Synthesis of β-fluoro-β-proline

Article abstract of DOI:10.1016/j.tetlet.2011.01.070

A synthetic strategy towards the novel amino acid β-fluoro-β- proline, a fluorinated analogue of β-proline, is elaborated. The synthesis commences from commercially available methyl 2-fluoroacrylate and involves three steps. The overall yield of β-fluoro-

Full text of DOI:10.1016/j.tetlet.2011.01.070

Tetrahedron Letters 52 (2011) 1300–1302
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Tetrahedron Letters
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Synthesis of b-fluoro-b-proline
⇑
Vladimir S. Yarmolchuk, Pavel K. Mykhailiuk , Igor V. Komarov
Enamine Ltd, Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic strategy towards the novel amino acid b-fluoro-b-proline, a fluorinated analogue of b-proline,
is elaborated. The synthesis commences from commercially available methyl 2-fluoroacrylate and
involves three steps. The overall yield of b-fluoro-b-proline is 57%.
Received 2 November 2010
Revised 21 December 2010
Accepted 14 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
b-Amino acids
Proline
Drug design
The beneficial effects of fluorine as a substituent in organic
compounds have stimulated intense research in organofluorine
chemistry. This is reflected by the numerous papers in this area
and by the commercial applications of organofluorine compounds
in pharmaceutical chemistry and agrochemistry.1,2 As a specific
class of fluorine-containing biologically active compounds, fluori-
nated b-amino acids are recognized as exciting building blocks
for the synthesis of b-peptides and antibiotics, as enzyme inhibi-
tors and as therapeutic agents.3,4 Nevertheless, in contrast to the
large number of synthetic approaches for the preparation of fluori-
nated acyclic b-amino acids, the synthesis of cyclic derivatives has
received much less development.5
Pyrrolidine 3-carboxylic acid, or b-proline (Fig. 1) is a con-
strained b-amino acid commonly used in the design of peptides
with enhanced stability towards hydrolysis by proteases.6 b-Pro-
line is also a potent agonist of the strychnine-sensitive glycine
receptor,7 serves as a building block for the preparation of novel
inhibitors of bacterial DNA gyrase8 and forms the central moiety
of a conformationally restricted, highly potent fibrinogen receptor
antagonist.9 In addition, b-proline has been used as an organocat-
alyst for the Mannich reaction10 between ketones and imines. It
is worth noting that the b-proline motif occurs frequently within
drug discovery programmes (Fig. 2).11 In this context, and in con-
tinuation of our interest in fluorinated analogues of pharmacolog-
ically relevant compounds,12 herein we report our studies on the
synthesis of the novel amino acid, b-fluoro-b-proline (1): a fluo-
rine-containing b-proline analogue.
CO2H
CO2H
F
N
H
N
H
β-proline
1
Figure 1. Structures of b-proline and b-fluoro-b-proline (1).
NH
HO
N
O
O
N
N
O
CO2H
merafloxacine
triclazate
Figure 2. Some representative pharmacologically relevant derivatives of b-proline:
triclazate (anticholinergic), merafloxacine (antibiotic).
The 1,3-dipolar cycloaddition between azomethine ylides and
alkenes is a potent method for the construction of substituted pyr-
rolidines.13 The cycloaddition reaction is accelerated by electron-
withdrawing substituents on the alkene.14 For example, this strat-
egy is used to prepare unsubstituted b-proline from methyl acry-
late.15 On the other hand, activated alkenes bearing additional
electronegative fluorine atoms are expected to be excellent
⇑
Corresponding author. Tel.: +38 066 2666399; fax: +38 044 537 32 53.
E-mail address: Pavel.Mykhailiuk@gmail.com (P.K. Mykhailiuk).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.070

V. S. Yarmolchuk et al. / Tetrahedron Letters 52 (2011) 1300–1302
1301
hydrogenation of the benzyl group in Bn-1 using 10% palladium
on charcoal as the catalyst accomplished the synthesis of amino
acid 1 in 80% yield. Importantly, the overall yield of the synthesis
was 57% from methyl 2-fluoroacrylate (4) over three steps.
Next, several representative transformations of amino acid 1
were performed (Scheme 3). The nitrogen atom in pyrrolidine 1
was protected with the most commonly used N-protecting groups
in amino acid chemistry—Fmoc and Boc. First, treatment of 1 with
Fmoc–Cl/Na2CO3 in 1,4-dioxane/water mixture for 24 h at room
temperature afforded the protected compound Fmoc-1, which is
suitable for peptide synthesis. Similarly, Boc-protection of amino
acid 1 following the standard Boc2O/Na2CO3 protocol resulted in
formation of the corresponding derivative Boc-1 in a good yield
of 71%.18
No HF elimination was observed during the synthesis of com-
pounds 1, Bn-1, Boc-1 and Fmoc-1 as was evident from the 13C
NMR spectral data. The above products appeared to be completely
stable, and hence they may be conveniently used in the synthesis
of fluorine-containing building blocks and, in particular, of various
b-proline-containing peptide mimics.
In summary, we have developed an efficient and practical syn-
thesis of the novel amino acid, b-fluoro-b-proline (1). Compound 1
is a fluorine-containing b-proline analogue. The synthesis com-
mences from commercially available methyl 2-fluoroacrylate (4)
and requires only three steps. The overall yield of the synthesis is
57%. Representative derivatives of amino acid 1, Bn-1, Boc-1 and
Fmoc-1 were also prepared. With rapid scalable synthesis, we ex-
pect compound 1 and its related derivatives described herein to
find wide applications in medicinal chemistry as b-proline ana-
logues.19–23
CO2PG
F
CO2H
F
CO2PG
F
+
N
H
N
PG
N
1
PG
PG: protecting group
Scheme 1. Retrosynthetic approach to b-fluoro-b-proline (1).
MeOH
ClCH2SiMe3
Ref.17
CH2O
NH2
Bn
SiMe3
MeO
SiMe3
HN
Bn
N
Ref.17
Bn
2
CO2Me
CO2Me
F
4
F
NaOH
TFA
N
CH2Cl2
95%
MeOH-H2O
75%
N
Bn
3
5
Bn
CO2H
CO2H
F
Pd/H2
F
MeOH
80%
N
N
H
Bn
Bn-1
1
Scheme 2. Synthesis of amino acid 1.
Acknowledgements
CO2H
F
The authors are very grateful to Enamine company and Prof. An-
drei Tolmachev for financial support of this work.
Fmoc-Cl
Na2CO3
N
90%
Fmoc
Fmoc-1
CO2H
F
References and notes
1. For example, see: (a) Kukhar, V. P.; Soloshonok, V. A. Fluorine-Containing Amino
Acids; John Wiley and Sons: New York, 1995; (b) Ojima, I.; McCarthy, J. R.;
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639; American Chemical Society: Washington, DC, 1996; (c) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
N
H
CO2H
Boc2O
Na2CO3
1
F
N
71%
2. For reviews, see: (a) Grygorenko, O. O.; Artamonov, O. S.; Komarov, I. V.;
Mykhailiuk, P. K. Tetrahedron 2011, 1, 803; (b) Hunter, L. Beilstein J. Org. Chem.
Boc
Boc-1
´
2010. doi:10.3762/bjoc.6.38; (c) OHagan, D. J. Fluorine Chem. 2010, 131, 1071; (d)
Sorochinsky, A. E.; Soloshonok, V. A. J. Fluorine Chem. 2010, 131, 127; (e) Purser,
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Scheme 3. Synthesis of Boc-1 and Fmoc-1.
´
J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992; (j) Isanbor, C.; OHagan,
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substrates for the synthesis of fluoropyrrolidines. However, this
strategy has received almost no attention.16
Our retrosynthetic approach to amino acid 1 was based on com-
mercially available methyl 2-fluoroacrylate, as a fluorine-contain-
ing electron-deficient alkene for the corresponding [3+2]
cycloaddition reaction (Scheme 1).
The synthesis of 1 commenced from N-methoxymethyl-N-(tri-
methylsilylmethyl)benzylamine (2), which was readily prepared
in two steps from benzylamine following the literature protocol
(Scheme 2).17 Next, azomethine ylide 3 was generated in situ from
compound 2 by adding trifluoroacetic acid. The key reaction be-
tween ylide 3 and methyl 2-fluoroacrylate (4) was performed in
dry dichloromethane at room temperature over 4 h, which resulted
in formation of the corresponding fluoropyrrolidine 5 in an excel-
lent yield of 95% after purification. Hydrolysis of the CO2Me group
in pyrrolidine 5 with 1 equiv of NaOH in MeOH/H2O mixture gave
N-benzyl protected compound 1 (Bn-1) in 75% yield. Finally,
3. (a) Aceña, J. L.; Simón-Fuentes, A.; Fustero, S. Curr. Org. Chem. 2010, 14, 928; (b)
Juaristi, E.; Soloshonok, V. Enantioselective Synthesis of b-Amino Acids; John
Wiley & Sons: Hoboken, New Jersey, 2005.
4. (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711; (b)
Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17, 621.
5. (a) Hende, E. V.; Verniest, G.; Deroose, F.; Thuring, J.-W.; Macdonald, G.; De
Kimpe, N. J. Org. Chem. 2009, 74, 2250; (b) Fustero, S.; Sanchez-Rosello, M.;
Sanz-Cervera, J. F.; Acena, J. L.; del Pozo, C.; Fernandez, B.; Bartolome, A.;
Asensio, A. Org. Lett. 2006, 8, 4633; (c) Fustero, S.; Bartolome, A.; Sanz-Cervera,
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1302
V. S. Yarmolchuk et al. / Tetrahedron Letters 52 (2011) 1300–1302
10. (a) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc. 2006, 128,
9630; (b) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.;
Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 1040.
11. A MDL Drug Data Report search in October 2010 revealed that 43 compounds
with a b-proline motif were under clinical testing.
12. (a) Mykhailiuk, P. K.; Voievoda, N. M.; Afonin, S.; Ulrich, A. S.; Komarov, I. V. J.
Fluorine Chem. 2010, 131, 217; (b) Mykhailiuk, P. K.; Radchenko, D. S.; Komarov,
I. V. J. Fluorine Chem. 2010, 131, 221; (c) Radchenko, D. S.; Mykhailiuk, P. K.;
Bezdudny, A. V.; Komarov, I. V. Synlett 2009, 1827; (d) Mykhailiuk, P. K.; Afonin,
S.; Ulrich, A. S.; Komarov, I. V. Synthesis 2008, 1757; (e) Mykhailiuk, P. K.;
Afonin, S.; Palamarchuk, G. V.; Shishkin, O. V.; Ulrich, A. S.; Komarov, I. V.
Angew. Chem., Int. Ed. 2008, 45, 5765; (f) Tkachenko, A. N.; Radchenko, D. S.;
Mykhailiuk, P. K.; Grygorenko, O. O.; Komarov, I. V. Org. Lett. 2009, 11, 5674.
13. (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765; (b) Pandey, G.; Banerjee,
P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
was extracted with Et2O (3 Â 100 mL). The aqueous phase was acidified with
6 N HCl at 5 °C to adjust the pH of the reaction mixture to pH 3. Saturated aq
NH3 solution (100 mL) was added and the aqueous phase was extracted with
EtOAc (3 Â 100 mL). The combined organic phase was dried over MgSO4 and
evaporated under vacuum to give acid Bn-1 (3.51 g, 0.016 mmol, 75% yield) as
a tarry oil, which solidified upon standing. 1H NMR (500 MHz; D2O; Me4Si), d:
2.35 (1H, m, 4-CHH), 2.53 (1H, m, 4-CHH), 2.35 (1H, m, NCHH), 3.49–3.59 (3H,
m, NCHH + NCH2), 4.25 (1H, d, J = 13.0 Hz, PhCHH), 4.29 (1H, d, J = 13.5 Hz,
PhCHH), 7.41 (5H, m, Ph). 13C NMR (125 MHz; D2O; Me4Si), d: 35.51 (d,
2JCF = 26.3 Hz, 4-CH2), 52.99 (s, PhCH2N), 58.87 (s, 5-CH2), 61.92 (d,
1
2JCF = 27.5 Hz, 2-CH2), 9.65 (d, JCF = 191.3 Hz, 3-CF), 129.36 (s, CH, Ph),
129.86 (s, CH, Ph), 130.41 (s, CH, Ph), 131.00 (s, quat-C, Ph), 174.10 (d,
2JCF = 23.8 Hz, CO2H). 19F NMR (477 MHz; D2O; Me4Si), d: À143.53 (quint,
3JFH = 23.9 Hz, F). GC–MS: 223 (M+). Anal. calcd for C12H14FNO2: C, 64.56; H,
6.32; N, 6.27. Found: C, 64.73; H, 6.52; N, 6.00.
14. (a) Mendiola, J.; Garcia-Cerrada, S.; de Frutos, O.; de la Puente, M. L.; Gu, R. L.;
Khau, V. V. Org. Process Res. Dev. 2009, 13, 292; (b) Yan, L.; Hale, J. J.; Lynch, C.
L.; Budhu, R.; Gentry, A.; Mills, S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.;
Milligan, J. A.; Shei, G.-J. Bioorg. Med. Chem. Lett. 2004, 14, 4861; (c) Delaney, E.
J.; Wood, L. E.; Klotz, I. J. Am. Chem. Soc. 1982, 104, 799; (d) MacLeod, A. M.;
Baker, R.; Freedman, S. B.; Patel, S.; Merchant, K. J. J. Med. Chem. 1990, 33, 2052.
15. Padwa, A., 1st ed. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Elmsford, New York, 1991; Vol. 4, pp 1069–1109.
16. (a) Qiu, Y.-L.; Ying, L.; Or, Y. S.; Wang, C.; Long, J. US2009/0004140 A1, 2009;
Chem. Abstr. 2009, 150, 98139.; (b) Mason, J. M.; Murkin, A. S.; Li, L.; Schramm,
V. L.; Gainsford, G. J.; Skelton, B. W. J. Med. Chem. 2008, 51, 5880; (c) Rogel, O.;
Rondeau, J.-M.; Rueeger, H.; Simic, O.; Sirockin, F.; Tintelnot-Blombey, M.
WO2007/140980 A1, 2007; Chem. Abstr. 2007, 147, 323011.; (d) Bonini, B. F.;
Boschi, F.; Franchini, M. C.; Fochi, M.; Fini, F.; Mazzanti, A.; Ricci, A. Synlett
2006, 543.
17. (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117; (b) Padwa, A.;
Dent, W. J. Org. Chem. 1987, 52, 235. and references cited therein..
18. Boc-1-OMe was reported in Deng, Y.; Shipps, G. W., Jr.; Cooper, A.; Nan, Y.;
Wang, T.; Siddiqui, M. A.; Zhu, H.; Sun, R.; Kelly, J.; Doll, R.; Desai, J.; Wang, J.;
Dong, Y.; Madison, V. S.; Xiao, L.; Hruza, A.; Shih, N. WO2007/097937 A1, 2007;
Chem. Abstr. 2007, 148, 54885, however, neither analytical or NMR data for this
compound was given.
21. 3-Fluoro-b-proline (1). Compound Bn-1 (3.51 g, 36.5 mmol) was dissolved in
anhydrous MeOH (150 mL) and 10% Pd on charcoal (0.70 g) was added. This
mixture was hydrogenated at room temperature at a H2 pressure of 20 atm for
10 h. The catalyst was filtered off and the filtrate was evaporated under
vacuum to afford the pure amino acid 1 (1.71 g, 80% yield) as a white solid.
Mp >200 °C. 1H NMR (500 MHz; D2O; Me4Si), d: 2.40 (2H, m, 4-CH2), 3.48 (1H,
m, NCHH), 3.56–3.67 (3H, m, NCHH + NCH2). 13C NMR (125 MHz; D2O; Me4Si),
2
2
d: 35.34 (d, JCF = 25.0 Hz, 4-CH2), 44.91 (s, 5-CH2), 54.17 (d, JCF = 28.8 Hz, 2-
CH2), 100.51 (d, 1JCF = 190.0 Hz, 3-CF), 173.55 (d, 2JCF = 23.8 Hz, CO2H). 19F NMR
3
(477 MHz; D2O; Me4Si), d: À150.09 (quint m, JFH = 28.6 Hz, F). Anal. calcd for
C5H8FNO2: C, 45.11; H, 6.06; N, 10.52. Found: C, 44.95; H, 6.17; N, 10.71.
22. N-Fmoc-3-fluoro-b-proline (Fmoc-1).
A solution of Fmoc-Cl in 1,4-dioxane
(0.52 g, 2.01 mmol) was added dropwise over 15 min to a solution (stirred at
0 °C) of 3-fluoro-b-proline (1) (0.25 g, 1.9 mmol) and Na2CO3 (1 g) in 1,4-
dioxane–H2O (50 mL, 2/3, v/v). After being stirred at this temperature for
30 min, the reaction mixture was left overnight at rt. H2O (500 mL) was added
and the mixture was extracted with Et2O (2 Â 50 mL). The aqueous phase was
acidified with dilute HCl to pH 1 and extracted with EtOAc (3 Â 100 mL). After
being dried (MgSO4) the solvent was evaporated to give Fmoc-1 (0.61 g,
1.17 mmol, 90% yield) as a white solid. Mp = 182–184 °C. 1H NMR (500 MHz;
DMSO-d6; Me4Si), d: 2.32 (2H, m, 4-CH2), 3.63–3.74 (4H, m, NCH2 + NCH2), 4.29
(1H, br s, CHCH2, Fmoc), 4.35 (2H, br s, CHCH2, Fmoc), 7.35 (2H, t, J = 7.5 Hz,
Fmoc), 7.43 (2H, t, J = 7.5 Hz, Fmoc), 7.66 (2H, br s, Fmoc), 7.91 (2H, d,
J = 7.0 Hz, Fmoc). 13C NMR (125 MHz; DMSO-d6; Me4Si; 2 conformers are
19. N-Benzyl-3-fluoro-b-proline methyl ester (5). A solution of TFA (0.4 mL) in dry
CH2Cl2 (10 mL) was slowly added to
a stirred solution of N-benzyl-N-
2
(methoxymethyl)-N-trimethylsilylmethylamine (2) (12.0 g, 0.050 mol) and
methyl 2-fluoroacrylate (4) (5.0 g, 0.048 mol) in dry CH2Cl2 (150 mL) at 0 °C.
CAUTION: exothermic reaction! The reaction mixture was stirred for an
additional 4 h at room temperature. An excess of aq saturated NaHCO3 solution
was added. The organic phase was washed with 100 mL of brine, dried over
Na2SO4 and evaporated under vacuum. The residue was purified by flash
column chromatography using hexane/EtOAc = 2/1 mixture as eluent to give
the pure product 5 (10.5 g, 95% yield) as a colourless oil. Rf = 0.5. 1H NMR
(500 MHz; CDCl3; Me4Si), d: 2.23–2.33 (1H, m, 4-CHH), 2.44–2.54 (1H, m, 4-
CHH), 2.69 (1H, q, J = 8.0 Hz, NCHH), 2.95–3.03 (3H, m, NCHH + NCH2), 3.71
(1H, d, J = 13.5 Hz, PhCHH), 3.74 (1H, d, J = 13.5 Hz, PhCHH), 3.83 (3H, s, OCH3),
7.28–7.36 (5H, m, Ph). 13C NMR (125 MHz; CDCl3; Me4Si), d: 37.11 (d,
2JCF = 23.8 Hz, 4-CH2), 52.77 (s, OCH3), 52.98 (s, PhCH2N), 59.70 (s, 5-CH2),
present), d: 34.42, 35.52 (2 d, JCF = 20.0 Hz, 4-CH2), 44.58, 45.05 (2 s, 5-CH2),
2
47.17 (s, CHCH2, Fmoc), 54.77, 55.35 (2 d, JCF = 28.8 Hz, 2-CH2), 67.14 (s,
1
CHCH2, Fmoc), 98.30, 99.64 (2 d, JCF = 191.3 Hz, 3-CF), 120.61 (s, CH, Fmoc),
125.54 (s, CH, Fmoc), 127.63 (s, CH, Fmoc), 128.17 (s, CH, Fmoc), 141.21 (s,
quat-C, Fmoc), 144.28 (s, quat-C, Fmoc), 154.16, 154.31 (2 s, NC@O), 169.88,
2
170.11 (2 d, JCF = 23.8 Hz, CO2H). 19F NMR (477 MHz; DMSO-d6; Me4Si; 2
conformers are present), d: À156.72, À157.23 (2 m, F). LC–MS: 355 (M+).
23. N-Boc-3-fluoro-b-proline (Boc-1). Boc2O (0.44 g, 2.01 mmol) was added to a
solution of 3-fluoro-b-proline (1) (0.25 g, 1.90 mmol) and Na2CO3 (1 g) in 1,4-
dioxane–H2O (70 mL, 1/1, v/v). After being stirred at this temperature for
30 min, the reaction mixture was stirred for an additional 48 h at room
temperature. H2O (500 mL) was added and the mixture was extracted with
Et2O (2 Â 50 mL). The aqueous phase was acidified with dilute HCl to pH 3 and
extracted with EtOAc (3 Â 100 mL). After being dried (MgSO4) the solvent was
evaporated to afford Boc-1 (0.31 g, 1.35 mmol, 71% yield) as a white solid.
Mp = 140–142 °C. 1H NMR (500 MHz; CDCl3; Me4Si), d: 1.48 (9H, m, C(CH3)3),
2.45 (2H, m, 4-CH2), 3.57 (1H, m, NCHH), 3.81 (3H, m, NCHH + NCH2). 13C NMR
(125 MHz; DMSO-d6; Me4Si; 2 conformers are present), d: 28.55 (s, C(CH3)3,
2
1
63.40 (d, JCF = 23.8 Hz, 2-CH2), 99.80 (d, JCF = 191.3 Hz, 3-CF), 127.21 (s, CH,
Ph), 128.37 (s, CH, Ph), 128.70 (s, CH, Ph), 139.53 (s, quat-C, Ph), 171.42 (d,
2JCF = 27.5 Hz, CO2Me). 19F NMR (477 MHz; CDCl3; Me4Si), d: À149.28 (quint,
3JFH = 28.6 Hz, F). GC–MS: 237 (M+). Anal. calcd for C13H16FNO2: C, 65.81; H,
6.80; N, 5.90. Found: C, 65.51; H, 6.43; N, 5.95.
2
20. N-Benzyl-3-fluoro-b-proline (Bn-1). A solution of NaOH (0.84 g, 0.021 mol) in
H2O (25 mL) was added dropwise over a period of 15 min to a stirred solution
of methyl ester 5 (5.00 g, 0.021 mol) in MeOH (100 mL)–H2O (50 mL) at 0 °C.
After the addition was complete the reaction mixture was stirred at room
temperature for 7 h. MeOH was evaporated in vacuum, and the aqueous phase
Boc), 34.55, 35.41 (2 d, JCF = 22.5 Hz, 4-CH2), 44.52, 44.78 (2 s, 5-CH2), 55.05,
2
55.07 (2 d, JCF = 23.8 Hz, 2-CH2), 79.49 (s, C(CH3)3, Boc), 98.35, 99.55 (2 d,
2
1JCF = 186.3 Hz, 3-CF), 153.69, 153.83 (2 s, NC@O), 170.18 (d, JCF = 21.3 Hz,
CO2H). 19F NMR (477 MHz; DMSO-d6; Me4Si; 2 conformers are present), d:
À155.61, À156.11 (2 m, F). LC–MS: 233 (M+).