Electrochemical Vicinal Difluorination of Alkenes: Scalable and Amenable to Electron-Rich Substrates

Article abstract of DOI:10.1002/anie.201912119

Fluorinated alkyl groups are important motifs in bioactive compounds, positively influencing pharmacokinetics, potency and conformation. The oxidative difluorination of alkenes represents an important strategy for their preparation, yet current methods are limited in their alkene-types and tolerance of electron-rich, readily oxidized functionalities, as well as in their safety and scalability. Herein, we report a method for the difluorination of a number of unactivated alkene-types that is tolerant of electron-rich functionality, giving products that are otherwise unattainable. Key to success is the electrochemical generation of a hypervalent iodine mediator using an “ex-cell” approach, which avoids oxidative substrate decomposition. The more sustainable conditions give good to excellent yields in up to decagram scales.

Full text of DOI:10.1002/anie.201912119

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Electrochemical Vicinal Difluorination of Alkenes: Scalable, and
Amenable to Electron-rich Substrates
Authors: Sayad Doobary, Alexi T. Sedikides, Henry P. Caldora, Darren
L Poole, and Alastair Lennox
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912119
Angew. Chem. 10.1002/ange.201912119
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10.1002/anie.201912119
Angewandte Chemie International Edition
COMMUNICATION
Electrochemical Vicinal Difluorination of Alkenes: Scalable, and
Amenable to Electron-rich Substrates
Sayad Doobary,[a] Alexi T. Sedikides,[a] Henry P. Caldora,[a] Darren L. Poole,[b] and Alastair J. J.
Lennox*[a]
ABSTRACT: Fluorinated alkyl groups are important motifs in bioactive
compounds, positively influencing pharmacokinetics, potency and
conformation. The oxidative difluorination of alkenes represents an
important strategy for their preparation, yet current methods are
limited in their alkene-types and tolerance of electron-rich, readily
oxidized functionalities, as well as in their safety and scalability.
Herein, we report a method for the difluorination of a number of
unactivated alkene-types that is tolerant of electron-rich functionality,
giving products that are otherwise unattainable. Key to success is the
electrochemical generation of a hypervalent iodine mediator using an
‘ex-cell’ approach, which avoids oxidative substrate decomposition.
The more sustainable conditions give good to excellent yields in up to
decagram scales.
selectivity, however 1a is light- and temperature-sensitive, highly
hygroscopic and expensive.[15] Thus, the in situ formation of 1a
using aryl-iodide, HF-salts and Selectfluor or mCPBA, was the
subject of elegant work by both Gilmour[16] and Jacobsen.[17] The
use of these stoichiometric oxidants then permits the use of sub-
stoichiometric quantities of the aryl-iodide catalyst.
[A] Vicinal Difluorides: Application
(Chiral)
Bioisostere
Gauche effect
F
F
F
F
F
F
H
H
H
H
H
H
F
F
σC-H → σ*C-F
H
ca. 1 kcal/mol
• lipophilicity • potency • stablity
= API
F
H
[B] Vicinal Difluorides: Preparation
F
[O]
[HF]
F
Cl
1993: Lal
Selectfluor
The inclusion of fluorine in bioactive compounds is becoming
more important:[1] since 2006, prevalence has increased from 6%
to 31% in the best-selling small-molecule drugs.[2] Fluorinating
alkyl groups can increase potency, lipophilicity and metabolic
stability,[3] while reducing the basicity of neighbouring amines,[4]
all of which can improve bioactivity and pharmacokinetics. The
vicinal difluoroethane unit has attracted recent attention,
particularly as a bioisostere of ethyl or trifluoromethyl groups[5]
(Figure 1A) and for its unique propensity to adopt a gauche
conformation in solution.[6] Exploiting this stereo-electronic effect
is an emerging strategy for molecular design,[7] and has found
application in, for example, organocatalysis[8] and peptide
mimics.[9]
Simple vicinal difluorides have been prepared from alkenes
with the use of ambiphilic fluoride reagents, F2 and XeF2.[10]
However, their extreme reactivity, toxicity and high cost render
their use impractical. While the required oxidizing equivalents are
self-contained in these reagents, subsequent methods have
relied on the combination of HF-salts and oxidants (Figure 1B).
Oxidation with the use of electrochemistry[11] or Selectfluor[12]
provided the earliest confirmations of this strategy. However, in
both cases the product selectivity is poor and the alkene-types
amenable to the reaction are limited, with success demonstrated
on only very simple substrates. Yoneda employed p-tolyl difluoro
l3-iodane (1a) as the oxidant,[13,14] which improved product
F
N
N
• Styrenyl only
-
2BF4
F
I
F
1998: Yoneda
Stoichiometric Tol-IF2
• Unactivated terminal
• 1a is very unstable
and expensive
Me
1a
2016:
In-situ Ar-IF2 (1)
formation with [O]
• Activated and
unactivated
• Electron-poor only
SelectFluor Gilmour
mCPBA Jacobsen
I
+
cat.
R
I
This work:
Electrochemical,
[O]-free
• New substrate classes:
electron rich
Me
• Scalable: +10 g
• Sustainable: H2 = sole
by-product
‘Ex-cell’ method:
- electron rich
- unactivated
- substituted
2H+
+2e-
I
Ar
-2e-
• Mild conditions: more
functional group tolerant
+2F-
F
I
F
-
Ar
1
H2
F
I
F
I+
Ar-I
F
F
Ar
Ar
F
F-
F-
Figure 1. [A] Significance and application of vicinal difluorides; [B]
Methods to prepare vicinal difluorides
While these examples represent great advances in accessing
vicinal difluorides, there is no general method for accessing these
motifs in compounds containing electron-rich moieties; due to
competitive substrate oxidation, resulting in either decomposition
or unselective fluorination. Moreover, owing to the potential of
fluorinated alkyl groups in high-value bioactive compounds, a
method that is readily scaled, and therefore is safe, inexpensive
and does not produce much waste, is still required.
To address these shortfalls, we sought to access the l3-
iodane 1 mediators[18] using electrochemical[19] oxidation. The
unique spatial control of redox events, along with the control of
potential and rate, should facilitate the expansion of substrate
classes. As well as the inherent safety and scalability of
electrochemistry,[20] the addition of a chemical oxidant is not
[a]
[b]
S. Doobary, A. T. Sedikides, H. P. Caldora, Dr. A. J. J. Lennox
School of Chemistry, University of Bristol,
Cantock’s Close, Bristol, BS8 1TS (UK)
a.lennox@bristol.ac.uk
Dr. D. L. Poole
Medicines Design, GSK Medicines Research Centre, Gunnels
Wood Rd, Stevenage, SG1 2NY (UK)
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201912119
Angewandte Chemie International Edition
COMMUNICATION
required, as protons can ultimately accept electrons at the
cathode to form H2 as the sole by-product, thereby rendering the
process more atom-economical.[21]
reaction conditions decreases with more HFIP present,[26,29]
resulting in
a milder oxidizing environment, which should
contribute to improved functional group tolerance. Finally, 19F
NMR analysis of a genuine sample of 1a, supported our
assumption that 1a was formed under the optimized conditions.[26]
The electrochemical generation of many hypervalent l3-
iodane species from aryl-iodides is known.[22] Difluoro l3-iodanes
(1) has been comparatively less explored,[23] with Waldvogel
recently reporting the only example in the presence of alkenes,[23e]
which are liable to preferentially oxidise. A number of additional
problems are reported to occur when 1 is generated at an
electrode,[24] which include dimerization, benzylic fluorination and
the formation of “many other complicated products”.[23d] The
application of high potentials with HF-salts also causes anode
passivation, where a non-conducting polymer coating forms on
the electrode surface that suppresses faradaic current and can
attenuate reaction.[25] Thus, our primary objective was to address
these issues in our optimisations.
We started by examining different aryl-iodide mediators for
the electrochemical difluorination of allylbenzene (2a) (Figure 2A).
No conversion to difluorinated alkane 3a was observed with the
use of 4-iodo-anisole (R = 4-OMe), the most readily oxidized
derivative we tested. However, we observed the formation of 3a
using aryl-iodides with higher oxidation potentials. Further
increases in potential beyond R = Me (tolyl) led to a subsequent
decline in yield, as direct substrate oxidation out-competes aryl-
iodide oxidation (ca. Eox = 1.9 V). Although iodotoluene gave the
highest yield of 3a, substantial quantities of benzylic fluorination
(to 4) were observed (<18%) (Figure 2B). We confirmed that 4
itself is a very poor mediator, as only 7% of 3a was returned when
using 4 in place of 1a.[26] As this side reaction requires
deprotonation, we reasoned that it should be attenuated by
reducing the availability of basic fluoride by increasing the
proportion of HF to amine (in mixes of commercially available
3HF•NEt3 and 9HF•py (amine = py or NEt3)). Indeed, by
increasing this ratio from 3 to 5.6, benzylic fluorination decreased
with an accompanying increase in product 3a (Figure 2B). This
trend also mirrors the enhanced activation of 1a with acid
expected from the presence of more HF. Further increases
beyond 5.6 maintained the lack of 4 formation, but led to a decline
in product 3a, possibly reflecting a decrease in fluoride activity.
This ‘sweet-spot’ demonstrates the delicate balance between
activation of 1a and deactivation of fluoride.
The influence of solvent was then examined. MeCN
performed worse than CH2Cl2, which was unsurprising
considering anode passivation is particularly predominant under
these conditions.[25] This insulating effect was reflected by a large
rise in cell potential during reaction compared to other solvents
tested,[26] none of which improved the yield beyond that of CH2Cl2.
However, when hexafluoro-isopropanol (HFIP) was added as a
co-solvent, higher yields of 3a were observed, as also noted in
other halogenation[27] and electrochemical reactions.[28] 30% HFIP
in CH2Cl2 led to the greatest enhancement.[26] Control reactions in
the absence of alkene revealed that the concentration of HFIP
determined the amount of 1a formation (Figure 2C) after the same
amount of charge was passed. The addition of
allylpentafluorobenzene (2e) to these mixtures confirmed its more
efficient transformation to 3e in the presence of more 1a.[26] To
rationalise the downward trend of 1a (Figure 2C), we observed a
reduced solubility of iodotoluene with increased HFIP. CV studies
revealed that the oxidation potential of iodotoluene under the
[A] Variation in Ar-I mediator:
tolyl = best
I
R
(1 equiv.)
F
4.5HF:amine, DCM
Pt:Pt, 2 mA
F
2a
3a
50
4-Me
40
16
14
12
10
8
70
60
50
40
30
20
10
0
n = 5.6
30 4-t-Bu
Mesityl
20
H
4-F
Naphthyl
10
4-OMe
0
4-CF3
6
4
2
0
4-NO2
1.5
1.7
1.9
2.1
2.3
E1/2 (V vs Fc/Fc+)
[B] Effect of HF:amine ratio:
3
4
5
6
7
highest [3a] & lowest [4] when n = 5.6
nHF:amine
I
I
nHF:amine
+
+
F
Ph
Ph
F
CH2Cl2
Me
F
Pt:Pt 2 mA
2a
3a
4
x = 30%
[C] Effect of [HFIP] in CH2Cl2
Highest [1a] when x = 30%
100
75
50
25
0
I
F
I
F
5.6HF:amine
4 F.mol-1
x% HFIP
in CH2Cl2
0
25
50
75
100
Me
Me
1a
x ([HFIP] in CH2Cl2) /%
[D] Selectivity controlled by presence of Tol-I mediator:
F
O
O
Me
O
Me
O
F
Me
F
5.6HF:amine
F
+
+
DCM:HFIP (7:3)
3as
No mediator: 30%
With Tol-I (1 eq.): 0%
11%
0%
0%
70%
2as
Figure 2. Reaction optimisation: electrolyses in undivided cell, 19F NMR yields.
[A] Yields of 3a from 2a (25 mM) in the presence of different aryl-iodides (1) 4
F.mol-1. E1/2 vs Fc/Fc+. [B] Yields of 4 (blue) and 3a (green) from 1a and 2a
(both 25 mM) in different HF:amine ratios after 4 F.mol-1. “Amine” = NEt3 or py.
[C] Yields of 1a after 4 F.mol-1, 12 mA (Pt||Pt) in different amounts of HFIP in
CH2Cl2. [D] Fluorination of 2as with and without Tol-I. 4 F.mol-1 passed at 12
mA (Pt||Pt).
The importance of the iodotoluene mediator to product
selectivity was confirmed by control reactions in its absence
(Figure 2D). Without iodotoluene, direct oxidation of 2as led to
benzylic, rather than alkene, fluorination with low mass balance.
The use of sub-stoichiometric quantities of the mediator led to a
decline in yield of 3a,[26] reflecting a mismatch of reaction-rates in
the electrochemical and chemical steps (EC mechanism). We
could drop the loading of iodotoluene to 20 mol% by applying 5
cycles of 0.7 F/mol with 6 hr stirring in between.[26] However, the
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‘In-cell’ method[a]
Electrolysis
vastly increased reaction time was deemed to be an inferior
adjustment to the conditions than using an equivalent of
iodotoluene and running the reaction in one go. Moreover, we are
able to recover pure iodotoluene in greater than 70% yields, and
thus recycle it for use in subsequent reactions.
With this ‘in-cell’ optimised method now in hand, we
proceeded to explore the substrate scope (Figure 3). Previously
published protocols do not report substrate classes that contain
electron-rich moieties, therefore, we initially avoided these
substrates. Indeed, electron-poor allyl arenes were well tolerated
(2a-e) and gave difluorinated products in good to excellent yields.
• < 27 mmol scale • Tol-I recovered
• Lowest E-factor • ElectraSyn
F
F
conditions[b]
= Electron poor substrates:
Eox >1.8 V
2a-s
(0.2-0.3 M)
3a-s
Allyl arenes
F
F
F
F
F
R
F
F
F
3d
F
F
F
F
R =
3e
4-H: 65% (81%) 3a
4-CF3: 73% (93%) 3b
2-Br: 73% (90%) 3c
72% (90%)
76% (93%)[c]
67% (80%)
7.3 mmol (g-scale): 60%
Long-chain
alkenes, 2f-h, returned
excellent yields,
demonstrating that a proximal aromatic ring is not necessary for
reactivity. Allylic ethers and amines (2i-t) were both tolerated if
containing electron poor (hetero)aromatics. Ester (2h), alcohol
(2f), sulfonate (2g) and halide (Br, Cl, e.g., 2l and 2q) functional
groups were all untouched, providing useful products for further
derivatization. While acid sensitive functionality, such as boc
groups, was not tolerated,[26] a cyclopropyl ring (2t) avoided
competing oxidative ring opening.[30]
Long-chain alkenes
O
F
O
HO
F
S
3f
50% (65%)
F
O
F
F
70% (96%)
3g
O
O
Me
F
72% (95%)
3h
MeO
Allyl ethers
The scalability of the method was demonstrated by yielding
gram-scale quantities of products 3e, 3i and 3s and a deca-gram-
scale quantity of 3s. In each of these cases, 70+% of pure
iodotoluene was recovered. The commercially available
ElectraSyn 2.0 set-up was also tested—in combination with a
PTFE vial—and was found to give product 3d in a comparable
yield to our set-up, validating the robustness of the conditions.
These ‘in-cell’ conditions performed worse with the more
N
O
F
O
F
R
F
F
3m
NO2
O
F
50% (65%)
R =
H:
61% (80%) 3i
F
7.3 mmol (g-scale): 55%
4-F: 62% (75%) 3j
3o
O
3n
F
NO2
N
F
4-NO2: 72% (80%) 3k
2-Br: 55% (70%) 3l
72% (87%)
35% (45%)
Allyl amines
electron-rich allyltoluene (2u) (Figure 4), returning only
a
N
F
N
F
moderate yield of difluorinated product 3u. This reactivity is
consistent with previous methods that also struggle with readily
oxidized substrate classes.[16] Therefore, a new approach was
sought to specifically gain access to products containing electron-
rich moieties. Analysis of a range of electron-rich substrates by
cyclic voltammetry revealed their preferential oxidation to
iodotoluene,[26] thereby eluding the vital formation of l3-iodane 1a.
To avoid this problem, an ‘ex-cell’ method was devised that
spatially and temporally separates the electrochemical oxidation
and fluorination steps, thereby avoiding competitive direct
oxidation of the substrates. Thus, conditions were re-optimized for
the initial formation of 1a in a divided cell, followed by the
subsequent addition of substrate 2u.[26] With this approach the
yield of 3u was raised from 45% to 73% (Figure 4).
N
Ts
F
Ts
3s
F
Ts
F
Br
R
R =
F
3t
H: 67% (75%) 3p
Cl: 70% (75%) 3q
CF3: 70% (70%) 3r
75% (80%)
3.6 mmol (g-scale): 85%
23.6 mmol (deca-g-scale): 80%
62% (75%)
Figure 3. [a] Isolated yields (NMR yields in parentheses). [b] 2 (1.2 mmol (0.3
M) or 0.8 mmol (0.2 M)) and iodotoluene (1 eq.) in 3 parts 5.6HF:amine (where
amine = py or NEt3) and 1 part CH2Cl2:HFIP (7:3); electrolysis: 8 mA (0.2 M) or
12 mA (0.3 M), 3.5 F.mol-1, Pt||Pt, undivided cell, then stirring (12 hrs). [c]
Reaction performed with Electrasyn 2.0 in a PTFE vial.
Anilines are a substrate class that have also not previously
been demonstrated, as they are very readily oxidized. Aniline 2aa
posed problems using the ‘in-cell’ method, cf. only 25% 3aa was
isolated. However, by adopting the ‘ex-cell’ method, this was
increased to 70%. The greater electron withdrawing effect of nosyl
(3ab) vs tosyl (3aa) translated into greater yields. Good to
excellent yields of other difluorinated anilines containing electron
rich and poor rings were generated (3ac-ag), including mesityl.
Other terminal alkenes containing electron-rich moieties were
tolerated, including an allyl amine (2am) and ether (2as).
Styrenes were tolerated if they were electron poor, such as 2ai,
otherwise geminal fluorination occurred (2ah), which is a process
that has previously been observed with this substrate class.[32]
Substituted styrenes (2aj-al) were also well tolerated.
The scope of electron-rich or easily oxidised substrates was
now tested with this ‘ex-cell’ method (Figure 4). Electron-rich allyl
arenes (2u-x) were now tolerated, returning moderate to very
good yields of product. Success was achieved with the extremely
electron rich dimethylaniline 2w, however, the anisole derivative
2y was less well tolerated, as it is known to undergo C-H
activation
to
generate
diaryliodonium
species.[31]
A
pharmaceutically relevant morpholine amide (2z) was also
tolerated.
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COMMUNICATION
‘Ex-cell’ method[a]
Method comparisons[c]
• New substrate classes:
Electron rich, aniline, internal
di- & tri-substituted
• Low E-factor
• Tolyl-I mediator recovered
SelectFluor
no cat
2 = 0.09 M
9HF•Py
SelectFluor
2 = 0.2 M,
Tol-I (0.2 eq.)
4.5HF:amine
Ref 16a
mCPBA
1) Electrolysis
F
I
2 = 0.04 M,
Ar-I (0.2 eq.)
9HF•9Py
conditions[b]
= Electron rich, readily
oxidised : Eox < 1.8 V
(vs Fc/Fc+)
F
F
2)
Me
3a-ar
2a-ar (0.2 M)
Ref 12
Ref 17a
Morpholine
Electron-rich allyl arenes
Me
O
N
F
F
F
F
F
F
F
F
Me2N
F
Me2N
MeO
Me
3v
F
3w
O
F
3u
3z
Me
Me
3y
30% (45%)
3x
40% (50%)
45% (52%)
37% (45%)
SelectFluor (<5%)
mCPBA (15%)
50% (55%)
60% (73%)
SelectFluor (41%)
mCPBA (54%)
(12%)
Selectfluor no
cat (<5%%)
SelectFluor (0%)
mCPBA (19%)
Selectfluor no cat (<5%%)
Anilines
F
F
I
F
Me
Me
N
Ns
F
N
F
N
Ns
F
N
F
N
Ts
F
N
F
F
Me Ns
3ac
F
F
Br Ns
3ae
60% (64%)
SelectFluor (0%)
mCPBA (49%)
F
F
F
Me Ns
F
3aa
3ab
3ad
3af
83% (85%)
SelectFluor (0%)
mCPBA (33%)
60% (63%)
55% (63%)
35% (37%)
70% (75%)
25% (35%)
Selectfluor no cat (0%)
NO2
Styrenes
F
F
F3C
NO2
Me Me
F
F
Me Me
Me Me
F
N
Ns
F
F
F
3ak
F
F
F
Me
3ah
CF3
3ai
F
3aj
83% (90%)
3ag
F
3al
Selectfluor: (50%)[e]
mCPBA: (63%)
40% (50%)[d]
45% (55%)[d]
F
80% (85%)
45% (46%)
80% (83%)
Selectfluor no cat (45%)
Electron-rich and substituted allyl amines
F
Me Me
F
Ph
N
F
Ph
N
Ts
Me
N
Ts
F
N
Ts
F
N
Ts
F
N
Me
Me
F
Me
F
F
F
Cl
dr 1.6:1
(2ao cis:trans
= 1.6:1) Selectfluor no cat (<5%)
Cl
Me
Cl
F
F
(
)-3ao 55% (58%)
Ph
Ph
(
3am
3ap
50% (55%)
3an
60% (62%)
)-3aq
60% (60%)
(2aq = cis)
(
)-3ar
57% (60%)
Selectfluor: (7%)
60% (62%)
mCPBA: (<5%)
dr 9:1
(2aq = trans)
dr 8:1
trans-Octene isomers
Electron-rich and substituted allyl ethers
F
F
F
O
F
O
F
O
F
F
F
Me
F
Me
F
Me
3as
65% (70%)
CF3
F
3ay
(<5%)
F
F
F
3av
3at
70% (75%)
(
)-3aw
3au
73% (80%)
(
)-3ax
(50%) dr = 5:1
dr = 5:1
(70%)
(15%)
Figure 4. [a] Isolated yields with NMR yields in parentheses, black = ‘in-cell’, green = ‘ex-cell’. [b] Electrolysis of iodotoluene (1.2 mmol, 0.2 M) in 3 parts 5.6HF:amine
and 1 part CH2Cl2:HFIP (7:3): 12 mA, 3.0 F.mol-1, Pt||Pt, divided cell, then addition of 2 (1.2 mmol), stir (12 hrs). [c] Selectfluor + Tol-I conditions from ref[16a]; mCPBA
+ Ar-I conditions from ref[17a]; Selectfluor conditions from ref[12]. [d] CHCl3 used instead of CH2Cl2 with 4.5HF:amine. [e] Styrene difluorination conditions from ref[16b]
.
Selectfluor conditions from ref16a generated only (17%) 3ap.
Substituted alkenes that are unactivated are problematic
substrates for other methods, and so we were pleased to discover
that our ‘ex-cell’ conditions readily translate electron-rich di- and
tri-substituted terminal and internal alkenes (2ag, 2an-ar, 2at-au).
Good to excellent yields were produced in each case. Both cis
and trans isomers of internal alkenes were viable substrates, and
their stereochemical information was translated to their products
with a diastereoselectivity between 5-9:1. Readily oxidised
trialkylamines (2aq-ar) were again tolerated functionality. To
ascertain the effect of steric bulk or hydrophobic shielding on
internal alkenes, 4 regio-isomers of trans-octene were tested in
the reaction (2av-ay). It was found that yields improved as the
bulk either side of the alkene decreased.
The difluorination of several electron-rich substrates using our
electrochemical method was compared to methods in the
literature, including those that employ Selectfluor and mCPBA
with aryl-iodide, and Selectfluor alone. In each of the examples
tested, the electrochemical method gave superior yields (Figure
4), thereby validating the importance of the ‘ex-cell’ approach. The
sustainability of the electrochemical method is reflected in the low
E-factor[33] (ratio of total waste to product) calculated for the
reaction,[34] which was consistently lower than the Selectfluor or
mCPBA methods. The main improvement to waste reduction
originates from the lack of a stoichiometric oxidant, which will also
contribute to enhanced safety[35] and lower cost[26] on-scale.
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Angewandte Chemie International Edition
COMMUNICATION
[11] a) W. Dmowski, T. Kozłowski, Electrochim. Acta 1997, 42, 513–523; b)
J. H. H. Meurs, W. Eilenberg, Tetrahedron, 1991, 47, 705-714
[12] G. S. Lal, J. Org. Chem., 1993, 58, 2791 – 2796.
In summary, an electrochemical vicinal 1,2-difluorination of
alkenes has been described, using a simple and user-friendly 2-
electrode setup with nucleophilic fluoride and iodotoluene as a
mediator. Moderate to excellent yields of fluorinated products are
demonstrated in a wide substrate scope. The ‘ex-cell’ method
allows access to new substrate classes that have otherwise
remained unattainable, including electron rich moieties, anilines
and substituted internal alkenes. The method is sustainable
(lower E-factor), safe, and high-yielding gram and decagram
scale reactions demonstrate the practicality of the process. We
therefore expect this method to facilitate access to this important
motif in a wider variety of compounds and contexts.
[13]
S. Hara, J. Nakahigashi, K. Ishi-i, M. Sawaguchi, H. Sakai, T. Fukuhara,
N. Yoneda, Synlett 1998, 495–496.
[14] Hypervalent iodine reagents have been used for a variety of fluorination
reactions. For an excellent review of this chemistry, see: S. V. Kohlhepp,
T. Gulder, Chem. Soc. Rev. 2016, 45, 6270–6288.
[15] a) J. C. Sarie, C. Thiehoff, R. J. Mudd, C. G. Daniliuc, G. Kehr, R. Gilmour,
J. Org. Chem. 2017, 82, 11792–11798; b) H. Sun, B. Wang, S. G.
DiMagno, Org. Lett. 2008, 10, 4413–4416.
[16] a) I. G. Molnár, R. Gilmour, J. Am. Chem. Soc. 2016, 138, 5004–5007;
b) F. Scheidt, M. Schäfer, J. C. Sarie, C. G. Daniliuc, J. J. Molloy, R.
Gilmour, Angew. Chem. Int. Ed. 2018, 57, 16431–16435.
[17] a) S. M. Banik, J. W. Medley, E. N. Jacobsen, J. Am. Chem. Soc. 2016,
138, 5000–5003; b) K.M. Haj.; S. M. Banik; E. N. Jacobsen, Org. Lett.
2019, 21, 4919–4923.
Acknowledgements
[18] R. Francke, R. D. Little, Chem. Soc. Rev. 2014, 43, 2492.
[19] Selected reviews: a) J.-I. Yoshida, K. Kataoka, R. Horcajada, A. Nagaki,
Chem. Rev. 2008, 108, 2265–2299 b) M. Yan, Y. Kawamata, P. S. Baran,
Chem. Rev. 2017, 117, 13230–13319; c) S. Möhle, M. Zirbes, E. Rodrigo,
T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57,
6018–6041; d) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S.
R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594–5619.
The authors would like to thank the Royal Society (University
Research Fellowship and Enhancement Award to AJJL) and
EPSRC (EP/G036764/1) for funding, Dr Lam (University of
Greenwich) for the PTFE ElectraSyn vial and Dawn White
(University of Bristol) for cyclopropyl substrate, 2t.
[20] G. G. Botte, Electrochem. Soc. Interface 2014, Fall, 49–55.
[21] a) E. J. Horn, B. R. Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2, 302–
308; b) B. A. Frontana-Uribe, R. D. Little, J. G. Ibanez, A. A. Palma, R.
Vasquez-Medrano, Green Chem. 2010, 12, 2099–2119.
Keywords: Electrochemistry • Fluorination • Hypervalent iodine
• Green Chemistry • Oxidation
[22] Selected examples: a) D. Kajiyama, K. Inoue, Y. Ishikawa, S. Nishiyama,
Tetrahedron 2010, 66, 9779–9784; b) D. Kajiyama, T. Saitoh, S.
Nishiyama, Electrochemistry 2013, 81, 319–324; c) T. Broese, R.
Francke, Org. Lett. 2016, 18, 5896–5899; d) O. Koleda, T. Broese, J.
Noetzel, M. Roemelt, E. Suna, R. Francke, J. Org. Chem. 2017, 82,
11669–11681; e) R. Möckel, E. Babaoglu, G. Hilt, Chem. Eur. J. 2018,
24, 15781–15785; f) M. Elsherbini, T. Wirth, Chem. Eur. J. 2018, 24,
13399–13407; g) R. Francke, T. Broese, A. F. Roesel, in PATAI’S Chem.
Funct. Groups, John Wiley & Sons, Ltd, Chichester, UK, 2018, pp. 1–22;
h) W.-C. Gao, Z.-Y. Xiong, S. Pirhaghani, T. Wirth, Synthesis (Stuttg).
2019, 51, 276–284; i) R. Francke, Curr. Opin. Electrochem. 2019, 15,
83–88. For a review, see: j) K. Liu, C. Song, A. Lei Org. Biomol. Chem.,
2018, 16, 2375.
[1]
J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014,
114, 2432–2506.
[2]
[3]
N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87,
1348–1349.
a) Q. A. Huchet, B. Kuhn, B. Wagner, N. A. Kratochwil, H. Fischer, M.
Kansy, D. Zimmerli, E. M. Carreira, K. Müller, J. Med. Chem. 2015, 58,
9041–9060; b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N.
A. Meanwell, J. Med. Chem. 2015, 58, 8315–8359.
[4]
[5]
M. Morgenthaler, E. Schweizer, A. Hoffmann-Röder, F. Benini, R. E.
Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, et
al., ChemMedChem 2007, 2, 1100–1115.
a) I. G. Molnár, C. Thiehoff, M. C. Holland, R. Gilmour, ACS Catal. 2016,
6, 7167–7173; b) N. Erdeljac, G. Kehr, M. Ahlqvist, L. Knerr, R. Gilmour,
Chem. Commun. 2018, 54, 12002–12005; c) Erdeljac, K. Bussmann, A.
Schöler, F. K. Hansen, R. Gilmour, ACS Med. Chem. Lett. 2019,
acsmedchemlett.9b00287.
[23] a) T. Sawamura, S. Kuribayashi, S. Inagi, T. Fuchigami, Org. Lett. 2010,
12, 644–646; b) T. Sawamura, S. Kuribayashi, S. Inagi, T. Fuchigami,
Adv. Synth. Catal. 2010, 352, 2757–2760; c) S. Hara, T. Hatakeyama,
S.-Q. Chen, K. Ishi-i, M. Yoshida, M. Sawaguchi, T. Fukuhara, N. Yoneda,
J. Fluor. Chem. 1998, 87, 189–192; d) T. Fuchigami, T. Fujita, J. Org.
Chem. 1994, 59, 7190–7192; e) J. D. Haupt, M. Berger, S. R. Waldvogel,
Org. Lett. 2019, 21, 242–245; f) H. Schmidt, H. Meinert, Angew. Chem.,
1960, 72, 109-110.
[6]
a) Wolfe, Acc. Chem. Res. 1972, 5, 102–111; b) D. O’hagan, H. S. Rzepa,
M. Schüler, A. M. Z. Slawin, Beilstein J. Org. Chem. 2006, 2,
10.1186/1860-5397-2-19; c) D. O’Hagan, Chem. Soc. Rev. 2008, 37,
308–319; d) C. Thiehoff, Y. P. Rey, R. Gilmour, Isr. J. Chem. 2017, 57,
92–100; e) L. Goodman, H. Gu, V. Pophristic, J. Phys. Chem. A 2005,
109, 1223–1229.
[24] ArIF2 species can be prepared using Selectfluor, see 15a and C. Ye, B.
Twamley, J. M. Shreeve, Org. Lett., 2005, 7, 3961 – 3964.
[25] T. Fuchigami, S. Inagi, Chem. Commun. 2011, 47, 10211–10223.
[26] See SI for details.
[7]
[8]
L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. Ed. 2011, 50,
11860–11871.
[27] a) H. K. Minhas, W. Riley, A. M. Stuart, M. Urbonaite, Org. Biomol. Chem.
2018, 16, 7170–7173; b) J. C. Sarie, J. Neufeld, C. G. Daniliuc, R.
Gilmour, ACS Catal. 2019, acscatal.9b02313; c) A. M. Arnold, A. Pöthig,
M. Drees, T. Gulder, J. Am. Chem. Soc. 2018, 140, 4344−4353.
[28] a) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R.
Waldvogel, Chem. Eur. J. 2015, 21, 12321–12325; b) Y. Imada, J. L.
Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R.
Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 12136–12140.
a) I. Molnár, M. Holland, C. Daniliuc, K. Houk, R. Gilmour, Synlett 2016,
27, 1051–1055; b) M. Aufiero, R. Gilmour, Acc. Chem. Res. 2018, 51,
1701–1710; c) A. Vega-Peñaloza, S. Paria, M. Bonchio, L. Dell’Amico, X.
Companyó, ACS Catal. 2019, 9, 6058–6072.
[9]
a) M. Schüler, D. O’Hagan, A. M. Z. Slawin, Chem. Commun. 2005,
4324; b) I. Yamamoto, M. J. T. Jordan, N. Gavande, M. R. Doddareddy,
M. Chebib, L. Hunter, Chem. Commun 2012, 48, 829–831; c) X.-G. Hu,
D. S. Thomas, R. Griffith, L. Hunter, Angew. Chem. 2014, 126, 6290–
6293.
[29] This is consistent with: I. Colomer, C. Batchelor-McAuley, B. Odell, T. J.
Donohoe, R. G. Compton, J. Am. Chem. Soc. 2016, 138, 8855–8861.
[30] a) S. M. Banik, K. M. Mennie, E. N. Jacobsen, J. Am. Chem. Soc. 2017,
139, 9152–9155; b) N. O. Ilchenko, M. Hedberg, K. J. Szabó, Chem. Sci.
2017, 8, 1056–1061.
[10] a) A. E. Feiring, S. Rozen, E. R. Wonchoba, J. Fluor. Chem. 1998, 89,
31–34; b) M. A. Tius, Tetrahedron 1995, 51, 6605–6634.
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COMMUNICATION
[31] M. Bielawski, M. Zhu, B. Olofsson, Adv. Synth. Catal. 2007, 349, 2610–
2618.
[34] E-factor: Electrochemical method ca. 4-600 (‘in-cell’), 800 (‘ex-cell’);
mCPBA ca. 2700; Selectfluor method ca. 1000. See SI for calculations.
[35] J. P. Adams, C. M. Alder, I. Andrews, A. M. Bullion, M. Campbell-
Crawford, M. G. Darcy, J. D. Hayler, R. K. Henderson, C. A. Oare, I.
Pendrak, et al., Green Chem. 2013, 15, 1542.
[32] a) F. Scheidt, J. Neufeld, M. Schäfer, C. Thiehoff, R. Gilmour, Org. Lett.
2018, 20, 8073–8076; b) S. M. Banik, J. W. Medley, E. N. Jacobsen,
Science 2016, 353, 51–4; c) N. O. Ilchenko, B. O. A. Tash, Kálmán J.
Szabó, Angew. Chem, Int. Ed. 2014, 53, 12897-12901.
[33] R. A. Sheldon, Green Chem. 2007, 9, 1273
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Text for Table of
Contents
Author(s), Corresponding
Author(s)*
F
I
F
R1
R1
F
R2
F
R2
H2
Page No. – Page No.
HF
R3
R3
Me
Title
Eox
>
1.8 V
Eox
<
1.8 V
- Electron-rich
- Substituted
- Unactivated
- Electron-poor
- Terminal
Deca-gram scale
H2 = sole by-product
Oxidant - free
Sustainable
‘In-cell' method
‘Ex-cell' method
20 examples
31 examples
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