Abstract:The first synthesis of methyl 2-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoacetate is described. This compound has been successfully used in a multicomponent enol-Ugi condensation with imines and isocyanides affording 4-aminoacyl-coumarin enamines in a highly atom-economic and convergent process. Furthermore, the postcondensation transformation of these adducts allows the straightforward synthesis of both unprotected amino amides and as yet unknown 2-hydroxychromenyl enamines.
“…We have recently reported the effective multicomponent enol-Ugi condensation of enols (15), aldehydes (12), amines (13) and isocyanides (14) leading to polysubstituted heterocyclic enamines (17; Scheme 2) [49][50][51]. The enol-Ugi condensation of 4-hydroxy-3-nitro-coumarin (15) and cyclohexyl isocyanide (14a) with different amines (13a-d) and aldehydes (12a-e) or the corresponding preformed imines (16a-k) leads to aminoacylcoumarins (17a-k) in good to excellent yields (Table 1).…”
Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.
“…We have recently reported the effective multicomponent enol-Ugi condensation of enols (15), aldehydes (12), amines (13) and isocyanides (14) leading to polysubstituted heterocyclic enamines (17; Scheme 2) [49][50][51]. The enol-Ugi condensation of 4-hydroxy-3-nitro-coumarin (15) and cyclohexyl isocyanide (14a) with different amines (13a-d) and aldehydes (12a-e) or the corresponding preformed imines (16a-k) leads to aminoacylcoumarins (17a-k) in good to excellent yields (Table 1).…”
Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.
“…Different 5- and 6-membered enolic heterocycles can be used, including pyrrolidine-2,3-diones, furane-2,3-diones, 3- and 4-hydroxycoumarins and dihydropyrimidines, resulting in different heterocyclic enamines ( 742 – 746 ; Fig. 3 ) [ 232 – 234 ]. Scheme 155 Mechanism of the enol-Ugi reaction Fig.…”
Stefano Marcaccini was one of the pioneers in the use of isocyanide-based multicomponent reactions in organic synthesis. Throughout his career at the University of Florence he explored many different faces of isocyanide chemistry, especially those geared towards the synthesis of biologically relevant heterocycles. His work inspired many researchers who contributed to other important developments in the field of multicomponent reactions and created a school of synthetic chemists that continues today. In this manuscript we intend to review the articles on isocyanide multicomponent reactions published by Dr. Marcaccini and analyse their influence on the following works by other researchers. With this, we hope to highlight the immense contribution of Stefano Marcaccini to the development of isocyanide chemistry and modern organic synthesis as well as the influence of his research on future generations. We believe that this review will not only be a well-deserved tribute to the figure of Stefano Marcaccini, but will also serve as a useful inspiration for chemists working in this field.
Graphical abstract
“…1). Functionalized chromenes are widely used to synthesize promising compounds in medicinal chemistry [28][29][30][31][32][33][34][35] . Wide-ranging pharmacological activity, such as antibacterial 36 , anti-inflammatory 37 , antimicrobial 38 , anti-proliferative 39 , hypotensive 40 , and antirheumatic 41 properties, have been reported for derivatives of chromenopyridine.…”
N,N'-(methylenebis(1,4-phenylene))bis-(2-cyanoacetamide) was exploited as a precursor for synthesing some bis (benzylidene 5a-c, pyridines 7, 8, 10a,b, chromene 14, benzochromene 15) derivatives containing diphenyl-methylene spacer via the reaction with each of aromatic aldehydes, pentane-2,4-dione, acetaldehyde/ malononitrile, arylidene-malononitriles, ethyl cinnamates, 2-hydroxybenzaldehyde, and 2-hydroxy-1-naphthaldehyde). Bis(chromeno[3,4-c]pyridines 16&18) were synthesized via Michael's addition of malononitrile or ethyl cyanoacetate to bis(chromene) derivative. The newly prepared compound structures were established via ir, NMR spectroscopic data.
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