Sequential Deconjugative Electrophilic Fluorination/Cross-Metathesis: Toward the Synthesis of Fluoro Analogues of Biologically Active Compounds

Abstract

General Methods and Materials 2 General Procedure for α-fluoro-β,γ-unsaturated amides 2 Procedure for Dehydroxyfluorination of α-hydroxy-β,γ-unsaturated 2 Procedure for cross metathesis of allylic fluoride 2 Characterization of the Products 2-9 NMR Spectra of Products 10-Experimental Section General Methods and Materials All reactions were conducted under an argon atmosphere and oven flamed glassware was used. Methylene chloride was distilled over calcium hydride under a nitrogen atmosphere. All other solvents and commercially available reagents were used as received. Reactions were monitored by TLC performed using 0.25 mm E. Merck 5735 Kiegelsel silica gel coated aluminum plates (60F254) using UV radiation (254 nm) as visualizing agent and using solutions of p-anisaldehyde-sulfuric acid-acetic acid in EtOH or KMnO 4-K 2 CO 3 in water followed by heating as developing agent. Flash column chromatography was carried out under pressure on Merck silica gel 40-60 mesh. 1 H NMR and 13 C NMR spectra were recorded at 25 °C on a Brucker Avance 300 MHz (1 H), 282 MHz (19 F) and 75 MHz (13 C), and calibrated using solvent as internal standard (1 H: CDCl 3 7.26 ppm; 13 C CDCl 3 77.16 ppm). Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), or a combination of these. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer using a ZnSe plate (ATR). High resolution mass spectra (HRMS) were recorded on a Thermo Finnigan MAT95XP and accurate to ± 0.001. I-Procedure for Dehydroxyfluorination of α-hydroxy-β,γ-unsaturated amide. A solution of Deoxo-Fluor (1.5 mmol, 1.5 equiv., 50% in THF) was added to a solution of 1 (1 mmol, 1 equiv.) in CH 2 Cl 2 (4 mL) at-78 °C placed in a round-bottom flask. After addition the solution was mixed at-78 °C for 1 h and the progress of the reaction was monitored by T.L.C. The reaction was allowed to cool to r.t and was then worked up by adding saturated. aqueous NaHCO 3 solution. The product was extracted into CH 2 Cl 2 (3 x 10 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude was purified over silica gel to give the fluoroolefin 2. II-General Procedure for Deconjugative Electrophilic Fluoration of γ-Silyl Butenamides A solution of allyltrimethylsilane 3a-o (1 equiv.) and Selectfluor (1.5 equiv.) in Acetonitrile (0.2M) was heated to reflux under argon. After completion, reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude was purified over silica gel to give the products 4a-o. III-Procedure for Cross Metathesis of allylic fluoride. In a flask, allylic fluoride 4 (0.5 mmol, 1equiv.) was dissolved in dry CH 2 Cl 2 (5 ml). Then 1-hexadecene (0.75 mmol, 1.5 equiv.) and 2 nd generation Hoveyda-Grubbs catalyst (7 mol%) were added and the reaction mixture was stir...

Efficient and Direct Synthesis of γ‐Amino‐α,β‐Unsaturated Amides by Catalyzed Allylic Substitution of α‐Fluoroenamides: Toward to Synthesis of Hybrid Peptides and Indolizidines

“…One example reports the use of a platinum catalyst in an allylic substitution reaction with an amine of a non‐functionalized allyl fluoride . Recently, we have developed a rapid process for access to functionalized α‐fluoroenamides from γ‐silylenamides . Herein, we disclose an efficient strategy for the synthesis of a variety of γ‐amino‐α,β‐unsaturated amides from readily available α‐fluoroenamide precursors through an intermolecular conjugative catalytic amination process.…”

Fluoride-Catalyzed Cross-Coupling of Silylamides to CF3–Acrylates: Access to Highly Functionalized Trifluoromethylated and Quaternary Fluorinated Molecular Architectures

“…In this aspect, β-trifluoromethyl-α,β-unsaturated nitrones, ketones, and esters are readily available for various organic transformations for the creation of C–C bonds such as Michael additions (Scheme A), Diels–Alder reactions, Friedel–Crafts reactions, metal-mediated conjugate additions, and other transformations. Recently, from silylamide type A and a cationic fluorine F + source (Selectfluor), we synthesized allylfluoride amides type B , which proved to be very good allylic systems in catalytic allylic substitution processes using different metals (Rh, Ir, Pt) combined with hard or soft nucleophiles (Scheme B) . During this work, we showed that the amide function displays an important role through its metal coordination effect.…”