Vilsmeier-Haack reaction mechanism

In a related reaction, the Gattermann aldehyde synthesis, the carbon monoxide of the previous reaction is replaced by hydrogen cyanide (Scheme 6.6). This reaction gives poor yields with benzene itself, but is successful with activated species such as aryl ethers and phenols. The reaction proceeds via an aryl imine and the mechanism is not dissimilar to that of the Vilsmeier-Haack reaction. 

The Vilsmeier-H2iack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier-Haack reaction works better with electron-rich carbocycles and heterocycles. Since pyrrole is very electron-rich, the Vilsmeier-Haack reaction readily takes place. Formylation of methyl pyrrole-2-carboxylate was achieved using the Vilsmeier-Haack reaction. The mechanism is shown below. The resulting methyl 5-formylpyrrole-2-carboxylate, in turn, was converted into nonpeptidic analogues of neurotesin(8-13), which are potential treatment for neuropsychiatric diseases such as schizophrenia and Parkinson s disease. 

There are numerous multistep processes that generate electrophiles. As examples of these types of reactions, we will consider the diazotization of anilines and the formation of chloroiminium ions in the Vilsmeier-Haack reaction. Aryl diazonium ions are useful in the modification of arenes by the Sandmeyer reaction and as electrophilic intermediates in diazonium coupling reactions for the synthesis of dyes and pigments. Several types of synthetic methods have been developed for this chemistry, and the mechanism varies depending on the methodology [13]. Under some conditions, the nitrosonium ion (18) initiates the process (Scheme 1.5). NjOj and NOCl have also been proposed as intermediates in diazotization—both are considered as nitrosonium ion carriers. The aniline reacts... 

SCHEME 1.6 Proposed mechanism for the Vilsmeier—Haack reaction. 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Figure 6.12 shows that carboxylic acids can also be converted into carboxylic chlorides without releasing HC1. This is possible when carboxylic acids are treated with the chloro-enamine A. First the carboxylic acid adds to the C=C double bond of this reagent electrophilically (mechanism Figure 3.40, see also Figure 3.42). Then, the addition product B dissociates completely to give the ion pair C it constitutes the isopropyl analog of the Vilsmeier-Haack intermediate B of the DMF-catalyzed carboxylic chloride synthesis of Figure 6.11. The new Vilsmeier-Haack intermediate reacts exactly like the old one (cf. previous discussion) The chloride ion undertakes an SN reaction at the carboxyl carbon. This produces the desired acid chloride and isobutyric N,N-dimethylamide.

Scheme 3. Synthesis of tryptamine building block 9 and mechanism of the Vilsmeier-Haack formylation reaction.

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