Carbon-sulfur bond formation of challenging substrates at low temperature by using Pd-PEPPSI-IPent

Article abstract of DOI:10.1002/chem.201102158

Aryl thiols made cool and quick: The coupling of alkyl, aryl, and silyl thiols to hindered, deactivated aryl bromides and chlorides has been achieved under the most mild temperatures yet reported (i.e., room temperature to 40°C). The bulk afforded by the di-2,6-(3-propylphenyl)imidazolium-derived Pd-PEPPSI-IPent catalyst is believed to actively promote the critical reductive elimination step of the catalytic cycle, thereby eliminating the formation of poisonous off-cycle dimeric resting states that have plagued Pd-catalyzed sulfination reactions.

Full text of DOI:10.1002/chem.201102158

COMMUNICATION
DOI: 10.1002/chem.201102158
Carbon–Sulfur Bond Formation of Challenging Substrates at Low
Temperature by Using Pd-PEPPSI-IPent**
Mahmoud Sayah and Michael G. Organ*[a]
Aryl ethers and thioethers[1] are moieties encountered in
the structure of a number of natural products and pharma-
ceutically relevant compounds. Classical methods to prepare
aryl thioethers, including the reaction of an aromatic com-
pound with sulfur and nucleophilic aromatic substitution
(NAS) of haloarenes with substituted thiophenols, often re-
quire forcing conditions and that can lead to disappointing
Scheme 1. Ligands that have been demonstrated to be effective in Pd-cat-
alyzed sulfination reactions.
yields.[2] The discovery in 1978 by Migita and co-workers[3]
that these NAS reactions could be catalyzed by Pd has been
followed up in the last decade by the development of im-
proved catalysts using a variety of metals to perform these
sulfination reactions with better selectivity and under milder
conditions.[4] While a couple of reports have disclosed a few
select examples that proceed at 708C or lower,[5] the bulk of
these catalyzed sulfinations have been done above this tem-
perature, typically at, or in excess of 1008C. Attempts to
couple challenging substrates, which are hindered, electroni-
cally disfavored, or both, all require temperatures in excess
of 1008C to proceed.[6] Here we report on the use of the dii-
sopentylphenylimidazolium (IPent) N-heterocyclic carbene
(NHC) ligand on Pd (i.e., 9) for the sulfination of haloar-
enes and heteroarenes with a variety of different types of
sulfur nucleophiles under the most generally mild conditions
yet reported.
Ligands that have demonstrated the most general applica-
tion in Pd-catalyzed sulfination reactions are shown in
Scheme 1. Within this collection, Josi-Phos is perhaps the
ligand that has been demonstrated to be the most active.
With this in mind we set out to compare the reactivity of
precatalyst 9 with Josi-Phos. Hartwig and co-workers have
proposed that a major impediment to Pd-catalyzed sulfina-
tion is movement of intermediates off the catalytic cycle
into thiolate-derived resting states (see Scheme 2).[5b] We
reasoned that the IPent ligand with its profound steric bulk
could accelerate reductive elimination sufficiently to miti-
gate such exchange reactions.
Scheme 2. Catalytic cycle for Pd-catalyzed sulfination.
Optimal conditions for sulfination with Josi-Phos have
been reported by Hartwig and co-workers (Table 1, en-
tries 1–4).[5a] Coupling of relatively active bromobenzene
with unhindered thiophenol proceeded well at 508C
(Table 1, entry 1), while chlorobenzene required higher tem-
perature (708C, Table 1, entry 3). When the oxidative addi-
tion partner became more hindered the bromide now re-
quired 1108C to complete (Table 1, entry 2) and the corre-
sponding chloride now failed to couple at all (0%), even
under the most forcing conditions (Table 1, entry 4). Pd-
PEPPSI-IPent has been demonstrated to be highly active in
low-temperature Suzuki–Miyaura,[11,12] Negishi,[13] and
Stille–Migita[14] couplings, thus we opted to examine its reac-
tivity focusing only on hindered 2,6-dimethyl substrates. Ini-
tially, no reactivity at all was observed at 408C (Table 1,
entry 5). We have observed that while organometallics
reduce 9 rapidly, aminations with alkylamines show induc-
tion periods that we have attributed to catalyst activation.[15]
With this in mind we examined activation using, first, mor-
pholine and indeed this led to excellent conversion at just
408C (Table 1, entry 6). With dibutylmagnesium (Table 1,
entry 7), a more effective reductant, everything could now
be nicely carried out at room temperature illustrating the
unprecedented reactivity of Pd-PEPPSI-IPent in sulfination.
[a] M. Sayah, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
[**] PEPPSI=pyridine, enhanced precatalyst, preparation, stabilization,
and initiation. IPent=diisopentylphenylimidazolium derivative.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102158.
Chem. Eur. J. 2011, 17, 11719 – 11722
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Table 1. Comparison of Josi-Phos and Pd-PEPPSI-IPent in the sulfination of hindered
aryl halides with thiophenol.
Alkyl thiols are known to be much more difficult
to couple than thiols at sp2-carbon centers.[17] None-
theless, coupling proceeded very well over a range
of alkyl centers including 18 (e.g., 25, 26, and 31), 28
(27 and 28), and 38 thiols (29, 30, and 32). We also
investigated hindered triisopropylsilylACHTNUTRGNE(NUG TIPS)-pro-
tected thiols as nucleophiles, a clever concept devel-
oped by Hartwig and co-workers to introduce
sulfur, after deprotection of the TIPS moiety, as a
single atom to generate aryl thiols that are not oth-
erwise readily available.[2] All of the examples at-
tempted (e.g., 33 to 37) worked very well at 408C
including heterocyclic oxidative addition examples
(e.g., 24, Table 2). So, in all cases, relative to exam-
ples published in the literature, Pd-PEPPSI-IPent
shows no apparent sensitivity to bulk imposed by
substituents placed ortho to the halide in sulfination
reactions.
Having demonstrated wide, general application
of this standard sulfination protocol using 9 at
408C, we decided to investigate the rates of these
reactions. From the representative examples that
we picked (e.g., 11 and 16, Table 2), it is clear that
Entry
R
H
R1
Me Br 3[b] DME, 50
X
Cat Solvent, Temp [8C] Additive
Yield [%][a]
1
2
3
4
5
6
7
8
–
–
–
–
–
91
93
83
0
Me Me Br 3[b] DME, 110
H
Me Cl 3[b] DME, 70
Me Me Cl 3[b] DME, 110
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
Cl
Br
Br
Br
Cl
Br
9
9
9
9
9
9
toluene, 40
toluene, 40
toluene, 23
toluene,[c] 70
toluene,[d] 23
toluene,[d] 23
0
morpholine (2.5 mol%) 99
Bu2Mg (8 mol%)
LiOiPr (20 mol%)
LiOiPr (20 mol%)
LiOiPr (20 mol%)
98
98
9
10
98[e]
99[f]
[a] Yields are reported on isolated products following silica gel chromatography; reac-
tions were performed in duplicate. [b] Josi-Phos ligand (3) was mixed with Pd(OAc)2
AHCTUNGTRENNUNG
to form the active catalyst (catalyst loading 1–3 mol%).[5a] [c] A mixture containing 6,
9, and LiOiPr was heated to 808C for 30 min, cooled to 238C, 7 and KOtBu added,
and the reaction mixture heated to 708C for 24 h. [d] A mixture containing 6, 9, and
LiOiPr was heated to 808C for 30 min, cooled to 238C, 7 and KOtBu added, and the
reaction mixture stirred at 238C for 24 h. [e] Reaction was halted after 6 h.
So as not to contaminate the sulfination products
by amination with catalytic morphline, and to im-
prove the practical aspects of handling a highly-
active organometallic like dibutylmagnesium, we
developed an activation protocol using LiOiPr.[16]
Catalyst activation occurred most reliably at 808C
and sulfination occurred smoothly, either at 708C
(Table 1, entry 8) or at room temperature (Table 1,
entries 9 and 10). Finally we examined the corre-
sponding hindered chloride (Table 1, entry 9) and
smooth conversion to product was again observed.
With the reaction optimization studies complete,
we examined the sulfination scope of aryl and het-
eroaryl halides and aryl sulfides at 408C (Table 2).
The reactions performed well under these mild con-
ditions, regardless of how sterically or electronically
deactivated the oxidative addition partner (see ex-
amples in Table 2). Similarly, hindrance on the sul-
fide (e.g., 14 and 24) was also nicely tolerated. Of
very special note is the coupling leading to aryl thi-
oether 18, which is derived from an oxidative addi-
tion partner that is both strongly sterically and elec-
tronically deactivated. There are no successful re-
ports of the coupling of this type of product in the
literature under any conditions; attempts to couple
using Josi-Phos under the conditions given in
Table 1 failed to provide any sulfinated product.
Heterocyclic halides couple with no issues, which is
ideal for the production of drug-like structures
(e.g., structures 19 through 24).
Table 2. Sulfination of aryl halides and heteroaryl halides with aryl sulfides catalyzed
by Pd-PEPPSI-IPent.[a,b]
With the thiophenol derivatives showing good re-
activity, attention was then focused on non-aromat-
ic thiols (Table 3).
[a] Yields are reported on isolated products following silica gel chromatography.
[b] Changes to reaction conditions are listed under the product.
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Pd-Catalyzed Sulfination Reactions
COMMUNICATION
Table 3. Sulfination of aryl halides with alkyl- and TIPS-protected sulfides catalyzed
by Pd-PEPPSI-IPent.[a,b]
for even the hindered and electronically deactivated
1-chloro-2,6-dimethylbenzene substrate demon-
strates that sulfination is complete after just 4–5 h
at room temperature with no induction period.[19]
To our knowledge, despite several reported at-
tempts,[5] no other catalyst has been able to perform
this conversion.
In summary, Pd-PEPPSI-IPent has been demon-
strated to be extremely reactive in metal-catalyzed
sulfination. The catalyst shows very broad substrate
scope including aryl and heteroaryl halides with
aryl, alkyl, and silyl sulfides under the most mild set
of generally applicable reaction conditions reported
to date. The reactions work well at 408C, but ap-
pears to work similarly well at room tempertature
(238C) with very good reaction rates.
Experimental Section
General sulfination conditions using Pd-PEPPSI-IPent: In a
glovebox, an oven-dried vial (4 mL screw-cap threaded)
equipped with magnetic stir bar was charged with Pd-PEPPSI-
IPent (4 mg, 2 mol%) and LiOiPr (3.7 mg, 20 mol%). The vial
was sealed with a Teflon-lined screw cap, removed from the
glove box, and the aryl/heteroaryl halide (1 equiv, 0.25 mmol)
was added by using a syringe followed by toluene (1 mL); al-
ternatively if the aryl/heteroaryl halide was a solid at room
temperature, it was dissolved in toluene and then transferred
to the vial. The resulting mixture was then stirred at 808C for
30 min to ensure precatalyst activation and then was cooled to
[a] Yields are reported on isolated products following silica gel chromatography.
[b] Changes to reaction conditions are listed under the product.
238C over approximately 5 min.
A solution of KOtBu
the reactions complete far sooner than the 24 h used as part
(1.5 equiv, 0.375 mmol) in toluene (1 mL) was then added at 238C by
using a syringe, before adjusting the temperature to the indicated value
to conduct the reaction. The aryl, alkyl, or TIPS thiol (1.2 equiv,
0.3 mmol) was then added dropwise and the reaction mixture stirred at
the indicated temperature and time. At this point the reaction mixture
was cooled (if necessary) to room temperature and the pH adjusted to 5
with 1m HCl (ca. 1 mL). The aqueous layer was extracted with diethyl
ether (3ꢁ1 mL) and the organic phases pooled, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Alternatively, in the case of
TIPS-protected thiols, the reaction mixture was directly filtered through
a small plug of celite, then eluted with diethyl ether (3 mL). After drying
over anhydrous Na2SO4, the solvent was removed in vacuo. The residue
from both workup procedures was purified subsequently by flash chro-
matography on silica gel.
of our standard protocol; both reactions were fully convert-
ed when samples were taken at 2 h. This encouraged us to
reinvestigate the temperature. Again we randomly chose ex-
amples of aryl bromides and chlorides from Tables 2 and 3
and found that even the most sterically hindered examples
couple well at room temperature (Table 4). The rate curve
Table 4. Room-temperature sulfinations with Pd-PEPPSI-IPent.[,18a,b]
Acknowledgements
The authors are grateful to the National Science and Engineering Coun-
cil of Canada (NSERC) and the Ontario Research and Development
Challenge Fund (ORDCF).
Keywords: cross-coupling · palladium · PEPPSI · sulfination
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Chem. Eur. J. 2011, 17, 11719 – 11722
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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[19] For the rate curve for the sulfination of 1-chloro-2,6-dimethylben-
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Received: July 13, 2011
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Published online: September 7, 2011
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Chem. Eur. J. 2011, 17, 11719 – 11722