Abstract
Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.
Highlights
Studies culminated with the discovery of hydrogen bonding phase-transfer catalysis (HB-PTC),[11] a new activation mode for PTC12 whereby a neutral hydrogen bond donor urea catalyst acts as a transport agent to bring solid cesium fluoride, CsF(s),[13] into solution in the form of a hydrogen bonded fluoride complex
Encouraged by initial calculations indicating that the energy required to solubilize KF(s) in dichloromethane is significantly reduced in the presence of bis-urea U*, we envisioned that asymmetric HB-PTC may be suitable for enantioselective fluorination with this more demanding fluoride source.[13]
Communication were selected as substrates for this study because desymmetrization with KF affords high value enantioenriched β-fluoroamines that are of considerable interest for applications in medicinal chemistry, especially for central nervous system drug discovery,[15,16] and catalyst design.[17]
Summary
Communication were selected as substrates for this study because desymmetrization with KF affords high value enantioenriched β-fluoroamines that are of considerable interest for applications in medicinal chemistry, especially for central nervous system drug discovery,[15,16] and catalyst design.[17]. Various N-heterocycles were tolerated including motifs frequently encountered in FDA approved drugs (e.g., piperidine, piperazine, pyrrolidine, morpholine);[23] this was demonstrated with the synthesis of β-fluoroamines 2c−i that were obtained in good yields and high enantioselectivities (up to 94% yield and 96:4 e.r.) Within this series, asymmetric HB-PTC gave access to fluorinated analogues of NMDA receptor antagonists 2e (MT-45)24a and 2g (diphenedine) in high enantioselectivity.24b−d The reaction is highly effective for substrates possessing two different N-. The reaction was investigated computationally by molecular dynamics (MD) simulations, and density functional theory (DFT) calculations (see SI for full details).[25] MD simulations in chloroform confirmed that N-alkylated catalyst(S)-3g forms a stable and persistent tridentate fluoride complex, with the alkylated urea in an anti-syn conformation.[26] MD was further used for conformational sampling for DFT calculations,[11,27] resulting in 15 DFT optimized transition structures (TSs) for ring-opening of diaryl-based aziridinium, leading to 2b. ASSOCIATED CONTENT between naphthyl ring and aziridinium Cα−H protons are present (Figure 2Bii).[28]
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