Thallates reactions with

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). 

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. 

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... 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give (V-acetylindole and N-acetyl-2-methylindole each in 45% yield [409]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 313 and 314 [410]. The regioselectivity was excellent with unsymmetrical alkynes. 

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. ... 

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... 

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... 

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. ... 

Reaction with substrates which are activated toward electrophilic substitution is generally complete within a few minutes at room temperature. Thallation of mildly deactivated substrates such as the halobenzenes requires longer reaction times at room temperature or about 30 minutes at reflux temperature (73°), and the deactivated substrates benzoic acid and a,a,a-trifluorotoluene are thallated after 21 and 98 hours reflux, respectively. For acid-sensitive substrates (e.g., thiophenes) the conditions of choice are solid TTFA in acetonitrile. The aryl-thallium ditrifluoroacetates usually crystallize from the reaction mixtures and are isolated by simple filtration, usually in analytically pure form. 

Regioselective thallation (see Section 2.03.4.2) can be used to introduce halogen at C4 or C7 of the indole ring. For example, 5,7 and 6,7-dibromoindole-3-carboxaldehyde can be converted to the corresponding 4-bromo derivative by reaction with T1(02CCF3)3 and CuBrj <89H(29)1663>. 

Controlled fluorination of benzene is difficult, but it can be accomplished by a two-step thallation procedure. Benzene reacts with thallium tris(trifluoroacetate), TI(0C0CF3)3, to give an organothallium intermediate. Further reaction with potassium fluoride and boron trifluoride gives the aryl fluoride. Propose a mechanism for the first step, the thallation of benzene. 

Phenylindoles may be conveniently synthesized by reaction of a 2-thallated anilide with a Cu(I)-acetylide followed by cyclization... 

Benzoic acid and substituted benzoic acids are readily thallated by thallium(III) trifluoroacetate. Subsequent reaction with palladium chloride and simple alkenes, allylic or vinyl halides, or vinyl esters result in the formation of isocoumarins eg ... 

The room teiiq erature reaction of simple aliphatic ketones with an aqueous solution of thalllum(III) chloride leads to the formation of the mono-oxoalkylthalllum(III>. derivatives (23) which are then converted to selectively monochlorinated a-monochlorlnated ketones (Scheme 9> . Methyl vinyl ketone Is 8 arylated by arylthalllum conq>ounds In a reaction which Is catalysed by lithium tetrachloropalladate (Scheme 10) . The thallatlon of anilides with thalllum(III) trifluoroacetate In a mixture of trlfluoroacetlc acid and ether affords the ortho-thallated derivatives (24>, which yield 2-acetamldotolanes on reaction with copper(I> phenylacetyllde In acetonitrile. Ortho-... 

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