Saturated Bioisosteres of ortho-Substituted Benzenes.

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed a similar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines.

Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the formation of 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines.

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction.

Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner-Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.

Complexation of molecular clips containing fragments of diphenylglycoluril and benzocrown ethers with paraquat and its derivatives.

The complexation of molecular clips containing fragments of diphenylglycoluril and benzocrown ethers with paraquat and its derivatives has been studied both in solution and in the solid state. In this paper we studied the influence of the crown ether ring size and the nature of the substituents at the nitrogen atoms of the paraquat derivatives on the composition and stability of these complexes.

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized.

The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an amine component in Ugi and Groebke-Blackburn-Bienaymé multicomponent reactions. The first example of an application of aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke-Blackburn-Bienaymé cyclocondensation are established and discussed. The heterocycles obtained were evaluated for their antibacterial activity and several of them demonstrated a weak antimicrobial effect, but for most of the compounds a 30-50% increase in biomass of Gram-positive strains (mainly B. subtilis) compared to control was observed.

Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage.

An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have been synthesized via an acylation of corresponding 6,7-dihydro-1H-indazol-4(5H)-one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH4 resulted in a formation of betulinic acid-indazolone hybrids in excellent yields. The configuration of the key compounds has been fully established by X-ray and 2D NMR analysis.

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids.

The regioselective three-component condensation of azomethine ylides derived from isatins and α-amino acids with acrylamides or aroylacrylic acids as dipolarophiles has been realized through a one-pot 1,3-dipolar cycloaddition protocol. Decarboxylation of 2'-aroyl-2-oxo-1,1',2,2',5',6',7',7a'-octahydrospiro[indole-3,3'-pyrrolizine]-1'-carboxylic acids is accompanied by cyclative rearrangement with formation of dihydropyrrolizinyl indolones.

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde.

The switchable three-component reactions of 5-amino-3-methylisoxazole, salicylaldehyde and N-aryl-3-oxobutanamides under different conditions were studied and discussed. The unexpected influence of the aryl substituent in N-aryl-3-oxobutanamides on the behavior of the reaction was discovered. The key influence of ultrasonication and Lewis acid catalysts led to an established protocol to selectively obtain two or three types of heterocyclic scaffolds depending on the substituent in the N-aryl moiety.

Diversity oriented heterocyclizations of pyruvic acids, aldehydes and 5-amino-N-aryl-1H-pyrazole-4-carboxamides: catalytic and temperature control of chemoselectivity.

Heterocyclization reactions of pyruvic acids, aromatic aldehydes and 5-amino-N-aryl-1H-pyrazole-4-carboxamides yielding four different types of final compounds are described. The reactions involving arylidenpyruvic acids lead with high degree of selectivity to either 4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acids or 5-[(2-oxo-2,5-dihydrofuran-3-yl)amino]-1H-pyrazoles, depending on the catalyst type or temperature regime. The interactions based on arylpyruvic acids can take place under kinetic or thermodynamic control producing 7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic acids or 3-hydroxy-1-(1H-pyrazol-5-yl)-1,5-dihydro-2H-pyrrol-2-ones, respectively.

Diversification of a thieno[2,3-d]pyrimidin-4-one scaffold via regioselective alkylation reactions.

The 2-aryl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-ones and 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones have been diversified by alkylation reactions, applying benzylchlorides and N-substituted 2-chloroacetamides as alkylating agents. Under the found uniform conditions the substitution direction does not depend on the structure of the alkylating agent and gives monoalkylated products in high yields with simple workup. The alkylation of the 2,3-dihydropyrimidin-4(1H)-one derivatives proceeds onto the N1-position; however, in the case of pyrimidin-4(3H)-ones the O-alkylated products are formed selectively. An alternative strategy for the synthesis of the N1-benzyl-2,3-dihydropyrimidin-4(1H)-one derivatives is also developed. It applies the redaction of N2-substituted Gewald's amides with aromatic aldehydes and allows simple introduction of various substituents in the final molecule.

Molecular structures of regioisomeric 7-arylidene hexahydroindazoles from (1)H NMR spectra.

The structural characterization of two regioisomeric products of the interaction of 2,6-bis-(4-methoxybenzylidene)-3R-methylcyclohexanone with methyl hydrazine was achieved using (1)H NMR spectral data, including chemical shifts, coupling constants and results of COSY and nuclear overhauser effect (NOE) experiments. Configurations of the new chiral centers in the (3S,3aR,6R,7E)-7-(4-methoxybenzylidene)-3,4,5,7-hexahydro-3-(4-methoxyphenyl)-2,6-dimethyl- and 2,4-dimethyl-2H-indazoles were assigned on the basis of experimental data combined with molecular modeling by the density functional theory (DFT) method. The distinction in the helical twisting power of studied compounds under addition to a nematic liquid crystal is discussed on the basis of peculiarities of the molecular structures.

Two polymorphs of morpholin-4-ium 2-(5-methyl-1H-1,2,4-triazol-3-ylsulfanyl)acetate.

Two polymorphs of the title organic salt (a very effective medicinal preparation with the commercial name thiotriazoline), C(4)H(10)NO(+).C(5)H(6)N(3)O(2)S(-), were obtained. The cations and anions are connected by hydrogen bonds and extend into two-dimensional networks. The main packing motifs are an R(4)(4)(12) cluster in the monoclinic form and a chain in the orthorhombic form.

Ethyl 5-[(1H-benzoimidazol-2-yl)amino-carbon-yl]-4-hydr-oxy-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxyl-ate-ethanol-methanol (4/2/1).

The asymmetric unit of the title compound, 4C(20)H(22)N(4)O(5)·2C(2)H(6)O·CH(4)O, contains two pyridine-3-carboxyl-ate mol-ecules, one ethanol mol-ecule and one methanol mol-ecule disordered about in a centre of symmetry. The pyridinone ring, the carbamide group and the bicyclic fragment in both independent mol-ecules are planar within 0.03 Šdue to the formation of intra-molecular O-H⋯O and N-H⋯O hydrogen bonds. The formation of these latter inter-actions also causes the redistribution of the electron density within the hydroxy-pyridone fragment, with the result that some bonds are elongated compared with values in the literature and some others are shorter. In the crystal phase, the pyridine-3-carboxyl-ate mol-ecules form layers parallel to (010), which are inter-linked through hydrogen bonds mediated by the bridging solvate mol-ecules. A terminal ethyl group in one of the mol-ecules is disordered over two sites of equally occupancy.

Ethyl 2-(4-hydr-oxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)acetate.

In the title compound, C(14)H(15)NO(4), the bicyclic fragment and the ester group form a dihedral angle of 86.7 (2)°. Inter-molecular O-H⋯O and C-H⋯O hydrogen bonding connects mol-ecules into a helix along the crystallographic b axis.

Conjugation and hyperconjugation in conformational analysis of cyclohexene derivatives containing an exocyclic double bond.

The equilibrium geometry, ring-inversion pathway barriers for analogues of cyclohexene with an exocyclic double bond have been studied using the MP2/6-311 G(d,p) level of theory. The equilibrium conformation of the ring depends on conjugation between the endocyclic and exocyclic double bonds. Interactions between conjugated double bonds include the pi-pi conjugation and interactions between the lone pair of the heteroatom of the exocyclic double bond and the sigma-antibonding orbital of the endocyclic single bond. In the case of the tetrahydrocycles with double bonds separated by a methylene group the balance between the pi --> sigma* hyperconjugation interactions between the exocyclic double bond and the neighboring methylene group and the n --> sigma* interaction between the lone pair of the heteroatom and the sigma-antibonding orbitals of the C(sp(2))-C(sp(3)) bond determine the geometrical parameters of the ring. The character of the potential-energy surface around the saddle point depends on the position of the exocyclic double bond and the orientation of the hydrogen atom attached to the heteroatom of the V group of the periodic table in the tetrahydrocycles with double bonds separated by a methylene group.

2-Bromo-methyl-N-isopropyl-7,8-dimeth-oxy-1,2-dihydro-1,3-oxazolo[3,2-a]quinoline-4-carboxamide.

In the title compound, C(18)H(21)BrN(2)O(5), conjugation between the π-donating N-C-O fragment and the π-withdrawing carbonyl group results in considerable redistribution of the electron density within the dihydropyridinol ring. This effect is also promoted by the formation of an intra-molecular N-H⋯O hydrogen bond. The five-membered heterocycle is disordered over two envelope conformations in a 0.35:0.65 ratio.

Ultrasonic-promoted three-component synthesis of some biologically active 1,2,5,6-tetrahydropyrimidines.

Multicomponent reactions and organic synthesis with ultrasonic activation have been used as key methods for the synthesis of tetrahydropyrimidine derivatives. The three-component condensation of 1,3-diarylprop-2-en-1-one with ammonia and aldehydes/acetone or N-substituted gamma-pyridones under ultrasonic irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 2-aryl(hetaryl)-4,6-diaryl-1,2,5,6-tetrahydropyrimidines and 2,4-diaryl-1,5,9-triazaspiro[5.5]undec-1-enes. The described synthetic protocol provides rapid access to novel and diversely substituted tetrahydropyrimidines libraries. The simple, primary biological screening showed 98% of inhibitory activity against Mycobacterium tuberculosis for one of tetrahydropyrimidines synthesized.

Heterocyclic analogues of cyclohexene: theoretical studies of the molecular structures and ring-inversion processes.

The equilibrium geometry, ring-inversion barrier, and pathway for heterocyclic analogues of cyclohexene have been studied using the MP2/6-311G(d,p) level of theory. It is concluded that the replacement of one methylene group in cyclohexene by heteroatom results in significant changes in the character of the potential-energy surface in comparison with cyclohexene. The equilibrium conformation of ring strongly depends on the position of the heteroatom due to the existence of the n-pi conjugation. However, the character of the ring-inversion process is determined by the nature of the heteroatom. In the case of sulfur- and selenium-containing rings, the boat or twist-boat conformation corresponds to an additional minimum on the potential-energy surface. Moreover, the barriers of the conformational transition from this conformer to two different half-chair forms are significantly different. Nitrogen-containing heterocycles possess two pairs of minima corresponding to the different configurations of the nitrogen atom. However, the transition between the two minima with the same configuration of the heteroatom proceeds only in two steps that include ring inversion and nitrogen inversion.

One-pot, multicomponent route to pyrazoloquinolizinones.

[reaction: see text] An efficient synthesis of 5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones based on the three-component condensation of 5-aminopyrazoles, aromatic aldehydes, and cyclic 1,3-diketones is described. The multicomponent reaction is performed under strongly basic conditions applying controlled microwave heating in a sealed vessel and involves an unusual base-mediated ring-opening/recyclization of the cyclic 1,3-diketone moiety.

2,3,4,6,7,8,9,10-Octa-hydro-pyrimido[1,2-a]azepin-1-ium 2-cyano-1-(2,6-dimethylanilino)-2-(phenyl-sulfonyl)ethenethiol-ate.

In the title compound, C(9)H(17)N(2) (+)·C(17)H(15)N(2)O(2)S(2) (-), the Csp(2)-N bonds in the tetra-hydro-pyrimidine ring of the cation are delocalized. The negative charge is localized on the S atom of the thione group. Cations and anions are linked by N-H⋯S inter-molecular hydrogen bonds.