Palladium-catalyzed cross-coupling of five-membered heterocyclic silanolates

Scott E Denmark, J. Baird, C. Regens

Research output: Contribution to journalReview articlepeer-review


The utilization of Pd-catalyzed reactions provides easy access to the construction of indoles that are ubiquitous in nature. However, further functionalization of a preexisting indole skeleton, especially at the C(2) position, has remained a synthetic challenge because of the strong influence of the heteroatom on the structural and electronic properties of the ring. In this article, development and optimization of a Pd-catalyzed cross-coupling reaction of 2-indolylsilanol derivatives with aryl halides is described. The applicability of the method was extended to the cross-coupling reactions of common π-rich heterocycles with aryl iodides and aryl bromides. Method development and optimization involved investigating mild conditions that would provide a silanol derivative that is shelf-stable, would easily couple with arylhalides, and would afford products in high yield. Various N-protected dimethyl(2-indolyl)silanols were prepared by metalation at the C(2) position and trapping with a silicon electrophile (Scheme 1; Eq. 1). Alkali metal dimethyl(2-indolyl)silanolates were also prepared using different protocols. (Chemical Equation Presented) It was observed that the isolated alkali metal silanolates, which are easily formed using a strong and kinetically fast base (e.g., NaH, NaHDMS), were shelf-stable and provided a significant rate enhancement and broader substrate scope. The use of Pd(0) catalysts solvated with CHCl3 such as Pd2(dba)3.CHCl3 facilitated the cross-coupling reactions of N-Boc-dimethylsilanol derivatives with aryl iodides (Table 1, entry 7). Employing preformed metal silanolates not only limited the formation of dimers but also prevented the onset of protiodesilylation, a common occurrence in cross-coupling reactions of 2-indolylsilanols. Cross-coupling reaction under the preformation protocol was found to be more efficient than the analogous copper-mediated process (Tables 2 and 3; Eqs. t2 and 3). Protection of indole nitrogen was shown to have a remarkable effect on the reactivity of the dimethyl(2-indolyl)silanolates. In general, silanolates containing electron-rich protecting groups (SEM and methyl) were more reactive than those with electron-poor protecting group (N-Boc) especially for alkylbromides and alklyhalides as electrophiles in cross-coupling reaction (Tables 4-6). The optimized conditions developed for the cross-coupling reaction of various dimethyl(2-indolyl)silanols with arylhalides were applied to the cross-coupling of 2-pyrrolyl-, 2-furyl-, and 2-thienylsilanolates and were observed to proceed smoothly with only minor modifications as regard to reaction conditions.

Original languageEnglish (US)
Pages (from-to)41-46
Number of pages6
Issue number2
StatePublished - Mar 2010
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry
  • Molecular Biology


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