Thallation-iodination

A dramatic illustration of the practical application of these observations is seen in the thallation-iodination of phenylethanol versus the acetate of phenylethanol the former gives o-iodophenylethanol, while the latter gives -iodophenylethanol. 

Snieckus described short syntheses of ungerimine (121) and hippadine by Suzuki couplings of boronic acid 118 with 7-bromo-5-(methylsulfonyloxy)indoline (116) and 7-iodoindoline (117), respectively [130]. Cyclization and aerial oxidation also occur. Treatment of 119 with Red-Al gave ungerimine (121) in 54% yield, and oxidation of 120 with DDQ afforded hippadine in 90% yield. Indoline 116 was readily synthesized from 5-hydroxyindole in 65% overall yield by mesylation, reduction of the indole double bond, and bromination. Indoline 117 was prepared in 67% yield from N-acetylindoline by thallation-iodination and basic hydrolysis. 

Both 4,6- and 3,4-dimethoxydibenzofurans were brominated at C-l [84AHC(35)2]. Iodination of 3 follows the same trends as other halogena-tions (65MI1). Dibenzofuran is lithiated at the 4- and thallated at the 2-position, providing access to 2- and 4-iodo derivatives (57IZV1391). 

Various iodinated pyiToles have been prepared by direct iodination [19,24] or via thallation [25]. For example, 3-iodo-V-TIPS-pyrrole is prepared in 61% yield from 6 [19], and 3,4-diiodo-2-formyl-l-methylpyrrole is available in 54% yield via a bis-thallation reaction [25]. 

Lithiation and mercuration are directed by the oxygen atom and occur at the 4-position, but thallation, achieved by treatment of dibenzofuran with thallium(III) isobutyrate at 110°C, affords the 2-thallium di(isobutyrate), which may be converted to the 2-iodo compound by reaction with iodine. Mercuration is achieved by treatment of dibenzofuran with mercuryfll) acetate at 150°C, and the resultant 4-mercuric acetate (56%) may also be converted to the iodo compound. ... 

Thallation also provides a route to 4-iodoindoles from the related 3-acyl compounds. Here the intermediate thallium compound can be treated with iodine and copper(I) iodide in DMF to effect the transformation (84H(22)797,93JCS(Pl)256l). 

Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction... 

Now, these arylthallium compounds are useful, not in themselves, but as intermediates in the synthesis of a variety of other aromatic compounds. Thallium can be replaced by other atoms or groups which cannot themselves be introduced directly into the aromatic ring - or at least not with the same regiospecificity. In this way one can prepare phenols (ArOH, Sec. 24.5) and aryl iodides (Sec. 25.3). Direct iodination of most aromatic rings does not work very well, but the process of thallation followed by treatment with iodide ion gives aryl iodides in high yields. 

Aryl iodides can be prepared by simple treatment of arylthallium compounds with iodine. As in the synthesis of phenols (Sec. 24.5) the thallation route has the advantages of speed, high yield, and orientation control (see Secs. 11.7 and 11.13)... 

Aromatic iodides (3,287). The definitive paper on the synthesis of aromatic iodides by the reaction of arylthallium ditrifluoroacetates with potassium iodide has been published.1 Four procedures have been developed. 1) Thallation is carried out as usual and then an aqueous solution of potassium iodide is added directly. 2) The intermediate arylthallium ditrifluoroacetate is isolated and then treated with potassium iodide. 3) For acid-sensitive substrates solid TTFA in acetonitrile is used for thallation. 4) These methods are unsuccessful with highly reactive compounds such as naphthalene and diphenyl. In such cases molecular iodine is used as the electrophilic reagent and TTFA is used as oxidant for the hydrogen iodide formed in the reaction. 

The distribution rates for iodination of monosubstituted benzene derivatives have been reported.2 Under conditions of thermodynamic control (elevated temperature), me la substitution is observed. Under conditions of kinetic control (room temperature), a significant preference for para substitution is observed for compounds containing ortho-ptira-direcung substituent groups. Ortho substitution results when chelation of TTFA with the directing substituent permits intramolecular delivery of the electrophile. For example, methyl benzoate gives almost exclusively ordio-thallation (95%). 

Conventional palladium(II)-catalyzed coupling methodology allowed the formation of a number of oligo 2-thienyl or selenienyls <90H(30)645>. The thallation reaction of selenophene affords the 2-thallated species which give 2-iodoselenophene upon iodination <90MI 213-06). 

Aromatic iodination via thallation has wide applicability (15). The iodine atom enters the same position as the thallium. Replacement of the hard trlfluoroacetoxy groups of the thallium derivatives with iodide is favored because Tl(III) is soft. 

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