Pyrroles alkyl-keto

The synthesis will therefore normally produce a 2,4-substituted pyrrole, with in addition an ester group or an acyl group at the 3-position, if a keto ster or a diketone respectively has been employed, and an ester group or an alkyl (aryl) group at the 5-position, according to the nature of the amino-ketone. 

The a-hydioxypyiioles, which exist piimadly in the tautomeric pyiiolin-2-one form, can be synthesized either by oxidation of pyrroles that ate unsubstituted in the a-position or by ting synthesis. P-Hydtoxypyttoles also exist primarily in the keto form but do not display the ordinary reactions of ketones because of the contributions of the polar form (25). They can be teaddy O-alkylated and -acylated (41). 

The regioselectivity depends on the substituents in the starting material but gives mainly the 1,2,3,5-tetrasubstituted pyrrole. Exhaustive investigations show that y0-keto esters react with ammonia or amine to give a y0-aminoacrylic ester (12) as a primary step. C-Alkylation of the enamine function in 12 by the haloketone produces the 1,2,3,5-substituted pyrrole 13, while AXalkylation leads to a 1,2,3,4-substituted pyrrole 14 ... 

Another classic method is that known as the Hantzsch pyrrole synthesis (Scheme 9.4). The nitrogen starting material is an enamine (9.2), which is prepared from a beta-keto ester and ammonia. The beta-position of the enamine is electron-rich and is alkylated with an alpha-haloketone. The amino and the carbonyl groups interact in the familiar way to close the ring. 

In a related work, Fu and eo-workers realized the AFC alkylation of indoles with p,y-unsaturated a-keto esters by using heteroarylidene-tethered bis(ox-azoline) 71a and Cu(OTf)2 in DCE at -78 Note that pyrrole was applied successfully in this catalytie system to afford the corresponding produets 73 in high yields with excellent enantioselectivity (Scheme 6.26). 

Ozonolyses of tetrahydro-lH-pyrido-[4,3-fe]-indoles resulted in the formation of a nine-membered keto-lactam, which could either be isolated or in situ cyclized to dihydropyrrolo[3,2-( ]quinolones, which can be derivatized by electrophilic aromatic substitution, selectively on the pyrrole moiety. In the ozonolysis reaction, alkyl cin-noline betaines were formed as side products, most likely via Cl side products. ... 

The oxidation of terminal acetylenes, like that of monosubstituted olefins, often results in inactivation of the P450 enzyme involved in the oxidation. In some instances, this inactivation involves reaction of the ketene metabolite with nucleophilic residues on the protein [196, 197], but in other instances it involves alkylation of the prosthetic heme group (Fig. 4.31). Again, as found for heme alkylation in the oxidation of olefins, the terminal carbon of the acetylene binds to a pyrrole nitrogen of the heme and a hydroxyl is attached to the internal carbon of the triple bond. Of course, as one of the two m-bonds of the acetylene remains in the adduct, keto-enol equilibration yields a final adduct structure with a carbonyl on the original internal carbon of the triple bond [182, 198]. It is to be noted that the oxidation of terminal triple bonds that produces ketene metabohtes requires addition of the ferryl oxygen to the imsubstituted, terminal carbon, whereas the oxidation that results in heme alkylation requires its addition to the internal carbon. As a rale, the ratios of metabolite formation to heme alkylation are much smaller for terminal acetylenes than for olefins. 

A series of 4-hydroxypyrroles was prepared by Groselj and colleagues. P-Ketoester 9 was heated in toluene with N,Al-dimethylformamide dimethyl acetal to furnish enaminone 10 after cychzation. Subsequent treatment of 10 with phenylhydrazine dehvered 4-hydroxypyrrole 11 in moderate to excellent yields. Pyrroles such as 11 exist in equihbrium with their keto form, and were successfully alkylated with benzyl bromide and methyl iodide. The intermediate enaminones could be isolated and characterized and proved useful in the synthesis of other functionalized heterocycles including dihydropyridines, pyrazines, and pyrimidines (13T11092). 

The synthesis of 3-(4-alkyl-4,5-dihydropyrrolo[l,2-a]quinoxalin-4-yl)-2/f-chromen-2-one derivatives by a three-component reaction of salicylaldehyde, p-keto esters, and l-(2-aminophenyl)pyrrole using piperidine-iodine as a dual system catalyst is reported (Table 3.2) (Alizadeh et al. 2014)... 

IL-anchored orffeo-phenylenediamine 97 was used as a common scaffold to construct skeletal diversity of novel heterocyclic molecules using various acids, isothiocyanate, and cyanogen bromide (Scheme 12). IL-supported 97 condensation with 3-nitrobenzoic acids followed by cyclization gave benzimidazole heterocycles 100. The ipso-fluoro displacement by primary amine and subsequent nitro reduction resulted benzimidazole-linked o-phenylenediamine 101. IL-grafted 101 was selected as a common scaffold to the synthesis of 2-alkyl-substituted l zs-benzimidazole 102, and pyrrole[l,2-fl]benzimidazolones 103 using various keto acids in one step (Scheme 12) [43]. IL-supported pyrrole[l,2-a]benzimidazolones 103 were treated with Lawesson s reagents to afford thiopyr-ido-benzimidazolone 106. 

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