Preparation of 3-arylmethylindoles as selective COX-2 inhibitors |
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Authors: | Jeffrey A Campbell Viola Bordunov Chris A Broka John Dankwardt Robert T Hendricks James M Kress Keith A.M Walker Jin-Hai Wang |
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Affiliation: | Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA |
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Abstract: | The 3-arylmethylation of indoles using TMSOTf/Et3SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO2 and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO2 and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO2-3-arylmethylindoles effective as selective COX-2 inhibitors. |
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Keywords: | Reductive indole alkylation 3-Arylmethylindole 3-Benzylindole COX-2 inhibitor TMSOTf Palladium |
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