Potential synthetic adaptogens: IV. Synthesis and study of basicity of new N-[(adamantan-1-yl)methyl]aniline derivatives

Article abstract of DOI:10.1134/S1070428017050049

Aiming at purposeful designing new conformationally labile bromantane analogs we performed experimental and theoretical evaluation of the basicity of new and formerly prepared compounds of this series. The connection was established between the chemical s

Full text of DOI:10.1134/S1070428017050049

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 663–672. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © I.A. Novakov, A.S. Babushkin, A.A. Vernigora, A.S. Mkrtchyan, M.B. Navrotskii, B.S. Orlinson, S.N. Voloboev, 2017, published in
Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 5, pp. 657–666.
Potential Synthetic Adaptogens:
1
IV. Synthesis and Study of Basicity
of New N-[(Adamantan-1-yl)methyl]aniline Derivatives
a
a
a
a
I. A. Novakov , A. S. Babushkin ,* A. A. Vernigora , A. S. Mkrtchyan ,
a
a
b
M. B. Navrotskii , B. S. Orlinson , and S. N. Voloboev
a
Volgograd State Technical University, Lenina pr. 28, Volgograd, 400005 Russia
e-mail: asbabyshkin@gmail.com
*
b
Open Joint Stocks Co “LUKOIL-Volgogradneftepererabotka,” Volgograd, Russia
Received March 10, 2017
Abstract—Aiming at purposeful designing new conformationally labile bromantane analogs we performed
experimental and theoretical evaluation of the basicity of new and formerly prepared compounds of this series.
The connection was established between the chemical structure and the basicity of compounds obtained and
preferred structures were determined for subsequent biological investigations.
DOI: 10.1134/S1070428017050049
Electrostatic charge of ionized molecules favors
their hydration in blood plasma and therefore the
arising complexes lose their lipophilicity to a large
extent. Since the lipid diffusion depends on the high
solubility in fats the drugs ionization can essentially
decrease their ability to penetrate membranes under in
vivo conditions [2].
investigation of N-[(adamantan-1-yl)methyl]aniline
derivatives 1–47 was carried out as well in order to
evaluate the ability of the fragment 1-AdCH2 to
transmit the inductive effect of the substituent located
in the position 3 of the adamantane scaffold and to
study the combined effect on pKBH of substituents in
the aromatic fragment of the molecule and in the
adamantane scaffold.
+
+
In this connection we determined pKBH of
bromantane structural analogs and the relative
concentration of their hydrophobic non ionized form at
the physiological blood pH 7.4. The basicity
The synthesis of compounds 1–3, 6–12, 17, 18, 21,
22, 27, 28, 38, and 47was described before [1, 3, 4].
Compounds 13, 16, 19, 20, 23, 26, 29–33, 36, 37, 39–
Scheme 1.
O
H
+
N
Ar
H
N
O
N
Ar
Ar
H
H
O+
NaOH
2
HC(O)OH
3
ArNH2
+
R
_
_
R
_HC(O)OH
R
_
+
_
R
CO , H O
Na , H O
2
2
2
3_62
48 52
_
1_47
5
R = H (1–10, 48), Br (11–20, 49), Cl (21–30, 50), CN (31–40, 51), OH (41–47, 52); Ar = Ph (1, 11, 21, 31, 41, 53), 4-
NC (2, 12, 22, 32, 42, 54), 3-O NC (3, 13, 23, 33, 43, 55), 4-H NC (4, 14, 24, 34, 44, 56), 3-H NC (5, 15, 25,
5, 45, 57), 4-HOC (6, 16, 26, 36, 58), 4-MeC (7, 17, 27, 37, 46, 59), 4-BrC (8, 18, 28, 38, 47, 60), 1-C10 (9, 19,
9, 39, 61), 2-C10 (10, 20, 30, 40, 62).
O
2
6
H
4
2
6
H
4
2
6
H
4
2
6 4
H
3
2
6
H
4
6
H
4
6
H
4
H
7
H
7
1
For communication III, see [1].
6
63

6
64
NOVAKOV et al.
Scheme 2.
H
H
H
H
H
N
+
N
+
N
HCl, SnCl2
H O
NaOH
H O
+
2
2
NO2
N
NH2
R
R
H
R
H
H
2
, 3, 12, 13, 22, 23,
2, 33, 42, 43
4, 5, 14, 15, 24, 25,
34, 35, 44, 45
3
+
4
3, and 46 were obtained with the use of Leuckart-
substituents in the linear equation pKBH = f(σ* ) also a
Ar
Wallach reaction from the corresponding adamantan-
-carbaldehydes 48–52 and aniline derivatives 53–62
low correlation coefficient was obtained both for N-
[(adamantan-1-yl)methyl]aniline derivatives and for
substituted anilines. The unsatisfactory correlation in
this case may be ascribed to a large contribution from
the resonance interaction of the substituent in the
aromatic fragment with the amino group. The
resonance of the substituent with the amino group is
especially pronounced for the para-substituted
phenylene fragments.
1
(
Scheme 1).
The derivatives containing a primary amino group
in the aromatic ring were obtained by the reduction of
the corresponding nitrocompounds with SnCl (Scheme 2).
2
Adamantan-1-carbaldehyde and its functional
derivatives were obtained by procedures [5, 6].
+
Some information was published on a correlation
between the pKBH of diaminaes of adamantane series
The processing of obtained pKBH values of
+
adamantane-1,3-diamine and (adamantane-1,3-diyl)bis-
and the rate constant of the formation of poly-
amidoacids [7]. To evaluate the inductive transmission
of the adamantane system we studied the basicity of
the derivatives of N-[(adamantan-1-yl)methyl]aniline
as a function of the inductive effect of the substituent
in the position 3 of the adamantane scaffold. To
estimate the substituent effect in the aromatic fragment
of the molecule we analyzed the dependence of the
basicity of studied compounds on the Hammett–Taft
σ°-constants which reflect the sum of inductive effect
and the polar response of the substituent. We also
estimated the dependence of the basicity on the
inductive constants of the aromatic fragment as a
whole.
(
methylamine) (Table 2) according to the linear
+
equation pKBH = f(σ*) (without consideration of the
data for amine unsubstituted at the position 3 of the
adamantane scaffold) gave a correlation dependence
which may be regarded as plausible (r 0.966). The
analysis of the dependence pKBH = f(σ*) for diamines
of adamantane series explored in [10] demonstrated
+
the lack of correlation (r 0.631).
These facts confirm the hypothesis on the absence
of universal values of inductive constants for alicyclic
systems [12]. Evidently the transmission value through
the carbon atom Z* is not constant for diverse reaction
C
series and depends on the values of effects of
electroneutral (dipole) and ionic substituents [12].
Besides the transmission value of a cyclic system Z*cycl
calculated for the same cycle in the same reaction in
different solvents is not constant [12] because of
specific solvation interaction of substituents with
various solvents. Consequently the absence of a linear
relationship pKBH = f(σ*) [10] for diamines of
adamantane series may be due to the solvation of the
primary amino group with MeNO molecules. The
solvation of the secondary amino group in N-
Since compounds 1–47 are virtually insoluble in
water the investigation was performed in MeNO
following procedure [8]. The pKBH values of amines in
2
+
question are presented in Table 1. For comparison the
+
pKBH values are given of some substituted amines in
MeNO2 [8], and also calculated values of these
compounds basicity in water [9]. The processing of
obtained basicity values according to the linear
+
2
+
equation pKBH = f(σ°) revealed relatively low cor-
relation with Hammett–Taft σ°-constants both for the
compounds under study and aniline derivatives (correla-
tion coefficients were r 0.822 and 0.734 respectively).
At the use of inductive constants of aromatic
[(adamantan-1-yl)methyl]anilines is less pronounced.
The Z* values for the aliphatic series vary in the
C
range 0.36–0.50. For various alicyclic systems the Z*C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

POTENTIAL SYNTHETIC ADAPTOGENS: IV. SYNTHESIS AND STUDY OF BASICITY
665
Table 1. Basicity of N-[(adamantan-1-yl)methyl]aniline derivatives 1–47 and a series of substituted anilines in MeNO
2
Experiment
Calculation (H
2
O)
+
Experiment
2
Calculation (H O)
Compound
no.
Compound no.
+
+
+
+
+
+
+
pKBH1
11.92
10.53
10.70
11.77
11.75
12.61
12.39
11.73
11.64
11.67
10.79
9.53
pKBH2
pKBH1
5.28
1.11
3.88
7.11
5.64
6.66
5.72
5.12
4.81
5.01
5.09
0.91
3.68
6.91
5.45
6.47
5.52
4.92
4.61
4.82
5.16
0.99
3.75
6.98
5.51
6.54
5.59
pKBH2
pKBH1
10.26
10.19
10.21
9.96
pKBH2
pKBH1
pKBH2
1
2
3
4
5
6
7
8
9
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
4.99
4.68
4.89
5.22
1.05
3.81
7.04
5.56
6.60
5.65
5.05
4.74
4.95
5.26
1.09
3.86
7.09
5.62
5.70
5.10
4.64
0.91
6.46
5.43
4.99
3.83
3.46
3.57
8.79
8.93
9.83
9.03
8.96
3.36
3.45
9.81
10.53
10.35
9.80
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
9.72
9.69
9.74
10.65
10.63
11.41
11.35
10.62
10.54
10.56
10.43
9.21
9.31
9.28
3.29
3.39
11.38
10.04
10.20
11.23
11.20
11.82
11.20
9.07
9.38
9.31
3.40
3.53
PhNH
2
4-O
4-H
2
2
2
NC
NC
NC
6
H
6
H
6
H
4
NH
NH
OH
2
5.18
9.35
4
4
2
11.85
10.91
9.80
6.73
3.04
10.29
10.27
11.03
10.96
9.25
9.20
3.31 4-H
3.42 4-MeC
6
H
4
NH
2
6
4-BrC H
4
NH
2
7.97
values calculated from Z*cycl fall in this range.
Consequently the inconsistencies in the Z*cycl values
may be formally ascribed to an assumption of some
variability of Z*C.
steps are apparently due to the steric hindrances of the
protonation by the fragment 1-AdCH and by its
2
electron-donor effect.
The comparison of the data obtained in the study of
substituent inductive effect transmission from one
nodal position to the other with the results obtained in
[14] at the investigation of dissociation of 3-substituted
adamantane-1-carbocylic acids demonstrated their
similarity. The only exclusion consists in omitting in
[14] in building the regression model the values
4-N-{[(Adamantan-1-yl)methyl]amino}anilines behave
in MeNO2 as monoacidic bases (Table 1). The
presence of an electron-acceptor substituent in the
position 3 of adamantane scaffold led to the
appearance of the second ionization step. The close
+
pKBH values for the first and the second ionization
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

6
66
NOVAKOV et al.
+
Table 2. pKBH of adamantane-1,3-diamine and (adaman-
Table 3. Inductive constants of substituents σ° and σ*
tane-1,3-diyl)bis(methylamine)
Substituent
at phenyl
+
Position
σ° [13]
Substituent σ* [11]
pKBH
Inductive constant
Compound
in nitro-
methane [10]
[
11]
NO
NH
2
3
4
3
4
4
4
4
–
–
0.70
0.73
Br
Cl
2.80
2.89
3.48
1.60
0.75
1.27
1.22
0.59
0.86
0.77
0.74
NH
2
(1,3-Ad)NH
2
σ*(NH
σ*(CH
2
) 0.878
16.70
16.67
14.32
15.57
2
–0.14
–0.38
–0.13
–0.15
0.26
CN
OH
NH
2
CH
2
(1,3-Ad)CH
2
NH
2
2
2
NH ) 0.50
+
+
N H
3
(1,3-Ad)NH
2
σ*(NH
σ*(CH
3
) 3.78
+
+
OH
6 5
C H
N H
3
CH (1,3-Ad)CH
2
2
NH
2
2
NH
3
) 1.08
CH
3
C
6
H
4
NO
2
-p
-m
-p
Br-p
Br
C
6
H
4
NO
2
α-Naphthyl
β-Naphthyl
0.048
0.062
C
6
H
4
CH
3
obtained for 3-hydroxtadamantane-1-carboxylic acid
as the most deviating. The sharp deviation of hydroxy
derivatives from the correlation straight line is due to
their abnormal solvation in 50% aqueous EtOH. At the
measurement of the basicity of N-[(adamantan-1-yl)-
C
6
H
4
α-Naphthyl
β-Naphthyl
methyl]anilines in MeNO no large deviation was
2
observed for the value of 3-(anilinomethyl)adamantan-
1
-ol from the correlation straight line indicating the
absence of specific solvation of the hydroxy group
with MeNO2.
EXPERIMENTAL
Melting points of compounds obtained were
measured on a Buchi M-565 apparatus at the heating
rate 1 deg/min (reported values were corrected). Н NMR
In the course of the performed investigation it was
established that the ability of the unit of adamantane-
1
1
,3-diyl to transmit inductive effects of the substituents
spectra were registered on a spectrometer Varian Mercury
affects the basicity of amines in MeNO . The basicity
2
3
00 BB at operating frequency 300 MHz, internal refe-
of the studied amines and inductive constants of the
substituents in the position 3 of adamantane scaffold
correlate plausibly within a framework of a linear
rence HMDS. IR spectra were recorded on a spectro-
photometer Specord M-82 from mulls in mineral oil
(
for solid samples). GS-MS analysis was performed on
+
equation pKBH = f(σ*). The lack of a linear
an instrument Varian Saturn-2100 at the electron ioni-
zation mode, 70 eV. The HPLC analysis was carried out
on a chromatographic system consisting of a pump block
Jasco PU-980, detector Jasco UV-975, admission system
Rheodyne, column Reprosil C18 AQ, 150 × 4.6 mm ×
3 µm; eluent flow rate 0.75 mL/min, λ 220 nm, 30°C,
mobile phase Н О–MeCN–85% H PO , 200 : 200 : 1.
dependence between the basicity and Hammett–Taft
constants (Table 3) may be ascribed to the large
contribution from the resonance interaction of the
substituent with the amino group.
The investigation of the substituent effect in the
aromatic fragment of the molecule and in the
adamantane scaffold on the basicity of compounds
under consideration demonstrates its complex and
multifactor dependence on the substituent effects and
on solvation interaction.
2
3
4
Mass spectra of studied compounds were registered
in a direct admission mode on an instrument Varian
Mat 111, electron impact, 70 eV, cathode emission at
2
40 µА. Elemental analysis was carried out on an
For predicting the possibility of fast and efficient
action on the human central nervous system the most
attractive compounds from the studied series seem to
be the substances possessing lower basicity, excluding
the nitro derivatives. The latter have no practical
interest for they can undergo reduction in vivo to the
corresponding aniline derivatives which probably
exhibit teratogenic and mutagenic activity.
analyzer Vario EL Cube.
The solutions after reaction completion and
extraction were concentrated on a rotary evaporator
Heidolph Hei-VAP Precision.
Used reagents were purchased from TCI Europe,
Alfa Aesar, and ABCR, and solvents from “Komponent-
Reaktiv” Co.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

POTENTIAL SYNTHETIC ADAPTOGENS: IV. SYNTHESIS AND STUDY OF BASICITY
667
Additional purification and drying of solvents was
performed by standard procedures [15].
normal and then at reduced pressure. The still residue
was purified by recrystallization.
Quntitative measurement of amines basicity in
nitromethane. The determination of amines pKBH was
N-[(3-Bromoadamantan-1-yl)methyl]-3-nitroani-
line (13). Yield 92%, yellow crystals, mp 119–121°C
+
performed by procedure [8]. Nitromethane of “pure”
grade was dried with P O and distilled twice on a
(
9
1
EtOH). Content of the main substance (HPLC)
9.10%. IR spectrum, ν, cm : 3392 (N–H), 1600 (Аr),
–1
2
5
Vigreux column at atmospheric pressure. In further
operations the fraction of bp 100.5–101.0°C was used.
522, 1294 (NO ), 1340, 1096, 978 (1,3-Ad), 680 (C–
2
1
Br). Н NMR spectrum (CCl ), δ, ppm: 1.48 d (4H,
Н
(
4
HClO of “chemically pure” grade was used for
8,9
Ad
2
5,7
4
), 1.58 s (2H, Н ), 2.05 m (2Н, Н ), 2.19 m
Ad Ad
titration as a 0.1 N solution in MeNO . The
4,6,10
2
6H, НAd ), 2.82 d (2H, CH NH), 4.25 s (1H, NH),
2
measurements were carried out using a potentiometer
pH-150 at 25±0.1°C. The solution was stirred by
bubbling with nitrogen. Electrodes were as follows:
glass electrode ESL-15-11 and silver silver chloride
electrode EVL-1M4.
6
3
3
.39–7.32 m (4Harom). Mass spectrum, m/z (I , %):
64, 366 (38.1, 37.2) [M] , 334, 336 (4.8, 4.7), 318,
20 (3.1, 3.0), 285 (17.6), 215, 213 (1.9, 2.0), 151
rel
+
(
(
100), 135 (15.8), 122 (4.8), 121 (3.9), 107 (14.0), 105
3.6), 93 (15.5), 92 (8.5), 81 (11.0), 79 (4.2), 67 (7.5),
Before the titration the instrument pH-150 was
tuned up using standard buffer solutions prepared from
reagents of “for pH-metrics” grade. The titrant (0.1N
65 (3.3), 56 (3.8), 53 (4.9), 46 (3.8). Found, %: С
56.21; Н 6.00; N 7.78. С17H21BrN O . Calculated, %:
2 2
C 55.90; H 5.79; N 7.67.
HClO4 solution in MeNO ) was added from a
2
4
-{[(3-Bromoadamantan-1-yl)methyl]amino}-
semimicro burette with a calibration step 0.02 mL. In
the titration 10 mL of the solution of compounds under
phenol (16). Yield 90%, colorless crystals, get blue at
prolonged storage in air, mp 128–129°С (PhMe).
Content of the main substance (HPLC) 99.30%. IR
spectrum, ν, cm : 1624 (Аr), 1396 [δ(NH)], 1358 [δ
OH)], 1340, 1100, 990, 762 (Ad), 680 (C–Br). Н
NMR spectrum (CCl ), δ, ppm: 1.50 d (4H, Н ), 1.62
s (2H, Н ), 2.08 m (2Н, Н ), 2.19 m (6H, НAd ),
.70 s (2H, CH NH), 3.28 s (1H, NH), 4.96 s (1H,
OH), 6.23–6.28 m (4Harom). Mass spectrum, m/z (I ,
%): 337, 335 (38.1, 40.0) [M] , 215, 213 (3.1, 3.2), 135
18.1), 122 (100), 107 (18.3), 93 (21.6), 81 (16.8), 79
13.4), 77 (9.6), 67 (3.8), 65 (4.8), 57 (2.6), 55 (1.6),
53 (1.3), 43 (3.3), 41 (1.8). Found, %: С 61.00; Н 6.41;
N 3.98. С H BrNO. Calculated, %: С 60.72; Н 6.59;
N 4.17.
–
3
–1
study was used, с 5·10 mol L . The reading of the
values on the instrument were performed after every
–
1
0
0
.04 mL, and near the equivalence point, after every
.02 mL, 0.5–1 min after the addition of the titrant
1
(
8
,9
4
Ad
portion when a constant potential was established. The
data obtained were drawn on a graph in coordinates pH–
titrant volume (V, mL). The equivalence point was
determined from the titration curve, also were found
2
Ad
5,7
Ad
4,6,10
2
2
rel
+
+
the semineutralization point and pKBH , which was
(
(
averaged from three titrations for each compound. All
results were reduced to the value of the standard
+
[
(PhNH) CNH], pK 17.2 [8].
2
BH
1
7
22
Reductive amination of adamantane-1-carb-
aldehyde, 3-chloro(3-bromo)adamantane-1-carb-
aldehyde, and 3-formyladamantane-1-carbonitrile
by Leuckart–Wallach reaction. General procedure.
A mixture of 0.1 mol of adamantane-1-carbaldehyde,
N-[(3-Bromoadamantan-1-yl)methyl]naphtha-
len-1-amine (19). Yield 91%, colorless crystals, get
blue at prolonged storage in air, mp 145–147°С
(petroleum ether, bp 30–50°С). Content of the main
0
.12 mol of arylamine, and 15 mL (18.4 g, 0.4 mol) of
–
1
anhydrous formic acid was stirred and heated for 20 min
at 60–70°С. After the end of carbon dioxide evolution the
reaction mixture was treated with 40 mL of 6 M water
solution of HCl, the mixture was boiled for 30 min,
cooled to 10–15°С, and filtered. The precipitate of the
obtained amine hydrochloride was stirred with 50 mL
of 5% aqueous NaOH for 15 min at 40–50°С. The free
base was extracted with tert-butyl methyl ether (3 ×
substance (GC-MS) 99.8%. IR spectrum, ν, cm : 3340
(NH), 1656 (Аr), 1340, 1096, 980 (1,3-Ad), 680 (C–
1
Br). Н NMR spectrum (CCl
), δ, ppm: 1.48 d (4H,
4
8
,9
2
5,7
Н
Ad ), 1.58 s (2H, НAd), 2.04 m (2Н, НAd ), 2.18 m
(6H, НAd ), 2.71 s (2H, CH NH), 3.31 s (1H, NH),
4
,6,10
2
6.21–7.08 m (7Harom). Mass spectrum, m/z (Irel, %):
+
371, 369 (28.3, 28.9) [M] , 215, 213 (2.1, 2.2), 156
(100), 135 (14.6), 127 (10.1), 107 (14.6), 101 (4.1), 93
(17.4), 92 (8.3), 81 (9.5), 80 (5.5), 79 (7.4), 67 (8.7),
65 (4.1), 56 (4.3), 53 (4.8), 46 (5.8). Found, %: С
2
00 mL), the organic phase was dried with anhydrous
K CO , filtered, and evaporated on a water bath first at
2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

6
68
NOVAKOV et al.
6
6
7.91; Н 6.44; N 4.00. С H BrN. Calculated, %: С
8.11; Н 6.53; N 3.78.
N-[(3-Chloroadamantan-1-yl)methyl]naphtha-
len-1-amine (29). Yield 90%, colorless crystals, get
blue at prolonged storage in air, mp 123–125°С
2
1
24
N-[(3-Bromoadamantan-1-yl)methyl]naphtha-
(
petroleum ether, bp 30–50°С). Content of the main
len-2-amine (20). Yield 89%, colorless crystals, get
light red at prolonged storage in air, mp 163–165°С
–
1
substance (GC-MS) 99.4%. IR spectrum, ν, cm : 1658
Аr), 1340 (NH), 1340, 1100, 980 (1,3-Ad), 788 (C–
(
(
petroleum ether, bp 30–50°С). Content of the main
1
–
1
Cl). Н NMR spectrum (CCl ), δ, ppm: 1.48 d (4H,
Н
(6H, НAd ), 2.70 s (2H, CH
4
substance (GC-MS) 98.7%. IR spectrum, ν, cm : 1656
Аr), 1340 (NH), 1340, 1100, 980 (1,3-Ad), 680 (C–
8
,9
2
5,7
), 1.56 s (2H, Н ), 2.05 m (2Н, Н ), 2.18 m
Ad Ad
Ad
(
4
,6,10
1
2
NH), 3.30 s (1H, NH),
Br). Н NMR spectrum (CCl ), δ, ppm: 1.48 d (4H,
Н
4
8
,9
2
5,7
6.21–7.09 m (7Harom). Mass spectrum, m/z (Irel, %):
), 1.56 s (2H, Н ), 2.05 m (2Н, Н ), 2.18 m
Ad
Ad Ad
+
4
,6,10
327, 325 (13.3, 41.0) [M] , 290 (12.5), 171, 169 (3.6,
(
6H, Н
), 2.70 s (2H, CH NH), 3.30 s (1H, NH),
2
Ad
1
1.1), 156 (100), 135 (13.4), 127 (14.0), 107 (12.8),
6
3
.25–7.09 m (7Harom). Mass spectrum, m/z (I , %):
rel
+
101 (4.6), 93 (18.9), 92 (8.4), 81 (10.2), 80 (4.8), 79
71, 369 (31.6, 32.3) [M] , 215, 213 (2.8, 2.9), 156
(
(
7.7), 67 (8.2), 65 (4.5), 56 (4.4), 53 (4.9), 46 (6.9), 43
5.0), 41 (2.8), 37 (4.8), 35 (14.7). Found, %: С 77.02;
(
(
100), 135 (18.6), 127 (10.8), 107 (16.2), 101 (4.1), 93
17.0), 92 (9.5), 81 (11.1), 80 (6.9), 79 (7.8), 67 (9.7),
Н 7.50; N 4.54. С H ClN. Calculated, %: С 77.40; Н
21
24
6
6
6
5 (5.6), 56 (4.0), 53 (4.0), 46 (3.9). Found, %: С
7.89; Н 6.80; N 4.11. С H BrN. Calculated, %: С
7
.42; N 4.30.
2
1
24
8.11; Н 6.53; N 3.78.
N-[(3-Chloroadamantan-1-yl)methyl]-3-nitro-
aniline (23). Yield 90%, yellow crystals, mp 114–115°C
N-[(3-Chloroadamantan-1-yl)methyl]naphtha-
len-2-amine (30). Yield 92%, colorless crystals, get
light red at prolonged storage in air, mp 138–140°С
(
petroleum ether, bp 30–50°С). Content of the main
(
EtOH). Content of the main substance (HPLC)
–
1
–
1
substance (GC-MS) 98.9%. IR spectrum, ν, cm : 1658
(
NMR spectrum (CCl ), δ, ppm: 1.48 d (4H, НAd ), 1.56
9
1
9.00%. IR spectrum, ν, cm : 3392 (NH), 1600 (Аr),
1
Аr), 1340 (NH), 1100, 980 (1,3-Ad), 788 (C–Cl). Н
522, 1294 (NO ), 1340, 1098, 980 (1,3-Ad), 788 (C–
2
8,9
1
4
Cl). Н NMR spectrum (CCl ), δ, ppm: 1.48 d (4H,
Н
4
2
5,7
4,6,10
8
,9
2
5,7
s (2H, НAd), 2.05 m (2Н, НAd ), 2.18 m (6H, НAd ),
2.71 s (2H, CH NH), 3.30 s (1H, NH), 6.25–7.09 m
7Harom). Mass spectrum, m/z (I , %): 327, 325 (12.6,
), 1.58 s (2H, Н ), 2.05 m (2Н, Н ), 2.18 m
Ad
Ad Ad
4
,6,10
2
(
6H, Н
), 2.82 d (2H, CH NH), 4.25 s (1H, NH),
2
Ad
(
rel
6
3
1
.39–7.32 m (4Harom). Mass spectrum, m/z (I , %):
rel
+
+
38.6) [M] , 290 (13.8), 171, 169 (4.5, 14.0), 156 (100),
22, 320 (10.5, 32.4) [M] , 292, 290 (1.1, 3.3), 171,
1
9
35 (14.8), 127 (13.2), 107 (14.6), 101 (5.1), 93 (18.8),
2 (9.0), 81 (10.3), 80 (5.3), 79 (7.5), 67 (8.4), 65
69 (2.6, 8.0), 151 (100), 135 (18.2), 122 (12.4), 107
(
(
16.8), 106 (4.8), 93 (28.5), 92 (13.2), 81 (27.7), 79
18.9), 67 (14.1), 57 (8.9), 55 (8.8), 43 (17.1), 41 (6.9),
(
(
5.8), 56 (4.8), 53 (5.5), 46 (7.3), 43 (5.4), 41 (2.8), 37
5.6), 35 (17.2). Found, %: С 77.11; Н 7.20; N 4.54.
3
7 (3.0), 35 (9.1). Found, %: С 64.00; Н 6.32; N 8.80.
С H ClN. Calculated, %: С 77.40; Н 7.42; N 4.30.
2
1
24
С H ClN O . Calculated, %: С 63.64; Н 6.60; N 8.73.
17
21
2
2
3
-(Anilinomethyl)adamantane-1-carbonitrile
4
-{[(3-Chloroadamantan-1-yl)methyl]amino}-
(
(
31). Yield 97%, colorless crystals, mp 97–99°С
petroleum ether, bp 30–50°С). Content of the main
substance (GC-MS) 98.00%. IR spectrum, ν, cm :
3376 (NH), 2236 (C≡N), 1600 (Аr), 1340, 1096, 972,
744 (1,3-Ad). Н NMR spectrum (CCl
phenol (26). Yield 93%, colorless crystals, get blue at
prolonged storage in air, mp 120–122°С (PhMe).
Content of the main substance (HPLC) 98.00%. IR
spectrum, ν, cm : 1624 (Аr), 1398 (NH), 1358 (OH),
340, 1100, 990 (1,3-Ad), 788 (C–Cl). Н NMR
spectrum (CCl ), δ, ppm: 1.50 d (4H, Н ), 1.62 s
2H, Н ), 2.08 m (2Н, Н ), 2.19 m (6H, НAd ),
.70 s (2H, CH NH), 3.28 s (1H, NH), 5.08 s (1H,
2
OH), 6.23–6.28 m (4Harom). Mass spectrum, m/z (I ,
–
1
–
1
1
1
4
), δ, ppm: 1.47
1
8
,9
2
8
,9
d (4H, НAd ), 1.58 m (2H, НAd), 1.75 s (2Н, CН2Ad),
1.88 d (4H, 2СН2Ad), 2.02 m (2Н, 2СНAd), 2.69 s (2H,
4
Ad
2
5,7
4,6,10
(
2
Ad Ad
CH NH), 3.38 s (1H, NH), 6.35–7.03 m (5Harom). Mass
2
+
spectrum, m/z (I , %): 266 (18.1) [M] , 160 (3.6), 135
(1.0), 106 (100), 93 (4.0), 92 (3.5), 81 (5.0), 79 (8.1),
7 (2.0), 65 (2.3), 56 (1.8), 53 (1.6), 43 (2.3), 42 (2.7),
1 (1.4). Found, %: С 80.91; Н 8.50; N 10.31.
rel
rel
+
%
): 293, 291 (12.9, 39.6) [M] , 256 (13.7), 171, 169
6
4
(
(
(
(
3.3, 10.3), 135 (11.4), 122 (100), 107 (16.2), 93
22.4), 81 (17.0), 79 (13.3), 77 (10.8), 67 (3.6), 65
5.7), 57 (4.5), 55 (1.9), 53 (2.0), 43 (4.0), 41 (2.1), 37
4.0), 35 (12.3). Found, %: С 70.30; Н 8.00; N 5.11.
С H N . Calculated, %: С 81.16; Н 8.32; N 10.52.
1
8
22
2
3-{[(4-Nitrophenyl)amino]methyl}adamantane-
С H ClNO. Calculated, %: С 69.97; Н 7.60; N 4.80.
1-carbonitrile (32). Yield 94%, yellow crystals, mp
1
7
22
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

POTENTIAL SYNTHETIC ADAPTOGENS: IV. SYNTHESIS AND STUDY OF BASICITY
669
1
58–160°C (MeOH). Content of the main substance
(O–H), 2240 (C≡N), 1624 (Аr), 1332, 1108, 1080 (1,3-
–
1
1
(
HPLC) 98.00%. IR spectrum, ν, cm : 3388 (NH),
Ad). Н NMR spectrum (CCl ), δ, ppm: 1.48 d (4H,
4
8
,9
2
Ad
2
1
236 (C≡N), 1600 (Аr), 1520, 1292 (NO ), 1340,
Н
), 1.58 m (2H, Н ), 1.75 s (2Н, СН2Ad), 1.88 d
2
Ad
1
096, 972, 744 (1,3-Ad). Н NMR spectrum (CCl ), δ,
(4H, 2СН2Ad), 2.03 m (2Н, 2СН ), 2.66 s (2H,
4
Ad
8
,9
2
Ad
ppm: 1.47 d (4H, Н ), 1.58 m (2H, Н ), 1.75 s (2Н,
CH NH), 3.26 s (1H, NH), 5.01 s (1H, OH), 6.25–6.80
Ad
2
СН2Ad), 1.88 d (4H, 2СН2Ad), 2.02 m (2Н, 2СНAd),
m (4H ). Mass spectrum, m/z (I , %): 282 (32.5)
arom
rel
+
2
7
3
.80, 2.86 s (2H, CH NH), 4.45 s (1H, NH), 6.38, 6.48,
[M] , 160 (3.2), 135 (1.8), 122 (100), 106 (4.3), 93
(5.0), 92 (2.8), 91 (1.9), 81 (5.5), 79 (8.3), 67 (2.5), 65
(2.8), 56 (4.7), 53 (5.1), 43 (3.2), 42 (3.8), 41 (0.7).
Found, %: С 76.40; Н 8.05; N 10.08. С H N O.
2
.90–7.96 m (4H ). Mass spectrum, m/z (I , %):
arom
rel
+
11 (19.3) [M] , 281 (4.6), 265 (1.0), 160 (4.0), 151
(
(
(
100), 135 (1.7), 121 (2.3), 106 (1.3), 93 (5.1), 92
3.6), 81 (5.9), 79 (9.3), 67 (2.3), 65 (1.9), 56 (1.9), 53
1.8), 46 (3.2), 43 (2.7), 42 (2.9), 41 (1.8). Found, %:
1
8
22
2
Calculated, %: С 76.56; Н 7.85; N 9.92.
3
-{[(1-Naphthyl)amino]methyl}adamantane-1-
С 69.57; Н 6.40; N 13.88. С H N O . Calculated, %:
1
8
21
3
2
carbonitrile (39). Yield 92%, colorless crystals, get
blue at prolonged storage in air, mp 149–151°С
С 69.43; Н 6.80; N 13.49.
3
-{[(3-Nitrophenyl)amino]methyl}adamantane-
(CCl ). Content of the main substance (GC-MS)
4
–
1
1
1
(
-carbonitrile (33). Yield 93%, yellow crystals, mp
23–125°C (MeOH). Content of the main substance
HPLC) 98.00%. IR spectrum, ν, cm : 2236 (C≡N),
99.8%. IR spectrum, ν, cm : 3400 (N–H), 2240
1
(C≡N), 1652 (Аr), 980 (1,3-Ad). Н NMR spectrum
–
1
8,9
2
(CCl ), δ, ppm: 1.47 d (4H, Н ), 1.58 m (2H, Н ),
4 Ad Ad
1
9
600 (Аr), 1522, 1294 (NO ), 1392 (NH), 1340, 1096,
1.75 s (2Н, СН2Ad), 1.88 d (4H, 2СН2Ad), 2.02 m (2Н,
2СН ), 2.73 s (2H, CH NH), 3.35 s (1H, NH), 6.21–
2
1
78 (1,3-Ad). Н NMR spectrum (CCl ), δ, ppm: 1.47
4
Ad
2
8
,9
2
Ad
d (4H, Н ), 1.58 m (2H, Н ), 1.75 s (2Н, СН2Ad),
1
CH NH), 4.09 s (1H, NH), 6.64–7.36 m (4Harom). Mass
spectrum, m/z (I , %): 311 (21.4) [M] , 281 (4.3), 265
7.09 m (7H ). Mass spectrum, m/z (I , %): 316
Ad
arom rel
+
.88 d (4H, 2СН2Ad), 2.02 m (2Н, 2СН ), 2.76 d (2H,
(38.5) [M] , 160 (3.2), 156 (100), 135 (3.4), 127 (4.0),
107 (15.6), 101 (5.2), 93 (19.3), 92 (6.5), 81 (10.3), 80
(5.6), 79 (7.3), 67 (5.1), 65 (5.8), 56 (3.8), 53 (4.8), 46
(5.8), 43 (3.0), 41 (3.1). Found, %: С 83.81; Н 8.00; N
8.89. С H N . Calculated, %: С 83.50; Н 7.64; N 8.85.
Ad
2
+
rel
(
(
1.1), 160 (5.6), 151 (100), 135 (2.0), 121 (3.1), 106
1.8), 93 (5.6), 92 (3.0), 81 (5.9), 79 (10.2), 67 (4.3),
22
24
2
6
4
5 (2.8), 56 (1.3), 53 (1.6), 46 (3.3), 43 (3.8), 42 (3.0),
1 (2.6). Found, %: С 69.05; Н 7.12; N 13.15.
3
-{[(2-Naphthyl)amino]methyl}adamantane-1-
carbonitrile (40). Yield 93%, colorless crystals, get
light red at prolonged storage in air, mp 156–158°С
С H N O . Calculated, %: С 69.43; Н 6.80; N 13.49.
1
8
21
3
2
3
-{[(4-Methylphenyl)amino]methyl}adamanta-
(CCl ). Content of the main substance (GC-MS)
4
–
1
ne-1-carbonitrile (37). Yield 95%, colorless crystals,
mp 113–115°С (petroleum ether, bp30–50°С). Content
of the main substance (GC-MS) 99.1%. IR spectrum,
ν, cm : 3376 (NH), 2238 (C≡N), 1600 (Аr), 1340,
096, 972 (1,3-Ad). Н NMR spectrum (CCl ), δ, ppm:
.47 d (4H, НAd ), 1.58 m (2H, Н ), 1.75 s (2Н,
СН2Ad), 1.88 d (4H, 2СН2Ad), 2.02 m (2Н, 2СНAd),
.11 s (3H, СН ), 2.69 s (2H, CH NH), 3.23 s (1H,
NH), 6.25–6.79 m (4Harom). Mass spectrum, m/z (Irel,
): 280 (48.3) [M] , 160 (3.1), 135 (1.6), 120 (100),
99.4%. IR spectrum, ν, cm : 3400 (N–H), 2240
1
(C≡N), 1652 (Аr), 1340, 1096, 980 (1,3-Ad). Н NMR
8
,9
spectrum (CCl ), δ, ppm: 1.47 d (4H, Н ), 1.58 m
4
Ad
–
1
2
(2H, Н ), 1.75 s (2Н, CН2Ad), 1.88 d (4H, 2СН2Ad),
Ad
1
1
1
2.03 m (2Н, 2СН ), 2.73 s (2H, CH NH), 3.26 s (1H,
4
Ad
2
8
,9
2
Ad
NH), 6.25–7.09 m (7Harom). Mass spectrum, m/z (Irel,
+
%): 316 (28.3) [M] , 160 (2.1), 156 (100), 135 (3.2),
2
127 (4.0), 107 (14.8), 101 (5.0), 93 (13.7), 92 (6.8), 81
(8.1), 80 (5.1), 79 (7.4), 67 (5.6), 65 (4.9), 56 (4.0), 53
(3.3), 46 (5.0), 43 (2.1), 41 (2.8). Found, %: С 83.16;
Н 8.01; N 8.85. С H N . Calculated, %: С 83.50; Н
3
2
+
%
1
06 (3.1), 93 (4.0), 92 (2.6), 91 (11.1), 81 (6.4), 79
2
2
24
2
(
(
8.4), 67 (2.0), 65 (2.3), 56 (4.8), 53 (3.1), 43 (2.8), 42
3.1), 41 (1.2). Found, %: С 80.98; Н 9.00; N 10.00.
7.64; N 8.85.
-(R-Anilinomethyl)adamantan-1-ol (41–43, 46)
general procedure). A mixture of 18.0 g (0.1 mol) of
3
С H N . Calculated, %: С 81.38; Н 8.63; N 9.99.
1
9
24
2
(
3
-{[(4-Hydroxyphenyl)amino]methyl}adaman-
3-hydroxyadamantane-1-carbaldehyde, 11.2 g (0.12 mol)
of aniline, and 15 mL (18.4 g, 0.4 mol) of anhydrous
HC(O)OH was stirred at heating at 60°C for 30 min.
After the end of carbon dioxide evolution the reaction
mixture was treated with 50 mL of 20% H SO
tane-1-carbonitrile (36). Yield 89%, colorless
crystals, get blue at prolonged storage in air, mp 150–
52°С (PhMe). Content of the main substance (HPLC)
8.00%. IR spectrum, ν, cm : 3392 (N–H), 3356
1
9
–
1
2
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

6
70
NOVAKOV et al.
solution, stirred at heating at 80°C for 30 min, and
cooled to 20°C. The precipitate of the sulfate of aniline
derivative was filtered off and stirred with 5% aqueous
NaOH. Amine was filtered off, dried, and purified by
recrystallization.
4-{[(Adamantan-1-yl)methyl]amino}anilines (4, 5,
14, 15, 24, 25, 34, 35, 44, 45) (general procedure).
Into a reactor 15 mL (0.833 mol) of water, 10 mL
(0.113 mol) of 35.2% aqueous HCl, 7.5 g (0.033 mol)
of SnCl
·H O was charged, and at stirring was added
2
2
0
.011 mol of N-[(adamantan-1-yl)methyl]nitroaniline.
3
-(Anilinomethyl)adamantan-1-ol (41). Yield
6%, colorless crystals, mp 156–158°С (toluene).
Content of the main substance (HPLC) 98.40%. IR
After charging all the reagents the mixture was heated
at 60°С and stirred for 1 h. The reaction mixture was
cooled to 20°С and 30 mL of 40% water solution of
NaOH was added. The product was extracted with 2-
methyltetrahydrofuran, water was removed by
azeotropic distillation with a Dean-Stark trap, the
solution was filtered and evaporated. Amine was
purified by recrystallization or by distillation under a
reduced pressure.
9
–
1
spectrum, ν, cm : 3380 (N–H), 3332 (O–H), 1604
Аr), 1332, 1096, 976, 748 (1,3-Ad). Mass spectrum,
m/z (I , %): 257 (25.0) [M] , 151 (6.6), 106 (100), 94
16.8), 93 (33.9), 92 (6.3), 81 (7.0), 79 (8.9), 67 (7.3),
5 (6.4), 56 (5.3), 53 (4.1), 45 (7.0), 44 (4.1), 43 (4.6),
(
+
rel
(
6
4
1 (14.7). Found, %: С 78.94; Н 8.89; N 5.50.
С H NO. Calculated, %: С 79.33; Н 9.01; N 5.44.
1
7
23
4
-{[(Adamantan-1-yl)methyl]amino}aniline (4).
3
-{[(4-Nitrophenyl)amino]methyl}adamantan-1-
Yield 83%, colorless crystals, get violet at storage in
air, mp 105–107°С. Content of the main substance
(HPLC) 98.00%. IR spectrum, ν, cm : 3380, 3292
N–H), 1620 (Аr), 1336, 1096, 984 (1-Ad). Н NMR
spectrum (CCl ), δ, ppm: 1.50 d (6Н, H
1.72 m (6Н, H
2H, CH NH), 2.94 m (1H, NH), 6.27 m (4Harom).
Mass spectrum, m/z (I , %): 256 (92.0) [M] , 135
ol (42). Yield 91%, yellow crystals, mp 178–179°C
toluene). Content of the main substance (HPLC)
8.00%. IR spectrum, ν, cm : 3388 (N–H), 3334
O–H), 1600 (Аr), 1520, 1292 (NO ), 1340, 1100, 976,
(
9
(
7
[
(
(
(
9
9
–
1
–
1
1
(
2
2
,8,9
), 1.63–
4
4
Ad
3,5,7
48 (1,3-Ad). Mass spectrum, m/z (I , %): 302 (16.5)
rel
.6,10
+
), 1.84–1.98 m (3H, H ), 2.60 s
M] , 272 (4.8), 256 (0.7), 151 (100), 107 (3.1), 106
4.4), 94 (6.8), 93 (11.3), 92 (3.6), 81 (9.0), 79
7.2), 67 (4.3), 65 (3.1), 56 (3.0), 53 (2.4), 45 (4.8), 44
6.7), 43 (4.0), 41 (3.2). Found, %: С 67.15; Н 6.98; N
(
2
+
rel
(
(
(
1
1
9.2), 121 (100), 107 (12.2), 106 (9.6), 93 (13.8), 92
6.1), 81 (7.4), 79 (9.8), 67 (2.7), 65 (4.3), 56 (3.0), 53
4.0), 42 (8.4), 41 (2.8). Found, %: С 80.00; Н 9.45; N
.25. С H N O . Calculated, %: C 67.53; H 7.33; N
17 22 2 3
.26.
-{[(3-Nitrophenyl)amino]methyl}adamantan-1-
ol (43). Yield 93%, yellow crystals, mp 158–160°C
1.00. С H N . Calculated, %: С 79.64; H 9.44; N
17 24 2
3
0.93.
-{[(Adamantan-1-yl)methyl]amino}aniline (5).
3
(
9
(
7
[
(
6
4
toluene). Content of the main substance (HPLC)
8.10%. IR spectrum, ν, cm : 3396 (N–H), 3332
O–H), 1604 (Аr), 1536, 1280 (NO ), 1338, 1096, 976,
–
1
Yield 80%, colorless crystals, get violet at storage in
air, mp 49–51°С (petroleum ether, bp 30–50°С).
Content of the main substance (HPLC) 98.10%. IR
spectrum, ν, cm : 3380, 3294 (N–H), 1600 (Аr), 1338,
100, 982 (1-Ad). Н NMR spectrum (CCl ), δ, ppm:
.50 d (6Н, H ), 1.62–1.70 m (H
3Н, H ), 2.61 s (2H, CH NH), 2.92 m (1H, NH),
.63–6.79 m (4H ). Mass spectrum, m/z (I , %):
arom rel
56 (88.3) [M] , 135 (11.0), 121 (100), 107 (14.2), 106
2
46 (1,3-Ad). Mass spectrum, m/z (I , %): 302 (14.2)
rel
–
1
+
M] , 272 (3.6), 256 (0.5), 151 (100), 107 (2.8), 106
1
1
1
(
5
2
(
3.9), 94 (6.1), 93 (10.0), 92 (2.1), 81 (8.8), 79 (6.3),
7 (4.0), 65 (2.8), 56 (2.6), 53 (2.1), 45 (3.2), 44 (4.2),
1 (4.1). Found, %: С 67.16; Н 6.98; N 9.25.
4
2
,8,9
4,6,10
), 1.84–1.98 m
3
,5,7
2
С H N O . Calculated, %: C 67.53; H 7.33; N 9.26.
1
7
22
2
3
+
3
-{[(4-Methylphenyl)amino]methyl}adamantan-
-ol (46). Yield 95%, colorless crystals, mp 163–165°С
toluene). Content of the main substance (HPLC)
8.3), 93 (12.4), 92 (7.5), 81 (8.9), 79 (11.7), 67 (2.8),
5 (8.5), 56 (4.7), 53 (4.8), 42 (8.8), 41 (3.5). Found,
: С 80.01; Н 9.05; N 11.00. С H N . Calculated, %:
1
(
9
(
6
%
–
1
17 24 2
8.70%. IR spectrum, ν, cm : 3392 (N–H), 3332
O–H), 1600 (Аr), 1340, 1100, 976, 746 (1,3-Ad).
Mass spectrum, m/z (I , %): 271 (38.0) [M] , 151
5.4), 120 (100), 107 (4.1), 106 (3.8), 94 (13.7), 93
19.9), 92 (7.8), 81 (10.7), 79 (11.0), 67 (6.2), 65 (5.3),
6 (4.1), 53 (4.3), 45 (7.8), 44 (5.2), 43 (6.0), 41 (8.4).
Found, %: С 80.00; Н 9.12; N 5.20. С H NO.
Calculated, %: С 79.66; Н 9.28; N 5.16.
С 79.64; H 9.44; N 10.93.
+
rel
4-{[(3-Bromoadamantan-1-yl)methyl]amino}ani-
line (14). Yield 88%, colorless crystals, get violet at
storage in air, mp 96–98°С (petroleum ether, bp 30–
50°С). Content of the main substance (HPLC) 98.00%.
IR spectrum, ν, cm : 3382, 3294 (N–H), 1620 (Аr),
1388, 1096, 980 (1,3-Ad), 680 (C–Br). Н NMR
(
(
5
–
1
1
8
25
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

POTENTIAL SYNTHETIC ADAPTOGENS: IV. SYNTHESIS AND STUDY OF BASICITY
671
8
,9
spectrum (CCl ), δ, ppm: 1.51 d (4H, Н ), 1.62 s
6.79 m (4Harom). Mass spectrum, m/z (I , %): 292, 290
(12.0, 36.8) [M] , 255 (5.1), 171, 169 (2.7, 8.4), 121
4
Ad
rel
2
5,7
4,6,10
+
(
2H, Н ), 2.09 m (2Н, Н ), 2.18 m (6H, НAd ),
Ad
Ad
2
.70 s (2H, CH NH), 2.98 m (1H, NH), 6.31 m
(100), 107 (19.3), 106 (8.4), 93 (12.2), 92 (5.3), 81
(5.9), 79 (6.4), 67 (2.2), 65 (7.0), 56 (2.8), 53 (5.1), 42
(8.0), 41 (4.6), 37 (2.1), 35 (6.4). Found, %: С 70.00;
Н 8.00; N 9.50. С H ClN . Calculated, %: С 70.21;
2
(
4Harom). Mass spectrum, m/z (I , %): 336, 334 (26.2,
rel
+
2
1
7.2) [M] , 255 (12.7), 215, 213 (3.1, 3.2), 121 (100),
07 (14.2), 106 (8.3), 93 (14.8), 92 (8.1), 81 (13.2), 79
1
7
23
2
(
4
15.6), 67 (3.1), 65 (5.5), 56 (3.2), 53 (4.2), 42 (8.2),
1 (2.6). Found, %: С 61.00; Н 7.05; N 8.50.
С H BrN . Calculated, %: С 60.90; H 6.91; N 8.36.
H 7.97; N 9.63.
-{[(4-Aminophenyl)amino]methyl}adamantane-
-carbonitrile (34). Yield 95%, colorless crystals, get
3
1
7
23
2
1
violet at storage in air, mp 134–136°С (CCl ). Content
3
-{[(3-Bromoadamantan-1-yl)methyl]amino}ani-
4
of the main substance (HPLC) 98.00%. IR spectrum, ν,
line (15). Yield 80%, colorless viscous fluid, gets
violet at storage in air, bp 179–181°С (1 mm Hg), d
.2083, nD 1.5456. Content of the main substance
HPLC) 98.00%. IR spectrum, ν, cm : 3382, 3294
N–H), 1388, 1340, 1100, 980 (1,3-Ad), 680 (C–Br).
Н NMR spectrum (CCl ), δ, ppm: 1.51 d (4H, Н ),
–1
2
4
0
cm : 3392, 3330 (N–H), 2238 (C≡N), 1600 (Аr), 1340,
1
2
0
1
1
096, 972 (1,3-Ad). Н NMR spectrum (CCl ), δ, ppm:
1
(
4
8
,9
2
–
1
.47 d (4H, Н ), 1.58 m (2H, Н ), 1.75 s (2Н,
Ad
Ad
СН2Ad), 1.88 d (4H, 2СН2Ad), 2.02 m (2Н, 2СНAd),
(
1
8,9
Ad
2
6
.69 s (2H, CH NH), 2.96–3.02 m (1H, NH), 6.31–
2
4
2
Ad
5,7
Ad
.81 m (4H ). Mass spectrum, m/z (I , %): 281
1
Н
6
(
(
(
.61 s (2H, Н ), 2.08 m (2Н, Н ), 2.18 m (6H,
arom
rel
+
4
,6,10
Ad
(
(
19.6) [M] , 160 (3.2), 135 (1.0), 121 (100), 107
10.3), 106 (5.1), 93 (10.0), 92 (4.5), 81 (5.8), 76 (6.8),
), 2.69 s (2H, CH NH), 2.94 m (1H, NH), 5.63–
2
.80 m (4Harom). Mass spectrum, m/z (I , %): 336, 334
rel
+
6
7 (1.8), 65 (8.0), 56 (3.0), 53 (5.0), 42 (7.4), 41 (3.8).
28.3, 28.9) [M] , 255 (14.3), 215, 213 (3.0, 3.1), 121
100), 107 (15.8), 106 (7.4), 93 (12.3), 92 (7.6), 81
14.2), 79 (16.8), 67 (3.3), 65 (5.8), 56 (2.7), 53 (3.8),
Found, %: С 77.01; Н 8.04; N 15.05. С H N .
18 23
3
Calculated, %: С 76.83; Н 8.24; N 14.93.
-{[(3-Aminophenyl)amino]methyl}adamantane-
-carbonitrile (35). Yield 93%, colorless crystals, get
4
2 (8.3), 41 (4.0). Found, %: С 60.72; Н 7.15; N 8.35.
3
С H BrN . Calculated, %: С 60.90; H 6.91; N 8.36.
1
7
23
2
1
violet at storage in air, mp 102–104°С (CCl ). Content
4
4
-{[(3-Chloroadamantan-1-yl)methyl]amino}ani-
of the main substance (HPLC) 98.00%. IR spectrum, ν,
line (24). Yield 83%, colorless viscous fluid, gets
violet at storage in air, bp 141–143°С (1 mm Hg), d
.1058, nD 1.5344. Content of the main substance
HPLC) 98.70%. IR spectrum, ν, cm : 3382, 3292
–1
2
4
0
cm : 3392, 3328 (N–H), 2238 (C≡N), 1600 (Аr), 1340,
1
2
0
1096, 974 (1,3-Ad). Н NMR spectrum (CCl ), δ, ppm:
4
1
(
(
8
,9
2
–
1
1.47 d (4H, Н ), 1.58 m (2H, Н ), 1.75 s (2Н, СН2Ad),
Ad Ad
1
.89 d (4H, 2СН2Ad), 2.02 m (2Н, 2СН ), 2.69 s (2H,
Ad
N–H), 1600 (Аr), 1388, 1096, 980 (1,3-Ad), 788 (C–
1
CH NH), 2.94–3.01 m (1H, NH), 5.63–6.79 m (4Harom).
2
Cl). Н NMR spectrum (CCl ), δ, ppm: 1.51 d (4H,
4
+
8
,9
Ad
2
5,7
Mass spectrum, m/z (I , %): 281 (21.7) [M] , 160 (3.8),
rel
Н
(
6
(
(
(
(
), 1.62 s (2H, Н ), 2.09 m (2Н, Н ), 2.18 m
Ad Ad
4
,6,10
135 (1.2), 121 (100), 107 (11.6), 106 (5.7), 93 (9.8), 92
6H, Н
), 2.70 s (2H, CH NH), 2.98 m (1H, NH),
2
Ad
(3.1), 81 (7.4), 76 (5.0), 67 (0.7), 65 (11.3), 56 (1.2), 53
.31 m (4Harom). Mass spectrum, m/z (I , %): 292, 290
rel
+
(4.7), 42 (5.9), 41 (2.2). Found, %: С 77.00; Н 8.44; N
10.8, 33.3) [M] , 255 (4.6), 171, 169 (3.0, 9.3), 121
100), 107 (18.9), 106 (9.5), 93 (13.4), 92 (6.8), 81
6.9), 79 (8.3), 67 (3.8), 65 (7.7), 56 (3.9), 53 (4.8), 42
9.1), 41 (5.3), 37 (3.3), 35 (10.2). Found, %: С 70.20;
Н 8.20; N 10.00. С H ClN . Calculated, %: С 70.21;
H 7.97; N 9.63.
1
4.95. С H N . Calculated, %: С 76.83; Н 8.24; N 14.93.
18
23
3
3
-{[(4-Aminophenyl)amino]methyl}adamantan-
1
-ol (44). Yield 91%, colorless crystals, get violet at
1
7
23
2
storage in air, mp 161–163°С (toluene). Content of the
–
1
main substance (HPLC) 97.80%. IR spectrum, ν, cm :
394–3326 (N–H, O–H), 1600 (Аr), 1340, 1100, 976
3
3
-{[(3-Chloroadamantan-1-yl)methyl]amino}ani-
+
(1,3-Ad). Mass spectrum, m/z (I , %): 272 (36.1) [M] ,
rel
line (25). Yield 81%, colorless viscous fluid, gets
violet at storage in air, bp 139–141°С (1 mm Hg), d
.1056, nD 1.5340. Content of the main substance
HPLC) 99.00%. IR spectrum, ν, cm : 3384, 3294 (N–
H), 1600 (Аr), 1388, 1100, 982 (1,3-Ad), 788 (C–Cl).
Н NMR spectrum (CCl ), δ, ppm: 1.51 d (4H, Н ),
2
4
0
151 (5.6), 121 (100), 107 (6.7), 106 (5.6), 94 (14.0), 93
(20.5), 92 (8.1), 81 (9.2), 79 (10.0), 67 (5.4), 65 (3.8),
56 (4.1), 53 (3.3), 45 (8.2), 44 (6.3), 43 (5.1), 41 (9.4).
Found, %: С 75.21; Н 9.10; N 10.30. С H N O.
2
0
1
(
–
1
1
7
24
2
1
8,9
Ad
Calculated, %: С 74.96; Н 8.88; N 10.28.
4
2
Ad
5,7
Ad
1
Н
.62 s (2H, Н ), 2.09 m (2Н, Н ), 2.18 m (6H,
3-{[(3-Aminophenyl)amino]methyl}adamantan-
1-ol (45). Yield 90%, colorless crystals, get violet at
4
,6,10
A d
), 2.69 s (2H, CH NH), 2.94 m (1H, NH), 5.63–
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

6
72
NOVAKOV et al.
storage in air, mp 132–134°С (toluene). Content of the
Voloboev, S.N., Pharm. Chem. J., 2017, vol. 50, p. 781.
doi 10.1007/s11094-017-1531-5
–
1
main substance (HPLC) 98.00%. IR spectrum, ν, cm :
394–3328 (N–H, O–H), 1596 (Аr), 1338, 1096, 976
3
5. Voloboev, S.N., Butenko, L.N., and Novakov, I.A., RF
+
(1,3-Ad). Mass spectrum, m/z (I , %): 272 (28.4) [M] ,
Patent no. 2163591, 1991, Byull. Izobret., 2001, no. 6.
rel
1
(
5
51 (4.2), 121 (100), 107 (4.6), 106 (4.8), 94 (15.1), 93
18.7), 92 (7.0), 81 (8.4), 79 (9.1), 67 (4.6), 65 (3.6),
6 (5.1), 53 (5.8), 45 (7.7), 44 (8.3), 43 (6.0), 41 (2.3).
Found, %: С 75.08; Н 9.00; N 10.41. С H N O.
6
. Voloboev, S.N., Butenko, L.N., and Novakov, I.A.,
Russ. J. Gen. Chem., 2001, vol. 71, p. 1121. doi
10.1023/A:1013178326353
1
8
24
2
7. Novakov, I.A., Val’dman, A.I., Orlinson, B.S.,
Val’dman, D.I., Panfilov, B.I., and Radchenko, S.S.,
Vysokomol. Soed. B, 1986, vol. 28, p. 497.
Calculated, %: С 74.96; Н 8.88; N 10.28.
The study was carried out under a financial support of
the Russian Science Foundation (grant no. 16-13-00100
8
. Korolev, B.A. and Stepanov, B.I., Izv. Vuzov, Ser.
Khim. Khim. Tekhnol., 1998, vol. 11, p. 1193.
“Structural analogs of bromantane and chlodantane with
modified conformational lability, potential adaptogens:
synthesis and biological activity”) with the use of
equipment of the Center of joint usage of FKMI
FGBOU VO Volg GTU and engineering center on the
basis of FGBOU VO Volg GTU.
9. http://www.chemicalize.org.
1
1
1
0. Korolev, B.A., Khardin, A.P., Radchenko, S.S.,
Novakov, I.A., and Orlinson, B.S., Zh. Org. Khim.,
1978, vol. 14, p. 1632.
1. Cherkasov, A.R., Galkin, V.I., and Cherkasov, R.A.,
Russ. Chem. Rev., 1996, vol. 65, p. 641. doi 10.1070/
RC1996v065n08ABEH000227
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017