Notes- N,N-Disubstituted Carboxamides as Agents for the Acylation of Pyrroles.

Kleinspehn, George G.; Briod, André E.

doi:10.1021/jo01064a618

Cited by 30 publications

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“…Because of the wide use of the Friedel−Crafts reaction in the pharmaceutical industry for the production of aromatic ketones, it is highly demanding to substitute acyl chlorides by unactivated substrates. 6 In this regard, although the Friedel− Crafts reactions using carboxylic acids, 7 esters, 8 and tertiary amides 9 as acylating agents have been documented, very few examples employing secondary amides as substrates have been reported. Early studies by Hurd and Webb involved only one example.…”

Section: ■ Introductionmentioning

confidence: 99%

Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides

Huang

Xiao

2016

J. Org. Chem.

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The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.

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Section: ■ Introductionmentioning

confidence: 99%

Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides

Huang

Xiao

2016

J. Org. Chem.

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TheVilsmeier Reaction of Fully Conjugated Carbocycles and Heterocycles

Jones

Stanforth

1996

Organic Reactions

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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.

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