Synthesis of aryl [35S]sulfones: Friedel-Crafts sulfonylation of aryl ethers with high specific activity [35S]methanesulfonyl chloride

Article abstract of DOI:10.1002/jlcr.1300

Lewis acid-assisted sulfonylation of anisole with [³⁵S] methanesulfonyl chloride afforded high specific activity aryl [ ³⁵S]sulfones. Demethylation and treatment with triflic anhydride gave the versatile [³⁵S]triflate 1 in

Full text of DOI:10.1002/jlcr.1300

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 347–349.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1300
Short Research Article
Synthesis of aryl [35S]sulfones: Friedel–Crafts sulfonylation of
aryl ethers with high specific activity [35S]methanesulfonyl
chloridey
MICHAEL A. WALLACE*, CONRAD RAAB, DENNIS DEAN and DAVID MELILLO
Department of Drug Metabolism, Merck Research Laboratories, P.O. 2000, Rahway, NJ 07065, USA
Received 26 January 2007; Revised 1 February 2007; Accepted 2 February 2007
Abstract: Lewis acid-assisted sulfonylation of anisole with [35S]methanesulfonyl chloride afforded high specific
activity aryl [35S]sulfones. Demethylation and treatment with triflic anhydride gave the versatile [35S]triflate 1 in
good overall yields. The [35S]sulfone triflate could be further functionalized by catalyzed aminations, Stille couplings,
and cyanation. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: [35S]methanesulfonyl chloride; aryl [35S]sulfones; [35S]sulfone triflate
Introduction
flate (A) which could be further functionalized by
catalyzed aminations, Stille couplings, and cyanation.
High specific activity 35S-labeled radioligands ð> 900
Ci=mmolÞ have previously been limited primarily to
alkyl and aryl [35S]sulfonamides.1 These tools have
proven to be very useful in biological applications,
including receptor occupancy and binding, and
offer some advantages over 3H and 125I-labeled radi-
oligands.2 While we have been able to broaden the
scope of accessible [35S]sulfonamide radioligands by
varying the alkyl group and using functionalized
aromatics,3 we sought to expand the range of our high
specific activity 35S-chemistry to include aryl [35S]sul-
fone-containing radioligands. It has been reported that
methanesulfonyl chloride can be added to aryl com-
Results and discussion
Our initial attempts were directed toward 35S-sulfony-
lation of bromobenzene and toluene with high specific
activity
[
35S]methanesulfonyl chloride. When no
methyl [35S]sulfone was observed with bromobenzene
or toluene under the described conditions,4 we
were forced to reconsider the suitability of the aryl
group.
Subsequent 35S-sulfonylation of a more electron-rich
arene, anisole, provided moderate yields of the desired
isomeric methyl [35S]sulfones as shown in Scheme 1. A
concentrated solution of [35S]methanesulfonyl chloride
in dichloromethane, anisole, and appropriate catalyst
were warmed to 808C for 4–6 h. The resulting ortho- and
para-isomers of the methoxy [35S]methyl sulfones were
purified and separated by preparative HPLC.
pounds in
a Friedel-type addition using bismuth
or indium catalyst.4 Herein, we report the Lewis
acid-assisted sulfonylation of anisole with [35S]metha-
nesulfonyl chloride to afford high specific activity
ð> 900 Ci=mmolÞ aryl
[
35S]sulfones. Separation of
Demethylation with boron tribromide5 cleanly gave
the [35S]phenol in quantitative yield. Treatment of the
phenol with triflic anhydride6 under biphasic condi-
tions (toluene, aqueous potassium phosphate) afforded
clean [35S]sulfone triflate 1 in 95% yield (scheme 2).
The [35S]sulfone triflate was stable in toluene and could
be used as a stock solution in subsequent reactions
without further purification.
regioisomers, followed by demethylation, and treat-
ment with triflic anhydride gave the versatile [35S]tri-
*Correspondence to: Michael A. Wallace, Department of Drug Metabo-
lism, Merck Research Laboratories P.O. 2000, Rahway, NJ 07065,
USA. E-mail: mike wallace@merck.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
The [35S]sulfone triflate 1 proved to be quite a versatile
intermediate and could be further functionalized
Copyright # 2007 John Wiley & Sons, Ltd.

348 M. A. WALLACE ET AL.
OCH3
OCH3
Bi(OTf)3
35S]MsCl
40% sulfone products
[
23% ortho
17% para
OCH3
O
S
O
O
S
O
*
*
OCH3
OCH3
In(OTf)3
35S]MsCl
22% sulfone products
[
OCH3
12% ortho
10% para
O
S
O
O
S
O
*
*
Scheme 1
OCH3
OTf
OH
Triflic anhydride
aq. K3PO4
BBr3
CH2Cl2
O
S
O
O
S
O
O
S
O
*
*
*
1
Scheme 2
OTf
Sn(Bu)3
LiCl, Pd(PPh3)4
80% radiochemical yield
O
S
O
O
S
O
*
*
OTf
HN
O
S
N
*
Pd2(dba)3, toluene
O
O
S
O
*
75% radiochemical yield
Scheme 3
through several standard triflate reactions, including
aminations7 and Stille-type couplings8 of which a few
examples are shown in Scheme 3.
from
[
35S]methanesulfonyl
chloride
which
is
stable and functionalizable through amine couplings
and carbon–carbon bond forming reactions. The
sequence of reactions is robust, providing clean
products even with many equivalents of reagents
and further enhances our efforts to provide a range of
structurally different 35S-radioligands for biological
applications.
Conclusion
We have developed
a
methodology to provide
a
high specific activity methyl
[
35S] sulfone triflate
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 347–349
DOI: 10.1002.jlcr

SYNTHESIS OF ARYL [35S]SULFONES 349
Frost CG, Hartley JP, Whittle AJ. Synlett 2001; 6:
830–832.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 347–349
DOI: 10.1002.jlcr