Palladium-catalyzed direct thiolation of aryl C-H bonds with disulfides

Article abstract of DOI:10.1002/chem.201304717

A catalytic variant of the direct thiolation of arenes, bearing directing groups, with disulfides or thiols has been developed under palladium and copper co-catalysis. Both sulfenyl moieties of the disulfide could be incorporated into the thiolated produc

Full text of DOI:10.1002/chem.201304717

DOI: 10.1002/chem.201304717
Communication
&
Synthetic Methods
Palladium-Catalyzed Direct Thiolation of Aryl CÀH Bonds with
Disulfides
Masayuki Iwasaki,[a] Miki Iyanaga,[a] Yuta Tsuchiya,[a] Yugo Nishimura,[a] Wenjuan Li,[b]
Zhiping Li,[b] and Yasushi Nishihara*[a, c]
has also been disclosed.[6] On the other hand, a general catalyt-
Abstract: A catalytic variant of the direct thiolation of
arenes, bearing directing groups, with disulfides or thiols
ic intermolecular direct thiolation of arenes has yet to be es-
tablished, although the direct oxidative thiolation, mediated
has been developed under palladium and copper co-catal-
by stoichiometric or substoichiometric amounts of copper(II)
ysis. Both sulfenyl moieties of the disulfide could be incor-
salts, is known.[7,8] Herein, we report a catalytic variant of the
porated into the thiolated products, therefore, the reac-
direct thiolation of aryl CÀH bonds with disulfides.[9]
tions reached completion with only half an equivalent of
We first investigated the reaction of 2-phenylpyridine (1a)[2]
disulfide, with respect to the starting arene. Experimental
with diphenyl disulfide (2a). The results are listed in Table 1.
Indeed, when 1a and 2a were treated with catalytic amounts
evidence suggested that the reaction proceeds through
a PdII/PdIV mechanism.
Table 1. Optimization of palladium-catalyzed direct thiolation of 2-phe-
nylpyridine (1a) with diphenyl disulfide (2a).[a]
Organosulfur compounds are useful building blocks in organic
synthesis.[1,2] Among these compounds, aryl sulfides are an im-
portant motif, frequently found in biologically and pharma-
ceutically active compounds.[3] Transition-metal-catalyzed thio-
lation of aryl halides with thiols is presently the most practical
method for the synthesis of highly functionalized aryl sulfide
scaffolds.[1] Although such reactions provide aryl sulfides fea-
turing a variety of functional groups, the need for aryl halides
as starting materials can limit the reaction scope.
Entry
Phosphine
Copper salt
Yield [%][b]
1
2
none
none
none
CuCl
33
45
3
4
5
6
7
8
9
none
PPh3
PEt3
P(tBu)3
P(2-MeC6H4)3
P(2,4,6-Me3C6H2)3
P(2,4,6-Me3C6H2)3
P(2,4,6-Me3C6H2)3
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
none
CuCl
58
58
44
66
82
90 (87)
43
Recently, transition-metal-catalyzed CÀH bond functionaliza-
tions of arenes bearing directing groups has been developed.[2]
A direct functionalization of CÀH bonds is an ideal synthetic
strategy, allowing straightforward access to various target mol-
ecules. The CÀH thiolation reaction of some reactive arenes
has been reported previously. For example, the electrophilic
thiolation of electron-rich arenes has been catalyzed by Lewis
acids.[4] Deprotonative thiolation of acidic arenes and heteroar-
enes is feasible with excess amounts of strong bases.[5] Palladi-
um-, ruthenium-, or iron-catalyzed intramolecular direct thiola-
tion to construct benzothiophene and benzothiazole skeletons
10
65
[a] The reactions were carried out using 2-phenylpyridine (1a, 0.2 mmol),
diphenyl disulfide (2a, 0.12 mmol), [PdCl2(NCPh)2] (10 mol%), phosphine
(20 mol%), and copper salt (10 mol%), in DMSO (0.50 mL) at 1408C, for
12 h. [b] Determined by 1H NMR spectroscopic analysis. Isolated yield
shown in parentheses.
[a] Dr. M. Iwasaki, M. Iyanaga, Y. Tsuchiya, Y. Nishimura, Prof. Dr. Y. Nishihara
Division of Earth, Life, and Molecular Sciences
of [PdCl2(NCPh)2], in DMSO at 1408C, the desired thiolated
product, 3aa, was obtained in 33% NMR yield (entry 1). The
palladium catalyst is essential for this reaction, and in its ab-
sence, no reaction took place. After a catalyst screening, [PdCl2-
(NCPh)2] was found to be the most successful catalyst, whereas
palladium(0) complexes, such as [Pd2(dba)3] (dba=dibenzylide-
neacetone) and [Pd(PPh3)4], were much less active. In the pres-
ence of other transition-metal species, such as CoBr2 and [RhCl-
(cod)]2 (cod=1,5-cyclooctadiene), the reactions did not pro-
ceed at all. We next tested the effect of copper salts as addi-
tives, including CuCl, CuCl2, Cu(OTf)2, Cu(OAc)2, and Cu(acac)2
(acac=acetylacetonato). The use of CuCl and CuCl2 resulted in
Graduate School of Natural Science and Technology, Okayama University
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan)
Fax: (+81)86-251-7855
E-mail: ynishiha@okayama-u.ac.jp
[b] W. Li, Prof. Dr. Z. Li
Department of Chemistry
Renmin University of China
Beijing 100872 (P. R. China)
[c] Prof. Dr. Y. Nishihara
Japan Science and Technology Agency, ACT-C
4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304717.
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Communication
slightly increased yields (entries 2 and 3), whereas the other
copper salts performed poorly. In the absence of palladium,
the catalytic reaction with 10 mol% of CuCl2 did not pro-
ceed.[7,8] The addition of phosphine ligands substantially influ-
enced the yields.[10] These results indicate that phosphine li-
gands could play a crucial role in the dissociation of the palla-
dium dimer to form the active monomeric species (see below).
Relatively, bulky ligands gave superior results (entries 4–8). Fi-
nally, trimesitylphosphine was found to be the best ligand, af-
fording 3aa in 87% yield (entry 8). The molar ratio of palladi-
um/phosphine species had a significant influence on the yield,
and a ratio of 1:2 was found to be the best. Notably, the reac-
tion proceeded efficiently with even 0.6 equivalents of 2a, sug-
gesting that under the oxidative reaction conditions, the re-
sulting arenethiols are oxidized to regenerate the correspond-
ing disulfides, which could be thiolation reagents.[11] Copper
salts are known to catalyze the oxidation of thiols to disul-
fides.[12] Indeed, the yield was decreased in the absence of
copper salts (entry 9). Because dimethyl sulfide was observed
by GC-MS, it is assumed that DMSO plays a dual role as the
solvent and the terminal oxidant.[11,12] The chemoselective
monothiolation is ascribed to the increased steric hindrance,
which retards further thiolation.
Table 2. Palladium-catalyzed direct thiolation of arenes (1) bearing direct-
ing groups, with diphenyl disulfide (2a).[a]
The reactions of a series of 2-phenylpyridine derivatives, 1,
bearing directing groups, with 2a were examined. The results
are summarized in Table 2. A wide range of 2-phenylpyridines
bearing electron-donating or electron-withdrawing groups in
the para-position underwent monothiolation smoothly to
afford 3ba–3ea in 31–70% yields. In all cases, dithiolated
products, 4, were not observed. Furthermore, 2-phenylpyri-
dines possessing functional groups in the ortho-position also
provided the desired thiolated products, 3 fa–3ha, exclusively.
In addition, the reaction of a naphthalene-containing substrate
can also be applied to the direct thiolation to form 3ia in 59%
yield. For the meta-substituted substrate, the selective thiola-
tion occurred at the less-hindered position to give 3ja. After
examination of several other directing groups, 2-(3-methyl)pyr-
idyl, 2-quinolyl, 2-pyrimidyl, and the bidentate 8-aminoquino-
line groups proved to be suitable for the thiolation reactions,
providing the desired products, 3ka–3oa, in good yields. Nota-
bly, the reactions of 2-phenylpyrimidine (1m) and N-(8-quino-
lyl)benzamide (1n) provided dithiolated products 4ma and
4na exclusively, unless the reaction site was substituted. These
results suggests that the mono- or difunctionalization selectivi-
ty depends on the directing groups employed.[13]
[a] The reactions were carried out by using arenes 1 (0.5 mmol), diphenyl
disulfide (2a, 0.6 equiv), [PdCl2(NCPh)2] (10 mol%), P(2,4,6-Me3C6H2)3
(20 mol%), and CuCl2 (10 mol%), in DMSO (0.4m) at 1408C, for 12 h. Iso-
lated yields are shown. [b] The reaction was performed by using 2a
(2 equiv) at 1608C. [c] 2a (1.2 equiv) was used.
Table 3. Palladium-catalyzed direct thiolation of 2-phenylpyridine (1a)
with thiolation reagents 2 or 5.[a]
Entry
Reagent
R
Product
Yield [%][b]
1
2
3
2b
2c
2d
2e
2 f
2g
2h
2i
p-MeOC6H4
p-CF3C6H4
o-MeC6H4
p-BrC6H4
p-ClC6H4
p-HOC6H4
2-thienyl
Me
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
60
53
56
61
57
58
45
30
78
4[c]
5[c]
6[c]
7
As shown in Table 3, a variety of diaryl disulfides, 2b–2h,
were explored in the palladium-catalyzed direct thiolation of
1a. The reactions of electron-rich and electron-deficient diaryl
disulfides 2 furnished the corresponding products, 3ab and
3ac, in good yields (entries 1 and 2). Sterically hindered diaryl
disulfide 2d also provided 3ad in 56% yield (entry 3). The re-
action of halogenated diaryl disulfides 2e and 2 f delivered
corresponding thiolated adducts 3ae and 3af, respectively,
and significantly, the chloro and bromo moieties remained
intact (entries 4 and 5). Notably, the unprotected hydroxy
group of 2g was well tolerated under the reaction conditions
(entry 6). Thiophene-containing disulfide 2h could also be uti-
8[d]
9[e]
5
–
3aa
[a] Conditions: 1a (0.5 mmol), disulfides
2 (0.6 equiv), [PdCl2(NCPh)2]
(10 mol%), P(2,4,6-Me3C6H2)3 (20 mol%), and CuCl2 (10 mol%), in DMSO
(0.4m) at 1408C, for 12 h. [b] Isolated yields. [c] Conditions: 1a
(0.5 mmol), disulfides 2 (0.5 equiv), [PdCl2(NCPh)2] (10 mol%), and P(2,4,6-
Me3C6H2)3 (20 mol%), in DMSO (0.4m) at 1208C, for 6 h. [d] Conditions:
1a (0.5 mmol), disulfides 2i (1.2 equiv), [PdCl2(NCPh)2] (10 mol%), CuCl2
(10 mol%), and K2S2O8 (1.2 equiv), in DMSO (0.4m) at 1108C, for 12 h.
[e] PhSH (5, 1.2 equiv) was used instead of 2.
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Communication
lized in this reaction (entry 7). Although aliphatic disulfides,
such as dibenzyl disulfide, did not participate in the reaction,
and 1a was recovered unchanged, dimethyl disulfide can be
utilized under modified conditions by using K2S2O8 as an addi-
tional oxidant (entry 8). It is noteworthy that the reaction of
benzenethiol (5) was also successful under the oxidative condi-
tions (entry 9).
tion of a thiolate group from the CuIII to PdII species, and re-
ductive elimination affording 3. Additionally, the reaction of 1a
with 2a in the presence of a catalytic amount of B smoothly
proceeded to give 3aa in 63% yield (Scheme 1c). This result
also supports the PdII/PdIV mechanism.
To gain mechanistic insights into the CÀH palladation, we
conducted an intramolecular competition reaction between
CÀH and CÀD bonds in 1a-d and a kinetic isotope effect (KIE)
of 1.2 was obtained (Scheme 2). This result indicates that the
Although the reaction mechanism of the present direct thio-
lation is not clear at this stage, one possible pathway is a Pd0/
PdII mechanism, initiated by oxidative addition of a disulfide to
Pd0, affording palladium(II) disulfide. This mechanism is analo-
gous to transition-metal-catalyzed direct arylation of aryl CÀH
bonds with aryl halides.[14] A CÀH palladation of arenes bearing
directing groups, followed by a CÀS reductive elimination, pro-
vides the thiolated products and the corresponding thiol,
while regenerating the Pd0 complex. The resulting thiol is oxi-
dized to regenerate a disulfide, with assistance from DMSO
and the copper(II) salt. However, because a stoichiometric reac-
tion of 2-phenylpyridine (1a) with (triphenylphosphine)palladi-
um disulfide dimer A, in the presence of trimesitylphosphine
and CuCl2, did not produce 3aa and most of 1a was recovered
(Scheme 1a), the Pd0/PdII mechanism is unlikely.
Scheme 2. Intramolecular and intermolecular KIE measurements.
CÀH bond cleavage in 1a is not a rate-determining step. This
assumption was confirmed by the same KIE observed in the in-
termolecular parallel experiment and intermolecular competi-
tive reaction between 1a and 1a-d5.[20] Therefore, oxidative ad-
dition of the disulfide to the (2-pyridylphenyl)palladium com-
plex is slower than cleavage of the CÀH bond. Although cyclo-
palladation has been implicated as the rate-determining step
of the related CÀH functionalization with stronger oxidants,[21]
a (2-pyridylphenyl)palladium intermediate might be the resting
state in the reaction with less-reactive disulfide reagents.[22]
In conclusion, we have developed a Pd and Cu co-catalyzed
direct thiolation of aryl CÀH bonds in arenes with disulfides or
thiols. The reaction proceeded with ortho-selectivity, induced
by the directing groups. Functional-group tolerance has been
demonstrated under mild oxidative reaction conditions with
DMSO. The present protocol offers a new method for prepar-
ing highly functionalized aryl sulfides in a more straightforward
manner.
Experimental Section
Scheme 1. Reactions of palladium complexes A and B.
Typical procedure for palladium-catalyzed direct thiolation
of arenes with disulfides
Another plausible mechanism is a PdII/PdIV mechanism,
which is similar to that for CÀH halogenation.[15] In this mecha-
nism, dimeric chloro(2-pyridylphenyl)palladium(II) B could par-
ticipate in oxidative addition of the disulfide to form a palladi-
um(IV) intermediate and the subsequent reductive elimination,
affording 3. It is known that the oxidation of the PdII center to
PdIV with diaryl disulfides undergoes the subsequent CÀS
bond-forming reductive elimination.[16,17] Indeed, treatment of
prepared complex B, derived from PdCl2 and 1a, with 2a af-
forded 3aa in 47% yield (Scheme 1b).[18] This mechanism is
also supported by the fact that less oxidizing dialkyl disulfides
are not suitable for the present thiolation. However, we cannot
rule out the reaction pathway involving oxidative addition of
disulfides to CuI species, forming CuIII species,[19] transmetala-
Synthesis of 2-[4-methoxy-2-(phenylthio)phenyl]pyridine (3ba):
Under an Ar atmosphere, copper(II) chloride (6.7 mg, 0.050 mmol),
bis(benzonitrile)palladium dichloride (19 mg, 0.050 mmol), and tri-
mesitylphosphine (39 mg, 0.10 mmol) were placed in a 20 mL
Schlenk tube. DMSO (1.3 mL) was then added at room tempera-
ture. After the resulting suspension was stirred for 10 min, 2-(4-me-
thoxyphenyl)pyridine (1b, 93 mg, 0.50 mmol) and diphenyl disul-
fide (2a, 66 mg, 0.30 mmol) were added to the mixture. The mix-
ture was stirred at 1408C for 12 h. Saturated sodium thiosulfate so-
lution (5 mL) was added to quench the reaction. The mixture was
extracted with ethyl acetate (5 mL) three times. The combined or-
ganic layers were dried over anhydrous sodium sulfate and con-
centrated under reduced pressure. The resulting residue was puri-
fied by silica-gel column chromatography (hexane/AcOEt, 2:1) to
provide 3ba (100 mg, 0.35 mmol, 70%).
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Acknowledgements
The authors gratefully thank Ms. Megumi Kosaka and Mr. Mo-
tonari Kobayashi at the Department of Instrumental Analysis,
Advanced Science Research Center, Okayama University, for
the measurements of elemental analyses and HRMS. We also
acknowledge SC NMR Laboratory of Okayama University for
the NMR spectra measurements. This work was partially sup-
ported by the MEXT program for promoting the enhancement
of research universities and the Yakumo Foundation for Envi-
ronmental Science.
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Keywords: 2-arylpyridine · aryl sulfides · direct thiolation ·
disulfides · palladium
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Received: December 3, 2014
Published online on February 2, 2014
Chem. Eur. J. 2014, 20, 2459 – 2462
www.chemeurj.org
2462
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim