, 52.6, 58.6, 121.1, 122.3,
3
1
1
24.0, 124.2, 126.6, 127.7, 129.5, 130.0, 130.1, 130.5,
31.6, 138.7, 139.5, 148.3, 150.0, 159.1. Positive-ion
to give title compound 3c as a white solid, yield 69%, mp
+
+
20
APCI-MS: m/z 420 [M+H] , 262 [Mꢁion B] , 247 [ion
60–61 ꢁC, ½aꢀ ¼ 34:0 (c 0.5, CH OH), ee >95%. Found:
D
3
+
+
+
A] (100%), 174 [ion B+NH ] , 157 [ion B] . Positive-
C 77.8; H 6.3; N 15.9. C H N requires C 78.0; H 6.3;
23 22 4
3
+
1
ion APCI-MS/MS of m/z 420: m/z 403 [M+HꢁNH ] ,
N 15.8. MW = 354. H NMR (d/ppm, 500 MHz, CD OD)
3
3
+
+
+
2
62 [Mꢁion B] , 247 [ion A] , 174 [ion B+NH ]
3.16 (2H, m, CH Ph), 3.90 (2H, 2 · d, J = 14.6, NHCH ),
3
2
2
+
(
100%), 157 [ion B] . Negative-ion APCI-MS: m/z 418
4.12 (1H, t, J = 7.2, NH CH), 6.94 (1H, s, H ), 7.04–7.44
2 im
ꢁ
ꢁ
ꢁ
[
[
MꢁH] (100%), 262 [Mꢁion B] , 245 [ion Aꢁ2H] , 172
(10H, m, ArH), 7.69 (1H, t, ArH), 7.80 (2H, d, ArH), 8.42
ꢁ
ꢁÅ
13
Mꢁion A] , 156 [ion BꢁH] . Negative-ion APCI-MS/
(1H, m, ArH). C NMR (d/ppm, 125 MHz, CD OD) 43.0,
3
ꢁ
MS of m/z 418: m/z 401 [MꢁHꢁNH ] , 262 [Mꢁion
52.6, 58.6, 121.1, 122.3, 124.0, 124.2, 126.6, 127.7, 129.5,
130.0, 130.1, 130.5, 131.6, 138.7, 139.5, 148.3, 150.0,
3
ꢁ
ꢁ
ꢁ
B] (100%), 245 [ion Aꢁ2H] , 172 [Mꢁion A] .
+
1
59.1. Positive-ion APCI-MS: m/z 355 [M+H] , 263
+
Å
+
5
.2.5. (1S)-2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)-N-(pyri-
[M+Hꢁion B] , 247 [ion A]
(100%), 109 [ion
B+NH ] . Positive-ion APCI-MS/MS of m/z 355: m/z
+
dine-2-ylmethyl) propanamine 3a. Prepared from chiral
amine 1c and pyridine-2-carbaldehyde by the method B
to give title compound 3a as a white solid, yield 62%, mp
3
+
+
247 [ion A] (100%), 109 [ion B+NH ] . Negative-ion
3
ꢁ
ꢁÅ
APCI-MS: m/z 353 [MꢁH] , 261 [MꢁHꢁion B] , 245
20
ꢁ
6
7–69 ꢁC, ½aꢀ ¼ ꢁ49:8 (c 0.5, CH OH), ee >95%. Found:
[ion Aꢁ2H] (100%). Negative-ion APCI-MS/MS of m/z
D
3
ꢁ
ꢁ
C 74.3; H 7.1; N 18.4. C H N requires C 74.5; H 7.2; N
353: m/z 261 [MꢁHꢁion B] (100%), 245 [ion Aꢁ2H] .
1
9
22
4
1
1
8.3. MW = 306. H NMR (d/ppm, 500 MHz, CD OD)
3
0
.92 (3H, d, J = 6.8, (CH ) CH), 1.09 (3H, d, J = 6.8,
5.2.8. 2-[(1S)-N-(3-Methyl-1-(2-phenyl-1H-imidazol-4-yl)-
butyl)aminomethyl]phenol 4. Prepared from chiral amine
1d and 2-hydroxybenzaldehyde by the method A to give
3
2
(
CH ) CH), 2.25 (1H, m, (CH ) CH), 3.83 (1H, d,
3 2 3 2
J = 7.1, NHCHCH(CH ) ), 4.03 (2H, 2 · d, J = 14.3,
NHCH ), 7.14 (1H, s, H ), 7.29–7.43 (5H, m, ArH),
3
2
title compound 4 as a white solid, yield 60%, mp 160–
2
im
1
3
20
7
.76–7.84 (3H, m, ArH), 8.5 (1H, m, ArH). C NMR (d/
162 ꢁC, ½aꢀD ¼ ꢁ28:0 (c 0.5, CH OH), ee >95%. Found:
3

F. Bure sˇ et al. / Tetrahedron: Asymmetry 17 (2006) 900–907
907
C 75.0; H 7.3; N 12.5; O 4.8. C H N O requires C 75.2; H
Acknowledgements
2
1
25
3
1
7
5
.5; N 12.5; O 4.8. MW = 335. H NMR (d/ppm,
00 MHz, CD OD) 0.86 (3H, d, J = 6.7, (CH ) CH), 0,89
The financial support of this research from the
Ministry of Education, Youth and Sport of the Czech
Republic (Project MSM 0021627501) is gratefully acknow-
ledged. M.H. acknowledges the support of grant project
No. 203/05/2106 sponsored by the Czech Science
Foundation.
3
3 2
(
3H, d, J = 6.6, (CH ) CH), 1.45 (1H, m, (CH ) CH),
3 2 3 2
1
.75+2.11 (2 · H, 2 · m, CHCH CH(CH ) ), 4.01 (2H, s,
2
3 2
NHCH ), 4.26 (1H, d, J = 6.4, NHCH), 6.76–6.81 (2H,
2
m, ArH), 7.12–7.18 (2H, m, ArH), 7.30 (1H, s, H ), 7.35
im
1
3
(
2H, t, ArH), 7.42 (2H, t, ArH), 7.86 (2H, d, ArH).
C
NMR (d/ppm, 125 MHz, CD OD) 21.8, 25.3, 26.3, 42.2,
3
4
1
6.9, 56.3, 116.4, 121.0, 126.7, 126.8, 130.1, 130.3, 131.4,
31.9, 132.4, 136.9, 149.1, 157.5. Positive-ion APCI-MS:
+
+Å
+
References
m/z 336 [M+H] , 229 [M+Hꢁion B] , 213 [ion A]
+
+
(
100%), 157 [ion Aꢁbutene] , 107 [ion B] . Positive-ion
+
1. Bure sˇ , F.; Kulh a´ nek, J. Tetrahedron: Asymmetry 2005, 16,
1347–1354.
2. Henry, L. Bull. Soc. Chim. Fr. 1895, 13, 999–1003.
. Evans, D. A.; Seidel, D.; Rueping, M.; Hon, Wai Lam; Shaw,
J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–
APCI-MS/MS of m/z 336: 229 [M+2Hꢁion B] , 213 [ion
+
+
A] (100%), 157 [ion Aꢁbutene] . Negative-ion APCI-
ꢁ
ꢁÅ
ꢁ
MS: 334 [MꢁH] (100%), 243 [MꢁHꢁC H ] , 228
7
7
3
ꢁ
ꢁ
[
Mꢁion B] , 211 [ion Aꢁ2H] , 122 [ion B+NH] . Nega-
ꢁ
tive-ion APCI-MS/MS of m/z 334: 228 [Mꢁion B] , 211
1
2693.
ꢁ
ꢁ
[
ion Aꢁ2H] (100%), 122 [ion B+NH] .
.3. Asymmetric catalysis (Henry reaction, standard
experiment)
4. Lu, S. F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron:
Asymmetry 2004, 15, 3433–3441.
5. Chinchilla, R.; N a´ jera, C.; S a´ nchez-Agull o´ , P. Tetrahedron:
Asymmetry 1994, 5, 1393–1402.
. Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.;
Lampronti, I.; Roberti, M.; Pollini, G. P. Tetrahedron:
Asymmetry 1997, 38, 2749–2752.
5
6
A mixture of chiral ligand (55 lmol) and copper (II) pre-
cursor (50 lmol) in ethanol (5 ml) was stirred for an hour
at room temperature in a Teflon coated flask. Nitrometh-
ane (0,54 ml; 10 mmol) and aldehyde (1 mmol) were then
added and the reaction mixture stirred until TLC (ethyl
acetate/hexane 1:4) showed reaction completion. Ethanol
was evaporated under reduced pressure and replaced by
ether. The precipitate was filtered off through a plug of sil-
ica and washed with ether. The ether extract was washed
with sodium bisulfite, water and dried with sodium sulfate.
Solvent was then removed under reduced pressure to give a
pure product. Additional purification was possible to carry
7
8
. Klein, G.; Pandiaraju, S.; Reiser, O. Tetrahedron Lett. 2002,
4
3, 7503–7506.
. Yu-Wu, Zong; Ping, Tian; Guo-Qiang, Lin Tetrahedron:
Asymmetry 2004, 15, 771–776.
9. El Blidi, L.; Crestia, D.; Gallienne, E.; Demuynck, C.;
Bolte, J.; Lem, M. Tetrahedron: Asymmetry 2004, 15, 2951–
2954.
1
1
1
0. Bernauer, K.; Deschenaux, R.; Taura, T. Helv. Chim. Acta
1
983, 66, 202, 2049–2058.
1. Brunner, H.; Niemetz, M. Monatsh. Chem. 2002, 133, 115–
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Tarrant, M. E.; Torlez, L. W.; Callahan, F. M.; Fabio, P. F.;
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J. Med. Chem. 1985, 28, 1704–1716.
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Collect. Czech. Chem. Commun. 1986, 51, 2135–2142.
1
out on silica (ethyl acetate/hexane 1:4). 2-Nitro-1-(4-nitro-
phenyl)ethanol H NMR (d/ppm, 500 MHz, CDCl ) 3.10
1
3
(
1H, br d, J = 4.1, CH(OH)CH NO ), 4.55–4.68 (1H, m,
2 2
CH(OH)CH NO ), 5.65 (1H, m, CH(OH)CH NO ), 7.64
2
2
2
2
1
3
(
1
2H, m, ArH), 8.30 (2H, m, ArH). C NMR (d/ppm,
25 MHz, CDCl ) 70.0, 80.7, 124.4, 127.1, 145.2, 148.3.
3