Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies

Abstract

The possibility to form new C-B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report experimental and computational data that allows the individuation of the structural requisites and of reaction conditions necessary to open alkyl aziridines using bis(pinacolate)diboron (B₂pin₂) in a regioselective nucleophilic addition reaction under copper catalysis.

Keywords: DFT study; aminoboronates; aziridines; copper catalysis; diboron reagents.

Scheme 1

State of the art (eq. (a–c)) and aim of the work (eq. (d)).

Scheme 2

Picolinoyl-protected aziridines 4–9c screened under optimized reaction conditions.

Scheme 3

Ring-opening reaction of aziridine 10 under copper-catalyzed borylative conditions.

Scheme 4

Preliminary mechanistic model applied to differently protected non-substituted aziridine (above) and to N-(2-picolinoyl)-methyl aziridine and aziridine 1c (below).

Figure 1

Comparative calculated reaction energy profile of N-mesyl-azirdine (blue) and N-(2-picolinoyl)-aziridine (black) using the mono-copper-boron borylation adduct (the ΔG values are in kJ/mol). See also Table 2 below.

Figure 2

Comparative calculated reaction energy profile between the first (blue) and the second model (black) using a dicopper-boron borylation adduct on the non-substituted aziridine (the ΔG values are in kJ/mol).

Figure 3

Reaction energy profile with the second model for the reaction of N-(2-picolinoyl)-methyl aziridine and 1c (the ΔG values are in kJ/mol).

Figure 4

Structure of intermediate I3a for compound 1c with highlighted the η⁶- coordination of the phenyl ring with the copper atom (orange).

Figure 5

Particular of the reaction energy profile comparison of the anti-Markovnikov pathway between 1c (without the Et₂O molecule; black) and N-2-picolinoyl-methyl aziridine (with the Et₂O molecule; blue). The ΔG values are in kJ/mol.