J . Org. Chem. 2000, 65, 2003-2006
2003
Syn th esis of 3-Tr iflu or oeth ylfu r a n s by P a lla d iu m -Ca ta lyzed
Cycliza tion -Isom er iza tion of (Z)-2-Alk yn yl-3-tr iflu or om eth yl
Allylic Alcoh ols
Feng-Ling Qing,* Wen-Zhong Gao, and J iewen Ying
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
Received September 15, 1999
Hydroiodonation of trifluoromethyl propargylic alcohols 1 regio- and stereoselectively produce (Z)-
2-iodo-3-trifluoromethyl allylic alcohols 2. (Z)-2-Alkynyl-3-trifluoromethyl allylic alcohols 5, available
through Pd(PPh3)4-mediated coupling of 2 and terminal alkynes 4, cyclize and subsequently
isomerize to 3-trifluoroethylfurans 6 upon catalysis under PdCl2(CH3CN)2 in THF at 5-10 °C.
In tr od u ction
introduction of the trifluoroethyl group (CF3CH2) to
organic compounds. It is well-known that 2,2,2-trifluo-
roethyl halides cannot be used as trifluoroethylation
agents by nucleophilic substitution because the trifluo-
romethyl group strongly deactivates the neighboring
carbon.7 Thus, alternative approaches using 2,2,2-trif-
luoroethyl phenyl iodonium triflate8 and a free-radical
addition of 2,2,2-trifluoroethyl iodide to electron-rich
terminal alkenes9 have been developed for introducing
the trifluoroethyl group into organic molecules. However,
these methods are limited because of low yields, the use
of expensive reagents, or unsuitability for the synthesis
of trifluoroethylfuran. Here, a novel synthesis of 3-trif-
luoroethylfurans based on palladium-catalyzed cycliza-
tion-isomerization of (Z)-2-alkynyl-3-trifluoromethyl al-
lylic alcohols is described.
There has been considerable interest in organofluorine
compounds as pharmaceutical and agrochemical agents.1
It is believed that the fluorine atom alters the physio-
chemical properties of organic compounds, thereby modi-
fying biological activity. This has been particularly true
for fluoroheterocycles.2 Furan and polysubstituted furans,
as one of the representative five-membered heterocycles,
play an important role in organic chemistry not only
because of their presence as structural units in many
natural products and in important pharmaceuticals but
also because they can also be employed in synthetic
chemistry as building blocks.3 Therefore, new methods
for the synthesis of fluorofurans have received consider-
able attention. Although monofluorofurans4 and trifluo-
romethylfurans5 are well documented, trifluoroethyl-
furans are much less known.6 This is ascribed to the
absence of practical and convenient methods for the
Resu lts a n d Discu ssion
P r ep a r a tion of (Z)-2-Iod o-3-tr iflu or om eth yl Al-
lylic Alcoh ols. Trifluoromethyl propargylic alcohols (1)
that were easily prepared from 2-bromo-3,3,3-trifluoro-
propene and aldehydes in the presence of 2 equiv of LDA
have been used as building blocks for the synthesis of
trifluoromethyl-containing compounds.10 Following our
previous work describing the stereoselective synthesis of
ethyl (Z)-4,4,4-trifluoro-3-iodobutenoate by hydroiodona-
tion of ethyl 4,4,4-trifluoro-2-butynoate,11 we now extend
this methodology to the synthesis of iodo-3-trifluoro-
methyl allylic alcohols from trifluoromethyl propargylic
alcohols 1. A mixture of 4,4,4-trifluoro-1-phenyl-2-butyn-
1-ol 1a (1.0 equiv) and sodium iodide (1.5 equiv) in acetic
acid was stirred at 70 °C for 8 h. 19F NMR monitoring of
the reaction mixture revealed that compound 1a had
disappeared, and the 19F NMR spectrum displayed a new
double peak at -18.0 ppm (J ) 7.0 Hz)12 corresponding
* To whom correspondence should be addressed. Fax: 86-21-
641661128. E-mail: flq@pub.sioc.ac.cn.
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M., Eds. Organofluorine Compounds in Medicinal and Biochemical
Applications; Elsevier: Amsterdam, 1993. (d) Resnati, G.; Soloshnok,
V. A. Fluoroorganic Chemistry: Synthetic Challenges and Biomedical
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(12) 19F NMR spectra (56.4 Hz) were recorded on a Varian EM-360L
instrument using CF3CO2H as an external standard, upfield positive.
10.1021/jo991463u CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/04/2000