The Vilsmeier Reaction of Non‐Aromatic Compounds

Abstract

This chapter extends the discussion to reactions between the Vilsmeier‐Haack reagent (subsequently referred to as the Vilsmeier reagent for brevity) and any other compounds in which a carbon‐carbon bond is formed. The discussion thus excludes reactions in which the Vilsmeier reagent acts as a chlorinating agent (for example in the preparation of acid chlorides), or in which it forms carbon‐oxygen or carbon‐nitrogen bonds, unless these are accompanied by formation of a carbon‐carbon bond. For a discussion of the nature of the reagent and of the mechanism of the reaction, the earlier chapter in vol. 49 should be consulted. There are also a number of reviews that deal at length with mechanisms of reactions involving the Vilsmeier reagent, notably those by Jutz and Marson, and hence this chapter will concentrate on applications, with brief mention of mechanisms when necessary. Wizinger has pointed out that alkenes could react with the Vilsmeier reagent, but his only examples were styrenes where the intermediate carbocation has considerable stability. Hydrolysis gives the cinnamaldehyde. In principle, any alkene which is not too sterically hindered can undergo this reaction, but the Vilsmeier reagent has low reactivity as an electrophile, and in practice activation is often necessary. The addition depends on the HOMO of the alkene, and anything increasing the HOMO energy will aid reaction, as for example further conjugation (dienes, trienes, etc.) or the presence of an electron‐donating substituent. Hence aldehydes and ketones are active in their enol forms, and enol ethers and enamines are good substrates. Indeed, all additions covered by this chapter can be regarded as alkene additions, even those on active methyl groups attached to electron‐deficient rings. As with any reaction involving carbocation intermediates, rearrangements are possible; the initial products are sometimes enamines, and this can give rise to polysubstitution. The substrates are grouped into eleven major subsections; references to reviews of particular relevance will be found in the appropriate subsection.

N,N‐Dimethylformamide: A Multipurpose Building Block

“…The formylation of numerous substrates, such as electronrich aromatic or heteroaromatic compounds, [6] as well as electron-rich alkenes and 1,3-dienes, [7] has been achieved by utilizing Vilsmeier reagents (2), which are usually prepared from N,N-disubstituted formamides and acid chlorides (Scheme 2). The relevant works have been well documented in many reviews.…”

Phenylpyrazole‐Based Hypervalent Phosphorus Compounds: From Positional Isomerism to Stacking Interactions

“…[28] To the best of our knowledge, organophosphorus(III) chlorides do not usually react with dimethylformamide.…”

Synthesis of pyridyl substituted pyrazolo[4,3-c]pyridines as potential inhibitors of protein kinases

“…[11][12][13] Unfortunately, an orienting Vilsmeier-Haak formylation 14 applied to 2-(4-methoxybenzyl)-2,4-dihydro-3H-pyrazol-3-one demonstrated that the PMB group does not survive the harsh conditions of this reaction. For this reason, the more stable but harder to cleave benzyl group and the even less vulnerable methyl group were considered as possible R 1 protecting groups.…”