Selective Monodefluorination and Wittig Functionalization of gem-Difluoromethyl Groups to Generate Monofluoroalkenes

Article abstract of DOI:10.1021/jacs.8b06770

Monodefluorination of gem-difluoromethyl groups is achieved using a frustrated Lewis pair (FLP) approach. Triarylphosphines and group 13 Lewis acids were surveyed as FLP components, with the combination of P(o-Tol)₃ and B(C₆F₅)₃ found to provide the best results, although the reaction is feasible with more economical components (PPh₃ and BF₃·OEt₂). The α-fluoroalkylphosphonium products arising from the reaction were of lower activity, in regard to further fluoride abstraction, as compared to difluoride starting materials, leading to highly selective monodefluorination. The activated substrates were subject to Wittig reaction protocols to generate a variety of monofluoroalkenes in moderate to high yields.

Full text of DOI:10.1021/jacs.8b06770

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Communication
Selective monodefluorination and Wittig functionalization of
gem-difluoromethyl groups to generate monofluoroalkenes
Dipendu Mandal, Richa Gupta, and Rowan D. Young
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06770 • Publication Date (Web): 17 Aug 2018
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Page 1 of 6
Journal of the American Chemical Society
Selective monodefluorination and Wittig functionalization of
1
2
3
4
gem-difluoromethyl groups to generate monofluoroalkenes
Dipendu Mandal†, Richa Gupta† and Rowan D. Young*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
5
6
7
8
9
ABSTRACT: Monodefluorination of gem-difluoromethyl groups is achieved using a Frustrated Lewis Pair (FLP) approach.
Triarylphosphines and group 13 Lewis acids were surveyed as FLP components, with the combination of P(o-Tol)3 and
B(C6F5)3 found to provide the best results, although the reaction is feasible with more economical components (PPh3 and
BF3.OEt2). The α-fluoroalkylphosphonium products arising from the reaction were of lower activity, in regards to further
fluoride abstraction, as compared to difluoride starting materials - leading to highly selective monodefluorination. The
activated substrates were subject to Wittig reaction protocols to generate a variety of monofluoroalkenes in moderate to
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high
yields.
Introduction:
Lewis acid mediated carbon-fluorine (C-F) bond activa-
tion and functionalization has developed greatly within
the last decade. The desire to transform C-F bonds into
other functional groups is derived from their increasing
abundance in societally important chemicals, such as
plastics, agrochemicals, pharmaceuticals, refrigerants,
and surfactants, and a need to either destroy such chemi-
cals, or convert such chemicals into more useful forms. As
such, a number of Lewis acid mediated synthetic methods
have been developed.1
Despite these recent achievements, Lewis acid controlled
C-C bond formation from C-F bonds in polyfluorides gen-
erally leads to ‘over-reaction’, where more than a single
fluoride is transformed.2 As such, stoichiometric monose-
lective C-F functionalization of polyfluorides is difficult to
achieve.3 Nonetheless, selective functionalization of
polyfluorides remains an attractive proposition, as it al-
lows the retention of fluoride in reaction products, and
therefore convenient access to a number of fluorine con-
taining motifs. Strategies that employ specific substrates
allowing kinetic3a (Figure 1A) or thermodynamic3b-l (Fig-
ure 1B) control of C-F functionalization have been report-
ed. However, a generic approach to selective defluorina-
tion is needed to allow the functionalisation of non-
specialised polyfluorocarbons with a diverse range of nu-
cleophiles.
The challenge in selective functionalization of polyfluoro-
carbons arises from the increased stability that C-F bonds
offer other proximal C-F positions. Most C-F functionali-
zation methods do not ‘deactivate’ products from further
unwanted functionalization. Thus, post-functionalized
products are either as reactive as or more reactive than
the polyfluorocarbon starting materials, resulting in a
distribution of substitution products.
Figure 1. (A, B) Previous examples of Lewis acid promoted selective
organofluoride functionalization. (C) Utilising FLP reactivity to ‘capꢀ
ture’ and ‘protect’ fluorocarbon fragments. After stoichiometric CꢀF
activation, functionalization of the ‘deactivated’ fluorocarbon can
occur. LA = Lewis acid, LB = Lewis base, FG = functional group.
Importantly, such an approach requires the use of nucle-
ophiles that do not irreversibly bind Lewis acid reagents,
preventing Lewis acid fluoride abstraction (akin to cata-
lyst poisoning). Such systems have been heavily reported
in Frustrated Lewis Pair (FLP) chemistry.6
In utilizing phosphine nucleophiles, the generation of
fluoroalkylated phosphonium salts facilitates the ability
to enact a number of reported C-C bond forming meth-
odologies.7 Herein, we report highly selective access to
monofluoroalkenes from gem-difluoroalkanes using Wit-
tig protocols.8 Monofluoroalkenes are important synthons
in organic and materials chemistries, and are present in a
number of agrochemicals, synthetic materials and phar-
maceuticals, thus direct access to such compounds from
polyfluorides is a highly desirable process.9
Proof-of-principle for the concept of selective C-F activa-
Upon the realization that no other anionic functional
group could be more deactivating than fluoride, we envis-
aged the incorporation of charge neutral nucleophiles
into intermediate carbocations4 generated from fluoride
abstraction. The resulting cationic products would be
‘deactivated’ towards further fluoride abstraction by Lewis
acids (Figure 1C). The cationic products could then be
further functionalized once stoichiometric selective fluo-
ride functionalization had been achieved. Indeed, this
concept has been utilized by Stephan for hydrodefluori-
nation reactions.5
tion
was
achieved
using
1-difluoromethyl-4-
methylbenzene (1) as a polyfluorocarbon substrate. With
the aim of further functionalization through Wittig pro-
tocol, triarylphosphines in combination with [B(C6F5)3]
(BCF), [Al(C6F5)3.(C7H8)] (ACF), BF3.(OEt2) and AlBr3 Lew-
is acids were tested as FLP partners.
Numerous FLP systems incorporating triarylphosphines
have been reported. For example, Stephan has reported
the activation of H2 using PMes3 and BCF.10 Furthermore,
PMes3 and P(o-Tol)3 have been reported to activate CO2
via FLP type reactivity.11 As such, we surveyed the com-
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Page 2 of 6
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Table 1. Optimization conditions for generation of phosphoni-
um salts [1a-c][anion].
Entry
LA
PAr3
Time
(h)
24
Yield
1
BCF
BCF
BCF
BCF
BCF
ACF
AlBr3
BF3.(OEt2)
BF3.(OEt2)
PMes3
P(o-Tol)3 24
20%
100%
100%
100%
<10%
49%
0%
2
3a
P(o-Tol)3
PPh3
P(o-Tol)3 24
P(o-Tol)3 24
P(o-Tol)3 24
P(o-Tol)3 24
2
24
10
11
12
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4a
5b, 6c, 7d
8e
9
10
11
55%
93
PPh3
24
Conditions: 0.031 mmol FLP, 0.028 mmol 1 in 0.5 mL DCM at 25 °C.
a
b
Yields determined by 19F NMR spectroscopy. Performed at 40 °C.
c
d
e
Toluene solvent. Acetonitrile solvent. Diethyl ether solvent. 1,2-
dichlorobenzene solvent.
Figure 3. Reaction scope for monodefluorination of gem-
Difluorocarbons 1-12. See ESI for reaction conditions. Isolated
yields given, reaction conversion indicated in brackets. Yield
a
based on 19F/31P NMR. b ACF used as Lewis acid.
The use of toluene led to Friedel-Crafts alkylation prod-
ucts, while MeCN masked the reactivity of the Lewis acid
resulting in no conversion. In diethyl ether, fluoride ab-
straction by BCF proceeded, but ether was found to react
with the intermediate carbocation to generate 1-
fluoromethyl-4-methyl-benzene.14 The use of pre-dried
solvents was essential, with the presence of water giving
rise to hydrophosphonium salts, [HPAr3][B(OH)(C6F5)3],
and compromising reaction yields.
Figure 2. Molecular structure of [1b][BF(C6F5)3]. Hydrogen
atoms (except H11) omitted, thermal ellipsoids shown at 50%.
Selected bond distances (Å) and angles (°): P1-C1, 1.894(6); C1-F1,
1.398(6); F11-H11, 2.353; P1-C1-F1, 105.8(3).
Varying the Lewis acid from BCF to ACF resulted in a rap-
id clean reaction, but the reaction proceeded to only half
conversion (based on 1). This is possibly due to the for-
mation of a fluoride bridged [F{Al(C6F5)3}2]- anion,15 re-
sulting in the need of at least two equivalents of ACF for
full consumption of 1. Due to reaction of ACF with chlo-
rinated aliphatic solvents,16 the reaction was performed in
1,2-dichlorobenzene. Attempts to utilize less expensive
Lewis acids gave mixed results (Table 1, entries 9-10). The
use of AlBr3 resulted in halodefluorination of 1, as report-
ed by us previously.1h Employing BF3.(OEt2) generated
[1b][BF4] cleanly, but with a lower yield of 55% over 24
hours. Surprisingly, the combination of BF3.(OEt2) and
PPh3 (Table 1, entry 11) performed better than both
BCF/PPh3 and BF3.(OEt2)/P(o-Tol)3. This may be attribut-
ed to the high solubility of the PPh3-BF3 adduct (cf. the
PPh3-BCF adduct that precipitates from solution at room
temperature). The success of BF3.(OEt2) and PPh3 render
this strategy cost-effective in larger scale syntheses of α-
fluoroalkylphosphonium salts. Indeed, the synthesis of
[1b][BF4] was repeated on gram scale with 3.3 mmol of
difluoride 1. In this instance, the reaction was continued
for 72 hours at room temperature, providing an isolated
yield of 86%.
mercially available phosphines, PMes3, P(o-Tol)3 and
PPh3.
The reaction between PMes3, BCF and 1 in DCM proceed-
ed very slowly at room temperature to generate
[1a][BF(C6F5)3] with ca. 20% yield after 24 hours (Table 1,
entry 1). Employing the less sterically crowded phosphine
P(o-Tol)3 with BCF and 1 dramatically improved the reac-
tion rate, with quantitative conversion after 24 hours (Ta-
ble 1, entry 2). Heating a DCM solution of P(o-Tol)3 with
BCF and 1 at 40 °C led to complete consumption of 1 in
two hours, and quantitative generation of product
[1b][BF(C6F5)3] based on 1 (Table 1, entry 3). Employing
PPh3 as a nucleophile resulted in no reaction at room
temperature. However, heating this reaction at 40 °C gen-
erated [1c][BF(C6F5)3] quantitatively after 24 hours of
heating (Table 1, entry 4), indicating that the Lewis ad-
duct [BCF-PPh3]12 may reversibly dissociate at elevated
temperatures.13 For further optimization, P(o-Tol)3 was
employed as the nucleophile of choice based on its supe-
rior reaction rate.
A survey of solvents (Table 1, entries 5-7) revealed DCM to
be the most suitable for the generation of [1b][BF(C6F5)3].
Phosphonium [1b][BF(C6F5)3] was recrystallized from
DCM/hexane in 86% yield. The 31P NMR spectrum of
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A molecular structure of [1b][BF(C6F5)3 confirmed the
1
2
3
4
5
6
7
8
spectroscopically implied connectivity (Figure 2). The
structure shows close contact between [1b]+ and the
[BF(C6F5)3]- anion arising from strong hydrogen bonding
between the calculated benzylic hydrogen position and
the boron fluoride (F11-H11 = 2.353 Å). The o-tolyl methyl
groups extend into the benzylic region, suggesting that
they may influence further reactivity of this position (vide
infra).
The optimized conditions, employing BCF and P(o-Tol)3
(Table 1, entry 2), were applied to a range of gem-
difluorocarbons (Figure 3). Benzyldifluoride substrates
generally performed well. Electron withdrawing substitu-
ents (4-5, 7-8) resulted in lower yields of phosphonium
products, primarily due to incomplete conversion. The
reaction conditions were found to tolerate substrates con-
taining halide (5, 7, 8), and ether (6) functional groups,
but performed poorly in the presence of ester groups (4).
Unprotected difluoromethylarenes (2, 9, 10, 11) also gave
high yields, avoiding Friedel-Crafts alkylation reactions.
Extending this reaction to allylic difluorides did not result
in rearrangement products, and cinnamyl difluoride (9)
generated a moderate yield (53%) of phosphonium prod-
uct [9b][BF(C6F5)3]. Polyaromatic (10) and heteroaromatic
(11) substrates worked well, however, the pyridyl deriva-
tive 12 gave no desired product, with only deprotonation
of the difluoromethyl position observed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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59
60
Figure 4. Aldehyde scope of Wittig reaction with α-
fluorobenzylphosphonium salt [1b][BF(C6F5)3]. See ESI for reac-
tion conditions. Yield determined by 19F NMR spectroscopy.
Under the standard reaction conditions (Table 1, entry 2),
fluoride abstraction of saturated 1,1-difluoroalkanes did
not proceed. Thus, the more fluorophilic ACF (2 equiva-
lents) was employed for selective monodefluorination of
1,1-difluorodecane (13) and 1,1-difluoroethane (14).
Selective
monodefluorination
of
13
generated
[13b][F{Al(C6F5)3}2] in ca 20% yield at room temperature
overnight, indicating the greater stability of 1,1-
difluoroalkanes as compared to benzylic difluorides. Re-
peating this reaction at 85 °C for 24 hours improved the
yield to 49%. Under the same conditions, monodefluori-
nation of 13 generated [14b][F{Al(C6F5)3}2] in 14% yield. 1,1-
difluorethane is a commercially available refrigerant gas
(R-152a), and is considered a possible replacement for the
heavily used 1,1,1,2-tetrafluoroethane (R-134a), due to its
lower Global Warming Potential. With increased use of
1,1-difluoroethane, methods of recycling used refrigerant
gas to generate valuable products will become increasing-
ly important.
Following monodefluorination of a range of difluorides,
functionalization of these molecules to neutral organic
products was undertaken. From a synthetic point-of-view,
C-C bond forming reactions are highly valued in organic
synthetic chemistry and offer direct routes to complex
molecules. Although a range of C-C bond forming reac-
tions have been reported for phosphonium salts, the most
widely employed is the Wittig reaction.17 Fluorinated ben-
zylic phosphonium salts are ideal for Wittig reactions,
given the high acidity of the benzylic proton, and the util-
ity of fluorostyrene derivatives.18
Figure 5. α-Fluoroalkylphosphonium scope of Wittig reaction
with benzaldehyde. See ESI for reaction conditions. Yield deter-
mined by 19F NMR spectroscopy.
[1b][BF(C6F5)3] provided clear evidence for retention of a
geminal fluorine within the product with a signal at 27.8
2
ppm displaying JPF of 82.3 Hz. Fluoride abstraction by
BCF was evident in the 19F NMR spectrum of
[1b][BF(C6F5)3], with a broad signal 187.8 ppm correspond-
ing closely to previously reported values for B-F in the
[BF(C6F5)3]- anion.5b The residual benzylic fluoride signal
was also observed at 189.1 ppm with 2JFP of 82.3 Hz.
Addition of 1.1 equivalents of lithium hexamethyldisilaz-
ane (LiHMDS) to a sample of [1b][BF(C6F5)3] in THF
quickly turned the colourless solution deep red. New 31P
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and 19F NMR signals at δP 2.5 and δF -233.5 (2JPF = 60.3 Hz)
recorded 30 minutes after base addition confirmed the
quantitative conversion of [1b][BF(C6F5)3] to its corre-
sponding ylide, [1b-H].
Page 4 of 6
6F5)3] (Figure 5). Generally, excellent yields (>80%) of
monofluoroalkenes were obtained. The exceptions to this
were [4b][BF(C6F5)3] and [7b][BF(C6F5)3], which gave poor
yields of their alkene products 33 (9%) and 36 (42%) re-
spectively. E-selectivity once again dominated, with E-
isomer products generally preferred in greater than 75%
bias, however, [9b][BF(C6F5)3] generated product 38 with
similar E,E- and E,Z-isomer ratios, and [7b][BF(C6F5)3]
actually showed a 2:1 preference for the generation of the
Z-isomer of 36 over the E-isomer.
1
2
3
4
5
6
7
8
Subsequent addition of benzaldehyde to the solution re-
sulted in formation of fluoroolefin 15 in 91% yield (E/Z =
75:16) over 16 hours at room temperature. Interestingly,
when [1c][BF(C6F5)3] is used as a starting material in the
same reaction, a yield of 49% (E/Z = 19:30) is achieved,
indicating the ability of the protecting phosphine to affect
the efficacy of the Wittig reaction.19
Figure 4 lists the scope of aldehydes in the Wittig reaction
with [1b][BF(C6F5)3]. Products from the addition of ben-
zaldehyde derivatives, 4-methylbenzaldehyde (16), 4-
bromobenzaldehyde (17), 4-thiomethoxybenzaldehyde
9
Finally, the practical utility of this reaction was demon-
strated through one-pot reactions performed in two steps
(Figure 5). [1b][BF(C6F5)3] was initially generated from 1,
P(o-Tol)3 and BCF in DCM over 16 hours before the sol-
vent system was exchanged for THF, and LiHMDS and
benzaldehyde were introduced to generate 15 in an overall
yield of 77% (based on 1). An analogous procedure gener-
ated 31 in 73% yield (based on 2).
In conclusion, we have developed a simple methodology
that preserves fluorofunctionality from geminal-
difluorocarbon starting materials. This is achieved via
protection of the monodefluorinated product from fur-
ther fluoride abstraction as a phosphonium cation. This
methodology was successfully applied to benzylic, allylic
and aliphatic 1,1-difluorocarbons. Although many cou-
pling reactions are possible from our isolated phosphoni-
um salts, we demonstrated the utility of this methodology
through a series of Wittig reactions to generate mono-
fluoroolefins.
10
11
12
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(18),
3,4-dichlorobenzaldehyde
(19),
2-
bromobenzaldehyde (20), 4-dimethylaminobenzaldehyde
(21), 4-nitrobenzaldehyde (22) and 4-cyanobenzaldehyde
(23) demonstrate a high functional group tolerance, and
provided moderate to high yields with high E-selectivity.
Benzaldehyde derivatives containing electron donating
groups tended to provide higher yields as compared to
electron withdrawing groups, however, product 20 (with
an ortho-bromo substituent) gave a respectable yield of
84%. The combination of high yield and E-selectivity pro-
vides the perfect platform to access Polycyclic Aromatic
Hydrocarbons (PAHs). Indeed, treatment of 20 with a
catalytic amount of palladium led to dehydrobrominative
aryl-aryl coupling, forming the PAH 10-fluoro-3-
methylphenanthrene (30) in 27% yield (based on 20-E).
Flourinated PAHs have been shown to have enhanced
biological activity and are widely used in materials chem-
istry.20
ASSOCIATED CONTENT
The Supporting Information, including experimental details,
is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*rowan.young@nus.edu.sg
Aliphatic aldehydes also performed well in the Wittig
reaction, with n-decanal generating 24 in 84% yield (E/Z =
52:32). Alkenyl groups were tolerated in coupling part-
ners, with cinnamaldehyde generating 25 in 49% yield
† These authors contributed equally.
(E/Z
=
34:15),
and
its
derivatives,
and
4-
4-
dimethylaminocinnamaldehyde
Notes
nitrocinnamaldehyde, generating 26 in 87% (E/Z = 72:15)
and 27 in 69% (E/Z = 6:63) yields respectively. Interesting-
ly, product 27 displays inverse regioselectivity, with the Z-
isomer favoured.
Paraformaldehyde was used directly as a coupling part-
ner, generating α-fluorostyrene 28 in 61% yield. α-
Fluorostyrene derivatives have been used in polymer
chemistry, but their synthesis often involves the applica-
tion of toxic hydrofluoric acid to alkynes.9,21
Employing 4-bromo-2-fluorobenzaldehyde led to the
formation of 29 in 57% yield. The structure of 29 closely
resembles a reported family of antimicrobial agents, and
offers a safer method to access these compounds as com-
pared to the reported synthesis that relies upon the use of
toxic trialkyltin reagents to install the fluoroalkene mo-
tif.22
Having established the ease by which gem-difluoro sub-
strates may be converted to monofluoroalkenes, we then
benchmarked the performance of the Wittig reaction with
phosphoniums [2b-11b][BF(C6F5)3] and benzaldehyde un-
der identical conditions to those employed for [1b][BF(C-
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National University of Singapore and the Sin-
gapore Ministry of Education for financial support (WBS R-
143-000-A05-112 and R-143-000-697-114, and Vemac Services
(Singapore) for the donation of R-152a gas.
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