5-Hydroxy-2,3-dihydrobenzofuran-derived polyfunctional antioxidants: 1. Synthesis of 2-dodecylthiomethyl-5-hydroxy-2,3-dihydrobenzofurans

Article abstract of DOI:10.1007/s11172-017-1850-4

2-Dodecylthiomethyl-5-hydroxy-2,3-dihydrobenzofurans, new sulfur-containing analogs of tocopherols, were synthesized based on methylphenols through the intermediate preparation of 4-alkoxy-2-allylphenols and then 5-alkoxy-2-iodomethyl-2,3-dihydrobenzofura

Full text of DOI:10.1007/s11172-017-1850-4

Russian Chemical Bulletin, International Edition, Vol. 66, No. 6, pp. 1024—1029, June, 2017
1024
5-Hydroxy-2,3-dihydrobenzofuran-derived polyfunctional antioxidants
1. Synthesis of 2-dodecylthiomethyl-5-hydroxy-2,3-dihydrobenzofurans
S. E. Yagunov,a S. V. Kholshin,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. E-mail: syagunov@yandex.ru
bNovosibirsk Institute of Antioxidants,
54a ul. Krasnyi prospekt, 630091 Novosibirsk, Russian Federation.
Fax: +7 (383) 217 0781
2-Dodecylthiomethyl-5-hydroxy-2,3-dihydrobenzofurans, new sulfur-containing analogs
of tocopherols, were synthesized based on methylphenols through the intermediate preparation
of 4-alkoxy-2-allylphenols and then 5-alkoxy-2-iodomethyl-2,3-dihydrobenzofurans.
Key words: 5-hydroxy-2,3-dihydrobenzofurans, sulfur-containing antioxidants, iodo-
cyclization.
Natural polyphenols and their derivatives (tocopherols,
5-hydroxy-2,3-dihydrobenzofuran thio derivatives, in the
structure of which the oxygen atom in the heterocycle is
replaced with a sulfur atom,3,4 as well as alkylthio-sub-
stituted tocopherols5 and alkylthiomethyl-substituted
flavonoids.6
hydroxycoumarans, flavonoids, etc.) play a key role in
maintaining the redox-homeostasis of living organisms
and in protection of cell structures from damaging effect
of activated oxygen metabolites.1,2 Functionalization of
the named compounds with sulfur-containing groups is
regarded by many researches as a promising way for devel-
opment of bioantioxidants with polyfunctional mode of
antioxidant action for the use in biology and medicine.
Thus, in the literature there are described methods for the
synthesis and antioxidant properties of -tocopherol and
Earlier, we have obtained dodecylthiomethyl-substi-
tuted 5-hydroxy-2,3-dihydrobenzofurans A and B and
showed that these compounds considerably exceed
-tocopherol in their ability to inhibit autooxidation of
methyl oleate.7 At the same time, it is known that the
presence of thioalkyl substituents at ortho-positions relative
to the phenol OH group can lead to the decrease in the
activity of the latter in the reactions with active radicals
because of the formation of the O—H∙∙∙S hydrogen bond.8,9
In this connection, the present work is devoted to the
synthesis of structural analogs of compounds A and B with
a dodecylthiomethyl substituent remote from the phenol
OH group, namely, 2-dodecylthiomethyl-5-hydroxy-2,3-
dihydrobenzofurans 1a—e.
Results and Discussion
The synthesis of the target compounds 1a—e was car-
ried out based on methylphenols through the intermediate
preparation of 4-alkoxy-2-allylphenols 2a—e (Scheme 1);
allylphenol 2a was obtained from 2,6-dimethylphenol by
a sequence of transformations shown in Scheme 2. The
synthesis of allylphenols 2b—e was described earlier in
our work.7
Iodocyclization of compounds 2 initially was carried
out according to the procedure described earlier10 in the
presence of Na2CO3. In this case, the yields of the target
iodo derivatives 6 were 65—75%. Later, we obtained com-
1
a
b
c
d
e
R1
Me
Me
H
R2
Me
H
Me
H
H
R3
H
Me
Me
Me
H
H
H
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1024—1029, June, 2017.
1066-5285/17/6606-1024 © 2017 Springer Science+Business Media, Inc.

S-Containing analogues of tocopherols
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1025
Scheme 1
pounds 6 in higher yields (87—93%) by carrying out iodo-
cyclization of compounds 2 with a larger excess of I2 in O2
atmosphere and in the absence of bases.
The reaction of compounds 6 with dodecanthiol was
carried out under conditions suggested earlier for the syn-
thesis of nonsymmetrical sulfides based on 4-(3-bromo-
propyl)-2,6-dimethylphenol,11 that allowed us to obtain
thio derivatives 7 in good yields (77—90%).
The attempts to convert benzofurans 7 to the target
compounds 1 upon treatment with HBr under conditions
used for the transformation of 2-ethoxyphenols to the
corresponding alkylpyrocatechols12 in good yields were
unsuccessful: the reaction led to the formation of a large
number of side products and resinification of the reaction
mixture. The application of BBr3, yet another reagent
widely used for selective cleavage of phenyl alkyl ethers,
turned out to be more efficient. The search of conditions
for the transformation of benzofurans 7 to compounds 1
was carried out on a model compound 7e. The reaction of
7e with BBr3 under conditions described in the work13 led
not only to the O-dealkylation of 7e, but also to the ring
opening with the formation of 2-[2-bromo-3-(dodecylthio)-
propyl]hydroquinone (8) (Scheme 3). The conversion of
hydroquinone 8 to the target benzofuran 1e required
a "recyclization", which initially was carried out by the
reflux with K2CO3 in acetone.14,15 Under these conditions,
the synthesis of 1e was accompanied by the formation of
side products; after a complete conversion of 8 the content
of 1e in the reaction mixture, according to the HPLC and
GC/MS data, did not exceed 85%. At the same time, we
made an observation that compound 8 upon storage
gradually loses HBr and converts to compound 1e. Taking
into account this fact, we tested a thermal version of the
cyclization: after the reflux of a solution of compound 8 in
toluene for 2 h, the HPLC and GC/MS data showed that
the content of 1e in the reaction mixture reached 98%.
R4 = Et (a—d), Me (e)
Reagents and conditions: i. I2, MeCN, ~20 C; ii. C12H25SH,
NaOH, EtOH, 60 C; iii. BBr3, DCM, ~20 C; iv. PhMe, .
Scheme 2
Scheme 3
Reagents and conditions: i. C6H12N4, AcOH, H2O; ii. EtI, K2CO3,
; iii. H2O2, HCOOH, DCM, ; iv. NaOH, EtOH, ~20 C;
v. C3H5Br, NaOH, DMF; vi. 200—220 C.
Reagents and conditions: ii. BBr3, DCM, ~20 C; ii. PhMe, .

1026
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Yagunov et al.
4-Hydroxy-3,5-dimethylbenzaldehyde (3) was obtained ac-
cording to the known procedure.17 A solution of 2,6-dimethyl-
phenol (45.8 g, 0.375 mol), urotropine (105.2 g, 0.75 mol) in
a mixture of AcOH (640 mL) and H2O (140 mL) was re-
fluxed for 4 h, cooled to room temperature, and poured into
water (4 L). A precipitate formed (44.1 g) was separated and
recrystallized from PhMe (180 mL) to obtain compound 3
(39.8 g, 70%) as colorless crystals with m.p. 115.5—117 C
(cf. Ref. 17: 109—112 C). Found (%): C, 72.09; H, 6.64. C9H10O2.
Calculated (%): C, 71.98; H, 6.71. UV, λmax/nm (log): 230 (4.32),
292 (4.20). IR, ν/cm–1: 3598 (OH), 1684 (C=O). 1H NMR,
: 2.30 (s, 6 H, ArCH3); 5.40 (br.s, 1 H, ArOH); 7.48 (s, 2 H,
ArH); 9.75 (s, 1 H, C(O)H). MS (EI, 70 eV), m/z (Irel (%)):
150 [M]+ (70), 149 [M – H]+ (100), 121 [M – H – CO]+ (16),
91 (27), 77 (27).
In the preparation of compounds 1a—d, the products of
the reaction of alkoxy derivatives 7a—d with BBr3 were
involved in the thermal cyclization without additional
purification.
It is obvious that the approach to the synthesis of sulfur-
containing benzofurans 1a—e suggested in the present work
can be also used for the preparation of their structural
analogs containing additional functional groups in the
alkylthiomethyl substituent. Thus, we used compound 6e
to obtain a thiopropionic acid derivative 10, which is
a hydrophilic analog of compound 1e (Scheme 4).
Scheme 4
4-Ethoxy-3,5-dimethylbenzaldehyde (4). Anhydrous K2CO3
(22.1 g, 0.16 mol) was added to a solution of benzaldehyde 3
(30.0 g, 0.2 mol) and EtI (48.4 g, 0.31 mol) in EtOH (160 mL)
and the mixture was refluxed for 4 h. Then, the solvent was
evaporated on a rotary evaporator, toluene (100 mL) and water
(50 mL) were added to the residue, the aqueous layer was sepa-
rated and treated with toluene (3×20 mL). The organic phases
were combined, washed with 5% aqueous solution of NaOH
(3×50 mL), water (3×50 mL), and a saturated solution of NaCl,
then dried with Na2SO4. The solvent was evaporated and the
residue was distilled in vacuo to obtain the product (33.4 g, 93%)
as a colorless light liquid, b.p. 91—94 C (1 Torr). Found (%):
C, 74.31; H, 8.02. C11H14O2. Calculated (%): C, 74.13; H, 7.92.
UV, λmax/nm (log): 267 (4.10). IR, ν/cm–1: 1698 (C=O).
1H NMR, : 1.42 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.29 (s, 6 H,
ArCH3); 3.85 (q, 2 H, OCH2CH3, J = 7.2 Hz); 7.46
(s, 2 H, ArH); 9.79 (s, 1 H, C(O)H). MS (EI, 70 eV), m/z (Irel (%)):
178 [M]+ (54), 149 [M – Et]+ (100), 121 [M – Et – CO]+ (11).
4-Ethoxy-3,5-dimethylphenol (5) was obtained according to
the known procedure.18 A mixture of benzaldehyde 4 (82.8 g,
0.465 mol), formic acid (98 mL, 91%, 2.34 mol), H2O2 (133 mL,
33%, 1.45 mol), and DCM (2.35 L) was refluxed for 15 h.
Then, the reflux condenser was replaced with a Liebig one
and DCM was distilled off from the reaction mixture, followed
by the addition of EtOH (1 L) and a solution of NaOH (113 g,
2.83 mol) in water (1.9 L) with cooling. The mixture was
stirred at room temperature for 1 h, EtOH was evaporated. The
mixture was acidified with aqueous HCl, extracted with DCM
(3×150 mL), washed with aqueous NaCl, and dried with Na2SO4.
The solvent was evaporated, the residue was distilled in vacuo,
the main fraction was crystallized from a mixture of light petro-
leum ether (120 mL) and toluene (100 mL) to obtain compound
5 (63.4 g, 82%) as colorless crystals, m.p. 84.5—86 C, with b.p.
113—116 C (1 Torr). Found (%): C, 72.61; H, 8.37. C10H14O2.
Calculated (%): C, 72.26; H, 8.49. UV, λmax/nm (log): 282
(3.43). IR, ν/cm–1: 3615 (OH). 1H NMR, : 1.37 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 2.17 (s, 6 H, ArCH3); 3.73 (q, 2 H,
OCH2CH3, J = 7.2 Hz); 4.70 (br.s, 1 H, ArOH); 6.34 (s, 2 H,
ArH). MS (EI, 70 eV), m/z (Irel (%)): 166 [M]+ (54), 137
[M – Et]+ (100), 123 (16), 109 (12).
Reagents and conditions: i. HSCH2CH2COOH, NaOH, EtOH,
60 C; ii. BBr3, DCM, ~20 C; iii. PhMe, .
Experimental
Commercially available reagents and solvent used in the
work were purchased from Sigma-Aldrich, Merck, and Reakhim.
Solvents before use were purified and dried according to the
standard procedures.16
1H NMR spectra were recorded on a Bruker DRX 600 spec-
trometer (600 MHz) in CDCl3 (for compounds 1—9) and
DMSO-d6 (for compound 10). IR spectra were recorded on an
Agilent Cary 600 Series FTIR spectrometer for solutions with
a concentration of (1.5—2.5)•10–2 mol L–1 in CCl4 (for com-
pounds 1, 2, 4—7), in a mixture of CHCl3—CCl4 (1 : 1, for
compound 8), in CHCl3 (for compounds 3 and 9) in 0.5-mm
thick cells with KBr and in KBr pellets (for compound 10). UV
spectra were recorded on a Shimadzu UV-1800 spectrometer in
solution of EtOH. GC analysis was carried out on an Agilent
7820A chromatograph (HP-5, 30 m×0.25 mm and HP-FFAP,
50 m×0.32 mm; carrier gas nitrogen), HPLC was performed on
an Agilent Infinity 1220 chromatograph (ZORBAX SB-C18,
5 m, 150×4.6 mm), GC/MS analysis was carried out on an
Agilent 7890B chromatograph (HP-5MS UI, 30 m×0.25 mm,
carrier gas helium) with an Agilent 5977A mass detector (EI,
70 eV). The peaks of ions with  10% intensity including the most
abundant isotopes are reported in the description of mass spectra.
Silufol plates (UV 254) were used for TLC. Melting points were
measured in a capillary tube on a MP50 Mettler Toledo heating
stage (the rate of heating 0.5 C min–1). All the reaction, if not
stated otherwise, were carried out under inert atmosphere and in
anhydrous solvents.
1-Allyloxy-4-ethoxy-3,5-dimethylbenzene. A reaction of
phenol 5 (24.9 g, 0.15 mol), allyl bromide (36.3 g, 0.3 mol), NaOH
(6.6 g, 0.165 mol) in DMF (270 mL), according to the known
procedure,19 gave 1-allyloxy-4-ethoxy-3,5-dimethylbenzene
(28.3 g, 92%), b.p. 113—114 C (1 Torr). Found (%): C, 74.94;
H, 8.31. C13H18O2. Calculated (%): C, 75.69; H, 8.80. UV,
λmax/nm (log): 280 (3.66). 1H NMR, : 1.37 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 2.21 (s, 6 H, ArCH3); 3.73 (q, 2 H, OCH2CH3,

S-Containing analogues of tocopherols
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1027
J = 7.2 Hz); 4.41 (dt, 2 H, CH2CH=CH2, J = 5.4 Hz, J = 1.8 Hz);
5.21 (dq, 1 H, CH2CH=CH2 J = 10.8 Hz, J = 1.8 Hz); 5.34 (dq,
1 H, CH2CH=CH2 J = 17.4 Hz, J = 1.8 Hz); 5.98 (m, 1 H,
CH2CH=CH2); 6.45 (s, 2 H, ArH). MS (EI, 70 eV), m/z
(Irel (%)): 206 [M]+ (31), 165 [M – C3H5]+ (18), 137 [M – C3H5 –
– C2H4]+ (100).
J = 7.2 Hz); 2.13 (s, 3 H, ArCH3); 2.99 (m, 1 H, H(3)); 3.23
(m, 1 H, CH2I); 3.34 (m, 1 H, H(3)); 3.41 (m, 1 H, CH2I); 3.88
(q, 2 H, OCH2CH3, J = 7.2 Hz); 4.81 (m, 1 H, H(2)); 6.39
(d, 1 H, H(6), J = 1.8 Hz); 6.45 (d, 1 H, H(4), J = 1.8 Hz). MS
(EI, 70 eV), m/z (Irel (%)): 318 [M]+ (100), 191 [M – I]+ (33),
163 [M – C2H4 – I]+ (30), 161 [M – Et – HI]+ (18), 148 (14),
135 (24).
2-Allyl-4-ethoxy-3,5-dimethylphenol (2a). 1-Allyloxy-4-
ethoxy-3,5-dimethylbenzene (28.3 g) was stirred for 3 h at
200—220 C, then distilled in vacuo and crystallized from hexane
(40 mL) to obtain product 2a (25.9 g, 84%), m.p. 95.5—96.5 C,
with b.p. 119—121 °C (1 Torr). Found (%): C, 76.12; H, 8.92.
C13H18O2. Calculated (%): C, 75.69; H, 8.80. UV, λmax/nm (log):
2-Iodomethyl-5-methoxy-2,3-dihydrobenzofuran (6e). The
yield was 87%. M.p. 62.0—63.3 C. Found (%): C, 41.49; H, 3.77;
I, 43.94. C10H11IO2. Calculated (%): C, 41.40; H, 3.82; I, 43.75.
1
UV, λmax/nm (log): 229 (3.87), 299 (3.63). H NMR, : 3.01
(m, 1 H, H(3)); 3.23 (m, 1 H, CH2I); 3.34 (m, 1 H, H(3)); 3.39
(m, 1 H, CH2I); 3.70 (s, 3 H, OCH3); 4.82 (m, 1 H, H(2)); 6.55
(dd, 1 H, H(6), J = 7.8 Hz, J = 2.4 Hz); 6.57 (d, 1 H, H(7),
J = 7.8 Hz); 6.64 (d, 1 H, H(4), J = 2.4 Hz). MS (EI, 70 eV),
m/z (Irel (%)): 290 [M]+ (100), 163 [M – I]+ (46), 148 [M – Me –
– I]+ (11), 135 (22), 131 (12).
1
287 (3.49). IR, ν/cm–1: 3616 (OH). H NMR, : 1.38 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 2.16 (s, 3 H, ArCH3); 2.17 (s, 3 H,
ArCH3); 3.33 (dt, 2 H, CH2CH=CH2, J = 5.4 Hz, J = 1.8 Hz);
3.71 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.57 (s, 1 H, ArOH); 4.94
(dq, 1 H, CH2CH=CH2, J = 16.8 Hz, J = 1.8 Hz); 4.99 (dq, 1 H,
CH2CH=CH2, J = 10.2 Hz, J = 1.8 Hz); 5.88 (m, 1 H,
CH2CH=CH2); 6.36 (s, 1 H, ArH). MS (EI, 70 eV), m/z
(Irel (%)): 206 [M]+ (58), 177 [M – Et]+ (100), 163 (15), 121 (12).
5-Ethoxy-2-iodomethyl-4,6-dimethyl-2,3-dihydrobenzofuran
(6a). A solution of I2 (3.80 g, 15 mmol) and compound 2a (1.55 g,
7.5 mmol) in MeCN (50 mL) was stirred for 48 h at ~20 C in
O2 atmosphere; MeCN was evaporated on a rotary evaporator,
the residue was dissolved in DCM (15 mL), washed with aqueous
solution of Na2S2O3, and dried with Na2SO4, the solvent was
evaporated. Compound 6a (2.22 g, 89%) was obtained as light
yellow crystals (with purity >99% by GC), m.p. 52.5—54.5 C.
Found (%): C, 46.31; H, 5.22; I, 37.54. C13H17IO2. Calcul-
ated (%): C, 47.00; H, 5.16; I, 38.20. UV, λmax/nm (log):
2-Dodecylthiomethyl-5-ethoxy-4,6-dimethyl-2,3-dihydro-
benzofuran (7a). Sodium hydroxide (0.063 g, 1.58 mmol) was
added to a solution of C12H25SH (0.32 g, 1.58 mmol) in EtOH
(1.5 mL). The mixture was stirred for 0.5 h at 60 C, then cooled
to 40 C, followed by the addition of a solution of 6a (0.50 g,
1.50 mmol) in EtOH (1.5 mL) and stirring for 2 h at 40 C. The
reaction mixture was cooled, acidified with aqueous solution of
HCl, and extracted with toluene (3×20 mL). The organic phase
was washed with aqueous solution of NaCl and dried with
Na2SO4, the solvent was evaporated, the residue was purified on
a SiO2 plate (eluent a mixture of toluene—hexane (2 : 3))
to obtain the product (0.50 g, 82%). M.p. 35.5—36.5 C.
Found (%): C, 72.29; H, 10.54; S, 8.01. C25H42O2S. Calculated (%):
C, 73.84; H, 10.41; S, 7.88. UV, λmax/nm (log): 291 (3.56).
1H NMR, : 0.88 (t, 3 H, S(CH2)11CH3, J = 7.2 Hz); 1.25—1.31
(m, 18 H, S(CH2)2(CH2)9CH3); 1.37 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 1.57 (m, 2 H, SCH2CH2); 2.12 (s, 3 H, ArCH3); 2.17
(s, 3 H, ArCH3); 2.55 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.65
(m, 1 H, CH2SC12H25); 2.83 (m, 1 H, CH2SC12H25); 2.88 (m,
1 H, H(3)); 3.16 (m, 1 H, H(3)); 3.71 (q, 2 H, OCH2CH3,
J = 7.2 Hz); 4.80 (m, 1 H, H(2)); 6.30 (s, 1 H, H(7)). MS (EI,
1
290 (3.56). H NMR, : 1.37 (t, 3 H, OCH2CH3, J = 7.2 Hz);
2.13 (s, 3 H, ArCH3); 2.18 (s, 3 H, ArCH3); 2.87 (m, 1 H, H(3));
3.19—3.26 (m, 2 H, H(3) + CH2I); 3.39 (m, 1 H, CH2I);
3.70 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.83 (m, 1 H, H(2));
6.32 (s, 1 H, H(7)). MS (EI, 70 eV), m/z (Irel (%)): 332 [M]+
(100), 303 [M – Et]+ (96), 175 [M – Et – HI]+ (57), 161 (36),
133 (16).
Compounds 6b—e were obtained similarly to iodo deriv-
ative 6a.
70 eV), m/z (Irel (%)): 406 [M]+ (80), 377 [M – Et]+ (14), 191
+
5-Ethoxy-2-iodomethyl-4,7-dimethyl-2,3-dihydrobenzofuran
(6b). The yield was 93%. M.p. 61.0—63.0 C. Found (%):
C, 47.34; H, 5.24; I, 37.88. C13H17IO2. Calculated (%): C, 47.00;
[M – CH2SC12H25
163 (12).
]
(14), 175 [M – Et – C12H25SH]+ (100),
Compounds 7b—e were obtained similarly to benzofuran 7a.
2-Dodecylthiomethyl-5-ethoxy-4,7-dimethyl-2,3-dihydro-
benzofuran (7b). The yield was 90%. M.p. 46.7—48.5 C.
Found (%): C, 73.38; H, 10.36; S, 7.81. C25H42O2S. Calculated (%):
C, 73.84; H, 10.41; S, 7.88. UV, λmax/nm (log): 295 (3.60).
1H NMR, : 0.88 (t, 3 H, S(CH2)11CH3, J = 7.2 Hz); 1.25—1.31
(m, 18 H, S(CH2)2(CH2)9CH3); 1.37 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 1.58 (m, 2 H, SCH2CH2); 2.04 (s, 3 H, ArCH3);
2.09 (s, 3 H, ArCH3); 2.57 (t, 2 H, SCH2C11H23, J = 7.2 Hz);
2.66 (m, 1 H, CH2SC12H25); 2.85 (m, 1 H, CH2SC12H25); 2.91
(m, 1 H, H(3)); 3.20 (m, 1 H, H(3)); 3.88 (q, 2 H, OCH2CH3,
J = 7.2 Hz); 4.80 (m, 1 H, H(2)); 6.31 (s, 1 H, H(6)). MS (EI,
70 eV), m/z (Irel (%)): 406 [M]+ (100), 204 [M – C12H25SH]+
(27), 191 [M – CH2SC12H25]+ (26), 175 [M – Et – C12H25SH]+
(38), 163 (13).
1
H, 5.16; I, 38.20. UV, λmax/nm (log): 294 (3.58). H NMR, :
1.44 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.13 (s, 3 H, ArCH3); 2.18
(s, 3 H, ArCH3); 2.98 (m, 1 H, H(3)); 3.30 (m, 1 H, CH2I); 3.35
(m, 1 H, H(3)); 3.49 (m, 1 H, CH2I); 3.96 (q, 2 H, OCH2CH3,
J = 7.2 Hz); 4.90 (m, 1 H, H(2)); 6.42 (s, 1 H, H(6)). MS (EI,
70 eV), m/z (Irel (%)): 332 [M]+ (100), 303 [M – Et]+ (25), 205
[M – I]+ (21), 175 [M – Et – HI]+ (35), 161 (19), 149 (13), 131 (11).
5-Ethoxy-2-iodomethyl-6,7-dimethyl-2,3-dihydrobenzofuran
(6c). The yield was 91%. M.p. 48.3—50.3 C. Found (%):
C, 47.29; H, 5.11; I, 38.71. C13H17IO2. Calculated (%): C, 47.00;
1
H, 5.16; I, 38.20. UV, λmax/nm (log): 296 (3.63). H NMR, :
1.39 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.08 (s, 3 H, ArCH3); 2.09
(s, 3 H, ArCH3); 2.99 (m, 1 H, H(3)); 3.23 (m, 1 H, CH2I); 3.34
(m, 1 H, H(3)); 3.41 (m, 1 H, CH2I); 3.89 (q, 2 H, OCH2CH3,
J = 7.2 Hz); 4.80 (m, 1 H, H(2)); 6.47 (s, 1 H, H(4)). MS (EI,
70 eV), m/z (Irel (%)): 332 [M]+ (100), 303 [M – Et]+ (18), 205
[M – I]+ (21), 176 [M – Et – I]+ (34), 161 (25), 131 (13).
5-Ethoxy-2-iodomethyl-7-methyl-2,3-dihydrobenzofuran (6d).
The yield was 92%. Found (%): C, 45.11; H, 4.87; I, 40.13.
C12H15IO2. Calculated (%): C, 45.30; H, 4.75; I, 39.89. UV,
λmax/nm (log): 297 (3.60). 1H NMR, : 1.35 (t, 3 H, OCH2CH3,
2-Dodecylthiomethyl-5-ethoxy-6,7-dimethyl-2,3-dihydro-
benzofuran (7c). The yield was 82%. M.p. 41.5—43.0 C.
Found (%): C, 73.62; H, 10.32; S, 7.69. C25H42O2S. Calcul-
ated (%): C, 73.84; H, 10.41; S, 7.88. UV, λmax/nm (log): 297
1
(3.66). H NMR, : 0.89 (t, 3 H, S(CH2)11CH3, J = 7.2 Hz);
1.25—1.31 (m, 18 H, S(CH2)2(CH2)9CH3); 1.37 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 1.58 (m, 2 H, SCH2CH2); 2.05 (s, 3 H,

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Yagunov et al.
ArCH3); 2.06 (s, 3 H, ArCH3); 2.56 (t, 2 H, SCH2C11H23,
J = 7.2 Hz); 2.64 (m, 1 H, CH2SC12H25); 2.83 (m, 1 H,
CH2SC12H25); 2.98 (m, 1 H, H(3)); 3.25 (m, 1 H, H(3)); 3.87
(q, 2 H, OCH2CH3, J = 7.2 Hz); 4.77 (m, 1 H, H(2)); 6.45 (s, 1 H,
product (1.03 g, 77%) with m.p. 103.9—104.9 C. Found (%):
C, 58.25; H, 5.97; S, 12.13. C13H16O4S. Calculated (%): C, 58.19;
H, 6.01; S, 11.95. UV, λmax/nm (log): 230 (3.90), 300 (3.65). IR,
1
ν/cm–1: 1713 (C=O). H NMR, : 2.66 (t, 2 H, CH2COOH,
H(4)). MS (EI, 70 eV), m/z (Irel (%)): 406 [M]+ (100), 204
J = 7.2 Hz); 2.75 (m, 1 H, CH2SCH2CH2COOH); 2.84—2.89
(m, 3 H, CH2CH2COOH, CH2SCH2CH2COOH); 3.01 (m, 1 H,
H(3)); 3.27 (m, 1 H, H(3)); 3.71 (s, 3 H, OCH3); 4.86 (m, 1 H,
H(2)); 6.55 (dd, 1 H, H(6), J = 8.4 Hz, J = 2.4 Hz); 6.58 (d, 1 H,
H(7), J = 8.4 Hz); 6.65 (d, 1 H, H(4), J = 2.4 Hz).
+
[M – C12H25SH]+ (30), 191 [M – CH2SC12H25
[M – Et – C12H25SH]+ (31), 163 (12).
]
(22), 175
2-Dodecylthiomethyl-5-ethoxy-7-methyl-2,3-dihydrobenzo-
furan (7d). The yield was 77%. Found (%): C, 74.09; H, 10.35;
S, 8.08. C24H40O2S. Calculated (%): C, 73.42; H, 10.27; S, 8.17.
2-Dodecylthiomethyl-5-hydroxy-4,6-dimethyl-2,3-dihydro-
benzofuran (1a). The reagent BBr3 (0.145 mL, 1.50 mmol) dis-
solved in DCM (1 mL) was added to a solution of 7a (209 mg,
0.514 mmol) in DCM (4.5 mL) cooled to –10 C. After 0.5 h,
the cooling was removed and the mixture was stirred for 12 h at
room temperature. After addition of distilled water (2 mL), the
mixture was stirred for 20 min and diluted with DCM (20 mL).
The organic phase was separated, washed with water, and dried
with Na2SO4. The solvent was evaporated, the residue was dis-
solved in toluene (50 mL) and refluxed for 2 h. Toluene was
evaporated, the residue was purified on a column with SiO2 (elu-
ent 12% EtOAc in hexane) and crystallized from MeCN (5 mL)
to obtain compound 1a (150 mg, 79%). M.p. 75.8—76.6 C.
Found (%): C, 72.32; H, 10.27; S, 8.38. C23H38O2S. Calcul-
ated (%): C, 72.96; H, 10.12; S, 8.47. UV, λmax/nm (log): 296
(3.62). IR, ν/cm–1: 3624 (OH). 1H NMR, : 0.88 (t, 3 H,
S(CH2)11CH3, J = 7.2 Hz); 1.25—1.38 (m, 18 H, S(CH2)2-
(CH2)9CH3); 1.56 (m, 2 H, SCH2CH2); 2.11 (s, 3 H, ArCH3);
2.16 (s, 3 H, ArCH3); 2.55 (t, 2 H, SCH2C11H23, J = 7.2 Hz);
2.65 (m, 1 H, CH2SC12H25); 2.82 (m, 1 H, CH2SC12H25); 2.91
(m, 1 H, H(3)); 3.19 (m, 1 H, H(3)); 3.96 (s, 1 H, ArOH); 4.79
(m, 1 H, H(2)); 6.29 (s, 1 H, H(7)). MS (EI, 70 eV), m/z
(Irel (%)): 378 [M]+ (100), 176 [M – C12H25SH]+ (83), 163
[M – C12H25SCH2]+ (90), 135 (22).
1
UV, λmax/nm (log): 234 (3.58), 299 (3.61). H NMR, : 0.88
(t, 3 H, S(CH2)11CH3, J = 7.2 Hz); 1.25—1.30 (m, 18 H,
S(CH2)2(CH2)9CH3); 1.35 (t, 3 H, OCH2CH3, J = 7.2 Hz); 1.58
(m, 2 H, SCH2CH2); 2.12 (s, 3 H, ArCH3); 2.56 (t, 2 H,
SCH2C11H23, J = 7.2 Hz); 2.66 (m, 1 H, CH2SC12H25); 2.84
(m, 1 H, CH2SC12H25); 2.99 (m, 1 H, H(3)); 3.26 (m, 1 H, H(3));
3.87 (q, 2 H, OCH2CH3, J = 7.2 Hz); 4.80 (m, 1 H, H(2)); 6.36
(d, 1 H, H(6), J = 1.8 Hz); 6.45 (d, 1 H, H(4), J = 1.8 Hz). MS
(EI, 70 eV), m/z (Irel (%)): 392 [M]+ (100), 190 [M – C12H25SH]+
(69), 177 [M – CH2SC12H25]+ (44), 161 [M – Et – C12H25SH]+
(40), 149 (21).
2-Dodecylthiomethyl-5-methoxy-2,3-dihydrobenzofuran (7e).
The yield was 80%. M.p. 40.0—41.4 C. Found (%): C, 71.87;
H, 10.03; S, 8.92. C22H36O2S. Calculated (%): C, 72.48; H, 9.95;
1
S, 8.79. UV, λmax/nm (log): 230 (3.84), 300 (3.62). H 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); 1.57 (m, 2 H, SCH2CH2); 2.55 (t, 2 H,
SCH2C11H23, J = 7.2 Hz); 2.67 (m, 1 H, CH2SC12H25); 2.83
(m, 1 H, CH2SC12H25); 3.01 (m, 1 H, H(3)); 3.27 (m, 1 H, H(3));
3.70 (s, 3 H, OMe); 4.82 (m, 1 H, H(2)); 6.54 (dd, 1 H, H(6),
J = 7.8 Hz, J = 2.4 Hz); 6.56 (d, 1 H, H(7), J = 7.8 Hz); 6.65
(d, 1 H, H(4), J = 2.4 Hz). MS (EI, 70 eV), m/z (Irel (%)): 364
[M]+ (100), 162 [M – C12H25SH]+ (84), 149 [M – C12H25SCH2]+
(73), 137 (12), 121 (16).
Compounds 1b—e and 10 were obtained similarly to benzo-
furan 1a.
2-[2-Bromo-3-(dodecylthio)propyl]hydroquinone (8). The
reagent BBr3 (0.57 mL, 6.0 mmol) dissolved in DCM (5 mL) was
added to a solution of compound 6e (0.73 g, 2.0 mmol) in DCM
(15 mL) cooled to –10 C. The cooling was removed after 0.5 h
and the mixture was stirred at room temperature for 12 h. Then
water (10 mL) was added, the mixture was stirred for 20 min and
diluted with DCM (20 mL). The organic phase was separated,
washed with water, and dried with Na2SO4. The solvent was
evaporated, the residue was dried in vacuo (1 Torr) to obtain the
product (0.84 g, 98%). UV, λmax/nm (log): 299 (3.62). IR,
2-Dodecylthiomethyl-5-hydroxy-4,7-dimethyl-2,3-dihydro-
benzofuran (1b) was purified on a column with SiO2 (eluent 15%
EtOAc in hexane) and crystallized from MeCN. The yield was
75%. M.p. 92.5—93.5 C. Found (%): C, 72.55; H, 10.19; S, 8.31.
C23H38O2S. Calculated (%): C, 72.96; H, 10.12; S, 8.47. UV,
1
λmax/nm (log): 299 (3.60). IR, ν/cm–1: 3619 (OH). H 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); 1.58 (m, 2 H, SCH2CH2); 2.06 (s, 3 H,
ArCH3); 2.07 (s, 3 H, ArCH3); 2.57 (t, 2 H, SCH2C11H23,
J = 7.2 Hz); 2.66 (m, 1 H, CH2SC12H25); 2.85 (m, 1 H,
CH2SC12H25); 2.92 (m, 1 H, H(3)); 3.20 (m, 1 H, H(3)); 3.96
(s, 1 H, ArOH); 4.82 (m, 1 H, H(2)); 6.26 (s, 1 H, H(6)). MS
(EI, 70 eV), m/z (Irel (%)): 378 [M]+ (100), 176 [M – C12H25SH]+
(93), 163 [M – C12H25SCH2]+ (97), 151 (13), 147 (13), 135 (25).
2-Dodecylthiomethyl-5-hydroxy-6,7-dimethyl-2,3-dihydro-
benzofuran (1c) was purified on a column with SiO2 (eluent 7%
EtOAc in hexane) and crystallized from hexane. The yield was
71%. M.p. 82.1—82.5 C. Found (%): C, 73.18; H, 10.05; S, 8.54.
C23H38O2S. Calculated (%): C, 72.96; H, 10.12; S, 8.47. UV,
1
ν/cm–1: 3608 (OH). H NMR, : 0.88 (t, 3 H, S(CH2)11CH3,
J = 7.2 Hz); 1.23—1.40 (m, 18 H, S(CH2)2(CH2)9CH3); 1.58
(m, 2 H, SCH2CH2); 2.58 (t, 2 H, SCH2C11H23, J = 7.2 Hz);
2.90—2.98 (m, 2 H, CH2SC12H25); 3.05 (m, 1 H, ArCH2); 3.46
(m, 1 H, ArCH2); 4.24 (s, 1 H, ArOH); 4.81 (m, 1 H, CHBr);
4.87 (s, 1 H, ArOH); 6.54 (dd, 1 H, H(5), J = 8.4 Hz, J = 2.4 Hz);
6.59 (d, 1 H, H(3), J = 2.4 Hz); 6.62 (d, 1 H, H(6), J = 8.4 Hz).
3-{[(5-Methoxy-2,3-dihydrobenzofuran-2-yl)methyl]thio}-
propionic acid (9) was obtained according to the known proce-
dure.20 Sodium hydroxide (0.41 g, 10.3 mmol) was added to
a solution of 3-mercaptopropionic acid (0.56 g, 5.3 mmol) in
EtOH (25 mL) and the mixture was stirred at 70 C until complete
dissolution of the alkali. Then, a solution of compound 6e (1.45 g,
5.0 mmol) in EtOH (5 mL) was added, followed by stirring for
4 h. The reaction mixture was cooled, acidified with aqueous
solution of HCl, and treated with toluene (3×20). The organic
phase was washed with water to pH = 7 and aqueous solution of
NaCl, dried with Na2SO4. The solvent was evaporated, the resi-
due (1.27 g) was crystallized from toluene (25 mL) to obtain the
1
λmax/nm (log): 301 (3.71). IR, ν/cm–1: 3620 (OH). H NMR,
: 0.88 (t, 3 H, S(CH2)11CH3, J = 7.2 Hz); 1.25—1.37 (m, 18 H,
S(CH2)2(CH2)9CH3); 1.57 (m, 2 H, SCH2CH2); 2.07 (s, 6 H,
ArCH3); 2.56 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.65 (m, 1 H,
CH2SC12H25); 2.84 (m, 1 H, CH2SC12H25); 2.96 (m, 1 H, H(3));
3.23 (m, 1 H, H(3)); 4.02 (s, 1 H, ArOH); 4.78 (m, 1 H, H(2));
6.39 (s, 1 H, H(4)). MS (EI, 70 eV), m/z (Irel (%)): 378 [M]+
(100), 176 [M – C12H25SH]+ (94), 163 [M – C12H25SCH2]+
(78), 151 (11), 147 (13), 135 (19).

S-Containing analogues of tocopherols
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1029
2-Dodecylthiomethyl-5-hydroxy-7-methyl-2,3-dihydrobenzo-
furan (1d) was purified on a column with SiO2 (eluent 12% EtOAc
in hexane) and crystallized from hexane. The yield was 80%. M.p.
58.8—59.3 C. Found (%): C, 72.11; H, 10.07; S, 9.18. C22H36O2S.
Calculated (%): C, 72.48; H, 9.95; S, 8.79. UV, λmax/nm (log):
Medicine: Structure, Properties, Mechanisms of Action], LAP
LAMBERT Academic Publishing, Saarbrücken, 2012, 488
pp. (in Russian).
2. B. Halliwell, J. M. C. Gutteridge, Free Radicals in Biology
and Medicine: Fifth Edition, Oxford University Press, Oxford,
2015, 1224 pp.
1
301 (3.63). IR, ν/cm–1: 3618 (OH). H NMR, : 0.88 (t, 3 H,
S(CH2)11CH3, J = 7.2 Hz); 1.25—1.37 (m, 18 H, S(CH2)2-
(CH2)9CH3); 1.57 (m, 2 H, SCH2CH2); 2.10 (s, 3 H, ArCH3);
2.56 (t, 2 H, SCH2C11H23, J = 7.2 Hz); 2.65 (m, 1 H,
CH2SC12H25); 2.84 (m, 1 H, CH2SC12H25); 2.98 (m, 1 H, H(3));
3.24 (m, 1 H, H(3)); 3.99 (s, 1 H, ArOH); 4.80 (m, 1 H, H(2));
6.29 (d, 1 H, H(6), J = 2.4 Hz); 6.38 (d, 1 H, H(4), J = 2.4 Hz).
MS (EI, 70 eV), m/z (Irel (%)): 364 [M]+ (90), 162 [M –
– C12H25SH]+ (100), 149 [M – C12H25SCH2]+ (81), 121 (21).
2-Dodecylthiomethyl-5-hydroxy-2,3-dihydrobenzofuran (1e)
was purified on a column with SiO2 (eluent 12% EtOAc in hexane)
and crystallized from hexane. The yield was 80%. M.p.
72.2—73.2 C. Found (%): C, 72.15; H, 9.62; S, 9.03. C21H34O2S.
Calculated (%): C, 71.95; H, 9.78; S, 9.15. UV, λmax/nm (log):
228 (3.96), 302 (3.73). IR, ν/cm–1: 3617 (OH). 1H NMR, : 0.88
(t, 3 H, S(CH2)11CH3, J = 7.2 Hz); 1.25—1.36 (m, 18 H,
S(CH2)2(CH2)9CH3); 1.57 (m, 2 H, SCH2CH2); 2.55 (t, 2 H,
SCH2C11H23, J = 7.2 Hz); 2.66 (m, 1 H, CH2SC12H25); 2.83
(m, 1 H, CH2SC12H25); 2.99 (m, 1 H, H(3)); 3.25 (m, 1 H, H(3));
4.24 (s, 1 H, ArOH); 4.81 (m, 1 H, H(2)); 6.45 (dd, 1 H, H(6),
J = 8.4 Hz, J = 2.4 Hz); 6.50 (d, 1 H, H(7), J = 8.4 Hz); 6.58
(d, 1 H, H(4), J = 2.4 Hz). MS (EI, 70 eV), m/z (Irel (%)): 350
[M]+ (73), 148 [M – C12H25SH]+ (100), 135 [M – C12H25SCH2]+
(90), 123 (13), 107 (25).
3. H. A. Zahalka, B. Robillard, L. Hughes, J. Lusztyk, G. W.
Burton, E. G. Janzen, Y. Kotake, K. U. Ingold, J. Org. Chem.,
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Prosenko, Russ. Chem. Bull., 2013, 62, 1395.
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Novosibirskogo gosudarstvennogo pedagogicheskogo universiteta
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3-[2-(5-Hydroxy-2,3-dihydrobenzofuran-2-yl)methylthio]
propionic acid (10). The yield was 43%. M.p. 123.5—125.0 C.
Found (%): C, 56.76; H, 5.51; S, 12.80; C12H14O4S. Calcul-
ated (%): C, 56.68; H, 5.55; S, 12.61. UV, λmax/nm (log): 229
(3.81), 302 (3.61). IR, ν/cm–1: 3404 (OH), 1685 (C=O).
1H NMR, : 2.51 (t, 2 H, CH2COOH, J = 7.2 Hz); 2.74 (t, 2 H,
SCH2CH2COOH, J = 7.2 Hz); 2.79 (m, 1 H, CH2SCH2CH2-
COOH); 2.85 (m, 1 H, CH2SCH2CH2COOH); 2.89 (m, 1 H,
H(3)); 3.21 (m, 1 H, H(3)); 4.82 (m, 1 H, H(2)); 6.44 (dd, 1 H,
H(6), J = 8.4 Hz, J = 3.0 Hz); 6.50 (d, 1 H, H(7), J = 8.4 Hz);
6.60 (d, 1 H, H(4), J = 3.0 Hz); 8.78 (s, 1 H, ArOH); 12.27 (br.s,
1 H, COOH).
14. D. E. Nichols, S. E. Snyder, R. Oberlender, M. P. Johnson,
X. Huang, J. Med. Chem., 1991, 34, 276.
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Chemicals, Elsevier, 2013, 1002.
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Kandalintseva, A. E. Prosenko, I. A. Grigor´ev, Russ. Chem. Bull.,
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References
1. E. B. Men´shchikova, V. Z. Lankin, N. V. Kandalintseva,
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Received November 22, 2016;
in revised form March 20, 2017