Aliphatic thioethers by s-alkylation of thiols via trialkyl borates

Article abstract of DOI:10.1080/10426500903213563

A simple and convenient one-pot procedure is described for the synthesis of thioethers via boron esters. This procedure involves in-situ generation of alkyl sulfates by reaction of trialkyl borates with concentrated sulfuric acid and subsequent reaction with thiols in the presence of pyridine. The reactions with boron esters of primary or secondary alcohols proceed cleanly at 100C and afford aliphatic thioethers in reasonable yields (59-93%) within 24 h. Interestingly, the 1H NMR spectra of the products showed no sign of positional isomerisms. The method fails however with thiophenol and does not yield aromatic thioethers, due to electrophilic substitution at the phenyl ring. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903213563

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ALIPHATIC THIOETHERS BY S-
ALKYLATION OF THIOLS VIA TRIALKYL
BORATES
Deniz Gunes a , Okan Sirkecioglu a & Niyazi Bicak a
a Istanbul Technical University, Department of Chemistry, Maslak,
Istanbul, Turkey
Version of record first published: 02 Aug 2010.
To cite this article: Deniz Gunes, Okan Sirkecioglu & Niyazi Bicak (2010): ALIPHATIC THIOETHERS
BY S-ALKYLATION OF THIOLS VIA TRIALKYL BORATES, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:8, 1685-1690
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Phosphorus, Sulfur, and Silicon, 185:1685–1690, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903213563
ALIPHATIC THIOETHERS BY S-ALKYLATION OF THIOLS
VIA TRIALKYL BORATES
Deniz Gunes, Okan Sirkecioglu, and Niyazi Bicak
Istanbul Technical University, Department of Chemistry, Maslak, Istanbul, Turkey
A simple and convenient one-pot procedure is described for the synthesis of thioethers via
boron esters. This procedure involves in-situ generation of alkyl sulfates by reaction of
trialkyl borates with concentrated sulfuric acid and subsequent reaction with thiols in the
presence of pyridine. The reactions with boron esters of primary or secondary alcohols
proceed cleanly at 100◦C and afford aliphatic thioethers in reasonable yields (59–93%)
within 24 h. Interestingly, the 1H NMR spectra of the products showed no sign of positional
isomerisms. The method fails however with thiophenol and does not yield aromatic thioethers,
due to electrophilic substitution at the phenyl ring.
Keywords Alkyl sulfates; thioethers; trialkyl borates
INTRODUCTION
Thioethers are valuable key intermediates in various organic syntheses.1 They are
precursors2–4 for sulfoxides and sulfones. Chiral sulfoxides are useful auxiliaries in asym-
metric syntheses. The sulfur ylides derived from thioethers have found extensive use in the
syntheses of epoxides5 and cyclopropanes.6 The formation of sulfonium salts by reaction of
alkyl halides with thioethers is a reversible process.7 The sulfonium salts with weak nucle-
ophilic anions act as initiating species in thermal- or photo-induced cationic polymerization
of oxiranes8 and vinyl ethers.9–11
Numerous methods for the synthesis of thioethers have appeared. S-Alkylation of
thiols with alkyl halides,12 anti-markovnikov addition of alkanethiols to alkenes,13 and
addition of thiols to carbonyl compounds with subsequent reduction of the generated thion-
ium ions14 are the most common ways to synthesize them. Other less common routes, such
as metal-mediated cross-coupling15 or metal-catalyzed hydrothiolation of alkynes16 and
Friedel–Crafts reaction of N-phenyl thiophthalimide with benzenes17 have been employed
for the synthesis of thioethers. Recently, Saxena et al. described an interesting procedure in
which thioethers are generated by oxidative coupling of thiols with alcohols in the presence
of nickel nanoparticles as catalyst.18
Received 15 April 2009; accepted 23 July 2009.
The Boron Research Institute of the Turkish Government is acknowledged for the financial support (BOREN-
2006-12-C11>> 17).
Address correspondence to Niyazi Bicak, Istanbul Technical University, Department of Chemistry, Maslak
34469, Istanbul, Turkey. E-mail: bicak@itu.edu.tr
1685

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D. GUNES ET AL.
RESULTS AND DISCUSSION
In this article, we report an alternative procedure for the alkylation of thiols to give
thioethers in good to excellent yields (see Table I). In this procedure, trialkyl borates are
employed as alkyl precursors. The preparation of boron esters of higher alcohols boiling
over 100◦C is a relatively simple task that can be achieved by azeotropic removal of water
from alcohol–boric acid mixtures at 115–130◦C, using toluene or benzene.19
Scheme 1
Removal of the toluene gives trialkyl borates as colorless liquids. The yields are
generally higher than 90% in proper conditions, and the products are pure enough (>98%)
for use in the follow-up reactions, without further purification. The resulting trialkyl borates
are converted into alkyl sulfates by reaction with equivalent amounts of sulfuric acid at room
temperature. Addition of a pyridine-thiol mixture to the reaction medium and subsequent
heating at 100◦C for 24 h gives thioethers in reasonable yields. The overall process consists
of alkylation of thiols via boron esters in a one-pot procedure as depicted in Scheme 1.
Direct heating of a mixture of tributyl borate with butanethiol and pyridine in the absence
1
of sulfuric acid, however, did not yield any thioether product. The H NMR spectrum of
the reaction mixture showed no trace of thioether, even after a reaction period of 48 h. This
Table I Synthesis of thioethers R
S Bu via trialkyl borates B(OR)3
R
Reaction time (h)
R
S
Bu
Yield (%)a
n-Butyl
6
24
30
24
24
24
24
24
24
C4H9
S
C4H9
64.0
88.0b
93.0
81.2c
78.8
68.4
71.0
58.7
65.0
n-Pentyl
Cyclohexyl
n-Octyl
2-Etylhexyl
2-Decyl
n-Dodecyl
C5H11 S C4H9
cyclo-C6H11
C8H17 C4H9
C4H9 CH(C2H5) CH2
C8H17 CH(CH3) C4H9
12H23 C4H9
S
C4H9
S
S C4H9
S
C
S
aConversion yields assigned by 1H NMR spectroscopy of the reaction mixture.
bIsolated yield 64.2%.
cIsolated yield 67.2%.

S-ALYKYLATION OF THIOLS VIA TRIALKYL BORATES
1687
implies that the acidity of the thiol group is not sufficient to protonate the oxygen atom of
the boron ester. In other words, trialkyl borates themselves cannot react as alkylating agents
but must be converted into alkyl sulfates for the successful alkylation of thiols. The use of
alkyl sulfates as alkylating agents for phenols and amines has been well documented in the
literature.20 Dimethyl sulfate is the most common ester of sulfuric acid, having extensive
use as a methylating reagent in organic chemistry.21 In recent years, this compound has
been replaced with methyl iodide in methylation reactions due to its potent carcinogenic
effects.22
The use of alkyl sulfates for the alkylation of thiols could be considered a more direct
way to synthesize thioether. However, most of the dialkyl sulfates are not commercially
available, and the classical method of their preparation involves sulfatation of alcohols either
with chlorosulfonic acid23,24 or with sulfur trioxide. Besides difficulties in handling of these
reagents, a number of side reactions such as dehydration, isomerization, and etherification
occur to some extent, depending on the reaction conditions.3 The direct sulfatation with
sulfuric acid, on the other hand, does not give satisfactory yields with higher alcohols and
exhibits the disadvantages of side reactions.4
Tertiary amine–sulfur trioxide complex salts, e.g., pyridine-SO3 and triethylamine-
SO3, have been demonstrated to be versatile and safe reagents for the sulfatation of primary
and secondary alcohols.5,6 However, the yields reported were in the range of only 30–60%
for C8–C16 alcohols.
Considering the difficulties in the common procedures, the in-situ generation of alkyl
sulfate intermediates by sulfuric acid according to the present procedure represents an
attractive alternative. In order to inspect the extent of the sulfate ester formation, an aliquot
of tributyl borate–sulfuric acid mixture (2/3 mol/mol) was digested in ether (10 mL per
1
gram) and filtered. Removal of the ether yielded a clear liquid residue. The H NMR
spectrum of this product (in CDCl3) indicated pure di-n-butyl sulfate (with 98% practical
yield), but no other isomers. This reveals that the alkylation of thiols under these condition
proceeds via dialkyl sulfate intermediates.
The reactions conducted at 100◦C for 24 h gave thioethers in good to excellent yields
(59–93%) as listed in Table I. Since thioethers are water-immiscible, they were isolated
simply by washing the reaction mixtures with aqueous sodium hydroxide solution and
subsequent distillation of the organic phases.
The reaction with butyl mercaptane and tributyl borate at room temperature gave only
32–34% of conversion yields within 48 h. The lower yields at room temperature must be
due to the less pronounced reactivity of the second alkyl group of dialkyl sulfates in the
alkylation process. Therefore 100◦C was chosen as the reaction temperature.
The 1H NMR spectra of the products prior to distillation of the organic phases showed
CH2 proton signals associated with the methylol groups of the alcohol, which is formed by
hydrolysis of the boron esters. Integral ratios of those peaks appearing around 3.5 ppm were
1
employed to estimate the conversion rates. In the H NMR spectrum of dibutyl sulfide, a
sharp triplet of S-CH2 protons is observed at 2.38 ppm. In addition, the terminal methyl
protons exhibit a triplet at 0.82 ppm and the methylene protons of the butyl group give two
multiplets centered at 1.45 and 1.35 ppm. The integral ratio of those protons is 2:3:2:2,
respectively. No other signals at around 2.5 ppm are observed, which implies the absence
1
of positional isomers in the thioether product. A similar H NMR pattern is observed in
the case of butyl isodecyl sulfide in which the S-CH2-protons of the butyl group and an
S-CH-proton of the isodecyl group show a complex signal with an integral for three protons
as expected.

1688
D. GUNES ET AL.
For the synthesis of aromatic thioethers by this procedure, thiophenol was utilized as
a thiol component. However, the reaction did not yield the expected phenyl alkyl sulfide.
Instead, the product was 2-butylthiophenol, indicating that the electrophilic substitution at
the phenyl ring is favored compared with the S-alkylation. Since alkyl phenols are beyond
the scope of the present work, this reaction was not studied any further. It is important to
note that we were not able to prepare benzyl butyl sulfide starting from tribenzyl borate,
because the addition of the sulfuric acid resulted in a violent explosion to give a yellow
solid. The solid product formed was identified as poly(1,4-phenylene-methylene) instead
of dibenzyl sulfate. Thus, the synthesis of benzyl thioethers by this procedure is not
possible. We have also attempted to synthesize symmetrical thioethers by reaction of the
dialkyl sulfates with sodium sulfide. Since sodium sulfide is insoluble in organic media,
the reaction of dibutyl sulfate was carried out with aqueous sodium sulfide solution at
ambient temperatures or at 100◦C. However, the 1H NMR spectra of the reaction mixtures
revealed a conversion of only 16–28% for the same period of reaction time, due to the
rapid hydrolysis of the dialkyl sulfates in water. To avoid hydrolysis of the alkyl sulfate, the
reaction was performed under heterogeneous conditions using anhydrous sodium sulfide
powder without additional solvent. The yield in this case was even lower (5–7%) owing to
insolubility of the sodium sulfide.
In conclusion, the alkylation of thiols with dialkyl sulfates generated in-situ from
trialkyl borates and sulfuric acid gave the corresponding thioethers in the presence of
pyridine. The reaction can be performed in one step and allows the preparation of aliphatic
thioethers in satisfactory yields. This procedure is, however, not applicable to alcohols and
thiols with aromatic moieties.
EXPERIMENTAL
Boric acid, thiophenol, 1-butanethiol, alcohols (1-butanol, 1-pentanol, cyclohexanol,
2-ethylhexanol, isodecanol, and 1-dodecanol), and all other chemicals were analytical grade
commercial products (Aldrich or E. Merck). They were used as supplied, unless otherwise
stated. Products were characterized by comparison with authentic samples, based on FT-
IR spectra (which were taken by a Perkin Elmer FT-IR Spectrum One B spectrometer)
1
and H NMR spectra (recorded in CDCl3 as solvent, using a Bruker 250 MHz NMR
spectrometer), boiling points, and TLC. The boron esters were prepared according to the
general procedure given in the literature.19 The boron esters derived from higher alcohols
(isodecanol, 1-dodecanol) were used without distillation.
Preparation of Thioethers
Concentrated H2SO4 (8.4 mL, 0.15 mol) was added dropwise to the trialkyl borate
(0.1 mol) in a 250 mL flask at 0◦C while stirring. Stirring was continued for 30 min. A
mixture of butanethiol (27 mL, 0.30 mol) and pyridine (26 mL, 0.30 mol) was then added
portionwise within 10 min, and the resulting mixture was heated at 100◦C for 24 h. After
cooling, NaOH solution (2 M, 200 mL) was added to the mixture. The oily phase was
washed with saturated NaCl solution (2 × 150 mL), dried with Na2SO4, and distilled under
vacuum. Purities of the products were checked by 1H NMR spectroscopy. If necessary, the
thioethers were redistilled.

S-ALYKYLATION OF THIOLS VIA TRIALKYL BORATES
1689
1H NMR spectra (δ, ppm in CDCl3) of the Thioethers
Dibutyl sulfide. (distilled product) 2.38 (t, 4 H, SCH2), 1.45 (m, 4 H, SCH2CH2),
1.12–1.35 (m, 4 H, CH2), 0.82 (t, 6 H, CH3). Butanol formed by hydrolysis of unreacted
tributyl borate shows a weak triplet at 3.43 ppm associated with its CH2OH group. This
peak disappears after distillation under reduced pressure.
Butyl pentyl sulfide. 2.38 (t, 4 H, SCH2), 1.43 (m, 4 H, SCH2CH2), 1.22–1.35 (m,
6 H, CH2) 0.80 (t, 6 H, CH3). Pentanol present in the reaction mixture prior to distillation
shows a weak triplet at 3.43 ppm associated with its CH2OH group. This peak disappears
after distillation under reduced pressure.
Butyl cyclohexyl sulfide. 2.47 (bs, H, SCH), 2.32 (t, 2 H, SCH2), 1.30–1.90 (m,
12 H, CH2), 1.18 (m, 2 H, 4-CH2), 0.80 (t, 3 H, CH3).
Butyl octyl sulfide. 2.33 (t, 4 H, SCH2), 1.40 (m, 4 H, SCH2CH2R), 1.15 (m, 12
H, CH2), 0.80 (t, 6 H, CH3). Protons of the CH2OH groups of octanol show a weak triplet
at 3.41 ppm.
Butyl 2-ethylhexyl sulfide. 2.49 (t, 2 H, SCH2), 2.33 (bs, 2 H, SCH2) 1.70 (m, 1
H, SCH2CHR), 1.20–1.60 (m, 12 H, CH2), 0.82 (m, 9 H, CH3). Residual 2-ethylhexanol
in the crude product shows proton signals (CH2OH) at 3.52 ppm as a weak triplet.
Butyl 2-decyl sulfide. 2.47 (bs, 2 H, SCH), 2.38 (m, 1 H, SCH2CH2R), 1.10–1.40
(m, 18 H, CH2), 1.00 (m, 3 H, CH3-CHS), 0.74 (t, 6 H, CH3). Residual decane-2-ol in the
crude product shows proton signals (CH2OH) at 3.45 ppm as a weak triplet.
Butyl dodecyl sulfide. 2.55 (m, 4 H, SCH2), 1.43 (m, 4 H, SCH2CH2R), 1.20
(m, 20 H, CH2), 0.80 (s, 6 H, CH3). Residual dodeanol in the crude product shows proton
signals (CH2OH) at 3.55.
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