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.     

Reaction of 3‐Hydroxyquinoline‐2,4‐diones with Inorganic Thiocyanates in the Presence of Ammonium or Alkylammonium Ions: the Unexpected Replacement of a Hydroxy Group by an Amino Group

3‐Hydroxyquinoline‐2,4‐diones react with KSCN in the presence of the NH$\rm{{_{4}^{+}}}$ ions to generate 2,3‐dihydro‐3‐thioxoimidazo[1,5‐c]quinazolin‐5(6H)‐ones, 2,3‐dihydro‐2‐thioxo‐1H‐imidazo[4,5‐c]quinolin‐4(5H)‐ones, and products of molecular rearrangement of the 3‐aminoquinolinedione intermediates. Starting compounds with a benzyl (Bn) group at C(3) afford 3‐aminoquinolinediones, even when only AcONH₄ is used. The results of the reaction between 3‐hydroxyquinoline‐2,4‐diones and KSCN in the presence of BuNH₂ show that replacing a OH group with a secondary NH₂ group is also possible.     

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.     

Efficient Synthesis of (3E)‐3‐[Amino(aryl)methylidene]chromane‐2,4‐diones (=(3E)‐3‐[Amino(aryl)methylene]‐2H‐1‐benzopyran‐2,4(3H)‐diones) via a Three‐Component Reaction

The Michael‐type addition of a 4‐hydroxycoumarin (=4‐hydroxy‐2H‐1‐benzopyran‐2‐one) 1 to a β‐nitrostyrene (=(2‐nitroethenyl)benzene) 2 in the presence of AcONH₄ leads to substituted (3E)‐3‐[amino(aryl)methylidene]chroman‐2,4‐diones (=(3E)‐3‐[amino(aryl)methylene]‐2H‐1‐benzopyran‐2,4(3H)‐diones) 4 (Table 1). High yields, short reaction time, and easy workup are advantages of this novel one‐pot three‐component reaction.     

Pinacol Rearrangement of 3,4‐Dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones: An Alternative Pathway to Viridicatin Alkaloids and Their Analogs

3‐Alkyl/aryl‐3‐hydroxyquinoline‐2,4‐diones were reduced with NaBH₄ to give cis‐3‐alkyl/aryl‐3,4‐dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones. These compounds were subjected to pinacol rearrangement by treatment with concentrated H₂SO₄, resulting in 4‐alkyl/aryl‐3‐hydroxyquinolin‐2(1H)‐ones. When a benzyl (Bn) group was present in position 3 of the starting compound, its elimination occurred during the rearrangement, and the corresponding 3‐hydroxyquinolin‐2(1H)‐one was formed. The reaction mechanisms are discussed for all transformations. All compounds were characterized by IR, ¹H‐ and ¹³C‐NMR spectroscopy, as well as mass spectrometry.     

Synthesis of [3,3′(4H,4′H)‐Bi‐2H‐1,3‐oxazine]‐4,4′‐diones and Their Hydrolysis

The [3,3′(4H,4′H)‐bi‐2H‐1,3‐oxazine]‐4,4′‐diones 3a – 3i were obtained by [2+4] cycloaddition reactions of furan‐2,3‐diones 1a – 1c with aromatic aldazines 2a – 2d (Scheme 1). So, new derivatives of bi‐2H‐1,3‐oxazines and their hydrolysis products, 3,5‐diaryl‐1H‐pyrazoles 4a – 4c (Scheme 3), which are potential biologically active compounds, were synthesized for the first time.     

One‐Pot,Three‐Component Synthesis of Novel Spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones in an Ionic Liquid as a Reusable Reaction Media

A facile one‐pot, three‐component protocol for the synthesis of novel spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones by condensing 1H‐indole‐2,3‐diones, 4H‐1,2,4‐triazol‐4‐amine and 2‐sulfanylpropanoic acid in [bmim]PF₆ (1‐butyl‐3‐methyl‐1H‐imidazolium hexafluorophosphate) as a recyclable ionic‐liquid solvent gave good to excellent yields in the absence of any catalyst (Scheme 1 and Table 2). The advantages of this protocol over conventional methods are the mild reaction conditions, the high product yields, a shorter reaction time, as well as the eco‐friendly conditions.     

Modified Riemschneider Reaction of 3‐Thiocyanatoquinolinediones

The Riemschneider reaction of 3‐thiocyanatoquinoline‐2,4(1H,3H)‐diones with conc. H₂SO₄ was investigated. Using different reaction conditions, 13 types of reaction products were isolated. Compounds bearing a Me, Et, or Bu group at C(3) afforded mainly [1,3]thiazolo[5,4‐c]quinoline‐2,4‐diones and 1,9b‐dihydro‐9b‐hydroxythiazolo[5,4‐c]quinoline‐2,4‐diones. In the case of the 3‐Bu derivatives of the starting compounds, C‐debutylation was also observed. If a Bn group is present at C(3), rapid C‐debenzylation of the starting thiocyanates occurred, yielding [1,3]oxathiolo[4,5‐c]quinoline‐2,4‐diones, and mixtures of mono‐, di‐, and trisulfides derived from 4‐hydroxy‐3‐sulfanylquinoline‐2‐ones. The reaction mechanism of all of the transformations is discussed. All new compounds were characterized by IR, ¹H‐ and ¹³C‐NMR, and EI and ESI mass spectra, and in some cases, ¹⁵N‐NMR spectra were also used to characterize new compounds.     

Investigation of the Reactions of Indole‐2,3‐diones with Biuret: A Novel Approach for the Synthesis of Spiro[indole‐triazines]

Reactions of indole‐2,3‐diones with biuret afforded 1,3‐dihydro‐3‐ureidoformimido‐2H‐indol‐2‐ones and spiro[3H‐indole‐3,2′(1′H )‐(1,3,5)triazine]‐2,4′,6′(1H ,3′H ,5′H )‐triones indicated these to be solvent dependent. The chemical structures of the products were elucidated by their comprehensive spectroscopic (IR, ¹H‐NMR, ¹³C‐NMR, ¹⁹F‐NMR, and Mass) as well as analytical analysis.     

Synthesis of Bis‐Heterocyclic 1H‐Imidazole 3‐Oxides from 3‐Oxido‐1H‐imidazole‐4‐carbohydrazides

The reaction of 1H‐imidazole‐4‐carbohydrazides 1 , which are conveniently accessible by treatment of the corresponding esters with NH₂NH₂?H₂O, with isothiocyanates in refluxing EtOH led to thiosemicarbazides (=hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling aqueous NaOH yielded 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones 5 , the reaction in concentrated H₂SO₄ at room temperature gave 1,3,4‐thiadiazol‐2‐amines 6 . Similarly, the reaction of 1 with butyl isocyanate led to semicarbazides 7 , which, under basic conditions, undergo cyclization to give 2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones 8 (Scheme 3). Treatment of 1 with Ac₂O yielded the diacylhydrazine derivatives 9 exclusively, and the alternative isomerization of 1 to imidazol‐2‐ones was not observed (Scheme 4). It is important to note that, in all these transformations, the imidazole N‐oxide residue is retained. Furthermore, it was shown that imidazole N‐oxides bearing a 1,2,4‐triazole‐3‐thione or 1,3,4‐thiadiazol‐2‐amine moiety undergo the S‐transfer reaction to give bis‐heterocyclic 1H‐imidazole‐2‐thiones 11 by treatment with 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione (Scheme 5).     

Synthesis of 3‐thiocyanato‐1H,3H‐quinoline‐2,4‐diones

4‐Hydroxy‐1H‐quinolin‐2‐ones ( 1 ) react with thiocyanogen in acetic acid to the corresponding 3‐thiocyanato‐1H,3H‐quinoline‐2,4‐diones ( 2 ) in good yields. In some cases, 3‐bromo‐1H,3H‐quinoline‐2,4‐diones ( 4 ) were isolated as minor reaction products. Compounds 2 are very reactive towards nucleophiles and easily hydrolyze to the corresponding 4‐hydroxy‐1H‐quinoline‐2‐ones ( 1 ).     

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.     

A Simple Multistep Conversion of 1,2‐Dihydro‐1,1‐dimethoxynaphthalen‐2‐ones to (3,4‐Dihydro‐3,4‐dioxonaphthalen‐2‐yl)acetates

On irradiation (λ=350 nm) in the presence of 1,1‐dimethoxyethene, naphthalene‐1,2‐dionemonoacetals 1 regioselectively afford 1,1,4,4‐tetramethoxycyclobuta[a]naphthalen‐3‐ones 3 . Sequential deprotection of these bis‐acetals first lead to 1,1‐dimethoxycyclobuta[a]naphthalene‐3,4‐diones 4 and then to cyclobuta[a]naphthalene‐1,3,4‐triones 6 , which, in turn, are converted into (3,4‐dihydro‐3,4‐dioxonaphthalen‐2‐yl)acetates 7 by treatment with SiO₂/MeOH/air.     

One‐Pot Synthesis of 3‐Alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones by the Reactions of 2‐(Azidomethyl)benzoates with NaH

A new and facile method for the general preparation of 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones has been developed. Thus, the reaction of 2‐(azidomethyl)benzoates with NaH affords, after workup with H₂O, 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones 2 . 2‐Substituted 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones 4 can be obtained by adding alkyl halides prior to workup with H₂O.     

Microwave‐Assisted Synthesis of Novel 2,4‐Dihydro‐5‐[4‐(trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones and Potentiometric Determination of Their pKa in Nonaqueous Solvents

The novel 4‐amino‐ or 4‐aryl‐substituted 2,4‐dihydro‐5‐[(4‐trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones 3a – 3g were synthesized by reaction of N‐(ethoxycarbonyl)‐4‐(trifluoromethyl)benzenehydrazonic acid ethyl ester ( 2 ) and primary amines or hydrazine by microwave irradiation. Compounds 3a – 3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu₄NOH) in four nonaqueous solvents, i.e., ⁱPrOH, ^tBuOH, MeCN, and N,N‐dimethylformamide (DMF). Also half‐neutralization potential values and the corresponding pK_a values were determined in all cases.     

Palladium‐Catalyzed Cyclization Reaction of o‐Haloanilines,CO2 and Isocyanides: Access to Quinazoline‐2,4(1H,3H)‐diones

Quinazoline‐2,4(1H,3H)‐diones are core structural subunits frequently found in many biologically important compounds. The reaction of 2‐​aminobenzonitrile and CO₂, which was frequently studied, only provided N3‐unsubstituted quinazoline‐2,4(1H,3H)‐dione compounds. Herein we report palladium‐catalyzed cyclization reactions of o‐haloanilines, CO₂ and isocyanides to prepare N3‐substituted quinazoline‐2,4(1H,3H)‐diones. Electron‐rich o‐bromoanilines participated in the cyclization reaction using Cs₂CO₃ at high temperature, and electron‐deficient o‐bromoaniline or o‐iodoaniline substrates conducted the reaction using CsF as base to deliver corresponding quinazoline‐2,4(1H,3H)‐dione products in good yields.     

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.     

Synthesis of Dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones via Azomethine Ylide 1,3‐Dipolar Cycloaddition

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 2‐arylmethylidene‐2,3‐dihydro‐1H‐pyrrolizin‐1‐ones afforded novel 1′‐methyl‐4′‐(aryl)‐1″H‐dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones in good yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy, mass spectrum, and elemental analysis.     

Studies on 4‐Thiazolidinones: Scope of the Reactions of 3‐Aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones with Cyanide and Cyanate Ions

Treatment of 3‐aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones 1 with CN^? and NCO^? effected the ring cleavage providing [(cyanocarbonothioyl)amino]benzenes 4 and arylisothiocyanates 5 , respectively. Similar treatment of 5‐(2‐aryl‐2‐oxoethyl) derivatives 2 afforded 2,4‐bis(2‐aryl‐2‐oxoethylidene)cyclobutane‐1,3‐diones 6 along with each of the preceding products. Treatment of the respective (E,Z)‐5‐(2‐aryl‐2‐oxoethylidene) analogues 3b and 3c with CN^? gave 4b and 4c and 2‐(arylcarbonyl)‐2‐methoxy‐4‐oxopentanedinitriles 7b and 7c , in addition to 3,6‐bis[2‐(4‐chlorophenyl)‐1‐methoxy‐2‐oxoethylidene]‐1,4‐dithiane‐2,5‐dione 8c , which has been generated from 3c . Reactions of 3c or 3d with NCO^? provided 5c or 5d , together with 8c or 8d as pure isomers. In the formation of the MeO products 7 and 8 , the solvent (MeOH) has participated. Structures of these products are based on microanalytical and spectroscopic data. Rationalizations for the above transformations are given.     

Cyclization vs. Elimination Reactions of 5‐Aryl‐5‐hydroxy 1,3‐Diones: One‐Pot Synthesis of 2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones

2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones were prepared in one step by cyclocondensation of 1,3‐diketone dianions with aldehydes. The use of HCl (10%) for the aqueous workup proved to be very important to avoid elimination reactions of the 5‐aryl‐5‐hydroxy 1,3‐diones formed as intermediates. The TiCl₄‐mediated cyclization of a 2‐aryl‐2,3‐dihydro‐4H‐pyran‐4‐one with 1,3‐silyloxybuta‐1,3‐diene resulted in cleavage of the pyranone moiety and formation of a highly functionalized benzene derivative.