Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

  1. Václav Jurčík,
  2. Alexandra M. Z. Slawin and
  3. David O'Hagan

EASTChem School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK

  1. Corresponding author email

Associate Editor: D. Dixon
Beilstein J. Org. Chem. 2011, 7, 759–766. https://doi.org/10.3762/bjoc.7.86
Received 09 Feb 2011, Accepted 22 May 2011, Published 06 Jun 2011

Abstract

The first synthesis of α-(trifluoromethyl)-β-lactam ((S)-1) is reported. The route starts from α-(trifluoromethyl)acrylic acid (2). Conjugate addition of α-(p-methoxyphenyl)ethylamine ((S)-3b), generated an addition adduct 4b which was cyclised to β-lactam 5b. Separation of the diastereoisomers by chromatography gave ((αS,3S)-5b). N-Debenzylation afforded the desired α-(trifluoromethyl)-β-lactam ((S)-1). The absolute stereochemistry of diastereoisomers 5 was determined by X-ray crystallographic determination of a close structural analogue, (αS,3S)-5c, and then 1H and 19F NMR correlation to the individual diastereoisomers of 5a and 5b.

Keywords: enantiomeric resolution; organofluorine building blocks; α-(trifluoromethyl)-β-lactam

Introduction

β-Lactams (azetidin-2-ones) have played a prominent role in medicinal chemistry and many structural variants have been prepared and elaborated [1]. Similarly, the CF3 group is an ubiquitous substituent in pharmaceutical research, where it is used to modify the activity of a drug candidate or to block adventitious metabolism and improve the pharmacokinetic profiles [2,3]. Likewise, the substituent is found widely distributed in agrochemical products [4]. The majority of CF3 containing compounds reported in the literature are CF3-aryl, CF3-ether [5,6] or CF3-heteroaromatic in nature, and these substituents have contributed significantly to the fine chemicals and related industries. However, there is an increasing awareness and demand for molecular building blocks which carry the CF3 group at a stereogenic centre [7,8] and some such motifs are emerging in new chemical entities licenced for the pharmaceuticals market, but also in organic materials area, e.g., liquid crystals [9]. Methodologies continue to emerge for the asymmetric introduction of the CF3 group [10-13]. In this contribution, we report a synthesis of α-(trifluoromethyl)-β-lactam (1) which allows access to its enantiomerically pure forms, (R)-1 and (S)-1 as illustrated in Figure 1.

[1860-5397-7-86-1]

Figure 1: Enantiomers of α-(trifluoromethyl)-β-lactam (1).

Results and Discussion

The synthesis shown in Scheme 1 follows a strategy developed [14] for enantiomers of the methyl analogue of 1, and starts from α-(trifluoromethyl)acrylic acid (2) which offered a commercially available source of the CF3 group. It was envisaged that conjugate addition of an enantiomerically pure amide such as (R)- or (S)-3 would generate the addition adducts, carboxylate salts 4, as a mixture of diastereoisomers. Cyclisation to the N-substituted β-lactams 5 would give a mixture of two stereoisomers which might be separated into their individual diastereoisomers 5 by chromatography. N-Benzyl deprotection of the individual diastereoisomers would then provide β-lactam 1 as a single enantiomer. At the outset, (S)-(α-phenyl)ethylamine (3a) was explored as the enantiomerically pure amine. In the event 4a was generated after aza-Michael addition as a mixture of two stereoisomers, without any obvious diastereoisomeric bias (1:1, 0% de) as judged by both 1H and 19F NMR. β-Lactam ring closure, using thionyl chloride and triethylamine gave the N-methylbenzyl-β-lactam 5a with a modest diastereoisomeric bias (~50% de) indicating some epimerisation of the α-trifluoromethyl stereogenic centre, to a thermodynamic product ratio. This was supported in an analytical reaction by the observation of deuterium exchange at this stereogenic centre after the addition of D2O to the reaction on work up. The major and minor diastereoisomers of 5a were separated by careful chromatography on silica gel into single stereoisomers. Completion of the syntheses required hydrogenolysis of the (S)-N-methylbenzyl moiety of 5a. A range of conditions and catalysts were explored for the hydrogenolysis of 5a, however cleavage of the C–N bond proved very difficult and a satisfactory method could not be found. Therefore, (S)-α-(p-methoxyphenyl)ethylamine (3b) was explored as an alternative amine for the aza-Michael reaction, as removal of this amine using ceric ammonium nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The diastereoisomers of 5b could be separated by careful chromatography over silica gel and this led to the recovery of each isomer as a major and a minor product. Finally, oxidative scission of the major β-lactam stereoisomer (αS,3R)-5b, using CAN was relatively straightforward generating β-lactam (S)-1 in 67% yield. This novel β-lactam is a crystalline solid, and a suitable crystal was subjected to X-ray structure analysis. The structure of 1 is shown in Figure 2a.

[1860-5397-7-86-i1]

Scheme 1: Synthetic route involving a diastereoisomeric separation to α-(trifluoromethyl)-β-lactam ((S)-1) from α-(trifluoromethyl)acrylic acid 2 and (S)-α-(p-methoxyphenyl)ethylamine (3b). Yields are quoted for the conversion of 4b.

[1860-5397-7-86-2]

Figure 2: X-ray structures of (a) β-lactam (S)-1 and (b) (αR,3R)-5c. (a) Determination of the absolute stereochemistry of (αR,3R)-5c by X-ray crystallography allowed an absolute assignment of β-lactam 1.

Accordingly, (S)-α-(p-methoxyphenyl)ethylamine (3b) emerged as the more satisfactory amine over 3a for the preparation of 1, due to the straightforward benzylic cleavage. Enantiomeric purity analysis of the resultant β-lactam 1 was evaluated by 19F NMR using a europium chiral shift reagent [Eu(hfc)3]. The comparison of a racemic sample of 1 and then a sample after diastereoisomer separation of 5b as described above, indicated that β-lactam 1 was prepared in an enantiomerically pure form. There was no evidence that benzylic cleavage of the (S)-α-(p-methoxyphenyl)ethyl moiety with CAN resulted in epimerisation at the stereogenic centre of the β-lactam.

Finally, it was necessary to determine the absolute configuration of the resultant β-lactam. To this end, X-ray crystallography of the major diastereoisomers of 5a and 5b was attempted after chromatographic separation. Despite considerable effort however we could not obtain crystals of single isomers of 5a or 5b suitable for X-ray structure analysis. Thus, a preparation of 5c was carried out as illustrated in Scheme 2. The presence of the naphthyl ring in amine (R)-3c rendered the resultant β-lactam diastereoisomers 5c more crystalline, and a single crystal X-ray structure was solved for the major-diastereomer revealing the (αR,3R)-5c configuration. The structure is shown in Figure 2b.

[1860-5397-7-86-i2]

Scheme 2: Synthesis of stereoisomers 5c. The stereochemistry of the major isomer (αR,3R)-5c was solved by X-ray structure analysis.

With this structural information in hand it was necessary to correlate to the stereoisomers of 5b. The 1H and 19F NMR spectra of the major and minor diastereoisomers of 5ac were now compared. Clear chemical shift trends are observed as illustrated and tabulated in Table 1 and Table 2. For example, in all cases, the 1H NMR chemical shifts of the C-3 hydrogens (Ha) of the β-lactam are shifted downfield in the major relative to the minor diastereoisomers. The non-equivalent faces of the planar β-lactam ring differentiates the two diastereotopic hydrogens at C-4 (Hb and Hc).

Table 1: Comparison of the 1H NMR data of Hb and Hc of the diastereoisomers of 5ac.

[Graphic 1]
  Ha Hb Hc
δ 1H [ppm] δ 1H [ppm] J1 [Hz] J2 [Hz] δ 1H [ppm] J1 [Hz] J2 [Hz]
S,3S)-5a major 3.78 3.39 8.38 5.40 3.13 4.20  
S,3R)-5a minor 3.64 3.20 6.24 2.60 3.21 6.76 6.06
S,3S)-5b major 3.78 3.36 6.43 6.18 3.11 6.18 2.83
S,3R)-5b minor 3.73 3.27 6.47 2.45 3.18 6.55 5.27
S,3R)-5c major 3.79 3.31 7.49 6.61 2.77 6.40 2.48
S,3S)-5c minor 3.76 3.25 6.66 2.12 2.85 6.85 6.00

Table 2: Comparison of the 19F NMR chemical shifts of the diastereoisomers of 5ac.

[Graphic 2]
  δ 19F major [ppm] J [Hz] δ 19F minor [ppm] J [Hz]
5a −68.72 8.73 −68.85 8.94
5b −69.21 8.36 −69.35 8.36
5c −68.62 9.14 −69.82 8.94

It is clear that for all three major isomers the 1H NMR signals for Hb and Hc have a larger chemical shift difference than that between the Hb and Hc signals of the minor isomers. Also the chemical shifts for Hb and Hc of the minor isomers lie within those of the major isomers. For the 19F NMR spectra shown in Table 2 the major isomers all have their trifluoromethyl signals downfield of the minor diastereoisomers.

On this basis, the NMR spectra of (αR,3R)-5c, where the absolute stereochemistry was determined by X-ray crystallography, allows the absolute stereochemistry of diastereoisomers 5a and 5b to be deduced by correlation, and it follows that benzylic cleavage of (S)-α-(p-methoxyphenyl)ethylamine (3b) gave rise to β-lactam (S)-1. Ready access to the (R)-1 enantiomer would require starting the synthetic route from (S)-α-(p-methoxyphenyl)ethylamine (3b).

Conclusion

In conclusion, a short single enantiomer synthesis of β-lactam (S)-1 is reported which took advantage of an aza-Michael addition between (S)-α-(p-methoxyphenyl)ethylamine (3b) and α-(trifluoromethyl)acrylic acid (2). Cyclisation and then chromatographic resolution of the β-lactam diastereoisomers 5b, followed by deprotection with ceric ammonium nitrate generated the β-lactam (S)-1. This contributes diversity to the known β-lactam motifs and incorporates the CF3 group.

Experimental

General

All reagents were obtained from commercial sources and were used without further purification unless otherwise stated. Air- and moisture-sensitive reactions were carried out under a positive pressure of argon in flame-dried glassware using standard Schlenk-line techniques. Dry CH2Cl2 was obtained from the Solvent Purification System MB SPS-800. Room temperature (RT) refers to 20–25 °C. Reaction temperatures of 0 °C were obtained in an ice/water bath. Reaction reflux conditions were obtained using an oil bath equipped with a contact thermometer. Solvent evaporations were carried out under reduced pressure on a Büchi rotary evaporator. Thin layer chromatography (TLC) was performed using Macherey-Nagel Polygram Sil G/UV254 plastic plates. Visualisation was achieved by inspection under UV light (255 nm). Column chromatography was performed using silica gel 60 (40–63 micron). NMR spectra were recorded on Bruker AVANCE 300, 400 or 500 MHz instruments. 1H and 13C NMR spectra were recorded in CDCl3 as solvent. 19F NMR spectra were referenced to CFCl3 as the external standard. Chemical shifts are reported in parts per million (ppm) and coupling constants (J) are given in Hertz (Hz). IR spectra were recorded on a Nicolet Avatar 360 FT-IR from a thin film (either neat or combined with nujol) supported between NaCl plates. Optical rotations [α]D are given in 10–1 deg cm2 g–1 and were measured using a Perkin Elmer Model 341 polarimeter. Mass spectrometric (m/z) data was acquired by electrospray ionisation (ESI). High resolution mass analyses were recorded on a Micromass LCT TOF mass spectrometer using ES ionisation in positive ion mode.

General aza-Michael procedure

NaHCO3 (840 mg, 10.0 mmol) was added to a solution of α-(trifluoromethyl)acrylic acid (2, 1.41 g, 10.0 mmol) in methanol (10 mL), and then after 30 min stirring, a single enantiomer amine 3 (10.0 mmol) was added. The reaction was stirred at RT for 24 h. The solvent was evaporated under reduced pressure to afford the aza-Michael product as a colourless oil (quant) which solidified upon standing. Optionally, the sodium salt was converted to the amino acid HCl salt by treatment with aq HCl, followed by evaporation of the water and redissolving the residual in DCM.

Synthesis of aza-Michael adduct diastereoisomers 4a

General procedure with α-(trifluoromethyl)acrylic acid 2 (431 mg, 3.08 mmol), NaHCO3 (258 mg, 3.02 mmol) and (S)-phenylethylamine (381 μL, 3.02 mmol) in methanol (20 mL), gave after 96 h 830 mg (95%) of the title compound as a mixture of diastereoisomers (93% purity). Product 4a was used without further purification. 1H NMR (400 MHz, CD3OD) 7.42–7.25 (m, 5H, Ar), 4.02–3.90 (m, 1H, PhCHCH3), 3.30–3.13 (m, 1H, CH2CHCF3), 3.10–2.91 (m, 1H, NCH2CH), 2.90–3.76 (m, 1H, NCH2CH), 1.44 (d, J = 6.7 Hz, 3H, CHCH3); 13C NMR (100 MHz, CD3OD) 172.3 (q, J = 2.0 Hz, COONa), 172.2 (q, J = 2.0 Hz, COONa), 143.9 (C-Ar), 143.5 (C-Ar), 129.9 (C-Ar), 129.8 (C-Ar), 128.9 (C-Ar), 128.8 (C-Ar), 128.1 (C-Ar), 128.0 (C-Ar), 126.8 (q, J = 278 Hz, CCF3), 126.9 (q, J = 278 Hz, CCF3), 59.6 (PhCHCH3), 59.0 (PhCHCH3), 52.6 (q, J = 25.0 Hz, CHCF3), 52.6 (q, J = 25.0 Hz, CHCF3), 52.1 (q, J = 25.0 Hz, CHCF3), 45.12 (q, J = 3.5 Hz, NCH2CH), 44.7 (q, J = 3.5 Hz, NCH2CH), 23.1 (CHCH3), 22.9 (CHCH3); 19F NMR (376 MHz, CD3OD) −69.0 (d, J = 9.3 Hz), −69.1 (d, J = 9.3 Hz); HRMS–ESI (m/z): Calcd for C12H14NO2F3Na, 284.0874; found, 284.0869.

Synthesis of aza-Michael adduct diastereoisomers 4b

General procedure with α-(trifluoromethyl)acrylic acid 2 (1.52 g, 10.8 mmol), NaHCO3 (912 mg, 10.8 mmol) and (S)-p-methoxyphenylethylamine (1.595 mL, 10.08 mmol) in methanol (20 mL), gave after 20 h 3.06 g (98%) of the title compound as a mixture of diastereoisomers (93% purity). The material was used without further purification. 1H NMR (400 MHz, CD3OD) 7.17–7.12 (m, 2H, Ar), 6.85–6.80 (m, 2H, Ar), 4.86 (q, J = 6.5 Hz, 1H, PhCHCH3), 3.74 (s, 3H, PhOCH3), 3.73–3.65 (m, 1H, CH2CHCF3), 3.27 (dd, J = 6.3 Hz, J = 6.3 Hz, 1H, NCH2CH), 3.01 (dd, J = 6.4 Hz, J = 2.7 Hz, 1H, NCH2CH), 1.52 (d, J = 6.7 Hz, 3H, CHCH3); 13C NMR (100 MHz, MeOD) 167.4 (NCOCH), 167.3 (NCOCH), 162.2 (C-Ar), 131.6 (C-Ar), 130.4 (C-Ar), 128.5 (C-Ar), 128.4 (C-Ar), 125.1 (q, J = 275 Hz, CF3), 125.5 and 125.1 (q, J = 275 Hz, CF3), 115.83 (C-Ar), 115.51 (C-Ar), 60.61 (PhCHCH3), 60.55 (PhCHCH3), 55.9 (PhOCH3), 48.2 (q, J = 30.2 Hz, CHCF3), 48.1 (q, J = 30.2 Hz, CHCF3), 42.6 (NCH2CH), 19.9 (CHCH3), 19.5 (CHCH3); 19F NMR (376 MHz, MeOD) −68.8 (d, J = 8.7 Hz, CHCF3), −68.9 (d, J = 8.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C13H16NO3F3Na, 314.0980; found, 314.0975.

Synthesis of aza-Michael adduct diastereoisomers 4c

General procedure with α-(trifluoromethyl)acrylic acid 2 (236 mg, 1.69 mmol), NaHCO3 (142 mg, 1.685 mmol) and (R)-1-naphthylethylamine (295.4 mg, 1.685 mmol) in methanol (10 mL), gave after 96 h 550 mg (98%) of the title compound as a mixture of diastereoisomers (89% purity). The material was used without further purification. 1H NMR (400 MHz, CD3OD) 8.20 (t, J = 8.2 Hz, 1H, H-Ar), 7.91–7.86 (m, 1H, Ar), 7.83–7.79 (m, 1H, Ar), 7.72–7.68 (m, 1H, Ar), 7.59–7.46 (m, 3H, Ar), 4.99–4.88 (m, 1H, PhCHCH3), 3.35–3.22 (m, 1H, CH2CHCF3), 3.21–3.09 (m, 1H, NCH2CH), 3.03–2.94 (m, 1H, NCH2CH), 1.57 and 1.56 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CD3OD) 172.2 (COONa), 172.0 (COONa), 139.5 (C-Ar), 138.9 (C-Ar), 135.5 (C-Ar), 132.48 (C-Ar), 132.45 (C-Ar), 130.08 (C-Ar), 135.05 (C-Ar), 129.2 (C-Ar), 129.15 (C-Ar), 127.5 (C-Ar), 127.4 (C-Ar), 126.8 (C-Ar), 126.75 (C-Ar), 126.7 (C-Ar), 126.6 (C-Ar), 124.2 (C-Ar), 123.7 (C-Ar), 123.5 (C-Ar), 54.5 (PhCHCH3), 54.1 (PhCHCH3), 52.5 (q, J = 25.0 Hz, CHCF3), 52.2 (q, J = 25.0 Hz, CHCF3), 45.2 (q, J = 3.0 Hz, NCH2CH), 44.9 (q, J = 3.0 Hz, NCH2CH), 22.51 (CHCH3), 22.46 (CHCH3); 19F NMR (375 MHz, CD3OD) −69.0 (d, J = 9.7 Hz, CHCF3), −69.1 (d, J = 9.7 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C16H16NO2F3Na, 334.1031; found, 334.1031.

General method for cyclisation of adducts 4 to β-lactams 5

The sodium salt of 4 (8.00 mmol) was dissolved in dry DCM (100 mL) and DMF (5 drops) was added. The mixture was cooled to 0 °C and then SOCl2 (2.78 mL, 40.00 mmol, 5 equiv) added dropwise. The reaction mixture was warmed to RT and stirred overnight. Solvent and excess of SOCl2 were removed under reduced pressure and the oily residue was redissolved in dry DCM (10 mL). The solution was heated to reflux while Et3N (5.38 mL, 39.75 mmol, 5 equiv) was added. The reaction mixture was diluted with water (10 mL) and extracted into DCM (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4) and solvent was removed under reduced pressure to give 4 as a mixture of two isomers, which were then separated by chromatography.

Preparation of diastereoisomers 5a

Sodium salt 4a (245 mg, 0.86 mmol) and SOCl2 (310 μL, 4.3 mmol) in DCM (20 mL), followed by Et3N (600 μL, 4.3 mmol), gave 5 as a yellow oily solid.

Major isomerS,3S)-5a (91 mg, 43%): [α]D20 −88.5 (c 0.34, CH2Cl2); IR (neat): 2978 (s), 1753 (vs), 1180 (s), 1120 (s), 892 (s), 699 (s), 571 (s) cm−1; 1H NMR (500 MHz, CDCl3) 7.42–7.27 (m, 5H, Ar), 4.97 (q, J = 7.0 Hz, 1H, ArCHCH3), 3.85–3.75 (m, 1H, CHCF3), 3.39 (dd, J = 7.3 Hz, J = 5.8 Hz, 1H, NCH2CH), 3.16–3.11 (m, 1H, NCH2CH), 1.64 (d, J = 7.0 Hz, 3H, CHCH3); 13C NMR (125 MHz, CDCl3) 159.4 (q, J = 4.0 Hz), 139.3 (C-Ar), 128.9 (C-Ar), 128.0 (C-Ar), 126.6 (C-Ar), 123.9 (q, J = 275 Hz, CF3), 52.0 (PhCHCH3), 51.1 (q, J = 30.1 Hz, CHCF3), 37.6 (q, J = 3.1 Hz, NCH2CH), 18.2 (CHCH3); 19F NMR (470 MHz, CDCl3) −68.72 (d, J = 8.8 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C12H12NOF3Na, 266.0769; found, 266.0769.

Minor isomerS,3R)-5a (29 mg, 14%): [α]D20 −36.7 (c 0.09, CH2Cl2); IR (neat): 2976 (s), 1756 (vs), 1184 (s), 1119 (s), 700 (s) cm−1; 1H NMR (500 MHz, CDCl3) 7.42–7.27 (m, 5H, Ar), 4.94 (q, J = 7.0 Hz, 1H, ArCHCH3), 3.80–3.71 (m, 1H, CHCF3), 3.30 (dd, J = 6.5 Hz, J = 2.2 Hz, 1H, NCH2CH), 3.22 (dd, J = 7.2 Hz, J = 6.0 Hz, 1H, NCH2CH), 1.67 (d, J = 7.1 Hz, 3H, CHCH3); 13C NMR (125 MHz, CDCl3) 159.3 (q, J = 4.2 Hz), 139.3 (C-Ar), 129.0 (C-Ar), 128.1 (C-Ar), 126.7 (C-Ar), 123.8 (q, J = 275 Hz, CF3), 52.5 (PhCHCH3), 51.3 (q, J = 30.8 Hz, CHCF3), 37.7 (q, J = 3.1 Hz, NCH2CH), 18.4 (CHCH3); 19F NMR (470 MHz, CDCl3) −68.85 (d, J = 9.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C12H12NOF3Na, 266.0769; found, 266.0766.

Preparation of diastereoisomers 5b

Sodium salt 4b (1.18 g, 3.77 mmol) and SOCl2 (1.36 mL, 18.8 mmol) in DCM (100 mL) and DMF (5 drops), followed by Et3N (2.6 mL, 39.8 mmol), gave 5b as a colourless oil.

Major isomerS,3S)-5b (447 mg, 43%): [α]D20 +96.5 (c 0.31, CH2Cl2); IR (neat): 2980 (s), 1756 (vs), 1612 (s), 1515 (s), 1372 (s), 1180 (s), 1120 (s), 1031 (s), 1010 (s), 835 (s) cm−1; 1H NMR (400 MHz, CDCl3) 7.30–7.25 (m, 2H, Ar), 6.95–6.90 (m, 2H, Ar), 4.94 (q, J = 6.5 Hz, 1H, PhCHCH3), 3.85 (s, 3H, PhOCH3), 3.84–3.73 (m, 1H, CH2CHCF3), 3.36 (dd, J = 6.0 Hz, J = 6.0 Hz, 1H, NCH2CH), 3.11 (dd, J = 6.3 Hz, J = 2.6 Hz, 1H, NCH2CH), 1.61 (d, J = 7.1 Hz, 3H, CHCH3); 13C NMR (100 MHz, CDCl3) 159.7 (NCOCH), 131.6 (C-Ar), 128.3 (C-Ar), 124.4 (q, J = 275 Hz, CF3) 114.6 (C-Ar), 55.8 (PhCHCH3), 51.7 (PhOCH3), 51.4 (q, J = 30.2 Hz, CHCF3), 37.9 (q, J = 3.3 Hz, NCH2CH), 18.6 (CHCH3); 19F NMR (376 MHz, CDCl3) −69.2 (d, J = 8.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C13H14NO2F3Na, 296.0874; found, 296.0868.

Minor isomerS,3R)-5b (140 mg, 14%): [α]D20 −42.1 (c 0.18, CH2Cl2); IR (neat): 2975 (s), 1760 (vs), 1611 (s), 1515 (s), 1370 (s), 1244 (vs), 1121 (s), 1031 (s), 1010 (s), 833 (s) cm−1; 1H NMR (400 MHz, CDCl3) 7.25–7.22 (m, 2 H, Ar), 6.94–6.90 (m, 2H, Ar), 4.91 (q, J = 7.0 Hz, 1H, PhCHCH3), 3.83 (s, 3H, PhOCH3), 3.78–3.68 (m, 1H, CH2CHCF3), 3.27 (dd, J = 6.4 Hz, J = 2.7 Hz, 1H, NCH2CH), 3.19 (dd, J = 6.3 Hz, J = 6.0 Hz, 1H, NCH2CH), 1.64 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) 159.3 (NCOCH), 131.3 (C-Ar), 127.9 (C-Ar), 123.9 (q, J = 275 Hz, CF3), 114.2 (C-Ar), 55.3 (PhCHCH3), 51.9 (PhOCH3), 51.0 (q, J = 31.2 Hz, CHCF3), 37.5 (q, J = 3.2 Hz, NCH2CH), 18.5 (CHCH3); 19F NMR (376 MHz, CDCl3) −69.35 (d, J = 8.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C13H14NO2F3Na, 296.0874; found, 296.0883.

Preparation of diastereoisomers 5c

From sodium salt 4c (500 mg, 1.50 mmol), SOCl2 (544 μL, 7.5 mmol) in DCM (20 mL), followed by Et3N (1.05 mL, 7.5 mmol) gave 5c as a yellow solid.

Major isomerR,3R)-5c (192 mg, 41%): [α]D20 −40.9 (c 0.15, CH2Cl2); IR (neat): 2981 (s), 1760 (vs), 1368 (s), 1260 (s), 1158 (s), 1122 (s), 1011 (s), 780 (s) cm−1; 1H NMR (500 MHz, CDCl3) 8.10 (d, J = 8.4 Hz, 1H, Ar), 7.92 (d, J = 7.8 Hz, 1H, Ar), 7.88 (d, J = 8.4 Hz, 1H), 7.64–7.58 (m, 1H, Ar), 7.58–7.46 (m, 3H, Ar), 5.78 (q, J = 6.7 Hz, 1H, ArCHCH3), 3.82–3.73 (m, 1H, CHCF3), 3.31 (dd, J = 7.1 Hz, J = 6.0 Hz, 1H), 2.77 (dd, J = 6.5 Hz, J = 2.6 Hz, 1H), 1.80 (d, J = 7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) 159.3 (q, J = 4.3 Hz, NCOCH), 133.9 (C-Ar), 133.7 (C-Ar), 130.9 (C-Ar), 129.2 (C-Ar), 128.9 (C-Ar), 127.0 (C-Ar), 126.2 (C-Ar), 123.7 (q, J = 275 Hz, CF3), 123.7 (C-Ar), 122.7 (C-Ar), 51.0 (q, J = 31.1 Hz, CHCF3), 47.9 (PhCHCH3), 37.4 (q, J = 3.2 Hz, NCH2CH), 17.8 (CHCH3); 19F NMR (470 MHz, CDCl3) −68.6 (d, J = 9.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C16H14NOF3Na, 316.0925; found, 316.0915.

Minor isomerR,3S)-5c (70 mg, 15%): [α]D20 −35.7 (c 0.14, CH2Cl2); IR (neat): 2978 (s), 1755 (vs), 1366 (s), 1191 (s), 1120 (s), 778 (s) cm−1; 1H NMR (500 MHz, CDCl3) 8.15 (d, J = 8.6 Hz, 1H, Ar), 7.92 (d, J = 8.6 Hz, 1H, Ar), 7.87 (d, J = 8.5 Hz, 1H), 7.63–7.58 (m, 1H, Ar), 7.58–7.48 (m, 3H, Ar), 5.79 (q, J = 6.8 Hz, 1H, ArCHCH3), 3.69–3.60 (m, 1H, CHCF3), 3.25 (dd, J = 6.5 Hz, J = 2.5 Hz, 1H), 2.86 (dd, J = 6.9 Hz, J = 6.2 Hz, 1H), 1.82 (d, J = 7.2 Hz, 3H, CHCH3); 13C NMR (125 MHz, CDCl3) 159.2 (q, J = 4.5 Hz, NCOCH), 133.9 (C-Ar), 133.8 (C-Ar), 130.9 (C-Ar), 129.2 (C-Ar), 129.0 (C-Ar), 127.1 (C-Ar), 126.2 (C-Ar), 125.1 (C-Ar), 123.9 (q, J = 275 Hz, CF3), 123.7 (C-Ar), 122.6 (C-Ar), 47.7 (PhCHCH3), 50.9 (q, J = 31.1 Hz, CHCF3), 37.2 (q, J = 3.0 Hz, NCH2CH), 17.7 (CHCH3); 19F NMR (470 MHz, CDCl3) −68.8 (d, J = 9.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C16H14NOF3Na, 316.0925; found, 316.0919.

(S)-3-(Trifluoromethyl)azetidin-2-one (S)-1

To a solution of (αS,3S)-5b (325 mg, 1.18 mmol) in a mixture of MeCN (8 mL) and water (2 mL), ceric ammonium nitrate (1.94 g, 3.54 mmol, 3 equiv) was added portionwise. The reaction mixture was stirred at RT for 16 h and then quenched with sat. sodium bicarbonate (5 mL). After 10 min of stirring (when gas evolution ceased), the mixture was extracted into Et2O (3 × 10 mL), the combined organic phases were dried (Na2SO4) and the solvent was removed. Purification on silica gel (20% EtOAc in petrol) gave (S)-1 as a colourless oil which solidified upon standing (110 mg, 67%). Mp 85 °C; [α]D20 +26.9 (c 0.09, CH2Cl2); IR (neat): 1707 (s), 1652 (s), 1180 (s), 1120 (s) cm−1; MS–ESI (m/z): 161.98 (M + Na); 1H NMR (400 MHz, CDCl3) 6.73 (bs, 1H, CH2NHCO), 3.91–3.81 (m, 1H, CHCF3), 3.47 (dd, J = 6.9 Hz, J = 6.3 Hz, 1H, NCH2CH), 3.37 (dd, J = 6.5 Hz, J = 3.0 Hz, 1H, NCH2CH); 13C NMR (100 MHz, CDCl3) 161.3 (q, J = 4.5 Hz, NCOCH), 123.7 (q, J = 275.8 Hz, CF3), 53.7 (q, J = 31.3 Hz, CHCF3), 36.7 (q, J = 3.5 Hz, NCH2CH); 19F NMR (376 MHz, CDCl3) −69.38 (d, J = 9.5 Hz, CHCF3); HRMS–ESI (m/z): Calcd for C4H4NOF3Na, 162.0143; found, 162.0147.

Crystallographic data

1 C4H4F3NO, M = 139.08, Monoclinic, space group P2(1), a = 9.226(11), b = 5.507(6), c = 11.229(12) Å, β = 99.401(13)°. V = 562.9(11) Å3, F(000) = 280, Z = 4, Dc = 1.641 Mg m−3, μ = 0.181 mm−1 (Mo-Kα, λ = 0.71073 Å). The data were collected at T = 93 (2) K, 5405 reflections (2.24 to 25.39°) were measured on a Rigaku Saturn 92 detector with 007 generator yielding 2016 unique data (Rint = 0.0777). Conventional R = 0.0194 for 1860 reflections with I ≥ 2σ, GOF = 1,011; 171 refined parameters. The largest peak in the residual map is 0.247 eÅ−3. Crystallographic data has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication (CCDC 821176).

R,3R)-5c C16H14F3NO, M = 293.28, Monoclinic, space group P2(1), a = 9.677(5), b = 6.094(3), c = 12.231(5) Å, β = 92.685(13)°. V = 720.5(5) Å3, F(000) = 304, Z = 2, Dc = 1.352 Mg m−3, μ = 0.949 mm−1 (Cu-Kα, λ = 1.54178 Å). The data were collected at T = 173 (2) K, 9149 independent reflections (3.62 to 25.35°) were measured on a Rigaku Saturn 92 detector with 007 generator yielding 2504 unique data (Rint = 0.0450). Conventional R = 0.0194 for 2416 reflections with I ≥ 2σ, GOF = 0.973; 191 refined parameters. The largest peak in the residual map is 0.124 eÅ−3. Flack parameter 0.08 (13). Crystallographic data has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication (CCDC 821177).

Acknowledgements

We thank the European Research Council for an Advanced Investigator Grant.

References

  1. Brandi, A.; Cicchi, C.; Cordero, F. M. Chem. Rev. 2008, 108, 3988–4035. doi:10.1021/cr800325e
    Return to citation in text: [1]
  2. O'Hagan, D. J. Fluorine Chem. 2010, 131, 1071–1081. doi:10.1016/j.jfluchem.2010.03.003
    Return to citation in text: [1]
  3. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. doi:10.1126/science.1131943
    Return to citation in text: [1]
  4. Jeschke, P. ChemBioChem 2004, 5, 570–589. doi:10.1002/cbic.200300833
    Return to citation in text: [1]
  5. Boiko, V. N. Beilstein J. Org. Chem. 2010, 6, 880–921. doi:10.3762/bjoc.6.88
    Return to citation in text: [1]
  6. Leroux, F. R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Beilstein J. Org. Chem. 2008, 4, No. 13. doi:10.3762/bjoc.4.13
    Return to citation in text: [1]
  7. Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455–529. doi:10.1021/cr100166a
    Return to citation in text: [1]
  8. Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 38, 711–713. doi:10.1002/(SICI)1521-3773(19990301)38:5<711::AID-ANIE711>3.0.CO;2-W
    Return to citation in text: [1]
  9. Kirsch, P. Modern fluoroorganic chemistry. Synthesis, reactivity, applications; Wiley-VCH: Weinheim, Germany, 2004.
    Return to citation in text: [1]
  10. Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986–4987. doi:10.1021/ja100748y
    Return to citation in text: [1]
  11. Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875–10877. doi:10.1021/ja9053338
    Return to citation in text: [1]
  12. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40, 589–590. doi:10.1002/1521-3773(20010202)40:3<589::AID-ANIE589>3.0.CO;2-9
    Return to citation in text: [1]
  13. Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2009, 48, 6324–6327. doi:10.1002/anie.200902457
    Return to citation in text: [1]
  14. Shustov, G. V.; Rauk, A. Tetrahedron: Asymmetry 1996, 7, 699–708. doi:10.1016/0957-4166(96)00065-1
    Return to citation in text: [1]
  15. Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2001, 3106–3111. doi:10.1039/B106389H
    Return to citation in text: [1]

© 2011 Jurčík et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

 
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