Synthesis of benzofuro[3,2-b]pyridines via palladium-catalyzed dual C-H activation of 3-phenoxypyridine 1-oxides

Article abstract of DOI:10.1021/ol5033464

An efficient oxidative cyclization to straightforward synthesis of benzofuro[3,2-b]pyridine 1-oxides with high regioselectivity via Pd-catalyzed intramolecular dual C-H activation was developed. The resulting products could be deoxygenated easily to the corresponding benzofuro[3,2-b]pyridines in excellent yields.

Full text of DOI:10.1021/ol5033464

Letter
pubs.acs.org/OrgLett
Synthesis of Benzofuro[3,2‑b]pyridines via Palladium-Catalyzed Dual
C−H Activation of 3‑Phenoxypyridine 1‑Oxides
Wei Sun,† Min Wang,*,† Yicheng Zhang,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: An efficient oxidative cyclization to straightforward synthesis of benzofuro[3,2-b]pyridine 1-oxides with high
regioselectivity via Pd-catalyzed intramolecular dual C−H activation was developed. The resulting products could be
deoxygenated easily to the corresponding benzofuro[3,2-b]pyridines in excellent yields.
Scheme 1. Synthesis of Benzofuro[3,2-b]pyridines
used benzofuroheterocycles are usually key core motifs in
Fmany natural products, pharmaceuticals, and optoelec-
tronically and biologically active compounds.1 Numerous
methods for their synthesis have been reported, including C−
O cyclization of 2-halobipheny-ols2 and 2-arylphenols,3 C−C
cyclization of 1-halo-2-phenoxybenzenes4 and diaryl ethers,5
and intramolecular decarboxylative6 and decarbonylative7 C−H
arylation of 2-phenoxybenzoic acids. Among these method-
ologies, transition-metal-catalyzed intramolecular dehydrogen-
ative C−C coupling of diphenyl ethers through C−H/C−H
double activation represents an extremely attractive approach,
which avoids the steps for installation of preactivated functional
groups and is highly efficient to target molecules from readily
available and environmentally benign starting materials.
Many heterocyclics bearing a benzofuro[3,2-b]pyridine
moiety have been found with various pharmaceutical and
biological activities, such as antiallergic, anti-inflammatory,
antimicrobial, and analgesic activity,8 cyclin-dependent kinase
inhibitors, and topoisomerase inhibitors.9 Therefore, develop-
ment of efficient methods for their preparation have received
great attention. Liu10 and Li11 described Pd/Cu-catalyzed
preparation of benzofuro[3,2-b]pyridine from dichloropyridine
or 2-chloro-3-pyridinol, but in limited examples (Scheme 1). In
2010, Funicello reported a multistep synthesis of benzofuro-
[3,2-b]pyridines from 3-bromobenzofuran via (benzofuran-3-
yl)iminotriphenylphosphorane through an aza-Wittig−electro-
cyclization process (Scheme 1).12 However, the preactivation of
pyridine ring with metal-containing functionalities or halides
could involve multistep procedures due to its low reactivity and
poor regioselectivity, which is neither atom-economical nor
environmentally friendly. In addition, the existing methods have
limitations as to the functional group tolerance and narrow
substrate scope.
by Fagnou in Pd-catalyzed direct regioselective C-2 arylation of
pyridine N-oxides with aryl bromides.13 Subsequently, various
efforts have been devoted to the functionalization of N-oxides,
including (hetero)arylation,14 alkynylation,14c,15 alkenylatio-
n,14a,b,d,16 alkylation,14b,c,15,17 amination/amidation,18 acyloxy-
lation,19 acylation,20 sulfonylation,21 et al.17c,22 via C−H bond
activation. Nonetheless, intramolecular oxidative C−H/C−H
cyclization for the construction of pyridine N-oxide fused
heterocycles has been not addressed so far. In a continuation of
our work on the C−H activation and cyclization,23 herein we
wish to illustrate an efficient and site-selective synthesis of
benzofuro[3,2-b]pyridine N-oxides from readily available and
stable 3-phenoxypyridine 1-oxides by Pd-catalyzed C−H/C−H
oxidative cyclization. The reaction exhibits excellent functional
group tolerance and is compatible with electron-donating or
Pyridine or other heteroarene N-oxides belong to an
important class of heteroaromatic motifs with distinctive
reactivity. Since 2005, a significant breakthrough was reported
Received: November 18, 2014
© XXXX American Chemical Society
A
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Letter
electron-withdrawing groups on the aromatic rings of 3-
phenoxypyridine 1-oxides. It is important to note that no
reaction was occurred for 3-phenoxypyridine. The obtained
benzofuro[3,2-b]pyridine N-oxides are easy to be transferred
into the corresponding benzofuro[3,2-b]pyridines by deoxyge-
nation under Pd/C reduction conditions (Scheme 1).
Scheme 2. Scope of C−H/C−H Oxidative Cyclization of 3-
a,b
Phenoxypyridine 1-Oxides
We initially investigate the reaction conditions for the
dehydrogenative cyclization of 3-(p-tolyloxy)pyridine 1-oxide
(1b) as model substrate, which was prepared from p-cresol and
3-bromopyridine.24 The results are listed in Table S1 in the
Supporting Information. The effect of solvent was examined,
and HOAc was found to be the best one among the tested
solvents (Table S1, entries 1−11). When the model reaction
was performed in the presence of Pd(OAc)2 (5.0 mol %) and
HOAc as solvent at 140 °C for 24 h, Ag2O is the most effective
oxidant among AgOAc, Ag2CO3, AgNO3, K2S2O8, BQ (1,4-
benzoquinone), Cu(OA)2, and PhI(OA)2 (Table S1, entries
12−18). To our delight, when Pd(PPh3)2Cl2 was employed
instead of Pd(OAc)2, the desired product 2b was obtained in
74% yield (Table S1, entry 19). Other Pd catalysts, PdCl2 and
Pd2(dba)3, afforded poor results, and no reaction was observed
in the absence of Pd. The optimized reaction conditions consist
of Pd(PPh3)2Cl2 (5.0 mol %), Ag2O (1.5 equiv), and HOAc
(solvent) at 140 °C for 24 h under air.
With the optimized reaction conditions in hand, the scope of
this dual C−H/C−H oxidative cyclization was investigated, as
shown in Scheme 2. A variety of 3-phenoxypyridine 1-oxides
were subjected to the reaction, and the desired products were
obtained in fair to good yields with excellent functional-group
tolerance. 3-Phenoxypyridine 1-oxide (1a) was underwent the
reaction to generate the corresponding product benzofuro[3,2-
b]pyridine 1-oxide (2a) in 65% yield. 3-Phenoxypyridine 1-
oxides containing an electron-donating substituent (Me, Et, iPr,
t
or Bu) in the ortho- or para-position of phenyl rings occurred
smoothly to give the desired products (2b−e,h,i) in 66−77%
yields. 3-Phenoxypyridine 1-oxides bearing phenyl in the ortho-
and para-position of the aryl rings gave the products 2f and 2j
in 59 and 63% yields. 3-Phenoxypyridine 1-oxides with a strong
electron-rich or electron-deficient substituent, such as methox-
yl, acetyl, benzoyl, ester, nitro, or amide groups on the benzene
rings, afforded the moderate yields of the desired products
(2g,l,p−t), inferior to that of those with non- or alkyl-
substituted 3-phenoxypyridine 1-oxides. For example, 3-(4-
methoxyphenoxy)pyridine 1-oxide (1g) and 3-(4-acetylphen-
oxy)pyridine 1-oxide (1p) resulted in the desired products 2g
and 2p in 53% yield. For substrates 1k and 1l in which methyl
and methoxyl groups were located at the meta-position
possessing two nonequivalent ortho-hydrogen on the phenyl
ring, interestingly, C−C bond formations occurred at the less
sterically hindered site in exclusive regioselectivity (2k and 2l).
Dimethyl-substituted products (2m−o) were also obtained in
moderate yields from the corresponding starting materials
(1m−o).
Remarkably, the catalytic system could tolerate C−Cl and
C−F bonds, which can provide further transformation (2u−x).
It should be noted that 3-(2-chlorophenoxy)pyridine 1-oxide
(1w) underwent exclusively oxidative C−H/C−H cyclization
rather than oxidative C−H/C−Cl coupling reaction, providing
2w in 54% yield. Furthermore, when 3-(naphthalen-2-yloxy)-
pyridine 1-oxide (1y) was employed, the cyclization occurred at
α-C−H position, showing excellent regioselectivity and good
reactivity (2y, 60% yield, the structure of 2y was confirmed by
X-ray diffraction analysis, shown in the Supporting Informa-
a
Reaction conditions: 1 (0.20 mmol), Pd(PPh3)2Cl2 (0.01 mmol),
b
Ag2O (1.5 equiv), HOAc (0.50 mL), air, 140 °C, 24 h. Isolated yield.
tion). Subsequently, substrates possessing methyl and phenyl in
pyridine rings were examined for their reactivity. Gratifyingly,
4-methyl-3-(p-tolyloxy)pyridine 1-oxide (1z), 3-methyl-5-(p-
tolyloxy)pyridine 1-oxide (1aa), 3-(4-ethylphenoxy)-5-phenyl-
pyridine 1-oxide (1ab), and 3-chloro-5-(4-nitrophenoxy)-
pyridine 1-oxide (1ac) also underwent the reaction to afford
the expected products 2z, 2aa, 2ab, and 2ac in moderate yields.
An attempt was made to prepare 3-pyridinyloxypyridine 1-
oxides, but failed.
With the obtained benzofuro[3,2-b]pyridine 1-oxides in
hand, they were easily reduced to the corresponding
benzofuro[3,2-b]pyridines in the presence of Pd catalyst on
charcoal.25 A variety of benzofuro[3,2-b]pyridine 1-oxides with
both electron-donating and electron-withdrawing groups on the
aromatic rings of substrates underwent the deoxygenation
smoothly to generate the corresponding products in good to
excellent yields (81−93% yields, Scheme 3), indicating the
reduction is not sensitive to the electronic and steric effect of
substituted groups. It should be noted that 2s and 2ac were
reduced into 3s and 3ac in high yields through the
deoxygenation and the reduction of nitro to amine processes.
It provides a practical and alternative route to a variety of
benzofuro[3,2-b]pyridines.
To gain insight into the reaction mechanism, an H/D
exchange experiment was conducted. When 3-([1,1′-biphenyl]-
B
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Letter
Scheme 3. Deoxygenation of Benzofuro[3,2-b]pyridine N-
Oxides to Benzofuro[3,2-b]pyridine
Scheme 5. Possible Mechanism for the Reactions
a,b
species, which was oxidized by Ag(I) to regenerate Pd(II)
species to complete the catalytic cycle. Finally, 2a was
deoxidized in the presence of Pd/C to give the deoxygenation
product 3a.
In summary, we have developed an efficient, novel, and
regioselective oxidative cyclization to straightforward synthesis
of benzofuro[3,2-b]pyridine 1-oxides via Pd-catalyzed intra-
molecular dual C−H activation. This catalytic system shows
excellent compatibility with numerous synthetically relevant
functional groups, thus affording a practical tool for the
preparation of a variety of substituted benzofuro[3,2-b]pyridine
1-oxides. The resulting products can be deoxygenated easily to
the corresponding benzofuro[3,2-b]pyridines in excellent
yields. Further investigations of the detailed reaction mecha-
nism and the application of this methodology are underway.
a
Reaction conditions: 2 (0.30 mmol), Pd/C (0.03 mmol), THF (1.0
b
mL), HCOONH4 (15 equiv), N2, rt, 12 h. Isolated yield.
4-yloxy)pyridine 1-oxide (1f) was subjected to the dual C−H/
C−H activation in CD3COOD in the presence Pd(PPh3)2Cl2
without Ag2O, a significant deuterium incorporation (37%) was
observed at the 2-position of pyridine ring, and only 5%
deuterium at the 6-position was incorporated (Scheme 4). In
Scheme 4. H/D Exchange and Kinetic Isotope Effect
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangmin204@chnu.edu.cn.
*E-mail: leiwang88@hotmail.com.
Notes
contrast, no deuterium incorporation was found at the phenyl
ring. According to this result, the first C−H activation occurred
at the more steric demanding C2-position of the pyridine oxide
ring. In addition, an intermolecular isotope kinetic experiment
was performed. When 1a and its deuterated analogue [D5]-1a
in 1:1 molar ratio were subjected to the reaction a kinetic
isotope effect (kH/kD = 1.0) was obtained (Scheme 4),
implicating that C−H bond cleavage of arenes is not the
rate-determining step in the reaction.
A possible reaction mechanism is proposed in Scheme 5 on
the basis of the above experiments and the previous
investigation.16b,22a First, PdII catalyst reacted with 3-phenox-
ypyridine 1-oxide (1a) via C−H bond activation to afford a C2-
palladated species A, which further underwent an intra-
molecular cyclization to form bis-arylpalladium species B via
another C−H bond activation. The obtained B underwent
reductive elimination to afford the product 2a and Pd(0)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is financially supported by the National Science
Foundation of China (Nos. 21372095, 21202057, and
21172092).
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