TheVilsmeier Reaction of Fully Conjugated Carbocycles and Heterocycles

Abstract

In 1925 Fischer, Müller, and Vilsmeier published a paper describing the reaction between phosphoryl chloride and N ‐methylacetanilide, giving a number of products, including the quinolinium salt and another salt. The probable course of the reaction was given in a paper by Vilsmeier and Haack in 1927, and they made the important discovery that the reagent obtained from N ‐methylformanilide and phosphoryl chloride, represented as a salt, would react with N,N ‐dimethylaniline, giving 4‐ N,N ‐dimethylaminobenzaldehyde. No 2‐substituted products were observed in this reaction. Other N,N ‐dialkylaniline derivatives, including 3, N,N ‐trimethylaniline and 1‐ N,N ‐dimethylaminonaphthalene were also successfully used as substrates to prepare aromatic aldehyde derivatives. The gradual development of the reagent for synthesis was accompanied by interest in the nature of the reagent. It was discovered that other acid chlorides (e.g., thionyl chloride, carbonyl chloride, and oxalyl chloride) could be used in the reaction and that substituted amides other than formamides gave ketones, although in generally poorer yields. Thionyl chloride frequently gives sulfur‐containing products. The most commonly used amide is dimethylformamide (DMF) and there is now a consensus that the reagent formed from DMF and most acid chlorides, other than phosphoryl chloride, can be represented by the structure given in the chapter, and this is illustrated for the reaction between DMF and carbonyl chloride. The salt is a stable compound and is often isolated before being reacted with a substrate. It seems likely that the most commonly used reagent, that made from DMF and phosphoryl chloride, is an equilibrium mixture of iminium salts. Recent unpublished spectroscopic studies have indicated that in DMF solution there is an equilibrium mixture of iminium compounds. One of the electrophilic chloroiminium salts then reacts with a substrate in an electrophilic substitution process yielding an iminium salt, which is usually hydrolyzed to the aromatic aldehyde. Vinylogous chloroiminium salts can be prepared from the corresponding vinylogous formamide derivatives and these yield, after hydrolysis, α,β‐unsaturated products. This particular reaction is generally limited to more reactive substrates. The formation of carbon–carbon bonds to fully conjugated carbocycles and heterocycles is the subject of this chapter; a subsequent chapter considers carbon–carbon bond‐formation reactions in alkenes (including heterosubstituted alkenes such as enamines and enol ethers), alkynes, and activated methyl and methylene compounds (aldehydes, ketones, carboxylic acid derivatives, and nitriles). It is not surprising that the Vilsmeier reaction has been the subject of many review articles of varying scope and length. With so many excellent reviews dealing with the Vilsmeier reaction, its mechanism, and the structure of the various electrophilic reagents, coverage is restricted to important concepts rather than reiterate all the literature material. A brief description of the mechanism and regiochemistry of the Vilsmeier reaction is presented and this is elaborated with appropriate cases that deal with specific compound types.

Heterocyclic Analogues of Xanthone and Xanthione. 1H-Pyrano[2,3-c:6,5-c]dipyrazol-4(7H)-ones and Thiones: Synthesis and NMR Data

“…2-Pyrazolin-5-ones 1 are either commercially available or can be easily prepared according to known methods [21]. Acid chlorides 2 , which can be considered as the key synthons in the approach presented, were prepared as follows: Vilsmaier-Haak formylation [22] of pyrazolones 1a and 1b , respectively, gave the 5-chloropyrazole-4-carbaldehydes 6 , which were oxidized to the corresponding carboxylic acids 7 by treatment with potassium permanganate [23]. Transformation of acids 7 into the appropriate acid chlorides 2 was accomplished with thionyl chloride in refluxing toluene [9,11,12].…”

Copper-Catalyzed Aerobic Methyl/Methylene Oxygenation and C-H Formylation with a DABCO-DMSO System for the Synthesis of Carbonyl Indoles and Pyrroles

“…Conventional C(3)-H formylation of indoles has relied exclusively on the Vilsmeier reaction using toxic phosphoryl chloride (POCl 3 ) and DMF. 15 This copper-catalyzed aerobic direct C(3)-H formylation of indole 3a in DMSO prompted us to investigate in more detail the optimization of the reaction conditions and the scope of the reaction (Table 3). 16,17 Screening of copper salts revealed that the use of Cu(OCOCF 3 ) 2 was optimal for this direct C(3)-H formylation (entry 6), giving 4a (= 2a) in 50% yield.…”

An Overview on Common Organic Solvents and Their Toxicity

“…At an elevated temperature DMF hydrolyzed by strong acid and base. It is also used as a reagents in many cases, like a reagent in the Vilsmeier-Haack reaction where it first convert to chloroiminium ion known as Vilsmeier reagent that attacks arenes [72]. Many research has been carried out to reveal the toxicity of DMF, viz hepatotoxicity [73,74] and other many more [75][76][77].…”