Categories: Synthesis of N-Heterocycles > benzo-fused N-Heterocycles >
Synthesis of imidazo[1,2-a]pyridines
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.
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.
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.