Indole, 4-, 5-, 6-, 7-bromo-, synthesis

Hegedus also described an efficient synthesis of 4-bromoindoIe (10) and 4-bromo-l-(4-toluenesulfonyl)indole (11) starting from 2-amino-6-nitrotoluene (9) [20]. The synthesis is lengthy but yields are good, and the method involves the Hegedus indole ring synthesis discussed later in this chapter. 

Indole-2-carboxylic acid, 5-bromo-l-hydroxy-tautomerism, 4, 197-198 Indolecarboxylic acid chloride synthesis, 4, 288... 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

An entirely different approach to 3-haloindoles involves a mercuration/iodination sequence, which has been adopted by Hegedus to prepare 4-bromo-3-iodo-l-(4-toluenesulfonyl)indole for use in the synthesis of ergot alkaloids [20,21], We will discuss this chemistry later. 

An excellent synthesis of 5-bromo- (18) and 5-iodoindole (19) involves protecting the indole double bond as sulfonate 16, acetylation to 17, and halogenation [27]. Indoline itself undergoes bromination at C-4 and C-7 [28]. 

Carrera and Sheppard improved upon a Leimgruber-Batcho indole synthesis [24] to prepare 6-bromoindole (20) in excellent overall yield from 4-bromo-2-nitrotoluene [29a], and Rapoport utilized this method to synthesize 4-, 5-, 6-, and 7-bromoindole [29b]. 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

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]. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

The next three procedures provide useful synthetic intermediates. A stereospecific synthesis of ETHYL (Z)-3-BROMO-2-PROPENOATE affords an alternative vinyl bromide partner for the coupling chemistry in the preceding procedure. A very simple but elegant illustration of the flash vacuum pyrolysis technique is used to prepare BENZOCYCLOBUTENONE from o-toluoyl chloride. Another member of the functionalized indole family of synthetic intermediates is presented in a four-step procedure for 5-METHOXYINDOLE-2-ACETIC ACID METHYL ESTER. 

Yasuhara et al. reported a total synthesis of furostifoline (224) by the oxidative photocyclization of 3-(indol-2-yl)-2-(isopropenyl)furan (1146), which was obtained by Sonogashira coupling of ethyl 2-ethynylphenylcarbamate (1143) with 3-bromo-2-propenylfuran (1142) (693). 

There are numerous other syntheses of indoles, and a modern example is the Wender synthesis. Here a 2-bromo-iV-(trifluoroacetyl)aniline in THF is deprotonated by butyllithium and then, in the same pot, reacted with fert-butyllithium to effect halogen-metal exchange to give the dilithiated derivative. To this intermediate is added an a-bromo ketone. A carbon-carbon bond is established first between the reactants, and then cyclization occurs to form a hydroxyindoline. Finally, dehydration generates the indole (Scheme 7.16). 

A Although it would be possible to convert 3-bromo-4-melhylani-line (7.2) into the corresponding hydrazine, by diazotization and reduction, react it with cyclohexanone, and then subject the product hydrazone to a Fischer indolization, the bromine substituent would still remain in the indole (note two isomers would form). Of course, this substituent could be displaced reductively using tributyltin hydride and a radical initiator [AIBN, azobis(isobuty-ronitrile)], but the overall synthesis is clumsy and non-selective and there should be a simpler route. 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

Indole synthesis. Fuhrer and Gschwend3 have converted N-pivaloylaniline into the dilithio derivative a by reaction with 2 equivalents of n-bulyllithium and have reported that orr/io-substituted derivatives are obtained in good yield by reaction of I Wilh an electrophile. The same species can be prepared somewhat more efficiently from iin o-bromo-N-pivaloylaniline (1) by bromine lithium exchange and N-deprotonation with methyllithium and r-butyllithium (equation I). This dilithium riegcnl can be used for synthesis of indoles.4 Thus it reacts with a bisclcctrophile... 

Pyridinium bromide perbromide efficiently brominates pyrroles already substituted by electron-withdrawing substituents and also gives a high yield of 3-bromoindole in its reaction with indole. In conjunction with sulfuryl chloride, it has been used in the synthesis of 3-bromo-2-chloro-, 2-bromo-3-chloro- and 2,3-dibromo-indole (81SC253). 3-Methylindole reacts with A-bromosuccinimide in acetic acid to give the 2-bromo derivative which reacts further with an excess of A-bromosuccinimide to yield 2,6-dibromo-3-methylindole (B-70MI30500, 72HC(25-2)127) whilst in aqueous or alcoholic media, 3-bromo-3-methylox-indole is produced (cf. Scheme 15). All of these reactions proceed via the 3-bromo-3A-indolium cation, but the course of the reaction depends not only upon the orientation or... 

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