One-step synthesis of unsymmetrical sulfides bearing hexafluorocumyl moiety

Article abstract of DOI:10.1080/00397911.2013.774018

A facile and convenient one-pot synthesis of novel unsymmetrical sulfides, 2′-alkylthio-and 2′-arylthio-1,1,1,3,3,3-hexafluoro-2-phenylpropan- 2-oles 1a-k, is presented. Physicochemical characterization; IR infrared; ¹H, ¹³C, and

Full text of DOI:10.1080/00397911.2013.774018

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One-Step Synthesis of Unsymmetrical
Sulfides Bearing Hexafluorocumyl Moiety
Adrian Zając a & Józef Drabowicz a b
a Department of Heteroorganic Chemistry , Center of Molecular and
Macromolecular Studies, Polish Academy of Sciences , Łódź , Poland
b Department of Chemistry , Jan Dlugosz University in Czestochowa,
Environmental Protection and Biotechnology , Częstochowa , Poland
Published online: 05 Sep 2013.
To cite this article: Adrian Zając & Józef Drabowicz (2013) One-Step Synthesis of Unsymmetrical
Sulfides Bearing Hexafluorocumyl Moiety, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:24, 3287-3293
To link to this article: http://dx.doi.org/10.1080/00397911.2013.774018
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Synthetic Communications1, 43: 3287–3293, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.774018
ONE-STEP SYNTHESIS OF UNSYMMETRICAL
SULFIDES BEARING HEXAFLUOROCUMYL MOIETY
1
Adrian Zaja˛c and Jozef Drabowicz
1,2
´
1Department of Heteroorganic Chemistry, Center of Molecular and
´ ´
Macromolecular Studies, Polish Academy of Sciences, Łodz, Poland
2Department of Chemistry, Jan Dlugosz University in Czestochowa,
Environmental Protection and Biotechnology, Cze˛stochowa, Poland
GRAPHICAL ABSTRACT
Abstract A facile and convenient one-pot synthesis of novel unsymmetrical sulfides,
20-alkylthio- and 20-arylthio-1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-oles 1a–k, is presen-
ted. Physicochemical characterization; IR infrared; 1H, 13C, and 19F NMR; and mass
spectral analyses of the obtained compounds are discussed as well.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Alkyl–aryl sulfides; diaryl sulfides; hexafluorocumylalcohol; ortholithiation;
unsymmetrical sulfides
Received January 10, 2013.
Address correspondence to Adrian Zaja˛c, Department of Heteroorganic Chemistry, Center of
´
Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łodz,
´
Poland. E-mail: a.zajac81@op.pl
3287

3288
A. ZAJA˛ C AND J. DRABOWICZ
INTRODUCTION
Physicochemical properties of unsymmetrical sulfides make them very interest-
ing divalent organosulfur derivatives. Some of them are biologically and pharmaco-
logically active.[1–3] Therefore they are used as pesticides,[4] antioxidants,[5] and
germicidal agents.[6] Other ones have applications in the formation of self-assembling
monolayers with interesting physical properties.[7,8] First of all, these compounds are
very useful in organic synthesis as precursors of higher-valent sulfur compounds, for
example, sulfoxides,[1,2,4,9–11] sulfones, and sulfonium salts.
During the years a number of methods for the synthesis of these compounds
have been described in the literature. Probably the most commonly used route is
based on an alkylation of thiols[1,5,12,13] or thiolates[4,7,14] with alkyl or aryl halides
in various conditions. Other protocols include aziridine ring opening with thiols,[15]
palladium-catalyzed cross-coupling reaction of compounds containing sulfur–boron
single bonds with organic electrophiles (Suzuki reaction),[16] sulfenylation of arenes
with arenesulfenyl chlorides,[6,17] reduction of thiolesters,[18] and metal-catalyzed
reductive coupling of disulfides with organic halides[3,19–22] or organoboronic
acids.[23,24]
DISCUSSION
The ortholithiation reaction of 1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol and
subsequent treatment with various electrophiles as a method of synthesis of the cor-
responding ortho-substituted derivativeshas been known for a long time[25] but is still
fruitfully used.[26–30] Nevertheless, usage of symmetrical disulfides as precursors of
an electrophile in this process has not been presented until now.
Here we report a facile protocol that allows the one-pot synthesis of
unsymmetrical sulfides bearing hexafluorocumyl moiety, 20-alkylthio- or 20-arylthio-
1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-oles 1a–k (except described elsewhere but
obtained by other methods, such as compounds 1a[31] and 1f[32]). It is based on
the use of commercially available 1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol (hexa-
fluorocumyl alcohol) 2 as a substrate. It reacts with n-butyllithium in the presence of
tetramethylethylenediamine (TMEDA) in tetrahydrofuran (THF) under nitrogen
with the formation of the dilithiated derivative 3. The generated dilithium salt was
allowed to react with the corresponding disulfide 4a–k in THF for 24 h and gave,
after standard work up, the expected unsymmetrical sulfides listed in Scheme 1.
The isolated crude residues were purified by column chromatography to afford the
corresponding pure products 1a–k in good yields. The products are colorless liquids,
except 1f and 1i–k, which are colorless solids with low melting points. They are stable
at room temperature under a laboratory atmosphere.
Scheme 1. Synthesis of sulfides 1a–k.

SYNTHESIS OF UNSYMMETRICAL SULFIDES
3289
Scheme 2. Attempts of synthesis of the sulfide 1e.
Generally, the yield strongly depends on the surroundings of the carbon atom
attached to the divalent sulfur atom. Thus, the yields are comparable for substituents
containing primary or secondary carbon atoms and decrease dramatically for di-t-
butyl disulfide. The fact can be easily explained by the increase of bulkiness of the
substituents. It should also be noted that for ethyl sulfide 1b the yield is surprisingly
less than for n-propyl analoge 1c. The fact is reproductible and remains unexplained.
The isolated yields for naphthyl and aza-aromatic analogs are lowest, which is most
likely due to more complex purification process in comparison with other analogs,
although yields established by NMR measurements were good. Because the yield
of the reaction is extremely poor for 1e, where R ¼ t-Bu we attempted to use S-t-
butyl methanethiosulfonate 5 instead of disulfide 4e (Scheme 2). It should be more
active because of the presence of a better leaving group, the methanesulfonyl moiety.
Unfortunately, all attempts failed and furnished only unchanged substrate 2 in
almost quantitative yield. The use of N-(t-butylsulfanyl)phthalimide 6 was ineffective
either (Scheme 2) and results in some other product, which will be described else-
were. Considering physicochemical properties of the newly prepared unsymmetrical
sulfides it is interesting to note that coefficient of light refraction for liquid products
increases with increasing of a number of carbon atoms, and for aryl analogs 1 g and h
is considerably greater than for alkyl compounds 1a–d.
EXPERIMENTAL
The melting points were measured on capillary apparatus and were not cor-
rected. For column chromatography, silica gel 60 (70-to 230-mesh ASTM) was used.
For preparative thin-layer chromatography (TLC), silica-gel 60 F254 200 ꢀ 200 ꢀ
2 mm preparative thin-layer chromatography (PLC) glass plates were used. The
NMR spectra were obtained using 200-MHz and 500-MHz spectrometers. The infra-
red (IR) spectra were recorded using Fourier transform infrared (FTIR) spec-
trometer by the thin film and KBr tablet methods. The mass spectra and

3290
A. ZAJA˛ C AND J. DRABOWICZ
high-resolution mass spectrometry (HRMS) were measured using a double-focusing
(BE geometry) mass spectrometer utilizing chemical ionization (CI) with isobutane
as an ionizating agent or electron ionization (EI) technique. The coefficients of light
refraction were measured using Abbe’s type refractometer.
Disulfides were synthesized by a previously published method.[31]
2’-Alkylthio- or 2’-Arylthio-1,1,1,3,3,3-hexafluoro-2-phenylpropan-
2-ols (1a–k): General Procedure
A solution of n-BuLi in hexane (10 mL, 2.5 M, 25 mmol) was transferred using
a syringe into dry round-bottom two-neck flask previously flushed out with nitrogen,
placed on a magnetic stirrer, and sealed with two rubber septa under nitrogen at rt.
TMEDA (0.57 mL, 3.75 mmol, 15%mol with respect to n-BuLi) was then added
dropwise to the stirred solution using a syringe. The solution became cloudy in a
while. After additional stirring (30 min) the reaction mixture was cooled to ca.
ꢁ10 ꢂC on an acetone = dry ice bath, and a solution of alcohol 2 (2.08 g, 8.5 mmol)
in dry THF (3 mL) was added dropwise using syringe during 10 min. After the
addition the mixture became clear. Then the reaction mixture was allow to reach
rt and was stirred for the next 24 h. After that, the mixture was cooled to ca.
ꢁ10 ꢂC on an acetone = dry ice bath again, and the corresponding disulfide 4a–k
(8.5 mmol) was added dropwise using a syringe over 10 min. After reaching rt the sol-
ution was stirred for 24 h, and the resulting solution was then transferred into a sep-
aration funnel and quenched with an equal volume of H2O and ca. 5% solution of
H2SO4 (5 mL). The two-phase system was then shaken for 1 min and extracted with
CH2Cl2 (3 ꢀ 30 mL). The combined organic extracts were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel (CHCl3), furnishing the
corresponding pure products 1a–k.
2’-Methylthio-1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol (1a)
1
Colorless liquid; yield: 2.09 g (85%); n2D5 ¼1.4613; Rf ¼ 0.8 (CHCl3). H NMR
(200 MHz, CDCl3): d ¼ 2.54 (s, 3H), 7.39–7.50 (m, 2H), 7.62–7.84 (m, 2H), 8.70
2
(s, 1H). 13C NMR (125 MHz, CDCl3): d ¼ 22.1, 80.9 (h, JC-F ¼ 29.7 Hz), 122.8
1
3
(q, JC-F ¼ 288.3 Hz), 128.9, 129.3 (h, JC-F ¼ 2.8 Hz), 130.1, 130.6, 134.7, 138.3.
19F NMR (188 MHz, CDCl3): d ¼ ꢁ73.80. IR (thin film): 3166 (O-H stretch), 1114
(C-F stretch), 707 (C-S stretch) cmꢁ1. MS (EI, 70 eV): m=z (%) ¼ 124.1 (11), 151.1
(19), 290.1 (100) [M]þ. HRMS-EI: m=z [M]þcalcd. for C10H8OSF6: 290.0200; found:
290.0197 (D 1,15696).
CONCLUSION
We developed a convenient protocol for the synthesis of 20-alkylthio- or
20-arylthio-1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-oles 1a–k from hexafluorocu-
myl alcohol 2 and the corresponding disulfides 4a–k and fully characterized the
new products. They can be considered as convenient precursors of optically active
higher-valent sulfur compounds.

SYNTHESIS OF UNSYMMETRICAL SULFIDES
3291
SUPPORTING INFORMATION
1
Full experimental details, and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
This project was financially supported (grants to JD) by a government fund
created to support science in the 2009–2012 period (N N204 144437) and in part
by the National Science Center fund awarded based on the decision UMO-2011=
01=B=ST5=06304.
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