Transition-metal-free C-S bond formation: A facile access to aryl sulfones from sodium sulfinates via arynes

Article abstract of DOI:10.1021/ol5018646

Sulfones have been attractive targets for synthetic organic chemists owing to their immense applications in medicinal, material, and synthetic chemistry. In this context, an efficient transition-metal-free process has been demonstrated, wherein a broad range of alkyl/aryl/heteroaryl sodium sulfinates react with varyingly substituted aryne precursors (o-silyl aryl triflates) under mild reaction conditions to afford structurally diverse sulfones in good to excellent yields.

Full text of DOI:10.1021/ol5018646

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free C−S Bond Formation: A Facile Access to Aryl
Sulfones from Sodium Sulfinates via Arynes
Virat G. Pandya and Santosh B. Mhaske*
CSIR-National Chemical Laboratory, Division of Organic Chemistry, Pune 411 008, India
S
* Supporting Information
ABSTRACT: Sulfones have been attractive targets for synthetic organic chemists owing to their immense applications in
medicinal, material, and synthetic chemistry. In this context, an efficient transition-metal-free process has been demonstrated,
wherein a broad range of alkyl/aryl/heteroaryl sodium sulfinates react with varyingly substituted aryne precursors (o-silyl aryl
triflates) under mild reaction conditions to afford structurally diverse sulfones in good to excellent yields.
ulfones are ubiquitous in pharmaceuticals,1 agrochemicals,2
3
Sand advanced organic materials.
They are versatile
intermediates in organic synthesis4 and used in well-known
organic transformations such as the Ramberg−Backlund
reaction5 and the Julia olefination.6 Particularly, aryl sulfones
are vital building blocks in organic4 and medicinal chemistry.7
They are commonly found in various drugs and possess a wide
range of biological properties (Figure 1).1,7,8
Figure 2. Latest advances in the field of sulfone synthesis.
Figure 1. Drugs and pesticide containing aryl sulfone motif.
esters, oxidative coupling of aryl boronic acids with aryl
sulfonyl chlorides or other Pd- and Cu-catalyzed coupling
reactions, and transition-metal-free synthesis from sodium
Development of efficient processes for the synthesis of
sulfone derivatives has been a subject of enduring interest due
to their compelling synthetic utility and substantial biological as
well as material applications. The latest advancements
sulfinates.13 However, to the best of our knowledge the highly
electrophilic aryne species has never been utilized to date for
the synthesis of aryl sulfones.
Arynes have been successfully used for the development of
authenticate the significance of this research area (Figure
several useful synthetic methodologies14 and total synthesis of
natural products.15 There are several methods available for
aryne generation,15a,16,17 but the Kobayashi’s protocol16 using
o-silyl aryl triflate and a fluoride source provides an excellent
opportunity to demonstrate the application of arynes in various
2).9−12 The methods by Jiang,9 Mascitti and Toste,10a and
Willis11a require a transition-metal catalyst, whereas the
methods by Manolikakes,12a,b Kumar,12c and Willis11c are
transition-metal-free. In addition to these recent advances
numerous procedures for the synthesis of sulfones have been
reported, which comprise the oxidation of sulfides and
sulfoxides, sulfonylation of arenes, reaction between organo-
magnesium and organolithium compounds with sulfonate
Received: June 27, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
useful synthetic methodologies. In continuation of our interest
in the development and application of aryne methodologies,18
we envisaged that the high reactivity of arynes could be
explored to access synthetically useful and biologically
important sulfone derivatives. In this context, we report herein
a facile access to various aryl sulfones via arynes.
Table 2. Preparation of Sulfones from Various Silyl
Triflates
a
The protocol was first optimized using o-silyl aryl triflate 1
and sodium benzenesulfonate 2 (Table 1). Three different
a
Table 1. Optimization Studies
b
entry
F− source (equiv)
additive
time
yield
1
2
3
4
5
6
7
8
9
CsF (5.5)
CsF (2.5)
CsF (2.0)
CsF (1.5)
KF (2.0)
−
A
A
A
A
−
−
−
−
6.0 h
6.0 h
7.0 h
7.0 h
6.0 h
1.5 h
2.5 h
3.0 h
5.0 h
86%
88%
82%
56%
67%
95%
94%
94%
72%
TBAF (2.5)
TBAF (1.5)
TBAF (1.1)
TBAF (1.0)
a
All the reactions were performed on 25 mg scale of o-silyl aryl triflate
b
1. A = 18-crown-6-ether (5 mol %).
commonly used fluoride sources were screened under various
conditions. Though CsF alone provided diaryl sulfone 3 in
good yield (entry 1), it was required in large excess. Use of
phase transfer catalyst 18-crown-6-ether reduced the required
amount of CsF to 2 equiv maintaining almost the same yield. A
further decrease in the amount of CsF reduced the yield
drastically. The combination of KF (2 equiv) and 18-crown-6-
ether provided sulfone 3 in a lower yield than that obtained
under similar conditions using CsF. Use of TBAF as a fluoride
source however proved to be fruitful and the final conditions
were optimized, wherein the treatment of o-silyl aryl triflate 1
(1 equiv) and sodium sulfinate 2 (1 equiv) with TBAF (1.1
equiv) at room temperature furnished the desired sulfone 3 in
excellent yield (entry 8). We believe that the high yields and
faster reaction could be due to the effect of TBAF acting as a
phase transfer catalyst in addition to being an efficient fluoride
source.
The generality and scope of the developed protocol to obtain
diaryl sulfones was demonstrated by varying o-silyl aryl triflates
(Table 2). The synthesis of diaryl sulfone 3 worked equally well
on a large scale (entry 1). Triflate 4 having two fluorine
substituents also provided the corresponding sulfone 5 in good
yield (entry 2). The substrates with two alkyl substituents meta
(triflate 6) and ortho (triflate 8) to the reaction center furnished
corresponding sulfones 7 and 9 respectively, but it is interesting
to note that the presence of both methyl substituents away
from the reaction center (entry 3) enables easy attack of a
nucleophile, thus providing an excellent yield in a shorter
reaction time. However, in the case of triflate 8 the steric
hindrance probably increases the reaction time and reduces the
yield. In the case of unsymmetrically substituted silyl triflate 10,
excellent regioselectivity was observed to obtain only the meta
substituted diaryl sulfone 11. Highly electron-rich silyl triflates
12, 14, and 16 furnished the desired sulfones 13, 15, and 17
respectively in good to excellent yields.
a
All the reactions were performed on 50 mg scale of o-silyl aryl
b
triflates. This reaction was also performed on 500 mg scale of o-silyl
aryl triflate 1.
The scope of the protocol was also established by varying
sodium sulfinates (Table 3). All the sodium sulfinates were
prepared easily by using literature procedures.12a Methyl
sodium sulfinate 18 furnished the alkyl-aryl sulfone 19 in
good yield. We could obtain sulfone 21 in only 45% yield from
butyl sodium sulfinate 20 using TBAF, but a very good yield
was observed with CsF. The reason behind this observation is
obscure. The alkyl substituted aryl sodium sulfinates 22 and 24
reacted smoothly to furnish diaryl sulfones 23 and 25
respectively in good yields. The sodium sulfinate 26 having
an electron-donating group requires much less reaction time as
compared to the sodium sulfinate 28 and 30 having electron-
withdrawing groups to give corresponding sulfones 27, 29, and
31 respectively. Fluorine substituted sodium sulfinate 32
provides diaryl sulfone 33 in very good yield. Similar to the
alkyl/aryl sodium sulfinates the heteroaryl sodium sulfinate 34
also worked well to furnish aryl-heteroaryl sulfone 35 having a
labile bromine substituent, thus indicating the mildness of the
developed protocol (entry 9, Table 3).
B
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Letter
a
Table 3. Preparation of Sulfones from Various Sulfinates
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.G.P. thanks UGC-New Delhi for the research fellowship.
S.B.M. gratefully acknowledges generous financial support from
DST, CSIR-ORIGIN, CSIR-OSDD New Delhi as well as CSIR-
NCL (start-up grant).
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In conclusion, we have demonstrated an efficient, transition-
metal-free approach for the synthesis of aryl sulfones starting
from easily accessible alkyl/aryl sodium sulfinates and o-silyl
aryl triflates. The developed protocol is mild and robust and
avoids the use of excess reagents or additives. It is capable of
delivering a diverse array of sulfones such as diaryl sulfones,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, and copies of NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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