Palladium-catalyzed α-selective alkenylation of imidazo[1,2-a]pyridines through aerobic cross-dehydrogenative coupling reaction

Article abstract of DOI:10.1002/ejoc.201403372

The palladium-catalyzed highly regioselective vinylation of imidazopyridines through a cross-dehydrogenative coupling reaction was developed. The reaction proceeds with the aid of molecular oxygen as the sole oxidant. A series of branched α-vinylated products were obtained with high efficiency.

Full text of DOI:10.1002/ejoc.201403372

Job/Unit: O43372
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Date: 20-12-14 12:34:06
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403372
Palladium-Catalyzed α-Selective Alkenylation of Imidazo[1,2-a]pyridines
through Aerobic Cross-Dehydrogenative Coupling Reaction
Monoranjan Ghosh,[a] Aswini Naskar,[a] Shubhanjan Mitra,[a] and Alakananda Hajra*[a]
Keywords: C–C coupling / Dehydrogenation / Alkenylation / Oxygen / Regioselectivity / Nitrogen heterocycles
The palladium-catalyzed highly regioselective vinylation of
imidazopyridines through a cross-dehydrogenative coupling
reaction was developed. The reaction proceeds with the aid
of molecular oxygen as the sole oxidant. A series of branched
α-vinylated products were obtained with high efficiency.
decades, aerobic palladium(II)-catalyzed reactions involving
C–H bond activation and functionalization have been
studied extensively, and numerous palladium-catalyzed ar-
ene–olefin coupling reactions have been developed.[10] Al-
though vinylation is a fundamental chemical transforma-
tion that is very useful for the synthesis of functionalized
organic molecules, it is notable that direct alkenylation of
imidazopyridines is very limited.[11] In fact, cross-de-
hydrogenative coupling for the functionalization of imid-
azopyridines is rare.[12] Thus, we became interested in the
direct alkenylation of imidazopyridines through the cross-
dehydrogenative coupling reaction.
In this context, our experiences in the syntheses of func-
tionalized imidazo[1,2-a]pyridine derivatives[13] together
with aerobic Pd catalysis[14] inspired us to explore the cou-
pling between imidazo[1,2-a]pyridine and vinylarene.
Herein, we report a highly regioselective aerobic Pd-cata-
lyzed vinylation of imidazo[1,2-a]pyridines (Scheme 1). This
ligand-free method affords only α-selective products and in-
volves molecular oxygen as the sole green oxidant. Among
various oxidants, molecular oxygen and air are recognized
as the most effective ones[15] from the context of green and
sustainable chemistry. Water is produced as the only by-
product, and the use of oxygen shows a great demand from
an industrial prospect.
Introduction
Imidazopyridines, in which the imidazole moiety is fused
with a pyridine ring, is an important class of biologically
active nitrogen-containing heterocycles.[1] Imidazopyridine
derivatives show a wide range of biological activities, in-
cluding antitumor, antiprotozoal, antiviral, antimicrobial,
antiherpes, and fungicidal activities.[2] They are also used as
β-amyloid formation inhibitors, GABA and benzodiazepine
receptor agonists, and cardiotonic agents.[3] Many commer-
cially available drugs such as zolpidem (used in the treat-
ment of insomnia), alpidem (as an anxiolytic agent), olprin-
one (for the treatment of acute heart failure), zolimidine
(used for the treatment of peptic ulcer), and necopidem and
saripidem (both working as anxiolytic agents) are derived
from this scaffold.[4] Owing to their diverse biological and
pharmaceutical activities, there is continuous effort to de-
velop newer strategies for the construction of functionalized
imidazopyridines.[5]
Atom-efficient cross-dehydrogenative coupling (CDC)
reactions are considered promising methods for new C–C
bond formation. These methods avoid the prefunctionaliza-
tion of starting materials (i.e., organohalides or organome-
tallic species), which thus makes the synthetic routes
straightforward and more efficient.[6] The cross-de-
hydrogenative coupling reaction of arenes and aromatic het-
erocycles with alkenes through C–H activation, particularly
Pd-catalyzed oxidative cross-coupling, namely, the Fuji-
wara–Moritani reaction[7] or the so-called oxidative Heck-
type reaction, has been proven to be the most reliable
method in the field of chemical syntheses.[8] For the alkenyl-
ation process, positional selectivity attracts much attention
owing to the formation of linear or branched olefins.[9] For
Scheme 1. Pd-catalyzed vinylation of imidazo[1,2-a]pyridine;
DMAc = N,N-dimethylacetamide.
[a] Department of Chemistry, Visva-Bharati (A Central
University),
Santiniketan 731235, West Bengal, India
Results and Discussion
E-mail: alakananda.hajra@visva-bharati.ac.in
http://www.visvabharati.ac.in/AlakanandaHajra.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403372.
Preliminary investigation of the reaction parameters was
performed by using 2-phenylimidazo[1,2-a]pyridine (1a,
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M. Ghosh, A. Naskar, S. Mitra, A. Hajra
SHORT COMMUNICATION
0.5 mmol) and styrene (2a, 2.5 mmol) as the model sub- reaction by using various imidazopyridines and vinylarenes
strates. Initially, the reaction was performed by employing (Table 2). Imidazopyridine moieties having a methyl substit-
Pd(OAc)2 (5 mol-%) in DMSO for 16 h under an atmo- uent at C-6 and C-7 produced the corresponding 3-alkenyl-
sphere of O2 (101.3 kPa). The olefinated product was ob- ated products in high yields. Moreover, chloro and fluoro
tained in 10% yield (Table 1, entry 1). After careful analysis substituents at C-2 of the phenyl ring of the imidazopyrid-
it was found that the selective α-vinylation occurred only at ines reacted very well (see products 3ga and 3ia). Cyano-
the C-3 position of the imidazopyridine ring. Encouraged substituted imidazopyridine also reacted smoothly under
by this result, we added Bu4NBr (2 equiv.) as an additive to the reaction conditions (see product 3fa). Moreover, imid-
the catalytic system, which we had used previously.[14] To
our delight, α-vinylated product 3aa was obtained in 45%
yield (Table 1, entry 2). Next, we checked the effect of the
different solvents such as DMF, DMAc (N,N-dimethylacet-
Table 2. Scope of the oxidative olefination of various imidazopyrid-
ines with vinylarenes.[a]
amide), NMP (N-methylpyrrolidone), and dioxane (Table 1,
entries 3–6). Interestingly, DMAc was found to be superior
to the other solvents, and it afforded the desired product in
75% yield (Table 1, entry 4). The amount of additive was
also important. The yield of the product decreased if
1 equiv. of Bu4NBr (TBAB) was used (Table 1, entry 7). No
significant increase in yield was observed upon increasing
the amount of TBAB (Table 1, entry 8). The use of Bu4NI
led to a decrease in the yield (Table 1, entry 9). The use of
other Pd catalysts such as PdCl2 and Pd(PPh3)2Cl2 was also
found to be ineffective (Table 1, entries 10 and 11). The ef-
fect of the catalyst loading was also studied. No improve-
ment in the yield was observed upon increasing the amount
of catalyst (Table 1, entry 12). The reaction produced only
52% of the desired product in ambient air without using
molecular oxygen (Table 1, entry 13). A significant decrease
in the yield was found upon lowering the temperature to
60 °C, even after 24 h (Table 1, entry 14).
Table 1. Optimization of the reaction parameters.[a]
Entry Catalyst
Additive (equiv.) Solvent Yield [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
–
DMSO
DMSO
DMF
DMAc
NMP
dioxane
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
10
45
50
75
65
10
45
77
40
Bu4NBr (2)
Bu4NBr (2)
Bu4NBr (2)
Bu4NBr (2)
Bu4NBr (2)
Bu4NBr (1)
Bu4NBr (3)
Bu4NI (2)
Bu4NBr (2)
9
10
11
12
13
14
15
Pd(PPh3)2Cl2 Bu4NBr (2)
trace
78[c]
52[d]
35[e]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Bu4NBr (2)
Bu4NBr (2)
Bu4NBr (2)
[a] Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), Pd catalyst
(5 mol-%), additive (2 equiv.), solvent (1.5 mL), 100 °C, 16 h.
[b] Yield of isolated product. [c] Pd(OAc)2 (10 mol-%). [d] In ambi-
ent air. [e] At 60 °C.
[a] Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol), Pd(OAc)2
(5 mol-%), TBAB (2 equiv.), DMAc (1.5 mL), 100 °C, 16 h.
Having established the optimized reaction conditions
(Table 1, entry 4), we studied the generality of this coupling [b] Yield of the isolated product.
2
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Pd-Catalyzed α-Selective Alkenylation of Imidazo[1,2-a]pyridines
azopyridine containing a thiophenyl substituent at C-2 af-
forded the desired product in 60% yield (see product 3ha).
Sterically hindered ortho-substituted vinylarenes furnished
the desired products in good yields (see products 3bd and
3id). Chloro-substituted vinylarenes also underwent vinyl-
ation efficiently (see products 3ac and 3bc). Notably, 1-oct-
ene produced the corresponding vinylated imidazopyridine
in good yield (see product 3be). Furthermore, 2-isobutyl-
imidazo[1,2-a]pyridine afforded the desired product in 59%
yield (see products 3ja), and 2,3-unsubstituted imidazopyr-
idine selectively produced the C-3 vinylated product ef-
ficiently in good yield (see product 3kb).
Experimental Section
Typical Procedure for the Synthesis of 2-Phenyl-3-(1-phenylvinyl)im-
idazo[1,2-a]pyridine (3aa): A sealed tube was charged with a mix-
ture of 2-phenylimidazo[1,2-a]pyridine (1a; 0.5 mmol, 97 mg) and
styrene (2a; 2.5 mmol, 0.290 μL). Pd(OAc)2 (5 mol-%, 6 mg),
TBAB (2 equiv., 322 mg), and DMAc (1.5 mL) were added under
an atmosphere of O2 (balloon, 101.3 kPa). The resulting mixture
was stirred at 100 °C for 16 h. Upon cooling to room temperature,
the mixture was extracted with ethyl acetate. The organic phase
was dried with anhydrous Na2SO4 and concentrated under reduced
pressure to get the crude residue, which was purified by column
chromatography (silica gel, 60–120 mesh; petroleum ether/ethyl
acetate = 9:1) to afford pure olefinated product 3aa (111 mg, 75%)
as a colorless oil.
On the basis of literature reports,[16] a plausible reaction
mechanism for the Pd-catalyzed aerobic oxidative C–H alk-
enylation of imidazopyridine is shown in Scheme 2. The re-
action is initiated by activation of styrene (2a) by Pd(OAc)2
to form intermediate A. Subsequent intermolecular nucleo-
philic attack by the 3-position of imidazopyridine moiety
1a to intermediate A produces intermediate B. Conse-
quently, β-hydride elimination from intermediate B pro-
duces corresponding branched α-product 3aa and HPdOAc
(C). The resultant palladium hydride (HPdOAc) then un-
dergoes a reductive elimination/oxidation sequence to re-
generate the active PdII catalyst by the aid of molecular
oxygen. Possibly, the ammonium salt stabilizes the catalyti-
cally active Pd species that is formed during the course of
reaction in the form of nanoclusters or nanoparticles.[17]
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, characterization data, and
NMR (1H and 13C) spectra of all compounds.
Acknowledgments
A. H. acknowledges financial support from the Council of Scien-
tific and Industrial Research (CSIR), New Delhi [grant number 02
(0168)/13/EMR-II]. The authors are thankful to the Department
of Science and Technology (DST)-FIST and University Grants
Commission (UGC)-SAP. M. G. thanks UGC and A. N. thanks
CSIR for their fellowships.
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In summary, we developed a PdII-catalyzed convenient
method for the vinylation of imidazo[1,2-a]pyridines. The
reaction proceeds through a cross-dehydrogenative coupling
path with the aid of molecular oxygen as the sole green
oxidant. The excellent regioselectivity of this method fur-
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Eur. J. Org. Chem. 0000, 0–0
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M. Ghosh, A. Naskar, S. Mitra, A. Hajra
SHORT COMMUNICATION
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Pd-Catalyzed α-Selective Alkenylation of Imidazo[1,2-a]pyridines
Cross-Dehydrogenative Coupling
M. Ghosh, A. Naskar, S. Mitra,
A. Hajra* .......................................... 1–5
Palladium-Catalyzed α-Selective Alkenyl-
ation of Imidazo[1,2-a]pyridines through
Aerobic Cross-Dehydrogenative Coupling
Reaction
The palladium-catalyzed highly regioselec-
tive vinylation of imidazopyridines through
a cross-dehydrogenative coupling reaction
is explored. The reaction proceeds with the
aid of molecular oxygen as the sole oxi-
dant. A series of branched α-vinylated
products are obtained with high efficiency.
Keywords: C–C coupling / Dehydrogen-
ation / Alkenylation / Oxygen / Regioselec-
tivity / Nitrogen heterocycles
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