Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts

Article abstract of DOI:10.1021/jacs.9b13260

Pyridine and related heterocyclic sulfinates have recently emerged as effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with (hetero)aryl halides. These sulfinate reagents are straightforward to prepare, stable to storage and coupling reaction conditions, and deliver efficient reactions, thus offering many advantages, compared to the corresponding boron-derived reagents. Despite the success of these reactions, there are only scant details of the reaction mechanism. In this study, we use structural and kinetic analysis to investigate the mechanism of these important coupling reactions in detail. We compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps, for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex formed post-transmetalation is the resting-state intermediate, and loss of SO₂ from this complex is turnover-limiting. We also investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)₂ to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver improved, lower temperature versions of these synthetically important processes.

Full text of DOI:10.1021/jacs.9b13260

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Article
Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-
Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts
Antoine de Gombert, Alasdair I. McKay, Christopher J. Davis, Katherine M. Wheelhouse,
and Michael C. Willis*
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sı Supporting Information
ABSTRACT: Pyridine and related heterocyclic sulfinates have
recently emerged as effective nucleophilic coupling partners in
palladium-catalyzed cross-coupling reactions with (hetero)aryl
halides. These sulfinate reagents are straightforward to prepare,
stable to storage and coupling reaction conditions, and deliver
efficient reactions, thus offering many advantages, compared to the
corresponding boron-derived reagents. Despite the success of these
reactions, there are only scant details of the reaction mechanism. In
this study, we use structural and kinetic analysis to investigate the
mechanism of these important coupling reactions in detail. We
compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps,
for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state
intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex
formed post-transmetalation is the resting-state intermediate, and loss of SO from this complex is turnover-limiting. We also
2
investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual
function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation
plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)2
to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver
improved, lower temperature versions of these synthetically important processes.
1
. INTRODUCTION
More generally, transition-metal-catalyzed desulfinative
cross-coupling has emerged as an effective method for C−C
1
The Suzuki−Miyaura reaction, in which a boron-based
coupling partner is combined with an aryl halide using a
palladium catalyst, has revolutionized synthetic chemistry in
7
bond formation. First employed for homocoupling with
8
stoichiometric palladium(II), sulfinate salts can now be
2
employed as the electrophilic coupling partner in Mizoroki−
the pharmaceutical industry. However, applying these
9
10
11
Heck, Suzuki−Miyaura, and Hiyama cross-coupling
reactions to the preparation of heteroaromatic derivatives has
long remained a challenge, because the corresponding
heterocycle-derived boronic acids (and related boron-based
reagents) can be challenging to prepare, unstable, base-
sensitive, and prone to protodeboronation and decomposition
under cross-coupling conditions. This is particularly true for
processes. Their use as nucleophilic coupling partners was
first reported in a 1992 patent, before being more widely
developed for both aromatic or five-membered O- and S-
heteroaromatic systems. Catalytic versions of homocoupling
12
13
14
15
reactions have also been reported. Together with decarbox-
ylation-based methods, desulfination can be considered as a
potentially more sustainable approach to cross-coupling
chemistry, relative to processes that require the preparation
and use of costly and sensitive organometallic reagents. The
3
pyridine and related diazene-derived boronic acids. In this
context, the Willis laboratory has recently reported the use of
4
5
pyridyl and heteroaryl sulfinate salts as nucleophilic reagents
in palladium-catalyzed cross-coupling reactions with aryl and
heteroaryl halides (Scheme 1a). These sulfinate salts, several of
which are now commercial products, are stable reagents and
deliver efficient reactions with challenging coupling partners,
thus addressing many of the limitations of their boron
counterparts. More recently, the use of related heteroaryl
allylsulfones, which function as latent sulfinate coupling
release of SO gas as the main byproduct should also be
2
considered in this context. While decarboxylation has been
Received: December 9, 2019
6
partners, has also been reported.
©
XXXX American Chemical Society
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A

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Scheme 1. Heterocyclic Sulfinate Coupling Reactions, a
Scheme 2. Substrates and Reactions To Be Studied
Generalized Mechanism, and Aims of the Study
For example, sodium 4-methylbenzenesulfinate 4 can be
combined with 1-bromo-4-fluorobenzene using Pd(OAc)2,
PCy , and K CO at 150 °C to deliver the cross-coupling
3
2
3
product 5 in 92% yield. Encouraged by the robustness of these
reaction conditions, we chose to compare the reactivity of
heterocyclic and carbocyclic sulfinate salts, as the carbocyclic
7
variants of this cross-coupling also require high temperatures.
Indeed, such carbocyclic sulfinate salts are inexpensive, bench-
1
6
17
studied both experimentally and theoretically, the intrinsic
stable reagents that can be easily prepared via a broad range of
2
3
20
difference between an sp -hybridized carbon center and an sp -
hybridized sulfur center precludes direct transposition of these
studies to the desulfinative variants. Similarly, although
carbonylation and sulfur dioxide insertion are related
methods. A lower temperature cross-coupling of such
reagents would potentially establish sulfinates as attractive
alternatives to the more-expensive boron-based reagents.
Heterocyclic sulfinate 1 and carbocyclic sulfinate 4, together
with aryl bromide 2, were therefore selected as the substrates
for our proposed mechanistic study.
18
processes, they can follow different mechanistic pathways.
To date, no mechanistic investigation of a desulfinative cross-
coupling process using sulfinate salts as nucleophilic coupling
2.2. Synthesis and Characterization of Organo-
metallic Intermediates. 2.2.1. Formation of the Active
Palladium(0) Species. Palladium(II) acetate is employed as
the palladium source for these desulfinative cross-coupling
reactions, and therefore the active Pd(0) species must be
generated via a reductive process. This step is often overlooked
in mechanistic studies, although the Pd(0) species could be
generated from several different pathways and, thus, give rise to
19
partners has been reported.
A generalized mechanism for desulfinative cross-coupling is
shown in Scheme 1b. Reduction of the Pd(II) precatalyst to
the active Pd(0) species is followed by oxidative addition of
the carbon-bromide bond to the transition metal. Trans-
metalation between the alkali metal sulfinate salt and the
oxidative addition complex generates a putative palladium
21
sulfinate intermediate. Extrusion of SO followed by reductive
different kinetic profiles, making the understanding of how
Pd(0) is formed crucial for the design of accurate kinetic
experiments (section 2.4). Phosphine oxidation has long been
2
elimination regenerates the Pd(0) catalyst and delivers
product. In the present study, we explore this mechanism
using two model sulfinate reagents, allowing the comparison of
carbocyclic and heterocyclic substrates. We describe the first
synthesis, characterization, and reactivity study of the putative
palladium sulfinate intermediates. Using a combination of
stoichiometric experiments and kinetic studies, we propose
different resting-state intermediates and turnover limiting steps
for the two different classes of sulfinate reagent. We also
investigate the role of the base, which is a crucial additive for
reactivity. The aim of these studies was to improve the
understanding of these synthetically important transforma-
tions, and also to provide insights for the development of
reactions which proceed using milder conditions, particularly
with regard to the high temperatures (120−185 °C) generally
22
known as a pathway for palladium zero generation, but
nucleophilic coupling partners such as organolithium
23
24
25
26
reagents, organostannanes, alcohols, and amines can
also mediate the reduction of Pd(II) precatalysts. Having
observed such reduction pathways, Buchwald and co-workers
judiciously used substoichiometric amounts of an aryl boronic
acid in order to ensure complete reduction of their Pd(II)
27
precatalysts. Furthermore, a synthetically useful dimerization
of two sulfinate salts using stoichiometric amounts of Pd(II)
8
was reported in the early 1970s. Therefore, we examined the
generation of the active catalyst in the presence of 4-
methylbenzenesulfinate 4 (Figure 1). The two coupling
partners 1-bromo-4-fluorobenzene 2 and 4-methylbenzenesul-
finate 4 were introduced to a Young’s NMR tube, together
with K CO and stoichiometric amounts of Pd(OAc) and
7
used in these reactions.
2
3
2
2
. RESULTS AND DISCUSSION
.1. Model Reactions. The coupling of the unsubstituted
sodium pyridine-2-sulfinate salt 1 with 1-bromo-4-fluoroben-
zene 2 proceeds in 95% yield as shown in Scheme 2. Although
these reactions were initially developed for pyridine sulfinate
PCy in a 2:1 ratio. The NMR tube was then gradually heated
3
2
at different temperatures and the reaction was monitored by
3
1
1
19
1
P{ H} and F{ H} NMR spectroscopy. The known
28
Pd(PCy ) (OAc) complex 6 was rapidly formed at room
3
2
2
3
1
1
temperature. Upon heating to 60 °C, the P{ H} resonance of
6 started to decay to a broad signal at 29.83 ppm,
corresponding to a set of broad doublets at 8.43 and 6.63
4
salts, before being extended to a larger class of heteroaromatic
substrates, they can also be applied to carbocyclic variants.
5
B
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Figure 2. (a) Synthesis of the palladium sulfinate complexes 7 and 10.
X-ray crystal structures (50% displacement ellipsoids) of (b) 7 and
(c) 10. All H atoms have been omitted for the sake of clarity.
Figure 1. 31P{ H} NMR spectra of the reaction between Ar−Br (2)
1
of extrusion of SO from such palladium sulfinate complexes
2
and Ar′SO Na (4) catalyzed by stoichiometric Pd(OAc) and PCy in
2
2
3
(
2
sections 2.2.3.2 and 2.5), and of oxidative addition (section
.2.2), are expected to be fast at such temperatures. Instead,
a Young’s NMR tube at various temperatures. [Legend: 6,
Pd(OAc) (PCy ) ; 7, (Ar′SO )Pd(PCy ) (OAc); 8, (Ar′)Pd-
2
3
2
2
3 2
the oxidative addition complex (4−F-C H )Pd(PCy ) (Br) 9
(
(
PCy ) (OAc); 8b, (Ar′)Pd(PCy ) (Br); and 9, (Ar)(Pd)-
6
4
3 2
3
2
3 2
PCy ) (Br); Ar = 4-F-C H ; Ar′ = 4-Me-C H .]
(δ = 20.08 ppm) was observed. Complex 8 can also undergo
P
3
2
6
4
6
4
an acetate/bromide exchange giving complex 8b (δ = 19.79
P
ppm), which can then undergo similar transformations leading
to the formation of palladium zero and homocoupling product.
Phosphine oxidation products were detected in trace amounts
only, which is consistent with the observation that Pd-
(PCy ) (OAc) 6 is not easily reduced to palladium(0) via
ppm in the 1H NMR spectrum (see the Supporting
Information (SI)).
The complex corresponding to these signals was isolated
from a separate reaction that was performed for 16 h at 60 °C.
Single crystals suitable for an X-ray diffraction (XRD) study
were grown from CH Cl /hexane and revealed a sulfinato-S
3
2
2
21a
phosphine oxidation in the absence of hydroxide bases.
When the cross-coupling was performed using 5−18 mol %
2
2
palladium complex 7 (Figures 2a and 2b). The structure
displays a square planar geometry around the Pd center, with a
trans arrangement of the phosphines. The Pd−S bond length
of 2.2755(4) Å in 7 is shorter than those in (dppf)Pd-
of Pd(OAc) and PCy in a 1:2 ratio, respectively, a linear
2
3
correlation was observed between the amount of homocou-
pling product (4,4′-dimethylbiphenyl) formed and the amount
of Pd(OAc) introduced (see the SI), which supports the
2
2
9
30
(
SO Me)Cl and (BINAP)Pd(SO C H Me)Cl (2.3262(9)
proposed reduction pathway of the precatalyst.
2
2
6
4
and 2.3331(7) Å, respectively). While the Pd−O bond length
When sodium pyridine-2-sulfinate 1 was employed as the
nucleophilic coupling partner, a different palladium complex
10 was isolated (Figures 2a and 2c). This complex also displays
a square planar geometry around the Pd center, with a pyridine
residue lying trans to the phosphine instead of a second
phosphine ligand as in 7. Two 2-pyridyl sulfinate groups are
of 2.0975(13) Å is notably longer than that in (PCy ) Pd-
3
2
(
OAc) (2.0288(17) Å), reflecting the strong trans influence of
2
the sulfinate ligand. The arrangement of the acetate and the 4-
methylbenzenesulfinate about the palladium affords a close
contact (2.578(2) Å) between the nonbound O atom of the
acetate and the 2-aryl-hydrogen of the 4-methylbenzenesulfi-
nate.
2
present in 10. One chelates the palladium in a κ N,O-mode,
affording a five-membered metallocycle. This mode of ligand
binding has precedence in copper 2-pyridyl sulfinate
Complex 7 then undergoes extrusion of SO to give complex
(δ = 18.50 ppm) having a molecular formula of (4-Me-
P
2
31
8
complexes. The second 2-pyridyl sulfinate coordinates the
palladium by the sulfur, trans to the oxygen binding. The Pd−S
bond length in 10 (2.2307(5) Å) is notably shorter than that in
7, possibly reflecting the decreased steric congestion in the
former.
C H )Pd(PCy ) (OAc). The corresponding phenyl complex
6
4
3 2
was reported and characterized by X-ray crystallography by
21a
Eastgate and co-workers. Above 100 °C, complex 8 is then
likely to undergo a second acetate/aryl sulfinate exchange to
form a palladium sulfinate complex (Ar′)Pd(PCy ) (O SAr′),
2.2.2. Oxidative Addition Complex. Once the active Pd(0)
species have been generated, the next step of the presumed
mechanism is the oxidative addition of the carbon−halide
bond to the Pd(0) intermediate. Oxidative addition of
bromobenzene to Pd(PCy ) has been investigated by Baird
3
2
2
followed by extrusion of SO and reductive elimination to
2
generate a palladium zero intermediate and 4,4′-dimethylbi-
phenyl, the homocoupling product. Neither of these two
intermediates were observed by NMR spectroscopy as the rate
3
2
C
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3
2
33
and co-workers and Hartwig and co-workers. Although
these studies were conducted in nonpolar solvents and at room
temperature, both concluded that the oxidative addition was an
irreversible process that involved the aryl bromide substrate
and the two-coordinate palladium zero complex Pd(PCy ) ,
3
2
leading to the formation of compounds with the generic
formula (Ar)Pd(PCy ) (Br). The oxidative addition complex
3
2
(
4-F-C H )Pd(PCy ) (Br) 9 was synthesized independently,
6 4 3 2
34
according to literature procedures, and proved to be a
competent catalyst for our sulfinate coupling reactions, giving
similar reaction rate and yield, compared to the mixture of
Pd(OAc) and PCy (see the SI).
2
3
2
.2.3. Palladium Sulfinate Complexes. For cross-coupling
processes in general, the transmetalation step, which involves
the oxidative addition complex and the nucleophilic coupling
partner, differs for each nucleophile, leading to a wide variety
of mechanisms and palladium intermediates. Such post-
transmetalation complexes have been characterized for several
3
5
36
37
nucleophiles, including alcohols, amines, thiols, and
3
8
carboxylic acids. However, despite having been reported as
efficient coupling partners, to the best of our knowledge, there
is no report of a post-transmetalation intermediate with a
nucleophilic sulfinate. A dimeric palladium sulfinate complex
with bridging Cl− anions has recently been reported by
39
Shavnya and co-workers; however, it is not relevant to an
oxidative addition/transmetalation sequence. In the studied
cross-coupling, putative palladium sulfinate intermediates
would arise from the displacement of the Br atom from
oxidative addition complex 9 by a metal sulfinate salt, as
described in Scheme 3.
Scheme 3. Putative Formation of the Palladium Sulfinate
Complexes
Figure 3. (a) Synthesis of the palladium sulfinate complexes 11 and
2. X-ray crystal structures (50% displacement ellipsoids) of (b) 11,
c) 12, and (d) 13. (e) Structure of 13. All H atoms have been
1
(
omitted for the sake of clarity.
Unlike carboxylate salts, metal sulfinate complexes can have
different coordination modes, binding through sulfur, oxygen,
or both. In the previous section, we have described two types
of palladium sulfinate complexes relevant to the reduction of
Pd(II) to Pd(0). In the following section, we describe the first
synthesis and characterization of post-transmetalation aryl
palladium sulfinate complexes.
4
0
sulfinate, affording a dimeric structure. The structure is similar
to that of [(PMe )Pd(CH CMe C H SO )] , which likewise
3
2
2
6
4
2
2
41
features a trans-phosphorus−sulfur configuration. The bond
lengths and angles observed in 11 also resemble those in
[(PMe )Pd(CH CMe C H SO )] .
3
2
2
6
4
2
2
2
.2.3.1. Synthesis and Characterization. We first attemp-
The diffusion coefficients obtained by DOSY NMR
spectroscopy predicted masses for complexes 11 and 12 in a
2:1 ratio, indicating that the former maintains its dimeric
structure in solution. The degree of aggregation in these
complexes is also maintained when either an electron-donating
or electron-withdrawing substituent is introduced at the
position para to the sulfinate group (see the SI).
ted to form the transmetalation complexes by heating the
oxidative addition complex 9 at moderate to elevated
temperatures (50−120 °C) in the presence of the carbocyclic
sulfinate salt 4. However, formation of biaryl 5 and/or
decomposition were observed. In the presence of silver nitrate,
the oxidative addition complex was entirely consumed at room
temperature, and we isolated the dimeric palladium sulfinate
complex 11 (Figures 3a and 3b). When the pyridine-2-sulfinate
substrate 1 was subjected to the same reaction conditions, the
monomeric palladium sulfinate complex 12 was obtained
A notable exception is when steric bulk, in the form of a tert-
butyl group, is placed at the 6-position of the pyridine. This
2
prevents the κ N,O-binding mode of the pyridine sulfinate,
thereby affording a dimeric solid-state structure 13 which
resembles that of the 4-methylbenzenesulfinate substituted
complex, 11 (Figure 3d). X-ray-suitable crystals could be
obtained from CH Cl /hexane recrystallization of crude
(
Figures 3a and 3c). The geometry about the palladium center
in 12 closely resembles that present in 10. The Pd−O bond
length in complex 12 (2.132(2) Å) is elongated, relative to that
in complex 10 (2.0975(13) Å), reflecting the greater trans
influence of the aryl ligand. A similar square planar geometry
about the palladium is observed in complex 11; however, the
absence of a pyridyl substituent on the sulfinate results in the
vacant site being occupied by the S atom of a neighboring
2
2
reaction mixtures; however, attempts to obtain analytically
pure samples for this compound were unsuccessful.
2.2.3.2. Reactivity. When the dimeric complex 11 was
subjected to 1.1 equiv of PCy , its resonance peak at δ = 27.77
3
P
ppm disappeared and was replaced by a doublet at δ = 21.95
P
D
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confirmed as a square planar palladium complex bearing two
phosphine ligands (Figure 4a). The solid-state structure of 14
closely resembles that of 7; however, unlike in the latter, the
sulfinate binds to palladium via the O atom, rather than a S
atom. This is consistent with a nucleophilic displacement of
the S atom from dimeric complex 11. While the addition of a
phosphine to the dimeric complex 11 occurs at room
temperature, the pyridine sulfinate containing palladacycle 12
was unreactive toward PCy , and compound 15 was not
3
observed, suggesting that the Pd−N bond in 12 is much
stronger than the Pd−S bond in dimeric complex 11 (Figure
4
b). Accordingly, formation of complex 12 was observed at
room temperature upon combining dimeric complex 11 and
sodium pyridine-2-sulfinate 1, whereas the reverse reaction was
not observed under the same conditions (Figure 4c). Exchange
between two carbocyclic sulfinates was not observed at room
temperature either, as dimeric complex 17 was not observed
when the more nucleophilic 4-methoxybenzene-sulfinate salt
1
6 was combined with dimeric complex 11 (Figure 4d).
However, the Pd−S bond of 11 could be cleaved upon
addition of excess pyridine (Figure 4e). A new complex was
observed by NMR spectroscopy and assigned as complex 18,
but its isolation was not possible, since 11 was recovered after
workup.
When 4-methylbenzenesulfinate palladium complex 11 was
heated at 90 °C in toluene-d , it was fully consumed within 20
8
min with concomitant formation of biaryl 5 (Figure 5, gray
diamonds). Complex 14 (generated in situ from 11 and PCy3)
reacted at a slower rate, but gave 84% conversion within 45
min (Figure 5, yellow triangles). Increasing the concentration
of PCy resulted in a significant decrease of the rate of SO
3
2
extrusion at 90 °C, suggesting that ligand dissociation is
necessary prior to desulfination (see the SI). The pyridine-2-
sulfinate palladacycle 12 in which the sulfinate chelates the
2
palladium in a κ N,O-mode only gave 11% conversion after 45
Figure 4. Reactivity of the palladium sulfinate complexes 11 and 12 at
room temperature in 1,4-dioxane/benzene-d6 5:1. X-ray crystal
structure (50% displacement ellipsoids) of 14. All H atoms have
been omitted for the sake of clarity. 16 = 4-MeO-C H −SO Na.
6
4
2
ppm, JP−F = 3.0 Hz. This new signal is very similar to the
resonance peak observed for the oxidative addition complex 9
(
δP = 20.20, JP−F = 3.0 Hz). Although the conversion was
Figure 5. Reactivity of the palladium sulfinate complexes upon
19
1
quantitative according to the F{ H} NMR spectrum, the new
complex was only isolated in 57% yield. Crystals suitable for
XRD were obtained, and the identity of complex 14 was
heating. Reactions were performed in toluene-d in a Young’s NMR
8
tube. Complex 14 was generated in situ from complex 11 and
tricyclohexylphosphine.
E
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min at 110 °C (Figure 5, green circles). Weakening the Pd−N
observed in the 19F{ H} spectrum when the bulky lithium 6-
(tert-butyl)pyridine-2-sulfinate 22 was used. This is consistent
with the observation of the dimeric crystal structure of the 6-
tert-butylsulfinate containing palladium complex 13, as the
1
bond by adding an electron-withdrawing group on the pyridyl
ring, as in complex 20, increased the rate of extrusion of SO in
2
toluene-d , as a 70% conversion was obtained after 45 min at
8
2
110 °C (Figure 5, blue squares). The relative rates of
formation of a κ N,O-chelate is hindered by the tert-butyl group,
consumption of the complexes shown in Figure 5 have been
shown to correspond to the rates of formation of the cross-
coupling products (see the SI).
Overall, these experiments show that the S−Pd bond present
in dimer 11 can readily be displaced by nitrogen- or
phosphorus-based nucleophiles. The formation of five-
membered-ring palladacycles with the pyridine-2-sulfinate
substrates renders the derived palladium sulfinate complexes
more thermodynamically stable, and dramatically slows the
showing that the bulky pyridine sulfinate salt behaves in a
manner similar to that of a carbocyclic substrate.
Since the concentration, stirring, and therefore kinetics in an
NMR tube are not accurately representative of the actual
reaction conditions, the two cross-coupling reactions involving
sodium pyridine-2-sulfinate 1 and sodium 4-methylbenzene-
sulfinate 4 were also performed in microwave tubes at a
relevant scale. The tubes were heated for 2 h at 150 °C, then
500 μL of the reaction mixture were transferred to an NMR
extrusion of SO . In addition, we have shown that complexes
2
tube containing 100 μL of benzene-d . The observed
6
1
1, 12, and 14 are competent catalysts for their respective
coupling reactions (see the SI).
.3. Identification of the Resting-State Intermediates.
resonance peaks were in agreement with the reactions
performed in the Young’s NMR tubes. One difference was
observed for the cross-coupling of pyridine-2-sulfinate salt 1 for
which the ratio between the oxidative addition complex 9 and
the pyridine sulfinate complex 12 was found to be 1:3.8 instead
of 1:1 (see the SI). The use of an appropriate reaction vial
equipped with a stirrer bar instead of Young’s NMR tube must
ease the transmetalation step, which involves the poorly
2
To identify the resting-state intermediates of the catalytic
reactions, the desulfinative cross coupling was monitored by
3
1
1
19
1
P{ H} NMR and F{ H} NMR spectroscopy. The reactions
were performed in a Young’s NMR tube with a higher loading
of Pd(OAc) and PCy (15 mol % and 30 mol %, respectively).
2
3
The observed resonance peaks were compared to the signals of
reference samples acquired in a 5:1 mixture of 1,4-dioxane/
soluble sulfinate salt, while the rate of extrusion of SO remains
2
2
unaffected and difficult, because of the strong κ N,O-chelation
benzene-d . Because of poor stirring of the heterogeneous
6
mode. As a consequence, the resting-state intermediate is
shifted from the oxidative addition complex 9 to the pyridine-
mixture in an NMR tube, the reaction kinetics were found to
be very slow. After 14 h at 150 °C, at which point biaryl 5 was
formed in 40% yield (∼2.7 turnovers), the resonance peak of
2
-sulfinate containing palladium complex 12.
Overall, these experiments show that the resting state of the
the oxidative addition complex 9 (δ = −124.26 ppm) was the
F
19
1
catalyst is highly dependent on the nature of the sulfinate
coupling partner and is more likely to be the oxidative addition
only other signal observed on the F{ H} spectrum along with
starting material, internal standard, and product (Figure 6a).
The corresponding characteristic doublet at δ = 20.08 ppm
P
was also observed in the 31P{ H} spectrum, along with free
1
PCy (δ = 9.24 ppm), phosphine oxide (δ = 45.65 ppm) and
3
P
P
compound 8 (δ = 19.80 ppm) (Figure 6c). Therefore, the
P
oxidative addition complex 9 is likely to be the resting-state
intermediate when using carbocyclic sulfinate 4. The same
experiment was performed with the pyridine-2-sulfinate
substrate 1. After 14 h of reaction at 150 °C, the conversion
to product 3 was lower than for the carbocyclic substrate (20%,
∼
1.3 turnovers). The oxidative addition product 9 was
observed in a 1:1 ratio with palladium sulfinate complex 12
(
Figure 6b). The corresponding phosphorus resonance peaks
(δ = 38.03 and δ = 20.08), along with free PCy oxidation
P
P
3
products, were also observed (Figure 6d).
In section 2.2.3.2, we have assessed the reactivity of the
palladium sulfinate complexes and demonstrated that weaken-
ing of the N−Pd bond facilitates the extrusion of SO from the
2
palladium pyridine-2-sulfinate complexes. When sodium 5-
(
trifluoromethyl)pyridine-2-sulfinate 19 was subjected to the
cross-coupling conditions in a Young’s NMR tube, the
corresponding palladium sulfinate complex 20 could not be
1
9
1
31
1
detected by F{ H} or P{ H} NMR, and the oxidative
addition complex 9 was the only observable complex by
1
9
1
F{ H} NMR spectrum (see the SI). Similarly, sodium
pyridine-4-sulfinate 21, which does not have the appropriate
substitution pattern to form a stabilizing N−Pd interaction,
only exhibited the resonance of the oxidative addition complex
Figure 6. Cross-coupling reactions performed in a Young’s NMR
19
1
tube. (a) F{ H} NMR spectrum of the reaction mixture involving
9
(see the SI). Unidentified minor resonances were detected at
19
1
sulfinate 4. (b) F{ H} NMR spectrum of the reaction mixture
3
1
1
δ = 19.81 ppm and δ = 20.17 ppm, together with free ligand
P
P
involving sulfinate 1. (c) P{ H} NMR spectrum of the reaction
3
1
1
and minor phosphine oxide peaks. Finally, the oxidative
addition complex 9 was once again the only resonance
mixture involving sulfinate 4. (d) P{ H} NMR spectrum of the
reaction mixture involving sulfinate 1.
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The initial rates were not affected by the concentration of
the electrophilic coupling partner (Figures 7a and 7b). This
zero-order behavior suggests that oxidative addition of the C−
Br bond into the Pd(0) species is not the turnover limiting step
under the reaction conditions. This observation is in
agreement with the observed resting-state intermediates in
section 2.3.
2
.4.2. Order in Sulfinate Salt and K CO . It was observed
2 3
that 0.010−0.10 M solutions of sodium 4-methylbenzenesulfi-
nate 4 or sodium pyridine-2-sulfinate 1 are heterogeneous at
1
50 °C. Therefore, the partial orders in sulfinate coupling
partner were not measured. Similarly, the order in potassium
carbonate was not obtained.
Figure 7. Initial rate plots for cross coupling between aryl bromide 2
and (a) sodium 4-methylbenzenesulfinate 4 (orange diamonds) and
2
.4.3. Order in Catalyst. To get the partial order in catalyst,
(b) sodium pyridine-2-sulfinate 1 (orange circles).
the initial rate of the reaction was measured for different
concentrations of Pd(OAc) and PCy , keeping the ligand to
2
3
palladium ratio fixed at two. The rate of the reaction involving
4-methylbenzenesulfinate sodium salt 4 was observed to be
approximately proportional to the square root of the total
concentration of palladium introduced, as palladium acetate:
0
.5
rate ∝ [Pd(OAc) ] (Figure 8a). Half order in catalyst can
2
generally be rationalized by an equilibrium between a
catalytically active complex and an off-cycle species. This can
be caused by dimerization of the active catalyst to form an
42
inactive dimer. Half-order dependence of the catalyst can
43
also arise from ligand dissociation. When the concentration
of Pd(OAc) was varied while the phosphine ligand was in
2
excess, such as [Pd(OAc) ]/[PCy ] < 0.10, the half-order
2
3
dependence on the concentration of palladium acetate was no
longer observed. Instead, the rate was observed to be directly
proportional to the concentration of Pd(OAc) : rate ∝
2
[
Pd(OAc) ] (Figure 8b).
Therefore, the half-order dependence observed can be taken
2
into account by a fast equilibrium between the catalytically
inactive oxidative addition intermediate (Ar)Pd(PCy ) (Br)
3
2
and the reactive intermediate (Ar)Pd(PCy )(Br) generated
3
after the loss of a phosphine ligand (Scheme 4). However, the
rate of oxidative addition is known to decrease dramatically
upon the addition of ligand, as the inactive tris-ligated
Figure 8. Initial rate plots for cross coupling between aryl bromide 2
and (a) 4-methylbenzenesulfinate 4 (green circles), (b) 4-methyl-
0
44
Pd (PCy ) can be formed. In order to verify that the switch
3
3
benzenesulfinate 4 using an excess of PCy (blue squares), (c) 4-
3
between half-order and first-order is not due to a change of
turnover-limiting step, the order in aryl bromide was
determined for a Pd/L ratio <0.10 (Figure 8c). A zero-order
case was obtained under these conditions, showing that the
oxidative addition is not rate-determining in the presence of
excess ligand.
methylbenzenesulfinate 4 using an excess of PCy (gold triangles),
3
and (d) pyridine-2-sulfinate 1 (red diamonds).
complex 9 for carbocyclic sulfinates or for pyridine-sulfinate
substrates that cannot form strong N−Pd bonds, due to
2
geometrical, steric, or electronic reasons. A strong κ
-
N,O
chelation as observed for the unsubstituted pyridine-2-sulfinate
group in the palladium sulfinate complex 12 was observed to
cause a change in the resting-state intermediate.
Scheme 4. Interpretation of the Initial Rates for the
Carbocyclic Sulfinate 4
2
.4. Initial Rate Studies. Productive catalytic reactions are
performed at 150 °C in 1,4-dioxane (boiling point (bp) = 101
C) and involve partially soluble reagents such as the sulfinate
°
salts and potassium carbonate, leading to suspensions rather
than homogeneous solutions. Therefore, the reactions could
not be accurately monitored by NMR spectroscopy and were
monitored using HPLC analysis of aliquots taken from the
reaction mixture via syringe, and the partial orders were
obtained using the initial rates of the reactions.
In order to assess the lability of PCy under the reaction
conditions, the analogous oxidative addition complex 23 was
3
synthesized with the electronically and sterically similar tri-
45
2
.4.1. Order in Aryl Bromide. The reactions of 4-
isopropylphosphine Pi-Pr3. When the two oxidative addition
complexes were heated at 75 °C in a 5:1 mixture of 1,4-
methylbenzenesulfinate 4 and pyridine-2-sulfinate 1 were
performed with different concentrations of aryl bromide 2
dioxane/benzene-d , statistical scrambling was obtained within
6
(
0.025−0.15 mM).
2 h and the mixed complex 24 was observed (Scheme 5).
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Scheme 5. Lability of PCy under the Reaction Conditions
3
Therefore, PCy is likely to be labile under the reaction
3
conditions, which supports the phosphine dissociation/trans-
metalation sequence.
The rate of the reaction involving sodium pyridine-2-
sulfinate 1 was directly proportional to the concentration of
palladium acetate: rate ∝ [Pd(OAc) ] (Figure 8d). There is no
2
longer a half-order dependence in Pd(OAc) as observed for
2
the carbocyclic sulfinate 4. This is in agreement with the
observation of different resting-state intermediates for
reactions involving substrates 1 and 4. For the former, the
first order dependence in Pd(OAc) is consistent with the
2
catalyst resting state being palladium sulfinate complex 12 and
the rate-determining step being the extrusion of SO . As a half-
2
order dependency is not observed for pyridine-2-sulfinate 1,
this suggests that the transmetalation is irreversible under these
reaction conditions.
2
.5. Comparison of the Rates of Transmetalation and
SO2 Extrusion. Stoichiometric reactions involving the
oxidative addition complex 9 or the palladium sulfinate
complexes 11 and 12 were performed in order to qualitatively
compare the rates of transmetalation and extrusion of SO . For
2
the reaction involving the oxidative addition complex 9, 2
equiv of the potassium sulfinate salts 25 or 26 were employed
Figure 9. Comparison of the rates of the SO extrusion and of the
2
sequence of transmetalation/SO
sulfinate 4 and pyridine-2-sulfinate 1. Pd (1.0 equiv), PCy (0−4.0
extrusion for both carbocyclic
2
(
Figure 9). The potassium salts were chosen for these
total
3
2
3
1
equiv), Ar SO K (2.0 equiv), Ar SO K (2.0 equiv). Ar = 4−F-C H ;
Ar = 4-Me-C H ; Ar = 2-pyridyl. [Legend: green circles, 0 equiv
stoichiometric studies, since evidence suggests that these are
the salts formed in the catalytic reactions when K CO is used
2
2
6
4
2
3
6
4
2
3
PCy ; blue squares, 1.0 equiv PCy ; gold triangles, 2.0 equiv PCy ; red
3
3
3
as the base (section 2.6.2). When the dimeric complex 11 was
diamonds, 3.0 equiv PCy ; and purple circles, 4.0 equiv. PCy .]
3
3
heated at 150 °C with 1−4 equiv of PCy , with respect to the
3
amount of palladium, full conversion to the corresponding
biaryl 5 was obtained within 2 min (Figure 9a). Although we
have demonstrated that added phosphine slows the rate of
extrusion of SO at 90 °C in toluene-d (see the SI), these data
metalation/SO2 extrusion sequence being cleavage of the
Pd−N bond of the palladacycle 12, which should be
independent of ligand concentration.
This set of stoichiometric experiments is in good agreement
with the partial orders in catalyst obtained using substoichio-
2
6
show that the concentration of ligand does not affect the rate
of extrusion of SO from the in-situ-generated complex 14 at
2
1
50 °C. However, the rate of the transmetalation/SO2
metric amounts of Pd(OAc) in section 2.4.
2
extrusion sequence was dramatically slowed upon the addition
2.6. Role of K CO . Unlike for the coupling of aryl halides
2
3
of PCy (Figure 9b). An excess of phosphine is likely shifting
the equilibrium between the transmetalation inactive (Ar)Pd-
with nucleophiles such as amines, alcohols, or thiols, there are
no acidic protons to be removed in the coupling of sulfinate
salts. Yet, a carbonate base, and, more specifically, potassium or
cesium carbonate, is a crucial additive for the reaction. In the
following section, we investigated the role of the carbonate
base and of its countercation.
3
(
(
PCy ) (Br) 9 and the transmetalation active (Ar)Pd(PCy )-
Br) toward 9, slowing the overall rate of product formation.
3
2
3
These observations are consistent with a turnover-limiting
transmetalation after the loss of ligand from oxidative addition
complex 9, as exposed in section 2.4.3.
For pyridine-2-sulfinate palladium complex 12, the rate of
extrusion of SO2 was much slower than for carbocyclic
complex 11 (Figure 9c). Indeed, independent of the
concentration of ligand, at least 20 min were necessary to
reach >90% conversion, compared to <2 min for the
carbocyclic system. The concentration of ligand did not affect
2.6.1. Role of the Carbonate. One molecule of sulfur
dioxide is extruded every time a molecule of the biaryl product
is generated. Therefore, since 5 mol % of Pd(OAc) is used, a
2
20:1 ratio between the gaseous byproduct and the catalyst is
reached at the end of the reaction. Since SO gas and SO
2
2
surrogates have been utilized in many palladium-catalyzed C−
20b,46
S bond-forming reactions,
the SO generated in the
2
the rate of SO extrusion at 150 °C. Compared to the reaction
present reactions is likely to coordinate to the palladium
center, potentially disrupting catalysis.
2
with the carbocyclic sulfinate in Figure 9b, ligand concen-
tration had little impact on the observed rate of product
Carbonate bases are reported to be efficient traps for SO2
gas in the waste stream from combustion in several industrial
processes. Given this, we hypothesized that a carbonate base
formation for the transmetalation/extrusion of SO sequence
2
47
with potassium pyridine-2-sulfinate 26 (Figure 9d). This is
consistent with the rate-determining step of the trans-
was necessary to trap the liberated SO in the reaction under
2
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Figure 10. Influence of SO2 and K CO on the reaction: (a)
2
3
generation of gaseous SO , solvents A and B; (b) reaction outcome;
2
and (c) rationalization of the role of K CO .
2
3
study, preserving the catalyst and allowing reasonable turnover
to be achieved. In order to test this, 0.05 M solutions of SO2
gas in 1,4-dioxane were prepared and divided into an empty
flask (A) or a flask containing K CO (B). These flasks were
2
3
then heated at 150 °C for 16 h, which are the standard reaction
time and temperature employed in productive catalytic cross-
coupling reactions (Figure 10a). The obtained solvents A and
B were then used for reactions between aryl bromide 2 and
carbocyclic and pyridine sulfinates 1 and 4, catalyzed by the
oxidative addition product 9. For both substrates, 3% product
Figure 11. Influence of the cation on the rate of the transmetalation
step.
(
less than one turnover) was obtained when using solvent A.
d
Scheme 6. Toward a Lower Temperature Cross-Coupling
Conversely, solvent B, which contained K CO , provided 81%
2
3
and 45% yields of products 5 and 3, respectively (Figure 10b).
These experiments show the importance of the carbonate base
47,48
to sequester SO . Based on literature reports,
we conclude
2
that sulfite anions are generated together with carbon dioxide,
as shown in Figure 10c.
2.6.2. Role of the Cation. We demonstrated in sections 2.4.
and 2.5 that the reaction involving pyridine-2-sulfinate sodium
salt 1 is limited by the rate of SO extrusion, which does not
2
involve the original sulfinate cation. Therefore, the role of the
cation was studied for the reaction involving the carbocyclic
sulfinate 4, in which the cation is likely to be involved between
the resting-state intermediate and the turnover-limiting step.
We also showed in section 2.5 that the rate of extrusion of SO2
is extremely fast, compared to the rate of transmetalation for
the carbocyclic substrate 4. Therefore, in the following section,
we have considered that the rate of product formation in the
reaction between the oxidative addition complex and a
sulfinate salt is representative of the rate of the transmetalation
step. The reactions were performed at 120 °C using 2 equiv of
sulfinate to 1 equiv of oxidative addition product 9 (Figure
1
1a).
Lithium sulfinate 27 showed almost no reactivity (2%
product formation in 2 h). Similarly, sodium sulfinate 4
provided 12% product within 2 h, whereas potassium sulfinate
25 reached 74% conversion to product (Figure 11b). Moving
further down in the alkaline metals group, cesium sulfinate 28
a
HPLC yield against 1,3,5-trimethoxybenzene. b19F NMR yield based
c
19
on starting material consumption.
fluoronaphtalene. Ar = 4-F-C H .
F NMR yield against 1-
d
6
4
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Scheme 7. Overall Mechanism
increased the rate significantly, with 84% product formation in
the same time. Tetrabutylammonium sulfinate 29 had a similar
initial rate, compared to the potassium sulfinate 20. However,
the conversion did not rise above 60%, even after 5 h. This
could be caused by Hofman-type elimination of the
ammonium salt, leading to substrate decomposition. The use
of 18-crown-6 only slightly increased the rate of anion
exchange with 79% yield after 2 h. However, a dramatic
increase in rate was observed with tetramethylammonium
sulfinate 30, which led to 86% yield within the first 10 min.
The low performance of the tetrabutylammonium sulfinate
salt, compared to the potassium, or cesium sulfinates suggests
that solubility of the sulfinate salt is not correlated to the rate
of the transmetalation step. Indeed, the tetrabutylammonium
sulfinate is entirely soluble in 1,4-dioxane at 120 °C, while the
alkali sulfinates are not. Tetramethylammonium salts have
silver additives to promote reactivity for these types of
substrates (Scheme 6a). However, for the heterocyclic sulfinate
1, only the corresponding palladium sulfinate complex 12 was
obtained (Scheme 6b).
This suggests that an additive-based strategy that accelerates
transmetalation will not be sufficient to achieve a lower
temperature cross-coupling for substrates able to strongly
2
chelate the palladium in a κ N,O-fashion. For these systems, in
addition to the transmetalation, there will be an additional
challenge in disrupting the stabilizing chelation to the Pd
center. This is consistent with the earlier results and was
confirmed by the reaction shown in Scheme 6c, in which the
sterically hindered 6-tert-butylpyridine-2-sulfinate salt 22
underwent a lower temperature cross coupling and delivered
biaryl 31 in 72% yield. However, the use of silver salts was
noncompatible with the catalytic reaction, presumably due to
51
49
their ability to also act as oxidants. The tetramethylammo-
nium alternative proved to be promising, providing the cross-
coupling product 5 in 85% yield in the stoichiometric reaction
between the oxidative addition complex 9 and the
tetramethylammonium sulfinate 30 at 100 °C (Scheme 6d).
We are currently investigating the use of such additives in the
catalytic reaction, as well as alternative strategies to achieve
lower temperature cross-couplings with carbocyclic and
heterocyclic substrates.
been used as silver surrogates to abstract halide atoms, which
might explain the excellent reactivity of sulfinate 30 in the
transmetalation step. When sodium sulfinate 4 was employed
in a 1:1 ratio with K CO at 150 °C, the transmetalation
2
3
occurred almost as quickly as the transmetalation involving
potassium sulfinate 25 (Figure 11c). This suggests that the role
of K CO , in addition to trapping liberated SO , is to take part
2
3
2
in a cation metathesis with the sodium sulfinate salt, thus
facilitating transmetalation.
2
.7. Toward Lower Temperatures. In section 2.2.3.1, the
3. CONCLUSION
use of the silver salt AgNO allowed the synthesis of a variety
3
of palladium sulfinate complexes at room temperature, starting
from the oxidative addition complex 9. In other words, this
additive allowed the transmetalation step to occur 125 °C
below the temperatures needed in the catalytic system,
presumably because of the high affinity between Ag and Br
atoms. To confirm the viability of this additive based strategy
for lowering the reaction temperature, stoichiometric reactions
were performed between the oxidative addition complex 9 and
carbocyclic and pyridyl sodium sulfinates 4 and 1 in the
The mechanism of the palladium-catalyzed desulfinative cross-
coupling of aryl halides and sulfinate salts was investigated.
The in situ reduction of the Pd(II) source to form the active
Pd(0) species was shown to be mediated by the homocoupling
of two sulfinate substrates. Novel palladium sulfinate
complexes were independently synthesized, characterized,
and proven to be competent intermediates in the catalytic
reaction. The resting-state catalyst and the rate-determining
step were identified. Their identity was heavily dependent on
the nature of the sulfinate coupling partner, more specifically
on the ability of the sulfinate to strongly chelate the palladium
5
0
presence of AgNO . Cross-coupling product 5 was obtained in
3
7
0% yield for the carbocyclic sulfinate, showing the potential of
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in a κ2N,O-mode. The kinetic data also suggest that both
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Richard Cooper (University of Oxford) is thanked for
assistance with X-ray structure analysis, and Nader Amin and
Tim Claridge (both University of Oxford) are thanked for
assistance with NMR spectroscopy analysis. A.d.G. is grateful
to the EPSRC Centre for Doctoral Training in Synthesis for
Biology and Medicine (EP/L015838/1) for a studentship, and
the generous support by GlaxoSmithKline, Vertex, AstraZe-
neca, Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, Janssen, Novartis, Pfizer, Syngenta,
Takeda, and UCB is gratefully acknowledged.
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