Synthesis of novel 6,7‐dihydro‐5H‐pyrimido[4,5‐e][1,4]diazepin‐8(9H)‐ones

A new method was developed for the synthesis of 6,7‐dihydro‐5H‐pyrimido[4,5‐e][1,4]diazepin‐8(9H)‐one derivatives. The key to construct the pyrimido[4,5‐e][1,4]diazepine core is the intramolecular amidation of N‐((4‐amino‐6‐chloropyrimidin‐5‐yl)methyl)‐substituted amino acid esters. This methodology was validated through the preparation of 13 representative 6,7‐dihydro‐5H‐pyrimido[4,5‐e][1,4]diazepin‐8(9H)‐ones in moderate to good yields. J. Heterocyclic Chem., (2011).     

An Unexpected Pyrimidine Ring Transformations in the Reaction of 4‐aryl‐5‐nitro‐6‐bromomethylpyrimidin‐2(1H)‐ones with Anilines

The reaction of 4‐aryl‐6‐bromomethyl‐5‐nitro‐3,4‐dihydropyrimidin‐2(1H)‐ones, containing three possible combinations of substituted and unsubstituted nitrogen atoms with anilines depending on the conditions leads to the products of ring contraction of the pyrimidinone ring into an imidazolone, as well as to the formation of 7‐aryl‐6,7‐dihydroisoxazolo[4,3‐d]pyrimidin‐5(4H)‐one derivatives, and in some cases to the 5‐aminopyrimidinones. The mechanisms of these unusual ring transformations are discussed.     

3‐(α‐Chlorobenzyl)quinoxalin‐2(1H)‐ones as Versatile Reagents for the Synthesis of 3‐Benzylquinoxalin‐2(1H)‐ones and Thiazolo[3,4‐a]quinoxalin‐4(5H)‐ones

Facile and efficient methods for the synthesis of 3‐benzylquinoxalin‐2(1H)‐ones and thiazolo[3,4‐a]quinoxalin‐4(5H)‐ones by the reaction of the readily available 3‐(α‐chlorobenzyl)quinoxalin‐2(1H)‐ones and thiourea have been developed, with multiple roles of the latter. Possible mechanisms are discussed. These two‐step sequences can be performed in a one‐pot manner to produce the desired products in moderate to high yields.     

Conversion of 3‐amino‐4‐arylamino‐1H‐isochromen‐1‐ones to 1‐arylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐ones: synthesis,spectroscopic characterization and the structures of four products and one ring‐opened derivative

An efficient synthesis of 1‐arylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐ones, involving the diazotization of 3‐amino‐4‐arylamino‐1H‐isochromen‐1‐ones in weakly acidic solution, has been developed and the spectroscopic characterization and crystal structures of four examples are reported. The molecules of 1‐phenylisochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₅H₉N₃O₂, (I), are linked into sheets by a combination of C—H…N and C—H…O hydrogen bonds, while the structures of 1‐(2‐methylphenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₆H₁₁N₃O₂, (II), and 1‐(3‐chlorophenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, C₁₅H₈ClN₃O₂, (III), each contain just one hydrogen bond which links the molecules into simple chains, which are further linked into sheets by π‐stacking interactions in (II) but not in (III). In the structure of 1‐(4‐chlorophenyl)isochromeno[3,4‐d][1,2,3]triazol‐5(1H)‐one, (IV), isomeric with (III), a combination of C—H…O and C—H…π(arene) hydrogen bonds links the molecules into sheets. When compound (II) was exposed to a strong acid in methanol, quantitative conversion occurred to give the ring‐opened transesterification product methyl 2‐[4‐hydroxy‐1‐(2‐methylphenyl)‐1H‐1,2,3‐triazol‐5‐yl]benzoate, C₁₇H₁₅N₃O₃, (V), where the molecules are linked by paired O—H…O hydrogen bonds to form centrosymmetric dimers.     

Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7‐Dihydrobenzisoxazolones

Regioselective methods for synthesis of hitherto unreported both 6,7‐dihydro‐1,2‐benzisoxazol‐4(5H)‐ones and 6,7‐dihydro‐2,1‐benzisoxazol‐4(5H)‐ones with perfluoroalkyl or halogenodifluoromethyl substituents have been developed. 3‐Polyfluoroalkyl‐6,7‐dihydro‐1,2‐benzisoxazol‐4(5H)‐ones were prepared by the cyclocondensation of 2‐polyfluoroalkanoylcyclohexane‐1,3‐diones with hydroxylamine. The regioisomeric 3‐polyfluoroalkyl‐6,7‐dihydro‐2,1‐benzisoxazol‐4(5H)‐ones were synthesized by the transformation of 2‐polyfluoroalkanoylcyclohexane‐1,3‐diones into their vinylogous chlorides, followed by the interaction of obtained crude 3‐chloro‐2‐polyfluoroalkanoyl‐2‐cyclohexen‐1‐ones with sodium azide in dimethylformamide.     

Ring Opening of 2‐(Benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones and 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones

Substituted 2‐(benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones are unstable under alkaline and acidic conditions, undergoing opening of the benzoxazinone ring. 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2‐hydroxy‐2H‐1,4‐benzoxazin‐3(4H)‐ones was observed only under mild alkaline conditions. Mechanisms of ring opening and degradation to 2‐aminophenol derivatives are proposed.     

Synthesis of 2,5,7‐Triaryl‐4,7(6,7)‐dihydropyrazolo[1,5‐a]pyrimidine‐3‐carbonitriles by Reaction of 5(3)‐Amino‐3(5)‐aryl‐1H‐pyrazole‐4‐carbonitriles with Chalcones

The reaction of 5(3)‐amino‐3(5)‐aryl‐1H‐pyrazole‐4‐carbonitriles with 1,3‐diaryl‐2‐propen‐1‐ones (chalcones) in refluxing DMF leads to 2,5,7‐triaryl‐4,7(6,7)‐dihydropyrazolo[1,5‐a]pyrimidine‐3‐carbonitriles. In DMSO solution, the latter exist in equilibrium of two tautomeric 4,7‐dihydropyrazolo[1,5‐a]pyrimidines and 6,7‐dihydropyrazolo[1,5‐a]pyrimidines in various ratios, depending on the nature of aryl substituents in chalcone building blocks.     

Synthesis of 1‐Amino‐5,6‐diaryl‐3‐cyano‐1H‐pyridin‐2‐ones and 6,7‐Diaryl‐4‐cyano‐3‐hydroxy‐1H‐[1,2]diazepines from Isoflavones

The one‐step cyclocondensation of substituted isoflavones (=3‐phenyl‐4H‐1‐benzopyran‐4‐ones) with cyanoacetohydrazide in the presence of KOH afforded a mixture of 1‐amino‐5,6‐diaryl‐3‐cyano‐1H‐2‐pyridin‐2‐ones and 6,7‐diaryl‐4‐cyano‐3‐hydroxy‐1H‐[1,2]diazepines.     

Microwave‐assisted synthesis of new regioisomeric 6,7‐dihydroindeno[1,2‐e]pyrimido[4,5‐b][1,4]diazepin‐5(5aH)‐ones

Novel 11‐amino‐6‐aryl‐6,7‐dihydroindeno[1,2‐e] pyrimido[4,5‐b][1,4]diazepin‐5(5aH)‐ones 4a‐f were prepared regioselectively by the tricomponent reaction of 4,5,6‐triaminopyrimidine 1, 1,3‐indandione 2 and aromatic aldehydes 3a‐f. The bicomponent approach, using 2,4,5,6‐tetraaminopyrimidine 5 and 2‐aryl‐ideneindandiones 6a‐f as reagents, afforded 9,11‐diamino‐6‐aryl‐6,7‐dihydroindeno[1,2‐e]pyrimido[4,5‐b]‐[1,4]diazepin‐5(5aH)‐ones 7a‐f in good yields and the regioisomeric 8,10‐diamino derivatives 8a‐c in lower yields. Both, bi‐ and tricomponent approaches were performed by microwave irradiation and all products were fully characterized by detailed NMR measurements.     

An easy route to 2‐substituted‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones and 7‐ones starting from the corresponding 2‐amino‐2‐oxazolines

The isomeric 2‐substituted‐7(5)‐methyl‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b and 7‐ones 2a‐b,7a were synthesized by cyclocondensation from the 5‐substituted‐2‐amino‐2‐oxazolines 1a‐b with biselectrophiles. In boiling ethanol, the reaction of 1a‐b with acetylenic esters led to a mixture of 2a‐b,7a with a small amount of (E)‐2‐N‐(2‐ethoxycarbonylethylene)‐5‐substituted‐2‐iminooxazolines 5a‐b . The ring annulation between 1a‐b and diketene gave the 2‐substituted‐7‐hydroxy‐7‐methyl‐2,3,6,7‐tetrahydro‐5H‐oxazolo[3,2‐ a ]pyrimidin‐5‐ones 4a‐b which can be easily dehydrated to provide the 2‐substituted‐7‐methyl‐2,3‐dihydro‐5H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b .     

Efficient microwave‐assisted synthesis and antioxidant activity of 4‐arylidene‐2‐phenyl‐1H‐imidazol‐5(4H)‐ones

The efficient synthesis of 4‐arylidene‐2‐phenyl‐1H‐imidazol‐5(4H)‐ones was achieved via microwave‐assisted reactions of 4‐arylmethylene‐2‐phenyloxazol‐5(4H)‐ones with urea in glycol. This approach provides a facile shortcut for the synthesis of this type of compounds with short reaction time, high yields, broad substrate scope and easy operation. Besides, the synthesized compounds were subject to the test of antioxidant activity, which is represented by their capacities for scavenging 1,1‐diphenyl‐2‐picrylhydrazyl, hydroxyl and superoxide anion free radicals. Bioassay of these compounds resulted in the finding of several 4‐arylidene‐2‐phenyl‐1H‐imidazol‐5(4H)‐ones with significant antioxidant activity. J. Heterocyclic Chem., (2012).     

Synthesis and Characterization of New (Z)‐5‐((1H‐1,2,4‐Triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones

Ten compounds of new (Z)‐5‐((1H‐1,24‐triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones ( 5a – j ) have been synthesized by the Knoevenagel condensation of 5‐((1H‐1,2,4‐triazol‐1‐ylmethyl)indolin‐2‐one ( 3 ) with 4‐substituted aromatic aldehydes ( 4a – j ).     

Facile Chemoselective synthesis of 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids and 3H,3’H‐Spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives

Oxidation of some derivatives of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐one have been investigated in detail using lead(IV) acetate in acetic acid under reflux conditions and periodic acid in aqueous ethanol at room temperature. We realized that during the first 5–15 minutes of the oxidation reactions in lead(IV) acetate/acetic acid system, 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives have been synthesized chemo selectively, while, if the reaction mixtures stirred for additional 3 hours, the main products would be 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids. Moreover, room temperature oxidation of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐ones by periodic acid (H₅IO₆), leads to the formation of 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives in good to excellent yields.     

Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

The chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐²H₂)‐ 1 , resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐²H₂)‐ 1a , resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric ²H‐labeled 5‐hydroxydecano‐4‐lactones 2 . The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ^® E). The enantiomers of threo‐ 2 were separated without derivatization on Lipodex ^® E; in contrast, the enantiomers of erythro‐ 2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐²H₂)‐ 1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐²H₂)‐ 2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐²H₂)‐ 2 showed 95% label at C(5), 68% label at C(2), and no ²H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of ²H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐ 2 , known as L‐factor, occurs temporarily before the antibiotic production, and (?)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐ 2 , is an anticancer agent.     

Reactions of 4‐Hydroxyquinolin‐2(1H)‐ones with Acenaphthoquinone: Synthesis of New 1,2‐Dihydroacenaphthylene‐spiro‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones)

Reaction of four equivalents of 4‐hydroxyquinolin‐2(1H)‐ones with one equivalent of acenaphthoquinone in absolute ethanol, containing catalytic triethylamine, gave 3,3′,3″,3?‐(1,2‐dihydroacenaphthylene)‐1,1,2,2‐tetrayl‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones) in a good to excellent yields. The structures of the products were elucidated by ¹H NMR, ¹³C NMR, NMR, IR, mass spectra, and elemental analyses.     

Synthesis of Analogues of Indole Alkaloids from Sea Sponges – Aplysinopsins by the Reaction of Amines with (4Z)‐4‐[(1H‐indol‐3‐yl)‐methylene]‐1,3‐oxazol‐5(4H)‐ones

A new two‐step approach toward the synthesis of aplysinopsin analogues 5‐(1‐R‐1H‐indol‐3‐ylmethylene)‐2‐aryl‐3,5‐dihydroimidazol‐4‐ones consisting in obtaining and reaction of 4‐(1‐R‐1H‐indol‐3‐ylmethilene)‐2‐Ar‐4H‐oxazol‐5‐ones with amines was developed. The configuration of starting compounds and final products was determined by ¹³С and ¹H‐nmr spectroscopy.     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

Synthesis of 3‐Acetyl‐4‐hydroxy‐1‐phenylpyridin‐2(1H)‐one Derivatives

The cyclization of aryl ketone anilides 3 with diethyl malonate to affords 4‐hydroxy‐6‐phenyl‐6H‐pyrano[3,2‐c]‐pyridin‐2,5‐diones 4 in good yields. 3‐Acetyl‐4‐hydroxy‐1‐phenylpyridin‐2(1H)‐ones 5 are obtained by ring‐opening reaction of 4‐hydroxy‐6‐phenyl‐6H‐pyrano[3,2‐c]‐pyridin‐2,5‐diones 4 in the presence of 1,2‐diethylene glycol. The reaction of 3‐acetyl‐4‐hydroxy‐1‐phenylpyridin‐2(1H)‐ones 5 with hydroxylamine hydrochloride produces 4‐hydroxy‐3‐[N‐hydroxyethanimidoyl]‐1‐phenylpyridin‐2(1H)‐ones 6 from which 3‐alkyloxyiminoacetyl‐4‐hydroxy‐1‐phenylpyridin‐2(1H)‐ones 7 are obtained by reacting with alkyl bromides or iodides in the presence of anhydrous potassium carbonate with moderate yields. The similar compounds can be synthesized on refluxing 3‐acetyl‐4‐hydroxy‐1‐phenylpyridin‐2(1H)‐ones 5 with substituted hydroxylamine hydrochloride in the presence of sodium bicarbonate with good yields. Most of the synthesized compounds are characterized by IR and NMR spectroscopic methods.     

Regio‐ and stereoselective synthesis of spiro[1‐benzothiepine‐4(5h), 3′(3h)‐pyrazol]‐5‐ones

Reaction of (4E)‐4‐arylmethylene‐3,4‐dihydro‐1‐benzothiepin‐5(2H)‐ones 3a‐e with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 4a, b ) in refluxing benzene, afforded 2′,4′,5′‐triaryl‐2,2′,3,4′‐tetrahydro‐spiro[1‐benzothiepine‐4(5H),3′(3H)‐pyrazol]‐5‐ones 5a‐i and not the isomeric forms spiro[1‐benzothiepine‐4(5H),4′(4H)‐pyrazol]‐5‐ones 6 in high regioselective manner. Single crystal X‐ray diffraction studies of 5a, f, g indicated that the isolated products are 3′R, 4′ S.