A mild and efficient new synthesis of aryl sulfones from boronic acids and sulfinic acid salts

Article abstract of DOI:10.1016/j.tetlet.2004.02.127

A new efficient and mild preparation of sulfones from boronic acids and sulfinic acid salts is reported. The cross-coupling reaction mediated by cupric acetate gives access to a variety of sulfones in excellent yield.

Full text of DOI:10.1016/j.tetlet.2004.02.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3233–3236
A mild and efficient new synthesis of aryl sulfones from boronic
acids and sulfinic acid salts
Christian Beaulieu,a,* Daniel Guay,a Zhaoyin Wanga and David A. Evansb
aDepartment of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
PO Box 1005, Pointe-Claire-Dorval, Quꢀebec, Canada H9R 4P8
bDepartment of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge MA 02138, USA
Received 16 February 2004; revised 18 February 2004; accepted 25 February 2004
Abstract—A new efficient and mild preparation of sulfones from boronic acids and sulfinic acid salts is reported. The cross-coupling
reaction mediated by cupric acetate gives access to a variety of sulfones in excellent yield.
Ó 2004 Elsevier Ltd. All rights reserved.
Sulfones are an important class of functional group in
organic chemistry and medicinal chemistry as well. Aryl
sulfones are widely used in medicinal chemistry and
found on several drugs, including the recently developed
selective COX-2 inhibitor Vioxx.1 Many methodologies
exist for the preparation of aryl sulfones. Among these
methods figure the oxidation of corresponding sulfides,2
the reaction of organolithium or Grignard reagents with
sulfonate esters3 and the sulfonylation of arenes,4 which
are attractive methods because of their simplicity.
However, the incompatibility of various functional
groups with these methods reduces their scope of
application. More recently, the metal-mediated cross
coupling reactions of sulfinic acid salts with aryl halides
and triflates were reported as mild alternatives to these
previous methods.5–8 Under these milder conditions,
more functional groups are tolerated, but these reactions
are limited to aryl bromides, aryl iodides, and aryl tri-
flates, and use air or moisture sensitive reagents.
copper to promote the formation of aryl ether, C–N
bond, and thioether from boronic acids under mild
conditions and in good yields. Based on these reports,
we sought to apply this methodology for the preparation
of aryl sulfones using sulfinic acid salts as reagents.
Herein, we wish to report the results from our investi-
gation that led to the development of this new mild and
efficient methodology.
To validate the proposed transformation and optimize
the reaction conditions, we used 3-biphenylboronic acid
and sodium methanesulfinate as testing substrates
(Scheme 1). For our first attempt, we applied the con-
ditions developed by Evans et al. for the formation of
biarylether,9 but replacing CH2Cl2 by DMFdue to
solubility problems (Scheme 1). The result from this first
reaction was encouraging, since the desired sulfone was
obtained in a 70% yield. The reaction was only 50%
complete after 12 h at rt, but heating the reaction mixture
at 60 °C for an additional 2 h led to complete conversion
of the starting material. Two side products were isolated
and identified as biphenyl coming from the reduction of
the boronic acid and as 3-hydroxy biphenyl, which is
probably related to water presence as described by
Evans et al.9 for the preparation of biaryl ether.
Taking into account the wide variety of boronic acids
and boronate esters commercially available or easily
accessible and the compatibility of these compounds
with numerous functional groups, we considered using
these boron derivatives as precursors in the preparation
of sulfones. Work published by Evans et al.,9 Lam
et al.,10 and more recently by Guy et al.11 demonstrated
the potential of cross coupling reactions mediated by
Cu(OAc)2 1.1 equiv
NEt3 2.0 equiv
O
S
O
OH
B
S
+
°
Me
Me
ONa
4A MS 200% wt/wt
O
OH
1
2
3
DMF
1.0 equiv.
2.0 equiv
rt or 60oC
Keywords: Aryl sulfone; Cross-coupling reaction; Boronic acid.
* Corresponding author. Tel.: +514-428-3297; fax: +514-428-4900;
e-mail: christian_beaulieu@merck.com
Scheme 1. Cross-coupling reaction between aryl boronic acid and
sodium methanesulfinate.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.127

3234
C. Beaulieu et al. / Tetrahedron Letters 45(2004) 3233–3236
In order to improve the yield of the reaction, we first
investigated temperature and solvent effects (Table 1).
To increase the rate, the reaction was repeated in DMF
at 60 °C and surprisingly the yield went down between
10% and 60% (Table 1, entry 1). Under the same con-
ditions, use of DMSO as solvent increased the yield to
86% (Table 1, entry 2). However, yields were very
modest with other solvents such as THF, isopropanol,
and 1-methyl-2-pyrrolidinone (Table 1, entries 3–5). In
these cases, the reaction was not as clean as for the
reaction done with DMFor DMSO and more reduction
of the boronic acid was observed. Then, we looked at
the reaction temperature, and it appeared that the
reaction was cleaner at rt than at 60 °C. In fact, more
reduction of the boronic acid was observed at higher
temperature. On the other hand, the cross coupling
reaction did not go to completion at room temperature
with NEt3 as base whether we used DMFor DMSO as
solvent. The presence of a base was found to be neces-
sary to the reaction, since only trace amount of sulfone
was isolated without it. Different bases were then eval-
uated to improve the rate and the yield of the reaction.
Organic and inorganic bases were screened, such as
DBU, cesium carbonate, cesium fluoride, pyridine, and
potassium carbonate. Potassium carbonate was the only
one that resulted in significant yield improvement over
NEt3. Moreover, the reaction was completed after 16 h
at rt using potassium carbonate when carried in DMSO.
Under these conditions, the desired sulfone was isolated
in 97% yield (Table 1, entry 6). As observed with NEt3,
lower yield (78%) was obtained at higher temperature
(Table 1, entry 7) despite a faster reaction rate. The
presence of O2 was found to be favorable to the reac-
tion, as observed for biaryl ether formation,9 and only a
trace amount of sulfone was formed when the reaction
was carried out under N2 atmosphere. Many copper
salts were tested [CuI, CuBr2, Cu(NO3)2, Cu(acac)2,
Cu(TFA)2] as reaction promoter, but they were all
inferior to Cu(OAc)2 and stoichiometric quantity of
copper reagent was necessary. From our optimization
work, the best conditions for the reaction were defined
as follows: 1 equiv of boronic acid, 1.5 equiv of sulfinic
ꢁ
acid salt, 1.1 equiv of Cu(OAc)2, 2 equiv (wt/wt) of 4 A
molecular sieves in DMSO at rt in a flask equipped with
an air drying tube.12
Table 1. Optimization of reaction conditions
Since many therapeutic agents bear a methyl sulfone
group, we mainly focused our efforts on cross coupling
reactions using sodium methanesulfinate. Following the
procedure described above, many methyl sulfones were
prepared in good to excellent yield as listed in Table 2.
As reported with our model substrate 3-biphenylboronic
acid (entry 1), the cross coupling reaction was highly
effective with a wide range of boronic acids13 with var-
ious functional groups. Electron rich and electron defi-
cient substrates reacted quite similarly to afford methyl
sulfones in comparable yield. The substitution pattern of
the aromatic ring did not greatly affect the reaction, and
ortho, para, and meta substitution were well tolerated.
O
S
O
OH
B
S
+
Me
Me
ONa
O
OH
1
2
3
Entry
Solvent
Temperature (°C)
NEt
60
Base
Yield (%)
1
2
3
4
5
6
7
DMF60
DMSO
THF60
iPrOH
NMP
60
86
15
30
30
97
78
3
NEt3
NEt
3
rt
NEt3
NEt3
60
rt
DMSO
DMSO
K2CO3
K2CO3
60
Table 2. Synthesis of sulfones from boronic acid
Cu(OAc)2 1.1 equiv
K2CO3 2.0 equiv
4A MS 200% wt/wt
O
S
O
OR
Ar
°
Ar
B
+
S
R'
ONa
R'
OR
DMSO, rt
O
Entry
1
Starting material
R0
Product
Yield (%)a
97
O
S
Me
OH
B
O
OH
OH
O
B
S
O
2
3
4
5
Me
Me
Me
Me
83
66
76
71b
OH
OH
B
O
S
O
OH
Cl
Cl
OH
B
O
S
O
OH
NC
NC
OH
B
O
S
O
OH
O
O

C. Beaulieu et al. / Tetrahedron Letters 45(2004) 3233–3236
3235
Table 2 (continued)
Entry
Starting material
R0
Product
Yield (%)a
OH
O
S
O
B
6
Me
83
OH
EtS
EtO
EtS
OH
O
S
O
EtO
B
7
8
Me
Me
89
69
OH
OH
O
S
O
AcHN
B
AcHN
Br
OH
OH
B
O
S
O
Br
9
Me
Me
70
78
OH
OH
O
MeO2C
B
MeO2C
S
O
10
OH
OH
B
O
S
O
11
Me
70
OH
OH
B
O
S
O
12
13
Me
Me
63b
80b
OH
O
S
O
B
S
O
O
MeO2C
MeO2C
Cl
OH
14
15
16
17
61
60
54
19
42
B
OH
Cl
O
O
OH
B
O
O
S
OH
Cl
S
Cl
S
OH
B
O
S
O
Me
Me
Me
OH
OH
O
S
O
B
OH
N
N
HO OH
B
O
S O
S
S
S
S
18
a Isolated yield.
b Reaction heated to 60 °C.
Of particular note is the sterically hindered 2,6-dimethyl-
benzene boronic acid, which reacted to give the corre-
sponding sulfone (entry 12) in good yield. In this case,
the reaction needed to be heated to 60 °C to go to
completion. Bromine and chlorine atom (entries 3 and 9)
were also well tolerated as substituents on the aryl
boronic acid and could be used for further functional-
ization on the aryl ring. Of particular interest is the
reaction with 3-acetamidobenzene boronic acid (entry
8), which afforded the methyl sulfone in good yield
compared to the corresponding reaction with aryl halide
substrates, which afford lower yield for similar cross
coupling reaction using copper salts.6 The reaction also
proceeded with a pinacol boronate ester in excellent
yield (entry 13), thus expanding the scope of the reac-
tion. In addition, this methodology can be extended to
the preparation of diaryl sulfones, which are also com-
pound of interest. Thus, following the same procedure,
diaryl sulfones were prepared in good yield (entries 14
and 15) from commercially available aryl sulfinic acid
salts. The cross coupling reaction also proceeded with
certain heterocyclic substrates such as thiophene-3-
boronic acid, pyridine-3-boronic acid, and thianthren-1-
boronic acid (entries 16–18) but totally failed to give the
expected sulfone when applied to 2-thiopheneboronic
acid. Yields obtained with these heterocyclic substrates

3236
C. Beaulieu et al. / Tetrahedron Letters 45(2004) 3233–3236
4. (a) Truce, W. E.; Klinger, T. C.; Brand, W. W. In Organic
Chemistry of Sulfur; Oae, S., Ed.; Plenum: New York,
1977; (b) Ueda, M.; Uchiyama, K.; Kano, T. Synthesis
1984, 323; (c) Graybill, B. M. J. Org. Chem. 1967, 32,
2931.
5. Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239.
6. Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423.
7. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M. Org.
Lett. 2002, 4, 4719.
8. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M.
Synlett 2003, 361.
9. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937.
were generally lower than those from cross coupling
reactions with nonheterocyclic boronic acids. However,
the reaction conditions were not optimized for hetero-
cyclic substrates and further optimization work will be
needed to improve the yield with these substrates.
These preliminary results illustrate the scope and effi-
ciency of this methodology for the synthesis of methyl
and aryl sulfones under extremely mild conditions.
Catalytic version of this process is also of interest and
further investigations are ongoing. The possibility of
extending this methodology to the preparation of vinyl
sulfones is also currently under evaluation.
10. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tettrahedron
Lett. 1998, 39, 2941.
11. Guy, R. K.; Prudencio, S. H.; Pendola, K. A. Org. Lett.
2000, 2, 2019.
References and notes
12. Typical experimental procedure: To a round bottom flask
equipped with an air drying tube (filled with drierite) was
added aryl boronic acid (1 equiv) to DMSO (0.25 M). To
the mixture was added 1.1 equiv of Cu(OAc)2, 1.5 equiv of
1. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleston,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutch-
inson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.;
Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.;
ꢁ
sodium sulfinate, 2 equiv of K2CO3, and 4 A MS (200% wt/
ꢀ
Leger, S.; Mancini, J.; OÕNeill, G. P.; Ouellet, M.; Percival,
M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
wt). The mixture was stirred for 16 h at rt and then filtered
on a Celite pad eluted with EtOAc. The filtrate was diluted
with EtOAc and aqueous saturated ammonium chloride
and the aqueous layers were extracted with EtOAc. The
combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography to afford the
desired product.
ꢀ
Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J.; Young, R.
N.; Zamboni, R. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
2. Schank, K. In The Chemistry of Sulfones and Sulfoxides;
Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; Wiley:
New York, 1988; Chapter 7.
3. (a) Gilman, H.; Beaver, N. J.; Meyers, C. H. J. Am. Chem.
Soc. 1925, 47, 2047; (b) Baarshers, W. H. Can. J. Chem.
1976, 54, 3056.
13. All boronic acids were from commercial source and used
as such for the reaction.