Indole Heck synthesis

The incredibly powerful and versatile Heck coupling reaction has found enormous utility in indole ring synthesis and in the elaboration of this important heterocycle. Due to the enormity... 

The incredibly powerful and versatile Heck coupling reaction has found enormous utility in the indole ring synthesis and in the elaboration of this important heterocycle. Due to the enormity of this topic, the section is divided into Heck reactions of indoles, the synthesis of the indole ring as developed by Hegedus, Mori-Ban, and Heck, and the Larock indole ring synthesis. 

An indole alkaloid synthesis employing a bona fide intramolecular Heck reaction was documented in Sundberg s preparation of 5,6-homoiboga derivatives [90]. Several attempts to construct S,6-homoiboga derivative 191 using inter- or intramolecular Heck reaction conditions with phosphine ligands led to poor yields. Application of Jeffery s ligand-free" phase-transfer... 

Scheme 35. Applications of 6-exo Heck cyclization in indole alkaloid synthesis...

Scheme 6.8 One-pot Ugi-Mizoroki-Heck synthesis of highly substituted indole derivatives.

Palladium-Catalyzed Indole Ring Synthesis Mori-Ban-Heck 593... 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

Another example of a one-pot indole synthesis, which proceeds through a Heck carbonylation and a Suzuki coupling, is shown below. The reaction conditions are similar to the previous example however microwave heating is employed [174] (Scheme 6.54). 

Yamazaki, Kondo and coworkers [78] reported on a combination of a Heck reaction and an animation on solid phase for the synthesis of indole carboxylate 6/1-148, employing an acetylated immobilized enamide 6/1-145 and a bifunctionalized... 

Again, using a Pd-catalyzed amidation as the first step, Edmondson and coworkers [162] developed a synthesis of 2,3-disubstituted indoles 6/1-340 by reaction of 6/1-337 and 6/1-338 with catalytic amounts of Pd2(dba)3 and the ligand 6/1-341. On order to achieve good results, a second charge of Pd had to be added after 12 h. In the first step the enaminone 6/1-339 is formed, which then cydizes in a Heck-... 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki-Heck ring closure <06JOC5340>. 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

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 vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

This indole C-7 Heck cyclization strategy was employed by Shao and Cai in a synthesis of anhydrolycorine-7-one from the requisite N-aroylindoline [275], by Miki in syntheses of pratosine and hippadine from substrates like 262 [276], and by Rigby to synthesize anhydrodehydrolycorine from an N-benzylhydroindolone [277, 278]. Thai and co-workers constructed examples of the new ring systems, pyrido[2 ,3-d ]pyridazino[2,3-a]indole (264) and pyrido[2 ,3 -Heck cyclizations on the appropriate 2-bromopyridine precursors (e.g., 263) at C-2 or C-7, respectively [279, 280]. Compound 264 undergoes oxidative-addition with methyl acrylate at the C-3 position. This resulting product (not shown) can also be obtained from 263 in a tandem Heck sequence with methyl acrylate (62% yield). 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

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. 

It has been known for sometime that 2-(2-bromoanilino)enones undergo Heck-type cyclizations to form indoles and carbazoles. Thus, Kibayashi reported the synthesis of 4-keto-l,2,3,4-tetrahydrocarbazoles in this manner [362], and Rapoport employed this reaction (296 to 297) to achieve an improved synthesis of 7-methoxymitosene [363]. A series of related mitosene analogs has been crafted using Pd chemistry by Michael and co-workers [364], They found that P(o-tol)3 was far superior to PPh3 in conjunction with Pd(OAc)2. 

This indole synthesis has been extended to P-tetrahydrocarbolines (300) [371], azaketotetrahydrocarbazoles [372], carbolines, carbazoles, and pyrido[l,2-a]benzimidazoles [373]. Examples of the former two reaction types are illustrated. An early Heck cyclization of 2-carboxy-2 -iododiphenylamine to 1-carbazolecarboxylie acid (73% yield) [374] has been generally overlooked by subsequent investigators. 

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

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