Fused Selenazolinium Salt Derivatives with a Se-N+ Bond: Preparation and Properties

Article abstract of DOI:10.1002/ejoc.201500582

Convenient methods for the preparation of stable, fused selenazolinium salt systems with a Se-N⁺ bond have been developed. The mechanism for the formation of the selenazole cycle was investigated in detail by conducting multinuclear NMR experiments. The ability of these compounds to form stable inner salts was demonstrated. We have shown the glutathione peroxidase (GPx) like properties of selenazolopyridinium salts by oxidizing sulfur-containing natural amino acids, as well as aromatic and heteroaromatic aldehydes. The molecular structures of most of the compounds were confirmed by X-ray diffraction studies.

Full text of DOI:10.1002/ejoc.201500582

FULL PAPER
DOI: 10.1002/ejoc.201500582
Fused Selenazolinium Salt Derivatives with a Se–N+ Bond: Preparation and
Properties
Pavel Arsenyan,*[a] Jelena Vasiljeva,[a] Sergey Belyakov,[a] Edvards Liepinsh,[a] and
Marina Petrova[a]
Keywords: Nitrogen heterocycles / Selenium heterocycles / Selenium / Regioselectivity / Cyclization
Convenient methods for the preparation of stable, fused
selenazolinium salt systems with a Se–N+ bond have been
developed. The mechanism for the formation of the selen-
azole cycle was investigated in detail by conducting multi-
nuclear NMR experiments. The ability of these compounds
to form stable inner salts was demonstrated. We have shown
the glutathione peroxidase (GPx) like properties of selen-
azolopyridinium salts by oxidizing sulfur-containing natural
amino acids, as well as aromatic and heteroaromatic alde-
hydes. The molecular structures of most of the compounds
were confirmed by X-ray diffraction studies.
on the substitution patterns of the substrates and on the
reaction conditions. anti-1,2-Addition was observed in the
case of PhSeCl(Br),[6g–k] and the corresponding halovinyl-
selenylbenzenes were usually formed regioselectively with a
substantial excess of one regioisomer. Nevertheless, the ad-
dition of PhSeCl to arylferrocenylethynes[6l] led to the for-
mation of two regioisomers in different ratios, and no re-
gioselectivity was observed in reactions of phenylselenyl-
fluoride[6m] with unsymmetrical alkynes. Additional contra-
dictory results have been reported in the case of selenium
halides. Quite recently, Amosova[6n] and co-workers showed
that selenium mono-, di-, and tetrahalides react with acetyl-
ene in a stereoselective manner, providing the correspond-
ing anti-addition products. On the other hand, in Braver-
man’s[6o] studies, the addition of SeCl2, SeBr2, or SeCl4 to
propargyl alcohols involves syn stereochemistry and an
anti-Markovnikov orientation. Theoretically, after the ad-
dition of selenium halides to the triple bond of 2-ethynyl
N-heterocycles, further cyclization may take place with the
formation of selenophene or selenazole cycles.
Introduction
In the last decade, the synthesis of chalcogen–nitrogen
compounds has begun to play an important role in the de-
sign and synthesis of materials, especially conducting, su-
perconducting, and magnetic materials.[1] The development
of an efficient method for the preparation of selenazolinium
salts with a Se–N+ bond is a topic of current interest. The
chemistry of Se–N bonds since the 1980s has been re-
viewed.[2] Heterocycles containing Se–N bonds, such as
ebselen, are clinically useful redox modulators and anti-
inflammatory agents.[3] In addition, organoselenium com-
pounds with intramolecular nonbonding Se··N interactions
have attracted much interest as mimics of glutathione
peroxidase (GPx) and thioredoxin reductase (TrxR).[4]
Furthermore, ebselen-like compounds are widely used as
catalysts in organic synthesis. Despite extensive chemical
studies and the various applications of selenium-containing
heterocycles, only a few examples of compounds containing
the Se–N+ bond have been reported.[5]
The cyclization of aryl(thienyl)alkyne derivatives in the
presence of selenium(I), (II), and (IV) halides has become
one of the most straightforward synthetic pathways for the
preparation of a wide variety of benzo[b]selenophenes and
selenophenothiophenes.[6a–f] Nevertheless, no studies on the
cyclization of ethynyl-substituted N-heterocycles have been
reported to date. Electrophilic selenium reagents, including
selenium halides, react with CϵC triple bonds by 1,2-ad-
dition, but the regio- and stereoselectivity depends strongly
Based on our experience with selenophene chemistry, we
focused on the addition regioselectivity of the various selen-
ium(II) and (IV) halides (SeCl2, SeCl4, SeOCl2, SeBr2,
SeBr4) to substituted 2-ethynyl N-heterocycles with the aim
of investigating the mechanism and developing methods for
the preparation of organoselenium heterocycles with Se–N+
bonds.
[a] Department of Medicinal Chemistry, Latvian Institute of
Organic Synthesis,
Aizkraukles 21, Riga 1006, Latvia
E-mail: pavel.arsenyan@lycos.com
http://www.osi.lv
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500582.
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Fused Selenazolinium Salt Derivatives
SeCl4 was necessary. Additional model compounds were
obtained by using 1-(pyridin-2-ylethynyl)cyclohexanol (2)
and 1,1-diphenyl-3-(pyridin-2-yl)prop-2-yn-1-ol (3) as start-
ing materials and treating them with Se(II) and Se(IV)
chlorides under the same reaction conditions (Table 1). The
hydroxycyclohexyl- and hydroxydiphenylmethyl-substituted
selenazolopyridinium chlorides 21 and 22, respectively, were
isolated in moderate yields (25–65%). Based on these re-
sults, the use of SeCl2 as a source of selenium halide was
established as being optimal considering the shorter reac-
tion time and higher yields, especially in the case of 22.
Results and Discussion
Our investigation started with the reaction of 2-methyl-
4-(pyridin-2-yl)but-3-yn-2-ol (1) with 1.5 equiv. selenium(II)
chloride (entry 1) prepared in situ in chloroform (Scheme 1,
Table 1). According to the LC-MS data, 30% conversion
was achieved after 8 h stirring. An excess of SeCl2 up to
2.5 equiv. was not sufficient. However, after 1 h stirring of
1 with 3.4 equiv. SeCl2, the reaction was complete, and the
desired 3-chloro-2-(2-hydroxypropan-2-yl)[1,2]selenazolo-
[2,3-a]pyridin-8-ium chloride (20) was isolated in nearly
quantitative yield (93%). Notably, the reaction was per-
formed in the dark to avoid the disproportionation of
SeCl2. The product was isolated as a salt, and excess selen-
ium was removed by adding aqueous methanol to the reac-
tion mixture and passing the alcoholic solution through an
ion-exchange resin previously treated with hydrochloric
acid. Therefore, we synthesized the first example of a novel
heterocyclic system containing a Se–N+ bond. To our
knowledge, only one similar fused heterocycle has been re-
ported,[7] 2-(2-pyridyl)phenylselenium(II) tribromomercura-
te(II). Encouraged by this positive result, we treated 1 in
dioxane with selenium(IV) chloride prepared in situ by dis-
solving SeO2 in concentrated hydrochloric acid. The reac-
Table 1. Selenohalogenation of 2-ethynylpyridines 1–3.[a]
Selenium halide
1 (R = Me) 2 [R = (CH2)5]
3 (R = Ph)
SeCl2
SeO2 + HCl
SeOCl2
SeBr2
SeBr4
20 (93)
20 (67)
23 (24)
24 (52)
24 (56)
24 (58)
21 (65)
21 (36)
21 (65)
25 (90)
25 (68)
25 (87)
22 (55)
22 (25)
22 (60)
26 (45)
26 (40)
26 (64)
SeO2 + HBr
[a] Isolated yields (%) are given in parentheses. The corresponding
methods are described in the Supporting Information.
1
The H, 13C, 77Se, and 15N NMR spectroscopic data for
tion was monitored by LC-MC and, after 5 h stirring, con- selenazolopyridinium chlorides 20–22 confirm the presence
version was complete and the desired product 20 was iso- of the Se–N+ bond. 77Se resonances were observed at δ =
lated in 65% yield. For complete conversion, 4.0 equiv. 1196.9 ppm (20), 1209.0 ppm (21), and 1218.2 ppm (22).
Scheme 1. Reaction of 2-ethynylpyridines with selenium halides.
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The observed 77Se chemical shifts are similar to those of [i.e., the Se1–C5–C11–N12 torsion angle is 0.7(2)°] and the
tert-butyl-1,3-diazabutadiene complexes with SeCl4 (δ = coordination polyhedron of the Se atom is a distorted octa-
934–1280 ppm).[5b,5c] 15N signals were observed at δ = hedron. To study the reaction of 1 with SeOCl2, the reac-
209.7 ppm (20) and 210.4 ppm (22). The changes in the tion was monitored directly in an NMR tube in anhydrous
shielding of the 1H, 13C, and 15N atoms in 20–22 compared dioxane and was repeated several times. The structures of
with those in pyridine derivatives 1–19 are characteristic of the intermediates were assigned from the 1H, 13C, 77Se
protonation of the nitrogen atom or the formation of the NMR, 1H-13C HMBC, 1H-13C HSQC, and IR spectro-
Se–N+ bond because of the absence of a lone pair on the scopic data (Scheme 2). Immediately after the reactants (1
pyridine nitrogen. The pyridine 15N resonance shifts to a and SeOCl2) were mixed, the only product in the solution
higher field; however, the 1H and 13C resonances of the C4H other than SeOCl2 was adduct IM1. Selenium oxychloride
fragments shift to lower field compared with those of the exhibits a broad resonance at δ = 1495 ppm in the 77Se
initial compounds. The molecular structures of selenazolo- NMR spectra. However, intermediate IM1 exhibits a broad
pyridines 20 and 22 were unambiguously confirmed by X- signal at δ = 1488 ppm. The changes in the shielding of the
ray diffraction analysis (Figure 1, left). The Se–N bond 1H and 13C atoms in molecule IM1 are characteristic of
lengths (1.883–1.888 Å) confirmed the formation of a cova- protonation of the nitrogen atom or the formation of a Se–
lent bond, and the Se··O distances were 2.521–2.538 Å.
N+ bond, which results in the absence of the lone pair of
To investigate selenium halide sources further, selenium electrons on the pyridine nitrogen. In a separate experi-
oxychloride was employed in the reaction with 1. SeOCl2 ment, the same trends in chemical shift were observed when
was prepared by treatment of selenium(IV) oxide with the adduct of 2-picoline and SeOCl2 was prepared. Ad-
2 equiv. chlorotrimethylsilane followed by distillation. The ditional information was obtained from the IR spectra. The
reaction was performed in anhydrous dioxane, because the appearance of
a new moderate absorption band at
use of chloroform as solvent resulted in decomposition of 1536 cm–1 in the spectrum of the mixture of 1 and SeOCl2
the reactant. The first experiments were unsuccessful. How- and the absence of this absorption in the individual IR
ever, increasing the amount of excess SeOCl2 to 6 equiv. spectra of 1 and SeOCl2 indicates the formation of a Se–
unexpectedly resulted in the precipitation of colorless crys- N+ bond in intermediate IM1. Additional confirmation
tals, which were obtained in 24% yield. Based on the results that this band is caused by the Se–N+ vibration was ob-
of X-ray analysis, the molecular structure of the obtained tained in a separate experiment in which 2-picoline was
compound was determined to be the previously unreported treated with SeOCl2. In the IR spectra of the free reactants,
2-(1,1,4-trichloro-5,5-dimethyl-5H-1,2-oxaselenol-3-yl)pyr- this band was also absent. However, this band appeared in
idine dioxane solvate (23; Figure 1, right). The selenium the spectrum of the mixture of 2-picoline with SeOCl2 in
atom is bonded to the electron-acceptor oxygen and to two dioxane. Notably, the stretching vibration of the CϵC triple
chlorine atoms, which induces the formation of an ad- bond at 2237 cm–1 in the spectrum of IM1 was shifted to
ditional bond to the dioxane solvate (σ-hole interactions[8]). higher frequency in the spectrum of 1, which as observed
In the crystal structure, the Se atom forms strong bonds at 2229 cm–1. The considerable line broadening and the
to nitrogen (2.675 Å) and to the dioxane oxygen (2.826 Å). shift of the OH stretching band to a lower frequency, from
Therefore, the oxaselenole and pyridine cycles are coplanar 3419 cm–1 (1) to ca. 3250 cm–1 (IM1), indicates that the
Figure 1. Molecular structure of 20 and the asymmetric unit of 23 [selected bond lengths (Å): Se1–O2 1.758(2), Se1–C5 1.918(2), Se1–
Cl6 2.373(1), Se1–Cl7 2.430(2), Se1–N12 2.675(2), Se1–O1d 2.826(2)]. Displacement ellipsoids are drawn at 50% probability level and H
atoms are shown as small spheres of arbitrary radii.
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Fused Selenazolinium Salt Derivatives
hydroxyl moiety can form an intramolecular H-bond (i.e., This compound was isolated only because of monocrystal
=O···HO–). Based on these results, it is concluded that in- precipitation from the reaction mixture as the dioxane solv-
termediate IM1 is an adduct of 1 and SeOCl2 with an Se– ate.
N+ bond.
In addition, the reaction with cyclohexyl derivative 2 and
SeOCl2 in dioxane was monitored in an NMR tube. Ac-
1
cording to the H, 13C, and 77Se NMR spectroscopic data,
selenazolopyridinium salt 21 formed as a single product via
the 2ϫ SeOCl2 adduct. Three resonances at δ = 1494.9
(SeOCl2), 1450.6 (2ϫ SeOCl2), and 1197.9 (21) ppm were
observed in the 77Se spectrum of the reaction mixture.
Compound 21 was isolated, and the 77Se resonance was ob-
served at δ = 1209.1 ppm in DMSO. Treatment of diphenyl-
ethynylpyridine (3) with SeOCl2 resulted in the formation
of the corresponding selenazolopyridinium chloride 22 in
60% yield. The yield of selenazolopyridinium salts depends
strongly on the nature of the selenium chloride used and on
the steric bulk of the substituents.
The addition of selenium(II) and (IV) bromides to 2-eth-
ynylpyridines 1–3 was then studied. Selenium(II) bromide
was obtained in situ by treatment of selenium with an equi-
molar amount of bromine in CCl4 in the dark. A solution
of 1–3 in anhydrous dioxane was added dropwise to SeBr2
at 0 °C. The temperature was subsequently increased to
20 °C over a period of 1 h, and the desired 3-bromoselen-
azolopyridinium salts were formed. Addition of the reagent
to the reaction mixture at 0 °C was necessary because of
the exothermic formation of the adduct of SeBr2 and the
initial pyridine. The formation of this adduct resulted in the
formation of undesired side products with higher molecular
weights. The optimal amount of SeBr2 for completing the
Scheme 2. Mechanism of the reaction of SeOCl2 with 1.
After a few days, the formation of two new species was conversion of 1–3 into the 3-bromoselenazolopyridinium
observed in the NMR spectra. The reaction proceeded over salts 24–26 was 3.4 equiv. Dimethyl derivative 24 and the
two weeks in parallel directions, yielding IM2 (by addition diphenyl analogue 26 were obtained in moderate yields (up
of SeOCl2 to the triple bond of IM1) and product 20. We to 52%). However, cyclohexyl-substituted selenazolinopyr-
suppose that selenazolopyridinium salt 20 was formed by idinium 25 was obtained in 90% yield (Table 1). The purifi-
intramolecular electrophilic attack of the selenium chloride cation of compounds 24–26, similar to the isolation pro-
group on the CϵC triple bond with the following exchange cedure employed for 20–22, was performed by pouring the
reaction of oxygen to chloro substituents in excess of reaction mixture into aqueous methanol followed by anion
SeOCl2 followed by elimination of chlorine molecule.[6a–e] exchange on ion-exchanging resin (Cl–). Commercially
During the reaction, the resonances of intermediate IM1 available selenium(IV) bromide was used as the selenium
completely disappeared. At the end of the reaction, only source, and its effectiveness as a reactant was studied. The
the signals of the two components, in an approximately desired 3-bromo derivatives 24–26 were isolated in moder-
equal ratio, remained in the spectrum of the reaction mix- ate yields (40–68%) when the reaction was performed in
1
ture. The multinuclear spectroscopic data (1H, 13C, H-13C anhydrous dioxane. Given that cyclization in aqueous solu-
1
HMBC, H-13C HSQC, 77Se) allow the structures of these tions without an inert atmosphere is convenient, we pre-
two components to be assigned as IM2 and 20. Four 77Se pared SeBr4 in situ by dissolving SeO2 in concentrated HBr
resonance signals at δ = 1495 (SeOCl2), 1488 (IM1), 1203 for the synthesis of selenazolopyridinium salts 24–26. To a
(20) and 1064 ppm (IM2) were observed in the spectra of freshly prepared aqueous selenium(IV) bromide solution,
the reaction mixture during the reaction. The integral inten- 1–3 were added dropwise at room temperature. This
sities of the last two signals were equal. Therefore, these method required a longer reaction time for full conversion
signals were assigned to 20 and IM2. Compound 20 was of the initial ethynylpyridine. The desired derivatives 24–26
isolated from the reaction mixture, and the 77Se resonances were obtained in moderate yields (58–87%).
of this compound were observed at δ = 1218 ppm in CDCl3
Given the convenience of this method, several 3-bromo-
and δ = 1196.9 ppm in dimethyl sulfoxide (DMSO). IM2 selenazolopyridinium salts were prepared. 2-Pentyl-3-
was not isolated. Novel oxaselenole dichloride 23 was bromoselenazolopyridinium chloride 27 was prepared in
formed by intramolecular cyclization with elimination of moderate yield (26%) by treating 2-hept-1-ynylpyridine (4)
HCl and, in the presence of an excess of selenium oxychlor- with SeBr4 in dioxane–water. 2-Hydroxymethyl and 2-(1-
ide, possible exchange reaction Se=O to the SeCl2 moiety. hydroxyethyl) derivatives 28 and 29 were obtained in 40 and
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P. Arsenyan et al.
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51% yield, respectively. With cycloalkyl substituents, the Table 2. Selected bond lengths and distances [Å] in a series of selen-
azolopyridinium salts.[a]
yield increased. The 2-(1-hydroxycyclopentyl) (30), 2-(1-
hydroxytetrahydropyranyl) (32), and 2-(1-hydroxycyclo-
heptyl) (33) selenazolopyridinium salts were obtained in
good yield (54–88%). The adamantyl-substituted analogue
Compound
Se–N
C–Se
Se···O
20
22
1.883(2)
1.888(1)
1.888(2)
1.878(2)
1.883(5)
1.886(2)
2.128(4)
1.879(2)
2.103(2)
1.895(3)
1.881(3)
1.888(5)
1.888(5)
1.868(7)
1.885(2)
1.877(2)
1.884(2)
1.886(3)
1.874(3)
1.892(3)
1.862(2)
1.869(2)
1.858(2)
1.858(2)
1.868(6)
1.867(2)
1.852(5)
1.876(2)
1.850(2)
1.857(4)
1.880(4)
1.881(6)
1.866(6)
1.859(7)
1.870(2)
1.897(2)
1.862(2)
1.863(3)
1.859(3)
1.859(3)
1.880(3)
1.882(3)
1.879(2)
1.879(2)
2.538(2)
2.521(2)
2.575(2)
2.538(2)
2.538(2)
2.544(2)
1.988(4)
2.499(2)
1.982(2)
2.575(3)
2.650(3)
2.539(5)
2.541(5)
2.515(7)
2.601(2)
3.360(2)
2.574(2)
2.550(3)
2.561(3)
2.563(3)
2.549(3)
2.693(3)
2.613(2)
2.637(2)
34 was prepared in 59% yield by stirring 2-pyridin-2-yl- 24
2–
25 (SeBr6
)
ethynyladamantan-2-ol with SeBr4 for 2 d. Notably, the
conversion of the hydroxyl group into the methoxy substit-
uent in cyclohexylethynylpyridine derivative 8 resulted in a
decreased yield of product 31 under these reaction condi-
tions. In addition, the phenyl methyl derivative 35 was syn-
thesized in 50% yield. Electron-donating substituents in the
pyridine cycle also decreased the yields of selenazolopyr-
idinium salts 36 and 37; however, the introduction of an
electron-withdrawing substituent such as cyano group led 32
to an increase in the yield of the desired fused heterocycle
38. This method is useful for the formation of polycyclic
system 1-bromo-2-(2-hydroxypropan-2-yl)-[1,2]selenazolo-
[3,2-a]isoquinolin-4-ium chloride (39) in 59% high yield.
With the aim of studying how oxygen-containing substitu-
ents such as formyl (17), acetyl (18), and methylhydroxy-
ethyl (19) could influence the product architecture and sta-
bility, the corresponding selenazolopyridinium salts 40–42
were prepared in high yields (78–81%). In general, isolated
compound yields depend on the nature of the selenium hal-
ide, initial pyridine 1–19 complex stabilization with selen-
ium halide, and selenazolopyridine system stability during
25 (Cl–)
25a
26
26a
30
31
32 (Cl–Br–)
33
34
35
40
41
42
58 (cation A) 1.871(3)
58 (cation B) 1.860(3)
60
64
1.877(2)
1.876(2)
[a] The corresponding data are presented in the Supporting Infor-
mation.
isolation. Substituents in the 6-position of pyridine stabilize proaches 0°. Therefore, no σ-hole interactions are present
complex formation and resulted in high yields of 40–42; between the Se and O atoms, and the Se–C bond length is
however, the absence of hydroxyl groups as well as electron- typically greater than the Se–N bond length. The packing
withdrawing substituents decreased the product yields in influence is especially pronounced in the crystal structures
connection with lower stability during chromatography and of 31 and 31ClBr, in which this distance increases from
crystallization.
2.515(7) to 2.541(5) Å. Likewise, in other bases of selen-
Determination of the structure of the selenazolo[2,3-a]- azolo[2,3-a]pyridinium salts the selenium atoms in 40–42
pyridinium salts using X-ray crystallographic data was chal- are bonded with the electron-acceptor N+ atom. This fea-
lenging. To identify N+ and C atoms in molecules using ture promotes the formation of additional bonds by means
X-ray diffraction data, the crystals must be high quality; of σ-hole interactions. In the crystal structure, the selenium
determining the N+ and C atoms from the bond lengths forms strong bonding with two oxygen atoms giving ad-
may be difficult because of considerable standard deviation ditional four- and five-membered cycles in the molecules
of the values in the presence of the heavy bromine and sel- 41. These cycles are almost coplanar to the selenazolo-
enium atoms. In selenazolo[2,3-a]pyridinium salts, intermo- [2,3-a]pyridinium system; the Se···O distances are 2.563(3)
lecular hydrogen bonds should be present between the N+– and 2.614(3) Å. Withal, in the crystal structure the bromine
H group and an acceptor atom. In selenazolo[2,3-a]pyridin- atom forms a weak bond [3.502(4) Å] with the π-system of
ium cations, the increased electronegativity of the carbon the acetonitrile molecule. The additional four- and five-
atoms bound to N+ promotes the formation of 7-CH···X membered cycles occur also in 40 and 41 [Se···O distances
intermolecular hydrogen bonds. For example, in compound are 2.550(3), 2.848(3) Å for 40 and 2.561(2), 2.575(3) Å for
30, the length of this hydrogen bond is 3.129(9) Å (Table 2). 41].
Strong σ-hole interactions between selenium and oxygen
Selenazolopyridinium salts 20–42 are unstable in strongly
atoms were observed in the cations of the selenazolo- basic solutions; these compounds decompose through eli-
[2,3-a]pyridinium salts, and these interactions resulted in mination of selenium. However, the slow addition of 0.5 m
lengthening of the Se–N bond compared with the Se–C aqueous NaOH to a solution of 25 or 26 in ethyl acetate
bond lengths in these cations. However, the Se···O distance at 0–5 °C to pH 8.0 allowed isolation of the corresponding
ranges from 2.499(2) (26) to 2.650(3) Å (31) (Table 2), zwitterionic salts 25a and 26a in good yield (Scheme 3).
which indicates that the specific weight of the mesomeric These compounds are stable and soluble in aprotic organic
form with the Se–O bond is significantly lower in these cat- solvents. We also discovered that this reaction is reversible.
ions. Adamantyl derivative 34 is an exception because of The addition of a methanolic HCl solution to a solution of
the steric bulk in the Se–C2–C10–O torsion angle [i.e., 25a and 26a in ethyl acetate at 0 °C led to near quantitative
–76.4(5)°]. However, in the other cations, this angle ap- conversion into the initial pyridinium chlorides 25 and 26.
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Fused Selenazolinium Salt Derivatives
(e.g., 20, 22, 25) suggest that the zwitterionic salts 25a and
26a exist in two mesomeric forms (A and B) that intercon-
vert.
The selenazolo[2,3-a]pyridinium salt system resembles
that of Ebselen, which is the first synthetic molecule that
can mimic glutathione peroxidase (GPx) activity,[10] and we
propose that these types of compounds can be used as cata-
lysts. Preliminary studies of the catalytic ability of the com-
pounds in this system were initiated by using sulfur oxid-
ation reactions. Cyclohexyl derivative 25 was chosen as a
model catalyst. Because l-cysteine and l-methionine, which
is also known as vitamin U, are the only natural amino
acids that contain a sulfur atom, we studied their oxidation
with hydrogen peroxide in methanol. l-Cysteine was quan-
titatively converted into its l-cysteine form 43 after only
10 min of stirring at room temperature in the presence of
5 mol-% 25. In addition, the l-methionine sulfur atom was
oxidized to the corresponding S-oxide 44 after 30 min stir-
ring. The precipitation of amorphous red selenium was not
observed, and the reaction mixtures were clear and color-
less. To determine the lowest amount of catalyst necessary,
cysteine oxidation was performed with 25 mol-% 25. After
10 min, the reaction was complete. The solvent was sub-
sequently evaporated, and the crude product was purified
by flash chromatography, which resulted in the recovery of
21 mol-% of selenazolopyridinium 25.
Scheme 3. Formation of zwitterionic salts 25a and 26a.
The molecular structures of 26 and 26a are shown in
Figure 2. The structures of the bases of the selenazolo[2,3-a]-
pyridinium salts possess a tricyclic condensed system of
six-, five- and four-membered rings. Notably, in 25a and
26a, the Se–N bonds are longer than the Se–O bonds (see
Table 2). These two bases may exist in two mesomeric forms
(i.e., A and B) that interconvert. The 77Se and 15N NMR
spectra of 25a and 26a were assessed to estimate which form
is dominant in solution. The 77Se resonances in the spectra
of the selenazolopyridinium derivatives were observed at
1196–1218 ppm. The formation of the Se–O bond leads to
shielding of the selenium atoms in zwitterionic salts 25a and
26a to ca. 100 ppm, and their chemical shifts are 1106 and
1118 ppm, respectively. The 15N chemical shift is 320.5 ppm
for ethynylpyridine 1. This value is typical for pyridines and
their derivatives.[9] When the nitrogen lone pair is involved
in the interaction, high-field shifts of the 15N signals are
observed for derivatives 20, 22, and 25, and their 15N sig-
A catalytic cycle involving 25 as a molecule with GPx-
nals are observed at 209.0, 212.7 and 210.4 ppm, respec- like activity is presented in Scheme 4. To verify the first
tively. However, the formation of an additional Se–O bond oxidation step of 25 with H2O2, the reaction was monitored
in 25a and 26a leads to a decrease in the interaction be- directly in an NMR tube in deuterated methanol and was
tween the selenium and nitrogen atoms because the 15N sig- repeated several times. The structure of intermediate IM3
nals shift downfield to 263.7 (25a) and 261.0 ppm (26a) was assigned from the 1H, 13C, 77Se NMR, and 1H-13C
compared with 20, 22, and 25. Intermediate values of the HMBC data. After the reactants (25 and H2O2) were mixed
15N chemical shifts for 25a and 26a relative to the 15N in CD3OD for 15 min, a few milligrams of ascorbic acid
chemical shifts for 1 and the selenazolopyridinium salts were added to prevent free radical formation. The major
Figure 2. Molecular structures of 26 and 26a. Displacement ellipsoids are drawn at 50% probability level and H atoms are shown as
small spheres of arbitrary radii.
Eur. J. Org. Chem. 2015, 5842–5855
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P. Arsenyan et al.
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product observed in solution was oxidized intermediate convenience of this method, several acids were prepared. 4-
IM3. As mentioned above, selenazolopyridinium chloride Bromobenzoic (46) and benzoic (47) acids were obtained
25 exhibits a resonance at δ = 1209 ppm in the 77Se NMR from 4-bromobenzaldehyde and benzaldehyde in 46 and
spectra. Furthermore, the 77Se chemical shift characteristic 92% yields, respectively. Surprisingly, 2-, 3-, and 4-pyridine-
of benzene seleninic acid (PhSeOOH) was detected at δ = carboxylic acids 48–50 were formed at room temp. in 2 h in
1173 ppm. According to our data, the only signal in the excellent yields (87–96%). Our attempts to oxidize aliphatic
77Se NMR spectra for intermediate IM3 was detected at δ = phenylacetaldehyde and phenylpropionaldehyde by using 25
1373 ppm. The chemical shift downfield by approximately as catalyst failed.
100 ppm confirms the cyclic nature of IM3; moreover,
For the next step of our studies we focused on the con-
changes in the shielding of the H and 13C atoms showed struction of fused selenazolinium systems with five-mem-
no significant deviations from those of initial 25. Intermedi- bered rings such as thiazole and imidazole. Initial ethynyl
ate IM3 remained stable for at least 30 min during NMR thiazoles and imidazoles were prepared by using the Sono-
experiments. Notably, we confirmed that the selenium atom gashira protocol with some modifications. In accordance
in selenazolopyridinium 25 is initially oxidized by hydrogen with previous reports and on our own experience[11] modifi-
peroxide to the selenoxide intermediate IM3, which reacts cations in the 2-position of thiazole and imidazole rings is
with l-cysteine to form the Cys-Se-OH adduct. The other usually challenging. It should be mentioned that the nature
l-cysteine molecule then reduces these species and regener- of the solvent mixture used in the reaction plays an ex-
ates the parent molecule 25. We assume that the selen- tremely important role. Thus, 2-methyl-4-(thiazol-2-yl)but-
azolinium cycle does not open during the formation of the 3-yn-2-ol (51) and 1-(1,3-thiazol-2-ylethynyl)cyclohexanol
intermediates because this ring opening could lead to (52) were prepared in a mixture of toluene, N,N-dimethyl-
1
irreversible consequences.
formamide (DMF), and Et3N at 80 °C using (Ph3P)2PdCl2
and CuI as catalysts. However, the synthesis of butynamine
53 and morpholine 54 were successfully performed in
DMF/diisopropylamine at room temperature in the pres-
ence of (Ph3P)4Pd and CuI. Notably, 2-ethynyl imidazoles
55 and 56 were obtained in N-methyl-2-pyrrolidinone
(NMP)/diisopropylethylamaine (DIEA) at 50 °C.
2-Methyl-4-(thiazol-2-yl)but-3-yn-2-ol (51) was chosen as
a model compound and treated with a range of selenium
halides (Table 4). Our first attempt to form the selenazolo-
thiazolium system by using 4 equiv. selenium(II) chloride as
a source of selenium was successful. According to the LC-
MS data, 87% conversion was achieved after 4 h stirring.
The desired 3-chloro-2-(2-hydroxy-2-methylethyl)[1,2]selen-
azolo[2,3-b]thiazolinium chloride (57) was isolated from the
reaction mixture in high yield (68%; Table 4). Notably, the
reaction was performed in the dark to avoid the dispropor-
Scheme 4. Mechanism of oxidation.
The use of 25 as aldehyde oxidation catalyst was also tionation of SeCl2. The product was isolated as a salt, and
studied (Table 3). 4-Trifluoromethylbenzaldehyde was cho- excess selenium was removed by adding aqueous methanol
sen as a model compound. First attempts to oxidize the to the reaction mixture and passing the alcoholic solution
aldehyde group to the acid by using hydrogen peroxide in through an ion-exchange resin that was previously treated
acetonitrile failed; however, the same reaction in tert-butan- with hydrochloric acid. The use of selenium oxychloride
ol gave 4-trifluoromethylbenzoic acid (45) in 10% yield. In- and selenium(IV) chloride prepared in situ as sources of
creasing the temperature to 35 °C had a positive impact and selenium for the formation of these types of compounds
the desired acid 45 was isolated in 60% yield. Given the was not suitable. Increasing the temperature reduced the
Table 3. Oxidation of aryl and heteroaryl aldehydes.
RCHO
Conditions
Product
Yield [%]
4-F3C-C6H4CHO
4-F3C-C6H4CHO
4-F3C-C6H4CHO
4-F3C-C6H4CHO
4-Br-C6H4CHO
PhCHO
2-PyCHO
3-PyCHO
4-PyCHO
H2O2, room temp., MeCN, 5d
H2O2, room temp., tBuOH, 1d
H2O2, 35 °C, tBuOH, 1d
tBuOOH, room temp., tBuOH, 1d
H2O2, 35 °C, tBuOH, 1d
4-F3C-C6H4COOH
4-F3C-C6H4COOH
4-F3C-C6H4COOH
4-F3C-C6H4COOH
4-Br-C6H4COOH
PhCOOH
2-PyCOOH
3-PyCOOH
4-PyCOOH
–
–
45
45
–
46
47
48
49
50
10
60
–
46
92
96
91
87
H2O2, 35 °C, tBuOH, 1d
H2O2, room temp., tBuOH, 2 h
H2O2, room temp., tBuOH, 2 h
H2O2, room temp., tBuOH, 2 h
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Fused Selenazolinium Salt Derivatives
product yield. Therefore, we synthesized the first example an inert atmosphere is convenient, herein SeBr4 prepared in
of a novel five-membered fused heterocyclic system contain- situ by dissolving SeO2 in conc. HBr was utilized.
ing an Se–N+ bond.
This method required a longer reaction time. Unfortu-
nately, only half of 51 converted in 2 d stirring; however,
the use of cyclohexene as an additive accelerated the con-
version to 89% in 24 h. The desired bromo-derivative 58
was obtained in high yield (52%). Given the convenience of
these methods, several fused thiazolo- and imidazoloselen-
azolinium salts were prepared. 7-Chloro-6-(2-hydroxy-
Table 4. Selenohalogenation of 2-ethynyl thiazole 51.[a]
Selenium halide
Conv. Product
Yield [%]
SeCl2 (4 equiv.)
SeOCl2 (4 equiv.)
SeO2 + HCl (2.5 equiv.)
SeBr2 (2 equiv.)
SeBr4 (1.5 equiv.)
SeBr4 + Cyclohexene (1.5 equiv.)
SeO2+HBr (1.5 equiv.)
SeO2+HBr + Cyclohexene
(1.5 equiv.)
87
72
8
57
57
57
58
58
58
58
58
68
26
–
23
26
38
–
32
54
50
50
89
propan-2-yl)-[1,2]selenazolo[3,2-b]thiazol-4-ium
chloride
(57) and its cyclohexyl analogue 59 were prepared in good
yields (68 and 60%, respectively) by treating ethynylthi-
azoles 51 and 52 with SeCl2. Bromoselenazolothiazolinium
salts 58 and 60, were successfully synthesized in similar
yields; however, the use of 6-(2-aminopropan-2-yl)-7-
bromo[1,2]selenazolo[3,2-b]thiazol-4-ium analogue 61 re-
sulted in a decreased yield under these reaction conditions.
Furthermore, according to LC-MS data, treatment of 4-[3-
(thiazol-2-yl)prop-2-yn-1-yl]morpholine (54) with SeBr4 in
dioxane/water led to the formation of the corresponding
fused selenazolinium salt; unfortunately, during isolation
followed by flash chromatography the cycle was opened. As
a result, diselenide 62 was isolated in 36% yield. Inspection
of the reactions of 2-ethynylimidazoles with selenium(II)
chloride and selenium(IV) bromide showed excellent
results.
The corresponding [1,2]selenazolo[3,2-b]imidazolinium
salts 63–66 were isolated in up to quantitative yields. The
crystal structure of 58 is interesting because the influence
of the crystal packing on the intramolecular Se···O interac-
tion is especially pronounced. In the asymmetric unit of 58
there are two independent cations (A and B) and anions
(see Figure 3). The molecular cation A forms a hydrogen
bond of OH···Cl type [O···Cl 3.033(5) Å, H···Cl 2.26 Å, O–
H···Cl 140°] with chloride anion, which lies practically in
symmetry (mirror) plane of this cation. Such conformation
of the hydroxyl group promotes increasing of the σ-hole
interaction between selenium and oxygen atoms and the
Se···O distance is 2.549(3) Å. In contrast, cation B forms
the OH···Cl hydrogen bond [O···Cl 3.090(4) Å, H···Cl
52
[a] The corresponding methods are described in the Supporting
Information.
In a continuation of our studies, the addition of selen-
ium(II) and (IV) bromides to 51 was studied (Scheme 5). A
solution of 51 in anhydrous dioxane was added dropwise to
SeBr2 at 0 °C. The temperature was subsequently increased
to 20 °C over a period of 1 h, and the desired 7-bromoselen-
azolothiazolinium salt 58 was isolated in moderate yield
(23%). Increasing the amount of SeBr2 used to complete
the conversion gave no positive result. We noticed lower
stability of selenazolothiazolinium salts compared with
selenazolopyridinium analogues in water/alcohol media
during workup followed by anion exchange on ion-exchang-
ing resin (Cl–). Commercially available selenium(IV) brom-
ide was also used as the selenium source, and its effective-
ness as a reactant was studied. The desired 7-bromo deriva-
tive 58 was isolated in the same moderate yield (26%).
However, the addition of a bromine scavenger such as cy-
clohexene in the reaction mixture had a positive impact and
desired product 58 was obtained in 38% yield. As men-
tioned above, the cyclization in aqueous solutions without
Figure 3. Asymmetric unit of 58 with labels of atoms and cations
and thermal ellipsoids. Displacement ellipsoids are drawn at 50%
probability level and H atoms are shown as small spheres of arbi-
trary radii.
Scheme 5. Reaction of 51–56 with selenium halides.
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5849

P. Arsenyan et al.
FULL PAPER
techniques with pulsed-field gradients. The magnetization from 1H
to 15N in HSQC spectra were transferred from 3,5-pyridine protons
to nitrogen by using coupling constants nJ(1H,15N) = 3 Hz. 15N
spectra were indirectly referenced to the internal spectrometer ref-
erence liquid ammonia. IR spectra were recorded with a Shimadzu
IR Prestige-21 Fourier-transform IR spectrometer in fine films or
KBr pellets of the chemically pure grade. The melting points were
determined with a digital melting point analyzer (Fisher), and the
results are given without correction. Diffraction data were collected
with a Nonius KappaCCD diffractometer using graphite mono-
chromated Mo Kα radiation (λ = 0.71073 Å). The crystal structures
were solved by direct methods and refined by full-matrix least-
squares.[12] Dioxane was dried with sodium; CH2Cl2, CHCl3, and
CCl4 were dried with CaH2. Synthesis, spectroscopic, and physical
data of ethynylpyridines 1–2, 4–8, and 12 have been reported pre-
viously. Some of the terminal alkynes were prepared according re-
ported procedures or obtained from commercial sources and used
as received.
2.21 Å, O–H···Cl 167°] with chloride, which deviates from
the cation plane significantly. The N7–Se1···O1–H torsion
angle is 116° (the Se1···O1–H angle is 88°) and the Se···O
distance is increased up to 2.693(3) Å, accordingly, the
length of the Se1–N7 covalent bond is reduced to
1.860(3) Å (see Table 2). Thus, the Se···O interaction can
vary in a case of one and the same compound. In the struc-
tures of cyclohexyl-substituted analogue 60 and [1,2]selen-
azolo[2,3-b]imidazolinium bromide 64 the Se···O distances
are 2.613(2) Å and 2.637(2) Å, respectively.
Conclusions
Simple and convenient methods for the preparation of
stable novel selenazolo[2,3-a]pyridinium systems with a Se–
N+ bond have been developed. The novel structures were
1
assigned by H-, 13C-, 77Se-, 15N-, 13C-1H HMBC, 13C-1H
Synthesis of 3-Chloroselenazoles
HSQC NMR, and unambiguously confirmed for 20 selen-
azolinium salts by X-ray analysis. The mechanism for the
formation of the selenazole cycle was investigated in detail
by multinuclear NMR studies. The ability of these com-
pounds to form stable inner salts was confirmed. We evalu-
ated the Gpx-like properties of the selenazolopyridinium
salts in the oxidation of sulfur-containing natural amino
acids and confirmed a mechanism of catalyst formation.
Notably, these types of compounds may serve as an inex-
pensive catalyst in the oxidation of aromatic and heteroaro-
matic aldehydes to the corresponding acids. These proper-
ties of selenazolinium salts open a way to their use as cata-
lysts in various oxidation reactions. Further work in this
research field will focus on the application of the elaborated
methodology for the construction of more advanced sys-
tems containing Se–N+ bonds, including the introduction
of the selenazolinium moiety in natural compounds with
the aim to studying these types of derivatives as redox mod-
ulators.
Method A: A solution of SeCl2 was prepared from Se (0.156 g,
2.00 mmol) and SO2Cl2 (0.270 g, 2.00 mmol) in anhydrous CHCl3
by stirring in the dark for 5 h at room temperature. A solution of
ethynylpyridine (0.50 mmol) in anhydrous dioxane was then added
dropwise at 0 °C. The cooling bath was removed and the mixture
was stirred at room temperature until the starting material disap-
peared (reaction monitored by LC-MS analysis). To the mixture
was added ethanol and the solution was filtered through paper.
The filtrate was eluted through ion-exchange resins treated with
hydrochloric acid. The solvent was evaporated and the crude prod-
uct was purified by column chromatography on silica gel (dichloro-
methane/methanol, 1:0 to 10:1).
Method B: To a solution of selenium dioxide (0.444 g, 4.00 mmol)
in HCl (0.45 mL), ethynylpyridine (1.00 mmol) in dioxane was
added and the mixture was stirred at room temperature for 24–
72 h. After the consumption of substrate (checked by LC-MS
analysis), the reaction mixture was worked up in the same way as
described in Method A.
Method C: To a solution of SeOCl2 (0.664 g, 4.00 mmol) in an-
hydrous dioxane (10 mL), prepared from SeO2 and Me3SiCl, 1
(0.161 g, 1.00 mmol) in anhydrous dioxane (5 mL) was added and
the mixture was stirred at room temperature for 24–48 h until the
starting material disappeared (reaction monitored by LC-MS
analysis). In the case of substrates 2 and 3, further equivalents of
SeOCl2 were required (respectively, 7.00 mmol and 10.00 mmol).
The reaction mixture was worked up in the same way as described
in Method A. Product 23 precipitated from the reaction mixture as
colorless crystals.
Experimental Section
General: Unless stated otherwise, all reagents and solvents were
purchased from commercial suppliers and used without further pu-
rification. Thin-layer chromatography (TLC) was performed using
MERCK Silica gel 60 F254 plates and visualized by UV (254 nm)
fluorescence. ZEOCHEM silica gel (ZEOprep 60/35–70 microns –
1
SI23501) was used for column chromatography. H NMR spectra
3-Chloro-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo[2,3-a]pyridin-
were recorded with a Varian-Mercury 400 MHz spectrometer in
dioxane at 25 °C. The one-dimensional 1H- and 13C- and two-di-
mensional 13C-1H HMBC and 13C-1H HSQC spectra of com-
pounds were recorded with Varian-Mercury 400 and Varian-MR
400 MHz spectrometers. Spectra were acquired by using standard
pulse sequences provided by the Varian spectrometer library. The
chemical shifts of the hydrogen and carbon atoms are presented in
ppm and were indirectly referred to the internal spectrometer refer-
ence of Me4Si in CDCl3. 77Se NMR spectra were recorded at
76.36 MHz at 25 °C with a Varian MR 400 MHz spectrometer and
were indirectly referred to the internal spectrometer reference of
Me2Se in C6D6. 15N NMR spectra were recorded at 25 °C with a
Varian UNITY INOVA 600 MHz spectrometer equipped with a
1
ium Chloride (20): Yield 93%; m.p. Ͼ200 °C. H NMR (400 MHz,
[D6]DMSO): δ = 1.73 (s, 6 H, 2CH3), 7.80 (ddd, J = 1.4, 6.4,
7.6 Hz, 1 H, 6-CH), 8.27 (ddd, J = 0.6, 1.4, 8.6 Hz, 1 H, 4-CH),
8.40 (s, 1 H, OH), 8.43 (ddd, J = 1.4, 7.6, 8.6 Hz, 1 H, 5-CH), 9.96–
10.00 (m, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ
= 26.9, 74.4, 105.9, 121.6, 123.7, 140.3, 143.0, 154.7, 173.0 ppm.
15N NMR (60.81 MHz, [D6]DMSO): δ = 209.0 ppm. 77Se NMR
(76.36 MHz, [D6]DMSO): δ = 1196.9 ppm. ESI-MS: m/z = 276
[M]. C10H12Cl2NOSe (312.08): calcd. C 38.52, H 3.85, N 4.49;
found C 38.21, H 3.65, N 4.27.
3-Chloro-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-a]pyridinium
1
Chloride (21): Yield 67%; oil. H NMR (400 MHz, [D6]DMSO): δ
cryoprobe. 15N spectra were recorded at 60.81 MHz, using HSQC = 1.21–1.31 (m, 1 H, cyclohexane), 1.65–1.71 (m, 5 H, cyclohex-
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Fused Selenazolinium Salt Derivatives
ane), 1.96 (d, J = 12.9 Hz, 2 H, cyclohexane), 2.17–2.25 (m, 2 H,
cyclohexane), 7.77 (ddd, J = 1.4, 6.4, 7.6 Hz, 1 H, 6-CH), 8.25
(ddd, J = 0.9, 1.4, 8.6 Hz, 1 H, 4-CH), 8.41 (ddd, J = 1.4, 7.6,
8.6 Hz, 1 H, 5-CH), 8.51 (br. s, 1 H, OH), 10.05 (dt, J = 0.9, 6.4 Hz,
1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 20.3,
24.1, 32.9, 76.6, 92.9, 121.5, 124.8, 140.4, 142.8, 156.4, 175.9 ppm.
77Se NMR (76.36 MHz, [D6]DMSO): δ = 1209.0 ppm. ESI-MS:
m/z = 316 [M]. C13H16Cl2NOSe (352.14): calcd. C 44.38, H 4.55,
N 3.98; found C 44.15, H 4.43, N 3.65.
1 H, OH), 8.81 (d, J = 3.7 Hz, 1 H, 6-CH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 20.3, 24.0, 33.3, 75.9, 104.6, 122.3,
135.4, 166.5, 179.3 ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ
= 1191.1 ppm. ESI-MS: m/z = 322 [M]. C11H14Cl2NOSSe·MeOH:
calcd. C 36.94, H 4.65, N 3.59; found C 36.80, H 4.68, N 3.52.
3-Chloro-N-methyl-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo-
[2,3-b]imidazolinium Chloride (63): Yield 80%; m.p. 140–142 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 1.63 (s, 6 H, 2CH3), 4.03 (s, 3
H, CH3), 7.66 (d, J = 2.1 Hz, 1 H, 6-CH), 7.84 (br. s, 1 H, OH),
8.05 (d, J = 2.1 Hz, 1 H, 5-CH) ppm. 13C NMR (100.6 MHz, [D6]-
3-Chloro-2-(hydroxydiphenylmethyl)[1,2]selenazolo[2,3-a]pyridin-
1
ium Chloride (22): Yield 60%; m.p. Ͼ200 °C. H NMR (400 MHz, DMSO): δ = 26.8, 35.1, 73.6, 97.2, 122.1, 126.4, 145.7, 171.4 ppm.
[D6]DMSO): δ = 7.42–7.54 (m, 10 H, 2C6H5), 7.83 (ddd, J = 1.4, ESI-MS: m/z = 279 [M]. C9H13Cl2N2OSe·0.8EtOH: calcd. C 36.18,
6.4, 7.6 Hz, 1 H, 6-CH), 8.22–8.24 (m, 1 H, 4-CH), 8.42 (ddd, J =
1.4, 7.6, 8.6 Hz, 1 H, 5-CH), 9.40 (br. s, 1 H, OH), 10.00 (d, J =
6.4 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
82.2, 109.3, 122.1, 122.1, 124.0, 127.9, 128.3, 128.7, 139.9, 142.8,
154.9, 169.2 ppm. 15N NMR (60.81 MHz, [D6]DMSO): δ =
210.4 ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ = 1218.1 ppm.
H 5.10, N 7.96; found C 35.98, H 5.12, N 7.89.
3-Chloro-N-methyl-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-b]-
imidazolinium Chloride (65): Yield 84%; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.22–1.32 (m, 1 H, cyclohexane), 1.57–
1.70 (m, 5 H, cyclohexane), 1.86 (d, J = 13.3 Hz, 2 H, cyclohexane),
2.06–2.14 (m, 2 H, cyclohexane), 4.06 (s, 3 H, CH3), 7.69 (d, J =
1.9 Hz, 1 H, 6-CH), 7.96 (br. s, 1 H, OH), 8.08 (d, J = 1.9 Hz, 1
H, 5-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 20.4, 24.1,
33.1, 35.2, 75.4, 96.9, 122.1, 126.1, 145.9, 172.6 ppm. 77Se NMR
(76.36 MHz, [D6]DMSO): δ = 1051.6 ppm. ESI-MS: m/z = 319
[M]. C12H17Cl2N2OSe (355.15): calcd. C 37.22, H 4.43, N 7.23;
found C 36.89, H 4.07, N 7.03.
IR (KBr): ν = 650, 700, 768, 950, 1018, 1208, 1468, 1526, 1572,
˜
1606, 2679, 2988 cm–1. ESI-MS: m/z = 400 [M]. HRMS (ESI): m/z
calcd. for C20H15ClNOSe+ [M+] 400.0002; found 400.0009.
C20H16Cl2NOSe (436.22): calcd. C 55.10, H 3.67, N 3.21; found C
54.27, H 3.38, N 3.23.
IM1 Intermediate: 1H NMR (400 MHz, dioxane/D2O): δ = 1.73 (s,
6 H, 2Me), 8.20 (d, J = 7.8 Hz, 1 H, 3-H), 8.73 (t, J = 7.8 Hz, 1
H, 4-H), 8.19 (dd, J = 5.8, 7.8 Hz, 1 H, 5-H), 9.00 (d, J = 5.8 Hz,
1 H, 6-H) ppm. 13C NMR (100.6 MHz, dioxane/D2O): δ = 30.4
(Me2C), 65.1 (C-Me), 73.5 (C-C-2), 107.8 (C-CMe2), 126.8 (C-5),
130.7 (C-3), 134.8 (C-2), 143.1 (C-6), 147.1 (C-4) ppm. 77Se NMR
(76.36 MHz, dioxane/D2O): δ = 1488 ppm.
Synthesis of 3-Bromoselenazoles
Method D: A solution of SeBr2 was prepared from Se (0.265 g,
3.40 mmol) and Br2 (0.544 g, 3.40 mmol) in anhydrous CCl4 (6 mL)
in the dark. After 4 h, a solution of ethynylpyridine (1.00 mmol) in
anhydrous dioxane (15 mL) was added dropwise at 0 °C. The cool-
ing bath was removed and the mixture was stirred at room tempera-
ture until the starting material disappeared (monitored by LC-MS
analysis). Ethanol was added and the mixture was filtered through
paper. The filtrate was eluted through ion-exchange resins treated
with hydrochloric acid. The solvent was evaporated and the crude
product was purified by column chromatography on silica gel
(dichloromethane/methanol, 1:0 to 10:1).
IM2 Intermediate: 1H NMR (400 MHz, dioxane/D2O): δ = 1.92 (s,
6 H, 2Me), 8.32 (dd, J = 5.9, 7.8 Hz, 1 H, 5-H), 8.47 (d, J = 7.8 Hz,
1 H, 3-H), 8.82 (t, J = 7.8 Hz, 1 H, 4-H), 9.09 (d, J = 5.9 Hz, 1 H,
6-H) ppm. 13C NMR (100.6 MHz, dioxane/D2O): δ = 26.7 (Me2C),
99.6 (C-Me2), 128.7 (C-5), 130.3 (C-3), 136.9 (=C-Se), 142.4 (C-2),
143.9 (C-6), 146.7 (C-4), 151.7 (C-Cl) ppm. 7 7 Se NMR
(76.36 MHz, dioxane/D2O): δ = 1064, 1488 ppm.
Method E: To a solution of selenium tetrabromide (0.798 g,
2.00 mmol) in anhydrous dioxane (8 mL), ethynylpyridine
(1.00 mmol) in anhydrous dioxane (16 mL) was added and the mix-
ture was stirred at room temperature for 24–72 h. After the con-
sumption of substrate (LC-MS), the reaction mixture was worked
up in as described in Method D.
[2-(2,2,4-Trichloro-5,5-dimethyl-2,5-dihydro[1,2]oxaselenol-3-yl)pyr-
idine] Dioxane Solvate (23): Yield 24 % (Method C); m.p. 148–
150 °C. 1H NMR (400 MHz, CDCl3/TMS): δ = 1.88 (s, 6 H,
2CH3), 7.45 (ddd, J = 1.2, 6.1, 7.6 Hz, 1 H, 5-CH-Py), 7.96 (td, J
= 1.6, 7.6 Hz, 1 H, 4-CH- Py), 8.13 (td, J = 1.2, 8.0 Hz, 1 H, 3-
CH-Py), 8.65 (ddd, J = 1.0, 1.6, 6.1 Hz, 1 H, 6-CH-Py) ppm. 13C
NMR (100.6 MHz, 1,4-[D8]dioxane): δ = 27.6, 67.0, 107.9, 108.0,
122.7, 125.3, 138.3, 146.5, 149.2. 15N NMR (60.81 MHz, CDCl3/
TMS): δ = 316.7 ppm. 77Se NMR (76.36 MHz, CDCl3/TMS): δ =
1148.0 ppm. C10H10Cl3NOSe·0.5dioxane: calcd. C 37.00, H 3.62,
N 3.60; found C 37.11, H 3.61, N 3.52.
Method F: To a solution of selenium dioxide (0.444 g, 4.00 mmol)
in HBr (0.45 mL), ethynylpyridine (1.00 mmol) in dioxane (10 mL)
was added and the mixture was stirred at room temperature for 24–
72 h. After the consumption of substrate (LC-MS), the reaction
mixture was worked up as described in Method D.
3-Chloro-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo[2,3-b]thiazolin-
3-Bromo-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo[2,3-a]pyridin-
ium Chloride (57): Yield 68% (Method A), 26% (Method C); oil. ium Chloride (24): Yield 58 %; m.p. 200–202 °C. 1H NMR
1H NMR (400 MHz, [D6]DMSO): δ = 1.69 (s, 6 H, 2CH3), 8.07
(d, J = 3.7 Hz, 1 H, 5-CH), 8.24 (br. s, 1 H, OH), 8.80 (d, J = 1.4, 6.4, 7.6 Hz, 1 H, 6-CH), 8.24 (ddd, J = 0.8, 1.4, 8.6 Hz, 1 H,
(400 MHz, [D6]DMSO): δ = 1.73 (s, 6 H, 2CH3), 7.77 (ddd, J =
3.7 Hz, 1 H, 6-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
26.8, 74.6, 90.4, 121.6, 135.6, 168.4, 180.4 ppm. ESI-MS: m/z = 282
[M]. C8H10Cl2NOSSe·MeOH: calcd. C 30.87, H 4.03, N 4.00;
found C 30.56, H 4.13, N 3.91.
4-CH), 8.41 (ddd, J = 1.4, 7.6, 8.6 Hz, 1 H, 5-CH), 10.10 (dt, J =
0.8, 6.4 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 26.7, 75.1, 93.3, 121.5, 124.8, 140.4, 142.9, 156.0,
175.0 ppm. ESI-MS: m/z = 321 [M]. HRMS (ESI): m/z calcd.
for C1 0 H1 1 BrNOSe+ [M+ ] 319.9184; found 319.9189.
C10H11BrClNOSe (355.52): calcd. C 33.66, H 3.36, N 3.93; found
C 33.47, H 3.15, N 3.71.
3-Chloro-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-b]thiazolinium
Chloride (59): Yield 60%; m.p. 166–168 °C. 1H NMR (400 MHz,
[D6]DMSO): δ = 1.18–1.33 (m, 1 H, cyclohexane), 1.58–1.71 (m, 5
H, cyclohexane), 1.93 (d, J = 13.1 Hz, 2 H, cyclohexane), 2.03–2.10
3-Bromo-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-a]pyridinium
(m, 2 H, cyclohexane), 8.06 (d, J = 3.7 Hz, 1 H, 5-CH), 8.34 (br. s, Chloride (25): Yield 90%; m.p. 164–166 °C. 1H NMR (400 MHz,
Eur. J. Org. Chem. 2015, 5842–5855
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5851

P. Arsenyan et al.
FULL PAPER
[D6]DMSO): δ = 1.23–1.32 (m, 1 H, cyclohexane), 1.65–1.72 (m, 5
H, cyclohexane), 1.92 (d, J = 13.3 Hz, 2 H, cyclohexane), 2.18–2.26
(m, 2 H, cyclohexane), 7.78 (ddd, J = 1.2, 6.4, 7.4 Hz, 1 H, 6-CH),
3-Bromo-2-(1-methoxycyclohexyl)[1,2]selenazolo[2,3-a]pyridinium
Bromide (31): Yield 35 % (Method F); m.p. Ͼ200 °C. 1H NMR
(400 MHz, CDCl3/TMS): δ = 1.31–1.38 (m, 1 H, cyclohexane),
8.24–8.27 (m, 1 H, 4-CH), 8.33 (br. s, 1 H, OH), 8.42 (ddd, J = 1.54–1.64 (m, 2 H, cyclohexane), 1.72–1.80 (m, 3 H, cyclohexane),
1.2, 7.4, 8.4 Hz, 1 H, 5-CH), 9.96 (d, J = 6.4 Hz, 1 H, 7-CH) ppm. 2.14 (d, J = 13.8 Hz, 2 H, cyclohexane), 2.22–2.30 (m, 2 H, cyclo-
13C NMR (100.6 MHz, [D6]DMSO): δ = 20.3, 24.1, 32.9, 76.8, hexane), 3.61 (s, 3 H, CH3O), 7.54–7.57 (m, 1 H, 6-CH), 8.17 (ddd,
93.1, 121.8, 124.9, 140.5, 142.6, 156.4, 175.4 ppm. 15N NMR J = 0.8, 1.4, 8.6 Hz, 1 H, 4-CH), 8.26 (ddd, J = 1.4, 7.2, 8.6 Hz, 1
(60.81 MHz, [D6]DMSO): δ = 212.7 ppm. 77Se NMR (76.36 MHz,
H, 5-CH), 11.22–11.26 (m, 1 H, 7-CH) ppm. 1 3 C NMR
[D ]DMSO): δ = 1209.4 ppm. IR (KBr): ν = 606, 781, 958, 1148, (100.6 MHz, CDCl3/TMS): δ = 21.3, 24.4, 33.4, 54.1, 82.4, 94.5,
˜
6
1249, 1375, 1429, 1517, 1564, 1605, 2691, 3098 cm–1. LC-MS: m/z 121.0, 124.7, 139.7, 144.9, 156.5, 173.5 ppm. ESI-MS: m/z = 375
= 361 [M]. HRMS (ESI): m/z calcd. for C13H15BrNOSe+ [M+]
359.9497; found 359.9504. C13H16BrClNOSe (396.59): calcd. C
35.48, H 3.44, N 3.18; found C 36.14, H 3.39, N 3.32.
[M]. C14H18Br2NOSe (455.07): calcd. C 36.92, H 3.07, N 3.41;
found C 37.87, H 3.78, N 3.20.
3-Bromo-2-(4-hydroxytetrahydropyranyl)[1,2]selenazolo[2,3-a]pyr-
3-Bromo-2-(hydroxydiphenylmethyl)[1,2]selenazolo[2,3-a]pyridinium idinium Chloride Bromide (32): Yield 64% (Method F); m.p. 182–
Chloride (26): Yield 64%; m.p. 178–181 °C. 1H NMR (400 MHz, 184 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 1.85 (d, J = 13.3 Hz,
[D6]DMSO): δ = 7.42–7.49 (m, 6 H, ArH), 7.52–7.55 (m, 4 H,
2 H, tetrahydropyran), 2.52–2.56 (m, 2 H, tetrahydropyran), 3.66–
ArH), 7.78–7.82 (m, 1 H, 6-CH), 8.24 (d, J = 8.4 Hz, 1 H, 4-CH), 3.72 (m, 2 H, tetrahydropyran), 3.86–3.91 (m, 2 H, tetra-
8.38–8.42 (m, 1 H, 5-CH), 9.48 (br. s, 1 H, OH), 9.93 (d, J = 6.3 Hz,
1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 82.8,
97.9, 122.0, 125.2, 128.2, 128.3, 128.6, 139.5, 140.4, 142.6, 156.3,
hydropyran), 7.80 (ddd, J = 1.2, 6.3, 7.4 Hz, 1 H, 6-CH), 8.31 (d,
J = 8.6 Hz, 1 H, 4-CH), 8.43 (ddd, J = 1.2, 7.4, 8.6 Hz, 1 H, 5-
CH), 8.96 (br. s, 1 H, OH), 9.79–9.82 (m, 1 H, 7-CH) ppm. 13C
171.2 ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ = 1220.0 ppm. NMR (100.6 MHz, [D6]DMSO): δ = 33.2, 61.9, 74.2, 93.8, 121.8,
ESI-MS: m/z = 445 [M]. C20H16BrClNOSe (480.67): calcd. C 49.94,
H 3.33, N 2.91; found C 49.76, H 3.11, N 2.76.
125.1, 140.6, 142.7, 156.5, 173.5 ppm. ESI-MS: m/z = 363 [M].
C12H14Br1,5Cl0,5NO2Se (420.79): calcd. C 34.25, H 3.35, N 3.33;
found C 34.19, H 3.09, N 3.29.
3-Bromo-2-pentyl[1,2]selenazolo[2,3-a]pyridinium Chloride (27):
Yield 26 % (Method F); m.p. 175–177 °C. 1H NMR (400 MHz,
3-Bromo-2-(1-hydroxycycloheptyl)[1,2]selenazolo[2,3-a]pyridinium
CDCl3/TMS): δ = 0.91 (t, J = 7.0 Hz, 3 H, CH3), 1.34–1.52 (m, 4 Bromide (33): Yield 88 % (Method F); m.p. Ͼ200 °C. 1H NMR
H, CH2), 1.68–1.76 (m, 2 H, CH2), 3.47–3.51 (m, 2 H, CH2), 7.32–
(400 MHz, [D6]DMSO): δ = 1.59–1.80 (m, 8 H, cycloheptane),
7.36 (m, 1 H, 6-CH), 8.01–8.03 (m, 2 H, 4-CH and 5-CH), 8.79 (d, 2.04–2.09 (m, 2 H, cycloheptane), 2.31–2.38 (m, 2 H, cyclohept-
J = 5.8 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, CDCl3/ ane), 7.78 (ddd, J = 1.2, 6.4, 7.4 Hz, 1 H, 6-CH), 8.26 (d, J =
TMS): δ = 13.8, 21.7, 29.0, 30.8, 35.7, 102.1, 121.7, 122.6, 139.9,
141.4, 149.8, 159.2 ppm. ESI-MS: m/z = 333 [M]. C12H16BrClNSe
(368.58): calcd. C 39.07, H 4.34, N 3.80; found C 38.92, H 4.09, N
3.64.
8.6 Hz, 1 H, 4-CH), 8.42 (ddd, J = 1.2, 7.4, 8.6 Hz, 1 H, 5-CH),
8.49 (br. s, 1 H, OH), 9.82 (d, J = 6.4 Hz, 1 H, 7-CH) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 20.7, 26.6, 37.3, 79.8, 93.0,
121.7, 124.9, 140.5, 142.5, 156.4, 176.9 ppm. ESI-MS: m/z = 375
[M]. C14H18Br2NOSe (455.07): calcd. C 36.92, H 3.07, N 3.41;
found C 36.87, H 3.75, N 3.11.
3-Bromo-2-(1-hydroxymethyl)[1,2]selenazolo[2,3-a]pyridinium
Chloride (28): Yield 40 % (Method F); m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 5.10 (s, 2 H, CH2), 5.16 (br. s, 1 H, 3-Bromo-2-(2-hydroxyadamantyl)[1,2]selenazolo[2,3-a]pyridinium
OH), 7.71 (ddd, J = 1.0, 6.1, 7.2 Hz, 1 H, 6-CH), 8.22 (d, J = Bromide (34): Yield 59 % (Method F); m.p. Ͼ200 °C. 1H NMR
8.4 Hz, 1 H, 4-CH), 8.35 (ddd, J = 1.0, 7.2, 8.4 Hz, 1 H, 5-CH),
(400 MHz, [D6]DMSO): δ = 1.61–1.65 (m, 2 H, adamantane),
9.52 (d, J = 6.1 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]- 1.71–1.74 (m, 2 H, adamantane), 1.84–1.91 (m, 4 H, adamantane),
DMSO): δ = 61.6, 103.7, 122.5, 123.7, 140.1, 141.8, 150.1, 2.03–2.07 (m, 4 H, adamantane), 2.32–2.35 (m, 2 H, adamantane),
156.8 ppm. ESI-MS: m/z = 293 [M]. C8H8BrClNOSe (328.47):
calcd. C 29.22, H 2.43, N 4.26; found C 29.01, H 2.23, N 4.03.
2.56 (br. s, 1 H, OH), 7.84–7.87 (m, 1 H, 6-CH), 8.44–8.49 (m,
2 H, 4,5-CH), 9.98 (d, J = 6.4 Hz, 1 H, 7-CH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 26.2, 26.4, 32.5, 34.4, 36.7, 48.5,
79.0, 98.0, 122.7, 126.0, 140.9, 142.8, 155.1, 169.7 ppm. ESI-MS:
m/z = 413 [M]. C17H20Br2NOSe (493.12): calcd. C 41.38, H 4.05,
N 2.84; found C 41.02, H 3.81, N 2.56.
3-Bromo-2-(2-hydroxyethyl)[1,2]selenazolo[2,3-a]pyridinium Chlor-
ide (29): Yield 51 % (Method F); m.p. 125–127 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.58 (d, J = 6.6 Hz, 3 H, CH3), 5.68
[qt, J = 13.3 Hz, 1 H, CH(OH)], 7.69 (ddd, J = 1.2, 6.1, 7.4 Hz, 1
H, 6-CH), 8.20 (d, J = 8.4 Hz, 1 H, 4-CH), 8.33 (ddd, J = 1.2, 7.4,
3-Bromo-2-(2-hydroxy-2-phenylethyl)[1,2]selenazolo[2,3-a]pyridin-
8.4 Hz, 1 H, 5-CH), 9.59 (d, J = 6.1 Hz, 1 H, 7-CH) ppm. 13C ium Bromide (35): Yield 50% (Method F); m.p. Ͼ200 °C. 1H NMR
NMR (100.6 MHz, [D6]DMSO): δ = 22.0, 68.5, 99.1, 122.0, 123.6,
140.0, 141.6, 151.4, 165.0 ppm. ESI-MS: m/z = 307 [M].
C9H10BrClNOSe (342.50): calcd. C 31.53, H 2.92, N 4.09; found
C 31.34, H 2.76, N 3.88.
(400 MHz, [D6]DMSO): δ = 2.15 (s, 3 H, CH3), 7.37–7.46 (m, 3 H,
ArH), 7.62–7.65 (m, 2 H, ArH), 7.80 (ddd, J = 1.4, 6.4, 7.6 Hz, 1
H, 6-CH), 8.21 (d, J = 8.6 Hz, 1 H, 4-CH), 8.40 (ddd, J = 1.4, 7.6,
8.6 Hz, 1 H, 5-CH), 9.81 (d, J = 6.4 Hz, 1 H, 7-CH) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 24.3, 77.6, 95.3, 121.9, 124.9,
3-Bromo-2-(1-hydroxycyclopentyl)[1,2]selenazolo[2,3-a]pyridinium
Bromide (30): Yield 82 % (Method F); m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.91–1.93 (m, 4 H, cyclopentane),
2.09–2.14 (m, 2 H, cyclopentane), 2.38–2.46 (m, 2 H, cyclopent-
ane), 7.75–7.79 (m, 1 H, 6-CH), 8.26 (d, J = 8.2 Hz, 1 H, 4-CH),
8.39–8.43 (m, 1 H, 5-CH), 9.94 (d, J = 5.9 Hz, 1 H, 7-CH) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 24.0, 38.5, 84.4, 93.3,
121.5, 124.8, 140.4, 142.7, 156.3, 173.5 ppm. ESI-MS: m/z = 347
[M]. C12H14Br2NOSe (427.02): calcd. C 33.72, H 3.28, N 3.28;
found C 33.44, H 3.05, N 3.03.
126.7, 128.3, 128.4, 140.5, 142.7, 156.0, 173.2 ppm. IR (KBr): ν =
˜
614, 697, 771, 911, 1111, 1231, 1454, 1524, 1569, 1605, 2705,
3108 cm–1. ESI-MS: m/z = 383 [M]. HRMS (ESI): m/z calcd. for
C 1 5 H 1 4 B r N O S e + [ M + ] 3 8 1 . 9 3 4 0 ; f o u n d 3 8 1 . 9 3 4 3 .
C15H14BrClNOSe (418.60): calcd. C 43.01, H 3.34, N 3.34; found
C 42.87, H 3.16, N 3.06.
3-Bromo-2-(1-hydroxycyclohexyl)-4-methyl[1,2]selenazolo[2,3-a]pyr-
idinium Chloride (36): Yield 51 %; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.18–1.31 (m, 1 H, cyclohexane), 1.64–
5852
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5842–5855

Fused Selenazolinium Salt Derivatives
1.72 (m, 5 H, cyclohexane), 1.88 (d, J = 13.3 Hz, 2 H, cyclohexane),
2.30–2.38 (m, 2 H, cyclohexane), 2.98 (s, 3 H, CH3), 7.60 (ddd, J
= 1.0, 6.2, 7.6 Hz, 1 H, 6-CH), 8.14 (dd, J = 1.0, 7.6 Hz, 1 H, 5-
CH), 9.62 (d, J = 6.2 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 20.4, 21.4, 24.0, 32.1, 77.9, 90.7, 120.6, 136.4,
140.6, 142.1, 153.5, 175.9 ppm. ESI-MS: m/z = 375 [M].
H), 8.90 (dd, J = 8.5, 1.3 Hz, 1 H, 6-H) ppm. 13 C NMR
(100.6 MHz, [D6]DMSO): δ = 20.78 (CH2-CH2-COH), 25.95 (CH2-
CH2-CH2-COH), 26.63 (CH3CO), 33.61 (2CH2-COH), 77.72 (C-
OH), 95.33 (C-3), 126.77 (C-6), 129.63 (C-4), 141.15 (C-5), 141.86
(N=C), 157.22 (C-7), 178.26 (C-2), 194.72 (C=O) ppm. 77Se NMR
(76.36 MHz, [D6]DMSO): δ = 1237.8 ppm. ESI-MS: m/z = 401.9
C14H17BrClNOSe (409.61): calcd. C 41.05, H 4.18, N 3.42; found [M]. HRMS (ESI): m/z calcd. for C15H17BrNO2Se+ [M+] 401.9602;
C 40.37, H 4.07, N 3.16.
found 401.9612. C15H17BBrF4NO2Se·MeCN (530.20): calcd. C
38.52, H 3.80, N 5.29; found C 38.41, H 3.77, N 5.23.
3-Bromo-2-(1-hydroxycyclohexyl)-5-methyl[1,2]selenazolo[2,3-a]pyr-
idinium Chloride (37): Yield 42 %; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.21–1.30 (m, 1 H, cyclohexane), 1.63–
1.73 (m, 5 H, cyclohexane), 1.93 (d, J = 13.1 Hz, 2 H, cyclohexane),
2.17–2.27 (m, 2 H, cyclohexane), 2.62 (s, 3 H, CH3), 7.64 (dd, J =
1.8, 6.6 Hz, 1 H, 6-CH), 8.11–8.13 (m, 1 H, 4-CH), 8.52 (br. s, 1
H, OH), 9.59–9.65 (m, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 20.3, 21.9, 24.1, 32.9, 76.6, 92.5, 123.1, 124.4,
141.7, 153.4, 156.0, 175.3 ppm. ESI-MS: m/z = 375 [M].
C14H17ClBrNOSe (409.60): calcd. C 41.05, H 4.18, N 3.42; found
C 40.56, H 4.04, N 3.26.
3-Bromo-2-(1-hydroxycyclohexyl)-7-(2-hydroxypropan-2-yl)[1,2]-
selenazolo[2,3-a]pyridin-8-ium Chloride (42): Yield 81 %; m.p.
Ͼ200 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 1.26 and 1.64 (two
m, 2 H, CH2-CH2-CH2-COH), 1.64 (m, 4 H, CH2-CH2-COH), 1.66
(s, 6 H, 2CH3), 1.91 and 2.24 (two m, 4 H, 2CH2-COH), 7.77 (dd,
J = 7.6, 1.1 Hz, 1 H, 6-H), 8.23 (dd, J = 7.6, 1.1 Hz, 1 H, 4-H),
8.41 (dd, J = 7.6, 7.6 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 20.71 (2CH2-CH2-COH), 24.62 (1CH2-CH2-CH2-
COH), 28.07 (2CH3), 33.5 (2CH2-COH), 73.15 [C(CH3)2OH],
77.56 (C-OH), 94.42 (C-3), 118.73 (C-6), 124.55 (C-4), 141.71 (C-
5), 157.11 (N=C), 159.55 (C-7), 175.62 (C-2) ppm. ESI-MS: m/z =
418 [M]. HRMS (ESI): m/z calcd. for C16H21BrNO2Se+ [M+]
417.9915; found 417.9922. C16H21BrClNO2Se (453.66): calcd. C
42.36, H 4.67, N 3.09; found C 42.33, H 4.69, N 3.04.
3-Bromo-2-(1-hydroxycyclohexyl)-5-cyano[1,2]selenazolo[2,3-a]pyr-
idinium Chloride (38): Yield 74 %; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.22–1.33 (m, 1 H, cyclohexane), 1.57–
1.73 (m, 5 H, cyclohexane), 1.93 (d, J = 13.1 Hz, 2 H, cyclohexane),
2.18–2.27 (m, 2 H, cyclohexane), 8.13 (dd, J = 1.8, 6.6 Hz, 1 H, 6-
CH), 8.83 (dd, J = 1.0, 1.8 Hz, 1 H, 4-CH), 10.20 (dd, J = 1.0,
6.6 Hz, 1 H, 7-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
20.3, 24.0, 32.9, 77.1, 94.1, 115.4, 121.60, 121.63, 129.0, 143.4,
156.9, 179.3 ppm. ESI-MS: m/z = 385 [M]. C14H14Br2N2OSe
(465.05): calcd. C 39.98, H 3.36, N 6.66; found C 39.57, H 3.23, N
6.35.
3-Bromo-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo[2,3-b]thiazolin-
ium Chloride (58): Yield 52 %; solid; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.69 (s, 6 H, 2CH3), 8.06 (d, J =
3.9 Hz, 1 H, 5-CH), 8.35 (br. s, 1 H, OH), 9.16 (d, J = 3.9 Hz, 1
H, 6-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 26.8, 74.2,
104.9, 122.4, 135.3, 166.2, 178.4 ppm. ESI-MS: m/z = 327 [M + 1].
HRMS (ESI): m/z calcd. for C8H9BrNOSSe+ [M+] 325.8748; found
325.8759. C8H9BrClNOSSe (361.54): calcd. C 26.50, H 2.78, N
3.86; found C 26.06, H 2.70, N 3.78.
3-Bromo-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo[2,3-a]isoquinol-
inium Bromide (39): Yield 59 %; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.82 (s, 6 H, 2CH3), 7.99 (ddd, J =
1.6, 7.2, 8.8 Hz, 1 H, ArH), 8.08–8.13 (m, 2 H, ArH), 8.25–8.26
(m, 1 H, ArH), 9.51 (d, J = 7.2 Hz, 1 H, 8-CH), 9.85–9.87 (m, 1
H, 9-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 26.2, 75.9,
94.9, 120.0, 124.1, 127.0, 128.5, 129.2, 133.1, 133.5, 134.7, 153.2,
181.5 ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ = 1150.0 ppm.
ESI-MS: m/z = 370 [M – 1]. C14H13Br2NOSe (450.03): calcd. C
37.37, H 2.91, N 3.11; found C 37.07, H 2.66, N 3.02.
3-Bromo-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-b]thiazolinium
Chloride (60): Yield 51 %; solid; m.p. Ͼ 200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.20–1.30 (m, 1 H, cyclohexane), 1.65–
1.71 (m, 5 H, cyclohexane), 1.93 (d, J = 12.9 Hz, 2 H, cyclohexane),
2.07–2.14 (m, 2 H, cyclohexane), 8.06 (d, J = 3.9 Hz, 1 H, 5-CH),
8.48 (br. s, 1 H, OH), 9.15 (d, J = 3.9 Hz, 1 H, 6-CH) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 20.3, 24.1, 33.2, 76.3, 90.0,
121.6, 135.7, 168.7, 181.3 ppm. ESI-MS: m/z = 367 [M + 1]. HRMS
(ESI): m/z calcd. for C11H13BrNOSSe+ [M+] 365.9061; found
365.9066. C11H13BrClNOSSe (401.61): calcd. C 32.90, H 3.26, N
3.49, S 7.98; found C 32.69, H 3.36, N 3.39, S 7.75.
3-Bromo-7-formyl-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-a]pyr-
idin-8-ium Chloride (40): Yield 78 %; m.p. Ͼ200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.28 and 1.69 (two m, 2 H, CH2-CH2-
CH2-COH), 1.69 (m, 4 H, CH2-CH2-COH), 1.98 and 2.26 (two m,
4 H, 2CH2-COH), 8.71 (dd, J = 8.9, 1.1 Hz, 1 H, 4-H), 8.77 (dd,
J = 8.9, 1.1 Hz, 1 H, 6-H), 8.78 (dd, J = 8.9, 7.6 Hz, 1 H, 5-H),
10.49 (s, 1 H, HCO) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ
= 20.83 (2CH2-CH2-COH), 24.68 (1CH2-CH2-CH2-COH), 33.52
(2CH2-COH), 77.72 (C-OH), 95.35 (C-3), 130.11 (C-4), 130.41 (C-
6), 141.05 (C-5), 141.91 (N=C), 157.73 (C-7), 178.84 (C-2), 188.37
(C=O) ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ = 1226.3 ppm.
ESI-MS: m/z = 387 [M – 1]. HRMS (ESI): m/z calcd. for
C 1 4 H 1 5 B r N O 2 S e + [ M + ] 3 8 7 . 9 4 4 6 ; fo u n d 3 8 7 . 9 4 5 4 .
C14H15BrClNO2Se (423.60): calcd. C 39.70, H 3.57, N 3.31; found
C 39.59, H 3.55, N 3.22.
1-(3-Bromoselenazolo[2,3-b]thiazol-2-yl)-1-methylethylamine Chlor-
ide (61): Yield 19%; oil. 1H NMR (400 MHz, CDCl3/TMS): δ =
1.48 (s, 6 H, 2CH3), 7.45 (d, J = 3.2 Hz, 1 H, 5-CH), 7.86 (d, J =
3.2 Hz, 1 H, 6-CH) ppm. 13C NMR (100.6 MHz, CDCl3/TMS): δ
= 24.4, 76.4, 119.3, 120.0, 129.8, 142.4, 159.0 ppm. ESI-MS: m/z =
326 [M].
1,2-Bis[(E)-1-bromo-3-morpholino-1-(thiazol-2-yl)prop-1-en-2-yl]di-
1
selane (62): Yield 36%; oil. H NMR (400 MHz, CDCl3/TMS): δ
= 2.44 (t, J = 4.5 Hz, 8 H, 2ϫ2NCH2), 3.24 (s, 4 H, 2CH2), 3.63
(t, J = 4.5 Hz, 8 H, 2ϫ2CH2O), 7.47 (d, J = 3.2 Hz, 1 H, 5-CH),
7.91 (d, J = 3.2 Hz, 1 H, 4-CH) ppm. 13C NMR (100.6 MHz,
CDCl3/TMS): δ = 52.1, 65.8, 66.7, 120.9, 126.1, 130.4, 142.4,
164.8 ppm. 77Se NMR (76.36 MHz, [D6]DMSO): δ = 567.66 ppm.
7-Acetyl-3-bromo-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-a]pyr-
idin-8-ium Tetrafluoroborate (41): Chloride was converted into
tetrafluoroborate by using silver tetrafluoroborate, yield 84%; m.p.
3-Bromo-N-methyl-2-(2-hydroxy-2-methylethyl)[1,2]selenazolo-
[2,3-b]imidazolinium Bromide (64): Yield 99%; m.p. Ͼ200 °C. 1H
1
Ͼ200 °C. H NMR (400 MHz, [D6]DMSO): δ = 1.2 and 1.69 (two
m, 2 H, CH2-CH2-CH2-COH), 1.68 (m, 4 H, CH2-CH2-COH), 1.95 NMR (400 MHz, [D6]DMSO): δ = 1.67 (s, 6 H, 2CH3), 4.11 (s, 3
and 2.27 (two m, 4 H, 2CH2-COH), 2.98 (s, 3 H, CH3CO), 8.68 H, CH3), 7.70 (d, J = 1.9 Hz, 1 H, 6-CH), 8.08 (d, J = 1.9 Hz, 1
(dd, J = 7.1, 1.3 Hz, 1 H, 4-H), 8.72 (dd, J = 8.5, 7.1 Hz, 1 H, 5- H, 5-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 26.7, 35.6,
Eur. J. Org. Chem. 2015, 5842–5855
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5853

P. Arsenyan et al.
74.3, 82.1, 121.7, 126.4, 146.8, 173.2 ppm. ESI-MS: m/z = 324 [M]. COH), 2.98 (s, 3 H CH3CO), 7.60 (ddd, J = 1.1, 5.1, 7.6 Hz, 1 H,
FULL PAPER
C9H13Br2N2OSe (403.98): calcd. C 26.76, H 3.24, N 6.93; found C
26.19, H 3.12, N 6.67.
6-H), 8.65 (dd, J = 1.1, 5.1 Hz, 1 H, 7-H), 7.99 (dd, J = 1.1, 7.6 Hz,
1 H, 4-H), 8.15 (dd, J = 1.1, 7.6 Hz, 1 H, 5-H) ppm. 13C NMR
(100.6 MHz, CD3OD): δ = 20.9 (2CH2-CH2-COH), 24.6 (1CH2-
CH2-CH2-COH), 26.6 (CH3CO), 36.3 (2CH2-COH), 77.7 (C-OH),
93.6 (C-3), 122.9 (C-4), 125.4 (C-6), 140.4 (C-5), 141.9 (N=C),
146.3 (C-7), 178.3 (C-2), 194.7 (C=O) ppm. 7 7 Se NMR
(76.36 MHz, CD3OD): δ = 1373.3 ppm.
3-Bromo-N-methyl-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3-b]-
imidazolinium Bromide (66): Yield 99%; m.p. 138–140 °C (decomp).
1H NMR (400 MHz, [D6]DMSO): δ = 1.18–1.31 (m, 1 H, cyclohex-
ane), 1.60–1.77 (m, 5 H, cyclohexane), 1.84 (d, J = 13.6 Hz, 2 H,
cyclohexane), 2.15–2.32 (m, 2 H, cyclohexane), 3.55 (s, 1 H, OH),
4.06 (s, 3 H, CH3), 7.70 (d, J = 2.0 Hz, 1 H, 6-CH), 8.20 (d, J =
2.0 Hz, 1 H, 5-CH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
20.5, 24.1, 32.9, 35.8, 76.1, 81.8, 121.7, 126.4, 145.7, 174.2 ppm.
77Se NMR (76.36 MHz, [D6]DMSO): δ = 1063.1 ppm. ESI-MS:
m/z = 364 [M]. C12H17BrClN2OSe·0.3H2O: calcd. C 35.59, H 4.38,
N 6.92; found C 35.59, H 4.02, N 6.69.
Oxidation of Aryl and Hetaryl Aldehydes: To a solution of aryl-
(hetaryl) aldehyde (1 mmol) and 2-mol-% 25 (8 mg) in MeCN
(5 mL), 25 % hydrogen peroxide solution in water (0.1 mL) was
added. After 2 h to 1 d (reaction monitored by TLC analysis) stir-
ring at room temp. or 35 °C, ascorbic acid (0.1 g) was added and
the solvent was evaporated. Crude product was purified by flash
chromatography to give the desired aryl(hetaryl) carboxylic acids
45–50, which were isolated in up to quantitative yield.
Synthesis of Zwitterionic Salts
To an emulsion of 25 or 26 (1 mmol) in a mixture of water (2 mL)
and ethyl acetate (8 mL), an aqueous solution of 0.5 n NaOH was
added dropwise at 0–5 °C to pH 8.0. Water was then decanted, the
organic layer was dried with MgSO4 and evaporated to yield the
corresponding betaines. Addition of methanolic HCl solution to a
solution of 25a and 26a in ethyl acetate at 0 °C led to reverse con-
version into initial pyridinium chlorides 25 and 26, correspond-
ingly, almost quantitatively.
Crystallographic Data: Diffraction data were collected at low tem-
perature with a Nonius KappaCCD diffractometer using graphite
monochromated Mo Kα radiation (λ = 0.71073 Å). The crystal
structures of 20, 22–24, 25 (SeBr62–), 25, 25a, 26, 26a, 30, 31, 32-
(Cl–Br–), 32–35, 40–42, 58, 60, and 64 were solved by direct meth-
ods[12a] and refined by full-matrix least-squares.[12b,12c] CCDC-
979622 (for 20), -979623 (for 22), -980448 (for 23), -979624 (for
24), -988234 [for 25 (SeBr62–)], -980049 (for 25), 980054 (for 25a),
-980050 (for 26), -980051 (for 26a), -980053 (for 30), -980057 (for
31), -990797 [for 32 (Cl–Br–)], -980056 for (for 32), -980055 (for
33), -980048 (for 34), -980052 (for 35), -1051661 (for 40), -1051664
(for 41), -1051662 (for 42), -1038499 (for 58), -1038500 (for 60),
and -1038501 (for 64) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
3-Bromo[1,2]selenazolo[2,3-a]pyridinium-2-cyclohexanolate (25a):
Yield 95%; m.p. 188–190 °C. 1H NMR (400 MHz, CDCl3/TMS):
δ = 1.22–1.30 (m, 1 H, cyclohexane), 1.64–1.78 (m, 5 H, cyclohex-
ane), 2.02–2.06 (m, 4 H, cyclohexane), 7.08 (ddd, J = 1.4, 5.6,
6.8 Hz, 1 H, 6-CH), 7.79 (ddd, J = 0.8, 1.4, 8.2 Hz, 1 H, 4-CH),
7.83 (ddd, J = 1.4, 6.8, 8.2 Hz, 1 H, 5-CH); 8.61 (dt, J = 1.4, 5.6 Hz,
1 H, 7-CH) ppm. 13C NMR (100.6 MHz, CDCl3/TMS): δ = 21.5,
25.2, 34.7, 83.4, 84.7, 118.0, 122.7, 136.4, 141.6, 155.9, 178.6 ppm.
15N NMR (60.81 MHz, CDCl3/TMS): δ = 263.7 ppm. 77Se NMR
Supporting Information (see footnote on the first page of this arti-
cle): Methods for the preparation, copies of the 1H, 13C NMR spec-
tra, and crystallographic data for compounds 20, 22–24, 25
(SeBr62–), 25, 25a, 26, 26a, 30, 31, 32(Cl–Br–), 32–35, 40–42, 58,
60, and 64.
(76.36 MHz, CDCl /TMS): δ = 1118.1 ppm. IR (neat): ν = 618,
˜
3
762, 944, 1140, 1270, 1451, 1540, 1595, 2927, 3316 cm–1. ESI-MS:
m/z = 360 [M]. C13H15BrNOSe (360.13): calcd. C 43.33, H 4.16, N
3.88; found C 43.86, H 4.28, N 3.76.
3-Bromo[1,2]selenazolo[2,3-a]pyridinium-2-diphenylmethanolate
(26a): Yield 80 %; m.p. 176–178 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.28–7.37 (m, 6 H, ArH), 7.39–7.42 (m, 1 H, 6-CH),
7.51–7.54 (m, 4 H, ArH), 7.88 (d, J = 8.2 Hz, 1 H, 4-CH), 8.10–
8.12 (m, 1 H, 5-CH), 9.00 (d, J = 5.7 Hz, 1 H, 7-CH) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 87.9, 88.2, 119.9, 122.7, 127.1,
127.2, 127.8, 138.0, 142.2, 143.4, 155.0, 175.8 ppm. 15N NMR
(60.81 MHz, CDCl3 /TMS): δ = 261.0 ppm. 7 7 Se NMR
Acknowledgments
Financial support for this work provided by the Latvian Council
of Science (grant number 447/2012) is gratefully acknowledged.
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Received: May 7, 2015
Published Online: August 4, 2015
Eur. J. Org. Chem. 2015, 5842–5855
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5855