α-Methylene-β-trichloroacetylamino Alkanoates from Trichloroacetimidates of the Baylis-Hillman Adducts

Abstract

The Baylis-Hillman adducts 1 were treated with a large amount of CCl₃CN in the presence of DBU without solvent to give in good yield the corresponding trichloroacetimidates 5 which by thermal [3.3]sigmatropic rearrangement were converted into the corresponding (E)-2-trichloroacetylaminomethyl-2-propenoates 6, exclusively. On the contrary, when compounds 5 were treated with a catalytic amount of DABCO in dichloromethane, 2-methylene-3-trichloroacetylamino esters 7 were obtained in good yield. Both 5a and 7a underwent iodocyclization, to give a cyclic intermediate precursor of a polyfunctionalized sequence, and the differences in stereoselectivity were in agreement with computational results.

Key words

amino acids - amides - rearrangement - cyclization - stereoselectivity

References

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• 10b

  Spectral data for the adduct A: ¹H NMR (CDCl₃, 200 MHz): δ = 1.42-1.76 (m, 6 H), 1.78-1.92 (m, 2 H), 2.56-2.71 (m, 2 H), 3.15-3.39 (m, 6 H). ¹³C NMR (CDCl₃, 50 MHz): δ = 19.5, 24.0, 26.8, 28.9, 32.0, 37.8, 48.7, 54.4, 77.2, 166.1.

• 11a

  The reactivity of the Baylis-Hillman adducts agrees with the relative acidity of the hydroxy functionality obtained from calculations. All the geometries were optimized at DFT level of theory. Ab initio DFT calculations were carried out using the GAUSSIAN 98 program package. For DFT calculations the hybrid functional B3LYP, which contains gradient corrections for both exchange and correlation was chosen. The molecular electrostatic potential and the frontier molecular orbital were calculated for all the compounds showing no remarkable differences. The stability of both the reactants and the conjugate bases was calculated referring to the isodesmic reactions and the correlated pK_a values and the geometry of both reactants and products were fully optimized at B3LYP/6-31G* theory level: 1c, ΔE 14.08 kcal/mol; 1d, ΔE 13.51 kcal/mol; 1b, ΔE 5.09 kcal/mol; 1e, ΔE 4.59 kcal/mol; 1a, ΔE 0.0 kcal/mol; 1g, ΔE -3.98 kcal/mol; 1i, ΔE -5.46 kcal/mol; 1h, ΔE -5.76 kcal/mol; 1k, ΔE -5.51 kcal/mol; 1j, ΔE -5.71 kcal/mol. For leading references, see:

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12

It is worth mentioning that molecular mechanics calculations carried out for all compounds 5 indicate the presence of a number of conformers within a short energy range. Rotameric mixtures are evidenced by the ¹H NMR spectra of the ethyl derivatives 5b,d,f,k, where a multiplet or a double quartet collapsing at 50 °C into a quartet takes place for the ethyl quartet.