Binding interactions between 3-aryl-1,2,4-oxadiazol-5-ones and a trisimidazoline base

Article abstract of DOI:10.1039/b009451j

The use of 1,2,4-oxadiazol-5-ones, a recently developed class of bioisosteric replacements for carboxylic acids in medicinal chemistry, as binding ligands in supramolecular complexes is reported and has been exemplified by the formation of non-covalent co

Full text of DOI:10.1039/b009451j

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Binding interactions between 3-aryl-1,2,4-oxadiazol-5-ones
and a trisimidazoline base
Anja Reichert,a Roland Fröhlich,b Roderick Fergusonc and Arno Kraft*a,c
1
a Institut für Organische Chemie und Makromolekulare Chemie II,
Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
b Institut für Organische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstr. 40,
D-48149 Münster, Germany
c Department of Chemistry, Heriot-Watt University, Edinburgh, UK EH14 4AS
Received (in Cambridge, UK) 24th November 2000, Accepted 3rd April 2001
First published as an Advance Article on the web 8th May 2001
The use of 1,2,4-oxadiazol-5-ones, a recently developed class of bioisosteric replacements for carboxylic acids
in medicinal chemistry, as binding ligands in supramolecular complexes is reported and has been exemplified
by the formation of non-covalent complexes between acidic 3-aryl-1,2,4-oxadiazol-5-ones and an imidazoline
base, 1,3,5-tris(4,5-dihydroimidazol-2-yl)benzene 1. The X-ray crystal structure of complex 6d illustrates how
the carbonyl oxygen and the nitrogen atom in the position α to the carbonyl group of the heterocyclic ligand
are hydrogen-bonded to the NH groups of tris(imidazoline) 1. A combination of 1H NMR dilution studies and
electrospray mass spectrometry-based competition experiments shows that 1,2,4-oxadiazol-5-ones bind more
strongly to receptor 1 than a comparable benzoate.
Introduction
Tetrazoles and 1,2,4-oxadiazol-5-ones are heterocyclic acids
that have attracted a lot of interest in medicinal chemistry. The
1,2,4-oxadiazol-5-one heterocycle is a relative newcomer among
binding groups in modern drug design. It has already become
a promising bioisosteric1 replacement for carboxylic acids,
for example, in non-peptide angiotensin II receptor antag-
onists2 (for lowering blood pressure) and in cholecystokinin
antagonists3 (for the treatment of certain neuropsychiatric dis-
orders). While pKa values† tend to be comparable, tetrazoles
and 1,2,4-oxadiazol-5-ones are more lipophilic than carboxylic
acids.1 The change in water solubility, binding affinity, meta-
bolic rate and bioavailability become important in the optimis-
ation of pharmacological properties during the development of
new drugs.
Their effectiveness as ligands should make acidic heterocycles
promising binding groups in supramolecular chemistry, too.
While studying non-covalent complexes with amidine bases,
we have recently been able to demonstrate that the replacement
of carboxylic acids by tetrazoles in complexes with hetero-
cyclic amidine 1 causes subtle changes in the binding mode
that affect the properties of the complexes both in the solid
and solution phase.4 Following a preliminary report on the
complexation of other acidic heterocycles,5 we now describe
details of the synthesis, crystal structure and solution bind-
ing studies of non-covalent complexes between several 1,2,4-
oxadiazol-5-ones and the relatively simple trisimidazoline
receptor 1.
Results and discussion
Synthesis
Scheme 1 Reagents and conditions: i, NH2OHؒHCl, Na2CO3, EtOH–
H2O, reflux; ii, EtOCOCl or 2-ethylhexyl chloroformate, NEt3, CHCl3,
25 ЊC; iii, xylene, reflux; iv, 1 (0.33 equiv.), EtOH, reflux.
The 3-step synthesis of 1,2,4-oxadiazol-5-ones is outlined in
Scheme 1.6,7 Nucleophilic addition of hydroxylamine to arom-
atic nitriles 2 gave amide oximes 3 which were esterified with
ethyl chloroformate or 2-ethylhexyl chloroformate‡ and cyclised
‡ Compared to the ethyl carbonate derivative, a 2-ethylhexyl carbonate
had a much higher solubility in non-polar solvents which, in the
absence of other solubilising groups, proved advantageous during
column chromatography.
† Two structurally related antihypertension drugs, one with a 1,2,4-
oxadiazol-5-one and another with a tetrazole group, were reported to
have pKa values of 6.1 and 5.3, respectively.6a,b
DOI: 10.1039/b009451j
J. Chem. Soc., Perkin Trans. 1, 2001, 1321–1328
This journal is © The Royal Society of Chemistry 2001
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Fig. 1 (a) Crystal structure of 6d. (b) Hydrogen bonding between two adjacent molecules of 6d (hydrogen atoms are omitted for clarity).
to the 3-aryl-1,2,4-oxadiazol-5-ones 5a–d in refluxing xylene.
When trisimidazoline base 1 was dissolved with 3 equiv. of a
1,2,4-oxadiazol-5-one in hot EtOH, the 1 : 3 salts 6 crystallised
in analytical purity upon cooling. Complexes 6a–d were charac-
terised by 1H and 13C NMR, IR, electrospray MS and elemental
analysis. The preparation of complexes with related hetero-
cycles followed an analogous procedure.
effects enforced by the long dodecyloxy side chains. Hydrogen
bonds are observed between the NH groups of protonated 1
and the deprotonated heterocycle, involving exclusively the
latter’s exocyclic oxygen and the ring nitrogen N4 adjacent to
the carbonyl group. Neither ring oxygen O1 nor ring nitrogen
N2 of the oxadiazolone act as H-bond acceptors.
Complexes of 1 with related heterocycles
Related heterocycles would be expected to show similar binding
modes. 3-Phenylisoxazol-5-one (10)11 and 5-methylisoxazol-3-
ol (11a)12 (with pKa values of 4.01 and 5.85, respectively, in
water) are both acidic enough for salt formation, yet their
respective complexes with 1 tended to be rather waxy, difficult
to crystallise and prone to thermal decomposition. In contrast,
saccharin 14 (with a pKa of 1.6 in water)13 gave a complex with
1 that was easily isolated and remained thermally stable up to
its melting point of 324 ЊC. Judging from the crystal structure
of 6d, the lack of a nitrogen atom adjacent to the carbonyl
group in ligand 10 might readily explain the compound’s failure
to give a stable complex. However, why isoxazol-3-ols 11a–b
caused similar problems despite the isoxazole ring nitrogen’s
known ability to act as a hydrogen-bond acceptor (cf. various
crystal structure of muscimol analogues)14 is unclear at the
moment. As will be shown later on, such difficulties in prepar-
ation or isolation do not necessarily correlate with low binding
affinities.
Crystal structure
Slow evaporation of a methanolic solution of complex 6d gave
needles suitable for X-ray analysis. The most striking feature of
the crystal structure is that all three oxadiazolone ligands bind
differently (Fig. 1a). One of the ligands shows a bifurcated
hydrogen bond between its carbonyl-O atom and two
imidazolinium-NH groups (O101 ؒ ؒ ؒ N12, O101 ؒ ؒ ؒ N55).
Another oxadiazolone binds through its carbonyl-O201 to
N15-H; in addition, ring nitrogen N206 (which is adjacent to
the ligand’s carbonyl group) is hydrogen-bonded to N32-H of
another nearby imidazoline. In contrast to previous crystal
structures of 1–carboxylic acid8a,9 and 1–tetrazole4 complexes,
the trisimidazoline core of 6d displays notable deviations
from planarity. As a result of the way all imidazoline groups
twist out of the plane of the trisimidazoline’s central benzene
ring, the third oxadiazolone ligand forms just one intramolec-
ular hydrogen bond (O301 ؒ ؒ ؒ N52). A second H-bond exists
to an adjacent molecule (N306 ؒ ؒ ؒ N35*), and two complexes
in the crystal thus assemble to a centrosymmetric H-bonded
dimer (Fig. 1b). Hydrogen bond lengths and angles are com-
piled in Table 1.
IR and 1H NMR spectra
All oxadiazolones gave rise to one or two characteristic IR
To the best of our knowledge, the crystal structure of 6d is
the first of a 1,2,4-oxadiazol-5-one that is not N-substituted.10
It illustrates two types of H-bonding patterns that are possible
for oxadiazolone ligands, even though the observed binding
arrangement may have been in part due to crystal packing
bands between 1775 cmϪ1 and 1820 cmϪ1.7 In contrast, the C᎐O
᎐
stretching frequency of the deprotonated heterocycle 9 as well
as of complexes 6a–d was reduced to about 1695 cmϪ1, indicat-
ing a weakening of the carbonyl bond owing to delocalisation
of the negative charge.
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Table 1 Hydrogen bond geometries
X ؒ ؒ ؒ HN hydrogen bond
X ؒ ؒ ؒ N distance/Å
X ؒ ؒ ؒ HN distance/Å
X ؒ ؒ ؒ HN angle/Њ
O101 ؒ ؒ ؒ H–N12
O101 ؒ ؒ ؒ H–N55
O201 ؒ ؒ ؒ H–N15
N206 ؒ ؒ ؒ H–N32
O301 ؒ ؒ ؒ H–N52
N306 ؒ ؒ ؒ H–N35*
2.86
2.99
2.68
2.86
2.68
2.85
2.02
2.14
1.82
2.09
1.83
2.01
163
166
168
148
166
162
Fig.
3
Job plot for the protonated tris(imidazoline) 8 binding
deprotonated oxadiazolone 9. The mole fraction x of 8 is defined as [8]/
([8]+[9]). The total concentration in CDCl3–CD3CN (6 : 1)§ was
maintained at 10Ϫ3 M, and the change in the HA NMR chemical shift
∆δ = δobserved Ϫ δ0 was determined for various compositions (δ0 is the
chemical shift of the HA singlet in 8). The maximum of the Job plot was
observed for a mole fraction of 0.25 as would be expected for a 1 : 3
complex.
Fig. 2 1H NMR spectra (40 MHz, 25 ЊC) of 6d in different solvents:
(a) in CD3OD; (b) in CDCl3. Solvent and water signals are marked
by ‘X’.
by vapour-pressure osmometry measurements in chloroform
(complex 6d, see Experimental) and by Job’s method16 of
continuous variation (Fig. 3).
Binding studies
Fast exchange,17b certainly on the NMR timescale, led to
scrambling between different binding modes in chloroform.
Association constants in CDCl3 were too large to be measured
accurately by NMR methods. To avoid complications from
multiple equilibria between 1 : 1 and higher complexes, we
resorted to a model system consisting of an equimolar mixture
of bisimidazoline 7a—with non-coordinating tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate (BArFϪ) counter-anions—
and the tetrabutylammonium salt of a deprotonated oxadi-
azolone (9) in a more competitive solvent mixture (CDCl3–
CD3OD, 97 : 3). Under these conditions complexation of a
second anion was suppressed, and binding could be evaluated
by simple 1 : 1 host–guest complex formation. An association
constant Ka of 1990 150 MϪ1 was derived by following the
change in the HA chemical shift of 7a during a typical 1H NMR
dilution experiment (Fig. 4).18 The deviation from planarity of
the trisimidazoline core, which is evident from the crystal
structure, suggests at first that the binding mode for oxadi-
azolones may be less favourable than for benzoates. Never-
theless, the Ka value of a deprotonated oxadiazolone (9)
binding to bisimidazoline 7a in CDCl3–CD3OD (97 : 3) was
determined to be about twice as large as for 4-tert-
butylbenzoate (Ka = 990 230 MϪ1)8 and slightly less than that
of 5-(4-tert-butylphenyl)tetrazolate (Ka = 2470 400 MϪ1) in
the same solvent mixture.4
The 1H NMR spectrum of a protonated trisimidazoline with
non-coordinating counter-anions (e.g., 8) displays a singlet at
δH ≈ 8.6 for the aromatic HA protons in both polar and non-
polar solvents. The chemical shift changes considerably upon
complex formation with carboxylate (δH ≈ 10.1 in CDCl3)8 or
tetrazolate ligands (δH ≈ 9.9 in CDCl3).4 Likewise, in the case of
1,2,4-oxadiazol-5-ones, no evidence for a 1 : 3 complex is found
in methanolic solution, whereas the HA singlet of chloroform-
soluble 6c–d undergoes a downfield shift of about 1 ppm to
δH ≈ 9.6 that is indicative of complexation (Fig. 2). Similar
diagnostic downfield shifts of aromatic proton signals have
been reported for isophthalamide receptors upon binding of
Electrospray mass spectra
1
barbiturates, halide anions and acetate.15 In all these cases, H
During the last years electrospray ionisation (ESI) mass
spectrometry has been recognised as an up-and-coming method
NMR downfield shifts correlate with close contacts between
ligand and aromatic receptor, which are also recognised in the
crystal structure of complex 6d (selected O ؒ ؒ ؒ H distances:
O101 ؒ ؒ ؒ H–C6 2.18 Å, O201 ؒ ؒ ؒ H–C2 2.39 Å, O301 ؒ ؒ ؒ
H–C4 2.59 Å). A 1 : 3 complex stoichiometry was confirmed
§ Owing to the insolubility of 8 in neat chloroform, a small amount of
the more polar acetonitrile had to be added as cosolvent.
J. Chem. Soc., Perkin Trans. 1, 2001, 1321–1328
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Fig. 4 Changes of the chemical shift of the HA signal upon dilution of
an equimolar solution containing 7a and 9 in CDCl3–CD3OD (97 : 3) at
25 ЊC. The curve represents the calculated isotherm for 1 : 1 binding.
for the high-throughput screening of combinatorial inhibitor
libraries in the presence of natural enzymes or receptors19,20
and, in one recent case, it has been successfully applied to the
study of synthetic complexes consisting of hydrogen-bonded
dimers of calixarene tetraureas.21 The method is based on the
notion that non-covalent complexes containing tightly bound
inhibitors give rise to stronger ion peaks in the mass spectrum
than more weakly bound ligands, always provided that the
enzyme–inhibitor [or receptor–(ant)agonist] complex is
charged, which is the case in most biochemical studies.
Even though the ions are transferred from solution into the
vacuum of the mass spectrometer, solution binding constants
and intensities of mass ion peaks generally correlate quite well.
Electrospray ionisation mass spectra were performed in
MeOH [or MeOH–MeCN (1 : 1)] in which the 1 : 3 complexes
were mostly dissociated and only the best ligands were expected
to show some residual binding to 1. Fig. 5a displays the positive
ion ESI mass spectrum of complex 6b. Not surprisingly, proton-
ated tris(imidazoline) 1 is the most abundant ion. Although a
neutral 1 : 3 complex—if it is present at all—eludes detection,
charged fragments of the complex are easily identified. The
dominant ions of interest are a singly protonated 1 : 1 adduct
of 1 and oxadiazolone 5b; a protonated 1 : 2 complex of 1 and
5b; and a doubly charged 1 : 1 adduct (1ؒ5b + 2 H+) at a lower
mass-to-charge ratio. In comparison, the ESI mass spectrum of
a complex of 1 with 4-tert-butylbenzoic acid (12)8 likewise
shows a 1 : 1 adduct (1ؒ12 + H+), but no ion originating from a
1 : 2 complex can be detected (Fig. 5b). A number of additional
ions have to be attributed to singly and doubly charged cluster
ions that involve neutral species. Except in the case of a tetra-
zole (e.g., 13) complex, where a whole series of cluster ions were
of the type 1 + n 13 + 2 H+ (with n = 1–7), these ions were
generally present in comparatively small amounts.
Competition experiments
The straightforward assignment of ions in the ESI mass
spectrum of complex 6b (Fig. 5a) promised that even mixtures
of complexes should be analysable by ESI-MS, at least in
principle. This way, we intended to check our previous results
from NMR dilution experiments by an independent method,
which promised to be not only faster but also more widely
applicable, especially in cases (e.g., 11a) when a tetrabutyl-
ammonium salt could not be obtained for NMR titration
studies. In particular, a single competition experiment would
greatly facilitate the comparison between two ligands under
identical conditions.20,22,23
The absence of unexpected or overlapping ion peaks in the
mass regions of interest made it possible to directly compare
differences in ion abundance, and hence in binding, of 1 : 1 and
1 : 2 adducts provided that equimolar mixtures of the two
complexes were used. Assignment of individual ions was
possible since in a mixture of a complex of 1 with a 1,2,4-
Fig. 5 (a) Electrospray mass spectrum of complex 6b in MeOH–
MeCN (1 : 1). (b) Electrospray mass spectrum of a complex of 1 with 4-
tert-butylbenzoic acid (12) in MeOH. (c) An electrospray mass
spectrum of a mixture containing equimolar amounts of complex 6b
and a complex of 1 with 4-tert-butylbenzoic acid (12) in MeOH. Peaks
marked by an asterisk denote singly and doubly charged cluster ions
involving neutral species.
oxadiazol-5-one (5b) or a carboxylic acid (12)8 the masses of
the base (1) and the two ligands (5b and 12) are sufficiently
different. Fig. 5c shows that ions of the respective singly and
doubly protonated 1 : 1 complexes are readily identified, and in
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ion pairs that are solvent-separated. In all probability solvato-
phobicity may well be a major factor, and the greater lipophilic-
ity of some of the heterocyclic acids compared to a carboxylate
will have to be considered. It has been previously reported that
1,2,4-oxadiazol-5-ones are more lipophilic than tetrazoles,6
which in turn have a higher lipophilicity than carboxylic acids.1
Care is therefore needed once solution binding constants in
non-polar solvents and abundances of mass ion peaks in
electrospray mass spectra [in polar solvents like MeOH or
MeOH–MeCN (1 : 1)] are correlated. Although the respective
conclusions for oxadiazolones vs. carboxylates seem to agree
quite well, the example with the tetrazole ligand (which binds
strongly in non-polar solvents, but apparently does not give rise
to an intense ion peak for its 1 : 1 complex in the electrospray
mass spectrum) demonstrates that there are limits to the
method.
Fig. 6 Ligands used in electrospray MS binding studies, arranged
according to the intensity of the mass ion peak of their 1 : 1 adduct
with protonated 1
All in all, the results emphasise a potential of the ESI-MS
technique for comparing supramolecular receptor–ligand
interactions in a manner similar to that used for rapid screening
assays aimed at identifying lead structures in the development
of new pharmaceutical drugs.
both cases oxadiazolone-containing ions are more abundant
than the corresponding complexes of the benzoate. Despite
the weak intensities of ions corresponding to protonated 1 : 2
complexes, the oxadiazolone-containing complex is still
recognised at m/z = 742, whereas the corresponding benzoate
complex (expected at m/z = 639) is not observed. Doubly
protonated 1 : 1 adducts (at m/z = 231 and 257), too, show an
intensity difference between the two ligands, although less
pronounced. Some additional ions could be attributed to singly
or doubly protonated oligomers and clusters of 1 and 5b; these
cluster ions were, however, comparatively small and not of
interest for this investigation.
By combining two to three complexes at a time, we have been
able to derive information about the binding affinity of various
ligands directly from the intensities of the protonated 1 : 1
adducts with trisimidazoline 1. Although these results remained
qualitative, it could be construed that the best ligands were 5b
and 11b, followed by benzoic acid 12 (Fig. 6). Both tetrazole 13
and saccharin 14 gave very weak ion peaks for 1 : 1 complexes
in any of the competition experiments. From this, it is evident
that of the two ligands, 5b and 12, the oxadiazolone binds more
strongly than the benzoate.
These findings correlate well with solution studies; there are
some minor discrepancies which can be attributed to changes in
solvent and binding system. Isoxazolol 11b turns out to be a
ligand with a binding affinity comparable to oxadiazolone 5b.
Against our expectations, tetrazole 13 performed poorly in
comparison, mainly owing to non-specific associations;17a
however, a quantitative study should take into account that 13
was included in a series of mixed cluster ions so that the total
intensity of tetrazole-containing ions may be more represent-
ative than the monitoring of just one arbitrarily chosen peak
(i.e., the monoprotonated 1 : 1 complex).¶ Saccharin showed
very weak binding; possibly, its larger acidity makes its complex
with 1 more salt-like, thereby preferring to dissociate in a more
polar solvent. There is a rough inverse correlation between ion
abundance of the 1 : 1 complexes and the pKa of the ligand: the
two least acidic ligands depicted in Fig. 6 (isoxazolol 11b and
oxadiazolone 5b) were found to show the strongest binding,
whereas saccharin with the highest acidity of the heterocycles
investigated gave rather weak ion peaks for its complex with 1.
Unlike our NMR binding studies in chloroform-rich solvents
(in which hydrogen bonding and electrostatic interactions
dominate), ESI-MS seems to measure the relative amounts of
Conclusion
Following their launch in medicinal chemistry, 1,2,4-oxadiazol-
5-ones have proven to be interesting acidic heterocycles that
can replace carboxylic acids as ligands in supramolecular
complexes. It could be deduced from 1H NMR dilution studies
and competition experiments by electrospray MS that a 3-aryl-
substituted 1,2,4-oxadiazol-5-one binds more strongly to basic
receptor 1 than a comparable benzoate.
Recent reports have indicated that both the carboxy terminus
of angiotensin and the acid group of tetrazole-based antag-
onistic drugs are known to interact with a protonated lysine and
a histidine—two basic amino acids—at the angiotensin II
receptor binding site.24 We note that, like the natural receptor,
protonated 1 with its meta-positioned imidazoline substituents
has pairs of cationic hydrogen bond donor groups in close
proximity. Our structural studies featuring oxadiazolone
complex 6d demonstrate how, in the presence of two nearby
NH hydrogen bond donor sites, a 1,2,4-oxadiazol-5-one forms
hydrogen bonds principally through the exocyclic carbonyl
oxygen and, at least in two out of three cases, the nitrogen α to
the carbonyl group. The simple model suggests several possible
binding modes for this ligand. It provides valuable information
about the binding affinity of a heterocyclic acid that has
become increasingly important as a pharmacophore in modern
drug design.
Experimental
General
All solvents were distilled prior to use. Melting points: Olympus
BH-2 polarisation microscope with Linkam TMS91 program-
mable sample heater. DSC: Mettler TC 11, DSC821e. NMR:
Varian VXR 300, Bruker DPX 400, DRX 500. TMS was used
as standard in the NMR measurements. The multiplicities of
13C signals were determined by DEPT experiments. IR: Bruker
Vector 22 FT-IR. EI-MS: Varian MAT 311 A (70 eV). CI-MS:
Finnigan INCOS 50. TLC: aluminium sheets with silica gel
60F254 (Merck). Chromatography: ICN silica gel 32–63 (ICN
Biomedicals). VPO: Knauer vapour-pressure osmometer;
number-average molar masses Mn were determined in chloro-
form (concentration range of 20–50 mg gϪ1). Elemental anal-
yses: Pharmazeutisches Institut der Heinrich-Heine-Universität
Düsseldorf.
¶ Previous studies have demonstrated that the formation of larger
aggregates is also observed in non-polar solvents in which complexes
between tetrazoles and 1 have a strong tendency to self-associate.4 The
completely planar structure of such tetrazole complexes was found to
be responsible for promoting π-stacking and salt-packing interactions.
The tendency of tetrazoles to produce series of charged cluster peaks
containing neutral tetrazole molecules has been noted in a different
context before.29
General procedure for 3-aryl-1,2,4-oxadiazol-5-ones 5
All 3-aryl-1,2,4-oxadiazol-5-ones were prepared by an adapted
J. Chem. Soc., Perkin Trans. 1, 2001, 1321–1328
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3-step procedure similar to a literature route.6a The corre-
sponding nitrile precursor 2 (35 mmol) was dissolved in EtOH
(130 cm3). A solution of hydroxylamine hydrochloride (70
mmol) and Na2CO3 (105 mmol) in water (40 cm3) was added
and refluxed for 5–8 hours. The solvent was then removed
in vacuo. After addition of water (200 cm3), an insoluble solid
could be collected by suction filtration. The crude amide oxime
3 (20 mmol) was dissolved in CHCl3 (50 cm3), treated with NEt3
(27 mmol) and ethyl chloroformate (21 mmol) or 2-ethylhexyl
chloroformate, and stirred at room temperature for 1–2 days.
The mixture was washed with ice-cold brine, the organic phase
was dried over Na2SO4, CHCl3 was removed in vacuo, and the
residue was dried. Cyclisation to the 1,2,4-oxadiazol-5-one 5
occurred upon heating a solution of the usually crude carbon-
ate ester (13 mmol) in xylene (150 cm3) to reflux for 6–8 h. After
removal of xylene by vacuum distillation, the crude product
was further purified by recrystallisation or column chrom-
atography as indicated.
(198 mg, 48%) as a colourless amorphous solid (Found: C, 63.5;
H, 8.6; N, 8.7. C25H40F3N3O2 requires C, 63.7; H, 8.6; N, 8.9%);
νmax (KBr)/cmϪ1 1695 (CO), 1383, 1326, 1169, 1122; δH(500
MHz, CDCl3) 0.98 (12 H, t, J 7.3), 1.41 (8 H, sextet, J 7.4),
1.60–1.67 (8 H, m), 3.25–3.29 (8 H, m), 7.48 (1 H, t, J 7.7), 7.58
(1 H, br d, J 7.7), 8.20 (1 H, br d, J 7.7), 8.28 (1 H, br s).
4-(2-Methoxyethoxymethoxy)benzonitrile 2c. The compound
was prepared as described in a method by Kremers and Meijer
for the treatment of hydroxymethylmalonates with MEM
chloride.25 A solution of MEM chloride (26.2 g, 210 mmol),
4-hydroxybenzonitrile (22.5 g, 190 mmol) and diisopropylethyl-
amine (39 cm3) in dry CH2Cl2 (275 cm3) was stirred at room
temperature until TLC analysis (with hexane–ethyl acetate,
2 : 1) indicated that conversion was complete. The reaction
mixture was then washed with saturated aqueous NaHCO3
(3 × 150 cm3), dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was distilled twice (Kugelrohr, 170–
180 ЊC/0.02 mbar) to furnish a light yellow liquid (36.0 g, 92%)
(Found: C, 63.0; H, 6.6; N, 6.7. C11H13NO3 requires C, 63.8; H,
6.3; N, 6.8%); νmax (film)/cmϪ1 2226, 1605, 1508, 1239, 1173,
1106, 983, 841; δH(500 MHz, CDCl3) 3.36 (3 H, s), 3.53–3.56
(2 H, m), 3.81–3.83 (2 H, m), 5.32 (2 H, s), 7.11, 7.58 (2 × 2 H,
AAЈXXЈ); δC(125 MHz, CDCl3) 59.0, 116.8, 133.9 (CH, CH3),
68.1, 71.4, 93.2 (CH2), 105.1, 119.1, 160.6 (CN, ipso-C); m/z
3-(4-Fluorophenyl)-1,2,4-oxadiazol-5(4H)-one 5a. Prepared in
two steps from the commercially available 4-fluorobenzamide
oxime (Aldrich) and 2-ethylhexyl chloroformate. Yield: 84%,
colourless solid, mp 206–210 ЊC (from xylene) (Found: C, 53.6;
H, 2.5; N, 15.5. C8H5FN2O2 requires C, 53.3; H, 2.8; N,
15.55%); νmax (KBr)/cmϪ1 1817 (CO), 1737, 1608, 1527, 1486,
1232, 1171, 957, 852, 763; δH(500 MHz, CDCl3–DMSO-d6,
7 : 1) 7.18–7.22 (2 H, m), 7.86–7.89 (2 H, m); δC(125 MHz,
CDCl3–DMSO-d6, 7 : 1) 116.3 (2JCF 22), 128.5 (3JCF 9) (CH),
119.9, 156.6, 160.5, 164.6 (1JCF 253) (ipso-C, C᎐O, C᎐N); m/z
+
+
(CI, NH3) 242 (M + NH3 + NH4 , 34%), 225 (M + NH4 , 100).
3-[4-(2-Methoxyethoxymethoxy)phenyl]-1,2,4-oxadiazol-
5(4H)-one 5c. Prepared in 3 steps from 2c (using the ethyl
carbonate route) without purification of the intermediates.
Yield: 42% (after column chromatography with CH2Cl2–
MeOH, 15 : 1), mp 120–122 ЊC (Found: C, 54.4; H, 5.2; N, 10.5.
C12H14N2O5 requires C, 54.1; H, 5.3; N, 10.5%); νmax (KBr)/cmϪ1
1781 (CO), 1614, 1475, 1239, 1100, 1085, 995; δH(500 MHz,
CDCl3) 1.36 (2 H, t, J 7.1), 3.38 (3 H, s), 3.56–3.59 (2 H, m),
3.83–3.86 (2 H, m), 4.32 (2 H, q, J 7.1), 5.33 (2 H, s), 7.17, 7.75
(2 × 2 H, AAЈXXЈ); δC(125 MHz, CDCl3) 59.0, 117.0, 127.8
᎐
᎐
(EI, 70 eV) 181, 180 (M+, 14, 100%), 137 (97), 121 (64), 109 (68).
3-(Trifluoromethyl)benzamide oxime 3b. Yield: 96%, colour-
less solid, mp 92 ЊC (after sublimation at 70 ЊC/10Ϫ4 mbar)
(Found: C, 47.1; H, 3.6; N, 13.7. C8H7F3N2O requires C, 47.1;
H, 3.5; N, 13.7%); νmax (KBr)/cmϪ1 3359, 2993, 1753, 1643,
1633, 1401, 1324, 1168, 1130, 1074; δH(500 MHz, CDCl3–
DMSO-d6, 5 : 2) 5.66 (2 H, br s), 7.53 (1 H, t, J 7.8), 7.62 (1 H,
br d, J 7.8), 7.94 (1 H, br d, J 7.8), 8.01 (1 H, br s), 9.80 (1 H, br
s); δC(125 MHz, CDCl3–DMSO-d6, 5 : 2) 122.2, 125.2, 128.7,
(CH, CH3), 68.1, 71.6, 93.2 (CH2), 115.8, 156.9, 160.6, 162.3
+
(ipso-C, C᎐N, C᎐O); m/z (CI, NH ) 301 (M + NH + NH ,
᎐
᎐
3
3
4
129.0 (CH), 124.0 (q, 1JCF 271), 129.6 (q, 2JCF 31), 134.2, 150.1
41%), 284 (M + NH4 , 100), 225 (35); Rf (CH2Cl2–MeOH,
+
+
(ipso-C, C᎐N); m/z (CI, NH ) 239 (M + NH + NH , 12%),
15 : 1) 0.35.
᎐
3
3
4
222 (M + NH4 , 95), 206, 205 (M + H+, 25, 100), 189 (54).
+
4-Dodecyloxybenzamide oxime 3d. Prepared from 2d.26 Yield:
83%, colourless solid (Found: C, 70.6; H, 10.0; N, 8.2.
C19H32N2O2 requires C, 71.2; H, 10.1; N, 8.7%); νmax (KBr)/cmϪ1
2920, 2852, 1653, 1611, 1520, 1395, 1253, 827; δH(500 MHz,
DMSO-d6) 0.85 (3 H, t, J 6.6), 1.20–1.44 (18 H, m), 1.70 (2 H,
quintet, J 7.2), 3.96 (2 H, t, J 6.3), 5.68 (2 H, s), 6.90, 7.58 (2 × 2
H, AAЈXXЈ), 9.42 (1 H, s); δC(125 MHz, DMSO-d6) 14.3,
114.2, 127.0 (CH, CH3), 22.4, 25.9, 29.0, 29.1, 29.1, 29.35,
29.39, 31.6, 67.8 (CH ), 114.2, 150.9, 159.6 (ipso-C, C᎐N); m/z
N 2-(Ethoxycarbonyloxy)-3-trifluoromethylbenzamidine
4b.
Yield: 99%, colourless solid, mp 98 ЊC (Found: C, 47.8; H, 4.1;
N, 10.1. C11H11F3N2O3 requires C, 47.8; H, 4.0; N, 10.1%); νmax
(KBr)/cmϪ1 3361, 1753, 1632, 1400, 1324, 1168, 1130; δH(500
MHz, CDCl3) 1.38 (3 H, t, J 7.2), 4.35 (2 H, q, J 7.2), 5.14 (2 H,
br s), 7.57 (1 H, t, J 7.8), 7.74 (1 H, br d, J 7.8), 7.91 (1 H, br d,
+
J 7.8), 7.95 (1 H, br s); m/z (CI, NH3) 311 (M + NH3 + NH4 ,
+
11%), 294 (M + NH4 , 68), 277 (M + H+, 38), 206 (49), 189
᎐
2
+
(100).
(CI, NH3) 338 (M + NH4 , 7%), 323, 322, 321 (M + H+, 17, 22,
100), 305 (23); Rf (CH2Cl2–MeOH, 9 : 1) 0.46.
3-[3-(Trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one 5b.
Yield: 71% (after chromatography with CH2Cl2–Et2O, 6 : 1),
mp 185–186 ЊC (decomp.) (Found: C, 46.8; H, 2.0; N, 11.9.
C9H5F3N2O2 requires C, 47.0; H, 2.2; N, 12.2%); νmax (KBr)/
cmϪ1 1815 (CO), 1736, 1351, 1338, 1308, 1179, 1138, 695;
δH(500 MHz, CDCl3–DMSO-d6, 7 : 1) 7.69 (1 H, t, J 7.9), 7.82
(1 H, br d, J 7.9), 8.09 (1 H, br d, J 7.9), 8.19 (1 H, br s); δC(125
MHz, CDCl3–DMSO-d6, 7 : 1) 123.1, 128.4, 129.4, 129.9
4-Dodecyloxy-N 2-(ethyloxycarbonyloxy)benzamidine
4d.
Yield: 92%, colourless solid (after chromatography with
hexane–ethyl acetate, 2 : 1) (Found: C, 67.6; H, 9.4; N, 6.9.
C22H36N2O4 requires C, 67.3; H, 9.2; N, 7.1%); νmax (KBr)/cmϪ1
2919, 1757, 1628, 1258; δH(500 MHz, CDCl3) 0.88 (3 H, t,
J 6.9), 1.25–1.48 (18 H, m), 1.35 (3 H, t, J 7.1), 1.78 (2 H, tt,
J 7.2 and 6.6), 3.90 (2 H, t, J 6.5), 3.90 (2 H, q, J 7.1), 5.10 (2 H,
s), 6.86, 7.59 (2 × 2 H, AAЈXXЈ), 9.42 (1 H, s); m/z (CI, NH3)
1
(broadened signals) (CH), 123.4 (q, JCF 271), 124.6, 131.2 (q,
2JCF 33), 156.4, 160.3 (ipso-C, C᎐N, C᎐O); m/z (EI, 70 eV) 230
410 (M + NH4 , 8%), 394, 393 (M + H+, 16, 100); Rf (hexane–
+
᎐
᎐
(M+, 90%), 187 (100), 171 (32), 145 (37), 139 (30), 109 (40), 75
(35); Rf (CH2Cl2–Et2O, 6 : 1) 0.1. A solution of 5b (200 mg,
0.869 mmol), aqueous NBu4OH (40%, 0.3 cm3, 0.5 mmol) and
NaOH (70 mg, 1.7 mmol) in water (10 cm3) was extracted with
CH2Cl2 (3 × 10 cm3). The combined organic extracts were
washed with brine (10 cm3) and water (10 cm3), dried (Na2SO4),
and concentrated in vacuo to afford tetrabutylammonium salt 9
ethyl acetate, 2 : 1) 0.26.
3-(4-Dodecyloxyphenyl)-1,2,4-oxadiazol-5(4H)-one 5d. Yield:
12%, colourless solid (after column chromatography with
CH2Cl2–Et2O, 2 : 1), mp 166 ЊC (Found: C, 69.4; H, 8.7; N, 8.0.
C20H30N2O3 requires C, 69.3; H, 8.7; N, 8.1%); νmax (KBr)/cmϪ1
2921, 2852, 1819 (CO), 1780, 1733, 1616, 1250; δH(500 MHz,
1326
J. Chem. Soc., Perkin Trans. 1, 2001, 1321–1328

View Article Online
CDCl3) 0.88 (3 H, t, J 7.0), 1.20–1.40 (16 H, m), 1.43–1.50 (2 H,
m), 1.77–1.85 (2 H, m), 4.02 (2 H, t, J 6.6), 7.01, 7.71 (2 × 2 H,
AAЈXXЈ), 10.91 (1 H, br s); δC(125 MHz, CDCl3) 14.5, 115.7,
128.2 (CH, CH3), 23.1, 26.4, 29.4, 29.7, 29.94, 29.97, 30.02,
(36 H, m), 1.75–1.81 (4 H, m), 3.97 (2 H, t, J 6.7), 3.99 (8 H, s),
6.91, 7.72 (2 × 4 H, AAЈXXЈ), 7.10 (1 H, t, J 7.9), 8.33 (2 H, dd,
J 7.9 and 1.3), 9.08 (1 H, br s).
30.04, 32.3, 68.8 (CH2), 114.7, 114.8, 129.8, 157.4, 162.95,
Complex with 10. Yield: 48% (from EtOH), waxy, light yellow
solid, mp 123 ЊC (Found: C, 65.7; H, 5.3; N, 16.4. C42H39N9O6
requires C, 65.9; H, 5.1; N, 16.5%); νmax (KBr)/cmϪ1 3126, 2968,
1611, 1576, 1475, 1417, 1290, 745, 698; δH(500 MHz, CDCl3–
DMSO-d6, 5 : 2) 3.99 (12 H, s), 4.74 (3 H, br s), 7.36–7.42 (6 H,
m), 7.63–7.68 (6 H, m), 7.78–7.82 (3 H, m), 8.78 (3 H, s).
+
162.99 (ipso-C, C᎐N, C᎐O); m/z (CI, NH ) 364 (M + NH ,
᎐
᎐
3
4
100%), 305 (35); Rf (CH2Cl2–Et2O, 2 : 1) 0.67.
General procedure for the preparation of the complexes
Imidazoline base 127 and 3-aryl-1,2,4-oxadiazol-5(4H)-one 5
(3 equiv.) were dissolved in hot ethanol (ca. 12–20 cm3 per
mmol 5). After filtration of the hot solution and concentration,
the crude product was crystallised from the solvent (mixture)
indicated for each complex and thoroughly dried at 50–100 ЊC/
10Ϫ5 mbar.
12
Complex with 11a.
Yield: 45% (from propan-2-ol). The
light yellow waxy solid decomposed rapidly upon standing,
probably owing to the high volatility of 11a; δH(500 MHz,
CDCl3) 2.22 (9 H, d, J 0.8), 4.06 (12 H, s), 5.47 (3 H, q, J 0.8),
9.19 (3 H, s), 10.25 (6 H, br s).
Complex 6a. Yield: 47% (from EtOH), off-white solid, mp
227–230 ЊC (Found: C, 56.8; H, 4.2; N, 20.3. C39H33F3N12O6
requires C, 56.9; H, 4.0; N, 20.4%); νmax (KBr)/cmϪ1 1655 (CO),
1604, 1420, 1385, 1222, 600; δH(500 MHz, CDCl3–CD3OD,
7 : 1) 4.00 (12 H, s), 7.11–7.22 (6 H, m), 7.76–7.86 (6 H, m), 8.54
(3 H, s).
28
Complex with 11b. Yield: 19% (from EtOH), yellow solid
(Found: C, 63.6; H, 5.3; N, 15.5. C42H39N9O6ؒ1.5 H2O requires
C, 63.6; H, 5.3; N, 15.9%); δH(500 MHz, CDCl3) 4.17 (s, 12 H),
6.09 (s, 3 H), 7.36–7.43 (m, 9 H), 7.66–7.70 (m, 6 H), 9.64
(s, 3 H).
Complex with 14. Yield: 75% (MeOH), colourless needles, mp
324 ЊC (Found: C, 51.8; H, 4.0; N, 15.1. C36H33N9O9S3 requires
C, 52.0; H, 4.0; N, 15.15%); νmax (KBr)/cmϪ1 3131b, 2969b,
1642, 1611, 1572, 1287, 1153, 603; δH(300 MHz, DMSO-d6)
4.12 (12 H, s), 7.56–7.71 (12 H, m), 8.80 (3 H, s), 11.0 (6 H,
br s).
Complex 6b. Yield: 66% (from EtOH), colourless needles,
mp 206–207 ЊC; νmax (KBr)/cmϪ1 1677 (CO), 1578, 1406, 1385,
1325, 1286, 1127, 696; δH(500 MHz, CDCl3–DMSO-d6, 7 : 1)
3.92 (12 H, s), 7.64 (3 H, br t, J 7.8), 7.75 (3 H, br d, J 7.8), 8.09
(3 H, br d, J 7.8), 8.15 (3 H, br s), 8.72 (3 H, s).
Complex 6c. Yield: 74% (from EtOH), colourless solid, mp
154–155 ЊC (Found: C, 56.5; H, 5.5; N, 15.3. C51H60N12O15
requires C, 56.7; H, 5.6; N, 15.55%); νmax (KBr)/cmϪ1 1674
(CO), 1658, 1611, 1425, 1386, 1228, 986, 983; δH(500 MHz,
CDCl3) 3.35 (9 H, s), 3.52–3.57 (6 H, m), 3.80–3.84 (6 H, m),
3.97 (12 H, s), 5.29 (6 H, s), 7.08, 7.69 (2 × 6 H, AAЈXXЈ), 9.60
(3 H, s).
Electrospray ionisation mass spectrometry
ESI mass spectra were recorded on a single quadrupole
Thermoquest Automass LC/GC benchtop mass spectrometer.
Samples were introduced as 0.5–1 mM solutions in HPLC-
grade methanol at flow rates of 15 µL minϪ1 via a Rheodyne
inlet (main solvent stream MeOH–H2O, 1 : 1). Representative
conditions for the positive ion mode were as follows: heated
capillary temperature 180 ЊC; cone voltages were set to 8 V to
avoid excessive dissociation of the non-covalent complexes; at
least 15 scans were averaged to improve the signal-to-noise
ratio. For competition experiments a solution containing 3
µmol of each complex in CD3OD was prepared and the ratio
Complex 6d. Yield: 47% (from EtOH), colourless crystals,
DSC: K1/83 (∆H 118 J gϪ1)/K2/186 (∆H 60 J gϪ1)/I (Found: C,
68.2; H, 8.4; N, 12.65. C75H108N12O9 requires C, 68.5; H, 8.7; N,
12.7%); νmax (KBr)/cmϪ1 2923, 2852, 1660 (CO), 1653, 1611,
1424, 1381, 1250; δH(500 MHz, CDCl3, 10Ϫ2 M) 0.88 (9 H, t,
J 6.9), 1.22–1.48 (54 H, m), 1.78 (6 H, tt, J 6.7 and 7.1), 3.94 (12
H, s), 3.97 (6 H, t, J 6.6), 6.92, 7.68 (2 × 6 H, AAЈXXЈ), 9.59 (3
H, s), 10.5 (6 H, br s); δH(500 MHz, CD3OD, 10Ϫ2 M) 0.89 (9 H,
t, J 6.9), 1.27–1.51 (54 H, m), 1.79 (6 H, tt, J 6.7 and 7.1), 3.96
(12 H, s), 4.03 (6 H, t, J 6.6), 7.00, 7.72 (2 × 6 H, AAЈXXЈ), 8.35
(3 H, s); δC(125 MHz, CDCl3) 14.1, 114.6, 127.8, 134.2 (CH,
CH3), 22.7, 26.0, 29.2, 29.35, 29.42, 29.58, 29.61, 29.64, 29.67,
31.9, 45.5, 68.2 (CH2), 121.1, 125.9, 160.9, 163.3, 166.7, 174.2
(ipso-C, C᎐N, C᎐O); M (VPO, CHCl , 33 ЊC) 1520 g molϪ1
1
of the components was determined by H NMR spectroscopy
and, if necessary, adjusted by addition of the minor component
until integration confirmed an equimolar mixture within an
acceptable error limit ( 10%). The solvent was then allowed to
evaporate and the residue was redissolved in methanol (5 mL).
X-Ray crystal structure analysis of 6d ||
Formula C75H110N12O10, M = 1339.75, colourless crystal
0.20 × 0.10 × 0.05 mm (from MeOH), a = 8.775(6) Å,
b = 14.312(3) Å, c = 30.069(7) Å, α = 85.76(2)Њ, β = 81.87(4)Њ,
γ = 85.32(4)Њ, V = 3718(3) Å3, ρcalcd = 1.197 g cmϪ3, µ = 6.42
᎐
᎐
n
3
(against benzil as standard; C75H108N12O9 requires 1322), 1530 g
molϪ1 (against polystyrene 2000 as standard).
cmϪ1
, empirical absorption correction via ψ scan data
Complex 7b. From 1,3-bis(4,5-dihydro-1H-imidazol-2-
yl)benzene8b,27 and 2b (2 equiv.). Yield: 76% (from CH3CN),
colourless crystals, mp 192–194 ЊC (decomp.) (Found: C, 53.3;
H, 3.4; N, 16.65. C30H24F6N8O4 requires C, 53.4; H, 3.6; N,
16.6%); νmax (KBr)/cmϪ1 1696 (CO), 1677, 1388, 1330, 1281,
1121, 696; δH(500 MHz, CDCl3–DMSO-d6, 7 : 2) 3.95 (8 H, s),
7.62 (2 H, br t, J 7.8), 7.67 (1 H, t, J 7.9), 7.71 (2 H, br d, J 7.8),
8.10 (2 H, br d, J 7.8), 8.13 (2 H, dd, J 7.8 and 1.7), 8.17 (2 H, br
s), 8.60 (1 H, t, J 1.7).
¯
(0.882 ≤ T ≤ 0.967), Z = 2, triclinic, space group P1 (No. 2),
λ = 1.54178 Å, T = 223 K, ω/2θ scans, 8233 reflections collected
(Ϫh, k, l), [(sinθ)/λ] = 0.50 ÅϪ1, 7581 independent and 2053
observed reflections [I ≥ 2 σ(I)], 392 refined parameters,
R = 0.096, wR2 = 0.204, max. residual electron density 0.52
(Ϫ0.30) e ÅϪ3. Owing to the weakly diffracting crystal and the
resulting amount of observed reflections all atoms were refined
with isotropic thermal parameters; hydrogens at solvent water
molecule were not found, others were calculated and refined
riding. Data set was collected with an Enraf Nonius CAD4
diffractometer, equipped with a sealed tube generator. Pro-
Complex 7c. From 1,3-bis(4,5-dihydro-1H-imidazol-2-
yl)benzene8b,27 and 2d (2 equiv.). Yield: 66% (from EtOH),
colourless crystals, mp 192–194 ЊC (decomp.) (Found: C, 69.1;
H, 8.4; N, 12.3. C52H74N8O6 requires C, 68.8; H, 8.2; N,
12.35%); νmax (KBr)/cmϪ1 2920, 2852, 1658 (CO), 1611, 1425,
1388, 1248; δH(500 MHz, CDCl3) 0.88 (6 H, t, J 6.9), 1.23–1.48
|| CCDC reference number 155042. See http://www.rsc.org/suppdata/
p1/b0/b009541j/ for crystallographic files in.cif or other electronic
format.
J. Chem. Soc., Perkin Trans. 1, 2001, 1321–1328
1327

View Article Online
12 (a) K. Frydenvang, L. Matzen, P.-O. Norrby, F. A. Sløk, T. Liljefors,
grams used: data collection, EXPRESS;30 data reduction,
MolEN;31 structure solution, SHELXS-97;32 structure refine-
ment, SHELXL-97;33 graphics (with unsystematical numbering
schemes), DIAMOND34 and SCHAKAL.35
P. Krogsgaard-Larsen and J. W. Jaroszewski, J. Chem. Soc., Perkin
Trans. 2, 1997, 1783; (b) N. Jacobsen, H. Kolind-Andersen and
J. Christensen, Can. J. Chem., 1984, 62, 1940.
13 D. L. Pain, B. J. Peart and K. R. H. Wooldridge, in Comprehensive
Heterocyclic Chemistry, ed. K. T. Potts, Pergamon, Oxford, 1984,
Vol. 6, Part 4B, p. 144.
14 (a) L. Brehm, P. Krogsgaard-Larsen and H. Hjeds, Acta
Chem. Scand., Ser. B, 1974, 28, 308; (b) L. Brehm and P.
Krogsgaard-Larsen, Acta Chem. Scand., Ser. B, 1974, 28, 625; (c)
E. Falch, L. Brehm, I. Mikkelsen, T. N. Johansen, N. Skjærbæk,
B. Nielsen, T. B. Stensbøl, B. Ebert and P. Krogsgaard-Larsen,
J. Med. Chem., 1998, 41, 2513.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft, Heriot-Watt
University and Professor G. Wulff for continuing support, and
Ms S. Johann for experimental help.
15 (a) S. K. Chang, D. Van Engen, E. Fan and A. D. Hamilton, J. Am.
Chem. Soc., 1991, 113, 7640; (b) K. Kavallieratos, C. M. Bertao and
R. H. Crabtree, J. Org. Chem., 1999, 64, 1675.
16 (a) P. Job, Ann. Chim., 1928, 9, 113; (b) M. T. Blanda, J. H. Horner
and M. Newcomb, J. Org. Chem., 1989, 54, 4626.
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