Comparative evaluation of antioxidant activity of 2-alkyl-4-methylphenols and their 6-n-octylaminomethyl derivatives

Article abstract of DOI:10.1007/s11172-019-2508-1

A series of 2-alkyl-4-methyl-6-n-octylaminomethylphenols (where alkyl is methyl or tert-butyl group, or terpene substituent) was synthesized. A comparative evaluation of the antioxidant properties of the starting alkyl- and terpenylphenols and their Mannich bases was carried out using in vitro assays. Structural features providing high antioxidant activity of these compounds were revealed.

Full text of DOI:10.1007/s11172-019-2508-1

Russian Chemical Bulletin, International Edition, Vol. 68, No. 5, pp. 985—992, May, 2019
985
Full Articles
Comparative evaluation of antioxidant activity of 2-alkyl-4-methylphenols
and their 6-n-octylaminomethyl derivatives*
E. V. Buravlev,a I. V. Fedorova,a and O. G. Shevchenkob
aInstitute of Chemistry, Komi Scientific Center, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167000 Syktyvkar, Russian Federation.
Fax: +7 (8212) 21 9916. E-mail: eugeneburavlev@gmail.com
bInstitute of Biology, Komi Scientific Center, Ural Branch of the Russian Academy of Sciences,
28 ul. Kommunisticheskaya, 167982 Syktyvkar, Russian Federation.
Fax: +7 (8212) 24 0163
A series of 2-alkyl-4-methyl-6-n-octylaminomethylphenols (where alkyl is methyl or
tert-butyl group, or terpene substituent) was synthesized. A comparative evaluation of the an-
tioxidant properties of the starting alkyl- and terpenylphenols and their Mannich bases was
carried out using in vitro assays. Structural features providing high antioxidant activity of these
compounds were revealed.
Key words: Schiff bases, Mannich bases, chelation ability, antioxidant activity, membrane-
protective activity, red blood cells, oxidative hemolysis.
Natural and synthetic antioxidants (AOs) are widely
used in modern medicine, but the mechanism of action
of these compounds in living cells is not so unambiguous
as it was considered fifty years ago and cannot be explained
by radical scavenging only. The most abundant class of
AOs is presented by phenol compounds, and the derivatives
with the screened hydroxy group (sterically hindered
phenols) are often used among the synthetic representa-
tives of the phenol compounds.1 In addition to traditional
alkylphenols, terpenylphenols can serve as the starting
compounds for the synthesis of new AOs. They represent
a special class of natural and semisynthetic compounds,
whose structures contain fragments with the hydrophilic
(phenol moiety) and lipophilic (isoprene moiety) proper-
ties.2 The use of these compounds can be substantiated by
a broad range of biological activity exhibited by terpenyl-
phenols with the isobornyl substituent.3—7 It should be
mentioned that the activity of 2,6-diisobornyl-4-methyl-
phenol in various model systems exceeds8—10 that of the
known phenol antioxidant 2,6-di-tert-butyl-4-methyl-
phenol (BHT).1
A convenient method for the modification of phenol
compounds is the introduction of the aminomethyl group,
which is often applied in the design of drugs and in me-
dicinal chemistry.11 This structural fragment can be formed
* Dedicated to Corresponding Member of the Russian Academy
of Sciences A. V. Kutchin on the occasion of his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0985—0992, May, 2019.
1066-5285/19/6805-0985 © 2019 Springer Science+Business Media, Inc.

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Buravlev et al.
Scheme 1*
R = Me (1, 7, 13, 19); But (2, 8, 14, 20);
(6, 12, 18, 24)
(3, 9, 15, 21);
(4, 10, 16, 22);
(5, 11 , 17, 23);
Reagents and conditions: i. HCOH, SnCl4, Bun N, toluene, reflux, 10 h16; ii. C8H17NH2, benzene, molecular sieves 4 Å, reflux, 3.5 h;
3
iii. NaBH4, EtOH, reflux, 30 min.
* The presented numbering of C atoms is used for convenience of interpretation of the NMR spectra, the numberings of the C atoms
of the bornyl and isobornyl structures coincide. Compounds 4 and 6 and their derivatives 10, 12, 16, 18, 22, and 24 are racemates for
which the structures of one of enantiomers are shown in Scheme 1.
using diverse synthetic approaches: via the Mannich reac-
tion,12 by the reduction of Schiff bases,13 the reaction of
the bromomethyl derivatives with amines,14 etc. We have
recently reported that among the N- and O-containing
derivatives of isobornylphenols the Mannich base with the
secondary amino group has a pronounced antioxidant
activity (AOA) on in vitro models.15 For detailed analysis
of the influence of the structures of the alkyl and terpene
substituents in the ortho-position to the hydroxy group on
the AOA, the range of the aminomethyl derivatives should
be extended by new analogs based on accessible alkyl- and
terpenylphenols and their antioxidant activity should be
evaluated by different method, which is the purpose of the
present study.
from aldehydes by the condensation with n-octylamine.
The reduction of imines afforded Mannich bases 19—24.
The synthesis of the target compounds is shown in
Scheme 1.
The data of 1H and 13C NMR spectroscopy, IR spectro-
scopy, and elemental analysis for new products 9, 13—18,
20, and 21 correspond to the expected structures, and the
characteristics of the other compounds are consistent with
published values.13,17—22 Imines 13—18 have the E-con-
figuration of the substituents relative to the C=N bond:
the NOESY experiments for these compounds show
cross-peaks between the proton of the N=CH group
(H 8.26—8.28) and protons of the NCH2 group
(H 3.40—3.71), as well as with the H(6´) proton
(H 6.86—6.90), indicating their spatial proximity.
The following parameters were estimated for the start-
ing alkyl- and terpenylphenols 1—6 and synthesized
Mannich bases 19—24: radical scavenging activity (RSA)
in test with 2,2-diphenyl-1-picrylhydrazyl (DPPH), AOA
on the substrate obtained from the brain of laboratory
mice, Fe2+-chelation ability (CA) in test with FerroZine™
Iron Reagent, hemolytic activity (cytotoxicity), and anti-
oxidant and membrane-protective (MP) properties using
erythrocytes of the laboratory mice blood. These model
systems were applied by us earlier when studying iso-
bornylphenols,14,15,21—27 xanthones,28,29 flavonoids,30
and sulfur-containing compounds.27,31 The reference
compound was BHT. The earlier synthesized analog of
compound 22, i.e., racemic 2-n-hexylaminomethyl-6-
isobornyl-4-methylphenol (25), was also used in a series
of experiments.15,22
Results and Discussion
Two commercially available compounds served as the
starting compounds: 2,4-dimethylphenol (1) and 2-tert-
butyl-4-methylphenol (2). In addition, 4-methyl-2-pre-
nylphenol (3) synthesized by the alkylation of 4-methyl-
phenol with prenol in the presence of montmorillonite
KSF clay** was used. Previously described 4-methylphe-
nols 4—6 with various structures of the bicyclic terpene
substituent, i.e. isobornyl, bornyl, and isocamphyl fragments,
were also used in the synthesis. Salicylaldehydes 7—12
were obtained from compounds 1—6 using a known
procedure,16 and Schiff bases 13—18 were synthesized
** This alkylation reaction will be considered in detail elsewhere.

2-Alkyl-4-methylphenol derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 5, May, 2019
987
Table 1. Comparative estimation of the RSA (test with DPPH), CA (test with FerroZine™ Iron Reagent), and AOA (test
on the substrate from the brain of laboratory animals)* for derivatives 1—6, 19—25, and ВНТ
Compound
RSA (% inhibition)
CA (%)
с = 100
TBA-RS/nmol mL–1
с = 100
с = 10
с = 100
с = 10
mol L–1
mol L–1
mol L–1
mol L–1
mol L–1
BHT
1
2
3
4
5
6
19
20
21
22
23
24
25
.—
11.3 1.1
12.5 0.5
4.7 0.5
11.4 0.6
12.6 0.7
10.8 0.9
16.3 1.0
8.6 0.6
15.3 0.9
11.1 0.6
16.1 1.1
16.8 1.1
12.3 0.9
16.0 1.1
3.00.3
6.01.7
7.01.5
3.70.2
18.80.5
3.90.2
3.00.1
4.71.3
4.70.1
3.20.1
4.00.2
6.60.1
4.00.2
5.00.1
4.70.1
5.50.1
5.00.1
5.90.7
59.50.5
31.30.1
34.80.4
4.80.1
11.80.3
44.40.4
58.60.2
59.10.1
50.40.6
49.00.6
48.70.4
58.30.6
49.20.5
46.5 0.7
27.9 1.2
47.8 0.9
56.9 1.1
46.4 0.8
62.1 1.4
42.9 1.3
59.4 0.9
47.9 1.8
62.2 1.7
64.2 1.6
56.5 1.4
64.1 0.8
6.01.0
5.91.8
8.01.3
3.00.8
79.60.5
42.41.1
74.50.6
57.41.3
73.50.9
66.81.4
56.51.3
* The ability of the studied compounds to inhibit the accumulation of products of lipid peroxidation (LPO) reacting with
2-thiobarbituric acid (TBA-reactive substances, TBA-RS) was estimated in the substrate obtained from the mice brain
(1 h after the Fe2+/ascorbate initiation of LPO). The concentration of TBA-RS in the control (without compounds) and
in intact (without initiated oxidation) samples was 85.03.1 and 41.32.6 nmol mL–1, respectively.
The results of studies on the non-cellular model sys-
tems (Table 1) allow us to conclude that at the concentra-
tions 100 and 10 mol L–1 the starting 4-methylphenols
1—6 and corresponding Mannich bases 19—25 are char-
acterized by the RSA, which is comparable with that of
BHT at the concentration of the compounds equal to
10 mol L–1. Much more substantial differences in activ-
ity between 4-methylphenols 1—6 and their derivatives
19—25 were revealed when the CA was estimated: the
introduction of the aminomethyl group enhances the effect
by 6.0—22.6 times. The high CA of phenols containing
the aminomethyl fragment in the ortho-position is also
known.12
The results of studying the AOA of the derivatives on
the model containing an emulsion of animal lipids showed
that at a concentration of 100 mol L–1 all synthesized
compounds, except for 2,4-dimethylphenol (1), can inhibit
the Fe2+/ascorbate-initiated accumulation of the second-
ary lipid peroxidation (LPO) products to the level sub-
stantially lower than the spontaneous one and are not
inferior to BHT in activity. Only 2-isobornyl-4-methyl-
phenol (4) retained high activity in this test system when
the concentration of the compounds was decreased by an
order of magnitude (down to 10 mol L–1). The exclusively
high AOA of this compound and its nearest analog,
2,4-dimethyl-6-isobornylphenol, was demonstrated ear-
lier.15 Note that the introduction of the aminomethyl group
into the ortho-position of 4-methylphenols 1—6 did not
provide the enhancement of the AOA of the products in
the considered test system. On the contrary, in the most
part of experiments, Mannich bases 19—24 inhibited the
Fe2+/ascorbate-initiated LPO substantially more weakly
than the corresponding 4-methylphenols 1—6 (see Table 1).
A similar dependence was observed for the initiation of
LPO by H2O2 (the data in Table 1 are omitted). It is known
that the introduction of the aminomethyl group with the
secondary amine fragment increases the polarity of the
compounds and, possibly, the effect observed is caused
by the so-called antioxidant polar paradox, according to
which in lipid emulsions the nonpolar AOs are more active
than the polar AOs.32,33
No relation between the RSA of the ВНТ derivatives
of various structures (test with DPPH) and their ability to
inhibit the Fe2+-initiated LPO in the heterogeneous me-
dium (evaluation of the accumulation of the 2-thiobarbi-
turic acid reactive substances (TBA-RS) in an emulsion
based on vitellus) was observed previously.34 This confirms
that various methods should be applied to study the AO
properties of compounds.35,36
The estimation of the hemolytic activity showed that
the studied compounds had no substantial cytotoxicity
against erythrocytes, and an insignificant hemolytic activ-
ity that did not exceed 9% was revealed only for some
products in a concentration of 10 mol L–1
.
An analysis of the MP properties and AOA studied
using erythrocytes of laboratory mice (Tables 2 and 3)
showed that the presence at the ortho-position of the
phenol fragment of the bicyclic terpene substituents and
its steric structure exerted a substantial effect on the abil-
ity of compounds to protect living cells from the toxic

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 5, May, 2019
Buravlev et al.
Table 2. Comparative estimation of the MPA and АОА for de-
rivatives 1—6 and 19—24 at concentration of 1 mol L–1 using
erythrocytes of laboratory mice
from decay and prevented the accumulation of the second-
ary LPO products, oxidation of native hemoglobin, and
oxidative degradation of the heme. These derivatives sub-
stantially exceeded the BHT reference by the majority of
parameters.
Compound
MPA (% hemolysis)
1 h 3 h 5 h
TBA-RS
/nmol mL–1
Thus, we pioneered in the comparative evaluation of
the antioxidant properties of 2-alkyl-4-methylphenols and
their 6-n-alkylaminomethyl derivatives. It is shown that
the studied compounds are characterized by high anti-
oxidant activity in diverse model systems. It is revealed
that the chelation ability of the compounds is mainly
determined by the presence of the aminomethyl substitu-
ent in the molecule, whereas the antioxidant and mem-
brane-protective activities in the cellular model system
depend substantially also on the structure of the alkyl/
terpene fragment. According to all parameters character-
izing the compounds as inhibitors of oxidation processes,
the most active are substituted 4-methylphenols 22—25,
whose structures contain the bicyclic terpene fragment
and n-alkylaminomethyl substituent, and the length of the
alkyl group at the nitrogen atom (C6H13 and C8H17 for
derivatives 25 and 22, respectively) exerts an insignificant
effect on the antioxidant properties in the considered test
systems. Thus, the high antioxidant activity of the Mannich
bases with n-alkyl fragments 22—25 in the cellular model
system can be due to the presence of several functional
groups in the molecule: the phenol hydroxy group provid-
ing radical scavenging activity, the secondary amino group
in the ortho-position providing high chelation ability, and
finally, two lipophilic fragments (terpene and n-octyl-
aminomethyl) favoring, most likely, the optimum interac-
tion of these compounds with the biomembrane.
Control
17.3 0.4 43.2 0.8 50.2 0.9
9.7 0.4 35.8 1.1 45.7 1.2
9.3 0.9 26.7 0.8 37.0 0.9
12.1 1.6 36.8 0.4 45.1 0.5
2.9 0.3 12.9 0.3 20.6 0.5
3.3 0.2 18.5 1.3 31.7 1.4
3.9 0.5 15.5 1.7 26.1 0.6
8.4 1.0 26.4 0.8 39.5 0.6
6.0 1.4 21.0 0.7 36.3 0.2
2.13 0.03
2.21 0.13
1.25 0.07
1.72 0.19
0.98 0.03
0.99 0.02
0.94 0.05
0.86 0.03
0.82 0.03
0.67 0.03
0.64 0.01
0.60 0.02
0.59 0.02
1
2
3
4
5
6
19
20
21
22
23
24
1.9 0.1
1.9 0.1
2.0 0.1
1.8 0.0
5.5 0.3 12.9 0.7
4.8 0.1 9.5 0.5
5.3 0.2 11.3 0.5
5.1 0.1 10.4 0.2
action of Н2О2. At a concentration of 1 mol L–1 (see
Table 2), compound 4 with the isobornyl fragment exhib-
ited the maximum activity among the starting 4-methyl-
phenols 1—6. Note that in this model system biological
activity of the derivatives also depends on the presence of
the n-alkylaminomethyl substituent in the molecule: the
ability to prevent the oxidative hemolysis of erythrocytes
and accumulation of the secondary LPO products are
substantially higher for Mannich bases 19—24 than those
for their precursors 1—6, which is likely caused by a high
CA of the latter (cf. data in Tables 1 and 2).
On the whole, the high MP and AO activities of the
studied compounds in the cellular model system are pro-
vided by a combination of the terpene fragment and
aminomethyl group, which follows from an analysis
of the data of the experiment performed at the concen-
tration of the compounds equal to 0.1 mol L–1 (see
Table 3). It was found that even at such a low concentra-
tion derivatives 22—25 efficiently protected erythrocytes
Experimental
The course of the reactions was monitored by TLC on the
Sorbfil plates (LLC IMID). The reaction products were detected
by the treatment of the plates with a KMnO4 solution (15 g of
KMnO4, 300 mL of H2O, and 0.5 mL of concentrated H2SO4).
Table 3. Comparative estimation of the MPA and АОА for derivatives 21—25 and ВНТ at a concentration of 0.1 mol L–1 using
erythrocytes of laboratory mice
Compound
MPA (% hemolysis)
3 h
TBA-RS /
metHb
/oxyHb*
Ifl
nmol mL–1
/arb. units**
1 h
5 h
Control
BHT
21
22
23
24
25
14.9 0.3
7.4 0.6
7.1 0.6
3.2 0.5
2.9 0.4
2.9 0.3
3.0 0.4
33.9 0.4
23.3 0.1
26.0 0.3
5.9 0.8
5.7 0.2
5.3 0.2
6.0 0.2
41.9 0.4
31.1 0.2
36.7 0.3
9.3 0.2
9.0 0.4
8.9 0.2
11.4 0.2
1.57 0.04
1.15 0.03
1.08 0.03
0.78 0.04
0.65 0.03
0.71 0.02
0.69 0.01
1.156 0.051
0.935 0.039
1.163 0.049
0.682 0.037
0.560 0.026
0.707 0.048
0.811 0.021
10.11 0.42
7.67 0.81
8.43 0.60
8.21 0.49
7.25 0.07
7.41 0.36
8.24 0.33
* metHb is methemoglobin, and oxyHb is oxyhemoglobin.
** The fluorescence intensity (Ifl) in the intact sample was 5.42 0.19 arb. units.

2-Alkyl-4-methylphenol derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 5, May, 2019
989
The 1Н and 13С NMR spectra of the obtained compounds were
recorded on a Bruker Avance II 300 spectrometer (300.17 (1H)
and 75.5 (13C) MHz) at room temperature. Signal assignment
was performed using the 13С NMR spectra recorded on the
J-modulation mode and the HSQC, HMBC, and NOESY
experiments. Diffuse reflectance IR spectra were recorded
on a Shimadzu IR Prestige 21 FT-IR spectrometer in KBr pel-
lets for solid compounds and neat for liquid compounds.
Melting points were determined on a Sanyo Gallenkamp MPD
350 instrument and were not corrected. The following reagents
were used without additional purification: montmorillonite KSF,
4-methylphenol, 2,4-dimethylphenol (1), prenol, n-octylamine,
2-tert-butyl-4-methylphenol (2), BHT, DPPH (Alfa Aesar), and
FerroZine™ Iron Reagent (sodium 5,6-diphenyl-3-(2-pyridyl)-
1,2,4-triazine-4´,4´´-disulfonic acid hydrate) (Sigma-Aldrich).
2-Isobornyl-4-methylphenol (4),20 2-isocamphyl-4-methylphe-
nol (6),37 and an enantioenriched sample of (+)-2-bornyl-4-
methylphenol (5) ([]D25 +29.1 (c 0.3, CHCl3); according to the
chiral HPLC data, ee >99%) were used in the syntheses.
H(6´)); 7.20 (s, 1 H, H(4´)); 9.83 (s, 1 Н, CH=O); 11.11 (s, 1 Н,
OH). 13C NMR (CDCl3), : 17.77 (C(5)); 20.32 (C(5´)CH3);
25.77 (C(4)); 27.29 (C(1)); 119.94 (C(1´)); 121.50 (C(2)); 128.67
(C(5´)); 130.08 (C(3´)); 131.04 (C(6´)); 133.34 (C(3)); 137.81
(C(4´)); 157.52 (C(2´)); 196.67 (CH=O).
2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-
exo-2-yl)benzaldehyde (10). Yellow powder, m.p. 100—101 С.
The yield was 68%. The spectral characteristics of the compound
correspond to those published earlier.20
2-Hydroxy-5-methyl-3-{(1R,2R,4S)-1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-yl}benzaldehyde (11). The yield was 40%.
22
Colorless powder, m.p. 121—123 C (methanol). []D +99.0
(с 0.31, CHCl3). The spectral characteristics of the compound
correspond to those published earlier.13
2-Hydroxy-5-methyl-3-(2,2,3-trimethylbicyclo[2.2.1]hept-
exo-5-yl)benzaldehyde (12). Light yellow oil. The yield was 71%.
The spectral characteristics of the compound correspond to those
published earlier.20
Synthesis of imines 13—18 (general procedure). Molecular
sieves 4 Å (four weights of aldehyde) and n-octylamine (0.25 mL,
1.5 mmol) were added to a solution of aldehyde 7—12 (1.5 mmol)
in anhydrous benzene (6 mL). The reaction mixture was refluxed
for 3.5 h under argon. After the completion of the reaction,
molecular sieves were filtered off and washed with CHCl3, and
the solvents were removed under reduced pressure.
(E)-2,4-Dimethyl-6-n-octyliminomethylphenol (13). Yellow-
brown oil. The yield was 0.376 g (96%). Found (%): C, 78.01;
H, 10.50; N, 5.51. C17H27NO. Calculated (%): C, 78.11; H, 10.41;
N, 5.36. IR (neat), /cm–1: 3453 (OH); 2926, 2855, 1474 (CH3,
CH2); 1634 (C=N); 1271 (C—O); 856, 781 (=С—Н).
1Н NMR (CDCl3), : 0.89 (t, 3 H, NCH2(CH2)6CH3, J = 6.1 Hz);
1.16—1.48 (m, 10 H, N(CH2)2(CH2)5CH3); 1.62—1.76 (m, 2 Н,
NCH2CH2(CH2)5CH3); 2.26 (s, 6 H, C(3´)CH3, C(5´)CH3);
3.57 (t, 2 Н, NCH2(CH2)6CH3, J = 6.7 Hz); 6.88 (s, 1 Н, C(6´)H);
7.00 (s, 1 Н, C(4´)H); 8.27 (s, 1 H, CH=N); 13.69 (s, 1 H, OH).
13C NMR (CDCl3), : 14.07 (NCH2(CH2)6CH3); 15.41
(C(3´)CH3); 20.31 (C(5´)CH3); 22.64, 27.19, 29.21, 29.33, 30.92,
31.83 (NCH2(CH2)6CH3); 59.51 (NCH2(CH2)6CH3); 117.69
(С(1´)); 125.62,126.81 (C(3´), C(5´)); 128.64 (C(6´)); 133.99
(C(4´)); 157.39 (C(2´)); 164.53 (CH=N).
1
According to the data of GLC and H NMR spectroscopy, the
purity of the compounds was >97%. Molecular sieves 4 Å were
calcined for 3 h at 140 С. Silica gel 0.06—0.2 mm (Alfa Aesar)
was used for column chromatography.
Analyses of the synthesized compounds were partially carried
out using the equipment of the Center for Collective Use
"Chemistry" of the Institute of Chemistry (Komi Scientific Center,
Ural Branch of the Russian Academy of Sciences). The activities
of the compounds were studied using the equipment of the Center
for Collective Use "Molecular Biology" of the Institute of Biology
(Komi Scientific Center, Ural Branch of the Russian Academy
of Sciences). Animals of the scientific collection of experimental
animals of the Institute of Biology (Komi Scientific Center, Ural
Branch of the Russian Academy of Sciences) were used (http://
www.ckp-rf.ru/usu/471933/).
4-Methyl-2-(3-methylbut-2-en-1-yl)phenol (3). Prenol
(0.94 mL, 9.25 mmol) and montmorillonite KSF (0.5 g) were
added to a solution of 4-methylphenol (0.5 g, 4.6 mmol) in
CH2Cl2 (5 mL). The reaction mixture was stirred at 40 С for
2 h. After the completion of the reaction, the clay was filtered off
and washed with CH2Cl2, the solvent was removed under reduced
pressure, and the product was isolated by column chromatogra-
phy using a petroleum ether—Et2O (5 : 1  3 : 1) system as an
eluent. Light yellow oil. The yield was 0.51 g (62%). The spectral
characteristics of compound 3 correspond to those published
earlier.17
(E)-2-tert-Butyl-4-methyl-6-n-octyliminomethylphenol (14).
Yellow-brown oil. The yield was 0.437 g (96%). Found (%):
C, 79.08; H, 11.11; N, 4.73. C20H33NO. Calculated (%): C, 79.15;
H, 10.96; N, 4.62. IR (neat), /cm–1: 3254 (OH); 2955,
2926, 2857, 1462 (CH3, CH2); 1634 (C=N); 1267 (C—O); 860,
781 (=С—Н). 1Н NMR (CDCl3), : 0.89 (t, 3 H, NCH2-
(CH2)6CH3, J = 6.1 Hz); 1.19—1.49 (m, 10 H, N(CH2)2-
(CH2)5CH3); 1.44 (s, 9 Н, C(CH3)3); 1.61—1.79 (m, 2 Н,
NCH2CH2(CH2)5CH3); 2.29 (s, 3 H, C(5´)CH3); 3.56 (t, 2 Н,
NCH2(CH2)6CH3, J = 6.9 Hz); 6.90 (s, 1 Н, C(6´)H); 7.12
(s, 1 Н, C(4´)H); 8.28 (s, 1 H, CH=N); 13.97 (s, 1 H, OH).
13C NMR (CDCl3), : 14.09 (NCH2(CH2)6CH3); 20.66
(C(5´)CH3); 22.65, 27.21, 29.21, 29.32, 30.91, 31.84 (NCH2-
(CH2)6CH3); 29.39 (C(CH3)3); 34.72 (C(CH3)3); 59.62 (NCH2-
(CH2)6CH3); 118.40 (С(1´)); 126.29 (C(5´)); 129.29 (C(6´));
130.15 (C(4´)); 137.12 (C(3´)); 158.31 (C(2´)); 165.08 (CH=N).
(E)-4-Methyl-2-(3-methylbut-2-en-1-yl)-6-n-octylimino-
methylphenol (15). Yellow-brown oil. The yield was 0.463 g (98%).
Found (%): C, 80.08; H, 10.31; N, 4.50. C21H33NO. Calculat-
Aldehydes 7—12 were synthesized from cresols 1—6 using
a known procedure.16
2-Hydroxy-3,5-dimethylbenzaldehyde (7). Yellow oil. The
yield was 49%. The spectral characteristics of compound 7 cor-
respond to those published earlier.18
3-tert-Butyl-2-hydroxy-5-methylbenzaldehyde (8). Yellow
powder, m.p. 73—74 С. The yield was 42%. The spectral char-
acteristics of compound 8 correspond to those published earlier.19
2-Hydroxy-5-methyl-3-(3-methylbut-2-en-1-yl)benzaldehyde
(9). Yellow oil. The yield was 55%. Found (%): C, 76.58; H, 7.78.
C13H16O2. Calculated (%): C, 76.44; H, 7.90. IR (neat),
/cm–1: 3264, 3142 (OH); 2970, 2918, 2855, 1458 (CH3, CH2);
1651 (C=O); 1261 (C—O); 1213 (C(CH3)2); 864, 793 (=С—Н).
1Н NMR (CDCl3), : 1.73 (s, 3 H, C(5)H3); 1.76 (s, 3 H,
C(4)H3); 2.31 (s, 3 H, C(5´)CH3); 3.34 (d, 2 H, C(1)H,
J = 7.3 Hz); 5.30 (br.t, 1 H, C(2)H, J ≈ 7.2 Hz); 7.18 (s, 1 H,
ed (%): C, 79.95; H, 10.54; N, 4.44. IR (neat), /cm–1
3455 (OH); 2957, 2926, 2855, 1464 (CH3, CH2); 1632 (C=N);
:

990
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 5, May, 2019
Buravlev et al.
1
1269 (C—O); 855, 793 (=С—Н). Н NMR (CDCl3), : 0.89
(t, 3 H, NCH2(CH2)6CH3, J = 6.0 Hz); 1.17—1.47 (m, 10 H,
N(CH2)2(CH2)5CH3); 1.58—1.79 (m, 2 Н, NCH2CH2(CH2)5-
CH3); 1.74 (s, 3 H, C(5)H3); 1.76 (s, 3 H, C(4)H3); 2.27 (s, 3 H,
C(5´)CH3); 3.37 (d, 2 H, C(1)H, J = 7.1 Hz); 3.57 (t, 2 Н,
NCH2(CH2)6CH3, J = 6.7 Hz); 5.30 (br.t, 1 H, C(2)H, J ≈ 7.0 Hz);
6.89 (s, 1 Н, C(6´)H); 6.99 (s, 1 Н, C(4´)H); 8.28 (s, 1 H,
CH=N); 13.73 (s, 1 H, OH). 13C NMR (CDCl3), : 14.07
(NCH2(CH2)6CH3); 17.79 (C(5)); 20.44 (C(5´)CH3); 22.64,
27.78, 29.21, 29.33, 30.91, 31.83 (NCH2(CH2)6CH3); 25.81
(C(4)); 27.19 (C(1)); 57.54 (NCH2(CH2)6CH3); 117.88 (C(1´));
122.42 (C(2)); 126.93 (C(5´)); 128.80 (C(6´)); 129.18, 132.55
(C(3), (C(3´)); 132.69 (C(4´)); 157.01 (C(2´)); 164.56 (CH=N).
(E)-4-Methyl-2-n-octyliminomethyl-6-(1,7,7-trimethylbi-
cyclo[2.2.1]hept-exo-2-yl)phenol (16). Yellow-brown oil. The
yield was 0.531 g (92%). Found (%): C, 81.12; H, 10.98; N, 3.72.
C26H41NO. Calculated (%): C, 81.41; H, 10.77; N, 3.65. IR
(neat), /cm–1: 3431 (OH); 2951, 2928, 2874, 2859, 1458 (CH3,
CH2); 1634 (C=N); 1263 (C—O); 860, 770 (=С—Н). 1Н NMR
(CDCl3), : 0.80 (s, 3 Н, C(10)H3); 0.85 (s, 3 Н, C(8)H3); 0.89
(t, 3 H, NCH2(CH2)6CH3, overlapped with the adjacent signals);
0.91 (s, 3 H, C(9)H3); 1.16—1.44, 1.47—1.75 (both m, 10 H, 6 Н,
1 Н(3), 1 Н(5), Н(6), NCH2(CH2)6CH3); 1.76—1.96 (m, 2 Н,
C(4)H, 1 C(5)H); 2.05—2.24 (m, 1 Н, 1 C(3)H); 2.29 (s, 3 H,
C(5´)CH3); 3.36 (t, 1 Н, C(2)H, J = 8.9 Hz); 3.42—3.56,
3.56—3.71 (both m, 1 Н each, NCH2(CH2)6CH3); 6.87 (s, 1 Н,
C(6´)H); 7.17 (s, 1 Н, C(4´)H); 8.27 (s, 1 H, CH=N); 13.83
(s, 1 H, OH). 13C NMR (CDCl3), : 12.29 (C(10)); 14.08
(NCH2(CH2)6CH3); 20.44 (C(9)); 20.81 (C(5´)CH3); 21.46
(C(8)); 22.65, 27.18, 29.20, 29.32, 30.91, 31.83 (NCH2(CH2)6-
CH3); 27.54 (C(5)); 34.06 (C(3)); 39.72 (C(6)); 44.56 (C(2));
45.78 (C(4)); 47.97 (C(7)); 49.85 (C(1)); 59.53 (NCH2(CH2)6-
CH3); 117.58 (С(1´)); 126.01 (C(5´)); 128.48 (C(6´)); 131.52
(C(4´)); 131.64 (C(3´)); 158.60 (C(2´)); 164.76 (CH=N).
(E)-4-Methyl-2-n-octyliminomethyl-6-{(1R,2R,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl}phenol (17). Yellow-brown oil.
1634 (C=N); 1265 (C—O); 858, 771 (=С—Н). 1Н NMR (CDCl3),
: 0.81—0.99 (m, 9 Н, C(8)H3, C(10)H3, NCH2(CH2)6CH3);
1.08 (s, 3 Н, C(9)H3); 1.17—1.51, 1.55—1.84 (both m, 13 H, 4 Н,
C(1)H, C(3)H, 1 C(6)H, C(7)H, NCH2(CH2)6CH3); 1.94
(s, 1 Н, 1 C(4)H); 2.24—2.36 (m, 1 H, 1 C(6)H); 2.29 (s, 3 H,
C(5´)CH3); 3.08 (t, 1 Н, C(5)H, J = 7.4 Hz); 3.56 (t, 2 Н,
NCH2(CH2)6CH3, J = 6.8 Hz); 6.86 (s, 1 Н, C(6´)H); 7.04
(s, 1 Н, C(4´)H); 8.26 (s, 1 H, CH=N); 13.78 (s, 1 H, OH).
13C NMR (CDCl3), : 14.07 (NCH2(CH2)6CH3); 16.30, 24.87
(C(8), C(10)); 20.71 (C(5´)CH3); 22.64, 27.19, 29.20, 29.32,
30.90, 31.83 (NCH2(CH2)6CH3); 27.65 (C(9)); 32.80 (C(6));
33.62 (C(7)); 39.58 (C(2)); 40.22 (C(5)); 48.84 (C(1)); 49.86
(C(3)); 51.13 (C(4)); 59.54 (NCH2(CH2)6CH3); 117.71 (С(1´));
126.44 (C(5´)); 128.15 (C(6´)); 129.17 (C(4´)); 135.12 (C(3´));
157.20 (C(2´)); 164.67 (CH=N).
Synthesis of amines 19—24 (general procedure). To a solution
of imine 13—18 (1.2 mmol) in anhydrous EtOH (40 mL) NaBH4
(0.23 g, 6.0 mmol) was added with stirring. The reaction mixture
was refluxed for 30 min. After the completion of the reaction, the
mixture was cooled to room temperature, and 2 M aqueous
solution of NaOH (10 mL) was added. The mixture was stirred
for 5 min, diethyl ether (30 mL) was added, and stirring was
continued for 15 min. The organic layer was washed with 2 M
aqueous solution of NaCl (4×25 mL) to pH  7.0 and dried
with anhydrous K2CO3, the solvent was removed under reduced
pressure, and the product was isolated by column chromato-
graphy using a petroleum ether—Et2O (100 : 110 : 1) system
as an eluent.
2,4-Dimethyl-6-n-octylaminomethylphenol (19). Pale beige
oil. The yield was 0.256 g (81%). The spectral characteristics of
compound 19 correspond to those published earlier.21
2-tert-Butyl-4-methyl-6-n-octylaminomethylphenol (20). Pale
beige oil. The yield was 0.286 g (78%). Found (%): C, 78.91;
H, 11.67; N, 4.64. C20H35NO. Calculated (%): C, 78.63; H, 11.55;
N, 4.58. IR (neat), /cm–1: 3314, 3295 (NH, OH); 2994,
2953, 2924, 2855, 1464 (CH3, CH2); 1242 (C—O); 860, 770
(=С—Н). 1Н NMR (CDCl3), : 0.89 (t, 3 H, NCH2(CH2)6CH3,
J = 6.3 Hz); 1.17—1.40 (m, 10 H, N(CH2)2(CH2)5CH3); 1.42
(s, 9 Н, C(CH3)3); 1.44—1.59 (m, 2 Н, NCH2CH2(CH2)5CH3);
2.25 (s, 3 H, C(5´)CH3); 2.65 (t, 2 Н, NCH2(CH2)6CH3),
J = 6.9 Hz); 3.93 (s, 2 H, ArCH2N), 6.69 (s, 1 Н, C(6´)H);
6.99 (s, 1 Н, C(4´)H). 13C NMR (CDCl3), : 14.06 (NCH2-
(CH2)6CH3); 20.74 (C(5´)CH3); 22.63, 27.12, 29.19, 29.37, 29.56,
31.79 (NCH2(CH2)6CH3); 29.56 (C(CH3)3); 34.57 (C(CH3)3);
48.62 (NCH2(CH2)6CH3); 53.12 (ArCH2N); 122.83 (С(1´));
126.44 (C(4´)); 126.82 (C(5´)); 126.84 (C(6´)); 136.50 (C(3´));
154.91 (C(2´)).
4-Methyl-2-(3-methyl-2-en-1-yl)-6-n-octylaminomethyl-
phenol (21). Pale beige oil. The yield was 0.324 g (85%). Found (%):
C, 79.51; H, 11.02; N, 4.28. C21H35NO. Calculated (%): C, 79.44;
H, 11.11; N, 4.41. IR (neat), /cm–1: 3316, 3292 (NH, OH);
2957, 2924, 2855, 1474 (CH3, CH2); 1250 (C—O); 858, 785
(=С—Н). 1Н NMR (CDCl3), : 0.89 (t, 3 H, NCH2(CH2)6CH3,
J = 6.3 Hz); 1.18—1.40 (m, 10 H, N(CH2)2(CH2)5CH3); 1.43—1.61
(m, 2 Н, NCH2CH2(CH2)5CH3); 1.74 (s, 3 H, C(5)H3); 1.75
(s, 3 H, C(4)H3); 2.22 (s, 3 H, C(5´)CH3); 2.66 (t, 2 Н, NCH2-
(CH2)6CH3), J = 7.0 Hz); 3.32 (d, 2 H, C(1)H, J = 7.1 Hz); 3.93
(s, 2 H, ArCH2N); 5.35 (br.t, 1 H, C(2)H, J ≈ 6.8 Hz); 6.66
(s, 1 Н, C(6´)H); 6.85 (s, 1 Н, C(4´)H). 13C NMR (CDCl3), :
14.06 (NCH2(CH2)6CH3); 17.77 (C(5)); 20.51 (C(5´)CH3);
22.63, 28.02, 29.19, 29.39, 29.59, 31.79 (NCH2(CH2)6CH3);
22
The yield was 0.575 g (95%). []D +102.0 (c 0.3, CHCl3).
Found (%): C, 81.63; H, 10.89; N, 3.49. C26H41NO. Calculat-
ed (%): C, 81.41; H, 10.77; N, 3.65. IR (neat), /cm–1: 3455
(OH); 2953, 2928, 2878, 2857, 1458 (CH3, CH2); 1634 (C=N);
1
1265 (C—O); 862, 760 (=С—Н). Н NMR (CDCl3), : 0.78
(s, 3 Н, C(10)H3); 0.88 (t, 3 H, NCH2(CH2)6CH3, J = 6.2 Hz);
0.94 (s, 3 Н, C(8)H3); 1.11 (s, 3 H, C(9)H3); 1.12—1.46, 1.47—1.92
(both m, 13 H, 5 Н, 1 C(3)H, C(4)H, C(5)H, C(6)H, NCH2-
(CH2)6CH3); 2.17 (br.tt, 1 Н, 1 C(3)H, J ≈ 12.4 Hz, J ≈ 3.9 Hz);
2.33 (s, 3 H, C(5´)CH3); 3.40—3.55, 3.55—3.71 (both m,
1 Н each, NCH2(CH2)6CH3); 3.83 (br.ddd, 1 Н, C(2)H, J ≈ 11.6 Hz,
J ≈ 5.3 Hz, J ≈ 1.8 Hz); 6.90 (s, 1 Н, C(6´)H); 7.12 (s, 1 Н,
C(4´)H); 8.28 (s, 1 H, CH=N); 13.71 (s, 1 H, OH). 13C NMR
(CDCl3), : 14.08 (NCH2(CH2)6CH3); 14.83 (C(10)); 18.81
(C(9)); 19.88 (C(8)); 20.81 (C(5´)CH3); 22.64, 27.17, 29.20,
29.31, 30.89, 31.82 (NCH2(CH2)6CH3); 28.56 (C(5)); 29.03
(C(6)); 34.96 (C(3)); 40.21 (C(2)); 45.72 (C(4)); 50.36, 50.55
(C(1), C(7)); 59.59 (NCH2(CH2)6CH3); 117.81 (С(1´)); 126.07
(C(5´)); 128.93 (C(6´)); 130.48 (C(3´)); 133.07 (C(4´)); 158.14
(C(2´)); 164.77 (CH=N).
(E)-4-Methyl-2-n-octyliminomethyl-6-(2,2,3-trimethylbi-
cyclo[2.2.1]hept-exo-5-yl)phenol (18). Yellow-brown oil. The
yield was 0.553 g (96%). Found (%): C, 81.54; H, 10.65; N, 3.73.
C
26H41NO. Calculated (%): C, 81.41; H, 10.77; N, 3.65. IR
(neat), /cm–1: 3439 (OH); 2957, 2928, 2859, 1458 (CH3, CH2);

2-Alkyl-4-methylphenol derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 5, May, 2019
991
25.80 (C(4)); 27.13 (C(1)); 48.82 (NCH2(CH2)6CH3); 52.85
(ArCH2N); 121.95 (C(1´)); 122.98 (C(2)); 126.41 (C(6´)); 127.47,
128.42 (C(3´); C(5´)); 128.98 (C(4´)); 132.00 (C(3); 153.59 (C(2´)).
4-Methyl-2-n-octylaminomethyl-6-(1,7,7-trimethylbicyclo[2.2.1]-
hept-exo-5-yl)phenol (22). Pale beige oil. The yield was 0.344 g
(73%). The spectral characteristics of compound 22 correspond
to those published earlier.22
4-Methyl-2-n-octylaminomethyl-6-{(1R,2R,4S)-1,7,7-tri-
methylbicyclo[2.2.1]hept-2-yl}phenol (23). Light yellow oil. The
yield was 0.361 g (78%). []D23 +64.6 (c 0.3, CHCl3). The spec-
tral characteristics of compound 23 correspond to those published
earlier.21
4-Methyl-2-n-octylaminomethyl-6-(2,2,3-trimethylbicyclo-
[2.2.1]hept-exo-5-yl)phenol (24). Light yellow oil. The yield was
0.347 g (75%). The spectral characteristics of compound 24 cor-
respond to those published earlier.21
The radical scavenging activity of the compounds was esti-
mated using a known procedure38 by their ability to react with
DPPH. The studied compounds in concentrations of 100 and
10 mol L–1 were introduced into a solution of DPPH in MeOH,
the mixtures were stirred, and 30 min after the absorbance of the
solution was measured at  = 517 nm on a Thermo Spectronic
Genesys 20 spectrophotometer.
purpose, 30 min after introduction of solutions of the studied
compounds (final concentration 1 and 0.1 mol L–1) to a suspen-
sion of red blood cells, hemolysis was initiated by the addition
of a solution of H2O2 (0.006%). The reaction mixture was incu-
bated at 37 С for 5 h in a temperature-controlled shaker with
slow stirring. An aliquot was taken from the incubation medium
at an interval of 60 min and centrifuged for 5 min (1600 g). The
degree of hemolysis was determined from the hemoglobin content
in the supernatant on a Thermo Spectronic Genesys 20 spectro-
photometer at  = 524 nm.46 The hemolysis percentage was
calculated by the ratio to complete hemolysis of the sample. The
content of TBA-RS was determined spectrophotometrically as
indicated above. The absorption spectrum was examined in the
range  = 540—640 nm to estimate the accumulation of the
products of hemoglobin oxidation. The contents of oxyhemo-
globin (oxyHb) and methemoglobin (metHb) were calculated
taking into account the corresponding molar absorption coeffi-
cients.47 To estimate the concentration of the products of heme
degradation formed by the oxidation of membrane-bound hemo-
globin by active oxygen species, the fluorescence intensity (Ifl)
at the maximum at  = 488 nm was used (Flyuorat-02-Panorama
spectrofluorimeter, excitation at  = 321 nm, emission at
 = 400—600 nm, increment of spectrum recording 2 nm).48—50
Each experiment was carried out 4—8 times. Statistical data
processing was performed using the Microsoft Office Excel 2007,
2010 program packages.
The chelation ability of the compounds was evaluated using
described procedures.39,40 A solution of the studied compounds
in a concentration of 100 mol L–1 was introduced into MeOH,
and then a solution of FeSO4 was added. The reaction was initi-
ated by the addition of a solution of FerroZine™ Iron Reagent,
the mixture was shaken up, and 10 min after the absorbance was
measured at  = 562 nm on a Thermo Spectronic Genesys 20
spectrophotometer.
This work was financially supported by the Ministry of
Science and Higher Education of the Russian Federation
(state tasks Nos. AAAA-A18-118012490385-8 and AAAA-
A18-118011120004-5).
The antioxidant activity was estimated by their ability to in-
hibit LPO in the substrate obtained from the brain of laboratory
mice.41,42 The brain was taken out, homogenized (10%) in
a physiological solution (pH 7.4), and centrifuged for 10 min.
Then the supernatant (S1)41,43 containing water, proteins, DNA,
RNA, and lipids (cholesterol, galactolipids, individual phos-
pholipids, and gangliosides) was sampled. The studied com-
pounds were introduced into the supernatant as solutions in
acetone (final concentrations 10 and 100 mol L–1). After 30 min,
LPO was initiated by the addition of freshly prepared FeCl2 and
ascorbic acid44 or a solution of H2O2 (0.006%), and the studied
samples were incubated at 37 С for 1 h with slow stirring in
a Biosan ES-20 temperature-controlled shaker. The content of
TBA-RS was determined on a Thermo Spectronic Genesys 20
spectrophotometer at  = 532 nm, and the molar absorption
coefficient equal to 1.56•105 L mol–1 cm–1 was used for the
calculations.42,45
Studies of the hemolytic activity (cytotoxicity), membrane-
protective and antioxidant properties. A suspension of red blood
cells of laboratory mice in a phosphate salt buffer (рН 7.4) was
used for evaluation. The toxicity of the compounds was evalu-
ated on the in vitro model from their ability to induce erythrocyte
hemolysis. Solutions of the compounds in acetone were added
to a suspension of erythrocytes in the final concentration equal
to 10 mol L–1, and the samples were incubated at 37 С for 5 h
in a Biosan ES-20 temperature-controlled shaker.
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Received November 22, 2018;
in revised form February 21, 2019;
accepted March 11, 2019