The first synthesis of 4-trifluoromethyl-2H-pyrans by palladium-catalyzed cyclization of (E)-3-alkynyl-3-trifluoromethyl allylic alcohols

Article abstract of DOI:10.1016/S0040-4039(00)01333-2

The cross-coupling of (Z)-3-iodo-3-trifluoromethyl allylic alcohols 4 with terminal alkynes 5 in the presence of Pd(PPh₃)₄ and CuI gave conjugated (E)-3-alkynyl-3-trifluoromethyl allylic alcohols 2 in high yield. 4-Trifluoromethyl-2H-pyrans 7 were prepared from the cyclization of 2 using PdCl₂(CH₃CN)₂ catalysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01333-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7727–7730
The first synthesis of 4-trifluoromethyl-2H-pyrans by
palladium-catalyzed cyclization of
(E)-3-alkynyl-3-trifluoromethyl allylic alcohols
Feng-Ling Qing* and Wen-Zhong Gao
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
Received 11 May 2000; revised 17 July 2000; accepted 1 August 2000
Abstract
The cross-coupling of (Z)-3-iodo-3-trifluoromethyl allylic alcohols 4 with terminal alkynes 5 in the
presence of Pd(PPh3)4 and CuI gave conjugated (E)-3-alkynyl-3-trifluoromethyl allylic alcohols 2 in high
yield. 4-Trifluoromethyl-2H-pyrans 7 were prepared from the cyclization of 2 using PdCl2(CH3CN)2
catalysis. © 2000 Elsevier Science Ltd. All rights reserved.
We recently described a novel route to 3-trifluoroethylfurans through palladium-catalyzed
cyclization-isomerization of (Z)-2-alkynyl-3-trifluoromethyl allylic alcohols (Scheme 1).1 This
reaction proceeds readily and affords a variety of trifluoroethylated furans in high yield.
Accordingly, we were interested in testing the feasibility of the synthesis of 3-trifluoromethyl-
furans 1 from (E)-3-alkynyl-3-trifluoromethyl allylic alcohols 2 (Scheme 1). Recently, cycloiso-
merization of non-fluorinated 3-alkynyl allylic alcohols to furans was achieved under basic
4
conditions2 or catalyzed by ruthenium,3 palladium and silver nitrate.5
Scheme 1.
* Corresponding author. Fax: 86-21-64166128; e-mail: flq@pub.sioc.ac.cn
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01333-2

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Trifluoromethyl propargylic alcohols 3 that were easily prepared from 2-bromo-3,3,3-tri-
fluoropropene and aldehydes in the presence of 2 equiv. LDA6 were used as the starting
materials for the syntheses of 2. Treatment of 3 with LiAlH4 and then I2 afforded the
(Z)-3-iodo-3-trifluoromethyl allylic alcohols 4.7 Reaction of 4a with terminal alkynes 5 in the
presence of Pd(PPh3)4 and CuI in triethylamine at 50°C gave conjugated (E)-3-alkynyl-3-tri-
fluoromethyl allylic alcohols 2 in high yield (Scheme 2).8
Scheme 2.
The palladium-catalyzed reaction of 4b with phenylacetylene under the same reaction condi-
tions led not to the expected conjugated (E)-3-alkynyl-3-trifluoromethyl allylic alcohol 2e, but
gave the ketone 6 instead. When 1.0 equiv. of triethylamine and THF was used as base and
solvent, respectively, in this coupling reaction, the expected product 2e was isolated in 79% yield.
As such, it can be concluded that compound 2e was formed first, but that it easily rearranged
to ketone 6 in the presence of triethylamine (Scheme 3). In the presence of 1.0 equiv. of
triethylamine, the palladium-catalyzed cross-coupling of 4b with 1-octyne gave 2f in 82% yield.
Scheme 3.

7729
With (E)-3-alkynyl-3-trifluoromethyl allylic alcohol 2 in hand, we were interested in exploring
the feasibility of using 2 in cycloisomerization reactions. The cycloisomerization of 2a under
palladium catalysis was then tested. When 2a was treated with PdCl2(CH3CN)2 (5 mol%) in
THF at 70°C for 30 min, compound 2a was totally converted, affording not the expected
product 1, but the 4-trifluoromethyl-2H-pyran 7a in 77% isolated yield (Scheme 5). A variety of
palladium complexes were tested and we found that PdCl2(CH3CN)2 and PdCl2(PhCN)2
exhibited similar activities leading to the complete conversion of 2a to 7a, while Pd(OAc)2,
Pd(PPh3)4 and PdCl2(PPh3)2 were inactive under similar reaction conditions. Treatment of 2b
and 2d with a catalytic amount of PdCl2(CH3CN)2 effected their smooth conversion to the
corresponding 4-trifluoromethyl-2H-pyrans 7b and 7d (Scheme 4). To the best of our knowl-
edge, this is the first synthesis of 4-trifluoromethyl-2H-pyrans. This result was different from the
palladium-catalyzed reaction of 3-alkynyl allylic alcohols, which produced substituted furans
exclusively.4e This is clearly due to the fact the trifluoromethyl group possesses powerful
electron-withdrawing properties, so the 6-endo-dig cyclization is favored.9
Scheme 4.
Exposure of 2c to the cyclization conditions afforded the 4-trifluoromethyl-2H-pyran 7c in
only 33% yield. This product was accompanied by compound 8 in 32% yield. Interestingly, the
reaction of 2f with catalytic PdCl2(CH3CN)2 led to the dienone 9 in 73% yield (Scheme 5).
Scheme 5.

7730
We have also examined the cyclization of the 1,1-dimethyl-3-alkynyl-3-trifluoromethyl allylic
alcohols 2g–h (Scheme 6). Treatment of these alcohols with catalytic PdCl2(CH3CN)2 in THF at
70°C produced the 4-trifluoromethyl-2H-pyrans 7g–h. These results further demonstrate that the
6-endo-dig cyclization is a favorable process for (E)-3-alkynyl-3-trifluoromethyl allylic alcohols.
Scheme 6.
In summary, we have described the first synthesis of 4-trifluoromethyl-2H-pyrans via Pd-
catalyzed cyclization of (E)-3-alkynyl-3-trifluoromethyl allylic alcohols.
Acknowledgements
We thank the National Natural Science Foundation of China for financial support.
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