Reduction of 3‐Aminoquinoline‐2,4(1H,3H)‐diones and Deamination of the Reaction Products

3‐Aminoquinoline‐2,4‐diones were stereoselectively reduced with NaBH₄ to give cis‐3‐amino‐3,4‐dihydro‐4‐hydroxyquinolin‐2(1H)‐ones. Using triphosgene (=bis(trichloromethyl) carbonate), these compounds were converted to 3,3a‐dihydrooxazolo[4,5‐c]quinoline‐2,4(5H,9bH)‐diones. The deamination of the reduction products using HNO₂ afforded mixtures of several compounds, from which 3‐alkyl/aryl‐2,3‐dihydro‐1H‐indol‐2‐ones and their 3‐hydroxy and 3‐nitro derivatives were isolated as the products of the molecular rearrangement.     

New Approaches to the Synthesis of 4‐(2‐Aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones and 3‐Ureidoindoles and a Study of Their Interconversion

3‐Alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 2 ) and 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) react in boiling concentrated HCl to give 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ). The same compounds were prepared by the same procedure from 2‐alkyl/aryl‐3‐ureido‐1H‐indoles ( 4 ), which were obtained from the reaction of 3‐alkyl/aryl‐3‐aminoquinoline‐2,4(1H,3H)‐diones ( 1 ) with 1,3‐diphenylurea or by the transformation of 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) and 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ) in boiling AcOH. The latter were converted into 1,3‐bis[2‐(2‐oxo‐2,3‐dihydro‐1H‐imidazol‐4‐yl)phenyl]ureas ( 5 ) by treatment with triphosgene. All compounds were characterized by ¹H‐ and ¹³C‐NMR and IR spectroscopy, as well as atmospheric pressure chemical‐ionisation mass spectra.     

C5‐Alkyl‐1,3,4‐Oxadiazol‐2‐ones Undergo Dealkylation upon Nitrogen Insertion to Form 2H‐1,2,4‐Triazol‐3‐ones: Synthesis of 1,2,4‐Triazol‐3‐one Hybrids with Triazolothiadiazoles and Triazolothiadiazines

The present study emphasizes on the dealklylation of 3‐aryl‐5‐alkyl‐2‐oxo‐Δ⁴‐1,3,4‐oxadiazoles when reacted with formamide resulting in the formation of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐ones as major product. Subsequent reactions of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐one gave triazolo[3,4‐b ][1,3,4]thiadiazoles and triazolo[3,4‐b ][1,3,4]thiadiazines derivatives incorporated with 1,2,4‐triazol‐3‐one.     

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 and Antiplatelet‐Activity Evaluation of α‐Methylidene‐γ‐butyrolactones Bearing 3,4‐Dihydroquinolin‐2(1H)‐one Moieties

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α‐methylidene‐γ‐butyrolactones bearing 3,4‐dihydroquinolin‐2(1H)‐one moieties. O‐Alkylation of 3,4‐dihydro‐8‐hydroxyquinolin‐2(1H)‐one ( 1 ) with chloroacetone under basic conditions afforded 3,4‐dihydro‐8‐(2‐oxopropoxy)quinolin‐2(1H)‐one ( 2a ) and tricyclic 2,3,6,7‐tetrahydro‐3‐hydroxy‐3‐methyl‐5H‐pyrido[1,2,3‐de][1,4]benzoxazin‐5‐one ( 3a ) in a ratio of 1 : 2.84. Their Reformatsky‐type condensation with ethyl 2‐(bromomethyl)prop‐2‐enoate furnished 3,4‐dihydro‐8‐[(2,3,4,5‐tetrahydro‐2‐methyl‐4‐methylidene‐5‐oxofuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 4a ), which shows antiplatelet activity, in 70% yield. Its 2′‐Ph derivatives, and 6‐ and 7‐substituted analogs were also obtained from the corresponding 3,4‐dihydroquinolin‐2(1H)‐ones via alkylation and the Reformatsky‐type condensation. Of these compounds, 3,4‐dihydro‐7‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 10b ) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC₅₀ of 0.23 μM . For the inhibition of platelet‐activating factor (PAF) induced aggregation, 6‐{[2‐(4‐fluorophenyl)‐2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxofuran‐2‐yl]methoxy}‐3,4‐dihydroquinolin‐2(1H)‐one ( 9c ) was the most potent with an IC₅₀ value of 1.83 μM .     

Reaction of 3‐Hydroxyquinoline‐2,4‐diones with Isocyanates and Thermally Induced Transformation of the Reaction Products

3‐Hydroxyquinoline‐2,4‐diones 1 react with isocyanates to give novel 1,2,3,4‐tetrahydro‐2,4‐dioxoquinolin‐3‐yl (alkyl/aryl)carbamates 2 and/or 1,9b‐dihydro‐9b‐hydroxyoxazolo[5,4‐c]quinoline‐2,4(3aH,5H)‐diones 3 . Both of these compounds are converted, by boiling in cyclohexylbenzene solution in the presence of Ph₃P or 4‐(dimethylamino)pyridine, to give 3‐(acyloxy)‐1,3‐dihydro‐2H‐indol‐2‐ones 8 . All compounds were characterized by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, as well as by EI mass spectrometry.     

Synthesis and Characterization of New 3‐(3‐Hydroxyphenyl)‐4‐ alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione Compounds

A series of 3‐(3‐hydroxyphenyl)‐4‐alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione compounds with general formula C_nH_2n+1CNO(CO)₂C₆H₄(C₆H₄OH) in which n are even parity numbers from 2 to 18. The structure determinations on these compounds were performed by FT‐IR spectroscopy which indicated that the terminal alkyl chain attached to the oxazepine ring was fully extended. Conformational analysis in DMSO at ambient temperature was carried out for the first time via high resolution ¹H NMR and ¹³C NMR spectroscopy.     

Microwave‐assisted synthesis of some 1,2,4‐triazol‐5‐one derivatives

A series of 3‐alkyl(aryl)‐4‐(p‐hydroxy‐phenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 2 were obtained from the reaction of alkyl (aryl) ester ethoxycarbonyl hydrazones 1 with p‐hydroxy aniline. The reaction of 1 with 1,4‐diamino benzene (1:1) to afford 3‐alkyl(aryl)‐4‐(p‐aminophenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 3 . The reaction of 3 with benzaldehyde gave 3‐alkyl(aryl)‐4‐(4′‐benzilidenamino)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 4 . All of the above reactions occurred under microwave heating and conventional methods. Their structures were confirmed by ¹H NMR, ¹³C NMR, IR, and elemental analyses. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:38–42, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20381     

Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative‐scale synthesis of target 3,4‐dihydro‐1(2H)‐isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large‐scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high‐temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)‐isoquinolinone ( 9 ). Catalytic hydrogenation of 9 provided the desired 3,4‐dihydro‐5‐methyl‐1(2H)‐isoquinolinone ( 2 ) in 65 % overall yield. Similar reduction of a commercially available 5‐hydroxy‐1(2H)‐isoquinolinone precursor 10 followed by an O ‐alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4‐dihydro‐1(2H)‐isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

Synthesis,NMR spectra and X‐ray data of chloro and dichloro derivatives of 3‐hydroxy‐2‐phenylquinolin‐4(1H)‐ones and their cytostatic activity

As known, some derivatives of quinolin‐4(1H)‐one possess interesting biological properties. The biological and cytostactic activity of 2‐substituted 3‐hydroxyquinolin‐4(1H)‐ones has not been reported yet. In this paper the synthesis of a series of chloro and dichloro 2‐phenyl‐3‐hydroxyquinolin‐4(1H)‐ones and their characterization by NMR spectra and X‐ray data is described. Their cytostatic properties have been evaluated and the results are reported.     

Original recyclization of S‐phenacyl derivatives of 4‐acylamino‐2‐mercapto‐1,3‐oxazoles and their analogues

Readily accessible acylamino(chloro)acetophenones, if treated with sodium rhodanide and α‐halogenocarbonyl compounds, provide 4‐acylamino‐5‐aryl‐2‐mercapto‐1,3‐oxazole derivatives which undergo recyclization on heating in polyphosphoric acid to give substituted 1,3‐thiazol‐2(3H)‐ones or 1,3‐thiazolidin‐2,4‐diones containing 2‐alkyl(aryl)‐5‐aryl‐1,3‐oxazol‐4‐yl residues at the N³ atom. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:432–437, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20317     

Synthesis and Characterization of 11‐Amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one Derivatives

A series of 2‐amino‐7‐methoxy‐4‐aryl‐4H‐chromene‐3‐carbonitrile compounds 2 were obtained by condensation of 3‐methoxyphenol with β‐dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesuflonic acid (TsOH) as catalyst. The title compounds 11‐amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one 4 were synthesized by cyclization of the intermediate enamines 3 in THF with K₂CO₃ /Cu₂Cl₂ as catalyst. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal structure of compound 4i was determined by single‐crystal X‐ray diffraction analysis.     

The reaction of 3,4‐diamino‐1,2,5‐oxadiazoles with formaldehyde

The compounds 5,6‐dihydro‐4H‐imidazo[4,5‐c][1,2,5]oxadiazole ( 3a , R?H), 4,6,10,12‐tetramethyl‐5,6,11,12‐tetrahydro‐4H,10H‐bis(1,2,5)oxadiazolo[3,4‐d:3′,4′‐I][1,3,6,8]tetraazecine ( 4b , R?CH₃), N³,N³′‐methylenebis‐3,4‐diamino‐1,2,5‐oxadiazole ( 5a , R?H) and N³,N³′‐methylenebis(N,N′‐dimethyl‐3,4‐diamino‐1,2,5‐oxadiazolee) ( 5b , R?CH₃) were synthesized from the reaction of formaldehyde with 3,4‐diamino‐1,2,5‐oxadiazole and N,N′‐3,4‐dimethylamino‐1,2,5‐oxadiazole in an acetonitrile.     

Synthesis of 2‐Aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones by Deprotective Cyclization of N‐{3‐[(2E)‐3‐Arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides in Water

A new and convenient method for the preparation of 2‐aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones 4 has been developed. Thus, N‐{3‐[(2E)‐3‐arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides 3 are synthesized from commercially available pyridin‐2‐amine using an easily performed three‐step sequence and are subjected to cyclization with deprotection under acidic conditions in H₂O to give the desired products. Similarly, 2‐aryl‐2,3‐dihydro‐1,7‐naphthyridin‐4(1H)‐ones 8 and 2‐aryl‐2,3‐dihydro‐1,6‐naphthyridin‐4(1H)‐ones 12 can be prepared from pyridin‐3‐amine and pyridin‐4‐amine, respectively.     

One‐Pot Synthesis of 4‐Substituted 3,4‐Dihydro‐3‐methoxyisocoumarins via Carboxylation of α‐Substituted 2‐Lithio‐β‐methoxystyrenes with Carbon Dioxide

A new type of isocoumarins (=1H‐isochromen‐1‐ones=1H‐2‐benzopyran‐1‐ones), 4‐substituted 3,4‐dihydro‐3‐methoxyisocoumarins 2 , can be obtained by a one‐pot process from α‐substituted 2‐bromo‐β‐methoxystyrenes 1 . Thus, lithium 2‐(1‐aryl(or methyl)‐2‐methoxyethenyl)benzoates are conveniently generated via the Br/Li exchange between 1 and BuLi, followed by the action of CO₂ on the resulting α‐substituted 2‐lithio‐β‐methoxystyrenes. Upon treating with concentrated HCl at room temperature, these lithium benzoates undergo lactonization to provide the desired 3,4‐dihydroisocoumarins 2 in relatively good yields.     

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.     

Synthesis of some new 1‐acyl‐5‐aryl‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐4,5‐dihydro‐1H‐pyrazole

Some new compounds (E)‐3‐aryl‐1‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐prop‐2‐en‐1‐ones 5a–e were prepared by 1‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐ethanone and various aromatic aldehydes. Then one pot reaction was happened by compounds 5a–e with hydrazine hydrate in acetic acid or propionic acid, respectively, to give the title compounds 1acyl‐5‐aryl‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐4,5‐dihydro‐1H‐pyrazoles 6a–i . All structures were established by MS, IR, CHN, ¹H‐NMR and ¹³C‐NMR spectral data. J. Heterocyclic Chem., (2012).     

The psuedo‐michael reaction of 2‐aminoimidazolines 2. Part 1. Synthesis and structure assignment of isomeric 5(1H)‐Oxo and 7(1H)‐Oxo‐2,3‐dihydroimidazo[1,2‐a]pyrimidine‐6‐carboxylates

The pseudo‐Michael reaction of 1‐aryl‐2‐aminoimidazolines‐2 with diethyl ethoxymethylenemalonate (DEEM) was investigated. Extensive structural studies were performed to confirm the reaction course. For derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent. When the reaction temperature was held at ?10 °C only the formation of 1‐aryl‐7(1H)‐oxo‐2,3‐dihydroimi‐dazo[1,2‐a]pyrimidine‐6‐carboxylates ( 4 ) was observed in contrast to earlier suggestions. Under the room temperature conditions, the same reaction yielded mixtures, with varying ratio, of isomeric 1‐aryl‐7(1H)‐oxo‐ ( 4a‐4f ) and 1‐aryl‐5(1H)‐oxo‐2,3‐dihydroimidazo[1,2‐a]pyrimidine‐6‐carboxylates ( 5a‐5f ). The molecular structure of selected isomers, 4b and 5c , was confirmed by X‐ray crystallography. Frontal chro‐matography with delivery from the edge was applied for the separation of the isomeric esters. The isomer ratio of the reaction products depended on the character of the substituents on the phenyl ring. The 1‐aryl‐7(1H)‐oxo‐carboxylates ( 4a‐4f ) were preferably when the phenyl ring contained H, 4‐CH₃, 4‐OCH₃ and 3,4‐Cl₂ substituents. Chloro substitution at either position 3 or 4 in the phenyl ring favored the formation of isomers 5a‐5f . The isomer ratios were confirmed both by ¹H NMR and chromatography. The reaction of the respective hydrobromides of 1‐aryl‐2‐aminoimidazoline‐2 with DEEM, in the presence of triethylamine, gave selectively 5(1H)‐oxo‐esters ( 5a‐5f ).     

Reaction of 3‐aminoquinoline‐2,4‐diones with isocyanates. Synthesis of novel 3‐(3′‐alkyl/arylureido)quinoline‐2,4‐diones and their cyclic carbinolamide isomers

3‐Alkyl/aryl‐3‐amino‐1H,3H‐quinoline‐2,4‐diones react with alkyl/aryl isocyanates to give novel 3‐alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones or 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones. In some cases, a mixture of both products was obtained and separated by fractional crystallization. All compounds were characterized by their ¹H, ¹³C, ir and ms data and some of them also by ¹⁵N nmr data.