Three isomeric forms of hydroxyphenyl‐2‐oxazoline: 2‐(2‐hydroxyphenyl)‐2‐oxazoline, 2‐(3‐hydroxyphenyl)‐2‐oxazoline and 2‐(4‐hydroxyphenyl)‐2‐oxazoline

Crystal structures are reported for three isomeric compounds, namely 2‐(2‐hydroxy­phenyl)‐2‐oxazoline, (I), 2‐(3‐hydroxy­phenyl)‐2‐oxazoline, (II), and 2‐(4‐hydroxy­phenyl)‐2‐oxazoline, (III), all C₉H₉NO₂ [systematic names: 2‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (I), 3‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (II), and 4‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (III)]. In these compounds, the deviation from coplanarity of the oxazoline and benzene rings is dependent on the position of the hydroxy group on the benzene ring. The coplanar arrangement in (I) is stabilized by a strong intra­molecular O—H⋯N hydrogen bond. Surprisingly, the 2‐oxazoline ring in mol­ecule B of (II) adopts a ³T₄ (^C2T_C3) conformation, while the 2‐oxazoline ring in mol­ecule A, as well as that in (I) and (III), is nearly planar, as expected. Tetra­mers of mol­ecules of (II) are formed and they are bound together via weak C—H⋯N hydrogen bonds. In (III), strong inter­molecular O—H⋯N hydrogen bonds and weak intra­molecular C—H⋯O hydrogen bonds lead to the formation of an infinite chain of mol­ecules perpendicular to the b direction. This paper also reports a theoretical investigation of hydrogen bonds, based on density functional theory (DFT) employing periodic boundary conditions.     

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.     

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).     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Alkylprop‐2‐enenitriles

The outcome of the photocycloaddition of cyclohex‐2‐enones to 2‐alkylprop‐2‐enenitriles differs basically from that of the corresponding 2‐alkylbut‐1‐en‐3‐ynes. While the latter afford mainly products resulting from 1,6‐cyclization of the intermediate triplet alkyl‐(prop‐2‐ynyl) 1,4‐biradical, the former give only cyclobutanecarbonitriles resulting from 1,4‐cyclization of the singlet alkyl‐cyanoalkyl 1,4‐biradical.     

Efficient Synthesis of Dialkyl (2Z)‐2‐[(E)‐1‐Aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates

The reaction of dialkyl acetylenedicarboxylates 4 with 1‐aryl‐2‐[(3‐arylquinoxalin‐2(1H)‐ylidene)ethanones 3 in the presence of Ph₃P leads to dialkyl (2Z)‐2‐[(E)‐1‐aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates 1 in good yields.     

Synthesis of 9‐[2‐(2‐hydroxymethyl‐2‐methyl‐, ‐(2‐acetoxymethyl‐2‐methyl‐, ‐(2,2‐di(hydroxymethyl)‐, and ‐(2,2‐Di(acetoxymethyl)‐1,3‐dioxan‐5‐yl)ethyl] derivatives of guanine and 2‐aminopurine

Synthesis of 9‐[2‐(2‐hydroxymethyl‐2‐methyl‐, ‐(2‐acetoxymethyl‐2‐methyl‐, ‐(2,2‐di(hydroxymethyl)‐, and ‐(2,2‐di(acetoxymethyl)‐1,3‐dioxan‐5‐yl)ethyl] derivatives of guanine and 2‐aminopurine, 2–9 , has been accomplished in seven to eight step sequences from readily available 1‐(tert‐butyldiphenylsilyloxy)‐acetone, 1,3‐di(tert‐butyldiphenylsilyloxy)acetone, and the diol 10 . Formation of cyclic ketals 11 and 12 was carried out successfully under an acidic condition using a catalytic amount of methanesulfonic acid along with excess anhydrous copper(II) sulfate in toluene. Subsequent reactions of desilylation, acetylation, hydrogenolysis, and bromination afforded the key intermediates 19 and 20 , which were coupled with 2‐amino‐6‐chloropurine to produce the purine compounds 21 and 22 in good yields. Guanine derivatives 2–5 were obtained from 21 and 22 by hydrolysis and acetylation, while the dechlorination and hydrolysis of 21 and 22 yielded the 2‐aminopurine compounds 6–9 .     

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).     

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.     

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.     

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 ).     

A series of substituted (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐phenylprop‐2‐en‐1‐ones

In the molecular structures of a series of substituted chalcones, namely (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐phenylprop‐2‐en‐1‐one, C₂₁H₁₅FO₂, (I), (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐fluorophenyl)prop‐2‐en‐1‐one, C₂₁H₁₄F₂O₂, (II), (2E)‐1‐(4‐chlorophenyl)‐3‐(2‐fluoro‐4‐phenoxyphenyl)prop‐2‐en‐1‐one, C₂₁H₁₄ClFO₂, (III), (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐methylphenyl)prop‐2‐en‐1‐one, C₂₂H₁₇FO₂, (IV), and (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐methoxyphenyl)prop‐2‐en‐1‐one, C₂₂H₁₇FO₃, (V), the configuration of the keto group with respect to the olefinic double bond is s‐cis. The molecules pack utilizing weak C—H...O and C—H...π intermolecular contacts. Identical packing motifs involving C—H...O interactions, forming both chains and dimers, along with C—H...π dimers and π–π aromatic interactions are observed in the fluoro, chloro and methyl derivatives.     

Synthesis and Reactivity of 2‐Pyrrolidino‐, 2‐N‐Methylpiperazino‐, 2‐Piperidino‐, and 2‐Morpholino‐1,3,4‐thiadiazines

A variety of 2‐pyrrolidino‐, 2‐N‐methylpiperazino‐, 2‐piperidino‐, and 2‐morpholino‐1,3,4‐thiadiazines were prepared by cyclocondensation of phenacyl halides with thiosemicarbazides. Heating of the products resulted in desulfurization and formation of pyrazoles. The rate of this process strongly depends on the substitution pattern of the 1,3,4‐thiadiazines.     

Reaction of 6‐Methyl‐2‐Thiouracil and 6‐Phenyl‐2‐Thiouracil with Chloro‐β‐Dicarbonyl and Bromo‐β‐Dicarbonyl Compounds and Their Nitrile Analogs

Derivatives of 2‐methylidene‐1,3‐dihydropyrimidin‐4‐ones 2a , 2b , 2c , 2d , 2e , 2f , 2g were synthesized by interaction of 6‐methyl‐2‐thiouracil and 6‐phenyl‐2‐thiouracil 1a , 1b with some activated halogenides: diethyl bromomalonate, ethyl 2‐chloro‐3‐oxobutanoate, ethyl 2‐bromocyanoacetate, 2‐bromo‐5,5‐dimethylcyclohexan‐1,3‐dione, and bromomalononitrile. The boiling of 1a with ethyl 2‐bromocyanoacetate in mixture of ethanol and EtONa results in intramolecular cyclization and formation of thiazolo[3,2‐a]pyrimidin‐5‐one 3 . Interaction of 1a with 3‐chloropentane‐2,4‐dione and 2‐bromo‐1,3‐diphenylpropane‐1,3‐dione yielded corresponding S‐substituted thiopyrimidines 4a , 4b . In general, the products of 1b S‐alkylation are less prone to sulfur extrusion. Reaction of 1b with diethyl bromomalonate in the absence of EtONa stops at the S‐alkylation step, while in the presence of EtONa in ethanol or PPh₃ in dioxane 2‐(ethoxycarbonylmethyl)thio‐6‐phenyl‐1,3‐dihydropyrimidin‐4(1H)‐one 6 is formed exclusively. Molecular structure and crystal structure of 2‐(1,1‐diethoxycarbonylmethyliden)‐6‐methyl‐1,3‐dihydropyrimidin‐4(1H)‐one 2a are discussed.     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Methylbut‐1‐en‐3‐yne

Irradiation (350 nm) of 2‐alkynylcyclohex‐2‐enones 1 in benzene in the presence of an excess of 2‐methylbut‐1‐en‐3‐yne ( 2 ) affords in each case a mixture of a cis‐fused 3,4,4a,5,6,8a‐hexahydronaphthalen‐1(2H)‐one 3 and a bicyclo[4.2.0]octan‐2‐one 4 (Scheme 2), the former being formed as main product via 1,6‐cyclization of the common biradical intermediate. The (parent) cyclohex‐2‐enone and other alkylcyclohex‐2‐enones 7 also give naphthalenones 8 , albeit in lower yields, the major products being bicyclo[4.2.0]octan‐2‐ones (Scheme 4). No product derived from such a 1,6‐cyclization is observed in the irradiation of 3‐alkynylcyclohex‐2‐enone 9 in the presence of 2 (Scheme 4). Irradiation of the 2‐cyano‐substituted cyclohexenone 12 under these conditions again affords only traces of naphthalenone 13 , the main product now being the substituted bicyclo[4.2.0]oct‐7‐ene 16 (Scheme 5), resulting from [2+2] cycloaddition of the acetylenic C−C bond of 2 to excited 12 .     

Synthesis of 1,3‐Dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates via Intramolecular Cyclization of 2‐[2‐(Dimethoxymethyl)phenyl]‐ 2‐hydroxyalkanoates Followed by Oxidation

A novel and efficient method for the preparation of 1,3‐dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates 4 under mild conditions has been developed. Thus, the reaction of [2‐(dimethoxymethyl)phenyl]lithiums, generated easily from 1‐bromo‐2‐(dimethoxymethyl)benzenes 1 , with α‐keto esters gives the corresponding 2‐[2‐(dimethoxymethyl)phenyl]‐2‐hydroxyalkanoates 2 . The TsOH‐catalyzed cyclization of these hydroxy acetals is followed by the oxidation of the resulting cyclic acetals 3 with PCC to give the desired products in satisfactory yields. The reaction of [2‐(dimethoxymethyl)‐4,5‐dimethoxyphenyl]lithium with (MeOC?O)₂, followed by treatment with NaBH₄ or organolithiums, affords 2‐[2‐(dimethoxymethyl)‐4,5‐dimethoxyphenyl]‐2‐hydroxyalkanoates 6 , which can similarly be transformed into the corresponding 1,3‐dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates 7 in reasonable yields.     

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.     

(2E)‐N‐(2‐Iodo‐4,6‐dimethylphenyl)‐2‐methylbut‐2‐enamide

The title compound, C₁₄H₁₈INO, crystallizes as +sc/+sp/+sc 2‐iodoanilide molecules (and racemic opposites) and shows significant intermolecular I...O interactions in the solid state, forming dimeric pairs about centres of symmetry. Under asymmetric Heck conditions, the S enantiomer of the dihydroindol‐2‐one was obtained using (R)‐(+)‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl [(R)‐BINAP], suggesting a mechanism that proceeds by oxidative addition to give the title (P) enantiomer of the compound and pro‐S coordination of the Re face of the alkene in a conformation similar to that defined crystallographically, except that rotation about the C—C bond of the butenyl group is required.     

Sesquiterpenoids and 2‐(2‐Phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐Phenylethyl)‐4H‐1‐benzopyran‐4‐one) Derivatives from Aquilaria malaccensis Agarwood

The four new sesquiterpenoids 1 – 4 , and the new 2‐(2‐phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐phenylethyl)‐4H‐1‐benzopyran‐4‐one) derivative 5 , together with the two known sesquiterpenoids 6 and 7 , the five known chromenones 8 – 12 , and 1‐hydroxy‐1,5‐diphenylpentan‐3‐one ( 13 ), were isolated from a 70% MeOH extract of Aquilaria malaccensis agarwood chips. Their structures were elucidated on the basis of comprehensive spectral analyses and comparison with literature data.     

Synthesis and antimicrobial activity of novel 2‐(aryl)‐3‐[5‐(2‐oxo‐2H‐3‐chromenyl)‐1,3‐oxazol‐2‐yl]‐1,3‐thiazolan‐4‐ones

A series of novel 2‐(aryl)‐3‐[5‐(2‐oxo‐2H‐3‐chromenyl)‐1,3‐oxazol‐2‐yl]‐1,3‐thiazolan‐4‐ones 4a , 4b , 4c , 4e , 4f , 4g , 4h , 4i , 4j have been synthesized and assayed for their antibacterial activity against Gram‐positive bacteria viz. Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538p), Micrococcus luteus (IFC 12708), and Gram‐negative bacteria viz. Proteus vulgaris (ATCC 3851), Salmonella typhimurium (ATCC 14028), Escherichia coli (ATCC 25922), and also antifungal activity against Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Among the screened compounds, 4d , 4e , 4f , 4g , and 4j exhibited potent inhibitory activity compared with the standard drug at the tested concentrations. The results reveal that, the presence of difluorophenyl in 4f and pipernyl ring in 4j at 2‐position of thiazolidine‐4‐one ring show significant inhibitory activity. The other compounds also showed appreciable activity against the test bacteria and fungi and emerged as potential molecules for further development. J. Heterocyclic Chem., 2011.