Gold-Catalyzed Hydrofluorination of Internal Alkynes Using Aqueous HF

Article abstract of DOI:10.1021/acs.orglett.9b03425

The gold-catalyzed hydrofluorination reaction of internal alkynes using hydrofluoric acid is reported. Notably, those conditions use one of the most economical sources of HF and are free of additional additives. Both symmetrical and unsymmetrical internal alkynes can be utilized, and the use of alkynes bearing a fluorinated group at the propargylic position as substrates allowed for a regioselective hydrofluorination reaction.

Full text of DOI:10.1021/acs.orglett.9b03425

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Hydrofluorination of Internal Alkynes Using
Aqueous HF
̈
Raphael Gauthier, Marius Mamone, and Jean-Franco̧ is Paquin*
́
́
́
́
́
CCVC, PROTEO, Departement de chimie, Universite Laval, 1045 Avenue de la Medecine, Quebec, Quebec G1V 0A6, Canada
S
* Supporting Information
ABSTRACT: The gold-catalyzed hydrofluorination reaction of internal alkynes using hydrofluoric acid is reported. Notably,
those conditions use one of the most economical sources of HF and are free of additional additives. Both symmetrical and
unsymmetrical internal alkynes can be utilized, and the use of alkynes bearing a fluorinated group at the propargylic position as
substrates allowed for a regioselective hydrofluorination reaction.
ecause of the importance of fluorinated molecules in
medicinal chemistry and in other fields,1 it is not surprising
We began our optimization using diphenylacetylene (1a) as
the model substrate using hydrofluoric acid (2 equiv of HF), and
the key results are presented in Table 1. Initial results were not
promising, as using 3 mol % of Ph3PAuCl with or without
AgOTf (3 mol %) did not provide the desired product (2a) with
no or very low conversion observed (Table 1, entries 1−2).
Switching from Ph3P to JohnPhos on the gold precatalyst offered
no improvement (Table 1, entry 3). At this point, a dinuclear
gold hydroxide complex, [{(JohnPhos)Au}2(μ-OH)]OTf,17
was evaluated considering that related complexes had been
used in various gold-catalyzed transformations including
hydration and hydroamination of alkynes.18 Using this complex,
product 2a was observed for the first time, though in low yield
(Table 1, entry 4). Heating the reaction at 40 °C provided a
modest improvement to 11% yield by NMR (Table 1, entry 5).
Better NMR yields were obtained when other solvents than
THF were used. Indeed, while using 1,2-dichloroethane (1,2-
DCE) provided 2a in 24% yield (Table 1, entry 6), the use of
toluene significantly improved the yield up to 62% (Table 1,
entry 7). Heating the reaction to 60 °C supplied 2a in a slightly
improved yield of 70% (Table 1, entry 8) while a drop in yield
was noted when running the reaction at 80 °C (Table 1, entry 9).
For those reactions, reproducibility was a major issue as
significant material lost was often observed overnight, and so,
the optimization was pursued at 40 °C. Raising the catalyst
loading to 3 mol % afforded 81% of 2a (Table 1, entry 10). It was
noted that using 2 equiv of HF was best, as using less (1 equiv) or
more (3 equiv) provided 2a in lower yields (Table 1, entries 11−
12). Finally, other amine-complexed hydrogen fluoride sources
such as Et3N·3HF (Table 1, entry 13), DMPU·HF (Table 1,
entry 14), and pyridine·HF (Table 1, entry 15) did not perform
as well as hydrofluoric acid under our reaction conditions. As
such, the ones reported in Table 1, entry 10 were chosen as the
optimal conditions.
B
that monofluorination of organic compounds still represents an
important research priority.2 The combination of gold catalysis
and fluorine chemistry has been a particularly fruitful partner-
ship in addressing this matter,3 and the development of an Au-
catalyzed hydrofluorination reaction of alkynes, as first reported
by Sadighi, can be considered as a key advancement (Scheme
1).4,5 To achieve this, a gold−carbene complex was used as the
catalyst in addition to Et3N·3HF as the HF source. However, the
reaction also required the use of acidic additives (KHSO4 and
PhNMe2·TfOH). A few years later, Hammond and co-workers
described a (JohnPhos)Au-catalyzed system using a newly
designed HF source (DMPU·HF).6 Nolan demonstrated that
NHC-gold bifluoride catalysts could promote a similar reaction
using Et3N·3HF and NH4BF4 as the additive.7 In 2017,
Hammond and co-workers reported the hydrofluorination of
alkynylsulfone using a (JohnPhos)Au-catalyzed system and
pyridine·HF (Olah’s reagent) as the HF source.8 Finally, Toste
described the gold-catalyzed hydrofluorination of electron-
deficient alkynes.9 In this case, a (RuPhos)Au system along with
Et3N·3HF as the HF source and p-chlorobenzoic acid as the
additive was utilized.
As all the system uses amine-complexed hydrogen fluoride
sources, we aimed at developing a reaction that would avoid this
class of reagent. To this end, we wondered if we could simply use
hydrofluoric acid, i.e. 48% aqueous HF. Even though the Mayr
nucleophilicity scale10 suggests that fluoride in water11 should be
more nucleophilic than water itself,12 using hydrofluoric acid
means that, in practice, any effort to develop a hydrofluorination
reaction could be thwarted by a competitive gold-catalyzed
hydration reaction of the same alkyne.13
Herein, we report the successful development of a gold-
catalyzed hydrofluorination of internal symmetrical and unsym-
metrical alkynes using aqueous HF. Notably, this reaction uses
one of the most economical sources of HF,14 is free of additional
additives, avoids the use of halogenated solvents,15 and provides
useful monofluoroalkenes as the final product.16
Received: September 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03425
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing aromatic (1a−g), heteroaromatic (1h), or aliphatic
substituents (1i−j) were subjected to the reaction. In most
cases, the corresponding (Z)-monofluoroalkene could be
isolated in moderate to good yields (52−84%) with the
exceptions of substrates with aromatic groups bearing a
substituent at the ortho position (1f−g) presumably for steric
reasons. In the latter cases, an incomplete conversion was noted
and the products (2f−g) were either isolated in 41% yield or
observed in 3% yield (estimated yield by NMR). In that series,
compounds 2a and 2i could not be isolated. For 2a, it could not
be separated from residual starting material whereas the high
volatility of 2i rendered its isolation difficult on the scale used.
We next turned our attention to unsymmetrical alkynes (R1 ≠
R2). First, substrates bearing a phenyl on one side and an
aliphatic chain on the other (1k−m) all provided their
corresponding (Z)-monofluoroalkenes (2k−m) in good yields
(71−87%) with moderate selectivity for the regioisomer bearing
the fluorine on the side of the aliphatic substituent. This
preference matches the one previously observed by others4,7 and
is likely due to the electron-donating nature of the alkyl
substituent. A number of alkynes with two different aromatic
substituents where one of them was a phenyl group were tested.
All the corresponding (Z)-monofluoroalkenes (2n−t) were
isolated in moderate to good yields (40−83%) as a mixture of
regioisomers (up to 82:18) consistent with the electronic nature
of the substituent. We also subjected a chloroalkyne (1u) and a
bromoalkyne (1v) to the reaction. In both cases, the
corresponding products (2u−v) could be isolated as a single
regio- and stereoisomer. These monofluoroalkenes are interest-
ing, as they open the door to further functionalization by
transformation of the carbon−halogen bond.16 When using
ethyl phenylpropiolate as the substrate, the desired product 2w
was isolated in low yield (34%) along with 50% of ethyl
benzoylacetate,19 the hydration product. Finally, terminal
alkynes are poor substrates under the current conditions with
<26% yield (NMR or isolated). In the case of 2x, 51% of 4-
Scheme 1. Gold-Catalyzed Hydrofluorination of Alkynes
We next investigated the scope of this transformation
(Scheme 2). First, a number of symmetrical alkynes (R1 = R2)
a
Table 1. Key Optimization Results for the Au-Catalyzed Hydrofluorination of 1a Using Hydrofluoric Acid
b
c
entry
[Au] cat. (mol %)
Ph3PAuCl (3)
HF source
solvent
temp (°C)
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
48% aq. HF
Et3N·3HF
DMPU·HF
pyridine·HF
THF
THF
THF
THF
21
21
21
21
40
40
40
60
80
40
40
40
40
40
40
2
0
6
0
0
0
d
Ph3PAuCl (3)
(JohnPhos)AuCl (3)
d
[{(JohnPhos)Au}2(μ-OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ-OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ-OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ-OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ−OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ-OH)]OTf (1.5)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
[{(JohnPhos)Au}2(μ-OH)]OTf (3)
11
39
27
68
93
95
91
74
79
51
36
14
4
THF
11
24
62
70
32
81
67
68
42
24
3
1,2-DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
e
f
a
b
1
See the Supporting Information for the detailed experimental procedures. Estimated by H NMR analysis of the crude mixture after workup
c
d
using 2-fluoro-4-nitrotoluene as the internal standard. Yield of 2a determined by 19F NMR analysis of the crude mixture after workup. AgOTf (3
mol %) was also added. 1 equiv of 48% aq. HF was used. 3 equiv of 48% aq. HF were used.
e
f
B
DOI: 10.1021/acs.orglett.9b03425
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Gold-Catalyzed Hydrofluorination of Alkynes Using Hydrofluoric Acid
a
b
See the Supporting Information for the detailed experimental procedures. Estimated by 19F NMR analysis of the crude mixture after workup
c
d
using 2-fluoro-4-nitrotoluene as the internal standard. Reaction performed on a 1 mmol scale. Contamined with ca. 5% of residual starting
e
f
material. Incomplete conversion. Isolated yield of the mixture. The major isomer is shown, and the ratio was determined by 19F NMR analysis of
g
h
i
the purified mixture. NMR analysis of the crude mixture showed a 93:7 ratio of regioisomers. 50% of ethyl benzoylacetate was also isolated. 51%
of 4-phenyl-2-butanone was also detected in the crude mixture by H NMR using 2-fluoro-4-nitrotoluene as the internal standard.
1
phenyl-2-butanone, the hydration product, was also detected in
the crude. While these results indicate a limitation of the present
system, i.e. a competitive hydration process, other successful
approaches have been reported to prepare this class of
compounds.6,7,9,16
Scheme 3. Gold-Catalyzed Hydrofluorination of Alkynes
Bearing a Fluorinated Substituent at the Propargylic
a
Position
Recently, we described the regioselective gold-catalyzed
hydration reaction of alkynes bearing a fluorinated group at
the propargylic position.20,21 In particular, we showed that the
presence of the fluorine-containing group was the origin for the
high regioselectivity observed. As such, we wondered if a
fluorinated group would have a similar effect in the hydro-
fluorination reaction, and the results are shown in Scheme 3.
Reaction of propargylic difluoride 3a produced the correspond-
ing (Z)-monofluoroalkene 4a as the sole product in 57% yield.
Reaction of CF3-alkyne 3b generated (Z)-monofluoroalkene 4b
in 49% yield. In this case, The (E)-stereoisomer was also present
in the crude mixture.22 Finally, when SF5-alkyne 3c was
submitted to the hydrofluorination, a single isomer of the
highly fluorinated alkene 4c was isolated in low yield presumably
a
See the Supporting Information for the detailed experimental
b
procedures. NMR analysis of the crude mixture showed a 85:15
ratio of stereoisomers.
because of the increased steric and withdrawing effect of the SF5
group,23 compared to the CF3 group.20b
In summary, we have described the gold-catalyzed hydro-
fluorination reaction of internal alkynes using hydrofluoric acid,
C
DOI: 10.1021/acs.orglett.9b03425
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) O’Connor, T. J.; Toste, F. D. Gold-Catalyzed Hydrofluorination
of Electron-Deficient Alkynes: Stereoselective Synthesis of β-Fluoro
Michael Acceptors. ACS Catal. 2018, 8, 5947−5951.
one of the most economical sources of HF. The corresponding
monofluoroalkenes, useful building blocks for life and material
sciences, were obtained in up to 87% yield.
(10) Mayr, H.; Ofial, A. R. Do general nucleophilicity scales exist? J.
Phys. Org. Chem. 2008, 21, 584−595.
ASSOCIATED CONTENT
■
(11) Nolte, C.; Ammer, J.; Mayr, H. Nucleofugality and Nucleophil-
icity of Fluoride in Protic Solvents. J. Org. Chem. 2012, 77, 3325−3335.
(12) Minegishi, S.; Kobayashi, S.; Mayr, H. Solvent Nucleophilicity. J.
Am. Chem. Soc. 2004, 126, 5174−5181.
(13) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of
Alkynes for the Construction of Molecular Complexity. Chem. Rev.
2015, 115, 9028−9072.
(14) The price per mmol (in American dollars) for the following
reagent was calculated using the largest amount available from a single
provider (September 2019): DMPU·HF ($5.25), pyridine·HF ($0.33),
Et3N·3HF ($0.21), 48% aq. HF ($<0.01).
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03425.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-francois.paquin@chm.ulaval.ca.
ORCID
(15) Toluene is considered a preferable solvent over chlorinated ones
such as CH2Cl2 and DCE; see: Byrne, F. P.; Jin, S.; Paggiola, G.;
Petchey, T. H. M.; Clark, J. H.; Farmer, T. J.; Hunt, A. J.; McElroy, R.;
Sherwood, J. Tools and techniques for solvent selection: green solvent
selection guides. Sustainable Chem. Processes 2016, 4, 1−24.
(16) For reviews on their synthesis, see: (a) van Steenis, J. H.; van der
Gen, A. Synthesis of terminal monofluoro olefins. J. Chem. Soc., Perkin
Trans. 1 2002, 2117−2133. (b) Zajc, B.; Kumar, R. Synthesis of
Fluoroolefins via Julia-Kocienski Olefination. Synthesis 2010, 2010,
1822−1836. (c) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.;
Paquin, J.-F. Synthetic Approaches to Monofluoroalkenes. Chem. Soc.
Rev. 2011, 40, 2867−2908. (d) Yanai, H.; Taguchi, T. Synthetic
Methods for Fluorinated Olefins. Eur. J. Org. Chem. 2011, 2011, 5939−
5954. (e) Hara, S. Stereoselective Synthesis of Mono-fluoroalkenes.
Top. Curr. Chem. 2012, 327, 59−86. (f) Pfund, E.; Lequeux, T.;
Gueyrard, D. Synthesis of Fluorinated and Trifluoromethyl-Substituted
Alkenes through the Modified Julia Olefination: An Update. Synthesis
2015, 47, 1534−1546. (g) Drouin, M.; Hamel, J.-D.; Paquin, J.-F.
Synthesis of Monofluoroalkenes: A Leap Forward. Synthesis 2018, 50,
881−955.
Jean-Franco̧ is Paquin: 0000-0003-2412-3083
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, the Fonds de
recherche du Quebec−Nature et technologies, and the
́
Universite Laval.
REFERENCES
■
(1) (a) Jeschke, P. Latest generation of halogen-containing pesticides.
Pest Manage. Sci. 2017, 73, 1053−1056. (b) Ragni, R.; Punzi, A.;
Babudri, F.; Farinola, G. M. Organic and Organometallic Fluorinated
Materials for Electronics and Optoelectronics: A Survey on Recent
Research. Eur. J. Org. Chem. 2018, 2018, 3500−3519. (c) Meanwell, N.
A. Fluorine and Fluorinated Motifs in the Design and Application of
Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822−5880.
(d) Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and
Agrochemicals; Haufe, G., Leroux, F. R., Eds.; Elsevier: London, 2019.
(2) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.;
Paquin, J.-F. Monofluorination of Organic Compounds: 10 Years of
Innovation. Chem. Rev. 2015, 115, 9073−9174.
(17) The same catalyst bearing a SbF6− counterion instead has been
̈
reported; see: Zhdanko, A.; Strobele, M.; Maier, M. E. Coordination
Chemistry of Gold Catalysts in Solution: A Detailed NMR Study.
Chem. - Eur. J. 2012, 18, 14732−14744.
́
(18) (a) Gaillard, S.; Bosson, J.; Ramon, R. S.; Nun, P.; Slawin, A. M.
Z.; Nolan, S. P. Development of Versatile and Silver-Free Protocols for
́
Gold(I) Catalysis. Chem. - Eur. J. 2010, 16, 13729−13740. (b) Ramon,
R. S.; Gaillard, S.; Poater, A.; Cavallo, L.; Slawin, A. M. Z.; Nolan, S. P.
[{Au(IPr)}2(μ-OH)]X Complexes: Synthetic, Structural and Catalytic
Studies. Chem. - Eur. J. 2011, 17, 1238−1246. (c) Michon, C.; Gilbert,
J.; Trivelli, X.; Nahra, F.; Cazin, C. S. J.; Agbossou-Niedercorn, F.;
Nolan, S. P. Gold(I) catalysed regio- and stereoselective intermolecular
hydroamination of internal alkynes: towards functionalised azoles. Org.
Biomol. Chem. 2019, 17, 3805−3811.
(3) (a) Hopkinson, M. N.; Gee, A. D.; Gouverneur, V. Gold Catalysis
and Fluorine. Isr. J. Chem. 2010, 50, 675−690. (b) Miro, J.; del Pozo, C.
Fluorine and Gold: A Fruitful Partnership. Chem. Rev. 2016, 116,
11924−11966.
(4) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P.
Reversible C−F Bond Formation and the Au-Catalyzed Hydro-
fluorination of Alkynes. J. Am. Chem. Soc. 2007, 129, 7736−7737.
(5) Miller and coworkers developed, using Sadighi’s conditions, a Au-
catalyzed directed hydrofluorination reaction of functionalized alkynes;
see: Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Regio- and
Stereoselective Synthesis of Fluoroalkenes by Directed Au(I) Catalysis.
Org. Lett. 2009, 11, 4318−4321.
(6) Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. Designer HF-
Based Fluorination Reagent: Highly Regioselective Synthesis of
Fluoroalkenes and gem-Difluoromethylene Compounds from Alkynes.
J. Am. Chem. Soc. 2014, 136, 14381−14384.
(7) Nahra, F.; Patrick, S. R.; Bello, D.; Brill, M.; Obled, A.; Cordes, D.
B.; Slawin, A. M.; O’Hagan, D.; Nolan, S. P. Hydrofluorination of
Alkynes Catalysed by Gold Bifluorides. ChemCatChem 2015, 7, 240−
244.
(19) Grayson, J. D.; Partridge, B. M. Mild Cu-Catalyzed Oxidation of
Benzylic Boronic Esters to Ketones. ACS Catal. 2019, 9, 4296−4301.
(20) (a) Hamel, J.-D.; Hayashi, T.; Cloutier, M.; Savoie, P. R.;
Thibeault, O.; Beaudoin, M.; Paquin, J.-F. Highly regioselective gold-
catalyzed formal hydration of propargylic gem-difluorides. Org. Biomol.
Chem. 2017, 15, 9830−9836. (b) Cloutier, M.; Roudias, M.; Paquin, J.-
F. Regioselective gold-catalyzed hydration of CF3- and SF5-alkynes.
Org. Lett. 2019, 21, 3866−3870.
(21) For an intramolecular version, see: Hamel, J.-D.; Paquin, J.-F. Au-
catalyzed intramolecular hydroalkoxylation of gem-difluorinated
alkynols. J. Fluorine Chem. 2018, 216, 11−23.
(22) See Supporting Information of details.
(23) Savoie, P. R.; Welch, J. T. Preparation and Utility of Organic
Pentafluorosulfanyl-Containing Compounds. Chem. Rev. 2015, 115,
1130−1190.
(8) Zeng, X.; Liu, S.; Hammond, G. B.; Xu, B. Divergent Regio- and
Stereoselective Gold-catalyzed Synthesis of α-Fluorosulfones and β-
Fluorovinylsulfones from Alkynylsulfones. Chem. - Eur. J. 2017, 23,
11977−11981.
D
DOI: 10.1021/acs.orglett.9b03425
Org. Lett. XXXX, XXX, XXX−XXX