Intramolecular s(N)2 reaction α- to a trifluoromethyl group: Preparation of 1-cyano-2-trifluoromethylcyclopropane

Article abstract of DOI:10.1016/S0957-4166(99)00253-0

The first intramolecular S(N)2 reaction of α-trifluoromethylated secondary alcohols by a carbanion is described. A stereoselective intramolecular cyclization of 3-substituted-3-cyano-1-trifluoromethylpropyl sulfonate via the cyano stabilized carbanion pro

Full text of DOI:10.1016/S0957-4166(99)00253-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2583–2589
Intramolecular SN2 reaction α- to a trifluoromethyl group:
preparation of 1-cyano-2-trifluoromethylcyclopropane
Toshimasa Katagiri, Minoru Irie and Kenji Uneyama ∗
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Received 21 May 1999; accepted 8 June 1999
Abstract
The first intramolecular SN2 reaction of α-trifluoromethylated secondary alcohols by a carbanion is described. A
stereoselective intramolecular cyclization of 3-substituted-3-cyano-1-trifluoromethylpropylsulfonate via the cyano
stabilized carbanion provides 1-substituted-1-cyano-2-trifluoromethylcyclopropanes in good yields. The product
has the opposite configuration to the starting alcohol at the carbon attached to trifluoromethyl group, revealing the
reaction takes place in SN2 manner with Walden inversion at the reaction center. © 1999 Elsevier Science Ltd. All
rights reserved.
1. Introduction
A low availability of optically active fluorinated compounds is a long-standing problem in the synthesis
of organofluorine compounds.1 One exception is optically active α-trifluoromethyl alcohols which are a
reliable class of fluorinated chiral building blocks due to a wide variety of methods for their preparation.2
On this basis, the development of stereospecific nucleophilic substitutions of the hydroxyl group of α-
trifluoromethylated alcohols with carbanions is needed to extend the utilization of these alcohols.
Displacement of the hydroxyl group of α-trifluoromethylated alcohols by a carbanion is very difficult,3
although there have been some reports on SN1-like substitution involving π-conjugation4 or neighboring
group participation of heteroatoms.5,6 To date, only a single such example of nucleophilic substitution
of 2,2,2-trifluoroethanol has been reported.7 A reaction of hindered α-trifluoromethylated secondary
alcohols with organometallic reagents has resulted in recovery of starting alcohols3 or the unexpected
production of tertiary alcohols,8 and no SN2 reaction has been reported.
The prevention of nucleophilic substitution by the vicinal fluorine atoms has been attributed to their
strong electron-withdrawing effect as well as to electrostatic repulsion between the lone pairs on the
fluorine atoms and the negatively charged nucleophile.9 The former effect results in shortened C–O bond
∗
Corresponding author. Tel: +81-86-251-8075; fax: +81-86-251-8021; e-mail: uneyamak@cc.okayama-u.ac.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00253-0

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of fluorinated alcohols,10 and the latter effect hinders an access of the nucleophile toward the carbon in
the SN2 reaction. We considered that the latter effect would be depressed somehow in an intramolecular
substitution.11 We designed an intramolecular cyclization, a cyclopropane synthesis as a model reaction
because an electrostatic repulsion between the CF3 group and the nucleophile would be reduced in
such a process. In this report, we describe the first intramolecular SN2 reaction of α-trifluoromethylated
secondary alcohols by a carbanion.
2. Results and discussion
Preparation of the starting materials, 4-substituted-4-cyano-1,1,1-trifluoro-2-butanols 1 by ring open-
ing reaction of 3,3,3-trifluoropropene oxide (TFPO)12 with substituted acetonitrile carbanions has been
described in our previous report.13 Mixtures of the two diastereomers of secondary alcohols 1 (about
30% de) were subjected to the subsequent cyclization without separation.
Starting compound 4-hydroxy-2-phenyl-5,5,5-trifluoropentanenitrile 1a was allowed to react with
p-TsCl in the presence of NaH, affording trifluoromethylated cyclopropane 2a as a sole product.
Optimization results on changing the leaving group, solvent, base, and temperature are summarized in
Table 1.
Table 1
Effect of leaving groups, solvents, bases, and temperature
The reactions with tosyl chloride, 2-mesitylenesulfonyl chloride, and trifluoromethanesulfonyl
chloride as activating agents for the OH group resulted in production of the cis-diastereomer 2a with
moderate to good diastereoselectivities (69–92% des). Meanwhile, the reaction of methanesulfonyl

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2585
chloride produced the trans-diastereomer, the opposite diastereomer of the 2a, as the major product with
low diastereoselectivity (24% de).
These results clearly revealed that the combination of p-TsCl with NaH in THF resulted in high yield
(83%) as well as high diastereomeric purity (92% de) in this cyclization.14 To confirm the configuration
of the major product, the trifluoromethylated cyclopropane 2a was converted to amide 4 having the chiral
acid moiety with a known absolute configuration via the reactions illustrated in Scheme 1.
Scheme 1.
Repeating recrystallization of the amide 4 from hexane gave colorless needles whose X-ray analysis
revealed the absolute configuration of the amide 4. Fig. 1 represents the ORTEP drawing of amide 4.
The geometry of the phenyl group and the trifluoromethyl group was found to be trans,15 and
the trifluoromethylated stereogenic carbon had the S configuration. These results clearly reveal that
the stereochemistry of the carbon attached to a trifluoromethyl group has been inverted during the
intramolecular nucleophilic substitution consistent with an SN2 mechanism.
The range of substituents investigated is summarized in Table 2. Carbanion moieties possessing a π-
conjugation system (entries 1–3, 5) could give the desired cyclopropanes in moderate to good yields.
Meanwhile, the carbanion moiety lacking such a π-system (entry 4) gave no desired cyclopropane.16
In conclusion, it has been found that an intramolecular process functions well for the nucleophilic
substitution of the α-trifluoromethyl secondary alcohols. The synthetic applications of (1-substituted-2-
trifluoromethyl)cyclopropyl cyanides 2 are now in progress.
3. Experimental
IR spectra were measured on a Hitachi model 270–30 infrared spectrometer. The 1H (200 MHz), 19
F
(188 MHz), and 13C (50.3 MHz) NMR spectra were recorded by Varian VXR apparatus and the chemical
1
shifts are reported in δ (ppm) values relative to TMS (δ 0.00 ppm for H and 13C NMR) and C6F6 (δ
0.00 ppm for 19F NMR). For the quantitative analysis by 19F NMR, 1,3-bis(trifluoromethyl)benzene was
used as an internal standard. Coupling constants (J) are reported in hertz. The NOESY was recorded
by a VXR-500 instrument. Optical rotation was measured in a cell with 50 mm length and 1 mL
capacity using a Horiba high sensitive polarimeter SEPA-300. Elemental analyses were performed
on Perkin–Elmer series II CHNS/O analyzer 2400. The EI-MS was performed on a Hewlett–Packard

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Figure 1. ORTEP depiction of N-[(1R,2S)-(2-trifluoromethyl-1-phenyl)cyclopropyl]methyl-(R)-2-bromo-propionamide 4
Table 2
Effect of substituents
HP5971A. All commercially available reagents were employed without further purification. THF and
Et2O were freshly distilled from Na and benzophenone, and CH3CN was distilled from CaH2 and stored
under nitrogen over molecular sieves. E. Merck silica gel (Kieselgel 60, 230–400 mesh) was employed
for chromatography. Enantiomeric excesses of 1-cyano-1-aryl-2-trifluoromethyl-cyclopropanes were
determined by GC analysis equipped with a chiral column (CP-Cyclodex-β-256M) on Shimadzu GC-
12A. Intensity measurements were carried out on a Rigaku RAXIS-IV imaging plate area detector.

T. Katagiri et al. / Tetrahedron: Asymmetry 10 (1999) 2583–2589
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3.1. (2-Trifluoromethyl-1-phenyl)cyclopropyl cyanide 2a
A THF solution (2 mL) of 1a (0.5 mmol, 0.115 g: starting from (S)-3,3,3-trifluoropropene oxide (75%
ee)) was added to a solution of TsCl (0.6 mmol, 0.114 g) and NaH (50–60% in liquid paraffin, 2.0 mmol,
0.076 g) in THF (3 mL). The mixture was stirred for 24 h at 0°C, and then treated with a saturated solution
of NH4Cl (2 mL, 3×). The organic layer was separated, and the aqueous layer was extracted with Et2O
(5 mL, 3×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. Purification on silica gel chromatography gave 0.079 g (75% yield (mixture of
major and minor diastereomers, 90% de), major diastereomer: 76.8% ee) of 2a as a yellowish oil. IR
1
(neat, mixture of major and minor diastereomers): 2260 cm−1; H NMR (CDCl3, major diastereomer):
δ 1.86 (ddq, J=6.2, 9.2, 1.4, 1H), 2.08 (dd, J=6.4, 6.9, 1H), 2.28 (ddq, J=6.9, 9.2, 6.2, 1H), 7.3–7.5
(m, 5H); 13C NMR (CDCl3, major diastereomer): δ 14.3, 18.1, 29.7 (q, J=38), 117.7, 123.7 (q, J=271),
126.7, 129.0, 129.3, 133.5; 19F NMR (CDCl3): δ 97.4 (d, J=6.4, major diastereomer), 99.3 (d, J=6.4,
minor diastereomer); EI-MS (rel. int.) major diastereomer: 211 (27, M+), 142 (100), 115 (100). Anal.
calcd mixture of major and minor diastereomers for C11H8F3N: C, 62.56; H, 3.82; N, 6.63. Found: C,
62.54; H, 4.12; N, 6.38.
3.2. [2-Trifluoromethyl-1-(4-methoxyphenyl)]cyclopropyl cyanide 2b
Yellowish oil, 64% yield (mixture of major and minor diastereomers, 89% de). IR (neat, mixture of
major and minor diastereomers): 2244 cm−1; 1H NMR (CDCl3, major diastereomer): δ 1.78 (ddq, J=6.2,
9.1, 1.3, 1H), 2.00 (dd, J=6.2, 6.9, 1H), 2.21 (ddq, J=6.8, 9.1, 6.6, 1H), 3.79 (s, 3H), 6.89 (d, J=8.9, 2H),
7.26 (d, J=8.9, 2H); 13C NMR (CDCl3, major diastereomer): δ 15.0, 18.3, 29.9 (q, J=38), 55.8, 115.2,
121.7, 128.6 (q, J=247), 128.9, 131.2, 160.5; 19F NMR (CDCl3): δ 97.6 (d, J=6.8, major diastereomer),
99.6 (J=7.6, minor diastereomer); EI-MS (rel. int.) major diastereomer: 241 (10, M+), 172 (30), 102 (43),
69 (100), 29 (92). Anal. calcd mixture of major and minor diastereomers for C12H10F3NO: C, 59.75; H,
4.18; N, 5.81. Found: C, 59.88; H, 4.40; N, 6.00.
3.3. [1-(4-Chlorophenyl)-2-trifluoromethyl]cyclopropyl cyanide 2c
Yellowish oil, 82% yield (mixture of major and minor diastereomers, 89% de). IR (neat, mixture of
major and minor diastereomers): 2251 cm−1; 1H NMR (CDCl3, major diastereomer): δ 1.73 (ddq, J=6.3,
9.1, 1.3, 1H), 1.99 (dd, J=6.3, 7.1, 1H), 2.14 (ddq, J=7.0, 9.1, 1.4, 1H), 7.1–7.3 (m, 4H); 13C NMR
(CDCl3, major diastereomer): δ 15.0, 18.7, 30.4 (q, J=40), 117.8, 124.0 (q, J=271), 128.7, 129.9, 130.1,
135.7; 19F NMR (CDCl3): δ 97.5 (d, J=6.0, major diastereomer), 99.5 (d, J=6.2, minor diastereomer);
EI-MS (rel. int.) major diastereomer: 247 (4, M+), 245 (17, M+), 210 (100), 190 (56), 176 (22), 149 (20),
140 (67), 114 (33). Anal. calcd mixture of major and minor diastereomers for C11H7ClF3N: C, 53.79; H,
2.87; N, 5.70. Found: C, 54.07; H, 3.17; N, 5.68.
3.4. [2-Trifluoromethyl-1-(1,1-diphenylmethylideneamino)]cyclopropyl cyanide 2d
Yellowish oil, 52%, (mixture of major and minor diastereomers, 32% de). IR (neat, mixture of major
1
and minor diastereomers): 2240 cm−1; H NMR (CDCl3; major diastereomer): δ 1.82 (m, 2H), 2.35
(m, 1H), 7.2–7.7 (m, 10H); 19F NMR (CDCl3): δ 101.4 (d, J=6.8, major diastereomer), 98.2 (d, J=6.0,
minor diastereomer); EI-MS (rel. int.) major diastereomer: 314 (3, M+), 218 (50), 165 (100). Anal. calcd

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mixture of major and minor diastereomers for C18H13F3N2: C, 68.79; H, 4.17; N, 8.91. Found: C, 68.66;
H, 4.51; N, 9.09.
3.5. [(1R,2R)-(2-Trifluoromethyl-1-phenyl)cyclopropyl]methylamine 3
To an Et2O solution (100 mL) of LiAlH4 (23.08 mmol, 1.84 g) was added 2a (75% ee, 23.1 mmol,
4.87 g) at −78°C under a nitrogen atmosphere. After the mixture was stirred for 3 h, 10% HCl aq. (15
mL) was added and the mixture was extracted with Et2O (100 mL). The extract was dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel
column chromatography to afford 1.52 g (7.1 mmol, 31%) of 3 (diastereomerically pure) as a yellowish
20
oil. IR (neat): 3400 cm−1; [α]D +27.9 (c 2.03, CHCl3); 1H NMR (CDCl3): δ 1.24–1.40 (m, 2H), 1.67
(br, 2H), 1.75–1.95 (m, 1H), 3.01 (s, 2H), 7.2–7.4 (m, 5H); 13C NMR (CDCl3): δ 14.1, 25.1 (q, J=36),
34.2, 45.8, 126.4 (q, J=271), 127.0, 128.3, 128.9, 141.2; 19F NMR (CDCl3): δ 102.7 (d, J=8.5); EI-MS
(rel. int.) 215 (33, M+), 118 (57), 30 (100). Anal. calcd for C11H12F3N: C, 61.39; H, 5.62; N, 6.51. Found:
C, 61.21; H, 5.75; N, 6.48.
3.6. N-[(1R,2S)-(2-Trifluoromethyl-1-phenyl)cyclopropyl]methyl-(R)-2-bromo-propionamide 4
A THF solution (20 mL) of DCC (4.7 mmol, 0.96 g) was added to a solution of 3 (2.3 mmol, 0.50 g)
and (R)-(+)-2-bromopropionic acid (2.8 mmol, 0.25 mL) and HOBt (3.5 mmol, 0.47 g) in THF (20 mL).
The mixture was stirred for 1 h at 0°C, and then warmed to room temperature, filtered and washed with
Et2O. The organic layer was separated, and the combined organic extracts were washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography
gave 0.68 g (83%) of 4 as a colorless powder. The compound 4 thus obtained was recrystallized from
hexane (3 mL, 5×), and diastereomeric purity was increased to >99.5% de, >99.5% ee (7% yield). Mp:
72°C; IR (KBr): 3280, 1670 cm−1; [α]D +24.1 (c 1.04, CHCl3); H NMR (CDCl3): δ 1.38–1.52 (m,
2H), 1.77 (d, J=7.2, 3H), 1.82–2.02 (m, 1H), 3.47 (dd, J=14.3, 4.8, 1H), 3.92 (dd, J=6.9, 14.2, 1H), 4.30
(q, J=7.0, 1H), 6.46 (br, 1H), 7.2–7.4 (m, 5H); 19F NMR (CDCl3): δ 102.3 (d, J=8.1); EI-MS (rel. int.)
350 (2, M+), 270 (95), 198 (100), 174 (100), 119 (95). Anal. calcd for C14H15BrF3NO: C, 48.02; H, 4.32;
N, 4.00. Found: C, 48.03; H, 4.53; N, 4.20.
20
1
3.7. Absolute configuration of the stereogenic centers were determined on the basis of the (R)-(+)-2-
bromopropionic acid moiety of amide 4
Crystal data for amide 4: C28H30Br2F6N2O2 for a pair of molecules having the same chemical structure
C14H15BrF3NO with different conformations. Mr=700.36 (for a pair of two molecules 350.18×2);
orthorhombic; P212121; a=9.524(0), b=33.19(7), c=9.561(7) Å, V=3023.(1) Å3, Z=4, Dx=1.539 g/cm3;
µ=27.54 cm−1 for Mo Kα radiation (λ=0.7107 Å). The structure was solved by a direct method (SIR
92), and refined by a full-matrix least-squares method. Final R was 0.066 and Rw was 0.061 for 1256
reflection with I0>3.00σ(I0).
Acknowledgements
We thank the SC-NMR Laboratory of Okayama University for 19F NMR analyses and the Venture
Business Laboratory of Graduate School of Okayama University for X-ray analysis. The financial support

T. Katagiri et al. / Tetrahedron: Asymmetry 10 (1999) 2583–2589
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from Monbusho (Grant-in-Aid for Scientific Research on Priority Areas, No. 706: Dynamic Control of
Stereochemistry) is gratefully acknowledged.
References
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16. Major product (>70%) of this reaction was 4-cyano-1,1,1-trifluoro-2-butyl tosylate, tosyl ester of the starting compound,
together with small amounts (<5%) of compounds of undefined structure.