Stereospecific Isomerization of Allylic Halides via Ion Pairs with Induced Noncovalent Chirality

A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z:E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (≤98%) to give chiral trifluoromethylated vinyl chlorides.


Optimization studies
Unless otherwise noted, the reaction was performed using 0.1 mmol 1a and 0.1 mmol of the chlorinated reagent in a 0.1 M solution at 0 °C overnight. b with 0.1 mmol of pyridine. c with 0.1 mmol of NEt3. d Other unknown product was formed. e 0.15 mmol of NCS and PPh3. The reaction was performed using 0.1 mmol 3a in a 0.1 M solution overnight. b Obtained using 19 F NMR spectroscopy. c 1,2,4,5-tetrachloronitrobenzene was used as internal standard (IS) d >95% of 3a recovered e Decomposition observed. f 100 °C instead of 60 °C. General procedure for the synthesis of allylic chlorides 2a-2o. 1 PPh3 and NCS (1.5 equiv.) were added to a solution of the corresponding allylic alcohol (1 equiv.) in dry THF (0.1 M) at 0 °C. The mixture was warmed to room temperature overnight and petroleum ether (5 mL per mmol of substrate) was added and stirred for 15 min. The resulting suspension was filtered and evaporated under reduced pressure. The resulting residue was purified using silica chromatography employing petroleum ether as eluent and yielding the desired allylic chlorides as pure products.

General procedure for the synthesis of allylic bromides 3a-3c
PPh3 and NBS (1.5 equiv.) were added to a solution of the corresponding allylic alcohol (1 equiv.) in dry THF (0.1 M) at 0 °C. The mixture was warmed to room temperature overnight and petroleum ether (5 mL per mmol of substrate) was added and stirred for 15 min. The resulting suspension was filtered and evaporated under reduced pressure. The final product was PPh 3, NBS THF, 0 °C S11 purified using silica chromatography doped with NEt3 (1%) employing petroleum ether as eluent yielding the desired allylic bromides.

General procedure for the synthesis of allylic fluorides 4a-4c. 2
To a solution of the corresponding allylic alcohol (1 equiv.) in dry DCM (0.1 M) at -78 °C, DAST (1 equiv.) was added carefully dropwise. The reaction was warmed to room temperature overnight and quenched with a saturated solution of NaHCO3. The mixture was extracted with DCM (3 x 5 mL per mmol of substrate), dried with MgSO4 and the solvent was reduced under vacuum. The final product was purified using silica chromatography employing petroleum ether as eluent.

General procedure for the base-catalyzed isomerization of allylic chlorides 2a-2n
The corresponding allylic chloride (0.18 mmol, 1 equiv.) and 1,5,7triazabicyclo[4.4.0]dec-5-ene (2.5 mg, 0.018 mmol, 0.1 equiv.) were placed in a pressure tube and toluene was added (1.8 mL). The mixture was then stirred at 60 °C overnight in an oil bath. The reaction was quenched with H2O (2 mL) and extracted with EtOAc (3 x 5 mL). The solvent was removed under reduced pressure yielding the desired vinyl chloride.

4-chloro-1,1,1-trifluorobut-3-en-2-yl)benzene (5i)
The title compound was synthesized according to the above procedure using (E)-(4-chloro-1,1,1-trifluorobut-2-en-2-yl)benzene as substrate. The final compound was not isolated and the conversion to the mixture of E and Z diastereomers was determined by integration of the CF3 of both starting material and product by 19 F NMR (Shown below

General procedure for the base-catalyzed isomerization of allylic bromides 3a-3c
The corresponding allylic bromide (0.18 mmol, 1 equiv.) and 1,5,7triazabicyclo[4.4.0]dec-5-ene (7.5 mg, 0.054 mmol, 0.3 equiv.) were placed in a pressure tube and toluene was added (1.8 mL). The mixture was then stirred at 100 °C overnight in an oil bath. The reaction was quenched with H2O (2 mL) and extracted with EtOAc (3 x 5 mL). The solvent was removed under reduced pressure yielding the desired vinyl bromide.

S23
bath. The reaction was quenched with H2O (2 mL) and extracted with EtOAc (3 x 5 mL). The solvent was removed under reduced pressure yielding the desired vinyl fluoride.

Determination of the absolute configuration of 5a
The absolute configuration of 5a was determined by performing its transformation to the corresponding b-trifluoromethylated ketone. The hydrolysis was accomplished using a modified literature procedure. 3 Vinyl chloride 5a (1 equiv.) was added to a mixture of EtSH (1 equiv.) and TiCl4 (2 equiv.) in DCM (0.3 M of 5a) at rt and the reaction was stirred overnight. After that, AcOH (0.3 M of 5a) and H2O (4 equiv) were added and the mixture stirred for 3h. The reaction was then quenched with a saturated solution of NaHCO3, extracted with DCM (3 x 5 mL), dried with MgSO4 and the solvent was reduced under vacuum. The final ketone was purified using silica chromatography employing petroleum ether and ethyl acetate as eluents. The pure final ketone was analysed and the data was compared to that reported in the literature. 4 HPLC: CHIRALCEL OD-H, flow rate 1.0 mL/min, isohexane/isopropanol (95/05) tmajor (S) = 5.0 min. tminor (R) = 6.4 min. and [a]D 20 -12 (c 0.66, CHCl3). It was concluded that the ketone had a (S) configuration so the starting material 5a had to have the same (S) configuration. The rest of the vinyl chlorides were assigned by analogy.

Mechanistic Investigations: Kinetic Isotope Effect
The Kinetic isotope effect of the TBD-catalyzed isomerization of allylic halides was calculated by performing parallel reactions with non-deuterated allylic chloride 2a and deuterated compound 2a-d. Individual reactions were run according to the general procedure and stopped at certain times. The resulted KIE was 5.4 ± 0.6 (figure S1 and S2).