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

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 2-substituted alkyl (4 SR ,6 RS )-4,6-diaryl-5,5-dicyano-1,4,5,6-tetrahydropyridi-ne-3-carboxylates


Introduction
A piperidine ring is a structural unit of a huge number of natural and synthetic biologically active compounds, many of which are widely used in medicine. About a third of all known alkaloids contain a piperidine ring in their structure. 1 Piperidine derivatives play a significant role in the discovery of drugs exhibiting various biological activities such as antihypertensive, 2 antimalarial, 3 neuroprotective, 4,5 antibacterial, 6 anticonvulsant 7 and antiinflammatory activity. 8 Also piperidine containing drugs are important therapeutic agents in the treatment of influenza, [9][10][11] diabetes, 12,13 viral infections including AIDS, 14,15 and cancer metastases. 16,17 Among pharmaceutical drugs, substituted 4-arylpiperidine and 4,6-diarylpiperidine derivatives, resembling a pharmacophore fragment of morphine, are of great importance. A number of valuable medicines with various physiological properties have been obtained on their basis, for example, analgesics, 18 neuroleptics, 19 antidepressants, 20 antiallergic drugs, 21 and many others.
At present, many strategies are known for constructing six-membered heterocycles with one nitrogen atom as the only hetero atom, and the overwhelming majority of them are a sequence of classical two-component reactions. This approach has a number of significant disadvantages. In a two-component paradigm, even relatively small and not too complex molecules often have to be synthesized using complex multistep synthesis, which leads to great labor costs and small overall yields, resulting in high cost of final products. This problem becomes especially pressing if several stereocenters are present in the target molecule, which must have a strictly defined configuration. Multicomponent synthesis has already become an instrument of classical organic synthesis. Multicomponent reactions are important processes, in which more than three different reactants directly get converted into one new structure bearing most of the atoms of these reactants. [22][23][24] The success of a multicomponent approach in assembling a piperidine ring was demonstrated as far back as in 1917 when a three-component assembly of tropinone, a key compound in the synthesis of atropine, was accomplished. Later, the synthesis of tropinone was improved. 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.
In continuation of our research on the multicomponent synthesis of alicyclic [38][39][40][41] and heterocyclic 42-48 derivatives from carbonyl compounds and C-H acids, we report the results of a novel one-pot five-component reaction between aromatic aldehydes, esters of 3-oxocarboxylic acid, nitriles and ammonium acetate for the direct highly stereoselective substituted 1,4,5,6-tetrahydropyridines formation.
In this conformation, bulky aryl substituents are located in sterically least hindered positions relative to each other.
The structure of 5o with three stereogenic centers was determined by means of NMR spectroscopy. The full NMR signal assignment has been carried out using 2D NMR techniques such as 1 H-1 H COSY, 1 H-13 C HSQC and 1 H-13 C HMBC (See supplementary materials). First of all, it was found signals of the tetrahydropyridine ring in 1 H and 13 C spectra. p-Hal-phenyl moieties are at the 2 nd , 4 th and 6 th positions and C 2 is substituted by p-Cl-phenyl fragment. All respective cross-peaks from H o /C # in the 1 H-13 C HMBC spectra are presented. Spatial arrangement of substitutions near C 5 was determined by analyzing 1 H-13 C spin coupling constant from the 13 C spectrum recorded with only ethyl CH2 proton decoupling. It was found carboxyl (d, J = 3.4 Hz) and nitrile (t, J = 8.3 Hz) carbon signal (Fig. 3). It can be concluded that nitrile group is in trans-position to the axial H 4 and H 6 while COOEt is in cis one due to JCOO-H is smaller than JCN-H. Carboxyl carbon has a spin coupling interaction only with H 4 . Thus, 5o has 4RS,5SR,6RS configuration.
To confirm the proposed mechanism, we monitored the reaction between 4-methylbenzaldehyde 1g, ethylcyanoacetate, methyl 3-(4-bromophenyl)-3-oxopropanoate 2f and ammonium acetate in methanol at room temperature. The starting compounds, symmetrical para-substituted in aromatic nuclei, were chosen for ease of identification of the reaction products by 1 H NMR spectroscopy. After 50 minutes of stirring, a thick white precipitate formed in the reaction mass. After filtration and drying, this compound (by high resolution mass spectrometry) was identified (by high resolution mass spectrometry) as C29H26BrN3O3, corresponding to methyl ester 5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4 -methyl)phenylpiperidine-3-carboxylic acid 6. In the recorded spectra of 1 H and 13 C 6, one set of signals was observed, which indicates the formation of one diastereomer.   The structure of 6 was confirmed by NMR spectroscopy methods including 2D NMR techniques such as 1 H-1 H COSY, 1 H-13 C HSQC, 1 H-13 C HMBC and 1 H-1 H NOESY ( Figure 4). The full assignment of NMR signals has been made (See supplementary materials). In the proton spectrum it was found signals from three para-substituted phenyls in aromatic region, two singlets from protons at heteroatoms (OH at 6.16 ppm and NH at 3.64 ppm), three signals from piperidine ring (δ5.05, 4.33 and 3.41 ppm) and three methyl signals (δ3.09, 2.33 and 2.28 ppm). Protons H4 and H3 are axial ones for the characteristic spin coupling constant (J = 12.3 Hz). Location of phenyl rings was determined by observing respective H o /C # and H # /C o cross-peaks. In addition, OH/C i (δH/C 6.16/143.9 ppm) cross-peak was found. The cross-peak from H 4 and H 6 (δH/H 5.05/4.33 ppm) in NOESY indicate that the protons are in the same half-space relatively piperidine ring. Thus, intermediate 2-hydroxypiperidine has the 2SR,3RS,4SR,6RS configuration.

Experimental Section
General. All melting points were measured with a Stuart SMP30 melting point apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded with a Bruker AM300 and Bruker DRX 500 at ambient temperature in DMSO-d6 or CDCl3 solutions. Chemical shift values are given in δ scale relative to Me4Si. The J values are given in hertz. Only discrete or characteristic signals for the 1H NMR are reported. IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets. HR-ESI-MS was measured on a Bruker microTOF II instrument; external or internal calibration was done with electrospray calibrant solution (Fluka). All starting materials were obtained from commercial sources and used without purification. All reactions were monitored with thin layer chromatography (TLC) and carried out with Merck precoated plates DC-AlufolienKieselgel60 F254. X-ray crystallographic analyses were performed with Bruker Quest D8 diffractometer.