A general and highly efficient method for the construction of aryl-substituted N-heteroarenes

Article abstract of DOI:10.1002/ejoc.201000962

A general, simple and highly efficient method has been developed for the Pd(OAc)₂-catalyzed ligand-free and aerobic Suzuki reaction of N-heteroaryl halides, which is strongly dependent on the molecular structure of solvent. A general, simple and highly efficient method has been developed for the Pd(OAc)₂-catalyzed ligand-free and aerobic Suzuki reaction of N-heteroaryl halides including 2-pyridyl bromides, 3-pyridyl bromides, 3-quinolyl bromides, 5-pyrimidyl bromides and 2-pyrazyl chloride, which is strongly dependent on the molecular structure of solvent.

Full text of DOI:10.1002/ejoc.201000962

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000962
A General and Highly Efficient Method for the Construction of
Aryl-Substituted N-Heteroarenes
Chun Liu,*[a] Na Han,[a] Xiaoxiao Song,[a] and Jieshan Qiu[a]
Keywords: C-C coupling / Palladium / Nitrogen heterocycles / Biaryl compounds
A general, simple and highly efficient method has been de- Suzuki reaction of N-heteroaryl halides, which is strongly de-
veloped for the Pd(OAc)2-catalyzed ligand-free and aerobic
pendent on the molecular structure of solvent.
Introduction
Results and Discussion
As aryl-substituted pyridines are the most common N-
heteroaryl units in pharmaceutically active compounds,[10]
we first investigated the Suzuki reaction of pyridyl bro-
mides.
After the development of three decades, the Suzuki reac-
tion has become one of the most useful methods for the
construction of biaryls.[1] To date, this chemistry is still full
of challenges and attracts attention of researchers from a
wide range of disciplines.[2] For example, the formation of
aryl-substituted N-heteroaryl compounds is of great impor-
tance in the synthesis of pharmaceuticals, natural products
and advanced functional materials.[3] However, N-het-
eroaryl halides are difficult substrates for the Suzuki reac-
tion due to the potential coordination of the nitrogen to the
active palladium species.[4] In recent years, the groups of
Buchwald,[5] Fu,[6] Plenio[7] and others[8] have reported a
variety of ligand-promoted protocols to activate these sub-
strates successfully.
Attempts have also been made to develop ligand-free ap-
proaches for such a transformation in an aqueous media,[9]
in which the nitrogen atoms are proposed to prefer to en-
gage in hydrogen bonding with water rather than coordinate
to the palladium.[7]
However, the water-involved ligand-free protocol usually
encounters with either a low reactivity or a narrow scope
with respect to N-heteroaryl halides.
According to the literature reports, 3-pyridyl bromides
are more reactive than the corresponding 2-pyridyl bro-
mides in the palladium-catalyzed ligand-free protocols.[9c–9e]
This reactivity difference has also been observed in the bro-
mine/magnesium exchange reactions.[11] Therefore, we
started the study of the cross-couplings of 3-pyridyl bro-
mides with arylboronic acids using 0.5 mol-% Pd(OAc)2 in
ethylene glycol at 80 °C under air. The results are collected
in Table 1. The cross-coupling of 3-bromopyridine with
phenylboronic acid completed in 15 min, resulting in a TOF
of 784 h–1 (Table 1, entry 1), which is the fastest and most
efficient example among the reported ligand-free ap-
proaches.[9c,12]
The Suzuki reactions of 3-bromopyridine with aryl-
boronic acids containing either electron-donating or elec-
tron-withdrawing groups provided excellent yields in short
time (Table 1, entries 2–4). Excitingly, the cross-couping of
o-tolylboronic acid with 3-bromopyridine proceeded quan-
titatively over 3 h, which is the first example that this cou-
pling reaction could complete in a ligand-free protocol
(Table 1, entry 3). Noticeably, 2-amino-3-bromo-5-methyl-
or 2-amino-5-bromopyridine, which is generally protected
prior to the cross-coupling reaction due to the retarding
effect of the amino group on the organometallic reaction,[13]
reacted with phenylboronic acid to afford the desired bi-
aryls in high yields, respectively (Table 1, entries 5 and 6).
To our delight, 2-methoxy-5-bromopyridine exhibited high
activity in the Pd(OAc)2/EG system even in the presence
of a 0.05 mol-% palladium loading (Table 1, entries 7–9),
providing a previously unreported high TOF up to
23520 h–1 (Table 1, entry 7).
To the best of our knowledge, a general and highly ef-
ficient approach for the construction of N-heterobiaryls via
the palladium-catalyzed ligand-free and aerobic Suzuki re-
action has not been reported. We describe herein a simple,
general and highly efficient method for the Pd(OAc)2-cata-
lyzed Suzuki reaction of N-heteroaryl halides in the absence
of a ligand in short reaction time under air in neat ethylene
glycol (EG).
[a] State Key Laboratory of Fine Chemicals, Dalian University of
Technology,
Zhongshan Road 158, Dalian 116012, China
E-mail: chunliu70@yahoo.com
We next explored the generality of the coupling reactions
between 2-pyridyl bromides and various arylboronic acids
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Eur. J. Org. Chem. 2010, 5548–5551

Synthesis of Aryl-Substituted N-Heteroarenes
Table 1. The Suzuki reaction of 3-pyridyl bromides with aryl- coupling of 2-bromo-5-fluoropyridine with p-tolylboronic
boronic acids.[a]
acid gave exclusively 5-fluoro-2-(p-tolyl)pyridine in 96%
yield after 10 min, showing high efficiency and good selec-
tivity (Table 2, entry 6). To our surprise, 2-bromo-6-methyl-
pyridine, an inactive substrate in aqueous system,[9a] exhib-
ited high activity in ethylene glycol (Table 2, entries 7 and
8).
Table 2. The Suzuki reaction of 2-pyridyl bromides with aryl-
boronic acids.[a]
[a] Reaction conditions: 3-bromopyridine (0.5 mmol), arylboronic
acids (0.75 mmol), K3PO4·7H2O (1 mmol), Pd(OAc)2 (0.5 mol-%),
ethylene glycol (4 mL), 80 °C, under air. The reaction was moni-
tored by TLC. [b] Isolated yields. [c] Pd(OAc)2 (0.05 mol-%).
in ethylene glycol. The results are summarized in Table 2.
A quantitative yield of 2-phenylpyridine was obtained in
the presence of 0.5 mol-% Pd(OAc)2 at 80 °C for 30 min in
air, resulting in a TOF of 396 h–1 (Table 2, entry 1). Al-
though this coupling provided a nearly half of the TOF
value with respect to that between 3-bromopyridine and
phenylboronic acid, it is the most efficient ones under li-
gand-free conditions.[9a–9d,9f,12,14] It is noteworthy that the
reaction between 2-bromopyridine and o-tolylboronic acid
could be conducted in 94% yield after 60 min (Table 2, en-
try 3), which is far more efficient than that carried out in
[a] Reaction conditions: 2-bromopyridine (0.5 mmol), arylboronic
acids (0.75 mmol), K3PO4·7H2O (1 mmol), Pd(OAc)2 (0.5 mol-%),
ethylene glycol (4 mL), 80 °C, under air. The reaction was moni-
tored by TLC. [b] Isolated yields.
To further investigate the scope and limitations of this
an aqueous system.[9a,9f] Arylboronic acids with electron- methodology, we carried out cross-couplings of other nitro-
deficient or electron-rich groups reacted smoothly with 2- gen-based heteroaryl halides with various arylboronic acids.
bromopyridine, affording high isolated yields in short time As shown in Table 3, 5-bromopyrimidine reacted smoothly
(Table 2, entries 2–5). For example, 4-fluorophenylboronic with arylboronic acids bearing different electronic effect
acid, with an electron-withdrawing group, completed the re- groups using 0.1 mol-% Pd(OAc)2 (Table 3, entries 1–3).
action with 2-bromopyridine in 20 min with 99% yield Obviously, it took much longer reaction time to complete
(Table 2, entry 5). The cross-coupling reactions between ar- the Suzuki reaction of 2-amino group substituted 5-bromo-
ylboronic acids and 2-pyridyl bromides bearing electron- pyrimidine requiring an increased palladium loading of
donating or electron-withdrawing groups were carried out 0.5 mol-%, highlighting the retarding effect of the amino
rapidly with excellent yields (Table 2, entries 6–11). The group on the coupling reaction.
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C. Liu, N. Han, X. Song, J. Qiu
SHORT COMMUNICATION
Table 3. The Suzuki reaction of N-heteroaryl halides with aryl-
boronic acids.[a]
It is clear that the hydroxy groups of solvent play an
important role in the reactivity of the Suzuki reaction.
Using methoxyl group instead of one of the hydroxy groups
of ethylene glycol resulted in obviously decreased reactivity,
thus, only 50% isolated yield of the 2-phenylpyridine was
reached after 60 min. Further replacing both hydroxy
groups of ethylene glycol with methoxyl groups provided
trace cross-coupling product in 30 min, while a quantitative
yield was reached in 30 min in ethylene glycol. Therefore,
ethylene glycol functions not only as a solvent but also as
a promoter in the Suzuki reaction of N-heteroaryl halides.
Although the nature of ethylene glycol as a promoter is un-
clear, we propose that an active palladium complex could
be formed in the catalytic cycle via hydroxy groups of the
solvent.
Conclusions
In conclusion, we have developed a general, ligand-free,
aerobic and very fast protocol for the constuction of N-
heterobiaryl derivatives via the Suzuki reaction of N-het-
eroaryl halides in ethylene glycol. Further investigation on
the reaction mechanism and synthetic application of this
protocol are ongoing in our laboratory.
[a] Reaction conditions: N-heteroaryl halides (0.5 mmol), aryl-
boronic acids (0.75 mmol), K3PO4·7H2O (1 mmol), Pd(OAc)2
(0.5 mol-%), ethylene glycol (4 mL), 80 °C, under air. The reaction
was monitored by TLC. [b] Isolated yields. [c] Pd(OAc)2 (0.1 mol-
%).
Experimental Section
Materials and Methods: All N-heteroaryl bromides and arylboronic
acids were used as received (Alfa Aesar, Avocado). All other chemi-
cals were purchased from commercial sources and used without
1
further purification. H NMR spectra were recorded on a Varian
Inova 400 spectrometer. Chemical shifts were reported in ppm rela-
tive to TMS. 13C NMR spectra were recorded at 100 MHz using
TMS as internal standard. Mass spectroscopy data of the products
were collected on a MS-EI instrument. All products were isolated
by short chromatography on a silica gel (200–300 mesh) column
using petroleum ether (60–90 °C), unless otherwise noted. Com-
The reaction of 3-bromoquinoline with phenylboronic
acid provided the product in 93% yield within 25 min
(Table 3 entry 6), much more efficient than that performed
in a silica-assisted aqueous protocol.[9c]
The steric effect on the arylboronic acid usually de-
creased the reactivity, therefore, only an 80% isolated yield
was obtained after 85 min in the case of o-tolylboronic acid
(Table 3, entry 7). It is noteworthy that 2-chloropyrazine is
a good coupling partner in the Pd(OAc)2/EG system
(Table 3, entries 8–9).
To understand the high efficiency of the Pd(OAc)2/EG
system for the Suzuki reaction of N-heteroaryl halides, the
cross-coupling of 2-bromopyridine with phenylboronic acid
was chosen to study the effect of solvent molecular struc-
ture on the reactivity under air using 0.5 mol-% Pd(OAc)2
at 80 °C. The results are illustrated in Scheme 1.
1
pounds described in the literature were characterized by H NMR
spectra to reported data.
General Procedure for the Suzuki Reaction of 3-Pyridyl Bromides or
Other N-Heteroaryl Halides with Arylboronic Acids: A mixture of
3-pyridyl bromide or other heteroaryl halides (0.5 mmol), aryl-
boronic acid (0.75 mmol), Pd(OAc)2 (0.5 mol-%, 0.56 mg),
K3PO4·7H2O (1 mmol, 338.4 mg) and ethylene glycol (4 mL) was
stirred at 80 °C for indicated time. The mixture was added to brine
(10 mL). The mixture was extracted with diethyl ether (10 mL). So-
dium hydroxide (10 mmol, 400 mg) was added to neutralize the su-
perfluous arylboronic acid. The mixture was transferred into brine
(10 mL) in order to extract the impurity which dissolved in the
aqueous solution and dissolve the superfluous base. The above-
mentioned three steps were repeated for three times. The solvent
was concentrated in vacuo and the product was isolated by short
chromatography on a silica gel (200–300 mesh) column.
General Procedure for Suzuki Reaction of 2-Pyridyl Bromides with
Arylboronic Acids: A mixture of 2-pyridyl bromide (0.5 mmol),
arylboronic acid (0.75 mmol), Pd(OAc)2 (0.5 mol-%, 0.56 mg),
K3PO4·7H2O (1 mmol, 338.4 mg) and ethylene glycol (4 mL) was
stirred at 80 °C for indicated time. The mixture was added to brine
(10 mL) and extracted four times with diethyl ether (4ϫ10 mL).
Scheme 1. Effect of the solvent molecular structure on the reactiv-
ity.
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Eur. J. Org. Chem. 2010, 5548–5551

Synthesis of Aryl-Substituted N-Heteroarenes
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5-(4-Fluorophenyl)-2-methoxylpyridine: Yield 99% (100.5 mg), m.p.
75 °C. 1H NMR (400 MHz, CDCl3, TMS): δ = 8.33 (d, J = 2.4 Hz,
1 H, Py), 7.74 (dd, J = 8.4, 2.4 Hz, 1 H, Py), 7.49–7.45 (m, 2 H,
Ph), 7.15–7.11 (m, 2 H, Ph), 6.81 (d, J = 8.4 Hz, 1 H, Py), 3.98 (s,
[3]
1
3 H, OCH3), ppm. 13C NMR: δ = 163.6 [d, J(13C,19F) = 8.0 Hz,
Ci], 161.2 (Ci), 144.8 (CPy), 137.4 (Ci), 134.1 [d, 3J(13C,19F) =
[4]
[5]
5
3.0 Hz, CPh], 129.2 (CPy), 128.3 [d, J(13C,19F) = 8.0 Hz, Ci], 115.9
[d, 2J(13C,19F) = 22.0 Hz, CPh], 110.9 (CPy), 53.57 (OCH3), ppm.
MS (EI): m/z (%) = 204, 203 (100) [M+], 175, 172, 146, 133, 132,
107, 83, 63.
2-Methoxy-5-(2-methylphenyl)pyridine: Yield 96% (95.5 mg), light-
yellow oil. 1H NMR (400 MHz, CDCl3, TMS): δ = 8.13 (d, J =
2.8 Hz, 1 H, Py), 7.54 (dd, J = 8.8, 2.4 Hz, 1 H, Py), 7.28–7.19 (m,
4 H, Ph), 6.79 (d, J = 8.4 Hz, 1 H, Py), 3.98 (s, 3 H, OCH3), 2.27
(s, 3 H, CH3), ppm. 13C NMR: δ = 163.3 (Ci), 146.7 (CPy), 139.7
(CPy), 138.3 (CPh), 135.9 (Ci), 130.7 (CPh), 130.6 (CPh), 130.1 (Ci),
127.8 (CPh), 126.2 (Ci), 110.3 (CPy), 53.6 (OCH3), 20.6 (CH3), ppm.
MS (EI): m/z (%) = 200, 199 (100) [M+], 198, 170, 169, 167, 154,
141, 128, 127, 115, 102, 89, 77, 63, 48, 39.
[6]
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The authors thank the financial support from State Key Labora-
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DUT, Graduate Student Reform Fund of DUT, the National Nat-
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Received: July 8, 2010
Published Online: September 6, 2010
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5551