A versatile catalyst system for enantioselective synthesis of 2-substituted 1,4-benzodioxanes

Abstract

We report the synthesis of enantiomerically enriched 1,4-benzodioxanes containing alkyl, aryl, heteroaryl, and/or carbonyl substituents at the 2-position. The starting 1,4-benzodioxines were readily synthesized via ring closing metathesis using an efficient nitro-Grela catalyst at ppm levels. Excellent enantioselectivities of up to 99:1 er were obtained by using the versatile catalyst system [Ir(cod)Cl]₂/BIDIME-dimer in the asymmetric hydrogenation of 2-substituted 1,4-benzodioxines. Furthermore, DFT calculations reveal that the selectivity of the process is controlled by the protonation step; and coordinating groups on the substrate may alter the interaction with the catalyst, resulting in a change in the facial selectivity.

Fig. 1. Examples of chiral 1,4-benzodioxane containing molecules.

Scheme 1. Synthesis of 1,4-benzodioxines.

Scheme 2. Asymmetric hydrogenation of 2-alkyl and 2-aryl-substituted 1,4-benzodioxines^a. ^aReaction conditions: 5 (0.2 mmol), [Ire(cod)Cl]₂ (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol, 40 equiv.), H₂ (600 psi), 50 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC. ^b5f (5.0 mmol, 1.14 g), [Ir(cod)Cl]₂ (0.005 mmol), L5 (0.015 mmol), THF (6 mL), MeOH (6 mL), AcOH (150 mmol, 30 equiv.), H₂ (600 psi), 70 °C for 24 h. ^c25 °C.

Scheme 3. Scope of Ir-catalyzed asymmetric hydrogenation of 2-heterocycle-substituted 1,4-benzodioxines^a. ^aUnless noted, standard reaction conditions: substrate 5 (0.2 mmol), [Ir(cod)Cl]₂ (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol), H₂ (600 psi), 50 or 70 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC. ^b50 °C. ^c70 °C. ^d[Ir(cod)Cl]₂ (2 mol%), BIDIME-dimer L5 (6 mol%).

Scheme 4. Scope of Ir-catalyzed asymmetric hydrogenation of 1,4-benzodioxines^a. ^a Reaction conditions: 5 (0.2 moll), [Ir(cod)Cl]₂ (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol), H₂ (600 psi), 50 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC.

Fig. 2. Proposed hydrogenation mechanism. See ESI for the computational analysis of the active catalyst formation. Computational study performed for R = Me and R = CO₂Me.

Fig. 3. Possible solvation equilibrium and proposed protonation transition states for coordinating and non-coordinating substrates.

Fig. 4. Energetics of the mode A protonation of the Me-substituted benzodioxine. Selectivity-determining conformations are shown. Free energy and enthalpy (in brackets) gaps are calculated using PBE-D2/6-311+G(d,p), Ir:LANL2DZ(f), IEFPCM-MeOH//PBE/6-31G(d), Ir:LANL2DZ. Values are in kcal mol^–1. Ligand L3 was used for the calculation to minimize conformational isomers; the experimental value was taken from 6h.

Fig. 5. Energetics of the mode B protonation of the CO₂Me-substituted benzodioxine. Selectivity-determining conformations are shown. Free energy and enthalpy (in brackets) gaps are calculated using PBE-D2/6-311+G(d,p), Ir:LANL2DZ(f), IEFPCM-MeOH//PBE/6-31G(d), Ir:LANL2DZ. Values are in kcal mol^–1. Ligand L3 was used for the calculation to minimize conformational isomers; the experimental value was taken from 6z.

Fig. 6. Stereochemical models for mode A and mode B protonations. Substrate approaches for face A and face B attacks are shown in blue and red respectively.

Fig. 7. Model of lowest energy mode B protonation for the 2-methoxycarbonyl-1,4-benzodioxine showing electronic stabilizing interactions (π–π and sp²CH–π interactions).