3-Fluorotetrahydropyran-4-one derivatives from homopropargyl acetal

Article abstract of DOI:10.1016/j.jfluchem.2014.01.019

A gold(I)-catalysed regioselective method for the preparation of 3-fluoro-tetrahydropyran-4-one derivatives from homopropargyl acetal is reported. A one-pot procedure based on a gold(I)-catalysed Petasis-Ferrier rearrangement/cyclization and subsequent fl

Full text of DOI:10.1016/j.jfluchem.2014.01.019

Accepted Manuscript
Title: 3-Fluorotetrahydropyran-4-one derivatives from
homopropargyl acetal
Author: Jon Erik Aaseng Naseem Iqbal Christian A. Sperger
Anne Fiksdahl
PII:
S0022-1139(14)00038-4
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.01.019
FLUOR 8266
To appear in:
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Received date:
Revised date:
Accepted date:
28-11-2013
24-1-2014
29-1-2014
Please cite this article as: J.E. Aaseng, N. Iqbal, C.A. Sperger, A. Fiksdahl,
3-Fluorotetrahydropyran-4-one derivatives from homopropargyl acetal, Journal of
Fluorine Chemistry (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.01.019
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*Graphical Abstract - Pictogram
Graphical Abstract
Page 1 of 12

*Graphical Abstract - Synopsis
Graphical Abstract (brief synopsis)
A one-pot gold(I)-catalysed regioselective method for the preparation of 3-fluoro-tetrahydropyran-4-
one derivatives from homopropargyl acetal is described. The transformation is based on a Petasis-
Ferrier rearrangement and a subsequent electrophilic fluorination. The 3-fluoro-pyran-4-one product
acts as a protected precursor of alkylfluoro-α,β-(E)-unsaturated ketone.
Page 2 of 12

*Highlights (for review)
Highlights:




We report a one-pot gold(I)-catalysed regioselective method for the preparation of 3-fluoro-
tetrahydropyran-4-one derivatives from homopropargyl acetal.
The 3-fluoro-pyran-4-one product may act as a protected precursor of alkylfluoro-α,β-(E)-unsaturated
ketone.
The mechanism of the transformation is based on a Petasis-Ferrier rearrangement and a subsequent
electrophilic fluorination.
The corresponding hemiacetals were not suitable substrates in the one-pot cyclization-fluorination
protocol.
Page 3 of 12

*Manuscript
SHORT COMMUNICATION
3-Fluorotetrahydropyran-4-one derivatives from homopropargyl acetal
Jon Erik Aaseng, Naseem Iqbal, Christian A. Sperger and Anne Fiksdahl*
Department of Chemistry, Norwegian University of Science and Technology, NTNU, Høgskoleringen,
NO-7491 Trondheim, Norway
Corresponding author: Anne Fiksdahl; E-mail: anne.fiksdahl@chem.ntnu.no; ph: (+47) 73594094
Abstract:
A gold(I)-catalysed regioselective method for the preparation of 3-fluoro-tetrahydropyran-4-one derivatives from
homopropargyl acetal is reported. A one-pot procedure based on a gold(I)-catalysed Petasis-Ferrier
rearrangement /cyclization and subsequent fluorination was developed. The 3-fluoro-pyran-4-one compound acts
as a protected precursor of alkylfluoro-α,β-(E)-unsaturated ketone, which was readily obtained by ring-cleavage.
Corresponding hemiacetals were not suitable substrates for the formation of the 3-halo-pyran derivatives. The
present transformation would represent a useful method to readily afford highly substituted 3-fluoro-
tetrahydropyran-4-ones.
Keywords: propargyl acetals / Gold / Petasis-Ferrier rearrangement /3-fluorinated tetrahydropyran-4-ones / fluoro-α,β-
unsaturated ketone.
Graphical Abstract
Highlights:

We report a one-pot gold(I)-catalysed regioselective method for the preparation of 3-fluoro-tetrahydropyran-4-one
derivatives from homopropargyl acetal.


The 3-fluoro-pyran-4-one product may act as a protected precursor of alkylfluoro-α,β-(E)-unsaturated ketone.
The mechanism of the transformation is based on a Petasis-Ferrier rearrangement and a subsequent electrophilic
fluorination.

The corresponding hemiacetals were not suitable substrates in the one-pot cyclization-fluorination protocol.
Submitted to the Journal of Fluorine Chemistry
1
Page 4 of 12

1. Introduction
We have recently investigated a variety of cyclization pathways of propargyl substrates, in particular propargyl acetals,
taking place by gold(I) catalysed reactions with vinylic compounds [1a-c]. Such propargyl derivatives are known to undergo
gold(I)-catalysed migration-fragmentations to give gold carbenoid intermediates which can be trapped with different
reagents, typically alkenes, to give different cycloaddition products. We have seen that the reaction pathway switches by
changing from propargylic esters to acetals. In contrast to the regular olefin cyclopropanation [1a] normally taking place
with propargyl esters, an atypical cyclopentenylation by a [2+3] cycloaddition reaction is the favoured reaction pathway for
the respective acetals [1b]. Our recent studies have also shown that propargyl acetals undergo gold[I]-catalysed [2+5]
cycloadditions with benzaldimines to afford benz[c]azepine products [1c]. An essential feature of the propargyl acetals was
their significantly higher reactivity relative to corresponding propargyl esters.
Homopropargylic derivatives are also versatile substrates for gold(I)-catalysed reactions. Gold(I)-catalysed cyclization of
homopropargyl substrates includes transformation of the respective alcohol [2a], ether [2b], amine [2c-e], amide [2f]
carbonate [2g-h], azide [2i], sulfoxide [2j] as well as acetal [2k] homopropargyl derivatives. Such reactions often take place
by simple 5-exo-dig or 6-endo-dig attack of the present heteroatom on the gold(I) activated alkyne moiety to give five- or
six-membered heterocyclic products, as demonstrated by the gold-catalysed oxycyclizations of alkynols for the preparation
of pyran derivatives [2l-m].
In contrast to the general 5-exo-dig or 6-endo-dig cyclizations of homopropargyl substrates, the gold(I)-catalysed Petasis-
Ferrier rearrangement of homopropargyl (hemi)acetals takes place by inclusion of the acetal moiety in the final cyclic
skeleton. This method has been developed for the cycloisomerization-rearrangement of homopropargyl hemiacetals (I) to
give a range of tetrahydropyran-4-ones (II, Scheme 1a) [2k]. Gold-catalysed Petasis-Ferrier rearrangements have also been
applied on propargyl substrates to afford benzo[b]oxepin-3(2H)-ones [3] and benzo[b]azepin-3-ones [4] from 2-(prop-2-
ynyloxy)- and 2-(N-(prop-2-ynyl)-N-tosylamino-benzaldehydes, respectively.
The introduction of fluorine in potential drug candidates can give improvements of biological properties [5-7]. Such
potential effects on biological activity have resulted in a dramatic increase in the interest for fluorinated drugs and
precursors, such as α-fluoro ketones [8-14] which also have been prepared by gold catalysis [15], as shown by the gold(I)-
catalysed alkoxyhalogenation [16] to give dihydro-α-fluoro-pyranones.
As tetrahydropyran-4-ones (Scheme 1) are valuable intermediates for the synthesis of a large variety of biologically active
compounds [17], we wanted to apply our experience on the highly reactive propargyl acetals to study gold(I)-catalysed
cyclization reaction of the extended homopropargyl acetal systems based on the Petasis-Ferrier rearrangement. In order to
include the incorporation of fluorine in pyran derivatives, we were aiming at developing one-pot procedures, combining
acetal formation, cyclization and halogenation. We herein report our investigations on such gold catalysed reactions to afford
highly substituted fluorinated pyran-4-one derivatives (Scheme 1b).
2. Results and Discussion
2.1. Petasis-Ferrier rearrangement and substrates.
Our studies on propargyl Petasis-Ferrier rearrangements were mainly carried out on arylhomopropargyl acetal 2 (Scheme
1b), while previous studies [2k] were based on alkylhomopropargyl substrates with a hemiacetal functionality (I, 4-
(ethoxyalkyl)oxy, Scheme 1a). In contrast to the hemiacetals (I), affording an additional stereogenic centre and
diastereomeric tetrahydropyran-4-one products, the corresponding cyclization of acetals (e.g. 2) would not afford
diastereomeric products (e.g. 7).
The proposed mechanism (Scheme 1a) [2k] involves oxycyclization of the hemiacetal and the gold(I)-activated alkyne
moieties in substrate I to give a vinyl gold(I) intermediate. A subsequent Petasis-Ferrier rearrangement by a ring-opening-
ring-closure process would proceed via an enolic gold(I) complex, favouring the cis-product. De-auration and a final
hydrolysis of vinyl ether II’ would regenerate the gold(I) catalyst and afford the tetrahydropyran-4-one product II.
Submitted to the Journal of Fluorine Chemistry
2
Page 5 of 12

Scheme 1. Gold(I)-catalysed cyclization reactions of homopropargyl (hemi)acetals
In our present study (Scheme 2), the homopropargyl alcohol precursor 1 was prepared in high yield (94%) by a Barbier type
propargylation of the appropriate benzaldehyde by a reactive zinc-cupper couple [18]. The homopropargyl methyl acetal 2
(66%) and the ethyl hemiacetal 3 (54%) were generated according to literature [19], while the preparation of the bromo-
analogue 4 (45%) was based on a modified literature protocol, including NBS [20]. Similar formation of the fluoro-analogue
[21], replacing NBS with Selectfluor, was unsuccessful.
2.2 Two-step process
Gold (I)-catalysed cyclization of homopropargyl acetal 2 afforded the tetrahydropyran-4-one products 7 (50%) by Petasis-
Ferrier rearrangement. Similar highly substituted tetrahydropyranones have been prepared by intramolecular hetero-Michael
addition of β-hydroxyenones [22]. The reaction was carried out in DCM at room temperature and was completed in 15 min
in the presence of 5 mol% of (acetonitrile)-[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate (5). In previous
analogues methods [2k] of propargyl hemiacetals (I, Scheme 1a), an additional one hour treatment with p-TsOH have been
required to afford hydrolysis of the vinyl ether precursor II’ to give the final tetrahydropyran-4-one products (II).
In order to selectively afford the vinyl methyl ether product 6 (77%), similar to the suggested precursor II’ in Scheme 1a, the
work-up procedure was altered by including a basic quench with NEt3. The vinyl pyran derivative 6 also readily provided
ketone 7 (60%) by treatment with p-TsOH (30 mol%). Gold-catalysed cyclization of hemiacetal 3 to produce ketone 8 (50%)
proved to be less reproducible and provided a more complex reaction mixture. The potential effect of triethylamine in the
work-up was not as distinct as for the first reaction.
A one-pot procedure from homopropargyl alcohol, including acetal formation and the subsequent cyclization, successfully
afforded product 6 in approximately the same yield (40%) as by preparation in two steps (50%). The bromo-analogues
hemiacetal 4 was unreactive and failed to undergo cyclization, probably due to the deactivating effect of the bromo-ethoxy
group in the initial oxycyclization step (Scheme1).
To adjust reaction conditions for further fluorination, which would require more polar solvents to dissolve the electrophilic
halogenation agent, test reactions were carried out, replacing DCM by alternative solvents, such as acetonitrile and
nitromethane. Nitromethane appeared to be a suitable alternative solvent, affording 70% of product 6 from acetal 2.
Reactions in acetonitrile gave complex product mixtures.
Direct fluorination of vinyl methyl ether 6 was performed with Selectfluor in nitromethane at room temperature. The
fluorination took place in a 3-regioselective manner and the 3-fluoro diastereomeric products 9a/9b (75% total yield) were
obtained from vinyl ether 6 in a 56:44 ratio, applying one equivalent of Selectfluor. Minor amount (9%) of the 3-fluoro-keto
product 10 was isolated, as well.
Submitted to the Journal of Fluorine Chemistry
3
Page 6 of 12

Scheme 2. Gold(I) promoted cyclization and fluorination of homopropargyl acetals
2.3. One-pot method
The compatibility of different gold catalysts with electrophilic halogenation reagents has previously been demonstrated [15,
16, 23]. Based on our introductory results, we were aiming at developing a one-pot procedure for the preparation of
fluorinated pyran derivatives. Introductory, we also carried out a study on the development of analogous one-pot protocols
for the corresponding Br- and I-pyran-4-ones [25].
Applying the combined [Au]-Selectfluor (1 equiv.) system, the 3-fluorinated pyran derivatives 9a/9b (45%) were obtained
from acetal 2 in slightly lower yield than by the corresponding two-step protocol (58%). Attempts to synthesise di-/poly-
fluorinated pyran derivatives were not promising, as such reaction with [Au]-Selectfluor (1-2 equiv.) seemed to afford
complex mixtures of mono-/difluorinated regio- and diastereomers. Also attempts to include the acetal formation step in a
potential three-step one-pot process from alcohol 1 to the fluorinated products 9a/9b were unsuccessful, as complex product
mixtures were obtained.
Through introductory studies, we successfully prepared brominated and iodinated pyran-4-one products, applying the
corresponding [Au]-NBS and [Au]-NIS systems [25]. Also, the combined [Au]-NIS principle has previously been used for
gold(I)-catalysed iodoalkoxylation of allenes, but failed to afford corresponding fluoro-incorporation with [Au]-Selectfluor
[24]. This is in contrast to our successful fluoro-incorporation with the combined [Au]-Selectfluor reagent systems applied
on the homopropargyl substrates. All the cyclizations, halogenations and the one-pot reaction were carried out within 15
min at room temperature, showing the high reactivity of both the homopropargyl acetal 2 and the pyran vinyl ether derivative
6 to undergo cyclization and fluorination, respectively. It seemed to be essential for successful one-pot reactions that the
substrate and the gold(I) catalyst were mixed prior to the addition of the Selectfluor halogenation reagent.
Attempts to provide the corresponding fluoro-cyclization-product, analogous to compound 9, in one-pot from hemiacetal 3
via pyranone intermediate 8, applying the [Au]-Selectfluor system, were unsuccessful, and the internally ethoxy-substituted
1-ethoxybut-3-ynyl product was formed as the major product [25]. As the gold-catalysed cyclization of hemiacetal 3 also
proved to be less reproducible (above), the homopropargyl hemiacetal turned out not to be a suitable substrate for the present
one-pot preparation of fluorinated pyran derivatives. We have previously observed that the propargyl ethyl hemiacetal
moiety may give deviating reactivity to afford different products [1c].
Submitted to the Journal of Fluorine Chemistry
4
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2.4. Acidic hydrolysis; product modification
The 3-fluorination reactions proceeded regioselectively through double-bond isomerization, as shown by the transformation
of the 3,4-vinyl ether 6 into the 3-fluoro-4,5-vinyl ethers (9, Scheme 2). As the vinyl pyran derivative 6 was readily
hydrolysed to provide ketone 7 by treatment with 30 mol% p-TsOH, compound 6 was treated with CSA or TFA at 0 0C
(Scheme 3) in order to test whether a double-bond isomerization of the non-halogenated precursors would take place by acid
catalysis. No isomerization into the 4,5-vinyl ether was observed, but some amounts of ketone 7 were detected. Thus, the
3,4- to 4,5-double-bond isomerization is only favoured through the halogenation process.
The fluorinated pyran product 9b was also treated with p-TsOH with the purpose of performing hydrolysis. The 3-fluoro
compound was more stable towards p-TsOH (30 mol%) hydrolysis than the non-fluorinated precursor 6, and no conversion
of the substrate was observed in 20 hrs (Scheme 3). On the other hand, by applying two equivalents of p-TsOH, the
hydrolysis of fluoro-compound 9b was successful. However, the instability of the hydrolysis product 9’ was demonstrated by
the fact that a subsequent ring cleavage instantly took place and the -fluoro conjugated keto product 11 (60%) was formed
as the major product with exclusive E-selectivity. Treatment of 3-fluoropyran 9b with TFA or CSA also failed to give
selective hydrolysis and the formation of the open-chained product 11 was observed, as well.
Scheme 3. Acid catalysed transformations of pyran derivatives
2.5. Fluoroalkyl (E)-α,β-unsaturated ketones
are important structures, present in many bioactive agents [14]. To the best of our knowledge, the presently described method
for preparation of the 4-fluoro-4-alkyl-(E)-alkene-3-one moiety from homopropargyl acetal, represented in product 11
(Scheme 4a), has not previously been reported. Basically, this new transformation includes both alkylation and fluorination
of the terminal 4-propargyl position. The 3-fluoro-pyran compound 9 represents a protected version of the fluoro-α,β-
unsaturated ketone 11. Fluoroalkyl (E)-α,β-unsaturated ketones have previously been prepared from allenyl carbinol esters
by gold catalytic acyloxy shift and subsequent reaction with Selectfluor (Scheme 4b)[14].
Scheme 4. Gold-catalysed transformations into fluoroalkyl (E)-α,β-unsaturated ketones
Submitted to the Journal of Fluorine Chemistry
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3. Conclusion
We have demonstrated the preparation of 3-fluoro-pyran-4-one derivative 9 from homopropargyl acetal 2 based on a gold(I)-
catalysed Petasis-Ferrier rearrangement / cyclization and subsequent regioselective 3-fluoro incorporation. Both a one-pot
protocol and a two-step procedure via the tetrahydropyran-4-one product 6 successfully afforded the fluoro-product 9.
Tetrahydropyran-4-one 6 could also be prepared in one-pot from homopropargyl alcohol 1 via acetal 2. The corresponding
homopropargyl hemiacetal 3 turned out not to be a suitable substrate for the formation of the 3-fluoro-pyran derivatives.
The present method may be useful to afford highly substituted 3-fluoro-tetrahydropyran-4-ones. 3-Fluoro-pyran-4-one
derivative 9 acts as a protected derivative of alkylfluoro-α,β-unsaturated ketone 11, which was readily obtained by acid
catalysed ring-cleavage. Such fluorinated products may be interesting as potential bioactive compounds or drug precursors.
4. Experimental
4.1. General
All reactions were performed under argon atmosphere. Commercial grade reagents were used as received. Dry solvents were
collected from a MB SPS-800 solvent purification system. All reactions were monitored by GLC and thin-layer
chromatography (TLC) using E. Merck silica gel 60 F254 (0.25 mm thickness). Flash chromatography was carried out using
Merck silica gel 60 (0.040-0.063 mm). High Throughput Flash Purification (HPFP) (SUPELCO®) was performed on
1
prepacked cartridges (VersaPak™). H and 13C NMR spectra were recorded using a Bruker Avance DPX 300 or 400 MHz
spectrometer, respectively. Chemical shifts are reported in ppm () downfield from tetramethylsilane (TMS) as internal
standard. Coupling constants (J) are reported in hertz (Hz). The attributions of the chemical shifts were determined by means
of COSY, HMQC and HMBC experiments. Melting points (m.p.) were determined using a Stuart apparatus. High resolution
mass spectra (HRMS) were determined with an Agilent 6520 QTOF MS instrument equipped with a MAT 95XL
(TermoQuest Finnigan) MS instrument. IR spectra were obtained with a Nicolet 20SXC FT-IR spectrometer by using a
Smart Endurance reflexion cell. (Acetonitrile)[(2-biphenyl)di-tert-butyl-phosphine)gold(I) hexafluoroantimonate (5) was
purchased from Aldrich. 1-(4-Methoxyphenyl)but-3-yn-1-ol (1) [24] was prepared according to an adopted procedure
described by Ma et al.[18].
4.2. 1-Methoxy-4-(1-(2-methoxypropan-2-yloxy)but-3-ynyl)benzene (2)
The title compound was prepared by a modified procedure described by Zhang and Zhang [19]. A solution of the
homopropargylic alcohol 1 (590 mg, 3.35 mmol) in 2-methoxy-propene (3.5 ml) was cooled to 0 ºC. PPTS (20 mg, 3 mol%)
was added, and the reaction continued for 20 min. The ice bath was removed and the reaction continued for 2 hours. The
reaction mixture was diluted with DCM (40 ml) and washed with water (2 x 20 ml) and brine (20 ml). The combined organic
layers were dried (MgSO4), filtered and concentrated. The residue was purified through silica gel flash column (VersaFlash)
chromatography (1% EtOAc in n-pentane). Compound 2 was obtained in 66% (549 mg) yield as a colourless oil; Rf = 0.40
(5% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.5 Hz, 2H, HAr), 6.86 (d, J = 8.9 Hz, 2H, HAr), 4.80 (t,
J = 6.7 Hz, 1H, OCH), 3.80 (s, 3H, CH3OAr), 3.12 (s, 3H,CH3O), 2.65 (ddd, J = 16.7, 6.2, 2.7 Hz, 1H, CH2), 2.51 (ddd, J =
16.6, 7.2, 2.7 Hz, 1H, CH2), 1.93 (t, J = 2.6 Hz, 1H, Halkyne), 1.41 (s, 3H, CH3C), 1.15 (s, 3H, CH3C). 13C NMR (100 MHz,
CDCl3) δ 158.8 (CAr), 135.7 (CAr), 127.6 (CAr), 113.5 (CAr), 101.2 (OCO), 81.4 (CH2Calkyne), 71.2 (HCCAr), 70.1 (HCalkyne),
55.2 (CH3OCAr), 49.4 (CH3O), 29.2 (CH2), 26.0 (CH3C), 25.1 (CH3C). IR (neat, cm-1) 3289 (w), 2991 (w), 1612 (w), 1512
(s), 1244 (s), 1146 (m), 1029 (s). HRMS (ESI) calcd for C12H17O3 (M-C3H3)+ 209.1172, obsd 209.1175.
4.3. 1-(1-(1-Ethoxyethoxy)but-3-ynyl)-4-methoxybenzene (3)
The title compound was prepared by a modified procedure described by Zhang and Zhang.4 A solution of the
homopropargylic alcohol 1 (423 mg, 2.40 mmol) in ethyl-vinyl ether (3 ml) at 0 ºC was added PPTS (24 mg, 4 mol%), and
the reaction was stirred for 17 hrs, as the temperature gradually increased towards rt. The reaction mixture was diluted with
DCM (30 ml) and washed with water (2 x 20 ml) and brine (20 ml). The combined organic layers were dried (MgSO4),
filtered and concentrated. The residue was purified by flash (VersaFlash) chromatography (3% EtOAc in n-pentane) to give
1
3 (322 mg, 54%; diastereomeric mixture) as a colourless oil; Rf = 0.39 (5% EtOAc in n-pentane). H NMR (400 MHz,
CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H, HAr), 7.27 (d, J = 8.9 Hz, 2H, HAr), 6.88 (d, J = 8.7 Hz, 2H, HAr), 6.87 (d, J = 8.7 Hz, 2H,
HAr), 4.80 (q, J = 5.5 Hz, 1H, OCHO), 4.74 (t, J = 6.8 Hz, 1H, OCHCAr), 4.63 (t, J = 6.7 Hz, 1H, OCHCAr), 4.56 (q, J = 5.4
Hz, 1H, OCHO), 3.81 (s, 3H, CH3O), 3.66-3.52 (m, 2H, CH2CH3), 3.29-3.17 (m, 2H, CH2CH3), 2.77-2.62 (m, 2H,
CH2Calkyne), 2.60-2.47 (m, 2H, CH2Calkyne), 1.95 (t, J = 2.6 Hz, 1H, HCalkyne), 1.94 (t, J = 2.6 Hz, 1H, HCalkyne), 1.29 (d, J =
5.3 Hz, 3H, CH3CH), 1.24 (d, J = 5.5 Hz, 3H, CH3CH), 1.19 (7, J = 7.0 Hz, 3H, CH3CH2), 1.04 (7, J = 7.1 Hz, 3H, CH3CH2).
13C NMR (100 MHz, CDCl3) δ 159.4 (CAr), 159.2 (CAr), 134.1 (CAr), 133.0 (CAr), 128.1 (CAr), 127.7 (CAr), 113.7 (CAr), 113.6
(CAr), 99.4 (OCO), 97.7 (OCO), 81.1 (CH2Calkyne), 75.6 (OCCAr), 75.5 (OCCAr l), 70.0 (HCalkyne), 69.9 (HCalkyne), 61.2
(CH3CH2O), 59.4 (CH3CH2O), 55.2 (CH3O), 28.2 (CH2Calkyne), 20.4 (CH3CH), 20.2 (CH3CH), 15.4 (CH3CH2), 15.0
Submitted to the Journal of Fluorine Chemistry
6
Page 9 of 12

(CH3CH2). IR (neat, cm-1) 3292 (w), 2977 (w), 1612 (m), 1512 (s), 1245 (s), 1173 (m), 1028 (s). HRMS (ESI) calcd for
C12H17O3 (M-C3H3)+ 209.1172, obsd 209.1171.
4.4. 1-(1-(2-Bromo-1-ethoxyethoxy)but-3-ynyl)-4-methoxybenzene (4)
The title compound was prepared by a modified procedure described by Panday et al.[5]. N-Bromosuccinimide (293 mg,
1.65 mmol) was dissolved in dichloromethane (3 ml), cooled to -25 ºC and added ethyl-vinyl ether (150 μl, 1.57 mmol).
After one hour, a solution of homopropargylic alcohol 1 (415 mg, 2.34 mmol) in dichloromethane (0.5 ml) was added. The
temperature was left to rise slowly towards room temperature for 18 h. After removal of solvent, the crude mixture was re-
dissolved in diethyl ether (50 ml) and washed with water (30 ml) and brine (30 ml). The organic phase was dried over
MgSO4. The residue was purified through silica gel flash column chromatography (3% EtOAc in n-pentane). Compound 4
was obtained in 45% yield (347 mg, diastereomeric mixture) as colourless oil; Rf = 0.41 (5% EtOAc in n-pentane). 1H NMR
(400 MHz, CDCl3) δ 7.30 (d, J = 9.0 Hz, 2H, HAr), 7.29 (d, J = 8.9 Hz, 2H, HAr), 6.89 (d, J = 8.9 Hz, 2H, HAr), 6.88 (d, J =
8.9 Hz, 2H, HAr), 4.78 (dd, J = 4.8, 4.2 Hz, 1H, OCHO), 4.74 (t, J = 7.0 Hz, 1H, OCHCAr), 4.66 (t, J = 6.7 Hz, 1H, OCHCAr),
4.54 (t, J = 5.5 Hz, 1H, OCHO), 3.82 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 3.74-3.46 (m, 2H, CH2CH3), 3.45-3.22 (m, 2H,
CH2Br), 2.80-2.68 (m, 2H, CH2Calkyne), 2.62-2.50 (m, 2H, CH2Calkyne), 1.97 (t, J = 2.7 Hz, 1H, HCalkyne), 1.96 (t, J = 2.6 Hz,
1H, HCalkyne), 1.23 (t, J = 7.0 Hz, 3H, CH3CH), 1.05 (t, J = 7.1 Hz, 3H, CH3CH2). 13C NMR (100 MHz, CDCl3) δ 159.7 (CAr),
159.5 (CAr), 133.1 (CAr), 131.8 (CAr), 128.3 (CAr), 127.9 (CAr), 113.9 (CAr), 113.8 (CAr), 101.3 (OCO), 98.9 (OCO), 80.8
(CH2Calkyne), 77.1 (OCCAr), 76.4 (OCCAr), 70.3 (HCalkyne), 70.1 (HCalkyne), 62.8 (CH3CH2O), 61.3 (CH3CH2O), 55.3 (CH3O),
32.4 (CH2Br), 31.8 (CH2Br), 28.1 (CH2Calkyne), 28.0 (CH2Calkyne), 15.3 (CH3CH2), 14.8 (CH3CH2). IR (neat, cm-1) 3296 (w),
2976 (w), 1611 (w), 1512 (s), 1247 (s), 1174 (m), 1109 (m), 1028 (s). HRMS (ESI) calcd for C12H16O3Br (M-C3H3)+
287.0277, obsd 287.0275.
4.5. General procedure for gold(I)-catalysed reactions (applied in Sections 4.6-8, 4.9b):
The gold catalyst 5 was dissolved in half of the total amount of dry solvent. Homopropargyl acetal was dissolved in the other
half of the dry solvent, and added under vigorous stirring (c = 100 mM). After 15 min, the reaction mixture was added
triethylamine (4-5 drops) prior to filtration, or was alternatively filtered directly. Purification of the crude product was
performed by column chromatography.
4.6. 4-Methoxy-2-(4-methoxyphenyl)-6,6-dimethyl-3,6-dihydro-2H-pyran (6)
The gold catalyst (5) (8.3 mg, 5 mol%) was dissolved in dry dichloromethane (1.0 ml) and added a solution of acetal 2 (52
mg, 0.21 mmol) in dichloromethane (1.0 ml). After 15 min of vigorous stirring, the solution was added triethylamine (4
drops) and subsequently filtered through Celite. The concentrated crude material was purified by flash (VersaFlash)
chromatography (3% EtOAc in n-pentane) to afford 6 (40 mg, 77%) as a colourless oil; Rf = 0.40 (3% EtOAc in n-pentane).
1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.7 Hz, 2H, HAr), 6.89 (d, J = 8.7 Hz, 2H, HAr), 4.74 (dd, J = 10.8, 3.3 Hz, 1H, H-
2), 4.61 (d, J = 1.9 Hz, 1H, H-5), 3.80 (s, 3H, CH3OCAr), 3.55 (s, 3H,CH3O), 2.38 (ddd, J = 16.1, 10.8, 2.0 Hz, 1H, H-3),
2.14 (dd, J = 16.1, 3.3 Hz, 1H, H-3), 1.36 (s, 6H, (CH3)2C). 13C NMR (100 MHz, CDCl3) δ 159.0 (CAr), 152.3 (C-4), 134.6
(CAr), 127.5 (CAr), 113.8 (CAr), 101.7 (C-5), 73.4 (C-6), 70.5 (C-2), 55.3 (CH3OCAr), 54.0 (CH3O), 35.3 (C-3), 31.3 (CH3C),
27.3 (CH3C). IR (neat, cm-1) 2969 (w), 1672 (m), 1614 (m), 1513 (s), 1382 (m), 1246 (s), 1210 (s), 1077 (s), 1027 (s).
HRMS (ESI) calcd for C15H20O3 (M+) 248.1407, obsd 248.1404.
4.7. 6-(4-Methoxyphenyl)-2,2-dimethyldihydro-2H-pyran-4(3H)-one (7)
Gold catalyst 5 (8.9 mg, 5 mol%) was dissolved in dry dichloromethane (1.3 ml) and added a solution of acetal 2 (57 mg,
0.23 mmol) in dichloromethane (1 ml). After 15 min of vigorous stirring, the solution was filtered through Celite. The
concentrated crude material was purified by flash (VersaFlash) chromatography (5% EtOAc in n-pentane) to afford 7 (27 mg,
50%) as a colourless solid; m.p 58-60 ºC; Rf = 0.09 (5% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.7
Hz, 2H, HAr), 6.90 (d, J = 8.9 Hz, 2H, HAr), 4.85 (t, J = 7.2 Hz, 1H, H-6), 3.80 (s, 3H, CH3OCAr), 2.54 (d, J = 13.6 Hz, 1H,
H-3), 2.52 (d, J = 7.5 Hz, 2H, H-5), 2.36 (d, J = 13.4 Hz, 1H, H-3), 1.45 (s, 3H, CH3C), 1.30 (s, 3H, CH3C). 13C NMR (100
MHz, CDCl3) δ 207.7 (C-4), 159.4 (CAr), 133.5 (CAr), 127.2 (CAr), 114.0 (CAr), 75.6 (C-2), 72.7 (C-6), 55.3 (CH3O), 53.2 (C-
3), 49.5 (C-5), 31.1 (CH3C), 24.0 (CH3C). IR (neat, cm-1) 2971 (w), 1713 (s), 1613 (w), 1513 (s), 1240 (s), 1169 (m), 1033
(s). HRMS (ESI) calcd for C14H19O3 (M+H)+ 235.1329, obsd 235.1328.
4.8. 2-(4-Methoxyphenyl)-6-methyldihydro-2H-pyran-4(3H)-one (8)
Gold catalyst 5 (10 mg, 5 mol%) was dissolved in dry dichloromethane (1.4 ml) and added a solution of acetal 3 (60 mg,
0.24 mmol) in dichloromethane (1 ml). After 15 min of vigorous stirring, the solution was filtered through Celite. The
concentrated crude material was purified by flash (VersaFlash) chromatography (5% EtOAc in n-pentane) to give 8 (27 mg,
50%) as a colourless oil; Rf = 0.24 (10% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H, HAr),
6.91 (d, J = 8.7 Hz, 2H, HAr), 4.60 (t, J = 7.2 Hz, 1H, H-2), 3.97-3.84 (m, 1H, H-6), 3.81 (s, 3H, CH3OCAr), 2.57 (d, J = 7.5
Hz, 2H, H-5), 2.46 (dd, J = 14.3, 2.8 Hz, 1H, H-3), 2.36 (dd, J = 14.4, 11.0 Hz, 1H, H-3), 1.40 (d, J = 6.2 Hz, 3H, CH3C).
13C NMR (100 MHz, CDCl3) δ 207.1 (C-4), 159.7 (CAr), 133.0 (CAr), 127.1 (CAr), 114.1 (CAr), 78.5 (C-2), 73.6 (C-6), 55.3
(CH3O), 49.4 (C-3), 49.3 (C-5), 22.2 (CH3C). IR (neat, cm-1) 2970 (w), 1719 (s), 1612 (m), 1513 (s), 1246 (s), 1175 (s), 1032
(s). HRMS (ESI) calcd for C13H16O3 (M+) 220.1094, obsd 220.1096.
Submitted to the Journal of Fluorine Chemistry
7
Page 10 of 12

4.9. 3-Fluoro-4-methoxy-6-(4-methoxyphenyl)-2,2-dimethyl-3,6-dihydro-2H-pyran (9a/9b)
Method a: Synthesis from dihydropyran 6 above:
Selectfluor (29 mg, 1 equiv) in nitromethane (0.5 ml), at room temperature, was added a solution of dihydropyran 6 (20 mg,
0.081 mmol) in nitromethane (0.5 ml). TLC indicated full conversion after 7 min, but the reaction was continued for a total
of 15 min. The reaction was added a saturated sodium bicarbonate solution (16 ml) and dichloromethane (16 ml). The
separated organic phase was dried over MgSO4. The concentrated crude material was purified by silica (VersaFlash)
chromatography (3% EtOAc in n-pentane) to afford a total yield of 75% (16 mg) of 9a/9b (ratio 56:44). Pure samples of 9a
and 9b were isolated from the mixture for further characterization. Minor amounts (< 10%) of the keto-product 10 were also
isolated.
Method b: One pot synthesis from acetal 2
Gold catalyst 5 (8.0 mg, 5 mol%) was dissolved in dry nitromethane (1.0 ml) and added a solution of acetal 2 (50 mg, 0.20
mmol) in nitromethane (1.0 ml). After 3 min stirring, Selectfluor (71 mg, 1 equiv.) was added in one portion. The reaction
continued for a total of 15 min, and filtered through Celite with the aid of dichloromethane (15 ml). A total yield of 45% (24
mg) of 9a/9b (ratio 53:47) was obtained. Pure samples of 9a and 9b were isolated from the mixture for further
characterization.
9a: Rf = 0.41 (5% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2H, HAr), 6.88 (d, J = 8.7 Hz, 2H,
HAr), 5.19 (dt, J = 5.8, 2.0 Hz, 1H, H-6), 4.84 (ddd, J = 52.3 Hz (2J(H-F)), 2.3, 0.7 Hz, 1H, H-3), 4.79 (s, 1H, H-5), 3.79 (s, 3H,
4
CH3OCAr), 3.61 (s, 3H, CH3O), 1.40 (d, J(H-F) = 3.8 Hz, 3H, CH3C), 1.38 (s, 3H, CH3C). 13C NMR (100 MHz, CDCl3) δ
159.4 (CAr), 149.8 (d, 2J(C-F) = 16.1 Hz, C-4), 134.1 (CAr), 128.7 (CAr), 113.9 (CAr), 99.8 (d, 3J(C-F) = 3.0 Hz, C-5), 88.9 (d, 1J(C-
2
3
= 181.1 Hz, C-3), 74.0 (d, J(C-F) = 19.1 Hz, C-2), 71.6 (C-6), 55.3 (CH3OCAr), 54.9 (CH3O), 27.5 (d, J(C-F) = 1.1 Hz,
F)
CH3C), 18.5 (d, 3J(C-F) = 4.0 Hz, CH3C). IR (neat, cm-1) 2936 (w), 1669 (w), 1610 (m), 1512 (s), 1248 (s), 1170 (s), 1032 (s).
HRMS (ESI) calcd for C15H19O3F (M+) 266.1313, obsd 266.1313.
9b: Rf = 0.32 (5% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H, HAr), 6.88 (d, J = 8.9 Hz, 2H,
HAr), 5.14 (d, J = 11.3 Hz, 1H, H-6), 4.84 (m, 1H, H-5), 4.36 (d, 2J(H-F) = 50.9 Hz, 1H, H-3), 3.80 (s, 3H, CH3OCAr), 3.58 (s,
3H, CH3O), 1.40 (d, 4J(H-F) = 3.0 Hz, 3H, CH3C), 1.33 (d, 4J(H-F) = 1.0 Hz, 3H, CH3C). 13C NMR (100 MHz, CDCl3) δ 160.0
(CAr), 149.3 (d, 2J(C-F) = 16.1 Hz, C-4), 133.9 (CAr), 128.8 (CAr), 114.0 (CAr), 102.1 (d, 3J(C-F) = 7.0 Hz, C-5), 88.7 (d, 1J(C-F)
179.0 Hz, C-3), 74.5 (d, 2J(C-F) = 19.0 Hz, C-2), 72.1 (d, 4J(C-F) = 3.0 Hz, C-6), 55.3 (CH3OCAr), 54.6 (CH3O), 24.7 (d, 3J(C-F)
=
=
8.0 Hz, CH3C), 21.4 (d, 3J(C-F) = 4.0 Hz, CH3C). IR (neat, cm-1) 2935 (w), 1671 (m), 1612 (w), 1513 (s), 1384 (m), 1248 (s),
1222 (s), 1171 (s), 1153 (s), 1034 (s). HRMS (ESI) calcd for C15H19O3F (M+) 266.1313, obsd 266.1313.
4.10. 3-Fluoro-6-(4-methoxyphenyl)-2,2-dimethyldihydro-2H-pyran-4(3H)-one (10)
The title compound was isolated in less than 10% from the synthesis of 9a/9b, from 6, as described above in Section 4.9a; Rf
= 0.27 (10% EtOAc in n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H, HAr), 6.91 (d, J = 8.7 Hz, 2H, HAr),
4.87 (dd, J = 8.2, 5.9 Hz, 1H, H-6), 4.83 (d, 2J(H-F) = 49.1 Hz, 1H, H-3), 3.81 (s, 3H, CH3OCAr), 2.75-2.69 (m, 2H, H-5), 1.54
(s, 3H, CH3C), 1.31 (d, J = 2.6 Hz, 3H, CH3C). 13C NMR (100 MHz, CDCl3) δ 201.5 (d, 2J(C-F) = 14.0 Hz, C-4), 159.6 (CAr),
1
2
132.1 (CAr), 127.2 (CAr), 114.1 (CAr), 96.2 (d, J(C-F) = 200.8 Hz, C-3), 78.0 (d, J(C-F) = 19.7 Hz, C-2), 72.7 (C-6), 55.4
(CH3O), 49.4 (C-5), 27.7 (CH3C), 18.4 (CH3C). IR (neat, cm-1) 2979 (w), 1737 (s), 1612 (w), 1514 (s), 1246 (s), 1172 (s),
1080 (s). HRMS (ESI) calcd for C14H17O3F (M+) 252.1156, obsd 252.1157.
4.11. (E)-4-Fluoro-5-hydroxy-1-(4-methoxyphenyl)-5-methylhex-1-en-3-one (11)
Fluorodihydropyran 9b (10 mg, 0.038 mmol) was dissolved in THF (2 ml) and added p-toluensulfonic acid monohydrate (14
mg, 2 equiv.). High conversion was observed (TLC) after 6 hrs of efficient stirring. Et3N (3-4 drops) was added prior to
filtration of the reaction mixture through Celite. The concentrated crude material was purified by flash (VersaFlash)
chromatography (10% EtOAc in n-pentane) to afford 11(5.7 mg, 60%); Rf = 0.09 (10% EtOAc in n-pentane). 1H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 15.6 Hz, 1H, H-1), 7.59 (d, J = 8.7 Hz, 2H, HAr), 7.12 (dd, J = 16.0, 4J(H-F) = 4.2 Hz, 1H, H-2),
4
6.93 (d, J = 8.9 Hz, 2H, HAr), 4.67 (d, 2J(H-F) = 48.6 Hz, 1H, H-4), 3.86 (s, 3H, CH3O), 3.11 (br s, 1H, OH), 1.34 (d, J(H-F)
=
4
2
1.7 Hz, 3H, H-6), 1.28 (d, J(H-F) = 1.7 Hz, 3H, CH3-H-5). 13C NMR (100 MHz, CDCl3) δ 198.1 (d, J(C-F) = 23.8 Hz, C-3),
162.3 (CAr), 145.5 (d, 4J(C-F) = 3.5 Hz, C-1), 130.9 (CAr), 127.0 (CAr), 117.7 (d, 3J(C-F) = 3.5 Hz, C-2), 114.5 (CAr), 98.4 (d, 1J(C-
2
3
3
= 192.5 Hz, C-4), 72.1 (d, J(C-F) = 20.5 Hz, C-5), 55.5 (CH3O), 25.9 (d, J(C-F) = 2.8 Hz, CH3C), 24.6 (d, J(C-F) = 1.5 Hz,
F)
CH3C). IR (neat, cm-1) 3466 (br), 2977 (w), 1680 (w), 1587 (s), 1569 (s), 1511 (s), 1423 (m), 1255 (s), 1171 (s), 1029 (s),
734 (s). HRMS (ESI) calcd for C14H17O3F (M+) 252.1156, obsd 252.1159.
4.12. General procedure for acid catalysed hydration of dihydropyrans 6 and 9b:
Experiments were performed with TsOH.H2O, according to the protocol described by Bae and co-workers [2k]. Weaker
acids, such as CSA and TFA were tested, as well. The amount of acid and the reaction times were also varied in modified
protocols.
Submitted to the Journal of Fluorine Chemistry
8
Page 11 of 12

Acknowledgements
We thank the The Royal Norwegian Society of Sciences and Letters and the Research Council of Norway for financial
support.
References
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Submitted to the Journal of Fluorine Chemistry
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