cine- and tele-Substitution reactions: review of work from 2002-2016

Abstract

This report brings new facts and achievements on the cine-and tele-substitutions reactions published in the last fifteen years. The reactions occurred primarily in such systems as nitroarenes, metal homoarene complexes, and five-or six-membered heteroarenes. Sometimes similar reactions were also observed in other systems, including non-aromatic. cine-and tele-Substitution reactions are presented here independently of their mechanisms.

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

“…Other examples of tele-substitution reactions have since been reported for a variety of aromatic systems ranging from simple pyrazine rings 6 ( Figure 1C) to more complex triazolopyrazine ring systems 7,8 (Figures 1D and 1E), the latter of which are of particular relevance to the present work. Despite these and other reports, [9][10][11][12] tele-substitution reactions are not well understood; they remain hard to predict and appear to be strongly substrate dependent. Interestingly, many of the known examples of tele-substitution involve aza-aromatic ring systems which are common in medicinal chemistry and drug discovery campaigns.…”

Cine-Substitutions at Five-Membered Hetarenes Enabled by Sulfonium Salts

“…Despite the high potential utility of reactions that change the substitution pattern, such cine - and tele -substitutions are rare. 1 − 3 Here we report cine -substitution reactions of electron-rich hetarylsulfonium salts with various nucleophiles. The starting materials are readily accessible through site-selective C–H functionalization, 4 and the physicochemical properties, namely, the ability to form ylides, distinguish the sulfonium leaving groups used in this chemistry from other (pseudo)halides.…”

“… 6 Addition of nucleophiles to electron-poor arenes, for example ortho to a nitro group, is possible, but nitrite is not a sufficiently good leaving group, so cine -substitutions with the elimination of nitrous acid are rare. 3 A special example of a cine -substitution—limited to cyanide addition to nitroarenes for the synthesis of benzoic acids—is the von Richter reaction 7 ( Figure 1 b), which circumvents the elimination of nitrite by intramolecular attack of the nitro group onto the cyano group after addition, followed by rearrangement and loss of dinitrogen to yield benzoic acids. 7b − 7d…”

“…Even site-selective C–H functionalization reactions, in the best case, dictate which single position is functionalized as a consequence of the reaction mechanism, so that the other positions are not easily accessible for functionalization. Despite the high potential utility of reactions that change the substitution pattern, such cine - and tele -substitutions are rare. − Here we report cine -substitution reactions of electron-rich hetarylsulfonium salts with various nucleophiles. The starting materials are readily accessible through site-selective C–H functionalization, and the physicochemical properties, namely, the ability to form ylides, distinguish the sulfonium leaving groups used in this chemistry from other (pseudo)­halides.…”

“…Reactions that proceed via an aryne intermediate through an elimination–addition mechanism lose the positional information on the starting material substituents in the aryne intermediate and therefore usually produce mixtures of cine - and ipso -substitution products . Addition of nucleophiles to electron-poor arenes, for example ortho to a nitro group, is possible, but nitrite is not a sufficiently good leaving group, so cine -substitutions with the elimination of nitrous acid are rare . A special example of a cine -substitutionlimited to cyanide addition to nitroarenes for the synthesis of benzoic acidsis the von Richter reaction (Figure b), which circumvents the elimination of nitrite by intramolecular attack of the nitro group onto the cyano group after addition, followed by rearrangement and loss of dinitrogen to yield benzoic acids. − …”