Partially fluorinated heterocycles from 4,4-bis(trifluoromethyl)-hetero-1, 3-dienes via C-F bond activation - Synthesis of 2-fluoro-3-(trifluoromethyl) furans

Article abstract of DOI:10.1007/s00706-007-0587-4

An efficient synthesis of 2-fluoro-3-(trifluoromethyl)furans was developed. Keystep of the reaction sequence is a [4 + 1] cycloaddition reaction of tin(II)chloride to 4,4-bis(trifluoromethyl)-1-oxabuta-1,3-dienes. At elevated temperatures the tin heterocy

Full text of DOI:10.1007/s00706-007-0587-4

Monatshefte fu¨r Chemie 138, 227–236 (2007)
DOI 10.1007/s00706-007-0587-4
Printed in The Netherlands
Partially Fluorinated Heterocycles from 4,4-Bis(trifluoromethyl)-hetero-1,3-
dienes via C–F Bond Activation – Synthesis of 2-Fluoro-3-
(trifluoromethyl)furans#
Klaus Burger1;ꢀ, Brigitte Helmreich1, Lothar Hennig1, Jan Spengler2, Fernando Albericio2,
and Annett Fuchs3
1
Department of Organic Chemistry, University of Leipzig, Leipzig, Germany
`
Department de Quimica Organica, Universitat de Barcelona, Parc Cientific, Barcelona, Spain
2
3
¨
Hochschule Zittau=Gorlitz, Fachbereich Mathematik und Naturwissenschaften, Zittau, Germany
Received April 28, 2006; accepted (revised) July 27, 2006; published online February 23, 2007
# Springer-Verlag 2007
Summary. An efficient synthesis of 2-fluoro-3-(trifluoro-
cerning fluorine-containing compounds in medicinal
methyl)furans was developed. Keystep of the reaction se-
quence is a [4þ 1] cycloaddition reaction of tin(II)chloride
to 4,4-bis(trifluoromethyl)-1-oxabuta-1,3-dienes. At elevated
temperatures the tin heterocycles are transformed into 1-
aryl-4,4-difluoro-3-(trifluoromethyl)but-3-en-1-ones which on
treatment with sodium hydride in dry DMF give 2-fluoro-3-
(trifluoromethyl)furans. The single fluorine bound to C-(2) can
be readily replaced by various N-, O-, S-, and C-nucleophiles
and dinucleophiles.
and agricultural chemistry as well as in material
science is still growing [4]. The trifluoromethyl
group is attractive since it is relatively non-toxic
and somewhat more stable than the difluoromethyl
and the monofluoromethyl group [5]. Originally the
trifluoromethyl group was considered to be chemi-
cally inert [6]. The C–F bond is the strongest single
bond connected to carbon [7]. Therefore, the de-
velopment of new methodology for C–F bond acti-
vation is a challenge to preparative chemists. An
arsenal of new fluorine-containing building blocks
of broad structural variety will be the result, adding
a new facette to preparative organofluorine chemis-
try [8, 9]. Recently, Fuchibe and Akiyama [10] re-
ported on a low-valent niobium-mediated double
activation strategy in which a C–F and a C–H bond
in close proximity in the same molecule are jointly
activated, leading to ring-closing and formation of
polycyclic systems (Scheme 1). Differently substi-
tuted o-phenyl-ꢀ,ꢀ,ꢀ-trifluorotoluenes, NbCl5 and
LiAlH4 were heated in DME under reflux for several
hours to give fluorenes with variable substituent pat-
tern in good yields [11].
Keywords. [4 þ 1] Cycloaddition; C–F Bond activation;
1-Aryl-4,4-difluoro-3-(trifluoromethyl)but-3-en-1-ones;Bridged
3-(trifluoromethyl)furans; 3-(Trifluoromethyl)tetrahydrocumaron.
Introduction
Incorporation of trifluoromethyl groups into strategi-
cal positions of biologically active compounds gen-
erally modifies the profile in a favorable way [1–3],
by increasing metabolic stability and lipophilicity,
enhancing in vivo absorption and transport rates,
and improving permeability through certain body
barriers. The number of publications and patents con-
ꢀ
uni-leipzig.de
Corresponding author. E-mail: burger@organik.chemie.
Primary and secondary perfluoroalkyl amines are
relatively unstable, but the situation is not as ex-
treme as that of the corresponding alcohols [12].
#
Dedicated to Prof. Dr. S. Hauptmann on the occasion of his
75th birthday

228
K. Burger et al.
group is degraded and finally its carbon atom is
incorporated as skeleton atom into the newly formed
ring system, while the second trifluoromethyl group
remains unchanged being incorporated as CF3-
group. Thus, hexafluoroacetone can be applied as
building block to introduce a single trifluoromethyl
group into target molecules.
Scheme 1
On the first view the ring transformation of 4,4-
bis(trifluoromethyl)-2H-thiazetes into 5-fluoro-4-
(trifluoromethyl)thiazoles on heating with SnCl2 [15]
(Scheme 3) is surprising. However, based on the
knowledge that there exists a thermally mobile
valence tautomeric equilibrium between the 4-mem-
bered heterocycle and the open-chain bis(trifluo-
romethyl) substituted hetero-1,3-diene [16], the
mechanism of the ring enlargement can be readily
explained. Now we report on the application of the
SnCl2-reaction to 4,4-bis(trifluoromethyl)-1-oxabuta-
1,3-dienes, a hetero-1,3-diene with only one hetero-
atom in the 1,3-diene skeleton.
Results and Discussion
Scheme 2
Enol ethers obtained from the reaction of methyl-
ketones and trimethylchlorosilane, react readily with
hexafluoroacetone to give [1:1] adducts [17]. O-
Deprotection can be achieved on treatment with
methanolic HCl at room temperature. The aldol ad-
ducts are stable compounds and can be dehydrated
with trifluoroacetic anhydride=pyridine at 0–20ꢁC
[18]. 4,4-Bis(trifluoromethyl)-1-oxa-1,3-dienes are
stable against moisture and can be purified by dis-
tillation or column chromatography and stored at room
temperature over months. Because of the structural
similarity of 4,4-bis(trifluoromethyl)-1-oxabuta-1,3-
dienes and 4,4-bis(trifluoromethyl)-1-oxa-3-azabuta-
1,3-dienes we expected similar reaction behavior
[19].
In general, fluoroalkyl groups attached to skeleton
atoms or heteroaromatic ring systems possessing
acidic hydrogen atoms like trifluoromethanol and
3,3,3-trifluoroalanine or 2-trifluoromethylimidazole
(Scheme 2) in basic media are readily transformed
into anionic species [13]. Concomitantly, the C–F
bonds are activated.
Activated trifluoromethyl groups react like ‘‘ortho-
fluorides’’ and therefore can be applied as a syn-
thetically useful functional group. This result is of
interest, especially in the case of geminal trifluoro-
methyl groups. We found that the geminal pair of
trifluoromethyl groups of 4,4-bis(trifluoromethyl)-
1-oxa-3-azabuta-1,3-dienes after transfer of two elec-
trons (anion activation via [4 þ 1] cycloaddition of
SnCl2 or direct electron transfer from certain metals)
react in a different way [14]. One trifluoromethyl
Indeed, the [4 þ 1] cycloaddition of SnCl2
(Scheme 4) works well already at room temperature
(1 ! 2). The Sn2þ species is oxidized to give a Sn4þ
species. During the cycloaddition process two elec-
Scheme 3

Synthesis of 2-Fluoro-3-(trifluoromethyl)furans
229
Scheme 4
Scheme 5
trons have been transferred from the metal centre
to the hetero-1,3-diene skeleton. A by-product 7
(Scheme 5) isolated in 5–6% yield, which was fully
characterized, indicates that a two electron transfer
takes place in an early step of the reaction sequence,
which is vital to ‘‘switch on’’ the activity of one of
the trifluoromethyl groups.
Scheme 6
dride or lithium diisopropylamide in dry polar apro-
tic solvents like DMF or DMSO at room temperature
(Scheme 6). Heteroaromatization of the oxapenta-
dienyl anion is the driving force for this reaction
[20].
At elevated temperatures the five-membered tin
heterocycle undergoes a heterolytic ring cleavage
to give a dipolar species (2 ! 3), where the negative
charge is accommodated in a bis(trifluoromethyl)
substituted allylic anion substructure and the posi-
tive charge at the metal centre. The negative charge
weakens the C–F bonds of the trifluoromethyl groups
and fluoride elimination becomes possible (3 ! 4)
(Scheme 4). After splitting off the Sn fragment an
oxapentadienyl anion 5 is formed. In the presence
of water, protonation of 5 is much faster than the
electrocyclic ring closure with elimination. Thus,
protonation of 5 stops the reaction sequence and
1-aryl-4,4-difluoro-3-(trifluoromethyl)but-3-en-1-ones
6 were isolated in 70–90% yield. The perfluorinated
fragment F3CC¼CF2 can be readily identified with
the help of the 13C and 19F NMR spectra. The trans-
formation of 6 into partially fluorinated furans 10
has been achieved on treatment with sodium hy-
Structural diversity can be achieved on nucleo-
philic displacement reactions of the single fluorine
bound to C-2 by N-, O-, S-, and C-nucleophiles [19,
21, 22] affording compounds of type 11–15, i.a. ary-
lation reactions with metal organic compounds like
phenyl lithium and phenyl magnesium bromide
proceed cleanly in good yields (Scheme 7). With
dinucleophiles symmetrically 16–18 and unsymmet-
rically bridged heterocycles 19 are readily available
(Scheme 8). From the NMR data it can be seen that
the skeleton of the furan ring remains unchanged
during the substitution procedures [23]. Therefore,
the SnCl2 reaction of bis(trifluoromethyl) substituted
hetero-1,3-dienes represents a general, concise ap-
proach to trifluoromethyl substituted five-membered
heterocycles, being well suited for the generation of
ensembles.

230
K. Burger et al.
Scheme 7
Scheme 8
Scheme 9

Synthesis of 2-Fluoro-3-(trifluoromethyl)furans
231
4,4-Difluoro-1-phenyl-3-(trifluoromethyl)but-3-en-1-one
The thioanalogues, 2-fluoro-3-(trifluoromethyl)thio-
phenes, have been obtained from 6 via oxygen=
sulfur exchange on heating with P2S5 without sol-
vent [22]. Likewise, they are susceptible to nucleo-
philic exchange reactions at C-2, but the reaction
rates of the nucleophilic fluorine substitution are
considerably lower than in the furan series.
Starting the above discussed SnCl2 reaction with
the hetero-1,3-diene 20 provides compound 21
(Scheme 9). Finally, the annelated furan – 2-fluoro-
3-(trifluoromethyl)-4,5,6,7-tetrahydrocumaron 22 –
was obtained on treatment of 21 with NaH in dry
DMF or DMSO.
(6a, C11H7F5O)
Yield 5.38 g (86%), bp 50ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3360,
1750, 1690, 1600, 1580, 1455 cmꢃ1 1H NMR (CDCl3):
;
ꢄ ¼ 3.85 (dd, J ¼ 2.0, 2.0 Hz, CH2), 7.48 (m, 2Ar-H),
7.66 (m, Ar-H), 7.97 (m, 2Ar-H) ppm; 13C NMR (CDCl3):
ꢄ ¼ 32.87 (CH2), 81.84 (ddq, J ¼ 14.0, 29.0, 36.0Hz,
C¼CF2), 122.76 (ddq, J ¼ 5.0, 13.0, 271.0 Hz, CF3), 128.06,
128.79, 133.80, 135.50 (Ar-C), 157.39 (ddq, J ¼ 303.0, 292.0,
4.0 Hz, ¼CF2), 192.65 (C¼O) ppm; 19F NMR (CDCl3):
ꢄ ¼ ꢃ0.65 (dtrq, J ¼ 16.0, 2.0, 11.0 Hz, ¼CFa), 3.29 (dtrq,
J ¼ 16.0, 2.0, 19.0 Hz, ¼CFb), 16.76 (dd, J ¼ 19.0, 11.0,
CF3) ppm; MS: m=z ¼ 231 [Mꢃ F]þ, 203 [231 ꢃ CO]þ, 183
[203ꢃ HF]þ, 145 [Mꢃ C6H5CO]þ, 105 [C6H5CO]þ, 77
[C6H5]þ.
2-Fluoro-3-(trifluoromethyl)furans 10 have been
used as versatile building blocks for the synthesis of
trifluoromethyl substituted butenolides and ꢀ-(tri-
fluoromethyl)-ꢁ-keto acids [24]. On further applica-
tions of trifluoromethyl substituted five-membered
heterocycles as building blocks in organofluorine
chemistry we report elsewhere [14].
4,4-Difluoro-1-(4-methylphenyl)-3-(trifluoromethyl)but-3-en-
1-one (6b, C12H9F5O)
Yield 6.00 g (91%), bp 58ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3320,
1750, 1690, 1610 cmꢃ1; 1H NMR (CDCl3): ꢄ ¼ 2.44 (s, CH3),
3.83 (dd, J ¼ 2.0, 2.0 Hz, CH2), 7.30 (m, 2Ar-H), 7.88 (m,
2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 21.55 (CH3), 32.77
(CH2), 81.89 (ddq, J ¼ 14.0, 28.0, 36.0 Hz, C¼CF2), 122.74
(ddq, J ¼ 7.0, 12.0, 272.0 Hz, CF3), 128.22, 129.49, 133.02,
144.88 (Ar-C), 157.37 (ddq, J ¼ 301.0, 292.0, 5.0 Hz, ¼CF2),
192.22 (C¼O) ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ1.19 (dtrq,
J ¼ 16.0, 2.0, 10.0 Hz, ¼CFa), 3.12 (dtrq, J ¼ 16.0, 2.0,
19.0Hz, ¼CFb), 16.77 (dd, J ¼ 19.0, 10Hz, CF3) ppm; MS:
m=z ¼ 264 [M]þ, 245 [M ꢃ F]þ, 217 [245 ꢃ CO]þ, 197
[217 ꢃ HF]þ, 145 [M ꢃ C7H7CO]þ, 119 [C7H7CO]þ, 91
[C7H7]þ.
Experimental
General
Solvents were purified and dried prior to use. Reagents
were used as purchased. Flash chromatography was per-
formed using silica gel (32–63 ꢂm) with solvent systems
given in the text. Melting points were determined with a
1
Tottoli apparatus (Fa. Bu¨chi). H (200, 360 MHz), 13C (50,
4,4-Difluoro-1-(2-methoxyphenyl)-3-(trifluoromethyl)but-3-en-
1-one (6c, C12H9,F5O2)
90 MHz), and 19F (188, 282 MHz) NMR spectra were
recorded on Bruker WP 200, Bruker AM 360, Jeol C 60
HL, and Jeol FX 90 Q spectrometers. TMS was used as ref-
erence for 1H and 13C NMR spectra (internal), and CF3COOH
for 19F NMR spectra (external). IR spectra were obtained
on Perkin Elmer 157 G and 257 spectrometers. Mass spectra
were recorded on a Varian MAT CH 5 spectrometer at 70eV.
Elemental analyses were performed with a CHNO–S Rapid
apparatus (Fa. Heraeus); their results agreed with calculated
values.
Yield 4.90 g (70%), bp 56ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3280,
1750, 1675, 1600, 1485, 1470, 1440 cmꢃ1
;
1H NMR
(CDCl3): ꢄ ¼ 3.86 (dd, J ¼ 2.0, 2.0 Hz, CH2), 3.95 (s,
OCH3), 7.03 (m, 2Ar-H), 7.52 (m, Ar-H), 7.82 (m, Ar-H)
ppm; 13C NMR (CDCl3): ꢄ ¼ 37.91 (CH2), 55.30 (OCH3),
82.45 (ddq, J ¼ 13.0, 29.0, 35.0 Hz, C¼CF2), 111.56,
120.73 (Ar-C), 121.42 (ddq, J ¼ 6.0, 13.0, 271.0 Hz, CF3),
126.0, 130.73, 134.56, (Ar-C), 157.28 (ddq, J ¼ 302.0,
271.0, 4.0 Hz, ¼CF2), 159.05 (Ar-C), 194.30 (C¼O)
ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ1.87 (dtrq, J ¼ 17.0, 2.0,
10.0Hz, ¼CFa), 2.26 (dtrq, J ¼ 17.0, 2.0, 19.0Hz, ¼CFb),
16.78 (dd, J ¼ 19.0, 10.0Hz, CF3) ppm; MS: m=z ¼ 280
[M]þ, 221 [M ꢃ CO–OCH3]þ, 135 [C7H7OCO]þ, 77
[C6H5]þ.
1-Aryl-4,4-difluoro-3-(trifluoromethyl)but-3-en-1-ones (6)
4,4-Bis(trifluoromethyl)-1-oxabuta-1,3-diene (1) [14] (25mmol)
and 5.64 g SnCl2 ꢂ 2H2O (25 mmol) were heated in a sol-
vent mixture of xylene (100 cm3) and THF (30 cm3) under
reflux until the starting material was consumed (19F NMR
analysis; reaction time: 2–24 h). After filtration, the solu-
tion was concentrated in vacuo and the residue was purified
by column chromatography (eluent: chloroform=hexanes,
1=1).
4,4-Difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)but-3-en-
1-one (6d, C11H6F6O)
Yield 5.56 g (83%), bp 60ꢁC=0.6 Torr; IR (film): ꢃꢀ¼ 3340,
1750, 1690, 1595, 1505, 1410 cmꢃ1 1H NMR (CDCl3):
;
ꢄ ¼ 3.82 (dd, J ¼ 2.0, 2.0 Hz, CH2), 7.17 (m, 2Ar-H), 8.00
(m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 32.81 (CH2),
81.73 (ddq, J ¼ 14.0, 29.0, 36.0 Hz, C¼CF2), 115.97 (d,
J ¼ 22.0 Hz, Ar-C3,C5), 122.71 (ddq, J ¼ 6.0, 13.0, 271 Hz,
CF3), 130.81 (d, J ¼ 10.0Hz, Ar-C2,C6), 131.97 (d, J ¼ 3.0 Hz,
A second product was isolated in 5–6% yield on column
chromatography and fully characterized in three cases.
Based on the spectra data we ascribe the by-product the
structure of 1-aryl-4,4,4-trifluoro-3-trifluoromethyl-1-buta-
nones 7.

232
K. Burger et al.
1-(4-Fluorophenyl)-4,4,4-trifluoro-3-(trifluoromethyl)-1-
Ar-C1), 157.45 (ddq, J ¼ 303.0, 292.0, 4.0 Hz, ¼CF2), 166.15
(d, J ¼ 256.0 Hz, Ar-C4), 191.12 (C¼O) ppm; 19F NMR
(CDCl3): ꢄ ¼ ꢃ30.02 (m, Ar-F), ꢃ0.94 (dtrq, J ¼ 15.0,
2.0, 11.0 Hz, ¼CFa), 3.41 (dtrq, J ¼ 15.0, 2.0, 19.0 Hz,
¼CFb), 16.72 (dd, J ¼ 19.0, 11.0 Hz, CF3) ppm; MS:
m=z ¼ 249 [M ꢃ F]þ, 221 [249 ꢃ CO]þ, 201 [221 ꢃ HF]þ,
145 [M ꢃ C6H4FCO]þ, 123 [C6H4FCO]þ, 95 [C6H4F]þ, 75
[95 ꢃ HF]þ.
butanone (7d, C11H7F7O)
Yield 0.43g (6%), bp 72ꢁC=15 Torr; IR (film): ꢃꢀ¼ 1690,
1
1600, 1510 cmꢃ1; H NMR (CDCl3): ꢄ ¼ 3.40 (d, J ¼ 5.0 Hz,
CH2), 4.17 (trsept, J ¼ 5.0, 8.0 Hz, CH), 7.18 (m, 2Ar-H),
8.02 (m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 32.78 (sept,
J ¼ 2.0 Hz, CH2), 42.95 (sept, J ¼ 30.0Hz, CH), 123.67 (m,
CF3), 128.43, 132.77, 135.14, 142.05 (Ar-C), 185.47 (C¼O)
ppm; 19F NMR (CDCl3): ꢄ ¼ 9.90 (d, J ¼ 8.0Hz, CH(CF3)2)
ppm; MS: m=z ¼ 288 [M]þ, 269 [Mꢃ F]þ, 249 [Mꢃ F, HF]þ,
123 [C6H4FCO]þ, 95 [C6H4F]þ, 75 [95 ꢃ HF]þ.
4,4-Difluoro-(4-chlorophenyl)-3-(trifluoromethyl)but-3-en-1-
one (6e, C11H6ClF5O)
Yield 6.26 g (88%), bp 56ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3360,
1750, 1690, 1590, 1575, 1405 cmꢃ1 1H NMR (CDCl3):
;
1-(4-Chlorophenyl)-4,4,4-trifluoro-3-(trifluoromethyl)-1-
butanone (7e, C11H7ClF6O)
ꢄ ¼ 3.82 (dd, J ¼ 2.0, 2.0 Hz, CH2), 7.46 (m, 2Ar-H), 7.90
(m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 32.84 (CH2),
81.55 (ddq, J ¼ 14.0, 29.0, 36.0 Hz, C¼CF2), 122.57 (ddq,
J ¼ 5.0, 13.0, 271.0Hz, CF3), 129.12, 129.46, 133.80, 140.38
(Ar-C), 157.34 (ddq, J ¼ 304.0, 292.0, 5.0 Hz, ¼CF2), 191.50
(C¼O) ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ0.90 (dtrq, J ¼ 15.0,
2.0, 10.0Hz, ¼CFa), 3.42 (dtrq, J ¼ 15.0, 2.0, 19.0Hz, ¼CFb),
16.70 (dd, J ¼ 19.0, 10.0Hz, CF3) ppm; MS: m=z ¼ 267=265
[M ꢃ F]þ, 239=237 [267=265 ꢃ CO]þ, 219=217 [239=
237 ꢃ HF]þ, 182 [219=217 ꢃ Cl]þ, 141=139 [C6H4ClCO]þ,
113=111 [C6H4Cl]þ.
Yield 0.38 g (5%), mp 59ꢁC; IR (KBr): ꢃꢀ¼ 3460, 1700, 1600,
1
1578, 1495cmꢃ1; H NMR (CDCl3): 3.39 (sept, J ¼ 5.0 Hz,
CH2), 4.17 (trsept, J ¼ 5.0, 8.0 Hz, CH), 7.49 (m, 2Ar-H), 7.92
(m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 32.46 (sept,
J ¼ 2.0 Hz, CH2), 43.03 (sept, J ¼ 30.0Hz, CH), 123.92 (m,
CF3), 129.42, 129.72, 133.75, 140.95 (Ar-C), 191.67 (C¼O)
ppm; 19F NMR (CDCl3): ꢄ ¼ 9.91 (d, J ¼ 8.0 Hz, CH(CF3)2)
ppm; MS: m=z ¼ 306=304 [M]þ, 267=265 [Mꢃ F, ꢃHF]þ,
141=139 [C6H4ClCO]þ, 113=111 [C6H4Cl]þ.
4,4,4-Trifluoro-1-(thien-2-yl)-3-(trifluoromethyl)-1-butanone
(7g, C9H6F6OS)
4,4-Difluoro-1-(5-methylfur-2-yl)-3-(trifluoromethyl)but-3-en-
1-one (6f, C10H7F5O2)
Yield 0.35g (5%), oil; IR (film): ꢃꢀ¼ 3280, 1665, 1515, 1420,
1
1400cmꢃ1; H NMR (CDCl3): ꢄ ¼ 3.37 (d, J ¼ 6.0 Hz, CH2),
Yield 4.39 g (69%), bp 49ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3340,
1
1750, 1675, 1590, 1510 cmꢃ1; H NMR (CDCl3): ꢄ ¼ 2.41
4.12 (sept, J ¼ 6.0, 8.0 Hz, CH), 7.19 (m, thienyl-H), 7.74 (m,
thienyl-H), 7.80 (m, thienyl-H) ppm; 13C NMR (CDCl3):
ꢄ ¼ 32.78 (sept, J ¼ 2.0 Hz, CH2), 42.95 (sept, J ¼ 30.0Hz,
CH), 123.67 (m, CF3), 128.43, 132.77, 135.14, 142.05 (thie-
nyl-C), 185.47 (C¼O) ppm; 19F NMR (CDCl3): ꢄ ¼ 9.90 (d,
J ¼ 8.0 Hz, C(CF3)2) ppm; MS: m=z ¼ 276 [M]þ, 237 [Mꢃ F–
HF]þ, 209 [237ꢃ CO]þ, 145 [Mꢃ C4H3SCO–HF]þ, 111
[C4H3SCO]þ, 83 [C4H3S]þ.
(s, CH3), 3.67 (dd, J ¼ 2.0, 2.0 Hz, CH2), 6.21 (m, furyl-H),
7.19 (m, furyl-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 13.55
(CH3), 32.00 (CH2), 81.37 (dtrq, J ¼ 13.0, 29.0, 35.0 Hz,
C¼CF2), 109.24, 119.66 (furyl-C), 122.65 (ddq, J ¼ 5.0,
13.0, 271.0 Hz, CF3), 150.16 (furyl-C), 157.42 (ddq, J ¼
302.0, 292.0, 4.0 Hz, ¼CF2), 158.43 (furyl-C), 180.87
(C¼O) ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ0.84 (dtrq, J ¼ 15.0,
2.0, 11.0Hz, ¼CFa), 3.37 (dtrq, J ¼ 15.0, 2.0, 20.0Hz, ¼CFb),
16.71 (dd, J ¼ 20.0, 11.0Hz, CF3) ppm; MS: m=z ¼ 254 [M]þ,
235 [M ꢃ F]þ, 207 [235 ꢃ CO]þ, 187 [207 ꢃ HF]þ, 145
[M ꢃ C5H5OCO]þ, 109 [C5H5OCO]þ, 81 [C5H5O]þ, 53
[81 ꢃ CO]þ.
5-Aryl-2-fluoro-3-(trifluoromethyl)furans (10); General
Procedure
To a stirred solution of 25mmol 6 in 100cm3 dry DMF at 0ꢁC
0.60g NaH (25 mmol) were added in small portions. Stirring
was continued at room temperature until 19F NMR analysis
indicates that the starting material was completely consumed
(12–24h). Then the reaction mixture was poured into 100cm3
ice-cold 1 N HCl. The mixture was extraced with 3ꢄ100 cm3
ether. The organic phase was dried over MgSO4 and concen-
trated in vacuo. Finally the residue was purified by column
chromatography (eluent: hexanes).
4,4-Difluoro-1-(thien-2-yl)-3-(trifluoromethyl)but-3-en-1-one
(6g, C9H5F5OS)
Yield 5.64g (88%), 48ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3360, 1750,
1670, 1520, 1420 cmꢃ1
;
1H NMR (CDCl3): ꢄ ¼ 3.80
(dd, J ¼ 2.0, 2.0 Hz, CH2), 7.17 (m, thienyl-H), 7.71
(m, thienyl-H), 7.78 (m, thienyl-H) ppm; 13C NMR (CDCl3):
ꢄ ¼ 33.22 (CH2), 81.62 (ddq, J ¼ 14.0, 29.0, 36.0Hz, C¼CF2),
122.66 (ddq, J ¼ 5.0, 13.0, 271.0Hz, CF3), 128.33, 132.50,
134.64, 142.20 (thienyl-C), 157.54 (ddq, J ¼ 303.0, 292.0,
4.0 Hz, ¼CF2), 185.53 (C¼O) ppm; 19F NMR (CDCl3):
ꢄ ¼ ꢃ0.51 (dtrq, J ¼ 15.0, 2.0, 11.0 Hz, ¼CFa), 3.31 (dtrq,
J ¼ 15.0, 2.0, 19.0Hz, ¼CFb), 16.73 (dd, J ¼ 19.0, 11.0Hz,
CF3) ppm; MS: m=z ¼ 256 [M]þ, 237 [M ꢃ F]þ, 209
[237 ꢃ CO]þ, 189 [208ꢃ HF]þ, 145 [Mꢃ C4H3SCO]þ, 111
[C4H3SCO]þ, 83 [C4H3S]þ.
2-Fluoro-5-phenyl-3-(trifluꢁoromethyl)furan (10a, C11H6F4O)
Yield 4.14 g (72%), bp 47 C=0.1 Torr; IR (film): ꢃ ¼ 1665,
1610, 1570, 1455, 1440 cmꢃ1; 1H NMR (CDCl3): ꢄ ¼ 6.61 (d,
J ¼ 3.0Hz, furyl-H), 7.36 (m, 3Ar-H), 7.52 (m, 2Ar-H) ppm;
13C NMR (CDCl3): ꢄ ¼ 91.63 (dq, J ¼ 7.0, 40.0Hz, furyl-C3),
102.63 (m, furyl-C4), 121.20 (dq, J ¼ 5.0, 266.0Hz, CF3),
123.39, 128.38, 128.50, 128.87 (Ar-C), 145.07 (furyl-C5),
153.86 (dq, J ¼ 285.0, 5.0 Hz, furyl-C2) ppm; 19F NMR
ꢀ

Synthesis of 2-Fluoro-3-(trifluoromethyl)furans
233
(CDCl3): ꢄ ¼ ꢃ30.08 (dq, J ¼ 3.0, 10.0Hz, ¼CF), 19.36 (d,
J ¼ 10.0Hz, CF3) ppm; MS: m=z ¼ 230 [M]þ, 211 [Mꢃ F]þ,
210 [M ꢃ HF]þ, 183 [211 ꢃ CO]þ, 182 [210 ꢃ CO]þ, 133
[M ꢃ CO–CF3]þ.
2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 91.99 (dq, J ¼ 7.0,
40.0Hz, furyl-C3), 103.32 (m, furyl-C4), 121.11 (dq, J ¼ 5.0,
266.0 Hz, CF3). 124.78, 126.98, 129.30, 134.57 (Ar-C),
144.14 (furyl-C5), 154.04 (dq, J ¼ 286.0, 5.0 Hz, furyl-C2)
ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ29.48 (dq, J ¼ 2.0, 11.0Hz,
¼CF), 19.35 (d, J ¼ 11.0 Hz, CF3) ppm; MS: m=z ¼
266=264 [M]þ, 246=244 [Mꢃ HF]þ, 229 [Mꢃ Cl]þ, 218=
216 [246=244 ꢃ CO]þ, 201 [229ꢃ CO]þ, 182 [201 ꢃ F]þ,
169=167 [Mꢃ CO–CF3]þ, 132 [167 ꢃ Cl]þ.
2-Fluoro-5-(4-methylphenyl)-3-(trifluoromethyl)furan
(10b, C12H8F4O)
Yield 4.15g (68%), mp 53ꢁC; IR (KBr): ꢃꢀ¼ 3440, 1675,
1595, 1505, 1450 cmꢃ1
;
1H NMR (CDCl3): ꢄ ¼ 2.36 (s,
CH3), 6.55 (d, J ¼ 3.0Hz, furyl-H), 7.18 (m, 2Ar-H), 7.43
(m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 21.14 (CH3),
91.47 (dq, J ¼ 7.0, 40.0 Hz, furyl-C3), 101.85 (m, furyl-C4),
121.25 (dq, J ¼ 5.0, 266.0 Hz, CF3), 123.43 (d, J ¼ 1.0 Hz),
125.74, 129.56, 138.63 (Ar-H), 145.37 (furyl-C5), 153.67
(dq, J ¼ 285.0, 5.0 Hz, furyl-C2) ppm; 19F NMR (CDCl3):
ꢄ ¼ ꢃ30.36 (dq, J ¼ 2.0, 11.0Hz, ¼CF), 19.22 (d, J ¼ 11.0Hz,
CF3) ppm; MS: m=z ¼ 244 [M]þ, 225 [Mꢃ F]þ, 224
[Mꢃ HF]þ, 196 [224ꢃ CO]þ, 147 [Mꢃ CO–CF3]þ.
2-Fluoro-5-(5-methylfur-2-yl)-3-(trifluoromethyl)furan
(10f, C10H6F4O2)
Yield 3.51 g (60%), bp 39ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 1680,
1615, 1590, 1570, 1450, 1410 cmꢃ1 1H NMR (CDCl3):
;
ꢄ ¼ 2.33 (s, CH3), 6.03 (m, furyl-H), 6.43 (d, J ¼ 3.0 Hz,
furyl-H), 6.45 (d, J ¼ 3.0 Hz, furyl-H) ppm; 13C NMR
(CDCl3): ꢄ ¼ 13.48 (CH3), 91.27 (dq, J ¼ 7.0, 40.0 Hz,
furyl-C3), 101.59 (m, furyl-C4), 107.61, 107.73 (furyl-C),
121.06 (dq, J ¼ 5.0, 266.0 Hz, CF3), 138.05 (furyl-C), 142.09
(furyl-C5), 153.08 (furyl-C), 153.33 (dq, J ¼ 285.0, 5.0Hz,
furyl-C2) ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ30.36 (dq, J ¼ 2.0,
11.0 Hz, ¼CF), 19.28 (d, J ¼ 11.0 Hz, CF3) ppm; MS:
m=z ¼ 234 [M]þ, 219 [M ꢃ CH3]þ, 215 [M ꢃ F]þ, 214
[Mꢃ HF]þ, 191 [219 ꢃ CO]þ, 187 [215ꢃ CO]þ, 186 [214ꢃ
CO]þ, 171 [191ꢃ HF]þ, 163 [191 ꢃ CO]þ, 137 [Mꢃ CO–
CF3]þ, 109 [C5H5OCO]þ.
2-Fluoro-5-(2-methoxyphenyl)-3-(trifluoromethyl)furan
(10c, C12H8F4O2)
Yield 4.42 g (68%), mp 39ꢁC; IR (KBr): ꢃꢀ¼ 3360, 1670,
1605, 1495, 1460, 1450, 1430 cmꢃ1 1H NMR (CDCl3):
;
ꢄ ¼ 3.93 (s, OCH3), 6.93 (d, J ¼ 3.0 Hz, furyl-H), 6.99 (m,
2Ar-H), 7.31 (m, Ar-H), 7.65 (m, Ar-H) ppm; 13C NMR
(CDCl3): ꢄ ¼ 55.24 (OCH3), 91.19 (dq, J ¼ 7.0, 40.0 Hz,
furyl-C3), 107.71 (m, furyl-C4), 110.90, 117.27, 120.71 (Ar-
C), 121.35 (dq, J ¼ 5.0, 266.0 Hz, CF3), 125.29, 129.08 (Ar-C),
141.85 (furyl-C5), 149.52 (dq, J ¼ 284.0, 5.0Hz, furyl-C2),
155.76 (d, J ¼ 2.0 Hz, Ar-C) ppm; 19F NMR (CDCl3): ꢄ ¼
ꢃ31.47 (dq, J ¼ 3.0, 11.0Hz, ¼CF), 19.40 (d, J ¼ 11.0Hz,
CF3) ppm; MS: m=z ¼ 260 [M]þ, 241 [M ꢃ F]þ, 240
[M ꢃ HF]þ, 225 [240 ꢃ CH3]þ, 217 [M ꢃ CH3–CO]þ, 197
[225 ꢃ CO]þ, 169 [197 ꢃ CO]þ, 163 [M ꢃ CO–CF3]þ, 133
[240 ꢃ C7H7O]þ.
2-Fluoro-5-(thien-2-yl)-3-(trifluoromethyl)furan
(10g, C9H4F4OS)
Yield 3.72 g (63%), bp 35ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 1665,
1
1450, 1425 cmꢃ1; H NMR (CDCl3): ꢄ ¼ 6.46 (d, J ¼ 3.0 Hz,
furyl-H), 7.02 (m, thienyl-H), 7.22 (m, thienyl-H), 7.26
(m, thienyl-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 91.66 (dq,
J ¼ 7.0, 40.0 Hz, furyl-C5), 102.62 (m, furyl-C4), 121.06
(dq, J ¼ 5.0, 266.0 Hz, CF3), 124.09 (d, J ¼ 2.0 Hz), 125.46,
127.73, 130.74 (thienyl-C), 140.86 (furyl-C5), 153.42 (dq,
J ¼ 286.0, 5.0 Hz, furyl-C2) ppm; 19F NMR (CDCl3):
ꢄ ¼ ꢃ30.30 (dq, J ¼ 3.0, 11.0 Hz, ¼CF), 19.31 (d, J ¼
11.0 Hz, CF3) ppm; MS: m=z ¼ 236 [M]þ, 217 [M ꢃ F]þ,
216 [M ꢃ HF]þ, 208 [M ꢃ CO]þ, 189 [217ꢃCO]þ, 188
[216ꢃ CO]þ, 139 [Mꢃ CO–CF3]þ.
2-Fluoro-5-(4-fluorophenyl)-3-(trifluoromethyl)furan
(10d, C11H5F5O)
Yield 4.34 g (70%), bp 41ꢁC=0.1 Torr; IR (film): ꢃꢀ¼ 3350,
1670, 1600, 1580, 1500, 1450, 1425 cmꢃ1; 1H NMR (CDCl3):
ꢄ ¼ 6.53 (d, J ¼ 3.0 Hz, furyl-H), 7.06 (m, 2Ar-H), 7.47 (m,
2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 91.71 (dq, J ¼ 7.0,
40.0Hz, furyl-C3), 102.36 (dq, J ¼ 2.0, 4.0 Hz, furyl-C4),
116.03 (d, J ¼ 22.0 Hz, Ar-C3,C5), 121.15 (dq, J ¼ 5.0,
266.0Hz, CF3), 124.76 (d, J ¼ 3.0 Hz, Ar-C1), 125.31 (dd,
J ¼ 1.0, 9.0 Hz, Ar-C2, C6), 144.29 (furyl-C5), 153.87 (dq,
J ¼ 285.0, 5.0 Hz, furyl-C2), 162.84 (d, J ¼ 249.0Hz, Ar-C4)
ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ34.29 (m, ¼CF), ꢃ30.20 (dq,
J ¼ 2.0, 10.0 Hz, ¼CF), 19.26 (d, J ¼ 10.0 Hz, CF3) ppm;
MS: m=z ¼ 248 [M]þ, 229 [Mꢃ F]þ, 228 [Mꢃ HF]þ, 201
[229 ꢃ CO]þ, 200 [228ꢃ CO]þ, 151 [Mꢃ CO–CF3]þ.
2-Ethoxy-5-phenyl-3-(trifluoromethyl)furan (11, C13H11F3O2)
To a solution of the freshly prepared alcoholate (6mmol) in
dioxane 0.70g 10a (3mmol) were added. After ca 60min the
reaction was complete (19F NMR analysis). Water (20 cm3)
was added and the reaction mixture was extracted with
3ꢄ20 cm3 CH2Cl2. After drying the organic phase with
MgSO4 the solvent was evaporated under reduced pres-
sure and the residue was purified by column chromatography.
Yield 0.74g (96%), mp 47ꢁC; IR (KBr): ꢃꢀ¼ 3400, 1635,
1
1600, 1560, 1460, 1440cmꢃ1; H NMR (CDCl3): ꢄ ¼ 1.44
(tr, J ¼ 7.0 Hz, CH3), 4.41 (q, J ¼ 7.0 Hz, OCH2), 6.61 (s,
furyl-H), 7.24 (m, Ar-H), 7.35 (m, 2Ar-H), 7.52 (m, 2Ar-H)
ppm. 13C NMR (CDCl3): ꢄ ¼ 15.66 (CH3), 69.59 (OCH2),
94.16 (q, J ¼ 38.0 Hz, furyl-C3), 104.30 (q, J ¼ 2.0 Hz,
furyl-C4), 123.47 (q, J ¼ 266.0 Hz, CF3), 123.77, 128.26,
129.59, 130.46 (Ar-C), 145.24 (furyl-C5), 157.43 (q,
5-(4-Chlorophenyl)-2-fluoro-3-(trifluoromethyl)furan
(10e, C11H5ClF4O)
Yield 4.36g (66%), mp 36ꢁC; IR (KBr): ꢃꢀ¼ 3440, 1680,
1615, 1590, 1570, 1495, 1450, 1410 cmꢃ1; 1H NMR (CDCl3):
ꢄ ¼ 6.65 (d, J ¼ 3.0 Hz, furyl-H), 7.35 (m, 2Ar-H), 7.44 (m,

234
K. Burger et al.
J ¼ 4.0 Hz, furyl-C2) ppm; 19F NMR (CDCl3): ꢄ ¼ 20.38
(s, CF3) ppm; MS: m=z ¼ 256 [M]þ, 228 [M ꢃ CO]þ,
227 [M ꢃ C2H5]þ, 209 [228 ꢃ F]þ, 208 [M ꢃ HF]þ, 180
[209 ꢃ C2H5]þ, 179 [208 ꢃ C2H5]þ, 105 [C6H5CO]þ, 77
[C6H5]þ.
sure and the residue was purified by column chromatography
(eluent: CH2Cl2). Yield 0.40g (55%), mp 67ꢁC; IR (KBr);
ꢃꢀ¼ 1766–1739, 1498, 1311 cmꢃ1
;
1H NMR (CDCl3): ꢄ ¼
3.83 (s, 2ꢄ CH3), 5.06 (s, CH), 6.70 (s, furyl-H), 7.09 (m,
2Ar-H), 7.63 (m, 2Ar-H) ppm; 13C NMR (CDCl3): ꢄ ¼ 50.5
(CH), 53.4 (2ꢄ OCH3), 103.0 (furyl-C4), 116.0 (d, J ¼
22.3Hz, Ar-C3,C5), 117.8 (q, J ¼ 37.5 Hz, furyl-C3), 122.2
(q, J ¼ 267.5 Hz, CF3), 125.4 (d, J ¼ 3.2 Hz, Ar-C1), 126.2
(d, J ¼ 8.0Hz, Ar-C2,C6), 144.0 (furyl-C5), 154.2 (furyl-C2),
2-(N-Methylimidazol-2-ylthio)-5-phenyl-3-
(trifluoromethyl)furan (12, C18H11F3OS)
To a solution of 0.72 g 10a (3mmol) and the corresponding
thio compound (0.70 g, 6 mmol) in 25 cm3 dioxane 0.07 g
NaH (3mmol) were added. After the reaction was complete,
the mixture was quenched with 20 cm3 water and extracted
with 3ꢄ25 cm3 ether. After drying the organic phase with
MgSO4, the solvent was evaporated in vacuo and the residue
was purified by column chromatography. Yield 0.98g (94%),
mp 133ꢁC; IR (KBr): ꢃꢀ¼ 3420, 1610, 1595, 1540, 1485,
162.9 (d, J ¼ 249.5Hz, Ar-C4) 165.4 (2ꢄ CO2CH3) ppm; 19
F
NMR (CDCl3): ꢄ ¼ ꢃ34.2 (m, 1F), 19.7 (s, CF3) ppm; MS:
m=z ¼ 360 [M]þ, 340 [Mꢃ HF]þ, 301 [Mꢃ CO2CH3]þ, 59
[CO2CH3]þ.
2,5-Diphenyl-3-(trifluoromethyl)furan (15a, C17H11F3O)
To a stirred solution of 2 mmol 10 in 20cm3 THF a 2.0M
phenyl lithium solution in THF (3.0cm3, 6 mmol) was added
at room temperature. After 1 h the reaction is complete
(19F NMR analysis). The mixture was quenched with
20 cm3 1 N HCl at 0ꢁC and extracted with 3ꢄ10 cm3 ether.
The organic phase was dried (MgSO4) and the solvent
was removed under reduced pressure. The crude product
was purified by column chromatography (eluent: hexanes).
Yield 0.38 g (66%), oil; IR (CHCl3): ꢃꢀ¼ 3400, 1625,
1
1460, 1400cmꢃ1; H NMR (CDCl3): ꢄ ¼ 3.81 (s, CH3), 6.76
(s, furyl-H), 7.03 (d, J ¼ 1.0 Hz, imidazolyl-H), 7.12 (d,
J ¼ 1.0 Hz, imidazolyl-H), 7.34 (m, 3Ar-H), 7.56 (m, 2Ar-H)
ppm; 13C NMR (CDCl3): ꢄ ¼ 33.90 (CH3), 104.29 (q,
J ¼ 2.0 Hz, furyl-C4), 121.70 (q, J ¼ 268.0 Hz, CF3), 122.00
(q, J ¼ 38.0 Hz, furyl-C3), 124.02, 124.15, 128.55, 128.72,
128.85, 130.36, 134.48 (Ar-C, imidazolyl-C), 141.19 (q,
J ¼ 4.0 Hz, furyl-C2), 156.82 (furyl-C5) ppm; 19F NMR
(CDCl3): ꢄ ¼ 19.69 (s, CF3) ppm; MS: m=z ¼ 324 [M]þ, 305
[Mꢃ F]þ, 255 [Mꢃ CF3]þ, 219 [Mꢃ C6H5CO]þ, 183 [Mꢃ
C4H5N2S–CO]þ, 105 [C6H5CO]þ, 77 [C6H5]þ.
1600, 1555, 1485, 1450, 1420 cmꢃ1 1H NMR (CDCl3):
;
ꢄ ¼ 6.88 (s, furyl-H), 7.32 (m, 2Ar-H), 7.44 (m, 4Ar-H),
7.72 (m, 2Ar-H), 7.79 (m, 2Ar-H) ppm; 13C NMR (CDCl3):
ꢄ ¼ 105.22 (q, J ¼ 3.0 Hz, furyl-C4), 114.21 (q, J ¼ 37.0 Hz,
furyl-C3), 122.82 (q, J ¼ 267.0 Hz, CF3), 123.98, 127.13 (q,
J ¼ 2.0 Hz), 128.34, 128.62, 128.72, 128.82, 128.25, 129.37
(Ar-C), 151.82 (q, J ¼ 4.0 Hz, furyl-C2), 152.92 (furyl-C5)
ppm; 19F NMR (CDCl3): ꢄ ¼ 21.39 (s, CF3) ppm; MS:
m=z ¼ 288 [M]þ, 269 [M ꢃ F]þ, 191 [M ꢃ CO–CF3]þ, 183
[Mꢃ CO–C6H5]þ, 144 [183 ꢃ HF–F]þ, 105 [C6H5CO]þ, 77
[C6H5]þ.
5-(4-Chlorophenyl)-2-[(2-hydroxyethyl)methylamino]-
3-(trifluoromethyl)furan (13, C14H13ClF3NO2)
A solution of equimolar amounts of 10e (0.80 g, 3 mmol) and
2-(methylamino)ethanol (0.23 g, 3 mmol) in 20cm3 dioxane
was stirred until the reaction was complete (19F NMR anal-
ysis). After quenching the mixture with 20 cm3 water the
organic phase was extracted with 3ꢄ20 cm3 ether. Further
work-up as above. Yield 0.90 g (94%), mp 69ꢁC; IR (KBr):
1
ꢃꢀ¼ 3320, 3230, 1600, 1465, 1430 cmꢃ1; H NMR (CDCl3):
5-(4-Fluorophenyl)-2-phenyl-3-(trifluoromethyl)furan
(15b, C17H10F4O)
ꢄ ¼ 1.74 (s, OH), 3.09 (q, J ¼ 1.0 Hz, NCH3), 3.51 (tr,
J ¼ 6.0 Hz, NCH2), 3.85 (tr, J ¼ 6.0 Hz, OCH2), 6.65 (s,
furyl-H), 7.31 (m, 2Ar-H), 7.41 (m, 2Ar-H) ppm; 13C NMR
(CDCl3): ꢄ ¼ 38.83 (q, J ¼ 2.0 Hz, NCH3), 54.96 (NCH2),
60.20 (OCH2), 93.74 (q, J ¼ 37.0Hz, furyl-C3), 105.75 (q,
J ¼ 3.0 Hz, furyl-C4), 123.43 (q, J ¼ 265.0Hz, CF3), 123.72,
128.40, 128.86, 132.27 (Ar-C), 142.95 (furyl-C5), 155.75
(q, J ¼ 4.0 Hz, furyl-C2) ppm; 19F NMR (CDCl3): ꢄ ¼ 25.87
(d, J ¼ 1.0 Hz, CF3) ppm; MS: m=z ¼ 321=319 [M]þ,
290=288 [M ꢃ OCH3]þ, 219=217 [M ꢃ C3H8NO–CO]þ,
141=139 [ClC6H4CO]þ, 113=111 [ClC6H4]þ.
Yield 0.39g (63%), oil; IR (film): ꢃꢀ¼ 1605, 1600, 1560, 1505,
1495, 1450, 1430, 1410 cmꢃ1; 1H NMR (CDCl3): ꢄ ¼ 6.82 (s,
furyl-H), 7.11 (m, 2Ar-H), 7.47 (m, 3Ar-H), 7.72 (m, 4Ar-H)
ppm; 13C NMR (CDCl3): ꢄ ¼ 104.90 (q, J ¼ 2.0Hz, furyl-
C4), 114.27 (q, J ¼ 38.0Hz, furyl-C3), 116.00 (d, J ¼ 22.0Hz,
Ar-C3,C5), 122.80 (q, J ¼ 267.0 Hz, CF3), 125.76 (d, J ¼
3.0 Hz, Ar-C4), 125.88 (d, J ¼ 8.0 Hz, Ar-C2,C6), 127.08
(d, J ¼ 2.0 Hz), 128.67, 129.35 (Ar-C), 151.87 (q, J ¼ 5.0 Hz,
Hz, furyl-C2), 152.12 (furyl-C5), 162.68 (d, J ¼ 249.0 Hz,
Ar-C4) ppm; 1H NMR (CDCl3): ꢄ ¼ ꢃ34.58 (m, Ar-F),
21.26 (s, CF3) ppm; MS: m=z 306 [M]þ, 287 [Mꢃ F]þ, 209
[Mꢃ CO–CF3]þ, 183 [Mꢃ CO–C6H4F]þ, 105 [C6H5CO]þ,
95 [C6H4F]þ, 77 [C6H5]þ.
5-(4-Fluorophenyl)-2-bis(methoxycarbonyl)methyl-3-
(trifluoromethyl)furan (14, C12H10F4N2O)
To a solution of 0.49 g 10d (2mmol) and 0.53 g dimethyl
malonate (4mmol) in 10 cm3 THF 0.12g NaH (5 mmol) were
added portionwise with cooling (0ꢁC). After 1 h the tempe-
rature was risen to 50ꢁC. When the reaction was complete
(19F NMR analysis) it was quenched with 1 N HCl at 0ꢁC
and extracted with 3ꢄ25cm3 ether. After drying the organic
phase (MgSO4) the solvent was removed under reduced pres-
1,4-Bis[5-(4-fluorophenyl)-3-(trifluoromethyl)fur-2-
yloxy]benzol (16, C28H14F8O4)
A mixture of 2 mmol 10 1 mmol of the corresponding dinu-
cleophile, and 0.12g KOH (2mmol) in 20cm3 dioxane was
stirred at 80ꢁC until the reaction was complete (8–12h,
19F NMR analysis). The reaction mixture was quenched with

Synthesis of 2-Fluoro-3-(trifluoromethyl)furans
235
20cm3 1 N HCl and extracted with 3ꢄ20 cm3 CH2Cl2.
After drying the organic phase with MgSO4, the solvent was
removed in vacuo. Finally the residue was purified by col-
umn chromatography (eluent: chloroform=hexanes, 1=3). Yield
1.48g (87%), mp 132ꢁC; IR (KBr): ꢃꢀ¼ 3440, 1650, 1605.
column chromatography (eluent: CHC3=hexanes, 1=1). Yield
0.61 g (38%, oil; IR (film): ꢃꢀ¼ 1650, 1600, 1455 cmꢃ1
;
1H NMR (CDCl3): ꢄ ¼ 3.17 (q, J ¼ 1.0Hz, NCH3), 3.79
(tr, J ¼ 5.0 Hz, NCH2), 4.56 (tr, J ¼ 5.0 Hz, OCH2), 6.44
(s, furyl-H), 6.62 (s, furyl-H), 6.98 (m, thienyl-H), 7.10
(m, thienyl-H), 7.19 (m, thienyl-H), 7.26 (m, 2Ar-H), 7.35
(m, 2thienyl-H) ppm; 13C NMR (CDCl3). ꢄ ¼ 38.95 (q,
J ¼ 2.0 Hz, NCH2), 51.90 (NCH2), 70.59 (OCH2), 92.66
(q, J ¼ 38.0 Hz, furyl-C3), 93.20 (q, J ¼ 39.0 Hz, furyl-
C3), 103.57 (q, J ¼ 2.0 Hz, furyl-C4), 106.01 (q, J ¼
3.0 Hz, furyl-C40), 122.21 (q, J ¼ 267.0 Hz, CF3), 122.76
(thienyl-C), 123.46 (q, J ¼ 265.0 Hz, CF3), 123.69 (Ar-
C), 124.40, 127.63 (thienyl-C), 128.39, 128.84, 131.90,
132.20 (Ar-C, thienyl-C), 140.44 (furyl-C5), 142.78 (furyl-
C5), 154.92 (q, J ¼ 4.0 Hz, furyl-C2), 155.43 (q, J ¼
4.0 Hz, furyl-C2) ppm; MS: m=z ¼ 537=535 [M]þ,
518=516 [M ꢃ F]þ, 320=318 [M ꢃ C9H4F3OS]þ, 304=302
[M ꢃ C9H4F3O2S]þ, 276=274 [304=302 ꢃ C2H4]þ, 233
[C9H4F3O2S]þ, 217 [C9H4F3OS]þ, 141=139 [ClC6H4]þ,
113=111 [ClC6H4]þ.
1575, 1500, 1440 cmꢃ1
;
1H NMR (CDCl3): ꢄ ¼ 6.66 (s,
2furyl-H), 7.06 (m, 4Ar-H), 7.10 (s, 4Ar-H), 7.51 (m, 4Ar-
H) ppm; 13C NMR (CDCl3): ꢄ ¼ 99.75 (q, J ¼ 39.0 Hz, furyl-
C3), 102.73 (q, J ¼ 2.0 Hz, furyl-C4), 115.98 (d, J ¼
22.0Hz, Ar-C3,C5), 118.33 (Ar-C2,C3), 121.77 (q, J ¼
267.0 Hz, CF3), 125.27 (J ¼ 4.0 Hz, Ar-C1), 125.41 (d,
J ¼ 8.0 Hz, Ar-C2,C6), 146.21 (furyl-C5), 152.43 (q, J ¼
5.0 Hz, furyl-C2), 152.80 (C-1, Ar-C1,C4), 162.59 (d, J ¼
249.0 Hz, Ar-C4) ppm; 19F NMR (CDCl3): ꢄ ¼ ꢃ34.58 (m,
2F), 19.44 (s, 2ꢄ CF3) ppm; MS: m=z ¼ 566 [M]þ, 547
[Mꢃ F]þ, 321 [Mꢃ C11H5O2F4]þ, 245 [C11H5O2F]þ, 123
[FC6H4CO]þ, 95 [FC6H4]þ.
1,3-Bis[5(4-fluorophenyl)-3-(trifluoromethyl)fur-2-yloxy]
benzene (17, C28H14F8O4)
Yield 0.56 g (50%), oil; IR (film): ꢃꢀ¼ 3400, 1655, 1600,
1570, 1505, 1485, 1445, 1415 cmꢃ1 1H NMR (CDCl3):
;
2-(1,1,3,3,3-Pentafluoropropen-2-yl)cyclohexanone
(21, C9H9F5O)
ꢄ ¼ 6.65 (s, 2furyl-H), 6.87 (s, Ar-H), 6.89 (m, 2Ar-H),
7.04 (m, 4Ar-H), 7.33 (m, Ar-H), 7.49 (m, 4Ar-H) ppm;
13C NMR (CDCl3): ꢄ ¼ 100.35 (q, J ¼ 39.0 Hz, furyl-C3),
102.07 (q, J ¼ 2.0 Hz, furyl-C4), 112.68 (Ar-C), 115.97
(d, J ¼ 22.0 Hz, Ar-C3,C5), 121.69 (q, J ¼ 267.0 Hz, CF3),
125.21 (d, J ¼ 3.0 Hz, Ar-C4), 125.46 (q, J ¼ 8.0 Hz, Ar-C-
2,C6), 130.90 (Ar-C), 146.55 (furyl-C5), 151.78 (q, J ¼
5.0 Hz, furyl-C2), 157.80 (Ar-C), 162.66 (d, J ¼ 249.0 Hz,
Ar-C4) ppm; MS: m=z ¼ 566 [M]þ, 547 [M ꢃ F]þ, 321
[Mꢃ C11H5O2F4]þ, 245 [C11H5O2F4]þ, 123 [FC6H4CO]þ, 95
[C6H4F]þ.
4.92 (20 mmol) 2-(1,1,1,3,3,3-hexafluoroisopropyliden)cyclo-
hexanone 20 [18c] and SnCl2 ꢂ 2H2O (4.52 g, 20mmol) were
heated for 6 h under reflux in a solvent mixture (xylene
60cm3, THF 6 cm3). After filtration the product was purified
by distillation in vacuo. Yield 3.60g (79%), 69ꢁC=15 Torr; IR
(film): ꢃꢀ¼ 1745, 1715, 1445 cmꢃ1
;
1H NMR (CDCl3):
ꢄ ¼ 1.73 (m, CH2), 1.90 (m, CH2), 2.01 (m, CH2), 2.13 (m,
CH2), 2.23 (m, CH2), 2.35 (m, CH2), 2.56 (m, CH2), 3.19 (m,
CH2) ppm; 13C NMR (CDCl3): ꢄ ¼ 25.15, 26.37, 31.73 (m),
41.34, 47.17, 85.51 (ddq, J ¼ 7.0, 11.0, 34.0Hz, C¼CF2),
122.98 (ddq, J ¼ 5.0, 14.0, 271.0 Hz, CF3), 156.96 (ddq,
J ¼ 293.0, 304.0, 4.0 Hz, C¼CF2), 204.11 (C¼O) ppm; 19F
NMR (CDCl3): ꢄ ¼ 2.04 (m, ¼CFa), 3.52 (m, ¼CFb), 17.97
(dd, J ¼ 10.0, 22.0 Hz, CF3) ppm; MS: m=z¼228 [M]þ, 200
[M ꢃ CO]þ, 184 [Mꢃ C2H4O]þ, 158 [Mꢃ C3H6CO]þ, 115
[184ꢃ CF3]þ, 89 [158ꢃ CF3]þ, 69 [CF3]þ, 55 [C4H7]þ,
42 [C3H6]þ, 41 [C3H5]þ.
2,6-Bis[5-phenyl-3-(trifluoromethyl)fur-2-yloxy]naphthaline
(18, C32H18F6O4)
Yield 0.48 g (41%), mp 187ꢁC; IR (KBr): ꢃꢀ¼ 3440, 1660,
1
1600, 1570, 1520, 1455, 1440 cmꢃ1; H NMR (acetone-d6):
ꢄ ¼ 7.21 (s, 2furyl-H), 7.35 (m, 2Ar-H), 7.42 (m, 4Ar-H), 7.50
(m, 2Ar-H), 7.69 (m, 4Ar-H), 7.73 (m, 2Ar-H), 8.06 (m, 2Ar-
H) ppm; 13C NMR (acetone-d6): ꢄ ¼ 100.26 (q, J ¼ 39.0 Hz,
furyl-C3), 104.29 (q, J ¼ 2.0 Hz, furyl-C4), 113.50, 119.46
(Ar-C), 123.09 (q, J ¼ 266.0Hz, CF3), 124.42, 129.25,
129.81, 129.86, 130.97, 132.34, Ar-C), 148.37 (furyl-C5),
153.44 (q, J ¼ 4.0 Hz, furyl-C2), 154.80 (Ar-C) ppm;
19F NMR (acetone-d6): ꢄ ¼ 19.87 (s, 2ꢄ CF3) ppm; MS:
m=z ¼ 580 [M]þ, 561 [M ꢃ F]þ, 353 [M ꢃ C11H6F3O2]þ,
227 [C11H6F3O2]þ, 179 [227 ꢃ HF–CO]þ, 126 [C10H6]þ,
105 [C6H5CO]þ, 77 [C6H5]þ.
2-Fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydrocumaron
(22, C9H8F4O)
To a solution of 4.56 g 21 (20 mmol) in 100cm3 DMSO 0.48 g
NaH (20 mmol) were added slowly at 0ꢁC with stirring.
Stirring was continued until the starting material was con-
sumed (19F NMR analysis). Then the reaction mixture was
poured into 30 cm3 ice-cold 1 N HCl and the mixture
was extracted with 3ꢄ30 cm3 pentane. The organic phase
was dried (MgSO4) filtered, and concentrated in vacuo.
Yield 0.88 g (21%), oil; IR (film): ꢃꢀ¼ 3440, 1675,
1
1450cmꢃ1; H NMR (CDCl3): ꢄ ¼ 1.79 (m, 2ꢄ CH2), 2.46
2-[Methyl[5-(4-chlorophenyl)-3-(trifluoromethyl)fur-
2-yl]amino]1-[5-(thien-2-yl)-3-(trifluoromethyl)fur-2-yl
oxyl]ethane (19, C23H16ClF6NO3S)
(m, 2ꢄ CH2) ppm; 13C NMR (CDCl3): ꢄ ¼ 20.43, 21.86,
22.02, 22.29 (C-4 ꢃ C-7), 115.91 (m, C-30), 116.71 (m, C-
3), 121.81 (dq, J ¼ 5.0, 266.0Hz, CF3), 141.76 (C-70),
153.65 (dq, J ¼ 284.0, 5.0Hz, C-2) ppm; 19F NMR (CDCl3):
ꢄ ¼ ꢃ34.03 (q, J ¼ 12.0Hz, ¼CF), 19.22 (d, J ¼ 12.0Hz, CF3)
ppm.
To a solution of 0.96 g 13 (3mmol) and 0.71 g 10g (3mmol) in
dioxane were stirred at 80ꢁC until the reaction was complete
(19F NMR analysis). After quenching with water (20 cm3)
work-up as described before. The residue was purified by

236
K. Burger et al.: Synthesis of 2-Fluoro-3-(trifluoromethyl)furans
Chem Rev 94: 373; (b) Burdeniuc J, Jedlicka B, Crabtree
RH (1997) Chem Ber 130: 145; (c) Richmond TG (1999)
In: Murai S (ed) Activation of Unreactive Bonds and
Organic Synthesis, Topics in Organometallic Chemistry,
Vol 3, Springer, Berlin, p 243; (d) Terao J, Watabe H,
Kambe N (2005) J Am Chem Soc 127: 3656; (e) Terao J,
Ikumi A, Kuniyasu H, Kambe N (2003) J Am Chem Soc
125: 5646; (f) Kim YM, Yu S (2003) JAm Chem Soc 125:
1696; (g) Steffen A, Sladek MI, Braun T, Neumann B,
Stammler H-G (2005) Organometallics 24: 4057; (h)
Saeki T, Takashima Y, Tamao K (2005) Synlett 1771
[12] Chambers RD (1973) Fluorine in Organic Chemistry,
John Wiley & Sons, p 241
[13] (a) Kitazume T, Ohnogi T (1988) Synthesis 614; (b)
Burger K, Wucherpfennig U, Brunner E (1994) In:
Katritzky AR (ed) Advanes in Heterocyclic Chemistry,
Vol 60, p 1
[14] Burger K, Hennig L, Spengler J, Albericio F (2006)
Heterocycles 69: 569
Acknowledgements
We are grateful to Deutsche Forschungsgemeinschaft
and Stiftung Volkswagenwerk for financial support.
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