Aerobic Copper Catalysis for Tandem Oxy-N-alkenylation of [1,2,3]Triazolo[1,5-a]pyridines

Article abstract of DOI:10.1002/adsc.201600580

N-Alkenylated triazolinone ylides were generated through copper-catalyzed oxy-N-alkenylation of triazolopyridines. The mechanistic course of this aerobic tandem reaction has been experimentally elucidated and primary photophysical data of the ylide products are also given. (Figure presented.).

Full text of DOI:10.1002/adsc.201600580

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DOI: 10.1002/adsc.201600580
Very Important Publication
Aerobic Copper Catalysis for Tandem Oxy-N-alkenylation of
[
1,2,3]Triazolo[1,5-a]pyridines
a,
a
a
Sreekumar Pankajakshan, * Wei Li Ang, Sivarampanicker Sreejith,
a
a,b,
Mihaiela Corina Stuparu, and Teck-Peng Loh *
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371
E-mail: pankajakshan@ntu.edu.sg or teckpeng@ntu.edu.sg
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026 People’s Republic of
b
China
Received: June 2, 2016; Revised: July 11, 2016; Published online: && &&, 0000
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/adsc.201600580.
Abstract: N-Alkenylated triazolinone ylides were
generated through copper-catalyzed oxy-N-alkeny-
lation of triazolopyridines. The mechanistic course
of this aerobic tandem reaction has been experi-
mentally elucidated and primary photophysical data
of the ylide products are also given.
a]pyridines to pyridinium triazolinone ylides
[
4b]
[Scheme 1, Eq. (1)]. The intriguing assumptions in
the proposed mechanism (an intrinsically electrophilic
oxygen radical oxygenating an electron-depleted tria-
zolium intermediate) warranted further experimental
confirmation. The synthesis of new variants of the
structurally novel triazolinone ylide framework was
Keywords: aerobic oxidation; copper catalysis; fluo-
rescence; nitrogen ylides; triazolopyridines
[
1,2,3]Triazolo[1,5-a]pyridines are unique triazole
[
1]
frameworks that offer versatile applications. Their
synthetic derivatizations hence are extremely desira-
ble but yet practically often challenging because of
the propensity of these molecules to react through the
ring opened diazo form which results in the expul-
sion of nitrogen, forming products devoid of the tria-
zole core. Although transition metal catalysis has
enabled several classes of heterocycles to be function-
alized, triazolopyridines remain poorly explored.
[
2]
[3]
[
4]
The use of hypervalent iodine compounds and, of
late, their bromine(III) analogues as oxidants and
electrophilic reagents in organic synthesis is continu-
ally growing due to their non-toxicity, selectivity and
[
5,6]
superior reactivity.
The potentiual of pre-formed
alkenyliodonium salts as alternatives to traditional
vinyl halides/triflates in heteroatom cross-coupling
has hardly been explored although they could offer
these reactions milder conditions and/or enable them
to proceed in the absence of specific ligands and ex-
[
7]
pensive metal catalysts. We have recently come up
with a copper-catalyzed aerobic methodology that fa- Scheme 1. Synthesis of N-arylated and N-alkenylated pyri-
cilitated the tandem conversion of [1,2,3]triazolo[1,5- dine triazolinone ylides.
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another priority. The following report describes how Table 1. Scope of different triazolopyridines towards oxy-N-
alkenylation.
the employment of alkenyliodonium reagents as elec-
trophiles allowed these targets to be successfully ach-
ieved [Scheme 1, Eq. (2)]. Pyridinium triazolinone
[
8]
ylides were found to be fluorescent compounds and
this report also provides primary emission data of the
new alkenylated derivatives.
The idea of oxy-N-alkenylation of triazolopyridines
could be effected under relatively less “forcing” con-
ditions owing to the subtle reactivity differences in-
volved. Taking advantage of the weaker iodine-alkene
covalent bond and the reputation of the phenyliodo-
[
9]
nio group as an excellent nucleofuge, the iodonium
salt employed could afford a structurally simpler (and
more economical) phenyl ligand in place of the mesi-
tyl moiety that was imperative for selective oxyaryla-
tion. It was also speculated that milder thermal condi-
tions should suffice owing to the enhanced lability of
the vinyliodonium fragment. We were delighted to
see that our assumptions were ratified when the
model reaction between the parent triazolopyridine
(
1a) and (E)-2-phenyl(styryl)iodonium tetrafluorobo-
1
rate (2a) proceeded cleanly (the crude H-NMR testi-
fied clean conversion with no competing N-arylation)
to furnish N-styrenated ylide (3a) [Scheme 1, Eq. (2)]
at a very mild reaction temperature. Unlike for oxyar-
ylation, copper(I) iodide was almost as efficacious as
the cationic copper salt whereas the indispensability
[
4b]
of cesium carbonate
was preserved (see the Sup-
porting Information for optimization details).
Having the optimized conditions in hand, we then
set out to explore how well differently substituted tri-
azolopyridines respond to oxy-N-alkenylation. A rea-
sonable range of substituents was tested and it was
gratifying to see them all tolerated (Table 1, products
3b–3j). It was hard to keep track of these reactions o). It was found that electronic effects of iodonium
using TLC as in all cases the triazole substrate was salts featuring styrene-type alkenes were marginal
consumed within 2–3 hours leaving behind an intense (Table 2, products 3k–n) as good conversions resulted
base line spot (vide infra) which was invariably con- even when a strongly electron-deficient trifluorometh-
sumed upon further stirring overnight. AS expected yl substitutent was present (Table 2, products 3n). Io-
electron-donating substituents afforded better conver- donium salt containing an aliphatic alkene group
sions possibly by increasing the electrophilic coordi- turned out to be poorly transferable and traces of
nating ability of the triazole nitrogen (Table 1, prod- competitive phenyl transfer contaminated the isolated
ucts 3b, 3d, and 3j). That the methyl group at C-4 po- product (Table 2, product 3o). Exclusive phenylation
sition turned out to be inhibitive (Table 1, entry 3c) took place when (1H-inden-2-yl)(phenyl)iodonium
speaks for the sensitivity of the system towards steric tetrafluoroborate (2g), the iodonium bearing a steri-
effects close to the reaction center. Halogen handles cally congested alkene was employed (Table 2, last
offered room for further modifications (Table 1, prod- entry). Vinyliodoniums like (E)-(4-methoxystyryl)-
ucts 3e and f) and a heterocyclic substituent could
ACHTUNGTRENNU(GN phenyl)iodonium tetrafluoroborate, (E)-phenyl(3-
also be accommodated (Table 1, product 3i). Triazole phenylprop-1-en-1-yl)iodonium tetrafluoroborate and
substrates with electron-withdrawing groups (Table 1, (E)-(2-(1H-inden-3-yl)vinyl)(phenyl)iodonium tetra-
products 3g and h) performed poorly although satis- fluoroborate were found to be unstable for use in our
factory yields were still obtained.
hands.
In an effort to further enrich the structural scope of
In order to further increase the scope of the oxy-N-
alkenylation strategy, hypervalent alkenyliodoniums triazolinone ylides, the compatibility of alkynyliodoni-
[
9]
[10]
carrying different alkene ligands were also tested um salts was then tested for a potential oxy-N-alky-
against the model substrate 1a (Table 2, products 3k– nylation of the triazole substrates. But the alkyne ana-
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Table 2. Scope of different alkene ligands towards the oxy-
N-alkenylation.
Scheme 3. Mechanistic studies ofn the oxy-N-alkenylation of
triazolopyridines.
ether and methanol (to remove any unreacted starting
materials and the phenyl iodide that was produced)
furnished a yellow solid. After several attempts, good
quality crystals were obtained and X-ray elucidation
proved the species to be N-alkenylated triazolopyridi-
[
11]
nium hexafluorophosphate salt (4) (Figure 1). Grat-
ifyingly, 4 was oxidized on exposure to molecular
logue was found to be too labile under the reaction oxygen in the presence of copper catalyst and cesium
conditions (even at room temperature) and the crude carbonate and triazolinone ylide (3p) was isolated in
1
H-NMR showed the exclusive formation of the 85% yield [Scheme 3, Eq. (4)]. Only traces of 3p was
homo-coupled diyne product (Scheme 2).
produced when either the copper salt or molecular
With the hope of trapping any crucial intermediate oxygen were missing [Scheme 4, Eq. (5) and (6)] and
that could provide a factual basis for the mechanistic no reaction observed in the absence of cesium car-
sequence of this cascade transformation, we designed bonate [Scheme 4, Eq. (7)].
a control experiment in which 6-chloro-[1,2,3]triazo-
lo[1,5-a]pyridine (1e) and (E)-(4-phenylstyryl)(phe- for oxy-alkenylation is proposed (Scheme 5). Accord-
nyl)iodonium tetrafluoroborate (2d) were treated in
the presence of a stoichiometric copper salt in DCE
Scheme 3, Eq. (3)]. The triazole got consumed and
Based on these findings, the mechanistic rational
ACHTUNGTRENNUNG
[
the reaction mixture turned into a yellow suspension
after six hours at room temperature. Filtration fol-
lowed by repeated washing of the solid with diethyl
Scheme 2. Homocoupling observed during the attempted
oxy-N-alkynylation of triazolopyridines.
Figure 1. Crystal structure of 4 (tert-butyl methyl ether, the
solvent used for crystallization was seen to be trapped).
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Table 3. Summary of UV/Vis absorption and fluorescence
[a]
data.
[a]
À5
Absorption peaks are measured in CH Cl (5.1ꢁ10 M).
2
2
Scheme 4. Control experiments on the oxygenation of 4.
emission properties of a few selected derivatives
Table 1, 3a, 3d, 3e, 3g–j) were investigated in di-
chloromethane and the data are summarized in
(
[
14]
Table 3. The ylidic structures, except for 3j, exhibit
broad absorptions with absorption bands centered in
the 300–430 region (Figure S1a, Supporting Informa-
tion). Ylide 3j on the other hand, displays relatively
sharper absorptions possibly owing to the tricyclic
backbone. Also, 3a, 3d, 3i and 3j were found to be
highly emissive with broad emission spectra while 3e,
3g and 3h exhibit no or weak emission in dichlorome-
thane, apparently due to the presence of potential
quenchers in the backbone (Figure
[
15]
S1b, Supporting Information).
The substituent
effect of the N-alkenyl group on absorption–emission
wavelength was marginal although the intensities of
both were clearly varied with changing of the N-sub-
stituent (Figure S2a and b, Supporting Information).
In summary, new variants of pyridinium triazoli-
Scheme 5. Plausible mechanism for the oxy-N-alkenylation none ylides were synthesized by a copper-catalyzed
of triazolopyridines.
tandem functionalization of triazolopyridines and the
mechanism of this tandem process was duly investi-
ingly, the tandem functionalization is considered to be gated with the isolation of the key triazolium inter-
initiated with the formation of an oxidatively added mediate. We hope to employ this reactivity towards
copper complex (A). The reductive elimination from aerobic oxygenations of other carbon centers tethered
A produced the triazolium species B and the forma- to electrophilic nitrogen handles. A preliminary
tion of the C–O bond is assumed through a radical re- survey on the photophysical properties of the prod-
organization of B before reacting with copper-peroxy ucts was also conducted. Most of the emissive ylides
radical. Elimination of copper followed by subsequent were associated with significantly high Stokes shifts
reduction of the N-radical C under the reaction condi- that could well enable these compact molecules to be
tions produces the ylide product thereby completing potential fluorophores. Future efforts will be focused
[
12]
the catalytic cycle.
Scheme 4, Eqs. (5) and (6)] strongly support the oxi-
dation phase to be a copper-catalyzed aerobic oxygen-
The control experiments on 4 along this direction also.
[
[13]
ation pathway. That a radical scavenger like 2,6-di-
tert-butyl-p-cresol (BHT) inhibited the oxygenation of
Experimental Section
4
further to testifies the involvement of radicals in
the oxidation stage of the oxy-alkenylation
Scheme 4, Eq. (8)].
General Procedure
[
To an oven-dried Schlenk tube were added the triazolopyri-
To our delight the triazolinone ylides were found to dine (0.1 mmol, 1 equiv.), (E)-2-phenyl(styryl)iodonium tet-
be emissive and preliminary UV/Vis absorption and rafluoroborate (0.12 mmol, 1.2 equiv.), catalyst (20 mmol%),
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and Cs CO (0.2 mmol, 2 equiv.). The tube was sealed, evac-
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2
3
uated and refilled with molecular oxygen (using an oxygen
balloon, repeated three times). 1 mL of dry DCE was added
and molecular oxygen was bubbled through the solution for
a few seconds. The reaction mixture was then heated at
[7] For palladium-catalyzed coupling of amines with vinyl
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published soon.
o
40 C under an oxygen balloon overnight. The brown sus-
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centrated under vacuum and purified through silica gel (ba-
sified with triethylamine) column chromatography (hexane/
ethyl acetate) to afford the desired product.
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pore Ministry of Education Academic Research Fund [Tier
9
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Aerobic Copper Catalysis for Tandem Oxy-N-alkenylation
of [1,2,3]Triazolo[1,5-a]pyridines
Adv. Synth. Catal. 2016, 358, 1 – 6
Sreekumar Pankajakshan,* Wei Li Ang,
Sivarampanicker Sreejith, Mihaiela Corina Stuparu,
Teck-Peng Loh*
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