Expedient Synthesis of a 72-Membered Isoxazolino-β-ketoamide Library by a 2·3-Component Reaction

Abstract

An efficient 2•3-component reaction (2•3CR; a 2-component reaction followed, in one pot, by a 3-component reaction) is presented for the synthesis of isoxazolino-β-ketoamides. This 2•3CR proceeds by (i) a Meldrum's acid-generated acyl ketene, which is trapped by an amine to form a β-ketoamide intermediate in a 2CR followed, in one pot, by (ii) a Mannich reaction followed by elimination of dimethyl amine•HCl to generate an α,β-unsaturated β-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot 2•3CR process delivers the targeted isoxazolino-β-ketoamide product. A total of 72 compounds are presented, all of which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

An efficient green protocol for the preparation of acetoacetamides and application of the methodology to a one-pot synthesis of Biginelli dihydropyrimidines. Expansion of dihydropyrimidine topological chemical space

“…30 The synthesis of amides from the reaction of 12 with amines or anilines has typically involved reuxing the substrates in toluene or xylene. 31 A few exceptions include reuxing in THF in the presence of NaOAc for 24 hours, 32 heating in a mixture of biphenyl and diphenyl ether, 33 microwave heating in: THF/DMA, 34 DMF, 35 or in the absence of solvent; 36 or by conventional heating in the presence of the amine, 37 or by the use of dichlorobenzene as solvent. 38 Initially we had prepared acetoacetanilides 15 by reuxing 12 and 14 in toluene.…”

Understanding the Regioselective and Molecular Mechanism of the TCE in Cycloaddtion Reaction (TCE+Cp) and Addition Reaction (TCE+HCl) using DFT calculation

“…Cyclic compounds are important pharmacophores in several pharmaceutical compounds [1][2][3]. They are also useful intermediates for synthesis of natural products and biologically active compounds [4][5][6][7][8][9][10].…”

An efficient method for the construction of polysubstituted 4-pyridones via self-condensation of β-keto amides mediated by P2O5 and catalyzed by zinc bromide

“…A lot of reports can be found in the literature concerning the construction of different heterocyclic compounds from β-keto amides by modification of the six different reactive positions [8–13]. Our interest in the fields of cleavage or construction of C–C and C–hetero bonds using β-keto amides and their derivatives as the substrates prompted us to exploit the reactivity of the six different reactive positions of β-keto amides [14–18].…”

“…β-Keto amide and their derivatives are desired classes of intermediates for the synthesis of nitrogen- and oxygen-containing heterocyclic compounds since they possess six reactive sites in the same molecule ( Scheme 1 ) [ 1 – 7 ]. A lot of reports can be found in the literature concerning the construction of different heterocyclic compounds from β-keto amides by modification of the six different reactive positions [ 8 – 13 ]. Our interest in the fields of cleavage or construction of C–C and C–hetero bonds using β-keto amides and their derivatives as the substrates prompted us to exploit the reactivity of the six different reactive positions of β-keto amides [ 14 – 18 ].…”