Temperature-controlled sequential Suzuki-Miyaura reactions for preparing unsymmetrical terphenyls

Article abstract of DOI:10.1039/c8ob01661e

A one-pot protocol of double Suzuki-Miyaura reactions has been developed for the synthesis of unsymmetrical terphenyls. In the absence of a ligand, potassium bromophenyltrifluoroborate reacts with arylboronic acid and then sequentially with a hetero/aryl bromide by controlling the reaction temperature, providing unsymmetrical p- and m-terphenyl compounds in moderate to good overall yields. This protocol provides a convenient and practical approach to unsymmetrical terphenyls under ligand-free and aerobic conditions.

Full text of DOI:10.1039/c8ob01661e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C8OB01661E
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ARTICLE
Temperature‐controlled sequential Suzuki–Miyaura reactions for
preparing unsymmetrical terphenyls
Received 00th January 20xx,
Accepted 00th January 20xx
Xinmin Li,a Chun Liu* a, b, Lei Wang,a Qing Ye,a Xin Jin,b Zilin Jina
DOI: 10.1039/x0xx00000x
A one‐pot protocol of double Suzuki–Miyaura reactions has been developed for the synthesis of unsymmetrical terphenyls.
In the absence of a ligand, potassium bromophenyltrifluoroborate reacts with arylboronic acid and then sequentially with
hetero/aryl bromide by controlling the reaction temperature, providing unsymmetrical p‐, m‐terphenyls compounds in
moderate to good overall yields. This protocol provides a convenient and practical approach to unsymmetrical terphenyls
under ligand‐free and aerobic conditions.
www.rsc.org/
O
Introduction
OMe
O
OMe
Unsymmetrical terphenyls and their analogues distributed
widely in mushrooms exhibit significant biological activities,
including potent immunosuppressant, neuroprotective, and
Me
HO
O
O
OMe
OMe
O
O
O
O
HO
OH
Kehokorins A
(Cytotoxic activity)
3,4,4'',5-Tetramethoxy-1,1':2',1''-terphenyl
antimicrobial
activities
(Scheme
1).1‐6
Additionally,
(Antitumor Activity)
unsymmetrical terphenyls are important structural motifs for
construction of various liquid crystals and fluorescent
compounds.7 Over the years, numerous synthetic strategies,
including transition‐metal catalyzed cross‐coupling reactions8‐
14 and cyclization reactions,15‐18 have been developed to access
these valuable molecules. However, harsh reaction conditions,
circuitous steps and low yields are still problems. The
palladium‐catalyzed Suzuki–Miyaura (SM) cross‐coupling
reaction has been recognized as a powerful tool for
construction of carbon‐carbon bonds, because of the broad
functional group tolerance and the low toxicity associated with
boron compounds.19, 20 The traditional SM reaction procedures
for preparing unsymmetrical terphenyls require multi‐step
reactions in the presence of a ligand: (i) preparing a biphenyl
intermediate by the SM reaction, (ii) halogenation of the
biphenyl intermediate, and (iii) proceeding the finally SM
reaction to provide unsymmetrical terphenyls.21, 22 Recently,
one‐pot double SM reactions for the synthesis of
OH
O
OH
OCH3
3',6'-Dimethoxy-4''-propoxy-[1,1':4',1''-terphenyl]-2',4-diol
(a-Glucosidase inhibition)
Scheme 1 Structures of bioactive unsymmetrical terphenyls
unsymmetrical tri(hetero)aryl derivatives (Scheme 2a). In 2015,
Watson’s group31 reported that bromophenyl
N‐
methyliminodiacetic acid boronates underwent one‐pot
sequential SM cross‐coupling smoothly by nucleophile
speciation control, and various unsymmetrical tri(hetero)aryl
derivatives were prepared in good yields (Scheme 2b).
Selective control of organoboron reactivity is a great
challenge in synthetic organic chemistry. Our group has been
focusing on the development of efficient SM reaction systems
with different arylboron compounds.32‐39 Herein, we report a
temperature‐controlled sequential SM coupling strategy for
the synthesis of unsymmetrical terphenyls using potassium
bromophenyltrifluoroborates as building blocks (Scheme 2c).
unsymmetrical terphenyls have received great attention.23‐25
variety of dielectrophilic reagents, such as dibromobenzene,26
A
27
29
1‐bromo‐4‐chlorobenzene,28,
and arene diazonium
tetrafluoroborate salts,30 have been used as building blocks to
couple with arylboron compounds for construction of
Results and discussion.
Our previous investigation found that potassium
aryltrifluoroborates usually took a longer time for a complete
cross‐coupling than arylboronic acids at room temperature.37,
This result led us to explore whether a chemo‐selective
cross‐coupling of arylboronic acids over potassium
a. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Linggong
Road 2, Dalian 116024, China; E‐mail: cliu@dlut.edu.cn
Eco‐chemical Engineering Cooperative Innovation Center of Shandong, Qingdao
b.
40
University of Science and Technology, Qingdao 266042, China.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
aryltrifluoroborates is possible. Therefore, we studied the
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selectivity under this multi‐organoboron systemViiesw Aprrtioclpe oOnsleinde
that 4‐bromobenzaldehyde cross‐couples with 1a
DOI: 10.103v9e/Cry8OfaBs0t16a6n1dE
Previous work:
a) Dielectrophilic reagent as the building block
R2
most of the base is consumed, which might suppress the
hydrolysis of potassium organotrifluoroborates.41 This
speculation was confirmed by a control experiment using a
loading of 5.0 equiv. base, the yield of 1d increased to 30%,
while the yield of 1c was decreased to 68% (Scheme 3).
Br
B(OH)2
+
B(OH)2
R1
R2
+
X
R1
X = -Br, -Cl, -N2BF4
b) Br-Ph-BMIDA as the building block
N
Based on the above results, we tried to use potassium 4‐
bromophenyltrifluoroborate as a building block to carry out
one‐pot double SM reactions with the aid of a stepwise
addition of reagents for a high chemo‐selectivity (Scheme 4).
The selective cross‐coupling reaction of muti‐organoboron
compounds was controlled by the reaction temperature. After
careful investigation on the base, solvent, and catalyst (see ESI
in detail), 1a was coupled with 2b under the conditions of 1
mol% Pd(OAc)2 and 2.0 equiv. of K2CO3 at room temperature.
The cross‐coupled product 2c was not necessary to be
separated, and then 2d, 1 mol% Pd(OAc)2 and 2.0 equiv. of
K2CO3 were added into the reaction mixture. An 80% yield of
the terphenyl product 2e was achieved at the reaction
R2
B
BPin
+
Cl
O
O
O
O
R1
+
R2
Br
R1
This work:
c) Br-Ph-BF3K as the building block via temperature control of a multi-nuclephile system.
B(OH)2
R2
Br
R1
R2
BF3K
Br
R1
step 1
one-pot step 2
Scheme 2 Approaches to unsymmetrical terphenyls by one‐pot double SM
reactions
temperature of 80 C.
cross‐coupling of 4‐methoxyphenylboronic acid (1a) and
BF3K
1 mol% Pd(OAc)2
2.0 eq K2CO3
EtOH/H2O
potassium
phenyltrifluoroborate
(
1b
)
with
4‐
BF3K
+
B(OH)2
bromobenzaldehyde in the presence of 1 mol% Pd(OAc)2 and
2.0 equiv. of K2CO3 in 50% aqueous ethanol at room
temperature (Scheme 3). It was interesting to observe a
notable chemo‐selectivity, and 1a was transformed into the
corresponding cross‐coupled product 1c with an 89% yield,
while 1b provided only a 10% yield of product 1d. The high
Br
0.5 h, under air
H3CO
2c
H3CO
2b
25 o
C
1a
Not Isolated
0.5 mmol
0.5 mmol
+
Br
NC
CN
add 1 mol% Pd(OAc)2
add 2.0 eq K2CO3
3.5 h, under air
2d
OCH3
0.5 mmol
80 o
C
2e
80% isolated yield
H3CO
OHC
1c
1 mol% Pd(OAc)2
Br
B(OH)2
+
BF3K
EtOH/H2O (2 mL/2 mL)
K2CO3, 25 oC, air, 1 h
Scheme4 One‐pot double SM reactions with potassium 4‐bromophenyltrifluoroborate
+
+
OHC
0.5 mmol
H3CO
0.5 mmol
1a
0.5 mmol
1b
We next explored the scope and limitations for this one‐pot
cross‐coupling protocol. As shown in Scheme 5, 20 unsymmetrical
p‐ and m‐terphenyl compounds with 26%‐90% yield were obtained,
and the results demonstrate that this reaction protocol is sensitive
to electronic characteristics of the substrates. The overall yields of
terphenyl compounds were largely dictated by the second step, and
aryl bromides bearing an electron‐withdrawing group (3a‐3c)
provided slightly better yields than those of bearing an electron‐
donating group (3d‐3f). The good overall yields were obtained while
using 2‐bromobenzonitrile as substrate for the second cross‐
coupling step (3g, 3h, 3i). On the contrary, ortho‐substituted
arylbononic acids used for the first step afforded low product yields
(3g, 3j). Potassium bromophenyltrifluoroborate bearing a chloro
group as building block was explored, and only trace product was
observed (3k). m‐Terphenyls were also prepared in this protocol,
and the corresponding products were obtained in 58% and 69%
yields (3l, 3m). However, potassium 2‐bromophenyltrifluoroborate
has low activity in this protocol (3n). Further study indicated that
the first step was effective with arylboronic acids bearing an
electronic donating group. In contrast, the second step was
effective with aryl bromides bearing an electronic withdrawing
group (3q, 3r). For example, an 84% yield of 3q was achieved by
using 4‐methoxyphenylboronic acid for the first step and 4‐
OHC
1d
(1) 2.0 equiv. K2CO3, 89% yiled of 1c, 10% yield of 1d
(2) 5.0 equiv. K2CO3, 68% yiled of 1c, 30% yield of 1d
Scheme 3 The competitive SM reactions of 4‐methoxyphenylboronic acid and
potassium phenyltrifluoroborate with 4‐bromobenzaldehyde in the presence of
different loadings of K2CO3
2 | J. Name., 2012, 00, 1‐3
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bromobenzaldehyde as the second coupling partner. However, only coupling partners could provide good yields of products (3s‐3v). 4‐
View Article Online
DOI: 10.1039/C8OB01661E
a 23% yield of 3q was obtained while using 4‐formylphenylboronic Pyridineboronic acid pinacol ester as the first step coupling partner
acid for the first step reaction and 1‐bromo‐4‐methoxybenzene for was ineffective (3w). While using potassium 6‐bromopyridin‐3‐
the second step. The more difficult cases of heteroaryl bromides as yltrifluoroborate as building block, only trace product was observed
substrates have been investigated, and we were pleased to find (3x).
that bromo‐pyridine and bromo‐pyrimidine as the second step
Br
R1
R1
Pd(OAc)2
25 o
B(OH)2
Br
BF3K +
R
Pd(OAc)2, 80 o
C
R
C
CN
NO2
F
3a, 86%
3d, 68%
3b, 82%
3e, 76%
3c, 80%
3f, 58%
OCH3
OCH3
OCH3
OCH3
NH2
NC
NC
NC
H3C
H3CO
3g, 86%
3g, 21%
3h, 83%
3i, 80%
CN
OCH3
Cl
H3CO
3j, 24%
3k, trace
CN
CN
OCH3
3l, 58%
3m, 69%
3n, trace
H3CO
CHO
H3CO
OHC
H3CO
3q, 84%
3r, 90%
3p, 78%
3r, 82%
3o, 80%
3q, 23%
H3CO
F
OCH3
F
OCH3
N
N
N
N
N
H3CO
NH2
3t, 81%
3u, 64%
3s, 67%
N
OCH3
H3CO
H3CO
CN
N
N
H3CO
OCH3
3w, traceb
3v, 81%
3x, trace
Scheme 5 a One‐pot double SM reactions. Reaction conditions: the first step, potassium bromophenyltrifluoroborate (0.5 mmol), arylboronic acid (0.5 mmol), K2CO3
(1.0 mmol), Pd(OAc)2 (1 mol%), EtOH/H2O (5 mL/5 mL), 25 C, under air, 0.5 h. The second step: adding aryl bromide (0.5 mmol), K2CO3 (1.0 mmol), Pd(OAc)2 (1 mol%),
80 C, 3.5 h, isolated yield. b Pyridine‐4‐boronic acid pinacol cyclic ester as coupling partner for the first step.
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W. Li, W. Gao, M. Zhang, Y.‐L. Li, L. Li, X.‐B. Li, W.‐Q. Chang,
Z.‐T. Zhao and H.‐X. Lou, J. Nat. Prod., 2016, 79, 2188‐
Conclusion
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2194.
DOI: 10.1039/C8OB01661E
In summary, we have developed a convenient one‐pot double
Suzuki–Miyaura reactions protocol for the synthesis of
unsymmetrical terphenyls. Potassium bromophenyltrifluoroborates
proceed chemo‐selective cross‐coupling with coupling partners by
controlling reaction temperature in the absence of any ligand. A
series of p‐and m‐ unsymmetrical terphenyls were prepared in good
yields.
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General remarks
All commercially available reagents (from Acros, Aldrich, Fluka)
were used without further purification. Potassium
aryltrifluoroborates were prepared from corresponding
arylboronic acids following the method reported in the
literature.42 All reactions were carried out under air
atmosphere. NMR spectra were recorded on a Brucker
Advance II 400 spectrometer using TMS as internal standard
1
(400 MHz for H NMR). The isolated yields of products were
15.
16.
17.
18.
obtained by short chromatography on a silica gel (200‐300
mesh) column using petroleum ether (60‐90
otherwise noted.
°C), unless
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General procedure for one‐pot double Suzuki‐Miyaura reaction.
A mixture of potassium bromophenyltrifluoroborate (0.5
mmol), arylboronic acid (0.5 mmol), K2CO3 (1 mmol), Pd(OAc)2
19.
20.
21.
C. Liu and X. Li, Chem. Rec., 2016, 16, 84‐97.
A. Suzuki, Angew. Chem. Int. Ed., 2011, 50, 6722‐6737.
K. Kawada, A. Arimura, T. Tsuri, M. Fuji, T. Komurasaki, S.
Yonezawa, A. Kugimiya, N. Haga, S. Mitsumori, M. Inagaki,
T. Nakatani, Y. Tamura, S. Takechi, T. Taishi, J. Kishino and
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S. Yonezawa, T. Komurasaki, K. Kawada, T. Tsuri, M. Fuji, A.
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Tamura, S. Takechi, T. Taishi and M. Ohtani, J. Org. Chem.,
1998, 63, 5831‐5837.
(1 mol%), EtOH/H2O (5 mL/5 mL) was stirred at 25 ºC under air
for 0.5 h. And then aryl bromide (0.5 mmol), K2CO3 (1 mmol),
and Pd(OAc)2 (1 mol%) were added to the reaction mixture
and stirred for 3.5 h at 80 C. The mixture was added to brine
(10 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were concentrated in vacuo and the
product was isolated by short chromatography.
22.
Acknowledgements
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The authors thank the financial support from the National
Natural Science Foundation of China (21776036, 21421005,
21276043, U1603103).
Notes and references
†
Electronic supplementary informaꢀon (ESI) available:
Characterization of cross‐coupled products. See DOI:
J. W. B. Fyfe, N. J. Fazakerley and A. J. B. Watson, Angew.
Chem. Int. Ed., 2017, 129, 1269‐1273.
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