General suzuki coupling of heteroaryl bromides by using tri-tert-butylphosphine as a supporting ligand

Article abstract of DOI:10.1002/ejoc.201402915

A general procedure for the fast Suzuki coupling of major families of heteroaryl bromides was realized by using Pd(OAc)₂/PtBu₃ as the catalyst. Many couplings were finished within minutes at room temperature in n-butanol. Different from previous studies, three typical heteroaryl bromides were systematically examined in couplings of various heteroaryl and aryl boronic acids. A fast, general coupling of heteroaryl bromides is realized by using a single palladium catalyst supported by tri-tert-butylphosphine.

Full text of DOI:10.1002/ejoc.201402915

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402915
General Suzuki Coupling of Heteroaryl Bromides by using
Tri-tert-butylphosphine as a Supporting Ligand
Yinjun Zou,[a] Guizhou Yue,[b] Jianwei Xu,[c] and Jianrong (Steve) Zhou*[a]
Keywords: Cross-coupling / Palladium / Heterocycles / Transmetalation / Fused-ring systems
A general procedure for the fast Suzuki coupling of major
families of heteroaryl bromides was realized by using
Pd(OAc)2/PtBu3 as the catalyst. Many couplings were fin-
ished within minutes at room temperature in n-butanol. Dif-
ferent from previous studies, three typical heteroaryl brom-
ides were systematically examined in couplings of various
heteroaryl and aryl boronic acids.
Introduction
Results and Discussion
Initially, we chose 2-bromopyridine and phenylboronic
acid as substrates to search for highly active catalysts. Aryl-
pyridines are often used in drug discovery. Under many re-
ported conditions, the model coupling was very slow,
Ͻ10% yield after 1 h at room temperature. After extensive
research, we found that Pd(OAc)2 and PtBu3 formed an ex-
ceptionally active catalyst. Almost quantitative yield was
observed after 5 min (Table 1, Entry 1). Furthermore, a
0.1 mol-% loading of a Pd catalyst can still give 95% yield
after 5 min. The air-stable PtBu3·HBF4 salt has been used
to release the free phosphine PtBu3 under basic conditions.
Other ligands are less active. For example, P(1-Ad)2Bu (Ad
= adamantyl) gave 74% yield under similar conditions
(Table 1, Entry 2). 2-(Dicyclohexylphosphino)-2Ј,4Ј,6Ј-tri-
isopropylbiphenyl (XPhos) provided 33% yield after 15 min
(Table 1, Entry 8). Free N-heterocyclic carbenes such as 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) showed
The coupling of heteroaryl groups is indispensable in to-
day’s synthesis of medicines and advanced materials.[1] For
this purpose, Suzuki coupling is routinely used to forge
these C(sp2)–C(sp2) single bonds.[2] For instance, Suzuki
coupling has been employed in the large-scale synthesis of
the Sartan family of antihypertensive drugs and the agro-
chemical Boscalid.[3] Organoboronic acids and esters are
bench-top-stable, and the byproducts after reactions are
nontoxic. Furthermore, many functionalized organoboron
reagents now can be easily accessed through metal-cata-
lyzed borylation of arenes[4] and aryl halides.[5]
In the past decade, many efforts have been devoted to
the Suzuki coupling of challenging substrates such as het-
eroaryl chlorides,[6] tosylates, and mesylates.[7] Couplings of
heteroaryl bromides, in comparison, are considered to be
easier, and thus, they are actually more frequently used in
synthesis. For example, Suzuki couplings of pyridyl,[8] thi-
enyl,[9] and indolyl bromides[10] were used to prepare medic-
inally active entities. In other applications, oligo- and poly-
thiophenes are frequently used in organic conducting mate-
rials and in photovoltaic cells.[11] In reality, each new set of
coupling partners requires optimization of the palladium
catalysts. A general Pd-catalyzed Suzuki coupling for het-
eroaryl bromides has been lacking.[12]
Table 1. The effect of ligands and Pd complexes on model Suzuki
coupling.
[a] Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences,
Nanyang Technological University
Entry
Ligand
5 min
15 min
Conv. [%] Yield [%] Conv. [%] Yield [%]
21 Nanyang Link, Singapore 637371
E-mail: jrzhou@ntu.edu.sg
1
2
3
4
5
6
7
8
PtBu3
P(1-Ad)2Bu
P(1-Ad)2Bn
PCy3
PPh3
P(o-Tol)3
SPhos
100
74
15
14
9
3
12
30
98
65
6
4
5
2
3
18
100
82
29
18
14
10
16
45
99
74
17
9
9
6
http://www.spms.ntu.edu.sg/cbc/FacultyResearch/
Individual%20Faculty/SZhou.html
[b] College of Basic Sciences, Sichuan Agricultural University
Ya’an, Sichuan, China 625014
[c] Institute of Materials Research and Engineering,
Agency for Science, Technology and Research
3 Research Link, Singapore 117602
6
33
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402915.
XPhos
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Y. Zou, G. Yue, J. Xu, J. Zhou
SHORT COMMUNICATION
poor reactivity. 1,3-Bis(diphenylphosphino)propane (dppp), bromides of pyridine, thiophene, and indole (Table 2). Pyr-
1,1Ј-bis(diphenylphosphino)ferrocene (dppf), 4,5-bis(di- idine and indole are electron-poor and electron-rich aza-
phenylphosphino)-9,9-dimethylxanthene (Xantphos), and cycles, respectively, that are widely used in drug discovery.
one of the Josiphos ligands gave Ͻ10% yield after 1 h (see Many couplings of 2-bromopyridine and 2-bromothio-
the Supporting Information). Pd(PtBu3)2 was as active as phene proceeded smoothly in aqueous n-butanol. In other
Pd(OAc)2/PtBu3.
cases that did not give good yields, the use of n-butanol or
We found that strong bases of alkali hydroxides and tert- dioxane solved the problem. Five-membered 2-heteroaryl
butoxides were very important for the fast coupling. In con- boronic acids of furan, thiophene, pyrrole, and indole
trast, weaker bases of carbonates and acetates caused much underwent either fast hydrolysis with water or protodebor-
slower coupling (see the Supporting Information). A high ylation. N-Methyl-3-bromoindole was deliberately chosen
concentration of hydroxide anion is known to accelerate to test the reactivity boundary of a very electron-rich azacy-
transmetalation through the intermediacy of palladium hy- cle. These types of N-alkylindolyl halides without activation
droxide complexes.[13]
by electron-withdrawing groups have rarely been used in
The use of aqueous alcohols was a prerequisite for the
fast coupling. For example, in pure MeOH, EtOH nBuOH,
and iPrOH, the yields were only 30–66% after 5 min (see
the Supporting Information). In comparison, if water was
included as a minor cosolvent, almost full conversion was
observed in 5 min in most solvents. Certainly, good solubil-
ity of the hydroxide base and PhB(OH)2 in aqueous
alcohols accelerated the transmetalation and contributed to
fast overall coupling. Faster transmetalation can also lead
to fast formation of active LPd0 catalysts from Pd(OAc)2
through double transmetalation and reductive elimination
of biphenyl.[14] Biphenyl was detected in the reaction mix-
ture after 1 min by GC.
Table 2. Coupling of major families of heteroarylboronic acids.[a]
The new method can be applied to many families of het-
eroaryl bromides (Scheme 1). Most examples finished the
reaction within a few minutes at room temperature. The
only one exception was 2-bromothiazole, which needed
heating at 80 °C. The observed fast couplings of many het-
erocycles confirmed the legitimacy of the model reaction in
Table 1.
Next, we explored the coupling efficiency of various het-
eroaryl boronic acids, together with three model heteroaryl
Scheme 1. Fast couplings of heteroaryl bromides with PhB(OH)2.
[a] Boc = tert-butoxycarbonyl.
2
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General Suzuki Coupling of Heteroaryl Bromides
Suzuki couplings.[15] Under standard conditions in aqueous used as advanced materials.[17] Our method allowed ef-
n-butanol, the main side reactions were the hydrolysis of ficient diarylation of 1,3-dibromoazulene. All products were
the aryl boronic acids and reduction of the C–Br bond. formed within minutes at room temperature without further
Logically, the use of dry n-butanol and dioxane solvents optimization of the conditions. The new method proved su-
solved these problems in most cases. In the coupling with perior to existing procedures.[18] In one example, coupling
the 3-pyridylboron reagent,[16] 2-methylbutan-2-ol was used of electron-poor p-F3CC6H4B(OH)2 led to 55% yield of the
to minimize the reduction of the C–Br bond.
product, and the main byproduct was by monoarylation
Similarly, couplings of the three heteroaryl bromides (ca. 30%).
were conducted with various aryl- and alkenylboronic acids
(Table 3). Most couplings were finished after a few minutes
at room temperature. Electron-donating and electron-with-
drawing groups could be present on the aryl rings. Again,
N-methyl-3-bromoindole coupled very slowly, and in some
examples, dioxane was used to prevent hydrolysis of the ar-
ylboronic acids. Couplings of 3-bromoindole carrying no
electron-withdrawing groups were generally more difficult
than couplings of the other two bromides. Hindered 2-mes-
itylboronic acid underwent efficient coupling if the base
and solvent were changed.
Table 4. Additional examples of Suzuki couplings.
Table 3. Couplings of aryl- and vinylboronic acids.
[a] pin = pinacolate.
Suzuki coupling has been used to prepare the biaryl
motif in an HIV protease inhibitor. The reaction proceeded
at 80 °C and required two loadings of Pd(PPh3)4
(Scheme 2a).[8a] In comparison, our method allowed the
coupling to proceed at room temperature with a Pd loading
of 0.1 mol-%. In a second comparison, a 3-arylindole deriv-
ative has been shown to enhance insulin sensitivity in the
treatment of type-2 diabetes. It was previously synthesized
through Suzuki coupling at 60 °C by using Pd(OAc)2/P(o-
Tol)3 (Scheme 2b).[19] Under our conditions, the same cou-
2-Bromopyridine and 2-bromothiophene coupled very pling could be performed at room temperature with a Pd
efficiently with many other organoboronic acids (Table 4). loading of 0.25 mol-%. The third example is pentabro-
Notably, some boron pinacolates of indole, thiophene, and mopseudilin, a natural product with interesting antibiotic
dithiophene reacted well. Some 1,3-diarylazulenes were and antitumor activities.[20] In a report by Maeda and
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Y. Zou, G. Yue, J. Xu, J. Zhou
SHORT COMMUNICATION
Scheme 2. Applications of the new Suzuki method.
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Conclusions
[3]
[4]
We developed a general method for the Suzuki coupling
of heteroaryl bromides by using one single catalyst formed
from Pd(OAc)2 and PtBu3. In many cases, extremely fast
couplings were observed at room temperature, which
proved more effective than many existing procedures.[22]
Supporting Information (see footnote on the first page of this arti-
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1
and copies of the H NMR and 13C NMR spectra.
Acknowledgments
We thank the Singapore National Research Foundation (NRF-
RF2008-10), the Singapore Ministry of Education – Academic Re-
search Funding (MOE2013-T2-2-057), and the Nanyang Techno-
logical University for financial support. We thank Johnson Mat-
they for some palladium salts.
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General Suzuki Coupling of Heteroaryl Bromides
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Received: July 13, 2014
Published Online: ᭿
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Y. Zou, G. Yue, J. Xu, J. Zhou
SHORT COMMUNICATION
Suzuki Coupling
Y. Zou, G. Yue, J. Xu,
a. J. Zhou* ....................................... 1–6
General Suzuki Coupling of Heteroaryl
Bromides by using Tri-tert-butylphosphine
as a Supporting Ligand
A
fast, general coupling of heteroaryl
ladium catalyst supported by tri-tert-butyl-
phosphine.
Keywords: Cross-coupling / Palladium /
Heterocycles / Transmetalation / Fused-
ring systems
bromides is realized by using a single pal-
6
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