Chiral benzisoselenazolones: Conformational analysis based on experimental and DFT calculated 77Se NMR

Article abstract of DOI:10.1016/j.tet.2013.10.049

A series of new enantiomeric N-substituted benzisoselenazol-3(2H)-ones were prepared from 2-(chloroseleno)benzoyl chloride and 9-amino-deoxyquinine (both 9-native and 9-epi) as well as the other chiral primary amines. The ⁷⁷Se NMR parameters for the obtained benzisoselenazolones were measured and theoretically calculated at the DFT level of theory using B97-2 hybrid functional and cc-pVTZ basis set. The DFT ⁷⁷Se chemical shifts for the lowest energy conformers were in agreement with the experimental data, while the conformers of higher energy showed markedly worse fit. Interestingly, the preferred conformation for 2-(1-arylalkyl)-benzisoselenazolones is the gauche type (Se-N-C-H≈±180), and it is in agreement with those observed in crystals (X-ray). The calculation predicts a much higher sensitivity for the ⁷⁷Se chemical shift of the conformation than for the corresponding ¹³C data. In the ⁷⁷Se NMR spectra of chiral benzisoselenazolones with added racemic or l-N-Boc-phenylglycine, chiral discrimination could not be observed mostly due to signal broadening. In the ¹H NMR spectra, the benzisoselenazole derived from epi-9-amino-deoxyquinine induced splittings of the amino acid signals, thus allowing for discrimination of the enantiomers.

Full text of DOI:10.1016/j.tet.2013.10.049

Tetrahedron 69 (2013) 10223e10229
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral benzisoselenazolones: conformational analysis based on
77
experimental and DFT calculated Se NMR
*
ꢀ
ꢀ
_
Mariola Zielinska-B1ajet, Przemys1aw J. Boratynski, Jerzy Palus, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2013
Received in revised form 23 September 2013
Accepted 7 October 2013
Available online 21 October 2013
A
series of new enantiomeric N-substituted benzisoselenazol-3(2H)-ones were prepared from
2-(chloroseleno)benzoyl chloride and 9-amino-deoxyquinine (both 9-native and 9-epi) as well as the
other chiral primary amines. The 77Se NMR parameters for the obtained benzisoselenazolones were
measured and theoretically calculated at the DFT level of theory using B97-2 hybrid functional and cc-
pVTZ basis set. The DFT 77Se chemical shifts for the lowest energy conformers were in agreement
with the experimental data, while the conformers of higher energy showed markedly worse fit. In-
terestingly, the preferred conformation for 2-(1-arylalkyl)-benzisoselenazolones is the gauche type
(SeeNeCeHzꢀ180ꢁ), and it is in agreement with those observed in crystals (X-ray). The calculation
predicts a much higher sensitivity for the 77Se chemical shift of the conformation than for the corre-
sponding 13C data. In the 77Se NMR spectra of chiral benzisoselenazolones with added racemic or
L
-N-Boc-phenylglycine, chiral discrimination could not be observed mostly due to signal broadening. In
the 1H NMR spectra, the benzisoselenazole derived from epi-9-amino-deoxyquinine induced splittings of
the amino acid signals, thus allowing for discrimination of the enantiomers.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Nuclear magnetic resonance spectroscopy is a particularly con-
venient method for studying selenium-containing compounds. The
Organoselenium compounds play an important role as reagents
and intermediates in organic synthesis. Electrophilic, nucleophilic
or radical selenium reagents lead to useful synthetic intermediates
applied in different transformations.1 Some selenium-containing
compounds have been used as chiral ligands2 and catalysts3 in or-
ganic reactions, and have also exhibited noticeable activity in
biological assays.4 In particular, Ebselen (2-phenyl-1,2-
benzisoselenazol-3(2H)-one, Fig. 1) has attracted much interest in
biology and chemistry due to its promising antioxidant and anti-
inflammatory activities.4 This compound and its analogues have
also been successfully used as oxygen5 and bromine6 transfer
catalysts.
selenium chemical shift is known to be exceptionally sensitive to
variations in the electronic environment of the nuclei and the
d (
77Se) scale extends for thousands of parts per million.7 Theo-
retical computation of 77Se NMR parameters has occasionally been
conducted and the magnetic shieldings of 77Se for simple molecules
have been predicted with reasonable accuracy.8 Thus, combined
theoretical and experimental approaches have helped in elucidat-
ing structural details including selenium oxidation state9 and the
geometries of the compounds.8,10 The molecules in the previously
studied sets were rather small, and of limited conformational
flexibility.
Since a conformational change within a chiral host could be
induced differently by each enantiomer of guest molecule, we
intended to examine the 77Se NMR data of enantiomeric organo-
selenium compounds as a chiral probe. Previously, enantiodiffer-
entiation in 77Se NMR spectroscopy was achieved in a mixture of
racemic 2-phenylselenylpropionic acid and chiral base,11 and by
derivatization experiments.12
With this objective in mind we report here how the 77Se
chemical shifts of the benzisoselenazolone moiety introduced to
the chiral scaffolds reflect conformations of whole molecules, and
whether such 77Se chemical shifts could be predicted by theoretical
computation.
Fig. 1. Ebselen.
* Corresponding author. E-mail address: jacek.skarzewski@pwr.wroc.pl (J.
_
Skarzewski).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.049

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10224
For the mentioned purpose we synthesized a series of new
method14 (Scheme 1). The remaining amine starting materials
1def were commercially available (Scheme 2).
chiral N-substituted benzisoselenazol-3(2H)-ones 2 with additional
functionalities of Cinchona alkaloid molecules (2aec), as well as
other units with different sterically demanding moieties (2def).
For all the benzisoselenazolones 2aef, as well as Me2Se and
Ebselen, the lowest energy conformations were determined by
calculations at the DFT B97-2/cc-pVTZ level of theory (Fig. 2).15 The
second lowest energy conformers were also considered. For com-
pounds 2a, 2b, 2d, and 2e, i.e., all 2-(1-arylalkyl)-benzisoselena-
zolones, it was found that the lowest energy conformers had
a SeeNeCeH dihedral angle around ꢀ180ꢁ. Such a conformation
was also prevalent in all the X-ray structures of similar com-
pounds.6,17e20 In these rotamers the large selenium atom is un-
expectedly located close to the aromatic ring suggesting stabilizing
interactions. Accordingly, conformations with a SeeNeCeH di-
hedral angle around 0ꢁ were significantly richer in energy (Table 2).
Interestingly, the remaining part of the chiral moieties of 2a and 2b
adopted their usual conformations, i.e., closed for native quinine
and open for the 9-epi isomer, respectively (Fig. 2). The optimized
2. Result and discussion
The enantiomeric benzisoselenazol-3(2H)-ones 2aef were
prepared from 2-(chloroseleno)benzoyl chloride4b and the corre-
sponding chiral amines 1aef in the presence of Et3N (or DBU) in
acetonitrile at room temperature. All products were obtained in
34e85% yield and their 77Se NMR spectra were measured
(Schemes 1 and 2, Table 1). 9S-Amino-deoxyquinine 1a and
9R-amino-deoxyquinine 1b were obtained from quinine (QN) fol-
lowing the literature procedure.13 9S-(3-Aminophenyl)-deoxy-
quinine (1c) was obtained in the diastereoselective Grignard
substitution of chloroquinine using the previously developed
Scheme 1. Synthesis of benzisoselenazolones 2aec from quinine.
Scheme 2. Synthesis of benzisoselenazolones 2def. Reaction conditions: Et3N, CH3CN, rt.

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10225
geometries were then used for the calculation of GIAO 77Se mag-
netic shieldings at the DFT level of theory using B97-2 hybrid
functional and cc-pVTZ basis set.8a,15,16 In addition, the much less
expensive GIAO/B3LYP/6-311Gþ(d,p) calculations were performed
on B3LYP/6-31G(d) level geometries.4g The DFT isotropic shieldings
Table 1
Experimental 77Se chemical shifts (CDCl3,114.7 MHz) and scaled calculated chemical
shifts at GIAO B97-2/cc-pVTZ and B3LYP/6-31G(d)//B3LYP/6-311Gþ(d,p) levels of
theory
Compound
Experimenta
77Se
(ppm)
Calculationc (ppm)
LW (Hz)b GIAO/B97-2d GIAO/B3LYPe
853.0 (1029.2) 824.8
(s d values of 0 and
) were scaled to chemical shifts assuming 77Se
d
960 ppm for Me2Se and Ebselen,4g respectively. The DFT 77Se
chemical shifts for the lowest energy conformers were in reason-
able agreement with the experimental data (rms error as low as
10 ppm, Fig. 3). However, as expected8 the quality of the predicted
77Se chemical shifts deteriorated when the calculations were per-
formed on a smaller basis set (Table 1). The correlation of experi-
mental and DFT 13C data, assigned by ordering, for the set of
molecules studied showed reasonable agreement, Fig. 4.
With the exception of 2c, the second lowest energy conformers
differ in the orientation of the benzisoselenazolone ring (Table 2).
This is manifested by a dramatic increase of the predicted 77Se
chemical shifts for 2aed, which are in much worse agreement with
the experimental values (rms error ca. 70 ppm; Fig. 3) than com-
putational data obtained for the lowest energy conformations.
However, the corresponding distinction by confronting calculated
(8S,9S)-2a
(8S,9R)-2b
(8S,9S)-2c
1S-2d
860.8 (880.5) 33 (83)
859.2 (866.8) 20 (51)
947.8 (955.5) 44 (51)
830.4
869.7 (913.8) 830.5
968.8 (1022.6) 966.6
835.3
841.1
935.6
804.5
813.4
913.3
1S-2e
844.6 (850.5) 17 (20)
(1R,4aS,10aR)-2f 932.8 (938.0) 22 (22)
a
Experimental data for 60 mM solutions of 2 in CDCl3, values in parentheses
correspond to spectra measured in the presence of 1 equiv of racemic N-Boc-
phenylgycine.
b
Half-height signal width.
Calculated GIAO chemical shifts for single lowest energy conformers scaled
c
versus dimethylselenide and Ebselen (77Se
d 0 and 960 ppm, respectively), values in
parentheses were calculated for quinuclidine-protonated cationic species.
d
Calculated using hybrid B97-2 functional with cc-pVTZ basis set and PCM sol-
vent model using gas phase geometries optimized at the same level of theory.8a,16
e
Calculated at B3LYP/6-311Gþ(d,p) level of theory and PCM solvent model for
gas phase geometries optimized at B3LYP/6-31G(d) level.4g
Fig. 2. Lowest energy conformations of 2aef in gas phase determined at the B97-2/cc-pVTZ level of theory, selenium atom is represented by an orange ball.
Table 2
Optimized B97-2/cc-pVTZ geometries and relative energies after zero point correction for benzisoselenazolones 2a, 2b, 2d, 2e and similar X-ray structuresa
Compound
R1
R2
SeeNeCeH dihedral angle (ꢁ)
D
Eb (kcal/mol)
lowest energy
2a (S)
2b (R)
2d (S)
2e (S)
Quinuclidine
Quinoline
Ph
1-Naphthyl
H
Me
4-MeC6H4
CO2Et
Quinoline
Quinuclidine
Me
Me
Carbacycle
Ph
PO(OPh)2
i-Bu
H
ꢂ178.2 [ꢂ122.6]c
ꢂ17.2
þ25.2
þ20.4
ꢂ3.6
4.97
4.84
2.54
3.54
0.11
2.63
6.65
3.92
NAf
þ173.1 [þ169.5]c
þ164.8
þ166.4
2f
ꢂ148.6
þ35.9
þ7.3a
þ35.4a
þ9.8a
NAf
X-ray (R)6
X-ray (S)17
X-ray (S)18
X-ray19
X-ray(S)20
(þ155.5; þ171.2)d ꢂ164.7a
(ꢂ169.1) ꢂ173.2a
(ꢂ174.1) þ170.5a
(ꢀ170.1)e ꢀ177.5a
(þ177.1; þ175.2)d þ171.9a
Ph
COeAlaOMe
iPr
þ38.2a
7.63
a
X-ray structures were reoptimized at the B97-2/cc-pVDZ level of theory, experimental data are given in parenthesis.
Difference in energy after zero point correction between the higher and lowest energy conformers.
Values calculated for protonated species.
Molecules at two independent positions.
Molecules at symmetry-related positions.
b
c
d
e
f
Converges to lowest energy conformer.

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Fig. 3. Correlation of experimental 77Se NMR chemical shifts for compounds 2aef and
computed GIAO/B97-2/cc-pVTZ 77Se isotropic shieldings for lowest energy geometries
(blue) and additional higher energy conformations (red), the diagonal line is drawn
between Me2Se and Ebselen references and represents ideal match.
Fig. 5. DFT/B97-2/cc-pVTZ optimized structure of [2aþH]þ
.
counterion and solvent molecules, as well as the dynamic effects of
the proton exchange.
This observation prompted us to evaluate benzisoselenazolones
as prospective chiral solvating agents (CSAs) for amino acid de-
rivatives in 77Se and 1H NMR spectroscopy.
The experiments were carried out by mixing equimolar
amounts of chiral compounds 2aef and racemic N-Boc-phenyl-
glycine or L-N-Boc-phenylglycine in CDCl3 (60 mM). After each
addition, 1H (600 MHz) and 77Se NMR (114.7 MHz) spectra were
acquired at 298 K. Unfortunately, chiral discrimination could not be
observed in the 77Se NMR spectra. The addition of glycine-derived
acid resulted in 77Se spectrum broadening (e.g., for 2a half-height
signal width was 81 Hz, Table 1). The previously reported 77Se
splittings11 for diastereomeric ion pairs were only up to 50 Hz. Thus
in our case, due to the broadening, anisochronous 77Se signals
would remain unresolved.
However, in the 1H NMR spectra, compound 2a induced split-
tings of DL-N-Boc-phenylglycine signals up to 0.21 ppm. The
recorded values for the induced chemical shifts, as well as the
splitting between the signals corresponding to each enantiomer of
the amino acid (Dd) are presented in Table 3. The signals from the
Fig. 4. Correlation of experimental 13C NMR chemical shifts and computed GIAO/B97-
2/cc-pVTZ 13C isotropic shieldings for lowest energy conformers of compounds 2aef
(blue), and for higher energy conformers (red, offset by 20 ppm for clarity).
Table 3
1H NMR chemical shifts of DL-N-Boc-phenylglycine alone (
d
), and in the equimolar
mixture with 2a (dD and dL), and induced difference in the chemical shifts for en-
a
antiomers (Dd
)
and experimental 13C chemical shifts revealed only slightly better
correlation for the DFT data of lowest energy conformers (see: R2
0.9982 vs 0.9975, Fig. 4). Clearly, the differences were not as pro-
nounced as in the 77Se NMR spectra.
Additionally, for compounds 2aec species protonated at the
nitrogen atom of the quinuclidine ring were optimized, and then
magnetic shieldings were calculated. In the case of compound 2a,
a significant change of geometry was predicted, and the additional
proton is expected to participate in the hydrogen bond with the
carbonyl of the isoselenazolone moiety (Fig. 5). This change is
manifested by a marked increase in the calculated 77Se shift (by
176 ppm). However, after the addition of 1 equiv of N-Boc-phe-
nylglycine, the observed 77Se shift increased only by 20 ppm. This
difference can be attributed to the specific interactions with the
Signalb
d
dD
dL
Dd
a
a
-H1
5.12
5.31
8.06
5.57
4.68
4.62
5.61
5.54
4.62
4.41
5.54
5.35
0.058
0.213
0.065
0.190
-H2
NH1
NH2
a
Signals in parts per million for 60 mM samples in CDCl3 (600 MHz).
Numbers 1 and 2 correspond to two rotamer populations arising from hindered
b
rotation along the amide bond.
amino acids moved upfield, as expected for deprotonation of the
carboxylic group.
In order to preliminarily test Ebselen analogue 2c as a possible
chiral oxygen-transfer catalyst,5 the oxidation of thioanisole with

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30% aqueous hydrogen peroxide was carried out (1 mol % 2c,
methanol, rt, 4 h) giving the respective racemic sulfoxide in 30%
yield. No sulfoxidation was observed without the catalyst.
In conclusion, our results document one of the first attempts to
retrieve useful information from the comparison of DFT and ex-
perimental 77Se chemical shifts for molecules of medium com-
plexity. The use of an extended basis set in DFT calculations was
needed to achieve good agreement with the experimental data.
Also, in most cases, the calculation predicts much higher sensitivity
for the 77Se chemical shift to the conformation than for the corre-
sponding 13C data. It was found that all 2-(1-arylalkyl)-benzisose-
lenazolones adopt the lowest energy conformation with
SeeNeCeH dihedral angle around ꢀ180ꢁ, thus locating the large
selenium atom close to the aromatic ring.
146.8, 147.6, 157.8. IR (KBr): 3336, 3208, 2937, 1622, 1509, 1460,
1237, 1031, 829, 754 cmꢂ1. HRMS (ESI): calcd for [C26H29N3OþH]þ
400.2383, found: 400.2385.
3.2.2. Preparation of 1,2-benzisoselenazol-3(2H)-ones 2aee. To the
stirred solution of the appropriate amine (1 mmol) in dry aceto-
nitrile (6 mL) was added dropwise by syringe a solution of
2-(chloroseleno)benzoyl chloride (0.254 g, 1 mmol) in CH3CN
(2 mL). After 30 min, Et3N (0.253 g, 0.348 mL, 2.5 mmol) or for 2c
DBU (0.381 g, 0.374 mL, 2.5 mmol) was added. The resulting mix-
ture was kept for 3e10 days at 25 ꢁC under argon. After removal of
solvent, the crude product was purified by column chromatography
on silica gel with 3 cm layer of anhydrous K2CO3 on the top of the
column (CH2Cl2/MeOH, 10:1; then CH2Cl2/MeOH, 5:1).
3. Experimental
3.1. General
3. 2. 2.1. 2-[(8S, 9S)-60-Methoxycinchonan-9-yl]-1, 2-
benzisoselenazol-3(2H)-one (2a). Yield 72%, white crystals, mp
219e220 ꢁC; Rf¼0.54 (CH2Cl2/MeOH/Et3N, 15:1:0.25); [
D þ96.7 (c
a
]
0.18, CH2Cl2). 1H NMR (300 MHz, CDCl3)
d 0.86e0.95 (m, 1H),
1H NMR and 13C NMR spectra were measured on a Bruker
Avance DRX (1H, 300 MHz and 600 MHz) spectrometer using TMS
as an internal standard. 77Se NMR spectra were recorded at
115 MHz on a Bruker Avance II 600 MHz spectrometer using Ph2Se2
as an external standard. The reported coupling constants were
those directly observed on the spectra. IR spectra were recorded on
a Perkin Elmer System 2000 FTIR. Optical rotations at 578 nm were
measured using an Optical Activity Ltd. Model AA-5 automatic
1.63e1.77 (m, 3H), 2.01e2.09 (m, 1H), 2.31e2.39 (m, 1H), 2.75e2.83
(m, 2H), 3.28 (dd, J¼13.6, 10.2 Hz, 1H), 3.55e3.60 (m, 2H), 4.01 (s,
3H), 5.10 (d, J¼15.7 Hz, 2H, CH2]), 5.90e6.01 (m,1H, CH]), 6.38 (d,
J¼4.9 Hz, 1H, C9H), 7.34e7.36 (m, 3H, ArH), 7.49 (d, J¼3.8 Hz, 2H,
ArH), 7.99 (d, J¼9.2 Hz, 3H, ArH), 8.79 (d, J¼4.5 Hz, 1H, ArH). 13C
NMR (75 MHz, CDCl3)
d 27.7, 27.8, 28.3, 39.6, 41.6, 53.8, 56.0, 56.3,
58.6, 101.8, 114.6, 118.4, 122.8, 123.9, 126.1, 127.6, 128.9, 131.6, 131.9,
141.8, 142.9, 145.0, 147.2, 158.5, 166.9. 77Se NMR (115 MHz, CDCl3):
€
polarimeter. Melting points were determined using a Boetius hot-
d 860.8. IR (KBr): 2934, 1637, 1509, 1443, 1329, 1243, 1024, 848,
stage apparatus. High-resolution mass spectra (HRMS) were
recorded on a Waters on LCD Premier XE HRMS apparatus using ESI
technique. Separations of products by chromatography were per-
formed on silica gel 60 (230e400 mesh) purchased from Merck.
Thin layer chromatography analyses were performed using silica
gel 60 precoated plates (Merck).
Quinine QN was purchased from Buchler GmbH, 9-epi-quinine
(epi-QN) was prepared by a standard procedure.21 9S-Amino-
deoxyquinine 1a and 9R-amino-deoxyquinine 1b were synthesized
from quinine and epi-quinine according to a general procedure
described in the literature.13 Amines 1def were commercially
available. 2-(Chloroseleno)benzoyl chloride was prepared from
anthranilic acid according to the known procedure.4b
738 cmꢂ1. HRMS (ESI): calcd for [C27H27N3O2SeþH]þ 506.1341,
found: 506.1341.
3.2.2.2. 2-[(8S,9R)-60-Methoxycinchonan-9-yl]-1,2-
benzisoselenazol-3(2H)-one (2b). Yield 34%, yellow oil; Rf¼0.34
(CH2Cl2/MeOH, 40:3);
(300 MHz, CDCl3) d 1.24e1.31 (m, 1H), 1.51e1.56 (m, 1H), 1.78e1.89
[
a
]
ꢂ58.0 (c 0.46, CH2Cl2). 1H NMR
D
(m, 3H), 2.31e2.35 (m, 1H), 2.61e2.68 (m, 1H), 2.84e2.91 (m, 1H),
2.97e3.04 (m, 1H), 3.20 (dd, J¼13.8, 10.0 Hz, 1H), 3.70 (q, J¼9.5 Hz,
1H), 3.94 (s, 3H), 5.04e5.13 (m, 2H, CH2¼), 5.90e6.01 (m, 1H, CH¼),
6.58 (d, J¼10.9 Hz, 1H, C9H), 7.28 (dd, J¼9.2, 2.7 Hz, 1H, ArH),
7.38e7.42 (m, 1H, ArH), 7.49e7.53 (m, 3H, ArH), 7.76 (d, J¼2.7 Hz,
1H, ArH), 7.95 (d, J¼9.2 Hz,1H, ArH), 8.05 (d, J¼7.8 Hz,1H, ArH), 8.82
(d, J¼4.6 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3)
d 24.7, 27.4, 27.6,
39.7, 41.8, 53.5, 55.9, 56.0, 57.0, 101.3, 114.6, 119.2,122.5,124.1, 126.4,
127.1, 128.4, 129.1, 131.6, 132.2, 138.4, 141.9, 143.1, 145.0, 147.5, 158.4,
3.2. Preparation
3.2.1. (8S,9S)-9-(3-Aminophenyl)-60-methoxycinchonan
(1c). 9S-
167.4. 77Se NMR (115 MHz, CDCl3):
d 859.2. IR (KBr): 2932, 1622,
Deoxy-9-chloroquinine22 (2.48 g, 7.23 mmol) was suspended in dry
toluene (30 mL), and a solution of 3-[bis(trimethylsilyl)amino]
phenylmagnesium chloride (1 M in THF, 10 mL, 10 mmol, 1.4 equiv)
was added. The mixture was refluxed for 12 h. Then, it was allowed
to attain room temperature and ammonia buffer was added,
extracted with CH2Cl2, and evaporated. The residue was taken up in
toluene and washed with 10% NaOH solution, dried over Na2SO4,
and evaporated. Chromatography (silicagel, CHCl3/MeOH 10:1)
afforded 2.30 g of product (80%) as off-white amorphous solid, mp
1592, 1509, 1444, 1328, 1242, 1028, 739 cmꢂ1. HRMS (ESI): calcd for
[C27H27N3O2SeþH]þ 506.1341, found: 506.1344.
3.2.2.3. 2-[3-((8S,9S)-60-Methoxycinchonan-9-yl)phenyl]-1,2-
benzisoselenazol-3(2H)-one (2c). Yield 66%, yellow crystals, mp
148e150 ꢁC; Rf¼0.50 (CH2Cl2/MeOH, 5:1); [
a
]
ꢂ44.4 (c 0.36,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d 0.83e0.92 (m, 1H), 1.60e1.72
(m, 3H), 1.92e1.97 (m, 1H), 2.28e2.34 (m, 1H), 2.74e2.83 (m, 2H),
3.24 (dd, J¼13.8, 10.1 Hz, 1H), 3.33e3.39 (m, 1H), 3.75e3.79 (m,
1H), 3.99 (s, 3H), 4.80 (d, J¼11.1 Hz, 1H, C9H), 5.04e5.10 (m, 2H,
CH2]), 5.88e5.99 (m, 1H, CH]), 7.21e7.24 (m, 1H, ArH), 7.27e7.29
(m, 2H, ArH), 7.34 (dd, J¼9.2, 2.6 Hz, 1H, ArH), 7.42e7.47 (m, 2H,
ArH), 7.49e7.54 (m, 1H, ArH), 7.58e7.66 (m, 2H, ArH), 7.97e8.01
(m, 2H, ArH), 8.08 (d, J¼7.7 Hz, 1H, ArH), 8.77 (d, J¼4.6 Hz, 1H,
79e82 ꢁC; [
a
]
D ꢂ64.7 (c 0.34, CH2Cl2). 1H NMR (300 MHz, CDCl3)
d:
0.82 (ddt, J¼13.7, 6.8, 1.8 Hz, 1H), 1.53e1.63 (m, 2H), 1.67e1.71 (m,
1H), 1.84e1.93 (m, 1H), 2.25e2.34 (m, 1H), 2.70e2.83 (m, 2H),
3.25e3.70 (br s, 2H, NH2), 3.25 (dd, J¼14.0, 10.1 Hz, 1H), 3.25e3.38
(m, 1H), 3.65e3.75 (m, 1H), 3.95 (s, 3H, OCH3), 4.66 (d, J¼10.7 Hz,
1H, C9H), 5.06 (dd, J¼10.7, 0.9 Hz, 1H), 5.07 (dt, J¼17.4, 1.5 Hz, 1H),
5.93 (ddd, J¼17.4, 10.2, 7.3 Hz, 1H), 6.44 (ddd, J¼7.9, 2.1, 0.8 Hz, 1H),
6.61 (t, J¼1.9 Hz, 1H), 6.81 (d, J¼7.9 Hz, 1H), 7.03 (t, J¼7.9 Hz, 1H),
7.33 (dd, J¼9.1, 2.7 Hz, 1H), 7.37 (d, J¼4.6 Hz,1H), 7.52 (br s, 1H), 7.99
(d, J¼9.1 Hz, 1H), 8.73 (d, J¼4.6 Hz, 1H). 13C NMR (75.5 MHz, CDCl3)
ArH). 13C NMR (75 MHz, CDCl3)
d 27.9, 28.1, 28.8, 39.5, 41.1, 49.5,
55.7, 56.6, 59.7, 101.9, 114.6, 119.8, 121.4, 123.1, 124.0, 124.6, 125.9,
126.5, 128.1, 128.8, 129.2, 129.4, 131.8, 132.5, 137.7, 139.6, 141.8,
143.3, 144.6, 146.3, 147.6, 158.0, 165.7. 77Se NMR (115 MHz, CDCl3):
d
947.8. IR (KBr): 2932, 1621, 1508, 1444, 1328, 1231, 1024,
d
: 27.9, 28.1, 28.8, 39.5, 41.0, 49.5, 55.6, 56.5, 59.6, 102.3, 114.0, 114.5,
114.8, 118.6, 119.7, 121.0, 128.9, 129.4, 131.8, 141.8, 143.0, 144.7, 146.6,
738 cmꢂ1. HRMS (ESI): calcd for [C33H31N3O2SeþH]þ 582.1654,
found: 582.1650.

ꢀ
M. Zielinska-Błajet et al. / Tetrahedron 69 (2013) 10223e10229
10228
3.2.2.4. 2-[(1S)-(1-Phenylethyl)]-1,2-benzisoselenazol-3(2H)-one
Supplementary data
(2d). Yield 72%, yellow crystals, mp 115.5e117 ꢁC; Rf¼0.75 (CH2Cl2/
MeOH, 20:1); [
a
]
D ꢂ129.0 (c 0.2, CH2Cl2). 1H NMR (300 MHz, CDCl3)
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.10.049.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
d
1.75 (d, J¼6.8 Hz, 3H), 5.92 (q, J¼6.8 Hz, 1H), 7.34e7.45 (m, 6H,
ArH), 7.54e7.56 (m, 2H, ArH), 8.06 (d, J¼8.0 Hz, 1H, ArH). 13C NMR
(75 MHz, CDCl3)
d 19.8, 52.9, 123.9, 126.2, 127.4 (2C), 128.2, 128.3,
128.8 (3C), 131.8, 138.2, 141.4, 166.7. 77Se NMR (115 MHz, DMSO-d6):
d
830.4. IR (KBr): 3062, 2974, 1603, 1445, 1336, 1247, 1183, 1096,
References and notes
1021, 739, 699 cmꢂ1. HRMS (ESI): calcd for [C15H13NOSeþNa]þ
326.0055, found: 326.0074.
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one (2e). Yield 85%, white crystals, mp 181e183 ꢁC (hexane/ben-
zene); [
a
]
D ꢂ223.4 (c 0.32, CH2Cl2). 1H NMR (600 MHz, CDCl3)
d
1.86
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7.44e7.49 (m, 3H, ArH), 7.52 (t, J¼7.8 Hz, 1H, ArH), 7.71 (d, J¼6.6 Hz,
1H, ArH), 7.84 (d, J¼6.9 Hz,1H, ArH), 7.88 (d, J¼8.4 Hz,1H, ArH), 8.09
~
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(t, J¼9.8 Hz, 2H, ArH). 13C NMR (75 MHz, CDCl3)
d 18.8, 49.0, 123.4,
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131.7, 133.9, 137.1, 138.6, 166.2. 77Se NMR (115 MHz, CDCl3):
d 844.6.
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_
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IR (KBr): 3052, 2974, 1593, 1444, 1324, 1246, 1182, 1112, 777, 738,
675 cmꢂ1. HRMS (ESI): calcd for [C19H15NOSeþH]þ 354.0392,
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3(2H)-one (2f). Yield 47%, solidifying yellow oil; Rf¼0.26
(CH2Cl2); [
a
]
þ20.0 (c 0.10, CH2Cl2). 1H NMR (600 MHz, CDCl3)
D
d
1.06 (s, 3H), 1.21 (d, J¼6.6 Hz, 6H, 2ꢃCH3), 1.23 (s, 3H), 1.35 (dt,
J¼13.2, 3.6 Hz, 1H), 1.59 (dd, J¼12.6, 3.6 Hz, 1H), 1.63 (br d,
J¼12.6 Hz, 2H), 1.66e1.70 (m, 1H), 1.75 (tt, J¼13.2, 3.6 Hz, 1H),
1.82e1.88 (m, 1H), 2.11 (dd, J¼13.2, 7.2 Hz, 1H), 2.26 (br d,
J¼12.6 Hz, 1H), 2.80 (sept, J¼6.6 Hz, 1H), 2.97e3.03 (m, 2H), 3.75
(d, J¼6.0 Hz, 2H), 6.89 (d, J¼1.2 Hz, 1H, ArH), 6.96 (dd, J¼8.2,
1.8 Hz, 1H, ArH), 7.14 (d, J¼8.2 Hz, 1H, ArH), 7.37e7.42 (m, 1H,
ArH), 7.55e7.58 (m, 2H, ArH), 8.02 (d, J¼7.9 Hz, 1H, ArH). 13C NMR
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(75 MHz, CDCl3)
d 18.7, 19.2, 19.4, 24.0 (2C), 25.7, 30.1, 33.5, 36.9,
37.6, 38.1, 39.2, 44.8, 56.5, 123.6, 123.8, 124.1, 126.2, 126.8, 126.9,
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d 932.8. IR (KBr): 2927, 1615, 1445, 1345, 1298, 1175, 821,
738, 676 cmꢂ1. HRMS (ESI): calcd for [C27H33NOSeþH]þ 468.1800,
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3.3. Calculations
The calculations presented here were carried at DFT/B97-2
(Tozer modification of hybrid functional)16 level of theory using
successively cc-pVDZ and cc-pVTZ basis sets by Gaussian 09 B01
code.15 All the geometries were fully optimized in vacuum, as evi-
denced by zero imaginary frequencies. The isotropic magnetic
shieldings for all nuclei were computed via GIAO method at the
B97-2/Cc-pVTZ level of theory using polarized continuum model
(PCM) for chloroform. The calculations included Me2Se and Ebselen
as reference compounds. For the X-ray structures (Table 2) only the
cc-pVDZ basis set was used, and the initial inputs included crys-
tallographic data,8,17e20 and geometries related by 180ꢁ change in
SeeNeCeH dihedral angle.
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Acknowledgements
This work was supported by a statutory activity subsidy from
the Polish Ministry of Science and Higher Education for the Faculty
of Chemistry of Wroc1aw University of Technology. We thank
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