Novel adamantane-bearing anilines and properties of their supramolecular complexes with β-cyclodextrin

Article abstract of DOI:10.1080/10610278.2011.593628

Several novel anilines bearing 1-adamantyl substituents that are useful for drug modification were synthesised from the corresponding 1-adamantyl (nitrophenyl) ketones. The host-guest systems of these prepared ligands with β-cyclodextrin (β-CD) were studi

Full text of DOI:10.1080/10610278.2011.593628

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Supramolecular Chemistry
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Novel adamantane-bearing anilines and properties of
their supramolecular complexes with β-cyclodextrin
Robert Vícha a , Michal Rouchal a , Zuzana Kozubková a , Ivo Kuřitka b , Radek Marek c d
Petra Branná a & Richard Čmelík e
,
a Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Náměstí
T. G. Masaryka, 275, 76001, Zlín, Czech Republic
b Polymer Centre, Faculty of Technology, Tomas Bata University in Zlín, Náměstí T. G.
Masaryka, 275, 76001, Zlín, Czech Republic
c National Centre for Biomolecular Research, Masaryk University, Kamenice 5/A4, 62500,
Brno, Czech Republic
d Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5/A4,
62500, Brno, Czech Republic
e Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří, 97, 60200, Brno, Czech
Republic
Published online: 14 Oct 2011.
To cite this article: Robert Vícha , Michal Rouchal , Zuzana Kozubková , Ivo Kuřitka , Radek Marek , Petra Branná &
Richard Čmelík (2011): Novel adamantane-bearing anilines and properties of their supramolecular complexes with β-
cyclodextrin, Supramolecular Chemistry, 23:10, 663-677
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Supramolecular Chemistry
Vol. 23, No. 10, October 2011, 663–677
Novel adamantane-bearing anilines and properties of their supramolecular complexes
with b-cyclodextrin
a
Robert Vıcha *, Michal Rouchal , Zuzana Kozubkova , Ivo Kuritka , Radek Marek , Petra Branna and Richard Cmelık
a
a
b
c,d
a
e
ˇ
´
´
ˇ
´
´
a
´
´
´
´
ˇ ´
ˇ ´
´
´
Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlın, Namestı T. G. Masaryka 275, 76001 Zlın, Czech
b
Republic; Polymer Centre, Faculty of Technology, Tomas Bata University in Zlın, Namestı T. G. Masaryka 275, 76001 Zlın, Czech
Republic; National Centre for Biomolecular Research, Masaryk University, Kamenice 5/A4, 62500 Brno, Czech Republic; Central
European Institute of Technology (CEITEC), Masaryk University, Kamenice 5/A4, 62500 Brno, Czech Republic; eInstitute of Analytical
ˇ´
Chemistry of the ASCR, v.v.i., Veverı 97, 60200 Brno, Czech Republic
c
d
(Received 26 October 2010; final version received 13 May 2011)
Several novel anilines bearing 1-adamantyl substituents that are useful for drug modification were synthesised from the
corresponding 1-adamantyl (nitrophenyl) ketones. The host–guest systems of these prepared ligands with b-cyclodextrin
(b-CD) were studied using electrospray ionisation mass spectrometry, NMR spectroscopy, titration calorimetry and semi-
empirical calculations. The complexes with 1:1 stoichiometry were found to predominantly exist as pseudorotaxane-like
threaded structures with the adamantane cage sitting deep in the cavity of b-CD close to the wider rim. Such geometry was
observed for all examined amines and is independent of their structure and/or presence of protic substituents.
Keywords: adamantane; amines; cyclodextrins; host–guest systems
1. Introduction
the steric hindrance of bulky adamantane may lead to
attenuation of the desired activity if the scaffold is
introduced too close to the active site of the drug (13),
hence the need for preparation and property investigation
of new suitable adamantane-bearing building blocks is
justified.
Since the first description of the antiviral activity of 1-
adamantylamine in 1964 (1), various compounds contain-
ing the adamantane scaffold have been shown to exhibit
antiviral (2), anticancer (3) and antimicrobial (4) activities;
such compounds have also been described as hypogly-
caemic (5), proapoptotic (6) and neuroprotective (7)
agents, as well as possible treatments for hypertension,
vascular inflammation (8) and tuberculosis (9). Adaman-
tane-bearing compounds can also serve as cannabinoid
receptor ligands (10). This well-founded interest is related
to a unique property of the adamantane cage that can
improve the characteristics of biologically active com-
pounds. As a result of its high lipophilicity, adamantane
should increase the rate of transfer of a modified drug
through cell membranes and thus facilitate the distribution
of the drug. On the other hand, the formation of
supramolecular complexes with b-cyclodextrin (b-CD)
(11) significantly increases drug’s solubility in water. CD
drug carrier systems have been studied extensively in
terms of solubility, bioavailability and stability (12). This
attention has yielded several commercial pharmaceutical
products based on CD host–guest complexes (12). The
adamantane-bearing amines are suitable candidates for
drug modification, e.g. as ligands in preclinically tested (3)
platinum derivate LA-12 (Figure 1, left) or as building
blocks for displacement of C6 substituent in purvalanol-
like promising anticancer drugs (Figure 1, right). However,
Although inclusion complexes of b-CD with 1-
adamantyl-based compounds have been studied for a
long time, previous efforts have focused on small ionic
guests (14). Some structural data have also been published
for more complex ligands (15). In most of these cases, the
nature of the inclusion complexes is determined by the
structure of host and/or guest molecule. It is reasonable to
suppose that the geometry and stability of host–guest
complexes are affected by substituents adjacent to the
adamantane cage. Therefore, we have prepared several
new potential building blocks with modulated polarity and
variable linker length between the adamantane and
benzene ring units. The host–guest complexes of these
prepared anilines and b-CD were investigated using
1
electrospray ionisation mass spectrometry (ESI-MS), H
and 13C NMR spectroscopy, and titration calorimetry.
2. Results and discussion
2.1 Synthesis of amines
The nitro intermediates were prepared following pre-
viously described procedures, including the ketone
*Corresponding author. Email: rvicha@ft.utb.cz
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2011 Taylor & Francis
http://dx.doi.org/10.1080/10610278.2011.593628
http://www.tandfonline.com

´
R. Vıcha et al.
664
Figure 1. Structural formulas for selected promising anticancer drugs.
preparation (16) and nitration with acetyl nitrate (17) as
shown in Scheme 1. Regioisomers were separated by
column chromatography, and compounds 3–5 were used
as starting materials for further reactions.
on Ra–Ni was employed in the preparation of amine 15
(Scheme 2). Attempts to prepare aminoalcohols from
compounds 3–5 in one step using less selective reducing
agents such as LiAlH4 or H2/Ra–Ni were not successful,
and complex mixtures were obtained.
Aminoketones 6–8 were prepared in methanolic HCl
solution using iron powder as a reducing agent. The iron
powder used in this reaction was obtained from iron
pentacarbonyl decomposition (purchased from commer-
cial source); use of iron fillings or turnings led to
considerably longer reaction times. Amines 6–8 are rather
unstable at room temperature as a free base (but may be
stored for several months at 2108C) and decompose to
dark brown oily products within a few days. Unfortunately,
transformation to their corresponding solid hydrochloride
salts via introduction of dry gaseous hydrogen chloride
into diethyl ether or hexane solution only provided oily,
brownish products.
Amines with non-polar hydrocarbon spacers between
the adamantane and benzene ring moieties (25–27) were
also prepared in two (via 1,3-dithianes) or three (via 1,3-
dithiolanes) steps. This synthesis involved the formation of
the corresponding S,S-acetals, followed by the reduction of
the nitro group by iron powder in alcohol/HCl mixture and
reduction/desulphurisation with H2 on Ra–Ni catalyst
(Scheme 3). Although the yields of the first step were
excellent (about 90% of isolated products 16–20), the
following steps were accompanied by some difficulties.
Nitrodithiane 18 was treated with Ra–Ni in ethanol under
hydrogen atmosphere and was successfully desulphurised.
The nitro group was also reduced under these conditions,
but an undesirable substitution occurred, and the
corresponding N-ethyl derivative was identified as the
main product. Dithiane 16, however, afforded required
amine 27 under the same conditions. Although the isolated
yield was not excellent, no side products were detected by
either TLC or GC analysis. Due to the very poor solubility
of dithioacetals in hexane, reduction with H2 could not be
performed without the use of a more polar solvent. We
attempted the reduction of dithiane 18 in a dioxane/hexane
mixture (1/1, v/v), but under such conditions, the nitro
group was reduced to an amino group, while the dithiane
Aminoalcohols 13–15 were prepared from nitroke-
tones in two steps. Selective reduction using NaBH4
proved to be very effective in our case, and we obtained
nitroalcohols 9–11 in excellent yields (,95%) in 30 min.
Reduction of the nitro group was carried out using iron
powder in a methanol/HCl (1/1, v/v; conc. HCl was used)
mixture. Amines 13 and 14 were isolated either as free
bases (pH adjustment followed by extraction) or directly as
hydrochloride salts. Attempted preparation of aminoalco-
hol 15 in the same manner failed due to undesirable
nucleophilic substitution, and methoxyamine 12 was
isolated in 85% yield. Therefore, catalytic hydrogenation
O
O
O
LiCl, CuCl, AlCl3
AcONO2
+
R' MgX
n
n
THF, DEE, 0°C
Ac2O, –15°C
NO2
R
Cl
1 R=Ad, R'=Ph, n=0
2 R=Ph, R'=CH2 Ad, n=1
3 para, n=0; 4 meta, n=0; 5 meta, n=1
Scheme 1. Reaction pathway leading to 1-adamantyl (nitrophenyl) ketones.

Supramolecular Chemistry
665
ions [M þ H]þ, accompanying the signals at m/z values
about two times as high (exactly [2 £ (M þ H) 2 1]þ or
[2 £ M þ 23]þ). The latter ions were observed when a
polar functional group (oxo or hydroxy) was present in the
amine molecule, as shown for amine 13 in Figure 2(a).
These signals are assumed to be related to associates of
dimer linked via hydrogen bonds with a proton or sodium
cation, respectively. The formation of analogous dimers in
the solid state has been observed for aminoalcohol 15 (18).
In the amine/b-CD mixtures, the protonated amine and
sodium adduct of b-CD, as well as protonated b-CD–
amine complex, were detected for all examined amines
(Table 1). Figure 2(b) shows a typical spectrum of an
equimolar mixture of b-CD and amine 27. The tandem
mass spectrum of the protonated complex showed a
characteristic fragmentation pattern, which confirms its
identity. The ions at m/z 1136, 974, 811, 649 and 487
resulted from the successive losses of amine and glucose
residues of the b-CD moiety (Figure 2(c)).
O
O
Fe
HCl (aq)
n
n
NO2
NH2
3-5
6-8
NaBH4 EtOH
R
OH
O
Fe, HCl
MeOH
n
n
NO2
NH2
9-11
12(R=CH3), 13 and 14(R=H)
H2, Ra-Ni
Dioxane
Meta substituted
n=0: 4, 7, 10, 13
n=1: 5, 8, 11, 14
NH2
Para substituted
n=0: 3, 6, 9, 12, 15
OH
15
Scheme 2. Synthesis of aminoketones and aminoalcohols.
ring did not react. As a result, the corresponding
aminodithiane derivative was isolated. Similarly, nitro-
dithiane 17 afforded the corresponding aminodithiane in
an ethanol/hexane reaction medium. Thus, a two-step
procedure was necessary for the smooth transformation of
nitrodithianes to the required amines. Iron in i PrOH/HCl
and Ra–Ni in dioxane were used for nitro group reduction
and desulphurisation, respectively (Scheme 3).
2.3 The geometry of host–guest complexes
The b-CD is a heptamer built up from glucopyranose units
linked by a-1,4-glycosidic bonds with a very well-known
structure (19) that it is often described as a doughnut with
rims of differing diameters. The larger diameter
corresponds to the secondary rim where secondary
hydroxyl groups at C2 and C3 are located; primary
hydroxyl groups at C6 are placed on the opposite smaller
primary rim due to the non-alternating orientation of the
glucose units. The interior of the cavity has steric
constraints due to H3 and H5 protruding into the cavity
(14c). Schematics with the relevant dimensions of b-CD
and the prepared amines are displayed in Figure 3.
The internal diameter of the cavity is likely to be
slightly smaller than the diameter of the nearly ball-shaped
adamantane moiety, which cannot pass through it easily
but still fit well in the interior of the b-CD cavity. As a
result, two distinct complexes may form. The adamantane
moiety can be located either at the primary rim region or at
the secondary rim region. In a solution, a reasonable
orientation of a short and, in most cases, charged,
substituent bound to adamantane is outside the b-CD
cavity (14c, 15a). Occupancy of the primary rim was
observed only when the secondary rim was blocked.
Higher thermodynamic stabilities were calculated for
complexes with the adamantane unit sitting in the
secondary rim (14c). However, it is reasonable to suppose
that a non-polar substituent of appropriate length may
thread through the cavity of b-CD. Thus, four possible
arrangements of 1:1 adamantane and b-CD complexes
should be considered. These arrangements are illustrated
in Figure 4.
2.2 ESI-MS analysis
Solutions of individual amines, as well their 1:1 mixtures
with b-CD, were studied by ESI-MS. The dominant ions
corresponding to the amines were the pseudomolecular
Meta substituted
Para substituted
m=1; n=0: 17, 21
m=n.a.; n=0: 4, 27 m=n.a.; n=0: 3, 25
m=1; n=0: 16
m=n.a.; n=1: 5, 26 m=0; n=0: 19, 23
m=0; n=1: 20, 24
NH2
m=1; n=1: 18, 22
27
H2, Ra-Ni
EtOH
m
O
BF3·Et2O
S
S
Dithiole
n
NO2
n
NO2
3-5
16-20
i ProH Fe, HCl
m
Ra-Ni
S
S
Dioxane
n
NH2
n
NH2
25, 26
21-24
All examined systems obey the fast exchange mode on
the NMR timescale, and thus only one set of signals was
Scheme 3. Synthesis of anilines with non-polar linker.

´
R. Vıcha et al.
666
Figure 2. ESI-MS data for amine 13 (a), equimolar mixture of amine 27 with b-CD (b), and MS2 spectrum of amine 27–b-CD
complex, target mass ¼ 1377 m/z (c).
observed in all cases. Unfortunately, the shifts observed
Table 1. Results of MS analyses – ionic species observed for
upon complexation for the host and guest protons were
amine with and without the presence of b-CD.
small (,1022 ppm), and determination of thermodynamic
Exact mass
parameters from NMR titrations was generally impossible.
[2·amine þ
[b-CD þ
[Amine þ H]þ
Amine Calc. Found Calc. Found
Na]þ
amine þ H]þ
Calc.
Found
6
7
8
256.2
256.2
270.2
272.2
258.2
272.2
258.2
346.2
360.2
346.2
242.2
256.2
242.2
256.1
256.1
270.1
272.1
258.1
272.1
258.1
346.1
360.2
346.3
242.8
256.3
242.1
533.4
533.4
561.4
565.4
537.4
565.4
537.4
714.4
742.4
714.4
505.4
533.4
505.4
533.3
533.3
561.3
–
537.2
1390.6 1390.6
1390.6 1390.6
1404.6 1404.6
1406.6 1406.6
1392.6 1392.6
1406.6 1406.7
1392.6 1392.6
1480.6 1480.7
1494.6 1494.7
1480.6 1480.8
1376.6 1376.7
1390.6 1390.7
1376.6 1376.6
12
13
14
15
21
22
24
25
26
27
565.4
537.2
–
–
–
–
–
–
Figure 3. Schematic representations of b-CD and the prepared
guest molecules with dimensions shown in nanometres.

Supramolecular Chemistry
667
Figure 4. Schematic representations of possible geometries of host–guest systems under consideration. S, secondary; P, primary; I,
internal; E, external. (Previously published (14) geometric parameters were considered.)
We observed reproducible complexation-induced shifts of
the well-resolved 1H NMR signals only for guest 14.
Although the Job plot for the H5 protons (Figure S1) of
the adamantane guest indicates a 1:1 stoichiometry, the
analysis of titration data was unsatisfactory. The fitting of
experimental data to the theoretical rectangular hyperbola
using the standard least square regression procedure
(MicroCal ORIGIN) led to an estimation of association
constant being ,40 M21, but the systematic discrepancy
between the theoretical data and best-fit curve is too high
(Figure S2). We attribute this discrepancy to the influence
of higher ordered, hydrogen-bonded complexes on the
observed chemical shifts. Nevertheless, the downfield
shifts for guest protons H4-6 (on the adamantane cage)
and upfield shifts for H1, H2A,B, H14 and H16–18 were
clearly observed (Figure S3).
dimension to assign the individual NOE contacts
unequivocally. A schematic of the host–guest complex
7·b-CD and its observed interactions are depicted in
Figure 5 (bottom). Both the observed interactions of
adamantane protons H4 and H5 with b-CD carbons C3
and the absence of interactions between these same
protons and b-CD carbons C5 indicate a positioning of
the adamantane cage inside the b-CD cavity with
bridgehead-substituted carbon C2 located close to the
secondary rim of b-CD. In addition, observed interactions
of phenyl protons H13 and H17 with b-CD carbons C6
and C5 support the proposed structural model in which
the aromatic part of the guest protrudes from the
secondary rim of b-CD (Figure 5). According to the
notation in Figure 4, the observed arrangement of the
examined host–guest complexes is assigned as SI.
The observed NOE interactions between guest
protons bound to the adamantane cage (H4–6 for guest
14) and inner hydrogen atoms of the CD cavity suggest
the formation of an inclusion complex with adamantane
positioned inside the b-CD cavity. The observation of
relatively strong NOE interactions between guest protons
H2 and b-CD-H5, together with weak (if any)
interactions with b-CD-H3, indicates the occupancy of
the secondary rim of b-CD by the adamantane cage.
Additionally, in the case of all hydroxylated guests (13–
15), the NOE interactions between the inner b-CD
hydrogen atoms and H6ax of adamantane are significantly
weakened or completely missing from the spectra,
whereas those with H6eq are observed. A portion of the
NOESY spectrum of a mixture of amine 14 and b-CD is
shown in Figure 5 (top). However, 1H NMR signals of b-
CD inner protons H3 and protons H6 of the secondary rim
were significantly overlapped in dimethyl sulphoxide
(DMSO) solution, and interpretation of the observed
cross-peaks in standard NOESY spectrum became
ambiguous. Therefore, we applied a 2D 1H–13C gs-
HMQC–NOESY experiment to increase the spectral
resolution by employing a carbon frequency in an indirect
The binding properties of prepared guests 6–8, 13–15
and 25–27 were studied using isothermal titration
calorimetry. All three aminoalcohols 13–15 exhibited
additional heat release during both titration and dilution
experiments; therefore, thermodynamic parameters could
not be determined. This observation may be reasonably
attributed to additional equilibria related to the dis-
sociation of dimers and/or higher associates of guest
molecules. In addition, dilution data of these aminoalco-
hols did not fit the theoretical curve using a simple
‘dissociation’ model, which takes into account only dimer
dissociation. Therefore, it is reasonable to assume
additional equilibria involving higher-ordered associ-
ations. Anilines 25 and 27 exhibited some exothermic
process that very slowly equilibrated. This slow equili-
bration thwarted the collection of usable data. The
obtained values of binding constants, enthalpies, entropies
and stoichiometries of the complexes for aminoketones 6–
8 and amine 26 are listed in Table 2. For the typical raw
data, integrated values of heat released and the fitted curve
for guest 7, see Supplementary data, Figure S4.

´
R. Vıcha et al.
668
Figure 5. A portion of the NOESY spectrum of a 1:1 mixture of guest 14 with b-CD (top); A portion of the gs-HMQC-NOESY spectrum
of a 1:1 mixture of guest 7 with b-CD (bottom). Detailed comment may be found in the text. Signals of host and guest nuclei are labelled
as b-CD and G, respectively.
Table 2. Thermodynamic parameters for inclusion complex formation of guest molecules and b-CD derived from calorimetric titration
experiments in DMSO/water (3/1, v/v) mixture at 308C.
Guest
K [M21
]
2DH [kJ mol21
]
2DS [J·K21 mol21
]
n
6
7
8
26
186 ^ 23
226 ^ 25
313 ^ 55
694 ^ 28
35 ^ 14
46 ^ 15
38 ^ 17
44 ^ 3
71
105
75
1.1 ^ 0.4
1.0 ^ 0.3
1.0 ^ 0.4
0.93 ^ 0.05
88

Supramolecular Chemistry
669
require equilibrium geometries generated by PM3,
combined with single-point energy calculations at higher
levels of theory, preferably density functional theory
(DFT) which accounts thermochemistry better than semi-
empirical methods, as these sequential methods are
reported in the recent literature and successfully applied
for the CDs (23).
A series of calculations, described in detail in the
Experimental section, yielded geometries and energies for
several examined positions. The most energetically
favoured geometries for amines 14 and 26, for both
directions of their virtual threading through the b-CD
cavity, are depicted in Figure 6, and selected geometric
parameters and energies are collected in Table 2. In the
case of amine 14, the adamantane cage occupies the
secondary or primary rim with distances of Cg1–Og being
shorter than 0.16 nm, with the benzene ring positioned on
the opposite side of the b-CD. In respect to the orientations
defined in Figure 4, they may be called as SI and PI,
respectively. In the case of amine 26, the respective
threading resulted in geometries with adamantane located
close to the secondary rim with the Cg1–Og being shorter
than 0.12 nm, i.e. SE and SI. For both examined amines,
the complex with SI geometry was the most populated in
the thermodynamic equilibrium.
Figure 6. Minimised structures of complexes of b-CD with
amine 26 and 14, respectively.
The calculations were performed for molecules in
vacuo, neglecting the fact that complex formation might
be driven by differences in solvation energies of the host–
guest complex and its building blocks. Moreover, the large
number of possible orientations of the b-CD’s hydroxyl
groups is beyond our consideration. Although only one
initial conformation of the CD was used for each
minimisation, the method provides a consistent indicator
of the hydrogen bond stabilisation effect as well. To assess
the importance of hydrogen bonding in the complex
formation, a modelling experiment was performed. Non-
polar parent hydrocarbon (PH) (24) was virtually threaded
through the b-CD’s cavity in the same way as described
above with the amines. Hence, we obtained analogous
results for PH and amines 14 and 26, as shown in Table 3.
Although partial stabilisation of this complex geometry
via intermolecular hydrogen bonds was expected, it is not
clearly manifested here. Therefore, we suggest only a
2.4 Computation
To support the structural conclusions about host–guest
complexes formulated from NMR analysis, we performed
the modelling of these complexes for amines 14 and 26
with b-CD at a semi-empirical level of theory. Semi-
empirical PM3 method (20) proved to perform well across
a diverse group of macrocycles, particularly for CDs (21).
Moreover, the PM3 method was selected among available
semi-empiricals because of its superiority to AM1 in
dealing with hydrogen-bonded molecules (22). Although
PM3 method chosen for our preliminary calculations
appeared to be a powerful tool in conformational studies of
supramolecular systems, computed relative energies
should be handled with the full awareness of the weakness
of semi-empiricals in relative energy estimations and
interpreted along with the corroborating experimental
data. An exhaustive, up-to-date theoretical study may
Table 3. Selected geometric parameters and free energies for complexes of amines 14, 26 and PH with b-CD.
Structure
d[nm]a
l [nm]
a[8]
b[8]
Stabilisation energy [kJ/mol]
14-SI
14-PI
26-SI
26-SE
PH-SI
PH-SE
þ0.0295
20.1534
þ0.0656
þ0.1173
þ0.0930
þ0.2223
0.0227
0.1534
0.0622
0.1158
0.0856
0.2199
142.48
163.49
16.10
36.74
139.54
30.25
50.31
90.00
71.47
80.83
66.99
81.57
2613.62
2604.14
2655.29
2633.66
2668.04
2650.19
For the definition of Cg1, Cg2, Og and P, see the experimental part. d is Cg1–Og distance, l is Cg1–P distance, a is Cg1–Og–Cg2 angle, b is Cg1–Og–P angle.
a The positive or negative sign implies location of adamantane cage in cavity close to the secondary or primary rim, respectively.

´
R. Vıcha et al.
670
small contribution of intermolecular H-bonds to the
stabilisation of the complex in the gas phase.
1JH-C ¼ 145 Hz with a subsequent NOE transfer of
700 ms. The spectrum was recorded in phase-sensitive
mode using the echo–antiecho protocol (27). The IR
spectra were recorded in a KBr disc with a Mattson 3000
FT-IR instrument. GC-MS analyses were run on a
Shimadzu QP-2010 instrument using a Supelco SLB-
5ms (30 m, 0.25 mm) column. Helium was employed as a
carrier gas in a constant linear flow mode (38 cm s21);
1008C/7 min, 258C/min to 2508C, hold for the required
time. Only peaks of relative abundance exceeding 5% are
listed. The electrospray mass spectra were recorded with
an Esquire LC ion trap mass spectrometer (Bruker
Daltonics, Bremen, Germany) equipped with an ESI
source. Sample solutions (8.8 mM in methanol/water, 1/1,
v/v) were introduced into the ion source at a flow rate of
3 ml/min via a metal capillary held at high voltage
(^3.5 kV). The other instrumental conditions were as
follows: drying gas temperature, 2508C; drying gas flow,
5 dm3/min and nebuliser pressure, 41.37 kPa. Nitrogen was
used as both nebulising gas and drying gas. The nozzle-
skimmer potential and octopole potential were modified
and optimised before each experiment. Isothermal titration
calorimetry measurements were done in a DMSO/H2O
(3/1, v/v) solvent mixture using a VP-ITC MicroCal
instrument at 308C. The concentrations of host in the cell
and guest in microsyringe were approximately 7.0 and
0.6 mM, respectively. The raw experimental data were
analysed using MicroCal ORIGIN software. The heats of
dilution were taken into account for each guest compound.
Data were fitted to a theoretical titration curve using the
‘one set of binding sites’ model.
3. Conclusions
Ten new anilines-bearing adamantane with linkers of
varying polarity and length were synthesised and fully
characterised using spectral methods. The inclusion
complexes of these anilines with b-CD were detected
using ESI-ion trap MS, and their structures were
determined by 2D NMR experiments in dimethyl
sulphoxide. In agreement with our experimental NMR
data and molecular modelling, the most populated
inclusion complex between b-CD and adamantane guests
with a long, uncharged substituent may be characterised as
a pseudorotaxane-like structure in which the adamantane
group is sitting deep in the CD cavity close to the wider
secondary rim of the b-CD and the substituent protrudes
from the primary rim. Association constants of the
prepared amines and b-CD were estimated to be on the
order of 102 M21 by isothermal calorimetric titrations.
These binding properties allowed us to consider the use of
these prepared amines in further research on drug
modification.
4. Experimental section
4.1 General
All starting compounds, reagents and solvents were
purchased from commercial sources in analytical quality
and were used without further purification. Adamantane-1-
carbonyl chloride (16) was prepared following a
previously published procedure. Melting points were
measured on a Kofler block and are uncorrected.
Elemental analyses (C, H, N, S) were performed on a
Thermo Fisher Scientific FlashEA 1112. Retention times
were determined using TLC plates (Alugram Sil G/UV)
from Macherey-Nagel and petroleum ether/ethyl acetate as
mobile phase. Three compositions of mobile phases were
used (v/v): system a (1/1), system b (4/1) and system c
(8/1). NMR spectra were recorded on a Bruker Avance 500
spectrometer operating at frequencies of 500.13 MHz (1H)
and 125.77 MHz (13C), and a Bruker Avance 300
spectrometer operating at frequencies of 300.13 MHz
4.2 Quantum chemical methods
All theoretical calculations were carried out using the
SPARTAN’08 software package (28). First, the initial
geometries of amines 14 and 26 and b-CD were optimised
with the PM3 method without imposing any symmetrical
restrictions. A hypothetical PH, 1-(1-adamantyl)-2-pheny-
lethane, was used as a non-polar reference to evaluate the
effect of hydrogen bonding. This hypothetical parent was
constructed and optimised using the same procedure as that
used for the amines. The input geometry for the
optimisation of b-CD was based on available crystal-
lographic data determined by XRD (19b). Initial approxi-
mations of amine–CD complexes were then constructed
using the optimised structures of both host and guest
molecules. As in the case of their constituents, no
restrictions were imposed on the complexes. To character-
ise the mutual orientations of the molecules, the following
values were defined: the centre of mass of the four
bridgehead carbons in adamantane skeleton (Cg1), the
centre of mass of the seven glycosidic oxygen atoms in b-
CD (Og), centre of mass of the six carbons of the benzene
ring (Cg2) and the best least squares plane of the seven
1
(1H) and 75.77 MHz (13C). H and 13C NMR chemical
shifts were referenced to the signal of solvent (1H:
d(residual CHCl3) ¼ 7.27 ppm, d(residual DMSO-
d5) ¼ 2.50 ppm; 13C: d(CDCl3) ¼ 77.23 ppm, d(DMSO-
d6) ¼ 39.52 ppm). The mixing time for NOESY (25)
experiment was adjusted to 500 ms, and the spin-lock for
1
ROESY was adjusted to 400 ms. The assignment of H
signals for b-CD was described previously (19d). The 2D
1H–13C gs-HMQC–NOESY spectrum (26) was measured
at resonance frequencies of 600.15 MHz (1H) and
150.67 MHz (13C). The HMQC step was adjusted for

Supramolecular Chemistry
671
glycosidic oxygen atoms in b-CD (P). The sign in the half-
space according to P was defined to be positive close to
wider secondary rim and negative close to narrower
primary rim. Initially, the amine was positioned along the
molecular sevenfold axis of b-CD at 11 Cg1–Og distances
ranging from 1.0 to 21.0 nm in increments of 0.2 nm. The
resulting geometries were optimised. These optimised
geometries represent the sequential local minima for an
amine passing through the CD cavity. The stabilisation
energy of complex formation was calculated as the
difference between the energy of the complex and the
sum of energies of the guest and host calculated
independently. The geometry with the absolute minimum
energy could in this way be described as the geometry of
inclusion complex. On the other hand, the rotation of the
guest moleculewithin the CD’s cavity was not tested, as it is
known that the optimisation process automatically finds the
best relative rotational orientation of the guest and host
molecules (29). Under real condition, one could expect
water-filled central cavity in CDs that must be displaced if a
guest is to enter which would stabilise any interaction due to
hydrophobic effects. Therefore, it is expected that basic
considerations for this virtual experiment are not
compromised by neglecting of water molecules in
calculations. Because both the CD and the amine have
non-equivalent sides following the threading route, two
distinct threading processes must be performed with each
amine. It was decided to arrange the threading process as
adamantane-on into the secondary and primary rim of the
CD, respectively.
d 28.6 (CH), 37.0 (CH2), 39.9 (CH2), 46.9 (C), 114.4 (CH),
129.3 (C), 131.0 (CH), 148.2 (C), 206.5 (CO) ppm. IR
(KBr): 3469 (m), 3347 (s), 2898 (s), 2847 (m), 1629 (s),
1586 (s), 1557 (m), 1517 (w), 1442 (m), 1322 (m), 1271
(s), 1241 (m), 1171 (s), 1112 (m), 986 (w), 929 (w), 841
(m), 751 (w), 643 (w), 614 (m), 511 (w) cm21. GC-MS
(EI, 70 eV); m/z (%): 65 (8), 79 (9), 92 (9), 93 (7), 120
(100), 121 (8), 135 (11), 255 (Mþ, 8).
4.3.2 1-Adamantyl-(3-aminophenyl)methanone (7) was
purified by column chromatography (silica gel, system a)
to yield 236 mg (88%) of a colourless crystalline powder.
Mp 97–1008C, Rf 0.20 (system b), anal. calcd for
C17H21NO: C, 79.96%; H, 8.29%; N, 5.49%; found C,
79.89%; H, 8.35%; N, 5.37. 1H NMR (CDCl3): d 1.75 (m,
6H, CH2(Ad)), 1.99 (m, 6H, CH2(Ad)), 2.07 (m, 3H,
CH(Ad)), 3.73 (bs, 2H, NH2), 6.72–6.77 (m, 2H, Ph), 6.91
(d, J ¼ 7.6 Hz, 1H, Ph), 7.16 (t, J ¼ 7.6 Hz, 1H, Ph) ppm.
13C NMR (CDCl3): d 28.4 (CH), 36.8 (CH2), 39.3 (CH2),
47.1 (C), 113.7 (CH), 116.8 (CH), 117.3 (CH), 128.9 (CH),
141.2 (C), 146.3 (C), 210.9 (CO) ppm. IR (KBr): 3474
(m), 3381 (s), 2900 (s), 2850 (m), 1662 (s), 1626 (m), 1593
(m), 1494 (m), 1446 (m), 1321 (m), 1295 (w), 1219 (m),
1180 (w), 991 (w), 793 (w), 731 (m), 682 (w), 649 (w)
cm21. GC-MS (EI, 70 eV); m/z (%): 41 (8), 55 (6), 65 (13),
67 (9), 77 (8), 79 (24), 81 (7), 91 (7), 92 (18), 93 (23), 107
(12), 120 (20), 135 (100), 136 (11), 227 (6), 255 (Mþ, 24),
256 (5).
4.3.3 2-(1-Adamantyl)-1-(3-aminophenyl)ethanone (8)
was purified by column chromatography (silica gel,
system b) to yield 289 mg (92%) of a pale orange
crystalline powder. Mp 66–688C, Rf 0.25 (system c), anal.
calcd for C18H23NO: C, 80.26%; H, 8.61%; N, 5.20%;
found C, 80.11%; H, 8.49%; N, 5.23%. 1H NMR (CDCl3):
d 1.65 (m, 12H, CH2(Ad)), 1.95 (m, 3H, CH(Ad)), 2.67 (s,
2H, CH2CO), 3.80 (s, 2H, NH2), 6.86 (d, 1H, J ¼ 6.9 Hz,
Ph), 7.20–7.33 (m, 3H, Ph) ppm. 13C NMR (CDCl3): d
29.0 (CH), 34.1 (C), 37.0 (CH2), 43.2 (CH2), 51.5 (CH2),
114.3 (CH), 119.3 (CH), 119.5 (CH), 129.4 (CH), 140.4
(C), 146.8 (C), 200.7 (CO) ppm. IR (KBr): 3459 (m), 3405
(m), 3328 (m), 2899 (s), 2846 (s), 1660 (s), 1627 (m), 1595
(m), 1453 (m), 1326 (m), 1287 (m), 1197 (w), 1162 (w),
1143 (w), 1096 (w), 991 (w), 903 (w), 884 (w), 777 (w),
691 (w), 677 (w) cm21. GC-MS (EI, 70 eV); m/z (%): 41
(8), 55 (5), 65 (18), 77 (7), 79 (12), 91 (10), 92 (42), 93
(19), 106 (6), 107 (10), 120 (100), 121 (14), 135 (20), 241
(5), 251 (6), 269 (Mþ, 51), 270 (10).
4.3 General procedure for nitro ketones reduction to
amino ketones 6–8
The ketone (1.05 mmol) was dissolved in methanol (30 ml)
and 6 ml of hydrochloric acid/water (v/v, 1/1) was added.
Into the refluxed and well-stirred mixture, a portions of an
iron powder (2.33 mmol) were added successively. The
reaction was stopped when TLC indicated the consump-
tion of all starting material. The mixture was poured onto a
5% solution of NaOH (40 ml) and extracted several times
with diethyl ether. Combined organic layers were washed
with brine and dried over sodium sulphate. The crude
product was obtained after evaporation of the solvent in
vacuo.
4.3.1 1-Adamantyl-(4-aminophenyl)methanone (6) was
purified by column chromatography (silica gel, system a)
to yield 257 mg (96%) of a yellow crystalline powder. Mp
79–818C, Rf 0.17 (system b), anal. calcd for C17H21NO: C,
79.96%; H, 8.29%; N 5.49%; found C, 80.05%; H, 8.12%;
4.4 General procedure for nitro ketones reduction to
nitro alcohols 9–11
1
N, 5.63%. H NMR (CDCl3): d 1.78 (m, 6H, CH2(Ad)),
2.07 (m, 9H, CH2 þ CH(Ad)), 6.69 (d, J ¼ 8.6 Hz, 2H,
The corresponding ketone (0.84 mmol) was dissolved in
warm ethanol (5 ml) and solution was cooled in ice bath. A
Ph), 7.72 (d, J ¼ 8.6 Hz, 2H, Ph) ppm. 13C NMR (CDCl3):

´
R. Vıcha et al.
672
small portion of starting material formed a soft precipitate.
The sodium borohydride (40 mg, 1.04 mmol) was added
into this dispersion in one portion at 08C. The reaction
mixture was vigorously stirred and temperature was
allowed to reach 208C. After the consumption of all
starting material (according to TLC), the mixture was
poured onto 1 m HCl (10 ml) and a pale yellow solid
precipitated. Mixture was extracted twice with diethyl
ether (10 ml), collected organic portions were washed with
brine and dried over Na2SO4. Crude product was obtained
after removing of the solvent in vacuo.
system c) to yield 220 mg (87%) of a colourless crystalline
powder. Mp 68–698C, Rf 0.51 (system c), anal. calcd for
C18H23NO3: C, 71.73%; H, 7.69%; N, 4.65%; found C,
71.56%; H, 7.44%; N, 4.83%. 1H NMR (CDCl3): d 1.50 (d,
J ¼ 2.6, 1H, AdCHAHB), 1.59–1.79 (m, 12H, CH2(Ad)),
1.88 (d, J ¼ 3.6 Hz, 1H, AdCHAHB), 2.02 (m, 3H,
CH(Ad)), 5.05 (m, 1H, PhCHOH), 7.52 (t, J ¼ 7.9 Hz, 1H,
Ph), 7.70 (d, J ¼ 7.6 Hz, 1H, Ph), 8.13 (d, J ¼ 8.3 Hz, 1H,
Ph), 8.23 (s, 1H, Ph) ppm. 13C NMR (CDCl3): d 28.9 (CH),
32.9 (C), 37.2 (CH2), 43.3 (CH2), 54.7 (CH2), 70.3 (CH),
120.9 (CH), 122.4 (CH), 129.6 (CH), 132.1 (CH), 148.6
(C), 149.0 (C) ppm. IR (KBr): 3380 (bs), 3090 (w), 3072
(w), 2899 (s), 2845 (s), 1525 (s), 1445 (m), 1349 (s), 1314
(w), 1199 (w), 1160 (w), 1103 (m), 1066 (m), 1014 (w),
969 (w), 827 (w), 802 (w), 740 (m), 722 (m), 698 (m), 676
(m) cm21. GC-MS (EI, 70 eV); m/z (%): 41(17), 43(5),
53(5), 55(12), 65(5), 67(22), 69(7), 77(21), 78(11), 79(35),
80(5), 81(21), 91(20), 92(11), 93(43), 94(8), 95(6),
105(13), 106(8), 107(28), 121(8), 134(6), 135(100),
136(14), 149(58), 150(15), 152(22), 266(17), 283(14).
4.4.1
1-Adamantyl-(4-nitrophenyl)methanol (9) was
purified by crystallisation from methanol to yield 233 mg
(96%) of a pale yellow crystals. Mp 191–1928C, Rf 0.11
(system b), anal. calcd for C17H21NO3: C, 71.06%; H,
7.37%; N, 4.87%; O, 16.70; found C, 71.34%; H, 7.45%;
N, 4.98%. 1H NMR (CDCl3): d 1.47–1.72 (m, 12H,
CH2(Ad)), 2.01 (m, 4H, CH(Ad), OH), 4.33 (s, 1H,
CHOH), 7.44 (d, J ¼ 8.1 Hz, 2H, Ph), 8.18 (d, J ¼ 8.5 Hz,
2H, Ph) ppm. 13C NMR (CDCl3): d 28.4 (CH), 37.1 (CH2),
37.7 (C), 38.3 (CH2), 82.3 (CH), 122.8 (CH), 128.8 (CH),
147.5 (C), 148.8 (C) ppm. IR (KBr): 3565 (s), 3112 (w),
3081 (w), 2908 (s), 2848 (s), 1600 (m), 1506 (s), 1450 (w),
1346 (s), 1312 (m), 1216 (w), 1168 (w), 1105 (m), 1038
(m), 977 (w), 938 (w), 855 (m), 830 (w), 800 (w), 760 (w),
720 (s), 701 (w), 637 (w), 740 (m) cm21. GC-MS (EI,
70 eV); m/z (%): 41 (8), 44 (14), 55 (6), 67 (8), 77 (8), 79
(18), 91 (5), 93 (17), 107 (10), 121 (6), 122 (14), 135 (100),
136 (12), 287 (Mþ, 4).
4.5 General procedure for nitro alcohols reduction to
amino alcohols 12–15
The alcohols 13 and 14 and methoxy compound 12 were
prepared from corresponding nitro alcohols in the same
way as the ketones 6–8.
4.5.1 4-[1-Adamantyl(methoxy)methyl]anilinium chlor-
ide (12·HCl) crystallised as the hydrochloride salt directly
from reaction mixture and no further purification was
necessary. Yield: 275 mg (85%) of a gold-yellow plate
crystals. Mp .3508C, Rf (free base) 0.27 (system b), anal.
calcd for C18H26ClNO: C, 70.22%; H, 8.51%; N, 4.55%;
found C, 69.94%; H, 8.37%; N, 4.75%. 1H NMR (DMSO-
d6): d 1.34–1.60 (m, 12H, CH2(Ad)), 1.89 (m, 3H,
CH(Ad)), 3.08 (s, 3H, OCH3), 3.71 (s, 1H, CHOCH3),
7.27–7.36 (m, 4H, Ph), 10.28 (bs, 3H, NHþ3 ) ppm. 13C
NMR (DMSO-d6): d 27.5 (CH), 36.5 (CH2), 37.7 (CH2),
56.9 (CH3), 90.8 (CH), 122.0 (CH), 129.3 (CH), 131.0 (C),
137.8 (C) ppm. IR (KBr): 3437 (bs), 2905 (s), 2847 (s),
2562 (s), 1625 (m), 1578 (m), 1556 (m), 1507 (s), 1452
(m), 1360 (w), 1347 (w), 1316 (w), 1241 (w), 1175 (w),
1133 (w), 1085 (s), 997 (w), 826 (w), 529 (m) cm21. GC-
MS (IE, 70 eV); m/z (%): 120 (7), 121 (6), 136 (100), 137
(9), 271 (Mþ, 2).
4.4.2
1-Adamantyl-(3-nitrophenyl)methanol (10) was
purified by column chromatography (silica gel, system b)
to yield 234 mg (97%) of a colourless crystalline powder.
Mp 104–1068C, Rf 0.20 (system b), anal. calcd for
C17H21NO3: C, 71.06%; H, 7.37%; N, 4.87%; found C,
70.83%; H, 7.18%; N, 4.55%. 1H NMR (CDCl3): d 1.27–
1.71 (m, 12H, CH2(Ad)), 1.99 (m, 3H, CH(Ad)), 2.10 (s,
1H, OH), 4.33 (s, 1H, CHOH), 7.49 (m, 1H, Ph), 7.59 (m,
1H, Ph), 8.12 (m, 2H, Ph) ppm. 13C NMR (CDCl3): d 28.9
(CH), 32.9 (C), 37.2 (CH2), 43.3 (CH2), 54.7 (CH2), 70.3
(CH), 120.9 (CH), 122.4 (CH), 129.6 (CH), 132.1 (CH),
148.6 (C), 149.0 (C) ppm. IR (KBr): 3543 (m), 3432 (m),
3106 (w), 3092 (w), 2906 (s), 2848 (s), 1525 (s), 1475 (w),
1448 (w), 1349 (s), 1312 (w), 1286 (w), 1194 (w), 1126
(w), 1088 (w), 1036 (m), 1021 (m), 982 (w), 930 (w), 909
(w), 896 (w), 813 (m), 722 (m), 693 (m), 661 (w), 618 (w)
cm21. GC-MS (EI, 70 eV); m/z (%): 41 (10), 55 (7), 67
(10), 77 (13), 78 (5), 79 (26), 81 (6), 91 (7), 93 (22), 105
(5), 107 (12), 135 (100), 136 (11).
4.5.2
1-Adamantyl-(3-aminophenyl)methanol (13):
Crude material was purified by column chromatography
(silica gel, system a) to yield 254 mg (94%) of a pale
yellow crystalline powder. Mp 137–1398C, Rf 0.11
(system b), anal. calcd for C17H23NO: C, 79.33%; H,
9.01%; N, 5.44%; found C, 79.57%; H, 9.15%; N, 5.72%.
4.4.3 2-(1-Adamantyl)-1-(3-nitrophenyl)ethanol (11)
was purified by column chromatography (silica gel,

Supramolecular Chemistry
673
1H NMR (CDCl3): d 1.49–1.66 (m, 12H, CH2(Ad)), 1.97
(m, 3H, CH(Ad)), 3.62 (bs, 2H, NH2), 4.12 (s, 1H,
CHOH), 6.60–6.67 (m, 3H, Ph), 7.10 (t, J ¼ 7.6 Hz, 1H,
(CDCl3): d 1.48–1.67 (m, 12H, CH2(Ad)), 1.97 (m, 3H,
CH(Ad)), 3.53 (bs, 2H, NH2), 4.11 (s, 1H, CHOH), 6.64
(d, J ¼ 8.3 Hz, 2H, Ph), 7.06 (d, J ¼ 8.1 Hz, 2H, Ph) ppm.
13C NMR (CDCl3): d 28.8 (CH), 29.9 (C), 37.5 (CH2),
38.5 (CH2), 83.1 (CH), 114.5 (CH), 128.9 (CH), 131.8 (C),
145.8 (C) ppm. IR (KBr): 3378 (m), 2905 (s), 2847 (m),
1615 (m), 1514 (m), 1447 (w), 1265 (m), 1175 (w), 1128
(w), 1046 (m), 844 (w), 811 (w), 572 (m), 535 (w), 481 (w)
cm21. GC-MS (EI, 70 eV); m/z (%): 77 (9), 79 (7), 93 (7),
94 (12), 120 (9), 121 (38), 122 (100), 123 (8), 135 (5), 257
(Mþ, 4).
1
Ph) ppm. H NMR (DMSO-d6): d 1.37–1.63 (m, 12H,
CH2(Ad)), 1.89 (m, 3H, CH(Ad)), 3.86 (d, J ¼ 3.8 Hz, 1H,
CHOH), 4.77 (d, J ¼ 3.8 Hz, 1H, CHOH), 4.85 (s, 2H,
NH2), 6.34–6.41 (m, 2H, Ph), 6.46 (s, 1H, Ph), 6.89 (t,
J ¼ 7.6 Hz, 1H, Ph) ppm. 13C NMR (CDCl3): d 28.6 (CH),
29.9 (C), 37.3 (CH2), 38.5 (CH2), 83.2 (CH), 114.3 (CH),
114.8 (CH), 118.7 (CH), 128.5 (CH), 142.8 (C), 145.9 (C)
ppm. IR (KBr): 3394 (m), 2901 (s), 2847 (m), 2359 (w),
1606 (m), 1490 (w), 1457 (m), 1302 (w), 1125 (w), 1036
(m), 885 (w), 750 (m), 730 (m), 700 (m), 667 (w), 585 (w),
418 (w) cm21. GC-MS (EI, 70 eV); m/z (%): 41 (8), 55 (7),
65 (5), 67 (10), 77 (16), 79 (24), 81 (7), 91 (6), 92 (5), 93
(25), 94 (17), 107 (13), 120 (6), 121 (54), 122 (13), 135
(100), 136 (11), 257 (Mþ, 20), 258 (4).
4.6 General procedures for nitrodithianes 16–18 and
nitrodithiolanes 19, 20 formation
The ketone (0.35 mmol) was dissolved in dichloromethane
(2 ml) and corresponding dithiol (1,2-ethanedithiol or 1,3-
propanedithiol; 0.55 mmol) was added. The solution was
cooled in ice bath to 08C and stirred for 30 min. After this
period, boron trifluoride-diethyl ether (1.00 mmol) was
added dropwise and the mixture was stirred at room
temperature until TLC indicated complete disappearance
of the starting material. The mixture was diluted with
CH2Cl2 (20 ml) and washed three times with 5% solution
of NaOH (10 ml). The organic layer was washed twice
with brine, dried over Na2SO4 and evaporated in vacuo.
4.5.3 2-(1-Adamantyl)-1-(3-aminophenyl)ethanol (14):
Crude material was purified by washing with hexane to
yield 234 mg (82%) of a colourless crystalline powder. Mp
142–1458C, Rf 0.57 (system a), anal. calcd for C18H25NO:
C, 79.66%; H, 9.28%; N, 5.16%; found C, 79.73%; H,
9.52%; N, 5.38%. 1H NMR (CDCl3): d 1.50 (d,
J ¼ 2.6 Hz, 1H, AdCHAHB), 1.59–1.79 (m, 12H,
CH2(Ad)), 1.88 (d, J ¼ 3.6 Hz, 1H, AdCHAHB), 2.02
(m, 3H, CH(Ad)), 5.05 (m, 1H, PhCHOH), 7.52 (t,
J ¼ 7.9 Hz, 1H, Ph), 7.70 (d, J ¼ 7.6 Hz, 1H, Ph), 8.13 (d,
J ¼ 8.3 Hz, 1H, Ph), 8.23 (s, 1H, Ph) ppm. 13C NMR
(CDCl3): d 28.9 (CH), 32.9 (C), 37.2 (CH2), 43.3 (CH2),
54.7 (CH2), 70.3 (CH), 120.9 (CH), 122.4 (CH), 129.6
(CH), 132.1 (CH), 148.6 (C), 149.0 (C) ppm. IR (KBr):
3380 (bs), 3090 (w), 3072 (w), 2899 (s), 2845 (s), 1525 (s),
1445 (m), 1349 (s), 1314 (w), 1199 (w), 1160 (w), 1103
(m), 1066 (m), 1014 (w), 969 (w), 827 (w), 802 (w), 740
(m), 722 (m), 698 (m), 676 (m) cm21. GC-MS (EI, 70 eV);
m/z (%): 41 (8), 55 (5), 65 (5), 67 (7), 77 (17), 79 (11), 81
(5), 91 (7), 92 (5), 93 (15), 94 (72), 95 (7), 107 (6), 120 (6),
121 (20), 122 (100), 123 (9), 135 (7), 253 (5), 271 (Mþ,
28), 272 (6).
4.6.1
2-(1-Adamantyl)-2-(3-nitrophenyl)-1,3-dithiane
(16) was purified by crystallisation from hexane/CH2Cl2
to yield 121 mg (92%) of yellow needles. Mp 191–1938C,
Rf 0.42 (system c), anal. calcd for C20H25NO2S2: C,
63.96%; H, 6.71%; N, 3.73%; S, 17.08%; found C,
64.23%; H, 6.55%; N, 3.37%; S, 17.12%. 1H NMR
(CDCl3): d 1.58 (m, 6H, CH2(Ad)), 1.83 (m, 8H, CH2(Ad),
SCH2CH2), 1.97 (m, 3H, CH(Ad)), 2.45 (m, 2H,
SCHAHB), 2.67 (m, 1H, SCHC), 2.71 (m, 1H, SCHD),
7.57 (t, J ¼ 7.9 Hz, 1H, Ph), 8.15 (d, J ¼ 8.3 Hz, 1H, Ph),
8.33 (d, J ¼ 7.9 Hz, 1H, Ph), 8.85 (s, 1H, Ph) ppm. 13C
NMR (CDCl3): d 25.4 (CH2), 27.8 (CH2), 28.9 (CH), 36.8
(CH2), 37.6 (CH2), 41.7 (C), 70.2 (C), 122.0 (CH), 127.4
(CH), 128.7 (CH), 138.6 (CH), 141.0 (C), 148.7 (C) ppm.
IR (KBr): 2904 (s), 2846 (s), 1521 (s), 1469 (w), 1447 (w),
1420 (w), 1351 (s), 1310 (w), 1273 (w), 1172 (w), 1093
(w), 1010 (w), 979 (w), 940 (w), 892 (w), 813 (w), 787 (w)
726 (m), 694 (m) cm21. GC-MS (EI, 70 eV); m/z (%): 41
(11), 55 (5), 67 (8), 77 (6), 79 (20), 81 (5), 91 (6), 93 (17),
107 (10), 120 (5), 135 (100), 136 (12), 224 (43), 225 (6),
240 (10), 375 (Mþ, 3).
4.5.4 1-Adamantyl-(4-aminophenyl)methanol (15): The
nitroalcohol 9 (259 mg, 0.90 mmol) was dissolved in
ethanol (40 ml) under H2 atmosphere and large excess of
Ra–Ni was added portionwise until starting material
disappeared. Ra–Ni was filtered off, the filtrate was
diluted with water and extracted several times with diethyl
ether. Collected organic portions were washed with brine,
dried over Na2SO4 and evaporated in vacuo. Crude
material was purified by column chromatography (silica
gel, system a) to yield 227 mg (98%) of a pale yellow
crystalline powder. Mp 143–1468C, Rf 0.41 (system a),
anal. calcd for C17H23NO: C, 79.33%; H, 9.01%; N,
4.6.2
2-(1-Adamantyl)-2-(4-nitrophenyl)-1,3-dithiane
(17) was purified by crystallisation from hexane/CH2Cl2
to yield 120 mg (91%) of yellow needles. Mp 218–2208C,
Rf 0.51 (system b), anal. calcd for C20H25NO2S2: C,
1
5.44%; found C, 79.09%; H, 9.23%; N, 5.28%. H NMR

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R. Vıcha et al.
674
63.96%; H, 6.71%; N, 3.73%; S, 17.08%; found C,
63.84%; H, 6.52%; N, 3.46%; S, 16.95%. 1H NMR
(CDCl3): d 1.57 (m, 6H, CH2(Ad)), 1.83 (m, 8H, CH2(Ad),
SCH2CH2), 1.97 (m, 3H, CH(Ad)), 2.46 (m, 2H,
SCHAHB), 2.67 (m, 1H, SCHC), 2.71 (m, 1H, SCHD),
8.20 (m, 4H, Ph) ppm. 13C NMR (CDCl3): d 25.3 (CH2),
27.8 (CH2), 28.9 (CH), 36.8 (CH2), 37.6 (CH2), 41.7 (C),
70.4 (C), 122.9 (CH), 133.6 (CH), 146.1 (C), 146.6 (C)
ppm. IR (KBr): 2908 (s), 2848 (s), 1598 (m), 1515 (s),
1447 (w), 1413 (w), 1349 (s), 1308 (s), 1283 (w), 1264 (w),
1110 (m), 1066 (w), 1011 (w), 976 (w), 930 (w), 855 (m),
839 (m), 794 (w), 727 (m), 696 (w) cm21. GC-MS (IE,
70 eV); m/z (%): 41 (9), 77 (5), 79 (17), 81 (5), 91 (5), 93
(14), 107 (8), 135 (100), 136 (12), 210 (5), 224 (21), 240
(5), 375(Mþ, 4).
cm21. GC-MS (EI, 70 eV); m/z (%): 41 (6), 67 (7), 77 (5),
79 (18), 81 (5), 91 (5), 93 (17), 107 (10), 135 (100), 136
(13), 196 (10), 210 (8), 361(Mþ, 3).
4.6.5
2-(1-Adamantylmethyl)-2-(3-nitrophenyl)-1,3-
dithiolane (20) was purified by crystallisation from
hexane/CH2Cl2 to yield 110 mg (84%) of a pale yellow
crystal. Mp 142–1488C, Rf 0.51 (system c), anal. calcd for
C20H25NO2S2: C, 63.96%; H, 6.71%; N, 3.73%; S,
17.08%; found C, 63.98%; H, 6.58%; N, 3.95%; S,
16.82%. 1H NMR (CDCl3): d 1.30 (m, 6H, CH2(Ad)), 1.51
(m, 6H, CH2(Ad)), 1.80 (m, 3H, CH(Ad)), 2.52 (s, 2H,
CCH2Ad), 3.06 (m, 2H, SCHAHB), 3.38 (m, 2H,
SCHAHB), 7.46 (t, J ¼ 7.9 Hz, 1H, Ph), 8.07 (d,
J ¼ 7.9 Hz, 1H, Ph), 8.15 (d, J ¼ 7.9 Hz, 1H, Ph), 8.71
(s, 1H, Ph) ppm. 13C NMR (CDCl3): d 28.8 (CH), 35.5 (C),
36.8 (CH2), 38.9 (CH2), 43.6 (CH2), 58.3 (CH2), 72.5 (C),
122.2 (CH), 123.0 (CH), 128.7 (CH), 134.1 (CH), 148.0
(C), 149.1 (C) ppm. IR (KBr): 3077 (w), 2921 (s), 2902 (s),
2888 (s), 2841 (s), 1524 (s), 1447 (w), 1348 (s), 1314 (w),
1277 (w), 1100 (w), 898 (w), 804 (w), 736 (m), 685 (m),
588 (w) cm21. GC-MS (EI, 70 eV); m/z (%): 41 (8), 55 (8),
67 (9), 79 (23), 93 (18), 107 (9), 135 (35), 149 (6), 180 (6),
226 (100), 227 (12), 228 (10), 375(Mþ, 2).
4.6.3
2-(1-Adamantylmethyl)-2-(3-nitrophenyl)-1,3-
dithiane (18) was purified by crystallisation from hexane
to yield 125 mg (92%) of yellow needles. Mp 174–1768C,
Rf 0.60 (system b), anal. calcd for C21H27NO2S2: C,
64.74%; H, 6.99%; N, 3.60%; S, 16.46%; found C,
64.58%; H, 7.17%; N, 3.87%; S, 16.72%. 1H NMR
(CDCl3): d 1.36 (m, 6H, CH2(Ad)), 1.51 (m, 6H,
CH2(Ad)), 1.78 (m, 3H, CH(Ad)), 1.94 (m, 2H,
SCH2CH2), 2.04 (s, 2H, AdCH2), 2.64 (m, 4H, SCH2),
7.54 (t, J ¼ 7.9 Hz, 1H, Ph), 8.13 (d, J ¼ 7.9 Hz, 1H, Ph),
8.33 (d, J ¼ 9.2 Hz, 1H, Ph), 8.86 (s, 1H, Ph) ppm. 13C
NMR (CDCl3): d 24.8 (CH2), 28.1 (CH), 28.9 (CH), 36.1
(C), 36.8 (CH2), 44.0 (CH2), 57.6 (C), 59.8 (CH2), 122.2
(CH), 125.1 (CH), 129.3 (CH), 136.0 (CH), 145.7 (C),
148.7 (C) ppm. IR (KBr): 3083 (w), 2899 (s), 2845 (s),
2672 (w), 1573 (w), 1523 (s), 1470 (w), 1448 (w), 1422
(m), 1350 (s), 1311 (m), 1281 (w), 1270 (m), 1101 (m),
1091 (w), 1079 (w), 1032 (w), 996 (w), 863 (w), 802 (m),
776 (w), 733 (m), 707 (w), 687 (m) cm21. GC-MS (EI,
70 eV); m/z (%): 41 (11), 55 (11), 67 (13), 69 (5), 77 (8), 79
(28), 81 (10), 91 (10), 93 (24), 107 (18), 135 (100), 136
(13), 239 (43), 315 (7), 389 (Mþ, 6).
4.7 General procedure for preparation of
aminodithianes 21 and 22
The corresponding nitrodithiane (0.44 mmol) was dis-
solved in dioxane (7 ml) and a suspension of Ra–Ni in
hexane was added to this solution. The mixture was stirred
and refluxed under hydrogen atmosphere. Further portions
of Ra–Ni were added until TLC indicated complete
disappearing of the starting material. The Ra–Ni was
filtrated off, resulting solution was diluted with water
(14 ml) and extracted with diethyl ether (6 £ 15 ml) and
hexane (1 £ 20 ml). Collected organic portions were
washed with water (3 £ 30 ml), brine (3 £ 15 ml) and
dried over Na2SO4.
4.6.4 2-(1-Adamantyl)-2-(4-nitrophenyl)-1,3-dithiolane
(19) was purified by crystallisation from hexane/CH2Cl2 to
yield 115 mg (91%) of colourless needles. Mp 185–1898C,
Rf 0.51 (system b), anal. calcd for C19H23NO2S2: C,
63.12%; H, 6.41%; N, 3.87%; S, 17.74%; found C,
63.41%; H, 6.51%; N, 4.12%; S, 17.45%. 1H NMR
(CDCl3): d 1.57 (m, 6H, CH2(Ad)), 1.79 (m, 6H,
CH2(Ad)), 1.99 (m, 3H, CH(Ad)), 2.98 (m, 2H, SCHAHB),
3.27 (m, 2H, SCHAHB), 7.97 (m, 2H, Ph), 8.10 (m, 2H,
Ph) ppm. 13C NMR (CDCl3): d 29.0 (CH), 36.6 (CH2),
38.8 (CH2), 39.9 (CH2), 41.3 (C), 86.4 (C), 121.6 (CH),
132.0 (CH), 146.8 (C), 151.6 (C) ppm. IR (KBr): 2903 (s),
2845 (m), 1600 (m), 1515 (s), 1447 (w), 1400 (w), 1345
(s), 1308 (w), 1145 (w), 1110 (m), 1014 (w), 979 (m), 853
(m), 842 (m), 809 (w), 728 (m), 697 (m), 638 (w), 503 (w)
4.7.1
2-(1-Adamantyl)-2-(4-aminophenyl)-1,3-dithiane
hydrochloride (21·HCl) was precipitated from hexane
solution of crude 21 by introducing dry HCl. Yield:
146 mg (87%) of a colourless crystalline powder. Mp 140–
1458C, Rf (free base) 0.24 (system b), anal. calcd for
C20H28ClNS2: C, 62.88%; H, 7.39%; N, 3.67%; S,
16.79%; found C, 62.73%; H, 7.19%; N, 3.62%; S,
16.98%. 1H NMR (CDCl3): d 1.42–1.60 (m, 8H, CH2(Ad)
þ CH2(dithiane)), 1.75 (m, 6H, CH2(Ad)), 1.92 (m, 3H,
CH(Ad)), 2.34 (m, 2H, CH2(dithiane)), 2.72 (m, 2H,
CH2(dithiane)), 7.43 (d, J ¼ 8.6 Hz, 2H, Ph), 7.92 (d,
J ¼ 8.6 Hz, 2H, Ph), 10.34 (bs, 3H, NH3) ppm. 13C NMR
(CDCl3): d 24.7 (CH2), 27.0 (CH2), 28.0 (CH), 36.3 (CH2),

Supramolecular Chemistry
675
37.0 (CH2), 41.6 (C), 69.8 (C), 122.4 (CH), 130.8 (C),
133.1 (CH), 136.5 (C) ppm. IR (KBr): 3466 (bs), 2905 (s),
2848 (s), 2597 (m), 1614 (w), 1541 (s), 1504 (m), 1447
(w), 1417 (w), 1359 (w), 1344 (w), 1306 (w), 1279 (w),
1024 (w), 978 (w), 836 (w), 789 (w), 526 (w) cm21. GC-
MS (EI, 70 eV); m/z (%): 41 (7), 77 (5), 79 (9), 91 (5), 93
(7), 106 (10), 120 (20), 135 (10), 136 (28), 210 (100), 211
(13), 212 (9), 345 (Mþ, 1).
crystalline powder. Mp 121–1248C, Rf 0.31 (system b),
anal. calcd for C19H25NS2: C, 68.83%; H, 7.60%; N,
4.22%; S, 19.34; found C, 68.73%; H, 7.45%; N, 4.53%; S,
19.02%. 1H NMR (CDCl3): d 1.56 (m, 6H, CH2(Ad)), 1.81
(m, 6H, CH2(Ad)), 1.96 (m, 3H, CH(Ad)), 2.99 (m, 2H,
SCHAHB), 3.23 (m, 2H, SCHAHB), 3.64 (s, 2H, NH2),
6.58 (d, J ¼ 8.6 Hz, 2H, Ph), 7.55 (d, J ¼ 8.6 Hz, 2H, Ph)
ppm. 13C NMR (CDCl3): d 29.1(CH), 36.8 (CH2), 38.4
(CH2), 40.0 (CH2), 41.4 (C), 87.3 (C), 113.2 (CH), 131.9
(CH), 133.2 (C), 145.0 (C) ppm. IR (KBr): 3417 (w), 2902
(s), 2370 (m), 2341 (m), 1622 (m), 1507 (m), 1280 (w),
1186 (w), 977 (w), 835 (w), 652 (w), 531 (w) cm21. GC-
MS (EI, 70 eV); m/z (%): 79 (6), 93 (5), 124 (5), 136 (20),
196 (100), 197 (12), 198 (9), 331 (Mþ, 1).
4.7.2
2-(1-Adamantylmethyl)-2-(3-aminophenyl)-1,3-
dithiane (22) was purified by column chromatography
(silica gel, system b) to yield 106 mg (67%) of a pale
yellow crystalline powder. Mp 127–1328C, Rf 0.38
(system b), anal. calcd for C21H29NS2: C, 70.14%; H,
8.13%; N, 3.90%; S, 17.83; found C, 70.33%; H, 7.94%;
N, 4.25%, S, 18.08%. 1H NMR (CDCl3): d 1.40–1.58 (m,
12H, CH2(Ad)), 1.78 (m, 3H, CH(Ad)), 1.85–1.96 (m, 4H,
SCH2CH2 þ CCH2Ad), 2.57 (m, 2H, SCHAHB), 2.78 (m,
2H, SCHAHB), 3.68 (bs, 2H, NH2), 6.58 (d, J ¼ 7.9 Hz,
1H, Ph), 7.14 (t, J ¼ 7.9 Hz, 1H, Ph), 7.37–7.39 (m, 2H,
Ph) ppm. 13C NMR (CDCl3): d 25.2 (CH2), 28.2 (CH2),
29.0 (CH), 36.0 (C), 37.0 (CH2), 43.6 (CH2), 59.6 (CH2),
113.9 (CH), 116.7 (CH), 120.6 (CH), 129.2 (CH), 143.3
(C), 146.6 (C) ppm. IR (KBr): 3443 (w), 3358 (w), 2363
(w), 1730 (w), 1614 (s), 1598 (s), 1489 (m), 1471 (w),
1448 (s), 1417 (w), 1346 (m), 1313 (m), 1277 (w), 1102
(w), 993 (w), 881 (w), 781 (m), 768 (w), 710 (w), 694 (w),
667 (w), 457 (w) cm21. GC-MS (EI, 70 eV); m/z (%): 41
(17), 53 (5), 55 (14), 65 (7), 67 (17), 77 (13), 79 (44), 81
(13), 91 (25), 92 (5), 93 (36), 106 (7), 107 (19), 117 (10),
118 (30), 119 (7), 135 (100), 136 (30), 210 (81), 211 (11),
212 (8), 224 (6), 251 (5), 252 (13), 253 (7), 284 (10), 285
(70), 286 (15), 359 (Mþ, 26), 360 (7).
4.8.2
2-(1-Adamantylmethyl)-2-(3-aminophenyl)-1,3-
dithiolane (24) was purified by column chromatography
(silica gel, system b) to yield 1013 mg (87%) of a pale
yellow crystalline powder. Mp 115–1208C, Rf 0.29
(system b), anal. calcd for C20H27NS2: C, 69.51%; H,
7.88%; N, 4.05%; S, 18.56; found C, 69.64%; H, 8.15%;
1
N, 4.27%; S, 18.33%. H NMR (CDCl3): d 1.35 (m, 6H,
CH2(Ad)), 1.53 (m, 6H, CH2(Ad)), 1.80 (s, 3H, CH(Ad)),
2.44 (s, 2H, AdCH2C), 3.10 (m, 2H, SCHAHB), 3.32 (m,
2H, SCHAHB), 3.65 (s, 2H, NH2), 6.52 (d, J ¼ 7.9 Hz, 1H,
Ph), 7.05 (t, J ¼ 7.9 Hz, 1H, Ph), 7.18 (m, 2H, Ph) ppm.
13C NMR (CDCl3): d 28.9 (CH), 35.4 (C), 36.9 (CH2),
38.5 (CH2), 43.2 (CH2), 58.4 (CH2), 73.7 (C), 113.8 (CH),
115.0 (CH), 118.7 (CH), 128.6 (CH), 145.8 (C), 146.9 (C)
ppm. IR (KBr): 3420 (w), 3345 (w), 2896 (s), 2844 (s),
1615 (m), 1597 (m), 1489 (m), 1445 (m), 1416 (w), 1363
(w), 1346 (w), 1313 (m), 1273 (w), 1103 (w), 994 (w), 781
(m), 694 (m), 452 (w) cm21. GC-MS (EI, 70 eV); m/z (%):
41 (6), 55 (6), 67 (6), 79 (17), 81 (5), 91 (8), 93 (13), 107
(6), 135 (23), 136 (12), 196 (100), 197 (12), 198 (9),
345(Mþ, 5).
4.8 General procedure for preparation of amino
dithiolanes 23 and 24
4.9 General procedure for preparation of anilines 25
and 26
The corresponding nitrodithiolane (3.37 mmol) was
dissolved in i PrOH (125 ml) and hydrochloric acid/water
(1/1, v/v, 20 ml) and an iron powder (424 mg, 7.59 mmol)
was added. Into the well-stirred and refluxed mixture,
further portions of an iron powder (424 mg, 7.59 mmol)
were added until TLC indicated complete disappearing of
the starting material. The mixture was poured onto a 5%
solution of NaOH (120 ml) and extracted several times
with diethyl ether. Combined organic layers were washed
three times with water (3 £ 15 ml) and dried over Na2SO4
overnight. The crude product was obtained after
evaporation of the solvent in vacuo.
The corresponding aminodithiolane (2.37 mmol) was
dissolved in dioxane (10 ml) and large excess of Ra–Ni
was added. The mixture was stirred and refluxed under an
Ar atmosphere. If repeated GC analysis showed no
significant progress, further portions of Ra–Ni were added
until the starting material was completely consumed. Ra–
Ni was filtered off, the filtrate was diluted with water and
extracted several times with diethyl ether. Collected
organic portions were washed with brine, dried over
Na2SO4 and evaporated in vacuo. The desired crude
product obtained as orange oil was subsequently converted
to the hydrochloride.
4.8.1 2-(1-Adamantyl)-2-(4-aminophenyl)-1,3-dithio-
lane (23) was purified by column chromatography (silica
gel, CHCl3) to yield 827 mg (74%) of a pale orange
4.9.1 4-(1-Adamantylmethyl)anilinium chloride
(25·HCl): The crude product was dissolved in hexane/-

´
R. Vıcha et al.
676
diethyl ether and 25·HCl precipitated when dry HCl was
introduced into solution. Yield: 579 mg (88%) of a
colourless microcrystalline powder. Mp 178–1888C, Rf
(free base) 0.28 (system b), anal. calcd for C17H24ClN: C,
73.49%; H, 8.71%; N, 5.04%; found C, 73.22%; H, 8.53%;
N, 4.81%. 1H NMR (DMSO-d6): d 1.43 (m, 6H, CH2(Ad)),
1.57 (m, 6H, CH2(Ad)), 1.90 (m, 3H, CH(Ad)), 2.38 (s,
2H, AdCH2Ph), 7.19 (d, J ¼ 7.9 Hz, 2H, Ph), 7.31 (d,
J ¼ 7.9 Hz, 2H, Ph), 10.43 (bs, 3H, NHþ3 ) ppm. 13C NMR
(DMSO-d6): d 27.9 (CH), 32.9 (C), 36.4 (CH2), 41.6
(CH2), 49.5 (CH2), 122.5 (CH), 129.4 (C), 131.3 (CH),
137.7 (C) ppm. IR (KBr): 2902 (s), 2848 (s), 1613 (w),
1573 (w), 1509 (m), 1450 (w), 1314 (w), 1205 (w), 817
(w), 601 (m), 526 (w), 485 (m) cm21. GC-MS (EI, 70 eV);
m/z (%): 41 (6), 55 (5), 67 (7), 77 (12), 79 (23), 81 (5), 91
(6), 93 (18), 106 (100), 107 (20), 135 (69), 136 (8), 241
(Mþ, 35), 242 (7).
CH2(Ad)), 1.91 (m, 3H, CH(Ad)), 2.38 (s, 2H, AdCH2Ph),
7.07–7.11 (m, 2H, Ph), 7.20 (d, J ¼ 7.9 Hz, 1H, Ph), 7.37
(t, J ¼ 7.9 Hz, 1H, Ph), 10.14 (bs, 3H, NHþ3 ) ppm. 13C
NMR (DMSO-d6): d 27.9 (CH), 32.9 (C), 36.4 (CH2), 41.6
(CH2), 49.8 (CH2), 120.3 (CH), 124.4 (CH), 128.7 (CH),
129.6 (CH), 131.8 (C), 139.4 (C) ppm. IR (KBr): 3421
(m), 2901 (s), 2846 (s), 2604 (m), 1602 (w), 1578 (m),
1518 (w), 1487 (m), 1452 (m), 1105 (w), 795 (m), 742 (w),
716 (w), 694 (m) cm21. GC-MS (EI, 70 eV); m/z (%): 41
(6), 67 (8), 77 (8), 79 (19), 91 (5), 93 (16), 106 (11), 107
(13), 135 (100), 136 (11), 241 (Mþ, 35), 242 (7).
Acknowledgements
This work was supported by Tomas Bata Foundation to R.V.,
Ministry of Education, Youth and Sports of Czech Republic
(Grant No. MSM7088352101 to R.V. and I.K.,
MSM0021622413 and LC06030 to R.M.) and institutional
research plan AV0Z40310501 to R.C.
4.9.2
3-[2-(1-Adamantyl)ethyl]anilinium chloride
(26·HCl): The crude product was dissolved in hexane
and 26·HCl precipitated when dry HCl was introduced
into solution. Yield: 491 mg (71%) of a colourless
microcrystalline powder. Mp 142–1508C, Rf (free base)
0.25 (system b), anal. calcd for C18H26ClN: C, 74.07%; H,
8.98%; N, 4.80%; found C, 73.86%; H, 9.17%; N, 4.63%.
1H NMR (DMSO-d6): d 1.30 (m, 2H, AdCH2), 1.52 (m,
6H, CH2(Ad)), 1.65 (m, 3H, CH2(Ad), 1.94 (s, 3H,
CH(Ad)), 2.55 (m, 2H, PhCH2), 7.22 (m, 3H, Ph), 7.36 (t,
J ¼ 7.9 Hz, 1H, Ph), 10.37 (bs, 3H, NH3) ppm. 13C NMR
(DMSO-d6): d 28.1 (CH), 28.2 (CH2), 32.0 (C), 36.6
(CH2), 41.7 (CH2), 46.0 (CH2), 120.3 (CH), 122.7 (CH),
127.8 (CH), 129.5 (CH), 131.8 (C), 145.1 (C) ppm. IR
(KBr): 3429 (w), 2901 (s), 2845 (s), 2676 (w), 2605 (m),
2362 (w), 1964 (w), 1598 (m), 1576 (w), 1518 (w), 1490
(m), 1451 (m), 1359 (w), 1314 (w), 1243 (w), 1101 (w),
1046 (w), 790 (w), 691 (m), 524 (w), 437 (w) cm21. GC-
MS (EI, 70 eV); m/z (%): 41 (15), 53 (7), 55 (11), 67 (15),
77 (23), 78 (6), 79 (42), 80 (5), 91 (16), 93 (34), 94 (7), 105
(5), 106 (46), 107 (67), 119 (22), 120 (49), 121 (7), 135
(59), 136 (7), 149 (8), 255 (Mþ, 100), 256 (21).
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4.9.3
3-(1-Adamantylmethyl)anilinium chloride
´
´
527–535. (b) Roubalova, E.; Kvardova, V.; Hrstka, R.;
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ˇ
(27·HCl) was prepared according to the procedure used
for previous amines. The nitrodithiane 16 (338 mg,
0.90 mmol) was dissolved in ethanol (40 ml) under H2
atmosphere and large excess of Ra–Ni was added
portionwise until starting material disappeared. The
crude product was dissolved in hexane and 27–HCl
precipitated when dry HCl was introduced into solution.
Yield: 188 mg (75%) of a colourless microcrystalline
powder. Mp 182–1878C, Rf (free base) 0.42 (system b),
anal. calcd for C17H24ClN: C, 73.49%; H, 8.71%; N,
ˇ
´
´
´
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