A general copper-catalyzed sulfonylation of arylboronic acids

Article abstract of DOI:10.1021/ol071396n

A general copper-catalyzed method for the sulfonylation of arylboronic acids with sulfinate salts is described. A variety of alkyl-aryl, diaryl, and alkyl-heteroaryl sulfones were synthesized in good yield.

Full text of DOI:10.1021/ol071396n

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3405-3408
A General Copper-Catalyzed
Sulfonylation of Arylboronic Acids
Anirban Kar,† Iliyas Ali Sayyed,† Wei Fun Lo,† Hanns Martin Kaiser,†,‡
Matthias Beller,†,‡ and Man Kin Tse*,†,‡
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock,
Albert-Einstein-Str. 29a, D-18059 Rostock, Germany, and Center for Life Science
Automation (CELISCA), UniVersity of Rostock, Friedrich-Barnewitz-Str. 8,
D-18119 Rostock-Warnemu¨nde, Germany
man-kin.tse@catalysis.de
Received June 13, 2007
ABSTRACT
A general copper-catalyzed method for the sulfonylation of arylboronic acids with sulfinate salts is described. A variety of alkyl
−aryl, diaryl,
and alkyl heteroaryl sulfones were synthesized in good yield.
−
The synthesis of sulfones has drawn much attention over
the years since they constitute useful building blocks in
organic chemistry as well as in medicinal chemistry. Because
of their chemical properties1 and promising biological
activities,2 especially, aryl and diaryl sulfones have emerged
as important synthetic targets in recent years. As an example,
aryl sulfones are the main constituent of many drugs, such
as the selective COX-2 inhibitor Vioxx3 (1) and the pros-
taglandin D2 (DP) antagonist MK-0524 (2),4 whereas the
diaryl sulfones 3 have been shown to inhibit the HIV-1
reverse transcriptase and represent an emerging class of
substances able to address the toxicity and resistance
problems of nucleoside inhibitors (Figure 1).5
Known procedures for aryl sulfone preparation are based
on the oxidation of the corresponding sulfides,6 the electro-
(3) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier,
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Y.; Le´ger, S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.; Percival, M. D.;
Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.; The´rien, M.; Vickers, P.;
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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, S.;
Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz, D.; Abraham, W.
M.; Jones, T.; McAuliffe, M.; Piechuta, H.; Nicoll-Griffith, D. A.; Wang,
Z.; Zamboni, R.; Young, R. N.; Metters, K. M. J. Med. Chem. 2007, 50,
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Buckheit, R. W., Jr.; Decker, W. D.; White, E. L.; Bader, J. P.; Boyd, M.
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Ciccarone, T. M.; MacTough, S. C.; Rooney, C. S.; Balani, S. K.; Condra,
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† Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock.
‡ University of Rostock, Center for Life Science Automation (CELISCA).
(1) (a) Hama, F.; Kondo, M. JP Patent 61271271, 1986; Chem. Abstr.
1987, 106, 213572. (b) Sato, K.; Ogoshi, T.; Shimizu, A. JP Patent
04120050, 1992; Chem. Abstr. 1992, 117, 150703. (c) Takahashi, T.;
Yoshino, T. JP Patent 2001260544, 2001; Chem. Abstr. 2001, 135, 264604.
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10.1021/ol071396n CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/27/2007

Scheme 1. Catalytic Sulfonylation with Different Ligands
(GC Yield)a
Figure 1. Structures of Vioxx (1), MK-0524 (2), and diaryl
sulfones 3.3-5
philic aromatic substitution of arenes with arenesulfonic acids
in the presence of strong acids7 or with arenesulfonyl
halides,8 the reaction of carbon electrophiles with sulfinate
salts,9 and the reaction of organomagnesium halides10 or
organolithium compounds11 with sulfonate esters. All these
simple and attractive procedures have their own drawbacks,
mainly due to the incompatibility with numerous functional
groups such as amines, olefins, and some nitrogen hetero-
cycles. Over the past decade, there has been a significant
improvement in metal-mediated coupling of sulfinic acid salts
with aryl halides and triflates12 as well as arylboronic acids
with sulfonyl chlorides13 as alternatives to these conventional
methods. However, the scope is limited to aryl bromides/
iodides or triflates, and the use of air- or moisture-sensitive
reagents is sometimes not avoidable. Recently, a copper-
mediated oxidative coupling reaction of arylboronic acid with
sulfinic acid salt was described.14 However, an excess of
copper acetate (with respect to the arylboronic acid) was
required. Hence, improved methods for the preparation of
diaryl sulfones are therefore highly desirable. In recent years,
we have applied catalytic reactions to the synthesis of new
pharmacologically interesting compounds.15 On the basis of
our previous work on copper-catalyzed reactions,16 we
thought that the use of an appropriate ligand or additive
would enable us to realize a catalytic version of the
a Reaction conditions: see Supporting Information.
sulfonylation of boronic acids to synthesize aryl sulfones
(Scheme 1). With the wide variety of commercially available
boronic acids and esters as well as the metal-catalyzed direct
C-H bond functionalization to the not easily accessible
boronates,17 catalytic sulfonylation of these boron-containing
compounds should be very versatile for the preparation of
sulfones. In light with these issues, here we report the first
copper-catalyzed oxidative coupling of arylboronic acids with
sulfinic acid salts. In our prototypical reaction, phenylboronic
acid and sodium methanesulfinate were reacted at 60 °C in
anhydrous DMSO in air in the presence of Cu(OAc)2, a
ligand, and K2CO3 as base. The initial screening of the
(6) Oae, S. Organic Sulfur Chemistry; CRC Press: Boca Raton, FL, 1992;
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Org. Lett., Vol. 9, No. 17, 2007

ligands clearly showed that the reaction can be performed
catalytically with 20 mol % of Cu(OAc)2. We have tested
different ligand types in our model reaction. Among these
ligands, tetradentate and bidentate N ligands gave poor results
irrespective of their donor atom and capacity. We realized
that only monodentate ligands can stabilize the generated
copper species for the required transformation, and indeed,
N-protected imidazoles were found to be the most suitable
ligands for this reaction with a loading of 20 mol % with
respect to the substrate.
Table 2. Catalytic Sulfonylation of Boronic Acidsa
In fact, when the ligand loading was increased to 40 mol
%, a substantial amount of conversion was observed and the
corresponding methyl sulfone was isolated in 64% yield
(Table 1). Following a previously reported protocol using a
Table 1. Cross-Coupling Reaction between Arylboronic Acid
and Sodium Methanesulfinatea
GC yield
entry
Cu(OAc)2
1-benzylimidazole
temp
(%)
1
2
3
1.1 equiv
20 mol %
20 mol %
-
rt
60 °C
60 °C
59
47
64
20 mol %
40 mol %
a Reaction conditions: see Supporting Information.
stoichiometric amount of copper at room temperature,12 the
same substrate gave only 59% of the desired product. These
results indicate that our catalytic system is even slightly more
efficient than the reported stoichiometric conditions. Reac-
tions with different additives, such as (CH3)4NBr, CsF,
chloramine-T, and 1,4-benzoquinone, were also performed
in the presence or absence of ligand; however, none of them
were able to improve the yield significantly. Further opti-
mization showed the best catalytic system was defined as
follows: 0.5 mmol of boronic acid, 1.5 equiv of sulfinic acid
salt, 20 mol % of Cu(OAc)2, 40 mol % of 1-benzylimidazole,
2 equiv of K2CO3, and 1.25 g of molecular sieves (4 Å) at
60 °C in anhydrous DMSO in a flask equipped with an air
drying tube. To the best of our knowledge, this is the first
example of copper-catalyzed sulfonylation of an arylboronic
acid.
A variety of aryl sulfones have been prepared employing
these reaction conditions, as shown in Table 2. This cross-
coupling reaction is quite general and can be easily applied
to a wide range of arylboronic acids. Both electron-rich and
electron-deficient substrates reacted with almost similar ease,
and the substrate variety indicates that the substitution pattern
in the aromatic ring does not have significant influence in
the reaction outcome. Bromo and chloro substituents on the
boronic acid part are also tolerated under the reaction
conditions, which could extend the scope of further func-
tionalization on the aromatic ring. The reaction also pro-
a Reaction conditions: see Supporting Information.
ceeded with pinacol boronate ester with good yield (Table
2, entry 6). Reaction of the 2-trifluoromethylphenylboronic
acid is noteworthy. In spite of the presence of a strong
Org. Lett., Vol. 9, No. 17, 2007
3407

electron-withdrawing group at the ortho position, it reacted
smoothly to provide the corresponding sulfone (Table 2, entry
9). Of particular interest is the reaction with 4-vinylphenyl-
boronic acid to the corresponding methyl sulfone. Although
the starting material polymerized, we were able to obtain a
moderate product yield (Table 2, entry 11). Under the same
reaction conditions, we were able to couple 4-hydroxyphe-
nylboronic acid to the corresponding methyl sulfone, but only
with moderate yield, most probably because of the reduction
of the in situ generated arylcopper species (Table 2, entry
10).18
The same method can also be extended to synthesize diaryl
or heteroaryl substrates, which are of particular interest for
potential drug applications. Arylsulfinate salts were ef-
ficiently coupled with arylboronic acids to provide diaryl
sulfones in good yields following the same reaction proce-
dure (Table 2, entries 13 and 14). Similarly, this reaction
was also possible with heterocyclic substrates, such as
thiophene-3-boronic acid and pyridine-4-boronic acid, though
the yields were somewhat lower (Table 2, entries 15 and
16). This method is also applicable to a vinyl sulfone. As
an example, phenylvinylboronic acid was coupled success-
fully to give the corresponding vinyl methyl sulfone in good
yield (Table 2, entry 17).
In summary, we have developed an efficient and general
method for a copper-catalyzed synthesis of methyl-aryl,
aryl-aryl, and heteroaryl sulfones with various functional
groups, which can also be extended to the preparation of
vinyl sulfones. Further studies to increase the catalytic
activity are currently underway in our laboratory.
Acknowledgment. We thank the State of Mecklenburg-
Western Pommerania, the Federal Ministry of Education and
Research (BMBF), and the Deutsche Forschungsgemein-
schaft (SPP 1118 and Leibniz-prize) for financial support.
Dr. C. Fischer, Mrs. C. Mewes, Mrs. A. Lehmann, Mrs. S.
Buchholz (all LIKAT), Dr. D. Go¨rdes, and Mr. E. Schmidt
(all CELISCA) are acknowledged for their technical and
analytical support.
Supporting Information Available: A typical experi-
mental procedure and characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Schmid, A.; Hollmann, F.; Bu¨hler, B. In Enzyme Catalysis in
Organic Synthesis, 2nd ed.; Drauz, K., Waldmann, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; Vol. III.
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Org. Lett., Vol. 9, No. 17, 2007