Sergey V. Ryabukhin

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.

Toward lead-oriented synthesis: one-pot version of Castagnoli condensation with nonactivated alicyclic anhydrides.

One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues. Utility of the method to multigram preparation of building blocks and synthetic intermediates was also demonstrated. The final products are obtained in high yields and diastereoselectivity. The method fits well in the concept of lead-oriented synthesis; in particular, it can be used for the design of lead-like compound libraries, even if the strictest cut-offs are applied to the physicochemical properties of their members.

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.

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.

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.

Application of chlorotrimethylsilane in Pictet–Spengler reaction

Chlorotrimethylsilane has been found to be an efficient condensing agent in the Pictet–Spengler reaction, affording an extremely straightforward synthetic route to tetrahydro-β-carboline derivatives and their analogs. The applicability of the method has been studied, and a representative library of structurally diverse products has been created.Graphical Abstract.

Beyond the Five and Six: Evaluation of Seven-Membered Cyclic Anhydrides in the Castagnoli-Cushman Reaction.

The Castagnoli-Cushman reaction with benzo[d]oxepine-2,4(1H,5H)-dione as an anhydride component allowed for preparation of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acids in 21-75% yields and with good trans diastereoselectivity. The method worked with imines generated from aromatic or α-branched aliphatic aldehydes and is amenable for both parallel synthesis and scale-up. The procedure for epimerization of the resulting trans-disubstituted tetrahydrobenzo[d]azepines to their cis isomers was also developed.

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold

An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid—a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C1-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.