Interaction of functionally-substituted 4-alkyl-2,6-di-tert-butylphenols with hydrohalic acids

Article abstract of DOI:10.1007/s11172-007-0169-y

Reactions of 4-alkyl-2,6-di-tert-butylphenols containing OH, SH, COOH, and COOMe groups in their para substituents with hydrogen chloride and hydrohalic acids were studied. One-step transformations of 2,6-di-tert-butyl-4-(ω- hydroxyalkyl)phenols to the corresponding 4-(ω-halogenoalkyl)phenols, as well as of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid and its esters to phloretic acid were proposed. 4-(3-Mercaptopropyl)phenol upon heating with conc. HBr undergoes condensation to 3-(4-hydroxyphenyl)propyl 4-(3-mercaptopropyl)phenyl sulfide as the main product.

Full text of DOI:10.1007/s11172-007-0169-y

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1119—1124, June, 2007
1119
Interaction of functionallyꢀsubstituted
4ꢀalkylꢀ2,6ꢀdiꢀtertꢀbutylphenols with hydrohalic acids*
A. E. Prosenko,aꢀ A. A. Skorobogatov,a O. I. Dyubchenko,a P. I. Pinko,a
N. V. Kandalintseva,a M. M. Shakirov,b and L. M. Pokrovskyb
aResearch Institute of Chemistry of Antioxidants, Novosibirsk State Pedagogical University,
28 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 268 1856. Eꢀmail: chemistry@ngs.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 334 4752. Eꢀmail: benzol@nioch.nsc.ru
Reactions of 4ꢀalkylꢀ2,6ꢀdiꢀtertꢀbutylphenols containing OH, SH, COOH, and COOMe
groups in their para substituents with hydrogen chloride and hydrohalic acids were studied.
Oneꢀstep transformations of 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ(ωꢀhydroxyalkyl)phenols to the correspondꢀ
ing 4ꢀ(ωꢀhalogenoalkyl)phenols, as well as of 3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propionic
acid and its esters to phloretic acid were proposed. 4ꢀ(3ꢀMercaptopropyl)phenol upon heating
with conc. HBr undergoes condensation to 3ꢀ(4ꢀhydroxyphenyl)propyl 4ꢀ(3ꢀmercaptoꢀ
propyl)phenyl sulfide as the main product.
Key words: 2,6ꢀdiꢀtertꢀbutylphenols, hydrobromic acid, paraꢀdihydrocoumaric alcohol,
phloretic acid, dealkylation, substitution of aromatic OH group.
Among biologically active phenolic compounds, funcꢀ
tionallyꢀsubstituted pꢀalkylphenols, such as 4ꢀ(βꢀhydroxyꢀ
ethyl)phenol (tyrosol),1 4ꢀ(γꢀhydroxypropyl)phenol (pꢀdiꢀ
hydrocoumaric alcohol), βꢀ(4ꢀhydroxyphenyl)propionic
(phloretic) acid, 4ꢀ(βꢀaminoethyl)phenol (tyramine),2
etc., are ranked particularly. Hitherto, these compounds
have not readily been available, since the suggested methꢀ
ods for their synthesis, based as a rule on the use of natuꢀ
ral raw materials,3,4 were multiꢀstep and laborious.5,6
Earlier, the synthesis of 4ꢀalkylphenols with chloro,
hydroxy, carboxy, or ester groups in the alkyl substituent
based on the thermal dealkylation7 of the corresponding
derivatives of 2,6ꢀdiꢀtertꢀbutylphenol or dealkylation in
the presence of protic acids, such as heteropolyacids8 and
conc. H2SO4,9 was described. In the present work, a posꢀ
R = H, n = 1 (1а), 2 (1b), 3 (1c); R = Me, n = 2 (1d);
R´ = H (3а), Me (3b)
sibility for the synthesis of functionallyꢀsubstituted pꢀalkylꢀ
phenols by the reactions of sterically hindered phenols
1—3 with hydrohalic acids was investigated.
ready at 80 °C on passage of hydrogen chloride through a
melt of alcohol 1b, which was indicated by appearance of
chloride 4 and alcohol 5 in the reaction mixture. An inꢀ
crease in the temperature of the melt up to 100 °C and
further up to 140 °C accelerated both processes and proꢀ
moted elimination of the second tertꢀbutyl group. No
products of the other possible reactions (isomerization
and Оꢀalkylation) under given conditions were observed,
which enabled us to make the following suggestion about
Specifically, we studied transformations of alcohol 1b
upon its heating with hydrogen chloride, hydrochloric,
hydrobromic, and hydroiodic acids.
The reactions of nucleophilic substitution of the alcoꢀ
holic ОН group and monoꢀdeꢀtertꢀbutylation began alꢀ
* Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1078—1083, June, 2007.
1066ꢀ5285/07/5606ꢀ1119 © 2007 Springer Science+Business Media, Inc.

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Prosenko et al.
transformations of alcohol 1b under action of hydrogen
chloride (Scheme 1).
content of the final product, viz., chloride 8, in the reacꢀ
tion mixture was as high as 93%.
Similarly, the corresponding 4ꢀ(ωꢀchloroalkyl)phenols
were obtained by reactions of alcohols 1а,d with HCl.
The reaction of alcohol 1b with conc. hydrochloric
acid was carried out either under atmospheric (reflux) or
under high (in a sealed tube, 110—180 °C) pressure. The
transformations of compound 1b occurred also according
to Scheme 1.
Scheme 1
The formation of the target product 8 under atmoꢀ
spheric pressure occurred with a remarkably lower rate
than with the use of hydrogen chloride. Thus after reflux
for 20 h, the content of chloride 8 in the reaction mixture
did not exceed 50%.
The conversion of alcohol 1b to the target product 8
upon its heating with hydrochloric acid in a sealed tube
was also incomplete: the content of chloride 6 in the
mixture of compounds 6 and 8 obtained varied from 55
to 81%, depending on the temperature and heating time.
Obviously, this result can be explained by accumulation
of tertꢀbutyl chloride in the reaction mixture and, conseꢀ
quently, by reversible transformation of product 8 to
chloride 6.
The reaction of alcohols 1 with hydrochloric acid unꢀ
der high pressure can be used for the preparative purꢀ
poses, taking into account the easiness of separation of
compounds 6 and 8 due to their different solubility in
aqueous alkalis. Earlier, in this way we synthesized
4ꢀ(2ꢀchloroethyl)ꢀ and 4ꢀ(4ꢀchlorobutyl)ꢀ2ꢀtertꢀbutylꢀ
phenols.11
Concentrated hydrobromic and hydroiodic acids were
found to be more efficient. Obviously, this is due to the
fact that HBr and HI, in contrast to hydrogen chloride,
form azeotropic mixtures with water with considerably
higher percentage of hydrogen halide and with higher
boiling points. Thus after reflux of alcohol 1b in conc.
HBr for 3 h with azeotropic distillation of the resulting
tertꢀbutyl bromide, the content of the target 4ꢀ(3ꢀbromoꢀ
propyl)phenol in the organic phase of the reaction
mixture reached 60%, and after 8 h, it increased to 91%.
In addition, alcohols 5 and 7, as well as 4ꢀ(3ꢀbromoꢀ
propyl)ꢀ2ꢀtertꢀbutylꢀ and ꢀ2,6ꢀdiꢀtertꢀbutylphenols, were
identified in the reaction mixture by GC/MS. This
allows us to consider that HBr brings about transformaꢀ
tions of alcohol 1b similar to those effected by HCl (see
Scheme 1).
Thiol 2, in contrast to alcohol 1b, does not undergo
deꢀtertꢀbutylation neither upon passage of hydrogen chloꢀ
ride through its melt nor under reflux with hydrochloric
acid. At the same time, complete conversion of thiol 2 to
the monoꢀ and diꢀdealkylation products 9 and 10, as well
as to (tertꢀbutylthio)propylphenols 11—13, takes place on
heating with conc. hydrochloric acid for 4.5 h at 160 °C.
Compounds 9—13 were identified by GC/MS with the
use of the authentic compounds obtained by alternative
The intermediate products 4—7 were identified by
GC/MS with the use of the authentic compounds obꢀ
tained by alternative syntheses: chlorides 4 and 6, by reꢀ
action of alcohol 1b with PCl3 in the presence of DMF10
or with hydrochloric acid; alcohols 5 and 7, by thermal
dealkylation of alcohol 1b. In contrast to the described
procedure7, dealkylation of the latter was carried out with
bubbling of an inert gas, which enabled us to reduce the
reaction time and to increase the yields of the target prodꢀ
ucts (in particular of alcohol 7) up to 76%.
The study of the dynamics of changes of the composiꢀ
tion of the reaction mixture during heating of alcohol 1b
in the flow of НCl (140 °C) revealed the initial accumulaꢀ
tion of alcohol 5, indicating the higher rate of elimination
of the first tertꢀbutyl group in comparison to the secꢀ
ond one. Apparently, the replacement of the alcoholic
ОН group by chlorine is a limiting step of the process:
after 10 h, the total amount of monoꢀorthoꢀsubstituted
alcohol 5 and chloride 6 in the reaction mixture was 9.3%,
while for alcohols 5 and 7 it was 21.6%. After 14 h, the

Reactions of alkyldiꢀtertꢀbutylphenols with HHal
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1121
Scheme 2
syntheses. The synthesis of sulfide 11 has been described
earlier.12
Sulfide 14 as the reaction product of thiol 2 with HBr
was isolated in a crystalline form, its structure and comꢀ
position were confirmed by elemental analysis, mass specꢀ
trometric and spectroscopic data. Thus the correlation of
the isotope lines М, М + 1, М + 2 and М + 3 in the mass
spectrum of product 14 corresponds to that expected for a
compound with the molecular formula С18H22OS2. In the
1Н NMR spectrum of this compound, a triplet of the
proton of the SH group (δ 1.39), a singlet of phenolic
proton (δ 5.50), and four doublets of aromatic hydrogen
atoms with relative intensities of 1 : 1 : 2 : 2 : 2 : 2 were
present. The chemical shifts of signals of two aromatic
protons (δ 6.75 and 7.02) correspond to those in the specꢀ
trum of thiol 10, and chemical shifts of another two proꢀ
tons are shifted downfield (δ 7.09 and 7.25).
The identification of compounds 14 and 15 among the
reaction products of thiol 2 with HBr is of particular
interest, since the substitution reaction of a sulfide funcꢀ
tion for the phenolic ОН group is virtually not docuꢀ
mented. Thus in the STN International database, we found
the only work13 close to the described transformations, in
which it was shown that the heating of phenol with thiols
and conc. hydrochloric acid for 48—119 h at 180 °C gave
the corresponding sulfides in 22—43% yield.
The deꢀtertꢀbutylation of thiol 2 on treatment with
HBr actively proceeded even under atmospheric pressure:
after 2.5 h of reflux with conc. HBr, its conversion to
products 9—13 was as high as 94%, and after 3.5 h, comꢀ
plete conversion occurred to give only products 9 and 10.
Thus, thiol 2 upon treatment with HHal, apparently,
undergoes the following transformations (Scheme 2).
After heating of thiol 2 with HBr for 6 h, mercaptoꢀ
propylphenol 10 was the main product of the reaction
with its content in organic phase of the reaction mixture
being 60%. In addition, the condensation products 14
and 15 (30 and 8%, respectively), as well as disulfide 16
(~2%) were also observed (Scheme 3). The presence of
compounds 14 and 16 in the reaction mixture was conꢀ
firmed with the use of the authentic samples obtained by
alternative syntheses (see Experimental). Compound 15
was not isolated in pure form. However, data from mass
spectrometry (the presence of the molecular ion peak
with m/z 468 and the correspondence of the correlation
of the isotope lines to that of the expected formula
С27H32OS3) allow us to suggest the structure shown in
Scheme 3.
Scheme 3

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Prosenko et al.
tor (EI, 70 eV). Column, НРꢀ5MS 30 m × 0.25 mm × 0.25 µm;
Concentrated HBr was found to be also an efficient
catalyst of deꢀtertꢀbutylation of acid 3а and its methyl
ester 3b: reflux of this compounds with HBr (≥30 wt.%)
for 1.5—2 h afforded phloretic acid (17) in 91—92% yield
(Scheme 4).
carrier gas, helium, 1 mL min–1. Temperature conditions of the
columns: 2 min at 50 °C, heating with the rate of 10 °C min–1
,
5 min at 280 °C. Temperature of injector, 280 °C, of the ion
source, 173 °C. The data were collected with the rate of
1.2 scan s–1 in the mass region 30—650 а.u.m.
Chromatographic analysis was performed on an
LKhМꢀ80МD chromatograph (model 5) with the thermal conꢀ
ductivity detector. Column 3 m × 3 mm, phase 3% OVꢀ17 on
NꢀSuper Chromaton (0.16—0.20 mm); carrier gas, helium,
30 mL min–1. Temperature of injector, 280 °C, of detecꢀ
tor, 290 °C. Temperature conditions of the columns: 220 °C
(isothermic) or from 150 to 220 °C (in programming conditions).
4ꢀ(3ꢀChloropropyl)phenol (8). Hydrogen chloride was passed
through a melt of alcohol 1b (13.2 g, 50 mmol) for 14 h at 140 °C
with the rate of 100—150 mL min–1. The resulting mixture
was distilled in vacuo, and a fraction with b.p. 120—125 °C
(1—2 Torr) was collected. Product 8 (7 g, 82%) was obtained,
m.p. 36—37 °C (from pentane). Found (%): С, 62.23; Н, 6.53;
Cl, 20.79. C9H11СlO. Calculated (%): С, 63.35; Н, 6.50;
Сl, 20.78. 1H NMR, δ: 1.70—2.15 (m, 2 Н, СН2СН2СН2);
2.63 (t, 2 Н, ArCH2, J = 7.5 Hz); 3.37 (t, 2 Н, СН2Сl, J =
6.5 Hz); 5.00 (s, 1 Н, ОН); 6.80, 7.14 (both d, 2 Н each, Ar,
J = 8.5 Hz).
4ꢀ(2ꢀChloroethyl)phenol was obtained similarly from alcoꢀ
hol 1а, the yield was 61%, m.p. 56—57 °C (from hexane).
Found (%): С, 61.29; Н, 5.94; Cl, 22.83. C8H9СlO. Calcuꢀ
lated (%): С, 61.35; Н, 5.79; Сl, 22.64. 1H NMR, δ: 2.98 (t, 2 Н,
ArCH2, J = 7.5 Hz); 3.66 (t, 2 Н, СН2Сl, J = 6.5 Hz); 5.02 (s,
1 Н, ОН); 6.68, 6.95 (both d, 2 Н each, Ar, J = 8.5 Hz).
4ꢀ(3ꢀChloroꢀ1ꢀmethylpropyl)phenol was obtained similarly
from alcohol 1d, the yield was 79%, b.p. 137—138 °C (5 Torr).
Found (%): С, 65.05; Н, 6.95; Cl, 19.08. C10H13СlО. Calcuꢀ
lated (%): С, 65.04; Н, 7.10; Сl, 19.20. 1H NMR, δ: 1.22 (d,
3 Н, Ме, J = 7 Hz); 1.93—2.99 (m, 2 Н, СНСН2СН2);
2.88—2.90 (m, 1 Н, ArCH); 3.27—3.33, 3.39—3.45 (both m,
1 Н each, СН2Сl); 6.23 (s, 1 Н, ОН); 6.78, 7.04 (both d,
2 Н each, Ar, J = 8.5 Hz).
Reaction of alcohol 1b with hydrochloric acid. Alcohol 1b
(5 g, 19 mmol) and hydrochloric acid (15 mL, 0.17 mol of HCl)
were placed in a 80ꢀmL tube made of thermostable glass, the
tube was sealed and kept in a thermostat equipped with a shakꢀ
ing device for 2 h at 180 °C. After cooling and opening of the
tube, the content was treated with benzene. The extract was
washed with water, treated with aq. NaOH, and the benzene
and aq. alkaline layers were separated. The benzene extract was
treated with hydrochloric acid, washed with water, dried with
Na2SO4, and the solvent was evaporated. 2ꢀtertꢀButylꢀ4ꢀ(3ꢀ
chloropropyl)phenol (6) (1.90 g, 44%) was obtained. Found (%):
С, 68.84; Н, 8.39; Cl, 15.57. C13H19СlО. Calculated (%):
С, 68.86; Н, 8.45; Сl, 15.64. 1H NMR, δ: 1.40 (s, 9 Н, But);
2.00—2.06 (m, 2 Н, СН2СН2СН2); 2.68 (t, 2 Н, ArCH2, J =
7.5 Hz); 3.52 (t, 2 Н, СН2Сl, J = 6.5 Hz); 4.85 (s, 1 Н, ОН);
6.56 (d, 1 Н, Ar, J = 8 Hz); 6.87 (dd, 1 Н, Ar, J = 8 Hz, J =
2 Hz); 7.07 (d, 1 Н, Ar, J = 2 Hz). The aq. alkaline layer was
neutralized with hydrochloric acid and treated with toluene.
The extract was washed with water, dried with Na2SO4, and the
solvent was evaporated. Chloropropylphenol 8 (1.46 g, 45%)
was obtained.
Scheme 4
R´ = H (а), Me (b)
This method for the synthesis of phloretic acid has
undeniable advantages over that covered by a patent,9
which is based on deꢀtertꢀbutylation of acid 3а and its
esters upon treatment with H2SO4: our method differs in
higher yield of the target product and does not require the
use of additional solvents.
In conclusion, in the present work it was shown that
on heating of 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ(ωꢀhydroxyalkyl)phenols
1 with hydrohalic acids, the parallel processes of deꢀtertꢀ
butylation and substitution of halogen atom for the aliꢀ
phatic ОН group took place. This allows one to convert
phenols 1 to the corresponding 4ꢀ(ωꢀhaloalkyl)phenols,
valuable intermediates in the synthesis of biologically acꢀ
tive compounds, in one step and in good yields.
It was found that 4ꢀ(3ꢀmercaptopropyl)phenol (10),
obtained upon heating of 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ(3ꢀmerꢀ
captopropyl)phenol (2) with conc. HBr undergoes
condensation under the reaction conditions to form
3ꢀ(4ꢀhydroxyphenyl)propyl[4ꢀ(3ꢀmercaptopropyl)phenyl]
sulfide (14) as the main product.
A method for the synthesis of phloretic acid by deꢀ
tertꢀbutylation of 3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxypheꢀ
nyl)propionic acid and its methyl ester upon treatment
with conc. HBr was proposed.
Experimental
Alcohols 1а—d 14,15 and thiol 2 16 were obtained according
to the described procedures. Acid 3а is a commercial product
from NIIKhIMPOLIMER. Ester 3b was synthesized by esterifiꢀ
cation of acid 3а with methyl alcohol.
NMR spectra were recorded on a Bruker DRX500 specꢀ
trometer with the working frequency of 500.13 MHz, for acid 17,
in D2O (SiМе4 as the standard), for other compounds, in СDСl3
(СHСl3 as the standard). Mass spectral analysis was performed
on a Finnigan MAT 8200 mass spectrometer.
Chromatoꢀmass spectrometry was performed on a Hewlett
Packard G1801A spectrometer, which included HP 5890 gas
chromatograph of the II series and НР 5971 massꢀselective detecꢀ
2ꢀtertꢀButylꢀ4ꢀ(3ꢀhydroxypropyl)phenol (5). Argon was
bubbled through a melt of alcohol 1b (25 g, 94 mmol) for 80 min

Reactions of alkyldiꢀtertꢀbutylphenols with HHal
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1123
at 315 °C, then the reaction mixture was cooled and dissolved in
toluene. The solution was sequentially treated with 5% and
10% aq. NaOH, the latter extract was neutralized with hydroꢀ
chloric acid and treated with toluene. The toluene extract was
washed with water, dried with Na2SO4, and the solvent was
evaporated. The residue was distilled in vacuo and the target
alcohol 5 (14.8 g, 75%) was obtained, b.p. 139—140.5 °C
(1 Torr), m.p. 47—49 °C (from hexane). Found (%): С, 75.16;
H, 9.88. C13H20O2. Calculated (%): C, 74.96; H. 9.68. 1H NMR,
δ: 1.39 (s, 9 Н, But), 1.57 (br.s, 1 Н, СН2ОН); 1.84—1.88 (m,
2 Н, СН2СН2СН2); 2.61 (t, 2 Н, ArCH2, J = 7.5 Hz); 3.69 (t,
2 Н, СН2ОН, J = 6.5 Hz); 5.28 (s, 1 Н, ОН); 6.57 (d, 1 Н, Ar,
J = 8 Hz); 6.86 (dd, 1 Н, Ar, J = 8 Hz, J = 2 Hz); 7.06 (d, 1 Н,
Ar, J = 2 Hz).
4ꢀ(3ꢀHydroxypropyl)phenol (7) was obtained similarly to alꢀ
cohol 5 upon heating of alcohol 1b for 11 h at 324 °C. The yield
was 76%, m.p. 55 °C (from CHCl3). Found (%): С, 71.17;
H, 8.08. C9H12O2. Calculated (%): C, 71.03; H. 7.95. 1H NMR,
δ: 1.85 (m, 2 Н, СН2СН2СН2); 2.62 (t, 2 Н, ArCH2, J =
7.5 Hz); 3.40 (s, 1 Н, СН2ОН); 3.63 (t, 2 Н, СН2ОН, J =
6.5 Hz); 6.73, 7.02 (both d, 2 Н each, Ar, J = 8 Hz); 7.86
(s, 1 Н, ОН).
2ꢀtertꢀButylꢀ4ꢀ(3ꢀmercaptopropyl)phenol (9). Chloride 6
(10.2 g, 45 mmol), 25% aq. NH4HS (10.7 mL, 67.4 mmol), and
ethanol (25 mL) were placed in a 80ꢀmL tube made of thermoꢀ
stable glass, the tube was sealed and kept in a thermostat equipped
with a shaking device for 4 h at 120 °C. After cooling and openꢀ
ing of the tube, the content was treated with benzene. The
extract was washed with water, dried with Na2SO4, and the
solvent was evaporated. The residue was distilled in vacuo to
obtain the target thiol 9 (8.52 g, 81%), b.p. 142—146 °С (3 Torr).
Found (%): С, 69.43; H, 9.07; S, 14.01. С13H20OS. Calcuꢀ
lated (%): С, 69.59; H, 8.98; S, 14.29. 1H NMR, δ: 1.13 (t, 1 H,
SH, J = 8 Hz); 1.40 (s, 9 H, But); 1.82 (m, 2 H, CH2CH2CH2);
2.58 (m, 4 H, CH2CH2CH2); 4.68 (s, 1 H, OH); 6.54 (d, 1 H,
Ar, J = 8 Hz); 6.86 (dd, 1 H, Ar, J = 8 Hz, J = 2 Hz); 7.04 (d,
1 H, Ar, J = 2 Hz).
tertꢀButyl 3ꢀ(3ꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propyl sulfide
(12). Thiol 2 (5 g, 17.8 mmol) and tertꢀbutylbromide (30 mL,
0.27 mol) were placed in a 80ꢀmL tube made of thermostable
glass, the tube was sealed and kept in a thermostat equipped with
a shaking device for 8 h at 150 °C. After cooling and opening of
the tube, the content was treated with benzene. The extract was
washed with water, dried with Na2SO4, and the solvent was
evaporated. The residue was chromatographed on silica gel with
hexane as the eluent. Sulfide 12 (1.8 g, 36%) was obtained.
Found (%): С, 72.98; H, 10.19; S, 11.64. С17Н28OS. Calcuꢀ
lated (%): С, 72.80; H, 10.06; S, 11.43. 1H NMR, δ: 1.31 (s,
9 H, SBut); 1.39 (s, 9 H, But); 1.98 (m, 2 Н, CH2CH2CH2);
2.55 (t, 2 H, CH2S, J = 8 Hz); 2.64 (t, 2 H, ArCH2, J = 7.5 Hz);
5.06 (s, 1 H, OH); 6.59 (d, 1 H, Ar, J = 8 Hz); 6.78 (dd, 1 H, Ar,
J = 8 Hz, J = 2 Hz); 7.07 (d, 1 H, Ar, J = 2 Hz).
tertꢀButyl 3ꢀ(4ꢀhydroxyphenyl)propyl sulfide (13) was obꢀ
tained similarly from thiol 10. The yield was 47%. Found (%):
С, 69.60; H, 9.04; S, 14.15. С13H20OS. Calculated (%): С, 69.59;
H, 8.98; S, 14.29. 1H NMR, δ: 1.31 (s, 9 H, But); 1.87 (m, 2 H,
CH2CH2CH2); 2.57 (t, 2 Н, CH2S, J = 8 Hz); 2.66 (t, 2 H,
ArCH2, J = 7.5 Hz); 4.80 (s, 1 H, ОН); 6.74, 7.04 (both d,
2 H each, Ar, J = 8.5 Hz).
Reaction of thiol 2 with hydrochloric acid. Thiol 2 (5 g,
17.8 mmol) and hydrochloric acid (23 mL, 0.21 mol of HCl)
were placed in a 80ꢀmL tube made of thermostable glass, the
tube was sealed and kept in a thermostat equipped with a shakꢀ
ing device for 4.5 h at 160 °C. After cooling and opening of the
tube, the content was treated with benzene. The extract was
washed with water, dried with Na2SO4, and the solvent was
evaporated. According to GC/MS data, the obtained product
contained thiol 9 (42%), thiol 10 (10%), sulfide 12 (46%) and
sulfide 13 (2%).
4ꢀ(3ꢀBromopropyl)phenol. Alcohol 1b (120 g, 0.45 mol) and
41% aq. hydrobromic acid (384 mL, 2.67 mol of HBr) were
refluxed for 12 h with azeotropic distillation of an HBr—H2O
mixture. Then the reaction mixture was cooled and treated with
toluene. The extract was washed with water, dried with Na2SO4,
and the solvent was evaporated. The residue was distilled in vacuo
and the target bromopropylphenol (87.9 g, 91%) was obtained,
b.p. 121—124 °C (1 Torr), m.p. 38—40 °C (from pentane).
Found (%): С, 50.33; Н, 5.21; Br, 36.97. C9H11BrO. Calcuꢀ
1
lated (%): С, 50.26; Н, 5.15; Br, 37.15. H NMR, δ: 2.08—2.14
(m, 2 Н, СН2СН2СН2); 2.70 (t, 2 Н, ArCH2, J = 7.5 Hz); 3.37
(t, 2 Н, СН2Br, J = 7 Hz); 5.00 (s, 1 Н, ОН); 6.76, 7.14 (both d,
2 Н each, Ar, J = 8 Hz).
4ꢀ(2ꢀBromoethyl)phenol was obtained similarly from alcoꢀ
hol 1а, the yield was 79%, b.p. 108—110 °C (1—2 Torr), m.p.
85—87 °C (from hexane). Found (%): С, 47.95; Н, 4.48;
Br, 40.00. C8H9BrO. Calculated (%): С, 47.79; Н, 4.51;
Br, 39.74. 1H NMR, δ: 3.00 (t, 2 Н, ArCH2, J = 7.5 Hz); 3.48 (t,
2 Н, СН2Br, J = 7.5 Hz); 5.03 (s, 1 Н, ОН); 6.71, 6.99 (both d,
2 Н each, Ar, J = 8.5 Hz).
4ꢀ(4ꢀBromobutyl)phenol was obtained similarly from alcoꢀ
hol 1с, the yield was 91%, b.p. 146—148 °C (3 Torr). Found (%):
С, 52.56; Н, 5.96; Br, 34.73. C10H13BrO. Calculated (%):
1
С, 52.42; Н, 5.72; Br, 34.87. H NMR, δ: 2.10—2.13 (m, 4 Н,
ArCH2(СН2)2); 2.62 (t, 2 Н, ArCH2, J = 7.5 Hz); 3.33 (t, 2 Н,
СН2Br, J = 7 Hz); 5.02 (s, 1 Н, ОН); 6.75, 7.10 (both d,
2 Н each, Ar, J = 8 Hz).
Reaction of thiol 2 with hydrobromic acid. A mixture of thiol 2
(20 g, 71.3 mmol) and hydrobromic acid (125 mL, 0.87 mol
of HBr) was refluxed for 6 h with azeotropic distillation of an
HBr—H2O mixture under flow of argon, then the reaction mixꢀ
ture was cooled and treated with toluene. The extract was washed
with brine, dried with Na2SO4, and the solvent was evaporated.
The residue was distilled in vacuo to yield 4ꢀ(3ꢀmercaptoꢀ
propyl)phenol (10) (6.72 g, 56%), b.p. 117—118 °C (1 Torr).
Found (%): С, 63.18; Н, 7.29; S, 19.17. С9Н12OS. Calcuꢀ
lated (%): С, 64.25; Н, 7.19; S, 19.06. 1H NMR, δ: 1.37 (t,
1 H, SH, J = 8 Hz); 1.85—1.89 (m, 2 Н, СН2СН2СН2);
2.47—2.52 (m, 2 Н, СН2S); 2.63 (t, 2 Н, ArCH2, J =
7.5 Hz); 4.95 (br.s, 1 Н, ОН); 6.75, 7.02 (both d, 2 Н each, Ar,
J = 8 Hz).
4ꢀ(3ꢀIodopropyl)phenol. Alcohol 1b (20 g, 76 mmol) and
45% aq. hydroiodic acid (57.6 mL, 0.3 mol of HI) were stirred
for 36 h at 120—130 °C. Then the reaction mixture was cooled
and treated with toluene. The extract was washed with water,
dried with Na2SO4, and the solvent was evaporated. The residue
was distilled in vacuo and the target iodopropylphenol (6.5 g,
36%) was obtained, b.p. 150—152 °C (2 Torr), m.p. 32 °C (from
pentane). Found (%): С, 41.18; Н, 4.35; I, 48.32. C9H11IО.
Calculated (%): С, 41.25; Н, 4.23; I, 48.42. 1H NMR, δ:
1.75—2.25 (m, 2 Н, СН2СН2СН2); 2.57 (t, 2 Н, ArCH2, J =
7.5 Hz); 3.04 (t, 2 Н, СН2I, J = 7 Hz); 6.09 (s, 1 Н, ОН); 6.63,
6.95 (both d, 2Н each, Ar, J = 8 Hz).

1124
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Prosenko et al.
The residue in the distillation flask was sequentially recrysꢀ
tallized from toluene and hexane to give 3ꢀ(4ꢀhydroxypheꢀ
nyl)propyl[4ꢀ(3ꢀmercaptopropyl)phenyl] sulfide (14) (2.84 g,
25%), m.p. 54—56 °C. Found (%): С, 67.77; Н, 7.00; S, 20.34.
С18Н22OS2. Calculated (%): С, 67.88; Н, 6.96; S, 20.13.
1H NMR, δ: 1.39 (t, 1 H, SH, J = 8 Hz); 1.89—1.92 (m, 4 Н,
СН2СН2СН2); 2.50—2.54 (m, 2 Н, СН2SН); 2.67—2.69 (m,
4 Н, ArCH2); 2.88 (t, 2 Н, СН2SAr, J = 7.5 Hz); 5.50 (br.s, 1 Н,
ОН); 6.75, 7.02, 7.09, 7.25 (all d, 2 Н each, Ar, J = 8 Hz).
MS (EI, 70 eV), m/z (Irel (%)): 318 [M]+ (33), 257
[M – HSCH2CH2]+ (2), 211 [M – HOC6H4CH2]+ (2), 184
[HSC6H4(CH2)3SH]+ (2), 149 [CH2=CHSC6H4CH2]+ (9), 134
[HOC6H4CH2CH=CH2]+ (100), 123 [HSC6H4CH2]+ (7), 107
[HOC6H4CH2] + (37), 91 [C7H7]+ (8), 77 [C6H5]+ (9).
3ꢀ(4ꢀHydroxyphenyl)propyl 4ꢀ(3ꢀmercaptopropyl)phenyl sulꢀ
fide (14). A mixture of thiol 10 (4.26 g, 25 mmol) and hydrobroꢀ
mic acid (30.5 mL, 0.24 mol of HBr) was kept for 16 h at
120—122 °C in an atmosphere of argon, then the reaction mixꢀ
ture was cooled and treated with toluene. The extract was washed
with water, dried with Na2SO4, and the solvent was evaporated.
The residue was distilled in vacuo. The residue in the distillaꢀ
tion flask was sequentially recrystallized from toluene and
hexane. The title compound 14 (2.6 g, 33%) was obtained,
m.p. 55—56 °C.
Bis[3ꢀ(4ꢀhydroxyphenyl)propyl] disulfide (16). Sodium hydrꢀ
oxide (0.8 g, 20 mmol) was dissolved in water (40 mL), then
thiol 10 (3 g, 17.9 mmol) was added under argon, and after its
dissolution, 30% aq. Н2О2 (2 mL, 19.5 mmol of Н2О2) was
added. The solution was stirred for 1 h at 20 °C, neutralized with
HCl, and treated with Et2O. The extract was washed with brine,
dried with Na2SO4, and the solvent was evaporated. Disulfide 16
(1.45 g, 84%) was obtained, m.p. 76—77 °C (from hexane).
Found (%): С, 64.71; Н, 6.77; S, 19.08. C18H22O2S2. Calcuꢀ
lated (%): С, 64.63; Н, 6.63; S, 19.17. 1H NMR, δ: 1.92 (m,
4 H, CH2CH2CH2); 2.60 (m, 8 H, CH2CH2CH2); 4.48 (s, 2 Н,
ОН); 6.65, 6.97 (both d, 4 H each, Ar, J = 8 Hz).
J = 7.5 Hz); 3.86 (t, 2 H, ArCH2, J = 7.5 Hz); 6.67, 7.01
(both d, 2 H each, Ar, J = 8.5 Hz).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 00ꢀ03ꢀ
32721); access to the STN International database was
made through the Novosibirsk STN Center in NIOKh
SB RAS.
References
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3ꢀ(4ꢀHydroxyphenyl)propionic acid (17). A mixture of acid 3а
(8 g, 28.7 mmol) and 41% aq. hydrobromic acid (24.5 mL,
0.17 mol of HBr) was refluxed for 2 h, then the reaction mixture
was cooled, the formed crystals were filtered off. The yield of
acid 17 was 4.4 g (92%), m.p. 132 °C (from toluene). Acid 17
was similarly obtained from ester 3b, the yield was 91%.
Found (%): С, 64.93; Н, 6.15. C9H10O3. Calculated (%):
С, 65.05; Н, 6.07. 1H NMR, δ: 2.60 (t, 2 H, CH2СООН,
13. S. Oae and R. Kiritani, Bull. Chem. Soc. Jpn, 1965, 38, 1381.
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Received February 9, 2007;
in revised form May 15, 2007