Thallium in organic synthesis. XXIII. Electrophilic aromatic thallation. Kinetics and applications to orientation control in the synthesis of aromatic iodides

Abstract

Aromatic thallation is shown to be a reversible, electrophilic substitution reaction with an energy of activation of 27 kcal/mol and a large steric requirement. The process of thallation followed by addition of aqueous potassium iodide represents a simple and facile synthesis of aromatic iodo compounds, and the factors (kinetic, thermodynamic, steric) which control the position of thallation (and hence of iodination) have been systematically explored. Meta substitution is achieved under conditions of thermodynamic control. Under conditions of kinetic control, ortho substitution results when chelation of the reagent (thallium(III) trifluoroacetate, TTFA) with the directing substituent permits intramolecular delivery of the electrophile, and para substitution results when such capabilities are absent. Thus appropriate manipulation of conditions can lead to control over orientation (ortho or meta or para) in the same electrophilic substitution reaction. The application of these observations to the selective synthesis of a number of aromatic iodo compounds is described.

Preparation of 7-Halo-indoles by Thallation of N-Formylindoline and Their Attempted Use for Synthesis of the Right-Hand Segment of Chloropeptin

“…10) Among them, there is an attractive report, in which Taylor et al 11) found that high ortho thallation occurred in substituted aromatic compounds such as benzoic acid, methyl benzoate. Also, they reported their use of the resulting arylthallium ditrifluoroacetates with aqueous KI giving selectively ortho substituted aryl iodide (Fig.…”

“…Various functional groups such as COOH, COOMe, CH 2 OH were used for regioselective thallation of substituted benzenes in the literature. 11) However, the formyl group, which is expected more easily to be removed, has not been used as a functional group for thallation up to date, so we examined use of the N-formyl group to perform selective thallation at 7Ј-C in indoline to obtain 7-substituted indolines (Chart 1).…”

A Mild Method for Regioselective Labeling of Aromatics with Radioactive Iodine

“…Whereas the reaction of the aryl thallium(III) bis(trifluoroacetate) intermediate with iodide affords solely the ipso-substituted product, [15] the initial thallation can yield mixtures of the three possible regioisomers, depending on the substrate and conditions. [16] The labeling is typically performed in pure trifluoroacetic acid (TFA). [16,17] In the case of substrates that cannot tolerate these conditions, addition of a cosolvent, such as MeCN, can usually prevent substrate degradation.…”

“…[16] The labeling is typically performed in pure trifluoroacetic acid (TFA). [16,17] In the case of substrates that cannot tolerate these conditions, addition of a cosolvent, such as MeCN, can usually prevent substrate degradation. [16] However, addition of a cosolvent also lowers the reactivity, which means that deactivated aromatics can be challenging to label.…”

“…[16,17] In the case of substrates that cannot tolerate these conditions, addition of a cosolvent, such as MeCN, can usually prevent substrate degradation. [16] However, addition of a cosolvent also lowers the reactivity, which means that deactivated aromatics can be challenging to label. When we exposed griseofulvin analogue 2 to the reaction conditions [Tl(OCOCF 3 ) 3 in neat TFA], hydrolysis to form griseofulvic acid (3, Figure 1) took place within minutes, but when milder conditions [Tl(OCOCF 3 ) 3 in MeCN/TFA, 7:3] were used, no conversion of 2 was observed.…”