Optically active imidazole N-oxides derived from l-prolinamine1

Article abstract of DOI:10.1016/j.tetasy.2013.07.013

Starting with (S)-1-benzylprolinamine and α-hydroxyimino ketones, enantiomerically pure bisheterocyclic imidazole N-oxides bearing the (S)-configured N-benzyl(pyrrolidin-2-yl)methyl residue were prepared. These N-oxides reacted with 2,2,4,4-tetramethylcyclobutane-1,3-dithione to give the corresponding optically active imidazole-2-thione derivatives via a sulfur transfer reaction. Reduction of the N-oxides with Raney-nickel led to deoxygenation, whereas catalytic hydrogenation (Pd/C) in ethanol occurred with simultaneous deoxygenation and debenzylation, leading to optically active 1-(pyrrolidin-2-yl)methyl-1H-imidazoles. Alkylation of the prepared imidazole N-oxides and their respective imidazoles with butyl and hexyl bromide and subsequent anion exchange gave optically active N-alkoxy- and N-alkylimidazolium tetrafluoroborates, respectively, with the properties of 'room temperature ionic liquids'.

Full text of DOI:10.1016/j.tetasy.2013.07.013

Tetrahedron: Asymmetry 24 (2013) 958–965
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Optically active imidazole N-oxides derived from L-prolinamine1
a,
a,
a
b,
⇑
⇑
⇑
´
Grzegorz Mloston , Aneta Wróblewska , Emilia Obijalska , Heinz Heimgartner
a
´
´
University of Łódz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łódz, Poland
b Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2013
Accepted 12 July 2013
Starting with (S)-1-benzylprolinamine and a-hydroxyimino ketones, enantiomerically pure bisheterocy-
clic imidazole N-oxides bearing the (S)-configured N-benzyl(pyrrolidin-2-yl)methyl residue were pre-
pared. These N-oxides reacted with 2,2,4,4-tetramethylcyclobutane-1,3-dithione to give the
corresponding optically active imidazole-2-thione derivatives via a sulfur transfer reaction. Reduction of
the N-oxides with Raney-nickel led to deoxygenation, whereas catalytic hydrogenation (Pd/C) in ethanol
occurred with simultaneous deoxygenation and debenzylation, leading to optically active 1-(pyrrolidin-
2-yl)methyl-1H-imidazoles. Alkylation of the prepared imidazole N-oxides and their respective imidazoles
with butyl and hexyl bromide and subsequent anion exchange gave optically activeN-alkoxy- and N-alkyl-
imidazolium tetrafluoroborates, respectively, with the properties of ‘room temperature ionic liquids’.
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Professor Ernst Schaumann on
the occasion of his 70th birthday
1. Introduction
tive ligands of potential importance for asymmetric synthesis.11
The non-protected prolinamine easily reacts with electron-defi-
The importance of imidazole derivatives in organic, bioorganic,
and medicinal chemistry as well as in material science is well doc-
umented.2–4 In recent years, numerous reports on the synthesis
and diverse applications of imidazole N-oxides have been pub-
lished.5 In contrast to six-membered N-heterocycles, imidazoles
cannot be converted into their corresponding N-oxides by treat-
ment with typical oxidizing reagents.6 Therefore, condensations
cient dicyanofumarates, and enantiomerically pure bicyclic pyraz-
inones are obtained chemoselectively.12
Our aim herein was the synthesis of a new series of optically ac-
tive imidazole derivatives containing the chiral pyrrolidine frag-
ment originating from L-prolinamine. Some of the products were
used for the preparation of new imidazole-based optically active
ionic liquids.
of
a-hydroxyimino ketones with methylidene amines (formalde-
hyde imines) were used as a convenient access to 2-unsubstituted
imidazole N-oxides.5a,7 Starting with optically active primary
amines, such as 1-phenylethylamine, trans-cyclohexane-1,2-dia-
2. Results and discussion
The preparation of the starting N-benzylated
be achieved from methyl -prolinate via aminolysis and reduction of
the amide13 or from -prolinol via the intermediate azide.11a In addi-
L-prolinamine 1 can
mine, as well as a-amino acid esters, the desired enantiomerically
L
pure imidazole N-oxides were obtained as the sole products.8
Some of them were tested as ligands for the asymmetric allylations
of aldehydes9 and in cyclopropanation reactions.10
L
tion, we developed a new approach to 1b based on a Mitsunobu
reaction via the intermediate phthalimide derivative (Scheme 1).
The condensation of 1 with paraformaldehyde led to methyli-
dene prolinamine 2, which spontaneously underwent trimeriza-
L
-Prolinamine ((2S)-pyrrolidin-2-yl)methylamine) is a useful
and widely applied building block for the synthesis of optically ac-
1. BnCl, KOH
phthalimide
Ph3P, DEAD
iPrOH
O
NH2NH2·H2O
EtOH
OH
NH2
CO2H
N
H
N
THF
N
2. LiAlH4
THF
N
Bn
N
Bn
1
O
Bn
Scheme 1.
⇑
Corresponding authors. Tel.: +48 42 635 57 61 (G.M.); +48 42 665 50 41 (A.W.); +41 44 635 42 82 (H.H.).
E-mail addresses: gmloston@uni.lodz.pl (G. Mloston´ ); anetka.wroblewska@gmail.com (A. Wróblewska), heimgart@oci.uzh.ch (H. Heimgartner).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.013

´
959
G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
tion to give the corresponding hexahydrotriazine 3 (Scheme 2). The
structure of 3 was confirmed by the 13C NMR spectrum, in which
no signal for the imino group (N@CH2) appeared. The trimerization
of methylidene amines is a typical reaction,14 and only in the case
of bulky substituents, for example, adamantan-1-yl, is the mono-
meric form stable under standard conditions.15 Herein, trimer 3
is believed to exist in solution in equilibrium with the monomeric
form 2.
Based on this result, we assumed that all of the prepared imid-
azole N-oxides 5 were enantiomerically pure. The same conclusion
was formulated in the case of other optically active imidazole N-
oxides described in our previous papers.8
2-Unsubstituted imidazole N-oxides are versatile starting mate-
rials for the preparation of other imidazole derivatives, such as the
parent imidazoles,8 imidazole-2-thiones,8 imidazolones,17 and
(imidazol-2-yl)acetates.18 In addition, imidazole N-oxides or the
N
HON
O
R1
R2
N
O
Bn
N
2
R1
4a-e
(CH2O)n
NH2
N
N
N
EtOH, reflux, 4 h
or
R2
MeOH, rt
24 h
Bn
Bn
AcOH, rt, 24 h
1
N
5a-e
Bn
Bn
N
N
N
4a, 5a R1 = R2 = Me
4b, 5b R1 = Me, R2 = Ph
4c, 5c R1 = R2 = Ph
1/3
N
4d, 5d R1 = PhNHCO, R2 = Me
4e, 5e R1 = 4-BrC6H4NHCO, R2 = Me
3
N
Bn
Scheme 2.
The latter reacts with
a
-hydroxyimino ketones 4a–e in boiling
corresponding parent compounds have been alkylated to give imid-
azolium salts, which display the properties of ionic liquids.8d,19
Treatment of imidazole N-oxides 5 with Raney-Ni in ethanol at
room temperature led smoothly to selective deoxygenation to
yield the corresponding imidazoles 6 (Scheme 3). Under these con-
ditions, no debenzylation of the pyrrolidine ring was observed. In a
control experiment, the reaction mixture was heated at reflux, and
in this case, a complex mixture of products was formed. Con-
versely, hydrogenolysis (H2, Pd/C) of 5c and 5d in ethanol led to
deoxygenation and debenzylation to yield 7a and 7b, respectively.
The 2-unsubstituted imidazole N-oxides 5a,c and e reacted with
2,2,4,4-tetramethylcyclobutane-1,3-dithione 8 via the so-called
‘sulfur-transfer reaction’ to give optically active imidazole-2-thi-
ones 9a–c (Scheme 3).20 In these reactions, imidazole N-oxides 5
react as ‘nitrone-like’ 1,3-dipoles, and after the 1,3-dipolar
ethanol (method A) or in glacial acetic acid at room temperature
(method B) to yield the desired optically active imidazole N-oxides
5a–e in good yields (Scheme 2). In order to examine the enantiopu-
rity of these products, a sample of 5a was dissolved in CDCl3 with
an equimolar amount of (tert-butyl)(phenyl)thiophosphinic acid
(MOD reagent).16 The 1H NMR spectrum showed only one set of
signals, whereas in the case of racemic 5a (rac-5a), the addition
of MOD led to the appearance of two sets of signals. Thus, in the
racemic product, the diagnostic H–C(2) signal of imidazole N-oxi-
des appeared as two singlets located at 8.87 and 8.86 ppm. Simi-
larly, one Me group gave two singlets at 1.95 and 1.94 ppm,
whereas the second Me group of both enantiomers absorbed as a
singlet at 2.08 ppm. Moreover, for all other signals observed, dupli-
cation was observed in the spectrum of rac-5a.
O
S
S
H
N
S
N
N
R1
R1
R1
O
O
+
8
N
Raney-Ni
EtOH, rt
N
N
N
N
R2
N
CHCl3, 0°C
R2
R2
Bn
Bn
Bn
9a-c
5a-e
6a-e
1 = R2 = Me
9b R1 = R2 = Ph
9c
9a
R
R
1 = 4-BrC6H4NHCO, R2 = Me
H2, Pd/C
EtOH
6a
R
1 = R2 = Me
6b R1 = Me, R2 = Ph
6c
R
1 = R2 = Ph
6d R1 = PhNHCO, R2 = Me
6e
N
R
1 = 4-BrC6H4NHCO, R2 = Me
R1
N
N
H
R2
7a-b
1 = R2 = Ph
7b R1 = PhNHCO, R2 = Me
7a
R
Scheme 3.

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G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
960
cycloaddition, the intermediate 1,4,2-oxathiazolidine undergoes a
fragmentation to yield 9 and 2,2,4,4-tetramethyl-3-thioxocyclobu-
tanone. The latter can undergo a ‘sulfur-transfer reaction’ with
molecule 5 once more, leading to 9 and 2,2,4,4-tetramethylcyclo-
butane-1,3-dione. The obtained imidazole-2-thiones 9 are charac-
terized by the thiourea moiety, which is of great importance in
asymmetric synthesis and organocatalysis.21
with the properties of optically active ‘room temperature ionic liq-
uids’ (RTILs).
The optically active products described herein are of interest as
potential ligands for asymmetric synthesis and for organocatalysis.
The readily available ionic liquids can be used as reaction media for
small-scale organic synthesis.
The alkylation of imidazoles with long-chain alkyl bromides
and subsequent anion exchange is a typical procedure for the prep-
aration of imidazolium salts with the characteristic behavior of io-
nic liquids (ILs).22 Optically active ionic liquids are of special
interest, but to date, proline-derived examples are rare.23 Thus,
imidazoles 6 were alkylated with butyl, hexyl, and octyl bromide
in boiling acetonitrile. The imidazolium bromides 10 thus obtained
were dissolved in acetone and treated with an equimolar amount
of NaBF4 at room temperature to give the corresponding tetra-
fluoroborates 11 (Scheme 4). All of them are liquids at room tem-
perature and, therefore, belong to the class of optically active ‘room
temperature ionic liquids’ (RTILs).
4. Experimental
4.1. General
Melting points were determined in a capillary using a Melt-
Temp. II apparatus (Aldrich) or STUART SMP30 and are uncor-
rected. The IR Spectra were recorded on a NEXUS FT-IR spectropho-
tometer in KBr; absorptions (m
) in cmꢀ1. The 1H and 13C{1H} NMR
spectra were measured on a Bruker Avance III instrument (600
and 150 MHz, resp.) using solvent signal as reference. Multiplicity
of signals in the 13C NMR spectra was established using the HMQC
technique. Chemical shifts (d) are given in ppm and coupling con-
CH2(CH2)nMe
X
N
N
R1
R1
Me(CH2)nCH2Br
MeCN, reflux
R
1 = R2 = Me, n = 4
b R1 = R2 = Me, n = 6
a
N
N
N
N
R2
R2
c
R
1 = Me, R2 = Ph, n = 2
d R1 = Me, R2 = Ph, n = 6
Bn
Bn
10 X = Br
6a,b
NaBF4
acetone, rt
11 X = BF4
Scheme 4.
In a recent paper, we described the synthesis of a new type of
ionic liquid containing a 3-alkoxyimidazolium cation.8d Similarly,
the alkylation of imidazole N-oxides 5 was carried out with equi-
molar amounts of the respective alkyl bromides in CHCl3 solution
at room temperature to give imidazolium bromides 12 (Scheme 5).
The latter were transformed into the corresponding tetrafluorobo-
rates 13 in the usual way. It is worth mentioning that under the ap-
plied reaction conditions, the alkylation of compounds 5 and 6
occurred selectively at the imidazole fragment.
stants J in Hz. Assignments of signals in 13C NMR spectra were
made on the basis of HMQC experiments. HR-MS: Bruker maXis
spectrometer; ESI-MS: Varian 500. Optical rotations were deter-
mined on a PERKIN–ELMER 241 MC polarimeter for k = 589 nm.
4.2. Starting materials
All solvents and reagents are commercially available and used
as received. (2S)-Benzylproline24 and
a-hydroxyimino ketones
420a were prepared according to known procedures.
OCH2(CH2)nMe
X
O
N
R1
N
a
R
1 = R2 = Me, n = 2
b R1 = R2 = Me, n = 6
Me(CH2)nCH2Br
R1
N
N
1 = Me, R2 = Ph, n = 2
N
MeCN, reflux
c
R
R2
d R1 = Me, R2 = Ph, n = 6
N
R2
Bn
R
1 = R2 = Ph, n = 2
e
Bn
12 X = Br
NaBF4
acetone, rt
5a-c
13 X = BF4
Scheme 5.
4.2.1. [(2S)-N-Benzylpyrrolidin-2-yl]methanol (N-benzylprolinol)
A solution of (2S)-benzylproline (3 g, 14.6 mmol) in THF (30 ml)
was cooled to 0 °C and a suspension of LiAlH4 in THF (2 M,
21.9 mmol, 12.4 ml) was added dropwise. The mixture was stirred
overnight at rt. Next, an aqueous solution of KOH (10%, 15 ml) was
added and the organic product was extracted with Et2O
(3 ꢁ 15 ml). The organic layers were combined and dried (Na2SO4).
After filtration, the solvent was evaporated and the crude, oily
product was distilled in a Kugel-Rohr (75–78 °C, 0.1 hPa). Yield:
3. Conclusion
The results described herein show that N-benzyl
L-prolinamine
is a useful starting material for the preparation of a new type of
optically active 2-unsubstituted imidazole N-oxides. Based on the
known reactivity of these N-oxides, they can be converted into a
variety of other optically active imidazole derivatives such as the
parent imidazoles and imidazole-2-thiones. The debenzylation
with simultaneous deoxygenation of imidazole N-oxides 5 leading
to imidazoles of type 7 can be achieved conveniently by hydrogen-
olysis under standard conditions. Alkylation of the prepared imid-
azole N-oxides as well as the corresponding imidazoles leads to N-
alkoxyimidazolium and N-alkylimidazolium salts, respectively,
2.0 g (71%). Colorless oil. IR (film):
v 3405br, 2961m, 2872m,
2799m, 1879w, 1810w, 1721w, 1496m, 1453m, 1211m, 1049w,
1029w, 849m, 839s, 699s. 1H NMR (CDCl3): d 7.32–7.25 (m, 5H,
HC(arom.)); 3.92, 3.32 (AB, JAB = 12.9, 2H, H2C–Ph); 3.61 (dd,

´
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G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
3
2
2JH,H = 10.8, JH,H = 3.6, 1H, H2C–OH); 3.38 (dd, JH,H = 10.8,
sure, and the resulting residue was purified by column chromatog-
raphy or by crystallization.
3JH,H = 1.8, 1H, H2C–OH); 2.96–2.90 (m, 1H, H2C(5)); 2.72–2.65
(m, 1H, HC(2)); 2.29–2.22 (m, 1H, H2C(5)); 1.93–1.85 (m, 1H,
H2C(3)); 1.82–1.75 (m, 1H, H2C(3)); 1.71–1.59 (m, 2H, H2C(4)).
13C NMR (CDCl3): d 139.4 (1 C(arom.)); 128.7, 128.3, 127.1 (5
CH(arom.)); 64.3 (C(2)); 61.8 (CH2–OH); 58.6 (CH2–Ph); 54.5
Procedure B: A mixture of 2 (10 mmol) and the corresponding 4
(10 mmol) in glacial acetic acid (15 ml) was magnetically stirred
overnight at rt. Next, HCl gas was bubbled through the mixture
for 1 h, after which Et2O (ca. 100 ml) was added and the colorless
precipitated hydrochloride was filtered, washed with cold Et2O
(3 ꢁ 20 ml), and dried under reduced pressure. The crude hydro-
chloride was dissolved in CH2Cl2 (25 ml), after which solid NaHCO3
(1.5 g) was added, and stirring was continued for 1 h until the evo-
lution of CO2 ceased. The inorganic salts were filtered off and the
solvent was removed. The crude products 5a–e were purified by
column chromatography or by crystallization.
(C(5)); 27.8 (C(3)); 23.5 (C(4)). ½a D25
ꢂ
¼ ꢀ58 (c 1.0, CHCl3); lit.25
½
a 2D5
ꢂ
¼ ꢀ59:9 (c 1.0, CHCl3).
4.2.2. 1-[(2S)-N-Benzylpyrrolidin-2-yl]methanamine 1
To the solution of triphenylphosphine (0.86 g, 3.3 mmol) and
phthalimide (0.48 g, 3.3 mmol) in THF (10 ml), N-benzylprolinol
(0.57 g, 3.0 mmol) dissolved in THF (2 ml) was added, and the solu-
tion was stirred magnetically for 10 min. After this time, diethyl
azodicarboxylate (DEAD) (0.62 g, 3.6 mmol) was added dropwise,
and the mixture obtained was heated at reflux for 8 h. Next, the
solvent was removed under reduced pressure, the obtained residue
was suspended in Et2O (50 ml) and stirred for 1 h. Then, the precip-
itate was separated by filtration and the filtrate was removed un-
der reduced pressure. The residue was dissolved in EtOH (20 ml),
after which hydrazine monohydrate (0.4 g, 8.0 mmol) was added,
the mixture was heated at reflux for 2 h, and after the addition of
HCl (1 M, 3 ml), heating was continued for 30 min. The precipitate
was filtered off and the solvents were removed under reduced
pressure. The residue obtained was treated with aqueous NaOH
(1 M, 5 ml), the organic product was extracted with Et2O
(3 ꢁ 25 ml), and the combined organic layers were dried (Na2SO4).
After filtration, the Et2O solution was concentrated under reduced
pressure to give 1 as a pale yellow oil. The crude product was dis-
tilled in a Kugel-Rohr (50–52 °C, 0.1 hPa). Yield: 0.4 g (70%). Color-
4.2.4.1. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-dimethyl-
1H-imidazole 3-oxide 5a. Yield: 2.5 g (88%). Colorless oil (SiO2,
MeOH/AcOEt, 1:1). IR (film):
v 3584–3028br, 2954m, 2926m,
2807m, 1627m, 1495m, 1453s, 1381m, 1338m, 1148m, 1041s,
843w, 733w, 702s. 1H NMR (CDCl3): d 7.94 (s, 1H, HC(2)); 7.35–
7.21 (m, 5H, HC(arom.)); 3.75, 3.54 (AB, JAB = 12.6, 2H, H2C–Ph);
2
3
2
3.68 (dd, JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.60 (dd, JH,H = 14.4,
3JH,H = 6.0, 1H, H2C–N); 3.04–2.99 (m, 1H, H2C(50)); 2.92–2.86 (m,
1H, HC(20)); 2.39–2.32 (m, 1H, H2C(50)); 2.15 (s, 3H, H3C–C(4));
2.05 (s, 3H, H3C–C(5)); 1.93–1.85 (m, 1H, H2C(30)); 1.75–1.69 (m,
1H, H2C(40)); 1.68–1.59 (m, 1H, H2C(40)); 1.49–1.43 (m, 1H,
H2C(30)). 13C NMR (CDCl3): d 138.9 (C(arom.)); 128.8, 128.5, 127.3
(5 CH(arom.)); 126.3 (1 C(imid.)); 124.9 (HC(2)); 121.0 (1 C(imid.));
63.2 (HC(20)); 60.1 (CH2–Ph); 54.8 (C(50)); 49.1 (CH2–N); 28.5
(C(30)); 23.3 (C(40)); 8.9 (CH3–C(4)); 7.3 (CH3–C(5)). HR-ESI-MS
(MeOH + HCOOH): 286.1909 (calcd 286.1914 for
C17H24N3O,
less oil. IR (film):
v
3365m, 3289br, 3027m, 2961m, 2871m,
[M+1]+). ½a 2D5
¼ ꢀ18 (c 1.0, CH2Cl2).
ꢂ
2791m, 1950m, 1877m, 1810m, 1495s, 1453s, 1372m, 1121m,
1072m, 1028s, 910m, 738s, 699s. 1H NMR (CDCl3): d 7.38–7.19
(m, 5H, HC(arom.)); 3.96, 3.30 (AB, JAB = 12.9, 2H, H2C–Ph); 2.97–
4.2.4.2. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4-methyl-5-
phenyl-1H-imidazole 3-oxide 5b. Yield: 1.3 g, 40% (method A),
2.7 g, 80% (method B). Colorless oil (SiO2, MeOH/AcOEt, 1:1). IR
2
3
2.90 (m, 1H, H2C(5)); 2.75 (dd, JH,H = 12.9, JH,H = 5.4, 1H, H2C–
2
3
NH2); 2.70 (dd, JH,H = 12.9, JH,H = 3.6, 1H, H2C–NH2); 2.58–2.53
(m, 1H, HC(2)); 2.25–2.17 (m, 1H, H2C(5)); 1.95–1.87 (m, 1H,
H2C(3)); 1.77–1.63 (m, 2H, H2C(4); 1H, H2C(3)). 13C NMR (CDCl3):d
139.9 (1 C(arom.)); 128.7, 128.7, 126.8 (5 CH(arom.)); 65.5 (C(2));
59.1 (CH2–Ph); 54.6 (C(5)); 44.1 (CH2–NH2); 28.0 (C(3)); 23.0 (C(4))
(film): v 3647–3028br, 2962m, 2876m, 2803m, 1683s, 1551m,
1496s, 1452m, 1381m, 1028m, 922w, 847w, 764m, 734m, 702m,
642s. 1H NMR (CDCl3): d 8.29 (s, 1H, HC(2)); 7.49–7.45 (m, 3H,
HC(arom.)); 7.32–7.29 (m, 2H, HC(arom.)); 7.26–7.24 (m, 3H,
HC(arom.)); 7.23–7.20 (m, 2H, HC(arom.)); 3.77 (dd, JH,H = 14.4,
JH,H = 4.8, 1H, H2C–N); 3.64–3.58 (m, 1H, H2C–Ph, 1H, H2C–N);
3.38 (AB, JAB = 12.9, 2H, H2C–Ph); 2.96–2.91 (m, 1H, H2C(50));
2.71–2.68 (m, 1H, H2C(20)); 2.28–2.22 (m, 1H, H2C(50)); 2.19 (s,
3H, H3C–C(4)); 1.75–1.73 (m, 1H, H2C(30)); 1.63–1.60 (m, 1H,
H2C(40)); 1.53–1.48 (m, 1H, H2C(40)); 1.33–1.29 (m, 1H, H2C(30)).
13C NMR (CDCl3): d 138.3 (1 C(arom.)); 130.7, 129.8, 129.4, 129.1,
129.1, 128.6, 127.5, 127.2 (9 signals for 10 CH(arom.), 2 C(arom.),
1 HC(2), 2 C(imid.)); 63.4 (HC(20)); 59.7 (CH2–Ph); 54.5 (C(50));
49.5 (CH2–N); 28.5 (C(30)); 23.3 (C(40)); 7.9 (H3C–C(4)). HR-ESI-
MS (MeOH + HCOOH): 348.2068 (calcd 348.2070 for C22H26N3O,
ppm. ½a 2D5
ꢂ
¼ ꢀ54 (c 1.0, CH2Cl2); lit.26
½
a 2D5
ꢂ
¼ ꢀ55 (c 9.97, CHCl3).
4.2.3. 1-[(2S)-N-Benzylpyrrolidin-2-yl]-N-methylidenemetha-
namine 2 (resp. the trimer 3)
To a magnetically stirred solution of 1 (1.81 g, 9.53 mmol) in
MeOH (10 ml), paraformaldehyde (0.30 g, 10 mmol) was added,
and the mixture was stirred overnight at rt. The solvent was then
removed under reduced pressure. The oil obtained was used in
the next step without purification. Yield: 1.92 g (98%). Pale yellow
oil. IR (film):
v 3361br, 3085m, 3061m, 3026m, 2960m, 2872m,
2788m, 1946m, 1875m, 1808m, 1604m, 1495s, 1453s, 1604m,
1155w, 1028m, 916m, 735s, 698s. 1H NMR (CDCl3): d 7.35–7.16
(m, 5H, HC(arom.)); 4.16, 3.23 (AB, JAB = 13.2, 2H, H2C–Ph); 3.47–
3.32 (br, 2H, N–CH2–N); 2.93–2.87 (m, 1H, HC(5)); 2.68 (dd,
[M+1]+). ½a 2D5
¼ ꢀ24 (c 1.0, CH2Cl2).
ꢂ
4.2.4.3. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-diphenyl-
1H-imidazole 3-oxide 5c. Yield: 2.6 g, 65% (method A), 3.1 g, 75%
(method B). Colorless crystals. Mp 160–161 °C (CHCl3/Et2O). IR
3
2JH,H = 12.9, JH,H = 4.8, 1H, H2C–N); 2.57–2.52 (m, 1H, HC(2));
2
3
2.42 (dd, JH,H = 12.9, JH,H = 6.6, 1H, H2C–N); 2.15–2.09 (m, 1H,
HC(5)); 1.98–1.88 (m, 1H, HC(3)); 1.75–1.60 (m, 2H, H2C(4); 1H,
H2C(3)). 13C NMR (CDCl3): d 139.9 (C(arom.)); 128.9, 128.2, 126.7
(5, CH(arom.)); 75.8 (N–CH2–N); 62.4 (C(2)); 59.6 (CH2–Ph); 57.6
(CH2–N); 54.2 (C(5)); 30.2 (C(3)); 22.6 (C(4)). ESI–MS: m/z 203
(KBr): v 3646–3027br, 2961m, 2876w, 2810m, 1736m, 1604m,
1495m, 1445m, 1346m, 1193m, 1076m, 1039s, 918m, 864s,
762s, 700s, 656 m. 1H NMR (CDCl3): d 8.35 (s, 1H, HC(2)); 7.55–
7.52 (m, 2H, HC(arom.)); 7.43–7.36 (m, 3H, HC(arom.)); 7.32–
7.28 (m, 2H, HC(arom.)); 7.27–7.19 (m, 8H, HC(arom.)); 3.75 (dd,
(100, [M+1]+). ½a D25
ꢂ
¼ ꢀ14 (c 1.0, CH2Cl2).
2JH,H = 14.0, JH,H = 4.2, 1H, H2C–N); 3.62 (dd, JH,H = 14.0,
3JH,H = 6.0, 1H, H2C–N); 3.63, 3.39 (AB, JAB = 13.2, 2H, H2C–Ph);
2.98–2.93 (m, 1H, H2C(50)); 2.79–2.72 (m, 1H, HC(20)); 2.31–2.24
(m, 1H, H2C(50)); 1.84–1.76 (m, 1H, H2C(30)); 1.69–1.62 (m, 1H,
H2C(40)); 1.60–1.51 (m, 1H, H2C(40)); 1.43–1.37 (m, 1H, H2C(30)).
13C NMR (CDCl3): d 138.7 (1 C(arom.)); 131.0, 130.2, 129.6, 129.5,
3
2
4.2.4. Synthesis of imidazole N-oxides 5
Procedure A: A solution of 2 (10 mmol) and the corresponding a-
hydroxyimino ketone 4 (10 mmol) in EtOH (5 ml) was heated at
reflux for 3 h. Next, the solvent was removed under reduced pres-

´
G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
962
129.1, 128.8, 128.5, 128.1, 128.0, 127.7, 127.3, 127.3, 126.7 (2
C(arom.), 15 HC(arom.), 2 C(imid.)); 126.9 (HC(2)) 63.1 (HC(20));
59.6 (CH2–Ph); 54.4 (C(50)); 49.1 (CH2–N); 28.4 (C(40)); 23.2
(C(30)). HR-ESI-MS (MeOH + HCOOH): 410.2228 (calcd 410.2227
1.81 (m, 1H, H2C(30)); 1.73–1.65 (m, 2H, H2C(40)); 1.57–1.49 (m,
1H, H2C(30)). 13C NMR (CDCl3): d 139.2 (1 C(arom.)); 132.0
(HC(2)); 129.8, 129.0, 126.7, 121.1, 120.2 (5 CH(arom.); 2 C(imid.));
63.5 (HC(20)); 59.1 (CH2–Ph); 54.7 (C(50)); 49.6 (CH2–N); 29.0
(C(30)); 23.3 (C(40)); 8.8 (H3C–C(4)); 7.2 (H3C–C(5)) ppm. HR-ESI-
MS (MeOH + HCOOH): 270.1961 (calcd 270.1965 for C17H24N3,
for C27H28N3O, [M+1]+). ½a D25
¼ ꢀ5 (c 1.0, CH2Cl2).
ꢂ
4.2.4.4. N-Phenyl-1-{[(2S)-N-benzylpyrrolidin-2-yl]methyl}-5-
methyl-1H-imidazole-4-carboxamide 3-oxide 5d. Yield: 3.0 g
[M+1]+). ½a 2D5
¼ ꢀ25 (c 1.0, CH2Cl2).
ꢂ
(78%). Colorless crystals. Mp 120–122 °C (Et2O). IR (KBr):
v
4.2.5.2. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4-methyl-5-
phenyl-1H-imidazole 6b. Yield: 1.2 g (70%). Pale yellow oil (SiO2,
3427br, 3171m, 3062m, 2978w, 2921w, 2798m, 1672s, 1619m,
1598m, 1560s, 1310s, 1273s, 759m, 750m, 701m, 630 m. 1H
NMR (CDCl3): d 12.98 (s, 1H, NH); 7.95 (s, 1H, HC(2)); 7.74–7.69
(m, 2H, HC(arom.)); 7.36–7.31 (m, 4H, HC(arom.)); 7.34–7.24 (m,
4H, HC(arom.)); 3.76, 3.63 (AB, JAB = 13.6, 2H, H2C–Ph); 3.76 (dd,
MeOH/AcOEt, 1:1). IR (film):
v 3583–3369br, 3059m, 3029m,
2948m, 2873m, 2796m, 1955m, 1888m, 1815m, 1688m, 1605w,
1493s, 1452m, 1207m, 1124m, 1029m, 966m, 701m. 1H NMR
(CDCl3): d 7.58 (s, 1H, HC(2)); 7.46–7.41 (m, 2H, HC(arom.));
7.39–7.35 (m, 1H, HC(arom.)); 7.30–7.26 (m, 4H, HC(arom.));
7.24–7.20 (m, 1H, HC(arom.)); 7.19–7.17 (m, 2H, HC(arom.));
3
2
2JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.66 (dd, JH,H = 14.4,
3JH,H = 5.40 Hz, 1H, H2C–N); 3.10–3.04 (m, 1H, H2C0(5)); 3.02–2.96
(m, 1H, H2C0(2)); 2.58 (s, 3H, H3C–C(5)); 2.47–2.40 (m, 1H,
H2C(50)); 2.00–1.91 (m, 1H, H2C(30)); 1.80–1.73 (m, 1H, H2C(40));
1.65–1.56 (m, 1H, H2C(40)); 1.48–1.41 (m, 1H, H2C(30)). 13C NMR
(CDCl3): d 157.9 (C@O); 138.7, 138.4 (2 C(arom.)); 131.5, 129.1,
129.0, 128.8, 127.7, 124.2, 121.7, 120.1 (10 CH(arom.), 2 C(imid.));
126.0 (HC(2)); 62.8 (HC(20)); 60.3 (CH2–Ph); 55.0 (C(50)); 48.7
(CH2–N); 28.4 (C(30)); 23.7 (C(40)); 10.0 (H3C–C(5)). HR-ESI-MS
2
3
2
3.92 (dd, JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.76 (dd, JH,H = 14.4,
3JH,H = 7.2, 1H, H2C–N); 3.55, 3.19 (AB, JAB = 13.2, 2H, H2C–Ph;
2.89–2.85 (m, 1H, H2C(50)); 2.63–2.57 (m, 1H, HC(20)); 2.18 (s,
3H, H3C–C(4)); 2.18–2.13 (m, 1H, H2C(50)); 1.73–1.65 (m, 1H,
H2C(30)); 1.62–1.50 (m, 2H, H2C(40)); 1.40–1.34 (m, 1H, H2C(30)).
13C NMR (CDCl3): d 139.4, 135.6 (2 C(arom.)); 136.9 (HC(2));
130.9, 130.5, 129.0, 128.9, 128.5, 128.1, 127.2 (7 signals for 10
HC(arom.) + 2 C(imid.)); 63.7 (C(20)); 59.5 (CH2–Ph); 54.6 (C(50));
49.8 (CH2–N); 29.1 (C(30)); 23.1 (C(40)); 13.4 (H3C–C(4)). HR-ESI-
MS (MeOH + HCOOH): 332.2121 (calcd 332.2121 for C22H26N3,
(MeOH + HCOOH): 391.2124 (calcd 391.2129 for
C23H27N4O2,
[M+1]+). ½a 2D5
¼ ꢀ27 (c 1.0, CH2Cl2).
ꢂ
4.2.4.5.
methyl}-5-methyl-1H-imidazole-4-carboxamide 3-oxide 5e. Yield:
3.8 g (81%). Colorless crystals. Mp 168–170 °C (Acetone). IR (KBr):
N-(4-Bromophenyl)-1-{[(2S)-N-benzylpyrrolidin-2-yl]
[M+1]+). ½a 2D5
¼ ꢀ25 (c 1.0, CH2Cl2).
ꢂ
v
4.2.5.3. 4,5-Diphenyl-1-{[(2S)-N-benzylpyrrolidin-2-yl]methyl}-
1H-imidazole 6c. Yield: 1.3 g (68%). Colorless crystals. Mp 118–
3432br, 3077m, 2975w, 2939w, 2919w, 2802m, 1675s, 1612s,
1556s, 1488s, 1309m, 1069m, 817m, 757m, 702s, 636m, 503m.
1H NMR (CDCl3): d 13.00 (s, 1H, NH); 7.91 (s, 1H, HC(2)); 7.63–
7.59 (m, 2H, HC(arom.)); 7.45–7.41 (m, 2H, HC(arom.)); 7.35–
7.31 (m, 2H, HC(arom.)); 7.29–7.25 (m, 3H, HC(arom.)); 3.65,
119 °C (CH2Cl2/hexane). IR (KBr):
v 3432br, 3085m, 2971m,
2927m, 2905m, 2786m, 2723w, 1603m, 1505m, 1452m, 1369m,
1256m, 774m, 698s, 653m. 1H NMR (CDCl3): d 7.76 (s, 1H,
HC(2)); 7.54–7.45 (m, 5H, HC(arom.)); 7.39–7.36 (m, 2H, HC(ar-
om.)); 7.33–7.28 (m, 2H, HC(arom.)); 7.27–7.21 (m, 5H, HC(ar-
2
3
3.54 (AB, JAB = 12.6, 2H, H2C–Ph); 3.67 (dd, JH,H = 14.4, JH,H = 4.8,
2
3
2
1H, H2C–N); 3.57 (dd, JH,H = 14.4, JH,H = 5.4, 1H, H2C–N); 3.09–
3.03 (m, 1H, H2C(50)); 3.02–2.95 (m, 1H, H2C(20)); 2.55 (s, 3H,
H3C–C(5)); 2.47–2.40 (m, 1H, H2C(50)); 2.00–1.91 (m, 1H,
H2C(30)); 1.80–1.72 (m, 1H, H2C(40)); 1.64–1.54 (m, 1H, H2C(40));
1.49–1.39 (m, 1H, H2C(30)). 13C NMR (CDCl3): d 157.9 (C@O);
138.7, 137.5 (2 C(arom.)); 132.0, 131.7, 129.0, 128.8, 127.8,
122.2, 121.5, 116.7 (1 C(arom.), 9 CH(arom.), 2 C(imid.)); 126.1
(HC(2)); 62.8 (HC(20)); 60.3 (CH2–Ph); 55.1 (C(50)); 48.8 (CH2–N);
28.4 (C(30)); 23.7 (C(40)); 10.0 (H3C–C(5)). HR-ESI-MS (MeOH + H-
om.)); 7.17–7.14 (m, 1H, HC(arom.)); 3.88 (dd, JH,H = 14.4,
2
3
3JH,H = 5.4, 1H, H2C–N); 3.74 (dd, JH,H = 14.4, JH,H = 7.2, 1H,
H2C–N); 3.58, 3.25 (AB, JAB = 12.6, 2H, H2C–Ph); 2.96–2.91 (m,
1H, H2C(50)); 2.72–2.66 (m, 1H, HC(20)); 2.26–2.19 (m, 1H,
H2C(50)); 1.83–1.76 (m, 1H, H2C(40)); 1.70–1.58 (m, 2H, H2C(30));
1.52–1.45 (m, 1H, H2C(40)). 13C NMR (CDCl3): d 139.2, 138.2,
134.9 (3 C(arom.)); 137.7 (HC(2)); 131.4, 131.3, 129.3, 129.0,
128.9, 128.7, 128.5, 128.3, 127.2, 126.8, 126.4 (15 CH(arom.), 2
C(imid.)); 63.7 (HC(20)); 59.6 (CH2–Ph); 54.6 (H2C(50)); 49.4
(CH2–N); 29.1 (C(40)); 23.2 (C(30)). HR-ESI-MS (MeOH + HCOOH):
COOH):
469.1230
(calcd
469.1234
for
C23H26BrN4O2,
[M(79Br)+1]+). ½a 2D5
ꢂ
¼ ꢀ22 (c 1.0, CH2Cl2).
394.2278 (calcd 394.2278 for
(c 1.0, CH2Cl2).
C
27H28N3, [M+1]+).
½
a 2D5
ꢂ
¼ ꢀ31
4.2.5. Synthesis of imidazoles 6
To a magnetically stirred solution of imidazole N-oxide 5
(5 mmol) in EtOH (15 ml), a suspension of freshly prepared Ra-
ney-Nickel in EtOH was added in small portions at rt. The progress
of the reaction was followed by TLC (SiO2, MeOH/AcOEt 1:1). Next,
the mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude products 6a–e were purified by chro-
matography or by crystallization.
4.2.5.4. N-Phenyl-1-{[(2S)-N-benzylpyrrolidin-2-yl]methyl}-5-
methyl-1H-imidazole-4-carboxamide 6d. Yield: 1.3 g (72%). Col-
orless crystals. Mp 82–84 °C (Et2O). IR (KBr):
v 3432br, 3270m,
3243m, 3121m, 3033m, 2969m, 2946m, 2779m, 1943w, 1968w,
1752w, 1660s, 1596s, 1537m, 1503s, 1440s, 1246s, 878m, 759s,
697s. 1H NMR (CDCl3): d 9.03 (s, 1H, NH); 7.70–7.67 (m, 2H, HC(ar-
om.)); 7.48 (s, 1H, HC(2)); 7.35–7.28 (m, 6H, HC(arom.)); 7.27–7.24
(m, 1H, HC(arom.)); 7.09–7.07 (m, 1H, HC(arom.)); 3.81 (dd,
3
2
4.2.5.1. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-dimethyl-
1H-imidazole 6a. Yield: 1.0 g (75%). Pale yellow oil (SiO2, MeOH/
2JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.76 (dd, JH,H = 14.4,
3JH,H = 6.0, 1H, H2C–N); 3.75, 3.49 (AB, JAB = 13.2, 2H, H2C–Ph);
3.04–2.98 (m, 1H, H2C(50)); 2.96–2.90 (m, 1H, HC(20)); 2.57 (s,
3H, H3C–C(5)); 2.39–2.31 (m, 1H, H2C(50)); 1.93–1.85 (m, 1H,
H2C(30)); 1.75–1.69 (m, 1H, H2C(40)); 1.67–1.58 (m, 1H, H2C(40));
1.54–1.46 (m, 1H, H2C(30)). 13C NMR (CDCl3): d 162.1 (C@O);
139.3, 138.7 (2 C(arom.)); 136.1 (HC(2)); 133.2, 131.5, 129.1,
128.9, 128.7, 127.5, 123.7, 119.7 (10 HC(arom.), 2 C(imid.)); 63.4
(HC(20)); 60.2 (CH2–Ph); 55.0 (H2C(50)); 49.0 (CH2–N); 29.0
(C(30)); 23.4 (C(40)); 9.9 (H3C–C(5)). HR-ESI-MS (MeOH + HCOOH):
AcOEt, 1:1). IR (film):
v 3428br, 2926m, 2854w, 2360w, 2342w,
1637w, 1560m, 1416m, 1245m, 1216m, 1045w, 1021w, 801m,
748m, 700m. 1H NMR (CDCl3): d 7.40 (s, 1H, HC(2)); 7.33–7.29
(m, 4H, HC(arom.)); 7.26–7.21 (m, 1H, HC(arom.)); 3.76 (dd,
3
2JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.76, 3.44 (AB, JAB = 13.2, 2H,
2
3
H2C–Ph); 3.66 (dd, JH,H = 14.4, JH,H = 7.2, 1H, H2C–N); 3.31–2.96
(m, 1H, H2C(50)); 2.87–2.82 (m, 1H, H2C(20)); 2.33–2.27 (m, 1H,
H2C(50)); 2.13 (s, 3H, H3C–C(4)); 2.06 (s, 3H, H3C–C(5)); 1.89–

´
963
G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
375.2178 (calcd 375.2179 for C23H27N4O, [M+1]+). ½a D25
ꢂ
¼ ꢀ11 (c
dithione 8 (2 mmol) in CHCl3 (2 ml) was added dropwise at 0 °C,
and stirring was continued overnight at rt. Next, the solvent was
evaporated under reduced pressure and the residue was washed
with hexane. The resulting material was purified by crystallization.
1.0, CH2Cl2).
4.2.5.5. N-(4-Bromophenyl)-1-{[(2S)-N-benzylpyrrolidin-2-yl]-
methyl}-5-methyl-1H-imidazole-4-carboxamide 6e. Yield: 2.3 g
(63%). Colorless oil (SiO2, MeOH/AcOEt, 1:3). IR (film):
v
3362br,
4.2.7.1. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-dimethyl-
1,3-dihydro-2H-imidazole-2-thione 9a. Yield: 0.8 g (68%). Color-
3180s, 3061m, 3028m, 2970m, 2872m, 2799m, 1951m, 1888m,
1671m, 1588m, 1506m, 1397m, 1241m, 1116m, 1060m, 1007s,
829s, 700m, 659m. 1H NMR (CDCl3): d 9.03 (s, 1H, NH); 7.69–7.57
(m, 2H, HC(arom.)); 7.48 (s, 1H, HC(2)); 7.44–7.41 (m, 1H, HC(ar-
om.)); 7.34–7.24 (m, 6H, HC(arom.)); 3.80–3.74 (m, 2H, H2C–N);
3.73, 3.50 (AB, JAB = 13.2, 2H, H2C–Ph); 3.04–2.98 (m, 1H, H2C(50));
2.96–2.91 (m, 1H, HC(20)); 2.55 (s, 3H, H3C–C(5)); 2.38–2.31 (m,
1H, H2C(50)); 1.94–1.86 (m, 1H, H2C(40)); 1.76–1.69 (m, 1H,
H2C(30)); 1.66–1.58 (m, 1H, H2C(30)); 1.53–1.46 (m, 1H, H2C(40)).
13C NMR (CDCl3): d 162.0 (C@O); 139.3, 137.8 (2 C(arom.)); 136.3
(HC(2)); 132.1, 129.1, 129.0, 128.7, 127.5, 121.2, 119.7, 116.1 (1
C(arom.), 9 CH(arom.), 2 C(imid.)); 63.4 (HC(20)); 60.2 (CH2–Ph);
55.0 (H2C(50)); 49.0 (CH2–N); 29.0 (C(30)); 23.4 (C(40)); 9.9 (H3C–
C(5)). HR-ESI-MS (MeOH + HCOOH): 453.1279 (calcd 453.1285 for
less crystals. Mp 108–110 °C (CH2Cl2/hexane). IR (KBr):
v 3432br,
3085m, 2943m, 2792m, 2522w, 1659s, 1499s, 1452m, 1393m,
1306m, 1127m, 1029m, 782m, 739s, 697s, 472s. 1H NMR (CDCl3):
d 11.45 (s, 1H, NH); 7.27–7.23 (m, 4H, HC(arom.)); 7.21–7.17 (m,
2
3
1H, HC(arom.)); 4.02 (dd, JH,H = 13.3, JH,H = 7.8, 1H, H2C–N); 3.78
2
3
(dd, JH,H = 13.3, JH,H = 6.0, 1H, H2C–N); 3.87, 3.45 (AB, JAB = 13.2,
2H, H2C–Ph); 3.41–3.34 (m, 1H, HC(20)); 2.99–2.94 (m, 1H,
H2C(50)); 2.28 (m, 1H, H2C(50)); 2.03 (s, 3H, H3C–C(4)); 2.01 (s,
3H, H3C–C(5)); 1.88–1.63 (m, 2H, H2C(40), 2H, H2C(30)). 13C NMR
(CDCl3): d 158.5 (C@S); 139.2 (1 C(arom.)); 129.0, 128.3, 127.0,
122.2, 119.9 (5 HC(arom.), 1 (C(arom.), 2 C(imid.)); 61.9 (HC(20));
60.5 (CH2–Ph); 54.8 (H2C(50)); 49.4 (CH2–N); 29.2 (C(40)); 23.6
(C(30)); 9.3 (H3C–C(5)); 9.2 (H3C–C(4)). HR-ESI-MS (MeOH + H-
C
23H26BrN4O, [M(79Br)+1]+). ½a D25
ꢂ
¼ ꢀ10 (c 1.0, CH2Cl2).
COOH): 302.1687 (calcd 302.1685 for
¼ ꢀ19 (c 1.0, CH2Cl2).
C
17H24N3S, [M+1]+).
½ ꢂ
a 2D5
4.2.6. General procedure for synthesis of imidazoles 7a and 7b
To a magnetically stirred solution of an imidazole N-oxide 5
(1 mmol) in MeOH (4 ml), 10% Pd/C (0.05 g) was added and the mix-
ture stirred under H2 atm until the reaction was complete (moni-
tored by TLC). Then, the solid was filtered through Celite and the
solvent was evaporated under reduced pressure. The product ob-
tainedwaspurifiedbycolumnchromatographyorbycrystallization.
4.2.7.2. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-diphenyl-
1,3-dihydro-2H-imidazole-2-thione 9b. Yield: 0.5 g (31%). Color-
less crystals. Mp 197–199 °C (EtOH). IR (KBr):
v 3432br, 3058m,
2937m, 2807m, 1602m, 1492s, 1397s, 1202m, 1160m, 1119m,
1073m, 1027m, 700s, 682m, 556s. 1H NMR (CDCl3): d 11.30 (s,
1H, NH); 7.46–7.40 (m, 3H, HC(arom.)); 7.36–7.33 (m, 2H, HC(ar-
2
om.)); 7.25–7.16 (m, 10H, HC(arom.)); 4.12 (dd, JH,H = 12.9,
2
3
4.2.6.1. 4,5-Diphenyl-1-{[(2S)-pyrrolidin-2-yl]methyl}-1H-imid-
azole 7a. Yield: 0.277 mg (87%). Colorless crystals. Mp 123–125 °C
3JH,H = 9.0, 1H, H2C–N); 3.94 (dd, JH,H = 12.9, JH,H = 4.2, 1H, H2C–
N); 3.76, 3.22 (AB, JAB = 12.9, 2H, H2C–Ph); 3.21–3.25 (m, 1H,
HC(20)); 2.81–2.76 (m, 1H, H2C(50)); 2.20–2.15 (m, 1H, H2C(50));
1.73–1.66 (m, 1H, H2C(40)). 13C NMR (CDCl3): d 161.4 (C@S);
140.1 (1 C(arom.)); 131.7, 129.6, 129.3, 129.1, 129.0, 128.9,
128.3, 128.1, 127.9, 126.9, 126.8, 125.5 (12 signals for 15 HC(ar-
om.), 3 C(arom.), 2 C(imid.)); 61.7 (HC(20)); 59.9 (CH2–Ph); 54.3
(C(50)); 49.3 (CH2–N); 29.1 (C(30)); 23.5 (C(40)). HR-ESI-MS
(CH2Cl2/hexane). IR (KBr):
v 3357br, 3049m, 2989m, 2834m,
2223w, 1509m, 1439m, 1357m, 1220m, 1033m, 907m, 895m,
802m, 731m. 1H NMR (CDCl3): d 7.74 (s, 1H, NH); 7.48–7.43 (m,
5H, HC(arom.)); 7.35–7.32 (m, 2H, HC(arom.)); 7.21–7.16 (m, 2H,
2
HC(arom.)); 7.16–7.10 (m, 1H, HC(arom.)); 3.77 (dd, JH,H = 12.0,
2
3
3JH,H = 6.0, 1H, H2C–N); 3.74 (dd, JH,H = 12.0, JH,H = 3.6, 1H, H2C–
N); 3.24–3.17 (m, 1H, HC(20)); 2.92–2.84 (m, 2H, H2C(50)); 1.78–
1.61 (m, 1H, H2C(30), 2H, H2C(40)); 1.32–1.24 (m, 1H, H2C(30). 13C
NMR (CDCl3): d 138.4, 137.4, 134.9, 131.3, 131.2, 129.3, 128.9,
128.6, 128.3, 126.8, 126.4 (10 HC(arom.), 2 (C(arom.), 3 C(imid.));
58.6 (HC(20)); 50.5 (CH2–N); 46.4 (H2C(50)); 29.4 (C(40)); 25.3
(C(30)). HR-ESI-MS (MeOH + HCOOH): 302.1687 (calcd 302.1685
(MeOH + HCOOH): 426.1998 (calcd 426.1999 for
C27H28N3S,
[M+1]+). ½a 2D5
¼ ꢀ14 (c 1.0, CH2Cl2).
ꢂ
4.2.7.3.
N-(4-Bromophenyl)-1-{[(2S)-N-benzylpyrrolidin-2-yl]
methyl}-5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carbox-
amide 9c. Yield: 0.8 g (41%). Colorless crystals. Mp 215 °C (EtOH)
(decomposition). IR (KBr): v 3432br, 3275m, 3125m, 3065m,
for C17H24N3S, [M+1]+). ½a D25
ꢂ
¼ ꢀ18 (c 1.0, CH2Cl2).
2952m, 2902w, 2787m, 1663s, 1625s, 1542s, 1489s, 1380m,
828m, 811m, 698m, 504m. 1H NMR (CDCl3): d 8.85 (s, 1H, HN);
7.73–7.66 (m, 2H, HC(arom.)); 7.45–7.41 (m, 2H, HC(arom.));
7.24–7.20 (m, 4H, HC(arom.)); 7.15–7.10 (m, 1H, HC(arom.));
4.11 (dd, JH,H = 13.3, JH,H = 5.8, 1H, H2C–N); 3.85 (dd, JH,H = 13.3,
JH,H = 6.0, 1H, H2C–N); 3.74, 3.19 (AB, JAB = 12.9, 2 H, H2C–Ph);
3.42–3.33 (m, 1H, H2C(50)); 3.08–3.02 (m, 1H, HC(20)); 2.57 (s,
3H, H3C–C(5)); 2.46–2.35 (m, 1H, H2C(50)); 1.92–1.85 (m, 1H,
H2C(40)); 1.83–1.68 (m, 2H, H2C(30), 1H H2C(40)). 13C NMR (CDCl3):
d 162.1 (C@S); 161.6 (C@O); 138.7, 138.0 (2 C(arom.)); 136.6
(HC(2)); 132.7, 129.6, 129.1, 128.9, 121.7, 119.7, 116.1 (9 HC(ar-
om.), 1 C(arom.)), 2 C(imid.)); 63.8 (C(20)); 60.9 (CH2–Ph); 55.3
(C(50)); 49.2 (CH2–N); 29.7 (C(30)); 23.1 (C(40)); 10.0 (H3C–C(5)).
HR-ESI-MS (MeOH + HCOOH): 485.1002 (calcd 485.1005 for
4.2.6.2.
1H-imidazole-4-carboxamide 7b. Yield: 0.235 mg (83%). Colorless
oil (SiO2, MeOH/AcOEt, 6:4). IR (film): 3366br, 3058m, 2961m,
5-Methyl-N-phenyl-1-{[(2S)-pyrrolidin-2-yl]methyl}-
v
2873m, 2246w, 1663m, 1597m, 1575m, 1442m, 1330m, 1243m,
1064m, 906m, 877m, 829m, 756m. 1H NMR (CDCl3): d 9.05 (s,
1H, NH); 7.68–7.64 (m, 2H, HC(arom.)); 7.47 (s, 1H, HC(2)); 7.33–
7.28 (m, 2H, HC(arom.)); 7.08–7.03 (m, 1H, HC(arom.)); 3.86 (dd,
3
2
2JH,H = 14.1, JH,H = 5.4, 1H, H2C–N); 3.78 (dd, JH,H = 14.1,
3JH,H = 7.8, 1H, H2C–N); 3.41–3.35 (m, 1H, HC(20)); 2.94–2.89 (m,
2H, H2C(50)); 2.60 (s, 3H, H3C–N); 1.93–1.86 (m, 1H, H2C(30));
1.84–1.68 (m, 2H, H2C(40)); 1.44–1.37 (m, 1H, H2C(30)). 13C NMR
(CDCl3): d 162.1 (C@O); 138.6 (1 C(arom.)); 135.9, 133.1, 131.5,
129.0, 123.7, 119.7 (5 HC(arom.), 3 C(imid.)); 58.2 (CH2–N); 50.1
(HC(20)); 46.5 (H2C(50)); 29.4 (C(30)); 25.4 (C(40)); 9.8 (CH3–N).
HR-ESI-MS (MeOH + HCOOH): 302.1687 (calcd 302.1685 for
C
23H26BrN4OS, [M+1]+). ½a D25
¼ ꢀ10 (c 1.0, CH2Cl2).
ꢂ
C
17H24N3S, [M+1]+). ½a D25
ꢂ
¼ ꢀ24 (c 1.0, CH2Cl2).
4.2.8. Synthesis of 3-alkylimidazolium tetrafluoroborates 11
A solution of imidazole 6 (5 mmol) and alkyl bromide (5 mmol)
in acetonitrile (5 ml) was heated at reflux for 16 h. The solvent was
removed under reduced pressure, and the resulting product was
washed with Et2O (3 ꢁ 5 ml), and dried under high vacuum for
4.2.7. Synthesis of imidazole-2-thiones 9
To a magnetically stirred solution of an imidazole N-oxide 5
(4 mmol) in CHCl3 (4 ml), 2,2,4,4-tetramethylcyclobutane-1,3-

´
G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
964
4 h. The imidazolium bromide obtained was stirred magnetically
with an equimolar amount of solid NaBF4 in acetone (5 ml) over-
night at rt. The resulting suspension was filtered through neutral
alumina (CHCl3) and the solvent evaporated under reduced
pressure.
4.2.8.4. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4-methyl-3-
octyl-5-phenyl-1H-imidazolium tetrafluoroborate 11d. Yield:
1.9 g (72%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3627w,
3557w, 3151m, 3062m, 2927m, 2857m, 2804m, 1966m, 1900m,
1822m, 1559m, 1496m, 1459m, 1208m, 1058m, 926m, 843m,
763s, 703m. 1H NMR (CDCl3): d 9.00 (s, 1H, HC(2)); 7.55–7.50 (m,
3H, HC(arom.)); 7.29–7.26 (m, 4H, HC(arom.)); 7.24–7.21 (m, 1H,
4.2.8.1. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-hexyl-4,5-
dimethyl-1H-imidazolium tetrafluoroborate 11a. Yield: 1.6 g
2
HC(arom.)); 7.18–7.16 (m, 2H, HC(arom.)); 3.99 (dd, JH,H = 14.0,
2
3
(75%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v
3648w, 3628w,
3JH,H = 5.4, 1H, H2C–N); 3.94 (dd, JH,H = 14.0, JH,H = 6.6, 1H, H2C–
N); 3.54, 3.43 (AB, JAB = 13.2, 2H, H2C–Ph); 3.00–2.96 (m, 1H,
H2C(50)); 2.94–2.90 (m, 1H, HC(20)); 2.42–2.37 (m, 1H, H2C(50));
2.16 (s, 3H, H3C–C(5)); 1.87–1.77 (m, 2H, H2C(alk.), 1H, H2C(40));
1.73–1.67 (m, 1H, H2C(30)); 1.60–1.52 (m, 1H, H2C(30)); 1.39–1.21
(m, 10H, H2C(alk.), 1H, H2C(40)); 0.87 (t, JH,H = 7.2, H3C(alk.)). 13C
NMR (CDCl3): d 139.3 (1 C(arom.); 136.2 (HC(2)); 131.7, 130.8,
130.7, 129.6, 128.9, 128.5, 127.5, 127.2, 125.5 (10 HC(arom.), 2
C(arom.) 2 C(imid.)); 62.6 (C(20)); 59.9 (CH2–Ph); 54.4 (H2C(50));
50.8 (CH2-N); 47.8, 31.9, 29.9, 29.2 (4 C(alk.)); 29.2 (C(30)); 28.3,
26.6 (2 C(alk.)); 23.7 (C(40)); 22.8 (C(alk.)); 14.2 (H3C(alk.)); 8.9
3566m, 3154m, 3087m, 2956m, 2931m, 2805m, 1818m, 1564m,
1455m, 1058br, 742m, 703m, 626m. 1H NMR (CDCl3): d 8.72
(HC(2)); 7.29–7.26 (m, 2H, HC(arom.)); 7.23–7.19 (m, 3H, HC(ar-
om.)); 4.01–3.95 (m, 1H, H2C–N, 2H, H2C(alk.)); 3.89 (dd,
3
2JH,H = 13.8, JH,H = 6.6, 1H, H2C–N); 3.59, 3.56 (AB, JAB = 13.2, 2H,
H2C–Ph); 3.16–3.11 (m, 1H, HC(20)); 3.10–3.06 (m, 1H, H2C(50));
2.50–2.45 (m, 1H, H2C(50)); 2.16 (s, 3H, H3C–C(4)); 2.12 (s, 3H,
H3C–C(5)); 2.05–1.98 (m, 1H, H2C(30)); 1.83–1.77 (m, 1H,
H2C(40)); 1.74–1.67 (m, 1H, H2C(40); 2H, H2C(alk.)); 1.55–1.50 (m,
1H, H2C(30)); 1.32–1.24 (m, 6H, H2C(alk.)); 0.85 (t, JH,H = 7.2, 3H, H3-
C(alk.)). 13C NMR (CDCl3): d 139.4 (1 C(arom.); 135.4 (HC(2));
128.9, 128.5, 127.3, 127.2, 126.0 (5 CH(arom.), 2 C(imid.)); 62.7
(HC(20)); 60.5 (CH2–Ph); 54.9 (H2C(50)); 50.8 (CH2–N); 47.4, 31.3,
29.9 (3 C(alk.)); 28.5 (C(40)); 26.1 (C(alk.)); 23.9 (C(30)); 22.6
(C(alk.)); 14.1 (H3C(alk.)); 8.7 (H3C–C(5)); 8.5 (H3C–C(4)).
(H3C–C(5)). ½a 2D5
¼ ꢀ27 (c 1.0, CH2Cl2).
ꢂ
4.2.9. Synthesis of 3-alkoxyimidazolium tetrafluoroborates 13
A solution of imidazole N-oxide 5 (5 mmol) and the correspond-
ing alkyl bromide (5 mmol) in CHCl3 (10 ml) was stirred magneti-
cally at rt for 72 h. The solvent was then removed under reduced
pressure and the crude product was washed with Et2O
(3 ꢁ 5 ml), and dried under high vacuum for 4 h. The imidazolium
bromide obtained was stirred magnetically with an equimolar
amount of solid NaBF4 in acetone (5 ml) at rt overnight. The result-
ing suspension was filtered through neutral alumina (Et2O) and the
solvent evaporated under reduced pressure.
½
a 2D5
ꢂ
¼ ꢀ35 (c 1.0, CH2Cl2).
4.2.8.2. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-dimethyl-
3-octyl-1H-imidazolium tetrafluoroborate 11b. Yield: 1.6 g
(70%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3584w, 3154m,
3087m, 2928m, 2857m, 2806m, 1733w, 1699w, 1565s, 1454m,
1202m, 1058br, 828w, 742m, 703m. 1H NMR (CDCl3): d 8.73 (s,
1H, HC(2)); 7.28–7.25 (m, 2H, HC(arom.)); 7.23–7.18 (m, 3H,
2
3
HC(arom.)); 3.98 (dd, JH,H = 14.4, JH,H = 5.4, 1H, H2C–N); 3.97–
4.2.9.1. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-butoxy-4,5-
dimethyl-1H-imidazolium tetrafluoroborate 13a. Yield: 1.8 g
2
3
3.94 (m, 2H, H2C(alk.)); 3.88 (dd, JH,H = 14.4, JH,H = 7.2, 1H, H2C–
N); 3.57, 3.55 (AB, JAB = 13.6, 2H, H2C–Ph); 3.16–3.11 (m, 1H,
H2C(20)); 3.10–3.05 (m, 1H, H2C(50)); 2.50–2.44 (m, 1H, H2C(50));
2.15 (s, 3H, H3C–C(4)); 2.10 (s, 3H, H3C–C(5)); 1.97–1.82 (m, 1H,
H2C(30)); 1.82–1.77 (m, 1H, H2C(30)); 1.74–1.67 (m, 1H, H2C(40),
2H, H2C(alk.)); 1.55–1.49 (m, 1H, H2C(40)); 1.31–1.21 (m, 10H, H2-
C(alk.)); 8.62 (t, JH,H = 6.9, H3C(alk.)). 13C NMR (CDCl3): d 139.3 (1
C(arom.); 135.4 (HC(2)); 128.9, 128.5, 127.2, 127.2, 126.0 (5 HC(ar-
om.), 2 C(imid.)); 62.6 (HC(20)); 60.4 (CH2–Ph); 54.9 (C(50)); 50.8
(CH2–N); 47.4, 31.8, 29.9, 29.2, 29.1 (5 C(alk.)); 28.4 (C(30)); 26.5
(C(alk.)); 23.9 (C(40)); 22.7 (C(alk.)); 14.2 (H3C(alk.)); 8.7 (H3C–
(78%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3585w, 3380m,
3140m, 2961m, 2874m, 2807m, 1684m, 1545m, 1496m, 1454m,
1259w, 1187w, 1058m, 936m, 848m, 820m, 735s, 703s, 613w.
1H NMR (CDCl3): d 9.28 (s, 1H, HC(2)); 7.31–7.14 (m, 5H, HC(ar-
2
om.)); 4.38–4.29 (m, 2H, H2C(alk.)); 4.09 (dd, JH,H = 14.4,
2
3
3JH,H = 4.8, 1H, H2C–N); 3.96 (dd, JH,H = 14.4, JH,H = 7.8, 1H, H2C–
N); 3.59, 3.56 (AB, JAB = 13.2, 1H, H2C–Ph); 3.19–3.11 (m, 1H,
H2C(50), 1H, HC(20)); 2.57–2.52 (m, 1H, H2C(50)); 2.15 (s, 3H, H3C–
C(4)); 2.08 (s, 3H, H3C–C(5)); 2.06–2.00 (m, 1H, H2C(30)); 1.86–
1.79 (m, 1H, H2C(40)); 1.79–1.71 (m, 2H, H2C(alk.), 1H, H2C(40));
1.56–1.44 (m, 2H, H2C(alk.); 1H, H2C(30)); 0.97 (t, JH,H = 7.2, H3-
C(alk.)). 13C NMR (CDCl3): d 139.2 (1 C(arom.)); 131.7 (HC(2));
129.0, 128.5, 127.3, 124.8, 123.5 (5 CH(arom.), 2 C(imid.)); 82.9
(C(alk.)); 62.5 (C(20)); 60.6 (CH2–Ph); 55.0 (C(50)); 50.9 (CH2–N);
29.9 (C(alk.)); 28.3 (C(30)); 24.0 (C(40)); 19.0 (C(alk.)); 13.9 (H3-
C(4)); 8.5 (H3C–C(5)). ½a D25
¼ ꢀ22 (c 1.0, CH2Cl2).
ꢂ
4.2.8.3. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-butyl-4-me-
thyl-5-phenyl-1H-imidazolium tetrafluoroborate 11c. Yield:
1.6 g (68%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3151m,
3084m, 2961m, 2874m, 2807m, 1559m, 1497m, 1453m, 1203m,
1058m, 846w, 765m, 703s. 1H NMR (CDCl3): d 8.91 (s, 1H,
HC(2)); 7.55–7.50 (m, 3H, HC(arom.)); 7.29–7.26 (m, 4H, HC(ar-
om.)); 7.24–7.21 (m, 1H, HC(arom.)); 7.17–7.15 (m, 2H, HC(ar-
C(alk.)); 8.7 (H3C-C(5)); 7.2 (H3C–C(4)). ½a D25
¼ ꢀ33 (c 1.0, CH2Cl2).
ꢂ
4.2.9.2. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-4,5-dimethyl-
3-octyloxy-1H-imidazolium tetrafluoroborate 13b. Yield: 1.7 g
(69%). Pale yellow oil (Al2O3, CHCl3). IR (film): v 3584w, 3566w,
2
om.)); 4.09–4.07 (m, 2H, H2C(alk.)); 3.97 (dd, JH,H = 14.0,
2
3
3JH,H = 5.4, 1H, H2C–N); 3.93 (dd, JH,H = 14.0, JH,H = 6.6, 1H, H2C–
N); 3.52, 3.43 (AB, JAB = 13.2, 2H, H2C–Ph); 3.00–2.96 (m, 1H,
H2C(50)); 2.93–2.88 (m, 1H, H2C(20)); 2.43–2.37 (m, 1H, H2C(50));
2.16 (s, 3H, H3C–C(4)); 1.86–1.76 (m, 1H, H2C(30), 2H, H2C(alk.));
1.74–1.66 (m, 1H, H2C(40)); 1.60–1.53 (m, 1H, H2C(40)); 1.44–1.38
(m, 2H, H2C(alk.)); 1.36–1.31 (m, 1H, H2C(30)); 0.97 (t, JH,H = 7.50 -
Hz, H3C(alk.)). 13C NMR (CDCl3): d 139.3 (1 C(arom.)); 136.2
(HC(2)), 131.7, 130.9, 130.7, 129.7, 128.9, 128.5, 127.5, 127.3,
125.6 (10 HC(arom.), 1 C(arom.), 2 C(imid.)); 62.6 (HC(20)); 59.9
(CH2–Ph); 54.4 (H2C(50)); 50.9 (CH2–N); 47.6, 31.8 (2 C(alk.));
28.4 (C(30)); 23.7 (C(40)); 19.8 (C(alk.)); 13.6 (H3C(alk.)); 8.9
3384m, 3139m, 3061m, 2928m, 2857m, 2807m, 1634m, 1546m,
1496w, 1454w, 1260w, 1059m, 945m, 807w, 736m, 703s, 648w.
1H NMR (CDCl3): d 8.91 (s, 1H, HC(2)); 7.27–7.19 (m, 3H, HC(ar-
om.)); 7.17–7.13 (m, 2H, HC(arom.)); 4.36–4.27 (m, 2H, H2C(alk.));
2
3
2
4.05 (dd, JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.93 (dd, JH,H = 14.4,
3JH,H = 7.8, 1H, H2C–N); 3.57, 3.55 (AB, JAB = 13.2, 2H, H2C–Ph);
3.16–3.10 (m, 1H, H2C(50), 1H, HC(20)); 2.57–2.52 (m, 1H,
H2C(50)); 2.15 (s, 3H, H3C–C(4)); 2.08 (s, 3H, H3C–C(5)); 2.07–
2.01 (m, 1H, H2C(30)); 1.86–1.80 (m, 1H, H2C(40)); 1.78–1.71 (m,
2H, H2C(alk.); 1H, H2C(40)); 1.54–1.49 (m, 1H, H2C(30)); 1.56–1.40
(m, 2H, H2C(alk.)); 1.35–1.24 (m, 8H, H2C(alk.)); 0.89 (t, JH,H = 7.2,
3H, H3C(alk.)). 13C NMR (CDCl3): d 139.4 (1 C(arom.)); 131.3
(H3C–C(4)). ½a 2D5
¼ ꢀ10 (c 1.0, CH2Cl2).
ꢂ

´
965
G. Mloston et al. / Tetrahedron: Asymmetry 24 (2013) 958–965
(HC(2)); 129.0, 128.5, 127.3, 124.8, 123.5 (5 C(arom.), 2 C(imid.));
62.4 (HC(20)); 60.6 (CH2–Ph); 54.9 (C(50)); 50.9 (CH2–N); 29.4,
28.3 (2 C(alk.)); 28.0 (C(30)); 25.7 (C(alk.)); 24.0 (C(40)); 22.8
(C(alk.)); 14.3 (H3C(alk.)); 8.7 (H3C–C(5)), 7.3 (H3C–C(4)).
59.8 (CH2–Ph); 54.1 (C(50)); 50.4 (CH2–N); 29.8 (C(alk.)); 23.6
(C(30)); 18.8 (C(40)); 13.7 (H3C(alk.)). ½a 2D5
¼ ꢀ16 (c.0, CH2Cl2).
ꢂ
5. Uncited reference
½
a 2D5
ꢂ
¼ ꢀ26 (c 1.0, CH2Cl2).
AUTHOR: PLEASE CITE REF. 1 IN THE TEXT.
4.2.9.3. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-butoxy-4-
methyl-5-phenyl-1H-imidazolium tetrafluoroborate 13c. Yield:
Acknowledgments
1.6 g (70%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3584w,
3366m, 3135m, 3061m, 2961m, 2874m, 2806m, 1679m, 1543m,
1496m, 1452m, 1380m, 1283w, 1058m, 934m, 822w, 756m,
736m, 702s. 1H NMR (CDCl3): d 9.08 (s, 1H, HC(2)); 7.53–7.48 (m,
3H, HC(arom.)); 7.28–7.13 (m, 7H, HC(arom.)); 4.52–4.43 (m, 2H,
A.W. thanks the National Science Center (Cracow) for financial
support (Grant Preludium # UMO-2012/07/N/ST5). The authors
thank PD Dr. L. Bigler, University of Zürich, for ESI-HRMS.
2
3
H2C(alk.)); 4.04 (dd, JH,H = 14.4, JH,H = 4.8, 1H, H2C–N); 3.95 (dd,
References
3
2JH,H = 14.4, JH,H = 7.8, 1H, H2C–N); 3.57, 3.45 (AB, JAB = 12.6, 2H,
H2C–Ph); 3.06–3.02 (m, 1H, H2C(50)); 2.91–2.86 (m, 1H, HC(20));
2.52–2.47 (m, 1H, H2C(50)); 2.16 (s, 3H, H3C–C(4)); 1.86–1.79 (m,
2H, H2C(alk.), 1H, H2C(30)); 1.78–1.71 (m, 1H, H2C(40)); 1.63–1.50
(m, 2H, H2C(alk.); 1H, H2C(40)); 1.43–1.28 (m, 1H, H2C(30)); 1.00
(t, JH,H = 7.2, 3H, H3C(alk.)). 13C NMR (CDCl3): d 139.3 (1 C(arom.));
132.1 (HC(2)); 130.9, 130.8, 129.7, 129.1, 129.0, 128.5, 127.3,
´
1. Part of the Diploma thesis, University of Łódz, 2011, and of the planned Ph.D.
Thesis of A.W., University of Łódz´.
2. (a) Katrizky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. In
Comprehensive Heterocyclic Chemistry III; Five-membered Rings with Two
Heteroatoms, Each with Their Fused Carbocylic Derivatives; Joule, J., Ed.;
Elsevier: Oxford, 2008, Vol. 4; (b) Joule, J.; Mills, K. Heterocyclic Chemistry, 5th
ed.; J. Wiley & Sons: Chichester, UK, 2010; (c) Bhatnagar, A.; Sharma, P. K.;
Kumar, N. Int. J. Pharm. Tech. Res. 2011, 3, 268–282.
3. Babizhayev, M. A. Life Sci. 2006, 78, 2343–2357.
124.9, 124.8 (10 HC(arom.);
1 C(arom.), 2 C(imid.)); 83.2
(C(alk.)); 62.3 (HC(20)); 60.1 (CH2–Ph); 54.4 (C(50)); 50.6 (CH2–N);
30.1 (C(alk.)); 27.9 (C(40)); 23.8 (C(30)); 19.1, 13.9 (2 C(alk.)); 7.5
4. Narasimhan, B.; Dharma, D.; Kumar, P. Med. Chem. Res. 2011, 20, 1119–1140.
5. (a) Nikitina, G. V.; Pevzner, M. S. Chem. Heterocycl. Compd. 1993, 127–151; (b)
Alcázar, J.; Begtrup, M.; de la Hoz, A. J. Chem. Soc., Perkin Trans. 1 1995, 2467–
2470; (c) Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew. Chem., Int. Ed.
2002, 41, 2290–2293; (d) Aquirre, G.; Boiani, M.; Cerecetto, H.; Gerpe, A.;
Gonzales, M.; Fernandez Sainz, Y.; Denicola, A.; Ochoa de Ocariz, C.; Nogal, J. J.;
Montero, D.; Escario, J. A. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 259–270.
6. Laus, G.; Schwärzler, A.; Bentivoglio, G.; Hummel, M.; Kahlenberg, V.; Wurst,
K.; Kristeva, E.; Schütz, J.; Kopacka, H.; Kreuz, C.; Bonn, G.; Anfriyko, Y.; Nauer,
G.; Schottenberger, H. Z. Z. Naturforsch. 2008, 63B, 447–464.
(H3C–C(4)). ½a 2D5
¼ ꢀ25 (c 1.0, CH2Cl2).
ꢂ
4.2.9.4. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-hexyloxy-4-
methyl-5-phenyl-1H-imidazolium tetrafluoroborate 13d. Yield:
1.9 g (76%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3584w,
3369m, 3135m, 3061m, 2930m, 2872m, 2807m, 1683m, 1542m,
1496m, 1453m, 1379m, 1283w, 1058m, 933m, 913m, 765m,
735m, 702s. 1H NMR (CDCl3): d 9.10 (s, 1H, HC(2)); 7.55–7.48 (m,
3H, HC(arom.)); 7.29–7.14 (m, 7H, HC(arom.)); 4.51–4.42 (m, 2H,
7. Lettau, H. Z. Chem. 1970, 10, 211–216.
8. (a) Mucha, P.; Mloston´ , G.; Jasin´ ski, M.; Linden, A.; Heimgartner, H. Tetrahedron:
Asymmetry 2008, 19, 1600–1607; (b) Mloston´ , G.; Mucha, P.; Urbaniak, K.;
Broda, K.; Heimgartner, H. Helv. Chim. Acta 2008, 91, 232–238; (c) Jasinski, M.;
Mloston´ , G.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2008, 91, 1916–1933;
´
2
3
H2C(alk.)); 4.04 (dd, JH,H = 14.0, JH,H = 4.8, 1H, H2C–N); 3.95 (dd,
´
´
´
(d) Mloston, G.; Romanski, J.; Jasinski, M.; Heimgartner, H. Tetrahedron:
Asymmetry 2009, 20, 1073–1080.
3
2JH,H = 14.0, JH,H = 7.8, 1H, H2C–N); 3.57, 3.45 (AB, JAB = 13.2, 2H,
9. Kwiatkowski, P.; Mucha, P.; Mloston´ , G.; Jurczak, J. Synlett 2009, 1157–1760.
H2C–Ph); 3.06–3.02 (m, 1H, H2C(50)); 2.92–2.87 (m, 1H, HC(20));
2.53–2.47 (m, 1H, H2C(50)); 2.16 (s, 3H, H3C–C(4)); 1.87–1.80 (m,
2H, H2C(alk.); 1H, H2C(30)); 1.78–1.71 (m, 1H, H2C(40)); 1.64–1.57
(m, 1H, H2C(40)); 1.51–1.46 (m, 2H, H2C(alk.)); 1.37–1.28 (m, 4H,
H2C(alk.), 1H, H2C(30)); 0.92 (t, JH,H = 6.9, 3H, H3C(alk.)). 13C NMR
(CDCl3): d 139.3 (1 C(arom.)); 132.1 (HC(2)); 131.0, 130.9, 129.6,
129.1, 129.0, 128.5, 127.3, 124.9, 124.8 (10 HC(arom.); 1 C(arom.),
2 C(imid.)); 83.5 (C(alk.)); 62.3 (HC(20)); 60.1 (CH2–Ph); 54.4
(C(50)); 50.6 (CH2–N); 31.6, 28.1 (2 C(alk.)); 27.9 (C(30)); 25.4
(C(alk.)); 23.8 (C(40)); 22.7 (C(alk.)); 14.2 (H3C(alk.)); 7.6 (H3C–
´
10. Mloston, G.; Mucha, P.; Heimgartner, H. Lett. Org. Chem. 2012, 9, 89–91.
11. (a) Morris, D. J.; Partridge, A. S.; Manville, C. V.; Racys, D. T.; Woodward, G.;
Docherty, G.; Wills, M. Tetrahedron Lett. 2010, 51, 209–212; (b) Cao, X.-Y.;
Zheng, J.-C.; Li, Y.-X.; Shu, Z.-C.; Sun, X.-L.; Wanf, B.-Q.; Tang, Y. Tetrahedron
2010, 66, 9703–9707.
12. Mloston´ , G.; Pieczonka, M. A.; Wróblewska, A.; Linden, A.; Heimgartner, H.
Heterocycles 2012, 86, 343–356.
13. Rispeus, M. T.; Gelling, O. J.; de Vries, A. H. M.; Meetsma, A.; van Bolhuis, F.;
Feringa, B. L. Tetrahedron 1996, 52, 3521–3546.
14. Ghandi, M.; Salimi, F.; Ohyaei, A. Molecules 2006, 11, 556–563.
15. Mloston, G.; Jasin´ ski, M. ARKIVOC 2011, vi, 162–175.
16. (a) Mloston´ , G.; Obijalska, E.; Tafelska-Kaczmarek, A.; Zaidlewicz, M. J. Fluorine
Chem. 2010, 131, 1289–1296; For a review, see: (b) Vassiliou, S. Curr. Org. Chem.
2011, 15, 2469–2480.
C(4)). ½a 2D5
¼ ꢀ17 (c 1.0, CH2Cl2).
ꢂ
´
17. Mloston, G.; Celeda, M.; Prakash, G. K. S.; Olah, G. A.; Heimgartner, H. Helv.
Chim. Acta 2000, 83, 728–738.
4.2.9.5. 1-{[(2S)-N-Benzylpyrrolidin-2-yl]methyl}-3-butoxy-4,5-
diphenyl-1H-imidazolium tetrafluoroborate 13e. Yield: 1.5 g
18. Mloston´ , G.; Jasin´ ski, M.; Heimgartner, H. Eur. J. Org. Chem. 2011, 2542–2547.
19. Mloston´ , G.; Mucha, P.; Tarka, R.; Urbaniak, K.; Linden, A.; Heimgartner, H. Pol.
J. Chem. 2009, 83, 1105–1114.
(53%). Pale yellow oil (Al2O3, CHCl3). IR (film):
v 3648w, 3584w,
´
20. (a) Mloston, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 1585–
3369w, 3135m, 3061m, 2961m, 2874m, 2808m, 1683m, 1494m,
1447m, 1271m, 1179m, 1058m, 934m, 819m, 763m, 735m,
700m, 607w. 1H NMR (CDCl3): d 9.24 (s, 1H, HC(2)); 7.50–7.20
(m, 15H, HC(arom.)); 4.26–4.19 (m, 1H, H2C–N, 2H, H2C(alk.));
1595; (b) Mloston´ , G.; Jasin´ ski, M.; Rygielska, D.; Heimgartner, H. Heterocycles
2011, 83, 765–776.
21. (a) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198; (b) Doyle, A.
G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
2
3
22. (a) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-VCH:
Weinheim, 2008; (b) Bica, K.; Gaertner, P. Eur. J. Org. Chem. 2008, 3235–
3250; (c) Chen, X.; Li, X.; Hu, A.; Wang, F. Tetrahedron: Asymmetry 2008, 19, 1–
14; (d) Headly, A. D.; Ni, B. Aldrichim. Acta 2007, 40, 107–117.
23. Xu, D.; Luo, S.; Yue, H.; Wang, L.; Lin, Y.; Xu, Z. Synlett 2006, 2569–2572.
24. Belokon, Y. N.; Tararov, V. I.; Maleev, V. I.; Savel’eva, T. F.; Ryzhov, M. G.
Tetrahedron: Asymmetry 1998, 9, 4249–4252.
25. Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1984,
2887–2893.
26. Belokon, Y. N.; Maleev, V. I.; Videnskaya, S. O.; Saporovskaya, M. B.; Tsyryapkin,
V. A.; Belikov, V. M. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1991, 40,
110–118.
4.10 (dd, JH,H = 13.8, JH,H = 7.2, 1H, H2C–N); 3.65, 3.49 (AB,
JAB = 13.2, 2H, H2C–Ph); 3.06–3.01 (m, 1H, H2C(50)); 2.98–2.92 (m,
1H, HC(20)); 2.53–2.47 (m, 1H, H2C(50)); 1.89–1.82 (m, 1H,
H2C(30)); 1.79–1.73 (m, 1H, H2C(40)); 1.64–1.56 (m, 2H, H2C(alk.);
1H, H2C(40)); 1.36–1.32 (m, 1H, H2C(30)); 1.31–1.24 (m, 2H, H2-
C(alk.)); 0.79 (t, JH,H = 7.5, 3H, H3C(alk.)). 13C NMR (CDCl3): d
139.3 (1 C(arom.)); 133.1 (HC(2)); 131.3, 130.9, 130.4, 129.8,
129.73, 129.68, 129.2, 129.1, 128.7, 127.6, 126.8, 124.6, 123.4 (15
HC(arom.), 2 C(arom.) 2 C(imid.)); 83.4 (C(alk.)); 62.3 (C(20));