Stereodivergent Alkyne Hydrofluorination Using Protic Tetrafluoroborates as Tunable Reagents

Article abstract of DOI:10.1002/anie.202006278

The discovery of safe, general, and practical procedures to prepare vinyl fluorides from readily available precursors remains a synthetic challenge. The metal-free hydrofluorination of alkynes constitutes an attractive though elusive strategy for their preparation. Introduced here is an inexpensive and easily handled reagent that enables the development of simple and scalable protocols for the regioselective hydrofluorination of alkynes to access both the E and Z isomers of vinyl fluorides. These reaction conditions were suitable for a diverse collection of alkynes, including several highly functionalized pharmaceutical derivatives. Computational and experimental mechanistic studies support C?F bond formation through vinyl cation intermediates, with the E- and Z-hydrofluorination products forming under kinetic and thermodynamic control, respectively.

Full text of DOI:10.1002/anie.202006278

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Stereodivergent Alkyne Hydrofluorination Using Protic
Tetrafluoroborates as Tunable Reagents
Authors: Rui Guo, Xiaotian Qi, Hengye Xiang, Paul Geaneotes, Ruihan
Wang, Peng Liu, and Yiming Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006278
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10.1002/anie.202006278
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Stereodivergent Alkyne Hydrofluorination Using Protic
Tetrafluoroborates as Tunable Reagents
Rui Guo#, Xiaotian Qi#, Hengye Xiang, Paul Geaneotes, Ruihan Wang, Peng Liu* and Yi-Ming Wang*
Dr. R. Guo, Mr. H. Xiang, Mr. P. Geaneotes, Ms. R. Wang, Prof. Dr. Y.-M. Wang
Department of Chemistry
University of Pittsburgh
Pittsburgh, Pennsylvania 15260, United States
E-mail: ym.wang@pitt.edu
Dr. X. Qi, Prof. Dr. P. Liu
Department of Chemistry
University of Pittsburgh
Pittsburgh, Pennsylvania 15260, United States
E-mail: pengliu@pitt.edu
# These authors contributed equally to this work
Supporting information for this article is given via a link at the end of the document
1
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Abstract: Vinyl fluorides play an important role in drug
development as bioisosteres for peptide bonds and are found in a
range of bioactive molecules. The discovery of safe, general and
practical procedures to prepare vinyl fluorides from readily available
hydrogen fluoride as the fluorinating reagents (Scheme 1B).[7-13]
In the Au-catalyzed systems, (Z)-vinyl fluorides are formed with
high stereoselectivity, and for aryl alkyl alkynes, the major
regioisomer formed is the one in which the fluorine is delivered
to the carbon adjacent to the alkyl group (β to the aryl group,
Scheme 1B, a). Since the initial report of Au-catalyzed alkyne
hydrofluorination in 2007, the scope of this process has seen
considerable expansion and now includes alkynes bearing
electron-withdrawing groups or directing groups, as well as
precursors remains
a
synthetic challenge.
The metal-free
hydrofluorination of alkynes constitutes an attractive though elusive
strategy for their preparation. Here we introduce an inexpensive
and easily-handled reagent that enabled the development of simple
and scalable protocols for the regioselective hydrofluorination of
alkynes to access both the E and Z isomers of vinyl fluorides.
These conditions were suitable for a diverse collection of alkynes,
including several highly-functionalized pharmaceutical derivatives.
Computational and experimental mechanistic studies support C–F
bond formation through vinyl cation intermediates, with the (E)- and
(Z)-hydrofluorination products forming under kinetic and
thermodynamic control, respectively.
terminal alkynes.
Nevertheless, the control of the
regioselectivity and E/Z-selectivity remains an outstanding
issue in a number of cases (Scheme 1B, a).[3b]
Introduction
The incorporation of fluorine into organic compounds plays a
significant role in the pharmaceutical and agrochemical
sciences, due to the element’s distinctive capability for
modulating the physical and chemical properties of
a
biologically active scaffold, including its solubility, metabolic
stability, potency, and bioavailability.[1] Among organofluorine
derivatives, vinyl fluorides constitute a privileged substructure
and an important target of chemical synthesis. In particular,
they can serve as metabolically and chemically stable
bioisosteres of amides and enols by mimicking the charge
distribution and dipole moments of these functional groups.[2] In
other contexts, they can also function as irreversible enzyme
inhibitors by acting as Michael acceptors (Scheme 1A).[2c]
Established synthetic methods to access vinyl fluorides
primarily employ olefination or elimination reactions that require
multistep transformations and the preparation or commercial
availability of prefunctionalized fluorinated precursors.[3] Among
methods that directly establish the carbon–fluorine bond, the
Pd-catalyzed synthesis of vinyl fluorides from the
corresponding triflates employs an alkali metal fluoride as a
readily available fluorine source.[4] In contrast, the metal-
catalyzed and noncatalytic electrophilic fluorination of various
vinylmetal species constitutes a flexible and versatile approach
that has given rise to a multitude of synthetic protocols.[5]
Finally, the dehydrative fluorination of ketones using
difluorosulfur(IV) reagents is another approach that has
appeared in the patent literature.[6]
As an alternative to the aforementioned approaches, the
hydrofluorination of alkynes represents a particularly general
and atom-economical synthesis of vinyl fluorides, especially
considering the broad range of alkyne substrates that are easily
accessed from inexpensive, commercially available building
Scheme 1. Strategies for the synthesis of vinyl fluorides
While the development of methods for the direct synthesis of
vinyl fluorides via C–F bond formation has provided more
opportunities to introduce the functional group and expanded
the range of synthetically accessible vinyl fluorides, currently
available methods suffer from one or more significant
drawbacks, including the expense and poor atom economy of
electrophilic fluorinating reagents ultimately derived from F2
gas,[3a] the corrosivity and toxicity hazards associated with HF-
based reagents, and the challenges of accessing large
blocks.
Several
metal-catalyzed
systems
for
the
hydrofluorination of alkynes have been developed in recent
years.[7-15] Following the initial disclosure of a Au-catalyzed
process by Sadighi and co-workers,[7] a number of coinage
metal complexes have been employed as catalysts for the
hydrofluorination of alkynes using Lewis base adducts of
2
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quantities of sophisticated ligands and transition metal catalysts.
These drawbacks limit the scalability and applicability of current
protocols. Consequently, the development of operationally
simple protocols and practical reagents for accessing vinyl
fluorides with control of regio- and stereochemistry remains an
ongoing challenge.
ionization of vinyl iodonium[27] and diazonium species,[28]
(pseudo)halide abstraction with Lewis acids,[29,30] as well as
protonation of alkynes with strong Brønsted acid or
a
Brønsted/Lewis acid complex.[31,32] Despite the challenging and
specialized conditions that are often required for their
generation, the versatility of this intermediate has led to a
recent renaissance in their synthetic applications.[33] In this
context, the hydrofluorination conditions reported here
represent an unprecedentedly mild, stereocontrolled, and
functional group compatible approach for utilizing these
intermediates.
Considering their low cost, high fluoride content, as well as
excellent
safety,
stability,
and
handling
profiles,
−
tetrafluoroborate (BF4 ) salts are particularly attractive sources
of nucleophilic fluorine.[16] However, aside from the well-
developed Balz-Schiemann process, they have seldom been
employed in the formation of C(sp2)−F bonds due to the weak
nucleophilicity of this anion, and the handful of examples in
which they are employed as fluorine sources in vinyl fluoride
synthesis generally entail the use of exotic functional groups or
strongly oxidizing conditions.[17] Given the canonical status of
the alkyne hydrochlorination, –bromination, and –iodination
reactions[18a] and mechanistic studies supporting a concerted
AdE3 mechanism or an AdE2 mechanism featuring a vinyl
cation intermediate for these processes,[18b,18c] we hypothesized
that a metal-free hydrofluorination could result from a mild and
selective protonation of the alkyne, followed by trapping of the
resultant Brønsted acid–alkyne complex or vinyl cation
Results and Discussion
Reaction development. We began the exploration of our
hydrofluorination strategy using (cyclohexylethynyl)benzene as
a starting material, inspired by the lack of literature precedent
employing secondary alkyl-substituted phenylacetylenes as
substrates for hydrofluorination (Table 1). We anticipated that
the preparation of various amine salts of HBF4 would allow for
the tuning of reagent acidity and provide control over
hydrofluorination reactivity. Thus, a diverse collection of amine
salts of HBF4 was evaluated. While it was found that reagents
based on triethylamine (A), pyridine (B), and 2-chloropyridine
(C) were unreactive in CHCl3 at room temperature or 70 °C
(entries 1-3), the more electron-poor 3,5-dichloropyridinium salt
−
intermediate by BF4 . Therefore, we posited that a suitable
fluoroboric acid (HBF4) equivalent could serve as a general and
practical hydrofluorinating reagent for alkynes.
By employing pyridine•9HF, the hydrofluorination of alkynes
using a base-modulated source of hydrogen fluoride was
already the subject of pioneering investigations by Olah and
coworkers in the 1970s.[19] More recent studies by Hammond,
Xu, and co-workers lead to the development of several
‘designer’ base-complexed sources of hydrogen fluoride.[20]
However, both reports indicate that, in general, even with
careful control of the reaction temperature (0 to 50 °C), HF-
amine reagents deliver the gem-difluoride bis(hydrofluorination)
product (Scheme 1B, b), without allowing for the isolation of the
presumed vinyl fluoride intermediate except in special cases
where the alkyne bears a donor heteroatom substituent (e.g.,
ynamide[21] or alkynyl sulfide substrates[22]).
Here, we report the discovery and development of a simple
and practical reagent for the stereodivergent hydrofluorination
of alkynes which, in most cases, delivers vinyl fluoride products
with excellent control of the regio- and stereoselectivity
(Scheme 1C). For certain substitution patterns, we report
complementary conditions for the synthesis of either the E or Z
isomer of the hydrofluorination product with good to excellent
E/Z ratios. The conditions reported here are tolerant of a variety
of functional groups, and we applied them to the late-stage
functionalization of drug derivatives and the synthesis of
fluorinated drug analogs.
(D) provided
a trace of the desired product (entry 4).
Continuing with more electron-deficient and strongly acidic
pyridinium salts, we found that the 2,6-dihalopyridinium salts (E
and F) were more efficient reagents, with the more electron-
deficient chlorinated reagent providing the desired product with
good yield and excellent stereoselectivity (Z/E > 50:1, entry 6).
2-Cyclohexylacetophenone, the product of alkyne hydration,
was found to be the major side product of the reaction. The
addition of LiBF4 (25 mol %) suppressed the formation of this
side product and further enhanced the yield (entry 7).
As anticipated, optimization of the reagent structure proved
critical for the development of a protocol for hydrofluorination.
The tetrafluoroborate salts were generated by the treatment of
an ethereal solution of the amine or pyridine with commercially
available HBF4•Et2O and were isolated by filtration. This
straightforward procedure was readily scaled to allow for the
synthesis of reagents on 50 mmol (> 10 g) scale. The acidity of
the pyridinium species was found to be a key factor, and
pyridinium salts effective for hydrofluorination had aqueous pKa
values of –2 or lower. On the other hand, for very weakly basic
aq.
pyridines (e.g., pentachloropyridine, pKa
~
–8),[34] the
abovementioned procedure did not give an isolable solid
material, presumably because the acidity of ethereal fluoroboric
acid was insufficient for quantitative protonation of the pyridine.
A mechanistic study of the process was performed through
kinetics experiments and density functional theory (DFT)
calculations. These studies support the intermediacy of vinyl
cations in the hydrofluorination reaction. They also provide
insight into the excellent stereochemical control and account for
the ability to selectively obtain the E or Z isomer through the
variation of reagent and reaction conditions. Previously, vinyl
cations have been generated through several approaches,[23]
including metal catalysis,[24,25] photochemical processes,[26]
Among the pyridinium salts examined (see SI for details), 2,6-
aq.
dichloropyridinium tetrafluoroborate (F, pKa
=
–2.86)[35]
possessed the best reactivity and handling properties. In
particular, reagent F was not especially hygroscopic and could
be stored as a colorless solid in the desiccator for at least a
week or in the glovebox indefinitely (> 3 months) without
noticeable deterioration or loss of activity. Thus, when the
hydrofluorination of (cyclohexylethynyl)benzene was repeated
3
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with the starting materials weighed and reaction tube sealed
under air, the decrease in yield was found to be modest, with
the yield of 2 decreased to 78% yield by 19F NMR, compared to
82% under standard conditions.
1
2
3
A
B
C
70
70
70
0
0
0
—
—
—
Lastly, we also examined HBF4•Et2O itself as another
potential reagent. Surprisingly, we found that treatment of the
model substrate with HBF4•Et2O (1.0 equiv) at room
temperature for 6 h resulted in the formation of desired
hydrofluorination product 1 in moderate yield (42% yield) and
good selectivity for the opposite E stereoisomer (E/Z = 11:1,
entry 9). Under these conditions, alkyne hydration was a
significant side reaction, with 2-cyclohexylacetophenone
formed in 30-35% isolated yield. On the other hand, the use of
this reagent at 70 °C resulted after 1 h in the complete
consumption of starting material and formation of a complex
mixture of products (tar), with neither of the stereoisomeric vinyl
fluoride products observed by 19F NMR. In spite of the modest
yields, we felt that this complementary protocol for generating
the E isomer may be of some synthetically utility. Moreover,
this intriguing stereochemical outcome prompted us to apply
experimental and computational tools to scrutinize the
mechanism of the hydrofluorination process.
4
5
6
7
8
9
D
70
70
70
70
r.t.
r.t.
< 5
45
1 : 5
36 : 1
> 50 : 1
> 50 : 1
1 : 5
E
F
74
F
F
82[a] (76)[b]
< 5
HBF4•Et2O
42[b]
1 : 11
10
HBF4•Et2O
70
0[c]
—
[a] LiBF4 (25 mol %) was added as an additive. [b] Isolated yield. [c] Reaction
time: 1 h, with complete conversion of the starting alkyne to tarry materials.
Substrate scope. Under these optimized conditions, we set
out to investigate the scope of this hydrofluorination reaction
(Scheme 2). Using reagent F for hydrofluorination, alkyl aryl
acetylenes bearing electron-withdrawing (e.g., products 9, 19,
20, 22) to electron-donating (e.g., products 23, 24, 25) aryl
substituents reacted effectively to afford the (Z)-configured
fluoroalkene products in moderate to good yields and excellent
regio- and stereoselectivities. Moreover, several common
functional groups on the aryl ring including a methyl ester (19),
a cyano group (20), a trifluoromethanesulfonyl ester (22), and a
phthalimide (23) were tolerated. Heteroaryl alkyl acetylenes,
including an indole and a furan likewise delivered the desired
product (24, 25). The structure of 22 was determined by single
crystal X-ray diffraction for confirmation of the alkene
stereochemistry.
Table 1. Optimization of reaction conditions for hydrofluorination
Entry
Fluorinating reagent
Temp./°C
Yield/%
Z/E
4
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Scheme 2. Substrate scope of alkynes. Condition A: fluorinating reagent F (1.0 equiv), LiBF4 (25 mol%), CHCl3 (0.2 M), 70 to 90 °C. Condition B: HBF4·Et2O (1.0
equiv), CHCl3 (0.2 M), r.t., 6 h. Condition C: fluorinating reagent F (3.0 equiv), CHCl3, 80 to 100 °C, 12 h. Condition D: fluorinating reagent F (2.0 equiv), DCE, 70
to 100 °C, 12 h. a1.0 equiv of Et2O•BF3 was used as additive. bgem-difluoroalkane (<5 % 19F NMR yield) was detected. cgem-difluoroalkane; the yield shown is the
combined yield of the vinyl fluoride and gem-difluoroalkane products. See the Supporting Information for detailed conditions.
5
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employed in this hydrofluorination to give the corresponding
monofluoroalkene as the major fluorination product with low to
moderate yields (61-70). In cases where yield was low (e.g., 61,
62) the major side product observed was the ketone hydration
product. With 1,2-dichloroethane as the solvent, symmetrical
diarylacetylenes could give corresponding monofluoroalkene
products in moderate to good yields and excellent Z-
selectivities (71-74). For unsymmetrical substrates, when one
of the benzene rings was substituted by an electron-
withdrawing group (e.g., 4-CO2Me, 2-Cl), the hydrofluorination
proceeded with excellent Z-selectivities and was regioselective
for fluorination nearer the more electron-rich aryl group (75-80).
Finally, it was found that by switching to chloroform as the
solvent, the monofluoroalkene product could be formed with E-
selectivity (81-84).
With the exception of terminal alkyl and dialkyl acetylenes,
the gem-difluoride product was either not observed (<1%) or
observed as very minor components (1–5% yield by 19F NMR)
of the crude product. However, a reduction in selectivity was
observed for a dialkylacetylene substrate, which gave the gem-
difluoroalkane in addition monofluorinated product (50, 4:1 Z/E,
5:3 vinyl fluorides/difluoroalkane). In the alkyl aryl acetylenes
and terminal acetylenes, no evidence of the other regioisomeric
hydrofluorination product could be observed (< 1%) in the
crude material by 19F NMR. In the case of the hydrofluorination
of diarylacetylenes, regioisomeric products were sometimes
observed. When direct comparisons were available (for 75, 77,
82), the regioisomeric ratios (15:1 to > 20:1) exceeded those
previous reported for the Au-catalyzed transformation (2:1 to
4.3:1).[12]
Synthetic applications. To demonstrate the potential
applicability of this new hydrofluorination method to the late-
stage modification of structurally complex substrates, including
biologically active molecules and natural products, we explored
several readily available alkynes derived from exo-norborneol
(85) and ferrocene (86), natural products (1S)-(+)-10-
camphorsulfonic acid (87) and estrone (88, 89), as well as drug
molecules probenecid (90), febuxostat (92) and telmisartan (94)
to afford monofluoroalkene products with moderate to good
yields and high regio- and stereoselectivities (Scheme 3a). In
addition, terminal alkyl-substituted alkynes derived from drug
molecules probenecid and febuxostat could also be employed
in the dihydrofluorination to form gem-difluorides with moderate
yields and exclusive regioselectivity (91, 93). These examples
demonstrated that our hydrofluorination and difluorination
protocols were suitable for the late-stage, protecting-group-free
modification of biologically active molecules and could tolerate
a range of functional groups and heterocycles including
ketones (87-89), esters (90-94), a ferrocene (86), a sulfonate
(87), a sulfonamide (90, 91), a nitrile (92, 93), a thiazole (92,
93), and benzimidazoles (94).
We next explored the scope of alkyl substituents on the
substrate. A range of primary, secondary, cyclic or acyclic alkyl-
substituted alkynes could be employed in the hydrofluorination
to furnish respective products again with moderate to good
yields and excellent regio- and stereoselectivities (27-39).
Remarkably, substrates with potentially sensitive functional
groups including a primary chloro (40, 46), a carboxymethyl
(41), a cyano (42), a pyridyl (43), and a phthalimido group (44)
also delivered the vinyl fluoride products in moderate to good
yields, highlighting the mildness and good functional group
tolerance of this protocol. This scalability of the procedure was
demonstrated by the gram-scale preparation of 44, which
proceeded with unchanged regio- and stereoselectivities and
only a slightly reduced yield (1.65 g, 64%). The protocol was
insensitive to steric effects on the alkyl substituent, with a
methyl group (47, 48) and a cyclododecyl (49) group giving
similar yields, both with excellent regio- and stereoselectivities.
It is noteworthy that in hydrofluorination reactions employing
alkyl aryl acetylenes, the vinyl fluoride products were delivered
exclusively with C–F bond formation taking place adjacent (α)
to the aryl group. These results complement Au-catalyzed
hydrofluorination procedures, which deliver the fluorine to the
carbon adjacent to the alkyl group, β to the aryl group.[7-12] This
divergence likely stems from the ability for the aryl group to
stabilize both an adjacent positive charge in the case of the
current metal-free process and an adjacent C(sp2)–Au bond in
case of the Au-catalyzed protocols to give the α– and β–
fluorinated regioisomers, respectively.
We also explored the scope of the complementary E-
selective hydrofluorination with HBF4•Et2O using a subset of the
previously investigated alkyl aryl acetylenes (condition B).
Substrates bearing mildly electron-withdrawing or electron-
donating substituents could afford the vinyl fluoride products
with moderate to very good E-selectivity (E/Z ratio from 4:1 to >
20:1) and modest to moderate yields (32% to 48% yield).
Electron poor substrates like 1-haloalkynes and ethyl
phenylpropiolate were also suitable substrates for this reaction.
In each case, a single regio- and stereoisomer was produced
(51-55). The reactivity order of the 1-halo-2-phenylacetylenes
was I > Br > Cl, reflecting the inductive electron withdrawing
power of the halogen. In the case of Cl and Br, the low and
moderate isolated yields resulted from incomplete conversion
of the starting material to the vinyl fluoride product.
The hydrofluorination reaction could also be applied to
terminal alkynes and diarylacetylenes. When using terminal
alkyl-substituted alkynes as substrates, gem-difluorides were
obtained as the primary products with exclusive internal
regioselectivity. A variety of functional groups such as a
phthalimide (57), a ketone (59), esters (58, 60), an indole (59),
as well as a ferrocene derivative (60) were well tolerated. On
the other hand, terminal aryl-substituted alkynes could be
6
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Scheme 3. Synthetic applications of stereodivergent alkyne hydrofluorination. a, The late-stage modification of biologically active molecules or complex natural
products. b, The synthesis of different fluorinated analog of drug molecules. c, The preparation of key intermediate for the synthesis of antimicrobial agents with
high regio- and Z/E-selectivities. See supporting information for detailed conditions.
To explore other applications of this chemistry, we prepared
95 on 5-mmol scale to access fluorinated analogs of
antihistamines cinnarizine (97), flunarizine (98) and antifungal
drug naftifine (99) (Scheme 3b). Via allylic bromination of 95,
we prepared a common brominated intermediate 96, which
could be applied to synthesize all three analogs. Moreover, we
also prepared vinyl fluoride 100, a known precursor for the
synthesis of antimicrobial agents (protein synthesis inhibitors)
through the coupling with 2-oxazolidone (Scheme 3c).[36,37]
These transformations demonstrate the excellent potential of
this method for future applications in a drug discovery setting.
Mechanistic discussion. The experimental results have
demonstrated that 2,6-dichloropyridinium tetrafluoroborate is an
effective fluorinating reagent for stereodivergent alkyne
hydrofluorination. As shown in Table 2, high levels of Z-
selectivity are obtained in a polar solvent (i.e. DCE, condition
D), while reactions in a less polar solvent (i.e. chloroform,
condition C) or under lower temperatures (see SI) completely
switch the stereoselectivity to favor E-products. Mechanistic
studies were then performed to investigate whether the
hydrofluorination occurs through a concerted or stepwise
mechanism and the origin of the divergent stereoselectivity.
DFT calculations[38] of the hydrofluorination of 1,2-
diphenylacetylene 101 indicated
a
stepwise AdE2-type
−
protonation-fluorination mechanism with a BF4 /vinyl cation ion-
pair intermediate (Figure 1). Prior to the alkyne protonation, the
H⋯F hydrogen bond in the fluorinating reagent F dissociates to
release a free pyridinium cation as the proton source. Two
protonation transition states were located (TS-1 and TS-1a), in
which the tetrafluoroborate anion is syn and anti to the
7
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−
pyridinium, respectively. Bonding interactions between BF4
hydrofluorination products. Fluorination of the highly
electrophilic vinyl cation with BF4− (via TS-2 and TS-2a) is facile,
which makes protonation (TS-1) the rate-determining step. This
mechanistic picture is consistent with experimental Hammett
analysis (Scheme 4C) and kinetics studies (see SI for details),
which indicated a ρ value of –3.43 consistent with previously
and the alkyne were not observed in either protonation
transition state, which is likely due to the weak nucleophilicity of
−
BF4 . The stepwise hydrofluorination mechanism is confirmed
by intrinsic reaction coordinate (IRC) calculations, which
indicated that TS-1 and TS-1a lead to BF4 /vinyl cation ion pairs
102 and 102a, respectively, rather than the direct formation of
−
reported
vinyl
cation-mediated
reactions[23]
and
Figure 1. Reaction energy profiles of the hydrofluorination of 1,2-diphenylacetylene 101 with 2,6-dichloropyridinium tetrafluoroborate. The bond lengths are in
angstrom. All energies were calculated at the M06-2X/6-311+G(d,p)/SMD(chloroform)//M06-2X/6-31+G(d)/SMD(chloroform) level of theory. See Fig. S10 and S11
in SI for the computational results with the cyclohexyl and methyl-substituted alkynes.
8
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first-order kinetics in alkyne and H+ and zero-order kinetics in
excess BF4− (Scheme 4C). The E-selective pathway (shown in
black in Fig. 1) is kinetically favored in both protonation and
fluorination steps. The syn-protonation transition state TS-1 is
more stable than the anti-TS (TS-1a) due to more favorable
–
electrostatic interactions between BF4 and the pyridinium
cation. The E-selective fluorination transition state TS-2 is 0.9
kcal/mol more stable than the Z-selective fluorination (TS-2a)
−
because of steric repulsions[21] between BF4 and the β-phenyl
group in TS-2a.[39] Therefore, regardless of whether ion pairs
102 and 102a have sufficient lifetime to interconvert prior to the
fluorination, kinetic E-selectivity is expected. The relatively low
barrier for the reverse reaction of E-81 (via TS-2, ∆G‡ = 23.6
kcal/mol) to generate the vinyl cation indicates the E-to-Z vinyl
fluoride isomerization may occur at elevated temperatures
through BF3-mediated fluoride anion elimination followed by
fluorination of the vinyl cation via TS-2a. A polar solvent, which
could stabilize ion-pair intermediates 102 and 102a, is expected
to promote such isomerization (see Fig. S15 in the SI for
energy profiles computed in DCE). Because the Z-stereoisomer
Z-71 is 2.3 kcal/mol more stable than E-71, high Z-selectivity is
expected under these thermodynamically controlled conditions.
In light of the strength of the C(sp2)–F bond (124 kcal/mol),[40]
the reversibility of C–F bond formation seemed surprising, and
we sought to obtain experimental support. The BF3-mediated
E/Z-vinyl fluoride isomerization was verified experimentally
under conditions with Et2O•BF3 (eqs 1 and 2). The addition of
2,6-di-tert-butylpyridine did not shut down the BF3-mediated
isomerization, which excludes the possibility that the presence
of a Brønsted acid is required for isomerization.[41] In certain
cases, (e.g., 86 and 87), we observed that better Z-selectivity
could be obtained by addition of exogenous Et2O•BF3 to
promote E-to-Z-isomerization (see the SI for detailed
conditions). In addition, the increase of the Z-product ratio over
a reaction time of 12 h at 70 °C further confirmed the
isomerization of the kinetic E-isomer to Z-vinyl fluoride in the
hydrofluorination of di-p-tolylacetylene (E/Z ratio from 6:1 to
1:2.4) (Scheme 4A). Further experimental study of the dielectric
constant of solvent suggested that higher Z-selectivity could be
obtained when increasing the dielectric constant of solvent (E/Z
ratio from 20:1 to 1:16.2) (Scheme 4B), which verified the
hypothesis that polar solvent could promote E-to-Z-vinyl
fluoride isomerization. The increase of reaction temperature
was also found to favor the formation of Z-vinyl fluoride (see the
SI for details).
Scheme 4. Mechanistic studies A. Change of the Z/E-ratio of the
hydrofluorination product over the course of reaction and the variation of
temperature. B. Dielectric constant study. C. Hammett-plot analysis for para-
substituted aryl cyclohexyl alkynes and kinetic studies. See supporting
information for detailed conditions.
D. Proposed mechanism for the
stereodivergent hydrofluorination of alkyne.
9
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10.1002/anie.202006278
Angewandte Chemie International Edition
RESEARCH ARTICLE
Based on these mechanistic studies, a general mechanism is
proposed to elucidate the stereoselectivity control in the alkyne
hydrofluorination (Scheme 4D). The rate-determining syn-
protonation of alkyne (k1) leads to an ion pair intermediate (I),
which then undergoes fluorination (k2) to afford the kinetically
favored E-vinyl fluoride. The thermodynamically more stable Z-
product is formed from the isomerization of the E-vinyl fluoride,
which takes place via BF3-mediated fluoride dissociation (k-2)
and isomerization of the ion pair intermediate (k3) followed by
Keywords: vinyl fluoride • fluorinating reagent • pharmaceutical
derivatization • vinyl cation • DFT study
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(e.g.
in
the
HBF4•Et2O
mediated
hydrofluorination), less polar solvents, and bulkier alkyne
substituents (e.g. R = aryl) that suppress the ion pair
isomerization (k3) and the Z-selective fluorination (k4) would
lead to higher E-selectivity under kinetic control.
Conclusion
We have developed a simple, practical, and metal-free strategy
for the regio- and stereoselective controlled mono- and
dihydrofluorination
of
alkynes
by
employing
2,6-
dichloropyridinium tetrafluoroborate as a new, safe, and stable
fluorinating reagent. Mechanistic and DFT studies reveal that
the stereoselectivity of hydrofluorination results from either
kinetic or thermodynamic control in a stepwise protonation-
fluorination pathway. We anticipate that this hydrofluorination
protocol will find wide applications in drug discovery and related
fields by facilitating the preparation of fluorinated molecules of
biological interest. Studies further exploiting the synthetic
applications of vinyl cation intermediates generated under
similar mild conditions are ongoing.
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Acknowledgements
We thank the University of Pittsburgh and the NIH
(R35GM128779) for financial support for this work. DFT
calculations were performed at the Center for Research
Computing at the University of Pittsburgh and the Extreme
Science and Engineering Discovery Environment (XSEDE)
supported by the National Science Foundation grant number
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10.1002/anie.202006278
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RESEARCH ARTICLE
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11
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RESEARCH ARTICLE
Entry for the Table of Contents
An inexpensive new reagent enables the development of metal-free protocols for stereodivergent hydrofluorination. Computations
and mechanistic data support the intermediacy of vinyl cations, which are trapped to deliver (E)- and (Z)-vinyl fluorides under kinetic
and thermodynamic control, respectively.
12
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