Efficient hydrogenation of benzaldoximes and Schiff bases on ceramic high-porosity palladium catalysts

Article abstract of DOI:10.1007/s11172-018-2230-4

An efficient catalytic method for the synthesis of benzyl- and dibenzylamines by hydrogenating oximes and Schiffbases was developed on palladium supported high-porosity foamed ceramic block catalyst. The multiple regeneration ability of the foamed ceramic block catalyst can significantly decrease the Pd consumption as compared to the use of the conventional 10%Pd/C catalyst. Owing to a high hardness of the foamed ceramic catalyst, the reaction mixture can rapidly be removed from the reactor without using filtering devices. The structures produced by the reaction are fragments of biologically active and natural molecules. Antiproliferative properties of dibenzylamines revealed on the sea urchin embryo model suggest that these compounds can be considered as promising agents for the design of new anticancer drugs.

Full text of DOI:10.1007/s11172-018-2230-4

Russian Chemical Bulletin, International Edition, Vol. 67, No. 8, pp. 1394—1400, August, 2018
1394
Efficient hydrogenation of benzaldoximes and Schiff bases
on ceramic high-porosity palladium catalysts
A. V. Ignatov,a A. E. Varakutin,b I. N. Solov´eva,b I. B. Karmanova,a I. A. Kozlov,c
M. N. Semenova,d and V. V. Semenova
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 137 2966. E-mail: vs@ioc.ac.ru
bD. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation
cNOATEQ Ltd.,
Building 10, 5 ul. Gabrichevskogo, 125367 Moscow, Russian Federation
dN. K. Koltzov Institute of Developmental Biology, Russian Academy of Sciences,
26 ul. Vavilova, 119334 Moscow, Russian Federation
An efficient catalytic method for the synthesis of benzyl- and dibenzylamines by hydro-
genating oximes and Schiff bases was developed on palladium supported high-porosity foamed
ceramic block catalyst. The multiple regeneration ability of the foamed ceramic block catalyst
can significantly decrease the Pd consumption as compared to the use of the conventional
10%Pd/C catalyst. Owing to a high hardness of the foamed ceramic catalyst, the reaction mix-
ture can rapidly be removed from the reactor without using filtering devices. The structures
produced by the reaction are fragments of biologically active and natural molecules. Anti-
proliferative properties of dibenzylamines revealed on the sea urchin embryo model suggest that
these compounds can be considered as promising agents for the design of new anticancer drugs.
Key words: hydrogenation, foamed ceramic Pd catalyst, oximes, benzylamines, poly-
methoxybenzenes, antiproliferative activity, sea urchin embryo.
Benzylamines (BAs) are the key fragments of many
drugs, agrochemicals, and natural molecules and are often
used in the modern organic chemistry.1—5 A new class of
psychotropic substances, viz., NBOMes (N-benzyloxy-
methyl derivatives of phenylethylamines), has recently
been prepared by the modification of amphetamines by
the N-benzyl fragment. Three of NBOMes are proposed
for application as legal controlled substances in many
countries.6—8
Diverse methods for the preparation of BAs have been
described, but the synthesis often gives a low yield or re-
quires dangerous and expensive reagents. Serious attention
is given to the development of selective methods for BAs
synthesis. Their efficient synthesis by the reduction of
benzonitriles has recently been described.9 An original
selective method for their preparation from benzyl alcohols
using the redox process on the polymer resins is known.10
The hydrogenation of benzoic acid amines on Rh, Ru,
and Pt with hydrogen as well as on Ir with triethylsi-
lane or hydrides of aluminium and boron is also an effi-
cient BA synthetic procedure.11 An interesting method
for the preparation of BAs by the amination of the side
chain in alkylquinones has been developed.12
Numerous methods are known for the synthesis of BAs
from the corresponding oximes (reduction with sodium
amalgam, formates, zinc in acid, etc.), but the catalytic
hydrogenation of benzaldoximes on the 10%Pd/C catalyst
seems to be the most convenient and selective method for
BAs preparation.13 However, a substantial drawback of
this procedure is a large consumption of Pd (1 wt.% of
the amount of the hydrogenated substrate) and its appli-
cation for the only one reaction cycle, whereas the
processes of Pd isolation and preparation of a new catalysts
are fairly laborious.
The development of efficient, ecologically safe, uni-
versal, and scalable methods for the synthesis of BAs,
which are appropriate for industry, is an urgent task.
Results and Discussion
Palladium containing highly hard support Sibunit is
a convenient and efficient catalyst for the hydrogenation
of complicated organic molecules. However, this cata-
lyst must be filtered off from the reaction mixture and
regenerated in a hydrogen flow before the next experi-
ment.14—16
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1394—1400, August, 2018.
1066-5285/18/6708-1394 © 2018 Springer Science+Business Media, Inc.

Hydrogenation on ceramic catalysts
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1395
Scheme 1
i. -Al2O3(6%)—Pd(2.1—2.4%), 10 atm, 20 C, 3—4 h,
MeOH—HCl.
Compound 1—3
R
Compound 1—3
R
a
g
Fig. 1. High-porosity block foamed ceramic catalysts with the
pore diameter to 1 mm.
b
c
h
i
The high-porosity foamed ceramic block catalysts with
supported Pd turned out to be efficient catalytic systems
for the hydrogenation of benzaldehyde oximes (Fig. 1).
High-porosity ceramic catalysts become more and more
popular owing to a wide choice of the structure and sizes,
high surface, low hydraulic resistance, and high thermal
and mechanical stability. Block foamed ceramic catalysts
with the cellular structure (block-cellular) are promising
systems in various liquid-phase catalytic syntheses of many
organic compounds.17—21
d
j
A block-cellular catalyst of this type can withstand
multiple (up to 30—40 times) regenerations directly in the
reactor at 400 C after each procedure of hydrogenation
without a significant activity loss. The reaction mixture
can rapidly be removed from the reactor without using
filtering devices due to a high porosity and hardness of the
catalyst.
e
f
k
In this work, we first of all selected for hydrogenation
benzaldehyde oximes (1a—k) with two to four methoxy
groups in the benzene ring, namely, the fragments observed
in numerous natural products (Scheme 1).
100 mL of МеОН) were needed to prepare hygroscopic
pyrazolylamine (3k) in the crystalline form. Poorly soluble
in methanol oximes (3i,j) were loaded into the reactor as
suspensions. Over the reaction time oximes were gradually
dissolved without decreasing the yield of the target BAs.
For hydrogenation, methanol was successfully replaced by
isopropyl alcohol, which was evaporated together with
water as an azeotropic mixture.
The obtained polymethoxybenzylamines (3a,b,g) can
be used for the synthesis of drug analogs, namely, poly-
methoxydibenzylamines (DBAs) (4a—g), by hydrogenation
on the high-porosity block catalysts. These structures
possess diverse biological activity.26 In particular, they are in-
hibitors of calcium channels27 and suppress cell division.28
The simplified derivatives of alkaloid chelerythrine (I)
were recently29 obtained by the modification of the chel-
erythrine structure. They are shown to induce the dose-
dependent arrest the cell cycle in the G0/G1 phase on the A549
and NCI-H1299 human cancer cells exhibiting a good
therapeutic window compared to the initial alkaloid.
The oximes were almost quantitatively obtained from
the corresponding benzaldehydes (2a—k) and hydroxyl-
amine, and then they were selectively hydrogenated to BAs
in methyl or isopropyl alcohol with the addition of aque-
ous HCl at 20 C and a pressure of 10 atm for 3—4 h
under mild conditions. In the absence of hydrochloric
acid, the yields decrease sharply because of the formation
of by-products. The optimized yields and physicochemical
parameters of the obtained BAs are presented in Table 1.
The possibility to conduct 30—40 cycles of regeneration
of the block catalyst enabled 150—200-fold reduction of
Pd consumption compared to the use of the conventional
10%Pd/C catalyst.
The reaction was well reproduced at different con-
centrations and loadings of oxime (2—5%, 1—10 g).
The change in hydrochloric acid concentration from
0.5 to 1.5% did not affect the reaction course. Minimum
amounts of hydrochloric acid (5 mL of 36% HCl per

1396
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Ignatov et al.
Table 1. Physicochemical parameters of benzylamines 3
Com-
pound
Yield (%)
M.p.*/C
1H NMR (, J/Hz)
+
NH3
CH2N+
HAr
OAlk
3a
3b
3c
94
95
97
260—261
(260—263)13
149—150
—
—
—
—
—
—
—
—
(148—150)13
230—232
8.28 (br.s, 3 H)
3.76 (m, 2 H)
6.79—6.84 (m, 2 H);
7.06 (d, 1 H, J = 1.5)
1.19 (t, 3 H, СH3, J = 7);
3.75 (s, 3 H, OCH3);
3.88 (q, 2 H, СH2, J = 7)
—
3d
3e
3f
98
76
96
99
95
93
221—223
(222—223)22
221—222
—
—
—
—
—
—
—
—
—
(220—221)23
190—191
—
—
(190—192)24
209—212
3g
3h
3i
8.54 (br.s, 3 H)
8.49 (br.s, 3 H)
8.32 (br.s, 3 H)
3.94
(q, 2 H, J = 5.6)
3.90 (br.s, 2 H)
6.93 (s, 2 H)
3.79 (s, 6 H, 2 OMe);
3.65 (s, 3 H, OMe)
(209—211)24
222—224
6.79 (d, 1 H, J = 1.4); 3.83 (s, 3 H);
(222)25
6.92 (d, 1 H, J = 1.4)
6.01 (s, 2 H, OCH2O)
145—150
3.75 (s, 2 H)
3.90 (s, 2 H)
3.87 (m, 2 H)
6.81 (s, 1 H)
3.75 (s, 3 H);
3.94 (s, 3 H);
6.02 (s, 2 H, OCH2O)
3.79 (s, 3 H);
3j
92
81
237—238
8.27 (s, 3 H)
8.35 (s, 3 H)
6.86 (s, 1 H)
3.90 (s, 3 H);
6.04 (s, 2 H, OCH2O)
3.83 (s, 3 H, NCH3)
3k
173—177
(decomp.)
7.53 (s, 1 H);
7.80 (s, 1 H)
* Literature data are given in parentheses.
mediate Schiff bases (5a—g) were easily obtained by reflux
of polymethoxybenzylamines (3a,b,g) and the correspond-
ing benzaldehydes (6) in toluene with the simultaneous
removal of water and without further purification were
hydrogenated on the block high-porosity catalysts to DBAs
4a—g. The yields and physicochemical parameters of the
synthesized DBAs are presented in Table 2.
Unlike oxime hydrogenation, the addition of HCl to
the reaction solution (Scheme 2) was not needed. The
hydrogenation proceeded smoothly in both methanol and
DMF. Usually the yields of DBA 4 in DMF were higher, as
a rule, due to a higher solubility of the initial Schiff bases (5).
Biological assays. The ability of DBA 4 to suppress cell
division was studied on a sea urchin Paracentrotus lividus
embryo model according to the previously developed
assay.31 The assay provides rapid and simple evaluation of
the antiproliferative activity of the tested molecules due
to feasible artificial fertilization, rearing, and observation,
as well as high permeability of eggs and embryos to various
compounds. The frequent synchronous cell division, with
the first mitotic cycle completion in 70–75 min post fer-
tilization followed by blastomere cleavage every 35–40 min,
makes it possible to monitor a test molecule effect during
several successive cell cycles. The obtained effect-inducing
threshold concentration, С/mol L–1, is presented below.
Dibenzylamines 4a—g can be considered as analogs of
natural antimitotics combretastatins (CA-2 and CA-4) with
the triatomic binding unit between rings A and B. The
replacement of the ethylene bridge in combretastatins by
linkers of various length (one to four carbon atoms) (II)
was reported. One of these compounds showed cytotoxic-
ity comparable with that of natural combretastatin.30
The syntheses of DBAs were carried out via the stan-
dard scheme by the condensation of BAs with benzalde-
hydes followed by hydrogenation (Scheme 2).29 Inter-
Compound 4a 4b 4c 4d 4e 4f 4g CA-2 CA-4
С*
4
>4
4
1
2
4
2
0.002 0.002

Hydrogenation on ceramic catalysts
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1397
Scheme 2
i. -Al2O3(6%)—Pd(2.1—2.4%), 10 atm, 20 C, 2 h.
Compound 4, 5
R1
R2
Compound 4, 5
R1
R2
a
e
b
f
c
d
g
Table 2. Physicochemical parameters of dibenzylamines 4
Com-
pound
Yield (%)
93
M.p./C
1H NMR (, J/Hz)
+
NH2
CH2N+
HAr
OAlk
4a
155—160
9.79 (br.s, 2 H)
3.99—4.06
(m, 4 H)
6.93—6.96 (m, 2 Н);
7.02—7.03 (dd, 1 Н,
J = 2.7); 7.07(d, 1 Н,
1.32 (t, 3 H, CH3, J = 7.0);
4.02 (q, 2 H, CH2, J = 7.0);
6.06 (s, 2 H, OCH2O)
J = 7.7); 7.22 (m, 2 H);
7.31 (t, 1 Н, J = 8.0)
6.97—6.98 (m, 2 H);
7.08—7.12 (m, 2 Н);
7.19—7.22 (m, 2 Н)
4b
4s
4d
4e
87
88
87
59
143—147
166—171
232—235
184—186
9.58 (s, 2 H)
9.71 (br.s, 2 H)
9.41 (br.s, 2 H)
9.68 (s, 2 H)
4.00 (br.s,
2 H);
1.14 (t, 3 H, CH3, J = 7.0);
3.80 (s, 3 H, OCH3);
3.93 (q, 2 H, CH2, J = 7.0);
6.05 (s, 2 H, OCH2O)
1.31 (t, 3 H, CH3, J = 7.0);
3.78 (s, 3 H, OCH3);
4.02 (q, 2 H, CH2, J = 7.0);
6.05 (s, 2 H, OCH2O)
4.25 (s, 8 H, OCH2CH2O)
4.07 (s, 2 H)
3.99—4.03
(m, 4 H)
6.93—6.95 (m, 2 H);
6.99—7.02 (m, 2 Н);
7.22—7.32 (m, 2 Н)
3.98 (t, 4 H,
J = 5)
6.89 (d, 2 Н, J = 8);
6.95—6.97 (dd, 2 Н,
J1 = 8.3, J2 = 1.5);
7.08 (d, 2 Н, J = 1.5)
6.95 (d, 1 Н, J = 8.0);
7.01 (d, 1 Н, J = 8.0);
7.20 (s, 1 Н);
4.05 (s, 4 H)
3.74 (s, 3 Н, ОСН3);
3.85 (s, 3 Н, ОСН3);
6.05 (s, 2 H, OCH2O)
7.35 (br.s, 1 Н);
7.40 (br.s, 1 Н)
4f
44
98
164—167
172—175
9.68 (br.s, 2 H)
8.82 (s, 2 Н)
4.03—4.06
(m, 4 H)
6.93 (s, 2 H);
3.66 (s, 3 Н, ОСH3);
3.77 (s, 3 Н, ОСH3);
3.79 (s, 6 Н, 2 ОСH3);
3.76 (s, 6 H, 2 OCH3);
3.63 (s, 3 H, OCH3);
3.58 (s, 3 H, OCH3)
6.98 (d, 2 Н, J = 8.5);
7.49 (d, 2 Н, J = 8.5)
6.64 (s, 2 Н);
4g
3.73 (br.s,
4 H)
6.70—6.84 (m, 3 H)

1398
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Ignatov et al.
50 mm) equipped with a thermocouple, an inlet tube for hydro-
gen supply, and heating jacket. The autoclave with the reaction
mixture was stirred using a platform shaking device (capacity of
120—160 min–1).
Thus, benzyl- and dibenzylamines can readily be ob-
tained in large amounts by the hydrogenation of oximes
and Schiff bases on the block high-porosity ceramic pal-
ladium catalysts. They possess antiproliferative properties
and could be of interest for the development of new anti-
tumor drugs.
Hydrogenation of oximes 1a—k (general procedure). A solution
of oxime 1a—k (23 mmol) in isopropyl alcohol (100 mL) was
loaded into the autoclave with the fluoroplastic bush, concen-
trated HCl (10.5 mL) was added, and a block of the regenerated
catalyst was fixed. Hydrogenation was conducted for 3—5 h at
20 C and a hydrogen pressure of 10 atm, which was maintained
at this level during the reaction. The reaction course was moni-
tored by TLC. After the initial oxime disappeared completely,
the reaction solution was poured out of the autoclave, the catalyst
block was washed with methanol (3×30 mL), and the combined
solutions were filtered from mechanical impurities. The solvent
was evaporated, and analytically pure aromatic benzylamines
3a—k were obtained.
When hydrogenation was conducted in methanol (100 mL),
solvent removal was followed by drying residue using azeotropic
distillation with isopropyl alcohol (250 mL). For the hydro-
genation of compound 1k, the reaction mixture was addi-
tionally purified by reflux with active carbon for 1 h. The block
catalyst was regenerated directly in the reactor at 400 C in
a hydrogen flow and further used in the next hydrogenation
procedure.
3,4-Methylenedioxybenzylamine hydrochloride (3a). The yield
was 94%. M.p. 260—261 C (cf. Ref. 13: m.p. 260—263 C).
Found (%): C, 51.26; H, 5.36; Cl, 18.86; N, 7.48; O, 17.03.
C8H10ClNO2. Calculated (%): C, 51.21; H, 5.37; Cl, 18.90;
N, 7.47; O, 17.05.
3,4-Ethylenedioxybenzylamine hydrochloride (3b). The yield
was 95%. M.p. 149—150 C (cf. Ref. 13: m.p.148—150 C).
Found (%): C, 53.66; H, 5.99; Cl, 17.56; N, 6.94; O, 15.85.
C9H12ClNO2. Calculated (%): C, 53.61; H, 6.00; Cl, 17.58;
N, 6.95; O, 15.87.
4-Methoxy-3-ethoxybenzylamine hydrochloride (3c). The
yield was 97%. M.p. 230—232 C. Found (%): C, 55.11; H, 7.42;
Cl, 16.30; N, 6.44; O, 14.73. C10H16ClNO2. Calculated (%):
C, 55.17; H, 7.41; Cl, 16.29; N, 6.43; O, 14.70.
4-Hydroxy-3-ethoxybenzylamine hydrochloride (3d). The yield
was 98%. M.p. 221—223 C (cf. Ref. 22: m.p. 222—223 C).
Found (%): C, 53.02; H, 6.94; Cl, 17.43; N, 6.89; O, 15.72.
C9H14ClNO2. Calculated (%): C, 53.08; H, 6.93; Cl, 17.41;
N, 6.88; O, 15.71.
4-Hydroxy-3-methoxybenzylamine hydrochloride (3e). The
yield was 76%. M.p. 221—222 C (cf. Ref. 23: m.p. 220—221 C).
Found (%): C, 50.72; H, 6.37; Cl, 18.67; N, 7.38; O, 16.86.
C8H12ClNO2. Calculated (%): C, 50.67; H, 6.38; Cl, 18.69;
N, 7.39; O, 16.87.
3-Hydroxy-4-methoxybenzylamine hydrochloride (3f). The
yield was 96%. M.p. 190—191 C (cf. Ref. 24: m.p. 190—192 C).
Found (%): C, 50.72; H, 6.37; Cl, 18.67; N, 7.38; O, 16.86.
C8H12ClNO2. Calculated (%): C, 50.67; H, 6.38; Cl, 18.69;
N, 7.39; O, 16.87.
Experimental
1H NMR spectra were recorded on a Bruker DRX-500 spec-
trometer (working frequency 500.13 Hz, DMSO-d6, Me4Si as an
internal standard). Mass spectra were detected on a Finnigan
MAT INCOS 50 quadrupole mass spectrometer (direct injection,
ionization energy 70 eV). Elemental analysis was carried out on
a Perkin—Elmer 2400 automated C,H,N microanalyzer. TLC
studies were conducted on the Merck 60F254 plates. Silica gel
Acros 0.035-0.070 mm 60A was used for preparative chromato-
graphy. Melting points were determined on a Boetius heating
stage and were not corrected.
Oximes of aromatic aldehydes 1a—k were prepared according
to earlier described procedures from the corresponding aldehydes
and hydroxylamine, Compound 1a, m.p. 104—105 C (cf. Ref. 32:
m.p. 106—107 C); 1b, m.p. 97—99 C (cf. Ref. 32: m.p.
98—99 C); 1с, m.p. 97—98 C cf. Ref. 33: m.p. 98 C); 1d, m.p.
104—106 C (cf. Ref. 34: m.p. 106 C); 1e, m.p. 122—123 C
(cf. Ref. 35: m.p. 123—124 C); 1f, m.p. 140—141 C (cf. Ref. 36:
m.p. 142 C); 1g, m.p. 92—93 C (cf. Ref. 37: m.p. 94—95 C);
1h, m.p. 158—159 C (cf. Ref. 25: m.p. 159—160 C); 1j, m.p.
157—158 C (cf. Ref. 38: m.p. 160 C); 1k, m.p. 78—80 C
(cf. Ref. 39: m.p. 80—81 C).
3,4-Methylenedioxy-2,5-dimethoxybenzaldehyde oxime (1i).
A 50% solution of NaCl (250 mmol) was rapidly added dropwise
with stirring to a mixture of aldehyde (100 mmol), water (25 mL),
ethanol (5 mL), ice (40 g), and hydroxylamine hydrosulfate
(110 mmol). The temperature of the mixture was maintained
within 20—25 C by adding ice. The reaction mixture was stirred
for 1 h, and then extracted with dichloromethane (2100 mL).
The aqueous layer was acidified to pH 6 by dropwise addition of
concentrated HCl. The precipitated crystals were filtered off on
a Büchner funnel, washed with distilled water (330 mL), and
dried to a constant weight. The yield was 93%. M.p. 166—168 C.
Found (%): C, 56.83; H, 6.21; N, 6.65; O, 30.31. C10H13NO4.
Calculated (%): C, 56.86; H, 6.20; N, 6.63; O, 30.30. 1H NMR,
: 3.79 (s, 3 H, OMe); 3.84 (s, 3 H, OMe); 6.08 (s, 2 H, OCH2O);
6.91 (s, HAr); 8.14 (m, 1 H, CHN); 11.11 (s, 1 H, NOH).
Hydrogenation in the liquid phase was conducted in a steel
autoclave with the fluoroplastic bush in which the commercially
available40 block-cellular high-porosity catalyst was placed.
A foamed ceramic material (-Al2O3) coated with the -Al2O3
sol (porosity 70—95%) was used as a support. The support was
impregnated with a Pd(NO3)2 solution and heated to 450 C to
coat the support with oxide PdO. Prior to hydrogenation, the
catalyst was reduced to metallic Pd with hydrogen at 50—55 C
in an autoclave with the aim to obtain the 2.4%Pd/6%-Al2O3
catalyst. A such block of the catalyst can be regenerated with
hydrogen 30—40 times without activity loss.
3,4,5-Trimethoxybenzylamine hydrochloride (3g). The yield
was 99%. M.p. 209—211 C (cf. Ref. 24: m.p. 209—211 C).
Found (%): C, 51.45; H, 6.89; Cl, 15.15; N, 5.98; O, 20.53.
C10H16ClNO3. Calculated (%): C, 51.40; H, 6.90; Cl, 15.17;
N, 5.99; O, 20.54.
3-Methoxy-4,5-methylenedioxybenzylamine hydrochloride
(3h). The yield was 95%. M.p. 222—224 C (cf. Ref. 25: m.p.
222 C). Found (%): C, 49.62; H, 5.57; Cl, 16.31; N, 6.43;
A block of the high-porosity block-cellular catalyst
(2—4%Pd/6%-Al2O3, diameter 40 mm, height 50 mm, average
pore diameter ~2 mm, block weight 31.6 g, porosity 70—95%)
was fixed at the center of a cylindrical autoclave (internal diameter

Hydrogenation on ceramic catalysts
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1399
O, 22.06. C9H12ClNO3. Calculated (%): C, 49.67; H, 5.56;
Cl, 16.29; N, 6.44; O, 22.05.
149 (66), 137 (23), 136 (11), 135 (10), 134 (10), 123 (85), 121 (11),
119 (5), 109 (12), 108 (18), 107 (14), 106 (19), 105 (48), 101 (6),
95 (10), 94 (46), 93 (15), 92 (8), 91 (15).
2,3-Dimethoxy-4,5-methylenedioxybenzylamine hydrochloride
(3i). The yield was 93%. M.p. 145—150 C. Found (%): C, 48.52;
H, 5.65; Cl, 14.33; N, 5.65; O, 25.84. C10H14ClNO4. Calculat-
ed (%): C, 48.48; H, 5.66; Cl, 14.34; N, 5.66; O, 25.86.
2,5-Dimethoxy-3,4-methylenedioxybenzylamine hydrochloride
(3j). The yield was 92%. M.p. 237—238 C. Found (%): C, 48.44;
H, 5.71; Cl, 14.33; N, 5.65; O, 25.85. C10H14ClNO4. Calculat-
ed (%): C, 48.49; H, 5.70; Cl, 14.31; N, 5.66; O, 25.84.
(1N-Methylpyrazol-4-yl)methanamine (3k) was purified addi-
tionally with active carbon. The yield was 71%. M.p. 173—177 C
(with decomp.). Found (%): C, 54.14; H, 8.08; N, 37.76. C5H9N3.
Calculated (%): C, 54.03; H, 8.16; N, 37.81.
Synthesis of Schiff bases (5a—g) from benzylamines (3a,b,g)
and benzaldehydes (general procedure). A solution of benzylamine
3a,b,g (4 mmol) and the corresponding aldehyde (4 mmol) in
toluene (50 mL) was refluxed under argon in a flask with a drying
column filled with sodium sulfate. The solvent was evaporated
on a rotary evaporator, and the residue was kept for 14 h in
a refrigerator. The precipitated crystals (or yellow oil) were washed
with hexane and then hydrogenated without further purification.
Synthesis of dibenzylamines (4a—g) (general procedure).
A solution of the Schiff base (2.6 mmol) in DMF (85 mL) and
the catalyst block were loaded into an autoclave with the fluoro-
plastic bush. Hydrogenation was carried out for 3—5 h at 20 C
and a hydrogen pressure of 10 atm, which was maintained during
the reaction. The reaction course was monitored by TLC. After
the complete disappearance of the initial Schiff base, the reaction
solution was poured out of the autoclave, the catalyst block was
washed with DMF (330 mL), the combined solutions were
filtered from mechanical impurities, and the solvent was evapo-
rated on a rotary evaporator.
N-(3-Bromo-4,5-dimethoxybenzyl)-3,4- methylenedioxybenz-
ylamine hydrochloride (4e). The yield was 59%. M.p.184—186 C.
Found (%): C, 49.05; H, 4.59; Br, 19.17; Cl, 8.50; N, 3.35;
O, 15.35. C17H19BrClNO4. Calculated (%): C, 49.00; H, 4.60;
Br, 19.18; Cl, 8.51; N, 3.36; O, 15.36. MS, m/z (Irel (%)): 381 [M]+
(7), 379 (9), 246 (13), 244 (15), 232 (23), 231 (23), 230 (26), 229
(22), 185 (5), 162 (6), 152 (5), 151 (45), 150 (75), 149 (14), 148 (14),
136 (31), 135 (100), 122 (6), 121 (9), 120 (8), 106 (8), 105 (14),
92 (5).N-(3,4,5-Trimethoxybenzyl)-4-methoxybenzylamine hydro-
chloride (4f). The yield was 44%. M.p. 164—167 C. Found (%):
C, 61.11; H, 6.83; Cl, 10.01; N, 3.97; O, 18.08. C18H24ClNO4.
Calculated (%): C, 61.10; H, 6.84; Cl, 10.02; N, 3.96; O, 18.09.
MS, m/z (Irel (%)): 317 [M]+ (11), 183 (11), 182 (100), 181 (28),
167 (21), 151 (25), 148 (8), 139 (5), 137 (7), 136 (40), 122 (7),
121 (55).
N-(3,4,5-Trimethoxybenzyl)-4-methoxy-3-hydroxybenzyl-
amine hydrochloride (4g). The yield was 98%. M.p. 172—175 C.
Found (%): C, 58.41; H, 6.55; Cl, 9.60; N, 3.80; O, 21.64.
C18H24ClNO5. Calculated (%): C, 58.46; H, 6.54; Cl, 9.59;
N, 3.79; O, 21.63. MS, m/z (Irel (%)): 333 [M]+ (39), 316 (8),
210 (5), 197 (5), 196 (26), 182 (100), 181 (46), 168 (5), 167 (18),
166 (8), 153 (6), 152(27), 151 (22), 150 (6), 148 (7), 139 (6), 138
(14), 137 (57), 136 (6), 124 (6), 123 (6), 122 (10), 109 (5), 94 (9).
Study of the antiproliferative activity of compounds on a sea
urchin embryo model.31 Experiments were carried out at the
Biological Laboratory of the N. K. Koltzov Institute of Develop-
mental Biology (Russian Academy of Sciences) in Cyprus. Adult
sea urchins, Paracentrotus lividus L. (Echinidae, Echinodermata),
were collected in the coastal area and kept in an aerated seawater
tank. Spawning was triggered by intracoelomic injection of
0.5 М KCl (1—2 mL). The resulting eggs were washed with
seawater filtered through a nylon filter and then fertilized by add-
N-(3-Ethoxybenzyl)-3,4-methylenedioxybenzylamine hydro-
chloride (4a). The yield was 93%. M.p. 155—160 C. Found (%):
C, 63.49; H, 6.25; Cl, 11.01; N, 4.34; O, 14.91. C17H20ClNO3.
Calculated (%): C, 63.45; H, 6.26; Cl, 11.02; N, 4.35; O, 14.92.
MS, m/z (Irel (%)): 285 [M]+ (6), 151 (10), 150 (100), 137 (9),
136 (90), 135 (83), 108 (26), 107 (15), 106 (7), 105 (6), 91 (5).
N-(3-Methoxy-2-ethoxybenzyl)-3,4-methylenedioxybenzyl-
amine hydrochloride (4b). The yield was 87%. M.p. 143—147 C.
Found (%): C, 61.38; H, 6.31; Cl, 10.11; N, 3.99; O, 18.20.
ing drops of diluted sperm. The embryos (600—2000 unit mL–1
)
were incubated in filtered seawater at room temperature
(18—23 °С) until thew beginning of active feeding (36—40 h,
mid-pluteus 2) under gentle agitation with a motor-driven plas-
tic paddle (60 rpm).
The stock solutions of chemical compounds were prepared
in DMSO followed by a 10-fold dilution with 96% ethanol.
The solubility of the test compounds was monitored using an
MBS-10 stereomicroscope. Combretastatins CА-2 and CА-4
synthesized according to the described procedure41 were used as
a positive control.
The compounds were tested in six-well cultural plates at
8—14 min post fertilization. An egg suspension (5 mL) was placed
in each well, and the corresponding volume of a solution of
the test compound was added to achieve the required final
concentration. The maximum concentration of the solvent
did not exceed the maximum tolerated one (1% for ethanol and
0.05% for DMSO). The two-fold decreasing concentrations of
compounds were used until the effect disappeared. The antipro-
liferative activity of test molecules was assessed by the lowest
(threshold) effective concentration altering fertilized eggs cleav-
age. The observations were carried out with a Biolam LOMO
optical microscope (St. Petersburg).
C
18H22ClNO4. Calculated (%): C, 61.45; H, 6.30; Cl, 10.08;
N, 3.98; O, 18.19. MS, m/z (Irel (%)): 315 [M]+ (6), 180 (22),
166 (20), 165 (7), 164 (7), 152 (10), 151 (9), 150 (79), 149 (11),
137 (19), 136 (22), 135 (100), 122 (15), 121 (8), 107 (6), 106 (7),
105 (8), 93 (6), 91 (6).
N-(3-Methoxy-4-ethoxybenzyl)-3,4-methylenedioxybenzyl-
amine hydrochloride (4c). The yield was 88%. M.p. 166—171 C.
Found (%): C, 61.51; H, 6.29; Cl, 10.06; N, 3.97; O, 18.17.
C18H22ClNO4. Calculated (%): C, 61.45; H, 6.30; Cl, 10.08;
N, 3.98; O, 18.19. MS, m/z (Irel (%)): 315 [M]+ (10), 180 (40),
166 (42), 165 (16), 162 (8), 152 (6), 151 (9), 150 (55), 138 (15),
137 (49), 136 (37), 135 (100), 123 (7), 122 (10), 121 (6), 106 (10),
105 (9), 94 (6), 93 (6).
N-(3,4-Ethylenedioxy)-3,4-ethylenedioxybenzylamine hydro-
chloride (4d). The yield was 87%. M.p. 231—235 C. Found (%):
C, 61.76; H, 5.77; Cl, 10.14; N, 4.01; O, 18.32. C18H20ClNO4.
Calculated (%): C, 61.80; H, 5.76; Cl, 10.13; N, 4.00; O, 18.30.
MS, m/z (Irel (%)): 313 [M]+ (27), 312 (14), 311 (31), 176 (63),
165 (29), 164 (100), 163 (13), 162 (9), 161 (8), 151 (23), 150 (61),
This work was financially supported by the Russian
Science Foundation (Project No. 18-13-00044).

1400
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Ignatov et al.
23. F. Liu, J. Yu, Y. Liu, Y. Chai, S. Zhao, B. Cu, C. Zhang,
M. Li, D. Wand, Pat. CN106366004 A, 2017; https://
patentscope.wipo.int/search/en/detail.jsf?docId=CN1927
69947&redirectedID=true.
24. D. D. John, W. H. W. Richard, Pat. US 2819273, 1956; https://
patentscope.wipo.int/search/en/detail.jsf?docId=US3573
0063&recNum=9&office=&queryString=2819273&prevFi
lter=&sortOption=Pub+Date+Desc&maxRec=9.
25. L. Rügheimer, G. Ritter, Chem. Ber., 1912, 45, 1340.
26. https://www.ebi.ac.uk/chembl.
References
1. L. Heuer, Benzylamine. Ullmann´s Encyclopedia of Industrial
Chemistry, Wiley, New York, 2006.
2. V. Farina, J. Reeves, J. C. Senanayake, J. Song, Chem. Rev.,
2006, 106, 2734.
3. K. Bujnowski, A. Adamczyk, L. Synoradzki, Org. Prep.
Proced. Int., 2007, 39, 153.
4. S. Kobayashi, H. Ishitani, Chem. Rev., 1999, 99, 1069.
5. S. Kobayashi, Y. Mori, J. Fossey, M. Salter, Chem. Rev., 2011,
111, 2626.
6. X. Wu, C. Eriksson, A. Wohlfarth, J. Wallgren, R. Kronst-
rand, M. Jofesson, J. Dahlen, P. Konradsson, Tetrahedron,
2017, 6393.
7. J. Casale, P. Hays, Microgram J., 2012, 84.
8. M. Braden, J. Parrish, J. Naylor, D. Nichols, Mol. Pharma-
col., 2006, 70, 1956.
9. Y. Saito, H. Ishitani, M. Ueno, S. Kobayashi, Chem. Open,
2017, 6, 211.
10. S. Ley, M. Bolli, B. Hinzen, A. Gervois, B. Hall, J. Chem.
Soc., Perkin Trans. 1, 1998, 2239
11. Y. Li, J. Molina de La Torre, K. Grabow, U. Bentrup,
K. Junge, S. Zhoy, A. Bruckner, M. Beller, Angew. Chem.,
Int. Ed., 2013, 52, 11577.
12. L. Mori-Quiroz, M. Clift, Org. Lett., 2016, 3446.
13. B. Su, M. Deng, Q. Wang, Adv. Synth. Catal., 2014, 356, 977.
14. L. N. Tolkacheva, V. P. Kislyi, S. Z. Taits, V. V. Semenov,
Russ. J. Org. Chem., 2002, 38, 150.
15. V. P. Kislyi, L. N. Tolkacheva, V. V. Semenov, J. Org. Chem.,
2002, 38, 269.
16. R. M. Mironenko, O. B. Belskaya, V. P. Talzi, V. A. Rodionov,
S. V. Sysolyatin, V. A. Likholobov, Russ. Chem. Bull., 2016,
65, 1535.
17. A. I. Kozlov, E. S. Lukin, Russ. Pat. 2233700, 2004; http://
bd.patent.su/2233000-2233999/pat/servl/servlet629c.html.
18. A. I. Kozlov, E. S. Lukin, I. A. Kozlov, V. P. Kolesnikov,
V. N. Grunskii, Glass Ceramics, 2005, 62, 206.
19. A. N. Pivkin, V. N. Grunskii, A. V. Bespalov, A. I. Kozlov,
J. Adv. Chem. and Chem. Tech., 2008, 22, 49.
20. E. V. Zaryanova, A. V. Ignatov, N. A. Lozynskaya, Tetra-
hedron, 2017, 73, 6887.
27. B. Kang, J. Oh, J. Lee, H. Rhim, T. Yune, H. Choo, Bioorg.
Med. Chem., 2015, 23, 6166.
28. R. Carrasco-Gomez, S. Keppner-Witter, M. Hieke, L. Lange,
G. Schneider, M. Schubert-Zsilavecz, E. Proschak, B. Spän-
kuch, Bioorg. Med. Chem. Lett., 2014, 24, 5063.
29. R. Yang, M. Tavares, S. Teixeira, R. Azevedo, D. Pietro,
T. Fernandes, A. Ferreira, G. Trossini, J. Barbuto, R. Parise-
Filho, Bioorg. Med. Chem., 2016, 24, 4600.
30. Z. Getahun, L. Jurd, P. Chu, C. Lin, E. Hamel, J. Med.
Chem., 1992, 35, 1058.
31. M. Semenova, A. Kiselyov, V. Semenov, BioTech., 2006,
40, 765.
32. D. Goyard, B. Kónya, A. S. Chajistamatiou, E. D. Chrysina,
J. Leroy, S. Balzarin, M. Tournier, D. Tousch, P. Petit,
C. Duret, P. Maurel, L. Somsák, T. Docsa, P. Gergely,
J. Praly, J. Azay-Milhau, S. Vidal, Eur. J. Med. Chem., 2016,
108, 444.
33. J. S. Buck, W. S. Ide, J. Am. Chem. Soc., 1932, 54, 3302.
34. C. Larsson, Chalmers Handl., 1947, 59, 21.
35. E. Wang, K. Huang, H. Chen, C. Wu, G. Lin, J. Chin. Chem.
Soc., 2004, 51, 619.
36. J. P. Ley, H. Bertram, Bioorg. Med. Chem., 2001, 9, 1879.
37. S. Ke, Z. Yang, L. Shi, M. Liu, Y. Liang, K. Wang, T. Long,
A. Jiang, Z. Zhang, Lett. Drug Des. Discov., 2015, 12, 771.
38. G. Ciamician, Gazz. Chim. Ital., 1888, 18, 136.
39. N. I. Shapranova, I. N. Somin, S. G. Kuznetsov, Chem.
Heterocycl. Comp., 1973, 9, 1013.
40. www.noateq.ru; www.chemblock.com.
41. V. Semenov, A. Kiselyov, I. Titov, I. Sagamanova, N. Ikizalp,
N. Chernysheva, D. Tsyganov, L. Konyushkin, S. Firgang,
R. Semenov, I. Karmanova, M. Raihstat, M. Semenova,
J. Nat. Prod., 2010, 73, 1796.
21. I. B. Karmanova, S. I. Firgang, L. D. Konyushkin, V. N.
Khrustalev, A. V. Ignatov, L. A. Kuznetsov, Yu. A. Pinchuk,
I. A. Kozlov, V. V. Semenov, Mendeleev Commun., 2016,
26, 66.
Received May 15, 2018;
in revised form May 20, 2018;
accepted May 24, 2018
22. A. Challis, G. Clemo, J. Chem. Soc., 1947, 613.