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The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

Reported here is the direct synthesis of naphthofurans and benzofurans from readily available phenols and α-haloketones promoted by titanium tetrachloride which combines Friedel–Crafts-like alkylation and intramolecular cyclodehydration into one step. This simple protocol allows for the formation of a variety of high value naphthofurans and benzofurans within which a series of cyclic and acyclic groups are readily incorporated. This process demonstrates the advantages of high levels of regioselectivity, broad substrate scope, and moderate to excellent yields.

Conditions have been established for the direct reaction of thiosemicarbazides with carboxylic acids in the presence of polyphosphate ester (PPE) to synthesize 1,2,4-triazole-3-thiol derivatives. The synthesis involves two consecutive steps: (i) acylation of the thiosemicarbazide with a carboxylic acid in chloroform in the presence of PPE at 90 °C using a hydrothermal reaction vessel, followed by (ii) cyclodehydration of the acylation product by treatment with an aqueous alkali solution. Using this new synthetic approach, 15 derivatives of 1,2,4-triazole-3-thiol were obtained, five of which were synthesized for the first time. The structures of the synthesized compounds were confirmed by NMR spectroscopy and mass spectrometry.

The main purpose of the study was the development of a new method for synthesis of 1,3,4-thiadiazol-2-amine derivatives in a one-pot manner using the reaction between a thiosemicarbazide and carboxylic acid without toxic additives such as POCl3 or SOCl2. The reaction was investigated in the presence of polyphosphate ester (PPE). It was found that, in the presence of PPE, the reaction between the thiosemicarbazide and carboxylic acid proceeds in one-pot through three steps with the formation of corresponding 2-amino-1,3,4-thiadiazole. Using the developed approach five, 2-amino-1,3,4-thiadiazoles were synthesized. The structures of all compounds were proven by mass spectrometry, IR, and NMR spectroscopies.

A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido alcohols promoted by trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of several hitherto unreported seven-membered iminothioethers bearing 2-aryl, alkenyl, aralkyl and alkyl substituents. The cyclodehydration reaction is likely to involve an S N 2-type displacement and affords good to excellent yields of the desired heterocycles in very short reaction times.

We have studied POCl 3 -catalyzed cyclodehydration reaction of 2-(4-chloro-2-oxoquinolin-1(2 H )-yl)acetohydrazide with benzoic acids. Unusually, we have found that p -methyl-, p -methoxy-, p -chloro-substituted and unsubstituted benzoic acids failed to undergo cyclodehydration and were converted into the corresponding anhydrides. Whereas, p -nitrobenzoic acid successfully underwent cyclodehydration and yielded 1,3,4-oxadiazole. Trying the same reaction with 2-(4-methyl-2-oxoquinolin-1(2 H )-yl)-acetohydrazide and p -nitrobenzoic acid, there was no cyclodehydration – two hydrazide molecules have condensed together. Newly synthesized 4-chloro-1-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]methyl}quinolin-2(1 H )-one and N '-[2-(4-methyl-2-oxoquinolin-1(2 H )-yl)acetyl]-4-nitrobenzohydrazide were evaluated for their anticancer activity against human lung cancer cells A549.

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.

A one-pot method was developed for the preparation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment, which entails the preparation of O-acylamidoximes and their subsequent cyclization using N,N′-dimethylacetamide as a solvent. The proposed method allows to significantly reduce the overall synthesis time by carrying out all steps sequentially in a single reactor, avoiding the step of isolation of the intermediate O-acylamidoxime, leading to the production of 5-alkenyl-1,2,4-oxadiazoles in high yields.

We have developed a simple and environmentally benign multi step method for synthesising 3,5-disubstituted-1,2,4-oxadiazoles under basic conditions via the cyclodehydration of amidoxime with carbonyldiimidazole. This approach offers several advantages, including good yields, a straightforward procedure, low cost, short reaction times, and utility for library synthesis in industrial applications. All synthesised compounds in this new series of 1,2,4-oxadiazoles were characterized using instrumental techniques such as 1H and 13C NMR spectroscopy and mass spectrometry (LCMS). A series of novel 1,2,4-oxadiazole derivatives were synthesized and evaluated for their in vitro antibacterial and antioxidant activities. The antibacterial screening revealed that all tested compounds exhibited potent activity, comparable to the reference drug, with variations in efficacy depending on specific structural modifications. Among them, compound 10g demonstrated the highest antibacterial activity, with a minimum inhibitory concentration (MIC) of 5 μg/mL against Escherichia coli and Bacillus subtilis, while compound 10h exhibited an MIC of 10 μg/mL. Antioxidant assessments identified compound 10f, which features a 2-hydroxy-6-methylpyridine linker, as the most promising antioxidant, with IC50 values of 22 ± 2.8 μg/mL for DPPH radical scavenging and 25 ± 4.4 μg/mL for hydroxyl radical scavenging. Density functional theory (DFT) calculations using implicit solvation models revealed energy gaps of 4.3223 eV for 10f and 4.3378 eV for 10g, indicating favorable electronic properties. Molecular docking studies predicted that 10g interacts with B. subtilis TagU, while 10f exhibits strong binding affinity toward rhomboid protease and NAD(P)H oxidase, findings further corroborated by molecular dynamics simulations. These insights highlight the therapeutic potential of these oxadiazole derivatives for antibacterial and antioxidant applications.

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N -dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.