A highly enantioselective Friedel-Crafts alkylation of electron-rich aromatic nucleophiles catalyzed by scandium(III) triflate-pyridyl(bis)oxazoline complexes has been accomplished. The reaction involves alpha,beta-unsaturated acyl phosphonates as electrophiles and primarily substituted indoles as nucleophiles. The reactive acyl phosphonate product is converted to the corresponding ester or amide in good overall yield by adding an alcohol or amine directly to the reaction mixture.
Herein,
we report the first examples of the synthesis of pyrroloindolines
by means of (3 + 2) dearomative annulation reactions between 3-substituted
indoles and highly reactive azaoxyallyl cations. Computational studies
using density functional theory (DFT) (B3LYP-D3/6-311G**++) support
a stepwise reaction pathway in which initial C–C bond formation
takes place at C3 of indole, followed by ring closure to give the
observed products. Insights gleaned from these calculations indicate
that the solvent, either TFE or HFIP, can stabilize the transition
state through H-bonding interactions with oxygen of the azaoxyallyl
cation and other relevant intermediates, thereby increasing the rates
of these reactions.
It is reported that Ga(OTf)(3) catalyzes the direct displacement of alcohols with sulfur nucleophiles. The products are versatile intermediates that can be utilized in carbon-carbon, carbon-sulfur bond formation or used in modified Julia olefination reactions. The only byproduct generated is water.
A number of synthetic strategies to the Cox-2 specific inhibitor 1 have been described. These studies have led to the identification of a novel pyridine construction using annulation of ketone 2 using a vinamidinium species 29 and ammonia in 97% assay yield. Three approaches to the synthesis of ketone 2 are described that allow for its preparation in large quantities in >65% overall yield from methyl 6-methylnicotinate.
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