Domino reactions with fluorinated five-membered heterocycles - Syntheses of trifluoromethyl substituted butenolides and γ-ketoacids

Article abstract of DOI:10.1007/s00706-005-0366-z

A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps - nucleophilic displacement reaction, Claisen, and finally Cope rearrangement - which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to α-trifluoromethyl-γ-ketoacids. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-005-0366-z

Monatshefte f€ur Chemie 136, 1763–1779 (2005)
DOI 10.1007/s00706-005-0366-z
Domino Reactions with Fluorinated
Five-membered Heterocycles – Syntheses
of Trifluoromethyl Substituted
Butenolides and c-Ketoacids#
Klaus Burger1;ꢀ, Lothar Hennig1, Annett Fuchs2;ꢀ
,
Dieter Greif2, Jan Spengler3, and Fernando Albericio3
1
Department of Organic Chemistry, University of Leipzig, D-04103 Leipzig, Germany
2
€
Hochschule Zittau=Gorlitz, Fachbereich Mathematik und Naturwissenschaften,
D-02763 Zittau, Germany
3
ꢀ
Institut de Recerca Biomedica de Barcelona, Parc Cientific Barcelona,
08028 Barcelona, Spain
Received January 5, 2005; accepted March 10, 2005
Published online September 27, 2005 # Springer-Verlag 2005
Summary. A new approach to trifluoromethyl substituted butenolides and their thioanalogues is
described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction
sequence includes three steps – nucleophilic displacement reaction, Claisen, and finally Cope rear-
rangement – which can be run as domino reaction. A modification of the domino reaction (transester-
ification instead of Cope rearrangement) provides a concise access to ꢀ-trifluoromethyl-ꢁ-ketoacids.
Keywords. 2-Fluoro-3-trifluoromethylthiophenes; 2-Fluoro-3-trifluoromethylfurans; Trifluoromethyl
substituted butenolides; ꢀ-Trifluoromethyl-ꢁ-keto acids; Domino reactions.
Introduction
Butenolides [2(5H)-furanones] [1, 2] are of interest to medicinal and agricultural
chemists since decades due to their large abundance, their high structural diver-
sity, and their broad biological activities. Compounds containing a butenolide sub-
structure are considered i.a. as potential insecticides, bactericides, fungicides,
antibiotics, anticancer agents, allergy inhibitors, antipsoriasis agents, and phos-
pholipase A2-inhibitors [3]. Furthermore, certain 3,4-disubstituted 2(5H)-furanones
act as highly selective inhibitors of COX-1, involved in inflammation and
other pain-inducing biological processes, allowing pain therapy without much
ꢀ
Corresponding authors. E-mail: burger@organik.chemie.uni-leipzig.de, a.fuchs@hs-zigr.de
Dedicated to Prof. Dr. R. D. Chambers on the occasion of his 70th birthday
#

1764
K. Burger et al.
Formula 1
of the unwanted side-effects of typical non-steroidal anti-inflammatory drugs
(NSAIDs) [4].
Consequently, numerous routes to this interesting class of compounds have
been developed [5]. However, fluoromodified members are still rare, although
modulation of pharmacokinetic properties by fluorine [6] and=or fluoroalkyl sub-
stitution [7, 8] has become a well established strategy for lead structure optimiza-
tion and has resulted in a large number of fluorinated drugs in clinical use [9]. A
number of properties, such as metabolic stability, lipophilicity, absorption, and
transport rates [10] as well as permeability through certain body barriers like the
blood=brain barrier can be affected in a favorable way [11].
In this paper we report on a new approach to trifluoromethyl substituted bute-
nolides and their thioanalogues as well as to trifluoromethyl substituted ꢁ-ketoacids
via domino reactions [12, 13] starting from readily available 2-fluoro-3-trifluoro-
methylthiophenes 1a–1c and -furans 4a–4f [14] (Formula 1).
Results and Discussion
We have demonstrated that 5-fluoro-4-trifluoromethyl-1,3-azoles, 2-fluoro-3-tri-
fluoromethyl-furans, and 2-fluoro-3-trifluoromethylthiophenes are useful building
blocks in organofluorine chemistry [15, 16], because the fluorine atom adjacent to
the trifluoromethyl group can be replaced by various N-, O-, and S-nucleophiles,
and dinucleophiles under relatively mild conditions to give trifluoromethyl-substi-
tuted heterocyclic compounds of biological relevance [17] and materials [18] with
interesting properties.
When NaH is added at 0ꢁC to a solution of 2-fluoro-3-trifluoromethylthiophene
1a and allyl alcohol (2 equivalents) in THF a nucleophilic displacement of the
single fluorine readily takes place to give allyl ether 2 in excellent yield. The
substitution process can be monitored by 19F NMR spectroscopy (Scheme 1).
Scheme 1

Domino Reactions with Fluorinated Five-membered Heterocycles
1765
The trifluoromethyl group of the starting material which resonates as doublet at
ꢂ ¼ 19.3 ppm (J ¼ 11.7 Hz) disappears, while a singlet (ꢂ ¼ 19.7 ppm) emerges.
Although compounds 2 turned out to be unstable on prolonged standing at room
temperature they were fully characterized. The reason for the instability of allyl
ethers of type 2 is the presence of a 1,5-hexadiene subunit, which is susceptible to
undergo a Claisen rearrangement. Claisen and Cope rearrangements of fluorinated
systems often proceed at surprisingly low temperatures [19]. The correct location
of the trifluoromethyl group within the 1,5-hexadiene skeleton can result in a
significant rate enhancement [20]. The final product which was formed quanti-
tatively upon standing at room temperature after three weeks shows a singlet at
ꢂ ¼ 6.9 ppm, which indicates that the trifluoromethyl group is now placed at a sp3
hybridized carbon atom. Structure 3 readily explains the spectroscopic data.
When 2-fluoro-3-trifluoromethylfuran 4a [21] was treated with allyl alcohol in
the presence of NaH under identical reaction conditions, a nucleophilic substitution
product 5 could not be detected even on monitoring the reaction by 19F NMR
spectroscopy. As first product of the reaction sequence we identified the Claisen
product 6 (Scheme 2). Compounds 6 are stable at room temperature, but in the
presence of an alcoholate a rapid cleavage of the lactone moiety takes place.
Therefore, in the presence of an excess of allyl alcohol and NaH ꢀ-trifluoromethyl
substituted ꢁ-ketoacid allylester 7 are the main products of the reaction sequence.
On acidic hydrolysis compounds 7 are readily transformed into ꢀ-trifluoromethyl
substituted ꢁ-keto acids 8.
In contrast, thioethers 9 or 10 obtained in very good yields on reaction of 1b or
4b with allyl mercaptane in the presence of NaH are thermally stable up to 140ꢁC
(Scheme 3). Above 140ꢁC an uncontrolled decomposition starts to give a mixture
Scheme 2
Scheme 3

1766
K. Burger et al.
of unidentified products. No evidence for a thio-Claisen rearrangement was
found [22].
Although, both compounds 3 and 6 possess a 1,5-hexadiene subunit, products
of a consecutive [3,3]-sigmatropic rearrangement have not been detected under the
reaction conditions applied. To link both sigmatropic processes together in a dom-
ino reaction we decided to try to activate the final Cope rearrangement. We sug-
gested that modification of the substituent pattern of the allyl alcohol is the easiest
way to meet this goal.
First, we reacted secondary allyl alcohols (HOCHR1CH¼CH2) and 1b or 1c at
0ꢁC in the presence of NaH to give quantitatively the nucleophilic substitution
product 11 within 1 h. 19F NMR control of the nucleophilic substitution process
reveals that already at room temperature the Claisen rearrangement starts to com-
pete. A singlet at ꢂ ¼ 19.4 ppm recorded in the 19F NMR spectrum which is char-
acteristic for the substitution product 11 disappears and upfield a new signal
1
at ꢂ ¼ 7.0 ppm appears (Scheme 4). From the H NMR spectra of 12b and 12c a
3
coupling constant of JHH ¼ 15 Hz can be extracted, characteristic for a trans-CC
double bond, but no indication for a consecutive [3,3]-sigmatropic process was
detected.
Compounds 4b=4c and HOCHR1H¼CH2 reacted to give trifluoromethyl sub-
stituted ꢁ-keto esters 15 as stable products (Scheme 5). The logical precursors 13
Scheme 4
Scheme 5

Domino Reactions with Fluorinated Five-membered Heterocycles
1767
and 14 could not be isolated nor identified on monitoring the process by 19F NMR
spectroscopy. Furthermore, no evidence for a second [3,3]-sigmatropic process was
obtained.
Therefore, we decided to introduce a phenyl group into C-(3) position of
the allyl alcohol and found, that substitution reactions with cinnamic alcohol in
the presence of NaH proceeded readily at 0ꢁC and were complete within a few
hours. The first compound we were able to isolate was the Claisen product 17,
which underwent already at room temperature a Cope rearrangement to give 18
(Scheme 6) on prolonged standing.
Domino reactions involving orbital symmetry controlled processes are known
[12]. The combination of reaction types, such as Diels-Alder reactions [23], [3 þ 2]-
cycloaddition reactions [24], and Mannich reactions [25] represents a valuable syn-
thetic tool for the construction of complex molecules, often in a stereoselective
way [26]. Domino reactions including sequences like Claisen=Cope rearrangements
[27] and Claisen=aza-Claisen rearrangements [28] have been successfully applied
Scheme 6
Scheme 7

1768
K. Burger et al.
in organic synthesis. Remarkable for the above discussed reaction sequence
1c ! 16 ! 17 ! 18 is the low temperature necessary to start the domino process.
From the reaction of furan 4d and cinnamic alcohol we were able to isolate and
characterize the Claisen product 20 and the open-chain product 21 (Scheme 7).
The yield of 21 depends on the amount of cinnamic alcohol used. These findings
demonstrate that the cleavage of the lactone ring by the alcoholate is still faster
than the Cope rearrangement.
Finally, when we introduced two alkyl groups into 3-position of the allyl alco-
hol we succeeded in running the reaction consisting of nucleophilic substitution,
Claisen, and Cope rearrangement as a domino reaction.
The development of methodology for incorporation of lipidic anchors into
biologically relevant compounds is of current interest. Therefore, we tested the
applicability of the new domino reaction for the introduction of lipidic side-chains
using commercially available C-10 and C-15 building blocks like geraniol, nerol,
and farnesol.
When compound 1a was reacted with geraniol at room temperature due to the
standard protocol the product of the nucleophilic substitution 22 was obtained in
78% yield (Scheme 8). The product is stable at room temperature, but on heating
Scheme 8

Domino Reactions with Fluorinated Five-membered Heterocycles
1769
Scheme 9
up to ca. 65ꢁC a consecutive reaction starts. Via Claisen product 23 (19F NMR:
ꢂ ¼ 17.9 ppm) the Cope product 24 (19F NMR: ꢂ ¼ 13.9 ppm) was formed in 79%
yield. Analogously, in the case of nerol compounds 25 and 26 were obtained and
fully characterized.
The reaction of 4c and geraniol at 0ꢁC in the presence of NaH gave two main
products: compound 29 (Cope product) and product 30 formed by alcoholytic ring
opening of the Claisen product 28 (Scheme 9). Now, in the case of 3,3-dialkyl
substituted allyl alcohols, the Cope rearrangement (28 ! 29) successfully com-
petes with the lactone cleavage (28 ! 30). Analogously, with nerol compounds
31 and 32 were obtained.
Analogously farnesol reacts with 4e to give 3-trifluoromethyl-2(5H)-furanones
35 with a lipidic C-15 tail and a head decorated with a lipophilic trifluoromethyl
group (Scheme 10). Compounds of type 35 and their thioanalogues seem to be
suitable model compounds to add drugs with poor pharmacokinetic properties
across the Michael system to improve the transport rates [29–32], to dock
them to membranes, and finally to guide them into cells. The presence of the

1770
K. Burger et al.
Scheme 10
trifluoromethyl group allows to monitor the binding procedure, the docking
process, and the transport through the membrane by 19F NMR spectroscopy.
Miscellaneous
Structural diversity can be generated by incorporating the double bond of the allyl
alcohol into exo- and endocyclic positions of carbocyclic and heterocyclic systems
Scheme 11

Domino Reactions with Fluorinated Five-membered Heterocycles
1771
of different ring size as well as into aromatic and heteroaromatic species with
variable substituent pattern. In addition, in the case of heteroaromatic and hetero-
cyclic systems the skeleton can be modified considerably. Applying the new strat-
egy, i.a. libraries of ꢀ-trifluoromethyl substituted ꢁ-keto acids, C-glycosides, and
amino acids become readily available via domino reactions in acceptable yields.
A typical example is the reaction of 2-fluoro-4-(4-fluorophenyl)-3-trifluoro-
methylfuran 4f with (ꢂ)-trans-pinocarveol to give compound 37 in 31% yield
(Scheme 11).
C-Glycosides are a class of compounds of current interest [33–35]. Now trifluoro-
methyl substituted members are readily available applying the above strategy. On
addition of NaH to a solution of 5-(4-chlorophenyl)-2-fluoro-3-trifluoromethylfuran
4b and 1,2-didesoxy-4,6-O-isopropylidene-D-arabino-1-hexapyranose [36, 37] in
THF at 0ꢁC a smooth reaction occurs. The product of a nucleophilic displacement
immediately undergoes a Claisen rearrangement followed by an alcoholytic
Scheme 12
Scheme 13

1772
K. Burger et al.
cleavage of the lactone ring (Scheme 12). The formation of compounds 39 and
40 was unequivocally proved by 19F NMR spectroscopy. The structure of the
C-glycoside 40 which was obtained in 33% yield was identified by APT, H,H-
and C,H-COSY spectra and homo decoupling experiments (Scheme 13).
On further applications of the new strategy, especially on the synthetic potential
concerning ꢀ-trifluoromethylamino acids and their incorporation into peptides we
report in due course.
Experimental
Solvents were purified and dried prior to use. Reagents were used as purchased. Melting points
(uncorrected) were determined on a Boetius heating table. Mass spectra were recorded on a VG
12–250 and a MAT 212 (Masslab) electron ionization spectrometer (EI-MS, EI¼ 70eV). IR spectra
were obtained with a FTIR spectrometer (Genesis ATI Mattson=Unicam) and a Specord M 80 (Fa. Carl
1
Zeiss, Jena). H (200.04 MHz), 13C (50.30MHz), and 19F (188.20 MHz) NMR spectra were recorded
1
on a Varian Gemini 2000 spectrometer. TMS was used as reference for H and 13C NMR spectra
(internal), and TFA for 19F NMR spectra (external). Flash chromatography was performed using silica
gel (32–63 ꢃm). Elemental analyses were performed with a CHNO-S-Rapid apparatus (Fa. Heraeus);
their results were within experimental errors.
Reactions of 1 and 4 with Allyl Alcohols; General Procedure
To an ice cold solution of 1 or 4 (2mmol) [21, 38] and the corresponding allyl alcohol (4mmol) in
THF (5cm3), NaH (0.12 g, 5 mmol) was added. Then the reaction mixture was stirred at 0ꢁC or room
temperature (3, 9, 10, 18, 22, 25, 35, 36, 40) or at 65ꢁC (24, 26), respectively, until the starting material
was consumed (19F NMR analysis). The reaction mixture was treated with an ice=water mixture and
extracted with ether. After drying the organic phase with MgSO4, the solvent was evaporated in vacuo.
The remaining crude product was purified by column chromatography (eluent: DCM=petroleum ether).
2-Allyloxy-5-phenyl-3-(trifluoromethyl)thiophene (2, C14H11F3OS)
Yield 96%; oil; 1H NMR (CDCl3): ꢂ ¼ 4.65 (dd, 4J ¼ 1.0 Hz, 3J ¼ 6.0 Hz, 2H), 5.35 (m, 1H), 5.46 (m,
1H), 6.01 (m, 1H), 7.06 (s, 1H), 7.23 (m, 1H), 7.35 (m, 2H), 7.43 (m, 2H) ppm; 13C NMR (CDCl3):
2
3
1
ꢂ ¼ 76.2, 112.7 (q, J ¼ 34.0 Hz), 118.2 (q, J ¼ 3.0Hz), 119.7, 122.1 (q, J ¼ 270 Hz), 125.1, 127.6,
129.0, 130.3, 131.2, 133.4, 163.6 (q, 3J ¼ 3.0 Hz) ppm; 19F NMR (CDCl3): ꢂ ¼ 19.7 (s, CF3) ppm; IR
(film): ꢄꢁ¼ 3400, 1720, 1580, 1520, 1415 cmꢂ1; MS (EI): m=z ¼ 257 [Mꢂ C2H3]þ, 244 [Mꢂ C3H4]þ,
216 [244 ꢂ CO]þ, 196 [216ꢂ HF]þ, 77 [C6H5]þ.
3-Allyl-5-phenyl-3-trifluoromethyl-3H-thiophen-2-one (3, C14H11F3OS)
Yield 100%; oil; 1H NMR (CDCl3): ꢂ ¼ 2.77 (dd, 2J ¼ 14.0Hz, 3J ¼ 7.0 Hz, 1H), 2.87 (dd,
3
2J ¼ 14.0Hz, J ¼ 8.0 Hz, 1H), 5.16 (m, 1H), 5.55 (m, 1H), 5.67 (m, 1H), 6.10 (s, 1H), 7.35 (m,
4
2
3H), 7.48 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 36.7 (q, J ¼ 2.0 Hz), 69.4 (q, J ¼ 25.0Hz), 114.2,
121.0, 123.8 (q, 1J ¼ 284.0 Hz), 126.5, 128.9, 129.0, 130.1, 132.2, 143.0, 200.2 ppm; 19F NMR
(CDCl3): ꢂ ¼ 6.9 (s, CF3) ppm; IR (film): ꢄꢁ¼ 3420, 1720, 1450 cmꢂ1; MS (EI): m=z ¼ 284 [M]þ,
257 [Mꢂ C2H3]þ, 256 [Mꢂ CO]þ, 243 [Mꢂ C3H5]þ, 215 [243 ꢂ CO]þ, 195 [215ꢂ HF]þ, 121
[C6H5CO]þ, 77 [C6H5]þ.
3-Allyl-5-p-tolyl-3-trifluoromethyl-3H-furan-2-one (6, C15H13F3O2)
1
2
3
Yield 40%; mp 77ꢁC; H NMR (CDCl3): ꢂ ¼ 2.39 (s, 3H), 2.74 (dd, J ¼ 13.9Hz, J ¼ 6.2 Hz, 1H),
2
3
3
3
2.85 (dd, J ¼ 13.9Hz, J ¼ 7.5 Hz, 1H), 5.16 (d, Jcis ¼ 10.1Hz, 1H), 5.23 (d, Jtrans ¼ 17.0Hz, 1H),
5.60 (m, 1H), 5.68 (s, 1H), 7.24 (m, 2H), 7.53 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 21.5, 35.6, 58.7
2
1
(q, J ¼ 27.9Hz), 96.8, 121.4, 123.8 (q, J ¼ 282.2 Hz), 124.2, 125.4, 129.2, 129.6, 144.2, 155.9,

Domino Reactions with Fluorinated Five-membered Heterocycles
1773
171.4ppm; 19F NMR (CDCl3): ꢂ ¼ 5.9 (s, CF3) ppm; IR (KBr): ꢄꢁ¼ 1805, 1652, 1288–1259, 1185–
1165 cmꢂ1; MS (EI): m=z (%) ¼ 282 [M]þ, 241 [Mꢂ CH2CH¼CH2]þ (100), 221 [241ꢂ HF]þ, 193
[241 ꢂ CO, –HF]þ, 120 [CH3C6H4COH]þ, 91 [CH3–C6H4]þ.
2-(2-Oxo-2-p-tolylethyl)-2-(trifluoromethyl)pent-4-enoic acid allylester (7, C18H19F3O3)
Yield 33%; oil; 1H NMR (CDCl3): ꢂ ¼ 2.41 (s, 3H), 2.89 (dd, 2J ¼ 14.0 Hz, 3J ¼ 6.2 Hz, 1H), 3.00 (dd,
3
2
2
2J ¼ 14.0Hz, J ¼ 7.4 Hz, 1H), 3.42 (d, J ¼ 17.8 Hz, 1H), 3.72 (d, J ¼ 17.8 Hz, 1H), 4.70 (m, 2H),
3
3
3
4.98 (d, Jtrans ¼ 17.2Hz, 1H), 4.99 (d, Jcis ¼ 10.5Hz, 1H), 5.22 (d, Jcis ¼ 10.5 Hz, 1H), 5.31 (d,
3Jtrans ¼ 17.2 Hz, 1H), 5.65 (m, 1H), 5.87 (m, 1H), 7.25 (m, 2H), 7.81 (m, 2H) ppm; 13C NMR
2
1
(CDCl3): ꢂ ¼ 21.6, 34.3, 38.2, 53.5 (q, J ¼ 23.9Hz), 66.6, 118.5, 120.0, 126.1 (q, J ¼ 285.0Hz),
128.0, 129.4, 131.5, 132.3, 133.9, 144.5, 168.2, 194.7ppm; 19F NMR (CDCl3): ꢂ ¼ 7.2 (s, CF3) ppm;
IR (film): ꢄꢁ¼ 1746, 1688, 1298–1270, 1225–1188 cmꢂ1; MS (EI): m=z (%) ¼ 340 [M]þ, 255
[Mꢂ COOCH2CH¼CH2]þ, 134 [C9H10O]þ, 119 [CH3C6H4CO]þ (100), 91 [CH3C6H4]þ.
2-(2-Oxo-2-p-tolylethyl)-2-(trifluoromethyl)pent-4-enoic acid (8, C15H15F3O3)
Yield 57%; oil; 1H NMR (CDCl3): ꢂ ¼ 2.40 (s, 3H), 2.91 (dd, 2J ¼ 14.0 Hz, 3J ¼ 6.2 Hz, 1H), 3.03 (dd,
2J ¼ 14.0Hz, 3J ¼ 7.4Hz, 1H), 3.47 (d, 2J ¼ 19.0Hz, 1H), 3.75 (d, 2J ¼ 19.0 Hz, 1H), 4.98 (d,
3
3Jtrans ¼ 17.2 Hz, 1H), 5.03 (d, Jcis ¼ 10.7Hz, 1H), 5.79 (m, 1H), 7.45 (m, 2H), 7.81 (m, 2H), 7.92
(s, 1H) ppm; 13C NMR (CDCl3): ꢂ ¼ 21.4, 34.3, 38.4, 53.2 (q, 2J ¼ 23.9 Hz), 120.2, 126.1 (q,
1J ¼ 285.0 Hz), 128.0, 129.4, 131.5, 133.9, 144.5, 172.2, 194.7 ppm; 19F NMR (CDCl3): ꢂ ¼ 7.2 (s,
CF3) ppm; IR (film): ꢄꢁ¼ 3020, 1725, 1695, 1585, 1455, 1298–1270, 1225–1188 cmꢂ1; MS (EI): m=z
(%) ¼ 300 [M]þ, 258 [Mꢂ C3H6]þ, 257 [Mꢂ C3H7]þ, 231 [Mꢂ CF3]þ, 119 [CH3C6H4CO]þ (100),
91[CH3C6H4]þ.
2-Allylsulfanyl-5-(4-chlorophenyl)-3-(trifluoromethyl)thiophene (9, C14H10ClF3S2)
Yield 88%; oil; 1H NMR (CDCl3): ꢂ ¼ 3.53 (d, 3J ¼ 7.1 Hz, 2H), 5.06 (m, 1H), 5.15 (m, 1H), 5.86 (m,
1
1H), 7.36 (m, 3H), 7.46 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 41.6, 119.0, 121.8 (q, J ¼ 272.3Hz),
3
2
3
122.1 (q, J ¼ 3.3 Hz), 126.8, 129.3, 131.3, 132.6, 134.4 (q, J ¼ 33.4Hz), 134.5, 136.1 (q, J ¼
2.9 Hz), 145.2ppm; 19F NMR (CDCl3): ꢂ ¼ 20.0 (s, CF3) ppm; IR (film): ꢄꢁ¼ 1493, 1441, 1387,
1272–1226, 1167–1096 cmꢂ1; MS (EI): m=z (%) ¼ 336=334 [M]þ, 295=293 [Mꢂ CH2CH¼CH]þ
(100), 231=229 [295=293 ꢂ S2]þ, 40 [CH2CH¼CH]þ.
2-Allylsulfanyl-5-(4-chlorophenyl)-3-(trifluoromethyl)furan (10, C14H10ClF3OS)
Yield 70%; oil; 1H NMR (CDCl3): ꢂ ¼ 3.56 (d, 3J ¼ 7.1 Hz, 2H), 5.02 (m, 1H), 5.09 (m, 1H), 5.88 (m,
1H), 6.76 (s, 1H), 7.38 (m, 2H), 7.56 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 38.6, 104.8 (q,
3J ¼ 2.5 Hz), 118.5, 122.1 (q, 1J ¼ 267.8 Hz), 123.1 (q, 2J ¼ 37.0Hz), 125.3, 127.7, 129.2, 133.0,
3
134.6, 145.9 (q, J ¼ 4.3 Hz), 155.2ppm; 19F NMR (CDCl3): ꢂ ¼ 19.5 (s, CF3) ppm; IR (film): ꢄꢁ¼
1536, 1480, 1396, 1248, 1174, 1129cmꢂ1; MS (EI): m=z (%) ¼ 320=318 [M]þ, 280=278
[Mꢂ CH2CH¼CH]þ, 113=111 [ClC6H4]þ, 40 [CH2CH¼CH]þ (100).
3-(But-2-enyl)-5-(4-chlorophenyl)-3-trifluoromethyl-3H-thiophen-2-one
(12b, C15H12ClF3OS)
Yield 60%; mp 40ꢁC; 1H NMR (CDCl3): ꢂ ¼ 1.61 (dd, 3J ¼ 6.6 Hz, 4J ¼ 1.5 Hz, 3H), 2.67 (dd,
3
2
3
3
2J ¼ 13.7Hz, J ¼ 6.9 Hz, 1H), 2.80 (dd, J ¼ 13.7 Hz, J ¼ 7.9Hz, 1H), 5.30 (dt, Jtrans ¼ 15.1Hz,
3J ¼ 7.7, 6.8 Hz, 1H), 5.62 (dq, Jtrans ¼ 15.1Hz, J ¼ 6.4 Hz, 1H), 6.07 (s, 1H), 7.40 (s, 4H) ppm;
3
3
13C NMR (CDCl3): ꢂ ¼ 17.9, 35.7, 69.9 (q, J ¼ 25.2Hz), 115.2, 121.1, 123.8 (q, J ¼ 284.1 Hz),
127.7, 129.2, 130.8, 132.2, 136.0, 141.6, 199.9ppm; 19F NMR (CDCl3): ꢂ ¼ 7.0 (s, CF3) ppm; IR
(KBr): ꢄꢁ¼ 1723, 1489, 1263–1242, 1187–1173 cmꢂ1; MS (EI): m=z (%) ¼ 334=332 [M]þ, 306=304
[Mꢂ CO]þ, 280=278 [M ꢂ CHCH¼CHCH3]þ, 260=258 [280=278 ꢂ HF]þ; 54 [CHCH¼CHCH3]þ
(100).
2
1

1774
K. Burger et al.
5-(4-Bromophenyl)-3-pent-2-enyl-3-trifluoromethyl-3H-thiophen-2-one
(12c, C16H14BrF3OS)
Yield 64%; oil; 1H NMR (CDCl3): ꢂ ¼ 0.88 (t, 3J ¼ 7.4 Hz, 3H), 1.96 (m, 2H), 2.67 (ddd, 2J ¼ 14.0Hz,
3J ¼ 8.0 Hz, 4J ¼ 1.2 Hz, 1H), 2.80 (ddd, 2J ¼ 14.0Hz, 3J ¼ 8.0 Hz, 4J ¼ 0.8 Hz, 1H), 5.26 (dt,
3
3Jtrans ¼ 15.1 Hz, 1H), 5.65 (dt, Jtrans ¼ 15.1Hz, 1H), 6.08 (s, 1H), 7.35 (m, 2H), 7.56 (m, 2H) ppm;
13C NMR (CDCl3): ꢂ ¼ 13.6, 25.5, 35.7, 70.0 (q, 2J ¼ 24.9Hz), 115.3, 118.9, 123.8 (q, 1J ¼ 284.3Hz),
124.3, 127.9, 131.2, 132.2, 139.3, 141.7, 199.9ppm; 19F NMR (CDCl3): ꢂ ¼ 7.0 (s, CF3) ppm; IR (film):
ꢄꢁ¼ 1719, 1487, 1263–1244, 1187–1149cmꢂ1; MS (EI): m=z (%) ¼ 392=390 [M]þ, 363=361
[Mꢂ CH3CH2]þ, 323=321 [Mꢂ CH3CH2–CH¼CHCH2]þ, 303=301 [323=321 ꢂ HF]þ, 69
[CH3CH2CH¼CHCH2]þ (100).
2-[2-(4-Chlorophenyl)-2-oxoethyl]-2-(trifluoromethyl)hex-4-enoic acid
1-methylallyl ester (15b, C19H20ClF3O3)
Yield 46% (mixture of diastereomers); mp 29ꢁC; 1H NMR (CDCl3): ꢂ ¼ 1.26=1.35 (d, 3J ¼ 6.0 Hz, 3H),
1.48 (d, 3J ¼ 4.0 Hz, 3H), 2.80 (dd, 2J ¼ 18.0 Hz, 3J ¼ 4.0Hz, 1H), 2.97 (dd, 2J ¼ 18.0 Hz, 3J ¼ 6.0 Hz,
1H), 3.38 (d, 2J ¼ 18.0Hz, 1H), 3.63 (d, 2J ¼ 18.0Hz, 1H), 5.0–5.3 (m, 2H), 5.3–5.4 (m, 2H), 5.4–5.5
(m, 1H), 5.7–5.9 (m, 1H), 7.44 (d, 3J ¼ 8.6 Hz, 2H), 7.85 (d, 3J ¼ 8.0Hz, 2H) ppm; 13C NMR (CDCl3):
ꢂ ¼ 17.7, 19.3=19.4, 33.1, 38.0, 53.7 (q, 2J ¼ 23.7 Hz), 72.8=72.9, 115.9=116.1, 124.7, 126.1 (q,
1J ¼ 285.1 Hz), 128.9, 129.2, 130.9, 134.9, 136.8=136.9, 139.8, 167.5, 194.1ppm; 19F NMR (CDCl3):
ꢂ ¼ 7.1 (s, CF3) ppm; IR (KBr): ꢄꢁ¼ 1742, 1692, 1590, 1404, 1285–1264, 1213–1192 cmꢂ1; MS (EI):
m=z (%) ¼ 390=388 [M]þ, 335=333 [M ꢂ CH2CH¼CHCH3]þ, 319=317 [Mꢂ OCH2CH¼CHCH3]þ,
291=289 [335=333 ꢂ CO2]þ, 271=268 [291=289 ꢂ HF]þ, 155=153 [ClC6H4COCH2]þ, 141=139
[ClC6H4CO]þ, 54 [C4H6]þ (100).
2-[2-(4-Bromophenyl)-2-oxoethyl]-2-(trifluoromethyl)hept-4-enoic acid
1-ethylallyl ester (15c, C21H24BrF3O3)
Yield 55% (mixture of diastereomers); oil; 1H NMR (CDCl3): ꢂ ¼ 0.65 (t, 3J ¼ 7.6 Hz, 3H), 0.78=0.90
(t, 3J ¼ 7.2 Hz, 3J ¼ 7.2 Hz, 2ꢃ3H), 1.56=1.66 (q, 3J ¼ 7.2 Hz, 3J ¼ 7.2 Hz, 2ꢃ2H), 1.77 (m, 2H), 2.76
2
3
2
3
2
(dd, J ¼ 16.1Hz, J ¼ 4.9 Hz, 1H), 2.91 (dd, J ¼ 16.1Hz, J ¼ 6.4 Hz, 1H), 3.34 (dd, J ¼ 17.7Hz,
2
J ¼ 3.3 Hz, 1H), 3.58 (d, J ¼ 17.7Hz, 1H), 5.13 (m, 1H), 5.19–5.28 (m, 2H), 5.32–5.37 (m, 2H),
5.64=5.72 (m, 2ꢃ1H), 7.70 (m, 2H), 7.53 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 9.56=9.61, 13.9, 25.9,
27.4=27.5, 33.3, 38.4, 54.3 (q, 2J ¼ 23.6Hz), 78.4=78.6, 117.6=117.7, 123.0, 126.6 (q, 1J ¼ 285.2Hz),
129.1, 129.8, 132.4, 135.7, 135.84=135.88, 138.6, 168.1, 194.7 ppm; 19F NMR (CDCl3): ꢂ ¼ 7.2 (s,
CF3) ppm; IR (film): ꢄꢁ¼ 1742, 1693, 1585, 1281–1265, 1210–1191 cmꢂ1; MS (EI): m=z (%) ¼ 460
[Mꢂ H]þ, 393 [Mꢂ C5H7]þ, 376 [Mꢂ C5H8O]þ, 348 [Mꢂ CH2¼CH–CH(CH2CH3)COO]þ, 307
[348 ꢂ CH3CH2CH]þ, 287 [307ꢂ HF]þ, 200=198 [C8H7OBr]þ (100), 185=183 [BrC6H4CO]þ.
5-(4-Bromophenyl)-3-(1-phenylallyl)-3-trifluoromethyl-
3H-thiophen-2-one (17, C20H14BrF3OS)
Yield 51%; mp 85ꢁC; 1H NMR (CDCl3): ꢂ ¼ 4.17 (d, 3J ¼ 9.7 Hz, 1H), 5.19 (d, 3Jcis ¼ 9.7 Hz, 1H), 5.25
(d, 3Jtrans ¼ 16.2Hz, 1H), 6.11 (m, 1H), 6.22 (s, 1H), 7.25–7.53 (m, 7H), 7.57 (m, 2H) ppm; 13C NMR
(CDCl3): ꢂ ¼ 53.8, 73.9 (q, 2J ¼ 23.6Hz), 113.5, 120.4, 123.4 (q, 1J ¼ 286.0 Hz), 124.5, 127.9, 128.0,
128.7, 128.8, 131.1, 132.3, 132.9, 137.6, 143.1, 199.9ppm; 19F NMR (CDCl3): ꢂ ¼ 11.1 (s, CF3) ppm; IR
(KBr): ꢄꢁ¼ 1710, 1242, 1171 cmꢂ1; MS (EI): m=z (%) ¼ 323=321 [Mꢂ C6H5CH¼CHCH2]þ, 214=212
[Mꢂ C6H5C(CF3)COCH¼CH2]þ, 226 [C6H5C(CF3)COCH¼CH2]þ, 117 [C6H5CH¼CHCH2]þ (100).
5-(4-Bromophenyl)-5-(3-phenylallyl)-3-trifluoromethyl-5H-thiophen-2-one
(18, C20H14BrF3OS)
1
3
3
Yield 29%; oil; H NMR (CDCl3): ꢂ ¼ 3.25 (m, 2H), 6.02 (dt, J ¼ 16.3 Hz, J ¼ 6.5 Hz, 1H), 6.55
3
3
(d, J ¼ 16.3 Hz, 1H), 7.32 (m, 7H), 7.56 (m, 2H), 8.02 (q, J ¼ 1.1 Hz) ppm; 13C NMR (CDCl3):

Domino Reactions with Fluorinated Five-membered Heterocycles
1775
1
ꢂ ¼ 43.7, 65.1, 120.0 (q, J ¼ 273.6Hz), 121.7, 122.9, 126.5, 128.2, 128.4, 128.7, 132.5, 133.0 (q,
3
2J ¼ 33.2Hz), 136.2, 136.4, 137.1, 161.7 (q, J ¼ 3.7 Hz), 190.6 ppm; 19F NMR (CDCl3): ꢂ ¼ 13.8
(s, CF3) ppm; IR (film): ꢄꢁ¼ 1696, 1340, 1169–1147 cmꢂ1; MS (EI): m=z (%) ¼ 440=438 [M]þ,
323=321 [M ꢂ C6H5CH¼CHCH2]þ, 117 [C6H5CH¼CHCH2]þ (100).
5-(2-Fluorophenyl)-3-(1-phenylallyl)-3-trifluoromethyl-3H-furan-2-one (20, C20H14F4O2)
1
3
3
Yield 10%; mp 67ꢁC; H NMR (CDCl3): ꢂ ¼ 4.20 (d, J ¼ 9.3 Hz, 1H), 5.21 (d, Jcis ¼ 10.3Hz, 1H),
3
5
5.32 (d, Jtrans ¼ 16.8Hz, 1H), 6.08 (m, 1H), 6.17 (d, J ¼ 2.5 Hz, 1H), 7.20–7.50 (m, 8H), 7.69 (m,
1H) ppm; 13C NMR (CDCl3): ꢂ ¼ 52.5, 63.8 (q, J ¼ 26.3Hz), 102.2 (d, J ¼ 16.9Hz), 115.3 (d,
2
4
2J ¼ 11.2Hz), 116.2 (d, J ¼ 21.8Hz), 120.6, 123.3 (q, J ¼ 283.8Hz), 124.6 (d, J ¼ 3.5Hz), 126.4,
127.9, 128.5, 128.9, 132.0 (d, 3J ¼ 9.1Hz), 133.4, 137.2, 150.6 (d, 3J ¼ 3.6Hz), 160.8 (d, 1J ¼
255.5Hz), 170.5ppm; 19F NMR (CDCl3): ꢂ ¼ ꢂ32.9 (m, 1F, arom. F), 10.1 (s, 3F, CF3) ppm; IR
(KBr): ꢄꢁ¼ 1814, 1646, 1494, 1280–1255, 1248, 1172–1147cmꢂ1; MS (EI): m=z ¼ 362 [M]þ, 334
[Mꢂ CO]þ, 245 [Mꢂ C6H5CH¼CHCH2], 117 [C6H5CH¼CHCH2].
2
1
3
2-[2-(2-Fluorophenyl)-2-oxoethyl]-3-phenyl-2-(trifluoromethyl)pent-4-enoic acid
3-phenylallylic ester (21, C29H24F4O3)
Yield 51%; oil; 1H NMR (CDCl3): ꢂ ¼ 3.72 (d, 2J ¼ 18.3 Hz, 1H), 3.81 (d, 2J ¼ 18.3 Hz, 1H), 4.34 (d,
2
3J ¼ 10.0Hz, 1H), 4.95 (dd, J ¼ 6.5 Hz,3J ¼ 1.1 Hz, 2H), 5.29 (m, 2H), 6.34 (m, 1H), 6.53 (m, 1H),
6.72 (d, 3J ¼ 15.9Hz, 1H), 7.19 (m, 2H), 7.32–7.50 (m, 11H), 7.83 (m, 1H) ppm; 13C NMR (CDCl3):
2
2
3
ꢂ ¼ 45.3, 53.9, 58.4 (q, J ¼ 22.6Hz), 66.4, 116.7 (d, J ¼ 23.9Hz), 119.1, 122.5, 124.7 (d, J ¼
2
1
3.2 Hz), 125.4 (d, J ¼ 13.2Hz), 125.9 (q, J ¼ 284.9 Hz), 126.8, 127.7, 128.2, 128.4, 128.7, 130.0,
3
1
130.8, 134.7, 135.0 (d, J ¼ 9.1Hz), 136.3, 138.4, 161.8 (d, J ¼ 252.9 Hz), 167.9, 192.8 ppm; 19F
NMR (CDCl3): ꢂ ¼ ꢂ30.7 (m, 1F, arom. F), 14.2 (s, 3F, CF3) ppm; IR (film): ꢄꢁ¼ 1745–1698, 1608,
1481, 1451, 1272, 1204–1179 cmꢂ1; MS (EI): m=z ¼ 379 [Mꢂ (CH2CH¼CHC6H5)]þ, 315
[Mꢂ COOCH2CH¼CHC6H5, –HF]þ, 247 [Mꢂ C6H5CH¼CHCH2, –OCH2CH¼CHC6H5 þ H]þ,
117 [C6H5CH¼CHCH2]þ.
2-(3,7-Dimethylocta-2,6-dienyloxy)-5-phenyl-3-(trifluoromethyl)thiophene (22, C21H23F3OS)
1
Yield 78%; oil; H NMR (CDCl3): ꢂ ¼ 1.64 (s, 3H), 1.71 (s, 3H), 1.79 (s, 3H), 2.17 (s, 4H), 4.74 (d,
3J ¼ 6.8 Hz, 2H), 5.12 (m, 1H), 5.55 (t, 3J ¼ 6.6 Hz, 1H), 7.11 (s, 1H), 7.29 (m, 1H), 7.38 (m, 2H), 7.50
(m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 16.8, 17.7, 25.6, 26.2, 39.6, 72.6, 112.6 (q, 2J ¼ 34.5Hz), 117.8,
118.3 (q, 3J ¼ 3.0 Hz), 122.3 (q, 1J ¼ 269.9 Hz), 123.6, 125.1, 127.0, 129.0, 130.1, 132.0, 133.6, 144.4,
164.0ppm; 19F NMR (CDCl3): ꢂ ¼ 19.8 (s, CF3) ppm; IR (film): ꢄꢁ¼ 2966–2857, 1708, 1338, 1258,
1152 cmꢂ1; MS (EI): m=z (%) ¼ 243 [Mꢂ (CH3)2C¼C(CH2)2C(CH3)¼CHCH2]þ, 137 [(CH3)2C¼
CH(CH2)2C(CH3)¼CHCH2]þ, 82 [C6H10]þ, 69 [(CH3)2C¼CHCH2]þ (100).
5-(2,7-Dimethylocta-2,6-dienyl)-5-phenyl-3-trifluoromethyl-5H-thiophen-2-one
(24, C21H23F3OS)
Yield 79%; oil; 1H NMR (CDCl3): ꢂ ¼ 1.61 (s, 3H), 1.63 (s, 3H), 1.71 (s, 3H), 2.04 (m, 4H), 3.10 (dd,
3
4
2J ¼ 7.3 Hz, J ¼ 2.1 Hz, 2H), 5.06 (m, 2H), 7.35–7.42 (m, 5H), 8.02 (q, J ¼ 1.3Hz, 1H) ppm; 13C
1
NMR (CDCl3): ꢂ ¼ 16.5, 17.6, 25.6, 26.4, 38.9, 39.7, 66.1, 117.0, 120.2 (q, J ¼ 273.1Hz), 123.8,
126.6, 128.6, 129.2, 131.8, 132.6 (q, 2J ¼ 33.2Hz), 138.3, 141.4, 162.5 (q, 3J ¼ 2.9 Hz), 191.3ppm; 19
F
NMR (CDCl3): ꢂ ¼ 13.9 (s, CF3) ppm; IR (film): ꢄꢁ¼ 2969–2856, 1707, 1446, 1339, 1285, 1149cmꢂ1
;
MS (EI): m=z (%) ¼ 380 [M]þ, 243 [Mꢂ (CH3)2C¼CH(CH2)2C(CH3)¼CHCH2]þ, 137 [(CH3)2C¼
CH–(CH2)2C(CH3)¼CHCH2]þ, 82 [C6H10]þ, 69 [(CH3)2C¼CHCH3]þ (100).
2-(3,7-Dimethylocta-2,6-dienyloxy)-5-phenyl-3-(trifluoromethyl)thiophene (25, C21H23F3OS)
1
Yield 6%; oil; H NMR (CDCl3): ꢂ ¼ 1.67 (s, 3H), 1.75 (s, 3H), 1.86 (s, 3H), 2.20 (s, 4H), 4.72
(d, 3J ¼ 6.9 Hz, 2H), 5.17 (m, 1H), 5.58 (t, 3J ¼ 7.4 Hz, 1H), 7.13 (s, 1H), 7.31 (m, 1H), 7.40 (m, 2H),
7.52 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 17.7, 23.6, 25.7, 26.6, 32.5, 72.4, 112.5 (q, 2J ¼ 34.8Hz),

1776
K. Burger et al.
118.3 (q, 3J ¼ 2.7 Hz), 118.7, 122.3 (q, 1J ¼ 269.5 Hz), 123.5, 125.1, 127.5, 129.0, 130.0, 132.5, 133.6,
144.4, 164.0 ppm; 19F NMR (CDCl3): ꢂ ¼ 19.8 (s, CF3) ppm; IR (film): ꢄꢁ¼ 2965–2857, 1708, 1515,
1410, 1286–1261, 1156–1124cmꢂ1; MS (FAB): m=z (%) ¼ 380 [M]þ, 243 [M ꢂ (CH3)2C¼CH
(CH2)2C(CH3)¼CHCH2]þ, 137 [(CH3)2C¼CH(CH2)2C(CH3)¼CHCH2]þ (100).
5-(3,7-Dimethylocta-2,6-dienyl)-5-phenyl-3-trifluoromethyl-5H-thiophen-2-one
(26, C21H23F3OS)
Yield 61%; oil; 1H NMR (CDCl3): ꢂ ¼ 1.61 (s, 3H), 1.69 (s, 6H), 2.03 (m, 4H), 3.06 (dd, 2J ¼ 7.3 Hz,
3J ¼ 2.6 Hz, 2H), 5.06 (m, 2H), 7.36–7.42 (m, 5H), 7.95 (q, 4J ¼ 1.9 Hz, 1H) ppm; 13C NMR (CDCl3):
ꢂ ¼ 17.7, 23.4, 25.7, 26.2, 32.3, 38.4, 65.7, 117.5, 120.1 (q, 1J ¼ 273.1 Hz), 123.7, 126.6, 128.6, 129.2,
2
3
132.2, 132.3 (q, J ¼ 33.2Hz), 138.3, 141.4, 162.4 (q, J ¼ 3.7 Hz), 191.3ppm; 19F NMR (CDCl3):
ꢂ ¼ 13.9 (s, CF3) ppm; IR (film): ꢄꢁ¼ 2967–2858, 1706, 1339, 1150cmꢂ1; MS (EI): m=z (%) ¼ 380
[M]þ; 243 [Mꢂ (CH3)2C¼CH(CH2)2C(CH3)¼CHCH]þ, 137 [(CH3)2C¼CH(CH2)2–C(CH3)¼
CHCH2]þ, 82 [C6H10]þ, 69 [(CH3)2C¼CHCH2]þ (100).
5-(4-Bromophenyl)-5-(3,7-dimethylocta-2,6-dienyl)-3-trifluoromethyl-5H-furan-2-one
(29, C21H22BrF3O2)
Yield 33%; oil; 1H NMR (CDCl3): ꢂ ¼ 1.54 (s, 3H), 1.56 (s, 3H), 1.67 (s, 3H), 1.98 (s, 4H), 2.74 (dd,
2J ¼ 15.0Hz, 3J ¼ 7.4 Hz, 1H), 2.85 (dd, 2J ¼ 14.7Hz, 3J ¼ 7.7 Hz, 1H), 4.94 (t, 3J ¼ 8.0 Hz, 1H), 5.00
(m, 1H), 7.26 (m, 2H), 7.52 (m, 2H), 7.94 (q, 3J ¼ 1.6 Hz, 1H) ppm; 13C NMR (CDCl3): ꢂ ¼ 16.4, 17.6,
1
2
25.7, 26.5, 38.5, 39.7, 89.5, 114.5, 119.5 (q, J ¼ 270.6Hz, CF3), 123.1, 123.7, 124.7 (q, J ¼ 37.1),
3
126.9, 132.2, 132.0, 136.1, 142.8, 158.4 (q, J ¼ 3.5 Hz), 164.7ppm; 19F NMR (CDCl3): ꢂ ¼ 13.3 (s,
CF3) ppm; IR (film): ꢄꢁ¼ 2968–2855, 1774, 1359, 1152 cmꢂ1; MS (EI): m=z (%) ¼ 444=442 [M]þ,
362=360 [M ꢂ C6H10]þ, 321=319 [Mꢂ (CH3)2C¼CH–(CH2)2C(CH3)¼CH2]þ, 307=305 [Mꢂ
(CH3)2C¼CH(CH2)2C(CH3)¼CHCH2]þ, 137 [(CH3)2C¼CH(CH2)2C(CH3)¼CHCH2]þ, 82 [C6H10]þ,
69 [(CH3)2C¼CHCH3]þ (100).
2-[2-(4-Bromophenyl)-2-oxoethyl]-3,7-dimethyl-2-trifluoromethyl-3-vinyloct-6-enoic acid
3,7-dimethylocta-2,6-dienyl ester (30, C31H40BrF3O3)
Yield 23%; oil; 1H NMR (CDCl3): ꢂ ¼ 1.26 (m, 4H), 1.54 (s, 3H), 1.58 (s, 3H), 1.65 (s, 6H), 1.70 (s,
2
2
2
6H), 2.07 (m, 4H), 3.45 (d, J ¼ 16.6Hz, 1H), 3.57 (d, J ¼ 16.6Hz, 1H), 4.70 (dd, J ¼ 12.0Hz,
3J ¼ 6.0 Hz, 1H), 4.81 (dd, 2J ¼ 12.0 Hz, 3J ¼ 6.0 Hz, 1H), 5.02 (m, 1H), 5.07 (m, 1H), 5.11 (d,
3Jtrans ¼ 17.9 Hz, 1H), 5.26 (d, 3Jcis ¼ 10.5Hz, 1H), 5.40 (dd, 3J ¼ 7.0 Hz, 1H), 6.01 (dd, 3J ¼ 10.5Hz,
3J ¼ 16.9Hz, 1H), 7.56 (m, 2H), 7.72 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 16.4, 17.6–17.7 (4ꢃCH3),
23.1, 25.6, 26.3, 36.1, 39.1, 39.5, 45.9, 59.8 (q, 2J ¼ 21.9 Hz), 62.3, 116.1, 117.7, 123.7, 124.0, 126.3
1
(q, J ¼ 287.2 Hz), 128.3, 129.5, 131.7, 131.9, 135.8, 143.1, 167.7, 194.2 ppm; 19F NMR (CDCl3):
ꢂ ¼ 18.5 (s, CF3) ppm; IR (film): ꢄꢁ¼ 2968–2927, 1738, 1696, 1584, 1210–1174 cmꢂ1; MS (FAB):
m=z (%) ¼ 463=461 [Mꢂ C10H15]þ; 445=443 [Mꢂ C10H17O]þ, 306 [463=461 ꢂ C6H4Br]þ, 185=183
[BrC6H4CO]þ, 153 [OCH2CH¼C(CH3)CH2CH2CH¼C(CH3)2]þ (100).
5-(4-Bromophenyl)-5-(3,7-dimethylocta-2,6-dienyl)-3-trifluoromethyl-5H-furan-2-one
(31, C21H22BrF3O2)
Yield 53%; oil; 1H NMR (CDCl3): ꢂ ¼ 1.57 (s, 3H), 1.67 (s, 6H), 1.97 (s, 4H), 2.77 (dd, 2J ¼ 15.0Hz,
3J ¼ 7.5 Hz, 1H), 2.83 (dd, 2J ¼ 15.0 Hz, 3J ¼ 7.5 Hz, 1H), 4.93 (t, 3J ¼ 8.0Hz, 1H), 5.03 (m, 1H), 7.27
(m, 2H), 7.51 (m, 2H), 8.03 (q, 3J ¼ 1.6 Hz, 1H) ppm; 13C NMR (CDCl3): ꢂ ¼ 17.6, 23.3, 25.6, 26.2,
1
2
31.9, 38.0, 89.5, 115.1, 119.6 (q, J ¼ 270.2 Hz), 123.0, 123.6, 124.3 (q, J ¼ 38.2 Hz), 126.9, 132.0,
132.2, 136.1, 142.3, 159.2 (q, 3J ¼ 3.5 Hz), 165.0ppm; 19F NMR (CDCl3): ꢂ ¼ 13.3 (s, CF3) ppm; IR
(film): ꢄꢁ¼ 2968–2858, 1777, 1359, 1152cmꢂ1; MS (EI): m=z (%) ¼ 444=442 [M]þ, 362=360
[Mꢂ C6H10]þ, 321=319 [Mꢂ (CH3)2C¼CH(CH2)2–C(CH3)¼CH2]þ, 307=305 [Mꢂ C10H17]þ, 137
[(CH3)2C¼CH–(CH2)2C(CH3)¼CHCH2]þ, 82 [C6H10]þ, 69 [(CH3)2C¼CHCH2]þ (100).

Domino Reactions with Fluorinated Five-membered Heterocycles
1777
2-[2-(4-Bromophenyl)-2-oxoethyl]-3,7-dimethyl-2-trifluoromethyl-3-vinyloct-6-enoic acid
3,7-dimethylocta-2,6-dienyl ester (32, C31H40BrF3O3)
Yield 14%; mp 41ꢁC; 1H NMR (CDCl3): ꢂ ¼ 1.26 (m, 4H), 1.56 (s, 3H), 1.58 (s, 3H), 1.65 (s, 6H), 1.74
2
2
(s, 6H), 2.09 (m, 4H), 3.40 (d, J ¼ 16.0Hz, 1H), 3.60 (d, J ¼ 16.0Hz, 1H), 4.75 (m, 2H), 5.07 (m,
2H), 5.11 (d, 3Jtrans ¼ 17.4Hz, 1H), 5.26 (d, 3Jcis ¼ 10.5Hz, 1H), 5.40 (dd, 3J ¼ 7.0 Hz, 1H), 5.81 (dd,
3J ¼ 10.5Hz,3J ¼ 17.4Hz, 1H), 7.56 (m, 2H), 7.72 (m, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 17.6, 17.7,
18.4, 23.4 (2ꢃCH3), 23.4, 25.7, 26.6, 32.1, 35.8, 38.1, 45.9, 60.5 (q, 2J ¼ 22.4Hz), 62.2, 116.3, 118.6,
1
123.6, 124.1, 126.2 (q, J ¼ 287.2 Hz), 128.3, 129.6, 131.7, 131.9, 135.9, 142.9, 167.6, 194.5 ppm;
19F NMR (CDCl3): ꢂ ¼ 19.3 (s, CF3) ppm; IR (KBr): ꢄꢁ¼ 2967–2925, 1734, 1687, 1584, 1212–
1172 cmꢂ1; MS (FAB): m=z (%) ¼ 463=461 [Mꢂ C10H15]þ, 445=443 [Mꢂ C10H17O]þ, 306
[463=461 ꢂ C6H4Br]þ, 185=183 [BrC6H4–CO]þ, 153 [OCH2CH¼C(CH3)CH2CH2CH¼C(CH3)2]þ
(100).
5-(4-Methoxyphenyl)-5-(3,7,11-trimethylduodeca-2,6,10-trienyl)-3-trifluoromethyl-
5H-furan-2-one (35, C27H33F3O3)
1
Yield 47%; oil; H NMR (CDCl3: ꢂ ¼ 1.55 (s, 3H), 1.60 (s, 3H), 1.68 (s, 3H), 1.81 (s, 3H), 2.03 (m,
8H), 2.94 (m, 2H), 3.84 (s, 3H), 4.72 (m, 2H), 5.42 (m, 1H), 6.50 (m, 2H), 7.71 (m, 2H) ppm; 13C
NMR (CDCl3): ꢂ ¼ 15.9, 16.3, 17.7, 25.8, 26.4, 26.8, 31.9, 39.8, 40.1, 55.6, 90.3 (m), 104.7, 111.6,
116.2, 119.9 (q, J ¼ 284.2Hz), 123.9, 124.4, 124.5 (m), 127.5, 132.6, 135.4, 141.8, 156.2, 159.7,
19
161.4 ppm; F NMR (CDCl3): ꢂ ¼ 13.9 (s, CF3) ppm; MS (EI) m=z ¼ 462 [M]þ.
2-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)-4-(4-fluorophenyl)-4-oxo-2-
trifluoromethylbutyric acid 6,6-dimethyl-2-methylenebicyclo[3.1.1]hept-3-yl ester
(37, C31H36F4O3)
1
2
Yield 31%; oil; H NMR (CDCl3): ꢂ ¼ 0.68 (s, 3H), 0.79 (s, 3H), 1.09 (d, J ¼ 8.5 Hz, 1H), 1.15 (s,
2
3H), 1.25 (s, 3H), 1.33 (d, J ¼ 10.2 Hz, 1H), 1.8–2.4 (m, 9H), 2.5 (m, 1H), 2.91 (s, 2H), 3.42 (d,
2J ¼ 18.0Hz, 1H), 3.66 (d, J ¼ 18.0Hz, 1H), 4.92 (s, 1H), 5.09 (s, 1H), 5.33 (m, 1H), 5.60 (m, 1H),
2
7.15 (m, 2H), 7.95 (dd, J ¼ 9.8 Hz, J ¼ 8.8 Hz, 2H) ppm; 13C NMR (CDCl3): ꢂ ¼ 21.5, 22.5, 26.2,
26.6, 28.2, 32.07, 32.1, 32.8, 36.9, 38.2, 38.7, 39.9, 40.6, 40.9, 47.4, 51.1, 54.6 (q, 2J ¼ 23.1Hz), 71.2,
115.3, 116.3 (d, 2J ¼ 22.1Hz), 124.8, 126.4 (q, 1J ¼ 285.4 Hz), 130.9 (d, 3J ¼ 9.5 Hz), 133.6 (d,
4J ¼ 3.0 Hz), 142.4, 149.6, 166.4 (d, 1J ¼ 255.4 Hz), 168.6, 194.5ppm; 19F NMR (CDCl3): ꢂ ¼
ꢂ26.8 (m, 1F), 8.7 (s, CF3); IR (film): ꢄꢁ¼ 2930, 1737, 1692, 1598, 1409, 1226–1161 cmꢂ1; MS
(EI): m=z (%) ¼ 532 [M]þ, 380 [M ꢂ C10H15O]þ, 41 [C3H5]þ (100).
3
3
4-(4-Chlorophenyl)-2-(2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxin-6-yl)-
4-oxo-2-(trifluoromethyl)butyric acid 2,2-dimethyl-4,4a,8,8a-
tetrahydropyrano[3,2-d][1,3]-dioxin-8-yl ester (40, C29H32ClF3O9)
1
Yield 33%; mp 160ꢁC; H NMR (CDCl3): ꢂ ¼ 1.36 (s, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.46 (s, 3H),
3.3–4.1 (m, 10H), 4.81 (dd, 3J ¼ 6.0 Hz, 3J ¼ 2.0 Hz, 1H), 4.97 (m, 1H), 5.58 (dd, 3J ¼ 7.7 Hz,
3J ¼ 1.8 Hz, 1H), 5.79 (dt, 2J ¼ 10.6Hz, J ¼ 2.0 Hz, 1H), 5.86 (d, 2J ¼ 10.6Hz, 1H), 6.36 (dd,
4
3
3
3J ¼ 6.1 Hz, J ¼ 1.5Hz, 1H), 7.46 (d, J ¼ 9.6 Hz, 2H), 7.85 (d, J ¼ 8.8 Hz, 2H) ppm; 13C NMR
(CDCl3): ꢂ ¼ 18.9, 19.0, 28.8, 29.1, 36.1, 58.5 (q, 2J ¼ 24.2Hz), 61.6, 62.8, 66.7, 69.7, 70.8, 72.2, 75.9,
99.8, 99.9, 124.8 (q, 1J ¼ 285.8 Hz), 126.3, 129.0, 129.4, 130.4, 135.1, 139.8, 145.8, 166.0, 193.1 ppm;
19F NMR (CDCl3): ꢂ ¼ 12.6 (s, CF3) ppm; IR (KBr): ꢄꢁ¼ 1750, 1698, 1640, 1590, 1375, 1230–1199,
1108 cmꢂ1; MS (FAB): m=z (%) ¼ 639 [Mþ Na]þ, 617 [Mþ H]þ, 559 [Mꢂ C3H5O]þ, 447
[Mꢂ C9H13O3]þ, 169 [C9H13O3]þ (100).
Acknowledgement
We are grateful to Deutsche Forschungsgemeinschaft for financial support.

1778
K. Burger et al.
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