A facile, general synthesis of 3,4-difluoro-6-substituted-2-pyrones

Article abstract of DOI:10.1021/jo060362a

Reaction of (2E)-2,3-difluoro-3-iodoacrylic acid with a variety of terminal acetylenes under cocatalysis of PdCl₂(PPh₃)₂ and Cul gave difluorinated 2-pyrones as the sole product in good yields.

Full text of DOI:10.1021/jo060362a

A Facile, General Synthesis of 3,4-Difluoro-6-substituted-2-pyrones
Yi Wang and Donald J. Burton*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
ReceiVed February 21, 2006
Reaction of (2E)-2,3-difluoro-3-iodoacrylic acid with a variety of terminal acetylenes under cocatalysis
of PdCl2(PPh3)2 and CuI gave difluorinated 2-pyrones as the sole product in good yields.
Introduction
fects.10 Consequently, much attention has been paid to the
synthesis of 2-pyrones by traditional methods,11 transition-metal-
catalyzed procedures,8,12 or nucleophilic phosphine catalysis of
allenoates and butynoates.13 However, to the best of our
knowledge, there is only one report of the preparation of 3,4-
difluoro-6-substituted-2-pyrones. England and co-workers re-
Fluorinated organic compounds have attracted the interest of
pharmaceutical chemists and agrochemists.1 Replacement of
hydrogen atoms by fluorine atoms in organic molecules causes
a relatively small steric perturbation but leads to major changes
in lipophilicity and polarity factors; thus, it often leads to
enhanced biological activity. 2-Pyrones2 are found in numerous
natural products that display important biological activities such
as anti HIV,3 telomerase inhibition,4 antimicrobial,5 antifungal,6
cardiotonic,7 pheromonal,8 androgen-like,9 and phytotoxic ef-
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10.1021/jo060362a CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
J. Org. Chem. 2006, 71, 3859-3862
3859

Wang and Burton
TABLE 1. Synthesis of 3,4-Difluoro-6-substituted-2-pyrones
SCHEME 1
SCHEME 2
SCHEME 3. Preparation of 3
a Isolated yield based on 3.
ported a synthetic route to this class of compounds via the
Diels-Alder reactions of perfluoroacryloyl fluorides with
monosubstituted acetylenes, followed by isomerization of the
adducts and hydrolysis in aqueous NaHCO3 (Scheme 1).14
Unfortunately, by this methodology, most of the fluorinated
2-pyrones derivatives were obtained in poor yields. Herein, we
wish to report a more efficient and general route to this class
of compounds.
phenylacetylene occurred very smoothly at room temperature,
and 19F NMR spectroscopy indicated there was a sole product
after the reaction was completed. To our surprise, the product
was found to be 3,4-difluoro-6-phenyl-2H-pyran-2-one 4 after
comparison of its NMR data with those in England’s report.14
A variety of acetylenes were employed under similar reaction
conditions, and only the 2-pyrone product was formed in each
case. These results are summarized in Table 1.
Results and Discussion
Both aromatic (entries 1, 4, and 5) and aliphatic acetylenes
(entries 2 and 3) worked well, as well as a heterocyclic acetylene
(entry 6). The presence of neither an electron-withdrawing group
(entry 4) nor an electron-donating group (entry 5) on the
aromatic rings affected the yield of the products. The relative
low yield in entry 6 was due to incomplete reaction even after
24 h at room temperature. Spectroscopic data of 4 are identical
to those reported by England and co-workers, and the assign-
ment of 2-pyrone was further confirmed by its single-crystal
X-ray diffraction.20
On the basis of our observed results, the following mechanism
is proposed to explain the formation of the 2-pyrone products
(Scheme 4). The Pd(0) is first formed in the presence of
phenylacetylene. In the first catalytic cycle, the iodoacid 3 reacts
with the alkyne under the catalysis of Pd(0) to produce the
ynenoic acid. Pd(0) species is regenerated after the first cycle
and is readily converted into Pd(II) in the solution containing
an acid moiety HX (X could be I-, Cl-, and/or (E)-CFId
CFCO2-). In the second catalytic cycle, the ynenoic acid is
further transformed into the final product under the catalysis of
Pd(II). Upon reductive elimination, the Pd(0) is regenerated to
yield 4.
Recently, cis-â-haloacrylic acids have been utilized for the
highly stereoselective synthesis of γ-(Z)-alkylidenebutenolides
and/or 2-pyrones under cocatalysis of palladium and
copper(I),15 Ag(I),16 Hg(II),17 and Zn(II).16 In most of these
cases, the 2-pyrones were observed only as the major side
products. Negishi and co-workers reported a convenient syn-
thesis of γ-(Z)-alkylidenebutenolides; however, the 2-pyrone was
obtained as a minor product (Scheme 2).17
Since we have recently reported the preparation of ethyl (E)-
2,3-difluoro-3-(tributylstannyl)acrylate 1 and studied its reaction
with organic halides18 and acid chlorides,19 it occurred to us
that 1 might be a possible precursor to the fluorinated cis-â-
haloacrylic acid, which could be further utilized to prepare the
corresponding fluorinated analogue of γ-(Z)-alkylidenebuteno-
lides and/or 2-pyrones. Treatment of 1 with iodine in ether
afforded the iodoester 2,19 which underwent saponification and
subsequent acidification to give the cis-iodo acid 3 (Scheme
3).
With acid 3 in hand, we investigated the possibility of the
synthesis of difluorosubstituted γ-alkylidenebutenolides under
the reported reaction conditions. Under the cocatalysis of PdCl2-
(PPh3)2 (2 mol %) and CuI (5 mol %), reaction of 3 with
At this point, the reason for the exclusive formation of the
fluorinated 2-pyrone is not clear. It is nevertheless tempting to
attribute the selectivity to the strong electronegativity of
fluorine.21 The presence of two fluorine atoms on the double
(14) England, D. C.; Donald, E. A.; Weigert, F. J. J. Org. Chem. 1981,
46, 144-147.
(15) (a) Lu, X.; Huang, X.; Ma. S. Tetrahedron Lett. 1993, 37, 5963-
5966. (b) Kotora M. Negishi, E. Tetrahedron Lett. 1996, 37, 9041-9042.
(c) Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707-6738. (d) Liu, F.;
Negishi, E. J. Org. Chem. 1997, 62, 8591-8594. (e) Negishi, E.;
Alimardanov, A.; Xu, C. Org. Lett. 2000, 2, 65-67.
(16) Anastasia, L.; Xu, C.; Negishi, E. Tetrahedron Lett. 2002, 43, 5673-
5676.
(20) CCDC 299095 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK.; fax: +44 1223 336033. Also see the Supporting
Information.
(17) Kotora, M.; Negishi, E. Synthesis 1997, 121-128.
(18) Wang, Y.; Burton, D. J. J. Org. Chem. 2005, 70, 10743-10746.
(19) Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 1109-1111.
(21) In ref 1d, pp 1-23.
3860 J. Org. Chem., Vol. 71, No. 10, 2006

Synthesis of 3,4-Difluoro-6-substituted-2-pyrones
SCHEME 4. Proposed Mechanism of the Formation of 4
SCHEME 7
Conclusion
In conclusion, difluorinated 2-pyrones were readily prepared
in a one-pot reaction from iodo acid 3 with a variety of terminal
alkynes. Cyclization of enynes with I2 afforded 5-iodo-6-
substituted 2-pyrones, which could be further utilized to
synthesize more functionalized fluorinated 2-pyrones (via transi-
tion-metal-catalyzed coupling reactions). These methods should
find application in the synthesis of fluorinated natural products.
SCHEME 5. Exclusive Formation of 2-Pyrones
Experimental Section
Preparation of (2E)-2,3-Difluoro-3-iodoacrylic Acid (3). To
a solution of 2 (0.23 g, 0.88 mmol) in THF (3 mL) was added
aqueous sodium hydroxide (1 mL, 3 M) dropwise at 0 °C. After 3
h at room temperature, the reaction was treated with aqueous HCl
until the pH was ∼1. Then the mixture was extracted with 25 mL
of ethyl acetate. The organic layer was washed with brine (5 mL),
dried over anhydrous Na2SO4, and concentrated by rotary evapora-
tion. The crude acid was recrystallized from hexane to yield 0.16
g of a white solid (yield 78%): mp 95-96 °C; 19F NMR (CDCl3)
SCHEME 6
1
δ -70.4 (d, J ) 10.6 Hz, 1 F), -130.0 (d, J ) 10.5 Hz, 1 F); H
NMR (CDCl3) δ 11.8 (br s); 13C NMR (CDCl3) δ 165.0 (dd, J )
28.4, 7.9 Hz), 140.0 (dd, J ) 264.2, 15.2 Hz), 108.8 (dd, J ) 336.5,
24.4 Hz); HRMS calcd 233.8989 for C3HF2IO2, found 233.8990.
General Procedure for the Preparation of 3,4-Difluoro-6-
substituted-2-pyrones. A round-bottomed flask was charged with
a stirring bar and nitrogen tee, (2E)-2,3-difluoro-3-iodoacrylic acid
3 (0.23 g, 1 mmol), CuI (10 mg, 0.05 mmol), PdCl2(PPh3)2 (14
mg, 0.02 mmol), and 5 mL of MeCN. Et3N (0.56 mL, 4 mmol)
and alkyne (1.1 mmol) were added sequentially under N2. After
the reaction was completed (the reaction progress was monitored
by TLC), the reaction mixture was diluted with ether (25 mL). The
mixture was filtered, and the filtrate was concentrated by rotary
evaporation. The crude residue was purified on silica gel (hexane/
ethyl acetate ) 10:1), and the pure product was obtained.
Preparation of 3,4-Difluoro-6-phenyl-2H-pyran-2-one (4). The
reaction mixture of 3 (0.23 g, 1 mmol), CuI (10 mg, 0.05 mmol),
PdCl2(PPh3)2 (14 mg, 0.02 mmol), Et3N (0.56 mL, 4 mmol), and
phenylacetylene (0.12 mL, 1.1 mmol) in 5 mL of MeCN was stirred
under N2 at room temperature for 24 h. Column chromatography
with a mixture of hexane and ethyl acetate (10:1) afforded 0.13 g
of a yellow solid: mp 130-132 °C; 19F NMR (CDCl3) δ -118.0
(dd, J ) 16.5, 8.5 Hz, 1 F), -163.9 (dd, J ) 16.5, 4.6 Hz, 1 F); 1H
NMR (CDCl3) δ 7.78-7.76 (m, 2 H), 7.54-7.46 (m, 3 H), 6.64
(dd, J ) 8.5, 4.6 Hz, 1 H); 13C NMR (CDCl3) δ 157.3 (dd, J )
22.9, 10.3 Hz), 157.0 (dd, J ) 11.6, 7.5 Hz), 156.7 (dd, J ) 271.8,
9.6 Hz), 133.3 (dd, J ) 252.0, 9.7 Hz), 131.6 (d, J ) 0.6 Hz),
129.7 (dd, J ) 3.3, 1.5 Hz), 129.2, 125.6 (d, J ) 1.0 Hz), 95.2
(dd, J ) 25.4, 3.2 Hz); HRMS calcd 208.0336 for C11H6F2O2, found
208.0336.
bond makes the triple bond partially polarized. The carboxylic
anion would attack the partially positive charged carbon to give
the 2-pyrone (via path a) rather than the other carbon on the
triple bond to give the γ-alkylidenebutenolide (via path b) as
illustrated in Scheme 5.
As an extension of this work, we were able to prepare 3,4-
difluoro-5-iodo-6-substituted-2-pyrones via the electrophilic
cyclization work developed by Larock and co-workers.11d
Treatment of 2 with alkynes (Sonogashira reaction22) under the
cocatalysis of PdCl2(PPh3)2 (2 mol %) and CuI (5 mol %)
afforded enynes 10 and 11, respectively. The reaction of 10
and 11 with I2 in CH2Cl2 gave the corresponding 5-iodo-2-
pyrones 12 and 13, respectively (Scheme 6).
Formation of 6-iodo-2-pyrones presumably follows the mech-
anism proposed by Larock and co-workers11d (Scheme 7).
Nucleophilic attack by the oxygen of carbonyl group on the
triple bond activated by coordination to I+ is followed by SN2
attack of the iodide.
Confirmation of the structure of the 5-iodo-2-pyrones rather
than iodo-substituted butenolides was verified by subsequent
reduction of the enynes. Treatment of 12 and 13 in the presence
of zinc dust in acetic acid23 yielded 4 and 5 in 67% and 66%
yield, respectively.
Preparation of Ethyl (2Z)-2,3-Difluoro-5-phenylpent-2-en-4-
ynoate (10). A round-bottomed flask was charged with a stirring
bar and nitrogen tee, PdCl2(PPh3)2 (14 mg, 0.02 mmol), CuI (10
mg, 0.05 mmol), and 4 mL of CH3CN. Ethyl (2E)-2,3-difluoro-3-
iodoacrylate 2 (0.26 g, 1 mmol), phenylacetylene (0.12 mL, 1.1
mmol), and Et3N (0.21 mL, 1.5 mmol) were added subsequently
(22) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(23) (a) Giza, C. A.; Hinman, R. L. J. Org. Chem. 1964, 29, 1453-
1461. (b) In Encyclopedia of Regents for Organic Synthesis; Paquette, L.
A., Ed.; John Wiley & Sons: Chichester, 1995; pp 5531-5534.
J. Org. Chem, Vol. 71, No. 10, 2006 3861

Wang and Burton
under N2. After 12 h, the mixture was diluted with ether (25 mL)
and filtered. The filtrate was concentrated, and the crude product
was purified on silica gel (hexane/ethyl acetate ) 20:1) and a yellow
oil was obtained (0.17 g, 74%): 19F NMR (CDCl3) δ -113.6 (d,
Reduction of 12. In a round-bottomed flask charged with a
stirring bar and nitrogen tee was added zinc dust (0.07 g, 1.1 mmol)
to a solution of 3,4-difluoro-5-iodo-6-phenylpyran-2-one (0.17 g,
0.51 mmol) in 3 mL of HOAc at room temperature. After the
mixture was refluxed under N2 for 2 h, it was cooled to room
temperature and diluted with ether (25 mL). The organic layer was
washed with aq NaHCO3 (5 mL) and brine (5 mL), dried, and
concentrated. The product was purified on silica gel (hexane/ethyl
acetate ) 10:1) to give a yellow solid (0.07 g, 67%): mp 130-
132 °C. 1H and 19F NMR spectroscopic data were identical to those
for 4.
1
J ) 9.9 Hz, 1 F), -139.0 (d, J ) 9.9 Hz, 1 F); H NMR (CDCl3)
δ 7.58-7.54 (m, 2 H), 7.44-7.38 (m, 3 H), 4.37 (q, J ) 7.1 Hz,
2 H), 1.37 (t, J ) 7.1 Hz, 3 H); 13C NMR (CDCl3) δ 159.6 (dd, J
) 28.0, 7.0 Hz), 142.6 (dd, J ) 263.6, 23.2 Hz), 138.8 (dd, J )
250.9, 24.4 Hz), 132.0 (dd, J ) 2.6, 1.3 Hz), 130.3, 128.6 (2C),
120.5 (dd, J ) 2.8, 1.6 Hz), 102.7 (dd, J ) 8.1, 5.1 Hz), 62.1,
14.2; HRMS calcd 236.0649 for C13H10F2O2, found 236.0655.
Preparation of 3,4-Difluoro-5-iodo-6-phenylpyran-2-one (12).
In a round-bottomed flask charged with a stirring bar and nitrogen
tee was stirred a solution of 2,3-difluoro-5-phenylpent-2-en-4-ynoic
acid ethyl ester (0.14 g, 0.59 mmol) and iodine (0.18 g, 0.71 mmol)
in 10 mL of CH2Cl2 under N2 at room temperature for 2 h. The
reaction mixture was then diluted with 50 mL of ether, washed
with 20 mL of aq Na2S2O3, and dried over Na2SO4. The solvent
was evaporated under vacuum, and the product was purified on
silica gel (hexane/ethyl acetate ) 10:1) to give a yellow solid (0.15
g, 76%): mp 93-94 °C; 19F NMR (CDCl3) δ -97.3 (d, J ) 15.2
Hz, 1 F), -159.5 (d, J ) 15.2 Hz, 1 F); 1H NMR (CDCl3) δ 7.73-
7.70 (m, 2 H), 7.52-7.48 (m, 3 H); 13C NMR (CDCl3) δ 157.7
(dd, J ) 7.8, 5.3 Hz), 156.5 (dd, J ) 23.1, 10.3 Hz), 155.5 (dd, J
) 267.9, 10.1 Hz), 132.4 (dd, J ) 257.8, 13.2 Hz), 132.1 (d, J )
2.7 Hz), 131.5, 129.5, 128.4, 62.1 (dd, J ) 28.3, 4.0 Hz); HRMS
calcd 333.9302 for C11H5IF2O2, found 333.9303.
Acknowledgment. We acknowledge the National Science
Foundation for their financial support of this work. We thank
Dr. Dale Swenson for determination of the X-ray crystal
structure. Y.W. thanks Dr. Qilong Shen for valuable discussions.
Supporting Information Available: Experimental procedure
for the synthesis of 5-9, 11, and 13 and their characterization by
1H, 19F, and 13C NMR and HRMS; copies of 1H, 19F, and 13C NMR
of compounds 3-13. Complete X-ray crystallographic data of
compound 4 (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JO060362A
3862 J. Org. Chem., Vol. 71, No. 10, 2006