Arylation of lithium sulfinates with diaryliodonium salts: A direct and versatile access to arylsulfones

Article abstract of DOI:10.1021/ol402235v

An efficient, transition-metal-free arylation of lithium sulfinates, which are readily accessible from reactions of organolithium reagents with sulfur dioxide, is described. Based on this method, a practical protocol for the direct transformation of (hetero)arenes and (hetero)aromatic halides into diarylsulfones was developed.

Full text of DOI:10.1021/ol402235v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Arylation of Lithium Sulfinates with
Diaryliodonium Salts: A Direct and
Versatile Access to Arylsulfones
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 August 6, 2013
ABSTRACT
An efficient, transition-metal-free arylation of lithium sulfinates, which are readily accessible from reactions of organolithium reagents with sulfur
dioxide, is described. Based on this method, a practical protocol for the direct transformation of (hetero)arenes and (hetero)aromatic halides into
diarylsulfones was developed.
Arylsulfones are important building blocks in organic
chemistry1 and especially in medicinal chemistry.2 The
arylsulfone fragment is found in various drugs, such as
the COX-2 inhibitor Vioxx3 or the prostaglandin D2
antagonist Laropiprant (Figure 1).4 Diarylsulfones have
been shown to exhibit antitumor activities5 or to inhibit
HIV-1 reverse transcriptase.6
(1) (a) Patai, S., Rappoport, Z., Stirling, C. J. M., Eds. The Chemistry
of Sulfones and Sulfoxides; Wiley: New York, 1988. (b) Simpkins, N. S.
Sulfones in Organic Synthesis; Pergamon Press: Oxford, 1993.
Figure 1. Biologically active arylsulfones.
(2) For some selected references, see: (a) Hartz, R. A.; Arvanitis,
A. G.; Arnold, C.; Rescinito, J. P.; Hung, K. L.; Zhang, G.; Wong, H.;
Langley, D. R.; Gilligan, P. J.; Trainor, G. L. Bioorg. Med. Chem. Lett.
2006, 16, 934–937. (b) Otzen, T.; Wempe, E. G.; Kunz, B.; Bartels, R.;
Because of their importance, numerous procedures for
the synthesis of arylsulfones have been reported, such as
the oxidation of sulfides,1 the sulfonylation of arenes,1 or
Pd- and Cu-catalyzed coupling reactions.7 Recently, we
reported a mild, transition-metal-free synthesis of diaryl-
sulfones from arylsulfinic acid sodium salts and diarylio-
donium salts (Scheme 1).8,9
€
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Gibbs, J. B.; Oliff, A. I.; Graham, S. L.; Hartman, G. D. Biorg. Med.
Chem. Lett. 1999, 9, 3301–3306. (b) Jones, T. R.; Webber, S. E.; Varney,
M. D.; Reddy, M. R.; Lewis, K. K.; Kathardekar, V.; Mazdiyasni, H.;
Deal, J.; Nguyen, D.; Welsh, K. M.; Webber, S.; Johnson, A.; Matthews,
D. A.; Smith, W. W.; Janson, C. A.; Bacquet, R. J.; Howland, E. F.;
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Bateman, K. P.; Chauret, N.; Day, S. H.; Levesque, J.-F.; Seto, C.; Silva,
J. H.; Trimble, L. A.; Carriere, M.-C.; Denis, D.; Greig, G.; Kargman,
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2007, 50, 794.
r
10.1021/ol402235v
XXXX American Chemical Society

While a wide variety of different diaryliodonium salts
are readily available or can be prepared efficiently,10À12 the
availability of sulfinic acid sodium salts is rather limited.13
In order to expand the scope of our method, we were
interested in the use of other, more easily accessible sulfinic
acid salts. We envisioned that the corresponding sulfinic
acid lithium salts 2 should display a similar reactivity
(Scheme 1). These lithium sulfinates can be prepared in a
very straightforward manner from the reaction of organo-
lithium compounds 1 with sulfur dioxide.14 Considering
the huge variety of well-known organolithium reagents,15
this approach would allow a modular synthesis of arylsulfones
using sulfur dioxide16 as the source for the sulfonyl
moiety. Herein, we wish to report a one-pot synthesis of
arylsulfones based on this concept.
Scheme 1. Routes to Arylsulfones Based on Diaryliodonium
Salts
(6) (a) Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B.; Novellino,
E.; Greco, G.; Massa, S.; Ettore, A.; Loi, A. G.; Scintu, F.; La Colla, P.
J. Med. Chem. 2000, 43, 1886–1891. (b) Neamati, N.; Mazumder, A.;
Zhao, H.; Sunder, S.; Burke, T. R.; Schultz, R. J.; Pommier, Y.
Antimicrob. Agents Chemother. 1997, 41, 385–393. (c) Artico, M.;
Silvestri, R.; Massa, S.; Loi, A. G.; Corrias, S.; Piras, G.; La Colla, P.
J. Med. Chem. 1996, 39, 522–530. (d) Williams, T. M.; Ciccarone, T. M.;
MacTough, S. C.; Rooney, C. S.; Balani, S. K.; Condra, J. K.; Emini,
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J. Med. Chem. 1993, 36, 1291–1294.
(7) (a) Kantam, L. M.; Neelima, B.; Sreedhar, B.; Chakravarti, R.
Synlett 2008, 10, 1455–1458. (b) Kar, A.; Sayyed, I. A.; Lo, W. F.;
Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9, 3405–3408. (c)
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J. Org. Chem. 2004, 69, 5608–5614. (d) Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Parisi, L. M. Synlett 2003, 3, 361–364. (e) Baskin,
J. M.; Wang, Z. Org. Lett. 2002, 4, 4423–4425. (f) Suzuki, H.; Abe, H.
Tetrahedron Lett. 1995, 36, 6239–6242.
We started our initial studies with benzene sulfinic acid
lithium salt (2a), which could be easily prepared in quanti-
tative yield from the reaction of phenyllithium (1a) and
sulfur dioxide and subsequent removal of the solvents.17
As expected the reaction between the lithium salt 2a and
diphenyliodonium triflate (3a) proceeded efficiently and
furnished diphenylsulfone (4a). The best results were
obtained in the polar aprotic solvents DMF, DMSO,
and NMP (Table 1, entries 1À3). Other solvents, such as
THF or dioxane, led to lower yields (entries 4 and 5). As
with sodium sulfinic acid salts, this reaction is insensitive to
air and moisture. Performing the reaction without the
exclusion of air and moisture, using commercial grade
DMF or DMSO, 4a was isolated in identical yields
(entries 6 and 7). In the case of sulfinic acid lithium salts,
the nature of the diphenyliodonium counterion XÀ has a
pronounced effect on the yield of the reaction. While
reactions with non-nucleophilic counterions, such as
OTfÀ, BF4À, or PF6À, furnished the product 4a in >80%
(8) Umierski, N.; Manolikakes, G. Org. Lett. 2013, 15, 188–191.
(9) Shortly after our communication, Kumar et. al reported an
almost identical procedure: Kumar, D.; Arun, V.; Pilania, M.; Shekar,
K. P. C. Synlett 2013, 24, 831–836.
(10) 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) Yusubov, M. S.;
Maskaev, A. V.; Zhdankin, V. V. ARKIVOC 2011, 370–409.
(11) For efficient routes to diaryliodonium 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,
9903–9905. (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. (i) Stang, P. J.; Zhdankin, V. V.; Tykwinski, R.;
Zefirov, N. S. Tetrahedron Lett. 1991, 32, 7497–7498.
(12) For some recent applications of diaryliodonium salts, see: (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. (d) Ackermann, L.;
Dell’Acqua, M.; Fenner, S.; Vicente, R.; Sandmann, R. Org. Lett.
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Chem. Soc. 2011, 133, 4260–4263. (f) Bigot, A.; Williamson, A. E.;
Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778–13781. (g) Ciana,
C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2011, 50, 458–462.
Table 1. Survey of Solvents and Influence of the Counteriona
entry
solvent
DMF
salt
XÀ
yield (%)b
1
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3a
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Cl
84
80
83
47
26
79c
86c
60
86
91
65
83
2
DMSO
NMP
3
4
1,4-dioxane
THF
5
6
DMSO
DMF
7
8
DMF
(13) Only a few sulfinic acid sodium salts are commercially available.
Most commonly the sodium salts have to be prepared from the corre-
sponding sulfonyl chlorides. See also ref 14.
(14) Truce, W. E.; Murphy, A. M. Chem. Rev. 1951, 48, 69–124.
(15) (a) Patai, S., Rappoport, Z., Marek, I., Eds. The Chemistry of
Organolithium Compounds; Wiley: New York, 2006. (b) Clayden, J.,
Baldwin, J. E., Willaims, R. M., Eds. Organolithium: Selectivity for
Synthesis; Pergamon: 2002.
9
DMF
PF6
BF4
OTs
OTf
10
11
12d
DMF
DMF
DMF
a Reaction conditions: 1.5 equiv of 2a and 1.0 equiv of 3 in 1.0 mL of
solvent at 90 °C for 24 h. b Isolated yield. c Reaction run without
exclusion of air or moisture. d Performed as one-pot reaction/without
isolating the salt 2a.
(16) For some recent examples of reactions with SO2, see: (a)
ꢀ
Woolven, H.; Gonzalez-Rodrıguez, C.; Marco, I.; Thompson, A. L.;
´
Willis, M. C. Org. Lett. 2011, 13, 4876–4878. (b) Nguyen, B.; Emmet,
E. J.; Willis, M. C. J. Am. Chem. Soc. 2010, 132, 16372–16373. (c)
Markovic, D.; Volla, C. M. R.; Vogel, P.; Varela-Alvarez, A.; Sordo,
J. A. Chem.;Eur. J. 2010, 16, 5969–5975. (d) Pandya, R.; Murashima,
T.; Tedeschi, L.; Barrett, A. G. M. J. Org. Chem. 2003, 68, 8274–8276.
(17) See Supporting Information for experimental details.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Arylation of Benzenesulfinic Acid Lithium Salt (2a)a
Table 3. Direct Lithiation Approach to Diarylsulfonesa
a Reaction conditions: 1.5 equiv of 2a and 1.0 equiv of 3 in 1.0 mL of
DMF for 24 h at 90 °C. b Isolated yield. c Tosylate as counterion.
d Together with 6% 4e.
a Reaction conditions: Sulfinate 2 (prepared from 1.5 equiv 5) and 1.0
equiv of 3a in 1.0 mL of DMF for 24 h at 90 °C. b Isolated yield.
c 2.0 mmol of 3a used.
yield (entries 1, 9, and 10), the yield decreased signifi-
cantly if the more nucleophilic counterions ClÀ and OTsÀ
were employed (entries 8 and 11).18,19 Since we were also
interested in developing a practical protocol for the direct
transformation of organolithium reagents into sulfones,
we merged the single steps into a one-pot sequence.
Reaction of PhLi (1a) with sulfur dioxide (typically 10
equiv),17 followed by removal of solvents and excess SO2
and subsequent treatment of the obtained crude lithium
sulfinate with Ph2IOTf (3a) in DMF, furnished diphenyl-
sulfone (4a) in 83% yield (entry 12).20
Various symmetrical diaryliodonium salts arylated 2a in
good to excellent yields (entries 1À5). Unsymmetrical
iodonium salts 3k and 3l selectively transferred the steri-
cally more demanding aryl moiety (entries 6 and 7).21 In
the case of the unsymmetrical iodonium reagent 3m, a
preferential transfer of the electron-poor trifluoromethyl-
phenyl group was observed (entry 8).
One of the most atom-economical22 routes to organo-
lithium reagents is the direct lithiation/deprotonation of
acidic CÀH functionalities.15 In combination with our
method, it allows the direct transformation of simple,
readily available arenes or heteroarenes into the correspond-
ing sulfones. This four-step, one-pot reaction sequence
With the optimized reaction conditions at hand, we
investigated the reaction of benzenesulfinic acid lithium
salt (2a) with different diaryliodonium salts (table 2).
(18) More nucleophilic counterions can undergo a competing SNAr
reaction with the diphenyliodonium reagent. For examples, see ref 12b
and: Merritt, E. A.; Olofsson, B. Eur. J. Org. Chem. 2011, 3690–3694.
(19) In the case of diphenyliodonium chloride 3b, 1-chloro-4-iodo-
benzene could be detected by GC/MS.
(20) For a similar alkylation of magnesium sulfinates, see: Wu, J.-P.;
Emeigh, J.; Su, X.-P. Org. Lett. 2005, 7, 1223–1225.
(21) For a detailed mechanistic investigation of this effect, see:
Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B.
Chem.;Eur. J. 2013, 19, 10334–10342.
(22) Trost, B. M. Science 1991, 254, 1471–1477.
Org. Lett., Vol. XX, No. XX, XXXX
C

consists of (1) generation of the organolithium reagent
from the corresponding arene or heteroarene using the
appropriate lithiation reagents and conditions;17 (2) reac-
tion of the lithium reagent with SO2; (3) removal of
solvents and excess SO2; and (4) reaction of the sulfinate
with the diaryliodonium salt (Table 3). Using this proce-
dure diphenylsulfone (4a) was obtained in 52% yield
starting from benzene (entry 1). More importantly, differ-
ent arenes bearing “directed metallation groups” (DMG),23
e.g. carbamate 5d or benzamide 5e, could be transformed
directly into the diarylsulfones 4k and 4l (entries 4
and 5). Different heteroarenes, such as thiophene (5f),
The halogenÀlithium exchange is another efficient
method for the preparation of organolithium reagents.15
This method is also compatible with our four-step one-pot
approach. Thus, aryllithium reagent 1c, prepared from
2-bromoanisol (6a), is treated with SO2, followed by the
removal of solvents and excess SO2. Reaction of the
remaining crude lithium sulfinate with diphenyliodonium
triflate (3a) furnished diarylsulfone 4j in 97% yield (Table 4,
entry 1). In a similar manner, other bromo- or iodoben-
zene derivatives 6bÀh as well as heterocycles, such as
bromopyridine 6i, could be transformed directly into the
corresponding diarylsulfones (entries 2À9).
To our delight, this method is not limited to (hetero)-
aryllithium reagents. Starting from primary, secondary, or
tertiary alkyllithium reagents 7aÀd, the desired alkylaryl-
sulfones 8aÀd were obtained in 76À93% yield (Scheme 2).
Table 4. Li/X-Exchange Approach to Diarylsulfonesa
Scheme 2. Synthesis of Aryl Alkyl Sulfones
To summarize, we have developed a convenient synthe-
sis of arylsulfones from sulfinic acid lithium salts and
diaryliodonium salts. This reaction has a very broad scope,
and both aryl and alkyl sulfinates were arylated efficiently.
Based on this method, we were able to develop a practical
protocol for the direct one-pot transformation of hetero-
(aromatic) halides or (hetero)arenes into arylsulfones. This
protocol consists of (1) generation of the organolithium
reagent via exchange or deprotonation; (2) reaction of the
lithium reagent with SO2; (3) removal of excess SO2; and
(4) treatment of the obtained crude sulfinate with the
diaryliodonium salt. Various aryl- and heteroarylsulfones
were synthesized using this straightforward procedure.
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
€
Gobel (Goethe-University) for his support and Rockwood
Lithium (Frankfurt) for the generous gift of chemicals.
a Reaction conditions: sulfinate 2 (prepared from 1.5 equiv 6) and 1.0
equiv of 3a in 1.0 mL of DMF for 24 h at 90 °C. b Isolated yield.
c 2.0 mmol of 3a used.
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.
N-methylpyrrol (5g), pyridine 5h, or ferrocene (5i), could
be functionalized in a similar manner (entries 6À9).
(23) Snieckus, V. Chem. Rev. 1990, 90, 879–933.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX