ORGN 717 |
| The 3-arylmethylation of indoles using TMSOTf/Et3SiH with a wide variety of substituted aldehydes and acetals has been accomplished. An intramolecular variant of this methodology involving cyclization of a substituted acetal provided access to a tetrahydro-ß-carboline scaffold normally only accessable through the Pictet-Spengler reaction. In addition, the preparative viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. A medicinally important application of this work 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. For indoles bearing both a 6-MeSO2 and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, a unique 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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Heterocycles and Aromatics
8:00 AM-12:00 PM, Thursday, 1 September 2005 Washington DC Convention Center -- Ballroom B, Oral
Division of Organic Chemistry |