Synthesis and antioxidant activity of 5-hydroxycoumarans,c 6-hydroxychromanes and sulfur-containing derivatives on their base

Article abstract of DOI:10.1007/s11172-013-0200-4

A synthesis of 5-hydroxycoumarans, 6-hydroxychromanes and their dodecylthiomethyl- substituted derivatives was accomplished based on methylphenols through the intermediate preparation of 2-allyl-4-alkoxyphenols. The sulfur-containing compounds synthesized

Full text of DOI:10.1007/s11172-013-0200-4

Russian Chemical Bulletin, International Edition, Vol. 62, No. 6, pp. 1395—1400, June, 2013
1395
Synthesis and antioxidant activity of 5ꢀhydroxycoumarans,
6ꢀhydroxychromanes and sulfurꢀcontaining derivatives on their base
S. E. Yagunov,a S. V. Khol´shin,a N. V. Kandalintseva,a,b and A. E. Prosenkoa,b
aNovosibirsk State Pedagogical University,
28 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 244 1856. Eꢀmail: syagunov@yandex.ru
bNovosibirsk Institute of Antioxidants,
54a ul. Krasnyi prospekt, 630091 Novosibirsk, Russian Federation.
Fax: +7 (383) 217 0781
A synthesis of 5ꢀhydroxycoumarans, 6ꢀhydroxychromanes and their dodecylthiomethylꢀ
substituted derivatives was accomplished based on methylphenols through the intermediate
preparation of 2ꢀallylꢀ4ꢀalkoxyphenols. The sulfurꢀcontaining compounds synthesized were
shown to be highly efficient as inhibitors of autooxidation of methyl oleate.
Key words: 5ꢀhydroxyꢀ2,3ꢀdihydrobenzofurans, 6ꢀhydroxychromanes, sulfurꢀcontaining
antioxidants, antioxidant activity.
By now, an increase in the intensity of the freeꢀradical
oxidation in living organisms (oxidation stress) was found
to lead to the emergence and development of a wide range
of diseases and pathological states.1 The phenolꢀtype
antioxidants of natural (ꢀtocopherol, flavonoids) and synꢀ
thetic origin (dibunol, mexidol)2,3 are frequently used for
prevention and correction of pathophysiological effects of
the oxidation stress. The mechanism of the phenol antiꢀ
oxidant actions is based on their ability to inactivate free
radicals.4 Many authors5—10 showed that the efficiency of
synthetic phenol antioxidants can be increased by introꢀ
duction in their molecules of thioalkyl groups capable of
reducing peroxides, precursor of free radicals. At the same
time, a possibility of the increase in the efficiency of natuꢀ
ral phenol antioxidants, in particular, ꢀtocopherol,
through the incorporation of sulfurꢀcontaining groups in
their structure was studied little. Thus, the series of
works11—13 described the synthesis of ꢀtocopherol anaꢀ
logs, the chromane ring oxygen atom of which was substiꢀ
tuted with the sulfur atom. According to the authors,13
such compounds are somewhat inferior to ꢀtocopherol
in the antiradical activity. At the same time, ꢀtocopherol
derivatives containing methylthioethyl substituent or
ethyl dimethyl sulfone group at position 2 inhibited oxidaꢀ
tion of rat brain homogenates more efficient than vitaꢀ
mine E.14
The synthesis of 5ꢀhydroxycoumarans and 6ꢀhydroxyꢀ
chromanes was performed based on methylphenols 1a—c
(Scheme 1). Treatment of compounds 1a—c with bromine
at –10 C furnished paraꢀbromophenols 2a—c. The reacꢀ
tion was carried out in chlorobenzene, since in the solꢀ
vents commonly used for this conversion (CCl4, CHCl3)
compounds 1a—c are not soluble enough at lowered temꢀ
peratures. The Ullmann reaction of bromophenols 2a—c
with sodium ethoxide led to compounds 3a—c in high
yields. This conversion was carried out in EtOH with DMF
and TMEDA additives in order to increase the solubility
of CuI compounds, that allowed us to apply milder condiꢀ
tions and increase selectivity of the reaction.15 The reacꢀ
tion of the synthesized ethoxyphenols 3a—c, as well as
4ꢀmethoxyphenol 3d, with allyl bromide and the reꢀ
arrangement of the thus formed phenyl allyl ethers 4a—d
were performed according to the procedure described earꢀ
lier.16 The resulting 2ꢀallylꢀ4ꢀalkoxyphenols 5a—d were
the key intermediate products in the synthesis of 5ꢀhydrꢀ
oxycoumarans 6a—d and 6ꢀhydroxychromanes 7c,d.
The heterocyclization and Oꢀdealkylation reactions
were carried out by heating of 2ꢀallylꢀ4ꢀalkoxyphenols 5a—d
with HBr in AcOH, which led to the target 5ꢀhydroxyꢀ2ꢀ
methylcoumarans 6a—d. This conversion could have proꢀ
ceed through the formation of the corresponding 5ꢀalkꢀ
oxycoumarans 8a—d and/or allylhydroquinones 9a—d as
the intermediate products (Scheme 2). The GLC studies
of the dynamics of the changes in the composition of the
reaction mixture in the course of the conversion 5d to 6d
showed that the process proceeded through the formation
of one intermediate product, which was isolated and charꢀ
In this connection, in the present work we carried out
a synthesis of new structural analogs of ꢀtocopherol,
dodecylthiomethylꢀsubstituted 5ꢀhydroxycoumarans and
6ꢀhydroxychromanes, and conducted comparative studies
of their antioxidant properties.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1395—1400, June, 2013.
1066ꢀ5285/13/6206ꢀ1395 © 2013 Springer Science+Business Media, Inc.

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Yagunov et al.
Scheme 1
R1
Me
Me
R2
H
Me
R3
H
H
R4
Et
Et
R1
Me
H
R2
H
H
R3
Me
H
R4
Et
Me
a
b
c
d
Reagents and conditions: i. Br2, PhCl, –10 C; ii. EtONa, CuI, TMEDA, DMF, EtOH, ; iii. C3H5Br, KOH, DMF; iv. 200—220 C;
v. HBr, AcOH, ; vi. NaBH4, Me2SO4, THF, H2O2, NaOH, H2O; vii. HBr, .
acterized as 5ꢀmethoxyꢀ2ꢀmethylcoumaran (8d). The fairꢀ
ly high yield of 8d (74%) indicates that the rate of heteroꢀ
cyclization under the selected conditions is considerably
higher than the rate of Oꢀdealkylation.
tion process was the first step,16 then the obtained prodꢀ
ucts, 4ꢀalkoxyꢀ2ꢀ(3ꢀhydroxypropyl)phenols, were heated
with HBr.
The introduction of the dodecylthiomethyl group in
the molecules of compounds 6c,d and 7c,d was performed
according to the procedure suggested earlier,17 which used
an original reagent, (N,Nꢀdiethylaminomethyl) dodecyl
sulfide (Scheme 3).
Scheme 2
Scheme 3
Reagents and conditions: Et2NCH2SC12H25, , AcOH.
The synthesis of 6ꢀhydroxychromanes 7c,d from 5c,d
The antioxidant activity of the compounds synthesized
was carried out in two steps: the hydroboration—oxidaꢀ
in comparison with ꢀtocopherol was tested in the model

Sulfurꢀcontaining derivatives of ꢀtocopherol
/days
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
1397
liquid chromatograph, capillary column (SEꢀ30, 12.5 m×0.22 mm),
carrier gas nitrogen. Thinꢀlayer chromatography was performed
on Silufol (UV 254) plates. Melting points were determined in
the capillary tube on a PTP appliance (PO Khimlaborpribor,
Russia).
Oxidation of methyl oleate (Acros Organics) was carried out
upon exposure to air at 60 C. The sample to be oxidized weighed
5 g, the concentration of the compounds under study was
1 mol g–1. During the experiment, the samples of 0.1 g in weight
were collected to determine the content of the peroxide comꢀ
pounds iron rhodanide method using a Specord UV VIS spectroꢀ
photometer. The time during which the peroxide number (PN)
reached 0.05% I2 was accepted as the induction period The startꢀ
ing PN for methyl oleate was 0.002% I2. Plotting the structure
and mathematical processing of kinetic curves were carried out
using the Origin 6.0 program.
4ꢀBromoꢀ2ꢀmethylphenol (2a). A solution of bromine (33.56 g,
0.21 mol) in chlorobenzene (100 mL) was added dropwise to
a solution of orthoꢀcresol 1a (21.61 g, 0.20 mol) in chlorobenzene
(300 mL) at –10 C over 4 h. Then, the mixture was heated to
room temperature, followed by the addition of 10% aqueous
solution of Na2SO3 (100 mL). The organic layer was separated,
the aqueous phase was treated with chlorobenzene (2×50 mL),
the organic phases were combined, washed with water, dried
with Na2SO4, the solvent was evaporated, the residue (38 g, the
content of the major compound (CMC) was 86% (GLC)) was
recrystallized from light petroleum (200 mL) to obtain the prodꢀ
uct (29.27 g, 78%) with m.p. 63—65 C (cf. Ref. 21: m.p. 63 C).
1H NMR, : 2.21 (s, 3 H, CH3); 4.55 (s, 1 H, OH); 6.57 (d, 1 H,
ArH, J = 8.4 Hz); 7.11 (dd, 1 H, ArH, J = 8.4 Hz, J = 2.4 Hz);
7.19 (d, 1 H, ArH, J = 2.4 Hz).
60
50
40
30
20
10
1
2
3
4
5
6
7
8
9
10
Fig. 1. Induction periods () of autooxidation of methyl oleate at
60 C without inhibitor (1), in the presence of ꢀtocopherol (2),
6c (3), 7c (4), 6d (5), 7d (6), 10c (7), 11c (8), 10d (9), 11d (10).
reaction of autooxidation of methyl oleate at 60 C, which
was earlier successfully used for the studies of antioxidant
activity of sulfurꢀcontaining phenol antioxidants of variꢀ
ous structure.7,18—20 The data obtained show (Fig. 1)
that compounds 6c,d and 7c,d in the concentration of
1 mol g–1 possess inhibiting activity close to that of
ꢀtocopherol. The introduction of the dodecylthiomethyl
substituents in the molecules of hydroxycoumarans and
hydroxychromanes, as we expected, led to the increase in
the antioxidant activity: the induction periods of monꢀ
ododecylthiomethylꢀsubstituted compounds 10c, 11c and
bisꢀdodecyl thiomethyl derivatives 10d, 11d exceeded that
of ꢀtocopherol by ~3 and 5 times, respectively. It should
be noted that thiomethylꢀsubstituted coumarans 10c,d
slightly exceeded the isomeric chromanes 11c,d in the antiꢀ
oxidant activity. This result correlated with the known
data,4 according to which hydroxycoumarans containing no
thio substituents exceed the corresponding hydroxychromꢀ
anes in the rate constants of the reactions with free radicals.
In conclusion, in this work we suggested and successꢀ
fully tested approaches to the synthesis of sulfurꢀcontainꢀ
ing analogs of ꢀtocopherol, viz., dodecylthiomethylꢀsubꢀ
stituted 5ꢀhydroxycoumarans and 6ꢀhydroxychromanes
from available methylphenols. The sulfurꢀcontaining comꢀ
pounds synthesized were shown to be highly efficient as
inhibitors of autooxidation of methyl oleate.
Compounds 2b,c were obtained similarly to 2a.
4ꢀBromoꢀ2,3ꢀdimethylphenol (2b). The yield was 74%, m.p.
1
89—91 C (cf. Ref. 22: m.p. 91 C). H NMR, : 2.20 (s, 3 H,
CH3); 2.35 (s, 3 H, CH3); 4.48 (s, 1 H, OH); 6.43 (d, 1 H, ArH,
J = 8.4 Hz); 7.17 (d, 1 H, ArH, J = 8.4 Hz).
4ꢀBromoꢀ2,5ꢀdimethylphenol (2c). The yield was 76%, m.p.
1
85—86 C (cf. Ref. 22: m.p. 87.5 C). H NMR, : 2.17 (s, 3 H,
CH3); 2.28 (s, 3 H, CH3); 4.35 (s, 1 H, OH); 6.56 (s, 1 H, ArH);
7.19 (s, 1 H, ArH).
4ꢀEthoxyꢀ2ꢀmethylphenol (3a). Sodium metal (9.20 g, 0.40 mol)
was dissolved in EtOH (120 mL), then a solution of 2a (18.70 g,
0.10 mol), CuI (4.00 g, 0.021 mol), and TMEDA (2.91 g,
0.025 mol) in DMF (20 mL) was added. The mixture was stirred
for 5 h at 95 C and cooled, followed by the addition of 2 M
aqueous NH4Cl (400 mL) and treatment with toluene (3×100 mL).
The organic phase was washed with 2 M aq. NH4Cl and brine,
dried with Na2SO4, the solvent was evaporated. The residue
(22.25 g, CMC 98% according to GLC) was distilled in vacuo to
obtain the product (19.51 g, 85%) as a resin crystallizing upon
cooling, m.p. 55—56 C (cf. Ref. 23: m.p. 55—55.5 C), b.p.
82—86 C (1 Torr). 1H NMR, : 1.37 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 2.19 (s, 3 H, ArCH3); 3.91 (q, 2 H, OCH2CH3,
J = 6.6 Hz); 4.70 (br.s, 1 H, OH); 6.49 (dd, 1 H, ArH, J = 8.4 Hz,
J = 3.0 Hz); 6.55 (d, 1 H, ArH, J = 8.4 Hz); 6.59 (d, 1 H, ArH,
J = 3.0 Hz).
Experimental
Reagents and solvents used in the work were commercially
available from Fluka, Acros, SigmaꢀAldrich, Reanal, Reakhim.
Before use, solvents were purified according to the standard proꢀ
cedures. Dodecyl (diethylaminomethyl) sulfide was obtained acꢀ
cording to the procedure published earlier.17
Compounds 3b,c were obtained similarly to 3a.
4ꢀEthoxyꢀ2,3ꢀdimethylphenol (3b). The yield was 90%, m.p.
113—114.5 C, b.p. 98—113 C (1 Torr). Found (%): C, 72.39;
H, 8.40. C10H14O2. Calculated (%): C, 72.26; H, 8.49. 1H NMR,
: 1.39 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.12 (s, 3 H, ArCH3);
1H NMR spectra were recorded on a Bruker AVꢀ600 spectroꢀ
meter (600 MHz) in CDCl3, using CHCl3 as a reference ( 7.24).
Chromatographic analysis was carried out on a LKhMꢀ80 gasꢀ

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Yagunov et al.
2.13 (s, 3 H, ArCH3); 3.90 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.30
(br.s, 1 H, OH); 6.42 (d, 1 H, ArH, J = 8.4 Hz); 6.46 (d, 1 H,
ArH, J = 8.4 Hz).
4ꢀEthoxyꢀ2,5ꢀdimethylphenol (3c). The yield was 86%, m.p.
80—82 C (cf. Ref. 24: m.p. 80.5—81.5 C), b.p. 111—115 C
(1 Torr). Found (%): C, 72.02; H, 8.31. C10H14O2. Calculated (%):
C, 72.26; H, 8.49. 1H NMR, : 1.38 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 2.11 (s, 3 H, ArCH3); 2.16 (s, 3 H, ArCH3); 3.91
(q, 2 H, OCH2CH3, J = 7.2 Hz); 4.10 (s, 1 H, OH); 6.45 (s, 1 H,
ArH); 6.48 (s, 1 H, ArH).
1ꢀAllyloxyꢀ4ꢀethoxyꢀ2ꢀmethylbenzene (4a). Sodium hydrꢀ
oxide (3.15 g, 79 mmol) was added to a solution of 3a (10.00 g,
66 mmol) in DMF (30 mL), the mixture was stirred for 30 min at
50 C, followed by a dropwise addition of allyl bromide (15.90 g,
0.131 mol) and stirring for 2 h at 60 C. The reaction mixture
was cooled, acidified with aq. HCl, and treated with toluene
(3×80 mL). The organic phase was washed with 15% aq. NaOH
(3×50 mL) and brine, dried with Na2SO4. The solvent was evapꢀ
orated to obtain compound 4a (12.20 g, 96%) as a light liquid
(CMC >99% according to GLC). Found (%): C, 75.12; H, 8.44.
C12H16O2. Calculated (%): C, 74.97; H, 8.39. 1H NMR, : 1.37
(t, 3 H, OCH2CH3, J = 7.2 Hz); 2.20 (s, 3 H, ArCH3); 3.91 (q, 2 H,
OCH2CH3, J = 7.2 Hz); 4.44 (dt, 2 H, CH2CH=CH2, J = 5.4 Hz,
J = 1.2 Hz); 5.21 (dd, 1 H, CH2CH=CH2, J = 10.2 Hz,
J = 1.2 Hz); 5.37 (dd, 1 H, CH2CH=CH2, J = 17.4 Hz,
J = 1.2 Hz); 6.01 (m, 1 H, CH2CH=CH2); 6.51 (dd, 1 H, ArH,
J = 9.0 Hz, J = 2.4 Hz); 6.61 (m, 2 H, ArH).
Compounds 5b—d were obtained similarly to 5a.
6ꢀAllylꢀ4ꢀethoxyꢀ2,3ꢀdimethylphenol (5b). The yield was
88%, m.p. 57.5—58.5 C, b.p. 105—110 C (1 Torr). Found (%):
C, 75.79; H, 8.63. C13H18O2. Calculated (%): C, 75.69; H, 8.80.
1H NMR, : 1.39 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.11 (s, 3 H,
ArCH3); 2.13 (s, 3 H, ArCH3); 3.32 (d, 2 H, CH2CH=CH2,
J = 6.0 Hz); 3.91 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.42 (s, 1 H,
OH); 5.15 (m, 2 H, CH2CH=CH2); 5.96 (m, 1 H, CH2CH=CH2);
6.37 (s, 1 H, ArH).
2ꢀAllylꢀ4ꢀethoxyꢀ3,6ꢀdimethylphenol (5c). The yield was
85%, m.p. 51—53 C, b.p. 100—106 C (1 Torr). Found (%):
C, 75.51; H, 8.58. C13H18O2. Calculated (%): C, 75.69; H, 8.80.
1H NMR, : 1.39 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.11 (s, 3 H,
ArCH3); 2.19 (s, 3 H, ArCH3); 3.39 (d, 2 H, CH2CH=CH2,
J = 4.2 Hz); 3.91 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.27 (s, 1 H,
OH); 5.02 (m, 2 H, CH2CH=CH2); 5.91 (m, 1 H, CH2CH=CH2);
6.46 (s, 1 H, ArH).
2ꢀAllylꢀ4ꢀmethoxyphenol (5d). The yield was 84%, b.p.
80—86 C (1 Torr) (cf. Ref. 26: b.p. 95 C (0.6 Torr)). Found (%):
C, 73.36; H, 7.15. C10H12O2. Calculated (%): C, 73.15; H, 7.37.
1H NMR, : 3.35 (d, 2 H, CH2CH=CH2, J = 6.6 Hz); 3.73 (s, 3 H,
OCH3); 5.10 (s, 1 H, OH); 5.19 (m, 2 H, CH2CH=CH2); 5.96
(m, 1 H, CH2CH=CH2); 6.59 (dd, 1 H, ArH, J = 8.4 Hz,
J = 3.0 Hz); 6.63 (d, 1 H, ArH, J = 3.0 Hz); 6.65 (d, 1 H, ArH,
J = 8.4 Hz).
5ꢀHydroxyꢀ2,7ꢀdimethylꢀ2,3ꢀdihydrobenzofuran (6a). A 46%
aq. HBr (0.15 mol, 22 mL) was added to a solution of 5a (6.73 g,
35.0 mmol) in AcOH (350 mL), the mixture was refluxed for 4 h.
Then, the solvent was evaporated on a rotary evaporator, the
residue was dissolved in toluene (100 mL), washed with 20%
aq. NaOH (3×60 mL), the aqueous layers were acidified with
aq. HCl and treated with ethyl acetate (5×40 mL). The extract
was washed with brine, dried with Na2SO4, the solvent was evapꢀ
orated. The residue was distilled in vacuo to obtain a colorless
resin (3.18 g, 55%) (CMC 99% according to GLC) crystallizing
on cooling, m.p. 62—64 C, b.p. 98—100 C (1 Torr). Found
(%): C, 73.36; H, 7.15. C10H12O2. Calculated (%): C, 73.15;
H, 7.37. 1H NMR, : 1.43 (d, 3 H, CH(CH3)CH2, J = 4.2 Hz);
2.10 (s, 3 H, ArCH3); 2.71 (m, 1 H, CH(CH3)CH2); 3.18 (m, 1 H,
Compounds 4b—d were obtained similarly to 4a.
1ꢀAllyloxyꢀ4ꢀethoxyꢀ2,3ꢀdimethylbenzene (4b). The yield was
95%. Found (%): C, 75.60; H, 8.86. C13H18O2. Calculated (%):
C, 75.69; H, 8.80. 1H NMR, : 1.30 (t, 3 H, OCH2CH3, J = 7.2 Hz);
2.03 (s, 3 H, ArCH3); 2.06 (s, 3 H, ArCH3); 3.82 (q, 2 H,
OCH2CH3, J = 7.2 Hz); 4.32 (dt, 2 H, CH2CH=CH2, J = 4.8 Hz,
J = 1.2 Hz); 5.11 (dd, 1 H, CH2CH=CH2, J = 10.2 Hz,
J = 1.2 Hz); 5.28 (dd, 1 H, CH2CH=CH2, J = 17.4 Hz,
J = 1.2 Hz); 5.92 (m, 1 H, CH2CH=CH2); 6.32 (m, 2 H, ArH).
1ꢀAllyloxyꢀ4ꢀethoxyꢀ2,5ꢀdimethylbenzene (4c). The yield was
96%, m.p. 50—51.5 C. Found (%): C, 75.62; H, 8.70. C13H18O2.
Calculated (%): C, 75.69; H, 8.80. 1H NMR, : 1.38 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 2.14 (s, 3 H, ArCH3); 2.17 (s, 3 H,
ArCH3); 3.93 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.43 (dt, 2 H,
CH2CH=CH2, J = 4.8 Hz, J = 1.2 Hz); 5.20 (dd, 1 H,
CH2CH=CH2, J = 10.2 Hz, J = 1.2 Hz); 5.36 (dd, 1 H,
CH2CH=CH2, J = 17.4 Hz, J = 1.2 Hz); 6.01 (m, 1 H,
CH2CH=CH2); 6.52 (s, 2 H, ArH).
CH(CH3)CH2); 4.76 (br.s,
1 H, OH); 4.80 (m, 1 H,
CH(CH3)CH2); 6.30 (d, 1 H, ArH, J = 2.4 Hz); 6.39 (d, 1 H,
ArH, J = 2.4 Hz).
Compounds 6b—d were obtained similarly to 6a.
5ꢀHydroxyꢀ2,6,7ꢀtrimethylꢀ2,3ꢀdihydrobenzofuran (6b) was
purified on a column with Al2O3 (5 degree of activity, eluent
toluene). The yield was 42%, m.p. 127—128 C (cf. Ref. 27: m.p.
126—128 C). 1H NMR, : 1.42 (d, 3 H, CH(CH3)CH2, J = 6.0 Hz);
2.07 (s, 6 H, ArCH3); 2.69 (m, 1 H, CH(CH3)CH2); 3.18 (m, 1 H,
CH(CH3)CH2); 3.97 (s, 1 H, OH); 4.76 (m, 1 H, CH(CH3)CH2);
6.34 (s, 1 H, ArH).
5ꢀHydroxyꢀ2,4,7ꢀtrimethylꢀ2,3ꢀdihydrobenzofuran (6c) was
purified on a column with Al2O3 (5 degree of activity, eluent
toluene). The yield was 56%, m.p. 96.5—98.5 C (cf. Ref. 28:
m.p. 97—99 C). 1H NMR, : 1.44 (d, 3 H, CH(CH3)CH2,
J = 6.0 Hz); 2.05 (s, 3 H, ArCH3); 2.06 (s, 3 H, ArCH3); 2.66
(m, 1 H, CH(CH3)CH2); 3.16 (m, 1 H, CH(CH3)CH2); 4.10
(s, 1 H, OH); 4.81 (m, 1 H, CH(CH3)CH2); 6.24 (s, 1 H, ArH).
5ꢀHydroxyꢀ2ꢀmethylꢀ2,3ꢀdihydrobenzofuran (6d). The
yield was 50%, b.p. 101—104 C (1 Torr). Found (%): C, 71.61;
H, 6.66. C9H10O2. Calculated (%): C, 71.98; H, 6.71. 1H NMR,
: 1.42 (d, 3 H, CH(CH3)CH2, J = 6.0 Hz); 2.69 (m, 1 H,
1ꢀAllyloxyꢀ4ꢀmethoxybenzene (4d). The yield was 92%, b.p.
1
88—93 C (1 Torr) (cf. Ref. 25: b.p. 92 C (1 Torr)). H NMR,
: 3.73 (s, 3 H, OCH3); 4.43 (dt, 2 H, CH2CH=CH2, J = 5.4 Hz,
J = 1.2 Hz); 5.22 (dd, 1 H, CH2CH=CH2, J = 10.2 Hz,
J = 1.2 Hz); 5.35 (dd, 1 H, CH2CH=CH2, J = 17.4 Hz,
J = 1.2 Hz); 5.99 (m, 1 H, CH2CH=CH2); 6.74 (m, 4 H, ArH).
2ꢀAllylꢀ4ꢀethoxyꢀ6ꢀmethylphenol (5a). Compound 4a (12.20
g, 63 mmol) was stirred for 2 h at 200 C then distilled in vacuo
(1 Torr) to obtain compound 5a (10.72 g, 89%) as colorless light
liquid, b.p. 82—86 C. Found (%): C, 74.71; H, 8.23. C12H16O2.
Calculated (%): C, 74.97; H, 8.39. 1H NMR, : 1.36 (t, 3 H,
OCH2CH3, J = 7.2); 2.19 (s, 3 H, ArCH3); 3.33 (d, 2 H,
CH2CH=CH2, J = 6.6); 3.91 (q, 2 H, OCH2CH3, J = 7.2); 4.41
(s, 1 H, OH); 5.15 (m, 2 H, CH2CH=CH2); 5.95 (m, 1 H,
CH2CH=CH2); 6.43 (d, 1 H, ArH, J = 3.0); 6.50 (d, 1 H,
ArH, J = 3.0).

Sulfurꢀcontaining derivatives of ꢀtocopherol
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
1399
CH(CH3)CH2); 3.17 (m, 1 H, CH(CH3)CH2); 4.82 (m, 1 H,
CH(CH3)CH2); 5.78 (s, 1 H, OH); 6.24 (dd, 1 H, ArH, J = 8.4 Hz,
J = 2.4 Hz); 6.49 (d, 1 H, ArH, J = 8.4 Hz); 6.57 (d, 1 H, ArH,
J = 2.4 Hz).
(d, 3 H, CH(CH3)CH2, J = 6.0 Hz); 1.56 (m, 2 H,
SCH2CH2(CH2)9CH3); 2.08 (s, 3 H, ArCH3); 2.11 (s, 3 H,
ArCH3); 2.40 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.68 (m, 1 H,
CH(CH3)CH2); 3.18 (m, 1 H, CH(CH3)CH2); 3.73 (m, 2 H,
ArCH2SC12H25); 4.78 (m, 1 H, CH(CH3)CH2); 5.86 (s, 1 H, OH).
4,6ꢀBis(dodecylthiomethyl)ꢀ5ꢀhydroxyꢀ2ꢀmethylꢀ2,3ꢀdiꢀ
hydrobenzofuran (10d). Dodecyl (diethylaminomethyl) sulfide
(4.53 g, 15.8 mmol) was added to a solution of 6d (1.13 g,
7.5 mmol) in AcOH (6 mL), the reaction mixture was stirred for
2 h at 140 C then cooled, diluted with water (30 mL), and
treated with toluene (3×10 mL). The combined organic phase
were washed with 15% aq. NaOH (3×10 mL) and brine, dried
with Na2SO4. The solvent was evaporated to obtain a resin
(4.91 g), which were purified on a column with Al2O3 (5 degree
of activity, eluent light petroleum) to obtain a colorless resin
crystallizing on cooling, m.p. 44—46 C. Found (%): C, 72.46;
H, 10.91; S, 11.28. C35H62O2S2. Calculated (%): C, 72.60;
H, 10.79; S, 11.08. 1H NMR, : 0.88 (m, 6 H, [S(CH2)11CH3]2);
1.24—1.33 (m, 36 H, [S(CH2)2(CH2)9CH3]2); 1.43 (d, 3 H,
CH(CH3)CH2, J = 6.6 Hz); 1.53 (m, 4 H, [SCH2CH2ꢀ
(CH2)9CH3]2); 2.35 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.40
(t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.76 (m, 1 H, CH(CH3)CH2);
3.27 (m, 1 H, CH(CH3)CH2); 3.66 (m, 4 H, Ar[CH2SC12H25]2);
4.83 (m, 1 H, CH(CH3)CH2); 6.35 (s, 1 H, OH); 6.39
(s, 1 H, ArH).
6ꢀHydroxyꢀ5,8ꢀdimethylchromane (7c). Sodium borohydride
(2.27 g, 60 mmol) was added to a solution of 5c (5.16 g, 25 mmol)
in THF (35 mL), followed by a dropwise addition of Me2SO4
(3.15 g, 25.0 mmol). The mixture was stirred at room temperaꢀ
ture for 1 h, cooled to 3—5 C, and dropwise diluted with water
(9.5 mL). Then, the mixture was heated to room temperatures,
followed by a sequential dropwise addition of a 3 M aq. NaOH
(3.00 g, 75 mmol) (25 mL) and 23% aq. H2O2 (13.6 mL,
75 mmol). The reaction mixture was stirred for 2 h, neutralized
with aq. HCl and treated with toluene (3×80 mL). The comꢀ
bined organic phases were washed with brine and dried with
Na2SO4. The solvent was evaporated to obtain the product
4ꢀethoxyꢀ2ꢀ(3ꢀhydroxypropyl)ꢀ3,6ꢀdimethylphenol (5.61 g) as
a colorless crystalline substance.
Further, the product obtained (5.61 g) was refluxed with
46% aq. HBr (21 mL, 0.175 mol) for 3 h, cooled, and treated
with toluene (3×80 mL). The combined organic phases were
washed with brine and dried with Na2SO4. The solvent was
evaporated, the residue was recrystallized from light petroꢀ
leum to obtain colorless crystals (2.97 g) with m.p. 124—126 C
(cf. Ref. 29: m.p. 126—127 C). 1H NMR, : 1.98 (m, 2 H,
OCH2CH2CH2Ar); 2.02 (s, 3 H, ArCH3); 2.05 (s, 3 H, ArCH3);
2.61 (t, 2 H, OCH2CH2CH2Ar, J = 6.6 Hz); 4.04 (s, 1 H, OH);
4.06 (m, 2 H, OCH2CH2CH2Ar); 6.31 (s, 1 H, ArH).
6ꢀHydroxychromane (7d) was obtained similarly to 7c. The
yield was 62%, m.p. 98—100 C (cf. Ref. 30: m.p. 99—100 C),
b.p. 115—122 C (1 Torr). 1H NMR, : 1.94 (m, 2 H,
OCH2CH2CH2Ar); 2.67 (t, 2 H, OCH2CH2CH2Ar, J = 6.6 Hz);
4.07 (t, 2 H, OCH2CH2CH2Ar, J = 5.4 Hz); 5.39 (s, 1 H, OH);
6.39 (d, 1 H, ArH, J = 3.0 Hz); 6.46 (dd, 1 H, ArH, J = 8.4 Hz,
J = 3.0 Hz); 6.55 (d, 1 H, ArH, J = 8.4 Hz).
5ꢀMethoxyꢀ2ꢀmethylꢀ2,3ꢀdihydrobenzofuran (8d). A 46% aq.
HBr (4.5 mL, 37.5 mmol) was added to a solution of 5d (1.23 g,
7.5 mmol) in AcOH (95 mL), the mixture was refluxed for 1 h.
Then, AcOH was evaporated on a rotary evaporator, the residue
was dissolved in toluene (20 mL), washed with 20% aq. NaOH
(3×20 mL) and brine, dried with Na2SO4. The solvent was evapꢀ
orated to obtain the product (0.91 g, 74%) (CMC >97% accordꢀ
ing to GLC). Found (%): C, 73.22; H, 7.31. C10H12O2. Calcuꢀ
lated (%): C, 73.15; H, 7.35. 1H NMR, : 1.42 (d, 3 H,
CH(CH3)CH2, J = 6.0 Hz); 2.74 (m, 1 H, CH(CH3)CH2); 3.23
(m, 1 H, CH(CH3)CH2); 3.70 (s, 3 H, OCH3); 4.82 (m, 1 H,
CH(CH3)CH2); 6.53 (s, 2 H, ArH); 6.62 (s, 1 H, ArH).
7ꢀDodecylthiomethylꢀ6ꢀhydroxyꢀ5,8ꢀdimethylchromane (11c)
was obtained similarly to 10c based on hydroxychromane 7c.
The yield was 90%, m.p. 49.5—51.5 C. Found (%): C, 73.04;
H, 10.15; S, 8.32. C24H40O2S. Calculated (%): C, 73.42; H, 10.27;
1
S, 8.17. H NMR, : 0.90 (t, 3 H, S(CH2)11CH3, J = 7.2 Hz);
1.25—1.35 (m, 18 H, S(CH2)2(CH2)9CH3); 1.56 (m, 2 H,
SCH2CH2(CH2)CH3); 1.98 (m, 2 H, CH2CH2CH2); 2.07
(s, 3 H, ArCH3); 2.10 (s, 3 H, ArCH3); 2.40 (t, 2 H, SCH2C11H23
,
J = 7.2 Hz); 2.62 (t, 2 H, CH2CH2CH2, J = 7.2 Hz); 3.76 (s, 2 H,
ArCH2SC12H25); 4.06 (t, 2 H, CH2CH2CH2, J = 5.4 Hz); 5.89
(s, 1 H, OH).
5,7ꢀBis(dodecylthiomethyl)ꢀ6ꢀhydroxychromane (11d) was
obtained similarly to 10d based on hydroxychromane 7d. The
yield was 76%, m.p. 44—46 C. Found (%): C, 72.69; H, 10.97,
S, 11.37. C35H62O2S2. Calculated (%): C, 72.60; H, 10.79, S,
11.08. 1H NMR, : 0.88 (m, 6 H, [S(CH2)11CH3]2); 1.24—1.33
(m, 36 H, [S(CH2)2(CH2)9CH3]2); 1.51—1.57 (m, 4 H,
[SCH2CH2(CH2)9CH3]2); 1.99 (m, 2 H, OCH2CH2CH2Ar);
2.34 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.44 (t, 2 H,
SCH2C11H23, J = 7.2 Hz); 2.78 (t, 2 H, OCH2CH2CH2Ar,
J = 6.6 Hz); 3.66 (s, 2 H, ArCH2SC12H25); 3.68 (s, 2 H,
ArCH2SC12H25); 4.04 (t, 2 H, OCH2CH2CH2Ar, J = 5.4 Hz);
6.39 (s, 1 H, OH); 6.43 (s,1 H, ArH).
6ꢀDodecylthiomethylꢀ5ꢀhydroxyꢀ2,4,7ꢀtrimethylꢀ2,3ꢀdiꢀ
hydrobenzofuran (10c). Dodecyl (diethylaminomethyl) sulfide
(1.58 g, 5.5 mmol) was added to a solution of 6c (0.89 g,
5.0 mmol) in AcOH (2.5 mL), the mixture was stirred for 2 h at
140 C and cooled, followed by the addition of water (30 mL)
and treatment with toluene (3×10 mL). The combined organic
phases were washed with 15% aq. NaOH (3×10 mL) and brine,
dried with Na2SO4. The solvent was evaporated to obtain a resin
(1.95g), which was purified on a column with Al2O3 (5 degree of
activity, eluent light petroleum) to obtain a colorless resin (1.73 g,
88%) crystallizing on cooling, m.p. 32—33 C. Found (%):
C, 73.21; H, 10.07; S, 8.29. C24H40O2S. Calculated (%): C, 73.42;
H, 10.27; S, 8.17. 1H NMR, : 0.88 (t, 3 H, S(CH2)11CH3,
J = 7.2 Hz); 1.25—1.35 (m, 18 H, S(CH2)2(CH2)9CH3); 1.43
This work was financially supported by the City Counꢀ
cil of Novosibirsk (Grant No. 47ꢀ12).
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Received December 3, 2012;
in revised form April 4, 2013