Catalyst-Free Insertion of Sulfoxonium Ylides into Aryl Thiols. A Direct Preparation of β-Keto Thioethers

Article abstract of DOI:10.1021/acs.orglett.6b01470

Insertion of sulfoxonium ylides into the S-H bond of aryl thiols without the need for a catalyst is demonstrated, furnishing β-keto thioethers in excellent yield in most cases. The method overcomes traditional syntheses that employ metal catalysts in combination with diazo compounds or toxic and hard-prepared haloketones. The experimental setup consists of mixing the reagents in acetonitrile at room temperature. Additional experimental as well as kinetic isotopic effect studies give some insight into the mechanism of this reaction.

Full text of DOI:10.1021/acs.orglett.6b01470

Letter
pubs.acs.org/OrgLett
Catalyst-Free Insertion of Sulfoxonium Ylides into Aryl Thiols.
A Direct Preparation of β‑Keto Thioethers
Rafael M. P. Dias and Antonio C. B. Burtoloso*
Instituto de Química de Sao Carlos, Universidade de Sao Paulo, CEP 13560-970 Sao Carlos, SP, Brazil
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* Supporting Information
ABSTRACT: Insertion of sulfoxonium ylides into the S−H bond of
aryl thiols without the need for a catalyst is demonstrated, furnishing
β-keto thioethers in excellent yield in most cases. The method
overcomes traditional syntheses that employ metal catalysts in
combination with diazo compounds or toxic and hard-prepared
haloketones. The experimental setup consists of mixing the reagents
in acetonitrile at room temperature. Additional experimental as well
as kinetic isotopic effect studies give some insight into the mechanism of this reaction.
rganosulfur compounds are well-known for their
importance in biology and chemistry.1 Beyond the
amino acids methionine and cysteine, the C−S bond is found
in many natural products and important drugs from the
pharmaceutical industry (Figure 1).2 Among organosulfur
low selectivity when N−H or O−H insertion can compete (or
O
other polar X−H bonds are present in the insertion partner),
the need for expensive catalysts, and limitations in scale-up.5
The second can provide very good yields6 but has the
disadvantage of using haloketones. It is well-known that most
haloketones are lachrymatory, unstable, not commercially
available, and must be prepared from toxic and reactive
8
reagents such as Br2 and NBS.9 Another problem arises when
nonsymmetrical haloketones with two enolizable carbons need
to be synthesized, many times leading to a mixture of isomers.10
The same drawback can be observed when amino acid derived
haloketones are needed. With respect to some recent and
different methods to prepare β-keto thioetheres, Samec7a,c has
described an one-pot transformation employing gold/palladium
catalysis in the presence of alkynes and aryl thiols. Zhang7b
employed gold carbenes from terminal alkynes to be trapped by
allylic sulfides, and Denmark7d described a Lewis base catalyzed
α-sulfenylation of silyl enol ethers in an enantioselective
fashion. Frongia7e used a Pummerer reaction from β-
ketosulfoxides to prepare β-ketothioethers, and Lee7f per-
formed C−S coupling of β-diketones with disulfides in the
presence of K2S2O8/I2.
Sulfur ylides were first described in 1930,11 but it was only
after the 1960s, with important contributions by Johnson and
LaCount,12 Franzen,13 and Corey and Chaykovsky,14 that they
received more attention. Although considerable growth in the
field has been observed over the years, most applications
continue to be related to epoxidation, cyclopropanation, and
aziridination reactions and [2,3] sigmatropic or Stevens
rearrangements.15 Metal-catalyzed decomposition of sulfonium
and sulfoxonium ylides is also described as a means of
generating carbenes that is equivalent to using diazo
compounds.16,7h In spite of the potential applications of these
Figure 1. Some organosulfur and β-keto thioethers.
substances, β-keto thioethers play important roles because
they are precursors to the well-known benzothiophenes and to
several Julia reagents.3 Moreover, they can be found in the
structures of several biologically active compounds and
synthetic intermediates (Figure 1).2,4
β-Keto thioethers are traditionally prepared5−7 in one of two
ways: metal-catalyzed S−H insertion into diazocarbonyl
compounds or nucleophilic substitution from haloketones in
the presence of thiolates. The first suffers from moderate yields,
Received: May 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compounds, the appearance of new methods and trans-
formations in the literature is less frequent than expected.
Herein, we describe a simple and direct means to access β-
keto thioethers from easily prepared keto sulfoxonium ylides
and commercially available aryl thiols. We envisioned that aryl
thiols could have enough acidity to protonate a keto
sulfoxonium ylide, furnishing a reactive sulfoxonium and a
nucleophilic thiolate. Fast displacement of DMSO by a free or
contact ion pair thiolate would lead to thioethers with no need
for an external catalyst.
After finding the best conditions under which to synthesize
β-keto thioether 2, we evaluated the scope of this reaction by
employing structurally different sulfoxonium ylides and aryl
thiols. We chose to use the monosubstituted sulfoxonium ylides
3 and 4, containing electron-donating and electron-withdrawing
groups in the aromatic ring, the less reactive disubstituted
sulfoxonium ylide 5, and the amino acid derived ylide 6 (Figure
2).
To evaluate our hypothesis, we began by employing keto
sulfoxonium 1 (easily prepared from dimethylsulfoxonium
methylide and benzoyl chloride) and an excess of benzenethiol
in one of three solvents (entries 1−3, Table 1). Interestingly,
Table 1. Optimization Conditions for the Reaction between
Sulfoxonium 1 and Benzenethiol
a
entry
benzenethiol (equiv)
solvent
yield (%)
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.0
2.0
2.0
1.0
1.0
MeOH
Me2CO
CH2Cl2
EtOH
57
67
60
79
70
74
83
88
92
89
82
79
98
2
3
4
5
i-PrOH
AcOEt
THF
6
7
8
DMSO
MeCN
MeNO2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
b
92
c
15
91
c
b
16
89
a
Yields determined by NMR with 1,2,4,5-tetramethylbenzene as an
b
c
internal standard. Isolated yield by column chromatography. 1.0
mol/L solution (0.5 mol/L in all other entries).
we could already detect the formation of keto thioether 2 in
moderate yields. In spite of dissimilar properties and dielectric
constants, the use of methanol (ε = 32.7), acetone (ε = 20.7),
or dichloromethane (ε = 8.9) furnished basically the same
yields of 2. Investigations into other types of solvents (entries
4−10) revealed that the best yields are obtained in polar aprotic
solvents with high dielectric constants, such as DMSO (ε =
46.7), nitromethane (ε = 35.9), and acetonitrile (ε = 37.5),
which gave yields of 88−92% (entries 8−10). Acetonitrile was
selected to screen further for the number of equivalents of
benzenethiol and concentration (entries 11−16). Dropping the
thiol to 1.2 or 1.0 equiv caused the yield to decrease to 82% and
79%, respectively. On the other hand, raising it to 2.0 equiv
boosted the yield to 98% in just 4 h. At 1.0 equiv, increasing the
concentration to 1.0 M led to a 91% yield. Although the
conditions in entry 13 provided the best yield, we elected to
proceed using the conditions in entry 15 because it employed
1.0 equiv of thiol.
Figure 2. Reaction scope for the synthesis of β-keto thioethers: (a) 1.5
equiv of arylthiol; (b) performed in MeNO2 as solvent; (c) 1.5 equiv
of arylthiol at 55 °C.
B
DOI: 10.1021/acs.orglett.6b01470
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As depicted in Figure 2, each of the chosen sulfoxonium
ylides provided β-keto thioethers in isolated yields varying from
62 to 94%. It is important to mention that the reaction is highly
chemoselective with respect to the aryl thiol. For example,
using aryl thiols with other nucleophilic groups, such as
hydroxyl, amino, and carboxylic acid, attached to the aromatic
ring did not cause competition reactions (Figure 2, compounds
10, 16−19). For comparison, we also performed these
reactions using diazo compounds 26 and 27 rather than
sulfoxonium ylides 1 and 5 (Scheme 1, charts A and B), but
Scheme 2. Kinetic Isotope Effects and Competitive Studies
Scheme 1. Comparison Studies Employing Diazo
Compounds 26 and 27 Instead of Sulfoxonium Ylides 1 and
5
Scheme 3. Synthesis of β-Ketothioethers from Alkyl Thiols
Using Diphenylphosphate as an Organocatalyst
practically no reactions took place. Moreover, a typical
rhodium-catalyzed S−H insertion using 4-aminothiophenol
and diazo compounds showed low chemoselectivity (Scheme 1,
chart C).
Kinetic isotope effects from ylides 1 and 5 revealed KH-to-KD
ratios of 2.0 and 3.1, respectively. This strongly suggests that
the first step is rate limiting (Scheme 2, charts A and B).
Moreover, complete protonation of ylide 1 with diphenyl
phosphate followed by addition of equimolecular amounts of
benzenethiol and benzyl mercaptan (compounds with different
nucleophilic strengths) furnished the same yields of compounds
2 and 28 (Scheme 2, chart C). This is evidence that the second
step may be very fast and does not discriminate between
nucleophiles with different reactivities. Additional evidence that
protonation of the ylide double bond plays an important role in
these transformations is the reaction of ylide 1 with the sodium
salt of benzenethiol. As expected, no reaction took place, and
100% of the starting materials were recovered. Additional
evidence is the application of our optimized conditions to the
less acidic alkyl thiols (pKa = 17 in DMSO) in place of aryl
thiols (pKa = 10 in DMSO), with all of the starting material
being recovered after 24 h. However, if diphenyl phosphate (20
mol %) is used as the proton source, insertion products could
be obtained in acetonitrile at 40 °C after 24 h (Scheme 3). This
is the first example of an organocatalytic approach from
sulfoxonium ylides. After performing all the above experiments,
a plausible mechanism for the insertion of sulfoxonium ylides
into aryl thiols is suggested in Figure 3.
β-Keto thioethers can be important building blocks in the
synthesis of benzothiophenes and several Julia reagents. To
demonstrate its applicability, thioether 2 was submitted to
Figure 3. Suggested mechanism for the reaction between sulfoxonium
ylides and thiophenols.
C
DOI: 10.1021/acs.orglett.6b01470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Vernier, J.-M.; El-Abdellaoui, H.; Holsenback, H.; Cosford, N.
D. P.; Bleicher, L.; Barker, G.; Bontempi, B.; Chavez-Noriega, L.;
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Scheme 4. Application of Thioether 2 in the Synthesis of
Benzothiophene 32
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In conclusion, we demonstrated that β-keto sulfoxonium
ylides can be powerful substrates for the synthesis of β-keto
thioethers and can substitute diazo compounds or haloketones.
The reaction setup is very simple and requires only the
preparation of a solution of the ylide and aryl thiol. High
chemoselectivity permits the use of a diverse number of
substituted aryl thiols, an implausible option in the existing
methods using diazo compounds or haloketones. Moreover, the
great stability of sulfoxonium ylides in addition to the fact that
they are solids makes them more attractive on an industrial
scale.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01470.
■
S
Experimental details, analytical data, and NMR spectra
(PDF)
(8) Diwu, Z.; Beachdel, C.; Klaubert, D. H. Tetrahedron Lett. 1998,
39, 4987.
(9) Chan Lee, J.; Jung Park, H. Synth. Commun. 2007, 37, 87.
(10) Hoffman, R. V.; Weiner, W. S.; Maslouh, N. J. Org. Chem. 2001,
66, 5790.
AUTHOR INFORMATION
Corresponding Author
■
(11) Ingold, C. K.; Jessop, J. A. J. Chem. Soc. 1930, 0, 713.
(12) Johnson, A. W.; LaCount, R. B. J. Am. Chem. Soc. 1961, 83, 417.
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(14) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
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1353.
*E-mail: antonio@iqsc.usp.br.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would thank FAPESP (Research Supporting Foundation of
the State of Sao Paulo) for financial support (2013/25504-1;
2013/18009-4). We also thank CNPq for a research fellowship
to A.C.B.B. (301079/2012-9) and a fellowship to R.M.P.D.
(2011/160522-0). We also thank IQSC-USP for facilities. The
(15) Li, A.-H; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341.
(16) Burtoloso, A. C. B.; Dias, R. M. P.; Leonarczyk, I. A. Eur. J. Org.
Chem. 2013, 2013, 5005 and references therein.
́
authors also thank Pierre Mothe Esteves (UFRJ) and Antonio
A. S. Curvelo (USP) for discussions, and FAPESP (2013/
50228-8; 2009/54040-8) for HRMS multi-user equipment.
REFERENCES
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DOI: 10.1021/acs.orglett.6b01470
Org. Lett. XXXX, XXX, XXX−XXX