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.     

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.     

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.     

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.     

Molecular rearrangement of 1‐substituted 3‐aminoquinoline‐2,4‐diones in their reaction with urea and nitrourea synthesis and transformations of reaction intermediates

1‐Substituted 3‐alkyl/aryl‐3‐amino‐1H,3H‐quinoline‐2,4‐diones ( 6 ) react with nitrourea to give 3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 10 ), 9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 11 ), and 3,3a‐dihydro‐5H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 12 ). Compounds 11 were dehydrated to 12 by the action of phosphorus pentoxide. All three types of compounds rearrange in boiling acetic acid to give three different types of products of molecular rearrangement. A proposed reaction mechanism is discussed.     

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.     

Synthesis of Hexahydrospiro[pyrazolo[3,4‐b]quinoline‐4,1′‐pyrrolo[3,2,1‐ij]quinoline‐2′,5(1H,4′H)‐diones] from 5,6‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione Using Fe3O4@Cu(OH)x as a Nanocatalyst

The tricyclic isatin, 5,6‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione, undergoes three‐component, one‐pot reactions with 1‐aryl‐3‐methylpyrazole‐5‐amines and cyclohexane‐1,3‐diones producing hexacyclic spiro products, hexahydrospiro[pyrazolo[3,4‐b]quinoline‐4,1‐pyrrolo[3,2,1‐ij]quinoline‐2′,5(1H,4′H)‐diones]. Comparable spiro condensation products are also obtained using 4‐hydroxy‐2H‐1‐benzopyran‐2‐one in place of cyclohexane‐1,3‐diones.     

Ring closure reactions of 3‐arylhydrazonoalkyl‐quinolin‐2‐ones to 1‐aryl‐pyrazolo[4,3‐c]quinolin‐2‐ones

4‐Hydroxy‐3‐arylhydrazonoalkyl‐2‐quinolones 6 or reactive derivatives such as 3‐arylhydrazonoalkyl‐4‐tosyloxy‐2‐quinolones 7 or 4‐chloro‐3‐arylhydrazonoalkyl‐2‐quinolones 14 , which are obtained via 3‐acyl‐4‐hydroxyquinolones 4, 10 or 3‐phenylarrmomethylene‐quinoline‐2,4‐diones 12 , cyclize in excellent yields to 1‐aryl‐pyrazolo[4,3‐c]quinolin‐4‐ones (11). The cyclization conditions were investigated by differential scanning calorimetry (DSC).     

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.     

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.     

Synthesis and thermolysis of the 2,3‐dihydro‐1H‐pyrole‐2,3‐diones,pseudopericyclic reactions of formyl(N‐phenylimidoyl)ketene: Experimental data and PM3 calculations

The reactions of the 2,3‐dihydro‐1H‐furan‐2,3‐dione 1 with Schiff bases 2a‐f at 60–70°C furnish the corresponding 2,3‐dihydro‐1H‐pyrole‐2,3‐diones 3a‐f . The heating of 3a‐d afforded the corresponding 4‐methoxybenzoyl(N‐arylimidoyl)k:etenes 4a‐d as intermediates which undergo a very facile cyclization to quinoline‐4‐ones 5a‐d . According to our PM3 calculations, fragmentation of 4‐formyl‐2,3‐dihydro‐1H‐pyrole‐2,3‐dione and 1,4‐cyclization of formyl(N‐phenylimidoyl)k:etene IN1 to azetin‐2‐one IN2 and oxe‐tone IN3 are pseudopericyclic reactions with two orbital connections, proceed via planar transition structures. Due to to the possibility of syn and anti conformations of the imine phenyl, there are eight E/Z‐iso‐mers of IN1 . In addition, we have also calculated reaction mechanism of formation of quinoline‐4‐ones by the PM3 method.     

Synthesis of 4‐Hydroxy‐3‐(2‐arylimidazo[1,2‐a]pyridin‐3‐yl)quinolin‐2(1H)‐ones in the Presence of DABCO as an Efficient Organocatalyst

The one‐pot, three‐component, synthesis of a new series of 4‐hydroxy‐3‐(2‐arylimidazo[1,2‐a]pyridin‐3‐yl)quinolin‐2(1H)‐ones in the presence of DABCO as a catalyst has been achieved using aryl glyoxal monohydrates, quinoline‐2,4(1H,3H)‐dione, and 2‐aminopyridine in H₂O/EtOH under reflux conditions. The cheapness of organocatalyst, simple workup, operational simplicity, regioselectivity, and high yields are some advantages of this protocol.     

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.     

Synthesis,Structure of Zwitterionic 2‐Amino‐N′‐(imidazolidin‐2‐ylidene)benzohydrazides,and Their Transformation into 3‐(Imidazolidin‐2‐ylideneamino)quinazolin‐4(1H)‐one Derivatives

The reaction of 2‐chloro‐4,5‐dihydroimidazole ( 5 ) with 2‐aminobenzohydrazides 6a–e led to the formation of 2‐amino‐N′‐(imidazolidin‐2‐ylidene)benzohydrazides as zwitterions 7a–e , which on treatment with carbon disulfide in the presence of triethylamine afforded 3‐(imidazolidin‐2‐ylideneamino)‐2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐ones 8a–e . Compounds 8a–d were further converted into the corresponding 3‐(imidazolidin‐2‐ylideneamino)quinazoline‐2,4(1H,3H)‐diones 9a–d using hydrogen peroxide–sodium hydroxide solution. The structures of the compounds prepared were established by elemental analyses, IR and NMR spectra as well as X‐ray crystallographic analyses of 7e and 9a .     

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.     

The Synthesis of 6‐Substituted Pyrido[2,3‐d]pyrimidine‐2,4(1H,3H)‐diones Using Aminomethylene Malondialdehydes and 6‐Aminouracils

Variously substituted aminomethylene malondialdehydes (2‐(3,3‐dimethylindolin‐2‐ylidene)malondialdehydes) were reacted with some 6‐aminouracils, to give 6‐(3,3‐dimethyl‐3H‐indol‐2‐yl)pyrido[2,3‐d]pyrimidine‐2,4‐(1H,3H)‐diones in good yields.     

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.     

Azopyrazolobenzylidene derivatives of 4‐amino‐1,2,4‐triazol‐3‐ones. Synthesis of 4‐{[4‐(3,5‐dimethyl‐1H‐pyrazol‐4‐yl)diazenyl]‐benzylidene}amino‐2‐aryl‐5‐methyl‐3H‐[1,2,4]‐triazol‐3‐ones

The Schiff bases 3a‐h obtained from 4‐amino‐1,2,4‐triazol‐3‐ones 1a‐h when subjected to Japp‐Klingemann reaction yielded the corresponding 3‐{2‐[(2‐aryl‐5‐methyl‐3H‐[1,2,4]‐triazol‐3‐one‐4‐yl)]‐iminophenyl}‐pentane‐2,4‐diones 4a‐h . These diones on cyclisation with N₂H₄ yielded the title compounds 5a‐h . The energetics of the Keto‐enol tautomers of the diones was calculated by semiemperical calculations using AM1 and PM3 methods. All these compounds were screened for their antimicrobial activity against few microbes and most of them exhibited fungal inhibition more than the reference drugs used.     

Synthesis of novel 5H‐Pyrimido[5,4‐b]mdole‐(1H,3H)2,4‐diones as potential ligands for the cloned α1‐adrenoceptor subtypes

A new series of 3‐[ω‐[4‐(4‐substituted phenyl)piperazin‐1‐yl]alkyl]‐5H‐pyrimido[5,4‐b]indole‐(1H,3H)‐2,4‐diones ( 3–10 and 12–13 ) were synthesized from the N‐(2‐chloroethyl)‐N'‐[3‐(2‐ethoxycarbonyl)indolyl] urea ( 1 ) or the N‐(3‐chloropropyl)‐N'‐[3‐(2‐ethoxycarbonyl)indolyl] urea ( 2 ) and a number of 1‐(4‐substi‐tuted‐phenyl)piperazines. 3‐[2‐[4‐(4‐Aminophenyl)piperazin‐1‐yl]ethyl]‐5H‐pyrimido[5,4‐b]indole‐(1H,3H)2,4‐dione ( 14 ) was obtained by reduction of the parent nitro compound 8 . The obtained 5H‐pyrimido[5,4‐b]indole‐(1H,3H)2,4‐dione derivatives were tested towards cloned α_1A, α_1B and α_1D adrenergic receptors subtypes in binding assays. Some compounds showed good affinity and selectivity for the α_1D‐adrenoceptor subtype.