Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper induced reactions

The bromination of 2-aminobenzonitrile (2) with molecular bromine (2 equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6, 14–18) utilizing Friedländer reactions. A convenient route is described for disubstituted derivat...

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Bibliographic Details
Published in:Tetrahedron 2016-09, Vol.72 (35), p.5323-5330
Main Authors: Ekiz, Makbule, Tutar, Ahmet, Ökten, Salih
Format: Article
Language:English
Subjects:
Bromotacrine
Cyanotacrine
Lithium-bromine exchange
Methoxytacrine
Tacrine
Thiomethyltacrine
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Summary:The bromination of 2-aminobenzonitrile (2) with molecular bromine (2 equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6, 14–18) utilizing Friedländer reactions. A convenient route is described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6 and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)3Cl, S2(Me)2]. Both were converted to the corresponding cyano derivatives (21–23) via copper-assisted nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in 25% yield. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2016.07.012