Heck reaction indole compounds

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

Transition-metal catalyzed reactions are now common and attractive routes to exotic indoles with substitution patterns which are otherwise difficult to realize. Using an intramolecular Heck reaction, the precursors 94 were converted to a number of 3-aryl-3-alkenyl oxindoles 95 in good yield and with good ee. The requisite compounds 94 are available in three steps from IV-benzylbenzoxazolin-2-one using palladium-based chemistry <03JA6261>. 

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 with the nickel-catalyzed synthesis of indole from 2-chloro-A -allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [111]. Compound 117, easily prepared from 2-bromo-A-acetylaniline and methyl bromocrotonate, was adopted as a cyclization precursor. Treatment of 117 with PdiOAc), (2 mol%), PhjP (4 mol%), and NaHCOj in DMF provided indole 118 via an intramolecular Heck reaction followed by olefin isomerization to afford the fully aromatic product. Although yields fr om the initial report were moderate, they have been greatly improved over the last two decades [112]. 

Even indoles bearing acyl or phenylsulfonyl substituents on nitrogen, are easily palladated at moderate temperatures, substitution occuring at C-3, or at the 2-position if C-3 is occupied. The metallated products are seldom isolated but allowed to react with acrylates, other alkenes (Heck reaction), or carbon monoxide in situ. Although electrophilic palladation normally requires one equivalent of palladium(II), the incorporation of reoxidants selective for Pd(0), such as t-butyl perbenzoate or copper(II) compounds, allows catalytic conversions to be carried out. ... 

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],... 

Eletriptan 29a, an anti-migraine compound developed by Pfizer, is produced using a Heck reaction as outlined in Scheme 8. In the medicinal chemistry route, the Heck reaction was performed between the vinyl sulfone 26 and the indole bromide 27a [37, 38]. However, during process development it was found that attempts to purify the Heck product 28a led to formation of a dimeric compound as a result of a Michael addition of the indole nitrogen onto the alkenylsulfone. Thus, in an improved process the indole 27a was acetylated prior to the Heck reaction [39]. The acetyl group was removed after hydrogenation of 28b to 29b. A different... 

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). 

Starting in 1977, Mori and Ban " at Hokkaido University discovered that Pd can catalyze the intramolecular reaction of o-halo-iV-allylanilines to indoles under Heck reaction conditions. It was the first intramolecuar Heck reaction to the synthesis of heterocycles. For example, the compound 1, which was prepared from methyl a-bromocrotonate (3) and 2-bromo-A-acetylaniline 4, was adopted as a starting material. It was treated with Pd(OAc)2 (2 mol%) and PPhs (4 mol%) in the presence of tetramethylethylenediamine (TMEDA, 200 moI%) under a stream of nitrogen at 125 °C for 5.5 h methyl l-acetyl-3-indolyl acetate was obtained in a yield of 43% via an intramolecular Heck... 

As the first application of Heck reaction in making heterocyclic compounds — namely indole derivatives, the Mori-Ban reaction has been widely used in variety synthesis of indoles. In a program to synthesize CC-1065 analogs, Sundberg prepared indole 19 from o-bromo-JV-allylaniline 18 in an excellent yield using the Jeffrey s conditions. Silver carbonate and sodium carbonate were less effective than triethylamine. 

Maes and co-workers have synthesized 5//-pyridazino[4,5-6]indole skeleton 39 through an intramolecular Heck reaction. Intermediate 38, 5-(2-bromo-4-(trifluoromethoxy)phenylamino)-2-benzyl-l,2-dihydropyridazin-3-(6//)-one was prepared via chemoselective Pd-catalyzed amination of 2-benzyl-5-iodopyridazin-3(2//)-one 36 and 2-bromo-4-(trifluoromethoxy)-benzenamine 37 in 66% yield and followed by an intra molecular cyclozition to yield the desired target compound 39 by a microwave iradiations. ... 

Several other examples of the utility of Pd-mediated reactions in synthesis of aryl and vinyl derivatives of pyrrole and indole were reported. Schmidt and coworkers examined arylation of 1-vinylpyrroles under Heck conditions. Reaction took place at the A-vinyl group. While the parent compound gave a mixture of -and -arylation, 2,3-dialkyl-1-vinylpyrroles preferred -substitution. <95RCB767> Grieb and Ketcha used Suzuki coupling conditions to prepare several 1-... 

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. 

A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requiranents there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substructure typical for very many starting materials, which were transformed to heterocycles by intramolecular Heck-type reactions (X = halide, Het = heteroatom). This type of substructure with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active compounds. 

Indole and isoquinolone nuclei are prominent structural units frequently found in numerous natural products and pharmaceutically active compounds. Thus, the search for new methodologies to obtain these scaffolds with different substitution patterns is a current major objective in organic synthesis. Similar to benzofuran synthesis, Aluraez et al. observed that the palladium-catalyzed cascade intramolecular alkyne aminopaUadation/intermolecular Heck-type coupling reaction under oxidative conditions is an efficient methodology for the synthesis of indole 217 and isoquinolone 219 derivatives, starting from readily available aniline 216 or benzamide 218 substrates and functional alkenes [77] (Scheme 6.60). 

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