Highly diastereoselective four-component synthesis of polysubstituted 2-piperidinones with three and four stereogenic centers

Iliyasov²,

et al. 2022

Arkivoc

Self Cite

A novel five-component stereoselective synthesis of polysubstituted tetrahydropyridines is reported. The Knoevenagel condensation -Michael addition -Mannich reaction -cyclization -dehydration cascade of aldehydes, esters of 3-oxocarboxylic acids C-H acids and ammonium acetate provides convenient access to 2substituted alkyl (4SR,6RS)-4,6-diaryl-5,5-dicyano-1,4,5,6-tetrahydropyridi-ne-3-carboxylates with two stereocenters and 3,5-dialkyl (4RS, 5SR,6RS)-5-cyano-2,4,6-triaryl-1,4,5,6-tetrahydropyri-dine-5,3-carboxylates with three stereocenters in 57-84% yields. It was established that formation of products proceeds via substituted 2-hydroxypiperidines with four stereocenters. Ammonium acetate plays a dual role, acting as a base and as a nitrogen source. Five bonds are formed as a result of multicomponent process. Structures of new compounds were confirmed by 1 H, 13 C NMR, IR, and mass spectral studies. The formation of single diastereomers was confirmed by singe crystal X-ray diffraction studies and 2D-NMR spectroscopy.

Section: Resultsmentioning

confidence: 99%

“…25 At present, this reaction is known as the Robinson-Schöpf reaction. Recently, a multicomponent synthesis of substituted piperidines was carried out applying ammonium acetate [26][27][28][29][30][31][32] , water ammonia [33][34][35] or amines 36,37 as a source of nitrogen.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective one-pot five-component synthesis of polysubstituted 1,4,5,6-tetrahydropyridines with two and three stereocenters

Iliyasov²,

et al. 2022

Arkivoc

Self Cite

“…We have carried out the multicomponent synthesis of substituted piperidines [ 41 , 42 , 43 , 44 , 45 ]. Ammonium acetate or aqueous ammonia were the nitrogen sources for piperidine cycles.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism

Iliyasov²,

et al. 2022

Molecules

Self Cite

The multicomponent reaction of aldehydes, cyano-containing C-H acids, esters of 3-oxocarboxylic acid and ammonium acetate led to unexpected results. The boiling of starting materials in methanol for one to two hours resulted in the formation of polysubstituted 1,4,5,6-tetrahydropyridines with two or three stereogenic centers. During the 2020 lockdown, we obtained key intermediates of this six-step domino reaction. A number of fast and slow reactions occurred during the prolonged stirring of the reaction mass at rt. Sequence: 1. Knoevenagel condensation; 2. Michael addition; 3. Mannich reaction; 4. cyclization—fast reactions and cyclization of the product polysubstituted 2-hydroxypiperidine—was isolated after 40 min stirring at rt. Further monitoring proved the slow dehydration of 2-hydroxypiperidine to obtain 3,4,5,6-tetrahydropyridine after 7 days. Then, four-month isomerization occurred with 1,4,5,6-tetrahydropyridine formation. All reactions were stereoselective. Key intermediates and products structures were verified by X-ray diffraction analysis. Additionally, we specified conditions for the selective intermediates’ preparation.

“…[34][35][36][37][38] Recently, we have carried out a multicomponent synthesis of substituted piperidines. [39][40][41][42][43] Ammonium acetate or aqueous ammonia were the nitrogen sources for piperidine cycle. This method was used in the synthesis of polysubstituted 2-hydroxy-2-trifluoromethylpiperidines 5-spyro connected with cycle or heterocycle (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

One-pot highly diastereoselective five-component synthesis of polysubstituted 2-hydroxy-2-trifluoromethylpiperidines with four and five stereogenic centers

Iliyasov²,

et al. 2022

Arkivoc

The Knoevenagel-Michael-Mannich-cyclization cascade of aldehydes, cyano-containing C-H acids, ethyl 4,4,4trifluoro-3-oxobutanoate and ammonium acetate provided convenient stereoselective formation of ethyl 5,5dicyano-4,6-diaryl-2-hydroxy-2-(trifluoromethyl)pi-peridine-3-carboxylates with four stereogenic centers and dialkyl 4,6-diaryl-5-cyano-2-hydroxy-2-(trifluoromethyl)piperidine-3,5-dicarboxylates with five stereogenic centers. The stereoselective formation of individual diastereomers was shown. The configuration of diastereomers was confirmed by NMR spectra and X-ray diffraction analysis. Ammonium acetate played dual role, acting as a base and as a nitrogen source.