A new method for thiomethylation of phenols

Article abstract of DOI:10.1007/s11172-010-0175-3

Alkyl diethylaminomethyl sulfides are convenient and efficient reagents for introduction of alkylthiomethyl groups into phenols.

Full text of DOI:10.1007/s11172-010-0175-3

Russian Chemical Bulletin, International Edition, Vol. 59, No. 4, pp. 861—863, April, 2010
861
A new method for thiomethylation of phenols
I. M. Bugaev and A. E. Prosenko
Research Institute of Antioxidant Chemistry, Novosibirsk State Pedagogical University,
28 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 244 1856. Eꢀmail: chemistry@ngs.ru
Alkyl diethylaminomethyl sulfides are convenient and efficient reagents for introduction of
alkylthiomethyl groups into phenols.
Key words: thiomethylation, phenols, aminothioacetals, aromatic electrophilic substitution.
Alkylthiomethylphenols are promising as antioxidants1
and bioantioxidants.2 Current approaches to their syntheꢀ
sis most often involve intermediate products already conꢀ
taining a methylene fragment in a phenol molecule. Manꢀ
nich bases are the most accessible compounds of this type;
however, replacement of the amino group occurs slowly
and only under harsh conditions.3 Alkylthiomethylphenols
can also be obtained by condensation of thiols with
formaldehyde and phenols.4
Thiomethylation of 2,6ꢀdimethylphenol with diethylꢀ
aminomethyl octadecyl sulfide (1b) also occurred smoothly.
A reaction between equimolar amounts of aminomeꢀ
thyl sulfide 1a and pꢀcresol gave the expected monoꢀ and
disubstitution products in a ratio of 2 : 1 (Scheme 2). The
yield of product 3a was 42%. The yield of product 3b was
21.5% with respect to pꢀcresol and 43% with respect to
reactant 1a.
It is known that aminomethyl sulfides react with
Cꢀnucleophiles such as phenylmagnesium bromide5 and
dithiocarboxylic acid esters6 to mostly give Mannich bases.
Aminothioacetals have been used7 as thiomethylating
agents: hydrochlorides of aminomethyl thioacetates and
aminomethyl thiobenzoates form thiomethyl derivatives
with 1,3ꢀdicarbonyl compounds and phenylacetaldehyde,
while phenol and phloroglucinol are inert under similar
conditions.
Scheme 2
We found that a reaction of diethylaminomethyl dodeꢀ
cyl sulfide (1a) with 2,6ꢀdimethylphenol in boiling acetic
acid gives 4ꢀ(dodecylthiomethyl)ꢀ2,6ꢀdimethylphenol (2a)
in high yield (Scheme 1). According to GLC data, the
98% conversion of the starting compounds was achieved
in 1 h and the final mixture contained only the starting
compounds and product 2a.
Using unsubstituted phenol in a threefold excess,
we attained selective monoalkylation (Scheme 3).
Scheme 1
Scheme 3
R = C12H25 (a); C18H37 (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 843—844, April, 2010.
1066ꢀ5285/10/5904ꢀ0861 © 2010 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 4, April, 2010
Bugaev and Prosenko
2,6ꢀDimethylꢀ4ꢀ(octadecylthiomethyl)phenol (2b). A mixture
of 2,6ꢀdimethylphenol (1.22 g, 10 mmol) and compound 1b (3.72 g,
10 mmol) was refluxed in glacial acetic acid (4 mL) for 1 h and
then cooled to ~20 °C. The precipitate that formed was washed
with water, recrystallized twice from ethanol, and washed with
ethanol. The yield of compound 2b was 3.38 g (80%), light cream
crystals, m.p. 71 °C. Found (%): C, 77.12; H, 11.52; S, 7.66.
C27H48OS. Calculated (%): C, 77.08; H, 11.50; S, 7.62.
1H NMR, δ: 0.88 (t, 3 H, CH3(CH2)17, J = 6.9 Hz); 1.24—1.28
(m, 30 H, (CH2)15); 1.51 (m, 2 H, CH2CH2S); 2.20 (s, 6 H,
ArCH3); 2.32 (t, 2 H, CH2CH2S, J = 7.2 Hz); 3.50 (s, 2 H,
SCH2Ar); 4.40 (s, 1 H, OH); 6.83 (s, 2 H, ArH).
HPLCꢀanalysis revealed no polyalkylated phenols in the
reaction mixture. The reaction products are 2ꢀ and
4ꢀ(dodecylthiomethyl)phenols 4a and 4b in a ratio of 7 : 1.
Therefore, orthoꢀsubstitution is more favorable under these
conditions.
The method we proposed for thiomethylation of pheꢀ
nols is simple and efficient; the reagent used is promising
for testing with other nucleophiles.
Experimental
2ꢀ(Dodecylthiomethyl)ꢀ4ꢀmethylphenol (3a) and 2,6ꢀbis(doꢀ
decylthiomethyl)ꢀ4ꢀmethylphenol (3b) were obtained from pꢀcresol
(10.81 g, 0.10 mol) as described for compound 2a. The organic
layer was washed in a separatory funnel with hot water until the
odor of pꢀcresol disappeared, dissolved in ethanol, and cooled to
0 °C. Compound 3b precipitated as a white crystalline solid. The
yield was 11.57 g (43% with respect to 1a), m.p. 43—44 °C.
Found (%): C, 73.87; H, 11.27; S, 11.97. C33H60OS2. Calculatꢀ
1
H NMR spectra were recorded on a Bruker AVꢀ600 inꢀ
strument in CDCl3. Melting points were determined on a PTP
instrument. Elemental analysis was performed at the checkꢀ
ing and analysis laboratory of the Research Institute of Antiꢀ
oxidant Chemistry (Novosibirsk State Pedagogical Universiꢀ
ty). Gas chromatography was carried out on an LKhMꢀ80
instrument; HPLC data were obtained on a Milikhromꢀ4 inꢀ
strument.
1
ed (%): C, 73.81; H, 11.26; S, 11.94. H NMR, δ: 0.88 (t, 6 H,
CH3(CH2)11, J = 6.9 Hz); 1.24—1.29 (m, 36 H, (CH2)9); 1.53
(m, 4 H, CH2CH2S); 2.23 (s, 3 H, ArCH3); 2.36 (t, 4 H,
CH2CH2S, J = 7.2 Hz); 3.69 (s, 4 H, SCH2Ar); 6.82 (s, 2 H,
ArH); 6.83 (br.s, 1 H, OH). Concentration of the mother liquor
gave compound 3a (13.51 g, 42%) as a yellow oil. Found (%):
C, 74.50; H, 10.66; S, 9.95. C20H34OS. Calculated (%): C, 74.47;
N,NꢀDiethylaminomethyl dodecyl sulfide (1a). Diethylamine
(87.8 g, 1.20 mol) was added to a suspension of paraformaldeꢀ
hyde (36.0 g, 1.20 mol) in ethanol (150 mL). The mixture was
stirred to homogenization for 0.5 h, whereupon dodecanethiol
(202.4 g, 1.00 mol) was added. After 0.5 h, the reaction mixture
was transferred to a separatory funnel, washed with warm water,
and dried over Na2SO4. The yield of compound 1a was 284.9 g
H, 10.62; S, 9.94. 1H NMR, δ: 0.89 (t, 3 H, CH3(CH2)11
,
20
J = 6.9 Hz); 1.24—1.31 (m, 18 H, (CH2)9); 1.53 (m, 2 H,
CH2CH2S); 2.24 (s, 3 H, ArCH3); 2.35 (t, 2 H, CH2CH2S,
J = 7.2 Hz); 3.69 (s, 2 H, SCH2Ar); 6.72 (d, 1 H, ArH,
J = 8.4 Hz); 6.80 (d, 1 H, ArH, J = 1.8 Hz); 6.82 (br.s, 1 H, OH);
6.90 (dd, 1 H, ArH, J = 8.4 Hz, J = 1.8 Hz).
(99%), colorless liquid, nD 1.4689. Found (%): C, 71.22;
H, 12.99; N, 4.86; S, 11.19. C17H37NS. Calculated (%): C, 71.01;
H, 12.97; N, 4.87; S, 11.15. 1H NMR, δ: 0.87 (t, 3 H, CH3(CH2)11
,
J = 6.9 Hz); 1.03 (t, 6 H, N(CH2CH3)2, J = 7.2 Hz); 1.24—1.34
(m, 18 H, (CH2)9); 1.53 (m, 2 H, CH2CH2S); 2.47 (t, 2 H,
CH2CH2S, J = 7.2 Hz); 2.54 (q, 4 H, N(CH2CH3)2, J = 7.2 Hz);
3.99 (s, 2 H, SCH2N).
2ꢀ(Dodecylthiomethyl)phenol (4a) and 4ꢀ(dodecylthiomethyl)ꢀ
phenol (4b) were obtained from phenol (28.23 g, 0.30 mol) as
described for compound 2a. The organic layer was washed in
a separatory funnel with hot water until the odor of phenol disꢀ
appeared. The product was dissolved in light petroleum and
cooled to –15 °C. Compound 4b precipitated as a white crystalꢀ
line solid. The yield was 3.66 g (12%), m.p. 71—72 °C. Found (%):
C, 74.07; H, 10.50; S, 10.39. C19H32OS. Calculated (%):
N,NꢀDiethylaminomethyl octadecyl sulfide (1b). A mixture of
paraformaldehyde (0.75 g, 25 mmol) and diethylamine (1.83 g,
25 mmol) in ethanol (5 mL) was heated with stirring on a water
bath (60 °C) for 0.5 h. Then premelted octadecanethiol
(5.73 g, 20 mmol) was added and the reaction mixture was
stirred for an additional 0.5 h and washed with water. The
yield of compound 1b was 7.32 g (98%), a colorless liquid solidiꢀ
fying at 16—17 °C, nD20 1.4702. Found (%): C, 74.41; H, 13.30;
N, 3.76; S, 8.65. C23H49NS. Calculated (%): C, 74.32; H, 13.29;
C, 73.97; H, 10.45; S, 10.39. 1H NMR, δ: 0.88 (t, 3 H, CH3(CH2)11
,
J = 6.9 Hz); 1.24 (m, 18 H, (CH2)9); 1.51 (m, 2 H, CH2CH2S);
2.32 (t, 2 H, CH2CH2S, J = 7.2 Hz); 3.57 (s, 2 H, SCH2Ar); 4.95
(br.s, 1 H, OH); 6.68 (d, 2 H, ArH, J = 8.4 Hz); 7.11 (d, 2 H,
ArH, J = 8.4 Hz). Concentration of the mother liquor gave
compound 4a (26.85 g, 87%) as a yellow oil. Found (%):
C, 74.05; H, 10.54; S, 10.36. C19H32OS. Calculated (%): C, 73.97;
N, 3.77; S, 8.63. 1H NMR, δ: 0.85 (t, 3 H, CH3(CH2)17
,
J = 7.2 Hz); 1.01 (t, 6 H, N(CH2CH3)2, J = 7.2 Hz); 1.24—1.34
(m, 30 H, (CH2)15); 1.51 (m, 2 H, CH2CH2S); 2.45 (t, 2 H,
CH2CH2S, J = 7.5 Hz); 2.52 (q, 4 H, N(CH2CH3)2, J = 7.2 Hz);
3.96 (s, 2 H, SCH2N).
H, 10.45; S, 10.39. 1H NMR, δ: 0.89 (t, 3 H, CH3(CH2)11
,
J = 7.2 Hz); 1.24—1.30 (m, 18 H, (CH2)9); 1.53 (m, 2 H,
CH2CH2S); 2.35 (t, 2 H, CH2CH2S, J = 7.2 Hz); 3.76 (s, 2 H,
SCH2Ar); 6.66 (br.s, 1 H, OH); 6.78 (td, 1 H, ArH, J = 7.2 Hz,
J = 1.0 Hz); 6.84 (dd, 1 H, ArH, J = 7.5 Hz, J = 1.0 Hz); 7.00
(dd, 1 H, ArH, J = 7.2 Hz, J = 1.0 Hz); 7.13 (td, 1 H, ArH,
J = 7.5 Hz, J = 1.0 Hz).
4ꢀ(Dodecylthiomethyl)ꢀ2,6ꢀdimethylphenol (2a). A mixture of
2,6ꢀdimethylphenol (12.22 g, 0.10 mol) and compound 1a (28.75 g,
0.10 mol) was refluxed in glacial acetic acid (24 mL) for 1 h.
On cooling to ~20 °C, the reaction mixture was diluted
with water, which resulted in crystallization of the organic layer.
The product was recrystallized from aqueous ethanol. The
yield of compound 2a was 32.06 g (95%), white crystals, m.p.
57—58 °C (cf. Ref. 2: m.p. 57—58 °C). 1H NMR, δ: 0.88 (t, 3 H,
CH3(CH2)11, J = 6.9 Hz); 1.25 (m, 18 H, (CH2)9); 1.52 (m, 2 H,
CH2CH2S); 2.20 (s, 6 H, ArCH3); 2.33 (t, 2 H, CH2CH2S,
J = 7.2 Hz); 3.51 (s, 2 H, SCH2Ar); 4.43 (s, 1 H, OH); 6.83
(s, 2 H, ArH).
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Alkylthiomethylation of phenols
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Received November 13, 2009;
in revised form January 15, 2010