Frustrated Lewis-Pair-Meditated Selective Single Fluoride Substitution in Trifluoromethyl Groups

Article abstract of DOI:10.1021/jacs.9b12167

Single fluoride substitution in trifluoromethylarenes is an ongoing synthetic challenge that often leads to "over-reaction", where multiple fluorides are replaced. Development of this reaction would allow simple access to a vast range of difluoromethyl derivatives of current interest to pharmaceutical, agrochemistry, and materials sciences. Using a catalytic frustrated Lewis pair approach, we have developed a generic protocol that allows a single substitution of one fluoride in trifluoromethyl groups with neutral phosphine and pyridine bases. The resulting phosphonium and pyridinium salts can be further functionalized via nucleophilic substitution, photoredox coupling, and electrophilic transfer reactions allowing the generation of a vast array of difluoromethyl products.

Full text of DOI:10.1021/jacs.9b12167

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Article
Frustrated Lewis pair meditated selective single
fluoride substitution in trifluoromethyl groups
Dipendu Mandal, Richa Gupta, Amit K Jaiswal, and Rowan D. Young
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Jan 2020
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Frustrated Lewis pair meditated selective single fluoride substitution
in trifluoromethyl groups
Dipendu Mandal†, Richa Gupta†, Amit K. Jaiswal, Rowan D. Young*
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Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
ABSTRACT: Single fluoride substitution in trifluoromethylarenes is an ongoing synthetic challenge that often leads to ‘over-reac-
tion’, where multiple fluorides are replaced. Development of this reaction would allow simple access to a vast range of difluoromethyl
derivatives of current interest to pharmaceutical, agrochemistry and materials sciences. Using a catalytic Frustrated Lewis Pair ap-
proach, we have developed a generic protocol that allows a single substitution of one fluoride in trifluoromethyl groups with neutral
phosphine and pyridine bases. The resulting phosphonium and pyridinium salts can be further functionalized via nucleophilic substi-
tution, photoredox coupling and electrophilic transfer reactions allowing the generation of a vast array of difluoromethyl products.
Introduction:
Substituting a single fluorine atom in trifluoromethyl groups
has been an enduring academic challenge. Apart from the car-
bon-fluorine (C–F) bond being the strongest carbon-element
single bond known,1 the bond dissociation energy of C–F bonds
tends to decrease as geminal fluorine atoms are substituted (Fig-
ure 1, A), leading to over-reaction for carbon positions with
more than one fluorine atom.2 Indeed, a generic method for the
nucleophilic substitution (a fundamental organic chemical
transformation) of a single fluoride atom in trifluoromethyl
groups remains unrealized. The ability to monoselectively func-
tionalize aliphatic polyfluorides is an attractive proposition, as
it would allow fast and convenient access to a number of fluo-
rine containing motifs with high chemical diversity in the bio-
logically relevant 3D chemical space.3 Despite the synthetic po-
tential of such a protocol, very few reports of monoselective C–
F functionalization exist for benzotrifluorides, all of which are
limited in their scope of benzotrifluorides and/or coupling part-
ners. Specifically, ortho-silyl benzotrifluoride substrates have
allowed kinetically controlled C–F functionalization in CF3
groups (Figure 1, B),4 Stephan reported controlled monohydro-
defluorination of PhCF3 using a silylium/phosphine adduct
(Figure 1, C),5 Single Electron Transfer (SET) approaches al-
low selective alkyldefluorination of electron poor benzotrifluo-
rides using alkene or enone reagents (Figure 1, D),6 and transi-
tion metal catalyzed monohydrodefluorination was exhibited on
para-protected benzotrifluoride derivatives by Lalic (Figure 1,
E).7
Figure 1. (A) Decreasing C–F bond strength with substitution of fluo-
rine with hydrogen in tetrafluoromethane. (B-E) Known approaches to
Recently, we reported a synthetic methodology that allowed se-
monoselective C–F functionalization. (F) Utilizing FLP reactivity to
lective single C–F bond activation in gem-difluorogroups.8 The
‘deactivate’ fluorocarbon motifs towards further fluoride abstraction by
Lewis acids to prevent ‘over-reaction’.
strategy was based on heterolytic cleavage and capture of car-
bocation and fluoride components of a C–F bond with a Frus-
trated Lewis Pair (FLP). Triaryl phosphine bases were em-
ployed in our FLP system, allowing subsequent Wittig cou-
To construct new carbon-element single bonds, we expanded
plings with aldehydes to provide fluoro-olefin products (Figure
our attention to other bases/leaving groups with established
1, F).
chemistry allowing single bond formation to sp3 carbon centers.
In theory, this concept could be extended to a wide variety of
To this end, we found success in the use of 2,4,6-triphenylpyri-
polyfluoride starting materials (including benzotrifluorides),
dine (TPPy). Pyridinium salts (in particular TPPy adducts) can
undergo nucleophilic substitution but are also capable of cross
given that any C–F bond on the captured cationic fragment
would be ‘deactivated’ towards further fluoride abstraction.
coupling, reductive coupling and borylation chemistry, thus
However, triaryl phosphoniums act as poor leaving groups from
TPPy is a very attractive leaving group.9 We document here,
sp3 carbon positions in traditional palladium coupling and nu-
cleophilic substitution chemistries,9 meaning that subsequent
functionalization of intermediate phosphonium salts is limited.
our efforts to apply FLP C–F activation methodology to more
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Table 1. Selected optimization conditions for C–F activation.
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entry BCF
base
time
M[X]
Yield (%)
loading
150%
1a
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
THT
pyridine
lutidine
TPPy
TPPy
TPPy
24 h
24 h
24 h
24 h
24 h
4 h
24 h
24 h
24 h
48 h
24 h
48 h
4 h
-
<1
<1
2a
20%
20%
20%
20%
20%
5%
20%
20%
20%
150%
20%
20%
0%
Li[BF4]
Li[B(C6F5)4] 20
3a
4
9
Me3SiOTf
Me3SiNTf2
Me3SiNTf2
Me3SiNTf2
Me3SiNTf2
Me3SiNTf2
Me3SiNTf2
-
<1
70
>95
86
<1
<1
20
<1
>95
87
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6a
7a
8b
9a
10
11a
12
13b
14
Me3SiNTf2
Me3SiNTf2
Me3SiNTf2
TPPy
48 h
<1
a In DCE at 80 °C. b In DCE at 60 °C. BCF = tris(pentafluorophenyl)bo-
rane, THT = tetrahydrothiophene, TPPy = 2,4,6-triphenylpyridine.
challenging aromatic trifluoromethyl groups to generate difluo-
romethyl products.
Results and Discussion
Treatment of p-Tol–CF3 (1a) with the FLP [B(C6F5)3] (BCF)
and P(o-Tol)3 led to no reaction at room temperature, and less
than 1% yield of the desired phosphonium salt after 24 h heating
at 80 °C (Table 1, entry 1). However, removal of the abstracted
fluoride from the reaction through precipitation of LiF or loss
of Me3SiF gas promoted the reaction and allowed for catalytic
quantities of BCF to be used. Indeed, the use of Me3SiNTf2 was
found to be effective even at room temperature, allowing high
yields of the desired phosphonium salt [p-TolCF2–P(o-
Tol)3][NTf2] (2a) to be generated (Table 1, entries 5-7).
Attempts using tetrahydrothiophene, pyridine or lutidine as the
base partner gave poor conversion or failed to react with 1a (Ta-
ble 1, entries 8-10). However, the nitrogen donor base 2,4,6-
triphenylpyridine10 (TPPy) generated the desired TPPy pyri-
dinium salt, 3a, almost quantitatively at room temperature after
48 h (60% yield after 24 h) with catalytic loadings of BCF (Ta-
ble 1, entry 12). Heating of reaction mixtures containing TPPy
led to a faster conversion of 1a to 3a (Table 1, entry 13), how-
ever, it was found that 3a decomposed at higher temperatures
over time, compromising the reaction yield. Finally, running the
reaction without any BCF catalyst failed to generate any 3a (Ta-
ble 1, entry 14). Although Me3SiNTf2 is a strong Lewis acid,
previously reported hydrodefluorination reactions also failed
when utilizing Me3SiOTf.11
Phosphonium salt 2a could be readily isolated via crystalliza-
tion in 67% isolated yield. The 13C NMR of 2a confirms the
substitution of a fluoride in 1a by phosphorus with the benzylic
carbon resonance at 121.3 ppm displaying one-bond couplings
to both phosphorus and the remaining two fluorine atoms (td,
1JCF = 270.6 Hz, 1JCP = 90.0 Hz). The 19F and 31P NMR spectra
of 2a also support monoselective substitution, with a doublet
signal δF -79.4 (2JFP = 109.0 Hz) arising from the benzylic fluo-
rines and a triplet signal at δP 31.8 (2JPF = 109.0 Hz) due to the
phosphonium center. A molecular structure of 2a displays the
Figure 2. Molecular structures of [p-TolCF2P(o-Tol)3][NTf2] (2a),
[PhCF2(TPPy)][NTf2] (3b). Hydrogen atoms and anions omitted, ther-
mal ellipsoids shown at 50%. See SI for crystallographic parameters.
connectivity in 2a with P(o-Tol)3 capturing the defluorinated
[p-Tol–CF2]+ fragment at the benzylic position as expected
(Figure 2).
The TPPy salt 3a was found to be stable in the reaction mixture
at room temperature for a number of days, allowing spectro-
scopic and spectrometric characterization. 19F NMR spectros-
copy of 3a revealed a signal at δF -55.5 arising from the benzylic
fluorine atoms. The 13C NMR spectrum revealed the benzylic
carbon signal at δC 122.3 to be a triplet (1JCF = 273 Hz), indicat-
ing a one-bond coupling to two fluorine atoms. Despite the ap-
parent stability of 3a, attempts to isolate and/or crystallize 3a
led only to decomposition products, however, evidence of its
connectivity was obtained from the molecular structures of the
related TPPy phenyl derivative 3b derived from Ph–CF3 (Figure
2), and from the transfer product 4k, where pyridine displaced
TPPy in 3a (Figure 4). Interestingly, the N–CF2 distance in 3b
is slightly elongated as compared to 4k {N1–C1 (3b) = 1.521(2)
Å cf. N1–C1 (4k) = 1.505(2) Å}, suggesting a slightly weaker
N–CF2 bond in 3b.
A brief survey of substrates revealed that P(o-Tol)3 could read-
ily substitute a single fluoride in a range of trifluoromethyl
groups (Figure 3). Electron donating groups as well as weakly
withdrawing groups were well tolerated (4a-d). More challeng-
ing bis(trifluoromethyl)benzene substrates could also be acti-
vated, and selective activation in one or both of the trifluorome-
thyl groups could be controlled with suitable reaction tempera-
tures. At 80 °C, monosubstitution dominated giving rise to
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products 2e and 2f, however, above 100 °C disubstitution be-
1
2
came dominant, and the bisphosphonium product 2g could be
obtained in 71% yield.
Selective activation of 2-trifluoromethylpyridine under forcing
conditions provided a mediocre 48% yield of 2i due to catalyst
inhibition by the starting material, however, the reaction was
shown to better tolerate less basic heteroaromatics such as fu-
ran, with 2h generated in 61% yield. Lastly, non-aromatic sys-
tems could also be monoselectively activated, with trifluoro-
methoxybenzene providing 2j in 50% yield and 2k generated in
71% yield from trifluoromethylthiobenzene.
Notably, SET selective C–F alkylation approaches do not toler-
ate aryl halides and furans, react poorly with electron rich ben-
zotrifluorides and are completely inactive for non-aromatic CF3
groups. Thus, the subsequent alkylation and hydrogenation of
P(o-Tol)3 positions (demonstrated below) is complementary to
SET methodologies.
As described above, triaryl phosphines are poor leaving groups
for SN2 substitutions, and in general, controlled nucleophilic
substitution of CF3 groups is not possible using existing chem-
istries. In contrast, the nucleophilic substitution chemistry of al-
kylated 2,4,6-triphenylpyridiniums under mild conditions is
well known.9a-c Thus, the ability to isolate selectively activated
TPPy–CF2R salts allows for the synthesis and storage of latent
electrophilic CF2R reagents. Conversely, the application of a
two-step process (where TPPy–CF2R salts are generated in situ)
allows access to a number of SN2 difluoromethyl products di-
rectly (Figure 4).
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Figure 3. Benzotrifluoride scope for monoselective C–F functionaliza-
tion using P(o-Tol)3. Yields determined by 19F NMR or 31P NMR spec-
troscopy. Isolated yields from large scale reactions in brackets. a Con-
ducted at 60 °C. b Conducted for 40 h. c In 1,2-DCB at 150 °C. d In 1,2-
DCB at 100 °C.
For instance, generation of p-Tol–CClF2 (4a), p-Tol–CBrF2
(4b) and p-Tol–CF2I (4c) in high yields could be achieved
through the treatment of in situ generated 3a with nucleophilic
Figure 4. Scope for one-pot monoselective SN2 functionalization of trifluoromethyl substrates. Note: the reaction in step 2 was typically complete in less
than 1 hour, but final yields were determined at 24 h by 19F NMR spectroscopy. Isolated yields from large scale reactions in brackets. a Step 1 performed at
60 °C in DCE. b Step 1 performed at 100 °C in 1,2-DCB.
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tetraalkylammonium halides. CF2X groups (X = Cl, Br, I) have
established palladium cross coupling and redox chemistries al-
lowing the formation of a range of difluoromethylene deriva-
tives from such starting materials.12
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Alkali metal inorganic salts were effective at displacing the
TPPy group, with sodium azide, sodium thiocyanate, sodium
nitrate, lithium (2-bromo)phenoxide, sodium acetate, lithium
(4-methoxy)phenoxide and sodium p-tolyl sulfide generating
products 4d-4j in moderate to high yields.
Neutral nucleophiles could also displace TPPy in 3a. Pyridine
and lutidine displaced TPPy to generate salts 4k and 4l in 93%
and 65% yields respectively. When using pyridine or lutidine
under C–F functionalization conditions (Table 1, entries 9-10),
4k could not be generated, and 4l could only be generated in
20% yield. Phosphonium salts 2a and 4m could be generated
almost quantitatively from addition of P(o-Tol)3 or PPh3 respec-
tively to 3a. Although 2a could be accessed directly using P(o-
Tol)3 as a base in step 1 (Figure 3), the displacement of TPPy
by less sterically encumbered phosphines allows access to a
greater range of phosphonium salts, including those containing
unhindered phosphines.
Expanding the reaction to other trifluoromethylarenes allowed
an assessment of functional group tolerance and effect on the
reaction. Benzotrifluoride (1b) provided near quantitative con-
version to the TPPy salt 3b, which could be isolated via crystal-
lization in 53% yield. The high NMR yield of this reaction
demonstrated that in the presence of TPPy Friedel-Crafts alkyl-
ation was not a dominant side-reaction. Treating in situ gener-
ated 3b with lithium (4-methoxy)phenoxide or TBAI generated
products 4n and 4o. Longer alkyl chains (n-butyl) in the para
position gave outstanding results with 4p being generated in
over 95% yield.
Introducing the more donating group –OMe at the para position
provided 4q in a moderate yield of 47%. In this reaction, it was
found that consumption of the trifluoromethylarene starting ma-
terial occurred very quickly, but the intermediate TPPy salt was
less stable and partially decomposed before TBAB could be in-
troduced. In contrast, using P(o-Tol)3 as the base in the C–F ac-
tivation step yielded phosponium salt 2c in 79% (Figure 3), re-
sulting from the higher stability of the phosphonium salt as
compared to the TPPy salt.
Fluoro-, chloro- and bromo-groups at the para position slowed
the rate of C–F activation, and generally required gentle heating
for step 1 to be completed in a reasonable timeframe. In contrast
to donating groups, TPPy salts with electron deficient benzylic
groups were found to have higher thermal stability, with little
decomposition after prolonged mild heating, thus the slower re-
action rates could be overcome by running step 1 at 60 °C. Em-
ploying 2-bromo-trifluoromethylbenzene, led to a final yield of
24% for 4x representing steric encumbrance to the FLP C–F
activation step. The yield of 4x could be improved to 48% with
a longer reaction time for step 1 (see SI).
Tolerance of non-aromatic unsaturated hydrocarbon groups was
demonstrated with the generation of 4y (56% yield) featuring a
phenyl acetylide group in the para position. Placement of aryl
groups in the benzotrifluoride para position resulted in high
yields of desired brominated products 4z and 4aa, however, aryl
groups in the ortho position led to very low yields of desired
brominated products. Closer inspection revealed step 1 to be al-
most quantitative in these reactions, but subsequent nucleo-
philic substitution of the TPPy occurred very slowly. A molec-
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Figure 5. C–C and C–H bond forming reactions for pyridinium and
phosphonium salts. See SI for detailed conditions. Conditions: A for
TPPy: PhC(O)Ph, NaSC6H4-4-F, DCE, r.t., 16 h. B for P(o-Tol)3/PPh3:
KOH (5 equiv.), THF, r.t. 1 h. Yields determined by 19F NMR spec-
troscopy.
ular structure of the intermediate 3s (see SI) revealed this sta-
bility likely arises from π-π stacking between the eclipsed ortho
aryl and the pyridinium groups.13
Strongly electron withdrawing groups such as CF3 deactivated
the benzotrifluoride substrates, with 1,4-bis(trifluorome-
thyl)benzene only generating the selectively brominated prod-
uct 4ag in 14% yield.
Lastly, C–F activation of non-aromatic trifluoromethyl groups
in trifluoromethoxybenzene and 4-trifluoromethoxytoluene to
generate products 4ah and 4ai in good yield demonstrated the
ability to enable selective nucleophilic substitution in non-aro-
matic CF3 groups for the first time. Controlled direct access to
α,α-difluoro ethers from trifluoromethyl ethers is not possible
using any other approach, and they are of increasing interest to
agrochemical and pharmaceutical sciences due to their high lip-
ophilicity.14
Both phosphonium and pyridinium salts have been reported to
facilitate C–C bond formation via photoredox coupling9d-o and
nucleophilic transfer reactions.15 Applying previously reported
protocols for C–C bond formation with phosphonium and pyri-
dinium salts allowed us to demonstrate the ability of this meth-
odology to readily access carbon substituted difluoride products
(Figure 4).
For example, benzaldehyde was reacted with phosphonium
salts 2a, 2b and 2d to generate products 5a-c, where the
difluorobenzyl group underwent nucleophilic transfer to ben-
zaldehyde (Figure 5, i). This selective coupling is unique to our
methodology.
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ASSOCIATED CONTENT
1
The Supporting Information, including experimental details, is
available free of charge on the ACS Publications website. Crystal
X-ray crystallographic data are available free of charge from the
Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk):
CCDC 1944140, 1944141, 1944142, 1944143 and 1963332 for
compounds 3b, 3s, 4k, 2a and 2g respectively.
2
3
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8
AUTHOR INFORMATION
9
Corresponding Author
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*rowan.young@nus.edu.sg
†These authors contributed equally
Figure 6. Plausible mechanism for catalytic generation of 3a.
ACKNOWLEDGMENT
We thank the Singapore Ministry of Education (R-143-000-A05-
112) and the Singapore Agency of Science, Technology and Re-
search (A*STAR) (R-143-000-B09-305) for funding.
Redox coupling reactions are well reported for phosphonium
and TPPy salts. To provide proof-of-principle for C–C redox
couplings, phosphonium salt 2b and TPPy salt 3b were subject
to reported redox coupling conditions12i using Hantzsch ester as
the reductant (Figure 5, ii). With Michael acceptors, both salts
produced good yields of the desired products 5d-f, however, un-
der these conditions, the phosphonium salt 2b outperformed the
pyridinium salt 3b. The general applicability of reported redox
couplings using phosphonium and pyridinium salts to difluoro-
methyl substrates is under ongoing investigation.
Finally, formal hydrodefluorination to difluoromethyl groups
(hydroxyl biosteres)16 was demonstrated from both phospho-
nium and TPPy salts with both nucleophilic transfer and redox
coupling conditions enabling the formation of 5g and 5h in ex-
cellent yields (Figure 5, iii).
Given that phosphonium/pyridinium C–C and C–H couplings
are reported to tolerate aromatic halides and furans, and perform
well for electron rich aromatic and non-benzylic positions, cou-
plings from phosponium/pyridinium difluoromethyl salts are
complimentary to reported SET mediated defluoroalkylations.6
Mechanistically, a possible reaction pathway for the generation
of 3a is illustrated in Figure 6. We suspected that fluoride ab-
straction is performed by BCF, and that Me3SiNTf2 acts to re-
generate BCF from [BF(C6F5)3]-, driving the reaction forward
via the formation of Me3SiF gas. To test this hypothesis,
Cs[BF(C6F5)3] was reacted with an equivalent of Me3SiNTf2 at
room temperature and found to quickly (< 10 minutes) generate
Cs[NTf2], BCF and Me3SiF (see SI). Additionally, small con-
centrations of [BF(C6F5)3]- are observed during and after the re-
action, and the reaction was found to be inactive in the absence
of BCF (using conditions from Table 1, entry 14) implying that
BCF is indeed the fluoride abstraction agent (c.f. direct transfer
to Me3SiNTf2). Similar findings were found for previously re-
ported catalytic pseudohalodefluorination.17
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Conclusion
We have developed an effective synthetic protocol to selec-
tively activate and functionalize a single fluoride position in
both aromatic and non-aromatic trifluoromethyl groups via
phosphonium and pyridinium salts. This protocol allows for a
wide variety of post functionalization, including the first in-
stance of nucleophilic substitution in non-customized benzotri-
fluorides, photoredox coupling and electrophilic transfer reac-
tions. In general, the pyridinium salts allow facile SN2 function-
alization as well as photoredox couplings. In contrast, the phos-
phonium salts are more robust, but only support photoredox
couplings and difluorobenzyl nucleophilic transfers.
Monodefluorination and Wittig Functionalization of gem-Difluorome-
thyl Groups to Generate Monofluoroalkenes. J. Am. Chem. Soc. 2018,
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