2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds

Article abstract of DOI:10.3390/molecules24234398

‘Desymmetrization’ of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH₂ derivatives (‘primary-tertiary diamines’). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained, which were deprotonated by treatment with triethylamine in the presence of elemental sulfur. Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur, yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines, amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were also studied.

Full text of DOI:10.3390/molecules24234398

molecules
Article
2
-Unsubstituted Imidazole N-Oxides as Novel
Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes
Derived from trans-1,2-Diaminocyclohexane and
Other Chiral Amino Compounds
Grzegorz Mlosto n´ 1,*, Małgorzata Celeda , Marcin Jasi n´ ski
1
1
, Katarzyna Urbaniak 1,
Przemysław J. Boraty n´ ski 2 , Peter R. Schreiner 3 and Heinz Heimgartner 4
1
Department of Organic and Applied Chemistry, University of Łód z´ , Tamka 12, PL-91-403 Łód z´ , Poland;
malgorzata.celeda@chemia.uni.lodz.pl (M.C.); marcin.jasinski@chemia.uni.lodz.pl (M.J.);
katarzyna.urbaniak@chemia.uni.lodz.pl (K.U.)
Department of Organic Chemistry, Wrocław University of Technology, Wyspia n´ skiego 27,
2
PL-50-370 Wrocław, Poland; przemyslaw.boratynski@pwr.edu.pl
Justus Liebig University, Institute of Organic Chemistry, Heinrich-Buff-Ring 17, D-35392 Giessen, Germany;
3
prs@uni-giessen.de
4
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland;
heinz.heimgartner@chem.uzh.ch
*
Correspondence: grzegorz.mloston@chemia.uni.lodz.pl; Tel.: +48-42-6355761
†
Dedicated to Professor Marek Zaidlewicz (Toru n´ ) on the occasion of his 80th birthday.
Academic Editors: Zbigniew Czarnocki and Joanna Szawkało
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 19 November 2019; Accepted: 29 November 2019; Published: 2 December 2019
Abstract: ‘Desymmetrization’ of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated
alkylation reagents leads to mono-NH derivatives (‘primary-tertiary diamines’). Upon reaction with
2
formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the
formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole
N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral
imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained,
which were deprotonated by treatment with triethylamine in the presence of elemental sulfur.
Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur,
yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous
reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines,
amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were
also studied.
Keywords: carbene sulfurization; chiral compounds; chiral nucleophilic carbenes; imidazole N-oxides;
imidazole-2-thiones; N-alkoxyimidazolium salts
1
. Introduction
Since 1991, after the isolation of the first stable 1,3-di(adamantyl)imidazol-2-ylidene [
has been a wealth of both structural studies and practical applications of nucleophilic N-heterocyclic
carbenes (NHCs) [ ]. At the same time, there is continuing demand for catalysts and ligands
for asymmetric synthesis [ ]. Chiral NHCs are particularly suitable for such applications, and
the elaboration of methods for the preparation of their precursors and subsequent applications in
1], there
2,3
4
asymmetric synthesis are intensively pursued [
5–
8]. One efficient method for the preparation of chiral
Molecules 2019, 24, 4398; doi:10.3390/molecules24234398
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NHCs is the introduction of a chiral fragment attached to the N-atom located within the heterocyclic
skeleton (chiral N-substituents).
It is therefore natural that one of the most important motifs in the structure of catalysts and
ligands for asymmetric catalysis derives from easily available and inexpensive enantiomerically pure
(R,R)-trans-1,2-diaminocylohexane (trans-DACH, Scheme 1) [9,10]. Numerous derivatives of this
exceptional diamine have been synthesized via functionalization of only one or both amino groups.
In recent years, much attention has been paid to so-called bifunctional catalysts, which are prepared
by modifications of the amino groups. Derivatives of type
building blocks for the synthesis of new bifunctional catalysts [11
the preparation of some bioactive compounds [13 17]. An efficient method for the ‘desymmetrization’
1
with a cyclic amine motif are promising
,12] and are important synthons for
–
of DACH, reported only in recent years, comprises two-fold N,N-alkylation of only one NH group
2
using α,ω-dihaloalkylating reagents as shown in Scheme 1 [12].
Scheme 1. trans-1,2-diaminocyclohexane (DACH) and its ‘desymmetrized’ derivatives
1 (Reproduced
with permission from [12]).
Along with trans-DACH, another primary amine widely explored in asymmetric synthesis is
-methylbenzylamine ( -MBA), but to date, reports on its application in the synthesis of chiral NHCs
are limited [ ]. Similarly, chiral -amino alcohols and amino esters have scarcely been explored.
α
α
6
β
Selected representatives of these two classes of compounds will also be involved in this study.
It is well established that the most efficient and preparatively useful method for the in situ
generation of imidazol-2-ylidenes 3 comprises the deprotonation of the corresponding imidazolium
salts of type 2 by treatment with a base (Scheme 2) [2,3].
Scheme 2. Formation of imidazol-2-ylidenes by deprotonation of imidazolium salts.
In our earlier publications, we described an efficient method for the synthesis of enantiomerically
pure bis- and mono-imidazole N-oxides derived either from trans-1,2-diaminocyclohexane [18
,19],
α
-methylbenzylamine [20], -amino alcohols [21], and amino acid esters [22]. In another study,
β
we demonstrated that 2-unsubstituted imidazole N-oxides including some chiral derivatives can
be O-alkylated by treatment with alkyl bromides [23]. However, these 1-alkoxyimidazolium salts
have never been used for the generation of N-alkoxy-substituted imidazol-2-ylidenes of type 3. In
a very recent publication, we reported the synthesis of non-symmetric imidazolium salts prepared
in a multistep synthesis starting with adamantyloxyamine [24]. In a test experiment, a symmetric
1,3-di(adamantyloxy)imidazolium salt was converted into the corresponding imidazole-2-thione
derivative via an intermediate NHC. Prompted by these results, we decided to synthesize a series of

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new chiral 1-alkoxyimidazolium salts derived from ‘desymmetrized’ trans-1,2-diaminocylohexane
derivatives of type , which can subsequently be used as precursors of chiral NHCs. The study was
1
extended by the involvement of
acid derivatives.
α-methylbenzylamine as well as selected amino alcohols and amino
2
. Results and Discussion
In contrast to DACH, which reacts with two equivalents of formaldehyde forming a dimeric
product identified as a tetraazaeicosane derivative [25], all ‘primary-tertiary’ diamines 1a reacted
with formaldehyde yielded the expected formaldimines 4a as solid products (Scheme 3). In
–d
–
d
the solid state they exist as hexahydro-1,3,5-triazines (trimers), which in polar, aprotic solvents
undergo almost total dissociation forming the monomeric imines. Similar observations were made
for cyclohexylformaldimine [26]. For example, formaldimine 4b dissolved in CDCl dissociates with
3
t1/2 of ca. 30 s at 298 K. On the other hand, the same imine observed in the C D solution exists as
6
6
an equilibrium mixture of trimeric and monomeric forms in a ratio of ca. 2.5:1. The structures of
1
13
1
formaldimines
4 were confirmed by H and C-NMR spectra in CDCl . For example, in the H-NMR
3
spectrum of 4b, the characteristic AB-system of the monomeric form located at 7.13 and 7.28 ppm with
13
J = 18 Hz was attributed to the N=CH group. In the C-NMR spectrum, the signal of this group
2
appeared at 151.0 ppm, and similar data were found for all formaldimines
4. However, in all samples,
the presence of trimeric forms interfered with the integration of signals. The presence of trimers was
revealed by signals of the CH groups located at 3.80–4.00 ppm. The products were unstable in solution
2
and underwent gradual decomposition over a period of weeks during storage at room temperature.
The molecular formulae of the stable, crystalline samples were confirmed by elemental analysis.
R
R
NH2
N
N=CH2
H C=O
2
trimers
-
H O
2
R
R
N
X
X
(
R,R)-1a-d
a: X = (CH ) ; b: X = CH
2
(R,R)-4a-d
2
0
c: X = (CH ) ; d: X = O
2
2
Scheme 3. Synthesis of monomeric formaldimines 4 from ‘primary–tertiary’ diamines 1.
In the case of 4e derived from (S)-
α
-methylbenzylamine ((S)-
α
-MBA), rapid trimerization led to
0
hexahydro-1,3,5-triazine 4 e (Scheme 4) in the course of its synthesis, and after isolation, it could be
used for further transformations only in this form [20]. An analogous tendency for trimerization was
also observed for 4f–h used in the study.
Scheme 4. Trimerization of formaldimine 4e derived from (S)-α-methylbenzylamine (α-MBA) [20]
(Reproduced with permission from [20]) and structures of analogous formaldimines 4f–i.

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In contrast, the alkoxyformaldimine 4i derived from (S)-α-methylbenzyloxyamine (α-MBOA) [27]
exists in CDCl solution in monomeric form, and in that case, no tendency to undergo trimerization was
3
observed even after three days at room temperature. Moreover, a similar behavior was observed in the
case of benzyloxyformaldimine (4j) prepared from benzyloxyamine (BOA) [28] and formaldehyde in
the course of the present study. Apparently, the presence of an alkoxy moiety reduces the electrophilicity
of the =CH unit and thereby formation of the trimeric forms is substantially disfavored.
2
Enantiomerically pure, (R,R)-configured 2-unsubstituted imidazole N-oxides
study as the key building blocks were prepared from enantiopure formaldimines , derived from the
corresponding amines , and -hydroxyiminoketones 5a in glacial acetic acid at room temperature [24].
6 used in this
4
1
α
,b
In the case of 4b, along with the (R,R)-configured stereoisomer, the (S,S)-enantiomer was also involved
in the study (Scheme 5 and Table 1).
Scheme 5. Synthesis of chiral (R,R)-configured imidazole N-oxides 6a–h (see also Table 1).
Table 1. Synthesis of imidazole N-oxides
6 and imidazole-2-thiones 9 from chiral formaldimines 4a–d
derived from ‘desymetrized’ trans-1,2-diaminocyclohexanes 1.
Config.
4
R
6
(%) 1
9
(%) 1
(
(
(
(
(
(
(
(
(
(
R,R)
R,R)
R,R)
R,R)
S,S)
S,S)
R,R)
R,R)
R,R)
R,R)
a
a
(CH2)4
(CH2)4
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)6
(CH2)6
Me
Ph
Me
Ph
Me
Ph
Me
Ph
a
b
c
d
c
d
e
f
g
h
65
93
90
65
95
83
78
89
86
66
a
b
c
d
c
d
e
f
g
h
62
70
60
82
47
62
42
70
67
81
b
b
b
b
c
c
d
d
(CH ) O(CH )
Me
Ph
2
2
2 2
(CH ) O(CH )
2 2
2
2
1
Yield of isolated compounds.
Reactions of 4 with α-hydroxyiminoketones 5 leading to imidazole N-oxides 6 were performed
at room temperature in glacial acetic acid. After isolation, the products were identified by
spectroscopic methods, and the most characteristic signal of HC(2) of the imidazole ring in the
1
H-NMR spectra appeared at ca. 8 ppm. Products
6 were alkylated with an equimolar amount of
benzyl bromide in CH Cl solution at room temperature. Due to the observed slow decomposition,
2
2
the (N-benzyloxy)imidazolium salts
7
were used for the next reaction step without further purification.
1
In the case of the azepane derivative 7e, the structure of the crude product was confirmed by H-NMR
spectroscopy. The characteristic HC(2)-signal was significantly shifted toward the lower field and
appeared at 11.35 ppm. In addition, chemoselective O-benzylation was confirmed by the appearance

Molecules 2019, 24, 4398
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of only one AB-system (5.67 and 5.72 ppm, J = 12.0 Hz) of the OCH Ph group. Thus, competitive
2
N-benzylation could be ruled out.
The obtained crude imidazolium salts
(Scheme 6). Their intermediacy was proven with known trapping reactions with elemental
sulfur [24,29,30] leading to non-enolizable imidazole-2-thiones. The deprotonation of was easily
achieved by treatment with triethylamine in pyridine. In the presence of elemental sulfur, the in
situ generated NHCs exclusively reacted with the desired imidazole-2-thiones (Scheme 6 and
7 were used as precursors of chiral imidazol-2-ylidenes
8
7
8
9
Table 1). Their structures were confirmed by spectroscopic data with the most characteristic signal
in the 13C-NMR spectra being the C(2)=S group resonating between 156 and 162 ppm. The obtained
imidazole-2-thiones 9a–h were shown to be optically active compounds. The optical rotation for all
these products was determined in CHCl solutions and no racemization under the reaction conditions
3
is expected.
Scheme 6. Preparation of imidazole-2-thiones 9a–h bearing a chiral substituent via intermediate
imidazol-2-ylidenes 8 (see also Table 1).
1
The inspection of the H-NMR spectra of
9 in CDCl solution at room temperature evidenced
3
complex signal patterns. It is likely that there are equilibria of different rotamers and/or conformers
1
existing in these solutions. To acquire more information, the H-NMR spectra of analytically pure
(R,R)-9b were recorded at different temperatures in a 1,1,2,2-tetrachloroethane solution. The spectrum
at 294 K showed a set of broadened signals in the region of 4.2–4.8 ppm attributed to the PhCH
2
O
fragment. In addition, two broad signals of H(C1) and HC(2) of the cyclohexane ring were found at 2.8
and 3.1 ppm. In the spectrum measured at 334 K, the benzylic region revealed one broad signal at
4.6 ppm and the signals of two distinct cyclohexane H-atoms were shifted high-field and overlap with
the -H-atoms of the pyrrolidine ring. This observation supports our assumption of the presence of a
α
dynamic equilibrium of different conformers of (R,R)-9b. An analogous explanation is valid for all
spectra of 9 bearing two Ph groups at C(4) and C(5) of the imidazole ring.
In extension of the studies performed with ‘desymmetrized’ trans-DACH derivatives, analogous
experiments were performed starting with enantiomerically pure functionalized primary amines.
Thus, the corresponding formaldimines 4f
0a by reaction with the -hydroxyiminoketone 5a under standard conditions (see Experimental
Section). In addition, enantiopure 10d, readily available by aminolysis of the corresponding ester
with (R)- -MBA [22] was used. The obtained imidazole N-oxides 10 were used for the preparation
of imidazolium salts 11a , which upon treatment with triethylamine in pyridine in the presence of
elemental sulfur gave the optically active imidazole-2-thiones 13a in good yields (Scheme 7). In
–h (Scheme 4) were converted into imidazole N-oxides
1
–
c
α
α
–d
–
d
these reactions, optically active N-butoxyimidazol-2-ylidenes of type 12 were the in situ generated
reactive intermediates.

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Scheme 7. Synthesis of optically active 3-butoxyimidazole-2-thiones 13.
1
In contrast to 9b
,d
,f, and
g
derived from (R,R)-trans-DACH, the H-NMR spectra of 13 clearly
indicated the presence of a single form in the solution. For example, the spectrum of compound 13b
showed only one multiplet for the CH O unit located at 4.34–4.41 ppm, and two characteristic singlets
2
of the Me groups at C(4) and C(5) of the imidazole ring at 1.72 and 2.09 ppm, respectively. In the
13
C-NMR spectrum, the signal of the C=S group appeared at 157.4 ppm.
In order to check whether steric hindrance is the reason for the existence of different conformers of 9,
four other compounds of that type (i.e., 15a
following the multistep procedure presented in Schemes 6 and 7. The starting 2-unsubstituted imidazole
N-oxides 14a are known compounds [20]. Upon treatment with alkylating reagents (benzyl bromide
–d derived from (S)-α-methylbenzylamine) were synthesized
,b
or n-pentyl bromide), they were converted into the corresponding imidazolium salts (Scheme 8). The
latter products without purification were treated with triethylamine in the presence of elemental sulfur,
yielding the desired 15a–d in good yields (66–81%).
R1
O
R1
OR2
2
1
. R Br/CHCl /rt
3
N
N
2
. NEt /Py/S /rt
3
8
R1
Ph
R1
Ph
S
N
N
Me
Me
14a,b
15a-d
1
1
2
a: R = Me
a: R = Me, R = CH Ph
(81%)
2
1
1
2
b: R = Ph
b: R = Me, R = (CH ) CH (77%)
2 4 3
1
2
c: R = Ph, R = CH Ph
(66%)
2
1
2
d: R = Ph, R = (CH ) CH (79%)
2
4
3
Scheme 8. 3-Alkoxyimidazole-2-thiones 15a–d derived from (S)-α-methylbenzylamine.
1
In that case, the less bulky (S)-
α-methylbenzyl residue was placed at the N(1) atom. The H-NMR
spectrum of 15a reveals the presence of the expected AB system of the PhCH O group at 5.45 and
2
5.58 (J = 10 Hz) ppm. This result emphasizes the importance of the steric demand in the series of
compounds 9 derived from bulky trans-1,2-diaminocyclohexane.
3
. Conclusions
Enantiomerically pure desymmetrized derivatives of trans-1,2-diaminocyclohexane containing one
free NH group (i.e., so called ‘primary-tertiary amines’) can be efficiently converted into corresponding
2
formaldimines. The initially obtained formaldimines were transformed into 2-unsubstituted
imidazole N-oxides, which upon treatment with benzyl bromide were selectively converted into
benzyloxyimidazolium salts. After deprotonation with triethylamine, the latter compounds generated
new types of chiral imidazol-2-ylidenes. Their appearance was evidenced by the trapping reaction
with elemental sulfur leading to chiral non-enolizable imidazole-2-thiones. The same procedure
applied to other optically active functionalized primary amines opens straightforward access for in

Molecules 2019, 24, 4398
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situ generated nucleophilic carbenes derived from imidazole (imidazol-2-ylidenes) bearing an alkoxy
group. This little-known class of alkoxy-substituted optically active NHCs is of interest for potential
applications in asymmetric synthesis and in organometallic chemistry for the preparation of transition
metal complexes. The multistep synthesis of the optically active imidazole-2-thiones occurs with
preservation of the stereochemistry. In addition, many derivatives of chiral 1,2-diamines [13
,15,31,32],
imidazolium salts [33 35] as well as numerous imidazole-2-thiones [36 37] display diverse biological
–
,
activities. Nevertheless, their alkoxy derivatives are practically unknown. For that reason, the new
types of ‘desymmetrized’ derivatives of trans-1,2-diaminocyclohexane and other optically active
primary amines reported in this work may also be of interest for medicinal chemistry.
4
. Materials and Methods
4
.1. General Information
Solvents and chemicals were purchased and used as received without further purification.
Products were purified by standard column chromatography on silica gel (230–400 mesh, Merck,
Kenilworth, NJ, USA). Unless stated otherwise, yields refer to analytically pure samples. NMR spectra
1
13
were recorded with a Bruker Avance III 600 MHz instrument ( H-NMR: 600 MHz; C-NMR: 151 MHz;
1
Bruker, Billerica, MA, USA). Chemical shifts are reported relative to solvent residual peaks ( H-NMR:
δ
= 7.26 ppm [CHCl3]; 13C-NMR:
δ = 77.0 ppm [CDCl ]). IR spectra were recorded with a FTIR NEXUS
3
spectrometer (as film or KBr pellets) or with a Cary 630 FTIR (Agilent Technologies, Santa Clara,
CA, USA) spectrometer, in neat. ESI-MS spectra were performed with a Varian 500-MS LC Ion Trap.
High-resolution mass spectrometry (HRMS) measurements were performed using Synapt G2-Si mass
spectrometer (Waters, Milford, MA, USA) equipped with an ESI source and quadrupole-Time-of-flight
mass analyzer. Elemental analyses were obtained with a Vario EL III (Elementar Analysensysteme
GmbH, Langenselbold, Germany) instrument. Optical rotations were determined with an Anton Paar
MCP 500 polarimeter (Anton Paar, Graz, Austria) at the temperatures indicated. Melting points were
determined in capillaries with a Stuart SMP30 apparatus with automatic temperature monitoring or
with a polarizing optical microscope (Opta-Tech, Warszawa, Poland), and are uncorrected.
4
.2. Starting Materials
The ‘primary–tertiary’ amines
1
(i.e., compounds (R,R)-1a
,
(R,R)-1b
,
(S,S)-1b,
(
R,R)-1c
of trans-1,2-diaminocyclohexane (trans-DACH), according to the literature procedure [12].
-Hydroxyiminoketones were prepared by nitrozation of ethyl methyl ketone in the case of
38] and by oximation of dibenzoyl in the case of 7b 39] based on the published procedures.
-Methylbenzyloxyamine ( -MBOA) [27] and benzyloxyamine (BOA) [40] were prepared based on
20], 4f 21], 4g 21], and 4h 22] were synthetized
from corresponding amino compounds and formaldehyde based on the published procedures.
,
and (R,R)-1d) were prepared from the respective, enantiopure diastereomers
α
5
7
α
a
[
[
α
modified literature procedures. Formaldimines 4e
[
[
[
[
4
.3. Synthesis of Formaldimines 4
4
.3.1. Reactions of ‘Primary-Tertiary’ Amines 1 with Formaldehyde—General Procedure
A solution of 5 mmol of the respective diamine
1 and 450 mg (15 mmol) of formaldehyde (used as
an aqueous solution) in 50 mL of benzene was heated in the Dean-Stark apparatus over 1.5 h. Next,
the solvent was evaporated and the crude products were obtained as colorless solids. Analytically
pure samples were obtained by recrystallization.
(
(
R,R)-N-[2-(Pyrrolidin-1-yl)cyclohexyl]methanimine ((R,R)-4a): Yield 855 mg (95%). Colorless crystals
◦
25
1
diisopropyl ether). M.p. 97–98 C. [α]D
= 135.30 (c 0.40, CHCl ). H-NMR (CDCl ): δ = 7.39 (d,
−
3 3
J = 17.2 Hz, 1H), 7.13 (d, J = 17.2 Hz, 1H), 2.93–2.97 (m, 1H), 2.66–2.71 (m, 1H), 2.52–2.62 (m, 4H),
.86–1.91 (m, 1H), 1.72–1.77 (m, 1H), 1.60–1.69 (m, 4H), 1.52–1.58 (m, 2H), 1.23–1.30 (m, 3H), 1.12–1.20
1

Molecules 2019, 24, 4398
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(
(
(
m, 1H) ppm. 13C-NMR (CDCl3):
vs), 2851 (s), 2801 (s), 1457 (m), 1384 (m), 1369 (m), 1183 (s), 1135 (vs), 997 (vs), 898 (m), 875 (m), 766
δ = 151.1, 74.4, 63.4, 48.4, 34.0, 24.6, 24.2, 23.9, 23.5 ppm. IR: ν 2920
−1
m) cm . C H N (180.29): calcd. C 73.28, H 11.18, N 15.54; found C 73.27, H 11.15, N 15.60.
11
20
2
(
R,R)-N-[2-(Piperidin-1-yl)cyclohexyl]methanimine ((R,R)-4b): Yield 756 mg (78%). Colorless crystals
◦
25
1
(
diethyl ether). M.p. 126–128 C. [α]D
= 130.92 (c 0.40, CHCl ). H-NMR (CDCl ): δ = 7.28 (d, J = 17.2
−
3 3
Hz, 1H), 7.13 (d, J = 17.2 Hz, 1H), 2.93 (td, J = 9.9, 5.2 Hz, 1H), 2.45–2.62 (m, 3H), 2.29–2.37 (m, 2H),
.8–11.86 (m, 1H), 1.72–1.79 (m, 1H), 1.58–1.69 (m, 3H), 1.44–1.51 (m, 2H), 1.30–1.40 (m, 4H), 1.10–1.25
m, 3H) ppm. 13C-NMR (CDCl3):
= 151.0, 72.4, 67.3, 49.6, 34.6, 26.6, 25.6, 25.1, 24.6, 23.6 ppm. IR:
924 (vs), 2849 (s), 1450 (m), 1381 (m), 1360 (m), 1191 (s), 1127 (vs), 1114 (vs), 1004 (vs), 911 (m), 876 (m),
1
(
2
7
δ
ν
–1
66 (m), 641 (m) cm . C H N (194.32): calcd. C 74.17, H 11.41, N 14.42; found C 74.17, H 11.38,
12 22 2
N 14.46.
(
S,S)-N-[2-(Piperidin-1-yl)cyclohexyl]methanimine ((S,S)-4b): Yield 775 mg (80%). Colorless crystals
◦
25
1
(
diethyl ether). M.p. 125–127 C. [α] = +140.97 (c 0.40, CHCl ). H-NMR (CDCl ):
δ = 7.28 (d, J = 17.2
D
3
3
Hz, 1H), 7.14 (d, J = 17.2 Hz, 1H), 2.94 (td, J = 9.9, 5.3 Hz, 1H), 2.46–2.61 (m, 3H), 2.28–2.36 (m, 2H),
.82–1.86 (m, 1H), 1.73–1.79 (m, 1H), 1.59–1.70 (m, 3H), 1.44–1.52 (m, 2H), 1.31–1.40 (m, 4H), 1.12–1.26
m, 3H) ppm. 13C-NMR (CDCl3):
= 151.1, 72.4, 67.3, 49.6, 34.6, 26.6, 25.6, 25.1, 24.6, 23.6 ppm. IR:
924 (vs), 2849 (s), 1450 (m), 1381 (m), 1360 (m), 1191 (s), 1127 (vs), 1114 (vs), 1004 (vs), 911 (m), 876 (m),
1
(
δ
ν
2
6
–1
41 (m) cm . C H N (194.32): calcd. C 74.17, H 11.41, N 14.42; found C 73.99, H 11.55, N 14.38.
12
22
2
(
(
R,R)-N-[2-(Azepan-1-yl)cyclohexyl]methanimine ((R,R)-4c): Yield 969 mg (93%). Colorless crystals
◦
25
1
diisopropyl ether). M.p. 112–114 C. [α] = –81.57 (c 0.40, CHCl ). H-NMR (CDCl ):
δ = 7.32 (d,
D
3
3
J = 17.3 Hz, 1H), 7.13 (d, J = 17.3 Hz, 1H), 2.90 (td, J = 10.0, 5.0 Hz, 1H), 2.64–2.68 (m, 2H), 2.59–2.64
m, 1H), 2.50–2.55 (m, 2H), 1.79–1.82 (m, 1H), 1.71–1.76 (m, 1H), 1.63–1.68 (m, 1H), 1.41–1.62 (m, 10H),
.15–1.24 (m, 3H) ppm. 13C-NMR (CDCl3):
= 151.1, 73.7, 68.6, 51.4, 34.5, 30.0, 27.0, 25.6, 25.3, 24.6
ppm. IR: 2920 (vs), 2849 (s), 1448 (m), 1355 (m), 1166 (m), 1131 (s), 993 (m), 907 (m), 874 (m) cm .
C H N (208.34): calcd. C 74.94, H 11.62, N 13.44; found C 75.10, H 11.73, N 13.61.
(
1
δ
−1
ν
13
24
2
(
(
(
R,R)-N-(2-Morpholinocyclohexyl)methanimine ((R,R)-4d): Yield 1.02 g (98%). Colorless crystals
◦
25
1
diisopropyl ether). M.p. 127–129 C. [α]D
d, J = 17.1 Hz, 1H), 7.14 (d, J = 17.1 Hz, 1H), 3.59–3.66 (m, 2H), 3.51–3.55 (m, 2H), 2.93 (td, J = 9.8,
.5 Hz, 1H), 2.50–2.60 (m, 3H), 2.40–2.46 (m, 2H), 1.83–1.88 (m, 1H), 1.75–1.79 (m, 1H), 1.65–1.70 (m,
=
−
124.52 (c 0.40, CHCl ). H-NMR (CDCl ): δ = 7.30
3 3
5
13
1
3
H), 1.57–1.63 (m, 2H), 1.16–1.26 (m, 3H) ppm. C-NMR (CDCl3):
4.6, 25.5, 24.6, 23.9 ppm. IR: 2920 (s), 2851 (s), 1450 (m), 1258 (m), 1112 (vs), 995 (s), 872 (m) cm .
C H N O (196.29): calcd. C 67.31, H 10.27, N 14.27; found C 67.07, H 10.39, N 14.23.
δ = 151.4, 72.5, 67.6, 67.0, 48.9,
–
1
ν
11
20
2
4
.3.2. Synthesis of Alkoxyformaldimines 4i–j—General Procedure
A solution of 3 mmol of the corresponding primary amine ((S)-MBOA or BOA) and 0.25 mL (ca.
3
mmol) of formaldehyde (as aqueous solution (37%)) in 40 mL benzene was heated in the Dean-Stark
apparatus until no formation of water was observed. After cooling to room temperature, the solvent
was evaporated and the colorless, oily liquids were used for further reactions without purification.
2
5
(
S)-(
α
-Methylbenzyloxy)methanimine (4i): Yield 404 mg (90%). Colorless liquid. [α]
= 11.90 (c 0.51,
−
D
1
CHCl ). H-NMR (CDCl ):
δ = 7.38–7.33, 7.30–7.27 (2m, 4H, 1H, Ph), 7.08, 6.43 (2d, 2H, J = 8.5 Hz,
CH ), 5.27 (q, J = 6.7 Hz, 1H), 1.56 (d, J = 6.7 Hz, 3H, Me) ppm. C-NMR (CDCl3): δ = 143.0 (t,
2
N=CH ), 137.4, 128.4, 127.6, 126.3 (s, 3d, Ph), 81.1 (d, CH), 21.8 (q, Me) ppm. HRMS (CI ): calcd for
3
3
13
=
+
2
+
C H NO [M + H] 150.0917; found 150.0919.
9
13
◦
Benzyloxy)methanimine (4j): Yield 360 mg (88%). Colorless liquid (ref. [41], bp 76 C/15 mmHg).
(
1
H-NMR (CDCl3):
δ = 7.40–7.35, 7.34–7.30 (2m, 4H, 1H, Ph), 7.09, 6.47 (2d, 2H, J = 8.2 Hz, =CH ), 5.14
2
13
(
s, 2H, -CH -) ppm. C-NMR (CDCl3):
δ = 137.4 (t, N=CH ), 137.3 (s, Ph), 128.3, 128.1, 127.8 (3d, Ph),
2
2
7
5.8 (t, -CH -) ppm.
2

Molecules 2019, 24, 4398
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4
.4. Synthesis of Imidazole N-Oxides 6—General Procedure
A solution of 1.1 mmol of the respective formaldimine
4
and 1 mmol of
α
-hydroxyiminoketone
5
in 3 mL of glacial acetic acid was stirred magnetically overnight. The next day, 1 mL of aqueous
hydrochloric acid was added and the solution was stirred for 15 min. Then, the resulting solution was
evaporated to dryness, the solid residue was dissolved in 20 mL of dichloromethane, and the obtained
solution was neutralized with 20 mL of diluted aqueous sodium hydroxide. The organic layer was
separated, dried over mgSO , filtrated, and evaporated. The resulting crude products were washed
4
with two portions (each ca. 10 mL) of diethyl ether, and after separation, the obtained thick oils or
amorphous solids were characterized spectroscopically and used for further transformations.
(
R,R)-4,5-Dimethyl-1-[2-(pyrrolidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((R,R)-6a): Yield 171.0 mg
1
(
65%). Colorless, viscous oil. H-NMR (CDCl ):
δ = 7.88 (s, 1H), 3.73 (td, J = 11.2, 3.5 Hz, 1H), 2.81–2.87
3
(
1
m, 1H), 2.45–2.49 (m, 2H), 2.37–2.41 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 2.00–2.03 (m, 1H), 1.93–1.97 (m,
13
H), 1.80–1.84 (m, 1H), 1.76–1.79 (m, 1H), 1.44–1.60 (m, 4H), 1.14–1.35 (m, 4H) ppm. C-NMR (CDCl3):
= 125.2, 123.0, 120.6, 62.1, 58.7, 48.0, 35.0, 25.2, 24.8, 24.6, 23.6, 8.8, 7.1 ppm. IR: 2927 (s), 1655 (m),
δ
ν
−1
+
1
448 (m), 1377 (m), 1332 (vs), 1191 (m), 1142 (m), 883 (s), 702 (s), 579 (s) cm . HRMS (ESI ): calcd for
+
C H N O [M + H] 264.2076; found 264.2082.
15
26
3
(
(
7
2
(
1
1
(
R,R)-4,5-Diphenyl-1-[2-(pyrrolidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((R,R)-6b): Yield 360.0 mg
◦
1
93%). Yellowish crystals. M.p. 189–191 C. H-NMR (CDCl ):
δ
= 8.12 (s, 1H), 7.49 (d, J = 7.9 Hz),
.35–7.39 (m, 3H), 7.18–7.23 (m, 5H), 3.74 (td, J = 11.7, 4.2 Hz, 1H), 2.86 (td, J = 11.1, 3.5 Hz, 1H),
.32–2.36 (m, 2H), 2.25–2.29 (m, 2H), 2.06–2.11 (m, 1H), 1.89–1.94 (m, 1H), 1.47–1.78 (m, 8H), 1.21–1.29
= 130.7, 129.6, 129.3, 129.1, 128.9, 128.0, 127.9,
27.8, 127.3, 127.0, 124.2, 62.3, 58.7, 47.6, 35.4, 25.2, 24.6, 24.0, 23.56, 23.51 ppm. IR: 2931 (m), 2808 (s),
448 (m), 1341 (m), 1321 (m), 1224 (m), 881 (m), 754 (s), 710 (s), 689 (vs), 658 cm . C H N O 0.5 H O
3
m, 1H), 1.08–1.18 (m, 3H) ppm. 13C-NMR (CDCl3):
δ
ν
−
1
·
2
5
29
3
2
387.52 + 9): calcd. C 75.72, H 7.62, N 10.60; found C 75.50, H 7.59, N 10.61.
(
(
R,R)-4,5-Dimethyl-1-[2-(piperidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((R,R)-6c): Yield 249.5 mg
◦
1
90%). Yellowish crystals. M.p. 68–71 C. H-NMR (CDCl ):
δ
= 7.70 (s, 1H), 3.75 (td, J = 11.5, 3.8 Hz,
3
1
1
6
H), 2.47–2.54 (m, 3H), 2.23–2.27 (m, 2H), 2.19 (s, 3H), 2.11 (s, 3H), 1.99–2.02 (m, 2H), 1.78–1.87 (m, 2H),
.45–1.52 (m, 1H), 1.37–1.42 (m, 2H), 1.24–1.33 (m, 7H) ppm. 13C-NMR (CDCl3):
7.7, 56.6, 50.0, 34.9, 26.5, 25.4, 25.0, 24.7 (2C signals overlap), 8.9, 7.2 ppm. IR:
δ
= 124.9, 123.4, 120.8,
ν
2926 (vs), 2853 (m),
–1
+
1
655 (br.m), 1450 (s), 1377 (m), 1331 (vs), 1103 (m), 881 (m), 702 (s), 579 (s) cm . HRMS (ESI ): calcd
+
for C H N O [M + H] 278.2232; found 278.2234.
16
28
3
(
S,S)-4,5-Dimethyl-1-[2-(piperidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((S,S)-6c): Yield: 263.5 g
◦
1
(
95%). Yellowish crystals. M.p. 51–54 C. H-NMR (CDCl ):
δ
= 7.87 (s, 1H), 3.70 (td, J = 11.5, 3.8 Hz,
3
1
1
H), 2.51–2.56 (m, 1H), 2.41–2.46 (m, 2H), 2.27–2.21 (m, 2H), 2.12 (s, 3H), 2.06 (s, 3H), 1.92–1.96 (m, 2H),
.71–1.80 (m, 2H), 1.46–1.53 (m, 1H), 1.29–1.35 (m, 2H), 1.18–1.25 (m, 7H) ppm. C-NMR (CDCl3):
13
δ
= 124.7, 122.8, 120.6, 67.6, 56.3, 49.9, 34.8, 26.3, 25.2, 24.9, 24.51, 24.46, 8.7, 7.1 ppm. IR: ν 2928 (vs),
855 (m), 1664 (br, m), 1450 (s), 1379 (s), 1332 (vs), 1101 (m), 881 (m), 704 (s), 581 (s) cm 1. HRMS (ESI+):
−
2
+
calcd for C H N O [M + H] 278.2232; found 278.2238.
16
28
3
(
(
R,R)-4,5-Diphenyl-1-[2-(piperidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((R,R)-6d): Yield 261.0 mg
◦
1
65%). Yellowish crystals. M.p. 192–194 C. H-NMR (CDCl ):
δ
= 8.00 (s, 1H), 7.57 (d, J = 7.5 Hz,
H), 7.39–7.45 (m, 3H), 7.23–7.29 (m, 5H), 3.82 (td, J = 11.5, 3.8 Hz, 1H), 2.61 (td, J = 11.3, 3.3 Hz, 1H),
.25–2.29 (m, 2H), 2.17–2.22 (m, 2H), 1.93–1.97 (m, 1H), 1.78–1.83 (m, 2H), 1.63–1.70 (m, 1H), 1.00–1.44
= 130.6, 129.6, 129.2, 128.9, 128.2, 127.9, 127.7, 127.36, 127.28, 124.1,
8.2, 56.7, 49.7, 35.7, 26.5, 25.3, 25.0, 24.7, 24.0 ppm. IR: 2929 (s), 2855 (m), 1444 (m), 1342 (m), 1205
3
2
2
(
m, 10H) ppm. 13C-NMR (CDCl3):
δ
6
(
ν
−
1
w), 1101 (w), 1034 (w), 784 (s), 710 (s), 691 (s) cm . C H N O (401.54): calcd. C 77.77, H 7.78, N
26
31
3
1
0.46; found C 77.56, H 7.88, N 10.59.

Molecules 2019, 24, 4398
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(
(
S,S)-4,5-Diphenyl-1-[2-(piperidin-1-yl)cyclohexyl]-1H-imidazole 3-oxide ((S,S)-6d): Yield: 333.0 mg
◦
1
83%) after purification on a short column. Yellowish crystals. M.p. 198–199 C. H-NMR (CDCl ):
3
δ
= 8.03 (s, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.40–7.45 (m, 3H), 7.23–7.29 (m, 5H), 3.81 (td, J = 11.6, 3.8 Hz,
H), 2.61 (td, J = 11.3, 3.4 Hz, 1H), 2.24–2.28 (m, 2H), 2.17–2.22 (m, 2H), 1.92–1.97 (m, 1H), 1.78–1.83 (m,
H), 1.68 (qd, J = 12.5, 3.3 Hz, 1H), 1.06–1.44 (m, 10H) ppm. 13C-NMR (CDCl3):
= 130.5, 129.6, 129.3,
28.95, 128.89, 127.95, 127.91, 127.79, 127.4, 127.1, 68.0, 56.9, 49.6, 35.4, 26.5, 25.3, 24.9, 24.6, 24.0 ppm.
1
2
1
IR:
δ
−1
ν 2928 (s), 2853 (m), 1444 (m), 1342 (m), 1205 (m), 1103 (m), 1034 (w), 786 (s), 712 (s), 693 (vs) cm .
+
+
HRMS (ESI ): calcd for C H N O [M + H] 402.2545; found 402.2546.
26
32
3
(
R,R)-1-[2-(Azepan-1-yl)cyclohexyl]-4,5-dimethyl-1H-imidazole 3-oxide ((R,R)-6e): Yield 227.1 g (78 %).
1
Colorless, viscous oil. H-NMR (CDCl ):
δ = 7.74 (s, 1H), 3.66 (td, J = 11.2, 3.9 Hz, 1H), 2.63–2.67 (m,
3
1
1
2
H), 2.53–2.58 (m, 2H), 2.37–2.42 (m, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.91–1.96 (m, 2H), 1.71–1.79 (m, 2H),
.15–1.53 (m, 12H) ppm. 13C-NMR (CDCl3):
= 124.7, 123.4, 120.1, 67.2, 57.3, 50.4, 35.0, 29.5, 26.5, 25.2,
5.0, 24.7, 8.6, 6.9 ppm. IR: 2924 (vs), 2853 (m), 1654 (s), 1448 (s), 1332 (s), 725 (vs), 704 (vs), 581 (m)
δ
ν
–1
+
+
cm . HRMS (ESI ): calcd for C H N O [M + H] 292.2389; found 292.2398.
17
30
3
(
R,R)-1-[2-(Azepan-1-yl)cyclohexyl]-4,5-diphenyl-1H-imidazole 3-oxide ((R,R)-6f): Yield: 369.6 mg
◦
1
(89%). Yellowish crystals. M.p. 64–68 C. H-NMR (CDCl ):
δ
= 8.06 (s, 1H), 7.50 (d, J = 7.7 Hz,
H), 7.37–7.41 (m, 3H), 7.19–7.24 (m, 5H), 3.75 (td, J = 11.4, 3.7 Hz, 1H), 2.71 (td, J = 11.3, 3.5 Hz, 1H),
.35–2.44 (m, 4H), 2.13–2.17 (m, 1H), 1.88–1.93 (m, 1H), 1.72–1.78 (m, 3H), 1.09–1.64 (m, 11H) ppm.
3
2
2
1
3
C-NMR (CDCl3):
δ
= 130.5, 129.7, 129.4, 129.0, 128.00, 127.96, 127.5, 127.0, 126.7, 125.9, 125.5, 68.3,
3
5
2
7.9, 50.5, 35.7, 29.7, 26.7, 25.2, 24.9 ppm (one signal of sp C atom not observed due to overlap). IR:
926 (s), 2855 (w), 1672 (m), 1444 (m), 1224 (w), 712 (s), 693 (br, s) 635 (m), 508 (br, m), 451 (br, m) cm 1.
ν
−
+
+
HRMS (ESI ): calcd for C H N O [M + H] 416.2702; found 416.2708.
17
34
3
(
R,R)-1-(2-Morpholinocyclohexyl)-4,5-dimethyl-1H-imidazole 3-oxide ((R,R)-6g): Yield: 240.1 mg (86%).
◦
1
Yellowish crystals. M.p. 85–87 C. H-NMR (CDCl ):
δ
= 9.06 (s, 1H), 3.76–3.82 (m, 1H), 3.58–3.66 (m,
3
1
2
1
2
8
H), 3.43–3.48 (m, 2H), 3.36–3.40 (m, 2H), 3.10 (td, J = 11.1, 3.1 Hz, 1H), 2.49–2.54 (m, 2H), 2.39–2.43 (m,
H), 2.15 (s, 3H), 2.09 (s, 3H), 1.95–2.04 (m, 2H), 1.86–1.93 (m, 1H), 1.76–1.82 (m, 2H), 1.42–1.50 (m, 1H),
.20–1.28 (m, 2H) ppm. 13C-NMR (CDCl3):
= 126.2, 124.4, 121.0, 67.3, 66.0, 57.2, 48.8, 34.2, 25.3, 24.9,
2929 (s), 2855 (m), 1654 (w), 1627 (br, w), 1450 (m), 1332 (s), 1112 (vs), 926 (m),
δ
4.5, 8.9, 7.1 ppm. IR
ν
1
−
+
+
61 (m), 725 (vs) cm . HRMS (ESI ): calcd for C H N O [M + H] 280.2025; found 280.2026.
15
26
3
2
(
R,R)-1-(2-Morpholinocyclohexyl)-4,5-diphenyl-1H-imidazole 3-oxide ((R,R)-6h): Yield: 266.3 mg
◦
1
(66%). Yellowish crystals. M.p. 152–155 C. H-NMR (CDCl ):
δ
= 8.08 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H),
.38–7.43 (m, 3H), 7.24–7.29 (m, 3H), 7.19 (d, J = 6.9 Hz, 2H), 3.84 (td, J = 11.6, 4.0 Hz, 1H), 3.44–3.51 (m,
H), 2.62 (td, J = 11.3, 3.1 Hz, 1H), 2.22–2.28 (m, 5H), 1.94–1.98 (m, 1H), 1.81–1.86 (m, 2H), 1.69–1.76 (m,
3
7
4
1
13
H), 1.25–1.33 (m, 1H), 1.16–1.24 (m, 1H), 1.08–1.15 (m, 1H) ppm. C-NMR (CDCl3): δ = 130.4, 129.7,
1
29.3, 129.0, 127.99, 127.92, 127.88, 127.4, 127.1, 123.9, 68.1, 67.3, 56.3, 48.6, 35.2, 25.2, 24.8, 24.2 ppm
2
(
one signal of an sp C atom not observed due to overlap). IR:
ν
2926 (s), 2857 (m), 1448 (m), 1341 (m),
−1
1
7
109 (s), 861 (s), 766 (s), 695 (vs), 665 (s), 633 (s) cm . C H N O2·0.5 H O (412.52): calcd. C 72.79, H
25
29
3
2
.33, N 10.18; found C 72.68, H 7.25, N 9.90.
4
.5. Synthesis of 3-Benzyloxyimidazolium Bromides 7—General Procedure
A solution of 0.5 mmol of crude imidazole N-oxide and 86 mg (0.5 mmol) benzyl bromide in
mL of CHCl was stirred magnetically overnight at room temperature. The next day, the solvent
6
1
3
was evaporated and the obtained crude imidazolium salts were triturated with diethyl ether. The
ethereal phase was separated and the non-soluble imidazolium salts were used for the generation
of carbenes and their reaction with elemental sulfur without further purification. Whereas di-Me
7
8
substituted imidazolium salts formed viscous, thick oils, the corresponding di-Ph derivatives were
obtained as amorphous solids. The structures of selected imidazolium salts were confirmed by running

Molecules 2019, 24, 4398
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1
1
the H-NMR spectra. A representative example of the H-NMR spectra registered for 7e is described
below and the scanned spectrum is presented in the Supplementary Materials.
(
R,R)-1-[2-(Azepan-1-yl)cyclohexyl]-4,5-dimethyl-3-benzyloxy-1H-imidazolium bromide((R,R)-7e):
1
H-NMR (CDCl3):
δ = 11.09 (s, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.27–7.37 (m, 3H), 5.70 (d, J= 10.0 Hz,
1
H), 5.57 (d, J= 10.0 Hz, 1H), 3.91 (br., 1H), 3.62 (br., 1H), 2.60 (br., 4H), 2.13–2.17 (m, 1H), 2.13 (s, 3H),
2.02–2.06 (m, 1H), 1.96–2.01 (m, 1H), 1.91 (s, 3H), 1.80–1.85 (m, 1H), 1.74–1.79 (m, 1H), 1.55–1.63 (m,
1
H), 1.47 (br., 2H), 1.29 (br., 6H), 1.18 (br., 2H) ppm.
4
.6. Synthesis of Non-Symmetric Imidazole-2-Thiones 9—General Procedure
The crude imidazolium salt obtained from 0.5 mmol of the corresponding imidazole N-oxide
and 86 mg (0.5 mmol) of benzyl bromide according to the general procedure (see above) was
7
6
dissolved in 1 mL of dry pyridine. Next, 38 mg (1.2 mmol) of elemental sulfur and 122 mg (1.2 mmol)
of triethylamine were added to the magnetically stirred, homogenous solution. Stirring at room
temperature was continued overnight. Next day, pyridine was removed under reduced pressure and
the residual semi-solid material was purified by preparative thin layer chromatography with silica
gel. A mixture of dichloromethane and methanol (99:1) was used as an eluent. Imidazole-2-thiones
9
formed a single fraction with R ca. 0.3. Solid products were additionally purified by crystallization.
f
(
R,R)-3-Benzyloxy-4,5-dimethyl-1-[2-(pyrrolidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole -2-thione
25
(
(R,R)-9a): Yield: 238.8 mg (62%). Colorless, viscous oil, purified by chromatography. [α]
= 91.15 (c
−
D
1
0
.40, CHCl ). H-NMR (CDCl ):
δ
= 7.32–7.44 (m, 5H), 5.75–5.80 (m, 1H), 5.42 (d, J = 10.0 Hz, 1H), 5.28
3
3
(
1
1
d, J = 10.0 Hz, 1H), 4.57–4.63 (m, 1H), 3.06–3.11 (m, 1H), 2.83–3.02 (m, 3H), 2.36 (s, 3H), 2.26–2.31 (m,
H), 1.72–2.13 (m, 8H), 1.81 (s, 3H), 1.38–1.51 (m, 3H) ppm. 13C-NMR (CDCl3):
29.5, 128.5, 121.1, 118.4, 78.1, 60.7, 58.4, 52.2, 29.6, 29.4, 24.1, 23.7, 22.6, 9.9, 7.7 ppm. IR
δ
= 155.1, 133.3, 130.2,
2929 (s), 2862
ν
(
6
m), 1377 (br, s), 1401 (br, s), 1321 (vs), 1140 (br, m), 1025 (m),954 (m), 913 (m), 836 (w), 751 (s), 697 (vs),
−
06 (w), 483 (s) cm . HRMS (ESI ): calcd for C H N OS [M + H] 386.2266; found 386.2274.
22 32 3
1
+
+
(
(
[
R,R)-3-Benzyloxy-4,5-diphenyl-1-[2-(pyrrolidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole -2-thione
◦
(R,R)-9b): Yield: 356.8 g (70%). Colorless crystals. M.p. 285–286 C (from MeOH/CH Cl ) (decomp.).
2
2
2
5
1
α]
= 36.65 (c 0.40, CHCl ). H-NMR (CDCl ): δ = (signals for both rotamers) 6.96–7.45 (m, 15H),
.95–5.47 (m, 3H), 3.44 and 3.74 (br., 1H), 2.14–2.70 (m, 4H), 0.80–1.96 (m, 12H) ppm. C-NMR (CDCl3):
= (signals for both rotamers) 157.3, 156.1, 133.2, 132.6, 131.1, 130.6, 129.4, 129.3, 129.0, 128.7, 128.2,
−
D
3 3
13
4
δ
1
28.0, 127.8, 126.4, 125.2, 124.5, 77.4, 61.7, 58.2, 55.0, 46.4, 33.3, 29.4, 26.0, 25.8, 25.0, 24.8, 23.8, 23.6, 22.1
ppm. IR: 2929 (m), 2797 (m), 1425 (m), 1358 (m), 1332 (m), 1306 (br, m), 1187 (w), 1073 (w), 965 (m),
11 (m), 786 (m), 753 (s), 695 (vs), 598 (m), 506 (m) cm . HRMS (ESI ): calcd. for C H N OS [M +
ν
−
1
+
9
32
36
3
+
H] 510.2579; found 510.2595. C H N OS (509.70): calcd. C 75.40, H 6.92, N 8.24, S 6.30; found C
32
35
3
7
5.30, H 6.91, N 8.24, S 6.14.
(
(
0
5
2
R,R)-3-Benzyloxy-4,5-dimethyl-1-[2-(piperidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole-2 -thione
25
(R,R)-9c): Yield: 239.5 mg (60%). Colorless, viscous oil, purified by chromatography. [α]
= 16.53 (c
−
D
1
.40, CHCl ). H-NMR (CDCl ):
δ
= 7.47 (d, J = 7.7 Hz, 2H), 7.32–7.37 (m, 3H), 5.46 (d, J = 10.5 Hz, 1H),
3
3
.32 (d, J = 10.5 Hz, 1H), 5.27 (td, J = 11.6, 3.7 Hz, 1H), 2.89 (td, J = 11.4, 2.8 Hz, 1H), 2.74–2.79 (m, 2H),
.23–2.27 (m, 2H), 2.08 (s, 3H), 1.94–2.02 (m, 2H), 1.83–1.88 (m, 1H), 1.73–1.78 (m, 1H), 1.70 (s, 3H),
1
1
.59 (qd, J = 12.5, 3.7 Hz, 1H), 1.29–1.52 (m, 8H), 1.17–1.25 (m, 1H) ppm. 13C-NMR (CDCl3):
δ
= 156.5,
34.2, 130.5, 129.1, 128.4, 119.4, 117.9, 77.6, 65.9, 58.5, 49.4, 32.0, 26.8, 25.9, 25.7, 24.9, 24.6, 10.5, 7.2 ppm.
2927 (vs), 2853 (m), 1403 (s), 1377 (s), 1330 (s), 1211 (m), 1105 (m), 963 (m), 911 (m), 749 (vs), 699
IR:
(
ν
−
vs), 479 (br.s) cm . HRMS (ESI ) calcd. for C H N OS [M + H] 400.2423; found: 400.2424.
23 34 3
1
+
+
(
(
S,S)-3-Benzyloxy-4,5-dimethyl-1-[2-(piperidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole-2 -thione
25
(S,S)-9c): Yield: 187.6 mg (47%). Colorless, viscous oil, purified by chromatography. [α] = +26.13
D
1
(c 0.40, CHCl ). H-NMR (CDCl ):
δ
= 7.46 (d, J = 7.5 Hz, 2H), 7.32–7.37 (m, 3H), 5.46 (d, J = 10.5 Hz,
3
3
1
H), 5.31 (d, J = 10.5 Hz, 1H), 5.26 (td, J = 11.9, 4.2 Hz, 1H), 2.89 (td, J = 11.4, 2.8 Hz, 1H), 2.74–2.78 (m,

Molecules 2019, 24, 4398
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2
1
1
H), 2.23–2.27 (m, 2H), 2.07 (s, 3H), 1.94–2.03 (m, 2H), 1.83–1.87 (m, 1H), 1.73–1.77 (m, 1H), 1.68 (s, 3H),
.58 (qd, J = 12.5, 3.7 Hz, 1H), 1.27–1.51 (m, 8H), 1.17–1.25 (m, 1H) ppm. 13C-NMR (CDCl3):
= 156.3,
34.2, 130.5, 129.1, 128.4, 119.4, 117.9, 77.6, 65.9, 58.5, 49.4, 32.0, 26.8, 25.8, 25.7, 24.9, 24.5, 10.5, 7.2 ppm.
2927 (vs), 2853 (m), 1403 (s), 1377 (s), 1328 (s), 1211 (m), 1105 (m), 963 (m), 911 (w), 749 (vs), 697
δ
IR:
(
ν
−
vs), 479 (br, s) cm . HRMS (ESI ): calcd for C H N OS [M + H] 400.2423; found 400.2426.
23 34 3
1
+
+
(
(
[
R,R)-3-Benzyloxy-4,5-diphenyl-1-[2-(piperidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole-2 -thione
◦
(R,R)-9d): Yield 429.4 mg (82%). Colorless crystals. M.p. 283–285 C (MeOH/CH Cl ) (decomp.).
2
2
2
5
26.77 (c 0.40, CHCl3). 1H-NMR (CDCl3):
α]
=
−
δ
= (signals for both rotamers in ca. 1:2 ratio)
.07–7.41 (m, 15H), 5.40 and 5.32 (d, J = 9.4 Hz, 1H), 4.61–4.67 (m) and 5.36 (td, J = 11.8, 3.4 Hz, total:
H), 4.98 and 5.12 (br. d, J = 9.4 Hz, 1H), 0.77–3.76 (m, 18H) ppm. 13C-NMR (CDCl3):
= (signals for
both rotamers) 157.6, 156.7, 133.2, 133.1, 132.4, 130.6, 130.42, 130.38, 129.5, 129.3, 129.22, 129.15, 128.92,
D
7
1
δ
1
1
28.87, 128.84, 128.6, 128.4, 128.3, 128.1, 128.02, 127.97, 127.8, 127.7, 126.9, 126.6, 126.40, 126.31, 124.9,
24.6, 124.3, 77.51, 77.49, 64.4, 59.9, 59.7, 49.1 (br.), 48.8 (br.), 33.2, 29.6, 27.1, 26.8, 26.0, 25.7, 25.2, 24.94,
2
4.91, 24.6, 23.5 ppm. IR:
ν 2924 (s), 2849 (w), 1442 (w), 1397 (s), 1321 (s), 1207 (m), 959 (m), 760 (s), 691
−1
(vs), 596 (m), 568 (m), 475 (w) cm . C H N OS (523.73): calcd. C 75.68, H 7.13, N 8.02, S 6.12; found
33
37
3
C 75.63, H 7.17, N 8.00. S 6.00.
(
(
S,S)-3-Benzyloxy-4,5-diphenyl-1-[2-(piperidin-1-yl)cyclohexyl]-1,3-dihydro-2H-imidazole-2 -thione
25
(S,S)-9d): Yield 324.7 mg (62%). Viscous oil (after chromatography). [α] = +22.42 (c 0.40, CHCl3).
D
1
H-NMR (CDCl3):
J = 9.3 Hz, 1H), 4.61–4.67 and 5.33–5.38 (m, 1H), 4.98 and 5.12 (br. d, J = 9.3 Hz, 1H), 0.78–3.74 (m, 18H)
ppm. 13C-NMR (CDCl3):
= (signals for both rotamers) 157.6, 156.7, 133.14, 133.06, 132.4, 130.6, 130.43,
30.40, 129.5, 129.4, 129.2, 128.93, 128.89, 128.88, 128.7, 128.5, 128.13, 128.05, 127.8, 127.7, 126.9, 126.7,
26.4, 125.9, 124.9, 124.6, 124.4, 77.53, 77.51, 64.4, 60.0, 59.7, 49.2 (br.), 33.2, 29.6, 27.1, 26.8, 26.0, 25.7,
5.2, 24.9, 24.6, 23.5 ppm. IR: 2927 (s), 2853 (m), 1444 (w), 1396 (w), 1321 (m), 1207 (m), 959 (m), 753
s), 693 (vs), 596 (m), 568 (m), 475 (w) cm . HRMS (ESI ): calcd for C H N OS [M + H] 524.2736;
δ = (signals for both rotamers in ca. 1:2 ratio) 7.07–7.41 (m, 15H), 5.41 and 5.32 (d,
δ
1
1
2
ν
−
1
+
+
(
33
38
3
found 524.2743. C H N OS (523.73): calcd. C 75.68, H 7.13, N 8.02, S 6.12; found C 75.64, H 7.10, N
33
37
3
8
.06, S 5.92.
(
(
R,R)-3-Benzyloxy-1-[2-(azepan-1-yl)cyclohexyl]-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione
(R,R)-9e): Yield: 173.7 mg (42 %).Viscous oil. [α]2
5
=
28.85 (c 0.40, CHCl3). 1H-NMR (CDCl3):
−
D
δ
= 7.46–7.48 (m, 2H), 7.33–7.36 (m, 3H), 5.38 (d, J = 10.4 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 5.21 (td,
J = 11.6, 3.4 Hz, 1H), 2.97 (td, J = 11.6, 2.7 Hz, 1H), 2.79–2.84 (m, 2H), 2.40–2.44 (m, 2H), 2.11 (s, 3H),
1
1
1
1
.93–2.01 (m, 2H), 1.82–1.86 (m, 1H), 1.73–1.77 (m, 1H), 1.74 (s, 3H), 1.57 (qd, J = 12.4, 3.3 Hz, 1H),
13
.31–1.52 (m, 10H) 1.16–1.25 (m, 1H) ppm. C-NMR (CDCl3):
19.2, 118.1, 77.9, 67.1, 59.4, 51.2, 32.1, 30.0, 26.6, 25.8, 25.7, 25.5, 10.6, 7.2 ppm. IR:
403 (s), 1377 (s), 1328 (s), 1170 (w), 1133 (w), 959 (m), 907 (m), 749 (vs), 697 (vs) cm . C H N OS
δ
= 156.6, 134.2, 130.3, 129.1, 128.4,
ν
2922 (vs), 2853 (m),
−
1
24
35
3
(413.62): calcd. C 69.69, H 8.53, N 10.16., S 7.75; found C 69.47, H 8.62, N 10.21, S 7.59.
(
(
[
R,R)-3-Benzyloxy-1-[2-(azepan-1-yl)cyclohexyl]-4,5-diphenyl-1,3-dihydro-2H-imidazole-2-thione
◦
(R,R)-9f): Yield: 376.4 mg (70%). Colorless crystals. M.p. 264–267 C (MeOH/CH Cl ) (decomp.).
2
2
2
5
27.17 (c 0.40, CHCl3). 1H-NMR (CDCl3):
α]
=
−
δ
= (signals for both rotamers in ca. 1:2 ratio)
.05–7.38 (m, 15H), 5.32 and 4.72 (td, J = 11.5, 3.6 Hz, 1H), 5.31 and 5.21 (d, J = 9.3 Hz, 1H), 5.02 (br.)
and 5.15 (d, J = 9.3 Hz, 1H), 3.69 (td, J = 11.7, 3.0 Hz, 0.3H), 3.28–3.36 (m, 0.3H), 2.75–2.80 (m, 1H),
.43–2.47 (m, 0.7H), 2.29–2.32 (m, 0.7H), 1.34–2.21 (m, 15H), 1.16 and 0.98 (qd, J = 12.8, 3.5 Hz, 1H),
D
7
2
13
1
1
1
.03–1.11 and 0.73–0.82 (m, 1H) ppm. C-NMR (CDCl3): δ = 158.0, 157.0, 133.2, 133.1, 132.5, 130.6,
30.37, 130.3, 129.6, 129.4, 129.2, 129.1, 128.9, 128.6, 128.15, 128.13, 128.10, 128.07, 127.9, 127.8, 127.7,
26.6, 126.4, 126.0, 125.0, 124.7, 77.62, 77.58, 66.1, 61.4, 60.5, 51.4 (br.), 50.5, 33.3, 30.05, 29.97, 29.8, 26.9,
2
9
7
6.6, 26.4, 26.0, 25.8, 25.23, 25.17 ppm. IR:
ν
2924 (s), 2853 (m), 1446 (m), 1356 (m), 1332 (m), 1073 (w),
−1
63 (w), 752 (s), 693 (vs) cm . C H N OS (537.76): calcd. C 75.94, H 7.31, N 7.81, S 5.96; found C
34
39
3
5.91, H 7.45, N 8.01, S 5.86.

Molecules 2019, 24, 4398
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(
(
[
R,R)-3-Benzyloxy-1-(2-morpholinocyclohexyl)-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione
◦
(R,R)-9g): Yield 135 mg (67%). Colorless crystals. M.p. 122–124 C (after chromatographic separation).
2
5
21.22 (c 0.40, CHCl3). 1H-NMR (CDCl3):
δ = 7.43–7.46 (m, 2H), 7.33–7.37 (m, 3H), 5.44
α]
=
−
D
(d, J = 10.4 Hz, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.27 (td, J = 11.9, 3.7 Hz, 1H), 3.52–3.57 (m, 2H), 3.45–3.50
m, 2H), 2.92 (dt, J = 11.4, 3.2 Hz, 1H), 2.85–2.90 (m, 2H), 2.30–2.34 (m, 2H), 2.08 (s, 3H), 1.97–2.02 (m,
(
2
H), 1.85–1.90 (m, 1H), 1.75–1.80 (m, 1H), 1.72 (s, 3H), 1.62 (qd, J = 12.4, 3.8 Hz, 1H), 1.42–1.51 (m, 1H),
13
1
.32–1.40 (m, 1H), 1.17–1.27 (m, 1H) ppm. C-NMR (CDCl3):
δ
= 156.5, 134.1, 130.5, 129.3, 128.6, 119.9,
2935 (br, m), 2851 (m) 2816
117.7, 77.8, 67.7, 65.4, 58.1, 48.6, 31.9, 25.8, 25.5, 24.5, 10.7, 7.3 ppm. IR:
ν
−
1
(w), 1451 (m), 1407 (s), 1334 (s), 1269 (s), 1146 (m), 1108 (vs), 915 (m), 855 (m), 754 (vs), 702 (m) cm .
C H N O S (401.56): calcd. C 65.80, H 7.78, N 10.46, S 7.98; found C 65.71, H 7.90, N 10.59, S 7.84.
22
31
3
2
(
(
[
R,R)-3-Benzyloxy-1-(2-morpholinocyclohexyl)-4,5-diphenyl-1,3-dihydro-2H-imidazole-2-thione
◦
(R,R)-9h): Yield 213 mg (81%). Colorless crystals. M.p. 279–281 C (MeOH/CH Cl ) (decomp.).
2
2
2
5
1
α]
=
−
43.58 (c 0.40, CHCl ). H-NMR (CDCl ):
δ
= (signals for both rotamers in ca. 1:1.2 ratio)
.07–7.43 (m, 15H), 5.40 and 5.33 (d, J = 9.4 Hz, 1H), 5.37 and 4.72 (td, J = 11.8, 3.3 Hz, 1H), 5.09 and
D
3
3
7
4
2
.92 (d, J = 9.4 Hz, 1H), 3.75 and 3.43 (td, J = 11.7, 3.7 Hz, 1H), 3.44–3.69 (m, 4H), 2.78 and 2.43 (br., 2H),
.09–2.28 (m, 3H), 1.87–1.93 and 2.01–2.06 (m, 1H), 1.66–1.78 (m, 3H), 1.40–1.49 (m, 1H), 1.20–1.27
13
and 0.92–1.00 (m, 1H), 1.09–1.17 and 0.81–0.89 (m, 1H) ppm. C-NMR (CDCl3):
rotamers) 157.9, 156.9, 133.13, 133.07, 132.5, 130.6, 130.5, 130.4, 129.6, 129.5, 129.4, 129.3, 129.1, 129.04,
29.02, 128.8, 128.3, 128.0, 127.9, 126.5, 126.34, 126.29, 125.3, 124.5, 77.72, 77.66, 68.0, 67.8, 63.8, 59.8,
9.47, 59.43, 48.3, 33.2, 29.6, 25.93, 25.75, 25.2, 25.0, 24.9, 23.7 ppm. IR: 2924 (br m), 2853 (m), 1401 (m),
360 (w), 1323 (m), 1112 (s), 965 (m), 861 (m), 762 (s), 699 (vs) cm . C H N O S (525.70): calcd. C
δ = (signals for both
1
5
1
7
ν
−
1
32
35
3
2
3.11, H 6.72, N 7.99; S 6.10; found C 73.12, H 6.76, N 7.93, S 6.03.
4
.7. Synthesis of Imidazole N-Oxides 10a–d
A solution of diacetyl monooxime (5a, 354 mg, 3.5 mmol) and the corresponding formaldimine
4
(3.0 mmol) in EtOH (10 mL) was refluxed for 3 h. The solvents were removed in vacuo, and
the resulting oil was washed with Et O (3
column chromatography on silica gel using AcOEt/MeOH mixtures as the eluent or by recrystallization
from the appropriate solvents to give spectroscopically pure imidazole N-oxides isolated as colorless
×
20 mL). The crude product 10 was either purified by
2
materials. Compounds 10a
imidazole N-oxide 10d was obtained in two steps by condensation of 5a with methyl glycinate-derived
formaldimine of type followed by aminolysis of the resulting product with -MBA as described [22];
the NMR spectra of the obtained samples matches the data reported in the literature.
[21] and 10c [22] were prepared following the analogous method, while
4
α
(
R)-1-(2-Hydroxy-1-phenylethyl)-4,5-dimethylimidazole 3-oxide (10b): Yield 474 mg (68%). Off-white
◦
20
1
solid. M.p. 198–200 C (CH Cl /Et O) (decomp.). [α] = +49.1 (c 0.22, CHCl ). H-NMR (CDCl ):
2
2
2
D
3
3
δ
= 9.17 (s, 1H, C(2)H), 8.72 (br.s, 1H, OH), 7.01–7.04, 7.27–7.35 (2m, 2H, 3H, Ph), 5.14 (dd, J = 3.8, 10.7
Hz, 1H, CHPh), 4.21 (dd, J = 10.7, 13.4 Hz, 1H, CH O), 3.95 (dd, J = 3.8, 13.4 Hz, 1H, CH O), 1.84, 2.10
2
2
(
2s, 3H each, 2Me) ppm. 13C-NMR (CDCl3):
Ph), 126.4 (s, C(4)), 124.9 (d, C(2)), 122.0 (s, C(5)), 63.9 (d, CHPh), 63.6 (t, CH O), 7.0, 8.9 (2q, 2Me) ppm.
δ = 136.6 (s, Ph), 128.3, 129.0 (2d, 3CH, Ph), 126.9 (d, 2CH,
2
−1
IR (neat):
ESI-MS (m/z): 465.4 (100, [2M + H] ), 233.3 (47, [M + H] ). C H N O (232.28): calcd. C, 67.22; H,
ν 3110 (s), 3025–2926 (br, m), 1450 (m), 1405 (m), 1351 (s), 1325 (m), 1208 (m), 1064 (s) cm .
+
+
13
16
2
2
6
.94; N, 12.06; found: C 67.05, H 6.95, N 12.22.
4
.8. Synthesis of Imidazolium Bromides 11a–d
To a solution of imidazole N-oxide 10 (1.0 mmol) in dry CH Cl (1.0 mL) was added an excess of
2
2
1-bromobutane (548 mg, 4.0 mmol) and the resulting mixture was stirred until the starting material
was fully consumed (TLC monitoring: SiO , EtOAc/MeOH 7:1). The solvents were removed under
2
reduced pressure to give the corresponding imidazolium bromide 11 quantitatively, which was used
for the next step without further purification.

Molecules 2019, 24, 4398
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(
S)-3-Butoxy-1-(2-hydroxypropyl)-4,5-dimethylimidazolium bromide [23] (11a): Reaction time: 2
20
1
d. Pale yellow oil. [α] = +16.0 (c 0.74, CHCl ). H-NMR (CDCl ):
δ
= 10.00 (s, 1H, C(2)H), 4.91 (br.d,
D
3
3
J
≈
5.9 Hz, 1H, OH), 4.47 (td, J = 2.1, 6.5 Hz, 2H, OCH , Bu), 4.34 (dd, J = 9.1, 14.0 Hz, 1H, NCH ), 4.22
2
2
(dd, J = 2.6, 14.0 Hz, 1H, NCH ), 4.16–4.22 (m, 1H, CHCH ), 2.26, 2.27 (2s, 3H each, 2Me), 1.77–1.81
2
3
(
m, 2H, Bu), 1.47–1.43 (m, 2H, Bu), 1.34 (d, J = 6.3 Hz, 3H, CHCH ), 0.98 (t, J = 7.4 Hz, 3H, CH , Bu)
3
3
ppm. 13C-NMR (CDCl3):
δ = 131.4 (br.d, C(2)), 123.6, 124.7 (2s, C(4), C(5)), 82.7 (t, OCH , Bu), 64.8 (d,
2
CHCH ), 53.5 (t, NCH ), 29.6 (t, CH , Bu), 20.4 (q, CHCH ), 18.7 (t, CH , Bu), 13.6 (q, CH , Bu), 7.1, 8.9
3
2
2
3
2
3
(
1
2q, 2Me) ppm. IR (neat):
139 (s), 1072 (s), 936 (s) cm
ν3308 (s), 2990–2876 (br, s), 1670 (m), 1634 (m), 1545 (m), 1457 (m), 1377 (m),
−1
.
(
R)-3-Butoxy-1-(2-hydroxy-1-phenylethyl)-4,5-dimethylimidazolium bromide (11b): Reaction time: 2
◦
25
1
d. Yellow solid. M.p. 124–127 C. [α] = +83.5 (c 1.79, CHCl ). H-NMR (CDCl ):
δ
= 10.50 (s, 1H,
C(2)H), 7.15–7.18, 7.32–7.38 (2m, 2H, 3H, Ph), 5.61 (dd, J = 3.8, 10.1 Hz, 1H, CHPh), 5.46 (br.s, 1H, OH),
.80 (pseudo-q, J 6.6 Hz, 1H, OCH , Bu), 4.52–4.59 (m, 2H, CH OH (1H), OCH (1H)), 4.10 (dd, J = 3.8,
3.2 Hz, 1H, CH OH), 2.06, 2.24 (2s, 3H each, 2Me), 1.79–1.84 (m, 2H, Bu), 1.49–1.55 (m, 2H, Bu), 0.98 (t,
D
3
3
4
1
≈
2
2
2
2
13
J = 7.4 Hz, 3H, CH , Bu) ppm. C-NMR (CDCl3):
δ = 134.2 (s, Ph), 131.4 (d , C(2)), 126.7, 129.3, 129.5
br
3
(
3d, 5CH, Ph), 124.3, 125.0 (2s, C(4), C(5)), 83.2 (t, OCH , Bu), 64.9 (d, CHPh), 62.4 (t, CH OH), 29.8 (t,
2
2
CH , Bu), 18.8 (t, CH , Bu), 13.7 (q, CH , Bu), 7.1, 9.1 (2q, 2Me) ppm. IR (neat):
ν 3248 (vs), 3027–2876
2
2
3
−1
(br, s), 1636 (m), 1541 (m), 1448 (s), 1359 (m), 1066 (s), 935 (s) cm .
(
R)-3-Butoxy-4,5-dimethyl-1-[1-(methoxycarbonyl)ethyl]imidazolium bromide [23] (11c): Reaction
time: 2 d. Pale yellow oil. [α]2
0
= 16.6 (c 0.51, CHCl ). The NMR data in accordance with those
−
D
3
reported in [23].
(
R)-3-Butoxy-4,5-dimethyl-1-[(N-phenylethyl)acetamido]imidazolium bromide (11d): Reaction time: 4
20
1
d. Pale yellow oil. [α] = +51.2 (c 0.52, CHCl ). H-NMR (CDCl ):
δ = 9.84 (s, 1H, C(2)H), 9.29 (d,
D
3
3
J = 7.8 Hz, 1H, NH), 7.14–7.17, 7.23–7.26, 7.39–7.42 (3m, 1H, 2H, 2H, Ph), 5.35, 5.45 (AB system, J = 16.1
Hz, 2H, NCH ), 4.95 (dq, J = 7.1, 7.8 Hz, 1H, CH(Ph)CH ), 4.32 (td, J = 1.4, 6.5 Hz, 2H, OCH , Bu), 2.14,
2
3
2
2
.17 (2s, 3H each, 2Me), 1.71–1.76 (m, 2H, Bu), 1.53 (d, J = 7.1 Hz, 3H, CH(Ph)CH ), 1.42–1.48 (m, 2H,
3
13
Bu), 0.94 (t, J = 7.4 Hz, 3H, CH , Bu) ppm. C-NMR (CDCl3):
δ
= 163.6 (s, C=O), 143.6 (s, Ph), 131.4
3
(
br.d, C(2)), 126.3, 126.9, 128.4 (3d, 5CH, Ph), 123.3, 125.9 (2s, C(4), C(5)), 82.6 (t, OCH , Bu), 50.3 (d,
2
CH(Ph)CH ), 49.7 (t, NCH ), 29.5 (t, CH , Bu), 22.4 (q, CH(Ph)CH ), 18.6 (t, CH , Bu), 13.6 (q, CH , Bu),
3
2
2
3
2
3
7
.0, 8.7 (2q, 2Me) ppm. IR (neat): ν 3200 (m), 3032–2872 (br, s), 1679 (vs, C=O), 1547 (s), 1448 (m), 1377
−
1
(m), 1250 (m) cm .
4
.9. Synthesis of Imidazole-2-thiones 13a–d and 15a–d
To a solution of the respective imidazolium bromide (1.0 mmol) in dry pyridine (4.0 mL) was
added triethylamine (150 µL) followed by elemental sulfur (33 mg, 1.1 mmol), and the resulting mixture
was stirred overnight. The solvents were removed under reduced pressure, and the crude product was
purified by standard column chromatography to give imidazole-2-thione of type 13 or 15, respectively.
(
S)-3-Butoxy-1-(2-hydroxypropyl)-4,5-dimethylimidazole-2-thione (13a): (chromatographic separation,
20
1
SiO , CH Cl /EtOAc 5:1); 209 mg (81%). Pale yellow oil. [α] = +1.3 (c 0.77, CHCl ). H-NMR (CDCl ):
2
2
2
D
3
3
δ
3
2
= 4.29–4.34 (m, 2H, OCH , Bu), 4.18–4.23 (m, 1H, CHCH ), 4.03 (dd, J = 8.7, 14.4 Hz, 1H, NCH ),
2 3 2
.97 (dd, J = 3.2, 14.4 Hz, 1H, NCH ), 3.28 (br.s, 1H, OH), 2.08, 2.12 (2s, 3H each, 2Me), 1.73–1.77 (m,
2
H, Bu), 1.46–1.53 (m, 2H, Bu), 1.25 (d, J = 6.3 Hz, 3H, CHCH ), 0.96 (t, J = 7.4 Hz, 3H, CH , Bu) ppm.
3
3
1
3
C-NMR (CDCl3):
δ = 156.2 (s, C=S), 118.5, 119.0 (2s, C(4), C(5)), 76.8 (t, OCH , Bu), 67.3 (d, CHCH ),
2 3
5
1.3 (t, NCH ), 29.8 (t, CH , Bu), 21.2 (q, CHCH ), 18.9 (t, CH , Bu), 13.7 (q, CH , Bu), 7.5, 9.1 (2q, 2Me)
2
2
3
2
3
ppm. IR (neat):
9
ν 3353 (s), 3040–2874 (br, m), 1433 (m), 1409 (s), 1375 (m), 1347 (m), 1127 (m), 1072 (m),
−
43 (m) cm . ESI-MS (m/z): 281.1 (53, [M + Na] ), 259.1 (100, [M + H] ), 208.1 (42). C H N O S
12 22 2 2
1
+
+
(258.38): calcd. C 55.78, H 8.58, N 10.84, S 12.41; found: C 55.57, H 8.65, N 10.76, S 12.21.

Molecules 2019, 24, 4398
15 of 18
(
R)-3-Butoxy-1-(2-hydroxy-1-phenylethyl)-4,5-dimethylimidazole-2-thione (13b): (chromatographic
20
separation, SiO , CH Cl /EtOAc 5:1); 240 mg (75%). Yellow oil. [α]
=
−10.8 (c 0.73, CHCl3).
2
2
2
D
1
H-NMR (CDCl3):
δ = 7.24–7.30, 7.32–7.35 (2m, 3H, 2H, Ph), 6.26 (m, 1H, CHPh), 4.60–4.65 (m, 1H,
CH OH), 4.34–4.42 (m, 3H, OCH (Bu) (2H), CH OH (1H)), 3.09 (br.s, 1H, OH), 2.09 (s, 3H, Me),
2
2
2
1
.79–1.84 (m, 2H, Bu), 1.72 (s, 3H, Me), 1.52–1.58 (m, 2H, Bu), 1.00 (t, J = 7.4 Hz, 3H, CH , Bu) ppm.
3
1
3
C-NMR (CDCl3):
δ = 157.4 (s, C=S), 136.7 (s, Ph), 126.9, 127.8, 128.7 (3d, 5CH, Ph), 118.8, 120.1 (2s,
C(4), C(5)), 76.8 (t, OCH , Bu), 62.8 (t, CH OH), 60.9 (d, CHPh), 29.9 (t, CH , Bu), 19.0 (t, CH , Bu), 13.8
2
2
2
2
(
1
q, CH , Bu), 7.4, 9.9 (2q, 2Me) ppm. IR (neat): ν 3347 (s), 3016–2874 (br, s), 1407 (s), 1333 (m), 1156 (m),
060 (m), 1031 (m) cm . ESI-MS (m/z): 343.1 (54, [M + Na] ), 321.2 (100, [M + H] ), 270.1 (45). HRMS
3
–1
+
+
(
ESI-TOF): calcd for C H N O S: 321.1637; found: 321.1640.
17 25 2 2
(
R)-3-Butoxy-4,5-dimethyl-1-[1-(methoxycarbonyl)ethyl]imidazole-2-thione (13c): (chromatographic
20
separation, SiO , CH Cl /EtOAc 95:5); 236 mg (83%). Yellow oil. [α]
=
−
45.4 (c 0.20, CHCl3).
2
2
2
D
1
H-NMR (CDCl3):
δ = 6.03 (d, J = 7.4 Hz, 1H, CHCH ), 4.31–4.39 (m, 2H, OCH , Bu), 3.74 (s, 3H,
3 2
OCH ), 2.02, 2.12 (2s, 3H each, 2Me), 1.75–1.80 (m, 2H, Bu), 1.62 (d, J = 7.4 Hz, 3H, CHCH ), 1.49–1.55
3
3
13
(
m, 2H, Bu), 0.98 (t, J = 7.4 Hz, 3H, CH , Bu) ppm. C-NMR (CDCl3):
δ
= 170.8 (s, C=O), 157.6 (s,
3
C=S), 117.4, 119.8 (2s, C(4), C(5)), 76.7 (t, OCH , Bu), 53.2 (d, CHCH ), 52.6 (q, OCH ), 29.9 (t, CH , Bu),
2
3
3
2
1
1
2
9.0 (t, CH , Bu), 16.0 (q, CHCH ), 13.8 (q, CH , Bu), 7.4, 9.8 (2q, 2Me) ppm. IR (neat):
ν
2932–2872 (m),
2
3
3
−1
743 (vs, C=O), 1407 (s), 1344 (m), 1224 (s), 1183 (s), 1109 (m), 1066 (s), 963 (m) cm . ESI-MS (m/z):
+
87.3 (100, [M + H] ). C H N O S (286.39): calcd. C 54.52, H 7.74, N, 9.78, S 11.19; found: C 54.58, H
13 22 2 3
7
.79, N 9.77, S 11.18.
(
R)-3-Butoxy-4,5-dimethyl-1-[(N-phenylethyl)acetamido]imidazole-2-thione (13d): (chromatographic
◦
20
separation, SiO , CH Cl /EtOAc 4:1); 238 mg (66%). Pale orange solid. M.p. 118–119 C. [α] = +2.7
2
2
2
D
1
(c 1.89, CHCl ). H-NMR (CDCl ):
δ
= 7.71 (br.d, J
≈
8.1 Hz, 1H, NH), 7.20–7.23, 7.25–7.30 (2m, 1H, 4H,
3
3
Ph), 5.00 (pseudo-p, J
J
1
≈
7.1 Hz, 1H, CH(Ph)CH ), 4.65, 4.70 (AB system, J = 14.9 Hz, 2H, NCH ), 4.35 (dt,
3 2
≈
6.6, 8.1 Hz, 1H, OCH , Bu), 4.28 (dt, J
≈
6.6, 8.1 Hz, 1H, OCH , Bu), 2.11, 2.13 (2s, 3H each, 2Me),
2
2
.76–1.81 (m, 2H, Bu), 1.50–1.56 (m, 2H, Bu), 1.43 (d, J = 7.0 Hz, 3H, CH(Ph)CH ), 0.99 (t, J = 7.4 Hz, 3H,
3
1
3
CH , Bu) ppm. C-NMR (CDCl3):
δ
= 166.2 (s, C=O), 156.3 (s, C=S), 143.1 (s, Ph), 125.8, 127.0, 128.4
3
(
3d, 5CH, Ph), 118.5, 119.5 (2s, C(4), C(5)), 76.9 (t, OCH , Bu), 49.3 (d, CH(Ph)CH ), 48.6 (t, NCH ), 29.8
2
3
2
(
ν
t, CH , Bu), 22.5 (q, CH(Ph)CH ), 18.9 (t, CH , Bu), 13.7 (q, CH , Bu), 7.4, 9.1 (2q, 2Me) ppm. IR (neat):
2 3 2 3
−1
3282 (m), 2956–2871 (br, m), 1662 (vs, C=O), 1549 (s), 1407 (s), 1372 (m), 1247 (m), 1003 (m) cm .
+
+
ESI-MS (m/z): 384.2 (100, [M + Na] ), 362.2 (21, [M + H] ), 311.1 (48), 241.1 (69). C H N O S (361.50):
19
27
3
2
calcd. C 63.13, H 7.53, N 11.62, S 8.87; found: C 63.04, H 7.80, N 11.70, S 8.76.
(
S)-3-Benzyloxy-4,5-dimethyl-1-(1-phenylethyl)imidazole-2-thione (15a): Yield: 275 mg (81%). Pale
◦
20
1
yellow crystals. M.p. 102–104 C (petroleum ether/CH Cl ). [α] = +110.5 (c 0.32, CHCl ). H-NMR
2
2
D
3
(
CDCl3):
δ = 7.58–7.53 (m, 2H), 7.43–7.40 (m, 3H), 7.37–7.34 (m, 2H), 7.30–7.26 (m, 3H), 6.80 (q, J = 7.3
Hz, 1H), 5.58, 5.45 (AB system, J = 10.0 Hz, 2H, OCH ), 1.83 (d, J = 7.3 Hz, 3H), 1.78, 1.63 (2s, 6H, 2Me)
2
ppm. 13C-NMR (CDCl3):
δ
= 157.3 (s, C=S), 126.4, 127.4, 128.5, 128.6, 129.3, 130.4 (6d, 10CH), 117.5,
20.7 134.0, 139 (4s), 77.9 (t, OCH ), 53.4 (d, CH), 7.2, 10.2, 17.3 (3q, 3Me) ppm. IR (neat): 2971 (m),
924 (m), 1449 (m), 1403 (s), 1375 (m), 1332 (s), 1299 (m), 1151 (m), 1025 (m), 956 (m), 909 (m), 747 (s),
1
2
6
ν
2
−1
97 (vs) cm . HRMS (ESI-TOF) calcd for C H N OS: 339.1531; found: 339.1535.
20
23
2
(
S)-4,5-Dimethyl-3-pentyloxy-1-(1-phenylethyl)imidazole-2-thione (15b): Yield: 245 mg (77%). Pale
◦
20
1
yellow crystals. M.p. 70–73 C (petroleum ether/CH Cl ). [α] = +125.9 (c 0.40, CHCl ). H-NMR
2
2
D
3
(CDCl3):
δ
= 7.28–7.39 (m, 5H), 6.76 (q, J = 7.3 Hz, 1H), 4.43–4.46 (pseudo q, J = 7.2 Hz, 1H, OCH2),
4
3
.37–4.40 (pseudo q, J = 7.2 Hz, 1H, OCH ), 2.09 (s, 3H, Me), 1.83–1.88 (m, 2H, CH ), 1.80 (d, J = 7.3 Hz,
2
2
H), 1.68 (s, 3H, Me), 1.49–1.53 (m, 2H, CH ), 1.41–1.45 (m, 2H, CH ), 0.96 (t, J = 7.3 Hz, 3H, CH ) ppm.
2
2
3
1
3
C-NMR (CDCl3):
δ
= 157.5 (C=S), 126.5, 127.3, 128.5 (3d, 5CH), 117.8, 119.9, 139.9 (3s), 76.9 (t, OCH2),
2954 (m), 2927
5
3.4 (d, CH), 22.5, 27.7, 27.9 (3t, 3CH ), 7.3, 10.1, 13.9, 16.8 (4q, 4Me) ppm. IR (neat):
ν
2
(
m), 1450 (m), 1410 (s), 1334 (s), 1299 (s), 1157 (m), 1027 (m), 1001 (s), 998 (m), 876 (m), 700 (vs), 687 (s)

Molecules 2019, 24, 4398
16 of 18
−1
cm . C H N OS (318.48): calcd. C 67.88, H 8.23, N 8.80, S 10.07; found: C 67.61, H 8.28, N 8.70,
18
26
2
S 10.06.
(
S)-3-Benzyloxy-4,5-diphenyl-1-(1-phenylethyl)imidazole-2-thione (15c): Yield: 305 mg (66%). Pale
20
1
yellow oil. [α] = +188.5 (c 0.40, CHCl ). H-NMR (CDCl ):
δ
= 7.30–7.32 (m, 2H), 7.20–7.25 (m, 10H),
D
3
3
7
.14–7.18 (m, 2H), 7.05–7.12 (m, 6H), 6.75 (br.s, 1H, CH -CH), 6.67 (br.s, 2H), 5.30, 5.32 (AB system, J =
3
13
1
1
1
2.5 Hz, 2H, OCH ), 1.62 (d, J = 6.5 Hz, 3H, CH -CH) ppm. C-NMR (CDCl3):
δ
= 158.4 (s, C=S),
24.1, 125.9, 126.2, 128.6, 129.8, 132.9 (6s), 126.9, 127.3, 127.9, 128.0, 128.1, 128.2, 128.3, 128.9, 129.1, 129.4,
30.6, 132.0 (12d, 20CH), 77.7 (t, OCH ), 54.6 (d, CH), 17.5 (q, CH ) ppm. IR (neat): 3032 (m), 2927
2
3
ν
2
3
(
m), 1496 (m), 1446 (m), 1395 (s), 1325 (m), 1316s, 1215 (m), 1187 (m), 1073 (m), 907 (m), 730 (s), 695 (vs)
−1
cm . HRMS (ESI-TOF): calcd for C H N O: 463.1844; found: 463.1849.
30
27
2
(
S)-3-Pentyloxy-4,5-diphenyl-1-(1-phenylethyl)imidazole-2-thione (15d): Yield: 350 mg (79%). Beige
◦
20
1
crystals. M.p. 78–81 C (petroleum ether/CH Cl ). [α] = +130.1 (c 0.30, CHCl ). H-NMR (CDCl ):
2
2
D
3
3
δ
= 7.20–7.25 (m, 9H), 7.06–7.09 (m, 4H), 6.67–6.73 (m, 3H, 2CHarom, CH-CH ), 4.31 (pseudo q, J = 6.8
3
Hz, 1H, OCH ), 4.14 (pseudo q, J = 6.8 Hz, 1H, OCH ), 1.63–1.66 (m, 2H, CH ), 1.59 (d, J = 6.8 Hz, 3H,
2
2
2
13
CH -CH), 1.24–1.27 (m, 2H, CH ), 1.19–1.23 (m, 2H, CH ), 0.83 (t, J = 7.3 Hz, 3H, CH ) ppm. C-NMR
3
2
2
3
(
CDCl3): δ = 158.6 (s, C=S), 126.9, 127.2, 127.9, 128.1, 128.2, 128.3, 128.9, 129.3, 132.0 (9d, 15CH), 124.4,
1
25.2, 126.0, 140.3 (4s), 76.9 (t, OCH ), 54.7 (d, CH), 22.2, 27.4, 27.8 (3t, 3CH ), 13.9, 17.5 (2q, 2CH ) ppm.
2 2 3
IR (neat):
(
ν
2968 (m), 2953 (m), 1448 (m), 1392 (s), 1321 (s), 1187 (m), 1026 (m), 1002 (m), 963 (m), 702
−
vs), 695 (vs) cm . C H N OS (442.62): C 75.98; H 6.83; N 6.33; S 7.24. Found: C 75.78; H 6.88; N
28 30 2
1
6
.58; S 7.50.
Supplementary Materials: Copies of H-NMR and 13C-NMR spectra of all new compounds are available online.
1
Author Contributions: Conceptualization, G.M. and P.R.S.; Methodology, G.M.; Software, P.J.B. and M.J.;
Validation G.M.; P.J.B.; Formal analysis, G.M., P.J.B., and H.H.; Investigation, G.M., M.C, M.J., and K.U.; Resources,
G.M. and P.R.S.; Data curation, M.J. and K.U.; Writing—original draft preparation, G.M., H.H., M.J., and
K.U.; Writing—review and editing, G.M., H.H., M.J., and P.R.S.; Visualization, M.J.; Supervision, G.M.; Project
administration, G.M. and P.R.S.; Funding acquisition, G.M. and P.R.S.
Funding: This research received external funding from the National Science Center (NCN, Cracow, Poland) and
the Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany) within the Beethoven-2 program.
Acknowledgments: The authors acknowledge the generous financial support within the Beethoven-2 funding
scheme: (a) National Science Centre, Cracow (G. Mlosto n´ , grant # 2016/23/G/ST5/04115/l) and (b) The Deutsche
Forschungsgemeinschaft (DFG, P.R. Schreiner, grant # Schr 597/34-1). Preparation of the analytically pure sample
of formaldimine 4i by Dr. Emilia Obijalska and Ms. Karolina Grzybowska (University of Ł
ód z´ ) is acknowledged.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of formaldimines, imidazole N-oxides and imidazole-2-thiones are available from
the authors.
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