Diastereoselectivity of the Addition of Propargylic Magnesium Reagents to Fluorinated Aromatic Sulfinyl Imines

The addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines gave homopropargyl amines with total regio- and diastereoselection. Complete reversal of diastereoselectivity can be achieved in some cases using coordinating (THF) or noncoordinating (DCM) solvents. Substituted propargylic magnesium reagents have been also tested toward fluorinated aryl sulfinyl imines affording chiral homoallenyl amines with good yields and selectivity control. DFT calculations helped to rationalize the origin of the experimental regio- and diastereoselectivities observed in each case.

II. General procedure for the condensation of N-tert-butanesulfinyl aldimines 1. S3 III. General procedure for the diastereoselective propargylation of sulfinyl imines. S5 IV. General procedure for the propargylation reaction in DCM. S9 V. X-ray structure of compound 3b. S14 VI. X-ray structure of compound 3'b. S20 VII. Computational methods. S26 VIII. Natural bond orbital (NBO) analysis of charges of the different atoms in sulfinyl imines. S26 IX. Cartesian coordinates of optimized structures. S33 X. References. S47 XI. 1 H, 13 C and 19 F NMR spectra of new compounds. S48

III.b. General procedure for the propargylation reaction to sulfinamides 3' in DCM.
First, a 1 M solution of Grignard reagent in diethyl ether was prepared by adding magnesium turnings (214 mg, 11 mmol), mercury chloride (II) (19 mg, 1.7 mol%), two iodine balls and Et2O (5 mL, 1 M) to a sealed tube under a nitrogen atmosphere. This mixture was cooled to 0 °C and propargyl bromide was added slowly (0.56 mL, 5 mmol). The mixture was then stirred at 35 °C for 1.5 h. After this time, the mixture was cooled to room temperature, the stirring stopped, and the solution was used as a reagent in the next step without purification.
Next, for the asymmetric propargylation, a solution of the corresponding fluorinated imine 1 (1 mmol) in DCM (0.1 M) was cooled to -48 °C. The freshly prepared Grignard reagent (1.5 mmol) was slowly added, and the reaction mixture was stirred at this temperature until the reaction was complete (TLC analysis, typically 18-24 h). The reaction mixture was then quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, concentrated and the crude mixture was purified by flash column chromatography using deactivated silica gel (n-hexane:EtOAc).
First, a 1 M solution of Grignard reagent in diethyl ether was prepared by adding magnesium turnings (214 mg, 11 mmol), mercury chloride (II) (19 mg, 1.7 mol%), two iodine balls and Et2O (5 mL, 1 M) to a sealed tube under a nitrogen atmosphere. This mixture was cooled to 0 °C and the corresponding bromide was added slowly (0.56 mL, 5 mmol). The mixture was then heated an oil bath and stirred at 35 °C for 1.5 h. After this time, the mixture was cooled to room temperature, the stirring stopped, and the solution was used as a reagent in the next step without purification.
For the next asymmetric propargylation, a solution of the corresponding fluorinated imine 1 (1 mmol) in DCM (0.1 M) was cooled to -48 °C. The freshly prepared Grignard reagent (1.5 mmol) was slowly added, and the reaction mixture was stirred at this temperature until the reaction was complete (TLC analysis, typically 18-24 h). The reaction mixture was then quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined S10 organic phases were dried over anhydrous Na2SO4, concentrated and the crude mixture was purified by flash column chromatography using deactivated silica gel (n-hexane:EtOAc).
According to general procedure, from 76 mg (0.36 mmol) of 1f, compound 4fc was obtained as a colorless oil after column chromatography on silica gel using n-hexane:EtOAc

Experimental
Single crystals of C14H15F4NOS [CCDC 2067822] were obtained by slow evaporation method at room temperature using chloroform as solvent. A suitable crystal was selected and mounted on a SuperNova, Single source at offset, Atlas diffractometer. The crystal was kept at 150.00(10) K during data collection. Using Olex2, [2] the structure was solved with the ShelXS [3] structure solution program using Direct Methods and refined with the ShelXL [4] refinement package using Least Squares minimization. Displacement ellipsoids are drawn at the 50% probability level.

VI. X-ray structure of compound 3'b (Deposition Number 2067817). Experimental
Single crystals of C14H15F4NOS [CCDC 2067817] were obtained by vapour diffusion method using dichloromethane and n-hexane (1:1) and slow evaporation in glass vial. A suitable crystal was selected and mounted on a SuperNova, Single source at offset, Atlas diffractometer. The crystal was kept at 150.00(10) K during data collection. Using Olex2, [2] the structure was solved with the ShelXS [3] structure solution program using Direct Methods and refined with the ShelXL [4] refinement package using Least Squares minimization. Displacement ellipsoids are drawn at the 50% probability level.     All DFT geometry optimizations were performed with the dispersion-corrected B97D functional [5] and 6-311+G(2d,2p) basis set as implemented within the Gaussian 16 series of programs. [6] Solvent effects were included with the conductor-like polarizable continuum model (CPCM) [7] to mimic the solvent (CH2Cl2 or THF) during both geometry optimizations and vibrational analysis. All energies presented for the reactant complex (RC), transition state (TS), and product (P) are given in Hartree. All energies have been corrected with zero-point energies (ZPE). Vibrational frequency calculations were performed at the same level of theory used for optimization. All transition states were verified to have only one negative eigenvalue in the Hessian matrix, describing the motion along the reaction coordinate. In addition, intrinsic reaction coordinate (IRC) [8] calculations were performed at the wB97D/6-311+G(2d,2p) level to verify the expected connections of the first-order saddle points with the local minima Found on the potential energy surface. Natural bond orbital (NBO) [9] analysis of charges was performed at TPSS-D3/def2-TZVPP level of theory. [10,11] Optimized structures were illustrated using CYLview20.3. [12] VIII. Natural bond orbital (NBO) analysis of charges of the different atoms in sulfinyl imines.

Sulfinyl imine 1a
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Sulfinyl imine 1b
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Sulfinyl imine 1c
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Sulfinyl imine 1d
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Sulfinyl imine 1e
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Sulfinyl imine 1f
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