Palladium-catalyzed direct arylation of methyl sulfoxides with aryl halides

Article abstract of DOI:10.1021/ja4009776

The palladium-catalyzed α-arylation of unactivated sulfoxides has been developed. The weakly acidic α-protons of sulfoxides are reversibly deprotonated by LiOtBu, and a palladium phosphine complex facilitates the arylation. A variety of aryl methyl sulfoxides were coupled with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including dimethyl sulfoxide) and aryl chlorides proved to be suitable under the optimized conditions. This method was utilized to synthesize bioactive benzyl sulfoxide intermediates.

Full text of DOI:10.1021/ja4009776

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Direct Arylation of Methyl Sulfoxides with Aryl
Halides
Tiezheng Jia,† Ana Bellomo,† Kawtar EL Baina,† Spencer D. Dreher,‡ and Patrick J. Walsh*,†
†Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
‡Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
Scheme 2. Suzuki Coupling of Bromosulfoxides and α-
Arylation of Carbonyls, Sulfones, and Sulfoxides
ABSTRACT: The palladium-catalyzed α-arylation of
unactivated sulfoxides has been developed. The weakly
acidic α-protons of sulfoxides are reversibly deprotonated
by LiOtBu, and a palladium phosphine complex facilitates
the arylation. A variety of aryl methyl sulfoxides were
coupled with aryl bromides. More challenging coupling
partners, such as alkyl methyl sulfoxides (including
dimethyl sulfoxide) and aryl chlorides proved to be
suitable under the optimized conditions. This method
was utilized to synthesize bioactive benzyl sulfoxide
intermediates.
ulfoxides exhibit a wide range of biological properties,
S
including anticancer,1a−d antihepatitis,1e and antibacterial
activity,1f and are useful bioisosteres.2 They are also important
intermediates in organic chemistry and have been widely used
as ligands in catalysis.3 The two most common approaches for
generating sulfoxides are (i) oxidation of sulfides4 and (ii)
substitution reactions of electrophilic sulfoxide derivatives with
organometallic nucleophiles5 (Scheme 1). Despite the popular-
the pKa of the α-hydrogens increases, however, such reactions
become more challenging. For example, the α-arylation of
unactivated sulfones was recently reported by Zhou et al. from
Merck (Scheme 2C).9 The higher pKa of methyl phenyl sulfone
(pKa = 2910a) relative to acetophenone (pKa = 24.710b) allowed
the Merck team to achieve deprotonation of the weakly acidic
sulfone with LiN(SiMe3)2 and transmetalation with ZnCl2
before the cross-coupling. In the case of methyl phenyl
sulfoxide [pKa = 33 in dimethyl sulfoxide (DMSO)10c], a
stronger base must be used for deprotonation, such as lithium
diisopropylamide,11a,b Li(i-Pr)(c-Hex),11b or n-BuLi.11c These
bases, however, are less practical for cross-coupling reactions
because of their limited compatibility with catalysts and
coupling partners. The challenge in developing the direct α-
arylation of unactivated sulfoxides was to identify a suitable
combination of base and catalyst. Herein we report the first
example of palladium-catalyzed direct arylation of methyl
sulfoxides with aryl halides (Scheme 2D). Interestingly, a little-
known indolyl phosphine outperformed the industry-standard
phosphines in this challenging reaction.
Scheme 1. Two Synthetic Approaches to Sulfoxides
ity of these methods, both suffer from limited functional group
tolerance because either strong oxidizing agents or reactive
organolithium or Grignard reagents are employed. Benzyl
phenyl sulfoxides have also been accessed by a Pd-catalyzed
Suzuki cross-coupling employing prefunctionalized coupling
partners (Scheme 2A).6 A more efficient and atom-economical
route to benzyl sulfoxides would be the direct arylation of
methyl sulfoxides. Despite the similarity of this approach to the
well-known α-arylation of carbonyl compounds,7 α-arylation of
unactivated sulfoxides is unknown.
Transition-metal-catalyzed cross-coupling reactions to form
C−C bonds are one of the most powerful tools in modern
organic synthesis.8 Among these, the α-arylation of carbonyl
compounds has received significant attention (Scheme 2B).7 As
We recently introduced approaches for direct arylation and
allylation of weakly acidic benzylic hydrogens of η6-arene
Received: October 15, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4009776 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
complexes of toluene, benzylic amines, benzylic ethers, and
diphenylmethane derivatives.12 Diphenylmethane derivatives
were arylated via a deprotonative cross-coupling procedure
(DCCP), even in the absence of arene-activating metals.13 The
DCCP entailed a reversible room-temperature deprotonation
of the weakly acidic benzylic protons of diphenylmethane (pKa
= 32) with concurrent palladium-catalyzed cross-coupling. On
the basis of the success of this method, we initiated efforts to
cross-couple methyl phenyl sulfoxide (1a) with bromobenzene
(2a) under reaction conditions similar to those for the DCCP
with diarylmethanes in the absence of arene-activating metals13
[KN(SiMe3)2, cyclopenyl methyl ether (CPME), 10 mol %
Pd(OAc)2, and 15 mol % NiXantPhos (L1 in Table 1)]. The
ligand, which was introduced by Kwong and co-workers,14b has
been successfully employed only in one study of the Suzuki−
Miyaura cross-coupling reaction. The microscale result using
L2 was successfully translated to laboratory scale, rendering
product 3a in 75% isolated yield. A decrease in temperature
(entry 7) or catalyst/ligand loading (entry 8) was detrimental
to the yield under these conditions. We next focused on the
identification of more suitable palladium sources, substrate
ratios, and temperatures. Of the conditions and ratios
examined, better results for the direct α-arylation were obtained
on the microscale employing Pd(OAc)2 (10 mol %), ligand L2
(15 mol %), and a 1a:2a ratio of 1:2 at 110 °C. Scaling the
reaction to 0.1 mmol and increasing the concentration from 0.1
to 0.2 M resulted in isolation of 3a in 93% yield (entry 9).
Further increasing the concentration to 0.3 M resulted in a
slightly lower yield (87%; entry 10), probably because of
reduced solubility of the sulfoxide and base at this
concentration. Therefore, 0.2 M was chosen for the substrate
scope study.
Table 1. Optimization of the α-Arylation of Methyl Phenyl
Sulfoxide (1a)
Under the optimized conditions in Table 1, entry 9, the
scope of the direct arylation of 1a with various aryl bromides
was investigated (Table 2). A wide range of substrates exhibited
Table 2. Substrate Scope of Aryl Bromides and Chlorides in
Pd-Catalyzed α-Arylation of Unactivated Sulfoxides
[Pd]/ligand
mol %
conc.
(M)
T
(°C)
yield
a
entry ligand
base
(%)
1
2
L1
L1
L2
L3
L4
L5
L2
L2
L2
L2
KN(SiMe3)2
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
10/15
10/15
10/20
10/20
10/20
10/20
10/20
5/10
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.3
80
80
27
42
75
16
23
44
40
40
3
110
110
110
110
80
4
5
6
7
8
110
110
110
b
9
10/20
10/20
93
10
LiOtBu
87
a
1
Determined by H NMR analysis of the crude reaction mixtures.
b
Isolated yield after chromatographic purification.
coupled benzyl sulfoxide product (3a) was formed in 27%
isolated yield at 80 °C (Table 1, entry 1). To build on this
promising result, we screened six bases [LiOtBu, NaOtBu,
KOtBu, LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2] and
four solvents using microscale high-throughput experimenta-
tion (HTE) techniques. The leading base from this screening
was LiOtBu in CPME, which generated the desired product 3a
in moderate yield (42%; entry 2). The search for more active
catalysts was continued with LiOtBu and CPME by testing a
series of sterically and electronically diverse mono- and
bidentate ligands. Of the 112 ligands examined, L2−L514
were promising (see the Supporting Information for details),
with N-(dicyclohexylphosphino)-2-(2′-tolyl)indole (L2) out-
performing the others (entry 3 vs 4−6). To the best of our
knowledge, this monodentate, bulky, electron-rich phosphine
a
For aryl chlorides, the palladium source was changed to 5 mol % Pd
b
dimer and 0.33 mmol of H2O was added. For aryl chlorides, the
c
solvent was toluene. For aryl chlorides, the reaction time was 24 h.
d
e
f
0.1 M, 36 h. 48 h. 1a (8 mmol), 2j (16 mmol), CPME (40 mL),
LiOtBu (24 mmol), 24 h.
excellent reactivity, including those with electron-donating (3b,
3c), electron-withdrawing (3d, 3e, 3h), and ortho or meta
substituents (3f, 3g). In the case of 4-bromochlorobenzene, a
concentration of 0.1 M was found to be optimal for
chemoselective activation of the bromide, providing 3e in
81% isolated yield. When the DCCP with 1a was scaled to 8
mmol (1.12 g) with 3-bromotrifluoromethylbenzene (2h), the
B
dx.doi.org/10.1021/ja4009776 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
product 3h was isolated in 85% yield. Sulfoxide 3h could be
used as the key intermediate in the synthesis of an anticancer
agent.1d
generation of 4i (77%), a key intermediate in an antivirus
compound.18
Coupling of sulfoxides with substituents other than methyl
may give rise to diastereomers. As anticipated, cross-coupling of
benzyl sulfoxide 3j led to the formation of a mixture of
diastereomers in a 1:1.3 ratio. Unfortunately, we were unable to
separate the diastereomers by column chromatography. The
mixture of sulfoxides was therefore oxidized to sulfone 5j in
90% yield (Scheme 3).19
Aryl chlorides are known to be more challenging substrates
than aryl bromides for a variety of cross-coupling reactions.15
When we employed aryl chlorides under our optimized
conditions for aryl bromides, only trace products were
observed. We suspected that catalyst activation might be
problematic and turned to Buchwald-type second-generation
catalysts.16 Thus, addition of L2 to the palladium dimer (see
Table 2) along with 0.33 mmol of H2O as an additive17 resulted
in an active catalyst toward aryl chlorides (Table 2). Sulfoxide
3a was isolated using 1a and chlorobenzene (2a′) in 69% yield.
Electron-donating (3b, 3c) and electron-withdrawing groups
(3d) were well-tolerated when the corresponding aryl chlorides
were used, as well as 1-naphthyl- (2g′) and meta-substituted
aryl chlorides (2f′, 2i′). Unfortunately, heterocyclic halides
were not viable substrates under these conditions.
Scheme 3. α-Arylation of 3j with 2a and Subsequent
Oxidation to Sulfone 5j
We then turned our attention to the aryl methyl sulfoxide
substrate scope using 4-bromo-tert-butylbenzene (2b) as the
coupling partner (Table 3). Electron-donating (4b, 4c),
Table 3. Substrate Scope of Aryl Methyl Sulfoxides in Pd-
Catalyzed α-Arylation Using 4-Bromo-tert-butylbenzene
(2b) as the Coupling Partner
Alkyl methyl sulfoxides are less acidic than aryl methyl
sulfoxides and represent a greater challenge. As shown in
Scheme 4, cyclohexyl methyl sulfoxide underwent a DCCP with
Scheme 4. α-Arylation of Alkyl Methyl Sulfoxides
2a to give the desired product in 88% yield after 24 h (eq 1).
Interestingly, DMSO, a common organic solvent with pKa =
35.1,10a could be utilized to prepare benzyl sulfoxides. Under
the same conditions used for cyclohexyl methyl sulfoxide,
mono- and bisarylated products were obtained with DMSO and
2a in yields of 48 and 24%, respectively (eq 2). To control the
selectivity, we adjusted the stoichiometry and optimized the
reaction conditions for DMSO. Ultimately, we successfully
generated either the mono- or dibenzylated product in isolated
yields of 76 and 71% when the DMSO/2a ratio was 10:1 or 1:8,
respectively (eqs 3 and 4).
a
90 °C, 48 h.
withdrawing (4e, 4f, 4g), m-methoxy (4f), and o-methyl (4a)
groups all led to good yields (81−87%) under our optimized
conditions for aryl bromides. In addition, methyl 1-naphthyl
sulfoxide furnished product 4h in 74% yield. Unfortunately, no
product was isolated from 2-pyridyl or 2-pyrimidyl methyl
sulfoxide, possibly because of chelation of nitrogen and sulfur
or oxygen to palladium. On the basis of this hypothesis, we
examined 3-pyridyl methyl sulfoxide and observed the
In summary, we have developed the first direct α-arylation of
unactivated alkyl and aryl methyl sulfoxides with aryl bromides.
Aryl chlorides also participate in the reaction when catalyzed by
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures and full characterization of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
pwalsh@sas.upenn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Foundation [CHE-0848460
(GOALI) and 1152488] for financial support. K.E.B. thanks
■
Universite
́
Pierre et Marie Curie and CROUS de Paris for
eot for
financial support. We thank Dr. Nicolas Fleury-Breg
helpful discussions on the use of precatalysts.
́
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