Palladacycle-catalyzed Suzuki-Miyaura reaction of aryl/heteroaryl halides with MIDA boronates in EtOH/H2O or H2O

Article abstract of DOI:10.1039/c4ra07486f

With good to excellent yields, a series of mono- or diheteroaryl compounds were synthesized via the palladacycle-catalyzed Suzuki-Miyaura reaction of various N-methyliminodiacetic acid (MIDA) boronates with aryl/heteroaryl halides in EtOH/H₂O or H₂O. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra07486f

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Palladacycle-catalyzed Suzuki–Miyaura reaction of
aryl/heteroaryl halides with MIDA boronates in
EtOH/H O or H O†
Cite this: RSC Adv., 2014, 4, 36262
2
2
a
a
a
a
a
a
Yabo Li, Jingran Wang, Zhiwei Wang, Mengmeng Huang,* Beiqi Yan, Xiuling Cui,
Yusheng Wu* and Yangjie Wu*a
ab
Received 11th May 2014
Accepted 6th August 2014
With good to excellent yields, a series of mono- or diheteroaryl compounds were synthesized via the
palladacycle-catalyzed Suzuki–Miyaura reaction of various N-methyliminodiacetic acid (MIDA) boronates
DOI: 10.1039/c4ra07486f
www.rsc.org/advances
2 2
with aryl/heteroaryl halides in EtOH/H O or H O.
under mild aqueous basic conditions to take part in Suzuki
reaction. To improve the existing technology, more recently,
Introduction
8
Mono- and diheteroaryl compounds as one of the most preva- Lipshutz and co-workers reported a catalytic system for the
lent and important motifs are ubiquitous in a wide range of reaction of aryl/heteroaryl MIDA boronates with aryl halides in
9
pharmaceutical building blocks, natural products, unnatural water. Their reaction protocol realized the value of environ-
nucleotides, molecule probes, advanced materials, and metal- mental conservation, however, unusual polymer phase transfer
1
complexing ligands. Although these compounds are generally catalyst TPGS-750-M and high catalytic loading (PdCl
2
(dtbpf))
2
synthesized via typical cross-coupling reactions, there are still were employed. Therefore, the development of effective and
some limitations for the synthesis of 2-heteroaryls such as the environmentally friendly protocols for Suzuki–Miyaura
instability of the building blocks, use of toxic metals, and coupling reaction of heteroaryl MIDA boronates with heteroaryl
3
4
5
inefficient couplings with aryl chlorides. Recently, the low halides is still needed. In the course of our investigation on
toxicity and high tolerance of organoboronic acids are widely the catalytic activity of cyclopalladated ferrocenylimines
10
used as one of the coupling partners in Suzuki reaction. Many (Scheme 1), herein, we report the palladacycle-catalyzed
progresses have been achieved in this eld, the reaction Suzuki–Miyaura coupling reaction involving various MIDA
conditions in most cases could not be well suited for the reac- boronates with aryl/heteroaryl halides in EtOH/H
2
O or H
2
O.
6
tion with inherently unstable 2-heteroaryl boronic acids. To
6b,7
solve this problem, professor Martin Burke and Gillis found
that the easily handled and stable MIDA-protected boronates
could slowly hydrolyze and release the active boronic acids
Results and discussion
Our initial experiments were focused on identifying reaction
conditions with 4-bromoanisole (1a) and phenylboronic acid
MIDA ester (2a). Palladacycle catalysts Cat.I-Cat.III (Scheme 1)
were selected for the reaction, Cat.II could provide superior
yield 76% of 3a (Table 1, entries 1–3). It was found that large
amounts of water were necessary to promote hydrolysis of MIDA
boronates (Table 1, entries 2 and 4). Some bases (e.g., Cs CO ,
2
3
K CO , and KOH) were evaluated, and the best choice was
Scheme 1 Palladacycle precatalysts used in this study.
2
3
K
3
PO
4
(84%; Table 1, entries 4–7). Surprisingly, the discovered
O (with 20% TBAB) or EtOH/H
(6 : 1) to give the excellent yields (Fig. 1). Other factors such as
reaction was carried out in H
2
2
O
a
College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical
Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan reaction temperature, reaction time, and catalyst loading were
Universities, Zhengzhou University, Zhengzhou, 450052, P. R. China. E-mail: wyj@
respectively investigated in two different solvents EtOH/H
2
O
zzu.edu.cn; hmm@zzu.edu.cn; Fax: +86-371-67767993
(
6 : 1) or H O (with 20% TBAB) (Fig. 2). It was found that the
2
b
Tetranov Biopharm, LLC, 75 Daxue Road, Zhengzhou, 450052, P.R. China. E-mail:
ꢀ
coupling reaction could smoothly proceed at 90 C to give
excellent yield. Although the conversion yield was reduced with
decreasing the catalyst loading, it was worth noting that the
yield could be given in 71–80% with 0.1 mol% catalyst. In
yusheng.wu@tetranovglobal.com
†
Electronic supplementary information (ESI) available. CCDC 965688. For ESI
and crystallographic data in CIF or other electronic format see DOI:
0.1039/c4ra07486f
1
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a
Table 1 Optimization of the reaction conditions
ꢀ
b
Entry
Cat. (mol%)
Base
Solvent (mL)
T ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
I (1)
K
K
K
K
3
3
3
3
PO
PO
PO
PO
4
4
4
4
DMF : H
DMF : H
DMF : H
DMF : H
DMF : H
DMF : H
DMF : H
2
2
2
2
2
2
2
O ¼ 9 : 1 (2)
O ¼ 9 : 1 (2)
O ¼ 9 : 1 (2)
O ¼ 9 : 1 (3)
O ¼ 9 : 1 (3)
O ¼ 9 : 1 (3)
O ¼ 9 : 1(3)
100
100
100
100
100
100
100
90
12
12
12
12
12
12
12
4
38
76
70
84
trace
trace
40
94
95
II (1)
III (1)
II (1)
II (1)
II (1)
II (1)
II (1)
II (1)
II (1)
II (1)
Cs
CO
KOH
2
CO
3
K
2
3
K
3
K
3
K
3
K
3
PO
PO
PO
PO
4
4
4
4
EtOH : H
2
O ¼ 6 : 1 (2.1)
9
H
2
O (20% TBAB) (2.5)
EtOH : H
O ¼ 6 : 1 (2.1)
O (20%TBAB) (2.5)
90
90
90
4
4
4
c
1
1
0
1
2
90
87
c
H
2
a
Reaction conditions: 4-bromoanisole (0.5 mmol), phenylboronic acid MIDA ester (0.52 mmol), base (2 mmol), solvent (2–3 mL), under a nitrogen
b
c
atmosphere. Isolated yield. Under an air atmosphere.
and 2-acetyl-3-bromothiophene could be converted to the
desired products in excellent yields in EtOH/H O and neat water
Table 2, 3h–3j, 3m, and 3o). 2-Phenylpyridinederivatives (3e, 3f,
2
(
and 3g) were obtained in excellent yields (93%, 90%, and 96%) in
EtOH/H O and moderate yields in H O (65%, 67%, and 80%).
2
2
This analogous phenomenon also occurred in the synthesis of
k, 3l, 3n, and 3p. Heteroaryl dibromides gave triaryl products 3q
and 3r in good to excellent yields in both solvents. Subsequently,
-bromopyridine and 2-bromothiophene were chosen to eval-
3
2
uate the reactivity of various heteroaryl substituted MIDA boro-
nates. The reaction of 3-pyridyl-, 2-thiophenyl-, 2-furanyl-,
2-benzofuranyl-, or 5-bebzofurazanboronic acid MIDA esters
with 2-bromoheteroaryls afforded 3u–3af in good to excellent
Fig. 1 Influence of solvents. Reaction conditions: 4-bromoanisole (0.5
mmol), phenyl boronic acid MIDA ester (0.52 mmol), K
Cat.II (1 mol%), solvent (2–3 mL) under nitrogen at 100 C in 12 h.
3
PO
4
(2 mmol),
ꢀ
addition, a lower yield was obtained when the reaction was
carried out under air atmosphere (Table 1, entry 10–11).
With the optimized reaction conditions, the substrate scope
of both catalytic systems (EtOH/H O or H O with 20% TBAB) was
2
2
investigated with a series of aryl/heteroaryl MIDA boronates and
aryl/heteroaryl bromides (Table 2). The desired products 3a and
3b were obtained in excellent yields regardless of the electronic
effect of functional groups on aryl bromides. Sterically hindered
ortho-substituted aryl bromides could be also transformed into
target products in good yields (Table 2, 3c and 3d). When the
reaction of methyl 2-bromobenzoate with 2a was carried out in
EtOH/H O, an ester-exchange reaction product of ethyl
2
a
Fig. 2 Influence of catalyst loading, reaction time and temperature.
2-biphenylcarboxylate was found in 20% yield by NMR spec-
ꢀ
b
The catalyst loading of Cat.II was optimized at 90 C in 4 h. Reaction
time was optimized with 1 mol% Cat.II at 90 C. The reaction
ꢀ
c
troscopy (Table 2 and 3c, ESI,† NMR spectra). 3-Bromopyridine,
3
-bromoquinoline, 4-bromoisoquinoline, 2-bromothiophene, temperature was optimized with 1 mol% Cat.II in 12 h.
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Table Suzuki–Miyaura
Paper
a,b
2
cross-coupling
of
aryl/heteroaryl Table 3 Suzuki–Miyaura cross-coupling of aryl/heteroaryl chlorides
a,b
bromides
a
Reaction conditions: aryl or heteroaryl chloride (0.5 mmol), boronic
acid MIDA ester (0.52 mmol), base (2 mmol), Cat.I (1 mol %), X-Phos
ꢀ
(
2
4 mol %), H
4 h. Isolated yield. EtOH/H
2
O (2.5 mL), TBAB (20 mol%), under nitrogen at 90 C in
b
c
ꢀ
2
O (6 : 1, 2.1 mL) at 90 C in 24 h.
Encouraged by the above results, aryl/heteroaryl chlorides
were then investigated with Cat.I (1 mol%) and 4 mol%
ꢀ
X-Phos in H
2
O at 90 C (Table 3). It was found that the yields of
3
ai, 3ak, and 3aj in EtOH/H
2
O were similar with their reaction
in H
2
O. Thus, considering the economic factor, our subse-
quent research was carried out in water. The modied cata-
lytic system was suitable for aryl/heteroaryl chlorides
substituted with electron-rich, electron-decient or sterically
hindered groups to afford the desired products 3a–3ak in
good to excellent yields. Under the standard reaction condi-
tions, 2-chlorothiophene could also react with a series of
a
Reaction conditions: aryl or heteroaryl bromide (0.5 mmol), boronic
acid MIDA ester (0.52 mmol), base (2 mmol), Cat.II (1 mol%), EtOH/ heteroaryl MIDA boronates to form the desired products
H
2
O (6 : 1, 2.1 mL) or H
2
O (2.5 mL) with TBAB (20 mol%), under
3
z–3af (Table 3) in moderate to excellent yields except 3t.
ꢀ
b
nitrogen at 90 C in 4 h. Isolated yield for EtOH/H
2
O and H
2
O.
c
d
e
Reaction time 12 h. 20 h. Heteroaryl bromide (0.5 mmol), boronic
acid MIDA ester (1.1 mmol), base (4 mmol), Cat.II (2 mol%), EtOH/
f
ꢀ
H O (6 : 1, 4.2 mL) or H O (3 mL), TBAB (40 mol%). 100 C in 24 h.
2
2
Conclusion
yields in both green solvents, except the coupling of 2-thio- In conclusion, mono- and diheteroaryls were synthesized via
phenylboronic acid MIDA ester with 2-bromothiopene in EtOH/ the palladacycle-catalyzed Suzuki–Miyaura reaction of
H
2
O (3z). However, the reaction of 2-pyridyl MIDA boronate with various MIDA boronates with aryl/heteroaryl halides in
0
2-bromopyridine gave only a trace amount of product 2,2 - EtOH/H
2
O or H
2
O. The desired cross-coupling products were
bipyridine by GC analysis. But changing 2-pyridine MIDA obtained in good to excellent yields. This modied catalytic
boronate to 6-methoxy-2-pyridylboronic acid MIDA ester, system was suitable not only for aryl or heteroaryl halides
surprisingly, heterobiaryls 3s and 3t were isolated in 30–51% substituted with electron-rich, electron-decient or sterically
yields in EtOH/H
mined by X-ray diffraction (ESI, Fig. S1†).
2
O and H
2
O.The structure of 3af was deter- hindered groups, but also for aryl/heteroaryl MIDA
boronates.
36264 | RSC Adv., 2014, 4, 36262–36266
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1
994, 66, 1551; (c) A. B. Smith III, T. J. Beauchamp,
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All reactions were run under nitrogen in Schlenk tubes using
vacuum lines. Palladacycle precatalysts, phenyl, 2-thiophene
and 3-pyridine boronic acid MIDA ester were prepared
according to the literature procedures. Unless otherwise noted,
chemical reagents used in experiments were purchased from
10
11
1
commercial suppliers without further purication. H NMR and
1
3
C NMR spectra were recorded on a 400 and 100 MHz instru-
ment using CDCl as the solvent at room temperature. High
3
resolution mass spectrometry data of the products were
collected on an LC/MS instrument. Melting points were
measured using a WC-1 microscopic apparatus and were
uncorrected. Thin-layer chromatography was visualized with UV
light (254 and 365 nm). Flash chromatography was performed
on silica gel (200–300 mesh).
2 For reviews, see: (a) A. Suzuki, Angew. Chem., Int. Ed., 2011,
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3
4
(a) K. Billingsley and S. L. Buchwald, J. Am. Chem. Soc., 2007,
heteroaryl bromides
129, 3358; (b) C. A. Fleckenstein and H. J. Plenio, Org. Chem.,
In a typical experiment, Cat.II (3.7 mg, 1 mol%), aryl/heteroaryl
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mmol) and K
3
PO
4
(425 mg, 2 mmol) were dissolved in EtOH/
O (2.5 mL with 20 mol% TBAB, 32 mg)
H
2
O (6 : 1, 2.1 mL) or H
2
under nitrogen atmosphere. Unless otherwise noted, the reac-
tion mixture was stirred at 90 C for 24 hours. Then, the
(
b) T. R. Bailey, Tetrahedron Lett., 1986, 27, 4407; (c)
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ꢀ
suspension was cooled to room temperature and extracted with
ethyl acetate (3 ꢁ 15 mL). The combined organic layers were
dried with Na SO . Aer evaporation of the solvents, the residue
2
2
4
1
was puried by silica gel column chromatography affording the
desired product.
5
6
1
2
209; (b) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed.,
002, 41, 4176.
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heteroaryl chlorides
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Germany, 2005, pp. 3–14; (b) D. M. Knapp, E. P. Gillis and
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68, 8502; (d) V. I. Potkin, N. A. Bumagin, S. K. Petkevich,
et al., Synthesis, 2012, 44, 151; (e) N. A. Bumagin,
S. K. Petkevich, A. V. Kletskov, et al., Chem. Heterocycl.
Compd., 2014, 49, 1515; (f) N. A. Bumagin, I. S. Veselov and
D. S. Belov, Chem. Heterocycl. Compd., 2014, 50, 19.
In a typical experiment, Cat.I (4.6 mg, 1 mol%), X-Phos (9.5 mg,
4
mol%), aryl/heteroaryl MIDA boronate (0.52 mmol), aryl/
heteroaryl chloride (0.5 mmol) and K PO (425 mg, 2 mmol)
were dissolved in H O (20 mol% TBAB, 32 mg, 2.5 mL) under
3
4
2
nitrogen atmosphere. Unless otherwise noted, the reaction
mixture was stirred at 90 C. Then, the suspension was cooled to
ꢀ
room temperature and extracted with ethyl acetate (3 ꢁ 15 mL).
The combined organic layers were dried with Na SO . Aer
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2
4
evaporation of the solvents the residue was puried by silica gel
column chromatography affording the desired product.
Acknowledgements
12, 2314.
We are grateful to the National Natural Science Foundation of
China (no. 21172200 and 21302172) for nancial support to this
research.
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