Categories: Synthesis of N-Heterocycles >

Synthesis of imidazoles

Name Reactions

Recent Literature

Starting from 1,2-diketones and urotropine in the presence of ammonium acetate, a simple and efficient solventless microwave-assisted enabled the synthesis of 4,5-disubstituted imidazoles.
G. Bratulescu, Synthesis, 2009, 2319-2320.

A NHC-copper-catalyzed isocyanide insertion into alcohol to form an N-arylformimidate intermediate and subsequent base-promoted cycloaddition with benzyl isocyanide derivatives enables a straightforward and high-yielding synthesis of 1,4-diaryl-1H-imidazoles.
B. Pooi, J. Lee, K. Choi, H. Hirao, S. H. Hong, J. Org. Chem., 2014, 79, 9231-9545.

Mild and efficient protocols provide 1,4,5-trisubstituted and 1,4-/4,5-disubstituted imidazoles regioselectively in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ from virtually any aldehyde and amine. Mono- and disubstituted oxazoles can also prepared.
J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan, A. Allen, M. A. Olsen, J. Org. Chem., 2000, 65, 1516-1524.

A ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes provides 2,4(5)-disubstituted imidazoles in good yields. A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling.
I. de Toledo, T. A. Grigolo, J. M. Bennett, J. M. Elkins, R. A. Pilli, J. Org. Chem., 2019, 84, 14187-14201.

A ZnCl₂-catalyzed [3 + 2] cycloaddition reaction of benzimidates and 2H-azirines provides multisubstituted imidazoles in good yields under mild reaction conditions. This transformation exhibits high functional group tolerance.
S. Shi, K. Xu, C. Jiang, Z. Ding, J. Org. Chem., 2018, 83, 14791-14796.

A simple and efficient approach allows the preparation of biologically active 2,4(5)-diarylimidazoles by parallel synthesis. The formation of 2-aroyl-4(5)-arylimidazoles as side products strongly depends on the reaction conditions employed.
V. Zuliani, G. Cocconcelli, M. Fantini, C. Ghiron, M. Rivara, J. Org. Chem., 2007, 72, 4551-4553.

A one-pot, four-component synthesis of 1,2,4-trisubstituted 1H-imidazoles was achieved in very good yields by heating a mixture of a 2-bromoacetophenone, an aldehyde, a primary amine, and ammonium acetate under solvent-free conditions.
M. Adib, S. Ansari, S. Feizi, J. A. Damavandi, P. Mirzaei, Synlett, 2009, 3263-3266.

Benzoic acid catalyzes an efficient multicomponent reaction of readily available vinyl azides, aromatic aldehydes, and aromatic amines to provide 1,2,5-trisubstituted imidazoles under metal-free conditions without generating any toxic waste. This convenient approach offers high functional group compatibility.
J. Li, X. Jia, J. Qiu, M. Wang, J. Chen, M. Jing, Y. Xu, X. Zheng, H. Dai, J. Org. Chem., 2022, 87, 13945-13954.

A regioselective 1,3-dipolar cycloaddition of 2H-azirines with nitrones provides 1,2,4,5-tetrasubstituted imidazoles in the presence of trifluoroacetic acid as catalyst. The mild protocol tolerates a broad range of aliphatic and aromatic substrates, and offers an efficient access to highly diverse, multisubstituted imidazoles in very good isolated yields.
A. Angyal, A. Demjén, J. Wölfling, L. G. Puskás, I. Kanizsai, J. Org. Chem., 2020, 85, 3587-3595.

An efficient electrochemical oxidative tandem cyclization of aryl ketones and benzylamines provides 1,2,4-trisubstituted-(1H)-imidazoles in very good yields under metal- and oxidant-free conditions. This direct C-N bond formation strategy offers a broad functional group tolerance.
Z. Yang, J. Zhang, L. Hu, A. Li, L. Li, K. Liu, T. Yang, C. Zhou, J. Org. Chem., 2020, 85, 5815-5824.

An improved and rapid one-pot synthesis of 2,4,5-triaryl imidazoles in a room temperature ionic liquid does not need any added catalyst. This one-pot methodology offers excellent isolated yields, simple work up procedures and efficient recovery and recycling of the ionic liquid.
S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel, R. J. Lahoti, K. V. Srinivasan, Tetrahedron, 2005, 61, 3539-3546.

A Schiff’s base complex nickel catalyst (Ni-C) enables a highly efficient one-pot microwave-assisted synthesis of 2,4,5-trisubstituted imidazoles in excellent yields from aldehydes, benzil, and ammonium acetate. The catalyst could be easily recovered by simple filtration and reused.
T. S. Chundawat, N. Sharma, P. Kumari, S. Bhagat, Synlett, 2016, 27, 404-408.

The low-melting mixture urea-ZnCl₂ as reaction medium efficiently catalyzes the reaction of a dicarbonyl compound, ammonium acetate, and an aromatic aldehyde to provide a broad range of triaryl-1H-imidazoles or 2-aryl-1H-phenanthro[9,10-d]imidazoles in very good yields. In addition, the eutectic solvent can be reused five times without loss of catalytic activity.
N. L. Higuera, D. Peña-Solórzano, C. Ochoa-Puentes, Synlett, 2019, 30, 225-229.

A copper-catalyzed, practical, and straightforward one-pot synthesis of multisubstituted imidazoles in good yields from arylacetic acids, N-arylbenzamidines, and nitroalkanes involves simultaneous activation of C–H and N–H bonds. The use of inexpensive copper sulfate as a catalyst and readily available starting materials makes this protocol economically viable.
S. D. Pardeshi, P. A. Sathe, K. S. Vadagaonkar, L. Melone, A. C. Chaskar, Synthesis, 2018, 50, 361-370.

A simple route via a copper-catalyzed [3 + 2] cycloaddition reaction provides multisubstituted imidazoles in good yields and high regioselectivity using oxygen as an oxidant without the addition of expensive catalysts.
D. Tang, P. Wu, X. Liu, Y.-X. Chen, S.-B. Guo, W.-L. Chen, J.-G. Li, B.-H. Chen, J. Org. Chem., 2013, 78, 2746-2750.

A rhodium(II)-catalyzed reaction of stable and readily available 1-sulfonyl triazoles with nitriles gives the corresponding imidazoles in good to excellent yields via rhodium iminocarbenoids intermediates.
T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan, V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972-14974.

An efficient copper-catalyzed regioselective diamination of terminal alkynes with amidines in the presence of Na₂CO₃, pyridine, a catalytic amount of CuCl₂·2H₂O, and oxygen (1 atm), allows the synthesis of diverse 1,2,4-trisubstituted imidazoles in good yields.
J. Li, L. Neuville, Org. Lett., 2013, 15, 1752-1755.

The copper-catalyzed reaction between two different isocyanides produces imidazoles in good yields. The mechanism is discussed.
C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662-10663.

Pummerer-like rearrangement induced cascade reactions including two carbon-nitrogen bond formations, and concomitant aromatization provide highly substituted imidazoles under mild reaction conditions. The reaction tolerates numerous functional groups and can be used for modifying natural products as well as pharmaceuticals.
R. Li, F. Zhou, X. Huang, J. Zhao, H. Zhang, J. Org. Chem., 2023, 88, 739-744.

The use of a copper catalyst allows the construction of aryl imidazolium salts in good yields from N-substituted imidazoles and diaryliodonium salts. The reaction tolerates a broad range of functional groups and provides a straightforward, efficient, and versatile route to unsymmetric aryl imidazolium as well as triazolium salts.
T. Lv, Z. Wang, J. You, J. Lan, G. Gao, J. Org. Chem., 2013, 78, 5723-5730.

A practical three-component domino reaction of α-nitroepoxides and cyanamide with a series of amines enables the synthesis of functionalized 2-aminoimidazole derivatives under mild conditions without any additives.
X. Guo, W. Chen, B. Chen, W. Huang, W. Qi, G. Zhang, Y. Yu, Org. Lett., 2015, 17, 1157-1159.

Reactions of propargylamines with carbodiimides, in the presence of 5 mol% of the titanacarborane monoamide [σ:η¹:η⁵-(OCH₂)(Me₂NCH₂)C₂B₉H₉]Ti(NMe₂), afford a new class of substituted 2-aminoimidazoles via [3+2] annulation in good to excellent yields. A possible reaction mechanism is proposed.
Y. Wang, H. Shen, Z. Xie, Synlett, 2011, 969-973.

A sequential Staudinger/aza-Wittig/Ag(I)-catalyzed cyclization/isomerization reaction of easily accessible propargylazide derivatives with triphenylphosphine, isocyanates, and amines provided fully substituted imidazoles in good overall yields.
J. Xiong, X. Wei, Z.-M. Liu, M.-W. Ding, J. Org. Chem., 2017, 82, 13735-13739.

KI mediates a noble-metal-free oxidative cyclization of enamines with tBuONO as an aminating reagent and oxidant. This formal [4 + 1] cycloamination reaction provides imidazole-4-carboxylic derivatives with wide substrate scope and good functional tolerance.
Y. Li, J. Qiu, P. Gao, L. Zhai, Z.-J. Bai, H.-J. Chen, J. Org. Chem., 2022, 87, 15380-15388.

A highly efficient and convenient method for the synthesis of 1,2,4,5-tetrasubstituted imidazoles from readily accessible 2-azido acrylates and nitrones proceeded under mild conditions without the assistance of any metal, acid, or base.
B. Hu, Z. Wang, N. Ai, J. Zheng, X.-H. Liu, S. Shan, Z. Wang, Org. Lett., 2011, 13, 6362-6365.

An iodine-mediated oxidative [4+1] cyclization of enamines with TMSN₃ provides 2,5-disubstituted imidazole-4-carboxylic derivatives. Mechanistic studies revealed that the reaction proceeds through a sequential removal of two nitrogen atoms from TMSN₃. The synthetic utility was demonstrated with a gram-scale reaction and various derivatization transformations of the products.
P. Gao, H. Chen, Z.-J. Bai, S. Zhang, M.-N. Zhao, D. Yang, Y. Li, J. Zhang, X. Wang, J. Org. Chem., 2021, 86, 10492-10500.

A copper-catalyzed three-component reaction of α,β-unsaturated ketoximes, paraformaldehyde, and amines provides imidazoles and dihydroimidazoles depending on the reaction conditions in good yields with a broad substrate scope.
G. Xu, C. Jia, X. Wang, H. Yan, S. Zhang, Q. Wu, N. Zhu, J. Duan, K. Guo, Org. Lett., 2022, 24, 1060-1065.

N-Alkyl enamines can be transformed into highly subsituted imidazoles in the presence of (diacetoxyiodo)benzene and TMSN₃ under catalysis of a copper salt such as Cu(OAc)₂ via a domino azidation/intramolecular C(sp³)-H amination. The present reaction provides an efficient method for the preparation of 4-(trifluoromethyl) imidazoles.
H. Ma, X. Zhang, L. Chen, W. Yu, J. Org. Chem., 2017, 82, 11841-11847.

A visible-light-mediated metal-free organic-dye-catalyzed dehydrogenative N-insertion provides highly substituted imidazoles and privileged dihydroisoquinoline-based imidazole derivatives. This sustainable, convenient, metal-free azidation/C-H aminative cyclization approach works without oxidants via a photoinduced iminyl radical as key intermediate for the nitrogen insertion.
S. M. Patel, E. Prasad P., M. Bakthadoss, D. S. Sharada, Org. Lett., 2021, 23, 257-261.

The combination of flavin and iodine catalyzes a facile and atom-economical oxidative cross-dehydrogenative coupling between amidines and chalcones to provide tetra-substituted imidazoles in good yields. The riboflavin-iodine catalytic system played multiple roles in substrate- and O₂-activation generating benign H₂O as the only byproduct.
A. Takeda, H. Okai, K. Watabe, H. Iida, J. Org. Chem., 2022, 87, 10372-10376.

A convenient and efficient FeCl₃/I₂-catalyzed aerobic oxidative coupling of amidines and chalcones provides tetrasubstituted imidazoles in high regioselectivity and yields. The reaction offers good functional group tolerance, and mild reaction conditions.
Y. Zhu, C. Li, J. Zhang, M. She, W. Sun, K. Wan, Y. Wang, B. Yin, P. Liu, J. Li, Org. Lett., 2015, 17, 3872-3875.

A multicomponent protocol enables the synthesis of highly substituted imidazole derivatives in excellent yield from various α-azido chalcones, aryl aldehydes, and anilines in the presence of erbium triflate as a catalyst.
K. Rajaguru, R. Suresh, A. Mariappan, S. Muthusubramanian, N. Bhuvanesh, Org. Lett., 2014, 16, 744-747.

A gold-catalyzed selective [3 + 2] annulation of 1,2,4-oxadiazoles with ynamides enables an atom-economical synthesis of fully substituted 4-aminoimidazoles. The reaction proceeds with 100% atom economy, exhibits good functional group tolerance, and can be conducted in gram scale.
Z. Zeng, H. Jin, J. Xie, B. Tian, M. Rudolph, F. Rominger, A. S. K. Hashmi, Org. Lett., 2017, 19, 1020-1023.

A gold-catalyzed formal [3 + 2] cycloaddition of ynamides with 4,5-dihydro-1,2,4-oxadiazoles provides a concise and regioselective access to highly functionalized 4-aminoimidazoles likely via the formation of an α-imino gold carbene intermediate followed by cyclization.
W. Xu, G. Wang, N. Sun, Y. Liu, Org. Lett., 2017, 19, 3307-3310.

A Rh(II)-catalyzed transannulation of 1,2,4-oxadiazoles and 1,2,4-oxadiazol-5-ones with N-sulfonyl-1,2,3-triazoles provides fully substituted 5-sulfonamidoimidazoles. Both reactions are completely regioselective.
J. O. Strelnikova, N. V. Rostovskii, G. L. Starova, A. F. Khlebnikov, M. S. Novikov, J. Org. Chem., 2018, 83, 11232-11244.

A step-economical access to polysubstituted aminoimidazoles via alkene vicinal C-N bonds formation of 2-bromo-2-alkenones with guanidine avoids a NH-protection/derivatization strategy. The reaction involves a tandem pathway of aza-Michael addition, S_N2, and a unique redox-neutral process and offers an excellent substrate scope.
S. K. Guchhait, N. Hura, A. P. Shah, J. Org. Chem., 2017, 82, 2745-2752.

In a gold-catalyzed synthesis of bicyclic imidazoles, a highly electrophilic α-imino gold carbene intermediate can react with a weakly nucleophilic nitrile, which is used as the reaction solvent, to deliver the desired product rapidly in an overall bimolecular [2 + 2 + 1] cycloaddition and in good yield. The competing intramolecular azide-alkyne click reaction, although likely also catalyzed by gold, is minimized by using AuCl₃ as the catalyst.
Y. Xiao, L. Zhang, Org. Lett., 2012, 14, 4662-4665.

2-Imidazolines were easily prepared in good yields from the reaction of aldehydes and ethylenediamine with iodine in the presence of potassium carbonate. The 2-imidazolines were smoothly oxidized to the corresponding imidazoles in good yields using (diacetoxyiodo)benzene at room temperature.
M. Ishihara, H. Togo, Synlett, 2006, 227-230.

A number of new reactions of IBX with heteroatom-containing substrates were discovered and their utility was demonstrated. IBX was used for the generation of imines from secondary amines in notably high yields, for the oxidative aromatization of nitrogen heterocycles and for the cleavage of dithianes.
K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem. Int. Ed., 2003, 42, 4077-4082.

A versatile and modular one-pot method allows the preparation of differently substituted symmetrical and unsymmetrical imidazolium salts from readily available formamidines and α-halo ketones. For many substitution patterns of the imidazolium salt products, this efficient strategy compares favorably with well-known processes in terms of yield, ease of synthesis, and robustness.
K. Hirano, S. Urban, C. Wang, F. Glorius, Org. Lett., 2009, 11, 1019-1022.

An efficient copper(I) bromide catalyzed N-arylation of azoles with a variety of aromatic bromides and iodides under mild conditions displayed great functional group compatibility and excellent reactive selectivity.
H. Chen, D. Wang, X. Wang, W. Huang, Q. Cai, K. Ding, Synthesis, 2010, 1505-1511.

A copper-catalyzed N-arylation reaction of imidazole proceeds under very mild conditions in the absence of additional ligand. This protocol tolerates an array of thermally sensitive functional groups, but also achieves high chemoselectivity.
L. Zhu, G. Li, L. Luo, P. Guo, J. Lan, J. You, J. Org. Chem., 2009, 74, 2200-2202.

N-Arylation of azoles and amines with arylboronic acids was efficiently carried out with heterogeneous copper(I) oxide in methanol at room temperature under base-free conditions. Various arylboronic acids and amines were converted to the corresponding N-arylazoles and N-arylamines in very good yields, demonstrating the versatility of the reaction.
B. Sreedhar, G. T. Venkanna, K. B. S. Kumar, V. Balasubrahmanyam, Synthesis, 2008, 795-799.

[Cu(OH)·TMEDA]₂Cl₂ catalyzes an intermolecular coupling of arylboronic acids with imidazoles in dichloromethane at room temperature to provide a variety of N-arylimidazoles in very good yields.
J. P. Collman, M. Zhong, Org. Lett., 2000, 2, 1233-1236.

A simple and efficient method enables the synthesis of N-alkynylheteroarenes from 1,1-dibromo-1-alkenes via a copper-catalyzed cross-coupling reaction. Good yields and functional-group tolerance were obtained with TMEDA as ligand using imidazole and benzimidazole substrates in dioxane.
M.-G. Wang, J. Wu, Z.-C. Shang, Synlett, 2012, 23, 589-594.

A series of N,N′-asymmetrically substituted imidazolium iodides have been synthesized, starting from N-arylimidazoles and the less expensive, but less reactive, 1-chlorobutane or (3-chloropropyl)trimethoxysilane. The addition of potassium iodide and the use of 1,2-dimethoxyethane as a solvent allowed the synthesis of multigram quantities of these salts.
A. M. Oertel, V. Ritleng, M. J. Chetcuti, Synthesis, 2009, 1647-1650.

N-Methylimidazole is a promising catalyst for aza-Michael reactions. Various N-heterocycles were introduced to α,β-unsaturated carbonyl compounds employing N-methylimidazole in a highly efficient, rapid and high yielding synthesis of N-heterocyclic derivatives.
B. K. Liu, Q. Wu, X. Q. Qian, D. S. Lv, X. F. Lin, Synthesis, 2007, 2653-2659.

2-Lithioimidazole was prepared using lithium metal in the presence of a catalytic amount of isoprene in THF at room temperature. By reacting this organolithium compound with carbonyl electrophiles 2-(hydroxyalkyl)imidazoles and 2-(aminoalkyl)imidazoles were obtained in good yields.
R. Torregrosa, I. M. Pastor, M. Yus, Tetrahedron, 2005, 61, 11148-11155.