Imidazoles aryl substituted in the 4(5)-position are central structures of many compounds which elicit important biological and pharmacological responses. Monosubstituted 4(5)-aryl-1H-imidazoles, for example, include compounds which display good in vitro antifungal activity,1 or are potent inhibitors of -glucosidase2 as well as show antiinflammatory properties.3 On the other hand, 2-alkyl-4(5)-aryl-1H-imidazoles include potent channel blockers4 and several 4(5)-aryl-5(4)-(4-fluorophenyl)-1H-imidazole derivatives are p38 mitogen-activated protein kinase inhibitor.5 As a consequence, much attention has been devoted to the development of efficient procedures for preparation of 4(5)-aryl substituted imidazole derivatives.6 Nevertheless, there are relatively few methods for the synthesis of monosubstituted 4(5)-aryl-1H-imidazoles 1 and disubstituted 2,4(5)-diaryl-1H-imidazoles 2. Moreover, these synthetic protocols suffer from being multistep synthesis, providing modest yields and / or requiring commercially unavailable and / or expensive reagents.7,8 Recently, in the course of our studies on the synthesis of arylazole derivatives,9 we became interested in the development of concise and effective novel approaches for the preparation of compounds of general formula 1 and 2 starting from cheap, commercially available starting materials. In this context, we recently developed a rapid, efficient and general protocol for the synthesis of imidazoles 1, which utilizes a Pd-catalyzed Suzuki-Miyaura type reaction between commercially available 4(5)-bromo-1H-imidazole (3) and arylboronic acids 4 under phase-transfer conditions (Scheme 1). Moreover, we succeeded in preparing several 2,4(5)-diaryl-1H-imidazole derivatives 2 by highly regioselective Pd-catalyzed and Cu-mediated direct C-2 arylation of 4(5)-aryl-1H-imidazoles 1 with aryl bromides and iodides 5 under base-free and ligandless conditions (Scheme 2).It should be noted that we had previously employed similar reaction conditions for the efficient and highly regioselective direct C-2 arylation of a large variety of heteroarenes which included 1-aryl-, 1-methyl- and 1-benzyl-1H-imidazoles, thiazole, oxazole, benzothiazole and free (NH)-imidazole, -benzimidazole and -indole.9a,c-e In conclusion, we have found that monosubstituted 4(5)-aryl-1H-imidazoles 1 can be efficiently and selectively prepared by PdCl2(dppf)-catalyzed Suzuki-Miyaura reaction of 4(5)-bromo-1H-imidazole (3) with arylboronic acids 4 under phase-transfer conditions. We have also shown that 2,4(5)-diaryl-1H-imidazoles 2 can be obtained in modest to good yields by highly selective Pd- and Cu-mediated C-2 arylation of 4(5)-aryl-1H-imidazoles 1 with aryl iodides and bromides. In our opinion these simple and convenient synthetic procedures will enable rapid access to a variety of pharmacologically significant imidazole derivatives.

Synthesis of 4(5)-aryl-1H-imidazoles and 2,4(5)-diaryl-1H-imidazoles via highly selective palladium-catalyzed arylation reactions / R. Rossi, S. Cauteruccio, F. Bellina. ((Intervento presentato al 6. convegno International School of Organometallic Chemistry tenutosi a Camerino nel 2007.

Synthesis of 4(5)-aryl-1H-imidazoles and 2,4(5)-diaryl-1H-imidazoles via highly selective palladium-catalyzed arylation reactions

S. Cauteruccio;
2007

Abstract

Imidazoles aryl substituted in the 4(5)-position are central structures of many compounds which elicit important biological and pharmacological responses. Monosubstituted 4(5)-aryl-1H-imidazoles, for example, include compounds which display good in vitro antifungal activity,1 or are potent inhibitors of -glucosidase2 as well as show antiinflammatory properties.3 On the other hand, 2-alkyl-4(5)-aryl-1H-imidazoles include potent channel blockers4 and several 4(5)-aryl-5(4)-(4-fluorophenyl)-1H-imidazole derivatives are p38 mitogen-activated protein kinase inhibitor.5 As a consequence, much attention has been devoted to the development of efficient procedures for preparation of 4(5)-aryl substituted imidazole derivatives.6 Nevertheless, there are relatively few methods for the synthesis of monosubstituted 4(5)-aryl-1H-imidazoles 1 and disubstituted 2,4(5)-diaryl-1H-imidazoles 2. Moreover, these synthetic protocols suffer from being multistep synthesis, providing modest yields and / or requiring commercially unavailable and / or expensive reagents.7,8 Recently, in the course of our studies on the synthesis of arylazole derivatives,9 we became interested in the development of concise and effective novel approaches for the preparation of compounds of general formula 1 and 2 starting from cheap, commercially available starting materials. In this context, we recently developed a rapid, efficient and general protocol for the synthesis of imidazoles 1, which utilizes a Pd-catalyzed Suzuki-Miyaura type reaction between commercially available 4(5)-bromo-1H-imidazole (3) and arylboronic acids 4 under phase-transfer conditions (Scheme 1). Moreover, we succeeded in preparing several 2,4(5)-diaryl-1H-imidazole derivatives 2 by highly regioselective Pd-catalyzed and Cu-mediated direct C-2 arylation of 4(5)-aryl-1H-imidazoles 1 with aryl bromides and iodides 5 under base-free and ligandless conditions (Scheme 2).It should be noted that we had previously employed similar reaction conditions for the efficient and highly regioselective direct C-2 arylation of a large variety of heteroarenes which included 1-aryl-, 1-methyl- and 1-benzyl-1H-imidazoles, thiazole, oxazole, benzothiazole and free (NH)-imidazole, -benzimidazole and -indole.9a,c-e In conclusion, we have found that monosubstituted 4(5)-aryl-1H-imidazoles 1 can be efficiently and selectively prepared by PdCl2(dppf)-catalyzed Suzuki-Miyaura reaction of 4(5)-bromo-1H-imidazole (3) with arylboronic acids 4 under phase-transfer conditions. We have also shown that 2,4(5)-diaryl-1H-imidazoles 2 can be obtained in modest to good yields by highly selective Pd- and Cu-mediated C-2 arylation of 4(5)-aryl-1H-imidazoles 1 with aryl iodides and bromides. In our opinion these simple and convenient synthetic procedures will enable rapid access to a variety of pharmacologically significant imidazole derivatives.
Settore CHIM/06 - Chimica Organica
Synthesis of 4(5)-aryl-1H-imidazoles and 2,4(5)-diaryl-1H-imidazoles via highly selective palladium-catalyzed arylation reactions / R. Rossi, S. Cauteruccio, F. Bellina. ((Intervento presentato al 6. convegno International School of Organometallic Chemistry tenutosi a Camerino nel 2007.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/222211
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