Flexible protocol for the chemo- and regioselective building of pyrroles and pyrazoles by reactions of Danishefsky's dienes with 1,2-diaza-1,3-butadienes.

The versatility of the Mukaiyama-Michael-type addition/heterocyclization of Danishefsky's diene with 1,2-diaza-1,3-butadienes was applied to the synthesis of both 4 H-1-aminopyrroles and 4,5 H-pyrazoles. Thus, the same reagents furnished different types of highly functionalized azaheterocycles essentially depending on their structure: as a matter of fact, R1 = COOR or CONR 2 differently affects the acidity of the proton at the adjacent carbon. An unexpected formation of 5 H-1-aminopyrroles from the reactions carried out in water was also observed.

Straightforward access to pyrazines, piperazinones, and quinoxalines by reactions of 1,2-diaza-1,3-butadienes with 1,2-diamines under solution, solvent-free, or solid-phase conditions.

The preparation of tetrahydropyrazines, dihydropyrazines, pyrazines, piperazinones, and quinoxalines by 1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes bearing carboxylate, carboxamide, or phosphorylated groups at the terminal carbon and subsequent internal heterocyclization is described. The solvent-free reaction of carboxylated 1,2-diaza-1,3-butadienes with the same reagents affords piperazinones, while phosphorylated 1,2-diaza-1,3-butadienes yield phosphorylated pyrazines. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-diamines produces pyrazines.

Efficient synthesis and environmentally friendly reactions of PEG-supported 1,2-diaza-1,3-butadiene.

[reaction: see text] Here, we report the protocol for the preparation of new poly(ethylene glycol)-supported 1,2-diaza-1,3-butadiene. In addition, we discuss an application of this supported reagent in an efficient and environmentally friendly one-pot synthesis of 2-thiazol-4-one derivatives by reaction with thioamides.

Unexpected behavior of the reaction between 1,2-diaza-1,3-butadienes and 3-dimethylaminopropenoates: a useful entry to new pyrrolines, pyrroles, and oxazolines.

We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 degrees C, this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopyrrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino and ester groups. We discuss the plausible mechanisms of the ring closure and opening.

Solvent-free reaction of some 1,2-diaza-1,3-butadienes with phosphites: environmentally friendly access to new diazaphospholes and E-hydrazonophosphonates.

[structures: see text] The present article describes the reaction between 1,2-diaza-1,3-butadienes and trialkyl phosphites, under an atmosphere of nitrogen and under solvent-free conditions, to give alkyl 3,3-dialkoxy-2H-1,2,3lambda5-diazaphosphole-4-carboxylates that, in turn, are converted into corresponding E-hydrazonophosphonates by treatment with THF:water (95:5). These latter compounds are obtained directly by the reaction of 1,2-diaza-1,3-butadienes with trialkyl phosphites in the presence of air. These compounds are useful for the further preparation of dialkyl (5-methyl-3-oxo-2,3-dihydro-1H-4-pyrazolyl)phosphonates and 2-dialkoxyphosphoryl-1,2,3-thiadiazoles.

Access to new 2-oxofuro[2,3-b]pyrroles and 2-methylenepyrroles through the reaction of 1,2-diaza-1,3-butadienes and gamma-ketoesters.

New and interesting 2-oxofuro[2,3-b]pyrroles and 19-methyl-15-oxa-20-azatricyclo[12.3.3.0(1,14)]icos-18-en-18-carboxylates have been obtained in good yields by the one-pot reaction, in basic medium, of 1,2-diaza-1,3-butadienes with diethyl or dimethyl acetylsuccinate or methyl 2-(1,3-dioxo-2-cyclotetradecyl)acetate, respectively, under mild conditions. Treatment of the same starting materials with diethyl 2-acetylglutarate, in acidic medium, afforded unknown 2-methylenepyrrole derivatives in high yields. Novel 4-(3-oxopropyl)-2,5-dimethyl-1H-pyrrole-3-carboxylates also have been achieved by reacting 1,2-diaza-1,3-butadienes with ethyl or methyl 4-acetyl-5-oxo-hexanoate.

A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines.

Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human breast cancer cell lines. The I3C tetramer suppressed the growth of both estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a cytostatic mechanism. At the molecular level, the tetramer inhibited cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer.

Expeditious synthesis of new 1,2,3-thiadiazoles and 1,2,3-selenadiazoles from 1,2-diaza-1,3-butadienes via Hurd-Mori-type reactions.

Alpha-substituted hydrazones obtained from 1,2-diaza-1,3-butadienes and methylenic or methinic activated substrates gave rise to a wide range of cyclic compounds. In particular, in the presence of thionyl chloride as solvent-reagent, they were transformed into 1,2,3-thiadiazoles,(1) with selenium oxychloride in new 4-substituted 2,3-dihydro-1,2,3-selenadiazoles, while with selenium dioxide, they were transformed into 4-substituted 1,2,3-selenadiazoles. We have also examined the nucleophilic behavior of 1,2,3-thiadiazole 4a in the reaction with 1,2-diaza-1,3-butadienes that produced, under basic conditions, 4-hydrazono-1-(1,2,3-thiadiazolyl)pentane derivatives. This event represents an interesting example of stereoselective synthesis because it leads exclusively to the formation of the RR/SS racemic mixture. These latter compounds, treated with thionyl chloride, gave the corresponding 1,3-di-1,2,3-thiadiazolylpropane derivatives, while with sodium methoxide they afforded 1,2,3-thiadiazolyl-2-oxo-2,3-dihydro-1H-pyrrole systems.

Straightforward entry into 5-hydroxy-1-aminopyrrolines and the corresponding pyrroles from 1,2-diaza-1,3-butadienes.

The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5-unsubstituted-1-aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3-butadienes and aldehydes is presented. These domino reactions offer the advantage of executing multistep transformation without intermediate workup procedures. The stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic acid derivatives are also studied.