A parallel solution-phase synthesis of substituted 3,7-diazabicyclo[3.3.1]nonanes

The parallel solution-phase synthesis of a series of building blocks and combinatorial libraries based on natural bispidine scaffold has been accomplished. Key reactions include catalytic hydrogenation of the (-)-cytisine heterocyclic system, followed by alkali-mediated ring cleavage. Using this approach, a series of new bispidine core building blocks for combinatorial synthesis with three points of diversity were effectively synthesized. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation reactions. Obtained combinatorial libraries of 3,4,7-trisubstituted bispidines are potentially useful in the discovery of novel physiologically active compounds.     

A novel mesoionic ring system: unusual cyclization of thio- and amino-acid derivatives of 6-azauracil

Novel mesoionic heterocyclic structures 8 have been obtained via the internal cyclization of thio- and amino-acid derivatives of 6-azauracil 7b-d. These compounds undergo ring-opening reactions with amines to yield the respective 6-azauracil amides (9) in good yields under microwave irradiation.     

Denitrocyclization in synthesis of dibenzo[b,f][1,4]thiazepin‐11(10h)‐ones and their derivatives

A convenient synthesis of the novel dibenzo[b,f][1,4]thiazepin‐11(10H)‐ones is reported. As a key step, the synthetic route includes intramolecular aromatic denitrocyclization of 2‐(2,4‐dinitro‐phenylsulfanyl)‐benzoic acid amides. Efficient procedures for denitrocyclization in the presence of different bases are developed. Reduction of the nitro group in the obtained heterocycles resulted in formation of primary amines, which were transformed into amides by acylation with different carboxylic acids. The synthesized compounds have a great potential of bioactivity and are useful objects for biomedicinal screening.     

One-step assembly of carbamoyl-substituted heteroannelated [1,4]thiazepines

We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.     

Natural products as templates for bioactive compound libraries: part 2. Novel modifications of vasicine (peganine) core via efficient and regioselective generation of 3-lithiodeoxyvasicine and its stereoselective addition to aliphatic ketones section sign

A general procedure for direct lithiation of deoxyvasicine was developed. 3-Lithiodeoxyvasicine intermediate was found to react with various aliphatic ketones providing derivatives of 3-(hydroxyalkyl)deoxyvasicine in good yields. Similar reaction with 4-alkylcyclohexanones yielded respective trans-adducts exclusively. This novel protocol was successfully scaled-up to result in multigram quantities of vasicine-containing core building blocks suitable for production of compound libraries. The described synthetic methodology offers access to a wide range of compounds with potentially beneficial biological profiles.     

Liquid-phase synthesis of combinatorial libraries based on 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine scaffold

The parallel solution-phase synthesis of more than 2200 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine carboxamides on a 50-100-mg scale has been accomplished. Key reactions include assembly of the pyrazolo[1,5-a]pyrimidine ring by condensation of 5-aminopyrazole derivatives with the corresponding trifluoromethyl-beta-diketones. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation and reduction methodologies. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures (crystallization from the reaction mixtures) to give high-purity final products. The scope and limitations of the developed approach are discussed.     

Synthesis of substituted 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolines and 4-oxo-3,4-dihydroquinazoline-2-thioles

We have developed a liquid-phase synthesis of combinatorial libraries of new disubstituted 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolines and trisubstituted 4-oxo-3,4-dihydroquinazoline-2-thioles. The former were prepared using two general procedures: (i) cyclization of substituted methyl anthranilates with isothiocyanates, or (ii) cyclization of substituted 2-(methylcarboxy)benzeneisothiocyanates with primary amines or hydrazines. 4-Oxo-3,4-dihydroquinazoline-2-thioles were prepared by S-alkylation of disubstituted 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolines with alkyl or aryl halides. The hydrolysis of methyl benzimidazo[1,2-c]quinazoline-6(5H)-thione-3-carboxylate led to the corresponding acid. This acid was utilized in the synthesis of new benzimidazo[1,2-c]quinazoline-6(5H)-thione-3-carboxamide and S-substituted 6-mecaptobenzimidazo[1,2-c]quinazoline-3-carboxamide libraries.     

Synthesis of substituted thienopyrimidine-4-ones

The parallel solution-phase synthesis of more than 3000 substituted thienopyrimidin-4-ones has been accomplished. Key reactions include assembly of the 2-thioxopyrimidin-4-one ring by condensation of isomeric aminothiophenecarboxylates or their appropriate reactive derivatives (isothiocyanates or dithiocarbamates) with the corresponding isothiocyanates or amines. The libraries from libraries were then obtained in good yields and purities using solution-phase alkylation and acylation methodologies. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures (crystallization from the reaction mixtures) to give high-purity final products. The scope and limitations of the developed approach are discussed.     

New four-component Ugi-type reaction. Synthesis of heterocyclic structures containing a pyrrolo[1,2-a][1,4]diazepine fragment

[reaction: see text] We present a convenient synthesis of novel heterocyclic structures containing pyrrolo[1,2-a][1,4]diazepine fragment using a novel modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.