Direct S-arylation of unactivated arylsulfoxides using [Pd(IPr*)(cin) Cl]

Article abstract of DOI:10.1021/cs400533e

The direct S-arylation of unactivated arylsulfoxides catalyzed by [Pd(IPr*)(cin)Cl] is described. Several arylmethylsulfoxides were coupled to various aryl halides in moderate to good yields (17 examples, 34-85%). Scope, limitations, and reaction mechanis

Full text of DOI:10.1021/cs400533e

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Letter
Direct S-arylation of unactivated arylsulfoxides using [Pd(IPr*)(cin)Cl]
Frederic Izquierdo, Anthony Chartoire, and Steven P. Nolan
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/cs400533e • Publication Date (Web): 20 Aug 2013
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Direct S-arylation of unactivated arylsulfoxides using
[Pd(IPr*)(cin)Cl]
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Frédéric Izquierdo, Anthony Chartoire and Steven P. Nolan*
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, UK. Fax: (+44) 1334 463 808; Tel:
(+44) 1334 463 763; E-mail: snolan@st-andrews.ac.uk.
Palladium, NꢀHeterocyclic Carbenes (NHCs), arylation, sulfoxide, crossꢀcoupling.
The direct S-arylation of unactivated arylsulfoxides catalysed by [Pd(IPr*)(cin)Cl] is described. Several arylmethylsulfoxides were
coupled to various aryl halides in moderate to good yields (17 examples, 34-85%). Scope, limitations and reaction mechanism are
discussed.
Pd2(dba)3 (5 mol%)
Xantphos (10 mol%)
Palladium-catalysed cross-coupling reactions are a popular
means of assembling C–C bonds and are nowadays a subject
of utmost importance in organic and organometallic chemis-
try.1 Because of the general utility of palladium-catalysed bond
forming protocols, the discovery of new reactivity involving
these well-developed ( and in numerous instances, well-
defined) systems is important. Such findings are oftentimes
achieved by introducing new ligands into metal-catalysed
reactions. Ongoing research in palladium chemistry focuses
significantly on the development of bulky yet flexible as well
as strong σ-donating ligands.2 N-heterocyclic carbenes (NHCs)
have been shown as very efficient examples of such ligands,
enabling original cross-coupling reactions.3 We have devel-
oped a range of multi-purpose well-defined palladium-NHC
pre-catalysts useful in numerous cross-coupling reactions.3-4
Sulfoxides are important moieties as intermediates in or-
ganic synthesis, and as ligands in catalysis.5 Moreover, they
are interesting as they are structural features of various biolog-
ically active compounds.6 Due to their wide range of utility,
their functionalisation using well-defined Pd-NHC complexes
was investigated. In this contribution, the unprecedented S-
arylation of unactivated arylsulfoxides is described using the
[Pd(IPr*)(cin)Cl] pre-catalyst.
O
S
t
Ar1
CO2 Bu
ArI, Ref 7a
Pd2(dba)3 (2 mol%)
Xantphos (5 mol%)
O
S
O
S
Ar1
Ar1
Ar
ArI, Ref 7c
O
S
[Pd(IPr*)(cin)Cl] (5 mol%)
ArBr, ArCl, This work
Ar1
Ph
Ph
Ph
Ph
N
N
Ph
Ph
Ph
Ph
Pd
O
Cl
PPh2
PPh2
Ph
[Pd(IPr*)(cin)Cl]
Xantphos
is the need for activated sulfoxides that are not commercially
available and must be prepared using a number of synthetic
steps (generally two or three).8a More recently, Walsh and co-
workers have reported on the α-arylation of sulfoxides.8c Alt-
hough α-arylation of ketones is a well-known reaction,9 the
sulfoxide equivalent proved to be more challenging. The reac-
tion makes use of 5-10 mol% of palladium, 20 mol% of the N-
(dicyclohexylphosphino)-2-(2'-tolyl)indole ligand and is per-
formed in CPME at 110 °C, in the presence of an excess of
LiOtBu as the base. Of note, the sequence uses a specific
phosphine to promote the reaction, illustrating once more that
the nature of the ligand is vital in cross-coupling catalysis.
Well-defined Pd-NHC complexes and especially the
[Pd(NHC)(cin)Cl] family have already proven to be very
efficient pre-catalysts in numerous cross-coupling reactions.2b,
The reactivity of palladium complexes towards sulfoxides
has been scarcely investigated in the literature.7-8 Poli and
Madec have notably reported the palladium catalyzed synthe-
sis of bis-arylated sulfoxides via inꢀsitu generated sulfenate
anions.7 The latter are formed from β-sulfinyl ester-7a or al-
lylsulfoxides7c using Pd2(dba)3 as the palladium source and
Xantphos as the ligand (Scheme 1). The system thus provides
an interesting range of substituted biarylsulfoxides after cross-
coupling with aryl halides. Nevertheless, despite its efficiency,
the methodology is restricted to the use of aryl iodides. The
use of aryl bromides leads to a decrease in the reactivity and
aryl chlorides are unreactive. Another drawback of this meth-
od
c, 4b, 10
As a consequence, their reactivity towards arylsulfox-
ides was examined.
The reaction between methylphenylsulfoxide and p-
bromotoluene was first examined employing the Walsh condi-
tions8c and a range of [Pd(NHC)(cin)Cl] pre-catalysts. KOtBu
was initially chosen rather than LiOtBu because of the benefi-
Scheme 1. S-arylation of activated and unactivated aryl-
sulfoxides via the generation of sulfenate anions.
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Yield (%)b
cial role of this base with the Pd-NHC systems in various
Entry
X
Product
other couplings.4b The reactivity of different palladium pre-
catalysts was evaluated (see supporting information). Amongst
them, only [Pd(IPr*)(cin)Cl)] allowed conversion of the start-
ing materials. The product was isolated in 63% yield, and was
found to result from the direct and selective S-arylation of the
sulfoxide (Scheme 2).
1
2
3
4
5
6
7
1
2
3
Br
Cl
I
82
71
ndc
4
5
Br
Cl
85
71
Scheme 2. Initial lead for S-arylation of methylphen-
ylsulfoxide.
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9
6
7
Br
Cl
73
55
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8
Br
67
9
10
Br
Cl
77
66
Interestingly, no α-arylated product was detected in the re-
action mixture. With this promising result in hand, optimiza-
tion was carried out (see supporting information). The reaction
reached complete conversion using p-bromotoluene (2 eq),
KOtAm (3 eq) as the base, [Pd(IPr*)(cin)Cl] (5 mol%) in
dioxane (1M) at 110°C for 20 h, and the desired compound
was isolated in an excellent yield (82%, Table 1, entry 1). In
contrast to the other Pd-NHC precatalysts, only
[Pd(IPr*)(cin)Cl)] was able to promote the reaction. This
result was attributed to the flexible steric bulk of the IPr*
ligand.2c, 11 Compared to the work of Poli,7 the use of activated
sulfoxides is not required, and the reaction occurred directly
using commercially available substrates. This new sequence
appears to provide a straightforward access to sulfenate ani-
ons.
With the optimized reaction conditions in hand, the scope
and limitations of the transformation were next studied (Table
1). At first, various arylmethylsulfoxides were coupled to p-
bromotoluene. The use of sulfoxides bearing methyl- or meth-
oxy- groups in paraꢀ or metaꢀ position afforded the expected
biarylsulfoxides in good yields (67-85%, entries 4, 6, 8). Me-
thyl(naphtalen-2-yl)sulfoxide was also successfully used,
yielding the desired product in a 77% yield (entry 9). As aryl
chlorides are known to be more challenging substrates in
cross-coupling reactions, their reactivity was next explored.
Interestingly, using p-chlorotoluene instead of p-bromotoluene
did not significantly affect the reaction. A slight decrease of
the yield of about 10% was observed, but the desired com-
pounds were still obtained in good yields (55-71%, entries 2,
5, 7, 10). On the other hand, p-iodotoluene exhibited much
lower catalytic activity. In this case, the reaction did not reach
completion and the formation of a complex mixture of prod-
ucts was observed by GC (entry 3). The reactivity of the deac-
tivated p-bromo and p-chloroanisoles was next studied (entries
11-14). The catalytic system proved to be less efficient in
these cases, the reactions not reaching completion and the
formation of several unidentified by-products was observed by
GC. However the expected compounds were still isolated in
Table 1. Scope of the S-arylation reaction.a
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12
Br
Cl
47
39
13
Br
39
14
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17
18
19
Br
Br
Br
Br
Br
Br
50
62
34
42
50
ndc
20
21
22
Br
Cl
I
0d
0d
0d
a
Reagents and conditions: arylsulfoxide (0.5 mmol), aryl hal-
ide (1.0 mmol), KOtAm (1.5 mmol), [Pd(IPr*)(cin)Cl] (5 mol%),
dioxane (0.5 mL, 1 M), 110°C, 20 h. b Isolated yield after chroma-
c
tography on silica gel. nd = not determined. An inseparable
mixture of coupling product, starting materials and unidentified
compounds was observed by GC.
methylphenylsulfoxide was observed.
d
No conversion of the
modest to moderate yields (39-50%). The effect of the sterics
of the bromide was next investigated and the coupling was
found to be highly sensitive to subtle modifications. Moving
the methyl group of the bromide partner from the paraꢀ to the
metaꢀ position resulted in a drop of the yield (entries 17 and 18
vs 1 and 9, 42% and 50% vs
Scheme 3. Proposed catalytic cycle for the direct S-arylation reaction.
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ficed to generate the sulfenate anion while the second one is
82% and 77%, respectively). On the other hand ortho-
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used to arylate the sulfoxide.
substituted bromides were not found to be suitable coupling
partners. Indeed, the reaction led to the formation of an insepa-
rable mixture of products (entry 19). It is noteworthy that Poli
and co-workers observed a similar decrease in reactivity using
allylsulfoxides.7c Finally, when activated halides were used, no
conversion of the methylphenylsulfoxide was observed (en-
tries 20-22).12 The new catalytic system was found to be com-
plementary to the ones reported in the literature.7 Indeed, using
the Poli protocol, the coupling was mainly limited to the use of
aryl iodides. Using our protocol, we were capable of promot-
ing the coupling using aryl bromides and chlorides. In terms of
efficiency (range of isolated yields), our system proved to be
globally as good (33-96% using the β-sulfinyl ester
sulfoxides7a) or more efficient (15-60% using the allyl sulfox-
ides7c). Moreover, the starting sulfoxides used here were either
commercially available or prepared in only one step.
Our attention finally focused on the mechanism of this
transformation, in order to understand how the methylsulfox-
ide bond was deconstructed. The proposed mechanism
(Scheme 3) is comprised of two different manifolds: cycles A
and B. During the course of our optimization experiments, we
isolated and characterized 1 as a by-product of the reaction. At
first (cycle A and cycle B), the palladium (0) active species
was formed inꢀsitu by activation of the pre-catalyst in the
presence of the base (KOR = KOtAm or KOtBu). Then, the
oxidative addition takes place leading to the formation of
complex 2. In the meantime, as postulated by Walsh and co-
workers,8c a reversible deprotonation of the weakly acidic α-
protons of the arylmethylsulfoxide by KOR affords the α-
sulfinyl anion 3. After ligand exchange (cycle A), complex 4
is subsequently formed. 4 may be in equilibrium with the
cleaved ionized carbenic form 4'. At this stage, no reductive
elimination was observed, the formation of the α-arylated
product never being detected in the reaction medium. The key
step of the catalytic cycle next highlights a nucleophilic attack
of the base on the carbon linking the sulfoxide moiety to the
palladium centre in complex 4 or 4'. For steric reasons, this
might be favored with complex 4'. This has the effect of re-
leasing complex 5 and sulfenate anion 6, which is necessary
for the reaction to proceed. After reductive elimination, com-
plex 5 yields byproduct 1 and regenerates the palladium (0)
active species. In cycle B, the sulfenate anion 6 reacts with
complex 2 to form 7. Finally, the desired biarylsulfoxide 8 is
formed after reductive elimination and the palladium (0) active
species is regenerated. As presented here, cycle A is necessary
for cycle B to take place. This explains why two equivalents of
halide are required for the success of the reaction. One is sacri-
In summary, we have developed a direct S-arylation of un-
activated arylsulfoxides using bromides and chlorides.
[Pd(IPr*)(cin)Cl] was shown to be the pre-catalyst of choice to
promote the reaction, the use of other [Pd(NHC)(cin)Cl] con-
geners being inefficient in this transformation. The reaction
proved to be sensitive to small modifications in the nature of
the halide. Especially, deactivated and sterically hindered
halides were not efficiently converted. However, several dif-
ferently substituted biarylsulfoxides were efficiently prepared
(17 examples, 34-85%). Interestingly, the reaction is comple-
mentary with other procedures described in the literature, and
chlorides were efficiently used for the first time in such a
coupling reaction.
ASSOCIATED CONTENT
Electronic Supplementary Information (ESI) available: Optimisa-
tion tables, spectroscopic data and copy of spectra for all com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* EaStCHEM School of Chemistry, University of St Andrews, St
Andrews, KY16 9ST, UK. Fax: (+44) 1334 463 808; Tel: (+44)
1334 463 763; E-mail: snolan@st-andrews.ac.uk.
ACKNOWLEDGMENT
We gratefully acknowledge the EC for funding through the sev-
enth framework programme SYNFLOW. Umicore is thanked for
its generous gifts of materials. SPN is a Royal Society Wolfson
Research Merit Award holder.
ABBREVIATIONS
NHCs,
N-Heterocyclic
Carbenes;
IPr*,
1,3-bis(2,6-
cin,
bis(diphenylmethyl)-4-methylphenyl)imidazo-2-ylidene;
cinnamyl = phenylallyl.
REFERENCES
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(12) Reactions between methylphenylsulfoxide and other activated
halides such as 1-bromo-4-nitrobenzene, 1-bromo-4-
(trifluoromethyl)benzene and 1-chloro-4-fluorobenzene were
attempted but failed to give the desired products.
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Graphical TOC
O
S
X
O
[Pd(IPr*)(cin)Cl]
S
R1
R1
R2
R2
KOtAm, dioxane
110 °C
+
17 examples
(34-85%)
Ph
Ph
Ph
Ph
N
N
Direct S-arylation:
Ph
Ph
Pd
Ph
Ph
Unactivated arylsulfoxides
Aryl chlorides and bromides
Cl
Ph
[Pd(IPr*)(cin)Cl]
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