Au-catalyzed intramolecular hydroalkoxylation of gem-difluorinated alkynols

Article abstract of DOI:10.1016/j.jfluchem.2018.09.009

The intramolecular hydroalkoxylation of gem-difluorinated alkynols was found possible under Au catalysis, allowing for the preparation of a series of fluorinated heterocycles. The nature of the solvent was found to be especially critical in the cyclizatio

Full text of DOI:10.1016/j.jfluchem.2018.09.009

Accepted Manuscript
Title: Au-Catalyzed Intramolecular Hydroalkoxylation of
gem-Difluorinated Alkynols
Authors: Jean-Denys Hamel, Jean-Fran c¸ ois Paquin
PII:
S0022-1139(18)30356-7
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.09.009
FLUOR 9223
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Received date:
Revised date:
Accepted date:
5-9-2018
25-9-2018
26-9-2018
Please cite this article as: Hamel J-Denys, Paquin J-Fran c¸ ois, Au-Catalyzed
Intramolecular Hydroalkoxylation of gem-Difluorinated Alkynols, Journal of Fluorine
Chemistry (2018), https://doi.org/10.1016/j.jfluchem.2018.09.009
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Au-Catalyzed Intramolecular Hydroalkoxylation of gem-
Difluorinated Alkynols
Jean-Denys Hamel and Jean-François Paquin*
PROTEO, CCVC, Département de chimie, Université Laval,Québec, QC, Canada G1V
0
A6
*Corresponding author. Tel.: +1 418 656-2131 ext. 11430; fax: +1 418 656-7916
E-Mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin)
GRAPHICAL ABSTRACT

HIGHLIGHTS



The intramolecular hydroalkoxylation of gem-difluorinated alkynols was found possible
under Au catalysis.
The nature of the solvent was found to be especially critical in the cyclization of gem-
difluorohomopropargylic alcohols.
In THF, gem-difluorohomopropargylic alcohols generated the corresponding 2,3-
dihydrofurans.

In toluene, the 2,3-dihydrofurans produced underwent subsequent aromatization to
the furan.
ABSTRACT:
The intramolecular hydroalkoxylation of gem-difluorinated alkynols was found possible
under Au catalysis, allowing for the preparation of a series of fluorinated heterocycles. The
nature of the solvent was found to be especially critical in the cyclization of gem-
difluorohomopropargylic alcohols as it dictated whether the resulting 2,3-dihydrofuran
underwent subsequent aromatization to the corresponding furan or not.
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sext = sextet, m =
multiplet, bs = broad signal. High-resolution mass spectra were obtained on a LC/MS–TOF
Agilent 6210 using electrospray ionization (ESI) or atmospheric pressure photoionization
(APPI). Infrared spectra were recorded using an ABB MB3000 FT-IR spectrometer.
Melting points were recorded on a Stanford Research System OptiMelt capillary melting
point apparatus and are uncorrected.

Keywords: gold catalysis; hydroalkoxylation; cyclization; propargylic gem-difluoride;
alkynol; furan; dihydrofuran
1
.
Introduction
Recent years have seen a surge in Au-catalyzed nucleophilic addition reactions to alkynes
owing to the strong propensity of gold catalysts to selectively activate alkynes over other
functional groups [1]. Regarding O-based nucleophiles, one finds that such nucleophilic
addition reactions typically give rise to the Markovnikov product [2,3]. A consequence of
this is that transformations of terminal alkynes usually display excellent regioselectivity,
whereas the use of internal alkynes generally results in poor regioselectivity. However, the
electronic nature of the substituents bound to either side of the alkyne is known to affect
the regioselectivity [4].
We have recently shown that the introduction of fluorine atoms can affect the
course of such a nucleophilic attack on internal alkynes. Indeed, through a Au-catalyzed
hydromethoxylation/hydrolysis sequence, we observed a perfect selectivity for the
formation of 3,3-difluoroketones from propargylic gem-difluorides (Scheme 1A) [5].
Applying this method to a substrate featuring a terminal alkyne even led to a complete
reversal of selectivity to the anti-Markovnikov product, a 3,3-difluoroaldehyde. The strong
electron-withdrawing character of the fluorine atoms [6] would be at the source of those
unusual regioselectivities, a proposal backed up by DFT calculations that show significant
depletion of electron density at the carbon of the alkyne distal to the difluoromethylene
unit [5]. Now, we wished to explore the possibility to perform such a Au-catalyzed addition

of a O-nucleophile to propargylic gem-difluorides in an intramolecular fashion. More
precisely, we envisioned that exposure of gem-difluorinated alkynols to a Au catalyst might
result in ring closure and the formation of fluorinated heterocyclic compounds. Such a
cyclization has already been shown possible either in presence of a base [7] or a silver
catalyst [8] for certain gem-difluorohomopropargylic alcohols (Scheme 1B) and our efforts
towards the development of a Au-catalyzed variant are summarized herein (Scheme 1C).
2
.
Results and discussion
First, we sought to develop a general synthetic route to the required gem-
difluorinated alkynols 1 that would allow for easy variation of the substituents. Moreover,
inspired by our previous work [5], we wished to introduce the fluorine atoms via the
deoxofluorination of ynones. We figured that either diols or α-hydroxyesters could be used
as starting material for this endeavor (Scheme 2). Indeed, those could initially be converted
into mono-THP-protected diols in one or two steps, respectively. Their subsequent
oxidation to the corresponding aldehyde followed by nucleophilic addition of an acetylide
led to ynols that could next be converted to the desired ynones upon another oxidation step.
Gratifyingly, we found that the THP protecting group was compatible with the subsequent
deoxofluorination step in neat DeoxoFluor [9]. In most cases, the HF-elimination side
product was formed in small amounts and could be separated by means of silica gel
chromatography. Finally, deprotection of the THP ether could be carried out in acidic
methanol to provide the expected gem-difluorinated alkynols. Luckily, while pairs of
diastereoisomers are formed at many points, this actually never complicated purifications
to a significant extent. Overall, we succeeded in the preparation of 9 gem-difluorinated
alkynols.

Now having a series of gem-difluorinated alkynols in hand, we elected gem-
difluorohomopropargylic alcohol 1a as the model substrate for the optimization study, and
1
9
product distribution was assessed by F NMR (Table 1). We once again took inspiration
of our prior work on the formal hydration of propargylic gem-difluorides to set a starting
point [5]. This had us choose Ph
3
PAuOTf, generated in situ from Ph PAuCl and AgOTf,
3
as the catalyst. However, as we did not wish to use methanol as solvent as to avoid a
competing hydromethoxylation reaction, we opted for THF instead (entry 1). Three
different fluorinated products arose from this transformation, all resulting from
nucleophilic attack onto the alkyne at the carbon away from the fluorinated end: the
expected intramolecular hydroalkoxylation product 2a, the hydration product 3a and the
cyclization/aromatization product 4a. Of those, 2,3-dihydrofuran 2a came out as the major
product at 74% as observed by 19F NMR. Using Et
O as the solvent afforded a pretty
O in the solvent was the
2
similar product distribution (entry 2). We surmised that trace H
2
cause behind the generation of 3a. As such, we found that the addition of molecular sieve
to the reaction medium suppresses its formation with the added benefit of almost no
conversion to 4a, thus resulting in a quasi-quantitative yield of 2a (entry 3). Conversely,
going away from ethereal solvents, we found that furan 4a was formed pretty much as the
sole fluorinated product, with no trace of 2a detectable after 18 hours (entries 4-6). In
toluene, this resulted in a 80% yield of 4a (entry 6). We hypothesize that this striking
difference in behavior between THF and toluene can be related to the Lewis basicity of the
solvent. Indeed, in toluene (a very weak Lewis base), any Lewis acidic species (Au, Ag,
etc) present could potentially interact with the fluorine atoms and promote an elimination
reaction leading to the furan. In THF (a stronger Lewis base), the same Lewis acidic species

would be trapped by the solvent, thus slow down significantly this side reaction. Regarding
the cyclization to 2a, we next wished to validate the necessity for both Ph PAuCl and
AgOTf, especially since a silver salt had already been used in the cyclization of some gem-
difluorohomopropargylic alcohols [8]. On its own, Ph PAuCl was found to be non-reactive
entry 7), whereas AgOTf resulted in a clean, but slow conversion to 2a (entry 8). Further
3
3
(
refinement of the system had us find that a reaction time of 1 hour was sufficient to reach
full conversion to 2a (entry 9), which stays true even when decreasing the catalyst loading
down to 1 mol% (entry 10). The transformation is also possible at a catalyst loading of 0.1
mol%, but conversion is incomplete after 1 hour (entry 11). We thus judged conditions in
entry 10 to be optimal for the cyclization of gem-difluorohomopropargylic alcohols to 2,3-
dihydrofuran derivatives. Besides, although this was not the primary goal initially, the
success we had in the preparation of 4a with the conditions of entry 6 prompted us to keep
those conditions for the preparation of other furan derivatives. Overall, the nature of the
solvent here causes a drastic difference in selectivity towards a product or another.
a
19
Estimated by F NMR using 2-fluoro-4-nitrotoluene as an internal standard.
b
4
Å MS was added to the reaction mixture.
Having established optimal conditions for the intramolecular hydroalkoxylation of
gem-difluorohomopropargylic alcohols, we wished to study the scope of the transformation
Scheme 3A). However, we rapidly found that 2,3-dihydrofurans 2 could not be isolated
(
by means of silica gel chromatography as this triggered their decomposition, mainly to the
corresponding furan 4. This instability of similar gem-difluorinated 2,3-dihydrofurans
[
8,10] and 2,3-dihydrothiophenes [11] has already been reported. Occasionally, simple
evaporation of the crude reaction mixture led to spontaneous polymerization to dark purple

material. Unable to isolate compounds 2 [12], we thus resorted to NMR yields for the whole
series. High to excellent yields of 2 were obtained in all cases, disregarding of the nature
1
2
of R and R . The best results came from substrates for which no substituent was present α
2
to the alcohol (R = H), namely in the preparation of 2,3-dihydrofurans 2a and 2d.
At this point, we had shown that the Au-catalyzed intramolecular
hydroalkoxylation of gem-difluorohomopropargylic alcohols was a rapid and clean
process, and we wondered what the influence of a longer spacer between the
difluoromethylene unit and the alcohol would be. Gratifyingly, we found that the
cyclization of 1h, a gem-difluorinated alkynol with a two-carbon linker, was just as
efficient under the exact same reaction conditions, with formation of 3,4-dihydro-2H-pyran
2
h in a 95% NMR yield (Scheme 3B). However, we found the product to decompose to
,3-dihydro-4H-pyran-4-one 5 upon attempts at purification over silica gel. For its part, the
2
formation of a 7-membered ring via the cyclization of 1i was found to be much slower
under the standard reaction conditions as the 2,3,4,5-tetrahydrooxepine 2i was only
observed in a 4% NMR yield. However, increasing the catalyst loading to 5 mol% and
extending the reaction time to 18 hours allowed for a 52% NMR yield of 2i along with full
conversion of 1i (Scheme 3C).
Finally, we sought to extend the cyclization/aromatization protocol to each gem-
difluorohomopropargylic alcohol that we had synthesized, and although a few furans 4
were found to be somewhat unstable over time, we were nonetheless able to handle them
long enough to carry out their purification by means of silica gel chromatography (Scheme
4
). Here, the overall trend in yield is opposite to that of the cyclization in THF in the sense
that better yields were obtained for gem-difluorohomopropargylic alcohols having a

2
substituent α to the alcohol (R ≠ H). The exception to this, however, is the reaction of
1
compound 1i featuring a terminal alkyne (R = H), which places as the worst substrate for
this transformation. Multiple products appear to be formed, of which furan 2g accounts for
a mere 9%, despite full conversion of the starting material.
3
.
Conclusion
In conclusion, based on our prior knowledge on the reactivity of propargylic gem-
difluorides with O-based nucleophiles in presence of Au catalysts, we conceived that a
regioselective intramolecular hydroalkoxylation reaction might be possible, provided that
gem-difluorinated alkynols were prepared. We found that this transformation was best
carried out in THF and was efficient at the formation of 5- to 7-membered rings, but that
the cyclization products were unstable to purification. We also noticed a dramatic change
in product selectivity when the cyclization of gem-difluorohomopropargylic alcohols was
carried out in toluene, where aromatization of the expected 2,3-dihydrofuran to the
corresponding furan was found to occur readily.
4
.
Experimental
4
.1
General information
All reactions were carried out under an argon atmosphere with dry solvents. Et O,
2
THF, CH
3
CN, CH
2
Cl and toluene were purified using a Vacuum Atmospheres Inc. solvent
2
purification system. All other commercially available compounds were used as received.
Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using
Silicycle silica gel 60 Å F254 TLC plates, and visualized under UV or by staining with
either potassium permanganate, p-anisaldehyde or phosphomolybdic acid. Flash column
1
13
chromatography was carried out on Silicycle silica gel 60 Å, 230–400 mesh. H, C and

19F NMR spectra were recorded in CDCl
at room temperature using Agilent DD2 500 and
3
1
13
Varian Inova 400 spectrometers. H and C NMR chemical shifts are reported in ppm
downfield of tetramethylsilane and are respectively referenced to tetramethylsilane (δ =
1
9
0
.00 ppm) and residual solvent (δ = 77.16 ppm). For F NMR, CFCl
3
is used as the external
of gem-
standard. Multiplicities are reported using the following 4.2 Preparation
difluorinated alkynols
4
.2.1 Preparation of 2,2-difluoro-4-phenylbut-3-yn-1-ol (1a).
-((Tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (6). Ethylene glycol (2.52 mL, 45.0
mmol) was dissolved in CH Cl (92 mL) and pyridinium p-toluenesulfonate (113 mg,
.450 mmol) was added. A solution of 3,4-dihydro-2H-pyran (2.74 mL, 30 mmol) in
CH Cl (22 mL) was then added dropwise over 1 hour. The resulting mixture was stirred
at room temperature for 18 hours, after which H O was added. The organic layer was
separated, washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The
desired product (2.41 g, 55%) was isolated as a pale yellow oil by flash chromatography
using 5% MeOH/CH Cl . Spectroscopic data was in agreement with the literature [13].
-((Tetrahydro-2H-pyran-2-yl)oxy)acetaldehyde (7). To a -78 °C solution of oxalyl
chloride (1.69 mL, 19.7 mmol) in CH Cl (150 mL) was added DMSO (2.80 mL, 39.4
mmol) and stirring was continued at -78 °C for 15 minutes. A solution of alcohol 6 (2.40
g, 16.4 mmol) in CH Cl (14 mL) was slowly added and the resulting solution was stirred
at -78 °C for 15 minutes. Et N (13.7 mL, 98.5 mmol) was added, the solution was stirred
at -78 °C for 20 minutes, and then allowed to reach room temperature over 40 minutes.
Saturated NaHCO was added and stirring was continued for 30 minutes. The resulting
mixture was extracted with CH Cl (3x), dried over Na SO , filtered, and concentrated in
2
2
2
0
2
2
2
2
4
2
2
2
2
2
2
2
3
3
2
2
2
4

vacuo. The desired product (1.80 g, 76%) was isolated as a yellow oil by flash
chromatography using 20% acetone/hexanes. Spectroscopic data was in agreement with
the literature [14].
4
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-ol (8). To a -78 °C solution
of phenylacetylene (1.50 mL, 13.7 mmol) in THF (35 mL) was added n-BuLi (2.5 mol/L
in hexanes, 5.47 mL, 13.7 mmol) and the mixture was stirred at -78 °C for 30 minutes, and
then at room temperature for 30 minutes. The solution was brought back to -78 °C and a
solution of aldehyde 7 (1.79 g, 12.4 mmol) in THF (6 mL) was added. The mixture was
stirred at room temperature for 1 hour, after which saturated NaHCO
mixture was extracted with Et O (3x), washed with brine, dried over Na
3
was added. The
2
2
SO , filtered, and
4
concentrated in vacuo. The desired compound (2.64 g, 86%) was isolated as a yellow oil
by flash chromatography using 25% EtOAc/hexanes. IR (ATR, diamond) ν = 3381, 2941,
-
1 1
2
7
3
868, 2201, 1491, 1261, 1070, 1024, 756, 690 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.44-
.43 (m, 2H), 7.33-7.27 (m, 3H), 4.78-4.64 (m, 2H), 4.00-3.93 (m, 2H), 3.84-3.78 (m, 1H),
1
3
.72 (m, 0.5H), 3.58-3.56 (m, 1H), 3.35 (d, 0.5H, J = 5.7 Hz), 1.88-1.53 (m, 6H); C NMR
(CDCl
3
, 126 MHz) δ 131.88, 131.87, 128.57, 128.56, 128.4, 122.64, 122.59, 100.4, 100.3,
8
7.2, 86.7, 85.5, 73.6, 72.8, 63.5, 63.0, 62.7, 62.6, 30.8, 30.7, 25.3, 25.2, 20.0, 19.7;
+
HRMS-ESI calcd for C15
H
19
O
3
[M+H] 247.1329; found 247.1329.
4
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-one (9). To a -78 °C
solution of oxalyl chloride (1.09 mL, 12.7 mmol) in CH Cl (95 mL) was added DMSO
1.81 mL, 25.5 mmol) and stirring was continued at -78 °C for 15 minutes. A solution of
propargylic alcohol 8 (2.62 g, 10.6 mmol) in CH Cl (11 mL) was slowly added and the
resulting solution was stirred at -78 °C for 15 minutes. Et N (8.9 mL, 63.7 mmol) was
2
2
(
2
2
3

added, the solution was stirred at -78 °C for 20 minutes, and then allowed to reach room
temperature over 40 minutes. Saturated NaHCO was added and stirring was continued for
0 minutes. The resulting mixture was extracted with CH Cl (3x), dried over Na SO ,
3
3
2
2
2
4
filtered, and concentrated in vacuo. The desired product (1.93 g, 74%) was isolated as a
yellow oil by flash chromatography using 15% EtOAc/hexanes. IR (ATR, diamond) ν =
-1 1
2
943, 2199, 1688, 1670, 1489, 1259, 1202, 1034, 756, 689 cm ; H NMR (CDCl
MHz) δ 7.58 (d, 2H, J = 7.1 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.30 (t, 2H, J = 7.6 Hz), 4.79 (t,
H, J = 3.4 Hz), 4.46 (m, 2H), 3.89 (m, 1H), 3.56 (m, 1H), 1.96-1.87 (m, 1H), 1.85-1.77
3
, 500
1
1
3
(
m, 2H), 1.67-1.54 (m, 3H); C NMR (CDCl
3
, 126 MHz) δ 185.1, 133.3, 131.1, 128.8,
[M+H]+
1
2
19.8, 98.5, 93.7, 86.0, 72.6, 62.2, 30.3, 25.4, 19.0; HRMS-ESI calcd for C15
H
17
O
3
45.1172; found 245.1171.
-((2,2-Difluoro-4-phenylbut-3-yn-1-yl)oxy)tetrahydro-2H-pyran (10). Ynone 9
1.78 g, 7.30 mmol) was charged into a polypropylene vial. DeoxoFluor (3.36 mL, 18.2
2
(
mmol) was added and the mixture was stirred at 55 °C for 18 hours. It was brought back
to 0 °C, diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated
NaHCO
3
. The mixture was stirred for 30 minutes, after which the organic layer was
SO , filtered, and concentrated in vacuo. The desired compound
864 mg, 44%) was isolated as a pale yellow oil by flash chromatography using 5%
separated, dried over Na
2
4
(
Et
2
O/hexanes. IR (ATR, diamond) ν = 2943, 2872, 2239, 1491, 1315, 1067, 1036, 964,
-1 1
7
66, 689 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.52 (d, 2H, J = 7.2 Hz), 7.43 (t, 1H, J = 7.4
Hz), 7.37 (t, 2H, J = 7.4 Hz), 4.85 (t, 1H, J = 3.3 Hz), 4.07 (q, 1H, J = 12.4 Hz), 3.96-3.89
(m, 2H), 3.58 (dtd, 1H, J = 11.1, 4.1, 1.4 Hz), 1.94-1.85 (m, 1H), 1.80-1.74 (m, 2H), 1.69-
1
9
1
.53 (m, 2H); F NMR (CDCl , 470 MHz) δ -91.6 (dt, 1F, J = 277, 12.5 Hz), -92.2 (dt,
3

1
3
1
1
F, J = 277, 11.7 Hz); C NMR (CDCl
3
, 126 MHz) δ 132.3 (t, JC-F = 2.2 Hz), 130.1, 128.6,
20.2 (t, JC-F = 2.8 Hz), 112.8 (t, JC-F = 235 Hz), 98.8, 87.9 (t, JC-F = 6.8 Hz), 80.4 (t, JC-F
=
38.9 Hz), 69.0 (t, JC-F = 31.2 Hz), 61.9, 30.2, 25.4, 18.7; HRMS-ESI calcd for
+
C
15
H
16
F
2
NaO
2
[M+Na] 289.1011; found 289.1015.
2
,2-Difluoro-4-phenylbut-3-yn-1-ol (1a). PPTS (78 mg, 0.31 mmol) was added to
a solution of propargylic fluoride 10 (826 mg, 3.10 mmol) in MeOH (31 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
547 mg, 97%) was isolated as a colorless oil by flash chromatography using 20%
EtOAc/hexanes. IR (ATR, diamond) ν = 3329, 2939, 2237, 1491, 1313, 1175, 1055, 912,
3
was added. The resulting mixture was extracted with
2
2
2
4
(
-1 1
7
54, 689 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.52 (d, 2H, J = 7.2 Hz), 7.43 (t, 1H, J = 7.4
1
9
Hz), 7.37 (t, 2H, J = 7.4 Hz), 3.99 (td, 2H, J = 12.1, 7.4 Hz), 2.09 (t, 1H, J = 7.4 Hz); F
1
3
NMR (CDCl
3
, 470 MHz) δ -94.8 (t, 2F, J = 12.3 Hz); C NMR (CDCl
3
, 126 MHz) δ 132.4
(t, JC-F = 2.3 Hz), 130.3, 128.7, 119.9 (t, JC-F = 2.8 Hz), 113.2 (t, JC-F = 235 Hz), 88.7 (t, JC-
F
= 6.9 Hz), 79.6 (t, JC-F = 39.3 Hz), 66.3 (t, JC-F = 31.5 Hz); HRMS-ESI calcd for C10
8
H FO
+
[
M-F] 163.0054; found 169.0044.
4
.2.1 Preparation of 3,3-difluoro-5-phenylpent-4-yn-2-ol (1b).
Ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (11). Ethyl lactate (1.15 mL,
0.0 mmol) was dissolved in CH Cl (13 mL), after which both 3,4-dihydro-2H-pyran
1
2
2
(
1.19 mL, 13.0 mmol) and pyridinium p-toluenesulfonate (10 mg, 0.040 mmol) were
added. The resulting mixture was stirred at room temperature for 18 hours, after which
saturated NaHCO was added. The organic layer was separated, dried over Na SO ,
3
2
4

filtered, and concentrated in vacuo. The desired product (2.02 g, 100%) was isolated as a
colorless oil by flash chromatography using 15% EtOAc/hexanes. Spectroscopic data was
in agreement with the literature [15].
2
-((Tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (12). A suspension of LiAlH
mg, 22.0 mmol) in Et O (10 mL) was cooled down to 0 °C, and to it was added a solution
of ester 11 (2.02 g, 10.0 mmol) in Et O (20 mL) over 1 hour. The resulting mixture was
stirred for an additional 1.5 hours at 0 °C, after which saturated NH Cl (5 mL) was added
dropwise at 0 °C. It was stirred until no more gas evolved, and then filtered to remove the
solids, making sure to wash them thoroughly with Et O. The resulting solution was dried
over Na SO , filtered, and concentrated in vacuo. The desired product (1.56 g, 97%) was
4
(835
2
2
4
2
2
4
isolated as a yellow oil by flash chromatography using 4% MeOH/CH
data was in agreement with the literature [15].
2
Cl . Spectroscopic
2
2
-((Tetrahydro-2H-pyran-2-yl)oxy)propanal (13). To a -78 °C solution of oxalyl
chloride (0.87 mL, 10.1 mmol) in CH Cl (75 mL) was added DMSO (1.44 mL, 20.3
mmol) and stirring was continued at -78 °C for 15 minutes. A solution of alcohol 12 (3.37
g, 21.1 mmol) in CH Cl (9 mL) was slowly added and the resulting solution was stirred at
78 °C for 15 minutes. Et N (7.1 mL, 50.7 mmol) was added, the solution was stirred at -78
C for 20 minutes, and then allowed to reach room temperature over 40 minutes. Saturated
was added and stirring was continued for 30 minutes. The resulting mixture was
extracted with CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The
2
2
2
2
-
3
°
NaHCO
3
2
2
2
4
desired product (1.11 g, 83%) was isolated as a pale yellow oil by flash chromatography
using 20% acetone/hexanes. Spectroscopic data was in agreement with the literature [16].

1
-Phenyl-4-((tetrahydro-2H-pyran-2-yl)oxy)pent-1-yn-3-ol (14). To a -78 °C
solution of phenylacetylene (0.83 mL, 7.6 mmol) in THF (18 mL) was added n-BuLi (2.5
mol/L in hexanes, 3.04 mL, 7.60 mmol) and the mixture was stirred at -78 °C for 30
minutes, and then at room temperature for 30 minutes. The solution was brought back to -
7
8 °C and a solution of aldehyde 13 (1.09 g, 6.91 mmol) in THF (5 mL) was added. The
mixture was stirred at room temperature for 1 hour, after which saturated NaHCO was
added. The mixture was extracted with Et O (3x), washed with brine, dried over Na SO ,
3
2
2
4
filtered, and concentrated in vacuo. The formation of the 4 possible pairs of
diastereoisomers was confirmed by NMR analysis of the crude reaction mixture. The crude
reaction mixture was used as is in the subsequent oxidation step with the transformation
being considered quantitative.
1
-Phenyl-4-((tetrahydro-2H-pyran-2-yl)oxy)pent-1-yn-3-one (15). To a -78 °C
solution of oxalyl chloride (0.71 mL, 8.29 mmol) in CH Cl (60 mL) was added DMSO
1.18 mL, 16.6 mmol) and stirring was continued at -78 °C for 15 minutes. A solution of
crude propargylic alcohol 14 (assumed to be quantitative, 6.91 mmol) in CH Cl (9 mL)
was slowly added and the resulting solution was stirred at -78 °C for 15 minutes. Et N (5.8
mL, 41.5 mmol) was added, the solution was stirred at -78 °C for 20 minutes, and then
allowed to reach room temperature over 40 minutes. Saturated NaHCO was added and
stirring was continued for 30 minutes. The resulting mixture was extracted with CH Cl
, filtered, and concentrated in vacuo. The desired product (1.67 g,
4%) was isolated as a yellow oil by flash chromatography using 10% EtOAc/hexanes. IR
2
2
(
2
2
3
3
2
2
(
3x), dried over Na
2
SO
4
9
-1 1
(
ATR, diamond) ν = 2943, 2870, 2195, 1672, 1121, 1020, 970, 876, 758, 689 cm ; H
NMR (CDCl , 500 MHz) δ 7.61-7.58 (m, 2H), 7.50-7.45 (m, 1H), 7.41-7.38 (m, 2H), 4.82
3

(t, 0.5H, J = 3.5 Hz), 4.78 (dd, 0.5H, J = 4.4, 3.0 Hz), 4.52 (q, 0.5H, J = 7.0 Hz), 4.34 (q,
0
3
.5H, J = 6.8 Hz), 4.02 (ddd, 0.5H, J = 12.1, 9.3, 3.1 Hz), 3.90 (ddd, 0.5H, J = 11.1, 8.0,
.3 Hz), 3.57-3.49 (m, 1H), 1.99-1.70 (m, 3H), 1.66-1.54 (m, 3H), 1.53 (d, 1.5H, J = 7.1
1
3
Hz), 1.45 (d, 1.5H, J = 6.8 Hz); C NMR (CDCl
3
, 126 MHz) δ 189.8, 188.7, 133.30,
1
7
33.26, 131.1, 130.9, 128.83, 128.77, 120.3, 120.0, 98.3, 97.5, 94.2, 93.8, 86.8, 86.4, 78.1,
7.4, 62.8, 62.4, 30.7, 30.6, 25.50, 25.49, 19.4, 19.2, 18.3, 16.9; HRMS-ESI calcd for
+
C
16
H
19
O
3
[M+H] 259.1329; found 259.1322.
2
-((3,3-Difluoro-5-phenylpent-4-yn-2-yl)oxy)tetrahydro-2H-pyran (16). Ynone 15
(1.51 g, 5.83 mmol) was charged into a polypropylene vial. DeoxoFluor (2.69 mL, 14.6
mmol) was added and the mixture was stirred at 55 °C for 24 hours. It was brought back
to 0 °C, diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated
NaHCO
separated, dried over Na
608 mg) was isolated as a yellow oil by flash chromatography using 5% Et
3
. The mixture was stirred for 30 minutes, after which the organic layer was
SO , filtered, and concentrated in vacuo. The desired compound
O/hexanes,
2
4
(
2
but partial loss of the THP protecting group occurred after evaporation. The product was
thus used as is in the subsequent THP removal step and the yield was determined over two
steps.
3
,3-Difluoro-5-phenylpent-4-yn-2-ol (1b). PPTS (55 mg, 0.22 mmol) was added to
a solution of semi-pure propargylic fluoride 16 (608 mg) in MeOH (22 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
411 mg, 36%) was isolated as a yellow oil by flash chromatography using 20%
3
was added. The resulting mixture was extracted with
2
2
2
4
(

EtOAc/hexanes. IR (ATR, diamond) ν = 3387, 2991, 2241, 1375, 1275, 1109, 1047, 987,
-1 1
7
54, 689 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.53 (d, 2H, J = 7.1 Hz), 7.43 (t, 1H, J = 7.4
Hz), 7.37 (t, 2H, J = 7.4 Hz), 4.12 (m, 1H), 2.20 (d, 1H, J = 5.4 Hz), 1.42 (d, 3H, J = 6.4
1
9
Hz); F NMR (CDCl
3
, 470 MHz) δ -95.9 (dd, 1F, J = 275, 6.9 Hz), -97.0 (dd, 1F, J = 274,
1
3
9
.9 Hz); C NMR (CDCl , 126 MHz) δ 132.4 (t, JC-F = 2.5 Hz), 130.2, 128.6, 120.0 (t, JC-
3
F
= 2.7 Hz), 115.3 (t, JC-F = 236 Hz), 88.9 (t, JC-F = 6.8 Hz), 79.3 (t, JC-F = 39.6 Hz), 70.7
10FO [M-F]+
(dd, JC-F = 30.5, 28.6 Hz), 16.5 (t, JC-F = 2.5 Hz); HRMS-ESI calcd for C11
H
1
4
77.0710; found 177.0711.
.2.3 Preparation of 2,2-difluoro-1,4-diphenylbut-3-yn-1-ol (1c).
Methyl 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (17). Methyl mandelate
3324 mg, 20.0 mmol) was dissolved in CH Cl (27 mL), after which both 3,4-dihydro-
H-pyran (2.37 mL, 26.0 mmol) and pyridinium p-toluenesulfonate (20 mg, 0.080 mmol)
(
2
2
2
were added. The resulting mixture was stirred at room temperature for 18 hours, after
which saturated NaHCO was added. The organic layer was separated, dried over Na SO ,
3
2
4
filtered, and concentrated in vacuo. The desired product (3.00 g, 60%) was isolated as a
colorless oil by flash chromatography using 15% EtOAc/hexanes. IR (ATR, diamond) ν =
-1 1
2
945, 2872, 1751, 1456, 1259, 1202, 1121, 1036, 966, 696 cm ; H NMR (CDCl , 400
3
MHz) δ 7.50-7.45 (m, 2H), 7.39-7.31 (m, 3H), 5.33 (s, 0.5 H), 5.25 (s, 0.5 H), 4.89 (t, 0.5H,
J = 3.0 Hz), 4.58 (t, 0.5H, J = 3.5 Hz), 3.95 (ddd, 0.5 H, J = 11.6, 7.8, 4.5 Hz), 3.73-3.67
1
3
(
m, 3.5H), 3.54-3.46 (m, 1H), 1.98-1.70 (m, 3H), 1.65-1.47 (m, 3H); C NMR (CDCl ,
3
1
01 MHz) δ 172.0, 171.3, 136.8, 136.4, 128.8, 128.7, 128.6, 128.5, 127.7, 127.3, 97.2,
9
6.7, 75.7, 62.5, 62.0, 52.41, 52.36, 30.4, 30.3, 25.44, 25.42, 19.2, 18.8; HRMS-ESI calcd
+
for C14
H
19
O
4
[M+H] 251.1278; found 251.1282.

2
-Phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (18). A suspension of
(993 mg, 26.2 mmol) in Et O (12 mL) was cooled down to 0 °C, and to it was
added a solution of ester 17 (2.98 g, 11.9 mmol) in Et O (24 mL) over 1 hour. The resulting
mixture was stirred for an additional 1.5 hours at 0 °C, and then at room temperature
overnight, after which saturated NH Cl (5 mL) was added dropwise at 0 °C. It was stirred
until no more gas evolved, and then filtered to remove the solids, making sure to wash them
thoroughly with Et O. The resulting solution was dried over Na SO , filtered, and
concentrated in vacuo. The desired product (2634 mg, 100%) was isolated as a pale yellow
LiAlH
4
2
2
4
2
2
4
oil by flash chromatography using 3% MeOH/CH
agreement with the literature [17].
2
Cl . Spectroscopic data was in
2
2
-Phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetaldehyde (19). To a -78 °C
solution of oxalyl chloride (1.21 mL, 14.1 mmol) in CH Cl (100 mL) was added DMSO
2.01 mL, 28.3 mmol) and stirring was continued at -78 °C for 15 minutes. A solution of
alcohol 18 (2.62 g, 11.8 mmol) in CH Cl (18 mL) was slowly added and the resulting
solution was stirred at -78 °C for 15 minutes. Et N (9.85 mL, 70.6 mmol) was added, the
solution was stirred at -78 °C for 20 minutes, and then allowed to reach room temperature
over 40 minutes. Saturated NaHCO was added and stirring was continued for 30 minutes.
The resulting mixture was extracted with CH Cl (3x), dried over Na SO , filtered, and
2
2
(
2
2
3
3
2
2
2
4
concentrated in vacuo. The desired product (2.13 g, 76%) was isolated as a pale yellow oil
by flash chromatography using 20% EtOAc/hexanes. IR (ATR, diamond) ν = 2943, 2870,
-
1 1
1
0
5
732, 1452, 1202, 1121, 1020, 970, 816, 698 cm ; H NMR (CDCl , 400 MHz) δ 9.65 (d,
3
.6H, J = 2.1 Hz), 9.62 (d, 0.4H, J = 1.7 Hz), 7.45-7.33 (m, 5H), 5.20 (d, 0.4H, J = 1.7 Hz),
.05 (d, 0.6H, 2.1 Hz), 4.93 (t, 0.4H, J = 3.2 Hz), 4.66 (dd, 0.6H, J = 4.6, 3.1 Hz), 3.95 (dt,

0
7
.6H, J = 11.3, 5.2 Hz), 3.70 (ddd, 0.4H, J = 12.3, 9.4, 3.2 Hz), 3.54 (ddd, 0.6H, J = 10.8,
1
3
.0, 3.6 Hz), 3.46 (dt, 0.4H, J = 10.3, 4.0 Hz), 1.99-1.72 (m, 3H), 1.65-1.48 (m, 3H); C
, 101 MHz) δ 199.3, 198.7, 134.2, 134.2, 129.1, 129.0, 128.9, 128.7, 127.6,
27.5, 97.7, 97.7, 83.5, 81.8, 63.1, 62.3, 30.5, 30.4, 25.4, 19.6, 18.9; HRMS-ESI calcd for
NMR (CDCl
3
1
+
C
13
H
17
O
3
[M+H] 221.1172; found 221.1179.
1
,4-Diphenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-ol (20). To a -78 °C
solution of phenylacetylene (0.36 mL, 3.30 mmol) in THF (7 mL) was added n-BuLi (2.5
mol/L in hexanes, 1.32 mL, 3.30 mmol) and the mixture was stirred at -78 °C for 30
minutes, and then at room temperature for 30 minutes. The solution was brought back
to -78 °C and a solution of aldehyde 19 (661 mg, 3.00 mmol) in THF (3 mL) was added.
The mixture was stirred at room temperature for 1 hour, after which saturated NaHCO
was added. The mixture was extracted with Et O (3x), washed with brine, dried over
Na SO , filtered, and concentrated in vacuo. The formation of the 4 possible pairs of
3
2
2
4
diastereoisomers was confirmed by NMR analysis of the crude reaction mixture. The crude
reaction mixture was used as is in the subsequent oxidation step with the transformation
being considered quantitative.
1
,4-Diphenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-one (21). To a -78 °C
solution of oxalyl chloride (0.31 mL, 3.6 mmol) in CH Cl (25 mL) was added DMSO
0.51 mL, 7.2 mmol) and stirring was continued at -78 °C for 15 minutes. A solution of
crude propargylic alcohol 20 (assumed to be quantitative, 3.00 mmol) in CH Cl (5 mL)
was slowly added and the resulting solution was stirred at -78 °C for 15 minutes. Et
2
2
(
2
2
3
N
(2.51 mL, 18.0 mmol) was added, the solution was stirred at -78 °C for 20 minutes, and
then allowed to reach room temperature over 40 minutes. Saturated NaHCO was added
3

and stirring was continued for 30 minutes. The resulting mixture was extracted with
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
559 mg, 58%) was isolated as a yellow oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 2941, 2868, 2203, 1672, 1119, 1022, 966, 908,
2
2
2
4
(
-1 1
7
7
56, 689 cm ; H NMR (CDCl
.45 (t, 1H, J = 7.4 Hz), 7.41-7.33 (m, 5H), 5.43 (s, 0.5H), 5.35 (s, 0.5H), 4.98 (t, 0.5H, J
3.1 Hz), 4.68 (t, 0.5H, J = 3.3 Hz), 4.02 (m, 0.5H), 3.73 (m, 0.5H), 3.57 (m, 0.5H), 3.50
3
, 500 MHz) δ 7.56 (d, 1H, J = 7.3 Hz), 7.53-7.49 (m, 3H),
=
1
3
(
m, 0.5H), 2.06-1.49 (m, 6H); C NMR (CDCl
3
, 126 MHz) δ 186.8, 184.8, 135.9, 135.6,
1
9
33.3, 133.2, 131.1, 131.0, 129.0, 128.9, 128.8, 128.75, 128.70, 128.2, 127.7, 120.1, 119.9,
7.6, 96.2, 95.3, 94.8, 86.7, 86.5, 83.3, 82.9, 62.17, 62.19, 30.5, 30.4, 25.5, 25.4, 19.0, 18.9;
+
HRMS-ESI calcd for C21
H
21
O
3
[M+H] 321.1485; found 321.1477.
2
-((2,2-Difluoro-1,4-diphenylbut-3-yn-1-yl)oxy)tetrahydro-2H-pyran (22). Ynone
2
1 (538 mg, 1.68 mmol) was charged into a polypropylene vial. DeoxoFluor (0.77 mL, 4.2
mmol) was added and the mixture was stirred at 55 °C for 24 hours. It was brought back
to 0 °C, diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated
NaHCO
separated, dried over Na
171 mg) was isolated as a yellow oil by flash chromatography using 5% Et
3
. The mixture was stirred for 30 minutes, after which the organic layer was
SO , filtered, and concentrated in vacuo. The desired compound
O/hexanes,
2
4
(
2
but could not be separated from impurities. The product was thus used as is in the
subsequent THP removal step and the yield was determined over two steps.
2
,2-Difluoro-1,4-diphenylbut-3-yn-1-ol (1c). PPTS (42 mg, 0.17 mmol) was added
to a solution of semi-pure propargylic fluoride 22 (171 mg) in MeOH (8 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room

temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
84 mg, 19%) was isolated as a yellow oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 3352, 3036, 2241, 1491, 1338, 1153, 1086, 1047,
3
was added. The resulting mixture was extracted with
2
2
2
4
(
-1 1
7
52, 685 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.57-7.55 (m, 2H), 7.44-7.32 (m, 6H), 7.34
1
9
(
(
t, 2H, J = 7.4 Hz), 5.05 (ddd, 1H, J = 9.6, 7.6, 4.0 Hz), 2.71 (d, 1H, J = 4.0 Hz); F NMR
13
CDCl
3
, 470 MHz) δ -93.0 (dd, 1F, J = 273, 7.2 Hz), -94.1 (dd, 1F, J = 274, 9.8 Hz); C
, 126 MHz) δ 135.4 (m), 132.3 (t, J = 2.4 Hz), 130.2, 129.3, 128.6, 128.4,
27.9, 120.0 (t, J = 2.7 Hz), 114.4 (t, J = 238 Hz), 89.8 (t, J = 6.9 Hz), 79.4 (t, J = 39.2
NMR (CDCl
3
1
+
Hz), 76.7 (dd, J = 30.5, 28.6 Hz).; HRMS-ESI calcd for C16
H
11
F
2
[M+H] -[H O] 241.0823;
2
found 241.0830.
4
.2.4 Preparation of 2,2-difluorododec-3-yn-1-ol (1d).
-((Tetrahydro-2H-pyran-2-yl)oxy)dodec-3-yn-2-ol (23). To a -78 °C solution of 1-
1
decyne (0.60 mL, 3.3 mmol) in THF (7 mL) was added n-BuLi (2.5 mol/L in hexanes, 1.32
mL, 3.30 mmol) and the mixture was stirred at -78 °C for 30 minutes, and then at room
temperature for 30 minutes. The solution was brought back to -78 °C and a solution of
aldehyde 7 (433 mg, 3.00 mmol) in THF (3 mL) was added. The mixture was stirred at
room temperature for 1 hour, after which saturated NaHCO
3
was added. The mixture was
, filtered, and concentrated
extracted with Et O (3x), washed with brine, dried over Na SO
2
2
4
in vacuo. The desired compound (400 mg, 43%) was isolated as a colorless oil by flash
chromatography using 20% EtOAc/hexanes. IR (ATR, diamond) ν = 3427, 2924, 2854,
-1 1
1
454, 1202, 1122, 1030, 906, 810, 723 cm ; H NMR (CDCl
3
, 500 MHz) δ 4.65 (dd, 0.5H,
J = 4.7, 3.0 Hz), 4.59 (dd, 0.5H, J = 5.3, 2.8 Hz), 4.54-4.50 (m, 1H), 3.97-3.92 (m, 1H),

3
1
1
7
1
2
.82 (d, 0.5H, J = 3.0 Hz), 3.81 (d, 0.5H, J = 2.9 Hz), 3.69-3.61 (m, 1H), 3.56-3.51 (m,
.5H), 3.00 (d, 0.5H, J = 5.5 Hz), 2.22-2.18 (m, 2H), 1.87-1.74 (m, 2H), 1.66-1.47 (m, 7H),
1
3
.37-1.27 (m, 10H); C NMR (CDCl , 126 MHz) δ 100.2, 100.1, 86.45, 86.47, 77.8, 77.4,
3
4.0, 73.0, 63.4, 62.8, 62.2, 31.8, 30.7, 30.6, 29.2, 29.1, 28.8, 28.5, 25.2, 25.1, 22.7, 19.9,
+
9.6, 18.72, 18.73, 14.1; HRMS-ESI calcd for C17
83.2271.
H
31
O
3
[M+H] 283.2268; found
1
-((Tetrahydro-2H-pyran-2-yl)oxy)dodec-3-yn-2-one (24). To a -78 °C solution of
oxalyl chloride (0.14 mL, 1.7 mmol) in CH Cl (12 mL) was added DMSO (0.24 mL, 3.34
mmol) and stirring was continued at -78 °C for 15 minutes. A solution of propargylic
alcohol 23 (393 mg, 1.39 mmol) in CH Cl (2 mL) was slowly added and the resulting
solution was stirred at -78 °C for 15 minutes. Et N (1.16 mL, 8.35 mmol) was added, the
solution was stirred at -78 °C for 20 minutes, and then allowed to reach room temperature
over 40 minutes. Saturated NaHCO was added and stirring was continued for 30 minutes.
The resulting mixture was extracted with CH Cl (3x), dried over Na SO , filtered, and
2
2
2
2
3
3
2
2
2
4
concentrated in vacuo. The desired product (328 mg, 81%) was isolated as a colorless oil
by flash chromatography using 15% EtOAc/hexanes. IR (ATR, diamond) ν = 2926, 2854,
-
1 1
2
1
4
5
1
2
208, 1691, 1674, 1263, 1132, 1038, 905, 731 cm ; H NMR (CDCl , 500 MHz) δ 4.72 (t,
3
H, J = 3.4 Hz), 4.33 (s, 1H), 3.85 (ddd, 1H, J = 11.7, 9.3, 3.1 Hz), 3.53 (dtd, 1H, J = 11.3,
.3, 1.7 Hz), 2.38 (t, 2H, J = 7.1 Hz), 1.91-1.83 (m, 1H), 1.78-1.72 (m, 2H), 1.65-1.52 (m,
13
H), 1.40 (p, 2H, J = 6.7 Hz), 1.33-1.27 (m, 8H), 0.88 (t, 3H, J = 6.8 Hz); C NMR (CDCl
26 MHz) δ 185.1, 98.4, 97.6, 78.9, 72.6, 62.2, 31.9, 30.2, 29.2, 29.1, 29.0, 27.7, 25.4,
2.8, 19.2, 19.0, 14.2; HRMS-ESI calcd for C17 [M+H]+ 281.2111; found 281.2101.
3
,
H
29
O
3

2
-((2,2-Difluorododec-3-yn-1-yl)oxy)tetrahydro-2H-pyran (25). Ynone 24 (321
mg, 1.14 mmol) was charged into a polypropylene vial. DeoxoFluor (0.53 mL, 2.9 mmol)
was added and the mixture was stirred at 55 °C for 24 hours. It was brought back to 0 °C,
diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated NaHCO
The mixture was stirred for 30 minutes, after which the organic layer was separated, dried
over Na SO , filtered, and concentrated in vacuo. The desired compound (192 mg, 55%)
was isolated as a yellow oil by flash chromatography using 5% Et O/hexanes. IR (ATR,
diamond) ν = 2928, 2856, 2253, 1456, 1300, 1128, 1076, 1038, 906, 729 cm ; H NMR
CDCl , 500 MHz) δ 4.79 (t, 1H, J = 3.2 Hz), 3.93 (td, 1H, J = 12.8, 11.8 Hz), 3.86 (dddd,
H, J = 11.1, 9.5, 2.7, 0.5 Hz), 3.78 (q, 1H, J = 12.0 Hz), 3.55 (dtd, 1H, J = 11.3, 4.1, 1.8
Hz), 2.28 (tt, 2H, J = 7.2, 5.2 Hz), 1.91-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.66-1.51 (m,
3
.
2
4
2
-1 1
(
3
1
1
9
5
H), 1.41-1.36 (m, 2H), 1.32-1.24 (m, 8H), 0.88 (t, 3H, J = 7.0 Hz); F NMR (CDCl
3
, 470
, 126 MHz) δ 112.4 (t, JC-F = 233.4 Hz), 98.7, 90.3
t, JC-F = 6.7 Hz), 72.6 (t, JC-F = 38.4 Hz), 69.1 (t, JC-F = 31.2 Hz), 61.9, 31.9, 30.2, 29.3,
13
MHz) δ -91.0 (m, 2F); C NMR (CDCl
3
(
2
9.1, 28.9, 27.8 (t, JC-F = 1.9 Hz), 25.4, 22.8, 18.8, 18.6 (t, JC-F = 2.3 Hz), 14.2; HRMS-
]+ 320.2396; found 320.2390.
ESI calcd for C17
H
32
F
2
NO
2
[M+NH
4
2
,2-Difluorododec-3-yn-1-ol (1d). PPTS (15 mg, 0.059 mmol) was added to a
solution of propargylic fluoride 25 (179 mg, 0.592 mmol) in MeOH (5.9 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
124 mg, 96%) was isolated as a pale yellow oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 3360, 2928, 2856, 2253, 1468, 1298, 1219, 1063,
3
was added. The resulting mixture was extracted with
2
2
2
4
(

-1 1
9
08, 735 cm ; H NMR (CDCl
3
, 500 MHz) δ 3.85 (tdt, 2H, J = 12.1, 7.4 Hz), 2.29 (tt, 2H,
J = 7.2, 5.2 Hz), 1.99 (tdt, 1H, J = 7.4, 1.8, 0.9 Hz), 1.59-1.53 (m, 2H), 1.41-1.26 (m, 10H),
1
9
13
0
.88 (t, 3H, J = 7.0 Hz); F NMR (CDCl
3
, 470 MHz) δ -93.9 (m, 2F); C NMR (CDCl ,
3
1
26 MHz) δ 112.7 (t, JC-F = 233 Hz) 91.2 (t, JC-F = 6.7 Hz), 71.9 (t, JC-F = 38.9 Hz), 66.4
(t, JC-F = 31.7 Hz), 31.9, 29.2, 29.1, 28.9, 27.8 (t, JC-F = 1.9 Hz), 22.8, 18.6 (t, JC-F = 2.4
Hz), 14.2; HRMS-ESI calcd for C12
H
24
F
2
NO [M+NH
4
]+ 236.1820; found 236.1799.
4
.2.5 Preparation of 3,3-difluorotridec-4-yn-2-ol (1e).
-((Tetrahydro-2H-pyran-2-yl)oxy)tridec-4-yn-3-ol (26). To a -78 °C solution of 1-
2
decyne (0.60 mL, 3.3 mmol) in THF (7 mL) was added n-BuLi (2.5 mol/L in hexanes, 1.32
mL, 3.30 mmol) and the mixture was stirred at -78 °C for 30 minutes, and then at room
temperature for 30 minutes. The solution was brought back to -78 °C and a solution of
aldehyde 13 (475 mg, 3.00 mmol) in THF (3 mL) was added. The mixture was stirred at
room temperature for 1 hour, after which saturated NaHCO
3
was added. The mixture was
, filtered, and concentrated
extracted with Et O (3x), washed with brine, dried over Na SO
2
2
4
in vacuo. The formation of the 4 possible pairs of diastereoisomers was confirmed by NMR
analysis of the crude reaction mixture. The crude reaction mixture was used as is in the
subsequent oxidation step with the transformation being considered quantitative.
2
-((Tetrahydro-2H-pyran-2-yl)oxy)tridec-4-yn-3-one (27). To a -78 °C solution of
oxalyl chloride (0.31 mL, 3.6 mmol) in CH Cl (25 mL) was added DMSO (0.51 mL, 7.2
mmol) and stirring was continued at -78 °C for 15 minutes. A solution of crude propargylic
alcohol 26 (assumed to be quantitative, 3.00 mmol) in CH Cl (5 mL) was slowly added
and the resulting solution was stirred at -78 °C for 15 minutes. Et N (2.51 mL, 18.0 mmol)
was added, the solution was stirred at -78 °C for 20 minutes, and then allowed to reach
2
2
2
2
3

room temperature over 40 minutes. Saturated NaHCO
continued for 30 minutes. The resulting mixture was extracted with CH
Na SO , filtered, and concentrated in vacuo. The desired product (564 mg, 64%) was
isolated as a yellow oil by flash chromatography using 10% EtOAc/hexanes.IR (ATR,
3
was added and stirring was
2
Cl (3x), dried over
2
2
4
-1 1
diamond) ν = 2926, 2854, 2206, 1676, 1456, 1202, 1124, 1020, 984, 874 cm ; H NMR
CDCl , 500 MHz) δ 4.78 (t, 0.5H, J = 3.5 Hz), 4.68 (t, 0.5H, J = 3.6 Hz), 4.40 (q, 0.5H, J
7.1 Hz), 4.21 (q, 1H, J = 6.8 Hz), 3.95 (ddd, 0.5H, J = 11.9, 9.3, 3.2 Hz), 3.87 (ddd, 0.5H,
J = 11.0, 7.9, 3.1 Hz), 3.53-3.46 (m, 1H), 2.40 (q, 2H, J = 6.8 Hz), 1.92-1.53 (m, 8H), 1.46-
(
3
=
1
3
1
1
3
1
.37 (m, 5H), 1.31-1.23 (m, 8H), 0.88 (t, 3H, J = 6.7 Hz); C NMR (CDCl , 126 MHz) δ
3
89.6, 188.6, 98.03, 97.99, 97.6, 97.4, 79.3, 79.1, 78.1, 77.2, 62.6, 62.2, 31.80, 31.78, 30.5,
0.4, 29.11, 29.10, 29.01, 28.98, 28.9, 27.70, 27.65, 25.4, 22.6, 19.3, 19.2, 19.1, 19.0, 18.0,
+
6.8, 14.1; HRMS-ESI calcd for C18
H
31
O
3
[M+H] 295.2268; found 295.2262.
2
-((3,3-Difluorotridec-4-yn-2-yl)oxy)tetrahydro-2H-pyran (28). Ynone 27 (557
mg, 1.89 mmol) was charged into a polypropylene vial. DeoxoFluor (0.87 mL, 4.7 mmol)
was added and the mixture was stirred at 55 °C for 24 hours. It was brought back to 0 °C,
diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated NaHCO
The mixture was stirred for 30 minutes, after which the organic layer was separated, dried
over Na SO , filtered, and concentrated in vacuo. The desired compound (306 mg, 51%)
was isolated as a yellow oil by flash chromatography using 5% Et O/hexanes. IR (ATR,
diamond) ν = 2928, 2856, 2253, 1456, 1340, 1223, 1124, 978, 910, 733 cm ; H NMR
CDCl , 500 MHz) δ 4.82 (t, 0.7H, J = 3.7 Hz), 4.82 (t, 0.3H, J = 3.1 Hz), 410-3.95 (m,
.3H), 3.90 (ddd, 0.7H, J = 11.4, 8.0, 3.1 Hz), 3.55-3.50 (m, 1H), 2.30-2.26 (m, 2H), 1.88-
3
.
2
4
2
-1 1
(
3
1
1
1
9
.52 (m, 8H), 1.39-1.27 (m, 13H), 0.88 (t, 3H, J = 6.8 Hz); F NMR (CDCl , 470 MHz) δ
3

-92.6 (ddt, 0.3F, J = 272, 9.7, 4.8 Hz), -92.8 (dm, 0.7F, J = 273 Hz), -93.4 (dm, 0.3F, J =
13
2
72 Hz), -93.8 (ddt, 0.7F, J = 273, 9.8, 4.9 Hz); C NMR (CDCl , 126 MHz) δ 114.8 (t,
3
J
C-F = 236 Hz), 114.1 (t, JC-F = 235 Hz), 100.1, 94.5, 90.4 (t, JC-F = 6.6 Hz), 90.0 (t, JC-F
=
=
6
5
1
.7 Hz), 74.8 (dd, JC-F = 29.0, 27.3 Hz), 72.4 (dd, JC-F = 77.0, 31.0 Hz), 72.2 (dd, JC-F
9.2, 29.7 Hz) 62.7, 61.4, 31.9, 30.6, 30.5, 29.3, 29.1, 29.1, 28.9, 27.9, 25.6, 25.5, 22.8,
9.4, 18.6 (m), 16.1 (t, JC-F = 2.6 Hz), 14.2, 13.3 (t, JC-F = 2.5 Hz); HRMS-ESI calcd for
C
18
H
34
F
2
NO
2
[M+NH
4
]+ 334.2552; found 334.2528.
3
,3-Difluorotridec-4-yn-2-ol (1e). PPTS (23.6 mg, 0.094 mmol) was added to a
solution of propargylic fluoride 28 (297 mg, 0.939 mmol) in MeOH (9.4 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
157 mg, 72%) was isolated as a pale yellow oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 3389, 2928, 2856, 2253, 1456, 1352, 1223, 1051,
3
was added. The resulting mixture was extracted with
2
2
2
4
(
-1 1
9
06, 735 cm ; H NMR (CDCl
3
, 500 MHz) δ 3.98 (dq, 1H, J = 10.1, 6.3 Hz), 2.30 (tt, 2H,
J = 7.2, 5.1 Hz), 2.08 (bs, 1H), 1.57 (p, 2H, J = 7.2 Hz), 1.42-1.24 (m, 13H), 0.88 (t, 3H, J
1
9
=
6.9 Hz); F NMR (CDCl
3
, 470 MHz) δ -94.9 (dm, 1F, J = 271 Hz), -96.1 (ddt, 1F, J =
71, 10.0, 5.0 Hz); C NMR (CDCl , 126 MHz) δ 114.9 (t, JC-F = 235 Hz), 91.3 (t, JC-F
.6 Hz), 71.4 (t, JC-F = 39.3 Hz), 70.7 (dd, JC-F = 30.9, 28.6 Hz), 31.9, 29.2, 29.1, 28.9, 27.9
13
2
6
3
=
(t, JC-F = 2.0 Hz), 22.8, 18.6 (t, JC-F = 2.4 Hz), 16.4 (t, JC-F = 2.4 Hz), 14.2.; HRMS-ESI
calcd for C13
H
26
F
2
NO [M+NH
4
]+ 250.1977; found 250.1960.
4
.2.6 Preparation of 2,2-difluoro-1-phenyldodec-3-yn-1-ol (1f).

1
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)dodec-3-yn-2-ol (29). To a -78 °C
solution of 1-decyne (0.60 mL, 3.30 mmol) in THF (7 mL) was added n-BuLi (2.5 mol/L
in hexanes, 1.32 mL, 3.30 mmol) and the mixture was stirred at -78 °C for 30 minutes, and
then at room temperature for 30 minutes. The solution was brought back to -78 °C and a
solution of aldehyde 19 (661 mg, 3.00 mmol) in THF (3 mL) was added. The mixture was
stirred at room temperature for 1 hour, after which saturated NaHCO
mixture was extracted with Et O (3x), washed with brine, dried over Na
3
was added. The
2
2
SO , filtered, and
4
concentrated in vacuo. The formation of the 4 possible pairs of diastereoisomers was
confirmed by NMR analysis of the crude reaction mixture. The crude reaction mixture was
used as is in the subsequent oxidation step with the transformation being considered
quantitative.
1
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)dodec-3-yn-2-one (30). To a -78 °C
solution of oxalyl chloride (0.31 mL, 3.6 mmol) in CH Cl (25 mL) was added DMSO
0.51 mL, 7.2 mmol) and stirring was continued at -78 °C for 15 minutes. A solution of
crude propargylic alcohol 29 (assumed to be quantitative, 3.00 mmol) in CH Cl (5 mL)
was slowly added and the resulting solution was stirred at -78 °C for 15 minutes. Et
2
2
(
2
2
3
N
(2.51 mL, 18.0 mmol) was added, the solution was stirred at -78 °C for 20 minutes, and
then allowed to reach room temperature over 40 minutes. Saturated NaHCO was added
3
and stirring was continued for 30 minutes. The resulting mixture was extracted with
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
584 mg, 55%) was isolated as a yellow oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 2926, 2854, 2210, 1676, 1452, 1202, 1121, 1036,
2
2
2
4
(
-1 1
9
08, 731 cm ; H NMR (CDCl , 500 MHz) δ 7.48 (d, 0.8H, J = 7.0 Hz), 7.42 (d, 1.2H, J
3

=
6.5 Hz), 7.38-7.33 (m, 3H), 5.31 (s, 0.4H), 5.23 (s, 0.6H), 4.89 (t, 0.4H, J = 3.2 Hz), 4.61
(t, 0.6H, J = 3.4 Hz), 3.98 (m, 0.6H), 3.70 (m, 0.4H), 3.56-3.46 (m, 1H), 2.35-2.31 (m, 2H),
1
3
1
.99-1.48 (m, 8H), 1.35-1.26 (m, 10H), 0.89 (t, 3H, J = 6.9 Hz); C NMR (CDCl , 126
3
MHz) δ 186.8, 184.8, 135.9, 135.6, 128.84, 128.76, 128.65, 128.58, 128.2, 127.8, 99.3,
9
2
8.8, 97.4, 96.1, 83.3, 82.9, 79.5, 79.4, 62.2, 62.1, 32.0, 31.9, 30.4, 29.3, 29.2, 29.15, 29.13,
8.9, 27.71, 27.69, 25.5, 25.4, 22.8, 19.30, 19.27, 19.0, 18.9, 14.2; HRMS-ESI calcd for
+
C
23
H
33
O
3
[M+H] 357.2424; found 357.2402.
2
-((2,2-Difluoro-1-phenyldodec-3-yn-1-yl)oxy)tetrahydro-2H-pyran (31). Ynone
3
0 (576 mg, 1.62 mmol) was charged into a polypropylene vial. DeoxoFluor (0.75 mL, 4.0
mmol) was added and the mixture was stirred at 55 °C for 24 hours. It was brought back
to 0 °C, diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated
NaHCO
separated, dried over Na
154 mg) was isolated as a yellow oil by flash chromatography using 5% Et
3
. The mixture was stirred for 30 minutes, after which the organic layer was
SO , filtered, and concentrated in vacuo. The desired compound
O/hexanes,
2
4
(
2
but could not be separated from impurities. The product was thus used as is in the
subsequent THP removal step and the yield was determined over two steps.
2
,2-Difluoro-1-phenyldodec-3-yn-1-ol (1f). PPTS (41 mg, 0.16 mmol) was added
to a solution of semi-pure propargylic fluoride 31 (154 mg) in MeOH (8 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO
CH Cl (3x), dried over Na SO , filtered, and concentrated in vacuo. The desired product
111 mg, 23%) was isolated as an orange oil by flash chromatography using 10%
EtOAc/hexanes. IR (ATR, diamond) ν = 3416, 2926, 2856, 2253, 1456, 1335, 1198, 1051,
3
was added. The resulting mixture was extracted with
2
2
2
4
(

-1 1
8
47, 698 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.50-7.48 (m, 2H), 7.40-7.35 (m, 3H), 4.92
(td, 1H, J = 8.8, 4.0 Hz), 2.61 (d, 1H, J = 4.1 Hz), 2.23 (tt, 2H, J = 7.1, 5.2 Hz), 1.48 (p,
1
9
2
H, J = 7.2 Hz), 1.31-1.23 (m, 10H), 0.89 (t, 3H, J = 6.9 Hz); F NMR (CDCl , 470 MHz)
3
1
3
δ -91.9 (dq, 1F, J = 270, 5.7 Hz), -92.8 (ddt, 1F, J = 271, 9.7, 5.1 Hz); C NMR (CDCl
26 MHz) δ 135.5 (t, JC-F = 2.1 Hz), 129.1, 128.2, 127.9, 113.9 (t, JC-F = 237 Hz), 92.3 (t,
C-F = 6.6 Hz), 76.6 (t, JC-F = 29.7), 71.5 (t, JC-F = 38.7 Hz), 31.9, 29.2, 29.1, 28.8, 27.7 (t,
3
,
1
J
J
C-F = 1.9 Hz), 22.8, 18.6 (t, JC-F = 2.3 Hz), 14.3; HRMS-ESI calcd for C18
]+ found 312.2133; found 312.2110.
H
28
2
F NO
[
M+NH
4
4
.2.7 Preparation of 2,2-difluoro-1-phenylbut-3-yn-1-ol (1g).
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-ol (32). To a 0 °C solution
of aldehyde 19 (740 mg, 3.36 mmol) in Et O (6.7 mL) was slowly added
1
2
ethynylmagnesium bromide (0.5 M in THF, 8.1 mL, 4.0 mmol), and the resulting mixture
was stirred at 0 °C for 30 minutes, and then at room temperature for 2 hours. Saturated
NH
4
Cl was added and the mixture was extracted with Et
2
O (3x), washed with brine (1x),
dried over MgSO
4
, filtered, and concentrated in vacuo. The formation of the 4 possible
pairs of diastereoisomers was confirmed by NMR analysis of the crude reaction mixture.
The crude reaction mixture was used as is in the subsequent oxidation step with the
transformation being considered quantitative.
1
-Phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)but-3-yn-2-one (33). To a 30 °C
solution of crude propargylic alcohol 32 (assumed to be quantitative, 3.36 mmol) in THF
5.4 mL) and DMSO (21.5 mL) was added 2-iodoxybenzoic acid (IBX, 2.82 g, 10.1 mmol).
(
The resulting mixture was stirred at 30 °C for 18 hours, after which water was added and
stirring was continued for 10 minutes. The suspension was filtered to remove the solids. It

was then extracted with Et
2
O, washed with brine (1x), dried over MgSO , filtered, and
4
concentrated in vacuo. The desired product (460 mg, 56%) was isolated as a yellow oil by
flash chromatography using 10% EtOAc/hexanes. IR (ATR, diamond) ν = 3358, 2943,
-
1 1
2
7
3
3
872, 2098, 1684, 1452, 1119, 1022, 966, 696 cm ; H NMR (CDCl , 500 MHz) δ 7.49-
3
.35 (m, 5H), 5.36 (s, 0.3H), 5.26 (s, 0.7H), 4.89 (t, 0.3H, J = 3.1 Hz), 4.63 (t, 0.7H, J =
.5 Hz), 3.96 (ddd, 0.7H, J = 11.7, 8.5, 3.8 Hz), 3.69 (ddd, 0.3H, J = 11.1, 9.7, 3.2 Hz),
13
.54 (m, 0.7H), 3.48 (m, 0.3H), 3.31 (s, 0.7H), 3.30 (s, 0.3H), 1.99-1.48 (m, 6H); C NMR
CDCl , 126 MHz) δ 186.2, 184.2, 135.0, 134.7, 129.1, 128.93, 128.89, 128.8, 128.1,
(
3
1
1
27.8, 97.5, 96.6, 83.3, 82.7, 82.31, 82.30, 79.9, 79.8 62.5, 62.1, 30.34, 30.30, 25.42, 25.36,
+
9.1, 18.8; HRMS-ESI calcd for C15
H
17
O
3
[M+H] 245.1172; found 245.1156.
2
-((2,2-Difluoro-1-phenylbut-3-yn-1-yl)oxy)tetrahydro-2H-pyran (34). Ynone 33
(446 mg, 1.82 mmol) was charged into a polypropylene vial. DeoxoFluor (0.84 mL, 4.6
mmol) was added and the mixture was stirred at 55 °C for 24 hours. It was brought back
to 0 °C, diluted with EtOAc and poured into a stirring mixture of EtOAc and saturated
NaHCO
separated, dried over Na
173 mg) was isolated as a yellow oil by flash chromatography using 10% Et
3
. The mixture was stirred for 30 minutes, after which the organic layer was
SO , filtered, and concentrated in vacuo. The desired compound
O/hexanes,
2
4
(
2
but could not be separated from impurities. The product was thus used as is in the
subsequent THP removal step and the yield was determined over two steps.
2
,2-Difluoro-1-phenylbut-3-yn-1-ol (1g). PPTS (47 mg, 0.183 mmol) was added to
a solution of semi-pure propargylic fluoride 34 (173 mg) in MeOH (8 mL). The resulting
mixture was stirred at 50 °C for 18 hours, at which point it was brought back to room
temperature and saturated NaHCO was added. The resulting mixture was extracted with
3