A novel and highly stereoselective route for the synthesis of non-racemic 3-substituted isoindolin-1-one targets

A new, versatile and highly stereoselective approach for the synthesis of non-racemic 3-substituted isoindolin-1-ones is described from a readily available chiral template. The potential of this new protocol is demonstrated through the synthesis of an enantiomerically enriched 3-alkyl N-H isoindolin-1-one target with an e.e. of 98%.     

A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives under Pd(OAc)2/HCOOH system

A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives from 2-formylbenzoic acid and amine under Pd(OAc)₂/HCOOH system has been described. The whole process is carried out in ligand-free conditions and furnished the desired products by reductive intramolecular cyclization. Furthermore, this procedure is applied successfully for the modification of natural products, such as vindoline and estrone.     

Syntheses of substituted 3-methyleneisoindolin-1-ones by a palladium-catalyzed Sonogashira coupling-carbonylation-hydroamination sequence in phosphonium salt-based ionic liquids

Two efficient approaches for the synthesis of isoindolin-1-one derivatives in phosphonium salt ionic liquids are described. The palladium-catalyzed carbonylation-hydroamination reaction of 1-halo-2-alkynylbenzene with amines afforded the substituted 3-methyleneisoindolin-1-ones in good yields and high selectivities in favor of the Z-isomers. The target molecules could also be synthesized by the Sonogashira coupling-carbonylation-hydroamination one-pot reaction of dihalides, alkynes, and amines. Both processes can be conducted under mild conditions and tolerate a wide array of functionalized substrates.     

Palladium-Catalyzed Cross-Coupling Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides

Potassium N-methyltrifluoroborate isoindolin-1-one was synthesized and used in Suzuki–Miyaura palladium-catalyzed cross-coupling reactions with aryl and heteroaryl chlorides to prepare 29 examples of substituted N-benzyl isoindolin-1-ones. The new approach benefits from mild reaction conditions that tolerate a variety of functional groups. In addition, because of the large number of commercially available aryl and heteroaryl chlorides that can serve as coupling partners, the approach readily provides access to libraries of substituted N-benzyl isoindolin-1-ones.     

The synthesis of isoindolin-3-ones,Phthalazin-4(3H)-ones and related systems

The reaction between methyl 2-cyanobenzoate and its pyridine analogues gave isoindolin-3-ones, phthalazin-4(3H)-ones and their corresponding aza analogues. Some reactions of 1-benzylaminoiminoisoindolin-3-one 5b were investigated.     

A new approach to the facile synthesis of mono- and disubstituted quinazolin-4(3H)-ones under solvent-free conditions

Quinazolin-4(3H)-one derivatives were synthesized successfully via a one-pot, three component reaction of isatoic anhydride and an orthoester with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions. This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure.     

Synthesis and absorption spectra of 2-substituted 5,8-dimethoxy-4H-1-benzothiopyran-4-one 1,1-dioxides

2,3-Dibromo-5,8-dimethoxy-4H-1-benzothiopyran-4-one (thiochromone) 1,1-dioxide which was a starting material to prepare sulfone analogues of 1,4-naphthoquinone dyes was easily prepared from 5,8-dimethoxythiochroman-4-one by oxidation and bromination. The reactions of 2,3-dibromo-5,8-dimethoxythiochromone 1,1-dioxide 4 with aliphatic and aromatic amines in ethanol below 20° gave 2-substituted derivatives 12a-e and at higher reaction temperature the amination gave 2-arylamino derivatives 13c-e debrominated at C -3. The visible absorption spectra of these derivatives were investigated by the PPP MO method.     

Proline-mediated formation of novel chroman-4-one tetrahydropyrimidines

Novel tricyclic N-benzylated chroman-4-one tetrahydropyrimidine derivatives have been prepared through a multi-component reaction between various 2-substituted chroman-4-one derivatives, N-methylenebenzylamine and a catalytic amount of proline under mild reaction conditions. The tricyclic structure of 1a was determined by NMR spectroscopy and confirmed by X-ray crystallography. An additional product, 2a, was isolated from the reaction mixture and its structure and conformation were determined by a combination of theoretical (Monte Carlo conformational search) and NMR-based (NOE and ³J_HH couplings) conformational analysis. The NMR analysis revealed one preferred geometry for 1a and 2a in CHCl₃ solution.     

Synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives via a TBAI-catalyzed radical cascade cyclization

We have developed a metal-free radical cascade reaction of N-substituted 2-aryl indoles with readily available sulfonyl hydrazides for the rapid construction of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives. With the TBAI–TBHP catalytic system, a broad series of structurally diverse indolo[2,1-a]isoquinolin-6(5H)-one derivatives were obtained in moderate to excellent yields. The reaction features mild reaction conditions, operationally easiness, scaled-up feasibility, and high functional-group-tolerance.     

An efficient one-pot multi-component synthesis of 3,4,5-substituted furan-2(5H)-ones catalyzed by tetra-n-butylammonium bisulfate

A facile one-pot synthesis of 3,4,5-substituted furan-2(5H)-one derivatives from a three-component reaction of aniline derivatives, dialkylacetylenedicarboxylates and aromatic aldehydes under mild conditions using tetra-n-butylammonium bisulfate as a catalyst has been developed.     

Formation of carbon-carbon single bonds from isocyanates and cyclic pentaoxyphosphoranes—VI : Synthesis of 4-oxazolones and 4-thiazolones,and a new type of chapman rearrangement

The reaction of 4,5-dimethyl-2,2,2-trimethoxy-2,2-dihydro-1,3,2-dioxaphospholene with carbomethoxy, carbopropoxy and N,N-diphenylcarbamyl isocyanates yields, respectively, 2-methoxy-, 2-propoxy- and 2- diphenylamino-5-acetyl-5-methyl-2-oxazolin-4-one. The reaction with carbophenoxy isocyanate gives two products in a proportion which depends on experimental conditions: 2-phenoxy-5-acetyl-5-methyl-2-oxalin-4-one (1:1 stoichiometry) and 1,3-dicarbophenoxy-5-acetyl-5-methyl-hydantoin (1:2 stoichiometry). The 2-substituted 4- oxazolones are hydrolyzed to 5-acetyl-5-methyl-oxazolidin-2,4-dione. The alkyl group of the 2-alkoxy-4-oxazolones migrates to the adjacent nitrogen to give 3-alkyl-5-acetyl-5-methyl-oxazolidin-2,4-diones. The dioxaphospholene reacts with 2-substituted 2-thiazolin-4,5-diones to give 2-substituted 5-acetyl-5-methyl-2-thiazolin-4-ones, including rhodanine derivatives.     

Modification of biologically active amides and amines with fluorine-containing heterocycles 6. Methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)propionate in cyclocondensation with 1,3-binucleophiles

A reaction of methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)propionate with 1,3-binucleophiles (N-benzylurea, N-substituted 3-aminocrotonates, N-substituted 3-aminocyclohexenones, and 6-aminouracyls), leading to the formation of fluorine-containing heterocyclic 3-methyl-1-phenylpyrazol-5-one derivatives, was studied.     

Efficient PhB(OH)2-catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under solvent free conditions

An efficient and practical one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones has been developed under solvent free-conditions using non-toxic and cheap phenylboronic acid as excellent catalyst. This strategy involves the sequential two-step Mannich/lactamization cascade reaction of inexpensive 2-formylbenzoic acid with primary amines and a wide variety of ketones, and an aldol/lactonization cascade reaction of 2-formylbenzoic acid with a broad range of ketones.     

Novel water-soluble sedative-hypnotic agents: isoindolin-1-one derivatives

We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(-), 5(-), 27(-), and 47(-) [JM-1232(-)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(-) [JM-1232(-)] is being considered as the most potential candidate for clinical trials in humans.     

Pinacol rearrangement of cyclopent-3-en-1,2-diols: Cyclopentenone formation and interrupting reaction

Cyclopentenyl carbocations formed as a result of the protonation of 3,4-substituted cyclopent-3-en-1,2-diols can give either cyclopent-2-en-1-one derivatives via pinacol rearrangement or interrupted reaction products similar to the Nazarov intermediate.     

3-Nitro-1,2,4-triazol-5-one derivatives

3-Nitro-1,2,4-triazol-5-one and its monomethyl derivatives react with methyl vinyl ketone to give products of addition to the ring N₁ and N₄ atoms. The reaction with formaldehyde and N-methylolacetamide proceeds only at the N₁ atom. The keto derivatives of 3-nitro-1,2,4-triazol-5-one undergo the Schmidt reaction to give the corresponding acetamides. A number of compounds that include functional groups in the N₁-alkyl substituent of the 3-nitro ring were obtained by treatment of the bases of N₁-substituted 3,5-dinitro-1,2,4-triazoles in aprotic media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552–558, April, 1981.     

Facile C21 functionalization through a novel functional group transfer reaction in 16 alpha,17 alpha-epoxy-3 beta-hydroxypregn-5-en-20-one and its applications

A novel functional group transfer reaction in 16 alpha,17 alpha-epoxy-3 beta-hydroxypregn-5-en-20-one by treatment with dry HCl affords 21-chloro-3 beta-hydroxy-pregn-5,16-dien-20-one, which has been utilized to obtain a number of C21-substituted derivatives.     

Michael addition approach for the synthesis of novel spiro compounds and 2-substituted malonic acid derivatives from Meldrum’s acid

Novel routes for the synthesis of spiro derivatives of Meldrum’s acid and 2-substituted malonic acid derivatives have been developed. Meldrum’s acid was monoalkylated using a Michael addition reaction. Mono-Michael adducts were then alkylated using substituted haloalkanes, which on condensation gave spiro derivatives of Meldrum’s acid. Bis Michael addition of Meldrum’s acid with 1,5-diaryl-1,4-pentadien-3-one gave directly a spiro derivative of Meldrum’s acid. These compounds and bis alkylated Meldrum’s acid derivatives, on acidic methanolysis gave 2-substituted malonic acids.     

N-Isocyaniminotriphenylphosphorane (Ph3PNNC) as a metal-free catalyst for the synthesis of functionalized isoindoline-1-ones

A novel application in the field of N-isocyaniminotriphenylphosphorane (Ph₃PNNC) chemistry has been introduced in this work. A series of substituted isoindolin-1-one ring systems has been successfully synthesized through a novel and efficient multicomponent reaction of methyl 2-formylbenzoate and primary amines in the presence of N-isocyaniminotriphenylphosphorane (Ph₃PNNC) as a catalyst. This one-pot three component reaction (3-CR) gives high yield using N-isocyaniminotriphenylphosphorane (Ph₃PNNC) as a metal-free catalyst under mild conditions.     

Umwandlung von Bicyclo [3.2.0]hept-2-en-6-on in Cyclopentadienessigsäure-Derivate

Conversion of Bicyclo [3.2.0]hept-2-en-6-one into Cyclopentadienylacetic Acid Derivatives The reaction of a mixture of 4exo-bromobicyclo [3.2.0]hept-2-en-6-one ( 2 ) and -7-one ( 3 ) with O- or N-nucleophiles yielded cyclopentadien-5′-yl-acetates 4a–f or-acetamides 4g–h . Due to their rapid isomerization, the products 4 were not isolated, but some of them were demonstrated spectroscopically or captured in situ with maleimide as 10′-substituted norbornene derivatives 7 . The formation of 4 from 2/3 involves a fragmentation of the bond between the carbonyl and the bridge-head C-atom, induced by the attacking nucleophile and the leaving Br-ion and aided by the relief of the four-membered ring strain. Some of the isomerization products of 4 , i.e. the cyclopentadiene-1′-yl- and 2′-yl-acetyl derivatives were captured with maleimide as the 1′- and 8′-substituted norbornene-derivatives 8 and 9 . Two C-nucleophiles did not induce the fragmentation: sodium acetylacetonate substituted the Br-atom and sodium (diethoxyphosphoryl)ethoxycarbonylmethide condensed with the carbonyl group of 2/3 , yielding 11/12 and 13/14 , respectively.