Palladium catalyzed diaryl sulfoxide generation from aryl benzyl sulfoxides and aryl chlorides

Article abstract of DOI:10.1021/acs.orglett.5b00092

Diaryl sulfoxides are synthesized from aryl benzyl sulfoxides and aryl chlorides via three sequential catalytic cycles all promoted by a NiXantPhos-based palladium catalyst. The key step is S-arylation of a sulfenate anion. An air- and moisture-stable precatalyst derived from NiXantPhos efficiently facilitates the transformation. Various functional groups, including those with acidic protons, were tolerated. This method can also be extended to methyl and dibenzyl sulfoxides substrates.

Full text of DOI:10.1021/acs.orglett.5b00092

Letter
pubs.acs.org/OrgLett
Palladium Catalyzed Diaryl Sulfoxide Generation from Aryl Benzyl
Sulfoxides and Aryl Chlorides
Tiezheng Jia,† Mengnan Zhang,† Irina K. Sagamanova,†,‡ Carol Y. Wang,† and Patrick J. Walsh*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡
̈
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16, 43007 Tarragona, Spain
S
* Supporting Information
ABSTRACT: Diaryl sulfoxides are synthesized from aryl
benzyl sulfoxides and aryl chlorides via three sequential
catalytic cycles all promoted by a NiXantPhos-based palladium
catalyst. The key step is S-arylation of a sulfenate anion. An air-
and moisture-stable precatalyst derived from NiXantPhos
efficiently facilitates the transformation. Various functional
groups, including those with acidic protons, were tolerated.
This method can also be extended to methyl and dibenzyl
sulfoxides substrates.
Scheme 1. Aryl sulfoxides synthesis via palladium catalyzed
C−S bond formation
ryl sulfoxides are important structural motifs in bioactive
1
2
Acompounds and marketed therapeutics. They are also
widely used as ligands in transition-metal catalysis.3 Significant
effort, therefore, has been devoted to their preparation. The
most popular methods for the synthesis of sulfoxides are
oxidation of sulfides and nucleophilic substitution of
sulfinamides or sulfinate esters.4
Transition-metal catalyzed cross-coupling reactions are
powerful methods to form C−S bonds5 and offer an alternative
approach to construct aryl sulfoxides. In 2007, Poli and Madec
reported the first diaryl sulfoxide generation via palladium-
catalyzed S-arylation between sulfenate anions6 and aryl
bromides and iodides.7 Sulfenate anions were generated in
situ via retro-Michael reaction (Scheme 1A). The same team
subsequently employed the Mislow−Braverman−Evans rear-
rangement of allylic sulfoxides and generated sulfenate anions
that were arylated in situ to provide diaryl sulfoxides (Scheme
1B).8 Aryl chloride substrates were noticeably absent from
these reports.
Very recently, the Nolan group reported an N-heterocyclic
carbene-based palladium catalyst for the conversion of methyl
sulfoxides to diaryl sulfoxides via a proposed Pd-carbene
intermediate (Scheme 1C).9 Although the reaction worked
with aryl bromides and chlorides, the only functionalized aryl
chloride employed was 4-chloro anisole.
sulfoxides were prepared from aryl bromides in good to
excellent yields. Given the scarcity of aryl chlorides that have
been successfully employed in the sulfenate anion arylation, and
the reduced costs and greater abundance of aryl chlorides
relative to aryl bromides, we viewed the inclusion of aryl
chlorides in this reaction as important. Herein, we report a
palladium-catalyzed diaryl sulfoxide formation from aryl benzyl
sulfoxides and aryl chlorides (Scheme 1E).
Simultaneously, we communicated10 diaryl sulfoxide for-
mation from aryl benzyl sulfoxides and aryl bromides using a
palladium catalyst based on van Lewueen’s NiXantPhos
ligand11 (Scheme 1D). A systematic study revealed that this
single palladium catalyst promoted three distinct trans-
formations to generate diaryl sulfoxides (Figure 1), including
α-arylation of benzyl sulfoxides (Cycle A), sulfenate anion
generation (Cycle B), and S-arylation of sulfenate anions
(Cycle C). Various diaryl sulfoxides and heteroaryl aryl
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00092
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Palladium catalyzed diaryl sulfoxides formation from aryl benzyl sulfoxides and aryl bromides via a triple relay mechanism.
We employed coupling partners benzyl phenyl sulfoxide (1a)
and 4-tert-butyl chlorobenzene (2a) as the model substrates to
identify reaction conditions. The optimized conditions for
coupling sulfoxide 1a with aryl bromides, which involved 5 mol
% Pd(dba)2/7.5 mol % NiXantPhos ligand (Figure 2) and 3
Table 1. Optimization of the Palladium-Catalyzed Diaryl
a
Sulfoxide Formation
b
entry
Pd/mol %
base
sol
assay yield (%)
c
1
Pd(dba)2/5
P1/2.5
P2/5
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiOtBu
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
DME
<5
15
34
29
43
27
11
0
c
2
3
c
4
P2/5
5
P2/5
6
P2/5
KOtBu
Figure 2. Structures of NiXantPhos and palladacyclic precursors P1
and P2.
7
P2/5
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiOtBu
8
P2/5
9
P2/5
0
10
11
12
P2/5
51
37
28
61
equiv of NaOtBu in CPME at 80 °C, were initially examined
(Table 1, entry 1).10 The desired diaryl sulfoxide product (3a)
was formed in less than 5% assay yield. We were concerned that
catalyst generation was an issue, so we used Buchwald’s
palladacyclic precatalysts,12 which proved to be effective in the
oxidative addition of aryl chlorides with NiXantPhos.13 Two
precatalysts (P1 and P2, Figure 2) were prepared according to
reported procedures12f,13 and used under the conditions of the
coupling reaction. When P1 was used with NiXantPhos, the
yield of 3a improved to 15%. The yield of 3a increased to 34%
when the precatalyst bearing NiXantPhos (P2) was utilized.
These low yields inspired us to screen bases that had been
successfully applied to other deprotonative cross-coupling
processes (DCCP). Thus, LiOtBu, KOtBu, LiN(SiMe3)2,
NaN(SiMe3)2, and KN(SiMe3)2 were investigated. In this
screen, LiOtBu gave the most promising result (43%, Table 1,
entry 5 vs entries 3 and 6−9). Three additional ethereal
solvents [DME (dimethoxyethane), dioxane, and THF) were
surveyed with DME giving a better yield (51%, Table 1, entry
10 vs entries 5, 11 and 12). Increasing the temperature of the
reaction from 80 to 110 °C led to a 61% yield of 3a (Table 1,
entry 13). Finally, doubling the reaction time to 24 h resulted in
3a in 74% assay yield (1H NMR) and 70% isolated yield (Table
1, entry 14). Further optimization did not lead to increased
yields. Thus, the optimized conditions were 5 mol %
palladacyclic P2, sulfoxide 1a as the limiting reagent, 2 equiv
P2/5
LiOtBu
dioxane
THF
P2/5
LiOtBu
d
13
P2/5
LiOtBu
DME
e
f
14
P2/5
LiOtBu
DME
74 (70 )
a
1 equiv of 1a, 2 equiv of 2a, and 3 equiv of base at 80 °C on 0.1
b
mmol scale for 12 h. Assay yield determined by 1H NMR by using 0.1
c
mmol of CH2Br2 as an internal standard. 7.5 mol % NiXantPhos used.
d
e
f
110 °C. 24 h. Isolated yield.
of aryl chloride, and 3 equiv of LiOtBu in DME at 110 °C for
24 h.
With the optimized conditions for the palladium-catalyzed
cross-coupling reaction of 1a and 2a, the substrate scope of aryl
chlorides was investigated (Scheme 2). The parent diphenyl
sulfoxide (3b) was generated from chlorobenzene (2b) in 72%
yield. Aryl chlorides bearing electron-withdrawing groups, such
as 4-F (2c) and 4-CN (2d), afforded the products in 85% and
63% yields, respectively. Both 1-chloronaphthalene (2e) and 3-
chloroanisole (2f) were suitable cross-coupling partners,
furnishing 3e and 3f in 70% and 87% yield, respectively. 4-
Chlorobenzophenone was successfully coupled, delivering 3g in
72% yield. Surprisingly, under the optimized conditions,
acetamide 2h and piperidine 2i afforded products 3h and 3i
both in 73% yield. Thus, the NiXantPhos ligated catalyst
successfully promoted both C−C and C−S bond formations
B
DOI: 10.1021/acs.orglett.5b00092
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Scheme 2. Substrate Scope of Aryl Chlorides in Palladium-
Catalyzed Diaryl Sulfoxides Synthesis with 1a
Scheme 3. Substrate Scope of Aryl Benzyl Sulfoxides in
Palladium-Catalyzed Diaryl Sulfoxides Formation with 2b
a
b
3 equiv PhCl used. 10 mol % P2 used.
To demonstrate the potential utility of our method, we
conducted a gram scale reaction with a heterocyclic aryl
chloride (Scheme 4). Thus, phenyl benzyl sulfoxide (5 mmol,
1.08 g) was coupled with 4-chloro-2-methylquinoline (2l) in
80% yield (1.07 g).
Scheme 4. Gram Scale Synthesis of 3l via Palladium
Catalyzed Diaryl Sulfoxide Generation
a
c
5equiv LiOtBu used. b 10 mol % P2 used. 48 h.
(Figure 2) faster than C−N bond formation (Buchwald−
Hartwig coupling14), leaving the N−H’s intact. Heterocyclic
sulfoxides, which often exhibit bioactivities,1 could also be
prepared. Thus, 4-pyrrolephenyl phenyl sulfoxide (3j), 4-
quinoline phenyl sulfoxide (3k), 2-methyl 4-quinoline phenyl
sulfoxide (3l), and (N-methyl)-6-indolyl phenyl sulfoxide (3m)
were generated in 74−81% yields. However, sterically hindered
aryl chlorides, such as mesityl chloride, and some heteroaryl
chlorides, such as 3-chloropyridine and 3-chlorothiophene,
could not be coupled under our conditions.
A variety of aryl benzyl sulfoxides were next explored in the
presence of 5 mol % NiXantPhos ligated precatalyst P2
(Scheme 3). Aryl benzyl sulfoxides bearing electron-donating
groups furnished diaryl sulfoxides 3n−3p in 78−83% yields.
For reasons that remain unclear, 1-(benzylsulfinyl)-4-methox-
ybenzene (1o) was not a viable substrate in our initial study.10
In contrast, in the present case 4-chloroanisole afforded 1o in
83% yield. Diaryl sulfoxides bearing electron-withdrawing 4-F
or 3-CF3 groups generated products in 77−78% yields.
Sulfoxides bearing larger substituents, such as 1-naphthyl (1e)
and 2-tolyl (1q), were also viable coupling partners, providing
3e and 3q in 80−81% yield. Alkyl benzyl sulfoxides are more
challenging substrates, because their α-C−H’s are less acidic
than aryl benzyl sulfoxides.15 Nonetheless, cyclohexyl benzyl
sulfoxide reacted with chlorobenzene to generate cyclohexyl
phenyl sulfoxide (3s) in 72% yield. Heteroaryl benzyl sulfoxides
are potentially useful coupling partners. The quinoline benzyl
sulfoxide underwent coupling to provide the heteroaryl aryl
sulfoxide 3k in 67% yield with 10 mol % catalyst.
We next set out to evaluate different types of sulfoxides as
precursors to diaryl sulfoxides. We previously demonstrated the
arylation of aryl methyl sulfoxides to generate aryl benzyl
sulfoxides,12h which are the substrates in the current study.
Combining these two methods, we treated phenyl methyl
sulfoxide with chlorobenzene under our standard conditions,
giving diphenyl sulfoxide (3b) in 77% yield (Scheme 5A).
Likewise, dibenzyl sulfoxide (1u) and chlorobenzene (2b)
could also be converted to diphenyl sulfoxide in 57% yield
(Scheme 5B). Considering four C(sp2)−Cl bonds have to be
Scheme 5. Preparation of Diphenyl Sulfoxide (3b) from
Methyl Phenyl Sulfoxide (1t) or Dibenzyl Sulfoxide (1u) and
Chlorobenzene (2b)
C
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Organic Letters
Letter
(9) Izquierdo, F.; Chartoire, A.; Nolan, S. P. ACS Catal. 2013, 3,
2190.
(10) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El Baina, K.; Zheng,
broken to generate each equivalent of 3b, the moderate yield is
reasonable.
In summary, aryl chlorides have been utilized as electrophiles
in the cross-coupling reactions with aryl benzyl sulfoxides to
produce diaryl sulfoxides. A variety of functional groups,
including those which might be expected to participate in
related coupling reactions (Buchwald−Hartwig) or undergo
addition reactions (CO, CN), were well tolerated. According
to the proposed mechanism, two C(sp2)−Cl bonds have to be
cleaved to generate one molecule of product. In order to do so,
an air and moisture stable NiXantPhos-derived palladacyclic
precatalyst was employed.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures, characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pwalsh@sas.upenn.edu.
Notes
(14) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (c) Hartwig, J.
F. Acc. Chem. Res. 2008, 41, 1534. (d) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation [CHE-1152488]
for financial support. I.K.S. thanks the Spanish MINECO
(Grant CTQ2012-38594-C02-01) and the Institute of Chem-
ical Research of Catalonia (ICIQ) Foundation for financial
support. C.Y.W. thanks the Vagelos Integrated Program in
Energy Research for financial support.
(15) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
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DOI: 10.1021/acs.orglett.5b00092
Org. Lett. XXXX, XXX, XXX−XXX