Approach to the library of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-component condensation.

A convenient procedure for the parallel synthesis of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-component condensation of active methylene compounds, aldehydes, and amines was developed. It was shown that the use of acetic acid as the reaction medium was suitable for the considerably reactive substrates with no additional functionalities. The substrates with low reactivity and those possessing carboxylic groups or additional basic centers required the use of DMF as the solvent and chlorotrimethylsilane as the reaction promoter was necessary. More than 3000 pyrrolones were synthesized by the developed procedure. To demonstrate the scope of the described approach 114 library representatives were fully characterized.

Combinatorial synthesis of chemical building blocks 1. Azomethines.

128 Azomethines were synthesized through condensation of carbonyl compounds with various amines in pyridine in the presence of Me(3)SiCl as promoter and water scavenger in 58-98 % yield. Et(3)N was added to reaction mixtures before precipitating the product with H(2)O to prevent acid catalyzed hydrolysis of the C=N bond. The scope and limitation of the method are discussed. High yields and simple setup/workup procedure make this method suitable for the combinatorial synthesis of azomethines, which are suitable as starting materials for high throughput synthesis of various combinatorial libraries. The azomethines synthesized were used as starting materials in a one-pot combinatorial synthesis of amines and amides.

High throughput synthesis of extended pyrazolo[3,4-d]dihydropyrimidines.

Thirteen 5-hetarylaminopyrazoles were synthesized in 62-93% yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles with electrophilic hetarylhalides under optimized conditions. Condensation of 5-hetarylaminopyrazoles with carbonyl compounds facilitated by AcOH or Me(3)SiCl furnished 23 pyrazolo[3,4-d]dihydropyrimidines in 69-86% yield. The target compounds were isolated through simple crystallization. The scope and limitation of the method are discussed.

3-haloquinolines by Friedländer reaction of α-haloketones.

A general approach to 3-fluoro-, 3-chloro-, and 3-bromoquinolines which relies on organosilane-promoted Friedländer reaction of α-haloketones is described. The scope of the methylene component as well as influence of the organosilane component on the outcome of the reaction is studied. The method can be used under parallel synthesis conditions.

Aminoheterocycles as synthons for combinatorial Biginelli reactions.

Chlorotrimethylsilane (TMSCl) has been utilized as an efficient promoter and water scavenger in the synthesis of diverse dihydropyrimidines via Biginelli type MCR-heterocyclization using aminoheterocycles. High yields and a simple workup of target compounds enable the facile generation of combinatorial libraries comprising more than 2,000 compounds of high structural and functional diversity. A representative set of 89 compounds is described.

Approach to the library of fused pyridine-4-carboxylic acids by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles.

A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.

Dry HCl in parallel synthesis of fused pyrimidin-4-ones.

The parallel solution-phase synthesis of substituted thieno[2,3- d]pyrimidin-6-carboxylic acids has been accomplished. This strategy relies on a cyclization of 2-aminothiophen-3,5-dicarboxylates with a set of nitriles, followed by hydrolysis to construct the library of corresponding acids. The convenient procedure for use and dosage of dry HCl for the reaction was elaborated and adapted for semiautomated solution-phase parallel synthesis. With the use of another (hetero)aromatic ortho-aminocarboxylate, mini-libraries of diverse fused pyrimidin-4-ones were synthesized. The scope and limitations of the approach are discussed.

Synthesis of quinolines from 3-formylchromone.

A facile and versatile procedure for the synthesis of 3-(2-hydroxybenzoyl)quinolines and 7H-chromeno[3,2-c]quinolin-7-ones was elaborated on the basis of TMSCl-mediated recyclization of 3-formylchromone with various anilines. Limitations and scope of this methodology were established, and a possible mechanism for the heterocyclizations was proposed.

A one-step fusion of 1,3-thiazine and pyrimidine cycles.

The chlorotrimethylsilane-promoted Biginelli type reactions of aldehydes, thiourea, and cyanoketones led to a diverse set of tetrahydropyrimidine-2(1H)-thiones. Under similar conditions, thioureas, benzaldehyde, and cyanoacetamide reacted to give first representatives of hexahydro-5H-pyrimido[5,4-e][1,3]thiazin-5-ones in high preparative yield.

Combinatorial Knoevenagel reactions.

Chlorotrimethylsilane (TMSCl) has been utilized as an efficient promoter and water scavenger in the Knoevenagel condensations of aromatic aldehydes with various methylene active compounds. High yields and a simple workup of target compounds enables the facile generation of combinatorial libraries comprising 11,000 compounds of high structural and functional diversity.

One-pot synthesis of 2,3-dihydro-1H-benzimidazoles.

A convenient one-pot method for the synthesis of 2,3-dihydro-1H-benzimidazoles has been elaborated. A set of 2,3-dihydro-1H-benzimidazoles was prepared from various ortho-dialkylaminoanilines and aldehydes using Me3SiCl as a condensation agent and pyridine as a basic medium.