Monophosphine ligands promote Pd-catalyzed C-S cross-coupling reactions at room temperature with soluble bases

Article abstract of DOI:10.1021/acscatal.9b01913

The Pd-catalyzed cross-coupling of thiols with aromatic electrophiles is a reliable method for the synthesis of aryl thioethers, which are important compounds for pharmaceutical and agricultural applications. Since thiols and thiolates strongly bind late transition metals, previous research has focused on catalysts supported by chelating, bisphosphine ligands, which were considered less likely to be displaced during the course of the reaction. We show that, by using monophosphine ligands instead, more effective catalysis can be achieved. Notably, compared to previous methods, this increased reactivity allows for the use of much lower reaction temperature, soluble bases, and base-sensitive substrates. In contrast to conventional wisdom, our mechanistic data suggest that the extent of displacement of phosphine ligands by thiols is, first, not correlated with the ligand bulk or thiol nucleophilicity and, second, not predictive of the effectiveness of a given ligand in combination with palladium.

Full text of DOI:10.1021/acscatal.9b01913

Research Article
Cite This: ACS Catal. 2019, 9, 6461−6466
pubs.acs.org/acscatalysis
Monophosphine Ligands Promote Pd-Catalyzed C−S Cross-Coupling
Reactions at Room Temperature with Soluble Bases
Jessica Xu, Richard Y. Liu, Charles S. Yeung,* and Stephen L. Buchwald*
†
†
,‡
,†
†
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States
‡
*
S Supporting Information
ABSTRACT: The Pd-catalyzed cross-coupling of thiols with
aromatic electrophiles is a reliable method for the synthesis of
aryl thioethers, which are important compounds for pharma-
ceutical and agricultural applications. Since thiols and thiolates
strongly bind late transition metals, previous research has
focused on catalysts supported by chelating, bisphosphine
ligands, which were considered less likely to be displaced
during the course of the reaction. We show that, by using
monophosphine ligands instead, more effective catalysis can be
achieved. Notably, compared to previous methods, this increased reactivity allows for the use of much lower reaction
temperature, soluble bases, and base-sensitive substrates. In contrast to conventional wisdom, our mechanistic data suggest that
the extent of displacement of phosphine ligands by thiols is, first, not correlated with the ligand bulk or thiol nucleophilicity and,
second, not predictive of the effectiveness of a given ligand in combination with palladium.
KEYWORDS: cross-coupling, thiol arylation, palladium catalysis, catalyst deactivation, phosphine ligands
ryl thioethers and derivatives such as sulfoxides and
sulfones are increasingly important classes of molecules in
the pharmaceutical industry and for other applications. For
successfully applied in the development of C−S cross-coupling,
which has instead relied primarily on catalysts derived from
tightly binding chelating bisphosphine ligands. These ligands
are thought to minimize deactivation by nucleophilic thiolate
A
1
2
instance, S-aryl fragments are found in marketed drugs that
3a
treat schizophrenia (perphenazine), autoimmune disorders
ligands (vide supra). Following pioneering studies by
3
b
6n,o
(
nelfinavir mesylate), rheumatoid arthritis and organ
Migita,
a few applications of Pd(PPh ) -catalyzed coupling
3 4
6r,s
3
c
3d
3e
rejection (azathioprine), cancer (axitinib, bicalutamide ),
of aryl halides with thiolate anions have been reported.
Currently, however, bidentate phosphine-based catalysts such
3f
and heart conditions (ticagrelor). Given the availability of
thiols and aryl halides or pseudohalides, metal-catalyzed cross-
coupling, including Pd-catalyzed C−S coupling in partic-
ular, has emerged as a popular synthetic route to these
6k
6m
as SL-J009 (L6) and XantPhos (L7) have emerged as the
ligands of choice for this transformation due to their to
improved generality, higher reactivity, and prolonged stability.
More recently, several elegant alternative strategies for
circumventing the phosphine displacement problem have
emerged, including the use of a strongly donating NHC
4
,5
6
compounds (Figure 1).
It is well-known that each of the elementary steps within the
catalytic cycle (see below, Figure 2A) is associated with a low
activation barrier: definitive mechanistic investigations by
II6p
I
ligand-supported Pd
or a dimeric Pd complex as a
6
q
6
k
catalyst. Despite significant advances with regard to
minimizing catalyst loading and maximizing turnover numbers,
substantial limitations still remain. Foremost, the requirement
to employ elevated temperatures renders the reaction
conditions incompatible with many functional groups and
medicinally important heterocycles. In particular, the combi-
nation of high temperature and strong base has been shown to
cause significant problems for even mildly base-sensitive
Hartwig, as well as reports of relevant stoichiometric
7
reactions involving palladium complexes, indicate that each
transformation can take place in seconds or minutes under
ambient conditions. Nevertheless, the leading catalytic
methods require elevated temperatures to obtain synthetically
useful yields. This discrepancy is typically attributed to the
proclivity of palladium-based catalysts to form off-cycle resting
state species in the presence of thiols. Two frequently cited
pathways for catalyst deactivation are (1) the formation of
13
substrates, such as indazoles. Furthermore, the requirement
for such substantial energy input is wasteful considering the
rapidity of the elementary steps under ambient conditions.
unreactive LPd(H)SR or [LPd(SR)2]− complexes
and (2) the displacement of the phosphine ligand by the
4a,5a,6a,d,h,k
4b,5a,6d,k−m
binding of multiple thiolate ligands.
Although monophosphine-ligated palladium catalysts have
Received: May 8, 2019
Revised: June 6, 2019
8
9
10
shown exceptionally high reactivity in C−C, C−N, C−O,
1
1
12
C−F, and C−CF cross-coupling, they have not yet been
3
©
XXXX American Chemical Society
6461
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466

ACS Catalysis
Research Article
13
cross-coupling conditions. Although nitrogenous hetero-
cycles such as indazole feature prominently in pharmaceuticals
and bioactive natural products, base-mediated Kemp elimi-
nation is a major side-reaction when strong bases and
14
prolonged heating are required. In our study, the cross-
coupling of this heteroaryl bromide was evaluated with 1-
decanethiol in the presence of triethylamine, a soluble, organic
base, and a number of oxidative-addition-complex precata-
1
5
lysts (P1−P5) derived from monophosphine catalysts
developed in our laboratory (for details, see the Supporting
Information). Additionally, precatalysts bearing the two most
frequently employed bisphosphine ligands, XantPhos (L6) and
SL-J009-1 (L7), were tested.
As shown in Table 1, after 2 h at room temperature, the
reactions using precatalysts derived from tBuBrettPhos (L2)
and tBuXPhos (L4) showed high yields of the desired product
(
97% and 100%, respectively). Reactions using complexes of
ligands with smaller P-Cy groups in lieu of P-tBu groups
resulted in diminished activity. Notably, at the low temper-
atures employed, catalysts bearing bisphosphine ligands (L6,
L7) failed to deliver useful amounts of the desired product. We
also determined that, when using a lower catalyst loading (0.2
mol %), tert-butanol is the best solvent for this transformation.
Aromatic thiols differ significantly from aliphatic thiols in
terms of acidity and nucleophilicity. Thus, unsurprisingly, the
reaction conditions developed for aliphatic thiols proved to be
suboptimal for the reactions of aryl thiols. For these substrates,
we evaluated a subset of precatalysts in the coupling of the
model aryl bromide with 4-methoxythiophenol. While catalysts
based on L2 and L4 provided limited yields, the AlPhos (L5)-
bound precatalyst provided a promising quantity of the C−S
coupled product (61%, Table 2, entry 5). However, in view of
the significant cost differences between tBuBrettPhos (L4) and
AlPhos (L5), a similarly effective method using an L4-based
precatalyst was desirable. Accordingly, with further optimiza-
tion, we were able to achieve the same high yield using
commercially available L4-G3 by using LHMDS, another
Figure 1. Overview of phosphine ligand development for Pd-catalyzed
C−S cross-coupling.
Other methods require the preformation of sodium thiolate
6
q
salts or rigorous exclusion of disulfide impuritieswhich
6
p
form readily from thiolsfrom the reaction mixture. Finally,
the vast majority of C−S coupling protocols rely on insoluble,
inorganic bases, which pose considerable challenges for
miniaturization and for continuous flow applications. In view
of the previous successes of biaryl monophosphine-based
palladium catalysts in addressing similar issues in related cross-
coupling reactions, we considered whether they might be
effective for catalytic C−S coupling, in spite of concerns
regarding thiolate-mediated deactivation.
8a
soluble base.
We selected 4-bromo-1-methylindazole as a model substrate,
since N-substituted indazoles and other base-sensitive hetero-
cycles have proven challenging under state-of-the-art C−S
Having discovered efficient conditions for coupling reactions
of both aliphatic and aromatic thiols, we examined their scope.
First, a variety of aliphatic thiols were efficiently coupled with
Figure 2. Mechanistic studies. See the Supporting Information for details. (a) Using triethylamine as the base, experiments conducted in benzene-
d6. (b) Using LHMDS as the base, experiments conducted in THF. (c) Yield of the catalytic reaction as determined by GC after 2 h. (d) Measured
in CDCl rather than benzene.
3
6
462
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466

ACS Catalysis
Research Article
a
Table 1. Evaluation of Catalysts and Reaction Conditions
for Pd-Catalyzed Alkyl Thiol Arylation
Table 3. Scope of the Aliphatic Thiol Coupling Reaction
a
a
Conditions: aryl bromide (0.1 mmol, 1.0 equiv), thiol (1.2 equiv),
triethylamine (2.0 equiv), precatalyst (indicated amount) in solvent
(
0.20 mL) for 2 h. The yield was determined by calibrated gas
chromatography (GC) using dodecane as an internal standard. See
the Supporting Information for more details.
a
Conditions: aryl bromide (1.0 mmol, 1.0 equiv), thiol (1.2 equiv),
16
triethylamine (2.0 equiv), precatalyst (1 mol %) in tert-butanol (2.0
mL). The precatalyst used and reaction time are indicated in
parentheses. Yields represent average isolated yields from two
independent replicates. For examples of reactant combinations that
fail to provide useful yields of coupling product under our conditions,
Table 2. Evaluation of Catalysts and Reaction Conditions
a
for Pd-Catalyzed Aryl Thiol Arylation
b
see Table S1. See the Supporting Information for details. THF was
used as the solvent instead of tert-butanol.
thiazole (2l), and a quinoline (2o), were transformed in high
yield, regardless of their electronic properties. Notably, many
protic substituents are well-tolerated, including a phenol (2b),
primary aniline (2c), carboxylic acids (2e, 2l), aliphatic
alcohols (2k, 2m), an amide (2n), and a sulfonamide (2g),
without competing C−N or C−O coupling. For substrates
with exceptionally low solubility in tert-butanol, THF can be
used as a solvent or cosolvent, and excellent isolated yields are
obtained (e.g., 2f, 2k).
The substrate scope of the aromatic thiol coupling was also
good (Table 4). Both electron-rich (3b, 3c) and electron-
deficient (3f, 3g) thiols were arylated in high yields.
Heterocyclic partners such as an unprotected indazole (3a),
an isoquinoline (3b), and hindered pyridines (3j−3l) reacted
well under these conditions. Importantly, no background
reactions such as nucleophilic aromatic substitution were
observed in the absence of palladium or ligand. Again, an
aniline (3d) and a phenol (3g) underwent the desired C−S
coupling transformation without competing C−N or C−O
a
Conditions: aryl bromide (0.1 mmol, 1.0 equiv), thiol (1.2 equiv),
triethylamine (2.0 equiv), precatalyst (indicated amount) in solvent
(
0.20 mL) for 2 h. The yield was determined by calibrated gas
chromatography (GC) using dodecane as an internal standard. See
b
the Supporting Information for more details. Using LHMDS (2.4
equiv) instead of triethylamine. For further reaction optimization
data, see Table S2 in the Supporting Information.
aryl or heteroaryl bromides, and many common functional
groups on either partner were tolerated under the mild
reaction conditions (Table 3). In particular, both 5- and 6-
membered heterocycle electrophiles, including an azaindole
(2f), a thiophene (2h), a benzothiazole (2i), a pyrazole (2j), a
6
463
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466

ACS Catalysis
Research Article
a
Table 4. Scope of the Aromatic Thiol Coupling Reaction
In the coupling of aliphatic thiols, contrary to our
expectations, free ligand was not observed in any case, except
when a precatalyst based on L1 was used. This indicated that,
at least at room temperature and with only a weak base
present, displacement of the phosphine ligand by alkyl
thiolate(s) is not a significant problem for either mono- or
bisphosphine ligands. Consistent with previous studies, the
failure of bisphosphine ligands L6 and L7 to form efficient
catalysts under these reaction conditions is not due to
phosphine displacement, but rather due to the formation of
alternative, stable off-cycle species: a L Pd dimer in the case of
2
6h
L6, and a hydridopalladium thiolate in the case of L7.
The analogous experiments using aromatic thiols further
underscore the difficulty of predicting the steady-state ligand
distribution in these coupling reactions. In these cases, most
ligands were observed to be in their unbound form during the
course of the reaction. Surprisingly, XantPhos (L6), a
bisphosphine ligand, was entirely unbound in its resting
state, while L5, the most sterically hindered monophosphine
ligand, remained partially Pd-bound. Finally, these data again
caution against inferring the competency of catalysts from their
resting statefor instance, in the case of the catalysts derived
from L2 and L4, although the phosphine appears to
completely dissociate during the reaction, the desired arylation
was still observed.
In summary, we have found that certain biaryl mono-
phosphine ligands form exceptionally effective catalysts that
promote C−S coupling reactions under mild conditions, with
soluble bases, and in the presence of many useful functional
groups. These catalysts are sufficiently active that they promote
thioether formation even when no phosphine-bound palladium
species is observable by NMR.
a
Conditions: aryl bromide (1.0 mmol, 1.0 equiv), thiol (1.2 equiv),
17
LHMDS (2.4 equiv), precatalyst (3 mol %) in THF (2.0 mL).
Yields represent average isolated yields from two independent
replicates. See the Supporting Information for details.
coupling. Finally, aryl bromides were chemoselectively
converted in the presence of aryl chlorides, and thus,
chloroarene products such as 3f, which are easily derivatized
by further cross-coupling, could be produced in high isolated
yield.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b01913.
■
*
S
The effectiveness of these monophosphine catalyst systems
raised important mechanistic questions. Historically, it has
been assumed that chelating bisphosphine ligands should bind
palladium more tightly and, thus, be less prone to thiol(ate)-
mediated displacement and deactivation. However, under our
conditions (room temperature, soluble base), monophosphine-
based catalysts clearly outperformed the state-of-the-art
bisphosphine systems. To resolve this discrepancy, we
considered the following explanations. First, it was possible
that the rate or extent of displacement of a given phosphine
from palladium by thiolate ligands did not follow conventional
predictions. For instance, perhaps biaryl monophosphine
ligands are particularly difficult to displace. Second, the
effectiveness of a given catalyst might not be well-predicted
by the distribution of ligand (Pd-bound or free) in the catalytic
resting state.
Additional experimental details, data, and figures
including structures and characterizations (PDF)
13
1
C and H NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: charles.yeung@merck.com.
*E-mail: sbuchwal@mit.edu.
ORCID
Richard Y. Liu: 0000-0003-0951-6487
Charles S. Yeung: 0000-0001-7320-7190
Stephen L. Buchwald: 0000-0003-3875-4775
■
Notes
The authors declare the following competing financial
interest(s): MIT has filed patents on ligands and precatalysts
that are described in this Article, from which S.L.B. and
former/current coworkers receive royalty payments.
To examine these hypotheses, we needed to establish the
resting state of various catalysts during the steady-state portion
of the catalytic reaction. Using NMR spectroscopy, we
followed reactions using precatalysts derived from L1−L7
under conditions similar to the optimal reaction conditions,
except with slightly elevated catalyst loading for more accurate
detection of intermediates (Figure 2B). We measured the
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R35GM122483.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
3
1
steady-state distribution of the ligand using P NMR
measurements made during the course of the coupling
reaction.
6
464
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466

ACS Catalysis
Research Article
Institutes of Health. We thank Dr. Tony Siu (Merck), Dr. Brett
A. Hopkins (Merck), Dr. Scott McCann (MIT), Dr. Andy
Thomas (MIT), and Dr. Christine Nguyen (MIT) for advice
on the preparation of this manuscript. We thank Jacob M.
Ganley (Merck) for assistance with preliminary experiments.
We are grateful to Sigma-Aldrich for gifts of ligands (XPhos,
BrettPhos, tBuXPhos, tBuBrettPhos) and Solvias for a gift of
the CyPF-tBu used in our research. We thank Rosina Ayore
Couplings via Single-Electron Transfer: Reactions of Thiols with Aryl
Halides Under Mild Conditions (0°C). J. Am. Chem. Soc. 2013, 135,
9
548−9552. (e) Kabir, M. S.; Lorenz, M.; Van Linn, M. L.; Namjoshi,
O. A.; Ara, S.; Cook, J. M. A Very Active Cu-Catalytic System for the
Synthesis of Aryl, Heteroaryl, and Vinyl Sulfides. J. Org. Chem. 2010,
7
5, 3626−3643. (f) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.;
van Koten, G. Ligand-Free Copper-Catalyzed C-S Coupling of Aryl
Iodides and Thiols. J. Org. Chem. 2008, 73, 5625−5628. (g) Jammi,
S.; Barua, P.; Rout, L.; Saha, P.; Punniyamurthy, T. Efficient Ligand-
Free Nickel-Catalyzed C−S Cross-Coupling of Thiols with Aryl
Iodides. Tetrahedron Lett. 2008, 49, 1484−1487. (h) Correa, A.;
Carril, M.; Bolm, C. Iron-Catalyzed S-Arylation of Thiols with Aryl
Iodides. Angew. Chem., Int. Ed. 2008, 47, 2880−2883. (i) Zhang, Y.;
Ngeow, K. C.; Ying, J. Y. The First N-Heterocyclic Carbene-Based
Nickel Catalyst for C−S Coupling. Org. Lett. 2007, 9, 3495−3498.
(
Merck) and Wilfredo Pinto (Merck) for collecting HRMS
data of aryl thioether products.
REFERENCES
■
(
1) For a review, see: Feng, M.; Tang, B.; Liang, S. H.; Jiang, X.
Sulfur Containing Scaffolds in Drugs: Synthesis and Application in
(
j) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Cobalt-Catalyzed Aryl−
Sulfur Bond Formation. Org. Lett. 2006, 8, 5613−5616.
6) For examples of C−S bond-forming reactions from aryl
pseudo)halides catalyzed by Pd, see: (a) Scattolin, T.; Senol, E.;
Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200−1216.
(
2) (a) Thuillier, A.; Metzner, P. Sulfur Reagents in Organic Synthesis;
(
Academic Press: New York, 1994. (b) Bernardi, F.; Csizmadia, I. G.;
Mangini, A. Organic Sulfur Chemistry. Theoretical and Experimental
Advances; Elsevier: Amsterdam, The Netherlands, 1985; Vol. 19.
(
Yin, G.; Guo, Q.; Schoenebeck, F. Site-Selective C−S Bond
Formation at C−Br over C−OTf and C−Cl Enabled by an Air-
Stable, Easily Recoverable, and Recyclable Palladium(I) Catalyst.
Angew. Chem., Int. Ed. 2018, 57, 12425−12429. (b) Qiao, Z.; Wei, J.;
Jiang, X. Direct Cross-Coupling Access to Diverse Aromatic Sulfide:
Palladium-Catalyzed Double C−S Bond Construction Using Na S O
(
c) Rayner, C. M. Advances in Sulfur Chemistry; JAI Press: Greenwich,
CT, 2000; Vol. 2.
3) (a) Rees, L. C. Chlorpromazine and Allied Phenothiazine
(
Derivatives. Br. Med. J. 1960, 2, 522−525. (b) Kaldor, S. W.; Kalish,
V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J.
A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman,
B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.;
Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H.
Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavail-
able Inhibitor of HIV-1 Protease. J. Med. Chem. 1997, 40, 3979−3985.
2
2
3
as a Sulfurating Reagent. Org. Lett. 2014, 16, 1212−1215. (c) Mao, J.;
Jia, T.; Frensch, G.; Walsh, P. J. Palladium-Catalyzed Debenzylative
Cross-Coupling of Aryl Benzyl Sulfides with Aryl Bromides: Synthesis
of Diaryl Sulfides. Org. Lett. 2014, 16, 5304−5307. (d) Valente, C.;
Pompeo, M.; Sayah, M.; Organ, M. G. Carbon−Heteroatom
Coupling Using Pd-PEPPSI Complexes. Org. Process Res. Dev. 2014,
(
2
(
c) Azathioprine, Azathioprine Sodium. In AHFS Drug Information
012. American Society of Health-System Pharmacists, 2012.
d) Wilmes, L. J.; Pallavicini, M. G.; Fleming, L. M.; Gibbs, J.;
1
8, 180−190. (e) Bastug, G.; Nolan, S. P. Carbon−Sulfur Bond
OMe
Formation Catalyzed by [Pd(IPr* )(cin)Cl] (cin = cinnamyl). J.
Org. Chem. 2013, 78, 9303−9308. (f) Teverovskiy, G.; Surry, D. S.;
Wang, D.; Li, K. L.; Partridge, S. C.; Henry, R. G.; Shalinsky, D. R.;
Hu-Lowe, D.; Park, J. W.; McShane, T. M.; Lu, Y.; Brasch, R. C.;
Hylton, N. M. (April 2007). AG-013736, A Novel Inhibitor of VEGF
Receptor Tyrosine Kinases, Inhibits Breast Cancer Growth and
Decreases Vascular Permeability as Detected by Dynamic Contrast-
Enhanced Magnetic Resonance Imaging. Magn. Reson. Imaging 2007,
Buchwald, S. L. Pd-Catalyzed Synthesis of Ar-SCF Compounds
3
Under Mild Conditions. Angew. Chem., Int. Ed. 2011, 50, 7312−7314.
(
g) Fernandez-Rodríguez, M. A.; Hartwig, J. F. One-Pot Synthesis of
́
Unsymmetrical Diaryl Thioethers by Palladium-Catalyzed Coupling
of Two Aryl Bromides and a Thiol Surrogate. Chem. - Eur. J. 2010, 16,
2
355−2359. (h) Alvaro, E.; Hartwig, J. F. Resting State and
2
5, 319−327. (e) Cockshott, I. D. Bicalutamide, Clinical Pharmaco-
kinetics and Metabolism. Clin. Pharmacokinet. 2004, 43, 855−878.
f) Jacobson, K. A.; Boeynaems, J.-M. P2Y Nucleotide Receptors:
Promise of Therapeutic Applications. Drug Discovery Today 2010, 15,
70−578.
4) For selected reviews on metal-catalyzed thioether synthesis, see:
a) Lee, C.-F.; Liu, Y.-C.; Badsara, S. S. Transition-Metal-Catalyzed
C−S Bond Coupling Reaction. Chem. - Asian J. 2014, 9, 706−722.
b) Eichman, C. C.; Stambuli, J. P. Transition Metal Catalyzed
Elementary Steps of the Coupling of Aryl Halides with Thiols
Catalyzed by Alkylbisphosphine Complexes of Palladium. J. Am.
́
Chem. Soc. 2009, 131, 7858−7868. (i) Fernandez-Rodríguez, M. A.;
(
Hartwig, J. F. A General, Efficient, and Functional-Group-Tolerant
Catalyst System for the Palladium-Catalyzed Thioetherification of
Aryl Bromides and Iodides. J. Org. Chem. 2009, 74, 1663−1672.
5
(
(
(
j) Lee, J.-Y.; Lee, P. H. Palladium-Catalyzed Carbon−Sulfur Cross-
Coupling Reactions with Indium Tri(organothiolate) and Its
(
Application to Sequential One-Pot Processes. J. Org. Chem. 2008,
Synthesis of Aryl Sulfides. Molecules 2011, 16, 590−608. (c) Be-
letskaya, I. P.; Ananikov, V. P. Transition-Metal-Catalyzed C−S, C−
Se, and C−Te Bond Formation via Cross-Coupling and Atom-
Economic Addition Reactions. Chem. Rev. 2011, 111, 1596−1636.
7
3, 7413−7416. (k) Fernandez-Rodríguez, M. A.; Shen, Q.; Hartwig,
́
J. F. A General and Long-Lived Catalyst for the Palladium-Catalyzed
Coupling of Aryl Halides with Thiols. J. Am. Chem. Soc. 2006, 128,
2180−2181. (l) Murata, M.; Buchwald, S. L. A General and Efficient
Method for the Palladium-Catalyzed Cross-Coupling of Thiols and
Secondary Phosphines. Tetrahedron 2004, 60, 7397−7403. (m) Itoh,
T.; Mase, T. A General Palladium-Catalyzed Coupling of Aryl
Bromides/Triflates and Thiols. Org. Lett. 2004, 6, 4587−4590.
(n) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-I.; Kato, Y.;
Kosugi, M. The Palladium Catalyzed Nucleophilic Substitution of
Aryl Halides by Thiolate Anions. Bull. Chem. Soc. Jpn. 1980, 53,
1385−1389. (o) Kosugi, M.; Shimizu, T.; Migita, T. Reactions of Aryl
Halides with Thiolate Anions in the Presence of Catalytic Amounts of
Tetrakis(Triphenylphosphine)Palladium: Preparation of Aryl Sulfides.
Chem. Lett. 1978, 7, 13−14. (p) Farmer, J.; Pompeo, M.; Lough, A. J.;
(
d) Ley, S. V.; Thomas, A. W. Modern Synthetic Methods for
Copper-Mediated C(aryl)−O, C(aryl)−N, and C(aryl)−S Bond
Formation. Angew. Chem., Int. Ed. 2003, 42, 5400−5449.
(
e) Kondo, T.; Mitsudo, T.-A. Metal-Catalyzed Carbon−Sulfur
Bond Formation. Chem. Rev. 2000, 100, 3205−3220.
5) For examples of C−S bond-forming reactions from aryl
pseudo)halides catalyzed by metals other than Pd, see: (a) Oderinde,
(
(
M. S.; Frenette, M.; Robbins, D. W.; Aquila, B.; Johannes, J. W.
Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols
With Aryl and Heteroaryl Iodides via Thiyl Radicals. J. Am. Chem. Soc.
2
016, 138, 1760−1763. (b) Jouffroy, M.; Kelly, C. B.; Molander, G.
A. Thioetherification via Photoredox/Nickel Dual Catalysis. Org. Lett.
2
016, 18, 876−879. (c) Venkanna, G. T.; Arman, H. D.; Tonzetich,
Organ, M. G. [(IPent)PdCl (morpholine)]: A Readily Activated
2
Z. J. Catalytic C−S Cross-Coupling Reactions Employing Ni
Complexes of Pyrrole-Based Pincer Ligands. ACS Catal. 2014, 4,
Precatalyst for Room-Temperature, Additive-Free Carbon−Sulfur
Coupling. Chem. - Eur. J. 2014, 20, 15790−15798. (q) Scattolin, T.;
Senol, E.; Yin, G.; Guo, Q.; Shoenebeck, F. Site-Selective C−S Bond
Formation at C−Br over C−OTf and C−Cl Enabled by an Air-Stable,
2
941−2950. (d) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. A New
Family of Nucleophiles for Photoinduced, Copper-Catalyzed Cross-
6
465
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466

ACS Catalysis
Research Article
Easily Recoverable, and Recyclable Palladium(I) Catalyst. Angew.
Chem., Int. Ed. 2018, 57, 12425−12429. (r) Hutton, J.; Jones, A. D.;
Lee, S. A.; Martin, D. M. G.; Meyrick, B. R.; Patel, I.; Peardon, R. F.;
Powell, L. Use of a Titanium Thienyl Anion and a Simple procedure
for Introducing a Thiol Group into Thiophene in the Development of
a Manufacturing Route to the 5-Lipoxygenase Inhibitor ZD4407. Org.
Process Res. Dev. 1997, 1, 61−67. (s) Haile, P. A.; Votta, B. J.;
Marquis, R. W.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R.; Charnley,
A. K.; Lakdawala, A. S.; Convery, M. A.; Lipshutz, D. B.; Desai, B. M.;
Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.;
Rivera, E. J.; Sun, H. H.; Nagilla, R.; Beal, A. M.; Finger, J. N.; Cook,
M. N.; King, B. W.; Ouellette, M. T.; Totoritis, R. D.; Pierdomenico,
M.; Negroni, A.; Stronati, L.; Cucchiara, S.; Ziolkowski, B.;
Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.;
Casillas, L. N. The Identification and Pharmacological Character-
ization of 6-(tert-Butylsulfonyl)-N-(5-Fluoro-1H-Indazol-3-yl)-
quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor
of RIP2 Kinase. J. Med. Chem. 2016, 59, 4867−4880.
Catalyzed Trifluoromethylation of Aryl Chlorides. Science 2010, 328,
1679−1681.
(13) Ganley, J. M.; Yeung, C. S. Unprotected Indazoles Are Resilient
to Ring-Opening Isomerization: A Case Study on Catalytic C−S
Couplings in the Presence of Strong Base. J. Org. Chem. 2017, 82,
13557−13562.
(14) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. Physical
Organic Chemistry of Benzisoxazoles. I. Mechanism of The Base-
Catalyzed Decomposition of Benzisoxazoles. J. Org. Chem. 1973, 38,
2
(
294−2301.
15) Ingoglia, B. T.; Buchwald, S. L. Oxidative Addition Complexes
as Precatalysts for Cross-Coupling Reactions Requiring Extremely
Bulky Biarylphosphine Ligands. Org. Lett. 2017, 19, 2853−2856.
(16) P4 and P*4 exist in equilibrium with a dearomatized isomer, as
described in the Supporting Information. For a detailed investigation
of this reversible rearrangement, see: Milner, P. J.; Maimone, T. J.; Su,
M.; Chen, J.; Mu, P.; Buchwald, S. L. Investigating the Dearomative
Rearrangement of Biaryl Phosphine- Ligated Pd (II) Complexes. J.
Am. Chem. Soc. 2012, 134, 19922−19934.
(
7) For synthetic applications of stoichiometric C−S bond
(
17) The precatalyst L4-CH Cl was purchased from Strem as the
2 2
formation from arylpalladium complexes, see: (a) Kubota, K.; Dai,
P.; Pentelute, B. L.; Buchwald, S. L. Palladium Oxidative Addition
Complexes for Peptide and Protein Crosslinking. J. Am. Chem. Soc.
dichloromethane solvate and was used as purchased. See the
Supporting Information for details.
2018, 140, 3128−3133. (b) Rojas, A. J.; Zhang, C.; Vinogradova, E.
V.; Buchwald, N.; Reilly, J.; Pentelute, B. L.; Buchwald, S. L.
Divergent Unprotected Peptide Macrocyclisation by Palladium-
Mediated Cysteine Arylation. Chem. Sci. 2017, 8, 4257−4263.
(
c) Vinogradova, E. V.; Zhang, C.; Spokoyny, A. M.; Pentelute, B.
L.; Buchwald, S. L. Organometallic Palladium Reagents for Cysteine
Bioconjugation. Nature 2015, 526, 687−691.
(
8) (a) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and
Preparation of New Palladium Precatalysts for C−C and C−N Cross-
Coupling Reactions. Chem. Sci. 2013, 4, 916−920. (b) Martin, R.;
Buchwald, S. L. Palladium-Catalyzed Suzuki−Miyaura Cross-
Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands.
Acc. Chem. Res. 2008, 41, 1461−1473.
(
9) (a) Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L.
Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst
Enables the Use of a Common Soluble Base in C−N Coupling. J. Am.
Chem. Soc. 2018, 140, 4721−4725. (b) Ruiz-Castillo, P.; Buchwald, S.
L. Applications of Palladium-Catalyzed C−N Cross-Coupling
Reactions. Chem. Rev. 2016, 116, 12564−12649. (c) Surry, D. S.;
Buchwald, S. L. Dialkylbiaryl Phosphines in Pd-catalyzed Amination:
a User’s Guide. Chem. Sci. 2011, 2, 27−50.
(
10) (a) Zhang, H.; Ruiz-Castillo, P.; Buchwald, S. L. Palladium-
Catalyzed C−O Cross-Coupling of Primary Alcohols. Org. Lett. 2018,
2
0, 1580−1583. (b) Cheung, C. W.; Buchwald, S. L. Palladium-
Catalyzed Hydroxylation of Aryl and Heteroaryl Halides Enabled by
the Use of a Palladacycle Precatalyst. J. Org. Chem. 2014, 79, 5351−
5
358. (c) Cheung, C. W.; Buchwald, S. L. Mild and General
Palladium-Catalyzed Synthesis of Methyl Aryl Ethers Enabled by the
Use of a Palladacycle Precatalyst. Org. Lett. 2013, 15, 3998−4001.
(
d) Wu, X.; Fors, B. P.; Buchwald, S. L. A Single Phosphine Ligand
Allows Palladium-Catalyzed Intermolecular C−O Bond Formation
with Secondary and Primary Alcohols. Angew. Chem., Int. Ed. 2011,
5
(
0, 9943−9947.
11) (a) Sather, A. C.; Buchwald, S. L. The Evolution of Pd(0)/
Pd(II)-Catalyzed Aromatic Fluorination. Acc. Chem. Res. 2016, 49,
146−2157. (b) Watson, D. A.; Teverovskiy, G.; Zhang, Y.; Garcia-
2
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Formation of ArF from
LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides.
Science 2009, 325, 1661−1664.
(
12) (a) Ferguson, D. M.; Bour, J. R.; Canty, A. J.; Kampf, J. W.;
Sanford, M. S. Stoichiometric and Catalytic Aryl−Perfluoroalkyl
Coupling at Tri-tert-butylphosphine Palladium(II) Complexes. J. Am.
Chem. Soc. 2017, 139, 11662−11665. (b) Cho, E. J.; Buchwald, S. L.
The Palladium-Catalyzed Trifluoromethylation of Vinyl Sulfonates.
Org. Lett. 2011, 13, 6552−6555. (c) Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. The Palladium-
6
466
DOI: 10.1021/acscatal.9b01913
ACS Catal. 2019, 9, 6461−6466