Categories: Synthesis of N-Heterocycles >
Synthesis of imidazoles and benzimidazoles
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 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 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.
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 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.
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.
A well-defined NHC-Pd(II)-Im complex enables a facile and alternative methodology for the direct C-H bond arylation of (benz)imidazoles with (hetero)aryl chlorides. Various activated, unactivated, and deactivated (hetero)aryl chlorides were used as arylating reagents to yield 2-(hetero)aryl (benz)imidazoles in good yields.
Z.-S. Gu, W.-X. Chen, L-X. Shao, J. Org. Chem., 2014, 79, 5806-5811.
A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles employs formic acid, iron powder, and NH4Cl as additive to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functional groups demonstrates the general utility of this procedure.
E. J. Hanan, B. K. Chan, A. A. Estrada, D. G. Shore, J. P. Lyssikatos, Synlett, 2010, 2759-2764.
The use of elemental sulfur as traceless oxidizing agent enables a remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines.
T. B. Nguyen, L. Ermolenko, W. A. Dean, A. Al-Mourabit, Org. Lett., 2012, 14, 5948-5951.
A broad range of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines via benzylamine oxidation, nitro reduction, condensation, and aromatization without any reducing or oxidizing agent. The method can be extended to afford various other diazaheterocycles.
T. B. Nguyen, J. Le Bescont, L. Ermolenko, A. Al-Mourabit, Org. Lett., 2013, 15, 6218-6221.
Brønsted acid catalyzed cyclization reactions of 2-amino thiophenols and anilines with β-diketones under oxidant- and metal-free conditions give 2-substituted benzothiazoles and benzimidazoles in good yields, respectively. Various groups such as methyl, chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.
M. S. Mayo, X. Yu, X. Zhou, X. Feng, Y. Yamamoto, M. Bao, Org. Lett., 2014, 16, 764-767.
The reaction of ortho-substituted anilines with functionalized orthoesters yields benzoxazole, benzothiazole, and benzimidazole derivatives in an efficient and connective methodology. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.
G. Bastug, C. Eviolitte, I. E. Markó, Org. Lett., 2012, 14, 3502-3505.
The preparation of benzimidazoles and imidazopyridines proceeds smoothly under mild conditions in isopropyl alcohol at 70°C using 2,2,2-trichloroethyl imidates as the acylating agents. Addition of sodium acetate proved to be beneficial In cases where cyclization proceeded slowly. For substrates with poor nucleophilicity, using the more inert tert-amyl alcohol enabled superior reactions.
S. Caron, B. P. Jones, L. Wei, Synthesis, 2012, 44, 3049-3054.
A convenient method for the synthesis of 2-substituted benzimidazoles and benzothizoles offers short reaction times, large-scale synthesis, easy and quick isolation of the products, excellent chemoselectivity, and excellent yields as main advantages.
K. Bahrami, M. M. Khodaei, F. Naali, J. Org. Chem., 2008, 73, 6835-6837.
A copper-catalyzed, one-pot, three-component reaction of 2-haloanilines, aldehydes, and NaN3 enabled the synthesis of benzimidazoles in good yields using catalytic amounds of CuCl and TMEDA in DMSO at 120°C for 12 h. The reaction tolarated many functional groups such as ester, nitro, and chloro.
Y. Kim, M. R. Kumar, N. Park, Y. Heo, S. Lee, J. Org. Chem., 2011, 76, 9577-9583.
Intramolecular N-arylations of amidines mediated by potassium hydroxide in DMSO at 120°C enable the preparation of diversely substituted benzimidazoles in good yields.
H. Baars, A. Beyer, S. V. Kohlhepp, C. Bolm, Org. Lett., 2014, 16, 536-539.
The use iodobenzene as a catalyst enables the synthesis of 1,2-disubstituted benzimidazoles by oxidative C-H amination of N″-aryl-N′-tosyl/N′-methylsulfonylamidines and N,N′-bis(aryl)amidines in the presence of mCPBA as terminal oxidant at room temperature. The reaction is general, and the target products can be obtained in good yields.
S. K. Alla, R. K. Kumar, P. Sadhu, T. Punniyamurthy, Org. Lett., 2013, 15, 1334-1337.
A fast and simple reaction of amidines gave benzimidazoles via iodine(III)-promoted oxidative C(sp3)-C(sp2) bond formation in nonpolar solvents, whereas the use of polar solvents favoured a C(sp2)-N bond formation to yield quinazolines. Further selective synthesis of quinazolines in polar solvent was realized using TEMPO as catalyst and K2S2O8 as the oxidant. No metal, base, or other additives were needed.
J.-P. Lin, F.-H. Zhang, Y.-Q. Long, Org. Lett., 2014, 16, 2822-2825.
CuI/l-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2-iodophenylcarbamates affords aryl amination products at room temperature, which undergo in situ additive cyclization under acidic conditions or heating to give substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones, respectively.
X. Diao, Y. Wang, Y. Jiang, D. Ma, J. Org. Chem., 2009, 74, 7974-7977.
An experimentally simple, general, efficient, and ligand-free synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles via intramolecular cyclization of o-bromoaryl derivatives is catalyzed by copper(II) oxide nanoparticles in DMSO under air. The heterogeneous catalyst can be recovered and recycled without loss of activity.
P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719-8725.
An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization at moderate temperature.
M. M. Guru, M. A. Ali, T. Punniyamurthy, J. Org. Chem., 2011, 76, 5295-5308.
A set of benzimidazoles, 3H-imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles was readily prepared from (hetero)aromatic ortho-diamines or ortho-aminothiophenol and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor agent, followed by oxidation with air oxygen.
S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, A. A. Tolmachev, Synthesis, 2006, 3715-3726.
A Pd-catalyzed amide coupling reaction enables a facile synthesis of imidazo[4,5-b]pyridines and -pyrazines. This reaction provides quick access to various substituted products. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP.
A. J. Rosenberg, J. Zhao, D. A. Clark, Org. Lett., 2012, 14, 1761-1767.
A highly efficient and versatile method for the synthesis of a series of 2-substituted N-H, N-alkyl, and N-aryl benzimidazoles containing a wide range of functional groups was achieved in one step via the Na2S2O4 reduction of o-nitroanilines in the presence of aldehydes.
D. Yang, D. Fokas, J. Li, L. Yu, C. M. Baldino, Synthesis, 2005, 47-56.
A simple and efficient procedure for the synthesis of substituted benzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes in the presence of H2O2 and HCl in acetonitrile at room temperature features short reaction time, easy and quick isolation of the products, and excellent yields.
K. Bahrami, M. M. Khodaei, I. Kavianinia, Synthesis, 2007, 417-427.
Various 2-arylbenzimidazoles were synthesized from phenylenediamines and aldehydes via a one-step process using hypervalent iodine as oxidant. This method features mild conditions, short reaction times, high yields, and a simple procedure.
L-H. Du, Y.-G. Wang, Synthesis, 2007, 675-678.
Addition of oxone to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF results in rapid formation of benzimidazoles under very mild conditions. Products are isolated in high purity in most cases by simple aqueous precipitation. The reaction is applicable to a wide range of substrates but does not allow the conversion of aldehydes that are sensitive to oxone under acidic reaction conditions.
P. L. Beaulieu, B. Haché, E. von Moos, Synthesis, 2003, 1683-1692.
A mild and efficient one-pot synthesis enables the preparation of 2-substituted benzimidazoles from 1,2-phenylenediamines and triacyloxyborane intermediates generated in situ from carboxylic acids and borane-THF. This protocol tolerates acid-labile functional groups.
W. Cui, R. B. Kargbo, Z. Sajjadi-Hashemi, F. Ahmed, J. F. Gauuan, Synlett, 2012, 23, 247-250.
Efficient and general cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl azide allow a one-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines in good yields.
J. She, Z. Jiang, Y. Wang, Synlett, 2009, 2023-2027.
A NaH-mediated reaction of carbonitriles and N-methyl-1,2-phenylenediamine allows the formation of N-methylbenzimidazole and tolerates acid-labile acetal protective groups. Products were further converted in Suzuki, Sonogashira, Heck and Buchwald-Hartwig reactions.
J. Sluiter, J. Christoffers, Synlett, 2009, 63-66.
An efficient oxidative protocol enables the synthesis of multisubstituted or fused tetracyclic benzimidazoles via a metal-free oxidative C-N coupling between the sp3 C-H and free N-H of readily available N1-benzyl/alkyl-1,2-phenylenediamines in the presence of oxygen and TEMPO.
D. Xue, Y.-Q. Long, J. Org. Chem., 2014, 79, 4727-4734.
A straightforward, efficient, and sustainable method for intramolecular N-arylation provides a library of benzimidazoles in high yields using Cu2O as the catalyst, DMEDA as the ligand, and K2CO3 as the base. Remarkably, the reaction was exclusively carried out in water, rendering the methodology highly valuable from both environmental and economical points of view.
J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, C. Chen, J. Org. Chem., 2011, 76, 716-719.
Various N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields depending upon the base used in the reaction. Triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine promoted the formation of N-arylindazoles.
B. C. Wray, J. P. Stambuli, Org. Lett., 2010, 12, 4576-4579.
An efficient Cu(I)-catalyzed cascade intermolecular addition/intramolecular C-N coupling process enables the synthesis of a wide variety of 2-heterobenzimidazoles from o-haloarylcarbodiimides and N- or O-nucleophiles.
X. Lv, W. Bao, J. Org. Chem., 2009, 74, 5618-5621.
Condensation of N-aryl-2-nitrosoanilines with triphenylphosphine gives substituted aryliminophosphoranes which in a subsequent reaction with alkyl isocyanates furnish 2-alkylaminobenzimidazole derivatives in high yields.
E. Łukasik, Z. Wróbel, Synlett, 2014, 25, 217-220.
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.
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.
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 syntheses 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 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.
A metal-free sequential dual oxidative amination of C(sp3)-H bonds under ambient conditions affords imidazo[1,5-a]pyridines in very good yields. The reaction involves two oxidative C-N couplings and one oxidative dehydrogenation process with six hydrogen atoms removed.
Y. Yan, Y. Zhang, Z. Zha, Z. Wang, Org. Lett., 2013, 15, 2274-2277.
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.
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.
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.
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.
An efficient three-component coupling reaction of substituted picolinaldehydes, amines, and formaldehyde produces imidazo[1,5-a]pyridinium ions in high yields under mild conditions, allowing the incorporation of diverse functionality and chiral substituents. Higher order condensations are also described that provide access to multidentate NHC ligands useful for a variety of applications.
J. T. Hutt, Z. D. Aron, Org. Lett., 2011, 13, 5256-5259.