Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates

The enantioselective synthesis of α-chlorinated carboxylic acid esters with er up to 99:1 and yields up to 82% was achieved via a one-pot multistep protocol starting from α-diazoketones. This process proceeds via a photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.


General Information
H-and 13 C-NMR spectra were recorded on a Bruker Avance III 300 MHz spectrometer with a broad band observe probe and a sample changer for 16 samples and on a Bruker Avance DRX 500 MHz spectrometer which are both property of the Austro Czech NMR Research Center "RERI uasb". The measurements were referenced on the solvent residual peak (CDCl3: δ 7.26 ppm for 1 H-NMR and δ 77.16 ppm for 13 C-NMR). NMR data are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz) and integrals. High resolution mass spectra were obtained using an Agilent QTOF 6520 with ESI source.
All chemicals were purchased from commercial suppliers and used without further purification unless otherwise stated.
As we already reported previously 1 , ionization of the (mostly literature known) chlorinated esters 2 could not be achieved employing an ESI source and thus high resolution mass spectrometry could not be carried with our equipment. On this account, low resolution EI ionization was performed to confirm product formation of the methyl esters via mass spectrometry. The strategy, where HRMS appropriate derivatives could be obtained by quenching the reaction with morpholine to form the corresponding morpholine amides, which was carried out in our previous report 1 , proofed to be not feasible for the reaction reported in this paper (please also refer to the results given in Scheme 2 of the main manuscript for product 2q) as the amine directly traps the ketene (preventing any catalyst additionchlorination) and thus only gives non-chlorinated phenyl acetic acid-based amides. S-3

Photoreactor Setup
Photochemical reactions were carried out using a photoreactor equipped with 6x5W blue LEDs (Emission maximum: 445 -450 nm, as seen in Figure S-2) which was built according to literature 2 (Dimensions: 8.9 cm × 8.9 cm × 9.6 cm). Regular screw cap vials (2 mL) were used as reaction vessels except for bigger scales (1 mmol) or lower temperature reactions (< 0°C) where a Schlenk flask was used instead. Cooling was achieved by submerging the reaction flask into ice water or an Acetone/liquid Nitrogen bath to roughly half of its height. The temperature was measured in a dummy vial via an electric thermometer. Without cooling the reaction vessel reached temperatures up to 40°C.

Preparation of α-Diazoketones
CAUTION: Diazo compounds are toxic and potentially explosive and should be handled with care in a well-ventilated fume hood 3 .

Preparation of diazoacetophenone derivatives (1b-m)
Important Safety Note: Diazomethane is potentially explosive, cancerogenic and toxic. Therefore, preparation and handling of diazomethane should be done in a well-ventilated fume hood, using an additional blast shield. The use of glass apparatus with ground joints and sharp surfaces should be avoided and Pasteur pipettes should be smoothed under a flame.
Diazoacetophenone derivatives 1b-m were prepared according to a procedure developed by De Kimpe et al. 5 where CaO is used as an acid scavenger in order to decrease to necessary amount of diazomethane. For the generation of diazomethane N-Nitroso-N-methylurea 12b was used, which was prepared according to literature 6 .

General Procedure for the Synthesis of α-Diazoketones
In a 40 mL test tube, 2 mL of KOH (40%) and 4 mL Et2O were cooled to 0°C in an ice bath and stirred slowly and 0.3 g (2.9 mmol) N-Nitroso-N-methylurea 12b was added in portions. After 30 min the stirring was stopped and the obtained yellow ethereal solution of diazomethane is separated by carefully transferring the ether phase into a second 40 mL test tube using a smoothed Pasteur pipette.
The solution was again cooled to 0°C and 0.18 g (3.2 mmol, 1.1 eq) of CaO is added. The corresponding benzoyl chloride derivative was dissolved in 1 mL Et2O and added dropwise to the stirred solution upon which gas formation was observed. After 4 h the reaction mixture had lost the intense yellow color and the CaO was filtered over a crucible (por 4). Diazoacetophenone derivatives 1b-m were purified by column chromatography (Heptanes/EtOAc: gradient 20:1 -5:1) and obtained as pale-yellow solids.

5,5-Dibromo-2,2-dimethyl-1,3-dioxane-4,6-dione (5):
In analogy to literature 8 , a mixture of 1.5 g (13 mmol) Meldrum's acid 12c in 10 mL NaOH (2M) was cooled to 0°C in an ice bath and 1.2 mL (26 mmol, 4.2 g, 2 eq) bromine were added dropwise. After a reaction time of 2h, an orange precipitate had formed. The desired product can be obtained via two different work-up procedures yielding the product in two different appearances. Variant a: The orange precipitate is filtered, washed with water and dried in a desiccator over silica gel overnight to yield 5 as an orange powder. Variant b: The whole reaction mixture is extracted with DCM and dried over Na2SO4 to obtain 5 as a clear oil. (2.1 g, 67%).
Both products give identical proton NMR and show the same reactivity in the bromination reaction.