Reaction of cyclopropane carboxylic acid derivatives with sulphur tetrafluoride - An example of a diastereoselective ring opening

Article abstract of DOI:10.1016/S0022-1139(00)00257-8

Cyclopropane carboxylic acid derivatives can be converted into trifluoromethyl group-containing compounds using SF₄. In the case of a bicyclic cyclopropane carboxylic acid lactone, similar treatment with sulphur tetrafluoride resulted in the cyclopropane ring opening in a diastereoselective manner.

Full text of DOI:10.1016/S0022-1139(00)00257-8

Journal of Fluorine Chemistry 104 (2000) 297±301
Reaction of cyclopropane carboxylic acid derivatives with sulphur
tetra¯uoride Ð an example of a diastereoselective ring opening
a,*
Z. Hell , Z. Finta , W. Dmowski , F. Faigl , Yu.M. Pustovit , L. Toke , V. Harmat
a
b
a
b,1
a
c
Í
aDepartment of Organic Chemical Technology, Technical University of Budapest, H-1521 Budapest, Hungary
bInstitute of Organic Chemistry, Polish Academy of Sciences, PL 01-224 Warsaw, Poland
c
È È
Department of Theoretical Chemistry, L. Eotvos University, H-1518 Budapest, Hungary
Received 29 November 1999; accepted 23 February 2000
Abstract
Cyclopropane carboxylic acid derivatives can be converted into tri¯uoromethyl group-containing compounds using SF4. In the case of a
bicyclic cyclopropane carboxylic acid lactone, similar treatment with sulphur tetra¯uoride resulted in the cyclopropane ring opening in a
diastereoselective manner. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Cyclopropane; Sulphur tetra¯uoride; Ring opening
1. Introduction
into other functional groups. An ef®cient method for the
transformation of the carboxylic group into a tri¯uoromethyl
group is treatment with SF4. The method has been
applied for the transformation of numerous aliphatic, aro-
matic and heterocyclic carboxylic acids into the appropriate
tri¯uoromethyl compounds with satisfactory to good yield
[6].
For the preparation of multisubstituted cyclopropane
carboxylic acid derivatives from CH-acids, e.g. malonic
acid esters and ole®nes, a new convenient phase transfer
catalytic method was developed [7]. If the CH-acid moiety
and the ole®nic bond are in the same molecule in a proper
position (e.g. as in the malonic acid substituted allylic esters
of type 1), an intramolecular reaction occurs yielding the
bicyclic cyclopropane carboxylic acid lactones 2. These
lactones and their carboxylic acid derivatives 3 [8] can serve
as good intermediates for the synthesis of biologically
valuable cyclopropane derivatives.
Organic compounds containing tri¯uoromethyl group
possess a great importance in pharmaceutical and agricul-
tural chemistry since the tri¯uoromethyl group, due to its
high electronegativity and lipophilicity, often induces sig-
ni®cant changes in the physiological properties of biologi-
cally active molecules [1,2]. Cyclopropane derivatives are
members of an important class of biologically active sub-
stances [3], and several methods for the synthesis of their
¯uoro [4] and tri¯uoromethyl [5] group containing analo-
gues have been published.
Introduction of the tri¯uoromethyl group into an organic
compounds may cause dif®cult problems because of the
expensive starting materials and tedious procedures. The
carboxylic acid derivatives are important synthons in
organic syntheses, since the carboxylic group can be easily
introduced into organic molecules and it can be transformed
* Corresponding author. Tel.: ‡361-463-1414; fax: ‡361-463-3648.
E-mail address: hell@oct.bme.hu (Z. Hell)
1 Present address: The Ukrainian Academy of Sciences, Institute of Organic Chemistry, Kyiv 252094, Ukraine.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 5 7 - 8

298
Z. Hell et al. / Journal of Fluorine Chemistry 104 (2000) 297±301
As the transformation of lactones 3 into tri¯uoromethyl
group-containing derivatives can result in the formation of
new valuable cyclopropane derivatives we examined the
reaction of compounds 3 with SF4.
2. Results and discussion
Relaying upon these results we attempted conversion of
bicyclic acid 3a into an appropriate tri¯uoromethyl deriva-
tive. Treatment of 3a with SF4 in dichloromethane at 608C
for 4 h provided acid ¯uoride 8a as the sole product. Further
treatment of this acid ¯uoride with SF4 in dichloromethane
at 808C resulted in a preparatively unseparable mixture of
products of (partial) halogen exchange 8b, as found by GC±
At ®rst we examined reactivities of simple cyclopropane
carboxylic acids (5a, 5b) towards SF4. The model com-
pounds 5 were prepared from malonic acid derivatives and
1,2-dibromoethane using the known phase transfer catalytic
method [9] followed by hydrolysis of esters 4 in methanolic
KOH.
The reaction of 5a with SF4 in an autoclave at 608C for
21 h resulted in the formation of two main products 6a and
6b. The structures of the products were determined by GC±
MS analysis. Similar results were obtained when 3a was
reacted with SF4 in dichloromethane at 808C for 6 h or
without the solvent at 708C for 21 h.
MS and NMR analysis; the desired tri¯uoro derivative 6a
and the intermediate acid ¯uoride 6b was formed in ca. 1.2:1
ratio.
In the light of the above mentioned results, it was a
challenge to investigate the reactivity of 2a towards sulphur
tetra¯uoride. The model compound does not contain a free
carboxylic acid function but two types of ester groups. Since
2a does not contain a free carboxylic group, one drop of
water was added into the reaction mixture to generate HF
from SF4. Incubation of this mixture at 808C for 6 h in an
autoclave following by the usual workup resulted in con-
sumption of the starting material and appearance of a new
crystalline substance as the major product accompanied by
resinous materials. The IR spectrum of the crude product
showed the presence of unchanged ester and lactone car-
bonyl groups, and a new set of the signals appeared at 3.33,
3.70 and 5.00 ppm in the 1H NMR spectra. 19F NMR spectra
showed a signal of a ¯uorine atom coupled to six hydrogens
The nitrile 5b proved to be more reactive; after 6 h at
608C the sole product detected was 7 (the intermediate acid
¯uoride was not observed). We isolated 7 with less than 40%
yield because of its high volatility and decomposition.

Z. Hell et al. / Journal of Fluorine Chemistry 104 (2000) 297±301
299
(doublet of septets). Recrystallization of the product yielded
the pure crystalline lactone 9a. The 1H and 19F NMR spectra
of this pure substance showed the same characteristic
signals between H-4 and H-5 unambiguously con®rming
the trans relationship between the two bulky substituents at
C-4 and C-5, consequently the ring opening occurred
stereospeci®cally. On the basis of the above spectroscopic
data, HRMS and LSIMS investigations, we proposed the
structure 9a.
Fig. 2. Packing view of the crystal of 9a.
3. Conclusions
Cyclopropane ring openings under acidic conditions are
well known reactions, e.g. [10]. However, the reaction of the
simple cyclopropane derivatives 5a,b with SF4 resulted in
the formation of the desired tri¯uoromethylated derivatives
without any detectable amount of ring-opened products. At
the same time, the conversion of 3a into the appropriate
tri¯uoromethyl derivative was unsuccessful, the acid ¯uor-
ide formation and the chlorine to ¯uorine exchange were the
dominant reactions. It seems that in compound 2a, the effect
of the two electron withdrawing carbonyl groups on C(1)
atom of the cyclopropane ring and the two electron donating
methyl groups at position C(2) makes this compound sus-
ceptible to the cyclopropane ring opening. It should be
emphasized that this reaction does not occur upon treatment
with anhydrous HF in the absence of SF4.
The relative stereochemistry of compound 9a was also
con®rmed by X-ray crystallographical data (Fig. 1). In the
crystal, the carbethoxy group and the 2-¯uoroisopropyl
group are in the trans position.
The main crystal building forces are the dipole±dipole
interactions (Fig. 2). The lactone carbonyl group is aligned
quasi antiparallel to the C7±O9 vector of its symmetry
equivalent molecule while the CF(CH3)2 group forms a
looser contact (transformation by the inversion centre (1,
Ê
0.5, 0), C2(1). . .O9(2) 3.500 A, O3(1). . .C7(2) 3.221 A,
Ê
Ê
Ê
F13(1). . .C10(2) 3.357 A, C14(1). . .O9(2) 4.131 A). There
are dipole±dipole interactions between the CF(CH3)2
groups related by inversion (inversion centre at (1, 0, 0),
Ê
C15(1). . .F13(2) 3.662 A). The CCl3 group is polarised by
the O and F atoms of the neighbouring molecules in the
crystal.
4. Experimental
Melting points were determined in capillaries and are
uncorrected. IR spectra were recorded on Perkin±Elmer
Spectrum 1600 and 2000 instruments. 1H NMR spectra
were recorded on Bruker AW-250 (250 MHz) or Varian
Gemini 200 (200 MHz) spectrometers, chemical shifts are
given on the d scale using TMS as internal standard. 19F
NMR spectra were recorded on Varian Gemini 200
(188 MHz) spectrometer, chemical shifts are given on the
d scale using CFCl3 as internal standard. GC±MS analyses
were performed with a Hewlett-Packard 5890 instrument
using a HP5 column and the following temperature pro-
gram: 608C for 4 min then warming with the rate of 208C/
min to 2008C.
Cyclopropanecarboxylic acid derivatives 4a,b were pre-
pared following the literature procedure [9]; 4b was used
without further puri®cation.
4.1. Hydrolysis of esters 4a,b
A solution of potassium hydroxide (0.56 g, 0.01 mol) in
ethyl alcohol (5 ml) was added dropwise to a stirred solution
Fig. 1. ORTEP drawing of compound 9a.

300
Z. Hell et al. / Journal of Fluorine Chemistry 104 (2000) 297±301
of 4 (0.01 mol) in ethyl alcohol (5 ml) at 258C. The reaction
mixture was stirred at 258C for the reaction time indicated
below, the solvent was evaporated, the residue was dissolved
in water (10 ml), extracted with chloroform (10 ml) then the
aqueous phase was acidi®ed with conc. HCl, and extracted
with chloroform (3Â10 ml). The combined organic phases
were dried over MgSO4 and the solvent was removed in
vacuo.
4a: reaction time: 6 h then standing overnight. Yellowish
oil, yield: 1.13 g (71.6%). IR (neat) n (cm 1): 1758, 1639,
1H NMR (250 MHz, CDCl3): 1.21±1.34 (m, 3H), 1.77 (s,
4H), 4.24 (q, 2H), 10.8 (s, 1H).
GC±MS data of derivatives 8b: 8b(xˆ1): m/z (rel. int.,
‡
ion): 273 (35, M ), 8b(xˆ2): m/z (rel. int., ion): 289 (29,
‡
M )
4.4. Reaction of the lactone 2a with SF4
A solution of the lactone 2a (316 mg, 1 mmol) in dichlor-
omethane (10 ml), one drop of water (a source of HF) and
SF4 (7 g, 65 mmol) were reacted at 208C for 16 h followed
by 9 h at 70±758C. A liquid reaction mixture was washed
with water (3Â30 ml), dried over MgSO4 and the solvent
was removed on a rotary evaporator. The residue was
dissolved in ether (10 ml), ®ltered (removal of elemental
sulphur) and evaporated. A semi-solid residue (300 mg) was
dissolved in a minimal amount of ether and left overnight in
a refrigerator for crystallization. Crystals were ®ltered off,
washed with cold ether (2Â1 ml) and dried in air to give a
white crystalline product (110 mg, yield 30%). mp 122±
1248C.
4b: reaction time: 1 h, white solid. Yield: 0.9 g (64.7%),
1
1
mp 125±1278C. IR (neat) n (cm ): 2269, 1747; H NMR
(250 MHz, CDCl3): 1.60 (s, 4H).
4.2. Reaction of cyclopropanecarboxylic acids (4) with SF4
The acid 4 (1 mmol) were placed in a 30 ml capacity
stainless steel autoclave. The autoclave was immersed in a
dry ice-acetone bath ( 788C), evacuated to ca. 2 Torr then
SF4 (7 g, 65 mmol) was condensed into it. The charged
autoclave was kept at 608C for 21 h (4a) or 6 h (4b). After
cooling down to ambient temperature, gaseous products
(SOF2, HF, excess of SF4) were let off and the liquid
reaction mixture was dissolved in dichloromethane
(20 ml), washed with water (3Â30 ml), dried over MgSO4
and the solvent was removed on a rotary evaporator. The
residue was dissolved in ether (10 ml), ®ltered (removal of
elemental sulphur) and evaporated.
Analysis: found: Cl, 32.0; F, 5.8%. Calculated for
C11H14Cl3FO4: Cl, 31.7; F, 5.7%.
3
1H NMR (200 MHz, DMSO-d6): 1.32 (t, JHH=7.1 Hz,
3
3
CH3CH2); 1.46 (d, JHF=21.0 Hz, CH3); 1.59 (d, JHF
3
=
21.0 Hz, CH); 3.33 (ddd, JHF=23.0 Hz, JHH=4.8 Hz and
3
3
3
2.7 Hz, 1H); 3.70 (d, JHH=4.8 Hz, 1H); 4.3 (qd, JHH
7.1 Hz, J=0.7 Hz, CH3CH2); 5.0 (d, 3JHH=2.7 Hz, 1H). 19
NMR (188 MHz, DMSO-d6): 142.2 (d sept, JHF=23 and
21 Hz, 1F).
IR (KBr) n (cm 1): 1735.1 and 1798.4 (vs, C=O).
MS (EI, 70 eV) m/e (rel. int., ion): 289 [5, (M COOH) ],
=
F
3
‡
‡ ‡
6a: colorless liquid. 1H NMR (250 MHz, CDCl3): 1.24±
273 [23 (M C(CH3)2F) ], 201 (20, C5H4Cl3O2 l), 197 (53,
‡ ‡ ‡
C10H13O4 ), 151 (100, C8H7O3 ), 123 (12, C7H7O2 ), 115
1.30 (m, 3H), 1.36 (d, 2H, JHFˆ36 Hz), 1.72 (d, 2H, JHH
ˆ
‡ ‡
14.4 Hz), 4.22 (m, 2H).
GC±MS m/z (rel. int, ion): 182 (3, M ), 137 [100,
(10, C5H7O3 ), 61 [25, C(CH3)2F ],
HRMS: 306.96969 (C9H11Cl3FO4) ; 286.96399 (C9H10-
‡
‡
‡
‡
‡
‡
‡
‡
(M C2H5O) ], 109 [28, (M COOC2H5) ], 69 (15, CF3 ).
6b: GC±MS m/z (rel. int, ion): 115 [100, (M C2H5O) ],
Cl3O4) ; 272.94964 [M C(CH3)2F]
‡
LSIMS: 341, 339, 337 (M‡H) ; 363, 359, 357 (M‡
‡
‡
‡
113 [30, (M COF) ], 87 [7, (M COOC2H5) ], 47 (10,
‡
Na) .
COF )
X-ray diffraction study: single crystals from 9a were
obtained by slow evaporation of the isopropyl alcoholic
solution of the compound. Data were collected on a Rigaku
7a: colorless liquid, decomposes.
GC±MS: m/z (rel. int., ion): 135 (25, M ), 116 [27,
‡
‡
‡
‡
Ê
(M F) ], 109 [17, (M CN) ], 69 (60, CF3) , 66 [100,
‡
AFC6S diffractometer (lˆ1.5418 A, Tˆ293 K). The crys-
(M CF3) ].
tal data were as follows: C11H14Cl3FO4, Mˆ335.57, crystal
size 0.25mmÂ0.4mmÂ0.45 mm, space group: P-1, aˆ
Ê
Ê
Ê
4.3. Reaction of 3a with SF4
9.914(9) A, bˆ10.330(8) A, cˆ8.333(4) A, aˆ113.64(4)8,
3
,
Ê 3
bˆ95.23(8)8,gˆ70.6(1)8,Vˆ737(1)A ,Dcalcˆ1.513 gcm
A solution of the lactone 3a (0.57 g, 2 mmol) in dichlor-
omethane (10 ml) was placed in a 30 ml capacity stainless
steel autoclave then SF4 (3.5 g, 32 mmol) was condensed
into it. The charged autoclave was kept at 608C for 4 h and a
liquid reaction mixture was washed with water (3Â30 ml),
dried over MgSO4 and the solvent was removed on a rotary
evaporator. The residue was dissolved in ether (10 ml),
®ltered (removal of elemental sulphur) and evaporated to
give compound 8a as a yellowish semisolid unstable sub-
stance, yield: 0.34 g. IR (neat) n (cm 1): 1791.4 (C=O),
1828.5 (COF).
Zˆ2, mˆ5.819 mm 1, Ntotˆ1433, Nobsˆ968 (I>2s(I) ),
2ymaxˆ125.00. Structure solution with direct methods
was carried out with the teXsan package [11]. The re®ne-
ment was carried out using the SHELXL-97 program [12] with
full matrix least squares method on F2. Rigid bond restraints
were included for the atoms of the lactam group in the
re®nement. Hydrogen atoms were generated and their posi-
tions were re®ned by the riding model. Final R indices:
R1ˆ0.0712, wR2ˆ0.1821 for I>2s(I), R1ˆ0.1205, wR2ˆ
0.2458 for all data. Full data are deposited at the Cambridge
Structural Database, Deposition No.: CCDC 139604.

Z. Hell et al. / Journal of Fluorine Chemistry 104 (2000) 297±301
301
[4] T. Taguchi, H. Sasaki, A. Shibuya, T. Morikawa, Tetrahedron Lett.
35 (1994) 913.
Acknowledgements
[5] U.M. NaÈgele, M. Hanack, Liebigs Ann. Chem. (1989) 847.
[6] W. Dmowski, Introduction of fluorine using sulfur tetrafluoride, in:
B. Baasner, H. Hagemann, J.C. Tatlow (Eds.), Methods in Organic
Chemistry, Vol. E 10 a, Houben±Weyl, Stuttgart, 1999.
The work was supported by the Hungarian Scienti®c
Research Found (OTKA Grant No. T-023046) and the
Hungarian Academy of Sciences (Project No. LTA16).
Í Â Â
[7] L. Toke, Z. Hell, G.T. Szabo, G. Toth, M. Bihari, A. Rockenbauer,
Tetrahedron 49 (1993) 5133.
Í
[8] Z. Hell, L. Toke, Synth. Comm. 26 (1996) 2127.
References
 Í
[9] J. Heiszmann, I. Bitter, K. Harsanyi, L. Toke, Synthesis (1987)
738.
[1] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications,
Elsevier, Amsterdam, 1993.
[10] K.B. Wiberg, S.R. Kass, J. Am. Chem. Soc. 107 (1985) 988.
[11] teXsan: Crystal Structure Analysis Package, Molecular Structure
Co., 1985, 1992, Houston, Texas.
[2] R.D. Chambers, Fluorine in Organic Chemistry, Wiley, New York,
1973.
[3] J. Salaun, Chem. Rev. 83 (1989) 1247.
[12] G.M. Sheldrick, SHELXL-97 program for the refinement of crystal
È
structures, University of Gottingen, Germany, 1997.