Efficient route for the preparation of benzyloxy-substituted benzenesulfonyl chlorides from mercaptophenols

Article abstract of DOI:10.1080/00397911.2010.492461

A consistently high-yielding route has been developed for the preparation of benzyloxybenzenesulfonyl chlorides from mercaptophenols. This route allows rapid preparation of intermediates for array chemistry.

Full text of DOI:10.1080/00397911.2010.492461

Synthetic Communications1, 41: 1805–1808, 2011
Copyright # GlaxoSmithKline
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492461
EFFICIENT ROUTE FOR THE PREPARATION OF
BENZYLOXY-SUBSTITUTED BENZENESULFONYL
CHLORIDES FROM MERCAPTOPHENOLS
Coline Jumeaux, David G. Cooper, Bruce T. Brown,
Ian T. Forbes, and Vincenzo Garzya
GlaxoSmithKline Neurosciences Centre of Excellence for Drug Discovery,
New Frontiers Science Park, Harlow, Essex, UK
GRAPHICAL ABSTRACT
Abstract A consistently high-yielding route has been developed for the preparation of ben-
zyloxybenzenesulfonyl chlorides from mercaptophenols. This route allows rapid preparation
of intermediates for array chemistry.
Keywords Aromatic compounds; disulfides; mercaptophenols; sulfonyl chlorides
INTRODUCTION
As part of our research, we sought an efficient route to a range of
benzyloxy-substituted benzenesulfonyl chlorides of structure 1 (Scheme 1). These
were required as key building blocks for array chemistry and also as protected phe-
nolic sulfonyl chloride precusors. Few examples of benzyloxy-substituted aromatic
sulfonyl chlorides are exemplified in the literature, and the current methods do not
fully explore the rapid preparation of a range of substituted benzyloxy analogs
across ortho, meta, and para isomers.[1,2] The current literature routes include forma-
tion of aromatic sulfonyl chloride from aromatic halides via formation of Grignard
intermediates[3] or halogen–metal exchange.[4] These methodologies allow to access
sulfonyl chlorides with good to moderate yields,[5] with the limitation of requiring
halogenated starting materials. Alternatively, direct chlorosulfonation with chloro-
sulfonic acid gives para-substituted analogs; unfortunately we have found this reac-
tion to be very capricious. All three mercaptophenol isomers 2 are readily available
and were therefore considered to be a suitable starting point. However, direct
Received April 22, 2010.
Address correspondence to Coline Jumeaux or Vincenzo Garzya, GlaxoSmithKline Neurosciences
Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex
CM19 5AW, UK. E-mail: coline.b.jumeaux@gsk.com; Vincenzo.2.Garzya@gsk.com
1805

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C. JUMEAUX ET AL.
Scheme 1. Reagents and conditions: (a) I2–MeOH, (b) NaH–DMF, (c) ArCH2Br–DMF, (d) Cl2–AcOH–
H2O or NCS–AcOH–H2O.
alkylation of mercaptophenols gives the corresponding S-alkyl derivative.[6] We envi-
saged that formation of the corresponding disulfide would enable selective alkylation
at oxygen and the disulfide could then be oxidatively cleaved to the corresponding
sulfonyl chloride. Thus we explored the possibility of preparing benzyloxybenzene-
sulfonylchoride by the route shown in Scheme 1.
The methodology reported herein has been successfully used in some of our
previous work.[7] Furthermore, there are other methods of accessing sulfonyl
chlorides from disulfides.[8,9]
RESULTS AND DISCUSSION
All of the disulfides of structure 3 are known and were prepared from the
corresponding mercaptophenols by treatment with iodine in methanol.[10] Alkylation
of these disulfides using sodium hydride in dimethylformamide (DMF) gave the
bis-O-alkylated products 4 in excellent yields (Table 1), providing the amount of
alkylating agent was limited to 2.2 equivalents. If excess alkylating agent was used,
the secondary alkylation occurred at sulfur. Treatment of the disulfide with either
chlorine[11] or N-chlorosuccinimide (NCS)[12,13] in a mixture of acetic acid and water
gave the desired sulfonyl chloride (Table 1). Consistently good yields were obtained
for the meta and para isomers whereas yields were slightly reduced for the ortho
Table 1. Sulfonyl chlorides prepared using this methodology
Sulfonyl chloride formationa
R
Isomer
Alkylation stepa yield (%)
100
Reagent
Yield (%)
4-F
para
"
Cl2
NCS
94
93
90
83
97
93
91
85
87
98
78
65
65
"
3-F
"
80
70
82
87
79
82
87
86
82
93
96
"
"
"
"
"
"
"
"
"
"
"
2-F
"
4-Me
2,4-diF
3,4-diF
4-Br
4-CF3
4-F
"
"
"
"
"
meta
"
4-Cl
4-F
ortho
"
4-Cl
aNMR and mass spectral data were fully consistent for the structures shown.

BENZYLOXYBENZENESULFONYL CHLORIDES
1807
isomers, presumably because of steric hindrance, though no attempts were made to
optimize conditions for this isomer.
All the sulfonyl chlorides prepared were reacted with a diverse range of amines
using standard literature conditions[14] in an array format, giving the corresponding
sulfonamides in >80% yield.
CONCLUSIONS
In summary, this methodology gives excellent yields to access benzyloxy-
substituted benzenesulfonyl chlorides and has the potential to be applied to the prep-
aration of further homologated analogs. For example, we have shown that equally
good yields can be obtained by substituting Ar(CH2)3Br or Ar(CH2)2Br for benzyl
bromide.
EXPERIMENTAL
Typical Experimental Procedure for Benzylation of Hydroxyphenyl
Disulfides Bis-[3-(4-fluorobenzyloxy)-phenyl]-disulfide
To a solution of bis-(3-hydroxyphenyl)-disulfide (0.84 g, 3.4 mmol) in DMF
(15 mL) was added sodium hydride 60% in oil (0.28 g, 7.0 mmol). The solution was
stirred for 10 min when 4-fluorobenzyl bromide (1.32 g, 7 mmol) was added, and
the solution stirred for another 16 h, poured onto water, and extracted with ethyl
acetate. The organic extracts were washed with dilute sodium hydroxide solution
and then brine and evaporated. Chromatography on silica gel eluting with 10% ethyl
acetate in hexane gave the desired bis-[3-(4-fluorobenzyloxy)-phenyl]-disulfide as a
1
white solid (1.34 g, 86% yield). Mass spectrum 467 (Mþ); H NMR: CDCl3 4.96
(4H, s), 6.83, (2H, m), 6.8–7.1 (8H, m), 7.2 (2H, m), 7.35 (4H, m).
Typical Experimental Procedure for Conversion of the Disulfides to
Sulfonyl Chlorides 3-(4-Fluorobenzyloxy)-benzenesulfonyl Chloride
A solution of bis-[3-(4-fluorobenzyloxy)-phenyl]-disulfide (1.3 g, 2.8 mmol)
in glacial acetic acid (20 mL) and water (5 mL) was cooled in an ice-water bath.
N-Chlorosuccinimide (1.9 g, 14 mmol) was added with stirring, and the solution
was allowed to warm to room temperature over 2 h. The reaction was then poured
into water and extracted with ethyl acetate. The organic extract was washed with
brine, dried with Na2SO4, filtered, and evaporated to give the title compound as a
1
white solid (1.65 g, 85% yield). H NMR: CDCl3 5.10 (2H, s), 7.08, (2H, m), 7.32
(1H, m), 7.44 (2H, m), 7.51 (1H, m), 7.55 (1H, m), 7.66 (1H, m).
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