A Catalytic Three-Component Aminofluorination of Unactivated Alkenes with Electron-Rich Amino Sources

Abstract

We present herein a copper-catalyzed three-component aminofluorination of unactivated alkenes with N-bromodialkylamines and readily available nucleophilic fluoride under the assistance of a bidentate auxiliary. This protocol exhibits excellent functional group tolerance toward a wide range of unactivated alkenes and N-bromodialkylamines to furnish the corresponding β-fluoroalkylamines in a highly regio- and diastereoselective manner. The appropriate choice of nucleophilic fluoro source is essential to make this reaction a reality. Further DFT calculations show that the exothermic ion exchange between external fluoride ion and Cu(II) intermediate provides additional driving force to the irreversible migratory insertion, which offsets the unfavorable reaction energetics associated with the subsequent C(sp³)-F reductive elimination. This finding offers a new avenue to catalytic intermolecular aminofluorination of unactivated alkenes with electron-rich amino sources via a remarkable reductive elimination of Cu(III) species to forge the C(sp³)-F bonds.

Keywords: C–F reductive elimination; aminofluorination; copper(III); unactivated alkenes; β‐fluoroamine.

Figure 1

The intermolecular aminofluorination of alkenes.

Figure 2

The design and preliminary evaluation of the intermolecular aminofluorination of unactivated alkenes with electron‐rich amino sources.

Scheme 1

Screening of nucleophilic fluoro sources. Standard conditions: 1a (0.40 mmol) dissolved in EtOH (2.0 mL) was added by syringe pump into the mixture of 2a (0.20 mmol) and nucleophilic fluorides (0.50 mmol) in EtOH (3.0 mL) in the presence of CuI (0.06 mmol) at 70 °C.

Figure 3

Substrate scope of unactivated alkenes. Standard conditions: 1a (0.40 mmol) dissolved in EtOH (2.0 mL) was added by syringe pump into the mixture of 2 (0.20 mmol) and TMAF (0.50 mmol) in EtOH (3.0 mL) in the presence of CuI (0.06 mmol) at 70 °C. Isolated yields. a) 1a (0.60 mmol) dissolved in MeOH (1.0 mL) was added into the reaction mixture in MeOH (1.0 mL). b) IPrCuCl (0.06 mmol) was used. c) CuTC (0.06 mmol) was used. d) 1a′ (0.60 mmol) dissolved in MeOH (1.0 mL) was added by syringe pump into the mixture of 2 (0.20 mmol), ethyl isocyanoacetate (0.06 mmol) and TMAF (0.50 mmol) in MeOH (1.0 mL) with Cu(OTf)₂ (0.06 mmol) at 70 °C.

Figure 4

Substrate scope of N‐bromodialkylamines. Standard conditions: 1 (0.40 mmol) dissolved in EtOH (2.0 mL) was added by syringe pump into the mixture of 2a (0.20 mmol) and TMAF (0.50 mmol) in EtOH (3.0 mL) in the presence of CuI (0.06 mmol) at 70 °C. Isolated yields. a) 1 dissolved in DCM (2.0 mL) was added into the reaction mixture.

Scheme 2

Synthetic utility. Conditions: a) BF₃⋅Et₂O (6.0 eq), EtOH, 100 °C, 15 h; b) (1) (Boc)₂O (2.0 eq), DMAP (0.2 eq), MeCN, 60 °C, 2 h; (2) NaBH₄ (3.0 eq), MeOH (3.0 eq), THF, 0 °C, 2 h; c) LiAlH₄ (3.0 eq), THF, 0°C, 2 h; d) DBU (2.0 eq), MeCN, 0°C, 1 h

Scheme 3

Control experiments.

Figure 5

Gibbs energy profiles (ΔG°_343.15) with and without nucleophilic fluoride TMAF calculated at the SMD(ethanol)/(U)M06/[6‐311++G(d,p)/SDD(Cu,I)]//SMD(ethanol)/(U)M06/[6‐31G(d)/LanL2DZ (Cu,I)] level. Spin densities are given in grey italic font.

Figure 6

Gibbs energy (ΔG°_343.15) of ion exchange between nucleophilic fluoro sources and Cu(II) bromide M5 calculated at the SMD(ethanol)/(U)M06/[6‐311++G(d,p)/SDD(Cu,I,Ag,Cs)]//(U)M06/[6‐31G(d)/LanL2DZ (Cu,I,Ag,Cs)] level.