Gold-Catalyzed Hydrofluorination of Electron-Deficient Alkynes: Stereoselective Synthesis of β-Fluoro Michael Acceptors

Article abstract of DOI:10.1021/acscatal.8b01341

The gold(I)-catalyzed, stereoselective hydrofluorination of electron-deficient alkynes with triethylamine trihydrogen fluoride (Et₃N·3HF) is described. Fluorinated α,β-unsaturated aldehydes, amides, esters, ketones, and nitriles were isolated i

Full text of DOI:10.1021/acscatal.8b01341

Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2018, 8, 5947−5951
Gold-Catalyzed Hydrofluorination of Electron-Deficient Alkynes:
Stereoselective Synthesis of β‑Fluoro Michael Acceptors
Thomas J. O’Connor and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 04720, United States
S
* Supporting Information
ABSTRACT: The gold(I)-catalyzed, stereoselective hydro-
fluorination of electron-deficient alkynes with triethylamine
trihydrogen fluoride (Et3N·3HF) is described. Fluorinated α,β-
unsaturated aldehydes, amides, esters, ketones, and nitriles
were isolated in moderate to good yields as single
diastereomers. In all but four cases, the (Z)-vinyl fluorides
were initially formed in ≥97% diastereoselectivity. This work
constitutes the first catalytic example of the diastereoselective preparation of a variety of β-alkyl, β-fluoro Michael acceptors from
alkynes. Additionally, the described work expands access to β-aryl, β-fluoro Michael acceptors to the synthesis of β-fluoro-α,β-
unsaturated amides and nitriles. The monofluoroalkenes formed through this strategy were readily transformed into other
fluorine-containing compounds, and the developed method was applied to the synthesis of a fluorinated analogue of Exoderil, a
topical antimycotic.
KEYWORDS: monofluoroalkenes, michael acceptors, hydrofluorination, gold catalysis, fluorine
monofluoroalkenes are synthesized with high diastereomeric
ratios.11
ew routes toward the selective fluorination of small
Nmolecules have been targeted in recent years due to the
differences in the physical and biological properties between
fluorinated compounds and those of their nonfluorinated
analogues.1 A fluorinated motif of particular interest is the
monofluoroalkene. Monofluoroalkenes are isosteric with
peptide bonds, and several bioactive compounds containing
this motif have been reported.2 Although several synthetic
protocols exist to access α-fluoro, α,β-unsaturated carbonyl
compoundsthe Horner−Wadsworth−Emmons reaction,3 the
Julia Olefination,4 the Peterson Olefination,5 and the
Reformatsky reaction6the stereoselective synthesis of β-
fluoro, α,β-unsaturated carbonyl compounds has proven to be a
challenge, especially if β-alkyl substituents are desired.7
Previous methods to access (Z)-β-fluoro-α,β-unsaturated
carbonyl compounds are limited by the formation of products
with low diastereoselectivities or yields,8 the requirement for
prefunctionalized starting materials,9 and narrow functional
group tolerance.9b,c,10 Because of these limitations, a stereo-
selective and functional-group-tolerant method to access (Z)-β-
alkyl, β-fluoro-α,β-unsaturated carbonyl compounds would be
highly desirable.
Since Sadighi’s seminal report of the gold-catalyzed hydro-
fluorination of internal alkynes in 2007, other research groups
have expanded the use of coinage metals for alkyne
hydrofluorination.12 Both Jiang, with excess AgF (Scheme
1a), and Nolan, with a catalytic amount of gold (Scheme 1b),
prepared β-aryl, β-fluoro-α,β-unsaturated esters or ketones
Scheme 1. Generation of β-Fluoro Michael Acceptors from
Alkynes with Coinage Metals
The hydrofluorination of electron-deficient alkynes is
perhaps the most direct method to generate (Z)-β-fluoro α,β-
unsaturated carbonyl compounds from commercially available
starting materials. Although some electron-deficient alkynes can
undergo hydrofluorination in the absence of a catalyst, the
diastereoselectivities of these reactions are generally moderate,
especially for β-alkyl substrates.8a,b,10 Traditional chromato-
graphic techniques often fail to separate (E) and (Z) isomers of
monofluoroalkenes; therefore, it is essential that the desired
Received: April 5, 2018
Revised: May 8, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acscatal.8b01341
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ACS Catalysis
Letter
from electron-deficient, unsymmetrical alkynes.12c,e However,
neither procedure reported the synthesis of β-alkyl, β-fluoro
Michael acceptors or utilized alternative electron-withdrawing
groups such as nitriles or amides. Alternative conditions were
described by Hammond and Xu for the gold-catalyzed
hydrofluorination of alkynes with a new DMPU/HF fluorinat-
ing reagent, but this procedure did not expand access to (Z)-β-
fluoro-α,β-unsaturated carbonyl compounds.12d The first gold-
catalyzed synthesis of a β-alkyl-β-fluoro Michael acceptor was
demonstrated by Hammond and Xu in 2017 (Scheme 1c).12f
Although β-alkyl-β-fluorovinylsulfones could be accessed in a
(Z)-selective manner, alkynes that did not bear a sulfonyl
groupsuch as aroyl and phosphonylfailed to undergo
hydrofluorination. Despite these advances in alkyne hydro-
fluorination by coinage metals, a general procedure to
synthesize a variety of (Z)-β-alkyl, β-fluoro Michael acceptors
from electron-deficient alkynes is still an unsolved challenge.
Herein, we report a method for the preparation of a diverse
array of β-alkyl, β-fluoro Michael acceptors from the gold-
catalyzed hydrofluorination of electron-deficient alkynes. In
addition to forming β-fluoro-α,β-unsaturated esters and
ketones, this method is the first gold-catalyzed procedure to
generate β-fluoro-α,β-unsaturated amides, nitriles, and alde-
hydes. A variety of β-alkyl as well as β-aryl substituents were
tolerated; notably, 3° alkyl, alkenyl, and o-tolyl. Furthermore,
we demonstrate that the monofluoroalkene products are
synthetically versatile fluorinated building blocks.
catalysts bearing NHC-ligands to gold catalysts bearing
phosphine ligands, modest improvements in both yield and
stereoselectivity were observed (entries 3 and 4). Unfortu-
nately, reactions conducted with several triaryl or trialkyl
phosphine gold(I) complexes as catalysts generated a purple
hue after several hours in the presence of Et3N·3HF, which has
been reported by others as a visual indication of catalyst
decomposition.13
Cationic-gold(I) complexes with dialkylbiarylphosphine
ligands are known to be more stable toward decomposition
pathways than cationic gold(I) complexes triaryl or trialkyl
phosphines.14 Upon switching the gold catalyst to CyJohnPho-
sAuCl, monofluoroalkene 1b was generated in 84% yield.
However, the stereoselectivity of the reaction conducted with
CyJohnPhosAuCl decreased relative to the stereoselectivity of
the reaction conducted with Cy3PAuCl as the catalyst (entry 3
and 4). Examination of a variety of dialkylbiaryl phosphinegold-
(I) complexes revealed that only reactions with RuPhos as the
ligand afforded the greatest Z:E selectivity of 1b (entries 6 and
7). For instance, in the presence of CyJohnPhos the yield of 1b
after 4 h was 85% but with a Z:E of 77:23.
In addition to the ligand effect on the reaction, both the
solvent and additive were found to influence the yield and
stereoselectivity of the hydrofluorination of alkynoate 1a.
Switching from potassium bisulfate to p-chlorobenzoic acid (p-
Cl BA), a more soluble acid coadditive, resulted in a modest
improvement in the yield of monofluoroalkene 1b (entry 8).
Reactions conducted with RuPhosAuCl and CH3CN as the
solvent afforded the hydrofluorination product in a further
improved yield while maintaining the Z-selectivity observed at
shorter reaction times (entry 8 and 9). The change in solvent
also ensured that the Z:E ratio did not decrease over time,
permitting easier reaction monitoring as alkene isomerization
was largely suppressed. Ultimately, reactions conducted in a
solvent mixture of CH3CN:CH2Cl2 maintained the high
stereoselectivity of the hydrofluorination of alkyne 1a while
affording alkene 1b in an improved yield (entry 9 and 10). The
beneficial improvement in the yield of 1b was observed with as
little as 10 mol % p-Cl BA (entry 11 and 12). Other acid
additives were examined, but benzoic acid derivatives appeared
to provide an optimal pKa range (see Supporting Information,
Table S4). Increasing the equivalents of Et3N·3HF did not have
a significant influence on the reaction (entry 13); however,
reactions with Et3N·2HF, Et3N·HF, and pyridine·HF (70%
HF) failed to generate alkene 1b (See Supporting Information).
Having identified suitable reactions conditions for the
hydrofluorination of alkyne 1a, we investigated the hydro-
fluorination of β-alkyl alkynoates, alkynones, alkynamides, and
alkynenitriles (Table 2). Methyl, 1° alkyl, 2° alkyl, and vinyl β-
substituted alkynoates underwent hydrofluorination in the
presence of Et3N·3HF in a Z-selective manner in good yields.
Notably, the final products were all isolated as a single
diastereomer after standard silica gel column chromatography.
Importantly, these results highlight this operationally simple,
one-step route to β-alkyl, β-fluoro Michael acceptors from
alkynes. The hydrofluorination reaction was also shown to be
scalable, as fluoroalkenes 3b and 5b were both prepared on a
gram scale in good yield and with excellent Z-selectivity. For
substrate 6a with a bulky β-substituents, a higher reaction
temperature was required to obtain the product in moderate
yield (6b). The hydrofluorination of alkynoates bearing β-vinyl
substituents provided straightforward access to fluorinated
dienes 7b and 8b. Hydrofluorination of the γ,δ-alkene of either
The hydrofluorination of ethyl 2-butynoate (1a) with Et3N·
3HF to form ethyl (Z)-3-fluorobut-2-enoate (1b) was selected
as a model reaction. Monofluoroalkene 1b formed in moderate
yields and low stereoselectivities under conditions similar to
those reported by Sadighi (see Table 1, entry 1).12a Reactions
employing AgBF4 as the silver salt afforded alkene 1b in greater
chemical yield compared to reactions conducted in the
presence of other silver salts (entry 1 and 2, see the Supporting
Information for further details). Upon switching from gold
Table 1. Effect of the Reaction Conditions on the
Hydrofluorination of 1a
yield [%]
b
entry
1
L
solvent
additive
(Z:E)
IPr
IPr
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH3CN
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
50 (66:34)
43 (70:30)
55 (60:40)
64 (75:25)
84 (55:45)
57 (56:44)
62 (97:3)
66 (97:3)
70 (97:3)
76 (96:4)
71 (96:4)
65 (96:4)
80 (96:4)
c
2
3
4
5
6
PPh3
PCy3
CyJohnPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
d
7
e
e
8
p-CI BA
p-CI BA
9
10
1:4 CH2CI2:CH3CN p-CI BA
1:4 CH2CI2:CH3CN p-CI BA
f
11
12
1:4 CH2CI2:CH3CN
none
g
13
1:4 CH2CI2:CH3CN p-CI BA
a
b
General reaction conditions: 0.2 mmol 1a, plastic vial. Yields and
Z:E ratios were determined by 19F NMR spectroscopy with 2,4-
c
d
dinitrofluorobenzene as an internal standard. 5 mol % AgSbF6. 4 h.
e
f
g
p-chlorobenzoic acid. 10 mol % p-CI BA. 3.0 equiv Et3N·3HF.
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Letter
Table 2. Scope of β-Alkyl, β-Fluoro Michael Acceptors
Table 3. Scope of β-aryl, β-fluoro Michael acceptors
a
Standard reaction conditions: 0.5 mmol 2−15a, 3.0 equiv Et3N·3HF,
1.0 equiv p-CI BA, 5 mol % RuPhosAuCl, 5 mol % AgBF4, 4:1
b
MeCN:CH2CI2 [0.7M], rt, 24 h. 2−15b isolated as a single isomer
a
Standard reaction conditions: 0.5 mmol 16−30a, 3.0 equiv Et3N·
3HF, 1.0 equiv p-CI BA, 5 mol % RuPhosAuCl, 5 mol % AgBF4, 4:1
c
except 11b. Detemined by 19F NMR spectroscopy with PhF as an
d
e
f
g
internal standard. 6.0 mmol scale. 5.0 mmol scale. 55 °C insoluble
b
MeCN:CH2CI2 [0.7M], rt, 24 h. 16−30b isolated as a single isomer.
h
i
product. 1.25 M, 4.0 equiv Et3N·HF. 1.25 M, 4.0 equiv Et3N·3HF.
c
Determined by 19F NMR spectroscopy with PhF as an internal
j
1.43 M, 4.5 equiv Et3N·3HF, 50 °C.
d
e
f
g
standard. 1.43 M, 45 °C. 45 °C. 4.5 mmol. 1.25 M, 55 °C, 4.0
equiv Et3N·3HF. 45 °C, 48 h, 4.0 equiv Et3N·3HF.
h
7a or 8a was not detected by 19F NMR spectroscopy. The
reaction conditions for the hydrofluorination of β-alkyl
alkynoates were also suitable for the hydrofluorination of β-
alkyl (hetero)aryl alkynones 9b and 10b. Although methyl
ketone 11a proved to be a challenging substrate, 11b was
isolated in good yield with only a trace amount of the E-isomer.
Both 2° and 3° β-alkyl alkynamides (12−14a) as well as
alkynonitrile derivative 15a underwent hydrofluorination to
provide 12−15b in moderate yields. Dec-2-ynal was the only
substrate that did not undergo hydrofluorination in a
diastereoselective manner under the standard conditions in
Table 2 (72%, Z:E = 51:49). However, conducting the reaction
at 5 °C did afford a Z:E ratio of >98:2 and 22% yield after 24 h.
Unfortunately, after 96 h at 5 °C, the yield increased to 51% but
the Z:E ratio decreased to 70:30.
To showcase the generality of this method, the hydro-
fluorination reactions of a variety of electron deficient alkynes
bearing β-aryl substituents were also explored (Table 3).
Generally, the yields of β-aryl-monofluoroalkenes 16−30b were
comparable to those of their β-alkyl-analogues 2−15b. In
contrast to previous procedures, even a monofluoroalkene
bearing an ortho-substituted aryl group (19b) was generated in
modest yield.12e Compared with the esters and ketones, even
the more electrophilic 2-phenylpropiolaldehyde afforded 27b in
a Z-selective manner. Moreover, both β-aryl alkynonitriles and
alkynamides were suitable substrates, generating otherwise
difficult to access fluorinated motifs (28−30b). Finally, this
methodology was found to be complementary to that reported
by Hammond and Xu (See Supporting Information, Table
S5)12f
The monofluoroalkenes generated from our catalytic process
underwent a series of transformations demonstrating that β-
fluoro Michael acceptors are valuable fluorinated building
blocks (Scheme 2). For example, ester 3b was reduced in the
presence of DIBAL−H to yield the fluorinated allylic alcohol 1c
in high yield.15 Aldehyde 27b underwent Wittig olefination in
modest yield to afford a 1-fluoro-2,4-diene 2c.16 In the presence
of a suitable 1,3-ylide, ester 5b underwent a regioselective [3 +
2] cycloaddition to generate a pyrrolidine with a quaternary
fluorine center (3c).17 Finally, amide 31b was reduced in the
presence of Meerwein’s salt to furnish a fluorine-containing
analogue of Exoderil 4c.18
In conclusion, we have developed a stereoselective hydro-
fluorination of electron-deficient alkynes catalyzed by a
RuPhos-ligated gold(I) complex. For the first time, direct
access to a variety of (Z)-β-alkyl, β-fluoro Michael acceptors
was achieved. In addition, (Z)-β-aryl, β-fluoro α,β-unsaturated
amides and nitriles were conveniently accessed with the
disclosed method. The synthetic potential of the resulting
monofluoroalkene was demonstrated with various trans-
formations of the products without the loss of the newly
installed fluorine atom, and with the synthesis of a fluorinated
analogue of Exoderil.
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Chemical Biology; John Wiley & Sons, Ltd, Chichester, U.K., 2009; pp
3−624.
Scheme 2. Diversification of Fluorinated Michael Acceptors
(2) (a) Landelle, G.; Bergeron, M.; Turcotte-Savard, M. O.; Paquin, J.
F. Synthetic Approaches to Monofluoroalkenes. Chem. Soc. Rev. 2011,
40, 2867−2908. (b) Yanai, H.; Taguchi, T. Synthetic Methods for
Fluorinated Olefins. Eur. J. Org. Chem. 2011, 2011, 5939−5954.
(3) Machleidt, H.; Wessendorf, R. Carbonyl-Fluorolefinierungen.
Justus Liebigs Ann. Chem. 1964, 674, 1−10.
(4) Zajc, B.; Kake, S. Exceptionally Mild, High-Yield Synthesis of α-
Fluoro Acrylates. Org. Lett. 2006, 8, 4457−4460.
(5) Welch, J. T.; Herbert, R. W. The Stereoselective Construction of
(Z)-3-Aryl-2-fluoroalkenoates. J. Org. Chem. 1990, 55 (16), 4782−
4784.
(6) Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.; Falck, J. R.
(Z)-α-Haloacrylates: An Exceptionally Stereoselective Preparation via
Cr(II)-Mediated Olefination of Aldehydes with Trihaloacetates. J. Am.
Chem. Soc. 2003, 125, 3218−3219.
(7) (a) Yanai, H.; Taguchi, T. Synthetic Methods for Fluorinated
Olefins. Eur. J. Org. Chem. 2011, 2011 (30), 5939−5954.
(b) 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. (c) Drouin, M.;
Hamel, J.-D.; Paquin, J.-F. Synthesis of Monofluoroalkenes: A Leap
Forward. Synthesis 2018, 50, 881−955.
(8) (a) Albert, P.; Cousseau, J. Tetrabutylammonium and Polymer-
supported Dihydrogentrifluoride: New Hydrofluorinating Reagents for
Electrophilic Alkynes. J. Chem. Soc., Chem. Commun. 1985, 961−962.
a
Yield given is for isolated product at specified scale. (a) 3b (2.32
n
mmol), DIBAL−H, CH2CI2, 0 °C. (b) BuLi, Ph3PMeBr, 27b (0.3
́
(b) Gorgues, A.; Stephan, D.; Cousseau, J. Mono-hydrofluorination of
mmol), THF, 0 °C. (c) 5b (0.3 mmol), ylide, TFA, 0 °C−rt. (d) 31a
(1.96 mmol), 5 mol % RuPhosAuCI, 5 mol % AgBF4, 1.0 equiv p-CI
BA, 4.0 equiv Et3N·3HF, 45 °C, 48 h, 4:1 MeCN:CH2CI2[1.25 M].
(e)Me3OBF4, 2,6-DI-tBu-pyridine, 31b (0.54 mmol), CH2CI2, rt;
NaBH4, MeOH, −10 °C.
Electrophilic Alkynes by the Liquid Biphasic CsF-H2O-DMF System
(DMF = N,N-dimethylformamide). J. Chem. Soc., Chem. Commun.
1989, 1493−1494. (c) Sano, K.; Fukuhara, T.; Hara, S. Regioselective
Synthesis of β-fluoro-α,β-unsaturated Ketones by the Reaction of β-
diketones with DFMBA. J. Fluorine Chem. 2009, 130, 708−713.
(9) (a) Zhang, J.; Liu, L.; Duan, J.; Gu, L.; Chen, B.; Sun, T.; Gong,
Y. Stereoselective One-Pot Sequential Dehydrochlorination/trans-
Hydrofluorination Reaction of β-Chloro-α,β-unsaturated Aldehydes or
Ketones: Facile Access to (Z)-β-Fluoro-β-arylenals/β-Fluoro-β-
arylenones. Adv. Synth. Catal. 2017, 359, 4348−4358. (b) Yoshida,
M.; Kawakami, K.; Hara, S. An Efficient Stereoselective Synthesis of
(E)-β-Fluoroalkenyliodonium Salts. Synthesis 2004, 2004, 2821−2824.
(c) Yoshida, M.; Komata, A.; Hara, S. Stereoselective Synthesis of
Fluoroalkenes via (Z)-2-Fluoroalkenyliodonium Salts. Tetrahedron
2006, 62, 8636−8645.
(10) (a) McElroy, K. T.; Purrington, S. T.; Bumgardner, C. L.;
Burgess, J. P. Lack of Polymerization of Fluorinated Acrylates. J.
Fluorine Chem. 1999, 95, 117−120. (b) Krishnan, G.; Sampson, P.
Synthesis of β-Fluoro-α,β-unsaturated Esters and Nitriles via a Fluoro-
Pummerer Rearrangement. Tetrahedron Lett. 1990, 31, 5609−5612.
(c) Patrick, T. B.; Neumann, J.; Tatro, A. Cycloaddition Reactions of
ethyl (E)- and (Z)-3-fluoropropenoate. J. Fluorine Chem. 2011, 132,
779−782.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b01341.
Experimental details and compound characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fdtoste@berkeley.edu.
ORCID
F. Dean Toste: 0000-0001-8018-2198
Notes
The authors declare no competing financial interest.
(11) (a) Zhao, Y.; Jiang, F.; Hu, J. Spontaneous Resolution of Julia-
Kocienski Intermediates Facilitates Phase Separation to Produce Z-
and E-monofluoroalkenes. J. Am. Chem. Soc. 2015, 137, 5199−5203.
(b) Thornbury, R. T.; Toste, F. D. Palladium-Catalyzed Defluorinative
Coupling of 1-Aryl-2,2-Difluoroalkenes and Boronic Acids: Stereo-
selective Synthesis of Monofluorostilbenes. Angew. Chem., Int. Ed.
ACKNOWLEDGMENTS
■
We acknowledge the National Institute of General Medical
Sciences (R35 GM118190) for financial support of this work.
T.J.O. thanks the NSF (DGE 1752814) for a predoctoral
fellowship.
2016, 55, 11629−11632. (c) Sommer, H.; Furstner, A. Stereospecific
̈
Synthesis of Fluoroalkenes by Silver-Mediated Fluorination of
Functionalized Alkenylstannanes. Chem. - Eur. J. 2017, 23, 558−562.
(d) Hu, J.; Han, X.; Yuan, Y.; Shi, Z. Stereoselective Synthesis of Z
Fluoroalkenes through Copper-Catalyzed Hydrodefluorination of
gem-Difluoroalkenes with Water. Angew. Chem., Int. Ed. 2017, 56,
13342−13346.
(12) (a) 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.
(b) Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Regio- and
Stereoselective Synthesis of Fluoroalkenes by Directed Au(I) Catalysis.
REFERENCES
■
(1) (a) Bizet, V.; Besset, T.; Ma, J.-A.; Cahard, D. Recent Progress in
Asymmetric Fluorination and Trifluoromethylation Reactions. Curr.
Top. Med. Chem. 2014, 14, 901−940. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem.
Soc. Rev. 2008, 37, 320−330. (c) Hagmann, W. K. The Many Roles for
Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359−4369.
(d) Muller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals:
Looking Beyond Intuition. Science 2007, 317, 1881−1886. (e) Yama-
zaki, T.; Taguchi, T.; Ojima, I. Fluorine in Medicinal Chemistry and
5950
DOI: 10.1021/acscatal.8b01341
ACS Catal. 2018, 8, 5947−5951

ACS Catalysis
Letter
Org. Lett. 2009, 11, 4318−4321. (c) Li, Y.; Liu, X.; Ma, D.; Liu, B.;
Jiang, H. Silver-Assisted Difunctionalization of Terminal Alkynes:
Highly Regio- and Stereoselective Synthesis of Bromofluoroalkenes.
Adv. Synth. Catal. 2012, 354, 2683−2688. (d) Okoromoba, O. E.; Han,
J.; Hammond, G. B.; Xu, B. Designer HF-Based Fluorination Reagent:
Highly Regioselective Synthesis of Fluoroalkenes and gem-Difluoro-
methylene Compounds from Alkynes. J. Am. Chem. Soc. 2014, 136,
14381−14384. (e) 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. (f) 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 For reviews
of gold catalysis and fluorine:. (g) Miro, J.; del Pozo, C. Fluorine and
Gold: A Fruitful Partnership. Chem. Rev. 2016, 116, 11924−11966.
(h) Hopkinson, M. N.; Gee, A. D.; Gouverneur, V. Gold Catalysis and
Fluorine. Isr. J. Chem. 2010, 50, 675−690.
́
(13) Bartolome, C.; Ramiro, Z.; Penas-Defrutos, M. N.; Espinet, P.
̃
Some Singular Features of Gold Catalysis: Protection of Gold(I)
Catalysts by Substoichiometric Agents and Associated Phenomena.
ACS Catal. 2016, 6, 6537−6545.
(14) (a) Malhotra, D.; Hammond, G. B.; Xu, B. Ligand Design in
Gold Catalysis and Chemistry of Gold-Oxonium Intermediates. Top.
Curr. Chem. 2014, 357, 1−24. (b) Gorin, D. J.; Sherry, B. D.; Toste, F.
D. Ligand Effects in Homogeneous Au Catalysis. Chem. Rev. 2008,
108, 3351−3378.
(15) Konno, T.; Ikemoto, A.; Ishihara, T. A New Entry to the
Construction of a Quaternary Carbon Center having a Fluorine Atom-
S(N)2’ Reaction of γ-Fluoroallylic Alcohol Derivatives with Various
Cyanocuprates. Org. Biomol. Chem. 2012, 10, 8154−8163.
(16) Zhu, S.; Guo, Z.; Huang, Z.; Jiang, H. Bioinspired Intra-
molecular Diels-Alder Reaction: A Rapid Access to the Highly-
Strained Cyclopropane-Fused Polycyclic Skeleton. Chem. - Eur. J.
2014, 20, 2425−2430.
(17) (a) Mason, J. M.; Murkin, A. S.; Li, L.; Schramm, V. L.;
Gainsford, G. J.; Skelton, B. W. A β-fluoroamine Inhibitor of Purine
Nucleoside Phosphorylase. J. Med. Chem. 2008, 51, 5880−5884.
(b) McAlpine, I.; Tran-Dube, M.; Wang, F.; Scales, S.; Matthews, J.;
Collins, M. R.; Nair, S. K.; Nguyen, M.; Bian, J.; Alsina, L. M.; Sun, J.;
Zhong, J.; Warmus, J. S.; O’Neill, B. T. Synthesis of Small 3-Fluoro-
and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry. J.
Org. Chem. 2015, 80, 7266−7274.
(18) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. Biomimetic
Entry to the Sarpagan Family of Indole Alkaloids: Total Synthesis of
(+)-Geissoschizine and (+)-N-Μethylvellosimine. J. Am. Chem. Soc.
2003, 125, 4541−4550.
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DOI: 10.1021/acscatal.8b01341
ACS Catal. 2018, 8, 5947−5951