Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones.
A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, alpha-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. Alpha-alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other alpha-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different alpha-acidic esters.
Scheffelaar
Rachel
R
Department of Chemistry & Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Paravidino
Monica
M
Znabet
Anass
A
Schmitz
Rob F
RF
de Kanter
Frans J J
FJ
Lutz
Martin
M
Spek
Anthony L
AL
Fonseca Guerra
Célia
C
Bickelhaupt
F Matthias
FM
Groen
Marinus B
MB
Ruijter
Eelco
E
Orru
Romano V A
RV
D002384:Catalysis; D003500:Cyclization; D004952:Esters; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D004952:Esters; D009570:Nitriles; D011728:Pyridones