Main, Calver A.
Novel titanium carbenoid reagents: diversity orientated synthesis of indoles and spirocycles.
PhD thesis, University of Glasgow.
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A new synthetic strategy for the preparation of a 96-member library of 2,5-disubstituted indoles involving traceless cleavage from resin is presented.
A boronate-bearing titanium alkylidene was prepared and used to convert 8 resin-bound esters into immobilised enol ethers. Cleavage from resin in mild acid with concomitant cyclisation yielded boronate-bearing indoles. Capitalising on the immobilised boronate functionality in enol ethers, Suzuki cross-coupling reactions were performed with 12 aryl iodides to give a 96-member library after cleavage from resin with mild acid. 79 members of the library were confirmed to be 2,5-disubstituted indoles.
Also reported is the use of tertiary butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to convert an aryl bromide into an arylboronate in the presence of a dithiane, with simultaneous reduction of an aryl azide to an amine. In a similar route, we synthesised dithiane for the attempted conversion of resin-bound esters into functionalised 7-azaindoles after cleavage from resin. Further investigation with a different ortho-nitrogen protecting group may yet prove successful.
Alkylidenation of lactones with functionalized titanium carbenoid reagents followed by acid-induced cyclisation of the resulting enol ethers constitutes a new method for the preparation of [4.4], [4.5], and [5.5] spiroacetals (1,6-dioxaspiro[4.4]nonanes, 1,6-dioxaspiro[4.5]decanes and 1,7-dioxaspiro[5.5]undecanes). The titanium carbenoids are easily generated from readily available thioacetals.
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