Zinc-mediated palladium-catalyzed formation of carbon-sulfur bonds

Article abstract of DOI:10.1021/jo900385d

(Chemical Equation Presented) A catalytic amount of zinc chloride in combination with a palladium catalyst ligated by a monodentate phosphine allows the coupling of aryl and alkyl thiols with aryl bromides in high yields. The addition of zinc chloride to a palladium catalyst system that reportedly failed to promote sulfide formation allows this once ineffective catalyst system to provide the sulfide product in good yield. This paper describes a high-yielding and general monodentate phosphine-ligated palladium catalyst for biaryl and alkyl aryl sulfide formation.

Full text of DOI:10.1021/jo900385d

ladium,5 nickel,6 copper,7 cobalt,8 and iron.9 A highly general
palladium catalyst to form biaryl sulfides and alkyl-aryl sulfides
from aryl bromides and chlorides was reported recently by
Hartwig.5a Hartwig’s palladium catalyst is composed of a
strongly coordinating bidentate ligand that resists displacement
by the thiolate anion, likely the cause of catalyst deactivation
in most of these reactions. For this reason, the use of palladium
catalysts ligated by monodentate phosphine ligands to form these
carbon-sulfur bonds has shown limited reaction scope, and in
many cases, completely failed to promote this coupling reaction.
The inefficiency of these catalysts to promote carbon-sulfur
bond formation is likely caused by the displacement of the
metal-bound phosphines by thiolates, producing an inactive
catalyst.5g While preparing aryl ketones with the Fukuyama
reaction,10 the formation of an appreciable quantity of aryl
sulfide in the presence of the palladium catalyst [Pd(µ-
Br)(PtBu3)]2 (1) was observed (Scheme 1).11 Because of the
previously described failures of palladium complexes of mono-
dentate phosphines to catalyze the formation of carbon-sulfur
bonds from aryl halides and thiols, we decided to investigate
the scope of this reaction and attempt to identify the factors
that allow this transformation to occur.
Zinc-Mediated Palladium-Catalyzed Formation of
Carbon-Sulfur Bonds
Chad C. Eichman and James P. Stambuli*
EVans Chemical Laboratories, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
stambuli@chemistry.ohio-state.edu
ReceiVed March 06, 2009
A catalytic amount of zinc chloride in combination with a
palladium catalyst ligated by a monodentate phosphine allows
the coupling of aryl and alkyl thiols with aryl bromides in
high yields. The addition of zinc chloride to a palladium
catalyst system that reportedly failed to promote sulfide
formation allows this once ineffective catalyst system to
provide the sulfide product in good yield. This paper
describes a high-yielding and general monodentate phos-
phine-ligated palladium catalyst for biaryl and alkyl aryl
sulfide formation.
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Metal-catalyzed cross-coupling reactions have revolutionized
how chemists synthesize small molecules. As evidence, a large
number of reviews have been devoted to metal-catalyzed cross-
coupling reactions.1 Because of their ability to stabilize unsatur-
ated metal complexes,2 bulky monodentate phosphines are
frequently used in combination with late transition metals as
catalysts for many cross-coupling reactions.1b However, these
catalysts typically do not promote the formation of carbon-sulfur
bonds because of the displacement of these ligands by the
thiolate coupling partners employed in these reactions.3
The challenge of finding a catalyst for the formation of
carbon-sulfur bonds, as well as the presence of arylsulfides in
drug candidates4 has sparked the development of new technol-
ogy to create this bond. A wide range of transition metals have
been used to catalyze this coupling reaction, including pal-
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10.1021/jo900385d CCC: $40.75
Published on Web 04/03/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4005–4008 4005

TABLE 1. Screening Conditions for the Palladium-Catalyzed
Arylation of Aryl and Alkyl Thiolsa
SCHEME 1. Potential Pathway for the Formation of Aryl
Sulfides
entry
PhX
RSH
ZnX2 (equiv)
T (°C)
t (h)
P:SMb
1
2
3
4
5
6
7
8
9
PhI
PhI
PhI
PhI
PhI
PhI
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
EtSH
EtSH
EtSH
EtSH
PhSH
PhSH
EtSH
EtSH
PhSH
PhSH
PhSH
EtSH
ZnI2 (1.1)
ZnI2 (0.5)
23
23
23
23
23
60
23
60
60
90
90
60
12
12
12
12
2
2
2
2
2
80:20
10:90
100:0
100:0
46:54
100:0
4:96
ZnI2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
ZnCl2 (0.64)
no zinc
The palladium-catalyzed Fukuyama reaction between a thioester
and organozinc reagent produces the corresponding ketone with
concomitant generation of a thiolate zinc halide, as shown in the
proposed, generalized catalytic cycle. A possible role of the thiolate
zinc halide may be to transfer the thiolate to palladium via
transmetalation step under our Fukuyama conditions (Scheme 1).
Under typical cross-coupling reaction conditions to form alkyl-
aryl sulfides, the sodium or potassium thiolate is generated in situ
from the corresponding base and thiol, exposing the palladium
catalyst to a large excess of the thiolate. The zinc likely acts as an
electrophilic buffer to protect the palladium center from attack by
the thiol anions, because of the strong coordination between zinc
and thiolate ligands.12 However, the zinc-thiolate interaction is
weak enough to allow transmetalation. Zinc metal has been
employed in palladium-,5c nickel-,6a and cobalt-8 catalyzed aryl
sulfide syntheses; however, the role of zinc was to reduce the
palladium(II), nickel(II), or cobalt(II) catalyst to palladium(0),
nickel(0), and cobalt(I), respectively.
98:2
24:76
100:0c
100:0
0:100
10
11
12
2
2
2
no zinc
a See the Supporting Information for complete experimental
procedures. b P:SM is the ratio of the sulfide product to starting aryl
halide according to GC analysis. c LiI (0.5 equiv) was added.
discussed in later sections (vide infra). Using the conditions
described above and outlined in Table 1, several organic and
inorganic bases that are commonplace in metal-catalyzed cross-
coupling reactions were tested. The use of potassium hydride,
sodium bis(trimethylsilyl) amide, or sodium tert-butoxide was
found to give the highest yields of product among the bases
screened. We chose to employ sodium tert-butoxide as base in
these reactions because of its ease of handling.
To investigate the scope of 1 as a catalyst for the formation
of aryl sulfides, different reaction conditions were evaluated by
modifying the identity and amount of the zinc reagent. Aryl
and alkyl thiols were reacted in the presence of iodobenzene,
base, and 1. Upon initial investigations, it became apparent that
the order of addition was extremely important. The thiol was
added to a THF solution of aryl halide, base, zinc chloride, and
1, and then reacted for 12 h. The results stemming from these
reaction conditions were inconsistent. Reproducible results were
obtained from the addition of thiol to a solution of the base in
THF, followed by introduction of the zinc salt into this mixture
with stirring, for 10 min. After this time, aryl halide was added
to the reaction, followed by catalyst 1, as a solution of THF
(Table 1). Using these general reaction conditions, we discov-
ered that zinc iodide and zinc chloride provided similar results,
and that the optimum amount of zinc was slightly higher than
0.5 equiv. The reactions of iodobenzene and ethanethiol
proceeded at ambient temperature, while reactions of iodoben-
zene and benzenethiol required warming to 60 °C. Similar
reactions of bromobenzene and ethanethiol or benzenethiol
required heating to 60 and 90 °C, respectively. In the absence
of the zinc reagent, the reaction of bromobenzene and ethaneth-
iol under our optimized conditions did not yield product.
Interestingly, the corresponding reaction of bromobenzene and
benzenethiol in the absence of zinc chloride did completely
convert the starting materials to product. When zinc chloride
was employed in the reaction of bromobenzene and ben-
zenethiol, a catalytic amount of lithium iodide was necessary
to increase the rate of the reaction. These results will be
With our optimized conditions in hand, we investigated the
scope of the coupling reaction of aryl bromides and alkyl thiols
using the monodentate phosphine ligated palladium catalyst 1.
As shown in Table 1, zinc chloride was necessary to allow the
formation of the alkyl aryl sulfide. Unlike the reactions of aryl
thiolates and aryl bromides, the addition of lithium iodide was
not necessary, likely due to the increased nucleophilicity of the
alkyl thiolates with respect to the aryl thiolates. Most all of the
alkyl thiols employed were coupled with aryl bromides in
excellent yields (Table 2). The use of ZnCl2 (0.64 equiv) was
necessary to ensure catalyst activity. The catalyst loading of 1
was low (0.5-2.0 mol %) and demonstrates the impressive
ability of ZnCl2 to keep the alkyl thiolate from decomposing
the palladium catalyst. Most of the reactions were complete
within 1-2 h. Unactivated aryl halides (entries 1 and 2) and
aryl halides containing electron-withdrawing groups (entries
3-5) or electron-donating groups (entries 6-9) were competent
partners in this coupling reaction. The use of hindered aryl
bromides (entries 7-9) or heterocyclic aryl bromides (entries
10 and 11) also formed the corresponding sulfide product in
good yields. Although seemingly unaffected by the presence
of the indole, the interaction of 2-pyridyl bromide and zinc
chloride under our standard conditions failed to produce the
corresponding aryl sulfide product. The affinity of the zinc
reagent toward the pyridyl group may allow faster decomposi-
tion of the palladium catalyst because of the formation of pyridyl
complexes of zinc.13 In the absence of zinc and at a higher
catalyst loading, tert-butyl-2-pyridyl sulfide was formed in 46%
yield.
(12) (a) Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl.
Chem. 2002, 74, 115. (b) Bertini, I.; Briganti, F.; ScozzafavaA. Handbook of
Metal-Ligand Interactions in Biological Fluids; Berton, G., Ed.; Marcel Dekker:
New York, 1995; Vol. 1, pp 175-191.
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4006 J. Org. Chem. Vol. 74, No. 10, 2009

TABLE 2. Palladium-Catalyzed Arylation of Alkyl Thiols
TABLE 3. Palladium-Catalyzed Arylation of Benzenethiola
a See the Supporting Information for complete experimental
procedures. b Yield is an average of two reactions. c 2.3 equiv of
NaOtBu was used. d E:Z ) 85:15 for starting material and product.
TABLE 4. Palladium-Catalyzed Arylation of Thiocresol and
2-Naphthalenethiola
a See the Supporting Information for complete experimental
procedures. b Yield is an average of two reactions. c KH (1.1 equiv) was
d
1
used as base. Yield was determined by H NMR spectroscopy.
We have established our current catalyst and conditions to
promote the coupling of aryl bromides and alkyl thiols in high
yields and with low catalyst loading. To examine the broad
applicability of this catalyst system in the formation of
carbon-sulfur bonds, we next examined reactions of aryl
bromides and aryl thiols. The conditions described in Table 2
(cat. 1, ZnCl2, NaOtBu) were applied to the palladium-catalyzed
cross-coupling reactions of aryl bromides and benzenethiol. In
the absence of lithium iodide, most of the reactions were quite
sluggish and provided low yields. However, the addition of a
substoichiometric amount of lithium iodide increased the rate
of the reaction dramatically. The beneficial effect of LiI may
be explained by the previously described anionic effects that
are observed in related palladium-catalyzed reactions.14 With
these modified conditions, a number of diverse bromide coupling
partners were employed (Table 3). Once again, electronic or
steric factors of the aryl bromide did not greatly influence the
yields of these reactions. This catalyst system also tolerated the
presence of functional groups, such as cyano (entry 4), car-
boxylic acid (entry 6), and hydroxy (entry 7), without a
significant loss in overall yield. The reactions of substrates that
contained acidic functional groups were conducted in the
presence of 2.3 equiv of NaOtBu. 3-Bromothiophene reacted
with benzenethiol to give the corresponding sulfide in 96% yield
(entry 10). These reaction conditions also catalyzed the coupling
of ꢀ-bromostyrene and benzenethiol in high yield and without
erosion of the double-bond stereoisomeric ratio (entry 11).
a See the Supporting Information for complete experimental
procedures. b Yield is an average of two reactions. c KH (1.1 equiv)
used as base, ZnCl2 and LiI were not used. d Yield determined by 1H
NMR spectroscopy.
This chemistry was then extended to palladium-catalyzed
arylations of thiocresol and 2-naphthalenethiol (Table 4). As
expected, the reactions proceeded smoothly to the desired
products with low loadings of palladium catalysts. Most all of
the substrates that were examined are listed in Table 4, as
(14) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 5–314.
J. Org. Chem. Vol. 74, No. 10, 2009 4007

catalyst 1 is general in scope. The rapid and relatively mild
reaction conditions allowed the reaction of 4-bromobenzalde-
hyde and thiocresol to proceed in almost quantitative yield. As
seen in the cross-coupling reaction of 2-bromopyridine and tert-
butyl thiol in Table 2, the reaction of 2-bromopyridine and
thiocresol provided mediocre yields of the desired product, even
in the presence of 2 mol % of palladium catalyst 1.
a slower transmetalation with the zinc thiolate complex.15
Therefore, the lithium salt may promote the reaction via anionic
effect, or somehow increase the rate of transmetalation by
interaction with the zinc thiolate. As expected, the thiolate anion
is less reactive, relative to potassium or sodium thiolates, when
zinc is the counterion.
In summary, we have reported a monodentate-ligated pal-
ladium catalyst that promotes the formation of alkyl-aryl and
biaryl sulfides from the corresponding aryl halides and alkyl or
aryl thiolates. The previous catalytic deactivation pathway
observed when using catalysts of this type in palladium-
catalyzed carbon-sulfur bond formations is avoided by employ-
ing a substoichiometric amount of zinc chloride. The zinc acts
to shield the palladium center from direct attack by the thiolate
anion, which ultimately would lead to catalyst deactivation via
displacement of the monodentate phosphine ligand. The benefit
of zinc in this chemistry is not limited to catalyst 1, but can
also allow palladium-catalyzed carbon-sulfur bond formations
of previously reported unreactive catalysts. These newly de-
veloped catalytic conditions provide an alternative to the use
of bidentate phosphine ligands for these reactions, demonstrate
the importance of zinc thiolate interactions in organometallic
chemistry,12a as well as present an alternative strategy that
employs a catalytic amount of zinc to combat catalyst deactiva-
tion via nucleophilic reagents.
We were interested to see if the benefit of zinc to keep the
thiolate away from the palladium until the transmetalation step
had the same effect on previous catalysts employed in the
palladium-catalyzed formation of carbon-sulfur bonds. There-
fore, we examined a result reported by Buchwald and co-
workers in 2004 (eq 1). Buchwald reported that the reaction of
4-bromoanisole and benzenethiol in the presence of a catalytic
amount of palladium acetate and the monodentate ligand,
JohnPhos (2-(di-tert-butylphosphino)biphenyl, failed to produce
the corresponding diaryl sulfide. Presumably, benzenethiolate
is deactivating the palladium catalyst via displacement of the
monodentate phosphine ligand. Indeed, the addition of 0.64
equiv of zinc chloride and 0.5 equiv of lithium iodide to the
catalyst generated from palladium acetate and JohnPhos afforded
the desired product in 72% yield. The addition of lithium iodide
(0.5 equiv) to the reaction mixture described in eq 1, in the
absence of zinc chloride, failed to provide any biaryl sulfide
product after 4 h.
Experimental Section
Typical Procedure. Under an inert atmosphere, THF (0.4 mL)
is added to a septum-capped vial containing NaOtBu (106 mg, 1.10
mmol) and a stir bar. Benzylthiol (118 µL, 1.00 mmol) is added
and the reaction mixture is stirred for 10 min. At this time, ZnCl2
(87 mg, 0.64 mmol) in THF (0.4 mL) is added and the reaction
mixture is stirred for 10 min. To this reaction mixture was added
1-bromonaphthalene (139 µL, 1.00 mmol) followed by [Pd(µ-
Br)(PtBu3)]2 (1) (7.7 mg, 0.0099 mmol) in THF (0.4 mL). The
reaction is stirred at 60 °C for 1 h. At this time, silica gel is added
to the reaction and the solvent is removed under vacuum. Purifica-
tion by column chromatography yields the sulfide (250 mg, 1.00
mmol, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3)
δ 4.15 (s, 2H), 7.19-7.27 (m, 5H), 7.32-7.36 (m, 1H), 7.47-7.56
(m, 3H), 7.73 (d, J ) 8 Hz, 1H), 7.84 (d, J ) 8 Hz, 1H), 8.42 (d,
J ) 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 39.5, 125.2, 125.7,
126.3, 126.6, 127.3, 128.6, 128.7, 129.1, 129.4, 133.2, 133.5, 134.0,
137.6; HRMS (ESI) calcd for C17H14S [M + Na]+ 273.0708, found
273.0712.
From the observations of the reactions presented, we believe
that zinc is moderating the reactivity of the thiolate anion to
ensure that the palladium catalyst is not deactivated. Below is
a summary of the findings in this study:
(1) Reactions with alkyl thiolates: The addition of an excess
of alkyl thiolate to 1 causes catalyst deactivation. The addition
of a zinc salt, such as zinc chloride, prevents catalyst deactiva-
tion, most likely due to the strong affinity that zinc has for
thiolate anion. Importantly, the thiolate complex is still allowed
to participate in the transmetalation step, and the addition of
lithium iodide is not needed in these reactions.
(2) Reactions with aryl thiolates: The addition of most aryl
thiolates to 1 does not appear to deactivate the catalyst.
However, the use of zinc in these reactions allows for cleaner,
higher yielding transformations. Furthermore, we observed that
some aryl bromides, such as 3-bromothiophene and 4-bro-
mobenzaldehyde, absolutely required the addition of zinc
chloride and lithium iodide. Lithium iodide was always neces-
sary when zinc chloride was used in reactions of arylthiolates.
Under these reaction conditions, lithium iodide may likely
undergo a halogen exchange reaction with the arylpalladium(II)
bromide that is generated from the oxidative addition of aryl
bromide to the unsaturated palladium(0) complex; however, this
newly formed arylpalladium(II) iodide complex might undergo
Acknowledgement. This work was generously supported by
Ohio State University. We also thank Johnson-Matthey for the
generous gift of [Pd(µ-Br)(PtBu3)]2.
Supporting Information Available: Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO900385D
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4008 J. Org. Chem. Vol. 74, No. 10, 2009