Synthesis and Glutathione Peroxidase-like activity of N-heterocyclic carbene derived cationic diselenides

Article abstract of DOI:10.1016/j.tet.2012.09.024

Water soluble cationic diselenide derivatives of benzimidazolin-2-selenones and imidazolin-2-selenones have been synthesized. The Glutathione Peroxidase-like (GPx-like) activities of cationic diselenides have been investigated for the first time. The GPx-like activities are found to be quite low as compared to the neutral imidazole based diselenide and intramolecularly coordinated diselenides. A mechanism for GPx-like activity has been proposed. The oxidation reactions of N-heterocyclic carbene derived selenones with hydrogen peroxide have been studied.

Full text of DOI:10.1016/j.tet.2012.09.024

Tetrahedron 68 (2012) 10561e10566
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Synthesis and Glutathione Peroxidase-like activity of N-heterocyclic carbene
derived cationic diselenides
,
b
Sudesh T. Manjare a, Harkesh B. Singh a , Ray J. Butcher
*
a Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
b Department of Chemistry, Howard University, 525 College Street NW, Washington DC 20059, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2012
Received in revised form 28 August 2012
Accepted 4 September 2012
Available online 12 September 2012
Water soluble cationic diselenide derivatives of benzimidazolin-2-selenones and imidazolin-2-selenones
have been synthesized. The Glutathione Peroxidase-like (GPx-like) activities of cationic diselenides have
been investigated for the first time. The GPx-like activities are found to be quite low as compared to the
neutral imidazole based diselenide and intramolecularly coordinated diselenides. A mechanism for GPx-
like activity has been proposed. The oxidation reactions of N-heterocyclic carbene derived selenones
with hydrogen peroxide have been studied.
Keywords:
Cationic diselenides
GPx
Ó 2012 Elsevier Ltd. All rights reserved.
Selenone
Oxidation reaction
Selenium dioxide
1. Introduction
Et
O
Me
H
N
Se
)
NMe2
Se
OMe
N
2
Glutathione Peroxidase (GPx) is an important selenoenzyme,
which functions as an antioxidant in the human body.1 This enzyme
acts as catalyst in the conversion of harmful peroxides to water/al-
cohol in the presence of cofactor glutathione. The synthesis of sele-
nium containing compounds, which mimic the properties of GPx has
attracted considerable current interest. Diaryl diselenides (1e14),2
(Fig. 1) Ebselen and Ebselen analogs2b,3 have been known to show
significant GPx-like activities. The catalytic cycle proposed for diaryl
diselenides is similar to that of the enzyme (Scheme 1). Selenol,
selenenic acid, and selenenyl sulphide are the key intermediates.
However, most of these diselenides are not water soluble and their
bioassays have to be carried out in organic solvents. Zhang and co-
workers have used block copolymer as matrix for solubilizing
diphenyl diselenide in water and examined the activity.4
Se
)
)
2
Se
H2N
COOH
Se
)
2
)
2
Fe
2
1
3
4
5
2
NHt-Boc
COOMe
Ph
O
N
N
O
Se
Se
)
)
)
Se
)
N
H
Se
)
2
2
2
Se
)
N
2
2
O
OMe
10
9
6
8
7
Cl
H
H
O
H
O
OMe
O
N
Se
)
2
Se
O
)
O
2
Se
)
2
Se
2
N
O
13
11
12
14
O
Recently, it has been shown that the imidazolin-2-selenones can
be easily converted to cationic diselenides.5e9 Son and co-
workers10 have reported the synthesis of a cationic diselenide by
reaction of N,N0-dimethylimidazolin-2-selenone in dichloro-
methane with mild hydrochloric acid (1 M) in the presence of air.
We thought that the use of cationic diselenides may show prom-
ising GPx-like activities due to the favored nucleophilic attack of
the cofactor thiol to the positively charged Se and weaker SeeSe
Fig. 1. Organo diselenides.
bond in cationic diselenides than in neutral imidazole based dis-
elenides. Also, due to their solubility in water, the bioassays could
be carried out in the desired aqueous medium. In this article, we
report the synthesis, characterization, and GPx-like activities of
water soluble N-heterocyclic carbene (NHC) derived cationic dis-
elenides. Attempts have been made to identify the intermediates
involved in the catalytic reaction with thiophenol and hydrogen
peroxide by mass spectrometry and NMR techniques.
* Corresponding author. E-mail address: chhbsia@chem.iitb.ac.in (H.B. Singh).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.024

10562
S.T. Manjare et al. / Tetrahedron 68 (2012) 10561e10566
R'
H2O
R'
H2O2
N
N
H2O2
CHCl3
rt., 2 h
O
Se
N
Se
N
R
O
E-SeOH
RSH
E-SeH
R
RSSR
19a R = 2-Py,
20a R = 2-Py,
20b R = n-Bu,
20c R = i-Pr
19b R = n-Bu,
19c
R = i-Pr
H2O
Methanol
E-SeSR
RSH
Crystalization
in Methanol
Scheme 1. GPx catalytic cycle.
2. Results and discussion
2.1. Synthesis
R'
N
R'
O
N
O
N
O Se O
O
N
R
Salts 15ae15e11,12 were prepared by following the literature
procedure. Precursor selenones 16a,11 16b,10 16c,12c 16e,13 and 16d
were prepared in good yield by a modified procedure14 where the
corresponding imidazolium salts were treated with in situ gener-
ated disodium diselenide15 instead of elemental selenium.16 Cat-
ionic diselenides 17a, 17b,10 17ce17e were synthesized by reacting
selenones 16ae16e with 1 M HCl in dichloromethane (Scheme 2).
The diselenides are moisture sensitive and get hydrolyzed to the
corresponding imidazolin-2-one at room temperature. Attempts to
crystallize 17a in methanol by slow evaporation gave the hydro-
lyzed ketone 18 (vide infra). All the compounds were characterized
by common NMR techniques. The 13C NMR spectra of diselenides
showed signals for the carbene carbons in the range
R' = 2-bromobenzyl
R
21a R = n-Bu
22a R = Py
21b R = i-Pr
22b R = i-Pr
Scheme 3. Synthesis of carbene derived selenium dioxide.
proton at
d 9.62 and 9.76 ppm, respectively, due to formation of
imidazolium salt 21a and 21b, respectively. Interestingly, 20a was
found to be more stable than 20b and 20c. It did not show the signal
for NCHN proton. This may be due to the presence of electron
withdrawing pyridyl substituent on one of the imidazole nitrogens,
which stabilizes the CeSe bond in 20a. The 13C NMR signal of car-
bene carbon of 20a (
benzimidazolin-2-selenone 19a (
and 20c, which are quite unstable in methanol, show 13C NMR
signals at 143.7 ppm and 142.3 ppm, which are close to that
observed for 3-(2-bromobenzyl)-1-butyl-1H-benzo[d]imidazol-3-
ium bromide ( 143.4 ppm) and 3-(2-bromobenzyl)-1-isopropyl-
1H-benzo[d]imidazol-3-ium bromide (
141.9 ppm), respectively.14
The 77Se NMR spectrum of 20a showed a significantly downfield
shifted signal at 1328 ppm, which is in the range reported for
related H2SeO3 (
1300 ppm).17 As expected both the salts 21a and
21b showed signals at 1044 ppm, which is close to the signal
d
153.3 ppm) is shifted upfield compared with
d
132.9e141.9 ppm, which are significantly upfield shifted com-
pared to selenones 16ae16e (
153.5e154.3 ppm). The 77Se NMR
spectra of 17ae17e exhibited peaks around 272e426 ppm, which
are significantly downfield shifted compared to the corresponding
selenones (
d
168.4 ppm). Compounds 20b
d
d
d
d
d
ꢀ13.4 to 47 ppm). In mass spectra of diselenides, the
d
molecular ion peak is not observed and the most intense peak
d
corresponds to [M/2ꢀCl]þ.
d
R
R'
R'
N
R'
N
d
N
N
Na2Se2
1M HCl
DCM
d
R''
R''
R''
Se
Se Se
R''
2Cl
t-BuOK,
N
N
N
N
R
obtained for the unidentified species obtained from oxidation of
imidazolin-2-selenone with hydrogen peroxide.2k The structure of
21a was further confirmed by single crystal X-ray analysis (vide
infra). Though 20a was stable enough in methanol for recording
NMR spectra, upon prolonged exposure (while growing crystal in
methanol by slow evaporation), it gave 22a. Similarly, 20c also
provided the hydrolyzed product 22b.18 The hydrolysis may have
occurred due to the moisture present in the system.
X
THF
R'
15a-15e
R
16a-16e
R
17a-17e
Crystalization
in methanol
X
R
R'
R''
Br 15a
i-Pr i-Pr
16a 17a
I
15b
Me
Me
Me
Me
Me
Et
H
H
H
H
16b 17b
16c 17c
16d 17d
16e 17e
N
N
O
Br 15c
Br 15d
Br 15e
n-Pr
i-Pr
18
2.2. Glutathione Peroxidase-like activity
Scheme 2. Synthesis of the cationic diselenides.
2.2.1. Coupled reductase assay. GPx-like activities of compounds
17ae17e were studied by the spectrophotometric method de-
scribed by Wilson et al.2a The GPx-like activities of neutral
imidazole-diselenide 72j and the diselenides with and without
intramolecular coordination (10, 12, and 13) (Fig. 1) were also de-
termined for comparison (Table 1). A typical test mixture contained
Cationic diselenides have generally been prepared by oxidation
of NHC derived selenones with tellurium, interhalogens,6 halo-
gens,7 TCNQ (tetracyanoquinodimethane),8,9 and HCl.10 Also, hy-
drogen peroxide is commonly used as oxidant in the GPx assay of
organoselenium antioxidant.3b However, its oxidation with hy-
drogen peroxide has not been systematically investigated.2l In view
of this, we attempted to oxidize benzimidazolin-2-selenones
19ae19c14 with hydrogen peroxide in chloroform (Scheme 3).
The reactions afforded precipitates of NHC derived selenium di-
oxide 20ae20c in good yields. The formation of 20ae20c was
confirmed by elemental analysis and IR spectroscopy. Compounds
20ae20c were found to be fairly soluble in methanol, however, the
compounds were found to be unstable in the solvent. This was
inferred from the 1H NMR spectra. The 1H NMR spectra of 20b and
20c in methanol-d6 showed signals corresponding to the NCHN
Table 1
Initial rates, yo (m
M minꢀ1) for the reduction of H2O2 by GSH
Compound
yo
(m
M minꢀ1
)
Compound
yo (m )
M minꢀ1
Control valuea
5ꢁ1
15ꢁ1
79ꢁ6
25ꢁ2
55ꢁ3
17e
7
10
12
13
47ꢁ4
130ꢁ4
77ꢁ2
17a
17b
17c
17d
152ꢁ5
94ꢁ1
a
The control values were obtained from the reduction of H2O2 by GSH in absence
of GPx samples.

S.T. Manjare et al. / Tetrahedron 68 (2012) 10561e10566
10563
GSH (2 mM), glutathione reductase (1.3 unit/mL), and NADPH
2.3. Molecular structure and crystal packing of compound
21a
(0.4 mM) in 0.1 M potassium phosphate buffer (pH 7.5 with EDTA
(1 mM)). The catalysts (2 mM) were added to the test mixture at
25 ꢂC and the reaction was started by the addition of H2O2 (1.6 mM).
The initial reduction rates were calculated from the oxidation rate
of NADPH at 340 nm at least 3e4 times and calculated from the first
5e10% of the reaction by using 6.22 mMꢀ1 cmꢀ1 as the extinction
coefficient for NADPH.
The molecular structure of 21a is depicted in Fig. 2a. The sele-
nium atom of the anion is in a tetrahedral geometry. One of the
oxygen atom (O2) of the CH3OSeO3 anion interacts with the proton
of the cation (CeH8A) forming hydrogen bond interaction
19
ꢂ
ꢀ
(CeH8A/O2 2.245(0) A; 169.6(2) ). Also the crystal packing of
ꢀ
The GPx-like activities of cationic diselenides 17ae17e (w15, 79,
21a shows intermolecular
pep stacking interactions (3.552(1) A)
25, 55, and 47
as compared to the compounds containing two intramolecularly
coordinated groups, i.e., compound 12 (w152
M minꢀ1), one in-
tramolecularly coordinated group, such as compound 13
(w94
M minꢀ1) and diphenyl diselenide (w77 M minꢀ1) (Table
1). The GPx-like activity of neutral imidazole-diselenide
(w130
M minꢀ1) was also significantly higher than the cationic
diselenides (15e79
M minꢀ1).
m
M minꢀ1, respectively) were found to be quite low
between two cations (Fig. 2b).
m
m
m
7
m
m
2.2.2. Plausible mechanism of GPx-Like activity. In order to un-
derstand the poor GPx-like activities of cationic diselenides, a series
of model reactions were carried out in deuterated water and the
reactions were monitored by the ESI mass spectrometryand the 77Se
NMR spectroscopy. A plausible mechanism of GPx-like activity is
shown in Scheme 4. When 1 equiv of thiophenol was added to the
cationic diselenide 17c in water, the mass spectrum showed frag-
ments corresponding to the cationic selenol (23) (m/z 191) and
selenosulphide (24) (m/z 299) along with other fragments (see
Supplementary data Fig. S57). The 77Se NMR spectrum of the re-
Fig. 2. a) The molecular structure of compound 21a. b) The crystal packing diagram of
compound 21a showing hydrogen bond interactions and interactions. Hydrogen
atoms (except those are involved in interactions) are omitted for clarity. Significant
bond lengths and bond angles: SeeO4 1.610(3), SeeO2 1.610(3), SeeO3 1.611(3), SeeO1
1.749(2), O4eSeeO1 101.69(13), O4eSeeO2 115.02(15), O2eSeeO3 112.00(14).
pep
action mixture (17cþPhSH in D2O) showed two signals (at
76 ppm for 23 and 24, respectively) and the 77Se NMR signal due to
the cationic diselenide 362 ppm) disappeared (see
d 15 and
d
(d
Supplementary data Fig. S56). Upon addition of the second equiv-
alent of thiophenol to the reaction mixture, the mass spectrum of
the mixture showed a strong peak centered at m/z 191, which sug-
gested the formation of the cationic selenol (23). This was further
confirmed by the 77Se NMR spectrum of the mixture in D2O, which
2.4. Molecular structures of compounds 18 and 22a
The molecular structures of compounds 18 and 22a are depicted
in Fig. 3a and c. Compound 18 has two molecules in the asymmetric
unit, which differ in orientation of the iso-propyl groups on the
nitrogen’s of the imidazole ring. In crystalꢂpacking diagram of 18
showed a single peak at d 19 ppm, which is assigned to 23. In the final
step, an excess of hydrogen peroxide was added to the reaction
mixture. This resulted in a white precipitate. The mass spectrum of
the white solid showed peaks at m/z 111 and m/z 222, which may be
due to the formation of oxidized compound 26 and 27, respectively
via 25. Also, the 77Se NMR spectrum of the white solid in methanol
ꢀ
the CeH13B/O1A (2.562(0) A; 164.2(4) ) and CeH3AA/O1B
ꢂ
ꢀ
(2.547(3) A; 151.8(3) ) intermolecular interactions are responsible
for the formation of ribbon like structure (Fig. 3b). The crystal
packing diagram of 22a shows CeH/O intermolecular secondary
bonding interactions (Fig. 3d), which are responsible for the for-
mation of the chain of molecules.
shows two peaks (d 1038 ppm and d 1298 ppm) confirming the
presence of compounds 26 and 27 in the reaction mixture. The poor
GPx-like activity of these compounds is probably due to the for-
mation of 26 and 27, which do not react further with thiophenol.
3. Conclusions
The dicationic diselenides are hygroscopic and hydrolyze to give
corresponding imidazolin-2-one. The oxidation of selenones with
hydrogen peroxide affords NHC derived selenium dioxide, which
are unstable in methanol. The GPx-like activities cationic dis-
elenides are found to be quite low as compared to the neutral and
intramolecularly coordinated diselenides. This lower GPx-like ac-
tivity may be due to formation of insoluble oxidized selenium
derivatives.
PhSH
PhSH
Ph
PhSSPh
Cl
Cl
Se
H
Cl
N
N
N
N
N
N
N
N
N
N
Se Se
Se S
+
Se
H
2Cl
23
23
m/z = 191 [M-Cl]+
24
17c
m/z = 190 [M/2-Cl]+
m/z = 191 [M-Cl]+
77Se NMR = 19 ppm
H2O2
m/z = 299 [M-Cl]+
Se NMR = 76 ppm
77Se NMR = 362 ppm
77Se NMR = 15 ppm 77
4. Experimental section
H2O
4.1. General considerations
-HCl
H2O2
O
Se
O
O
O
N
N
N
Cl
N
N
O
O
Se
All the manipulations were carried out under nitrogen or argon
atmosphere using standard Schlenk techniques unless otherwise
noted. Solvents were purified and dried by standard procedures
and were distilled prior to use. All the chemicals were purchased
from various commercial sources and used as such. The synthesis
and characterization data for known compounds 15be15e, 16b,
+
Se
N
OH
26
27
25
m/z = 111 [M-CH3SeO4]+
77Se NMR = 1038 ppm
m/z = 222 [M]+
77Se NMR = 1298 ppm
Scheme 4. Plausible mechanism of GPx-like activity.

10564
S.T. Manjare et al. / Tetrahedron 68 (2012) 10561e10566
4.09 (t, J¼7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 1.84 (sext, J¼7.1 H z, 2H,
CH2), 0.97 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 153.5 (NCN), 118.9 (CH), 118.0 (CH), 50.1 (CH2), 35.9 (CH2),
21.3 (CH3), 9.9 (CH3); 77Se NMR (57 MHz, CDCl3):
d
(ppm) ꢀ4.5;
HRMS for C7H13N2Se: (m/z) calcd 205.0244; found. 205.0245 [M]þ.
4.3. General procedure for the synthesis of compounds
17ae17e
The selenones 16ae16e were dissolved in dichloromethane
(5 mL) and 1 M aq HCl (5 mL) was added to it. The reaction mixtures
were kept open in fume hood for 5e6 h. The colorless aq layers
slowly turned to yellow after 6 h. The aq layer was separated
carefully and evaporated to give yellow colored hygroscopic prod-
ucts 17ae17e in good yield.
4.3.1. Synthesis of 1,2-bis(1,3-diisopropyl-1H-benzo[d]imidazol-
2(3H)-ylidene)diselane-1,2-diium chloride (17a). The reagents used
were selenone 7 (0.3 g, 1.07 mmol), dichloromethane, and HCl.
Yield: 90 mg (27%). Mp 150e152 ꢂC; 1H NMR (400 MHz, D2O):
d
(ppm) 7.86 (bs, 4H, ArH), 7.43 (brs, 4H, ArH), 5.1 (brs, 4H, CH), 1.2
(brs, 24H, CH3); 13C NMR (100 MHz, D2O):
d
(ppm) 141.9 (NCN),
131.4 (ArC), 127.5 (ArC), 115.4 (ArC), 55.9 (CH), 19.7 (CH3); 77Se NMR
(57 MHz, D2O):
d
(ppm) 426.4; ESI-MS: 282.06 [M/2ꢀCl]þ.
4.3.2. Synthesis of 1,2-bis(1,3-dimethyl-1H-imidazol-2(3H)-ylidene)
diselane-1,2-diium chloride (17b).10 The reagents used were sele-
none 16b (0.19 g, 1.10 mmol), dichloromethane, and HCl. Yield:
180 mg (77%). 1H NMR (400 MHz, D2O):
d
(ppm) 7.50 (s, 4H, CH),
(ppm) 137.8 (NCN),
2.52 (s, 12H, CH3); 13C NMR (100 MHz, D2O):
d
125.2 (CH), 37.4 (CH3); 77Se NMR (57 MHz, D2O):
d (ppm) 272.2;
ESI-MS: 175.99 [M/2ꢀCl]þ.
4.3.3. Synthesis of 1,2-bis(1-ethyl-3-methyl-1H-imidazol-2(3H)-yli-
dene)diselane-1,2-diium chloride (17c). The reagents used were
selenone 16c (0.15 g, 0.79 mmol), dichloromethane, and HCl. Yield:
Fig. 3. a) The molecular structure of compound 18. b) The crystal packing diagram of
compound 18. c) The molecular structure of compound 22a. d) The crystal packing
diagram of compound 22a showing CeH/O hydrogen bonding and p/p interactions.
Hydrogen atoms (except those are involved in interactions) are omitted for clarity.
Significant bond lengths and bond angles of compound 18: C1AeO1A 1.189(7),
C1BeO1B 1.247(6), O1AeC1AeN1A 130.4(6), O1BeC1BeN1B 124.9(5); compound 22a:
O1eC1 1.222(2), N1eC1 1.374(2), O1eC1eN1 125.85(17), O1eC1eN2 127.97(17).
160 mg (88%). 1H NMR (400 MHz, D2O):
d
(ppm) 7.69 (bs, 1H, CH),
7.63 (bs, 1H, CH). 3.99 (bs, 4H, CH2), 3.57 (bs, 6H, CH3), 1.23 (bs, 6H,
CH3); 13C NMR (100 MHz, D2O):
(ppm) 134.9 (NCN), 128.1 (CH),
d
126.1 (CH), 47.9 (CH2), 38.7 (CH3), 16.0 (CH3); 77Se NMR (57 MHz,
D2O):
d
(ppm) 364.3; ESI-MS: 190.00 [M/2ꢀCl]þ.
16c, and 16e are given in the Supplementary data. Melting points
were recorded on a Veego VMP-I melting point apparatus in cap-
illary tubes and were uncorrected. 1H (400 MHz) and 13C
(100 MHz) nuclear magnetic resonance spectra were recorded on
Varian VXR 400S or Bruker AV 400 spectrometers at 25 ꢂC. The
77Se (57.22 MHz or 76.3 MHz) spectra were recorded on a Varian
VXR 300S and Bruker AV 400 spectrometers. Chemical shifts are
cited with respect to Me4Si as internal standard for 1H and Me2Se
for 77Se as external standards. Elemental analyses were performed
on a Carlo Erba Model 1106 elemental analyzer. The HRMS and ESI-
MS spectra were recorded on a Q-Tof micro (YA-105) mass
spectrometer.
4.3.4. Synthesis of 1,2-bis(1-methyl-3-propyl-1H-imidazol-2(3H)-
ylidene)diselane-1,2-diium chloride (17d). The reagents used were
selenone 16d (0.50 g, 2.46 mmol), dichloromethane, and HCl. Yield:
370 mg (63%). 1H NMR (400 MHz, D2O):
d (ppm) 7.56 (m, 4H, CH),
3.87 (t, J¼6.6 Hz, 4H, CH2), 3.52 (s, 6H, CH3), 1.61 (sext, J¼7.4 Hz, 4H,
CH2), 0.76 (t, J¼7.3 Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3): 133.8
(NCN),126.7 (CH),125.5 (CH), 52.7 (CH2), 37.5 (CH3), 23.1 (CH2), 10.2
(CH3); 77Se NMR (57 MHz, D2O):
d (ppm) 341.3; ESI-MS: 204.02
[M/2ꢀCl]þ.
4.3.5. Synthesis of 1,2-bis(1-isopropyl-3-methyl-1H-imidazol-2(3H)-
ylidene)diselane-1,2-diium chloride (17e). The reagents used were
selenone 16e (0.3 g, 1.48 mmol), dichloromethane, and HCl. Yield:
4.2. Synthesis of 1-methyl-3-propyl-1H-imidazole-2(3H)-se-
290 mg (83%). 1H NMR (400 MHz, D2O):
d (ppm) 7.78 (s, 2H, CH),
lenone (16d)
7.67 (s, 2H, CH), 4.76 (sept, 2H, CH), 3.61 (s, 6H, CH3), 1.35 (d,
J¼6.7 Hz,12H, CH3); 13C NMR (100 MHz, D2O):
d (ppm) 132.9 (NCN),
Salt 15d (3.12 g, 15.22 mmol) was added to the reaction mixture
of disodium diselenide (1 equiv, prepared in situ) in dry THF
(40 mL) and the reaction mixture was stirred for 5e6 h followed by
the addition of potassium tert-butoxide (1.71 g, 15.22 mmol) at
room temperature. The reaction was quenched by adding water and
extracted with chloroform. The collected organic layer was dried
over sodium sulfate and evaporated to give selenone 16d. Yield:
127.1 (CH), 122.3 (CH), 54.8 (CH2), 37.0 (CH3), 21.8 (CH3); 77Se NMR
(57 MHz, D2O):
d
(ppm) 373.7; ESI-MS: 204.02 [M/2ꢀCl]þ.
4.4. General procedure for the synthesis of compounds
20ae20c
The syntheses of NHC derived selenium dioxides 20ae20c were
carried out by the addition of hydrogen peroxide (30% solution in
1.95 g (63%). 1H NMR (400 MHz, CDCl3):
d
(ppm) 6.88 (m, 2H, CH),

S.T. Manjare et al. / Tetrahedron 68 (2012) 10561e10566
10565
water) to the solution of selenones 19ae19c in chloroform at room
temperature. After completion of the reactions, sodium sulfate was
added to the reaction mixtures and filtered. The residues obtained
after evaporation of filtrate were washed with diethyl ether to af-
ford white solid compounds 20ae20c.
Diffraction Gemini diffractometer. The data were corrected for
Lorentz, polarization, and absorption effects. The structures were
determined by routine heavy-atom methods using SHELXS 9720
and Fourier methods and refined by full-matrix least squares
with the non-hydrogen atoms anisotropic and hydrogen with fixed
isotropic thermal parameters of 0.07 A using the SHELXL 9721
program. The hydrogen’s were partially located from difference
electron density maps, and the rest were fixed at predetermined
positions. Scattering factors were from common sources.22 Details
of the X-ray data collection parameters are given in Table 2. Crys-
tallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos. CCDC:
889460 (18), 889461 (21a) and 889462 (22a). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
2
ꢀ
4.4.1. Synthesis of 1-(2-bromobenzyl)-3-(pyridin-2-yl)-1H-benzo[d]
imidazole-2(3H)-selenium dioxide (20a). The reagents used were
hydrogen peroxide (0.12 mL, 1.02 mmol) and selenone 19a (0.15 g,
0.34 mmol) in chloroform (15 mL). Yield: 100 mg (64%). 1H NMR
(400 MHz, CDCl3):
d
(ppm) 8.59 (m, 1H, ArH), 8.18 (d, J¼8.2 Hz, 1H,
ArH), 8.11 (dd, J¼8.6 Hz, J¼1.1 Hz, 1H, ArH), 7.87 (dt, J¼7.6 Hz,
J¼1.8 Hz, 1H, ArH), 7.60 (dd, J¼8.0 Hz, J¼1.2 Hz, 1H, ArH), 7.26e7.08
(m, 6H, ArH), 6.90 (dd, J¼7.3 Hz, J¼1.0 Hz, 1H, ArH), 5.25 (s, 2H,
CH2); 13C NMR (100 MHz, CDCl3):
d (ppm) 153.3 (NCN), 150.4 (ArC),
148.2 (ArC), 138.4e113.3 (13C) (ArC), 108.5 (ArC), 44.9 (CH2); 77Se
NMR (57 MHz, CD3OD):
d
(ppm) 1328.0; FTIR (cmꢀ1): 1707, 1489,
1470, 1438, 1399, 1384, 746; ESI-MS: (m/z) [MꢀOBr]þ 380.0,
[MꢀSeO2]þ 364.0; Anal. Calcd for C19H14BrN3O2Se (%): C, 48.02; H,
2.97; N, 8.84. Found: C, 47.76; H, 3.05; N, 8.65.
Table 2
Details of the X-ray data collection and refinement parameters for 18, 21a, and 22a
Compound
18
21a
22a
4.4.2. Synthesis of 1-(2-bromobenzyl)-3-butyl-1H-benzo[d]imidaz-
ole-2(3H)-selenium dioxide (20b). The reagents used were selenone
19b (0.10 g, 0.23 mmol) in chloroform (20 mL) and hydrogen per-
oxide (0.08 mL, 0.70 mmol). Yield: 14 mg (13%). FTIR (cmꢀ1): 1552,
1156, 939, 902, 760; Anal. Calcd for C18H19BrN2O2Se (%): C, 47.60; H,
4.22; N, 6.17. Found: C, 47.91; H, 4.00; N, 5.71.
Formula
Mr
C13H18N2O
218.29
Monoclinic
P21/n
10.3011(9)
8.6854(9)
28.502(4)
90
92.196(11)
90
C19H23BrN2O4Se
502.26
Monoclinic
C2/c
19.8774(8)
9.3252(4)
22.1982(10)
90
102.846(2)
90
C17H17BrN2O
345.24
Monoclinic
P21/n
12.1417(3)
10.1146(3)
12.2008(3)
90
95.7630(10)
90
System
Space group
ꢀ
a[A]
ꢀ
b[A]
ꢀ
c[A]
a
b
g
[ꢂ]
[ꢂ]
[ꢂ]
4.4.3. Synthesis of 1-(2-bromobenzyl)-3-isopropyl-1H-benzo[d]im-
idazole-2(3H)-selenium dioxide (20c). The reagents used were hy-
drogen peroxide (0.21 mL, 1.82 mmol) and selenone 19c (0.15 g,
0.37 mmol)inchloroform (15 mL). Yield 14 mg (9%). FTIR (cmꢀ1): 1558,
1487, 1427, 1028, 946, 900, 765, 744; Anal. Calcd for C17H17BrN2O2Se
(%): C, 46.38; H, 3.89; N, 6.36. Found: C, 46.63; H, 3.51; N, 6.05.
3
ꢀ
V[A ]
2548.2(5)
8
4011.7(3)
8
1490.79(7)
4
Z
Size [mm3]
0.51ꢃ0.28ꢃ0.12
0.35ꢃ0.25ꢃ0.15
0.36ꢃ0.24ꢃ0.18
rcalcd [Mg/m3]
1.138
1.663
1.538
m
[mmꢀ1
]
0.575
9931
4588
0.1324
3.891
35868
4994
0.0417
2.758
3771
3039
0.0389
Refls. collected
Observed reflns
4.4.4. Data for 3-(2-bromobenzyl)-1-butyl-1H-benzo[d]imidazol-3-
R1 [I>2
s
(I)]
(I)]
ium methyl selenate (21a). 1H NMR (400 MHz, CD3OD):
d (ppm)
wR2 [I>2
s
0.3457
0.0795
0.0752
9.62 (s, 1H, NCHN), 8.03 (d, J¼8.0 Hz, 1H, ArH), 7.87 (d, J¼8.0 Hz, 1H,
ArH), 7.74e7.66 (m, 3H, ArH), 7.54 (d, J¼6.9 Hz, 1H, ArH), 7.47 (t,
J¼7.0 Hz, 1H, ArH), 7.38 (t, J¼7.3 Hz, 1H, ArH), 5.84 (s, 2H, CH2), 4.57
(t, J¼7.0 Hz, 2H, CH2), 1.99 (qt, J¼7.3 Hz, 2H, CH2), 1.42 (sext,
J¼7.3 Hz, 2H, CH2), 0.99 (t, J¼7.2 Hz, 3H, CH3); 13C NMR (100 MHz,
Acknowledgements
H.B.S. gratefully acknowledges the Department of Science and
Technology, New Delhi for the Ramanna Fellowship. S.T.M. is
thankful to CSIR, New Delhi for SRF and SAIF, IITB for spectral data
analysis.
CD3OD):
d (ppm) 143.7 (NCN), 134.9 (ArC). 133.5 (ArC), 133.0 (ArC),
132.9 (ArC), 132.7 (ArC), 132.5 (ArC), 129.8 (ArC), 128.4 (ArC), 125.0
(ArC), 114.9 (ArC), 114.8 (ArC), 52.5 (CH2), 48.5 (CH2), 32.3 (CH2),
20.7 (CH2), 13.8 (CH3); 77Se NMR (57 MHz, CD3OD):
d (ppm) 1044.2;
Anal. Calcd for C19H23BrN2O4Se (%): C, 45.44; H, 4.62; N, 5.58.
Found: C, 45.18; H, 4.78; N, 5.22.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.09.024.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.4.5. Data for 3-(2-bromobenzyl)-1-isopropyl-1H-benzo[d]imida-
zol-3-ium methyl selenate (21b). 1H NMR (400 MHz, CD3OD):
d
(ppm) 9.76 (s, 1H, NCHN), 8.07 (d, J¼8.4 Hz,1H, ArH), 7.78e7.63 (m,
4H, ArH), 7.45e7.36 (m, 3H, ArH), 5.87 (s, 2H, CH2), 5.13(sept, J¼6.6Hz,
1H, CH), 1.75 (d, J¼6.6 Hz, 6H, CH3); 13C NMR (100 MHz, CD3OD):
References and notes
d
(ppm) 142.3 (NCN),134.9 (ArC).133.6 (ArC),133.1 (ArC),132.5 (ArC),
132.3 (ArC), 132.1 (ArC), 129.7 (ArC), 128.5 (ArC), 124.6 (ArC), 115.2
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