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 Pseudo‐Peptides Containing a Quinazolinone Skeleton via Ugi Four‐Component Reaction

A simple and efficient synthesis of quinazolinone pseudo‐peptide derivatives based on a new 3‐amino‐1,2,3,4‐tetrahydro‐4‐oxoquinazoline‐2‐carboxylic acid via Ugi four‐component reaction has been developed. This reaction was conducted under mild conditions with a broad scope of substrates.     

Tetrahydro‐1,5‐benzoxazepines and tetrahydro‐1H‐1,5‐benzodiazepines by a tandem reduction‐reductive amination reaction

A tandem reduction‐reductive amination reaction has been applied to the synthesis of (±)‐4‐alkyl‐2,3,4,5‐tetrahydro‐1,5‐benzoxazepines and (±)‐4‐alkyl‐1‐benzoyl‐2,3,4,5‐tetrahydro‐1H‐1,5‐benzodiazepines. The nitro aldehydes and ketones required for 1,5‐benzoxazepine ring closures were prepared by nucleophilic aromatic substitution of the alkoxides from several 3‐buten‐1‐ol derivatives with 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Precursors for the 1,5‐benzodiazepines were prepared by similar addition of N‐(3‐butenyl)benzamide anions to 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Catalytic hydrogenation of the nitro carbonyl compounds using 5% palladium‐on‐carbon in methanol then gave the target heterocycles by a tandem reduction‐reductive amination sequence. The 1,5‐benzoxazepines were isolated in high yield following chromatographic purification; the 1,5‐benzodiazepines were isolated as solids directly from the hydrogenation mixture and possessed differentiated functionality on the two nitrogen atoms.     

A Novel and Efficient Synthesis of 3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐ones (=3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐1‐benzopyran‐2‐ones)

An efficient one‐pot synthesis of 3‐[(4,5‐dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐one (=3‐[(4,5‐dihydro‐1H‐pyrrol‐3yl)carbonyl]‐2H‐1‐benzopyran‐2‐one) derivatives 4 by a four‐component reaction of a salicylaldehyde 1 , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one, a benzylamine 2 , and a diaroylacetylene (=1,4‐diarylbut‐2‐yne‐1,4‐dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H‐1‐benzopyran‐2‐one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 5‐Amino‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐selones

The reaction of S‐methylisothiosemicarbazide hydroiodide (=S‐methyl hydrazinecarboximidothioate hydroiodide; 1 ), prepared from thiosemicarbazide by treatment with MeI in EtOH, and aryl isoselenocyanates 5 in CH₂Cl₂ affords 3H‐1,2,4‐triazole‐3‐selone derivatives 7 in good yield (Scheme 2, Table 1). During attempted crystallization, these products undergo an oxidative dimerization to give the corresponding bis(4H‐1,2,4‐triazol‐3‐yl) diselenides 11 (Scheme 3). The structure of 11a was established by X‐ray crystallography.     

Asymmetric Hydroformylation of Vinylfurans Catalyzed by {(11bS)‐4‐{[(1R)‐2′‐Phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f]‐ [1,3,2]dioxaphosphepin}rhodium(I) [RhI{(R,S)‐binaphos}] Derivatives

The asymmetric hydroformylation of 2‐ and 3‐vinylfurans ( 2a and 2b , resp.) was investigated by using [Rh{(R,S)‐binaphos}] complexes as catalysts ((R,S)‐binaphos = (11bS)‐4‐{[1R)‐2′‐phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin; 1 ). Hydroformylation of 2 gave isoaldehydes 3 in high regio‐ and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with NaBH₄ successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme 3).     

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.     

Chemoselective Route for Synthesis of N‐Aryl‐3‐oxochromeno[2,3‐c]pyrazole‐2(3H)‐carbothioamide Derivatives

A chemoselective route for the synthesis of chromeno[2,3‐c]pyrazole‐2(3H)‐carbothioamide derivatives by a five‐component reaction of salicylaldehyde, malononitrile, NH₂NH₂?H₂O, aryl isothiocyanate, and H₂O in EtOH/AcOH mixture is reported. This new protocol has the advantages of high yields, short reaction times, ease of operation, and simple purification. All structures were confirmed by IR, ¹H‐ and ¹³C‐NMR, and MS analyses. A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Synthesis of 4‐Aryl‐4,6‐dihydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐diones from Biginelli Compounds

Biginelli compounds 1 were first brominated at Me? C(6) with 2,4,4,6‐tetrabromocyclohex‐2,5‐dien‐1‐one to give Br₂CH? C(6) derivatives 2 . The hydrolysis of the 6‐(dibromomethyl) group of 2c to give the 6‐formyl derivative 3c in the presence of an expensive Ag salt followed by reaction with N₂H₄?H₂O yielded tetrahydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐dione ( 4c ; Scheme 1). However, treatment of the 6‐(dibromomethyl) derivatives 2 directly with N₂H₄?H₂O led to the fused heterocycles 4 in better overall yield (Schemes 1 and 2; Table).     

Synthesis of a Novel Series of 2,3‐Disubstituted Quinazolin‐4(3H)‐ones as a Product of a Nucleophilic Attack at C(2) of the Corresponding 4H‐3,1‐Benzoxazin‐4‐one

A new series of 2,3‐disubstituted quinazolin‐4(3H)‐one derivatives was synthesized by nucleophilic attack at C(2) of the corresponding key starting material 2‐propyl‐4H‐3,1‐benzoxazin‐4‐one (Scheme 2). The reaction proceeded via amidinium salt formation (Scheme 3) rather than via an N‐acylanthranilimide. The structure of the prepared compounds were elucidated by physical and spectral data like FT‐IR, ¹H‐NMR, and mass spectroscopy.     

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.     

Synthesis of 1,3‐Selenazol‐2(3H)‐imines

The reaction of N,N′‐diarylselenoureas 16 with phenacyl bromide in EtOH under reflux, followed by treatment with NH₃, gave N,3‐diaryl‐4‐phenyl‐1,3‐selenazol‐2(3H)‐imines 13 in high yields (Scheme 2). A reaction mechanism via formation of the corresponding Se‐(benzoylmethyl)isoselenoureas 18 and subsequent cyclocondensation is proposed (Scheme 3). The N,N′‐diarylselenoureas 16 were conveniently prepared by the reaction of aryl isoselenocyanates 15 with 4‐substituted anilines. The structures of 13a and 13c were established by X‐ray crystallography.     

Synthesis of Isoindolo[2,1‐a]quinazoline‐5,11‐dione Derivatives via the Reductive One‐Pot Reaction of N‐Substituted 2‐Nitrobenzamides and 2‐Formylbenzoic Acids

Various isoindolo[2,1‐a]quinazoline‐5,11‐dione derivatives 3 were synthesized in good yields by means of the reductive reaction of N‐substituted 2‐nitrobenzamides 1 and 2‐formylbenzoic acids 2 in the presence of SnCl₂?2 H₂O under reflux in EtOH (Scheme, Table). The procedure needed two steps, the reduction of the nitro group of the 2‐nitrobenzamide and ring closure by nucleophilic addition of the NH₂ group to both the formyl and carboxylic acid C?O groups.     

Regioselective Synthesis of the 5,6‐Dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one Skeleton: A New Class of Compounds

We hereby report the first preparation of the 5,6‐dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one ( 3 ) and its derivatives starting from methyl 3‐(methoxycarbonyl)furan‐2‐acetate ( 8 ). The ester functionality connected to the methylene group was regiospecifically converted to the desired monohydrazide 9 . Conversion of 9 into the acyl azide 10 followed by Curtius rearrangement gave the corresponding isocyanate derivative 11 (Scheme 2). Reaction of 11 with different nucleophiles produced urethane and urea derivatives (Scheme 3). Intramolecular cyclization reactions provided the target compounds (Scheme 5). Removal of the amine‐protecting group formed the title compound 3 .     

A Novel,One‐Pot Four‐Component Route to 2′‐Thioxo‐2′,3′‐dihydrospiro[indole‐3,6′‐[1,3]thiazin]‐2‐one Derivatives

An efficient route to 2′,3′‐dihydro‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives is described. It involves the reaction of isatine, 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one, and different amines in the presence of CS₂ in dry MeOH at reflux (Scheme 1). The alkyl carbamodithioate, which results from the addition of the amine to CS₂, is added to the α,β‐unsaturated ketone, resulting from the reaction between 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one and isatine, to produce the 3′‐alkyl‐2′,3′‐dihydro‐4′‐phenyl‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses.     

Efficient Synthesis of Novel Coumarin‐3‐carboxamides (=2‐Oxo‐2H‐1‐benzopyran‐3‐carboxamides) Containing Lipophilic Spacers

The novel coumarin‐3‐carboxamides (=2‐oxo‐2H‐1‐benzopyran‐3‐carboxamides) 5a – 5g containing lipophilic spacers were synthesized through the Ugi‐four‐component reaction (Scheme 1). The reactions of aromatic aldehydes 1 , 4,4′‐oxybis[benzenamine] or 4,4′‐methylenebis[benzenamine] as diamine 2 , coumarin‐3‐carboxylic acid (=2‐oxo‐2H‐benzopyran‐3‐carboxylic acid; 3 ), and alkyl isocyanides 4 lead to the desired substituted coumarin‐3‐carboxamides 5a – 5g at room temperature with high bond‐forming efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl₃.     

A Novel Synthetic Approach to (±)‐Desoxynoreseroline

(±)‐Desoxynoreseroline ( 3 ), the basic ring structure of the pharmacologically active alkaloid physostigmine ( 1 ), was synthesized starting from 3‐allyl‐1,3‐dimethyloxindole ( 9 ). The latter was prepared from the corresponding 2H‐azirin‐3‐amine 6 by a BF₃‐catalyzed ring enlargement via an amidinium intermediate 7 (Scheme 1). An alternative synthesis of 9 was also carried out by the reaction of N‐methylaniline with 2‐bromopropanoyl bromide ( 12 ), followed by intramolecular Friedel–Crafts alkylation of the formed anilide 13 to give Julian's oxindole 11 . Further alkylation of 11 with allyl bromide in the presence of LDA gave 9 in an excellent yield (Scheme 3). Ozonolysis of 9 , followed by mild reduction with (EtO)₃P, gave the aldehyde 14 , whose structure was chemically established by the transformation to the corresponding acetal 15 (Scheme 4). Condensation of 14 with hydroxylamine and hydrazine derivatives, respectively, gave the corresponding imine derivatives 16a – 16d as a mixture of syn‐ and anti‐isomers. Reduction of this mixture with LiAlH₄ proceeded by loss of ROH or RNH₂ to give racemic 3 (Scheme 5).     

Synthesis and Selected Transformations of 1H‐Imidazole 3‐Oxides Derived from Amino Acid Esters

A series of new optically active 1H‐imidazole 3‐oxides 5 with a substituted acetate group at N(1) as the chiral unit were prepared by the reaction of α‐(hydroxyimino) ketones, α‐amino acid methyl esters, and formaldehyde. In an analogous reaction, ethyl 2‐(hydroxyimino)‐3‐oxobutyrate and 1,3,5‐trialkylhexahydro‐1,3,5‐triazines gave 3‐oxido‐1H‐imidazole‐4‐carboxylates 14 , which easily rearranged into the 2‐oxo derivatives 15 . Selected examples of N‐oxides 5 could be transformed into the corresponding 2,3‐dihydro‐1H‐imidazole‐2‐thione derivatives 10 via a ‘sulfur‐transfer reaction’, and the reduction of the histidine derivative 5i with Raney‐Ni yielded the optically active 2,3‐bis(imidazolyl)propanoate 12 . Furthermore, reaction of the (1H‐imidazol‐1‐yl)acetates with primary amines yielded the corresponding acetamides.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

From Blue Azulenes to Blue Heptalenes – New Strongly Polarized π‐Convertible Heptalenes

The 1,5,6,8,10‐pentamethylheptalene‐4‐carboxaldehyde ( 4b ) (together with its double‐bond‐shifted (DBS) isomer 4a ) and methyl 4‐formyl‐1,6,8,10‐tetramethylheptalene‐5‐carboxylate ( 15b ) were synthesized (Schemes 3 and 7, resp.). Aminoethenylation of 4a / 4b with N,N‐dimethylformamide dimethyl acetal (=1,1‐dimethoxy‐N,N‐dimethylmethanamine=DMFDMA) led in DMF to 1‐[(1E)‐2‐(dimethylamino)ethenyl]‐5,6,8,10‐tetramethylheptalene‐2‐carboxaldehyde ( 18a ; Scheme 9), whereas the stronger aminoethenylation agent N,N,N′,N′,N″,N″‐hexamethylmethanetriamine (=tris(dimethylamino)methane=TDMAM) gave an almost 1 : 1 mixture of 18a and 1‐[(1E)‐2‐(dimethylamino)ethenyl]‐5,6,8,10‐tetramethylheptalene‐4‐carboxaldehyde ( 20b ; Scheme 11). Carboxylate 15b delivered with DMFDMA on heating in DMF the expected aminoethenylation product 19b (Scheme 10). The aminoethenylated heptalenecarboxaldehydes were treated with malononitrile in CH₂Cl₂ in the presence of TiCl₄/pyridine to yield the corresponding malononitrile derivatives 23b, 24b , and 26a (Schemes 13 and 14). The photochemically induced DBS process of the heptalenecarboxaldehydes as ‘soft’ merocyanines and their malononitrile derivatives as ‘strong’ merocyanines of almost zwitterionic nature were studied in detail (Figs. 10–29) with the result that 1,4‐donor/acceptor substituted heptalenes are cleaner switchable than 1,2‐donor/acceptor‐substituted heptalenes.