Aromatic compounds formylation

Aldehyde Synthesis. Formylation would be expected to take place when formyl chloride or formic anhydride reacts with an aromatic compound ia the presence of aluminum chloride or other Friedel-Crafts catalysts. However, the acid chloride and anhydride of formic acid are both too unstable to be of preparative iaterest. 

Aromatic compounds are formylated also by dichioromethyl methyl ether or trialkyl orthoformates (128). 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation. An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

Another formylation reaction, which is named after Gattermann, is the Gatter-mann-Koch reaction. This is the reaction of an aromatic substrate with carbon monoxide and hydrogen chloride (gas) in the presence of a Lewis acid catalyst. Similar to the Gattermann reaction, the electrophilic agent 9 is generated, which then reacts with the aromatic substrate in an electrophilic aromatic substitution reaction to yield the formylated aromatic compound 10 ... 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

Although limited to electron-rich aromatic compounds and alkenes, the Vilsmeier reaction is an important formylation method. When yV,A-dimethylformamide is used in excess, the use of an additional solvent is not necessary. In other cases toluene, dichlorobenzene or a chlorinated aliphatic hydrocarbon is used as solvent. ... 

This procedure illustrates formylation by N,N-dimethylamino-methoxymethylium methyl sulfate, a compound which can be produced readily by reaction of easily available materials. 6-(Dimethylamino)fulvene is a useful intermediate for the synthesis of various f used-ring nonbenzenoid aromatic compounds. 

Carbon monoxide, hydrogen cyanide, and nitriles also react with aromatic compounds in the presence of strong acids or Friedel-Crafts catalysts to introduce formyl or acyl substituents. The active electrophiles are believed to be dications resulting from diprotonation of CO, HCN, or the nitrile.64 The general outlines of the mechanisms of these reactions are given below. 

Aromatic compounds, 13 108-109 13 680. See also Aromatics acylation of, 12 173-181 amination of, 12 184 arylation of, 12 170-171 Cycloalkylation of, 12 169 in diesel fuel, 12 425 formylation of, 12 178 Friedel-Crafts acylation of, 12 174 Friedel-Crafts alkylation of, 12 164 nitration of, 12 182-183 oxidative coupling of, 19 654 sulfonation of, 12 181 sulfonation reagents for, 23 521-524 Aromatic-containing polymers, sulfonation of, 23 535-536... 

A ketone can also be formed with a Friedel-Crafts acylation. The process requires an acid chloride and an aromatic compound. An aldehyde can t be formed by this procedure because the appropriate acid chloride, formyl chloride (HCOCl), is unstable and decomposes to carbon monoxide and hydrogen chloride. Figure 10-12 illustrates the preparation of acetophenone from benzene and acetyl chloride. 

Peracid oxidation of the D-homo-oestrone derivative (59) gave the C-ring aromatic compound (60). ° Mono- or tri-formylation with DMF-POCI3 of 17-methylene-steroids led to the unsaturated aldehydes (61) or the dimethylamino-bisaldehydes (62) which were readily converted with NHa-EtOH into the heterocycles (63). 14-Azidopregnanes are available from the reactions of A -... 

Other Formylations. Formyl fluoride, the only known stable formic acid derivative, can be used to perform Friedel-Crafts-type acylation to form aromatic aldehydes. The method was developed by Olah and Kuhn.105 Although a number of Lewis acids may be used, BF3 is the best catalyst. It is dissolved in the aromatic compound to be formylated then formyl fluoride is introduced at low temperature and the reaction mixture is allowed to warm up to room temperature. The aldehydes of benzene, methylbenzenes, and naphthalene were isolated in 56-78% yields. Selectivities are similar to those in the Gattermann synthesis ( toiuene benzene = 34.6, 53.2% para isomer). The reacting electrophile was suggested to be the activated HCOF BF3 complex and not the free formyl cation. Clearly there is close relationship with the discussed CO—HF—BF3 system. 

Although less reactive than many aromatic aldehydes, formyl-pyrroles and -indoles undergo base-catalyzed reactions with a variety of activated methylene compounds to yield compounds of the type (431) and (432), where, for example, X, Y = C02Et, C02Et COMe,... 

Formylation of the less reactive phenol and anisole with CO in HF-BF3 was found to require at least stoichiometric amount of the acid for effective transformation (50 equiv. of HF, 2 equiv. of BF3, 50 bar CO, 45°C).445 Conversion increases with increasing reaction time but results in decreasing paralortho ratios suggesting a change from kinetic control to thermodynamic control and the reversibility of formylation. Furthermore, the amount of byproducts (mainly diphenylmethane derivatives) originating from reactions between substrates and products also increases. Additional studies in ionic liquids showed that imidazolium cations with increased chain lengths—for example, l-octyl-3-methylimidazolium salts—are effective in the formylation process. This was attributed to the enhanced solubility of CO in the ionic liquid medium. Tris(dichloromethyl)amine, triformamide, and tris (diformylamino)methane have recently been applied in the formylation of activated aromatic compounds in the presence of triflic acid at low temperature (— 10 to 20°C) albeit yields are moderate.446... 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

The Vilsmeier reaction is the formylation of reactive aromatic compounds by using a combination of phosphorus oxychloride and N,N-dimethylformamide, followed by a hydrolytic workup. 

Importantly, a Friedel-Crafts formylation has not yet been successful. Formyl chloride and formic anhydride are not stable reagents. The mixed anhydride H—C(=0)—O—C(=0)CH3 acts as a formylating reagent in reactions with many nucleophiles (cf. Section 6.3.3). However, in reactions with aromatic compounds under Friedel-Crafts conditions, it acts as an acetylating agent rather than as a formylating agent. Last but not least, formic acid and mineral acids proceed to react via the acylium ion H—C=0 to form carbon monoxide and water in an OC-elimination. We ll solve this problem later. 

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