A general and long-lived catalyst for the palladium-catalyzed coupling of aryl halides with thiols

Article abstract of DOI:10.1021/ja0580340

A general catalytic system for the coupling of aryl halides and sulfonates with thiols based on the use of the CyPF-t-Bu ligand (1) is reported. The reactions catalyzed by complexes of 1 occur in excellent yields with broad scope and exhibit extraordinary turnover numbers and high tolerance of functional groups. Turnover numbers usually exceed those of previous catalysts by 2 or 3 orders of magnitude. In addition, the reactions of aryl tosylates with alkane thiols to form aryl sulfides are reported for the first time. Finally, the synthesis of a diarylsulfide from two bromoarenes was accomplished using a hydrogen sulfide surrogate. Copyright

Full text of DOI:10.1021/ja0580340

Published on Web 01/31/2006
A General and Long-Lived Catalyst for the Palladium-Catalyzed Coupling of
Aryl Halides with Thiols
Manuel A. Ferna´ndez-Rodr´ıguez, Qilong Shen, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, PO Box 208107 New HaVen, Connecticut 06520-8107
Received November 25, 2005; E-mail: john.hartwig@yale.edu
Table 1. Palladium-Catalyzed Coupling of Aryl Chlorides with
Palladium-catalyzed coupling has become a principal method of
forming aromatic carbon-heteroatom bonds. Among this class of
reactions, the synthesis of arylamines and aryl ethers from aryl
halides has experienced significant development.1-4 However,
parallel studies to develop the synthesis of aryl sulfides have been
less fruitful.5,6 Migita first reported the coupling of iodo and bromo-
arenes with thiols using Pd(PPh3)4 as catalyst,7,8 and many ligands
have now been tested for this reaction.9-15 However, the published
reactions occur with low turnover numbers (TON e 50), encompass
chloroarenes containing only nitrile and ester functionality,11 and do
not include any reactions of aryl tosylates. These drawbacks have
limited the use of this reaction to prepare sulfides with biological
activity or sulfides that lead to biologically active compounds.16
The limitations of these reactions could result from the notorious
sensitivity of late metal catalysts to substrates containing reactive
sulfur functionality. Although palladium thiolates form easily and
undergo relatively fast reductive eliminations with aryl groups,17-19
the lifetime and concentrations of the catalysts used for the coupling
of aryl halides with thiols are likely to be limited by displacement
of dative ligands by thiolates to form anionic thiolate complexes
or by the formation of bridging thiolate complexes that undergo
slow reductive elimination.17 Thus, a more reactive catalyst for the
coupling of thiolates might contain a bisphosphine that binds the
metal strongly enough to prevent formation of anionic or bridging
thiolate complexes, while simultaneously promoting oxidative
addition and reductive elimination.
Thiols Using CyPF-t-Bu Liganda
With these requirements in mind, we considered that the restricted
backbone conformation, steric hindrance, and strong electron
donation of the Josiphos ligand, CyPF-t-Bu (1 in Table 1),20 could
create practical catalysts for the coupling of thiols with aryl
chlorides and tosylates. We show here that complexes generated
from this ligand couple a broad range of thiols with aryl halides
and sulfonates, and that reactions conducted with the Josiphos ligand
occur with turnover numbers and tolerance of functional groups
that far surpass those of previous catalysts. This catalyst also allows
diarylsulfides to be prepared from two different bromoarenes and
a hydrogen sulfide surrogate.
a Reactions were conducted using a 1:1 ratio of Pd(OAc)2 to ligand, 1
mmol of ArCl and thiol, and NaOtBu (1.1 equiv) at 110 °C in DME (1.5
mL), except for reactions of ArSH in entries 2, 10-13, 16, and 18-19,
which were carried out using Pd(dba)2 and KOtBu in toluene (1.5 mL).
b Isolated yield. c Performed at 70 °C. d 93% conversion. e LiHMDS used
as base. f 2.4 equiv of NaOtBu. g Cs2CO3 used as base. h 1.02 equiv of
NaOtBu.
side products (Table 1, entry 2). Reactions under the standard
conditions, but without catalyst, formed mostly disulfides and less
than 5% of the desired aryl sulfides.
We initially assessed catalyst activity by conducting the coupling
of the electron-rich 4-chloroanisole with 1-octanethiol. These studies
showed that 0.1 mol % of equimolar amounts of Pd(OAc)2 and
ligand in DME (1,2-dimethoxyethane) at 110 °C21 with NaOtBu
(1.1 equiv) as base formed the aryl sulfide in high yield in less
than 4 h (Table 1, entry 1). Reactions of alkylthiols with weaker
carbonate or phosphate bases occurred to low conversions and
formed large amounts of dialkyl disulfide. Reactions in other
solvents or at lower temperatures also either occurred to lower
conversions, required longer reaction times, or both. The coupling
of aromatic thiols under the same conditions produced undesired
symmetrical sulfides in a 5-10% combined yield,11,22 but reactions
of aromatic thiols with KOtBu as base and Pd(dba)2 as precursor
in toluene formed the aryl sulfide in high yield with only traces of
Reactions of a series of aryl chlorides and thiols were evaluated
under these conditions, and the results are summarized in Table 1.
Primary, secondary, and tertiary aliphatic thiols and aromatic thiols
were successfully coupled with activated and nonactivated aryl
chlorides. Excellent yields in short reaction times were obtained
using 1 or 2 orders of magnitude less catalyst than had been used
in previous couplings to form aryl sulfides (8500 turnovers, entry
4). Even the more sterically demanding substrates coupled in high
yield using catalyst loadings in the range of 0.25-1 mol % (entries
16-19). Reactions at lower temperatures (70 °C) simply required
increasing the amount of catalyst to 2-3 mol % and increasing
reaction times to 24 h (entries 6, 9, and 13).
This coupling of chloroarenes with thiols is tolerant of a wide
range of common functional groups (Table 1, entries 20-30).
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10.1021/ja0580340 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
SH)26 as a hydrogen sulfide surrogate in high yield, and the resulting
protected thiol coupled with p-bromotoluene in the presence of the
same catalyst and CsF. Using this protocol, a representative
unsymmetrical diaryl sulfide was isolated in 80% overall yield,
starting from two different aryl bromides.
Table 2. Coupling of Aryl Bromides, Iodides, and Sulfonates with
Thiols Catalyzed by Pd(OAc)2 and CyPF-t-Bu Ligandsa
In summary, we have described a general, highly efficient and
functional-group-tolerant catalyst system for the coupling of aryl
halides and triflates with thiols that typically occur with TONs that
are 2 or 3 orders of magnitude higher than those of related couplings
by previous catalysts. The results of these studies are consistent
with the hypothesis that ligand 1 overcomes the tendency of
thiolates to inactivate previous catalysts by displacement of the
dative ligand. Studies of the mechanism of this coupling process
will be the subject of future work.
Acknowledgment. We thank the NIH-NIGMS (GM-55382) for
support of this work. M.F.-R. thanks the Ministerio de Educacio´n
y Ciencia for a MEC Fulbright fellowship.
a Reactions conducted using a 1:1 ratio of Pd(OAc)2 to ligand, 1 mmol
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds and complete ref 16. This
material is available free of charge via the Internet at http://pubs.acs.org.
of both ArCl and thiol, and 1.1 equiv of NaOtBu at 110 °C in DME (1.5
c
mL). b Isolated yield. ∼90% conversion.
Chloroarenes bearing a nitrile, ketone, amide, and carboxylic acid,
as well as unprotected amino and aromatic or aliphatic hydroxyl
groups, coupled under the standard conditions to form the corre-
sponding aryl sulfide in good to excellent yields. Moreover,
reactions of aryl chlorides with ester or aldehyde groups that are
incompatible with nucleophilic alkoxide bases occurred in high yield
in the presence of the weaker Cs2CO3 base (entries 24 and 25).
Having obtained results on the coupling of chloroarenes, we
probed the scope of the reactions of other aryl halides and sulfonates
(Table 2). As expected, the coupling of aryl bromides and iodides
is even more efficient than the analogous coupling of chlorides.
For example, reactions of p-bromotoluene with octane- and
benzenethiol in the presence of only 10-100 ppm of catalyst
afforded excellent yields of sulfide product, corresponding to 99 000
and 9800 turnovers (entries 1 and 4). Reactions of the related
iodoarenes occurred with 84 000 and 82 000 turnovers (entries 7
and 10). These values are 2 or 3 orders of magnitude greater than
those produced by previous catalysts. In addition, reactions of
bromoarenes can be performed at 90 or 50 °C using 1 mol %
catalyst (entries 2, 3, and 5, 6). Furthermore, coupling of iodoarenes
occurred at room temperature with only 0.5 mol % catalyst (entries
8-9, and 11-12). No appreciable amounts of byproducts were
detected from reactions of aromatic thiols.
Aryl sulfonates are attractive alternatives to aryl halides because
they can be easily synthesized from phenols. In the presence of
potassium or sodium carbonate base, the coupling of phenyl triflate
with aliphatic and aromatic thiols occurred with 0.25 and 2.0 mol
% catalyst (entries 13 and 14). A 2 mol % combination of metal and
ligand catalyzed the first coupling of an aryl tosylate with a thiol
(entry 15).23-25 In contrast to the reaction of octanethiol, the reaction
of benzenethiol with the aryl tosylate did not occur (entry 16).
Because of the greater availability of aryl halides than of aromatic
thiols, the coupling of two aryl halides with a hydrogen sulfide
surrogate would be an attractive alternative to the coupling of an
aryl halide with an aromatic thiol. As shown in eq 1, the coupling
of phenyl bromide occurred with triisopropylsilanethiol (TIPS-
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