Pd-catalyzed oxidative C-H/C-H cross-coupling of pyridines with heteroarenes

Article abstract of DOI:10.1039/c3sc50348h

We have developed for the first time a general, concise and highly selective method for the C2-heteroarylation of pyridines and related azines with a broad range of heteroarenes via a two-fold C-H activation, which streamlines the previous approaches that require the activated azine N-oxide as the coupling partner.

Full text of DOI:10.1039/c3sc50348h

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Pd-catalyzed oxidative C–H/C–H cross-coupling of
pyridines with heteroarenes†
Cite this: DOI: 10.1039/c3sc50348h
*
Bo Liu, Yumin Huang, Jingbo Lan, Feijie Song and Jingsong You
Received 4th December 2012
Accepted 21st February 2013
We have developed for the first time a general, concise and highly selective method for the C2-
heteroarylation of pyridines and related azines with a broad range of heteroarenes via a two-fold C–H
activation, which streamlines the previous approaches that require the activated azine N-oxide as the
coupling partner.
DOI: 10.1039/c3sc50348h
www.rsc.org/chemicalscience
works by Bergman, Ellman, Nakao and Hiyama demonstrated
selective C2–H alkylation or alkenylation, and selective C4–H
Introduction
alkylation of pyridines by nickel/Lewis acid catalysis.13 Recently,
the Yu group developed a novel Pd-catalyzed arylation and
olenation at the pyridine C3 position based on a ligand-
assisted strategy.12,14 The Sames group realized the C3/C4
selective arylation of pyridines containing strong electron-
withdrawing groups.10 Furthermore, other important discov-
eries in this area, including carboxamide directed arylation and
radical arylation were disclosed by Yu9 and Baran et al.11 In spite
of signicant progress in C–H/C–X-type arylation of pyri-
dines,8–12 direct C–H heteroarylation of pyridines surprisingly
remains under-represented, which is probably attributed to the
general reluctance of heteroaryl halides or pseudohalide to
undergo the coupling reactions.16 Thus, the oxidative C–H/C–H
heteroarylation of pyridines with various heteroarenes should
be an ideal alternative to afford pyridine-containing
Biheteroaryls containing pyridines and related azines (e.g.,
quinolines, isoquinolines, pyrimidines, pyrazines, pyridazines
and quinoxalines) present privileged architectural units
frequently found in natural products, pharmaceuticals, bioac-
tive molecules, ligands and other functional synthetic materials
(Scheme 1).1 Catalytic oxidative C–H/C–H cross-coupling
between two (hetero)arenes would be one of the most attractive
approaches to forge these bi(hetero)aryl units. Since the
pioneering work by Fagnou and co-workers on the transition
metal-catalyzed oxidative C–H/C–H coupling of indoles with
unactivated arenes set up a stage for this eld of study,2
signicant progress has been made to assemble various bi(he-
tero)aryl scaffolds.3 While a variety of heteroarenes have shown
to be adequate coupling substrates,4 the dehydrogenative
(hetero)arylation of pyridine and related azine derivatives still
remains particularly challenging, due to the poor electron
density of the ring and the strong tendency to bind to a metal
center through the nitrogen atom, that may lead to metal
sequestration and deactivation.5,6 More recently, we and others
achieved the C2-selective heteroarylations of azine N-oxides
with p-electron excessive ve-membered heterocycles to form
unsymmetrical biheteroaryls (Scheme 2).7 From an academic
and step-economic point of view, it would be highly desirable to
directly use an unactivated azine instead of the activated azine
N-oxide as a coupling partner.
The transition metal-catalyzed direct C–H functionalization
of pyridines has long been identied as a great challenge by the
synthetic organic chemistry community.8–15 The pioneering
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College
of Chemistry, State Key Laboratory of Biotherapy, West China Medical School, Sichuan
University, 29 Wangjiang Road, Chengdu 610064, PR China. E-mail: jsyou@scu.edu.
cn; Fax: +86 28-85412203; Tel: +86 28-85412203
† Electronic supplementary information (ESI) available: Data and copies of NMR
and MS spectra for all new compounds, and experimental procedures. CCDC
906804–906808. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3sc50348h
Scheme 1 Selected medicinal and natural molecules containing 2-hetero-
arylated pyridines.
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Results and discussion
We started our investigation by the heterocoupling of pyridine
1a with 2-methylthiophene 2a as a model reaction to optimize
the reaction conditions (Table 1). As shown in Table 1, several
parameters (e.g., oxidant, ligand and additive) were studied.
Initial reaction screening led to disappointing results in the
absence of either oxidant or Pd(II) salt (Table 1, entries 1 and 2).
Among the oxidants investigated, AgOAc was the best choice
(Table 1, entries 3–8). Aer screening various ligands, 1,10-
phenanthroline monohydrate (L1) gave the best result (Table 1,
entries 8–12). Subsequently, we investigated the amount of the
ligand used, and found that 0.5 equivalent of 1,10-phenan-
throline monohydrate was the most effective (Table 1, entries 8,
14–18). When the reaction was conducted in the presence of
10 mol% of Pd(OAc)2, the product yield was improved to 51%
(Table 1, entry 17). Considering that pivalic acid could promote
the concerted metalation/deprotonation process (CMD), we
added pivalic acid as the additive in the catalytic system. To our
delight, the use of PivOH signicantly improved the catalytic
efficiency (Table 1, entries 19 and 20). Thus, the best results
were obtained by using 3.0 equiv. of AgOAc as the oxidant, 0.5
equiv. of 1,10-phenanthroline monohydrate (L1) as the ligand,
Scheme 2 Evolution of palladium-catalyzed oxidative heteroarylation of pyri-
dines via double C–H activation.
biheteroaryls. However, we may face obstacles: (1) the low
reactivity at the C-2 and C-6 positions of pyridines; (2) the
notorious tendency of heteroarenes to undergo oxidative
homocoupling under transition metal-catalyzed conditions in
comparison with simple arenes and alkenes;17–19 (3) the inade-
quate stability of heteroarenes in the coupling process; (4) the
binding of the heteroatom in both the substrate and product to
metal complex that may prevent the catalyst from interacting
with the reactive C–H bonds; and (5) the regiocontrol of C–H
activation of both substrates. Herein, we disclose the discovery,
development and solution to meet these substantial challenges.
Table 1 Optimization of the reaction conditionsa
Entry
Pd(OAc)2
Oxidant
Ligand
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
—
Ag2CO3
—
BQ
O2
Cu(OAc)2
Ag2O
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
L1 (15 mol%)
phen (15 mol%)
L2 (15 mol%)
L3 (15 mol%)
L4 (15 mol%)
—
L1 (20 mol%)
L1 (30 mol%)
L1 (50 mol%)
L1 (50 mol%)
L1 (100 mol%)
L1 (50 mol%)
L1 (50 mol%)
L1 (50 mol%)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
n.d
n.d
n.d
n.d
n.d
Trace
Trace
24
23
11
22
16
15
30
37
43
51
46
66
73
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
9
10
11
12
13
14
15
16
17
18
19
20
21c
—
—
PivOH (0.5 equiv.)
PivOH (1.0 equiv.)
PivOH (1.0 equiv.)
73
a
Reactions were carried out using palladium source (5–10 mol%), oxidant (3.0 equiv.), ligand (15–100 mol%), additive (0.5–1.0 equiv.), pyridine 1a
(25.0 equiv.) and 2-methylthiophene 2a (0.5 mmol) at 140 ꢀC for 24 h. b Isolated yield based on 2a. c 2,2,6,6-Tetramethylpiperidinooxy (20 mol%) was
added. BQ ¼ benzoquinone, PivOH ¼ pivalic acid, n.d. ¼ not detected, L1 ¼ 1,10-phenanthroline monohydrate, L2 ¼ 2,9-dimethyl-1,10-
phenanthroline, L3 ¼ 4,7-diphenyl-1,10-phenanthroline, L4 ¼ 2,20-bipyridine.
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Scheme 3. Our catalytic system accelerated the C2-hetero-
arylation of pyridine with a wide array of electron-rich hetero-
arenes (e.g., indole, furan, thiophene, etc.) (Scheme 3, 3a–3k). It
was surprising to nd that the acidic C–H bonds of various
azoles (e.g., indazole, imidazopyridine, xanthines, etc.) could
also undergo the cross-coupling with pyridine in satisfactory
yields (Scheme 3, 3l–3o). It is of note that the coupling of N-
methylindole occurred at the indole C2 position rather than the
naturally preferential C3 selectivity (Scheme 3, 3k). In contrast,
the previously reported couplings took place at the indole C3
position while pyridyl N-oxide was used as the coupling
partner.7 No matter the functional groups of heteroarenes were
electron-donating, electron-withdrawing, or sterically hindered,
all of them afforded moderate to good yields. The current
catalytic system was highly tolerant to a variety of functional
groups such as halide, acyl, nitro, amide, ester, nitrile and
hydroxyl groups on heteroarenes. These chemoselectivities
would enable the cross-coupling products to be used in further
transformations. The cross-coupling was regioselective at the
C2 position of pyridine, and other regioisomeric products were
not observed. X-Ray analysis of single crystals 3f, 3k, 3o, 4c and
4f conrmed that the oxidative C–H/C–H cross-coupling
occurred at the C2 position on the pyridine ring (Fig. S3, ESI†).20
We subsequently applied this protocol to other pyridine
derivatives for the synthesis of C2-heteroaryl-substituted pyri-
dines in good yields (Scheme 4, 4a–4j). To our surprise, pyri-
dines bearing both electron-donating and electron-withdrawing
groups could afford the desired products. In addition to these
substituted pyridines, this catalytic system also effectively
promoted the cross-coupling of a relatively wide range of azines
(e.g., pyrimidine, quinoline, quinoxaline, pyrazine, pyridazine,
etc.) with 2-methylthiophene to give moderate to good yields
with excellent regioselectivity (Scheme 4, 4k–4p). It should be
stressed that unreacted starting materials still remained in the
lower yielding reactions. The C2 vs. C6 selectivity of the
C3-substituted pyridines was dependent on the steric and
electronic characteristics of the substituents. For example, the
C3-pivalamido, phenyl and ester substituted pyridines prefered
to give the C6-substituted pyridines probably due to the steric
hindrance, and only trace amounts of the C2-substituted
products were detected (Scheme 4, 4a–4c). The C3-uoro and
chloro pyridines predominantly afforded the C2-substituted
products, possibly attributed to electronic effects, and only trace
amounts of the C6-substituted products were observed (Scheme
4, 4d–4j). The relatively reactive C1–H position of isoquinoline
underwent the cross-coupling process with 2-methylthiophene
to afford 4l as a single product in 57% yield (Scheme 4, 4l).
It is of note that the current Pd-catalyzed oxidative C–H/C–H
cross-coupling reactions exhibited several advantages,
including: (1) the homocoupling products of each coupling
partner were almost not detected; (2) the process showed an
exclusive C2-regioselectivity of pyridine; (3) the mono-hetero-
arylated adducts of pyridines and related azines were obtained
only; and (4) the reaction was performed without problems on
gram scale, delivering 71% yield of the desired product 3a.
To get some insights into the mechanism of this novel Pd-
catalyzed oxidative C–H/C–H functionalization of pyridines, the
Scheme 3 Palladium-catalyzed heteroarylation of pyridine with various heter-
oarenes. For all reactions 0.5 mmol of heteroarene and 25.0 equiv. of pyridine
were used under an N2 atmosphere. Yields of isolated product are based on
heteroarene.
and 1.0 equiv. of PivOH as the additive in the presence of
ꢀ
Pd(OAc)2 (10 mol%) at 140 C for 24 h.
With optimized conditions in hand, we explored the scope of
this process with respect to heteroarenes summarized in
Scheme 4 Heteroarylation of pyridines and related azines with various heter-
oarenes. For all reactions 0.5 mmol of heteroarene and 1.0 mL of azine were used
under an N2 atmosphere. Yields of isolated product are based on heteroarene;
[a] N-(pyridin-3-yl)pivalamide (5 mmol) and DMF (0.5 mL).
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and its deuterated derivative d1-2j (Scheme 5, eqn (3)), thereby
indicating that the C–H bond cleavage of 2j was not involved in
a rate determining step.
On the basis of the above observations, we assumed the
plausible catalytic cycle illustrated in Scheme 6, including: (1)
initial coordination of pyridine with Pd via the nitrogen atom to
form the complex IM1, which subsequently encountered a
“trans-effect” into the p-acceptor IM2; (2) C2–H cleavage of IM2
to give the 2-pyridylpalladium(II) intermediate IM3 via a
carboxylate-assisted concerted metalation/deprotonation (CMD)
pathway; (3) a regioselective C–H substitution of furan with IM3
to yield the key heterocoupling intermediate IM4, followed by
reductive elimination to produce the desired product; and (4)
regeneration of the Pd(II) species from Pd(0) by the oxidation of
AgOAc (Scheme 6). It is of note that whether in the presence or
absence of phenanthroline monohydrate, the reaction occurred
preferentially at the C2 site of pyridine (Table 1). Thus, we
rationalized that phenanthroline monohydrate described herein
served as the ligand to increase the catalytic efficiency. In
contrast, the role of phenanthroline ligand postulated by Yu was
correlated to the C3-selective functionalization of pyridine
derivatives through the “trans effect”.12,14
Scheme 5 Kinetic isotope effect.
Conclusions
In conclusion, we have advanced for the rst time a general and
highly selective methodology for the direct C2-heteroarylation of
pyridine and related azine rings with
a wide range of
heteroarenes. In comparison with previous approaches of azine
N-oxides, the current method is advantageous for the rapid
synthesisofa libraryofpyridine-containingbiheteroarylswithout
detours because of its concise operation and wide availability of
starting materials. Studies on further applications of this direct
oxidative C–H/C–H heteroarylation is ongoing in our laboratory.
Acknowledgements
This work was supported by grants from the National Basic
Research Program of China (973 Program, 2011CB808600), the
National NSF of China (nos 21025205, 21272160, 21172155 and
21021001), and the Outstanding Young Scientist Award of
Sichuan Province (2012JQ0002). We thank the Centre of Testing
Scheme 6 Plausible catalytic cycle of oxidative C–H/C–H cross-coupling of
pyridine with heteroarene.
following experiments were carried out. Addition of 2,2,6,6-tet-
ramethyl-1-piperidinyloxy (TEMPO, 20 mol%) as a radical
scavenger had a negligible effect on the coupling reaction
between pyridine 1a and 2-methylthiophene 2a, which ruled out
a radical pathway (Table 1, entry 21). Subsequently, both inter-
and intra-kinetic isotope effects (KIE) were investigated with
regard to the C–H/D bonds for both coupling partners. A
primary KIE of 2.78 was observed between pyridine 1a and its
deuterated derivative d5-1a (Scheme 5, eqn (1)), which was in
accordance with the Pd-mediated C–H cleavage mechanism. A
signicant kinetic isotope effect (kH/kD ¼ 3.0) was observed in
an intramolecular competition reaction of pyridine-d1 (Scheme
5, eqn (2)). These observations indicated that the C2–H bond
breaking of 1a might be related with the rate-limiting step. In
addition, no signicant KIE value (kH/kD ¼ 1.12) was observed in
an intermolecular competition reaction between benzofuran 2j
&
Analysis, Sichuan University for NMR and X-ray
measurements.
Notes and references
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906807 (4f).
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