Alkylation of electron-rich aromatic

Preformed Carbocationic Intermediates. Propargyl cations stabilized by hexacarbonyl dicobalt have been used to effect Friedel-Crafts alkylation of electron-rich aromatics, such as anisole, /V, /V- dim ethyl a n il in e and 1,2,4,-trimethoxybenzene (24). Intramolecular reactions have been found to be regio and stereo-selective, and have been used ia the preparatioa of derivatives of 9JT- uoreaes and dibenzofurans (25). 

In a series of important papers, MacMillan described the alkylation of electron rich aromatic and heteroaromatic nucleophiles with a,P-unsaturated aldehydes, using catalysts based upon the imidazoUdinone scaffold, further establishing the concept and utility of iminium ion activation. In line with the cycloaddition processes described above, the sense of asymmetric induction of these reactions can be rationalised through selective (F)-iminium ion formation between the catalyst and the a,P-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking one diastereoface of the reactive Jt-system towards nucleophilic attack (Fig. 3). 

Triflic acid is also efficient in the alkylation of electron-rich aromatics (anisole, 1,3-dimethoxybenzene, 2-methylfurane, pyrrole, benzofurane, indole) with secondary benzylic alcohols and 3-phenylallyl alcohols (50°C, 1-9 h, 66-95% yield).201 Benzene, toluene, and halobenzenes are also alkylated with hydroxy-biindantetraone 53 in triflic acid within 1-2h202 [Eq. (5.78)]. Suprisingly, however, the primary products (with the exception of the 4-methylphenyl-substituted compound) undergo rearrangement upon prolonged treatment to yield alkenes... 

Nitroalkenes are widely used in the eatalytie AFC alkylation of electron-rich aromatic rings such as indoles, pyrroles, electron-rich furans, and phenols. The literature up to 2009 dealing with catalytic AFC alkylation of aromatic compounds with nitroalkenes has been reviewed. In this section, only very recent progress on the development on catalytic AFC alkylation of nitroalkenes will be diseussed. 

Fine-tuning of the substrate and reaction conditions is also critical for the asymmetric F-C alkylation of electron-rich aromatic compounds with functionalized aldehydes, ketones and imines. Both the regioselectivity and enantioselectivity of these alkylation reactions can be mediated through use of a complexing chiral catalyst. The catalyst may be either a Lewis or Bronsted base. 

Titanium-mediated intramolecular Friedel-Crafts acylation and alkylation are important methods for construction of fused-ring systems (Scheme 29).107 As well as aromatics, olefin units also react in the same way.108 Alkylation of electron-rich olefins such as enol ethers or silyl enol ethers proceeds effectively in the presence of TiCl4.109... 

The metal-catalyzed addition of aromatic substrates to a- or 7r-systems, also known as Friedel-Crafts alkylation, belongs to one of the most powerful strategies for the formation of C-C bonds [75-77]. Nevertheless, relatively few enantioselective catalytic approaches have been reported that use this reaction manifold, despite the widespread availability of electron-rich aromatics and the chemical relevance of the resulting products. 

The Friedel-Crafts reaction is polar (ionic) alkylation or acylation of electron-rich aromatics by alkyl cation or acyl cation species, derived from the reactions of alkyl halides or acyl halides with A1C13. Therefore, electron-rich aromatics such as anisole are very reactive, but electron-deficient aromatics such as pyridine are inert. 

In the previous sections, the reactions of nucleophilic alkyl and acyl radicals with electron-deficient aromatics via SOMO-LUMO interaction have been described. At this point, we introduce the reactions of electrophilic alkyl radicals and electron-rich aromatics via SOMO-HOMO interaction, though the study is quite limited. Treatment of ethyl iodoacetate with triethylborane in the presence of electron-rich aromatics (36) such as pyrrole, thiophene, furan, etc. produces the corresponding ethyl arylacetates (37) [50-54]. 

The 5-alkyl-2-dimethylamino-l,3-dithiolium -thiolate mesoions 371 underwent chlorination with sulfuryl chloride to form the corresponding sulfenyl chlorides 372 which reacted in situ with a number of electron-rich aromatic compounds to produce arylthio-substituted 1,3-dithiolium salts 373 (Scheme 48) <2004EJ01455>. 

Instead of dienes, aromatic substrates can also participate in tandem cyclopropanation/Cope rearrangement sequences893 894. Rhodium(II) trifluoroacetate catalyzed decomposition of 17 affords the unstable bicyclo[3.2.2] compound 149 in 29% yield893. The reactions of anisol and 1-methoxynaphthalene with 17 show that in the case of electron-rich aromatics side reactions (alkylation reactions) can compete with cyclopropanation reactions due to dipolar intermediates and products 150 and 151, respectively, are formed893. 

Addition of electron-rich aromatic systems to the 1,2,4-triazine ring can easily be achieved by preliminary activation of the heterocyclic system by protonation or alkylation. Addition of the following nucleophiles to the 1,2,4-triazinium ion (129) has been observed indoles, pyrroles, anilines, phenols, and aminothiazoles. The 1,6-dihydro-1,2,4-triazines (130) can be isolated in most cases and oxidized in a second step to the aromatic 1,2,4-triazine system (Scheme 20). 1,2,4-Triazin-5(2i/)-ones also undergo this reaction. 5-Unsubstituted 1,2,4-triazine 4-oxides (131) can be transformed into 5-substituted 1,2,4-triazine 4-oxides (Equation (14)) <86KGS1535, 92H(33)93l, 95UP 611-01>. 

Compared to the intramolecular aromatic alkylation with nucleophilic radicals, the analogous process with electrophilic radicals is far less common. Citterio carefully studied the Mn(OAc)3-mediated intramolecular homolytic aromatic substitution of various dialkyl malonates [71, 73]. He showed that the reaction is well suited for the formation of 5- (see 45), 6- (see 46) and 7-membered benzanellated rings (see 47). For cyclizations forming a 6-membered ring, high yields were obtained in the alkylation of electron-rich as well as electron-poor arenes. However, the formation of the 7-membered ring occurred only with electron-rich arenes. Cerium(IV) ammo-... 

Hydroxylation of electron-rich aromatic rings, A -oxidation of amines, S-oxidation of alkyl sulphides and the conversion of aldehyde and ketones to acids and esters (apparent Baeyer-Villiger reactions) are amongst reactions catalysed by this class of flavoenzymes. 

The reaction of vinylcarbenoids is not limited to dienes but may also be extended to a variety of electron-rich aromatics. Rhodium(II) trifluoroacetate catalyzed decomposition of 4 in the presence of benzene results in the formation of the unstable bicyclo[3.2.2] system 63 (Scheme 23). Direct hydrogenation of 63 results in the formation of 64 from 4 in 29% overall yield. Similar reactions occur with other alkyl benzenes, although these reactions are not of practical utility because mixtures of unstable isomeric products are formed. 

The conjugate Friedel Crafts alkylation is a powerful strategy for the chemical modification of electron-rich aromatic substrates allowing the building up of complex structures, which is very often the synthetic tool of choice when preparing a highly substituted heterocyclic compound. Developments in... 

Given the fact that the catalytic AFC alkylation reactions of electron-rich aromatic rings with electrophilic reagents such as carbonyl compounds, electron-deficient alkenes, and compounds with carbon-carbon double bonds bearing a leaving group in the allylic position have been developed... 

SCHEME 5.5 Ready access to nonnatural aromatic a-amino adds (17) via copper-catalyzed asymmetric FC alkylation of electron-rich benzenes. 

In this segment, You and coworkers documented the snitabUity of the in situ genwated electrophilic indolinium in the chiral Br0nsted acid-mediated enantioselective decoration of electron-rich aromatic hydrocarbons [34]. Both alcohols and NTs amide compounds proved suitability for the enantioselective alkylation of alkoxy-substituted benzenes in inter- and intramolecular fashion. Contact ion pairing between the chiral BA anion and the indolinium intermediate was accounted as active species during the enantiodiscriminating event of the alkylation reaction (Scheme 5.20). 

Several of these // -disubstituted [ C]formamides have demonstrated utility in C-[ " C]formylations of electron-rich aromatic and heteroaromatic substrates via the Vilsmeyer-Haack reaction °. In the presence of POCI3, Cl2(0)P0P(0)Cl2, (COCl)2 or (CF3S02)20 they can C-formylate benzene and naphthalene derivatives that possess an electron-releasing substituent (0-alkyl, S-alkyl, A -dialkyl) as well as anthracene, pyrrole. 

In order to achieve high yields, the reaction usually is conducted by application of high pressure. For laboratory use, the need for high-pressure equipment, together with the toxicity of carbon monoxide, makes that reaction less practicable. The scope of that reaction is limited to benzene, alkyl substituted and certain other electron-rich aromatic compounds. With mono-substituted benzenes, thepara-for-mylated product is formed preferentially. Super-acidic catalysts have been developed, for example generated from trifluoromethanesulfonic acid, hydrogen fluoride and boron trifluoride the application of elevated pressure is then not necessary. 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

The results obtained with different amines cannot be explained merely on the effects of amine basicity. Thus, to obtain complete hydrogenation of Q to DHQ, the basicity has to be tailored by other factors such as the steric hindrance of the amine and its electronic interaction with the catalyst active sites this seems to be favored by the presence of an electron-rich aromatic ring. Of note, the positive effect of substituted aromatic amines, with a 49% DHQ yield being obtained for ethylanilines, is independent of the substituent position of the alkyl group. 

The electronic character of aromatic groups at the a-C of nitrones affects both, the yields and the stereoselections (Table 2.28). Electron-rich aromatic groups increase enantioselectivities but decrease the yields (entries 1-3). Electron-deficient ones slightly decrease enantioselectivities but increase the reaction rates (entries 4 and 5). The electronic properties of A-bound aromatic groups of nitrones has almost no obvious impact on the enantio-selections (entries 6-10). Both, electron-deficient and electron-rich aromatic groups afford good enantioselectivities and diastereoselectivities. Nitrone with a A-bound furyl group furnishes, in moderate yield, the best ee but the lowest diastereoselectivity (entry 9). a-Alkyl and A-alklyl nitrones fail to react (entries 11 and 12). 

Carbocations have also been obtained by protonation of photochemically generated carbenes (see Eq. 17), by the fragmentation of photochemically generated cation radicals (see Eq. 18), and by the addition of one photochemically generated cation to an arene (or aUcene) to generate a second cation. As illustrated in Eq. 19, the last method has been employed to convert invisible carbocations into visible ones. Short-hved aryl cations and secondary alkyl cations are quenched by electron-rich aromatics such as mesitylene and 1,3,5-trimethoxybenzene in HEIP to give benzenium ions that can be observed by LEP in this solvent. 

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