Thallation intermediates

Another general approach to benzene-ring haloindoles involves thallation chemistry. Hollins and co-workers demonstrated that C-4 thallation occurs readily in a series of 3-acylindoles 31, affording 4-iodoindoles 32 following treatment of the thallated intermediates with KI [38]. 

Somei improved this methodology by quenching the appropriate thallated intermediate with 12/CuI/DMF to give 4-iodoindole-3-carboxaldehyde in 94% yield [39], and he extended this method to achieve efficient syntheses of C-7 haloindoles [40, 41], For example, 7-iodoindole (33) was prepared in good overall yield from A-acetylindoline as illustrated. Thallation at C-5 is a minor (5%) pathway. 

Somei improved this methodology by quenching the appropriate thallated intermediate with I2/CUI/DMF to give 4-iodoindole-3-carboxaldehyde in 94% yield [39], and he... 

Indole-5-boronic add has also been used successfully in Suzuki coupling <92H(34)1395). Organothallium derivatives have also been used in Suzuki coupling reactions. The 4-substituted thallation intermediate from indole-3-carboxaldehyde can be coupled with both aryl and vinyl-boronic acids (Equation (122)) <86CPB397i>. 

Aryl- or alkenylpalladium comple.xcs can be generated in situ by the trans-metallation of the aryl- or alkenylmercury compounds 386 or 389 with Pd(Il) (see Section 6). These species react with 1,3-cydohexadiene via the formation of the TT-allylpalladium intermediate 387, which is attacked intramolecularlv by the amide or carboxylate group, and the 1,2-difunctionalization takes place to give 388 and 390[322]. Similarly, the ort/trt-thallation of benzoic acid followed by transmetallation with Pd(II) forms the arylpalladium complex, which reacts with butadiene to afford the isocoumarin 391, achieving the 1,2-difunctionalization of butadiene[323]. 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

The thallium intermediates can be useful in directing substitution to specific positions when the site of thallation can be controlled in an advantageous way. The two principal means of control are chelation and the ability to effect thermal equilibration of arylthallium intermediates. Oxygen-containing groups normally direct thallation to the ortho position by a chelation effect. The thermodynamically favored position is... 

Aryltrimethylsilanes has been found to be a useful complement to direct thallation in the preparation of arylthallium(III) intermediates. The thallium(III) replaces the silyl substituent and the scope of the reaction is expanded to include some EWGs, such as trifluoromethyl. How does the silyl group function in these systems ... 

Arythallium bis(trifluoroacetates) (prepared by 2-22) can be converted to phenols by treatment with lead tetraacetate followed by triphenylphosphine and then dilute NaOH.3"5 The entire process, including the thallation reaction, can be carried out in a single reaction vessel without isolation of any of the intermediate products, so that this is a method of accomplishing the conversion ArH — ArOH. Diarylthallium trifluoroacetates undergo the same reaction.3"6... 

Thallation of 3-acylindoles gives the 4-thallated products, which can be converted to both the 4-nitro and 4-azido derivatives in copper(II)-promoted processes (89H(29)643). The nitro compound is formed by heating the organothallium intermediate with sodium nitrite and copper sulfate in DMF at 100°C. This methodology has been used in a total synthesis of indolactam-V (90T6623). 

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). 

EDA Complexes as Intermediates in Mercuration and Thallation. Comparison of Their Ground and CT Excited States... 

No transient intermediates other than the ir-complex are observed in either the UV-visible or ESR spectra. On the other hand, the thallation of pentamethylbenzene proceeds only 26% to nuclear substitution, the remainder being accounted for by side products resulting from side chain substitution and dimer formation (equation 34). 

Indeed the diversion to side products during thallation coincides with the direct obsovation of the arene radical cation as a transient intermediate both by UV-visible and ESR spectroscopy. A similar dichotomy between the products of mercuration and thallation exists with durene, albeit to a lesser degree. Finally no discrepancy is observed with mesitylene, nuclear substitution occuiring exclusively in both mercuration and thallation. Such a divergence between mercuration and thallation can be reconciled by the formulation in Scheme 6 if they difier by the extent to which di sive separation (ki) occurs in equation (31). All factors being the same, diffusive separation of the radical pair from thallium(III) should... 

The study of mercuration and thallation provides a shaip focus on the experimental delineation of stepwise and concerted mechanisms for arene activation. Thus the unequivoc demonstration of arene radical cations as key intermediates in thallation, particularly of durene and pentamethylbenzene, is consistent with a stepwise (electron-transfer) mechanism for arene activation (compare Scheme 6 and equation 39). 

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. 

Much simpler and more direct is a recently developed route via thallation. An aryithallium compound is oxidized by lead tetraacetate (in the presence of triphenylphosphine, PhjP) to the phenolic ester of trifluoroacetic acid, which on hydrolysis yields the phenol. The entire sequence, including thallation, can be carried out without isolation of intermediates. Although the full scope of the method has not yet been reported, it has two advantages over the diazonium route (a) the speed and high yield made possible by the fewer steps and (b) orientation control in the thallation step. (Review 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. 

Recently phthalic anhydride has been synthesised by thallation followed by carbonation of the organothalium intermediate... 

The formation of iodobenzene by treatment of phenylthallium(III) compounds with potassium iodide was reported, without experimental details, by Challenger et al in the 1930 s. 2,113 jhe potential and synthetic interest of this iododethallation reaction was extensively studied by McKillop and Taylor in the early 1970 s.8 7-89 Although arylthallium(III) compounds prepared by reaction of the arenes with thallium tris(trifluoroacetate) (84) can be isolated, they can also be directly converted into aryl iodides by addition of aqueous potassium iodide to the thallation reaction mixture. An intermediate arylthallium(III) diiodide (91) was suggested to be formed and to decompose intramolecularly to lead to the aryl iodide. ... 

Indolines are useful intermediates for the synthesis of indoles with substituents in the carbocyclic ring. In electrophilic substitutions, they behave like anilines the example shows iV-acetylindoline undergoing regioselective 7-thallation. Nitration of indoline 2-carboxylic acid gives the 6-nitro-derivative separation... 

One important mechanism for homogeneous catalytic activation of aromatic C—H bonds is electrophilic attack by transition-metal complexes on the aromatic substrates. It is presumed t -aryl complexes are important intermediates in these reactions, but they are rarely isolated. Direct electrophilic metallation of aromatic substrates is closely related to reactions observed with nontransition metals ( 5.6., auration 5.7.2., mercuration and 5.3., thallation - ). References to metal-aryl complexes synthesized by electrophilic attack on arenes by transition metals are sununarized in Table 1. Reviews are available " . 

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