Organic Chemistry Portal
Reactions > Organic Synthesis Search
Categories: Synthesis of N-Heterocycles >
Synthesis of imidazoles
Van Leusen Imidazole Synthesis
Van Leusen Three-Component Reaction
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.
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.
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.
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.
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.
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.
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 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 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.
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 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, SN2, 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.
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.
1-Methylimidazole or N-methylimidazole is an aromaticheterocyclic organic compound with the formula CH3C3H3N2. It is a colourless liquid that is used as a specialty solvent, a base, and as a precursor to some ionic liquids. It is a fundamental nitrogen heterocycle and as such mimics for various nucleoside bases as well as histidine and histamine,
With the N-methyl group, this particular derivative of imidazole cannot tautomerize. It is slightly more basic than imidazole, as indicated by the pKa's of the conjugate acids of 7.0 and 7.4. Methylation also provides a significantly lower melting point, which makes 1-methylimidazole a useful solvent.
1-Methylimidazole is prepared mainly by two routes industrially. The main one is acid-catalysed methylation of imidazole by methanol. The second method involves the Radziszewski reaction from glyoxal, formaldehyde, and a mixture of ammonia and methylamine.
- (CHO)2 + CH2O + CH3NH2 + NH3 → H2C2N(NCH3)CH + 3 H2O
The compound can be synthesized on a laboratory scale by methylation of imidazole at the pyridine-like nitrogen and subsequent deprotonation. Similarly, 1-methylimidazole may be synthesized by first deprotonating imidazole to form a sodium salt followed by methylation.
- H2C2N(NH)CH + CH3I → [H2C2(NH)(NCH3)CH]I
- H2C2(NH)(NCH3)CH + NaOH → H2C2N(NCH3)CH + H2O + NaI
In the research laboratory, 1-methylimidazole and related derivatives have been used as mimic aspects of diverse imidazole-based biomolecules.
1-Methylimidazole is also the precursor for the synthesis of the methylimidazole monomer of pyrrole-imidazole polyamides. These polymers can selectively bind specific sequences of double-stranded DNA by intercalating in a sequence dependent manner.
Ionic liquid precursor
1-Methylimidazole alkylates to form dialkyl imidazolium salts. Depending on the alkylating agent and the counteranion, various ionic liquids result, e.g. 1-butyl-3-methylimidazolium hexafluorophosphate ("BMIMPF6"):
BASF has used 1-methylimidazole as a means to remove acid during their industrial-scale production of diethoxyphenylphosphine. In this biphasic acid scavenging using ionic liquids (BASIL) process, 1-methylimidazole reacts with HCl to produce 1-methylimidazolium hydrochloride, which spontaneously separates as a separate liquid phase under the reaction conditions.
- 2 MeC3N2H3 + C6H5PCl2 + 2 C2H5OH → 2 [MeC3N2H4]Cl + C6H5P(OC2H5)2
- ^Albert, A., Heterocyclic Chemistry, 2nd ed.; 1968 Athlone Press, ISBN 0-485-11092-X
- ^Ebel, K., Koehler, H., Gamer, A. O., & Jäckh, R. "Imidazole and Derivatives." In Ullmann’s Encyclopedia of Industrial Chemistry; 2002 Wiley-VCH, doi:10.1002/14356007.a13_661
- ^Bronislaw Radziszewski (1882). "Ueber die Constitution des Lophins und verwandter Verbindungen" [By the Constitution of the Lophins and related compounds]. Berichte der deutschen chemischen Gesellschaft (in German). 15 (2): 1493–1496. doi:10.1002/cber.18820150207.
- ^Gilchrist, T. L., Heterocyclic Chemistry, 2nd ed.; 1992 Longman Scientific & Technical, ISBN 0-582-06420-1
- ^Grimmett, M. R., Imidazole and Benzimidazole Synthesis; 1997 Academic Press, ISBN 0-12-303190-7
- ^Gupta, R. R., Kumar, M., Gupta, V., Heterocyclic Chemistry II: Five Membered Heterocycles; 1999 Springer, ISBN 3-540-65252-3
- ^Baird, Eldon E.; Dervan, Peter B. (1996). "Solid Phase Synthesis of Polyamides Containing Imidazole and Pyrrole Amino Acids". Journal of the American Chemical Society. 118 (26): 6141–6. doi:10.1021/ja960720z.
- ^ abMeindersma, G. Wytze; Maase, Matthias; De Haan, André B. (2007). "Ionic Liquids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.l14_l01. ISBN 978-3-527-30673-2.
- ^Dupont, J.; Consorti, C.; Suarez, P.; de Souza, R. (2004). "Preparation of 1-Butyl-3-methyl imidazolium-based Room Temperature Ionic Liquids". Organic Syntheses. ; Collective Volume, 10, p. 184
- ^Welton, Tom (11 November 2015). "Solvents and sustainable chemistry". Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences. 471 (2183): 20150502. doi:10.1098/rspa.2015.0502.