Tandem reaction of heterocyclic ketene aminals with diazoesters: Synthesis of pyrimidopyrrolidone derivatives

A tandem reaction of heterocyclic ketene aminals (HKAs) with diazoesters in the presence of a Cu catalyst is demonstrated for the efficient synthesis of pyrimidopyrrolidone derivatives. The reaction shows a broad substrate scope and excellent functional group tolerance. Our method provides rapid access to diverse pyrimidopyrrolidones in moderate to excellent yields under mild reaction conditions.     

Regioselective synthesis of fused ring heterocyclic derivatives of ketene aminals and their biological activities

A regioselective and convenient methodology was developed to synthesize heterocyclic derivatives, bearing imidazole, piperidines, and azepines rings. The N-arylnitrones derived from 3-formylchromones were selected to react with heterocyclic ketene aminal to furnish the structurally attractive and pharmacologically important fused ring heterocycles. The N-arylnitrone moiety of 3-formylchromone was used to activate the formyl group for regioselective fused ring heterocycles synthesis, whereas, the effect of substituents at aryl functionality of nitrones were studied to improve the yield of target fused ring heterocyclic products. The synthesized compounds (10-12) were evaluated for their in vitro cytotoxic and antifungal influences. In cytotoxic (brine shrimp lethality) assay, compound 11e was found to be active with LD₅₀ = 4.1 × 10⁻⁶ μg/mL.     

The reaction of aroyl‐substituted heterocyclic ketene aminals with aryl azides

The aroyl‐substituted heterocyclic ketene aminals 1 or 2 reacted with p‐chlorophenyl azide ( 3a ) to give the polysubstituted 1,2,3‐triazoles 4 or 5 , as well as the fused heterocycles 6 or 7 . Compounds 1 and 2 reacted with p‐nitrophenyl azide ( 3b ) much faster, and polysubstituted 1,2,3‐triazoles 8 or 9 were obtained as sole products. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:387–391, 2000     

Acetyl ketene aminals in Nenitzescu reaction

Nenitzescu reaction of acetyl ketene aminals (N,N-acetals) was investigated. The interaction of 2-acetyl-1-amino-1-anilinoethene with benzoquinone gave 3-acetyl-2-amino-7a-hydroxy-1-phenyl-5,7a-dihydro-1H-indol-5-one, which was then transformed into 3-acetyl-2-amino-6-chloro-5-hydroxy-1-phenylindole. The reaction of benzoquinone with 2-acetyl-1-amino-1-benzoylaminoethene led to the corresponding hydroquinone-adduct which was oxidized to 4-acetylamino-5-(2,5-dihydroxyphenyl)-2-phenyloxazole. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 160–165, January, 1999.     

Synthesis of fused hydroxy dihydropyrroles and unexpected dihydropyrazine and dihydroquinoxaline derivatives based on heterocyclic ketene aminals

The one-pot four-component synthesis of highly functionalized fused hydroxyl dihydropyrroles and dihydropyrazines from readily available diamines, 1,1-bis (methylsulfanyl)-2-nitroethene, phenylglyoxal monohydrates, and C-H acids have been developed. This strategy provides an efficient, catalyst-free approach for easy access to various new hydroxyl-dihydropyrrole and dihydropyrazine rings in good to high yields. The products were confirmed by ¹H and ¹³C NMR, IR, mass, and X-ray crystal structure analyses.     

Silver(I)-mediated coupling reaction of heterocyclic ketene aminals (HKAs) with bis(phenylsulfonyl)sulfides to synthesis of benzenesulfonothioyl-HKAs

An efficient and convenient method was developed for the preparation of 2-benzenesulfonothiol-HKAs via a silver(I)-mediated direct sulfenylation of heterocyclic ketene aminals (HKAs). The method involves a variety of functionalized substrates, leading to α-arylthioyl HKAs in a mild, easy operation, and mild reaction conditions.     

氰基取代的含杂环烯酮缩胺的合成及其波谱和结构特性

由氰基乙酸酯或丙二腈先制得氰基取代的烯酮缩硫醇, 然后与二胺反应合成了氰基取代的含杂环烯酮缩胺, 测定了它们的UV、IR、^1H及^1^3C NMR等波谱, 并测定了其中两个化合物的晶体结构, 对所得的波谱和结构特性进行了讨论。     

Synthesis of novel tetracyclo-isocoumarins via AcOH-catalyzed cascade reaction of heterocyclic ketene aminals with 2,2-dihydroxy-2H-indene-1,3-dione

A facile synthesis of tetracyclo-isocoumarins based on the AcOH-catalyzed cyclocondensation and rearrangement reaction between heterocyclic ketene aminals and 2,2-dihydroxy-2H-indene-1,3-dione is described. This method provides direct access to tetacyclo-isocoumarins, a class of compounds with potential broad spectrum biological activities.     

One-pot synthesis and conformational features of n,n'-disubstituted ketene aminals

N,N'-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N'-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is described. Most of these aminals exist in rotameric equilibrium around the central C=C bonds in solution, and the rotamers are stabilized by intramolecular hydrogen bonding both in solution and in solid states.     

Cascade reaction synthesis of multisubstituted bicyclic pyridone derivatives

An efficient synthesis of novel bicyclic pyridone derivatives via cascade reaction of heterocyclic ketene aminals (HKAs) and 4-arylmethylene-2-phenyloxazol-5(4H)-ones in the presence of acetic acid has been established. Significantly, the protocol affords a straightforward approach to the construction of multisubstituted bicyclic pyridones in which one C–O bond was cleaved and new C–C and C–N bonds were formed in one pot under mild conditions.     

Formation of pyrimidin-4-one derivatives in the reaction of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones with ketene aminals

N. D. Zelenskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 5, pp. 1225–1226, May, 1992.     

Synthesis of the novel pyrimido[1,6-a]pyrimidine and imidazo[1,2-c]pyrimidine derivatives based on heterocyclic ketene aminals

A concise and efficient route for the synthesis of pyrimido[1,6-a]pyrimidines and imidazo[1,2-c]pyrimidines by simply refluxing a reaction mixture of different heterocyclic ketene aminals and N,N′-bis(arylmethylidene)arylmethane was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery.     

Palladium(II)-catalyzed cyclization of heterocyclic ketene aminals with (E)-ethyl 2,3-diiodoacrylates: selective synthesis of bicyclic pyrroles and bicyclic pyridones

A concise and efficient synthesis of novel bicyclic pyrroles has been achieved by PdCl₂-catalyzed cyclic condensation of six-membered heterocyclic ketene aminals (HKAs) or seven-membered HKAs with ethyl 2,3-diiodoacrylate and diethyl 2,3-diiodofumarate in the presence of Cs₂CO₃, respectively. A series of novel bicyclic pyridones have also been obtained via five-membered HKAs with diethyl 2,3-diiodofumarate under the optimized conditions in moderate yields. These reactions are the first application of a transition metal to catalyze the building blocks HKAs to form the bicyclic pyrrole library via condensation reaction.     

Recent developments in the heterocyclic ketene aminal-based synthesis of heterocycles

Research on Chemical Intermediates - Small poly-functionalized heterocycles are frequently found in pharmacophores and play important roles in drug discovery. Heterocyclic ketene aminals (HKAs) are...     

烯酮缩胺与芳基异硫氰酸酯的反应: 合成异噻唑化合物 的一个途径

具有不同取代基的五状和非环状的烯酮缩胺与芳基异硫氰酸酯在两酮中回流,可高产率地获得α-碳加成产物,该产物在溴存在下可氧化关环生成异噻唑类化合物。     

The regiospecific N‐sulfonylation and N‐phosphorylation of benzoyl‐substituted heterocyclic ketene aminals

The regiospecific N‐sulfonylation and N‐phosphorylation of benzoyl‐substituted heterocyclic ketene aminals have been investigated. In the presence of sodium hydride, benzoyl‐substituted heterocyclic ketene aminals 1 or 2 reacted with p‐toluenesulfonyl chloride 3 to give (E)‐1‐(p‐toluenesulfonyl)‐2‐(aroylmethylene)imidazolidine 4 or (E)‐1‐(p‐toluenesulfonyl)‐2‐(aroylmethylene)hexahydropyrimidine 5, respectively. Under the same condition, 1 reacted with diethyl chlorothiophosphate 6 to give diethyl [2‐(aroylmethylene)imidazolidin‐1‐yl]thiophosphate 7. However, 2 failed to react with 6 to give N‐phosphorylated products. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 297–301, 1999     

Activated nitriles in heterocyclic synthesis. The reaction of cinnamonitrile derivatives with active methylene reagents

The reaction of substituted cinnamonitrile derivatives with cyanoacetanilide and with ethyl acetoacetate produced several new polyfunctional pyridine and pyran derivatives. Evidence for assigned structure of the reaction products and the possible mechanisms of their formation is presented.     

A novel and facile synthesis of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles via heterocyclic ketene aminals and Konevenagel adducts formed by phthalic anhydride and ethyl cyanacetate

An efficient synthetic pathway to 2-oxo-1,2-dihydropyridine-fused 1,3-diaza heterocycles from heterocyclic ketene aminals,phathalic anhydride and ethyl cyanacetate was established.This protocol involved aza-ene reaction/imine-enamine tautomerization/enamine-ester exchange/ring-opening reaction sequence.     

Synthesis of pyrimidine derivatives by the reaction of ketene dithioacetals with amides

Reactions of methyl 2-cyano-3,3-bis(methylthio)acrylate ( 1a ) with carboxamides 2a-g in the presence of sodium hydride in a mixture of benzene and N,N-dimethylacetamide took place displacement with the methylthio group to give the corresponding methyl 3-N-acylamino-2-cyano-3-(methylthio)acrylates 3a-g which were readily converted to the corresponding pyrimidine derivatives at reflux in methanol in good yields. Reactions of 2-cyano-3,3-bis(methylthio)acrylonitrile ( 1b ) with the carboxamides 2a-f gave directly pyrimidine-5-carbonitrile derivatives 7a-f . Ketene dithioacetals 1a,b smoothly reacted with thioamide 2g or urea 2h,i to give the expected pyrimidine derivatives 9,10a,b . Polyfunctionalized pyrimidines, thus obtained, were also used for the synthesis of fused pyrimidine derivatives.