A practical synthesis and applications of (E)-diphenyl-β- (trifluoromethyl)vinylsulfonium triflate

Article abstract of DOI:10.1055/s-0032-1316792

(E)-Diphenyl-β-(trifluoromethyl)vinylsulfonium triflate, readily prepared from 2-bromo-3,3,3-trifluoroprop-1-ene in two steps, undergoes double alkylation with active methylene compounds in dimethyl sulfoxide or ethyl acetate, in an open vessel at room te

Full text of DOI:10.1055/s-0032-1316792

PAPER
▌3489
paper
A Practical Synthesis and Applications of (E)-Diphenyl-β-(trifluoromethyl)vi-
nylsulfonium Triflate
Trifluoromethyl-Containing Cyclopropanes
Noritaka Kasai,a Ryoko Maeda,a Hiroshi Furuno,b Takeshi Hanamoto*a
a
Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering, Saga University, Honjo-machi,
Saga 840-8502, Japan
b
Institute for Materials Chemistry and Engineering (IMCE), Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Fax +81(952)288548; E-mail: hanamoto@cc.saga-u.ac.jp
Received: 02.08.2012; Accepted after revision: 10.09.2012
tial.4c,5 Herein, we present the results of our continued re-
Abstract: (E)-Diphenyl-β-(trifluoromethyl)vinylsulfonium triflate,
search on the reactivity of 2 including a practical method
readily prepared from 2-bromo-3,3,3-trifluoroprop-1-ene in two
for its synthesis.
steps, undergoes double alkylation with active methylene com-
pounds in dimethyl sulfoxide or ethyl acetate, in an open vessel at
room temperature, to provide the corresponding trifluoromethyl-
ated cyclopropane derivatives in excellent yields. The cyclopro-
(Scheme 1).4c Reaction of 2-bromo-3,3,3-trifluoroprop-1-
pane, ethyl 1-cyano-2-(trifluoromethyl)cyclopropanecarboxylate is
subjected to a ring-opening reaction followed by cyclization to af-
We have reported previously a straightforward, one-step
synthesis of 2 from the corresponding E-sulfide 1
ene with thiophenol in ethanolic potassium hydroxide af-
forded a crude mixture of two stereoisomers (E/Z = 9:1),
which after careful purification by column chromatogra-
phy gave the requisite sulfide 1. To improve the efficiency
of this protocol it would be advantageous if the minor Z-
sulfide could be isomerized into the E-sulfide under the
same quaternization conditions, thereby avoiding separa-
tion of 1. To put this idea into practice, we found that qua-
ternization of 1 (E/Z = 9:1) with diphenyliodonium
triflate (Ph2IOTf) in the presence of a catalytic amount of
copper(I) chloride in 1,2-dichloroethane (DCE) at reflux
temperature for four hours proceeded to afford exclusive-
ly the desired product, (E)-2, in excellent yield (Scheme
1). Moreover, the work-up procedure employed enabled
column-free purification of 2 from the crude reaction mix-
ture (see experimental section). In addition, the reaction
could be easily scaled-up to provide 2 (8.9 g, 21 mmol) in
89% yield. These procedures for the synthesis of salt 2
greatly enhanced its practical availability.
ford a trifluoromethylated dihydroaminothiophene, which on oxi-
dation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone furnishes
the corresponding trifluoromethylated aminothiophene in a high
88% yield.
Key words: vinylsulfonium salts, heterocycles, cyclization, fluo-
rine, ylides
Vinylsulfonium salts represent versatile building blocks
for the synthesis of organic molecules of high complexi-
ty.1 They act as a two-carbon source toward appropriate
nucleophiles. For example, Aggarwal and co-workers
demonstrated the synthesis of nitrogen-containing hetero-
cycles using a simple vinylsulfonium salt.2 In contrast,
there are fewer reported syntheses of substituted vinylsul-
fonium salts,1a,1c–e despite the fact that the introduction of
a wide range of functional groups at the vinyl positions of
the salt would enhance the diversity of subsequent reac-
tions. From a biological point of view, the addition of one,
two, or three fluorine atoms to a molecule often confers
unique properties in terms of increased lipophilicity,
which in turn changes in vivo absorption and transport
rates.3 The trifluoromethyl group (CF3), belonging to this
category, plays a significant role due to its unique stereo-
electronic properties. We have been engaged in research
on the development of versatile fluorine-containing build-
ing blocks, which can be prepared from readily available
fluorinated molecules.4 In this context, we were motivated
to develop an efficient preparation of the corresponding
trifluoromethylated vinylsulfonium salts, and to investi-
gate their possible synthetic applications. We originally
elaborated a simple preparation of (E)-diphenyl-β-(trifluo-
romethyl)vinylsulfonium triflate (2) from commercially
available 2-bromo-3,3,3-trifluoroprop-1-ene in two steps,
and have already demonstrated briefly its synthetic poten-
F3C
CF3
Br
KOH
+
PhSH
EtOH
SPh
94%, 1 (E/Z = 9:1)
F3C
F3C
+
CuCl(I)
DCE, reflux
–
+
Ph2IOTf
SPh
SPh2•OTf
89%, 2
E/Z = 9:1
Scheme 1 An improved synthesis of vinylsulfonium salt 2
With an improved procedure toward vinylsulfonium salt 2
in hand, we next examined its reactivity. We had already
accomplished the simple preparation of trifluoromethyl-
aziridine derivatives in high yields by reacting 2 with a va-
riety of primary amines.4c If we could expand this strategy
by using an appropriate C-nucleophile instead of an N-nu-
cleophile, it might be possible to synthesize the corre-
sponding trifluoromethyl-cyclopropane derivatives.5,6
SYNTHESIS 2012, 44, 3489–3495
Advanced online publication: 27.09.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316792; Art ID: SS-2012-F0636-OP
© Georg Thieme Verlag Stuttgart · New York

3490
N. Kasai et al.
PAPER
According to the reported procedure, the reaction of diiso- products (Table 2, entries 5 and 6). In these cases, the re-
propyl malonate (3a) (1.0 equiv) and the salt 2 (1.05 actions themselves proceeded smoothly to afford the cor-
equiv) was investigated in the presence of potassium car- responding cyclopropane derivatives 4e and 4f according
bonate (3.0 equiv) in dichloromethane–water (1:1), in an to GC–MS analysis. We speculated that the low yields of
open vessel at room temperature (Equation 1).7 The reac- the isolated products were due to difficulties in extracting
tion proceeded slowly to afford the desired product 4a in the readily water-soluble products (4e and 4f) from the
only 9% yield (according to GC–MS), along with a large aqueous crude reaction mixtures. To avoid aqueous work-
amount of unreacted 3a (Table 1, entry 1). Among the var- up, we instead employed ethyl acetate as the solvent.
ious solvents examined, ethyl acetate and dimethyl sulf- Thus, non-aqueous work-up conditions (see experimental
oxide proved to be the most suitable. When the reaction section) provided the desired products 4e and 4f in high
was conducted using potassium carbonate (3.0 equiv) in 92% and 84% yields (Table 2, entries 11 and 12). It is
ethyl acetate, the desired product 4a was produced in 95% noteworthy that the cyclopropane products 4b–e contain-
yield (according to GC–MS) in a shorter reaction time ing two different electron-withdrawing groups were ob-
(0.5 h), and with no by-products detected (Table 1, entry tained as single stereoisomers. The cis stereochemistry
5). Furthermore, the reaction went to completion in di- between the cyano and trifluoromethyl groups in the prod-
methyl sulfoxide giving 4a in quantitative yield (accord- ucts 4b and 4c was determined by comparison with the re-
ing to GC–MS, Table 1, entry 6). Notably, attempts to ported NMR spectroscopic data.5,6r The reason for the
reduce the amount of potassium carbonate resulted in lon- exclusive formation of the cis isomers was attributed to
ger reaction times (Table 1, entries 7 and 8).
the lower steric congestion between the cyano and trifluo-
romethyl groups. We tentatively assigned products 4d and
4e as cis isomers by similar comparison of their NMR
spectroscopic data.
F3C
F3C
i
i
K2CO3, r.t.
CO2 Pr
CO2 Pr
+
i
i
CO2 Pr
CO2 Pr
solvent
air
SPh2•OTf
F3C
2
3a
4a
F3C
EWG1
EWG2
EWG1
EWG2
K2CO3, 0.5 h
+
Equation 1
Table 1 Optimization of the Reaction Conditionsa
r.t., solvent
air
SPh2•OTf
2
3
4
Equation 2
Entry
K2CO3
(equiv)
Solvent
Time
(h)
Yield
(%)b
To demonstrate the possibility of manipulation of the cy-
ano group, product 4b was subjected to a ring-opening re-
action with commercially available ammonium
tetrathiomolybdate [(NH4)2MoS4] in ethanol at reflux
temperature for three hours, according to a slightly modi-
fied procedure.7 Initial ring-opening followed by subse-
quent ring-closure gave the corresponding five-membered
cyclized product 5 in 95% yield. Oxidation of 5 with 2,3-
dichloro-5,6-dicyano-p-benzoquinone (DDQ) in dichlo-
romethane at room temperature over 24 hours resulted in
the formation of thiophene 6 in 88% yield (Scheme 2).
This compound has been reported as a precursor to thio-
phene-based c-Jun N-terminal kinase (JNK) inhibitors.8
1
2
3
4
5
6
7
8
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
CH2Cl2–H2O (1:1)
24
9
CH2Cl2–MeNO2 (1:1) 24
0
CH2Cl2–Et2O (1:1)
THF
24
24
0.5
0.5
5
6
63
EtOAc
95
DMSO
99 (92)c
95
DMSO
DMSO
24
95
a The reactions were carried out on 0.1 mmol scale using 2 (1.05
equiv) and 3a (1.0 equiv) in the specified solvent (1 mL) at room tem-
perature.
Finally, to compare the reactivity between vinyl diphenyl
sulfonium triflate2 and (E)-diphenyl-β-(trifluorometh-
yl)vinylsulfonium triflate (2), we investigated the synthe-
sis of the corresponding morpholine derivatives. The
reaction of 2 with 2-tosylaminoethanol 7 was performed
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the
base (Scheme 3). In contrast to our expectations, the de-
sired cyclization reaction did not take place. Instead, an
unanticipated addition–elimination product, identified as
the trifluoromethylated vinylamine derivative 9, was ob-
tained in 78% yield. Reaction of 2 with 2-methyl-2-tosyl-
aminopropanol 10, under the same conditions, gave the
corresponding trifluoromethylated vinyl ether derivative
12 in 65% yield. The structures of 9 and 12 were deter-
b GC–MS yield.
c Yield of isolated product in parentheses.
Having identified the optimum reaction conditions, we
next set out to examine the scope of the cyclopropanation
reaction of 2 with various active methylene compounds
3b–f (Equation 2), and the results are summarized in
Table 2. The reactions of 3b–d proceeded efficiently to
furnish the corresponding products 4b–d in good to high
yields of isolated products (Table 2, entries 2–4). We em-
ployed two highly polar activated methylene compounds,
3e and 3f, possessing amide or imide groups, which re-
sulted in formation of only trace amounts of the expected
Synthesis 2012, 44, 3489–3495
© Georg Thieme Verlag Stuttgart · New York

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Trifluoromethyl-Containing Cyclopropanes
3491
Table 2 Examination of the Scope of the Cyclopropanation Reaction of 2a
Entry
Substrate
EWG1
EWG2
Solvent
Product
Yield (%)b
1
2
3
4
5
3a
3b
3c
3d
3e
CO2i-Pr
CN
CO2i-Pr
CO2Et
DMSO
DMSO
DMSO
DMSO
DMSO
4a
4b
4c
4d
4e
92
76c
86
CN
SO2Ph
CN
P(O)(OEt)2
CONH2
88
CN
traced
O
MeN
NMe
O
6
3f
DMSO
4f
traced
O
CO2i-Pr
CN
7
3a
3b
3c
3d
3e
CO2i-Pr
CO2Et
EtOAc
MeOAce
EtOAc
EtOAc
EtOAc
4a
4b
4c
4d
4e
87
98
92
72
92
8
9
CN
SO2Ph
10
11
CN
P(O)(OEt)2
CONH2
CN
O
MeN
NMe
O
12
3f
EtOAc
4f
84
O
a The reactions were carried out using 2 (1.05 equiv), 3 (1.0 equiv) and K2CO3 (3 equiv) at room temperature for 0.5 h.
b Yield of isolated product.
c Volatile product.
d See text.
e Methyl acetate (MeOAc) was used as the solvent due to the volatility of product 4b.
F3C
CO2Et
NH2
CO2Et
NH2
F3C
F3C
DDQ
(NH4)2MoS4
CN
EtOH, reflux
3 h
CH2Cl2, r.t.
24 h
CO2Et
S
S
4b
5, 95%
6, 88%
Scheme 2 Synthesis of trifluoromethyl-containing thiophene 6
mined on the basis of spectroscopic analyses. Additional- of the methine proton next to the trifluoromethyl group. In
ly, the structure of ether 12 was determined fact, this proton should be abstracted by the ylide 15. As a
unambiguously by X-ray crystallographic analysis (Fig- result, the subsequent elimination should proceed smooth-
ure 1).
ly to furnish the trifluoromethyl vinylamine derivative 9.
In the case of 10, the steric effect of the geminal dimethyl
groups might prevent nucleophilic attack. Instead, the ter-
minal primary alkoxide anion would attack at the β-posi-
tion of 2 to generate the corresponding ylide, which would
undergo transformation by way of a similar reaction path
to that described for the formation of 9, giving the product
12. These results led us to suspend further attempts toward
the synthesis of trifluoromethyl-containing morpholine
derivatives due to inherent properties of 2.
A plausible mechanism for the reactions described above
is depicted in Scheme 4. We initially envisaged that 2
would be attacked at the β-position by the anion generated
from 7 with 1,8-diazabicyclo[5.4.0]undec-7-ene to give
the corresponding sulfur ylide 13. Subsequent proton
transfer followed by intramolecular cyclization (14 → 8)
would afford the trifluoromethyl-containing morpholine
derivative 8 and diphenyl sulfide. However, on the basis
of our findings, we propose an alternative mechanism for
this reaction. Attention to the strong electron-withdrawing In conclusion, we have described conditions for the con-
properties of the trifluoromethyl group in the intermediate venient preparation of 2, which did not require column
ylide led us to speculate on the enhancement of the acidity chromatography, and for the efficient cyclization reac-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3489–3495

3492
N. Kasai et al.
PAPER
Ts
N
Ts
N
Ts
N
Ts
CF3
CF3
CF3
N
CF3
O
H
SPh2•OTf
O
SPh2•OTf
O
O
F3C
NHTs
OH
DBU (2 equiv)
CH2Cl2, r.t.
8
+
SPh2•OTf
13
14
8
Ts
N
CF3
2
Ts H
N
Ts
N
Ts
N
7
CF3
CF3
CF3
OH
9
O
SPh2•OTf
O
H
SPh2•OTf
OH
H
Ts
N
CF3
15
16
9
Scheme 4 A plausible mechanism for the reaction of 2 with amino al-
cohol 7
O
F3C
NHTs
OH
DBU (2 equiv)
CH2Cl2, r.t.
11
+
SPh2•OTf
O
CF3
2
10
All solvents and starting materials were commercially available and
used as received without further purification, unless otherwise not-
ed. CH2Cl2, DCE, and DBU were distilled from CaH2. Column
chromatographic separation was carried out using Silica Gel 60
(particle size 63–210 μm), spherical (Kanto Chemical Co.). Melting
points were measured with a YANACO micro melting point appa-
ratus and are uncorrected. IR spectra were recorded on a Bruker
NTs
H
12
Scheme 3 Reaction of 2 with amino alcohols 7 and 10
1
VERTEX70-S spectrometer. H, 13C NMR, and 19F NMR spectra
were recorded on Varian NMR System 400HFX or JEOL JNM-AL
300 FT-NMR spectrometers. GC–MS spectra were obtained using
an Agilent 5975C spectrometer. High-resolution mass spectra were
recorded on a high-performance double-focusing JEOL JMS-
HX110A mass spectrometer. Elemental analyses were obtained us-
ing a CHNcorder Yanako MT-5 or MT-6 by the Service Center of
the Elementary Analysis of Organic Compounds, Kyushu Universi-
ty.
Phenyl β-(Trifluoromethyl)vinyl Sulfide (1)9
A 300 mL round-bottom flask equipped with a magnetic stir bar was
charged with EtOH (50 mL) and KOH (3.3 g, 59 mmol). To the
stirred soln were successively added thiophenol (5.0 mL, 49 mmol)
and 3,3,3-trifluoro-2-bromoprop-1-ene (1.3 mL, 58 mmol) at 0 °C.
The resulting mixture was gradually warmed to ambient tempera-
ture overnight. The reaction was quenched with sat. aq NH4Cl soln
and the organic layer separated from the mixture. The aq layer was
extracted with hexane (3 × 30 mL). The combined organic layer was
dried over Na2SO4 and concentrated in vacuo. The resulting oily
residue was purified by silica gel chromatography (hexane) to give
a 9:1 mixture of E/Z-1.
Yield: 9.4 g (94%); colorless oil.
1H NMR (400 MHz, CDCl3): δ (E-isomer) = 5.42 (dq, J = 15.3, 6.5
Hz, 1 H), 7.14 (dq, J = 15.3, 2.0 Hz, 1 H), 7.34–7.50 (m, 5 H).
1H NMR (400 MHz, CDCl3): δ (Z-isomer): = 5.64 (dq, J = 10.9, 8.2
Hz, 1 H), 6.87 (dq, J = 10.9, 0.8 Hz, 1 H), 7.34–7.50 (m, 5 H).
19F NMR (376 MHz, CDCl3): δ (E-isomer) = –63.5 (d, J = 4.1 Hz).
19F NMR (376 MHz, CDCl3): δ (Z-isomer) = –61.1 (d, J = 8.2 Hz).
Figure 1 The ORTEP view of 12 with thermal ellipsoids shown at the
50% probability level
The spectroscopic data were consistent with those reported in the
literature.
(E)-Diphenyl-β-(trifluoromethyl)vinylsulfonium Triflate (2)
A 100 mL two-necked flask equipped with a magnetic stir bar, a
stopcock and a three-way stopcock, was charged with phenyl β-(tri-
fluoromethyl)vinyl sulfide (1) (4.99 g, 24.5 mmol) in DCE (10 mL)
under Ar. To this soln was added diphenyliodonium triflate (10.02
g, 23.3 mmol), CuCl (242.5 mg, 2.45 mmol) and a catalytic amount
of Cu wire. The mixture was heated at reflux temperature for 4 h.
tions of 2 in an open vessel at room temperature. These re-
actions are operationally simple and employ readily
available reagents under mild conditions. Further efforts
are underway to expand the scope of salt 2 for the synthe-
sis of a wide range of fluorinated compounds.
Synthesis 2012, 44, 3489–3495
© Georg Thieme Verlag Stuttgart · New York

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Trifluoromethyl-Containing Cyclopropanes
3493
After cooling to r.t., the mixture was filtered through a Celite pad
and the filtrate concentrated in vacuo. Hexane (ca. 300 mL) was
added to the residue to give a crude pale colored precipitate. This
precipitate was washed with hexane and then recrystallized from
acetone–Et2O to afford the desired product.
1H NMR (400 MHz, CDCl3): δ = 1.38 (t, J = 7.3 Hz, 3 H), 1.95–
2.01 (m, 2 H), 2.61–2.70 (m, 1 H), 4.33 (q, J = 7.3 Hz, 2 H).
19F NMR (376 MHz, CDCl3): δ = –68.8 (d, J = 5.5 Hz).
The spectroscopic data were consistent with those reported in the
literature.
Yield: 8.90 g (89%); white solid; mp 68.1–70.5 °C.
1-(Phenylsulfonyl)-2-(trifluoromethyl)cyclopropanecarboni-
trile (4c)5,6r
The product was prepared from phenylsulfonylacetonitrile (3c)
(54.4 mg, 0.3 mmol) in EtOAc (1 mL) using general method B (see
Table 2, entry 9).
IR (KBr): 3066, 3047, 1645, 1583, 1478, 1449, 1279, 1226, 1152,
1031, 999, 873, 748, 683 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.98 (dq, J = 14.7, 5.9 Hz, 1 H),
7.71–7.83 (m, 6 H), 7.88–7.93 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 120.0 (q, J = 273.4 Hz), 120.6 (q,
J = 320.1 Hz), 123.6, 126.7 (q, J = 6.9 Hz), 130.9, 131.8, 135.2,
137.3 (q, J = 37.4 Hz).
Yield: 76.3mg (92%); white solid; mp 111.3–111.7 °C.
1H NMR (400 MHz, CDCl3): δ = 2.05 (t, J = 5.5 Hz, 1 H), 2.24–
2.28 (m, 1 H), 2.83–2.92 (m, 1 H), 7.69 (t, J = 7.4 Hz, 2 H), 7.79–
7.85 (tm, J = 7.4 Hz, 1 H), 7.97–8.02 (dm, J = 8.4 Hz, 2 H).
19F NMR (283 MHz, CDCl3): δ = –66.3 (d, J = 6.5 Hz), –79.9 (s).
19F NMR (376 MHz, CDCl3): δ = –66.2 (d, J = 5.5 Hz).
Anal. Calcd for C16H12F6O3S2: C, 44.65; H, 2.81. Found: C, 44.66;
H, 2.92.
The spectroscopic data were consistent with those reported in the
literature.
Cyclopropanes 4a and 4d; General Method A
A 50 mL flask (open to air) equipped with a magnetic stir bar was
charged with the appropriate active methylene compound 3 (0.5
mmol, 1.0 equiv) and K2CO3 (1.5 mmol, 3.0 equiv) in DMSO (2
mL). To the resulting mixture was added compound 2 (0.525 mmol,
1.05 equiv) at r.t. After stirring for 0.5 h, the reaction mixture was
quenched with H2O. The organic layer was separated and the aq lay-
er extracted with hexane–Et2O (3:1, 3 × 2 mL). The combined or-
ganic layer was dried over Na2SO4 and concentrated in vacuo. The
residual oil was purified by silica gel chromatography (hexane, then
Et2O) to give cyclopropane 4a or 4d.
Diethyl [1-Cyano-2-(trifluoromethyl)cyclopropyl]phosphonate
(4d)
The product was prepared from diethyl (cyanomethyl)phosphonate
(3d) (48 μL, 0.3 mmol) in DMSO (3 mL) using general method A
(see Table 2, entry 4).
Yield: 72.1 mg (88%); colorless oil.
IR (NaCl): 2990, 2245, 1451, 1413, 1259, 1190, 1157, 1092, 1023,
872, 798, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.39–1.45 (m, 6 H), 1.84–1.89
(dm, J = 8.0 Hz, 1 H), 1.87–1.92 (dm, J = 8.0 Hz, 1 H), 2.53–2.61
(m, 1 H), 4.22–4.31 (m, 4 H).
Diisopropyl 2-(Trifluoromethyl)cyclopropane-1,1-dicarboxyl-
ate (4a)
The product was prepared from diisopropyl malonate (3a) (95 μL,
0.5 mmol) using general method A (see Table 2, entry 1).
13C NMR (100 MHz, CDCl3): δ = 8.0, 9.9, 15.1, 16.0, 16.1, 25.9 (q,
J = 38.1 Hz), 64.4, 64.5, 114.2, 123.1 (q, J = 273.3 Hz).
19F NMR (376 MHz, CDCl3): δ = –65.9 (d, J = 6.8 Hz).
Yield: 129.4 mg (92%); colorless oil.
IR (NaCl): 2985, 2941, 1732, 1469, 1413, 1376, 1359, 1320, 1279,
1219, 1154, 1102, 967, 909, 895, 832 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 6.0 Hz, 6 H), 1.28 (t,
J = 6.0 Hz, 6 H), 1.51 (dd, J = 9.4, 5.4 Hz, 1 H), 1.77 (dd, J = 7.0,
5.4 Hz, 1 H), 2.54 (dquin, J = 9.4, 7.0 Hz, 1 H), 5.05 (sept, J = 6.0
Hz, 1 H), 5.11 (sept, J = 6.0 Hz, 1 H).
GC–MS (EI, 70 eV): m/z (%) = 270 (1) [M – 1]+, 244 (69), 216
(100), 215 (17), 198 (48), 196 (19), 146 (15), 91 (12), 81 (33), 69
(5).
Anal. Calcd for C9H13F3NO3P: C, 39.86; H, 4.83; N, 5.17. Found:
C, 39.89; H, 4.73; N, 5.20.
13C NMR (100 MHz, CDCl3): δ = 15.0, 21.0, 21.2, 21.4, 21.5, 26.8
(q, J = 38.1 Hz), 33.5, 69.5, 70.3, 124.1 (q, J = 272.5 Hz), 164.5,
167.7.
19F NMR (376 MHz, CDCl3): δ = –65.4 (d, J = 7.0 Hz).
GC–MS (EI, 70 eV): m/z (%) = 281 (1) [M – 1]+, 223 (21), 199 (27),
1-Cyano-2-(trifluoromethyl)cyclopropanecarboxamide (4e)
The product was prepared from 2-cyanoacetamide (3e) (75.7 mg,
0.9 mmol) in EtOAc (3 mL) using general method B (see Table 2,
entry 11).
Yield: 147.2 mg (92%); white solid; mp 115.2–116.0 °C.
IR (KBr): 3399, 3175, 2256, 1703, 1628, 1387, 1287, 1198, 1083,
1010, 962, 819, 559, 519 cm–1.
1H NMR (400 MHz, D2O): δ = 2.02 (dd, J = 8.8, 7.0 Hz, 1 H), 2.13
(t, J = 7.0 Hz, 1 H), 2.89 (dquin, J = 8.8, 7.0 Hz, 1 H).
182 (8), 181 (100), 144 (1), 134 (3), 128 (2), 114 (6), 69 (1).
Anal. Calcd for C12H17F3O4: C, 51.06; H, 6.07. Found: C, 51.31; H,
6.17.
Cyclopropanes 4b, 4c, 4e and 4f; General Method B
13C NMR (100 MHz, DMSO-d6): δ = 18.4, 18.7, 28.5 (q, J = 37.5
Hz), 117.2, 125.0 (q, J = 273.0 Hz), 165.3.
19F NMR (376 MHz, CDCl3): δ = –63.42 (d, J = 7.0 Hz).
GC–MS (EI, 70 eV): m/z (%) = 178 (18) [M]+, 177 (31), 135 (29),
115 (60), 111 (18), 109 (100), 88 (22), 84 (11), 69 (21), 64 (15).
A 50 mL (open to air) flask equipped with a magnetic stir bar was
charged with the appropriate active methylene compound 3 (1.44
mmol, 1.0 equiv) and K2CO3 (4.32 mmol, 3.0 equiv) in MeOAc (5
mL). To the resulting mixture was added compound 2 (1.50 mmol,
1.05 equiv) at r.t. After stirring for 0.5 h, the mixture was filtered
through a Celite pad. After washing the Celite pad with Et2O, the
combined filtrate was concentrated in vacuo. The residual oil was
purified by silica gel chromatography (hexane, then Et2O) to give
cyclopropane 4b, 4c, 4e or 4f.
Anal. Calcd for C6H5F3N2O: C, 40.46; H, 2.81; N, 15.73. Found: C,
40.56; H, 2.81; N, 15.85.
5,7-Dimethyl-1-(trifluoromethyl)-5,7-diazaspiro[2.5]octane-
4,6,8-trione (4f)
The product was prepared from 1,3-dimethylbarbituric acid (3f)
(46.8 mg, 0.3 mmol) in EtOAc (1 mL) using general method B (see
Table 2, entry 12).
Ethyl 1-Cyano-2-(trifluoromethyl)cyclopropanecarboxylate
(4b)5,6r
The product was prepared from ethyl cyanoacetate (3b) (150 μl,
1.44 mmol) using general method B (see Table 2, entry 8).
Yield: 63.1 mg (84%); white solid; mp 123.2–124.0 °C.
Yield: 290.9 mg (98%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3489–3495

3494
N. Kasai et al.
PAPER
IR (KBr): 2360, 2341, 1678, 1428, 1383, 1263, 1162, 1098, 1033,
756, 668, 647 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.22–2.26 (m, 1 H), 2.51 (dd,
J = 8.4, 4.3 Hz, 1 H), 2.78–2.84 (m, 1 H), 3.35 (s, 3 H), 3.36 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 23.2, 29.8, 29.9, 32.3, 37.4 (q,
J = 39.7 Hz), 124.9 (q, J = 274.1 Hz), 152.5, 166.0, 167.8.
Yield: 60.6 mg (78%); colorless oil.
IR (NaCl): 3542, 2930, 1598, 1354, 1165, 974, 684 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.10 (t, J = 5.5 Hz, 1 H), 2.44 (s,
3 H), 3.56 (t, J = 5.5 Hz, 2 H), 3.74 (q, J = 5.5 Hz, 2 H), 5.85–5.87
(m, 1 H), 6.13–6.15 (m, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.73 (d,
J = 8.1 Hz, 2 H).
19F NMR (376 MHz, CDCl3): δ = –59.47 (d, J = 8.2 Hz).
13C NMR (75 MHz, CDCl3): δ = 21.5, 51.7, 59.5, 120.9 (q,
J = 276.5 Hz), 125.9 (q, J = 3.3 Hz), 127.8, 129.7, 133.7 (q,
J = 34.7 Hz), 135.3, 144.4.
GC–MS (EI, 70 eV): m/z (%) = 251 (12) [M + 1]+, 250 (100) [M]+,
222 (10), 193 (14), 192 (14), 181 (76), 165 (30), 124 (34), 108 (45),
69 (13).
19F NMR (283 MHz, CDCl3): δ = –60.1 (s).
Anal. Calcd for C9H9F3N2O3: C, 43.21; H, 3.63; N, 11.20. Found:
C, 43.43; H, 3.61; N, 11.12.
GC–MS (EI, 70 eV): m/z (%) = 214 (2), 155 (16), 124 (11), 91
(100), 77 (2), 65 (23), 54 (8).
Anal. Calcd for C12H14F3NO3S: C, 46.60; H, 4.56; N, 4.53. Found:
C, 46.74; H, 4.65; N, 4.65.
2-Amino-3-ethoxycarbonyl-4-trifluoromethyl-4,5-dihydrothio-
phene (5)
A 100 mL flask equipped with a magnetic stir bar was charged with
cyclopropane 4b (284.7 mg, 1.37 mmol) in EtOH (10 mL), and to
this mixture was added ammonium tetrathiomolybdate
[(NH4)2MoS4] (426.8 mg, 1.64 mmol) at r.t. The mixture was heated
at reflux temperature for 3 h, cooled to r.t., filtered through a Celite
pad and the pad washed with CH2Cl2. The combined organic layer
was concentrated in vacuo. The residual oil was purified by silica
gel chromatography (Et2O) to give dihydrothiophene 5.
1-(1,1,1-Trifluoroprop-2-en-2-yloxy)-2-methyl-N-tosylpropan-
2-amine (12)
A 25 mL two-necked flask equipped with a magnetic stir bar, a stop-
cock and a three-way stopcock, was charged with 2 (104.0 mg, 0.23
mmol) in CH2Cl2 (1.5 mL) under Ar. To the resulting soln were add-
ed 2-methyl-2-(tosylamino)propane-1-ol 10 (64.0 mg, 0.26 mmol)2d
and DBU (70.0 μL, 0.47 mmol). After stirring for 3 h, the reaction
mixture was quenched with H2O. The organic layer was separated
and the aq layer extracted with CH2Cl2 (2 × 2 mL). The combined
organic layer was dried over Na2SO4 and concentrated in vacuo.
The residual oil was purified by silica gel chromatography (hexane–
EtOAc, 3:1) to give ether 12.
Yield: 314.3 mg (95%); white solid; mp 119.2–120.3 °C.
IR (KBr): 3371, 3276, 3183, 1649, 1612, 1512, 1410, 1382, 1358,
1281, 1228, 1155, 1110, 1028, 931, 907, 814, 774, 725, 687, 659
cm–1.
Yield: 51.8 mg (65%); white solid; mp 72.5–73.4 °C.
IR (KBr): 3259, 1655, 1386, 1326, 1155, 985, 676 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.270 (s, 3 H), 1.272 (s, 3 H), 2.41
(s, 3 H), 3.55 (s, 2 H), 4.30 (br s, 1 H), 4.77 (d, J = 3.1 Hz, 1 H), 4.83
(s, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.4, 24.6, 55.7, 74.5, 88.0 (q,
J = 3.7 Hz), 119.5 (q, J = 273.4 Hz), 126.9, 129.6, 139.8, 143.2,
146.6 (q, J = 34.9 Hz).
1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3 H), 3.26 (d,
J = 12.1 Hz, 1 H), 3.56 (dd, J = 12.1, 9.0 Hz, 1 H), 3.97 (dq, J = 9.0,
8.2 Hz, 1 H), 4.12 (dq, J = 10.8, 7.1 Hz, 2 H), 4.22 (dq, J = 10.8, 7.1
Hz, 2 H), 6.40 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.4, 30.3, 48.3 (q, J = 28.8 Hz),
59.3, 87.0, 127.1 (q, J = 283.4 Hz), 165.9, 167.0.
19F NMR (376 MHz, CDCl3): δ = –74.6 (d, J = 8.2 Hz).
GC–MS (EI, 70 eV): m/z (%) = 241 (44) [M]+, 196 (30), 172 (100),
146 (12), 144 (26), 126 (30), 100 (18), 99 (14), 95 (3), 69 (2).
19F NMR (283 MHz, CDCl3): δ = –73.8 (s).
Anal. Calcd for C8H10F3NO2S: C, 39.83; H, 4.18; N, 5.81. Found:
C, 40.08; H, 4.19; N 5.73.
GC–MS (EI, 70 eV): m/z (%) = 214 (1), 213 (4), 212 (30)
[Me2CNHTs]+, 155 (44), 139 (2), 91 (100), 70 (2), 65 (15), 55 (4).
HRMS−FAB: m/z [M + H]+ calcd for C14H19F3NO3S: 338.1059;
found 338.1038.
2-Amino-3-ethoxycarbonyl-4-(trifluoromethyl)thiophene (6)8b
A 25 mL flask equipped with a magnetic stir bar was charged with
dihydrothiophene 5 (38.2 mg, 0.17 mmol) in CH2Cl2 (1 mL), and to
the resulting mixture was added DDQ (47.7 mg, 0.21 mmol) at r.t.
After stirring for 24 h, the mixture was filtered through a Celite pad
and the filtrate concentrated in vacuo. The residual solid was puri-
fied by silica gel chromatography (Et2O) to give thiophene 6.
Crystal Data for 12
(C14H18F3NO3S): M = 337.35, T = 123(2) K, monoclinic, space
group P21/c, a = 9.705(3) Å, b = 11.102(3) Å, c = 14.580(5) Å,
V = 1558.7 Å3, Z = 4, Dx = 1.438 Mg·m–3, m = 0.250 mm–1,
l = 0.71073 Å, qmax = 27.47°, 3553 measured reflections, 1926
independent reflections, 206 refined parameters, GOF = 1.084,
R[F2 > 2s(F2)] = 0.1020, wR(F2) = 0.3606. The structure was solved
by direct methods (SIR200210) and the non-hydrogen atoms were
refined anisotropically by full-matrix least-squares procedures on
F2 for all reductions (SHELXL9711). All hydrogen atoms were po-
sitioned geometrically and refined as riding. CCDC 883928
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via
Yield: 33.3 mg (85%); white solid; mp 70.1–70.3 °C.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.1 Hz, 3 H), 4.30 (q,
J = 7.1 Hz, 2 H), 6.27 (br s, 2 H), 6.75 (s, 1 H).
19F NMR (376 MHz, CDCl3): δ = –61.0 (s).
The spectroscopic data were consistent with those reported in the
literature.
2-[N-(1,1,1-Trifluoroprop-2-en-2-yl)-N-tosylamino]ethanol (9)
A 25 mL two-necked flask equipped with a magnetic stir bar, a stop-
cock and a three-way stopcock, was charged with 2 (111.0 mg, 0.25
mmol) in CH2Cl2 (1 mL) under Ar. To the resulting soln were added
2-(tosylamino)ethanol 7 (66.0 mg, 0.30 mmol)2d and DBU (75.0 μL,
0.50 mmol). After stirring for 2 h, the reaction mixture was
quenched with H2O. The organic layer was separated and the aq lay-
er extracted with CH2Cl2 (2 × 2 mL). The combined organic layer
was dried over Na2SO4 and concentrated in vacuo. The residual oil
was purified by silica gel chromatography (hexane–EtOAc, 1:1) to
give alcohol 9.
www.ccdc.cam.ac.uk/data_request/cif,
or
by
emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44(1223)336033.
Acknowledgment
We greatly thank F–Tech Co., Ltd for the gift of 2-bromo-3,3,3-
trifluoroprop-1-ene and Central Glass Co., Ltd for the gift of trifluo-
romethanesulfonic acid. We are grateful to Prof. Junji Inanaga at the
Synthesis 2012, 44, 3489–3495
© Georg Thieme Verlag Stuttgart · New York

PAPER
Trifluoromethyl-Containing Cyclopropanes
3495
Institute for Materials Chemistry and Engineering, Kyushu Univer-
sity for helpful discussion. This work was performed under the Co-
operative Research Program of ‘Network Joint Research Center for
Materials and Devices’. We also thank Prof. Srinivasan Chan-
drasekaran at the Indian Institute of Science, Bangalore for personal
communications regarding tetrathiomolybdate.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3489–3495