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

Article abstract of DOI:10.3762/bjoc.7.86

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-lacta

Full text of DOI:10.3762/bjoc.7.86

Single enantiomer synthesis of
α-(trifluoromethyl)-β-lactam
Václav Jurčík, Alexandra M. Z. Slawin and David O'Hagan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 759–766.
EASTChem School of Chemistry and Centre for Biomolecular
Sciences, University of St Andrews, North Haugh, St Andrews, Fife,
KY16 9ST, UK
doi:10.3762/bjoc.7.86
Received: 09 February 2011
Accepted: 22 May 2011
Published: 06 June 2011
Email:
David O'Hagan* - do1@st-andrews.ac.uk
Associate Editor: D. Dixon
* Corresponding author
© 2011 Jurčík et al; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
enantiomeric resolution; organofluorine building blocks;
α-(trifluoromethyl)-β-lactam
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-(trifluoro-
methyl)-β-lactam ((S)-1). The absolute stereochemistry of diastereoisomers 5 was determined by X-ray crystallographic determi-
nation of a close structural analogue, (αS,3S)-5c, and then 1H and 19F NMR correlation to the individual diastereoisomers of 5a
and 5b.
Introduction
β-Lactams (azetidin-2-ones) have played a prominent role in CF3 group at a stereogenic centre [7,8] and some such motifs
medicinal chemistry and many structural variants have been are emerging in new chemical entities licenced for the pharma-
prepared and elaborated [1]. Similarly, the CF3 group is an ceuticals market, but also in organic materials area, e.g., liquid
ubiquitous substituent in pharmaceutical research, where it is crystals [9]. Methodologies continue to emerge for the asym-
used to modify the activity of a drug candidate or to block metric introduction of the CF3 group [10-13]. In this contribu-
adventitious metabolism and improve the pharmacokinetic tion, we report a synthesis of α-(trifluoromethyl)-β-lactam (1)
profiles [2,3]. Likewise, the substituent is found widely distri- which allows access to its enantiomerically pure forms, (R)-1
buted in agrochemical products [4]. The majority of CF3 and (S)-1 as illustrated in Figure 1.
containing compounds reported in the literature are CF3-aryl,
CF3-ether [5,6] or CF3-heteroaromatic in nature, and these Results and Discussion
substituents have contributed significantly to the fine chemicals The synthesis shown in Scheme 1 follows a strategy developed
and related industries. However, there is an increasing aware- [14] for enantiomers of the methyl analogue of 1, and starts
ness and demand for molecular building blocks which carry the from α-(trifluoromethyl)acrylic acid (2) which offered a
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Beilstein J. Org. Chem. 2011, 7, 759–766.
stereogenic centre after the addition of D2O to the reaction on
work up. The major and minor diastereoisomers of 5a were sep-
arated by careful chromatography on silica gel into single
stereoisomers. Completion of the syntheses required hydrogen-
olysis 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 alter-
native amine for the aza-Michael reaction, as removal of this
Figure 1: Enantiomers of α-(trifluoromethyl)-β-lactam (1).
commercially available source of the CF3 group. It was envis- amine using ceric ammonium nitrate (CAN) oxidation offered a
aged that conjugate addition of an enantiomerically pure amide milder deprotection method [15]. The aza-Michael reaction
such as (R)- or (S)-3 would generate the addition adducts, proved straightforward to generate 4b and then cyclisation
carboxylate salts 4, as a mixture of diastereoisomers. Cyclisa- again using thionyl chloride and triethylamine gave β-lactams
tion to the N-substituted β-lactams 5 would give a mixture of 5b in a 40% de, presumably again a thermodynamically biased
two stereoisomers which might be separated into their indi- isomer ratio. The diastereoisomers of 5b could be separated by
vidual diastereoisomers 5 by chromatography. N-Benzyl depro- careful chromatography over silica gel and this led to the
tection of the individual diastereoisomers would then provide recovery of each isomer as a major and a minor product.
β-lactam 1 as a single enantiomer. At the outset, (S)-(α- Finally, oxidative scission of the major β-lactam stereoisomer
phenyl)ethylamine (3a) was explored as the enantiomerically (αS,3R)-5b, using CAN was relatively straightforward gener-
pure amine. In the event 4a was generated after aza-Michael ad- ating β-lactam (S)-1 in 67% yield. This novel β-lactam is a crys-
dition as a mixture of two stereoisomers, without any obvious talline solid, and a suitable crystal was subjected to X-ray struc-
diastereoisomeric bias (1:1, 0% de) as judged by both 1H and ture analysis. The structure of 1 is shown in Figure 2a.
19F NMR. β-Lactam ring closure, using thionyl chloride and
triethylamine gave the N-methylbenzyl-β-lactam 5a with a Accordingly, (S)-α-(p-methoxyphenyl)ethylamine (3b) emerged
modest diastereoisomeric bias (~50% de) indicating some as the more satisfactory amine over 3a for the preparation of 1,
epimerisation of the α-trifluoromethyl stereogenic centre, to a due to the straightforward benzylic cleavage. Enantiomeric
thermodynamic product ratio. This was supported in an analyt- purity analysis of the resultant β-lactam 1 was evaluated by
ical reaction by the observation of deuterium exchange at this 19F NMR using a europium chiral shift reagent [Eu(hfc)3]. The
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.
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Beilstein J. Org. Chem. 2011, 7, 759–766.
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 crystal-
lography allowed an absolute assignment of β-lactam 1.
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 epimerisa-
tion at the stereogenic centre of the β-lactam.
Finally, it was necessary to determine the absolute configur-
ation of the resultant β-lactam. To this end, X-ray crystallog-
raphy of the major diastereoisomers of 5a and 5b was attempted
after chromatographic separation. Despite considerable effort
Scheme 2: Synthesis of stereoisomers 5c. The stereochemistry of the
major isomer (αR,3R)-5c was solved by X-ray structure analysis.
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 It is clear that for all three major isomers the 1H NMR signals
β-lactam diastereoisomers 5c more crystalline, and a single for Hb and Hc have a larger chemical shift difference than that
crystal X-ray structure was solved for the major-diastereomer between the Hb and Hc signals of the minor isomers. Also the
revealing the (αR,3R)-5c configuration. The structure is shown chemical shifts for Hb and Hc of the minor isomers lie within
in Figure 2b.
those of the major isomers. For the 19F NMR spectra shown in
Table 2 the major isomers all have their trifluoromethyl signals
With this structural information in hand it was necessary to downfield of the minor diastereoisomers.
correlate to the stereoisomers of 5b. The 1H and 19F NMR
spectra of the major and minor diastereoisomers of 5a–c were On this basis, the NMR spectra of (αR,3R)-5c, where the abso-
now compared. Clear chemical shift trends are observed as lute stereochemistry was determined by X-ray crystallography,
illustrated and tabulated in Table 1 and Table 2. For example, in allows the absolute stereochemistry of diastereoisomers 5a and
all cases, the 1H NMR chemical shifts of the C-3 hydrogens 5b to be deduced by correlation, and it follows that benzylic
(Ha) of the β-lactam are shifted downfield in the major relative cleavage of (S)-α-(p-methoxyphenyl)ethylamine (3b) gave rise
to the minor diastereoisomers. The non-equivalent faces of the to β-lactam (S)-1. Ready access to the (R)-1 enantiomer would
planar β-lactam ring differentiates the two diastereotopic hydro- require starting the synthetic route from (S)-α-(p-meth-
gens at C-4 (Hb and Hc).
oxyphenyl)ethylamine (3b).
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Beilstein J. Org. Chem. 2011, 7, 759–766.
Table 1: Comparison of the 1H NMR data of Hb and Hc of the diastereoisomers of 5a–c.
Ha
Hb
Hc
δ 1H [ppm]
δ 1H [ppm]
J1 [Hz]
J2 [Hz]
δ 1H [ppm]
J1 [Hz]
J2 [Hz]
(αS,3S)-5a major
(αS,3R)-5a minor
(αS,3S)-5b major
(αS,3R)-5b minor
(αS,3R)-5c major
(αS,3S)-5c minor
3.78
3.64
3.78
3.73
3.79
3.76
3.39
3.20
3.36
3.27
3.31
3.25
8.38
6.24
6.43
6.47
7.49
6.66
5.40
2.60
6.18
2.45
6.61
2.12
3.13
3.21
3.11
3.18
2.77
2.85
4.20
6.76
6.18
6.55
6.40
6.85
6.06
2.83
5.27
2.48
6.00
Table 2: Comparison of the 19F NMR chemical shifts of the diastereoisomers of 5a–c.
δ 19F major [ppm]
J [Hz]
δ 19F minor [ppm]
J [Hz]
5a
5b
5c
−68.72
−69.21
−68.62
8.73
8.36
9.14
−68.85
−69.35
−69.82
8.94
8.36
8.94
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Beilstein J. Org. Chem. 2011, 7, 759–766.
Conclusion
sodium salt was converted to the amino acid HCl salt by treat-
In conclusion, a short single enantiomer synthesis of β-lactam ment with aq HCl, followed by evaporation of the water and
(S)-1 is reported which took advantage of an aza-Michael addi- redissolving the residual in DCM.
tion between (S)-α-(p-methoxyphenyl)ethylamine (3b)
and α-(trifluoromethyl)acrylic acid (2). Cyclisation and Synthesis of aza-Michael adduct diastereoisomers
then chromatographic resolution of the β-lactam diastereo- 4a
isomers 5b, followed by deprotection with ceric ammonium General procedure with α-(trifluoromethyl)acrylic acid 2 (431
nitrate generated the β-lactam (S)-1. This contributes mg, 3.08 mmol), NaHCO3 (258 mg, 3.02 mmol) and (S)-
diversity to the known β-lactam motifs and incorporates the CF3 phenylethylamine (381 μL, 3.02 mmol) in methanol (20 mL),
group.
gave after 96 h 830 mg (95%) of the title compound as a mix-
ture 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),
Experimental
General
All reagents were obtained from commercial sources and were 3.30–3.13 (m, 1H, CH2CHCF3), 3.10–2.91 (m, 1H, NCH2CH),
used without further purification unless otherwise stated. Air- 2.90–3.76 (m, 1H, NCH2CH), 1.44 (d, J = 6.7 Hz, 3H,
and moisture-sensitive reactions were carried out under a CHCH3); 13C NMR (100 MHz, CD3OD) 172.3 (q, J = 2.0 Hz,
positive pressure of argon in flame-dried glassware using COONa), 172.2 (q, J = 2.0 Hz, COONa), 143.9 (C-Ar), 143.5
standard Schlenk-line techniques. Dry CH2Cl2 was obtained (C-Ar), 129.9 (C-Ar), 129.8 (C-Ar), 128.9 (C-Ar), 128.8
from the Solvent Purification System MB SPS-800. Room (C-Ar), 128.1 (C-Ar), 128.0 (C-Ar), 126.8 (q, J = 278 Hz,
temperature (RT) refers to 20–25 °C. Reaction temperatures of CCF3), 126.9 (q, J = 278 Hz, CCF3), 59.6 (PhCHCH3), 59.0
0 °C were obtained in an ice/water bath. Reaction reflux condi- (PhCHCH3), 52.6 (q, J = 25.0 Hz, CHCF3), 52.6 (q, J = 25.0
tions were obtained using an oil bath equipped with a contact Hz, CHCF3), 52.1 (q, J = 25.0 Hz, CHCF3), 45.12 (q, J = 3.5
thermometer. Solvent evaporations were carried out under Hz, NCH2CH), 44.7 (q, J = 3.5 Hz, NCH2CH), 23.1
reduced pressure on a Büchi rotary evaporator. Thin layer chro- (CHCH3), 22.9 (CHCH3); 19F NMR (376 MHz, CD3OD)
matography (TLC) was performed using Macherey-Nagel Poly- −69.0 (d, J = 9.3 Hz), −69.1 (d, J = 9.3 Hz);
gram Sil G/UV254 plastic plates. Visualisation was achieved by HRMS–ESI (m/z): Calcd for C12H14NO2F3Na, 284.0874;
inspection under UV light (255 nm). Column chromatography found, 284.0869.
was performed using silica gel 60 (40–63 micron). NMR
spectra were recorded on Bruker AVANCE 300, 400 or 500 Synthesis of aza-Michael adduct diastereoisomers
MHz instruments. 1H and 13C NMR spectra were recorded in 4b
CDCl3 as solvent. 19F NMR spectra were referenced to CFCl3 General procedure with α-(trifluoromethyl)acrylic acid 2 (1.52
as the external standard. Chemical shifts are reported in parts g, 10.8 mmol), NaHCO3 (912 mg, 10.8 mmol) and (S)-p-meth-
per million (ppm) and coupling constants (J) are given in Hertz oxyphenylethylamine (1.595 mL, 10.08 mmol) in methanol (20
(Hz). IR spectra were recorded on a Nicolet Avatar 360 FT-IR mL), gave after 20 h 3.06 g (98%) of the title compound as a
from a thin film (either neat or combined with nujol) supported mixture of diastereoisomers (93% purity). The material was
between NaCl plates. Optical rotations [α]D are given used without further purification. 1H NMR (400 MHz, CD3OD)
in 10–1 deg cm2 g–1 and were measured using a Perkin 7.17–7.12 (m, 2H, Ar), 6.85–6.80 (m, 2H, Ar), 4.86 (q, J = 6.5
Elmer Model 341 polarimeter. Mass spectrometric (m/z) Hz, 1H, PhCHCH3), 3.74 (s, 3H, PhOCH3), 3.73–3.65 (m, 1H,
data was acquired by electrospray ionisation (ESI). High resolu- CH2CHCF3), 3.27 (dd, J = 6.3 Hz, J = 6.3 Hz, 1H, NCH2CH),
tion mass analyses were recorded on a Micromass 3.01 (dd, J = 6.4 Hz, J = 2.7 Hz, 1H, NCH2CH), 1.52 (d, J = 6.7
LCT TOF mass spectrometer using ES ionisation in positive ion Hz, 3H, CHCH3); 13C NMR (100 MHz, MeOD) 167.4
mode.
(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
General aza-Michael procedure
NaHCO3 (840 mg, 10.0 mmol) was added to a solution of (C-Ar), 60.61 (PhCHCH3), 60.55 (PhCHCH3), 55.9 (PhOCH3),
α-(trifluoromethyl)acrylic acid (2, 1.41 g, 10.0 mmol) in meth- 48.2 (q, J = 30.2 Hz, CHCF3), 48.1 (q, J = 30.2 Hz,
anol (10 mL), and then after 30 min stirring, a single enan- CHCF3 ), 42.6 (NCH2 CH), 19.9 (CHCH3 ), 19.5
tiomer amine 3 (10.0 mmol) was added. The reaction was (CHCH3); 19F NMR (376 MHz, MeOD) −68.8 (d,
stirred at RT for 24 h. The solvent was evaporated under J = 8.7 Hz, CHCF3), −68.9 (d, J = 8.1 Hz, CHCF3);
reduced pressure to afford the aza-Michael product as a colour- HRMS–ESI (m/z): Calcd for C13H16NO3F3Na, 314.0980;
less oil (quant) which solidified upon standing. Optionally, the found, 314.0975.
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Beilstein J. Org. Chem. 2011, 7, 759–766.
Synthesis of aza-Michael adduct diastereoisomers
4c
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
General procedure with α-(trifluoromethyl)acrylic acid 2 (236 Hz, 3H, CHCH3); 13C NMR (125 MHz, CDCl3) 159.4 (q, J =
mg, 1.69 mmol), NaHCO3 (142 mg, 1.685 mmol) and (R)-1- 4.0 Hz), 139.3 (C-Ar), 128.9 (C-Ar), 128.0 (C-Ar), 126.6
naphthylethylamine (295.4 mg, 1.685 mmol) in methanol (10 (C-Ar), 123.9 (q, J = 275 Hz, CF3), 52.0 (PhCHCH3), 51.1 (q, J
mL), gave after 96 h 550 mg (98%) of the title compound as a = 30.1 Hz, CHCF3), 37.6 (q, J = 3.1 Hz, NCH2CH), 18.2
mixture of diastereoisomers (89% purity). The material was (CHCH3); 19F NMR (470 MHz, CDCl3) −68.72 (d, J = 8.8 Hz,
used without further purification. 1H NMR (400 MHz, CD3OD) CHCF3); HRMS–ESI (m/z): Calcd for C12H12NOF3Na,
8.20 (t, J = 8.2 Hz, 1H, H-Ar), 7.91–7.86 (m, 1H, Ar), 266.0769; found, 266.0769.
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, Minor isomer (αS,3R)-5a (29 mg, 14%): [α]D20 −36.7 (c 0.09,
CH2CHCF3), 3.21–3.09 (m, 1H, NCH2CH), 3.03–2.94 (m, 1H, CH2Cl2); IR (neat): 2976 (s), 1756 (vs), 1184 (s), 1119 (s), 700
NCH2CH), 1.57 and 1.56 (d, J = 6.7 Hz, 3H); 13C NMR (100 (s) cm−1; 1H NMR (500 MHz, CDCl3) 7.42–7.27 (m, 5H, Ar),
MHz, CD3OD) 172.2 (COONa), 172.0 (COONa), 139.5 (C-Ar), 4.94 (q, J = 7.0 Hz, 1H, ArCHCH3), 3.80–3.71 (m, 1H,
138.9 (C-Ar), 135.5 (C-Ar), 132.48 (C-Ar), 132.45 (C-Ar), CHCF3), 3.30 (dd, J = 6.5 Hz, J = 2.2 Hz, 1H, NCH2CH), 3.22
130.08 (C-Ar), 135.05 (C-Ar), 129.2 (C-Ar), 129.15 (C-Ar), (dd, J = 7.2 Hz, J = 6.0 Hz, 1H, NCH2CH), 1.67 (d, J = 7.1 Hz,
127.5 (C-Ar), 127.4 (C-Ar), 126.8 (C-Ar), 126.75 (C-Ar), 126.7 3H, CHCH3); 13C NMR (125 MHz, CDCl3) 159.3 (q, J = 4.2
(C-Ar), 126.6 (C-Ar), 124.2 (C-Ar), 123.7 (C-Ar), 123.5 Hz), 139.3 (C-Ar), 129.0 (C-Ar), 128.1 (C-Ar), 126.7 (C-Ar),
(C-Ar), 54.5 (PhCHCH3), 54.1 (PhCHCH3), 52.5 (q, J = 25.0 123.8 (q, J = 275 Hz, CF3), 52.5 (PhCHCH3), 51.3 (q, J = 30.8
Hz, CHCF3), 52.2 (q, J = 25.0 Hz, CHCF3), 45.2 (q, J = 3.0 Hz, Hz, CHCF3), 37.7 (q, J = 3.1 Hz, NCH2CH), 18.4 (CHCH3);
NCH2CH), 44.9 (q, J = 3.0 Hz, NCH2CH), 22.51 (CHCH3), 19F NMR (470 MHz, CDCl3) −68.85 (d, J = 9.1 Hz, CHCF3);
22.46 (CHCH3); 19F NMR (375 MHz, CD3OD) −69.0 (d, J = HRMS–ESI (m/z): Calcd for C12H12NOF3Na, 266.0769; found,
9.7 Hz, CHCF3), −69.1 (d, J = 9.7 Hz, CHCF3); HRMS–ESI 266.0766.
(m/z): Calcd for C16H16NO2F3Na, 334.1031; found, 334.1031.
Preparation of diastereoisomers 5b
General method for cyclisation of adducts 4 to
Sodium salt 4b (1.18 g, 3.77 mmol) and SOCl2 (1.36 mL,
β-lactams 5
18.8 mmol) in DCM (100 mL) and DMF (5 drops), followed by
The sodium salt of 4 (8.00 mmol) was dissolved in dry DCM Et3N (2.6 mL, 39.8 mmol), gave 5b as a colourless oil.
(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) Major isomer (αS,3S)-5b (447 mg, 43%): [α]D20 +96.5 (c 0.31,
added dropwise. The reaction mixture was warmed to RT and CH2Cl2); IR (neat): 2980 (s), 1756 (vs), 1612 (s), 1515 (s),
stirred overnight. Solvent and excess of SOCl2 were removed 1372 (s), 1180 (s), 1120 (s), 1031 (s), 1010 (s), 835 (s) cm−1;
under reduced pressure and the oily residue was redissolved in 1H NMR (400 MHz, CDCl3) 7.30–7.25 (m, 2H, Ar), 6.95–6.90
dry DCM (10 mL). The solution was heated to reflux while (m, 2H, Ar), 4.94 (q, J = 6.5 Hz, 1H, PhCHCH3), 3.85 (s, 3H,
Et3N (5.38 mL, 39.75 mmol, 5 equiv) was added. The PhOCH3), 3.84–3.73 (m, 1H, CH2CHCF3), 3.36 (dd, J = 6.0
reaction mixture was diluted with water (10 mL) and Hz, J = 6.0 Hz, 1H, NCH2CH), 3.11 (dd, J = 6.3 Hz, J = 2.6 Hz,
extracted into DCM (3 × 10 mL). The combined organic 1H, NCH2CH), 1.61 (d, J = 7.1 Hz, 3H, CHCH3); 13C NMR
phases were washed with brine (10 mL), dried (Na2SO4) and (100 MHz, CDCl3) 159.7 (NCOCH), 131.6 (C-Ar), 128.3
solvent was removed under reduced pressure to give 4 as a mix- (C-Ar), 124.4 (q, J = 275 Hz, CF3) 114.6 (C-Ar), 55.8
ture of two isomers, which were then separated by chromatog- (PhCHCH3), 51.7 (PhOCH3), 51.4 (q, J = 30.2 Hz, CHCF3),
raphy.
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;
Preparation of diastereoisomers 5a
Sodium salt 4a (245 mg, 0.86 mmol) and SOCl2 (310 μL, 4.3 found, 296.0868.
mmol) in DCM (20 mL), followed by Et3N (600 μL, 4.3 mmol),
gave 5 as a yellow oily solid.
Minor isomer (αS,3R)-5b (140 mg, 14%): [α]D20 −42.1 (c 0.18,
CH2Cl2); IR (neat): 2975 (s), 1760 (vs), 1611 (s), 1515 (s),
Major isomer (αS,3S)-5a (91 mg, 43%): [α]D20 −88.5 (c 0.34, 1370 (s), 1244 (vs), 1121 (s), 1031 (s), 1010 (s), 833 (s) cm−1;
CH2Cl2); IR (neat): 2978 (s), 1753 (vs), 1180 (s), 1120 (s), 892 1H NMR (400 MHz, CDCl3) 7.25–7.22 (m, 2 H, Ar), 6.94–6.90
(s), 699 (s), 571 (s) cm−1; 1H NMR (500 MHz, CDCl3) (m, 2H, Ar), 4.91 (q, J = 7.0 Hz, 1H, PhCHCH3), 3.83 (s, 3H,
7.42–7.27 (m, 5H, Ar), 4.97 (q, J = 7.0 Hz, 1H, ArCHCH3), PhOCH3), 3.78–3.68 (m, 1H, CH2CHCF3), 3.27 (dd, J = 6.4
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Beilstein J. Org. Chem. 2011, 7, 759–766.
Hz, J = 2.7 Hz, 1H, NCH2CH), 3.19 (dd, J = 6.3 Hz, J = 6.0 Hz, (1.94 g, 3.54 mmol, 3 equiv) was added portionwise. The reac-
1H, NCH2CH), 1.64 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, tion mixture was stirred at RT for 16 h and then quenched with
CDCl3) 159.3 (NCOCH), 131.3 (C-Ar), 127.9 (C-Ar), 123.9 (q, sat. sodium bicarbonate (5 mL). After 10 min of stirring (when
J = 275 Hz, CF3), 114.2 (C-Ar), 55.3 (PhCHCH3), 51.9 gas evolution ceased), the mixture was extracted into Et2O (3 ×
(PhOCH3), 51.0 (q, J = 31.2 Hz, CHCF3), 37.5 (q, J = 3.2 Hz, 10 mL), the combined organic phases were dried (Na2SO4) and
NCH2CH), 18.5 (CHCH3); 19F NMR (376 MHz, CDCl3) the solvent was removed. Purification on silica gel (20% EtOAc
−69.35 (d, J = 8.1 Hz, CHCF3); HRMS–ESI (m/z): Calcd for in petrol) gave (S)-1 as a colourless oil which solidified upon
C13H14NO2F3Na, 296.0874; found, 296.0883.
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)
Preparation of diastereoisomers 5c
From sodium salt 4c (500 mg, 1.50 mmol), SOCl2 (544 μL, 7.5 6.73 (bs, 1H, CH2NHCO), 3.91–3.81 (m, 1H, CHCF3), 3.47
mmol) in DCM (20 mL), followed by Et3N (1.05 mL, 7.5 (dd, J = 6.9 Hz, J = 6.3 Hz, 1H, NCH2CH), 3.37 (dd, J = 6.5
mmol) gave 5c as a yellow solid.
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),
Major isomer (αR,3R)-5c (192 mg, 41%): [α]D20 −40.9 (c 0.15, 53.7 (q, J = 31.3 Hz, CHCF3), 36.7 (q, J = 3.5 Hz, NCH2CH);
CH2Cl2); IR (neat): 2981 (s), 1760 (vs), 1368 (s), 1260 (s), 19F NMR (376 MHz, CDCl3) −69.38 (d, J = 9.5 Hz, CHCF3);
1158 (s), 1122 (s), 1011 (s), 780 (s) cm−1; 1H NMR (500 MHz, HRMS–ESI (m/z): Calcd for C4H4NOF3Na, 162.0143; found,
CDCl3) 8.10 (d, J = 8.4 Hz, 1H, Ar), 7.92 (d, J = 7.8 Hz, 1H, 162.0147.
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, Crystallographic data
1H, CHCF3), 3.31 (dd, J = 7.1 Hz, J = 6.0 Hz, 1H), 2.77 (dd, J 1 C4H4F3NO, M = 139.08, Monoclinic, space group P2(1),
= 6.5 Hz, J = 2.6 Hz, 1H), 1.80 (d, J = 7.2 Hz, 3H, CHCH3); a = 9.226(11), b = 5.507(6), c = 11.229(12) Å, β = 99.401(13)°.
13C NMR (75 MHz, CDCl3) 159.3 (q, J = 4.3 Hz, NCOCH), V = 562.9(11) Å3, F(000) = 280, Z = 4, Dc = 1.641 Mg m−3,
133.9 (C-Ar), 133.7 (C-Ar), 130.9 (C-Ar), 129.2 (C-Ar), 128.9 μ = 0.181 mm−1 (Mo-Kα, λ = 0.71073 Å). The data
(C-Ar), 127.0 (C-Ar), 126.2 (C-Ar), 123.7 (q, J = 275 Hz, CF3), were collected at T = 93 (2) K, 5405 reflections (2.24
123.7 (C-Ar), 122.7 (C-Ar), 51.0 (q, J = 31.1 Hz, CHCF3), 47.9 to 25.39°) were measured on a Rigaku Saturn 92 detector
(PhCHCH3), 37.4 (q, J = 3.2 Hz, NCH2CH), 17.8 (CHCH3); with 007 generator yielding 2016 unique data (Rint =
19F NMR (470 MHz, CDCl3) −68.6 (d, J = 9.1 Hz, CHCF3); 0.0777). Conventional R = 0.0194 for 1860 reflections
HRMS–ESI (m/z): Calcd for C16H14NOF3Na, 316.0925; found, with I ≥ 2σ, GOF = 1,011; 171 refined parameters. The
316.0915.
largest peak in the residual map is 0.247 eÅ−3.
Crystallographic data has been deposited with the Cambridge
Minor isomer (αR,3S)-5c (70 mg, 15%): [α]D20 −35.7 (c 0.14, Crystallographic Data Centre as supplementary publication
CH2Cl2); IR (neat): 2978 (s), 1755 (vs), 1366 (s), 1191 (s), (CCDC 821176).
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 (αR,3R)-5c C16H14F3NO, M = 293.28, Monoclinic, space group
Hz, 1H), 7.63–7.58 (m, 1H, Ar), 7.58–7.48 (m, 3H, Ar), 5.79 (q, P2(1), a = 9.677(5), b = 6.094(3), c = 12.231(5) Å,
J = 6.8 Hz, 1H, ArCHCH3), 3.69–3.60 (m, 1H, CHCF3), 3.25 β = 92.685(13)°. V = 720.5(5) Å3, F(000) = 304, Z = 2,
(dd, J = 6.5 Hz, J = 2.5 Hz, 1H), 2.86 (dd, J = 6.9 Hz, J = 6.2 Dc = 1.352 Mg m−3, μ = 0.949 mm−1 (Cu-Kα, λ = 1.54178 Å).
Hz, 1H), 1.82 (d, J = 7.2 Hz, 3H, CHCH3); 13C NMR (125 The data were collected at T = 173 (2) K, 9149 independent
MHz, CDCl3) 159.2 (q, J = 4.5 Hz, NCOCH), 133.9 (C-Ar), reflections (3.62 to 25.35°) were measured on a Rigaku Saturn
133.8 (C-Ar), 130.9 (C-Ar), 129.2 (C-Ar), 129.0 (C-Ar), 127.1 92 detector with 007 generator yielding 2504 unique data (Rint
(C-Ar), 126.2 (C-Ar), 125.1 (C-Ar), 123.9 (q, J = 275 Hz, CF3), = 0.0450). Conventional R = 0.0194 for 2416 reflections with I
123.7 (C-Ar), 122.6 (C-Ar), 47.7 (PhCHCH3), 50.9 (q, J = 31.1 ≥ 2σ, GOF = 0.973; 191 refined parameters. The largest peak in
Hz, CHCF3), 37.2 (q, J = 3.0 Hz, NCH2CH), 17.7 (CHCH3); the residual map is 0.124 eÅ−3. Flack parameter 0.08 (13).
19F NMR (470 MHz, CDCl3) −68.8 (d, J = 9.1 Hz, CHCF3); Crystallographic data has been deposited with the Cambridge
HRMS–ESI (m/z): Calcd for C16H14NOF3Na, 316.0925; found, Crystallographic Data Centre as supplementary publication
316.0919.
(CCDC 821177).
(S)-3-(Trifluoromethyl)azetidin-2-one (S)-1
To a solution of (αS,3S)-5b (325 mg, 1.18 mmol) in a mixture We thank the European Research Council for an Advanced
Acknowledgements
of MeCN (8 mL) and water (2 mL), ceric ammonium nitrate Investigator Grant.
765

Beilstein J. Org. Chem. 2011, 7, 759–766.
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