Reactions under Friedel-Crafts Conditions

TTiis intramolecular mode of reaction was also observed with the more nucleophilic solvents toluene or anisole (82MI1). This behavior was found to be different from that of the 3-fluorenylmethylene analogs, which under the same conditions undergo intermolecular alkylation to give butadi-enecarboxylic acids [78IJC(B)502]. 

Furanones having no exocyclic double bond at position 3 behave differently under Friedel-Crafts conditions. Tlius, 41 react with A1C13 in benzene 

This difference in behavior between furanones 41 and those having an exocyclic double bond at position 3 (which under the same conditions produce acids) was attributed to the fact that the latter can afford resonance stabilized carbocations because of the extended conjugation with the aryli-dene moiety in position 3. 

The behavior of the 2(3//)-furanone 43 and of the 2(5//)-furanone 45 as alkylating agents was studied in an attempt to show the effect of the position of the double bond on the reaction mode. Compound 43 reacts with AICI3 in the presence of benzene, toluene, or anisole to give 4-aryl-2,4-diphenylbut-3-enoic acids (44), which are formed by an intermolecular alkylation reaction. On the other hand, the reaction of 45 under the same 

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Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

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... 

Under Friedel-Crafts conditions, /n j -l,2-dibenzoylethylene [959-28-4] is synthesized by the reaction of one mole of fumaryl chloride with two moles of benzene (30) (see Friedel-CRAFTSreactions). 

Acylation of 3-alkyl-6-hydroxy-l,2-benzisoxazole has also been reported (77JIC875) under Friedel-Crafts conditions to give the 7-acyl product. Fries rearrangement of 6-acetoxy-3-methyl-1,2-benzisoxazole in the presence of AICI3 at 140 °C also provides a route to the 7-acetyl-6-hydroxy derivatives (73UC541). Reactions of these kind are rare in this series. 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

Scheme 5.1-45 The reaction between 1-chloropropane and benzene under Friedel-Crafts conditions.

Substituted 2-phenoxyphenylacetic acids readily cyclize under Friedel-Crafts conditions or acid catalysis to give dibenz[Z>,/]oxepin-10(l l//)-ones.71 85,104- 108 When this reaction is carried out in methanolic hydrochloric acid the 10-methoxy-substituted dibenz[6,/]oxepin system 9a can be isolated.109 5-(Nitro-2-phenoxyphenyl)-2-oxopropanoic acid undergoes cyclization in the presence of polyphosphoric acid yielding the carboxylated dibenzoxepin 9b.107... 

Beside these free radical reactions of sulfur dioxide, its electrophilic reactions generating sulfmates with organometallic compounds - or sulfinic acids with arenes under Friedel-Crafts conditions are well known. To complete these three-component syntheses, the sulfmates prepared first are transformed to sulfones by reactions with appropriate electrophiles, discussed earlier in this chapter, i.e. equation 82. 

Transition metal complexes containing Si-OH groups have been isolated in low yield after hydrolysis of the products formed in the reaction between (Me2N)2SiCl2 and ferrocene under Friedel-Crafts conditions [Eq. (25)] (151). 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

Electrophilic attack at carbon occurs regioselectively at the C-l position, although the reaction shown in Scheme 34 might interfere to give small amounts of C-3-substituted product. This was illustrated by some examples in CHEC(1984). Additional recent examples include acylations under Friedel-Crafts conditions <1998H(48)1015, 2001CPB799>. 

Rearrangement can also occur after the initial alkylation. The reaction of 2-chloro-2-methylbutane with benzene under Friedel-Crafts conditions is an example of this behavior.30 With relatively mild Friedel-Crafts catalysis such as BF3 or FeCl3, the main... 

Perimidines are readily acylated under Friedel-Crafts conditions in the carbocyclic ring. Treatment of 2-alkylper-imidines 96 (R = H or Me) with the POCI3 and DMF under Vilsmeier reaction conditions gave a mixture of the 4(9)- and 6(7)-carbaldehydes 97 and 98, although only moderate yields of each were obtained <2006CHE92>. 

The possibility of acetylating the pyrrole nitrogen atom of 9a was investigated. The reaction was performed in the presence of different bases, and the highest yield of the corresponding compound 9b was achieved for potassium tert-butoxide. As should be expected, even trace amounts of this compound are absent from the acylation products of thienopyrrole 9a under Friedel-Crafts conditions <20020L387>. 

Cyclization of the product (27-2) under Friedel-Crafts conditions gives the desired indolinone (27-3). Reaction of the carbanion obtained on treatment of that with 3-chloropropyldimethylamine then gives the alkylation product (27-4). It should be noted that, in spite of this extra step, the scheme is greatly simplified by starting with the very readily available tertiary amine. The superfluous methyl group is then removed by reaction of (27-4) with ethyl chloroformate in the current version of the Von Braun reaction. There is thus obtained amedalin (27-5). Reduction of the amine by any of several methods, for example diborane, leads to the antidepressant daledalin (27-6) [28]. 

Another important path of research, especially to organic chemists, resulted from a discovery by Woodward, Rosenblum, and Whiting at Harvard University in 1952 (128). These investigators noted the failure of ferrocene to undergo Diels-Alder reactions and its resistance to catalytic hydrogenation. They reasoned that because of its remarkable stability, ferrocene might behave like an aromatic substance. These suppositions proved to be the case, as ferrocene was readily acylated under Friedel-Crafts conditions to form acyl derivatives. Indeed, the name ferrocene was given to biscyclopentadienyliron because of its chemical similarity to benzene (128). 

Phenylalkenes also undergo intramolecular alkylation under Friedel-Crafts conditions to yield five- or six-membered cyclic products (indan or tetralin derivatives, respectively). This cyclialkylation145,146,175 may actually also be considered as an isomerization reaction. 

Acetylbenzo[6]tellurophene is also formed in isolable quantities. Benzo[6]selenophene is converted into 2-acyl derivatives by reaction with acid chlorides in the presence of aluminum chloride, whereas similar Friedel-Crafts acylation of benzo[6]thiophene yields 3-substituted products. When the 2-position is blocked, formylation can be directed into the 3-position. Thus treatment of 2-bromobenzo[6]selenophene with dichloromethyl butyl ether (Cl2CHOBu) and titanium tetrachloride yields the 3-formyl derivative (72BSF3955). If the 2- and 3-positions of benzo[6]selenophene are blocked with methyl groups, acylation under Friedel-Crafts conditions occurs in the 6-position (78CR(C)(287)333>. 

Reaction of 5,6-diphenyl-1,2,4-triazin-3-one (215) or 5,6-diphenyl-l,2,4-triazine-3-thione (216) with benzene under Friedel-Crafts conditions led to the isolation of 5,5,6-triphenyl-4,5-dihydro-l,2,4-triazin-3-one (217) and -3-thione (218) respectively (76IJC(B)273). Reacting under similar conditions (C6H6/A1C13) the 6-styryl compounds (219-221) are converted into the corresponding 6-(2,2-diphenylethyl) derivatives, e.g. (222) from (219) (75IJC1098). 

Although there is evidence that chromone syntheses which proceed by the cyclization of phenyl esters under Friedel-Crafts conditions may involve a Fries rearrangement and hence require the formation of one bond adjacent to the heteroatom, syntheses of chromones from phenols will be considered together in this section. The Simonis reaction (530R(7)l)... 

Dihydro-2// -1 -benzothiopyrans (thiochromans) are in almost all their chemistry simply aromatic sulfides. Acylation of the benzene ring under Friedel-Crafts conditions goes, predictably, in position 6, unless blocked, when reaction occurs at position 8 (79MI22506). An even more constrained system (90) may be cyclized efficiently to (91) (equation 35) (76JHC123), though even here a disproportionated product was also formed. 

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