Recent development in the synthesis of pyrrolin-4-ones/pyrrolin-3-ones

Pyrrolin-4-ones/pyrrolin-3-ones and its derivatives are important heterocyclic systems which are observed in vast variety of natural products, pharmaceuticals, and biologically important compounds. Different researchers all across the world have developed different synthetic methodologies for the construction of functionalized pyrrolin-4-ones/pyrrolin-3-one scaffolds such as the transition-metal catalyzed/mediated cycloisomerizations of 1-aminoynones and dimerization of enaminones or α-diazo-β-oxoamides etc. The present review article summarizes various reports on the synthesis of various simple and functionalized pyrrolin-4-ones/pyrrolin-3-ones from 2000 onward.     

Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues

The synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahydropyrimidine derivatives under different reduction conditions. The reduction reaction also induced a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen bond.     

Derivatives of imidazo[4,5-e]-2,1-benzisoxazole and synthesis of substituted benzimidazoles from them

A series of imidazo[4,5-e]-2,1-benzisoxazole derivatives was synthesized by reacting benzyl cyanide with 1,2-disubstituted 5-nitrobenzimidazoles; their reduction gave 1,2-disubstituted 4-benzoyl-5-aminobenzimidazoles. Acylation, oximation, and diazotization reactions with subsequent replacement of the diazo group by iodine were investigated. In the reaction with DMFA diethyl acetal, amidines were obtained, whose cyclization by the action of ammonia leads to imidazo[4,5-f]quinazoline derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1082–1085, August, 1986.     

An improved synthesis and some reactions of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate

The reaction of ethyl 2-(dimethylamino)methylene-3-oxobutanoate with diethyl oxalate in the presence of sodium hydride in THF gave diethyl 4-oxo-4H-pyran-2,5-dicarboxylate, from which 4-oxo-4H-pyran-2,5-dicarboxylic and 4-oxo-1-phenyl-1,4-dihydropyridine-2,5-dicarboxylic acids and their derivatives were obtained in good yields.     

Preparation of 2-fluoromalonic esters and related compounds from hexafluoropropene

Dimethyl and diethyl fluoromalonates were prepared from hexafluoropropene by its exhaustive alcoholysis or alternatively its ammonolysis and alcoholysis. Fluoromalonates thus obtained or their alkylated derivatives were condensed with o-phenylenediamine or its substituted derivatives to give a number of 1H-3-fluoro-1,5-dibenzodiazepin-2,4(3H,5H)-diones.     

Synthesis of 4-dialkylaminopyridine derivatives through ring-rearrangement of 3-nitro-2H-pyran-2-one acetamidines

A new synthesis of substituted 4-dialkylaminopyridines was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Secondary amines were reacted with the amidines in a sealed tube and in ethanol as the solvent yielding exclusively 4-dialkylaminopyridine derivatives or a mixture with 4-methylpyridine derivative, depending on the C-α-linked substituents of the starting amidine. Structural elucidation of the 4-dialkylaminopyridines revealed their existence as two tautomeric forms, depending on the solvent.     

CF3S(O)n-containing enaminones as precursors for the synthesis of pyrimidine-4(3H)-ones

Methyl 3-(dimethylamino) acrylates containing trifluoromethylsulfenyl-, trifluoromethylsulfinyl-, and trifluoromethylsulfonyl groups were synthesized and their utility demonstrated by reactions with aliphatic and aromatic amidines to produce 2,5-substituted 4(3H)-pyrimidones. Cyclization reactions of enaminones with urea or thiourea led to 5-substituted uracil or 2-thiouracil derivatives, respectively.     

Reaction of ω-cyanoacetophenone and some of its derivatives with secondary amines. New synthesis of aminopyridine derivatives

ω-Cyanoacetophenone (1a) and its derivatives 1b-c react with morpholine (or piperidine) to give mainly 2,4-diaryl-3-eyano-6-morpholino- (or piperidino-) pyridine derivatives (5) ; relative β-aminoeinnamonitriles 6 and very small amounts of amidines 4 are also obtained. When pyrrolidine is used compounds 5 cannot be detected and enamines 6 are the main product. A mechanism involving the intermediate formation of enamines 6 (as electrophiles) and of carbanions 11 (as nucleophiles) is proposed to explain this new synthesis of aminopyridine derivatives.     

Unsaturated hydantoin derivatives XI. Synthesis and rearrangement of some ethyl esters of α-substituted hydantoest-δ5,α-acetic acids

α-Substituted (CH₃, C₆H₅, OCH₃, OC₆H₅, Cl, and F) hydantoin-Δ^5,α -acetates were obtained from diethyl oxaloacetates and urea, and their 3-methyl derivative s were obtained from N-methylurea or by methylation of the nitrogen-unsubstituted hydantoins with diazomethane; theα-nitro derivative was obtained by nitration of unsubstituted ethyl hydantoin-Δ^5,α -acetate with nitric acid in acetic acid, and ethyl hydantoin-Δ^5,α -glycolate was obtained from hydantoin and diethyl oxalate. All of the synthesized hydantoin-Δ^5,α -acetates, except for theα-nitro andα-hydroxy derivatives, are converted to the corresponding 3- and 5-substituted orotic acids.     

NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N‒O bond formation

A reaction involving an efficient NBS-mediated oxidative N?O bond formation has been established for the synthesis of 1,2,4-oxadiazoles from readily accessible N-acyl amidines. The features of this synthetic method include simplicity of operation, mild reaction conditions, short reaction times, high yields, and eco-friendliness. The reaction also works well with crude N-acyl amidines obtained by amidation of simple benzoic acids and amidines to produce biologically relevant 1,2,4-oxadiazoles in a scalable fashion.     

Synthesis of electroactive hydrazones derived from 3-(10-alkyl-10H-phenothiazin-3-yl)-2-propenals and their corresponding 3,3′-bispropenals

3-(10-Alkyl-10H-phenothiazin-3-yl)-2-propenals and their corresponding 3,3′-bispropenals that represent a previously unexplored class of functionalised phenothiazine derivatives were prepared upon reacting N-alkylated 3-bromo- and 3,7-dibromo-10H-phenothiazines with acrolein diethyl acetal under Pd catalysis. The obtained heterocyclic 2,3-unsaturated aldehydes were condensed with N-methyl-N-phenylhydrazine and N,N-diphenylhydrazine resulting in mono- and dihydrazones that act as effective hole transporting materials. Thermal, optical, electrochemical and photophysical properties of the synthesised new organic electroactive derivatives have been investigated.     

Aza-Wittig reaction of N-phosphorylalkyl phosphazenes with carbonyl compounds and phenylisocyanate. Synthesis of 4-amino-3-phosphoryl-2-azadienes and pyrazine-phosphonates

Simple and functionalized N-phosphorylalkyl imines and N-phosphorylalkyl-N′-phenyl-carbodiimides are obtained by aza-Wittig reaction of phosphazenes derived from aminophosphonates with carbonyl compounds and phenyl isocyanate. The reaction with dimethylformamide diethyl acetal (DMF-DEA) of these functionalized imines leads to the synthesis of 4-amino-3-phosphoryl-2-azadienes. N-Phosphorylmethyl imine derived from benzaldehyde can be used for the preparation of substituted pyrrole-phosphonates, while acid treatment of 4-dimethylamino-3-diethylphosphoryl-1-phenyl-2-azadiene gives diethyl 5-diethylphosphorylpyrazin-2-ylphosphonate.     

2-Amidinylindole-3-carbaldehydes: synthesis of new tetracyclic compounds containing the pyrrolo[1,2-c]1,4-diazepine ring

2-Amidinylindol-3-carbaldehydes bearing an α-alkoxycarbonyl substituent on the cyclic-tertiary amine moiety were prepared. Pyrolysis of these amidines in diethylenglycol-monoethyl ether produced mainly a pyrrolo[1′,2′-1,2]-1,4-diazepino[5,6-b]indol-7,11-dione. A similar result was obtained starting from 2-amidinylbenzofuran-3-carbaldehyde.     

Copper(I)-catalyzed synthesis of 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one via intramolecular alkyne hydroamination

The 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives were obtained via intramolecular alkyne hydroamination reaction of 2-amino-N′-arylbenzohydrazide and alkynal diethyl acetal in the presence of CuBr and Cs₂CO₃. This new procedure provides an efficient method to construct fused tricyclic heterocycle containing both pyrazole and quinazoline analogues.     

Nitrenic reactivity of diazirines

Butyl 3-bromo-3H-diazirine-3-carboxylate (7) and 3-bromo-3-phenyl-3H-diazirine (17) exhibit nitrenic reactivity with phenylmagnesium bromide or tetrabutylammonium cyanide. The formation of several N,N′-disubstituted amidines is attributed to the intermediacy of 1-phenyl or 1-cyano-1H-diazirines possessing a singlet imidoylnitrene character at the N2 atom. Most notably, the reaction of 7 with PhMgBr in diethyl ether affords 2-hydroxy-2,2,N-triphenylacetamidine (9) and 2-methyl-5,5-diphenyl-4-phenylamino-2,5-dihydrooxazole (10) as products derived from nitrene insertion to the ether α-C–H bond.     

Structure and Fluxional Behavior of Phenylmercury Derivatives of N,N'-Diarylform(benz)amidines

Activation barriers for fast 1,3-N,N' migrations of phenylmercury groups in the corresponding derivatives of N,N'-di(p-tolyl)form(benz)amidines have been calculated by density functional theory B3LYP/Gen, 6-311++G(d,p)/SDD to be ΔE _ZPE ^≠ = 4.5 and 3.0 kcal/mol. The results correspond to the data of dynamic NMR, which have shown the upper limit of activation barriers of these rearrangements (ΔG^≠) to be below 8 kcal/mol. The calculations have shown that the most stable is the E-syn form of N-phenylmercury-N,N'-di(p-tolyl)form(benz)amidines stabilized by supplementary intramolecular coordination of mercury atom with imine nitrogen atom of the amidine triad.     

Chemoselective Heck arylation of acrolein diethyl acetal catalyzed by an oxime-derived palladacycle

A dimeric 4-hydroxyacetophenone oxime-derived palladacycle has been used as a very efficient precatalyst for the chemoselective arylation of acrolein diethyl acetal to give either cinnamaldehyde derivatives or 3-arylpropanoate esters by proper choice of the reaction conditions. The synthesis of cinnamaldehyde derivatives can be performed by Heck reaction of acrolein diethyl acetal with iodo-, bromo- or chloroarenes in N,N-dimethylacetamide (DMA) using K₂CO₃ as base at 120 °C and tetra-n-butylammonium acetate (TBAA) and KCl as additives, followed by acid workup. In the case of 3-arylpropanoate esters the corresponding arylation of acrolein diethyl acetal with iodoarenes can be performed at 90 °C in aqueous DMA using (dicylohexyl)methylamine as base, whereas for bromoarenes the reaction has to be performed at 120 °C using tetra-n-butylammonium bromide (TBAB) as additive. Alternatively, this process can be performed under microwave irradiation. These couplings take place in good yields and with lower catalyst loading than with palladium(II) acetate as well as in shorter reaction times and with lower excess of acrolein diethyl acetal.     

Gold(I)‐Catalyzed Aminohalogenation of Fluorinated N′‐Aryl‐N‐Propargyl Amidines for the Synthesis of Imidazole Derivatives under Mild Conditions

A procedure for the synthesis of fluorinated imidazole derivatives from propargyl amidines has been developed. Under gold(I) catalysis, propargyl amidines were converted into 5‐fluoromethyl imidazoles in the presence of Selectfluor through a cascade cyclization/fluorination process. In contrast, imidazole‐5‐carbaldehydes were obtained in high yields when N‐iodosuccinimide (NIS) was used as the halogenating reagent. The polarity of the solvent and light had significant impact on the formation of the carbaldehydes. These transformations showed excellent functional‐group tolerance. An unfluorinated substrate with an electron‐withdrawing group also underwent aminohalogenation to give the corresponding product in good yield. Mechanistic investigation revealed the general pathways of these transformations.     

New chiral thiols and C2-symmetrical disulfides of Cinchona alkaloids: ligands for the asymmetric Henry reaction catalyzed by CuII complexes

Seven Cinchona alkaloids were reacted with thioacetic acid and Bu₃P/diethyl diazadicarboxylate in THF at 0–25 °C to give the corresponding thiolacetates with complete inversion of configuration at the substitution center. The thus obtained chiral thiolesters were converted into thiols and these compounds were oxidized to the respective disulfides of C₂-symmetry. Both C-9 thioles and disulfides were tested as chiral ligands in the Cu-catalyzed asymmetric Henry reaction. When the thiol derivatives of an 8,9-like configuration were applied in the reaction of benzaldehyde and nitromethane, the obtained nitroaldol was of the same absolute configuration as the catalyst and the observed enantioselectivity was up to 83% ee. These ligands gave higher ees than the corresponding thioethers, disulfides, and thioles of 8,9-unlike configuration. The results obtained are in agreement with the proposed transition-state model involving nucleophilic attack of a deprotonated nitromethane directed preferably at one side of the O-complexed benzaldehyde.     

Highly efficient synthesis of 2′,3′-didehydro-2′,3′-dideoxy-β-nucleosides through a sulfur-mediated reductive 2′,3′-trans-elimination. From iodomethylcyclopropanes to thiirane analogs

Taking into account the thiophilic properties of iodine, a very simple methodology to achieve 2′,3′-didehydro-2′,3′-dideoxy-β-nucleosides in high yield was performed, using mild, and inexpensive conditions, by means of the treatment of 2′-deoxy-3′,5′-dibenzoyl-2′-iodo-β-nucleoside derivatives with NaHS. The process has shown to be highly dependent of the relative geometry between the iodine atom and the adjacent leaving group. In this way, different essays carried out with pyranose derivatives have concluded in no reaction when the vicinal groups to eliminate do not adopt a trans-diaxial disposition. In addition, the treatment of 2-iodomethyl-cyclopropane-1,1-dicarboxylic acid diethyl ester under the same conditions softly and readily leads to the obtention of a mixture of the expected 2-allyl-malonic acid diethyl ester (as the minor product) and the thiirane derivative 2-thiiranylmethyl-malonic acid diethyl ester (as the major product). In this case, the responsible of the reaction progress are the nucleophilic properties of the sulfur atom rather than the thiophilic character of the iodine atom.