Highly efficient and functional-group-tolerant catalysts for the palladium-catalyzed coupling of aryl chlorides with thiols

Article abstract of DOI:10.1002/chem.200600949

The cross-coupling reaction of aryl chlorides with aliphatic and aromatic thiols catalyzed by palladium complexes of the strongly binding bisphosphine CyPF-tBu ligand (1) is reported. Most of the reactions catalyzed by complexes of ligand 1 occur with turnover numbers that exceed those of previous catalysts by two orders of magnitude. The reactions occur with excellent yields, broad scope and high tolerance of functional groups. Coupling of aryl halides with thiols in the presence of low loadings of catalysts derived from other Josiphos type ligands, as well as ligands of other structural types, are also described.

Full text of DOI:10.1002/chem.200600949

FULL PAPER
DOI: 10.1002/chem.200600949
7782
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Chem. Eur. J. 2006, 12, 7782 – 7796
Pagination corrected Oct. 17, 2006

FULL PAPER
Highly Efficient and Functional-Group-Tolerant Catalysts for the Palladium-
Catalyzed Coupling of Aryl Chlorides with Thiols
Manuel A. Fernµndez-Rodríguez, Qilong Shen, and John F. Hartwig*[a]
Abstract: The cross-coupling reaction
of aryl chlorideswith aliphatic and aro-
matic thiolscatalyzed by palladium
complexesof the tsrongly binding bi-s
ACHTREUNGphosphine CyPF-tBu ligand (1) isre-
ported. Most of the reactions catalyzed
turnover numbersthat exceed those of
previouscatalytsby two ordersof
magnitude. The reactionsoccur with
excellent yields, broad scope and high
tolerance of functional groups. Cou-
pling of aryl halideswith thiolsin the
presence of low loadings of catalysts
derived from other Josiphos type li-
gands, as well as ligands of other struc-
tural types, are also described.
Keywords: aryl chlorides
·
aryl
sulfides · cross-coupling · palladium
by complexesof ligand 1 occur with
Introduction
In 1978 and 1980 Migita and co-workersfirst reported the
coupling of iodo- and bromoareneswith thiolsin the pre-s
[21,22]
Aryl sulfides[1,2] are valuable intermediatesin organic ysn-
thesis of biologically and pharmaceutically active molecules,
of organic materials, or intermediates to these molecules. A
number of aryl sulfides have shown potential clinical appli-
cations. These applications include the treatment of inflam-
mation by acting asantagonitssof the interaction between
leukocyte function-associated antigen-1 and both intracellu-
lar adhesion molecule-1 (LFA-1/ICAM-1)[3,4] and vascular
cell adhesion molecule-1 (VCAM-1).[5] The applicationsof
aryl sulfides also include treatment of Alzheimerꢁs and Par-
kinsonꢁs diseases by acting as muscarinic[6] or nicotinic[7] re-
ceptor antagonists, treatment of asthma and obstructive pul-
monary disease by acting as a 5-lipoxygenase inhibitor,[8]
treatment of human immunodeficiency virus(HIV) by in-
hibiting HIV-1 protease[9] and treatment of cancer astubulin
polymerization inhibitors.[10,11] Palladium-catalyzed cross-
ence of [Pd
A
In the last decade, more
efficient catalyst systems containing bidentate phosphines or
dialkylphosphine oxides ligands have been described for this
reaction.[23–29] Nevertheless, these protocols display three
major drawbacksthat reduce their ability to form sulfidesin
a practical fashion. First, the published catalysts have short
lifetimes; low turnover numbers (TON ꢁ 50) are typically
achieved. Second, the coupling of thiolswith aryl chlorides
isundeveloped, and aryl chloridesare the most useful of the
haloarenesbecaues of their wider availability and lower
cost.[30] Third, the previouscouplingsto form uslfideshave
occurred with narrow scope. The demonstrated tolerance of
the reactionsto potentially reactive functional groupshas
been limited to haloarenescontaining nitrilesand
esters.[23–27]
Nickel- and copper-catalyzed coupling of thiolswith aryl
[31,32]
ꢀ
coupling reactionsthat form carbon heteroatom bonds
halideshasalso been reported.
However, these process-
have recently emerged asan extremely powerful ysnthetic
organic method.[12–19] In particular, the synthesis of aromatic
aminesand ethersfrom aryl halidesor pesudohalideshas
been extensively studied and developed into practical meth-
odology. In contrast, the analogous synthesis of aryl sulfides
esrequire either high temperaturesor high catalyst loadings.
Further, these reactions have typically been conducted with
aryl iodides.[33,34]
Palladium thiolatesform eaisly and undergo relatively
fast reductive eliminations with aryl groups.[35–37] Thus, the
current limitationson the aromatic thiation could reuslt
from the notorious sensitivity of late metal catalysts to sub-
strates containing reactive sulfur functionality. The lifetime
and concentrationsof the catalystsused for the coupling of
haloareneswith thiolsislikely to be limited by factorssuch
asdisplacement of dative ligandsby thiolatesto form anion-
ic thiolate complexes I or the formation of bridging thiolate
complexes II that undergo slow reductive elimination
[20]
hasreceived lesattention.
[a] Dr. M. A. Fernµndez-Rodríguez, Q. Shen, Prof. Dr. J. F. Hartwig
Department of Chemistry, Yale University
P.O. Box 208107, New Haven, CT 06520-8107 (USA)
Fax : (+1)203-432-6144
E-mail: john.hartwig@yale.edu
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J. F. Hartwig et al.
(Figure 1).[36] Therefore, a more reactive catalyst for the cou-
pling of thiolates might contain a bisphosphine that binds
the metal strongly enough to prevent formation of anionic
or bridging thiolate complexes I and II, while simultaneous-
ly promoting oxidative addition and reductive elimination.
Results and Discussion
Establishment of reaction conditions: We initially selected
the coupling of electron-rich 4-chloroanisole with 1-octane-
thiol as model system to assess the catalyst activity and to
determine the optimum reaction conditions. The experi-
mentswere conducted uinsg equimolecular amountsof
0.1 mol% PdCATHRE(UNG OAc)2 and CyPF-tBu ligand 1 and several
bases (1.1 equiv), solvents and reaction temperatures
(Table 1). Reactionscontaining different baesswere con-
ducted at 1008C in DME (1,2-dimethoxyethane),[40] and the
formation of aryl sulfide was measured by GC after 18 h.
Reactionsconducted with NaO tBu, KOtBu and NaHMDS
(NaNACHTREU(GN SiMe3)2) occurred with moderate to good conversions
(Table 1, entries1–3), while reactions with weaker carbo-
nate, phosphate and amine bases (not listed in Table 1) oc-
curred to <5% conversion and formed large amounts of di-
octyldisulfide.
Reactionsat 110 8C occurred to higher conversions. Reac-
tionsat thistemperature conducted with NaO tBu asbaes
occurred to full conversion in less than 4 h and with an ex-
cellent yield of sulfide (Table 1, entry 4). In contrast, reac-
tionsconducted with KO tBu base proceeded to 94% con-
version and 87% isolated yield after 18 h (Table 1, entry 5).
Reactionsconducted with NaO tBu in 1,4-dioxane occurred
in high yield after similar times as the reactions with
NaOtBu in DME (Table 1,
ꢀ
Figure 1. General mechanism for the palladium-catalyzed C S bond-
forming reactions.
Based on this hypothesis, we considered that the restrict-
ed backbone conformation, steric hindrance, and strong
electron donation of the Josiphos ligand CyPF-tBu (1-di-
cyclohexylphosphino-2-di-tert-butylphosphinoethylferroceno,
1, in Table 1)[38] could create practical catalysts for the cou-
Table 1. Optimization of palladium-catalyzed coupling reaction of 4-chloroanisole with 1-octanethiol using
entry 6), while reactionsin
other solvents, such as toluene,
DMF or DMSO, formed only
traces of the desired aryl sul-
fide.
CyPF-tBu ligand (1).[a]
Further studies were also
conducted to fine-tune the cata-
lyst loading and palladium pre-
cursor. These studies revealed
that a decrease in the catalyst
loading to 0.05% resulted in in-
complete conversion of this
electron-rich chloroarene, even
at extended reaction times
(Table 1, entry 7). However, re-
actionsof electron-neutral and
electron-poor chloroarenesde-
scribed later in this paper do
Entry
Base
Solvent
T [8C][b]
t [h]
Conversion [%] (yield)[c]
1
2
3
4
5
6
NaOtBu
KOtBu
NaHMDS
NaOtBu
KOtBu
NaOtBu
NaOtBu
NaOtBu
DME
DME
DME
DME
DME
1,4-dioxane
DME
100
100
100
110
110
110
110
110
18
18
18
<4
18
5
84
80
57
100 (98)
94 (87)
100 (94)
93 (85)
100 (96)
7[d]
8[e]
48
7
DME
[a] All the experimentswere conducted with a 1:1 ratio of metal to ligand, 1 mmol of both 4-chloroanisole and
1-octanethiol, and 1.1 equiv base in 1.5 mL solvent. [b] Bath temperature. [c] Determined by GC analysis. Iso-
lated yieldsare indicated in parentheses. [d] 0.05% catalyst loading employed. [e] [Pd
precursor.
ACHTRE(UNG dba)2] used as palladium
pling of thiolswith aryl halide.s In work previously commu-
occur with lower loadings. These studies also showed that
the catalyst system derived from [Pd(dba)2] and the one de-
rived from Pd(OAc)2 are similar, but that the one derived
from [Pd(dba)2] reacts slightly slower (Table 1, entry 8).
nicated, we have shown that complexes generated from this
ligand couple a broad range of thiolswith aryl halidesand
pseudohalides and that reactions conducted with the Josi-
phosligand occur with turnover numbersand tolerance of
functional groups that far surpass those of previous cata-
lysts.[39] Herein, we report a thorough study of the scope and
limitationsin the coupling of aryl chlorideswith thiolsusing
this catalyst system. In addition, we report an evaluation of
other common ligands, as well as a preformed catalyst pre-
cursor [(CyPF-tBu)PdCl2], under conditionsof low catalyts
loading.
ACHTREUNG
AHCTREUNG
AHCTREUNG
Ligand influence on the thiation of aryl chlorides at low cat-
alyst loadings: After having established conditions for the
coupling of chloroareneswith alkyl thiolsuisng the combi-
nation of PdACTHRE(UNG OAc)2 and CyPF-tBu as catalyst, we surveyed
palladium complexes of a series of ligands for these reac-
tions at low catalyst loadings. The structures of these ligands
and a summary of the results of this study are shown in
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Cross-Coupling
FULL PAPER
Figure 2. Each reaction wasconducted at 110 8C for 24 h
with 0.1 mol% of ligand and PdACTHRE(UNG OAc)2, and conversions to
the desired sulfide were measured by GC.
Reactionswere conducted with esveral membersof the
Josiphos family of ligands (1–6) aswell asbidentate pho-s
fashion to the reactions of 1-octanethiol. Also similar to the
reactionsof the alkane thiol, reactionsof thiophenol cata-
lyzed by complexes of the other bisphosphines, including
DPEphos, Xantphos and DiPPF, occurred in low yield.
Thus, CyPF-tBu (1) clearly generated the most active cata-
lyst for the coupling of thiophenol.
Under the standard conditions developed, however, 4-me-
thoxyphenyl phenyl sulfide A wasformed with isgnificant
amounts of undesired symmetrical sulfides
B and C
(Scheme 1). Formation of these by-products was first de-
Scheme 1. By-productsformed from the coupling of 4-chloroanisole with
thiophenol.
ꢀ
scribed for a nickel-catalyzed C S bond-forming reaction,
and a tentative mechanism for the aryl–aryl scrambling was
proposed.[41] The amount of symmetrical sulfides formed
from reactionsof electron-deficient aryl halidesand/or elec-
tron donating aromatic thiolsislower than the amount of
these side products formed from reactions of electron-rich
or electron-neutral aryl halides. For example, large amounts
of these symmetrical byproducts were observed from the
coupling of unactivated chloroareneswith an electron-rich
aromatic thiol in the presence of the combination of Pd-
AHCTRE(UNG OAc)2 and DiPPF as catalyst. The formation of these by-
[25]
products was suppressed by the use of NEt3 assolvent.
To prevent the formation of the symmetrical diaryl sul-
fides we determined the effect of base, solvent, and catalyst
loading for the reaction of 4-chloroanisole with thiophenol.
These results are summarized in Table 2. A significant de-
pendence of the amount of side product on the nature of
the base and its counterion was observed. The quantity of
symmetrical sulfides was only 2% when the reaction was
conducted with KOtBu asbase, rather than 9% when it was
conducted with NaOtBu (Table 2, entries1 and 2); signifi-
cant amountsof B and C were formed from reactionscon-
ducted with NaHMDS and LiHMDS asbaes (Table 2, en-
tries3–4). Reactions conducted with other bases such as
NaOH, carbonatesand aminesgave low converisonsto
products.
The solvent also affected the amount of the side products
B and C. Reactionsin 1,4-dioxane and toluene formed
lower amountsof B and C. Even with NaOtBu asbase, only
4% of these materials were formed in these two solvents.
Ultimately, the highest isolated yield and selectivity were
achieved when the reactionswere conducted in toluene in
the presence of KOtBu asbase (Table 2, entries5–8). Reac-
tionsin toluene with KO tBu as base in the presence of only
0.1 mol% catalyst afforded the coupled product after 6 h at
1108C in high yields with less than 1% of the side products
(Table 2, entry 9).
Figure 2. Effect of ligand on the coupling of aryl chlorideswith thiolsat
0.1 mol% catalyst loading. Reaction conditions: 4-chloroanisole
(1 mmol), RSH (1 mmol), PdACHTRE(UNG OAc)2/ligand (0.1 mol%), NaOtBu
(1.1 mmol) in DME (1.5 mL) at 1108C for 24 h.
phines 7–12 that were previously reported for couplings of
aryl halideswith thiol.s Among the Joisphosfamily of li-
gands, CyPF-tBu (1) clearly generated the most active cata-
lyst, affording full conversion to the aryl sulfide in less than
4 h. Reactions catalyzed by complexes of Josiphos-type li-
gands 2 and 5, which are less rigid and less electron donating
than 1, occurred to moderate conversions (ca. 50%), even
after 24 h. Reactions conducted with the less sterically de-
manding analogues 3, 4 and 6 formed moderate to small
amounts of the desired sulfide. Catalysts based on BINAP,
tol-BINAP or DPPF were completely ineffective for this
coupling. Catalysts based on DPEphos, Xantphos and even
DiPPF, which were reported to promote thiationsof unacti-
vated chloroarenesunder ismilar reaction conditionsbut
with higher catalyst loading,[25] afforded conversions of less
than 30% when used in 0.1 mol% quantities.
A parallel study of the coupling of 4-chloroanisole with
thiophenol wasconducted. The reactionsof thiophenol con-
ducted with the Josiphos ligands 1–6 occurred in a similar
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7785

J. F. Hartwig et al.
Table 2. Optimization of palladium-catalyzed coupling reaction of 4-chloroanisole with thiophenol using
decrease the catalyst loading of
reactionsconducted with the
Josiphos ligand by increasing
the temperature to 1408C in a
sealed reaction vessel or by
changing the solvent to diethy-
lene glycol diethyl ether (b.p.
1888C) led to incomplete con-
versions and formation of disul-
fide side product.
Sterically demanding ortho-
substituted chloroarenes cou-
pled in high yield using catalyst
loadingsup to 0.5 mol%
(Table 3, entries13 and 18–21).
CyPF-tBu ligand (1).[a]
Entry
Base
Solvent
Pd source
Loading [%]
t [h]
A:B:C [%][b]
1
2
3
4
5
6
7
8
NaOtBu
KOtBu
NaHMDS
LiHMDS
NaOtBu
KOtBu
NaOtBu
KOtBu
KOtBu
DME
DME
DME
DME
1,4-dioxane
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
C
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.5
0.1
12
12
12
12
12
12
12
12
6
91:4:5
98 (93):1:1
71:15:14
56:24:20
96:2:2
97 (87):2:1
98 (93):1:1
>98 (97):1:<1
>98 (95):<1:<1
>99.5 (98):<0.5:–
>99.5 (98):<0.5:–
9
10
11
KOtBu
KOtBu
[Pd
[Pd
A
12
<4
ACHTREUNG
Even
a
di-ortho-substituted
[a] All the experimentswere conducted with a 1:1 ratio of metal to ligand, 1 mmol of both 4-chloroanisole and
thiophenol, and 1.1 equiv base at 1108C in 1.5 mL solvent. [b] Distribution of sulfides determined by GC. Iso-
lated yield of desired sulfide A is indicated in parentheses.
chloroarene reacted with a hin-
dered tertiary thiol, although a
higher catalyst loading and long
reaction time were necessary to
The palladium source also affected the amount of side
product. Reactionsconducted with [Pd (dba)2] and Josiphos
ligand 1 ascatalyts generated only traces( <0.5%) of by-
product (Table 2, entry 10). Reactionsconducted with only
0.1 mol% [PdACHTREUNG(dba)2] and Josiphos ligand 1 occurred in high
achieve good yield and conversion in this case (Table 3,
entry 22). Reactionscould alos be conducted at lower tem-
peratures(70 8C) by simply increasing the amount of cata-
lyst to 2.0 mol% and increasing reaction times to 24 h
(Table 3, entries8, 11 and 17).
AHCTREUNG
yield in less than 4 h to form the desired diaryl sulfide in es-
sentially quantitative yield (Table 2, entry 11).
Thus, our studies on reaction conditions showed that the
Although a majority of the reactions was assembled in a
drybox, identical catalyst activity was observed for reactions
performed under inert atmosphere using common Schlenk
techniques (Table 3, compare entries 3 and 5). Using these
techniques, the coupling reaction was conducted with
5 mmol of chlorobenzene without a decrease in yield or cat-
alyst efficiency (Table 3, entry 6).
Studieson the csope of the coupling of arene thiolsare
summarized in Table 4. Again, very high yields in short reac-
tion timeswere obtained using one or two ordersof magni-
tude less catalyst loading than was needed for analogous
couplings with prior systems. In contrast to prior reactions
that occurred in high yieldswith the combination of unacti-
vated chloroarenesand electron-rich arenethiolsor elec-
tron-deficient chloroareneswith electron-neutral aromatic
thiols,[25] the current system coupled either electron-rich,
electron-neutral or electron-deficient chloroareneswith
electron-rich or electron-neutral aromatic thiols.
Unhindered chloroarenesreacted with aromatic thiols
without formation of side products in the presence of 0.05–
0.5 mol% catalyst (Table 4, entries 1–3, 5–12). No significant
increase in the loading was necessary for the coupling of
sterically demanding aromatic thiols, even when electron-
rich aryl chlorideswere used (Table 4, entries13–14). Reac-
tionsconducted at lower temperature (70 8C) occurred to
high conversion and in good yield after 48 h in the presence
of 3.0 mol% catalyst (Table 4, entry 4).
Reactionsof ortho-substituted chloroarenes also occurred,
but some of these couplings were accompanied by formation
of symmetrical diaryl sulfide side products. The reactions of
electron-rich thiolswith ortho-substituted chloroarenes and
the reaction of 2-chloroanisole with thiophenol occurred in
combination of Pd
most effective for the coupling of aryl chlorides with aliphat-
ic thiolsand that the combination of [Pd (dba)2]/CyPF-tBu/
ACHTREU(NG OAc)2/CyPF-tBu/NaOtBu/DME was
AHCTREUNG
KOtBu/toluene wasmost effective for reactionsof aromatic
thiols. Reactions under the standard conditions, but without
catalyst, formed mostly disulfides. Less than 5% of the aryl
sulfide was formed.
Scope of the reaction—Coupling of unactivated aryl chlor-
ides: Reactionsof a esriesof aryl chlorideswith aliphatic
and aromatic thiolswere conducted under the optimized re-
action conditionswith the combination of palladium and Jo-
siphos ligand 1 as catalyst; the results are given in Tables 3
and 4.
Reactionsof aliphatic thiolswith chloroarenesare usm-
marized in Table 3. These data show that primary, secon-
dary, and tertiary aliphatic thiolsreacted to form the corre-
sponding sulfides in excellent yields within short reaction
times. Reactions were conducted with catalyst loadings in
the range of 0.01 to 0.1 mol%. These loadings are one or
two orders of magnitude lower than those in previous stud-
iesof thisreaction (Table 3, entries1–7, 9–10, 12–16). For in-
stance, the coupling of chlorobenzene with 1-octanethiol oc-
curred in 85% yield with only 100 ppm of catalyst, corre-
sponding to a turnover number of 8500 (Table 3, entry 4).
Thisvalue ismore than two ordersof magnitude higher
than that for the analogouscoupling of an unactivated chloro-
arene with a primary thiol catalyzed by the combination of
PdACHTREUNG
(OAc)2 and DiPPF (48 turnovers).[25] Further attemptsto
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Cross-Coupling
FULL PAPER
Table 3. Palladium-catalyzed coupling of aryl chlorideswith alkyl thiols
Table 4. Palladium-catalyzed coupling of aryl chlorideswith aryl thiols
using CyPF-tBu ligand.[a]
using CyPF-tBu ligand.[a]
Yield [%][b]
98
Product
Entry
1
Cat. [mol%]
0.1
Yield [%][b]
98
Product
Entry
1
Cat. [mol%]
0.1
2
3
4
0.1
91
91
85
92
93
2
0.1
95
0.05
0.01
0.05
0.05
3
0.1
3.0
95
83
5[c]
6[c,d]
4[c]
5
6
0.1
0.05
98
86
7
0.05
2.0
97
97
8[e]
7
0.1
95
93
98
99
9
0.05
95
8[d]
9[d]
10
0.1
10
0.05
2.0
91
89
11[e]
0.25
0.25
12
13
0.1
82
92
0.05
11
12
0.25
0.5
97
89
14
15
0.05
0.05
96
98
16
0.05
2.0
97
91
13
0.25
94
17[e]
18
19
20
0.25
0.25
0.25
90
95
97
14
0.25
97
15[e]
16[f]
0.1
3.0
84
95
21
22
0.5
3.0
89
17
1.0
92
77[f]
18
1.0
0.5
97
70
19[g]
[a] All experimentswere conducted with a 1:1 ratio of metal to ligand,
1 mmol of both chloroarene and alkyl thiol, and NaOtBu (1.1 equiv) in
DME (1.5 mL) for 2–24 h at 1108C. [b] Isolated yield of an average of
two runs. [c] Reactions performed without using a drybox. [d] 5 mmol
scale. [e] Reaction performed at 708C. [f] 82% conversion after 36 h.
20[g]
21
0.25
3.0
70
–
high yieldswithout formation of side products(Table 4, en-
tries17–18). The reaction of 1-chloronaphthalene with thio-
phenol in the presence of only 0.1 mol% catalyst formed
the coupled product in good yield, but 10% of the undesired
symmetrical sulfides also formed. This side product was
eliminated by conducting the reaction at the lower tempera-
ture of 908C (3 mol% catalyst). The reactions of 2-chloroto-
luene with thiophenol and with 2-isopropylbenzenthiol did
[a] All experimentswere conducted with a 1:1 ratio of metal to ligand,
1 mmol of both chloroarene and aryl thiol, and KOtBu (1.1 equiv) in tol-
uene (1.5 mL), requiring 2–24 h of heating at 1108C to complete. [b] Iso-
lated yield of an average of two runs. [c] Reaction conducted at 708C
and stopped after 48 h at 90% conversion. [d] 1.1 equiv LiHMDS were
used as base. [e] ~10% symmetrical sulfides were observed. [f] Reaction
conducted at 908C. [g] ~20% symmetrical sulfides were observed.
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J. F. Hartwig et al.
Table 5. Palladium-catalyzed coupling of functionalized aryl chlorides
not occur at the lower temperature, and reactionsat 110 8C
in the presence of 0.25–0.5 mol% catalyst formed the cou-
pled productsin 70% yield with about 20% of side products
(Table 4, entries19–20). Further, the reaction of 2,6-dimeth-
yl chlorobenzene with thiophenol did not occur (Table 4,
entry 21).
with aliphatic thiolsusing CyPF- tBu ligand.[a]
Entry
Cat. [mol%]
Yield [%][b]
Product
1[c]
2[c]
0.05
0.01
90
79
Coupling of functionalized aryl chlorides: The efficiency of
the present catalyst system prompted us to evaluate the tol-
erance of this process to the presence of functional groups
that might be expected to poison the catalyst or to react
with thiolate nucleophiles. The coupling of a wide range of
functionalized aryl chlorideswith aliphatic thiolsissummar-
ized in Table 5. Chloroarenesbearing a nitrile, ketone, car-
boxylic acid, amide, protected or free amino groups, and ar-
omatic or aliphatic hydroxyl groupscoupled under the
standard conditions to form the corresponding aryl sulfide
in good to excellent yields(Table 5, entries1–8 and 12–18).
The catalyst loading for some of these reactions are ex-
tremely low, and even reactionsof electron-rich and hin-
dered substrates occurred with loadings at or below
2.0 mol%.
Reactionsof aryl chlorideswith etser or aldehyde func-
tionalitiesthat occur in modets yield or are incompatible
with nucleophilic alkoxide bases occurred in high yield in
the presence of the weaker Cs2CO3 base (Table 5, entries 10,
11). However, couplings of chloroarenes possessing enoliza-
ble keto functionality were unsuccessful, even with weaker
bases (not included in Table 5). Although both the rate and
the yield of the formation of sulfides from chloroarenes con-
taining electron-withdrawing groupsin the para- and ortho-
positions were higher in the presence of our catalyst system
than in the absence of catalyst, uncatalyzed processes did
occur in good yieldsand conversionsafter longer times(24–
48 h vs <4 h with the palladium catalyst) at 1108C (Table 5,
entries21, 23, 25 vs 22, 24, 26) with the electron-poor
chloroarenes.
3[c]
0.05
0.1
86
76
4
5
6
0.05
0.01
67
71
7
8
0.05
0.01
98
91
9[d]
0.1
0.5
56
72
10[e]
11[e]
12
0.25
0.25
91
99
13[c]
14
0.25
1.0
96
91
15
16
0.5
2.0
85
97
17[d]
18[e]
0.5
0.5
93
67
The reaction of 1-chloro-2-fluorobenzene with 1-octane-
thiol gave a mixture of the expected aryl sulfide product
and a small amount (8%) of ortho-chlorophenyl sulfide
19
20
0.1
78[f]
98[g]
ꢀ
from reaction at the C F bond (Table 5, entry 19). Never-
0.25
theless, the analogous reaction with a secondary thiol in the
presence of 0.25 mol% of catalyst afforded the expected
ortho-fluorophenyl sulfide with only traces of product from
21[c]
0.01
-
93
86
22[c,h]
ꢀ
thiation of both carbon halogen bonds(Table 5, entry 20).
We envisioned that the minor side product could be formed
by an uncatalyzed nucleophilic substitution at the activated
ꢀ
23[c]
0.01
–
90
79 (91)
24[c,h]
25[c]
0.25
–
80
77
C F bond. Indeed, reaction of 1-chloro-2-fluorobenzene
with 1-octanethiol in the absence of catalyst afforded 75%
conversion to the product from substitution at the fluoride,
26[c,h]
[a] All experimentswere conducted with a 1:1 ratio of metal to ligand,
1 mmol of both chloroarene and alkyl thiol, and 2.4 equiv NaOtBu,
unless otherwise stated, in DME (1.5 mL), requiring 2–6 h of heating at
1108C to complete. [b] Isolated yield of an average of two runs. Conver-
sions in incomplete reactions indicated in parentheses. [c] 1.1 equiv
NaOtBu were employed. [d] 1.02 equiv NaOtBu were used. [e] Reaction
performed using 1.1 equiv CsCO3 as base. [f] Estimated by 1H NMR
(400 MHz) of a mixture with the related aryl sulfide from the reaction at
ꢀ
and the C Cl bond remained intact, asshown in Scheme 2.
In contrast to these results with electron-poor aryl fluorides,
ꢀ
no C S bond formation wasdetected from reaction of unac-
tivated aryl fluorides, such as 1-fluoro-4-methylbenzene, in
the presence of catalyst (Scheme 2).
The scope of reactions of functionalized aryl chlorides
with aromatic thiols is summarized in Table 6. In contrast to
ꢀ
C F bond (8% yield). [g] Tracesof dithiolation product were obesrved.
[h] Uncatalyzed reaction.
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Chem. Eur. J. 2006, 12, 7782 – 7796

Cross-Coupling
FULL PAPER
Table 6. Palladium-catalyzed coupling of functionalized aryl chlorides
with aryl thiolsusing CyPF- tBu ligand.[a]
Entry
1[c]
Cat. [mol%]
0.1
Yield [%][b]
93
Product
Scheme 2. Nucleophilic aromatic substitution of activated fluoroarenes.
2[c]
0.1
95
74
70
80
the couplings of less functionalized chloroarenes, no sym-
metrical sulfides were detected from reaction of the chlor-
oarenesin Table 6 under the tsandard conditionsinvolving
3
0.25
0.25
0.25
PdACHTREUNG(OAc)2 and ligand 1 ascatalyts, NaO tBu asbaes and
4
DME asoslvent. Like the reactionsof aliphatic thiol,s the
coupling reactionsfollowing thisprotocol were tolerant of
nitrile, ketone, carboxylic acid, amide, protected and free
amino groups, and aromatic hydroxyl groups (Table 6, en-
tries1–4 and 6–8). These reactions occurred in good to ex-
cellent yield with 0.10 to 2.0 mol% catalyst. Even 1-chloro-
2-fluorobenzene coupled with thiophenol in excellent yield
5[d,e]
6
7
0.25
0.25
99
91
ꢀ
without a competitive background reaction at the C F
bond. However, both the uncatalyzed and catalyzed reac-
tions of 2-chlorobenzonitrile furnished the corresponding
sulfide in good yield (Table 6, entries 10–11).
8
2.0
91
For reasons we do not understand, the coupling of aro-
matic thiolsconducted with the weaker carbonate base were
unsuccessful. As a result, the coupling of aromatic thiols did
not occur in the presence of aldehyde groups, and reactions
with methyl 3-chlorobenzoate formed 80% of the desired
sulfide with 10–15% of the product from transesterification
(Table 6, entry 5).
9[d]
1.0
0.25
–
96
99
87
10[c]
11[c,f]
[a] All experimentswere conducted with a 1:1 ratio of metal to ligand,
1 mmol of both ArCl and thiol, and 2.4 equiv NaOtBu, unless otherwise
stated, in DME (1.5 mL), requiring 2–5 h of heating at 1108C to com-
plete. [b] Isolated yield. [c] 1.1 equiv NaOtBu were employed. [d] Re-
action performed using 1.1 equiv KOtBu and toluene asoslvent. [e] 10–
15% transesterification compound were also isolated. [f] No catalyzed re-
action.
ACHTREUNG[CyPF-tBu)PdCl2] as catalyst precursor: These data re-
vealed that an equimolecular combination of metal to ligand
isadequate to promote the coupling of chloroareneswith
both aliphatic and aromatic thiols. Thus, a palladium com-
plex containing a single CyPF-tBu ligand would be an alter-
ꢀ
native catalyst precursor for the C S bond-forming reac-
tions. The use of such a compound would alleviate the need
to generate the metal–ligand complex in situ. As expected,
[(CyPF-tBu)PdCl2]
formsin
high
yield
from
[(CH3CN)2PdCl2] and Josiphos ligand 1 (Scheme 3). Studies
yields, reaction times and catalyst loadings for the coupling
of aliphatic thiolscatalyzed by [(CyPF- tBu)PdCl2] were
comparable to those catalyzed by the combination of Pd-
AHCTRE(UNG OAc)2 and ligand 1 (Table 7, entries1–3, 5–6 vsTable 3, en-
tries1, 3, 14, 16, 21). The reaction of aromatic thiols cata-
lyzed by [(CyPF-tBu)PdCl2] wasalos efficient (Table 7, en-
tries7–12). Only one example in this set of reactions re-
quired a slight increase in the catalyst loading (0.25 mol%
for Table 7, entry 7 vs0.10 mol% for Table 4, entry 7). Re-
actionscatalyzed by [(CyPF- tBu)PdCl2] also occurred with
remarkable functional group tolerance. For instance, reac-
tionsof aryl chloridesbearing nitrile, ketone, amide and
free amino and aromatic hydroxyl groupsoccurred in high
yields under conditions similar to those of the couplings cat-
Scheme 3. Synthesis of [(CyPF-tBu)PdCl2].
on reactionscatalyzed by thiscomplex are presented in this
section. We studied reactions of this compound because it is
more stable over the long-term than the complex formed
from ligand 1 and PdACHTRE(UNG OAc)2.
Representative experiments were performed with the new
PdII complex using the combination of solvent and base de-
veloped for the different thiols. As shown in Table 7, the
alyzed by PdACTHRE(UNG OAc)2 and ligand 1 (Table 7, entries13–17).
Chem. Eur. J. 2006, 12, 7782 – 7796
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7789

J. F. Hartwig et al.
Conclusion
highly efficient catalysts for the coupling of chloroarenes
with thiols. Reactions catalyzed by the complexes generated
In summary, we have shown that palladium complexes gen-
in situ from PdACTHEURNG(OAc)2 or [PdACHTRE(UNG dba)2] and ligand 1 and reac-
erated from the Josiphos ligand CyPF-tBu are general,
tionscatalyzed by [(CyPF- tBu)PdCl2] occur with turnover
numbersthat are typically two ordersof magnitude higher
than those of related couplings by previous catalysts. The
ability to conduct reactions with low catalyst loadings illus-
tratesthat the CyPF- tBu ligand resists deactivation process-
esthat could occur by dipslacement of dative ligandswith
thiolates. The process exhibits a broad scope and a high tol-
erance for functionality, such as fluoro, cyano, keto, free car-
boxylate, amido, carboalkoxy, carboxaldehyde, aromatic and
aliphatic hydroxyl and amino functionalities. Only reactions
of hindered aryl chlorideswith aromatic thiolsand reactions
of aromatic thiolswith chloroarenescontaining carboxalde-
hyde functionality proceed to partial conversion or form sig-
nificant amountsof side products. Related thiationsof more
reactive bromo- and iodoarenes, which overcome these few
limitationsof the reactionsof chloroarene,s aswell asstud-
ies of the mechanism of the coupling process are in prog-
ress.
Table 7. Palladium-catalyzed coupling of aryl chlorideswith thiolsuisng
[(CyPF-tBu)PdCl2] complex.[a]
Entry
1
Cat. [mol%]
0.1
Yield [%][b]
97
Product
2
3
0.05
0.05
97
94
4
0.05
98
5
6
0.05
0.5
93
96
Experimental Section
General considerations: All reactions were assembled under an inert at-
mosphere. Reactions were conducted in 4 mL vials sealed with a cap con-
taining a PTFE septum. All glassware was oven-dried, evacuated and
purged with nitrogen immediately prior to use. All reaction temperatures
7
0.25
0.25
0.5
88
97
90
8[c]
refer to bath temperature.s All common reagentsaswell asPd
ACHTREUNG(OAc)2
and bisphosphine ligands 7–12 were obtained from commercial suppliers
and used without further purification. CyPF-tBu (1-dicyclohexylphosphi-
no-2-di-tert-butylphosphinoethylferroceno) as well as the other commer-
cial available Josiphos-type ligands 3–6 were obtained from SolviasAG
9
and Strem Chemicalsand used without purification. [Pd ACHTRE(UNG dba)2] waspre-
10
11
0.25
0.1
94
98
pared according to literature procedures.[42] Toluene was degassed by
purging with nitrogen for 45 min and dried with a solvent purification
system containing a 1 m column of activated alumina. 1,2-Dimethoxy-
ethane (DME, 99.9% purity, HPLC grade) wasused without further pu-
rification, but was stored under nitrogen. Other solvents were dried by
standard methods. Reactions performed at 1108C in DME (b.p. 858C)
were conducted using the standard vials and caps cited above; no loss of
12[d]
13
0.5
77
91
1
solvent was observed. H, 13C and 31P{1H} NMR spectra were recorded in
CDCl3 on 400 MHz or 500 MHz spectrometers with tetramethylsilane or
0.05
residual protiated solvent used as
a reference. Abbreviations for
1H NMR splitting patterns are: s, singlet; brs, broad singlet; d, doublet; t,
triplet; q, quartet; quint, quintet; sext, sextet; sept, septet; oct, octet; dd,
doublet of doublets; dt, doublet of triplets; td, triplet of doublets; tt, trip-
let of triplets; m, multiplet. The coupling constants are reported in Hertz
(Hz). Flash column chromatography was carried out on silica gel (230–
240 mesh). The yields of the coupled products included in all tables refer
to isolated yields and are the average of two runs. Products that had
been reported previously were isolated in greater than 95% purity, as de-
termined by 1H NMR spectroscopy and capillary gas chromatography
(GC). GC analyses were obtained with a DB-1301 narrow bore column
suitable for use with a fast temperature ramp (max 1208Cminꢀ1). Ele-
mental Analyses were performed by Atlantic Microlab, Inc., Norcross,
Georgia 30071.
14
0.1
0.5
0.5
80
66
92
15[e]
16[e]
17[e]
0.5
96
[a] Experimentswere conducted with 1 mmol of both ArCl and thiol,
and 1.1 equiv NaOtBu at 1108C in DME (1.5 mL). Reactionswith un-
functionalized chloroareneswere carried out in toluene (1.5 mL) in the
presence of 1.1 equiv KOtBu. [b] Isolated yield. [c] Reaction performed
using 1.1 equiv LiHMDS. [d] 18% symmetrical sulfides were also ob-
served. [e] 2.4 equiv NaOtBu were employed.
Synthesis of Josiphos type ligand 2 (1-dicyclohexylphosphino-2-di-tert-bu-
tylphosphinomethylferroceno): This bisphosphine was prepared accord-
[43]
ing to literature proceduresfor related ferrocenyl ligands.
Yellow solid
(95% yield); 1H NMR (CD2Cl2): d=4.67 (brs, 1H), 4.16 (m, 1H), 4.10 (s,
5H), 4.09–4.05 (m, 1H), 2.70 (m, 2H), 2.28–2.22 (m, 1H), 2.14–2.05 (m,
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Cross-Coupling
FULL PAPER
2H), 1.87–1.60 (m, 13H), 1.47–1.36 (m, 4H), 1.27–1.01 (m, 2H), 1.21 (d,
J=10.8 Hz, 9H), 1.07 (d, J=10.8 Hz, 9H); 31P{1H} NMR (CD2Cl2): d=
26.0 (s), 11.8 (s); elemental analysis calcd (%) for C31H50P2Fe: C 68.88, H
9.32; found: C 68.85, H 9.47.
(m, 8H), 0.74 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3): d=135.7, 133.1,
129.7 (2C), 129.5 (2C), 34.3, 31.7, 29.2, 29.10, 29.06, 28.7, 22.6, 20.9, 14.0.
4-Methylphenyl octyl sulfide (Table 3, entry 8): A solution of PdACHTREUNG(OAc)2
(4.4 mg) and CyPF-tBu (11 mg) in DME (1 mL) was used as catalyst; the
reaction wasconducted at 70 8C; 97% yield.
Preparation of stock solution A (1.0”10ꢀ2 m): DME (1.0 mL) wasadded
2-Methylbutyl phenyl sulfide (Table 3, entry 9):[45] 50 mL of stock solution
A were used; column chromatography: hexane; colorless liquid (95%
to a mixture of PdACHTREUNG(OAc)2 (2.2 mg) and CyPF-tBu (5.5 mg). The resulting
orange solution was stirred at room temperature for 1 min prior to subse-
quent reactions.
1
yield). H NMR (CDCl3): d=7.25–7.22 (m, 2H), 7.20–7.15 (m, 2H), 7.08–
General procedure for the palladium-catalyzed coupling of aryl chlorides
with aliphatic thiols: The appropriate quantity of stock solution A was
added to a 4 mL vial containing the aryl chloride (1.00 mmol) and
sodium tert-butoxide (106 mg, 1.10 mmol) in DME (1.5 mL). The aliphat-
ic thiol (1.00 mmol) wasthen added, and the vial sealed with a cap con-
taining a PTFE septum. The mixture was heated at 1108C until the
7.04 (m, 1H), 2.86 (dd, J=6.0, 12.6 Hz, 1H), 2.66 (dd, J=7.6, 12.6 Hz,
1H), 1.57 (m, 1H), 1.45 (m, 1H), 1.18 (m, 1H), 0.94 (d, J=6.6 Hz, 3H),
0.82 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3): d=137.5, 128.7 (2C), 128.6
(2C), 125.4, 40.6, 34.4, 28.7, 18.8, 11.2.
1-Methylpropyl phenyl sulfide (Table 3, entry 10):[44] 50 mL of stock solu-
tion A were used; column chromatography: hexane; colorless liquid
(91% yield). 1H NMR (CDCl3): d=7.32–7.29 (m, 2H), 7.20–7.16 (m,
2H), 7.13–7.09 (m, 1H), 3.07 (sext, J=6.6 Hz, 1H), 1.57 (m, 1H), 1.45
(m, 1H), 1.18 (d, J=6.6 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H); 13C NMR
(CDCl3): d=135.4, 131.7 (2C), 128.6 (2C), 126.4, 44.7, 29.4, 20.4, 11.4.
chloroACHTREUNGarene wasconus med, asdetermined by GC. Silica gel (0.5 g) was
added, and the solvents were evaporated under reduced pressure. The
crude residue was purified by column chromatography on silica gel using
hexane or a mixture of hexane and ethyl acetate aseluent. Aryl sulfides
were isolated in the yields reported in Table 3.
4-Methoxyphenyl octyl sulfide (Table 3, entry 1):[33] 100 mL of stock solu-
tion A were used; column chromatography: hexane/ethyl acetate 50:1;
colorless liquid (98% yield). 1H NMR (CDCl3): d=7.25 (d, J=8.6 Hz,
2H), 6.76 (d, J=8.6 Hz, 2H), 3.71 (s, 3H), 2.73 (t, J=7.4 Hz, 2H), 1.50
(quint, J=7.4 Hz, 2H), 1.30 (quint, J=7.4 Hz, 2H), 1.22–1.14 (m, 8H),
0.80 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=158.6, 132.8 (2C), 126.9,
114.4 (2C), 55.2, 35.7, 31.7, 29.3, 29.09, 29.06, 28.6, 22.6, 14.0.
Octyl phenyl sulfide (Table 3, entry 2):[44] 100 mL of stock solution A were
used; column chromatography: hexane; colorless liquid (91% yield).
1H NMR (CDCl3): d=7.25–7.23 (m, 2H), 7.21–7.16 (m, 2H), 7.09–7.06
(m, 1H), 2.83 (t, J=7.4 Hz, 2H), 1.57 (quint, J=7.4 Hz, 2H), 1.34 (quint,
J=7.4 Hz, 2H), 1.21–1.18 (m, 8H), 0.80 (t, J=7.1 Hz, 3H); 13C NMR
(CDCl3): d 137.0, 128.7 (4C), 125.5, 33.5, 31.7, 29.09, 29.06 (2C), 28.8,
22.6, 14.0.
1-Methylpropyl phenyl sulfide (Table 3, entry 11): A solution of Pd-
AHCTRE(UNG OAc)2 (4.4 mg) and CyPF-tBu (11 mg) in DME (1 mL) wasused ascata-
lyst; the reaction was conducted at 708C; 89% yield.
2-Methyl-2-propyl 4-trifluoromethylphenyl sulfide (Table 3, entry 12):
100 mL of stock solution A were used; column chromatography: hexane;
colorless liquid (82% yield). 1H NMR (CDCl3): d=7.56 (d, J=7.9 Hz,
2H), 7.50 (d, J=7.9 Hz, 2H), 1.23 (s, 9H); 13C NMR (CDCl3): d=137.6,
137.3 (2C), 130.5 (q, 2JC,F =32.6 Hz), 125.2 (q, 3JC,F =3.8 Hz), 124.5 (q,
1JC,F =272.5 Hz), 46.6, 30.9 (3C); elemental analysis calcd (%) for
C11H13F3S: C 56.39, H 5.59; found: C 56.59, H 5.60.
1-Naphthalenyl octyl sulfide (Table 3, entry 13):[46] 50 mL of stock solution
A were used; column chromatography: hexane; colorless liquid (92%
yield). 1H NMR (CDCl3): d=8.45 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.2 Hz,
1H), 7.74 (d, J=8.2 Hz, 1H), 7.60–7.52 (m, 3H), 7.43 (t, J=8.2 Hz, 1H),
3.0 (t, J=7.5 Hz, 2H), 1.71 (quint, J=7.5 Hz, 2H), 1.49–1.45 (m, 2H),
1.30 (brs, 8H), 0.92 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3): d=134.2,
133.8, 132.8, 128.4, 127.3, 126.7, 126.1, 126.0, 125.5, 124.9, 34.1, 31.7, 29.1
(3C), 28.8, 22.6, 14.0.
Octyl phenyl sulfide (Table 3, entry 3): 50 mL of stock solution A were
used; colorless liquid (91% yield).
Octyl phenyl sulfide (Table 3, entry 4): 10 mL of stock solution A were
Octyl 2-thiophenyl sulfide (Table 3, entry 14):[47] 50 mL of stock solution
A were used; column chromatography: hexan; colorless liquid (96%
yield). 1H NMR (CDCl3): d=7.23 (dd, J=5.4, 1.3 Hz, 1H), 7.02 (dd, J=
3.5, 1.3 Hz, 1H), 6.88 (dd, J=5.4, 3.5 Hz, 1H), 2.70 (t, J=7.3 Hz, 2H),
1.53 (quint, J=7.3 Hz, 2H), 1.33–1.27 (m, 2H), 1.20 (brs, 8H), 0.80 (t,
J=6.9 Hz, 3H); 13C NMR (CDCl3): d=134.9, 133.1, 128.7, 127.3, 38.9,
31.7, 29.3, 29.1, 29.0, 28.3, 22.6, 14.0.
used; colorless liquid (85% yield).
Preparation of stock solution B (1.0”10ꢀ2 m): Pd
ACHTRE(UNG OAc)2 (2.2 mg) and
CyPF-tBu (5.5 mg) were added in air to a 4 mL vial. The flask was sealed
with a cap containing a PTFE septum and then evacuated and backfilled
with N2. DME (1.0 mL) wasthen added to the vial by syringe, and the re-
sulting orange solution was stirred at room temperature for 1 min prior
to subsequent reactions.
Representative procedure without using a drybox
Cyclohexyl 3-methylphenyl sulfide (Table 3, entry 15):[48] 50 mL of stock
solution A were used; column chromatography: hexane, then hexane/
ethyl acetate 50:1; colorless liquid (98% yield). 1H NMR (CDCl3): d=
7.14–7.07 (m, 3H), 6.95–6.93 (m, 1H), 3.02 (tt, J=10.4, 3.7 Hz, 1H), 2.24
(s, 3H), 1.92–1.89 (m, 2H), 1.71–1.67 (m, 2H), 1.55–1.51 (m, 1H), 1.33–
1.13 (m, 5H); 13C NMR (CDCl3): d=138.4, 134.8, 132.4, 128.8, 128.5,
127.4, 46.4, 33.3 (2C), 26.0, 25.7 (2C), 21.2.
Cyclohexyl 4-methylphenyl sulfide (Table 3, entry 16):[48] 50 mL of stock
solution A were used. ; column chromatography: hexane, then hexane/
ethyl acetate 50:1; colorless liquid (97% yield). 1H NMR (CDCl3): d=
7.23 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 2.93 (tt, J=10.5, 3.8 Hz,
1H), 2.24 (s, 3H), 1.89–1.86 (m, 2H), 1.69–1.66 (m, 2H), 1.53–1.49 (m,
1H), 1.30–1.11 (m, 5H); 13C NMR (CDCl3): d=136.7, 132.7 (2C), 131.1,
129.4 (2C), 47.0, 33.3 (2C), 26.0, 25.7 (2C), 21.0.
A) 1mmol scale (Table 3, entry 5): An oven-dried test tube with a screw
cap containing a PTFE-lined septum was evacuated and backfilled with
N2. To the flask was added NaOtBu (106 mg, 1.10 mmol) and a stir bar.
The flask was evacuated and heated to remove the moisture present in
the base; then evacuated and backfilled with N2 three times. To the flask
wasthen added chlorobenzene (102 mL, 1.00 mmol), DME (2.0 mL),
50 mL of stock solution B, and 1-octanethiol (173 mL, 1.00 mmol), which
were stored and handled under an inert atmosphere. The resulting mix-
ture wasstirred for 6 h at 110 8C until the chlorobenzene wasconsumed,
asdetermined by GC. Silica gel (0.5 g) wasthen added, and oslvents
were evaporated under reduced pressure. The crude residue was purified
by column chromatography on silica gel using hexane as eluent to give
octyl phenyl sulfide as a colorless liquid (205 mg, 92%).
B) 5mmol scale (Table 3, entry 6): NaOtBu (0.53 g, 5.50 mmol), chloro-
benzene (0.51 mL, 5.00 mmol), DME (10.0 mL), 250 mL of stock solution
B, and 1-octanethiol (0.87 mL, 5.00 mmol) were used following the same
procedure described above to give, after 18 h, octyl phenyl sulfide as a
colorless liquid (1.03 g, 93%).
4-Methylphenyl octyl sulfide (Table 3, entry 7):[33] 50 mL of stock solution
A were used. Column chromatography: hexane, then hexane/ethyl ace-
tate 50:1; colorless liquid (97% yield). 1H NMR (CDCl3): d?=7.10 (d,
J=8.1 Hz, 2H), 6.95 (d, J=8.1 Hz, 2H), 2.73 (t, J=7.4 Hz, 2H), 2.17 (s,
3H), 1.48 (quint, J=7.4 Hz, 2H), 1.26 (quint, J=7.4 Hz, 2H), 1.17–1.08
Cyclohexyl 4-methylphenyl sulfide (Table 3, entry 17): A solution of Pd-
AHCTRE(UNG OAc)2 (4.4 mg) and CyPF-tBu (11 mg) in DME (1 mL) wasused ascata-
lyst; the reaction was conducted at 708C; 91% yield.
Cyclohexyl 2-methylphenyl sulfide (Table 3, entry 18):[48] 250 mL of stock
solution A were used; column chromatography: hexan; colorless liquid
(90% yield). 1H NMR (CDCl3): d=7.41–7.39 (m, 1H), 7.22–7.20 (m,
1H), 7.18–7.13 (m, 2H), 3.12 (tt, J=10.4, 3.7 Hz, 1H), 2.43 (s, 3H), 2.02–
2.00 (m, 2H), 1.82–1.79 (m, 2H), 1.66–1.64 (m, 1H), 1.47–1.28 (m, 5H);
13C NMR (CDCl3): d=139.3, 134.5, 131.2, 130.1, 126.3, 126.1, 45.8, 33.3
(2C), 26.0, 25.7 (2C), 20.7.
Chem. Eur. J. 2006, 12, 7782 – 7796
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7791

J. F. Hartwig et al.
2-Methylphenyl octyl sulfide (Table 3, entry 19): 250 mL of stock solution
A were used; column chromatography: hexane; colorless liquid (95%
yield). 1H NMR (CDCl3): d=7.15 (d, J=8.2 Hz, 1H), 7.06–7.03 (m, 2H),
6.98–6.95 (m, 1H), 2.79 (t, J=7.4 Hz, 2H), 2.27 (s, 3H), 1.57 (quint, J=
7.5 Hz, 2H), 1.38–1.32 (m, 2H), 1.19 (brs, 8H), 0.80 (t, J=6.9 Hz, 3H);
13C NMR (CDCl3): d=137.0, 136.4, 129.9, 127.1, 126.2, 125.1, 32.7, 31.7,
29.1 (2C), 28.9 (2C), 22.6, 20.2, 14.0; elemental analysis calcd (%) for
C15H24S: C 76.20, H 10.23; found: C 76.41, H 10.17.
(98% yield). 1H NMR (CDCl3): d=7.22–7.20 (m, 2H), 7.17–7.14 (m,
2H), 7.11–7.03 (m, 4H), 6.92 (m, 1H), 2.18 (s, 3H); 13C NMR (CDCl3):
d=138.9, 136.0, 135.1, 131.7, 130.6 (2C), 129.0 (2C), 128.9, 128.2, 127.9,
126.7, 21.2.
3-Methylphenyl phenyl sulfide (Table 4, entry 6): 50 mL of stock solution
C were used; 86% yield.
4-Methylphenyl 4-methoxyphenyl sulfide (Table 4, entry 7):[51] 100 mL of
stock solution C were used; column chromatography hexane/ethyl ace-
tate 50:1; white solid (95% yield). 1H NMR (CDCl3): d=7.47 (d, J=
8.8 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 6.96 (d, J=
8.8 Hz, 2H), 3.87 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3): d=159.3,
135.9, 134.21 (2C), 134.15, 129.6 (2C), 129.2 (2C), 125.4, 114.7 (2C),
55.1, 20.8.
3-Methylphenyl 4-methylphenyl sulfide (Table 4, entry 8):[52] 100 mL of
stock solution C and LiHMDS (184 mg, 1.10 mmol) were used; column
chromatography; hexane; colorless liquid (93% yield). 1H NMR
(CDCl3): d=7.28–7.25 (m, 2H), 7.16–7.07 (m, 5H), 6.97 (d, J=7.3 Hz,
1H), 2.31 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3): d=138.7, 137.2, 136.5,
131.9 (2C), 131.5, 130.5, 129.9 (2C), 128.8, 127.3, 127.0, 21.2, 21.0.
2-Methoxyphenyl octyl sulfide (Table 3, entry 20): 250 mL of stock solu-
tion A were used; column chromatography: hexane/ethyl acetate 50:1;
colorless liquid (97% yield). 1H NMR (CDCl3): d=7.23 (dd, J=7.6,
1.6 Hz, 1H), 7.15–7.12 (m, 1H), 6.90 (td, J=7.6, 1.3 Hz, 1H), 6.82 (dd,
J=8.0, 1.3 Hz, 1H), 3.86 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 1.65 (quint, J=
7.6 Hz, 2H), 1.43 (m, 2H), 1.31–1.22 (m, 8H), 0.87 (t, J=6.9 Hz, 3H);
13C NMR (CDCl3): d=156.9, 128.4, 126.4, 125.1, 120.8, 110.1, 55.5, 31.7,
31.6, 29.0 (2C), 28.8, 28.7, 22.5, 13.9; elemental analysis calcd (%) for
C22H31O2S: C 73.49, H 8.69; found: C 73.76, H 8.82.
2,5-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 3, entry 21):[25]
500 mL of stock solution A were used; column chromatography: hexane;
colorless liquid (89% yield). 1H NMR (CDCl3): d=7.26 (s, 1H), 7.06 (d,
J=7.9 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.20
(s, 9H); 13C NMR (CDCl3): d=140.5, 139.4, 135.0, 131.7, 130.0, 129.6,
46.9, 31.0 (3C), 21.2, 20.6.
4-Methylphenyl phenyl sulfide (Table 4, entry 9): 250 mL of stock solution
C and LiHMDS (184 mg, 1.10 mmol) were used; column chromatogra-
1
phy: hexane; colorless liquid (98% yield). H NMR (CDCl3): d=7.21 (d,
J=8.0 Hz, 2H), 7.19–7.14 (m, 4H), 7.11–7.05 (m, 1H), 7.03 (d, J=8.0 Hz,
2H), 2.25 (s, 3H); 13C NMR (CDCl3): d=137.5, 137.0, 132.2 (2C), 131.2,
130.0 (2C), 129.7 (2C), 128.9 (2C), 126.3, 21.0.
Di-4-methoxyphenyl sulfide (Table 4, entry 10):[28] 250 mL of stock solu-
tion C were used; column chromatography: hexane/ethyl acetate 50:1;:
white solid (99% yield). 1H NMR (CDCl3): d=7.26 (d, J=8.8 Hz, 4H),
6.81 (d, J=8.8 Hz, 4H), 3.76 (s, 6H); 13C NMR (CDCl3): d=158.8 (2C),
132.6 (4C), 127.3 (2C), 114.6 (4C), 55.2 (2C).
2,6-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 3, entry 22):[25]
A
solution of Pd(OAc)2 (6.6 mg) and CyPF-tBu (16.5 mg) in DME (1 mL)
ACHTREUNG
was used as catalyst; column chromatography: hexane; colorless liquid
(77% yield; 82% conversion after 36 h of reaction). 1H NMR (CDCl3):
d=7.04 (brs, 3H), 2.49 (s, 6H), 1.21 (s, 9H); 13C NMR (CDCl3): d=
145.2 (2C), 132.1, 128.2, 127.9 (2C), 49.1, 31.5 (3C), 23.0 (2C).
Preparation of stock solution C (1.0”10ꢀ2 m): Toluene (1.0 mL) was
added to a mixture of [PdACHTRE(UNG dba)2] (2.2 mg) and CyPF-tBu (5.5 mg). The
3-Methylphenyl 4-methoxyphenyl sulfide (Table 4, entry 11): 250 mL of
resulting purple solution was stirred at room temperature for 1 min prior
to subsequent reactions.
stock solution C were used; column chromatography: hexane/ethyl ace-
1
tate 50:1; colorless liquid (97% yield). H NMR (CDCl3): d=7.38 (d, J=
General procedure for the palladium-catalyzed coupling of aryl chlorides
with aromatic thiols: The appropriate quantity of stock solution C was
added to a 4 mL vial containing the aryl chloride (1.00 mmol) and potasi-
um tert-butoxide (123 mg, 1.10 mmol) in toluene (1.5 mL). The aromatic
thiol (1.00 mmol) wasthen added, and the vial sealed with a cap contain-
ing a PTFE septum. The mixture was heated at 1108C until the chloroar-
ene wasconusmed, asdetermined by GC. Silica gel (0.5 g) wasthen
added, and solvents were evaporated under reduced pressure. The crude
residue was purified by column chromatography on silica gel using
hexane or a mixture of hexane and ethyl acetate aseluent. Aryl sulfides
were isolated in the yields reported in Table 4.
4-Methoxyphenyl phenyl sulfide (Table 4, entry 1):[49] 100 mL of stock sol-
ution C were used; column chromatography: hexane/ethyl acetate 50:1;
colorless liquid (98% yield). 1H NMR (CDCl3): d=7.23 (d, J=8.8 Hz,
2H), 7.06–7.02 (m, 2H), 7.00–6.93 (m, 3H), 6.71 (d, J=8.8 Hz, 2H), 3.62
(s, 3H); 13C NMR (CDCl3): d=159.7, 138.5, 135.3 (2C), 128.8 (2C), 128.1
(2C), 125.7, 124.2, 114.9 (2C), 55.3.
Diphenyl sulfide (Table 4, entry 2):[49] 100 mL of stock solution C were
used; column chromatography: hexane; colorless liquid (95% yield).
1H NMR (CDCl3): d=7.26–7.24 (m, 4H), 7.21–7.18 (m, 4H), 7.16–7.13
(m, 2H); 13C NMR (CDCl3): d=135.7 (2C), 130.9 (4C), 129.1 (4C),
126.9 (2C).
4-Methylphenyl phenyl sulfide (Table 4, entry 3):[49] 100 mL of stock solu-
tion C were used; column chromatography: hexane; colorless liquid
(95% yield). 1H NMR (CDCl3): d=7.21 (d, J=8.0 Hz, 2H), 7.19–7.14
(m, 4H), 7.11–7.05 (m, 1H), 7.03 (d, J=8.0 Hz, 2H), 2.25 (s, 3H);
13C NMR (CDCl3): d=137.5, 137.0, 132.2 (2C), 131.2, 130.0 (2C), 129.7
(2C), 128.9 (2C), 126.3, 21.0.
8.8 Hz, 2H), 7.09 (t, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.96–6.91 (m, 2H), 6.85
(d, J=8.8 Hz, 2H); 13C NMR (CDCl3): d=159.6, 138.6, 138.1, 135.0
(2C), 128.8, 128.7, 126.6, 125.3, 124.4, 114.8 (2C), 55.1, 21.2; elemental
analysis calcd (%) for C14H14OS: C 73.01, H 6.13; found: C 73.27, H 6.57.
Phenyl 4-trifluoromethylphenyl sulfide (Table 4, entry 12):[53] 500 mL of
stock solution C were used; column chromatography: hexane; colorless
liquid (89% yield). 1H NMR (CDCl3): d=7.47–7.45 (m, 4H), 7.39–7.35
(m, 3H), 7.28–7.24 (m, 2H); 13C NMR (CDCl3): d=142.8, 133.5 (2C),
132.4, 129.6 (2C), 128.6, 128.2 (2C), 128.1 (q, 2JC,F =32.6 Hz), 125.7 (d,
1
3JC,F =3.8 Hz), 124.0 (q, JC,F =271.6 Hz).
2-Isopropylphenyl 4-methoxyphenyl sulfide (Table 4, entry 13):[54] 250 mL
of stock solution C were used; column chromatography: hexane/ethyl
acetate 50:1; white solid (94% yield). 1H NMR (CDCl3): d=7.44 (d, J=
8.8 Hz, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.31–7.27 (m, 1H), 7.17–7.13 (m,
2H), 6.99 (d, J=8.8 Hz, 2H), 3.88 (s, 3H), 3.68 (sept, J=6.9 Hz, 1H),
1.38 (d, J=6.9 Hz, 6H); 13C NMR (CDCl3): d=159.2, 147.5, 135.6, 134.2
(2C), 130.0, 126.6, 126.2, 125.4, 125.3, 114.8 (2C), 55.1, 30.2, 23.2 (2C).
2-Isopropylphenyl 4-methylphenyl sulfide (Table 4, entry 14): 250 mL of
stock solution C were used; column chromatography: hexane/ethyl ace-
tate 50:1; colorless liquid (97% yield). 1H NMR (CDCl3): d=7.32 (dd,
J=7.7, 1.4 Hz, 1H), 7.26–7.14 (m, 4H), 7.11–7.06 (m, 3H), 3.54 (sept, J=
6.8 Hz, 1H), 2.32 (s, 3H), 1.22 (d, J=6.8 Hz, 6H); 13C NMR (CDCl3):
d=149.2, 136.4, 133.8, 132.7, 132.3, 130.6 (2C), 129.8 (2C), 127.6, 126.4,
125.7, 30.4, 23.4 (2C), 20.9, elemental analysis calcd (%) for C16H18S: C
79.29, H 7.49; found: C 78.99, H 7.57.
1-Naphthalenyl phenyl sulfide (Table 4, entry 15):[46] 100 mL of stock solu-
tion C were used; column chromatography hexane/ethyl acetate 50:1;
colorless liquid (84% yield); 10% of symmetrical sulfides were also
formed. 1H NMR (CDCl3): d=8.26 (s, 1H), 7.71–7.53 (m, 3H), 7.37–7.0
(m, 8H); 13C NMR (CDCl3): d=136.8, 134.1, 133.5, 132.4, 131.1, 129.1,
129.0 (2C), 128.9 (2C), 128.5, 126.8, 126.3, 126.0, 125.7, 125.5.
4-Methylphenyl phenyl sulfide (Table 4, entry 4): A solution of [PdACHTRE(UNG dba)2]
(6.6 mg) and CyPF-tBu (16.5 mg) in toluene (1.0 mL) wasuesd ascata-
lyst; the reaction was heated at 708C until no further reaction wasob-
served (93% conversion); 83% yield.
3-Methylphenyl phenyl sulfide (Table 4, entry 5):[50] 100 mL of stock solu-
1-Naphthalenyl phenyl sulfide (Table 4, entry 16): A solution of [Pd-
tion C were used; column chromatography: hexane; colorless liquid
ACHTRE(UNG dba)2] (6.6 mg) and CyPF-tBu (16.5 mg) in toluene (1.0 mL) wasused as
7792
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Chem. Eur. J. 2006, 12, 7782 – 7796

Cross-Coupling
FULL PAPER
catalyst; the reaction was heated at 908C until reaction wascomplete
(48 h); 95% yield.
2,5-Dimethylphenyl 4-methoxyphenyl sulfide (Table 4, entry 17):[25]
13C NMR (CDCl3): d=171.9, 136.8, 136.5, 132.5, 129.8, 128.8, 128.1, 44.7,
29.4, 20.4, 11.3; elemental analysis calcd (%) for C11H14O2S: C 62.83, H
6.71; found: C 62.87, H 6.80.
3-(2-Methyl-2-propylsulfanyl)benzoic acid (Table 5, entry 5):[55] 50 mL of
stock solution A were used; column chromatography: hexane/ethyl ace-
tate 5:1, then 3:1; white solid (67% yield). 1H NMR (CDCl3): d=12.01
(brs, 1H), 8.30 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H),
7.46 (t, J=7.8 Hz, 1H), 1.31 (s, 3H); 13C NMR (CDCl3): d=171.8, 142.6,
138.7, 133.6, 130.3, 129.6, 128.6, 46.3, 30.9 (3C).
1000 mL of stock solution C were used; column chromatography: hexane/
ethyl acetate 50:1
!
20:1; colorless liquid (92% yield). 1H NMR
(CDCl3): d=7.27 (d, J=8.8 Hz, 2H), 7.03 (d, J=7.6 Hz, 1H), 6.89 (d, J=
7.6 Hz, 1H), 6.86–6.82 (m, 3H), 3.75 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H);
13C NMR (CDCl3): d=159.2, 136.1, 135.9, 134.3, 133.8 (2C), 130.1, 130.0,
127.1, 124.9, 114.8 (2C), 55.1, 20.8, 19.7.
2-Methoxyphenyl phenyl sulfide (Table 4, entry 18):[49] 1000 mL of stock
solution C were used; column chromatography: hexane/ethyl acetate
50:1; colorless liquid (97% yield). 1H NMR (CDCl3): d=7.42–7.40 (m,
2H), 7.36 (t, J=7.4 Hz, 2H), 7.32–7.27 (m, 2H), 7.14 (dt, J=7.8, 1.7 Hz,
1H), 6.96–6.90 (m, 2H), 3.91 (s, 3H); 13C NMR (CDCl3): d=157.1, 134.3,
131.4, 131.3 (2C), 129.0 (2C), 128.2, 126.9, 123.9, 121.1, 110.7, 55.7.
2-Methylphenyl phenyl sulfide (Table 4, entry 19):[49] 500 mL of stock sol-
ution C were used; column chromatography: hexane; colorless liquid
(70% yield); ~20% of symmetrical sulfides were also formed. 1H NMR
(CDCl3): d=7.47–7.19 (m, 9H), 2.50 (s, 3H); 13C NMR (CDCl3): d=
136.0, 133.6, 132.9, 130.9, 130.5, 129.5 (2C), 129.0 (2C), 127.8, 126.6,
126.2, 20.5.
3-(2-Methyl-2-propylsulfanyl)benzoic acid (Table 5, entry 6): 10 mL of
stock solution A were used; 71% yield.
3-(2-Methyl-2-propylsulfanyl)benzamide (Table 5, entry 7): 50 mL of stock
solution A were used; column chromatography: hexane/ethyl acetate 1:1
mixture; white solid (98% yield). 1H NMR (CDCl3): d=7.99 (t, J=
1.7 Hz, 1H), 7.85 (dt, J=7.8, 1.4 Hz, 1H), 7.68 (td, J=7.8, 1.7 Hz, 1H),
7.41 (t, J=7.8 Hz, 1H), 6.70–6.48 (m, 2H), 1.29 (s, 9H); 13C NMR
(CDCl3): d=169.2, 140.6, 135.9, 133.7, 133.4, 128.6, 127.7, 46.2, 30.8 (3C);
elemental analysis calcd (%) for C11H15NOS: C 63.12, H 7.22, N 6.69;
found: C 62.92, H 7.19, N 6.57.
3-(2-Methyl-2-propylsulfanyl)benzamide (Table 5, entry 8): 10 mL of stock
solution A were used; 91% yield.
2-Isopropylphenyl 2-methylphenyl sulfide (Table 4, entry 20):[54] 250 mL of
stock solution C were used; column chromatography: hexane; colorless
liquid (70% yield); ~20% of symmetrical sulfides were also formed.
1H NMR (CDCl3): d=7.26 (d, J=7.6 Hz, 1H), 7.19–7.14 (m, 2H), 7.07 (t,
J=7.3 Hz, 1H), 7.02–6.99 (m, 3H), 6.95 (d, J=7.6 Hz, 1H), 3.43 (sept,
J=6.7 Hz, 1H), 2.31 (s, 3H), 1.17 (d, J=6.7 Hz, 6H); 13C NMR (CDCl3):
d=149.3, 138.3, 135.3, 132.9, 131.9, 130.9, 130.3, 127.6, 126.7, 126.54,
126.49, 125.8, 30.5, 23.4 (2C), 20.3.
Methyl 3-cyclohexylsulfanylbenzoate (Table 5, entry 9):[25] 100 mL of
stock solution A and NaOtBu (98 mg, 1.02 mmol) were used; column
chromatography: hexane/ethyl acetate 50:1; pale yellow oil (56% yield).
1H NMR (CDCl3): d=7.97 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.48 (d, J=
7.9 Hz, 1H), 7.28–7.24 (m, 1H), 3.83 (s, 3H), 3.10–3.05 (m, 1H), 1.90–
1.86 (m, 2H), 1.69–1.67 (m, 2H), 1.54–1.51 (m, 1H), 1.33–1.15 (m, 5H);
13C NMR (CDCl3): d=166.5, 136.0, 135.8, 132.3, 130.6, 128.6, 127.5, 52.0,
46.4, 33.1 (2C), 25.8, 25.6 (2C).
General procedure for the palladium-catalyzed coupling of functionalized
aryl chlorides with aliphatic and aromatic thiols: The appropriate quanti-
ty of stock solution A was added to a 4 mL vial containing the aryl chlor-
ide (1.00 mmol) and NaOtBu (230 mg, 2.40 mmol), unless otherwise
stated, in DME (1.5 mL). The thiol (1.00 mmol) was then added, and the
vial sealed with a cap containing a PTFE septum. The mixture was
heated at 1108C until the chloroarene wasconus med, asdetermined by
GC. Silica gel (0.5 g) wasadded, and the solventswere evaporated under
reduced pressure. The crude residue was purified by column chromatog-
raphy on silica gel using hexane or mixtures of hexane and ethyl acetate
as eluent. Aryl sulfides were isolated in the yields reported in Tables 5
and 6.
Methyl 3-cyclohexylsulfanylbenzoate (Table 5, entry 10): 500 mL of stock
solution A and Cs2CO3 (359 mg, 1.10 mmol) were used; 72% yield.
3-(2-Methyl-2-propylsulfanyl)benzaldehyde (Table 5, entry 11): 250 mL of
stock solution A and Cs2CO3 (359 mg, 1.10 mmol) were used; column
chromatography: hexane/ethyl acetate 50:1; colorless oil (91% yield).
1H NMR (CDCl3): d=10.03 (s, 1H), 8.02 (t, J=1.6 Hz, 1H), 7.88 (dt, J=
7.6, 1.6 Hz, 1H), 7.79 (dt, J=7.6, 1.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H),
1.31 (s, 9H); 13C NMR (CDCl3): d=191.5, 143.0, 138.2, 136.5, 134.2,
129.4, 128.9, 46.2, 30.7 (3C); elemental analysis calcd (%) for C11H14OS:
C 68.00, H 7.26; found: C 67.88, H 7.45.
N-(3-(2-Methylbutylsulfanyl)phenyl) acetamide (Table 5, entry 12):
250 mL of stock solution A were used; column chromatography: hexane/
ethyl acetate 3:1, then 1:1; white solid (99% yield). 1H NMR (CDCl3):
d=8.45 (brs, 1H), 7.58 (s, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.16 (t, J=
7.9 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 2.89 (dd, J=6.0, 12.6 Hz, 1H), 2.70
(dd, J=7.6, 12.6 Hz, 1H), 2.14 (s, 3H), 1.63 (oct, J=6.6 Hz, 1H), 1.54–
1.46 (m, 1H), 1.27–1.19 (m, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.87 (t, J=
6.8 Hz, 3H); 13C NMR (CDCl3): d=169.0, 138.4, 138.3, 128.9, 123.9,
119.6, 117.0, 40.2, 34.2, 28.5, 24.2, 18.7, 11.0; elemental analysis calcd (%)
for C13H19NOS: C 65.78, H 8.07, N 5.90; found: C 65.54, H 8.12, N 5.89.
3-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 1): 50 mL of
stock solution A and NaOtBu (106 mg, 1.10 mmol) were used; column
chromatography: hexane/ethyl acetate 50:1; white solid (90% yield).
1H NMR (CDCl3): d=7.82 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.65 (d, J=
7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 1.30 (s, 9H); 13C NMR (CDCl3): d=
141.5, 140.2, 134.7, 132.0, 129.1, 118.1, 112.6, 46.7, 30.8 (3C); elemental
analysis calcd (%) for C11H13NS: C 69.07, H 6.85, N 7.32; found: C 69.25,
H 6.78, N 7.25.
3-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 2): 10 mL of
stock solution A and NaOtBu (106 mg, 1.10 mmol) were used; 79%
yield.
3-(2-Methyl-2-propylsulfanyl)aniline (Table 5, entry 13): 250 mL of stock
solution A and NaOtBu (106 mg, 1.10 mmol) were used; column chroma-
tography: hexane/ethyl acetate 20:1, then 5:1; yellow oil (96% yield).
1H NMR (CDCl3): d=7.10 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H),
6.87 (s, 1H), 6.67 (dd, J=7.8, 2.5 Hz, 1H), 3.71 (brs, 2H), 1.29 (s, 9H);
13C NMR (CDCl3): d=146.1, 133.2, 129.0, 127.5, 123.7, 115.4, 45.6, 30.9
(3C); elemental analysis calcd (%) for C10H15NS: C 66.25, H 8.34, N
7.73; found: C 66.16, H 8.34, N 7.76.
3-Benzoylphenyl cyclohexyl sulfide (Table 5, entry 3): 50 mL of stock sol-
ution A and NaOtBu (106 mg, 1.10 mmol) were used; column chromatog-
raphy: hexane/ethyl acetate 50:1, then 20:1; colorless oil (86% yield).
1H NMR (CDCl3): d=7.90–7.78 (m, 3H), 7.62–7.56 (m, 3H), 7.47 (t, J=
7.9 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 3.16 (tt, J=10.4, 3.7 Hz, 1H), 2.0–
1.96 (m, 2H), 1.78–1.75 (m, 2H), 1.62–1.59 (m, 1H), 1.42–1.21 (m, 5H);
13C NMR (CDCl3): d=195.9, 138.0, 137.2, 136.0, 134.9, 132.4, 132.2, 129.9
(2C), 128.5, 128.1 (2C), 127.8, 46.2, 33.0 (2C), 25.8, 25.5 (2C); elemental
analysis calcd (%) for C19H20OS: C 76.98, H 6.80; found: C 76.95, H 6.79.
4-(2-Methyl-2-propylsulfanyl)phenol (Table 5, entry 14):[56] 1000 mL of
stock solution A were used; column chromatography: hexane/ethyl ace-
1
tate 5:1, then 3:1; white solid (91% yield). H NMR (CDCl3): d=7.39 (d,
J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 5.62 (brs, 1H), 1.26 (s, 9H);
13C NMR (CDCl3): d=156.3, 139.0 (2C), 123.4, 115.5 (2C), 45.6, 30.6
(3C).
3-(1-Methylpropylsulfanyl)benzoic acid (Table 5, entry 4): 100 mL of
stock solution A were used; column chromatography: hexane/ethyl ace-
tate 5:1, then 3:1; pale yellow oil (76% yield). 1H NMR (CDCl3): d=
11.92 (brs, 1H), 8.12 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.9 Hz,
1H), 7.39 (t, J=7.9 Hz, 1H), 3.25 (sext, J=6.6 Hz, 1H), 1.73–1.64 (m,
1H), 1.62–1.53 (m, 1H), 1.31 (d, J=6.6 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H);
3-(2-Methylbutylsulfanyl)phenol (Table 5, entry 15): 500 mL of stock solu-
tion A were used; column chromatography: hexane/ethyl acetate 20:1;
yellow oil (85% yield). 1H NMR (CDCl3): d=7.04 (t, J=7.9 Hz, 1H),
6.80 (m, 1H), 6.72 (t, J=2.1 Hz, 1H), 6.53 (m, 1H), 5.90–4.20 (brs, 1H),
Chem. Eur. J. 2006, 12, 7782 – 7796
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7793

J. F. Hartwig et al.
2.84 (dd, J=12.3, 5.7 Hz, 1H), 2.65 (dd, J=12.3, 7.6 Hz, 1H), 1.58 (oct,
J=6.6 Hz, 1H), 1.49–1.40 (m, 1H), 1.22–1.13 (m, 1H), 0.93 (d, J=6.6 Hz,
3H), 0.82 (d, J=7.4 Hz, 3H); 13C NMR (CDCl3): d=155.6, 139.1, 129.8,
120.7, 115.0, 112.5, 40.2, 34.3, 28.7, 18.8, 11.1; elemental analysis calcd
(%) for C11H16OS: C 67.30, H 8.22; found: C 67.52, H 8.27.
7.69 (m, 1H), 7.58 (td, J=7.6, 1.5 Hz, 1H), 7.49 (td, J=7.5, 1.2 Hz, 1H),
1.36 (s, 9H); 13C NMR (CDCl3): d=138.7, 136.4, 133.5, 132.1, 129.1,
121.1, 118.0, 48.7, 30.8 (3C).
2-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 26): No cata-
lyzed reaction. NaOtBu (106 mg, 1.10 mmol) and the reaction heated for
24 h; 77% yield.
2-Octylsulfanylphenol (Table 5, entry 16):[57]
A solution of PdACHTRE(UNG OAc)2
3-Cyanophenyl phenyl sulfide (Table 6, entry 1):[54] 100 mL of stock solu-
tion A and NaOtBu (106 mg, 1.10 mmol) were used; column chromatog-
raphy: hexane/ethyl acetate 50:1; colorless liquid (93% yield). 1H NMR
(CDCl3): d=7.46–7.31 (m, 9H); 13C NMR (CDCl3): d=139.8, 133.2 (2C),
132.7, 132.0, 131.5, 129.7 (2C), 129.5, 129.4, 128.7, 118.1, 113.2.
(4.4 mg) and CyPF-tBu (11 mg) in DME (1 mL) as catalyst was used;
column chromatography: hexane/ethyl acetate 50:1; yellow liquid (97%
yield). 1H NMR (CDCl3): d=7.38 (dd, J=7.6, 1.5 Hz, 1H), 7.17 (dt, J=
7.6, 1.5 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.80–6.76 (m, 1H), 6.70 (brs,
1H), 2.60 (t, J=7.5 Hz, 2H), 1.50–1.43 (m, 2H), 1.31–1.17 (m, 10H), 0.79
(t, J=6.8 Hz, 3H); 13C NMR (CDCl3): d=156.8, 135.8, 130.8, 120.6,
119.1, 114.6, 36.7, 31.7, 29.5, 29.04, 28.98, 28.5, 22.5, 14.0.
3-Benzoylphenyl phenyl sulfide (Table 6, entry 2): 100 mL of stock solu-
tion A and NaOtBu (106 mg, 1.10 mmol) were used; column chromatog-
raphy: hexane/ethyl acetate 50:1, then 20:1; colorless oil (95% yield).
1H NMR (CDCl3): d=7.75–7.71 (m, 3H), 7.62 (dt, J=7.6, 1.3 Hz, 1H),
7.57–7.53 (m, 1H), 7.48–7.23 (m, 9H); 13C NMR (CDCl3): d=195.7,
138.3, 137.2, 136.9, 134.1, 133.6, 132.5, 131.9 (2C), 131.2, 129.9 (2C),
129.3 (2C), 128.9, 128.2 (2C), 128.1, 127.7; elemental analysis calcd (%)
for C19H14OS: C 78.59, H 4.86; found: C 78.65, H 4.87.
3-(4-Methoxyphenylsulfanyl)benzoic acid (Table 6, entry 3):[54] 250 mL of
stock solution A were used; column chromatography: hexane/ethyl ace-
tate 3:1, then 1:1; white solid (74% yield). 1H NMR (CDCl3): d=7.90
(brs, 1H), 7.86–7.83 (m, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.36–7.31 (m, 2H),
6.92 (d, J=9.0 Hz, 2H), 3.83 (s, 3H); 13C NMR (CDCl3): d=171.8, 160.1,
140.1, 135.9 (2C), 132.6, 129.9, 129.0, 128.9, 127.2, 122.8, 115.2 (2C), 55.3.
3-Phenylsulfanylbenzamide (Table 6, entry 4):[60] 250 mL of stock solution
A were used; column chromatography: hexane/ethyl acetate 1:1; white
solid (70% yield). 1H NMR (CDCl3): d=7.75 (t, J=1.8 Hz, 1H), 7.65
(dt, J=7.6, 1.3 Hz, 1H), 7.43–7.26 (m, 7H), 6.40–6.18 (m, 2H); 13C NMR
(CDCl3): d=168.9, 137.4, 134.3, 134.2, 133.5, 131.8 (2C), 129.4 (2C),
129.3, 128.9, 127.7, 125.6.
Methyl 3-phenylsulfanylbenzoate (Table 6, entry 5):[41] 250 mL of stock
solution C and KOtBu (123 mg, 1.10 mmol) were used. The reaction was
conducted in toluene (1.5 mL); column chromatography: hexane/ethyl
acetate 50:1, then 20:1; colorless liquid (80% yield; 10–15% of tert-butyl
ester derivative was also observed). 1H NMR (CDCl3): d=8.01 (t, J=
1.8 Hz, 1H), 7.88 (dt, J=7.9, 1.3 Hz, 1H), 7.46 (m, 1H), 7.38–7.25 (m,
6H), 3.89 (s, 3H); 13C NMR (CDCl3): d=166.4, 137.0, 134.6, 134.5, 131.6
(2C), 131.3, 131.1 (2C), 129.3, 129.1, 127.9, 127.6, 52.2.
4-(1-Hydroxyethyl)phenyl 2-methyl-2-propyl sulfide (Table 5, entry 17):
500 mL of stock solution A and NaOtBu (98 mg, 1.02 mmol) were used;
column chromatography: hexane/ethyl acetate 20:1, then 5:1; colorless
oil (93% yield). 1H NMR (CDCl3): d=7.50 (d, J=8.0 Hz, 2H), 7.33 (d,
J=8.0 Hz, 2H), 4.91 (q, J=6.6 Hz, 1H), 1.95 (brs, 1H), 1.50 (d, J=
6.6 Hz, 3H), 1.28 (s, 9H); 13C NMR (CDCl3): d=146.3, 137.5 (2C), 131.5,
125.4 (2C), 70.0, 45.8, 30.9 (3C), 25.1; elemental analysis calcd (%) for
C12H18OS: C 68.52, H 8.63; found: C 68.49, H 8.63.
4-(1-Hydroxyethyl)phenyl 2-methyl-2-propyl sulfide (Table 5, entry 18).
500 mL of stock solution A and Cs2CO3 (359 mg, 1.10 mmol) were used;
67% yield.
2-Fluorophenyl octyl sulfide (Table 5, entry 19): 100 mL of stock solution
A were used; column chromatography; hexane/ethyl acetate 50:1 mixture
(78% yield). It could not be separated of the corresponding aryl sulfide
ꢀ
from the reaction at C F bond (8% yield). The following spectroscopic
data were obtained from the mixture. 1H NMR (CDCl3): d=7.28–7.24
(m, 1H), 7.11–7.06 (m, 1H), 7.00–6.92 (m, 2H), 2.80 (t, J=7.3 Hz, 2H),
1.53 (quint, J=7.6 Hz, 2H), 1.40–1.27 (m, 2H), 1.18 (brs, 8H), 0.79 (t,
J=6.8 Hz, 3H); 13C NMR (CDCl3): d=161.2 (d, 1JC,F =244.6 Hz), 131.4,
127.7 (d, 3JC,F =7.7 Hz), 124.2 (d, 3JC,F =3.9 Hz), 123.7 (d, 2JC,F =27.6 Hz),
2
115.4 (d, JC,F =23.0 Hz), 33.1, 31.7, 29.1 (2C), 29.0, 28.6, 22.5, 14.0.
2-Fluorophenyl 1-methylpropyl sulfide (Table 5, entry 20): 250 mL of
stock solution A were used; column chromatography: hexane; colorless
liquid (98% yield). Tracesof the product of dithiolation were obesrved
and could not be separated. 1H NMR (CDCl3): d=7.42 (td, J=7.6,
1.8 Hz, 1H), 7.26–7.21 (m, 1H), 7.09–7.03 (m, 2H), 3.22 (sext, J=6.6 Hz,
1H), 1.70–1.61 (m, 1H), 1.59–1.47 (m, 1H), 1.25 (d, J=6.6 Hz, 3H), 1.00
N-(3-Phenylsulfanyl)phenyl acetamide (Table 6, entry 6): 250 mL of stock
solution A were used; column chromatography: hexane/ethyl acetate 1:1;
colorless oil (99% yield). 1H NMR (CDCl3): d=7.80 (brs, 1H), 7.46 (d,
J=8.1 Hz, 1H), 7.39 (t, J=1.8 Hz, 1H), 7.36–7.19 (m, 6H), 7.02 (d, J=
7.8 Hz, 1H), 2.09 (s, 3H); 13C NMR (CDCl3): d=168.7, 138.6, 136.8,
134.9, 131.5 (2C), 129.5, 129.1 (2C), 127.3, 126.1, 121.4, 118.4, 24.4; ele-
mental analysis calcd (%) for C14H13NOS: C 69.11, H 5.39, N 5.76;
found: C 69.04, H 5.37, N 5.77.
3-Phenylsulfanylaniline (Table 6, entry 7):[61] 250 mL of stock solution A
were used; column chromatography: hexane/ethyl acetate 5:1; yellow oil
(91% yield). 1H NMR (CDCl3): d=7.35–7.32 (m, 2H), 7.29–7.20 (m,
3H), 7.05 (t, J=8.1 Hz, 1H), 6.73–6.68 (m, 1H), 6.61–6.09 (m, 1H), 6.53–
6.50 (m, 1H), 3.60 (brs, 2H); 13C NMR (CDCl3): d=147.0, 136.3, 135.6,
130.9 (2C), 129.8, 129.0 (2C), 126.8, 120.8, 116.9, 113.8.
(t, J=7.4 Hz, 3H); 13C NMR (CDCl3): d=162.3 (d, 1JC,F =245.4 Hz),
2
134.7, 128.9 (d, 3JC,F =8.4 Hz), 124.1 (d, 3JC,F =3.8 Hz), 122.1 (d, JC,F
=
2
17.6 Hz), 115.6 (d, JC,F =13.8 Hz), 44.3, 29.5, 20.3, 11.2.
Benzyl 4-benzoylphenyl sulfide (Table 5, entry 21):[58] 10 mL of stock solu-
tion A and NaOtBu (106 mg, 1.10 mmol) were used; column chromatog-
raphy: hexane/ethyl acetate 20:1, then 5:1; white solid (93% yield).
1H NMR (CDCl3): d=7.75 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H),
7.59–7.55 (m, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.38 (d, J=7.6 Hz, 2H), 7.35–
7.25 (m, 5H), 4.23 (s, 2H); 13C NMR (CDCl3): d=195.6, 143.4, 137.6,
136.2, 134.3, 132.1, 130.5 (2C), 129.7 (2C), 128.62 (2C), 128.55 (2C),
128.1 (2C), 127.4, 126.6 (2C), 37.1.
Benzyl 4-benzoylphenyl sulfide (Table 5, entry 22): No catalyzed reaction.
NaOtBu (106 mg, 1.10 mmol) were used; 86% yield.
4-Cyanophenyl cyclohexyl sulfide (Table 5, entry 23):[48] 10 mL of stock
solution A and NaOtBu (106 mg, 1.10 mmol) were used; column chroma-
tography: hexane/ethyl acetate 20:1; white solid (90% yield). 1H NMR
(CDCl3): d=7.53 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 3.32 (tt, J=
10.2, 3.5 Hz, 1H), 2.06–2.03 (m, 2H), 1.84–1.80 (m, 2H), 1.69–1.65 (m,
1H), 1.49–1.27 (m, 5H); 13C NMR (CDCl3): d=143.9, 132.1 (2C), 128.4
(2C), 118.8, 108.3, 44.8, 32.8 (2C), 25.8, 25.5 (2C).
4-(2-Isopropylphenylsulfanyl)phenol (Table 6, entry 8): A solution of Pd-
AHCTRE(UNG OAc)2 (4.4 mg) and CyPF-tBu (11 mg) in DME (1 mL) wasused ascata-
lyst; column chromatography: hexane/ethyl acetate 20:1, then 5:1; pale
yellow oil (91% yield). 1H NMR (CDCl3): d=7.22–7.16 (m, 3H), 7.13–
7.08 (m, 1H), 7.00–6.93 (m, 2H), 6.74–6.70 (m, 2H), 5.28 (brs, 1H), 3.43
(m, 1H), 1.16 (dd, J=6.8, 1.8 Hz, 6H); 13C NMR (CDCl3): d=155.3,
147.7, 135.5, 134.4 (2C), 130.1, 126.7, 126.3, 125.6, 125.5, 116.4 (2C), 30.2,
23.2 (2C); elemental analysis calcd (%) for C15H16OS: C 73.73, H 6.60;
found: C 73.45, H 6.64.
4-Cyanophenyl cyclohexyl sulfide (Table 5, entry 24): No catalyzed reac-
tion. NaOtBu (106 mg, 1.10 mmol) were used and the reaction heated for
48 h; 79% yield, 91% conversion.
2-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 25):[59] 250 mL of
stock solution A and NaOtBu (106 mg, 1.10 mmol) were used; column
chromatography: hexane/ethyl acetate 50:1, then 20:1; yellow liquid
(80% yields). 1H NMR (CDCl3): d=7.73 (dd, J=7.6, 1.5 Hz, 1H), 7.71–
2-Fluorophenyl phenyl sulfide (Table 6, entry 9):[62] 1000 mL of stock solu-
tion C and KOtBu (123 mg, 1.10 mmol) were used. The reaction was con-
ducted in toluene (1.5 mL); column chromatography: hexane wasused as
eluent; colorless liquid (96% yield). 1H NMR (CDCl3): d=7.18–7.05 (m,
1
7H), 6.94–6.86 (m, 2H); 13C NMR (CDCl3): d=161.0 (d, JC,F
=
7794
www.chemeurj.org
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Chem. Eur. J. 2006, 12, 7782 – 7796

Cross-Coupling
FULL PAPER
246.9 Hz), 134.0, 133.3, 130.8 (2C), 129.3, 129.2 (2C), 127.2, 124.6 (d,
4-Methylphenyl 4-methoxyphenyl sulfide (Table 7, entry 7): 250 mL of
stock solution D were used; 88% yield.
2
2
3JC,F =10.7 Hz), 122.6 (d, JC,F =17.6 Hz), 115.8 (d, JC,F =22.23 Hz).
2-Cyanophenyl phenyl sulfide (Table 6, entry 10):[59] 250 mL of stock solu-
tion A and NaOtBu (106 mg, 1.10 mmol) were used; column chromatog-
raphy: hexane/ethyl acetate 20:1 mixture; colorless liquid (99% yield).
1H NMR (CDCl3): d=7.54 (d, J=8.0 Hz, 1H), 7.39–7.37 (m, 2H), 7.34–
7.29 (m, 4H), 7.19–7.15 (m, 1H), 7.03 (d, J=8.0 Hz, 1H); 13C NMR
(CDCl3): d=142.1, 133.5, 133.4 (2C), 132.9, 131.6, 129.7, 129.6 (2C),
128.8, 126.3, 116.8, 112.6.
4-Methylphenyl phenyl sulfide (Table 7, entry 8): 250 mL of stock solution
D and LiHMDS (184 mg, 1.10 mmol) were used; 97% yield.
Phenyl 4-trifluoromethylphenyl sulfide (Table 7, entry 9): 3.7 mg of
[(CyPF-tBu)PdCl2] were used; 90% yield.
2-Isopropylphenyl 4-methoxyphenyl sulfide (Table 7, entry 10): 250 mL of
stock solution D were used; 94% yield.
1-Naphthalenyl phenyl sulfide (Table 7, entry 11): 100 mL of stock solu-
2-Cyanophenyl phenyl sulfide (Table 6, entry 11): No catalyzed reaction.
NaOtBu (106 mg, 1.10 mmol) and the reaction heated for 24 h; 87%
yield.
tion D were used; 98% yield, <2% of symmetrical sulfides were detect-
ed.
2-Methylphenyl phenyl sulfide (Table 7, entry 12): 3.7 mg of [(CyPF-
tBu)PdCl2] were used; 77% yield, 18% of symmetrical sulfides were also
formed.
Synthesis of [(CyPF-tBu)PdCl2]: Josiphos CyPF-tBu (55 mg, 0.10 mmol)
wasadded to a solution of (CH 3CN)2PdCl2 (26 mg, 0.10 mmol) in CH2Cl2
(5.0 mL) and the resulting mixture was stirred for 30 min at room tem-
perature. The reaction mixture wasfiltered through Celite and the result-
ing solution concentrated under vacuum to approximately 1.0 mL. Red
needle crystals (65 mg, 90% yield) were obtained by layering with
3-Cyanophenyl 2-methyl-2-propyl sulfide (Table 7, entry 13): 50 mL of
stock solution D were used; 91% yield.
3-Benzoylphenyl cyclohexyl sulfide (Table 7, entry 14): 100 mL of stock
solution D were used; 80% yield.
1
hexane and cooling at ꢀ108C. H NMR (CDCl3): d=4.85 (s, 1H), 4.55 (s,
3-Phenylsulfanylbenzamide (Table 7, entry 15): 3.7 mg of [(CyPF-
tBu)PdCl2] and NaOtBu (230 mg, 2.40 mmol) were used; 66% yield.
1H), 4.53 (s, 1H), 4.25 (s, 5H), 3.60–3.75 (m, 1H), 3.00–3.10 (m, 1H),
2.50–2.60 (m, 1H), 2.27–2.90 (m, 1H), 2.13–2.25 (m, 2H), 2.00–2.10 (m,
1H), 1.97 (dd, J=9.0, 7.5 Hz, 3H), 1.70–1.95 (m, 4H), 1.20–1.30 (m, 8H),
1.63 (d, J=13.0 Hz, 9H), 1.30–1.45 (m, 4H), 1.23 (d, J=14.5 Hz, 9H);
13C NMR (CDCl3): d=96.5 (dd, J=13.3, 5.5 Hz), 71.9 (d, J=2.5 Hz), 69.9
(d, J=9.1 Hz), 69.8 (5C), 69.6 (d, J=9.2 Hz), 69.3 (t, J=5.7 Hz), 41.60
(d, J=35.5 Hz), 41.57 (d, J=8.2 Hz), 40.6 (d, J=11.2 Hz), 37.6 (d, J=
35.5 Hz), 34.5 (t, J=9.1 Hz), 32.0 (d, J=1.9 Hz, 3C), 31.1 (d, J=1.9 Hz,
3C), 30.0, 29.2, 28.1, 27.6 (d, J=6.8 Hz), 27.3 (d, J=10.2 Hz), 27.0 (d, J=
12.6 Hz), 26.9 (d, J=5.2 Hz), 26.8 (d, J=3.8 Hz), 26.1 (d, J=1.9 Hz),
25.6, 18.0 (d, J=6.7 Hz); elemental analysis calcd (%) for
C32H52Cl2FeP2Pd: C 52.51, H 7.16; found: C 52.72, H 7.38.
3-Phenylsulfanylaniline (Table 7, entry 16): 3.7 mg of [(CyPF-tBu)PdCl2]
and NaOtBu (230 mg, 2.40 mmol) were used; 92% yield.
3-(2-Methylbutylsulfanyl)phenol (Table 7, entry 17): 3.7 mg of [(CyPF-
tBu)PdCl2] and NaOtBu (230 mg, 2.40 mmol) were used; 96% yield.
Acknowledgements
We thank the NIH-NIGMS (GM-55382) for support of this work. M.
Fernµndez-Rodríguez isindebted to the Ministerio de Educación y Cien-
cia for a MEC/Fulbright postdoctoral fellowship.
Preparation of stock solution
(7.3 mg) was diluted in THF (1.0 mL) and the resulting orange solution
was stirred at room temperature for 1 min prior to subsequent reactions.
D
(1.0”10ꢀ2 m): [(CyPF-tBu)PdCl2]
General procedure for the palladium-catalyzed coupling of aryl chlorides
with thiols using [(CyPF-tBu)PdCl2] complex: The appropriate quantity
of stock solution D was added to a 4 mL vial containing the aryl chloride
(1.00 mmol) and base (1.10 mmol) in 1.5 mL of solvent (NaOtBu and
DME for aliphatic thiols, KOtBu and toluene for aromatic thiols, unless
otherwise stated). The thiol (1.00 mmol) was then added, and the vial
sealed with a cap containing a PTFE septum. The mixture was heated at
1108C until the chloroarene wasconsumed, asdetermined by GC. Silica
gel (0.5 g) wasadded and the oslventswere evaporated under reduced
pressure. The crude residue was purified by column chromatography on
silica gel using hexane or a mixture of hexane and ethyl acetate as
eluent. Aryl sulfides were isolated in the yields reported in Table 7.
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4-Methoxyphenyl octyl sulfide (Table 7, entry 1): 100 mL of stock solution
D were used; 97% yield.
Octyl phenyl sulfide (Table 7, entry 2): 50 mL of stock solution D were
used; 97% yield.
Cyclohexyl 4-methylphenyl sulfide (Table 7, entry 3): 50 mL of stock solu-
tion D were used; 94% yield.
2-Methylbutyl 3-methoxyphenyl sulfide (Table 7, entry 4): 50 mL of stock
solution D were used; column chromatography: hexane/ethyl acetate
50:1; colorless liquid (98% yield). 1H NMR (CDCl3): d=7.07 (t, J=
7.9 Hz, 1H), 6.80–6.76 (m, 2H), 6.59–6.56 (m, 1H), 3.67 (s, 3H), 2.84 (dd,
J=12.5, 5.9 Hz, 1H), 2.64 (dd, J=12.5, 7.6 Hz, 1H), 1.60–1.52 (m, 1H),
1.49–1.39 (m, 1H), 1.22–1.11 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 0.81 (t,
J=7.1 Hz, 3H); 13C NMR (CDCl3): d=159.6, 138.8, 129.4, 120.5, 113.7,
110.9, 55.0, 40.2, 34.3, 28.7, 18.8, 11.1; elemental analysis calcd (%) for
C12H18OS: C 68.52, H 8.63; found: C 68.32, H 8.68.
Octyl 2-thiophenyl sulfide (Table 7, entry 5). 50 mL of stock solution D
were used; 93% yield.
2,5-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 7, entry 6): 3.7 mg
of [(CyPF-tBu)PdCl2] were used; 96% yield.
Chem. Eur. J. 2006, 12, 7782 – 7796
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: July 4, 2006
Published online: September 29, 2006
7796
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Chem. Eur. J. 2006, 12, 7782 – 7796