Suzuki–Miyaura Coupling of (Hetero)Aryl Sulfones: Complementary Reactivity Enables Iterative Polyaryl Synthesis

Article abstract of DOI:10.1002/anie.201908336

Ideal organic syntheses involve the rapid construction of C?C bonds, with minimal use of functional group interconversions. The Suzuki–Miyaura cross-coupling (SMC) is a powerful way to form biaryl linkages, but the relatively similar reactivity of electrophilic partners makes iterative syntheses involving more than two sequential coupling events difficult to achieve without additional manipulations. Here we introduce (hetero)aryl sulfones as electrophilic coupling partners for the SMC reaction, which display an intermediate reactivity between those of typical aryl (pseudo)halides and nitroarenes. The new complementary reactivity allows for rapid sequential cross-coupling of arenes bearing chloride, sulfone and nitro leaving groups, affording non-symmetric ter- and quateraryls in only 2 or 3 steps, respectively. The SMC reactivity of (hetero)aryl sulfones is demonstrated in over 30 examples. Mechanistic experiments and DFT calculations are consistent with oxidative addition into the sulfone C?S bond as the turnover-limiting step. The further development of electrophilic cross-coupling partners with complementary reactivity may open new possibilities for divergent iterative synthesis starting from small pools of polyfunctionalized arenes.

Full text of DOI:10.1002/anie.201908336

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Accepted Article
Title: The Suzuki−Miyaura Coupling of (Hetero)Aryl Sulfones:
Complementary Reactivity Enables Iterative Polyaryl Synthesis
Authors: Paul Chatelain, Abhijit Sau, Christopher N. Rowley, and
Joseph Moran
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908336
Angew. Chem. 10.1002/ange.201908336
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10.1002/anie.201908336
Angewandte Chemie International Edition
COMMUNICATION
Suzuki−Miyaura
Coupling
of
(Hetero)Aryl
Sulfones:
Complementary Reactivity Enables Iterative Polyaryl Synthesis
Paul Chatelaina, Abhijit Saua, Christopher N. Rowleyb and Joseph Morana*
Abstract: Ideal organic syntheses involve the rapid construction of C-
C bonds, with minimal use of functional group interconversions. The
Suzuki-Miyaura cross-coupling (SMC) is a powerful way to form biaryl
linkages, but the relatively similar reactivity of electrophilic partners
makes iterative syntheses involving more than two sequential
coupling events difficult to achieve without additional manipulations.
Here we develop (hetero)aryl sulfones as electrophilic coupling
partners for the SMC reaction, which display an intermediate reactivity
between those of typical aryl (pseudo)halides and nitroarenes. The
new complementary reactivity allows for rapid sequential cross-
coupling of arenes bearing chloride, sulfone and nitro leaving groups,
affording non-symmetric ter- and quateraryls in only 2 or 3 steps,
respectively. The SMC reactivity of (hetero)aryl sulfones is
demonstrated in 30 examples. Mechanistic experiments and DFT
calculations are consistent with oxidative addition into the sulfone C–
S bond as the turnover-limiting step. The further development of
electrophilic cross-coupling partners with complementary reactivity
may open new possibilities for divergent iterative synthesis starting
from small pools of polyfunctionalized arenes.
expanding the breadth of pseudohalides to include those
displaying intermediate reactivity would unlock the
complementary reactivity necessary to execute multiple
sequential biaryl couplings in a rapid, iterative manner. This is
particularly attractive because of the wide potential therapeutic
applications of terphenyls.[4],[24],[3],[25] In this regard, SMC reactions
of aryl sulfones offer an opportunity to fill this void (Scheme 1a).
Aryl sulfones offer a synthetic handle to tune their reactivity, and
can direct ortho, meta and para functionalization,[26],[27],[28],[29] while
remaining robust to hydrolysis. Sulfones have spiked interest in
various cross-coupling reactions,[30],[26],[31] including the
benzyl,[32],[33] vinyl[34] and tetrazolyl[35] SMC reaction. Surprisingly,
a general method for the SMC reaction of aryl sulfones has not
appeared. Herein, we describe the discovery and development of
the SMC reaction of (hetero)aryl sulfones, which possess an
intermediate level of reactivity between aryl chlorides and
nitroarenes, thus allowing for rapid access to non-symmetric ter-
and quateraryl compounds via iterative coupling sequences.
Scheme 1. Relative reactivity of aryl electrophiles in the
Suzuki-Miyaura reaction
The Suzuki-Miyaura coupling (SMC) reaction is broadly
used in academia and industry for the synthesis of bioactive
molecules, agrochemicals and organic materials, as exemplified
by the 2010 Nobel Prize in chemistry.[1] In biaryl synthesis, by far
the most commonly used application of the SMC, the
electrophilic partner is typically an aryl halide (-I, -Br, -Cl) or
pseudohalide (-OTf). Even with such a well-developed reaction, it
can be surprisingly difficult to orchestrate short, iterative
sequences of SMC reactions to access non-symmetric ter- and
quateraryl compounds because of the relatively small or
O
O
S
Br
Cl
R
Slow
Fast
?
NO2
OTf
I
Easy access
to teraryls
O
OH
OMe
HO
unpredictable
reactivity
differences
between
available
OH
electrophilic partners.[2],[3],[4] For example, aryl triflates may react
faster or slower than aryl chlorides, depending on the conditions
and substrate.[2] Halides and pseudohalides have been used with
success for sequential cross-coupling reactions such as in the
elegant sequential Negishi couplings by Schoenebeck and
coworkers.[5],[6] However, apart from a few exceptions,[2],[4] the
synthesis of polyaromatics via sequential SMC reactions remains
mostly limited to specific substrates or require iterative functional
group manipulations.[7],[8],[9],[10],[11] Efforts have been made to
couple new, challenging electrophilic partners, such as a recently
O
O
OH
OH
OH
OH
Gliocladinin B
Anti tumoral activity
OMe
HO
HO
R1O
Terprenin
IgE Suppressant
IC50 = 0.18nM
Our initial experiments focused on identifying aryl sulfones
capable of acting as electrophilic coupling partners (Table 1).
When RuPhos was used as ligand in the presence of K3PO4,
catalytic Pd(acac)2, and a small amount of DMSO, diphenyl
sulfone underwent coupling with 4-methoxyphenylboronic acid at
130 °C (entry 1). Phenyl methyl sulfone and its mono- and di-
fluorinated analogs were not reactive (entry 2-4), but
trifluoromethylphenyl sulfone underwent smooth coupling even at
80 °C (entry 5). The presence of DMSO as additive was found to
be important for high yields (entry 6). Other additives capable of
solubilizing the inorganic base had a similar, though lesser effect
(entry 7), whereas water had a detrimental effect (entry 8). Bis-
sulfoxides that could potentially act as ligands were not effective
(entry 9). DMSO could not be used as the solvent (entry 10), but
the reaction could be carried out efficiently in the absence of
DMSO by using micellar water (entry 11).[36],[37] Related functional
developed
SMC
reaction
of
nitroarenes.[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23]
However,
P. Chatelain, Dr. A. Sau, Prof. Dr. J. Moran.
University of Strasbourg, CNRS, ISIS UMR 7006,
67000 Strasbourg, France.
E-mail: moran@unistra.fr
Prof. Dr. C. N. Rowley
Memorial University of Newfoundland, 283 Prince Philip Drive, St.
John's, NL, Canada, A1B 3X7
This article is protected by copyright. All rights reserved.

10.1002/anie.201908336
Angewandte Chemie International Edition
COMMUNICATION
groups, such as trifluoromethyl sulfoxides or trifluoromethyl
ketones, did not undergo coupling under these conditions (see
Supporting Information). The non-symmetric deactivated di-aryl
sulfone 1-(phenylsulfonyl)-3,5-bis(trifluoromethyl)benzene only
underwent cross-coupling on the electron-poor arene (entry 12).
Competition experiments comparing aryl sulfones with other
electrophiles demonstrated an SMC reactivity at least two orders
of magnitude slower than aryl chlorides, but at least two orders
faster than nitroarenes and aryl tosylates, under standard
conditions (Scheme 2). Interestingly, using XPhos as ligand in
place of RuPhos does not enable cross-coupling of sulfones at
80 °C (Table S1).
The optimized conditions were then applied to a variety of
aryl CF3 sulfones and aryl boronic acids (Table 2). Electron
donating or withdrawing groups were well-tolerated on the boronic
acid or on the sulfone. Coupling was selective for sulfone moieties
over nitro groups (3, 11, 23-25, 31), which opens the possibility
Table 2. Substrate scope
Pd(acac)2 (5 mol%)
RuPhos (20 mol%)
K3PO4 (3 equiv)
O
S
O
R2
R1
B(OH)2
R2
DMSO (10 µL)
CF3
R1
+
Dioxane, 80 °C
NO2
NMe2
CF3
OMe
Table 1. Evaluation of reaction parameters
Pd(acac)2 (5 mol%)
OMe
RuPhos (20 mol%)
K3PO4 (3 equiv)
additive (1% v/v)
OMe
SO2R
+
1, 95%
2, 82%
3, 68%
4, 99%
5, 90%
(HO)2B
Dioxane, 80 °C
1
CHO
NPh2
S
entry
1
R
additive
DMSO
Yield 1 (%)a
Ph
14b
6, 97%
7, 27%
8, 98%
NO2
9, 89%
2
CH3
CH2F
CHF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
DMSO
DMSO
DMSO
DMSO
-
<1
<1
<1
95
55
38
77
5
3
OHC
S
N
4
5
NC
NC
NC
10, 93%
11, 91%
13, 65%
12, 25%
6
7
H2Oc
NPh2
F
CF3
OMe
8
HMPA
(PhSOCH2)2
-
d
9
NC
NC
NC
NC
<1e
90f
<1
14, 82%
16, 75%
15, 84%
17, 75%
10
11
12
-
NPh2
CF3
OMe
3,5-bis(CF3)Ph
DMSO
aIsolated yield. b130 °C. c0.2% (v/v). d50 mol%. eDMSO as a solvent.
f2% (w/w) Tocopherol methoxypolyethylene glycol succinate solution
in water as a solvent. acac = acetylacetone; DMSO = dimethyl
OMe
MeO
MeO
F
18, 56%
19, 55%
NO2
21, 73%
20, 84%
NMe2
Me
sulfoxide; HMPA
=
hexamethylphosphoramide; RuPhos
=
2-
dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl.
O2N
O2N
Me
O
S
O
Ar B(OH)2
[Pd]/XPhos
22 °C
CHO
F
22, 60%
Cl
Ar
Ar
F
CF3
a)
23, 78%
24, 68%
25, 54%
OMe
:
:
F
1
>99
CN
O
O
O
Ar B(OH)2
[Pd]/RuPhos
80 °C
N
NO2
OTs
Ar
Ar
Ar
Ar
S
CF3
N
N
29, 70%
N
N
b)
c)
26, 81%
28, 72%
OMe
27, 75%
>99
>99
1
1
F
O2N
O
Ar B(OH)2
[Pd]/RuPhos
80 °C
S
MeO
OMe
CF3
30, 86%
31, 73%
:
Scheme 2. Competition studies of sulfonyl arene versus: a)
chloroarene, reaction conditions: Pd(OAc)2 (1 mol%), XPhos (3 mol%),
K3PO4 (3 equiv), THF, 22 °C, 17 h; b) nitroarene or c) aryl tosylate,
reaction conditions: Pd(acac)2 (5 mol%), RuPhos (20 mol%), K3PO4
OMe
Anti-leukemia activity ref [25]
OMe
OMe
OMe
MeO
(3 equiv), dioxane,
80 °C, 17 h. BrettPhos
=
2-
MeO
(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-
biphenyl; THF = tetrahydrofuran; XPhos = 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl.
This article is protected by copyright. All rights reserved.

10.1002/anie.201908336
Angewandte Chemie International Edition
COMMUNICATION
for sequential cross-coupling employing the recently disclosed
nitro SMC reaction.[12] Bulky boronic acids underwent cross-
coupling in excellent yields (8-10, 17, 21 and 29). Thiophene
boronic acids were also well-tolerated (6 and 13) although
pyridine boronic acids did not react. 2-Fluoroaryl substitution on
the sulfone partner did not impair reactivity (20, 22, 23). 2-Pyridyl
sulfones (26-29) and meta- and para- substituted biaryl sulfones
underwent cross-coupling in good yields to afford 30 and 31, the
latter two of which are analogs of anti-leukemia compounds.[22]
The main limitation of the scope occurs in the case of boronic
acids bearing aldehyde groups, where cross-coupling occurred in
lower yields in some cases (7, 12 and 22).
To gain insight into the mechanism, a stoichiometric
reaction between (1,5-cyclooctadiene)bis(trimethylsilylmethyl)-
palladium, a Pd(0) precursor, and PhSO2CF3 in the presence of
RuPhos was undertaken to isolate the reaction intermediate X1
(eq 1).
O
O
S
O
S
CF3
(3.0 equiv)
F3C
SiMe3
SiMe3
O
Pd PCy2
Pd
(eq 1)
RuPhos (0.9 equiv)
i-PrO
THF, 40 °C, 72 h
i-PrO
X1 (X-ray), 37%
Taking advantage of the very different conditions required
for cross-coupling of aryl chlorides (22 °C, using XPhos as ligand),
aryl sulfones (80 °C, using RuPhos as ligand) and nitroarenes
(130 °C, using BrettPhos as ligand), we developed a sequential
SMC protocol for the synthesis of non-symmetric terphenyls and
quaterphenyls (Scheme 3). SMC of the chloro group of a 2-chloro
phenylsulfone with 3-nitrophenylboronic acid gave biphenyl 1a,
followed by SMC of the sulfone group with 4-N-carbazole-
phenylboronic acid to give terphenyl 1b, before a final SMC of the
nitro group to afford quaterphenyl 1c. Chloro, sulfone and nitro
leaving groups can be differentiated on the same aryl ring, as
evidenced by a chloro-selective SMC of 1-chloro-2-nitro-4-
((trifluoromethyl)-sulfonyl)benzene to give biphenyl 2a, followed
by a sulfone-selective SMC to give 2b. Compounds 30 and 31
were prepared in an analogous fashion, described in the SI.
The X-ray crystal structure of X1 revealed that after
oxidative addition, the palladium is bound to the oxygen of the
sulfinate, suggesting that the palladium complex rearranges, after
oxidative addition into the C–S bond, to minimize dipole
interactions in the apolar solvent used for crystallization.[38] The
structure is otherwise similar to what has been observed for
oxidative addition to arylhalides[39] and nitroarenes,[12] with the
palladium in a square planar geometry. A stoichiometric reaction
between X1 and 4-methoxyphenylboronic acid at 25 °C, but under
otherwise standard conditions, afforded biaryl
1 in nearly
quantitative yield, suggesting that oxidative addition is the
turnover-limiting step in the catalytic cycle. Using X1 (5 mol%) to
couple 4-methoxyphenylboronic acid and PhSO2CF3 under
otherwise standard conditions afforded 1 in 62% yield, whereas
the presence of excess RuPhos (20 mol%) increased the yield to
95%, suggesting the beneficial effect of excess RuPhos stems
from its ability to delay catalyst decomposition. To track the fate
of the leaving group, a typical crude reaction mixture (specifically,
that described in Table 1, entry 5) was extracted with D2O,
revealing the presence of trifluoromethanesulfinate as the only
compound visible by 19F NMR. Therefore, although oxidative
addition into sulfonyl chlorides is known to release SO2 and
Me2N
B(OH)2
NO2
NMe2
NCarb
B(OH)2
c
B(OH)2
a
Cl
b
1c
1b
1a
76%
64%
34%
SO2CF3
sulfone-
SMC
chloro-
SMC
nitro-
SMC
chloride, here the leaving group remains intact as
trifluoromethanesulfinate.[18]
a
NCarb
DFT calculations were undertaken to further probe the
reaction mechanism and complement our experimental
observations. Since the experiments described above support
oxidative addition as being turnover-limiting, as might be
expected in an SMC reaction with a challenging electrophile,2 the
Gibbs energy profiles for the insertion of the catalyst into the C–S
bonds of PhSO2Ph and PhSO2CF3 were calculated using B3LYP-
D3/def2-TZVP. The first step is the exchange of a coordinated
solvent molecule (dioxane) for the substrate to form a π-complex
and is slightly favored for PhSO2CF3 (Figure 1). The Gibbs energy
of the transition state corresponding to oxidative addition into the
C–S bond has an activation energy for PhSO2Ph that is 5.8
kcal/mol higher than for PhSO2CF3, consistent with the observed
experimental trend for the overall catalytic reaction and coinciding
with the increased polarization of the C–S bond in the latter case.
The S-bound Pd intermediate is close in energy to the observed
O-bound XRD structure X1. The full computational details,
structures, and a rendering of the transition state structure are
included in Supporting Information.
OMe
B(OH)2
OMe
OMe
Cl
NO2
B(OH)2
NPh2
NO2
a
b
NO2
62 %
75%
2b
SO2CF3
2a
chloro-
SMC
sulfone-
SMC
SO2CF3
NPh2
Scheme 3. Synthesis of non-symmetric terphenyls and
quaterphenyls by taking advantage of the relative SMC reactivity:
chloroarenes> sulfonylarene > nitroarenes. a: Pd(OAc)2 (1 mol %),
XPhos (3 mol%), K3PO4 (3 equiv), THF, 22 °C, 17 h; b: standard
conditions; c: Pd(acac)2 (5 mol%), BrettPhos (20 mol%), 18-
crown-6 (10 mol%), K3PO4 (3 equiv), dioxane, 130 °C, 48 h.
NCarb = N-carbazole.
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10.1002/anie.201908336
Angewandte Chemie International Edition
COMMUNICATION
O
O
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i-PrO
i-PrO
2.3
‡
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XO2S
Pd PCy2
i-PrO
-3.5
i-PrO
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i-PrO
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i-PrO
-24.0
O
S
-22.7
-25.5
X = CF3
X = Ph
X
O
-26.1
-28.4
Pd PCy2
i-PrO
-29.1
XO2S
Pd PCy2
i-PrO
i-PrO
i-PrO
π-complex
XRD structure
oxidative addition
Figure 1. Calculated Gibbs energies for the oxidative
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addition of palladium into the aryl sulfone C–S bond. Most notably,
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enabling the facile synthesis of non-symmetric ter- and
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complementary reactivity in other cross-coupling reactions will
further streamline approaches to iterative synthesis.
Acknowledgements
J.M. thanks the European Research Council (ERC) (grant
agreement n° 639170) and ANR LabEx “Chemistry of Complex
Systems” (ANR-10-LABX-0026 CSC). A.S. thanks the EU for a
H2020 Marie Skłodowska Curie Fellowship (792101). P.C. thanks
the French government for an MRT fellowship. CNR thanks
NSERC of Canada for funding through the Discovery Grants
program (application 418505-2012) and Compute Canada for
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Notes
The authors declare no competing financial interest.
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10.1002/anie.201908336
Angewandte Chemie International Edition
COMMUNICATION
Keywords: Aryl sulfones; Suzuki−Miyaura Coupling; palladium catalysis; teraryl; quaterphenyl.
Entry for the Table of Contents:
COMMUNICATION
B(OH)2
O
S
O
R2
R2
R1
Paul Chatelain, Abhijit Sau, Christopher
N. Rowley, Joseph Moran*
CF3
Pd Catalysis
R1
ꢀ Chloro >> sulfones >> nitro groups
ꢀ Rapid access to non-symmetric ter-and quaterphenyls
Page No. – Page No.
Aryl sulfones undergo Suzuki-Miyaura coupling with intermediate reactivity between
aryl halides and nitroarenes, enabling the iterative synthesis of non-symmetric
polyaromatics.
Suzuki−Miyaura Coupling of
(Hetero)Aryl Sulfones:
Complementary Reactivity Enables
Iterative Polyaryl Synthesis
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