Synthesis and characterization of fused imidazole heterocyclic selenoesters and their application for chemical detoxification of HgCl2

Article abstract of DOI:10.1039/c7nj03908e

A new series of selenoester derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine was synthesized under mild conditions using a simple methodology by the reaction of in situ generated sodium selenocarboxylates with 2-(chloromethyl)imidazo[1,2

Full text of DOI:10.1039/c7nj03908e

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Synthesis and characterization of fused imidazole heterocyclic
selenoesters and their application for chemical detoxification of
HgCl2
Received 00th January 20xx,
Accepted 00th January 20xx
Nidhi Sharma,a Sanjeev Kumar,a Sangit Kumar,b S. K. Mehta*a, K. K. Bhasin*a
DOI: 10.1039/x0xx00000x
A new series of selenoester derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine were
synthesized under mild conditions using a simple methodology by the reaction of in situ generated
sodium selenocarboxylates with 2-(chloromethyl)imidazo[1,2-a]pyridine/pyrimidine (3a-b) in water
and ethanol. Excellent yields of phenyl/4-tolyl selenoesters of imidazo[1,2-a]pyridine/pyrimidine (6a-
www.rsc.org/
b
and 6e-f) were obtained in water, whereas 4-methoxyphenyl/4-chlorophenyl/2-thienyl
selenoesters of imidazo[1,2-a]pyridine/pyrimidine (6c-d and 6g-i) could only be synthesized in
ethanol. Further, a series of reactions of 6e were carried out as a model compound in order to study
the reaction behavior of selenoesters with mercury (II) chloride (HgCl2). The deprotection of
compound 6e by HgCl2 was carried out in the presence of K2CO3 under different conditions to obtain
bis(imidazo[1,2-a]pyrimidin-2-ylmethyl)selenide
diselenide ( ) along with small amount of less soluble bis((imidazo[1,2-a]pyrimidin-2-ylmethyl)
selanyl)mercury (10). The mercury-selenium complex 10 has a short shelf life and decomposes to
give HgSe which was characterized using EDX analysis. The structure of compound was established
(8) and bis(imidazo[1,2-a]pyrimidin-2-ylmethyl)
9
9
with X-ray crystallography. The formation of HgSe indicates that the selenoester derivatives may
prove useful in the treatment of HgCl2 induced toxicity.
selenomethionine protects against mercury induced toxicity by
increasing the antioxidant defence in biological systems9 and
by demethylation of methyl mercury.10 Thione and selone
1. Introduction
Organoselenium compounds have gained much significance in
the last few decades due to their immense biological
applications as antioxidant agents,1 anti-inflammatory agents,2
anti-tumor agents3 and for their ability to induce apoptosis in
various cancer cells.4 Organoselenium compounds are known
to act as glutathione peroxidase mimetics5 and their anti-
oxidant activity is attributable to their free hydroxyl radical
scavenging ability.1,6 Besides all these biological applications,
organoselenium compounds also act as detoxifying agents by
coordinating with certain chalcophilic metal compounds such
as mercuric chloride (HgCl2) and methylmercury.7
derivatives containing a carbon-sulfur and carbon-selenium
double bond also mediate the protolytic cleavage of Hg-C bond
of organomercurials.
11 Besides Hg-C bond cleavage, the thione
and selone derivatives have been shown to be effective in
detoxifying organomercurials through formation of less toxic
HgS and HgSe nanoparticles.12 HgSe is an inorganic species
which is insoluble in water and organic solvents. Its formation
has been observed in marine mammals and sea birds after
detoxification of mercury.13
Organoselenium compounds such as diaryl diselenides are
also supposed to inhibit mercury poisoning through formation
of stable Hg-Se complex by firstly getting converted into the
selenols. Selenols are more nucleophilic than thiols and form
stable complexes with Hg after leaching mercury complexed
with thiols,14(a) with subsequent oxidation of thiols in vivo.14
Selenoesters act as protected selenols and are stable as
compared to the selenol derivatives, they can be deprotected
easily to provide selenols and selenolates.15 Due to their
capability of in vivo selenol generation, selenoesters easily
bind with certain metals present in metalloproteins in biological
systems making them important candidates for the treatment of
various ailments such as thromboembolic disorders16 and HIV.17
However, the interactions of selenoesters with mercury (II) salts
have not been extensively explored.
HgCl2 poses serious health threats since it is readily soluble
in water resources. HgCl2 and methylmercury are toxic due to
their large affinity towards thiols thereby depleting glutathione
(GSH) level in the body.8 Inorganic selenium i.e. selenite has
been shown to have significant protection against mercury
induced toxicity by binding with mercury in an equimolar ratio
to form a stable Se-Hg complex in plasma and thus reducing
the mercury deposition. Organoselenium derivatives such as
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Selenoesters are organoselenium compounds having
Journal Name
selenium atom adjacent to carbonyl group. They are
precursors of acyl radicals18 which have been used in the
synthesis of α,β-unsaturated ketones19 and various complex
proteins due to accelerated rates of native chemical ligation.20
Selenoesters have also been explored as liquid crystalline
materials.21 In addition, selenoester derivatives have found to
exhibit significant anti-tumor activities22 and have potential as
multi-targeted therapeutics for the treatment of alzheimer’s
disease.23 They also act as multidrug resistance reversing
agents in cancer cells.24 These relatively labile organoselenium
derivatives can be prepared by the cleavage of diselenides
for the treatment of toxicity caused by HgCl2 in biological
systems.
2. Results and discussion
with
various
metals,25
polyethylene
glycol-400/
2.1 Chemistry
hypophosphorous acid,26 sodium borohydride27 or rongalite28
as reductive system followed by addition of acyl chlorides or
acid anhydrides as well. PhSeZn-halides29 and tributyltin aryl
selenides30 also react with acid chlorides under mild conditions
to give various aromatic and aliphatic selenoesters. An
alternative simple and metal free method involves the reaction
of aroyl chlorides with sodium hydrogen selenide followed by
addition of alkyl halides using water as the solvent to give
selenoesters as products.31
Imidazo[1,2-a]pyridine
and
imidazo[1,2-a]pyrimidine
selenoester derivatives were synthesized in two steps. The first
step in the synthesis of selenoesters involved the preparation
of 2-(chloromethyl)imidazo[1,2-a]pyridine/pyrimidine
which were synthesized by the cyclocondensation of 2-
aminopyridine36/2-aminopyrimidine37
1a-b with 1,3-
(3a-b)
(
)
dichloroacetone in the presence of 1,2-dimethoxyethane (1,2-
DME) as the solvent in accordance with Tschitschibabin
reaction (Scheme 1).
The heterocyclic selenoesters based on thiophene moiety
have been synthesized and studied extensively for their
electrochemical behavior.32 Selenoester derivatives of
heterocycles such as dihydropyrimidinone have been known
for their activity against alzheimer’s disease.23 Imidazo[1,2-
a]pyridine and imidazo[1,2-a]pyrimidine are two fused
heterocyclic systems with a bridgehead nitrogen atom and
their derivatives have been known for a long time for their
antibacterial, antifungal33 and anti-inflammatory34 activities.
There are few reports related to the synthesis of imidazo[1,2-
a]pyridine and imidazo[1,2-a]pyrimidine selenide derivatives.35
However, the area of imidazo[1,2-a]pyridine/pyrimidine
selenoesters and metal selenides synthesis has not been
explored yet.
The selenoesters were prepared by adding aroyl chlorides
(
4a-e) to an aqueous solution of sodium hydrogen selenide,
generated in situ by reduction of elemental selenium with
sodium borohydride. The reaction resulted in the in situ
formation of aryl sodium selenocarboxylates (5a-e) to which
reactants 3a-b were added (Scheme 2). After stirring the
reaction mixture for few hours, the selenoester (6a-b and 6e-f
)
were precipitated from the aqueous phase.
Exploring the above methodology, attempt was made to
synthesize different selenoesters of imidazo[1,2-a]pyridine and
imidazo[1,2-a]pyrimidine. However, in case of aroyl chlorides
4c-e (4-chloro benzoyl, 4-methoxy benzoyl and thiophene-2-
carbonyl chlorides respectively), the yield of selenoesters
obtained was almost negligible due to the rapid hydrolysis of
these aroyl chlorides to the corresponding acids in water. For
aroyl chlorides 4c-e, water was replaced with ethanol for the
synthesis of selenoesters (Scheme 2).23 In ethanol the hydrolysis of
aroyl chlorides was repressed and selenoesters (6c-d, 6g-i) were
obtained in good yields. The use of ethanol is also favourable by
environmental point of view as ethanol is a green solvent.38
Keeping the above discussed points in mind, in the present
work, a series of selenoester derivatives (6a-i) of imidazo[1,2-
a]pyridine and imidazo[1,2-a]pyrimidine have been
synthesized under mild conditions using water and ethanol as
solvents followed by their deprotection in the presence of
combined system of K2CO3 and HgCl2 under different
conditions. The formation of complex 10 and HgSe shows that
there is a great possibility that selenoesters may prove useful
Scheme 2 General scheme for synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine selenoesters 6a-i
2 | J. Name., 2012, 00, 1-3
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2.2 Mercury detoxification
Using the above methodology, the reaction of selenoester 6e
with HgCl2 and K2CO3 was also repeated in water. The use of
water as the reaction medium for the generation of HgSe as
the end product from selenoesters at room temperature
indicates the applicability of selenoesters for the detoxification
of HgCl2 at physiological conditions.
In recent years, there has been a continuous interest in the
synthesis of organic heterocyclic metal chalcogenides, especially
organic mercury chalcogenides39 due to their applications in the
synthesis of semiconducting nanoparticles40 and opto-electronics.41
Hence, the present work was aimed at studying the selenoester-
HgCl2 interactions in order to prepare bis((imidazo[1,2-a]pyrimidin-
2-ylmethyl)selanyl)mercury (10), consequently a series of reactions
of selenoesters with HgCl2 were carried out.
All the synthesized compounds were characterized with 1H,
13C NMR and mass spectrometry along with 77Se NMR, HRMS
studies and CHNS analysis of some of the representative
selenoester derivatives (ESI, page S2-S20†). The 1H NMR
spectra of all the selenoester derivatives (6a-i) showed signals
of both imidazo[1,2-a]pyridine/pyrimidine moiety and the
aroyl group present, alongwith a peak around δ 3.5 which
indicates the presence of water. The ES-MS of all the
selenoester derivatives showed base peak corresponding to
[M+1]+. The 77Se NMR spectra of compounds 6a and 6e
showed peaks at δ 597.05 and δ 597.07 which confirmed the
formation of these selenoester derivatives (ESI, page S19†).
The formation of the mercury complex 10 was confirmed with
mass spectrometry (ESI, page S18†). However, the mercury
complex could not be isolated from the reaction mixture due
to its less solubility in organic solvents and decomposition to
form HgSe. The formation of HgSe was confirmed by EDXRF
(Energy dispersive X-ray fluorescence) and the composition of
selenium and mercury was found to be 1:1.
The mercury complex 10 may be formed via two routes i.e.
by the deprotection of selenoesters in the presence of
potassium carbonate (K2CO3) to form corresponding selenolate
ion followed by its reaction with HgCl2 or by the reaction of
HgCl2 with selenoester catalyzed by K2CO3. Herein, initially the
deprotection of selenoester 6e with K2CO3 was carried out in
THF under an inert atmosphere (Scheme 3). Compound 6e was
hydrolyzed to form potassium imidazo[1,2-a]pyrimidin-2-
ylmethaneselenolate (
HgCl2 solubilized in THF. The reaction led to the formation of
anticipated mercury complex 10, however, compound was
7) which was subsequently treated with
8
obtained as the major reaction product as evidenced by 1H, 13
NMR and ESI-MS reported earlier by our group.35(b) The mass
spectral studies (ES-MS) of the reaction mixture showed the
C
molecular ion peaks corresponding to both of the diselenide
and mercury complex 10 at m/z 425.1499 and 625.2388,
respectively. The selenolate ion ( ) is formed as the reaction
intermediate is proved by the formation of monoselenide
and diselenide The mercury complex 10 eventually
9
7
2.3 X-ray crystallography
8
The
ylmethyl)diselenide (
methanol at room temperature. The diselenide (
crystals
of
) were grown by slow evaporation in
) crystallizes
bis(imidazo[1,2-a]pyrimidin-2-
9.
9
decomposed to give HgSe after keeping for 4-5 days in
reaction solvent at room temperature. The formation of HgSe
as the end product reveals the potential of selenoester
derivatives as useful candidates for detoxification of HgCl2.
In the second route, complex 10 was obtained by
deprotection of selenoester 6e by HgCl2 in combination with
K2CO3 in acetonitrile with the subsequent conversion of 6e into
corresponding acid. It was observed that higher yield of
complex 10 was obtained in the latter route. It is important to
note that the yield of HgSe obtained depends entirely on the
method used for the deprotection of selenoesters rather than
the concentration of HgCl2, as ½ equivalent of HgCl2 is
9
in Pca21 space group with two water molecules:
a =
21.0903(13); b = 4.5204(3); c = 17.9165(10); α = 90o; β = 90o; γ
= 90o; V = 1708.10 Ǻ3 and Z = 4. The ORTEP and packing
diagrams of compound
9 are shown in Fig. 1 and Fig. 2. The
details of crystal data and structure refinement have been
depicted in Table 1 and the relevant bond lengths and bond
angles have been given in Table 2.
The X-ray crystallographic data shows that the Se1-Se2
bond distance is 2.300 Ǻ whereas the Se1-C1 and Se2-C8 bond
lengths are 1.964 and 1.968 Ǻ, respectively. From crystal
structure parameters it is clear that in compound
9 both the
sufficient to give 100% yield of mercury complex 10 39(a)
The
.
rings are almost perpendicular to each other with Se2-Se1-C1
bond angle 99.98o and Se1-Se2-C8 bond angle 100.58o. Both
the imidazo[1,2-a]pyrimidine rings are planar with N1-C7-N3-
C4 and N5-C14-N6-C10 torsional angles almost planar (179.48o
and 179.72o). The distance of N1….O1 of imidazo[1,2-
a]pyrimidine moiety and water molecule is 2.848 Ǻ while the
deprotection of thioesters in the presence of Hg2+ usually
results in the formation of insoluble salts of mercury along
with the generation of corresponding thiols due to acid
hydrolysis of thioesters in aqueous medium.42,43 In the present
studies, the selenol generated after acid hydrolysis underwent
oxidation to form monoselenide 8.
Scheme 3 Deprotection of compound 6e in the presence of K2CO3 and HgCl2 under different conditions and formation of HgSe
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Table 1 Crystal data and structure refinement for compound
Journal Name
9
Parameters
9
Empirical formula
Formula weight
Temperature
C14 H16 N6 O2 Se2
458.25
296(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Orthorhombic
P c a 21
Unit cell dimensions
a = 21.0903(13) Å, α= 90°
b = 4.5204(3) Å, β= 90°
c = 17.9165(10) Å, γ = 90°
Volume
3
1708.10(18) Å
Z
4
Density (calculated)
3
1.782 g/cm
Absorption coefficient
-1
4.350 mm
Fig.2 Packing diagram of compound 9
2.4 Computational Studies
F(000)
904
Crystal size
3
0.08 x 0.06 x 0.05 mm
Theta range for data collection
Index ranges
1.931 to 25.792°.
The structures of all the synthesized selenoesters and compounds
8-9 were fully optimized using DFT by GAUSSIAN 03 program at
B3LYP level and 6-31 G (d) was adopted as basis set (ESI, Table
S1†). The optimized energy was obtained for all the selenoester
derivatives and compounds 8-9 and band gap was also calculated
(Table S2† and Fig. S1). The results calculated by theoretical
studies were in close agreement with those obtained by X-ray
-25<=h<=25, -5<=k<=5, -21<=l<=21
Reflections collected
13629
Independent reflections
Completeness to theta = 25.242°
Refinement method
3030 [R(int) = 0.0303]
100.0 %
2
Full-matrix least-squares on F
Data / restraints / parameters
3030 / 1 / 224
0.988
2
Goodness-of-fit on F
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0319, wR2 = 0.0591
R1 = 0.0465, wR2 = 0.0628
0.492(6)
crystallography for compound
the theoretical and experimental values of Se2-Se1-C1 bond angle
may be due to the reason that compound is present in the
9 (Table 2). The slight difference in
Absolute structure parameter
Extinction coefficient
9
n/a
crystal lattice as a diselenide molecule interacting with two water
molecules in solid state while in theoretical calculations the
structure has been optimized in gaseous state.
Largest diff. peak and hole
-3
0.461 and -0.334 e.Å
N1….O2 distance is 4.832 Ǻ. On the other hand the C12….O2
distance is 2.511 Ǻ. These distances are shorter than the sum
of their van der waals radii which indicates that the water
molecues play a significant role in the crystallization of the
diselenide molecules. Besides the water molecules, the other
interactions present are N4…H4, N5…H3 etc.
2.5 EDXRF studies
The selenium mercury complex 10 decomposes to give HgSe which
Table 2 Comparison of experimental and theoretical bond lengths,
bond angles and dihedral angles for compound 9
Experimental
value (X-ray)
Theoretical
value (DFT)
Bond length (Ǻ)
Se1-Se2
2.300
2.300
Se1-C1
Se2-C8
1.964
1.968
Bond angle (o)
1.960
1.960
C9-C8-Se2
Se2-Se1-C1
Se1-C1-C2
Se1-Se2-C8
113.37
113.19
109.47
112.69
100.44
99.98
112.22
100.58
Dihedral angle (o)
C8-Se2-Se1-C1
Se2-Se1-C1-C2
Se1-Se2-C8-C9
N1-C7-N3-C4
109.49
109.97
72.77
72.50
Fig. 1 X-ray crystal structure of bis(imidazo[1,2-a]pyrimidin-2-
ylmethyl)diselenide (9)
80.38
80.43
179.48
180.00
-180.00
N5-C14-N6-C10
179.72
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Mass spectrometery was carried out on Waters Q-TOF
micromass. 77Se NMR was recorded on a Bruker BioSpin GmbH
operating at 76.31 MHz. The EDXRF spectra were obtained on
a Hitatchi SU8010 scanning electron microscope.
3.1.1 General procedure for the synthesis of selenoesters in
water (6a-b and 6e-f)
To a stirred suspension of grey selenium (0.25 g, 3.16 mmol) in
deoxygenated water (30 mL) was added sodium borohydride
(0.25 g, 6.5 mmol). The reaction mixture was stirred and a
colourless solution of NaHSe was formed. Then the reaction
mixture was cooled to 0 oC and aroyl chloride was added (3.16
mmol). The reaction mixture was again stirred for 1 h. A yellow
solution was formed and 2-(chloromethyl)imidazo[1,2-
a]pyridine/pyrimidine (0.52 g, 3.15 mmol) was added at 0 oC. A
white solid was formed within 2 h. The product was collected
by filtration and washed with distilled water (3 x 20 mL). The
product was purified with column chromatography using
hexane:ethyl acetate (2:3) as the eluent.
Fig.3 EDX analysis of HgSe formed in acetonitrile
3.1.2 Se-(imidazo[1,2-a]pyridin-2-ylmethyl) benzoselenoate
(6a)
Yield: 60%. Brown solid. M. p. 83-85 oC. IR (neat, ν cm-1): 3131,
3080, 2921, 1707, 1580, 1447, 1312, 1246, 1170, 1013, 887,
769, 707, 624, 457, 429. 1H NMR (400 MHz, CDCl3): δ (ppm)
8.01 (dt, J = 6.8, 1.0 Hz, 1H), 7.90 (dd, J = 8.3, 1.1 Hz, 2H), 7.64
– 7.53 (m, 3H), 7.44 (q, J = 7.8 Hz, 2H), 7.16 (ddd, J = 9.1, 6.8,
1.2 Hz, 1H), 6.75 (td, J = 6.8, 1.0 Hz, 1H), 4.51 (s, 2H). 13C NMR
(100MHz, CDCl3): δ (ppm) 194.70, 144.81, 143.91, 138.74,
133.73, 132.33, 129.85, 128.81, 128.15, 127.19, 125.52,
125.04, 117.01, 112.60, 110.55, 21.65. 77Se NMR (76.31 MHz,
CDCl3): δ (ppm) 597.05. Anal. calcd for C15H12N2OSe (%): C,
57.14; H, 3.80; N, 8.88. Found: C, 57.16; H, 3.82; N, 8.70. ES-
MS: m/z 317.90, [M+H]+. HRMS: m/z 316.6434, calculated for
[C15H12N2OSe + H]+: 316.0115.
3.1.3
Se-(imidazo[1,2-a]pyridin-2-ylmethyl)
4-
methylbenzoselenoate (6b)
Fig.4 EDX analysis of HgSe formed in water
o
Yield: 65%. White solid. M. p. 90-93 C. IR (neat, ν cm-1): 3136,
3036, 1663, 1604, 1497, 1360, 1274, 1167, 1015, 891, 814,
1
738, 614, 480, 432. H NMR (400 MHz, CDCl3): δ (ppm) 8.01
was characterized using EDX analysis (Fig. 3 and Fig. 4). The EDX
spectra showed the presence of well defined peaks corresponding
to mercury and selenium. The ratio of Hg and Se in the given
samples of HgSe was also determined which comes out to be 1:1 as
calculated by EDX analysis.
(dt, J = 6.8, 1.1 Hz, 1H), 7.82 – 7.76 (m, 2H), 7.58 (s, 1H), 7.55 –
7.50 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (ddd, J = 9.1, 6.8, 1.3
Hz, 1H), 6.72 (td, J = 6.8, 1.1 Hz, 1H), 4.46 (s, 2H), 2.38 (s, 3H).
13C NMR (100MHz, CDCl3): δ (ppm) 194.10, 145.09, 144.68,
144.48, 136.29, 129.45, 127.31, 125.47, 124.48, 117.27,
112.24, 110.43, 21.99, 21.72. Anal. calcd for C16H14N2OSe (%):
C, 58.37; H, 4.29; N, 8.51. Found: C, 58.24; H, 4.23; N, 8.48. ES-
MS: m/z 331.04, [M+H]+.
3. Experimental
3.1.4
Se-(imidazo[1,2-a]pyrimidin-2-ylmethyl)
3.1 Chemistry
benzoselenoate (6e)
All the reactions involving selenium were carried out in an
inert atmosphere of nitrogen. Selenium (CDH, purity >99.0%),
2-aminopyrimidine (Sigma Aldrich), 2-aminopyridine (SRL) and
aroyl chlorides (Sigma Aldrich) were purchased and used
without any further purification. Products were purified by
column chromatography using silica gel (99%, 60-120mesh). 1H
and 13C NMR spectra were recorded on a Bruker Avance II 400
MHz spectrophotometer in CDCl3 or DMSO-d6. Infrared spectra
were obtained on a Thermo Scientific Fisher spectrometer.
Yield: 55%. White solid. M. p. 79-81 oC. IR (neat, ν cm-1): 3160,
3088, 1665, 1581, 1447, 1373, 1243, 1198, 1000, 928, 788,
753, 687, 588, 486, 435. 1H NMR (400 MHz, DMSO-d6): δ (ppm)
8.88 (dd, J = 6.7, 2.0 Hz, 1H), 8.48 (dd, J = 4.1, 2.0 Hz, 1H), 7.88
(dd, J = 8.3, 1.1 Hz, 2H), 7.84 (s, 1H), 7.69 (tt, J = 7.1, 1.2 Hz,
1H), 7.54 (t, J = 7.8 Hz, 2H), 6.98 (dd, J = 6.7, 4.1 Hz, 1H), 4.43
(s, 2H). 13C NMR (100MHz, DMSO-d6): δ (ppm) 193.53, 149.83,
147.38, 144.57, 138.06, 134.67, 134.04, 129.08, 126.70,
109.20, 108.51, 22.03. 77Se NMR (76.31 MHz, CDCl3): δ (ppm)
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597.07. Anal. calcd for C14H11N3OSe (%): C, 53.18; H, 3.51; N, Yield: 34%. White solid. M. p. 116-118 oC. IR (neat, ν cm-1):
13.29. Found: C, 53.11; H, 3.46; N, 13.26. ES-MS: m/z 318.00, 3317, 3129, 3076, 1916, 1661, 1572, 1483, 1395, 1295, 1123,
[M+H]+. HRMS: m/z 317.6581, calculated for [C14H11N3OSe + 1013, 888, 793, 746, 615, 555, 463, 434. 1H NMR (400MHz,
H]+: 317.0067.
DMSO-d6): δ (ppm) 8.83 (dd, J = 6.8, 2.0 Hz, 1H), 8.47 (dd, J =
4- 4.1, 2.0 Hz, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.54 (d, J =
8.7 Hz, 2H), 6.95 (dd, J = 6.7, 4.1 Hz, 1H), 4.45 (s, 2H). 13C NMR
3.1.5
Se-(imidazo[1,2-a]pyrimidin-2-ylmethyl)
methylbenzoselenoate (6f)
Yield: 60%. White solid. M. p. 86-88 C. IR (neat, ν cm-1): 3170, (100MHz, DMSO-d6): δ (ppm) 192.34, 157.63, 149.62, 147.42,
2913, 1912, 1659, 1604, 1500, 1338, 1244, 1163, 985, 890, 144.51, 139.27, 136.57, 134.38, 130.81, 129.02, 128.24,
785, 697, 621, 456. 1H NMR (400MHz, CDCl3): δ (ppm) 8.50 109.11, 108.39, 22.21. Anal. calcd for C14H10ClN3OSe (%): C,
(dd, J = 4.1, 2.0 Hz, 1H), 8.33 (dd, J = 6.7, 2.0 Hz, 1H), 7.79 (d, J 47.95; H, 2.87; N, 11.98. Found: C, 47.88; H, 2.79; N, 11.89. ES-
= 8.2 Hz, 2H), 7.57 (s, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.82 (dd, J = MS: m/z 351.95, [M+H]+.
o
6.7, 4.1 Hz, 1H), 4.47 (s, 2H), 2.39 (s, 3H). 13C NMR (100MHz, 3.1.10
Se-(imidazo[1,2-a]pyrimidin-2-ylmethyl)
4-
CDCl3): δ (ppm) 194.13, 149.68, 146.91, 144.82, 136.19, methoxybenzoselenoate (6h)
132.87, 129.50, 127.30, 108.78, 108.65, 21.74. Anal. calcd for Yield: 37%. Grey solid. M. p. 100-102 oC. IR (neat, ν cm-1): 3002,
C15H13N3OSe (%): C, 54.55; H, 3.97; N, 12.72. Found: C, 54.46; 2847, 1655, 1573, 1505, 1418, 1342, 1246, 1164, 1019, 887,
H, 3.85; N, 12.71. ES-MS: m/z 332.10, [M+H]+.
783, 646, 613, 456. 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.82
3.1.6 General procedure for the synthesis of selenoesters in (dd, J = 6.7, 2.0 Hz, 1H), 8.46 (dd, J = 4.1, 2.0 Hz, 1H), 7.85 (d, J
ethanol (6c-d and 6g-i) = 8.9 Hz, 2H), 7.79 (s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 6.93 (dd, J =
To a stirred suspension of grey selenium (0.375 g, 4.74 mmol) 6.7, 4.1 Hz, 1H), 4.40 (s, 2H), 3.87 (s, 3H). 13C NMR (100MHz,
in ethanol (30 mL) was added sodium borohydride (0.36 g, DMSO-d6): δ (ppm) 191.16, 163.77, 157.62, 149.47, 147.39,
9.48 mmol). The reaction mixture was stirred and a colourless 145.09, 134.29, 130.73, 128.99, 113.97, 109.97, 108.98,
solution of NaHSe was formed. Then the reaction mixture was 108.31, 55.35, 21.62. Anal. calcd for C15H13N3O2Se (%): C,
o
cooled to 0 C and aroyl chloride was added (3.16 mmol). The 52.03; H, 3.78; N, 12.14. Found: C, 51.95; H, 3.66; N, 12.06. ES-
reaction mixture was again stirred for 1 h. A yellow solution MS: m/z 348.04, [M+H]+.
was
formed
and
2-(chloromethyl)imidazo[1,2- 3.1.11 Se-(imidazo[1,2-a]pyrimidin-2-ylmethyl) thiophene-2-
a]pyrimidine/pyridine (0.52 g, 3.15 mmol) was added at 0 oC. A carboselenoate (6i)
white solid was formed within 2 h. The product was collected Yield: 45%. White solid. M. p. 77-79 C. IR (neat, ν cm-1): 3162,
o
by filtration and purified with column chromatography using 3084, 1659, 1499, 1398, 1242, 1164, 1048, 984, 869, 781, 718,
1
hexane:ethyl acetate (2:3) as the eluent.
670, 632, 435. H NMR (400MHz, DMSO-d6): δ (ppm) 8.86 (dd,
4- J = 6.7, 2.0 Hz, 1H), 8.47 (dd, J = 4.1, 2.0 Hz, 1H), 8.00-7.95 (m,
1H), 7.86 (dd, J = 3.9, 1.1 Hz, 1H), 7.82 (s, 1H), 7.21 (dd, J = 4.9,
3.1.7
Se-(imidazo[1,2-a]pyridin-2-ylmethyl)
methoxybenzoselenoate (6c)
Yield: 49%. White solid. M. p. 101-104 oC. IR (neat, ν cm-1): 3.9 Hz, 1H), 6.95 (dd, J = 6.7, 4.1 Hz, 1H), 4.44 (s, 2H). 13C NMR
2840, 1682, 1576, 1504, 1416, 1362, 1217, 1101, 1022, 891, (100MHz, DMSO-d6): δ (ppm) 183.69, 149.64, 147.41, 144.64,
759, 694, 647, 527, 481, 436. 1H NMR (400 MHz, CDCl3): δ 142.58, 134.47, 134.32, 132.01, 128.21, 109.15, 108.39, 22.11.
(ppm) 8.01 (dt, J = 6.8, 1.0 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.62 (d, Anal. calcd for C12H9N3OSSe (%): C, 44.73; H, 2.82; N, 13.04.
J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.16 (ddd, J = 9.1, 6.7, 1.2 Hz, 1H), Found: C, 44.67; H, 2.71; N, 13.15. ES-MS: m/z 323.98, [M+H]+.
6.95 – 6.87 (m, 2H), 6.75 (td, J = 6.8, 1.1 Hz, 1H), 4.46 (s, 2H), 3.1.12
Synthesis
of
bis(imidazo[1,2-a]pyrimidin-2-
3.85 (s, 3H). 13C NMR (100MHz, CDCl3): δ (ppm) 192.67, ylmethyl)selenide (8) and bis(imidazo[1,2-a]pyrimidin-2-
144.71, 144.11, 132.00, 131.61, 129.50, 125.50, 125.10, ylmethyl)diselenide (9)
116.92, 113.95, 113.51, 112.64, 110.52, 55.54, 21.20. Anal. To a stirred solution of selenoester 6e (0.0230 g, 0.073 mmol)
calcd for C16H14N2O2Se (%): C, 55.66; H, 4.09; N, 8.11. Found: C, in 20 mL THF was added K2CO3 (0.0100 g, 0.073 mmol) under
55.59; H, 4.00; N, 8.13. ES-MS: m/z 347.05, [M+H]+.
nitrogen. After all the K2CO3 was dissolved, HgCl2 (0.0099 g,
3.1.8 Se-(imidazo[1,2-a]pyridin-2-ylmethyl) thiophene-2- 0.0365 mmol) in 10 mL THF was added and the reaction
carboselenoate (6d)
mixture was stirred for 20 h. White precipitate was formed
o
Yield: 64%. Pink solid. M. p. 79-81 C. IR (neat, ν cm-1): 3133, which was collected by filtration and dissolved in methanol.
3076, 1659, 1494, 1335, 1272, 1188, 1047, 866, 781, 750, 718, Purification with column chromatography (chloroform) gave
673, 632, 429. 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.44 (dt, J compound
= 6.8, 1.1 Hz, 1H), 8.00 (dd, J = 4.9, 1.1 Hz, 1H), 7.88 (dd, J =
8 and 9 as the reaction products.
3.9, 1.1 Hz, 1H), 7.85 (s, 1H), 7.48-7.41 (m, 1H), 7.25-7.19 (m, 3.1.13 Bis(imidazo[1,2-a]pyrimidin-2-ylmethyl)selenide (8)
2H), 6.83 (td, J = 6.8, 1.1 Hz, 1H), 4.42 (s, 2H). 13C NMR Yield: 65%. White solid.
(100MHz, DMSO-d6): δ (ppm) 183.94, 144.11, 142.82, 134.63,
132.68, 132.21, 128.42, 127.81, 126.55, 124.64, 116.05, 3.1.14 Bis(imidazo[1,2-a]pyrimidin-2-ylmethyl)diselenide (9)
111.88, 110.73, 22.03. Anal. calcd for C13H10N2OSSe (%): C, Yield: 11%. White solid. M. p. 165-167 oC. IR (neat, ν cm-1):
48.60; H, 3.14; N, 8.72. Found: C, 48.48; H, 3.09; N, 8.66. ES- 3121, 3084, 3002, 2921, 2855, 2766, 1916, 1608, 1500, 1426,
MS: m/z 323.00, [M+H]+.
1396, 1245, 1160, 986, 838, 749, 637, 571, 487. 1H NMR
4- (400MHz, DMSO-d6): δ (ppm) 8.83 (dd, J = 6.7, 2.0 Hz, 1H), 8.47
(dd, J = 4.0, 2.0 Hz, 1H), 7.76 (s, 1H), 6.94 (dd, J = 6.7, 4.1 Hz,
3.1.9
Se-(imidazo[1,2-a]pyrimidin-2-ylmethyl)
chlorobenzoselenoate (6g)
6 | J. Name., 2012, 00, 1-3
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1H), 4.20 (s, 2H). 13C NMR (100MHz, DMSO-d6): δ (ppm) ethanol ceased the hydrolysis of aroyl chorides completely and
149.55, 147.51, 144.96, 134.26, 108.92, 108.33, 25.95. Anal. corresponding selenoesters (6a-i) were obtained in good
calcd for C15H12N2OSe (%): C, 36.70; H, 3.52; N, 18.34. Found: yields. Further, the selenoester derivative 6e was studied for
C, 36.68; H, 3.43; N, 18.28. ES-MS: m/z 425.1499, [M+H]+.
its reaction behaviour with HgCl2, which is a toxic metal salt
and imposes several health problems. The deprotection of
3.1.15 Synthesis of HgSe
A mixture of selenoester 6e (0.1153 g, 0.365 mmol), HgCl2 compound 6e with K2CO3 in THF was carried out followed by
(0.1982 g, 0.730 mmol) and K2CO3 (0.2017 g, 1.460 mmol) was addition of HgCl2, the reaction again gave monoselenide as
stirred in 20 mL of CH3CN and 0.21 mL of methanol or 20 mL the major product alongwith compounds 10 and HgSe in
8
9,
of water under inert atmosphere. The reaction mixture was trace amounts. However, the reaction of HgCl2 in the presence
stirred at room temperature for 20 h. Pale yellow solution was of K2CO3 with compound 6e led to deprotection of the
formed which was kept at room temperature for 4-5 days. The selenoester and mercury complex 10 was formed as the major
insoluble black HgSe formed was collected by filtration and product. A mechanistic study of HgSe formation shows that the
washed repeatedly with a mixture of water and acetonitrile mercury complex 10 formed after deprotection of selenoester
and dried under vacuum.
6e undergoes decomposition with elimination of non-toxic
mercury selenide (HgSe) to give monoselenide The
3.1.16 HgSe
8.
The precipitated HgSe obtained by the reaction of selenoester structures of all the synthesized compounds were optimized
6e with HgCl2 and K2CO3 in different solvents are detailed by DFT. The values of theoretically determined parameters
below.
were found to be in close agreement with experimental values
for compound . The formation of complex 10 and HgSe after
In THF Yield: 15%. Black solid.
In CH3CN Yield: 40%. Black solid.
In water Yield: 35%. Black solid.
9
the reaction of compound 6e with HgCl2 shows that in future it
may be possible to use selenoester derivatives for the
treatment of mercury induced toxicity as these derivatives
have high affinity towards HgCl2 and get easily hydrolyzed
under physiological conditions.
3.2 X-ray crystallographic studies
Suitable crystals of compound
9 were obtained by slow
evaporation of its solution in methanol. The single-crystal
diffraction studies were carried out on a Bruker SMART APEX II
CCD diffractometer (Mo-Kα, λ = 0.71073 Å). The crystal
structure was solved with the ShelXT-2014/5 structure solution
program and by using Olex2 as the graphical interface.44 The
program SAINT (version 8.27B) was used for integration of the
intensity of reflections and scaling. The program SADABS was
used for absorption correction. The crystal structure was
refined using the 2017/1 of ShelXL using Least Squares
minimisation.44 All hydrogen atoms were included in idealized
positions, and a riding model was used. Non-hydrogen atoms
were refined with anisotropic displacement parameters. The
crystal structure was deposited at Cambridge Crystallographic
Data Centre and was assigned the number CCDC 1564403.
3.3 Computational studies
Conflicts of Interest
There are no conflicts of interest to declare.
Acknowledgements
KKB is grateful to CSIR, New Delhi for Emeritus Scientist
Scheme India 21(0967)/13/EMR-II and UGC for research
project F. No. 43-254/2014(SR). NS and SK thank CSIR, New
Delhi, India for their research fellowships (grant no.
09/135(0675)/2012-EMR-I and 09/135(0674)/2012/EMR-I).
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