Indoles Mizoroki-Heck reaction

Various cyclic compounds can be prepared by the reaction of ketones with bifunctional aryl halides. The jS-naphthol derivative 52 was obtained by a-arylation of dibenzyl ketone (14) with o-bromobenzaldehyde derivative 51, followed by aldol condensation [38], Also the indole derivative 54 was synthesized by the reaction of cyclohexanone with 2-iodoaniline (53). Formation of 54 may be explained by enamine formation at first, followed by intramolecular Mizoroki-Heck reaction, rather than via a-arylation [39],... 

Indoles or heterocycles containing an indole skeleton were the first products to be prepared by intramolecular heterocyclic Mizoroki-Heckreaction. In 1977, the first intramolecular Mizoroki-Heck reaction was reported by Mori et al. [7], who prepared indole 3 by cyclization of (Fl-methyl 4-(N-(2-bromophenyl)acetamido)but-2-enoate (1) in the presence of palladium acetate, triphenylphosphine and iVA/ A A -tetramethylethylenediamine (Scheme 6.4). 

A recent procedure describes a one-pot, two-step mutlicomponent reaction of bromoani-lines 13, aldehydes 14, acids 15 and isocyanides 16 yielding polysubstituted indoles 18 [34]. It is based on a Ugi four-component reaction yielding the precursor 17 for the in situ performed classical intramolecular Mizoroki-Heck reaction, thereby providing a facile access to highly substituted dihydro-indoles, l//-indoles and l//-indole-2-carboxyhc... 

A huge number of similar examples preparing indoles or related derivatives via intramolecular Mizoroki-Heck reactions can be found in the literature [35-39] enumerating them all would be impossible. 

Barluenga et al. [87] developed a one-pot synthesis for indoles from o-bromoanilines and alkenyl bromides via a cascade alkenyl amination/Mizoroki-Heck reaction. In order to improve the yields of their procedure, they studied the cyclization of preformed imine 113 to indole 114 in the presence of DavePhos and X-Phos as supporting ligands (Scheme 6.30). 

A combination of a Mizoroki-Heck reaction and a C—N coupling on solid phase was reported by Yamazaki et al. [105] in the synthesis of indole carboxylate 197 employing immobilized A-acetyldehydroalanine (194) and a bifunctionalized arene 195. In these transformations, 196 is the intermediate. The best results were obtained with o-dibromoarenes such as 195b and 195d using the Pd2(dba)3/P-r-Bu3/Cy2NMe catalytic system developed by Littke and Fu [106]. The protocol was also extended to the synthesis of isoquinolines [107] (Scheme 8.50). 

In domino processes starting with a Sonogashirareaction, the second is usually an amination or a hydroxylation to give y-lactones, furans or indoles however, there are also a few examples where a Mizoroki-Heck reaction is performed as the second step. 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

Five-membered cycles have also been prepared by intramolecular Mizoroki-Heck reactions on solid phase, as the syntheses of indole and benzofinan derivatives published by Zhang and Maryanoff [23] show (Scheme 14.6). 

Scheme 7.53 Different modes of cyclization palladium(ll)-catalyzed oxidative Mizoroki-Heck reactions of indoles.

The above approach of an intermolecular ortho-alkylation followed by an intermolecular Mizoroki-Heck coupling was later extended to heteroaryl iodides by Lautens [48], Using a Pd(OAc)2/triarylphosphine catalyst system, 3-iodothiophene, -benzothiophene, and -indole were transformed to the o/t/zo-alkylation/Mizoroki-Heck coupling products in good to excellent yields (Scheme 17). Unfortunately, 2-iodoheteroaryls were found to be poor substrates for the reaction. 

Cossy and cowoikers [52] described a combination of a Mizoroki-Heck and a Suzuki reactiou usiug ynamides and boronic acids to give indole and 7-azaindole derivatives 88, and its application to the total synthesis of the isoindolobenzazepine alkaloid lennoxamine (89) [53]. Thus, reaction of 86 with 87 using Pd(OAc)2 as catalyst led to 88 in moderate to high yield. This strategy was also applied to the synthesis of indoline-based kinase inhibitors by Player and coworkers [54]. Moreover, it has been shown that a carbonylation... 

Edmondson et al. [138] developed a synthesis of 2,3-disubstituted indoles using an am-ination as the first step (Scheme 8.67). The reaction of 264 and 265 with catalytic amounts of Pd2(dba)3 and the ligand 268 gave compound 267 in high yield. To get to the final indole, a second charge of palladium had to be added after 12 h, otherwise only the amination product was isolated. It can be assumed that in the first step the enaminone 266 is formed, which then cyclizes in a Mizoroki-Heck-type reaction to give 267. In a similar way, reaction of 264 and 269 led to 270 by an acyl migration in the Mizoroki-Heck cyclization product. 

---