Expanding the repertoire of cyclopropenium ion phase transfer catalysis: Benzylic fluorination

Article abstract of DOI:10.1016/j.tet.2018.04.083

The application of cyclopropenium ion as a phase transfer catalyst for benzylic fluorination in high yields is reported. Integral to the mechanisms of these fluorination reactions was the role of in situ derived cyclopropenium fluoride complexes, the existence of which was supported by ¹H, ¹⁹F NMR and UV–Vis spectroscopy. Density functional theory calculations were applied to gain insight into the mechanism of these reactions.

Full text of DOI:10.1016/j.tet.2018.04.083

Accepted Manuscript
Expanding the repertoire of cyclopropenium ion phase transfer catalysis: Benzylic
fluorination
Katie Dempsey, Roya Mir, Ivor Smajlagic, Travis Dudding
PII:
S0040-4020(18)30488-5
10.1016/j.tet.2018.04.083
TET 29498
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 April 2018
Revised Date: 24 April 2018
Accepted Date: 25 April 2018
Please cite this article as: Dempsey K, Mir R, Smajlagic I, Dudding T, Expanding the repertoire of
cyclopropenium ion phase transfer catalysis: Benzylic fluorination, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.04.083.
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ACCEPTED MANUSCRIPT
Leave this area blank for abstract info.
Expanding the Repertoire of Cyclopropenium
Ion Phase Transfer Catalysis: Benzylic Fluorination
Katie Dempsey, Roya Mir, Ivor Smaklagic, and Travis Dudding*
Department of Chemistry, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1

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1
Expanding the Repertoire of Cyclopropenium Ion Phase Transfer
Catalysis: Benzylic Fluorination
Katie Dempsey, Roya Mir, Ivor Smajlagic and Travis Dudding*
Department of Chemistry, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario,
Canada, L2S 3A1
Abstract:
The application of cyclopropenium ion as a phase transfer catalyst for benzylic
fluorination in high yields is reported. Integral to the mechanisms of these fluorination
reactions was the role of in situ derived cyclopropenium fluoride complexes, the
1
19
existence of which was supported by H, F NMR and UV-Vis spectroscopy. Density
functional theory calculations and quantum theory of atoms in molecules (QTAIM) were
applied to gain insight into the mechanism of these reactions.
Keywords: • cyclopropenium cation • fluorination • phase transfer catalysis • hydrogen
bond • benzylic fluorination.
1
. Introduction
The influential role of phase transfer catalysis (PTC) on chemical synthesis spans
1
decades and its impact in academia and industry continues to gain traction. Contributing
to this status has been a myriad of factors, including operational simplicity, general use of
mild reaction conditions and inexpensive reagents/solvents, plus scalability. Catalyst
mediated transport of reactive intermediates between different phases (bi- and/or tri-
phasic), further adds to its utility as it reduces by-product formation arising from
1
,2
incompatible chemical reactivity.
Today several classes of phase transfer catalysts exist with each having distinct
advantages in terms of chemical reactivity. Classic in this respect are ammonium and
phosphonium cations, which find widespread use in shuttling anionic species between
3
,4
phases. Conversely, crown ethers by way of host-guest complexation enabled phase
3
,5
6
7
8
transfer of cations. Imidazolium , triazolium , and tetraaminophosphonium ions have
also shown utility as phase transfer catalysts with the mode of action in these cases
deriving from various non-covalent interactions including π-π stacking, cation-
*
Corresponding author.
Email address: tdudding@brocku.ca

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2
9
,10
π interactions, and H-bonding.
Furthermore, our group recently pioneered the use of
1
1
cyclopropenium analogues as phase transfer catalysts, while in a contemporary work
Lambert and co-workers reported the use of tris(dialkylamino)cyclopropenium salts as
1
2
phase transfer catalyst.
In terms of phase transfer catalyzed applications, C−N, C−O, and C−C bond-forming
1
3
protocols are arguably the most well-established, whereas, C−F bond formation remains
1
4
less explored. This is despite the value of fluorinated compounds in drug design,
1
8
agrochemicals, material science, F positron emission tomography (PET) imaging and
1
5
pharmaceuticals. In fact, it has been estimated that 20 to 30% of pharmaceutical
molecules contain at least one fluorine, thus highlighting the importance of developing
1
6
methodologies for preparing organofluorine compounds.
That aside, tert-
butylammonium fluoride (TBAF) has been widely used in phase transfer catalyzed
1
7
fluorination reactions , however, associated with its use are drawbacks, e.g., it is
hydroscopic, undergoes Hoffman E -elimation between 40 - 77 °C (2 Torr), has a low
2
-
fluoride to total reagent mass ratio (F = 7.3% of total mass of NBu F) and stoichiometric
4
or greater amounts are generally needed in practice. Moreover, elimination by-products
1
8
are often observed when using anhydrous TBAF owing to its strong basicity. Lastly, the
isolation of water-soluble products, such as sugars from TBAF, can be challenging as
1
9
standard work-up protocols call for aqueous acid/base washes.
Recently, alternative methods for C−F bond formation have been explored using
2
0
phase transfer conditions. For instance, Toste and co-workers reported the use of a
chiral phosphate salt together with a poorly soluble fluorinating reagent in
2
1
enantioselective fluorination of allylic alcohols, while in 2016 Tamamura and co-
workers developed a mild fluorination method for pyrroles using a combination of
2
2
Selectfluor, a lipophilic anionic phase transfer catalyst, and base. Further, a series of
dicarboxylic acid precatalysts were recently developed by Hamashima that, upon
deprotonatation, act as anionic phase transfer catalysts for asymmetric fluorination of
2
3
alkenes.
Inspired by this precedent, the prospect of employing a cyclopropenium ion (1) or
−
corresponding ion pair 1ꢀCl as a phase transfer catalyst for C−F bond forming
fluorination incited our curiosity. Especially, as it would add to the rich history of

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3
2
4,25
cyclopropeniums,
while building upon our interest in these compounds. An interest
−
−
−
that notably has led to the reported use of 1ꢀCl as well as derivatives 2ꢀCl and 3ꢀ2 Cl
11,26,27
as phase transfer catalysts by our group (Figure 1a).
In building upon this precedent
we disclose herein a novel cyclopropenium ion mediated phase transfer catalyzed
2
8
1
19
reaction enabling benzylic fluorination. One arrived at through H, F NMR and
UV/Vis spectroscopic studies as well as density functional theory (DFT) calculations
providing insight into the catalytic role of in situ derived cyclopropenium fluoride
−
−
complexes such as 1ꢀF or computed DFT-1ꢀF (Figure 1b). Notably, this catalytic
approach in comparison to protocols utilizing onium salts (e.g., TBAF) for benzylic
fluorination typically uses lower catalyst loadings, does not require excess drying of
1
8
reagents, and affords higher yields.
N(iPr)2
N(iPr)2
N(iPr)2
(
(
iPr)2N
iPr)2N
Cl
H
Cl
2 Cl
N(iPr)2
Me
N
(iPr)2N
NH HN
N( Pr)2
i
N
a)
b)
N
Me
1
Cl
2
Cl
3
2 Cl
(
iPr)2N
N(iPr)2
R-LG
R
F
H
Solution phase
Nucleophilic F-
LG
Fꢀ
1
F
DFT-1
F
Phase Transfer
Interface
Solid phase
reservoir of F-
(
iPr)2N
N(iPr)2
Clꢀ
H
1
Cl
Fꢀ M+ Fꢀ M+ Fꢀ M+ Fꢀ M+ Fꢀ M+ Fꢀ M+
Fꢀ Fꢀ
R = Substrate
LG = Leaving Group
M = Cs, K
Fꢀ M+ Fꢀ M+ Fꢀ M+ Fꢀ M+
M+
M+
−
−
−
Figure 1. (a) Previously reported cyclopropenium phase transfer catalysts 1ꢀCl , 2ꢀCl and 3ꢀ2 Cl . (b)
−
Structure DFT-1ꢀF computed at the wB97XD/6-311+G(d,p)/def2TZV level.
2
. Results and discussion
At the outset of this work to explore the prospect of developing our envisioned
benzylic fluorination approach, benzyl bromide (4a) (1 equiv.) and KF (3 equiv.) were

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4
−
reacted under various conditions using cyclopropenium ion 1ꢀCl as a phase transfer
catalyst (Table 1, entries 1 – 10). These various attempts, however, afforded fluorination
product 5a in low conversions (Table 1, entries 1 – 10); albeit the use of propionitrile as a
solvent and a catalyst loading of 15 mol % were identified as promising lead conditions
(Table 1, entry 7). Reasoning the in situ generation of posited fluoride adducts such as
−
1
ꢀF was unfavourable we turned to spectroscopic studies to gain insight into their
formation and stability.
Table 1. Screening of the reaction conditions.
[a]
Entry
Solvent
Catalyst
mol %)
Temp. (°C)
Conversion
(
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
10
10
10
15
15
15
15
15
15
15
40
60
80
40
60
80
80
80
80
80
~5
~5
~5
~5
~5
10
20
0
3 5
C H N
[b]
THF
[
c]
1,2-DME
0
[
d]
1
0
MTBE
0
[
a]
1
[b]
[c]
Conversion based on
H
NMR
Tetrahydrofuran
1,2-
Dimethoxyethane [d] Methyl tert-butyl ether
1
To this end, H NMR titration studies involving the addition of KF (0.2 – 0.8 equiv.)
−
to a solution of 1ꢀCl (CD CN, 0.07 M) at 298 K resulted in a very slight upfield shift of
3
2
the parent cyclopropenium C(sp) –H signal (ꢀδ = 0.03 ppm) suggestive of only a weak
−
interaction between cyclopropenium (1) and F (see supporting information (SI)).

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5
Further, in a separate experiment tetra-butylammonium fluoride (TBAF) (0.2 equiv.) was
−
added to a solution of 1ꢀCl (CD
3
CN, 0.07 M) at 298 K resulting in an immediate, more
−
significant upfield shift of the signal of 1ꢀCl at 7.75 ppm to 7.71 ppm (Figure 2a, spectra
A and B). Cooling the sample to 253.9 K then resulted in splitting of the peak at 7.71
ppm into a pair of well-resolved signals at 7.69 ppm and 7.78 ppm from which the
1
9
presence of at least two or more different species can be inferred (see SI). Likewise, F
NMR revealed a broad signal at -149 ppm at room temperature (Figure 2b, spectra A) that
upon cooling to 250.3 K resolved into two peaks at 149.20 and 149.98 ppm (Figure 2b,
2
9
spectra B). Subsequent warming of the sample to room temperature followed by
addition of further TBAF equivalents then led to a gradual downfield shift of the
2
cyclopropenium C(sp) –H hydrogen signal at 7.71 ppm to 7.78 ppm (Figure 2a, spectra C,
D and E).
B
A
b)
E
D
C
B
A
a)
1
−
Figure 2. (a) Comparison H NMR spectra at 400 MHz of 1ꢀCl in CD CN at 298 K upon titrations with
3
1
9
TBAF- black (0.0 equiv.), red (0.2 equiv.), green (0.4 equiv.), blue (0.6 equiv.), yellow (0.8 equiv.) (b)
F
−
NMR of 1ꢀF in CD
3
CN (A) in presence of TBAF (0.2 equiv.) at 298.1 K (400 MHz) and (b) in presence of
TBAF (0.2 equiv. at 250.3 K (600 MHz).

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6
−
To further probe the formation of complexes of 1ꢀF the UV-Vis spectra of a
−
solution of 1ꢀCl in CH CN was monitored as subsequent aliquots of TBAF (0.2 equiv.)
3
were added. Resulting from these additions was the notable appearance of a broad band
−
at ~325 nm, presumably associated with the formation of 1ꢀF complexes originating
from non-covalent interactions (Figure 3).
3.000
2.500
2.000
1.500
1.000
0.500
0.000
0.0 equiv.
0.2 equiv.
0.4 equiv.
0.6 equiv.
0.8 equiv.
1.0 equiv.
1.2 equiv.
1.4 equiv.
2.0 equiv.
200.0 250.0 300.0 350.0 400.0 450.0
Wavelength (nm)
-4
−
Figure 3. UV-Vis titration of 5 × 10 M solution of 1ꢀCl in acetonitrile with 0-2.0 equiv. TBAF.
−
With evidence for the formation complexes of 1ꢀF and still hopeful that metal
fluorides could be used in this methodology, owing to their low cost and general stability,
we turned our attention to the use of CsF as an alternative fluoride source. The reasoning
-1
-1
being the lower lattice energy of CsF (740 kJ mol ) relative to KF (821 kJ mol ) would
−
facilitate salt metathesis leading to the formation of 1ꢀF . Supporting this premise were
NMR experiments repeated using dry CsF in place of TBAF, which resulted in similar
trends as those seen with TBAF (see SI).
Working from these observation the fluorination of benzyl bromide (4a) (0.5 mmol)
−
with CsF (1.5 mmol) and 1ꢀCl (15 mol%) was attempted which, to our liking, afforded
benzyl fluoride (5a) in 87% isolated yield (Table 2, entry 1). However, when the reaction
of benzyl bromide was performed under the same conditions in the absence of catalyst
−
1
ꢀCl only a small amount of product was observed (5% yield, see SI). Motivated by this
promising result the substrate scope of this reaction methodology was further explored.

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7
Accordingly, 4-nitrobenzyl bromide (4b) having electron-withdrawing nitro group
reacted to provide 5b in 5 h, whereas 2-(bromomethyl)naphthalene (4c) was converted to
product 5c in slightly lower yield of 84%, after 7 h (entries 2 and 3). In comparison,
substrate 4d with an inductively electron-withdrawing and resonance electron-donating
p-chloro substituent provided 5d in 89% yield (entry 4). Similarly, the reaction of
electron-donating p-methyl substituted 4e afforded product 5e in 92% yield, while
exchanging the bromide for a tosylate leaving group attenuated reactivity (entries 5 and
6
). Meanwhile, the reaction of bulky o-iodo substituent 4g resulted in product 5g in a
reduced yield of 81% after 10 h, as might be expected owing to sterics (entry 7). Next, in
entertaining the question of regioselectivity, 4h was reacted to afford S 2 displacement
N
’
product 5h with no S
N
2 product formation observed (entry 8). This reaction methodology
proved to be selective for primary substrates as demonstrated by substrate 4i, where only
low conversion of the starting material to the fluorinated product was observed after 24 h
(
entry 9). Finally, to explore reactivity beyond benzylic substitution, aliphatic substrate 4j
was reacted resulting in 6.8:1 substitution/elimination product ratio with 5j formed in
4% yield, along with recovered starting material (entry 10).
5
−
Table 2. Fluorination of Substrates 5a-j using Catalyst 1ꢀCl .
Entry
Substrate
Product
Time
Yield
(%)
(
h)
1
2
7
87
93
5
7
3
F
84
5c

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8
4
8
89
5
6
7
7
92
85
7
8
10
10
81
83
[
a]
9
24
48
<5
[a]
1
0
54
[
a]
1
Yield was calculated based on H NMR.
To account for the above reactivity the DFT computed benzylic fluorination
≠
-1
transition state TS1, with a Gibbs free energy of activation (ꢀG ) of 18.7 kcal mol ,
−
arising from complex 1′ꢀF and substrate 4a is proposed. Salient features of this
transition state structure include a CꢀꢀꢀF bond forming distance of 2.1 Å and CꢀꢀꢀBr
bond breaking distance of 2.5 Å. Further, in the context of the Hammond Postulate, TS1
3
0
typifies an early transition state as supported by the computed Wiberg bond indices of
0
.5 for the breaking CꢀꢀꢀBr bond and 0.2 for the forming CꢀꢀꢀF bond. From TS1 the
−
formation of product 5a along with regeneration of complex 1ꢀF was found to be an
exergonic process.

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9
Scheme 1. Reaction Coordinate for Catalyzed Benzylic Fluorination (wB97XD/6-
[
a]
3
11+G(d,p)/def2TZV).
N(iPr)2
N(iPr)2
δ
2
.5 Å
H
Br
2.1 Å
δ
H
F
H
TS1
18.7]
[
4
a + 1′ F−
0.0]
[
5
a + 1′ Br−
36.8]
[
-
1
[
a]
Relative free energies are shown in brackets (kcal mol ).
3
. Conclusion
In expanding the utility of cyclopropenium ions as phase transfer catalysts, a
benzylic fluorination reaction methodology affording organofluorines has been reported
1
19
using inexpensive metal fluoride, CsF. H, F NMR and UV-Vis spectroscopy, as well as
computational studies have identified in situ derived cyclopropenium fluoride complexes
as intermediates in this reaction methodology. Notably, these complexes originate from
weak, yet additively significant non-covalent interactions. The mechanistic findings of
this work offer insights transferable to a wide range of areas, e.g., asymmetric catalysis,
bioengineering and host-guest molecular ion sensing. Accordingly, ongoing efforts in our
laboratory are directed towards expanding the repertoire of cyclopropenium-mediated
phase transfer catalysis.

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10
4
. Experimental Section
Computational Methodology. Calculations were carried out using the density functional
3
1
32
WB97XD and the 6-311+G(d,p)/def2TZV basis set using the Gaussian 09 and
GaussView v5.0.8 programs. To account for solvent effects, the integrated equation
3
3
formalism polarized continuum solvation model (IEFPCM) was used throughout the
computations. All minima were confirmed by the presence of only real vibrational
frequencies.
Materials and Methods. Materials were obtained from commercial suppliers and were
used without further purification unless otherwise stated. Cesium fluoride (CsF) was
dried under high vacuum with heating to 65 °C. All reactions were conducted under an
inert atmosphere (N ) and monitored by thin layer chromatography (TLC) using silica gel
2
6
0 F254. Flash column chromatography was performed over silica gel (230-400 mesh).
1
13
NMR spectra were recorded on a 300 MHz spectrometer ( H 300 MHz, C 75.5 MHz,
1
9
F 292.4 MHz) in CDCl unless specified otherwise. The observed chemical shifts are
3
reported
as
δ-values
(ppm)
relative
to
tetramethylsilane
(TMS).
3
4
35
36
Tetrachlorocyclopropene, cyclopropenium chloride and benzyl tosylate derivative
were prepared according to literature procedures and the spectra matched accordingly.
General Procedure for the Cyclopropenium-Catalyzed Fluorination of Benzylic
−
Substrates (5a-j) with CsF. A dry RBF was charged with reported 1·Cl (21 mg, 0.15
mmol), 4-nitrobenzylbromide (85 mg, 0.5 mmol), and CsF (227 mg, 1.5 mmol) and
o
dissolved in propionitrile (1 mL). The resulting mixture was heated to 65 C under reflux
for 7 hours. Solvent was removed and product was purified by flash chromatography
1
(
hexanes to ethyl acetate = 6:1) to provide 5b as a yellow oil. H NMR (300 MHz,
o
CDCl , 25 C): ꢀ = 5.34-5.50 (d, J = 47.8 Hz, 2H), 7.43 (m, 5H).
3
1
1
(
Fluoromethyl)benzene (5a). Product was extracted with hexane to provide 5a as a clear
1
o
colourless oil. (48 mg, 87% yield), H NMR (300 MHz, CDCl
3
, 25 C): ꢀ = 5.34-5.50 (d,
J = 47.8 Hz, 2H), 7.43 (m, 5H).
1
1
1
1
-(Fluoromethyl)-4-nitrobenzene (5b). (72 mg, 93% yield), H NMR (300 MHz,
o
CDCl
3
, 25 C): ꢀ = 5.45-5.60 (d, J = 46.7 Hz, 2H), 7.53-7.56 (d, J = 8.28 Hz, 2H), 8.25-
8
.28 (d, J = 8.34 Hz, 2H).

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11
1
1
1
2
3
-(Fluoromethyl)naphthalene (5c). (67 mg, 84% yield), H NMR (300 MHz, CDCl , 25
o
C): ꢀ = 5.50-5.65 (d, J = 47.7 Hz, 2H), 7.51-7.57 (m, 3H), 7.86-7.92 (m, 4H).
3
7
1
1
-(Fluoromethyl)-4-chlorobenzene (5d) (64 mg, 89% yield), H NMR (300 MHz,
o
CDCl
3
, 25 C): ꢀ = 5.29-5.45 (d, J = 47.6 Hz, 2H), 7.32-7.35 (dd, J = 1.41, 8.40 Hz, 2H),
7
.38-7.41 (d, J = 8.46 Hz, 2H).
3
8
1
1
-(Fluoromethyl)-4-methylbenzene (5e). (57 mg, 92% yield), H NMR (300 MHz,
o
CDCl
3
, 25 C): ꢀ = 2.41 (d, J = 2.25 Hz, 3H), 5.29-5.45 (d, J = 48.2 Hz, 2H), 7.23-7.25
(d, J = 8.01 Hz, 2H), 7.30-7.34 (dd, J = 1.89, 7.98 Hz, 2H).
1
1
1
o
(
Fluoromethyl)benzene (5f). (47 mg, 85% yield), H NMR (300 MHz, CDCl
3
, 25 C): ꢀ
=
5.34-5.50 (d, J = 47.8 Hz, 2H), 7.43 (m, 5H).
1
1
-(Fluoromethyl)-2-iodobenzene (5g). (96 mg, 81% yield), H NMR (300 MHz, CDCl ,
3
o
2
5 C): ꢀ = 5.34-5.50 (d, J = 47.2 Hz, 2H), 7.06-7.11 (t, J = 7.50, 14.6 Hz, 1H), 7.40-7.49
1
3
o
(
m, 2H), 7.86-7.89 (d, J = 7.89 Hz, 1H); C NMR (75.5 MHz, CDCl , 25 C): ꢀ = 86.7-
3
8
1
8.9 (d, J = 170.7 MHz), 128.2-128.3 (d, J = 9.69 Hz), 128.5, 130.1 (d, J = 1.99 MHz),
19
o
39.2.; F NMR (292 MHz, CDCl , 25 C) ꢀ = -213.2 (t, J = 48.9, 1F) (HRMS (EI): m/z
3
+
calcd for C H FI (M ): 235.9500; found: 235.9491.
7
6
3
9
1
(
E)-(3-Fluoroprop-1-en-yl)benzene (5h). (57 mg, 83% yield), H NMR (300 MHz,
o
CDCl
3
, 25 C):ꢁꢀ = 4.96-5.15 (ddd, J = 1.26, 6.06, 46.9 Hz, 2H), 6.33-6.46 (m, 1H), 6.69-
6
.76 (dd, J = 5.13, 15.9 Hz, 1H), 7.30-7.46 (m, 5H).
Acknowledgements
The authors thank Sharcnet for computing resources. Financial support was provided by
the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery
Grant (201404410).
Appendix A: Supplementary Data
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(

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