Pyrroles indole alkylation reactions

The two-phase alkylation reactions have been extended to the acylation of simple heteroaromatic systems. Generally, the required conditions are milder than those employed for the alkylation reactions, but an excess of the acylating agent is usually required, owing to its facile hydrolysis in the basic media. Thus, benzimidazole and its 2-alkyl and 2-aryl derivatives have been benzoylated [46], and pyrrole and indole have been converted into a range of A-acyl [47, 48] and A-sulphonyl derivatives [48-53] (Table 5.35 and Table 5.36). 

Flouk has also considered the alkylation reactions of pyrroles and indoles using the same class of catalyst. The report addresses the fact that while catalyst 12 provides high ees in the alkylation of pyrroles (Scheme 15), the same is not true of indoles and catalyst 21 is required instead (Scheme 16). A thorough examination of the accessible transition states for the reaction of iminium ion 184 with pyrrole and with indole led to the conclusion that the two reactions occur through different transition states. Pyrrole adopts a closed transition state reminiscent of that of the Diels-Alder reaction whereas indole adopts an open transition state (Fig. 19) [233]. 

Interestingly, enantioselective alkylation reactions [64] were also developed using, for instance, Cu(OTf)2, [65], [Cu(SbF6)2, Zn(OTf)2] [66], Cu(C104)2-6H20 [67] or Sc (OTf)3 [68] in combination with diverse chiral ligands. Remarkably, organocatalytic alkylations of pyrroles, indoles and anilines by 3-phenylpropenal have been also developed [69]. 

C-Alkylation of pyrroles and indoles can be mediated by alumina in association with the appropriate halide. 3-Indolyl sugar derivatives have been obtained by alkylation reactions of indolylmagnesium bromide. This type of alkylation has been extended to ring-fused indoles 105 and yields 3//-indole derivatives 106 in good yields. 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

Due to the ambident reactivity of pyrroles and indoles, alkylations of such jt-excessive heterocycles can provide a mixture of N- and C-alkylated products. It is therefore of note that Bogdal has been able to achieve the regioselective N-alkylation of a number of azaheterocycles (i.e., pyrrole, imidazole, pyrazole, indole and carbazole) in "dry" media under microwave irradiation <97H(45)715>. The reactions were carried out by simply adsorbing a mixture of the heterocyclic compound, an alkyl halide and a catalytic amount of tetrabutylammonium bromide on a solid support (e.g., KOH, K2CO3), followed by irradiation in an open vessel for 1-10 min. Alternatively, the direct benzylation of pyrrole by the thermal decomposition of N-benzyl-N-nitrosobenzamide, which is believed to proceed by an essentially free carbocation, afforded only the C-2 and C-3 substituted pyrroles <97JOC8091>. 

To date, many electrophilic reagents, such as alkyl halides, alkenes, alkynes, carbonyl compounds, epoxides, alcohols, and ethers, have been investigated in AFC alkylation reactions. On the other hand, the reactive 5-membered heteroaromatic compounds, such as indole, pyrrole, furan, and thiophene derivatives, and electron-rich benzene derivatives have been successfully applied in AFC alkylation reactions. Indole and pyrrole derivatives are most popular substrates due to their high reactivity and account for almost 80% of the published methodologies. A variety of chiral organometal-lic catalysts and organocatalysts are employed in the catalytic AFC alkylation reactions with high enantiomeric control. 

Most AFC alkylation reactions are focused on relatively reactive furans, pyrroles, and indoles, whereas benzene derivatives are much less explored. The Wang group reported the organocatalytic asymmetric synthesis of chromane and dihydrobenzopyrane derivatives 121 from readily available 1-naphthols and a,p-unsaturated aldehydes by the AFC alkylation/cyclization cascade reaction (Scheme 6.49). The process appeared to have a broad substrate... 

Gordillo R, Carter J, Houk KN (2004) Theoretical explorations of enantioselective alkylation reactions of pyrroles and indoles organoeatalyzed by chiral imidazolidinones. Adv Synth Catal 346 1175 1185. doi 10.1002/adsc.200404107... 

After discovering the catalytic activity of aldehydes, Xu and co-workers later extended the method to TM-free aldehyde-catalyzed C-alkylation of secondary alcohols with primary alcohols [199] and catalyst-free C-alkylation reactions of methyl ketones with alcohols [200]. In 2013, Wu and co-workers also reported a closely related TM-free ketone-initiated C-alkylation of indole and pyrrole with secondary alcohols [201]. Similarly, Shi and co-workers employed conjugated ketones to catalyze the TM-free A/-alkylation reaction of amines with alcohols in 2015 (Scheme 42) [202], which is mainly suitable for benzylic and heterobenzylic alcohols, and anilines and heteroarylamines. Different ketones showed variant activities in the reaction (the catalysts were added in the same amount of 50 mg regardless of their molecular weights). In mechanistic studies such as the control reactions of the ketone catalyst and the substrate alcohol, up to 92 % ratio of the corresponding alcohol derived from reduction of the ketone catalyst can be detected in addition to formation of aldehdye intermediates derived from substrate alcohol. 

More recently, Palomo and co workers reported the application of Cu(OTf)2/(13) for highly enantioselective addition of pyrroles and indoles to a -hydroxy enones [10]. The a -hydroxy enone substrate-Cu(OTf)2/(13) catalyst system provides for excellent enantioselectivities with a variety of P substituents. It is also noteworthy that remarkable increases in enantioselectivity were observed in Friedel-Crafts alkylations of indoles when reactions were conducted under refluxing conditions (Scheme 17.5). 

PEG 1000, diethylether of PEG 1000, dibutylether of PEG 1000, and di-ethylether of PEG 4000 were used as PTCs in an aqueous-benzene solvent system to N-alkylate pyrrole, indole, and several other nitrogen heterocycles by the following reaction [147] ... 

Scope and Limitations. Carbonyl Component. For practice purposes this reaction is limited to aromatic aldehydes, of which a wide variety has been studied, and to a,/3-unsaturated aliphatic aldehydes. The sub-stitutents on the ring of the aromatic aldehydes include alkyl, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, acyloxy, carbethoxy, nitro, and various combinations of two or more of these groups. Aldehydes of the naphthalene, pyrene, biphenyl, thiophene, furmi, pyrrole, indole, chro-mane, coumarane, and thiazole series also have been employed. 

SCHEME 19 Alkylation reaction of pyrrole and indole with styrene oxide. 

Alkylation Reactions of Indole Friedel-Crafts alkylation of indoles and pyrroles with epoxides has been efficiently carried out over three-dimensional (3D) mesoporous aluminosilicates catalysts (AlKlT-5) in water at room temperature (Scheme 19) [88]. The autiiors found that mesoporous silica materials containing an interconnected large-pore cage-type mesoporous system with 3D porous networks supposed to be more valuable than porous materials containing a hexagonal pore structure with a one-dimensional array of pores. 

Photoreaction of 2-pyridone with aliphatic and aromatic amines leads to addition of the amines at C4 and C6 to give mixtures of dihydropyridone products (Scheme 15). All of these reactions appear to derive from a single electron transfer process. Tertiary aliphatic amines such as triethylamine 150 yield pyridones 151 and 152 (2 1) plus the reductively coupled pyridone dimer 153. Pyrrole 154 leads to a similar mixture of 4- and 6-substituted dihydropyridones 155 and 156 (1 1). Dimethylpyrrole 157 and indole 158 lead to analogous products of 4- and 6-substition of the pyridone (at C3 of the pyrrole 157). N-Methyl pyrrole 159, however, does not yield photoproducts. When the N-methyl pyrrole is alkyl substituted at C2 (160), addition to the pyridone yields 161 and 162 (1 1). ... 

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

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