Friedel-Crafts reactions formylation

Aromatics containing electron releasing groups such as phenols, dim ethyl am in oben 2en e and indole are formylated by 2-ethoxy-l,3-dithiolane in the presence of boron trifluoroetherate, followed by hydrolysis (114). The preformed dithiolanium tetrafluoroborate also undergoes Friedel-Crafts reaction with aromatics such as dim ethyl am in oben 2en e and indole (115), and was used to generate dithiolanium derivatives (formyl precursors) from the enoltrimethylsilyl ether derivatives (116). 

Whereas the above reactions are appHcable to activated aromatics, deactivated aromatics can be formylated by reaction with hexamethylenetetramine in strong acids such as 75% polyphosphoric acid, methanesulfonic acid, or trifluoroacetic acid to give saUcylaldehyde derivatives (117). Formyl fluoride (HCOF) has also been used as formyl a ting agent in the Friedel-Crafts reaction of aromatics (118). Formyl fluoride [1493-02-3] in the presence of BF was found to be an efficient electrophilic formyl a ting agent, giving 53% para-, 43% ortho- and 3.5% meta-tolualdehydes upon formylation of toluene (110). 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

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. 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCb-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with A -bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. ° However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chIoro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with t-butyl chloride in the presence of Feds, only 5-t-butyl monosubstituted and... 

Fluorenecarboxylic acid, 33, 37 Formaldehyde, 30, 51 33, 72 a-Formylethyl methyl ketone, 32, 34 Formyl isobutyl ketone, 32, 34 Friedel-Crafts reaction, 30, 1 31, 88 32, 10... 

Two new methods of formation of C-C bond at C-2 of glycals, with retention of the glycal double bond, have been published recently. Vilsmeier-Hack reaction is involved in the formylation of glycals [180], A Friedel-Crafts reaction of acyl chlorides with glycals, in the presence of aluminium chloride, is required for the C-2 acylation of glycals (Scheme 49) [181]. 

Tetrahydrobenzo[ ]thiophene behaves like thiophene in electrophilic substitution reactions. Thus, it is formylated with a mixture of vV-methylformanilide and phosphorus oxychloride,436 iodinated in the presence of mercuric oxide,193 and brominated by V-bromosuccinimide,193 all in the 2-position in Friedel-Crafts reactions with acetyl chloride,194-436 propionyl chloride,436 succinic... 

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... 

The Gatterman-Koch synthesis is a variant of the Friedel-Crafts acylation in which carbon monoxide and HC1 generate an intermediate that reacts like formyl chloride. Like Friedel-Crafts reactions, the Gatterman-Koch formylation succeeds only with benzene and activated benzene derivatives. 

The work-up with aqueous Na2CC>3 hydrolyses the inline salt and removes any acid formed. This method is particularly useful because it works well with M NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel-Crafts reaction. 

Ethylphenoxazine reacts with V-methylformanilide in the presence of phosphorus oxychloride in o-dichlorobenzene to give 3-formyl-10-ethylphenoxazine.37 The formyl group enters para to the nitrogen atom as in the Friedel-Crafts reaction with 10-ethyl -phenoxazine (30). 

The ring system (1) did not undergo any other electrophilic substitution reactions (nitration, sulfonation, Friedel-Crafts, Vilsmeier formylation), was inert to sodamide, could not be metalated with butyllithium and could not be readily oxidized with hydrogen peroxide to an AC-oxide (66JOC265). Compound (1) could not be reduced at atmospheric pressure by hydrogen but at 3 atm using a palladium-charcoal catalyst the 5,6,7,8-tetrahydro derivative (90) was obtained (75G1291). 

From Hydrocarbons.—An interesting method sometimes applicable for the preparation of aromatic aldehydes is from the hydrocarbons by means of the Friedel-Craft reaction, as modified by Gattermann and Koch with carbon monoxide and hydrochloric acid in the presence of CuCl. In this reaction formyl chloride, which is unknown in the free condition, is probably first formed by the union of the carbon monoxide and hydrochloric acid. 

The hydrocarbon then reacts with the formyl chloride in the presence of CuCl as in the Friedel-Craft reaction with the elimination of hydrochloric acid as follows ... 

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