Formylation, aromatic

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. ... 

The use of HF-BF3 mixture as catalyst for aromatic formylation has been reported mostly in the patent literature (refs. 10, 11). Formylations of alkylbenzenes can be obtained with good yields (Fig. 3). 

Formyl fluoride in presence of boron trifluoride forms a complex which has been used in aromatic formylations of alkylbenzenes (ref. 22, Table 1). 

It is therefore worth considering now the mechanism of isotopic fractionation during a chemical transformation, and to illustrate this with the case of aromatic formylation. 

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. 

Basically, we may consider three kinds of aromatic formylation which are likely to involve significant differences in the nature of isotopic fractionation ... 

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... 

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. 

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. 

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... 

All reported studies as well as our own work suggested that HF and BF3 in (at least) stoichiometric amounts are required for effective formylation with CO. Under these conditions this methodology for effecting aromatic formylation is not economically viable. Industrial application of formylation using CO will require the development of new catalysts or methodology to allow the use of HF/BF3 in a catalytic way. In this regard... 

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