Aromatic formylation reactions

In organic chemistry, the aromatic formylation reactions show great diversity and several hundred examples may be found in the literature (ref. 9) although only a few reactions are of any industrial interest. It should be kept in mind, however, that very highly priced H, C or 0 enriched vanillins are required to adulterate the synthetic commercial vanillins in order to match the isotopic contents found in vanilla beans. From this point of view, some exotic formylation reactions may be of great interest for the fraudsters. 

Whereas the formyl cation could not be directly observed by NMR spectroscopy its intermediacy has been well established in aromatic formylation reactions In order to account for the failure to observe the formyl cation, it has been suggested that CO is protonated in acid media to generate protosolvated formyl cation a very reactive electrophile. Protosolvation of the carbonyl oxygen allows facile deprotonation of the methine proton, thus resulting in rapid exchange via involvement of the isoformyl cation. 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

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 formylation of a phenol 1 with chloroform in alkaline solution is called the Reimer-Tiemann reaction. It leads preferentially to formation of an ortho-formylated phenol—e.g. salicylic aldehyde 2 —while with other formylation reactions, e.g. the Gattermann reaction, the corresponding /jara-formyl derivative is obtained as a major product. The Reimer-Tiemann reaction is mainly used for the synthesis of o-hydroxy aromatic aldehydes. 

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). 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Formylation Reaction of (C6HsS),CH (2) with 1 generates the carbocation (C6H5S)2C H, which reacts with phenols or aromatic ethers to give the thioacetals (3), which are readily hydrolyzed to aldehydes. The formylation shows high pnra-preference. Example ... 

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. 

As far as KIE of aromatic formylations are concerned, most of the works published deal with the determination of kH/kD. A recent review (ref. 10) has drawn up an inventory of kH/kD values for typical formylation precursors and reactions... 

The classical Vilsmeier-Haack reaction - involves electrophilic substitution of a suitable carbon nucleophile with a chloromethyleneiminium salt, for example salt (1). Suitable carbon nucleophiles are generally electron-rich aromatic compounds such as V,N-dimethylaniline (2), alkene derivatives such as styrene (3) or activated methyl or methylene compounds such as 2,4,6-trinitrotoluene (4 Scheme I). These compounds (2-4) react with salt (1) giving, after loss of hydrogen chloride, the corresponding im-inium salts (5-7). Hydrolysis of iminium salt (5) affords aldehyde derivative (8) and this transformation (Ar—H - Ar—CHO) is the well-known Vilsmeier-Haack formylation reaction. Hydrolysis of iminium... 

As concerns the factors leading to the observed reactivity scale, it is our opinion that the relative ground-state energies play a more important role than the relative stabilities of the intermediate carbocations. From a qualitative point of view, it is observed that the more aromatic is the starting molecule, the smaller is the rate of substitution. The order of reactivity is in fact the reverse of the order of the ground-state aromaticities, as determined by several different approaches thiophene > selenophene > tellurophene > furan (see Section II,C). A quantitative confirmation of this hypothesis has been obtained by analysis of the activation parameters for the formylation reaction.57... 

A variety of carbonyl compounds can be prepared, using tin hydride as a radical mediator. Table 1 illustrates examples of radical formylation of several organic halides. The reaction can be applied to aromatic formylation [18] but not to stable radicals such as allyl, benzyl, alkoxymethyl, a-cyanoalkyl, and a-acylalkyl radicals. 

Electrophilic aromatic substitution reactions of compounds 10 occur in a fashion characteristic for heterocyclic analogues of azulene, and are specific at positions 5 and 7 <1994CB1479>. Thus, 10a (R = H, R = Ph) was successfully brominated, formylated, and acylated, as shown in Scheme 7. 

Another strategy, involving a Duff reaction (or hexamine aromatic formylation), offered an alternative approach to febuxostat (1) in six steps from inexpensive 4-hydroxybenzonitrile 35 as the starting material. This route is intellectually interesting as... 

Electrophilic aromatic substitution reactions are a very important class of chemical reactions that allow the introduction of substituents on to arenes by replacing a hydrogen atom covalently bonded to the aromatic ring structure by an electrophile. The most common reactions of this type are aromatic nitrations, halogenations, Friedel-Crafts alkylations and acylations, formylations, sulfonations, azo couplings and carboxylations - to name just a few. 

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