Asymmetric [4 + 2] annulation of 5H-thiazol-4-ones with a chiral dipeptide-based Brønsted base catalyst

We have developed a new family of dipeptide-based multifunctional Brønsted base organocatalysts capable of the asymmetric [4 + 2] annulation of 5H-thiazol-4-ones with electron-deficient alkenes.


General information General procedures and methods
Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Dried solvents and liquid reagents were transferred by oven-dried syringes or hypodermic syringe cooled to ambient temperature in a desiccator. Reactions mixtures were stirred in 4 mL sample vial with Teflon-coated magnetic stirring bars unless otherwise stated. Moisture in non-volatile reagents/compounds was removed in high vacuo by means of an oil pump and subsequent purging with nitrogen. Solvents were removed in vacuo under ~30 mmHg and heated with a water bath at 30-40 o C using rotary evaporator with aspirator. The condenser was cooled with running water at 0 o C.
All experiments were monitored by analytical thin layer chromatography (TLC). TLC was performed on pre-coated plates, 60 F 254 . After elution, plate was visualized under UV illumination at 254 nm for UV active material. Further visualization was achieved by staining KMnO 4 , ceric molybdate, or anisaldehyde solution. For those using the aqueous stains, the TLC plates were heated on a hot plate.
Columns for flash chromatography (FC) contained silica gel 200-300 mesh. Columns were packed as slurry of silica gel in petroleum ether and equilibrated solution using the appropriate solvent system. The elution was assisted by applying pressure of about 2 atm with an air pump.
Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet), quintet, m (multiplets), dd (doublet of doublets), dt (doublet of triplets), and br (broad). Coupling constants (J) were recorded in Hertz (Hz). The number of proton atoms (n) for a given resonance was indicated by nH. The number of carbon atoms (n) for a given resonance was indicated by nC. HRMS was reported in units of mass of charge ratio (m/z). Mass samples were dissolved in DCM and MeOH (HPLC Grade) unless otherwise stated. Optical rotations were recorded on a polarimeter with a sodium lamp of wavelength 589 nm and reported as follows;

Materials
All commercial reagents were purchased with the highest purity grade. They were used without further purification unless specified. All solvents used, mainly petroleum ether (PE) and ethyl acetate S4 (EtOAc), were distilled. Anhydrous CH 2 Cl 2, CHCl 3 and DCE were freshly distilled from CaH 2 and stored under N 2 atmosphere. THF, Et 2 O and toluene were freshly distilled from sodium/benzophenone before use. All compounds synthesized were stored in a −20 o C freezer and light-sensitive compounds were protected with aluminium foil.

Exploration towards reactions between 5H-oxazol-4-ones and alkenes
III (10 mol% The results indicated that the reactions of 5H-oxazol-4-one with a series of activated alkenes under the established reaction conditions only presented conjugate addition adducts, and the corresponding annulation adducts were not observed yet. The moderate yields for 4-oxo-4-arylbutenone and methyleneindolinone as the substrates are produced by the instability of 5H-oxazol-4-one in the reactions.

Computational methods
All quantum chemical calculations were carried out with Gaussian 09 1 . All ΔG values are reported relative to the individual free starting materials 1, 2 and catalyst III.

Optimization of minimum and transition state (TS) structures were first carried out with
Becke's three parameter 2 and Lee-Yang-Parr's 3 B3LYP density functional using Pople's 4 6-31G(d,p) basis set under the SMD 5 polarizable continuum solvent model (toluene parameters). It is important to note that Simón and Goodman 6 showed that B3LYP/ 6-31G(d) is herein termed MN12-SX/SMD. 8 The newer meta-hybrid non separable gradient MN12-SX functional was assessed to perform better in chemical energetics and thus preferred over M06-2X. 9 In conjunction with the MN12-SX/SMD, the Wiegend and Aldrich's def2-TZVPP triple zeta quality basis set was used. 10 Second order derivative or Hessian of the completed calculations were checked to verify transition state structures having only one negative eigenvalue and none for minimum.
Gibbs free energies in solution were calculated from the geometries, frequencies and improved energies using a thermocycle in which the gas-phase was treated using the standard textbook formulae for an ideal gas under the harmonic oscillator / rigid rotor approximation, and the Gibbs free energies of solvation (in toluene) were then calculated using the SMD continuum solvation model. Corrections were included to consider passage of 1 atm gas into 1M in solution, ΔG 1atm→1M as follows 11 : where dN is the number of moles of gas change from reactant to product and ln(RT/P) equals to 1.89 at 298 K. We have recently shown that this approach provides an excellent quantitative description of the temperature dependent behavior of solution-phase Diels-Alder reactions. 12 Electron density topological analyses based on the reduced density gradient was carried out with NCIplot 13 to qualify regions of non-covalent interactions especially hydrogen bonding