Pyrroles Friedel-Crafts alkylation

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]. 

Moreover, phosphoric acid (5)-3r (5 mol%, R = SiPhj) bearing a bulky triphe-nylsilyl group turned out to be a suitable catalyst for the asymmetric Friedel-Crafts alkylation of iV-alkyl pyrroles 31 with M-benzoyl-protected aldimines 32 (Scheme 12) [23]. 2-Pyrrolyl amines 33 were obtained in high yields (66-97%) and moderate to high enantioselectivities (42 to >99% ee). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the case of sulfonation and nitration milder reagents can be employed, i.e. the pyridine-sulfur trioxide complex and acetyl nitrate, respectively. Attempts to carry out the Friedel-Crafts alkylation of furan are often unsuccessful because the catalysts required cause polymerization. 

Table 9 Friedel-Crafts Alkylation of Substituted Pyrroles...

We still have to make the pyrrole with the alkyl side chain for this acylation reaction. Friedel-Crafts alkylation is not an option but pyrroles are reactive enough to do the Mannich reaction. Formaldehyde and an amine combine to give another iminium salt 107 that reacts with A-methyl pyrrole to give, after rearomatisation 109 the substituted pyrrole 110. 

Another advantage of this approach is that we can now use electrophilic substitution on the pyrrole to add the rest of the molecule. So the secondary benzylic alcohol 106 might well cyclise to 105 with Lewis acid catalysis as the cation will be reasonably stable and the reaction is intramolecular. But the Friedel-Crafts alkylation to give 107 will not succeed as the cation would be primary. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

For computational studies on the Friedel-Crafts alkylation of pyrroles and indoles catalyzed by chiral imidazolidinones, see R. Gordillo, J. Carter, K.N. Houk, Adv. Synth. Catal. 

General Procedure for Organocatalytic Friedel-Crafts Alkylation of Pyrroles [39]... 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

An enantioselective organocatalytic (with tetrahydro-47/-imidazol-4-one-based catalysts of type 456-HX) Friedel-Crafts alkylation of pyrroles 455 by ot, 3-unsaturated aldehydes generates 3-pyrrolyl carbonyls 457, useful synthons for the construction of a variety of biomedical agents (Equation 108) <2001JA4370, 2002JA1172, 2004ASC1175, 2005JA15051 and references therein>. 

The Friedel-Crafts alkylation of the parent pyrrole and of substituted indoles with a,P-unsaturated acyl phospho-nates 468 <2003JA10780> and 2-acyl iV-methylimidazoles 469 catalyzed by the chiral bis(oxazolinyl)pyridine (pybox)/scandium(lIl) triflate complex 467 exhibits good enantioselectivities over a broad range of substrates (Scheme 97, Equation 113) <2005JA8942>. The desired alkylation products 470-472 were formed in good yields and enantioselectivities. 

Subsequently, MacMillan reported the second-generation MacMillan s catalyst Sb for the Friedel-Crafts alkylation reaction of pyrrole to, form a,p-unsaturated aldehydes (Equation 10.15) [32]. 

The total synthesis (Scheme 25) of ( )-rhazinilam was achieved by viewing the alkaloid as a derivative of a 3-phenylpyrrole. Thus 2-methoxycarbonyl-4-(2-nitrophenyl)pyrrole was first synthesized and then the aliphatic portion of the molecule introduced by alkylation at the pyrrole nitrogen [ —>(111)] and the carbon skeleton completed by intramolecular Friedel-Crafts alkylation [— (112)] at the only available pyrrole a-position. 

A simple example of electrophilic substitution is the VUsmeier formylation with DMF and POCI3, showing that indole has similar reactivity, if different regioselectivity, to pyrrole. If the 3-position is blocked, reaction occurs at the 2-position and this at first seems to suggest that it is aU right after all to take the electrons the wrong way round the five-membered ring. This intramolecular Friedel—Crafts alkylation is an example. 

Scheme 4.55 Enantioselective conjugate Friedel-Crafts alkylation of pyrroles with nitrostyrenes catalyzed by 60d.

The intermolecular hydroarylation of indoles or pyrroles with alkynes in the presence of cationic gold(I) catalysts leads to 2 1-adducts With (Z)-2-en-4-yn-l-ols as an unsaturated reaction partner, indoles are converted into dihydrocyclohepta[ )] indoles in a one-pot reaction sequence that involves a gold-catalyzed intermolecular Friedel-Crafts alkylation followed by an intramolecular hydroarylation (Scheme 4-9). ... 

Less common 2-substituted indole derivatives can be prepared by Friedel-Crafts alkylation of 4,7-dihydroindoles with a,p-unsaturated aldehydes, followed by oxidation with p-benzoquinone [317]. 4,7-Dihydroindoles, which can be considered as 2,3-disubstituted pyrroles, react with a wide variety of aromatic and aliphatic enals... 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

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). 

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. 

The generation of an iminium ion of a, 3-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the cx-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a,j3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(5-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

The first organocatalytic asymmetric carbon nucleophilic addition to enals was reported by MacMillan in 2001 [15]. MacMillan reported the first Friedel-Craft alkylation between N-substituted pyrroles and enals promoted by catalyst 7. The reaction renders the final compounds in good yields and enantioselectivities (Scheme 33.4). 

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