Intermolecular Friedel-Crafts

As described above, propargylic alcohols can serve as electrophilic aUcyl equivalents in intermolecular Friedel-Crafts reactions. However, the related intramolecular... 

During distillation of the technical chloride, hydrogen chloride was evolved, air was bubbled through to remove it, and there was an explosion. This was attributed to a polycondensation (intermolecular Friedel-Craft) reaction, possibly catalysed by oxidation products. 

The chloride is usually (but not always) stabilised in storage by addition of aqueous alkali or anhydrous amines as acid acceptors. A 270 kg batch which was not stabilised polymerised violently when charged into a reactor. Contact of the chloride (slightly hydrolysed and acidic) with rust led to formation of ferric chloride which catalysed an intermolecular Friedel-Craft reaction to form polybenzyls with evolution of further hydrogen chloride. Contact of unstabilised benzyl chloride with aluminium, iron or rust should be avoided to obviate the risk of polycondensation. See Benzyl bromide Molecular sieve... 

Fully substituted furan as depicted below was prepared from a Baylis-Hillman adduct in the presence of sulfuric acid in a moderate yield. Intermolecular Friedel-Crafts reaction is one of steps to give rise to the final tetrasubstituted furan <06T8798>. 

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. 

In a substituted aromatic solvent (e.g., m-xylene), the acid chlorides (96, X = Cl) exclusively give the intermolecular Friedel-Crafts reaction, leading to ketones (99, Ar = ra-xylyl).240... 

Cyclodehydration. Neat, anhydrous CH3S020H is at least as useful as polyphosphoric acid for cyclization of 3-arylpropanoic acids and 4-arylbutanoic acids to indanones and tetralones.1 However, it does not appear to be useful for intermolecular Friedel-Crafts condensation. Examples ... 

First, intermolecular Friedel-Crafts alkylations take place as mono functionalizations of the aromatic ring when the primary product cannot take up any additional alkyl group for steric reasons (Figure 5.28, formation of A and B). 

In contrast to the intramolecular case just mentioned, in intermolecular Friedel-Crafts alkylations secondary carbenium ion intermediates often have sufficient time to undergo a Wagner-Meerwein rearrangement (cf. Section 14.3.1). This can lead to the formation of an unexpected alkylation product or product mixtures ... 

Cross-linking reactions require an intermolecular Friedel-Crafts reaction between tertiary cations and positions of the phenyl group made less reactive by the presence of bulky groups on the indane structure. Electrophilic attack of benzylic cation 29 (Fig. 5) upon unsubstituted positions of the phenyl group of 15 is sterically inhibited. 

In the laboratory of K. Krohn, the total synthesis of phytoalexine (+)-lacinilene C methyl ether was completed. In order to prepare the core of the natural product, an intermolecular Friedel-Crafts acylation was carried out between succinic anhydride and an aromatic substrate, followed by an intramolecular acylation. After the first acylation, the 4-keto arylbutyric acid was reduced under Clemmensen reduction conditions (to activate the aromatic ring for the intramolecular acylation). 

McMills, M. C., Wright, D. L., Weekly, R. M. Synthesis of highly functionalized arene systems. Novel selectivities of intra- and intermolecular Friedel-Crafts reactions. Synth. Commun. 2002, 32, 2417-2425. 

The intermolecular Friedel-Crafts alkylation with benzyUc and aUyUc halides occurs at room temperature in CH2CI2. Diarylmethanes are also obtained in moderate yields from arenes and benzyl alcohols on heating the mixtures with InCls 4H2O and acetylacetone at 120°. l-VinyltetraUn and 4-vinyltetrahydrDisoquinoline derivatives are readily formed by an intramolecular aUylation. ... 

Anderson, K. W. and Tepe, J. J. 2002. The first intermolecular Friedel-Crafts acylation with P-lactams. Org. Lett. 4 459M61. 

The intermolecular hydroarylation of indoles or pyrroles with alkynes in the presence of cationic gold(I) catalysts leads to 2 1-adducts With (Z)-2-en-4-yn-l-ols as an unsaturated reaction partner, indoles are converted into dihydrocyclohepta[ )] indoles in a one-pot reaction sequence that involves a gold-catalyzed intermolecular Friedel-Crafts alkylation followed by an intramolecular hydroarylation (Scheme 4-9). ... 

Intermolecular Friedel-Crafts acylation of various substituted alkyl alkoxyben-zenes 1257 with oxalyl chloride using 1,2-dichloroethane [942] or carbon disulfide [943] as solvent gives rise to benzils 1258. 

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. 

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