Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

A versatile nitro-Mannich/lactamisation cascade for the direct stereoselective synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles has been developed. A highly enantioenriched substituted 5-nitropiperidin-2-one was synthesised in a four component one-pot reaction combining an enantioselective organocatalytic Michael addition with the diastereoselective nitro-Mannich/lactamisation cascade. Protodenitration and chemoselective reductive manipulation of the heterocycles was used to install contiguous and fully substituted stereocentres in the synthesis of substituted piperidines.


General experimental
All reactions were performed under an atmosphere of dry nitrogen unless otherwise stated. All glass apparatus were oven dried and cooled under vacuum before use.

Solvents and reagents
Bulk solutions were evaporated under reduced pressure by using a Büchi rotary evaporator. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl radical. Dichloromethane and toluene were distilled from calcium hydride prior to use. Petroleum ether refers to the distilled light petroleum of fraction (40-65 °C). Reagents used were obtained from commercial suppliers and used without purification

Chromatography
Column chromatography was carried out by using Merck Kieselgel 60 silica gel (230-400 mesh). All reactions were followed by thin-layer chromatography (TLC) where practical, with Merck Kieselgel 60 F 254 (230-400 mesh) fluorescent treated silica, which were visualised under UV light (250 nm) or by staining with aqueous acidic ammonium molybdate or aqueous basic potassium permanganate solutions, as appropriate.

Spectroscopy
All 1 H and 13 C NMR spectra were recorded on a Bruker 500, 400 MHz or Varian 300 MHz spectrometer and are quoted in ppm for measurements against a TMS internal standard. Unless otherwise stated all experiments were carried out in d-chloroform as solvent. Chemical shifts () are given in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). The 1 H NMR spectra are reported as follows: σ/ppm (multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sxt = sextet, m = multiplet, bs = broad singlet, "d" = apparent doublet, "dd" = apparent doublet of doublet, "dt" = apparent doublet of triplet), number of protons, coupling constants J/Hz (where appropriate) and assignment). DEPT 135 and two-dimensional (COSY, HMQC, HMBC) NMR spectroscopy were used where appropriate to assist the assignment of signals in the 1 H and 13 C NMR spectra. n.O.e experiments were used to determine the relative configuration. Low-resolution mass spectrometry (EI, CI) was recorded on a Fissions VG Trio 2000 quadrupole mass spectrometer. High-resolution mass spectra (accurate mass) were recorded on a Thermo Finnigan Mat 95XP mass spectrometer. Infrared spectra were recorded on an ATI Mattson: Genesis Series FTIR spectrometer from a thin film deposited onto a sodium chloride plate. Only selected maximum absorbances (v max ) are reported. Optical rotations were recorded by using an Optical Activity AA-1000 polarimeter; [α] D values are reported in 10 −1 deg cm 2 g −1 ; concentration (c) is given in g/100 mL at 589 nm. were refined with SHELXL [3]; all nonhydrogen atoms were refined with anisotropic displacement parameters and hydrogen atoms were positioned geometrically. Compounds 6e and 11c were refined with the CRYSTALS suite [5].

General procedure A for Michael addition of nucleophiles 7 to nitroolefin 8
A solution of nitroolefin 8, nucleophile 7 and DABCO in THF was stirred at RT until TLC analysis showed that all starting material had been consumed. The mixture was then concentrated in vacuo and the crude product was purified by flash column chromatography to yield the title compound 6.

Synthesis and characterization of 6e
According to the general procedure A (for 32.3 mmol, 4.500 g of 8b used 42.1 mmol, 6.609 g of 7a; 9.7 mmol, 1.088 g of DABCO and 45 mL of THF; 72 h; the reaction was performed with exclusion of light). 6e (

General procedures B for nitro-Mannich / lactamisation cascade
Michael adduct 6 (0.49 mmol) was placed in a suitable solvent (MeOH or water, 3.5 mL, c = 0.14 M) at rt. To the mixture was added amine 4 (2 equiv, 0.98 mmol) and aldehyde 3 (2 equiv, 0.98 mmol), and the mixture was heated under reflux in MeOH (at 70 °C in water) until the starting material had been consumed by TLC analysis. The mixture was then concentrated in vacuo and subjected to flash column chromatography.

Synthesis and characterization of 1c
According to the general procedure B (for 1.70 mmol, 0.500 g of 6c used 2.20 mmol, 165 μL, of allylamine (4a)

General procedure C for the nitro-group removal
A lactam 1 or 2 was suspended in toluene (c = 0.05 M) under an atmosphere of N 2 . Bu 3 SnH (5 equiv) and AIBN (0.2 equiv) were added, the mixture was degassed and filled with N 2 . This operation was repeated three times. The mixture was stirred under reflux until all of the starting material had been consumed (TLC monitoring, typically 3-7 hours). The mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography to yield spirocycle 10.

Synthesis and characterization of 10b
According to general procedure C (for 4.90 mmol, 1.900 g of 1j used 0.98 mmol, 0.160 g of AIBN; 24.50 mmol, 6.59 mL of Bu 3 SnH and 98 mL of toluene; under reflux; 6h) 10b (

General procedure D for the chemoselective reduction of 10
LiAlH 4 (3 equiv, 1 M solution in THF) was added dropwise to a solution of 10 in toluene (c = 0.05 M) at -78 ºC. The mixture was warmed to -20 ºC and stirred for 1 h. The mixture was cooled to -78 ºC, formic acid (71 equiv) was added dropwise with care and the mixture was warmed to rt with stirring. After 24 h Rochelle salt (20% solution in water, 20 mL per 1 mmol of 10) was added, the pH was adjusted to 10 over 10 min by addition of solid K 2 CO 3 until two clear phases appeared. Et 2 O was added (10 mL per mmol of 10), the emulsion was extracted, the organic phase was separated and the water phase was further extracted (2 × 10 mL of CH 2 Cl 2 per mmol of 10). The combined organics were dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by column chromatography (Et 2 O → Et 2 O/MeOH 90:10) to afford 11.