Selective Mechanochemical Monoarylation of Unbiased Dibromoarenes by in Situ Crystallization

Article abstract of DOI:10.1021/jacs.0c01739

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of liquid, unbiased dibromoarenes under mechanochemical conditions selectively afford the monoarylated products. The lower reactivity of the crystalline monoarylated products relative to the liquid starting materials should be attributed predominantly to the low diffusion efficiency of the former in the reaction mixture, which results in a selective monoarylation. The present study sheds light on a novel approach using in situ phase transitions in solids to design selective organic transformations that are difficult to achieve via conventional solution-based synthesis.

Full text of DOI:10.1021/jacs.0c01739

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Communication
Selective Mechanochemical Monoarylation of
Unbiased Dibromoarenes by In-situ Crystallization
Tamae Seo, Koji Kubota, and Hajime Ito
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2020
Downloaded from pubs.acs.org on April 27, 2020
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Journal of the American Chemical Society
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Selective Mechanochemical Monoarylation of Unbiased
Dibromoarenes by In-situ Crystallization
Tamae Seo,† Koji Kubota,*,†,‡ and Hajime Ito*,†,‡
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†Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628,
Japan
‡Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Hokkaido 060-
8628, Japan
Supporting Information Placeholder
A.
Solution-based conditions
ABSTRACT: Palladium-catalyzed Suzuki-Miyaura cross-
coupling reactions of liquid, unbiased dibromoarenes under
mechanochemical conditions selectively afford the
monoarylated products. The lower reactivity of the crystalline
monoarylated products relative to the liquid starting materials
should be attributed predominantly to the low diffusion
efficiency of the former in the reaction mixture, which results
in a selective monoarylation. The present study sheds light on
a novel approach using in-situ phase transitions in solids to
design selective organic transformations that are difficult to
achieve via conventional solution-based synthesis.
X
M
X
first
second
arylation
X
X
X
arylation
M
X
M
k1
k2
M
X
solvent
=
≒
k1
k2
low selectivity
in soluion
mixture
B.
Mechanochemical conditions using ball milling
X
in-situ crystallization
k4
M
X
faster first
arylation
X
X
X
M
M
X
Recently, mechanochemical organic transformations using
a ball mill have attracted considerable interest as a green
and sustainable synthetic technique.1 Apart from the
environmental benefits, mechanochemical approaches
could potentially provide exciting opportunities to access
large areas of hitherto unexplored chemical space that
exhibit reactivity and selectivity different to that of
conventional solution-based reactions.1 Although some
unique reactivity patterns have already been discovered,1d,
X
ball milling
conditions
M
X
M
slower
second
arylation
X
k3
k3 > k4
high selectivity
X
X
liquid
=
C. This work: In-situ crystallization-driven monoarylations
o-, m-, p-
Ar2
in-situ
crystallization
Br
selective
monoarylation
Ar1
Ar1
2-16
the development of site- and chemoselective synthetic
strategies using mechanochemistry that enable the rapid
cat. Pd / ligand
ball mill
Br
Br
liquid
crystalline solid
construction
of
molecular
complexity
remains
+
Ar2
Ar2
unexplored.13
cat. Pd / ligand
Ar2
Ar1
Ar1
+
Mono-selective
Suzuki-Miyaura
cross-coupling
in solution
(HO)2B
Br
Ar2
reactions of dihaloarenes would represent an ideal method
for the synthesis of functionalized aryl halides, which are
useful building blocks for the construction of complex
polyaromatic structures.17-22 Conventionally, chemists rely
on the use of starting materials that bear different halide
groups with a relatively large reactivity difference or the
use of an excess of dihaloarenes to achieve high selectivity
toward monoarylation.17 However, many of these
approaches are costly and wasteful. Although the
monoarylation of unbiased dihaloarenes with certain halide
groups through elaborate catalyst design and/or the fine-
tuning of reaction parameters such as temperature, solvent,
and additives has been reported,18-22 the exploration of
conceptually new and generally applicable strategies to
control and improve the monoarylation selectivity remains
in high demand.
mixture
tBu2P
tBu2P
MeO
iPr
iPr
iPr
iPr
or
ligand
=
iPr
iPr
MeO
tBuXPhos
tBuBrettPhos
Figure 1. Concept of in-situ crystallization-driven selective
transformations using mechanochemistry.
We have previously reported broadly applicable solid-
state cross-coupling reactions using mechanochemistry.23,24
In these previous studies, we discovered a considerable
reactivity gap between liquid and solid aryl halides under
the solvent-free cross-coupling reactions that are typical for
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Journal of the American Chemical Society
Page 2 of 7
mechanochemistry. This is probably due to the relatively
major product (3d/4d = 30:70). We confirmed that the
starting material 1d still remained after the
mechanochemical reaction (22% recovery of 1d).
Unfortunately, prolonging the reaction time or increasing
catalyst loading did not lead to a higher conversion of 1d
(See the SI for details).
1
2
3
4
5
6
7
8
poor mixing efficiency of the solid reactants under the
mechanochemical conditions, which results in a lower
reactivity compared to liquid substrates. Ondruschka and
co-workers also reported the similar phenomenon in the
mechanochemical Suzuki-Miyaura coupling reactions.25
Inspired by this unique profile of mechanochemical cross-
coupling reactions, we hypothesized that a new and
complementary approach to control chemical reactivity and
selectivity could be developed through a mechanistically
distinct approach. Specifically, we envisioned that in-situ
crystallization of the arylation products could be used to
develop a selective mechanochemical monoarylation of
dihaloarenes (Figure 1). Under conventional, solution-
based conditions, Suzuki-Miyaura cross-coupling reactions
of unbiased dihaloarenes tend to provide a mixture of
mono- and diarylated products (Figure 1A and 1C).17 Under
Hu’s solution-based conditions, cross-coupling reactions of
dihaloarenes selectively provide the diarylated products via
a preferential oxidative addition mechanism.26 However,
our working hypothesis is based on the notion that one of
the two halide moieties could potentially be selectively
arylated under mechanochemical conditions when the
liquid starting material is more reactive than the
corresponding monoarylated crystalline solid (Figure 1B
and 1C).23,24 This unique approach, based on in-situ phase
transitions, would provide an efficient route to structurally
complex polyaromatic compounds via selective stepwise
cross-coupling strategies.
Initially, we conducted preliminary kinetic studies to
confirm the reactivity difference between liquid and solid
monohalides as test substrates in mechanochemical cross-
coupling reactions (Figure 2). Reactions were conducted in
a Retch MM400 ball mill in a stainless-steel milling jar (1.5
mL) at 25 Hz using one stainless-steel ball (diameter: 3 mm).
As periodic sampling of the mechanochemical reaction runs
would require stopping the mill and opening the jar, each
data point was obtained from an individual reaction. In the
presence of a catalytic amount of Pd(OAc)2/tBuXPhos27,28
and 1,5-cyclooctadiene (1.5-cod) as a liquid grinding
additive,1,23,24 the mechanochemical cross-coupling of liquid
bromobenzene (1a) with phenylboronic acid (2a)
proceeded readily to afford the coupling product (3a) in
good yield after an induction period of 40 min (Figure 2a).
Low conversion rates were observed when solid aryl
halides (1b and 1c) were employed (Figure 2a). This result
suggests a considerable reactivity gap between liquid and
solid aryl halides in such mechanochemical cross-coupling
reactions. This is probably due to the relatively poor mixing
efficiency of the crystalline solid reactants under the
applied mechanochemical conditions, where organic
molecules are arranged tightly and regularly.29 In contrast,
the reactivity of liquid and solid aryl halides (1a–1c) was
almost similar to that under conventional solution
conditions (Figure 2b).
mechanochemical conditions
liquid
solid
Pd(OAc)2 (3 mol %)
tBuXPhos (4.5 mol %)
CsF (3.0 equiv)
Br
Br
or
9
H2O (3.7 equiv)
1,5-cod (0.20 L/mg)
ball milling (25 Hz)
R1
R2
3a
or
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: R1 = Ph, R2 = H
: R1 = H, R2 = 2-naph
1a
1b
1c
Pd(OAc)2 (3 mol %)
tBuXPhos (4.5 mol %)
CsF (3.0 equiv)
+
R2
R1
2a
1.2 equiv
H2O (3.7 equiv)
toluene, 50 C
: R1 = Ph, R2 = H
: R1 = H, R2 = 2-naph
(HO)2B
3b
3c
solution conditions
Figure 2. Kinetic studies under mechanochemical and
solution-based conditions.
Scheme 1. Monoarylation of Unbiased 1,2-
Dibromobenzene (1d) under Mechanochemical
Conditionsa,b
Br
Pd(OAc)2 (3 mol %)
tBuXPhos (4.5 mol %)
CsF (3.0 equiv)
NMe2
1d
liquid
NMe2
Br
+
+
H2O (3.7 equiv)
ball milling or
NMe2
Br
in toluene solution
NMe2
3d
4d
(HO)2B
2b
1.2 equiv
3d/4d = 90:10
ball mill: 78%,
solution: 43%,
3d 4d
/
= 30:70
aMechanochemical conditions: 1d (0.30 mmol), 2 (0.36 mmol),
Pd(OAc)2 (0.009 mmol), tBuXPhos (0.0135 mmol), CsF (0.9
mmol), H2O (20 μL), and 1,5-cod (0.20 μL/mg) in a stainless-
steel ball-milling jar (1.5 mL) with a stainless-steel ball
(diameter: 3 mm). Solution conditions: 1d (0.30 mmol), 2 (0.36
mmol), Pd(OAc)2 (0.009 mmol), tBuXPhos (0.0135 mmol), CsF
(0.9 mmol), H2O (20 μL), and toluene (0.1 M), 50 °C, 24 h. bNMR
yields are shown.
Next, we examined mechanochemical mono-selective
cross-coupling reactions of 1,2-dibromobenzenes with
different arylboronic acids (Table 1).29 Under the applied
mechanochemical conditions, the reactions of liquid 1,2-
dibromobenzene
(1d)
and
1,2-dibromo-4,5-
Based on this preliminary investigation, we proceeded
difluorobenzene (1e) with p-methoxyboronic acid (2c)
provided the corresponding monoarylated products (3e
and 3f) with excellent monoarylation selectivity (3e/4e =
92:8; 3f/4f = 92:8). On the other hand, under solution
conditions, product mixtures were obtained (3e/4e =
to
monoarylation of liquid 1,2-dibromobenzene (1d) with 4-
(dimethylamino)phenylboronic acid (2b) under
investigate
the
in-situ
crystallization-driven
mechanochemical conditions (Scheme 1), which furnished
monoarylated 3d in good yield with high selectivity (78%
yield; 3d/4d = 90:10). In contrast, under solution
conditions, the diarylated product was obtained as the
60:40; 3f/4f
=
65:35). 2-Naphthaleneboronic acid
derivatives (2d and 2e) were cleanly coupled with 1d to
provide the corresponding monoarylated products (3g and
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Journal of the American Chemical Society
are shown. cGC yields are shown.
3h) in good yield with high selectivity. 1-
1
2
3
4
5
6
7
8
Naphythaleneboronic acid derivatives (2f and 2g) also
provided the corresponding monoarylation products (3i, 3j
and 3k) with excellent selectivity under mechanochemical
conditions. We found that the cross-coupling of 1d with 3-
Next, we investigated the monoarylation of 1,3-
dibromobenzene (1f) (Table 2).30 We found that the use of
tBuBrettPhos instead of tBuXPhos generally afforded
higher yields of the monoarylation product 5 (see the SI for
details). The mechanochemical cross-coupling reactions
with aryl boronic acids (2c, 2d, 2i, and 2f) afforded the
corresponding monoarylation products (5a–5d) with good
to high selectivity. In sharp contrast, under solution
conditions, the diarylated products were obtained as major
products.
(trifluoromethyl)phenylboronic acid (2h) provided
a
mixture of mono- and diarylated products (3l/4l = 65:35)
under mechanochemical conditions, which could probably
be rationalized in terms of 3l being a liquid. This result is
consistent with our proposed mechanism.
9
Table 1. In-situ Crystallization-driven Monoarylation of
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1,2-Dibromobenzenesa
Table 2. In-situ Crystallization-driven Monoarylation
Br
of 1,3-Dibromobenzene (1f)a
Pd(OAc)2 (3 mol %)
tBuXPhos (4.5 mol %)
CsF (3.0 equiv)
1
Ar1
liquid
Ar2
Ar2
Ar2
Br
Ar2
Pd(OAc)2 (5 mol %)
Ar1
+
Ar1
+
Ar2
tBuBrettPhos (7.5 mol %)
CsF (3.0 equiv)
Br
H2O (3.7 equiv)
1,5-cod (0.20 L/mg)
ball milling (25 Hz)
99 min
Br
Ar2
Ar2
+
+
H2O (3.7 equiv)
1,5-cod (0.20 L/mg)
ball milling (25 Hz)
99 min
3
4
(HO)2B
(HO)2B
2
Br
1f
liquid
solid
1.2 equiv
Ar2
Br
2
5
6
1.2 equiv
NMe2
OMe
OMe
OMe
NMe2
OMe
OMe
Me
Me
+
+
Br
Br
+
Me
Me
3d
4d
3e
4e
NMe2
+
b
b
Br
Me
Br
3d 4d 3d 4d 90:10
3e 4e 3e/4e = 92:8
+ , )
ball mill: 78% (
+
,
/
=
)
ball mill: 89% (
3d
3e
isolated yield of : 68%
isolated yield of : 72%
b
b
3d 4d 3d 4d
3e 4e 3e 4e
5a
6a
5b
6b
solution: 43% (
+
,
/
= 30:70)
solution: 41% (
+
,
/
= 60:40)
OMe
Me
5b 6b 5b/6b = 95:5
)
5b
isolated yield of : 56%
b
c,d
5a 6a 5a/6a = 88:12
ball mill: 72% (
solution: 39% (
+
,
)
ball mill: 68% (
solution: 42% (
+
,
OMe
F
OMe
OMe
5a
isolated yield of : 63%
b
c
F
5a 6a 5a 6a
5b 6b 5b 6b
+ , / = 49:51)
+
,
/
= 38:62)
+
+
F
Br
F
Br
3f
ball mill: 78% (
4f
3f 4f 3f 4f 92:8
3g
4g
+
+
b
c
3g 4g 3g 4g 91:9
+
,
/
=
)
ball mill: 77% (
+
,
/
=
)
3f
3g:
isolated yield of : 68%
isolated yield of
3g 4g 3g 4g
= 61:39)
66%
Br
Br
b
c
5c
6c
3d 4d 3f 4f
solution: 29% (
+
,
/
= 65:35)
solution: 36% (
+
,
/
5d
6d
OMe
OMe
c
5c 6c 5c 6c 82:18
)
ball mill: 75% (
+
,
/
=
c,e
5c
isolated yield of : 55%
5d 6d 5d 6d 85:15
)
isolated yield of : 41%
ball mill: 56% (
+
,
/
=
c
5c 6c 5c 6c
= 59:41)
solution: 29% (
+
,
/
5d
b
5d 6d 5d 6d
= 32:68)
solution: 66% (
+
,
/
+
+
Br
Br
aFor experimental details see the SI. b1H NMR yields are shown.
cGC yields are shown. d1,5-cod (0.10 μL/mg) was used. e1,5-cod
(0.80 μL/mg) and tBuXPhos were used; reaction time: 3 h.
3h
4h
3i
4i
OMe
c
c
3h 4h 3h 4h 89:11
3i 4i 3i 4i 97:3
+ , / = )
ball mill: 80% (
+
,
/
=
)
ball mill: 64% (
To explore the scope of the in-situ crystallization
3h
isolated yield of : 65%
3i
isolated yield of : 54%
c
c
3h 4h 3h 4h
3i 4i 3i 4i
solution: 28% (
+
,
/
= 59:41)
solution: 30% (
+
,
/
= 70:30)
strategy further, other classes of dibromoarenes were
tested (Table 3).30 The reaction of
a liquid 1,4-
Me
Me
dibromobenzene derivative with fluorine atoms (1g) using
tBuBrettPhos also smoothly furnished the corresponding
monoarylated product (7a) with high selectivity under the
mechanochemical conditions (7a/8a = 90:10). This method
could also be successfully applied to dibromothiophenes
(1h and 1i), providing the desired monoarylation products
(7b and 7c) with high selectivity (7b/8b = 91:9; 7c/8c =
88:12). Notably, the reactions of these substrates in solution
using the same catalytic system afforded a mixture of mono-
and diarylated products.
In order to obtain mechanistic insights, we used powder
x-ray diffraction (PXRD) analyses to determine whether
crystalline solids of monoarylated products are formed
during the reactions (Figure 3). For that purpose, the crude
mixture of the cross-coupling reaction between 1d and 2e
F
F
F
+
+
Br
F
Br
Me
3j
ball mill: 71% (
4j
3j 4j 3j 4j 96:4
3k
4k
b
c
3k 4k 3k 4k 98:2
)
+
,
/
=
)
ball mill: 69% (
+
,
/
=
3j
3k
isolated yield of : 50%
isolated yield of : 58%
b
c
3j 4j 3j 4j
3k 4k 3k 4k
+ , / = 80:20)
solution: 30% (
+
,
/
= 71:29)
solution: 25%, (
CF3
c
CF3
3l 4l 3l 4l 65:35
)
ball mill: 81% (
+
,
/
=
+
3l
isolated yield of : 52%
Br
3l
liquid
c
3l 4l 3l 4l
= 24:76)
solution: 57% (
+
,
/
4l
F3C
aFor experimental details, see the SI. b1H or 19F NMR yields
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Journal of the American Chemical Society
under the mechanochemical conditions was analyzed by
Page 4 of 7
the Pd(OAc)2/DavePhos/1,5-cod catalyst system, which is
more active in the solid state than Pd(OAc)2/tBuXPhos or
Pd(OAc)2/tBuBrettPhos.24 We found that the desired
unsymmetrically diarylated products (9a–9d) were
obtained in good to moderate yield over 2 steps.32,33 These
results suggest that the one-pot mechanochemical coupling
strategy enables the rapid and modular construction of
complex polyaromatic structures under simple operational
conditions in air from readily available starting materials.
PXRD (Figure 3).31 The diffraction peaks that correspond to
crystalline 3h were observed, suggesting that "in-situ
crystallization" of 3h occurred during the reaction. This
result supports our proposed mechanism for the selectivity
toward monoarylation under mechanochemical conditions.
1
2
3
4
5
6
7
8
Table 3. In-situ Crystallization-driven Monoarylation of
Other Classes of Substratesa
Pd(OAc)2 (3 mol %)
tBuBrettPhos (4.5 mol %)
CsF (3.0 equiv)
Ar2
Ar2
Table 4. One-pot Sequential Arylations of Unbiased
Dibromoarenesa,b
9
Br
Ar1
Ar2
Ar1
+
Ar1
+
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13
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60
H2O (3.7 equiv)
1,5-cod (0.20 L/mg)
ball milling (25 Hz)
99 min
(HO)2B
Br
Br
Ar2
one-pot procedure
w/o work up
2
1
7
8
1.2 equiv
liquid
cat. Pd(OAc)2 cat. Pd(OAc)2
cat. ligand
CsF, H2O
cat. DavePhos
CsF, H2O
Ar2
OMe
OMe
Br
PCy2
F
Ar1
Ar1
Me2N
F
Ar2-B(OH)2
1,5-cod
ball milling
99 min
Ar3-B(OH)2
ball milling
99 min
S
Br
Br
Ar3
7a
7b
1
9
Br
OMe
DavePhos
OMe
+
+
S
first arylation
with tBuXPhos
first arylation with
tBuBrettPhos
MeO
F
OMe
F
second arylation
with DavePhos
8a
7a 8a 7a/8a = 90:10
8b
7b 8b 7b/8b = 91:9
)
F
MeO
F
b
c,d
ball mill: 72% (
solution: 54% (
+
,
)
ball mill: 55% (
+
,
7a
7b
O
isolated yield of : 53%
isolated yield of : 48%
S
S
b
c,d
9a
67% yield
(2 steps)
9b
7a 8a 7a 8a
7b 8b 7b 8b
+ , / = 28:72)
+
,
/
= 63:37)
solution: 37% (
61% yield
(2 steps)
Me
second arylation
with DavePhos
OMe
OMe
OMe
OMe
second arylation
with DavePhos
b
7c 8c 7c/8c = 88:12
)
ball mill:71% (
+
,
S
OMe
Me
Me
OMe
OMe
OMe
7c
isolated yield of : 61%
+
O
S
b
OMe
7c 8c 7c 8c
= 53:47)
solution: 15% (
+
,
/
S
S
Me
Br
first arylation
with tBuBrettPhos
second arylation
with DavePhos
7c
8c
first arylation
with tBuXPhos
OMe
MeO
9c
9d
aFor experimental details, see the SI. b1H or 19F NMR yields are
63% yield (2 steps)
48% yield (2 steps)
c
d
shown. GC yields are shown. tBuXPhos was used instead of
tBuBrettPhos.
aFor experimental details, see the SI. bIsolated yields are shown.
To demonstrate the applicability of this newly
developed methodology to the synthesis of bioactive
molecules, we completed the synthesis of an anti-tumor-
active Combretastatin A-4 analogue (10) using
mechanochemistry (Scheme 2).34 We confirmed that
sequential mechanochemical arylations allowed the rapid
one-pot synthesis of 10 in good yield (54% over 2 steps)
from commercially available 3,4-dibromothiophene (1i).
The reported solution conditions require an excess of 1i,
and if reduced to one equivalent, only a very low selectivity
toward monoarylation is observed (7c/8c = 25:75; see the
SI for details).34 It can be feasibly expected that
crystallization-driven mechanochemical cross-couplings
will find further applications in the selective synthesis of
bioactive compounds.
OMe
Pd(OAc)2 (3 mol %)
OMe
tBuXPhos (4.5 mol %)
Br
KF (10 equiv)
+
Br
H2O (3.7 equiv)
1,5-cod (0.20 L/mg)
ball milling (25 Hz)
(HO)2B
1d
2e
3h
Br
1.2 equiv
Scheme 2. Rapid Synthesis of Anti-tumor-active
Combretastatin A-4 Analogue (10) via One-pot
Sequential
Mechanochemical
Cross-coupling
Reactiona,b
Figure 3. Powder X-ray diffraction analysis of the crude
reaction mixture of 3h.
To demonstrate the practical utility of this method, we
investigated a direct one-pot sequential arylation protocol
using mechanochemistry (Table 4). For that purpose, the
crude mixture of 3 was directly subjected to a one-pot solid-
state cross-coupling using different aryl boronic acids and
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Journal of the American Chemical Society
first
arylation
from mystical to practical. Green Chem. 2018, 20, 1435–1443. (h) Bolm,
C.; Hernández, J. G. Mechanochemistry of gaseous reactants. Angew.
Chem., Int. Ed. 2019, 58, 3285–3299. (i) Tan, D.; García, F. Main group
mechanochemistry: from curiosity to established protocols. Chem. Soc.
Rev. 2019, 48, 2274–2292.
OMe
OMe
1
2
3
4
5
6
7
8
cat. Pd(OAc)2
cat. tBuBrettPhos cat. DavePhos
CsF, H2O
cat. Pd(OAc)2
Br
Br
S
S
CsF, H2O
OMe
Ar1-B(OH)2
1,5-cod
ball milling
99 min
Ar2-B(OH)2
ball milling
99 min
(2) Komatsu, K.; Wang, G.-W.; Murata, Y.; Shiro, M. Synthesis and X-
ray structure of dumb-bell-shaped C120. Nature 1997, 387, 583–586.
(3) Belenguer, A. M.; Friščić, T.; Day, G. M.; Sanders, J. K. M. Solid-state
dynamic combinatorial chemistry: reversibility and thermodynamic
product selection in covalent mechanosynthesis. Chem. Sci. 2011, 2,
696–700.
10
54% yield
(2 steps)
1i
commercially
available
second
arylation
OMe
one-pot procedure
w/o work up
anti-tumor-active
Combretastatin A-4 analogue
(4) Zhao, Y.; Rocha, S. V.; Swager, T. M. Mechanochemical synthesis
of extended iptycenes. J. Am. Chem. Soc. 2016, 138, 13834–13837.
(5) Hernández, J. G.; Macdonald, N. A. J.; Mottillo, C.; Butler, I. S.;
9
aFor experimental details, see the SI. bIsolated yield is shown.
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25
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60
In summary, we have developed selective
monoarylation reactions for dibromoarenes based on in-
situ crystallization under mechanochemical conditions.
Suzuki–Miyaura cross-coupling reactions of unbiased
dibromoarenes in solution tend to provide a mixture of
mono- and diarylated products. However, we discovered
that mechanochemical conditions promote cross-coupling
reactions that are selective toward the monoarylation of a
wide range of substrates. Based on a mechanistic study, we
propose that this selectivity results in all likelihood from the
conversion of liquid starting materials into less reactive
crystalline monoarylated products under the applied
Friščić, T.
A mechanochemical strategy for oxidative addition:
remarkable yields and stereoselectivity in the halogenation of
organometallic Re(I) complexes. Green Chem. 2014, 16, 1087–1092.
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monitored by in situ Raman spectroscopy. Chem. Commun. 2014, 50,
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(9) Haley, R. A.; Zellner, A. R.; Krause, J. A.; Guan, H.; Mack, J. Nickel
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Development of C-N coupling using mechanochemistry: catalytic
coupling of arylsulfonamides and carbodiimides. Angew. Chem., Int. Ed.
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(11) Śtrukil, V.; Gracin, D.; Magdysyuk, O. V.; Dinnebier, R. E.; Friščić,
T. Trapping reactive intermediates by mechanochemistry: elusive aryl
N-thiocarbamoylbenzotriazoles as bench-stable reagents. Angew.
Chem., Int. Ed. 2015, 54, 8440–8443.
(12) Shi, Y. X.; Xu, K.; Clegg, J. K.; Ganguly, R.; Hirao, H.; Friščić, T.;
García, F. The first synthesis of the sterically encumbered adamantoid
phosphazane P4(NtBu)6: enabled by mechanochemistry. Angew. Chem.,
Int. Ed. 2016, 55, 12736–12740.
(13) Howard, J. L.; Brand, M. C.; Browne, D. L. Switching
chemoselectivity: using mechanochemistry to alter reaction kinetics.
Angew. Chem., Int. Ed. 2018, 57, 16104–16108.
(14) Kubota, K.; Pang, Y.; Miura, A.; Ito, H. Redox reactions of small
organic molecules using ball milling and piezoelectric materials.
Science 2019, 366, 1500–1504.
(15) Sim, Y.; Tan, D.; Ganguly, R.; Li, Y.; García, F. Orthogonality in
main group compounds: a direct one-step synthesis of air- and
moisture-stable cyclophosphazanes by mechanochemistry. Chem.
Commun. 2018, 54, 6800–6803.
(16) Koby, R. F.; Hanusa, T. P.; Schley, N. D. Mechanochemically
driven transformations in organotin chemistry: stereochemical
rearrangement, redox behavior, and dispersion-stabilized complexes.
J. Am. Chem. Soc. 2018, 140, 15934–15942.
(17) (a) Palladium-catalyzed coupling reactions: practical aspects
and future developments. Molnár, Á., Ed.; Wiley-VCH: Weinheim, 2013.
(b) Metal-catalyzed cross-coupling reactions. Meijere, A.; Diederich F.
Ed.; Wiley-VCH: Weinheim, 2008. (c) Miyaura, N.; Suzuki, A. Palladium-
catalyzed cross-coupling reactions of organoboron compounds. Chem.
Rev. 1995, 95, 2457–2483. (d) Johansson Seechurn, C. C. C.; Kitching, M.
O.; Colacot, T. J.; Snieckus, V. Palladium‐Catalyzed Cross‐Coupling: A
Historical Contextual Perspective to the 2010 Nobel Prize. Angew.
Chem., Int. Ed. 2012, 51, 5062–5085.
(18) Dong, C.-G.; Liu, T.-P.; Hu, Q.-S. Monoarylation of dibromoarenes
by simple palladium catalyst systems: efficient synthesis of
bromobiaryls from dibromoarenes and arylboronic acids. Synlett 2009,
1081–1086.
mechanochemical
demonstrated
conditions.
rapid, one-pot mechanochemical
We
furthermore
a
sequential coupling procedure that represents an efficient
and step-economic route to valuable synthetic targets from
readily available starting materials.
ASSOCIATED CONTENT
Supporting Information
Methods
and
Materials,
supplementary
graphics,
characterization data, and references.
AUTHOR INFORMATION
Corresponding Author
hajito@eng.hokudai.ac.jp
kbt@eng.hokudai.ac.jp
ACKNOWLEDGMENT
This work was financially supported by the Japan Society for
the Promotion of Science (JSPS) via KAKENHI grants 18H03907,
17H06370, and 19K15547; the JST via CREST grant
JPMJCR19R1; the Institute for Chemical Reaction Design and
Discovery (ICReDD), which has been established by the World
Premier International Research Initiative (WPI), MEXT, Japan.
REFERENCES
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(32) The symmetrically diarylated products are major byproducts of
the mechanochemical one-pot sequential cross-coupling reactions. For
example, the reaction of 1e afforded 9b (65%), 8a (8%), and 11 (18%)
(see below).
1
2
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4
OMe
OMe
F
S
F
F
F
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9
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equiv) in the presence of Pd(OAc)2/tBuXPhos under mechanochemical
conditions afforded 9b (10%), 8a (2%), and 11 (22%). When the same
reaction was performed in toluene at 50 °C, 9b (34%), 8a (38%), and
11 (27%) were obtained. These results demonstrate the utility of the
stepwise mechanochemical coupling strategy for the selective
synthesis of unsymmetrically diarylated products.
10
11
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Genazzani,
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Suzuki
coupling
of
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(30) We confirmed that in all cases starting materials still remained
after the reactions.
(31) When CsF was used as a base, the diffraction peaks that
correspond to 3h could not be clearly confirmed because the
diffraction intensity of CsBr contained in the crude mixture was very
strong. Therefore, KF was used instead of CsF for the experiment.
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Insert Table of Contents artwork here
1
2
3
4
5
6
7
selective
monoarylation
o-, m-, p-
Br
Ar1
Pd cat., base
Ar2-B(OH)2
Ar2
Ar2
Ar1
Ar1
ball milling
Ar2
Br
liquid
Br
crystalline solid
8
proposed mechanism
9
in-situ crystallization
X
first
arylation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
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53
54
55
56
57
58
59
60
X
M
X
X
X
X
X
M
X
slower
second
arylation
ball milling
M
X
X
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