Copper-Catalyzed Synthesis of Activated Sulfonate Esters from Boronic Acids, DABSO, and Pentafluorophenol

Article abstract of DOI:10.1021/acs.orglett.8b02445

The synthesis of pentafluorophenyl (PFP) sulfonate esters based on the Pd-catalyzed sulfination of aryl and heteroaryl boronic acids is reported. The sulfinate intermediates are converted in situ to the corresponding sulfonate esters using a copper-catalyzed oxidative process, providing a broad range of PFP esters in good yields.

Full text of DOI:10.1021/acs.orglett.8b02445

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Synthesis of Activated Sulfonate Esters from
Boronic Acids, DABSO, and Pentafluorophenol
Vincent Vedovato,† Eric P. A. Talbot,‡ and Michael C. Willis*,†
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, United
Kingdom
‡GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
S
* Supporting Information
ABSTRACT: The synthesis of pentafluorophenyl (PFP)
sulfonate esters based on the Pd-catalyzed sulfination of aryl
and heteroaryl boronic acids is reported. The sulfinate
intermediates are converted in situ to the corresponding
sulfonate esters using a copper-catalyzed oxidative process,
providing a broad range of PFP esters in good yields.
Scheme 1. Preparation of Pentafluorophenyl Sulfonate
Esters
ulfonyl-derived functional groups, such as sulfones,
Ssulfonamides, and sulfonate esters, are of proven value in
organic chemistry and feature as intermediates or as final
compounds in a wide variety of applications.1 A common
method to prepare these molecules is to combine an
electrophilic sulfonyl derivative with an appropriate nucleo-
philic component. Sulfonyl chlorides are often the electrophile
of choice for these reactions, and they benefit from wide
commercial availability and high reactivity.2 High chemical
reactivity can also lead to disadvantages and can make the
synthesis and purification of sulfonyl chlorides challenging and
can also limit stability to long-term storage.3 Efforts to
overcome these limitations include the in situ generation of
sulfonyl chlorides4 as well as the identification of alternative
electrophilic species.3,5 Pentafluorophenyl (PFP) sulfonate
esters have emerged as effective sulfonyl chloride mimics and
generally enjoy the benefits of high crystallinity and bench
stability while maintaining useful electrophilicity.6 A significant
disadvantage of aryl PFP sulfonate esters is that their synthesis
usually requires a sulfonic acid, or related salt, as starting
material, and these have limited commercial availability
(Scheme 1a).6c
We envisaged an alternative route to PFP sulfonate esters
that employed boronic acidsone of the most diverse sets of
monomers available for discovery chemistryas the starting
material, in combination with catalytic sulfinylation methods
using a sulfur dioxide surrogate (Scheme 1b).7,8 We, and
others, have reported a variety of catalysts and sulfur dioxide
sources for the formation of sulfinates (1) from boronic acids,9
and so the challenge was to identify reaction conditions that
would allow the in situ conversion of the sulfinate
intermediates into the required pentafluorophenyl sulfonate
esters (1 → 2).
the SO2 source to generate sulfinate 1a, and then explored a
variety of conditions to convert the sulfinate into the required
PFP sulfonate ester. Initial reactions employing I2 or NBS in
combination with pentafluorophenol were not effective
(entries 1 and 2);10 however, the addition of Cu(OAc)2 as a
catalyst significantly improved these yields (entries 3 and 4).
Following evaluation of several oxidants and copper salts, we
found that the use of K2S2O8 as the oxidant, CuBr2 as the
catalyst, and the addition of molecular sieves provided
sulfonate ester 2a in good yield (entries 5−10). The addition
of NaBr was found to further increase the yield, allowing the
sulfonate ester to be isolated in 86% yield (entry 11). The
requirement for the use of a copper catalyst was confirmed
(entry 12).
With the optimal reaction conditions in hand, we then
examined the scope of this transformation with respect to the
boronic acid substrate. As shown in Scheme 2, a wide range of
boronic acids were found to be suitable substrates for this
transformation. Boronic acids bearing substituents at all
To assess the viability of our proposed route we studied the
conversion of 4-tolylboronic acid into PFP sulfonate ester 2a
(Table 1). We used our reported procedure for sulfinate
formation,9a employing Pd(OAc)2 as a catalyst and DABSO as
Received: August 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02445
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Reaction Optimization for the Formation of
Pentafluorophenyl Sulfonate Ester 2a
Scheme 2. Evaluation of Reaction Scope with Respect to
Boronic Acid
a
a
b
entry
catalyst
[O]
additive
yield (%)
1
2
I2
NBS
<2
0
3
4
5
6
7
8
9
10
11
12
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
Cu(OAc)2
Cu(OAc)2
CuBr2
I2
NBS
13
37
42
30
34
65
69
75
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
3 Å MS
3 Å MS
3 Å MS + NaBr
3 Å MS + NaBr
CuBr2
92 (86)
0
a
Reaction conditions: (i) boronic acid (0.5 mmol), DABSO (0.5
mmol), TBAB (0.15 mmol), Pd(OAc)2 (0.025 mmol), MeOH [0.16
M]; then pentafluorophenol (0.25 mmol), Na2S2O8 (0.5 mmol),
CuBr2 (0.05 mmol), NaBr (0.15 mmol), NEt3 (1.0 mmol), 3 Å MS,
b
rt, 18 h. Determined by 19F NMR spectroscopy using fluorobenzene
as an internal standard. Isolated yield in parentheses.
positions of the aromatic ring, including a variety of electron-
donating substituents, delivered the expected sulfonate esters
in good yields (2a−n). Notable examples included the use of a
free phenol (2i) as well as amido (2j,k) and amino groups (2l).
Benzodioxane (2n) and methylenedioxyphenyl boronic acid
(2m) provided sulfonate esters in high yields. Boronic acids
featuring electron-withdrawing substituents (2o−r) were also
tolerated, although the isolated yields were slightly reduced
relative to the electron-donating examples. 4-Bromophenylsul-
fonate ester (2q) was produced on multigram scale from a 10
mmol reaction. More complex products, such as trisubstituted
example 2s and tyrosine-derived 2t, were obtained in good
yields. We then turned our attention to heteroaromatic boronic
acids. Heterocycles such as benzofuran (2u), indole (2v), and
7-azaindole (2w) afforded the corresponding sulfonate esters
in good yields. However, the indazole boronic acid only
delivered the desired product in low yield (2x). We were
pleased to see that pyridine boronic acids could also be
tolerated (2y,z) as well as a thiophene substrate (2aa). The
final example in Scheme 2 shows that alkenyl boronic acids can
also be included (2ab).
Although a broad range of boronic acids are widely available,
we also wanted to demonstrate that alternative substrate
classes could be employed for PFP sulfonate formation.
Accordingly, aryl bromide 3 was converted into PFP sulfonate
ester 2ac using our reported Pd(0)-catalyzed reaction
conditions for the first step of the sequence, followed by the
optimized copper-catalyzed process (Scheme 3).11 While this
transformation establishes that aryl bromides are viable
substrates in this chemistry, the longer reaction times needed
to achieve sulfinate formation, relative to the boronic acid
examples (16 h vs 30 min), favor the use of the boron-based
reagents.
a
Reaction conditions: boronic acid (0.5 mmol), DABSO (0.5 mmol),
Pd(OAc)2 (0.025 mmol), TBAB (0.25 mmol), MeOH [0.16 M], 80
°C, 30 min, then PFPOH (0.25 mmol), Na2S2O8 (0.5 mmol), CuBr2
(0.05 mmol), NaBr (0.15 mmol), Et3N (1.0 mmol), 3 Å MS, rt, 18 h.
b
c
d
No TBAB used. Sulfination step, 1 h. Sulfination step, 3 h.
e
MeOH/1,4-dioxane (1:1) [0.16 M] used as solvent.
To demonstrate the utility of the PFP sulfonate esters
produced in this study, we chose to transform the 4-
bromophenylsulfonate ester (2q) into a range of products of
interest (Scheme 4). Treatment of sulfonate 2q with the
B
DOI: 10.1021/acs.orglett.8b02445
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Scheme 3. PFP Sulfonate Ester Synthesis Starting from an
Aryl Bromide 3
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02445.
Experimental procedures and full characterization for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.willis@chem.ox.ac.uk.
ORCID
Scheme 4. Reactivity of PFP Sulfonate Esters
Michael C. Willis: 0000-0002-0636-6471
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank GlaxoSmithKine and the University of Oxford for
their support of this study.
■
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■
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