Quinolone analogues 7 [1‐6]. Synthesis of 3‐Heteroaryl‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

The 3‐heteroaryl‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones 6a‐e were synthesized by the oxidative‐hydrolytic ring transformation of the 3‐heteroaryl‐1,2‐diazepino[3,4‐b]]quinoxaline‐5‐carbonitriles 9a‐c , which were obtained by the 1,3‐dipolar cycloaddition reaction of the 2‐(2‐heteroarylmethylene‐1‐methylhydrazino)quinoxaline 4‐oxides with 2‐chloroacrylonitrile. The assignment of the thiophene and furan ring protons was carried out through the data of the NOE, decoupling, and coupling constants.     

Photocycloaddition Reactions of 2‐(Alk‐3‐en‐1‐ynyl)cyclohex‐2‐enones

The newly synthesized 2‐(alk‐3‐en‐1‐ynyl)cyclohex‐2‐enones 4 undergo photodimerization (chemo‐ and regio‐)selectively at the exocyclic C?C bond to give diastereoisomeric mixtures of 1,2‐dialkynyl‐1,2‐dimethylcyclobutanes. On irradiation of 4 in the presence of 2‐chloroacrylonitrile, cyclobutane formation occurs again (chemo‐ and regio‐)selectively at the exocyclic C?C bond to afford diastereoisomeric mixtures of 2‐alkynyl‐1‐chloro‐2‐methylcyclobutanecarbonitriles. Similarly, compounds 4 undergo photoaddition to 2,3‐dimethylbuta‐1,3‐diene exclusively at the exocyclic C?C bond to afford mixtures of [2+2] and [4+2] cycloadducts.     

Thiourea‐Catalyzed Asymmetric Michael Addition of Carbazolones to 2‐Chloroacrylonitrile: Total Synthesis of 5,22‐Dioxokopsane,Kopsinidine C,and Demethoxycarbonylkopsin

A modified Takemoto catalyst enabled the asymmetric Michael addition of carbazolones to 2‐chloroacrylonitrile to afford 3,3‐disubstituted carbazolones with excellent enantioselectivity. This method was successfully applied to total syntheses of three Kopsia alkaloids which featured an unprecedented Mn^III‐mediated oxidative cyclization to create the caged ring system and a SmI₂‐mediated reductive coupling as key steps.     

Thiourea‐Catalyzed Asymmetric Michael Addition of Carbazolones to 2‐Chloroacrylonitrile: Total Synthesis of 5,22‐Dioxokopsane,Kopsinidine C,and Demethoxycarbonylkopsin

A modified Takemoto catalyst enabled the asymmetric Michael addition of carbazolones to 2‐chloroacrylonitrile to afford 3,3‐disubstituted carbazolones with excellent enantioselectivity. This method was successfully applied to total syntheses of three Kopsia alkaloids which featured an unprecedented Mn^III‐mediated oxidative cyclization to create the caged ring system and a SmI₂‐mediated reductive coupling as key steps.     

Synthesiss of novel 3‐(2‐thienyl)‐1,2‐diazepino[3,4‐b]quinoxalines with algicidal activity

The reaction of the quinoxaline N‐oxide 1 with thiophene‐2‐carbaldehyde gave 6‐chloro‐2‐[1‐methyl‐2‐(2‐thienylmethylene)hydrazino]quinoxaline 4‐oxide 5 , whose reaction with 2‐chloroacrylonitrile afforded 8‐chloro‐2,3‐dihydro‐4‐hydroxy‐1‐methyl‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]quinoxaline‐5‐carbonitrile 6 . The reaction of compound 6 with various alcohols in the presence of a base effected alcoholysis to provide the 5‐alkoxy‐8‐chloro‐2,3,4,6‐tetrahydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 7a‐d . The reaction of compounds 7a and 7b with diethyl azodicarboxylate effected dehydrogenation to give the 5‐alkoxy‐8‐chloro‐4,6‐dihydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 8a and 8b , respectively. Compounds 8a and 8b were found to show good algicidal activities against Selenastrum capricornutum and Nitzchia closterium.     

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

A flexible approach, applicable on a gram scale, to chiral 2‐endo‐substituted 9‐oxabispidines was developed. The key intermediate, a cis‐configured 6‐aminomethylmorpholine‐2‐carbonitrile, was prepared from (R)‐3‐aminopropane‐1,2‐diol and 2‐chloroacrylonitrile. The 2‐endo substituent was introduced by Grignard addition, cyclization, and exo‐selective reduction, thus furnishing the enantiomerically pure bi‐ and tricyclic 9‐oxabispidines in 19–59 % yield. The CuCl₂ complex of the tricyclic 9‐oxabispidine, which carries an 2‐endo,N‐anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S‐configured β‐nitro alcohols in 91–98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9‐oxabispidines delivered the enantiocomplementary R‐configured products in 33–57 % ee. The respective transition states were discussed.     

Anion‐π Catalysis: Focus on Nonadjacent Stereocenters

Anion‐π interactions have been recently introduced to catalysis with the idea to stabilize anionic intermediates on π‐acidic surfaces. Realized examples include enolate, enamine and iminium chemistry, domino processes and Diels–Alder reactions. Moving on from the formation of contiguous stereogenic centers on π‐acidic surfaces, herein we report the first asymmetric anion‐π catalysis of cascade reactions that afford nonadjacent stereocenters. Conjugate addition‐protonation of achiral disubstituted enolate donors to 2‐chloroacrylonitrile generates 1,3‐nonadjacent stereocenters with moderate enantioselectivity and diastereoselectivity. The explored catalysts operate with complementary naphthalenediimide and fullerene surfaces with highly positive quadrupole moments and high polarizability, respectively, and proximal amine bases. We find that anion‐π catalysts can increase the diastereoselectivity of the reaction beyond the maximal 1:4.0 dr with conventional catalysts to maximal 5.3:1 dr on the large fullerene surfaces. The enantioselectivity of anion‐π catalysts, best on the confined naphthalenediimide surfaces with strong quadrupole moment, exceed the performance of conventional catalysts except for comparable results with a new, most compact, surprisingly powerful bifunctional control catalyst. Simultaneously increased rates and stereoselectivities compared to control catalysts without π‐acidic surface support that contributions of anion‐π interactions to the catalytic cascade process are significant.     

An Efficient Synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one Derivatives via Multi‐Component Approach

An easy, highly efficient and a new convenient one‐pot, two‐step approach to the synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one is described. These compounds were synthesized from 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐4‐hydroxy‐6‐methyl‐3,4‐dihydro‐2H‐pyran‐2‐one and α‐bromoketones in good yields. The compounds 4 were synthesized by a multi‐component reaction between 1 , 2 , and 3 and the prominent features of this protocol are mild reaction conditions, operation simplicity, and good to high yields of products.     

New domino‐reaction for the synthesis of N4‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines and 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine

The model morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide (1) reacts with phenacyl bromides to afford N⁴‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines (4) or N⁴‐(4,5‐diphenyl‐1,3‐oxathiol‐2‐yliden)‐2‐phenyl‐4‐aminoquinazoline ( 5 ) by a thermodynamically controlled reversible reaction favoring the enolate intermediate, while the 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine ( 8 ) was produced by a kinetically controlled reaction favoring the C‐anion intermediate. ¹H nmr, ¹³C nmr, ir, mass spectroscopy and x‐ray identified compounds ( 4 ), ( 5 ) and ( 8 ).     

Polymorphism of 3‐(5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)‐ and 3‐[5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐2‐yl]‐2H‐chromen‐2‐ones

This study of 3‐(5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)‐2H‐chromen‐2‐one, C₁₇H₁₀N₂O₃, 1 , and 3‐[5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐2‐yl]‐2H‐chromen‐2‐one, C₁₆H₉N₃O₃, 2 , was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the `head‐to‐head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar‐layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.     

Synthesis and Solid‐state Reaction of 1‐[3′‐(Benzotriazol‐2″‐yl)‐4′ ‐hydroxybenzoyl]‐3‐methyl‐5‐pyrazolones

A new kind of UV stabilizers, 1‐(3′‐(benzotriazol‐2″‐yl)‐4′‐hydroxy‐benzoyl)‐3‐methyl‐5‐pyrazolones (1a‐d), was synthesized with the aim to bind them chemically to certain polymers. The reaction of 1d with substituted benzaldehydes 4 in the molten state at 150°C and in the solid state at room temperature produced the condensation products l‐(3′‐(5″‐chlorobenzotriazol‐2″‐yl)‐4′‐hydroxyl‐5′‐chlorobenzoyl)‐3‐methyl‐4‐arylmethylene‐5‐pyrazolones (2) and 4,4′‐arylmethylene‐bis [1‐(3′‐(5″‐chloro‐benzotriazol‐2″‐yl)‐4′‐hydroxy‐5′‐chloro‐benzoyl)‐3‐methyl‐5‐pyrazolone] s (3), respectively, as the major product. On the other hand, the reaction of 1d with 4 at 50°C in chloroform solution proceeded non‐selectively to give a mixture of 2 and 3.     

Preparation of 2‐phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline and 2‐methyl‐4‐oxo‐3,4‐dihydroquinazoline derivatives formation

The cyclization of phenacyl anthranilate has been studied with the aim to develop the synthesis of 2‐(2′‐aminophenyl)‐4‐phenyloxazole. However, a different course of the reaction than expected was observed. 2‐Phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 3a ) was formed by the reaction of phenacyl anthranilate ( 2 ) with ammonium acetate under various conditions. 3‐Hydroxy‐2‐phenyl‐4(1H)‐quinolinone ( 4 ) arose by heating compound 3a in acetic acid. The same compound was obtained by melting compound 3a , but the yield was lower. Different types of products resulted in the reaction of compound 3a with acetic anhydride. Under mild conditions acetylated products 2‐acetoxymethyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 7a ) and 2‐acetoxymethyl‐3‐acetyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 8 ) were prepared. If the reaction was carried out under reflux of the reaction mixture, molecular rearrangement took place to give cis and trans 2‐methyl‐4‐oxo‐3‐(1‐phenyl‐2‐acetoxy)vinyl‐3,4‐dihydroquinazolines ( 9a and 9b ). All prepared compounds have been characterised by their ¹H, ¹³C and ¹⁵N NMR spectra, IR spectra and MS.     

First synthesis of 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol from 1‐ and 2‐naphthol derivatives

Two new structurally isomeric, 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol ( 1 ) and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol ( 3 ) have been synthesized from 2‐acetyl‐1‐naphthol and ethyl‐3‐hydroxy‐2‐naphthoate, respectively, involving Grignard reaction, dehydration of the corresponding tertiary alcohols, and hetero Diels–Alder dimerization. The two benzochromenes ( 1 and 3 ) have been fully characterized by IR, NMR, and HRESIMS data. Their structures are further supported by crystallography of their corresponding acetates ( 2 and 4 ). J. Heterocyclic Chem., (2011).     

The Synthesis of 2‐(Chromon‐2/3‐yl)‐3‐(5‐thione‐4‐hydro‐1,3,4‐thiadiazol‐2‐yl)‐4‐oxo‐thiazolidine

2‐Formylchromones and 3‐formylchromones as the first materials singly reacted with 2‐amino‐5‐mercapto‐1,3,4‐thiadiazole to give the corresponding Schiff bases, which on cyclocondensation with mercapto‐acetic acid in 1,4‐dioxane yielded target compounds named 4‐oxo‐thiazolidines. The structures of all the synthetic compounds were confirmed by elemental analysis and IR, ¹H NMR, LC‐MS (ESI) spectral data.     

Synthesis of 5‐methyl‐4‐oxo‐2‐(coumarin‐3‐yl)‐N‐aryl‐3,4‐dihydrothieno[2,3‐d]‐pyrimidine‐6‐carboxamides

Possible approaches to synthesis of 5‐methyl‐4‐oxo‐2‐(coumarin‐3‐yl)‐N‐aryl‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐6‐carboxamides 4 have been discussed. It is shown that the preferable approach is cyclization of 2‐iminocoumarin‐3‐carboxamides 1 , utilizing 5‐amino‐3‐methyl‐N²‐arylthiophene‐2,4‐dicarboxamides 2 as binucleophilic reagents. The proposed procedure allowed us to easily obtain 4 in two stages, using common reagents. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:341–346, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20303     

An Innovative Protocol for the Synthesis of 3‐(Pyridin‐2‐yl)‐5‐sec‐aminobiphenyl‐4‐carbonitriles and 9,10‐Dihydro‐3‐(pyridine‐2‐yl)‐1‐sec‐aminophenanthrene‐2‐carbonitriles

Herein, we present an innovative, novel, and highly convenient protocol for the synthesis of 3‐(pyridin‐2‐yl)‐5‐sec‐aminobiphenyl‐4‐carbonitriles ( 6a , 6b , 6c , 6d , 6e , 6f , 6g ) and 9,10‐dihydro‐3‐(pyridine‐2‐yl)‐1‐sec‐aminophenanthrene‐2‐carbonitriles ( 10a , 10b , 10c , 10d , 10e ), which have been delineated from the reaction of 4‐sec‐amino‐2‐oxo‐6‐aryl‐2H‐pyran‐3‐carbonitrile ( 4a , 4b , 4c , 4d , 4e , 4f , 4g ) and 4‐sec‐amino‐2‐oxo‐5,6‐dihydro‐2H‐benzo[h]chromene‐3‐carbonitriles ( 9a , 9b , 9c , 9d , 9e ) with 2‐acetylpyridine ( 5 ) through the ring transformation reaction by using KOH/DMF system at RT. The salient feature of this procedure is to provide a transition metal‐free route for the synthesis of asymmetrical 1,3‐teraryls like 3‐(pyridin‐2‐yl)‐5‐sec‐aminobiphenyl‐4‐carbonitriles ( 6a , 6b , 6c , 6d , 6e , 6f , 6g ) and 9,10‐dihydro‐3‐(pyridine‐2‐yl)‐1‐sec‐aminophenanthrene‐2‐carbonitriles ( 10a , 10b , 10c , 10d , 10e ). The novelty of the reaction lies in the creation of an aromatic ring from 2H‐pyran‐2‐ones and 2H‐benzo[h]chromene‐3‐carbonitriles via two‐carbon insertion from 2‐acetylpyridine ( 5 ) used as a source of carbanion.     

Hantzsch reaction of 3‐(2‐bromoacetyl)‐4‐hydroxy‐chromen‐2‐one. Synthesis of 3‐(thiazol‐4‐yl)‐4‐hydroxy coumarines

3‐Acetyl‐4‐hydroxy‐chromen‐2‐one ( 1 ) was brominated with phenyltrimethylammonium tribromide to afford 3‐(2‐bromoacetyl)‐4‐hydroxy‐chromen‐2‐one ( 2 ) whose reactions with thiourea, thioacetamide and ammonium dithiocarbamate gave respectively 3‐(2‐amino‐thiazol‐4‐yl)‐4‐hydroxy‐, 4‐hydroxy‐3‐(2‐phenyl‐thiazol‐4‐yl)‐ and 4‐hydroxy‐3‐(2‐mercapto‐thiazol‐4‐yl)chromen‐2‐one. In a similar manner, com pound 2 was treated with four 1‐substituted‐2‐thioureas and thiobenzamide to give the corresponding 4‐hydroxy‐3‐(thiazol‐4‐yl)‐chromen‐2‐one derivatives.     

4‐(2‐Hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine and the 2‐(2,3‐dimethoxyphenyl)‐, 2‐(3,4‐dimethoxyphenyl)‐ and 2‐(2,5‐dimethoxyphenyl)‐substituted derivatives

The 1,5‐benzodiazepine ring system exhibits a puckered boat‐like conformation for all four title compounds [4‐(2‐hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₁H₁₈N₂O, (I), 2‐(2,3‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (II), 2‐(3,4‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (III), and 2‐(2,5‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (IV)]. The stereochemical correlation of the two C₆ aromatic groups with respect to the benzodiazepine ring system is pseudo‐equatorial–equatorial for compounds (I) (the phenyl group), (II) (the 2,3‐dimethoxyphenyl group) and (III) (the 3,4‐dimethoxyphenyl group), while for (IV) (the 2,5‐dimethoxyphenyl group) the system is pseudo‐axial–equatorial. An intramolecular hydrogen bond between the hydroxyl OH group and a benzodiazepine N atom is present for all four compounds and defines a six‐membered ring, whose geometry is constant across the series. Although the molecular structures are similar, the supramolecular packing is different; compounds (I) and (IV) form chains, while (II) forms dimeric units and (III) displays a layered structure. The packing seems to depend on at least two factors: (i) the nature of the atoms defining the hydrogen bond and (ii) the number of intermolecular interactions of the types O—H...O, N—H...O, N—H...π(arene) or C—H...π(arene).     

Synthesis and Antifungal Screening of 2‐(2‐Aryl‐4‐methyl‐thiazol‐5‐yl)‐5‐((2‐aryl/benzylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole Derivatives

A new series of synthesis and biological screening of 2‐(2‐aryl‐4‐methyl‐thiazol‐5‐yl)‐5‐((2‐aryl/benzylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole derivatives 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i was achieved by condensation of 2‐(2‐aryl/benzylthiazol‐4‐yl)acetohydrazide 2a , 2b , 2c with 4‐methyl‐2‐arylthiazole‐5‐carbaldehyde 3a , 3b , 3c followed by oxidative cyclization of N'‐((4‐methyl‐2‐arylthiazol‐5‐yl)methylene)‐2‐(2‐aryl/benzylthiazol‐4‐yl)acetohydrazide 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i using iodobenzene diacetate as oxidizing agent. All the synthesized compounds were screened for their in vitro antifungal activity against Candida albicans, Candida tropicalis, Aspergillus niger, and Aspergillus flavus. Some of the synthesized compounds showed good antifungal activity.