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

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• 作者：Makbule Ekiz^a ; ^b ; Ahmet Tutar^b ; ^{atutar@sakarya.edu.tr" class="auth_mail" title="E-mail the corresponding author} ; Salih Ö ; kten^c ; ^{salihokten@kku.edu.tr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tacrine ; Bromotacrine ; Cyanotacrine ; Lithium-bromine exchange ; Thiomethyltacrine ; Methoxytacrine
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：72
• 期：35
• 页码：5323-5330
• 全文大小：712 K

文摘

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.