Copper-catalyzed direct oxidative annulation of N-iminopyridinium ylides with terminal alkynes using O2 as oxidant

Article abstract of DOI:10.1039/c2cc33706a

The aerobic direct dehydrogenative annulation of N-iminopyridinium ylides with terminal alkynes leading to pyrazolo[1,5-a]pyridine derivatives has been developed.

Full text of DOI:10.1039/c2cc33706a

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Copper-catalyzed direct oxidative annulation of N-iminopyridinium ylides
with terminal alkynes using O2 as oxidantwz
Shengtao Ding,a Yuepeng Yana and Ning Jiao*ab
Received 23rd May 2012, Accepted 28th June 2012
DOI: 10.1039/c2cc33706a
The aerobic direct dehydrogenative annulation of N-iminopyridinium
ylides with terminal alkynes leading to pyrazolo[1,5-a]pyridine
derivatives has been developed.
As coupling partners, terminal alkynes have been widely employed
in Sonogashira couplings.14 However, the catalytic dehydrogenative
coupling of Csp2–H with terminal alkynes still remains a challenging
issue,15 due to the difficulties of avoiding the dimerization of
terminal alkynes under oxidative conditions.
Pyridine moieties are key structural units and exist widely in
a large number of natural products, functional materials,
pharmaceuticals, and ligands.1 The search for efficient and
convergent modifications of pyridine derivatives through direct
C–H functionalization presents a direct and atom-economic
process for the synthesis of pyridine-containing compounds,
and therefore has attracted considerable attention.2–9 In the
past decades, the Rh,2 Ru,3 Pd,4 Ir,5 Ni,6 Zr,7 Ln,8 and Ag9
catalyzed C–H functionalization of pyridines have been significantly
developed. In comparison to these transition metal catalysts,
C–H functionalization of pyridine derivatives with inexpensive
Cu catalysts has rarely been reported,10,11 even though Cu was
the first transition metal shown to promote C–H arylation.12,13
Recently, Daugulis and coworkers have disclosed the novel CuI/
phen catalyzed arylation reaction of pyridine N-oxide (eqn (1)).10
The first CuBr2 catalyzed direct alkenylation of N-iminopyridinium
ylides was reported by Charette’s group (eqn (2)).11
Recently, Su and coworkers realized the first Cu-catalyzed
direct alkynylation of an aromatic C–H bond with terminal
alkynes.15c We envisioned that the direct alkynylation of
pyridine derivatives could be achieved by appropriate oxidative
Cu-catalysis. Herein, we report the first aerobic oxidative dehydro-
genative annulation of N-iminopyridinium ylides with terminal
alkynes via direct alkynylation. The significance of the present
finding is threefold: (1) this method provides a novel copper
catalysts for the C–H activation of pyridine derivatives with
alkynes; (2) natural, inexpensive, and environmentally friendly
molecular oxygen16 was used as the oxidant making this method
very simple and practical and (3) this relatively inexpensive
Cu-catalysts provides an efficient and straightforward approach
to pyrazolo[1,5-a]pyridine derivatives, which are important
components of pharmaceutically active compounds.17
Under our hypothesis, the investigation was initially started
with the reaction between pyridinium ylide 1a and phenyl-
ethyne 2a in a Cu/O2 catalytic system. The direct alkynylation
product was not detected, but a trace amount of the dehydro-
genative annulation product 3a was obtained when CuI
(10 mol%) was employed as the catalyst (Table S1, ESIz). The
yield was slightly promoted to 27% on addition of 10 mol%
Ag2CO3 (Table S1, ESIz). After screening different parameters
(see ESIz), 3a was obtained in 74% yield under the optimized
conditions (CuI 10 mol%, Ag2CO3 10 mol%, DABCO 2.0 equiv.,
O2). The 20% yield under air indicated the importance of O2 in
this transformation (see ESIz).
ð1Þ
ð2Þ
ð3Þ
Under the standard conditions, this reaction exhibited
broad substrate scope with respect to terminal alkynes
(Table 1). Substrates bearing either electron-donating (para-,
meta-, or ortho-substituted) or -withdrawing substituents were
well tolerated, leading to the corresponding products in moderate
to good yields (Table 1, 3a–3j). Especially, the attainments of
chloro and bromo products with high yields paved a convenient
way for the synthesis of more complicated derivatives via cross-
coupling reactions (Table 1, 3g & 3h). The heterocyclic alkynes
performed differently in this transformation, which may be
due to their distinct in electronic charateristics. For instance,
the reaction of 1a with 2-ethynylpyridine did not lead to the
a State Key Laboratory of Natural and Biomimetic Drugs,
Peking University, School of Pharmaceutical Sciences,
Peking University, Xue Yuan Rd., 38, Beijing 100191,
People’s Republic of China. E-mail: jiaoning@bjmu.edu.cn;
Fax: +86-010-8280-5297; Tel: +86-010-8280-5297
b State Key Laboratory of Organometallic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, People’s Republic of China
w This article is part of the ChemComm ‘Emerging Investigators 2013’
themed issue.
z Electronic supplementary information (ESI) available: See DOI:
10.1039/c2cc33706a
c
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Chem. Commun.

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Table 1 The aerobic dehydrogenative annulations of 1a with different
alkynes (2)a,b
Table 2 The aerobic dehydrogenative annulations of N-iminopyridinium
ylides (1) with 2ba
a
Standard reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), CuI
(10 mol%), Ag2CO3 (10 mol%), DABCO (0.4 mmol), PhCl (2 mL)
b
under O2 (1 atm) for 48 h. Isolated yields.
relevant product, while 3-ethynylthiophene afforded the product
3l in a 67% yield.
This dehydrogenative transformation was then expanded to
various N-iminopyridinium ylides (Table 2). Moderate yields
were obtained under these standard conditions (Table 2). This
might be due to the easy decomposition of these ylides. Product
3m was afforded by the reaction of 4-benzyl pyridinium ylide 1b
with 1-chloro-4-ethynylbenzene 2b with the oxidization of benzyl
to benzoyl under the oxidative conditions (Table 2, entry 1). A
mixture of 3p and 3q was obtained when meta-chloro pyridinium
ylide was employed as the substrate (Table 2, entry 4).
a
Standard reaction conditions: 1 (0.2 mmol), 2b (0.6 mmol), CuI
(10 mol%), Ag2CO3 (10 mol%), DABCO (0.4 mmol), PhCl (2 mL)
b
c
under O2 (1 atm) for 48 h. Isolated yields. The ratio of 3p and 3q
1
was determined by H NMR.
alkynes to pyridinium ylide 1 to form dihydropyridines18 and
followed aromatization. Furthermore, a kinetic isotope effect
experiment was carried out to make the mechanism more clear
(ESIz). The kinetic isotope effect (kH/kD = 2.2) was observed
by comparison with the rates of 1a and the deuterated ylide
[D5]-1a. Meanwhile, the 17% deuterium incorporation at the
3-position suggests the possibility of the protonation process.
To understand the mechanism, several experiments were
carried out. A trace amount of the product 3a was afforded in
the absence of Ag2CO3 (Table S1, entry 1) and this reaction
could hardly happen in the absence of CuI, even when 1 equiv.
amount of Ag2CO3 was employed (eqn (4)). We envisioned
that copper acetylide 4, which is generated from the alkyne 2a
with copper under aerobic basic conditions, could be an
intermediate in this process. To test this possibility, the reaction
of 1a with 4 was conducted under different conditions.
ð5Þ
ð6Þ
ð7Þ
ð4Þ
The yield was slightly promoted after the addition of Ag+
(eqn (5) and (6)). Compared with the result in the absence of
Ag+ (20%, entry 7, Table 1), it may be concluded that Ag+
might assist the formation of the copper acetylide. The addition of
DABCO improved the yield significantly (eqn (7)). As we learned,
the base plays several roles in this transformation, such as assisting
the formation of copper acetylide, the dehydrogenation of substrate
1, and the expulsion of benzoyl moiety. When a similar reaction
was carried out under argon, no corresponding addition product
dihydropyridine derivatives was detected (eqn (8)), which may
exclude the pathway through Cu-catalyzed addition of terminal
ð8Þ
On the basis of above results, a proposed mechanism for the
reaction is illustrated in Scheme 1. The initial copper acetylide
4 is generated from alkyne 2 with Cu(I) catalyst assisted by
Ag2CO3 under basic conditions. Subsequently, the oxidative
insertion of copper acetylide 4 into the pyridinium ylide 1
forms Cu(III) intermediate 511 via C–H bond functionalization.
Intermediate 5 undergoes reductive elimination to afford the
direct alkynylation intermediate 6, in which the alkyne can be
c
Chem. Commun.
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Scheme 1 The proposed mechanism for this aerobic dehydrogenative
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annulations.
activated by copper catalyst. Subsequent 5-endo cyclization of
6 via the anti-aminocupration of the alkyne attacked by the
amido nitrogen generates 7, which can be converted into 8 via
a protonation process. Finally, product 3 is afforded via the
rearomatization of 8. DABCO assists the expulsion of the
benzoyl moiety in this process. We can not exclude that DABCO
plays another role of ligand on Cu to facilitate the reaction.19
In conclusion, we have demonstrated the aerobic direct dehydro-
genative annulations of terminal alkynes for pyrazolo[1,5-a]-
pyridine derivatives. Further studies to discover the synthetic
applications of this reaction are ongoing in our group.
Financial support from National Basic Research Program
of China (973 Program 2009CB825300), National Science
Foundation of China (No. 21172006), and Peking University
are greatly appreciated. We thank Peng Feng in this group for
reproducing the results of 3e and 3m.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.