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.     

One‐pot Combinatorial Synthesis of Benzo[4,5]imidazo‐[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one Derivatives

A series of novel fused tetracyclic benzo[4,5]imidazo[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one derivatives were synthesized via the reaction of aryl aldehyde, 2H‐thiopyran‐3,5(4H,6H)‐dione, and 1H‐benzo[d]imidazol‐2‐amine in glacial acetic acid. This protocol features mild reaction conditions, high yields and short reaction time.     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

Synthesis of New Furo[3,4‐b]quinolin‐1(3H)‐one Scaffolds Derived from γ‐Lactone‐Fused Quinolin‐4(1H)‐ones

In the context of our aim of discovering new antitumor drugs among synthetic γ‐lactone‐ and γ‐lactam‐fused 1‐methylquinolin‐4(1H)‐ones, we developed a rapid access to 5‐methyl‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinoline‐8,9(5H,6H)‐dione ( 9 ) exploiting the γ‐lactone‐fused chloroquinoline 10 previously synthesized in our laboratory (Scheme 1). We also elaborated efficient synthetic methods allowing for a rapid access to two nonclassical bioisosteres of 9 , i.e., a deoxy and a carba analogue. The deoxy analogue 11 was prepared in two steps from the γ‐lactone‐fused quinoline 13 which was also the synthetic precursor of 10 (Scheme 1). The carba analogue 6,9‐dihydro‐5‐methyl‐9‐methylene‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinolin‐8(5H)‐one ( 12 ) was easily prepared by HCl elimination from the 9‐(chloromethyl)dioxolofuroquinoline 15 , which was obtained via a three‐component one‐pot reaction from N‐methyl‐3,4‐(methylenedioxy)aniline (=N‐methyl‐1,3‐benzodioxol‐5‐amine; 16 ), commercially available chloroacetaldehyde, and tetronic acid ( 17 ) (Scheme 2).     

An Efficient One‐Pot Synthesis of Substituted 1H‐Naphtho[2,1‐b]pyrans and 4H‐1‐Benzopyrans (=Chromenes) under Solvent‐Free Microwave‐Irradiation Conditions

A facile heterogeneous synthesis of 3‐amino‐1‐aryl‐1H‐naphtho[2,1‐b]pyran and 2‐amino‐4‐aryl‐4H‐1‐benzopyran derivatives 3 and 5 , respectively, was carried out efficiently by one‐pot three‐component coupling of an aromatic aldehyde 1 , an active methylene compound 2 , and naphthalen‐2‐ol or a phenol 4 in the presence of 5‐Å molecular sieves under solvent‐free microwave‐irradiation conditions (Scheme 1 and 2, Tables 1 and 2). The catalyst was recovered and recycled (Table 3).     

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.     

A Facile Synthesis of New Pyrazolo[3,4‐d]pyrimidine Derivatives via a One‐Pot Four‐Component Reaction with Sodium Acetate Supported on Basic Alumina as Promoter

An efficient one‐pot procedure for the synthesis of 3‐amino‐6‐aryl‐2‐phenylpyrazolo[3,4‐d]pyrimidine derivatives, through the reaction of aldehydes, malononitrile, benzamidine hydrochloride, and hydrazine hydrate in the presence of basic alumina‐supported sodium acetate (AcONa/Al₂O₃) under reflux conditions, is reported. This protocol has some advantages, including the use of a simple and one‐pot synthetic approach to attain pyrazolo[3,4‐d]pyrimidine directly from four readily available starting materials, simple workup, high overall yields of the products, and the simultaneous conversion of a NO₂ to an amino group, offering an opportunity to synthesize more complex structures.     

Two‐ and Three‐Component Reactions Leading to New Enamines Derived from 2,3‐Dicyanobut‐2‐enoates

The three‐component reactions of 1‐azabicyclo[1.1.0]butanes 1 , dicyanofumarates (E)‐ 5 , and MeOH or morpholine yielded azetidine enamines 8 and 9 with the cis‐orientation of the ester groups at the C?C bond ((E)‐configuration; Schemes 3 and 4). The structures of 8a and 9d were confirmed by X‐ray crystallography. The formation of the products is explained via the nucleophilic addition of 1 onto (E)‐ 5 , leading to a zwitterion of type 7 (Scheme 2), which is subsequently trapped by MeOH or morpholine ( 10a ), followed by elimination of HCN. Similarly, two‐component reactions between secondary amines 10a – 10c and (E)‐ 5 gave products 12 with an (E)‐enamine structure and (Z)‐oriented ester groups. On the other hand, two‐component reactions involving primary amines 10d – 10f or NH₃ led to the formation of the corresponding (Z)‐enamines, in which the (E)‐orientation of ester groups was established.     

Synthesis of 4‐Aryl‐3‐Methyl‐1‐Phenyl‐1H‐Benzo[h]Pyrazolo[3,4‐b]Quinoline‐5,10‐diones Using Diammonium Hydrogen Phosphate as an Efficient and Versatile Catalyst in Water

A simple and efficient synthesis of 4‐aryl‐3‐methyl‐1‐phenyl‐1H‐benzo[h]pyrazolo[3,4‐b]quinoline‐5,10‐diones has been accomplished by the one‐pot condensation reaction of 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐amine, aldehydes and 2‐hydroxynaphthalene‐1,4‐dione in water in the presence of diammonium hydrogen phosphate.     

The First Ring‐Enlargement of a 1‐Azabicyclo[1.1.0]butane to a 1‐Azabicyclo[2.1.1]hexane

The reactions of 3‐phenyl‐1‐azabicyclo[1.1.0]butane ( 4 ) with dimethyl dicyanofumarate ((E)‐ 8 ) and dimethyl dicyanomaleate ((Z)‐ 8 ) lead to the same mixture of cis‐ and trans‐4‐phenyl‐1‐azabicyclo[2.1.1]hexane 2,3‐dicarboxylates (cis‐ 11 and trans‐ 11 , resp.; Scheme 3). This result of a formal cycloaddition to the central C? N bond of 4 is interpreted by a stepwise reaction mechanism via a relatively stable zwitterionic intermediate 10 , which could be intercepted by morpholine to give a 1 : 1 : 1 adduct 12 , which undergoes a spontaneous elimination of HCN to yield the fumarate 13 (Scheme 4).     

Reactions of Hydrazonoyl Halides 571: Reactions of 1‐Bromo‐2‐(5‐Chlorobenzofuranyl)Ethanedione‐1‐Phenylhydrazone

Pyrrolo[3,4‐c]pyrazole‐4,6‐diones, pyrazoles, pyrazolo[3,4‐d]pyridazines, and pyrazolo[3,4‐d]pyrimidines were prepared via 1‐bromo‐2‐(5‐chlorobenzofuran‐2‐yl)ethanedione‐1‐phenylhydrazone with N‐arylmalemides and active methylene. All newly synthesized compounds were confirmed by elemental analysis and spectral data.     

Synthesis of 9,9‐Disubstituted 9H‐Pyrrolo[1,2‐a]indoles by Hydriodic Acid‐Catalyzed Cyclization of 1‐[2‐(1‐Aryl(or methyl)ethenyl)phenyl]‐1H‐pyrroles

A novel method is reported for the synthesis of 9,9‐disubstituted 9H‐pyrrolo[1,2‐a]indoles. Cyclization of 1‐[2‐(1‐aryl(or methyl)ethenyl)phenyl]‐1H‐pyrroles, which can be easily prepared from 2‐(1‐aryl(or methyl)ethenyl)anilines, proceeds smoothly, in general, at 0° in the presence of a catalytic (or an equimolar) amount of HI in MeCN to provide the desired products.     

New Methods for the Synthesis of 3‐Amino‐6,7‐Dihydro‐5H‐Cyclopenta[c]Pyridine‐4‐Carbonitriles and Cyclopenta[d]Pyrazolo[3,4‐b]Pyridines via a Smiles‐type Rearrangement

By reaction with sodium ethoxide and as a function of their structures, 2‐[(1‐alkyl(aryl)‐4‐cyano‐6,7‐dihydro‐5H‐cyclopenta[c ]pyridin‐3‐yl)oxy]acetamides 11 gave 1‐amino‐5‐alkyl(aryl)‐7,8‐dihydro‐6H‐cyclopenta[d ]furo[2,3‐b ]pyridine‐2‐carboxamides 10 and/or 1‐alkyl(aryl)‐3‐amino‐6,7‐dihydro‐5H‐cyclopenta[c ]pyridine‐4‐carbonitriles 12 .     

One‐Pot Synthesis of 1,4‐Oxathiino[2,3‐b]quinoxalines or ‐pyrazines from 2,3‐Dichloroquinoxaline or ‐pyrazine and 1‐Aryl‐2‐bromoalkan‐1‐ones

An efficient one‐pot synthesis of novel heterocyclic derivatives, 2‐aryl‐1,4‐oxathiino[2,3‐b]quinoxalines or ‐pyrazines 5 , via the reaction of 2,3‐dichloroquinoxaline or ‐pyrazine with Na₂S?9 H₂O, and subsequent treatment of the resulting 2‐chloro‐3‐sodiosulfanylquinoxaline or ‐pyrazine 2 with 1‐aryl‐2‐bromo‐1‐alkanones and then NaH under mild conditions is described.     

One‐Pot Diastereoselective Synthesis of Densely Functionalized 2H‐Indeno[2,1‐b]furans. Single‐Crystal X‐Ray Structure of Dimethyl 8,8a‐Dihydro‐8‐oxo‐8a‐(2,2,2‐trichloroethoxy)‐2H‐indeno[2,1‐b]furan‐2,3‐di­carboxylate

Highly reactive 1 : 1 intermediates were produced in the reaction of Ph₃P and dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates). Protonation of these intermediates by alcohols (2,2,2‐trichloroethanol, propargyl alcohol (=prop‐2‐yn‐1‐ol), MeOH, benzyl alcohol, and allyl alcohol (=prop‐2‐en‐1‐ol) led to vinyltriphenylphosphonium salts 4 , which underwent a Michael addition reaction with the conjugate base to produce the corresponding stabilized phosphonium ylides 5 (Scheme). Wittig reaction of the stabilized phosphonium ylides with ninhydrin ( 6 ) led to the corresponding densely functionalized 2H‐indeno[2,1‐b]furans 10 in fairly good yields (Table 1). The structures of the final products were confirmed by IR, ¹H‐ and ¹³C‐NMR spectroscopy, and mass spectrometry. The configuration of dimethyl 8,8a‐dihydro‐8‐oxo‐8a‐(2,2,2‐trichloroethoxy)‐2H‐indeno[2,1‐b]furan‐2,3‐dicarboxylate ( 10a ) was established by a single‐crystal X‐ray structure determination, establishing that the one‐pot multicomponent condensation reaction was completely diastereoselective.     

A New Four‐Component Reaction for the Synthesis of Spiro[4H‐indeno[1,2‐b]pyridine‐4,3′‐[3H]indoles]

A new four‐component synthesis of spiro[4H‐indeno[1,2‐b]pyridine‐4,3′‐[3H]indoles] and spiro[acenaphthylene‐1(2H),4′‐[4H‐indeno[1,2‐b]pyridines] by the reaction of indane‐1,3‐dione, 1,3‐dicarbonyl compounds, isatins (=1H‐indole‐2,3‐diones) or acenaphthylene‐1,2‐dione, and AcONH₄ in refluxing toluene in the presence of a catalytic amount of pyridine is reported.     

Synthesis of Novel Disubstituted Pyrazolo[1,5‐a]pyrimidines,Imidazo[1,2‐a]pyrimidines,and Pyrimido[1,2‐a]benzimidazoles Containing Thioether and Aryl Moieties

A series of novel 6‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]‐7‐phenylpyrazolo[1,5‐a]pyrimidines, 5‐phenyl‐6‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]imidazo[1,2‐a]pyrimidines, and 2‐phenyl‐3‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]pyrimido[1,2‐a]benzimidazoles have been synthesized in four steps starting with 2‐hydroxyacetophenone. The intermediate 3‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]‐4H‐1‐benzopyran‐4‐ones reacted with pyrazol‐3‐amines, 5‐methylpyrazol‐3‐amine, and 1H‐imidazol‐2‐amine, 1H‐benzimidazol‐2‐amine via a cyclocondensation to give the title compounds in the presence of MeONa as base, respectively. The approach affords the target compounds in acceptable‐to‐good yields. The new compounds were characterized by their IR, NMR, and HR mass spectra.     

Diversity‐Oriented Synthesis of Novel 2′‐Aminospiro[11H‐indeno[1,2‐b]quinoxaline‐11,4′‐[4H]pyran] Derivatives via a One‐Pot Four‐Component Reaction

A sequential one‐pot four‐component reaction for the efficient synthesis of novel 2′‐aminospiro[11H‐indeno[1,2‐b]quinoxaline‐11,4′‐[4H]pyran] derivatives 5 in the presence of AcONH₄ as a neutral, inexpensive, and dually activating catalyst is described (Scheme 1). The syntheses are achieved by reacting ninhydrin ( 1 ) with benzene‐1,2‐diamines 2 to give indenoquinoxalines, which are trapped in situ by malono derivatives 2 and various α‐methylenecarbonyl compounds 4 through cyclization, providing the multifunctionalized 2′‐aminospiro[11H‐indeno[1,2‐b]quinoxaline‐11,4′‐[4H]pyran] analogs 5 . This chemistry provides an efficient and promising synthetic way of proceeding for the diversity‐oriented construction of the spiro[indenoquinoxalino‐pyran] skeleton.     

Synthesis of 3‐Alkoxybenzo[c]thiophen‐1(3H)‐ones by Hydrolysis of N‐Substituted 3‐Alkoxybenzo[c]thiophen‐1(3H)‐imines Derived from 1‐Bromo‐2‐(dialkoxymethyl)benzenes and Isothiocyanates

A convenient procedure for the preparation of a new type of thiophthalides, 3‐alkoxybenzo[c]thiophen‐1(3H)‐ones 4 and 9 has been developed. Thus, 1‐(dialkoxymethyl)‐2‐lithiobenzenes, generated by Br/Li exchange between 2‐bromo‐1‐(dialkoxymethyl)benzenes 1 and 6 , and BuLi, react with isothiocyanates to afford N‐substituted 2‐(dialkoxymethyl)benzothioamides 2 and 7 , which, on treatment with a catalytic amount of TsOH?H₂O, give N‐substituted 3‐alkoxybenzo[c]thiophen‐1(3H)‐imines 3 and 8 . The latter are hydrolyzed under acidic conditions to the desired products 4 and 9 , respectively.     

Synthesis of 2,3‐Diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ol Derivatives by the Reaction of Aryl(3‐isocyanopyridin‐4‐yl)methanones with Aryl Grignard Reagents

The reaction of aryl(3‐isocyanopyridin‐4‐yl)methanones 1 , easily prepared from commercially available pyridin‐3‐amine, with aryl Grignard reagents gave, after aqueous workup, 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ols 2 . These rather unstable alcohols were O‐acylated with Ac₂O in pyridine in the presence of a catalytic amount of 4‐(dimethylamino)pyridine (DMAP) to afford the corresponding 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐yl acetates 3 in relatively good yields.