Subject Friedel-Crafts reaction

The importance of the solvent, in many cases an excess of the quatemizing reagent, in the formation of heterocyclic salts was recognized early. The function of dielectric constants and other more detailed influences on quatemization are dealt with in Section VI, but a consideration of the subject from a preparative standpoint is presented here. Methanol and ethanol are used frequently as solvents, and acetone,chloroform, acetonitrile, nitrobenzene, and dimethyl-formamide have been used successfully. The last two solvents were among those considered by Coleman and Fuoss in their search for a suitable solvent for kinetic experiments both solvents gave rise to side reactions when used for the reaction of pyridine with i-butyl bromide. Their observation with nitrobenzene is unexpected, and no other workers have reported difficulties. However, tetramethylene sulfone, 2,4-dimethylsulfolane, ethylene and propylene carbonates, and salicylaldehyde were satisfactory, giving relatively rapid reactions and clean products. Ethylene dichloride, used quite frequently for Friedel-Crafts reactions, would be expected to be a useful solvent but has only recently been used for quatemization reactions. ... 

Under Lewis-acid-catalyzed conditions, electron-rich arenes can be added to alkenes to generate Friedel-Crafts reaction products. This subject will be discussed in detail in Chapter 7, on aromatic compounds. However, it is interesting to note that direct arylation of styrene with benzene in aqueous CF3CO2H containing H2PtCl6 yielded 30-5% zram-PhCH CHR via the intermediate PhPt(H20)Cl4.157 Hydropheny-lation of olefins can be catalyzed by an Ir(III) complex.158... 

Intramolecular Friedel-Crafts reactions can sometimes compete with organosil-icon hydride reductions of benzylic-type alcohols to cause formation of undesired products. An example is the attempted reduction of alcohol 26 to the corresponding hydrocarbon. When 26 is treated with triethylsilane in trifluoroacetic acid at room temperature for 15 hours, a mixture of the two fluorene isomers 27 and 28 is obtained in a combined yield of 45%. None of the hydrocarbon structurally related to the substrate alcohol 26 is obtained.171 Whether this problem could be circumvented by running the reduction at a lower temperature or with a different acid remains subject to experimentation. 

When (190) was subjected to a Friedel-Crafts reaction with benzoyl chloride, the result was an analog of coralyne with a phenyl rather than a methyl group at position 8. Kametani et al. (74YZ478) have carried out a parallel study using the Vilsmeier-Haack reaction to produce norcoralyne. 

The well-established stabilization of a positive charge on carbon p to silicon has been utilized in very versatile methods for the control of aliphatic Friedel-Crafts reactions. The specificity of this stabilization lies behind the utility of both alkenyl- and allyl-silanes as substrates for electrophilic substitutions, and acylations in particular. These classes offer complementary regiospecificities in controlling both the site of acylation and the location of the double bond. This promotion of simple substitution is one of the most significant advances in aliphatic Friedel-Crafts acylations of recent times, and has recently been the subject of an exhaustive review. ... 

The ability to open the furan ring by oxidation has also been utilized for synthesis of trialkylacetic acids A 2-furoic ester is first subjected to a Friedel-Crafts reaction with a tertiary alkyl halide, and the 5-alkyl-2-furoic acid obtained from the product by hydrolysis is then oxidized by alkaline permanganate to the trialkylacetic acid 154... 

Nitroalkanes as alkylating agents in Friedel-Crafts reactions. An interesting reaction was recently reported by Casini and co-workers (64). They found that Friedel-Crafts reaction of benzylic or tertiary nitro compounds with benzene gave normal alkylation products (8) and (9) respectively. 2-Nitropropane gave cumene (10) subject to further transformations. 

The key step is the selective C—H bond activation of two methyl groups of an ortho-tert-hutyl in the Schiff base 434. Treatment of 434 with Pd(OAc)2 afforded the palladacycle 435 in 75 % yield by the help of rather strong coordination to N and O functions. The first functionalization was achieved by the reaction with the alkenylboronic acid to yield the alkylated product 436 in 86 % yield, which was converted to 437 by the Friedel-Crafts reaction. Then the second palladacycle formation from 437 provided two diastereomers 438, which were, without isolation, subjected to carbonylation (40 atm) at room temperature. Treatment of crude reaction mixture with silica gel cleaved the Schiff base and spontaneous lactonization occurred to give a mixture of the lactones 439 and 440 (6 1). The main product was N-alkylated to yield 441. Finally, the fourth ring was constructed by a Heck-type reaction on the aromatic ring to give the desired compound. 

Aluminium chloride (anhydrous) [7446-70-0] M 133.3, m 192.6 , d 2.465. Sublime it several times in an all-glass system under nitrogen at 30-50mm pressure. It has also been sublimed in a stream of dry HCl and has been subjected to a preliminary subhmation through a section of granular aluminium metal [for manipulative details see Jensen Chem Soc 79 1226 1957]. It fumes in moist air. Used in Friedel-Crafts reaction. 

Apart from the arene substrate and an alkyl halide or acyl halide/acid anhydride, Friedel-Crafts alkylations and acylations most often involve a Lewis acid promoter in the form of a metal halide, like AlCl. Several species may function as the active electrophile, and both acyl halide/metal halide complexes and acylium ions have been observed experimentally. The complex forming ability of these metal halides complicates all mechanistic evaluations, and Friedel-Crafts reactions have rarely been the subject of quantum chemical mechanistic studies. 

The formation of carbon-carbon bonds in aromatic systems often takes place by an electrophilic attack on the ring by a carbonium ion or a species with carbonium ion character. The large family of reactions related to Friedel-Crafts reaction are of this type. In aliphatic chemistry carbon electrophiles are more likely to be encountered as carbonyl groups or as such compounds as halides and tosylates, which are subject to nucleophilic displacement. Many examples of these types of reactions have been discussed, particularly in Chapters 1, 2, and 6. There are also some valuable synthetic procedures in which carbon-carbon bond formation results from electrophilic attack by a carbonium ion on an alkene. It is this group of reactions that we will now consider. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

One of the most common uses of [ C]acetyl chloride is its Lewis acid- (AICI3, SnCLi) catalyzed Friedel-Crafts reaction with aromatic or heteroaromatic substrates to produce labeled aryl/heteroaryl methyl ketones. As these intermediates are subject to several types of transformations, they have been used as key intermediates for the synthesis of a wide variety of a,)8-functionalized aryl/heteroaryl alkyl target compounds. For example, aryl/ heteroaryl methyl ketones can be (a) halogenated in the methyl group to provide substrates for reaction with carbon or nitrogen nucleophiles, (b) deprotonated so as to react with appropriate electrophilic partners, (c) subjected to stereoselective carbonyl group reduction to alcohols, or (d) reduced to aryl/heteroaryl alkyls. Such transformations can be conducted sequentially in many combinations. 

When alpha-chloromethyl ethers are subjected to the Friedel-Crafts reaction with benzene, the principal product is benzyl chloride rather than a l enzyl ether. In the case of alpha-chbromethyl propyl ethei , the benzyl ether is produced in 30 per cent yield together with benzyl chloride ... 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

Thus ring acylation of phenols is observed under Friedel-Crafts conditions because the presence of aluminum chloride causes that reaction to be subject to thermodynamic (equi librium) control... 

The large scale preparation of the drug candidate 2 was accomplished via the Sugasawa reaction (an ortho-selective Friedel-Craft acylation on anilines) and the asymmetric addition to ketimines. Understanding the reaction mechanism and reaction parameters is the only way to gain confidence that the reactions will perform as required upon scale up. Below we discuss both subjects in detail. 

---