Unusual N,Se-heterocycles with cyclic Se–N+ bond of isoselenazolopurinium type

Article abstract of DOI:10.1016/j.mencom.2019.01.033

Treatment of 8-alkynylcaffeine or -adenine derivatives with in situ generated SeBr₄ caused their annulation with the formation of isoselenazolium ring. The salts obtained are regarded as glutathione peroxidase mimetics.

Full text of DOI:10.1016/j.mencom.2019.01.033

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 96–98
Unusual N,Se-heterocycles with cyclic Se–N+ bond
of isoselenazolopurinium type
Pavel Arsenyan,* Jelena Vasiljeva, Anna Ivanova and Sergey Belyakov
Latvian Institute of Organic Synthesis, LV-1006, Riga, Latvia. E-mail: pavel@osi.lv
DOI: 10.1016/j.mencom.2019.01.033
NH2
N
O
R
Me
Se
Treatment of 8-alkynylcaffeine or -adenine derivatives with
in situ generated SeBr4 caused their annulation with the
formation of isoselenazolium ring. The salts obtained are
regarded as glutathione peroxidase mimetics.
Me
N
N
N
N
N
Br
R
Br
N
O
N
Se
Me
OH
In the last decade, the synthesis of compounds containing Se–N
bond has begun to play an important role in the design of
potentially bioactive molecules.1(a)–(c) Heterocycles with Se–N
bonds, such as ebselen (2-phenyl-1,2-benzoselenazol-3-one),
are clinically useful redox modulators and anti-inflammatory
agents.1(d)–(h) Despite extensive chemical studies and numerous
applications of selenium-containing heterocycles, only a moderate
number of compounds containing Se–N+ bond have been reported
so far. Recently we described the synthesis of stable fused
isoselenazolium salt systems with a Se–N+ bond based on
cyclization of ethynyl N-heterocycles with selenium(ii) and (iv)
halides.2(a) Due to the presence of this bond, such compounds
exhibit the glutathione peroxidase (GPx) like activity and can
serve as mild oxidants.2(b) Some of selenazolium salts possess
antibacterial activity. Isoselenazolium salts induce DNA double-
strand breaks at moderate doses.2(c),(d) Keeping in mind that
modification of natural compounds could lead to even more
interesting results, in continuation of our research in the field of
selenium chemistry,3 here we report the method of introduction
of annulated isoselenazolium ring into caffeine and adenine
derivatives.
nature of the catalyst and solvent, with the 1:1 mixture of
N-methylpyrrolidinone (NMP) and toluene as the reaction medium
having provided the desired products in higher yields. Next, since
reactions in aqueous solutions without an inert atmosphere are
always preferable, 8-alkynylcaffeines were treated with solutions
of freshly prepared aqueous selenium(iv) bromide by dissolving
SeO2 in 48% hydrobromic acid. The desired isoselenazolo-
caffeinium salts 2a,b† were isolated in 38 and 58% yields,
respectively. Unfortunately, these compounds were unstable on
silica gel during flash chromatography. Derivatives 2a,b were
purified by crystallization from acetonitrile. Note that these com-
pounds are the first representatives of isochalcogenazolocaffeines
with isochalcogenazole cycle annulated at 7- and 8-positions of
purine system.
Figure 1(a) shows a structure of cation of salt 2a.‡ The torsion
angle N(12)–Se(1)···O(14)–H and valence angle Se(1)···O(1)–H
promote an increase in the intramolecular interaction between
†
Compounds 2a,b (general procedure). Alkyne 1a,b (1 mmol) in dioxane
(10 ml) was added to a solution of selenium dioxide (0.444 g, 4 mmol)
in HBr (0.45 ml), and the mixture was stirred at room temperature for
24 h. After consumption of substrate (LC-MS), ethanol (40 ml) was
added and the solution was filtered through paper. The filtrate was passed
through ion-exchange resin which was pre-treated with hydrochloric acid.
The solvent was evaporated and the crude product was recrystallized
from acetonitrile.
6-Bromo-7-(2-hydroxyprop-2-yl)-1,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetra-
hydro-1H-[1,2]selenazolo[2,3-e]purin-9-ium hexabromoselenate(iv) 2a.
Yield 34%, mp 177–180°C. 1H NMR (400 MHz, DMSO-d6) d: 4.33 (s,
3H, N5Me) 3.67 (s, 3H, N3Me), 3.28 (s, 3H, N1Me), 1.73 (s, 6H, 2Me).
MS (ESI), m/z: 435.1. Found (%): C, 21.16; H, 2.32; N, 7.32. Calc. for
C26H32Br8N8O6Se3·2H2O (%): C, 20.57; H, 2.30; N, 8.00.
8-Ethynyl caffeines 1a,b were chosen as model compounds
for the study. The introduction of the alkynyl moiety at 8-posi-
tion of caffeine was based on Sonogashira-type coupling
reaction (Scheme 1).4 We found that the yields of the products
in the palladium-catalyzed cross-coupling of terminal acetylenes
HCºCC(OH)R2 and 8-bromocaffeine strongly depended on the
O
O
Me
Me
Me
Me
N
N
N
N
i
Br
C C C(OH)R2
6-Bromo-7-(1-hydroxycyclohexyl)-1,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetra-
hydro-1H-[1,2]selenazolo[2,3-e]purin-9-ium hexabromoselenate(iv) 2b.
Yield 54%, mp 160–162°C. 1H NMR (400 MHz, DMSO-d6) d: 4.37 (s,
3H, N5Me), 3.69 (s, 3H, N3Me), 3.27 (s, 3H, N1Me), 2.19–2.27 (m, 2H,
cyclohexyl), 1.91–1.96 (d, 2H, cyclohexyl, J 13.3 Hz), 1.61–1.71 (m,
5H, cyclohexyl), 1.21–1.30 (m, 1H, cyclohexyl). 13C NMR (100.6 MHz,
DMSO-d6) d: 153.8, 149.4, 107.1, 148.3, 77.8, 66.2, 33.8, 32.6, 30.3,
28.3, 23.9, 20.4. Found (%): C, 24.47; H, 2.64; N, 6.89. Calc. for
C32H40Br8N8O6Se3·2H2O (%): C, 23.58; H, 2.75; N, 7.04.
N
N
O
N
O
N
Me
Me
1a,b
O
N
Me
Me
N
N
Br
ii
0.5 SeBr62–
N
O
Se
‡
C(OH)R2
Monocrystals grown for X-ray analyses differed in anion and solvate
Me
a R = Me
b R + R = (CH2)5
molecule compositions.
2a,b
Crystallographic data for 2a [tetrabromoselenate(ii), solvate with
–
MeCN]. C30H38Br6N10O6Se3 (M = 1351.04), triclinic, space group P1, at
163 K: a = 9.4447(2), b = 10.5194(2) and c = 11.0932(2) Å, a = 85.8949(9),
Scheme 1 Reagents and conditions: i, HCºCC(OH)R2, [Pd], PhMe–NMP;
ii, SeO2, conc. HBr, dioxane, ~20°C, 24 h.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2019, 29, 96–98
NH2
N
NH2
N
(a)
Br(17)
C(18)
N(4)
O(19)
N
N
N
N
i
N
Br
C
C
C(OH)R2
C(3)
C(2)
C(10)
C(9)
C(5)
C(16)
N
C(11)
N(6)
C(20)
C(15)
C(13)
OH
OH
N(12)
C(7)
3
4a,b
N(8)
Se(1)
O(14)
O(21)
NH2
N
C(OH)R2
Cl–/Br–
Br
C(22)
Se
N
N
N
ii
(b)
O(24)
C(18)
N(13)
C(22)
Se(1)
C(23)
a R = Me
b R + R = (CH2)5
C(3)
N(6)
C(10)
C(21)
N(2)
N(4)
C(5)
C(9)
C(8)
C(20)
OH
C(19)
5a,b
C(12)
C(11)
N(7)
Scheme 2 Reagents and conditions: i, HCºCC(OH)R2, (Ph3P)2PdCl2, CuI,
DMF, Et3N, ~20°C, 18 h; ii, SeO2, conc. HBr, dioxane, ~20°C, 24 h, then
ion-exchange (Cl–) resin.
Br(17)
C(14)
C(15)
O(16)
the formation of Se–N+ bond. For comparison, 77Se in ebselen
(Se–N) resonates at 959 ppm.5 Note that adenine derivatives were
more stable in physiological media compared with caffeinium
salts.
Figure 1 ORTEP diagram of cations of compounds (a) 2a and (b) 5b with
atomic labels and thermal ellipsoids (50%).
selenium and oxygen with Se···O distance of 2.539(3) Å. The
Se(1)–C(2) covalent bond [1.869(3) Å] in cation is shorter than
Se(1)–N(12) bond [1.876(3) Å]. In addition, in the crystal struc-
ture there are hydrogen bonds of OH···Br type [O···Br 3.414(3) Å,
H···Br 2.51 Å, ÐO–H···Br 153°] between cation and tetrabromo-
selenate(ii) anion, halogen bonds between anion and Br(17)
atom [Br···Br distance is 3.363(2) Å] and s-hole interactions
between Se(1) atom and solvent (acetonitrile) molecule [Se···O
distance is 3.183(3) Å]. Moreover, isoselenazolocaffeinium salts
are the only condensed purines containing formally quaternary
nitrogen atom, which forms covalent bond with endocyclic
heteroatom.
Analogous adenine salts were accessed from 8-bromo-
9-(2-hydroxyethyl)adenine 35 (Scheme 2), which was converted
into 8-alkynyl derivatives 4a,b.§ Their further cyclization with
in situ prepared SeBr4 gave isoselenazoloadeninium bromides 5a,b in
76–77% yields.¶ The singlet signal of selenium in 77Se NMR
spectrum of salt 5a was detected at 1105.5 ppm, which confirmed
§
4-[9-(2-Hydroxyethyl)adenin-8-yl)-2-methylbut-3-yn-2-ol 4a. 2-Methyl-
but-3-yn-2-ol (630 mg, 7.75 mmol), (Ph3P)2PdCl2 (95.3 mg, 0.136 mmol)
and CuI (15.8 mg, 0.129 mmol) were dissolved in dry DMF (15 ml) in
round bottom flask under argon atmosphere at ~20°C, then Et3N (5 ml)
was added. The solution was degassed by flushing argon for 20 min.
Then 8-bromo-9-(2-hydroxyethyl)adenine 3 (500 mg, 1.94 mmol) dis-
solved in DMF (5 ml) was added to the stirred reaction mixture. After
48 h, DMF was distilled off in vacuo. The residue was washed with
diethyl ether (35 ml). The product was filtered off and recrystallized from
acetonitrile. Light yellow solid (335 mg, 66%) was obtained, mp > 200°C
(decomp.). 1H NMR (400 MHz, DMSO-d6) d: 8.15 (s, 1H), 7.35 (s, 2H),
5.75 (s, 1H), 4.94 (t, 1H, J 5.7 Hz), 4.21 (t, 2H, J 5.9 Hz), 3.77 (q, 2H,
J 5.8 Hz), 1.51 (s, 6H).
1-{2-[6-Amino-9-(2-hydroxyethyl)-9H-purin-8-yl]ethynyl]cyclohexan-
1-ol 4b. Compound 4b was prepared similarly. Yield 64%. 1H NMR
(400 MHz, DMSO-d6) d: 8.15 (s, 1H), 7.36 (br.s, 2H), 4.94 (t, 1H, J 5.7
Hz), 4.23 (t, 2H, J 5.7 Hz), 3.77 (q, 2H, J 5.7 Hz), 1.98–1.84 (m, 2H),
1.76–1.39 (m, 7H), 1.36–1.20 (m, 1H).
¶
4-Amino-8-bromo-9-(2-hydroxyethyl)-7-(2-hydroxyprop-2-yl)-9H-
[1,2]selenazolo[3,2-f]purin-5-ium bromide/chloride 5a. Selenium(iv)
oxide (170 mg, 3.92 mmol) was dissolved in 48% HBr (1.5 ml) and
stirred at room temperature for 15 min. A solution of compound 6
(100 mg, 0.383 mmol) in dioxane (12 ml) was added dropwise at 2–4°C.
Then the mixture was stirred at ~20°C for 24 h. The reaction was quenched
with ethyl acetate (50 ml) and washed with sodium bicarbonate solution
(20 ml). The organic phase was separated and the aqueous phase was
extracted with ethyl acetate (2×30 ml). The combined organic phases
were washed with brine (40 ml), and then dried with anhydrous sodium
sulfate. Evaporation of the solvent left the crude product, which was
purified by column chromatography over silica gel (light petroleum–
ethyl acetate, 8:2). The bromide anion was partly replaced with chloride
one by anion-exchange resin (HCl), producing salt 5a (126 mg, 76%).
1H NMR (400 MHz, DMSO-d6) d: 8.45 (s, 1H, C2H), 8.30 (br.s, 2H,
NH2), 4.79 (t, 2H, CH2N, J 5.6 Hz), 3.83 (t, 2H, CH2OH, J 5.6 Hz), 1.75
(s, 6H, 2Me). 13C NMR (101 MHz, DMSO-d6) d: 180.7, 155.2, 150.9,
150.8, 150.4, 111.0, 83.1, 75.4, 59.3, 45.7, 26.5. 77Se NMR (DMSO-d6)
d: 1105.5. MS (ESI), m/z: 420.1.
b = 84.2797(9) and g = 73.7263(8)°, V = 1051.61(4) Å3, Z = 1, dcalc
=
= 2.133 g cm–3, m(MoKa) = 8.377 mm–1, F(000) = 648. Total of 8169
reflections were measured, 5395 independent reflections (Rint = 0.0393)
were used in a further refinement, which converged to wR2 = 0.828 and
GOF = 1.068 for all independent reflections [R1 = 0.0319 was calculated
against F for 4794 observed reflections with I > 2s(I)].
Crystallographic data for 5b. C15H19Br1.5Cl0.5N5O2Se (M = 517.90)
–
are triclinic, space group P1, at 293 K: a = 6.9791(2), b = 8.6795(4) and
c = 16.3447(6) Å, a = 92.639(2), b = 94.592(2) and g = 108.120(2)°,
V = 935.33(6) Å3, Z = 2, dcalc = 1.839 g cm–3, m(MoKa) = 5.302 mm–1,
F
(000) = 510. Total of 5974 reflections were measured and 4076
independent reflections (Rint = 0.0371) were used in a further refinement.
The refinement converged to wR2 = 0.1274 and GOF = 1.059 for all
independent reflections [R1 = 0.0527 was calculated against F for 3244
observed reflections with I > 2s(I)].
The measurements were performed on a Bruker-Nonius KappaCCD
diffractometer with graphite-monochromated MoKa radiation (l =
= 0.71073 Å). The structure was solved by direct methods, and the non-
hydrogen atoms were located from the trial structure and then refined
anisotropically with SHELXL using a full-matrix least-squares procedure
based on F2. The hydrogen atoms were located from differential Fourier
synthesis and also from geometrically calculated positions and refined
using riding model.
4-Amino-8-bromo-7-(1-hydroxycyclohexyl)-9-(2-hydroxyethyl)-9H-
[1,2]selenazolo[3,2-f]purin-5-ium bromide/chloride 5b. Salt 5b was
1
prepared analogously. Yield 77%, mp 188–194°C (decomp.). H NMR
(400 MHz, DMSO-d6) d: 9.00 (br.s, 1H, OH), 8.45 (s, 1H, C2H), 8.25
(br.s, 2H, NH2), 4.79 (t, 2H, CH2N, J 5.6 Hz), 3.83 (t, 2H, CH2OH,
J 5.6 Hz), 2.33–2.24 (m, 2H, cyclohexyl), 1.94–1.91 (m, 2H, cyclohexyl),
1.75–1.65 (m, 5H, cyclohexyl), 1.35–1.22 (m, 1H, cyclohexyl). 13C NMR
(101 MHz, DMSO-d6) d: 181.3, 155.2, 150.9, 150.8, 150.6, 111.1, 82.9,
77.4, 59.3, 45.8, 32.8, 24.1, 20.6. MS (ESI), m/z: 459.9.
CCDC 1041474 and 1860964 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
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Mendeleev Commun., 2019, 29, 96–98
After treatment with ion-exchange resin, crystals of salt 5b
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In summary, first examples of modified isoselenazolocaf-
feinium(adeninium) salts were obtained in acceptable yields
under mild reaction conditions, from 8-alkynylpurine derivatives.
Experiments on estimating the scope of this transformation and
testing antiproliferative activity of cyclic Se–N+ bond containing
condensed xanthines are underway.
This work was supported by project ERAF 1.1.1.1/16/A/294.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.01.033.
Received: 13th August 2018; Com. 18/5665
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