Synthesis of 5,6-dehydrokawain and some fluorinated analogues

Article abstract of DOI:10.1080/00397911.2018.1455212

An efficient methodology for the synthesis of 6-styrenylpyrone in a four-step sequence is reported. The reactions were performed under catalyst-free conditions with mild and affordable reagents to produce 5,6-dehydrokawain and fluorinated derivatives in good to excellent overall yields (72–86%) on a multigram scale. Two novel difluorinated derivatives are reported here for the first time.

Full text of DOI:10.1080/00397911.2018.1455212

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of 5,6-dehydrokawain and some
fluorinated analogues
Grace Obi & Fanie R. Van Heerden
To cite this article: Grace Obi & Fanie R. Van Heerden (2018) Synthesis of 5,6-dehydrokawain
and some fluorinated analogues, Synthetic Communications, 48:12, 1482-1486, DOI:
10.1080/00397911.2018.1455212
To link to this article: https://doi.org/10.1080/00397911.2018.1455212
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 12, 1482–1486
https://doi.org/10.1080/00397911.2018.1455212
Synthesis of 5,6-dehydrokawain and some fluorinated
analogues
Grace Obi and Fanie R. Van Heerden
School of Chemistry and Physics, University of KwaZulu-Natal, Pietermaritzburg, South Africa
ABSTRACT
ARTICLE HISTORY
Received 18 January 2018
An efficient methodology for the synthesis of 6-styrenylpyrone in
a four-step sequence is reported. The reactions were performed
under catalyst-free conditions with mild and affordable reagents
to produce 5,6-dehydrokawain and fluorinated derivatives in
good to excellent overall yields (72–86%) on a multigram scale.
Two novel difluorinated derivatives are reported here for the
first time.
KEYWORDS
2-Pyrone; 5,6-
dehydrokawain; fluorinated;
Wittig reaction; Claisen
reaction
GRAPHICAL ABSTRACT
Introduction
The 2-pyrone (α-pyrone) moiety is present in many natural products and is also a
structural feature in various pharmacologically active complex molecules, such as the
tipranavir, a protease inhibitor that is used in combination therapy to treat HIV.[1–3]
Various 2-pyrones have been used as key intermediates in the synthesis of biologically
active compounds due to the presence of an electron-rich conjugated diene and an ester
group.[4]
This report focuses on the synthesis of naturally occurring 5,6-dehydrokawain
containing the 2-pyrone moiety and fluorine derivatives thereof. 5,6-Dehydrokawain
(desmethoxyyangonin) (1a) has been isolated from Alpinia zerumbet (syn. Alpinia speciosa),
a species of the Zingiberaceae plant family.[5,6] This compound is a major component in
Alpinia leaves and rhizomes together with dihydro-5,6-dehydrokawain and other related
pyrones.[7,8] 5,6-Dehydrokawain (1a) is associated with a wide range of biological activities
such as anti-HIV,[8] antiulcer,[9] antiobesity,[10] anti-inflammatory,[11] antioxidant activity,[12]
cytostatic activity against cancer cell lines,[13] osteogenic effects,[14,15] and inhibition of skin
disease-related enzymes.[16]
CONTACT Fanie R. Van Heerden
vanheerdenf@ukzn.ac.za
School of Chemistry and Physics, University of
KwaZulu-Natal, Private Bag X01, Scottsville 3209, Pietermaritzburg, South Africa.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
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Despite the biological importance of 2-pyrones and the related functionalized 6-styrenyl
pyrones (which can serve as precursors in the synthesis of more complex natural products),
optimized and efficient routes toward their synthesis are not available.
It has been shown in several studies that the incorporation of fluorine in molecules often
enhances their biological activities.[17–20] Due to the increasing attention on fluorinated
drugs, we decided to synthesize a range of fluorinated derivatives of 5,6-dehydrokawain.
We aim to explore their biological activity in our future endeavors as these compounds
have not yet been investigated.
The synthesis of 5,6-dehydrokawain (1a) and related compounds was reported by
Amaral et al.[21] They used a palladium-catalyzed Heck reaction between 4-methoxy-6-
vinyl-5,6-dihydro-2-pyrone and an aryl iodide but reported disappointing results and
low yields. Moro and coworkers[22] reported the synthesis of these compounds using a
Heck arylation of allylic esters in the presence of arenediazonium salts but also obtained
low yields. In addition, some of the catalyst and ligands used in these reactions are expens-
ive and difficult to synthesize. Aldol reactions using an excess of magnesium methoxide
and aryl aldehyde have been reported but also resulted in low yields.[23] A one-pot aldol
reaction of aldehydes and potassium tert-butoxide in dry DMF with slightly improved
yields was reported by Kraus and Wanninayake for the synthesis of 6-styrenylpyrones.[24]
Schmidt et al. constructed 6-substituted pyrones by converting 5-hydroxy-3-oxopent-4-
enoic acids into stable bis-potassium salts and treatment of this with trifluoroacetic anhy-
dride and trifluoroacetic acid afforded substituted 4-hydroxy-2H-pyran-2-ones in a fair
yield.[25]
We investigated these methods but achieved very low yields (5–25%). Since larger
amounts of compounds were needed, it was decided to explore an alternative synthetic
route using readily available cheap starting materials and mild reaction conditions.
Results and discussion
Herewith, an expedient, effective, and easy route toward the synthesis of 5,6-dehydroka-
wain and other 6-styrenylpyrones is presented. The synthesis of bioactive 5,6-dehydroka-
wain (1a) and five fluorinated analogues was performed as shown in Scheme 1 in good to
excellent yields (72–86% overall yield). This was achieved by the treatment of benzaldehyde
2a or its corresponding fluorinated derivatives 2b–f with (carbethoxymethylene)triphenyl-
phosphorane (3) in dichloromethane for 16 h to afford the corresponding ethyl cinnamates
4a–f.[26]
The synthesis of styrenyldiketoester intermediates 5a–f was achieved by reacting the
corresponding ester and the dianion of ethyl acetoacetate formed by treatment of this
reagent with LDA and tetramethylethylenediamine (TMEDA) in THF according to the
method described by Douglas et al.[27] and Dong et al.[28] This reaction resulted in the for-
mation of several keto-enol tautomers that could not be separated. Attempts to characterize

1484
G. OBI AND F. R. VAN HEERDEN
Scheme 1. Synthesis of 5,6-dehydrokawain (1a) and its fluorinated derivatives 1b–f from the
corresponding benzaldehyde.
the pure form of these intermediates using silica gel column chromatography were unsuc-
cessful as also described by Douglas et al.[27] As a result, the mixture was used without
further purification. Subsequently, 6a–f were obtained smoothly by DBU-promoted cycli-
zation of styrenyldiketoester intermediates 5a–f by refluxing in benzene overnight, using a
method described by Cervello et al.[29] Methylation of the cyclized products with dimethyl
sulfate afforded the final products in excellent yields. Compounds 1a[21] and 1b[30] have
been reported previously and spectroscopic data are consistent with the reported values.
The synthesized fluorinated compounds contain one fluorine atom in the ortho, meta, or
para positions (1b–d) of the phenyl ring or two fluorine atoms on the 3,4- or 2,3-positions
of the phenyl ring (1e and 1f). Compounds 1a–f (Fig. 1) were obtained on a 2-gram scale.
Figure 1. Structures and overall yields of the final products 1a–f.

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1
Characterization of the synthesized compounds was based on 19F NMR, H NMR, 13C
NMR, mass spectrometry, and IR spectroscopy. The structures of compounds 6a–f were
1
confirmed by the presence of diagnostic unsaturated proton resonances in the H NMR
(DMSO-d6) spectrum at δH 5.35–5.40 and δH 6.25–6.34 as two doublets with a small
coupling constant (J ¼ 2.0 Hz) and the presence of a hydroxy proton resonances at δH
11.78–12.01. The carbonyl resonance in the 13C NMR (DMSO-d6) at δC 170.0–170.2
further confirmed the structures of these compounds. The 19F NMR (DMSO-d6) resonance
at δF −143.30 to −111.61 was used to confirm the presence of fluorine in the fluorine-
containing compounds.
Conversion of compounds 6a–f into 1a–f was confirmed by the disappearance of the
broad OH peak and the appearance of a methoxy singlet ranging from δH 3.81 to 3.83
1
in the H NMR (CDCl3) spectrum.
Experimental
General
All air- and moisture-sensitive reactions were performed in flame-dried glassware under an
inert gas (argon or nitrogen) atmosphere. Reactions were monitored using thin-layer
chromatography (TLC, silica gel 60254, aluminum backed). Visualization of the TLC plates
was achieved using an iodine tank and/or fluorescence on exposure to short wavelength
UV (254 nm). Solvents were dried and purified following standard procedures. Compounds
were characterized using Bruker 400 or 500-MHz ultrashield nuclear magnetic resonance
(NMR) spectrometers at frequencies of 399.995 MHz (1H NMR), 100.4296 MHz
(13C NMR), and 470 MHz (19F NMR) at 298 K with chemical shifts (δ) given in parts per
million (ppm) downfield from tetramethylsilane as the internal standard and coupling
constants (J) in Hertz (Hz). High-resolution mass spectrometry (HRMS) was performed
on a Waters LCT Premier time-of-flight mass spectrometer with electrospray ionization in
the positive mode [HRMS-ESI-(þ)]. IR spectra were recorded on a Perkin Elmer Spec-
trometer (100 FT-IR) with universal attenuated total reflectance (ATR) sampling accessory.
Melting points were recorded using a Stuart melting point apparatus and were uncorrected.
General procedure for the preparation of 6a–f
To the corresponding styrenyldiketoester intermediates 5 (0.9 mmol) in 5 mL of benzene,
DBU (0.16 g, 1 mmol) was added. The reaction mixture was refluxed for 20 h, acidified to
pH 1 by the addition of 1 M HCl (4 mL), and stirred for 15 min. Ethyl acetate (15 mL) was
added and the organic layer was separated, washed with brine, dried over MgSO4 and con-
centrated in vacuo. The crude product was purified using column chromatography with
hexane-EtOAc (1:1) as an eluant to yield 6.
Conclusion
In summary, a convenient method for the synthesis of 5,6-dehydrokawain derivatives with
excellent yields which can be performed on a multigram scale was developed. Two
difluorinated 5,6-dehydrokawain derivatives (1e and 1f) are reported for the first time. This
method does not require any expensive catalyst or harsh reaction conditions and serves as
an easy route to other functionalized 6-styrenylpyrones derivatives.

1486
G. OBI AND F. R. VAN HEERDEN
Funding
This work was supported by the University of KwaZulu-Natal and the National Research Foundation
of South Africa (NRF) (Grant No: 98345, 2017).
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