Modification of quercetin by (dodecylsulfanyl)methyl group

Article abstract of DOI:10.1007/s11172-019-2438-y

A simple and efficient synthetic protocol for alkylthiomethylation of quercetin was proposed. New sulfur-containing quercetin derivatives were obtained by the reaction of this flavonoid with (N,N-diethylaminomethyl)dodecyl sulfide.

Full text of DOI:10.1007/s11172-019-2438-y

194
Russian Chemical Bulletin, International Edition, Vol. 68, No. 1, pp. 194—196, January, 2019
Modification of quercetin by (dodecylsulfanyl)methyl group
T. K. Bagavieva, S. E. Yagunov,а S. V. Kholshin, and A. E. Prosenko
а
а
а,b
аNovosibirsk State Pedagogical University,
2
8 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 244 1856. E-mail: syagunov@yandex.ru
b
Novosibirsk Institute of Antioxidants,
5
4а ul. Krasnyi prospekt, 630091 Novosibirsk, Russian Federation.
Fax: +7 (383) 217 0781
A simple and efficient synthetic protocol for alkylthiomethylation of quercetin was proposed.
New sulfur-containing quercetin derivatives were obtained by the reaction of this flavonoid with
(
N,N-diethylaminomethyl)dodecyl sulfide.
Key words: quercetin, alkylthiomethylation, sulfur-containing antioxidants.
One of the promising directions of development of
research in the field of synthesis and study of properties
of flavonoid chalcogen-containing derivatives.
highly efficient antioxidants for biological and medical
application is the modification of natural antioxidants,
tocopherols and flavonoids, by chalcogen-containing
groups. Recently synthesized S-, Se-, and Te-containing
analogs of tocopherols were shown to possess high anti-
oxidant activity.1 At the same time, only few examples
of flavonoid chalcogen-containing derivatives are found
in the literature, however, the available data indicate their
high inhibitory activity and valuable biological proper-
The earlier found approach to the efficient synthesis
of thio derivatives of alkylphenols, 5-hydroxy-2,3-dihydro-
benzofurans, and 6-hydroxychromans by the reaction with
9
,10
(N,N-diethylaminomethyl)dodecyl sulfide
is used in
—3
the present work for modification of quercetin. We found
that reflux of a solution of quercetin (1), citric acid, and
(N,N-diethylaminomethyl)dodecyl sulfide in methoxy-
ethanol led to compound 2 (Scheme 1) in 65% yield. Thirty
minutes after the beginning of the reaction, the mixture
4
—8
ties.
These circumstances substantiate the broader
Scheme 1
Reagents and conditions: i. Et NCH SC H , citric acid, MeOCH CH OH, ; ii. CH O, morpholine, EtOH, 60 С; iii. C H25SH,
2
2
12 25
2
2
2
12
MeOCH CH OH, .
2
2
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0194—0196, January, 2019.
066-5285/19/6801-0194 © 2019 Springer Science+Business Media, Inc.
1

(
Alkylsulfanyl)methyl derivative of quercetin
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 1, January, 2019
195
had the following composition (HPLC data): 10% of
compound 1, 87% of product 2, and 3% of compound 3.
The formation of compound 3 and the absence in the
system of products isomeric to compound 2 indicates that
the process 123 proceeds sequentially, not sequentially
parallel, as might be expected. The observed regioselec-
Found (%): C, 65.24; H, 7.15; S, 6.37. C28H36O7S. Calcul-
ated (%): C, 65.09; H, 7.02; S, 6.21. UV,  /nm (lg): 261
max
–
1
1
(
0
4.32). IR, /cm : 3581 (OH), 3387 (OH∙∙∙O). H NMR, :
.84 (t, 3 H, S(CH ) CH , J = 6.8 Hz); 1.05—1.35 (m, 18 H,
2 11
3
S(CH ) (CH ) CH ); 1.58 (pent, 2 H, SCH CH , J = 7.2 Hz);
2
2
2 9
3
2
2
2
6
1
.46 (t, 2 H, SCH CH , J = 7.2 Hz); 3.87 (s, 2 H, CH SC H );
.28 (s, 1 H, H(6)); 6.88 (d, 1 H, H(5´), J = 8.4 Hz); 7.60 (dd,
H, H(6´), J = 8.4 Hz, J = 2.0 Hz); 7.75 (d, 1 H, H(2´),
2 2 2 12 25
8
,11
tivity is consistent with the data in the works,
accord-
ing to which aminomethylation of quercetin also pro-
ceeded selectively at position 8. To finalize determining
the structure of compound 2, we carried out an alternative
synthesis of 2 by the reaction of amine 4 (obtained by
J = 2.0 Hz); 9.33 (br.s, 1 H, OH (3´)); 9.43 (br.s, 1 H, OH(3));
9
1
.62 (br.s, 1 H, OH(4´)); 10.93 (br.s, 1 H, OH(7)); 12.50 (br.s,
H, OH(5)).
2
-(3,4-Dihydroxyphenyl)-6,8-bis-[(dodecylsulfanyl)methyl]-
8
a known procedure ) with dodecanethiol, the yield of 2
3,5,7-trihydroxy-4H-chromen-4-one (3). M.p. 167.5—169.5 C.
was 20% (calculated on compound 1). The spectral and
chromatographic characteristics of compound 2 obtained
by different methods are identical, which confirms its
authenticity.
Thus, in the present work the reaction of quercetin
with (N,N-diethylaminomethyl)dodecyl sulfide exempli-
fied the possibility of modifying flavonoids by a dodecyl-
sulfanylmethyl fragment.
Found (%): C, 67.83; H, 8.63; S, 8.44. C H O S . Calcul-
41
62
7 2
ated (%): C, 67.36; H, 8.55; S, 8.77. UV,  /nm (lg): 264
max
–
1
1
(4.33). IR, ν/cm : 3458 (OH), 3336 (OH∙∙∙O). H NMR, :
.82 (t, 6 H, S(CH ) CH , J = 6.0 Hz); 1.01—1.35 (m, 36 H,
0
2 11
3
S(CH ) (CH ) CH ); 1.45 (pent, 4 H, SCH CH , J = 7.2 Hz);
2 2
2 9
3
2
2
2
.41 (t, 2 H, SCH CH , J = 7.2 Hz); 2.46 (t, 2 H, SCH CH ,
2 2 2 2
J = 7.2 Hz); 3.78 (s, 2 H, CH SC H ); 4.01 (s, 2 H, CH SC H );
2
12 25
2
12 25
6
.88 (d, 1 H, H(5´), J = 8.4 Hz); 7.60 (dd, 1 H, H(6´), J = 8.4 Hz,
J = 2.0 Hz); 7.75 (d, 1 H, H(2´), J = 2.0 Hz); 9.32 (s, 1 H,
OH(3´)); 9.46 (s, 1 H, OH(3)); 9.61 (s, 1 H, OH(4´)); 10.01
Experimental
(
br.s, 1 H, OH(7)); 12.97 (s, 1 H, OH(5)).
Method B. A mixture of compound 4 (115 mg, 0.29 mmol)
1H NMR spectra were recorded on a Bruker DRX 600
and dodecanethiol (58 mg, 0.29 mmol) in methoxyethanol
(400 μL) was refluxed for 7 h, cooled to room temperature, and
poured into distilled water (20 mL). The precipitate was sepa-
rated, washed with water, dried, washed with hot hexane
(3×5 mL), and recrystallized from a mixture of MeCN—water
(7 : 1, 15 mL) to obtain 30 mg (20%) of the product. The physi-
cochemical and spectral properties of compound 2 obtained by
methods A and B are identical.
spectrometer (600 MHz) for solutions in DMSO-d . The sig-
6
1
nals in the H NMR spectra were assigned based on the
Н— C HSQS and Н— C HMBC spectra of quercetin.
1
13
1
13
12
IR spectra were recorded in KBr pellets on a Varian 640-IR
instrument. UV spectra were recorded on a Shimadzu UV-1800
spectrometer in EtOH solution. HPLC analysis was per-
formed on an Agilent Infinity 1220 instrument (ZORBAX SB-C18,
5
μm, 150×4.6 mm). Melting points were determined in a ca-
pillary on an MP50 Mettler Toledo apparatus (heating at
References
–
1
1.0 С min ). Compound 4 was obtained from quercetin ac-
8
cording to a known procedure. (N,N-Diethylaminomethyl)
dodecyl sulfide was synthesized according to the procedure pub-
lished earlier.
Synthesis of compounds 2 and 3. Method А. A solution of
quercetin (3.02 g, 10.0 mmol) and citric acid monohydrate (2.10 g,
1. J. Poon, V. P. Singh, J. Yan, L. Engman, Chem. Eur. J., 2015,
21, 2447.
2. J. Poon, J. Yan, V. P. Singh, P. J. Gates, L. Engman, J. Org.
Chem., 2016, 81, 12540.
9
1
0.0 mmol) in methoxyethanol (30 mL) was heated to boiling,
3. S. E. Yagunov, S. V. Kholshin, N. V. Kandalintseva, A. E.
Prosenko, Russ. Chem. Bull., 2018, 67, 1452.
4. J. C. S. Malan, J. A. Steenkamp, J. P. Steynberg, D. A. Young,
E. V. Brandt, D. Ferreira, J. Chem. Soc., Perkin Trans. 1,
1990, 209.
5. T. Tanaka, R. Kusano, I. Kouno, Bioorganic Med. Chem.
Lett., 1998, 8, 1801.
6. K. Kajiya, H. Hojo, M. Suzuki, F. Nanjo, S. Kumazawa,
T. Nakayama, J. Agric. Food Chem., 2004, 52, 1514.
7. I. L. Martins, C. Charneira, V. Gandin, J. L. Ferreira da Silva,
G. C. Justino, J. P. Telo, A. J. S. C. Vieira, C. Marzano,
A. M. M. Antunes, J. Med. Chem., 2015, 58, 4250.
8. E. V. Buravlev, O. G. Shevchenko, I. Y. Chukicheva, A. V.
Kutchin, Chem. Pap., 2018, 72, 201.
followed by the addition of a solution of (N,N-diethylamino-
methyl)dodecyl sulfide (2.88 g, 10.0 mmol) in methoxyethanol
(
10 mL). The mixture was refluxed for 30 min, cooled to room
temperature, and poured into distilled water (500 mL). The
formed crystals were collected by filtration, washed on the filter
with water to pH ≈ 7, and dried. Then, the crystals were washed
with hot hexane (3×50 mL) and recrystallized from a mixture of
MeCN—water (7 : 1, 200 mL) to obtain product 2 (3.36 g, 65%)
as a bright yellow crystalline powder. Compound 3 was isolated
from the mother liquor by HPLC and recrystallized from EtOH,
the yield was 50 mg (0.7%).
2
-(3,4-Dihydroxyphenyl)-8-[(dodecylsulfanyl)methyl]-3,5,7-
trihydroxy-4H-chromen-4-one (2). M.p. >160 C (decomp.).

196
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 1, January, 2019
Bagavieva et al.
9
. I. M. Bugaev, A. E. Prosenko, Russ. Chem. Bull., 2010,
5
12. E. Kyriakou, A. Primikyri, P. Charisiadis, M. Katsoura, I. P.
Gerothanassis, H. Stamatis, A. G. Tzakos, Org. Biomol.
Chem., 2012, 10, 1739.
9, 861.aaa
0. S. E. Yagunov, S. V. Kholshin, N. V. Kandalintseva, A. E.
Prosenko, Russ. Chem. Bull., 2013, 62, 1395.
1
Received September19, 2018;
in revised form October 25, 2018;
1
1. T. K.-D. Hoang, T. K.-C. Huynh, T. H.-T. Do, T.-D. Nguyen,
Chem. Pap., 2018, 72, 1399.
accepted November 8, 2018