Thallate

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]. 

Thallation of aromatic compounds with thallium tris(trifluoroacetate) proceeds more easily than mercuration. Transmetallation of organothallium compounds with Pd(II) is used for synthetic purposes. The reaction of alkenes with arylthallium compounds in the presence of Pd(Il) salt gives styrene derivatives (433). The reaction can be made catalytic by use of CuCl7[393,394], The aryla-tion of methyl vinyl ketone was carried out with the arylthallium compound 434[395]. The /9-alkoxythallium compound 435, obtained by oxythallation of styrene, is converted into acetophenone by the treatment with PdCh[396]. 

Directed thallation has been useful for synthesis of some 4- and 7-substituted indoles. Electrophilic thallation directed by 3-substituents is a potential route to 4-substituled indoles. 3-Formyl[7], 3-acetyi[8] and 3-ethoxycarbonyl[7] groups can all promote 4-thallation. 1-Acetylindoline is the preferred starting... 

The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

Mercuration-Thallation. Mercuric acetate and thallium ttifluoroacetate react with benzene to yield phenyHnercuric acetate [62-38-4] or phenylthaHic ttifluoroacetate. The arylthalHum compounds can be converted iato phenols, nitriles, or aryl iodides (31). 

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). 

Preparation of bromoindoles by replacement of metallic substituents have included oxidation of indolylmagnesium bromide by p-nitrobenzoic acid to give 3-bromoindole (67BSF1294), thallation procedures (illustrated in Scheme 18 also applied to the synthesis of chloroindoles) [85H(23)3113 86H(24)3065 87CPB3146, 87H(26)2817 89H(29)1163], and the use of lithium derivatives. The thallation reactions provide access particularly to 4- and 7-bromoindoles. Quenching the protected 2-lithium derivative of indole with 1,2-dibromotetrachloroethane gave an 87% yield of 2-bromoindole (92JOC2495). 

Mercuration of aromatic compounds can be accomplished with mercuric salts, most often Hg(OAc)2 ° to give ArHgOAc. This is ordinary electrophilic aromatic substitution and takes place by the arenium ion mechanism (p. 675). ° Aromatic compounds can also be converted to arylthallium bis(trifluoroacetates), ArTl(OOCCF3)2, by treatment with thallium(III) trifluoroacetate in trifluoroace-tic acid. ° These arylthallium compounds can be converted to phenols, aryl iodides or fluorides (12-28), aryl cyanides (12-31), aryl nitro compounds, or aryl esters (12-30). The mechanism of thallation appears to be complex, with electrophilic and electron-transfer mechanisms both taking place. 

A simple, high-yield procedure for the conversion of ArTlXj into ArjTlX compounds has recently been described 90). This symmetrization reaction, the mechanism of which is not known, can be effected by treatment of the ArTlX2 compound either with triethyl phosphite or with hot aqueous acetone. As a wide variety of ArTlXj compounds can now be easily prepared by electrophilic thallation of aromatic substrates with thallium(III) trifluoroacetate (q. v.), symmetrization represents the method of choice for the preparation of the majority of ArjTlX compounds. Only about twenty mixed compounds, RR TIX, have been prepared so far, and the only general synthetic procedure available consists of a disproportionation reaction between an RTIX2 species and another organometallic reagent [e.g., Eqs. (5)-(7)]. 

TFA. Electrophilic aromatic thallation with TTFA therefore constitutes a simple and general procedure for the preparation of monoarylthallium(III) derivatives and has been the subject of detailed kinetic, mechanistic, and synthetic investigations. These aspects of the thallation reaction are discussed at length below. 

With the ArH ArTlX2 Arl reaction sequence available as a rapid and reliable probe for aromatic thallation, a detailed study was undertaken of the various factors affecting orientation in this electrophilic metallation process (153). The results, which are summarized below, demonstrate that aromatic thallation is subject to an almost unprecedented degree of orientation control coupled with the ease with which thallium can then be displaced by other substitutent groups (this aspect of the synthetic exploitation of aromatic thallation is discussed in detail below), the sequential processes of thallation followed by displacement represent a new and versatile method for aromatic substitution which both rivals and complements the classic Sandmeyer reaction. 

Aromatic thallation has been shown to be a reversible electrophilic substitution reaction with an energy of activation of approximately 27 kcal/mole and an extremely large steric requirement 153). The consequence of the latter feature of aromatic thallation is that there is a significant preference for para substitution in thallation of simple monosubstituted benzeno id compounds. It will be seen by examination of Table VI that the amount of para substitution increases as the size of the substituent increases (for... 

Isomer Distributions in the Thallation of Aromatic Compounds at Room Temperature... 

Exact values for the percentage of thallation in the other positions were not obtained. 

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. 

In summary, then, the orientation of electrophilic thallation can be controlled by an appropriate manipulation of reaction conditions. Under conditions of kinetic control, ortho substitution results when chelation of the electrophilic reagent (TTFA in the studies described above) with the directing substituent permits intramolecular delivery of the electrophile, and para substitution results when such capabilities are absent this latter result is an expression of the very large steric requirements of the bulky thallium electrophile. Under conditions of thermodynamic control, however, meta substitution is observed. 

From the point of view of the synthetic organic chemist, the importance of aromatic thallation, and the remarkable degree of orientation control which can be exercised over this process, lies in the ease with which the resulting ArTlXj compounds can be converted into substituted aromatic derivatives in which the new substituent group has entered the ring at the position to which thallium was originally attached. Syntheses of phenols, nitroso compounds, biaryls, aromatic nitriles, thiophenols, and deuterated aromatic compounds have all been achieved these results are summarized briefly below. 

Yields in the above reactions can often be improved by the addition of 1 mole of triphenylphosphine directly to the trifluoroacetic acid solution of the reactants immediately before final work-up. It would appear that the triphenylphosphine functions as a scavenger for TTFA released in the metal-metal exchange reaction, thus protecting the final phenol from further electrophilic thallation and/or oxidation. Validation of the metal-metal exchange mechanism was obtained indirectly by isolation and characterization of an ArTlX2/LTTFA complex directly from the reaction mixture. NMR analysis revealed that this complex still possessed an intact aryl-thallium bond, indicating that it was probably the precursor to the transmetallation products, an aryllead tristrifluoroacetate and TTFA. 

The aryl-thallium bond is thus apparently capable of displacement either by electrophilic or by suitable nucleophilic reagents. Coupled with its propensity for homolytic cleavage (spontaneous in the case of ArTlIj compounds, and otherwise photochemically induced), ArTlXj compounds should be capable of reacting with a wide variety of reagents under a wide variety of conditions. Since the position of initial aromatic thallation can be controlled to a remarkable degree, the above reactions may be only representative of a remarkably versatile route to aromatic substitution reactions in which organothallium compounds play a unique and indispensable role. 

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. 

Under the same reaction conditions, -keto esters which have been alkylated on the a-carbon atom (thus leading to 3,4-disubstituted 5-pyrazolones upon treatment with hydrazine) give allenic esters in good (50-70%) yield (158). The mechanism (Scheme 36) again appears to involve thallation of the enamine tautomer of the 5 -pyrazolone, but deprotonation now takes place... 

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