Synthesis of adamantyl-containing phenylpiperidines

Article abstract of DOI:10.1007/s10593-015-1792-4

The reduction of quaternary 1-(adamantan-1-yl)pyridinium salts with sodium borohydride in ethanol gave 1-(adamantan-1-yl)-1,2,3,6-tetrahydropyridines that reacted with benzene in trifluoromethanesulfonic acid medium, leading to the formation of 1-(adamantan-1-yl)-phenylpiperidines with various spatial orientation of the phenyl substituent. The structure of the obtained phenylpiperidines was confirmed by the spectral dataset. The thermodynamic stability calculations for the conformers of phenylpiperidines were performed with the B3LYP/6-311++(d,p) method.

Full text of DOI:10.1007/s10593-015-1792-4

DOI 10.1007/s10593-015-1792-4
Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
Synthesis of adamantyl-containing phenylpiperidines
Vera A. Shadrikova1*, Evgeny V. Golovin1, Vadim A. Shiryaev1,
Marat R. Baimuratov1, Victor B. Rybakov2, Yuri N. Klimochkin1
1 Samara State Technical University,
244 Molodogvardeiskaya St., Samara 443100, Russia;
е-mail: shadricova@yandex.ru
2 Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia;
e-mail: rybakov20021@yandex.ru
Submitted September 9, 2015
Accepted after revision November 5, 2015
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(10), 891–898
The reduction of quaternary 1-(adamantan-1-yl)pyridinium salts with sodium borohydride in ethanol gave 1-(adamantan-1-yl)-1,2,3,6-
tetrahydropyridines that reacted with benzene in trifluoromethanesulfonic acid medium, leading to the formation of 1-(adamantan-1-yl)-
phenylpiperidines with various spatial orientation of the phenyl substituent. The structure of the obtained phenylpiperidines was
confirmed by the spectral dataset. The thermodynamic stability calculations for the conformers of phenylpiperidines were performed
with the B3LYP/6-311++(d,p) method.
Keywords: adamantane derivatives, phenylpiperidine, pyridinium salts, 1,2,3,6-tetrahydropyridine, conformer, DFT, hydroarylation,
reduction.
Tetrahydropyridine and piperidine rings are important
structural features in many drug molecules and other
biologically active compounds.1 Several examples of aryl-
substituted piperidines are shown in Figure 1 (haloperidol
(A), vesamicol (В), pethidine (S), trihexyphenidyl (D)), and
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Е).
These compounds are used for the treatment of
neurological and psychiatric disorders, such as Alzheimer's
and Parkinson's diseases, schizophrenia, and other
conditions.2a–d The tetrahydropyridine derivative MPTP (Е)
is used for modeling the symptoms of Parkinon's disease in
order to study its etiology and pathogenesis, as well as for
the development of new treatment methods.2e,f
Certain amines with cage type structures, such as
aminoadamantane, have biologically active derivatives that
exhibit a broad spectrum of effects.3 Amantadine (F),
memantine (G), and related drugs are used for combination
therapy of Parkinson's and Alzheimer's diseases. The high
pharmacological potential of piperidine and adamantane
fragments attract interest with regard to the development of
new molecules with such structural motifs, structural
characterization, and the study of biological properties.
Figure 1. Some examples of biologically active piperidine and adamantane derivatives used in medicine.
0009-3122/15/5110-0891©2015 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
N-Substituted arylpiperidines can be obtained by various
The reduction of 2-(adamantan-1-yl)isoquinolinium
bromide (1f) gave 2-(adamantan-1-yl)-1,2,3,4-tetrahydro-
isoquinoline 2f in 90% yield (Scheme 3).
methods,4 including the Friedel–Crafts alkylation of arenes
with 1,2,3,4-tetrahydropyridines.5 While continuing our
study of adamantyl derivatives of pyridine,6 we converted
adamantylpyridinium bromides to the corresponding tetra-
hydropyridines with the purpose of further transformation to
previously unknown phenyl-substituted 1-(adamantan-1-yl)-
piperidine systems. It can be proposed that the presence of
a bulky cage type moiety in the structures may modify the
reactivity of both pyridinium salts and adamantyl-
containing tetrahydropyridines.
Scheme 3
There were characteristic absorption bands in IR spectra of
compounds 2a–f, corresponding to the stretching vibrations of
С–Н bonds in the adamantane fragment in the region of
2916–2897 cm–1 and at 2850 cm–1. The double bond
vibrations in 1,2,3,6-tetrahydropyridines 2а–е were
observed in the region of 1635–1617 cm–1. The methine
The most convenient and commonly used method for
the preparation of 1-substituted 1,2,3,6-tetrahydropyridines
is the reduction of quaternary pyridinium salts with sodium
borohydride in a protic solvent medium.7 The treatment of
1-(adamantan-1-yl)pyridinium bromide (1а) with sodium
borohydride in methanol at 0°С leads to a 4:1 mixture of
reduction products 2а and 3а according to GC-MS data
(Scheme 1). The presence of 1-(adamantan-1-yl)piperidine
(3а) as a side product significantly complicated the isolation
and purification of the target tetrahydropyridine 2а.
Decreasing the reaction temperature to –20°С resulted in the
same mixture of products 2а:3а in a 9:1 ratio.
1
protons in compounds 2а,b,e gave H NMR signals in the
range from 5.35 to 5.86 ppm. The presence of only one
methine proton signal in 1Н NMR spectrum of
tetrahydropyridine 2с at 5.53 ppm and the absence of
alkene proton signals in the spectrum of compound 2d
confirmed the formation of only one product with fully
substituted double bond. The methyl group at the С-3 atom
in tetrahydropyridine 2е occupied a pseudoequatorial
position. A doublet signal of three methyl group protons
Scheme 1
1
appeared in Н NMR spectrum of the alkene at 0.93 ppm
(3J = 6.7 Hz), which is characteristic of 3e-methyl-
Cl–
H
Cl–
H
Br–
Ad
substituted 1,2,3,6-tetrahydropyridines.8 The resonance
1) NaBH4, MeOH, 0°C, 1.5 h
2) HCl, CH2Cl2
+
1
N
1a
N
N
signals of four aromatic protons in Н NMR spectrum of
Ad
Ad
2a
3a
the tetrahydroisoquinoline 2f were observed in the region
of 7.17–7.22 ppm.
Ad = Adamantan-1-yl
The method of arylpiperidine synthesis by reaction of
1,2,3,6-tetrahydropyridines with arenes in trifluoromethane-
sulfonic acid (TfOH) medium has been already described,5а
but the configuration of substituents in the obtained
products was not then established, and the effect of
substituent orientation in the heterocycle on the reaction
stereoselectivity was not determined.
When this reaction was performed in ethanol at –20°С,
the formation of piperidine 3а as a side product was not
observed. Under these conditions the reduction of
adamantylpyridinium bromides 1а–е to 1-(adamantan-1-yl)-
1,2,3,6-tetrahydropyridines 2а–е was achieved in good yields
(Scheme 2, Table 1).
The N-adamantylated 1,2,3,6-tetrahydropyridines 2а–е
were used in a Friedel–Crafts alkylation reaction of
benzene. The bulky adamantane substituent, similarly to
tert-butyl group,9 increased the energy barrier to piperidine
ring inversion, playing the role of a conformational anchor.
Due to this effect, we were able to achieve stereoselective
synthesis of phenyl-substituted 1-(adamantan-1-yl)piperi-
dines 4а–е in good yields (Scheme 4, Table 2). The
reaction was performed in excess TfOH at room
temperature for 30 h. We should note that elimination of
adamantane fragment caused by the stability of 1-adaman-
tanyl cation was not observed under these conditions,
which is characteristic of adamantyl-containing tertiary
amines and amides in acidic media.10
IR spectra of compounds 4а–е contained characteristic
С–Н absorption bands of the adamantyl group in the
regions of 2916–2897 and 2854–2846 cm–1, and C–C bonds
of the phenyl group in the region of 1600–1442 cm–1.
1Н NMR spectra of compounds 4а–е contained the signals
of five aromatic protons of the phenyl ring in the region of
7.12–7.55 ppm. The assignment of 1H and 13C NMR
Scheme 2
Table 1. Yields of 1,2,3,6-tetrahydropyridines 2a–e
Product
2a
R1
H
R2
H
R3
H
Yield, %
89
90
85
89
88
H
Me
H
H
2b
Н
Ме
Me
Me
2c
H
Me
H
2d
Me
2e
892

Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
Scheme 4
Table 2. Products and yields of Friedel–Crafts alkylation of
benzene with 1,2,3,6-tetrahydropyridines 2а–е
Figure 2. Newman projection of a part of phenylpiperidine 4а
molecule relative to the С(3)–С(4) bond.
Starting tetrahydropyridine
Product
Yield, %
94
Ph
Ad
N
equatorial position of the aromatic ring (Fig. 3а). Thus, the
adamantane and phenyl substituents in piperidines 2а,b
were arranged in 1,4-trans-diequatorial configuration.
When benzene was alkylated with 5-methyltetrahydro-
pyridine 2c, only 3-methyl-3-phenylpiperidine 4с was
formed (Table 2). 13С NMR spectrum of compound 4с
contained four signals of secondary carbon atoms and one
signal of a quaternary carbon atom in the region of 23.7–
55.7 ppm, belonging to 3,3-disubstituted piperidine ring.
Based on 2D NOESY spectrum, it was established that the
phenyl ring occupied an equatorial position, because its
ortho protons (7.42 ppm) were coupled through space only
with the diastereotopic protons at С-2 and С-4 atoms of the
piperidine system (four cross peaks) and with the methyl
group protons (1.25 ppm) (Fig. 3b). The adamantane and
phenyl substituents in the piperidine 4с were in a 1,3-cis-di-
equatorial configuration, which is characteristic of 1,3-di-
substituted piperidines.12
4a
96
89
N
Ad
Me
2c
41*
90
Me
Me
Ad
Cl–
N
H
Ph
4e
* Isolated by fractional crystallization from an mixture with minor isomer.
signals for compounds 4а–е was based on DEPT-135 13C
NMR spectra, as well as on 1H–13C HMBC, 1H–13C
HETCOR, and NOESY 2D NMR experiments.
When benzene was alkylated with tetrahydropyridines
2а and 2b, the 1-(adamantan-1-yl)-4-phenylpiperidines 4а
and 4b were formed. The selective arylation at only С-4
position was confirmed by the presence of two 13C NMR
signals due to the piperidine ring methylene groups in
DEPT correlation spectra of these compounds (34.4 and
45.1 ppm in the spectrum of compound 4а; 37.9 and 40.8 ppm
in the spectrum of compound 4b). The adamantane moiety
in piperidines 4а and 4b occupied a sterically more
favorable equatorial position.11 The equatorial orientation
Figure 3. The spatial interactions of hydrogen atoms in 2D NOESY
spectra of phenylpiperidines 4b and 4с.
In the case when hydroarylation was performed with
tetrahydropyridine 2d, a 6.7:1 mixture of phenylpiperidines
1
was obtained according to Н NMR spectral data. The
proton signal of methyl group at the С-3 atom in the major
isomer 4d was found at higher field (0.54 ppm), compared
to the 3-СН3 signal of the minor isomer (0.73 ppm).
Fractional recrystallization from EtOH allowed to isolate
only phenylpiperidine 4d as hydrochloride in 41% yield.
The structure of hydrochloride 4d was unequivocally
established by X-ray structural analysis (Fig. 4). The
phenyl substituent and 3-СН3 group occupied equatorial
positions in the obtained product. Due to a gauche
interaction between the 3еq-СН3 and 4аx-СН3 methyl
groups, their 13С NMR signals were shifted upfield and
were located at 13.6 and 14.8 ppm, respectively. A similar
shifting of 13С NMR signals of the methyl groups is
characteristic of 3еq,4аx-dimethyl-4-arylpiperidines.13 There
were three cross peaks in 2D NOESY spectrum of
compound 4d, corresponding to the coupling through space
(Fig. 5а) of aromatic ortho protons (7.54 ppm) only with
1
of the phenyl ring in piperidine 4а was confirmed by Н
NMR spectral data. The signal due to the proton at the С-4
atom appeared as a triple triplet at 2.46 ppm (3J = 3.9,
3J = 12.1 Hz); the difference in vicinal coupling constants bet-
ween the 4-CH proton and the diastereotopic protons at C-3
and C-5 atoms indicated that it was axially oriented (Fig. 2).
The equatorial orientation of phenyl ring in piperidine
4b was confirmed by 2D NOESY spectrum. The spectrum
contained evidence of distant interaction of the phenyl ring
ortho protons (7.34 ppm) with axial (1.76–1.82 ppm) and
equatorial (2.11–2.17 ppm) protons at piperidine C-3 and C-5
atoms. The methyl group protons were close to the axial
2,6-СН2 protons (2.70–2.75 ppm), which is possible only with
893

Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
compounds 4b–e, which differed depending on the axial
and equatorial orientation of the phenyl substituents. The
calculations were performed in accordance with DFT
theory, using the B3LYP method with 6-311++(d,p) basis
set, taking into account solvation effects in chloroform with
the IEFPCM polarizable continuum model and including
the thermochemical effects at 298 K temperature (Table 3).
The calculations showed that in the case of piperidines
4с and 4d the thermodynamically favored conformer had
an equatorial orientation of the phenyl substituent. The
conformer with axially oriented phenyl substituent was
thermodynamically favored in the case of piperidines 4b
and 4е.
We calculated the geometry of monocationic (I) and
dicationic (II) intermediates, which can arise from the
tetrahydropyridine 2b via a protonation step (Fig. 6). The
calculations showed that the dication II was highly
unstable. Destabilized intermediates of this type would
participate in an alkylation reaction even with such
deactivated arene as nitrobenzene.15 Since it was
demonstrated experimentally that no such reaction takes
place,5 the existence of dication II as a kinetically
independent particle appears to be unlikely.
One of the most convenient parameters used for
estimating the reactivity is the global electrophilicity index
introduced by Parr.16 Quantum-chemical calculations
showed that the structure I did not correspond to an energy
minimum, and its geometry optimization resulted in a
transformation to open-chain product via cleavage of the
bond between С-2 and С-3 atoms in the piperidine ring.
The dication II was characterized with very high
electrophilicity index (89.6 eV), significantly exceeding the
electrophilicity of common cations.17
Figure 4. The molecular structure of compound 4d with non-
hydrogen atoms represented by thermal vibration ellipsoids of
50% probability.
the axial protons at С-3 and С-5 atoms of the piperidine
ring (3.02–3.12 and 3.12–3.22 ppm, respectively) and with
the 4-СН3 protons (1.24 ppm).
1
Based on Н and 13С NMR spectral data for the isomer
mixture, it appears that the minor product was 1-(adaman-
tan-1-yl)-3,4-dimethyl-3-phenylpiperidine – the result of an
attack at the intermediate cationic center at the С-3 atom of
the piperidine ring.
Alkylation of benzene with tetrahydropyridine 2е gave
compound 4е as the sole product with axial orientation of
the phenyl substituent, isolated as hydrochloride in 90%
yield. The structure of piperidine 4е was established from its
2D NMR dataset. NOESY cross peaks indicated a spatial coupl-
ing of the aromatic ortho protons (7.21–7.29 ppm) only with the
equatorial proton at the С-2 atom (4.02 ppm) and the axial
proton at the С-5 atom (a multiplet at 2.50–2.64 ppm) of
the piperidine ring (Fig. 5b). The equatorial orientation of
methyl group at the С-5 atom confirmed the pseudoequatorial
orientation of the 3-СН3 group in the starting alkene 2е.
The cationic center at the С-4 atom in the dication II
was practically planar, and for this reason, the 4-СН3 group
had no substantial influence on the direction of attack. An
equatorial attack leading to 4еq-phenylpiperidine 4b most
probably is kinetically favored, since in this case the
piperidine ring in transition state has a "chair" type
conformation. An axial attack would have led to an
Table 3. The calculated free energy values for conformers 4b–e
with equatorial (G0eq) and axial (G0ax) orientation of phenyl group
Figure 5. The spatial interactions of hydrogen atoms in 2D NOESY
spectra of phenylpiperidines 4d and 4e.
G0
,
G0
,
ax
ΔG298
Hartree
,
ΔG298
,
kJ/mol
eq
Compound
Hartree
Hartree
The formation of the single isomer 4е was apparently
caused by the lack of steric hindrance against axial attack.
An equatorial attack was problematic due to the 5-СН3
group and pseudoaxial protons at the С-2 and С-4 atoms,
which acted as steric obstacles to the approach of benzene
molecule towards the cationic center.
Despite performing the synthesis of phenylpiperidines
4b–e at room temperature, we could not exclude the
possible formation of thermodynamically favored products,
since it is known that such systems are capable of
isomerization in acidic media.14
–911.567174 –911.567985 0.000811
–911.566680 –911.566335 –0.000345
–951.294004 –951.290536 –0.003468
–951.298295 –951.301667 0.003372
2.13
4b
4c
4d
4e
–0.91
–9.11
8.85
In order to thermodynamically evaluate the conformer
stability of the obtained phenylpiperidines in hydrochloride
form, we calculated the relative energy for isomers of
Figure 6. The structures of cationic intermediates involved in
arylation of tetrahydropyridine 2b.
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Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
intermediate twist conformation of piperidine ring. The
2.54 (2Н, m, 3-СН2); 3.60–3.63 (4Н, m, 2,6-СН2); 5.66–
5.67 (1Н, m) and 5.85–5.86 (1Н, m, 4,5-СН); 10.08 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm: 23.6 (СН2); 29.3
(СН Ad); 35.6 (СН2 Ad); 35.7 (СН2 Ad); 42.2 (СН2); 43.8
(СН2); 63.6 (C Ad); 121.6 (CH=); 125.9 (CH=). Mass
spectrum (free amine), m/z (Irel, %): 217 [M]+ (84), 160
(100), 135 [Ad]+ (46), 79 (14). Found, %: С 71.07; Н 9.50;
N 5.41. С15Н24ClN. Calculated, %: С 70.98; Н 9.53; N 5.52.
1-(Adamantan-1-yl)piperidine hydrochloride (3а).
Yield 0.14 g (10%), white powder, mp 309–311°С (mp 311–
dependence of reaction product structure on the direction of
attack by the reagent on the cyclohexene or related system can
be interpreted within the framework of Furst–Plattner effect.18
Thus, we have developed a method for selective reduc-
tion of 1-(adamantan-1-yl)pyridinium salts to adamantyl-
containing 1,2,3,6-tetrahydropyridines. The hydroarylation
of tetrahydropyridines in trifluoromethanesulfonic acid
allowed to stereoselectively prepare 1-(adamantan-1-yl)-
phenylpiperidines. It was established that hydroarylation
resulted mainly in products with equatorial orientation of
phenyl group, and stereoselective formation of phenyl-
piperidine with axial orientation of the phenyl substituent
was observed only in the case of 1-(adamantan-1-yl)-3,5-di-
methyl-1,2,3,6-tetrahydropyridine.
1
313°C)21. H NMR spectrum, δ, ppm (J, Hz): 1.59 (6Н, s,
3СН2 Ad); 1.79–1.86 (6Н, m, 3СН2); 1.92 (6H, s, 3CH2
Ad); 2.10 (3H, s, 3CH Ad); 3.43–3.60 (4Н, m, 2,6-СН2);
10.06 (1Н, br. s, NH). Mass spectrum (free amine), m/z
(Irel, %): 219 [M+] (20), 162 (100). Found, %: С 70.33;
Н 10.18; N 5.53. С15Н26ClN. Calculated, %: С 70.42;
Н 10.24; N 5.48.
Experimental
IR spectra were recorded on a Shimadzu IRAffinity-1
FT-IR spectrometer in KBr pellets. 1Н and 13С NMR
spectra (400 and 100 MHz, respectively), as well as DEPT
and two-dimensional 1H–13C HMBC, 1H–13C HETCOR, and
NOESY (mixing time 0.6 s) spectra were acquired on a
JEOL JNM-ESCX 400 instrument in DMSO-d6 (com-
pounds 2a–f, 3а) and CDCl3 (the rest of the compounds),
the internal standard was TMS. Mass spectra were recorded
on a Thermo Finnigan DSQ GC-MS instrument with a
BPX5 capillary column (30 m×0.32 mm), EI ionization at
70 eV. Elemental analysis was performed on a Euro Vector
EA-3000 automated CHNS-analyzer. Melting points were
determined on a PTP-M apparatus (Russia) by the capillary
method. Thin-layer chromatography was performed on Sorbfil
plates, visualization with iodine vapor. The starting
quaternary salts 1a–f were obtained according to published
procedures.6,19 The thermodynamic stability of phenyl-
piperidine conformers was calculated with the GAUSSIAN
g09a software.20
Reduction of 1-(adamantan-1-yl)pyridinium bromide
(1a). Sodium borohydride (0.31 g, 7.5 mmol) was added
portionwise over 30 min to a stirred solution of compound
1a (1.47 g, 5 mmol) in methanol (10 ml) at 0°С. The
cooling bath was then removed and the reaction mixture
was stirred for another 1 h. The reaction mixture was
diluted with water (50 ml), and the product was extracted
with dichloromethane (3×15 ml). The combined organic
extracts were washed with water and dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum, giving
a mixture of products 2а and 3а (1.05 g). The mixture was
dissolved in dichloromethane, saturated with HCl, (10 ml)
then the solvent was evaporated under vacuum. The residue
was purified by recrystallization from a 3:1 mixture of
acetonitrile and THF, giving tetrahydropyridine hydro-
chloride 2а. The piperidine hydrochloride 3а was then
isolated from the remaining mother liquors.
Reduction of 1-(adamantan-1-yl)pyridinium bromides
1a–f (General method). Sodium borohydride (0.94 g,
22.5 mmol) was added portionwise with stirring over 30 min
to a solution of salt 1a–f (15 mmol) in ethanol (25 ml)
cooled to –20°С. Then the cooling bath was removed, and
the reaction mixture was stirred for another 1 h. The
reaction mixture was diluted with water (100 ml), and the
product was extracted with dichloromethane (3×25 ml). The
combined organic extracts were washed with water and
dried over anhydrous Na2SO4. The solvent was evaporated
under vacuum, giving the corresponding tetrahydropyridine
2a–f. The product was dissolved in dichloromethane,
saturated with HCl, (15 ml) followed by evaporation of the
solvent at reduced pressure. The residue was purified by
recrystallization from chloroform, giving the respective
hydrochloride.
1-(Adamantan-1-yl)-1,2,3,6-tetrahydropyridine hydro-
chloride (2а). Yield 3.40 g (89%), white powder. The
melting point and spectra matched compound 2а obtained by
reduction of salt 1а in MeOH at 0°С.
1-(Adamantan-1-yl)-4-methyl-1,2,3,6-tetrahydropyri-
dine hydrochloride (2b). Yield 3.61 g (90%), white
powder, mp 259–261°С. IR spectrum, ν, cm–1: 3633, 3383,
2897 (С–Н Ad), 2850 (С–Н Ad), 2665, 2592, 2484, 1627,
1
1442, 1365, 1064, 906, 802, 779. H NMR spectrum, δ,
ppm (J, Hz): 1.62–1.73 (9Н, m, 3СН2 Ad, 4-СН3); 1.85–
1.98 (6Н, m, 3СН2 Ad); 2.05 (3Н, s, 3СН Ad); 2.12–2.22
(1Н, m), 2.42–2.55 (1Н, m), 2.70–2.85 (1Н, m) and 3.45–
3.67 (3Н, m, 2,3,6-СН2); 5.35 (1Н, s, 5-СН); 10.12 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm: 22.5 (СН3); 28.1
(СН2); 29.3 (CH Ad); 35.6 (CH2 Ad); 35.7 (CH2 Ad); 42.2
(CH2); 43.5 (CH2); 63.3 (C Ad); 115.4 (C-5); 133.5 (C-4).
Mass spectrum (free amine), m/z (Irel, %): 231 [M]+ (50),
217 (84), 174 (100), 135 [Ad]+ (69), 79 (34). Found, %:
С 71.86; Н 9.69; N 5.15. С16Н26ClN. Calculated, %:
С 71.75; Н 9.78; N 5.23.
1-(Adamantan-1-yl)-1,2,3,6-tetrahydropyridine hydro-
chloride (2а). Yield 0.60 g (45%), white powder, mp 280–
282°С. IR spectrum, ν, cm–1: 3400, 2908 (С–Н Ad), 2850
(С–Н Ad), 2574, 2470, 1635, 1452, 1367, 1066, 912, 669.
1H NMR spectrum, δ, ppm (J, Hz): 1.59 (6Н, s, 3СН2 Ad);
1.90–1.98 (6H, m, 3CH2 Ad); 2.11 (3H, s, 3CH Ad); 2.46–
1-(Adamantan-1-yl)-5-methyl-1,2,3,6-tetrahydropyridine
hydrochloride (2c). Yield 3.41 g (85%), white powder,
mp 252–254°С. IR spectrum, ν, cm–1: 3413, 2912 (С–Н
Ad), 2850 (С–Н Ad), 2653, 2572, 2476, 1620, 1454, 1365,
1
1064, 910, 659. H NMR spectrum, δ, ppm (J, Hz): 1.58
(6Н, s, 3СН2 Ad); 1.63 (3Н, s, СН3); 1.96 (6Н, s, 3СН2 Ad);
895

Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
2.09 (3Н, s, 3СН Ad); 2.42–2.54 (1Н, m), 2.62–2.72 (1Н,
methanesulfonic acid (10 ml, 11.3 mmol) was added
portionwise with stirring to a solution of 1,2,3,6-tetra-
hydropyridine 2a–e (5 mmol) in benzene (10 ml), while
cooling the reaction mixture on an ice bath. After stirring
for 30 h at 25°С, the reaction mixture was poured on ice,
adjusted with 30% NaOH to pH 10–11, and extracted with
dichloromethane (3×15 ml). The combined organic extracts
were dried over anhydrous Na2SO4 and evaporated at reduced
pressure. The products 4a–с were purified by recrystallization
from a 15:1 mixture of hexane and ethyl acetate.
m) and 3.36–3.55 (4Н, m, 2,3,6-СН2); 5.53 (1Н, s, 4-СН);
10.36 (1Н, br. s, NH). 13C NMR spectrum, δ, ppm: 20.6
(СН3); 23.1 (СН2); 29.4 (3СН Ad); 35.6 (3СН2 Ad); 35.7
(3СН2 Ad); 41.9 (СН2); 46.7 (СН2); 63.6 (С Ad); 120.0
(С-4); 128.6 (С-5). Mass spectrum (free amine), m/z (Irel, %):
231 [M]+ (65), 217 (32), 175 (70), 135 [Ad]+ (100), 79
(15). Found, %: С 71.79; Н 9.84; N 5.32. С16Н26ClN.
Calculated, %: С 71.75; Н 9.78; N 5.23.
1-(Adamantan-1-yl)-4,5-dimethyl-1,2,3,6-tetrahydro-
pyridine hydrochloride (2d). Yield 3.76 g (89%), white
powder, mp 230–232°С. IR spectrum, ν, cm–1: 3383, 2912
(С–Н Ad), 2850 (С–Н Ad), 2735, 2634, 2430, 1617, 1458,
1369, 1056, 898, 817, 540. 1H NMR spectrum, δ, ppm (J, Hz):
1.50–1.70 (12H, m, 3СН2 Ad, 4,5-СН3); 1.86–2.05 (6Н, m,
3СН2 Ad); 2.11 (3Н, s, 3СН Ad); 2.15–2.23 (2H, m) and
3.42–3.70 (4Н, m, 2,3,6-СН2); 9.83 (1Н, br. s, NH). 13C
NMR spectrum, δ, ppm: 16.4 (СН3); 18.3 (СН3); 29.1
(СН2); 29.3 (СН Ad); 35.6 (СН2 Ad); 35.8 (СН2 Ad); 42.3
(СН2); 47.2 (СН2); 63.4 (С Ad); 120.3 (С-4(5)); 125.4
(С-5(4)). Mass spectrum (free amine), m/z (Irel, %): 245
[M]+ (63), 230 (100), 188 (62), 135 [Ad]+ (76), 79 (16).
Found, %: С 72.35; Н 9.93; N 5.04. С17Н28ClN.
Calculated, %: С 72.44; Н 10.01; N 4.97.
1-(Adamantan-1-yl)-4еq-phenylpiperidine (4a). Yield
1.4 g (94%), colorless needles, mp 111–113°С. IR
spectrum, ν, cm–1: 3442, 2910 (С–Н Ad), 2848 (С–Н Ad),
1598, 1494, 1452, 1311, 1097, 1018, 950, 821, 750, 698.
1H NMR spectrum, δ, ppm (J, Hz): 1.58–1.70 (6Н, m,
3СН2 Ad); 1.72–1.91 (10Н, m, 3СН2 Ad, 3,5-СН2); 2.10
(3Н, br. s, 3СН Ad); 2.22–2.32 (2Н, t, 3J = 11.4,
3
3
2,6-CHax); 2.46 (1Н, tt, J = 3.9, J = 12.1, 4-СHax); 3.27
3
(2Н, d, J = 11.9, 2,6-CHеq); 7.15–7.19 (1Н, m, Н-4 Ph);
7.22–7.30 (4Н, m, Н-2,3,5,6 Ph). 13C NMR spectrum, δ,
ppm: 29.8 (СН Ad); 34.4 (3,5-СН2); 37.0 (СН2 Ad); 38.5
(СН2 Ad); 43.4 (4-CH); 45.1 (2,6-СН2); 54.6 (С Ad); 126.0
(С-4 Ph); 127.0 (С-2,6 Ph); 128.4 (С-3,5 Ph); 146.7 (С-1
Ph). Mass spectrum, m/z (Irel, %): 295 [M]+ (40), 238 (100),
201 (6), 135 [Ad]+ (100), 91 (8). Found, %: С 85.29;
Н 9.95; N 4.81. С21Н29N. Calculated, %: С 85.37; Н 9.89;
N 4.74.
1-(Adamantan-1-yl)-3,5-dimethyl-1,2,3,6-tetrahydro-
pyridine hydrochloride (2e). Yield 3.72 g (88%), white
powder, mp 248–250°С. IR spectrum, ν, cm–1: 3352, 2904
(С–Н Ad), 2850 (С–Н Ad), 2755, 2639, 2423, 1622, 1458,
1-(Adamantan-1-yl)-4аx-methyl-4еq-phenylpiperidine
(4b). Yield 1.48 g (96%), colorless crystals, mp 98–100°С.
IR spectrum, ν, cm–1: 3394, 2912 (С–Н Ad), 2846 (С–Н
Ad), 1600, 1496, 1446, 1315, 1122, 1076, 960, 821, 763,
1
1378, 1047, 977, 815. H NMR spectrum, δ, ppm (J, Hz):
0.93 (3H, d, 3J = 6.7, 3-СН3); 1.52–1.62 (6Н, s, 3СН2 Ad);
1.64 (3Н, s, 5-СН3); 1.88–2.15 (10Н, m), 2.24–2.34 (1H,
m), 2.68 (1Н, br. s) and 3.52–3.62 (2Н, m, 3СН2 Ad, 3СН Ad,
2,3,6-СН2); 5.40 (1Н, s, 4-CH); 10.25 (1Н, br. s, NH).
13C NMR spectrum, δ, ppm: 18.3 (СН3); 20.4 (СН3); 28.6
(3-СН); 29.4 (СН Ad); 35.6 (СН2 Ad); 35.7 (СН2 Ad);
46.6 (СН2); 48.0 (СН2); 63.6 (С Ad); 126.7 (С-4); 127.8
(С-5). Mass spectrum (free amine), m/z (Irel, %): 245 [M]+
(98), 230 (45), 188 (100), 164 (10), 135 [Ad]+ (99), 79
(43). Found, %: С 72.32; Н 9.95; N 5.06. С17Н28ClN.
Calculated, %: С 72.44; Н 10.01; N 4.97.
1
702, 547. H NMR spectrum, δ, ppm (J, Hz): 1.20 (3Н, s,
4аx-СН3); 1.54–1.66 (6Н, m, 3СН2 Ad); 1.70 (6Н, s, 3СН2
Ad); 1.76–1.82 (2Н, m, 3,5-CHax); 2.05 (3Н, br. s, 3СН
Ad); 2.11–2.17 (2Н, m, 3,5-CHеq); 2.56–2.64 (2Н, m,
2,6-CHеq); 2.70–2.75 (2Н, m, 2,6-CHax); 7.13–7.18 (1Н,
m, Н-4 Ph); 7.27–7.36 (4Н, m, Н-2,3,5,6 Ph). 13C NMR
spectrum, δ, ppm: 29.7 (4ах-СН3); 29.8 (СН Ad); 36.4
(С-4); 37.0 (СН2 Ad); 37.9 (3,5-СН2); 38.5 (СН2 Ad); 40.8
(2,6-СН2); 54.5 (С Ad); 125.5 (С-4 Ph); 125.9 (С-2,6 Ph);
128.3 (С-3,5 Ph); 149.4 (С-1 Ph). Mass spectrum, m/z (Irel,
%): 309 [M]+ (100), 253 (84), 215 (12), 135 [Ad]+ (42), 79
(14). Found, %: С 85.46; Н 10.04; N 4.59. С22Н31N.
Calculated, %: С 85.38; Н 10.10; N 4.53.
2-(Adamantan-1-yl)-1,2,3,4-tetrahydroisoquinoline hydro-
chloride (2f). Yield 4.10 g (90%), light-yellow powder, mp
235–238°С. IR spectrum, ν, cm–1: 3413, 2916 (С–Н Ad),
2850 (С–Н Ad), 2472, 2408, 1454, 1365, 1110, 1056, 898,
750. 1H NMR spectrum, δ, ppm (J, Hz): 1.62 (6H, s, 3СН2
Ad); 2.03 (6Н, s, 3СН2 Ad); 2.15 (3Н, s, 3СН Ad); 2.92–
2.96 (1Н, m), 3.00–3.09 (1Н, m), 3.21–3.26 (1H, m), 3.80–
3.82 (1Н, m) and 4.35–4.37 (2Н, m, 1,3,4-СН2); 7.17–7.22
(4Н, m, Н-5,6,7,8); 10.41 (1Н, br. s, NH). 13C NMR
spectrum, δ, ppm: 26.5 (СН2); 29.4 (СН Ad); 35.6 (СН2
Ad); 35.8 (СН2 Ad); 43.0 (СН2); 46.0 (СН2); 64.1 (С Ad);
127.0 (СН Ar); 127.4 (СН Ar); 127.8 (СН Ar); 128.6
(СН Ar); 130.0 (C Ar); 132.8 (C Ar). Mass spectrum (free
amine), m/z (Irel, %): 267 [M]+ (40), 210 (100), 173 (18),
135 [Ad]+ (29), 117 (27), 105 (53), 91 (24), 79 (34). Found,
%: С 75.24; Н 8.67; N 4.50. С19Н26ClN. Calculated, %:
С 75.10; Н 8.62; N 4.61.
1-(Adamantan-1-yl)-3аx-methyl-3еq-phenylpiperidine
(4c). Yield 1.37 g (89%), colorless crystals, mp 50–51°С.
IR spectrum, ν, cm–1: 3375, 2904 (С–Н Ad), 2850 (С–Н
Ad), 1600, 1492, 1446, 1311, 1114, 1099, 987, 821, 756,
1
694, 540. H NMR spectrum, δ, ppm (J, Hz): 1.25 (3Н, s,
3аx-СН3); 1.44–1.66 (9Н, m, 3СН2 Ad, 5-СН2, 4-CHax);
1.71 (6Н, s, 3СН2 Ad); 1.83–1.87 (1H, m, 4-CHеq); 2.07
(3Н, br. s, 3СН Ad); 2.42–2.52 (1Н, m, 6-CHax); 2.61–
2.65 (1Н, m, 2-CHax); 2.68–2.82 (2Н, m, 2,6-CHеq); 7.17
3
3
3
(1Н, dd, J = 7.0, J = 8.0, Н-4 Ph); 7.31 (2Н, t, J = 8.0,
3
3
Н-3,5 Ph); 7.42 (2Н, dd, J = 7.0, J = 8.0, Н-2,6 Ph).
13C NMR spectrum, δ, ppm: 23.7 (5-СН2); 27.7 (СН3); 29.9
(СН Ad); 37.1 (СН2 Ad); 37.4 (4-СН2); 38.2 (С-3); 38.8
(СН2 Ad); 45.3 (6-СН2); 53.9 (С Ad); 55.7 (2-СН2); 125.5
(С-4 Ph); 126.2 (С-2,6 Ph); 128.0 (С-3,5 Ph); 149.8
Alkylation of benzene with 1-(adamantan-1-yl)-1,2,3,6-
tetrahydropyridines 2a–e (General method). Trifluoro-
896

Chemistry of Heterocyclic Compounds 2015, 51(10), 891–898
(С-1 Ph). Mass spectrum, m/z (Irel, %): 309 [M]+ (26), 252
by direct method and refined by full matrix method of least
squares in anisotropic approximation for non-hydrogen
atoms. All calculations were performed with the SHELX-97
software suite.22 The molecule was visualized with the
Mercury software, version 3.5.1.23 The structural parame-
ters of compound 4d were deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1416385).
(62), 178 (77), 135 [Ad]+ (100). Found, %: С 85.49; Н 10.02;
N 4.61. С22Н31N. Calculated, %: С 85.38; Н 10.10; N 4.53.
1-(Adamantan-1-yl)-3еq,4аx-dimethyl-4еq-phenylpipe-
ridine hydrochloride (4d). The obtained mixture of
isomers (1.50 g, 83%) was dissolved in dichloromethane,
saturated with HCl, (5 ml); the solvent was evaporated, and
the hydrochloride 4d was isolated by fractional recrystal-
lization from EtOH. Yield 0.75 g (41%), colorless crystals,
mp 267–270°С. IR spectrum, ν, cm–1: 3425, 2912 (С–Н Ad),
2850 (С–Н Ad), 2499, 2453, 1600, 1473, 1442, 1369, 1056,
The Supplementary information file containing the data
of 1H and 13C NMR spectra, 1H–13C HMBC, 1H–13C
HETCOR,
and
NOESY
two-dimensional
NMR
1
1033, 894, 756, 698. H NMR spectrum, δ, ppm (J, Hz):
experiments for compounds 2a–f, 4a–е, as well as the log
files for calculating the energy of conformers 4b–е is
available online at http://link.springer.com/journal/10593.
3
0.54 (3Н, d, J = 6.9, 3еq-СН3); 1.24 (3Н, s, 4аx-СН3);
3
1.58 (1Н, d, J = 14.7, 5-CHеq); 1.67 (6Н, s, 3СН2 Ad);
2.13 (6Н, s, 3СН2 Ad); 2.21 (3Н, br. s, 3СН Ad); 2.59 (1Н,
q, J = 11.9, 2-CHax); 2.80–2.92 (1Н, m, 6-CHax); 3.02–
3.12 (1Н, m, 5-CHax); 3.12–3.22 (1Н, m, 3-CHax); 3.35
This work was supported by a grant from the Russian
Scientific Fund (project No. 15-13-0084).
3
3
(1Н, d, J = 11.9, 2-CHеq); 3.54 (1Н, d, J = 10.6,
6-CHеq); 7.12–7.16 (1Н, m, Н-4 Ph); 7.25–7.30 (2Н, m,
Н-3,5 Ph); 7.52–7.55 (2Н, m, Н-2,6 Ph); 9.69 (1Н, br. s,
NH). 13C NMR spectrum, δ, ppm: 13.6 (3еq-СН3); 14.8
(4ax-СН3); 29.6 (СН Ad); 35.7 (СН2 Ad); 36.3 (3-СН);
36.4 (СН2 Ad); 37.2 (5-CH2); 38.7 (С-4); 41.6 (6-CH2);
46.9 (2-CH2); 64.2 (С Ad); 126.3 (С-2,6 Ph); 126.5 (С-4
Ph); 128.5 (С-3,5 Ph); 146.3 (С-1 Ph). Mass spectrum (free
amine), m/z (Irel, %): 323 [M]+ (76), 266 (100), 136 (19),
135 [Ad]+ (16), 79 (14). Found, %: С 76.65; Н 9.58; N 3.98.
С23Н34ClN. Calculated, %: С 76.74; Н 9.52; N 3.89.
References
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intractable mixture of hydrochlorides 4d and the minor
isomer.
1-(Adamantan-1-yl)-3еq,5еq-dimethyl-3аx-phenylpipe-
ridine hydrochloride (4e). The obtained piperidine was
dissolved in dichloromethane (5 ml) saturated with HCl,
then the solvent was evaporated, and the residue was
recrystallized from acetonitrile. Yield 1.62 g (90%), colorless
crystals, mp 185–187°С. IR spectrum, ν, cm–1: 3394, 2916
(С–Н Ad), 2854 (С–Н Ad), 2198, 1496, 1446, 1303, 1107,
1
925, 759, 729, 698. H NMR spectrum, δ, ppm (J, Hz):
3
1.00 (3Н, d, J = 6.4, 5-СН3); 1.12–1.20 (1Н, m, 4-CHax);
1.24 (3Н, s, 3-СН3); 1.67 (6Н, br. s, 3СН2 Ad); 2.05–2.30
(10Н, m, 3СН Ad, 3СН2 Ad, 6-CHax); 2.50–2.64 (3Н, m,
2
2,5-CHax, 4-CHеq); 3.59 (1Н, d, J = 11.0; 6-CHеq); 4.02
2
(1Н, d, J = 11.0, 2-CHеq); 7.21–7.29 (3Н, m, H-2,4,6 Ph);
7.35–7.42 (2Н, m, H-3,5 Ph); 9.60 (1Н, br. s, NH). 13C NMR
spectrum, δ, ppm: 19.2 (5-СН3); 25.7 (СН-5); 29.7
(СН Ad); 33.3 (3-СН3); 35.6 (СН2 Ad); 36.2 (СН2 Ad);
38.8 (С-3); 42.5 (4-СН2); 52.0 (6-СН2); 54.2 (2-СН2); 66.2
(С Ad); 125.6 (С-2,6 Ph); 127.4 (С-4 Ph); 129.5 (С-3,5
Ph); 141.5 (С-1 Ph). Mass spectrum (free amine), m/z (Irel,
%): 323 [M]+ (40), 266 (100), 178 (62), 164 (18), 135 [Ad]+
(58), 79 (28). Found, %: С 76.82; Н 9.60; N 3.95. С23Н33N.
С23Н34ClN. Calculated, %: С 76.74; Н 9.52; N 3.89.
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suitable for X-ray structural analysis were grown from a
1:1 mixture of CHCl3 and i-PrOH by slow evaporation at
room temperature. Monocrystal X-ray structural study of
compound 4d was performed on an Enraf-Nonius CAD-4
diffractometer (CuKα radiation). The structure was solved
897

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