Thioetherification of Chloroheteroarenes: A Binuclear Catalyst Promotes Wide Scope and High Functional-Group Tolerance

Article abstract of DOI:10.1002/chem.201403337

A constrained binuclear palladium catalyst system affords selective thioetherification of a wide range of functionalized arenethiols with chloroheteroaromatic partners with the highest turnover numbers (TONs) reported to date and tolerates a large variety of reactive functions. The scope of this system includes the coupling of thiophenols with six- and five-membered 2-chloroheteroarenes (i.e., functionalized pyridine, pyrazine, quinoline, pyrimidine, furane, and thiazole) and 3-bromoheteroarenes (i.e., pyridine and furane). Electron-rich congested thiophenols and fluorinated thiophenols are also suitable partners. The coupling of unprotected amino-2-chloropyridines with thiophenol and the successful employment of synthetically valuable chlorothiophenols are described with the same catalyst system. DFT studies attribute the high performance of this binuclear palladium catalyst to the decreased stability of thiolate-containing resting states. Palladium loading was as low as 0.2 mol %, which is important for industrial application and is a step forward in solving catalyst activation/deactivation problems.

Full text of DOI:10.1002/chem.201403337

DOI: 10.1002/chem.201403337
Full Paper
&
CÀS Cross-Coupling
Thioetherification of Chloroheteroarenes: A Binuclear Catalyst
Promotes Wide Scope and High Functional-Group Tolerance
Mꢀlanie Platon,[a] Novi Wijaya,[b] Vincent Rampazzi,[a] Luchao Cui,[b] Yoann Rousselin,[a]
Mark Saeys,*[b, c] and Jean-Cyrille Hierso*[a, d]
Abstract: A constrained binuclear palladium catalyst system
affords selective thioetherification of a wide range of func-
tionalized arenethiols with chloroheteroaromatic partners
with the highest turnover numbers (TONs) reported to date
and tolerates a large variety of reactive functions. The scope
of this system includes the coupling of thiophenols with six-
and five-membered 2-chloroheteroarenes (i.e., functionalized
pyridine, pyrazine, quinoline, pyrimidine, furane, and thia-
zole) and 3-bromoheteroarenes (i.e., pyridine and furane).
Electron-rich congested thiophenols and fluorinated thio-
phenols are also suitable partners. The coupling of unpro-
tected amino-2-chloropyridines with thiophenol and the suc-
cessful employment of synthetically valuable chlorothiophe-
nols are described with the same catalyst system. DFT stud-
ies attribute the high performance of this binuclear palladi-
um catalyst to the decreased stability of thiolate-containing
resting states. Palladium loading was as low as 0.2 mol%,
which is important for industrial application and is a step
forward in solving catalyst activation/deactivation problems.
Introduction
Thioethers are recurrent building blocks in many natural prod-
ucts and pharmacologically important molecules, often con-
taining aromatic or heteroaromatic groups (Figure 1).[1,2] The
palladium-catalyzed coupling of iodoarenes and bromoarenes
with thiols was first reported by Migita and co-workers by
using [Pd(PPh3)4] without additional supporting ligands.[3]
Driven by ligand developments, the scope and the reaction
conditions for CÀS coupling have since dramatically im-
proved.[4–11] Synthetic progress was also achieved for copper-
based catalyst systems[12] and other less commonly used
metals.[13,14] However, the latter systems remain generally less
efficient in terms of substrate scope. Several important issues
have been identified for CÀS coupling reactions:[15,16] 1) cata-
lysts can be poisoned by thiols, 2) coupling chloroarenes with
[a] Dr. M. Platon, V. Rampazzi, Dr. Y. Rousselin, Prof. Dr. J.-C. Hierso
Institut de Chimie Molꢀculaire de Universitꢀ de Bourgogne (ICMUB)
UMR-CNRS 6302, 9, Avenue Alain Savary, 21078 Dijon (France)
E-mail: hiersojc@u-bourgogne.fr
Figure 1. Pharmacologically relevant thioethers: a) Modulators of fatty acid
amide hydrolase (FAAH); b) ligands for serotonin transporters for positron
emission tomography (PET) diagnosis and treatment of neurodegenerative
diseases; c) an inhibitor of prion replication.
[b] N. Wijaya, L. Cui, Prof. Dr. M. Saeys
National University of Singapore
Department of Chemical and Biomolecular Engineering
4 Engineering Drive 4, 117585 Singapore (Singapore)
E-mail: saeys@nus.edu.sg
arenethiols is more challenging than with aliphatic thiols,[9b]
3) the competing formation of symmetrical diaryl thioethers
from reversible CÀS bond formation may occur,[17] and 4) cou-
pling reactions that involve functionalized thiols are demand-
ing.[18] Similar limitations are found with heteroaromatic sub-
strates, which, moreover, contain N, O, or S heteroatoms, thus
making them potential competing ligands. Hence, the efficient
catalytic coupling of heteroaromatic chlorides with thiophenol
[c] Prof. Dr. M. Saeys
Chemical and Pharmaceutical Engineering
Singapore—MIT Alliance, National University of Singapore
4 Engineering Drive 3, 117576 Singapore (Singapore)
[d] Prof. Dr. J.-C. Hierso
Institut Universitaire de France (IUF)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403337.
Chem. Eur. J. 2014, 20, 1 – 12
1
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
and functionalized thiophenols with a wide scope and valuable
turnover numbers (TONs) has not been reported to date.
Figure 2 summarizes examples of heteroaryl aryl thioethers
formed by coupling arylthiols with heteroaryl halides, mainly
iodides and some bromides, and the corresponding reported
TONs.
Results and discussion
Effect of polydentate ligands on thioetherification activity
In recent studies, high TONs have been reported for a range of
coupling reactions that have used ferrocenylpolyphosphane
supporting ligands. By combining the robustness and air toler-
ance of the ferrocene platform with the polydentate chelating
properties of the phosphorus donors,[19] palladium-catalyzed
CÀC cross-couplings reactions,[20] the direct CÀH functionaliza-
tion of heteroaromatic compounds,[21] and CÀO bond forma-
tion have been successful.[22] We examined their performance
for the CÀS coupling of heteroarylchlorides with functionalized
thiophenols, which have remained underexplored substrates.
To evaluate the role of the supporting ligands, the palladium-
catalyzed arylation of thiophenols 1a and 1b with 2-chloro-
pyridine (2a) was studied for a set of ferrocenylpolyphosphane
ligands L1–L8 (Figure 3), as summarized in Table 1.
Figure 2. Heteroaryl aryl thioethers formed by coupling of arylthiols with
heteroaryl iodides and bromides by using the following catalytic systems:
a) [Pd2(dba)3]/bis(2-diphenylphosphanophenyl) ether (DPEphos);[5]
b) [Pd2(dba)3]/4,5-bis(diphenylphosphano)-9,9-dimethylxanthene (Xant-
phos);[6] c) [{Pd(m-Br)P(tBu)3}2]/ZnCl2;[10] d) Pd(OAc)2/[2-(dicyclohexylphospha-
no)ferrocenyl]ethyl-di-tert-butylphosphane (CyPF-tBu).[9b] dba=dibenzylide-
neacetone. TON=turnover number.
We detail herein a new constrained binuclear palladium cat-
alyst, which incorporates a robust air-stable 1,1’,3,3’-tetrakis(di-
phenylphosphano)ferrocene ligand, that promotes the selec-
tive coupling of a wide range of functionalized arenethiols at
the highest TONs reported to date and tolerates a large variety
of heteroaromatic partners. The reaction scope includes the
coupling of thiophenols with 2-chloroheteroarenes (i.e., func-
tionalized pyridine, pyrazine, quinoline, pyrimidine, furane, and
thiazole) and functionalized 3-bromoheteroarenes (i.e., pyri-
dine and furane). Electron-rich congested thiophenols and
electron-poor fluorinated and trifluoromethylated thiophenols
are also suitable partners. The facile and selective coupling of
unprotected amino-2-chloropyridines with thiophenol and the
successful employment of synthetically valuable chlorothio-
phenols are described with the same catalyst system.
Figure 3. Ferrocenyl di-, tri-, and tetraphosphanes L1–L8 screened as sup-
porting ligands for the palladium-catalyzed formation of heteroaryl aryl thio-
ethers.
The existence of a highly reactive binuclear catalyst species
was confirmed by isolating the binuclear palladium complex
that results from the insertion of palladium into a CÀCl bond
at room temperature. DFT studies support our ligand-screening
efforts and attribute the high performance of the binuclear
palladium catalyst to the decreased stability of thiolate-con-
taining resting states.
Explorative experiments indicate that [{Pd(h3-allyl)(m-Cl)}2] in
toluene with tBuONa as a base is an appropriate starting mate-
rial. The use of more polar solvents (i.e., THF, 1,2-dimethoxy-
ethane (DME), and dioxane) was not required. K3PO4, which is
ideal for CÀO coupling,[22] was inefficient here. Pd(OAc)2 as
a metal source was generally less efficient. No thioetherifica-
tion was detected in the absence of palladium or with palladi-
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
2
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
um under ligand-free conditions (Table 1, entries 1 and 2).
After optimization of the palladium/ligand content at
0.2 mol% (Table 1, entries 3–10), three ferrocenylphosphane li-
gands displayed satisfactory coupling of thiophenol (1a) with
2a (ligands L4, L5, and L7: Table 1, entries 6, 7 and 9,
respectively).
Surprisingly, the constrained tridentate ligand L6, which
showed excellent performance for CÀO coupling was unsuc-
cessful for CÀS coupling. Instead, ferrocenylphosphane ligands
1,1’-bis(diphenylphosphano)ferrocene (DPPF; L1) and L7,
which presumably form large bite-angle bidentate palladium
complexes, were more successful. For lower catalyst loading
(i.e., 0.02–0.1 mol% of [Pd]/L), incomplete conversion was ob-
served overnight with L4, L5, and L7.
Table 1. Palladium-catalyzed heteroarylation of arenethiols 1a and 1b
with 2-chloropyridine (2a) at 0.1 mol% catalyst loading of [{PdCl(h3-
C3H5)}2] and 0.2 mol% L1–L8.[a]
To discriminate the performance of L4, L5, and L7 further,
the coupling of 2a with the more-demanding substituted thio-
phenol para-thiocresol (1b) was tested.[23] On the basis of
a fairly good performance for CÀO coupling,[22] we expected
the best performance for triphosphane ligands L4 and L5. Sur-
prisingly, the most efficient ligand was again the tetradentate
phosphane L7 (Table 1, entry 14). Complete conversion of 3b
was observed at 0.2 mol% [Pd]/L, whereas the ferrocenyltri-
phosphane ligands did not promote the reaction at such low
catalyst loading (Table 1, entries 12 and 13). The unexpected
performance of L7 was somewhat reinforced by the reasona-
ble performance of the diphosphane ligand L1 (Table 1,
entry 11) with a structure similar to L7.
Intrigued by the mode of coordination of ligand L7, we ana-
lyzed the reaction under conditions in which the preparation
of the precatalyst was carried out in situ (Figure 4). The crystal-
lization of a binuclear palladium complex C1 occurs overnight
to form an unprecedented structure in which L7 coordinates
the Pd center in a bis-k2 mode (see the X-ray structure in
Figure 4). C1 has a binuclear coordination and resembles the
1,1’-P coordination of DPPF (L1) and its derivatives. This coordi-
nation mode, which involves heteroannular (bridging) coordi-
nation with a large bite angle, can be related to the superior
performance of L7.
Thiophenol
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
–
[Pd]
0
0
[Pd]/L1
[Pd]/L2
[Pd]/L3
[Pd]/L4
[Pd]/L5
[Pd]/L6
[Pd]/L7
[Pd]/L8
[Pd]/L1
[Pd]/L4
[Pd]/L5
[Pd]/L7
50
5[c]
13[c]
99
99
0
99
0
62[c]
0
0
99
[a] [{PdCl(h3-C3H5)}2]/ligand=1:2, thiophenol (2 mmol), 2a (2 mmol),
tBuONa (2 mmol), toluene (5 mL), 1158C, 17 h, under argon. [b] Average
of two or more runs. [c] Yield determined by GC analysis.
Scope of the Pd catalyst system incorporating tetradentate
ligand L7
Having identified
a
suitable
system for the thioetherification
of thiophenol with 2-chloropyri-
dines at a low catalyst loading,
the scope of this [Pd]/2L7 cata-
lyst was evaluated for a wide
range of functionalized sub-
strates (Tables 2–7). We first ex-
amined the coupling of function-
alized 2-chloropyridines with
thiophenol 1a. This reaction pro-
ceeds in the presence of
0.1 mol% of [{PdCl(h3-C3H5)}2]/L7
to afford the corresponding het-
eroaryl aryl ethers 3a and
3c–e (Table 2, entries 1–4) in ex-
cellent yields (88–98%) and with
high TONs between 440 and
490. These TONs are up to 30-
times higher than the state-of-
the-art (Figure 2), even though
Figure 4. Binuclear palladium complex C1 obtained from the room-temperature oxidative addition of CHCl3 sol-
vent to the [Pd0]/L7 precatalyst (top). ORTEP diagram of the X-ray molecular structure of C1 (bottom). The hydro-
gen atoms have been omitted for clarity and thermal ellipsoids are drawn at the 50% probability level.
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
3
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
chloride substrates were used instead of iodides or bromides.
Substrates 2b–d demonstrate that this catalyst system per-
forms equally well for electron-withdrawing and electron-
donating groups, such as cyano, methoxy, and methyl groups,
at the C3, C4, and C6 positions of the heteroaromatic substrate
(Table 2, entries 2–4).
catalyst system was successfully extended to other classes of
six-membered 2-chloroheteroarene to afford the quinolinyl,
pyrazinyl, and pyrimidinyl thioethers 3g, 5, and 7 (Table 2, en-
tries 6–8), respectively, with yields over 95%. Even the elec-
tron-rich 3-chloro-6-methoxypyridazine was successfully cou-
pled to thiophenol with a yield of the isolated product 9 of
92%. Five-membered heteroaromatic compounds also ap-
peared suitable substrates because 11 and 13 were formed
from 2-chlorothiazole and 2-bromofurane in yields of 81 and
93%, respectively. Compound 13 was synthesized from furyl-
bromide because the furylchloride was unreactive. The only re-
ported example of a thiazole thioetherification analogous to
11 used iodobenzothiazole as the substrate with a reported
TON of 22 (Figure 2).[5]
Thioetherification of usually challenging 3-halopyridines[24]
introduces an interesting diversity into potentially useful phar-
maceutical building blocks that are complementary to 2-halo-
pyridines (e.g., nicotine analogues). However, 3-chloro- and 3-
bromopyridine are significantly less reactive than the 2-halo-
pyridines. Although 3-chloropyridines were unreactive with our
catalyst system, the targeted C3-functionalized pyridine deriva-
tive 15a was produced in good yield (86%, TON=43) by using
the [Pd]/L7 catalyst system at 2.0 mol% (i.e., 1 mol% of
[{PdCl(h3-C3H5)}2]) and 3-bromopyridine as the substrate
(Table 3, entry 1).
Table 2. Scope of chloroheteroarenes coupled with thiophenol (1a).[a]
Halide
Product
Yield
[%][b]
TONs
490
475
445
440
210
485
1
2
3
4
5
6
98
95
89
88
84[c]
Table 3. Coupling of 3-bromoheteroarenes with thiophenol (1a).[a]
Halide
Product
Yield
[%][b]
TONs
43
97
1
2
3
86
78
84
7
8
9
97
485
490
230
39
98
42
92[c]
4
5
85
43
10
11
93
465
203
81[c]
75[c]
188
[a] Conditions: [{PdCl(h3-C3H5)}2] (0.1 mol%)/ligand L7=1:2, 1a (2 mmol),
heteroaryl halide (2 mmol), tBuONa (2.8 mmol), toluene (5 mL), 1158C,
17 h, under argon. [b] Average of two or more runs. [c] [{PdCl(h3-C3H5)}2]
(0.2 mol%)/ligand L7=1:2.
[a] Conditions: [{PdCl(h3-C3H5)}2] (1.0 mol%)/ligand L7=1:2, 1a (2 mmol),
heteroaryl bromide (2 mmol), tBuONa (2.8 mmol), toluene (5 mL), 1158C,
17 h, under argon. [b] Average of two or more runs. [c] [{PdCl(h3-C3H5)}2]
(0.2 mol%)/ligand L7=1:2.
For a high yield of 3 f (Table 2, entry 5), the [{PdCl(h3-C3H5)}2]
catalyst loading had to be increased to 0.2 mol%, thus illustrat-
ing that an electron-donating methyl group at the C5 position
of 2-chloropyridine has a deactivating effect. The scope of the
We were glad to observe thioetherification with electron-
rich 3-bromopyridines with methoxy or methyl substituents at
the C4, C5, or C6 positions (15b–d, Table 3, entries 2–4, respec-
tively) in high yields of 78–85% and with reasonable TONs of
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
4
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
39–43. Surprisingly, the coupling of 3-bromofuryl was even
easier,[25] and 17 (Table 3, entry 5) was obtained in yields and
with TONs comparable to the C2-substituted furyl 13 (Table 2,
entry 11).
Table 5. Coupling of functionalized thiophenols with 2-chloropyridines.[a]
Thiophenol
Product
Yield
[%][b]
TONs
Examination of pharmacologically important aryl and hetero-
arylsulfides reveals that amino groups are often present
(Figure 1). Therefore, we anticipate that selectively coupling
amino-functionalized halopyridines with thiophenol will be
synthetically useful, especially with unprotected primary
amines that can be easily converted into valuable secondary
and tertiary amines. To the best of our knowledge, such a con-
vergent Pd-based method to synthesize aminopyridine thio-
ethers has not been reported. By using our catalytic system at
1.0 mol%, amino 2-chloropyridines 18a–d with an unprotected
amino function at the C3, C4, C5, or C6 position were selective-
ly coupled to thiophenol to produce 19a–d in excellent yields
of 74–85% (Table 4, entries 1–4, TON=37–43). Despite the
presence of both an active Pd/phosphane complex and
a strong tBuONa base, no concurrent CÀN coupling occurred,
thus making the time-consuming protection of NH2 groups un-
necessary with this catalytic system.
1
2
98
490
89[c]
223
3
4
93
465
225
90[c]
5
6
1e
83[c]
208
475
Table 4. Coupling of unprotected amino-2-chloropyridines with thiophe-
nol (1a).[a]
95
Halide
Product
Yield
[%][b]
TONs
1
2
85
81
43
7
8
95
475
228
41
37
43
91[c]
9
0[c]
0
3
4
74
85
10
11
0[c]
0
[a] Conditions: [{PdCl(h3-C3H5)}2] (1.0 mol%)/ligand L7=1:2, 1a (2 mmol),
heteroaryl chloride (2 mmol), tBuONa (2.8 mmol), toluene (5 mL), 1158C,
17 h, under argon. [b] Average of two or more runs.
91
455
To confirm the wide scope of our catalyst system further, we
examined various substituted arenethiols as substrates for cou-
pling with chloropyridines (Tables 5–7). Electron-rich thiophe-
nols with methyl groups at the C2 or C4 position were easily
coupled with 2-chloropyridine by using the [{PdCl(h3-C3H5)}2]/
L7 catalyst system at 0.1 mol%. Thus, compounds 3b and 3i
were obtained in yields above 93% with TONs between 465
and 490 (Table 5, entries 1 and 3, respectively). C3-methylated
thiophenol 1c appeared to be more reluctant, and 0.2 mol%
of catalyst was needed to successfully couple this compound
with 2a; consequently, thioether 3h was obtained in 89%
yield, but with a lower TON of 223 (Table 5, entry 2).
[a] Conditions: [{PdCl(h3-C3H5)}2] (0.1 mol%)/ligand L7=1:2, 1a (2 mmol),
heteroaryl chloride (2 mmol), tBuONa (2.8 mmol), toluene (5 mL), 1158C,
17 h, under argon. [b] Average of two or more runs. [c] [{PdCl(h3-C3H5)}2]
(0.2 mol%)/ligand L7=1:2.
In the presence of 0.2 mol% of catalyst, the heavily ortho-
congested dimethylated thiol 1e could be efficiently coupled
to both 2a and its ortho-cyano derivative 2b to afford 3j and
3k in very good yields of 90 and 83% with TONs of 225 and
208 (Table 5, entries 4 and 5, respectively). A high TON of 475
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
5
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
was also obtained for the coupling of the dialkylated thiophe-
nol 1 f with 2a (Table 5, entry 6), thus showing that a bulky
tert-butyl group in the meta position does not inhibit the effi-
ciency of our catalyst system. Methoxythiophenols 1g–i on the
other hand appeared to be very sensitive to the position of
the methoxy group, and the success of the coupling depends
on its position. C3- and C4-methoxy thiophenols were coupled
in yields of the isolated products 3m and 3n above 90% and
with TONs of 475 and 228 (Table 5, entries 7 and 8), respective-
ly. However, C2-methoxy-functionalized thiophenol could not
be coupled (Table 5, entry 9), possibly due to a combination of
steric hindrance and a strong electronic influence. Consistently,
the ortho-congested 1-naphtylthiol did not couple to 2-chloro-
pyridine either, whereas coupling of 2-naphtylthiol was ach-
ieved in 91% yield (Table 5, entries 10 and 11, respectively).
20a and 20c were easily coupled to 3-cyano-2-chloropyridine
(2b) to give heteroaryl aryl thioethers 21d and 21c in yields
above 90% (Table 6, entries 4 and 5, respectively). These
heteroaryl aryl thioethers incorporate valuable reactive func-
tions on both aromatic rings.
Table 7. Coupling of electron-poor and fluorinated thiophenols with 2-
chloropyridines.[a]
Thiophenol
Product
Yield
[%][b]
TONs
455
1
2
3
91
22a
96
480
Table 6. Coupling of chlorinated thiophenols with 2-chloropyridines.[a]
Thiophenol
Product
Yield
[%][b]
TONs
435
0
24 (98)
120
1
2
87
4
5
6
25 (97)[c]
41 (95)[c]
0[c]
63
103
0
0[c]
3
4
5
91
96
92
455
480
460
[a] Conditions: [{PdCl(h3-C3H5)}2] (0.1 mol%)/ligand L7=1:2, thiophenol
derivative (2 mmol), 2-chloropyridine (2 mmol), tBuONa (2.8 mmol), tolu-
ene (5 mL), 1158C, 17 h, under argon. [b] Yields of the isolated products
are averages of two or more runs (in bracket GC/NMR yields).
[c] [{PdCl(h3-C3H5)}2] (0.2 mol%)/L7=1:2.
20a
20a
Coupling with arenethiols that bear electron-withdrawing
substituents is more challenging and, even with the most
active catalysts reported,[5–15] successful coupling with such
substrates has not been reported. However, fluorinated arenes
are present in a number of important pharmaceuticals and
agrochemicals and are of great interest for PET molecular
imaging.[26] Under our standard conditions, para-fluorothiophe-
nol (22a) couples easily with 2-chloropyridine and its 3-cyano
derivative to give 23a and 23b in yields above 90% and with
high TONs of 455 and 480 (Table 7, entries 1 and 2), respective-
ly. Full conversion of meta-fluorothiophenol (22b) and ortho-
fluorothiophenol (22c) into 23c and 23d (Table 7, entries 3
[a] Conditions: [{PdCl(h3-C3H5)}2] (0.1 mol%)/ligand L7=1:2, thiophenol
derivative (2 mmol), 2-chloropyridine (2 mmol), tBuONa (2.8 mmol), tolu-
ene (5 mL), 1158C, 17 h, under argon. [b] Average of two or more runs.
[c] [{PdCl(h3-C3H5)}2] (0.2 mol%)/ligand L7=1:2.
We next examined the synthetically useful chlorine-function-
alized thiophenols (Table 6), which may permit further conver-
gent syntheses. We anticipated selectivity challenges, for ex-
ample, head-to-tail CÀS homocoupling of thiophenols. Howev-
er, such reactivity was not detected and most of the targeted
cross-coupling reactions afforded excellent yields and high
TONs. para-Chlorothiophenol (20a) and ortho-chlorothiophe-
nol (20c) were converted into thioethers 21a and 21c in 87
and 91% yields (Table 6, entries 1 and 3), respectively. No by-
products were observed. However, meta-chlorothiophenol
(20b) was unreactive, even when the loading of catalyst was
increased to 0.2 mol% (Table 6, entry 2). Chlorothiophenols
1
and 4), respectively, was afforded, as shown by consistent H,
19F NMR spectroscopic and GC analysis, by using a slightly
higher catalyst loading of 0.2 mol% for 22c. However, chroma-
tography purification limited the yield of the isolated product
to around 25%. The coupling of the electron-poor para-tri-
fluoromethylthiophenol (24) was also successful, but again the
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
6
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
yield of the isolated product 25 was decreased due to purifica-
tion issues (41% yield, TON=103; Table 7, entry 5). The pres-
ence of an electron-withdrawing carboxyl group in the ortho
position appeared to be a limitation. No coupling was detect-
ed for 26, even at a catalyst loading of 0.2 mol% (Table 7,
entry 6).
energy barrier is significantly higher for [Pd]/L6 (i.e., D°GA =
158 kJmolÀ1), thus making the OA step somewhat sluggish for
the latter catalyst system. Furthermore, the relatively strong
PdÀS bonds make the TM step very favorable with a calculated
reaction free energy of DrGA =À80 kJmolÀ1 for [Pd]/L7 (see Ta-
ble SI.1 in the Supporting Information).
Therefore, we focused the DFT calculations on the effect of
ligands L1, L6, and L7 on the thermodynamic stability of the
[Pd(L)(SAr)(H)] and [Pd(L)(SAr)2] resting states and compared
their stability with the reaction free energy for the CÀS RE step
(Figure 5, Table 8). The calculations show that the CÀS RE step
is significantly more favorable than the SÀH or SÀS RE steps
from the resting states and that [Pd(L)(SAr)2] is the more stable
resting state. Hence, these PdÀS resting states are kinetically
relevant and can also determine the catalytic activity for the
coupling of heteroarenes to thiophenols described herein.
DFT analysis of the role of the supporting ligands
To elucidate the role of binuclear complexes from L7 on the
thioetherification activity, we studied the catalytic cycle for 2-
chloropyridine coupling with thiophenol by using DFT calcula-
tions. Note also that L6 showed excellent performances for
CÀO coupling,[22] but was inexplicably unsuccessful for CÀS
coupling. In the related coupling of aryl chlorides with thiols
(non-heteroaromatic) by using electron-rich chelating [2-(dicy-
clohexylphosphano)ferrocenyl]ethyl-di-tert-butylphosphane
(CyPF-tBu),[15a] kinetic measurements concluded that resting
states with strong PdÀS bonds determine the readiness of the
catalyst system to re-enter the catalytic cycle. This experimen-
tal study suggested also that the three elementary steps in the
catalytic cycle, namely, oxidative addition (OA), transmetalla-
tion (TM), and reductive elimination (RE), proceed rapidly for
these substrates and this catalyst system, even at room tem-
perature. It was concluded that resting states (analogues to
the structures given in Figure 5) with strong PdÀS bonds de-
termine the readiness of the catalyst system to re-enter the
catalytic cycle.
Table 8. Calculated reaction enthalpies (DrHA), reaction Gibbs free ener-
gies (DrGA), and activation free energies (D°GA) at 1158C and in toluene
[kJmolÀ1] for reductive elimination from the [Pd(L)(SAr)2] and [Pd(L)-
(SAr)(H)] resting states and from the [Pd(L)(SAr)(HetAr)][a] reaction inter-
mediate (Figure 5).
[Pd(L)(SAr)(H)]
[Pd(L)(SAr)2]
[Pd(L)(SAr)(HetAr)]
DrHA
DrGA
DrHA DrGA D°GA DrHA DrGA D°GA
L6[b]
L6[c]
L1
113
29
70
39
À30
À2
162
79
100
103
122
81
12
13
11
49
127[d]
74
À10
37
39
49
À8 79[e]
À77
81
75
–
À48
À49
À27
72
73
–
L7
75
À3
CyPF-tBu 105
36
[a] HetAr=2-pyridinyl. [b] RE from the most stable square-planar dicoor-
dinated structure Iso.1 to the corresponding dicoordinated Pd0 complex
P1 (see Figure SI1.a in the Supporting Information). [c] RE from the di-
coordinated structure Iso.1 to the tricoordinated Pd0 complex P2 (see
Figure SI1.b in the Supporting Information). [d] Barrier for the lowest-
energy reaction path via the bridging L6.TS2SÀS complex (see Figure 6
and Figure SI2.b in the Supporting Information). [e] Barrier for the lowest-
energy reaction path via the pentacoordinated L6.TS3CÀS complex (see
Figure 6 and Figure SI3.c in the Supporting Information).
The difference in CÀS coupling activity between L7, L1, and
L6 (L6 promoted CÀO coupling but not CÀS coupling) is of
fundamental interest for clarification. Several PdII and Pd0 struc-
tures were identified for the coordination of the tridentate L6
ligand (see Figure 6 and Figure SI.1 in the Supporting Informa-
tion). For PdII structures, the square-planar geometry in which
the palladium center coordinates to the top ferrocene ring
(Iso.1 in Figure 6a) is the most stable isomer. The RE step from
Iso.1 leads to the dicoordinated P1 (Figure 6e). Subsequently,
P1 relaxes to the more stable tricoordinated P2 isomer
(Figure 6 f).
Figure 5. Kinetically relevant resting states and the reaction intermediate re-
lated to the arylation, alkylation, and heteroarylation of thiophenols.
In the present case, the calculated activation free-energy
barrier of D°GA =108 kJmolÀ1 for the OA to [Pd]/L7 (see Table
SI.1 in the Supporting Information) leads to an initial pseudo-
first-order rate coefficient of 10 sÀ1 under our experimental
conditions, which is fast relative to the RE step. This outcome
is further supported by the rapid insertion of palladium into an
unactivated alkyl CÀCl bond at room temperature for the [Pd]/
L7 system (see above). Comparatively, the activation free-
The lower stability of the [Pd(L1)(SAr)2] and [Pd(L7)(SAr)2]
resting states with DrGA values of 13 and 11 kJmolÀ1, respec-
tively, correlates well with the high reactivity observed in the
presence of the L1 and L7 ligands (Table 8). The [Pd(L6)(SAr)2]
resting state is much more stable with DGrA =81 kJmolÀ1. The
[Pd(CyPF-tBu)(SAr)2] resting state has an intermediate PdÀS
bond strength and a DGrA value of 49 kJmolÀ1. The slightly
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
in the resting state. Figure 7 plots the reaction free energies
from Table 8 as a function of this bite angle.
A larger reactant bite angle weakens the PdÀS bonds and
destabilizes the PdII resting state. For the [Pd(L)(SAr)2] struc-
tures in Table 2, both the bite angle and the substituents on
the phosphorus atoms change. To confirm that changes in bite
angle are the dominant factor, we also computed reaction free
energies for a series of [Pd(PMe3)2(SAr)2] structures with con-
strained P–Pd–P bite angles. A similar trend is found for this
set (Figure 7), thus confirming that the increased bite angle is
responsible for the decreased stability of the [Pd(L1)(SAr)2] and
[Pd(L7)(SAr)2] resting states.
The energy profile and key transition states for the RE step
from the [Pd(L)(SAr)2] resting state and the [Pd(L)(SAr)(HetAr)]
reaction intermediate are shown in Figure 8 for L6 and L7. Be-
cause the palladium center shuttles between the three phos-
phorus donors, we calculated several possible RE pathways for
ligand L6. However, the most favorable RE pathway for
[Pd(L6)(SAr)(HetAr)] passes through the penta-coordinated
transition state L6.TS3CÀS (see Figure 8 and Figure SI3.c in the
Supporting Information). Coordination of the third out-of-
plane phosphane group stabilizes the C-S RE transition state
by 12 kJmolÀ1 relative to the bridging square-planar transition
state L6.TS2CÀS (see Figures SI3.b and SI7 in the Supporting In-
formation). Hence, coordination of the third out-of-plane phos-
phane group also facilitates CÀS reductive elimination and
brings the activation barrier for the tridentate L6 ligand
(D°GA =79 kJmolÀ1; Table 8) close to the C–S RE barriers for
the tetradentate L7 and bidentate L1 ligands (D°GA =73 and
72 kJmolÀ1, respectively; see Figure SI8 in the Supporting Infor-
mation). This occurs despite the significantly less-favorable re-
action Gibbs free energy and increased electron-donation from
the alkylphosphane group on the bottom ferrocene ring. How-
ever, a similar transition-state stabilization was not found for
the RE step from the [Pd(L6)(SAr)2] resting state (Figure 8), and
the most-favorable reaction pathway goes via the bridging
square-planar transition state L6.TS2SÀS (see Figure 8 and Fig-
ure SI2.b in the Supporting Information). To reach the transi-
tion state, the palladium atom first needs to shuttle from the
Iso.1-type structure to the bridging Iso.2-type isomer
L6.Iso2SÀS, which is less stable by 33 kJmolÀ1 (see Figure 6a
Figure 6. Pertinent resting states and Pd0 structures: a) [PdII]/L6 with Pd che-
lated to the top ferrocene ring (Iso.1), b) [PdII]/L6 with Pd bridging the ferro-
cene rings (Iso.2), c) [PdII]/L1 and [PdII]/L7 (additional dotted lines), d) [PdII]/
CyPF-tBu, e) [Pd0]/L6 with chelated Pd (complex P1), f) [Pd0]/L6 with tricoor-
dinated Pd (complex P2).
lower stability of the [Pd]/L7 resting states also correlates with
the higher activity for this ligand. Note that the decreased sta-
bility stems from a more favorable reaction entropy (DrS=195
and 184 JmolÀ1 K for L7 and L1, respectively; see Table SI.2 in
the Supporting Information), which more than compensates
for the slightly less favorable reaction enthalpy (DrHA =103 and
100 kJmolÀ1 for L7 and L1, respectively).
The PdÀS bond strength and, hence, the stability of the four
[Pd(L)(SAr)2] complexes correlates with the P–Pd–P bite angle
and
b and the Supporting Information). This additional
33 kJmolÀ1 increases the overall barrier to escape from the
resting state to D°GA =127 kJmolÀ1. For SÀS coupling, coordi-
nation of the third out-of-plane phosphane group further de-
stabilizes the transition state by 19 kJmolÀ1 (L6.TS3SÀS, D°GA =
146 kJmolÀ1; see Figures SI2.c and SI7 in the Supporting Infor-
mation). Hence, the stability of the resting state makes L6 an
ineffective supporting ligand for the analogous thioetherifica-
tion. The barrier to re-enter the catalytic cycle is much lower
for the L7 ligand (D°GA =75 kJmolÀ1), which is likely responsi-
ble for the excellent performance for this ligand. The difference
in the SÀS RE barrier for L7 and L1 (D°GA =81 kJmolÀ1, which
is a higher barrier to re-enter the cycle; see L1.TSSÀS in Figures
SI8 and SI2.d in the Supporting Information) is remarkable con-
sidering the similar reaction free energies and similar CÀS RE
barriers for both ligands; however, this difference correlates
Figure 7. Effect of the P–Pd–P bite angle on the reductive-elimination reac-
tion free energies (DrGA; Table 2) for the [Pd(L)(SAr)2] resting state for L=L1,
L6, L7, and CyPF-tBu, and for the [Pd(PMe3)2(SAr)2] resting state with con-
strained P–Pd–P angles.
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
8
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Figure 8. Free-energy profiles for [Pd(L)(SAr)2] (right) and [Pd(L)(SAr)(HetAr)] (left) reductive elimination with L6 and L7 supporting ligands. Alternative reaction
pathways can be found in Figure SI7 (see the Supporting Information). The calculated reaction free energies and the free-energy barriers at 1158C and in tolu-
ene are indicated [kJmolÀ1]. Only the lowest-energy pathways are shown and the optimized structures can be found in the Supporting Information.
well with their experimentally observed difference in activity
and possibly occurs from the increased rigidity of binuclear
coordination.
The activation barrier to escape from the [Pd(L6)(SAr)2] resting
state of D°GA =127 kJmolÀ1 is significantly higher than for the
[Pd(L1)(SAr)2] and [Pd(L7)(SAr)2] resting states (D°GA =81 and
75 kJmolÀ1, respectively). These calculated barriers correlate
well with the [Pd]/L performance in demanding CÀS bond-for-
mation reactions (low Pd catalyst loading, demanding thiols,
and functionalized 2-chloroheteroarenes or 3-bromohetero-
arenes), and thus, low barriers to escape from the resting state
correspond to better catalyst performance. Complementing
the DFT studies, the existence of highly reactive binuclear cata-
lyst species was confirmed by isolating the binuclear palladium
complex C1 that results from the insertion of two palladium
centers coordinated by L7 into an unactivated alkyl CÀCl bond
at room temperature. Among the notable achievements of the
catalytic system described herein, electron-rich congested thio-
phenols and electron-poor fluorinated and trifluoromethylated
thiophenols were coupled easily. The facile and selective cou-
pling of unprotected amino-2-chloropyridines with thiophenol
and the successful employment of synthetically valuable
chlorothiophenols were also described. Thus, the effect of mul-
tiple-coordinating ligands at low metal loading may provide in-
spiration to consider robust polydentate air-stable ferrocenyl-
polyphosphane ligands for challenging cross-coupling reac-
tions with heteroarenes as a viable alternative to the electron-
Conclusion
A palladium catalyst that incorporates a robust air-stable
1,1’,3,3’-tetrakis(diphenylphosphano)ferrocene ligand (L7) has
been shown to provide selective coupling of a wide range of
functionalized arenethiols at the highest TONs reported to
date and tolerates a large variety of heteroaromatic partners.
To evaluate the role of the supporting ligands, the palladium-
catalyzed arylation of thiophenol with 2-chloropyridine was
studied for a set of ferrocenylpolyphosphane ligands, thus
demonstrating the superior performance of tetradentate L7
over tridentate phosphane L6 and bidentate DPPF (L1). To elu-
cidate the origin of the superior performance of the tetraden-
tate ligand L7, we evaluated the effect of ligands L6, L1, and
L7 (L) on the thermodynamic stability and the reactivity of the
[Pd(L)(SAr)(H)] and [Pd(L)(SAr)2] resting states and compared
the kinetics of these complexes with the CÀS reductive elimi-
nation (RE) step. The CÀS RE step was significantly more favor-
able than the SÀH or SÀS RE steps from the resting states, and
[Pd(L)(SAr)2] was the more-stable resting state. The PdÀS rest-
ing states explain the relative activities of the catalyst systems.
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
9
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
(m; C5-Cp), 81.0 (m; C2+C3-Cp), 76.2 ppm (m; C1-Cp); EI-MS
(2008C): m/z (%): 923 (100) [M+], 845 (10) [MÀPh+], 737 (10)
[MÀPPh2+]; elemental analysis calcd (%) for C58H46FeP4: C 75.50, H
5.02; found: C 75.30, H 4.93.
rich monophosphanes and diphosphanes that are often the
popular choice in this field.
Experimental Section
Catalytic thioetherification reactions
General conditions
In a typical experiment, the thiophenol derivative (2 mmol), hetero-
aromatic halide (2 mmol), [{PdCl(h3-C3H5)}2] (0.002 mmol, 0.1 mol%),
L7 (0.004 mmol, 0.2 mol%), and tBuONa (4 mmol) were introduced
into a Schlenk tube equipped with a magnetic stirring bar. The
Schlenk tube was purged several times with argon, toluene (5 mL)
was added, and the Schlenk tube was placed in an oil bath at
1208C. The reactants were allowed to stir for 17 h (the reaction
times were not optimized). A sample of the reaction mixture was
analyzed by GC and GC-MS analysis to determine the conversion
and selectivity before purification. At room temperature, the reac-
tion mixture was then diluted with diethyl ether (5 mL), filtered,
and concentrated. The crude material was purified by flash chro-
matography on silica gel.
All the reactions and workup procedures were performed in an
inert argon atmosphere by using conventional vacuum-line and
Schlenk techniques. The reactions were carried out in oven-dried
(1158C) glassware. The solvents were distilled over appropriate
drying and deoxygenating agents prior to use. 1H, 31P, 19F, and
13C NMR spectroscopy was performed on a 600 or 500 MHz Bruker
Avance II and a 300 MHz Bruker Avance spectrometer. Electrospray
exact-mass spectrometric analyses were performed on a Bruker mi-
croOTOF-Q instrument at the PACSMUB of the Institut de Chimie
Molꢀculaire de l’Universitꢀ de Bourgogne (ICMUB—UMR CNRS
6302). The elemental analyses were performed on a Fisons EA 1108
apparatus. The GC and GC-MS analyses were performed, respec-
tively, on a Supelco equity-5 capillary column on a Shimadzu GC-
2014 (GC) or an HP-5 capillary column (30 m; GC-MS). Except for
ligand L7, the polyphosphanes used in the present study are com-
mercially available from Strem Chemicals (under the name Hierso-
PHOS). CCDC-902497 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work was supported by the CNRS (M.P.) under the 3MIM
program (P4-project on Palladium Cross-Coupling Methodolo-
gy), the Singapore—MIT Alliance (N.W. and L.C.), the France-
Singapore MERLION program (V.R.) jointly from the French Min-
istry of Foreign Affairs and the National University of Singa-
pore, and the Rꢀgion Bourgogne (PARI-SMT8). We thank S.
Royer and D. Poinsot for their technical support.
Computational methods
The reaction free energies and activation free-energy barriers were
calculated by using DFT with the PBE0 functional[27] (DFT-PBE0) as
implemented in the Gaussian09 package[28] and by using the
def2-SV(P) basis set to optimize the structures and compute ther-
mal and entropy corrections with the rigid rotor-harmonic oscilla-
tor approximation.[29] To minimize basis-set superposition errors,
single-point electronic energies were further calculated for all the
final structures by using a larger def2-TZVP basis set. The reported
free energies combine the def2-TZVP electronic energies with
def2-SV(P) thermal and entropy calculations. Gibbs free energies
were computed at 1158C. Solvent effects for toluene were included
by using the solvation model density (SMD).[30] All the possible
conformations were considered, and only the structures with the
lowest Gibbs free energy in toluene at 1158C computed with the
def2-SV(P) basis set are reported.
Keywords: binuclear catalyst · density-functional calculations ·
phosphane ligands · tetradentate ligands · thioetherification
[1] a) Z. Yu in Homogeneous Catalysis for Unreactive Bond Activation (Ed.: Z.-
J. Shi), Wiley-VCH, Weinheim, 2014; b) L. Wang, W. Hea, Z. Yu, Chem.
Soc. Rev. 2013, 42, 599; c) L. Ackermann, Modern Arylation Methods,
Wiley-VCH, Weinheim, 2009.
[2] a) P. Emond, J. Vercouillie, R. Innis, S. Chalon, S. Mavel, Y. Frangin, C.
Halldin, J.-C. Besnard, D. Guilloteau, J. Med. Chem. 2002, 45, 1253;
b) B. C. H. May, J. A. Zorn, J. Witkop, A. C. Wallace, G. Legname, S. B.
Prusiner, F. E. Cohen, J. Med. Chem. 2007, 50, 65.
[3] a) M. Kosugi, T. Shimizu, T. Migita, Chem. Lett. 1978, 13–14; b) T. Migita,
T. Shimizu, Y. Asami, J. Shiobara, Y. Kato, M. Kosugi, Bull. Chem. Soc. Jpn.
1980, 53, 1385–1389; c) M. Kosugi, M. Kameyama, T. Migita, Chem. Lett.
1983, 927.
Synthesis of tetraphosphane L7
[4] G. Y. Li, Angew. Chem. 2001, 113, 1561; Angew. Chem. Int. Ed. 2001, 40,
1513.
[5] U. Schopfer, A. Schlapbach, Tetrahedron 2001, 57, 3069.
[6] T. Itoh, T. Mase, Org. Lett. 2004, 6, 4587.
[7] M. Murata, S. L. Buchwald, Tetrahedron 2004, 60, 7397.
[8] C. Mispelaere-Canivet, J.-F. Spindler, S. Perrio, P. Beslin, Tetrahedron
2005, 61, 5253–5259.
[9] a) M. A. Fernꢂndez-Rodrꢃguez, Q. Shen, J. F. Hartwig, J. Am. Chem. Soc.
2006, 128, 2180; b) M. A. Fernꢂndez-Rodrꢃguez, J. F. Hartwig, Chem. Eur.
J. 2006, 12, 7782.
[10] C. C. Eichman, J. P. Stambuli, J. Org. Chem. 2009, 74, 4005.
[11] C.-F. Fu, Y.-H. Liu, S.-M. Peng, S.-T. Liu, Tetrahedron 2010, 66, 2119.
[12] For representative examples, see: a) L. Rout, T. K. Sen, T. Punniyamurthy,
Angew. Chem. 2007, 119, 5679; Angew. Chem. Int. Ed. 2007, 46, 5583;
b) M. Carril, R. SanMartin, E. Domꢃnguez, I. Tellitu, Chem. Eur. J. 2007, 13,
5100; c) R. Xu, J.-P. Wan, H. Mao, Y. Pan, J. Am. Chem. Soc. 2010, 132,
15531.
1,3-Bis(diphenylphosphano)cyclopentadienyl
lithium
(13.17 g,
30 mmol) in THF (200 mL) was added to a suspension of FeCl2
(1.98 g, 15 mmol) in THF (70 mL) at 208C. After 4 h at reflux, the re-
action mixture was quickly filtered through a 2 cm pad of silica,
and the resulting filtrate was evaporated under vacuum. The oil
was purified by column chromatography on a silica gel with tolu-
ene/hexane (1:1) to give an orange solution. The solvent was
evaporated and crystallization in hot ethanol was conducted to
yield L7 as a bright-orange solid, which was air-stable for months
1
(5.75 g, 6.23 mmol, 42%). M.p. 1808C; H NMR (C6D6): d=7.03–7.50
(m, 40H; Ph), 4.40 (s, 2H; Cp), 3.97 ppm (s, 4H; Cp); 31P NMR
(C6D6): d=À22.46 ppm (s); 13C NMR (C6D6): d=139.3 (m; i-Ph),
134.0 (pt, JPC+P’C =30 Hz; o’’’-Ph), 133.7 (pt, JPC+P’C =60 Hz; o’’-Ph),
133.3 (pt, JPC+P’C =60 Hz; o’-Ph), 133.1 (pt, JPC+P’C =30 Hz; o-Ph),
128.5 (pd, JPC+P’C =23 Hz; m-Ph), 128.2 (pt, JPC+P’C =7 Hz; p-Ph), 83.0
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
10
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[13] From iron salts, see: a) A. Correa, M. Carril, C. Bolm, Angew. Chem. 2008,
120, 2922; Angew. Chem. Int. Ed. 2008, 47, 2880; b) J.-R. Wu, C.-H. Lin,
C.-F. Lee, Chem. Commun. 2009, 4450; from cobalt, see: c) Y.-C. Wong,
T. T. Jayanth, C.-H. Cheng, Org. Lett. 2006, 8, 5613.
[14] From bimetallic systems, see for Fe/Cu: a) X. Ku, H. Hang, H. Jiang, H.
Liu, J. Comb. Chem. 2009, 11, 338; see for Pd/Cu: b) Z. Duan, S. Ranjit, P.
Zhang, X. Liu, Chem. Eur. J. 2009, 15, 3666.
[15] a) E. Alvaro, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 7858; b) G. Mann,
D. Baranano, J. F. Hartwig, A. L. Rheingold, I. A. Guzei, J. Am. Chem. Soc.
1998, 120, 9205; c) D. Baranano, J. F. Hartwig, J. Am. Chem. Soc. 1995,
117, 2937; d) S. Shekhar, P. Ryberg, J. F. Hartwig, J. S. Mathew, D. G.
Blackmond, E. R. Strieter, S. L. Buchwald, J. Am. Chem. Soc. 2006, 128,
3584.
Eur. J. 2006, 12, 5142; b) T. Hatakeyama, S. Hashimoto, K. Ishizuka, M.
Nakamura, J. Am. Chem. Soc. 2009, 131, 11949; c) G. Gribble, J. J. Li in
Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist
(Eds.: J. Baldwin, R. M. Williams, J.-E. Bꢅckvall), Pergamon, Amsterdam,
2000.
[25] Five-membered-ring heteroaryl halides are usually more demanding
substrates: L. Salvi, N. R. Davis, S. Z. Ali, S. L. Buchwald, Org. Lett. 2012,
14, 170.
[26] Fluorine and Health: Molecular Imaging, Biomedical Materials and Phar-
maceuticals (Eds.: A. Tressaud, G. Haufe), Elsevier, Amsterdam, 2008.
[27] C. Adamo, V. Barone, J. Chem. Phys. 1999, 110, 6158.
[28] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyen-
gar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg,
S. Dapprich, A. D. Daniels, ꢆ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cio-
slowski, and D. J. Fox, Gaussian, Inc., Wallingford, CT, 2009.
[29] F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297.
[30] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378.
[16] J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534.
[17] T. Yamamoto, Y. Sekine, Inorg. Chim. Acta 1984, 83, 47.
[18] For reviews, see: a) T. Kondo, T.-a. Mitsudo, Chem. Rev. 2000, 100, 3205;
b) I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111, 1596.
[19] a) J.-C. Hierso, A. Fihri, V. V. Ivanov, B. Hanquet, N. Pirio, B. Donnadieu, B.
Rebiꢄre, R. Amardeil, P. Meunier, J. Am. Chem. Soc. 2004, 126, 11077.
[20] J.-C. Hierso, A. Fihri, R. Amardeil, P. Meunier, H. Doucet, M. Santelli, V. V.
Ivanov, Org. Lett. 2004, 6, 3473.
[21] a) D. Roy, S. Mom, M. Beaupꢀrin, H. Doucet, J.-C. Hierso, Angew. Chem.
2010, 122, 6800; Angew. Chem. Int. Ed. 2010, 49, 6650; b) D. Roy, S.
Mom, D. Lucas, H. Cattey, J.-C. Hierso, H. Doucet, Chem. Eur. J. 2011, 17,
6453.
[22] M. Platon, L. Cui, S. Mom, P. Richard, M. Saeys, J.-C. Hierso, Adv. Synth.
Catal. 2011, 353, 3403.
[23] As reported in reference [10], in the presence of 2 mol% Pd, only
a 47% yield of 3b was achieved while all other related thioethers were
easily formed.
[24] 3-Halopyridines are notably difficult to couple by transition-metal-cata-
lyzed reactions; see: a) O. Navarro, N. Marion, J. Mei, S. P. Nolan, Chem.
Received: April 30, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
11
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
A constrained binuclear palladium
catalyst system affords selective cou-
pling of a wide range of functionalized
arenethiols to six- and five-membered
chloroheteroarenes at the highest turn-
over numbers (TONs) reported to date
(see picture; DPPF=1,1’-bis(diphenyl-
phosphano)ferrocene). DFT calculations
support the ligand-screening efforts and
attribute the high performance of this
binuclear catalyst, which incorporates
a “super-DPPF”, to the decreased stabili-
ty of thiolate-containing resting states.
&
CÀS Cross-Coupling
M. Platon, N. Wijaya, V. Rampazzi, L. Cui,
Y. Rousselin, M. Saeys,* J.-C. Hierso*
&& – &&
Thioetherification of
Chloroheteroarenes: A Binuclear
Catalyst Promotes Wide Scope and
High Functional-Group Tolerance
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
12
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!