Indolines thallation

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. 

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). 

Some effected the coupling of phenyl-, 2-fuiyl-. and 1-hexenylboronic acids with 4-thallated indole-3-carboxaldehyde (Pd(OAc),/DMF) to give 4-substituted 3-formylin-doles [148]. Regioselective thallation of indole-3-carboxaldehyde is achieved using thallium tris-trifluoroacetate in 77% yield. Indole 129, which is available by the Buchwald zirconium indoline synthesis, was used by Buchwald to synthesize 130 via a Suzuki protocol [149]. Boronate ester 130 is prepared by the hydroboration of3-methyl-1-butyne with catechol borane. Indole 131 had been used in earlier studies to synthesize the clavicipitic acids. 

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... 

Synthesis of indoles via 2,3-dihydroindoles (indolines) is sometimes done in order to achieve a specific substitution pattern in the carbocyclic ring <67RCR753>. Indolines, being aniline derivatives, readily undergo electrophilic substitution at C5. Indolines can also be used to achieve selective 7-substitution. The 1-Boc derivative of indoline can be lithiated at C7 <92H(34)i03i> and 1-acetyl-indoline is thallated at C7 <89H(29)643>. These organometallic intermediates can be functionalized and then aromatized to indoles. There are a number of methods which have been developed for oxidative aromatization of dihydroindoles. Table 3 cites some examples. 

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