FeCl₃⋅6H₂O‐Catalyzed Intermolecular‐Cascade Cyclization of Acetoacetanilide: Aldehyde‐Tuned Synthesis to Valuable 2‐Pyridone Analogues

Abstract

The first ever breakthrough toward activation of β-ketoacetanilide and subsequent C-C and C-N bond-forming intermolecular-cascade cyclization processes is demonstrated by development of the unprecedented Lewis acid property of non-toxic FeCl(3)⋅6H(2)O. Aromatic, aliphatic, α,β-unsaturated, chiral sugar-based and chromone aldehydes were regio- and stereoselectively cyclized with acetoacetanilides toward construction of valuable N-containing highly functionalized 2-pyridones (see scheme for an example).

ArCH(OMe)2 - a PtIV-catalyst originator for diverse annulation catalysis

“…The reported synthesis of 2-pyridones includes multistep strategies, microwave and metathesis protocols, the one-pot Blaise reaction, direct synthesis involving the oxidative annulation of α,β-unsaturated amide and ketone, and our recently reported ring opening of chromone aldehydes with tandem cascade cyclisation738. Substituted 2-pyridones are potential candidates for antihepatitis B, antitumor, human rhinovirus (HRV) 3C protease (3CP) inhibitor and noncompetitive antagonist related to epilepsy3940.…”

“…Catalysis123456789101112 is a frontier research field in the chemical sciences and their allied branches as catalysis plays a pivotal role in the synthesis of almost every chemical, pharmaceutical, agrochemical and material required for the rapid development of mankind, especially our highly-demanding modern society. A catalyst promoter or initiator9101112 is a cocatalyst which is crucial for significant improvement of reaction rate and/or selectivity13 in some catalysis reactions.…”

“…Development of new benign and robust strategies is desirable such as discovery of new atom-economical domino reactions181920 towards direct synthesis of several target molecules using an efficient catalytic system. Acetoacetanilide ( 1 , Figure 1) is a commercially available inexpensive laboratory reagent that has found very limited application in synthetic organic chemistry, including synthesis of the lepidone, martinellic acid derivative21, unsymmetrical urea22 and our recently reported FeCl 3 .6H 2 O-catalysed diastereoselective construction of trans -1,2,3,4-tetrahydro-2-pyridones7. Furthermore, the three important reactive centres (C 2 -H, C 4 -H and N-H) of acetoacetanilide can be exploited in a selective and cascade fashion for annulation with designed propargyl compounds ( 2 , 3 etc.).…”

An Exploration of Organocatalyst 1,4-Diazabicyclo[2.2.2]octane in the Direct Regioselective and Chemoselective γ-Addition of β-Keto Amide on Isatin to Afford Structurally Diverse Molecular Frameworks

“…[2a,5] Recently b-keto amides, especially acetoacetanilides, have been explored as an easily available, structurally flexible, and versatile starting material in chemical synthesis for the construction of diverse functionalized complex molecular systems. [6] In this context, we planned the functionalization of the oxindole nucleus by the reaction of acetoacetanilides with isatin electrophiles.…”

Eco-friendly synthesis of diverse and valuable 2-pyridones by catalyst- and solvent-free thermal multicomponent domino reaction

“…13 They are also used as a versatile synthon for the synthesis of a variety of other nitrogen-containing heterocyclic compounds like β-lactams, quinolizidines, pyridines, piperidines, and indolizidine alkaloids. [15][16][17][18][19][20][21][22][23][24][25] The typical strategies involve Ni(0), Rh(I), or Ru(II)-catalyzed cycloaddition of 1,6-diynes with isocyanates, 15 ring-closing metathesis of α-amino acrylamides, 16 t-BuOK-mediated condensation of enones with cyanoacetamides, 17 tandem Blaise reaction of nitriles with propiolates, 18 FeCl 3 ·6H 2 O-catalyzed intramolecular cascade reaction of acetoacetanilide with 3-formyl chromone, 19 CsF-catalyzed reaction of α,β-unsaturated diester chromones with aromatic amines, 20 Ni-catalyzed reaction of alkynes via azazirconacycles, 21 1,4addition reaction of 2-( phenylsulfinyl)acetamide to α,β-unsaturated ketones followed by cyclization and elimination of sulfoxide, 22 nucleophilic addition of malonic esters to alkynyl imines, 23 intramolecular ketene trapping of functionalized enamine-dioxinones, 24 and gold-catalyzed cycloisomerization of N-alkenyl alkynylamides. [15][16][17][18][19][20][21][22][23][24][25] The typical strategies involve Ni(0), Rh(I), or Ru(II)-catalyzed cycloaddition of 1,6-diynes with isocyanates, 15 ring-closing metathesis of α-amino acrylamides, 16 t-BuOK-mediated condensation of enones with cyanoacetamides, 17 tandem Blaise reaction of nitriles with propiolates, 18 FeCl 3 ·6H 2 O-catalyzed intramolecular cascade reaction of acetoacetanilide with 3-formyl chromone, 19 CsF-catalyzed reaction of α,β-unsaturated diester chromones with aromatic amines, …”