Regio- And stereoselective synthesis of fluoroalkenes by Directed Au(I) catalysis

Article abstract of DOI:10.1021/ol9016782

Au-catalyzed hydrofluorlnation reactions of a range of functionalized alkynes are reported. In the presence of an appropriate directing group, localized with particular spacing from the pendant alkyne, regloselectlve and predictable conversion of the alky

Full text of DOI:10.1021/ol9016782

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4318-4321
Regio- and Stereoselective Synthesis of
Fluoroalkenes by Directed Au(I)
Catalysis
Benjamin C. Gorske, Curren T. Mbofana, and Scott J. Miller*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520
scott.miller@yale.edu
Received July 22, 2009
ABSTRACT
Au-catalyzed hydrofluorination reactions of a range of functionalized alkynes are reported. In the presence of an appropriate directing group,
localized with particular spacing from the pendant alkyne, regioselective and predictable conversion of the alkyne to the Z-vinyl fluoride may
be achieved. In selected cases, yields and selectivities are excellent. Additional experiments with two directing groups installed have established
some initial principles with respect to a hierarchy of directing groups and their capacity for influencing hydrofluorination regioselectivity.
Fluorine is an element of special interest in organic chem-
istry. Its electronegativity, highest of all the known elements,
contributes to its special properties, which include formation
of strong bonds to carbon,1 low atomic polarizability,2 and
strong inductive characteristics.3 The field of medicinal
chemistry has especially benefited from the development of
chemical techniques for incorporating fluorine into organic
molecules. Fluorine is now routinely introduced to impart
metabolic stability to medicinal compounds.4 Coupled with
its electronegativity, fluorine’s small size has made it an
attractive choice for isosteric substitutions of hydrogen or
other functional groups, especially those containing oxygen.
In this regard, fluoroalkene isosteres of peptide amide bonds
have become increasingly prevalent as structural and mecha-
nistic probes in both biological5 and chemical studies.6
In light of the importance of fluoroalkenes, many efforts
toward efficient regio- and stereoselective syntheses of these
moieties have been reported.7 Of these, we were especially
intrigued by a methodology developed by Sadighi and co-
workers employing a Au(I) catalyst8 to add HF across an
alkyne.9 Using Et3N·3HF as a nucleophilic fluorine source,
KHSO4 as an additive, and various cocatalysts, trans-
hydrofluorination was achieved in good yields (Scheme 1).
(5) (a) Garrett, G. S.; Emge, T. J.; Lee, S. C.; Fischer, E. M.; Dyehouse,
K.; McIver, J. M. J. Org. Chem. 1991, 56, 4823. (b) Bartlett, P. A.; Otake,
A. J. Org. Chem. 1995, 60, 3107. (c) Otaka, A.; Mitsuyama, E.; Watanabe,
J.; Watanabe, H.; Fujii, N. Biopolymers 2004, 76, 140. (d) Urban, J. J.;
Tillman, B. G.; Cronin, W. A. J. Phys. Chem. A 2006, 110, 11120.
(6) Jakobsche, C. E.; Peris, G.; Miller, S. J. Angew. Chem., Int. Ed.
2008, 47, 6707.
(7) (a) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol.
Chem. 2007, 5, 1151. (b) Sano, S.; Kuroda, Y.; Saito, K.; Ose, Y.; Nagao,
Y. Tetrahedron 2006, 62, 11881. (c) Narumi, T.; Tomita, K.; Inokuchi, E.;
Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332,
and references therein.
(1) Cox, J. D.; Gundry, H. A.; Head, A. J. Trans. Faraday Soc. 1964,
60, 653.
(2) Bondi, A. J. Phys. Chem. 1964, 68, 441.
(8) For recent reviews of Au catalysis in organic chemistry, see (a) Li,
Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239. (b) Arcadi, A. Chem.
ReV. 2008, 108, 3266. (c) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
ReV. 2008, 108, 3351.
(3) Banks, H. D. J. Org. Chem. 2006, 71, 8089.
(4) Bo¨hm, H,-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller,
K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
10.1021/ol9016782 CCC: $40.75
Published on Web 08/27/2009
 2009 American Chemical Society

Scheme 1
.
Au-Catalyzed Hydrofluorination of Alkynes
Scheme 2.
Ester-Directed Hydrofluorination of Alkynesa
Modest regioselectivity for alkyl/aryl alkyne substrates was
improved by adding electron-withdrawing groups to the
aromatic ring substituents. Although other alkyne hydroha-
logenations using Au catalysis have been reported, these
reactions utilize electrophilic halogen sources, for the most
part excluding fluorine.10 Also, the substrate scope of these
reactions has been limited to propargyl acetates.
Given our interest in fluoroolefins as mechanistic probes,6
we sought to expand the methodology for Au-catalyzed
nucleophilic fluorination of alkynes by developing new
avenues for regiocontrol that would expand both the utility
and substrate scope of the reaction. Specifically, we envi-
sioned a classical heteroatom-directed reaction that might
confer a high degree of selectivity for a broad range of
substrates.11 Here we report the realization of this design in
the carbonyl-directed hydrofluorination of alkynes under Au(I)
catalysis. We demonstrate that this concept is broadly applicable
and engenders regioselectivities that exceed those originally
reported for this reaction system. As such, this methodology
could facilitate access to new compounds for fundamental
research and the development of pharmaceuticals.
We commenced our investigations by examining ester 1.
We were intrigued to observe that hydrofluorination of this
substrate under the conditions in eq 1 (Scheme 1) exclusively
yielded Z-products as a 40:60 mixture of regioisomers 2a
and 2b (Scheme 2, eq 2). A significant amount of the minor
regioisomer 2a was obtained, which was fluorinated at the
site distal to the ester and opposite that expected for
hydrofluorination of simple alkylaryl internal alkynes, sug-
gesting that the ester exhibited a directing effect. This
directing effect was significantly more pronounced with
dialkyl alkyne substrate 3, giving 91:9 regioselectivity, again
with exclusive Z-stereoselectivity (Scheme 2, eq 2). We then
examined alkynes 5, 7, and 9 to determine how the
regioselectivity is affected by the length of the alkyl chain
connecting the alkyne and the directing ester (Scheme 2, eqs
3-5). Substrate 5 was found to favor regioisomer 6b (19:
81), approaching the regioselectivity expected for an un-
functionalized alkylarylalkyne (7:93)9 and suggesting that
the directing effect of the ester is attenuated, but not
abolished, by the insertion of a single methylene unit in 5
a Yields reported as the average combined yield of all isomers for two
reactions, unless otherwise noted. Isomeric ratios determined by 19F NMR.
b Yield determined using an internal 19F NMR standard. c Isolated yield of
the major product.
vs 1. Shortening the distance between the carbonyl group
and the alkyne by removal of a methylene unit from 1 (as in
7) largely suppressed the formation of regioisomer 8b
compared to 2b. Interestingly, although 9 gave similar yields
of regioisomer 10, the minor product in this case was an
allylic fluoride 11. Propargyl acetates are known to undergo
a variety of skeletal rearrangements in the presence of
cationic Au, including 1,2- and 1,3-acyl shifts to give Au
vinyl carbenoids and Au allenes, respectively.12 The allylic
fluoride could be envisioned to arise from nucleophilic attack
of F- on the intermediate formed by such a 1,3-acyl shift.
We also examined ꢀ,γ-alkynyl ester substrate 12, but yields
were poor, possibly due to facile enolization of this com-
pound.
Since propargyl esters easily rearrange and cannot com-
pletely overcome the innate regioisomeric preferences in the
hydrofluorination of arylalkylalkynes, we sought to examine
other, more robust directing groups that might coordinate
more strongly to Au and enhance regioselectivity (Table 1).
Among these, carbamate-bearing compounds proved par-
ticularly revealing. The 2,2,2-trichloroethoxycarbonyl (Troc)
group proved to be a superior directing group, delivering
fluoroalkenes exclusively over other rearranged products with
excellent regioselectivity for both alkylarylalkynes (entry 1,
92:8; 69% yield) and dialkylalkynes (entry 2, >50:1; 57%
yield). Intriguingly, a minor isomer in the latter case proved
(9) Akana, J. A.; Bhattacharyya, K. X.; Mu¨ller, P.; Sadighi, J. P. J. Am.
Chem. Soc. 2007, 129, 7736.
(12) (a) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan,
S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718. (b) Mauleo´n, P.;
Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513. (c) Marion,
N.; D´ıez-Gonza´lez, S.; de Fre´mont, P.; Noble, A. R.; Nolan, S. P. Angew.
Chem., Int. Ed. 2006, 45, 3647.
(10) (a) Yu, M.; Zhang, G.; Zhang, L. Tetrahedron 2009, 65, 1846. (b)
Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147.
(11) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.
Org. Lett., Vol. 11, No. 19, 2009
4319

impact on the regioselectivity of the reaction (regioselec-
tivities from 92:8 to >50:1 were observed in this series; yields
65-74%). In fact, regioselectivity improved modestly when
a phenyl group was exchanged for an isopropyl group at
this position (Table 1, entries 4 and 6), while substrates with
a terminal butyl group (entries 3 and 5) reacted with complete
regioselectivity. Overall, these results demonstrate that the
Troc group is a stable, general, and potent directing group
for the regioselective hydrofluorination of alkynes.
Table 1. Nitrogen-Containing Directing Groups for
Hydrofluorination of Alkynes
Surprisingly, no reaction was observed with tertiary amine-
bearing substrate 26. This observation is interesting since
the reaction conditions include 1.5 equiv of triethylamine
as a component of the fluorinating reagent. However,
phthalimide 27 was found to exhibit excellent regioselectivity
(>50:1). In reactions of substrate 27, the presence of a
terminal methyl group once again resulted in formation of
small amounts of E-fluoroalkene.
We subsequently wished to expand the scope of our study
to include doubly functionalized alkynes 29 and 30 (Scheme
3). In so doing, we aspired to determine the relative directing
Scheme 3.
Hydrofluorination of Dicarbonyl Substratesa
a Yield determined using an internal 19F NMR standard and reported as
the average combined yield of all isomers for two reactions.
abilities of various types of carbonyl groups in the context
of a direct competition experiment. Unfortunately, attempts
to hydrofluorinate 29 were unsuccessful, yielding primarily
unreacted substrate. Likewise, hydrofluorination of 30 also
did not proceed appreciably but did deliver comparably small
quantities of E- and Z-fluoroalkene. These findings, together
with the lack of reactivity observed for substrate 26, suggest
that bis-functionalized alkynes can interrupt the catalytic
cycle. To gain insight as to the cause of this interruption,
we attempted to ascertain the nature of the initial Au-substrate
a Reported as the average combined yield of all isomers for two reactions,
unless otherwise noted. b Yield determined using an internal 19F NMR
standard.
to be the E-fluoroalkene. The Boc group was considered as
an alternative but was avoided given its potential vulner-
ability to HF. In addition, intramolecular attack of the Au-
activated alkyne by the carbamoyl carbonyl followed by loss
of the tert-butyl group has been reported to give cyclic
urethanes in analogous reactions.13 Notably, no cyclization/
cleavage products of this type were detected with Troc-
substituted compounds.
We further examined the scope of this methodology by
investigating both dialkyl- and alkylarylsubstrates with
sterically demanding substituents at the junction between the
directing group and the alkyne (Table 1, entries 3-6). We
were pleased to observe that these modifications had little
1
complex. H NMR indicated that the chemical shifts of the
complexed substrate, including those of the acetyl group and
urethane proton, were significantly altered. This data raises
the possibility that the presence of two directing groups either
(a) inhibits the rate of nucleophilic attack of the Au-activated
alkyne by fluoride, possibly in a competitive mode (32), or
(b) compromises the activation of the alkyne by the Au
catalyst, perhaps via an inductive effect. A further possibility
invokes the bidentate nature of the bis-functionalized alkynes
as a potential cause for sequestration of the metal such that
4320
Org. Lett., Vol. 11, No. 19, 2009

productive complexation to the alkyne cannot occur (Figure
1, 33 and 34), an attractive hypothesis considering the
Figure 1. Possible intermediates representing interruptions of the
catalytic cycle for the hydrofluorination of 29.
Figure 2. A mechanistic hypothesis for the directed hydrofluori-
nation of alkynes.
perturbation of both the acetyl and urethane signals in the
1H NMR spectrum.14 These ideas remain speculative at this
time and await further experimental examination before a
definitive explanation may be advanced.
In summary, we have achieved the regio- and stereose-
lective synthesis of fluoroalkenes by using carbonyl groups
to direct the Au(I)-catalyzed hydrofluorination of alkynes.
Troc-carbamates were found to be the best directing group,
both in terms of regioselectivity and stability to the reaction
conditions, delivering the desired fluoroalkenes with signifi-
cant regioselectivity in all cases examined. Such reactions
may be useful for the synthesis of fluoroolefins of interest
in medicinal and physical organic chemistry. Future work
will entail generalization of these reactions further, potentially
in a ligand-dependent way through studies of catalyst
modification.
In light of what is known about the mechanism of this
reaction,9 we have considered the mechanistic hypothesis
shown in Figure 2 as a possible basis for the successful cases
of regioselectivity we have observed. Following counterion
exchange with silver tetrafluoroborate, the Au catalyst could
complex to both the carbonyl oxygen and the alkyne of the
substrate (35). Nucleophilic attack of the activated alkyne
by fluoride could then occur such that the more energetically
favored ring is preferentially formed in intermediate 36.
Protonation of the Au and reductive protodeauration of 37
would extrude the product 38 and regenerate the active
catalytic species. Given the trend observed in Scheme 2, it
appears that n ) 1 (Figure 2) is optimal for regioselectivity
within this substrate class. These mechanistic proposals are
hypothetical and preliminary and await further experimental
work for possible validation.
Acknowledgment. We are grateful to the National Science
Foundation (CHE-0848224) and the National Institutes of
Health (R01-GM068649), each for partial support of this
research.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Hashmi, A. S. K.; Salathe´, R.; Frey, W. Synlett 2007, 1763.
(14) Au(I)-alkene complexes containing an N-heterocyclic carbene
ligand have also been reported; see: Brown, T. J.; Dickens, M. G.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 6350, and references
therein.
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