Copper-catalyzed aerobic carboxygenation and N-arylation of [1,2,3]triazolo[1,5-a]pyridines towards pyridinium triazolinone ylides

Article abstract of DOI:10.1039/c4cc10061a

Copper-catalyzed aerobic oxyarylation of [1,2,3]triazolo[1,5-a]pyridines is developed. Notably molecular oxygen was utilized as one of the reagents and the transformation resulted in the formation of novel pyridinium triazolinone ylides. A basic mechanism for the one-pot process is proposed and further functionalization of the ylidic products were also presented.

Full text of DOI:10.1039/c4cc10061a

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CopperꢀCatalyzed Aerobic Carboxygenation and
Nꢀarylation of [1,2,3]Triazolo[1,5ꢀa]pyridines
towards pyridinium triazolinone ylides
Cite this: DOI:
10.1039/x0xx00000x
Sreekumar Pankajakshan,*a Zhi Guang Chng,a Rakesh Gangulya and Teck Peng
Loh*a,b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copperꢀcatalyzed aerobic oxyarylation of [1,2,3]Triazolo[1,5ꢀ iodobenezene and phenyl triflate as coupling partners for the
a]pyridines is developed. Notably molecular oxygen was model triazolopyridine substrate (1a) were disappointing (Table
utilized as one of the reagents and the transformation 1, entries
a
&
b). Employing
a
more electrophilic
resulted in the formation of novel pyridinium triazolinone phenyl(mesityl)iodonium triflate4 having a nonꢀlabile mesityl
ylides. A basic mechanism for the oneꢀpot process is proposed moiety did induce reactivity and the starting materials gave way
and further functionalization of the ylidic products were also to a new product in 12 h at 90 oC. Comprehensive Xꢀray
presented.
structural elucidation unambiguously confirmed the product to
be an unexpected zwitterꢀionic pyridinium triazolinone ylide
[1,2,3]ꢀTriazoles are important nitrogenꢀrich heterocycles
(
2a, 34%) produced as a result of C7ꢀoxygenation and Nꢀ
arylation.5, We attributed the oxygenation to the molecular
oxygen present in the reaction flask and incorporation of it was
confirmed through carrying out the reaction under 18O (vide
infra). Product 2a possessed a novel heterocyclic structure to
the best of our knowledge and the observed catalytic CꢀH
oxygenation using molecular oxygen as the reagent is a
transformation of great interest owing to the apparent economic
and environmental advantages.7 Driven by these prospects, we
went on to fineꢀtune the reaction efficiency (See SI for
optimization studies). Copper(I) salts were generally more
6
having widespread application in medicine, biology and
material science.1 [1,2,3]Triazolo[1,5ꢀa]pyridines constitute key
yet unique members of the triazole family. They also offer
potential access to biologically important pyridine derivatives,
energetic and small molecule fluorescent materials.2 Though
homogeneous transition metalꢀcatalysis has made significant
strides in making functionalized monocyclicꢀtriazoles, the
reports on functionalization of triazolopyridines have been
scant and features only a single report based on transition
metalꢀcatalysis till date.2c This dearth in activity and the
potential of these derivatives inspired us to venture into the
functionalization of [1,2,3]Triazolo[1,5ꢀa]pyridines and this
report discloses the initial findings.
effective than Cu(II) and
a
relatively more cationic
Tetrakis(acetonitrile)copper(I) hexafluorophosphate was found
to be the catalyst of choice (no reaction was observed in the
absence copper ).
Table 1. Scope of arene electrophiles towards oxyarylation of
1a
At the outset, we set out to explore the possible C/Nꢀ
arylations of triazolopyridines as a continuum of our own
interest in metalꢀcatalyzed directed and nonꢀdirected arylations
of nitrogen containing organic molecules.3 Copper salts were
the preferred catalysts and the initial attempts with
a Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
b Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui, P. R. China 230026.
Electronic Supplementary Information (ESI) is available:
Experimental procedure and characterization data of new
compounds. CCDC for 2a is 1035312 and CCDC for 3a is 1035311.
See DOI: 10.1039/c000000x/

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DOI: 10.1039/C4CC10061A
Common ligands for copper led to sluggish reactions possibly permissible9 with both
due to competitive binding with the metal centre. Expectedly an offering useful yields whereas
oxygen atmosphere accelerated the reaction and curiously the deactivating
transformation was of a very solvent and a baseꢀsensitive one. (Table 3, 2t
p
ꢀanisyl and
p
ꢀfluorophenyl groups
more electronically
a
m
ꢀnitrophenyl moiety took longer reaction time
2u and 2v). [1,2,3]triazolo[1,5ꢀa]quinolone also
,
Polar coordinating solvents like DMF, tꢀBuOH and dioxane Table 3. Substrate scope for the oxyarylation reaction
induced either decomposition or noꢀreaction and caesium
carbonate stayed as the optimal base. (see SI for details).
Having identified the optimal conditions, the scope of different
aryl(mesityl)iodonium triflates
to oxyarylate the model
substrate (1a) was tested (Tableꢀ2, entries 2aꢀn). Gratifyingly,
the reaction accommodated a range of electronically different
groups on the labile aryl ring with electronꢀwithdrawing groups
having a noticeable deceleration effect (Table 2, compare 2a
2j 2k). Useful synthetic handles like halogens, nitro and ester
were among the groups that could be installed (Table 2, entries
2b 2j, and 2m). A heterocylic aromatic ring was also Nꢀ
, 2i,
&
ꢀd,
arylated notwithstanding the mediocre isolated yield (Table 2,
entry 2n) The reaction seemed to be averse to steric effects on
the orthoꢀposition of the transferred aryl group as was
evidenced from the
entry 2e 2l).
oꢀmethyl and oꢀester substitutions (Tableꢀ2,
&
Table 2. Reaction scope with different aryl(mesityl)iodonium
triflates
underwent the reaction smoothly to deliver the corresponding
ylide product (Table 2, 2s). Interestingly, oxygenation of a C3ꢀ
methyl substituted carbon was also observed as demethylation
of 1j took to the formation of 2a (Table 3, last entry).
The precise redox mechanism of the oxyarylation reaction
seems to be rather complex and as of now we are able to
propose only a speculative picture. The highly oxidative
reaction conditions (molecular oxygen, hypervalent iodine)
point towards
a Cu(II)/Cu(III) catalytic cycle and the
oxygenation is taken to follow a radical pathway through
putative copper(II)ꢀperoxo species.7,10 The involvement of
radicals was experimentally supported by the observation that a
radical scavenger like 2,6ꢀDiꢀtertꢀbutylꢀpꢀcresol (BHT) totally
inhibited the model reaction (Scheme 1, eq.1). Utilization of an
18O atmosphere incorporated the isotopically labelled oxygen at
the carbonyl group of the product 2iʹ (Scheme 1, eq.2).
TfO-
Cu(MeCN)4PF6 (20 mol%)
Cs2CO3 (2 equiv)
BTC (1 equiv)
H
I
Having established the effectiveness of electronically different
aryl partners, we next turned to investigate if the same could be
extended to different [1,2,3]Triazolo[1,5ꢀa]pyridine substrates
(Table 3, entries 2oꢀv). These compounds were easily
synthesized by the oxidative cylization of the corresponding
hydrazones and were found to be mostly stable to the reaction
conditions.8 Phenyl(mesityl)iodonium triflate was employed as
the model electrophile and standard reaction conditions were
applied. It was found that the presence of a methyl group
(1)
(2)
Decomposition
N
N
DCE, O2, 80 oC, 1 h
N
N
1b
TfO-
I
18O
N
H
Cu(MeCN)4PF6 (20 mol%)
Cs2CO3 (2 equiv)
N
N
N
N
DCE, 18O2, 80 oC, 4 h
1b
2i' ( 95%)
significantly improved the reaction rate (Table 3, 2o
& 2p). It
was noteworthy that halogen substituents were tolerated under
the reaction reactions with no competing dehalogenation or Cꢀ
Scheme 1. Mechanistic studies
arylation (Table 3, 2q
& 2r). Aryl substituents on C7 were

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DOI: 1C0.O10M39M/CU4CNCI1C0A0T61IOA N
to this library. Present research is largely inclined towards these
directions.
Decomposition of the model reaction was observed under strict
inert conditions even in the presence of 1 equivalent of the
copper salt. These observations testify the role of molecular
oxygen as the oxygenation reagent as well as the oxidant (vide
infra).
Based on these observations a tentative mechanism was
proposed (Scheme 2). Cu(II) species that was generated by the
swift aerobic oxidation of Cu(I) undergoes an oxidativeꢀaryl
transfer (probably disproportionationꢀinduced) to form an arylꢀ
Cu(III) species.10, 11, 12 The highly electrophilic Cu(III) complex
was then coordinated to the triazole nitrogen. Reductive
elimination of the intermediate
the copper(I) center led to the formation of peroxoꢀcopper(II)
species . The CꢀO bond formation is conceived through a
A followed by reoxidation of
Scheme 3. Synthetic modifications of pyridinium triazolinone
ylides
B
homolytic electron redistribution driven by the ensuing
aromatization of the pyridinium ring forming the transient Nꢀ
.
radical C 13 Elimination of CuIIꢀOH followed by single electron
Conclusion
In summary, an aerobic, copperꢀcatalyzed tandem oxyarylation of
[1,2,3]Triazolo[1,5ꢀa]pyridines using aryliodonium triflates is
reported. The oneꢀpot reaction led to the formation of pyridinium
triazolinone ylides which are novel heterocyclic structures. The
synthetic modification of these molecules is briefly addressed and
ongoing efforts are directed towards further manipulation of their
potential to be synthetic precursors and fluorescent probes.
reduction of the nitrogen center in
C would generate the
product thereby closing the catalytic cycle.14
Acknowledgements
We gratefully acknowledge the Nanyang Technological
University, Singapore Ministry of Education Academic
Research Fund (ETRP 1002 111, MOE2010ꢀT2ꢀ2ꢀ067, MOE
2011ꢀT2ꢀ1ꢀ013) for the funding of this research. We thank Prof.
Shunsuke Chiba for his valuable mechanistic inputs. Dr. Y. X.
Li is acknowledged for the Xꢀray support.
Notes and references
Scheme 2. Plausible mechanism
1
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& 2). The azopyridinium moiety in these compounds offers an
activated aromatic ring and taking advantage of it we were able
to induce a palladiumꢀcatalyzed ortho-selective direct arylation
on 2a to produce the C7ꢀarylated derivative 3a (Scheme 3, eq.
1).15, 16 The pyridinium ring could also be subjected to mild
catalytic hydrogenation as was shown with 2b to yield the
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would open access to variety of substituted
4. (Scheme 3, eq. 2).
a
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pyridines/piperidines though our initial trials towards this target
were met with little success.17 Triazolinones are known to be
useful pharmacophores18 in drug discovery and our oxyarylated
ylidic structures could be interesting complementary additions
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DOI: 10.1039/C4CC10061A
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possible Nꢀstabilization of the copperꢀperoxo complex. Decomposition
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aryl(mesityl)iodonium triflate reagent.
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