Simple synthesis of 1,1-bis(trifluoromethyl)cyclopropanes

Article abstract of DOI:10.1016/j.jfluchem.2011.06.022

A new, simple synthesis of 1,1-bis(trifluoromethyl)cyclopropanes has been discovered. It is based on the reaction of readily available 2,2-bis(trifluoromethyl)thietanes with tertiary phosphines in a polar solvent, which leads to an unusual desulfurization

Full text of DOI:10.1016/j.jfluchem.2011.06.022

Journal of Fluorine Chemistry 133 (2012) 61–66
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Simple synthesis of 1,1-bis(trifluoromethyl)cyclopropanes
b
Viacheslav A. Petrov a, , Will Marshall
*
a DuPont Central Research and Development1, Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, United States
b DuPont Corporate Center for Analytical Sciences, Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
A new, simple synthesis of 1,1-bis(trifluoromethyl)cyclopropanes has been discovered. It is based on the
reaction of readily available 2,2-bis(trifluoromethyl)thietanes with tertiary phosphines in a polar
solvent, which leads to an unusual desulfurization process, resulting in the formation of 1,1-
bis(trifluoromethyl)-2-alkoxy cyclopropanes. The process of the corresponding thietanes appears to be
Received 7 June 2011
Accepted 18 June 2011
Available online 24 June 2011
sensitive to the steric volume of the atom connected to carbon in
a-position to sulfur.
Keywords:
ß 2011 Elsevier B.V. All rights reserved.
2,2-Bis(trifluoromethyl)thietanes
Reaction with phosphines
Desulfurization
Formation of 1,1-
bis(trifluoromethyl)cyclopropanes
1. Introduction
details on the synthesis and reaction of trifluoromethylated
cyclopropanes can be found in a comprehensive and detailed
review published recently [11].
Trifluoromethylated cyclopropanes were originally prepared by
the reaction of activated fluoroolefins with diazomethane [1,2],
followed by thermal or photochemical decomposition of the
pyrazoline intermediate. Although quite versatile, this method has
limited application due to the hazardous nature of diazomethane.
Later, trifluoromethyl-containing diazirines were introduced,
serving as a source of the corresponding carbene, which can be
added across the double bond (see Ref. [3,4]). Metal-catalyzed
reactions of fluorinated diazoalkanes with olefins used for
diastereo- and enantio-selective synthesis of trifluoromethylated
cyclopropanes have been developed in recent years [5]. Other
methods include the reaction of sulfonium ylides with fluorinated
olefins [6] and a synthesis involving optically active 2-trifluor-
omethyl oxirane [7]. Most of these methods are limited to the
synthesis of cyclopropanes containing only one CF3 group. The
reaction of cyclopropane carboxylic acids with SF4 developed by
the Dmowski and the Yagupol’ski research groups is probably the
most general method for the preparation of trifluoromethylated
cyclopropanes, including compounds carrying multiple CF3-
groups [8–10], although the necessity to handle gaseous, corrosive
and toxic sulfur tetrafluoride severely limits this method. More
In this study we report an unprecedented and simple method
for the preparation of 1,1-bis(trifluoromethyl)cyclopropanes,
which bear a substituent in the 2-position. The process involves
the reaction of 2,2-bis(trifluoromethyl)4-R-thietanes (R = OAlk,
NR2) with tertiary phosphines, leading to a high yield of the
corresponding cyclopropanes.
2. Results and discussion
Hydrocarbon sulfides are not reactive towards tertiary phos-
phines, and can be prepared by the reaction of di-[12,13], or tri-
[14] sulfides with (R2N)3P at ambient or elevated temperature.
Popkova reported a similar process for partially fluorinated
disulfides [15], which has been also adopted for the synthesis of
polyfluoroalkyl thiiranes [16]. The desulfurization process was also
used in a high yield synthesis of non-fluorinated thietanes from
1,2- dithiolanes [17,18], since hydrocarbon thietanes are stable
under the reaction conditions and do not undergo further
desulfurization.
Lately, we have been studying the reactivity of hexafluor-
othioacetone [19–23] towards different olefinic systems, and have
developed a simple synthesis of a variety of 2,2-bis(trifluoro-
methyl)thietanes, and 1,2- and 1,3-dithiolanes [22,23]. 2,2-
Bis(trifluoromethyl)thietanes have interesting reactivity and are
able not only to react with strong acids [24] and oxidizing agents
* Corresponding author. Tel.: +1 302695 1958; fax: +1 302695 8281.
E-mail address: viacheslav.a.petrov@usa.dupont.com (V.A. Petrov).
1
Publication No 2011-370.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.022

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V.A. Petrov, W. Marshall / Journal of Fluorine Chemistry 133 (2012) 61–66
[21], but also show an unusual reactivity towards nucleophilic
reagents [25–27], and undergo ring-expansion reactions in the
presence of sulfur/metal fluoride catalysts [22,25] or activated
aluminum powder [21]. Accumulated experimental data suggest
that the sulfur atom in 2,2-bistrifluoromethyl-4-alkoxythietanes
bears a significant positive charge, which makes 2,2-bis(trifluor-
omethyl)thietanes unique and distinctly different from its
hydrocarbon counterparts.
In this study, it was found that 2,2-bis(trifluoromethyl)-4-
alkoxythietanes 1a–g exhibit unusual and unexpected reactivity
towards tertiary phosphines. Indeed, the addition of 1a–g to a
solution of P(C4H9–n)3 results in an exothermic reaction with the
formation of a 1:1 mixture of the corresponding cyclopropane
2a–g and S55P(C4H9–n)3 (Eq.(1)).
(3)
It should be pointed out that the ring contraction of thietanes
has some generality and can be used for the preparation of
1,1-bis(trifluoromethyl)cyclopropanes bearing other substitu-
ents in position 2. For example, the treatment of thietane 1h by
P(C4H9–n)3 led to 2i, isolated in 61% yield after crystallization
(Eq. (4))
(1)
CF3
5-25 oC, 12h
CF3
CF3
DMF
+ P(C4H9)3
S
The reaction is exceptionally clean and the corresponding
cyclopropanes of ꢀ97–99% purity were isolated after vacuum
transfer of the product into a cold trap under dynamic vacuum,
followed by water wash to remove residual solvent. The addition of
P(C4H9–n)3 should be carried out at sub-ambient temperature,
since the reaction is exothermic and at elevated temperatures
(>30–40 8C) it may produce by-products derived from a ring-
expansion process. Cyclopropane 2e, prepared using this protocol,
was found to be acid-sensitive. Despite the fact that the
desulfurization process led to clean formation of 2e (NMR), drying
of this material over MgSO4, resulted in its partial conversion into
alcohol 2h, (Eq. (2)). The product was isolated as a mixture of 2e
and 2h.
- S=P(C4H9)3
R
CF3
2i, 61%
R
(4)
1h
R=
N
The structure of 2i was confirmed by single crystal X-ray
diffraction (Fig. 1).
19F NMR spectra of all cyclopropanes exhibit two quartets
(J = ꢀ7 Hz). In 13C NMR spectra of all cyclopropanes 2a–h the
resonances of the carbon bearing two CF3 groups (septet,
J = ꢀ30–34 Hz) are significantly shifted upfield relative the
corresponding signals in the thietanes 1a–g (
d
= ꢀ30 ppm vs.
d
= ꢀ46 ppm).
The NMR spectrum of cyclopropane 2i has some peculiarities.
While the 19F spectrum is similar to spectra of other cyclopropanes,
the 1H spectrum exhibits 8 (instead of the expected 4) aromatic
resonances for the carbazole substituent. Similarly, the 13C spectrum
contains 12 resonances for aromatic carbons, along with 5 signals for
the cyclopropane and CF3 groups. All these data indicate restricted
rotation of the carbazole unit around the C–C bond on the NMR time
scale (probably due to strong steric interaction with CF3 substituent,
located on same side of cyclopropane ring). This hypothesis is also
consistent with single crystal X-ray diffraction data. Indeed, the
distance between the fluorine of the CF3 group pointed towards the
(2)
The desulfurization process is sensitive to both solvent polarity
and the nucleophilicity of the phosphine. For example, in THF the
reaction of 1d and P(C4H9–n)3 was very slow (ꢀ20% conversion
after 1 month at 25 8C). Using 1a, it was also demonstrated that
triphenylphosphine was much less active in this process (4 months
(THF) and 1 week (DMF), respectively at 25 8C to reach >95%
conversion), while both [(CH3)2N]3P and [(C2H5)2N]3P have very
high reactivity, reacting rapidly and exothermically with either 1a
or b and producing the corresponding cyclopropanes quantita-
tively (NMR experiments).
We also demonstrated that compounds 2a–d can be prepared in
65–75% yield in a one-pot process, starting with hexafluoropro-
pene, sulfur and vinyl ether (or cyclic dimer of HFTA and vinyl
ether), followed by the treatment of the generated in situ thietane
by P(C4H9–n)3 (Eq. (3)).
˚
nitrogen of the carbazole (F1 and N1) is only 2.790 A, while ‘‘half-
length’’ of the carbazole fragment (the distance N1-H8(H10)) is
˚
4.491 A and clearly is long enough toprevent free rotation around the
C–N bond.
The IR spectra of the new cyclopropanes all exhibit a band at
ꢀ1450 cmꢁ1, which is not present in IR spectra of the starting
thietanes. Mass spectra typically exhibit a parent ion (see Tables 1
and 2).
The ring contraction process seems to be sensitive to the size of
the substituent on the thietane ring. For example, the reaction of

V.A. Petrov, W. Marshall / Journal of Fluorine Chemistry 133 (2012) 61–66
63
Table 1
Preparation of 1,1-bis(trifluoromethyl)cyclopropanes from thietanes.
Entry no.
Compound no.
Yield (%)
b.p. 8C (mmHg); (m.p. 8C)
MS
1
2
2a
2b
2ca
2d
2e
2f
86
110–111
128–129
124–125
148–149c
–
222(M+, C7H8F6O+)
236(M+, C8H10F6O+)
236(M+, C8H10F6O+)
250(M+, C9H12F6O+)
235[(MꢁCH3)+, C8H9F6O+]
276(M+, C11H14F6O+)
257(M+, C7H7ClF6O+)
194(M+, C5H4F6O+)
343 (M+, C17H11F6N+)
238(M+, C7H8F6S+)
71
3
75–81
90b
70d
65
4
5
6
192–193c
–
7
2g
2h
2i
89
8
–
–
9
61
136–137
30–32/0.7e
10
11
2j
30
2k
Quant.
a
Purity 97%, contaminated by DMF, 3%.
Crude, purity 98%.
b
c
Sivoloboff method.
d
e
Calc. yield.
Crude, purity 97%, Sivoloboff method.
thietane 1i bearing a 4-C2H5S– substituent results in the formation
of a mixture of cyclopropane 2j and dihydrothiophene 3a [21].
excess the phosphine solution in DMF resulted in rapid formation
of cyclopropanes 2a and b in 65–75% yield (Eq. (7)).
(7)
(5)
NMR monitoring of the reaction mixture of 4a and PBu3 (ratio
1:1), revealed the formation of approximately equal amounts of
the cyclopropane 2a and the thietane 1a, while the addition of
Cyclopropane 2j was isolated in this reaction in 31% yield. The
NMR analysis of the crude reaction mixture revealed the presence
of F2P(C4H9–n)3, which was likely the byproduct of a ring
expansion process.
While the cyclopropane 2j is still the major product in the
reaction of 1i, polycyclic thietanes 1l and 1m under the same
reaction conditions produced exclusively the corresponding
dihydrothiophenes 3c [21] and 3d [21] (Eq. (6)), while the
formation of the cyclopropanes was not observed.
(6)
It should also be pointed out that 1,2-dihydrothiolanes are also
Fig. 1. Crystal structure of 2i with thermal ellipsoids drawn to the 30% probability
react with PBu3. For example, the addition of 4a or b to a two-fold
level.

64
V.A. Petrov, W. Marshall / Journal of Fluorine Chemistry 133 (2012) 61–66
R
CF3
CF3
R3P
H
RO
S
CF3
CF3
CF3
PBu3
S
I
B
A
-S=PBu3
R
CF3
CF3
CF2
S
PBu3
F
II
R
2
-F2PBu3
CF3
F
R
S
3
Scheme 1.
second mole of the phosphine led to complete conversion to 2a,
indicating that the thietane was an intermediate in this process.
We believe that the mechanism of the reaction responsible for
the conversion of thietanes into cyclopropanes involves nucleo-
philic attack of phosphine on an electropositive atom of sulfur of
the thietane ring, leading to intermediate I (Scheme 1).
Path A involves intramolecular attack of the (CF3)2C carbanion
on the carbon bearing an excellent leaving group (–S–PBu3),
leading to nucleophilic cyclization with the formation of cyclo-
propane 2 and S55PBu3. It should be pointed out that the order of
the reactivity of tertiary phosphines with thietanes
2
(Ph3P ꢂ Bu3P, (R2N)3P) is in good agreement with the nucleophilic
nature of this step. The fact that more basic, but less nucleophilic,
triethylamine was found to be inert in the reaction with thietane
2a under similar conditions also supports this mechanism. Path B
involves the migration of fluoride ion from a CF3 group to
phosphorous with the formation of alkene-containing fluoropho-
sphorane II and intramolecular cyclization with the formation of
dihydrothiophene 3 and F2PBu3.
The balance between the two reaction pathways seems to
depend on the steric volume of the substituent at the carbon
bearing sulfur in intermediate I. Since substituent R in the
alkoxy group of thietanes 2a–g does not affect the outcome of
the reaction at all (in all cases cyclopropanes formed exclusive-
ly), one can assume that the size of the atom directly connected
to this carbon is more important than the steric volume of the
whole substituent. Indeed, in the reaction of thietanes with PBu3
having relatively small atoms, such as oxygen or nitrogen (van
˚
der Waals radii 1.52 and 1.55 A [28], compounds 1a–g and 1h,
respectively), the corresponding cyclopropanes 2a–g and 2h
were formed predominantly. In the case of 1h, the crude product
contained ꢀ5% of the corresponding dihydrothiophene (by
NMR). In the case of thietanes 1i and 1k, which contain larger
S or C atoms in same position (van der Waals radii 1.80 and
˚
1.70 A [28], respectively), the reaction results in the formation of
appreciable amounts of the dihydrothiophenes 3a and
b
(Eq. (5)).
The exclusive formation of dihydrothiophenes 3c and 3d is
probably the result of the rigid structure of both starting materials.
Indeed, both 1l and 1m exist exclusively as cis- [19] and exo- [22]
isomers, respectively, which means that both intermediate III and

V.A. Petrov, W. Marshall / Journal of Fluorine Chemistry 133 (2012) 61–66
65
3c
FFAP capillary column and either TCD (GC) or mass-selective (GS/
MS) detectors, respectively. Dry DMF and THF, PPh3, PBu3,
[(CH3)2N]3P (Aldrich) [(C2H5)2N]3P (Lancaster) were purchased
and used without further purification. Thietanes 1 were prepared
according modified procedure using CsF as a catalyst [22]. The
synthesis of 1h and similar materials will be reported separatly.
Due to the relatively low boiling points of the majority of
cyclopropanes, elemental analysis was not attempted for these
new materials. The purity of all isolated compounds established by
GC and NMR spectroscopy was at least 97%. Compounds 3c, d were
identified by 1H and 19F NMR [21].
-F2PBu3
CF3
CF3
CF3
CF3
S
PBu3
O
O
S
1l
PBu3
III
CF3
F3C
4.1. Crystallography
CF3
CF3
PBu3
S
X-ray data for 2i were collected at ꢁ100 8C using a Bruker 1 K
CCD system equipped with a sealed tube molybdenum source and
a graphite monochromator. The structure was solved and refined
using the Shelxtl [29] software package, refinement by full-matrix
least squares on F2, scattering factors from Int. Tab. Vol. C Tables
4.2.6.8 and 6.1.1.4. Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC #816328. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 1223 336033 or e mail: deposit@ccdc cam ac
uk.
S
1m
PBu3
IV
-F2PBu3
3d
Scheme 2.
IV will have carbanion and sulfur substituents on the same side of
cycle (Scheme 2).
In detailed mechanistic studies of the desulfurization process of
hydrocarbon disulfides carried out by Harpp and Gleason [13], it
was demonstrated that the reaction proceeds with inversion of
configuration, which means that the nucleophile attacks the
carbon of the R3C–SP+ (R0)3 intermediate from the backside,
leading to a complete inversion of configuration. Assuming that a
similar mechanism operates in the case of the reaction of
thietanes 1 and phosphines, the attack of the carbanion on the
carbon bearing the leaving group in intermediate I (Scheme 1)
should proceed from the less-hindered side, through the
transition where the incoming nucleophile and the leaving group
are located on different sides of the plane and free rotation around
the C–C bond allows intermediate I to rapidly adopt the required
geometry. However, due to the geometry of the starting material
in the case of thietanes 1l and 1m, the reaction with phosphine led
to intermediates III and IV, respectively, with a cis- relationship of
both substituents. This geometry is not suitable for intramolecu-
lar nucleophilic substitution, however, it is sufficient for fluoride
ion migration to phosphorous, leading to exclusive formation of
dihydrothiophenes 3c and d, rather than the corresponding
cyclopropanes.
4.2. Reaction of Thietanes 1a–k with PBu3 (typical procedure)
The corresponding thietane 1a–i (10–75 mmol) was added at 5–
10 8C to an agitated solution of PBu3 (10–20 mol.% excess) in 30–
100 mL of dry DMF at the rate which allow to maintain internal
temperature <10 8C. The reaction mixture was agitated at ambient
temperature for 2–6 h, and the product/DMF mixture was trans-
ferred at 25–40 8C into ꢁ78 8C cold trap under dynamic vacuum (1–
3 mm Hg) over 1–3 h. The reaction mixture was washed with water
and dried over MgSO4. Cyclopropanes prepared in this way typically
had purity 97–98% and were contaminated by 2–3% of DMF (NMR).
Cyclopropanes of >99% purity were obtained by distillation.
The reaction of thiolanes 4a and b were carried out similarly,
but using a two-fold excess of PBu3.
Compound 2i was isolated by diluting the reaction mixture
with water (300 mL), extracting with hexane (3 ꢃ 100 mL),
washing by water (3 ꢃ 300 mL), drying over MgsO4 and solvent
removal under reduced pressure. The semi-liquid residue was
washed by a small amount of cold hexane (ꢀ5 mL) and crystallized
from hexane.
The reaction of thietanes 1k–m with PBu3 were carried out in
NMR tube. The thietane was added at 0 8C to a solution of two-fold
excess PBu3 in DMF. Products 2k and 3a–d were not isolated, but
characterized in mixture by 19F NMR spectroscopy.
3. Conclusion
A simple procedure for the conversion of readily available
2,2-bis(trifluoromethyl)thietanes into the corresponding cyclo-
propanes under the action of tertiary phosphines was
developed. This reaction is unprecedented, and to the best of
our knowledge has not been reported for hydrocarbon
analogs. The corresponding cyclopropanes were isolated, fully
characterized, and the structure of the compound bearing a
carbazole substituent was confirmed by single crystal X-ray
diffraction.
Yields, MS, NMR and IR data are given in Tables 1 and 2.
Acknowledgements
Authors are grateful to Dr. C. Junk for helpful discussion and
suggestions and Timothy Bentz for technical support and Karin
Karel for proofreading the manuscript.
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