Intramolecular ring-opening from a CO2-derived nucleophile as the origin of selectivity for 5-substituted oxazolidinone from the (salen)Cr-catalyzed [aziridine + CO2] coupling

Abstract

The (salen)Cr-catalyzed [aziridine + CO₂] coupling to form oxazolidinone was found to exhibit excellent selectivity for the 5-substituted oxazolidinone product in the absence of any cocatalyst. Quantum mechanical calculations suggest that the preferential opening of the substituted C-N bond of the aziridine over the unsubstituted C-N bond is a key factor for this selectivity, a result that is supported by experiment with several phenyl-substituted aziridines. In the presence of external nucleophile such as dimethyl aminopyridine (DMAP), the reaction changes pathway and the ring-opening process is regulated by the steric demand of the nucleophile.

Fig. 1. A proposed catalytic cycle for the formation of 5- and 4-substituted oxazolidinones from the coupling of aziridine and CO₂ in the sole presence of the (salen)Cr^IIICl catalyst. The pathway indicated by the blue arrow produces the major product.

Fig. 2. The computed structures of N-propyl aziridine (left) and intermediate 3 (right) after aziridine attack on the electrophilic carbon of the [(salen)Cr^IIICl] ← OCO intermediate. The bond lengths are in Å.

Fig. 3. A comparison of the difference in ground-state energies between N-propyl-5-aryl- and N-propyl-4-aryl oxazolidinones with different p-substituents. Conformational geometries were optimized using DFT and the M06/cc-pVTZ(-f)//M06/LACVP** parameterization scheme.

Fig. 4. A plot of the differences in charge between C² and C³ of the coordinated aziridine in intermediate 3 against the Hammett σ_p⁺ values showing a strong correlation (R² = 0.94 for the best fit line), suggesting a significant influence of the p-substituent on the developing carbocationic charges on C². This trend agrees with the experimentally observed selectivity for reaction 1 in the absence of DMAP cocatalyst (see Fig. 9 below), where electron-donating substituents exhibit higher selectivity.

Fig. 5. The complete free-energy profile for the formation of the major 5-substituted oxazolidinone product from the (salen)Cr^IIICl-catalyzed [aziridine + CO₂] coupling in the absence of DMAP cocatalyst. All energy values have been solvation-corrected. The TS marked as * was not located computationally and is only shown for illustrative purposes.

Fig. 6. The 3-TS_major transition-state structure (right) for the formation of 5-substituted oxazolidinone, obtained through a synchronous and concerted pathway from intermediate 3 (left), where both C–N bond cleavage and C–O bond formation take place concomitantly. The “lengths” for both bonds (in Å) are indicated on the structure. For clarity, all of the hydrogens have been removed except for that on the C² carbon where C–O bond formation is taking place.

Fig. 7. The transition state structure 3-TS_minor (right) for the formation of 4-substituted oxazolidinone, obtained through an asynchronous, concerted pathway form the corresponding intermediate 3_rot (left). The “lengths” for the relevant C–N and C–O bonds (in Å) are indicated on the structure. For clarity, all hydrogens have been removed.

Fig. 8. Experimental selectivity for 5-substituted oxazolidinone over the 4-substituted isomer as observed by Hammett competition experiment between p-substituted N-propyl-2-arylaziridines and the parent N-propyl-2-phenylaziridine. The selectivity decreases as the aryl group becomes more electron-withdrawing.

Fig. 9. A Hammett correlation of reaction rates for the N-propyl-2-arylaziridine substrate (relative to the parent N-propyl-2-phenylaziridine) shown in reaction 2 against σ_p⁺ values. A linear decrease is observed as more electron-withdrawing substituents are placed on the 2-aryl group of the N-propyl-2-arylaziridine substrate. Relative reaction rate constants are obtained against the rate for N-propyl-2-phenyl aziridine.

Fig. 10. A plausible mechanism through which the erosion of selectivity in the presence of DMAP can be explained.

Fig. 11. The variation in rate for the coupling reaction between N-propyl-2-phenylaziridine and CO₂ catalyzed by (salen)Cr^IIICl in the presence of varying amounts of DMAP cocatalyst (eqn (3)). Reaction conditions: N-propyl-2-phenylaziridine (0.322 g, 2 mmol), (salen)Cr^IIICl catalyst (12.6 mg, 0.02 mmol), DMAP cocatalyst (varying amounts: 0.45 to 1.70 equiv. with respect to catalyst), 400 psig CO₂, CH₂Cl₂ (3.7 mL), rt, 24 h.

Fig. 12. Kinetic plots of the coupling reaction between N-propyl-2-phenylaziridine and CO₂ catalyzed by (salen)Cr^IIICl. General reaction conditions: N-ⁿpropyl-2-phenylaziridine (varying amounts, between 0.088 g and 0.228 g; 0.55 mmol to 1.42 mmol), catalyst (5.8 mg, 0.01 mmol), 400 psig CO₂, CH₂Cl₂ (1.8 mL), rt, 24 h. Top: in the absence of DMAP cocatalyst. Bottom: in the presence of 2 equiv. of DMAP cocatalyst (2.45 mg, 0.02 mmol).