Electron-rich aromatics acylation

Arenediazonium ions are relatively weak electrophiles, and therefore react only with electron-rich aromatic substrates like aryl amines and phenols. Aromatic compounds like anisole, mesitylene, acylated anilines or phenolic esters are ordinarily not reactive enough to be suitable substrates however they may be coupled... 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

Electron-rich aromatic compounds such as durene, p-dimethoxybenzene, mesitylene, anisole, thiophene, and fluorene can be benzoylated or acetylated by the corresponding Af-acylimidazole in trifluoroacetic acid to give the corresponding benzophenone or acetophenone derivative in good yield (Method A). As the actual acylating agent, a mixed anhydride of trifluoroacetic acid and benzoic acid has been proposed 1973... 

Mechanistically, this reaction can be interpreted in terms of an electron-rich aromatic ring undergoing an intramolecular electrophilic attack by a potential acyl cation. The acidic conditions serve to increase the electrophilicity of the side-chain and to assist in dehydration. 

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]. 

Against this background it is important that—quite fitting in this still new millennium— the first catalytic Friedel-Crafts acylations of (still relatively electron-rich) aromatic compounds were reported (Figure 5.35). Trifluoromethane sulfonates ( triflates ) of rare-earth metals, e. g., scandium(III)triflate, accomplish Friedel-Crafts acylations with amounts of as little as 1 mole percent. Something similar is true of the tris(trifluoromethanesulfonyl)-methides ( triflides ) of rare-earth metals. Unlike conventional Lewis acids, the cited rare-earth metal salts can form 1 1 complexes with the ketone produced, but these are so unstable that the Lewis acid can re-enter the reaction. Whether this works analogously for the third catalytic system of Figure 5.35 is unclear. 

BF3 Et20 reacts with fluorinated amines to form salts which are analogous to Vils-meier reagents, Arnold reagents, or phosgene-immonium salts (Eq. 77) [131]. These salts can be used to acylate electron-rich aromatic compounds, introducing a fluorinated carbonyl group (Eq. 78). 

Catalytic acylation of electron-rich aromatics is achieved with a combination of InCls and silver perchlorate (Scheme 8.114) [157]. Acetic anhydride, acetyl chloride and isopropenyl acetate serve as satisfactory acyl donors. By using an InCl3-impreg-nated Si-MCM-41 catalyst at low concentration, acylation of aromatic compounds (benzene, toluene, p-xylene, mesitylene, anisole, naphthalene, methylnaphfhalene, and methoxynaphfhalene) by acyl chlorides (benzoyl chloride, phenylacetyl chloride, propionyl chloride, or butyryl chloride) can be accomplished rapidly (3 h) at 80 °C in high yield, even in the presence of moisture in the aromatic substrate or solvent (dichloroethane) (Scheme 8.115) [158], In(OTf) j is an efficient catalyst in the sulfonylation of both activated and deactivated aromatic compounds (Scheme 8.116) [159]. 

Acylation of electron-rich aromatics is reported to occur efficiently and very easily through mixed carboxylic-triflic anhydrides without any catalyst. The reaction can be applied to methoxy- and alkylarenes and thiophene, with acetic and benzoic acid, in a neat mixture, or in nitromethane (65%-98% yield) at room temperature or at 45°C. 

Some further studies still deal with the Friedel-Crafts acylation in fluorous fluids. These fluids all have very unusual properties such as high density and high stability, low solvent strength and extremely low solubility in water and organic compounds, and, finally, nonflammability. These properties allow their easy handling and reuse. Friedel-Crafts acylation of electron-rich aromatic substrates can be very efficiently performed in a fluorous biphasic system (FBS), which represents a benign technique for phase separation, and catalyst immobilization and recycling. 

The Friedel-Crafts alkylation is one of the oldest synthetic methodologies known. The catalytic asymmetric version of the reaction [311] enables the preparation of important chiral building blocks. Electron-rich aromatic and heteroaromatic compounds have been productively used in organocatalyzed enantioselective inter- and intramolecular Friedel-Craft-[312] type conjugate additions over different Michael acceptors such as, a,p-unsaturated aldehydes, a,P-unsaturated ketones, nitroole-fins, and a,p-unsaturated acyl phosphonates. 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

Gatti N (1990) Electrogenerated acid-catalyzed acylation of electron-rich aromatics. Tetrahedron Lett 31 3933-3936. doi 10.1016/S0040-4039(00) 97510-5... 

Iodine (2% mol) can be used as a catalyst for the acetylation of electron-rich aromatic compounds with aliphatic and aromatic acyl chlorides or anhydrides in 25-93% yields [8]. In successful acylations, the violet-colored refluxing mixture disappears after 15-30 min. Heterocyclic compounds such as furan and thiophene derivatives undergo easy acylation in the presence of variable amounts of iodine. The process is of particular synthetic interest since these heterocycle compounds are... 

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