Efficient synthetic methods for unsaturated 3,4,5-trimethoxybenzyl sulfides and ethers

Article abstract of DOI:10.1134/S107042801611004X

Convenient and efficient procedures were developed for preparation of 3,4,5-trimethoxybenzyl sulfides and ethers containing vinyl, allyl, and propargyl groups proceeding from 3,4,5-trimethoxybenzyl alcohol, elemental sulfur, and thiourea in basic and basi

Full text of DOI:10.1134/S107042801611004X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 11, pp. 1571–1575. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.A. Potapov, V.A. Panov, M.V. Musalov, S.A. Zhivet’eva, M.V. Musalova, A.G. Khabibulina, S.V. Amosova, 2016, published in
Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 11, pp. 1579–1583.
Efficient Synthetic Methods for Unsaturated
3,4,5-Trimethoxybenzyl Sulfides and Ethers
V. A. Potapov, V. A. Panov, M. V. Musalov, S. A. Zhivet’eva,
M. V. Musalova, A. G. Khabibulina, and S. V. Amosova*
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
*e-mail: amosova@irioch.irk.ru
Received July 12, 2016
Abstract—Convenient and efficient procedures were developed for preparation of 3,4,5-trimethoxybenzyl
sulfides and ethers containing vinyl, allyl, and propargyl groups proceeding from 3,4,5-trimethoxybenzyl
alcohol, elemental sulfur, and thiourea in basic and basic-reductive systems (hydrazine hydrate‒KОН‒DMF,
NaBH4‒EtOH, KОН‒DMSO). The effective method of the synthesis of 1,1'-[disulfandiylbis(methylene)]bis-
(3,4,5-trimethoxybenzene) consists in the reduction of the elemental sulfur to disulfide anion with hydrazine
hydrate in the presence of KОН followed by the reaction with 3,4,5-trimethoxybenzyl chloride under the
conditions of phase-transfer catalysis or in DMF.
DOI: 10.1134/S107042801611004X
Natural and synthetic substances with a high
antioxidant activity are an indispensable part of
contemporary medical preparations. Among the natural
antioxidants alongside vitamins flavonoids (catechins,
quercetin, and resveratrol) are worth mentioning [1].
The majority of flavonoids have in their structure
benzene rings with electron-donor hydroxy-, methoxy-,
and methyl groups [1]. Many lignins belong to natural
antioxidants. In some lignins an antitumor activity was
found [2]. Resveratrol exhibits antitumor,
antiphlogistic, cardio- and neuroprotector properties
[3].
substances with a potential biological activity and
valuable semiproducts for organic synthesis [6]. We
developed effective synthetic methods for unsaturated
3,4,5-trimethoxybenzyl sulfides and ethers, the
majority of which were not previously described in the
literature. These compounds contain unsaturated
groups (allyl, propargyl, and vinyl) that provide a
possibility of further transformation and preparation of
new derivatives. These compounds can be applied as
activated substrates in reactions with chalcogen halides
where the addition to the unsaturated group may
combine with the electrophilic aromatic substitution
leading to the formation of fused rings (we have pre-
viously performed a number of such reactions [7–10]).
3,4,5-Trimethoxybenzyl fragment is present in the
structure of a number of drugs (trimethoprim,
trimethozine, trimebutine) [11].
A number of organosulfur compounds also possess
a high biological activity [4, 5]. Garlic and onion are
known to contain a complex of biologically active
organosulfur compounds exhibiting antithrombotic,
antimicrobial, and antioxidant properties [5]. A high
bactericidal activity is shown by allicin containing in
the molecule an allylsulfanyl group [5].
Using elemental sulfur and 3,4,5-trimethoxybenzyl
chloride 1 we obtained disulfide 2 under the conditions
of the phase transfer catalysis and in the system
hydrazine hydrate‒KОН‒DMF (Scheme 1). Both
methods afford compound 2 in a high yield (90‒93%).
The methods are based on the generation from the
elemental sulfur of disulfide anion at the action of
hydrazine hydrate and potassium hydroxide. The
disulfide anion enters in the reaction of nucleophilic
A combination in a molecule of an unsaturated
sulfur-containing group and an aromatic fragment with
strong electron-donor substituents may provide a
strong biological activity. One of the main lines in our
studies is the development of efficient preparation
methods for unsaturated organochalcogen compounds,
1571

POTAPOV et al.
1572
Scheme 1.
_
.
N2H4 H2O KOH
S
K2S2
MeO
K2S2 + 2 MeO
MeO
OMe
OMe
OMe
MeO
MeO
MeO
N2H4 H2O_KOH_H2O_C6H6_BnEt3NCl
.
_
_
.
Cl
N2H4 H2O KOH DMF
S
S
1
2
OMe
OMe
MeO
MeO
MeO
MeO
MeO
2
NaBH4_EtOH
OMe +
HC CH
_
_
.
S
S
N2H4 H2O KOH DMF,
110_120oC
S
MeO
2
3
substitution with 3,4,5-trimethoxybenzyl chloride.
Under the conditions of the phase transfer catalysis the
reaction proceeds in a two-phase system hydrazine
hydrate‒KОН‒Н2О‒benzene‒BnEt3NCl. Compound 2
is a white odorless crystalline substance.
hydrazine hydrate‒KОН‒DMF‒H2O sulfide 3 was
obtained in 85% yield.
By the reaction of chloride 1 with S-allyl- and S-
propargylisothiouronium bromides 4 and 5 sulfides 6
and 7 were obtained in 96 and 91% yields respectively.
The reactions proceed at boiling the solutions of
isothiouronium salts 4 and 5 in ethanol with chloride 1
in the presence of potassium hydroxide. A little less
efficient was the method of compounds 6 and 7
preparation by the reduction of compound 2 in the
systems hydrazine hydrate‒KОН‒DMF or NaBH4‒
EtOH with subsequent reaction of the 3,4,5-
trimethoxybenzylthiolate anion with allyl bromide or
propargyl bromide (yield of compounds 6 and 7 82‒
86%) (Scheme 2).
Sulfide 3 was obtained in a yield of up to 94% by
nucleophilic addition of 3,4,5-trimethoxybenzyl-
thiolate anion to acetylene (Scheme 1).
Sulfide 3 was prepared from compound 2 using two
reduction systems: NaBH4‒EtOH and hydrazine
hydrate‒KОН‒DMF‒H2O. At the treatment of
compound 2 with sodium borohydride or with
hydrazine hydrate and potassium hydroxide 3,4,5-
trimethoxybenzylthiolate anion is generated that
undergoes
a nucleophilic addition to acetylene
furnishing sulfide 3. Water or ethanol behave as proton
donors. The reaction proceeds under acetylene
pressure in a pressure reactor at 110–120°С. The
system NaBH4‒EtOH was somewhat more effective:
The yield of the product was 92%, and in the system
The reactions of 3,4,5-trimethoxybenzyl alcohol 8
with acetylene, allyl, and propargyl bromides afforded
ethers 9–11 in 96, 94, and 91% yields respectively.
The reactions occurred in DMSO in the presence of
potassium hydroxide (Scheme 3). The vinylation of
Scheme 2.
_
MeO
KOH
MeO
MeO
+
HN
Br
R
S
MeO
+
EtOH
H2N
S
R
Cl
MeO
MeO
MeO
4, 5
OMe
OMe
OMe
6, 7
1
MeO
MeO
RBr
NaBH4_EtOH
R
2
MeO
MeO
S
S
S
MeO
6, 7
2
R = CH2CH=CH2 (4, 6), CH2C≡CH (5, 7).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

EFFICIENT SYNTHETIC METHODS FOR UNSATURATED 3,4,5-TRIMETHOXYBENZYL
1573
Scheme 3.
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
HC CH
RBr
R
OH KOH_DMSO
KOH_DMSO
O
O
9, 10
8
11
R = CH2CH=CH2 (9), CH2C≡CH (10).
alcohol 8 proceeds under acetylene pressure of 10–12 at
in a pressure reactor. In order to obtain high yields of
compounds 9 and 10 it is necessary to prepare
preliminary potassium 3,4,5-trimethoxybenzylate by
the reaction of alcohol 8 with potassium hydroxide.
were prepared by a known method by boiling ethanol
solution of thiourea with allyl or propargyl bromide
[14].
1,1'-[Disulfandiylbis(methylene)]bis(3,4,5-trime-
thoxybenzene) (2). а. To 0.32 g (10 mmol) of elemen-
tal sulfur (powder) was added at stirring a solution of
0.8 g (12 mmol) of 85% potassium hydroxide in 4 mL
of water and 2 mL of hydrazine hydrate. The mixture
was stirred for 16 h at room temperature, then thereto
was added 0.05 g of BnEt3NCl, and a solution of 2.2 g
(10.2 mmol) of chloride 1 in 15 mL of benzene, and
the reaction mixture was boiled at stirring for 12 h.
The organic layer was separated, the water layer was
extracted with benzene (2 × 20 mL). The combined
organic solution was dried with Na2SO4, the solvent
was distilled off on a rotary evaporator. The residue
was recrystallized from ethanol. Yield 1.92 g (90%),
Propargyl ether 10 was formerly prepared by the
reaction of alcohol 8 with sodium hydride in THF or
DMF followed by the reaction with propargyl halides
[12, 13]. The yield of compound 10 after the
purification by column chromatography on silica gel
was 85% [12]. Propargyl ether 10 was used as initial
compound in the synthesis of magnofargesin [13] that
had been previously isolated from the magnolia genus
plant Magnolia fargesii. The magnofargesin with the
3,4,5-trimethoxybenzene fragment in the molecule
possesses a high antiischemic and antiasthmatic action
[13]. In the highly effective method of synthesis of
ether 10 (yield 94%) that we have developed the
available potassium hydroxide is used instead of
sodium hydride, and the additional purification by
column chromatography is not required.
1
white crystals, mp 118‒119°С. Н NMR spectrum, δ,
ppm: 3.61 s (4Н, SCH2), 3.82 s (6Н, OCH3), 3.86 s
(12Н, OCH3), 6.48 s (4Нarom). 13С NMR spectrum, δ,
ppm: 43.97 (SCH2), 56.18 (OCH3), 60.84 (OCH3),
106.51 (НCarom), 132.83 (Carom), 137.73 (ОCarom),
153.28 (ОCarom). Found, %: С 56.55; Н 6.32; S 14.83.
C20H26O6S2. Calculated, %: С 56.32; Н 6.14; S 15.04.
The structure of compounds obtained was proved
1
by H, 13C NMR spectra and confirmed by the data of
elemental analysis. The obtained compounds are new
promising semiproducts with a potential biological
activity. The presence in the compounds of unsaturated
groups provides a possibility of functionalization and
preparation of new derivatives.
b. To a mixture of 0.32 g (10 mmol) of elemental
sulfur (powder), 5 mL of DMF, and 2 mL of hydrazine
hydrate was added at stirring 0.8 g (12 mmol) of 85%
potassium hydroxide. The mixture was stirred for 16 h
at room temperature, then a solution of 2.2 g (10.2 mmol)
trimethoxybenzyl chloride in 5 mL of DMF was
added, the reaction mixture was stirred for 1 h at room
temperature and 6 h at 70‒80°С. 30 mL of benzene
and 50 mL of water were added. The organic layer was
separated, the water layer was extracted with benzene
(3 × 20 mL), combined organic solutions were washed
with water, dried with Na2SO4, and filtered. On
removing the solvent on a rotary evaporator the residue
was recrystallized from ethanol. Yield 1.98 g (93%).
EXPERIMENTAL
NMR spectra were registered on a spectrometer
Bruker DPX-400 in CDCl3 at operating frequencies
400.13 (1Н) and 100.61 (13С) MHz, reference HMDS.
Dried and distilled solvents were used in the reactions.
Melting points were measured on an instrument
Boёtius (PHMK 05 VEB Wagetechnik Rapido).
Elemental analysis was carried out on an analyzer
Thermo Flash EA1112. Chloride 1 was obtained in
90% yield from alcohol 8 and sulfuryl chloride in the
presence of pyridine. Isothiouronium salts 4 and 5
1,2,3-Trimethoxy-5-[(ethenylsulfanyl)methyl]-
benzene (3). To a solution of 0.43 g (1 mmol) of
disulfide 2 in 40 mL of ethanol was added by portions
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

POTAPOV et al.
1574
0.2 g of sodium borohydride, and the mixture was
stirred for 16 h at room temperature. The mixture was
heated at 110‒120°С in a rotating pressure reactor of
250 mL capacity at acetylene pressure of 10‒12 atm
for 5 h. The solvent was distilled off from the mixture,
the residue was washed with ССl4 and filtered. After
the removal of the solvent from the filtrate the residue
was dried in a vacuum. Yield 0.45 g (94%), yellowish
liquid. 1Н NMR spectrum, δ, ppm: 3.78 s (3Н, OCH3),
3.80 s (6Н, OCH3), 3.82 s (2Н, SCH2), 5.12 d (1Н,
=CH2, 3J 16.5 Hz), 5.16 d (1Н, =CH2, 3J 10.3 Hz), 6.34
d.d (1Н, =CHS, J 10.3, J 16.5 Hz), 6.52 s (2Нarom).
13С NMR spectrum, δ, ppm: 36.68 (SCH2), 56.12
(OCH3), 60.79 (OCH3), 106.12 (НCarom), 111.68
(=CH2), 132.06 (=CHS), 132.72 (Carom), 137.27
(ОCarom), 153.29 (ОCarom). Found, %: С 60.24; Н 6.87;
S 13.05. C12H16O3S. Calculated, %: С 59.97; Н 6.71; S
13.34.
55.88 (OCH3), 60.59 (OCH3), 71.26 (≡СН), 79.67
(≡С), 105.81 (НCarom), 132.72 (Carom), 136.92 (ОCarom),
152.99 (ОCarom). Found, %: С 62.13; Н 6.57; S 12.43.
C13H16O3S. Calculated, %: С 61.88; Н 6.39; S 12.71.
1,2,3-Trimethoxy-5-{[(prop-2-en-1-yl)oxy]methyl}-
benzene (9). To 3.5 g (53 mmol) of 85% potassium
hydroxide was added a solution of 10 g (50.5 mmol) of
alcohol 8 in 40 mL of DMSO, and the mixture was
heated at 50–70°С while stirring till the dissolution of
KОН, then the heating was switched off. On cooling
the mixture to room temperature a solution of 7 g
(56.9 mmol) of allyl bromide in 10 mL of DMSO was
added, and the mixture was stirred for 16 h. Then the
mixture was heated (50‒60°С) at stirring till the
completion of the reaction (5 h). The mixture was
diluted with 200 mL of water, the reaction product was
extracted into ethyl acetate (4 × 50 mL). The organic
phase was washed with water, dried with Na2SO4, the
solvent was distilled off, the residue was dried in a
3
3
1,2,3-Trimethoxy-5-{[(prop-2-en-1-yl)sulfanyl]-
methyl}benzene (6). To a solution of 3 g (15.22 mmol)
of allylisothiouronium bromide 4 in 60 mL of ethanol
was added dropwise at stirring a solution of 2.7 g
(41 mmol) of KОН in 40 mL of ethanol, the mixture
was stirred for 0.5 h, then was added dropwise at
stirring a solution of 3 g (13.85 mmol) of chloride 1 in
20 mL of ethanol. The mixture was stirred for 16 h at
room temperature, 100 mL of ССl4 and 200 mL of
water was added, the organic layer was separated, the
water layer was extracted with ССl4 (2 × 50 mL),
combined organic solutions were washed with water,
dried with Na2SO4, and filtered. On removing the
solvent and drying in a vacuum yield 3.38 g (96%),
1
vacuum. Yield 11.54 g (96%), yellowish liquid. Н
NMR spectrum, δ, ppm: 3.76 s (3Н, OCH3), 3.82 s
(6Н, OCH3), 3.99 m (2Н, ОCH2), 4.38 s (2Н, ОСН2),
3
3
5.18 d (1Н, =CH2, J 9.3 Hz), 5.30 d (1Н, =CH2, J
17.1 Hz), 5.91 m (1Н, =CH), 6.50 c (2Нarom). 13С NMR
spectrum, δ, ppm: 55.61 (OCH3), 59.03 (OCH3), 70.43
(ОCH2), 71.68 (ОCH2), 104.69 (НCarom), 116.09 (=CH2),
133.48 (Carom), 134.92 (=CH), 137.89 (ОCarom), 153.24
(ОCarom). Found, %: С 65.82; Н 7.78. C13H18O4.
Calculated, %: С 65.53; Н 7.61.
1,2,3-Trimethoxy-5-{[(prop-2-yn-1-yl)oxy]-me-
thyl}benzene (10) was obtained similarly to com-
pound 9 from alcohol 8 and propargyl bromide. Yield
1
yellowish liquid. Н NMR spectrum, δ, ppm: 3.03 d
1
3
94%, yellowish liquid. Н NMR spectrum, δ, ppm:
(2Н, SCH2, J 7.1 Hz), 3.58 s (2Н, SCH2), 3.80 s (3Н,
4
OCH3), 3.82 s (6Н, OCH3), 5.07 d (1Н, =CH2, 3J 17.3 Hz),
2.49 t (1Н, CH, J 2.4 Hz), 3.77 s (3Н, OCH3), 3.83 s
(6Н, OCH3), 4.13 d (2Н, ОCH2, 4J 2.4 Hz) 4.48 d (2Н,
ОCH2), 6.52 s (2Нarom). 13С NMR spectrum, δ, ppm:
55.79 (OCH3), 56.57 (ОCH2), 60.01 (OCH3), 71.10
(ОCH2), 74.82 (≡СН), 79.89 (≡С), 105.29 (НCarom),
132.63 (Carom), 138.21 (ОCarom), 153.37 (ОCarom).
Found, %: С 65.81; Н 7.01. C13H16O4. Calculated, %:
С 66.09; Н 6.83.
3
5.10 d (1Н, =CH2, J 10.0 Hz), 5.78 m (1Н, =CH),
6.51 s (2Нarom). 13С NMR spectrum, δ, ppm: 34.00
(SCH2), 35.21 (SCH2), 55.76 (OCH3), 60.29 (OCH3),
106.07 (НCarom), 116.88 (=CH2), 133.32 (Carom),
134.17 (=CH), 137.14 (ОCarom), 153.03 (ОCarom).
Found, %: С 61.15; Н 6.96; S 12.39. C13H18O3S.
Calculated, %: С 61.39; Н 7.13; S 12.61.
1,2,3-Trimethoxy-5-[(ethenyloxy)methyl]ben-
zene (11). A mixture of 15 g (75.76 mmol) of alcohol 8,
7.5 g (113.6 mmol) of 85% potassium hydroxide, and
120 mL of DMSO was heated at 110–120°С in a
rotating pressure reactor of 1 liter capacity at acetylene
pressure of 10‒12 atm for 5 h. The mixture was diluted
with 300 mL of water, the reaction product was
extracted into ethyl acetate (4 × 50 mL). The organic
1,2,3-Trimethoxy-5-{[(prop-2-yn-1-yl)sulfanyl]-
methyl}benzene (7) was obtained similarly to com-
pound 6 from propargylisothiouronium bromide 5 and
1
chloride 1 in ethanol. Yield 91%, yellowish liquid. Н
4
NMR spectrum, δ, ppm: 2.26 t (1Н, CH, J 2.5 Hz),
3.05 d (2Н, SCH2, 4J 2.5 Hz), 3.76 s (3Н, OCH3), 3.78
s (6Н, OCH3), 3.79 s (2Н, SCH2), 6.51 s (2Нarom). 13С
NMR spectrum, δ, ppm: 18.37 (SCH2), 35.57 (SCH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

EFFICIENT SYNTHETIC METHODS FOR UNSATURATED 3,4,5-TRIMETHOXYBENZYL
1575
3. Baur, J.A., and Sinclair, D.A., Nat. Rev. Drug Discov.,
phase was washed with water, dried with Na2SO4, the
solvent was distilled off. To purify the residue it was
passed through a small bed of alkaline alumina (eluent
ether). Yield 15.45 g (91%), yellowish liquid. 1Н NMR
spectrum, δ, ppm: 3.73 s (3Н, OCH3), 3.75 s (6Н,
2006, vol. 5, p. 493.
4. Yin, M., Hwang, S., and Chan, K., J. Agric. Food
Chem., 2002, vol. 50, p. 6143.
5. Block, E., Garlic and Other Alliums. The Lore and the
Science, Cambridge: Royal Society of Chemistry, 2009.
6. Potapov, V.A., Musalov, M.V., Musalova, M.V., and
Amosova, S.V., Curr. Org. Chem., 2016, vol. 20,
p. 136.
3
OCH3), 4.00 d (1Н, =CH2, J 6.8 Hz), 4.22 d (1Н,
=CH2, 3J 14.3 Hz), 4.58 s (2Н, OCH2), 6.45‒6.52 m (3Н,
=CHО, CНarom). 13С NMR spectrum, δ, ppm: 55.75
(OCH3), 60.05 (OCH3), 69.95 (OCH2), 87.22 (=CH2),
106.81 (НCarom), 132.32 (Carom), 138.16 (ОCarom),
151.61 (=CHО), 153.51 (ОCarom). Found, %: С 64.54;
Н 7.35. C12H16O4. Calculated, %: С 64.27; Н 7.19.
7. Potapov, V.A., Musalov, M.V., and Amosova, S.V.,
Tetrahedron Lett., 2011, vol. 52, p. 4606.
8. Musalov, M.V., Potapov, V.A., and Amosova, S.V.,
Russ. Chem. Bull., 2011, vol. 60, p. 767.
Spectral studies were performed on the equipment
of the Baikal analytic Center of joint usage of the
Siberian Branch, Russian Academy of Sciences.
9. Potapov, V.A., Khuriganova, O.I., and Amosova, S.V.,
Russ. J. Org. Chem., 2010, vol. 46, p. 1421.
10. Musalov, M.V., Potapov, V.A., and Amosova, S.V.,
Russ. J. Org. Chem., 2011, vol. 47, p. 948.
11. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
The work was carried out under the financial
support of the Russian Scientific Foundation (grant
no. 14-13-01085).
Moscow: Novaya Volna, 2014.
12. Suman, P., Ramalinga Murthy, T., Rajkumar, K.,
Srikanth, D., Dayakar, Ch., Kishor, C., Addlagatta, A.,
Kalivendi, S.V., and China Raju, B., Eur. J. Med.
Chem., 2015, vol. 90, p. 603.
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