P. K. Mykhailiuk et al.
FULL PAPER
(2S)-2-(Trifluoromethyl)pyrrolidine (3): Pyrrolidone (S)-1 (30.6 g,
0.20 mol) was dissolved in dry THF under an atmosphere of argon,
and the solution was cooled in an ice bath. BH3·Me2S (45.6 g,
57 mL, 0.60 mol) was added to the solution over 1 h. The mixture
was then stirred at reflux for 2 h, cooled to –20 °C, and treated
with a saturated solution of HCl in methanol (200 mL). CAU-
TION: Vigorous evolution of gas. After the addition, the mixture
was kept at –20 °C for 1 h and then warmed to room temperature.
The volatile products were removed in vacuo, and the residue was
dissolved in dry toluene and heated to 60–70 °C. The solvent was
then removed under reduced pressure. The latter procedure was
repeated three times, and the residue was dried under high vacuum
at 60 °C. The hydrochloride of (S)-3 obtained in this way was
treated with a 40% aqueous NaOH (100 mL), and the product was
distilled at atmospheric pressure. The distillate was redistilled from
NaOH pellets to obtain (S)-3 (22.8 g, 0.16 mol, 82% yield) as a
Acknowledgments
Authors are very thankful to Prof. Andrey A. Tolmachev and En-
amine Ltd. company for financial support.
[1] a) I. Ojima, J. R. McCarthy, J. T. Welch, Biomedical Frontiers
of Fluorine Chemistry, ACS Symposium Series 639, American
Chemical Society, Washington, DC, 1996; b) D. O’Hagan,
H. S. Rzepa, Chem. Commun. 1997, 645; c) P. Kirsch, Modern
Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004; d) L.
Hunter, Beilstein J. Org. Chem. 2010, 6, 38 (DOI:10.3762/
bjoc.6.38).
[2] a) D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071; b) K.
Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881; c) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320; d) C. Isanbor, D. O’Hagan, J. Fluorine
Chem. 2006, 127, 303; e) J.-P. Bégué, D. Bonnet-Delpon, J. Flu-
orine Chem. 2006, 127, 992; f) K. L. Kirk, J. Fluorine Chem.
2006, 127, 1013.
1
colorless liquid. B.p. 86–92 °C. [α]2D0 = +9.3 (c = 1.17, MeOH). H
NMR (500 MHz, CDCl3, Me4Si): δ = 3.66 (m, 1 H, NCHCF3),
3.03 (t, 3JH,H = 6.0 Hz, 2 H, NCH2), 2.03–1.86 (m, 4 H, NH, CH2,
CHH), 1.77 (m, 1 H, CHH) ppm. 13C NMR (125 MHz, CDCl3,
[3] W. K. Hagmann, J. Med. Chem. 2008, 51, 4360.
1
2
Me4Si): δ = 126.92 (q, JC,F = 277.5 Hz, CF3), 58.66 (q, JC,F
=
[4] a) R. Smits, B. Koksch, Curr. Top. Med. Chem. 2006, 16, 1483;
b) B. Koksch, N. Sewald, H.-J. Hofmann, K. Burger, H.-D.
Jakubke, J. Pept. Sci. 1997, 3, 157; c) B. Koksch, D. Ullmann,
H.-D. Jakubke, K. Burger, J. Fluorine Chem. 1996, 80, 53; d)
M. Molteni, C. Pesenti, M. Sani, A. Volonterio, M. Zanda, J.
Fluorine Chem. 2004, 125, 1735.
3
28.8 Hz, NCHCF3), 47.07 (s, NCH2), 25.82 (q, JC,F = 1.3 Hz,
CH2CHCF3), 25.54 (s, CH2) ppm. 19F NMR (477 MHz, CDCl3,
3
CFCl3): δ = –77.3 (d, JF,H = 5.2 Hz, CF3) ppm. MS: m/z = 139.
C5H8F3N (139.12): calcd. C 43.17, H 5.80, N 10.07; found C 43.31,
H 5.95, N 9.81.
[5] V. P. Kukhar, V. A. Soloshonok, Fluorine-Containing Amino
Acids, John Wiley and Sons, New York, 1995.
[6] a) P. Bravo, G. Resnati, Tetrahedron: Asymmetry 1990, 1, 661;
b) P. K. Mikhailiuk, S. Afonin, A. N. Chernega, E. B. Rusanov,
M. O. Platonov, G. G. Dubinina, M. Berditsch, A. S. Ulrich,
I. V. Komarov, Angew. Chem. Int. Ed. 2006, 45, 5659; c) P. K.
Mykhailiuk, S. Afonin, G. V. Palamarchuk, O. V. Shishkin,
A. S. Ulrich, I. V. Komarov, Angew. Chem. Int. Ed. 2008, 45,
5765; d) P. K. Mykhailiuk, N. M. Voievoda, S. Afonin, A. S.
Ulrich, I. V. Komarov, J. Fluorine Chem. 2010, 131, 217; e) C.
Benhaim, L. Bouchard, G. Pelletier, J. Sellstedt, L. Kristofova,
S. Daigneault, Org. Lett. 2010, 12, 2008; f) X.-L. Qiu, F.-L.
Qing, J. Org. Chem. 2002, 67, 313; g) G. Chaume, M.-C. V.
Severen, S. Marinkovic, T. Brigaud, Org. Lett. 2006, 8, 6123;
h) P. K. Mykhailiuk, S. Afonin, A. S. Ulrich, I. V. Komarov,
Synthesis 2008, 1757.
X-ray Diffraction Study of (5S)-5-(trifluoromethyl)pyrrolidin-2-one
(1): The pyrrolidone ring adopts an envelope conformation. The
deviation of the C3 atom from the mean plane of the remaining
atoms of the ring is –0.34 Å. The trifluoromethyl group occupies
the axial position and is turned in such way that the C5–F3 bond
is antiperiplanar relative to the N1–C4 bond (the C1–N1–C4–C5
and N1–C4–C5–F3 torsion angles are 106.6(3) and 179.6(2)°,
respectively). In the crystal phase, molecules of 1 form infinite
chains (Figure 1, Supporting Information) along the [0 1 0] crystal-
lographic direction due to the formation of N1–H1N···O1Ј (0.5 –
x, 0.5 + y, 1 –z) intermolecular hydrogen bonds (H···O 1.96 Å, N–
H···O 168°). Crystals of 1 (C5H6F3NO) are monoclinic. At 100 K
a = 9.378(3) Å, b = 6.972(2) Å, c = 10.461(3) Å, β = 113.40(3)°, V
= 627.7(3) Å3, Mr = 153.11, Z = 4, space group C2, dcalcd. = 1.620 g/
cm3, μ (Mo-Kα) = 0.171 mm–1, F(000) = 312. Intensities of 2052
reflections (1457 independent, Rint = 0.050) were measured with an
Xcalibur-3 diffractometer (graphite monochromated Mo-Kα radia-
tion, CCD detector, ω-scanning, 2Θmax = 60°). The structure was
solved by direct methods by using the SHELXTL package.[14] The
positions of the hydrogen atoms were located from electron density
difference maps and refined by riding model with Uiso = 1.2 Ueq of
the carrier atom. The hydrogen atom forming the intermolecular
hydrogen bond was refined in isotropic approximation. Full-matrix
least-squares refinement against F2 in anisotropic approximation
for non-hydrogen atoms by using 1434 reflections was converged
to wR2 = 0.031 [R1 = 0.037 for 578 reflections with F Ͼ 4σ(F), S
= 0.624]. CCDC-776859 (for 1) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[7] a) C. Nájera, M. Yus, Tetrahedron: Asymmetry 1999, 10, 2245;
b) S. K. Panday, J. Prasad, D. K. Dikshit, Tetrahedron: Asym-
metry 2009, 20, 1581.
[8] a) D. W. Konas, J. K. Coward, Org. Lett. 1999, 1, 2105; b)
D. W. Konas, J. K. Coward, J. Org. Chem. 2001, 66, 8831.
[9] a) W. Dmowski, Houben Weyl: Methods of Organic Chemistry
(Eds. B. Baasner, H. Hagemann, J. C. Tatlow), Thieme, Stutt-
gart, 1999, vol. E10a, p. 321; b) D. S. Radchenko, P. K. Myk-
hailiuk, A. V. Bezdudny, I. V. Komarov, Synlett 2009, 1827; c)
Z. Hella, Z. Finta, W. Dmowski, F. Faigl, Y. M. Pustovit, L.
Toke, V. Harmat, J. Fluorine Chem. 2000, 104, 297; d) D. A.
Sibgatulin, A. V. Bezdudny, P. K. Mykhailiuk, N. M. Voievoda,
I. S. Kondratov, D. M. Volochnyuk, A. A. Tolmachev, Synthe-
sis 2010, 1075.
[10] Synthesis of racemic 1 by reduction of methyl 5,5,5-trifluoro-
4-nitropentanecarboxylate is described in: M. Negele, B.
Baasner, H.-J. Bertram, J. Hartwig, DE4029054, 1993.
[11] For the reviews on GABA, see: a) P. Krogsgaard-Larsen, B.
Frolund, F. S. Jorgensen, A. Schousboe, J. Med. Chem. 1994,
37, 2489; b) E. Roberts, E. Eidelberg, Int. Rev. Neurobiol. 1960,
2, 279; c) E. Roberts, Adv. Neurol. 1986, 44, 319.
[12] Synthesis of racemic 2 is described in: a) P. Bey, M. Jung (Mer-
rell Tourade et Compagnie), US4326071, 1982; b) N. N. Ser-
geeva, A. S. Golubev, L. Hennig, K. Burger, Synthesis 2002,
2579; c) W. Wan, J. Hou, H. Jiang, Z. Yuan, G. Ma, G. Zhao,
J. Hao, Eur. J. Org. Chem. 2010, 1778.
Supporting Information (see footnote on the first page of this
article): Copies of NMR spectra, determination of the optical
purity of compounds 1–3, and X-ray diffraction study of com-
pound 1.
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Eur. J. Org. Chem. 2011, 1782–1785