In this study, we report the development of efficient synthetic strategies for the preparation of novel 2'-carboxyl isoflavones and their recyclization products, pyrazoles and oxazoles. Utilizing ...readily accessible starting materials and mild reaction conditions, the synthesis affords valuable compounds with good to excellent yields. The presence of diverse functional groups, including hydroxyl, carboxyl, and carboxamido moieties, renders these molecules attractive for biological screening and targeted structural modifications. This work unveils new avenues for the design of compounds exhibiting a wide range of beneficial properties and opens new opportunities for future research into intramolecular interactions of proximal functional groups.
Synthesis and physicochemical characterization of all possible cis‐ and trans‐1,3‐disubstituted cyclobutane‐derived amines and carboxylic acids bearing mono‐, di‐ and trifluoromethyl groups at the ...C‐3 position is disclosed. Tetramethylammonium fluoride (TMAF)‐ or morpholinosulfur trifluoride (Morph‐DAST)‐mediated nucleophilic fluorination of appropriate cis‐ and trans‐diastereomeric substrates was used as the key step for the preparation of CH2F‐ and CHF2‐substituted derivatives. To obtain the corresponding cis‐ and trans‐isomeric CF3‐substituted derivatives, resolution of known 3‐(trifluoromethyl)cyclobutanecarboxylic acid (obtained as a mixture of diastereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl‐substituted cyclobutane‐derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissociation constants (pKa) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physicochemical properties relevant to further drug discovery applications.
Scalable and efficient approaches towards the synthesis of cis‐ and trans‐1,3‐disubstituted mono‐, di‐ and trifluoromethylcyclobutane building blocks are disclosed. Effects of the fluoroalkyl substituents and other structural features on their physicochemical properties (pKa, LogP, and aqueous solubility) are evaluated.
This microreview provides a comprehensive analysis of synthetic approaches to chromeno2,3-
c
pyrrol-9(2
H
)-ones, a promising class of compounds that incorporate chromene and pyrrole frameworks. ...Starting from their earliest mentions and encompassing the latest advancements, this review categorizes the synthetic methods based on the structure of the starting materials.
An approach to the preparation of hereto unknown parent 5- and 7-azachromones was developed. The key step relied on the NaHmediated condensation of isomeric 2(4)-acetyl-3-hydroxypyridines (obtained ...from isomeric 3-hydroxypyridine carboxylic acids) with ethyl formate. Physicochemical studies revealed that no significant changes in lipophilicity and slightly higher basicity values were observed upon introduction of the nitrogen atom into the parent chromone; therefore, 5- and 7-azachromones can be used as direct analogs of this classical heterocyclic fragment. The synthetic utility of azachromones was demonstrated by the preparation of a series of 3,4-dihydro-2
H
-pyrano3,2-
b
pyridines and -2,3-
c
pyridines. The catalytic hydrogenation of the pyranone ring of azachromones was performed for the selective preparation of isomeric azachromanols, which could be oxidized with MnO
2
(to azachromanones) or involved into Barton–McCombie deoxygenation (for the synthesis of the non-substituted derivatives).
An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH2/NHBoc, OH, SH, or SO2F groups attached to the carbocycle ...either directly or via a CH2 unit) relying on the divergent strategy is described. This class of compounds provides sp3 -enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis- and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer–Pople puckering parameters and exit vector (EVP) plots.
An efficient and practical synthetic procedure for libraries of diversified 1,2-dihydrochromeno2,3-
c
pyrrole-3,9-diones using a multicomponent process is presented. A convenient synthetic procedure ...for obtaining functionalized 3-(2-hydroxyphenyl)-4,5-dihydropyrrolo3,4-
c
pyrazol-6(1
H
)-ones via ring-opening strategy has also been developed. This protocol was found to be compatible with a wide range of substituents and paves the way for the practical synthesis of title compounds with a broad range of substituents under mild condition. The products can be easily isolated by crystallization without the use of chromatography.
Graphic abstract
A convenient method was developed for the synthesis of novel isoquinolin-1(2
H
)-ones, 1-chloroisoquinolines, and 1-aminoisoquinolines with a heterocyclic substituent in position 3
via
a ...recyclization of 3-hetarylisocoumarins with (NH
4
)
2
CO
3
. 1-Aminoisoquinolines were efficiently obtained from corresponding 1-chloro-3-hetarylisoquinolines (obtained by interaction of isoquinolin-1(2
H
)-ones with POCl
3
) and cyclic secondary amines (morpholine or 1-methylpiperazine). Literature data and preliminary results of biological assays allow to consider 1-amino-3-hetarylisoquinolines a promising family of anticancer compounds.
An approach to a series of new 5‐amino‐4‐cyanoxazoles is described. Synthesis of the title compounds relied on a two‐step sequence including heterocyclization of 2‐amido‐3,3‐dichloroacrylonitriles ...with aliphatic secondary amines (dimethylamine, morpholine), primary aliphatic amines with active functional groups (2‐aminoethanol and glycine ethyl ester), and aniline. An efficient and straightforward protocol introduces a carboxylate group at the C‐2 position of 5‐amino‐4‐cyanoxazoles, connected to the heterocycle directly or through an aliphatic linker. This carboxylic group is an attractive motif that can be found in a variety of drug‐relevant compounds and also used for further modifications. Furthermore, efficient transformations of selected trisubstituted compounds were used to demonstrate their rich synthetic potential – e. g., as precursors to 2‐(4‐cyano‐5‐(dimethylamino)oxazol‐2‐yl)acetamides, oxazole‐containing macrocyclic structures, 2‐(oxazol‐2‐yl)acetamides, amino pyrazoles, 3‐(4‐cyano‐5‐aminoxazol‐2‐yl)coumarins, and oxazole amino acids.
An approach for the synthesis of new 5‐amino‐4‐cyanoxazoles with carboxylate group at the C‐2 position, connected to the heterocycle directly or through an aliphatic linker, was developed. This process features readily available starting materials, simple operations, and good to high yields. Wide synthetic applicability of the obtained compounds was also successfully demonstrated by further modifications.
Radical reactions occupy a significant place in synthetic organic chemistry and significantly complement and expand modern approaches to the synthesis of substituted coumarins. This minireview ...summarizes various synthetic approaches to the construction of the coumarin system, based on radical cascade reactions starting with aryl alkynoates. The methods considered for constructing the coumarin system include cyclization reactions with the formation of two C–C bonds, as well as one C–C bond and C–P, C–S, C–Se, C–Hal bonds.
This research focuses on the synthesis and
in vitro
anticancer evaluation of functionalized 2-aryl-5-(4-piperazin-1-yl)oxazoles and 5-(4-arylsulfonyl) piperazin-1-yl-2-phenyloxazoles. Oxazoles are a ...versatile class of compounds with diverse biological activities, making them attractive targets in medicinal chemistry. We incorporated amino and sulfonamide functionalities into the oxazole scaffold, as they have shown potential for interacting with biological targets. The synthesis of target oxazole derivatives was accomplished using 2-aroylamino-3,3-dichloroacrylonitriles as starting materials and employing efficient reaction conditions. The resulting compounds exhibited structural features that make them promising candidates for further chemical modifications and biological evaluations. Additionally, a series of sulfonamides were synthesized from 5-(piperazin-1-yl)oxazole-4-carbonitrile hydrochloride, offering diverse bioactivity and versatile structural characteristics. However, no potent inhibitors of malignant cell growth were identified among the tested compounds. Nevertheless, we categorized the investigated substances into two distinct groups based on their activity profile. Group A, comprising sulfonamides, displayed pronounced anticancer activity against breast cancer and melanoma cell lines. On the other hand, group B, the 2-aryl-5-(4-R-piperazin-1-yl)oxazole-4-carbonitriles, exhibited a moderate effect primarily on renal cancer cell lines. These findings provide valuable insights for further structural modifications in the quest for more potent anticancer agents.
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