Vilsmeier-Haack/Friedel Crafts

Section C of Table 11,5 gives some examples of Friedel-Crafts and Vilsmeier-Haack acylations of indoles. 

Furan can also be acylated by the Vilsmeier-Haack method. Acylation of furans can also be carried out with acid anhydrides and acyl halides in the presence of Friedel-Crafts catalysts (BF3-Et20, SnCU or H3PO4). Reactive anhydrides such as trifluoroacetic anhydride, however, require no catalyst. Acetylation with acetyl p-toluenesulfonate gives high yields. 

Thiophene is also readily acylated under both Friedel-Crafts and Vilsmeier-Haack conditions and similarly to pyrrole and furan gives 2-acylated products. An almost quantitative conversion of thiophene into its 2-benzoyl derivative is obtained by reaction with 2-benzoyloxypyridine and trifluoroacetic acid. The attempted preparation of 2-benzoylthiophene under standard Friedel-Crafts conditions, however, failed (80S139). 

Substituted pyrazoles are formylated (Vilsmeier-Haack reaetion) and aeetylated (Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in positions 3 and 5 facilitate the reaetion (80ACH(105)127,80CHE1), but the heteroatoms eompete with the C-substitution. For instanee, when the amino derivative (91 R = = Ph, R = H)... 

Isoxazoles are presently known to undergo hydrogen exchange, nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, Vilsmeier-Haack formylation, and mercuration. The Friedel-Crafts reaction on the isoxazole nucleus has not yet been reported. 

Friedel-Crafts acylation usually fails (72AHC(14)43), but 3-substituted l-methyl-2,1-benzisothiazole 2,2-dioxides can be acetylated at the 5-position (73JHC249). l-Methyl-2,1-benzisothiazol-3-one can be chlorsulfonated at the 5-position (78JHC529). Vilsmeier-Haack formylation causes cleavage of the isothiazole ring (80JCR(S)197). 

Vilsmeier-Haack and Friedel-Crafts reactions, bromination, debromination, debenzylation in indole series and their synthetic application 99YZ35. 

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. 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

Methoxybenzo[J>]thiophene undergoes Friedel-Crafts acylation in the 7-position if this position is blocked, then substitution occurs exclusively in the 2-position.614 It undergoes Vilsmeier-Haack formylation to give its 7-formyl derivative.93... 

Alkoxybenzo[6]thiophenes undergo electrophilic substitution in the 2-position. Thus, 6-ethoxybenzo[6]thiophene affords its 2-bromo, 2-formyl, and 2-acetyl derivatives on bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation, respectively,424 and 6-methoxybenzo[6]thiophene undergoes Friedel-Crafts reaction with /3-carbomethoxypropionyl chloride in the 2-position.618... 

Dimethoxy- and 5,6-methylenedioxybenzo[6]thiophene undergo bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation in the 2-position (see Section VI, A).189 With nitric acid, however, 5,6-methylenedioxybenzo[6]thiophene affords an unidentified mononitro derivative, which is not the 2-nitro compound.548... 

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

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