Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation

Abstract

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies.

Fig. 1. Background and stretchable ligands for asymmetric allenylation of pyrazolones.

a Selected examples of biologically active pyrazolones with a chiral center. b Asymmetric spirocyclization of pyrazolones with 2,3-allenyl acetates. c Stretchable chiral pocket for asymmetric allenylation. EWG electron-withdrawing group, TMS trimethylsilyl, LG leaving group.

Fig. 2. The selected data of optimization with some commercially available chiral ligands.

^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), Pd₂(dba)₃•CHCl₃ (2.5 mol%), and L1-4 (12 mol%) or L5-11 (6 mol%) unless otherwise noted. ^bThe yields of (S)-3aa and 4aa as well as the recovery of 1a were determined by the ¹H NMR analysis of the crude product using mesitylene as the internal standard and the ee of isolated (S)-3aa was determined by chiral HPLC. ^cThe reaction time was 4 h. ^dL11 (5 mol%) was used and the reaction time was 3 h. Cbz benzyloxycarbonyl, THF tetrahydrofuran, DMF N,N-dimethylformamide, n.d. not determined.

Fig. 3. Concept and synthesis of the ZYC-Phos ligands.

a The concept of ZYC-Phos ligands from the Feng’s ligands and the Trost ligands. b The synthesis of ZYC-Phos ligands. EDCI 1-ethyl-(3-dimethylaminipropyl)carbodiimide hydrochloride, NHS N-hydroxysuccinimde, DMSO dimethyl sulfoxide, DCM dichloromethane, DACH (1 R,2 R)-1,2-diaminocyclohexane, DADPE (1 R,2 R)-1,2-diphenyl-1,2-diaminoethane, DMAP 4-dimethylaminopyridine.

Fig. 4. ORTEP representation and sythetic applications.

a ORTEP representation of (S)-3ak. b The gram-scale reaction and applications: reaction conditions: (i) Pd₂(dba)₃•CHCl₃ (2.5 mol%), DACH-ZYC-Phos-C1 (5.0 mol%), toluene, 60 °C, 13 h; (ii) [Rh(CO)₂Cl]₂ (5.0 mol%), AgSbF₆ (12.5 mol%), CO balloon, toluene, 50 °C, 13 h; (iii) ortho-(propen-2-yl)phenol (3.0 equiv), Pd(OAc)₂ (7.5 mol%), 2,2’-bipy (7.5 mol%), Cu(OAc)₂•H₂O (0.5 equiv), toluene, 110 °C, 18 h; (iv) TiCl₄ (1.5 equiv), dichloromethane, −78 °C, 2.5 h, rt, 5.5 h. TMS trimethylsilyl, Cbz benzyloxycarbonyl, y. isolated yield.

Fig. 5. A proposal mechanism and some experiments for Pd-ligand complexes.

a A mechanism for the allenylation of pyrazolone. b Synthesis of Pd(II)-DACH-ZYC-Phos-C1 complex III. c ORTEP representations of Pd(II)-ligand complexes III and IV. H-atoms are omitted for clarity. d The reaction of pyrazolone 2a and allene 1a with complex III. Cbz benzyloxycarbonyl, DACH (1 R,2 R)-1,2-diaminocyclohexane.

Fig. 6. DFT calculations for DACH-ZYC-Phos-C1-ligated palladium catalyst.

DFT-optimized structures and relative energies of stereo-determining C−C bond formation transition states of the reaction of 1b with 2a catalyzed by the DACH-ZYC-Phos-C1-ligated palladium catalyst. Hydrogen-bonding interactions are shown as red dash lines; selected bond lengths (Å) and bond angles (°) are listed. BE bond energy.

Fig. 7. DFT calculations for the DACH-Phenyl-Trost-ligated palladium catalyst.

a DFT-optimized structures and relative energies of ee determining C−C bond formation transition states for the reaction of 1b with 2a catalyzed by the DACH-Phenyl-Trost-ligated palladium catalyst. Hydrogen-bonding interactions are shown as red dash lines; selected bond lengths (Å) are listed. b The reaction of 1b and 2a with DACH-Phenyl-Trost ligand. Cbz benzyloxycarbonyl, DACH (1 R,2 R)-1,2-diaminocyclohexane, y. NMR yield.