Copper(i)-catalyzed sulfonylative Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1039/C6SC05483H

Using a simple copper(i) catalyst has allowed a high yielding sulfonylative-Suzuki-Miyaura cross-coupling reaction to be developed. The process provides a single step route to diaryl sulfones from the direct combination of aryl boronic acids, sulfur dioxide and aryl iodides, and represents the first sulfonylative variant of a classic cross-coupling reaction. Sulfur dioxide is delivered from the surrogate reagent, DABSO. Variation of the reaction conditions allowed interruption of the sulfonylative-Suzuki coupling, resulting in the formation of a presumed Cu-sulfinate intermediate. These sulfinates could be trapped as their sodium salts and treated with electrophiles to allow access to arylalkyl sulfones, β-hydroxyl sulfones, sulfonamides and sulfonyl fluorides.

Full text of DOI:10.1039/C6SC05483H

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EDGE ARTICLE
Copper(I)-catalyzed sulfonylative Suzuki–Miyaura
cross-coupling†
Cite this: DOI: 10.1039/c6sc05483h
*
Yiding Chen and Michael C. Willis
Using a simple copper(I) catalyst has allowed a high yielding sulfonylative-Suzuki–Miyaura cross-coupling
reaction to be developed. The process provides a single step route to diaryl sulfones from the direct
combination of aryl boronic acids, sulfur dioxide and aryl iodides, and represents the first sulfonylative
variant of a classic cross-coupling reaction. Sulfur dioxide is delivered from the surrogate reagent,
DABSO. Variation of the reaction conditions allowed interruption of the sulfonylative-Suzuki coupling,
resulting in the formation of a presumed Cu–sulfinate intermediate. These sulfinates could be trapped as
their sodium salts and treated with electrophiles to allow access to arylalkyl sulfones, b-hydroxyl
sulfones, sulfonamides and sulfonyl fluorides.
Received 15th December 2016
Accepted 16th February 2017
DOI: 10.1039/c6sc05483h
rsc.li/chemical-science
Introduction
The Suzuki–Miyaura cross-coupling reaction1 is the preeminent
method for forming carbon–carbon bonds in the pharmaceu-
tical industry.2 This classic reaction combines aryl boronates
and boronic acids with aryl halides under the action of a palla-
dium catalyst, delivering biaryl products in an efficient manner.
The popularity of this method stems from the wide availability
and low-toxicity of boron-derived substrates, mild reaction
conditions, associated good functional group tolerance, and
general robustness of the transformations. Carbonylative
versions of these reactions have also been developed,3 in which
a molecule of carbon monoxide is incorporated in the coupling
reaction, diverting the process from biaryl formation and
resulting in a ketone product.4 However, despite the electronic
similarity between carbon monoxide and sulfur dioxide,5 a sul-
fonylative variant, which would provide valuable sulfone prod-
ucts, has not been realized (Fig. 1a). When the utility of the
sulfone functional group is considered – they feature in
numerous biologically active molecules, including many mar-
keted pharmaceuticals and agrochemicals (Fig. 1b), are
common motifs in designed materials, and they serve as
versatile intermediates for organic synthesis – this absence is
striking.6 In this Edge Article, we show that by using a copper(I)
catalyst, a high yielding sulfonylative-Suzuki–Miyaura cross-
coupling reaction is possible.
Department of Chemistry, University of Oxford, Chemical Research Laboratory,
Manseld Road, Oxford, OX1 3TA, UK. E-mail: michael.willis@chem.ox.ac.uk
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6sc05483h
Fig. 1 (a) Variants of the Suzuki–Miyaura cross-coupling reaction, and
(b) examples of biologically relevant sulfones.
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conditions, and these are shown in Table 1. The ESI† provides
full details, however, the key variations are noted in Table 1. The
use of an electron-rich bipyridine ligand, L4,24 in combination
with the copper salt Cu(MeCN)4BF4 and the polar aprotic
solvent DMPU, allowed an efficient transformation to be
achieved.
Results and discussion
A variety of methods are available for the synthesis of
sulfones,6,7 including a number of transition metal-catalyzed
approaches.8 However, many of these classical syntheses are
either multi-step, or employ harmful, non-selective reagents,
signicantly detracting from their utility. Recent years have
seen catalytic methods for sulfur dioxide incorporation9 emerge
as useful tools for the preparation of sulfonyl-derived functional
groups.10 In particular, palladium-catalyzed aryl sulnate
formation has been reported using both aryl halides11 and aryl
boronic acids12 as the starting aryl substrates. The sulnates
formed in these reactions can be converted to sulfones, usually
by employing a simple electrophilic trap, but this is typically
achieved in the second step of the overall reaction.12b Separately,
aryl sulnates have been employed as nucleophiles in a number
of palladium-catalyzed coupling reactions with aryl halides.8f,13
We postulated that the integration of these two separate
palladium-catalyzed transformations into a single reaction
would provide a convenient route for the formation of diary-
lsulfones, while maintaining many of the desirable features of
the classic Suzuki–Miyaura cross-coupling reaction. Despite the
encouraging precedents for the separate steps of the proposed
coupling, we were never able to achieve the transformation
using palladium catalysis. A possible complicating factor with
these reactions is the known palladium-catalyzed desulnative
coupling of aryl sulnates and aryl halides.14
We then used the optimized reaction conditions to explore
the scope of the reaction with respect to the variation of the aryl
iodide coupling partner, while maintaining phenyl boronic acid
as the second aryl component (Table 2). Generally, the process
was tolerant of a broad range of both electron-donating and
electron-withdrawing functional groups, located at all positions
on the aromatic ring. The notable examples include product 3g,
which features sulfur atoms with two different oxidation states,
an arrangement that would be challenging to prepare using
standard sulfone methodology, and sulfone products 3i and 3j
which contain free primary amine and phenol groups, respec-
tively. Reactive functional groups such as aldehyde (3n), ketone
(3k) and nitrile (3l) were also incorporated without incident.
Heterocycle-derived iodides could be transformed to sulfones,
with indole (3t), quinoline (3u), pyridine (3v) and pyrazole (3w)
derived products being obtained. The products 3x and 3y
demonstrate that alkenyl iodide substrates can also be
employed. These scoping experiments were routinely per-
formed on a 0.2 mmol scale, however, larger scale reactions
Despite this set back, we were still drawn to the advantages
that a sulfonylative Suzuki–Miyaura coupling would provide, in
particular, the ability to prepare sulfones from the combination
of aryl halides and aryl boronic acids – arguably the two
coupling partners of choice for synthetic chemists – would
provide a conceptually simple, direct route to these valuable
products. We turned our attention to the use of alternative
catalysts, and were aware that copper(I) catalysts have also been
reported to promote the coupling of aryl sulnates with aryl
halides.15,16 Although copper-catalyzed aryl sulnate formation
using sulfur dioxide has also been reported, only the less-
available aryl triethoxysilanes can be used as substrates,17 with
the use of boronic acids as substrates being unknown.18 Despite
this crucial step being unprecedented, we were attracted to the
cost-of-goods and sustainability advantages that are potentially
available with copper-catalyzed transformations,19 relative to
those using palladium, and elected to explore the development
of a copper(I)-catalyzed process. Indeed, these advantages have
also been recognized in the development of Cu(I)-catalyzed
variants of the classic Suzuki–Miyaura cross-coupling reac-
tion,20 as well as a carbonylative version.21
Table 1 Selected optimization data for the formation of sulfone 3a
from the coupling of aryl iodide 1a and boronic acid 2aa
Entry
Variation from eqn (1)
Yield
1
2
3
4
5
6
7
8
9
Cs2CO3 added (2.0 equiv.)
No Cu, no ligand
No ligand
L1 (10%)
L2 (10%)
16%
0%
25%
40%
47%
44%
49%
70%
60%
3%
L3 (10%)
DMF as solvent
130 ꢀ
24 h
C
10
O2 atmosphere
We began our investigation by exploring the coupling of 4-
iodotoluene 1a, phenyl boronic acid 2a, and sulfur dioxide. To
avoid the direct use of gaseous sulfur dioxide, we employed
a surrogate reagent,22 the bis-adduct of sulfur dioxide combined
with DABCO, DABSO, which is a bench stable colorless solid
and is commercially available.23 Pleasingly, aer a variety of
copper(I) salts, ligands, solvents, reaction temperatures and
additives were explored, we were able to identify a set of optimal
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), DABSO (0.3 mmol, 1.5
equiv.), 2a (0.6 mmol, 3.0 equiv.), solvent (1.0 mL). Yields were
measured by HPLC using an internal standard.
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Table 2 Variation of the aryl iodide coupling partner in the copper- Table 3 Variation of the aryl boronic acid coupling partner in the
catalyzed sulfonylative Suzuki–Miyaura reactiona
copper-catalyzed sulfonylative Suzuki–Miyaura reactiona
a
Ar
¼
4-morpholino–C6H4. Reaction conditions: aryl iodide 1
(0.2 mmol, 1.0 equiv.), DABSO (0.3 mmol, 1.5 equiv.), boronic acid 2
(0.6 mmol, 3.0 equiv.), Cu(MeCN)4BF4 (10 mol%), L4 (10 mol%),
DMPU (1.0 mL), 110 ꢀC, 36 h. Isolated yields.
a
Reaction conditions: aryl iodide 1 (0.2 mmol, 1.0 equiv.), DABSO
(0.3 mmol, 1.5 equiv.), phenyl boronic acid 2a (0.6 mmol, 3.0 equiv.),
Cu(MeCN)4BF4 (10 mol%), L4 (10 mol%), DMPU (1.0 mL), 110 ꢀC,
36 h. Isolated yields. b Using 4-bromo-iodobenzene as substrate.
the iodide component, heterocyclic variants (4r,s) and alkenyl
boronic acids were also useful substrates, with the latter deliv-
ering unsaturated sulfone products (4t,u).
One of the key challenges in developing a direct copper-
catalyzed sulfonylative Suzuki–Miyaura reaction was establish-
ing the viability of the copper-catalyzed sulnate formation
from the combination of an aryl boronic acid and sulfur
dioxide. Although the broad scope of the targeted reaction, as
shown in Tables 2 and 3, goes a signicant way towards vali-
dating this hypothesis, we wanted to develop reaction condi-
tions that would allow the copper-catalyzed synthesis of discrete
sulnate intermediates. This would then allow these interme-
diates to be trapped with a variety of electrophiles to deliver
structurally diverse products, and would complement the
recently described palladium-catalyzed variant of this
were also possible. For example, sulfone 3e was synthesised on
a semi-preparative 1 gram scale (5 mmol).
A signicant variation of the boronic acid coupling partner
was also possible (Table 3). Either 4-iodotoluene or 4-
morpholino-iodobenzene was employed as the coupling partner
in these transformations, with the choice being dictated by the
ease of product purication. A broad range of useful function-
alities could be introduced using this chemistry, for example,
ether (4d), sulde (4e), alcohol (4f), amine (4g), carbamate (4h),
amide (4i), aryl chloride (4l,n,o), silane (4m), and aldehyde (4q)
groups were all tolerated under the reaction conditions. As with
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transformation.12 By employing a stoichiometric amount of (6a–e).25 The use of epoxides as the electrophiles provides b-
NaBF4 in combination with Cu(MeCN)4BF4 as a catalyst, we hydroxy sulfones (6f–j).25b Treatment with in situ generated
were able to interrupt the sulfonylative Suzuki coupling and chloroamines provides sulfonamides (6k–o),26 and treatment
realize an efficient method for the preparation of copper sul- with NFSI, which is a source of electrophilic uorine, generates
nates from aryl boronic acids (Table 4). Metal sulnates are not the corresponding sulfonyl uorides (6p–t).27
useful products in their own right, and are in fact challenging to
isolate, however, they can be converted to a selection of useful
sulfonyl-derived functional groups by treatment with appro-
Conclusions
priate electrophiles. For example, in situ treatment of the sul- In realizing a copper-catalyzed sulfonylative Suzuki–Miyaura
nate with an alkyl bromide delivers alkylaryl sulfone products cross-coupling, a work-horse reaction of the pharmaceutical
industry has been transformed to deliver valuable sulfone
products. This process represents the rst true sulfonylative-
variant of a classic cross-coupling process. A good variation of
Table 4 Copper-catalyzed sulfinate formation and onwards conver-
both coupling partners is possible, delivering sulfone products
sion to alkylaryl sulfones, b-hydroxy sulfones, sulfonamides and
sulfonyl fluoridesa
in high yields. The demonstration that the combination of
copper(I) catalysts, aryl boronic acids and a sulfur dioxide
surrogate generates aryl sulnate intermediates is also signi-
cant, and bodes well for the development of new reactions
which exploit these key intermediates, access to which has been
limited when using benign, readily available substrates and
sustainable catalysts.
Acknowledgements
We thank the EPSRC for the support of this study.
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