Designer HF-Based fluorination reagent: Highly regioselective synthesis of fluoroalkenes and gem -difluoromethylene compounds from alkynes

Article abstract of DOI:10.1021/ja508369z

Hydrogen fluoride (HF) and selected nonbasic and weakly coordinating (toward cationic metal) hydrogen-bond acceptors (e.g., DMPU) can form stable complexes through hydrogen bonding. The DMPU/HF complex is a new nucleophilic fluorination reagent that has high acidity and is compatible with cationic metal catalysts. The gold-catalyzed mono- and dihydrofluorination of alkynes using the DMPU/HF complex yields synthetically important fluoroalkenes and gem-difluoromethlylene compounds regioselectively.

Full text of DOI:10.1021/ja508369z

Communication
pubs.acs.org/JACS
Designer HF-Based Fluorination Reagent: Highly Regioselective
Synthesis of Fluoroalkenes and gem-Difluoromethylene Compounds
from Alkynes
Otome E. Okoromoba, Junbin Han, Gerald B. Hammond,* and Bo Xu*
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
S
* Supporting Information
and Et3N (pKBHX = 1.98)4 and at same time is much less basic
than pyridine and Et3N (Figure 1). Thus, the DMPU/HF
ABSTRACT: Hydrogen fluoride (HF) and selected
nonbasic and weakly coordinating (toward cationic
metal) hydrogen-bond acceptors (e.g., DMPU) can form
stable complexes through hydrogen bonding. The DMPU/
HF complex is a new nucleophilic fluorination reagent that
has high acidity and is compatible with cationic metal
catalysts. The gold-catalyzed mono- and dihydrofluorina-
tion of alkynes using the DMPU/HF complex yields
synthetically important fluoroalkenes and gem-difluoro-
methlylene compounds regioselectively.
espite its usefulness, the incorporation of fluorine into
D
organic molecules remains a synthetic challenge.1
Fluorination reagents can be classified as electrophilic or
nucleophilic. Nucleophilic fluorination reagents are usually less
expensive than their electrophilic counterparts (e.g., Selectfluor,
NFSI). Most, if not all, fluorinating reagents (electrophilic or
nucleophilic) are made from hydrogen fluoride (HF). Thus, an
HF-based reagent would be ideal in terms of cost and atom
economy, but HF itself is a hazardous gas at room temperature
and is very difficult to handle. Complexes of HF with organic
bases such as Olah’s reagent (pyridine/HF complex)2 and
triethylamine/HF complex3 are liquids at room temperature, so
they are easier to handle. Pyridine/HF and triethylamine/HF
have been explored extensively as nucleophilic sources of
fluorine,2a but these organic bases are not without problems:
they reduce the acidity of the system and may interfere with
many metal catalysts. For example, pyridine can complex
strongly with many transition metals and therefore reduce their
activities.
Figure 1. Comparison of DMPU/HF with pyridine/HF and Et3N/HF.
complex should have higher acidity than the pyridine/HF and
triethylamine/HF complexes. Also, DMPU is weakly coordinat-
ing to most metal catalysts, so it is unlikely to interfere strongly
with most transition-metal catalysts. Moreover, DMPU is a very
weak nucleophile, so it will not compete with HF in nucleophilic
reactions. Therefore, the HF/DMPU complex should be an ideal
fluorination reagent,5 especially in transition-metal-catalyzed
reactions.6 Herein we are glad to report a proof of concept
application of the DMPU/HF complex in the gold-catalyzed,
highly regioselective mono- and dihydrofluorination of alkynes.
Fluoroalkenes are important synthetic building blocks and
targets,7 but they are made from a shallow pool of fluoroalkene
synthons8 or their preparation requires lengthy procedures that
are not functional-group-friendly.9 Typical synthetic methods of
fluoroalkenes include tandem addition−reduction,9a tandem
addition−elimination,10 Shapiro reaction,7b Julia−Kocienski
olefination,11 and Peterson olefination.12 Sadighi and co-workers
have reported a SIPr−Au catalyzed monohydrofluorination of
alkynes using Et3N/HF,13 but because of the low acidity of the
We propose that HF and selected nonbasic, non-nucleophilic,
and weakly coordinating (toward cationic metal) hydrogen-bond
acceptors can form stable complexes through hydrogen bonding.
These HF complexes can act as new nucleophilic fluorination
reagents. In 2009, Laurence and co-workers reported a
comprehensive database of hydrogen-bond basicity (measured
by pKBHX).4 For most compounds, pKBHX is in the range of 1 to 5,
where a bigger number indicates higher hydrogen-bond basicity.4
We used this database as a guideline to select an ideal hydrogen-
bond acceptor. Among many hydrogen-bond acceptors in
Laurence’s database, we considered 1,3-dimethyl-3,4,5,6-tetrahy-
dro-2(1H)-pyrimidinone (DMPU) as an ideal hydrogen-bond
acceptor to form a complex with HF. DMPU is inexpensive and
readily available. Even more important, DMPU (pKBHX = 2.82) is
a better hydrogen-bond acceptor than pyridine (pKBHX = 1.86)
Received: August 14, 2014
Published: September 26, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
Et3N/HF system, stoichiometric amounts of acid and acidic
cocatalyst have to be used. Also, this method works only for
internal alkynes, where there is no reliable way to control the
regioselectivity. By taking advantage of the unique properties of
our DMPU/HF reagent, we were able to mono- and
dihydrofluorinate both terminal and internal alkynes in a highly
regioselective fashion.
Table 2. Substrate Scope for Monohydrofluorination of
Alkynes 1
a
We used the monohydrofluorination of alkyne 1a as our model
reaction. The fluorination agents alone were not able to
fluorinate 1a (Table 1, entries 1−3), and a strong acid (TfOH)
Table 1. Optimization of the Reaction Conditions for
a
Monohydrofluorination of Alkynes
2a
3a
a
b
entry
HF source
pyridine/HF
catalyst
t (h)
(%)
(%)
1
2
−
−
−
24
48
48
24
24
5
0
0
0
0
Bu4N+OTf−/HF
DMPU/HF
pyridine/HF
DMPU/HF
pyridine/HF
DMPU/HF
DMPU/HF
3
0
0
4
TfOH (100%)
TfOH (100%)
Au-1 (5%)
0
0
5
0
0
6
13
48
32
99
99
83
3
7
Au-1 (5%)
5
52
68
<1
<1
0
8
Au-1 (5%)
24
3
9
DMPU/HF (1.2 equiv) Au-1 (5%)
DMPU/HF (1.2 equiv) Au-1 (2%)
DMPU/HF (1.2 equiv) Au-1 (1%)
10
11
3
5
a
Concentrations of HF sources: pyridine/HF (70%), DMPU/HF
b
(65% w/w). Determined by GC−MS.
was not an effective mediator either (entries 4−5). The HF/
DMPU complex we prepared contains 65 wt % HF,
corresponding to an HF:DMPU molar ratio of around
11.8:1.14 We recently reported acid-assisted activation of an
imidogold precatalyst as a superior way to generate cationic gold
compared with the common silver-based methodology.15 We
found that our DMPU/HF system is acidic enough to activate
the imidogold precatalyst (Au-1). Indeed, the DMPU/HF
system is much more efficient in the fluorination of 1a than the
commonly used pyridine/HF complex (entries 6 and 7). The
DMPU/HF/Au-1 system is highly reactive but it gave a mixture
of monofluorinated product 2a and difluorinated product 3a
(entry 8). We were able to achieve selective monofluorination by
reducing the amount of fluorination reagent from 3 to 1.2 equiv
(entry 9), and the good yield and selectivity of product 2a were
maintained even at lower gold precatalyst loadings of 2% and 1%
(entries 10 and 11).
With the optimized conditions in hand, we investigated the
scope of the monohydrofluorination of alkynes (Table 2). Clean
and regioselective transformations were observed for all of the
terminal alkynes tested (Table 2, entries 1−8). The reaction also
worked well for internal alkynes, although longer reaction times
and higher loadings of gold catalyst were needed (entries 9−11).
This reaction also has good functional group tolerance: an alkyne
with a strong electron-withdrawing group (entry 9) and an
alkyne with an acidic C−H group and an ester group (entry 12)
a
Conditions: Alkyne 1 (0.5 mmol) and DMPU/HF (65 wt %, 1.2
b
equiv) in DCE at 55 °C for 3 h. Isolated yields (other yields are 19F
NMR yields).
gave the corresponding fluoroalkenes in good yields and
selectivity.
We found that in the monohydrofluorination of acceptor-
substituted terminal alkyne 1m, the DMPU/HF/Au-1 system
yielded a completely different regioisomer compared with the
literature report, where no catalyst was used. Thus, the
uncatalyzed addition of HF to 1m gave the Michael addition
product 4 (Scheme 1b),16 whereas our DMPU/HF/Au-1 system
reversed the tendency toward Michael addition to give 2m
instead as the only isomer (Scheme 1a).
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Scheme 1. Selectivity of the DMPU/HF/Au-1 Fluorination
System
Ga(OTf)3 can significantly speed up this conversion (eq 1,
condition 2).
With the optimized conditions for dihydrofluorination of
alkynes in hand, we investigated the substrate scope of this
transformation (Table 4). This reaction worked very well for
both terminal and internal alkynes.
The DMPU/HF/Au-1 system is highly effective for alkyne
hydrofluorination, but it is not a good catalyst for hydro-
fluorination of alkenes (Scheme 1c). In other words, alkene
groups are well-tolerated. For example, a 1:1 mixture of 1-octene
(5) and 1-octyne (1b) gave only alkyne hydrofluorination
product 2b under the conditions of our model reaction.
Table 4. Substrate Scope for Dihydrofluorination of Alkynes
a
1
gem-Difluoromethylene (CF2)-containing compounds are
important building blocks and targets in organic synthesis.7a,17
In this regard, dihydrofluorination of an alkyne is a
straightforward and atom-economical way to synthesize CF2-
containing compounds 3. Olah and co-workers reported a
synthesis of difluorinated alkanes with limited scope and
selectivity.2b As shown above (Table 1, entry 8), we observed
the formation of 3a during our search for optimal conditions for
the synthesis of 2a. We believed that further hydrofluorination of
fluoroalkenes 2 would give the dihydrofluorination products 3,
but as we saw in Scheme 1c, our DMPU/HF/Au-1 system is not
a good catalytic system for the hydrofluorination of alkenes, so
complete conversion of 2 to 3 is difficult. We then explored the
possibility of using a cocatalyst or additive that could catalyze the
further hydrofluorination of 2 to give the desired product 3
(Table 3). Additional nucleophilic fluorine sources (CsF and
a
Alkyne 1 (0.5 mmol), DMPU/HF (65 wt %, 3.0 equiv), and KHSO4
b
(1.5 equiv) in DCE at 55 °C for 12 h. Isolated yield (other yields are
19F NMR yields).
The usefulness of our method was further validated by the
synthesis of fluorocarbocycles via ring-closing metathesis (RCM)
reactions (Scheme 2).8 Because fluoroalkenes can be prepared
Table 3. Optimization of the Conditions for
Dihydrofluorination of Alkynes 1
Scheme 2. Synthesis of Fluorocarbocycles
entry
additive
t (h)
2a (%)
3a (%)
1
2
3
4
5
CsF (100%)
24
24
24
24
24
15
85
4
AgF (100%)
96
KCTf3 (10%)
Ga(OTf)3 (10%)
KHSO4 (150%)
67
33
99
99
<0.5
<1
efficiently using our new method and alkene groups are well-
tolerated, we can envision a diverse set of fluorocycles made by
the combination of alkyne monohydrofluorination and RCM
reactions.
In summary, our new fluorination reagent DMPU/HF not
only is easily handled but also is an efficient fluorination system
for the regioselective mono- and dihydrofluorination of alkynes.
Further applications of this new fluorination reagent as well as
commercialization discussions are currently being conducted in
our laboratory.
AgF; entries 1 and 2) were moderately effective, but could not
convert all of the 2a to 3a. The weak Lewis acid KCTf3 (entry 3)
was not effective either, but the stronger acids Ga(OTf)3 and
KHSO4 (entries 4−5) helped to produce 3a with very good
selectivity. Because KHSO4 is relatively inexpensive and readily
available, we selected KHSO4 as our cocatalyst for the synthesis
of 3.
To get a clearer understanding of the role of a Lewis acid like
Ga(OTf)3 in the formation of gem-difluoromethylene com-
pounds 3 we conducted a control experiment (eq 1). DMPU/HF
alone can convert 2a to 3a without any catalyst, but this reaction
is sluggish (eq 1, condition 1). However, a Lewis acid like
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Schlosser, M.; Brugger, N.; Schmidt, W.; Amrhein, N. Tetrahedron
̈
2004, 60, 7731.
AUTHOR INFORMATION
■
(11) Zhu, L.; Ni, C.; Zhao, Y.; Hu, J. Tetrahedron 2010, 66, 5089.
(12) Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81.
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(14) The boiling point of DMPU/HF complex (65 wt % HF) is not
well defined (HF evaporates continuously in the range of 50−120 °C).
The HF in the DMPU/HF complex also evaporates slowly in open air at
55 °C (see the Supporting Information for details).
Corresponding Authors
gb.hammond@louisville.edu
bo.xu@louisville.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Han, J.; Shimizu, N.; Lu, Z.; Amii, H.; Hammond, G. B.; Xu, B.
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(16) Patrick, T. B.; Neumann, J.; Tatro, A. J. Fluorine Chem. 2011, 132,
We are grateful to the National Institutes of Health (R15
GM101604-01) for financial support. O.E.O. is grateful to the
University of Louisville for a McSweeney Diversity Endowed
Fellowship.
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