Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.


General Information:
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, on a Bruker Avance DRX 500 MHz spectrometer, and on a Bruker Avance III 700 MHz spectrometer with an Ascend magnet and TCI cryoprobe which are property to the Austro Czech NMR Research Center "RERI uasb". All NMR spectra 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 Thermo Fisher Scientific LTQ Orbitrap XL hybrid FT mass spectrometer with an ESI source and an Agilent G1607A coaxial sprayer and an Agilent QTOF 6520 with ESI source. EI concentration c is given in g/100 mL). Preparative column chromatography was carried out using Davisil LC 60A 70-200 MICRON silica gel. Thin layer chromatography was performed on Macherey-Nagel pre-coated TLC plates (silica gel, 60 F254, 0.20 mm, ALUGRAM ® Xtra SIL). TLC plates were visualized under 254 nm UV lamp. Enantiomeric ratios (e.r.) were determined by HPLC analysis using a Dionex Summit HPLC system with a CHIRALCEL OJ-H (4.6 × 250 mm, 5 µm), CHIRAL ART Amylose-SA (4.6 mm × 250 mm, 5 µm) and CHIRAL ART Cellulose-SB (4.6 mm × 250 mm, 5 µm) chiral stationary phase. All chemicals were purchased from commercial suppliers and used without further purification unless otherwise stated. All aryl ester starting materials 1 and Se-ITU1 were synthesized according to recently reported protocols. 1, 2 NMR data of all esters matched those reported in literature (1a, 1b, 1d, 1g and 1m 3 ; 1e, 1f and 1h 4 ; 1i 5 ; 1k 6 ; 1j and 1l 7 ). Ester 1c has been used before 8 , but to the best of our knowledge no 1 H-and 13 C-NMR spectra thereof have been reported yet (these details can be found in section 3).
As it was observed previously 9 , ionization of chlorinated esters 3 proofed to be problematic using an ESI source. Hence, (low resolution) EI ionization was performed to confirm product formation of the methyl esters via mass spectrometry. HRMS data given for products 3 in the following section refer to the corresponding morpholine amides 3 Morpholine (obtained by quenching the reaction mixture with morpholine), as those compounds were detectable with electrospray ionization.

NMR and HRMS Monitoring of the Chlorination Reaction: HRMS monitoring
In step 1, the achiral catalyst ITU4 (20 mol%) was added to a solution of aryl ester 1a pNP (0.1 mmol) in 1 mL THF. After this, a small aliquot was removed and analysed by HRMS. The formation of intermediate I ITU4 was visible while also free ITU4 was present. Next, NCS (0.2 mmol) was added and again a small aliquot was removed and analysed. Satisfyingly, the formation of chlorinated intermediate II ITU4 could be observed.

NMR monitoring
The same reaction was also analysed with 1 H-NMR spectroscopy. First, an 1 H-NMR spectrum of an equimolar mixture of ester 1a pNP together with ITU4 in CDCl3 was recorded. Here, not too much of a difference to the spectra of the pure compounds was visible (also see figure 3, blue, red and green spectra). However, upon closer examination the formation of some free p-NO2 phenol was observable (two doublets with J = 9.1 Hz at 8.1 and 6.9 ppm, figure 2).

II ITU4
In a next step, 1 eq. of NCS was added to the NMR tube and another 1 H-spectrum was recorded (figure 3, purple spectrum). First, a clear low field shift of the ITU4 signals is visible, indicating N-acylation of the catalyst (addition of ITU4 to 1a). In addition, when compared to the spectrum of pure chlorinated ester 1a pNP (figure 3, black spectrum), immediate a-chlorination could be detected. Characteristic therefore is the disappearance of the -CH2 signal at around 3.9 ppm and the appearance of the -CH signal at around 5.6 ppm.

Synthesis and Characterisation data of pfp ester 1c:
Ester 3c was prepared according to literature. 1 2-(m-tolyl)acetic acid (1.00 g, 6.7 mmol) and EDC ⋅ HCl (1.67 g, 8.7 mmol) were dissolved in anhydrous DCM and stirred for 10 min at r.t. Then, pentafluoro phenol (1.86 g, 10.1 mmol) was added and the mixture was further stirred for 16 h at r.t. Then, water was added, the phases were separated, and the aqueous phase was washed with DCM trice. The combined organic layers were dried over Na2SO4, filtered, and concentrated on the rotary evaporator. Purification by column chromatography on silica using DCM as eluent gave ester 1c in a yield of 1.52 g (74%).

General procedure for the α-chlorination of aryl esters followed by an immediate alcohol quench (0.1 mmol scale)
The respective pfp-Ester 1 (0.1 mmol) and benzotetramisole (BTM, ITU3; 2.5 mg, 10 mol%) were dissolved in 1 mL THF in a cooling Schlenk flask and cooled to -60 °C. Then, NCS (2; 26.7 mg, 0.2 mmol) was added, and the mixture was stirred at -60 °C for 63 h. After this period, 2 mL of the respective alcohol (MeOH, EtOH or iPrOH) were added at -60 °C. Then, the circulation chiller was turned off and the mixture was allowed to slowly warm to r.t. and stirred for a total of 8 h. It was filtered over Na 2 SO 4 , washed with DCM and evaporated to dryness. The crude products were purified by column chromatography on silica (heptanes -heptanes/DCM 1/3).

mmol scale procedure for the synthesis of 3d OMe
Ester 1d (316 mg, 1.0 mmol) and BTM (ITU3; 25.0 mg, 10 mol%) were dissolved in 10 mL THF in a cooling Schlenk flask and cooled to -60 °C. Then, NCS (2; 267 mg, 2.0 mmol) was added, and the mixture was stirred at -60 °C for 63 h. After this, 20 mL pre-cooled MeOH (at -60 °C, using an acetone/N2 bath) were slowly added with syringe. The mixture was further stirred at -60 °C for 1 h, then the circulation chiller was turned off, the mixture was slowly warmed to r.t. and further stirred at r.t. for 8 h. The mixture was filtered over Na2SO4, washed with DCM and evaporated to dryness. The crude product was purified by column chromatography on silica (heptanes -heptanes/DCM 1/3). Product ester 3d OMe was obtained in a yield of 142 mg (71%).

General procedure for the α-chlorination of aryl esters followed by an amine quench (0.1 mmol scale)
Pfp ester 1a (30.2 mg, 0.1 mmol) and BTM (ITU3; 2.5 mg, 10 mol%) were dissolved in 2 mL THF in a cooling Schlenk flask and cooled to -60 °C. Then, NCS (2; 26.7 mg, 0.2 mmol) was added, and the mixture was stirred for 63 h. After this period, the amine (benzylamine or morpholine, 10 eq) was added at -60 °C. After this, the circulation chiller was turned off and the mixture further stirred for 8 h at r.t.
1 mL NaHCO3 was added, the phases separated, and the aqueous phase extracted with Et2O trice. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness. The crude products were purified by column chromatography on silica using heptanes/EtOAc 2/1. Racemic samples of the chlorinated methyl esters for HPLC analysis were prepared using achiral ITU4 instead of BTM. Racemic samples of the other esters and amides were obtained from commercial α-chloro phenylacetyl chloride following reported procedures. 10,11,12 Characterization data for α-chlorinated methyl esters

Perfluorophenyl 2-chloro-2-phenylacetate 3a pfp
By omitting the described alcohol/amine quench (vide supra) and using water followed by extractive workup instead, also chlorinated pfp ester 3a pfp could be obtained. However, this compound proofed to be difficult to isolate via column chromatography and rather unstable. The compound was not accessible via HRMS (ESI). Product formation was confirmed by the synthesis of 3a pfp from commercial α-chloro phenylacetyl chloride and comparison of NMR spectra.