Friedel-Crafts type reactions electrophilic activation

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

Friedel-Crafts type reactions of strongly deactivated arenes have been the subject of several recent studies indicating involvement of superelectrophilic intermediates. Numerous electrophilic aromatic substitution reactions only work with activated or electron-rich arenes, such as phenols, alkylated arenes, or aryl ethers.5 Since these reactions involve weak electrophiles, aromatic compounds such as benzene, chlorobenzene, or nitrobenzene, either do not react, or give only low yields of products. For example, electrophilic alkylthioalkylation generally works well only with phenolic substrates.6 This can be understood by considering the resonance stabilization of the involved thioalkylcarbenium ion and the delocalization of the electrophilic center (eq 4). With the use of excess Fewis acid, however, the electrophilic reactivity of the alkylthiocarbenium ion can be... 

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

The gold-catalyzed reaction of alkynes with aromatic units has been extensively studied [105-107]. This reaction allows the synthesis of polycyclic aromatic and heteroaromatic systems via Friedel-Crafts-type processes. Although, the C-H activation of aryl compounds by gold(lll) has been known for more than 70 years, it is accepted that the Friedel-Crafts-type reaction proceeds via [Au(alkyne)] complexes and subsequent electrophilic aromatic substitution with the arenes or heteroarene compounds. 

Dicationic Carbonyl Compound In general, stable carbocations do not react with non activated benzene. In 1991, Shudo et al demonstrated that multiply positively charged (dicationic and tricationic) species have sufficient electrophilicity toward benzene. In the presence of super Bronsted acids (TfOH, TfOH-SbFs), Friedel-Crafts type reaction of benzene was carried out with cinnamaldehyde, its derivatives, and nitromethane (Scheme 2.13) [34]. 

Ferrocene behaves in many respects like an aromatic electron-rich organic compound which is activated toward electrophilic reactions.In Friedel-Crafts type acylation of aromatic compounds with acyl halides, ferrocene is lO times more reactive than benzene and gives yields over 80%. However, ferrocene is different from benzene in respect to reactivity and yields in the Friedel-Crafts alkylation with alkyl halides or olefins. The yields of ferrocene alkylation are often very low. and the separations of the polysubstituted byproducts are tedious. 

Extensions of the electrophilic activation of the alkyne moiety as well as an alkene moiety have been developed and applied. The applications include various reactions, for instance, Friedel-Crafts type alkylations,323 anchimeric assistance of heteroatomic moiety generally followed by rearrangements (see below), implementation of more sophisticated functional groups such as ynamides and allenynes, which are discussed below. 

While its precise role remains unclear, the catalyst 3m is supposed not only to activate the electrophile (26), but also to lower the nucleophilicity of the amide nitrogen atom (Fig. 5). The latter interaction may account for a chemoselective Friedel-Crafts-type alkylation versus an aza-Darzens reaction. 

Other Formylations. Formyl fluoride, the only known stable formic acid derivative, can be used to perform Friedel-Crafts-type acylation to form aromatic aldehydes. The method was developed by Olah and Kuhn.105 Although a number of Lewis acids may be used, BF3 is the best catalyst. It is dissolved in the aromatic compound to be formylated then formyl fluoride is introduced at low temperature and the reaction mixture is allowed to warm up to room temperature. The aldehydes of benzene, methylbenzenes, and naphthalene were isolated in 56-78% yields. Selectivities are similar to those in the Gattermann synthesis ( toiuene benzene = 34.6, 53.2% para isomer). The reacting electrophile was suggested to be the activated HCOF BF3 complex and not the free formyl cation. Clearly there is close relationship with the discussed CO—HF—BF3 system. 

Related classes of gitonic superelectrophiles are the previously mentioned protoacetyl dications and activated acyl cationic electrophiles. The acyl cations themselves have been extensively studied by theoretical and experimental methods,22 as they are intermediates in many Friedel-Crafts reactions. Several types of acyl cations have been directly observed by spectroscopic methods and even were characterized by X-ray crystal structure analysis. Acyl cations are relative weak electrophiles as they are effectively stabilized by resonance. They are capable of reacting with aromatics such as benzene and activated arenes, but do not generally react with weaker nucleophiles such as deactivated arenes or saturated alkanes. 

Many mechanisms in organic chemistry start with an acid/base reaction. This may be just a simple Bronsted-Lowry protonation of a hydroxyl group, which results in the activation of a C-OH bond or it may be a Lewis acid/base reaction as, for example, when aluminium trichloride complexes with a halogenoalkane in the first step of the Friedel-Crafts reaction. In each case, the initial intermediate usually reacts further and leads to the desired product. In inorganic chemistry, the acid/base reaction may be all that is of interest, e.g. the treatment of a carbonate with an acid to liberate carbon dioxide. However, it is unusual in organic chemistry for the acid/base reaction to be an end in itself. It is for this reason that acid/base characteristics are normally considered as a property of the molecule, similar to the nucleophilic and electrophilic properties to which they are closely related, rather than as a fundamental reaction type as is the case in inorganic chemistry. 

The stability of the -C -Si< bond has been known for a long time But on the other hand they are reactive compounds which undergo either - as precursors to vinylsilanes - various types of addition reactions or - as only silyl-protected acetylenes - an electrophilic substitution under Friedel-Crafts conditions in presence of catalytic amounts of Lewis acids The — SiR3 moiety has a highly useful protecting and/or activating function. 

Friedel-Craft Reactions. The Friedel-Craft alkylation and acylation are key reactions for A-methylindole derivatization. These two reactions enable the functionalization of the C3 position and involve the activation of the electrophile by Lewis acid. Numerous types of electrophiles have been applied. 

---