Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1002/anie.202109146

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd⁰-catalyzed cross-coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi-step transformations. Here we introduce base-activated, latent sulfinate reagents: β-nitrile and β-ester sulfones. We show that under the cross-coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium-catalyzed desulfinative cross-coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi-step substrate elaboration, and amenable to scale-up.

Full text of DOI:10.1002/anie.202109146

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic
Coupling Partners in Palladium-Catalyzed Cross-Coupling
Reactions
Authors: Xinlan A. F. Cook, Loïc R. E. Pantaine, David C. Blakemore,
Ian B. Moses, Neal W. Sach, Andre Shavnya, and Michael C.
Willis
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202109146
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10.1002/anie.202109146
Angewandte Chemie International Edition
COMMUNICATION
Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic
Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions
Xinlan A. F. Cook,[a] Loïc R. E. Pantaine,[a] David C. Blakemore,[b] Ian B. Moses,[c] Neal W. Sach,[d] Andre
Shavnya,[b] and Michael C. Willis*[a]
[a]
X. A. F. Cook, Dr. L. R. E. Pantaine, Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Dr. D. C. Blakemore, A. Shavnya
[b]
Medicine Design, Pfizer Inc.
Eastern Point Road, Groton, CT 06340 (USA)
I. B. Moses
Pharmaceutical sciences, Pfizer Inc.
Discovery Park, Ramsgate Road, CT13 9ND (UK)
N. W. Sach
[c]
[d]
Medicine Design, La Jolla Laboratories, Pfizer Inc.,
10777 Science Center Drive, San Diego CA 92121 (USA)
Supporting information for this article is given via a link at the end of the document.
9b]
utilizing phosphorane[9a,
or sulfurane[9c] intermediates.
Abstract: Heteroaromatic sulfinates are effective nucleophilic
reagents in Pd(0)-catalyzed cross-coupling reactions with aryl halides.
However, metal sulfinate salts can be challenging to purify, solubilize
in reaction media, and are not tolerant to multi-step transformations.
Here we introduce base-activated, latent sulfinate reagents; β-nitrile
and β-ester sulfones. We show that under the cross-coupling
conditions, these species eliminate to generate the sulfinate salt in
situ, which then undergoes efficient palladium-catalyzed desulfinative
cross-coupling with (hetero)aryl bromides to deliver a broad range of
biaryls. These latent sulfinate reagents have proven to be stable
through multi-step substrate elaboration, and amenable to scale-up.
Correspondingly, the ‘2-pyridyl organometallic cross-coupling
problem’[9d] has become a benchmark for challenging biaryl
cross-coupling reactions, and a springboard for innovation.
However, a general approach is yet to be established, as
many of the solutions reported are plagued with limited
heterocycle scopes, difficult reagent preparation, or substrate-
specific re-optimization.
Me
OMe
OMe
N
N
N
N
HO
N
N
Cl
N
Ph
Me
S
Me
O
O
CH2(CH2)7CH3
Introduction
Fungicide
Caerulomycin G
Natural Product
Etoricoxib (Arcoxia)
Arthritis (Inflammation)
Cross-coupling processes are ubiquitous in synthetic
chemistry as a dependable method to construct biaryl
scaffolds, and are established as a “go to” strategy for carbon-
carbon bond formation.[1] The Suzuki-Miyaura cross-coupling
(SMC), which utilizes boron-derived species as nucleophilic
coupling partners, is the most popular variant for C(sp2) –
C(sp2) bond formation.[2] This is due to the commercial
accessibility of boronic acids and boronate reagents, the mild
H3C(H2C)7H2C
N
N
Me
Me
HN
NCS
F3C
Ru
N
NCS
N
N
HO
N
NH
Me
HOOC
Me
COOH
F
F
O
O
OH
dFCF3ppy
Pyridine dipyrrolate ligand
Self-Assembly Cage Formation
Z-907 dye
Dye-sensitised Solar Cells
Ligand for Metal Catalysis
Figure 1. Select examples of 2-pyridyl derivatives with varied applications.
reaction conditions, and the plethora of research conducted
Our laboratory has previously contributed to solving
these challenges, establishing heteroaromatic sulfinate salts
as efficient reagents in Pd-catalyzed desulfinative cross-
coupling reactions with aryl halides (Figure 2a).[11]
Desulfinative cross-coupling processes avoid the use of
stoichiometric organometallic reagents and only release SO2
as a by-product. Although the use of aryl sulfinate salts in
desulfinative cross-couplings was first reported in the early
1990s,[12] only in recent years has substantial research into
3]
into these transformations.[2a,
However, traditional cross-
coupling tools, including the Suzuki-Miyaura approach, fall
short when it comes to tackling notoriously difficult heteroaryl-
heteroaryl coupling reactions.[4] Heteroaromatic boron
reagents, in particular 2-pyridyl variants, are especially
challenging to prepare and couple due to their propensity to
undergo
protodeboronation.[5]
2-Arylpyridines,
and
bi(hetero)aryls in general, are prevalent as motifs in
therapeutic and agrochemical molecules,[6] as ligands in metal
catalysis,[7] and as key units in functional materials[8] (Figure
1). Due to the importance of these frameworks there has been
significant research towards rectifying this problem,[4, 9] key
examples of which include the development of slow release
boronate reagents,[10] and contractive coupling methodologies
their use as nucleophilic coupling partners in Pd-mediated
[14]
reactions
been
implemented.[13],
Importantly,
heteroaromatic sulfinate salts are generally more air- and
moisture-stable than the corresponding boronic acids, and are
now becoming commercially available.[15]
1
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10.1002/anie.202109146
Angewandte Chemie International Edition
COMMUNICATION
Despite being efficient coupling partners, the purification
of metal sulfinate salts, as well as their poor solubility in
organic media, pose challenges and hinder their ability to be
carried through multi-step synthetic sequences. To address
this, our laboratory pioneered the use of latent sulfinates in
cross-coupling reactions. This concept exploits neutral,
organosoluble, and easily accessible protected sulfinates that
can be selectively unmasked under coupling conditions. The
first generation of latent sulfinate reagents developed were
allylsulfones (Figure 2b).[16] Owing to the lability of the allyl
group under Pd-catalysis, no additives were required for the
release of the sulfinate coupling partner. However, this also
limited the use of such substrates in other palladium-catalyzed
processes, and in alkene functionalization reactions.
conjugate addition into acrylonitrile and subsequent oxidation
(the order of these steps could also be reversed, Scheme
1a,b),[11a, 11b] from aryl halides via the sodium 3-methoxy-3-
oxopropane-1-sulfinate (SMOPS) reagent (Scheme 1c),[17c] or
by utilizing SO2 surrogates, such as DABSO, to form the
19e, 20]
parent sulfinate,[19b,
(Scheme 1d).
followed by conjugate addition
(a) Conjugate addition/oxidation
H2O2
F3C
CN
Et3N
Na2WO4· 2H2O
F3C
F3C
N
(5 mol%)
N
N
S
MeCN, 45 o
C
EtOH, RT
N
SH
N
S
O
O
1a
(b) Oxidation/conjugate addition
CN
AcOH
H2O, reflux
N
H2O2, NaOH
EtOH:H2O
N
S
N
SH
N
SO2Na
O
O
1b
Previous work in the Willis laboratory:
(a) Heteroaromatic metal sulfinates (2017)
(c) Cu-mediated sulfone formation and sulfinate release/conjugate addition
Me
Pd(OAc)2 (5.0 mol%)
ligand (10 mol%)
CO2Me
Me
1)
R1
NaO2S
Me
CN
AcOH
H2O, reflux
N
X
K2CO3 (1.5 - 2.0 equiv.)
N
N
N
N
CuI, DMSO, 110 °C
R2
R1
R2
1,4-dioxane
heat, 18 h
S
N
SO2M
2) NaOMe
Br
SO2Na
O
O
1k
MeOH, RT
> 80 examples, 11 - 99%
1.5 - 2.0 equiv
M = Na or Li
1.0 equiv
With P(Cy)3, 150 °C
(d) Metalation/sulfination/conjugate addition
X = Cl or Br
> 30 examples, 69 - 97%
With P(tBu)2Me·HBF4, 120 °C
Me
CN
AcOH
n-BuLi
THF, -78 °C
Me
Me
N
N
S
O O
then TIMSO
- 78 °C to rt
H2O, reflux
N
SO2Li
N
Br
(b) Heteroaromatic allylsulfones as latent sulfinates (2018)
Pd(OAc)2 (5.0 mol%)
P(tBu)2Me
HBF4 (10 mol%)
1g
R1
·
X
Cs2CO3 or K2CO3
Scheme 1. Synthesis of b-nitrile sulfones. TIMSO = N-Me-pyrrolidine SO2
R1
N
R2
R2
adduct.
N
S
1,4-dioxane or DMF
120 - 130 °C
O
O
> 50 examples, 38 -88%
X = Cl or Br
Pd-labile
The use of β-nitrile sulfones in Pd-mediated cross-
coupling was initially investigated through the reaction of the
pyridine sulfone 1a with 4-bromoanisole 2a (Table 1).
Encouragingly, the desired biaryl product 3a was obtained in
a 29% yield under the original conditions reported for the use
of 2-pyridyl metal sulfinate salts (Entry 1).[11b] A strong solvent
dependence was quickly observed, as substituting 1,4-
dioxane for toluene more than doubled the yield of biaryl 3a
(Entry 2). The presence of K2CO3 proved to be essential to
Metal sulfinate salts
- Robust cross-coupling
- Insoluble salts
- Difficult to purify and isolate
- Not suitable for multi-step elaboration
Allylsulfones
- Efficient coupling via in situ sulfinate
- Stable & organic soluble
- Suitable for multi-step elaboration
- Sensitive to Pd-mediated chemistry
- Incompatible with alkene transformations
This work:
(c) Heteroaromatic β-nitrile and β-ester sulfones as latent sulfinates
Pd(0)
Ar-X
R1
R1
R1
base
O
EWG
N
S
N
N
S
M
R2
O
O
O
SO2
EWG
sulfinate released
in situ
reaction success, in agreement with the reported mechanism
EWG = -CN or -CO2Me
11d]
of the transformation.[11c,
A range of ligands were
β-nitrile sulfones and β-ester sulfones:
R1
R1
N
evaluated and electron-rich, bulky monodentate phosphine
ligands performed best (see Supporting Information). Whilst
the optimum ligand for the allylsulfone work, P(tBu)2Me×HBF4,
showed good activity (Entry 3), CataCXium® A (PAd2Bu) was
shown to be superior for this process giving biaryl 3a in 84%
yield (Entry 4). Addition of acetic acid to the system was key
for achieving high yields of the desired product at 130 °C
(Entries 5-6). Other bases and acids were explored; however,
none performed as well (see Supporting Information).
Considering the poor solubility of sulfinate salts in toluene, the
combination of base and acid could potentially create a
buffered system, enabling a more gradual release of the
sulfinate from the heteroaromatic sulfone. Lastly, by adjusting
the stoichiometry of the pyridine sulfone to a slight excess (1.1
equiv), we were able to achieve an 88% yield of biaryl 3a at
120 °C (Entry 8). The acrylonitrile by-product was not
observed, and is assumed to be removed by evaporation.
We began the reaction scope exploration by varying the
electrophilic partner in combination with sulfone 1a (Table 2a).
Aryl bromides were found to couple more efficiently than aryl
chlorides, as shown by the 61% yield of compound 3a
- Base-activated
- Efficient cross-coupling via in situ sulfinate salt
- Stable & readily prepared
- Amenable to multi-step elaboration
- Scalable
- Compatible with other Pd-mediated reactions
N
N
S
O
O
O
S
OMe
O
O
Figure 2. Introduction to previous and current work: (a) heteroaromatic
sulfinates, (b) heteroaromatic allylsulfones and (c) this work: β-nitrile sulfones
and β-ester sulfones in cross-coupling reactions.
This work explores
heteroaromatic sulfinates:
a
new generation of latent N-
β-nitrile and β-ester
sulfones (Figure 2c).[9f],[17] The active sulfinate species are
released via E1cB elimination under the basic cross-coupling
conditions.[18] These base-labile reagents, in contrast to the
Pd-labile allylsulfones, are more amenable to orthogonal Pd-
catalyzed reactions and typical alkene transformations.
Results and Discussion
Heteroaromatic sulfones can be readily accessed from
commercially available starting materials, either directly from
thiols, halides or via the sulfinate salt.[17c,
19]
The β-nitrile
sulfones were primarily accessed from thiols through
2
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10.1002/anie.202109146
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COMMUNICATION
Table 1. Selected optimization studies of the desulfinative coupling.[a]
obtained from 4-chloroanisole, compared to 88% using 4-
bromoanisole. This selectivity could be advantageously
exploited and chlorobiaryl 3b was obtained in a high 80% yield.
The reaction yield remained high when varying the position of
the methyl substituent on the aryl bromide (3c-3f), although a
slight increase in temperature to 130 °C was needed for some
ortho-substituted aryl bromides (3e, 3f). Under these reaction
conditions, pyridine sulfone 1a provides an efficient synthesis
of the pyridine 3h used widely as a ligand in photocatalyst
Pd(OAc)2
ligand
K2CO3
F3C
F3C
Br
N
+
N
solvent (0.1 M)
N
S
OMe
O
O
OMe
1a
2a
3a
Entry
Ligand
Solvent
Additive
Temp., °C Yield, %[b]
1
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
150
150
150
150
130
130
130
120
29[c][d]
67
PCy3
PCy3
-
-
-
-
2
7b]
complexes and luminescent platinum complexes.[7a,
P(tBu)2Me
·
HBF4
3
76
The reaction has
a broad functional group tolerance,
4
CataCXium A
CataCXium A
84
59
delivering high yields when employing aryl halides containing
esters, ketones, nitriles, protected amines and alcohols,
thiophenes, substituted pyridines, quinolines, quinoxalines
and napthalenes (3i-3s).
-
5
CataCXium A AcOH (1 equiv)
6
84
7[e]
8[e]
CataCXium A
91[d]
AcOH (1 equiv)
88[d]
CataCXium A AcOH (1 equiv)
[a] Reaction conditions: 1a (0.20 mmol, 1.0 equiv), 4-bromoanisole (0.20 mmol,
1.0 equiv), K2CO3 (0.30 mmol, 1.5 equiv), Pd(OAc)2 (5.0 mol%), ligand (10
mol%), solvent (0.10 M), [b] HPLC yields determined by using p-tolylether as
an internal standard, [c] Run on a 0.40 mmol scale, [d] Isolated yield, [e] Using
1.1 equiv of 1a. CataCXium A = PAd2Bu.
Table 2. Scope of the desulfinative cross-coupling of heteroaromatic β-nitrile sulfones with (hetero)aryl halides.[a]
Pd(OAc)2
CataCXium A
K2CO3, AcOH
Br
R1
R1
R2
N
N
R2
N
S
toluene, 18 h
120 °C
O
O
1
2
3
(a) Variation of (hetero)aryl halide coupling partners with β-nitrile sulfone 1a
F3C
F3C
F3C
F3C
F3C
F3C
F3C
Me
Me
Me
N
N
N
N
N
N
N
OMe
Cl
Me
Me
3a, 88%, 61%[b,c]
3b, 80%
F3C
3c, 80%
3d, 95%
F3C
3e, 91%[b]
3f, 65%[b]
3g, 91%[b]
F3C
F3C
F3C
F3C
F
N
N
N
N
N
N
OMe
Me
CN
OTBDMS
F3C
NHBoc
F
O
O
3h, 75%[b]
3i, 87%
3j, 83%
3k, 91%
3l, 78%
3m, 75%
F3C
F3C
F3C
F3C
F3C
N
CO2Me
N
N
N
N
N
N
N
N
N
S
N
N
NBoc
3n, 74%
3o, 76%
3p, 87%[b]
3q, 75%
3r, 97%
3s, 80%
(b) Variation of heteroaromatic β-nitrile sulfones with (hetero)aryl halides
N
N
Me
N
Me
N
Me
N
N
Me
N
N
N
Me
N
Me
N
N
N
OMe
CN
N
OMe
N
SEM
3t, 94%[b]
3u, 88%
3v, 84%
3w, 67%[b]
3x, 73%[b]
3y, 94%[b]
Me
Me
N
N
N
N
N
N
N
N
N
Me
OMe
OMe
OMe
3z, 77%
3aa, 95%[b]
3ab, 74%[b]
3ac, 83%[b]
Me
3ad, 59%[b]
3ae, 90%
3af, 93%[b]
N
N
MeO
N
Me
MeO
N
N
N
CO2Me
OMe
CN
CN
OMe
OMe
3ag, 49%[b]
3ah, 95%
3ai, 98%[b]
3aj, 63%[b]
3ak, 82%
3al, 64%
[a] Isolated yields. Reaction conditions: pyridine sulfone (0.22 mmol, 1.1 equiv), aryl halide (0.20 mmol, 1.0 equiv), K2CO3 (0.30 mmol, 1.5 equiv), AcOH (0.02, 1.0
equiv), Pd(OAc)2 (5.0 mol%), CataCXium A (10 mol%), toluene (0.10 M), 120 °C, 18 h. [b] Reaction run at 130 °C. [c] Using 4-chloroanisole. Temperatures stated
are those of the aluminium heating block
3
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10.1002/anie.202109146
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COMMUNICATION
On variation of the nucleophilic coupling partner (Table
2b), we found that the 6- and 5-methyl substituted pyridine
sulfones behave similarly to the electron-deficient 5-
trifluoromethyl pyridine sulfone 1a (3t, 3u, 3z). Pleasingly, the
more challenging couplings to access biaryls, such as
pyrimidines (3v-3w), SEM-protected pyrazole (3x) and
imidazo[1,2-a]pyrazine (3y), were achieved in good to high
yields. Increasing the steric hindrance at the reaction site via
substitution at the 3-position of the pyridine, was also well
tolerated, giving 95% of 2-arylpyridine 3aa. Increasing the
reaction temperature to 130 °C was often necessary to
achieve good yields when using unsubstituted pyridine
sulfones (3ab-3ag). This is in good agreement with our
previous mechanistic studies, which show that extrusion of
SO2 during the catalytic cycle is easier with electron-deficient
or sterically bulky substrates.[11c] Electron-rich pyridine
sulfones also performed well under these reaction conditions
(3ah, 3ai). Notably, indole 3aj and pyrazine 3ak were
synthesized in good to high yields. This methodology can also
be extended to carbocyclic substrates, as shown with
compound 3al, obtained in 64% from p-tolyl β-nitrile sulfone.
To demonstrate the generality and robustness of base-
labile latent sulfinates, we extended our approach to explore
the use of β-ester sulfones. In comparison to β-nitrile sulfones,
the synthetic routes towards β-ester substrates are more
straightforward, mainly due to β-methylester sulfones being
established intermediates in the synthesis of metal
sulfinates.[9f, 17c, 19a] The aforementioned SMOPS reagent is
commercially available and provides a one-step route to the
β-methylester
sulfone
functionality.[21]
Additionally,
commercially available methyl 3-mercaptopropionate can also
be reacted directly with heteroaromatic halides, or facilitated
by metal catalysis if required,[22] which in turn can be followed
by S-oxidation to give β-methylester sulfones. Thus, synthetic
routes towards β-ester sulfones allow better use of the vast
libraries of readily accessible heteroaryl halides.
In contrast to the nitrile derivatives, β-ester sulfones
generally performed better when the AcOH additive was
omitted from the system. Under such conditions, the reactivity
and functional group tolerance of these alternative latent
sulfinates were found to be comparable to the β-nitrile
sulfones, giving the desired biaryls in high yields (Table 3, 3a,
3b, 3i, 3k, 3q). The free alcohol product 3l-OH was pleasingly
obtained in a 65% yield from the telescoped deprotection of
protected alcohol 3l. Similar to the β-nitrile sulfone system,
raising the reaction temperature to 130 °C was required for
efficient coupling of the unsubstituted pyridyl β-ester sulfone
(3ac, 3ae, 3af, 3an). Interestingly, the coupling of the
unsubstituted pyridine sulfone to give the biaryl 3ac, was poor
yielding under the optimized conditions, despite complete
consumption of the sulfone. However, addition of acetic acid
(1.5 equiv) into the reaction allowed for the dramatic increase
in the yield of product 3ac from 29% to 91%. The 4-pyridyl β-
ester sulfone worked comparably to the 2-pyridyl reagent,
giving 4-arylpyridines 3ag and 3ao.
Table 3. Scope of the desulfinative cross-coupling of heteroaromatic β-ester sulfones with (hetero)aryl halides.[a]
Pd(OAc)2
CataCXium A
K2CO3
Br
R1
O
R1
R2
N
R2
N
S
OMe
toluene, 18 h
120 °C
O
O
4
2
3
R2 = OMe, 3a, 87%
Cl, 3b, 71%
F3C
F3C
F3C
CO2Me, 3i, 79%
CN, 3k, 73%
OTBDMS, 3l, 69%
OH, 3l-OH, 65%
N
N
Me
N
Me
N
N
N
N
N
N
N
R2
N
[c]
CN
3q, 65%[b]
3am, 57%
3u, 82%
3w, 53%[b]
NC
N
N
N
N
N
N
N
N
N
OMe
N
OMe
N
OMe
N
Me
NBoc
MeO
O
3ac, 29%,[b] 91%[b,d]
OMe
3ae, 51%[b]
3af, 81%[b]
3an, 99%[b]
3ag, 89%
3ao, 80%[b]
3ap, 57%[b]
O
O
CF3
MeO
Me
N
N
Me
N
H
N
N
N
N
N
SF5
OMe
CN
OMe
OMe
CN
OMe
3aq, 80%
3ar, 95%[b]
3as, 99%[b]
3ah, 66%
3ai, 62%[b]
3at, 75%
3al, 64%[b]
Me
N
N
F3C
O
N
N
N
N
N
S
N
N
NMe2
N
N
N
N
N
NBoc
O
BocHN
CF3
3au, 91%
3av, 59%
3aw, 99%
3ax, 57%[b]
3ay, 83%
[a] Isolated yields. Reaction conditions: sulfone (0.3 mmol, 1.5 equiv), aryl bromide (0.2 mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%), CataCXium A (10 mol%), K2CO3
(0.4 mmol, 2.0 equiv), toluene (2 mL), 120 oC, 18 h. [b]Run at 130 °C. [c] Telescoped deprotection of protected phenol product directly after cross-coupling reaction:
reaction temperature lowered to 85 °C, ethanol (2 mL), 2 M aq. solution of K2CO3 (0.2 mL, 0.4 mmol), 18 h. [d] Reaction run with AcOH (0.3 mmol, 1.5 equiv).
Temperatures stated are those of the aluminium heating block.
4
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10.1002/anie.202109146
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COMMUNICATION
All nucleophilic coupling partners with electron-withdrawing
substituents on the pyridine core, such as a nitrile (3ap) or an
ester (3aq), as well as quinoxaline sulfones (3at), performed
well, as did electron-rich β-ester examples (3ah,3ai). Similar
to the β-nitrile sulfone system, substituents next to the
sulfinate coupling site were well tolerated (3ar-3as). More
complex, nitrogen-rich frameworks 3au and 3av, were
constructed from the corresponding 2-quinoline and 2-
quinoxaline sulfones. The pyrimidine containing molecule 3aw,
an intermediate of a class of RORc modulators,[23] was
synthesized in a 99% yield. Pleasingly, the challenging
coupling of benzothiazole β-methyl ester sulfone to give
benzothiazole 3ax, a product related to PET scanning
radiopharmaceutical Flutemetamol (18F) was achieved.[24]
Lastly, we were able to prepare complex biaryl 3ay, containing
a fragment of arthritis drug celecoxib, in 83% yield.[25]
The success of the latent sulfinates (Tables 2 and 3)
inspired the design and brief exploration of diethyl succinate
sulfones 5. Upon generation of the sulfinate salt, this
alternative masking group releases non-toxic, high-boiling
diethyl fumarate as the by-product, making this system more
amenable to cross-coupling on larger scale. Additionally, the
majority of these reagents can be readily isolated as solids.
Encouragingly, the succinate pyridine sulfone 5 performed
well under the same conditions employed for the β-methyl
ester sulfone (Table 4). These reagents react efficiently and
comparably to their β-nitrile and β-ester counterparts, as
exemplified through a representative set of biaryls (Table 4).
(p-tolyl)pyridine (3ac) was also obtained using the 2-pyridyl
succinate sulfone 5a.
F3C
Pd(OAc)2
CataCXium A
K2CO3, AcOH
(a)
F3C
Br
N
N
N
S
OMe
anisole, 18 h
130 °C
OMe
O
O
3a, 97% (246 mg)
1a
2a
2b
Pd(OAc)2
CataCXium A
K2CO3, AcOH
Br
N
N
+
anisole, 18 h
130 °C
N
S
Me
Me
O
O
1b
3ac, 73% (124 mg)
(b)
(c)
Pd(OAc)2
CataCXium A
K2CO3
F3C
F3C
Br
Br
O
N
N
N
S
OMe
anisole, 18 h
130 °C
OMe
OMe
O
O
4a
2a
3a, 88% (222 mg)
Pd(OAc)2
CataCXium A
K2CO3
CO2Et
CO2Et
N
anisole, 18 h
130 °C
S
Me
Me
3ac, 52% (88 mg)
O
O
5a
2b
Scheme 2. Scale up of the cross-coupling reactions of base-labile latent
sulfinate reagents. Reaction conditions: (a) pyridine sulfone (1.5 mmol, 1.5
equiv), 4-bromoanisole (1.0 mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%), CataCXium
A (10 mol%), K2CO3 (2.0 mmol, 2.0 equiv), AcOH (1.5 mmol, 1.5 equiv), anisole
(0.1 M), 130 °C, 18 h. (b) and (c) pyridine sulfone (1.5 mmol, 1.5 equiv), 4-
bromoanisole (1.0 mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%), CataCXium A (10
mol%), K2CO3 (2.0 mmol, 2.0 equiv), anisole (0.1 M), 130 °C, 18 h. Isolated
yields; internal temperatures measured.
To highlight the compatibility of β-nitrile and β-methyl
ester sulfone with multi-step substrate functionalization, we
investigated the stability and utility of these latent groups
through a series of transformations around the pyridine core,
primarily focusing on oxidative and palladium-mediated
reactions. Firstly, using O-allyl pyridine sulfone 6, we explored
oxidative transformations at the alkene functionality (Scheme
3). Pyridine 6 was oxidized under Wacker-type conditions[26]
to give the desired ketone product 7 in a 44% yield, and the
resultant ketone was further reacted to access biaryl 3bb.
Furthermore, through a hydroboration-oxidation sequence we
could achieve a 65% yield of the combined alcohol products
(8a,b); this is a transformation that would not be possible
using the corresponding allylsulfone. The primary alcohol 8a
was then successfully coupled to give 60% of the desired 2-
arylpyridine 3bc.
Table 4. Scope of the desulfinative cross-coupling of succinate sulfones with
aryl bromides.[a]
Pd(OAc)2
CataCXium A
K2CO3
R1
Br
CO2Et
CO2Et
R1
R2
N
+
R2
toluene, 130 °C
N
S
O
O
5
2
3
F3C
Me
N
N
N
CN
Me
OMe
N
3a, 83%[b]
3u, 99%
3ac, 96%
N
CO2Me
N
N
NBoc
3az, 96%
3ba, 48%
[a] Isolated yields. Reaction conditions: pyridine succinate sulfone (0.3 mmol,
1.5 equiv), aryl bromide (0.2 mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%),
CataCXium A (10 mol%), K2CO3 (0.4 mmol, 2.0 equiv), toluene (0.1 M), 130 °C,
18 h. [b] Reaction run at 120 °C.
The described reactions of our masked sulfinates were
routinely performed on 0.2 mmol scale in sealed reaction vials.
However, we were keen to show that the chemistry could be
translated to larger, non-pressurized reaction vessels. To
investigate this, the cross-coupling of sulfones 1a or 4a with
4-bromoanisole 2a to give biaryl 3a was re-visited. The key
substitution of toluene for higher boiling anisole, and a
reaction temperature of 130 °C allowed the reactions of both
masked sulfinates species to be run effectively on a 1.0 mmol
scale (Scheme 2). Pleasingly, an unoptimized 52% yield of 2-
5
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10.1002/anie.202109146
Angewandte Chemie International Edition
COMMUNICATION
(a) Bifunctional pyridine cross-coupling sequence
(a) Wacker-type oxidation
O
Pd(dba)2 (5.0 mol%)
O
O
Pd(OAc)2 (10 mol%)
DMP (5.0 equiv.)
TBAB (10 mol%)
tfp (10 mol%)
K2CO3 (2.0 equiv)
O
Me
O
Br
N
S
OMe
O
N
S
O
O
OMe
MeCN:H2O (7:1)
50 °C, 48 h
O
O
EWG +
(HO)2B
EWG
THF:H2O (4:1)
16 h, 40 °C
N
S
N
S
6
7, 44%
O
O O
O
(1.5 equiv)
(1.0 equiv)
EWG = CN (9a)
CO2Me (9b)
EWG = CN (10a, 72%)
Pd(OAc)2
CataCXium A
K2CO3
Br
CO2Me (10b, 78%)
O
Br
Me
toluene, 130 °C
CN
Conditions
a or b
2c
N
CO2Me
2d
CN
a
b
EWG = CN:
Pd(OAc)2
CataCXium A
K2CO3, AcOH
3bb, 42%
EWG = CO2Me:
Pd(OAc)2
CataCXium A
K2CO3
toluene, 120 °C
95%
(b) Hydroboration and oxidation
HO
O
O
O
O
N
toluene, 120 °C
N
S
OMe
OMe
74%
CO2Me
11
O
O
O
BH3·Me2S (0.6 equiv.)
0 °C - rt, THF, 4 h
O
8a, 55%
(b) Ir-catalyzed borylation
then H2O,
NaBO3· 4H2O (2.0 equiv.)
0 °C - rt, 15 h
N
S
OMe
+
[Ir(OMe)(1,5-cod)]2 (2.5 mol%)
dtbpy (5.0 mol%)
Bpin
OH
O
O
O
O
B2pin2 (1.0 equiv)
Me
6
Me
N
S
O
OMe
Me
N
S
O O
OMe
N
S
THF, 24 h, 60 °C
O
O
O
8b, 10%
12, 68%
4b
Br
(c) Borylated pyridine sulfone cross-coupling sequence
Me
2b (1.0 equiv.)
Pd(OAc)2 (10 mol%)
CataCXium A (20 mol%)
K2CO3 (3.5 equiv.)
Pd(OAc)2 (5.0 mol%)
XPhos (10 mol%)
K3PO4 (2.0 equiv)
pTol
Bpin
Br
O
O
+
HO
O
HO
O
O
dioxane:H2O (2:1)
70 °C
Me
N
S
OMe
Me
2b (1.0 equiv)
Me
N
S
OMe
O
O
O O
N
N
S
OMe
toluene:DMSO (1:1)
130 °C, 18 h
O
O
12 (1.5 equiv)
13, 62%
Me
Me
8a (1.5 equiv.)
3bc, 60%
Br
Scheme 3. Oxidative transformations of O-allyl pyridine sulfone 6. DMP = Dess-
Martin periodinane.
Conditions
b
CN
2c
Me
N
Lastly, we explored the bidirectional elaboration of
masked pyridine reagents by installing two cross-coupling
reaction sites that could be selectively transformed (Scheme
4). 5-Bromopyridine sulfones 9a-b successfully underwent
Suzuki-Miyaura cross-coupling (SMC) with phenyl boronic
acid to give the biaryl sulfones (10a-b) in 72% and 78% yields,
when using β-nitrile or β-ester masking groups,
respectively.[27] In both cases the latent sulfinate group was
stable under these reaction conditions. Sequentially these
products were submitted to desulfinative coupling conditions
to give the desired diarylpyridine compound 11 in high yields.
To further demonstrate the compatibility of this chemistry with
transition metal-mediated processes, the boronate ester
containing substrate 12 was prepared using an Ir-catalyzed
borylation reaction (Scheme 4b).[28] The bifunctional pyridine
12 underwent SMC with 4-bromotoluene 2b to give sulfone 13
in 62% yield;[29] notably, the masked sulfinate functionality
remained intact. Finally, diarylpyridine 14 was obtained in
excellent 92% yield from biaryl sulfone 13 using our standard
cross-coupling protocol.
CN
14, 92%
Scheme 4. Transition-metal mediated, multi-step cross-coupling sequences of
2-pyridyl latent sulfinate reagents. tfp = tri(2-furyl)phosphine. dtbpy = 4,4’-di-tert-
butyl-2,2’-dipyridyl.
triisopropylbiphenyl.
XPhos
=
2-dicyclohexylphosphino-2’,4’,6’-
Conclusion
We have designed and developed β-nitrile and β-ester
sulfones as efficient base-labile latent sulfinate reagents in
palladium-catalyzed cross-coupling reactions. This method
has been used to construct challenging heteroaryl-
(hetero)aryl linkages, allowing access to a diverse range of 2-
arylpyridines and pharmaceutically relevant fragments. The
scope of electrophilic partners is broad, displaying a good
tolerance of multiple functional groups, and substitution
patterns, delivering the desired cross-coupled products in
good to high yields. In addition, both latent sulfinate groups
are stable and can be carried through multistep elaboration,
notably oxidative and palladium-mediated transformations.
We have further shown the successful use of the succinate
sulfone masking group, which releases a benign by-product
on activation. Due to the prevalence of the pyridine motif in
medicinal chemistry and the robustness of this chemistry, we
anticipate this method will find wide application.
Acknowledgements
X.A.F.C is grateful to EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/ L015838/1) for a
studentship, generously supported by Pfizer, GlaxoSmithKline,
Vertex, AstraZeneca, Diamond Light Source, Defence
Science and Technology Laboratory, Evotec, Janssen,
Novartis, Syngenta, Takeda and UCB. X.A.F.C also thanks
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202109146
Angewandte Chemie International Edition
COMMUNICATION
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the Clarendon Fund for a scholarship and support. L.R.E.P.
acknowledges financial support from the European Union’s
Horizon 2020 research and innovation programme under the
Marie Sklodowska-Curie grant agreement DeCoChem No
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10.1002/anie.202109146
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
R
Pd
EWG
N
S
base
O
O
EWG
EWG = -CN or -CO2Me
Base-activated
latent sulfinates
R
O
N
S
M
O
Sulfinate released
in situ
R
Ar
X
SO2
N
Ar
β-nitrile sulfones β-ester sulfones
✓Stable & readily prepared
✓Multi-step elaboration
✓Scalable
>35 examples
>30 examples
49-98%
42-99%
Next generation, base-activated latent sulfinate reagents have been successfully developed for use in the construction of
heteroaromatic frameworks, such as 2-arylpyridines. Under Pd-catalyzed conditions, these species unmask to give the sulfinate in
situ, which then undergoes efficient desulfinative cross-coupling with an array of (hetero)aryl halides. These reagents are stable,
readily prepared and amenable to multi-step synthetic sequences.
Institute and/or researcher Twitter usernames: @RhPdCu @OxfordChemistry @OxfordSynthesis
8
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