Metal-free synthesis of diaryl sulfones from arylsulfinic acid salts and diaryliodonium salts

Article abstract of DOI:10.1021/ol303248h

An efficient, high-yielding, and transition-metal-free synthesis of diaryl sulfones from arylsulfinic acid salts and diaryliodonium salts has been developed. The mild reaction conditions tolerate a range of functional groups, and unsymmetrical diaryliodonium salts show high chemoselectivity.

Full text of DOI:10.1021/ol303248h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Metal-Free Synthesis of Diaryl Sulfones
from Arylsulfinic Acid Salts and
Diaryliodonium Salts
000–000
Natalie Umierski and Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology, Goethe University Frankfurt,
Frankfurt am Main, Germany
g.manolikakes@chemie.uni-frankfurt.de
Received November 26, 2012
ABSTRACT
An efficient, high-yielding, and transition-metal-free synthesis of diaryl sulfones from arylsulfinic acid salts and diaryliodonium salts has
been developed. The mild reaction conditions tolerate a range of functional groups, and unsymmetrical diaryliodonium salts show high
chemoselectivity.
1
Diaryl sulfones are useful synthetic intermediates and
2
exhibit interesting biological properties. For example,
strong acids typically require harsh reaction condi-
1
tions. Recently, Pd- or Cu-catalyzed coupling reac-
diaryl sulfones have been shown to possess antifungal,
antibacterial, or antitumor activities or to inhibit HIV-1
reverse transcriptase.
tions between arylsulfinic acid salts and aryl halides or
aryl boronic acids have been developed as a milder
3
4À6
alternative.
However, the use of toxic and expensive
Numerous approaches for their preparation have been
reported. Traditional procedures such as the oxidation of
sulfides or the sulfonylation of arenes in the presence of
transition metals significantly limits the applicability of
these processes.
(
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1
997, 40, 677–683.
1
0.1021/ol303248h r XXXX American Chemical Society

In recent years diaryliodonium salts have attracted
considerable attention as powerful electrophilic arylation
a
7
reagents. They have been employed in metal-catalyzed
,8
9
Table 1. Survey of Solvents and Influence of the Counterion
1
0
and, more importantly, in metal-free arylation reactions,
such as the metal-free arylation of oxygen nucleophiles
1
1
recently reported by the group of Olofsson.
In the course of our investigations toward new synthetic
methods for the synthesis of sulfonyl-group containing
molecules, we became interested in the use of diaryliodonium
salts as possible arylating agents for sulfur nucleophiles.
Herein, we present our results on the metal-free arylation
of sulfinic acid sodium salts 1 with diaryliodonium salts 2.
In preliminary studies, we investigated the reaction of
benzenesulfinic acid sodium salt (1a) with diphenyliodo-
nium triflate (2a). To our delight this reaction takes place
in the absence of any metal catalyst or additional base.
While a variety of solvents can be used for this reaction
À
b
entry
solvent
THF
salt
X
yield (%)
c
1
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Cl
77
2
1,4-dioxane
toluene
DMSO
NMP
65
59
94
96
94
3
4
5
6
DMF
d
7
DMF
90
8
DMF
95
96
96
96
9
DMF
PF
BF
OTs
6
10
11
DMF
4
(
Table 1, entries 1À7), the best results were obtained with
polar aprotic solvents such as N,N-dimethylformamide
DMF), dimethyl sulfoxide (DMSO), or N-methyl-2-pyr-
DMF
a
Reaction conditions: 1.0 equiv of 1a and 1.1 equiv of 2 in 1.0 mL of
solvent at 90 °C for 24 h. Isolated yield. Reaction performed at 80 °C.
Reaction run without exclusion of air or moisture.
b
c
(
1
2,13
d
rolidone (NMP).
Interestingly, this reaction is quite insensitive to air and
moisture. When the reaction was set up and run without an
inert atmosphere using commercial grade DMF (entry 7),
3a was isolated in almost equally good yield. The nature of
the counterion had no influence on the yield, and different
diphenyliodonium salts worked as efficiently (entries 8À11).
With the optimized conditions in hand, we next explored
the scope of this reaction. As shown in Table 2, various
arylsulfinic acid sodium salts are suitable substrates re-
gardless of their electronic or steric properties. Both electron-
rich and -poor sulfinic acid sodium salts 1c and 1g lead
to the desired diarylsulfones 3c and 3g in excellent
yields (entries 3 and 7). Reaction of the bromo-substituted
substrate 1d delivered diarylsulfone 3d (entry 4) that could
be easily further modified using cross-coupling chemistry.
Steric hindrance, often problematic in metal-catalyzed
(
7) For reviews on diaryliodonium salts, see: (a) Merritt, E. A.;
Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052–9070. (b) Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (c) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2002, 102, 2523–2584. (d) Stang, P. J.; Zhdankin,
V. V. Chem. Rev. 1996, 96, 1123–1178.
(
8) For efficient routes to diaryl iodonium salts, see: (a) Bielawski,
M.; Olofsson, B. Org. Synth. 2009, 86, 308–314. (b) Bielawski, M.; Aili,
D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602–4607. (c) Zhu, M.;
Jalalian, N.; Olofsson, B. Synlett 2008, 4, 592–596. (d) Bielawski, M.;
Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610–2618. (e)
Hossain, M. D.; Kitamura, T. Bull. Chem. Soc. Jpn. 2007, 80, 2213. (f)
Hossain, M. D.; Ikegami, Y.; Kitamura, T. J. Org. Chem. 2006, 71,
9
903–9905. (g) Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetra-
hedron Lett. 2000, 41, 5393. (h) Kitamura, T.; Matsuyuki, J.; Taniguchi,
H. Synthesis 1994, 147–148. (i) Stang, P. J.; Zhdankin, V. V.; Tykwinski,
R.; Zefirov, N. S. Tetrahedron Lett. 1991, 32, 7497–7498.
(9) (a) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011,
14
coupling reactions, does not pose a problem. The steri-
1
33, 4260–4263. (b) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am.
Chem. Soc. 2011, 133, 13778–13781. (c) Ciana, C.-L.; Phipps, R. J.;
Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011,
cally veryhindered (1,3,5-triisopropyl)benzenesulfinic acid
sodium salt (1j) was phenylated in 61% yield (entry 10).
This method can be extended to heteroarylsulfinic acid
sodium salts 1kÀm to synthesize arylheteroaryl sulfones
50, 458–462. (d) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps,
R. J.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 463–466. (e)
Wagner, A. M.; Sanford, M. S. Org. Lett. 2011, 13, 288–291. (f) Xiao,
B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc.
3
kÀm, which are of particular interest for the development
2010, 132, 468–469. (g) Bedford, R. B.; Webster, R. L.; Mitchell, C.
3
a,c,d
J. Org. Biomol. Chem 2009, 7, 4853–4857. (h) Deprez, N. R.; Sanford,
M. S. J. Am. Chem. Soc. 2009, 131, 11234–11241. (i) Phipps, R. J.;
Gaunt, M. J. Science 2009, 323, 1593–1597. (j) Phipps, R. J.; Grimster,
N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172–8174. (k) Kalyani,
D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
of new drugs
salts, such as methanesulfinic acid sodium salt (1n), did not
react under these conditions.
(entries 12À14). Only alkylsulfinic acid
We next examined the reactivity of other symmetrical
and unsymmetrical diaryliodonium salts. The reaction of
benzenesulfinic acid sodium salt (1a) with various symme-
trical diaryliodonium salts 2 furnished the phenylarylsul-
fones of type 3 in moderate to excellent yields (Table 3,
entries 1À7). Halogen-substituted substrates 2jÀl effi-
ciently arylated 1a (entries 5À7). Steric hindrance in the
diaryliodonium salt was not a problem. Reaction of ortho-
or bis(ortho)-substituted salts 2g and 2h delivered the
diarylsulfones 3n and 3o in very high yields (entries 2 and 3).
Unsymmetrical salts 2m and 2n selectively transferred
1
27, 7330–7331.
(10) (a) Ackermann, L.; Dell’Acqua, M.; Fenner, S.; Vicente, R.;
Sandmann, R. Org. Lett. 2011, 13, 2358–2360. (b) Dohi, T.; Ito, M.;
Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Angew. Chem., Int.
Ed. 2010, 49, 3334–3337. (c) Morimoto, K.; Yamaoka, N.; Ogawa, C.;
Nakae, T.; Fujioka, H.; Dohi, T.; Kita, Y. Org. Lett. 2010, 12, 3804–
3807. (d) Eastman, K.; Baran, P. S. Tetrahedron 2009, 65, 3149–1354. (e)
Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am.
Chem. Soc. 2009, 131, 1668–1669. (f) Caroll, M. A.; Wood, R. A.
Tetrahedron 2007, 63, 11349–11354.
(11) (a) Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem.;Eur. J.
2012, 18, 14140–14149. (b) Petersen, T. B.; Khan, R.; Olofsson, B. Org.
Lett. 2011, 13, 3462–3465. (c) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.,
Jr.; Olofsson, B. Org. Lett. 2011, 13, 1552–1555.
12) This might be due to the improved solubility of the sulfinic acid
sodium salts in polar solvents.
13) While slightly higher yields were obtained in NMP and DMSO,
(
(
(14) Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
the removal of DMF from the reaction is considerably easier.
Bolm, C.; Wiley VCH: Weinheim, 2004.
B
Org. Lett., Vol. XX, No. XX, XXXX

a
a
Table 2. Phenylation of (Hetero)arylsulfinic Acid Salts
Table 3. Arylation of Benzenesulfinic Acid Sodium Salt (1a)
a
1
.0 equiv of 1a and 1.1 equiv of 2 in 1.0 mL of DMF for 24 h at
b c d
9
0 °C. Isolated yield. Tosylate as counterion. Reaction run in NMP.
a
1
.0 equiv of 1 and 1.1 equiv of 2a in 1.0 mL of DMF at 90 °C for
b
c
4 h. Isolated yields of analytically pure product. Reaction performed
with 1.1 equiv of 1 and 1.0 equiv of 2a. Reaction run with 1.1 equiv of 1
and 1.0 equiv of 2a in DMSO.
The chemoselectivity of unsymmetrical diaryliodonium
2
d
salts was further investigated using (2-methylphenyl)
2,4,6-trimethylphenyl)iodonium triflate (2p) and (2-
methylphenyl)(2,4,6-triisopropylphenyl)iodonium triflate
2q) as model substrates (Scheme 1). In the reaction of 2p
(
(
the bulky ortho-substituted aryl moiety, furnishing pro-
ducts 3n and 3j (entries 8 and 9). In the case of the
unsymmetrical diaryliodonium salt 2o, the electron-poor
trifluoromethylphenyl moiety was transferred with ex-
cellent chemoselectivity (entry 10). Thus, unsymmetrical
diaryliodonium salts could be used as an alternative in
cases where the symmetric salt is expensive or difficult to
prepare.
with benezenesulfinic acid sodium salt (1a) a mixture of
the two diarylsulfones 3n and 3r was obtained, with the
sterically more demanding mesityl group being transferred
preferentially (ratio 3n to 3r: 3.6:1). Excellent selectivity
was observed with unsymmetric salt 2q, which transferred
only the tri(isopropyl)phenyl group (TRIP). Interestingly,
we observed contrasting chemoselectivity trends in the
presence of catalytic amounts of CuI. Transfer of the less
Org. Lett., Vol. XX, No. XX, XXXX
C

electron-rich arylgroups and the transferof a bulky, ortho-
substituted aryl group is favored over the transfer of less
a
Scheme 1. Selectivity Studies
10g,11,15
bulky aryl groups.
metal catalyst contrasting selectivities are observed.
In the presence of a transition
9
a,b,g,j
Transfer of more electron-rich or less bulky aryl groups is
preferred, and the bulky TRIP group is often introduced as
a nontransferable dummy ligand.
In summary, we have developed an efficient, transition-
metal-free synthesis of diarylsulfones starting from readily
available arylsulfinic acid salts and diaryliodonium salts.
The reaction conditions are mild and robust and avoid
the use of excess reagents or additives. The scope of this
reaction is quite broad and includes the synthesis of
halogen-substituted or sterically hindered diarylsulfones
as well as heteroarylsulfones.
a
Reaction conditions: 1.0 equiv of 1a and 1.1 equiv of 2 in 1.0 mL of
DMF at 90 °C for 24 h.
Acknowledgment. This work was financially supported
by the Fonds der Chemischen Industrie (Liebig Fellowship
to G.M.) and the Goethe-University (Nachwuchs im
Fokus-Program). We would like to thank Prof. Michael
G o€ bel (Goethe-University Frankfurt) for his support and
Rockwood Lithium (Frankfurt) for the generous gift of
chemicals.
bulky aryl group is favored. Reaction of 2p furnished a
mixture of 3n and 3r with the less sterically demanding aryl
group being transferred more readily (ratio 3n to 3r: 1:3.4).
In the case of diaryliodonium salt 2q, only product 3r was
observed.
The observed chemoselectivity trends are in agreement
with previous reported selectivities. In metal-free reactions
electron-poor aryl groups are transferred prefentially over
Supporting Information Available. Experimental pro-
cedures and characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
15) (a) Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.;
Shiro, M. J. Am. Chem. Soc. 1999, 121, 9233–923. (b) Oh, C. H.; Kim,
J. S.; Jung, H. H. J. Org. Chem. 1999, 64, 1338–1340.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX