Carbonyl compounds Friedel-Crafts alkylation

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. 

Phenols are such good nucleophiles that protonated carbonyl compounds functionalize two phenol molecules. The first phenol molecule reacts in an Ar-SE reaction by the carboxonium ion formed in an equilibrium reaction. Subsequently, the second equivalent of phenol becomes the substrate of a Friedel-Crafts alkylation. The electrophile is the benzyl cation that is formed from the initially obtained benzyl alcohol and the acid. Protonated acetone is only a weak electrophile for electronic and steric reasons it contains two electron-donating and relatively large... 

Alkylations. Friedel-Crafts alkylation and allylation of carbonyl compounds are effectively catalyzed by MCjSiNTfj. 

Tab. 8.28 Reductive Friedel-Crafts alkylation of aromatics with carbonyl compounds...

Polyalkylation, an advantage here, can be a nuisance with Friedel-Crafts alkylations as can the rearrangement of primary alkyl halides. Thus, the alkyl halide (8) gives a mixture of (9> and (10) with benzene and if we want to make compound (11) we must use the Friedel-Crafts acylation, which suffers from neither of these disadvantages, and then reduce the carbonyl group (see Chapter 24). 

To disconnect a 1,3-diX compound not at the carbonyl oxidation level we must first alter the oxidation level by FGI, If the TM contains no oxygen substituent, we must produce one by substitution. Japanese chemists wished lo study the stereochemistry of the Friedel-Crafts alkylation and chose to make optically active (43) for this purpose. Disconnection of the ester reveals a 1,3-diX relationship, and adjustment of the oxidation level to the acid (44) takes us back to simple starting materials. 

Friedel-Crafts reactions are conversions that form one additional carbon-carbon bond with an aromatic compound, catalysed by strong Lewis acids. Inportant reactions are Friedel-Crafts alkylation, Friedel-Crafts acylation and carbonylation. 

TBDMS triflate-activated carbonyl compounds have also been trapped intramolecularly with carbon-carbon double bonds, such as in the intramolecular Friedel-Crafts alkylation of a furan (eq 20).i ... 

Neither Friedel-Crafts alkylation nor acylation occurs on aromatic rings that have —NO, —SO H, —C=N, or any carbonyl-containing group that is bonded directly to the aromatic ring. The carbonyl-containing compounds include aldehydes, ketones, carboxylic acids, and esters. All of these substituents make the benzene ring less reactive, as we will shortly discover (Section 13.5). 

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). 

As mentioned above, a range of enantioselective transformations have been established using chiral phosphoric acids via the activation of imines and related nitrogen-substituted substrates. In contrast, the activation of carbonyl compounds, including a,P-unsaturated carbonyl compounds, by chiral phosphoric acids has been limited. In 2008, Zhou, He, and coworkers achieved the asymmetric Friedel-Crafts alkylation reaction of indole derivatives with 1,3-diaryl a,p-unsaturated... 

Asymmetric Friedel-Crafts alkylations of indoles with a,p-unsaturated carbonyl compounds have been and continue to be of significant interests in synthesizing chiral indole alkaloids. Following the very successful iminium-catalysis with enals by MacMillan s catalyst [47], Chen and Melchiorre have independently reported asymmetric Friedel-Crafts alkylation of indoles with a,P-unsaturated aryl ketones [48] using similar cinchona-alkaloid derived catalysts 77 and 91, respectively (Scheme 5.24) [49]. In both cases, the proper choice of an acidic additive has been shown to be essential for catalytic activity and stereoselectivity. 

Other acids have also been explored. For instance, a heleropoly acid catalyzed Friedel-Crafts alkylation of indole and pyrrole with enones and electron-deficient olefins in water at room temperature, affording good yields at 0.3mol% catalyst loading [112]. Similarly, a carbon-based solid add was shown to catalyze effidendy the reaction of indoles with a,p-unsaturated carbonyl compounds in water, and the... 

Preparation of the C-labelled compound 65 was accomplished in a manner analogous to Scheme 14. Friedel-Crafts acylation of 44 was conducted with [2- C]-chloroacetyl chloride under aluminum trichloride catalysis to give the radiolabelled intermediate 64 (48 mCi/mmol). The carbonyl group of 64 was reduced with triethylsilane and the resulting alkyl chloride was reacted with piperazine 40 to provide C-labelled ziprasidone (65). The HCI salt of 65 was formed resulting m a final compound with a specific activity of 9.6 mCi/mmol. 

In the present paper we have studied four acid catalyzed reaotions involving carbonyl compounds alkylation of benzene with formaldehyde, esterification of phenylacetic acid, Friedel-Crafts acylation by phenylpropanoyl chloride, and the cross aldolic condensation of acetophenone with benzaldehyde in the presence of three Hp zeolites with different framework Si-to-Al... 

Electrophilic ring closure of aryl-substituted compounds such as alkenes, halides, alcohols, and carbonyl compounds called cyclialkylation can be induced by conventional Friedel-Crafts catalysts309 and by superacids. Examples are also known in which an intermolecular alkylation step is followed by intramolecular alkylation of the intermediate to furnish a cyclic product. 

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