Palladium-catalyzed three-component diaryl sulfone synthesis exploiting the sulfur dioxide surrogate DABSO

Article abstract of DOI:10.1002/anie.201305369

SO(2) efficient: A three-component palladium-catalyzed coupling of aryl lithium compounds; sulfur dioxide (provided by the easy-to-handle solid surrogate, DABSO); and aryl, heteroaryl, and alkenyl (pseudo)halides yields a diverse library of sulfones. An electron-poor XantPhos-type ligand suppresses aryl-aryl exchange and is key to obtaining high yields.

Full text of DOI:10.1002/anie.201305369

Angewandte
Chemie
DOI: 10.1002/anie.201305369
Modular Synthesis
Palladium-Catalyzed Three-Component Diaryl Sulfone Synthesis
Exploiting the Sulfur Dioxide Surrogate DABSO**
Edward J. Emmett, Barry R. Hayter, and Michael C. Willis*
Aryl, heteroaryl, and alkenyl sulfones play a prominent role
in organic and medicinal chemistry. Not only are they
versatile intermediates in organic synthesis[1], but they are
also of particular pharmaceutical relevance, and exhibit an
extensive and broad range of biological activities
(Scheme 1).[2] In addition, sulfone-containing polymers dis-
which sodium sulfinates couple with aryl, heteroaryl, or
alkenyl halides,[8] or boronic acids.[9] However, the require-
ment for stoichiometric phase-transfer additives, high temper-
atures, and the use of undesirable solvents or ionic liquids, are
significant drawbacks. An analogous palladium-catalyzed
approach has also been developed using (pseudo)halides as
coupling partners, although it too features the use of
stoichiometric additives and high temperatures, and conse-
quently suffers from limited scope.[10,11] In addition to these
problems, the variety of sulfones prepared by these metal-
catalyzed methods is poor; only a small number of sodium
sulfinates (typically methyl, phenyl, and p-tolyl) have been
used to demonstrate the scope. This reflects the very limited
commercial availability of sodium sulfinates, perhaps as
a result of impractical or limited synthetic routes. Organo-
metallic addition to sulfur dioxide gas[12] (followed by cation
exchange) and reduction of the sulfonyl chloride[12,13] are two
such examples, but both have shortcomings such as the harsh
conditions associated with sulfonyl chloride formation or the
use of toxic gaseous sulfur dioxide. Taken together, these
limitations present a clear mandate for the development of
a more general, modular synthesis of sulfones, with the
versatility to allow ready variation of both groups attached to
the SO2 linker.[14]
Scheme 1. Pharmaceuticals featuring an aryl sulfone unit.
play novel properties as materials.[3] Although there are
a variety of methods known for the preparation of sulfones,
the majority of these processes feature associated limitations.
For example, oxidation of the corresponding sulfide relies on
functional-group compatibility with oxidizing agents and the
availability of catalysts to promote selectivity for sulfone
formation over sulfoxide formation; in addition, the prepa-
ration of the required sulfide substrate often involves the use
of foul-smelling thiols.[4,5] Friedel–Crafts-type sulfonylation of
arenes is limited not only by the generally harsh reaction
conditions, but also by the inherent regioselective bias
imposed by the electronic and steric properties of the arene
substrate.[5,6]
We have recently developed DABSO (1), which is a solid,
bench-stable complex formed between 1,4-diazabicyclo-
[2.2.2]octane (DABCO) and two sulfur dioxide molecules,[15]
as an easy-to-handle surrogate for sulfur dioxide gas
(Scheme 2). We have demonstrated its use in known reactions
In response to these limitations, the use of transition-
metal-catalyzed cross-coupling has been exploited as a route
to sulfones.[7] The most utilized has been copper catalysis, in
[*] E. J. Emmett, Prof. M. C. Willis
Scheme 2. A convergent three-component sulfone synthesis exploiting
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
DABSO, an easy-to-handle solid replacement for sulfur dioxide gas.
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
of sulfur dioxide,[16] as well as in a novel palladium-catalyzed
aminosulfonylation of aryl, heteroaryl, and alkenyl halides to
yield medicinally important sulfonamides.[17] Herein, we
Dr. B. R. Hayter
Oncology Innovative Medicines, AstraZeneca
Alderley Park, Macclesfield, Cheshire, SK10 4TG (UK)
report on
a three-component convergent synthesis of
a broad range of aryl, heteroaryl, and alkenyl sulfones,
employing palladium catalysis and DABSO (Scheme 2).
Given our previous demonstration of the efficient addi-
tion of Grignard reagents to DABSO to form magnesium
halide sulfinate salts,[16] we envisioned that these would
[**] This work was supported by the EPSRC and AstraZeneca. DABSO is
a solid, bench-stable complex formed between DABCO and two
sulfur dioxide molecules.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305369.
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couple with (pseudo)halides to form sulfones in a similar
fashion to the reported sodium salt examples using transition
metal catalysis. Unfortunately, after testing a variety of
catalytic conditions, we were not able to achieve this.
Suspecting that this was due to the difference in the nature
of the counter ions, we elected to study the addition of
organolithiums to form the more closely related lithium
sulfinates. We chose to explore palladium rather than copper
catalysis because the reported conditions for sodium salts
were the most amenable to our organolithium proposal.[10,11]
We were mindful, however, of the precedent for certain metal
sulfinates to undergo palladium-catalyzed desulfonylative
cross-couplings, whereby extrusion of SO2 from the palla-
dium-bound sulfinate ultimately leads to a biaryl product.[18]
We began our investigations with the addition of PhLi
solution to a suspension of DABSO in THF at À408C.
Pleasingly, HPLC analysis revealed that quantitative con-
version to the lithium sulfinate 2 was achieved; only traces of
benzene from deleterious protonation were detected. This
crude sulfinate suspension was then combined with [Pd2-
(dba)3] (dba = dibenzylideneacetone), XantPhos, Cs2CO3,
nBu4NCl, and p-tolyl iodide; the conditions reported for
reactivity;[10] many other ligands, including those with similar
structures, such as DPEPhos, as well as alkyl phosphines
(which cannot undergo this exchange process), demonstrated
little or no activity.[22] With the XantPhos architecture
established as optimal, we next explored electronic and
steric variations of this unique backbone.[23] These ligands
were evaluated under the cross-coupling conditions previ-
ously established (Table 1). Alkyl (entries 3–5) and sterically
Table 1: Evaluation of XantPhos-type ligands to improve selectivity
through the suppression of aryl–aryl exchange.[a]
Entry Ligand
Pd source
I/Br Conversion [%][d] 3a:4a–f[d]
1
XantPhos Pd(OAc)2
XantPhos [Pd2(dba)3]
I
I
I
I
I
I
I
I
100
100
–
–
–
40
trace
95
–
50
3:1
2:1
–
–
–
1:1
–
3:1
–
5:1
7:2
4:1
15:1
2[b]
3
5a
5b
5b
5c
5d
5e
5 f
5 f
Pd(OAc)2
Pd(OAc)2
[Pd2(dba)3]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd2(dba)3]
4
5[b]
6
1
sodium sulfinate coupling.[10] Analysis of the crude H NMR
7
8
9
spectrum indicated the presence of the desired sulfone 3a,
albeit at a low conversion (see the Supporting Information).
However, by switching to Pd(OAc)2, conversion increased to
65% and it was also found that the nBu4NCl additive was
effectively redundant. Postulating that the incomplete con-
version was a result of the lower temperature used relative to
that for the sodium salt, the solvent was switched from THF to
1,4-dioxane, and the reaction heated at 858C. Gratifyingly,
a quantitative conversion was achieved (Scheme 3).
I
I
Br
10[b]
11[c]
XantPhos Pd(OAc)2
100
100
100
12[b,c] 5 f
[Pd2(dba)3] Br
13[c]
5 f
Pd(OAc)2
Br
[a] Reaction conditions: PhLi (1.4 equiv), DABSO (0.75 equiv), 1,4-
dioxane (0.18m) then p-tolyl halide (1 equiv, 0.35 mmol), palladium
source (10 mol% Pd), ligand (10 mol%), Cs2CO3 (1.5 equiv). [b] With
nBu4NCl additive (1.5 equiv). [c] Performed at 1108C. [d] Determined by
1H NMR spectrum integration to the nearest 5%.
hindering aryl substituents (entries 3 and 7) on the XantPhos
backbone led only to recovered starting material. As
expected, a more electron-rich phosphine gave more aryl–
phenyl transfer product (entry 6).[21] Electron-poor phos-
phines, which have been reported to suppress transfer for
the arylation of ureas,[20] gave similar or a small increase in
selectivity as hoped, but for the more selective reaction, the
conversion was poor (entries 8-10). However, by switching to
the aryl bromide substrate in place of the iodide substrate,
and increasing the temperature of the reaction, full conver-
sion was achieved with high selectivity when using the 3,5-
bis(CF3)-substituted XantPhos 5 f (entry 13). Using these
optimized conditions, the scope of the aryl bromide coupling
partner was next investigated (Scheme 4).
m-Tolyllithium 6a was chosen to demonstrate the syn-
thesis of sulfones that have not been prepared through
sodium sulfinate coupling. A stock solution was readily
synthesized by using lithium–halogen exchange between
butyllithium and 3-bromotoluene in dibutylether, which is
a Lewis-basic solvent in which lithium–halogen exchange is
Scheme 3. Initial investigation of the generation and Pd-catalyzed
coupling of lithium sulfinate 2.
Unfortunately, upon purification, two different sulfone
products were isolated. Desired sulfone 3a was present in
70% yield together with 23% of diphenylsulfone. From the
observation that a phenyl group was always incorporated in
place of the aryl halide fragment upon varying the organo-
lithium component, we deduced that this side product was
a result of aryl–phenyl exchange with the XantPhos ligand.
Such exchange processes are known in arylation of electron-
poor nucleophiles and in Suzuki couplings.[19–22] Conditions
for the palladium coupling step were fully explored, with the
choice of base, additive, solvent, palladium source, and
temperature being investigated. However, no improvement
in selectivity whilst maintaining good conversion of starting
material was observed.[22] Finally, variation of the phosphine
ligand was undertaken. We found that, in agreement with the
work of Cacchi et al., the XantPhos backbone was key to
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Scheme 5. Scope of the aryl lithium component in the Pd-catalyzed
preparation of sulfones through the coupling of lithium sulfinates with
aryl halides. Coupling conditions as described in Table 1, entry 13.
[a] Organolithium used as commercial solution. [b] From the corre-
sponding alkenyl tosylate. [c] Biaryl formation observed.
palladium-catalyzed coupling worked well for a broad range
of aryl sulfinates, including those with electron-donating,
neutral, and electron-withdrawing functionality; trifluoro-
methyl, chloro, and silane functional groups were all success-
fully tolerated. Unfortunately, heterocyclic lithium 2-thienyl-
sulfinate led to biaryl formation from desulfonylative cou-
pling through SO2 extrusion,[18] while ortho-substituted lith-
ium 2-anisyl sulfinate resulted in the recovery of aryl bromide
starting material.
Scheme 4. Scope of the aryl halide component in the Pd-catalyzed
preparation of sulfones through coupling with lithium sulfinates.
Coupling conditions as described in Table 1, entry 13. [a] When using
the alkenyl tosylate, K3PO4 (1.5 equiv) employed in the place of
Cs2CO3.
A limitation of our presented methodology was the
inability to include functionality positioned ortho to the
sulfone moiety. To address this issue, we exploited the
capacity of the sulfone functional group to direct ortho
metalation.[25] We demonstrated this through two regioselec-
tive ortho functionalizations of sulfone 8d by using the co-
operative effect of meta-disposed directing groups to give
1,2,3-trisubsituted aryl sulfones 9 and 10 in good yields (not
optimized, Scheme 6).
As a proof of the versatility and applicability of the
presented methodology, we sought to demonstrate the syn-
thesis of a significant target molecule. GSK-742457 (11) is
a quinoline-based drug molecule that is currently under
development for treating Alzheimerꢀs disease.[26] We envis-
aged disconnection to the known bis-halogenated quinoline
derivative 12.[27] In the forward direction, palladium-catalyzed
sulfonylation of 12 would generate chloro derivative 13, and
a subsequent palladium-catalyzed Buchwald–Hartwig amina-
tion would produce the target medicinal agent (Scheme 7).
The proposed sequence was successfully achieved, with the
sulfonylation being realized in 70% yield, and the amination
in 68% yield (both not optimized). This is an attractive route
to the target system via the bis-halogenated quinoline 12,
kinetically facile and yet aryl lithiums are more stable to
storage than in Et2O or THF.[24] A wide range of aryl and
heteroaryl bromides coupled in good to excellent yields
(Scheme 4). Electron-rich substrates performed well, with C-,
O-, S- ,and N-based functionality all tolerated. Electron-poor
aryl bromides also proved to be compatible, with ester, amide,
aldehyde, chloro, and trifluoromethyl functional groups
retained. The use of unprotected anilines, aryl fluoride, and
napthyl derivatives demonstrated further scope. We estab-
lished additional versatility by using heteroaromatic pyridyl,
thiophenyl, and benzofuryl bromides, as well as using iodide
or triflate substrates in place of bromide. Unfortunately,
ketones and arenes bearing ortho substituents led to no
reaction. Provided that K3PO4 was used in place of Cs2CO3,
alkenyl tosylates could be successfully employed as the
electrophilic coupling partner and allowed access to the
corresponding aryl–alkenyl sulfone products.[11]
Next, we investigated the scope of the organolithium
species (Scheme 5). Using 3-bromoanisole as the standard
coupling partner, a range of aryl lithiums were successfully
subjected to the optimized conditions. Pleasingly, all the
organolithiums prepared added, as expected, to DABSO to
form the corresponding lithium sulfinate, and the subsequent
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Scheme 7. Synthesis of GSK-742457 using the combination of a Pd-
catalyzed aryl halide–lithium sulfinate coupling, and a Pd-catalyzed aryl
halide amination. Conditions: a) Sulfonylation with aryl lithium (see
Table 1, entry 13). b) Pd(OAc)2, RuPhos, NaOtBu, piperazine, 1,4-
dioxane, 908C, 16 h. RuPhos=2-Dicyclohexylphosphino-2’,6’-diisopro-
poxybiphenyl.
which provides a suitable branch point for the rapid
preparation of analogues.
In summary, we have demonstrated the synthesis of
a broad range of aryl, heteroaryl, and alkenyl sulfones
through a convergent three-component palladium-catalyzed
coupling approach. This method allows the straightforward
production of varied sulfones through the union of two
readily available coupling partners; an aryl lithium species[28]
and aryl, heteroaryl, or alkenyl (pseudo)halides; with SO2
provided by the easy-to-handle bench-stable solid surrogate
DABSO. The use of an electron-poor XantPhos-type ligand
offers much improved yields over XantPhos itself. In addition,
ortho functionality can be introduced by exploiting the ability
of the sulfone group to direct ortho metalation. A demon-
stration of the utility of the methodology was achieved
through the synthesis of a medicinal agent that is currently in
development, utilizing a versatile bis-halogenated quinoline
as the starting material. Finally, evidence for the nontrivial
nature of the preparation of aryl–aryl (and related) sulfones is
found in the observation that of the 36 sulfone products
reported herein, more than 90% are novel compounds.
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groups represents a significant constraint.
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Received: June 21, 2013
Published online: && &&, &&&&
Keywords: aryl lithium reagents · palladium · sulfones ·
.
sulfur dioxide · synthetic methods
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[23] These were all prepared through double ortho lithiation of 9,9-
dimethylxanthene, followed by trapping with the appropriate
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Communications
Modular Synthesis
E. J. Emmett, B. R. Hayter,
M. C. Willis*
&&&& — &&&&
Palladium-Catalyzed Three-Component
Diaryl Sulfone Synthesis Exploiting the
Sulfur Dioxide Surrogate DABSO
SO(2) efficient: A three-component pal-
ladium-catalyzed coupling of aryl lithium
compounds; sulfur dioxide (provided by
the easy-to-handle solid surrogate,
(pseudo)halides yields a diverse library of
sulfones. An electron-poor XantPhos-type
ligand suppresses aryl–aryl exchange and
is key to obtaining high yields.
DABSO); and aryl, heteroaryl, and alkenyl
6
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