Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas.

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-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.

Noncovalent Chelation by Halogen Bonding in the Design of Metal-Containing Arrays: Assembly of Double σ-Hole Donating Halolium with CuI-Containing O,O-Donors.

Five new copper(I) complexes─composed of the paired dibenzohalolium and [CuL2]- (L = 1,2,4-oxadiazolate) counterions in which O,O-atoms of the anion are simultaneously linked to the halogen atom─were generated and isolated as the solid via the three-component reaction between [Cu(MeCN)4](BF4), sodium 1,2,4-oxadiazolates, and dibenzohalolium triflates (or trifluoroacetates). This reaction is different from the previously reported CuI-catalyzed arylation of 1,2,4-oxadiazolones by diaryliodonium salts. Inspection of the solid-state X-ray structures of the complexes revealed the strong three-center X···O,O (X = Br, I) halogen bonding occurred between the oxadiazolate moieties and dibenzohalolium cation. According to performed theoretical calculations, this noncovalent interaction (or noncovalent chelation) was recognized as the main force in the stabilization of the copper(I) complexes. An explanation for the different behavior of complexes, which provide either chelate or nonchelate binding, is based on the occurrence of additional -CH3···π interactions, which were also quantified.

Unusual Formation of 1,2,4-Oxadiazine Core in Reaction of Amidoximes with Maleic or Fumaric Esters.

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.

Synthesis, Structure, and Antiproliferative Action of 2-Pyridyl Urea-Based Cu(II) Complexes.

Relying on a recently suggested protocol that furnishes convenient access to variously substituted 2-pyridyl ureas, twelve hitherto unknown Cu(II) complexes have been synthesized in the present work and their structures were evaluated by elemental analysis, HRMS, IR spectroscopy, and X-ray diffraction study. Two structural motifs ([Cu(L)2Cl]+[Cl]- or (Cu(L)2Cl2) depending on the substitution pattern on the 2-pyridine fragment were revealed. In addition, antiproliferative action of the obtained compounds have been investigated against lung cancer cell lines (A549, NCI-H460, NCI-H1975), and healthy WI-26 VA4 cells were used to monitor non-specific cytotoxicity. Two nitro-group substituted complexes Cu(U3)2Cl2 (IC50 = 39.6 ± 4.5 µM) and Cu(U11)2Cl2 (IC50 = 33.4 ± 3.8 µM) demonstrate enhanced activity against the drug resistant NCI-H1975 cells with moderate selectivity toward normal WI-26 VA4 cells. The antiproliferative mechanism of cell death underlying the growth inhibitory effect of the synthesized complexes was studied via additional experiments, including the cell cycle analysis and the apoptosis induction test. Reassuringly, certain 2-pyridyl urea-based Cu(II) complexes exerted cell line-specific antiproliferative effect which renders them valuable starting points for further unveiling the anticancer potential of this class of coordination compounds.

π-π Noncovalent Interaction Involving 1,2,4- and 1,3,4-Oxadiazole Systems: The Combined Experimental, Theoretical, and Database Study.

A series of N-pyridyl ureas bearing 1,2,4- (1a, 2a, and 3a) and 1,3,4-oxadiazole moiety (1b, 2b, 3b) was prepared and characterized by HRMS, 1H and 13C NMR spectroscopy, as well as X-ray diffraction. The inspection of the crystal structures of (1-3)a,b and the Hirshfeld surface analysis made possible the recognition of the (oxadiazole)···(pyridine) and (oxadiazole)···(oxadiazole) interactions. The presence of these interactions was confirmed theoretically by DFT calculations, including NCI analysis for experimentally determined crystal structures as well as QTAIM analysis for optimized equilibrium structures. The preformed database survey allowed the verification of additional examples of relevant (oxadiazole)···π interactions both in Cambridge Structural Database and in Protein Data Bank, including the cocrystal of commercial anti-HIV drug Raltegravir.

Catalyst-free synthesis of substituted pyridin-2-yl, quinolin-2-yl, and isoquinolin-1-yl carbamates from the corresponding hetaryl ureas and alcohols.

A novel catalyst-free synthesis of N-pyridin-2-yl, N-quinolin-2-yl, and N-isoquinolin-1-yl carbamates utilizes easily accessible N-hetaryl ureas and alcohols. The proposed environmentally friendly technique is suitable for the good-to-high yielding synthesis of a wide range of N-pyridin-2-yl or N-quinolin-2-yl substituted carbamates featuring electron-donating and electron-withdrawing groups in the azine rings and containing various primary, secondary, and even tertiary alkyl substituents at the oxygen atom (48-94%; 31 examples). The DFT calculation and experimental study showed that the reaction proceeds through the intermediate formation of hetaryl isocyanates. The method can be applied to obtain N-isoquinolin-1-yl carbamates, although in lower yields, and ethyl benzo[h]quinolin-2-yl carbamate has also been successfully synthesized (68%).

Azine Steric Hindrances Switch Halogen Bonding to N-Arylation upon Interplay with σ-Hole Donating Haloarenenitriles.

An interplay between 4-bromo- and 4-iodo-5-nitrophthalonitriles (XNPN, X=Br or I) and any one of the azines (pyridine 1, 4-dimethylaminopyridine 2, isoquinoline 3, 4-cyanopyridine 4, 2-methylpyridine 5, 2-aminopyridine 6, quinoline 7, 1-methylisoquinoline 8, and 2,2'-bipyridine 9) proceeds differently depending on steric and electronic effects of the heterocycles. Sterically unhindered azines 1-3 underwent N-arylation to give the corresponding azinium salts (characterized by 1 H and 13 C{H} NMR and high-resolution ESI-MS). In contrast, azines 4-9 with sterically hindered N atoms or bearing an electron-withdrawing substituent, form stable co-crystals with XNPN, where two interacting molecules are bound by halogen bonding. In all obtained co-crystals, X⋅⋅⋅N structure-directed halogen bonds were recognized and theoretically evaluated including DFT calculations (PBE0-D3/def2-TZVP level of theory), QTAIM analysis, molecular electrostatic potential surfaces, and noncovalent interaction plot index. Estimated energies of halogen bonding vary from -7.6 kcal/mol (for 6 ⋅ INPN) to -11.4 kcal/mol (5 ⋅ INPN).