Bromide-mediated ortho-deprotonation in the synthesis of chiral, nonracemic ferrocene derivatives

Bromide-mediated methods for the synthesis of 1,2,3- and 1,3-substituted ferrocenes are described. Starting from monosubstituted ferrocene derivatives {Fc-R-1, R-1 = 1-dimethylaminoethyl [CH(NMe2)Me], p-tolylsulfinyl [4-MeC6H4S(O)], (2-methoxymethylpyrrolidin-1-yl)methyl [2-MeOCH2(C4H7N)CH2], ephedrine derivative CH2N(Me)CH(Me)CH(Ph)OMe, and dimethylaminomethyl [CH2(NMe2)]} achiral, racemic and chiral, nonracemic 1,2,3-trisubstituted ferrocene derivatives are accessible through two consecutive ortho-lithiations. In the first deprotonation step bromide is introduced stereoselectively into position 2. In the second step, the use of Li-TMP (TMP = 2,2,6,6-tetramethylpiperidine) as the base leads to deprotonation of the ortho-position next to bromide, and subsequent reaction with different electrophiles gives a variety of 1,2,3-trisubstituted ferrocene derivatives. Removal of the central bromide substituent leads to 1,3-disubstituted derivatives, including pincer-type ferrocene ligands.