Indoles nitroalkene reactions with

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

In 2004, Ricci and coworkers reported a sustainable Friedel-Crafts adulation of nitroalkenes with various aromatic and heteroaromatic substrates utilising 10 mol% of thiourea 8 under solvent-free reaction conditions. When applied to indoles, this method provides excellent yields and high selectivities (Scheme 19.8). Additionally, allqrlation at the difficult 2-position of the 3-methylindole was accomplished in a solvent-free reaction with the assistance of microwave irradiation (MW). 

Akiyama et al. [33] were the first to introduce chiral phosphoric acids to the FCA reaction of nitroalkenes, and they found that the addition of 3-A molecular sieves dramatically improved both the reactivity and selectivity of the reaction between (3-nitrostryrene and indole (Scheme 9.13). A catalytic working model was proposed that phosphoric acid performed as a bifunctional catalyst to activate both indole and nitroalkene. This methodology was further extended to the reactions with pyrroles as nucleophiles [34] and fluoroalkylated nitroalkenes as electrophiles [35]. 

The enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes is one of the most important carbon-bond-forming reactions for the preparation of biologically active compounds, such as indole alkaloids [39], Although several chiral catalysts have been investigated for the reaction, the enantioselectivities are not always satisfactory. Akiyama and coworkers developed a highly enantioselective Friedel-Crafts reaction of nitroalkenes 77 with indoles 75 using chiral phosphoric acid Ih (Scheme 11.21) [40]. They found that the addition of molecular... 

You and coworkers employed 4,7-dihydroindoles 79 instead of indoles 75 in the Friedel-Crafts reaction with nitroalkenes 77 (Scheme 11.22) [41]. Catalyst Ig with a 9-anthryl group displayed excellent performance. The notable point in this reaction is the use of the syringe pump technique to achieve high enantioselectivities and suppress the background reaction. Subsequent oxidation of Friedel-Crafts adducts 80 by p-benzoquinone afforded 2-substituted indole derivatives 81 in excellent yields without racemization. This approach and the simple asymmetric Friedel-Crafts reaction of indoles are complementary methods for obtaining the different substitution patterns of chiral indole derivatives. 

Nitroalkenes react enantioselectively (ee usually 40%) with indoles using chiral hydrogen-bonding bis-sulfonamides as catalysts [e.g. to form (41)].44 An enantioselective reaction (usually ee 83-95%) has been shown to occur between indoles and ethyl ... 

Lin JH, Zhang CP, Zhu ZQ et al (2009) A novel pyrrohdinium ionic liquid with 1,1,2,2-tetra-fluoro-2-(l,l,2,2-tetrafluoroethoxy)ethanesulfonate anion as a recyclable reaction medium and efficient catalyst for Friedel-Crafts alkylations of indoles with nitroalkenes. J Fluorine Chem 130 394-398... 

Owing to its Lewis acidity, zinc complex 106 lends itself to schemes for alkylation of electron-rich arenes and heteroarenes such as pyrroles by way of conjugate addition. An even more valuable method is the 3-component condensation that unites indole with a nitroalkene and an aldehyde. Three contiguous stereocenters are established in a controlled manner and in an absolute sense by conducting the reaction in the presence of CuOTf, 126, and hexafluoroisopropanol. ... 

Compounds 32a, 32b and 32c were each obtained as mixtures of three diastereomers in 74, 59 and 53 % yield respectively. The major diastereomer in each product mixture arose from a completely endo-selective [4 -f 2] cycloaddition and an exo,anti-selective [3 + 2] cycloaddition anti with respect to the aryl-group). The electron-releasing 3 -indole and 2 -pyrrole substituents on the nitroethene (31b and 31c) clearly had a decelerating effect on the reaction rate. Conversion of the enol ether (14) in the formation of 32b and 32c was only 80 %, imder the above-mentioned reaction conditions, while complete conversion of the enol ether (14) was observed in the case where the nitroalkene was substituted with a phenyl or an electron-withdrawing 3 -pyridine substituent. 

The conjugate addition of indoles to electrophilic alkenes has been known for many years with early examples including methyl vinyl ketone [203] and nitroethylene [204]. A range of new catalysts have been explored. These include a variety of protic and Lewis acids. There has also been exploration of various supported catalysts. Both protic and Lewis acids have also been used in conjunction with ionic liquids, usually imidazolium salts. Many of these studies have been carried out with 1,3-diarylpropen-1-ones as the reactants, but some also include enones such as methyl vinyl ketone and cyclic enones. Chiral catalysts can give enantio-selective additions. Much of the work with chiral catalysts has been summarized by Bandini, MeUoni, Tommasi and Umani-Ronchi [205]. For the most part, the successful reactions have used either enones or nitroalkenes. There are few reports, for example, of addition to acrylate esters. 

Nitroalkenes are not the only substrates employed as electrophiles in these conjugate Friedel-Crafts alkylations using chiral phosphoric acids as catalysts. In fact, the first reports in this field were focused on the reaction of indoles with p,y-unsaturated ot-ketoesters as Michael acceptors, which underwent clean... 

In 2013, chiral imidazoline-aminophenol ligands 138 combined with copper salts were successfully applied by the same group in the AFC reaction of indoles with isatin-derived nitroalkenes 139. By employing the appropriate catalyst, CuOTf/138a or Cu(OTf)2/138a, the reaction of isatin-derived nitroalkene with indole proceeded smoothly to afford 3,3 -bisindole derivatives 140 in up to 99% yield with 92% ee. l,l,l,3,3,3-Hexafluoro-2-propanol (HFIP) was found to be crucial to this transformation, with a positive effect on catalyst activity (Scheme 6.61). 

In 2011, Wan and co-workers developed bis-sulfonamide diamines as a new type of ligands for the Cu-catalyzed AFC alkylation of indoles with nitroalkenes. Ligand screening revealed that 141 was the optimal ligand. In the presence of 5 mol% Cu(OTf)2 and 141 in PhCFj, the AFC reaction of indoles with various aromatic nitroalkenes occurred smoothly to afford the corresponding products in excellent yields (88-99%) and enantioselectivity (88-97% ee) (Scheme 6.62). The reaction was not sensitive to air and moisture. 

Scheme 6.61 AFC reaction of indoles with isatin-derived nitroalkenes 140 catalyzed by Cu/138a complex reported by Aral.

Recently, the Jia group reported AFC alkylation reactions of p,p-disub-stituted nitroalkenes with indoles. The AFC alkylation of indoles with p-CFa-p-disubstituted nitroalkenes 148 and acyclic a-substituted-p-nitroacry-lates 149 was achieved by using Ni(Cl04)2/bisoxazoline 147 complex as a catalyst, affording indoles bearing an all-carbon quaternary stereogenic center in good yields with excellent enantioselectivity (up to 97% ee) (Scheme 6.67). ... 

Other organometallic reagents such as Pt and Rh complexes are also found to be compatible catalysts in the AFC reactions. Song and co-workers reported the synthesis of the cationic pincer Pt" aqua complex 150 derived from a chiral bis(imidazolinyl)phenyl ligand. With 5 mol% of Pt complex 150 in toluene, the AFC alkylation of indoles with nitroalkenes proceeded to afford a variety of nitroalkylated indoles in good yields (up to 81%) with moderate to good enantioselectivity (up to 83% ee) (Scheme 6.68). 

Figure 6.7 A proposed model for asymmetric induction of the Ni-catalyzed AFC alkylation reactions of p,p-disubstituted nitroalkenes with indoles.

In 2009, You and co-workers developed a chiral phosphoric acid-catalyzed AFC reaction of nitroalkenes with 4,7-dihydroindoles. With slow addition of nitroalkene by syringe pump, the reaction proceeded to completion in 2 hours with only 0.5 mol% catalyst. The corresponding adducts were obtained in excellent yields (93-98%) with up to 97% ee. 2-Substituted indole derivatives were obtained by oxidation of AFC adducts with 2 equivalents of j3-benzoquinone without losing any ee value. You and co-workers... 

NitroaUCBnes. Organocatalytic enantioselective reaction of indoles with nitroalkenes appeared recently using chiral sulfonyl vicinal diamine 13 or chiral thiourea 14 as catalysts, which improved the electrophihcity of nitroalkene by double... 

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