Aldehydes Friedel-Crafts alkylation

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

Direct electrophilic substitution of benz- and dibenz-azepines remains relatively unexplored. Most substituted benzazepines have been prepared from benzene precursors bearing the desired substituents (74AHC(17)45). The bulk of the reported electrophilic substitutions have been carried out on 5//-dibenz[6,/]azepine (74CRV101), MO calculations on which predict that substitution should occur at the 2- and 4-positions, i.e. para and ortho to the azepine ring nitrogen. These predictions are borne out by Friedel-Crafts alkylation and acylation studies, although it is apparent that a second alkyl group enters at the 8- rather than at the 4-position. Formylation under Vilsmeier conditions yields the 2-aldehyde. As noted earlier (Section 5.16.3.4), however, the 10,11-dihydro system exhibits different behavior and acylates at the benzylic 10,11-positions. Nitration with mixed acids of the... 

Carbonyl compounds, particularly aromatic aldehydes, when activated with electrophilic catalysts, can also react with aromatics.241 The process is often called condensation or reductive alkylation, but it is actually a multistep Friedel-Crafts alkylation reaction. 

The synthesis of alkylbenzenes may be classified under (a) the Wurtz-Fittig reaction (b) the reduction of aryl aldehydes and ketones and (c) and Friedel-Crafts alkylation reaction. 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

The use of other nucleophilic species to perform Friedel-Crafts alkylations to a,/ -unsaturated aldehydes has also been investigated, with success. For example, indoles [14, 83] and anilines [18, 84] have been added to a,/ -unsaturated aldehydes, providing 1,4-addition products in good yields and excellent enantioselec-tivities. Again, the importance of such an approach is demonstrated by the suc-... 

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>. 

Reductive Friedel-Crafts alkylation Benzylic alcohols obtained from the InClj-catalyzed alkylation with aldehydes can be reduced in situ by a hydrosilane (e.g., chlorodimethylsilane). The latter process is also catalyzed by Lewis acid. 

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]. 

Since 1972, updates on Friedel-Crafts alkylation, aromatic aldehyde synthesis, nitration, etc., were regularly published in books and extensive reviews. However, improvements in Friedel-Crafts acylations were scantly considered, despite the great practical application of the aromatic ketones in different fields of the fine and pharmaceutical chemistry. 

Reductive Friedel-Crafts alkylation. The reagent is actually a double salt, GaCl GaClj, and advantages can be taken of the reducing power of Ga(I) and the Lewis acidity of Ga(III). Thus the reaction of aldehydes, ketones, or acetals with are-nes directly affords alkylarenes. 

The approach to haplophytine proposed by Fukuyama and Tokuyama et al. did not rely on the synthesis of aspidophytine previously reported [75]. One of the main synthetic problems was the connection of the left-hand segment to the indole moiety of aspidophytine. Retrosynthetically, Fischer indole synthesis of the fully elaborated left-hand fragment 186 and the tricychc ketone 187 gave haplophytine. 186 was generated through oxidative skeletal rearrangement from precursor 188, which was accessible from indole 189 by Friedel-Crafts alkylation. Optically active ketone 187 was assembled through a stereoselective intramolecular Mannich reaction from aldehyde 190 (Scheme 33). 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

Several possibilities for a large-scale synthesis of mesitylacetic acid 12, a central building block in the synthesis of spiromesifen 8a, were examined (Scheme 28.4.2). Using the classical standard route, mesitylene 13 is transferred into mesityl acetonitrile 14 via chloromethylation and cyanide exchange, which is then saponified to the aryl acetic acid. Another route examined is the Friedel-Crafts alkylation of mesitylene with 1,3-dichloro-propene to the adduct 15, which is ozo-nolyzed to the corresponding aldehyde in the form of its dimethyl acetal and than further oxidized with hydrogen peroxide under acidic conditions to mesityl acetic... 

In related synthetic approaches intermediate phthalidotetralins have been prepared through Friedel-Crafts alkylation of tetrahns with bromophthalides [24,25], or through reaction of specifically lithiated ring D [26] or AB [27,28] precursors with aldehydes. Thus addition of aldehyde 18 to the ortho lithiated chromium complex 19, decomplexation, and treatment with acid and then base gave the phthalides 20 which were converted to ( )-ll-deoxydaunomycinone 7 [28]. 

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