Palladium catalyzed aryl(alkyl)thiolation of unactivated arenes

Article abstract of DOI:10.1021/ol4036209

A general palladium-catalyzed aryl(alkyl)thiolation of various substituted unactivated arenes is accomplished for the synthesis of diverse unsymmetrical diaryl(alkyl) sulfides in good yield employing electrophilic sulfur reagent 6 derived from succinimide. The developed strategy was coupled with intramolecular arylation of a C-H bond to afford dibenzothiphene derivatives, an important moiety in material science as organic semiconductors.

Full text of DOI:10.1021/ol4036209

Letter
pubs.acs.org/OrgLett
Palladium Catalyzed Aryl(alkyl)thiolation of Unactivated Arenes
Perumal Saravanan and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai − 600 036, India
S
* Supporting Information
ABSTRACT: A general palladium-catalyzed aryl(alkyl)-
thiolation of various substituted unactivated arenes is
accomplished for the synthesis of diverse unsymmetrical
diaryl(alkyl) sulfides in good yield employing electrophilic
sulfur reagent 6 derived from succinimide. The developed
strategy was coupled with intramolecular arylation of a C−H
bond to afford dibenzothiphene derivatives, an important
moiety in material science as organic semiconductors.
Scheme 1. Approaches towards the Synthesis of Diaryl
Sulfides
iaryl sulfides (or arylalkyl sulfides) are potential scaffolds
Dfound in biologically important natural products such as
the Lissoclibadin and Lissoclinotoxin family of natural
products1 and natural product inspired drug molecules such
as AZD4407, a 5-lipoxygenase inhibitor (Figure 1).2 In material
science, dibenzothiophene derivatives, a fused form of diary-
lsulfides, are ubiquitous subunits present in a number of organic
semiconductors.3
respectively, and copper catalyzed arylthiolation of the acidic
C−H of heterocycles such as benzoxazole, benzothiazole, and
indole with diaryldisulfides or arylthiols.10 Furthermore, the
direct aryl thiolation of unactivated arenes was also reported
with transition metal catalyzed or metal-free arylthiolation with
diaryldisulfides and oxidizing agent (Scheme 1).11 However,
these reactions also suffer from the requirement of specific to
selected substrates, such as 2-phenylpyridine and trimethox-
ybenzene, and the need for a stoichiometric copper complex or
highly oxidizing agent. Thus, the development of a mild and
general direct arylthiolation of simple arenes is highly
warranted. Due to the high importance of diaryl sulfides and
our interest in the functionalization of C−H bonds,12 we herein
reveal the palladium-catalyzed direct arylthiolation of C−H
bonds of unactivated arenes.13
Figure 1. Representative examples of biologically important aryl
sulfide.
While these diaryl sulfides can be synthesized through the
reaction of arylmagnesium halides4 or arylboronic acid
derivatives5 with a suitable electrophilic arylsulfur reagent and
catalyst, the widely adopted method is the transition metal
catalyzed/mediated C−S cross-coupling of aryl halides or its
equivalent with thiols and its derivatives (Scheme 1).6
Nonetheless, general problems associated with these reactions
are the use of expensive aryl halides, high catalyst loading due
to sulfide poisoning,7 or addition of superstoichiometric
amounts of additives (generally metal salts) and harsh reaction
conditions.
Alternatively, most economic and benign routes to the
synthesis of diaryl sulfides is the direct arylthiolation of widely
present C−H bonds employing an appropriate thiolating
reagent. The known examples includes copper mediated
alkylthiolation of chelation assisted C−H with dimethyldisul-
fide8 or dimethylsulfoxide9 using air or K2S2O8 as an oxidant,
The direct phenylthiolation of mesitylene 1 to mesitylphenyl
sulfide 2 was chosen as a model reaction. Initially, the
palladium-catalyzed phenylthiolation of mesitylene was inves-
tigated employing various readily accessible electrophilic
Received: December 14, 2013
Published: January 17, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol4036209 | Org. Lett. 2014, 16, 848−851

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Letter
arylthiolation reagents (3−6).14 The reaction of mesitylene 1
with palladium acetate (5 mol %) and diphenyldisulfide 3 in
trifluoroacetic acid (TFA) at room temperature furnished the
expected mesitylphenyl sulfide 2 in an isolable yield (Table 1,
Scheme 2. Palladium-Catalyzed Phenylthiolation of Arenes:
Scope and Limitation
a
Table 1. Palladium-Catalyzed Arylthiolation of Arenes:
a
Optimization
b
c
entry
PhS+ source (3−6)
solvent
time (h)
yield (%)
1
2
3
4
3
4
5
6
6
6
6
6
6
6
6
TFA
6
18
87
19
95
20
11
29
0
TFA
6
TFA
24
TFA
45 min
12
d
5
TFA
6
7
AcOH
MsOH
TfOH
TFA
48
6
e
8
f
15 min
45 min
45 min
45 min
9
67
90
79
g
10
TFA
h
11
TFA
a
Reaction conditions: Mesitylene (5 equiv), 3−6 (1 equiv), Pd(OAc)2
b
(5 mol %), solvent (1 mL), rt, time. Time required for consumption
c
of reagent 3−6. Isolated yield based on arylthiolating reagent.
d
e
f
Without Pd(OAc)2. Reagent decomposed quickly. 3 equiv of
g
h
mesitylene. 2 mol % of Pd(OAc)2. 5 mol % of PdCl2 was used.
a
Reaction conditions: 6 (1 equiv), arene (5 equiv), Pd(OAc)2 (2 mol
%), TFA (0.5 mL), rt, 45 min. All are isolated yields. b 4 h. c 1 equiv of
arene and 2 equiv of 6. Based on H NMR.
d
1
disubstituted and 1,2,3-trisubstituted arenes furnished the
corresponding products (2da, 2ea, 2ga, and 2ha) in good
yield with excellent selectivity. 3,5-Dimethylanisole and 3-
bromoanisole gave a mixture of para- and ortho-arylthiolated
product in a 5:1 and 1:9 ratio, respectively. Interestingly, simple
substrates such as anisole, naphthalene, and toluene and a
carbocycle such as fluorene also furnished the corresponding
arylthiolated product (2ka, 2pa, 2ja, and 2qa) in moderate to
good yield under the optimized conditions. The arylthiolation
of para-xylene afforded the diarylthiolated compound (2na and
2od) as the sole product. It is worth noting that the free
hydroxyl group and electron withdrawing (carboxylate) group
(β-naphthaol and ethyl 3-hydroxy-2-naphthoate) were also
tolerated under the present arylthiolating conditions. Fur-
thermore, arylthiolated heteroarenes (2ra and 2sa) are also
achieved in good yield.
Successively, the scope of reagent 6 with various arylthiol
partners was also examined under the optimized arylthiolation
conditions (Scheme 3). Reagent 6 with simple arylthiols such
as p-tolylthiol and 2-naphthalenethiol furnished the arylthio-
lated product 2ab and 2af in 83% and 84% yield, respectively.
Both electron donating (p-methoxybenzenethiol) and electron
withdrawing group (p-nitrobenzenethiol and p-benzoylben-
zenethiol) substitution on the arylthiol partner was tolerated
well and afforded the products (2ah, 2cj, and 2ak) in excellent
yield. Halogenated diaryl sulfides (2ac, 2ad, and 2ag),
precursors for the synthesis of sulfur based heterocycles, were
achieved in good yield from corresponding substituted reagent
6. Interestingly, 4,6-dimethylpyrimidine-2-thiol substituted
reagent 6, a heterocycle based thiol, underwent a smooth
entry 1). A similar result was observed with reagent 5.
Interestingly, a high yield of 2 was obtained using reagents 4
and 6; among them reagent 615 was found to be superior to
reagent 4 since the reaction with the former required only 45
min to give product 2 in 95% yield (Table 1, entries 2 and 4).
In the absence of palladium acetate, the complete decom-
position of 6 was observed after 12 h and product 2 was
isolated in very low yield (Table 1, entry 5). Changing the
reaction medium to acetic acid (AcOH), methanesulfonic acid
(MsOH), or trifluoromethanesulfonic acid (TfOH) reduced
the formation of sulfide 2 (Table 1, entries 6−8). Reducing the
equivalents of mesitylene from 5 to 3 decreased the yield of 2
(Table 1, entry 9). Interestingly, the decrease in the catalyst
loading to 2 mol % also afforded the sulfide 2 in comparable
yield (Table 1, entries 4 and 10). Replacing palladium acetate
with palladium chloride gave the sulfide 2, but with a low yield
(Table 1, entry 11). From the optimization studies, we chose
the following conditions for studying the generality of the
methodology: Arene (5 equiv), 6 (1 equiv), Pd(OAc)2 (2 mol
%), TFA, rt, 45 min.
Next, various substituted arenes were subjected under the
optimized conditions to reagent 6 to examine the generality of
the developed strategy (Scheme 2). The arylthiolation of
mesitylene gave the corresponding mesitylphenyl sulfide 2aa in
95% isolated yield. A similar result was obtained with the
formation of (trimethoxyphenyl)phenyl sulfide 2ca. Sterically
hindered 1,3,5-triisopropylbenzene also underwent a smooth
reaction to afford 2ba in 77% yield. The arylthiolation of 1,3-
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Organic Letters
Letter
79% overall yield over two steps. Subsequently, other
substituted diaryl sulfides (2dd and 2ed) were also examined
under the optimized conditions to yield the corresponding
dibenzothiophenes (7b and 7c) in good yield. Thus, the
developed intramolecular arylation of the C−H bond of a diaryl
sulfide can be applied to synthesize the other substituted
dibenzothiophenes as well. In addition, benzo[a]phenoxathiine
8 was also synthesized through the copper mediated C−O
cross-coupling of 2ld employing the reported protocol in 74%
yield (Scheme 4b).
Scheme 3. Palladium-Catalyzed Arylthiolation of Mesitylene:
Scope and Limitation
a
As shown in Scheme 5, we postulated the mechanism for the
arylthiolation of arenes with 6 based on the earlier reports on
Scheme 5. Plausible Mechanism for the Formation of Diaryl
Sulfide
a
Reaction conditions: 6 (1 equiv), arene (5 equiv), Pd(OAc)2 (2 mol
b
%), TFA (0.5 mL), rt, 45 min. All are isolated yields. 4 h.
reaction to afford the aryl(heteroaryl) sulfide 2ai in 79% yield.
In addition to the arylthiols, alkyl thiols also can be employed
to afford the arylalkyl sulfides. Arylalkyl sulfides (2cl and 2cm)
were achieved in good yield from corresponding reagent 6.
After the synthesis of various diarylsulfides, the utility of the
synthesized diaryl sulfides was demonstrated by converting
them into sulfur based heterocycles. At first, we envisaged the
synthesis of benzothiophenes, an important moiety present in
various organic semiconductors, through intramolecular
arylation of the C−H bond (Scheme 4a). The appropriate
substrate 2kd was synthesized employing the present strategy
and subjected to the intramolecular arylation employing a
palladium catalyst.12,16 Based on the optimized conditions (see
Supporting inforamtion) dibenzothiophene 7a was isolated in
the palladium-catalyzed C−H functionalization of arenes.12,17
Initially, highly electrophilic palladium trifluoroacetate A,
generated from palladium acetate and TFA, reacts with arenes
1 to afford the arylpalladium(II) species B through C−H
functionalization. Oxidative insertion of B into the N−S bond
of 6 would lead to the palladium(IV) species C. The formation
of product 2 could be achieved via the reductive elimination of
the aryl and arylthio moiety from C, which concomitantly
produced the species D. Finally, ligand exchange will furnish
the active palladium species A to complete the catalytic cycle
and the same reacts with another arene to continue the
subsequent cycle.
Scheme 4. Synthesis of Dibenzothiophene and
Benzo[a]phenoxathiine Derivatives
In conclusion, we have disclosed the direct palladium-
catalyzed aryl(alkyl)thiolation of C−H bonds of unactivated
arenes. The readily accessible succinimide based electrophilic
reagent 6 enables the synthesis of diverse unsymmetrical diaryl
or arylalkyl sulfides from readily available arenes in good yield
and selectivity under mild conditions. Futhermore, reaction
conditions were also optimized for the palladium-catalyzed
intramolecular arylation of C−H bonds of diaryl sulfides to
afford dibenzothiophene derivatives, a highly important frame-
work in material science. The synthesis of benzophenoxathiine
was also accomplished through C−O cross-coupling.
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental methods, characterizations data, and H and 13C
NMR spectra of isolated compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: anbarasansp@iitm.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Indian Institute of Technology Madras,
Department of Science and Technology (DST), and Council
of Scientific & Industrial Research (CSIR) for financial support.
P.S. thanks CSIR for a fellowship.
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