Dipolar additions with 1-(4,6-dimethylpyrimidin-2-yl)- and 1-(4,6-dimethoxy-s-triazin-2-yl)-3-oxidopyridinium betaines

Cycloaddition to 1-(4,6-dimethylpyrimidin-2-yl)- and 1-(4,6-dimethoxy-s-triazin-2-yl)-3-oxidopyridinium betaines across the 2,6-positions of the pyridine rings with indene, acenaphthylene and ethyl cinnamate gave substituted 8-aza[3.2.1]bicycIooct-3-en-2-ones, whereas the [6π + 4π] cycloaddition reaction with 6,6-dimethylfulvene gave a tricyclo[6.3.1.0^2.6]dodeca-2,(6),4,9-trien-11-one. Structural and configurational assignments of the cycloadducts were deduced from ¹H nmr and ir spectral data.     

Facile Synthesis of Some 3-(Benzimidazol-2-yl)- and 3,6-Di(Benzimidazol-2-yl)-9-ethyl-9H-carbazoles

A simple and efficient synthesis of novel 3-(benzimidazol-2-yl)- and 3,6-di(benzimidazol-2-yl)-9-ethyl-9H-carbazoles is described. The synthetic approach for the preparation of 2-substituted benzimidazoles 4–8 and bis-benzimidazoles 9–12 was achieved by the condensation of carbazole-3-carbaldehyde 2 and carbazole-3,6-dicarbaldehyde 3 with o-phenyldiamines in dimethylformamide or dimethylsulfoxide in moderate to excellent yield. The identities of synthesized compounds were confirmed using ¹H NMR, ¹³C NMR, infrared (IR), and high-resolution mass spectrometry (HRMS).     

Synthesis and anticancer activity studies of novel 1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)uracil and (6′-substituted)-7- or 9-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-7H- or 9H-purines

On the basis of a molecular variation on an isosteric replacement (F→H) from the prototype (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil, the derivative (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)uracil 4 was prepared. Later on, the pyrimidine base was substituted by the purine moiety with the objective of increasing both the lipophilicity and the structural diversity of the target molecules. The 6′-halogen substituent of the (RS)-9- or 7-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-9H- or 7H-purines shows an interesting reactivity, which is presented and discussed. The anticarcinogenic potential of the target molecules is reported against the MCF-7 cancer cell line.     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Efficient Synthesis of 6-(1H-1,2,4-Triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane

Ethyl 2-amino-4-methyl-5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2, obtained from Gewald reaction of 1-(1H-1,2,4-triazol-1-yl)acetone 1 with ethyl cyanoacetate and sulfur, was transferred into iminophosphorane 3. Further reaction of 3 with aromatic isocyanates gave carbodiimides 4, which were treated subsequently with a secondary amine to give 6-(1H-1,2,4-triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones 6 in good yields in the presence of a catalytic amount of sodium ethoxide.     

Synthesis of some isomeric 4-ethoxycarbonyl-3-and 5-(1- and 2-hydroxyalkyl)-1,3- and 1,5-dimethylpyrazoles from 3-(2H)furanones and 2,3-dihydro-4-pyrones

The title compounds were prepared by reaction of 3-(2H)furanones and 2,3-dihydro-4-pyrones with methylhydrazine or alternatively by methylation of the corresponding N-unsubstituted pyrazoles. ¹³C and ¹H nmr were used to assign the isomeric 3-methyl or 5-methyl structures.     

Diels-alder reaction of (E)-4-(2-nitroethenyl)-1H-imidazoles and methyl (E)-3-(1-imidazol-4-yl)propenoates

Diels-Alder reaction of methyl (E)-3-(1H-imidazol-4-yl)propenoates 2, 3a-c and (E)4-(2-nitroethenyl)-1H-imidazoles 3d,e with 2,3-dimethyl-1,3-butadiene, cyclopentadiene, and cyclohexa-1,3-diene gave the corresponding cycloadducts 6–9 .     

DFT studies on tautomeric preferences of 1-(pyridin-2-yl)-4-(quinolin-2-yl)butane-2,3-dione in the gas phase and in solution

Density functional theory (DFT) calculations show that in vacuum such α-diketone as 1-(pyridin-2-yl)-4-(quinolin-2-yl)butane-2,3-dione is much less stable than its enolimine–enaminone ((1Z,3Z)-3-hydroxy-4-(pyridin-2-yl)-1-(quinolin-2(1H)-ylidene)but-3-en-2-one) and dienaminone tautomers ((1Z,3Z)-1-(pyridin-2-yl)-4-(quinolin-2-yl)buta-1,3-diene-2,3-diol). Other its tautomers (multiple basic and acidic centers in their molecules enable multiple proton transfer to take place) are even more labile. Strength of the intramolecular hydrogen bonds and aromatic character of the (quasi)rings [proved by the Harmonic Oscillator Model of Aromaticity (HOMA) index] in their molecules were found to be responsible for the observed tautomeric preferences. Polar and basic solvent disfavors and favors the enolimine and enaminone tautomers, respectively.     

Interaction of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methyl-thieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine with Raney nickel

3-Amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methylthieno[2,3-b]pyridine was synthesized by the reaction of 2(1H)-thioxopyridine-3-carbonitrile with 3-chloromethylisoxazole in the presence of two equivalents of KOH. Boiling of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-meth-ylthieno[2,3-b]pyridine with Raney nickel results in 4-aminothieno[2,3-b;4,5-b′]dipyridine or 5-(4-amino-2-pyridyl)pyridine depending on the reaction conditions. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 669–670, March, 2008.     

Synthesis of 5-Hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]pyridin-2-ones and Their Esters

New 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano-[2,3-c]pyridin-2-ones and their esters were synthesized. The structure of obtained compounds was determined through a complete ¹H NMR analysis.     

Synthesis of 1,5-Disubstituted 3-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-pyrazolines

Summary. A series of 1,5-disubstituted 3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-pyrazolines were synthesized by the reaction of α,β-unsaturated ketones derived from dehydroacetic acid and hydrazine in hot acetic acid or propionic acid. The structures of all new compounds were elucidated by microanalyses, ¹H and ¹³C NMR, IR, and mass spectroscopic measurements.     

Novel one-pot multicomponent synthesis of (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-dione derivatives

Abstract

An expeditious, one-pot multicomponent reaction has been developed for the synthesis of (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-dione derivatives. Condensation of 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol with phthalic anhydride and aromatic aldehyde afforded the (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-diones in acetic acid medium with excellent yields. All the synthesized compounds were characterized by their analytical and spectral data.     

Potential antipsychotic agents. Part 8. Antidopaminergic properties of a potent series of 5-substituted (−)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybcnzaimides. Synthesis via common lithio intermediates

A series of 5-substituted (?)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with (S)-1-ethylpyrrolidine-2-methylaruine (→ 14–16 , 18–21 ). The acids required were prepared in a regiospecific manner from 5-bromo-2,3-dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8 ), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC1³CCl³ or MeSSMe), and hydrolyzed (→ 9–13 ). Alternatively, (-)-(S)-5-bromo-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-di-methoxybenzamide was treated with KH followed by BuLi and an electrophile (I₂ or Me³SiCl) to give the 5-iodo and 5-(trimethylsilyl) derivatives 17 and 22 , respectively. All 5-substituted amides were highly potent inhibitors of [³H]spiperone binding in rat striatal membranes with IC⁵⁰ values of 0.5 to 5 nM (Table 3). Thus, a relatively large steric bulk can be accomodated in the position para to the 2-MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine-induced behavioural responses in the same dose range as haloperidol and raclopride (Table 4). This new group of benzamides is suitable for investigations of dopamine D-2 receptors in labelled or unlabelled form.     

Synthesis and Antimicrobial Activity of 2-Substituted-3-((3-(6-Nitrobenzo[D]thiazol-2-yl)-4-oxo-3,4-Dihydroquinazolin-2-yl)Methyl)-1,3,4-thiadiazol-3-ium-5-thiolate

Abstract

A new series of 2-substituted-3-((3-(6-nitrobenzo[d]thiazol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-1,3,4-thiadiazol-3-ium-5-thiolate 6(a–j) was synthesized starting from anthranilic acid 1. The structures of the newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectra, and elemental analysis. The final compounds were tested for their antimicrobial activity against several microbes.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text and tables.]     

Synthesis of 1,5-Disubstituted 3-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-pyrazolines

A series of 1,5-disubstituted 3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-pyrazolines were synthesized by the reaction of α,β-unsaturated ketones derived from dehydroacetic acid and hydrazine in hot acetic acid or propionic acid. The structures of all new compounds were elucidated by microanalyses, ¹H and ¹³C NMR, IR, and mass spectroscopic measurements.     

Five-Membered 2,3-Dioxo Heterocycles: XLVI. Reaction of 5-Aryl-4-quinoxalinyl-2,3-dihydrofuran-2,3-diones with Aldehydes and Ketones. Molecular and Crystalline Structure of 5-(3-p-Tolylquinoxalin-2-yl)-4H-1,3-dioxine- 2-spiro-2'-adamantan-4-one

Aroyl(quinoxalinyl)ketenes generated by thermolysis of 5-aryl-4-(3-arylquinoxalin-2-yl)-2,3-di-hydrofuran-2,3-diones act as dienes in [4 + 2]-cycloaddition at the carbonyl group of aldehydes and ketones to afford 2-substituted 6-aryl-5-(3-arylquinoxalin-2-yl)-4H-1,3-dioxin-4-ones. The structure of 5-(3-p-tolylquino-xalin-2-yl)-4H-1,3-dioxine-2-spiro-2'-adamantan-4-one was proved by X-ray analysis.     

A convenient synthesis of (z)-3-(α-alkoxycarbonyl-α-cyanomethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines and related compounds

(Z)-3-(α-Alkoxycarbonyl-α-cyanomethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines 3 and (Z)-3-(α-alkoxycarbonyl-α-cyanomethylene)-3,4-dihydrobenzo[g]quinoxalin-2(1H)-ones 5 possessing various alkoxycarbonyl groups were prepared in good yields directly from the reaction of dialkyl (E)-2,3-dicyanobutendioates 1 with o-phenylenediamine ( 2 ) or with 2,3-diaminonaphthalene ( 4 ), respectively. Furthermore, 2,3-diaminopyridine ( 6 ) and 3,4-diaminopyridine ( 7 ) were reacted with the diethyl ester 1b to give (Z)-2-(α-cyano-α-ethoxycarbonylmethylene)-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one ( 8 ) and (Z)-3-(α-cyano-α-ethoxycarbonylmethylene)-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 9 ), respectively. The structural studies of 3, 5, 8 , and 9 were carried out by nmr experiments in some details.     

Synthesis and structure of 6-substituted 9-(2-ethoxy-1,3-dioxan-5-yl)purines

The reaction of 4-chloro-5-amino-6-(1,3-dihydroxy-2-propyl)aminopyrimidine with excess ethyl orthoformate gave a cyclic acetal, viz., 6-chloro-9-(2-ethoxy-1,3-dioxan-5-yl)purine, amination of which yielded 6-amino-9-(2-ethoxy-1,3-dioxan-5-yl)purine. The presence of two configurational isomers with a diaxial orientation of the purine ring and the ethoxy group in the trans isomer and an equatorial orientation of the ethoxy group in the cis isomer was established for these compounds by ¹H and ¹³C NMR and IR spectroscopy. The three-dimensional structure of trans-6-chloro-9-(2-ethoxy-1,3-dioxan-5-yl)purine was determined by an x-ray difraction study, and the trans-diaxial orientation of the purine ring and the ethoxy group was confirmed; it is shown that the dioxane ring is in an anti conformation relative to the purine ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 976–983, July, 1979.     

A synthetic approach for (S)-(3-benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone,a selective CB2 receptor agonist

(S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone, a selective CB2 receptor agonist, was obtained from 3-hydroxy-4-iodo benzoic acid in nine steps with 97.4% ee and 3.4% total yield, which involved palladium catalyzed tandem intramolecular Heck/Suzuki cross coupling reaction, chemical resolution with (+)-norephedrine and Wolf–Kishner reaction as the key steps. (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone will be evaluated in vivo studies and this approach will be applied in the optimization process of CB2 receptor agonist.