A New Approach to the Synthesis of N‐Alkylated 2‐Substituted Azetidin‐3‐ones

Abstract

We report a one-pot methodology for the synthesis of N-alkylated 2-substituted azetidin-3-ones based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates, obtained in turn in three steps from levulinic acid. IntroductionSince the azetidin-3-one core has been used as a precursor for the synthesis of the natural sphingosine-type alkaloids penaresidines A and B and penazetidin A, [1] or as an intermediate in the synthesis of polyoxin antibiotics, [2,3] a number of different methodologies to obtain these fourmembered heterocycles have previously been described. [4] Cyclisation based on rhodium carbenoid intramolecular NH insertion has been developed by Seebach for the preparation of some azetidine-containing amino alcohol and amino acid derivatives [5] and by Vederas et al. for the synthesis of keto-glutamine analogues, [6] while De Kimpe has recently reported the synthesis of 4-alkyl-1-benzhydryl-2-(methoxymethyl)azetidin-3-ol as the result of stereoselective alkylation at the C-4 position of the corresponding azetidin-3-one obtained through a high-temperature reaction of an N-(diphenylmethylidene)-3-bromoamine precursor. [7] Azetidin-3-ones could also be obtained from the corresponding azetidin-3-ol precursors by use of pyridinium dichromate or Swern-type oxidation conditions. [8] As part of a recently started program aiming at the transformation of non-food/non-feed agricultural products, byproducts and waste materials into commodity chemicals we were interested in fine chemistry application of polyfunctionalised building blocks. One such derivative is 4-oxopentanoic acid or levulinic acid (LA; 1), traditionally obtained through the controlled degradation of hexose sugars by mineral acids.[9] The increasing number of patents directed towards the production of levulinic acid demonstrates its potential as an important basic chemical that could now be cost-efficiently produced from raw materials such as wood, [a] 2440A mechanistic interpretation of these reactions and an attempted enantioselective approach are also described. Germany, 2006) starch, cellulose-containing waste materials, recycled paper, or agricultural residues.[10]Beside its conversion into methyltetrahydrofuran, a fuel extender, or into δ-aminolevulinic acid, a biodegradable broad spectrum herbicide, [11] levulinic acid (1) also offers a great number of other synthetic transformations, [12] such as the synthesis of fused heterocycles prepared from norbornane amino acids and diamines [13] or the synthesis of the antibiotic lissoclinolide. [14] For a recent synthetic endeavour we needed ethyl 5-bromo-4-oxopent-2-enoate (3a) as key intermediate. This levulinic acid derivative appeared to be an even more versatile intermediate for further transformations such as Diels-Alder reactions, coupling reactions, nucleophilic substitutions and conjugate additions, and it was speculated that nucleophilic substitution combined with intramolecular Michael reaction should ope...

Novel Syntheses of Azetidines and Azetidinones

“…N -Substituted azetidin-3-ones 279 are obtained in a one-pot methodology by treatment of primary amines with alkyl 5-bromo-4-oxopent-2-enoates 277 (Scheme ) …”

Pyridazinone Derivatives Limit Osteosarcoma-Cells Growth In Vitro and In Vivo

“…Pyridazinone derivatives bearing indole or 5-methoxy-indole moieties (named 3a and 3c , respectively; Figure 1 ) were obtained by a three-step sequence starting from levulinic acid. After the preparation of the α,β-unsaturated levulinate [ 30 ], regiospecific introduction of the heterocyclic system was carried out on this intermediate by a Friedel–Crafts-type reaction, followed by condensation with hydrazine leading to the formation of the desired functionalized pyridazinones with good yields [ 31 , 32 , 33 ].…”

Inhibition of Recruitment and Activation of Neutrophils by Pyridazinone-Scaffold-Based Compounds

“…Pyridazinone derivatives bearing indole (4aa) or 5-methoxy-indole (4ba) moieties were obtained by a three-step synthesis starting from levulinic acid. After preparation of the α, β-unsaturated levulinate intermediate [57] regiospecific introduction of the heterocyclic system was carried out via a Friedel-Crafts-type reaction, followed by condensation with hydrazine leading to the formation of the desired functionalized dihydropyridazinones with good yields [58][59][60]. A final oxidation step using manganese dioxide allowed us to obtain corresponding pyridazinone derivatives named 4aa and 4ba.…”