Palladium(II)-Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox-Neutral, Phosphine-Free Transformation

Article abstract of DOI:10.1002/anie.201508370

A redox-neutral palladium(II)-catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)₂ catalyst, in combination with the sulfur dioxide surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high-yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C- or N-based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one-pot, two-step process.

Full text of DOI:10.1002/anie.201508370

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201508370
German Edition: DOI: 10.1002/ange.201508370
Synthetic Methods
Palladium(II)-Catalyzed Synthesis of Sulfinates from Boronic Acids
and DABSO: A Redox-Neutral, Phosphine-Free Transformation
Alex S. Deeming, Claire J. Russell, and Michael C. Willis*
Abstract: A redox-neutral palladium(II)-catalyzed conversion
of aryl, heteroaryl, and alkenyl boronic acids into sulfinate
intermediates, and onwards to sulfones and sulfonamides, has
been realized. A simple Pd(OAc)2 catalyst, in combination
with the sulfur dioxide surrogate 1,4-diazabicyclo[2.2.2]octane
bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and
high-yielding conversion of the boronic acids into the corre-
sponding sulfinates. Addition of C- or N-based electrophiles
then allows conversion into sulfones and sulfonamides,
respectively, in a one-pot, two-step process.
diazabicyclo[2.2.2]octane), has been combined with pre-
formed organometallic reagents to generate metal sulfinates
which can then undergo in situ conversion into sulfones[8] and
sulfonamides.[9–11] A palladium-catalyzed preparation of am-
monium sulfinates has also been reported by our laboratory,
and allows (hetero)aryl iodides and DABSO to be efficiently
combined using a palladium(0) catalyst and iPrOH as
reductant (Scheme 1a).[12] A similar transformation was
T
he sulfonyl group, which is embedded in sulfones, sulfon-
amides, sulfonate esters, and sulfinic acids, is a structural motif
with numerous uses. These important functional groups
contribute significant physiochemical properties,[1] as well as
varied synthetic utility,[2] and a wide range of pharmaceutical
and agrochemical applications are known.[3,4]
Sulfones and sulfonamides are the most prominent
sulfonyl-containing molecules, and general and simple meth-
ods for their construction are in high demand. Classical
syntheses which are commonly employed include sulfide
oxidation[5] and sulfonyl chloride-amine coupling,[6] to access
sulfones and sulfonamides, respectively. Limitations of such
strategies include the use of odorous thiols and functional-
group-restricting oxidative conditions in the sulfone synthesis,
and harsh acidic treatment of arenes to access sulfonyl
chloride precursors by electrophilic aromatic sulfonation. In
addition, electrophilic substitution processes impose con-
straints on the substitution patterns which can be readily
prepared.
Scheme 1. Catalytic sulfnate synthesis. a,b) Examples involving a Pd0/II
cycle. c) This work, involving a redox neutral PdII system.
developed by Shavnya and co-workers with the formation
of sulfinates from aryl halides using K2S2O5 as the sulfur
dioxide source and formate as the reductant (Scheme 1b).[13]
While these processes serve as effective means of accessing
sulfonyl-containing compounds, they suffer from either the
use of specialized and expensive phosphine ligands or high
catalyst and ligand loadings, and are also slow reactions
(typically 16–18 h). The need for supporting ligands presum-
ably arises from the operation of a Pd0/II cycle.
To address these shortcomings we targeted the develop-
ment of a palladium(II) catalytic system employing boronic
acids as substrates in combination with DABSO. Such
a process would be redox-neutral, should allow greater
functional-group tolerance, and should avoid the requirement
for specialized, often costly, phosphine ligands. Toste and co-
workers recently disclosed a process for the conversion of aryl
boronic acids into sulfinates using K2S2O5 and gold(I)
catalysis.[14] This elegant study demonstrates the viability of
a redox-neutral sulfinate synthesis, albeit in a gold(I) mani-
fold, but suffers from the use of high catalyst loadings and
limited onwards sulfinate reactivity with products obtained in
moderate yields. Herein, we outline the successful develop-
Alternative routes to a variety of sulfonyl derivatives can
be achieved from the direct insertion of sulfur dioxide into
suitably functionalized substrates. For example, the SO2-
surrogate DABSO,[7] DABCO·(SO2)2 (DABCO = 1,4-
[*] A. S. Deeming, Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
Dr. C. J. Russell
Syngenta, Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG42 6EY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508370.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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ment of a one-pot, redox-neutral palladium(II)-catalyzed
preparation of sulfinate derivatives from boronic acid sub-
strates. A phosphine-free catalyst allows the rapid conversion
of boronic acids into the corresponding sulfinates, and then
onwards to a variety of sulfones and sulfonamides (Sche-
me 1c).[15–17]
Initial investigations quickly revealed that the union of p-
tert-butylphenylboronic acid, DABSO, and tert-butyl bromo-
acetate could be achieved by the use of Pd(OAc)2 as the
catalyst with Et3N as the base in a 1,4-dioxane/MeOH solvent
mixture. The addition of TBAB resulted in a small increase in
yield, thus allowing isolation of the sulfone 1a in 83%
(Scheme 2a). A brief assessment of the scope of boronic acids
epoxides and O-hydroxylaminesulfonic acid. Such couplings
generally require water as a solvent.[18]
To achieve a more general process we were motivated to
pursue the proposed synthesis of sulfinate derivatives with
subsequent in situ trapping in a two-step format. We postu-
À
lated that the palladium sulfinate generated after Pd C SO2
insertion was responsible for the observed low reactivity with
simple electrophiles, and that a Lewis acid or ligand could aid
À
Pd O(S) bond cleavage to release an alternative metal
sulfinate and turnover the palladium(II) catalyst. While initial
attempts were unsuccessful, upon introducing a Brønsted acid
in the form of TFA into the reaction [p-tolylboronic acid with
DABSO and Pd(OAc)2, without Et3N], the sulfinic acid 2b
(for structure see Scheme 3) was observed in 75% yield
(HPLC). When performing the same transformation in the
absence of both TFA and Et3N, 2b was formed in 92% yield,
thus translating into a 88% yield of the sulfone 1b after base
treatment and alkylation (Scheme 3).
Scheme 3. Base-free, one-pot, two-step sulfone synthesis. Pd(OAc)2
(10 mol%).
With this key observation that the desired boronic acid
sulfination could be achieved by simple treatment with
Pd(OAc)2 and DABSO in a short reaction time (30 min),
further assessment of the reaction conditions revealed that
lower palladium(II) loadings could effect this transformation
and that MeOH was integral as a cosolvent (see the
Supporting Information for details). On examination of the
boronic acid scope of the reaction, using these optimized
reaction conditions, it was quickly established that varying the
electronics of the aryl boronic acid was detrimental to
reactivity. Substrates bearing p-fluoro and p-tert-butyl func-
tionalities resulted in immediate biphenyl and palladium(0)
formation. This side-reaction could be suppressed by employ-
ing TBAB as an additive in a low loading (0.25 equiv). A full
examination of the reaction scope was then conducted, and by
employing triethylamine and tert-butyl bromoacetate, as the
electrophilic trap, a range of sulfones could be accessed
(Table 1).[19] Substrates bearing electron-donating and elec-
tron-withdrawing groups, as well as ortho-, meta-, and para-
substitution patterns were all well tolerated in this system.
Pleasingly, sensitive functional groups such as phenol (1m),
amide (1n), amine (1p), and indole (1u) moieties were
compatible with sulfones obtained in good yields.
Scheme 2. Boronic acid and electrophile scope in the one-step
palladium(II)-catalyzed sulfone synthesis. Reaction conditions: Boronic
acid (0.25 mmol, 1 equiv), Pd(OAc)2 (10 mol%), DABSO (1 equiv),
Et3N (2 equiv), MeOH/1,4-dioxane (1:1) [0.16m], RX (0.75 mmol).
Isolated yields. [a] 1008C. TBAB=tetra-n-butylammonium bromide.
and electrophiles compatible with this one-pot, one-step
process was carried out (Scheme 2b). Aryl boronic acids
bearing electron-donating and electron-withdrawing substitu-
ents proved to be effective substrates (1a–e), and simple
heteroaromatic variants were also well tolerated (1 f).
Alkenyl boronic acids were found to be lower yielding (1g).
Aromatic BF3K salts were compatible with this system (1e).
In terms of suitable electrophiles, only activated alkyl halides
(1a,h–j) proved to be effective in this process with simple
alkyl halides affording none of the desired products (e.g.,
butyl bromide). A further limitation with this one-step
format, was that the solvent for the sulfinate functionalization
was confined to 1,4-dioxane/MeOH, thus resulting in the
incompatibility of more elaborate electrophiles such as
The incorporation of the methylthio-substituted boronic
acid (1l) promotes the use of this chemistry over traditional
sulfide oxidation strategies, where access to such mixed
oxidation-state S products would not be possible. Pleasingly,
a variety of heteroaromatic groups were well tolerated in this
reaction, with thiophene and furan substrates delivering the
corresponding products in acceptable yields (1 f and 1s),
while examples incorporating pyridine (1r), benzodioxane
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Table 1: Scope with respect to the boronic acid in the one-pot, two-step
Table 2: Scope with respect to the C electrophile in the one-pot, two-step
palladium(II)-catalyzed sulfone synthesis.[a]
palladium(II)-catalyzed sulfone synthesis.[a]
[a] Reaction conditions for sulfinate derivatization step: E+ (3 equiv), 1,4-
dioxane/MeOH, 808C, 1 h. [b] Ph2I+ClÀ (3 equiv), 1,4-dioxane/MeOH,
808C, 6 h. [c] E+ (2 equiv), DMAc, 1008C, 1 h. [d] E+ (3 equiv), DMSO,
808C, 2 h. [e] Epoxide (5 equiv), H2O, 908C, 6 h. DMAc=
N,N-dimethylacetamide, DMSO=dimethylsulfoxide.
The methodology could be extended to allow the use of N-
electrophiles. Both primary and substituted sulfonamides
could be prepared by combining the in situ generated
sulfinates with either O-hydroxylaminesulfonic acid or N-
chloroamines (also generated in situ; Table 3).[10a]
[a] Reaction conditions: 1) Boronic acid (0.25 mmol, 1 equiv), Pd(OAc)2
(5 mol%), DABSO (1 equiv), TBAB (0.25 equiv), 1,4-dioxane/MeOH
(1:1) [0.16m], 808C. 2) Et3N (2 equiv) RT, 1 min then tert-butyl
bromoacetate (3 equiv), 808C, 30 min. [b] Without TBAB. [c] Sulfination
step for 3 h. [d] Sulfination step for 1 h.
Table 3: The use of N electrophiles to access sulfonamides.[a]
(1q), and indazole (1t) functionalities performed well.
Alkenyl boronic acids could be employed as substrates, with
styryl and straight-chain alkenyl variants giving products in
modest yields (1v,w), and the cyclohexenyl boronic acid
afforded the corresponding sulfone in high yield (1x).
We next looked to expand the scope of sulfonyl-contain-
ing products beyond those accessible with the one-step
procedure (Scheme 2), and were pleased to find that a variety
of C-based electrophiles could be employed (Table 2).
Alkylations could be achieved by maintaining 1,4-dioxane/
MeOH as the solvent and simple alkyl iodides were found to
perform well (1y,z). Diaryl sulfones were accessible using
either an aryl iodonium salt (1aa)[20] or through SNAr
chemistry (1ab and 1ac).[21] Modification of the reaction
conditions for the derivatization of the sulfinic acid deriva-
tives allowed the chemistry to be extended to epoxide ring
opening. For example, use of cyclohexene oxide delivered the
sulfone 1ad in good yield. The b-hydroxy sulfone 1ae was
prepared using this one-pot process in moderate yield, and is
significant as it corresponds to the methyl ester derivative of
the anti-androgen pharmaceutical Casodex.[22]
Sulfinate derivatization step: [a] Et3N, RT then H2NSO3H (2 equiv), H2O,
RT, 2 h or R1R2NH (5 equiv), NaOCl (3 equiv), H2O, RT, 16 h.
Finally, we were able to demonstrate the application of
this one-pot sulfone synthesis on a preparative scale. Using
a 1 mol% catalyst loading and a slightly extended sulfination
reaction time, the sulfone 1b was isolated in 90% yield on
a 3.5 gram scale (Scheme 4). Importantly, this larger scale
reaction was performed open to air.
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In summary, we have developed a one-pot, redox-neutral
and ligand-free synthesis of sulfinic acid derivatives. By
simply treating boronic acid substrates with DABSO and low
loadings of Pd(OAc)2, sulfinic acid intermediates were
formed and subsequently coupled with a variety of electro-
philes in situ, to access a broad range of sulfones and
sulfonamides. In addition to this, a one-step reaction was also
developed, thus allowing preparation of sulfones using
activated alkyl halides.
Acknowledgments
[12] E. J. Emmett, B. R. Hayter, M. C. Willis, Angew. Chem. Int. Ed.
2014, 53, 10204; Angew. Chem. 2014, 126, 10368.
This work was supported by the EPSRC and Syngenta.
[13] A. Shavnya, S. B. Coffey, A. C. Smith, V. Mascitti, Org. Lett.
2013, 15, 6226.
Keywords: electrophiles · oxidation · palladium · sulfur ·
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[15] Wu and co-workers have reported a palladium(0)-catalyzed aryl
boronic acid based synthesis of aminosulfonamides: S. Ye, J. Wu,
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[16] Buchwald and co-workers have reported the palladium(0)-
catalyzed coupling of aryl boronic acids and phenyl chlorosulfate
to deliver aryl sulfonyl chlorides: J. R. DeBergh, N. Niljianskul,
S. L. Buchwald, J. Am. Chem. Soc. 2013, 135, 10638.
[17] After submission of this manuscript, related chemistry, employ-
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synthesis of sulfones appeared online: A. Shavnya, K. D. Hesp,
V. Mascitti, A. C. Smith, Angew. Chem. Int. Ed. 2015, 54, 13571;
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synthetic methods
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Received: September 7, 2015
Published online: November 24, 2015
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