Low temperature domino reactions. A ready access to trifluoromethyl substituted butenolides and their thioanalogues

Article abstract of DOI:10.1016/S0040-4039(01)00013-2

Domino reactions are described, including nucleophilic substitution, Claisen rearrangement and Cope rearrangement, which provide ready access to trifluoromethyl substituted butenolides and their thioanalogues, starting from 2-fluoro-3-trifluoromethyl furans and thiophenes, respectively.

Full text of DOI:10.1016/S0040-4039(01)00013-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1657–1659
Low temperature domino reactions. A ready access to
trifluoromethyl substituted butenolides and their thioanalogues†
Klaus Burger,* Annett Fuchs, Lothar Hennig and Brigitte Helmreich
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Received 22 November 2000; revised 23 December 2000; accepted 28 December 2000
Abstract—Domino reactions are described, including nucleophilic substitution, Claisen rearrangement and Cope rearrangement,
which provide ready access to trifluoromethyl substituted butenolides and their thioanalogues, starting from 2-fluoro-3-tri-
fluoromethyl furans and thiophenes, respectively. © 2001 Elsevier Science Ltd. All rights reserved.
Due to their large abundance and their biological activ-
ities butenolides have been studied extensively.1,2
When compounds 1 are treated at 0°C with allyl
alcohol in the presence of a base, e.g. NaH, allyl
ethers 2 are formed in excellent yields, which slowly
undergo a Claisen rearrangement at room tempera-
ture to give 3-allyl-3-trifluoromethyl-2(3H)thiophen-
ones 3.
The development of synthetic methodology for the
regioselective introduction of short-chain perfluoroalkyl
groups into organic molecules is of current interest.3
Fluoromodification often confers unique properties on
a molecule, e.g. in terms of increased metabolic stability
and lipophilicity, which in turn optimises in vivo
absorption and transport rates. As a consequence, the
pharmacokinetic profiles are often improved.4
Under identical reaction conditions, partially fluori-
nated furans 4 and allyl alcohol react to give the
Claisen product 6. The intermediate 5 could not be
observed even on monitoring the progress of the reac-
tion by 19F NMR spectroscopy. Compounds 6 are
stable at room temperature, but in the presence of
allyl alcoholate a rapid cleavage of the lactone ring
occurs (6“7). In the presence of an excess of alcoho-
late, 7 is the main product of the reaction. On
hydrolysis compounds 7 are transformed into g-keto
acids 8, which are preparatively interesting multifunc-
tional, trifluoromethylated building blocks.
We have demonstrated that 5-fluoro-4-trifluoromethyl-
1,3-azoles, 2-fluoro-3-trifluoromethylfurans and 2-
fluoro-3-trifluoromethylthiophenes are useful building
blocks in organic fluorine chemistry.5 The fluorine atom
adjacent to the trifluoromethyl group can be replaced
under mild conditions by various nucleophiles, giving
ready access to compounds of biological relevance.6
Keywords: 3-trifluoromethyl-2(3H)furanones; 3-trifluoromethyl-2(5H)furanones; 3-trifluoromethyl-2(3H)thiophenones; 3-trifluoromethyl-2(5H)-
thiophenones; domino reactions; membrane transport systems.
* Corresponding author. Fax: (49) 341 9736599; e-mail: burger@organik.chemie.uni-leipzig.de
†
Dedicated to Professor Ralf Miethchen on the occasion of his 60th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00013-2

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K. Burger et al. / Tetrahedron Letters 42 (2001) 1657–1659
Although, both compounds 3 and 6 possess a 1,5-hexa-
diene substructure, no Cope rearrangement could be
observed. To weaken the C(3)ꢀC(4) bond of the Cope
system we decided to introduce additional substituents
via 3-substituted allyl alcohols. Substitution reactions
of compounds 1 and 4 with cinnamic alcohol in the
presence of NaH proceed readily at 0°C within a few
hours. Starting from 1 the first compound of the reac-
tion sequence we were able to isolate was the Claisen
product 10, which slowly undergoes a Cope rearrange-
ment at room temperature to form 11. Domino
reactions7 involving [3,3]-sigmatropic processes are
described.8 A combination of reaction types, such as
Diels–Alder reactions,9 [3+2]-cycloaddition reactions,10
and Mannich reactions,8c provides a valuable synthetic
tool for the construction of complex molecules, often in
a stereoselective way.11 Domino reactions, including
sequences like Claisen/Cope rearrangements,12 and
Claisen/aza-Claisen rearrangements,13 have been
applied successfully in organic synthesis. However, it is
remarkable that the reaction sequence 1“9“10“11
described, including a Claisen and a Cope rearrange-
ment, proceeds smoothly at room temperature.
Claisen product 16 which can be detected on monitor-
ing the reaction by 19F NMR spectroscopy [l=17.9
ppm (s)], the Cope product 17 [l=13.9 ppm (s)] is
formed in 79% isolated yield.
When 4 and geraniol are reacted at 0°C in the presence
of NaH two products are obtained: the Cope product
20 and product 21 formed by transesterification of the
Claisen product 19. In case of the reaction of 3,3-disub-
stituted allyl alcohols, the Cope reaction (19“20) can
successfully compete with lactone cleavage via the alco-
holate (19“21). The reaction sequence consisting of
nucleophilic substitution, Claisen rearrangement and
Cope rearrangement (4“18“19“20) is, to the best of
our knowledge, the first example of a domino reaction
where two [3,3]-sigmatropic reactions proceed at 0°C.
Claisen and Cope rearrangements of fluorinated sys-
tems often take place at low temperatures.14 The correct
location of the trifluoromethyl group within the rear-
rangement system can result in a significant rate
enhancement.15
The reaction sequence provides an elegant method for
incorporation of lipophilic anchors with up to 20 car-
bon atoms into the C-5 position of butenolides and
their thioanalogues. Likewise, compounds 22, obtained
on hydrolysis from 21, are equipped with a tri-
fluoromethyl group together with a long lipophilic car-
bon side chain. Therefore, compounds of this type may
be considered as interesting candidates for the develop-
ment of transport systems to guide drugs with poor
pharmacokinetic profiles through membranes and
across the blood/brain barrier. The Michael system
present in compounds of type 17 and 20 provides an
ideal functionality to form conjugates, i.e. with peptides
In the furan series we were able to isolate the Claisen
product 13 and an open-chain product 14. The yield of
14 depends on the molar ratio of the starting materials.
In the presence of an excess of cinnamic alcohol the
ester 14 is the main product of the reaction. These
findings demonstrate that cleavage of the lactone ring
by the alcoholate is still much faster than the Cope
rearrangement.
Substitution product 15 was obtained from 1 and
geraniol at room temperature in 78% yield. On heating
15 up to 65°C a rearrangement can be initiated. Via the

K. Burger et al. / Tetrahedron Letters 42 (2001) 1657–1659
1659
and peptidomimetics. Furthermore, the presence of the
trifluoromethyl group enables us to monitor the pas-
sage of such species through membranes by 19F NMR
spectroscopy.
6. (a) Burger, K.; Ho¨ß, E.; Geith, K. Synthesis 1990, 360–365;
(b) Hu¨bl, D.; Ganzer, M.; Arndt, F.; Rees, R. G. Ger.
Offen. DE 3,614,229, 1988; Chem. Abstr. 1988, 109,
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7. For a review, see: Tietze, L. Chem. Rev. 1996, 96, 115–136.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (Bu
277/20-1) and the Fonds der Chemischen Industrie for
financial support.
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