Synthesis and crystal structure of (4s)-4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)- 2,2-dimethyl-1,3-oxazolidine

Article abstract of DOI:10.3987/COM-14-S(K)54

The synthesis of (4S)-4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)- 2,2-dimethyl-1,3-oxazolidine 6 was performed in 7 steps starting from veratraldehyde 7. A new oxidizing system TBHP-ebselen 12 was used for oxidation of 4,5-dimethoxy-2-methylbenzaldehyde 11 into carboxylic acid 13, being the crucial step of the synthesis. The latter was transformed first to chiral amide 14 using (S)-phenylalaninol and then cyclised to oxazolidine 6. The spatial structure and the absolute configuration of the latter one was confirmed by X-ray study.

Full text of DOI:10.3987/COM-14-S(K)54

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HETEROCYCLES, Vol. 90, No. 1, 2015
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 730 - 739. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2014, Accepted, 23rd July, 2014, Published online, 25th July, 2014
DOI: 10.3987/COM-14-S(K)54
SYNTHESIS AND CRYSTAL STRUCTURE OF
(4S)-4-BENZYL-3-(4,5-DIMETHOXY-2-METHYLBENZOYL)-
2,2-DIMETHYL-1,3-OXAZOLIDINE
Maria Chrzanowska,a* Zofia Meissner,a Joanna M. Chrzanowska,a and
Andrzej K. Gzellab
aFaculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614
Poznań, Poland; e-mail: marylch@amu.edu.pl
bFaculty of Pharmacy, Poznan University of Medical Sciences, Grunwaldzka 6,
60-780 Poznań, Poland
Abstract – The synthesis of (4S)-4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)-
2,2-dimethyl-1,3-oxazolidine 6 was performed in 7 steps starting from
veratraldehyde 7. A new oxidizing system TBHP-ebselen 12 was used for oxidation
of 4,5-dimethoxy-2-methylbenzaldehyde 11 into carboxylic acid 13, being the
crucial step of the synthesis. The latter was transformed first to chiral amide 14
using (S)-phenylalaninol and then cyclised to oxazolidine 6. The spatial structure
and the absolute configuration of the latter one was confirmed by X-ray study.
Oxazolidines 1, 2 having at nitrogen atom a chiral auxiliary deriving from commercially available
aminoalcohols, e.g. (1R,2R)-norephedrine, (S)- and (R)-phenylalaninol, have been used as building blocks
in our stereoselective synthesis of 8-oxoberbines 4, alkaloids which do not possess oxygenated
substituents in ring D.1,2 The key step of the synthesis, in which a new stereogenic centre at C13a was
created, involved the addition of laterally lithiated chiral o-toluamide type 1 or 2, to imine 3. This
addition proceeded stereoselectively and led directly to protoberberine alkaloids, type 4 (Figure 1).
To apply the same methodology for the synthesis of protoberberine alkaloids having oxygenated
substituents in ring D, e.g. 8-oxoxylopinine 5,3 an amide with methoxy-substituents in aromatic ring was
needed. Thus, we undertook the synthesis of chiral 4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)-2,2-
dimethyl-1,3-oxazolidine 6.
This paper is dedicated to Prof. Isao Kuwajima on the occasion of his 77th birthday.

HETEROCYCLES, Vol. 90, No. 1, 2015
731
RO
RO
4
5
N
3
2
MeO
MeO
RO
RO
6
B

3a R = Me
A
7
N
O

N
C
O
8
3b R+R =CH2
13a
13
1
R1

9
O
N
D
12
OMe
10
 R2
11
5
OMe
4a R = Me
4b R+R = CH2
O
1 R1 = Me, R2 = Ph
2 R1 = CH2Ph, R2 = H
Figure 1. Starting compounds and products in alkaloids synthesis
The performed synthesis of the title compound 6 is presented in Scheme 1. The synthesis started from
commercially available veratraldehyde 7, which was brominated regioselectively using bromine in acetic
acid to afford 2-bromo-4,5-dimethoxybenzaldehyde 8.4 Extension of the reaction time from 5 h to 24 h
increased the yield of product 8 from the literature 80% to quantitative amounts. In the next step the
aldehyde function in 8 was protected in the form of cyclic acetal in the reaction with ethylene glycol in the
presence of catalytic amounts of p-toluenesulfonic acid. Exchange of bromine substituent for methyl group
in compound 9 to give methylated derivative 10 was achieved in the reaction with n-butyllithium and
methyl iodide.5 Deprotection of the acetal function in compound 10 was performed with 10% HCl in
diethyl ether leading to aldehyde 11 in 96% yield. Selective oxidation of
4,5-dimethoxy-2-methylbenzaldehyde 11 to benzoic acid 13 was the crucial step of the synthesis. Looking
for environmentally friendly oxidizing agent, to avoid using metal containing agents such as
AgNO3/NaOH,5 we choose tert-butyl hydroperoxide (TBHP) with a catalytic amount of selenium
compound, 2-phenyl-benzisoselenazol-3(2H)-one (ebselen) 12, introduced by Młochowski et. al.6-8
According to their procedure, to a solution of aldehyde 11 in tert-butanol, catalytic amount of ebselen 12
was added followed by tert-butyl hydroperoxide and then the mixture was stirred at 70 ºC for 48 h. As a
result crude acid 13 was isolated in 93% yield and purified by column chromatography. Treatment of acid
13 with SOCl2 in situ and then with (S)-phenylalaninol led to amide 14 in 84% yield. It was recrystallised
from methanol/diethyl ether to give crystalline amide 14 in the form of white needles showing mp 186 –
188 ºC, [α]D – 40.12 (c 0.41, CHCl3). The structure of the new amide 14 was confirmed by spectral
characteristics and elemental analysis. Oxazolidine 6 was prepared in 49% yield via a reaction of amide 14
with 2,2-dimethoxypropane (DMP), catalyzed by p-toluene sulfonic acid, in refluxing benzene under an
argon atmosphere. The crude reaction product was purified by column chromatography on silica gel

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(hexane/ethyl acetate) and recrystallized from diethyl ether yielding oxazolidine 6 as white crystals with
mp 118 – 120 ºC, [α]D – 46.03 (c 0.315, CHCl3).
Scheme 1. Synthesis of oxazolidine 6
The correctness of oxazolidine 6 structure was confirmed by spectral characteristics, elemental analysis
and crystal X-ray diffraction. The spatial geometry of the molecule of 6 is presented in Figure 2. A
summary of data collection and refinement parameters is given in Table 1, while selected geometric
parameters are presented in Table 2. The results of the X-ray diffraction study confirmed the absolute
configuration 4S of the compound studied, by refinement of the Flack parameter.9 The 4S configuration
could be postulated also on the basis of the source of chirality – (S)-phenylalaninol. The benzyl residue at
the stereogenic atom C4 is β-oriented and occupies a pseudo-axial position, as can be seen from the angle
between C4–C21 bond vector and Cremer & Pople oxazolidine ring plane normal of 15.11(7)°.10
Moreover, the conformation of N3C4 bond is antiperiplanar with respect to C21C22 bond [torsion
angle N3C4C21C22: -170.96(9)°]. The mean plane of the phenyl ring of the benzyl residue is
oriented at an angle of 20.45(6)º to the least squares plane of the non-planar oxazolidine ring. Comparable
observations have been made for (4S)-4-benzyl-2,2-dimethyl-3-o-toluoyl-1,3-oxazolidine 2 obtained
using a similar method.11

HETEROCYCLES, Vol. 90, No. 1, 2015
733
Figure 2. X-Ray crystal structure (ORTEP plot) of 6
The o-tolyl system of the 4,5-dimethoxy-2-methylbenzoyl moiety forms an angle of 71.69(3)º to the
approximately planar tertiary amide group (C2/N3/C4/C8/O9, r.m.s. = 0.0443 Å). Orientation of the
C11-atom with methyl substituent in the o-tolyl system is determined by the torsion angle
O9C8C10C11 of 66.36(13)º indicating synclinal (+sc) conformation of O9C8 and C10C11 bonds.
The methoxy groups at C13 and C14 of the 4,5-dimethoxy-2-methylbenzoyl moiety are tilted to a small
but statistically significant extent. The vectors of the O17C18 and O19C20 bonds are inclined to the
mean plane of phenyl ring at the angles of 6.81(8) and 9.18(7)º,10 respectively.
The C=O group of the amide function is synperiplanar with respect to the C2–N3 bond of oxazolidine
ring [torsion angle C2N3C8O9: 1.96(15)°].
In the solid state, the oxazolidine ring has an envelope conformation [puckering parameters12 Q =
0.3754(11) Å and  = 322.75(16)°]. The deviation of C5 from the almost planar system formed by the
other four atoms of the heterocyclic ring is 0.5748(16) Å.
In conclusion, we have synthesised (4S)-4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)-2,2-dimethyl-1,3-
oxazolidine 6 and fully characterised by physical and spectroscopic data. Compounds 6 can serve as
building block in the synthesis of 1-substituted tetrahydroisoquinoline alkaloids, including
protoberberines, using the lateral methodology. The absolute configuration of the molecule of oxazolidine
6 was confirmed by X-ray study as 4S.
EXPERIMENTAL
Melting points were determined on a Koffler block and are uncorrected. IR spectra: Bruker FT-IR IFS
113V. NMR spectra: Varian Gemini 300, with TMS as the internal standard. Mass spectra: AM D402.
Optical rotations: Perkin-Elmer polarimeter 242B at 20 ºC. Elemental analyses: Vario EL III. Analytical

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HPLC: Waters HPLC system with Chiralcel OD-H column. Merck DC-Alufolien Kieselgel 60254 were
used for TLC and Kieselgel 60 (70-230 mesh ASTM) for column chromatography. All compounds were
purchased from Aldrich Chemical Co. and used as received.
THF was freshly distilled from LiAlH4, benzene and toluene – from sodium wire.
Table 1. Crystal data and structure refinement for (4S)-4-benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)-2,2-
dimethyl-1,3-oxazolidine 6
Formula
C22H27NO4
369.45
Formula weight
Temperature/K
Wavelength/Å
Crystal system
Space group
a/Å
293(2)
1.54178
Orthorhombic
P212121
9.90321(17)
9.94191(14)
20.2832(3)
1997.02(5)
4 (1)
b/Å
c/Å
V/Å3
Z (Z’)
Dc/g cm-3
1.229
μ/m m-1
0.678
F(000)
792
Crystal size/mm
Θ range
0.35*0.30*0.10
4.36–76.25º
Max/min. indices h, k, l
No. of data collected
Independent Reflections
-12 ≤ h ≤ 12,-12 ≤ k ≤ 12, -25 ≤ l ≤ 25
29708
4189 (Rint = 0.0175)
Completeness to θmax = 76.25º /% 100
Restraints/Parameters
4189/0/249
Goodness-of-fit on F2
1.048
R1 = 0.0277, wR2 = 0.0769
R1 = 0.0280, wR2 = 0.0776
0.088 and -0.145
Final R indices [I > 2I)]
R indices (all data)
Largest diff. peak and hole /eÅ3

HETEROCYCLES, Vol. 90, No. 1, 2015
735
Table 2. Selected geometric parameters (Å, º) for 6
Bond lengths
O(1) – C(5)
O(1) – C(2)
C(2) – N(3)
N(3) – C(4)
N(3) – C(8)
C(4) – C(5)
C(8) – O(9)
C(8) – C(10)
1.4264(14)
1.4331(13)
1.4855(13)
1.4690(12)
1.3535(13)
1.5146(15)
1.2295(12)
1.5023(13)
Bond angles
C(5) – O(1) – C(2)
O(1) – C(2) – N(3)
C(8) – N(3) – C(4)
C(8) – N(3) – C(2)
C(4) – N(3) – C(2)
N(3) – C(4) – C(5)
O(9) – C(8) – N(3)
O(9) – C(8) – C(10)
N(3) – C(8) – C(10)
O(17) – C(13) – C(12)
O(17) – C(13) – C(14)
O(19) – C(14) – C(15)
O(19) – C(14) – C(13)
C(13) – O(17) – C(18)
C(14) – O(19) – C(20)
Torsion angles
108.06(8)
102.44(8)
126.04(8)
122.99(8)
110.54(8)
99.34(8)
122.19(9)
120.71(9)
117.10(8)
124.99(10)
115.39(9)
125.17(9)
115.67(9)
116.58(10)
117.04(8)
C(2) – N(3) – C(8) – O(9)
N(3) – C(4) – C(21) – C(22)
N(3) – C(8) – C(10) – C(11)
C(4) – C(21) – C(22) – C(23)
C(4) – C(21) – C(22) – C(27)
O(9) – C(8) – C(10) – C(11)
C(14) – C(13) – O(17) – C(18)
C(13) – C(14) – O(19) – C(20)
1.96(15)
-170.96(9)
-114.58(10)
82.39(13)
-97.54(12)
66.36(13)
172.70(10)
-169.46(9)
2-Bromo-4,5-dimethoxybenzaldehyde (6-bromoveratraldehyde) 8
The veratraldehyde 7 (5.0 g, 30 mmol) was dissolved in acetic acid (30 mL), then the solution of bromine
(10.0 g, 63.0 mmol) in acetic acid (20.0 mL) was added dropwise over 15 min. The mixture was stirred at
room temperature overnight. Water was added (70 mL) and the mixture was cooled to 4 °C. The product
was filtered off and purified by recrystallisation from MeOH/water mixture (6:1 v/v). Product 8 was
obtained in quantitative yield (7.35 g), mp 148 – 150 °C (lit.4 mp 148 – 150 °C). 1H NMR (CDCl3) δ 3.92
1
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 7.06 (s, 1H, ArH), 7.42 (s, 1H, ArH), 10.20 (s, 1H, CHO). H NMR
spectrum of compound 8 is in agreement with data given in literature.15
2-(2-Bromo-4,5-dimethoxyphenyl)-1,3-dioxolane 9
2-Bromo-4,5-dimethoxybenzaldehyde 8 (3.95 g, 16.1 mmol), ethylene glycol (2.0 g, 32.2 mmol) and

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HETEROCYCLES, Vol. 90, No. 1, 2015
p-toluenesufonic acid (0.055 g, 0.3 mmol) were refluxed in benzene under Dean-Stark apparatus over 2 h.
The mixture was cooled to room temperature and washed first with 1% NaOH and then with water.
Phases were separated; the organic phase was dried over Na2SO4 and evaporated to give 4.48 g (96%) of
white solid of 9. 1H NMR (CDCl3) δ 3.88 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 3.96 – 4.20 (m, 4H, CH2),
5.99 (s, 1H, CH), 7.02 (s, 1H, ArH), 7.11 (s, 1H, ArH). MS m/z 290 (M+ +1, 44), 289 (M+, 38), 288 (45),
287 (34), 259 (6), 246 (98), 245 (70), 244 (100), 243 (62), 229 (32), 218 (53), 216 (54), 201 (16), 173
(18), 149 (22), 122 (11), 107 (14), 94 (42), 50 (34). Spectral data of compound 9 are in agreement with
data given in literature.4,16
2-(4,5-Dimethoxy-2-methylphenyl)-1,3-dioxolane 10
The solution of 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane 9 (9.29 g, 32.1 mmol) in dry THF (50
mL) was cooled to – 72 °C under argon atmosphere and n-BuLi ( 22.1 mL of 1.6 M solution in hexane)
was added. After 30 min at – 72 °C methyl iodide (21.7 g, 152.9 mmol) solution in THF (10 mL) was
added dropwise upon stirring and the mixture was stirred for next 2 h at this temperature. After that time
the mixture was allowed to warm up to room temperature and the 20% NH4Cl was added. Product was
extracted with Et2O (4 x 25 mL). Organic extracts were combined and dried over Na2SO4. After
evaporation of solvents the crude product was obtained as brown oil in quantitative yield (7.4 g). The
crude product was pure enough to be used for the next step of synthesis. The pure analytical sample of 10,
1
as a white solid, was obtained after chromatography on silica gel (CH2Cl2/MeOH, v/v 200:1). H NMR
(CDCl3) δ 2.35 (s, 3H, ArCH3), 3.87 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 3.89 – 3.98 (m, 2H, CH2), 4.02 –
4.22 (m, 2H, CH2), 5.90 (s, 1H, CH), 6.67 (s, 1H, ArH), 7.09 (s, 1H, ArH). MS m/z 225 (M+ +1, 17), 224
(M+, 100), 209 (6), 193 (9), 179 (52), 165 (24), 152 (77) 137 (16), 121 (11) 109 (12), 91 (10), 73 (15) 65
(11). 1H NMR spectrum of compound 10 is in agreement with data given in literature.5
4,5-Dimethoxy-2-methylbenzaldehyde 11
The crude product 10 (7.4 g) was dissolved in Et2O (150 mL) and stirred with 10% HCl (30 mL) for 2 h
at room temperature. The phases were separated. The aqueous phase was thoroughly extracted with Et2O
(3 x 25 mL). The combined organic layers were dried over Na2SO4. Evaporation of solvent gave an oil
which solidified on standing. The crude product was chromatographed on silica gel (CH2Cl2 and
CH2Cl2/MeOH, 200:1, v/v) affording 5.55 g (96%) of 4,5-dimethoxy-2-methylbenzaldehyde 11 as an oil,
which solidified on standing. The analytical sample of 11 was crystalized from Et2O mp 71 – 73 °C (lit.17
mp 73 – 74 °C). IR (KBr) 1677cm-1. 1H NMR (CDCl3) δ 2.64 (s, 3H, ArCH3), 3.92 (s, 3H, CH3O), 3.95 (s,
3H, CH3O), 6.69 (s, 1H, ArH), 7.35 (s, 1H, ArH), 10.22 (s, 1H, CHO). MS m/z 181 (M+ +1, 14), 180 (M+,
100), 179 (42), 165 (32), 151 (22), 137 (10), 121 (8), 109 (33), 91 (17), 77 (32), 65 (27). Spectral data of
compound 11 are in agreement with data given in literature.5,17
2-Methyl-4,5-dimethoxybenzoic acid 13

HETEROCYCLES, Vol. 90, No. 1, 2015
737
To a solution of 4,5-dimethoxy-2-methylbenzaldehyde 11 (2.37 g, 13.2 mmol) in t-butanol (27 mL) the
catalyst – ebselen 12 (0.181 g, 0.66 mmol) and then t-butyl hydroperoxide (3.3 mL, 70% solution in
water) were added upon stirring. The mixture was stirred for 48 h at 70 °C. t-Butanol was evaporated in
vacuo. The residue was dissolved in CH2Cl2 (100 mL) and stirred with 5% HCl (52 mL) for 2 h. Phases
were separated. The aqueous one was extracted with CH2Cl2 (3 x 25 mL). Combined organic extracts
were dried over Na2SO4 and then evaporated to give an orange solid which was purified by
chromatography on silica gel (CH2Cl2/MeOH, 150:1, v/v). Acid 13 was recrystallized from
EtOAc/hexane yielding 1.19 g (46%) of pure product. Mp 142 – 144 ºC (lit.5 mp 139 – 141 °C). IR (KBr)
2965, 1690 cm-1. 1H NMR (CDCl3) δ 2.63 (s, 3H, ArCH3), 3.92 (s, 3H, CH3O), 3.94 (s, 3H, CH3O), 6.73
(s, 1H, ArH), 7.62 (s, 1H, ArH). MS m/z 196 (M+, 100), 181 (27), 150 (28) 135 (65) 107 (26), 66 (10), 51
(12). Spectral data of compound 13 are in agreement with data given in literature.5,13,14
(2S)-2-(4,5-Dimethoxy-2-methylbenzamide)-3-phenylpropanol 14
Acid chloride was prepared in situ from 2-methyl-4,5-dimethoxybenzoic acid 13 (0.785 g, 4 mmol) by
refluxing with SOCl2 (4 mL) and a drop of DMF for 1 h. The excess of SOCl2 was removed in vacuo,
affording white precipitate of acid chloride, which was dissolved in CH2Cl2 (20 mL) and carefully added
to the mixture of (S)-(–)-phenylalaninol (0.726 g, 4.8 mmol) in CH2Cl2 (150 mL) and 0.5 M KOH (26
mL) at 0 °C. The mixture was stirred vigorously for 1.5 h and precipitated product was filtered off.
Addidtional amount of the product was recovered from the filtrate by extraction with CH2Cl2 (3 x 30 mL).
Organic phases were dried over Na2SO4. Solvent was evaporated in vacuo affording white residue, which
was combined with precipitate and it was recrystallized from MeOH/Et2O yielding 1.11 g (84%) of pure
product 14. Mp 186 – 188 °C. [α]D – 40,12 (c 0.41, CHCl3). IR (KBr) 3334 (NH), 3279 (OH), 1634
(C=O) cm-1.1H NMR (CDCl3) δ 1.61 (s, 1H, disappears on treatment with D2O, OH), 2.28 (s, 3H, CH3),
2.88 – 3.08 (m, 2H, ArCH2), 3.70 – 3.91 (m, 2H, CH2OH), 3.78 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 4.34
– 4.43 (m, 1H, CHN), 5.89 (d, J = 7,1 Hz, 1H, NH), 6.64 (s, 1H, ArH), 6.68 (s, 1H, ArH), 7.24 – 7.34 (m,
13
5H, ArH). C NMR (CDCl3) δ 19.52 (CH3Ar), 36.53 (CH2), 53.51 (CH), 55.87 (CH3O), 56.04 (CH3O),
62.21 (CH2), 110.37 (CH), 113.69 (CH), 126.82 (CH), 127.51(C), 128.8 (2 x CH), 129.16 (C), 129.22 (2
x CH), 137.65 (C), 146.59 (C), 150.00 (C), 170.50 (C=O). MS m/z 329 (M+, 12), 311 (1), 298 (1), 238
(12), 220 (3), 195 (15), 179 (100), 151 (11), 136 (8), 107 (3), 91 (19), 65 (9). Anal. Calcd. for: C19H23NO4
x 1/3 H2O: C 68.04; H 7.11; N 4.18. Found: C 67.87; H 6.81; N 3.95. HPLC [hexane/propan-2-ol = 15:7,
flow rate 0.5 mL/min, tR = 19.59 min].
(4S)-4-Benzyl-3-(4,5-dimethoxy-2-methylbenzoyl)-2,2-dimethyl-1,3-oxazolidine 6
To amide 14 (1.106 g, 3.4 mmol) in dry benzene (70 mL), 2,2-dimethoxypropane (5.6 g, 53.8 mmol) and
p-toluensulfonic acid monohydrate (5.59 g, 0.87 mmol) were added and the mixture was refluxed for 2 h.
It was then cooled to room temperature and washed with 1% NaOH. Organic phase was dried over

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Na2SO4 and the solvent was evaporated in vacuo. The crude reaction product was chromatographed on
silica gel (hexane/EtOAc, 85:15 and 80:20, v/v). Pure oxazolidine 6 as white crystals was obtained in
49% yield (0.616 g) after recrystallization from Et2O. Mp 118 – 120 °C. [α]D –46,03 (c 0,315; CHCl3). IR
(KBr) 1635 (C=O) cm-1. 1H NMR (CDCl3) δ 1.71 (s, 3H, CH3), 1.87 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.65
– 2.77 (m, 2H, ArCH2), 3.60 – 3.80 (m, 3H, CH2O, CHN), 3.88 (s, 3H, CH3O), 3.93 (s, 3H, CH3O), 6.77
13
(s, 1H, ArH), 6.84 (s, 1H, ArH), 7.15 – 7.20 (m, 5H, ArH). C NMR (CDCl3) δ 18.49 (ArCH3), 23.11
(CH3), 27.03 (CH3), 40.34 (ArCH2), 56.05 (CH3O), 56.25 (CH3O), 61.02 (CH), 66.15 (CH2), 76.58 (C),
95.40 (C), 109.13 (CH), 113.30 (CH), 126.53 (CH), 128.56 (2 x CH), 128.82 (2 x CH), 129.81 (C),
137.34 (C), 147.03 (C), 149.11 (C), 167.49 (C=O). MS m/z 369 (M+, 4), 311 (1), 278 (4), 220 (2), 179
(100), 151 (7), 121 (3), 91 (5), 65 (4). Anal. Calcd. for C22H27NO4 x 1/8 H2O: C 71.08; H 7.38; N 3.78.
Found: C 71.11; H 7.34; N 3.75. HPLC [hexane/propan-2-ol = 3:1, flow rate 0.5 mL/min, tR = 22.19
min].
X-Ray structure determination for compound 6
X-Ray diffraction measurements were carried out on a SuperNova Dual Atlas diffractometer.18 The
structure of 6 was solved by direct methods using the SHELXS-97 program.19 The H atoms were
positioned geometrically and were refined using a riding model, with C–H = 0.96 Å (CH3), 0.97 Å (CH2),
0.98 Å (Csp3H), 0.93 Å (CarH) and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C) for methyl H atoms. The methyl
groups were refined as rigid groups, which were allowed to rotate. The structure was refined by the
full-matrix least-squares method on F2s using the SHELXL-97 program.19 The crystal data, together with
the details concerning the data collection and structure refinement are given in Table 1, and selected
geometry parameters in Table 2. Molecular illustration was prepared using ORTEP-3 for Windows.20
Software used to prepare material for publication was WINGX20 - and PLATON.10 The crystallographic
data in the CIF form are available as Electronic Supplementary Information from the Cambridge
Crystallographic
Data
Centre,
deposition
number
CCDC
941501;
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.uk).
ACKNOWLEDGEMENTS
We are very grateful to Professor Jacek Młochowski and Dr. Halina Wójtowicz-Młochowska (Wrocław
University of Technology, Wrocław, Poland) for a gift of 2-phenyl-benzisoselenazol-3(2H)-one (ebselen)
used in the presented research.
This work was supported by the research grant from the Ministry of Sciences and Higher Education No.
N204 032 32/0794 and by the research grant from the Polish National Science Centre (NCN) No.
2011/01/D/ST5/06627.

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REFERENCES
1. M. Chrzanowska and A. Dreas, Tetrahedron: Asymmetry, 2004, 15, 2561.
2. M. Chrzanowska, A. Dreas, and M. D. Rozwadowska, Tetrahedron: Asymmetry, 2004, 15, 1113.
3. F. A. Davis and P. K. Mohanty, J. Org. Chem., 2002, 67, 1290.
4. J. L. Charlton and M. M. Alauddin, J. Org, Chem., 1986, 51, 3490.
5. R. D. Clark and A. Jahangir, J. Org. Chem., 1988, 53, 2378.
6. J. Młochowski, W. Peczyńska-Czoch, M. Piętka-Ottlik, and H. Wójtowicz, The Open Catalysis
Journal, 2011, 4, 54.
7. H. Wójtowicz, M. Brząszcz, K. Kloc, and J. Młochowski, Tetrahedron, 2001, 57, 9743.
8. J. Młochowski, M. Brząszcz, M. Chojnacka, M. Giurg, and H. Wójtowicz, ARKIVOC, 2004, iii, 226.
9. H. D. Flack, Acta Cryst. A, 1983, 39, 876.
10. A. L. Spek, Acta Cryst. D, 2009, 65, 148.
11. A. K. Gzella, M. Chrzanowska, A. Dreas, and Z. Meissner, Acta Cryst. E, 2010, 66, o2850.
12. D. Cremer and J. A. Pople, J. Am. Chem. Soc., 1975, 97, 1354.
13. T. Fukuda and M. Iwao, Heterocycles, 2007, 74, 701.
14. M. Lang, A. Muhlbauer, C. Graf, J. Beyer, S. Lang-Fugmann, K. Polborn, and W. Steglich, Eur. J.
Org. Chem., 2008, 816.
15. J. L. Charlton and D. M. Coltart, Can. J. Chem., 1996, 74, 88; B. Kuenburg, L. Czollner, J. Frohlich,
and U. Jordis, Org. Process Res. Dev., 1999, 3, 425; R. Olivera, R. SanMartin, E. Dominguez, X.
Solans, M. K. Urtiaga, and M. I. Arriortua, J. Org. Chem., 2000, 65, 6398.
16. C. Che, S. Li, Z. Yu, F. Li, S. Xin, L. Zhou, S. Lin, and Z. Yang, ACS Comb. Sci., 2013, 15, 202.
17. J. L. Charlton, K. Koh, and G. L. Plourde, Can. J. Chem., 1990, 68, 2028; P. S. Manchand, P. Rosen,
P. S. Belica, G. V. Olivia, A. V. Perrotta, and H. S. Wong, J. Org. Chem., 1992, 57, 3531.
18. CrysAlis PRO. Agilent Technologies Ltd, Yarnton, England, 2013.
19. G. M. Sheldrick, Acta Cryst. A, 2008, 64, 112.
20. L. J. Farrugia, J. Appl. Cryst., 2012, 45, 849.