Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a Mechanistic Rationale

Abstract The Cu‐catalyzed reaction of substituted α‐diazoesters with fluoride gives α‐fluoroesters with ee values of up to 95 %, provided that chiral indane‐derived bis(oxazoline) ligands are used that carry bulky benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently homogeneous solution of CsF in C6F6/hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF in the biphasic mixture CH2Cl2/HFIP also provides good results. DFT studies suggest that fluoride initially attacks the Cu‐ rather than the C‐atom of the transient donor/acceptor carbene intermediate. This unusual step is followed by 1,2‐fluoride shift; for this migratory insertion to occur, the carbene must rotate about the Cu−C bond to ensure orbital overlap. The directionality of this rotatory movement within the C 2‐symmetric binding site determines the sense of induction. This model is in excellent accord with the absolute configuration of the resulting product as determined by X‐ray diffraction using single crystals of this a priori wax‐like material grown by capillary crystallization.

. Structure of complex [L3•Cu(MeCN)]BF4 in the solid state. H atoms have been removed for clarity.       The low-angle reflection [0 0 2] was shadowed by the beamstop and has been removed from the data set before the final refinement cycles. The crystal was grown from the liquid in a long glass capillary. The maximum crystal size was estimated based on the diffraction geometry. For data acquisition, a fixed chi angle of 54.7 degree was chosen to ensure that the exposed crystalline volume was as small as possible consistent with a high redundancy. Complete data of the compound are available under the CCDC number CCDC-1966679.
Results of ambient to low temperature Differential scanning calorimetry of tert-Butyl (S)-2-fluoro-2phenylacetate, to determine the phase transition temperatures and possible polymorphism. Experiments where performed on a METTLER TOLEDO DSC 820 measuring module for thermal analysis. Two cycles with different cooling and heating rates where used for the probe.  6, 151.3, 138.9, 138.1, 133.8, 130.4, 128.8, 126.3, 125.7, 123.0, 121.6, 83.4, 76.8, 50.8, 45.5, 39.6, 34.7, 31.5, 3  NOEs between the tert-butyl groups and the indane backbone indicate the presence of a "closed" conformation, where the 3,5-di-tert-butyl groups shield one half space each. It has to be kept in mind, however, that NMR averages over all the conformations that are equilibrating faster than NMR timescale. The recorded number of signals shows that the structure is C2 symmetric in solution. The rotation about the C22-C23 is faster than the NMR timescale because H24/H28 and H31/H35 are magnetically equivalent.

INITIAL LIGAND SCREENING
The use of [Rh2(S-PTTL)4] (instead of Cu(+1)/L) as the catalyst furnished only trace amounts of product; the ee was not determined Figure S7. Ligand screening: the tested ligands are roughly custered according to the induced enantioselectivity (note, however, the greatly varying yields); all reactions were performed on a 0.150 mmol scale according to the representative procedure (see below) using CH2Cl2 (instead of C6F6); NMR yields are given relative to mesitylene serving as internal standard; data marked * refer to the methyl ester 2a instead of tert-butyl ester 2b S12 S13 S14 [a] All reactions were performed according to representative procedure for fluorination reactions using CH2Cl2 instead of C6F6 with 0.150 mmol of the diazo compound 1b. [b] NMR yields relative to mesitylene are given. S15 [a] All reactions were performed according to representative procedure for fluorination reactions (see below) but using CH2Cl2 instead of C6F6; [b] NMR yields relative to mesitylene are given; [c] 5 mL of the solvent instead of 1.5 mL; [d] fresh batch of copper source; [e] additional 18-crown-6 ether (1 equiv.) was added; [f] 1.5 equiv. of HFIP instead of 10 equiv.; [g] additional perfluoro-tert-BuOH (10 equiv.) was added; [h] 5 h instead of 12 h reaction time; [i] 1 h instead of 12 h reaction time; [j] performed at 10 °C instead of rt; [k] at 0 °C instead of rt; [l] at 10 °C instead of rt; [m] no ligand; [n] using the preformed complex

SUBSTRATES
tert-Butyl 2-phenylacetate (1b). The compound was prepared by adaptation of a literature procedure. 11 Dry tert-BuOH (2 mL, 20.9 mmol) was mixed with THF (40 mL) in a flame-dried Schlenk flask. The solution was cooled to 0 °C before n-butyllithium (1.6 M in hexanes, 12.6 mL, 20.2 mmol) was added dropwise. The mixture was stirred for 10 min before a solution of methyl phenylacetate (3.62 g, 24.1 mmol) in THF (10 mL) was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature overnight. Water (30 mL) was added and the mixture extracted with CH2Cl2 (3 x, 30 mL). The combined organic layers were dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (silica, pentane/tert-butyl methyl ether = 30/1) to give the title compound as a colorless oil ( tert-Butyl 2-(4-(trifluoromethyl)phenyl)acetate (S21). This compound was prepared by adaptation of a literature procedure. 16 2-(4-(Trifluoromethyl)phenyl)acetic acid (1.30 g, 6.42 mmol) and dry tert-BuOH (6.00 mL, 62.7 mmol) were dissolved in CH2Cl2 (50 mL) in a flame-dried Schlenk flask. After the addition of pyridine (2.60 mL, 32.1 mmol), phosphoryl trichloride (0.80 mL, 8.58 mmol) was added dropwise. The mixture was stirred for 4 h before aqueous HCl (2 M, 30 mL) was introduced. The mixture was extracted with CH2Cl2 (3 x, 40 mL), the combined organic layers were dried over MgSO4 and concentrated, and the crude product was purified by flash chromatography (silica, hexanes/EtOAc = 50/1) to yield the title compound as a colorless oil (1. (2-(tert-Butoxy)-2-oxoethyl)zinc bromide. This compound was prepared similar to a literature procedure. 17 A 100 mL 2-necked round bottom flask equipped with a condensor was flame-dried and then charged with zinc powder (1.45 g, 22.2 mmol). THF (5 mL) and TMSCl (0.10 mL, 0.79 mmol) were added and the mixture was warmed to 50 °C. A solution of tert-butyl bromo acetate (1.50 mL, 10.3 mmol) in THF was added dropwise at this temperature. Once the addition was complete, the mixture was cooled to ambient temperature and stirring was continued for 1.5 h. Excess zinc was allowed to settle and the supernatant was separated via cannula. The resulting yellow solution was directly used in the next step. tert-Butyl 2-(4-(methylsulfonyl)phenyl)acetate (S23). In a flame-dried Schlenk flask, 2-(4-(methylsulfonyl)phenyl)acetic acid (1.01g, 4.69 mmol) was dissolved in CH2Cl2 (40 mL). Dry tert-BuOH (4.50 mL), pyridine (2.30 mL) and phosphoryl chloride (0.60 mL, 6.44 mmol) were added subsequently. The mixture was stirred for 1.5 h at rt. Aqueous HCl (2 M, 40 mL) was added and the mixture was extracted with CH2Cl2 (3 x, 30 mL). The combined organic layers were dried over MgSO4 and concentrated, and the crude material was purified by flash chromatography (silica, hexanes/EtOAc = 7/2) to yield the title compound as a colorless solid (1.20 g, 94 % yield

SUPPORTING COMPUTATIONAL DATA
The structures were optimized with the ORCA 4.1.2 program package 23 employing the BP86 functional 24,25 together with the def2-SVP basis set 26 and D3 dispersion correction including Becke-Johnson damping (D3-BJ). 27 The resolution-of-identity (RI) approximation was utilized to speed up the calculations. 28,29 Inclusion of implicit solvent effects was achieved by employing the Conductor-like Polarizable Continuum Model (CPCM) 30,31 by using the ORCA default values for CH2Cl2. Stationary points were characterized by the analytical calculation of the Hessian. This level of theory is denoted as BP86-D3(BJ)-CPCM/def2-SVP. Transition states were optimized with the same methodology. They were identified by possessing one imaginary frequency corresponding to the respective reaction path and characterized via calculations of the intrinsic reaction coordinate (IRC) to connect the two minima in question. Thermodynamic corrections at ambient conditions (298.15 K, 1 atm) from the frequency calculations were used to obtain Gibbs free energies ΔG for the reaction mechanism. The BP86-D3(BJ)-CPCM/def2-SVP optimized structures were employed in single point calculations with the larger def2-TZVPP basis set 26 to obtain more accurate energies, denoted as BP86-D3(BJ)-CPCM/def2-TZVPP//BP86-D3(BJ)-CPCM/def2-SVP.
In order to estimate the rotational barriers, constrained optimizations at BP86-D3(BJ)-CPCM/def2-TZVPP level of theory were carried out in which the respective dihedral angles were changed in small steps (2° for the ester rotation, 4° for the rotation around the copper carbene bond) and kept fixed while the rest of the structure was allowed to relax.
Calculation of the electrostatic potential (ESP) of structure 2 was carried out by generation of a wave function file at BP86-D3(BJ)-CPCM/def2-SVP level using the program MultiWFN 3.6. 32 S46 Figure S18. Optimized structures of minima and transition states calculated at BP86-D3(BJ)-CPCM/def2-SVP level of theory; bond lengths in Å, angles in °. Experimental values are shown in parentheses. Hydrogen atoms omitted for clarity. Figure S19. Rotational barrier for the copper-carbene (CuC1) bond in [L3Cu=CPh(COOtBu)]BF4. Shown is the clockwise and counter-clockwise displacement from equilibrium of the carbene moiety against the copper complex in °. Energies are given in kcal/mol and were calculated at BP86-D3(BJ)-CPCM/def2-TZVPP level of theory by constrained optimization. Figure S20. Barrier for the rotation of the ester group (C1C3 bond) in [L3Cu=C(COOtBu)(Ph)]BF4. Shown is the clockwise and counter-clockwise displacement from equilibrium in °. Energies are given in kcal/mol and were calculated at BP86-D3(BJ)-CPCM/def2-TZVPP level of theory by constrained optimization.