Synthesis of anabasine-containing aminomethyl derivatives of 6-hydroxyaurones

Article abstract of DOI:10.1007/s10593-019-02444-2

[Figure not available: see fulltext.] Aminomethylation of aurones was studied by using anabasine. The reaction in the case of 6-hydroxyaurones was shown to selectively provide 7-aminomethyl-6-hydroxyaurones, while 5-aminomethyl-6-hydroxy-7-methylaurones could be obtained by transamination of 5-dimethylaminomethyl derivatives of 6-hydroxy-7-methylaurones in the presence of anabasine.

Full text of DOI:10.1007/s10593-019-02444-2

DOI 10.1007/s10593-019-02444-2
Chemistry of Heterocyclic Compounds 2019, 55(3), 212–216
Synthesis of anabasine-containing aminomethyl
derivatives of 6-hydroxyaurones
1
2
Antonina V. Popova , Svitlana P. Bondarenko ,
3
1
Valentina I. Vinogradova , Mykhaylo S. Frasinyuk *
1
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1
Murmanska St., Kyiv 02094, Ukraine; е-mail: mykhaylo.frasinyuk@ukr.net
2
3
National University of Food Technologies,
8 Volodymyrska St., Kyiv 01601, Ukraine; е-mail: svitlana.bondarenko@ukr.net
6
Academician S. Yu. Yunusov Institute of Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, 77 Mirzo
Ulugbek St., Tashkent 700170, Uzbekistan; e-mail: 1946viv@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
019, 55(3), 212–216
Submitted February 20, 2019
Accepted March 25, 2019
2
O
O
Ar
HO
62–79%
N
H
N
O
N
N
(
CH2O)n
O
Ar
abs EtOH
DMAP
HO
R

, 12–16 h
N
R=H, Me
O
N
i-PrOH
, 3–5 h CH2(NMe2)2
9–93%

7
O
Ar
HO
Me
O
N
H
Me2N
HO
N
O
Ar
1
,4-dioxane, , 12–16 h
Me
57–87%
Aminomethylation of aurones was studied by using anabasine. The reaction in the case of 6-hydroxyaurones was shown to selectively
provide 7-aminomethyl-6-hydroxyaurones, while 5-aminomethyl-6-hydroxy-7-methylaurones could be obtained by transamination of
5
-dimethylaminomethyl derivatives of 6-hydroxy-7-methylaurones in the presence of anabasine.
Keywords: anabasine, benzofuran-3(2Н)-one, 6-hydroxyaurone, aminomethylation, Mannich base.
atom has helped to mitigate the toxicity.2 In addition,
alkaloids isolated from the roots of Alangium chinense,
identified as derivatives of (2S)-N-(2-hydroxybenzyl)-
anabasine, can suppress the development of inflammatory
a,3
Anabasine (3-[(2S)-piperidin-2-yl]pyridine) (1) and its
derivatives have been characterized as cholinesterase
1
inhibitors, as well as agonists of nicotinic acetylcholine
2
receptors, which are currently considered as important
4
targets in the drug discovery efforts aimed at treating
neurological disorders. Due to its high toxicity, the
practical applications of anabasine in medicine and
agriculture are quite limited. At the same time, alkylation
or acylation of this alkaloid at the piperidine ring nitrogen
processes in the peripheral nervous system.
One of the promising routes for modification of
anabasine involves its transformations via the Mannich
reaction. According to the literature data, anabasine has
been successfully used in aminomethylation of acetylenes
0
009-3122/19/55(3)-0212©2019 Springer Science+Business Media, LLC
212

Chemistry of Heterocyclic Compounds 2019, 55(3), 212–216
5
in the presence of CuCl, while N-benzyl derivatives of
anabasine have been obtained in reductive amination
reactions.6
reactivity of anabasine, arising from the presence of an
electron-withdrawing pyridine ring, as well as caused by
steric hindrance, prevented the occurrence of electrophilic
substitution reaction at the С-5 atom of benzylidene-
benzofuran-3(2Н)-one ring, which exhibited less reactivity
than the С-7 position.
We selected aurones in the role of СН substrates for
aminomethylation reactions involving anabasine, because
aurones represent a minor subclass of flavonoids that have
been previously aminomethylated in the presence of simple
In order to achieve aminomethylation of aurones at the
С-5 position, we developed a method for transamination of
5-dimethylaminomethyl derivatives 5а–е that, as we have
7
amines. In addition, it is known that their derivatives act as
8
cholinesterase inhibitors.
7b
It was found that our proposed method for the amino-
previously demonstrated, can be synthesized in high
yields by using the reactions of 6-hydroxy-7-methyl-
aurones 4а–е with bis(dimethylamino)methane. It was
shown that heating Mannich bases 5а–е with an excess of
anabasine (1) in 1,4-dioxane was accompanied by the
formation of aurone aminomethyl derivatives 6а–е
containing an anabasine moiety.
9
methylation of isoflavones in the presence of anabasine (1)
was also effective for reactions involving 6-hydroxy-
aurones 2а–e. The reactions of the starting aurones 2а–е
with anabasine (1) and paraformaldehyde in absolute EtOH
in the presence of 4-(dimethylamino)pyridine (DMAP)
proceeded regioselectively and were accompanied by the
formation of 7-aminomethyl derivatives 3а–е (Scheme 1),
which was confirmed by the spin-spin coupling constant of
The structures of our obtained anabasine-containing
Mannich bases – aurones 3а–е and 6а–е – were confirmed
by the methods of NMR spectroscopy and mass
8
.4–8.9 Hz observed between the Н-4 and Н-5 protons.
1
spectrometry. Н NMR spectra of these compounds
Scheme 1
contained not only the signals of aurone and anabasine
moieties, but also two doublets of methylene group with
spin-spin coupling constants of 13.9–15.1 Hz that were
characteristic for geminal protons.
Thus, we have developed methods for the synthesis of
anabasine-containing derivatives of 6-hydroxyaurones.
Aminomethylation of benzylidenebenzofuran-3(2Н)-one
ring in the presence of anabasine proceeded at position 7
under Mannich reaction conditions, while transamination
of 5-(dimethylaminomethyl)aurones by the action of
anabasine provided convenient synthetic access to
5
-(anabasin-1-yl)methyl
-methylaurones.
derivatives
of
6-hydroxy-
7
Experimental
Н and C NMR spectra were acquired on Varian
1
13
Mercury 400 (400 and 100 MHz, respectively) and Bruker
Avance 500 (500 and 125 MHz, respectively) instruments,
using TMS as internal standard. Mass spectra were
recorded on an Agilent 1100 HPLC system (atmospheric
pressure chemical ionization). Elemental analysis was
performed on a vario MICRO cube automatic СНNS-
analyzer. The reaction progress and purity of the obtained
compounds were controlled by TLC on Merck 60 F254 plates,
Heating of 6-hydroxy-7-methylaurones 4а–е with
anabasine (1) and paraformaldehyde either in absolute
EtOH or in 1,4-dioxane did not produce the expected
aminomethylation products. Apparently, the moderate
using CHCl –MeOH (9:1, 19:1) and EtOAc as eluents.
3
Synthesis of 6-hydroxyaurones 2a–e and 4a–e (General
method). A solution of 6-hydroxybenzofuran-3(2Н)-one
Scheme 2
O
NMe2
O
N
H
N
O
R1
CH (NMe )
R1
R3
2
2 2
N
1
N
R1
O
HO
HO
O
R2
i-PrOH, , 3–5 h
R2
1,4-dioxane
, 12–16 h
57–87%
O
Me
Me
HO
7
9–93%
R2
Me
6a–e
R4
R3
R4
4a–e
5a–e
R4
R3
1
, (CH O)n
2
1
2
4
3
1
3
2
4
abs EtOH, DMAP
12–16 h
a R = R = R = H, R = OMe; b R = R = OMe, R = R = H;
1
4
2
3
1
4
2
3
,
c R = R = H, R = R = OMe; d R = R = H, R + R = OCH O;
2
1
4
2
3
e R = R = OMe, R = R = H
13
2

Chemistry of Heterocyclic Compounds 2019, 55(3), 212–216
(
1.50 g, 10 mmol, for the synthesis of compounds 2a–e) or
-hydroxy-7-methylbenzofuran-3(2Н)-one (1.64 g, 10 mmol,
(2Z)-6-Hydroxy-2-(4-methoxybenzylidene)-7-{[(2S)-
6
2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzofuran-3(2H)-
for the synthesis of compounds 4a–e) and aromatic
aldehyde in a 1:1 mixture of DMF–ЕtOH (50 ml) was
treated by adding 50% aqueous solution of KОН (2.3 ml).
The mixture was stirred at room temperature for
one (3a). Yield 337 mg (76%), yellow crystals, mp 193–
1
195°С. H NMR spectrum (400 MHz, CDCl
3
), δ, ppm
(J, Hz): 1.46–1.62 (1H, m), 1.69–1.89 (3H, m), 1.89–2.01 (2H,
m), 2.28–2.41 (1H, m), 3.26–3.37 (1H, m) and 3.41–3.50
4
–6 h (the completion of reaction was determined by TLC).
Then the reaction mixture was poured into vigorously
stirred hot H O (50 ml) and neutralized with concentrated
HCl to рН 4–5. The precipitate that formed was filtered
off, washed with H O, dried, and crystallized from a 1:1
(1H, m, CH and CH piperidine); 3.64 (1H, d, J = 14.9) and
2
3.93 (1H, d, J = 14.9, CH
2
); 3.86 (3H, s, 4'-OCH ); 6.60
3
2
(1H, d, J = 8.4, H-5); 6.72 (1H, s, =CHAr); 6.97 (2H, d,
J = 8.4, H-3',5'); 7.31 (1H, dd, J = 8.0, J = 4.8, H-5''); 7.53
(1H, d, J = 8.4, H-4); 7.73 (2H, d, J = 8.4, H-2',6'); 7.76–
7.82 (1H, m, H-4''); 8.53 (1H, dd, J = 4.8, J = 1.6, H-6'');
2
mixture of DMF–МеОН. The obtained NMR spectra
7
c,8c
10
13
of compounds 2а–e
and 4а,c matched the literature
8.65 (1H, d, J = 2.3, H-2''). C NMR spectrum (125 MHz,
data.
CDCl ), δ, ppm: 24.6; 25.6; 36.0; 51.2; 54.2; 55.5; 67.0;
3
(
2Z)-2-(2,4-Dimethoxybenzylidene)-6-hydroxy-7-methyl-
104.5; 111.8; 113.5; 113.8; 114.6; 124.3; 124.8; 125.3;
133.0; 135.0; 137.6; 146.8; 149.7; 160.8; 165.4; 166.5;
1
-benzofuran-3(2H)-one (4b). Yield 2.59 g (83%), yellow
1
+
crystals, mp 287–289°С. H NMR spectrum (400 MHz,
DMSO-d ), δ, ppm (J, Hz): 2.20 (3H, s, 7-CH ); 3.84 (3H, s)
and 3.89 (3H, s, 2',4'-OCH ); 6.65 (1H, d, J = 2.5, H-3');
.69–6.81 (2H, m, H-5,5'); 7.01 (1H, s, =CHAr); 7.44 (1H,
d, J = 8.4, H-4); 8.15 (1H, d, J = 8.7, H-6'); 11.00 (1H, br. s,
182.7. Mass spectrum, m/z (Irel, %): 443 [M+H] (100).
6
3
Found, %: C 73.05; H 6.70; N 6.56. C27
Calculated, %: C 73.28; H 5.92; N 6.33.
H
26
N
2
O .
4
3
6
(2Z)-2-(2,4-Dimethoxybenzylidene)-6-hydroxy-7-{[(2S)-
2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzofuran-3(2H)-
1
3
6
-OH). C NMR spectrum (125 MHz, DMSO-d
6
), δ, ppm:
one (3b). Yield 293 mg (62%), yellow crystals, mp 193–
1
7
1
1
.6; 55.5; 55.9; 98.2; 103.9; 106.6; 107.6; 111.9; 112.8;
195°С. H NMR spectrum (400 MHz, CDCl
3
), δ, ppm
13.3; 122.5; 132.2; 146.3; 159.7; 162.3; 163.7; 165.6;
(J, Hz): 1.51–1.65 (1H, m), 1.73–2.02 (5H, m), 2.28–2.40 (1H,
m), 3.29–3.37 (1H, m) and 3.41–3.48 (1H, m, CH and CH
piperidin); 3.64 (1H, d, J = 14.9) and 3.94 (1H, d, J = 14.9,
CH ); 3.88 (3H, s) and 3.90 (3H, s, 2',4'-OCH ); 6.47 (1H,
+
81.8. Mass spectrum, m/z (Irel, %): 313 [M+H] (100).
2
Found, %: C 69.37; H 5.41. C18
H
16
O . Calculated, %:
5
C 69.22; H 5.16.
2
3
(
2Z)-2-(1,3-Benzodioxol-5-ylmethylidene)-6-hydroxy-
d, J = 2.4, H-3'); 6.61 (1H, d, J = 8.5, H-5); 6.65 (1H, dd,
J = 8.5, J = 2.4, H-5'); 7.29 (1H, s, =CHAr); 7.33 (1H, dd,
J = 8.0, J = 4.8, H-5''); 7.56 (1H, d, J = 8.5, H-4); 7.78–
7.85 (1H, m, H-4''); 8.06 (1H, d, J = 8.5, H-6'); 8.55 (1H,
dd, J = 4.8, J = 1.6, H-6''); 8.66 (1H, d, J = 2.3, H-2'').
7
-methyl-1-benzofuran-3(2H)-one (4d). Yield 2.34 g
1
(
79%), yellow crystals, mp 293–295°С. H NMR spectrum
);
.10 (2H, s, OCH O); 6.71 (1H, s, =CHAr); 6.76 (1H, d,
(
400 MHz, DMSO-d
6
), δ, ppm (J, Hz): 2.19 (3H, s, 7-CH
3
6
2
13
J = 8.4, H-5); 7.03 (1H, d, J = 8.4, H-7'); 7.44 (1H, d,
J = 8.4, H-4); 7.46 (2H, d, J = 8.4, H-6'); 7.52 (1H, d,
C NMR spectrum (125 MHz, CDCl ), δ, ppm: 24.6; 25.6;
3
36.0; 51.2; 54.1; 55.5; 55.6; 66.9; 98.1; 104.4; 105.7;
106.0; 113.2; 114.0; 114.6; 124.2; 124.6; 132.7; 134.9;
137.7; 146.8; 149.6; 160.3; 162.4; 165.2; 166.2; 182.6.
13
J = 1.6, H-4'); 10.95 (1H, br. s, 6-OH). C NMR spectrum
(
125 MHz, DMSO-d
6
), δ, ppm: 7.6; 101.6; 107.6; 108.9;
+
1
1
09.9; 110.5; 112.0; 112.6; 122.6; 126.4; 126.9; 146.5; 147.8;
Mass spectrum, m/z (Irel, %): 473 [M+H] (100). Found, %:
48.5; 163.9; 165.7; 181.8. Mass spectrum, m/z (Irel, %):
C 71.40; H 6.11; N 6.02. C28
C 71.17; H 5.97; N 5.93.
H
28
N
2
O . Calculated, %:
5
+
2
97 [M+H] (100). Found, %: C 69.17; H 4.00. C17
H O .
12 5
Calculated, %: C 68.92; H 4.08.
(2Z)-2-(2,3-Dimethoxybenzylidene)-6-hydroxy-7-{[(2S)-
2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzofuran-3(2H)-
(
2Z)-2-(2,5-Dimethoxybenzylidene)-6-hydroxy-7-methyl-
1
-benzofuran-3(2H)-one (4e). Yield 2.84 g (91%), yellow
one (3c). Yield 374 mg (79%), yellow crystals, mp 184–
1
1
crystals, mp 295–297°С. H NMR spectrum (400 MHz,
DMSO-d ), δ, ppm (J, Hz): 2.18 (3H, s, 7-CH ); 3.79 (3H, s)
and 3.84 (3H, s, 2',5'-OCH ); 6.76 (1H, d, J = 8.4, H-5);
.93–7.06 (3H, m, =CHAr, H-3',4'); 7.43 (1H, d, J = 8.4,
186°С. H NMR spectrum (400 MHz, CDCl
3
), δ, ppm
6
3
(J, Hz): 1.48–1.64 (1H, m), 1.74–1.89 (3H, m), 1.92–2.01 (2H,
3
m), 2.28–2.40 (1H, m), 3.28–3.37 (1H, m) and 3.40–3.48
6
(1H, m, CH and CH piperidine); 3.63 (1H, d, J = 15.1) and
2
1
3
H-4), 7.76 (1H, d, J = 3.1, H-6'). C NMR spectrum
3.93 (1H, d, J = 15.1, CH
2
); 3.89 (3H, s) and 3.90 (3H, s,
(
125 MHz, DMSO-d
6
), δ, ppm: 7.4; 55.1; 56.1; 103.2;
2',3'-OCH ); 6.62 (1H, d, J = 8.4, H-5); 6.97 (1H, dd,
3
1
07.6; 112.0; 112.4; 112.5; 114.9; 117.2; 121.0; 122.7; 147.6;
J = 8.3, J = 1.4, H-4'); 7.15–7.22 (1H, m, H-5'); 7.23 (1H,
s, =CHAr); 7.33 (1H, dd, J = 8.0, J = 4.7, H-5''); 7.57 (1H,
d, J = 8.4, H-4); 7.70 (1H, dd, J = 8.0, J = 1.4, H-6'); 7.77–7.83
(1H, m, H-4''); 8.55 (1H, dd, J = 4.8, J = 1.6, H-6''); 8.65
1
52.5; 152.9; 164.0; 165.8; 181.9. Mass spectrum, m/z
+
(
I
18
rel, %): 313 [M+H] (100). Found, %: C 69.01; H 4.92.
C
H
16
O . Calculated, %: C 69.22; H 5.16.
5
13
Synthesis of 7-(anabasin-1-yl)-7-hydroxyaurones 3а–е
(1H, d, J = 2.7, H-2''). C NMR spectrum (125 MHz,
(
(
General method). A hot solution of 6-hydroxyaurone 2a–e
CDCl ), δ, ppm: 24.6; 25.6; 36.0; 51.2; 54.2; 56.0; 61.7;
3
2 mmol) in absolute EtOH (15 ml) was treated by adding
67.0; 104.5; 105.5; 113.5; 113.6; 113.7; 123.0; 124.3;
125.0; 126.9; 134.9; 137.6; 148.5; 149.2; 149.7; 152.9;
165.6; 166.8; 182.8. Mass spectrum, m/z (Irel, %): 473
anabasine (1) (0.80 ml, 5 mmol), paraformaldehyde (150 mg,
equivalent to 5 mmol of formaldehyde), and DMAP
+
(
5 mg). The reaction mixture was refluxed for 12–16 h,
[M+H] (100). Found, %: C 70.92; H 6.21; N 6.05.
then cooled and the solvent was evaporated at reduced
pressure. The obtained residue was purified by silica gel
column chromatography using EtOAc as eluent.
C
28
H
28
N
2
O . Calculated, %: C 71.17; H 5.97; N 5.93.
5
(2Z)-6-Hydroxy-7-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]-
methyl}-2-(2,3,4-trimethoxybenzylidene)-1-benzofuran-
2
14

Chemistry of Heterocyclic Compounds 2019, 55(3), 212–216
3
(2H)-one (3d). Yield 327 mg (65%), yellow crystals,
one (5d). Yield 600 mg (85%), yellow crystals, mp 192–
1
1
mp 121–123°С. H NMR spectrum (400 MHz, CDCl
δ, ppm (J, Hz): 1.48–1.63 (1H, m), 1.72–2.02 (5H, m), 2.27–
.39 (1H, m), 3.28–3.37 (1H, m) and 3.39–3.47 (1H, m,
piperidine); 3.62 (1H, d, J = 14.9) and 3.95
1H, d, J = 14.9, CH ); 3.89 (3H, s), 3.95 (3H, s) and 3.96
3H, s, 2',3',4'-OCH ); 6.61 (1H, d, J = 8.4, H-5'); 6.84
1H, d, J = 8.9, H-5); 7.16 (1H, s, =CHAr); 7.34 (1H, dd,
3
),
194°С. H NMR spectrum (400 MHz, CDCl
3
), δ, ppm
); 3.70
O); 6.71 (1H, s, =CHAr);
6.89 (1H, d, J = 8.1, H-7'); 7.27–7.35 (2H, m, H-4',6'); 7.56
(J, Hz): 2.30 (3H, s, 7-CH
3
); 2.38 (6H, s, N(CH
)
3 2
2
(2H, s, CH
2
); 6.05 (2H, s, OCH
2
CH and CH
2
1
3
(
(
(
2
(1H, s, H-4). C NMR spectrum (100 MHz, CDCl ),
3
3
δ, ppm: 7.8; 44.1; 62.5; 101.6; 108.6; 108.8; 110.5; 111.2;
112.7; 117.8; 121.3; 127.0; 127.2; 147.2; 148.2; 148.8;
165.7; 166.3; 183.4. Mass spectrum, m/z (Irel, %): 354
J = 7.9, J = 4.8, H-5''); 7.56 (1H, d, J = 8.4, H-4); 7.78–7.83
+
(
1H, m, H-4''); 7.85 (1H, d, J = 8.9, H-6'); 8.55 (1H, dd,
[M+H] (100). Found, %: C 67.71; H 5.19; N 4.08.
13
J = 4.8, J = 1.6, H-6''); 8.65 (1H, d, J = 2.2, H-2''). C NMR
C
20
H
19NO . Calculated, %: C 67.98; H 5.42; N 3.96.
5
spectrum (100 MHz, CDCl
3
), δ, ppm: 24.5; 25.5; 35.9;
(2Z)-5-[(Dimethylamino)methyl]-2-(2,5-dimethoxybenzyl-
5
1
1
1.1; 54.1; 56.1; 60.9; 61.9; 66.9; 104.3; 105.8; 107.8;
idene)-6-hydroxy-7-methyl-1-benzofuran-3(2H)-one (5e).
13.3; 113.8; 119.6; 124.2; 124.7; 126.6; 134.9; 137.6;
Yield 642 mg (87%), yellow crystals, mp 155–156°С.
1
42.2; 147.5; 149.6; 153.8; 155.1; 165.2; 166.3; 182.5.
H NMR spectrum (400 MHz, CDCl
3
), δ, ppm (J, Hz): 2.27
+
Mass spectrum, m/z (Irel, %): 503 [M+H] (100). Found, %:
(3H, s, 7-CH
3
); 2.37 (6H, s, N(CH
3
)
2
); 3.69 (2H, s, CH
); 6.85 (1H, d,
2
);
C 69.14; H 6.24; N 5.39. C29
C 69.31; H 6.02; N 5.57.
H
30
N
2
O
6
. Calculated, %:
3.85 (3H, s) and 3.87 (3H, s, 2',5'-OCH
3
J = 9.0, H-3'); 6.91 (1H, dd, J = 9.0, J = 3.0, H-4'); 7.30
(2Z)-6-Hydroxy-7-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]-
(1H, s, =CHAr); 7.32 (1H, s, H-4); 7.93 (1H, d, J = 3.0, H-6').
13
methyl}-2-(3,4,5-trimethoxybenzylidene)-1-benzofuran-
(2H)-one (3e). Yield 377 mg (75%), yellow crystals, mp 194–
C NMR spectrum (125 MHz, CDCl ), δ, ppm: 7.7; 44.2;
3
3
55.7; 56.3; 62.5; 105.1; 108.5; 112.1; 112.8; 115.8; 117.3;
117.8; 121.5; 122.4; 148.4; 153.4; 153.5; 165.7; 166.4;
1
1
96°С. H NMR spectrum (400 MHz, CDCl
Hz): 1.49–1.62 (1H, m), 1.71–2.03 (5H, m), 2.18–2.29 (1H,
m) and 3.20–3.38 (2H, m, CH and CH piperidine); 3.56
1H, d, J = 14.7, CH ); 3.92–3.96 (7H, m, CH
3
), δ, ppm (J,
+
183.5. Mass spectrum, m/z (Irel, %): 370 [M+H] (100).
2
Found, %: C 68.07; H 6.44; N 3.98. C21
Calculated, %: C 68.28; H 6.28; N 3.79.
H
23NO .
5
(
3
2
2
,
',5'-OCH
3
); 3.91 (3H, s, 4'-OCH
3
); 6.61 (1H, d, J = 8.5,
Synthesis of 5-(anabasin-1-yl)-6-hydroxy-7-methyl-
aurones 6а–е (General method). A hot solution of the
appropriate compound 5a–e (1 mmol) in 1,4-dioxane
(5 ml) was treated by adding anabasine (1) (0.32 ml,
2 mmol). The reaction mixture was refluxed for 12–16 h,
then cooled, and the solvent was evaporated at reduced
pressure. The obtained residue was purified by silica gel
column chromatography using EtOAc as eluent.
H-5); 6.67 (1H, s, =CHAr); 7.08 (2H, s, H-2',6'); 7.32 (1H,
dd, J = 7.9, J = 4.8, H-5''); 7.54 (1H, d, J = 8.5, H-4); 7.70–
13
7
.78 (1H, m, H-4''); 8.51–8.57 (2H, m, H-2'',6''). C NMR
spectrum (125 MHz, CDCl ), δ, ppm: 24.6; 25.6; 35.7; 51.3;
3
5
1
1
5
4.6; 56.1; 61.2; 67.7; 104.4; 108.6; 111.7; 113.6; 124.4;
25.0; 128.1; 134.9; 137.5; 139.7; 147.6; 149.5; 150.0;
53.3; 165.4; 166.4; 182.5. Mass spectrum, m/z (Irel, %):
+
03 [M+H] (100). Found, %: C 69.52; H 6.16; N 5.41.
(2Z)-6-Hydroxy-2-(4-methoxybenzylidene)-7-methyl-
5-{[(2S)-2-(pyridine-3-yl)piperidin-1-yl]methyl}-1-benzo-
furan-3(2H)-one (6a). Yield 315 mg (69%), yellow
C
29
H
30
N
2
O . Calculated, %: C 69.31; H 6.02; N 5.57.
6
Synthesis of dimethylaminomethyl-6-hydroxy-7-methyl-
1
aurones 5a–e (General method). A hot solution of the
appropriate 6-hydroxyaurone 4a–e (2 mmol) in i-PrOH
crystals, mp 130–132°С. H NMR spectrum (400 MHz,
CDCl ), δ, ppm (J, Hz): 1.50–1.56 (1H, m), 1.72–2.14 (5H,
3
(
(
15 ml) was treated by adding bis(dimethylamino)methane
0.33 ml, 2.4 mmol). The reaction mixture was refluxed for
m), 2.17–2.20 (1H, m) and 3.18–3.29 (2H, m, CH and CH
piperidine); 2.30 (3H, s, 7-CH ); 3.10 (1H, d, J = 14.0) and
3.98 (1H, d, J = 14.0, CH ); 3.87 (3H, s, 4'-OCH ); 6.75
2
3
3
–5 h, then cooled, diluted with hexane (15–20 ml), the
2
3
precipitate that formed was filtered off and crystallized
from 1:2 mixture of i-PrOH–hexane. The physicochemical
and spectral characteristics of compounds 5а,c were
(1H, s, =CHAr); 6.98 (2H, d, J = 8.6, H-3',5'); 7.18 (1H, s,
H-4); 7.35 (1H, dd, J = 7.9, J = 4.8, H-5''); 7.78 (1H, d,
J = 8.0, H-4''); 7.86 (2H, d, J = 8.6, H-2',6'); 8.57 (1H, d,
7b
13
described in our earlier work.
J = 4.0, H-6''); 8.62 (1H, d, J = 2.3, H-2''). C NMR spectrum
(2Z)-6-Hydroxy-5-[(dimethylamino)methyl]-2-(2,4-di-
(125 MHz, CDCl ), δ, ppm: 7.8; 24.6; 25.6; 35.7; 53.4;
3
methoxybenzylidene)-7-methyl-1-benzofuran-3(2H)-one
55.4; 58.5; 67.0; 108.5; 111.4; 113.1; 114.5; 117.4; 121.5;
124.2; 125.6; 133.1; 135.0; 137.6; 147.1; 149.6; 160.7;
164.5; 166.1; 183.4. Mass spectrum, m/z (Irel, %): 457
(
5b). Yield 583 mg (79%), yellow crystals, mp 173–175°С.
1
H NMR spectrum (400 MHz, CDCl
3H, s, 7-CH ); 2.35 (6H, s, N(CH
.85 (3H, s) and 3.86 (3H, s, 2',4'-OCH
3
), δ, ppm (J, Hz): 2.28
); 3.67 (2H, s, CH );
); 6.45 (1H, d,
+
(
3
3
3
)
2
2
[M+H] (100). Found, %: C 73.51; H 6.03; N 6.27.
3
C
28
H
28
N
2
O . Calculated, %: C 73.66; H 6.18; N 6.14.
4
J = 2.4, H-3'); 6.61 (1H, dd, J = 8.7, J = 2.4, H-5'); 7.28
(2Z)-2-(2,4-Dimethoxybenzylidene)-6-hydroxy-7-methyl-
(
(
2H, s, =CHAr, H-4); 8.26 (1H, d, J = 8.5, H-6'); 10.94
1H, br. s, 6-OH). C NMR spectrum (125 MHz, CDCl ),
5-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzo-
furan-3(2H)-one (6b). Yield 278 mg (57%), yellow
13
3
1
δ, ppm: 7.7; 44.1; 55.5; 55.7; 62.5; 98.1; 105.5; 105.7;
crystals, mp 129–131°С. H NMR spectrum (400 MHz,
1
1
3
08.4; 113.1; 115.0; 117.6; 121.2; 133.0; 147.2; 160.2;
CDCl ), δ, ppm (J, Hz): 1.46–1.56 (1H, m), 1.72–1.95 (5H,
3
62.3; 165.2; 166.1; 183.5. Mass spectrum, m/z (Irel, %):
m), 2.13–2.18 (1H, m) and 3.18–3.28 (2H, m, CH and CH
piperidine); 2.29 (3H, s, 7-CH ); 3.09 (1H, d, J = 14.2) and
3.98 (1H, d, J = 14.2, CH ); 3.87 (6H, s, 2',4'-OCH ); 6.46
2
+
70 [M+H] (100). Found, %: C 68.52; H 6.39; N 3.52.
3
C
21
(
H
23NO
5
. Calculated, %: C 68.28; H 6.28; N 3.79.
2
3
2Z)-2-(1,3-Benzodioxol-5-ylmethylidene)-5-[(dimethyl-
(1H, d, J = 2.4, H-3'); 6.63 (1H, dd, J = 8.7, J = 2.4, H-5');
7.18 (1H, s, H-4); 7.29 (1H, s, =CHAr); 7.34 (1H, dd, J = 7.8,
amino)methyl]-6-hydroxy-7-methyl-1-benzofuran-3(2H)-
2
15

Chemistry of Heterocyclic Compounds 2019, 55(3), 212–216
J = 4.8, H-5'''); 7.74–7.83 (1H, m, H-4''); 8.26 (1H, d, J = 8.7,
H-6'); 8.56 (1H, dd, J = 4.8, J = 1.6, H-6''); 8.62 (1H, d,
58.5; 67.1; 105.2; 108.5; 112.0; 113.0; 115.8; 117.3; 117.5;
121.7; 122.3; 124.2; 135.0; 137.6; 148.2; 149.6; 149.7; 153.4;
153.5; 164.5; 166.0; 183.3. Mass spectrum, m/z (Irel, %):
13
J = 2.3, H-2''). C NMR spectrum (125 MHz, CDCl ),
3
+
δ, ppm: 7.8; 24.7; 25.6; 35.8; 53.4; 55.6; 55.7; 58.5; 67.1;
487 [M+H] (100). Found, %: C 71.81; H 6.42; N 5.84.
9
8.2; 105.7; 108.5; 113.4; 115.0; 117.3; 121.5; 124.2; 133.1;
C
29
H
30
N
2
O
5
. Calculated, %: C 71.59; H 6.21; N 5.76.
135.0; 137.7; 147.2; 149.6; 160.3; 162.3; 164.1; 165.9; 183.3.
+
Supplementary information file containing Н and 13С
1
Mass spectrum, m/z (Irel, %): 487 [M+H] (100). Found, %:
C 71.33; H 6.34; N 5.71. C29
H
30
N
2
O
5
. Calculated, %:
NMR spectra of all the synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
C 71.59; H 6.21; N 5.76.
(2Z)-2-(3,4-Dimethoxybenzylidene)-6-hydroxy-7-methyl-
References
5
-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzo-
1
. (a) Tilyabaev, Z.; Dalimov, D. N.; Kushiev, Kh. Kh.;
furan-3(2H)-one (6c). Yield 424 mg (87%), yellow
1
Gafurov, M. B.; Abduvakhabov, A. A. Chem. Nat. Compd.
crystals, mp 125–127°С. H NMR spectrum (400 MHz,
1
994, 30, 15. [Khim. Prirod. Soedin. 1994, 19.]
CDCl ), δ, ppm (J, Hz): 1.46–1.56 (1H, m), 1.69–1.83 (5H,
3
(
b) Rozengart, E. V.; Basova, N. E.; Suvorov, A. A. J. Evol.
Biochem. Physiol. 2006, 42, 11. [Zh. Evol. Biokhim. i Fiziol.
006, 42, 11.]
m), 1.89–1.92 (1H, m), 3.09–3.12 (1H, m) and 3.17–3.29
(
(
1H, m, CH and CH
1H, d, J = 14.0, CH
, 3',4'-OCH ); 6.74 (1H, s, =CHAr); 6.93 (1H, d, J = 8.3,
2
piperidine); 2.28 (3H, s, 7-CH
3
); 3.11
2
2
), 3.94 (3H, s) and 3.96–4.01 (4H, m,
2
. (a) Nasirov, S. Kh.; Khazbievich, I. S. Pharmacology of
Anabasis aphylla L. Alkaloids and Clinical Use of Anabasine
Hydrochloride [in Russian]; Anichkov, S. V., Ed.; FAN:
Tashkent, 1982. (b) Bhatti, B. S.; Strachan, J.-P.; Breining, S. R.;
Miller, C. H.; Tahiri, P.; Crooks, P. A.; Deo, N.; Day, C. S.;
Caldwell, W. S. J. Org. Chem. 2008, 73, 3497. (c) Lee, S. T.;
Wildeboer, K.; Panter, K. E.; Kem, W. R.; Gardner, D. R.;
Molyneux, R. J.; Chang, C.-W. T.; Soti, F.; Pfister, J. A.
Neurotoxicol. Teratol. 2006, 28, 220. (d) Mastropaolo, J.;
Rosse, R. B.; Deutsch, S. I. Behav. Brain Res. 2004, 153, 419.
CH
2
3
H-5'); 7.18 (1H, s, H-4); 7.31–7.40 (2H, m, H-6',5''); 7.67
1H, d, J = 2.0, H-2'); 7.74–7.80 (1H, m, H-4''); 8.56 (1H,
dd, J = 4.8, J = 1.6, H-6''); 8.62 (1H, d, J = 2.3, H-2'').
(
13
C NMR spectrum (125 MHz, CDCl ), δ, ppm: 7.6; 24.6;
3
2
1
1
1
5.6; 35.7; 53.4; 55.8; 56.0; 58.5; 67.0; 108.3; 111.2;
11.6; 113.0; 113.3; 117.5; 121.6; 124.2; 125.6; 125.8;
35.0; 137.6; 147.1; 149.0; 149.6; 150.4; 164.5; 165.9;
+
83.2. Mass spectrum, m/z (Irel, %): 487 [M+H] (100).
(
e) Sarkar, T. K.; Basak, S.; Wainer, I.; Moaddel, R.;
Found, %: C 71.72; H 6.40; N 5.51. C29
Calculated, %: C 71.59; H 6.21; N 5.76.
H
30
N
2
O .
5
Yamaguchi, R.; Jozwiak, K.; Chen, H.-T.; Lin, C.-C. J. Med.
Chem. 2004, 47, 6691.
(
2Z)-2-(1,3-Benzodioxol-5-ylmethylidene)-6-hydroxy-
3
. Anichkov, S.; Khromov-Borisov, N.; Zakharova, N.; Gaft, S.;
Bekhtereva, É.; Rudenko, A. Pharm. Chem. J. 1976, 10,
7
-methyl-5-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]methyl}-
1
-benzofuran-3(2H)-one (6d). Yield 301 mg (64%), yellow
1
478. [Khim.-Farm. Zh. 1976, 10(11), 53.]
1
crystals, mp 134–136°С. H NMR spectrum (400 MHz,
4
. Zhang, Y.; Liu, Y.-B.; Li, Y.; Ma, S.-G.; Li, L.; Qu, J.;
Zhang, D.; Chen, X.-G.; Jiang, J.-D.; Yu, S.-S. J. Nat. Prod.
2013, 76, 1058.
CDCl
m), 2.13–2.19 (1H, m) and 3.17–3.29 (2H, m, СН and СН
piperidine); 2.29 (3H, s, 7-CH ); 3.10 (1H, d, J = 13.9) and
.97 (1H, d, J = 13.9, CH ); 6.04 (2H, s, OCH O); 6.69
3
), δ, ppm (J, Hz): 1.48–1.56 (1H, m), 1.72–1.95 (5H,
2
5. (a) Kabdraisova, A. Z.; Faskhutdinov, M. F.; Yu, V. K.;
Praliev, K. D.; Fomicheva, E. E.; Shin, S. N.; Berlin, K. D.
Chem. Nat. Compd. 2007, 43, 437. [Khim. Prirod. Soedin. 2007,
3
3
2
2
(
1H, s, =CHAr); 6.87 (1H, d, J = 8.1, H-7'); 7.17 (1H, s,
3
60.] (b) Mavrov, M. V.; Zlotin, S. G. Russ. Chem. Bull., Int.
H-4); 7.29 (1H, dd, J = 8.1, J = 1.7, H-6'); 7.34 (1H, dd,
J = 7.9, J = 4.7, H-5''); 7.54 (1H, d, J = 1.7, H-4'); 7.74–
Ed. 2007, 56, 1637. [Izv. Akad. Nauk, Ser. Khim. 2007, 1576.]
(
c) Mavrov, M. V.; Zlotin, S. G. Russ. Chem. Bull., Int. Ed.
7
.81 (1H, m, H-4''); 8.53–8.58 (1H, m, H-6''); 8.59–8.65
13
2009, 58, 1921. [Izv. Akad. Nauk, Ser. Khim. 2009, 1860.]
(
1H, m, H-2''). C NMR spectrum (125 MHz, CDCl
3
),
6
7
. Tlegenov, R. T. Chemistry of Raw Materials of Plant Origin
δ, ppm: 7.8; 24.6; 25.6; 35.7; 53.4; 58.5; 67.0; 101.6; 108.6;
[in Russian], 2008, (1), 115.
1
08.8; 110.5; 111.4; 113.0; 117.5; 121.5; 124.2; 127.1; 135.0;
. (a) Popova, A. V.; Bondarenko, S. P.; Frasinyuk, M. S. Chem.
Heterocycl. Compd. 2016, 52, 592. [Khim. Geterotsikl.
Soedin. 2016, 52, 592.] (b) Bondarenko, S. P.; Frasinyuk, M. S.
Chem. Heterocycl. Compd. 2018, 54, 765. [Khim. Geterotsikl.
Soedin. 2018, 54, 765.] (c) Popova, A. V.; Frasinyuk, M. S.;
Bondarenko, S. P.; Zhang, W.; Xie, Y.; Martin, Z. M.; Cai, X.;
Fiandalo, M. V.; Mohler, J. L.; Liu, C.; Watt, D. S.; Sviripa, V. M.
Chem. Pap. 2018, 72, 2443.
1
1
37.6; 147.1; 148.2; 148.8; 149.6; 149.7; 164.6; 166.0;
+
83.3. Mass spectrum, m/z (Irel, %): 471 [M+H] (100).
Found, %: C 71.71; H 5.31; N 6.20. C28
Calculated, %: C 71.48; H 5.57; N 5.95.
H
26
N
2
O .
5
(2Z)-2-(2,5-Dimethoxybenzylidene)-6-hydroxy-7-methyl-
5
-{[(2S)-2-(pyridin-3-yl)piperidin-1-yl]methyl}-1-benzo-
furan-3(2H)-one (6e). Yield 385 mg (79%), yellow
1
8
. (a) Mughal, E. U.; Sadiq, A.; Murtaza, S.; Rafique, H.; Zafar, M. N.;
Riaz, T.; Khan, B. A.; Hameed, A.; Khan, K. M. Bioorg. Med.
Chem. 2017, 25, 100. (b) Liew, K.-F.; Chan, K.-L.; Lee, C.-Y. Eur.
J. Med. Chem. 2015, 94, 195. (c) Lee, Y. H.; Shin, M. C.; Yun,
Y. D.; Shin, S. Y.; Kim, J. M.; Seo, J. M.; Kim, N.-J.; Ryu, J. H.;
Lee, Y. S. Bioorg. Med. Chem. 2015, 23, 231.
crystals, mp 194–196°С. H NMR spectrum (400 MHz,
CDCl ), δ, ppm (J, Hz): 1.50–1.56 (1H, m), 1.72–1.95 (5H,
3
m), 2.14–2.20 (1H, m) and 3.18–3.29 (2H, m, СН and СН
2
piperidine); 2.28 (3H, s, 7-CH
3
); 3.10 (1H, d, J = 14.0) and
); 3.85 (3H, s) and 3.88 (3H, s,
); 6.85 (1H, d, J = 9.0, H-3'); 6.92 (1H, dd,
3
2
.98 (1H, d, J = 14.0, CH
',5'-OCH
2
3
9. Bondarenko, S. P.; Frasinyuk, M. S.; Mrug, G. P.;
Vinogradova, V. I.; Khilya, V. P. Chem. Nat. Compd. 2018,
J = 9.0, J = 3.1, H-4'); 7.18 (1H, s, H-4); 7.30 (1H, s,
=
CHAr); 7.35 (1H, dd, J = 8.0, J = 4.8, H-5''); 7.71–7.81
5
4, 1068. [Khim. Prirod. Soedin. 2018, 907.]
(
1H, m, H-4''); 7.92 (1H, d, J = 3.1, H-6'); 8.55–8.57 (1H,
10. Popova, A. V.; Bondarenko, S. P.; Podobii, E. V.;
Frasinyuk, M. S.; Vinogradova, V. I. Chem. Nat. Compd.
2017, 53, 708. [Khim. Prirod. Soedin. 2017, 603.]
1
3
m, H-6''); 8.62 (1H, s, H-2''). C NMR spectrum (125 MHz,
CDCl ), δ, ppm: 7.7; 24.6; 25.6; 35.7; 53.4; 55.7; 56.3;
3
2
16