Transformations of 1-phenethyl-1,2,3,6-tetrahydropyridines in the presence of trifluoromethanesulfonic acid

Article abstract of DOI:10.1007/s10593-020-02748-8

[Figure not available: see fulltext.] 1-Phenethyl-1,2,3,6-tetrahydropyridines undergo intramolecular Friedel–Crafts reaction in trifluoromethanesulfonic acid medium, resulting in the formation of azatricyclic structures. It was shown that the direction of

Full text of DOI:10.1007/s10593-020-02748-8

DOI 10.1007/s10593-020-02748-8
Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
Transformations of 1-phenethyl-1,2,3,6-tetrahydropyridines
in the presence of trifluoromethanesulfonic acid
Vera A. Shadrikova1*, Alexander S. Popov1, Maria V. Termelyova1,
Marat R. Baimuratov1, Yuri N. Klimochkin1
1 Samara State Technical University,
244 Molodogvardeiskaya St., Samara 443100, Russia; е-mail: shadrikova.va@samgtu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(7), 909–914
Submitted May 6, 2020
Accepted May 28, 2020
1-Phenethyl-1,2,3,6-tetrahydropyridines undergo intramolecular Friedel–Crafts reaction in trifluoromethanesulfonic acid medium,
resulting in the formation of azatricyclic structures. It was shown that the direction of this reaction depended on the position of the
substituent relative to the multiple bond in tetrahydropyridine. The structures of the obtained compounds were confirmed by a set of
spectral analysis methods.
Keywords: hexahydroazonine, 1-phenethyl-1,2,3,6-tetrahydropyridine, tetrahydroazocine, Friedel–Crafts reaction, hydroarylation.
Despite the two hundred years of accumulated know-
ledge in the field of morphan derivatives and related
compounds, there is a continuing interest among organic
chemists in developing more potent analogs of opiate
alkaloids, which would lack the side effects typical for this
family of drugs: rise of tolerance and dependence after
prolonged use, respiratory system suppression, immuno-
deficiency, hyperalgesia, and others.1 The common
structural motif of such compounds is the benzomorphan
nucleus (Fig. 1). One of the synthetic routes that provides
access to these compounds involves transformations of
1,2,3,6-tetrahydropyridine derivatives.2
In a continuation of our research in the area of electro-
philic reactions involving 1-substituted tetrahydro-
pyridines,3 we achieved the transformation of 1-phenethyl-
1,2,3,6-tetrahydropyridines 2a–h into the benzomorphan
analogs 3a–h through a Friedel–Crafts reaction that was
catalyzed by trifluoromethanesulfonic acid (TfOH). The
application of superacids in the role of catalysts for organic
synthesis reactions often provides access to new, complex
molecular structures or enables the introduction of new
functional groups into the molecules of previously known
compounds.4
The starting 1,2,3,6-tetrahydropyridines 2a–h were
obtained via the reduction of 1-phenethylpyridinium
bromides 1a–h,5a–d which, in turn, were obtained by
standard quaternization reactions of pyridine and its
analogs with phenethyl bromide5e,f (Scheme 1, Table 1).
Subsequently, the reactions of 1,2,3,6-tetrahydro-
pyridines 2a–h with TfOH provided the cyclic products of
intramolecular Friedel–Crafts reaction (1,4,5,6-tetrahydro-
2H-3,6-ethano[3]benzazocines 3а–е and 7-methyl-
1,2,4,5,6,7-hexahydro-3,7-methano[3]benzazonines 3f–h)
in moderate yields (Scheme 2, Table 2). The reaction was
performed in an excess of TfOH by heating for 48 h
Figure 1. Some structural analogs of benzomorphan, which have
found medicinal uses as analgesic drugs: pentazocine (A),
phenazocine (B), and nalbuphine (C).
0009-3122/20/56(7)-0909©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
Table 2. The products of intramolecular Friedel–Crafts reactions
of 1,2,3,6-tetrahydropyridines 2а–h
Scheme 1
Starting tetrahydropyridine
Products
Yield*, %
35
N
Ph
2a
Table 1. The yields of 1,2,3,6-tetrahydropyridines 2a–h
Com-
Yield*,
%
R1
R2
R3
R4
R5
32
58
pound
H
Me
Н
H
H
H
H
H
H
H
H
87
92
85
67
63
83
74
80
2a
2b
2c
H
Ме
Me
Me
H
H
H
Me
H
H
H
H
2d
2e
H
Me
Me
Me
Me
H
H
H
H
2f
H
Me
H
H
H
2g
57
H
H
Me
2h
* The obtained preparative yields of compounds 2a–h are given.
(control by TLC method, eluent i-PrOH). It should be noted
that tetrahydropyridines 2a,b containing an unsubstituted
multiple bond were less prone to cyclization, compared to
the 4- and 5-substituted analogs 2c–h (Table 2).
53
49
41
41
Scheme 2
IR spectra of compounds 3a–h featured the characte-
ristic absorption bands of C–C Ar bonds in the range of
1660–1438 cm–1. The formation of benzo-fused structures
was confirmed by examining 1Н NMR spectra of
compounds 3a–h, which contained proton signals in the
range of 1.50–6.30 ppm, assigned to the 1-azabicyclo-
decane nucleus, as well as four aromatic proton signals in
the range of 6.98–7.35 ppm. 13С NMR spectra of
compounds 3a–h contained the carbon signals of
o-phenylene moiety in the range of 123.1–146.8 ppm. The
spectral characteristics of the synthesized bicyclic products
3a–h were in a good agreement with those of the
previously reported products from hydroarylation reactions
of 1,2,3,6-tetrahydropyridines.3
Me
Me
N
3h
* The obtained preparative yields of compounds 3a–h are given.
60.9 ppm, along with one signal of a tertiary carbon atom
(at 41.9 ppm in the spectrum of compound 3а) or a
quaternary carbon atom (at 36.0 ppm in the spectrum of
compound 3с), confirming the formation of the proposed
1,4,5,6-tetrahydro-2H-3,6-ethano[3]benzazocine structure.
The two-dimensional 1H–13C HMBC spectrum of
compound 3с featured characteristic cross peaks due to
remote coupling of 6-СН3 protons with the carbon atoms at
positions 6, 6а, 5, and 12 (Fig. 2). Analogous correlations
Tetrahydropyridines 2а–е underwent intramolecular
cyclization in the presence of TfOH, resulting in the
formation of 1,4,5,6-tetrahydro-2H-3,6-ethano[3]benzazo-
1
cines 3а–е (Table 2). The assignment of signals in H, 13C
NMR spectra and structure determination for compounds
3a–е was achieved on the basis of 13C DEPT-135 spectra,
as well as two-dimensional 1H–13C HMBC, 1H–13C
HETCOR, and 1H–13C HSQC experiments. Only four
signals of secondary carbon atoms were observed in
13С NMR spectra of compounds 3а,с in the range of 32.9–
were observed in H–13C HMBC spectra of compounds
1
3b,d; the exo position of 4-СH3 group was determined on
the basis of data from NOESY experiment.
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Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
Me
Me
C+
a)
R2 Me
R2
+ 2H+
R2
Ph
R1
SEAr
H
N
R1
R1
N
– 2H+
N
Ph
2a–e
3a–e
A
Figure 2. Some correlations in 1H–13C HMBC spectra of
compounds 3с,e,f.
b)
R1
Me
C+
R1
R1
Me
Me
+ 2H+
SEAr
– 2H+
H
N
R2
Ph
N
R2
The reaction of 4,5-dimethyltetrahydropyridine 2е with
TfOH led to the formation of a product mixture in 10:1
ratio according to the results of GC-MS analysis, from which only
azocine 3e could be separated (Table 2). The minor product could not
be isolated as individual compound. The protons of exo-5-СН3 group
gave a doublet signal that was shifted upfield relative to the proton
signal of the 6-СН3 group. Due to the gauche interaction between the
5-СН3 and 6-СН3 methyl groups, an upfield shift of these signals
was observed in 13С NMR spectrum of compound 3e (by
17.7 and 23.8 ppm, respectively).6 The assignment of
proton and carbon NMR signals relied on the data from\\\\\
1H–13C HMBC and 1H–13C HSQC experiments (Fig. 2).
The cyclization products obtained from 5-methyl-
tetrahydropyridines 2f–h in TfOH medium were 7-methyl-
1,2,4,5,6,7-hexahydro-3,7-methano[3]benzazonines 3f–h
(Table 2), the structure of which was also confirmed by a
set of one-dimensional and two-dimensional NMR
experiments. 1Н NMR spectra of compounds 3f,g contained
the proton signals of 12-СН2 bridge group as two singlets
at 6.22 and 6.30 ppm, respectively. The spectrum of
azonine 3h contained two doublet signals with J = 8.0 Hz
(1.77 and 4.32 ppm), assigned to the protons of 12-СН3 and
12-СН groups. Characteristic cross peaks were observed in
1H–13C HMBC spectrum of azonine 3f, due to the distant
interactions of 7-СН3 group protons with the carbon atoms
at positions 5, 6, 7а, and 12 (Fig. 2). Analogous correlations
R2
Ph
N
B
2f–h
3f–h
Figure 3. The intramolecular Friedel–Crafts reaction pathway for
tetrahydropyridines (а) 2a–e and (b) 2f–h.
and for determining the biological activity of the
synthesized cyclic structures.
Thus, we have demonstrated the possibility of a one-step
synthesis of benzo-fused cyclic structures using an
intramolecular Friedel–Crafts reaction, starting from
available 1-phenethyl-1,2,3,6-tetrahydropyridines. It was
established that by starting from unsubstituted or 4-methyl-
substituted tetrahydropyridines it was possible to obtain
1,4,5,6-tetrahydro-2H-3,6-ethano[3]benzazocines,
5-methyltetrahydropyridines were converted to 7-methyl-
1,2,4,5,6,7-hexahydro-3,7-methano[3]benzazonines.
while
Experimental
IR spectra were recorded on a Shimadzu IRAffinity-1
FT-IR spectrometer for samples in KBr pellets or by using
a Specac Quest diamond ATR accessory (p/n GS10800-B).
1Н and 13С NMR spectra (400 and 100 MHz, respectively),
as well as DEPT correlation spectra and the two-
dimensional 1H–13C HMBC, 1H–13C HSQC, 1H–13C
HETCOR, and NOESY spectra were acquired on a JEOL
JNM-ESCX400 spectrometer in CDCl3, using TMS as
internal standard. The atom numbering in 1Н and 13С NMR
signal assignment does not follow the IUPAC nomenclature
and is provided in Figure 2. Mass spectra were recorded on
a Thermo Finnigan Trace DSQ GC-MS instrument equipped
with a BPX5 capillary column (30 m × 0.32 mm), EI
ionization (70 eV). Elemental analysis was performed on a
EuroVector EA3000 automatic CHNS-analyzer. The
melting points were determined by a capillary method on a
SRS OptiMelt MPA100 apparatus. TLC analysis was
performed on aluminum foil plates coated with silica gel
(Macherey-Nagel Xtra SIL G UV254), visualization was
achieved using UV light and iodine vapor.
Quaternary salts 1a–c,е–g and tetrahydropyridines
2a,c,e,f were obtained according to published proce-
dures.2g,5
Preparation of 1-(2-phenethyl)pyridinium bromides
1d,h (General method). A solution of (2-bromoethyl)-
benzene (5.0 g, 27 mmol) in MeCN (15 ml) was treated by
adding the appropriate 2,4- or 2,3-lutidine (3.0 g, 28 mmol),
then the reaction mixture was heated at reflux for 9 h. The
crystals that precipitated were filtered off and purified by
recrystallization from a 5:1 mixture of Me2CO–EtOH.
1
were observed in H–13C HMBC spectra of compounds
3h,g. The 5-СН3 group in azonine 3g had an endo
orientation; the 12-СН3 group in azonine 3h had an anti
orientation according to its NOESY spectrum.
The formation of two types of bicyclic molecules from
tetrahydropyridines 2a–h as a result of an intramolecular
Friedel–Crafts reaction is explained by the effect of
substituent at the multiple bond on the structure of the
formed electrophilic species. It is known that 1,2,3,6-
tetrahydropyridines in acidic medium are capable of double
protonation, resulting in the formation of superelectrophilic
species.7 For unsubstituted and 4-methyl-substituted 1,2,3,6-
tetrahydropyridines 2a–e, the protonation characteristically
occurrs at position 5, leading to carbocation А (Fig. 3a), the
relative stability of which can be explained by the geometric
distance from the ammonium nitrogen atom (compounds
2a,b) and the influence of the 4-СН3 group (compounds 2с–
е), which was established by Klumpp and coworkers.7а In
the case of 5-methyltetrahydropyridines 2f–h, the
protonation occurred at position 4, with the formation of the
more stable tertiary carbocation (dication B, Fig. 3b).7а
The obtained results will be useful for further
investigations of the stereochemical effects on reactivity
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Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
1H NMR spectrum, δ, ppm (J, Hz): 1.05 (3Н, d,
2,4-Dimethyl-1-(2-phenethyl)pyridinium bromide (1d)
was obtained from 2,4-lutidine. Yield 5.50 g (70%),
colorless crystals, mp 234–236°С. IR spectrum, ν, cm–1:
3020, 2993, 2943, 1635, 1452, 1059, 827, 752, 738, 698,
621, 543, 499, 470, 441, 437, 420, 401. 1H NMR spectrum,
δ, ppm (J, Hz): 2.54 (3H, s, CH3); 2.61 (3H, s, CH3); 3.27
(2H, t, J = 6.9, CH2); 5.05 (2H, t, J = 6.9, CH2); 7.08–7.12
(2H, m, H Ar); 7.19–7.24 (3H, m, H Ar); 7.54–7.59 (2H,
m, H Ar); 9.34 (1H, d, J = 6.2, H Ar). 13C NMR spectrum,
δ, ppm: 20.6 (CH3); 22.0 (CH3); 36.9 (CH2); 58.5 (CH2);
126.7 (CH); 127.7 (CH); 129.1 (СH); 129.2 (CH); 130.1
(CH); 135.4 (C); 145.9 (CН); 153.6 (C); 158.6 (C). Found,
%: С 61.60; Н 6.25; N 4.85. С15Н18BrN. Calculated, %:
С 61.65; Н 6.21; N 4.79.
J = 6.6, 2-СН3); 1.67 (3H, s, 4-CH3); 1.78–1.83 (1Н, m, CH2);
2.14–2.22 (1Н, m, CH2); 2.62–2.68 (1Н, m, CH2); 2.76–
2.82 (3Н, m, CH2); 2.83–2.88 (1Н, m, CH); 3.04–3.21 (2Н,
m, CH2); 5.36–5.39 (1Н, m, 5-СН); 7.16–7.31 (5Н, m,
H Ph). 13C NMR spectrum, δ, ppm: 15.3 (2-CH3); 23.1
(4-CH3); 33.9 (СH2); 38.2 (СH2); 49.4 (СH2); 51.8 (2-СH);
55.7 (СH2); 118.6 (5-СH); 126.0 (СH Ph); 128.4 (2CH Ph);
128.8 (2CH Ph); 131.7 (C-4); 140.8 (С Ph). Mass
spectrum, m/z (Irel, %): 215 [M]+ (8), 130 (20), 110 (100).
Found, %: С 83.73; Н 9.80; N 6.47. С15Н21N. Calculated, %:
С 83.67; Н 9.83; N 6.50.
3,5-Dimethyl-1-(2-phenethyl)-1,2,3,6-tetrahydropyri-
dine (2g). Yield 2.38 g (74%), yellow oil. IR spectrum,
ν, cm–1: 2924, 2798, 1452, 1371, 1344, 1309, 1122, 1078,
2,3-Dimethyl-1-(2-phenethyl)pyridinium bromide (1h)
was obtained from 2,3-lutidine. Yield 6.70 g (85%),
colorless crystals, mp 226–228°С. IR spectrum, ν, cm–1:
3005, 2920, 1637, 1450, 1056, 827, 752, 738, 698, 621,
1
1018, 815, 746, 698. H NMR spectrum, δ, ppm (J, Hz):
0.96 (3Н, d, J = 7.1, 3-СН3); 1.66 (3H, s, 5-CH3); 1.90–
1.95 (1Н, m, CH2); 2.43–2.44 (1H, m, CH2); 2.62–2.73
(3Н, m, CH2); 2.84–2.89 (3H, m, CH2); 3.04–3.08 (1H, m,
CH); 5.31 (1H, s, 4-CH), 7.17–7.31 (5H, m, H Ph).
13C NMR spectrum, δ, ppm: 19.3 (3-CH3); 20.9 (5-CH3);
30.9 (3-СН); 33.9 (СH2); 57.0 (СH2); 58.0 (СH2); 60.3
(СH2); 126.0 (4-СH); 126.2 (СH Ph); 128.4 (2CH Ph);
128.8 (2CH Ph); 131.4 (C-5); 140.6 (С Ph). Mass
spectrum, m/z (Irel, %): 215 [M]+ (8), 130 (20), 110 (100).
Found, %: С 83.63; Н 9.90; N 6.47. С15Н21N. Calculated,
%: С 83.67; Н 9.83; N 6.50.
1
543, 495, 470, 441, 437, 420. H NMR spectrum, δ, ppm
(J, Hz): 2.45 (3H, s, CH3); 2.62 (3H, s, CH3); 3.25 (2H, t,
J = 8.0, CH2); 5.14 (2H, t, J = 8.0, CH2); 7.10–7.25 (5H,
m, H Ar); 7.66 (1H, t, J = 8.0, H Ar); 8.13 (1H, d, J = 8.0,
H Ar); 9.29 (1H, d, J = 8.0, H Ar). 13C NMR spectrum,
δ, ppm: 17.4 (CH3); 20.4 (CH3); 36.6 (CH2); 60.0 (CH2);
125.1 (CH); 127.7 (СH); 129.1 (CH); 129.2 (CH);
135.3 (C); 138.5 (C); 144.5 (CH); 145.7 (CH); 153.9 (С).
Found, %: С 61.72; Н 6.12; N 4.80. С15Н18BrN.
Calculated, %: С 61.65; Н 6.21; N 4.79.
5,6-Dimethyl-1-(2-phenethyl)-1,2,3,6-tetrahydropyri-
dine (2h). Yield 2.58 g (80%), yellow oil. IR spectrum,
ν, cm–1: 2924, 2798, 1452, 1371, 1344, 1309, 1122, 1078,
Preparation
of
1-phenethyl-1,2,3,6-tetrahydro-
pyridines 2b,d,g,h (General method). A solution of the
appropriate salt 1b,d,g,h (15 mmol) in MeOH (20 ml) was
cooled to 0°С and treated by portionwise addition of
NaBH4 (0.85 g, 22.5 mmol) over 30 min. The cooling bath
was then removed and the reaction mixture was stirred for
an additional 1 h, followed by dilution with H2O (100 ml)
and extraction with CH2Cl2 (3×25 ml). The combined
organic extracts were washed with H2O and dried over
anhydrous Na2SO4. The solvent was evaporated at reduced
pressure providing the correponding tetrahydropyridines
2b,d,g,h, which were used further without additional
purification.
1
1018, 815, 746, 698. H NMR spectrum, δ, ppm (J, Hz):
1.13 (3Н, d, J = 7.1, 6-СН3); 1.67 (3H, s, 5-CH3); 1.97
(1Н, d, J = 8.0, CH2); 2.17–2.23 (1H, m, CH2); 2.64–2.87
(6Н, m, CH, CH2); 3.10 (1H, d, J = 8.0, CH2); 5.45 (1H, br. s,
4-CH); 7.17–7.31 (5H, m, H Ph). 13C NMR spectrum,
δ, ppm: 14.5 (6-CH3); 21.4 (5-CH3); 24.5 (СH2); 34.6
(СH2); 43.6 (СH2); 50.6 (СH2); 57.4 (6-СН); 119.8 (4-СH);
126.0 (СH Ph); 128.4 (2CH Ph); 128.8 (2CH Ph); 136.8
(C-5); 140.7 (С Ph). Mass spectrum, m/z (Irel, %): 215 [M]+
(8), 130 (20), 110 (100). Found, %: С 83.61; Н 9.90;
N 6.55. С15Н21N. Calculated, %: С 83.67; Н 9.83; N 6.50.
Preparation of azocines 3а–е and azonines 3f–h by
reactions of 1-(2-phenethyl)-1,2,3,6-tetrahydropyridines
2a–h with TfOH (General method). A solution of the
appropriate tetrahydropyridine 2a–h (5 mmol) in
anhydrous CH2Cl2 (1.5 ml) was cooled to 0°С and treated
by portionwise addition of TfOH (4.4 ml, 50 mmol) over
1 h. The cooling bath was then removed, and the reaction
mixture was stirred under argon atmosphere at reflux for
48 h. The reaction mixture was poured onto ice, adjusted
with 20% NaOH solution to pH 12–13, extracted with
CH2Cl2 (3×40 ml), and washed with saturated NaCl solution.
The combined organic extracts were dried over anhydrous
Na2SO4 and evaporated at reduced pressure. The residue was
separated by column chromatography, eluent CHCl3, and the
isolated products were recrystallized from Me2CO.
2-Methyl-1-(2-phenethyl)-1,2,3,6-tetrahydropyridine
(2b). Yield 2.77 g (92%), colorless oil. IR spectrum, ν, cm–1:
3024, 2908, 2796, 2765, 2358, 1602, 1496, 1452, 1371,
1
1124, 1029, 962, 817, 769, 746, 698. H NMR spectrum,
δ, ppm (J, Hz): 1.07 (3Н, d, J = 8.0, 2-СН3); 1.13–1.16 (1Н,
m, CH2); 1.85–1.93 (1Н, m, CH2); 2.27–2.36 (1Н, m, CH);
2.66–2.97 (4Н, m, CH2); 3.18 (2Н, br. s, CH2); 5.66–5.72
(2Н, m, 4,5-СН); 7.18–7.30 (5Н, m, H Ph). 13C NMR
spectrum, δ, ppm: 15.0 (2-CH3); 33.1 (CH2); 33.7 (СH2);
49.1 (СH2); 51.4 (2-СH); 55.8 (СH2); 124.3 (СH); 124.7
(СН); 126.1 (СH Ph); 128.4 (CH Ph); 128.8 (CH Ph); 140.6
(С Ph). Mass spectrum, m/z (Irel, %): 201 [M]+ (8), 130
(20), 110 (100). Found, %: С 83.60; Н 9.40; N 7.00.
С14Н19N. Calculated, %: С 83.53; Н 9.51; N 6.96.
2,4-Dimethyl-1-(2-phenethyl)-1,2,3,6-tetrahydropyri-
dine (2d). Yield 2.16 g (67%), yellow oil. IR spectrum,
ν, cm–1: 2991, 2943, 1635, 1568, 1467, 1452, 1159, 1080,
1041, 1031, 854, 829, 752, 698, 543, 501, 487, 411.
10-Azatricyclo[8.2.2.02,7]tetradeca-2,4,6-triene (3а).
Yield 0.33 g (35%), white powder, mp 195–197°С.
IR spectrum, ν, cm–1: 2929, 2796, 2760, 1604, 1489, 1465,
912

Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
1444, 1371, 1256, 1124, 1029, 995, 732, 698, 638, 455.
115 (85), 96 (25), 91 (35), 77 (10), 42 (40). Found, %:
С 83.70; Н 9.85; N 6.45. С15Н21N. Calculated, %: С 83.67;
Н 9.83; N 6.50.
1H NMR spectrum, δ, ppm (J, Hz): 1.81–2.04 (2H, m,
5,12-CH2); 2.18–2.30 (2H, m, 5,12-CH2); 2.66–2.80 (6H,
m, 2,4,11-CH2); 2.84–3.01 (3H, m, 1-CH2, 6-СН); 7.09–
7.31 (4H, m, H Ar). 13C NMR spectrum, δ, ppm: 32.9
(5,12-CH2); 34.4 (1-CH2); 41.9 (6-CH); 50.0 (2CH2,
4,11-CH2); 60.2 (2-CH2); 125.3 (7-CH); 127.0 (8-CH);
128.6 (9-CH); 128.8 (10-CH); 138.0 (C-6а); 140.2 (C-1а).
Mass spectrum, m/z (Irel, %): 187 [M]+ (54), 172 (50), 129
(40), 128 (52), 115 (100), 103 (40), 91 (60), 58 (28), 42
(60). Found, %: С 83.45; Н 9.10; N 7.45. С13Н17N.
Calculated, %: С 83.37; Н 9.15; N 7.48.
(12S)-1,12-Dimethyl-10-azatricyclo[8.2.2.02,7]tetradeca-
2,4,6-triene (3e). Yield 0.56 g (53%), light-yellow powder,
mp 197–199°С. IR spectrum, ν, cm–1: 3427, 2958, 2927,
1724, 1601, 1579, 1462, 1379, 1267, 1118, 1070, 1038,
1
955, 743, 480. H NMR spectrum, δ, ppm (J, Hz): 1.19
(3H, d, J = 8.0, 5-CH3); 1.33 (3H, s, 6-CH3); 1.54–1.80
(3H, m, 5-СН, 12-CH2); 2.81–3.16 (4H, m, 2CH2); 3.34–
3.89 (4H, m, 2CH2); 7.05–7.30 (4H, m, H Ar). 13C NMR
spectrum, δ, ppm: 17.7 (5-CH3); 25.1 (СН2); 23.8 (6-CH3);
35.9 (6-CH); 41.9 (СН); 52.2 (CH2); 52.4 (CH2); 56.6
(CH2); 56.7 (CH2); 124.7 (CH); 128.7 (CH); 128.8 (CH);
130.2 (CH); 137.1 (C-1а); 144.8 (C-6а). Mass spectrum,
m/z (Irel, %): 215 [M]+ (50), 214 (20), 200 (60), 187 (20),
172 (60), 158 (40), 143 (38), 130 (40), 129 (80), 128 (100),
115 (90), 96 (20), 91 (40), 77 (20), 57 (20), 42 (40). Found, %:
С 83.62; Н 9.90; N 6.48. С15Н21N. Calculated, %: С 83.67;
Н 9.83; N 6.50.
(11S)-11-Methyl-10-azatricyclo[8.2.2.02,7]tetradeca-
2,4,6-triene (3b). Yield 0.32 g (32%), white powder,
mp 201–203°С. IR spectrum, ν, cm–1: 2924, 2798, 1452,
1440, 1371, 1344, 1309, 1122, 1078, 1018, 815, 746, 698,
1
455. H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, d,
J = 8.0, 4-CH3); 1.70–1.82 (2H, m, 5,12-CH2); 2.10–2.27
(2H, m, 5,12-CH2); 2.50–2.91 (8H, m, CH2, CH); 7.04–
7.33 (4H, m, H Ar). 13C NMR spectrum, δ, ppm: 18.3
(CH3); 29.8 (CH2); 35.7 (6-CH); 38.5 (CH2); 40.7 (CH2);
55.5 (CH2); 56.1 (СН2); 56.4 (4-CH); 124.5 (7-CH); 126.3
(8-CH); 128.5 (9-CH); 128.8 (10-CH); 139.9 (C-6а); 146.1
(C-1а). Mass spectrum, m/z (Irel, %): 201 [M]+ (64), 200
(30), 186 (100), 185 (26), 173 (36), 172 (50), 158 (82), 157
(22), 143 (34), 141 (22), 130 (36), 129 (80), 128 (100), 127
(50), 117 (26), 116 (40), 115 (96), 110 (22), 91 (38), 77
(22), 42 (52). Found, %: С 83.50; Н 9.54; N 6.93. С14Н19N.
Calculated, %: С 83.53; Н 9.51; N 6.96.
1-Methyl-10-azatricyclo[8.3.1.02,7]tetradeca-2,4,6-triene
(3f). Yield 0.49 g (49%), pink powder, mp 210–212°С.
IR spectrum, ν, cm–1: 2976, 2954, 2931, 2854, 1489, 1463,
1438, 1373, 1355, 1089, 1020, 1004, 987, 945, 860, 792,
1
763, 744, 412. H NMR spectrum, δ, ppm (J, Hz): 1.39
(3H, s, CH3); 2.00 (1H, td, J = 13.3, J = 3.2, 5-CH2); 2.12
(1H, d, J = 12.8, 5-CH2); 2.83 (1H, dd, J = 17.4, J = 3.4,
1-CH2); 3.55 (1H, t, J = 13.7, CH2); 3.88–3.99 (2H, m,
CH2); 4.00–4.07 (1H, m, 6-CH2); 4.17 (1Н, dt, J = 12.3,
J = 2.0, CH2); 4.33 (1H, dd, J = 14.2, J = 3.0, CH2); 4.50
(1H, d, J = 13.7, 6-CH2); 6.22 (2H, s, 12-CH2); 6.96 (1H,
d, J = 7.5, H-11); 7.09 (1H, td, J = 7.8, J = 1.4, H-8); 7.20–
7.28 (2H, m, H-9,10). 13C NMR spectrum, δ, ppm: 31.6
(1-CH2); 31.8 (CH3); 37.6 (5-CH2); 40.4 (C-7); 61.0
(2,4-CH2); 61.3 (6-CH2); 73.5 (12-CH2); 127.3 (8-CH);
128.1 (9-CH); 128.6 (10-CH); 131.0 (11-CH); 136.2
(C-1а); 141.0 (C-7а). Mass spectrum, m/z (Irel, %): 201 [M]+
(62), 200 (28), 186 (98), 185 (22), 173 (32), 172 (48), 158
(80), 143 (32), 129 (80), 128 (100), 127 (48), 117 (26), 116
(38), 115 (96), 110 (23), 91 (38), 77 (22), 42 (52). Found,
%: С 83.59; Н 9.40; N 7.01. С14Н19N. Calculated, %:
С 83.53; Н 9.51; N 6.96.
1-Methyl-10-azatricyclo[8.2.2.02,7]tetradeca-2,4,6-triene
(3с). Yield 0.58 g (58%), white powder, mp 211–213°С.
IR spectrum, ν, cm–1: 2976, 2954, 1496, 1463, 1438, 1373,
1355, 1089, 1004, 860, 763, 746. 1H NMR spectrum, δ, ppm
(J, Hz): 1.21 (3H, s, CH3); 1.78–1.80 (2H, m, 5,12-CH2);
2.10–2.20 (2H, m, 5,12-CH2); 2.40–2.62 (6H, m,
1,2,4,11-CH2); 2.71–2.81 (2H, m, 1,2-CH2); 7.11–7.18
(2H, m, H-7,10); 7.20–7.28 (2H, m, H-8,9).
13C NMR spectrum, δ, ppm: 29.6 (CH3); 33.4 (1-CH2); 36.0
(6-CH); 37.2 (5,12-CH2); 50.3 (4,11-CH2); 60.9 (2-CH2);
123.5 (7-CH); 125.8 (10-CH); 128.7 (8,9-CH); 137.7
(C-1а); 146.8 (C-6а). Mass spectrum, m/z (Irel, %): 201 [M]+
(50), 200 (49), 186 (86), 173 (26), 172 (54), 158 (62), 143
(22), 129 (80), 128 (100), 116 (40), 115 (72), 77 (28), 42
(47). Found, %: С 83.59; Н 9.47; N 6.93. С14Н19N.
Calculated, %: С 83.53; Н 9.51; N 6.96.
(12R)-1,12-Dimethyl-10-azatricyclo[8.3.1.02,7]tetradeca-
2,4,6-triene (3g). Yield 0.41 g (41%), yellow powder,
mp 208–210°С. IR spectrum, ν, cm–1: 3024, 2949, 2920,
2866, 1660, 1602, 1487, 1454, 1377, 1363, 1128, 1085,
(11S)-1,11-Dimethyl-10-azatricyclo[8.2.2.02,7]tetradeca-
2,4,6-triene (3d). Yield 0.61 g (57%), light-yellow powder,
mp 217–218°С. IR spectrum, ν, cm–1: 2976, 2955, 2936,
1497, 1464, 1456, 1439, 1356, 1288, 1217, 1028, 988, 945,
1
1039, 758, 746, 698, 572. H NMR spectrum, δ, ppm
(J, Hz): 0.99 (3Н, d, J = 8.0, 5-СН3); 1.43 (3H, s, 7-CH3);
1.70–1.85 (2H, m, 5-CH, 6-CH2); 2.13 (1H, d, J = 12.0,
6-СН2); 2.84 (1H, dd, J = 12.0, J = 4.0, 1-CH2); 3.59 (1H,
t, J = 16.0, 4-СН2); 3.76–3.89 (1H, m, 4-СН2); 3.98–4.09
(1H, m, 1-CH2); 4.41 (1Н, dd, J = 16.0, J = 2.0, 2-СН2);
4.55 (1H, d, J = 16.0, 2-СН2); 6.30 (2Н, s, 12-СН2); 6.98
(1H, d, J = 7.3, H-11); 7.12 (1H, t, J = 6.4, H-8); 7.24–7.31
1
793, 708, 638, 617, 571, 536, 505, 486, 465. H NMR
spectrum, δ, ppm (J, Hz): 1.17 (3H, d, J = 8.0, 4-CH3);
1.24 (3H, s, 6-CH3); 1.51–1.86 (4H, m, 5,12-CH2); 2.38–
2.90 (7H, m, CH2, CH); 7.14–7.28 (4H, m, H Ar).
13C NMR spectrum, δ, ppm: 20.5 (4-CH3); 24.0 (6-CH3);
35.9 (6-CH); 36.2 (CH2); 39.1 (CH2); 48.7 (CH2); 49.4
(CH2); 55.4 (CH2); 64.3 (4-CH); 123.1 (CH); 126.4 (CH);
128.3 (CH); 128.5 (CH); 137.4 (C-1а); 144.1 (C-6а). Mass
spectrum, m/z (Irel, %): 215 [M]+ (55), 214 (32), 200 (58),
187 (15), 172 (42), 158 (45), 130 (30), 129 (70), 128 (100),
13
(2H, m, H-9,10). C NMR spectrum, δ, ppm: 18.0 (5-CH3);
24.6 (5-СН); 31.7 (7-CH3); 31.8 (1-CH2); 40.7 (C-7); 46.6
(6-СН2); 61.1 (2-CH2); 66.1 (4-CH2); 73.6 (12-CH2); 127.3
(10-CH); 128.1 (8-CH); 128.6 (9-CH); 131.1 (11-CH);
136.0 (C-1а); 141.0 (C-7а). Mass spectrum, m/z (Irel, %): 215
913

Chemistry of Heterocyclic Compounds 2020, 56(7), 909–914
[M]+ (65), 200 (80), 199 (25), 173 (30), 172 (100), 158
(60), 130 (35), 129 (68), 128 (66), 115 (66), 91 (35), 77
(16), 42 (33). Found, %: С 83.79; Н 9.73; N 6.48. С15Н21N.
Calculated, %: С 83.67; Н 9.83; N 6.50.
102, 5955. (d) Coe, J. W.; Brooks, P. R.; Vetelino, M. G.;
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Raymond, T. J.; Bilsky, E. J.; Aceto, M. D.; May, E. L.;
Harris, L. S.; Coop, A.; Dersch, C. M.; Rothman, R. B.;
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2010, 40, 3716.
(14R)-1,14-Dimethyl-10-azatricyclo[8.3.1.02,7]tetradeca-
2,4,6-triene (3h). Yield 0.41 g (41%), yellow powder,
mp 203–205°С. IR spectrum, ν, cm–1: 3024, 2949, 2920,
2966, 1661, 1603, 1487, 1454, 1377, 1364, 1329, 1258,
1
1128, 1086, 1040, 758, 746, 698, 573. H NMR spectrum,
3. (a) Shadrikova, V. A.; Golovin, E. V.; Shiryaev, V. A.;
Baymuratov, M. R.; Rybakov, V. B.; Klimochkin, Yu. N. Chem.
Heterocycl. Compd. 2015, 51, 891. [Khim. Geterotsikl. Soedin.
2015, 51, 891.] (b) Shadrikova, V. A.; Golovin, E. V.;
Kuznetsova, E. A.; Rostova, M. Yu.; Klimochkin, Yu. N. Russ.
J. Org. Chem. 2016, 52, 1452. [Zh. Org. Khim. 2016, 52, 1461.]
4. (a) Ponra, S.; Majumdar, K. C. RSC Adv. 2016, 6, 37784.
(b) King, F. D.; Aliev, A. E.; Caddick, S.; Tocher, D. A. Org.
Biomol. Chem. 2011, 9, 1547. (c) Bolsakova, J.; Jirgensons, A.
Chem. Heterocycl. Compd. 2017, 53, 1167. [Khim. Geterotsikl.
Soedin. 2017, 53, 1167.] (d) Zerov, A. V.; Starova, G. L.;
Suslonov, V. V.; Khoroshilova, O. V.; Vasilyev, A. V. Org.
Lett. 2018, 20, 784. (e) Golushko, A. A.; Khoroshilova, O. V.;
Vasilyev, A V. J. Org. Chem. 2019, 84, 7495. (f) Ryabukhin, D. S.;
Fukin, G. K.; Vasilyev, A. V. Tetrahedron 2014, 70, 7865.
(g) Tkachenko, I. M.; Mankova, P. A.; Rybakov, V. B.;
Golovin, E. V.; Klimochkin, Yu. N. Org. Biomol. Chem. 2020,
18, 465. (h) Vlad, P. F.; Ungur, N. D.; Perutskii, V. B. Chem.
Heterocycl. Compd. 1991, 27, 246. [Khim. Geterotsikl. Soedin.
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δ, ppm (J, Hz): 1.30 (3H, s, 7-CH3); 1.53–1.70 (2Н, m,
CH2), 1.77 (3H, d, J = 8.0, 12-СН3); 1.94–2.02 (3Н, m,
CH2); 2.75–2.90 (2H, m, CH2); 3.02 (1H, t, J = 10.0, CH2);
3.42 (1H, t, J = 12.0, CH2); 3.74 (1H, t, J = 12.0, CH2);
4.32 (1H, d, J = 8.0, 12-CH); 7.05 (1Н, d, J = 8.0, H Ar);
7.15 (1H, t, J = 8.0, H Ar); 7.27 (1Н, t, J = 8.0, H Ar); 7.35
(1H, d, J = 8.0, H Ar). 13C NMR spectrum, δ, ppm: 14.4
(12-CH3); 16.0 (СН2); 30.7 (7-CH3); 31.7 (СН2); 32.4
(CH2); 42.8 (C-7); 46.5 (СН2); 53.9 (CH2); 55.7 (12-CH2);
127.3 (10-CH); 127.9 (8-CH); 129.3 (9-CH); 131.5
(11-CH); 137.0 (C-1а); 142.6 (C-7а). Mass spectrum, m/z
(Irel, %): 215 [M]+ (60), 200 (70), 199 (20), 173 (35), 172
(100), 158 (60), 143 (20), 130 (35), 129 (70), 115 (70), 91
(35), 77 (20), 42 (30). Found, %: С 83.72; Н 9.80; N 6.52.
С15Н21N. Calculated, %: С 83.67; Н 9.83; N 6.50.
This work received financial support from the Ministry
of Education and Science of the Russian Federation within
the framework of the Project part of the State Assignment
No. 0778-2020-0005, using the equipment at the Samara
State Technical University Collective Use Center ''Physico-
chemical Investigation of Substances and Materials''.
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