1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of ...different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of
-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work-up. However, it requires the preparation and isolation of
-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.
A new route for the synthesis of quinazolin-2,4(1
3
)-diones and thieno 2,3-
pyrimidine-2,4(1
,3
)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed ...method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of
-aryl-
'-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.
The nucleophilic addition of 3-(4-cyanopyridin-2-yl)-1,1-dimethylurea (1) to cis-Pt(CNXyl)2Cl2 (2) gave a new cyclometallated compound 3. It was characterized by NMR spectroscopy (1H, 13C, 195Pt) and ...high-resolution mass spectrometry, as well as crystallized to obtain two crystalline forms (3 and 3·2MeCN), whose structures were determined by X-ray diffraction. In the crystalline structure of 3, two conformers (3A and 3B) were identified, while the structure 3·2MeCN had only one conformer 3A. The conformers differed by orientation of the N,N-dimethylcarbamoyl moiety relative to the metallacycle plane. In both crystals 3 and 3·2MeCN, the molecules of the Pt(II) complex are associated into supramolecular dimers, either {3A}2 or {3B}2, via stacking interactions between the planes of two metal centers, which are additionally supported by hydrogen bonding. The theoretical consideration, utilizing a number of computational approaches, demonstrates that the C···dz2(Pt) interaction makes a significant contribution in the total stacking forces in the geometrically optimized dimer 3A2 and reveals the dz2(Pt)→π*(PyCN) charge transfer (CT). The presence of such CT process allowed for marking the C···Pt contact as a new example of a rare studied phenomenon, namely, tetrel bonding, in which the metal site acts as a Lewis base (an acceptor of noncovalent interaction).
We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via ...the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents’ electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, 1H, and 13C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction.
Metal mediated coupling of isocyanides with substituted N-(pyridine-2-yl) ureas was first used to incorporate privileged biological motifs into platinum metal complexes. We synthesized two ...palladium(II) and two platinum(II) cyclometallated species with oxadiazole cores. The compounds were isolated in good yields (61–73%) and characterized by high-resolution mass spectrometry and 1H, 13C, and 195Pt NMR spectroscopies. The structures of three complexes were additionally elucidated by X-ray diffraction analysis. These complexes indeed showed cytotoxic activity. The species bearing the 1,3,4-oxadiazole moiety exhibit more potency than the ones with the 1,2,4-oxadiazole ring. Particularly, the cytotoxic effect of both 1,3,4-oxadiazole-based complexes towards T98G cells significantly exceeds the common antitumor metal-drug cisplatin.
A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno 2,3-dpyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed ...method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N′-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.
The nucleophilic addition of 3-(4-cyanopyridin-2-yl)-1,1-dimethylurea (1) to cis-Pt(CNXyl)sub.2Clsub.2 (2) gave a new cyclometallated compound 3. It was characterized by NMR spectroscopy (sup.1H, ...sup.13C, sup.195Pt) and high-resolution mass spectrometry, as well as crystallized to obtain two crystalline forms (3 and 3·2MeCN), whose structures were determined by X-ray diffraction. In the crystalline structure of 3, two conformers (3A and 3B) were identified, while the structure 3·2MeCN had only one conformer 3A. The conformers differed by orientation of the N,N-dimethylcarbamoyl moiety relative to the metallacycle plane. In both crystals 3 and 3·2MeCN, the molecules of the Pt(II) complex are associated into supramolecular dimers, either {3A}sub.2 or {3B}sub.2, via stacking interactions between the planes of two metal centers, which are additionally supported by hydrogen bonding. The theoretical consideration, utilizing a number of computational approaches, demonstrates that the C···dzsup.2(Pt) interaction makes a significant contribution in the total stacking forces in the geometrically optimized dimer 3Asub.2 and reveals the dsub.z sup.2(Pt)→π*(PyCN) charge transfer (CT). The presence of such CT process allowed for marking the C···Pt contact as a new example of a rare studied phenomenon, namely, tetrel bonding, in which the metal site acts as a Lewis base (an acceptor of noncovalent interaction).
A new method for the synthesis of pyridine‐ and quinoline‐N‐oxides containing a ureido or carbamoyl fragment in position 2 has been developed. This method concluded in the oxidation of relatively ...readily available substituted N,N‐dimethyl‐N′‐(pyridine‐2‐yl)ureas to the corresponding N‐oxides, followed by modification of the dimethylureide moiety. Being heated to 90 °C in the presence of amines in a solution of DMF or chlorobenzene, N‐oxide of N,N‐dimethyl‐N′‐(pyridine‐2‐yl)urea undergoes a transamination reaction without loss of the N‐oxide function. This produces N‐oxides of N‐alkyl/aryl‐N’‐(pyridine‐2‐yl)ureas in 24–99 % yields, (about 30 examples). Values of the NH protons chemical shifts are a good criterion for the selectivity of the reaction. The reaction is also applicable to N‐oxides of ureas substituted in the pyridine ring and to the quinoline congener. N‐Oxides of pyridine/quinoline‐containing carbamates can be similarly prepared by heating N‐oxides of N,N‐dimethyl‐N′‐(pyridine‐2‐yl)/(quinoline‐2‐yl)‐urea in an appropriate alcohol solution at 120 °C.
A new method for the synthesis of pyridine‐ and quinoline‐N‐oxides containing a ureido or carbamoyl fragment in position 2 is concluded in the oxidation of substituted N,N‐dimethyl‐N′‐(pyridine‐2‐yl)ureas to the corresponding N‐oxides, followed by modification of the dimethylureide moiety. The method produces N‐oxides of N‐alkyl/aryl‐N’‐(pyridine‐2‐yl)ureas in yields up to 99 % (including the ones bearing oxidative‐sensitive fragments).
The nucleophilic addition of 3-(4-cyanopyridin-2-yl)-1,1-dimethylurea (
) to
-Pt(CNXyl)
Cl
(
) gave a new cyclometallated compound
. It was characterized by NMR spectroscopy (
H,
C,
Pt) and ...high-resolution mass spectrometry, as well as crystallized to obtain two crystalline forms (
and
·2MeCN), whose structures were determined by X-ray diffraction. In the crystalline structure of
, two conformers (
and
) were identified, while the structure
·2MeCN had only one conformer
. The conformers differed by orientation of the
,
-dimethylcarbamoyl moiety relative to the metallacycle plane. In both crystals
and
·2MeCN, the molecules of the Pt(II) complex are associated into supramolecular dimers, either {
}
or {
}
, via stacking interactions between the planes of two metal centers, which are additionally supported by hydrogen bonding. The theoretical consideration, utilizing a number of computational approaches, demonstrates that the C···
(Pt) interaction makes a significant contribution in the total stacking forces in the geometrically optimized dimer
and reveals the
(Pt)→π*(PyCN) charge transfer (CT). The presence of such CT process allowed for marking the C···Pt contact as a new example of a rare studied phenomenon, namely, tetrel bonding, in which the metal site acts as a Lewis base (an acceptor of noncovalent interaction).
Palladiumureas with Oxadiazole Periphery Geyl, Kirill K; Baykova, Svetlana O; Andoskin, Pavel A ...
Inorganics,
12/2022, Letnik:
10, Številka:
12
Journal Article
Recenzirano
Metal mediated coupling of isocyanides with substituted N-(pyridine-2-yl) ureas was first used to incorporate privileged biological motifs into platinum metal complexes. We synthesized two ...palladium(II) and two platinum(II) cyclometallated species with oxadiazole cores. The compounds were isolated in good yields (61–73%) and characterized by high-resolution mass spectrometry and sup.1 H, sup.13 C, and sup.195 Pt NMR spectroscopies. The structures of three complexes were additionally elucidated by X-ray diffraction analysis. These complexes indeed showed cytotoxic activity. The species bearing the 1,3,4-oxadiazole moiety exhibit more potency than the ones with the 1,2,4-oxadiazole ring. Particularly, the cytotoxic effect of both 1,3,4-oxadiazole-based complexes towards T98G cells significantly exceeds the common antitumor metal-drug cisplatin.
