Synthesis, Structure, and Antiradical Activity of New Methano[1,3]Thiazolo[2,3-d][1,3,5]Benzoxa-Diazocine Derivatives

Article abstract of DOI:10.1007/s10593-014-1613-1

The reaction of 2,6-methano[1, 3, 5]benzoxadiazocines, obtained in Biginelli reaction, with chloroacetic acid derivatives produced previously unknown tricyclic methano[1,3]thiazolo[2,3-d][1,3,5]benz-oxadiazocines, the structure of which was proved by ¹H NMR spectroscopy and X-ray structural analysis. The methano[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocines showed no antiradical activity in contrast to the starting 2,6-methano[1,3,5]benzoxadiazocines.

Full text of DOI:10.1007/s10593-014-1613-1

DOI 10.1007/s10593-014-1613-1
Chemistry of Heterocyclic Compounds, Vol. 50, No. 10, January, 2015 (Russian Original Vol. 50, No. 10, October, 2014)
SYNTHESIS, STRUCTURE, AND ANTIRADICAL ACTIVITY
OF NEW METHANO[1,3]THIAZOLO[2,3-d][1,3,5]BENZOXA-
DIAZOCINE DERIVATIVES
1
2
3
4
*
I. V. Kulakov , S. A. Talipov , Z. T. Shulgau , and T. M. Seilkhanov
The reaction of 2,6-methano[1,3,5]benzoxadiazocines, obtained in Biginelli reaction, with chloroacetic
acid derivatives produced previously unknown tricyclic methano[1,3]thiazolo[2,3-d][1,3,5]benz-
1
oxadiazocines, the structure of which was proved by Н NMR spectroscopy and X-ray structural
analysis. The methano[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocines showed no antiradical activity in
contrast to the starting 2,6-methano[1,3,5]benzoxadiazocines.
Keywords: 2H-2,6-methano[1,3,5]benzoxadiazocines, salicylic aldehyde, thiourea, Biginelli reaction,
intramolecular heterocyclization, X-ray structural analysis.
There has been a recent significant increase in the number of publications devoted to the chemistry of
3
,4-dihydropyrimidin-2-ones(thiones) 1, 2, obtained by three-component condensation in Biginelli reaction. The
reasons for this include not only the preparative accessibility of 3,4-dihydropyrimidin-2-ones(thiones) 1, 2, but
also the broad spectrum of pharmacological activity characteristic of these compounds, including analgesic,
antibacterial, antihypertensive, and other properties [1-3], which motivate the further study of such compounds.
The mechanism of Biginelli reaction is now well understood [4], many derivatives of 3,4-dihydro-
pyrimidin-2-ones 1 and 3,4-dihydropyrimidine-2-thiones 2 with various functional substituents have been
synthesized, many preparative methods have been developed and patented, including solvent-free microwave-
assisted procedures, and highly effective catalysts have been discovered, leading to significant increase of yields
and shorter reaction times [5-13].
The range of applications for 3,4-dihydropyrimidine-2-thiones was also extended when 4-(3-hydroxy-
phenyl)pyrimidine-2-thione derivative 3 was synthesized, which is known as monastrol, a compound
characterized by a completely new mechanism of anticancer activity through specific influence on cell division
(
mitosis) [14]. It is not surprising that synthesis of new derivatives of monastrol 3 has been recently performed
by the research groups of Bose [15] and Dondoni [16].
_
*
______
To whom correspondence should be addressed, e-mail: kulakov@chemomsu.ru.
1
Omsk F. M. Dostoevskii State University, 55а Mira Ave., Omsk 644077, Russia.
Institute of Bioorganic Chemistry, 83 Mirzo Ulug'bek St., Tashkent 100125, Uzbekistan; e-mail:
2
samat_talipov@yahoo.com.
3
Center for Life Sciences, Inc., 53 Kabanbay batyra Ave., Astana 010000, Kazakhstan; e-mail:
zarina.shulgau@nu.edu.kz.
4
Sh. Ualikhanov Kokshetau State University, 76 Abay St., Kokshetau 020000, Kazakhstan; e-mail:
tseilkhanov@mail.ru.
_
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1604-1613, October, 2014.
Original article submitted August 15, 2014.
009-3122/15/5010-1477©2015 Springer Science+Business Media New York
0
1477

OH
2
1
O
R
O
R
O
1
R
O
2
R
NH
EtO
Me
NH
HN
3
R
N
X
N
H
S
X
N
H
H
4
1
2
(X = O)
(X = S)
3
(monastrol)
Nevertheless, despite more than century of studying Biginelli reaction, new and interesting facts are still
being discovered. Thus, when 3-hydroxybenzaldehyde, acetoacetic ester, and thiourea are used in the classical
Biginelli reaction, the major product is monastrol 3. Derivatives of 2-hydroxybenzaldehyde are known to
behave in many reactions differently than simple aromatic aldehydes due to the adjacent positions of hydroxyl
and aldehyde groups, and this is often used in various types of heterocyclization [17]. In particular, doubts about
the direction of Biginelli reaction with 2-hydroxybenzaldehyde were expressed in a review article [13]. The
authors of another publication [18] established 20 years ago that the condensation of salicylic aldehyde, urea (or
thiourea), and some derivatives of acetoacetic ester in the presence of catalytic amounts of hydrochloric acid did
not produce the standard cyclization products, 4-aryl-3,4-dihydropyrimidin-2-ones(thiones) 1, 2, but rather the
derivatives of 2-methyl-4-thioxo-3,4,5,6-tetrahydro-2Н-2,6-methano[1,3,5]-benzoxadiazocine 4, the chemical
and biological properties of which have not yet been investigated. Similar compounds were later obtained by
using other dicarbonyl compounds or aliphatic alicyclic ketones [19].
However, a recent report [20] showed that, depending on the reaction conditions, at various temperature
regimes and in the presence of trichloroacetic acid as catalyst, products may be obtained from Biginelli
reactions in two possible directions, either the the standard cyclization products 3,4-dihydropyrimidin-
2-ones(thiones) 1, 2 (when refluxing in ethanol for 2-4 h), or benzoxadiazocine 4 (when heating in ethanol at
40°С for 7-9 h). We should note that the formation of 3,4-dihydropyrimidin-2-ones(thiones) based on
2-hydroxybenzaldehyde has not been described before. At the same time, literature sources [18, 20] propose
various and contradictory mechanisms for the formation of methano[1,3,5]benzoxadiazocines 4, which do not
allow to unequivocally conclude about kinetic or thermodynamic control over the formation of the
aforementioned cyclization products. For example, in the work [21] similarly to [18] (over 6-8 hours of
refluxing in methanol), and in contrast to method [20], a solvent-free reaction under microwave irradiation
produced only methano[1,3,5]benzoxadiazocines 4.
We studied the possible cyclization of 2-hydroxybenzaldehyde or 5-bromo-2-hydroxybenzaldehyde
with thiourea and acetoacetic ester or acetylacetone into the corresponding heterocyclic derivatives 4a-d (Table
1
). Heating in DMF at 110-130°С in the presence of acetic acid allowed to obtain compounds 4a-d in
approximately 30% yields; refluxing in ethanol in the presence of MnCl catalyst gave the target products in
2
higher yields and better purity. At the same time, the standard cyclization products, 3,4-dihydropyrimidine-
2
-thiones were not isolated, in contrast to previously reported data [20]. The best yields and purity of target
products were obtained by performing the cyclization in 2-propanol at 45-55°С in the presence of trifluoroacetic acid.
1
R
O
Me
HN
2
R
2-PrOH
CF COOH
2
1
O
CHO
OH
10
O
O
S
3
3
11
+
+
9
1
R
4
5–55°C
5
Me
H N
NH2
6
2
S
N
6
–10 h
2
H
7
R
4
a–d
1
2
1
2
1
2
1
2
a R = OEt, R = H; b R = Me, R = H; c R = OEt, R = Br; d R = Me, R = Br
1
478

TABLE 1. Physicochemical Characteristics of Compounds 4a-d, 5a-d
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
Mp, °C
Yield*, %
47
С
H
N
4
a
C
14
H
16
14
N
N
2
2
O
O
3
2
S
S
57.09
5.82
5.52
9.74
9.58
228-229
5
7.52
60.01
9.52
45.57
5.29
45.95
5.76
57.51
7.82
59.90
9.59
46.36
6.73
47.63
7.26
4
4
4
5
5
5
5
b
c
C
C
C
C
C
C
C
13
14
13
16
15
16
15
H
H
H
H
H
H
H
5.02
5.38
4.32
4.07
3.48
3.84
4.57
4.85
4.89
4.67
3.31
3.68
3.17
3.44
10.84
10.68
7.16
7.55
8.54
8.21
8.14
8.43
9.08
9.27
6.69
6.81
7.19
7.35
218-220
225-226
221-222
150-152
179-180
182-184
180-182
59
43
49
92
95
91
85
5
15BrN
13BrN
2
2
O
O
3
2
S
S
4
d
a
b
c
4
16
14
N
N
2
2
O
O
4
3
S
S
5
5
15BrN
13BrN
2
2
O
O
4
3
S
S
4
d
4
_
*
______
Product yield without recrystallization. In the case of compounds 5a-d,
yields are indicated for reaction with chloroacetamide.
1
The structure of heterocyclic derivatives 4a-d was unequivocally confirmed by IR and Н NMR
spectroscopy, mass spectrometry (Table 2), as well as X-ray structural analysis (Fig. 1), which showed the
presence of only single (2S,6S,11R)-enantiomer in the monocrystal. We should note that the 6-CH proton in the
1
Н NMR spectra of compounds 4a-d appeared as a double doublet (interaction with 11-СН and 5-NH protons),
while the signal of 11-СН proton was a doublet (compounds 4a,с) or unsplit singlet (compounds 4b,d). The
1
possibility of ethoxycarbonyl group rotation around С(11)–COOEt bond was manifested in Н NMR spectra of
compounds 4a,с by the presence of duplicated signals of OCH protons.
2
Fig. 1. The molecular structure of ester 4c.
We interpreted the complications in performing this reaction as due to several parallel reactions – a
possible three-component Biginelli condensation of the starting reagents into the ethyl ester of 4-(5-bromo-
2
-hydroxyphenyl)-6-methyl-2-thioxo-3,4-dihydropyrimidine-5-carboxylic acid, as well as the associated
condensation reaction of 2-hydroxybenzaldehyde and acetoacetic ester. Thus, reaction of 5-bromo-2-hydroxy-
benzaldehyde with thiourea and acetoacetic ester in DMF allowed to isolate 3-acetyl-6-bromo-2Н-chromen-
2
-one in approximately 5% yield.
1
479

1
480

3
,4-Dihydropyrimidine-2-thiones 2 attract the attention of many chemistry researchers by the presence
of several reactive nucleophilic centers, enabling various reactions of mono- and dialkylation and acylation
22, 23].
We previously demonstrated a convenient method for the cyclization of 4-aryl-3,4-dihydropyrimidine-
-thiones into 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidines [24] and explored some details of intramolecular
[
2
cyclization [25]. While continuing these investigations, we attempted to perform analogous heterocyclization
with derivatives of [1,3,5]benzoxadiazocine 4a-d. Compounds 4a-d were found to cyclize quite readily upon
refluxing in toluene or benzene with slight excess of methyl or ethyl chloroacetate in the presence of
triethylamine, forming previously unreported tricyclic methano[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocines
5
a-d.
1
1
1
O
R
O
R
O
R
Me
HN
Me
N
O
Me
N
O
O
Cl
O
7
5
Y
13
8
Et N, toluene
3
11
S
N
HS
N
N
S
2
2
, 4–6 h
2
H
H
10
R
R
R
4
a–d
1
2
O
5a–d
1
2
1
2
1
2
1
2
a R = OEt, R = H; b R = Me, R = H; c R = OEt, R = Br; d R = Me, R = Br; Y = OMe, OEt, NH
2
It was also shown that using α-chloroacetamide in this reaction instead of methyl chloroacetate led to
not only higher yields and better purity of target products, but also easier isolation of products from the reaction
mixture. The formation of methano[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocine derivatives 5a-d was proved by
the absence of NH and thio group absorption bands in the IR spectra, and the lack of the NH proton signals in
1
Н NMR spectra. The methylene protons of thiazole ring in compounds 5b-d were non-equivalent and
1
manifested as two doublets with spin-spin coupling constants of 17.4-17.5 Hz. The Н NMR spectra for the
products from reactions of compound 4a-d with chloroacetic amide or esters did not contain additional ester or
amide group signals, pointing to the fact that reaction did not stop at alkylation stage, but rather led to
intramolecular cyclization with thiazole ring formation.
Of particular interest was the structural study of products from the reactions of [1,3,5]benzoxa-
diazocines 4a-d with chloroacetic acid derivatives and the differences of these compounds from the previously
described thiazolopyrimidines [24], because the participation of 3-NH or 5-NH protons in the thione-thiol
tautomerism may lead to the formation of methano[1,3]thiazolo[3,2-c][1,3,5]benzoxadiazocine or methano-
[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocine, respectively. With this goal we performed an X-ray structural
study of compound 5с, the structure of which is presented in Figure 2.
Fig. 2. Spatial structure of ester 5с (two independent molecules are shown without taking the mutual orientation
into account).
1
481

The crystal structure of compound 5с, similarly to the previously studied 5-(2,4-dimethoxyphenyl)-
-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid [24], contained two geometrically
7
independent molecules 5с and 5с (two enantiomers (5R,11R,13S) and (5S,11S,13R), respectively) packed in one
1
2
independent unit cell. The bond lengths and valence angles in the structure were close to standard values [26]. The
structure 5с consisted of a central eight-membered oxadiazocine ring O(1)C(5)N(4)C(3)N(12)C(11)C(15)C(14),
1
connected by methane bridge with the ester group, and thus forming two fused rings – pyrimidine
N(4)C(3)N(12)C(11)C(13)С(5) and pyran O(1)C(5)C(13)C(11)C(15)C(14) – with the С(13) atom in common.
The oxadiazocine ring was fused from one side with the benzene ring and from the other side with the
thiazolidine ring.
Similarly to our previously obtained related structure [24], the thiazolidine ring in each molecule was
nearly planar with sulfur atom deviating from the plane of other atoms by 0.09 Å, while the О(2) and О(6)
atoms of carbonyl groups were in that plane. The pyrimidine ring assumed a nearly ideal "sofa" conformation
13
31
(
ΔCs = 1.14 Å and ΔCs = 4.37 Å) with the bridging С(13) and С(31) atoms in molecules 5с and 5с deviating by
1 2
0.70 and 0.74 Å, respectively. This ring could also assume a "twist-boat" conformation as in the structure of 5-nitro-
4
-(2-nitrophenyl)-6-phenyl-3,4-dihydro-1Н-pyrimidin-2-one [27]. The pyran rings in molecules 5с and 5с also
1
2
assumed a "sofa" conformation. The bromine atom in both molecules had equatorial orientation and was located
in phenyl ring plane (torsion angles С(7)–С(8)–С(9)–Br(1) -178.95°, С(30)–С(29)–С(28)–Br(2) 177.61°).
While continuing the search for new types of compounds with antioxidant activity [28], some of the
obtained compounds were tested for antiradical effect towards the radical cation 2,2'-azinobis-
+
·
+·
(
3-ethylbenzothiazoline-6-sulfonic acid) (ABTS ). The quench rates of ABTS were compared for the studied
compounds against a standard, semisynthetic water-soluble analog of vitamin E, (±)-6-hydroxy-2,5,7,8-tetra-
methylchromane-2-carboxylic acid (commercial name Trolox). The use of Trolox enabled the expression of
antiradical activity through Trolox Equivalent Antioxidant Capacity (TEAC), where TEAC values indicate the
+
·
concentration of Trolox in mmol/l (mM) that quenches ABTS with effectiveness equivalent to 1 mM of the
analyzed compound.
We established as a result of our study that the starting compounds 4a-c exhibited antiradical activity
+
·
against ABTS with TEAC values 0.62±0.04 (62% of Trolox activity), 0.75±0.03 (75% of Trolox activity), and
.27±0.11 (activity 1.27 times exceeding that of Trolox), respectively. Compounds 5a-c did not exhibit
1
antiradical activity under the test conditions.
Thus, derivatives of 2-methyl-4-thioxo-3,4,5,6-tetrahydro-2Н-2,6-methano[1,3,5]benzoxadiazocine
were used to obtain previously unknown tricyclic derivatives of 5-methyl-1-oxo-1,2,5,11-tetrahydro-
1
5
,11-methano[1,3]thiazolo[2,3-d][1,3,5]benzoxadiazocine, the structure of which was proved by Н NMR
spectroscopy and X-ray structural analysis. The synthesized methano[1,3]thiazolo[2,3-d][1,3,5]benzoxa-
diazocines were demonstrated to have no antiradical activity, in contrast to the starting 2,6-methano-
[1,3,5]benzoxadiazocines, probably due to the lack of active NH protons in their molecules.
EXPERIMENTAL
1
IR spectra were recorded on an Infralum FT-801 spectrometer. H NMR spectra were acquired on
Bruker DRX-400 (400 MHz, compounds 4, 5 a,b) and Bruker DRX-500 (500 MHz, compounds 4, 5 c,d)
instruments in DMSO-d , with TMS as internal standard. Mass spectra were recorded on a Finnigan MAT Incos
6
5
0 instrument with direct introduction of sample (EI ionization, 70 eV). Elemental analysis was performed on a
Carlo Erba 1106 CHN instrument. Melting points were determined on a Boetius apparatus. The reaction
progress and the purity of the obtained compounds were controlled by TLC on Sorbfil plates, visualization with
iodine vapor or under UV light.
Synthesis of Ethyl 2-Methyl-4-thioxo-3,4,5,6-tetrahydro-2Н-2,6-methano[1,3,5]benzoxadiazocine-
1
1-carboxylate (4a), 1-(2-Methyl-4-thioxo-3,4,5,6-tetrahydro-2Н-2,6-methano[1,3,5]benzoxadiazocin-
1
482

1
1-yl)ethanone (4b), and their 8-Bromo Derivatives 4c,d (General Method). Method A. A mixture of
acetoacetic ester or acetylacetone (24 mmol), finely ground thiourea (1.5 g, 20 mmol), 2-hydroxybenzaldehyde
or 5-bromo-2-hydroxybenzaldehyde (20 mmol), and CF COOH (0.3 ml) in 2-PrOH (30 ml) was stirred at
3
4
6
5-55°C until complete dissolution of thiourea (1-2 h), followed by stirring at room temperature for additional
-10 h. The reaction mixture with precipitated product was then cooled, the precipitate was filteted off, washed
with cold 2-PrOH, and dried. Evaporation of filtrate yielded additional 10-20% crop of product. The obtained
compounds were recrystallized several times from 2-PrOH or EtOH until constant melting temperature was
achieved.
Ethyl 8-Bromo-2-methyl-4-thioxo-3,4,5,6-tetrahydro-2Н-2,6-methano[1,3,5]benzoxadiazocine-
1
5
1-carboxylate (4c). Method B. A mixture of acetoacetic ester (2.60 g, 20 mmol), thiourea (1.60 g, 21 mmol),
-bromo-2-hydroxybenzaldehyde (4.02 g, 20 mmol), and 3-5 drops of АсОН in DMF (5 ml) was heated for 3 h
at 110-130°С in a flask with reflux condenser, then treated with EtOH (5 ml) and refluxed for additional 3 h. The
precipitated crystals of 3-acetyl-6-bromo-2Н-chromen-2-one were filteted off and washed with EtOH. The
filtrate was diluted with ice water (100 ml). Water layer was decanted from the dark-red oil that separated, the
oil was washed with water several times and recrystallized several times from 1:1 mixture of 2-PrOH–hexane.
Yield 35%, colorless transparent crystals.
Method C. A mixture of acetoacetic ester (2.60 g, 20 mmol), thiourea (1.60 g, 21 mmol), 5-bromo-
2
-hydroxybenzaldehyde (4.02 g, 20 mmol), and MnCl ·2H O (3.20 g, 20 mmol) in EtOH (15 ml) was heated in
2 2
a flask with reflux condenser for 6 h. The solution was poured into a mixture of ice water (300 ml) and ice
100 g). The light-yellow precipitate that formed was filteted off and recrystallized from a 1:1 mixture of
(
2
-PrOH–hexane. Yield 40%.
Synthesis of Ethyl 5-Methyl-1-oxo-1,2,5,11-tetrahydro-5,11-methano[1,3]thiazolo[2,3-d][1,3,5]benzoxa-
diazocine-13-carboxylate
(5а),
13-Acetyl-5-methyl-5,11-dihydro-5,11-methano[1,3]thiazolo[2,3-d]-
[
1,3,5]benzoxadiazocin-1(2H)-one (5b), and their 9-Bromo Derivatives 5c,d (General Method). A mixture
of methano[1,3,5]benzoxadiazocine 4a-d (2.0 mmol), methyl chloroacetate or chloroacetamide (2.2 mmol), and
Et N (0.4 g, 4.0 mmol) in anhydrous toluene (10 ml) or benzene in the case of reaction with chloroacetamide
3
was refluxed for 4-6 h in a flask with reflux condenser. The precipitated crystals of Et N·HCl were filteted off,
3
and washed with small amount of benzene, which was then combined with the filtrate and evaporated. The
residue was triturated with hexane to fine powder. Several recrystallization steps, first from a 1:1 mixture of
2
-PrOH–hexane, then from pure 2-PrOH yielded light-yellow crystals.
X-Ray Structural Investigation of Compound 4с. Crystals of compound 4с (C H BrN O S,
1
4
15
2
3
M 371.26) were grown over 3 days from EtOH. A colorless prismatic crystal (0.25×0.40×0.60 mm) was selected
for the study. X-ray structural study was performed at room temperature on an Xcalibur Oxford Diffraction
diffractometer with CCD-detector (CuKα radiation, λ 1.5418 Å, Enhance (Cu) X-ray Source fine focus X-ray
tube, graphite monochromator). Crystals were monoclinic; a 17.104(2), b 8.660(12), c 20.544(3) Å; α 90.0,
3
β 94.206(1), γ 90.0°; V 3034.8(2) Å ; Z 8; С2/с space group. The experimental data were collected by using the
CrysAlisPro software [29]. The integrated intensities were measured by ω-scanning method, with
monochromatization by reflection from a graphite crystal. After averaging the equivalent reflections and
removal of weak reflections with I < 2σ(I), working array of 2640 reflections was obtained. Correction for
absorption was performed by multiscan method with the CrysAlisPro software suite [29]. The structure was
solved by direct method using the SHELXS-97 software suite [30] and refined by full matrix least squares
method with the SHELXL-97 software [31]. All non-hydrogen atoms were refined anisotropically. Hydrogen
atom positions were calculated from stereochemical criteria and refined by using the "rider" model. The
probability factor after final refinement of positional and anisotropic thermal parameters R 0.0384. The
1
molecular graphics were created by the XP program in the SHELXTL-Plus software suite [32]. Complete X-ray
structural data set for compound 4c was deposited at the Cambridge Crystallographic Data Center (deposit
CCDC 1024097).
1
483

X-ray Sructural Investigation of Compound 5с. The unit cell parameters and intensities of 6672
independent reflections for compound 5c (C16 S, M 411.28) were determined on an Xcalibur Oxford
2 4
H15BrN O
Diffraction diffractometer with CCD-detector (CuKα radiation, λ 1.5418 Å, Enhance (Cu) X-ray Source fine
focus X-ray tube, graphite monochromator, θ/2θ-scanning, 2θ < 38°) at 20°С. Crystals were monoclinic;
3
3
а 9.6212(3), b 21.1372(4), с 8.40730(10) Å; α 90.0, β 102.992(2), γ 90.0°; V 1665.99(6) Å ; d 1.456 g/cm ; Z 4;
calc
P2 space group. Calculations were performed with 4497 reflections of intensity I > 2σ(I). The structure was
1
solved directly with the SIR-2002 software [33] and refined by full matrix least squares analysis in anisotropic
approximation for non-hydrogen atoms. Hydrogen atom positions were calculated geometrically and refined by
using the "rider" model. The final probability factors were R 0.0451, wR 0.1179. Geometry was refined with
1
2
the SHELXL-97 software [31]. The complete X-ray structural data set for compound 5c was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC 773784).
Biological Studies. The antiradical activity of compounds 4а-с, 5а-с was studied with regard to the
+
·
radical cation 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS ), using Antioxidant Assay Kit from
Sigma-Aldrich according to the user manual supplied by manufacturer. The method was based on the principle
of ferrylmyoglobin radical formation from metmyoglobin and hydrogen peroxide, which oxidizes ABTS with
+
·
the formation of a radical cation ABTS . Adding various antiradical agents to the solution results in their
+
·
+·
interaction with ABTS and rapid consumption ("quenching") of the latter. The consumption of ABTS is
accompanied by characteristic spectral changes, allowing to record the reaction rate [34].
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1
2
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