Vilsmeier cyclization of α-acetyl-α-aroyl ketene-N,S-acetals: direct and efficient synthesis of halogenated pyridin-2(1H)-ones

Abstract

An efficient synthetic route to 3-aroyl-5-formyl-4-halo pyridin-2(1H)-ones has been developed via Vilsmeier cyclization of 2-(ethylthio(arylamino)methylene)-1-alkylbutane-1,3-dione.

Chemistry of Ketene N,S-Acetals: An Overview

“…Under identical conditions as described, 43 were prepared in high yields by Yu et al using β-dicarbonyl compounds as the active methylene components and bromoethane as alkylating reagent (Table ). The reaction favored the formation of ketene N , S -acetals in Z isomers, probably due to steric hindrance operating through thermodynamic control, so that the relatively larger Ar 1 NH group is located in cis with the acetyl group (smaller than aroyl group), and the structure of ( Z )- 43a was confirmed by X-ray crystallographic analysis.…”

“…104−106 In the presence of a relatively weak base, K 2 CO 3 , 107 a series of ketene N,S-acetals including 2e (see Scheme 2) having two electron-withdrawing groups are prepared in high to excellent yields by use of the more CH-acidic methylene compounds as substrates (Scheme 12). Under identical conditions as described, 43 were prepared in high yields by Yu et al 108 using β-dicarbonyl compounds as the active methylene components and bromoethane as alkylating reagent (Table 1). The reaction favored the formation of ketene N,S-acetals in Z isomers, probably due to steric hindrance operating through thermodynamic control, so that the relatively larger Ar 1 NH group is located in cis with the acetyl group (smaller than aroyl group), and the structure of (Z)-43a was confirmed by X-ray crystallographic analysis.…”

“…They found that 144 was active against Trypanosoma cruzi Y strain, which can cause Chagas' disease. 166 Yu et al 108 found that under Vilsmeier reaction conditions (VR, POCl 3 /DMF or PBr 3 /DMF), 33 (see section 2.2, Table 1) acting as a 1,5-C,N-dinucleophile enabled the synthesis of halogenated pyridin-2(1H)-ones (Scheme 34, 22 examples, 74− 85% yields) via a mechanism probably involving formation of iminium species as intermediates and thus driving the intramolecular cyclization as the key step to furnish halogenated 149 (Scheme 34). In the synthesis of 149, Vilsmeier reagent plays the double roles of both a one-carbon electrophile and a halogenating agent.…”

“…In the synthesis of 149, Vilsmeier reagent plays the double roles of both a one-carbon electrophile and a halogenating agent. 6,108,167 Alkenoyl (including cinnamoyl) ketene S,S-acetals, prepared by base-promoted condensation of acetyl ketene S,S-acetals with aldehydes, are useful synthetic intermediates for the synthesis of six-membered carbo-and heterocyclic compounds. 7,168−172 In comparison, the synthetic applications of alkenoyl ketene N,Sacetals are rare.…”

K2CO3-accelerated amidation of carboxylic acids using α-oxo ketene-N,S-acetals as amine surrogates

“…18 As part of the continuous progress, we recently reported the [5 + 1] annulation reaction of α-oxo ketene- N , S -acetals (R 4 = CH 3 ) and a Vilsmeier reagent to form pyridin-2(1 H )-ones (Scheme 1a (4)). 19 However, the synthetic exploitation of the amino group of these substrates by C–N bond cleavage is difficult to achieve due to the extended conjugation along the framework, which imparts double-bond character to the C–N bond. Therefore, this type of reaction remains unexplored to date.…”