Design and scalable synthesis of new chiral selectors. Part 2: Chiral ionic liquids derived from diaminocyclohexane and histidine

Article abstract of DOI:10.1021/op200082a

We disclose the conception and synthesis of new chiral selectors useful for enantioselective liquid-liquid extraction processes (ELLE). We report synthetic methods giving access to substantial amounts of the compounds, at least at the multigram scale. Two series are examined, i.e. ionic liquids based on diaminocyclohexane (DACH) and histidine, respectively.

Full text of DOI:10.1021/op200082a

ARTICLE
pubs.acs.org/OPRD
Design and Scalable Synthesis of New Chiral Selectors. Part 2: Chiral
Ionic Liquids Derived from Diaminocyclohexane and Histidine
Viacheslav Zgonnik,† Silvia Gonella,‡ Marie-Rose Maziꢀeres,† Frꢁedꢁeric Guillen,§ Gꢁerard Coquerel,‡
Nathalie Saffon,^ and Jean-Christophe Plaquevent*,†
†CNRS-UMR 5068, LSPCMIB, Universitꢁe Paul Sabatier, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France
‡UPRES-EA 3233, SMS, IRCOF, Universitꢁe de Rouen, rue Tesniꢀere, F-76821 Mont-Saint-Aignan Cedex, France
§CNRS-UMR 6014, COBRA, IRCOF, Universitꢁe de Rouen, rue Tesniꢀere, F-76821 Mont-Saint-Aignan Cedex, France
^ICT, FR 2599, Universitꢁe Paul Sabatier, 118 route de Narbonne, F-31062, Toulouse Cedex 9, France
ABSTRACT: We disclose the conception and synthesis of new chiral selectors useful for enantioselective liquidꢀliquid
extraction processes (ELLE). We report synthetic methods giving access to substantial amounts of the compounds, at least at
the multigram scale. Two series are examined, i.e. ionic liquids based on diaminocyclohexane (DACH) and histidine,
respectively.
processes, this kind of methods relies on the formation of solid
diastereomeric salts that are separated by filtration. However,
filtration, drying and handling of substantial amounts of solids
may be uneasy.3 New approaches on liquid-phase resolution
methods may circumvent the problem of handling large amounts
of solid materials. For example, in 2008 was reported the
successful extraction of one enantiomer into an organic phase
by selective coordination to a hydrophobic selector, leaving the
uncomplexed enantiomer in the aqueous phase.4 Thus, resolu-
tion of racemic N-benzyl R-amino acids has been achieved by a
liquidꢀliquid extraction process using a lipophilic chiral
salenꢀcobalt(III) acetate complex. As a result, the (S)-enantio-
mer predominated in the aqueous phase, while the (R)-enantio-
mer was driven into the organic phase by complexation to cobalt.
The complexed (R)-amino acid was then quantitatively released
by a reductive (CoIIIꢀCoII) counter-extraction. Both enantio-
mers were obtained with more than 90% ee. The major drawback
of this approach resided in the necessity to use rather harsh
conditions (reduction with NaBH4) to release the complexed
amino acid. In 2009 was reported another new biphasic chiral
extraction for the separation of mandelic acid enantiomers.5 The
segregation of mandelic acid enantiomers was studied with O,O0-
dibenzoyl-(2S,3S)-4-toluoyl-tartaric acid (DTTA) in the organic
phase and β-CD derivatives in the aqueous phase; the influence
of the extractant types, concentrations and pH was investigated.
β-CD derivatives have stronger recognition abilities for (S)-
mandelic acid than for (R)-mandelic acid, while DTTA prefer-
entially recognizes (R)-mandelic acid. The highest enantiose-
paration efficiency (with a maximum enantioselectivity of 1.527)
is obtained at pH 2.7 and a 2:1 ratio of [D-(1)-DTTA]:[HP-β-
CD]. The results indicate that the biphasic (i.e., having a chiral
selector in each phase) chiral extraction is of stronger ability than
1. INTRODUCTION
Traditional methods for the separation of racemic mixtures
include crystallization of diastereomeric salts, chiral chromatography
and enzymatic resolution. Each method may have certain advan-
tages (efficiency, ease of handling, economy, etc.) over the others for
a particular chiral compound. However, the selection and optimiza-
tion of the method can only be performed on a case-by-case basis.
Therefore, there is a continuous need for the search of both new
chiral tools and alternative general strategies, able to resolve racemic
mixtures in a cost, time and waste saving manner. A promising
methodology relies on the ability of a chiral selector to discriminate
between the two enantiomers of a racemate, thus making the
enantiomeric separation of racemic mixtures possible, for example,
by transport across a chiral membrane, or by liquidꢀliquid extrac-
tion with a chiral host, in the case of hydrophilic substrates.1
As part of our continuous program on the search of new chiral
selectors,2 we wish to disclose our strategies and efforts for the con-
ception and synthesis of new tools useful for liquid phase resolution
processes (so-called ELLE).1 In all cases, we designed synthetic
methods allowing access to substantial amounts of the compounds,
at least at multigram scale. In this paper we focus on two series:
(i) on “chiral benzathines” (CBs), these chiral selectors being
designed for enantioselective recognition either in the
solid or the liquid state, and giving access to a fundamen-
tally new class of salts belonging to the third generation of
ionic liquids, i.e. “chiral ionic liquid benzathines” (CILBs).
These new tools open a new possibility for resolutions
processes via liquidꢀliquid demixtion (vide infra).
(ii) we generalized our previous studies on chiral ionic liquids
derived from (S)-histidine, in order to obtain more
hydrophobic salts for liquidꢀliquid separations.
2. BACKGROUND OF ELLE PROCESSES AND NEW
INSIGHTS
Special Issue: INTENANT
A series of recent publications describes new insights in the
field of optical resolution. Usually, when applied to large-scale
Received: March 30, 2011
Published: June 08, 2011
r
2011 American Chemical Society
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Figure 2. Targeted DACH derivatives (“chiral benzathines”).
Figure 1. (R)-BrHPP. Benzathine salt.
the monophasic (i.e. having a chiral selector in only one phase)
chiral extraction. Most of these studies have been recently
reviewed.1,6
Room-temperature ionic liquids (RTILs) are, as their name
implies, low-melting salts resulting from the adequate combina-
tion of organic cations with various noncoordinating anions.
They have a wide liquidus temperature range, and are able to
dissolve a large range of species including organic, inorganic and
organometallic compounds.7 Interestingly, they do not show any
detectable vapor pressure at near or room temperature and
usually possess high thermal stability. Therefore, RTILs are often
considered as novel environmentally benign solvents in chemical
reactions, multiphase bioprocess operation, batteries and fuel
cells investigations.
Armstrong and co-workers reported [bmim][PF6]ꢀwater
distribution coefficients for a set of 40 compounds including
three aromatic amino acids.8 Also interestingly, Smirnova et al.
reported that in the presence of 0.05ꢀ0.10 mol Lꢀ1 dicyclohex-
ano-18-crown-6, the amino acids glycine, tryptophan, leucine
and alanine can be extracted efficiently by [bmim][PF6] from an
aqueous solution.9 Thus, literature gives a few successful exam-
ples of liquidꢀliquid extraction using ionic liquids, but not in an
enantiodiscriminating manner at this stage.
Figure 3. Prepared (1S,2S)-DACH-based chiral benzathines.
Scheme 1. Synthesis of symmetric DACH-based compounds
Our idea is to combine the two approaches described before,
i.e. to benefit from RTILs properties for liquidꢀliquid resolution.
In other terms, we are currently investigating the development of
liquidꢀliquid selective extraction of enantiomers by chiral ionic
liquids.10 As discussed before, the attraction of such a method is
that it may circumvent the use of excessive handling of solids,
which is associated with classical resolution by crystallization of
diastereomeric salts; on a production scale this is often the
slowest step in the process. A very recent report describes the
first successful approach in this field.11
For this purpose, we selected diaminocyclohexane (DACH)
as the ideal starting material, because of its availability as both
enantiomers, and of the previous applications of its derivatives in
various asymmetric processes.14 The required structures must
possess at least one moiety able to be either alkylated or
protonated in order to obtain ionic liquids. We thus selected
pyridine derivatives of DACH as targets (Figure 2). Although
some examples of this series have been previously described
(vide infra), literature still lacks complete information on the
synthesis and comparison of all isomers. Our first set of experi-
ments was thus devoted to the systematic preparation and study
of all possible compounds in this family.
3. CHIRAL IONIC LIQUIDS FROM DACH
Our interest for this series of chiral selectors is a direct
consequence of a previous collaborative study between our
research groups and a pharmaceutical start-up (Innate-Pharma,
Marseilles, France). Indeed, we were interested at this time in the
synthesis and purification of the enantiomers of BrHPP, an
immunostimulant phosphoantigen (Figure 1).12 We finally ob-
served that nice crystallization occurred when using benzathine, a
well-known biocompatible diamine, for preparing BrHPP salts
(Figure 1). This allowed purification as well as easy handling and
stabilization of the compound.13
We assumed that this behavior was due to the especially strong
ionic interactions between the anionic and cationic partners
of the salt. As a consequence, we imagined that if we could use
chiral derivatives of benzathine, we could expect strong enan-
tiodiscriminating properties towards the enantiomers of chiral
compounds.
Indeed, depending on aryl substituents Ar1 and Ar2, the
physicochemical properties of the compound itself as well as of
its salts may be quite different. In our search for new chiral ionic
liquids, it was thus useful to examine the structure/melting point
relationship in this series, as well for symmetric as for dissym-
metric derivatives.
3.1. Synthesis of the Parent Diamines. This study was one of
our main goals in the frame of the INTENANT program.15 We
choose to synthesize all the possible products of reaction
between (1S,2S)-diaminocyclohexane with benzene-, pyridine-
2-, pyridine-3- and pyridine-4-carboxaldehydes (Figure 3). As we
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Figure 4. Ellipsoid drawing (50% probability) of the molecular structure of (1S,2S)-1d, HCl, H2O.
Scheme 2. Synthesis of mixed and dissymmetric DACH-based diamines
were not interested by the well-known dibenzyl derivative that
lacks an additional nucleophilic position, we engaged on the
synthesis of the nine possible targets: three compounds are mixed
(bearing both phenyl and pyridyl residues), three are symmetric
(bearing two identical pyridyl residues) and another three are
dissymmetric (bearing two different pyridyl residues). At the
beginning of this project in 2008, only two compounds in this
series were known, i.e. 1a and 1d.16 In 2009 was reported the
synthesis of (R,R)-enantiomers of compounds 1e and 1i.17
Finally, this study represents the first complete data for the
whole set of compounds.
The general procedure for the synthesis of symmetric 1,2-
diaminecyclohexane-based compounds 1d, 1e and 1f is depic-
ted in Scheme 1. It classically relies on a reductive amination
process.16ꢀ18
After purification by column chromatography, the preparation
of the corresponding hydrochloride salts was carried out with
3 equiv of 1 M HCl. Hydrochlorides were dried under vacuum
and recrystallized from i-PrOH. Full characterization of diamine
[(S,S)-1d] hydrochloride was performed by single-crystal dif-
fraction. In the asymmetric unit are present: two molecules of
diamine (S,S)-1d, four chloride anions and three water molecules
(Figure 4). Positions of hydrogen atoms were located unam-
biguously by means of Fourrier difference function. Worthy of
note is that only one of the secondary amine nitrogen is
protonated, as is also only one of two pyridine rings. This
behavior was not obvious before X-ray analysis, as we initially
expected to observe two similarly protonated nitrogens, either
the two secondary amines or the two pyridines. This observation
was of main importance for our study since it opened the road for
the construction of protic ionic liquids (vide infra). This also may
explain the unexpected difficulty encountered when we tried to
perform a selective alkylation on the pyridine rings.19
For the synthesis of mixed and dissymmetric DACH-based
diamines, we modified the procedure as shown in Scheme 2. The
modification consists of a sequence of two reductive amination
reactions using two different aldehydes successively. Intermedi-
ate compounds 2aꢀc were isolated and characterized. Final
compounds were obtained after crystallization with overall yield
20ꢀ40% and transformed in their hydrochloride salts that
proved to be much more stable than the parent diamines, which
slowly decomposed when stored in free form.
3.2. Preparation of DACH-Based Diamine Ionic Liquids. An
ionic liquid is a salt having a melting point below the boiling point
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Scheme 3. Diamine salts preparation
Figure 5. Conception of histidinium-based ionic liquid.
expected, the best choice to create ionic liquids, which is coherent
with general observations from literature. In this series, the melt-
ꢀ
ing points deꢀcrease following the anion order: Clꢀ > BF4
>
PF6ꢀ > NTf2
.
In addition to this study, we used hydrochloric acid to prepare
mono-, bis- and tris-hydrochlorides of 1c. As expected, NMR 1H
analyses showed that HCl protonates at first one of the secondary
amine functions, next the second secondary amine function, and
finally the nitrogen atom of one pyridine ring. These observa-
tions in solution for 1c, nHCl, differ from those of crystalline 1d,
HCl, X-ray analyses of which showed that both of the secondary
amines and one of the pyridine rings is protonated (Figure 4).
However, the actual position of proton(s) when these com-
pounds are either dissolved in ionic liquids or in the form of ionic
liquids remains unknown thus far. One can wonder if protons in
an ionic environment can pass from aliphatic to aromatic nitro-
gen atom by diffusion processes. Current studies are engaged in
our group to unravel this behavior.
Table 1. Selected physical properties of diamine salts
salt
Tm or Tg ꢀC
[R]D c = 1, MeOH
1c, HPF6
ꢀ18.7 (Tg)
+40.1
79 (Tm)
ꢀ19.1 (Tg)
81 (Tm)
99
1f, HPF6
+41.7
1c, HBF4
1f, HBF4
1c, HNTf2
1f, HNTf2
+69.7
+58.5
+36.2
+58.5
113
0.3 (Tg)
5.1 (Tg)
of water.7 According to this definition, any kind of salt having a
melting temperature below 100 ꢀC may be called an ionic liquid.
One of the most commonly used methods to make ionic liquids
is the alkylation of a heterocyclic moiety by n-alkyl chains. The
melting point of the ionic liquids obtained from a given hetero-
cycle depends both on the alkyl substituent(s) and the counter-
anion. Commonly used anions in ionic liquid chemistry are
bis(trifluoromethanesulfonyl)imide, hexafluorophosphate and
tetrafluoroborate. These noncoordinating anions efficiently de-
localize the negative charge, thus lowering the melting point.
Thus, we decided to synthesize the corresponding salts of our
diamines with hexafluorophosphoric acid (HPF6), tetrafluoro-
boric acid (HBF4) and bis(trifluoromethanesulfonyl)imide (HNTf2).
Hydrochloric acid salts were also prepared to compare their
melting points with those of the different salts obtained. A
collection of eight diamine salts was prepared (Scheme 3) start-
ing from two diamines 1c and 1f. We selected these two examples
for comparing mixed and symmetric samples. The physical
properties of received salts are compared in Table 1.
First, we were delighted to observe that two compounds from
Table 1 are liquids at room temperature, albeit quite viscous.
Compound 1c, HNTf2, has a glass transition temperature of
+0.3 ꢀC, and its structural analogue 1f, HNTf2, has a glass
transition temperature of +5.1 ꢀC. Hexafluorophosphate salts
have even lower glass transitions but crystallize after some days,
while chorides (not presented in the table) are high-melting
solids (mp > 150 ꢀC). Compound 1c, HBF4, is also just in the
range of an ionic liquid, with a melting point of 99 ꢀC, forming
colorless monoclinic crystals in water. These kinds of low-
melting-point salts, having a proton instead of an alkyl chain,
are called protic ionic liquids.
4. SYNTHESIS AND PROPERTIES OF CHIRAL HISTIDI-
NIUM-BASED IONIC LIQUIDS
Since our insights for liquid-phase resolution procedures rely
on a final extraction of one enantiomer in aqueous medium, the
hydrophobicity of the ionic liquids is a prerequisite. This point is
the major drawback of the previously studied CILBs in which
most examples are quite hydrophilic. Some years ago we envi-
sioned (S)-histidine, a commercially available natural amino acid,
as a key chiral starting material for the elaboration of dissym-
metric imidazolium moieties by direct modification of the side
chain, thus leaving free the amino acid function of the obtained
chiral ionic liquids.20 In the context of liquidꢀliquid resolution
with chiral ionic liquids, the amino acid part seems to be the best
candidate for separation processes because of possible strong
acidꢀbase interactions. Indeed, the side chain of histidine
possesses an imidazole ring from which an imidazolium cation
(one of the most commonly used cation in ionic liquids) can be
constructed. The chiral bifunctional unit of the amino acid remains
unchanged (Figure 5). However the histidinium salts having a
free amino and/or acid function were quite hydrophilic, pre-
venting their use as solvent for selective extraction of enantio-
mers from an aqueous phase.
The imidazolium cationic part can be modified by varying the
substituent on the heterocyclic nitrogen atoms (without modify-
ing the amino acid salt). Desymmetrization of the imidazolium
cation generally lowers the melting point. The melting points of
organic salts are closely related to the symmetry of ions: the more
asymmetric, the lower the melting point. The symmetry allows
efficient stacking of ions in the crystal. Conversely, the asymme-
try of the cation creates a distortion in the crystal lattice, leading
to a decrease in melting temperature. Histidine has three nucleo-
philic nitrogen atoms with different reactivities. For regioselec-
tive alkylation of the nitrogen atoms in the imidazole ring, they
each must be treated independently. The chosen strategy was
All the salts of HPF6, HBF4 and HNTf2 acids show a rather
good correlation with our expectations: mixed (and thus non-
symmetrical) 1c derivatives have generally lower melting tem-
peratures that the symmetrical 1f analogues. Also, NTf2ꢀ is, as
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Scheme 4. Protected histidinium-based ionic liquid preparation
Scheme 5. One-pot deprotection of amino acids and ion
metathesis
Table 2. DSC analyses and optical rotations of ionic liquids
7aꢀc and 8aꢀf
number
code
Tg ꢀC
[R]D c = 1, MeOH
7a
7b
7c
8a
8b
8c
8d
8e
[mbHis-Boc-OMe]-[Br]
[moHis-Boc-OMe]-[Br]
[mDodecHis-Boc-OMe]-[Br]
[mbHis-OMe]-[NTf2]
[mbHis]-[NTf2]
ꢀ9.2
ꢀ23.5
ꢀ37.3
ꢀ44.6
ꢀ16.6
ꢀ18.7
ꢀ29.6
ꢀ28.5
ꢀ15.8
ꢀ12.4
ꢀ10.5
+4.3
+0.9
[moHis-OMe]-[NTf2]
[moHis]-[NTf2]
+1.8
+2.3
[mDodecHis]-[NTf2]
+0.9
isoelectric point of the amino acid. All the resulting ionic liquids
can be dissolved in either acidic or basic aqueous solution and
then reprecipitated when shifting pH near to 7. At neutral pH,
close to the isoelectric point, the amino acid exists in zwitterionic
form, which decreases its solubility. Selective precipitation can be
used as a suitable purification method for hydrophobic ionic
liquids containing an amino acid part.
This method was scaled up to multigram quantity and showed
good results as a simple preparation of hydrophobic ionic liquids
containing an amino acid part in the structure. To determine the
melting points of every salt, DSC analysis was performed. All
compounds 7aꢀc and 8aꢀe have glass transition points below
0 ꢀC, confirming their ionic liquid nature (Table 2).
A clear structure/glass transition temperature relationship
occurs in the series of bromides 7aꢀc. Increasing alkyl chain
length decreases glass transition point. Optical rotation measure-
ments confirm chirality conservation after all reaction steps
(Table 2). The optical rotation of bromides 7aꢀc is counter-
clockwise, while all other ionic liquids 8aꢀe turn polarized light
clockwise.
previously developed by our team,20 and allowed selective
alkylation of both nitrogen atoms of the imidazole ring without
affecting the nitrogen atom of the amino acid part (Scheme 4,
compound 7a).
In order to increase their hydrophobicity, we prepared histidi-
nium bearing longer alkyl chains on N-3 (7b and 7c, Scheme 4). In
our previous work,20 compound 7a was directly engaged in ꢀa
metathesis step with LiNTf2, KPF6 or NaBF4. Afterwards, all NTf2
salts were deprotected using common methods for amino acid
chemistry. Nevertheless, this strategy led to several variations
according to the experimental procedure. Indeed, we sometimes
obtained salts that were soluble in water even when containing
the hydrophobic NTf2ꢀ anion. This was explained by the partial
reformation of the very hydrophilic hydrochloride salt during the
final deprotection step by means of HCl.
We thus developed a new strategy in order to obtain hydro-
phobic bifunctional ionic liquids in substantial amount. Ion
metathesis was moved to the last step of synthesis, after the
deprotection of Boc group by an acidic treatment and/or saponi-
fication of the methyl ester group (Scheme 5).
Deprotection step(s) along with anion metathesis were car-
ried out in one pot. The resulting ionic liquid precipitated
from aqueous solution when adjusting the pH to 7, near to the
5. CONCLUSION
In this paper we disclose the conception and synthesis of new
chiral selectors useful for liquid-phase resolution processes. In all
cases, we select synthetic methods giving access to substantial
amounts of the compounds, at least at multigram scale. We first
focus on “chiral benzathines” (CBs). This series gives access to a
fundamentally new class of salts belonging to the third generation
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of ionic liquids, i.e. “chiral ionic liquid benzathines” (CILBs).
Second, we generalize and improve the access to histidine-
derived ionic liquids. All these new tools open a new possibility
for resolutions processes in the liquid state. Our preliminary
studies for liquid-phase recognition are promising, and our
studies for applications in the field of resolution processes are in
progress.
Mo KR radiation (wavelength = 0.71073 Å) by using φ- and
ω-scans on a Bruker-AXS kappa APEX II Quazar diffractometer
using a 30-W air-cooled microfocus source (ImS) with focusing
multilayer optics at a temperature of 193(2) K. The data were
integrated with SAINT,21 and an empirical absorption correction
with SADABS was applied.22 The structure was solved by direct
methods (SHELXS-97)23 and refined against all data by the full-
matrix least-squares methods on F2 (SHELXL-97).24
1d, HCl, H2O: C36H58Cl4N8O3, M = 792.70, monoclinic,
space group P21, a = 16.8959(13) Å, b = 7.2352(6) Å, c =
17.3497(14) Å, β = 96.293(4)ꢀ, R = γ = 90ꢀ, V = 2108.1(3)Å 3,
Z = 2, crystal size 0.30 ꢁ 0.08 ꢁ 0.06 mm3, 40826 reflections
collected (9233 independent, Rint = 0.0556), 502 parameters,
14 restraints, R1 [I > 2σ(I)] = 0.0480, wR2 [all data] = 0.1126,
absolute structure parameter: 0.02(5), largest diff. peak and hole:
6. EXPERIMENTAL SECTION
6.1. General Information. The following solvents and re-
agents were dried prior to use: CH2Cl2, Et2O, THF, MeOH,
Et3N (distilled from calcium hydride, stored over potassium
hydroxide pellets). Benzaldehyde, pyridine-2-carboxaldehyde,
pyridine-3-carboxaldehyde, pyridine-4-carboxaldehyde and ben-
zylamine were distilled before use. EtOH, petroleum ether,
toluene and other starting materials were obtained from com-
mercial suppliers or prepared according to literature procedures.
Optical rotations were measured on a Perkin-Elmer model 241
polarimeter for the sodium D line (589 nm) at RT.
Melting points were determined by Mettler Toledo MP50
automatic melting point system. Each sample was approximately
5 mg in weight and was analyzed in glass capillaries. Melting
points were determined at inflection point and verified using
internal video record.
Differential scanning calorimetry was performed using Mettler
Toledo DSC1 STAR system. Melting points or glass transition
states were determined on temperature rising curves on half-
distance of baseline change. Glass transitions were measured with
relaxation when it was present.
NMR spectroscopic data were obtained with Bruker Advance
300 and Bruker Advance 400. Chemical shifts are quoted in parts
per million (ppm) relative to residual solvent peak using tables of
chemical shifts of solvents. The chemical shifts are expressed in
ppm. The coupling constants (J) are expressed in Hz. The multi-
plicities of the signals are abbreviated as: s (singlet), d (doublet),
t (triplet), q (quadruplet), dd (doublet of doublet), etc.
Mass spectrometry (MS) data were obtained on the PE Sciex
API 365 and Applied Biosystems Q Trap spectrometer.
Elemental analyses were obtained from Perkin-Elmer micro-
analyser CHNS series 2 for H, C and N elements.
0.302 and ꢀ0.264 e Åꢀ3, respectively.
3
6.3. General Procedure for Synthesis of Symmetric DACH-
Based Diamines. To a stirred solution of 2- or 3- or 4-pyridi-
necarboxaldehyde (2 equiv) in methanol was added slowly
(1S,2S)-(+)-1,2-cyclohexanediamine (1 equiv) in methanol using
a syringe pump. The mixture was stirred for 2 h at ambient
temperature, followed by addition of anhydrous sodium sulfate,
and was stirred further for another 15 min. The mixture was
filtered, and with stirring was added sodium borohydride (4 equiv)
in portions over a period of 30 min. The mixture was refluxed for
1 h, and then cooled to ambient temperature followed by
addition of distilled water. The solvent was removed under
reduced pressure leading to a white solid. The solid was dissolved
in water, followed by addition of KOH 1 M solution to pH g 10,
and was extracted successively three times with dichloromethane.
The combined organic layer was dried with Na2SO4, filtered and
slowly evaporated under reduced pressure, resulting in yellow oil
(75ꢀ95% yield). Purification was performed by column chro-
matography on SiO2. Eluents: EtAc/MeOH/Et3N = 88:10:2.
After the column chromatography was carried out, the hydro-
chlorides were prepared with 3 equiv of 1 M HCl. Hydrochlor-
ides were dried under vacuum and recrystallized from i-PrOH
with total yield 30ꢀ60% starting from DACH.
(1S,2S)-N1,N2-Bis(pyridin-4-ylmethyl)cyclohexane-1,2-diamine
1f, 3HCl, H2O: yield: overall 25% (4.17 g); yellow solid, mp =
20
1
210 ꢀC; [R]D = +64.5 (c 1, water); H NMR (300.18 MHz,
D2O), ppm: 1.14ꢀ1.21 (m, 4 H); 1.67ꢀ1.76 (m, 2H); 2.12ꢀ
2.26 (m, 2H); 2.75ꢀ2.84 (m, 2H); 4.16 (d, 2H, J = 15,9); 4.38
(d, 2H, J = 15,9); 7.9 (d, 4H, J = 6,3); 8.6 (d, 4H, J = 6.3); 13C
NMR (75.48 MHz, D2O), ppm: 23.8; 28.6; 59.9; 126.8; 141.8;
156.4; mass, CI (NH3)(MeOH/H2O): 297; analysis, calculated
for C18H29Cl3N4O: C, 51.01; H, 6.90; N, 13.22, found: C, 51.09;
H, 7.18; N, 13.27.
Measurement of pH was performed using WTW 315i pH/mV
pocket meter, calibrated to three points using commercial
standard solutions of pH 10.01, 7.00 and 4.00.
Analytical thin layer chromatography (TLC) was performed
using Merck silica gel F25460 precoated plates. Chromatograms
were observed under UV light and/or were visualised by heating
plates after dipping in 10% phosphomolybdic acid in ethanol or
Dragendorff reagent. Column chromatographies were carried
out with SDS 35ꢀ70 μm flash silica gel or aluminium oxide
90 active basic 0.063ꢀ0.200 mm from Merck.
(1S,2S)-N1,N2-Bis(pyridin-3-ylmethyl)cyclohexane-1,2-diamine
1e, 3HCl, 2H22O0: yield: overall 39% (4.68 g); white solid, mp =
1
243 ꢀC; [R]D = +51.6 (c 1, water); H NMR (300.18 MHz,
6.2. Crystal Structure Determination. Crystallographic data
(excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation no. CCDC-816872 (1d, HCl). These data can be obtained
free of charge via www.ccdc.cam.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033 or e-mail: deposit@ccdc.cam.ac.uk).
To determine the structures of compounds the selected
crystals were mounted on a glass fiber using perfluoropolyether
oil and cooled rapidly to 193 K in a stream of cold N2. X-ray intensity
data of crystals were collected with graphite-monochromated
D2O), ppm: 1.14ꢀ1.21 (m, 4 H); 1.67ꢀ1.76 (m, 2H); 2.12ꢀ
2.26 (m, 2H); 2.83ꢀ2.84 (m, 2H); 4.12 (d, 2H, J = 14.2); 4.35
(d, 2H, J = 14.2); 7.93 (dd, 2H, J1 = 5.8, J2 = 8.1); 8.51 (d, 2H,
J = 8.2); 8.65 (d, 2H, J = 5.7); 8.74 (s, 2H); 13C NMR (75.48 MHz,
D2O), ppm: 21.9; 26.2; 45.1; 58.6; 127.4; 132.1; 141.7; 141.8;
147.8; mass, ES+ (MeOH/H2O): 297, 189, 147; analysis, cal-
culated for C18H31Cl3N4O2: C, 48.93; H, 7.07; N, 12.68, found: C,
48.62; H, 7.44; N, 12.57.
(1S,2S)-N1,N2-Bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine
1d, 3HCl, H2O: yield: overall 22% (3.15 g); grey solid, mp =
20
1
190 ꢀC; [R]D = +50.2 (c 1, water); H NMR (300.18 MHz,
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D2O), ppm: 1.16ꢀ1.32 (m, 4 H); 1.64ꢀ1.78 (m, 2H); 2.20ꢀ
2.29 (m, 2H); 2.83ꢀ2.94 (m, 2H); 4.17 (d, 2H, J = 15.7); 4.40
(d, 2H, J = 15.7); 6.57 (m, 2H); 7.64 (d, 2H, J = 8.0); 8.11 (t, 2H,
J = 7.8); 8.42 (d, 2H, J = 5.5); 13C NMR (75.48 MHz, D2O),
ppm: 23.1; 28.1; 46.0; 59.5; 125.6; 125.8; 143.0; 144.5; 150.4;
mass, CI (NH3) (MeOH/H2O): 297; analysis, calculated for
C18H29Cl3N4O: C, 51.01; H, 6.90; N, 13.22, found: C, 51.00; H,
6.96; N, 13.11.
(d, 1H, J = 13.7); 4.51 (d, 1H, J = 13.0); 4.67 (d, 1H, J = 13.7);
7.48 (m, 5H); 8.13 (dd, 1H, J1 = 5.8, J2 = 8.2); 8.74 (d, 1H, J =
8.2); 8.86 (d, 1H, J = 5.8); 8.95 (s, 1H); 13C NMR (75.48 MHz,
D2O), ppm: 22.0; 22.1; 26.0; 26.5; 45.4; 49.1; 57.7; 58.3; 127.7;
129.3; 129.8; 130.2; 132.8; 142.0; 142.1; 148.0; mass, ES+
(MeOH/H2O): 296, 189, 147; analysis, calculated for C19H30-
Cl3N3O: C, 53.97; H, 7.15; N, 9.94, found: C, 54.40; H, 7.28;
N, 9.94.
(1S,2S)-N1-Benzyl-N2-(pyridin-2-ylmethyl)-cyclohexane-1,2-
diamine 1a, 3HCl, H2O: yield: overall 21% (2.68 g); light-violet
6.4. General Procedure for Synthesis of Mixed and Dis-
symmetric DACH-Based Diamines. To a stirred solution of 2-
or 3- or 4-pyridinecarboxaldehyde (2 equiv) in methanol, (1S,2S)-
(+)-1,2-cyclohexanediamine (1 equiv) in methanol was added
slowly, using a syringe pump. The mixture was stirred for 2 h at
ambient temperature, followed by addition of anhydrous sodium
sulfate, and was stirred further for another 15 min. The mixture
was filtered, and with stirring was added sodium borohydride
(2 equiv) in portions over a period of 30 min. The mixture was
refluxed for 1 h, and then cooled to ambient temperature
followed by addition of distilled water. The solvent was removed
under reduced pressure, leading to a white solid. The solid was
dissolved in water, followed by addition of a 1 M KOH solution
to pH g 10 and extracted successively three times with dichlor-
omethane. The combined organic layer was slowly evaporated
under reduced pressure, resulting in yellow oil (85ꢀ95% yield).
To a stirred solution of precedent compound (1 equiv) in
methanol was slowly added benzaldehyde (1 equiv). The mixture
was stirred for 2 h at ambient temperature, followed by addition
of anhydrous sodium sulfate, and was stirred further for another
15 min. The mixture was filtered, and to this mixture was added
sodium borohydride (2 equiv) in portions with stirring over a
period of 30 min. The mixture was refluxed for 1 h and then
cooled to ambient temperature followed by addition of distilled
water. The solvent was removed under reduced pressure, leading
to a white solid. The solid was dissolved in water, followed by
addition of KOH, 1 M solution, to pH g 10 and extracted
successively three times with dichloromethane. The combined
organic layer was slowly evaporated under reduced pressure,
resulting in yellow oil (75ꢀ85% yield). Purification was per-
formed by column chromatography on SiO2. Eluents: EtAc/
MeOH/Et3N = 88/10/2 for dissymmetric compounds and 96/
2/2 for mixed products, i.e. containing benzyl residue. After the
column chromatography was carried out, the hydrochlorides
were prepared with 3 equiv of 1 M HCl. Hydrochlorides were
dried under vacuum and recrystallized from i-PrOH with total
yield 20ꢀ40% starting from DACH.
20
1
solid, mp = 209 ꢀC; [R]D = +41.3 (c 1, water); H NMR
(300.18 MHz, D2O), ppm: 1.21ꢀ1.35 (m, 3 H); 1.44ꢀ1.55 (m,
1H); 1.77ꢀ1.89 (m, 2H); 2.27ꢀ2.36 (m, 2H); 2.84 (m, 1H);
3.13 (m, 1H); 4.13 (dd, 2H, J1 = 16.5; J2 = 13.2); 4.35 (dd, 2H,
J1 = 16.6; J2 = 13.2); 7.37ꢀ7.45 (m, 5H); 7.76 (m, 2H);
8.31ꢀ8.40 (m, 2H); 13C NMR (75.48 MHz, D2O), ppm: 23.2;
23.5; 26.8; 29.7; 46.5; 47.8; 58.1; 59.2; 125.5; 125.6; 129.3;
129.7; 130.8; 141.9; 145.3; 153.3; mass, ES+ (MeOH/H2O):
296, 189, 144; analysis, calculated for C19H30Cl3N3O: C, 53.97;
H, 7.15; N, 9.94, found: C, 54.30; H, 7.48; N, 10.09.
(1S,2S)-N1-(Pyridin-3-ylmethyl)-N2-(pyridin-4-ylmethyl)-cyclo-
hexane-1,2-diamine 1i, 3HCl, 2H2O: yield: overall 29% (2.94 g);
beige solid, mp = 194 ꢀC; [R]D20 = +65.6 (c 1, water); 1H NMR
(300.18 MHz, D2O), ppm: 1.16ꢀ1.38 (m, 4 H); 1.64ꢀ1.78 (m,
2H); 2.18ꢀ2.30 (m, 2H); 2.78ꢀ3.03 (m, 2H); 4.09 (d, 2H, J =
16.2); 4.23 (d, 2H, J = 14.0); 4.37 (d, 2H, J = 16.2); 4.43 (d, 2H,
J = 14.0); 7.95 (m, 3H); 8.53 (d, 1H, J = 8.4); 8.60ꢀ8.68 (m,
3H); 8.78 (s, 1H); 13C NMR (75.48 MHz, D2O), ppm: 23.1;
27.4; 28.3; 45.1; 47.9; 59.3; 59.9; 126.5; 126.6; 127.7; 133.6;
141.3; 142.0; 147.5; 147.6; mass, ES+ (MeOH/H2O): 297, 189,
147; analysis, calculated for C18H31Cl3N4O2: C, 48.93; H, 7.07;
N, 12.68, found: C, 48.13; H, 7.90; N, 12.43.
(1S,2S)-N1-(Pyridin-2-ylmethyl)-N2-(pyridin-4-ylmethyl)-cyclo-
hexane-1,2-diamine 1h, 3HCl, 2H2O: yield: overall 20% (2.48 g);
beige solid, mp =173 ꢀC; [R] D20 = +44 (c 1, H2O); 1H NMR
(300.18 MHz, D2O), ppm: 1.12ꢀ1.39 (m, 4 H); 1.66ꢀ1.79
(m, 2H); 2.16ꢀ2.31 (m, 2H); 2.73 (m, 1H); 3.00 (m, 1H); 4.05
(d, 1H, J1 = 16.3); 4.35 (d, 1H, J = 15.4); 4.37 (d, 1H, J = 16.3);
4.57 (d, 1H, J = 15.4); 7.66 (m, 2H); 8.02 (d, 2H, J = 6.6); 8.22 (t,
1H, J = 7.9); 8.42 (d, 1H, J = 5.1); 8.7 (d, 2H, J = 6.7); 13C NMR
(75.48 MHz, D2O), ppm: 23.3; 23.4; 26.9; 29.8; 46.6; 46.9; 58.7;
61.5; 125.7; 126.1; 127.2; 141.4; 141.8; 146.1; 152.6; 153.4;
mass, ES+ (MeOH/H2O): 297; analysis, calculated for C18H31-
Cl3N4O2: C, 48.93; H, 7.07; N, 12.68, found: C, 48.73; H, 6.78;
N, 11.89.
(1S,2S)-N1-Benzyl-N2-(pyridin-4-ylmethyl)-cyclohexane-1,2-
diamine 1c, 3HCl, H2O: yield: overall 21% (7.15 g); beige solid,
mp = 204 ꢀC; [R]D20 = +57.8 (c 1, water); 1H NMR (300.18 MHz,
D2O), ppm: 1.18ꢀ1.51 (m, 4 H); 1.66ꢀ1.78 (m, 2H); 2.18ꢀ
2.32 (m, 2H); 2.93ꢀ3.03 (m, 1H); 3.07ꢀ3.17 (m, 1H); 4.05
(dd, 2H, J1 = 13.1, J2 = 16.1); 4.29 (dd, 2H, J1 = 13.1, J2 = 16.1);
7.31 (m, 5H); 7.87 (d, 2H, J = 6.7); 8.59 (d, 2H, J = 6.7); 13C
NMR (75.48 MHz, D2O), ppm: 22.6; 22.8; 26.3; 27.7; 47.7;
48.5; 58.2; 58.4; 126.5; 129.3; 129.7; 130.5; 136.9; 141.3; 156.2;
mass, ES+ (MeOH/H2O): 296, 189, 147; analysis, calculated for
C19H30Cl3N3O: C, 53.97; H, 7.15; N, 9.94, found: C, 54.17; H,
7.32; N, 9.93.
(1S,2S)-N1-(Pyridin-2-ylmethyl)-N2-(pyridin-3-ylmethyl)-cyclo-
hexane-1,2-diamine 1g, 3HCl, 2H2O: yield: overall 29% (2.89 g);
white solid, mp = 221 ꢀC; [R]D20 = +60.9 (c 1, water); 1H NMR
(300.18 MHz, D2O), ppm: 1.08ꢀ1.47 (m, 4 H); 1.64ꢀ1.80 (m,
2H); 2.21ꢀ2.32 (m, 2H); 2.68 (m, 1H); 3.04 (m, 1H); 4.03
(d, 1H, J1 = 16.2); 4.33 (dd, 2H, J1 = 16.3, J2 = 13.8); 4.54 (d, 1H,
J2 = 13.8); 7.74 (dd, 2H, J1 = 16.8, J2 = 17.5); 8.00 (t, 1H, J = 6.5);
8.25 (t, 1H, J = 8.3); 8.40 (d, 1H, J = 6.0); 8.58 (d, 1H ; J=8.1);
8.73 (d, 1H, J = 8.0) ; 8.84 (s, 1H); 13C NMR (75.48 MHz, D2O),
ppm: 23.3; 23.4; 26.8; 29.7; 44.5; 46.8; 58.6; 61.2; 125.8; 126.2;
127.9; 131.9; 141.3; 142.3; 146.2; 148.4; 153.1; mass, ES+
(MeOH/H2O): 297, 189, 144; analysis, calculated for C18H31-
Cl3N4O2: C, 48.93; H, 7.07; N, 12.68, found: C, 48.96; H, 7.29;
N, 12.59.
(1S,2S)-N1-Benzyl-N2-(pyridin-3-ylmethyl)-cyclohexane-1,2-
diamine 1b, 3HCl, H2O: yield: overall 29% (3.96 g); white solid,
20
1
mp = 225 ꢀC; [R]D = +41.6 (c 1, water); H NMR (300.18
MHz, D2O), ppm:: 1.45 (m, 2H); 1.68 (m, 2H); 1.87 (m, 2H);
2.43ꢀ2.47 (m, 2H); 3.55 (m, 2H); 4.24 (d, 1H, J = 13.0); 4.38
6.5. Preparation of DACH Diamine-Based Ionic Liquids.
The corresponding DACH diamine-based compound, in the
form of hydrochloride hydrate, was added to 1 M water solution
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of KOH up to pH g 12. The resulting mixture was extracted
three times with CH2Cl2. Combined organic layers were evapo-
rated and dried under vacuum line. As a typical example, the
preparation of 1f, HNTf2, was carried out by adding one equi-
valent of bis(trifluoromethanesulfonyl)imide (5 mmol, 1.4 g) in
CH3CN to 1.48 g (5 mmol) of the compound 1f in the form of
free base. The obtained mixture was stirred for 30 min, evapo-
rated and dried under vacuum line. The same procedure was
repeated for all other compounds of this series.
DSC = +5.1 ꢀC (glass transition); [R]D20 = +38.5 (c 1, MeOH);
1H NMR (300.18 MHz, CD3CN), ppm: 1.31 (m, 4H); 1.84 (m,
2H); 2.33 (m, 2H); 2.64 (m, 2H); 3.93 (d, 2H, J = 14.1 Hz); 4.18
(d, 2H, J = 14.1 Hz); 7.40 (d, 4H, J = 6.0 Hz); 8.57 (d, 4H, J = 6.0
Hz); 13C NMR (75.48 MHz, CD3CN), ppm: 23.9; 28.5; 47.6;
59.6; 120.1 (q, 2C, J = 320 Hz); 123.8; 145; 149.8; 19F NMR
(282.37 MHz, CD3CN), ppm: ꢀ80.12 (s); mass, ES+ (MeOH):
297, 189, ESꢀ (MeOH): 280; analysis, Calculated for C20H25F6-
N5O4S2: C, 41.59; H, 4.36; N, 12.13, found: C, 41.45; H, 4.31;
N, 11.82.
6.6. Chiral Ionic Liquids Based on Histidinium Salts. Alky-
lation Step. The synthesis, purification and full analytical data for
compounds 5, 6 and 7a have been previously published.20 To the
compound 6 (3.3 mmol, 0.95 g) was added n-octylylbromide
(16.5 mmol, 2.9 mL). The reaction medium was heated at 90 ꢀC
overnight. The resulting biphasic mixture was concentrated in
vacuo and dried over the vacuum line at 60 ꢀC for 10 h to give
yellow, viscous oil. The same procedure was repeated for
compounds 7a and 7c.
(S)-4-(2-(tert-Butoxycarbonylamino)-3-methoxy-3-oxopropyl)-
1-methyl-3-octyl-1H-imidazol-3-ium bromide 7b [moHis-
Boc-OMe]-[Br]:. yield: 98% (1.96 g); yellow viscous oil,
DSC = ꢀ23.5 ꢀC (glass transition); [R]D20 = ꢀ12.4 (c 1, MeOH);
1H NMR (300.18 MHz, MeOD), ppm: 0.90 (3H, t); 1.31 (9H,
s); 1.41 (12H, m); 1.88 (2H, m); 3.07ꢀ3.29 (2H, m); 3.78 (3H,
s); 3.88 (3H, s); 4.17 (2H, m); 4.47 (1H, m); 7.37 (1H, s); 8.92
(1H, s); 13C NMR (75.48 MHz, MeOD), ppm: 13.1; 22.3; 26.1;
27.2; 28.8; 28.9; 29.5; 31.5; 35.1; 51.8; 52.2; 118.4; 121.7;
131.6; 171.1; mass ESI+ (MeOH): 396; 340; analysis, calculated
for C21H38BrN3O4: C, 52.94; H, 8.04; N, 8.82, found: C, 52.73;
H, 7.94; N, 8.77.
(1S,2S)-N1-Benzyl-N2-(pyridin-4-ylmethyl)cyclohexane-1,2-
diamine 1c, HBF4: yield: 99% (1.92 g); brown solid, mp = 99 ꢀC;
[R]D20 = +69.7 (c 1, MeOH); 1H NMR (300,18 MHz, MeOD),
ppm: 1.04ꢀ1.52 (m, 4H); 1.81 (m, 2H); 2.27 (m, 2H); 2.49 (dt,
1H, J1 = 11 Hz, J2 = 4 Hz); 2.79 (dt, 1H, J1 = 11 Hz, J2 = 4 Hz);
3.72 (d, 1H, J = 14.7 Hz); 3.98 (d, 1H, J = 14.7 Hz); 4.21 (AB,
2H, JAB = 13.2); 7.42 (m, 6H); 8.45 (d, 2H, J = 6.2 Hz); 13C
NMR (75,48 MHz, MeOD), ppm: 23.9; 24.2; 27.2; 30.2; 58.1;
60.2; 123.9; 129.0; 129.2; 129.3; 131.9; 147.5; 152.2; 31B NMR
(96, 29 MHz, MeOD), ppm: ꢀ0.83 (s); 19F NMR (282,37 MHz,
MeOD), ppm: ꢀ154.0 (s); mass, ES+ (MeOH): 296, 216, ESꢀ
(MeOH): 87; analysis, calculated for C19H26BF4N3: C, 59.55; H,
6.84; N, 10.96, found: C, 59.16; H, 6.68; N, 10.74.
(1S,2S)-N1-Benzyl-N2-(pyridin-4-ylmethyl)cyclohexane-1,2-
diamine 1c, HPF6: yield: 100% (2.22 g); light-brown solid, mp =
79 ꢀC; [R]D20 = +40.1 (c 1, MeOH); 1H NMR (300,18 MHz,
MeOD), ppm: 1.13ꢀ1.54 (m, 4H); 1.87 (m, 2H); 2.34 (m, 2H);
2.62 (td, 1H, J1 = 10.8, J2 = 3.9); 2.89 (td, 1H, J1 = 11.1, J2 = 3.8);
3.85 (d, 1H, J = 15.6 Hz); 4.16 (d, 1H, J = 15.6 Hz); 4.24 (d, 1H,
J = 13.2 Hz); 4.34 (d, 1H, J = 13.2 Hz); 7.43ꢀ7.53 (m, 5H); 7.77
(d, 2H, J = 6.0 Hz); 8.61 (d, 2H, J = 5.8 Hz); 13C NMR (75,48
MHz, MeOD), ppm: 23.8; 24.1; 27.1; 30.2; 48.4; 58.1; 60.1;
124.6; 129.1; 129.2; 129.4; 131.6; 145.1; 149.5; 31P NMR
(121,49 MHz, MeOD), ppm: ꢀ143.2 (sept, J = 708.5 Hz); 19F
NMR (282,37 MHz, MeOD), ppm: ꢀ72.7 (d, J = 708.8 Hz);
HRMS (DCI, CH4): calcd for C19H26N3 (M + H+) 296.2127;
found 296.2117.
(S)-4-(2-(tert-Butoxycarbonylamino)-3-methoxy-3-oxopropyl)-
3-dodecyl-1-methyl-1H-imidazol-3-ium bromide 7c [mDodecHis-
Boc-OMe]-[Br]: yield: 95% (1.69 g); yellow viscous oil, DSC =
20
1
ꢀ37.3 ꢀC (glass transition); [R]D = ꢀ10.5 (c 1, MeOH); H
NMR (300.18 MHz, acetone-d6), ppm: 0.90 (3H, t); 1.30 (9H, s);
1.41 (18H, m); 2.06 (2H, m); 2.95 (1H, m); 3.37 (2H, m); 3.75
(3H, s); 4.06 (s, 3H); 4.38 (2H, m); 4.47 (1H, m); 7.72 (1H, s); 9.99
(1H, s);13C NMR (75.48 MHz, MeOD), ppm: 13.1; 22.4; 25.5; 26.0;
27.2; 28.8; 29.1; 29.3; 29.4; 31.7; 32.6; 33.0; 35.1; 51.8; 52.2; 81.6;
121.7; 131.7; 153.8; 171.0; mass ESI+ (MeOH): 452; 396; analysis,
calculated for C25H46BrN3O4: C, 56.38; H, 8.71; N, 7.89, found: C,
56.49; H, 8.34; N, 7.59.
(1S,2S)-N1,N2-Bis(pyridin-4-ylmethyl)cyclohexane-1,2-diamine
1f, HPF6: yield: 100% (2.21 g); light-brown solid, mp = 81 ꢀC;
[R]D20 = +41.7 (c 1, MeOH); 1H NMR (300,18 MHz, MeOD),
ppm: 1.36ꢀ1.41 (m, 4H); 1.84 (m, 2H); 2.33 (m, 2H); 2.74
(m, 2H); 4.07 (d, 2H, J = 14.5 Hz); 4.25 (d, 2H, J = 14.3 Hz);
7.60 (d, 4H, J = 5.5 Hz); 8.59 (s, 4H); 13C NMR (75,48 MHz,
MeOD), ppm: 24.0; 28.7; 59.5; 124.2; 148.2; 154.3; 31P NMR
(121,49 MHz, MeOD), ppm: ꢀ143.2 (sept, J = 708.6 Hz); 19F
NMR (282,37 MHz, MeOD), ppm: ꢀ72.7 (d, J = 708.7 Hz);
HRMS (DCI, CH4): calcd for C18H25N4 (M + H+) 297.2079;
found 297.2072.
Synthesis of Histidiniums-Based Ionic Liquids (Amino Ester
Derivatives). A solution of HCl, 1.25 N in methanol (10 equiv),
was added to a stirred solution of histidinium bromide in dry
methanol. The mixture was stirred at room temperature for 3 h.
The solvents were evaporated, and the residue was partitioned
between water and dichloromethane. After separation, the aqu-
eous phase was concentrated under reduced pressure to afford
the product as yellow oil. To the resulting oil was added distilled
water and LiNTf2 (1 equiv). The resulting mixture was neutra-
lized to precipitate yellow oil-like compound, which was dec-
anted, washed with distilled water and dried under vacuum line.
The synthesis, purification and full analytical data for compounds
8a have been previously published.20
(S)-4-(2-Amino-3-methoxy-3-oxopropyl)-1-methyl-3-octyl-
1H-imidazol-3-ium, NTf2 8c [moHis-OMe]-[NTf2]: yield:
60%(1.77g);yellowviscousoil, DSC=ꢀ18.7 ꢀC (glass transition);
[R]D20 = +1.8 (c 1, MeOH); 1H NMR (300.18 MHz, DMSO-
d6), ppm: 0.85 (t, 3 H); 1.25 (m, 10 H); 1.73 (m, 2H); 3.30
(m, 2H); 3.18 (m, 1 H); 3.75 (s, 3 H); 7.53 (s, 1 H), 9.09 (s, 1 H);
(1S,2S)-N1-Benzyl-N2-(pyridin-4-ylmethyl)cyclohexane-1,2-
diamine 1c, HNTf2: yield: 100% (2.89 g); yellow viscous wax,
DSC = +0.3 ꢀC (glass transition); [R]D20 = +36.2 (c 1, MeOH);
1H NMR (300.18 MHz, CDCl3), ppm: 0.95ꢀ1.54 (m, 4H); 1.80
(m,2H);2.17(m,2H);2.44(m, 1H);2.41(m, 1H);3.62(d,1H,J=
14.0 Hz); 3.83 (d, 1H, J = 14.0 Hz); 4.04 (d, 1H, J=13.2 Hz); 4.18
(d, 1H, J = 13.2 Hz); 7.19 (d, 2H, J = 5.9 Hz); 7.36 (m, 5H); 8.15
(d, 2H, J = 5.9 Hz); 13C NMR (75.48 MHz, CD3CN), ppm: 24.0;
24.3; 27.3; 30.5; 48.6; 48.7; 57.7; 60.7; 113.3ꢀ126.1 (q, 2C, J = 317
Hz); 123.9; 129.3; 129.7; 130.1; 130.6; 148.4; 149.8; 19F NMR
(282.37 MHz, CD3CN), ppm: ꢀ80.15 (s); mass, ES+ (MeOH):
296, 216, ESꢀ (MeOH): 280; analysis, calculated for C21H26F6-
N4O4S2: C, 43.75; H, 4.55; N, 9.72, found: C, 44.23; H, 4.85; N, 9.34.
(1S,2S)-N1,N2-Bis(pyridin-4-ylmethyl)cyclohexane-1,2-dia-
mine 1f, HNTf2: yield: 100% (2.88 g); yellow viscous wax,
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Organic Process Research & Development
ARTICLE
13C NMR (75.48 MHz, CDCl3), ppm: 17.0; 26.2; 28.5; 30.0;
32.7; 32.8; 33.4; 35.4; 39.1; 55.0; 56.3; 117.4ꢀ130.1 (q, 2C,
J = 311 Hz); 126.3; 126.6; 133.8; 174.1; 19F NMR (282.37 MHz,
MeOD), ppm: ꢀ79.5 (s); mass ESI+ (MeOH): 296, ESIꢀ
(MeOH): 280.
Plaquevent, J.-C. Design and scalable synthesis of new chiral selectors.
Part 1: Synthesis and characterization of a new constrained cyclo-
peptide from unnatural bulky aminoacids. Tetrahedron 201110.1016/j.
tet.2011.06.032; available online 16 June 2011.For the next paper in this
series, see: (b) Rougeot C.; Guillen F.; Coquerel G.; Plaquevent J.-C.
Design and Multigram Synthesis of New Chiral Selectors. Part 3:
Synthesis and Characterization of Functionalized “Hooked” Cyclodex-
trins. 2011. Manuscript in preparation.
Synthesis of Histidinium-Based Ionic Liquids (Amino Acid
Derivatives). Procedure for the compound 8d, which was re-
peated for all other compounds of this series: a solution of 1 M
HCl in water (6.5 mmol, 6.5 mL) was added to a stirred solution
of histidinium bromide 7b (3.25 mmol, 1.55 g). The mixture was
stirred at room temperature for 3 h. To the resulting mixture was
added KOH, 1 M water solution (6.5 mmol, 6.5 mL), and the
mixture was stirred at room temperature for 3 h. After that,
1 equiv of LiNTf2 was added. The solution was stirred for 2 h at
room temperature. Then, it was neutralized to pH = 7 using HCl
solution to precipitate the oil-like yellow substance, which was
separated from the water layer, washed with distilled water and
dried in vacuo. The synthesis, purification and full analytical data
for compound 8b have been previously published.20
(S)-4-(2-Amino-2-carboxyethyl)-1-methyl-3-octyl-1H-imi-
dazol-3-ium, NTf2 8d [moHis]-[NTf2]: yield: 68% (1.73 g);
yellow viscous oil, DSC = ꢀ29.6 ꢀC (glass transition); [R]D20 =+2.3
(c 1, MeOH); 1H NMR (300.18 MHz, D2O), ppm: 0.93
(t, 3 H); 1.34ꢀ1.43 (m, 12 H); 1.90 (m, 2H); 3.33 (m, 2H);
3.78 (m, 1 H); 3.92 (s, 3 H); 7.45 (s, 1 H); 8.43 (s, 1H); 13C
NMR (75.48 MHz, MeOD), ppm: 13.0; 22.3; 26.1; 28.8; 28.9;
29.5; 31.5; 35.1; 47.0; 53.0; 113.5ꢀ126.2 (q, 2C, J = 320.4 Hz);
121.9; 122.2; 130.4, 136.2; 19F NMR (282.37 MHz, MeOD),
ppm: ꢀ79.5 (s); mass ESI+ (MeOH): 282, ESI- (MeOH): 280;
analysis, calculated for C17H28F6N4O6S2: C, 36.30; H, 5.02; N,
9.96, found: C, 36.26; H, 4.80; N, 9.62.
(3) Dzygiel, P.; Monti, C.; Piarulli, U.; Gennari, C. Org. Biomol.
Chem. 2007, 5, 3464.
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Gennari, C. Eur. J. Org. Chem. 2008, 7, 1253.
(5) Tang, K.; Yi, J.; Huang, K.; Zhang, G. Chirality 2009, 21, 390.
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Heeres, H. J. Org. Process Res. Dev 2009, 13, 911.
(7) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, 2nd ed.;
Wiley: Weinheim, 2008.
(8) Carda-Broch, S.; Berthod, A.; Armstrong, D. W. Anal. Bioanal.
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Pletnev, I. V. Anal. Bioanal. Chem. 2004, 378, 1369.
(10) For reviews on the chemistry of chiral ionic liquids, see:
(a) Baudequin, C.; Brꢁegeon, D.; Levillain, J.; Guillen, F.; Plaquevent,
J.-C.; Gaumont, A.-C. Tetrahedron: Asymmetry 2005, 16, 3921. (b)
Plaquevent, J.-C.; Levillain, J.; Guillen, F.; Malhiac, C.; Gaumont, A.-C.
Chem. Rev. 2008, 108, 5035.
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(14) Kouklovsky C.; Langlois Y. e-EROS, Encyclopedia of Reagents for
Organic Synthesis; 2001, 10.1002/047084289X.rn00145.
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(16) Newman, P. D.; Williams, P. A.; Stephens, F. S.; Vagg, R. S.
Inorg. Chim. Acta 1991, 183, 145.
(17) Zhang, G.; Yashima, E.; Woggona, W.-D. Adv. Synth. Catal.
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(18) Goodwin, T. J.; Vagg, R. S.; Williams, P. A. J. Proc. R. Soc. N. S.
W. 1984, 117, 1.
(S)-4-(2-Amino-3-methoxy-3-oxopropyl)-3-dodecyl-1-methyl-
1H-imidazol-3-ium, NTf2 8e [mDodecHis]-[NTf2]: yield: 85%
(1.73 g); yellow viscous oil, DSC = ꢀ28.5 ꢀC (glass transition);
[R]D20 = +0.9 (c 1, MeOH); 1H NMR (300.18 MHz, MeOD),
ppm: 0.89 (t, 3 H); 1.29ꢀ1.41 (m, 20 H); 1.87 (m, 2H); 3.07 (m,
1 H); 3.77 (s, 3 H); 4.16 (m, 2 H); 7.32 (s, 1 H), 8.83 (s, 1 H);
13C NMR (75.48 MHz, MeOD), ppm: 13.1; 22.4; 26.1; 27.2;
27.3; 28.8; 29.1; 29.3; 29,3; 29.4; 31.1; 35.0; 46.8; 52.9;
117.7ꢀ122.0 (q, 2C, J = 320.4 Hz); 117.7; 121.7; 132.2, 136.2;
173.6; 19F NMR (282.37 MHz, MeOD), ppm: ꢀ79.5 (s); mass
ESI+ (MeOH): 338, ESIꢀ (MeOH): 280; analysis, calculated for
C21H36F6N4O6S2: C, 40.77; H, 5.87; N, 9.06, found: C, 40.46; H,
5.94; N, 8.84.
(19) Zgonnik V. Dissertation, Universitꢁe Paul Sabatier: Toulouse
(France). In preparation.
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2006, 47, 1245. (b) Brꢁegeon, D.; Levillain, J.; Guillen, F.; Plaquevent,
J.-C.; Gaumont, A.-C. Amino Acids 2008, 35, 175.
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’ AUTHOR INFORMATION
Corresponding Author
*plaquevent@chimie.ups-tlse.fr.
’ ACKNOWLEDGMENT
We thank Dr. Martin Hedberg for the generous gift of (1S,2S)-
DACH. We are grateful for the support of this study within
INTENANT and the Grant FP7-NMP2-SL2008-214129 by the
European Union.
’ REFERENCES
(1) For a recent review, see: Schuur, B.; Verkuijl, B. J. V.; Minnaard, A. J.;
de Vries, J. G.; Heeres, H. J.; Feringa, B. L. Org. Biomol. Chem. 2011, 9, 36.
(2) For the previous paper in this series, see: (a) Ferron, L.; Guillen,
F.; Coste, S.; Coquerel, G.; Cardina€el, P.; Schwartz, J.; Paris, J.-M.;
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