Categories: Synthesis of N-Heterocycles > benzo-fused N-Heterocycles >
Synthesis of imidazo[1,2-a]pyridines
Recent Literature
A CuI-catalyzed aerobic oxidative synthesis of imidazo[1,2-a]pyridines
from 2-aminopyridines and acetophenones is compatible with a broad range of
functional groups. The reaction also enables the formation of
alkenyl-substituted imidazoheterocycles by using unsaturated ketones as
substrates. Preliminary mechanistic studies indicate that this reaction proceeds
through a catalytic Ortoleva-King reaction.
Y. Zhang, Z. Chen, W. Wu, Y. Zhang, W. Su, J. Org. Chem., 2013,
78, 12494-12504.
The combination of flavin and iodine catalyzes an aerobic oxidative C-N
bond-forming process for the facile synthesis of imidazo[1,2-a]pyridines.
This dual catalytic system can also be applied to the one-pot, three-step
synthesis of 3-thioimidazo[1,2-a]pyridines from aminopyridines, ketones,
and thiols.
H. Okai, K. Tanimoto, R. Ohkado, H. Iida,
Org. Lett., 2020, 22, 8002-8006.
A coupling of 2-aminopyridine with phenylacetophenones, phenylacetones, or
β-tetralone in the presence of CBrCl3 provides disubstituted
3-phenylimidazo[1,2-a]pyridine in very good isolated yields at 80°C
within 5 h. The 2-aminopyridine acts as an α-bromination shuttle by transferring
Br from CBrCl3 to the α-carbon of the carbonyl moiety.
I. I. Roslan, K.-H. Ng, J.-E. Wu, G.-K. Chuah, S. Jaenicke, J. Org. Chem.,
2016, 81, 9167-9174.
A copper(I)-catalyzed aerobic oxidative coupling of ketoxime acetates with
simple pyridines for the synthesis of imidazo[1,2-a]pyridines tolerates a
wide range of functional groups and affords a series of valuable imidazo[1,2-a]pyridines
in high yields under mild conditions.
Z.-H. Ren, M.-N. Zhao, Y. Yi, Y.-Y. Wang, Z.-H. Guan,
Synthesis, 2016, 48, 1920-1926.
A simple and efficient protocol enables the synthesis of 3-arylimidazo[1,2-a]pyridines
by a catalyst-free cascade process from 2-aminopyridine and
1-bromo-2-phenylacetylene or 1,1-dibromo-2-phenylethene in yields up to 86%.
Z. Wu, Y. Pan, X. Zhou, Synthesis, 2011,
2255-2260.
The reaction between 2-chloropyridines and 2H-azirines provides
imidazo[1,2-a]pyridines, an heterocyclic moiety commonly found in
medicinal chemistry leads and drugs. Thorough optimization of the activation/cyclization
resulted in good yields for a variety of substituted heterocycles.
F. Vuillermet, J. Bourret, G. Pelletier, J. Org. Chem., 2021, 86,
388-402.
A rapid, copper-catalyzed aerobic dehydrogenative cyclization of pyridines with
ketone oxime esters enables an environmentally friendly synthesis of
imidazo[1,2-a]pyridines.
H. Huang, X. Ji, X. Tang, M. Zhang, X. Li, H. Jiang, Org. Lett., 2013,
15, 6218-6221.
Microwave irradiation enables an expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed,
three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines.
This methodology offers high availability of commercial reagents and great
efficiency in expanding molecule diversity.
Y. Wang, B. Frett, H.-y. Li, Org. Lett., 2014,
16, 3016-3019.
The switchable roles of allylic alcohol and molecular iodine as reagents and
catalysts enable regioselective allylic alkylation and iodination of
imidazoheterocycles. While iodine catalyzes the allylation of a library of
imidazoheterocycles and other electron-rich heterocycles, a mixture of allylic
alcohol and I2 is also beneficial for the iodination of
imidazoheterocycles at room temperature.
S. Paul, T. Choudhuri, S. Das, R. Pratap, A. K. Bagdi, J. Org. Chem., 2024, 89,
1492-1504.
An iron-catalyzed denitration reaction enables the synthesis of
3-methyl-2-arylimidazo[1,2-a]pyridine derivatives in good yields from
aminopyridines and 2-methyl-nitroolefins. The procedure is simple and
inexpensive and tolerates various functional groups.
H. Yan, S. Yang, X. Gao, K. Zhou, C. Ma, R. Yan, G. Huang, Synlett, 2012, 23,
2961-2962.
An aqueous synthesis gives methylimidazo[1,2-a]pyridines,
imidazo[1,2-a]pyrazines, and imidazo[2,1-a]isoquinolines without
any deliberate addition of catalyst. Using acetonitrile as solvent, Ag-catalyzed
intramolecular aminooxygenation produced imidazo[1,2-a]pyridine-3-carbaldehydes
in good yields.
D. C. Mohan, S. N. Rao, S. Adimurthy, J. Org. Chem., 2013,
78, 1266-1272.
With a mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO4
with glucose, an efficient and eco-friendly multicomponent cascade reaction of A3-coupling
of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig
cycloisomerization, and prototropic shift has afforded therapeutically important
versatile N-fused imidazoles.
S. K. Guchhait, A. L. Chandgude, G. Priyadarshani, J. Org. Chem., 2012,
77, 4438-4444.
A one-pot reaction of aldehydes, 2-aminopyridines, and terminal alkynes, in
the presence of the copper(I) iodide-CuI-NaHSO4•SiO2 combination catalyst in
refluxing toluene, generates the corresponding imidazo[1,2-a]pyridines in high to excellent yields.
S. Mishra, R. Ghosh, Synthesis, 2011,
3463-3470.
N-Phenacylpyridinium bromides, which were prepared in situ from the
addition of pyridines to α-bromoketones, undergo nucleophilic addition of
ammonium acetate under microwave irradiation and solvent-free conditions to
afford the corresponding imidazo[1,2-a]pyridines in excellent yields.
M. Adib, A. Mohamadi, E. Sheikhi, S. Ansari, H. R. Bijanzadeh, Synlett, 2010,
1606-1608.
A facile formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and
alcohols or thiols enables a transition-metal-free three-component reaction for
the construction of imidazo[1,2-a]pyridines.
H. Cao, X. Liu, L. Zhao, J. Cen, J. Lin, Q. Zhu, M. Fu, Org. Lett., 2014,
16, 146-149.
Copper(I)- and palladium(II)-catalyzed cyclizations enable a convenient
synthesis of functionalized imidazo[1,2-a]pyridine aldehydes/ketones and
3-vinyl imidazo[1,2-a]pyridines. These one-pot reactions proceed smoothly
with commercially available catalysts and afford the products in good yields.
H. Cao, X. Liu, J. Liaou, J. Huang, H. Qiu, Q. Chen, Y. Chen, J. Org. Chem.,
2014,
79, 11209-11214.
A carbon tetrabromide mediated oxidative carbon-nitrogen bond formation of
2-aminopyridines or 2-aminopyrimidines with β-keto esters or 1,3-diones provides
substituted imidazo[1,2-α]pyridines or imidazo[1,2-α]pyrimidines under mild and
metal-free conditions.
C. Huo, J. Tang, H. Xie, Y. Wang, J. Dong, Org. Lett., 2016, 18,
1016-1019.
A convenient one-pot, three-component reaction of aryl ketones with 2-amino-N-heterocycles
and dimethyl sulfoxide as a methylene donor provides 3-aroylimidazo[1,2-a]-N-heterocycles
in good yields in the presence of K2S2O8 and a
catalytic amount of I2.
Y. Zhang, R. Chen, Z. Wang, L. Wang, Y. Ma, J. Org. Chem., 2021, 86,
6239-6246.
A practical intramolecular C-H functionalization reaction of N-aryl
enamines with molecular iodine as the sole oxidant in the presence of copper
iodide (CuI) provides diverse imidazo[1,2-a]pyridine and indole
derivatives via I2-mediated oxidative C-N and C-C bond formation,
respectively. This reaction also works well with crude enamines.
J. Liu, W. Wei, T. Zhao, X. Liu, J. Wu, W. Yu, J. Chang, J. Org. Chem.,
2016, 81, 9326-9336.
An efficient copper-catalyzed reaction of N-(2-pyridinyl)enaminones
provides multisubstituted imidazo[1,2-a]pyridines.
S. Cacchi, A. Ciogli, N. Demitri, G. Fabrizi, F. Ghirga, A. Goggiamani, A.
Iazetti, D. Lamba, Synthesis, 2018, 50,
3513-3519.
Thermal and microwave-assisted rapid reactions of aminopyridines and
α-bromo-β-keto esters enable the synthesis of highly substituted imidazo[1,2-a]pyridines
under solvent-free conditions. Reactions carried out under microwave irradiation
give the highest yields of products in reaction times of less than two minutes.
K. C. Chunavala, G. Joshi, E. Suresh, S. Adimurthy, Synthesis, 2011,
635-641.
The use of a KH2PO4/K2HPO4 buffer
enabled an electrochemical oxidative regioselective C-H cyanation of
imidazo[1,2-a]pyridines using readily available TMSCN as the cyano source.
This protocol was compatible with a broad range of substituted imidazo[1,2-a]pyridines
and provided the C3 cyanated products in good yields.
T. Cui, Y. Zhang, C. Dai, J. Lin, P. Liu, P. Sun, J. Org. Chem., 2021, 86,
15897-15905.
An ultrasound-promoted three-component reaction provides C3-cyanomethylated
imidazo[1,2-a]pyridines under catalyst-free, oxidant-free, and mild
conditions. A series of C3-cyanomethylated imidazo[1,2-a]pyridines were rapidly
prepared with satisfactory yields and good functional group compatibility.
. Zhang, Y. Zhang, J. Zhang, Q. Wu, H. Yang, Synlett, 2022,
33,
264-268.
Gold-catalyzed formal 1,3-dipolar annulation between readily accessible N-pyridinylsulfilimines
and ynamides provides a diverse set of imidazole derivatives. These
functionalized cyclic products can undergo further transformations to afford
diverse imidazole frameworks.
X. Tian, L. Song, M. Rudolph, Q. Wang, X. Song, F. Rominger, A. S. K. Hashmi, Org. Lett., 2019, 21,
1558-1601.
An efficient microwave-assisted metal-free amino benzannulation of
aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)methanone with dialkylamines
affords various 2,8-diaryl-6-aminoimidazo[1,2-a]pyridines in good yield.
M. Nagaraj, M. Boominathan, S. Muthusubramanian, N. Bhuvanesh, Synlett, 2012, 23,
1353-1357.
Dibenziodolium triflate displays high catalytic activity
for the Groebke-Blackburn-Bienaymé Reaction that leads to a series of imidazopyridines.
This salt can play the role of a hybrid hydrogen- and halogen-bond-donating organocatalyst, which electrophilically activates the carbonyl and imine groups.
M. V. Il'in, A. A. Sysoeva, A. S. Novikov, D. S. Bolotin, J. Org. Chem., 2022, 87,
4569-4579.
A zinc iodide catalyzed reaction of 2-aminopyridines and α-amino carbonyl
compounds in the presence of oxygen affords 3-aminoimidazo[1,2-a]pyridines
in good yields.
X. Han, C. Ma, Z. Wu, G. Huang,
Synthesis, 2016, 48, 351-356.
In a regioselective and high-yielding Groebke-Blackburn-Bienaymé reaction,
glyoxylic acid is used as formaldehyde equivalent leading to a regioselective,
mild, convenient, and effective synthesis of 3-aminoalkyl imidazoazines.
A. Sharma, H.-y. Li, Synlett, 2011, 1407-1412.
3-Aminoimidazo[1,2-a]pyridines are rapidly synthesized via a facile and
mild cyclodehydration mediated by the activation of N-Boc-protected
2-aminopyridine-containing amides by triflic anhydride in the presence of
2-methoxypyridine followed by a clean deprotection-aromatization sequence in the
presence of K2CO3. Various functional groups and
substitution patterns were tolerated under the optimized procedure.
S. Régnier, W. S. Bechara, A. B. Charette, J. Org. Chem.,
2016, 81, 10348-10356.
A copper-catalyzed one-pot
procedure enables the synthesis of imidazo[1,2-a]pyridines
with aminopyridines and nitroolefins using air as oxidant. This general reaction appears to be very suitable for
the construction of various imidazo[1,2-a]pyridines.
R.-L. Yan, H. Yan, C. Ma, Z.-Y. Ren, X.-A. Gao, G.-S. Huang, Y.-M. Liang, J. Org. Chem., 2012,
77, 2024-2028.
An oxidative diamination of nitroalkene with 2-aminopyridine for the synthesis
of 2-nitro-3-arylimidazo[1,2-a]pyridines with complete regioselectivity has been
achieved under mild and aerobic reaction conditions using an iron catalyst.
2-nitroimidazo[1,2-a]pyridines can also be synthesized directly from
styrenes.
K. Monir, A. K. Bagdi, M. Ghosh, A. Hajra, Org. Lett.,
2014,
16, 4630-4633.
Sodium dichloriodide mediates the reaction of 2-aminopyridines and nitrostyrenes
to give various 3-nitro-2-arylimidazo[1,2-a]pyridines in good yields. The
procedure is simple and various functional groups are tolerated in this reaction
system.
P. B. Jagadhane, V. N. Telvekar,
Synlett, 2014, 25, 2636-2638.
The combination of KMnO4/AcOH mediates a C-H
trifluoromethylation at C-3 of imidazopyridines and C-8 of quinoxalines with
readily available Langlois reagent via a radical pathway. This protocol
showed broad substrate scope and afforded good yields of both
products.
M. E. Firuz, S. Raijai-Daryasarei, F. Rominger, A. Biglari, S. Balalaie, J. Org. Chem., 2023, 88,
10599-10608.
Efficient catalyst/metal-free annulations enable the synthesis of several
imidazo[1,2-a]pyridines from readily available vinyl azides and
2-aminopyridines. In this remarkably high yielding and atom economical protocol,
products can be isolated in highly pure form by simply evaporating the reaction
solvent.
P. R. Adiyala, G. S. Mani, J. B. Nanubolu, K. C. Shekar, R. A. Maurya, Org. Lett.,
2015,
17, 4308-4311.