A Short, Gram-Scale Synthesis of 2,5-Disubstituted Furans
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Experimental Section
Synthesis of α-Chloraldehydes 9a–d: In a round-bottomed flask
(500 mL), a solution of the aldehyde [0.35 m] in CH2Cl2 (200 mL)
was cooled to 0 °C by using an ice bath. NCS (1.05 equiv.) was then
added with vigorous stirring, followed by l-proline (0.1 equiv.), and
the reaction mixture was warmed gradually to room temperature.
The progress of the reaction was monitored by 1H NMR spec-
troscopy. After completion of the reaction (4–8 h), the crude mix-
ture was cooled to –78 °C, pentane (200 mL) was added, and the
resulting precipitate was removed by filtration. The filtrate was con-
centrated by using a rotary evaporator connected to a water aspira-
tor. This precipitation/concentration operation was repeated, and
the resulting oil was distilled under vacuum to yield the desired α-
chloroaldehyde. The semipurified α-chloroaldehydes could be
stored at –15 °C as solutions in THF for up to 2 weeks without
noticeable degradation. The spectroscopic data derived from each
α-chloroaldehyde was in accord with that reported previously.
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Synthesis of β-Ketochlorohydrins: To a cold (0 °C), stirred solution
of diisopropylamine (1.2 equiv.) in THF (0.5 m) was added n-butyl-
lithium dropwise (2.5 m in hexanes, 1.1 equiv.), and the mixture was
stirred for 15 min. The resulting mixture was cooled to –78 °C, and
a solution of the ketone (1.0 equiv.) in THF (1.0 m) was added
dropwise at a rate of 0.1 mL per minute. After stirring for 30 min,
the α-chloroaldehyde (1.2 equiv.) was added as a solution (1.0 m) in
THF at –78 °C, and the reaction mixture was stirred for an ad-
ditional 30 min. The mixture was then treated with saturated aque-
ous NH4Cl, diluted with ethyl acetate and water, and the phases
were separated. The aqueous phase was extracted ethyl acetate
(3ϫ), and the combined organic phase was washed with brine
(10 mL), dried with MgSO4, and concentrated to provide a crude
oil, which was used without further purification.
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Preparation of Furans: The crude β-ketochlorohydrin was sus-
pended in water (50 mL) and heated at reflux for 12 h. The reaction
mixture was then cooled to room temperature and extracted with
CH2Cl2 (3ϫ). The combined organic layer was washed with brine,
dried (MgSO4), and concentrated. The crude furan was purified by
flash column chromatography (cyclohexane).
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Supporting Information (see footnote on the first page of this arti-
cle): General experimental details, characterization data, and copies
1
of the H NMR and 13C NMR spectra for all final products.
Acknowledgments
This work was supported by a Discovery Grant from the Natural
Sciences and Engineering Research Council (NSERC) of Canada
to R. B. and D. B. L., a Michael Smith Foundation for Health Re-
search Career Investigator Award to R. B., and an NSERC Post-
graduate Scholarship to S. C. S. D. was partially supported by
Teaching and Learning Center Grant for Undergraduate Research
Immersion (SFU).
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A single example of the thermal cyclization of a β-keto-
chlorohydrin to a 2,5-disubstituted furan has been reported,
Eur. J. Org. Chem. 2013, 3219–3222
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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